WO2016199943A1 - Heterocyclic compounds - Google Patents

Heterocyclic compounds Download PDF

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Publication number
WO2016199943A1
WO2016199943A1 PCT/JP2016/068023 JP2016068023W WO2016199943A1 WO 2016199943 A1 WO2016199943 A1 WO 2016199943A1 JP 2016068023 W JP2016068023 W JP 2016068023W WO 2016199943 A1 WO2016199943 A1 WO 2016199943A1
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Prior art keywords
group
compound
membered
optionally substituted
optionally
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PCT/JP2016/068023
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French (fr)
Inventor
Anish Bandyopadhyay
Robindro SARANGTHEM
Dinesh Barawkar
Rajesh BONAGIRI
Goraksha KHOSE
Shailesh SHINDE
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Takeda Pharmaceutical Company Limited
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Publication of WO2016199943A1 publication Critical patent/WO2016199943A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to a novel heterocyclic compound having an inhibitory action on binding of bromodomain and extra-terminal domain family protein (hereinafter sometime to ' be referred to as "BET family protein”) to protein having acetylated lysine, and useful an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like, and a
  • composition containing the compound, and the like containing the compound, and the like.
  • Bromodomain and extra-terminal domain (BET) protein family is a family consisting of BRD2, BRD3, BRD4 and BRDT. These proteins recognize acetylated lysine residue via
  • Cytokine is a protein secreted by the cells of immune system, and signals specific cells. There are a large variety of cytokines, and they almost involve immunity and inflammation, and also involve cellular growth, cellular differentiation, cellular death, wound healing and the like (non-Patent
  • BET protein family usually plays a role in
  • Non-Patent Document 2 a Non-Patent Document 2 .
  • Tociliz.umab which is an anti-IL-6 receptor antibody has been approved as a IL-6 signal blocker, and etanercept, infliximab, adalimumab and the like, which are therapeutic agents for chronic rheumatoid arthritis and the like, have been approved as a TNFcc signal blocker.
  • BET family protein inhibitor can be a therapeutic agent for autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like, which are cytokine- mediated diseases.
  • autoimmune diseases and/or inflammatory diseases e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.
  • inflammatory diseases e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis
  • Examples of the compound having a structure similar to the compound described in the present specification include the following compounds.
  • Patent document 1 describes a compound represented by the formula:
  • X 2 is [C(R 6 ) (R 7 )] n or the like,
  • R 6 and R 7 are each alkyl, arylalkyl, heteroarylalkyl or the like, and
  • R 3 is heteroaryl or the like
  • H1/H4 receptor inhibitor an H1/H4 receptor inhibitor, and is useful an agent for the prophylaxis or treatment of pruritus, eczema, atopic ' dermatitis and the like.
  • Patent document 2 describes a compound represented by the formula:
  • Z 1 and Z 2 are both C, or one of Z 1 and Z 2 is N and the other is C,
  • X is a polar substituent
  • R 6 is C5-12 heteroaryl or the like
  • Z 5 is N, NR 5 , CR 5 or the like, and
  • R 5 is hydrogen, C6-12 heteroarylalkyl or the like,
  • Pirn Pirn
  • Fit and/or CK2 kinases inhibitor an agent for the prophylaxis or treatment of psoriasis and the like.
  • Patent Document 2 WO 2010/135571
  • Non-Patent Document 2 Mol Cell. 2014 Jun 5; 54 (5) : 728-736
  • the present invention aims to provide a novel
  • heterocyclic compound having an inhibitory action on binding of BET family protein to protein having acetylated lysine
  • BET family protein inhibitory action an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory
  • diseases e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.
  • cancer e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.
  • a compound represented by the below- mentioned formula (1) unexpectedly has an BET family protein inhibitory action, and therefore, is useful as an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like, and completed the present invention based on these findings.
  • autoimmune diseases and/or inflammatory diseases e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.
  • the present invention provides the following.
  • R 1 is an optionally .substituted 5-membered aromatic
  • ring A is an optionally further substituted benzene ring
  • R 2 and R 3 are each independently a hydrogen atom or a
  • X a and Y a are each independently a nitrogen atom or a carbon atom
  • R 4a is a substituent
  • X b and Y b are each independently a nitrogen atom or a carbon atom
  • R b is a hydrogen atom or a substituent
  • X c is a nitrogen atom or a carbon atom
  • R 4c is a hydrogen atom or a substituent
  • R 2 and R 3 are each independently
  • X a is a nitrogen atom
  • Y a is a nitrogen atom
  • X b is a nitrogen atom
  • Y b is a nitrogen atom
  • X° is a nitrogen atom
  • R 4c is an optionally substituted Cis alkyl group
  • Ci-6 alkylsulfonylamino group a Ci-6 alkylsulfonylamino group
  • C 6 -i4 arylsulfonylamino group optionally substituted by a Ci-6 alkyl group
  • a medicament comprising the compound or salt of the above- mentioned [1] .
  • a method of inhibiting brdmodomain and extra terminal domain family protein in a mammal which comprises
  • a method for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases in a mammal which comprises administering an effective amount of the compound or salt of the above-mentioned [1] to the mammal.
  • a method for the prophylaxis or treatment of psoriasis or atopic dermatitis in a mammal which comprises administering an effective amount of the compound or salt of the above- mentioned [1] to the mammal.
  • R 1A is an optionally substituted 5-membered aromatic
  • ring A A is an optionally further substituted benzene ring
  • R 2A and R 3A are each independently a hydrogen atom or a substituent
  • X aa and Y aa are each independently a nitrogen atom or a carbon atom
  • R 4aa is a substituent
  • X ba and Y ba are each independently a nitrogen atom or a carbon atom
  • R 4ba is a hydrogen atom or a substituent
  • X ca is a nitrogen atom or a carbon atom
  • R 4ca is a hydrogen atom or a substituent
  • Compound (I) has a superior BET family protein inhibitory action, and is useful as an agent for ' the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like.
  • autoimmune diseases and/or inflammatory diseases e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.
  • Figure 1 shows effect of the compounds of Example 4.7 and Example 9.6 on ear thickness in Imiquimod induced-mouse model of psoriasis.
  • Figure 2 shows effect of the compounds of Example 9.9 and Example 9.10 on ear thickness in Imiquimod induced-mouse model of psoriasis.
  • Figure 3 shows effect of the compound of Example 4.7 on ear thickness in Imiquimod induced-mouse model of psoriasis.
  • halogen atom examples include fluorine, chlorine, bromine and iodine.
  • C X - 6 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,. sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
  • examples of the "optionally halogenated Ci_ 6 alkyl group” include a Ci- 6 alkyl group
  • examples of the "C 2 - 6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-
  • examples of the "C 2 -6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl and 4-methyl-2-pentynyl
  • examples of the "C3-10 ⁇ cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [ 3.2.1 ] octyl and adamantyl.
  • examples of the "optionally halogenated C3-10 " cycloalkyl group” include a C3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2- difluorocyclopropyl, 2 , 3-difluorocyclopropyl , cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl .
  • examples of the "C3-10 cycloalkenyl group” include cyclopropenyl , cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • examples of the "C6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.
  • aralkyl group include benzyl, phenethyl, naphthylmethyl and phenylpropyl .
  • examples of the "Ci- 6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • examples of the "optionally halogenated Ci- 6 alkoxy group” include a Ci_ 6 alkoxy group
  • cycloalkyloxy group include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and
  • alkylthio group include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
  • examples of the "optionally halogenated Ci-6 alkylthio. group” include a Ci- 6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms.
  • difluoromethylthio trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4 , 4 , 4-trifluorobutylthio, pentylthio and hexylthio.
  • examples of the "Ci_ 6 alkyl- carbonyl group” include acetyl,- propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 3-methylbutanoyl , 2-methylbutanoyl, 2 , 2-dimethylpropanoyl, hexanoyl and heptanoyl.
  • examples of the "optionally halogenated Ci- 6 alkyl-carbonyl group” include a Ci-6 alkyl- carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl , trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • examples of the "Ci_ 6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , butoxycarbonyl,
  • examples of the "C6-1 aryl- carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
  • aralkyl-carbonyl group include phenylacetyl and
  • examples of the "5- to 14- membered aromatic heterocyclylcarbonyl group” include
  • examples of the "3- to 14- membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and
  • examples of the "mono- or di-Ci-6 alkyl-carbamoyl group” include methylcarbamoyl
  • examples of the "mono- or di-C 7 -i6 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl .
  • examples of the "Ci- 5 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl .
  • examples of the "optionally halogenated Ci_e alkylsulfonyl group” include a Ci-6
  • alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include
  • examples of the "C6-14 ⁇ arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl .
  • substituted include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an
  • optionally substituted heterocyclic group an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, ⁇ an optionally
  • hydrocarbon group (including “hydrocarbon group” of
  • “optionally substituted hydrocarbon group” include a Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C 2 -e alkynyl group, a C3-10
  • cycloalkyl group a C3-10 cycloalkenyl group, a C6-14 aryl group and a C 7 _i6 aralkyl group.
  • examples of the "optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent (s) selected from the following substituent group A.
  • a C 6 -i4 aryloxy group e.g., phenoxy, naphthoxy
  • Ci-6 alkyl-carbonyloxy group e.g., acetoxy
  • a C 6 -i4 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • a C 6 -i4 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • Ci-6 alkoxy-carbonyloxy group e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy
  • a Cs-14 aryl-carbamoyloxy group e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy
  • a 5- to 14-membered aromatic heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy
  • Ci_ 6 alkylsulfonyloxy group e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy
  • a C7-16 aralkyloxy-carbonyl group e.g., benzyloxycarbonyl, phenethyloxycarbonyl
  • a C 6 -i4 aryl-carbamoyl group e.g., phenylcarbamoyl
  • a 5- to 14-membered aromatic heterocyclylcarbamoyl group e.g., pyridylcarbamoyl, thienylcarbamoyl
  • a 5- to 14-membered aromatic heterocyclylsulfonyl group e.g., pyridylsulfonyl, thienylsulfonyl ) ,
  • a Ce-14 arylsulfinyl group e.g., phenylsulfinyl , 1- naphthylsulfinyl , 2-naphthylsulfinyl ) ,
  • a 5- to 14-membered aromatic heterocyclylsulfinyl group e.g., pyridylsulfinyl, thienylsulfinyl
  • a mono- or di-Ci_ 6 alkylamino group e.g., methylamino, . ethylamino, propylamino, isopropylamino, butylamino,
  • a mono- or di-C 6 -i4 arylamino group e.g., phenylamino
  • a 5- to 14-membered aromatic heterocyclylamino group e.g., pyridylamino
  • Ci-6 alkyl-carbonylamino group e.g., acetylamino
  • a (Ci-6 alkyl) (Ci_ 6 alkyl-carbonyl ) amino group e.g., N- acetyl-N-methylamino
  • a C 6 -i4 aryl-carbonylamino group e.g., phenylcarbonylamino, naphthylcarbonylamino
  • Ci-6 alkoxy-carbonylamino group e.g.,
  • Ci-6 alkylsulfonylamino group e.g., methylsulfonylamino, ethylsulfonylamino
  • a C 6 -i4 arylsulfonylamino group optionally substituted by a Ci-6 alkyl group e.g., phenylsulfonylamino
  • the number of the above-mentioned substituents in the "optionally substituted hydrocarbon group” is, for example, 1 30 to 5, preferably 1 to 3.
  • the respective substituents may be the same or different.
  • heterocyclic group (including “heterocyclic group” of
  • examples of the "aromatic heterocyclic group” include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • aromatic heterocyclic group examples include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl , oxazolyl ' , isoxazolyl, pyridyl,
  • pyrazinyl pyrimidinyl, pyridazinyl, 1, 2 , 4-oxadiazolyl, 1,3,4- ⁇ oxadiazolyl, 1 , 2 , 4-thiadiazolyl , 1, 3, 4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like;
  • benzothiophenyl benzofuranyl, benzimidazolyl, benzoxazolyl , benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
  • furopyridinyl pyrrolopyridinyl , pyrazolopyridinyl ,
  • pyrrolopyrimidinyl pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2, 3-b] thienyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl , naphthyridinyl,
  • quinoxalinyl ' quinazolinyl, cinnolinyl, carbazolyl, ⁇ - carbolinyl, phenanthridinyl , acridinyl, phenazinyl,
  • non- aromatic heterocyclic group examples include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • non-aromatic heterocyclic group examples include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl,
  • dihydrobenzisothiazolyl dihydronaphtho [2, 3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl , tetrahydrothieno [2 , 3-c] pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl ,
  • examples of the "nitrogen- containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom.
  • examples of the "optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent ( s ) selected from the
  • the number of the substituents in the "optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of the substituents , is two or more, the respective substituents may be the same or different.
  • acyl group examples include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a
  • sulfamoyl group and a phosphono group each optionally having "1 or 2 substituents selected from a Ci- 6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-1 aryl group, a C7-16 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an
  • Ci-6 alkoxy group optionally halogenated Ci-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group" .
  • acyl group also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group.
  • the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group
  • the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group
  • hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded ' sulfinyl group.
  • acyl group examples include a formyl group, a carboxy group, a Ci-6 alkyl-carbonyl group, a C 2 -6
  • alkenyl-carbonyl group e.g., crotonoyl
  • a C3-10 cycloalkyl- carbonyl group e.g., cyclobutanecarbonyl
  • cycloheptanecarbonyl a C3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl ) , a Ce-14 aryl-carbonyl group, a C 7 _i6
  • heterocyclylcarbonyl group " a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a Cg-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl,
  • a C 7 _i6 aralkyloxy-carbonyl group e.g., benzyloxycarbonyl, phenethyloxycarbonyl
  • a carbamoyl group a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C 2 -6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C3-io cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl ) , a mono- or di-C6-i 4 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C 7 _i6 aralkyl-carbamoyl group, a 5- to 14-member
  • cycloalkyl-thiocarbamoyl group e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl
  • a mono- or di-C6-i4 aryl-thiocarbamoyl group e.g., phenylthiocarbamoyl
  • a mono- or di-C 7 -i 6 aralkyl- thiocarbamoyl group e.g., benzylthiocarbamoyl
  • heterocyclylthiocarbamoyl group e.g., pyridylthiocarbamoyl
  • a sulfino group e.g., a sulfino group
  • a Ci_ 6 alkylsulfinyl group e.g., methylsulfinyl, ethylsulfinyl
  • a sulfo group a Ci- 6
  • alkylsulfonyl group a C 6 -i4 arylsulfonyl group, a phosphono group and a mono- or di-Ci-e alkylphosphono group (e.g., aiBt ⁇ iy " xp ⁇ nbspnbno ; aiisopropyxp'nfrspTrdnOv dibutylphosphono) .
  • examples of the "optionally substituted amino group” include an amino group optionally having "1 or 2 substituents selected from a Ci- ⁇ alkyl group, a- C 2 -6 alkenyl group, a . C3-10 cycloalkyl group, a C 6 -i4 aryl ' group, a C 7 -i6 aralkyl group, a Ci_ 6 alkyl-carbonyl group, a C6-1 aryl- carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14— membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci- 6 alkyl-carbamoyl group, a mono- or di-C7
  • optionally substituted amino group examples include an amino group, a mono- or di- (optionally
  • heterocyclylcarbonylamino group e.g., nicotinoylamino, isonicotinoylamino
  • a mono- or di-3- to 14-membered non- aromatic heterocyclylcarbonylamino group e.g.,
  • piperidinylcarbonylamino a mono- or di-Ci_ 6 alkoxy- carbonylamino group (e.g., tert-butoxycarbonylamino) , a 5- to 14-membered aromatic heterocyclylamino group (e.g.,
  • pyridylamino a carbamoylamino group, a (mono- or di-Ci- 6 alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C 7 _i6 aralkyl-carbamoyl ) amino group (e.g.,
  • benzylcarbamoylamino a Ci-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) , a Ce-i4
  • arylsulfonylamino group e.g., phenylsulfonylamino
  • a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl) amino group e.g., N-acetyl-N- methylamino
  • a (Ci_6 alkyl) (CQ-H aryl-carbonyl ) amino group e.g., N-benzoyl-N-methylamino
  • examples of the "optionally substituted carbamoyl group” include a carbamoyl group
  • a Ci-6 alkyl group optionally having "1 or 2 substituents selected from a Ci-6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C 6 - 14 aryl group, a C7-16 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C 7 _i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a.3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic
  • heterocyclic group a carbamoyl group, a mono- or di-Ci- 6 alkyl- carbamoyl group and a mono- or di-C 7 _i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
  • carbamoyl group include a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C 2 -6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C 3 _io cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,
  • cyclohexylcarbamoyl a mono- or di-C 6 -i4 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C 7 _i 6 aralkyl-carbamoyl group, a mono- or di-Ci- 6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl ) , a mono- or di-C6-i4 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,
  • examples of the "optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a Gi- 6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C 6 - 14 aryl group, a C7-16 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-1 aryl-carbonyl group, a C 7 _i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic
  • heterocyclic group a carbamoyl group, a mono- or di-Ci_ 6 alkyl- carbamoyl group and a mono- or di-C 7 _i 6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
  • thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl , ethylthiocarbamoyl , dimethylthiocarbamoyl,
  • diallylthiocarbamoyl a mono- or di-C 3 -i 0 cycloalkyl- thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl ,
  • cyclohexylthiocarbamoyl a mono- or di-C 6 -i4 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C 7 _i6 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl ,
  • phenethylthiocarbamoyl phenethylthiocarbamoyl
  • a mono- or di-Ci-6 alkyl-carbonyl- thiocarbamoyl group e.g., acetylthiocarbamoyl
  • propionylthiocarbamoyl a mono- or di-C 6 -i 4 aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) .
  • a mono- or di-C 6 -i 4 aryl-carbonyl- thiocarbamoyl group e.g., benzoylthiocarbamoyl
  • a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group e.g., pyridylthiocarbamoyl
  • examples of the . "optionally substituted sulfamoyl group” include a sulfamoyl group
  • Ci-6 alkyl group optionally having "1 or 2 substituents selected from a Ci-6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C 6 - 14 aryl group, a C 7 _i 6 aralkyl group, a Ci- 6 alkyl-carbonyl group, a C 6 -i4 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic
  • heterocyclic group a carbamoyl group, a mono- or di-Ci_ 6 alkyl- carbamoyl group and a mono- or di-C 7 _i 5 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
  • sulfamoyl group include a sulfamoyl group, a mono- or di-Ci- 6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N- methylsulfamoyl) , a mono- or di-C 2 -6 alkenyl-sulfamoyl group (e.g., diallylsulfamoyl) , a mono- or di-C 3 _i 0 cycloalkyl- sulfamoyl group (e.g., cyclopropylsulfamoyl,
  • a mono- or di-Ci- 6 alkyl-sulfamoyl group e.g., methylsulfamoyl, eth
  • cyclohexylsulfamoyl a mono- or di-C 6 -i4 aryl-sulfamoyl group (e.g., phenylsulfamoyl ) , a mono- or di-C 7 _i 6 aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl ) , a mono- or di-Ci-6 alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl , propionylsulfamoyl) , a mono- or di-C 6 -i4 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl ) and a 5- to 14-membered
  • aromatic heterocyclylsulfamoyl group e.g., pyridylsulfamoyl .
  • examples of the "optionally substituted hydroxy group” include a hydroxy group optionally having "a substituent selected from a Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C 7 _ 16 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-14 aryl- carbonyl group, a C 7 -i 6 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C 7 -i6 aralky
  • Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a Ci-6 alkoxy group, a J C 2 -6
  • alkenyloxy group e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy
  • a C3-10 cycloalkyloxy group e.g., cyclohexyloxy
  • Ce-14 aryloxy group e.g., phenoxy, naphthyloxy
  • a C 7 _i6 aralkyloxy group e.g., benzyloxy, phenethyloxy
  • Ci_ 6 alkyl- carbonyloxy group e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • a C 6 -i4 aryl-carbonyloxy group e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • a C 6 -i4 aryl-carbonyloxy group
  • heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g.,. piperidinylcarbonyloxy
  • a Ci-6 alkoxy-carbonyloxy group e.g., tert-butoxycarbonyloxy
  • heterocyclyloxy group e.g., pyridyloxy
  • carbamoyloxy group e.g., a carbamoyloxy group
  • Ci_6 alkyl-carbamoyloxy group e.g., methylcarbamoyloxy
  • C 7 -i6 aralkyl-carbamoyloxy group e.g., benzylcarbamoyloxy
  • a Ci_6 alkylsulfonyloxy group e.g., methylsulfonyloxy
  • ethylsulfonyloxy ethylsulfonyloxy
  • a C6-14 arylsulfonyloxy group e.g., phenylsulfonyloxy
  • examples of the "optionally substituted sulfanyl group” include a sulfanyl group
  • sulfanyl group include a sulfanyl (-SH) group, a Ci_ 6 alkylthio group, a C 2 -e alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio ) , a C 3 _i 0 cycloalkylthio group (e.g., cyclohexylthio) , a Ce-14 arylthio group (e.g., phenylthio,
  • naphthylthio a C-i6 aralkylthio group (e.g., benzylthio,
  • Ci- 6 alkyl-carbonylthio group e.g.,
  • examples of the "optionally substituted silyl group” include a silyl group optionally
  • 25 group include a tri-Ci- 6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl) .
  • hydrocarbon ring include a C6-14 aromatic hydrocarbon ring, C 3 _ 30 10 cycloalkane and C3-10 cycloalkene.
  • aromatic hydrocarbon ring include benzene and naphthalene.
  • cycloalkane examples include cyclopropane, cyclobutane, cyclopentane, 35 cyclohexane, cycloheptane and cyclooctane.
  • cycloalkene include cyclopropene , cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
  • heterocycle include an aromatic heterocycle and a non-
  • aromatic heterocycle each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • heterocycle include a 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, as a ring- constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • aromatic heterocycle a 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, as a ring- constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • 5- or - 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine,
  • pyrimidine pyridazine, 1, 2, 4-oxadiazole, 1, 3, 4-oxadiazole, 1, 2, 4-thiadiazole, 1 , 3 , 4-thiadiazole , triazole, tetrazole, triazine and the like;
  • aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole,
  • benzothiazole benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine,
  • imidazopyrazine imidazopyrimidine
  • thienopyrimidine imidazopyrimidine
  • oxazolopyrimidine thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2 , 3-b] thiophene, phenoxathiine, indole, isoindole, lH-indazole, purine, isoquinoline,
  • non- aromatic heterocycle examples include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • heterocycle include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline,
  • tetrahydropyrimidine tetrahydropyridazine , dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, - thiomorpholine , azepanine, diazepane, azepine, azocane,
  • tricyclic non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho [2 , 3-b] thiophene,
  • examples of the "nitrogen- containing heterocycle” include a “heterocycle” containing at least one nitrogen atom as a ring-constituting atom.
  • R 1 is an optionally substituted 5-membered aromatic heterocyclic group.
  • examples of the "5-membered aromatic heterocyclic group" of the "optionally substituted 5- membered aromatic heterocyclic group” for R 1 include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
  • R 1 optionally has 1 to 3 substituents at substitutable position(s).
  • substituents include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective
  • R 1 is preferably an optionally substituted isoxazolyl or an optionally substituted pyrazolyl.
  • R 1 is more preferably isoxazolyl or pyrazolyl, each of which is optionally substituted by 1 to 3 Ci_ 6 alkyl groups
  • R 1 is more preferably isoxazolyl optionally ⁇ substituted by 1 to 3 Ci_ 6 alkyl groups (e.g.,
  • Ring A is an optionally further substituted benzene ring.
  • the "benzene ring" of the "optionally further substituted benzene ring" for ring A optionally has 1 or 2 substituents, in addition to R 1 and R 3 .
  • substituents include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.
  • Ring A is preferably a benzene ring having no substituent, in addition to R 1 and R 3 .
  • R 2 and R 3 are each independently a hydrogen atom or a substituent.
  • R 2 and R 3 are preferably each independently
  • an optionally substituted hydrocarbon group preferably an optionally substituted C3-10 cycloalkyl group, more preferably an optionally substituted C3-6 cycloalkyl group
  • an optionally substituted hydrocarbon group preferably an optionally substituted C3-10 cycloalkyl group, more preferably an optionally substituted C3-6 cycloalkyl group
  • an optionally substituted heterocyclic group [preferably an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group (preferably an optionally substituted 3- to 8-membered (preferably 4- to 6- membered) monocyclic non-aromatic heterocyclic group) , and an optionally substituted 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocyclic group (preferably an
  • an optionally substituted amino group (preferably an amino group optionally having 1 or 2 Ci-6 alkyl groups optionally having 1 to 3 substituents selected from substituent group A) , or
  • an optionally substituted hydroxy group (preferably a hydroxy group optionally having a Ci_ 6 alkyl group optionally having 1 to 3 substituents selected from substituent group A) , or
  • an optionally substituted sulfanyl group (preferably a sulfanyl group optionally having a Ci- 6 alkyl group optionally having 1 to 3 substituents selected from substituent group A) .
  • R 2 and R 3 are more preferably each independently
  • a halogen atom e.g., a chlorine atom
  • an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group preferably an optionally substituted 3- to 8-membered (preferably 4- to 6- membered) monocyclic non-aromatic heterocyclic group, more preferably an optionally substituted 3- to 8-membered
  • nitrogen-containing monocyclic non-aromatic heterocyclic group e.g., azetidinyl
  • a hydroxy group optionally having a Ci-6 alkyl group (e.g., methyl, ethyl) , or
  • a sulfanyl group optionally having a Ci- 6 alkyl group (e.g., methyl) .
  • R 2 and R 3 are further more preferably each independently (1) a hydrogen atom
  • a halogen atom e.g., a chlorine atom
  • a 5- or 6-membered monocyclic aromatic heterocyclic group e.g., isoxazolyl
  • 1 or 2 Ci-6 alkyl groups e.g. , methyl
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylthio group e.g., methylthio
  • a halogen atom e.g., a chlorine atom
  • monocyclic non-aromatic heterocyclic group preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl) ) ,
  • a 5- or 6-membered monocyclic aromatic heterocyclic group e.g., isoxazolyl
  • 1 or 2 Ci_ 6 alkyl groups e.g. , methyl
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylthio group e.g., methylthio
  • Ci_6 alkoxy group e.g., methoxy
  • R 2 and R 3 are further more
  • a halogen atom e.g., a chlorine atom
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylthio group e.g., methylthio
  • a halogen atom e.g., a chlorine atom
  • a- C3-10 cycloalkyl group preferably a C 3 - 6 cycloalkyl group (e.g., cyclopropyl)
  • a 3- to 8-membered preferably 4- to 6-membered
  • monocyclic non-aromatic heterocyclic group preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl)
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylthio group e.g., methylthio.
  • Ci-6 alkoxy group e.g., methoxy
  • R 2 and R 3 are further more
  • a halogen atom e.g., a chlorine atom
  • monocyclic non-aromatic heterocyclic group preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, ' pyrrolidinyl ) ) ,
  • Ci-e alkyl groups e.g., methyl, ethyl
  • an amino group optionally having 1 or 2 Ci-e alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 hydroxy groups, or
  • Ci-6 alkoxy group e.g., methoxy
  • a halogen atom e.g., a chlorine atom
  • a cyano group e.g., a cyano group
  • monocyclic non-aromatic heterocyclic group preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl ) ) , or
  • Ci_ 6 alkyl groups e.g., methyl, ethyl
  • an amino group optionally having 1 or 2 Ci_ 6 alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 hydroxy groups
  • Ci-6 alkoxy group e.g., methoxy
  • R 2 and R 3 are further more preferably each independently
  • Ci-6 alkoxy group e.g., methoxy
  • Ci-6 alkoxy group e.g., methoxy
  • X a and Y a are each independently a nitrogen atom or a carbon atom, and R 4a is a substituent, and
  • X b and Y b are each independently a nitrogen atom or a carbon atom
  • R 4b is a hydrogen atom or a substituent
  • X c is a nitrogen atom or a carbon atom
  • R 4c is a hydrogen atom or a substituent
  • X a is preferably a nitrogen atom.
  • Y a is preferably a nitrogen atom.
  • R a is preferably
  • an optionally substituted hydrocarbon group preferably an optionally substituted Ci-6 alkyl group, an optionally
  • an optionally substituted heterocyclic group preferably an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group, more preferably an optionally substituted 3- to 8-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group) , or
  • an optionally substituted amino group (preferably an amino group optionally having 1 or 2 C 6 -io aryl groups optionally having 1 to 3 substituents selected from substituent group A) .
  • R 4a is more preferably
  • Ci-e alkyl group e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl
  • an optionally substituted C3-10 cycloalkyl group preferably an optionally substituted C3-6 cycloalkyl group (e.g.,
  • an amino group optionally having 1 or 2 Ce- ⁇ aryl groups e.g., phenyl
  • substituent group A preferably a halogen atom (e.g., a. fluorine atom, a chlorine atom) , a cyano group, a Ci_ 6 alkoxy group (e.g., methoxy) .
  • R 4a is further more preferably
  • a C1-6 alkyl group e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl
  • substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • Ci-6 alkoxy group e.g., methoxy
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl
  • Ci-3 alkylenedioxy group e.g., methylenedioxy
  • C3-10 cycloalkyl group e.g., cyclopentyl
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group e.g., thienyl, thiazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl
  • a 5- to 14-membered aromatic heterocyclic group e.g., thienyl, thiazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl
  • Ci-6 alkyl group e.g., methyl
  • Ci-6 alkoxy group e.g., methoxy
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl)
  • aromatic heterocyclic group preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl)
  • a C 6 -io aryl group e.g., phenyl
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • monocyclic non-aromatic heterocyclic group e.g., tetrahydropyranyl
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • X b is preferably a nitrogen atom.
  • Y b is preferably a nitrogen atom.
  • R 4b is preferably an optionally substituted hydrocarbon group (preferably an optionally substituted Ci- 6 alkyl group, an optionally substituted ⁇ - ⁇ aryl group) .
  • R 4b is more preferably
  • Ci_ 6 alkyl group e.g., methyl, ethyl, isobutyl
  • R 4b is further more preferably
  • Ci-6 alkyl group e.g., methyl, . ethyl, isobutyl
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl
  • halogen atoms e.g., a fluorine atom
  • Ci-6 alkoxy group e.g., methoxy
  • a C3-10 cycloalkyl group e.g.-, cyclopropyl, cyclohexyl
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrazolyl) ) optionally substituted by 1 to 3 Ci_ 6 alkyl groups (e.g., methyl), or
  • halogen atom e.g., a fluorine atom
  • Ci-6 alkoxy group e.g., methoxy
  • halogen atoms e.g., a fluorine atom
  • X° is preferably a nitrogen atom.
  • R 4c is preferably an optionally substituted hydrocarbon group (preferably an optionally substituted Ci- 6 alkyl group) .
  • R 4c is more preferably an optionally substituted Ci- 6 alkyl group (e.g., methyl, ethyl).
  • R 4c is further more preferably a Ci- 6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3 substituents selected from
  • a halogen atom e.g., a fluorine atom
  • Ci-6 alkoxy group e.g., methoxy
  • halogen atoms e.g., a fluorine atom
  • a C3-10 cycloalkyl group e.g., cyclopropyl, cyclohexyl
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl)).
  • the ring represented by the formula (a) optionally has 1 or 2 substituents at substitutable position(s), in addition to R 4a .
  • substituents include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different. ,
  • the rings represented by the formula (a) preferably have no substituent, in addition to R 4a .
  • the ring represented by the formula (b) optionally has 1 or 2 substituents at substitutable position(s), in addition to R b .
  • substituents include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.
  • the rings represented by the formula (b) preferably have ho substituent, in addition to R b .
  • the ring represented by the formula (c) optionally has 1 or 2 substituents at substitutable position(s), in addition to R c .
  • substituents include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.
  • the rings represented by the formula (c) preferably have no substituent, in addition to R 4c .
  • compound (I) include the following compounds .
  • R 1 is an optionally substituted isoxazolyl or an optionally substituted pyrazolyl
  • Ring A is an optionally further substituted benzene ring; R 2 and R 3 are each independently
  • a halogen atom e.g., a chlorine atom
  • an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group preferably an optionally substituted 3- to 8-membered (preferably 4- to 6- membered) monocyclic non-aromatic heterocyclic group, more preferably an optionally substituted 3- to 8-membered
  • nitrogen-containing monocyclic non-aromatic heterocyclic group e.g., azetidinyl
  • Ci_ 6 alkyl groups e.g., methyl, ethyl
  • substituent group A preferably hydroxy
  • a hydroxy group optionally having a Ci-6 alkyl group (e.g., methyl, ethyl) , or
  • X a is a nitrogen atom
  • Y a is a nitrogen atom
  • R 4a is.
  • Ci- 6 an optionally substituted Ci- 6 , alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl) ,
  • heterocyclic group e.g., tetrahydropyranyl
  • substituent group A preferably a halogen atom (e.g., a fluorine atom, a chlorine atom), a cyano group, a Ci- 6 alkoxy group (e.g., methoxy) ) ,
  • X b is a nitrogen atom
  • Y is a nitrogen atom
  • Ci- 6 alkyl group e.g., methyl, ethyl, isobutyl
  • X c is a nitrogen atom
  • R 4c is an optionally substituted Ci_6 alkyl group (e.g., methyl, ethyl) ,
  • R 1 is isoxazolyl or pyrazolyl, each of which is optionally substituted by 1 to 3 Ci_6 alkyl groups (e.g., methyl);
  • Ring A is a benzene ring having no substituent, in addition to R 1 and R 3 ;
  • R 2 and R 3 are each independently
  • a halogen atom e.g., a chlorine atom
  • monocyclic non-aromatic heterocyclic group preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl ) ) ,
  • Ci-e alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylthib group e.g., methylthio
  • a halogen atom e.g., a chlorine atom
  • monocyclic non-aromatic heterocyclic group preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl ) ) ,
  • a 5- or 6-membered monocyclic aromatic heterocyclic group e.g., isoxazolyl
  • 1 or 2 Ci-6 alkyl groups e.g., methyl
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylthio group e.g., methylthio
  • Ci_6 alkoxy group e.g., methoxy
  • X is a nitrogen atom
  • Y a is a nitrogen atom
  • Ci-6 alkyl group e.g., methyl, ethyl, propyl
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • Ci-6 alkoxy group e.g., methoxy
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl
  • Ci-3 alkylenedioxy group e.g., methylenedioxy
  • a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group preferably a 3- to 8- membered (preferably 5- or 6-membered) monocyclic non- aromatic heterocyclic group (e . g. , tetrahydropyranyl)
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group e.g., thienyl, thiazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl
  • Ci-6 alkyl group ' e.g., methyl
  • Ci-6 alkoxy group e.g., methoxy
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group preferably a 5- or 6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl)
  • aromatic heterocyclic group preferably a 5- or 6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl)
  • a Ce-io aryl group e.g., phenyl
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkoxy group e.g., methoxy
  • X is a nitrogen atom
  • Y b is a nitrogen atom
  • R b is
  • Ci_ 6 alkyl group e.g., methyl, ethyl, isobutyl
  • a C 6 -io aryl group e.g., phenyl
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • Ci-6 alkoxy group e.g., methoxy
  • a C3-10 cycloalkyl group e.g., cyclopropyl
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group preferably a 5- or 6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrazolyl) ) optionally substituted by 1 to 3 Ci-
  • halogen atom e.g., a fluorine atom
  • Ci-6 alkoxy group e.g., methoxy
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • X c is a nitrogen atom
  • R c is a Ci-6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3 substituents selected from
  • a halogen atom ' e.g., a fluorine atom
  • Ci-6 alkoxy group e.g., methoxy
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • a C3-10 cycloalkyl group e.g., cyclopropyl
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group preferably a 5- or .6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl) ) ,
  • R 1 is isoxazolyl or pyrazolyl, each of which is optionally substituted by 1 to 3 Ci_ 6 alkyl groups (e.g., methyl);
  • Ring A is a benzene ring having no substituent, in addition to
  • R 2 and R 3 are each independently
  • a halogen atom e.g., a chlorine atom
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylthio group e.g., methylthio
  • a halogen atom e.g., a chlorine atom
  • monocyclic non-aromatic heterocyclic group preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl) ) ,
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylthio group e.g., methylthio
  • Ci-6 alkoxy group e.g., methoxy
  • X a is a nitrogen atom
  • Ci_6 alkyl group e.g., methyl, ethyl, propyl
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl
  • halogen atoms e.g., a fluorine atom
  • a ' Ci-6 alkoxy group e.g., methoxy
  • 1 to 3 halogen atoms e.g., a fluorine atom
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl
  • Ci-3 alkylenedioxy group e.g., methylenedioxy
  • a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group preferably a 3- to 8- membered (preferably 5- or 6-membered) monocyclic non- aromatic heterocyclic group (e . g. , tetrahydropyranyl)
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group e.g., thienyl, thiazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl
  • Ci-6 alkyl group e.g., methyl
  • Ci-6 alkoxy group e.g., methoxy
  • a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group preferably a 5- or 6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl) )

Abstract

The present invention provides a compound represented by the formula (I) wherein each symbol is as defined in the specification, or a salt thereof has an BET family protein inhibitory action, and is useful as an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like.

Description

DESCRIPTION
HETEROCYCLIC COMPOUNDS
Technical Field
[0001]
The present invention relates to a novel heterocyclic compound having an inhibitory action on binding of bromodomain and extra-terminal domain family protein (hereinafter sometime to' be referred to as "BET family protein") to protein having acetylated lysine, and useful an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like, and a
composition containing the compound, and the like.
[0002]
(Background of the Invention)
Bromodomain and extra-terminal domain (BET) protein family is a family consisting of BRD2, BRD3, BRD4 and BRDT. These proteins recognize acetylated lysine residue via
bromodomain, and bind to acetylated histone or the other acetylated protein. The interaction plays an important role in various gene expressions including cytokine production.
Cytokine is a protein secreted by the cells of immune system, and signals specific cells. There are a large variety of cytokines, and they almost involve immunity and inflammation, and also involve cellular growth, cellular differentiation, cellular death, wound healing and the like (non-Patent
Document 1) .
BET protein family usually plays a role in
inflammatory/immune response via gene expression such as IL-6 and TNFcc, however, the excessive interaction thereof involves many immune-related diseases such as infection, rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis and the like, and cancer (non-Patent Document 2) .
Tociliz.umab which is an anti-IL-6 receptor antibody has been approved as a IL-6 signal blocker, and etanercept, infliximab, adalimumab and the like, which are therapeutic agents for chronic rheumatoid arthritis and the like, have been approved as a TNFcc signal blocker. From the foregoing, BET family protein inhibitor can be a therapeutic agent for autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like, which are cytokine- mediated diseases.
[0003]
Examples of the compound having a structure similar to the compound described in the present specification include the following compounds.
[0004]
(1) Patent document 1 describes a compound represented by the formula:
[0005]
Figure imgf000003_0001
[0006]
wherein
X2 is [C(R6) (R7)]n or the like,
R6 and R7 are each alkyl, arylalkyl, heteroarylalkyl or the like,, and
R3 is heteroaryl or the like,
as an H1/H4 receptor inhibitor, and is useful an agent for the prophylaxis or treatment of pruritus, eczema, atopic' dermatitis and the like.
[0007]
(2) Patent document 2 describes a compound represented by the formula:
[0008]
Figure imgf000004_0001
[0009]
wherein
Z1 and Z2 are both C, or one of Z1 and Z2 is N and the other is C,
X is a polar substituent,
R6 is C5-12 heteroaryl or the like,
Z5 is N, NR5, CR5 or the like, and
R5 is hydrogen, C6-12 heteroarylalkyl or the like,
as a Pirn, Fit and/or CK2 kinases inhibitor, and is useful an agent for the prophylaxis or treatment of psoriasis and the like.
Document List
Patent Document
[0010]
[Patent Document 1] US 2011/0257137
[Patent Document 2] WO 2010/135571
Non-Patent Document
[0011]
[Non-Patent Document 1] Curr Opin Cell Biol. 1991
Apr; 3 (2) : 171-5
[Non-Patent Document 2] Mol Cell. 2014 Jun 5; 54 (5) : 728-736
Summary of the Invention
Problems to be Solved by the Invention
[0012] The present invention aims to provide a novel
heterocyclic compound having an inhibitory action on binding of BET family protein to protein having acetylated lysine
(hereinafter sometime to be referred to as "BET family protein inhibitory action"), and useful an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory
diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like.
Means of Solving the Problems
[0013]
The present inventors have conducted intensive studies, and have found that a compound represented by the below- mentioned formula (1) unexpectedly has an BET family protein inhibitory action, and therefore, is useful as an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like, and completed the present invention based on these findings.
Accordingly, the present invention provides the following.
[1] A compound represented by the formula (I) :
[0014]
Figure imgf000005_0001
[0015]
wherein R1 is an optionally .substituted 5-membered aromatic
heterocyclic group;
ring A is an optionally further substituted benzene ring;
R2 and R3 are each independently a hydrogen atom or a
substituent; and
ring B is
a ring represented by the formula:
[0016]
Figure imgf000006_0001
[0017]
wherein
Xa and Ya are each independently a nitrogen atom or a carbon atom, and
R4a is a substituent, and
wherein said ring optionally further substituted,
a ring represented by the formula:
[0018]
Figure imgf000006_0002
[0019]
wherein
Xb and Yb are each independently a nitrogen atom or a carbon atom, and
Rb is a hydrogen atom or a substituent, and
wherein said ring is optionally further substituted, or a ring represented by the formula:
[0020]
Figure imgf000007_0001
[0021]
wherein
Xc is a nitrogen atom or a carbon atom, and
R4c is a hydrogen atom or a substituent, and
wherein said ring is optionally further substituted;
or a salt thereof.
[0022]
[2] The compound or salt of the above-mentioned [1], wherein R1 is an optionally substituted isoxazolyl or an optionally substituted pyrazolyl;
R2 and R3 are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) an optionally substituted C3-10 cycloalkyl group,
(5) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group,
(6) an optionally substituted 5- to 14-membered aromatic heterocyclic group,
(7) an amino group optionally having 1 or 2 Ci-6 alkyl groups optionally having 1 to 3 substituents selected from the following substituent group A,
(8) a hydroxy group, optionally having a Ci-6 alkyl group, or (9) a sulfanyl group optionally having a Ci-6 alkyl group; and Ring B is
a ring represented by the formula:
[0023]
Figure imgf000008_0001
[0024]
wherein
Xa is a nitrogen atom;
Ya is a nitrogen atom; and
R4a is
(1) an optionally substituted Ci_6 alkyl group,
(2) an optionally substituted C3-10 cycloalkyl group,
(3) an optionally substituted C6-io aryl group,
(4) an optionally substituted 3- to 14-membered non- aromatic heterocyclic group, or
(5) an amino group optionally having 1 or 2 Ce-io aryl groups optionally having 1 to 3 substituents selected from the following substituent group A,
a ring represented by the formula:
[0025]
Figure imgf000008_0002
[0026]
wherein
Xb is a nitrogen atom;
Yb is a nitrogen atom; and
R4b is
(1) an optionally substituted Ci-6 alkyl group, or
(2) an optionally substituted C6-io. aryl group, or
a ring represented by the formula:
[0027]
Figure imgf000009_0001
[0028]
wherein
X° is a nitrogen atom; and
R4c is an optionally substituted Cis alkyl group,
[substituent group A]
(1) a halogen atom,
(2) a nitro group,
(3) a cyano group,
(4) an oxo group,
(5) a hydroxy group,
(6) an optionally halogenated Ci-6 alkoxy group,
(7) a C6-i4 aryloxy group,
(8) a C7-16 aralkyloxy group,
(9) a 5- to 14-membered aromatic heterocyclyloxy group,
(10) a 3- to 14-membered non-aromatic heterocyclyloxy group,
(11) a Ci-6 alkyl-carbonyloxy group,
(12) a Ce-14 aryl-carbonyloxy group,
(13) a Ci-6 alkoxy-carbonyloxy group,
(14) a mono- or di-Ci_6 alkyl-carbamoyloxy group,
(15) a C6-14 aryl-carbamoyloxy group,
(15) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group,
(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group,
(18) an optionally halogenated Ci_5 alkylsulfonyloxy group,
(19) a, C6-14 arylsulfonyloxy group optionally substituted by a Cx-6 alkyl group,
(20) an optionally halogenated Ci-6 alkylthio group,
(21) a 5- to 14-membered aromatic heterocyclic group,
(22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group,
(24) a carboxy group,
(25) an optionally halogenated Ci_6 alkyl-carbonyl group,
(26). a C6-i4 aryl-carbonyl group,
(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,
(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,
(29) a Ci-6 alkoxy-carbonyl group,
(30) a C6-i4 aryloxy-carbonyl group,
(31) a C7-i6 aralkyloxy-carbonyl group,
(32) a carbamoyl group,
(33) a thiocarbamoyl group,
(34) a mono- or di-Ci-6 alkyl-carbamoyl group,
(35) a C6-14 aryl-carbamoyl group,
(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group,
(37) a 3- to 14^membered non-aromatic heterocyclylcarbamoyl group,
(38) an optionally halogenated Ci_6 alkylsulfonyl group,
(39) a C6-i4 arylsulfonyl group,
(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group,
(41) an optionally halogenated Ci-6 alkylsulfinyl group,
(42) a -iA arylsulfinyl group,
(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group,
(44) an amino group,
(45) a mono- or di-Ci-6 alkylamino group,
(46) a mono- or di-C6-i4 arylamino group,
(47) a 5- to 14-membered aromatic heterocyclylamino group,
(48) a C7-16 aralkylamino group,
(49) a' formylamino group,
(50) ' a Ci-6 alkyl-carbonylamino group,
(51) a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl ) amino group,
(52) a C6-14 aryl-carbonylamino group,
(53) a C3-6 alkoxy-carbonylamino group,
(54) a C7-16 aralkyloxy-carbonylamino group,
(55) a Ci-6 alkylsulfonylamino group, (56) a C6-i4 arylsulfonylamino group optionally substituted by a Ci-6 alkyl group,
(57) an optionally halogenated Ci-s alkyl group,
(58) a C2-6 alkenyl group,
(59) a C2-6 alkynyl group,
(60) a C3-10 cycloalkyl group,
(61) a C3-10 cycloalkenyl group and
(62) a C6-i4 aryl group.
[0029]
[3] 7- (3, 5-dimethylisoxazol-4-yl) -8-methoxy-N-methyl-l- (2- pyridylmethyl) - [1, 2, 4] triazolo [4, 3-a] quinoxalin-4-amine or a salt thereof.
[4] 4- [8-methoxy-l- (2-pyridylmethyl ) -[1,2, 4 ] triazolo [ 4 , 3- a] quinoxalin-7-yl] -3, 5-dimethyl-isoxazole or a salt thereof.
[5] 7- (3, 5-dimethylisoxazol-4-yl) -8-methoxy-l- (2- pyridylmethyl) - [1, 2, 4] triazolo [4, 3-a] quinoxalin-4-amine or a salt thereof.
[0030]
[6] A medicament comprising the compound or salt of the above- mentioned [1] .
[7] The medicament of the above-mentioned [6], which is
bromodomain and extra terminal domain family protein inhibitor.
[8] The medicament of the above-mentioned [6], which is an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases.
[9] The medicament of the above-mentioned [6], which is an agent for the prophylaxis or treatment of psoriasis or atopic dermatitis.
[0031] '
[10] The compound or salt of the above-mentioned [1] for use in the. prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases.
[11] The compound or salt of the above-mentioned [1] for use in the prophylaxis or treatment of psoriasis or atopic
dermatitis. [0032] '
[12] A method of inhibiting brdmodomain and extra terminal domain family protein in a mammal, which comprises
administering an effective amount of the compound or salt of the above-mentioned [1] to the mammal.
[13] A method for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases in a mammal, which comprises administering an effective amount of the compound or salt of the above-mentioned [1] to the mammal.
[14] A method for the prophylaxis or treatment of psoriasis or atopic dermatitis in a mammal, which comprises administering an effective amount of the compound or salt of the above- mentioned [1] to the mammal.
[0033]
[15] Use of the compound or salt of the above-mentioned [1] for the production of an agent for the prophylaxis or
treatment of autoimmune diseases and/or inflammatory diseases.
[16] Use of the compound or salt of the above-mentioned [1] for the production of an agent for the prophylaxis or
treatment of psoriasis or atopic dermatitis.
[0034]
[17] A compound represented by the formula (II):
[0035]
Figure imgf000012_0001
[0036]
wherein
R1A is an optionally substituted 5-membered aromatic
heterocyclic group;
ring AA is an optionally further substituted benzene ring;
R2A and R3A are each independently a hydrogen atom or a substituent; and
ring BA is
a ring represented by the formula:
[0037].
Figure imgf000013_0001
[0038]
wherein
Xaa and Yaa are each independently a nitrogen atom or a carbon atom, and
R4aa is a substituent, and
wherein said ring is optionally further substituted,
a ring represented by the formula:
[0039]
Figure imgf000013_0002
[0Ό40]
wherein
Xba and Yba are each independently a nitrogen atom or a carbon atom, and
R4ba is a hydrogen atom or a substituent, and
wherein said ring is optionally further substituted, or a ring represented by the formula:
0041]
Figure imgf000013_0003
[0042]
wherein
Xca is a nitrogen atom or a carbon atom, and
R4ca is a hydrogen atom or a substituent, and
wherein said ring is optionally further substituted;
or a salt thereof.
Effect of the Invention
[0043]
Compound (I) has a superior BET family protein inhibitory action, and is useful as an agent for' the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like.
Brief Description of the Drawings
[0044]
Figure 1 shows effect of the compounds of Example 4.7 and Example 9.6 on ear thickness in Imiquimod induced-mouse model of psoriasis.
Figure 2 shows effect of the compounds of Example 9.9 and Example 9.10 on ear thickness in Imiquimod induced-mouse model of psoriasis.
Figure 3 shows effect of the compound of Example 4.7 on ear thickness in Imiquimod induced-mouse model of psoriasis.
[0045]
[Detailed Description of the Invention]
The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition.
In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.
In the present specification, examples of the "CX-6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,. sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2- dimethylbutyl, 3 , 3-dimethylbutyl and 2-ethylbutyl.
, In the present specification, examples of the "optionally halogenated Ci_6 alkyl group" include a Ci-6 alkyl group
optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl , ethyl, 2- bromoethyl, 2, 2, 2-trifluoroethyl, tetrafluoroethyl ,
pentafluoroethyl, propyl, 2 , 2-difluoropropyl, 3,3,3- trifluoropropyl, isopropyl, butyl, 4 , 4 , -trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, hexyl and 6, 6 , 6-trifluorohexyl .
In the present specification, examples of the "C2-6 alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-
2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4- methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
In the present specification, examples of the "C2-6 alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl and 4-methyl-2-pentynyl
In the present specification, examples of the "C3-10 ■ cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [ 3.2.1 ] octyl and adamantyl.
In the present specification, examples of the "optionally halogenated C3-10 "cycloalkyl group" include a C3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2- difluorocyclopropyl, 2 , 3-difluorocyclopropyl , cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl .
In the present specification, examples of the "C3-10 cycloalkenyl group" include cyclopropenyl , cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
In the present specification, examples of the "C6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.
In the present specification, examples of the wC7_i6
aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl .
[0046]
In the present specification, examples of the "Ci-6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the "optionally halogenated Ci-6 alkoxy group" include a Ci_6 alkoxy group
optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2 , 2 , 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4 , 4 , 4-trifluorobutoxy, isobutoxy, sec- butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the "C3-10
cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and
cyclooctyloxy .
In. the present specification, examples of the "Ci_6
alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
In the present specification, examples of the "optionally halogenated Ci-6 alkylthio. group" include a Ci-6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4 , 4 , 4-trifluorobutylthio, pentylthio and hexylthio.
In the present specification, examples of the "Ci_6 alkyl- carbonyl group" include acetyl,- propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 3-methylbutanoyl , 2-methylbutanoyl, 2 , 2-dimethylpropanoyl, hexanoyl and heptanoyl.
In the present specification, examples of the "optionally halogenated Ci-6 alkyl-carbonyl group" include a Ci-6 alkyl- carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl , trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
In the present specification, examples of the "Ci_6 alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl .
In the present specification, examples of the "C6-1 aryl- carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the "C7-16
aralkyl-carbonyl group" include phenylacetyl and
phenylpropionyl .
In the present specification, examples of the "5- to 14- membered aromatic heterocyclylcarbonyl group" include
nicotinoyl, isonicotinoyl , thenoyl and furoyl.
In the present specification, examples of the "3- to 14- membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and
pyrrolidinylcarbonyl .
In the present specification, examples of the "mono- or di-Ci-6 alkyl-carbamoyl group" include methylcarbamoyl,
ethylcarbamoyl, dimethylcarbamoyl , diethylcarbamoyl and N- ethyl-N-methylcarbamoyl .
In the present specification, examples of the "mono- or di-C7-i6 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl .
In the present specification, examples of the "Ci-5 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl .
In the present specification, examples of the "optionally halogenated Ci_e alkylsulfonyl group" include a Ci-6
alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include
methylsulfonyl , difluoromethylsulfonyl,
trifluoromethylsulfonyl, ethylsulfonyl , propylsulfonyl,
isopropylsulfonyl, butylsulfonyl, 4 , 4 , 4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl .
In the present specification, examples of the "C6-14 ■ arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl .
[0047]
In the present specification, examples of the
"substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an
optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, · an optionally
substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.
In the present specification, examples of the
"hydrocarbon group" (including "hydrocarbon group" of
"optionally substituted hydrocarbon group") include a Ci_6 alkyl group, a C2-6 alkenyl group, a C2-e alkynyl group, a C3-10
cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group and a C7_i6 aralkyl group.
[0048]
. In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group optionally having substituent (s) selected from the following substituent group A.
[substituent group A] (1) a halogen atom,
(2) a nitro group,
(3) a cyano group,
(4) an oxo group,
' (5) a hydroxy group,
(6) an optionally halogenated Ci-6 alkoxy group,
(7) a C6-i4 aryloxy group (e.g., phenoxy, naphthoxy) ,
(8) a C7-16 aralkyloxy group (e.g., benzyloxy) ,
(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy) ,
(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy) ,
(11) a Ci-6 alkyl-carbonyloxy group (e.g., acetoxy,
propanoyloxy) ,
(12) a C6-i4 aryl-carbonyloxy group (e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy) ,
(13) a Ci-6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) ,
(14) a mono- or di-Ci-6 alkyl-carbamoyloxy group (e.g.,
methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy) ,
(15) a Cs-14 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy) ,
(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy) ,
(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy) ,
(18) an optionally halogenated Ci_6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy) ,
(19) a Ce-14 arylsulfonyloxy group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy) ,
(20) an optionally halogenated Ci_6 alkylthio group,
(21) a 5- to 14-membered aromatic heterocyclic group,
(22) a 3- to 14-membered non-aromatic heterocyclic group,
(23) a formyl group, (24) a carboxy group,
(25) an optionally halogenated Ci_6 alkyl-carbonyl group,
(26) a C6_i4 aryl-carbonyl group,
(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,
(29) a Ci-6 alkoxy-carbonyl group,
(30)" a C6-i4 aryloxy-carbonyl group (e.g., phenyloxycarbonyl , 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl ) ,
(31) a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl ) ,
(32) a carbamoyl group,
(33) a thiocarbamoyl group,
(34) a mono- or di-Ci-6 alkyl-carbamoyl group,
(35) a C6-i4 aryl-carbamoyl group (e.g., phenylcarbamoyl) ,
(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl) ,
(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl ) , (38) an optionally halogenated Ci-6 alkylsulfonyl group,
(39) a C6-i4 arylsulfonyl group,
(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl ) ,
(41) an optionally halogenated Ci-6 alkylsulfinyl group,
(42) a Ce-14 arylsulfinyl group (e.g., phenylsulfinyl , 1- naphthylsulfinyl , 2-naphthylsulfinyl ) ,
(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl) ,
(44) an amino group,
(45) a mono- or di-Ci_6 alkylamino group (e.g., methylamino, . ethylamino, propylamino, isopropylamino, butylamino,
dimethylamino, diethylamino, dipropylamino, dibutylamino, N- ethyl-N-methylamino) ,
(46) a mono- or di-C6-i4 arylamino group (e.g., phenylamino) , (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino) ,
(48) a C7-16 aralkylamino group (e.g., benzylamino) ,
(49) a formylamino group,
(50) a Ci-6 alkyl-carbonylamino group (e.g., acetylamino,
5 propanoylamino, butanoylamino) ,
(51) a (Ci-6 alkyl) (Ci_6 alkyl-carbonyl ) amino group (e.g., N- acetyl-N-methylamino) ,
(52) a C6-i4 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino) ,
10 (53) a Ci-6 alkoxy-carbonylamino group (e.g.,
methoxycarbonylamino, ethoxycarbonylamino,
propoxycarbonylamino, butoxycarbonylamino, tert- butoxycarbonylamino) ,
(54) a C7-16 aralkyloxy-carbonylamino group (e.g.,
15 benzyloxycarbonylamino) ,
(55) a Ci-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) ,
(56) a C6-i4 arylsulfonylamino group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonylamino,
20 toluenesulfonylamino) ,
(57) an optionally halogenated Ci-6 alkyl group,
(58) a C2-6 alkenyl group,
(59) a C2-6 alkynyl group,
(60) a C3-10 cycloalkyl group,
25 (61) a C3-10 cycloalkenyl group and
(62) a C6-i4 aryl group.
[0049]
The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 30 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
In the present specification, examples of the
"heterocyclic group" (including "heterocyclic group" of
·?<; "nnt ί nna 11 v siihst i iit- pH hp prnr.vr l ι r nrmnn") ί ri r. l Hp ( i ) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
[0050]
In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl , oxazolyl', isoxazolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, 1, 2 , 4-oxadiazolyl, 1,3,4- ■ oxadiazolyl, 1 , 2 , 4-thiadiazolyl , 1, 3, 4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and
8- to 14-membered fused polycyclic (preferably bi or
tricyclic) aromatic heterocyclic groups such as
benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl , benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
benzotriazolyl, imidazopyridinyl, thienopyridinyl,
furopyridinyl , pyrrolopyridinyl , pyrazolopyridinyl ,
oxazolopyridinyl , thiazolopyridinyl , imidazopyrazinyl ,
imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl ,
pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2, 3-b] thienyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl , naphthyridinyl,
quinoxalinyl,' quinazolinyl, cinnolinyl, carbazolyl, β- carbolinyl, phenanthridinyl , acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl and the like. [0051]
In the present specification, examples of the "non- aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "non-aromatic heterocyclic group" include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl,
tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl , pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl,
tetrahydroisothiazolyl, tetrahydrooxazolyl ,
tetrahydroisooxazolyl, piperidinyl, piperazinyl,
tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl , dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl , morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and
9- to 14-membered fused polycyclic (preferably bi or
tricyclic) non-aromatic heterocyclic groups such as
dihydrobenzofuranyl, dihydrobenzimidazolyl ,
dihydrobenzoxazolyl, dihydrobenzothiazolyl ,
dihydrobenzisothiazolyl, dihydronaphtho [2, 3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl , tetrahydrothieno [2 , 3-c] pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl ,
tetrahydrophenanthridinyl , hexahydrophenothiazinyl ,
hexahydrophenoxazinyl, tetrahydrophthalazinyl,
tetrahydronaphthyridinyl, tetrahydroquinazolinyl,
tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β- carbolinyl, tetrahydroacrydinyl , tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.
[0052]
In the present specification, preferable examples of the "7- to 10-membered bridged heterocyclic group" include
quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl .
In the present specification, examples of the "nitrogen- containing heterocyclic group" include a "heterocyclic group" containing at least one nitrogen atom as a ring-constituting atom.
In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group optionally having substituent ( s ) selected from the
aforementioned substituent group A.
The number of the substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of the substituents , is two or more, the respective substituents may be the same or different.
[0053]
In the present specification, examples of the "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a
sulfamoyl group and a phosphono group, each optionally having "1 or 2 substituents selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-1 aryl group, a C7-16 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an
optionally halogenated Ci-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group" .
Examples of the "acyl group" also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group.
Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the
hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded' sulfinyl group.
Preferable examples of the "acyl group" include a formyl group, a carboxy group, a Ci-6 alkyl-carbonyl group, a C2-6
alkenyl-carbonyl group (e.g., crotonoyl) , a C3-10 cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl,
cyclopentanecarbonyl, cyclohexanecarbonyl,
cycloheptanecarbonyl) , a C3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl ) , a Ce-14 aryl-carbonyl group, a C7_i6
aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group," a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a Cg-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl,
naphthyloxycarbonyl) , a C7_i6 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) , a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C3-io cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl ) , a mono- or di-C6-i4 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C7_i6 aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl) , a thiocarbamoyl group, a mono- or di-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl ) , a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl) , a mono- or di-C3_io
cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C6-i4 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C7-i6 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl,
phenethylthiocarbamoyl) , a 5- to 14-membered aromatic
heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) , a sulfino group, a Ci_6 alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl ) , a sulfo group, a Ci-6
alkylsulfonyl group, a C6-i4 arylsulfonyl group, a phosphono group and a mono- or di-Ci-e alkylphosphono group (e.g.,
Figure imgf000026_0001
aiBt†iy"xp~nbspnbno ; aiisopropyxp'nfrspTrdnOv dibutylphosphono) .
[0054]
In the present specification, examples of the "optionally substituted amino group" include an amino group optionally having "1 or 2 substituents selected from a Ci-ς alkyl group, a- C2-6 alkenyl group, a . C3-10 cycloalkyl group, a C6-i4 aryl' group, a C7-i6 aralkyl group, a Ci_6 alkyl-carbonyl group, a C6-1 aryl- carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14— membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C7-i6 aralkyl-carbamoyl group, a Ci-6
alkylsulfonyl group and a C6-i4 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from
substituent group A".
Preferable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally
Figure imgf000026_0002
Ί.1-6 ' Ι'κ ΐ ΓΒΐα ηυ ""g ou ' erg. ,-mteVnyxaiirrtio,
trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino) , a mono- or di-C2-6 alkenylamino group (e.g., diallylamino) , a mono- or di-C3_io cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino) , a mono- or di-C6-i4 arylamino group (e.g., phenylamino) , a mono- or di-C7_i6 aralkylamino group (e.g., benzylamino, dibenzylamino) , a mono- or di- (optionally halogenated Ci_6 alkyl) -carbonylamino group- (e.g., acetylamino, propionylamino) , a mono- or di-C6-i4 aryl- carbonylamino group (e.g., benzoylamino) , a mono- or di-C7-i6 aralkyl-carbonylamino group (e.g., benzylcarbonylamino) , a mono- or di-5- to 14-membered aromatic
heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino) , a mono- or di-3- to 14-membered non- aromatic heterocyclylcarbonylamino group (e.g.,
piperidinylcarbonylamino) , a mono- or di-Ci_6 alkoxy- carbonylamino group (e.g., tert-butoxycarbonylamino) , a 5- to 14-membered aromatic heterocyclylamino group (e.g.,
pyridylamino) , a carbamoylamino group, a (mono- or di-Ci-6 alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C7_i6 aralkyl-carbamoyl ) amino group (e.g.,
benzylcarbamoylamino) , a Ci-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) , a Ce-i4
arylsulfonylamino group (e.g., phenylsulfonylamino) , a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl) amino group (e.g., N-acetyl-N- methylamino) and a (Ci_6 alkyl) (CQ-H aryl-carbonyl ) amino group (e.g., N-benzoyl-N-methylamino) .
[0055]
In the present specification, examples of the "optionally substituted carbamoyl group" include a carbamoyl group
optionally having "1 or 2 substituents selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6- 14 aryl group, a C7-16 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7_i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a.3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic
heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl- carbamoyl group and a mono- or di-C7_i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of the optionally substituted
carbamoyl group include a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C3_io cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,
cyclohexylcarbamoyl) , a mono- or di-C6-i4 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C7_i6 aralkyl-carbamoyl group, a mono- or di-Ci-6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl ) , a mono- or di-C6-i4 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,
pyridylcarbamoyl) .
[0056]
In the present specification, examples of the "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a Gi-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6- 14 aryl group, a C7-16 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-1 aryl-carbonyl group, a C7_i6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic
heterocyclic group, a carbamoyl group, a mono- or di-Ci_6 alkyl- carbamoyl group and a mono- or di-C7_i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of. the optionally substituted
thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl , ethylthiocarbamoyl , dimethylthiocarbamoyl,
diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl) , a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g.,
diallylthiocarbamoyl) , a mono- or di-C3-i0 cycloalkyl- thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl ,
cyclohexylthiocarbamoyl) , a mono- or di-C6-i4 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C7_i6 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl ,
phenethylthiocarbamoyl) , a mono- or di-Ci-6 alkyl-carbonyl- thiocarbamoyl group (e.g., acetylthiocarbamoyl,
propionylthiocarbamoyl) , a mono- or di-C6-i4 aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) .
[0057]
In the present specification, examples of the . "optionally substituted sulfamoyl group" include a sulfamoyl group
optionally having "1 or 2 substituents selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6- 14 aryl group, a C7_i6 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-i4 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic
heterocyclic group, a carbamoyl group, a mono- or di-Ci_6 alkyl- carbamoyl group and a mono- or di-C7_i5 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of the optionally substituted
sulfamoyl group include a sulfamoyl group, a mono- or di-Ci-6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N- methylsulfamoyl) , a mono- or di-C2-6 alkenyl-sulfamoyl group (e.g., diallylsulfamoyl) , a mono- or di-C3_i0 cycloalkyl- sulfamoyl group (e.g., cyclopropylsulfamoyl,
cyclohexylsulfamoyl) , a mono- or di-C6-i4 aryl-sulfamoyl group (e.g., phenylsulfamoyl ) , a mono- or di-C7_i6 aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl ) , a mono- or di-Ci-6 alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl , propionylsulfamoyl) , a mono- or di-C6-i4 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl ) and a 5- to 14-membered
aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl ) .
[0058]
In the present specification, examples of the "optionally substituted hydroxy group" include a hydroxy group optionally having "a substituent selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7_ 16 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-14 aryl- carbonyl group, a C7-i6 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C7-i6 aralkyl-carbamoyl group, a Ci-6
alkylsulfonyl group and a C6-i4 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from
substituent group A".
Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a Ci-6 alkoxy group, aJ C2-6
alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) , a C3-10 cycloalkyloxy group (e.g., cyclohexyloxy) , a Ce-14 aryloxy group (e.g., phenoxy, naphthyloxy) , a C7_i6 aralkyloxy group (e.g., benzyloxy, phenethyloxy) , a Ci_6 alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy) , a C6-i4 aryl-carbonyloxy group
(e.g., benzoyloxy) , a C7-i6 aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy) , a 5- to 14-membered aromatic
heterocyclylcarbonyloxy group (e.g., nicotinoyloxy) , a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g.,. piperidinylcarbonyloxy) , a Ci-6 alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy) , a 5- to 14-membered aromatic
heterocyclyloxy group (e.g., pyridyloxy) , a carbamoyloxy group, a Ci_6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy) , a
C7-i6 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy) , a Ci_6 alkylsulfonyloxy group (e.g., methylsulfonyloxy,
ethylsulfonyloxy) and a C6-14 arylsulfonyloxy group (e.g., phenylsulfonyloxy) .
[0059]
In the present specification, examples of the "optionally substituted sulfanyl group" include a sulfanyl group
optionally having "a substituent selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-i4 aryl group, a C7-i5 aralkyl group, a Ci-6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3
substituents selected from substituent group A" and a
halogenated sulfanyl group.
5 Preferable examples of the optionally substituted
sulfanyl group include a sulfanyl (-SH) group, a Ci_6 alkylthio group, a C2-e alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio ) , a C3_i0 cycloalkylthio group (e.g., cyclohexylthio) , a Ce-14 arylthio group (e.g., phenylthio,
10. naphthylthio) , a C-i6 aralkylthio group (e.g., benzylthio,
phenethylthio) , a Ci-6 alkyl-carbonylthio group (e.g.,
acetylthio, propionylthio, butyrylthio, isobutyrylthio,
pivaloylthio) , a C6-14 aryl-carbonylthio group (e.g.,
benzoylthio) , a 5- to 14-membered aromatic heterocyclylthio
15 group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio) .
[0060]
In the present specification, examples of the "optionally substituted silyl group" include a silyl group optionally
20 having "1 to 3 substituents selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-14 aryl group and a C7_i6 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of the optionally substituted silyl
25 group include a tri-Ci-6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl) .
[0061] .
In the present specification, examples of the
"hydrocarbon ring" include a C6-14 aromatic hydrocarbon ring, C3_ 30 10 cycloalkane and C3-10 cycloalkene.
In the present specification, examples of the "C6-i4
aromatic hydrocarbon ring" include benzene and naphthalene.
In the present specification, examples of the "C3-10
cycloalkane" include cyclopropane, cyclobutane, cyclopentane, 35 cyclohexane, cycloheptane and cyclooctane. In the present specification, examples of the "C3-10
cycloalkene" include cyclopropene , cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
In the present specification, examples of the
"heterocycle" include an aromatic heterocycle and a non-
. aromatic heterocycle, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
[0062] .
In the present specification, examples of the "aromatic
" heterocycle" include a 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, as a ring- constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocycle"
include 5- or - 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine,
pyrimidine, pyridazine, 1, 2, 4-oxadiazole, 1, 3, 4-oxadiazole, 1, 2, 4-thiadiazole, 1 , 3 , 4-thiadiazole , triazole, tetrazole, triazine and the like; and
8- to 14-membered fused polycyclic (preferably bi or
tricyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole,
benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine,
pyrazolopyridine, oxazolopyridine, thiazolopyridine,
imidazopyrazine, imidazopyrimidine, thienopyrimidine,
furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine,
oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2 , 3-b] thiophene, phenoxathiine, indole, isoindole, lH-indazole, purine, isoquinoline,
quinoline, phthalazine, naphthyridine, quinoxaline,
quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxathiine and the like. [0063]
In the present specification, examples of the "non- aromatic heterocycle" include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic
heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline,
thiazolidine, tetrahydroisothiazole, tetrahydrooxazole,
tetrahydroisoxazole, piperidine, piperazine,
tetrahydropyridine, dihydropyridine, dihydrothiopyran,
tetrahydropyrimidine, tetrahydropyridazine , dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, - thiomorpholine , azepanine, diazepane, azepine, azocane,
diazocane, oxepane and the like; and
9- to 14-membered fused polycyclic (preferably bi or
tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho [2 , 3-b] thiophene,
tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno [2 , 3-c] pyridine,
tetrahydrobenzazepine, tetrahydroquinoxaline,
tetrahydrophenanthridine, hexahydrophenothiazine,
hexahydrophenoxazine, tetrahydrophthalazine,
tetrahydronaphthyridine, tetrahydroquinazoline,
tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β- carboline, tetrahydroacridine, tetrahydrophenazine,
tetrahydrothioxanthene, octahydroisoquinoline and the like.
In the present specification, examples of the "nitrogen- containing heterocycle" include a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom. [0064]
The definition of each symbol in the formula (I) is explained in detail in the following.
[0065]
R1 is an optionally substituted 5-membered aromatic heterocyclic group.
[0066]
In the present specification, examples of the "5-membered aromatic heterocyclic group" of the "optionally substituted 5- membered aromatic heterocyclic group" for R1 include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, 1, 2, 4-oxadiazolyl, 1,3,4- oxadiazolyl, 1, 2, -thiadiazolyl, 1 , 3 , 4-thiadiazolyl , triazolyl, tetrazolyl and the like.
[0067]
The "5-membered aromatic heterocyclic group" of the
"optionally substituted 5-membered aromatic heterocyclic group" for R1 optionally has 1 to 3 substituents at substitutable position(s). Examples of the substituent include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective
substituents may be the same or different.
[0068]
R1 is preferably an optionally substituted isoxazolyl or an optionally substituted pyrazolyl.
[0069]
R1 is more preferably isoxazolyl or pyrazolyl, each of which is optionally substituted by 1 to 3 Ci_6 alkyl groups
(e.g. , methyl) .
[0070]
In another embodiment, R1 is more preferably isoxazolyl optionally■ substituted by 1 to 3 Ci_6 alkyl groups (e.g.,
methyl) .
[0071]
Ring A is an optionally further substituted benzene ring. [0072]
The "benzene ring" of the "optionally further substituted benzene ring" for ring A optionally has 1 or 2 substituents, in addition to R1 and R3. Examples of the substituent include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.
[0073]
Ring A is preferably a benzene ring having no substituent, in addition to R1 and R3.
[0074]
R2 and R3 are each independently a hydrogen atom or a substituent.
[0075]
R2 and R3 are preferably each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) an optionally substituted hydrocarbon group (preferably an optionally substituted C3-10 cycloalkyl group, more preferably an optionally substituted C3-6 cycloalkyl group) ,
(5) an optionally substituted heterocyclic group [preferably an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group (preferably an optionally substituted 3- to 8-membered (preferably 4- to 6- membered) monocyclic non-aromatic heterocyclic group) , and an optionally substituted 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocyclic group (preferably an
optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group) ] ,
(6) an optionally substituted amino group (preferably an amino group optionally having 1 or 2 Ci-6 alkyl groups optionally having 1 to 3 substituents selected from substituent group A) , or
(7) an optionally substituted hydroxy group (preferably a hydroxy group optionally having a Ci_6 alkyl group optionally having 1 to 3 substituents selected from substituent group A) , or
(8) an optionally substituted sulfanyl group (preferably a sulfanyl group optionally having a Ci-6 alkyl group optionally having 1 to 3 substituents selected from substituent group A) .
[0076]
R2 and R3 are more preferably each independently
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) an optionally substituted C3-10 cycloalkyl group (preferably an optionally substituted C3-6 cycloalkyl group (e.g.,
cyclopropyl) ) ,
(5) an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group (preferably an optionally substituted 3- to 8-membered (preferably 4- to 6- membered) monocyclic non-aromatic heterocyclic group, more preferably an optionally substituted 3- to 8-membered
(preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl,
pyrrolidinyl ) ) ,
(6) an optionally substituted 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group (preferably an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., isoxazolyl ) ) ,
(7) an amino group optionally having 1 or 2 - Ci-6 alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 substituents selected from substituent group A (preferably hydroxy) ,
(8) a hydroxy group optionally having a Ci-6 alkyl group (e.g., methyl, ethyl) , or
(9) a sulfanyl group optionally having a Ci-6 alkyl group (e.g., methyl) .
[0077]
R2 and R3 are further more preferably each independently (1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl) ) ,
(5) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to
8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl ) ) ,
(6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., isoxazolyl) optionally having 1 or 2 Ci-6 alkyl groups (e.g. , methyl) ,
(7) an amino group optionally having 1 or 2 Ci-6 alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 hydroxy groups,
(8) a hydroxy group,
(9) a Ci-6 alkoxy group (e.g., methoxy, ethoxy) , or
(10) a Ci-6 alkylthio group (e.g., methylthio) .
[0078]
Still more preferably,
R2 is
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a C3_io cycloalkyl group (preferably a C3_6 cycloalkyl group (e.g., cyclopropyl)),
(5) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl) ) ,
(6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., isoxazolyl) optionally having 1 or 2 Ci_6 alkyl groups (e.g. , methyl) ,
(7) an amino group optionally having 1 or 2 Ci-6 alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 hydroxy groups,
(8) a Ci-6 alkoxy group (e.g., methoxy, ethoxy) , or
(9) a Ci-6 alkylthio group (e.g., methylthio) , and
R3 is
(1) a hydrogen atom,
(2) a hydroxy group, or
(3) a Ci_6 alkoxy group (e.g., methoxy).
' [0079]
In another embodiment, R2 and R3 are further more
preferably each independently
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl) ) ,
(5) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to
8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl) ) , (6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., isoxazolyl) optionally having 1 or 2 Ci-e alkyl groups (e.g. , methyl) ,
(7) an amino group optionally having 1 or 2 Ci-5 alkyl groups (e.g., methyl, ethyl),
(8) a hydroxy group,
(9) a Ci-6 alkoxy group (e.g., methoxy, ethoxy), or
(10) a Ci-6 alkylthio group (e.g., methylthio).
[0080]
Still more preferably,
R2 is
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a- C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl)), (5) a 3- to 8-membered (preferably 4- to 6-membered) monocyclic non-aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl) ) , (6) a 5- to 6-membered monocyclic aromatic heterocyclic group
(e.g., isoxazolyl) optionally having 1 or 2 Ci-6 alkyl groups
(e.g., methyl ) ,
(7) an amino group optionally having 1 or 2 Ci-6 alkyl groups (e.g., methyl, ethyl),
(8) a Ci-6 alkoxy group (e.g., methoxy, ethoxy) , or
(9) a Ci-6 alkylthio group (e.g., methylthio.) , and
R3 is
(1) a hydrogen atom,
(2) a hydroxy group, or
(3) a Ci-6 alkoxy group (e.g., methoxy). - [0081]
In another embodiment, R2 and R3 are further more
preferably each independently
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, ' pyrrolidinyl ) ) ,
(5) an amino group optionally having 1 or 2 Ci-e alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 hydroxy groups, or
(6) a Ci-6 alkoxy group (e.g., methoxy).
[0082]
Still more preferably,
R2 is
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom), (3) a cyano group,
(4) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl ) ) , or
(5) an amino group optionally having 1 or 2 Ci_6 alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 hydroxy groups, and
R3 is
(1) a Ci-6 alkoxy group (e.g., methoxy) .
[0083]
In another embodiment, R2 and R3 are further more preferably each independently
(1) a hydrogen atom, or
(2) a Ci-6 alkoxy group (e.g., methoxy).
[0084]
Still more preferably,
R2 is
(1) a hydrogen atom, and
R3 is
(1) a Ci-6 alkoxy group (e.g., methoxy).
[0085]
Ring B is
a ring represented by the formula:
[0086]
Figure imgf000040_0001
[0087]
wherein
Xa and Ya are each independently a nitrogen atom or a carbon atom, and R4a is a substituent, and
wherein said ring is optionally further substituted, a ring represented by the formula:
[0088]
Figure imgf000041_0001
[0089]
wherein
Xb and Yb are each independently a nitrogen atom or a carbon atom, and
R4b is a hydrogen atom or a substituent, and
wherein said ring is optionally further substituted, or a ring represented by the formula:
[0090]
Figure imgf000041_0002
[0091]
wherein
Xc is a nitrogen atom or a carbon atom, and
R 4c is a hydrogen atom or a substituent, and
wherein said ring is optionally further substituted.
[0092]
Xa is preferably a nitrogen atom.
Ya is preferably a nitrogen atom.
[0093]
Ra is preferably
(1) an optionally substituted hydrocarbon group (preferably an optionally substituted Ci-6 alkyl group, an optionally
substituted C3-i0 cycl'oalkyl group, an optionally substituted C6 10 aryl group) ,
(2) an optionally substituted heterocyclic group (preferably an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group, more preferably an optionally substituted 3- to 8-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group) , or
(3) an optionally substituted amino group (preferably an amino group optionally having 1 or 2 C6-io aryl groups optionally having 1 to 3 substituents selected from substituent group A) .
[0094]
R4a is more preferably
(1) an optionally substituted Ci-e alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl) ,
(2) an optionally substituted C3-10 cycloalkyl group (preferably an optionally substituted C3-6 cycloalkyl group (e.g.,
cyclopropyl) ) ,
(3) an optionally substituted Cg-io aryl group (e.g., phenyl),
(4) an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group (preferably an optionally substituted 3- to 8-membered (preferably 5- or 6- membered) monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl ) ) , or
(5) an amino group optionally having 1 or 2 Ce-ιο aryl groups (e.g., phenyl) optionally having 1 to 3 substituents selected from substituent group A (preferably a halogen atom (e.g., a. fluorine atom, a chlorine atom) , a cyano group, a Ci_6 alkoxy group (e.g., methoxy) ) .
[0095]
R4a is further more preferably
(1) a C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl) optionally substituted by 1 to 3 substituents selected from
(a) a C6-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituentrs selected from
(i) a halogen atom (e.g., a fluorine atom, a chlorine atom) ,
(ii) a cyano group,
(iii) a carboxy group,
(iv) a Ci-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) ,
(v) a Ci-6 alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) ,
(vi) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl ) ,
(vii) a C6-io aryl group (e.g., phenyl),
(viii) a C6-io aryloxy group (e.g., phenoxy) , and
(ix) a Ci-3 alkylenedioxy group (e.g., methylenedioxy) , (b) a C3-10 cycloalkyl group (e.g., cyclopentyl) ,
(c) a 3- to 14-membered (preferably 4- to 10-membered)' non- aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group (e . g . , tetrahydropyranyl ) , and
(d) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (e.g., thienyl, thiazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl) optionally substituted by 1 to 3 substituents selected from
(i) a Ci-6 alkyl group, (e.g., methyl), and
(ii) a Ci-6 alkoxy group (e.g., methoxy),
(2) a C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl ) ) optionally substituted by 1 to 3
substituents selected from
(a) a C6-io aryl group (e.g., phenyl), and
(b) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl)),
(3) a C6-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),
(4) a 3- to 8-membered (preferably 5- or 6-membered)
monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) ) , or
(5) an amino group optionally having 1 or 2 C6-io aryl groups (e.g., phenyl) optionally having 1 to 3 substituents selected from
(a) a halogen atom (e.g., a fluorine atom, a chlorine atom),
(b) a cyano group, and
(c) a C]_6 alkoxy group (e.g.,- methoxy) ) .
[0096]
Xb is preferably a nitrogen atom.
Yb is preferably a nitrogen atom.
[0097]
R4b is preferably an optionally substituted hydrocarbon group (preferably an optionally substituted Ci-6 alkyl group, an optionally substituted Οε-ιο aryl group) .
[0098]
. R4b is more preferably
(1) an optionally substituted Ci_6 alkyl group (e.g., methyl, ethyl, isobutyl) , or
(2) an optionally substituted Ce-i0 aryl group (e.g., phenyl).
[0099]
R4b is further more preferably
(1) a Ci-6 alkyl group (e.g., methyl, . ethyl, isobutyl)
optionally substituted by 1 to 3 substituents selected from
(a) a C6-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom (e.g., a fluorine atom, a chlorine atom) , .
(ii) a Ci-6 alkyl group (e.g., methyl) optionally
substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) , and
(iii) a Ci-6 alkoxy group (e.g., methoxy),
(b) a C3-10 cycloalkyl group (e.g.-, cyclopropyl, cyclohexyl) , and
■(c) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrazolyl) ) optionally substituted by 1 to 3 Ci_6 alkyl groups (e.g., methyl), or
(2) a C6-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom (e.g., a fluorine atom), and
(b) a Ci-6 alkoxy group (e.g., methoxy) optionally
substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).
[0100]
X° is preferably a nitrogen atom.
[0101]
R4c is preferably an optionally substituted hydrocarbon group (preferably an optionally substituted Ci-6 alkyl group) .
[0102]
R4c is more preferably an optionally substituted Ci-6 alkyl group (e.g., methyl, ethyl).
[0103]
R4c is further more preferably a Ci-6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3 substituents selected from
(a) a C6-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom (e.g., a fluorine atom), and
(ii) a Ci-6 alkoxy group (e.g., methoxy) optionally
substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) ,
(b) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclohexyl) , and
(c) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl)).
[0104]
The ring represented by the formula (a) optionally has 1 or 2 substituents at substitutable position(s), in addition to R4a. Examples of the substituent include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different. ,
[0105]
The rings represented by the formula (a) preferably have no substituent, in addition to R4a.
[0106]
The ring represented by the formula (b) optionally has 1 or 2 substituents at substitutable position(s), in addition to Rb. Examples of the substituent include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.
[0107]
The rings represented by the formula (b) preferably have ho substituent, in addition to Rb.
[0108]
The ring represented by the formula (c) optionally has 1 or 2 substituents at substitutable position(s), in addition to Rc. Examples of the substituent include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.
[0109]
The rings represented by the formula (c) preferably have no substituent, in addition to R4c.
[0110]
Preferable examples of compound (I) include the following compounds .
[0111]
[Compound A]
Compound (I) wherein
R1 is an optionally substituted isoxazolyl or an optionally substituted pyrazolyl;
Ring A is an optionally further substituted benzene ring; R2 and R3 are each independently
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) an optionally substituted C3-i0 cycloalkyl group (preferably an optionally substituted C3-6 cycloalkyl group (e.g.,
cyclopropyl) ) ,
(5) an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group (preferably an optionally substituted 3- to 8-membered (preferably 4- to 6- membered) monocyclic non-aromatic heterocyclic group, more preferably an optionally substituted 3- to 8-membered
(preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl,
pyrrolidinyl ) ) ,
(6) an optionally substituted 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic 'group (preferably an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., isoxazolyl) ) ,
(7) an amino group optionally having 1 or 2 Ci_6 alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 substituents selected from substituent group A (preferably hydroxy) ,
(8) a hydroxy group optionally having a Ci-6 alkyl group (e.g., methyl, ethyl) , or
(9) a sulfanyl group optionally having a Ci-6 alkyl group (e.g., methyl); and
Ring B is
a ring represented by the formula:
0112]
Figure imgf000047_0001
wherein'
Xa is a nitrogen atom;
Ya is a nitrogen atom; and
R4a is.
(1) an optionally substituted Ci-6, alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl) ,
(2) an optionally substituted C3-10 cycloalkyl group
(preferably an optionally substituted C3-6 cycloalkyl group (e.g. , cyclopropyl) ) ,
(3) an optionally substituted C6-10 aryl group (e.g., phenyl),
(4) an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group
(preferably an optionally substituted 3- to 8-membered
(preferably 5- or 6-membered) monocyclic non-aromatic
heterocyclic group (e.g., tetrahydropyranyl) ) , or
(5) an amino group optionally having 1 or 2 C6-10 aryl groups (e.g., phenyl) optionally having 1 to 3 substituents
selected from substituent group A (preferably a halogen atom (e.g., a fluorine atom, a chlorine atom), a cyano group, a Ci-6 alkoxy group (e.g., methoxy) ) ,
a ring represented by the formula:
[0114]
Figure imgf000048_0001
[0115]
wherein
Xb is a nitrogen atom;
Y is a nitrogen atom; and
R4b is
(1) an optionally substituted Ci-6 alkyl group (e.g., methyl, ethyl, isobutyl) , or
(2) an optionally substituted Ce-ιο aryl group (e.g., phenyl), or
a ring represented by the formula:
0116]
Figure imgf000049_0001
[0117]
wherein
Xc is a nitrogen atom; and
R4c is an optionally substituted Ci_6 alkyl group (e.g., methyl, ethyl) ,
or a salt thereof.
[0118]
[Compound B]
Compound (I) wherein
R1 is isoxazolyl or pyrazolyl, each of which is optionally substituted by 1 to 3 Ci_6 alkyl groups (e.g., methyl);
Ring A is a benzene ring having no substituent, in addition to R1 and R3;
R2 and R3 are each independently
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl) ) ,
(5) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl ) ) ,
(6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., isoxazolyl) optionally having 1 or 2 Ci_6 alkyl groups
(e.g., methyl) , (7) an "amino group optionally having 1 or 2 Ci-6 alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 hydroxy groups,
(8) a hydroxy group,
(9) a Ci-e alkoxy group (e.g., methoxy, ethoxy) , or
(10) a Ci-6 alkylthib group (e.g., methylthio)
[preferably
R2 is
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl) ) ,
(5) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl ) ) ,
(6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., isoxazolyl) optionally having 1 or 2 Ci-6 alkyl groups (e.g., methyl) ,
(7) an amino group optionally having 1 or 2 Ci-6 alkyl groups (e.g., methyl,, ethyl) optionally having 1 to 3 hydroxy groups,
(8) a Ci-6 alkoxy group (e.g., methoxy, ethoxy), or
(9) a Ci-6 alkylthio group (e.g., methylthio), and
R3 is
(1) a hydrogen atom,
(2) a hydroxy group, or
(3) a Ci_6 alkoxy group (e.g., methoxy)]; and
Ring B is
a ring represented by the formula:
[0119]
Figure imgf000051_0001
[0120]
wherein
X is a nitrogen atom;
Ya is a nitrogen atom; and
R4a is
(1) a Ci-6 alkyl group (e.g., methyl, ethyl, propyl,
isopropyl, butyl, isobutyl) optionally substituted by 1 to 3 substituents selected from
(a) a C6-io aryl group (e.g., phenyl) optionally
substituted by 1 to 3 substituents selected from
(i) a halogen atom (e.g., a fluorine atom, a chlorine atom) ,
(ii) a cyano group,
(iii) a carboxy group,
(iv) a Ci-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) ,
(v) a Ci-6 alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) ,
(vi) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl ) ,
(vii) a C6-io aryl group (e.g., phenyl),
(viii) a C6-io aryloxy group (e.g., phenoxy) , and
(ix) a Ci-3 alkylenedioxy group (e.g., methylenedioxy) ,
(b) a C3-10 cycloalkyl group (e.g., cyclopentyl ) ,
(c) a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group (preferably a 3- to 8- membered (preferably 5- or 6-membered) monocyclic non- aromatic heterocyclic group (e . g. , tetrahydropyranyl) , and' (d) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (e.g., thienyl, thiazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl) optionally substituted by 1 to 3 substituents selected from
(i) a Ci-6 alkyl group '(e.g., methyl), and
(ii) a Ci-6 alkoxy group (e.g., methoxy) ,
(2) a C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl) ) optionally substituted by 1 to 3 substituents selected from
(a) a C6-io aryl group (e . g. , phenyl) , and
(b) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (preferably a 5- or 6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl)),
(3) a Ce-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),
(4) a 3- to 8-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group (e.g.,
tetrahydropyranyl) ) , or
(5) an amino group optionally having 1 or 2 C6-io aryl groups (e.g., phenyl) optionally having 1 to 3 substituents selected from
(a) a halogen atom (e.g., a fluorine atom, a chlorine atom) ,
(b) a cyano group, and
(c) a Ci-6 alkoxy group (e.g., methoxy)),
a ring represented by the formula:
[0121]
Figure imgf000052_0001
[0122] wherein
X is a nitrogen atom;
Yb is a nitrogen atom; and
Rb is
(1) a Ci_6 alkyl group (e.g., methyl, ethyl, isobutyl) optionally substituted by 1 to 3 substituents selected from . (a) a C6-io aryl group (e.g., phenyl) optionally
substituted by 1 to 3 substituents selected from
(i) a halogen atom (e.g., a fluorine atom, a chlorine atom) ,
(ii) a Ci-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) , and
(iii) a Ci-6 alkoxy group (e.g., methoxy) ,
(b) a C3-10 cycloalkyl group (e.g., cyclopropyl,
cyclohexyl) , and
(c) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (preferably a 5- or 6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrazolyl) ) optionally substituted by 1 to 3 Ci-
6 alkyl groups (e.g., methyl), or
(2) a C6-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom (e.g., a fluorine atom), and
(b) a Ci-6 alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) , or
a ring represented by the formula:
0123]
Figure imgf000053_0001
[0124; wherein
Xc is a nitrogen atom; and
Rc is a Ci-6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3 substituents selected from
(a) a C6-io aryl group (e.g., phenyl) optionally
substituted by 1 to 3 substituents selected from
(i) a halogen atom' (e.g., a fluorine atom), and
(ii) a Ci-6 alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) ,
(b) a C3-10 cycloalkyl group (e.g., cyclopropyl,
cyclohexyl) , and
(c) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (preferably a 5- or .6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl) ) ,
or a salt thereof.
[0125]
[Compound B-a]
Compound (I) wherein
R1 is isoxazolyl or pyrazolyl, each of which is optionally substituted by 1 to 3 Ci_6 alkyl groups (e.g., methyl);
Ring A is a benzene ring having no substituent, in addition to
R1 and R3;
R2 and R3 are each independently
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl)),
(5) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to
8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl) ) (6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., isoxazolyl) optionally having 1 or 2 Ci_6 alkyl groups (e.g., methyl) ,
(7) an amino group optionally having 1 or 2 Ci-g alkyl groups (e.g., methyl, ethyl),
(8) a hydroxy group,
(9) a Ci-6 alkoxy group (e.g., methoxy, ethoxy) , or
(10) a Ci-6 alkylthio group (e.g., methylthio)
[preferably
R2 is
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl) ) ,
(5) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl) ) ,
(6) a 5- to 6-membered monocyclic aromatic heterocyclic group (e.g., isoxazolyl) optionally having 1 or 2 Ci-6 alkyl groups
(e.g. , methyl ) ,
(7) an amino group optionally having 1 or 2 Ci-6 alkyl groups (e.g., methyl, ethyl),
(8) a Ci-6 alkoxy group (e.g., methoxy, ethoxy), or
(9) a Ci-6 alkylthio group (e.g., methylthio), and
R3 is
(1) a hydrogen atom,
(2) a hydroxy group, or
(3) a Ci-6 alkoxy group (e.g., methoxy)].; and
Ring B is
a ring represented by the formula:
[0126]
Figure imgf000056_0001
[0127]
wherein
Xa is a nitrogen atom;
- Ya is a nitrogen atom; and
R4a is
(1) a Ci_6 alkyl group (e.g., methyl, ethyl, propyl,
isopropyl, butyl, isobutyl) optionally substituted by 1 to 3 substituents selected from
(a) a C6-io aryl group (e.g., phenyl) optionally
substituted by 1 to 3 substituents selected from
(i) a halogen atom (e.g., a fluorine atom, a chlorine atom) ,
(ii) a cyano group,
(iii) a carboxy group,
(iv) a Ci-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) , _
(v) a' Ci-6 alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) ,
(vi) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl )
(vii) a C6-io aryl group (e.g., phenyl),
(viii) a C6-io aryloxy group (e.g., phenoxy) , and
(ix) a Ci-3 alkylenedioxy group (e.g., methylenedioxy)
(b) a C3-10 cycloalkyl group (e.g., cyclopentyl) ,
(c) a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group (preferably a 3- to 8- membered (preferably 5- or 6-membered) monocyclic non- aromatic heterocyclic group (e . g. , tetrahydropyranyl) , and (d) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (e.g., thienyl, thiazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl) optionally substituted by 1 to 3 substituents selected from
(i) a Ci-6 alkyl group (e.g., methyl), and
(ii) a Ci-6 alkoxy group (e.g., methoxy) ,
(2) a C3-10 cycloalkyl group (preferably a C3-6 cycloalkyl group (e.g., cyclopropyl) ) optionally substituted by 1 to 3 substituents selected from
(a) a C6-10 aryl group (e.g., phenyl), and
(b) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (preferably a 5- or 6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl) ) ,
(3) a C6-10 aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),
(4) a 3- to 8-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group (e.g.,
tetrahydropyranyl) ) , or
(5) an amino group optionally having 1 or 2 C6-10 aryl groups (e.g., phenyl) optionally having 1 to 3 substituents selected from
(a) a halogen atom (e.g., a fluorine atom, a chlorine atom) , '
(b) a cyano group, and
(c) a Ci-6 alkoxy group (e.g., methoxy))
or a salt thereof.
[0128]
[Compound B-b]
Compound (I) wherein
R1 is isoxazolyl optionally substituted by 1 to 3 Ci_6 alkyl groups (e.g., methyl);
Ring A is a benzene ring having no substituent, in addition to R1 and R3; R2 and R3 are each independently
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl) ) ,
(5) an amino group optionally having 1 or 2 Ci-6 alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 hydroxy groups, or
(6) a Ci-6 alkoxy group (e.g., methoxy)
[preferably
R2 is
(1) a hydrogen atom,
(2) a halogen atom (e.g., a chlorine atom),
(3) a cyano group,
(4) a 3- to 8-membered (preferably 4- to 6-membered)
monocyclic non-aromatic heterocyclic group (preferably a 3- to 8-membered (preferably 4- to 6-membered) nitrogen-containing monocyclic non-aromatic heterocyclic group (e.g., azetidinyl, pyrrolidinyl)), or
(5) an amino group optionally having 1 or 2 Ci_6 alkyl groups (e.g., methyl, ethyl) optionally having 1 to 3 hydroxy groups, and
R3 is
(1) a Ci-6 alkoxy group (e.g., methoxy)]; and
Ring B is
a ring represented by the formula:
[0129]
Figure imgf000059_0001
[0130]
wherein
Xb is a nitrogen atom;
Yb is a nitrogen atom; and
R4b is
(1) a Ci_6 alkyl group (e.g., methyl, ethyl, isobutyl) optionally substituted by 1 to 3 substituents selected from
(a) a C6-io aryl group (e.g., phenyl) optionally
substituted by 1 to 3 substituents selected from
(i) a halogen atom (e.g., a fluorine atom, a chlorine atom) ,
(ii) a Ci-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) , and
(iii) a Ci-6 alkoxy group (e.g., methoxy) ,
(b) a C3-10 cycloalkyl group (e.g., cyclopropyl,
cyclohexyl) , and
(c) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (preferably a 5- or 6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl, pyrazolyl) ) optionally substituted by 1 to 3 Ci_ 6 alkyl groups (e.g., methyl), or
(2) a C6-10 aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from
(a) a 'halogen atom (e.g., a fluorine atom), and
(b) a Ci-6 alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) ,
or a salt thereof.
[0131] [Compound B-c]
. Compound (I) wherein
R1 is isoxazolyl optionally substituted by 1 to 3 Ci_6 alkyl groups (e.g., methyl);
Ring A is a benzene ring having no substituent, in addition R1 and R3;
R2 and R3 are each independently
(1) a hydrogen atom, or
(2) a Ci-6 alkoxy group (e.g., methoxy)
[preferably
R2 is
(1) a hydrogen atom, and
R3 is
(1) a Ci-6 alkoxy group (e.g., methoxy)]; and
Ring B is
a ring represented by the formula:
0132]
Figure imgf000060_0001
[0133]
wherein
Xc is a nitrogen atom; and
R4c is a Ci-6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3 substituents selected from
(a) a C6-io aryl group (e.g., phenyl) optionally
substituted by 1 to 3 substituents selected from
(i) a halogen atom (e.g., a fluorine atom), arid
(ii) a Ci-6 alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom) ,
(b) a C3-10 cycloalkyl group (e.g., cyclopropyl,
cyclohexyl) , and (c) a 5- to 14-membered (preferably 5- or 10-membered) aromatic heterocyclic group (preferably a 5- or 6- membered monocyclic aromatic heterocyclic group (e.g., pyridyl) ) ,
or a salt thereof.
[0134]
When compound (I) is in a form of a salt, examples thereof include' metal salts, an ammonium salt, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid, and the like.
Preferable examples of the metal salt include alkali metal salts such as sodium salt/ potassium salt and the like;
alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; an aluminum salt, and the like Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2 , 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, Ν,Ν'- dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic aci tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like. Preferable examples . of the salt with basic amino acid include salts with arginine, lysin ornithine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
Among them, a pharmaceutically acceptable salt is
preferable. For example, when a compound has an acidic
functional group, examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc. ) , alkaline earth metal salts (e.g., calcium salt,
magnesium salt etc.) and the like, ammonium salt etc., and when a compound has a basic functional group, examples thereof include salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, - maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
[0135]
Compound (I) may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes are provided as one embodiment of the invention, and are illustrated by the following representative process. Necessary starting materials may be obtained by standard
procedure of organic chemistry. The preparation of such
starting materials is described in conjunction with the
following representative process and within the following examples. Alternatively, necessary starting materials are obtained by a method known per se or a method analogous
thereto .
[0136]
The starting material and/or the production intermediate for the compound (I) may form a salt. While the salt is not particularly limited as long as the reaction can be performed, examples thereof include those similar to the salts of
compound (I) and the like.
[0137]
When the starting material has an amino group, a carboxyl group, a hydroxy group or a heterocyclic group, these groups may be protected by a protecting group generally used in
peptide chemistry and the like. By removing the protecting group as necessary after the reaction, the objective compound can be obtained. The protection and deprotection can be
performed according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 3rd Ed", John Wiley and Sons, Inc. (1999) (Theodora W. Greene, Peter G. M. Wuts) . Preferable examples of the protecting group include a tert-butylcarbamate group, a benzylcarbamate group, a benzyl group, a methyl group, an ethyl group, a tert-butyl and the like.
[0138]
The compound obtained in each step can be used directly as the reaction mixture or as a crude product for the next reaction. It can also be isolated from a reaction mixture by a conventional method, and can be easily purified by a
separation means such as recrystallization, distillation, chromatography and the like. When the compound in the formula is commercially available, a commercially available product can also be used directly.
[0139]
Unless otherwise specified, each symbol in the general formulas in the schemes is as defined above.
[0140]
Compound (I) is prepared as outlined in Schemes below:
[0141]
Scheme-I (Schemes-1 and 2 in Example)
Figure imgf000063_0001
[0142]
wherein Hal is halogen, and R is Ci-6 alkyl, Compound of formula (II) can be reacted with compound rmula (III) to provide compound of formula (IV), which can be cyclized to provide compound of formula (V) wherein R2 is hydrogen. Compound of formula (V) can be reduced to provide compound of formula, (VI), which can be oxidized to provide compound of formula (VII) . Compound of formula (VII) can be cyclized to provide compound of formula (VIII) wherein ring B is
[0143]
Figure imgf000064_0001
[0144]
Compound of formula (VIII) can be reacted with R1-LG wherein LG is a leaving group to provide compound of formula (I) wherein R2 is hydrogen and the other symbols are as defined above. Alternatively, compound of formula (VIII) can be halogenated to provide compound of formula (IX) , which can be selectively converted to compound of formula (X) . Compound of formula (X) can be reacted with nucleophile R2-Y (e.g., R2-NH2, R2-0H, Zn(CN)2 etc.) to provide compound of formula (I) wherein R2 is other than hydrogen and the other symbols are as defined above. In this method, compound (II) and compound (III) used as starting materials may be a commercially available product, or can also be produced according to a method known per se or a method. analogous thereto.
[0145]
Scheme-II (Scheme-3 in Example)
Figure imgf000065_0001
Figure imgf000065_0002
XIII IX
[0146]
wherein Hal is halogen, and R is Ci_6 alkyl.
Compound of formula (V) as obtained in Scheme I can be halogenated to provide compound of formula (XI), which can be reduced to provide compound of formula (XII) . Compound of formula (XII) can be oxidized to provide compound of formula (XIII). Compound of formula (XIII) can be cyclized to provide compound of formula (IX) wherein ring B is
[0147]
Figure imgf000065_0003
Compound of formula (IX) can be reacted with R1-LG wherein LG is as defined above, and reacted with R2-Y to provide compound of formula (I) wherein R2 is other than hydrogen and the other symbols are as defined above.
[0149]
Scheme-Ill (Schemes-4, 6, 7 and 8 in Example)
Figure imgf000066_0001
Figure imgf000066_0002
[0150]
wherein Hal is halogen, and R' is Ci-6 alkyl.
Compound of formula (XIV) can be reacted with glycine ester to provide compound of formula (XV) , which can be cyclized to provide compound of formula (XVI) wherein R2 is hydrogen. Compound of formula (XVI) can be halogenated to provide compound of formula (XVII), which can be converted to compound of formula (XVIII) . Compound of formula (XVIII) can be cyclized to provide compound of formula (XIX) wherein ring B is
[0151]
Figure imgf000066_0003
[0152]
Compound of formula (XIX) can.be reacted with R1-LG wherein LG is as defined above to provide compound of formula (I) wherein R2 is hydrogen and the other symbols are as defined above. Alternatively, compound of formula (XVI) can be reacted with R1-LG wherein LG is as defined above to provide compound of formula (XX) , which can be halogenated to provide compound of formula (XXI) . Compound of formula (XXI) can be converted to compound of formula (XXII) . Compound of formula (XXII) can be-converted to compound of formula (XXIII), which can be cyclized to provide compound of formula (I) wherein ring B is [0153]
Figure imgf000067_0001
R2 is hydrogen and the other symbols are as defined above.
[0155]
Scheme-IV (Scheme-9 in Example)
Figure imgf000067_0002
[0156]
wherein Hal is halogen, and R' is Ci_6 alkyl.
Compound of formula (XXIV) can be reacted with alkyl oxalyl chloride to provide compound of formula (XXV) , which can be cyclized to provide compound of formula (XXVI) .
Compound of formula (XXVI) can be halogenated to provide compound of formula (XXVII) , which can be converted to
compound of formula (XXVIII) . Compound of formula (XXVIII) can be cyclized to provide compound of formula (IX) wherein ring B is
0157]
Figure imgf000067_0003
[0158] Compound of formula (IX) can be reacted with R1-LG wherein LG is as defined above, and reacted- with R2-Y to provide compound of formula (I) wherein R2 is other than hydrogen and the other symbols are as defined above.
[0159]
Scheme-V (Scheme-10 in Example)
Figure imgf000068_0001
[0160]
wherein Hal is halogen.
Compound of formula (XXIX) can be reacted with Meldrums acid to provide compound of formula (XXX) , which is cyclized to provide compound of formula (XXXI) wherein R2 is hydrogen and the other symbols are as defined above. Compound of formula (XXXI) can be nitrated to provide compound of formula (XXXII), which can be halogenated to provide compound of formula (XXXIII) . Compound of formula (XXXIII) can be reacted with amine R'NH2 to provide compound of formula (XXXIV) , which can be reduced to provide compound of formula (XXXV) . Compound of formula (XXXV) can be cyclized to provide compound of formula (XIX) wherein ring B is
Figure imgf000068_0002
[0162] Compound of formula (XIX) can be reacted with R1-Y wherein Y is as defined above to provide compound of formula (I) wherein R2 is hydrogen and the other symbols are as defined above.
[0163]
Compound (I) contains a stereoisomer depending on the kind of a substituent, and each stereoisomer and a mixture thereof are encompassed in the present invention.
Compound (I) may be a hydrate or a non-hydrate.
When desired, compound (I) can be synthesized by
performing deprotection reaction, acylation reaction,
alkylation reaction, hydrogenation reaction, oxidation
reaction, reduction reaction, reaction of carbon chain
extension, substituent exchange reaction singly or two or more thereof in combination.
When the objective product is obtained as a free form by the above-mentioned reaction, it can be converted to a salt according to a conventional method, or when the objective product is obtained as a salt, it can be converted to a free form or other salt according to a conventional method. The thus-obtained compound (I) can also be isolated and purified from a reaction mixture according to a known method such as phase transfer, concentration, solvent extraction,
distillation, crystallization, recrystallization,
chromatography and the like.
When compound- ( I ) contains a configurational isomer, a diastereomer, a conformer and the like, each can be isolated according to the above-mentioned separation and purification methods, if desired. In addition, when compound (I) is racemic, d-form and 1-form can be isolated according to a conventional optical resolution.
[0164]
In each. of the above-mentioned reactions, when the
compound, has a functional group such as an amino group, a hydroxy group or a carboxyl group, the reaction can be carried out after a protecting group generally used in peptide chemistry and the like is introduced into these groups. By removing the protecting group as necessary after the reaction, the objective compound can be obtained.
Examples of the protecting group include formyl, Ci-6 alkyl-carbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl , Ci-6 alkoxy-carbonyl (e.g., methoxycarbonyl , ethoxycarbonyl etc.), phenyloxycarbonyl, C7-i0 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl etc . ) , trityl, phthaloyl and the like, each of which is optionally substituted. Examples of the
substituent include a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), Ci_6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl etc.), nitro and the like. The number of substituents is, for example, 1 to 3.
The removal method of the protecting group can be carried out according to a method known per se, and for example, a method using acid, base, ultraviolet rays, hydrazine,
phenylhydrazine, sodium N-methyldithiocarbamate,
tetrabutylammonium fluoride, palladium acetate and the like, a reduction method, and the like can be employed.
[0165]
The thus-obtained compound (I), other reaction
intermediate therefor and starting materials thereof can be isolated and purified from a reaction mixture according to a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC) , moderate-pressure preparative liquid chromatography (moderate- pressure preparative LC) and the like.
[0166]
A salt of compound (I) can be produced according to a method known per se. For example, when compound (I) is a basic compound, it can be produced by adding an inorganic acid or organic acid, or when compound (I) is an acidic compound, by adding an organic base or inorganic base. When compound (I) contains an optical isomer, each- optical isomer and a mixture thereof are encompassed in the scope of the present invention, and these isomers can be
subjected to optical resolution or can be produced
respectively, according to a method known per se, if desired.
When compound (I) contains a configurational isomer, a diastereomer, a conformer and the like, each can be isolated according to the above-mentioned separation and purification methods, if desired. In addition, when compound (I) is racemic, S-form and R-form can be isolated according to a conventional optical resolution.
When compound (I) contains a stereoisomer, each isomer and a mixture thereof are encompassed in the present invention.
[0167]
Compound (I) may be a prodrug, and the prodrug of
compound (I) refers to a compound which is converted to
compound (I) as a result of a reaction with an enzyme, gastric acid, etc. under physiological conditions in vivo, thus a compound that undergoes enzymatic oxidation, reduction,
hydrolysis etc. to convert to compound (I) and a compound that undergoes hydrolysis and the like by gastric acid, etc. to convert to compound (I) .
[0168]
Examples of the prodrug for compound (I) include
(1) a compound obtained by subjecting an amino group in
compound (I) to acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in compound
(1) to eicosanoylation, alanylation, pentylaminocarbonylation, ( 5-methyl-2-oxo-l, 3-dioxolen-4-yl) methoxycarbonylation,
tetrahydrofurylation, pyrrolidylmethylation,
pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation,
cyclopropylcarbonylation and the like) ;
(2) a compound obtained by subjecting a hydroxy group in
compound (I) to acylation, alkylation, phosphorylation or bbration (e.g., a compound obtained by subjecting a hydroxy group in compound (I) to acetylation, palmitoylation,
propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation and the like) ; (3) a compound obtained by subjecting a carboxyl group in compound (I) to esterification or amidation (e.g., a compound obtained by subjecting a carboxyl group in compound (I) to ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification,
pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, ( 5-methyl-2-oxo- 1, 3-dioxolen-4-yl) methyl esterification,
cyclohexyloxycarbonylethyl esterification or methylamidation and the like) and the like. Any of these compounds can be produced from compound (I) according to a method known per se.
[0169]
A prodrug of compound (I) may also be one which is converted to compound (I) under physiological conditions as described in "IYAKUHIN no KAIHATSU (Development of
Pharmaceuticals)", Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990) .
[0170]
In the present specification, compound (I) and a prodrug thereof are sometimes collectively abbreviated as "the
compound of the present invention".
[0171]
When compound (I) has isomers such as optical isomer, stereoisomer, positional isomer, rotamer and the like, such isomers and a mixture thereof are also encompassed in compound (I). For example, when compound (I) has optical isomers, an optical isomer resolved from this compound is also encompassed in compound (I). These isomers can be obtained as a single product according to synthesis methods or separation methods known per ≤e (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.). Compound (I) may be a crystal, and a single crystal form and a mixture of crystal forms are both encompassed in
compound (I) . The crystal can be produced by crystallizing according to a crystallization method known per se.
Compound (I) may be a hydrate, a non-hydrate, a solvate or a non-solvate.
Compound (I) may be labeled with an isotope (e.g., 3H, nC, 1C, 18F, 35S, 125I etc.) and the like.
Compound (I) also encompasses a deuterium conversion form wherein 1H is converted to 2H(D) .
Compound. (I) may be a pharmaceutically acceptable
cocrystal or a salt thereof. The cocrystal or a salt thereof means a crystalline substance constituted with two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability etc.). The cocrystal or a salt thereof can be produced according to a cocrystallization method known per se.
Compound (I) may also be used as a PET tracer.
■ [0173]
The compound of the present invention has low toxicity, and can be used as it is or in the form of a pharmaceutical composition by mixing with a pharmacologically acceptable carrier etc. to mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an agent for the
prophylaxis or treatment of various diseases mentioned below.
[0174]
As pharmacologically acceptable carriers, various organic . or inorganic carrier substances conventionally used as
preparation materials can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid
preparations, or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid
preparations, and the like, and preparation additives such as preservative, antioxidant, colorant, sweetening agent and the like can be added as necessary.
[0175]
When the compound of the present invention is used as an ointment, the ointment is prepared by mixing the compound of the present invention with a general ointment base so that the concentration is adjusted to about 0.001 to 3% (W/W) ,
preferably about 0.01 to 1% (W/W). The preparation of ointment preferably comprises a powderization step of the compound of the present invention, and a sterilization step of the
formulation. The ointment is administered once to four times a day depending on condition of the patient.
[0176]
Examples of the ointment base include purified lanolin, white vaseline, macrogol, plastibase, liquid paraffin and the like .
[0177]
Preferable examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinated starch, dextrin, crystalline cellulose, low-substituted
hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthesis aluminum silicate and magnesium alumino metasilicate .
[0178]
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.
[0179]
Preferable examples of the binder include gelatinated starch, sucrose, gelatin, gum arabic, methylcellulose,
carboxymethylcellulose, sodium carboxymethylcellulose,
crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.
[0180]
Preferable examples of the' disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium
carboxymethylcellulose, croscarme'llose sodium, sodium
carboxymethyl starch, light anhydrous silicic acid and low- substituted hydroxypropylcellulose .
[0181]
Preferable examples of the solvent include water for injection, physiological brine, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.
[0182]
Preferable examples of the solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.
[0183]
Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium
chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol,
polyvinylpyrrolidone, sodium carboxymethylcellulose,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; polysorbates, and
polyoxyethylene hydrogenated castor oil.
[0184]
Preferable examples of the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.
[0185]
Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, citrate and the like.
Preferable examples of the soothing agent include benzyl alcohol .
[0186]
Preferable examples of the preservative include p- oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
Preferable examples of the antioxidant include sulfite and ascorbate.
[0187]
Preferable examples of the colorant include aqueous water-soluble food tar colors (e.g., food colors 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 dyes (e.g., aluminum salt of the above-mentioned water-soluble food tar color) and natural dyes (e.g., β-carotene, chlorophyll, ferric oxide red) .
[0188]
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia .
[0189]
Examples of the dosage form of the pharmaceutical
composition include oral preparations such as tablet
(including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet), capsules (including soft capsule, microcapsule) , granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion) , external preparations (e.g., dermal preparation, ointment), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal' preparation, pulmonary preparation (inhalant), eye drop and the like.
These- can be respectively safely administered orally or parenterally (e.g., topically, rectally, intravenously
administered) .
[0190]
These preparations may be a release control preparation (e.g., sustained-release microcapsule) such as an immediate- release preparation, a sustained-release preparation and the like.
[0191]
The pharmaceutical composition can be produced according to a method conventionally used in the field of pharmaceutical formulation, for example, the method described in the Japanese Pharmacopoeia, and the like.
[0192]
While the content of the compound of the present
invention in the pharmaceutical composition varies depending on the dosage form, dose of the compound of the present invention and the like, it is for example, about 0.1 to 100 wt% .
[0193]
During production of an oral preparation, coating may be applied as necessary for the purpose of masking of taste, enteric property or durability.
[0194]
Examples of the coating base to be used for coating include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.
[0195]
As the sugar coating base, sucrose is used. Moreover, one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
[0196]
Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ] , polyvinylpyrrolidone etc.; and polysaccharides such as pullulan etc.
[0197]
Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate etc.; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name) ] , methacrylic acid copolymer LD
[Eudragit L-30D55 (trade name) ] , methacrylic acid copolymer S [Eudragit S (trade name)] etc.; and naturally occurring substances such as shellac etc.
[0198]
Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose etc.; and acrylic polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name) ] , ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name) ] etc.
[0199]
The above-mentioned coating bases may be used after mixing with two or more kinds thereof at appropriate ratios. For coating, for example, a light shielding agent such as titanium oxide, red ferric oxide and the like can be used.
[0200]
The compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) 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) .
[0201]
Since the compound of the present invention have superior BET family protein inhibitory action, they are also useful as safe medicaments based on such action.
For example, the medicament of the present invention containing the compound of the present invention can be used for a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as an agent for the
prophylaxis or treatment of autoimmune diseases and/or
5 inflammatory diseases, specifically, the diseases described in (1) - (6) below.
[0202]
(1) inflammatory diseases (e.g., acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome,
0 chronic obstructive pulmonary disease (COPD) , inflammatory
bone disease, inflammatory pulmonary disease, inflammatory bowel disease, celiac disease, hepatitis, systemic
inflammatory response syndrome (SIRS) , postoperative or
posttraumatic inflammation, pneumonia, nephritis, meningitis,5 cystitis, pharyngolaryngitis , gastric mucosal injury,
meningitis, spondylitis, arthritis, dermatitis, chronic
pneumonia, bronchitis, pulmonary infarction, silicosis,
pulmonary sarcoidosis etc.);
(2) autoimmune diseases (e.g., psoriasis, rheumatoid arthritis,0 inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis etc.), Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylopoietic
spondylarthritis, polymyositis, dermatomyositis (DM) ,
polyarteritis nodosa (PN) , mixed connective tissue disease
5 (MCTD) , scleroderma, profundus lupus erythematosus, chronic
thyroiditis, Graves' disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft versus host disease,D Addison's disease, abnormal immunoresponse, arthritis,
dermatitis, radiodermatitis, pulmonary fibrosis (e.g.,
idiopathic pulmonary fibrosis etc.) etc.) (especially,
psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis,
5 systemic lupus erythematosus, graft versus host disease, pulmonary fibrosis etc.);
(3) osteoarticular degenerative diseases (e.g., rheumatoid arthritis, osteoporosis, osteoarthritis etc.);
(4) neoplastic diseases [e.g., malignant tumor, angiogenesis glaucoma, infantile hemangioma, multiple myeloma, acute
myeloblastic leukemia, chronic sarcoma, multiple myeloma, chronic myelogenous leukemia, metastasis melanoma, Kaposi's sacroma, vascular proliferation, cachexia, metastasis of the breast cancer, cancer (e.g., colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor etc.), lung cancer (e.g., non- small cell lung cancer, small cell lung cancer, malignant mesothelioma etc.), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer etc.), gastric cancer (e.g., mucinous adenocarcinoma, adenosquamous carcinoma etc. ) , papillary
adenocarcinoma, breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer etc.), ovarian cancer (e.g., ovarian epithelial carcinoma,
extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor etc.), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone dependent
prostate cancer etc.), liver cancer (e.g., primary liver
cancer, extrahepatic bile duct cancer etc.), thyroid cancer (e.g., medullary thyroid carcinoma etc.), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma in kidney and urinary duct etc.), uterine cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma etc.), melanoma, sarcoma, urinary
bladder cancer, hematologic cancer and the like including multiple myeloma, hypophyseal adenoma, glioma, acoustic
neurinoma, retinoblastoma, pharyngeal cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, urinary duct cancer, testis tumor, vulvar cancer, cervix, cancer, endometrial cancer, uterus sarcoma, cholionic disease, vaginal cancer, skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin' s disease, myelodysplastic syndrome, acute lymphocytic leukemia, chronic lymphocytic leukemia, adult T cell leukemia, chronic bone marrow proliferative disease, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary etc. ) ;
(5) cardiovascular diseases (e.g., heart disease (e.g., cardiac hypertrophy, acute heart failure and chronic heart failure including congestive, cardiomyopathy, angina pectoris, myocarditis, arrhythmia, tachycardia, myocardial infarction etc. ) , myocardial ischemia, venous insufficiency, heart failure after myocardial infarction, hypertension, cor
pulmonale, arteriosclerosis including atherosclerosis (e.g., aortic aneurysm (e.g., thoracoabdominal aortic aneurysm etc.), coronary atherosclerosis, cerebral atherosclerosis, peripheral arterial disease, arteriosclerosis obliterans, chronic
arterial occlusion etc.), intervention (e.g., percutaneous transluminal coronary angioplasty, stent placement, coronary angioscopy, intravascular ultrasound, thrombolysis therapy etc.), vascular hypertrophy or vascular occluson and organ dysfunction after heart transplant, vascular reocclusion and restenosis after bypass surgery etc.);
(6) hormone-dependent diseases (e.g., sex hormone-dependent cancers (e.g., prostate cancer, uterine cancer, breast cancer, pituitary tumor etc.), prostatic hyperplasia, endometriosis, uterine fibroid, precocious puberty,, dysmenorrhea, amenorrhea, premenstrual syndrome, polycystic ovary syndrome etc.).
[0203]
The medicament of the present invention can be preferably used as an agent for the prophylaxis or treatment of
rheumatoid arthritis, multiple sclerosis, idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus, cancer and the like.
[0204]
Here, the above-mentioned "prophylaxis" of a disease means, for example, administration of a medicament containing the compound of the present invention to patients who are expected to have a high risk of the onset due to some factor relating. to the disease but have not developed the disease or patients who have developed the disease but do not have a subjective symptom, or administration of a medicament
containing the compound -of the present invention to patients who are feared to show recurrence of the disease after
treatment of the disease,
and the like.
[0205]
The dose of the compound of the present invention varies depending on the administration subject, route of
administration, target disease, symptoms, etc. For example, when it is administered orally to an adult patient (body weight 60 kg), its dose is about 0.01 to 100 mg/kg body weight per dose, preferably 0.05 to 30 mg/kg body weight per dose, more preferably 0.1 to 10 mg/kg body weight per dose and this amount is desirably administered in 1 to 3 portions daily.
[0206]
For the prophylaxis or treatment of various diseases, the compound of the present invention can also be used together with other drugs. In the following, a medicament to be used when the compound of the present invention is used together with other drug is referred to as "the combination agent of the present invention".
For example, when the compound of the present invention is used as a BET family protein inhibitor, it can be used in combination with the following drugs.
[0207]
(1) non-steroidal anti-inflammatory drug (NSAIDs)
(i) Classical NSAIDs alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin,
mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone,
allopurinol, sodium aurothiomalate, hyaluronate sodium, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone or a salt thereof and the like.
(ii) cyclooxygenase inhibitor (COX-1 selective inhibitor, COX- 2 selective inhibitor etc.)
salicylic acid derivatives (e.g., celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin, loxoprofen and the like.
(iii) nitric oxide-releasing NSAIDs
(iv) JAK inhibitor
tofacitinib, ruxolitinib and the like.
[0208]
(2) disease-modifying anti-rheumatic drugs (DMARDs)
(i) Gold preparation
auranofin and the like.
(ii) penicillamine
D-penicillamine and the like.
(iii) aminosalicylic acid preparation
sulfasalazine, mesalazine, olsalazine, balsalazide and the like.
(iv) antimalarial drug
chloroquine and the like.
(v) pyrimidine synthesis inhibitor
leflunomide and the like. (vi) prograf
[0209]
(3) anti-cytokine drug
(I) protein drug
(i) TNF inhibitor
etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, PASSTNF-a, soluble TNF- receptor, TNF-a binding protein, anti-TNF- antibody and the like.
(ii) interleukin-1 inhibitor
anakinra (interleukin-1 receptor antagonist) , soluble interleukin-1 receptor and the like.
(iii) interleukin-6 inhibitor
tocilizumab (anti-interleukin-6 receptor antibody) , anti- interleukin-6 antibody and the like.
(iv) interleukin-10 drug
interleukin-10 and the like.
(v) interleukin-12/23 inhibitor
ustekinumab, briakinumab (anti-interleukin-12/23
antibody) and the like.
( I I ) non-protein drug
(i) MAPK inhibitor
BMS-582949 and the like.
(ii) gene modulator
inhibitor of molecule involved in signal transduction, such as NF-K, NF-κΒ, IKK-1, IKK-2, AP-1 and the like, and the like.
(iii) cytokine production inhibitor
iguratimod, tetomilast and the like.
(iv) TNF-a converting enzyme inhibitor
(v) interleukin-ΐβ converting enzyme inhibitor
VX-765 and the like.
(vi) interleukin-6 antagonist
HMPL-004 and the like.
(vii) interleukin-8 inhibitor
IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin and the like.
(viii) chemokine antagonist
CCR9 antagonist (CCX-282, CCX-025) , MCP-1 antagonist and the like.
(ix) interleukin-2 receptor antagonist - denileukin, diftitox and the like.
(x) therapeutic vaccines
TNF- vaccine and the like.
(xi) gene therapy drug
gene therapy drugs aiming at promoting the expression of gene having an anti-inflammatory action such as interleukin-4 , interleukin-10, soluble interleukin-1 receptor, soluble TNF-a receptor and the like.
(xii) antisense compound
ISIS 104838 and the like.
[0210]
(4) integrin inhibitor
natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like .
(5) immunomodulator (immunosuppressant)
methotrexate, cyclophosphamide, MX-68, atiprimod
dihydrochloride, BMS-188667, CKD-461, rimexolone, cyclosporine tacrolimus, gusperimus, azathiopurine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like.
(6) steroid
dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide,
fluocinolone acetonide, predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone, fluorometholone,
beclomethasone dipropionate, estriol and the like.
( 7 ) · angiotensin converting enzyme inhibitor
enalapril, captopr l, ramipril, lisinopril, cilazapril, perindopril and the like. [0211]
(8) angiotensin II receptor antagonist
candesartan, candesartan cilexetil, azilsartan,
azilsartan medoxomil, valsartan, irbesartan, olmesartan, eprosartan and the like.
(9) diuretic drug
hydrochlorothiazide, spironolactone, furosemide,
indapamide, bendrofluazide, cyclopenthiazide and the like.
(10) cardiotonic drug
digoxin, dobutamine and the like.
(11) β receptor antagonist
carvedilol, metoprolol, atenolol and the like.
(12) Ca sensitizer
MCC-135 and the like.
(13) Ca channel antagonist
nifedipine, diltiazem, verapamil and the like.
(14) anti-platelet drug, anticoagulator
heparin, aspirin, warfarin and the like.
(15) HMG-CoA reductase inhibitor
atorvastatin, simvastatin and the like.
[0212]
(16) contraceptive
(i) sex hormone or derivatives thereof
gestagen or a derivative thereof (progesterone, 17a- hydroxy progesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate,
norethindrone, norethindrone acetate, norethynodrel,
levonorgestrel, norgestrel, ethynodiol diacetate, desogestrel, norgestimate, gestodene, progestin, etonogestrel, drospirenone, dienogest, trimegestone, nestorone, chlormadinone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM- 310525) or a combination agent of a gestagen or a derivative thereof and an estrogen or a derivative thereof (estradiol, estradiol benzoate, estradiol cypionate, estradiol
dipropionate, estradiol enanthate, estradiol hexahydrobenzoate, estradiol phenylpropionate, estradiol undecanoate, estradiol valerate, estrone, ethinylestradiol, mestranol) and the like, (ii) antiestrogen
ormeloxifene, mifepristone, Org-33628 and the like.
(iii) spermatocide
ushercell and the like.
[0213]
(17) antibacterial agent
(i) sulfa drug
sulfamethizole, sulfisoxazole , sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like.
(ii) quinolone antibacterial agent
nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.
(iii) antiphthisic
isoniazid, ethambutol (ethambutol hydrochloride) , p- aminosalicylic acid (calcium p-aminosalicylate ) , pyrazinamide, ethionamide, protionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
(iv) antiacidfast bacterium drug
diaphenylsulfone, rifampicin and the like.
(v) antiviral drug
idoxuridine, acyclovir, vidarabine, gancyclovir. and the like. '
(vi) anti-HIV agent
zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir and the like.
(vii) antispirochetele
(viii) antibiotic
tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin,
cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil, cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or a salt a salt thereof, griseofulvin, lankacidin-group [Journal of
Antibiotics (J. Antibiotics), 38, 877-885(1985)], azole compound [2- [ (1R, 2R) -2- (2, 4-difluorophenyl) -2-hydroxy-l- methyl-3- (lH-1, 2, 4-triazol-l-yl) propyl] -4- [4- (2, 2, 3, 3- tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2, 4-triazolone,
fluconazole, itraconazole and the like] and the like.
[0214]
(18) antifungal agent
(i) polyethylene antibiotic
amphotericin B, nystatin, trichomycin and the like.
(ii) griseofulvin, pyrrolnitrin and the like.
(iii) cytosine metabolism antagonist
flucytosine and the like.
(iv) imidazole derivative
econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole and the like.
(v) triazole derivative
fluconazole, itraconazole and the like.
(vi) thiocarbamic acid derivative
trinaphthol and the like.
(19) antiprotozoal agent
metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.
[0215]
(20) antitussive and expectorant drug ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol
hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride., alloclamide,
chlophedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terbutaline, oxymetebanol , morphine hydrochloride, dextromethorfan hydrobromide, oxycodone
hydrochloride, dimemorphan phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethyl cysteine hydrochloride, carbocysteine and the like.
(21) sedative
chlorpromazine hydrochloride, atropine sulfate,
phenobarbital, barbital, amobarbital, pentobarbital,
thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazepam, haloxazolam, triazolam, flunitrazepam,
bromovalerylurea, chloral hydrate, triclofos sodium and the like.
[0216]
(22) anesthetic
(I) local anesthetic
cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine
hydrochloride, ethyl aminobenzoate, oxethazaine and the like.
(II) general anesthetic
(i) inhalation anesthetic
ether, halothane, nitrous oxide, isoflurane, enflurane and the like..
(ii) intravenous anesthetic
ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital and the like.
(23) antiulcer drug
histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrone, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and the like.
(24 ). antiarrhythmic agent
(i) sodium channel blocker
quinidine, procainamide, disopyramide, ajmaline, lidocaine, mexiletine, phenytoin and the like.
(ii) β-blocker
propranolol, alprenolol, bufetolol hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride and the like.
(iii) potassium channel blocker
amiodarone and the like.
(iv) calcium channel blocker
verapamil, diltiazem and the like.
[0217]
(25) hypotensive diuretic drug
hexanethonium bromide, clonidine hydrochloride,
hydrochlorothiazide, trichlormethiazide, furosemide,
ethacrynic acid, bumetanide, mefruside, azosemide,
spironolactone, potassium canrenoate, triamterene, amiloride, acetazolamide, D-mannitol, isosorbide, aminophylline and the like.
(26) anticoagulant
heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate, ozagrel sodium, ethyl icosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole, tisokinase, urokinase, streptokinase and the like.
(27) tranquilizer
diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like.
(28) antipsychotic
chlorpromazine hydrochloride, prochlorperazine,
trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride,
haloperidol, bromperidol, spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.
[0218]
(29) antitumor drug
6-0- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside,
fluorouracil, tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride,
bleomycin hydrochloride, peplomycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone,
testosterone propionate, testosterone enanthate, mepitiostane fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelin acetate and the like.
(30) hypolipidemic drug
clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2- phenylpropoxy) phenyl] propionate [Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull), 38, 2792-2796 (1990)],
pravastatin, simvastatin, probucol, bezafibrate, clinofibrate nicomol, cholestyramine, dextran sulfate sodium and the like.
(31) muscle relaxant
pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen,
chlormezanone, mephenesin, chlorzoxazone, eperisone,
tizanidine and the like. (32) antiepileptic drug
phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione, carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate, clonazepam, diazepam, nitrazepam and the like.
[0219]
(33) antidepressant
imipramine, clomipramine, noxiptiline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride and the like.
(34) antiallergic drug
diphenhydramine, chlorpheniramine, tripelennamine, metodilamine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglicate, tranilast, repirinast, amlexanox,
ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast and the like.
(35) cardiac stimulants
trans—π-oxocamphor, terephyllol, aminophylline,
etilefrine, dopamine, dobutamine, denopamine, aminophylline, vesnarinone, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
(36) vasodilator
oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine, methyldopa, guanabenz and the like.
(37) vasoconstrictor
dopamine, dobutamine denopamine and the like.
(38) hypotensive diuretic
hexanethonium bromide, pentolinium, mecamylamine,
ecarazine, clonidine, diltiazem, nifedipine and the like.
(39) therapeutic drug for diabetes
tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, glymidine, glipizide, phenformin, buformin, metformin and the like .
[0220]
(40) antinarcotic
levallorphan, nalorphine, naloxone or a salt thereof and the like.
liposoluble vitamins
(i) vitamin A
vitamin Ai, vitamin A2 and retinol palmitate
(ii) vitamin D
vitamin Di, D2, D3, D4 and D5
(iii) vitamin E
a-tocopherol, β-tocopherol, γ-tocopherol , δ-tocophero dl- a-tocopherol nicotinate and the like..
(iv) vitamin K
vitamin Ki, K2/ K3 and K4
(v) folic acid
vitamin M and the like.
(42) vitamin derivative
various derivatives of vitamins, for example, vitamin D3 derivatives such as 5, 6-trans-cholecalciferol, 2,5- hydroxycholecalciferol, 1-a-hydroxycholecalciferol and the like, vitamin D2 derivatives such as 5 , 6-trans-ergocalciferol and the like, and the like.
(43) antiasthmatic
isoprenaline hydrochloride, salbutamol sulfate,
procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline
sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglicate , tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlkast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisone, hydrocortisone sodium succinate, beclometasone dipropionate and the like.
(44) therapeutic agent for pollakisuria/anischuria
flavoxate hydrochloride and the like.
(45) therapeutic agent for atopic dermatitis
sodium cromoglicate and the like.
(46) therapeutic agent for allergic rhinitis
sodium cromoglicate, chlorpheniramine maleate,
alimemazine tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine, mequitazine and the like.
(47) hypertensor
dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
[0221]
(48) others
(i) T cell inhibitors
(ii) inosine monophosphate dehydrogenase (I PDH) inhibitor
mycophenolate mofetil and the like.
(iii) adhesion molecule inhibitor
ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, ICA -1 and the like.
(iv) thalidomide
(v) cathepsin inhibitor
(vi) matrix metalloprotease (MMPs) inhibitor
V-85546 and the like.
(vii) glucose-6-phosphate dehydrogenase inhibitor
(viii) Dihydroorotate dehydrogenase (DHODH) inhibitor (ix) phosphodiesterase IV(PDE IV) inhibitor
roflumilast, CG-1088 and the like.
(x) phospholipase A2 inhibitor
(xi) iNOS inhibitor
VAS-203 and the like.
(xii) microtubule stimulating drug
paclitaxel and the like.
(xiii) microtuble inhibitor reumacon and the like.
(xiv) MHC class II antagonist
(xv) prostacyclin agonist
iloprost and the like.
(xvi) CD4 antagonist
zanolimumab and the like.
(xvii) CD23 antagonist
(xviii) LTB4 receptor antagonist
DW-1305 and the like.
(xix) 5-lipoxygenase inhibitor
zileuton and the like.'
(xx) cholinesterase inhibitor
galanthamine and the like.
(xxi) tyrosine kinase inhibitor
Tyk2 inhibitor (the compounds described in WO
2010/142752) and the like.
(xxii) cathepsin B inhibitor
(xxiii) adenosine deaminase inhibitor
pentostatin and the like.
(xxiv) osteogenesis stimulator
(xxv) dipeptidylpeptidase inhibitor
(xxvi) collagen agonist
(xxvii) capsaicin cream
(xxviii) hyaluronic acid derivative
synvisc (hylan G-F 20 ) , orthovisc and the like.
(xxix) glucosamine sulfate
(xxx) amiprilose
(xxxi) CD-20 inhibitor '
rituximab, ibritumomab, tositumomab, ofatumumab .and the like.
(xxxii) BAFF inhibitor
belimumab, tabalumab,' atacicept, A-623 and the like.
(xxxiii) CD52 inhibitor
alemtuzumab and the like.
(xxxiv) IL-17 inhibitor secukinumab (AIN-457) , LY-2439821, AMG827 and the like, (xxxv) hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandins and the like.
[0222]
For combined use, the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention or the concomitant drug can be administered to an administration subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the dose clinically used, and can be
appropriately selected depending on an administration subject, administration route, disease, combination and the like.
The administration form of the combined use is not particularly limited, and the compound of the present
invention and a concomitant drug only need to be combined on administration. Examples of such administration mode include the following:
(1) administration of a single preparation obtained by
simultaneously processing the compound of the present
invention and the concomitant drug, (2) simultaneous
administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route, (3) administration of two kinds of preparations of the
compound of the present invention and the concomitant drug, which have been separately produced, by the same
administration route in a staggered manner, (4) simultaneous . administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the
compound of the present invention and the concomitant drug, which have been separately produced, by different
administration routes in a staggered manner (e.g., administration in the order of. the compound of the present invention and the concomitant drug, or in the reverse order) and the like.
The mixing ratio of the compound of the present invention and a concomitant drug in the combination agent of the present invention can be appropriately selected based on the subject of administration, administration route, disease and the like.
For example, while the content of the compound of the present invention in the combination agent of the present invention varies depending on the preparation form, it is generally about 0.01 - 100 wt%, preferably about 0.1 - 50 wt%, more preferably about 0.5 - 20 wt%, of the whole preparation.
[0223]
The content of the concomitant drug in the combination agent of the present invention varies depending on the
preparation form, and generally about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, further preferably about 0.5 to 20% by weight, of the entire preparation.
While the content of the additive such as a carrier and the like in the combination agent of the present invention varies depending on the form of a preparation, it is generally about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the preparation.
When the compound of the present invention and the concomitant drug are separately prepared, the same content may be adopted.
The dose of the combination agent varies depending on the kind of the compound of the present invention, administration route,- symptom, age of patients and the like. For example, for oral administration to patients (body weight about 60 kg) with inflammatory bowel disease (IBD) , about 0.1 mg/kg body weight - about 30 mg/kg body weight, preferably about 1 mg/kg body weight - 20 mg/kg body weight, of compound (I) can be
administered once to several portions per day.
The dose of the pharmaceutical composition of the present invention as a sustained-release preparation varies depending on the kind and content of compound (I), dosage form, period of sustained drug release, subject animal of administration (e.g., mammals, such as mouse, rat, hamster, guinea pig, rabbit, cat, dog, bovine, horse, swine, sheep, monkey, human etc.), and administration object. For example, for application by parenteral administration, about 0.1 to about 100 mg of
compound (I) needs to be released from the administered
preparation per 1 week.
[0224]
Any amount of the concomitant drug can be adopted as long as the side effects do not cause a problem. The daily dosage in terms of the concomitant drug varies depending on the
severity, age, sex, body weight, sensitivity difference of the, subject, administration period, interval, and nature,
pharmacology, kind of the pharmaceutical preparation, kind of effective ingredient, and the like, and not particularly
restricted, and the amount of a drug is, in the case of oral administration for example, generally about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, further preferably about 0.1 to 100 mg, per 1 kg of a mammal and this is generally
administered once to 4-times, divided in a day.
When the combination agent of the present invention is administered, the compound of the present invention and the concomitant drug can be administered simultaneously, or may be administered in a staggered manner. When administered at a time interval, the interval varies depending on the effective ingredient, dosage form and administration method, and, for example, when the concomitant drug is administered first, a method in which the compound of the present invention is
administered within time range of from 1 minute to 3 days, preferably from 10 minutes to 1 day, more preferably from 15 minutes to 1 hour, after administration of the concomitant drug is an example. When the compound of the present invention is administered first, a method in which the concomitant drug is administered within time range of from 1 minute to 1 day, preferably" from 10 minutes to 6 hours, more preferably from 15 minutes to 1 hour after administration of the compound of the present, invention is an example.
Examples
[0225]
The present invention, is explained in detail in the following by referring to Preparations, Examples, Experimental Examples and Formulation Examples, which are not to be
construed as limitative, and the invention may be changed within the scope of the present invention.'
[0226]
In the following Examples, the "room temperature" generally means about 10°C to about 35°C. The ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified. % means wt%, unless otherwise specified.
[0227]
In silica gel column chromatography, basic silica gel means use of aminopropylsilane-bound silica gel. In HPLC (high performance liquid chromatography) , C18 means use of
octadecyl-bound silica gel. The ratios of elution solvents are volume mixing ratios, unless otherwise specified.
[0228]
1H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier-transform type NMR. For the analysis, ACD/SpecManager (trade name) and the like were used. Peaks with very mild protons such as a hydroxy group, an amino group and the like are not described.
[0229]
MS (mass spectrum) was measured by LC/MS (liquid
chromatography mass spectrometer) . As ionization method, ESI (Electro Spray Ionization) method or APCI (Atomospheric
Pressure Chemical Ionization) method was used. The data indicates those found. Generally, a molecular ion peak is observed. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed.
[0230]
Experimental Procedure
[0231]
Scheme 1
Figure imgf000100_0001
[0232]
Diethyl 2- [ (3-iodo-4-methoxy-anilino) methylene]propanedioate (2)
Compound 1 (2.5 g, 10 mmol) and diethyl
ethoxymethylenemalonate (2.1 ml, 10.5 mmol) were mixed
together, and the mixture was heated to 130°C for 30 minutes. The liberated ethanol was evaporated under reduced pressure. The reaction mixture was poured into diisopropyl ether (20 ml) , and the resulted precipitate was collected by filtration and then dried to give the title compound 2 (3.39 g, 80%) .
XHNMR (400 MHz, DMSO-d6) δ: 10.58 (d, J = 14 Hz, 1H) , 8.24 (d, J = 14.4 Hz, 1H) , 7.82 (s, 1H) , 7.38 (dd,. J = 2.8, 8.8 Hz, 1H) , 6.99 (d, J = 8.8 Hz, 1H) , 4.19-4.14 (m, 2H) , 4.12-4.06 (m, 2H) , 3.79 (s, 3H) , 1.25-1.19 (m, 6H) .
[0233]
Ethyl 7-iodo-6-methoxy-4-oxo-lH-quinoline-3-carboxylate (3)
Compound 2 (3.9 g, 9.3 mmol) was added to preheated diphenyl ether at 260°C in portion wise for 10 minutes. The reaction mixture was stirred at 260°C for 10 minutes. The black solution was cooled to room temperature, hexane was added to this reaction mixture, and the resulted precipitate was collected by filtration, washed with hexane and dried to give the title compound 3 (1.98 g, 57%).
XHNMR (400 MHz, OMSO-d6) δ: 12.22 (brs, 1H) , 8.50 (s, 1H) , 8.11 (s, 1H) , 7.51 (s, 1H) , 4.21 (q, J = 6.8, 2H) 3.89 (s, 3H) ,
1.28 (t, J = 6.8 Hz, 3H)
[0234]
Ethyl 4-chloro-7-iodo-6-methoxy-quinoline-3-carboxylate (4)
Compound 3 (5.3 mmol) was dissolved in POCI3 (5 ml), the solution was heated at 120°C for 3 hours, allowed to cool to room temperature and poured into crushed ice, and then the mixture was slowly quenched with addition of solid NaHC03 upto pH = 8. The mixture was extracted with ethyl acetate (3 X 50 ml) , and the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using ethyl acetate- hexane as eluent to give the title compound 4 (85%) .
1HNMR (400 MHz, DMSO-di) δ : 8.97 (s, 1H) , 8.63 (s, 1H) , 7.51 (s, 1H) , 3.43 (q, J= 7.2, 2H) , 4.05 (s, 3H) , 1.38 (t, J = 7.2 Hz, 3H) .
[0235]
(4-Chloro-7-iodo-6-methoxy-3-quinolyl)methanol (5)
Compound 4 (2 g, 5.1 mmol) was dissolved in
dichloromethane, and then DIBAL-H (15.5 ml, 15.3 mmol) was added slowly thereto at 0°C. The reaction mixture was allowed to stir at room temperature for 6 h, quenched with a little crushed ice and stirred for 30 minutes. The solid was filtered off and washed with 5% methanol in dichloromethane (150 ml) . The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column
chromatography to give the title compound 5 (1.2 g, 67%).
"""HNMR (400 MHz, DMSO-d6) δ : 8.82 (s, 1H) , 8.56 (s, 1H) , 7.40 (s, 1H), 5.66 (t, J = 5.6 Hz, 1H) , 4.79 (d, J = 5.6 Hz, 2H) , 4.02 (s, 3H) .
[0236]
4-Chloro-7-iodo-6-methoxy-quinoline-3-carbaldehyde (6)
Activated manganese dioxide (6 g, 68.9 mmol) was added to a stirred solution of compound 5 (1.2 g, 3.4 mmol) in dichloromethane (150 ml) . After 1, h, the reaction mixture was filtered through celite, and the filtrate was washed with 2% methanol in dichloromethane and concentrated under reduced pressure to give the title compound 6 (0.9 g, 75%) .
1HNMR (400 MHz, CDC13) δ : 10.68 (s, 1H) , 9.11 (s, 1H) , 8.69 (s, 1H) , 7.47 (s, 1H) , "4.09 (s, 3H) .
[0237]
Compound 7 : General method for synthesis of pyrazole
derivatives
A mixture of compound 6 (60 mg, 0.17 mmol) and
appropriate hydrazine derivative (0.26 mmol) in t-BuOH was stirred in RT for 1 h and refluxed for 24 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 ml) . The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified on silica-gel column to give the title compound 7 (40-50%) .
[0238]
Compound 8 : General method for Suzuki coupling
A mixture of compound 7 (0.10 mmol), 3,5- dimethylisoxazole-4-boronic acid (27 mg, 0.2 mmol) and cesium carbonate (125 mg, 0.4 mmol) in dimethoxyethane : water (4:1) was degassed .with argon for 10 minutes.
Tetrakis (triphenylphosphine) palladium (0) (0.025 mmol) was added thereto, and the reaction mixture was heated 5 h at 90°C. The reaction mixture was cooled to room temperature and
diluted with ethyl acetate (20 ml) . The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified on silica-gel column to give the title compound 8 (-40-50%) .
■ [0239] .
The following compounds of Examples were synthesized according to Scheme 1:
[0240]
Table 1
Figure imgf000103_0001
isoxazole
4-[l-[(2- (CDC13) : δ 9.15 (s, fluorophenyl ) met IH) , 8.32 (s, IH) , hyl] -8-methoxy- 7.98 (s, IH) , 7.42 pyrazolo [4,3- (s, IH), 7.26-7.31 c] quinolin-7- (m, IH) , 7.18 (t, J = yi]-3,5- 8 Hz, IH) , 7.02 (t, J dimethyl- = 8 Hz, IH) , 6.78 (t,
Figure imgf000104_0001
isoxazole J = 8 Hz, IH) , 6.15
(s, 2H) , 3.76 (s, 3H) , 2.33 (s, 3H) , 2.18 (s, 3H)
4-[l-[ (2- (CDCI3) : δ 9.16 (s, chlorophenyl ) met IH) , 8.33 (s, IH) , hyl] -8-methoxy- 7.98 (s, IH) , 7.51 pyrazolo [4,3- (d, J = 8 Hz, IH) , c] quinolin-7- 7.27 (s, IH) , 7.17 yi]-3,5- (s, IH) , 7.10 (t, J = dimethyl- 8 Hz, IH) , 6.48 (d, J
Figure imgf000104_0002
isoxazole = 8 Hz, IH) , 6.17 (s,
2H) , 3.66 (s, 3H) , 2.32 (s, 3H) , 2.16 (s, 3H)
4-[l-[ (4- (CDCI3) : δ 9.15 (s, fluorophenyl ) met IH) , 8.30 (s, IH) , hyl] -8-methoxy- 7.99 (s, IH) , 7.37 pyrazolo [4,3- (s, IH) , 7.11-7.13 c] quinolin-7- (m, 2H) , 7.05 (t, J = yi]-3,5- 8 Hz, 2H) , 6.07 (s,
Figure imgf000104_0003
dimethyl- 2H), 6.07 (s, 2H) , isoxazole 3.70 (s, 3H) , 2.33
(s, 3H), 2.18 (s, 3H)
Figure imgf000105_0001
(m, 1H), 3.92 (s,
3H) , 2.33 (s, 3H) ,
2.23 (d, J = 7.6 Hz ,
3H) , 2.18 (s, 3H)
4- [8-methoxy-l- (CDC13) : δ 9.13 (s,
(2- 1H) , 8.64 (d, J = 4.8 pyridylmethyl) py Hz, 1H) , 8.31 (s, razolo [4,3- 1H) , 7.97 (s, 1H) , c] quinolin-7- 7.75 (s, 1H) , 7.61 yl]-3,5- (d, J = 7.2 Hz, 1H) , dimethyl- 7.26-7.24 (m, 1H) ,
Figure imgf000106_0001
isoxazole 6.98 (d, J = 8.0 Hz,
1H) , 6.19 (s, 2H) , 3.86 (s, 3H) , 2.33
(s, 3H)
4- [ 8-methoxy-l- (CDCI3) : δ 9.15 (s,
(1- 1H) , 8.34' (s, 1H) , phenylethyl) pyra 7.97 (s, 1H) , 7.47 zolo [4, 3- (s, 1H), 7.35-7.26 c] quinolin-7- (m, 3H), 7.17-7.15 yi]-3,5- (m, 2H) , 6.36-6.34 dimethyl- (m, 1H) , 3.74 (s,
Figure imgf000106_0002
isoxazole 3H) , 2.32 (s, 3H) ,
2.21-2.19 (m, 3H) , 2.17 (s, 3H)
4-[l-[ (3- (CDCI3) : δ 9.15 (s, chlorophenyl ) met 1H), 8.31 (s, 1H) , hyl] -8-methoxy- 7.99 (s, 1H), 7.35 pyrazolo [4,3- (s, 1H) , 7.31-7.3 (m, c] quinolin-7- 2H) , 7.20 (s, 1H) , yi]-3,5- 7.03 (d, J = 0.64 Hz,
Figure imgf000106_0003
dimethyl- 1H) , 6.06 (s, 2H) , isoxazole 3.71 (s, 3H) , 2.33
(s, 3H) , 2.18 (s, 3H)
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
[0241]
Scheme 2
Figure imgf000111_0002
[0242]
l-Benzyl-4-chloro-7-iodo-8-me hoxy-pyrazolo [4, 3-c] quinoline (9)
Solid mCPBA (1.04 mmol) was added to the solution of compound 7 (0.87 mmol) in dichloromethane at 0°C, and the solution was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated NaHC03 solution and stirred for 30 minutes. The reaction mixture was diluted with dichloromethane, and the organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to give the crude corresponding N-oxide. The crude iV-oxide was dissolved in P0C13 (1.0 ml), and then the solution was heated for 10 min at 110°C. The reaction mixture was poured into cold saturated NaHC03 solution. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was purified on silica-get column to give the title compound 9 (100 mg) .
XHNMR (400 MHz, CDC13) δ: 8.58 (s, 1H) , 8.28 (s, 1H) , 7.33-7.29 (m, 3Ή), 7.14 (s, 1H) , 7.09-7.07 (m, 2H) , 6.06 (s, 2H) , 3.96 (s, 3H) .
[0243]
Example 2.1: 4- (l-Benzyl-4-chloro-8-me hoxy-pyrazolo [4 , 3- c] quinolin-7-yl) -3 , 5-dime hyl-isoxazole (10)
A mixture of compound 9 (40 mg, 0.09 mmol), 3,5- dimethylisoxazole-4-boronic acid (27 mg, 0.1 mmol) and cesium carbonate (65 mg, 0.2 mmol) in dimethoxyethane : ater (4:1) was degassed with argon for 5 minutes.
Tetrakis (triphenylphosphine) palladium(O) (0.01 mmol) was added thereto, and the reaction mixture was heated 2 h at 90°C. The reaction mixture was cooled to room temperature and diluted, with ethyl acetate (20 ml) . The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified on preparative TLC to give the title compound 10 (40%).
1HNMR (400 MHz, CDC13) δ: 8.32 (s, 1H) , 7.89 (s, 1H) , 7.38-7.32 (m, 4H), 7.16-7.14 (m, 2H) , 6.09 (s, 2H) , 3.64 (s, 3H) , 2.31 (s, 3H) , 2.16 (s, 3H) .
[0244]
Example 2.2: l-Benzyl-7- (3 , 5-dime hylisoxazol-4-yl) -8-methoxy- . pyrazolo [4 , 3-c] quinoline-4-carbonitrile (11)
A mixture of compound 10 (0.12 mmol) , zinc cyanide (0.24 mmol) , dppf (0.02 mmol) and Zn powder (0.08 mmol) in DMF was degassed with argon for 5 minutes.
Tris (dibenzylideneacetone) dipalladium ( 0 ) chloroform adduct (0.01 mmol) was added thereto, and the reaction mixture was heated 16 h at 100°C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 ml) . The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified on preparative TLC to give the title compound 11 (40%) .
1HNMR (400 MHz, CDC13) δ: 8.47 (s, 1H) , 8.04 (s, 1H) , 7.38-7.34 (m, 4H) , 7.14-7.12 (m, 2H) , 6.13 (s, 2H) , 3.68 (s, 3H) , 2.32 (s, 3H) , 2.16 (s, 3H) .
[0245]
Scheme 3
Figure imgf000113_0001
[0246]
Ethyl 2 , 4-dichloro-7-iodo-6-methoxy-quinoline-3-carboxylate (12)
Solid mCPBA (4.0 mmol) was added to the solution of compound 4 (2.65 mmol) in chloroform at 0°C, and then the mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated NaHC03 solution and stirred for further 30 minutes. The organic layer was separated, washed water and brine, dried over sodium sulfate and concentrated to give crude product. This product was purified by passing through a short silica-gel column by using ethyl acetate-hexane to give the pure corresponding W-oxide. The N-oxide thus obtained was dissolved in P0C13 (5.0 ml), and the solution was heated for 10 min at 110°C. The reaction mixture was poured into ice-NaHC03 mixture. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified on silica- get column to give the title compound 12 (60%) .
1HNMR (400 MHz, CDC13) δ: 8.56 (s, 1H) , 7.32 (s, 1H) , 4.54 (q, J = 7.2 Hz, 2H) , 4.06 (s, 3H) , 4.54 (t, J= 7.2 Hz, 3H) .
[0247]
(2 , 4-Dichloro-7-iodo-6-methoxy-3-quinolyl)methanol (13)
A solution of compound 12 (600 mg, 1.45 mmol) in
dichloromethane was cooled at -78°C, and 3.0 ml of DIBAL-H (1M solution in toluene) was added dropwise thereto. The reaction mixture was stirred for 2 h and then quenched with few drops of methanol and 0.2 ml of water. The reaction mixture was diluted with dichloromethane, stirred for 30 min and filtered through celite. The filtrate was concentrated, and the residue was purified on silica-gel column to give the title compound 13 (400 mg) .
XHNMR (400 MHz, CDC13) δ: 8.50 (s, 1H) , 7.40 (s, 1H) , 5.46-5.44 (m, 1H) , 4.86-4.85 (m, 2H) , 4.04 (m, 3H) .
[0248]
2 , 4-Dichloro-7-iodo-6-methoxy-quinoline-3-carbaldehyde (14)
A mixture of compound 13 (400 mg) and Dess Martin periodinane (600 mg) in dichloromethane was stirred for 4 h at room temperature. The reaction mixture was quenched with saturated NaHC03 solution and diluted with dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was purified on silica-gel column to give the title compound 14 (260 mg) .
^N R (400 MHz, CDC13) δ: 10.46 (s, 1H) , 8.59 (s, 1H) , 7.52 (s, 1H) , 4.06-4.04 (m, 3H) .
[0249]
4-Chloro-7-iodo-8-methoxy-lH-pyrazolo [4 , 3-c] quinoline (15)
A mixture of compound 14 (250 mg) and hydrazine
monohydrate in dioxane was stirred at room temperature for 1 h and then heated 6 h at 60°C. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHC03 solution and brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified on silica-get column to give the title compound 15 (150 mg) .
[0250]
3-Bromo-4-chloro-7-iodo-8-methoxy-lH-pyrazolo [4 , 3-c] quinoline (16)
N-Bromosuccinimide (1.48 g, 8.35 mmol) was added to a solution of compound 15 (2.0 g, 5.57 mmol) in DMF (30 mL) at room temperature. After complete addition, the resulting mixture was heated to 50°C. After 5 hour, water and ice were added to the reaction, and resulting solid was collected by filtration, washed with water and dried to give the title compound 16 (2.0 g, 82%).
XHNMR (400 MHz, CDC13) δ: 14.98 (s, 1H) , 8.48 (s, 1H) , 7.84 (s, 1H) , 4.00-3.99 (m, 3H) .
[0251]
3-Bromo-4-chloro-7-iodo-8-methoxy-1- (2- pyridylmethyl)pyrazolo [4 , 3-c] quinoline (17)
A mixture of compound 16 (0.31 mmol), K2C03 (0.62 mmol) and 2- (Bromomethyl) pyridine hydrobromide (0.62 mmol) was heated in anhydrous N, -dimethylformamide (2 ml) at 80°C. The reaction mixture was stirred for 2 hour, cooled to room temperature and diluted with ethyl acetate (20 ml) . The organic layer was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to give the title compound 17. 1HNMR (400 MHz, CDC13) δ : 8.49-8.45 (m, 2H) , 7.80 (dt, J = 2, 7.6Hz, 1H) , 7.58 (s, 1H) , 7.34-7.29 (m, 2H) , 6.28 (m, 2H) , 3.82 (m, 3H) .
[0252]
4- [3-Bromo-4-chloro-8-methoxy-l- (2-pyridylmethyl)pyrazolo [4 ,3- c] quinolin-7-yl] -3 , 5-dimethyl-isoxazole (18)
The preparation of compound 18 from compound 17 was carried out in a manner similar to that described for the preparation of compound 10.
1HNMR (400 MHz, CDC13) δ : 8.52 (d, J= 4.4 Hz, 1H) , 7.95 (s, 1H) , 7.82 (dt, J = 1.2, 7.2 Hz, 1H) , 7.73 (s, 1H) , 7.36-7.32 (m, 2H) , 6.30 (m, 2H) , 3.79 (m, 3H) , 2.29 (s, 3H) , 2.08 (s, 3H)
[0253]
4- [4-Chloro-8-methoxy-l- (2-pyridylmethyl)pyrazolo [4 , 3- c] quinolin-7-yl] -3 , 5-dimethyl-isoxazole (19)
To a solution of compound 18 (1.0 eq. ) in MeOH was added Pd/C (10% w/w) . The reaction was stirred under H2 atmosphere by using hydrogen balloon for 30 minutes and filtered through celite. The celite was washed with MeOH, and the combined filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound 19 (50%) .
[0254]
Compound 20: General method for amine coupling
A mixture of compound 18 (1.0 eq. ) and amine (5.0 eq. ) in ji-butanol was heated at 140°C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified to give the. title compound 20 (50-60%) .
[0255]
Compound 21: General method for debromination
To compound 20 (1.0 eq. ) in MeOH was added Pd/C (10% w/w). The reaction was stirred under H2 atmosphere by using H2 balloon for 1 h and then filtered through celite. The celite was washed with MeOH (200 ml) , and the filtrate was
concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound 21 (30-40%) .
[0256]
The following compounds of Examples were synthesized according to. Scheme 3:
[0257]
Table 2
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
[0258] Scheme 4
Figure imgf000120_0001
[0259]
(2-Bromo-4-fluoro-phenyl) ethyl carbonate (23)
A solution of compound 22 (7.0 g, 36.6 mmol), DMAP (224 mg, 1.83 mmol) and triethylamine (10 ml, 73.30 mmol) in DCM (70 ml) was cooled to 0°C, then treated with ethyl
chloroformate (7 ml, 73.30 mmol) dropwise, allowed to warm to room temperature and stirred for 5 h. The reaction mixture was quenched with sat. NaHC03 solution, and washed with brine (1 X 100 ml) . The organic layer was dried over anhydrous Na2S04, filtered and concentrated to give the title crude compound 23 (8.25 g, 85%) .
XHNMR (400 MHz, CDC13) δ: 7.35 (dd, J= 2.4, 3.2 Hz, 1H) , 7.20 (dd, J = 4.8, 5.2 Hz, 1H) , 7.08-7.03 (m, 1H) , 4.35 (q, J= 7.6 Hz, 2H) , 1.40 (t, J= 7.2 Hz, 3H) .
[0260]
(2-Bromo-4-fluoro-5-nitro-phenyl) ethyl carbonate (24)
Compound 23 (8.25 g, 31.36 mmol) was added portion wise to cone. H2SO4 (45 ml) to give a colorless homogeneous solution. This solution was then cooled to 0°C, and KN03 (3.48 g, 34.48 mmol) was added thereto portion wise over a period of 15 min maintaining the internal temperature below 5°C. The reaction was stirred for 2 h at RT and poured on ice water, and the aqueous layer was extracted with DCM (3 X 50 ml) . The combined organic layer was washed with saturated NaHC03, water and brine. The organic layer was dried over anhydrous Na2S04, filtered and concentrated to give the title compound 24 (8.8 g, 91%). 1HNMR (400 MHz, CDC13) δ: 8.02 (d, J = 6.8 Hz, 1H) , 7.62 (d, J = 10.0 Hz, 1H) , 4.39 (q, J = 7.2 Hz, 2H) , 1.43 (t, J= 7.2 Hz, 3H) .
[0261]
2-Bromo-4-fluoro-5-nitro-phenol (25)
To a solution of compound 24 (8.5 g, 27.6 mmol). in dry methanol (100 ml) was added KOH (3.86 g, 69 mmol) portion wise at 0°C. After the addition was complete, the reaction mixture was allowed to warm at room temperature and stirred for 2 h. The reaction mixture was acidified with IN HC1. The solvent was evaporated, and water was added thereto. The aqueous layer was extracted with DCM (2 X 50 ml) . The combined organic layer was washed with brine (1 X 100 ml) , dried over anhydrous Na2S04, filtered and concentrated to give the title compound 25 (6.42 g, 99%) .
1HNMR (400 MHz, CDC13) δ: 7.72 (d, J = 6.4 Hz, 1H) , 7.49 (d, J
= 9.2 Hz, 1H) , 5.99 (brs, 1H) .
[0262]
1-Bromo-5-fluoro-2-methoxy-4-nitro-benzene (26)
To a solution of compound 25 (6.4 g, 27.1 mmol) in dry acetone (65 ml) was added K2C03 (7.48 g, 54.2 mmol) at 0°C.
Methyl Iodide (2.0 eq. ) was added dropwise thereto, and after complete addition, the reaction mixture was warmed to 50°C and stirred for 16 h. The reaction mixture was cool to room
temperature, diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2S04, filtered and concentrated to give the title compound 26 (6.6 g, 97%).
LHNMR (400 MHz, CDCI3) δ: 7.57-7.54 (m, 2H) , 3.97 (s, 3H) .
[0263]
Ethyl 2- (5-bromo-4-methoxy-2-nitro-anilino) acetate (27)
A mixture of compound 26 (40.0 mmol), glycine ethyl ester hydrochloride (5.58 g, 80.0 mmol) and NaHC03 (200 mmol) in dry DMSO (150 ml) was stirred 4 h at 100°C. The reaction was then cooled to room temperature and quenched with water. The solid was collected by filtration, washed thoroughly with water and dried under vacuum to give the title compound 27 (9.0 g, 67%).
[0264]
Mixture of 6-Bromo-7-methoxy-3 , 4-d_ihydro-lH-quinoxalin-2-one (28) and 6-bromo-7-me hoxy-lH-quinoxalin-2-one (29)
To a stirred solution of compound 27 (9 g, 27 mmol) in acetic acid (100 ml) was added iron powder (5.3 g, 94 mmol), and the mixture was stirred at 120°C for one hour. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was washed with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sat.NaHC03, water and brine, dried over Na2SO,j, filtered and concentrated under reduced pressure to give a mixture of the title compounds 28 and 29 (6 g).
[0265]
6-Bromo-7-methoxy-1H-quinoxalin-2-one (29)
25% H202 (20 ml) was added slowly to a suspension of the mixture of compounds 28 and 29 (6 g) obtained in the previous step in 10% aqueous NaOH solution (30 ml) at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then allowed to stir at room temperature for 2 hours (till clear solution was formed) . Once the clear solution was formed, it was heated at 80°C and stirred for half an hour, and then AcOH was added thereto slowly till pH =7 at 0°C. The solid was filtered and dried to give the title compound 29 (4.2 g) .
[0266]
6-Bromo-2-chloro-7-methoxy-quinoxaline (30)
Compound 29 (673 mg, 2.66 mmol) was added to cold phosphorous oxychloride (4 mL) in portions to give a slurry. To the resulting slurry was added N, N-dimethylaniline (0.4 ml, 2.93 mmol) dropwise below 15°C. The brick red mixture was refluxed for 15 min, and the resulting dark brown clear solution was then cooled to ambient temperature. The mixture was poured into ice cold water (40 ml) and basified slowly with 40% aq. NaOH to pH 8. The solid was collected by filtration, washed with water (2x10) and dried to give the title compound 30. (511 mg) .
XHNMR (400 MHz, DMSO-d6) : δ 8.85 (s, 1H) , 8.43 (s, 1H 7.57 (s, 1H) , 4.05 (s, 3H) .
[0267]
6-Bramo-7-methoxy-lH-quinoxalin-2-one hydrazone (31)
Hydrazine monohydrate (13.3 ml, 267.3 mmol) was added dropwise to a stirred suspension of compound 30 (29 g, 106.9 mmol) in methanol (290 ml) , and the resulting mixture was refluxed 16 h. The reaction mixture was cooled to room temperature, and the solid was collected by filtration, washed with methanol, and dried under vacuum to give the title compound 31. (24 g, 84%) .
1HNMR (400 MHz, DMSO-d6) δ : 8.77 (brs, 1H) , 8.21 (s, 1H) , 7.96 (s, 1H) , 7.09 (s, 1H) , 4.5 (brs, 2H) , 3.94 (s,. 3H) .
[0268]
Compound 32 : General method for triazole cyclization
Method-A: A mixture of compound 31 (0.37 mmol) and appropriate carboxylic acid (0.41 mmol) was refluxed in P0C13 (2 ml) for 1 hours. The reaction mixture was cooled to room temperature and poured into crushed ice. The solid was collected by filtration and dried under vacuum to give the title compound 32 (50-60%) .
[0269]
Method-B: To a stirred solution of compound 31 (1.85 mmol) and appropriate carboxylic acid (2.04 mmol) in DMF (5 ml) were added DIPEA (2.78 mmol) and HATU (2.78 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 16h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was triturated in methanol, and the solid was collected by filtration to give the
corresponding amide intermediate (1.34 mmol), which was mixed with N, O-bis (trimethylsilyl) acetamide (9.4 mmol) and
hexamethyl disilazane (33.5 mmol), and the mixture was stirred at 120° for 16 h. The reaction mixture was cooled to room temperature and carefully quenched with methanol and water. The solid was collected by filtration through Buchner funnel, washed with hexane and dried in vacuum to give the title compound 32 (70-75%) .
[0270] .
Compound 33 : General method for Suzuki coupling
Method C: To a solution of compound 32 (0.12 mmol) and aryl boronic acid (0.38 mmol) in D E (2 ml) was added Cs2C03 (0.38 mmol) in water (0.5 ml) . The mixture was degassed with N2 for 30 minutes, tetrakis (triphenylphosphine) palladium(O) (0.006 mmol) was added thereto, and the resulting mixture was heated at 105°C for 2 h. The mixture was cooled to room temperature, poured into water and extracted with DCM. The organic layer was washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound 33 (50-60%) .
[0271]
Method D: To a solution of compound 32 (0.12 mmol) and aryl boronic acid (0.38 mmol) in 1,4-Dioxane (2 ml) was added K2C03 (0.38 mmol) in water (0.5 ml). The mixture was degassed with N2 for 30 minutes, [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium ( II ) (0.012 mmol) was added thereto, and the resulting mixture was heated at 100°C for 16 h. The mixture was cooled to room temperature, poured into water and extracted with DCM. The organic layer was washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound 33 (50-60%) .
[0272] ■ '
4- [8-methoxy-l- (2-pyridylmethyl) - [1,2,4] triazolo [4 , 3- a] quinoxalin-7-y1] -3 , 5-dimethyl-isoxazole :
To a stirred solution of compound 31 (2.8 g, 10.36 mmol) and 2-pyridylacetic acid (2.0 g, 11.52 mmol) in DMF (20 ml) were added DIPEA (3 ml, 17.28 mmol) and HATU (6.5 g, 17.28 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 16h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was triturated in methanol, and the solid was collected by
filtration to give N- [ ( Z ) - ( 6-bromo-7-methoxy-lH-quinoxalin-2- ylidene) amino] -2- (2-pyridyl) acetamide (2.3 g, 52%), which was mixed with N, O-bis (trimethylsilyl) acetamide (10.2 ml, 41.4 mmol) and hexamethyl disilazane (31.4 ml, 148.2 mmol), and the mixture was stirred at 120°C for 16 h. The reaction mixture was cooled to room temperature and carefully quenched with methanol and water. The solid was collected by filtration, washed with hexane and dried in vacuum to give 7-bromo-8- methoxy-1- (2-pyridylmethyl) -[1,2,4] triazolo [4, 3-a] quinoxaline
(32) (2.0 g, 91%) .
To a solution of compound 32 (2.0 g, 5.42 mmol) and 3,5- dimethylisoxazole-4-boronic acid (2.3 g, 16.2 mmol) in 1,4- Dioxane (16 ml) was added K2CO3 (1.49 g, 10.84 mmol) in water (4 ml) . The mixture was degassed with N2 for 30 minutes,
[1, 1 '-bis (diphenylphosphino) ferrocene] dichloropalladium ( II ) (0.22 g, 0.27 mmol) was added thereto, and the resulting mixture was heated at 100°C for 16 h. The mixture was cooled to room temperature, poured into water and extracted with DCM. The organic layer was washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound 4- [ 8-methoxy-l- ( 2-pyridylmethyl ) - [1,2,4] triazolo [4, 3-a] quinoxalin-7-yl ] -3, 5-dimethyl-isoxazole
(33) (1.6 g, 76%) .
[0273]
The following compounds of Examples were synthesized according to Scheme 4 : [0274] Table 3
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
isoxazole
Figure imgf000131_0001
Figure imgf000132_0001
isoxazole
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
isoxazole 3H)
Figure imgf000141_0001
Figure imgf000142_0001
[0275]
racemic compounds were separated using Chiral HPLC
Figure imgf000142_0002
[0276]
R = methyl :
4.53.1: First enantiomer ^NMR (400 MHz, CDCI3) δ : 9.17 (s
8.60 (d, J = 4.4 Hz, IH) , 7.97 (s, IH) , 7.84 (s, IH) , 7.65
7.61 (m, IH), 7.24-7.21 (m, IH) , 7.15 (d, J= 7.6 Hz, IH) , 5.25 -5.24 (m, 1H) , 3.98 (s, 3H) , 2.30 (s, 3H) , 2.15 (s, 3H) , 2.14 (d, J = 4.0 Hz, 3H) .
4.53.2: Second enantiomer XHNMR (400 MHz , CDC13) δ: 9.17 (s, 1H) , 8.60 (d, J= 4.4 Hz, 1H) , 7.97 (s, 1H) , 7.84 (s, 1H) , 7.65-7.61 (m, 1H) , 7.24-7.21 (m, 1H) , 7.15 (d, J = 7.6 Hz, 1H) , 5.25 -5.24 (m, 1H) , 3.98 (s, 3H) , 2.30 (s, 3H) , 2.15 (s, 3H) , 2.14 (d, J = 4.0 Hz , 3H) .
[0277]
R = isopropyl:
4.54.1: First enantiomer 1HNMR (400 MHz, CDC13) δ: 9.13 (s, 1H) , 8.54 (d, J = 4.4 Hz, 1H) , 8.47 (s, 1H) , 7.84 (s, 1H) , 7.66-
7.61 (m, 1H) , 7.43 (d, J = 7.6 Hz, 1H) , 7.18 (m, 1H) , 4.65 (d, J = 10 Hz, 1H) , 4.19 (s, 3H) , 3.26-3.24 (m, 1H) , 2.32 (s, 3H) , 2.18 (s, 3H) , 1.14 (d, J = 6.4 Hz, 3H) , 0.89 (d, J = 7.2 Hz, 3H) .
4.54.2: Second enantiomer ^HNMR (400 MHz, CDC13) δ: 9.13 (s, 1H) , 8.54 (d, J = 4.4 Hz, 1H) , 8.47 (s, 1H) , 7.84 (s, 1H) , 7.66-7.61 (m, 1H) , 7.43 (d, J= 7.6 Hz, 1H) , 7.18 (m, 1H) , 4.65 (d, J = 10 Hz, 1H) , 4.19 (s, 3H) , 3.26-3.24 (m, 1H) , 2.32 (s, 3H) , 2.18 (s, 3H) , 1.14 (d, J = 6.4 Hz, 3H) , 0.89 (d, J = 7.2 Hz, 3H) .
[0278]
R = ethyl:
4.55.1: First enantiomer 1HNMR (400 MHz, CDC13) δ: 9.15 (s, 1H) , 8.58 (d, J = 2.0 Hz, 1H) , 8.18 (s, 1H) , 7.84 (s, 1H) , 7.62 (t, J = 1.8 Hz, 1H) , 7.24-7.19 (m, 2H) , 4.96 - .93 (m, 1H) , 4.08 (s, 3H) , 2.60 (m, 1H) , 2.49 (m, 1H) , 2.31 (s, 3H) , 2.16 (s, 3H) , 1.13 (t, J - 7.6 Hz, 3H) .
4.55.2: Second enantiomer 1HNMR (400 MHz, CDC13) δ: 9.15 (s, 1H) , 8.58 (d, J = 2.0 Hz, 1H) , 8.18 (s, 1H) , 7.84 (s, 1H) ,
7.62 (t, J = 1.8 Hz, 1H) , 7.24-7.19 (m, 2H) , 4.96 -4.93 (m, 1H), 4.08 (s, 3H), 2.60 (m, 1H) , 2.49 (m, 1H) , 2.31 (s, 3H) , 2.16 (s, 3H) , 1.13 (t, J = 7.6 Hz, 3H) .
[0279]
R = cyclopropyl : 4.56.1: First enantiomer 1HNMR (400 MHz, CDC13) δ: 9.17 (s, 1H) , 8.55 (d, J = 4.4 Hz, 1H) , 8.01 (brs, 1H) , 7.83 (s, 1H) , 7.63- 7.67 (m, 1H) , 7.36 (d, J = 8.4 Hz, 1H) , 7.24-7.21 (m, 1H) , 4.25 (s, 1H) , 4.05 (s, 3H) , 2.30 (s, 3H) , 2.17 (s, 1H) , 2.04 (s, 3H) , 0.89-0.63 (m, 3H) , 0.40-0.37 (m, 1H) .
4.56.2: Second enantiomer 1HNMR (400 MHz, CDC13) δ: 9.17 (s, 1H) , 8.55 (d, J = 4.4 Hz, 1H) , 8.01 (brs, 1H) , 7.83 (s, 1H) , 7.63-7.67 (m, 1H) , 7.36 (d, J = 8.4 Hz, 1H) , 7.24-7.21 (m, 1H) , 4.25 (s, 1H) , 4.05 (s, 3H) , 2.30 (s, 3H) , 2.17 (s, 1H) , 2.04 (s, 3H) , 0.89-0.63 (m, 3H) , 0.40-0.37 (m, 1H) .
[0280]
Scheme-5
Figure imgf000144_0001
[0281]
Example 5.1: 3- [ [7- (3 , 5-dimethylisoxazol-4-yl) -8-methoxy-
[1,2,4] triazolo [4 , 3-a] quinoxalin-l-yl]methyl]benzoic acid (34)
A solution of compound 33 (50 mg, 0.138 mmol) and NaOH (27.6 mg, 0.69 mmol) in water (2 ml) was stirred at reflux for 16 h. The reaction mixture was cooled to 0°C, acidified with 2M HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced
pressure, and the residue was triturated in ethyl acetate to give the title compound 34 (60%).
1HNMR (400 MHz, DMSO-d6) δ: 13.0 (brs, 1H) 9. 26 (s, 1H) , 7.98 (s, lH) , 7.94- (s, 1H) , 7.87-7.85 (m, 1H) , 7.51 (s, 1H), 7.48- 7.68 (m, 2H) , 5.19 2H), 3.77 (s, 3H), 2.27 (s, 3H) , 2.06 (s, 3H) .
[0282]
Scheme-6
Figure imgf000145_0001
R = 2-Pyridyl
R1 = R2 = H; n = 1
Figure imgf000145_0002
[0283]
Example 6.1: 7- (3 , 5-Dimethylisoxazol-4-yl) -1- (2- pyridylmethyl) -[1,2,4] triazolo [4 , 3-a] quinoxalin-8-ol (35)
BBr3 (0.5 ml) was added to a solution of compound 33 (100 mg) in DCM (20 ml) at room temperature, and the reaction mixture was stirred at 45°C for 24 h. The reaction mixture was poured into cold saturated NaHC03 solution and stirred for 10 min. The organic layer was separated, washed with water and brine and concentrated. The residue was purified on
preparative TLC to give the title compound 35.
1HNMR (400 MHz, CDC13) δ: 10.95 (brs, 1H) , 9.14 (s, 1H) , 8.40 (d, J = 4.8 Hz, 1H) , 7.90 (s, 1H) , 7.80 (dt, 1.6, 7.6 Hz, 1H) , 7.70 (s, 1H) , 7.27 (dd, J= 5.6, 7.2 Hz, 1H) , 5.06 (s, 2H) , 2.30 (s, 3H) . 2.13 (s, 3H) .
[0284]
Scheme 7
N
Figure imgf000145_0003
[0285] Ethyl 2- (5-brom9-2-nitro-anili.no) acetate (37)
A solution of compound 36 (1 g, 4.5 mmol) , glycine ethyl ester hydrochloride (0.7 g, 5 mmol) and diisopropylethylamine (0.9 g, 6.8 mmol) in acetonitrile (20 ml) was refluxed for 2 h. This reaction mixture was diluted with water and extracted
(2x75 ml) with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to give the title compound 37 (80%).
1HNMR (400 MHz, CDC13) δ: 8.45 (brs, 1H) , 8.07 (d, J = 8.0 Hz, 1H) , 6.86-6.83 (m, 2H) , 4.32 (q, J= 6.8 Hz> 2H) , 4.06 (d, J = 4.0 Hz, 2H) , 1.33 (t, J = 8.0 Hz, .3H) .
[0286]
6-Bromo-3 , 4-dihydro-lH-quinoxalin-2-one (38)
.-To the solution of compound 37 (1.2 g, 4 mmol) in acetic acid (15 ml) was added slowly iron powder (850 mg, 16 mmol) , and then the mixture was stirred at reflux for 1 h. The
reaction mixture was poured into crushed ice and then quenched with solid NaHC03 at 0°C. The solid was filtered off through celite, and the celite pad was washed with water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to give the title compound 38 (70%) .
1HNMR (400 MHz, DMSO-d6) δ: 10.40 (s, 1H) , 6.79 (s, 1H) , 6.7 0 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H) , 6.26 (br s, 1H) , 3.74 (s, 2H) .
[0287]
6-Bromo-lH-quinoxalin-2-one (39)
A suspension of compound 38 (850 mg) in 10 % aqueous NaOH (10 ml) was slowly added 25 % H202 (5 ml) at 0°C while stirring. The reaction mixture was stirred at 0-°C for lh and then allowed to stir at room temperature for 2 h (till clear solution was . formed) . Once the clear solution was formed, it was stirred at 80°C for half an hour. The mixture was cooled to 0°C, and then AcOH was added slowly thereto till pH 7. The solid was
collected by filtration and dried under vacuum to give the title compound 39 (600 mg, 70%) .
1HNMR (400 MHz, DMSO-d6) δ: 12.46 (brs, 1H) , 8.20 (s, 1H) , 7.98 ■ (d, J= 2.4 Hz, 1H) , 7.70 (dd, J = 8.8, 2.0 Hz, 1H) , 7.25 (d, J = 8.4 Hz, 2H) .
[0288]
6-Bromo-2-chloro-quinoxaline (40)
Compound 39 (600 mg, 2.66 mmol) was added to cold
phosphorous oxychloride (4 mL) in portions wise to give a slurry. To the resulting slurry was added drop wise N,N- dimethylaniline (0.4 ml, 2.93 mmol) below 15°C. The brick red mixture was refluxed for 15 min, and the resulting dark brown clear solution was then cooled to ambient temperature. It was added to ice cold water (40 mL) , and the mixture was basified slowly with 40% aq. NaOH to pH 8. The solid was collected by filtration, washed with water (2x10 mL) and dried to give the title compound 40 (70%) .
[0289]
(6-Bromoquinoxalin-2-yl) hydrazine (41)
To a solution of compound 40 (420 mg, 1.73 mmol) in ethanol (5 ml) was added excess hydrazine monohydrate (1.5 ml), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the solid residue was washed with diethyl ether, and dried in vacuo to give the title compound 41 (80%) .
[0290]
Compound 42 : General method for triazole cyclization
The preparation of compound 42 from compound 41 was carried out in a manner similar to that described for the preparation of compound 32 according to Method-A (50-60%) .
[0291]
Compound 43 : General method for Suzuki coupling
The preparation of compound 43 from compound 42 was carried out in a manner similar to that described for the preparation of compound 33 according to Method-C (50-60% yield) .
[0292]
The following compounds of Examples were synthesized according to Scheme 7:
[0293]
Table 4
Figure imgf000148_0001
[0294]
Scheme 8
Figure imgf000149_0001
[0295]
6- (3 , 5-Dimethylisoxazol-4-yl) -7-methoxy-lH-quinoxalin-2-one (44)
The preparation of compound 44 from compound 29 was carried out in a manner similar to that described for the preparation of compound 33 according to Method C (60% yield) .
[0296]
4- (2-Chloro-7-methoxy-quinoxalin-6-yl) -3 , 5-dimethyl-isoxazole (45)
To a mixture of compound 44 (4.42 mmol) and P0C13 (91.50 mmol) was added N, N-dimethylaniline (0.22 mmol). The resulting mixture was refluxed for 15 minutes. The mixture was cooled to room temperature, and P0C13 was evaporated under reduced
pressure. The residual P0C13 was quenched with H20, and the aqueous layer was extracted with DCM (3 times) . The combined organic layers were washed with water, brine, dried over Na2S04, filtered, and concentrated under reduced pressure to give the title compound 45 (80%) .
[0297]
[6- (3 , 5-Dimethylisoxazol-4-yl) -7-methoxy-quinoxalin-2- yl] hydrazine (46)
Hydrazine hydrate (17.30 mmol) was added to a solution of compound 45 (3.46 mmol) in methanol at room temperature. The resulting solution was refluxed for 12 h. The solid was
collected by filtration, washed with methanol and dried to give the title compound 46 (80%).
[0298]
Compound 47: General method for coupling with isocyanate To a stirred solution of compound 46 (1.0 eq. ) in DCM was added appropriate isocyanate (1.0 eq) . The resulting mixture was stirred at room temperature for overnight. The solid was collected by filtration, washed with EtOAc and dried to give the title compound 47 (60-70%) .
[0299]
Compound 48 : General method for triazole cyclization
A heterogeneous mixture of compound 47 (1.0 eq.) in phosphorous oxychloride (10 eq. ) was refluxed for 4h. The homogenous solution was allowed to cool to room temperature. Excess P0C13 was evaporated in vacuo, and resulting residue was quenched with saturated sodium bicarbonate solution. The solid was collected by filtration and washed with water and DCM to give the title compound 48 (40-50%) .
[0300]
The following compounds of Examples were synthesized according to Scheme 8 :
[0301]
Table 5
Figure imgf000150_0001
Figure imgf000151_0001
amihe
Figure imgf000152_0001
[0302]
Scheme 9
Figure imgf000152_0002
[0303]
3-Iodo-4-methoxy-aniline (50)
NH4C1 (38.3 g, 716.8 mmol) dissolved in H20 (-100 ml) was added to a solution of compound 49 (50g, 179.2 mmol) in ethanol (600 mmol). Iron powder (40.15 g, 716.8) was added to this mixture, and the mixture was refluxed for 5 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound 50. (42 g, 93%) .
XHNMR (400 MHz , DMSO-d$ δ: 7.02 (d, J = 2.4 Hz, 1H) , 6.72 (d, J= 8.8 Hz, 1H) , 6.55 (dd, J = 2.8, 8.8 Hz, 1H) , 4.81 (brs, 2H) , 3.66 (s, 3H) .
[0304]
N- (3-Iodo-4-methoxy-phenyl) -acetamide (51)
Acetyl chloride (18.4 ml, 259 mmol) was added drop wise to a stirred solution of compound 50 (43.0 g, 172.6 mmol) and triethylamine (73 ml, 518 mmol) in DCM at 0°C. After complete addition, the reaction mixture was stirred at room temperature for lh. The reaction mixture was quenched with water, and the organic layer was separated, washed with water and brine and dried over Na2S04. The solvent was evaporated under reduced pressure to give the title compound 51 (39 g, 67%) .
^NMR (400 MHz, DMSO-d6 δ: 9.84 (brs, 1H) , 8.06 (d, J =.2.8 Hz, 1H) , 7.48 (dd, J= 2.8, 8.8 Hz, 1H) , 6.94 (d, J = 8..8 Hz, 1H) , 3.77 (s, 3H) , 2.0 (s, 3H) .
[0305]
N- (5-Iodo-4-methoxy-2-nitro-phenyl) -acetamide (52)
Concentrated nitric acid (78 ml) was added to acetic anhydride (390 ml) cooled to -10°C (internal temp) . To this solution was added compound 51 (39 g, 134 mmol) portion wise at a rate which maintained an internal temperature below -5°C. The solution was stirred for lh while warming to room
temperature. The solution was then poured into an ice-water mixture, and the mixture was extracted several times with ethyl acetate. The combined extracts were washed with 10%
NaHC03, water and brine, dried over Na2S04, filtered, and
concentrated under vacuum. The residue was triturated in methanol to give the title compound 52. (36 g, 80%).
XHNMR (400 MHz, DMSO-d6 δ: 10.06 (brs, 1H) , 8.02 (s, 1H) , 7.45 (s, 1H) , 3.90 (s, 3H) , 2.02 (s, 3H) .
[0306]
5-Iodo-4-methoxy-2-nitro-aniline (53) Concentrated H2S04 (60 ml) was added drop wise to a stirred suspension of compound 52 (36 g, 107.1.mmol) in
methanol (1.3 lit), and the mixture was refluxed for 4h. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and water. The organic layer was separated, washed with sat.NaHC03 solution and brine, dried over Na2S04, filtered and concentrated under vacuum to give the title compound 53 (31g, 98%) .
XHNMR (400 MHz, OMSO~d6) δ: 7.63 (s, 1H) , 7.33 (s, 1H) , 7.20 (brs, 1H) , 3.77 (s, 3H) .
[0307]
Ethyl 2- (5-iodo-4-methoxy-2-nitro-anilino) -2-oxo-acetate (54)
Ethyl oxalyl chloride (17.7 ml, 158.1 mmol) was added dropwise at 0°C to a stirred solution of compound 53 (31.0 g, 105.4 mmol) and triethylamine (29.6 ml, 210.8 mmol) in THF
(160 ml) . After complete addition, the reaction mixture was stirred at room temperature for lh. The mixture was quenched with water and extracted with ethyl acetate, and the combined extracts were washed with water and brine and dried over Na2S04. The solvent was evaporated under reduced pressure to give the title compound 54 (40 g, 96%) .
XHNMR (400 MHz, DMSO-d6) δ: 8.40 (s, 1H) , 7.58 (s, 1H) , 4.33 (q, J = 6.8 Hz, 2H) , 1.32 (t, J = 6.8 Hz, 3H) .
[0308]
6-Iodo-7-niethoxy-l , 4-dihydroquinoxaline-2 , 3-dione (55)
Iron powder (28.4 g, 507.6 mmol) was added to a stirred solution of compound 54 (40g, 101.5 mmol) in acetic acid (250 ml), and the resulting mixture was heated to reflux. After - 4h, the acetic acid was evaporated under reduced pressure, and the residue was filtered through Buchner funnel and washed with MeOH : DCM (1:9). The solvent was evaporated under reduced pressure to give the title compound 55 (Crude amount 50 g contains inorganic material) .
[0309]
2 , 3-Dichloro-6-iodo-7-methoxy-quinoxaline (56) POCI3 (1 L) was added slowly to the crude compound 55
(104 g, 183.6 mmol) obtained from the previous step. After complete addition, the resulting mixture was heated to reflux for overnight. The reaction mixture was cooled to room
temperature and poured into crushed ice. The solid was
collected by filtration and dried under vacuum to give the title compound 56 (46.6 g) .
1HNMR (400 MHz, DMSO-d6) .5: 8.59 (s, 1H) , 7.49 (s, 1H) , 4.03 (s, 3H) .
[0310]
(3-Chloro-6-iodo-7-me hoxy-quinoxaliii-2-yl) -hydrazine (57)
Hydrazine monohydrate (14 ml, 289.6 mmol) was added drop wise to a stirred suspension of compound 56 (46.6 g, 131.6 mmol) in ethanol (900 ml), and the mixture was stirred at room temperature for overnight. The solid was collected by
filtration, washed with ethanol and dried under vacuum to give the title compound 57 (45 g, 98%) .
XHNMR (400 MHz, DMSO-d6) δ : 8.94 (brs, 1H) , 8.15 (s, 1H) , 7.08 (s, 1H) , 4.63 (brs, 2H) , 3.93 (s, 3H) .
[0311]
Compound 58 : General method for triazole cyclization
Compound 57 (40 g, 114.2 mmol) and appropriate carboxylic acid were refluxed in POCI3 for 4 hours. The reaction mixture was cooled to room temperature and poured into crushed ice.
The solid was collected by filtration, washed with water and dried under vacuum to give the title compound 58 (60-70%) .
[0312]
Compound 59: General method for Suzuki coupling
The preparation of compound 59 from compound 58 was carried out in a manner similar to that described in the
preparation of compound 33 according to Method D (60%).
[0313]
Compound 60 : General method for Suzuki coupling
The preparation of compound 60 from compound 58 was carried out in a manner similar to that described in the preparation of compound 33 according to Method C (50-60%) .
[0314]
Compound 62 : General method for CI-replacement reaction in compound 60
7- (3 , 5-Dimethylisoxazol-4-yl) -8-methoxy-l- (2-pyridylmethyl) - [1 , 2 , 4] triazolo [4 , 3-a] quinoxaline-4-carbonitrile (Ri = CN, Ar = 2-pyridyl)
A mixture of compound 60 (0.28 mmol) and zinc cyanide (0.85 mmol) in DMF (6 ml) was degassed with N2 for 10 min, and then Pd(PPh3)4 (0.028 mmol) was added thereto. The resulting mixture was heated at 120°C for 16h. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2S04. The solvent was evaporated, and the residue was purified by column
chromatography to give the title compound (23%).
[0315]
7- (3 ,5-Dimethylisoxazol-4-yl) -1- [ (3-fluorophenyl)methyl] -8- methoxy- [1,2,4] triazolo [4 , 3-a] quinoxaline-4-carbonitrile (Ri = CN, Ar = 3-fluorophenyl)
. A mixture of compound 60 (0.22 mmol) and zinc cyanide (0.68 mmol) in DMF (6 ml) was degassed with N2 for 10 min, and then Pd(PPh3)4 (0.022 mmol) was added thereto, and the mixture was placed in oil bath and heated it at 120°C for 16 hours.
The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined.
extracts were washed with water and brine and dried over Na2S04.
The residue was purified by column chromatography using 230-
400 mesh silica and methanol in DCM (0-5%) as eluent. The solvent was evaporated under reduced pressure to give the title compound (25%).
[0316]
4- [4,8-Dimethoxy-l- (2-pyridylmethyl) -[1,2,4] triazolo [4 , 3- a] quinoxalin-7-yl] -3 , 5-dimethyl-isoxazole (Ri = OMe, Ar = 2- pyridyl) A mixture of compound 60 (0.095 mmol) in 3 ml of ammonia in methanol (2.0 M) was stirred in screw cap vial at room temperature for 16 h. The solvent was evaporated under reduced pressure, and the residue was purified using preparative TLC to give the title compound (50%) .
[0317]
4- [4-Cyclopropy1-8-methoxy-1- (2-pyridylmethyl) -
[1,2,4] triazolo [4 , 3-a] quinoxalin-7-yl] -3 , 5-dimethyl-isoxazole
(Ri = Cyclopropyl, Ar = 2-pyridyl)
A mixture of compound 60 (0.095 mmol), cyclopropylboronic acid (0.47 mmol), K3P04 (0.47 mmol) and tricyclohexylphosphine (0.019 mmol) in dry toluene (2 ml) and water (0.4 ml) was degassed with N2 for 30 min, and then Pd(0Ac)2 (0.004 mmol) was added thereto. The resulting mixture was heated at 100°C for 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, and the organic layer was separated, washed with water and brine and dried over Na2S04. The solvent was evaporated, and the residue was purified by preparative TLC to. give the title compound (35%).
[0318]
4- [4-Ethoxy-8-methoxy-l- (2-pyridylmethyl) -[1,2,4] riazolo [4,3- a] quinoxalin-7-yl] -3, 5-dimethyl-isoxazole (Ri = OEt, Ar = 2- pyridyl)
Sodium ethoxide (0.14) was added to a stirred solution of compound 60 (0.071 mmol) in ethanol (2 ml). The resulting mixture was stirred at room temperature for overnight. The mixture was quenched with sat.NH4Cl solution and extracted with ethyl acetate. The combined extracts were washed with water and brine and dried over Na2S04. The solvent was evaporated, and the residue was purified by preparative TLC to give the title compound (65%).
[0319]
7- (3 , 5-Dimethylisoxazol-4-yl) -8-methoxy-1- (2-pyridylmethyl) - [1,2,4] triazolo [4, 3-a] quinoxalin-4-amine (Ri = NEfe , Ar = 2- pyridyl) Compound 57 (40 g, 114.2 mmol) and 2-pyridylacetic acid (21.8 g, 125.7 mmol) were refluxed in P0C13 (400 ml) for 4 hours. The reaction mixture was cooled to room temperature and poured into crushed ice. The solid was collected by filtration, washed with water and dried under vacuum to give the title compound 58 (34 g, 66%) .
To a solution of compound 58 (29 g, 64.3 mmol) and 3,5- dimethylisoxazole-4-boronic acid (27.3 g, 192.9 mmol) in. DME (360 ml) was added Cs2C03 (62.8 g, 192.9 mmol) in water (90 ml). The mixture was degassed with N2 for 30 minutes,
tetrakis (triphenylphosphine) palladium ( 0 ) (3.71 g, 3.2 mmol) was added thereto, and the resulting mixture was heated at
105°C for 2 h. The mixture was cooled to room temperature, poured into water and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give compound 60
(6.3 g, 23%) .
Liq. NH3 was purged into a solution of compound 60 (0.095 mmol) in 1,4-dioxane (2 ml) at 0-5°C in a sealed tube. The resulting mixture was stirred it at 100°C for 24 h. The
solvent was evaporated under reduced pressure, and the residue was purified using preparative HPLC to give the title compound (45%) .
[0320]
4- [4- (Azetidin-l-yl) -8-methoxy-l- (2-pyridylmethyl) -
[1,2,4] riazolo [4 , 3-a] quinoxalin-7-yl] -3 , 5-dimethyl-isoxazole (Ri = Azetidin-l-yl, Ar = 2-pyridyl)
A mixture of compound 60 (0.095 mmol), azetidine
hydrochloride (0.14 mmol) and K2C03 (0.28 mmol) in D F was stirred at 80°C for 16 h. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and. brine and dried over Na2S04. The solvent was evaporated, and the residue was purified using preparative
HPLC to give the title compound (40%) . [0321]
7- (3 ,5-Dimethylisoxazol-4-yl) -8-methoxy-N,N-dimethyl-1- (2- pyridylmethyl) -[1,2,4] riazolo [ , 3-a] quinoxalin-4-amine (Ri = ΝΜβ2, Ar = 2-pyridyl)
A mixture of compound 60 (0.095 mmol) and dimethylamine
(2.0 in methanol) (1.5 ml) was stirred at 80°C in sealed tube for 16 h. The solvent was evaporated under reduced pressure, and the residue was purified by preparative TLC to give the title compound (40%).
[0322]
7- (3,5-Dimethylisoxazol-4-yl) -N-ethyl-8-methoxy-1- (2- pyridylmethyl) -[1,2,4] riazolo [4 , 3-a] quinoxalin-4-amine (Ri = NEt, Ar = 2-pyridyl)
A mixture of compound 60 (0.095 mmol) and ethylamine (2.0 M in THF) (1.5 ml) was stirred at 80°C in sealed tube for 16 h. The. solvent was evaporated under reduced pressure, and the residue was purified by preparative TLC to give the title compound (30%) .
[0323]
Compound 61 : General method for Cl-replacement reaction in compound 58
7-Iodo-8-methoxy-N-methyl-1- (2-pyridylmethyl) - [1 , 2 , 4] triazolo [4 , 3-a] quinoxalin-4-amine (Ri = NMe, Ar = 2- pyridyl)
- Compound 57 (40 g, 114.2 mmol) and 2-pyridylacetic acid (21.8 g, 125.7 mmol) were refluxed in P0C13 (400 ml) for 4 hours. The reaction mixture was cooled to room temperature and poured into crushed ice. The solid was collected by filtration, washed with water and dried under vacuum to give the title compound 58 (34 g, 66%) .
A mixture of compound 58 (0.095 mmol) and methylamine (2 mL, 2.0 M in THF) was stirred at 80°C in sealed tube for 16 h. The reaction mixture was cooled to room temperature, and the residue was triturated in DCM. The solid was collected by filtration, again triturated in water and collected by filtration. The solid was washed with hexane and dried in vacuum to give the title compound (53%) .
1HNMR (400 MHz, OMSO-d6)6: 8.45 (brs d, J = 4.8 Hz, IH) , 8.05 (d, J= 5.2 Hz, IH), 7.79 (dt, J = 7.2, 2.0 Hz, IH), 7.43 (s, 2H) , 7.39 (d, J = 7.6 Hz, IH) , 7.31-7.28 (m, IH) , 5.16 (s, 2H) , 3.60 (s, 3H) , 3.03 (d, J = 4.4 Hz, 3H) , 2.24 (s, 3H) , 2.04 (s, 3H) .
[0324]
7-Iodo-8-methoxy-4-methyls lfanyl-1- (2-pyridylmethyl) - [1,2,4] triazolo [4 , 3-a] quinoxaline (Ri = SMe, Ar = 2-pyridyl)
A mixture of compound 58 (100 mg, 0.22 mmol) and sodium thiomethoxide (15 mg, 0.26 mmol) in DMF was heated at 60°C for 15 h. The reaction mixture was diluted with 5% methanol in DCM. The organic layer was separated, washed with water and brine and dried over Na2S0 . The solvent was evaporated under
reduced pressure, and the crude residue was purified to give the title compound (59%) as a yellow solid.
[0325]
Compound 62 : General method for Suzuki coupling
The preparation of the compound 62 from compound 61 was carried out in a manner similar to that described in the
preparation of compound 33 according to Method D (50-60%) .
[0326]
The following according to Examples were synthesized according to Scheme
[0327]
Table 6
Figure imgf000160_0001
Figure imgf000161_0001
4-carbonitrile (s, 3H)
Figure imgf000162_0001
Figure imgf000163_0001
amine
Figure imgf000164_0001
[4,3- 4.8, 7.2 Hz, IH) , 5.23 a] quinoxalin-7- (s, 2H) , 3.69 (s, 3H) , yi]-3,5- 2.71 (s, 3H) , 2.27 (s, dimethyl- 3H) , 2.06 (s, 3H) isoxazole
[0328]
Scheme 10
Figure imgf000165_0001
[0329]
5- [ (3-Iodo-4-methoxy-anilino)methylene] -2 , 2-dimethyl-1 , 3- dioxane-4 , 6-dione (63)
To a solution of compound 50 (22.0 g, 883 mmol) in
ethanol (120 ml) were added trimethyl orthoformate (10.6 ml, 97.1 mmol) and Meldrums acid (15.2 g, 106 mmol). The resulting mixture was heated to reflux for 2 h, cooled to room
temperature and filtered. The filtrate was washed with ethanol and dried under vacuum to give the title compound 63 (29.0 g, 80%) .
1HNMR (400 MHz, DMSO-dc) δ : 11.15 (d, J = 14.8 Hz, IH) , 8.42 (d, J = 14.4 Hz, IH) , 8.01 (d, J = 2.8 Hz, IH) , 7.56 (dd, J = 6.0, 8.8 Hz, IH) , 7.01 (d, J = 9.2 Hz, IH) , 3.81 (s, 3H) , 1.64 (s, 6H) .
[0330]
7-Iodo-6-methoxy-quinolin-4-ol (64)
Compound 63 (29.0 g, 71.9 mmol) was added in portion wise to boiling diphenyl ether (180 ml) . 10 minutes after
completion of addition, the reaction mixture was cooled to room temperature, diluted with diethyl ether and ethyl acetate (5:1), and filtered. The obtained solid was washed with ethyl acetate and dried under vacuum to give the title compound 64 (76%) .
^NMR (400 MHz , DMSO-d6J δ: 11.67 (brs, 1H) , 8.04 (s, 1H) , 7.86 (t, J = 6.8 Hz, 1H) , 7.44 (s, 1H) , 6.01 (d, J = 7.2 Hz, 1H) , 3.89 (s, 3H) .
[0331]
7-Iodo-6-methoxy-3-nitro-quinolin-4-ol (65)
Nitric acid (7 ml) was added slowly to a solution of compound 64 (19.0 g, 63.1 mmol) in propanoic acid (220 ml) at room temperature, followed by heating to 100°C for 1 h. After cooling with an ice bath, the precipitate was collected by filtration, and washed with pentane to give the title compound 65 (14 g, 65%) as a yellow solid.
1HNMR (400 MHz, OMSO-d6) δ: 12.92 (brs, 1H) , 9.15 (s, 1H) , 8.19 (s, 1H) , 7.58 (s, 1H) , 3.95 (s, 3H) .
[0332]
4-Chloro-7-iodo-6-methoxy-3-nitro-quinoline (66)
A suspension of compound 65 (12.0 g, 34.6 mmol) in POCI3 (50 ml) was refluxed for 16 h. After cooling, the solvent was evaporated in vacuum. The resulting residue was poured into saturated aqueous NaHC03, and the mixture was extracted with DCM, washed with water, and dried over Na2S04. The solvent was evaporated under reduced pressure to give title the compound
66 (80%) .
XHNMR (400 MHz, DMSO-d^ <5; 9.23 (s, 1H) , 8.73 (s, 1H) , 7.56 (s, 1H) , 4.08 (s, 3H) .
[0333]
Compound 67 : General method for amine coupling
A mixture of compound 66 (0.96 mmol) and amine (1.92 mmol) in acetonitrile (5 ml) was heated to 60°C for 2 h. The mixture was cooled to room temperature and extracted with DCM. The organic layer was washed with saturated aqueous NaHC03, water and brine and dried over a2S04. The solvent was
evaporated under reduced pressure to give the title compound 67 (yield 60-70%) .
[0334]
Compound 68 : General method for nitro reduction
To a solution of compound 67 (1.06 mmol) in a mixture of ethanol (5 ml) and HC1 (1 ml) was added SnCl2 2H20 (2.12 mmol). The reaction mixture was heated to 40°C for 1 h. IN NaOH was added thereto, and the mixture was extracted with DCM. The organic layer was washed with water and brine, dried over
Na2S04 and concentrated. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 95:5) to give the title compound 68 (50-60%) .
[0335]
Compound 69: General method for cyclization
Glyoxilic acid (0.21 mmol) was added to a suspension of compound 68 (0.21 mmol) in THF (2 ml), and the mixture was stirred under argon atmosphere for 30 minutes at room
temperature. Diisopropylethylamine (0.42 mmol) and HATU (0.23 mmol) were added thereto and the mixture was stirred continued another 2 h at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and the solution was washed with water and brine, dried over Na2S04, filtered and concentrated. The solvent was evaporated under reduced pressure to give the title compound 69 (30-50%) .
[0336]
Compound 70: General method for Suzuki coupling
The preparation of the compound 70 from compound 69 was carried out in a manner similar to that described in the preparation of compound 33 according to Method C (50-60%) .
[0337]
The following compounds of Examples were synthesized according to Scheme 10: [0338] Table 7
Figure imgf000168_0001
Figure imgf000169_0002
Figure imgf000169_0001
c] quinolin-2-one 3H) 8-(3,5-, (CDC13) : δ 9.18 (s, dimethylisoxazol- 1H) , 8.51 (s, 1H) , 4-yl)-l-[ (4- 7.96 (s, 1H) , 7.49 (s, fluorophenyl ) meth 1H) , 7.36-7.33 (m,
10.8 yl] -9-methoxy- 2H) , 7.16 (t, J = 8.4 pyrazino [2,3- Hz, 2H) , 5.79 (brs, c] quinolin-2-one 2H) , 3.23 (s, 3H) ,
2.33 (s, 3H) , 2.17 (s, 3H)
1- (CDCI3) : δ 9.14 (s,
(cyclopropylmethy 1H) , 8.44 (s, 1H) , 1) -8- (3, 5- 8.27 (s, 1H) , 8.01 (s, dimethylisoxazol- 1H) , 4.70 (d, J = 5.2
10.9
4-yl) -9-methoxy- Hz, 2H) , 4.03 (s, 3H) , pyrazino [2,3- 2.41 (s, 3H) , 2.26 (s, c] quinolin-2-one 3H.) , 1.48-1.45 (m,
1H) , 0.78-0.76 (m, 4H)
8- (3,5- (CDCI3) : δ 9.02 (s, dimethylisoxazol- 1H) , 8.69 (s, 1H) , 4-yl) -9-methoxy- 8.20 (s, 1H) , 7.85 (s, l-[ (4- 1H) , 7.27 (d, J = 8.8
10.10 methoxyphenyl) met Hz, 2H) , 6.85 (d, J = hyl] pyrazino [2,3- 8.8 Hz, 2H) , 5.61 (s, c] quinolin-2-one 2H) , 4.04 (s, 3H) ,
3.76 (s, 3H) , 2.35 (s, 3H) , 2.20 (s, 3H)
[0339]
Scheme
Figure imgf000171_0001
[0340]
Methyl 4-bromo-2 , 6-difluoro-3-nitro-benzoate (72)
Concentrated sulfuric acid (26.52 ml, 498 mmol) was added drop wise to fuming nitric acid (15.0 mL, 318.7 mmol) at 0°C. After stirring for 5 min at 0°C, methyl 4-bromo-2,6- difluorobenzoate 71 (25.0 g, 99.6 mmol) was added portion wise thereto. The ice bath was removed, and the reaction mixture was stirred for 1 h at ambient temperature. The mixture was poured into ice-water, and the resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give the title compound 72 (29.0 g, 99% yield) as a white . solid.
1HNMR(400 MHz, DMSO-d6) : δ 8.10 (dd, J = 2.0 Hz, 2.4 Hz, 1H) , 3.92 (s, 3H) .
[0341]
Methyl 2-amino-4-bromo-6-fluoro-3-nitro-benzoate (73)
To a solution of compound 72 (29.0 g, 97.98 mmol) in methanol (70.0 mL) was added 29% aqueous solution of ammonium hydroxide (15 mL, 91.22 mmol). After stirring for 16 h at ambient temperature, the reaction mixture was concentrated in vacuo. The solid was triturated with methanol and collected by filtration, and dried in vacuo to give the title compound 73 (22 g, 76% yield) as a light yellow solid.
1HNMR(400 MHz, DMSO-d6) : δ 7.12 (brs, 2H) , 7.04 (d, J = 10 Hz, 1H) , 3.3.86 (s, 3H) .
[0342]
Methyl 2-amino-4-bromo-6-methoxy-3-nitro-benzoate (74)
To a solution of sodium methoxide (5.50 g, 102 mmol) in methanol (100 mL) was added compound 73 (22.0 g, 75.0 mmol) at 0°C. After complete addition, ice bath was removed, and the reaction mixture was stirred at ambient temperature for 4 h and then quenched with IN aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give the title compound 74 (18.0 g, 78% yield) as a yellow solid.
1HNMR(400 MHz, DMSO-d6) : δ 6.74 (brs, 1H) , 6.30 (brs, 2H) 3.81
(s, 3H) , 3.79 (s, 3H) .
[0343]
Methyl 2- [bis (tert-butoxycarbonyl) amino] -4-bromo-6-me hoxy-3- nitro-benzoate (75)
DMAP (14.4 g, 118 mmol) was added to a solution of compound 74 (18.0 g, 59.0 mmol) in tetrahydrofuran (170 mL) followed by drop wise addition of di-tert-butyl dicarbonate (27.1 g, 118 mmol) in tetrahydrofuran (70 mL) at room
' temperature. The resulting mixture was stirred for 6h and
quenched with water followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude material was purified on
silica gel column to give . the title compound 75 (24.0 g, 80%). 1HNMR (400 MHz, DMSOdi) : δ 7.89 (s, 1H) , .3.95 (s, 3H) , 3.78 (s, 3H) , 1.31 (s, .18H) .
[0344]
Methyl 4-amino-2- (tert-butoxycarbonyl) amino-6-methoxy-3-nitro- benzoate (76) A dry three-neck round bottle flask, equipped with a magnetic stirrer bar, septum, and a condenser with a nitrogen inlet-outlet, was charged with compound 75 (5.0 g, 9.9 mmol) , benzophenone imine (2.6 g, 11.8 mmol), Pd2(dba)3 (1.0 g, 0.99 mmol), ((+)-BINAP (1.2.3 g, 1.98 mmol) and the sodium tert- butoxide (1.5 g, 15.6 mmol). Dry toluene (50 mL) was added, and the resulting mixture was heated to 100°C for 6 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (3x100 mL) . The combined organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude limine adduct was dissolved in THF, and 1.0 N HC1 (32 ml) was added thereto at 0°C. The resulting mixture was stirring at room temperature for 2h. The reaction mixture was neutralized with NaHC03 solution and extracted with ethyl acetate. The organic extract was washed with brine and dried over sodium sulfate. The solvent was removed, and the crude material was purified on silica gel column to give the title compound 76 (2.1 g, 63%)
[0345]
Methyl 3 , 4-diamino-2- (tert-butoxycarbonyl) amino-6-methoxy- benzoate (77)
10% Palladium on activated carbon (0.8 g) was added to a solution. of compound 76 (2.5 g, 5.0 mmol) in methanol, and the mixture was hydrogenated under hydrogen atmosphere for 16 h. The reaction mixture was filtered through celite pad and washed thoroughly with methanol-dichloromethane . The filtrate was concentrated to give the crude title compound 77 (2.0 g) which was directly used in the next step.
[0346]
Compound 79: Pyrazine ring formation
General procedure: Dicarbonyl compound 78 (4.8 mmol) was added to a solution of compound 77 (2.4 mmol) in ethanol, and the resulting mixture was refluxed for 3 h, cooled to room
temperature and concentrated. The obtained residue was dissolved in ethyl acetate, and the solution was washed with water and brine and dried over sodium sulfate. The organic layer was concentrated, and the crude material was purified on silica-gel column chromatography to give the title compound 79.
[0347]
Methyl 5- (tert-butoxycarbonylamino) -7-methoxy-quinoxaline-6- carboxylate (R = H)
This compound was synthesized by the general procedure as describe above for compound 79 (45%) ..
1HNMR (400 MHz , DMSO-d6) : δ 9.15 (s, 1H) , 8.98 (s, 1H) , 8.82 (s, 1H) , 7.38 (s, 1H), 3.96 (s, 3H) , 3.79 (s, 3H) , 1.42 (s, 9H)
[0348]
Methyl 5- (tert-butoxycarbonylamino) -7-methoxy-2 , 3-dimethyl- quinoxaline-6-carboxylate (R = Me)
This compound was synthesized by the general procedure as describe above for compound 79 (40%).
^NMR (400 MHz, CDC13) : δ 8.57 (brs, 1H) , 7.05 (s, 1H) , 3.94 (s, 3H) , 3.93 (s, 3H) , 2.70 (s, 6H) , 1.42 (s, 9H)
[0349]
Compound 80 : Hydrolysis of ester
General procedure: Compound 79 (1.5 mmol) was dissolved in
THF-methanol, and a solution of sodium hydroxide (6.0 mmol) in water was added thereto. The resulting mixture was heated at 80°C for 16h, cooled to room temperature and concentrated. The residue was diluted with 5 ml of water, and the mixture was extracted with diethyl ether. The aqueous layer was carefully acidified with dilute HC1 to pH ~6 and extracted with 5%
methanol in dichloromethane . The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound 80 which was directly used in next step .
[0350]
5- ( tert-Butoxycarbonylamino) -7-methoxy-quinoxaline-6- carboxylic acid (R = H) This compound was synthesized by the general procedure as describe above for compound 80
[0351]
5- (tert-Butoxycarbonylamino) -7-methoxy-2 , 3-dimethy1- quinoxaline-6-carboxylic acid (R = Me)
This compound was synthesized by the general procedure as describe above for compound 80
[0352]
Compound 81 : Amide formation
General procedure: Compound 80 (1.2 mmol) was dissolved in THF (6 mL) , and to the solution were added HOBt (3.0 mmol), EDCI (3.0 mmol) and N M (6.0 mmol) . The resulting mixture was stirred at room temperature for 3 h and then cooled at 0°C.
N¾ gas was purged for 10 min to the reaction mixture, and the mixture was stirred for 3 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was removed, and the crude residue was purified by silica gel chromatography to give the title compound 81.
[0353]
tert-Butyl N- (6-carbamoyl-7-methoxy-quinoxalin-5-yl) carbamate (R = H)
This compound was synthesized by the general procedure as describe above for compound 81.
XHNMR (400 MHz, DMSO-d6) : δ 8.88 (d, J = 1.6 Hz, 1H) , 8.81 (d, J= 1.6 Hz, 1H) , 8.62 (s, 1H) , 7.63 (s, 1H) , 7.43 (s, 1H) , 7.40 (s, 1H) , 3.96 (s, 3H) , 1.39 (s, 9H) .
[0354]
tert-Butyl N- (6-carbamoyl-7-methoxy-2 , 3-dimethyl-quinoxalin-5- yl) carbamate (R = Me)
This compound was synthesized by the general procedure as describe above for compound 81.
1HNMR (400 MHz, DMSO-d6) : δ 8.42 (s, 1H) , 7.56 (s, 1H) , 7.39 (s, 1H) , 7.30 (s, 1H) , 3.90 (s, 3H) , 2.65 (s, 3H) , 2.62 (s, 3H) , 1.40 (s, 9H) . [0355]
Compound 82 : BOC-deprotection
General procedure: Trifluoroacetic acid (1 ml) was added to a solution of compound 81 (0.6 mmol) in dichloromethane (5 ml) at 0°C. After stirring for 6 h at room temperature, the reaction mixture was concentrated. The residue was dissolved in dichloromethane, and the solution was washed with saturated NaHC03 solution. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The crude material was purified on silica-gel column to give the title compound 82.
[0356]
5-amino-7-methoxy-quinoxaline-6-carboxamide (R = H)
The compound was synthesized by the general procedure as describe above for compound 82.
^ MR (400 MHz, DMSO-d6) : δ 8.83 (d, J = 1.6 Hz, 1H) , 8.60 (d, J = 1.6 Hz, 1H) , 7.74 (brs, 1H) , 7.57 (s, 1H) , 7.51 (brs, 2H) , 6.63 (s, 1H) , 3.95 (s, 3H) .
[0357]
5-amino-7-methoxy-2 , 3-dimethyl-quinoxaline-6-carboxamide (R = Me)
This compound was synthesized by the general procedure as describe above for compound 82.
[0358]
Compound 83 : Quinazolinone ring ormation
General procedure: A mixture of compound 82 (0.16 mmol), substituted benzaldehyde (0.24 mmol), p-toluenesulfonic acid (15 mg) and sodium hydrogen sulfite (0.24 mmol) in N,N- dimethyl acetamide (4 mL) was heated with stirring at 140°C for 16h. After cooling to room temperature, the reaction mixture was poured into aqueous NaHC03 solution and extracted three times with 5% MeOH in ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude material was purified on silica gel column to give the title compound 83 (30 - 50%) . [0359]
The following compounds of Examples were synthesized according to Scheme 11:
[0360]
Table 8
Example Structure IUPAC Name 1HNMR (400 MHz)
2- [4- (2- (DMSO-d5) : δ 12.64 hydroxyethoxy (brs, 1H) , 9.00 (d, J
Figure imgf000177_0001
)-3,5- = 1.2 Hz, 1H) , 8.97 dimethyl- (d, J = 2.0 Hz, 1H) , phenyl ] -5- 8.06 (s, 2H) , 7. 33
11.1
methoxy-3H- (s, 1H) , 4.91 (t, J = pyrazino [2,3- 6.0 Hz, 1H) , 4.04 (s, h] quinazolin- 3H) , 3.88-3.86 (m, 4-one 2H) , 3.76-3.72 (m,
2H) , 2.33 (s, 6H)
5-methoxy-2- (DMSO-di) : δ 12.69
[4-(2- (brs, 1H) , 8.99 (d, J
Figure imgf000177_0002
methoxyethoxy = 2.0 Hz, 1H) , 8.95
)-3,5- (d, J = 2.0 Hz, 1H) , dimethyl- 8.06 (s, 2H) , 7.30 (s,
11.2
phenyl] -3H- 1H) , 4.03 (s, 3H), pyrazino [2 , 3- 3.99-3.97 (m, 2H) , h] quinazolin- 3.68-3.66 (m, 2H) , 4-one 3.35 (s, 3H) , 2.34- 2.32 (m, 6H)
2- [4- (2- (DMSO-di) : δ 12.72 ethoxyethoxy) (brs, 1H), 9.0 (s,
Figure imgf000177_0003
-3,5- . 1H) , 8.97 (s, 1H),
dimethyl- 8.06 (s, 2H) , 7.32
11.3 phenyl ] -5- 1H) , 4.04 (s, 3H),
methoxy-3H- 3.99-3.97 (m, 2H) , pyrazino [2,3- 3.71-3.69 (m, 2H) , h] quinazolin- 3.56-3.51 (m, 2H) , 4-one 2.35 (s, 6H) , 1.16 J = 6,8 Hz, 3H)
5-methoxy-2- (DMSO-d5) : δ 12.55
[4-(2- (brs, 1H), 8.03 (s, methoxyethoxy 2H) , 7.23 (s, 1H), )-3,5- 3.98-3.96 (m, 5H) , dimethyl- 3.68-3.65 (m, 2H) ,
11.4
phenyl] -8, 9- 3.35 (s, 3H) , 2.74 (s, dimethyl-3H- 3H) , 2.70 (s, 3H) , pyrazino [2,3- 2.34 (s, 6H)
h] quinazolin- 4-one
[0361]
Scheme 12
Figure imgf000178_0001
[0362]
Methyl 4-acetyl-2- [bis (tert-butoxycarbonyl) amino] -6-methoxy-3- nitro-benzoate (84)
A solution of compound 75 (2.0 g, 3.94 mmol) , 1- ethoxyvinyltributyltin (1.5 g, 4.73 mmol) and PdCl2 (PPh3)2 (500 mg, 0.71 mmol) in 50 ml of 1,4-dioxane was refluxed for 5 h under argon atmosphere. The dark brown reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude material was dissolved in tetrahydrofuran (50 ml) , and IN HCI (1.0 mL) was added thereto. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with saturated solution of NaHC03. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed, and the crude material was purified on silica-gel column to give the title compound 84 (1.3 g 70%).
1HN R (400 MHz, DMSO-d6) : δ 7.65 (s, 1H) , 4.01 (s, 3H) , 3.8 (s,
3H) , 2.67 (s, 3H) , 1.25 (s, 18H) .
[0363]
Methyl 2- [bis (tert-butoxycarbonyl) amino] -4- [N-hydroxy-C- methyl-carbonimidoyl] -6-methoxy-3-nitro-benzoate (85)
A mixture of compound 84 (1.3 g, 2.76 mmol) and NH2OH HC1 (229 mg, 3.3 mmol) in 20 ml of MeOH was refluxed for 5h. After cooling to room temperature, the reaction mixture was
concentrated in vacuo, and the residue was dissolved in ethyl acetate. The solution was washed with brine, dried over sodium sulfate and concentrated to give the crude title compound 85 (1.1 g) which was used in the next step without purification.
[0364]
Methyl 3-amino-2- [bis (tert-butoxycarbonyl) amino] -4- [N-hydroxy- C-methyl-carbonimidoyl] -6-methoxy-benzoate (86)
Compound 85 (1.1 g) was dissolved in methanol, and 500 mg of Pd/C (10% w/w) was added thereto. The reaction mixture was stirred under H2 atmosphere for 8 h, filtered through a celite pad and washed with MeOH. The combined filtrate was
concentrated under reduced pressure to give the title compound 86 (800 mg) which was used in the next step without
purification.
[0365]
Methyl 7- [bis (tert-butoxycarbonyl) amino] -5-methoxy-3-methy1- lH-indazole-6-carboxylate (87)
Compound 86 (800 mg, 1.77 mmol) was dissolved in
dichloromethane, and triethylamine (0.8 ml, 7.1 mmol) was added thereto. The reaction mixture was cooled to 0°C, and methanesulfonyl chloride (0.163 mL, 2.12. mmol) was added dropwise thereto. The resulting reaction mixture was stirred for 20 min, quenched with saturated NaHC03 solution and diluted with dichloromethane . The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified on silica-gel column to give the title compound 87 (500 mg) . 1HN R (400 MHz, DMSO-d6) : δ 12.99 (s, 1H) , 7.27 (s, 1H) , 3.83
(s, 3H) , 3.75 (s, 3H) , 2.47 (s, 3H) , 1.25 (s, 18H) .
[0366]
Compound 88 : Alkylation
General procedure: NaH (50 mg, 1.4 mmol, 60% mineral oil) was added to a solution of compound 87 (0.92 mmol) in anhydrous N, N-dimethylformamide (5 ml) at 0°C. After stirring for 30 min, the corresponding AriCH2Br (Arx = benzyl, 2-pyridyl, 1.4 mmol) was added thereto, and the mixture was stirred for 1 h at room temperature. The reaction was quenched with saturated NH4C1 solution and diluted with ethyl acetate (20 ml) . The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified on silica gel column to give the title compound
88.
[0367]
Methyl l-benzyl-7- [bis (tert-butoxycarbonyl) amino] -5-methoxy-3- methyl-indazole-6-carboxylate (Ari = phenyl)
This compound was synthesized by the general procedure as describe above for compound 88 (50%) .
1HNMR (400 MHz, DMSO-d6) : δ 7.39 (s, 1H) , 7.29 - 7.22 (m, 3H) , 6.95 - 6.93 (m, 2H) , 5.42 (s, 2H) , 3.86 (s, 3H) , 3.74 (s, 3H) , 2.49 (s, 3H) , 1.25 (s, 18H) .
[0368]
Methyl 7- [bis (tert-butoxycarbonyl) amino] -5-methoxy-3-methyl-l- (2-pyridylmethyl) indazole-6-carboxylate (Ari = 2-pyridyl)
This compound was synthesized by the general procedure as describe above for compound 88 (45%).
1HNMR (400 MHz, DMSO-d6) δ : 8.47 (d, J = 4.0 Hz, 1H) , 7.68 - 7.64 (m, 1H) , 7.42 (s, 1H) , 7.25 - 7.22 (m, 1H) , 6.48. (d, J = 7.6 Hz, 1H) , 5.51 (s, 2H) , 3.87 (s, 3H) , 3.73 (s, 3H) , 2.52 (s, 3H) , 1.25 (s, 18 H) .
[0369]
Compounds 89 and 90:
General procedure: Compound 88 (0.6 mmol) was dissolved in
THF-methanol (1:1, 6 ml), and a solution of sodium hydroxide (1.8 mmol) in water (2 ml) was added thereto. The resulting mixture was heated at 80°C for 16h. After cooling to room temperature, the reaction mixture was concentrated, and the residue was diluted with 3 ml of water, and the mixture was extracted with diethyl ether. The aqueous layer was carefully acidified with dilute HC1 to pH ~6 and extracted with 5%
methanol in dichloromethane (three times) . The combined
organic layer was washed with brine, and dried over sodium sulfate. The solvent was removed, and the crude material was dissolved in tetrahydrofuran (6 mL) followed by addition of HOBt (1.2 mmol), EDCI (1.2 mmol) and N M (4.0 mmol)
respectively. The resulting mixture was stirred at room
temperature for 3h and then cooled at 0°C . NH3 gas was purged for 10 min, and the mixture was stirred for 3h at room
temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed, and the crude residue was purified by silica gel column chromatography to give a mixture of compounds 89 and 90.
[0370]
Compound 91 :
General procedure: Trifluoroacetic acid (1 ml) was added to the mixture of compounds 89 and 90 (200 mg) in dichloromethane (5 ml) at 0°C. After stirring for 6h at room temperature, the reaction mixture was concentrated. The residue was dissolved in dichloromethane, and the solution was washed with saturated NaHC03 solution and brine, dried over sodium sulfate, and concentrated. The crude material was purified on silica-gel column to give the title compound 91. [0371]
7-Amino-1-benzy1-5-methoxy-3-methy1-indazole-6-carboxamide (Ar = phenyl)
This compound was synthesized by the general procedure a describe above for compound 91.
1HNMR (400 MHz , DMSO-d6) : δ 7.60 (brs, 1H) , 7.39 (brs, 1H) , 7.25 - 7.19 (m, 3H) , 7.02 - 7.01 (m, 2H) , 6.44 (s, 1H) , 6.22 (s, 2H) , 5.72 (s, 2H) , 3.79 (s, 3H) , 2.38 (s, 3H) .
[0372]
7-Amino-5-methoxy-3-methyl-l- (2-pyridylmethyl) indazole-6- carboxamide (Ari = 2-pyridyl)
This compound was synthesized by the general procedure a describe above for compound 91.
"""HNMR (400 MHz , DMSO-d6) : δ 8.52 (d, J = 5.2 Hz, 1H) , 7.78 - 7.74 (m, 1H) , 7.60 (brs , 1H) , 7.39 (brs, 1H) , 7.32 - 7.28 (m, 1H)', 7.11 (d, J = 7.6 Hz, 1H) , 6.68 (brs, 2H) , 6.42 (s, 1H) , 5.73 (s, 2H) , 3.76 (s, 3H) , 2.34 (s, 3H) .
[0373]
Compound 92 : Quinazolinone ring formation
The preparation of compound 92 from compound 91 was carried out in a similar manner to that described for the preparation of compound 83 (30%-50%) .
[0374]
The following compounds of Examples were synthesized according to Scheme
[0375]
Table 9
Figure imgf000182_0001
Figure imgf000183_0001
β-one 3H) , 2.23 (s, 6H) l-benzyl-8- (DMSO-d6) : δ 12.15 [4-(2- (brs, 1H) , 7.79 (s, hydroxyethoxy 2H) , 7.28-7.19 (m,
Figure imgf000184_0001
)-3,5- 3H) , 7.12-7.10 (m, dimethyl- 3H) , 6.29 (s, 2H) , phenyl ] -5- 4.90 (s, 1H) , 3.89 methoxy-3- (s, 3H) , 3.84-3.81 methyl-7H- (m, 2H) , 3.72-3.70 pyrazolo [4,3- (m, 2H) , 2.52 (s, h] quinazolin- 3H) , 2.25 (s, 6H) 6-one
5-methoxy-8- (D SO-d5) : δ 12.15 [4-(2- (brs, 1H) , 8.56 (d, J methoxyethoxy = 5.2 Hz, 1H) , 7.78
Figure imgf000184_0002
)-3,5- (s, 2H) , 7.62 (t, J = dimethyl- 8 Hz, 1H) , 7.24-7.21 phenyl] -3- (m, 1H) , 7.16 (s, methyl-1- (2- 2H). , 6.59 (d, J = pyridylmethyl 8.0Hz, 2H) , 3.94-3.93 ) -7H- (m, 2H) , 3.90 (s, pyrazolo [4,3- 3H) , 3.65-3.63 (m, h] quinazolin- 2H) , 3.45 (s, 3H) ,
6-one 2.56 (s, 3H) , 2.22
(s, 6H)
8- [4- (2- (DMSO-d5) : δ 12.20 hydroxyethoxy (brs, 1H) , 8.55 (d, J )-3,5- . = 4.8 Hz, 1H) , 7.77
Figure imgf000184_0003
dimethyl- (s, 2H) , 7.62 (dt, J phenyl ] -5- = 7.6, 1.6 Hz, 1H) , methoxy-3- 7.23-7.59 (m, 1H) , methyl-1- (2- 7.14 (brs, 1H) , 6.59 pyridylmethyl (d, J = 8.0 Hz, 1H) , ) -7H- 6.29 (s, 2H) , 4.89 pyrazolo [4,3- (t, J = 5.2 Hz, 1H) , h] quinazolin- . 3.90 (s, 3H) , 3.82
6-one (t, J = 4.8 Hz, 2H) ,
3.71 (q, J = 4.8 Hz,
2H) , 2.55 (s, 3H) ,
2.26 (s, 6H)
[0376]
Scheme
Figure imgf000185_0001
[0377]
Methyl 2- [bis (tert-butoxycarbonyl) amino] -6-methoxy-4- (methylamino) -3-nitro-benzoate (93)
Potassium carbonate (2.73 g, 19.80 mmol) and cuprous chloride (1.56 g, 15.84 mmol) were added to compound 75 (10.0 g, 19.80 mmol) in dry N, N-dimethylformamide (100 mL) in sealed tube. After stirring for 5-10 min, methyl amine (9.90 mL, 2.0M in tetrahydrofuran, 19.80 mmol) was added drop-wise thereto. The resultant solution was stirred for 16h at 100°C and then poured into ice water. The solid was filtered, washed with water and dried in vacuo to give the title compound 93 (5.0 g, 55%. yield) as a yellow solid.
1HNMR(400 MHz, DMSO-d6) : δ 7.80 (d, J = 4.8Hz, IH) , 6.37 (s, 1H) , 3.91 (s, 3H) , 3.69 (s, 3H) , 2.96 (d, J = 4.8 Hz, 3H) , 1.30 (s, 18H) .
[0378]
Methyl 3-amino-2- [bis (tert-butoxycarbonyl) amino] -6-methoxy-4- (methylamino)benzoate (94)
A mixture of compound 93 (5.0 g, 10.98 mmol) and 10% Pd/C (500 mg) in methanol (50 mL) was stirred under hydrogen atmosphere at room temperature for 16h. The catalyst was then removed by filtration using celite. The filtrate was
concentrated in vacuo, and the crude residue was purified by flash column chromatography to give the title compound 94 (4.0 g,. 85%) .
XHNMR (400 MHz, DMSO-d6) : δ 6.10 (s, 1H) , 5.40 (d, J = 5.2Hz, 1H), 3.95 (s, 2H) , 3.70 (s, 3H) , 3.60 (s, 3H) , 2.78 (d, J = 5.2 Hz, 3H) , 1.32 (s, 18H) .
[0379]
Methyl 4- [bis (tert-butoxycarbonyl) amino] -6-methoxy-l-methyl-2- oxo-3H-benzimidazole-5-carboxylate (95)
Triphosgene (3.63 g, 12.23 mmol) was added to a mixture of compound 94 (4.0 g, 9.41 mmol) and DIPEA (3.28 mL, 18.82 mmol) in tetrahydrofuran (75 mL) at 0°C. After complete addition, the resulting mixture was stirred at same
temperature for 30 min, quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound 95 (3.75 g, 88%) .
^NMR (400 MHz, DMSO-d5) : δ 11.18 (br s, 1H) , 6.96 (s, 1H) , 3.81 (s, 3H), 3.68 (s, 3H) , 4.43 (br s, 3H) , 1.30 (s, 18H) .
[0380]
4--toino-6-methoxy-l-methyl-2-oxo-3H-benzimidazole-5-carboxylic acid (96)
To a solution of compound 95 (1.0 g, 2.21 mmol) in tetrahydrofuran (10 mL) was added NaOH (117 mg, 4.43 mmol) in water (2 mL) and methanol (3 mL) . The mixture was warmed to 50°C and stirred for 14h. After cooling to room temperature, the reaction mixture was concentrated, the residue was diluted with 5 ml of water, and the mixture was extracted with diethyl ether. The aqueous layer was carefully acidified with dilute HC1 to pH ~6 and extracted with 5% methanol in dichloromethane (three times) . The combined organic layer was washed with brine, and dried over sodium sulfate. The crude material (470 mg) was dissolved in dichloromethane (6 mL), and TFA (2 mL) was added thereto. The reaction was stirred at room
temperature for overnight. The solvent was removed under vacuo to give the title compound 96 (400 mg, 98%).
1HN R (400 MHz, DMSO-d6) : δ 12.21 (brs, 2H) , 10.21 (brs, 2H) , 6.26 (s, 1H) , 3.82 (s, 3H) , 3.23 (s, 3H) .
[0381]
4-Amino-6-methoxy-1-me hyl-2-oxo-3H-benzimidazole-5- carboxamide (97)
The preparation of compound 97 from compound 96 was carried out in a similar manner to that described for the preparation of compound 81 (75%).
1HNMR (400 MHz, DMSO-d6) : δ 10.15 (brs, 1H) , 7.55 (brs, 1H) , 7.18 (brs, 1H) , 6.46 (brs, 2H) , 6.20 (s, IH) , 3.82 (s, 3H) , 3.23 (s, 3H) .
[0382]
Compound 98 : Quinazolinone ring formation
The preparation of compound 98 from compound 97 was carried out in a similar manner to that described for the preparation of compound 83 (30%-50%) .
[0383]
The following compounds of Examples were synthesized according to Scheme 13:
[0384]
Table 10
Figure imgf000187_0001
h] quinazoline
-2 , 6-dione
o 0 5-methoxy-8- (D S0-d5) : δ 11.81 r iT— [4-(2- (brs, l.H) , 11.42 (brs, methoxyethoxy 1H) , 7.91 (s, 2H) ,
)-3,5- 6.90 (s, 1H) , 3.90- dimethyl- 3.87 (m, 2H) , 3.88 (s,
13.2 phenyl ] -3- 3H) , 3.65-3.62 (m,
methyl-1 , 7- 2H) , 3.37 (s, 3H), dihydroimidaz 3.34 (s, 3H) , 2.30 (s, o[4,5- 6H)
h] quinazoline
-2 , 6-dione
8- (4-hydroxy- (DMSO-di) : δ 11.56
3 , 5-dimethyl- (brs, 1H) , 11.34 (s, phenyl ) -5- 1H) , 8.92 (brs, 1H) ,
Figure imgf000188_0001
methoxy-3- 8.09 (s, 2H) , 6.86 (s,
13.3 methyl-1 , 7- 1H) , 3.88 (s, 3H) ,
dihydroimidaz 3.36 (s, 3H) , 2.24 (m, o[4,5- 6H)
h] quinazoline
-2, 6-dione
[0385]
Scheme 14
Figure imgf000188_0002
[0386] Compound 99: Alkylation
General procedure: NaH (8.86 mmol) was added at 0°C to a solution of compound.95 (4.43 mmol) in dry N,N- dimethylformamide followed by dropwise addition of
corresponding AriCH2Br (Ari = benzyl, 2-pyridyl, 4.87 mmol). The resulting mixture was stirred for 30 min at room
temperature, and then poured into ice water. The solid was filtered and dried to give the title compound 99.
[0387]
Methyl 3-benzyl-4- [bis (tert-butoxycarbonyl) amino] -6-methoxy-l- methyl-2-oxo-benzimidazole-5-carbox late (Ari = phenyl)
The compound was synthesized by the general procedure as describe -above for compound 99.
1HNMR (400 MHz , DMSO-d6) : δ 7.30-7.26 (m, 3H) , 7.23-7.21 (m, 1H) , 7.14 (s, 1H) , 7.03 (d, J= 7.2Hz, 1H) , 4.95 (s, 2H) , 3.85 (s, 3H) , 3.45 (s, 3H) , 3.34 (s, 3H) , 1.17 (s, 18H) .
[0388]
Me hyl 4- [bis (tert-bu oxycarbonyl) amino] -6-methoxy-1-methyl-2- oxo-3- (2-pyridylmethyl) benzimidazole-5-carboxylate (Ari = 2- pyridyl)
The compound was synthesized by the general procedure as describe above for compound 99.
1HNMR (400 MHz, DMSO-d6) : δ 8.44 (d, J = 5.2Hz, 1H) , 7.70 (dt, J = 8.0, 2.0Hz, 1H) , 7.24-7.21 (m, 1H) , 7.15 (s, 1H) , 6.95 (d, J = 7.6Hz, 1H) , 5.05 (s, 2H) , 3.85 (s, 3H) , 3.65 (s, 3H) , 3.44 (s, 3H) , 1.17 (s, 18H) .
[0389]
Compound 100 : BOC deprotection
General procedure: The preparation of compound 100 from compound 99 was carried out in a similar manner to that described for the preparation of compound 82.
[0390]
Methyl 4-amino-3-benzyl-6-methoxy-1-methyl-2-oxo- benzimidazole-5-carboxylate (Ari = phenyl) XH NMR(400 MHz, DMSO-d6) : δ 7.32-7.28 (m, 2H) , 7.25-7.23 (m, 1H) , 7.17 (d, J = 7.2Hz, 2H) , 6.36 (s, 1H) , 5.26 (s, 2H) , 5.17 (s, 2H) , 3.74 (s, 3H) , 3.72 (s, 3H) , 3.18 (s, 3H) .
[0391]
Methyl 4-amino-6-methoxy-1-methyl-2-oxo-3- (2- pyridylmethyl)benzimidazole-5-carboxylate (Ari = 2-pyridyl)
1HNMR(400 MHz, DMSO-dS) : δ 8.53 (d, J = 4.4Hz, 1H) , 7.83 (dt, J = 7.6, 1.6Hz, 1H), 7.37-7.33 (m, 2H) , 6.34 (s, 1H) , 5.83 (s, 2H) , 5.25 (s, 2H), 3.74 (s, 6H) , 3.30 (s, 3H) .
[0392]
Compound 101 : Ester hydrolysis
General procedure: The preparation of compound 101 from
compound 100 was carried out in a similar manner to that described for the preparation of compound 80.
[0393]
4-Amino-3-benzy1-6-methoxy-1-methy1-2-oxo-benzimidazole-5- carboxylic acid (Ari = phenyl)
1HNMR(400 MHz, DMS0-d6) : δ 12.50 (br s, 1H) , 7.31-7.28 (m, 3H) , 7.24-7.23 (m, 1H) , 7.18-7.16 (m, 1H) , 6.32 (s, 1H) , 5.97 (s, 2H), 5.25 (s, 2H), 3.81 (s, 3H) , 3.31 (s, 3H) .
[0394]
4-Amino-6-methoxy-1-methy1-2-oxo-3- (2- pyridylmethyl)benzimidazole-5-carboxylic acid (A i = 2-pyridyl)
1HNMR(400 MHz, DMS0-d6) : δ 12.2 (br s, 1H) , 8.53 (d, J= 4.0Hz, 1H) , 7.82 (dt, J = 8.0, 2.0Hz, 2H) , 7.37-7.32 (m, 2H) , 6.35 (s 1H) , 6.29 (br s, 1H) , 5.26 (s, 2H) , 3.80 (s, 3H) , 3.30 (s, 3H)
[0395]
Compound 102 : Amide formation
General procedure: The preparation of compound 102 from
compound 101 was carried out in a similar manner to that described for the preparation of compound 81.
[0396]
4-Amino-3-benzyl-6-methoxy-1-methyl-2-oxo-benzimidazole-5- carboxomide (Ari = phenyl) 1HNMR(400 MHz/ DMSO-d6) : δ 7.51 (br s, 1H) , 7.31-7.28 (m, 3H) , 7.24-7.23 (m, 1H) , 7.18-7.16 (m, 2H) , 6.32 (s, 1H) , 5.97 (s, 2H) , 5.25 (s, 2H) , 3.81 (s, 3H) , 3.31 (s, 3H) .
[0397]
4-Amino-6-methoxy-l-methyl-2-oxo-3- (2- pyridylme hyl) benzimidazole-5-carboxomide (Ari = 2-pyridyl)
1HNMR(400 MHz, DMSO-d6) : δ 8.53 (d, J = 4.8Hz, 1H) , 7.8 (dt, J = 7.6, 1.2Hz, 1H) , 7.52 (br s, 1H) , 7.35-7.32 (m, 3H) , 6.55
(br s, 2H) , 6.31 (s, 1H) , 5.26 (s, 2H) , 3.81 (s, 3H) , 3.30 (s, 3H) .
[0398]
Compound 103 : Quinazolinone ring formation
The preparation of compound 103 from compound 102 (Arx = phenyl, 2-pyridyl) was carried out in a similar manner to that described for the preparation of compound 83.
[0399]
The following compounds of Examples were synthesized according to Scheme 14:
[0400]
Table 11
Figure imgf000191_0001
l-benzyl-5- (DMSO-d6) : δ 11.95 methoxy-8- (4- (brs, 1H) , 7.62 (s, methoxy-3, 5- 2H) , 7.30-7.26 (m,
Figure imgf000192_0001
dimethyl- 2H) , 7.23-7.19 (m,
14.2 phenyl ) -3- 3H) , 7.02 (s, 1H), methyl-7H- 5.66 (s, 2H) , 3.92 imidazo [4,5- (s, 3H), 3.67 (s, h] quinazoline 3H) , 3.46 (s, 3H) , -2 , 6-dione 2.19 (s, 6H)
l-benzyl-5- (DMSO-d5) : δ 11.95 methoxy-3- (brs, 1H), 10.55 methyl-8- (5- (brs, 1H) , 7.52 (s,
Figure imgf000192_0002
methyl-3-oxo- 1H) , 7.45 (s, 1H),
4H-1, 4- 7.26-7.18 (m, 5H) ,
14.3
benzoxazin-7- 7.01 (s, 1H) , 5.56 yl)-7H- (s, 2H) , 4.57 (s, ■imidazo [4,5- 2H) , 3.91 (s, 3H) , h] quinazoline 3.45 (s, 3H) , 2.19 -2 , 6-dione (s, 3H)
o l-benzyl-8- (DMSO-d6) : δ 11.95
[4-(2- (brs, 1H) , 7.63 (s, ethoxyethoxy) 2H) , 7.29-7.19 (m, -3,5- 5H) , 7.01 (s, 1H) , dimethyl- 5.67 (s, 2H) , 3.91-
14.4 phenyl] -5- 3.89 (m, 5H) , 3.65 methoxy-3- (t, J = 4.4 Hz, 2H) , methyl-7H- 3.50 (q, J = 7.2 Hz, imidazo [4,5- 2H) , 3.48 (s, 3H) , h] quinazoline 2.20 (s, 6H) , 1.14 -2 , 6-dione (t, J = 7.2 Hz, 3H) l-benzyl-5- (DMSO-d5) : δ 12.00 methoxy-8- [ 3- (brs, 1H) , 7.93 (d, J
14.5 (2- = 8.8 Hz, lH) , 7.86
Figure imgf000192_0003
methoxyethyl ) (s, 1H) , 7.33 (d, J =
-2-oxo-l , 3- 8.4 Hz, 1H) , 7.27-
Figure imgf000193_0001
Figure imgf000194_0001
methyl-1- (2- Hz ,1H) , 7.02 (d, J =
pyridylmethyl 8.4 Hz, 2H) , 5.70 (s,
) -7H- 2H) , 4.89 (brs, 1H) , imidazo [4,5- 3.92 (s, 3H) , 3.81- h] quinazoline 3.79 (m, 2H) , 3.72-
-2 , 6-dione 3.70 (m, 2H) , 3.48
(s, 3H) , 2.15 (s, 6H) l-benzyl-5- (DMSO-d ) : δ 11.60 methoxy-8- [5- (brs, 1H) , 8.28 (d, J methoxy-6- (4- = 8.4 Hz, 2H) , 8.04 methylsulfiny (d, J = 8.8 Hz, 1H) ,
Figure imgf000195_0001
lphenyl) -2- 7.79 (d, J = 8.4 Hz, pyridyl] -3- 2H) , 7.34 (d, J = 9.2
14.12
methyl-7H- Hz, 1H) , 7.33-7.19 imidazo [4,5- (m, 5H) , 7.05 (s, h] quinazoline 1H) , 5.65 (s, 2H) , -2 , 6-dione 3.95 (s, 3H) , 3.92
(s, 3H) , 3.46 (s, 3H) , 2.80 (s, 3H)
[0401]
Scheme 15
Figure imgf000195_0002
[0402]
3 , 4-Dihydroxy-5-nitro-benzaldehyde (105) Compound 104 (10 g, 50.76 mmol) was added to a stirred suspension of AICI3 (7.44 g, 55.83 mmol) in dry chloroform (150 mL) at 0°C. Pyridine (18.0 mL, 223.35 mmol) was dropwise added to the resulting mixture, and the mixture was refluxed for 16h. The mixture was cooled to room temperature and poured into ice water. The solid was filtered, and the residue was purified by silica gel column chromatography to give the title compound
105 (8.0 g, 86%) .
1HNMR (400 MHz, DMSO-d6) : δ 10.91 (br s, 2H) , 9.81 (s, 1H) , 7.98 (d, J= 2.0 Hz, 1H) , 7.46 (d, J = 2.0Hz, 1H) .
[0403]
6-Nitrobenzene-l,2,4-triol (106)
IN NaOH (21.85 mL, 21.85 mmol) was added to a solution of compound 105 (8.0 g, 43.71 mmol) in mixture of MeOH-H20 (1:2, 225 mL) at room temperature. 30% H202 (24.6 mL) was added to the resulting mixture slowly, and after complete addition, the mixture was stirred at 60°C for 3h. The mixture was cooled to room temperature and concentrated to one-third volume. The residue was cooled to 0°C. The solid was collected by vacuum filtration, washed with H20 and dried to .give the title
compound 106 (5.0 g, 75%).
^NMR (400 MHz, DMS0-d6) : δ 10.00 (br s, 1H) , 9.45 (br s, 2H) , 6.69 (d, J = 2.8 Hz, 1H) , 6.62 (d, J= 3.2 Hz, 1H) .
[0404]
5-Nitro-2,3-dihydro-l,4-benzodioxin-7-ol (107)
1, 2-Dibromoethane (2.23 mL, 25.80 mmol) was added
dropwise to a mixture of compound 106 (5.0 g, 32.25 mmol) and potassium carbonate (8.90 g, 64.51 mmol) in dry N,N- dimethylformamide at room temperature. The reaction mixture was heated at 80°C for 4h. On completion, the reaction mixture was filtered, and the filtrate was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the crude material was purified over column chromatography to give the title compound 107 (3.5 g, 55%) .
1HNMR (400 MHz, DMSO-d6) : δ 9.80 (s, 1H) , 6.85 (d, J = 2.8 Hz, 1H), 6.62 (d, J= 3.2 Hz, 1H) , 4.31-4.28 (m, 4H) .
[0405]
7-Met oxy-5-nitro-2 , 3-dihydro-l , 4-benzodioxine (108)
Methyl iodide (2.21 mL, 35.53 mmol) was added at room temperature to a mixture of compound 107 (3.5 g, 17.76 mmol) and potassium carbonate (4.90 g, 35.53 mmol) in dry N,N- dimethylformamide . The resulting mixture was heated at 80°C for 4 h. On completion, the reaction mixture was filtered, and the filtrate was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give the title compound 108 (3.6 g, 96%). ^ MR (400 MHz, DMSO-d6) : δ 7.05. (d, J = 2.8 Hz, 1H) , 6.85 (d, J = 2.8 Hz, 1H) , 4.35-4.32 (m, 4H) , 3.74 (s, 3H) .
[0406]
7-Methoxy-2 , 3-dihydro-l , 4-benzodioxin-5-amine (109)
10% Pd/C (400 mg) was added to a solution of compound 108
(3.6 g, 17.06 mmol) in methanol (30 mL) . The resulting mixture was stirred under hydrogen atmosphere for 2h. The catalyst was then removed by filtration using celite pad and washed with methanol (100 mL) . The filtrate was concentrated, and the residue was purified by flash column chromatography to give the title compound 109 (3.0 g, 99%) .
^NMR (400 MHz, DMSO-d6) : δ 5.83 (d, J= 3.2 Hz, 1H) , 5.66 (d, J = 2.8 Hz, 1H), 4.70 (br s, 2H) , 4.16-4.13 (m, 4H) , 3.58 (s, 3H) . ■
[0407]
6-Methoxy-3 , 9-dihydro-2H- [1 , 4] dioxino [2 , 3-g] indole-7 , 8-dione (110)
Oxallyl chloride (30 mL) was added to compound 109 (3.0 g, 17.06 mmol), and the resulting mixture was heated at 120°C for 3h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was
triturated with methanol. The solid was filtered and washed with ¾0. The crude material was purified by silica gel column chromatography to give the title compound 110 (2.6 g, 67%). ^ MR (400 MHz, DMSO-d5) : δ 11.88 (s, 1H) , 6.85 (s, 1H) , 4.48- 4.40 (m, 2H) , 4.28-4.26 (m, 2H) , 3.77 (s, 3H) .
[0408]
5-Amino-7-methoxy-2 , 3-dihydro-l , 4-benzodioxine-6-carboxylic acid (111)
30% Aqueous hydrogen peroxide (15 mL) was added drop-wise to a stirred suspension of compound 110 (2.6 g, 11.06 mmol) in 10% aqueous sodium hydroxide (15 mL) at 0°C. The reaction mixture was stirred at 50°C for 30 min and then allowed to reach room ' temperature . The mixture was filtered, and the filtrate was acidified to pH ~4 with aqueous IN hydrochloric acid. The solid was collected by filtration, washed thoroughly with cold water and dried under vacuum to give the title compound 111 (1.2 g, 50%).
1HNMR (400 MHz , DMSO-d6) : δ 9.72 (br s, 1H) , 6.56 (s, 1H) , 4.30-4.16 (m, 4H) , 3.69 (s, 3H) , 3.39 (s, 2H) .
[0409]
5-Amino-7-methoxy-2 , 3-dihydro-l , 4-benzodioxine-6-carboxamide (112)
The preparation of compound 112 from compound 111 was carried out in a similar manner to that described for the preparation of compound 81 (400 mg, 40%) was obtained.
1HNMR (400 MHz, DMSO-d6) : δ 7.60 (br s, 2H) , 7.38 (s, 1H) , 6.25-6.18 (m,.2H), 3.82-3.80 (m, 5H) , 3.60 (s, 2H) .
[0410]
Compound 113: Quinazolinone ring formation
The preparation of compound 113 from compound 112 was carried out in a similar manner to that described for the preparation of compound 83.
[0411] The following compounds of Examples were synthesized according to Scheme 15:
■ [0412]
Table 12
Figure imgf000199_0001
[0413]
Formulation Example 1 (production of capsule)
1) compound of Example 1 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.
[0414]
Formulation Example 2 (production of tablet)
1) compound of Example 1 30 g
2) lactose 50 g
3) cornstarch 15 g
4) calcium carboxymethylcellulose 44 g
5) magnesium stearate 1 g,
1000 tablets total 140 g
The total amount of 1), 2) and 3) and 4) (30 g) is
kneaded with water, vacuum dried, and sieved. The sieved powder is mixed with 4) (14 g) and 5) (1 g), and the mixture is punched by a tableting machine, whereby 1000 tablets
containing 30 mg of the compound of Example 1 per tablet are obtained .
[0415]
Formulation Example 3 (production of ointment)
1) compound of Example 1 0.5 g
2) liquid paraffin 1 g
3) white vaseline 98.5 g
Total 100 g
1) and 2) are mixed well in a mortar, and 3) is added gradually thereto with kneading to make the total weight 100 g. The obtained kneaded product is filled into tubes in parts to give an ointment .
[0416]
Experimental Example 1
Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assays :
The binding of compounds to Bromodomain/s BRD4-BD(N) was. assessed using TR-FRET assay that measures the binding of tetra-acetylated histone H4 peptide to the bromodomain.
[0417]
BRD4-BD(N) Bromodomain protein: Recombinant Human Bromodomains BRD4-BD (N) (A. A 49-170) was expressed in E-coli cells (from pET28a vector) with a six- His tag at the N-terminal. The his-tagged BRD4-BD (N) was purified from E-coli cells by sonication followed by nickel affinity column (HisTrap HP, GE 17-5247-01) purification. The purified protein (>90% pure) was ' quantified by protein estimation by BCA protein estimation method. The purified protein was used for bromodomain - peptide binding assay as follows .
[0418]
Assay Protocol :
All assay components were dissolved in assay buffer composition of 50mM HEPES, pH7.5, 50mM NaCl, 0.5mM CHAPS.
Compounds were pre-incubated with lOOnM His-tagged BRD4-BD (N) for 15 minutes followed by addition of 200nM tetra-Acetylated histone H4 peptide coupled to biotin (Millipore, cat 12-379) . The bromodomain protein and peptide interaction was detected by addition of 2nM Europium cryptate labelled streptavidin (Cisbio610SAKLA) and ΙΟηΜ XL-665-labelled anti-6His antibody (Cisbio 61HisXLA) in assay buffer containing 0.05% (v/v) BSA and 400mM KF. Following incubation for 60 minutes, TR- FRET was measured (excitation 320nm, emission 615 nm and 665nm) .
[0419]
Table 13-1
Figure imgf000201_0001
1.9 87.100
1.10 100.000
1.11 93.500
1.12 97.000
1.13 92.700
1.14 99.000
1.15 100.000
1.16 95.100
1.17 85.500
1.18 89.000
1.19 93.400
1.20 30.000
1.21 96.800
1.22 97.500
1.23 48.000
1.24 95.700
1.25 97.700
1.26 72.000
1.27 96.800
1.28 96.400
1.29 96.600
1.30 82.300
2.1 100.000
2.2 100.000
3.1 95.300
3.2 95.700
3.3 93.600
3..4 98.100
3.5 96.400
3.6 91.200
3.7 59.400
4.1 43.500 4.2 28.100
4.3 91.500
4.4 85.700
4.5 97.600
4.6 71.500
4.7 81.000
4.8 73.000
4.9 95.500
4.10 97.800
4.11 82.300
4.12 59.700
4.13 99.400
4.14 93.800
4.15 95.100
4.16 39.700
4.17 63.600
4.18 50.900
4.19 56.00
4.20 70.600
4.21 100.000
4.22 72.000
4.23 89.900
4.24 85.800
4.25 90.100
4.26 72.700
4.27 93.000
4.28 92.600
4.29 28.000
4.30 9.800
4.31 8.000
4.32 45.000
4.33 30.200 4.34 18.000
4.35 64.600
4.36 72.600
4.37 64.200
4.38 58.500
4.39 100.000
4.40 100.000
4.41 56.100
4.42 62.400
4.43 35.800
4.44 54.500
4.45 50.500
4.46 100.000
4.47 78.500
4.48 90.600
4.49 53.000
4.50 52.100
4.51 21.500
4.52 57.500
4.53 100.000
4.53.1 40.700
4.53.2 100.000
4.54 94.900
4.54.1 31.600
4.54.2 97.000
4.55.1 23.500
4.55.2 93.000
4.56.1 44.500
4.56.2 .8.9.500
5.1 36.500
6.1 37.000
7.1 51.600 . 7.2 30.700
8.1 63.900
8.2 51.700
8.3 100.000
8.4 96.000
8.5 100.000
8.6 64.800
9.1 18.300
9.2 97.900
9.3 81.800
9.4 28.800
9.5 51.800
9.6 72.900
9.7 75.500
9.8 96.500
9.9 90.300
9.10 95.900
9.11 80.600
9.12 93.700
9.13 95.600
9.14 82.500
10.1 30.000
10.2 26.000
10.3 20.000
10.4 ■ 94.000
10.5 11.500
10.6 35.000
10.7 27.000
10.8 43.000
10.9 72.000
10.10 45.500 [0420]
Table 13-2
Figure imgf000206_0001
[0421]
Experimental Example 2
Effect of BET inhibitors in Imiquimod induced-psoriasis model in BALB/c Mice
Objective:
To study effect of BET inhibitors (Compounds of Example 4.7, Example 9.6, Example 9.9 and Example 9.10) in Imiquimod (IMQ) induced-psoriasis model in BALB/c mice
Protocol :
Male BALB/c mice (8-10 weeks old) weighing 22-25 g were used in this study. Commercially available hair remover cream (Veet) was applied on the back of each animal on Day 0. From Day 1 onwards Imiquimod cream (~ 130 mg) was applied topically on the back of mice and ~ 5 mg on both ears daily till the end of the study (Day 14). Animals were treated by topically applying test compounds from Day 1 to Day 14.
Following were the treatment groups:
■ Naive (Vaseline application)
■ Vehicle, Cream Base, QD+IMQ
■ Compound of Example 4.7, 1% and 5% w/w cream, QD+IMQ
■ Compound of Example 9.6, 5% w/w cream, QD+IMQ
■ Compound of Example 9.9, 5% w/w cream, QD+IMQ
■ Compound of Example 9.10, 5% w/w cream, QD+IMQ
■ Betamethasone cream: 0.05% cream, 50 mg QD+IMQ
In the sepification, QD (quaque die) means once-daily dosing.
Ear thickness was measured (twice a week) by a micrometer as a parameter of inflammation. The study was terminated on Day 14 and animals were sacrificed.
Satellite Group for pharmacokinetic/pharmacodynamics
(n=3./mice/time point)
■ Compound of Example 4.7, 50 mg, (5%w/w cream), QD+IMQ
Skin and plasma were collected on Day 1 and Day 14at 1, 6 and 24 hr post compound application. Three animals were sacrificed at each time point. Results: Effect on Ear thickness (shown in Figures 1 and 2)
• Vehicle treated group showed significant increase in ear thickness compared to naive group starting Day 4 onwards.
• Compound of Example 4.7 at 1 and 5% cream showed 21 and 25% reduction (significant) in ear thickness starting Day 8 onwards compared to vehicle group at the end of study.
• Compound of Example 9.6 at 5% cream showed -15% reduction (significant) in ear thickness on Day 14 compared to vehicle.
• Betamethasone 0.05% cream showed ~35-40% reduction in ear thickness starting Day 8 onwards compared to vehicle group.
• Compounds of Example 9.9 and Example 9.10 at 5% cream showed ~21% reduction (significant) in ear thickness starting Day 8/11 onwards till the end of treatment period compared to vehicle .
[0422]
No adverse effect or abnormal clinical signs were observed in any of the treatment group compared to vehicle at the end of study period.
[0423]
Experimental Example 3
Effect of BET inhibitor in Imiquimod induced-psoriasis model in BALB/C Mice (Dose response study)
Objective:
To study effect of BET inhibitor (Compound of Example 4.7) topical application in Imiquimod induced-psoriasis model in BALB/c mice
Protocol :
Male BALB/c mice (8-10 weeks old) weighing 22-25 g were used in this study. Commercially available hair remover cream (Veet) was applied on the back of each animal on Day 0. From. Day 1 onwards Imiquimod cream (~ 130 mg) was applied topically on the back of mice and ~ 5 mg on both ears daily till the end of the study (Day 14). Animals were treated by topically . applying test compoiunds from Day 1 to Day 14.
Following were the treatment groups: ■ Naive (Vaseline application)
■ Vehicle: Cream Base, QD+IMQ
■ Compound of Example 4.7, 50 mg, (1%, 2.5% and 5%w/w
cream) , QD+IMQ
■ Betamethasone cream: 0.05% cream, 50 mg QD+IMQ
Ear thickness was measured (twice a week) by. a micrometer as a parameter of inflammation and study was terminated on Day 15 and animals were sacrificed
Satellite Group for pharmacokinetic/pharmacodynamics
(n=3/mice/time point)
■ Compound of Example 4.7, 50 mg, (2.5% and 5%w/w cream), QD+IMQ
Skin and plasma was collected on Day 1 and Day 15 post 1, 6 and 24 hr post compound application. Three animals were sacrificed at each time point.
Results: Effect on Ear thickness (shown in Figure 3)
• Vehicle treated group showed significant increase in ear thickness compared to naive group starting day 4 onwards.
• Compound of Example 4.7 at 1, 2.5 and 5% cream showed ~48, 70 and 64% reduction in ear thickness respectively at the end of treatment period compared to vehicle group at the end of study.
Plasma concentration Efficacy treatment group is shown in Table 14, and plasma concentration Satellite pharmacokinetic group 2.5% and 5% treatment group is shown in Tables 15 and 16.
[0424]
Table 14: Plasma and Skin concentration (u ) from efficacy treatment group on Day 15
Figure imgf000209_0001
[ 0425 ]
Table 15 : Plasma and skin cone . from Imiquimod induced- psoriasis study in BALB/c mice (Compound of Example 4.7) (Satellite arm- 2.5% cream; n=3/time point)
Figure imgf000210_0001
[ 0426 ]
Table 16: Plasma and skin cone, from Imiquimod induced- psoriasis study in BALB/c mice (Compound of Example 4.7) (Satellite arm- 5% cream; n=3/time point)
Figure imgf000210_0002
[ 0427 ] No adverse effect or abnormal clinical signs was observed in any of the treatment group compared to vehicle at the end of study period.
Industrial Applicability
5 [0428]
Compound (I) has a superior BET family protein inhibitory action, and is useful as an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases (e.g., rheumatoid arthritis, multiple sclerosis, idiopathic io pulmonary fibrosis, psoriasis, atopic dermatitis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, systemic lupus erythematosus etc.), cancer and the like.
[0429]
This application is based on patent application No.
15 1750/DEL/2015 filed on June 11, 2015 in India, the contents of which are encompassed in full herein.

Claims

A compound represented by the formula
Figure imgf000212_0001
wherein
R1 is an optionally substituted 5-membered aromatic
heterocyclic group;
ring A is an optionally further substituted benzene ring;
R2 and R3 are each independently a hydrogen atom or a
substituent; and
ring B is
a ring represented by the formula:
Figure imgf000212_0002
wherein
Xa and Ya are each independently a nitrogen atom or a carbon atom, and
R4a is a substituent, and
wherein said ring is optionally further substituted, a ring represented by the formula:
Figure imgf000212_0003
wherein
Xb and Yb are each independently a nitrogen atom or a carbon atom, and '
R4b is a hydrogen atom or a substituent, and
wherein said ring is optionally further substituted, or a rin represented by the formula:
Figure imgf000213_0001
wherein
Xc is a nitrogen atom or a carbon atom, and
R4c is a hydrogen atom or. a substituent, and
wherein said ring is optionally further substituted;
or a salt thereof.
2. The compound or salt of claim 1, wherein
R1 is an optionally substituted isoxazolyl or an optionally substituted pyrazolyl;
R2 and R3 are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) an optionally substituted C3-10 cycloalkyl group,
(5) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group,
(6) an optionally substituted 5- to 14-membered aromatic heterocyclic group,
(7) an amino group optionally having. 1 or 2 Ci-6 alkyl groups optionally having 1 to 3 substituents selected from the following substituent group A,
(8) a hydroxy group optionally having a Ci_6 alkyl group, or
(9) a sulfanyl group optionally having a Ci-6 alkyl group; and Ring B is
a ring represented by the formula:
Figure imgf000214_0001
wherein
Xa is a nitrogen atom;
Ya is a nitrogen atom; and
R4a is
(1) an optionally substituted Ci-6 alkyl group,
(2) an optionally substituted C3-10 cycloalkyl group,
(3) an optionally substituted Ce-ιο aryl group,
(4) an optionally substituted 3- to 14-membered non- aromatic heterocyclic group, or
(5) an amino group optionally having 1 or 2 Ce-ιο aryl groups optionally having 1 to 3 substituents selected from the following substituent group A,
a ring represented by the formula:
Figure imgf000214_0002
wherein
Xb is a nitrogen atom;
Yb is a nitrogen atom; and
(1) an optionally substituted Ci-6 alkyl group,, or
(2) an optionally substituted C6-10 aryl group, or
a rin represented by the formula:
Figure imgf000214_0003
c wherein
Xc is a nitrogen atom; and
R4c is an optionally substituted Ci-6 alkyl group,
[substituent group A]
(1) a halogen atom,
(2) a nitro group,
(3) a cyano group,
(4) an oxo group,
(5) a hydroxy group,
(6) an optionally halogenated Ci-6 alkoxy group,
(7) a C6-i4 aryloxy group,
(8) a C7-i6 aralkyloxy group,
(9) a 5- to 14-membered aromatic heterocyclyloxy group,
(10) a 3- to 14-membered non-aromatic heterocyclyloxy group, (11) a Ci-6 alkyl-carbonyloxy group,
(12) a C6-i4 aryl-carbonyloxy group,
(13) a Ci-6 alkoxy-carbonyloxy group,
(14) a mono- or di-Ci_6 alkyl-carbamoyloxy group,
(15) a C6-i4 aryl-carbamoyloxy group,
(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group,
(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group,
(18) an optionally halogenated χ-ς, alkylsulfonyloxy group, (19) a C6-i4 arylsulfonyloxy group optionally substituted by a Ci-6 alkyl group,
(20) an optionally halogenated Ci-S alkylthio group,
(21) a 5- to 14-membered aromatic heterocyclic group,
(22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group,
(24) a carboxy group,
(25) an optionally halogenated Ci-6 alkyl-carbonyl group,
(26) a C6-i4 aryl-carbonyl group,
(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,
(29) a Ci-6 alkoxy-carbonyl group,
(30) a C6-i4 aryloxy-carbonyl group,
(31) a C7-16 aralkyloxy-carbonyl group,
(32) a carbamoyl group,
(33) a thiocarbamoyl group,
(34) a mono- or di-Ci-6 alkyl-carbamoyl group,
(35) a C6-i4 aryl-carbamoyl group,
(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group
(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group,
(38) an optionally halogenated Ci-6 alkylsulfonyl group,
(39) a C6-14 arylsulfonyl group,
(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group,
(41) an optionally halogenated Ci-6 alkylsulfinyl group,
(42) a C6-i4 arylsulfinyl group,
(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group,
(44) an amino group,
(45) a mono- or di-Ci-e alkylamino group,
(46) a mono- or di-C6-i4 arylamino group,
(47) a 5- to 14-membered aromatic heterocyclylamino group,
(48) a C7-16 aralkylamino group,
(49) a formylamino group,
(50) a Ci-6 alkyl-carbonylamino group,
(51) a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl) amino group,
(52) a C6-i4 aryl-carbonylamino group,
(53) a Ci-6 alkoxy-carbonylamino group,
(54) a C7-16 aralkyloxy-carbonylamino group,
(5.5) a Ci-6 alkylsulfonylamino group,
(56) a C6-i4 arylsulfonylamino group optionally substituted by
Cl-6 alkyl group,
(57) an optionally halogenated Ci-e alkyl group,
(58) a C2-6 alkenyl group,
(59) a C2-6 alkynyl group,
(60) a C3-10 cycloalkyl group, (61) a C3-10 cycloalkenyl group
(62) a C6_i4 aryl group.
3. 7- (3, 5-dimethylisoxazol-4-yl) -8-methoxy-N-methyl-l- (2- pyridylmethyl) -[ 1, 2, 4 ] triazolo [4 , 3-a] quinoxalin-4-amine or a salt thereof.
4. 4- [8-methoxy-l- (2-pyridylmethyl ) -[1,2,4] triazolo [ 4 , 3- a] quinoxalin-7-yl] -3, 5-dimethyl-isoxazole or a salt thereof.
5. 7- ( 3 , 5-dimethylisoxazol-4-yl ) -8-methoxy-l- (2- pyridylmethyl) - [1, 2, 4] triazolo [4, 3-a] quinoxalin-4-amine or a salt thereof.
6. A medicament comprising the compound or salt of claim 1.
7. The medicament of claim 6, which is bromodomain and extra terminal domain family protein inhibitor.
8. The medicament of claim 6, which is an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases.
9. The medicament of claim 6, which is an agent for the prophylaxis or treatment of psoriasis or atopic dermatitis.
10. The compound or salt of claim 1 for use in the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases.
11. The compound or salt of claim 1 for use in the prophylaxis or treatment of psoriasis or atopic dermatitis.
12. A method of inhibiting bromodomain and extra terminal domain family protein in a mammal, which comprises administering an effective amount of the compound or salt claim 1 to the mammal.
13. A method for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases in a mammal, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal .
14. A method for the prophylaxis or treatment of psoriasis or atopic dermatitis in a mammal, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal .
15. Use of the compound or salt of claim 1 for the production of an agent for the prophylaxis or treatment of autoimmune diseases and/or inflammatory diseases.
16. Use of the compound or salt of claim 1 for the production of an agent for the prophylaxis or treatment of psoriasis or atopic dermatitis.
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GB2572526A (en) * 2017-06-22 2019-10-09 Curadev Pharma Ltd Heterocyclic small molecule modulators of human STING
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