WO2005097129A2 - 6-azaindole compound - Google Patents

6-azaindole compound Download PDF

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Publication number
WO2005097129A2
WO2005097129A2 PCT/US2005/011531 US2005011531W WO2005097129A2 WO 2005097129 A2 WO2005097129 A2 WO 2005097129A2 US 2005011531 W US2005011531 W US 2005011531W WO 2005097129 A2 WO2005097129 A2 WO 2005097129A2
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group
pyrrolo
compound
hydrogen atom
pyridin
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PCT/US2005/011531
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French (fr)
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WO2005097129A3 (en
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Yoshiaki Horiguchi
Hiroshi Imoto
Mark A. Wolf
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Takeda Pharmaceutical Company Limited
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Priority to EP05732504A priority Critical patent/EP1732566A4/en
Priority to JP2007506366A priority patent/JP2007531744A/en
Priority to US11/547,308 priority patent/US7608627B2/en
Publication of WO2005097129A2 publication Critical patent/WO2005097129A2/en
Publication of WO2005097129A3 publication Critical patent/WO2005097129A3/en

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    • 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
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Definitions

  • the present invention relates to a 6-azaindole compound having a superior I ⁇ B kinase inhibitory activity and useful as a pharmaceutical agent such as an agent for preventixig or treating diabetes and the like- Background Art
  • IKB kinase (sometimes to be abbreviated as IKK in the specification) is a kinase complex having a molecula-r weight of not less than 900 kilodaltons that phosphorylates I ⁇ B.
  • This complex includes kinase subunits such as IKK ⁇ (IKK-1 ) , IKK ⁇ (IKK-2), regulatory subunit IKK ⁇ (NEMO) and the like _ IKK phosphorylates serine 312 of IRS-1, which ⁇ s an insulin receptor substrate, and the like, and induce s insulin resistance by inhibiting the phosphorylation of tyro sine of IRS-1 that should originally occur (J. Biol. Chem., 277, p. 8115 (2002)). Therefore, an IKK inhibitor is expected to improve insulin resistance observed in type II diabe tes and obesity. In addition, IKK is known to significantly con- ribute as one factor in the signal transduction pathway of NF- ⁇ B transcription factor.
  • NF- B is generally bound with inhibitory protein I ⁇ B and present as an inactive type in cytoplasm. Once IKK phosphorylates I ⁇ B, this triggers ubiquitination of I ⁇ B and degradation of I ⁇ B proceeds .
  • NF- ⁇ B liberated by the degradation of I ⁇ B is translocated into the nucleus, where it activates transcription of the target gene and acceLerates production of inflammatory cytokines such as tumor aecrosis factor (TNF) , IL-1 etc.; cell adhesion factors such as ICAM-1 (Intercellular Adhesion Molecule-1) etc.; and enzyme.-s such as cyclooxygenase COX2 (Cyclooxygenase-2) and the like.
  • TNF tumor aecrosis factor
  • ICAM-1 Intercellular Adhesion Molecule-1
  • enzyme.-s such as cyclooxygenase COX2 (Cyclooxygenase-2) and the like.
  • NF-KB is deeply involved, in inflammation and irr--mune ⁇ responses .
  • ''l ⁇ A -'irfe* known to activate NF- ⁇ B by phosphorylation of NF- ⁇ B subunits and histone.
  • an IKK inhibitor is expected to suppress activation of HSFF-KB and be useful as an agent for preventing or treating autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis), inflammatory dis -eases (e.g., osteoarthrosis, atherosclerosis, atopic derma"titis, chronic obstructive pulmonary disease, endotoxin shock, sepsis), ischemic diseases and the like or as an immunosuppressant .
  • autoimmune diseases e.g., rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis
  • inflammatory dis -eases e.g., osteoarthrosis, atherosclerosis, atopic derma"titis, chronic obstructive pulmonary disease, endotoxin shock, sepsis
  • ischemic diseases e.g., rheumatoid arthritis,
  • NF-KB acts as an anti- apoptosis factor or growth factor in cancer cells
  • a-n IKK inhibitor that suppresses activation of NF-KB is expected to be useful as an agent for preventing or treating cancer (J. Clin. Invest., 107, pp. 241-246 (2001)).
  • 6-azaindole compounds the following compounds have been reported.
  • Disclosure of the Invention ⁇ n object of the present invention is to provide a 6- azaindole compound having a superior I ⁇ B kinase inhi-Ioitory activity and useful as a pharmaceutical agent such a s an agent for preventing or treating diabetes and the like.
  • invention relates to ( 1 ) a compound represented by the formula
  • R 1 , R 2 , R 3 or R 6 for example, a halogen atom, a cyano group, a nitro group, an amidino group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted mercapto group and the like can be mentioned.
  • halogen atom for example, fluorine, chlorine, bromine and iodine can be mentioned.
  • hydrocarbon group of the “optionally substituted hydrocarbon group”
  • a) C ⁇ -6 alkyl groups e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl
  • C 2 -6 alkenyl groups e.g., vinyl, allyl, isopropenyl, 2- butenyl
  • C 2 -6 alkynyl groups e.g., ethynyl, propargyl, 2-butynyl
  • C3-8 cycloalkyl groups optionally substituted by the above- mentioned C1-6 alkyl group and optionally condensed with a benzene ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohept
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • C ⁇ - 3 alkylenedioxy groups e.g., methylenedioxy, ethylenedioxy
  • a nitro group e.g., a cyano group, a hydroxy group
  • an optionally halogenated C ⁇ - 6 alkoxy group e.g., an optionally halogenated d- 6 alkylthio group
  • C 6 - ⁇ 4 aryloxy groups e.g., phenoxy, naphthoxy
  • 5- to 7-membered heterocyclic oxy groups e.g., tetrahydropyranyloxy
  • halogenated C ⁇ - 6 alkoxy group for example, a C ⁇ - 6 alkoxy group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , such as methoxy, ethoxy, propoxy, butoxy, pentyloxy and the like can be mentioned.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • halogenated C ⁇ -6 alkylthio group for example, a C ⁇ -6 alkylthio group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like can be mentioned.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • methylthio difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4, 4, 4-trifluorobutylthio, pentylthio, hexylthio and the like.
  • the "5- to 7-membered heterocyclic group" of the aforementioned “optionally substituted 5- to 7-membered heterocyclic group” for example, a 5- to 7-membered heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and the like can be mentioned.
  • the 5- to 7-membered heterocyclic group include 5- to 7-membered non-aromatic heterocyclic groups such as pyrrolidinyl (e.g., 1-, 2- or 3- pyrrolidinyl); imidazolidinyl (e.g., 1-, 2-, 4- or 5- imidazolidinyl) ; imidazolinyl (e.g., 2- or 4-imidazolinyl) ; pyrazolidinyl (e.g., 2-, 3- or 4-pyrazolidinyl) ; piperidinyl (e.g., 1-, 2-, 3- or -piperidinyl) ; piperazinyl (e.g., 1- or 2-piperazinyl) ; tetrahydropyranyl; morpholinyl; thiomorpholinyl and the like; and 5- to 7-membered aromatic heterocyclic groups such as thienyl (e.g., 2- or 3-thienyl);
  • halogenated C ⁇ - ⁇ alkyl- carbonyl group for example, a C ⁇ - 6 alkyl-carbonyl group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the like can be mentioned. Specific examples thereof include acetyl, monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the like.
  • C ⁇ - 6 alkoxy-carbonyl group for example, ethoxycarbonyl, eth.oxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like can be mentioned.
  • heterocyclic carbonyl group of the aforementioned “optionally substituted heterocyclic carbonyl group”
  • nicotinoyl, isonicotinoyl, thenoyl (e.g., 2-thenoyl, 3-thenoyl) , furoyl (e.g., 2-furoyl, 3-furoyl) , morpholinocarbonyl, piperidinocarbonyl, pyrrolidin-1- ylcarbonyl, indolylcarbonyl and the like can be mentioned.
  • heterocyclic carbamoyl group of the aforementioned “optionally substituted heterocyclic carbamoyl group”
  • halogenated C ⁇ -6 alkylsulfonyl group for example, a C ⁇ - 6 alkylsulfonyl group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert- butylsulfonyl and the like can be mentioned.
  • fluorine e.g., fluorine, chlorine, bromine, iodine
  • Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4, 4, 4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
  • a C ⁇ _ 6 alkyl-carboxamido group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), such as acetamido, propanamido, butanamido and the like can be mentioned. Specific examples thereof include acetamido, trifluoroacetamido, propanamido, butanamido and the like.
  • ⁇ fet ⁇ alkyl group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl can be mentioned.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl, propyl, 3, 3, 3-trifluoropropyl, isopropyl, butyl, 4,4,4- trifluorobutyl ⁇ isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, hexyl, 6,6,6- trifluorohexyl and the like.
  • a C 3 - 6 cycloalkyl group optionally hav ⁇ ng 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4- dichlorocyclohexyl, 2, 2, 3, 3-tetrafluorocyclopentyl, 4- chlorocyclohexyl and the like.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • heterocyclic group of the “optionally substituted heterocyclic group” exemplified as the substituent for R 1 and the like, for example, (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7 to r, , r composer disturb , , , etc.
  • aromatic heterocyclic group for example, 4 to 14-membered (preferably 4 to 10-membered) aromatic heterocyclic groups containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and the like can be mentioned.
  • aromatic heterocyclic group examples include 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, furazanyl, pyranyl and th.e like; and condensed polycyclic (preferably bi- or tri-cyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, naphtho [2,
  • non-aromatic heterocyclic group for example, a 4 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and the like can be mentioned.
  • non-aromatic heterocyclic group examples include monocyclic non-aromatic , - ;h as azetidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrothiazolyl , tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydropyrimidinyl, tetrahydropyridazinyl
  • nitrogen-containing non-aromatic heterocyclic groups (preferably monocyclic n ⁇ trogen-containing non-aromatic heterocyclic groups) , such as azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl , pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, dihydropyridinyl, tetrahydropyrimidinyl, tetrahydropy-ridazinyl, azepanyl, morpholiny
  • the "7 to 10-membered bridged heterocyclic group” include quinuclldinyl, 7- azabicyclo[2.2 ,l]heptanyl and the l ke.
  • substituent of the "optionally substituted heterocyclic group” those exemplified as the substituent of the aforementioned “optionally substituted 5- to 7-membered heterocyclic group” can be mentioned.
  • the number of substituents is, for example, 1 to 3. When the number of substituents is 2 or more, respective substituents may be the same or differen .
  • acyl group of the "opt-Lonally substituted acyl group” exemplified as the substituent for R 1 and the like for example, -COR 15 , -CO-OR 15 , -S0 2 R 15 , -SOR 15 , -PO(OR 15 ) (OR 16 ) [R 15 and R 16 are the same or different and each is a hydrogen atom, a hydrocarbon group or a heterocyclic group] and the like can be mentioned.
  • the “hydrocarbon group” fo R 15 or R 16 the "hydrocarbon group” exemplified for "optionally substituted hydrocarbon group” exemplified as the substituent for R 1 and the like can be mentioned.
  • the hydrocarbon group is preferably a C ⁇ - 6 alkyl group, a C 2 - 6 alkenyl group, a C 3 - 8 cycloalkyl group, a C 3 -. 8 cycloalkenyl group, a C 6 - ⁇ 4 aryl group, a C 7 _ ⁇ 9 aralkyl group and the like .
  • the "heterocyclic group” fox R 15 or R 16 the "heterocyclic group” exemplified for the "optionally substituted heterocyclic group” exemplified as the substituent for R 1 and the like can be mentioned.
  • heterocyclic group ife" e ⁇ ⁇ '-iyy-y; ' oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl, -benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, pyrrolidinyl, piperidinyl, piperazinyl and the like.
  • the acyl group may have 1 to 3 substituents at substitutable position (s), and such substituent includes, for example, optionally halogenated C ⁇ _ 6 alkyl groups (e.g., methyl, ethyl); optionally halogenated C ⁇ _ 6 alkoxy groups (e.g., methoxy, ethoxy) ; halogen atoms (e.g., fluorine, chlorine, bromine, iodine) ; nitro group; hydroxy g-roup; amino group optionally mono- or di- substituted by C ⁇ _ 6 alkyl groups (e.g., methyl, ethyl); C ⁇ _ 6 alkoxy-carboxamido -groups (e.g., tert- butoxycarboxamido) and the like .
  • substituent includes, for example, optionally halogenated C ⁇ _ 6 alkyl groups (e.g., methyl, ethyl); optionally halogenated C ⁇ _ 6 al
  • acyl group include a formyl group, carboxyl group, C ⁇ - 6 alkyl-carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl), C 2 - 6 alkenyl-carbonyl groups (e.g., crotonoyl) , C 3 - 8 cycloalkyl-carbonyl groups (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3 - 8 cycloalkenyl-carbonyl groups (e.g., 2-cyclohexenecarbonyl) , C 6 -i 4 aryl-carbonyl groups (e.g., benzoyl, 1-naphthoyl, 2-naphth
  • nitrogen-containing heterocycle for example, a 5- to 7-membered nitrogen-containing heterocycle containing at least one nitrogen atom as a ring constituting atom besides carbon atom, and further, 1 or 2 -heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom can be mentioned.
  • the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.
  • the optionally substituted amino group include amino group, mono- or di-C ⁇ -6 alkylamino groups (e.g., methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino) , mono- or di-C 2 -6 alkenylamino groups (e.g., diallylamino) , mono- or di-C 3 -8 cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino) , mono- or di-C 6 ⁇ i4 arylamino groups (e.g., phenylamino) , mono- or di-C 7 -i9 aralkylamino groups (e.g., benzylamino, dibenzylamino) , mono- or di- (optionally halogenated C1-6 alkyl) -carbonylamino groups (e.
  • carbamoyl group examples include carbamoyl group, orxo- or di-C ⁇ -6 alkyl- carbamoyl groups (e.g., methylcarbamoyl, eth-ylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N- methylcarbamoyl) , mono- or di-C 2 - 6 alkenyl-c rbamoyl groups (e.g., diallylcarbamoyl) , mono- or di-C 3 - 8 cy-cloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl, cyclohexiylcarbamoyl) , mono- or di-C 6 - ⁇ 4 aryl-carbamoyl groups (e.g., phenylcarbamoyl)
  • carbamoyl group
  • the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-C ⁇ - 6 alkyl- sulfamoyl groups (e.g., methylsulfamoyl, eth ⁇ ylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl—N- methylsulfamoyl) , mono- or di-C 2 -6 alkenyl-sulfamoyl groups (e.g., diallylsulfamoyl) , mono- or di-C 3 - 8 cycloalkyl-sulfamoyl groups (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl) , mono- or di-C 6 -i 4 aryl-sulfamoyl groups (e.g., methyl
  • hydroxy g-roup and mercapto group each optionally substituted by the substituent selected from the "optionally substituted hydrocarbon gjroup", "optionally substituted acyl group” and “optionally substituted heterocyclic group” exemplified as the substituent for R 1 and the like can be mentioned.
  • the “optionally substituted hydroxy group” and “optionally substituted mercapto group” are preferably hydroxy group and mercapto group each optionally substituted by a "substituent selected from C ⁇ - 6 alkyl group, C 2 -6 alkenyl-.
  • Preferable examples of the optionally substituted hydroxy group include hydroxy group, C ⁇ - 6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, see-but oxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hex;yloxy) , C 2 _ 6 alkenyloxy groups (e.g., allyloxy, crotyloxy, 2-peni- ⁇ enyloxy, 3-hexenyloxy) , C 3 _ 8 cycloalkyloxy groups (e.g., cyclohex ⁇ yloxy) , C 6 - ⁇ 4 aryloxy groups (e.g., phenoxy, naphthyloxy) , C7-19 aralkyloxy groups (e.g., benzyloxy, phenethyloxy) , C ⁇ _ 6 alkyl- carbony
  • the optionally substituted mercapto group include mercapto group, C ⁇ _ 6 alkylthio groups (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio) , C 2 _6 alkenylthio groups (e.g., allylthio, crotylthio, 2- pentenylthio, 3-hexenylthio) , C 3 _ 8 cycloalkylthio groups
  • C ⁇ _ 6 alkylthio groups e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-but
  • R 1 , R 2 , R 3 or R 6 is preferably a halogen atom, an optionally substituted amino group and the like.
  • the optionally substituted amino group an amino group, a mono- or di- j-ig aralkylamino group and the l ke are preferable.
  • R 1 , R 2 , R 3 and R 6 are preferably hydrogen atoms.
  • substituent for R 7 those exemplified for the aforementioned R 1 and the like can be used. Of these, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group and the like are preferable.
  • the substituent for R 7 is preferably a C ⁇ -6 alkyl group, a Ce-i4 aryl group (preferably, phenyl) , a C 7 - 1 9 aralkyl group or a monocyclic aromatic heterocyclic group (preferably thienyl, furyl) , each of which may have 1 to 3 substituents selected from a halogen atom, a C ⁇ - 6 alkyl group, an optionally halogenated C ⁇ - 6 alkoxy group and the like.
  • R 8 , R 9 or R 10 for example, cyano group, amidino group, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted acyl group, optionally substituted carbamoyl group and the like exemplified as the aforementioned R 1 and the like can be mentioned.
  • the "optionally substituted heterocyclic group” is limited to a group bonded via a carbon atom. , , resume( .
  • the "group bonded via a carbon atom" for R 8 or R 9 is preferably, (1) an amidino group; (2) a C ⁇ -6 alkyl group optionally having 1 to 3 substituents selected from a hydroxy group, an optionally halogenated C ⁇ - 6 alkoxy group, a carboxyl group, an amino group, a mono- or di- C ⁇ _6 alkylamino group, a 5- to 7-membered heterocyclic group (preferably pyrrolidinyl, imidazolyl, morpholinyl) , a Ci-e alkoxy-carbonyl group, a carbamoyl group, a mono- or di-C ⁇ -6 alkyl-carbamoyl group, a C 6 -i 4 aryl-carbamoyl group (preferably phenylcarbamoyl) , a C ⁇ _ 6 alkoxy-carboxamido group, a 5- to 7- membered heterocyclic oxy group (preferably te
  • the "group bonded via a carbon atom" for R 10 is preferably (1) a C 1 -6 alkyl group; (2) C 6 -i4 aryl group (preferably phenyl) optionally having 1 to 3 substituents selected from a halogen atom, a C ⁇ - 6 alkyl group, an optionally halogenated C ⁇ -6 alkoxy group and the like; (3) a C 7 -.1 9 aralkyl group; (4) a heterocyclic group (preferably 2- or 3-thienyl; 2- or 3- furyl; 2-, 3- or 4-pyridyl) bonded via a carbon atom; and the like.
  • a C 6 - 14 aryl group preferably phenyl
  • an aromatic heterocyclic group and the like can be mentioned.
  • aromatic heterocyclic group those exemplified as the "optionally substituted heterocyclic group" exemplified for the aforementioned R 1 and the like can be used.
  • a C 6 -i4 aryl group preferably phenyl
  • a 5 or 6-membered aromatic heterocyclic group preferably thienyl, furyl, pyridyl
  • the "optionally substituted heterocyclic group bonded via a nitrogen atom" for Het for example, a group bonded via a nitrogen atom from the “optionally substituted heterocyclic groups” exemplified as the aforementioned R 1 and the like can be mentioned.
  • 1-pyrrolidinyl, 1-piperazinyl, 4-morpholinyl or 4-thiomorpholinyl optionally having 1 to 3 substituents selected from an optionally halogenated C ⁇ _ 6 alkyl group, an optionally halogenated C ⁇ _ 6 alkyl-carbonyl group and the like is preferable.
  • hydrocarbon group for R 12 for example, those exemplified as the "optionally substituted hydrocarbon group" exemplified as the aforementioned R 1 and the like are used. Of these, a C ⁇ - 6 alkyl group, a C 6 -i4 aryl group (preferably phenyl) and the like are preferable.
  • the "optionally substituted hydrocarbon group” is preferably a C ⁇ -6 alkyl group, a C 3 -s cycloalkyl group or a C7-19 having 1 to 3 substituents selected from 5- to 7-membered heterocyclic groups (preferably thienyl, furyl, pyridyl, morpholinyl, thiomorpholinyl) .
  • the "optionally substituted heterocyclic group” is preferably a monocyclic non-aromatic heterocyclic group (preferably piperidinyl) optionally having 1 to 3 substituents selected from a C7- 1 9 aralkyl group and the like.
  • the "optionally substituted acyl group” is preferably a C 1 -6 alkyl-carbonyl group, a Cs- 14 aryl-carbonyl group (preferably benzoyl) or an aromatic heterocyclic carbonyl group (preferably nicotinoyl, isonicotinoyl) each optionally having 1 to 3 substituents selected from a C ⁇ - 6 alkoxy- carboxamido group and the like.
  • the nitrogen-containing heterocyclic group of the "nitrogen-containing heterocyclic group optionally having substituents (provided that the nitrogen-containing heterocyclic group is not an oxopyrrolidinyl group or an oxopiperazinyl group)" formed by R 13 and R 14 together with the adjacent nitrogen atom is, for example, a 5- to 7-membered nitrogen-containing heterocyclic group containing at least one nitrogen atom as a ring constituting atom besides carbon atom, and optionally having 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom can be mentioned.
  • the nitrogen-containing heterocyclic group examples include 1-pyrrolidinyl, 1-imidazolidinyl, 1- pyrazolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4- thiomorpholinyl and the like.
  • the nitrogen-containing heterocyclic group may have 1 to 3 substituents at substitutable position (s) and as such substituent, a halogen atom, an optionally halogenated C ⁇ - 6 alkyl group, an optionally halogenated C ⁇ - 6 alkoxy group and the like can be mentioned.
  • a halogen atom an optionally halogenated C ⁇ - 6 alkyl group, an optionally halogenated C ⁇ - 6 alkoxy group and the like can be mentioned.
  • Tne w nitr6gfen'- ⁇ -? ⁇ rrtaining heterocyclic group optionally having substituents is preferably 1-piperidinyl and the like.
  • R 13 ' and R 14 ' are the same as R 13 and R 14 , except that the nitrogen-containing heterocyclic group of the "nitrogen-containing heterocyclic group optionally having substituents" formed by these together with the adjacent nitrogen atom may be an oxopyrrolidinyl group or an oxopiperazinyl group.
  • the compound (I' ) is preferably compound (I).
  • R 1 , R 2 , R 3 and R 6 are hydrogen atoms;
  • R 4 is a hydrogen atom;
  • R 10 is (1) a hydrogen atom; (2) a C ⁇ _ 6 alkyl group; (3) a C ⁇ -14 aryl group (preferably phenyl) optionally having 1 to 3 substituents selected from a halogen atom, a Ci-e alkyl group, an optionally halogenated C ⁇ - 6 alkoxy group and the like; (4) a C 7 - 19 aralkyl group; or (5) a heterocyclic group (preferably 2- or 3-thienyl/ 2- or 3-furyl; 2-, 3- or 4-pyridyl) bonded via a carbon atom.
  • the salt of compound (I) or (I' ) is preferably a pharmacologically acceptable salt, and is exemplified by salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids .
  • salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts and ammonium salts.
  • salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid., oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • salts with basic amino acids include salts with arginine, lysine, ornithine, etc.
  • preferable salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.
  • a prodrug of compound (I) refers to a compound capable of being converted to compound (I) by the actions of an enzyme, gastric juice, or the like, under physiological conditions in vivo, specifically a compound capable of being converted to compound (I) upon enzymatic oxidation, reduction, hydrolysis, or the like, or a compound capable of being converted to compound (I) upon hydrolysis or the like by gastric juice or the like.
  • prodrugs of compound (I) include compounds derived hy acylation, alkylation or phosphorylation of the amino group of compound (I) (e.g., compounds derived by eicosanoylation, alanylation, pentylaminocarbonylation, (5- methyl-2-oxo-l, 3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, tert-butylation of the amino group of compound (I)); compounds derived by acylation, alkylation, phosphorylation or boration of the hydroxy group of compound (I) (e.g., compounds derived by acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation of the hydroxy group of compound (I)); and compounds derived by esterification or amidation of the carboxy group of compound (I
  • the prodrug of compound (I) may be one capable of being converted to compound (I) under physiological conditions, as described in "Iyakuhin No Kaihatsu (Development of Drugs)", vol. 7, Molecular Designing, published by Hirokawa Shoten, 1990, pages 163 - 198.
  • the prodrug of compound (I' ) the same as the prodrug of compound (I) is used.
  • Compounds (I), compounds (I') and prodrug thereof are of low toxicity and can be used as an agent for preventing or treating the various diseases mentioned below in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, bovines, horses, swine, monkeys) , as such or in the form of pharmaceutical compositions prepared by admixing with a pharmacologically acceptable carrier, etc.
  • Examples of the dosage forms of the pharmaceutical preparations such as tablets (including sublingual tablet, orally disintegrating tablet) , capsules (including soft capsules and microcapsules) , granules powders, troches, syrups, emulsions, suspensions; and non-oral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions) , external preparations (e.g., dermal preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories) , pellets, preparations for nasal administration, preparations for transpulmonary administration (inhalant) and eye drops.
  • injections e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions
  • external preparations e.g., dermal preparations, ointments
  • compositions can be prepared by conventional methods in the fields of pharmaceutical manufacturing techniques, for example, methods described in the Japanese Pharmacopoeia While the content of the compound of the present invention in a pharmaceutical composition varies depending on the dosage form, dose of the compound the present invention and the like, it is, for example, about 0.1 - 100 weight % .
  • the compound of the present invention has a superior I ⁇ B kinase inhibitory activity and can be used as an agent for preventing or treating various diseases in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, bovines, horses, swine, monkeys) . Furthermore, since the compound of the present invention has a selective I ⁇ B kinase inhibitory activity, it shows low toxicity (e.g., acute toxicity, chronic _ ⁇ __ _ _ _ _ _ _ _ fe i i y ⁇ "> ⁇ -? ⁇ iifefe'c b ⁇ i%y, cancinogenecity, genetic toxicity) and causes a ferwer side effects.
  • low toxicity e.g., acute toxicity, chronic _ ⁇ __ _ _ _ _ _ _ fe i i y ⁇ "> ⁇ -? ⁇ iifefe'c b ⁇ i%y, cancinogenecity
  • I ⁇ B kinase IKK ⁇ (I K-1) , IKK ⁇ (IKK-2) , regulatory subunit IKK ⁇ (NEMO) and the like can be mentioned.
  • the compound of the present invention also has a NF- ⁇ B inhibitory (transcription inhibitory) activity, TNF- ⁇ inhibitory (production inhibitory) activity and the like.
  • the compound of the present invention can be used as, for example, an agent for preventing or treating diabetes (e.g., type I diabetes, type II diabetes, gestational diabetes etc.); an agent for preventing or treating hyperlipidemia (e.g., hypertriglyceridemia, hypercholestexolemia, hypo-high-density- lipoproteinemia, postprandial hyperlipemia etc.); an agent for preventing or treating arteriosclerosis; an agent for preventing or treating impaired glucose tolerance (IGT) ; an insulin secretagogue; and an agent for preventing progress from impaired glucose tolerance to diabetes .
  • diabetes e.g., type I diabetes, type II diabetes, gestational diabetes etc.
  • hyperlipidemia e.g., hypertriglyceridemia, hypercholestexolemia, hypo-high-density- lipoproteinemia, postprandial hyperlipemia etc.
  • arteriosclerosis e.g., an agent for preventing or treating impaired glucose tolerance (IGT) ; an insulin secretagogue
  • the compound of the present invention can be used as an agent for preventing or treating, for example, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, diabetic hyperosmolar coma, infectious disease (e.g., respiratory infectious disease, urinary tract infectious disease, gastrointestinal infectious disease, skin/soft tissue infectious disease, inferior limb infectious disease) , diabetic gangrene, xerostomia, lowered sense of hearing, cerebrovascular disorder, peripheral blood circulation disorder], obesity, osteoporosis, cachexia (e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious disease cachexia or cachexia due to acquired immunodeficiency syndrome) , fatty liver, hypertension, polycystic ovary syndrome, renal disease (e.g., diabetic nephropathy, __ ___ ⁇ _ _ _ _
  • infectious disease e
  • ⁇ o ⁇ ri ⁇ iftfl ⁇ feT ⁇ jA-fe ⁇ -rame ulosclerosis nephrotic syndrome, hypertensive nephrosclerosis, end stage renal disease
  • muscular dystrophy cardiac infarction, angina pectoris, cerebrovascular disorder (e.g., cerebral infarction, stroke), insulin resistance syndrome, syndrome X, metabolic syndrome (a condition associated with at least one of type II diabetes, impaired glucose tolerance and insulin resistance and at least two of obesity, lipid metabolism abnormality, hypertension and -nicroalbuminuria in combination), Gushing' s syndrome, hiyperinsulinemia, sensory disorder in hyperinsulinemia, tumors (e.g., leukemia, breast cancer, prostate cancer, skin cancer), -irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (e.g., spondylitis deformans, osteoarthritis, atopic dermatitis, chronic obstructive pulmonary disease, endotoxin shock, se
  • inflammatory diseases
  • the compound of the present invention is used an an immunosuppressant .
  • the compound of the present invention is also used for '' ""' the' 1 '--e'c ' -i ⁇ a'ry * ' rdpferois and suppression of progression of the above-mentioned various diseases (e.g., cardiovascular event such as cardiac infarction and the like) .
  • the dose of the compound of the present invention varies depending on administration subject, administration route, target disease, clinical condition, etc., it is, for instance, about 0.01 to 100 mg/kg body weight, preferably 0.05 to 30 rng/kg body weight, more preferably 0.1 to 10 mg/kg body weight, as a usual dosage per administration for oral administration to an adult diabetic patient.
  • the compound of the present invention can be used in combination with a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, a chemotherapeutic agent, an immunotherapeutic agent, antith-rombotic agent and the like (hereinafter abbreviated as a combination drug) .
  • a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, a chemotherapeutic agent, an immunotherapeutic agent, antith-rombotic agent and the like.
  • a combination drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, a chemotherapeutic agent, an immunotherapeutic agent, antith-rombotic agent and the like.
  • the compound of the present invention and a combination drug may be administered as two kinds of preparations respectively containing an active ingredient, or as a single preparation containing both active ingredients .
  • Tre dose of the combination drug can be appropriately selected based on the dose which is clinically employed.
  • the proportion of the compound of the present invention and the combination drug can be appropriately selected according to the administration subject, administration route, target disease, clinical condition, combination, and other factors. I'. T .'it , : i .. 1 i rT. -*
  • the combination drug may be used in an amount of 0.01 to 100 parts by -weight per part by weight of the compound of the present invention.
  • insulin preparations e.g., animal insulin preparations extracted from the bovine or swine pancreas; human insulin preparations synthesized by a genetic engineering technique using Escherichia cold, or a yeast, insulin zinc; protamine zinc insulin; fragment or derivative of insulin (e.g., 1NS-1 and the like); oral insulin preparations), insulin sensitizers (e.g., pioglitazone orr its salt (preferably hydrochloride), rosiglitazone or its salt (preferably maleate) , Reglixane, GI- 262570, Netoglitazone, DRF-2593, BM-13.1258, KRP-297, R— 119702, CS-011, FK-61 , compounds described in WO99/58510 (e.g.
  • inhibitors e.g., NVP-DPP-278, PT-10O, P32/98, LAF237, P93/01, TS-021
  • ⁇ 3 agonists e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140
  • gluconeogjenesis inhibitors e.g., glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists
  • SGLT sodium-glucose cotransporter
  • ll ⁇ -HSDl inhibitors e.g., BVT- 3498
  • adiponectin or its agonist IKK inhibitors (e.g., AS— 2868)
  • th_e therapeutic agent for diabetic complications examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat (SNK-860), AS-3201, CT-112) , neurotrophic factors and its increasing agents (e.g., NGF, NT-3, BDNF, neurotrophin production secretion promoters (e.g., 4- (4-chlorophenyl) -2- (2- methyl-1-imidazolyl ) -5- [3- (2-methylphenoxy)propyl] oxazole) described in WOOl/14372), neuranegenesis promoters (e.g., Y— 128), PKC inhibitors (e.g., LY-333531) , AGE inhibitors (e.g., ALT946, pimagedine, pyratoxathine, N-phenacylthiazolium bromide (ALT766)
  • thioctic acid e.g., tiapuride, mexiletine
  • cerebral vasodilators e.g., tiapuride, mexiletine
  • somatostatin receptor agonist e.g., BIM23190
  • ASK-1 apoptosis signal regulating kinase-1
  • antihyperlipidemic agent examples include HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvas tatin, fluvastatin, itavastatin pitavastatin, rosuvastatin or their salts (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compound.
  • HMG-CoA reductase inhibitors e.g., pravastatin, simvastatin, lovastatin, atorvas tatin, fluvastatin, itavastatin pitavastatin, rosuvastatin or their salts (e.g., sodium salt, calcium salt)
  • salts e.g., sodium salt, calcium salt
  • squalene synthase inhibitors e.g., compound.
  • Avasimibe, Eflucimibe Eflucimibe
  • anion exchange resins e.g., cholestylamine
  • probuchol e.g., nicomol, niceritrol
  • nicotinic pharmaceutical agents e.g., nicomol, niceritrol
  • ethyl icosapentate e.g., phytosterol (e.g., soysterol, ⁇ -oryzanol) and the like.
  • hypotensive agent examples include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril) , angiotensin IZ antagonists (e.g., candesartan cilexetil, losartan, epr ⁇ sartan, valsartan, termisartan, irbesartan, olmesartan medoxomil, tasosartan, l-[[2'-(2,5- dihydro-5-oxo-4H-l, 2, 4-o ⁇ cadiazol-3-yl)biphenyl-4-yl]methyl] -2- ethoxy-lH-benzimidazole-7-carboxylic acid), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine) , potassium channel openers (e.g., levcromaka
  • antiobesity agent examples include antiobesity drugs acting on the central nervous system (e.g. dexfenfluramine, fenfluramine, phentermine, sibutramine, anfepramon, dexamphetamin-e, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP— 7941; compounds described in WO01/82925 and WO01/87834) ; neuropeptide Y antagonists (e.g., CP-422935) ; cannabinoid receptor antagonists (e.g., SR-141716, SR-147778); ghrelin antagonists; ll ⁇ -HSDl inhibitors (e.g., BVT-3498)), pancreatic lipase inhibitors (e.g.
  • MCH receptor antagonists e.g., SB-568849; SNAP— 7941; compounds described in
  • ALT-962 e.g. orlistat, ALT-962
  • ⁇ 3 agonists e.g. CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS- 196085, AZ-40140
  • anorectic peptides e.g. leptin, CNTF (Ciliary Neurotrophic Factor)
  • cholecystokinin agonists e.gj.
  • chemotherapeutic agent examples include alkylating agents (e.g., cyclophosph-amide, ifosamide) , metabolic antagonists (e.g., methot rexate, 5-fluorouracil or derivative thereof), antitumor antibiotics (e.g., mitomycin, adriamycin) , plant-derived antitumor agents (e.g., vincristine, vindesine, Taxol) , cisplatin, carboplatin, etoposide.
  • alkylating agents e.g., cyclophosph-amide, ifosamide
  • metabolic antagonists e.g., methot rexate, 5-fluorouracil or derivative thereof
  • antitumor antibiotics e.g., mitomycin, adriamycin
  • plant-derived antitumor agents e.g., vincristine, vindesine, Taxol
  • 5- fluorouracil derivatives such as Furtulon and Neo-Furtulon are preferable.
  • the immunotherapeutic agent include microorganism- or bacteriu ⁇ m-derived components (e.g., muramyl dipeptide derivatives, Picibanil) , immunopotentiator polysaccharides (e.g., lentinan, schizophyllan, krestin) , genetically engineered cytokines (e.g., interferons, interleukins (IL) ) , colony stimulating factors (e.g., granulocyte colony stimula-ting factor, erythropoietin) , etc.
  • cytokines e.g., interferons, interleukins (IL)
  • colony stimulating factors e.g., granulocyte colony stimula-ting factor, erythropoietin
  • interleukins such as IL-1, IL-2, IL-12 and the like are preferable.
  • antithrombotic: agent for example, heparin (e.g., heparin sodium, heparin calcium, dalteparin sodium) , warfarin (e.g., warfarin potassium) , antithrombin agents (e.g., aragatroban) , thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase) , platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like can be mentioned.
  • heparin e.g., heparin sodium, heparin calcium, dalteparin
  • drugs confirmed to exhibit a cachexia ameliorating effect in animal models and clinical applications, namely, cyclooxygenase inhibitors (e.g., indomethacin) , progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g. dexaxnethasone) , metoclopramide pharmaceuticals, tetrahydrocannabinol pharmaceuticals, fat _ , _ _
  • g agents e.g., eicosapentanoic acid
  • growth hormones IGF-1
  • the above combination drugs can ioe used as a mixture of two or more species in an appropriate ratio.
  • the combination drug is preferably an insulin preparation, an insulin sensitizer, an ⁇ -glucosidase inhibitor, a biguanide, an insulin secretagogue (preferably sulfonylurea) , and the like.
  • a superior effect such as (1) the dose of the compound of the piresent invention and/or a combination drug can be reduced as compared to single administration of the compound of the present invention or a combination drug, (2) a sustained treatment effect can be designed by selecting a combination drug having different action and mechanism from the compound of the present invention,, (3) a synergistic effect can be afforded by a combined use of the compound of the present invention and a combination drug, and the like, can be achieved.
  • compouxnd (I) The production methods of compouxnd (I) are explained in the following.
  • Compounds (I) can be produced by a method known per se, such as Method A-Method I shown below or a method analogous thereto.
  • a starting compound may be used in the fTorm of a salt and as such salt, those exemplified for the salts of compound (I) can be used.
  • a compound obtained in each Step can be isolated and ⁇ urliffife- ⁇ i ⁇ A ⁇ H ⁇ sepa ation and purification methods, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • the compound obtained in each Step can be directly used for the next reaction without isolation and in the form of a reaction mixture containing the compound.
  • R 11 is a hydrogen atom or a C ⁇ _ 6 alkyl group (e.g., methyl, ethyl) and other symbols are as defined above.
  • compound (II) is subj ected to reduction reaction to give compound (I-l)
  • compound ( I-l) is subjected to an oxidation reaction to give compound ( 1-2)
  • compound (I- 2) is reacted with an organic metal reagent to give compound (1-3)
  • compound (1-3) is subjected to an oxidation reaction to give compound (1-4)
  • compound (1-4) is reacted with compound (III) to give compound (1-5) .
  • Step 1 compound (1-4) is reacted with compound (IV) to give compound (1-6) (Step 1)
  • compound (II) is subjected to reduction reaction to give compound (I-l) .
  • This reaction is carried out by a method known per se. That is, this reaction is carried out according to a conventional method in t-he presence of a reducing agent in a solvent that does not adversely affect the reaction or without solvent.
  • a reducing agent for example, sodium borohydride,
  • the amount of the reducing agent to be used is generally about 0.5 to about 20 molar equivalents, preferably aboi t 1 to about 10 molar equivalents, relative to compound (II) .
  • the solvent that does not adversely affect the reaction for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; water; alcohols such as methanol, ethanol, isopropanol and the like, and the like can be mentioned. Two or more kinds of the se solvents may be mixed before use at an appropriate ratio .
  • the reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C.
  • the reaction time is generally about 0.5 to about 20 hrs .
  • Step 2 the compound (I-l) is subjected to an oxidation reaction to give compound (1-2) .
  • This reactions is carried out by a method known per se . That is, this reaction is carried out according to a conventional method in the presence of an oxidant in a solvent that does not advers ely affect the reaction or without solvent.
  • an oxidant for example, metal oxidants such as manganese dioxide, pyridinium chlorochromate, pyridinium- dichromate, ruthenium oxide and the like can be mentioned.
  • the amount of the oxidant to be used is generally about 0.5 - about 20 molar equivalents, preferably about 1 - a-bout 10 molar equivalents, relative to compound (I-l) .
  • the solvent that does not adversely affect the reaction for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofxiran, dioxane, diethyl ether and the like; halogenated hydrocarbons and the like; and the like- can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio.
  • the reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C.
  • Step 3 In this Step, compound (1-2) is reacted with an organic metal reagent to give compound (1-3) .
  • This reaction is carried out by a method known per se. That is, this reaction is carried out according to a conventional method in a solvent that does not adversely affect the reaction or without solverxt,
  • organic metal reagent Grignard reagents represented by the formula: HalMgR 10 (Hal is a halogen atom (e.g., chlorine, bromine) and R 10 is as defined above), organic; lithium reagents represented by the formula: LiR 10 (the symbol is as defined above) and the like can be mentioned.
  • the organic metal reagent can be produced according to a method known per se.
  • the solvent that does not adversely affect the reaction for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio.
  • the amount of the organic metal reagent to be used is generally about 0.5 to about 20 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (1-2) .
  • the reaction temperature is generally about -100 to about 150°C, preferably about -80 to about 100°C.
  • Step 4 (1-3) is subjected to an oxidation reaction to give compound (1-4) .
  • This reaction is carried out in the same manner as in the aforementioned Step 2.
  • Step 5 In this step, compound (1-4) is reacted with compound (III) to give compound (1-5) .
  • This reaction is carried out by a method known per se. That is, this reaction is carried out according to a conventional method in a solvent that does not adversely affect the reaction or without solvent.
  • compound (III) for example, hydroxylamine, N- alkylhydroxylamine or a salt thereof can be mentioned.
  • a salt here, for example, hydrochloride, oxalate and the like can be mentioned.
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; alcohols such as ethanol, methanol and the like; amides such as N,N- dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; aliphatic carboxylic acids such as acetic acid and the like; water and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio.
  • the amount of the compound (III) to be used is generally about 1 to about 20 molar equivalents, preferably about 2 to about 10 molar equivalents, relative to compound (1-4) .
  • the reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C.
  • the reaction time is generally about 0.5 to about 20 hrs. This reaction may be carried out in the presence of an acid or a neutralizing agent.
  • Step 6 As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid and the like can ' " '''le ro-.rf i ; on : 9V ' "As"" the' 1 "neutralization agent, for example, bases such as pyridine, triethylamine, sodium carbonate, sodium acetate and the like can be mentioned.
  • the acid for example, hydrochloric acid, sulfuric acid, acetic acid and the like can ' " '''le ro-.rf i ; on : 9V ' "As"
  • the' 1 "neutralization agent for example, bases such as pyridine, triethylamine, sodium carbonate, sodium acetate and the like can be mentioned.
  • Step 6 In this step, compound (1-4) is reacted with compound (IV) to give compound (1-6) .
  • This reaction is carried out by a method known per se . That is, this reaction is carried out according to a conventional
  • compound (IV) for example, aminoguanidine, semicarbazide and a salt thereof can be mentioned.
  • a salt for example, hydrochloride, acetate and the like can be mentioned.
  • the solvent that does not adversely affect the reaction those exemplified in the aforementioned Step 5 are used.
  • the amount of the compound (IV) to be used is generally about 1 to about 20 molar equivalents, preferably about 1.2 to about 10 molar equivalents, relative to compound (1-4) .
  • the reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C.
  • the reaction time is generally about 0.5 to about 20 hrs. This reaction may be carried out in the presence of an acid or a neutralizing agent.
  • the acid for example, hydrochloric acid, sulfuric acid, acetic acid and the like can be mentioned.
  • neutralization agent for example, bases such as pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium acetate and the like can be mentioned.
  • the compound (II), compound (III) and compound (IV) used as starting compounds in the above-mentioned Method A can be produced by a method known per se .
  • the compound (II') which is a compound (II) group and R 6 is a hydrogen atom, can be produced by the following Method B or a method analogous thereto. [Method B]
  • Step 1 compound (V) is reacted with an oxalic acid ester and a potassium salt to give compound (VI) , and compound (VI) is subjected to reduction reaction under acidic conditions to give compound (II 1 ).
  • Step 1 compound (V) is reacted with an oxalic acid ester and a potassium salt to give compound (VI) .
  • This reaction is carried out by a method known per se . That is, this reaction is carried out according to a conventional method in the presence of a potassium salt in a solvent that does not adversely affect the reaction or without solvent.
  • oxalic acid ester a compound represented by the formula (C0 2 R 1:L ') 2 wherein the symbol is as defined above is used.
  • dimethyl oxalate, diethyl oxalate and the like can be mentioned.
  • potassium salt for example, potassium tert- butoxide, potassium ethoxide and the like can be mentioned.
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; alcohols '•'Iic-ht M' tftahol and the like; amides such as N,N- dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio.
  • the amount of the oxalic acid ester to be used is generally about 1 to about 20 molar equivalents, preferably about 1.2 to about 10 molar equivalents, relative to compound (V) .
  • the amount of the potassium salt to be used is generally about 1 to about 20 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (V) .
  • the reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C.
  • the reaction time is generally about 0.5 to about 20 hrs.
  • Step 2 In this step, compound (VI) is subjected to reduction reaction under acidic conditions to give compound (II'). This reaction is carried out by a method known per se.
  • this reaction is carried out according to a conventional method in the presence of a reducing agent and an acid a solvent that does not adversely affect the reaction or without solvent.
  • a reducing agent for example, iron, zinc and the like can be mentioned.
  • the acid for example, acetic acid, hydrochloric acid and the like can be mentioned.
  • the solvent that does not adversely affect the reaction those exemplified in the aforementioned Method A, step 5, are used.
  • the amount of the reducing agent to be used is generally about 1 to about 20 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (VI) . sr i ' i i ,•• !
  • E!fe acid to be used is generally about 1 to about 100 molar equivalents, preferably about 1 to about 20 molar equivalents, relative to compound (VI) .
  • the reaction temperature is generally about 0 to about 150°C, preferably about 10 to about 100°C.
  • the reaction time is generally about 0.5 to about 20 hrs.
  • the compound (V) and an oxalic acid ester which are used as starting compounds in the above-mentioned Method B can be produced according to a method known per se .
  • compound (III) can be produced by means of the following Method C or a method analogous thereto. [Method C]
  • Step 1 compound (VII) is reacted with N- hydroxyphthalimide to give compound (VIII) and compound (VIII) is reacted with methylhydrazine to give compound (III) .
  • Step 1 compound (VII) is reacted with N- hydroxyphthalimide to give compound (VIII) .
  • This reaction is carried out by a method known per se. That is, this reaction is carried out in the presence of an organic phosphorus compound and an electrophilic agent in a solvent that does not adversely affect the reaction or without solvent.
  • 'iriosphorus compound for example, triphenylphosphine, tributylphosphine and the like can be mentioned.
  • electrophilic agent for example, diethyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbonyldipiperidine and the like can be mentioned.
  • ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; and the like can be mentioned. Two or more kinds of these solvents may Toe mixed before use at an appropriate ratio.
  • the amount of N-hydroxyphthalimide to be used is generally about 1 to about 5 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (VII) .
  • the amount of the organic phosphorus compound and electrophilic agent to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, relative to compound (VII) .
  • the reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C.
  • the reaction time is generally about 0.5 to about 40 hrs.
  • Step 2 In this step, compound (VIII) is reacted with iuethylhydrazine to give compound (III) . This reaction is carried out by a method known per se.
  • this reaction is carried out in a solvent that does not adversely affect the reaction or without solvent.
  • a solvent that does not adversely affect the rea'c i' ⁇ n ⁇ if ⁇ ' e' dmj-flS;"" aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; alcohols such as ethanol, methanol and the like; amides such as N,N- dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; water and the like can be mentioned.
  • the amount of methylhydrazine to be used is generally about 1 to about 5 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (VIII) .
  • the reaction temperature is generally about -50 to about
  • the reaction time is generally about 0.5 to about 40 hrs.
  • the compound (VII) used as a starting compound in the above-mentioned Method C can be produced according to a method known per se.
  • Compound (1-7) which is compound (I) wherein R 4 is a hydrogen atom and R 5 is Het-CO- and compound (1-7') which is compound (I) wherein R 4 is a hydrogen atom and R 5 is Ar-(CH 2 )n- NH-CO- are produced by, for example, the following Method D or a method analogous thereto.
  • condensation agent for example, carbodiimide condensation reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, l-ethyl-3- dimethylaminopropylcarbodiimide, hydrochloride thereof and the like; phosphoric acid condensation reagents such as diethyl cyanophosphate, diphenyl phosphoryl azide and the like; carbonyldiimidazole, 2-chloro-l, 3-dimethylimidazolium tetrafluoroborate and the like can be mentioned.
  • carbodiimide condensation reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, l-ethyl-3- dimethylaminopropylcarbodiimide, hydrochloride thereof and the like
  • phosphoric acid condensation reagents such as diethyl cyanophosphate, diphenyl phosphoryl azide and the like
  • amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers «"' su ⁇ h" ' ci'-l' , '%fe;'Sahy ' -!o « ; ⁇ dioxane, diethyl ether and the like; ethyl acetate; water and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio.
  • the amount of compound (IX) and compound (IX') to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (II-l) •
  • the amount of condensation agent to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (II-l) .
  • a suitable condensation promoter e.g., l-hydroxy-7- azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide.
  • the reaction efficiency can be generally improved by adding an organic amine base such as triethylamine and the like.
  • the amount of the above-mentioned condensation promoter and the organic amine base to be used is generally about 0.1 to about 10 molar equivalents, preferably about 0.3 to about 3 molar equivalents, relative to compound (II-l) .
  • the reaction temperature is generally, about -30°C to about 100°C.
  • the reaction time is generally about 0.5 to about 60 hrs.
  • the compound (II-l), compound (IX) and compound (IX') used as starting compounds in the above-mentioned Method D can be produced according to a method known per se .
  • Compound (1-8) which is compound (I) wherein R 4 is a R 13 R 1 NCH - can be produced by, for example , the following Method E or a method analogous thereto . [Method E]
  • compound (1-2) is reacted with compound (IX'') to give compound (1-8) .
  • This reaction is carried out by a method known per se . That is, this reaction is generally carried out in the presence of a reducing agent in a solvent that does not adversely affect the reaction or without solvent.
  • a reducing agent for example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like can be mentioned.
  • the solvent that does not adversely affect the reaction those exemplified in the aforementioned Method A, Step 1, can be used.
  • the amount of compound (IX'') to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (1-2) .
  • the amount of the reducing agent to be used is generally about 0.5 to about 20 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (1-2) .
  • the reaction temperature is generally, about -50°C to about 150°C, preferably about -10°C to about 100°C.
  • the reaction time is generally about 0.5 to about 20 hrs.
  • the compound compound (IX'') used as a starting compound in the above-mentioned Method E can be produced according to a method known per se .
  • the compound (1-9) used as a starting compound in the above-mentioned Method F can be produced by, for example, the aforementioned Method A or a method analogous thereto.
  • compound (X) can be produced according to a method known per se .
  • Compound (1-5') which is compound (1-5) wherein R 8 is a group bonded via a carbon atom, can be also produced by, for example, the following Method G or a method analogous thereto. " Mefch ' ⁇ ' '"* ' • ' ' ral! "
  • L is a leaving group
  • R 8 ' is a group bonded via a carbon atom
  • other symbols are as defined above.
  • L halogen atoms (e.g., fluorine, chlorine, bromine, iodine)
  • C ⁇ - 6 alkylsulfonyloxy groups e.g., methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy
  • C 6 _ ⁇ o arylsulfonyloxy group e.g.,
  • C ⁇ -. 6 alkyl groups e.g., methyl, ethyl
  • C ⁇ _6 alkoxy groups e.g., methoxy, ethoxy
  • acyloxy groups e.g., trichloroacetoxy, trifluoroacetoxy and the like
  • compound (1-9) is reacted with compound (XI) to give compound (1-5').
  • This reaction is carried out by a method known per se . That is, this reaction is generally carried out in the presence of a base in a solvent that does not adversely affect the reaction or without solvent.
  • alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate and the like
  • amines such as pyridine, triethylamine, N,N-dimetlylaniline, 1,8- diazabicyclo [5.4.0] undec-7-ene and the like
  • metal hydrides such as sodium hydride, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate and the like
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like
  • aromatic hydrocarbons such as benzene, ftollb ⁇ n' ⁇ ; ;r *»yile e « ' &® ⁇ l-i!fe like
  • ethers such as tetrahydrofuran, dioxane, diethyl ether and the like
  • ketones such as acetone, 2-butanone and the like
  • halogenated hydrocarbons such as chloroform, dichloromethane and the like
  • amides such as N,N- dimethylformamide and the like
  • sulfoxides such as dimethyl sulfoxide and the like; and the like
  • the amount of compound (XI) and the base to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, relative to compound (I- 9) .
  • the reaction temperature is generally about -50°C to about 150°C, preferably about -10°C to about 100°C.
  • the reaction time is generally about 0.5 to about 20 hrs.
  • the compound (XI) used as a starting compound in the above-mentioned Method G can be produced according to a method known per se .
  • Compound (1-12) which is compound (I) wherein R 1 , R 2 , R 3 and R 4 are each a hydrogen atom, R 5 is R 10 CH(OH)- and.
  • R 6 is R 15 S0 2 -; and compound (1-13) which is compound (I) wherein R 1 , R 2 , R 3 , R 4 and 6 are each a hydrogen atom and R 5 is 10 CH(OH)- can be produced by, for example, the following Method H or a method analogous thereto.
  • Step 1 compound (XII) is reacted with compound (XIV) to give compound (XIII) .
  • This reaction is carried out by a method known per se . That is, this reaction is generally carried out in the presence of a base in a solvent that does not adversely affect the reaction or without solvent.
  • alkali metal salts such as potassium hydro-xide, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate and the like
  • amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8— diazabicyclo [5.4.0] undec-7-ene and the like
  • metal hydrides such as potassium hydride, sodium hydride and the like
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide,- potassium tert-loutoxide and the like
  • alkali metal amides such as lithium diisopropylamide and the like
  • the amount of compound (XIV) and the base to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, relative to compound (XII) ⁇
  • the reaction temperature is generally, about -100°C to about 150°C, preferably about -80°C to about 100°C.
  • the reaction time is generally about 0.5 to about 20 hrs.
  • Step 2 In this Step, compound (XIII) is reacted with compound (XV) to give compound (1-12) .
  • This reaction is carried out by a method known ]per se . That is, this reaction is generally carried out in the presence of a base in a solvent that does not adversely affect the reaction or without solvent.
  • P alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate and the like; amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8- diazabicyclo[5.4.0]undec-7-ene, N,N,N',N'- tetramethylethylenediamine and the like; metal hydrides such as potassium hydride, sodium hydride and the like; alkali metal alkoxides such as sodiiam methoxide, sodium ethoxide, potassium tert-butoxide and the like; and alkali metal amides such as lithium diisopropylamide and the like can be mentioned.
  • amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8- diazabicyclo[5.4.0]undec-7-ene, N,N,N',N'- tetramethylethylenediamine and the like
  • the amount of compound (XV) and the base to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, relative to compound (XIII) .
  • the reaction temperature is generally, about -100°C to about 150°C, preferably about -80°C to about 100°C.
  • the reaction time is generally about 0.5 to about 20 hrs. (Step 3) In this Step, compound (1-12) is reacted with hydroxide ion to give compound (1-13) . This reaction is carried out by a method known per se .
  • this reaction is generally carried out in a solvent that does not adversely affect the reaction or without solvent.
  • the hydroxide ion for example, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; and the like can be mentioned.
  • the solvent that does not adversely affect the reaction those exemplified in the aforementioned Method A, ' » us , . «' « t ' ⁇
  • the amount of the hydroxide i-on to be used is generally about 1 to about 50 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (1-12) .
  • the reaction temperature is cjenerally about 0°C to about 150°C, preferably about 10°C to about 100°C.
  • the reaction time is generaliy about 0.5 to about 20 hrs.
  • the compound (XII) , compound (XIV) and compound (XV) used as starting compounds in the above—mentioned Method H can be produced according to a method known per se .
  • Step 2 In this Step, compound (1-15) is subjected to oxidation reaction to give compound (1-16) . This reaction is carried out in the same manner as in the aforementioned Method A, Step 4.
  • Step 3 In this Step, compound (1-16) is ---reacted with compound (III) to give compound (1-17) . This rea-ction is carried out in the same manner as in the aforementioned Method A, Step 5.
  • Step 4) In this Step, compound (1-16) is --reacted with compound (IV) to give compound (1-18) . This reaction is carried out in the same manner as in the aforementioned Method A, Step 6.
  • the compound (1-14) used as a sta-trting compound in the above-mentioned Method I can be produced according to a method known per se .
  • a protecting group generally used for these groups in peptide chemistry and the like may be introduced. By removing the protecting group as necessary after the reaction, the object compound can be obtained.
  • amino-protecting group fo-- example, formyl group, (e.g., acetyl, propionyl), C ⁇ - 6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl) , benzoyl group, C-n aralky-L-carbonyl groups (e.g., benzylcarbonyl), C 7 -.
  • formyl group e.g., acetyl, propionyl
  • C ⁇ - 6 alkoxy-carbonyl groups e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl
  • benzoyl group C-n aralky-L-carbonyl groups (e.g., benzylcarbonyl), C 7 -.
  • aralkyloxy-carbonyl groups e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl
  • trityl group e.g., phthaloyl group
  • phthaloyl group N,N-dimethylaminomethylene group
  • silyl groups e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, te-t-rt- butyldiethylsilyl
  • C 2 - 6 alkenyl groups e.g., 1-s.llyl
  • These groups may be substituted by 1 to 3 substituents selected from halogen atoms (e.g.,- fluorine, chlorine, bromine, iodine), C ⁇ _ 6 alkoxy groups (e.g., methoxy, ethoxy, propoxy) , nitro group and the like .
  • halogen atoms e.g.,- fluorine, chlorine, bromine, iodine
  • C ⁇ _ 6 alkoxy groups e.g., methoxy, ethoxy, propoxy
  • C ⁇ - 6 alkyl groups e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl
  • C7- 11 aralkyl groups e.g., benzyl
  • phenyl group e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl
  • C7- 11 aralkyl groups e.g., benzyl
  • phenyl group e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl
  • C7- 11 aralkyl groups e.g., benzyl
  • phenyl group e.g., trityl group
  • silyl groups e.g., trimethylsilyl r triethylsilyl, dimethylphenylsilyl, ter
  • These groups may be substituted by 1 to 3 substituents selected from halogen atoms (e.g., fluorine, chlorine, bromine, iodine), C 1 -6 alkoxy groups (e.g., methoxy, ethoxy, propoxy), rxitro group and the like .
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • C 1 -6 alkoxy groups e.g., methoxy, ethoxy, propoxy
  • rxitro group e.g., rxitro group and the like .
  • Ci-s alkyl groups e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl
  • phenyl group trityl group
  • C 7 -u aralkyl groups e.g., benzyl
  • formyl group C ⁇ - 6 alkyl-carbonyl groups (e.g., acetyl, propionyl), benzoyl group, C-n aralkyl-carbonyl groups (e.g., benzylcarbonyl) , 2-tetrahydropyranyl group, 2- tetrahydrofuranyl group
  • silyl groups e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldim-ethylsilyl, tert-butyldiethylsilyl
  • these protective groups can be removed by a method known per se, e.g., the method described in -Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). For example, there may be used methods employing an acid, a base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fHuoride, palladium acetate, a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) , or the like, the reduction method, and the like.
  • a trialkylsilyl halide e.g., trimethylsilyl iodide, trimethylsilyl bromide
  • compound (I) contains an optical isomer, a stereoisomer, a position isomer, or a rotation isomer
  • these isomers are also contained as compound (I) and can each be obtained as a single substance by means of a method known per se of synthesis or separation.
  • an optical isomer is present in compound (I)
  • the optical isomer separated from said compound is also included in compound (I) .
  • These isomers can be produced by a method known per se .
  • the compound (I) may be a crystal and both single crystal and mixtures of crystals are encompassed in compounol (I) .
  • the crystal of compound (I) (hereinafter sometimes to be abbreviated as crystal of the present invention) can- be produced by crystallization, by applying a crystalli zation method known per se to compound (I) .
  • the compound (I) may also be in the form of solvate (e.g., hydrate) or non-solvates, which are also encompasse in compound (I) .
  • j i, I X be labeled with an isotope (e.g., 3 H, 1 C, 35 S, 125 I and the like) and the like, which are also encompassed in compound (I) .
  • the present invention is explained in detail by referring to the following Reference Examples, Examples, Experimental Examples and Formulation Examples, which are not to be construed as limitative.
  • Reference Examples and Examples mean the following. s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, brs : broad singlet, J: coupling constant
  • room temperature means a temperature of 1°C to 30°C
  • % means percent by weight, unless otherwise indicated particularly.
  • the gene manipulation methods described in the following Reference Examples followed a method described in a book (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or a method described in the attached protocol of the reagent.
  • SEQ ID NOs of the sequence listing in the present specification show the following sequences.
  • [SEQ ID NO: 1] A base sequence of primer used for PCR in Reference Example 1A below.
  • [SEQ ID NO: 2] A base sequence of primer used for PCR in Reference Example 1A below.
  • [SEQ ID NO: 3] A base sequence of primer used for PCR in Reference Example 2A below.
  • [SEQ ID NO: 4] * A"' , ba , Be*' l S'e ⁇ -eh'ce l, « ⁇ f" r - ⁇ .er used for PCR in Reference Example 2A below.
  • PCR was performed according to a protocol attached to LA Taq DNA polymerase (TAKARA SHUZO CO., LTD.). The obtained PCR product was electrophoresed on an agarose gel (1%) and a 2.3 kb DNA fragment containing IKK ⁇ gene was recovered from the gel and digested with restriction enzymes Nhe I and Kpn I.
  • Reference Example 3A Preparation of active IKK ⁇ Sf-21 cells (Invitrogen) were sown in 150 ml of Sf-900 II SFM medium (Invitrogen) containing 10% fetal calf serum to 1x10 s cells/ml and cultured at 27°C for 24 hrs. To the obtained culture medium were added 150 ⁇ l of virus stock BAC-IKKB of recombinant baculovirus obtained in Reference Example 1A and the cells were further cultured for 60 hrs. The culture medium was centrifuged (3000 rpm, 10 min) to separate the cells, and the cells were washed once with PBS.
  • the cells were suspended in 10 ml of a cytolysis buffer (25 mM HEPES (pH 7.5), 1% Triton X, 130 mM sodium chloride, 1 mM EDTA, ImM Dithiothreitol, 25 mM ⁇ -glycerophosphate, Protease inhibitor Complete (Boeringer) , 1 mM Sodium orthovanadate) , and treated 4 times in a homogenizer (POLYTRON) at 20000 rpm for 30 sec to rupture the cells.
  • the cell rupture suspension was centrifuged (40000 rpm, 45 min.), and active IKK ⁇ was purified from the obtained supernatant using Anti-FLAG M2 Affinity Gel (Sigma) .
  • the plasmid pGEIKB obtained in Reference Example 2A was transformed into Escherichia coli JM109 (TOYOBO) to give an ampicillin resistant strain pGEIKB/JMl09.
  • the pGEIKB/JMl09 strain was cultured in 150 ml of LB medium (10 g/1 tryptone, 5 g/1 yeast extract, 10 g/1 sodium chloride) supplemented with 50 ⁇ g/ml ampicillin overnight at 200 rpm, 37°C.
  • the culture medium (15 ml) was added to a fresh LB medium (150 ml) and cultured at 37°C for 2 hrs at 200 rpm. 1 mM IPTG (Wako Pure Chemical Industries, Ltd.) was added and the medium was further cultured for 6 hrs. The culture medium was centrifuged at 8000 rpm for 10 min. The cells were recovered, washed with PBS and frozen at -80°C. The cells were suspended in 15 ml of a cytolysis buffer (1% Triton X-containing PBS, 1 mM APMSF) and the suspension was ultrasonicated in iced water using a cytolysis buffer (1% Triton X-containing PBS, 1 mM APMSF) and the suspension was ultrasonicated in iced water using
  • SONIFIER450 (BRANSON) to rupture the cells.
  • the cell rupture suspension was centrifuged (14000 rpm, 15 min., 4°C) and GST- I ⁇ B ⁇ fused protein was purified from the obtained supernatant using Redipack GST Purification Module (Amersham Pharmacia Biotech) and desalted using a NAP-25 column (Amersham Pharmacia Biotech) .
  • Redipack GST Purification Module (Amersham Pharmacia Biotech) and desalted using a NAP-25 column (Amersham Pharmacia Biotech) . Examples Unless otherwise noted, reagents and solvents were used as received from commercial suppliers .
  • Proton and carbon nuclear magnetic resonance spectra were obtained on a Bruker AC 300 or a Bruker AV 300 spectrometer at 300 MHz for proton and 75 MHz for carbon. Spectra are given in ppm ( ⁇ ) and coupling constants, J, are reported in Hertz.
  • Tetramethylsilane was used as an internal standard for proton spectra and the solvent peak was used as the reference peak for carbon spectra.
  • Infrared spectra were obtained on a Nicolet Nexus 470 (ATR) spectrometer.
  • Mass spectra were obtained on a Perkin Elmer Sciex 100 atmospheric pressure _ a Shimadzu QP-5000 mass spectrometer (CI) , or a Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) mass spectrometer.
  • Thin-layer chromatography (TLC) was performed using Analtech silica gel plates and visualized by ultraviolet (UV) light, iodine, or 20 wt % phosphomolybdic acid in ethanol.
  • HPLC analyses were obtained using a Phenomenex Synergi Hydro-RP column (250 x 4.6 mm) with UV detection at 223 nm (Methods A, B and D) .
  • Preparative HPLC was performed using a Phenomenex Luna C18(2) column (250 * 21.2 mm) with Luna C18(2) guard column (60 x 21.2 mm) and UV detection at 223 nm (Method C) .
  • A Water with 0.05% v/v Trifluoroacetic Acid
  • B Acetonitrile with 0.05% v/v Trifluoroacetic Acid
  • A. Water with 0.05% v/v Trifluoroacetic Acid
  • B Acetonitrile with 0.05% v/v Trifluoroacetic Acid ⁇ r r*' "?' " !I i; ds f Id "If S MK ' ,t ⁇ h”Ibd ' l” ⁇ __:: ⁇ " TM3f-- "ii enomenex Luna C18 (2) column]
  • A Water with 0.05% v/v Trifluoroacetic Acid
  • B Acetonitrile with 0.05% v/v Trifluoroacetic Acid
  • A Water with 0.05% v/v Trifluoroacetic Acid
  • B Acetonitrile with 0.05% v/v Trifluoroacetic Acid
  • Ethyl 7-chloro-lH-pyrrolo [2, 3-c] pyridine-2-carboxylate (preparation described in Reference Example 1) (240 mg, 1.07 mmol), phenol (500 mg, 5.35 mmol) and cyclohexylamine (1.1 mL, 10.7 mmol) were combined in a sealed tube and heated at 100°C for 6 h. The reaction tube was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL) , washed with 2 N sodium hydroxide (10 mL) and brine (10 mL) , dried over magnesium sulfate, and evaporated to provide 538 mg of dark brown viscous oil.
  • the aqueous layer was extracted with dichloromethane (2 x 50 mL) .
  • the combined organic extracts were washed with 1 N HCl (100 mL) and brine (100 mL) , dried (Na 2 S0 4 ) , filtered, and concentrated in vacuo.
  • the residue was purified by chromatography (silica gel, 10% ethyl acetate/hexanes) to provide 2- (dibenzylamino) -4-methyl-3-nitropyridine (1.53 g, 4.59 mmol, 75%) as a bright yellow oil which solidified upon hexanes/ethyl acetate) ; 1 H NMR ( 300 MHz, CDCI 3 ) 52 .
  • the solid was transferred to a vial and dried under vacuum at 30°C for 2 h to provide potassium (1-2) -1- [2- (dibenzylamino) -3-nitropyridin-4-yl] -3-ethoxy-3-oxoprop-l-en- 2-olate (1.63 g, 3.46 mmol, 76%) as a light orange solid. This product was immediately used without purification or identification.
  • reaction mixture was warmed to 10°C and quenched by the addition of saturated NHC1 (5 mL) .
  • the reaction mixture was diluted with H 2 0 (20 iriL) and extracted with EtOAc (2 x 40 mL) .
  • the combined extracts were dried (Na 2 S0) and concentrated under reduced pressure.
  • Methylhydrazine (2.16 ml, 40.68 mmol) was added dropwise to a suspension of 2- [ (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2- yl) oxy] acetamide (2.0 g, 9.04 mmol) in MeOH/CH 2 Cl 2 (2:8, 100 iH ' iy! "i i o ⁇ p ' h 3" 1i ⁇ t ⁇ on mixture was stirred at 0°C for 10 min and then at room temperature for 6 h. The solvent was removed in vacuo. The solid was triturated with methylene chloride and filtered.
  • the crude imine intermediate (1.3 g, 3.6 mmol) was dissolved in methanol (18.3 mL) , cooled to 0°C and placed under a nitrogen atmosphere, and sodium borohydride (0.14 g, 3.6 mmol) was carefully added. Upon complete addition of sodium borohydride, the ice/water bath was removed and the reaction mixture was stirred overnight (18 h) . The reaction mixture was quenched with water and concentrated to remove methanol. The residue was diluted with ethyl acetate, and the product was extracted with 2 N HCl (3x) . The combined extracts were washed with ethyl acetate.
  • the acidic extracts were made basic (pH 10) with 6 N NaOH then extracted with ethyl acetate (3x) .
  • the combined organic extracts were dried over Na 2 S0, filtered and concentrated to give a yellow foam.
  • the crude foam was dissolved in methanol and ethereal HCl was added. This mixture was concentrated to dryness, and then triturated with ethyl acetate.
  • Phenyl [1- (phenylsulfonyl) -IH-pyrrolo [2, 3-c]pyridin-2- yl]methanone (Reference Example 13) (2.2 g, 6.1 mmol) and 10% aq NaOH (70 mL) in EtOH (135 mL) was heated to reflux. After 14 h, the mixture was concentrated under reduced pressure to remove most of the EtOH. The mixture was diluted with H 2 0 (50 mL) and extracted with EtOAc (2 x 100 mL) . The combined extracts were washed with saturated NaCl (25 L) , dried (Na 2 S0 4 ) and concentrated under reduced pressure.
  • tert-butyl 2- [ [ (3-furyl) (1H- pyrrolo [2, 3—c]pyridin-2-yl) methylene] amino] oxy] ethylcarbamate (50 mg, 45%) as a yellow solid.
  • tert-Butyl 2- [ [ (3-furyl) (IH-pyrrolo [2, 3-c] pyridin-2- yl)methylene] amino] oxy] ethylcarbamate (50 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (5 mL) and the solution was stirred at room temperature for 1 h.
  • Phenyl (IH-pyrrolo [2 ,3- ⁇ ]py-cridin-2-yl) methanone oxime To a mixture of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (Example 35) (161 mg, 0.72 mmol) and hydroxylamine hydrochloride (100 mg, 1.45 mmol) in ethanol (3.6 mL) were added Li0H'H 2 O (120 mg, 2.16 mmol) and water (1.0 was heated under reflux until TLC analysis indicated consumption of the ketone. The mixture was concentrated to dryness.
  • Example 40 To a solution of 1-phenyl-l- (IH-pyrrolo [2, 3-c]pyridin-2- yl)methylamine dihydrochloride (Example 40) (51 mg, 0.17 mmol), N,N-diisopropylethylamine (DIPEA) (0.15 mL, 0.85 mmol) and nicotinic acid (22 mg, 0.18 mmol) in methylene chloride (2.0 mL) was added l-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC-HCl) (30 mg, 0.20 mmol) followed by a catalytic amount of 4-dimethylaminopyridine (DMAP) .
  • DIPEA N,N-diisopropylethylamine
  • EDC-HCl l-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride
  • the reaction mixture was stirred at room temperature overnight (20 h) under a ⁇ 2 atmosphere. TLC analysis showed the starting amine, therefore the reaction mixture was heated to reflux. After refluxing overnight, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and water. The organic layer was washed with water, 1 M citric acid, saturated NaHC0 3 , and saturated NaCl. TLC analysis showed that the majority of desired product was extracted into the 1 M citric acid washing. The citric acid extracts were made basic with 15% NaOH solution and extracted with methylene chloride. The organic extracts were dried over Na 2 S0 4 , filtered and concentrated to dryness.
  • Example 43 Using the procedure described for Example 43 with isonicotinic acid at room temperature, the reaction was stopped once 1-phenyl-l- (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylamine was consumed as judged by TLC analysis. Upon addition of water a solid precipitated.
  • Example 43 Using the procedure described for Example 43 with benzoic acid at room temperature, the reaction was stopped once 1- phenyl-1- (IH-pyrrolo [2, 3-c]pyridin-2-yl)methylamine was consumed as judged by TLC analysis. Upon addition of water a solid precipitated.
  • Phenyl (IH-pyrrolo [2 ,3-c]pyridin-2-yl)methanol To a solution of (7-chloro-lH-pyrrolo [2, 3-c]pyridin-2- yl) (phenyl)methanol (Example 26) (2.10 g, 8.12 mmol) a-nd ammonium formate (3.07 g, 48.7 mmol) in methanol (28 mL) was added 10% Pd/C (0.21 g) . The reaction mixture was refluxed for 1.5 h. TLC analysis showed the starting material was consumed. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated to dryness. The crude mixture was dissolved in EtOAc and water.
  • Example 53 1- [5- (Dibenzylamino) -IH-pyrrolo [2, 3-c]pyridin-2- yl] ethanol (Example 53) was oxidized using manganese dioxide to provide 1- [5- (dibenzylamino) -IH-pyrrolo [2, 3-c]pyridin-2- yl] ethanone following the procedure described for Example 139 using tetrahydrofuran as a solvent.
  • Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- [2- (dimethylamino) ethyl] oxime was prepared as a yellow solid following the procedure described for Example 58 using commercially available dimethyl aminoethyl chloride :
  • X E NMR 500 MHz, CD 3 OD
  • ⁇ 2.99 (6H, s) , 3.31 (3H,s), 3.68-3.72 (2 H, m) , 7.07 (1 H, s), 7.47-7.63 (5 H, m) , 8.16-8.28 (2H, m) , 9.25 (IH, s);
  • HPLC Methodhod A
  • 96.8 % (AUC) , t R 13.3 min.
  • Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl)methanone 0- (2- methoxyethyl) oxime was prepared as an orange oil following the procedure described for Example 58 using commercially available 2-chloroethyl methyl ether: 1 H NMR (300 MHz, CDC1 3 ) ⁇ 3.38 (0.6H, s), 3.54 (2.4H,s), 3.70-3.83 (2 H, m) , 4.35-4.55 (2H, m) , 6.38 (0.2H, s) , 6.53(0.8H, s) , 7.40-7.69 (6H, m) , 8.23-8.25 (1 H, m) , 8.86-8.91 (IH, m) , 9.25 (0.2H, br s) ,
  • Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- (2- aminoethyl ) oxime hydrochloride was prepared by treating tert- butyl 2- [ [ [phenyl (IH-pyrrolo [2, 3-c]pyridin-2- yl) methylene] amino] oxy] ethylcarbamate (Example 60) with ethereal hydrogen chloride as an off-white solid (a mixture of isomers) : mp 176-184°C dec; X H NMR (500 MHz, CD 3 OD) 6 3.22 (2H, br s), 3.37 (2H, br s) , 4.44-4.81 (2H, m) , 6.68 (0.17 H, s) 7.00 (0.83 H, s), 7.37-7.54 (6H, m) , 7.97-8.20 (IH, m) , 8.96 (0.17 H, br s), 9.14 (0.
  • the reaction mixture was poured into stirring cold water (25 mL) and extracted with ethyl acetate (3 * 10 mL) . The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. Purification by Biotage chromatography (1 to 10% methanol in methylene chloride) produced an oil. The oil was dissolved in ethyl acetate (5 mL) and ethereal hydrogen chloride (0.45 mL of a 1 M solution in diethyl ether) was added. The reaction mixture was stirred for 1 h and the precipitate formed.
  • reaction mixture was cooled to -30°C and additional 2.0 M isopropylmagnesium bromide in diethyl ether (0.22 mL, 0.44 mmol) was added.
  • the reaction mixture was stirred for another 1 h, while warming to room temperature .
  • the reaction mixture was poured into a 2 : 1 solution of saturated ammonium chloride and water, and extracted with ethyl acetate (3*) .
  • the combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated.
  • Example 80 2 -Methyl- 1 - ( IH-pyrrolo [ 2 , 3 - ⁇ ] pyriciin- 2 -yl ) - 1 -propanone
  • Example 90 tert-Butyl 3- [ [ [phenyl (IH-pyrrolo [2 ,3-c]pyridin-2- yl)methylene] amino] oxy]pyrrolidine-l-carboxylate
  • phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (Example 35) (90 mg, 0.40 mmol)
  • tert-butyl 3- (aminooxy)pyrrolidine-l-carboxylate (Reference Example 9) (82 mg, 0.40 mmol) in isopropanol (6 mL) was added 4 A molecular sieves. The pH of the solution was adjusted to pH 4-5 with glacial acetic acid.
  • Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- pyrrolidin-3-yloxime dihydrochloride (12.3 mg, 33%) was prepared as an off-white amorphous solid from tert-butyl 3- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] pyrrolidine-1-carboxylate (Example 90) following the procedure described for Example 77, except 1:1 trifluoroacetic acid/CH 2 Cl 2 was used:
  • Phenyl (IH-pyrrolo [2 ,3-c]pyaridin-2-yl) methanone O-piperidin-4- yloxime dihydrochloride A mixture of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (Example 35) (300 mg, 1.34 mmol) and tert-butyl 4- (aminooxy) piperidine-1-carboxylate (Reference Example 10) (289 mg, 1.34 mmol) in EtOH (30 mL) was adjusted to pH 4-5 with HCl (1.9 mL of a 1 N HCl solution in diethyl ether, 1.9 mmol) . The reaction mixture was heated to reflux.
  • Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone O- piperidin-4-yloxime dihydrochloride was prepared from tert- butyl 4- [ [ [phenyl (IH-pyrrolo [2, 3 — c] pyridin-2- yl) methylene] amino] oxy] piperidine-1-carboxylate (Isomer A) following the procedure described for Example 95 (24.9 mg, 98%) as a white solid (geometry of the oxime double bond undefined) .
  • Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- piperidin-4-yloxime dihydrochloride was prepared from tert- butyl 4- [ [ [phenyl (IH-pyrrolo [2, 3—c]pyridin-2- yl) methylene] amino] oxy] piperidine-1-carboxylate (Isomer B) following the procedure described for Example 95 (32.0 mg, 21%) as a white solid (isomer of Example 104, geometry of the oxime double bond undefined) .
  • Example 107 and Example 108
  • Pb-enyl (IH-pyrrolo [2, 3-c] pyridin-2 -yl) methanone 0- piperidin-3-yloxime dihydrochloride was prepared from tert- butyl 3— [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2 - yl) methylene] amino] oxy] piperidine-1-carboxylate (Isomer A) following the procedure described for Example 95 (28.9 mg, 38%) as a white solid (geometry of the oxime double bond undefined) .
  • Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone O- piperidin— 3-yloxime dihydrochloride was prepared from tert- butyl 3-[ C [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] piperidine-1-carboxylate (Isomer B) following the procedure described for Example 95 (47.9 mg, 38%) as a white solid (isomer of Example 107, geometry of the oxime double bond undefined) .
  • Example 109 (12.3 mg) as an amber oil:
  • Example 111 ter t-Butyl 2- [ [ [phenyl (iJE-pyrrolo [2 , 3-c]pyridin-3- yl) methylene] amino] oxy] ethylcarbamate tert-Butyl 2- [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-3- yl) methylene] amino] oxy] ethylcarbamate (429.2 mg, 89%) was prepared as a white foam using phenyl (IH-pyrrolo [2, 3- c] pyridin-3-yl) methanone (Reference Example 8) and tert-butyl [2- (aminooxy) ethyl] carbamate following the procedure described ( 90:10 methylene chloride /methanol) ; E NMR (300 MHz, CD 3 0D) ⁇ l.38-1.39 (9H, s) , 3.40-3.44 (2H, m) , 3.17-3.
  • Example 116 tert-Butyl 2- [ [ [ (4-chlorophenyl) (lH-pyrrolo[2 ,3-c]pyridin-2- yl)methylene] amino] oxy] ethylcarbamate tert-Butyl 2- [[[ (4-chlorophenyl) (lH-pyr-rolo [2, 3- c]pyridin-2-yl) methylene] amino] oxy] ethylcarbamate was prepared from (4-chlorophenyl) ( IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone (Example 103) and tert-butyl [2- (aminooxy) eth;yl] carbamate following the procedure described for Example 104.
  • Example 119 (4-Methylphenyl) (IH-pyrrolo [2 ,3- ⁇ ]pyridin-2-yl) methanone O- (2- aminoethyl) oxime bis (hydrogen trifluoroacetate) tert-Butyl 2- [[[ (4-methylphenyl) (IH-pyrrolo [2, 3- c] pyridin-2-yl) methylene] amino] oxy] ethylcarbamate (Example 118 j Isomer B) (22 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (3 mL) at 0°C and the reaction mixture was stirred for 4 h . The solvent was removed under vacuum and the excess trifluoroacetic acid was co-evaporated with toluene (3 * 10 _
  • Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- methyloxime hydrochloride was prepared from phenyl (IH- pyrrolo [2, 3-c] pyridin-2-yl) methanone (Example 35) and 0- methylhydroxylamine hydrochloride following the procedure described for Example 104 (geometry of the oxime double bond undefined) .
  • Example 122 Example 122
  • the solvent was removed under vacuum and the excess trifluoroacetic acid was co-evaporated with toluene (3 ⁇ ) .
  • the trifluoroacetic acid salt was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. The residue was dissolved in ethyl acetate and ethereal hydrogen chloride (2 ml of a 1 M solution) was added.
  • Example 116 Isomer A (22 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (3 mL) and the reaction mixture was stirred for 3 h. The solvent was removed under vacuum and the excess trifluoroacetic acid was co-evaporated with toluene (2 x 10 mL) .
  • Example 128 and Example 129 tert-Butyl methyl [2- [ [ [phenyl (IH-pyrrolo [2 ,3-c] yridin-2- yl)methylene] amino] oxy] ethyl] carbamate
  • Example 136 (Pyridin-4-yl) (IH-pyrrolo [2 ,3- ⁇ ]pyridin-2-yl) methanone [ 1- (Phenylsulfonyl) -IH-pyrrolo [2, 3-c] pyridin-2- yl] (pyridin-4-yl) methanol (Reference Example 22, 217 mg, 0.59 mmol) was dissolved in ethanol (10 mL) . A 10% solution of sodium -hydroxide (6 mL) was added and the reaction mixture was i .'o" ' urr d then stirred at ambient temperature for the wee-kend. The solvent was removed under vacuum.
  • Example 1 A mixture of (7-chloro-lH-pyrrolo [2, 3-c]pyridin-2- yl)methanol (Example 1) (2.81 g, 15.4 mmol), manganese (IV) oxide (16 g) and dichloromethane (250 mL) was stirred under an atmosphere of nitrogen for 16 h. The mixture was filtered through a pad of diatomaceous earth, washing generously with hot acetone.
  • Lithium aluminum hydride (105 mg, 2.11 mmol) was added in w t'rl ⁇ pWicrf-s of ethyl 5-chloro-lH-pyrrolo [2, 3- c]pyridine-2-carboxylate (410 mg, 1.83 mmol) in tetrahydrofuran (15 mL) under stirring at 0°C under a nitrogen atmosphere .
  • the reaction mixture was warmed to room temperature and then heated to 60°C for 3 h.
  • the reaction mixture was quenched by the gradual addition of hydrated sodium sulfate.
  • the sodium sulfate was removed by filtration and washed thoroughly with tetrahydrofuran to give a yellow filtrate, which was concentrated to a brown solid.
  • reaction m!--; , -t ⁇ irfe , " 'd ⁇ '-lTM ⁇ tifrfed”'fox” another 1 h, warming to 0°C.
  • the reaction mixture was poured into a 2 : 1 solution of saturated ammonium chloride and water, and extracted with ethyl-, acetate (3 ⁇ ) .
  • the combined organic extracts were washed with water and brine, and dried over sodium sulfate.
  • reaction solution was left standing at 4°C for 20 min. and acid insoluble fraction was transferred to a GF/C filter (PACKARD JAPAN KK) using a cell harvester (PACKARD JAPAN KK) and washed with 250 mM ptiosphoric acid solution.
  • the plate after washing was dried at --5°C for 60 min., 40 ⁇ l of MicroSinti 0 (PACKARD JAPAN KK) was added and the radioactivity was determined using TopCount (PACK- RD JAPAN KK) .
  • the concentration (IC50) of the test compound neoessary for 50% inhibition of the amount of 32 P uptake by the a.cid insoluble fraction was calculated using PRISM 3.0 (Gr- ⁇ aphPad Software, Inc.). The results are shown in Table 1. Table 1 test compound IC50 (Example number) ( ⁇ M) 91 1.7
  • the 6-azaindole compound of the present invention has a superior I ⁇ B kinase inhibitory activity, and is useful as a pharmaceutical agent such as an agent for preventing or treating diabetes and the like.

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Abstract

A compound represented by the formula (I) wherein R1, R2, R3 and R6 are the same or different and each is a hydrogen atom or a substituent; one of R4 and R5 is a hydrogen atom and the other is a group represented by the formula: -C(=X)-R7 wherein X is N-O-R8 or N-NH-R9 wherein R8 and R9 are the same or different and each is a hydrogen atom or a group bonded via a carbon atom; and R7 is a hydrogen atom or a substituent, and the like and a salt thereof have a superior IκB kinase inhibitory activity, and useful as pharmaceutical agents such as agents for preventing or treating diabetes and the like.

Description

DESCRIPTION 6-AZAINDOLE COMPOUND Technical Field The present invention relates to a 6-azaindole compound having a superior IκB kinase inhibitory activity and useful as a pharmaceutical agent such as an agent for preventixig or treating diabetes and the like- Background Art IKB kinase (sometimes to be abbreviated as IKK in the specification) is a kinase complex having a molecula-r weight of not less than 900 kilodaltons that phosphorylates IκB. This complex includes kinase subunits such as IKKα (IKK-1 ) , IKKβ (IKK-2), regulatory subunit IKKγ (NEMO) and the like _ IKK phosphorylates serine 312 of IRS-1, which ±s an insulin receptor substrate, and the like, and induce s insulin resistance by inhibiting the phosphorylation of tyro sine of IRS-1 that should originally occur (J. Biol. Chem., 277, p. 8115 (2002)). Therefore, an IKK inhibitor is expected to improve insulin resistance observed in type II diabe tes and obesity. In addition, IKK is known to significantly con- ribute as one factor in the signal transduction pathway of NF-κB transcription factor. NF- B is generally bound with inhibitory protein IκB and present as an inactive type in cytoplasm. Once IKK phosphorylates IκB, this triggers ubiquitination of IκB and degradation of IκB proceeds . NF-κB liberated by the degradation of IκB is translocated into the nucleus, where it activates transcription of the target gene and acceLerates production of inflammatory cytokines such as tumor aecrosis factor (TNF) , IL-1 etc.; cell adhesion factors such as ICAM-1 (Intercellular Adhesion Molecule-1) etc.; and enzyme.-s such as cyclooxygenase COX2 (Cyclooxygenase-2) and the like. In this way, NF-KB is deeply involved, in inflammation and irr--mune β responses . ''l^A -'irfe* known to activate NF-κB by phosphorylation of NF-κB subunits and histone. Therefore, an IKK inhibitor is expected to suppress activation of HSFF-KB and be useful as an agent for preventing or treating autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis), inflammatory dis -eases (e.g., osteoarthrosis, atherosclerosis, atopic derma"titis, chronic obstructive pulmonary disease, endotoxin shock, sepsis), ischemic diseases and the like or as an immunosuppressant . Moreover, since NF-KB acts as an anti- apoptosis factor or growth factor in cancer cells, a-n IKK inhibitor that suppresses activation of NF-KB is expected to be useful as an agent for preventing or treating cancer (J. Clin. Invest., 107, pp. 241-246 (2001)). In the meantime, as 6-azaindole compounds, the following compounds have been reported.
Figure imgf000003_0001
(J. Chem. Soc, Perkin 1, 1973, pp. 1546-1556)
Figure imgf000003_0002
(J. Chem. Soc, Perkin Trans. 1, 1996, pp. 2633-2642 ). Disclosure of the Invention Δn object of the present invention is to provide a 6- azaindole compound having a superior IκB kinase inhi-Ioitory activity and useful as a pharmaceutical agent such a s an agent for preventing or treating diabetes and the like. I! i . . , ,, .• f ~ . ," t - """• « *•' ¥he '1"p-?fese!n%( " invention relates to ( 1 ) a compound represented by the formula
Figure imgf000004_0001
wherein R1, R2, R3 and R6 are the same or different and each is a hydrogen atom or a substituent; one of R4 and R5 is a hydrogen atom and the other is 1) a group represented by the formula: -C(=X)-R7 wherein X is N-O-R8 or N-NH-R9 wherein R8 and R9 are the same or different and each is a hydrogen atom or a group bonded via a carbon atom, and R7 is a hydrogen atom or a substituent, 2) a group represented by the formula: -C(=0)-R10 wherein R10 is a hydrogen atom or a group bonded via a carbon atom; 3) a group represented by the formula: -CH(OH)-R10 wherein R10 is a hydrogen atom or a group bonded via a carbon atom; 4) a group represented by the formula: -C(=0)-NH- (CH2)n-Ar wherein n is 0, 1 or 2, and Ar is an aromatic group; 5) a group represented by the formula: -C(=0)-Het wherein Het is an optionally substituted heterocyclic group bonded via a nitrogen atom; or 6) a group represented by the formula: -CH (R12) -NR13R14 wherein R12 is a hydrogen atom or a hydrocarbon _ „ a
Figure imgf000005_0001
-p «™4rid R14 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R13 and R14 form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic group optionally having substituents (provided that the nitrogen-containing heterocyclic group is not an oxopyrrolidinyl group or an oxopiperazinyl group) except when R4 is a group represented by the formula: ~C(=0)-R10 wherein R10 is as defined above, and R5 is a hydrogen atom; except tert-butyl 5- (benzyloxy) -3- (3-ethoxy-2-fluoro-l- hydroxy-3-oxopropyl) -IH-pyrrolo [2, 3-c] pyridine-1-carboxylate; [5- (benzyloxy) -IH-pyrrolo [2, 3-c] yridin-3-yl]methanol; ethyl 3- (hydroxymethyl) -lff-pyrrolo [2, 3-c]pyridine-5- carboxylate; IH-pyrrolo [2, 3-c]pyridine-3-carbaldehyde oxime; ethyl 5-{ [5- (benzyloxy) -IH-pyrrolo [2, 3-c] pyridin-2- yl] carbonyl} -2, 4-dimethyl-lH-pyrrole-3-carboxylate; 5- (benzyloxy) -lH-pyrrolo[2, 3-c]pyridine-2-carbaldehyde; 5-methoxy-lH-pyrrolo [2, 3-c]pyridine-2-carbaldehyde; [5- (benzyloxy) -IH-pyrrolo [2, 3-c] pyridin-2-yl]methanol; (5-methoxy-lH-pyrrolo [2, 3-c] pyridin-2-yl) ethanol; and [2- ( { [4- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) - 1, 3-thiazol-2-yl] amino} carbonyl) -5-methoxy-lH-pyrrolo [2, 3- c]pyridin-l-yl] acetic acid, or a salt thereof [sometimes to be abbreviated as compound (I) in the specification] ; (2) a prodrug of compound (I); (3) compound (I) wherein one of R4 and R5 is a hydrogen atom, and the other is a group represented by the formula: -C(=X)-R7 wherein X and R7 are as defined in the aforementioned (1); [[•■■"(il)Ie'ofo S'-l-IS1>•(' I * ™wliϊfein R4 is a hydrogen atom, and R5 is a group represented by the formula: ~C(=0)-R10 wherein R10 is as defined in the aforementioned (1) ; (5) compound (I) wherein R1, R2 and R3 are each a hydrogen atom; (6) a pharmaceutical agent comprising compound (I) or a prodrug thereof and a pharmacologically acceptable carrier; (7) a method for inhibiting IκB kinase in a mammal, which comprises administering an effective amount of a compound represented by the formula
Figure imgf000006_0001
wherein R1, R2, R3 and R6 are the same or different and each is a hydrogen atom or a substituent; one of R4' and R5' is a hydrogen atom and the other is 1) a group represented by the formula: -C(=X)-R7 wherein X is N-O-R8 or N-NH-R9 wherein R8 and R9 are the same or different and each is a hydrogen atom or a group bonded via a carbon atom, and R7 is a hydrogen atom or a substituent, 2) a group represented by the formula: -C(=0)-R10 wherein R10 is a hydrogen atom or a group bonded via a carbon atom; 3) a group represented by the formula: -CH(OH)-R10 wherein R10 is a hydrogen atom or a group bonded via a carbon atom; 4) a group represented by the formula: -C(=0)-NH- P
Figure imgf000007_0001
n ig Q f 1 or 2 f and Ar is an aromatic group; 5) a group represented by the formula: -C(=0)-Het wherein Het is an optionally substituted heterocyclic group bonded via a nitrogen atom; or 6) a group represented by the formula: -CH(R12)- NR13'R14' wherein R12 is a hydrogen atom or a hydrocarbon group; R13' and R14' are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R13 and R14' form, together with the adjacent nitrogen atom, a nitrogen- containing heterocyclic group optionally having substituents, or a salt thereof [sometimes to be abbreviated as compound (I' ) in the specification] or a prodrug thereof to said mammal; (8) a method for preventing or treating diabetes in a mammal, which comprises administering an effective amount of compound (I' ) or a prodrug thereof to said mammal; (9) a method for preventing or treating an inflammatory disease in a mammal, which comprises administering an effective amount of compound (I' ) or a prodrug thereof to said mammal; (10) an agent for inhibiting IκB kinase, which comprises compound (I') or a prodrug thereof; (11) an agent for preventing or treating diabetes, which comprises compound (I' ) or a prodrug thereof; (12) an agent for preventing or treating an inflammatory disease, which comprises compound (I' ) or a prodrug thereof; (13) use of compound (I' ) or a prodrug thereof, for the production of an agent for inhibiting IκB kinase; __ , _ ^ ρi»)-''^^ ™?^* όmj^ folti^(4' ) or a prodrug thereof, for the production of an agent for preventing or treating diabetes; (15) use of compound (I') or a prodrug thereof, for the production of an agent for preventing or treating an inflammatory disease; and the like .
The definition of each symbol used in the present specification is explained in detail in the following. As the substituent for R1, R2, R3 or R6, for example, a halogen atom, a cyano group, a nitro group, an amidino group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted mercapto group and the like can be mentioned. Here, as the "halogen atom", for example, fluorine, chlorine, bromine and iodine can be mentioned. As the "hydrocarbon group" of the "optionally substituted hydrocarbon group", for example, a) Cι-6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl); b) C2-6 alkenyl groups (e.g., vinyl, allyl, isopropenyl, 2- butenyl) ; c) C2-6 alkynyl groups (e.g., ethynyl, propargyl, 2-butynyl) ; d) C3-8 cycloalkyl groups optionally substituted by the above- mentioned C1-6 alkyl group and optionally condensed with a benzene ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, dihydroindenyl) ; e) C3-8 cycloalkenyl groups optionally substituted by the above- mentioned Cι_6 alkyl group and optionally condensed with a m _ _
''"-.erizeπe •«" 1^ <•' ( &vg :" "";cγclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl) ; f) Cε-14 aryl groups optionally substituted by the above- mentioned Cι-6 alkyl group (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2—anthryl, biphenyl) ; g) C7-19 aralkyl groups optionally substituted by the above- mentioned C1-6 alkyl group (e.g., benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2- naphthylmethyl, 2, 2-diphenylethyl, 3-phenylpropyl, 4- phenylbutyl, 5-phenylpentyl) ; and the like can be mentioned.
As the substituent of the "optionally substituted hydrocarbon group", for example, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), Cι-3 alkylenedioxy groups (e.g., methylenedioxy, ethylenedioxy) , a nitro group, a cyano group, a hydroxy group, an optionally halogenated Cι-6 alkoxy group, an optionally halogenated d-6 alkylthio group, C6-ι4 aryloxy groups (e.g., phenoxy, naphthoxy) , 5- to 7-membered heterocyclic oxy groups (e.g., tetrahydropyranyloxy) , an amino group, mono- or di-Ci-e alkylamino groups (e.g., methylamino, ethylamino, propyla ino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N- methylamino) , an optionally substituted 5- to 7-membered heterocyclic group, a formyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, an optionally halogenated Cχ-5 alkyl-carbonyl group, a C1-6 alkoxy-carbonyl group, Cs-i4 aryl-carbonyl groups (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) r an optionally substituted heterocyclic carbonyl group, C6-i4 aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl) , C7-19 aralkyloxy- carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) , mono- or di-Cι_6 alkyl-carbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, P*''dC±eTtVyI'U-t,i'cS,atOb'a=!;m-.o.-y-h^'N..i..-'atthyl-N„.-methylcarbamoyl) , carbamoyl-Ci- alkyl-carbamoyl groups (e.g., carbamoylmethylcarbamoyl, carbamoylethylcarbamoyl) , C6-ι4 aryl-carbamoyl groups (e.g., phenylcarbamoyl) , an optionally substituted heterocyclic carbamoyl group, an optionally halogenated Cι-6 alkylsulfonyl group, C6-i4 arylsulfonyl groups (e.g., phenylsulfonyl, 1- naphthylsulfonyl , 2-naphthylsulfonyl) , a formylamino group, an optionally halogenated Cι-6 alkyl-carboxamido group, C3-i4 aryl- carboxamido groups (e.g., phenylcarboxamido, naphthylcarboxamido) , Cι-6 alkoxy-carboxamido groups (e.g., methoxycarboxamido, ethoxycarboxamido, propoxycarboxamido, butoxycarboxami o, tert-butoxycarboxamido) , Cι-6 alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino) , Cι_6 alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy) , Cβ-14 aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy) , Cχ-6 alkoxy- carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) , mono- or di-Cι-6 alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy) , Cβ-i4 aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy) , 5 or 6-membered heterocyclic carbonyloxy groups (e.g., nicotinoyloxy) and the like can be mentioned. The number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, respective substituents may be the same or different.
As the aforementioned "optionally halogenated Cι-6 alkoxy group", for example, a Cι-6 alkoxy group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , such as methoxy, ethoxy, propoxy, butoxy, pentyloxy and the like can be mentioned. Specific examples
Figure imgf000011_0001
^'"'t reor ^ϊA'6-;tøe,'',,me ,h'd,x'. difluoromethoxy, trifluoromethoxy, ethoxy, 2, 2, 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4, 4, 4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like. As the aforementioned "optionally halogenated Cχ-6 alkylthio group", for example, a Cχ-6 alkylthio group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like can be mentioned. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4, 4, 4-trifluorobutylthio, pentylthio, hexylthio and the like.
As the "5- to 7-membered heterocyclic group" of the aforementioned "optionally substituted 5- to 7-membered heterocyclic group", for example, a 5- to 7-membered heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and the like can be mentioned. Preferable examples of the 5- to 7-membered heterocyclic group include 5- to 7-membered non-aromatic heterocyclic groups such as pyrrolidinyl (e.g., 1-, 2- or 3- pyrrolidinyl); imidazolidinyl (e.g., 1-, 2-, 4- or 5- imidazolidinyl) ; imidazolinyl (e.g., 2- or 4-imidazolinyl) ; pyrazolidinyl (e.g., 2-, 3- or 4-pyrazolidinyl) ; piperidinyl (e.g., 1-, 2-, 3- or -piperidinyl) ; piperazinyl (e.g., 1- or 2-piperazinyl) ; tetrahydropyranyl; morpholinyl; thiomorpholinyl and the like; and 5- to 7-membered aromatic heterocyclic groups such as thienyl (e.g., 2- or 3-thienyl ) ; furyl (e.g., 2- or 3-furyl) ; pyrrolyl (e.g., 1-, 2- or 3-pyrrolyl) ; imidazolyl (e.g., 1-, 2- or 4- i1F1Xiiftø""'ι "1'!"έ-'z'ϊ"olP^"lfr-iv! ""°"|'i't•''hi-ffca•*'--uo".^""y>'±"'s,i" (e.g. , 2-, 4- or 5-thιazolyl) ; oxazolyl (e.g., 2-, 4- or 5-oxazolyl) ; isothiazolyl (e.g., 3- isothiazolyl) ; isoxazolyl (e.g., 3-isoxazolyl) ; pyridyl (e.g., 2-, 3- or 4-pyridyl) ; pyrazolyl (e.g., 1-, 3- or 4-pyrazolyl) ; pyrazinyl (e.g., 2-pyrazinyl) ; pyrimidinyl (e.g., 2-, 4- or 5- pyrimidinyl) ; pyridazinyl (e.g., 3- or 4-pyridazinyl) ; oxadiazolyl (e.g., 1, 2, 4-oxadiazol-5-yl; 1, 2, 4-oxadiazol-3- yl) ; thiadiazolyl (e.g., 1, 2 , 4-thiadiazol-5-yl; 1,2,4- thiadiazol-3-yl) ; triazolyl (e.g., 1, 2, 3-triazol-l-yl; 1,2,3- triazol-4-yl; 1, 2, 4-triazol-l-yl; 1, 2, 4-triazol-3-yl) ; tetrazolyl (e.g., 1- or 5-tetrazolyl) ; pyranyl (e.g., 2-, 3- or 4-pyranyl) and the like.
As the aforementioned "optionally halogenated Cι-δ alkyl- carbonyl group", for example, a Cι-6 alkyl-carbonyl group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the like can be mentioned. Specific examples thereof include acetyl, monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the like. As the aforementioned "Cι-6 alkoxy-carbonyl group", for example, ethoxycarbonyl, eth.oxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like can be mentioned. As the "heterocyclic carbonyl group" of the aforementioned "optionally substituted heterocyclic carbonyl group", for example, nicotinoyl, isonicotinoyl, thenoyl (e.g., 2-thenoyl, 3-thenoyl) , furoyl (e.g., 2-furoyl, 3-furoyl) , morpholinocarbonyl, piperidinocarbonyl, pyrrolidin-1- ylcarbonyl, indolylcarbonyl and the like can be mentioned. As the "heterocyclic carbamoyl group" of the aforementioned "optionally substituted heterocyclic carbamoyl group", for example, morpholinocarbamoyl, piperidinocarbamoyl, |f''iy r-LdViic;c-;i-'' ;-ri'6 ϊ »' l:;i '* 2-pyridylcar-oamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl) , thienylcarbamoyl (e.g., 2- thienylcarbamoyl, 3-thienylcarbamoyl) , indolylcarbamoyl and the like can be mentioned. As the aforementioned "optionally halogenated Cι-6 alkylsulfonyl group", for example, a Cι-6 alkylsulfonyl group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert- butylsulfonyl and the like can be mentioned. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4, 4, 4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like. As the aforementioned "optionally halogenated Cι-6 alkyl- carboxamido group", for example, a Cι_6 alkyl-carboxamido group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), such as acetamido, propanamido, butanamido and the like can be mentioned. Specific examples thereof include acetamido, trifluoroacetamido, propanamido, butanamido and the like.
As the substituent of the aforementioned "optionally substituted 5- to 7-membered heterocyclic group", "optionally substituted heterocyclic carbonyl group" and "optionally substituted heterocyclic carbamoyl group", for example, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), Cι-3 alkylenedioxy groups (e.g., methylenedioxy, ethylenedioxy), a nitro group, a cyano group, an oxo group, an optionally halogenated Cι-6 alkyl group, carbamoyl-Cι-6 alkyl groups (e.g., carbamoylmethyl) , an optionally halogenated C3-6 cycloalkyl group, Cβ-14 aryl groups (e.g., phenyl, naphthyl) , C7-19 aralkyl
Figure imgf000014_0001
, an optionally halogenated Cι_6 alkoxy group, an optionally halogenated Cι_s alkylthio group, a hydroxy group, an amino group, mono- or di-Cι-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino) , a formyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, an optionally halogenated Cι_6 alkyl-carbonyl group, a Cι-6 alkoxy-carbonyl group, C6-i4 aryl-carbonyl groups (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) , mono- ox di-Cι-6 alkyl- carbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N- methylcarbamoyl) , mono- or di-C7-i9 aralkyl-carbamoyl groups (e.g., benzylcarbamoyl) , an optionally halogenated Cι-6 alkylsulfonyl group, C6-ι4 arylsulfonyl groups (e.g., phenylsulfonyl) , a sulfamoyl group, mono- ox di-Cι-6 alkyl- sulfamoyl groups (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N- methylsulfamoyl) , a formylamino group, an optionally halogenated Cι-6 alkyl-carboxamido group, Cι-6 alkoxy-carboxamido groups (e.g., methoxycarboxamido, ethoxycarboxamido, propoxycarboxamido, butoxycarboxamido) , Cι-6 alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino) , Cι-6 alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy) , Cι-6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, buto_κycarbonyloxy) , 5 or 6-membered aromatic heterocyclic groups (e.g., tetrazolyl, thiazolyl, oxazolyl) and the like can be mentioned. The number of substituents is, for example, 1 to 3. When the number of substituents is 2 or more, respective substituents may be the same or different.
As the aforementioned "optionally halogenated Cι-6 alkyl ,-„. p. ... ^ ,„, ,- „,(ι „,.
*"!'gτcfop^E ,:;ϊfet^^ alkyl group optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl can be mentioned. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl, propyl, 3, 3, 3-trifluoropropyl, isopropyl, butyl, 4,4,4- trifluorobutyl^ isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, hexyl, 6,6,6- trifluorohexyl and the like. As the aforementioned "optionally halogenated C-6 cycloalkyl group", for example, a C3-6 cycloalkyl group optionally hav±ng 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4- dichlorocyclohexyl, 2, 2, 3, 3-tetrafluorocyclopentyl, 4- chlorocyclohexyl and the like. As the "optionally halogenated Cι-6 alkoxy group", "optionally halogenated Cι_6 alkylthio group", "optionally halogenated Cι-6 alkyl-carbonyl group", "Cι-6 alkoxy-carbonyl group", "optionally halogenated Ci-e alkylsulfonyl group" and "optionally halogenated χ-6 alkyl-carboxamido group", those respectively recited as the "substituent" of the aforementioned "optionally substituted hydrocarbon group" can be mentioned. As the "heterocyclic group" of the "optionally substituted heterocyclic group" exemplified as the substituent for R1 and the like, for example, (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7 to r, ,r„ „ ,, ,„ „„,„ „.„, ,„
«*'"i{,Θ--'-πα^--τ&-ter--rfe'ti'-"'to'-r±tei^e'c-i^^He e--erocycl±c group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom can be mentioned. Here, as the "aromatic heterocyclic group", for example, 4 to 14-membered (preferably 4 to 10-membered) aromatic heterocyclic groups containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and the like can be mentioned. Preferable examples of the "aromatic heterocyclic group" include 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, furazanyl, pyranyl and th.e like; and condensed polycyclic (preferably bi- or tri-cyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, naphtho [2, 3-b] thiophenyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, ph-enothiazinyl, phenoxazinyl, phthali ido and the like.
As the "non-aromatic heterocyclic group", for example, a 4 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom and the like can be mentioned. Preferable examples of the "non-aromatic heterocyclic group" include monocyclic non-aromatic
Figure imgf000017_0001
,- ;h as azetidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrothiazolyl , tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, tetrahydropyranyl, azepanyl, morpholinyl, thiomorpholinyl, diazepanyl, azepinyl, azocanyl, diazocanyl and the like; and condensed polycyclic (preferably bi~ or tri-cyclic) non- aromatic heterocyclic groups such as dihydrobenzof ranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho [2 , 3-b] thiophenyl, tetrahydroisoquinolyl, tetrahydroquinolyl, indolinyl, isoindolinyl, tetrahydrothieno [2 , 3-c] pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl , t etrahydrophenanthridinyl , hexahydrophenothiazinyl , hexahydrophenoxazinyl , tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl , "tetr ahydrocinnolinyl , tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tet-rahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like .
Of the above-mentioned "non-aromatic heterocyclic groups"' , nitrogen-containing non-aromatic heterocyclic groups (preferably monocyclic n±trogen-containing non-aromatic heterocyclic groups) , such as azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl , pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl,
Figure imgf000018_0001
dihydropyridinyl, tetrahydropyrimidinyl, tetrahydropy-ridazinyl, azepanyl, morpholinyl, thio orpholinyl, diazepanyl, azepinyl, azocanyl, diazocanyl and the like are preferable. Preferable examples of the "7 to 10-membered bridged heterocyclic group" include quinuclldinyl, 7- azabicyclo[2.2 ,l]heptanyl and the l ke. As the substituent of the "optionally substituted heterocyclic group", those exemplified as the substituent of the aforementioned "optionally substituted 5- to 7-membered heterocyclic group" can be mentioned. The number of substituents is, for example, 1 to 3. When the number of substituents is 2 or more, respective substituents may be the same or differen .
As the acyl group of the "opt-Lonally substituted acyl group" exemplified as the substituent for R1 and the like, for example, -COR15, -CO-OR15, -S02R15, -SOR15, -PO(OR15) (OR16) [R15 and R16 are the same or different and each is a hydrogen atom, a hydrocarbon group or a heterocyclic group] and the like can be mentioned. As the "hydrocarbon group" fo R15 or R16, the "hydrocarbon group" exemplified for "optionally substituted hydrocarbon group" exemplified as the substituent for R1 and the like can be mentioned. The hydrocarbon group is preferably a Cι-6 alkyl group, a C2-6 alkenyl group, a C3-8 cycloalkyl group, a C3-.8 cycloalkenyl group, a C6-ι4 aryl group, a C7_ι9 aralkyl group and the like . As the "heterocyclic group" fox R15 or R16, the "heterocyclic group" exemplified for the "optionally substituted heterocyclic group" exemplified as the substituent for R1 and the like can be mentioned. The heterocyclic group ife" eέ ϊ'-iyy-y;'
Figure imgf000019_0001
oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl, -benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, pyrrolidinyl, piperidinyl, piperazinyl and the like. The acyl group may have 1 to 3 substituents at substitutable position (s), and such substituent includes, for example, optionally halogenated Cι_6 alkyl groups (e.g., methyl, ethyl); optionally halogenated Cι_6 alkoxy groups (e.g., methoxy, ethoxy) ; halogen atoms (e.g., fluorine, chlorine, bromine, iodine) ; nitro group; hydroxy g-roup; amino group optionally mono- or di- substituted by Cι_6 alkyl groups (e.g., methyl, ethyl); Cι_6 alkoxy-carboxamido -groups (e.g., tert- butoxycarboxamido) and the like . Preferable examples of acyl group include a formyl group, carboxyl group, Cι-6 alkyl-carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl), C2-6 alkenyl-carbonyl groups (e.g., crotonoyl) , C3-8 cycloalkyl-carbonyl groups (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C3-8 cycloalkenyl-carbonyl groups (e.g., 2-cyclohexenecarbonyl) , C6-i4 aryl-carbonyl groups (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) , C7-ι9 aralkyl-carbonyl groups (e.g., benzylcarbonyl, phenetbylcarbonyl) , aromatic heterocyclic carbonyl groups (e.g., nicotinoyl, isonicotinoyl) , non-aromatic heterocyclic carbonyl groups (e.g., pyrrolidinylcarbonyl, pipeπdinylcarbonyl) , Cι-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl , ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl) , C6-i4 aryloxy-carbonyl groups (e.g., phenyloxycarbonyl^ naphthyloxycarbonyl) , C7-ι9 aralkyloxy-carbonyl groups (e.g-, benzyloxycarbonyl, phenethyloxycarbonyl) , Cι_6 alkylsulfinyl groups (e.g., methylsulfinyl, ethylsulfinyl) , Cι-6 alkylsulfonyl groups (e.g., methylsulfonyl, ethylsulfonyl), C6-ι4 arylsulfonyl groups (e.g.,
Figure imgf000020_0001
'"pfe'bi-.pfe.ono group, mono- or dι-Cι-6 alkylphosphono groups (e . g . , dime thylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) and the like .
As the "optionally substituted amino group", "optionally substituted carbamoyl group" and Λ,optionally substituted sulfamoyl group" exemplified as the substituent for R1 and the like, for example, amino group, carbamoyl group and sulfamoyl group each optionally substituted by 1 or 2 substituents selected from (1) "optionally substituted hydrocarbon group", "optionally substituted acyl group" and "optionally substituted heterocyclic group" recited as examples of the substituent for R1 and the like; and (2) carbamoyl group optionally having 1 or 2 substituents selected from Cι-6 alkyl groups (e .g., methyl, ethyl), C3-8 cycloalkyl groups (e.g., cyclopropyl, cyclohexyl), C6-i4 aryl groups (e.g., phenyl) and C7-i9 aralkyl groups (e.g., benzyl) can be mentioned. When nitrogen atom constituting these amino group, carbamoyl group and sulfamoyl group is substituted by 2 substituents, these substituents may form a nitrogen- containing heterocycle together with the adjacent nitrogen atom. As the "nitrogen-containing heterocycle", for example, a 5- to 7-membered nitrogen-containing heterocycle containing at least one nitrogen atom as a ring constituting atom besides carbon atom, and further, 1 or 2 -heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom can be mentioned. Preferable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like. The "optionally substituted amino group", "optionally substituted carbamoyl group" and '"optionally substituted ^ β ir. _. . ,, ^ -,.
^-^lti£ϊιriyy^l^^ύ ^" --i^-Φeferably amino group, carbamoyl group and sulfamoyl group each optionally substituted by 1 or 2 substituents selected from Cι-.6 alkyl group, C2-6 alkenyl group, C3-8 cycloalkyl group, C6-i4 aryl group, C7-19 a-xalkyl group, Cι-6 alkyl-carbonyl group, C6-ι4 aryl-carbonyl group, C7-19 aralkyl- carbonyl group, aromatic heterocyclic carbonyl group, non- aromatic heterocyclic carbonyl group, Cχ-6 alk:oxy-carbonyl group, aromatic heterocyclic group, carbamoyl group,- mono- or di-Cι-6 alkyl-carbamoyl group and mono- or di-C7_ι9 aralkyl-carbamoyl group, each of which may have 1 to 3 substituents selected from halogen atoms (e.g., fluorine, chlorine, bromine, iodine), optionally halogenated Cχ-6 alkoxy group, hydrroxy group, nitro group, amino group and carbamoyl group. Preferable examples of the optionally substituted amino group include amino group, mono- or di-Cι-6 alkylamino groups (e.g., methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino) , mono- or di-C2-6 alkenylamino groups (e.g., diallylamino) , mono- or di-C3-8 cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino) , mono- or di-C6~i4 arylamino groups (e.g., phenylamino) , mono- or di-C7-i9 aralkylamino groups (e.g., benzylamino, dibenzylamino) , mono- or di- (optionally halogenated C1-6 alkyl) -carbonylamino groups (e.g., acetylamino, propionylamino) , mono- or di-C6-.ι aryl- carbonylamino groups (e.g., benzoylamino) , mono- or di-C7-ιg aralkyl-carbonylamino groups (e.g., benzylcarbonylamino) , mono- or di-aromatic heterocyclic carbonylami o groups (e.g., nicotinoylamino, isonicotinoylamino) , mono- or di-non-aromatic heterocyclic carbonylamino groups (e.g., piperidmylcarbonylammo) , mono- or di-Cι_6 al Lkoxy-carbonylamino groups (e.g., tert-butoxycarbonylamino) , aromatic heterocyclic amino groups (e.g., pyridylamino) , carbamoyla-mino groups, (mono- or di-Ci-e alkyl-carbamoyl) amino groups (e.g.,
Figure imgf000022_0001
or di-C7-ι9 aralkyl- carbamoyl) amino groups (e.g., benzylcarbamoy amino) and the like. Preferable examples of the optionally substituted carbamoyl group include carbamoyl group, orxo- or di-Cι-6 alkyl- carbamoyl groups (e.g., methylcarbamoyl, eth-ylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N- methylcarbamoyl) , mono- or di-C2-6 alkenyl-c rbamoyl groups (e.g., diallylcarbamoyl) , mono- or di-C3-8 cy-cloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl, cyclohexiylcarbamoyl) , mono- or di-C6-ι4 aryl-carbamoyl groups (e.g., phenylcarbamoyl) , mono- or di-C7_19 aralkyl-carbamoyl groups (e.g., benzylcarbamoyl, phenethylcarbamoyl) , mono- or di-Cι-6 alkyl- carbonyl-carbamoyl groups (e.g., acetylcarba-imoyl, propionylcarbamoyl) , mono- or di-C6-i4 aryl-carbonyl-carbamoyl groups (e.g., benzoylcarbamoyl) , aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl) , in-orpholinocarbonyl group and the like .
Preferable examples of the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-Cι-6 alkyl- sulfamoyl groups (e.g., methylsulfamoyl, eth^ylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl—N- methylsulfamoyl) , mono- or di-C2-6 alkenyl-sulfamoyl groups (e.g., diallylsulfamoyl) , mono- or di-C3-8 cycloalkyl-sulfamoyl groups (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl) , mono- or di-C6-i4 aryl-sulfamoyl groups (e.g., phenylsulfamoyl) , mono- or di-C7-ιg aralkyl-sulfamoyl groups (e_g., benzylsulfamoyl, phenethylsulfamoyl) , mono- or di-Ci-g alkyl- carbonyl-sulfamoyl groups (e.g., acetylsulfarnoyl, propionylsulfamoyl) , mono- or di-C3-.-.4 aryl-carbonyl-sulfamoyl groups (e.g., benzoylsulfamoyl) , aromatic heterocyclic ft, Ji j! .-■ ft i 1 iru IT .>' ••» "ϊi ST" "";ΪI •«
* sulϊ m if!^r6ϋ. -3TOS(e,E.'g'. " pyridylsulfamoyl) and the like .
As the "optionally substituted hydroxy group" and "optionally substituted mercapto group" exemplified as the substituent for R1 and the like, for example, hydroxy g-roup and mercapto group each optionally substituted by the substituent selected from the "optionally substituted hydrocarbon gjroup", "optionally substituted acyl group" and "optionally substituted heterocyclic group" exemplified as the substituent for R1 and the like can be mentioned. The "optionally substituted hydroxy group" and "optionally substituted mercapto group" are preferably hydroxy group and mercapto group each optionally substituted by a "substituent selected from Cι-6 alkyl group, C2-6 alkenyl-. group, C3-8 cycloalkyl group, Cε-14 aryl group, C7-19 aralkyl grouip, Cι_6 alkyl-carbonyl group, Cε-i4 aryl-carbonyl group and arom«atic heterocyclic group, each of which may have 1 to 3 substituents selected from halogen atoms (e.g., fluorine, chlorine, bromine, iodine), optionally halogenated Cι~6 alkoxy group, hydroxy group, nitro group, amino group and carbamoyl group".
Preferable examples of the optionally substituted hydroxy group include hydroxy group, Cι-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, see-but oxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hex;yloxy) , C2_6 alkenyloxy groups (e.g., allyloxy, crotyloxy, 2-peni-ιenyloxy, 3-hexenyloxy) , C3_8 cycloalkyloxy groups (e.g., cyclohex^yloxy) , C6-α4 aryloxy groups (e.g., phenoxy, naphthyloxy) , C7-19 aralkyloxy groups (e.g., benzyloxy, phenethyloxy) , Cι_6 alkyl- carbonyloxy groups (e.g., acetyloxy, propionyloxy, butyz-ryloxy, isobutyryloxy, pivaloyloxy) , C6-14 aryl-carbonyloxy groups (e.g., benzoyloxy) , aromatic heterocyclic oxy groups (e.g., pyridyloxy) and the like . « i! ι- ! ' -mil1 'lm|l -ml- ,.' ,-fo, „,iS„ „„,t- „, -(■ mft- Preferable examples of the optionally substituted mercapto group include mercapto group, Cι_6 alkylthio groups (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio) , C2_6 alkenylthio groups (e.g., allylthio, crotylthio, 2- pentenylthio, 3-hexenylthio) , C3_8 cycloalkylthio groups (e.g., cyclohexylthio) , Cε-14 arylthio groups (e.g., phenylthio, naphthylthio) , C7_19 aralkylthio groups (e.g., benzylthio, phenethylthio) , Cι-6 alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio) , C6-i4 aryl-carbonylthio groups (e.g., benzoylthio) , aromatic heterocyclic thio groups (e.g., pyridylthio) and the like.
The substituent for R1, R2, R3 or R6 is preferably a halogen atom, an optionally substituted amino group and the like. Here, as the optionally substituted amino group, an amino group, a mono- or di- j-ig aralkylamino group and the l ke are preferable. R1, R2, R3 and R6 are preferably hydrogen atoms.
One of R4 and R5 is a hydrogen atom and the other is 1) a group represented by the formula: -C(=X)-R7 wherein X is N-O-R8 or N-NH-R9 wherein R8 and R9 are the same or different and each is a hydrogen atom or a group bonded via a carbon atom; and R7 is a hydrogen atom or a substituent, 2) a group represented by the formula: -C(=0)-R10 wherein R10 is a hydrogen atom or a group bonded via a carbon atom; 3) a group represented by the formula: -CH(OH)-R10 wherein Rlσ is a hydrogen atom or a group bonded via a carbon atom; 4) a group represented by the formula: -C (=0) -NH- (CH2) n-Ar wherein n is 0, 1 or 2, and Ar is an aromatic group;
Figure imgf000025_0001
'^5'')"' ^'gtOT^ fe rlsfen^bl^by the formula: -C(=0)-Het wherein Het is an optionally substituted heterocyclic group bonded via a nitrogen atom; or 6) a group represented by the formula: -CH (R12) -NR13R14 wherein R12 is a hydrogen atom or a hydrocarbon group; R13 and R14 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R13 and R14 form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic group optionally having substituents (provided that the nitrogen- containing heterocyclic group is not an oxopyrrolidinyl group or an oxopiperazinyl group) . As the substituent for R7, those exemplified for the aforementioned R1 and the like can be used. Of these, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group and the like are preferable. The substituent for R7 is preferably a Cι-6 alkyl group, a Ce-i4 aryl group (preferably, phenyl) , a C7-19 aralkyl group or a monocyclic aromatic heterocyclic group (preferably thienyl, furyl) , each of which may have 1 to 3 substituents selected from a halogen atom, a Cι-6 alkyl group, an optionally halogenated Cι-6 alkoxy group and the like.
As the "group bonded via a carbon atom" for R8, R9 or R10, for example, cyano group, amidino group, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, optionally substituted acyl group, optionally substituted carbamoyl group and the like exemplified as the aforementioned R1 and the like can be mentioned. However, the "optionally substituted heterocyclic group" is limited to a group bonded via a carbon atom. ,, „(. „ff r δ όv^r7iMi' i -'''"fe , fbrfai,ly substituted acyl group" is limited to -COR15 or -CO-OR15 (R15 is as defined above) . The "group bonded via a carbon atom" for R8 or R9 is preferably, (1) an amidino group; (2) a Cα-6 alkyl group optionally having 1 to 3 substituents selected from a hydroxy group, an optionally halogenated Cι-6 alkoxy group, a carboxyl group, an amino group, a mono- or di- Cι_6 alkylamino group, a 5- to 7-membered heterocyclic group (preferably pyrrolidinyl, imidazolyl, morpholinyl) , a Ci-e alkoxy-carbonyl group, a carbamoyl group, a mono- or di-Cι-6 alkyl-carbamoyl group, a C6-i4 aryl-carbamoyl group (preferably phenylcarbamoyl) , a Cι_6 alkoxy-carboxamido group, a 5- to 7- membered heterocyclic oxy group (preferably tetrahydropyranyloxy) and the like; (3) a C7-19 aralkyl group; (4) a heterocyclic group (preferably 2- or 3-pyrrolidinyl; 2-, 3- or 4-piperidinyl) bonded via a carbon atom and optionally having 1 to 3 substituents selected from a Cι-6 alkoxy-carbonyl group and the like; (5) a carbamoyl group; and the like.
The "group bonded via a carbon atom" for R10 is preferably (1) a C1-6 alkyl group; (2) C6-i4 aryl group (preferably phenyl) optionally having 1 to 3 substituents selected from a halogen atom, a Cι-6 alkyl group, an optionally halogenated Cχ-6 alkoxy group and the like; (3) a C7-.19 aralkyl group; (4) a heterocyclic group (preferably 2- or 3-thienyl; 2- or 3- furyl; 2-, 3- or 4-pyridyl) bonded via a carbon atom; and the like. _ ,, •••• S grOirratc"'xoup for Ar, for example, a C6-14 aryl group (preferably phenyl) , an aromatic heterocyclic group and the like can be mentioned. As the aromatic heterocyclic group, those exemplified as the "optionally substituted heterocyclic group" exemplified for the aforementioned R1 and the like can be used. Of these, a C6-i4 aryl group (preferably phenyl) , a 5 or 6-membered aromatic heterocyclic group (preferably thienyl, furyl, pyridyl) and the like are preferable.
As the "optionally substituted heterocyclic group bonded via a nitrogen atom" for Het, for example, a group bonded via a nitrogen atom from the "optionally substituted heterocyclic groups" exemplified as the aforementioned R1 and the like can be mentioned. Of these, 1-pyrrolidinyl, 1-piperazinyl, 4-morpholinyl or 4-thiomorpholinyl optionally having 1 to 3 substituents selected from an optionally halogenated Cι_6 alkyl group, an optionally halogenated Cι_6 alkyl-carbonyl group and the like is preferable.
As the hydrocarbon group for R12, for example, those exemplified as the "optionally substituted hydrocarbon group" exemplified as the aforementioned R1 and the like are used. Of these, a Cι-6 alkyl group, a C6-i4 aryl group (preferably phenyl) and the like are preferable.
As the "optionally substituted hydrocarbon group", "optionally substituted heterocyclic group" and "optionally substituted acyl group" for R13 or R14, those exemplified for the aforementioned R1 and the like are used. Here, the "optionally substituted hydrocarbon group" is preferably a Cι-6 alkyl group, a C3-s cycloalkyl group or a C7-19
Figure imgf000028_0001
having 1 to 3 substituents selected from 5- to 7-membered heterocyclic groups (preferably thienyl, furyl, pyridyl, morpholinyl, thiomorpholinyl) . The "optionally substituted heterocyclic group" is preferably a monocyclic non-aromatic heterocyclic group (preferably piperidinyl) optionally having 1 to 3 substituents selected from a C7-19 aralkyl group and the like. The "optionally substituted acyl group" is preferably a C1-6 alkyl-carbonyl group, a Cs-14 aryl-carbonyl group (preferably benzoyl) or an aromatic heterocyclic carbonyl group (preferably nicotinoyl, isonicotinoyl) each optionally having 1 to 3 substituents selected from a Cι-6 alkoxy- carboxamido group and the like. The nitrogen-containing heterocyclic group of the "nitrogen-containing heterocyclic group optionally having substituents (provided that the nitrogen-containing heterocyclic group is not an oxopyrrolidinyl group or an oxopiperazinyl group)" formed by R13 and R14 together with the adjacent nitrogen atom is, for example, a 5- to 7-membered nitrogen-containing heterocyclic group containing at least one nitrogen atom as a ring constituting atom besides carbon atom, and optionally having 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom can be mentioned. Preferable examples of the nitrogen-containing heterocyclic group include 1-pyrrolidinyl, 1-imidazolidinyl, 1- pyrazolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4- thiomorpholinyl and the like. The nitrogen-containing heterocyclic group may have 1 to 3 substituents at substitutable position (s) and as such substituent, a halogen atom, an optionally halogenated Cι-6 alkyl group, an optionally halogenated Cι-6 alkoxy group and the like can be mentioned. „„.. « ,. Tne wnitr6gfen'-ι-?σrrtaining heterocyclic group optionally having substituents" is preferably 1-piperidinyl and the like.
In the formula (I), (1) a compound wherein one of R4 and R5 is a hydrogen atom, the other is a group represented by the formula: -C(=X)-R7 wherein X and R7 are as defined above; and (2) a compound wherein R4 is a hydrogen atom, and R5 is a group represented by the formula: -C(=0)-R10 wherein R10 is as defined above are preferable,
In the formula (I' ) , R13' and R14' are the same as R13 and R14, except that the nitrogen-containing heterocyclic group of the "nitrogen-containing heterocyclic group optionally having substituents" formed by these together with the adjacent nitrogen atom may be an oxopyrrolidinyl group or an oxopiperazinyl group. The compound (I' ) is preferably compound (I).
As an example of preferable compound (I), the following compound can be mentioned, [compound A] A compound wherein R1, R2, R3 and R6 are hydrogen atoms; one of R4 and R5 is a hydrogen atom, and the other is a group represented by the formula: -C(=X)-R7; X is N-O-R8 or N-NH-R9; R8 and R9 are the same or different and each is (1) a hydrogen atom; (2) an amidino group; (3) a Cι-6 alkyl group optionally having 1 to 3 substituents selected from a hydroxy group, an optionally halogenated Cι_s alkoxy group, a carboxyl group, an amino group, a mono- or di-Cι-6 alkylamino group, a 5- to 7- membered heterocyclic group (preferably pyrrolidinyl, imidazolyl, morpholinyl) , a Cι_6 alkoxy-carbonyl group, a ιr« if'"' •"![ <- ft > I 1-- «'' -B •■'! Ξ" ""t -ft lt oa--4baιτfd[y ^'r1ou ,' wϊrtι-5n, - or dι-Cι-6 alkyl-carbamoyl group, a C6-i4 aryl-carba oyl group, a Cι_6 alkoxy-carboxamido group, a 5- to 7-membered heterocyclic oxy group (preferably tetrahydropyranyloxy) and the like; (4) a C7-19 aralkyl group; (5) a heterocyclic group (preferably 2- or 3-pyrrolidinyl; 2-, 3- or 4-piperidinyl) bonded via a carbon atom and optionally having 1 to 3 substituents selected from a Cι_6 alkoxy-carbonyl group and the like; or (6) a carbamoyl group; and R7 is (1) a hydrogen atom; or (2) a C1-6 alkyl group, a Cs-ι4 aryl group (preferably phenyl), a C7-19 aralkyl group or a monocyclic aromatic heterocyclic group (preferably thienyl, furyl) each optionally having 1 to 3 substituents selected from a halogen atom, a Cι-6 alkyl group, an optionally halogenated Cι-6 alkoxy group and the like.
[compound B] A compound wherein R1, R2, R3 and R6 are hydrogen atoms; R4 is a hydrogen atom; R5 is a group represented by the formula: -C(=0)-R10; and R10 is (1) a hydrogen atom; (2) a Cι_6 alkyl group; (3) a Cε-14 aryl group (preferably phenyl) optionally having 1 to 3 substituents selected from a halogen atom, a Ci-e alkyl group, an optionally halogenated Cι-6 alkoxy group and the like; (4) a C7-19 aralkyl group; or (5) a heterocyclic group (preferably 2- or 3-thienyl/ 2- or 3-furyl; 2-, 3- or 4-pyridyl) bonded via a carbon atom.
The salt of compound (I) or (I' ) is preferably a pharmacologically acceptable salt, and is exemplified by salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids . „ ,,„„. r , , '" P'fe''fferaibie*'S a |-:ϊfes of the salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts and ammonium salts. Preferable examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc. Preferable examples of the salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Preferable examples of the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid., oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Preferable examples of the salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Examples of preferable salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. A prodrug of compound (I) refers to a compound capable of being converted to compound (I) by the actions of an enzyme, gastric juice, or the like, under physiological conditions in vivo, specifically a compound capable of being converted to compound (I) upon enzymatic oxidation, reduction, hydrolysis, or the like, or a compound capable of being converted to compound (I) upon hydrolysis or the like by gastric juice or the like. Examples of the prodrugs of compound (I) include compounds derived hy acylation, alkylation or phosphorylation of the amino group of compound (I) (e.g., compounds derived by eicosanoylation, alanylation, pentylaminocarbonylation, (5- methyl-2-oxo-l, 3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation,
Figure imgf000032_0001
tert-butylation of the amino group of compound (I)); compounds derived by acylation, alkylation, phosphorylation or boration of the hydroxy group of compound (I) (e.g., compounds derived by acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation of the hydroxy group of compound (I)); and compounds derived by esterification or amidation of the carboxy group of compound (I) (e.g., compounds derived by ethyl esterification, phenyl esterification, carboxymethy1 esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarhonyloxyethyl esterification, pht alidyl esterification, (5-methyl-2-oxo-l, 3-dioxolen-4- yl) ethyl esterification, cyclohexyloxycarbonylethyl esterification, or methylamidation of the carboxy group of compound (I)). These compounds can be produced from compound (I) by methods known per se . The prodrug of compound (I) may be one capable of being converted to compound (I) under physiological conditions, as described in "Iyakuhin No Kaihatsu (Development of Drugs)", vol. 7, Molecular Designing, published by Hirokawa Shoten, 1990, pages 163 - 198. As the prodrug of compound (I' ) , the same as the prodrug of compound (I) is used. Compounds (I), compounds (I') and prodrug thereof (hereinafter also referred, to as "compound of the present invention") are of low toxicity and can be used as an agent for preventing or treating the various diseases mentioned below in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, bovines, horses, swine, monkeys) , as such or in the form of pharmaceutical compositions prepared by admixing with a pharmacologically acceptable carrier, etc. Examples of the dosage forms of the pharmaceutical
Figure imgf000033_0001
preparations such as tablets (including sublingual tablet, orally disintegrating tablet) , capsules (including soft capsules and microcapsules) , granules powders, troches, syrups, emulsions, suspensions; and non-oral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions) , external preparations (e.g., dermal preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories) , pellets, preparations for nasal administration, preparations for transpulmonary administration (inhalant) and eye drops. These can be orally or parenterally administered safely. These preparations may be controlled-release preparations (e.g., sustained-release microcapsules) such as rapid release preparations, sustained-release preparations and the like. The pharmaceutical composition can be prepared by conventional methods in the fields of pharmaceutical manufacturing techniques, for example, methods described in the Japanese Pharmacopoeia While the content of the compound of the present invention in a pharmaceutical composition varies depending on the dosage form, dose of the compound the present invention and the like, it is, for example, about 0.1 - 100 weight % .
The compound of the present invention has a superior IκB kinase inhibitory activity and can be used as an agent for preventing or treating various diseases in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, bovines, horses, swine, monkeys) . Furthermore, since the compound of the present invention has a selective IκB kinase inhibitory activity, it shows low toxicity (e.g., acute toxicity, chronic _ ^ __ _ _ _ _ fe i i y^">^ι-?αiifefe'c bδi%y, cancinogenecity, genetic toxicity) and causes a ferwer side effects. As used herein, as IκB kinase, IKKα (I K-1) , IKKβ (IKK-2) , regulatory subunit IKKγ (NEMO) and the like can be mentioned. The compound of the present invention also has a NF-κB inhibitory (transcription inhibitory) activity, TNF-α inhibitory (production inhibitory) activity and the like. The compound of the present invention can be used as, for example, an agent for preventing or treating diabetes (e.g., type I diabetes, type II diabetes, gestational diabetes etc.); an agent for preventing or treating hyperlipidemia (e.g., hypertriglyceridemia, hypercholestexolemia, hypo-high-density- lipoproteinemia, postprandial hyperlipemia etc.); an agent for preventing or treating arteriosclerosis; an agent for preventing or treating impaired glucose tolerance (IGT) ; an insulin secretagogue; and an agent for preventing progress from impaired glucose tolerance to diabetes .
The compound of the present invention can be used as an agent for preventing or treating, for example, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, diabetic hyperosmolar coma, infectious disease (e.g., respiratory infectious disease, urinary tract infectious disease, gastrointestinal infectious disease, skin/soft tissue infectious disease, inferior limb infectious disease) , diabetic gangrene, xerostomia, lowered sense of hearing, cerebrovascular disorder, peripheral blood circulation disorder], obesity, osteoporosis, cachexia (e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious disease cachexia or cachexia due to acquired immunodeficiency syndrome) , fatty liver, hypertension, polycystic ovary syndrome, renal disease (e.g., diabetic nephropathy, __ __ ^ _ _ _
''"^±oϊriέiftfl^ήfeT^jA-fe^^-rame ulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end stage renal disease) , muscular dystrophy, cardiac infarction, angina pectoris, cerebrovascular disorder (e.g., cerebral infarction, stroke), insulin resistance syndrome, syndrome X, metabolic syndrome (a condition associated with at least one of type II diabetes, impaired glucose tolerance and insulin resistance and at least two of obesity, lipid metabolism abnormality, hypertension and -nicroalbuminuria in combination), Gushing' s syndrome, hiyperinsulinemia, sensory disorder in hyperinsulinemia, tumors (e.g., leukemia, breast cancer, prostate cancer, skin cancer), -irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (e.g., spondylitis deformans, osteoarthritis, atopic dermatitis, chronic obstructive pulmonary disease, endotoxin shock, sepsis, low back pain, gout, postoperative or posttraumatic inflammation, swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including nonalcoholic fatty hepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, gastric inucosal injury (including gastric mucosal injury caused by aspirin)), autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis) , viral diseases (e.g., cytomegalovirus pneumonia, common cold by adenovirus, conjunctivitis, acquired immunodeficiency syndrome, ixveitis) , endotherial hypertrophy, multiple sclerosis, atherosclerosis, Alzheimer's disease, diseases associated with abnormal vascular proliferation such as retinopathy and the like, anorexia, malaise, chronic fatigue syndrome, metabolic bone diseases such as bone cancer pain and the like, deterioration of organ during pretransplantation preservation, visceral fat syndrome and the like. In addition, the compound of the present invention is used an an immunosuppressant . The compound of the present invention is also used for ''""'the'1 '--e'c'-iσa'ry*' rdpferois and suppression of progression of the above-mentioned various diseases (e.g., cardiovascular event such as cardiac infarction and the like) . While the dose of the compound of the present invention varies depending on administration subject, administration route, target disease, clinical condition, etc., it is, for instance, about 0.01 to 100 mg/kg body weight, preferably 0.05 to 30 rng/kg body weight, more preferably 0.1 to 10 mg/kg body weight, as a usual dosage per administration for oral administration to an adult diabetic patient. This dose is desirably administered 1 to 3 times a day. The compound of the present invention can be used in combination with a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, a chemotherapeutic agent, an immunotherapeutic agent, antith-rombotic agent and the like (hereinafter abbreviated as a combination drug) . On such occasions, the timing of administration of the compound of the present invention and that of the combination drug is not limited. They may be administered simultaneously or at staggered times to the administration subject. Moreover, the compound of the present invention and a combination drug may be administered as two kinds of preparations respectively containing an active ingredient, or as a single preparation containing both active ingredients . Tre dose of the combination drug can be appropriately selected based on the dose which is clinically employed. The proportion of the compound of the present invention and the combination drug can be appropriately selected according to the administration subject, administration route, target disease, clinical condition, combination, and other factors. I'. T .'it ,: i .. 1 i rT. -*
"'"Itr fcAses wnS'rfe τro"'tt-kτ.-i-nistration subject is human, for instance, the combination drug may be used in an amount of 0.01 to 100 parts by -weight per part by weight of the compound of the present invention. Examples of the "therapeutic agent for diabetes include insulin preparations (e.g., animal insulin preparations extracted from the bovine or swine pancreas; human insulin preparations synthesized by a genetic engineering technique using Escherichia cold, or a yeast, insulin zinc; protamine zinc insulin; fragment or derivative of insulin (e.g., 1NS-1 and the like); oral insulin preparations), insulin sensitizers (e.g., pioglitazone orr its salt (preferably hydrochloride), rosiglitazone or its salt (preferably maleate) , Reglixane, GI- 262570, Netoglitazone, DRF-2593, BM-13.1258, KRP-297, R— 119702, CS-011, FK-61 , compounds described in WO99/58510 (e.g. , (E) -4-[4- (5-methyl-2-ρhenyl-4- oxazolylmethoxy) benzyl oxyimino] -4-phenylbutyric acid) , compounds described in O01/38325, Tesaglitazar, BMS-298585, BM-13-1258, LM-4156, MBX-102, LY-519818, MX-6054, LY-510929, Balaglitazone, T-131 or its salt, THR-0921) , PPARγ agonists, PPARγ antagonists, PPΑR7 /α dual agonists, α~glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate) , biguanides (e.g., phenformin, etformin, bufor in or their salts (e.g., hydrochloride, fu arate, succinate) ) , insulin secretagogues [sulfonylureas (e.g., tolbuta ide, glibencla ide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate] , GPR40 agonist, GLP-1 receptor agonists [e.g., GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib (8, 35) hGLP-1 (7, 37)NH2 , CJC-1131], amylin agonists (e.g., pramlintide) , phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate) , ffi If"" "'IT' ,-' B IS « "'■■ iT'u KV -' "ft "it iS"~' '""U »iE
11 dip1ept¥cfflψepti1ddis:gτ-i-.V,t" inhibitors (e.g., NVP-DPP-278, PT-10O, P32/98, LAF237, P93/01, TS-021) , β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140), gluconeogjenesis inhibitors (e.g., glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists), SGLT (sodium-glucose cotransporter) inhibitors (e.g., T-1095) , llβ-HSDl inhibitors (e.g., BVT- 3498), adiponectin or its agonist, IKK inhibitors (e.g., AS— 2868), leptin resistance improving drug, somatostatin receptor agonist (e.g., compounds described in O01/25228, WO03/42204, W098/44921, W098/45285, W099/22735 etc.), glucokinase activator (e.g., Ro-28-1675) and the like. Examples of th_e therapeutic agent for diabetic complications include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat (SNK-860), AS-3201, CT-112) , neurotrophic factors and its increasing agents (e.g., NGF, NT-3, BDNF, neurotrophin production secretion promoters (e.g., 4- (4-chlorophenyl) -2- (2- methyl-1-imidazolyl ) -5- [3- (2-methylphenoxy)propyl] oxazole) described in WOOl/14372), neuranegenesis promoters (e.g., Y— 128), PKC inhibitors (e.g., LY-333531) , AGE inhibitors (e.g., ALT946, pimagedine, pyratoxathine, N-phenacylthiazolium bromide (ALT766), -VLT-711, EXO-226, Pyridorin, Pyridoxamine) , active oxygen scavengers (e.g. thioctic acid), cerebral vasodilators (e.g., tiapuride, mexiletine) , somatostatin receptor agonist (e.g., BIM23190) and apoptosis signal regulating kinase-1 (ASK-1) inhibitor.
Examples of the antihyperlipidemic agent include HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvas tatin, fluvastatin, itavastatin pitavastatin, rosuvastatin or their salts (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compound.
Figure imgf000039_0001
, such as N- [ [ (3R, 5S) -1- (3-acetoxy-2, 2- dimethylpropyl) -7-chloro—5- (2, 3-dimethoxyphenyl) -2-oxo- 1,2,3, 5-tetrahydro-4, l-be.nzoxazepin-3-yl] acetyl] piperidine-4- acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate) , ACAT inhibitors (e.g. , Avasimibe, Eflucimibe) , anion exchange resins (e.g., cholestylamine) , probuchol, nicotinic pharmaceutical agents (e.g., nicomol, niceritrol) , ethyl icosapentate, phytosterol (e.g., soysterol, γ-oryzanol) and the like. Examples of the hypotensive agent include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril) , angiotensin IZ antagonists (e.g., candesartan cilexetil, losartan, eprσsartan, valsartan, termisartan, irbesartan, olmesartan medoxomil, tasosartan, l-[[2'-(2,5- dihydro-5-oxo-4H-l, 2, 4-o∑cadiazol-3-yl)biphenyl-4-yl]methyl] -2- ethoxy-lH-benzimidazole-7-carboxylic acid), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine) , potassium channel openers (e.g., levcromakalim, L-27152, A-.L 0671, NIP-121) and clonidine . Examples of the antiobesity agent include antiobesity drugs acting on the central nervous system (e.g. dexfenfluramine, fenfluramine, phentermine, sibutramine, anfepramon, dexamphetamin-e, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP— 7941; compounds described in WO01/82925 and WO01/87834) ; neuropeptide Y antagonists (e.g., CP-422935) ; cannabinoid receptor antagonists (e.g., SR-141716, SR-147778); ghrelin antagonists; llβ-HSDl inhibitors (e.g., BVT-3498)), pancreatic lipase inhibitors (e.g. orlistat, ALT-962), β3 agonists (e.g. CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS- 196085, AZ-40140), anorectic peptides (e.g. leptin, CNTF (Ciliary Neurotrophic Factor)), cholecystokinin agonists (e.gj. lintitript, FPL-15849), feeding deterrent (e.g., P-57) and the iF'l±je 5*OiS X 1153,1 Examples of the chemotherapeutic agent include alkylating agents (e.g., cyclophosph-amide, ifosamide) , metabolic antagonists (e.g., methot rexate, 5-fluorouracil or derivative thereof), antitumor antibiotics (e.g., mitomycin, adriamycin) , plant-derived antitumor agents (e.g., vincristine, vindesine, Taxol) , cisplatin, carboplatin, etoposide. Among these, 5- fluorouracil derivatives such as Furtulon and Neo-Furtulon are preferable. Examples of the immunotherapeutic agent include microorganism- or bacteriuαm-derived components (e.g., muramyl dipeptide derivatives, Picibanil) , immunopotentiator polysaccharides (e.g., lentinan, schizophyllan, krestin) , genetically engineered cytokines (e.g., interferons, interleukins (IL) ) , colony stimulating factors (e.g., granulocyte colony stimula-ting factor, erythropoietin) , etc. Among these, interleukins such as IL-1, IL-2, IL-12 and the like are preferable. As the antithrombotic: agent, for example, heparin (e.g., heparin sodium, heparin calcium, dalteparin sodium) , warfarin (e.g., warfarin potassium) , antithrombin agents (e.g., aragatroban) , thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase) , platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like can be mentioned. Furthermore, drugs confirmed to exhibit a cachexia ameliorating effect in animal models and clinical applications, namely, cyclooxygenase inhibitors (e.g., indomethacin) , progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g. dexaxnethasone) , metoclopramide pharmaceuticals, tetrahydrocannabinol pharmaceuticals, fat _ , _ _
^' et,bolli;'Sm'|i teelϊ<-.ira,b-h.,g agents (e.g., eicosapentanoic acid), growth hormones, IGF-1, and antibodies to the cachexia- inducing factor TNF-α, LIF, IL-6 or oncostatin M and the like, can be also used in combination with the compound of the present invention. The above combination drugs can ioe used as a mixture of two or more species in an appropriate ratio. The combination drug is preferably an insulin preparation, an insulin sensitizer, an α-glucosidase inhibitor, a biguanide, an insulin secretagogue (preferably sulfonylurea) , and the like. By combining the compound of the present invention and a combination drug, a superior effect such as (1) the dose of the compound of the piresent invention and/or a combination drug can be reduced as compared to single administration of the compound of the present invention or a combination drug, (2) a sustained treatment effect can be designed by selecting a combination drug having different action and mechanism from the compound of the present invention,, (3) a synergistic effect can be afforded by a combined use of the compound of the present invention and a combination drug, and the like, can be achieved. The production methods of compouxnd (I) are explained in the following. Compounds (I) can be produced by a method known per se, such as Method A-Method I shown below or a method analogous thereto. In each of the following production methods, a starting compound may be used in the fTorm of a salt and as such salt, those exemplified for the salts of compound (I) can be used. A compound obtained in each Step can be isolated and ^urliffife-^^^i^A^ H ^^sepa ation and purification methods, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The compound obtained in each Step can be directly used for the next reaction without isolation and in the form of a reaction mixture containing the compound.
Compound (I-l) which is compound (I) whverein R4 is a hydrogen atom and R5 is a hydroxymethyl group; compound (1-2) which is compound (I) wherein R4 is a hydrogem atom and R5 is a formyl group; compound (1-3) which is compound (I) wherein R4 is a hydrogen atom and R5 is R10CH(OH)~; compound (1-4) which is compound (I) wherein R4 is a hydrogen atom and R5 is R10CO-; compound (1-5) which is compound (I) wherein R4 is a hydrogen atom and R5 is R10C (=NOR8) -; and compound (1-6) which is compound (I) wherein R4 is a hydrogen atom and R5 is R10C(=NNHR9) - can be produced by, for example, Method A below or a method analogous thereto.
,,„, , .»|P" ," it u ic n ic" ..• .-|i •■![ p™ -'ϊ, ..a w ['Meth "'A']"1' i! " m« !f" »•">' '»«'' <*
Figure imgf000043_0001
wherein R11 is a hydrogen atom or a Cι_6 alkyl group (e.g., methyl, ethyl) and other symbols are as defined above. In this method, compound (II) is subj ected to reduction reaction to give compound (I-l), compound ( I-l) is subjected to an oxidation reaction to give compound ( 1-2), compound (I- 2) is reacted with an organic metal reagent to give compound (1-3), compound (1-3) is subjected to an oxidation reaction to give compound (1-4) , and compound (1-4) is reacted with compound (III) to give compound (1-5) . Alternatively, compound (1-4) is reacted with compound (IV) to give compound (1-6) (Step 1) In this Step, compound (II) is subjected to reduction reaction to give compound (I-l) . This reaction is carried out by a method known per se. That is, this reaction is carried out according to a conventional method in t-he presence of a reducing agent in a solvent that does not adversely affect the reaction or without solvent. As the reducing agent, for example, sodium borohydride,
Figure imgf000044_0001
,r l thiύm^Dbtcf ydr-'C-S,™' 1' 3-ithium aluminum hydride, diisobutylaluminum hydride and the like can be mentioned. The amount of the reducing agent to be used is generally about 0.5 to about 20 molar equivalents, preferably aboi t 1 to about 10 molar equivalents, relative to compound (II) . As the solvent that does not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; water; alcohols such as methanol, ethanol, isopropanol and the like, and the like can be mentioned. Two or more kinds of the se solvents may be mixed before use at an appropriate ratio . The reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C. The reaction time is generally about 0.5 to about 20 hrs . (Step 2) In this step, the compound (I-l) is subjected to an oxidation reaction to give compound (1-2) . This reactions is carried out by a method known per se . That is, this reaction is carried out according to a conventional method in the presence of an oxidant in a solvent that does not advers ely affect the reaction or without solvent. As the oxidant, for example, metal oxidants such as manganese dioxide, pyridinium chlorochromate, pyridinium- dichromate, ruthenium oxide and the like can be mentioned. The amount of the oxidant to be used is generally about 0.5 - about 20 molar equivalents, preferably about 1 - a-bout 10 molar equivalents, relative to compound (I-l) . As the solvent that does not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofxiran, dioxane, diethyl ether and the like; halogenated hydrocarbons
Figure imgf000045_0001
and the like; and the like- can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio. The reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C. The reaction time is generally about 0.5 to about 20 rs . (Step 3) In this Step, compound (1-2) is reacted with an organic metal reagent to give compound (1-3) . This reaction is carried out by a method known per se. That is, this reaction is carried out according to a conventional method in a solvent that does not adversely affect the reaction or without solverxt, As the organic metal reagent, Grignard reagents represented by the formula: HalMgR10 (Hal is a halogen atom (e.g., chlorine, bromine) and R10 is as defined above), organic; lithium reagents represented by the formula: LiR10 (the symbol is as defined above) and the like can be mentioned. The organic metal reagent can be produced according to a method known per se. As the solvent that does not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio. The amount of the organic metal reagent to be used is generally about 0.5 to about 20 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (1-2) . The reaction temperature is generally about -100 to about 150°C, preferably about -80 to about 100°C. The reaction time is generally about 0.5 to about 20 hrs . (Step 4)
Figure imgf000046_0001
(1-3) is subjected to an oxidation reaction to give compound (1-4) . This reaction is carried out in the same manner as in the aforementioned Step 2. (Step 5) In this step, compound (1-4) is reacted with compound (III) to give compound (1-5) . This reaction is carried out by a method known per se. That is, this reaction is carried out according to a conventional method in a solvent that does not adversely affect the reaction or without solvent. As compound (III), for example, hydroxylamine, N- alkylhydroxylamine or a salt thereof can be mentioned. As a salt here, for example, hydrochloride, oxalate and the like can be mentioned. As the solvent that does not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; alcohols such as ethanol, methanol and the like; amides such as N,N- dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; aliphatic carboxylic acids such as acetic acid and the like; water and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio. The amount of the compound (III) to be used is generally about 1 to about 20 molar equivalents, preferably about 2 to about 10 molar equivalents, relative to compound (1-4) . The reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C. The reaction time is generally about 0.5 to about 20 hrs. This reaction may be carried out in the presence of an acid or a neutralizing agent. As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid and the like can '"'''le ro-.rf i;on:9V' "As"" the'1"neutralization agent, for example, bases such as pyridine, triethylamine, sodium carbonate, sodium acetate and the like can be mentioned. (Step 6) In this step, compound (1-4) is reacted with compound (IV) to give compound (1-6) . This reaction is carried out by a method known per se . That is, this reaction is carried out according to a conventional method in a solvent that does not adversely affect the reaction or without solvent. As compound (IV), for example, aminoguanidine, semicarbazide and a salt thereof can be mentioned. As a salt here, for example, hydrochloride, acetate and the like can be mentioned. As the solvent that does not adversely affect the reaction, those exemplified in the aforementioned Step 5 are used. The amount of the compound (IV) to be used is generally about 1 to about 20 molar equivalents, preferably about 1.2 to about 10 molar equivalents, relative to compound (1-4) . The reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C. The reaction time is generally about 0.5 to about 20 hrs. This reaction may be carried out in the presence of an acid or a neutralizing agent. As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid and the like can be mentioned. As the neutralization agent, for example, bases such as pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium acetate and the like can be mentioned. The compound (II), compound (III) and compound (IV) used as starting compounds in the above-mentioned Method A can be produced by a method known per se . For example, the compound (II'), which is a compound (II)
Figure imgf000048_0001
group and R6 is a hydrogen atom, can be produced by the following Method B or a method analogous thereto. [Method B]
Figure imgf000048_0002
wherein R11' is a Cι-6 alkyl group and other symbols are as defined above. In this method, compound (V) is reacted with an oxalic acid ester and a potassium salt to give compound (VI) , and compound (VI) is subjected to reduction reaction under acidic conditions to give compound (II1). (Step 1) In this step, compound (V) is reacted with an oxalic acid ester and a potassium salt to give compound (VI) . This reaction is carried out by a method known per se . That is, this reaction is carried out according to a conventional method in the presence of a potassium salt in a solvent that does not adversely affect the reaction or without solvent. As the oxalic acid ester, a compound represented by the formula (C02R1:L')2 wherein the symbol is as defined above is used. As concrete examples thereof, dimethyl oxalate, diethyl oxalate and the like can be mentioned. As the potassium salt, for example, potassium tert- butoxide, potassium ethoxide and the like can be mentioned. As the solvent that does not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; alcohols '•'Iic-ht M'
Figure imgf000049_0001
tftahol and the like; amides such as N,N- dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio. The amount of the oxalic acid ester to be used is generally about 1 to about 20 molar equivalents, preferably about 1.2 to about 10 molar equivalents, relative to compound (V) . The amount of the potassium salt to be used is generally about 1 to about 20 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (V) . The reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C. The reaction time is generally about 0.5 to about 20 hrs. (Step 2) In this step, compound (VI) is subjected to reduction reaction under acidic conditions to give compound (II'). This reaction is carried out by a method known per se. That is, this reaction is carried out according to a conventional method in the presence of a reducing agent and an acid a solvent that does not adversely affect the reaction or without solvent. As the reducing agent, for example, iron, zinc and the like can be mentioned. As the acid, for example, acetic acid, hydrochloric acid and the like can be mentioned. As the solvent that does not adversely affect the reaction, those exemplified in the aforementioned Method A, step 5, are used. The amount of the reducing agent to be used is generally about 1 to about 20 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (VI) . sr i ' ii ,•• !'Φ'eir '"&iϊføul'-*O,-!''"' ;E!fe acid to be used is generally about 1 to about 100 molar equivalents, preferably about 1 to about 20 molar equivalents, relative to compound (VI) . The reaction temperature is generally about 0 to about 150°C, preferably about 10 to about 100°C. The reaction time is generally about 0.5 to about 20 hrs. By further subjecting compound (II') obtained by the above-mentioned Method B to hydrolysis, compound (II) wherein R6 and R11 are hydrogen atoms can be produced. Here, hydrolysis is performed according to a method known per se. The compound (V) and an oxalic acid ester which are used as starting compounds in the above-mentioned Method B can be produced according to a method known per se . For example, compound (III) can be produced by means of the following Method C or a method analogous thereto. [Method C]
Figure imgf000050_0001
wherein the symbol in the formula is as defined above. In this method, compound (VII) is reacted with N- hydroxyphthalimide to give compound (VIII) and compound (VIII) is reacted with methylhydrazine to give compound (III) . (Step 1) In this step, compound (VII) is reacted with N- hydroxyphthalimide to give compound (VIII) . This reaction is carried out by a method known per se. That is, this reaction is carried out in the presence of an organic phosphorus compound and an electrophilic agent in a solvent that does not adversely affect the reaction or without solvent. y,s"i 'ήe"ii, r a, ±^"; 'iriosphorus compound, for example, triphenylphosphine, tributylphosphine and the like can be mentioned. As the electrophilic agent, for example, diethyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbonyldipiperidine and the like can be mentioned. As the solvent that does not adversely affect the -reaction, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; and the like can be mentioned. Two or more kinds of these solvents may Toe mixed before use at an appropriate ratio. The amount of N-hydroxyphthalimide to be used is generally about 1 to about 5 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (VII) . The amount of the organic phosphorus compound and electrophilic agent to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, relative to compound (VII) . The reaction temperature is generally about -50 to about 150°C, preferably about -10 to about 100°C. The reaction time is generally about 0.5 to about 40 hrs. (Step 2) In this step, compound (VIII) is reacted with iuethylhydrazine to give compound (III) . This reaction is carried out by a method known per se. That is, this reaction is carried out in a solvent that does not adversely affect the reaction or without solvent. As the solvent that does not adversely affect the rea'c i'όn"), ^ifσ' e' dmj-flS;"" aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; alcohols such as ethanol, methanol and the like; amides such as N,N- dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; water and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio. The amount of methylhydrazine to be used is generally about 1 to about 5 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (VIII) . The reaction temperature is generally about -50 to about
150°C, preferably about -10 to about 100°C. The reaction time is generally about 0.5 to about 40 hrs. The compound (VII) used as a starting compound in the above-mentioned Method C can be produced according to a method known per se. Compound (1-7) which is compound (I) wherein R4 is a hydrogen atom and R5 is Het-CO- and compound (1-7') which is compound (I) wherein R4 is a hydrogen atom and R5 is Ar-(CH2)n- NH-CO- are produced by, for example, the following Method D or a method analogous thereto.
, .,„, .„„ „, „ „ „ ,„-- „ ,„ PMe't dW '^H"
Figure imgf000053_0001
(I-7') wherein the symbols in the formula are as defined above. In this method, compound (II-l) which is compound (II) wherein R11 is a hydrogen atom is reacted with compound (IX) to give compound (1-7), or compound (II-l) is reacted with compound (IX' ) to give compound (1-7' ) . This reaction is carried out by a method known per se. That is, this reaction is generally carried out in the presence of a condensation agent in a solvent that does not adversely affect the reaction or without solvent. As the condensation agent, for example, carbodiimide condensation reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, l-ethyl-3- dimethylaminopropylcarbodiimide, hydrochloride thereof and the like; phosphoric acid condensation reagents such as diethyl cyanophosphate, diphenyl phosphoryl azide and the like; carbonyldiimidazole, 2-chloro-l, 3-dimethylimidazolium tetrafluoroborate and the like can be mentioned. As the solvent that does not adversely affect the reaction, for example, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers «"' suόh"'ci'-l','%fe;'Sahy '-!o«;ϊ dioxane, diethyl ether and the like; ethyl acetate; water and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio. The amount of compound (IX) and compound (IX') to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (II-l) • The amount of condensation agent to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (II-l) . When the aforementioned carbodiimide condensation reagents are used as the condensation agent, the reaction efficiency can be improved by adding, where necessary, a suitable condensation promoter (e.g., l-hydroxy-7- azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide) . In addition, when the aforementioned phosphoric acid condensation reagents are used as the condensation agent, the reaction efficiency can be generally improved by adding an organic amine base such as triethylamine and the like. The amount of the above-mentioned condensation promoter and the organic amine base to be used is generally about 0.1 to about 10 molar equivalents, preferably about 0.3 to about 3 molar equivalents, relative to compound (II-l) . The reaction temperature is generally, about -30°C to about 100°C. The reaction time is generally about 0.5 to about 60 hrs. The compound (II-l), compound (IX) and compound (IX') used as starting compounds in the above-mentioned Method D can be produced according to a method known per se .
Compound (1-8) which is compound (I) wherein R4 is a
Figure imgf000055_0001
R13R1 NCH - can be produced by, for example , the following Method E or a method analogous thereto . [Method E]
Figure imgf000055_0002
wherein the symbols in the formula are as defined above. In this method, compound (1-2) is reacted with compound (IX'') to give compound (1-8) . This reaction is carried out by a method known per se . That is, this reaction is generally carried out in the presence of a reducing agent in a solvent that does not adversely affect the reaction or without solvent, As the reducing agent, for example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like can be mentioned. As the solvent that does not adversely affect the reaction, those exemplified in the aforementioned Method A, Step 1, can be used. The amount of compound (IX'') to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 3 molar equivalents, relative to compound (1-2) . The amount of the reducing agent to be used is generally about 0.5 to about 20 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (1-2) . The reaction temperature is generally, about -50°C to about 150°C, preferably about -10°C to about 100°C. The reaction time is generally about 0.5 to about 20 hrs. The compound compound (IX'') used as a starting compound in the above-mentioned Method E can be produced according to a method known per se . !-" !-- ,
Figure imgf000056_0001
-which is compound ( I ) wherein R4 is a hydrogen atom and R5 is R7CH (NH2) -; and compound ( 1-11 ) which is compound ( I ) wherein R4 is a hydrogen atom and R5 is R7CH (NHCOR15) - can be produced, for example , by the following Method F or a method analogous thereto . [Method F]
Figure imgf000056_0002
wherein the symbols in the formula are as defined above. In this method, compound (1-9) which is compound (I) wherein R4 is a hydrogen atom and R5 is R7C(=NOH)- is subjected to reduction reaction to give compound (1-10) and compound (I- 10) is reacted with compound (X) to give compound (1-11) . (Step 1) In this Step, compound (1-9) is subjected to reduction reaction to give compound (1-10) . This reaction is carried out in the same manner as in the aforementioned Method A, Step 1. (Step 2) In this Step, compound (1-10) is reacted with compound (X) to give compound (1-11) . This reaction is carried out in the same manner as in the aforementioned Method D. The compound (1-9) used as a starting compound in the above-mentioned Method F can be produced by, for example, the aforementioned Method A or a method analogous thereto. In addition, compound (X) can be produced according to a method known per se .
Compound (1-5') which is compound (1-5) wherein R8 is a group bonded via a carbon atom, can be also produced by, for example, the following Method G or a method analogous thereto. " Mefch 'Φ ''"* '•'' ral!"
Figure imgf000057_0001
(1-9) (1-5') wherein L is a leaving group, R8' is a group bonded via a carbon atom, and other symbols are as defined above. 5 As the leaving group for L, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) ; optionally halogenated Cι-6 alkylsulfonyloxy groups (e.g., methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy); C6_ιo arylsulfonyloxy group (e.g.,
-20 phenylsulfonyloxy, naphthylsulfonyloxy) optionally having 1 to 3 substituents selected from Cι-.6 alkyl groups (e.g., methyl, ethyl), Cι_6 alkoxy groups (e.g., methoxy, ethoxy) and nitro group; acyloxy groups (e.g., trichloroacetoxy, trifluoroacetoxy and the like) and the like can be mentioned.
-25 In this method, compound (1-9) is reacted with compound (XI) to give compound (1-5'). This reaction is carried out by a method known per se . That is, this reaction is generally carried out in the presence of a base in a solvent that does not adversely affect the reaction or without solvent.
20 As the base, for example, alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate and the like; amines such as pyridine, triethylamine, N,N-dimetlylaniline, 1,8- diazabicyclo [5.4.0] undec-7-ene and the like; metal hydrides
25 such as potassium hydride, sodium hydride and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like can be mentioned. As the solvent that does not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, ftollb^n'^;;r*»yile e«'&®^^l-i!fe like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; ketones such as acetone, 2-butanone and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; amides such as N,N- dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; and the like can be mentioned. Two or more kinds of these solvents may be mixed before use at an appropriate ratio. The amount of compound (XI) and the base to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, relative to compound (I- 9) . The reaction temperature is generally about -50°C to about 150°C, preferably about -10°C to about 100°C. The reaction time is generally about 0.5 to about 20 hrs. The compound (XI) used as a starting compound in the above-mentioned Method G can be produced according to a method known per se . Compound (1-12) which is compound (I) wherein R1, R2, R3 and R4 are each a hydrogen atom, R5 is R10CH(OH)- and. R6 is R15S02-; and compound (1-13) which is compound (I) wherein R1, R2, R3, R4 and 6 are each a hydrogen atom and R5 is 10CH(OH)- can be produced by, for example, the following Method H or a method analogous thereto.
Figure imgf000058_0001
(XIII) (1-12) wherein the symbols in the formula are as defined above . In this method, compound (XII ) is reacted with compound (XIV) to give compound (XIII ) , and compound (XIII ) is reacted If-'it ,,.»,, ■■■j[ „, t,. j, jj , ,{„,,, ™ ^r .,., E ft,-,, „-,-, .,,. ^
« w±tϊr' dβmpburra; {«?¥<)««*&*-. ™'gιve compound (1-12), and compound (I- 12) is reacted -with hydroxide ion to give compound (1-13) _ (Step 1) In this Step, compound (XII) is reacted with compound (XIV) to give compound (XIII) . This reaction is carried out by a method known per se . That is, this reaction is generally carried out in the presence of a base in a solvent that does not adversely affect the reaction or without solvent. As the base, for example, alkali metal salts such as potassium hydro-xide, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate and the like; amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8— diazabicyclo [5.4.0] undec-7-ene and the like; metal hydrides such as potassium hydride, sodium hydride and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide,- potassium tert-loutoxide and the like; and alkali metal amides such as lithium diisopropylamide and the like can be mentioned. As the solvent that does not adversely affect the reaction, those exemplified in the aforementioned Method G can be used. The amount of compound (XIV) and the base to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, relative to compound (XII) ■ The reaction temperature is generally, about -100°C to about 150°C, preferably about -80°C to about 100°C. The reaction time is generally about 0.5 to about 20 hrs. (Step 2) In this Step, compound (XIII) is reacted with compound (XV) to give compound (1-12) . This reaction is carried out by a method known ]per se . That is, this reaction is generally carried out in the presence of a base in a solvent that does not adversely affect the reaction or without solvent. raιι
P
Figure imgf000060_0001
alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, potassium carbonate and the like; amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8- diazabicyclo[5.4.0]undec-7-ene, N,N,N',N'- tetramethylethylenediamine and the like; metal hydrides such as potassium hydride, sodium hydride and the like; alkali metal alkoxides such as sodiiam methoxide, sodium ethoxide, potassium tert-butoxide and the like; and alkali metal amides such as lithium diisopropylamide and the like can be mentioned. Two or more kinds of these bases may be mixed before use at an appropriate ratio. As the solvent that does not adversely affect the reaction, those exemplified in the aforementioned Method G can be used. The amount of compound (XV) and the base to be used is generally about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, relative to compound (XIII) . The reaction temperature is generally, about -100°C to about 150°C, preferably about -80°C to about 100°C. The reaction time is generally about 0.5 to about 20 hrs. (Step 3) In this Step, compound (1-12) is reacted with hydroxide ion to give compound (1-13) . This reaction is carried out by a method known per se . That is this reaction is generally carried out in a solvent that does not adversely affect the reaction or without solvent. As the hydroxide ion, for example, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; and the like can be mentioned. As the solvent that does not adversely affect the reaction, those exemplified in the aforementioned Method A,
Figure imgf000061_0001
' »us, .«'«t' < The amount of the hydroxide i-on to be used is generally about 1 to about 50 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (1-12) . The reaction temperature is cjenerally about 0°C to about 150°C, preferably about 10°C to about 100°C. The reaction time is generaliy about 0.5 to about 20 hrs. The compound (XII) , compound (XIV) and compound (XV) used as starting compounds in the above—mentioned Method H can be produced according to a method known per se .
Compound (1-15) which is compound (I) wherein R1, R2, R3, R5 and R6 are each a hydrogen atom and R4 is R10CH(OH)-; compound (1-16) which is compound ( I) wherein R1, R2, R3, R5 and R6 are each a hydrogen atom and R4 i_s R10CO-; and compound (I- 17) which is compound (I) wherein R-1, R2, R3, R5 and R6 are each a hydrogen atom and R4 is R10C (=NOR8) -; and compound (1-18) which is compound (I) wherein R1, R2, R3, R5 and R6 are each a hydrogen atom and R4 is R10C (=NNHR9) — can be produced by, for example, the following Method I or a method analogous thereto. [Method I]
Figure imgf000061_0002
wherein the symbols in the formula are as defined above. In this method, compound (1-14) is reacted with an organic metal reagent to give compoxind (1-15) , compound (1-15] IP'! ic■-. 'fel-i ''fe l'^' σ^d i^i' ϊon reaction to give compound (1-16) and compound (1-16) is reacted with compound (III) to give compound (1-17) . Alternatively, compoun-d (1-16) is reacted with compound (IV) to give compound (1-18) . (Step 1) In this Step, compound (1-14) is reacted with an organic metal reagent to give compound (1-15) . This reaction is carried out in the same manner as in the aforementioned Method A, Step 3. (Step 2) In this Step, compound (1-15) is subjected to oxidation reaction to give compound (1-16) . This reaction is carried out in the same manner as in the aforementioned Method A, Step 4. (Step 3) In this Step, compound (1-16) is ---reacted with compound (III) to give compound (1-17) . This rea-ction is carried out in the same manner as in the aforementioned Method A, Step 5. (Step 4) In this Step, compound (1-16) is --reacted with compound (IV) to give compound (1-18) . This reaction is carried out in the same manner as in the aforementioned Method A, Step 6. The compound (1-14) used as a sta-trting compound in the above-mentioned Method I can be produced according to a method known per se .
In each of the aforementioned reactions, when a starting compound has an amino group, a carboxyl group, a hydroxy group or a carbonyl group as a substituent, a protecting group generally used for these groups in peptide chemistry and the like may be introduced. By removing the protecting group as necessary after the reaction, the object compound can be obtained. As the amino-protecting group, fo-- example, formyl group,
Figure imgf000063_0001
(e.g., acetyl, propionyl), Cι-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl) , benzoyl group, C-n aralky-L-carbonyl groups (e.g., benzylcarbonyl), C7-.14 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl) , trityl group, phthaloyl group, N,N-dimethylaminomethylene group, silyl groups (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, te-t-rt- butyldiethylsilyl) , C2-6 alkenyl groups (e.g., 1-s.llyl) and the like can be mentioned. These groups may be substituted by 1 to 3 substituents selected from halogen atoms (e.g.,- fluorine, chlorine, bromine, iodine), Cι_6 alkoxy groups (e.g., methoxy, ethoxy, propoxy) , nitro group and the like . As the carboxyl-protecting group, for example, Cι-6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl), C7-11 aralkyl groups (e.g., benzyl), phenyl group, trityl group, silyl groups (e.g., trimethylsilyl r triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, tert-butyldiphenylsilyl) , C2-6 alkenyl groups (e.g., 1-allyl) and the like can be mentioned. These groups may be substituted by 1 to 3 substituents selected from halogen atoms (e.g., fluorine, chlorine, bromine, iodine), C1-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy), rxitro group and the like . As the hydroxy-protecting group, for example, Ci-s alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl), phenyl group, trityl group, C7-u aralkyl groups (e.g., benzyl), formyl group, Cι-6 alkyl-carbonyl groups (e.g., acetyl, propionyl), benzoyl group, C-n aralkyl-carbonyl groups (e.g., benzylcarbonyl) , 2-tetrahydropyranyl group, 2- tetrahydrofuranyl group, silyl groups (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldim-ethylsilyl, tert-butyldiethylsilyl), C2_6 alkenyl groups (e.g. , 1-allyl) and -;> ,n, ,„ , , ,. - ,„„. ^ „„,„ ,,. ...j „j- ---, - , -
* the" iMe'fei bd1"meτ-fe--©ϊned. These groups may be substituted by 1 to 3 substituents selected from halogen atoms (e.g., fluorine, chlorine, bromine, iodine), Cχ-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy), nitro group and the like. As the carbonyl-protecting group, for example, cyclic acetals (e.g., 1, 3-dioxane) , non-cyclic acetals (e.g., di-Cι-6 alkyl acetals) and the like can be mentioned. In addition, these protective groups can be removed by a method known per se, e.g., the method described in -Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). For example, there may be used methods employing an acid, a base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fHuoride, palladium acetate, a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) , or the like, the reduction method, and the like. When compound (I) contains an optical isomer, a stereoisomer, a position isomer, or a rotation isomer, these isomers are also contained as compound (I) and can each be obtained as a single substance by means of a method known per se of synthesis or separation. For example, when an optical isomer is present in compound (I), the optical isomer separated from said compound is also included in compound (I) . These isomers can be produced by a method known per se . The compound (I) may be a crystal and both single crystal and mixtures of crystals are encompassed in compounol (I) . The crystal of compound (I) (hereinafter sometimes to be abbreviated as crystal of the present invention) can- be produced by crystallization, by applying a crystalli zation method known per se to compound (I) . The compound (I) may also be in the form of solvate (e.g., hydrate) or non-solvates, which are also encompasse in compound (I) . j i, I X
Figure imgf000065_0001
be labeled with an isotope (e.g., 3H, 1 C, 35S, 125I and the like) and the like, which are also encompassed in compound (I) . The present invention is explained in detail by referring to the following Reference Examples, Examples, Experimental Examples and Formulation Examples, which are not to be construed as limitative. The present invention may be modified without deviating from the scope of the invention. The abbreviations in Reference Examples and Examples mean the following. s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, brs : broad singlet, J: coupling constant In Reference Examples and Examples, room temperature means a temperature of 1°C to 30°C, and % means percent by weight, unless otherwise indicated particularly. The gene manipulation methods described in the following Reference Examples followed a method described in a book (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or a method described in the attached protocol of the reagent.
The SEQ ID NOs of the sequence listing in the present specification show the following sequences. [SEQ ID NO: 1] A base sequence of primer used for PCR in Reference Example 1A below. [SEQ ID NO: 2] A base sequence of primer used for PCR in Reference Example 1A below. [SEQ ID NO: 3] A base sequence of primer used for PCR in Reference Example 2A below. [SEQ ID NO: 4] * A"',ba,Be*'lS'e^-eh'cel,«σf" r -ιπ.er used for PCR in Reference Example 2A below.
Reference Example 1A Cloning of human IKKβ gene and preparation of recombinant baculovirus Cloning of human IKKβ gene was performed by a PCR method using a primer set: IKKB-U: 5'- CAAAGCTAGCATGAGCTGGT CACCTTCCCT GAC- 3' (SEQ ID NO: 1 ) and IKKB-L: 5'- CAAAGGTACCTTACTTGTCGTCATCGTCTTTGTAGTCGGAGGCTTGCTCCAGGCAGCTGTGC -3' (SEQ ID NO: 2) prepared by reference to the base sequence of IKKβ gene reported by Mercurio F. et al. (Science, 278, 860-866 (1997)) and employing human leukocyte cDNA (Clontech; trade name: QUICK-Clone cDNA) as a template. A PCR was performed according to a protocol attached to LA Taq DNA polymerase (TAKARA SHUZO CO., LTD.). The obtained PCR product was electrophoresed on an agarose gel (1%) and a 2.3 kb DNA fragment containing IKKβ gene was recovered from the gel and digested with restriction enzymes Nhe I and Kpn I. The DNA after the restriction enzyme treatment was electrophoresed on an agarose gel (1%) and the resulting DNA fragment was recovered and ligated to plasmid pFASTBACl (Invitrogen) digested with restriction enzymes Nhe I and Kpn I to give an expression plasmid pFB-IKKB. The base sequence of the insertion fragment was confirmed and found to match the object sequence. Using BAC-TO-BAC Baculovirus Expression System (Invitrogen) , virus stock BAC-IKKB of the recombinant baculovirus was prepared. Reference Example 2A Cloning of human IκBα gene Cloning of human IκBα gene was performed by amplifying a gene encoding 54 amino acids on N terminal of IκBα by a PCR ,;.-„ ».(,-. j, « « (£"« if-ft jC".. t. „μ _;[ j..™. w»Sl ,fl l''' t Od,U's-cn,gv'''a' --,iι ermrset : IKB-U: 5'- AAAGAATTCATGTTCCAGGCGGCCGAGCGCCCC -3' (SEQ ID NO: 3) and IKB-L: 5'- AAACCCGGGTCA GAGGCGGATCTCCTGCAGCTCCTT -3' (SEQ ID NO: 4) prepared by reference to the base sequence of IκBα gene reported by Haskill, S. et al. (Cell, 65, 1281-1289, (1991)) and using human spleen cDNA (Clontech, trade name: QUICK-Clone cDNA) as a template . A PCR was performed according to a protocol attached to Pfu DNA polymerase (Stratagene) . The obtained PCR product was electrophoresed on an agarose gel (1%) and a 183 bp DNA fragment containing IκBα gene was recovered from the gel and digested with restriction enzymes EcoRI and Smal, after which inserted into a 4.9 kb EcoRI-Smal fragment of plasmid pGEX4T-l (Amersham Pharmacia Biotech) to give a plasmid pGEIKB. Reference Example 3A Preparation of active IKKβ Sf-21 cells (Invitrogen) were sown in 150 ml of Sf-900 II SFM medium (Invitrogen) containing 10% fetal calf serum to 1x10s cells/ml and cultured at 27°C for 24 hrs. To the obtained culture medium were added 150 μl of virus stock BAC-IKKB of recombinant baculovirus obtained in Reference Example 1A and the cells were further cultured for 60 hrs. The culture medium was centrifuged (3000 rpm, 10 min) to separate the cells, and the cells were washed once with PBS. The cells were suspended in 10 ml of a cytolysis buffer (25 mM HEPES (pH 7.5), 1% Triton X, 130 mM sodium chloride, 1 mM EDTA, ImM Dithiothreitol, 25 mM β-glycerophosphate, Protease inhibitor Complete (Boeringer) , 1 mM Sodium orthovanadate) , and treated 4 times in a homogenizer (POLYTRON) at 20000 rpm for 30 sec to rupture the cells. The cell rupture suspension was centrifuged (40000 rpm, 45 min.), and active IKKβ was purified from the obtained supernatant using Anti-FLAG M2 Affinity Gel (Sigma) . Re--fe,t ridi,i"ES lϊe"^ t"Preparation of recombinant I Bα The plasmid pGEIKB obtained in Reference Example 2A was transformed into Escherichia coli JM109 (TOYOBO) to give an ampicillin resistant strain pGEIKB/JMl09. The pGEIKB/JMl09 strain was cultured in 150 ml of LB medium (10 g/1 tryptone, 5 g/1 yeast extract, 10 g/1 sodium chloride) supplemented with 50 μg/ml ampicillin overnight at 200 rpm, 37°C. The culture medium (15 ml) was added to a fresh LB medium (150 ml) and cultured at 37°C for 2 hrs at 200 rpm. 1 mM IPTG (Wako Pure Chemical Industries, Ltd.) was added and the medium was further cultured for 6 hrs. The culture medium was centrifuged at 8000 rpm for 10 min. The cells were recovered, washed with PBS and frozen at -80°C. The cells were suspended in 15 ml of a cytolysis buffer (1% Triton X-containing PBS, 1 mM APMSF) and the suspension was ultrasonicated in iced water using
SONIFIER450 (BRANSON) to rupture the cells. The cell rupture suspension was centrifuged (14000 rpm, 15 min., 4°C) and GST- IκBα fused protein was purified from the obtained supernatant using Redipack GST Purification Module (Amersham Pharmacia Biotech) and desalted using a NAP-25 column (Amersham Pharmacia Biotech) . Examples Unless otherwise noted, reagents and solvents were used as received from commercial suppliers . Proton and carbon nuclear magnetic resonance spectra were obtained on a Bruker AC 300 or a Bruker AV 300 spectrometer at 300 MHz for proton and 75 MHz for carbon. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz.
Tetramethylsilane was used as an internal standard for proton spectra and the solvent peak was used as the reference peak for carbon spectra. Infrared spectra were obtained on a Nicolet Nexus 470 (ATR) spectrometer. Mass spectra were obtained on a Perkin Elmer Sciex 100 atmospheric pressure _
Figure imgf000069_0001
a Shimadzu QP-5000 mass spectrometer (CI) , or a Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) mass spectrometer. Thin-layer chromatography (TLC) was performed using Analtech silica gel plates and visualized by ultraviolet (UV) light, iodine, or 20 wt % phosphomolybdic acid in ethanol. HPLC analyses were obtained using a Phenomenex Synergi Hydro-RP column (250 x 4.6 mm) with UV detection at 223 nm (Methods A, B and D) . Preparative HPLC was performed using a Phenomenex Luna C18(2) column (250 * 21.2 mm) with Luna C18(2) guard column (60 x 21.2 mm) and UV detection at 223 nm (Method C) .
Method A [Phenomenex Synergi Hydro-RP column] :
Figure imgf000069_0002
A = Water with 0.05% v/v Trifluoroacetic Acid B = Acetonitrile with 0.05% v/v Trifluoroacetic Acid
Method B [Phenomenex Synergi Hydro-RP column]
Figure imgf000069_0003
A. = Water with 0.05% v/v Trifluoroacetic Acid B = Acetonitrile with 0.05% v/v Trifluoroacetic Acid ιr r*' "?' " !I i; ds f Id "If S MK ' ,tΛh"Ibd ' l" <__::■ " ™3f-- "ii enomenex Luna C18 (2) column]
Figure imgf000070_0001
A = Water with 0.05% v/v Trifluoroacetic Acid B = Acetonitrile with 0.05% v/v Trifluoroacetic Acid
Method D (Phenomenex Synergi Hydro-RP column)
Figure imgf000070_0002
A = Water with 0.05% v/v Trifluoroacetic Acid B = Acetonitrile with 0.05% v/v Trifluoroacetic Acid
Reference Example 1
7-Chloro-lH-pyrrolo[2 ,3-c]pγridine-2-carboxylic acid
To a heterogeneous solution of potassium ethoxide (6.56 g, 77.9 mmol) in diethyl ether (55 mL) , was slowly added diethyl oxalate (10.6 mL, 77.9 mmol). A slight exotherm resulted. After stirring 5 min, a homogeneous yellow solution resulted, but after 10 min, a heterogeneous yellow slurry was observed. Addition of 2-chloro-4-methyl-3-nitropyridine (13.45 g, 77.9 mmol) as a solid, with a diethyl ether rinse (23 L) , resulted in a dark violet solution with a dark precipitate. The mixture was stirred at room temperature overnight (21 h) . The solid «"'pYeblp¥tSte as 'f±' ired, rinsed thoroughly with diethyl ether, and air-dried to give potassium ( 1Z) -1- (2-chloro-3- nitropyridin-4-yl) -3-ethoxy-3-oxoprop-l-en-2-olate (19.8 g, 63.6 mmol, yield 81%) as an orange solid. The crude product was used directly without further purification or identification.
Potassium ( 1Z) -1- (2-chloro-3-nitropyridin-4-yl) -3-ethoxy- 3-oxoprop—l-en-2-olate (19.8 g, 63.6 mmol) was dissolved in acetic acid (908 mL) and the solution was treated with iron powder (14.6 g, 280.9 mmol). The reaction mixture was warmed to 60°C and stirred overnight (18.5 h) . TLC analysis indicated consumption of the starting material, therefore the reaction mixture was filtered through diatomaceous earth to remove the catalyst. The filtrate was concentrated to dryness. The residue was treated with methylene chloride (ca. 400 L) and filtered through a plug of silica. Eluting with methylene chloride removed insolubles, and further elution with methylene chloride/ethyl acetate (50:50) provided ethyl 7- chloro-lH—pyrrolo [2, 3-c]pyridine-2-carboxylate (10.3 g, 45.8 mmol, yield 72%) as a yellow solid after concentration: Rf 0.80 (silica gel, 50:50 hexanes/ethyl acetate); mp 152-157°C; τE NMR (300 MHz, CD3OD) 61.43 (3H, t, J = 7.0 Hz), 4.44 (2H, q, J = 7.1 Hz), 7.27 (IH, s) , 7.65 (IH, d, J = 5.7 Hz), 7.95 (IH, d, J = 5.4 Hz); ESI MS m/z 224 [CιoHgClN202 + H] +; HPLC (Method A) >99% (AUC) , tR = 16.6 min.
Ethyl 7-chloro-lff-pyrrolo [2 , 3-c] pyridine-2-carboxylate (0.64 g, 2.85 mmol) was dissolved in tetrahydrofuran (5.7 mL) and methanol (6.8 mL) . To the mixture was added 3 N KOH (2.85 mL) . After stirring overnight (15.5 h) at room temperature, the reaction mixture was concentrated to dryness. The residue was dissolved in water. This aqueous solution was made acidic ip' if"'' """" '*' \l 'Λ «'-" )f"» rc-"" ■'' ■■'«■ ••'& κ"" "" -ft , , - .,
* (pHls 3 ) uu^s 3! ' "R ™HΘ-L'"ϊ(i "*The precipitate was collected by filtration. The precipitate was dissolved in methanol and concentrated to dryness to afford 7-chloro-liϊ-pyrrolo [2, 3- c]pyridine-2-carbo-xylic acid (0.53 g, 2.7 mmol, 94%) as a yellow powder: mp 210-214°C; λR NMR (300 MHz, CD3OD) 57.25 (IH, s), 7.65 (IH, d, J = 5.4 Hz), 7.94 (IH, d, J = 5.4 Hz); ESI MS m/z 195 [C8H5C1N202 - H]~; HPLC (Method A) >99% (AUC) , tR = 12.2 min. Reference Example 2
N-Cyclohexyl-lH-py-crolo [2 , 3-c] pyridine-2-carboxamide
Ethyl 7-chloro-lH-pyrrolo [2, 3-c] pyridine-2-carboxylate (preparation described in Reference Example 1) (240 mg, 1.07 mmol), phenol (500 mg, 5.35 mmol) and cyclohexylamine (1.1 mL, 10.7 mmol) were combined in a sealed tube and heated at 100°C for 6 h. The reaction tube was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL) , washed with 2 N sodium hydroxide (10 mL) and brine (10 mL) , dried over magnesium sulfate, and evaporated to provide 538 mg of dark brown viscous oil. The viscous oil was purified by chromatography (Si02; 3:1 hexanes/ethyl acetate) to give 7- chloro-N-cyclohexyl-lH-pyrrolo [2, 3-c] pyridine-2-carboxamide as an off-white powder (218 mg, 0.785 mmol, 74%) : XE NMR (300 MHz, CD3OD) 51.20-1.55 ( 6H, m) , 1.65-2.10 (4H, m) , 3.90 (IH, m) , 7.21 (IH, s), 7.61 (IH, d, J = 5.4 Hz), 7.93 (IH, d, J = 5.4 Hz); ESI MS m/z 278 [C14H1SC1N30 + H] + . 7-Chloro-N-cyclohexyl-lH-pyrrolo [2, 3-c] pyridine-2- carboxamide (230 mg, 0.828 mmol), triethylamine (0.25 mL) and palladium (II) chloride (3 mg, 2 mol%) were combined in N,N- dimethylformamide (5 mL) under an atmosphere of hydrogen. The ^"^'ga'fct όϊi^ t'ur'e'^a'^rieated at 60°C for 3 h. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration through a pad of diatomaceous earth and washed with ethyl acetate. Evaporation of the solvents provided crude product (169 mg, 84%) as an off-white solid. Purification by chromatography (Si02; 0-10% methanol in methylene chloride, 1 00 mL) afforded N-cyclohexyl-lH- pyrrolo [2, 3-c]pyridine-2-carboxamide (101 mg, 0.414 mmol, 50%) as fine, white needles: mp 298-301°C, XH NMR (300 MHz, CD3OD) δ 1.20-1.55 (6H, m) , 1.65-2.10 (4H, m) , 3.90 (IH, m) , 7.21 (IH, s), 7.15 (IH, s), 7.65 (IH, d, J = 5.7 Hz), 8.09 (IH, d, J = 5.7 Hz), 8.77 (IH, s) ; ESI MS m/z 244 [C4Hι7N30 + H]+; HPLC (Method A) >99% (AUC) , fcR = 13.2 min. Reference Example 3
Ethyl 7- (dibenzylamino) —IH-pyrrolo [2 ,3-c]pγridine-2- carboxylate To a stirred solution of 2-chloro-4-methyl-3- nitropyridine (1.06 g, 6.14 mmol) in tetrahydrofuran (12 mL) under an atmosphere of nitrogen were added dibenzylamine (2.4 mL, 13 mmol) and sodium carbonate (684 mg, 6.45 mmol). The mixture was warmed to reflux for 48 h and cooled to room temperature. The mixture was diluted with dichloromethane (100 mL) and water (100 mL) , and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 50 mL) . The combined organic extracts were washed with 1 N HCl (100 mL) and brine (100 mL) , dried (Na2S04) , filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel, 10% ethyl acetate/hexanes) to provide 2- (dibenzylamino) -4-methyl-3-nitropyridine (1.53 g, 4.59 mmol, 75%) as a bright yellow oil which solidified upon
Figure imgf000074_0001
hexanes/ethyl acetate) ; 1H NMR ( 300 MHz, CDCI3) 52 . 32 ( 3H, s ) , 4 . 45 ( 4H, s ) , 6. 70 ( IH, d, J = 4 . 9 Hz ) , 7 . 16-7 . 19 ( 4H, m) , 7 .21-7 . 34 ( 6H, m) , 8 . 16 ( IH, d, J = 4.9 Hz); ESI MS m/z 334 [C20Hι9N3O2 + H] + .
A slurry of potassium ettioxide (391 mg, 4.64 mmol) in diethyl ether (4 mL) under N2 was cooled to 0°C under vigorous stirring. Diethyl oxalate (0.63 mL, 4.65 mmol) was added, and the mixture was stirred for 5 min. A solution of 2- (dibenzylamino) -4-methyl-3-nitropyridine (1.52 g, 4.56 mmol) in diethyl ether (3 mL) was added, and the mixture was stirred for 16 h while slowly warming to room tempature, during which time a precipitate formed. The solid was collected on a sintered glass frit and rinsed several times with additional diethyl ether. The solid was transferred to a vial and dried under vacuum at 30°C for 2 h to provide potassium (1-2) -1- [2- (dibenzylamino) -3-nitropyridin-4-yl] -3-ethoxy-3-oxoprop-l-en- 2-olate (1.63 g, 3.46 mmol, 76%) as a light orange solid. This product was immediately used without purification or identification.
Potassium ( 1Z) -1- [2- (dibenzylamino) -3-nitropyridin-4-yl] - 3-ethoxy-3-oxoprop-l-en-2-olate (1.63 g, 3.46 mmol) was dissolved in glacial acetic acid (21 mL) and treated with iron powder (851 mg, 15.2 mmol). This mixture was warmed to 60°C for 3.5 h and cooled to room temperature . The slurry was filtered through diatomaceous earth to remove the catalyst, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, gradient 0-50% ethyl acetate/dichloromethane) to pro-vide ethyl 7- (dibenzylamino) - liϊ-pyrrolo [2, 3-c] pyridine-2-car.boxylate (902 mg, 68%) as a tan solid: Rf 0.55 (silica gel, 67:33 hexanes/ethyl acetate); p 120-123°C; XH NMR (300 MHz, CDC13) 51.27 (3H, t, J = 7.1 Hz),
Figure imgf000075_0001
, 4.91 (4H, s), 7.03 (IH, J = 5.9 Hz), 7.06 (IH, d, J = 1.8 Hz), 7.27-7.38 (10H, m) , 7.89 (IH, d, J = 5.7 Hz), 8.67 (IH, br s) ; APCI MS m/z 386 [C24H23N302 + H] +; HPLC (Method A) >99% (AUC) , tR = 17.7 min.
Reference Example 4
7- (Dibenzylamino) -IH-pyrrolo [2 ,3-σ]pyridine-2-carboxylic acid A mixture of ethyl 7- (dibenzylamino) -IH-pyrrolo [2, 3- c]pyridine-2-carboxylate (Reference Example 3) (500 mg, 1.30 mmol), 2 M sodium hydroxide solution (6 mL) , tetrahydrofuran (3 mL) and ethanol (3 mL) was refluxed for 2 h. The mixture was neutralized by addition of 1 M hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was crystallized from ethyl acetate to give 7- (dibenzylamino) -IH-pyrrolo [2, 3-c] pyridine-2-carboxylic acid (100 mg, 22%) as pale brown amorphous solid. Additional material (348 mg, 75%; 97% overall yield) was obtained from the mother liquid: Rf 0.01 (silica gel, ethyl acetate); mp 114- 120°C; αH NMR (300 MHz, DMSO- 6) δ4.82 (4H, br s), 7.18-7.35 (12H, m) , 7.68 (IH, d, J = 6.0 Hz); ESI MS m/z 358 [C22Hι9N302 + H]+; HPLC (Method A) 98.8% (AUC), tR = 17.7 min.
Reference Example 5
Ethyl 5- (dibenzylamino) -IH-pyrrolo [2 ,3-σ]pyridine-2- carboxylate
To a mixture of 2-chloro-4-methyl-5-nitropyridine (5.44 g, 26.3 mmol) and dibenzylamine (5.04 mL, 26.3 mmol) in toluene (13.1 mL) was added sodium carbonate (5.58 g, 52.6 mmol). r'n iT- '"p" ,-' R ϊ -",'? H-MC ■' ■■:> -it it'"" "Hi' "if
R'~ -ftfe'-: SΕ--_.:-.<'£'ih.g " rfde!--™!fa«("nιtrogen atmosphere under reflux for 36 h, the reaction mixture was filtered to remove the sodium carbonate. The filtrate was concentrated to provide the crude material as a light orange oil. The crude oil was dissolved in methylene chloride and treated with 2 N HCl. The resulting precipitate was filtered off and discarded. The filtrate was washed with 2 N HCl and the acidic layers were back-extracted with methylene chloride. The combined extracts were washed with saturated NaHC03, dried over Na2S04, filtered and concentrated to provide 2- (dibenzylamino) -5-nitro-4- methylpyridine (8.97 g, 102% theoretical) as a light yellow solid: XH NMR (300 MHz, CDC13) 52.53 (3H, s), 4.85 (4H, s) , 6.27 (IH, s), 7.19-7.37 (10H, m) , 9.05 (IH, s) . To a suspension of potassium ethoxide (2.21 g, 26.3 mmol) in diethyl ether (20 mL) was added diethyl oxalate (3.57 mL, 26.3 mmol) under a nitrogen atmosphere. Th.e reaction exhibited a slight exotherm and the reaction mixture was stirred for 20 min. The heterogeneous mixture became a homogeneous orange solution and then became a heterogeneous thick slurry and the stirring was ceased. In a separate container 2- (dibenzylamino) -5-nitro-4-methylpyridine (8.76 g, 26.3 mmol) was diluted with diethyl ether (14.3 mL) to give a suspension. The suspension was added to the slurry obtained above. The mixture was manually stirred using a glass rod, then sonicated for 20 min resulting in a thick black heterogeneous solution. The reaction mixture was allowed to stand under a nitrogen atmosphere overnight. The resulting solid was collected by filtration and rinsed with diethyl ether to give potassium ( 1Z) -1- [2- (dibenzylamino) -5-nitropyridin-4—yl] -3-ethoxy-3- oxoprop-l-en-2-olate (9.5 g, 76%) as a deep red solid: 1H NMR (300 MHz, CD3OD) 51.17 (3H, t, J = 7.0 Hz), 3.58 (2H, q, J = 6.9 Hz), 4.82 (4H, s) , 7.22-7.32 (11H, ) , 8.74 (IH, s) , 8.80 ιp g r ,/s![)i :s e 5 -t 531
To a solution of potassium (1-2) -1- [2- (dibenzylamino) -5- nitropyridin-4-yl] -3-ethoxy-3-oxoprop-l-en-2-olate (5.0 g, 10.6 mmol) in acetic acid (151.4 mL) was added iron powder (2.43 g, 43.5 mmol) under a nitrogen atmosphere. The mixture was warmed to 60°C and stirred for 2 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to ca. 100 mL in volume. The concentrate was poured into rapidly stirring water (ca. 200 mL) . The precipitate was observed. Ethyl acetate (150 mL) was added and the mixture was stirred until the solid was dissolved. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2χ) . The combined extracts were washed with dilute NaHC03 and saturated NaCl, and dried over Na2S04. The solution was dark red. Consequently, activated charcoal (Darco G-60, 1.20 g) was added to the solution. After filtration through diatomaceous earth, the filtrate was concentrated to dryness to afford a dark brown solid. The solid was sonicated in toluene (ca. 75 mL) for 30 min. After standing at room temperature overnight, the solid was collected by filtration and rinsed with toluene to give ethyl 5- (dibenzylamino) -IH-pyrrolo [2, 3-c]pyridine-2-carboxylate (0.80 g, 19%) as a yellow solid. Further manipulation of the mother liquors provided additional material (0.19 g, 5%) : mp 169-174°C; XH NMR (300 MHz, CD3OD) 51.38 (3H, t, J = 7.0 Hz), 4.37 (2H, q, JT = 7.0 Hz), 4.75 (4H, s) , 6.64 (IH, d, J = 0.9 Hz), 6.85 (IH, d, J = 0.9 Hz), 7.21-7.27 (10H, m) , 8.48 (IH, s); ESI MS m/z 386 [C24H23N302 + H]+; HPLC (Method A) >99% (AUC), tR = 20.1 min .
Reference Example 6
Figure imgf000078_0001
[2 ,3-c] yridine-2-carboxamide
AT-Cycloperityl-lH-pyrrolo [2, 3-c] pyridine-2-carboxamide (20 mg, 43%) was prepared as an off-white solid following the procedure described for Example 27 using 7-chloro-N- cyclopentyl-lH-pyrrolo [2, 3-c] pyridine-2-carboxamide and ethanol as a solvent: mp 220-224°C; lE NMR (300 MHz, CD3OD) 51.22-2.18 (8H, rn) , 4.28-4.42 (IH, m) , 7.27 (IH, s) , 7.82 (IH, d, J = 5.8 Hz) , 8.15 (IH, d, J = 5.8 Hz) , 8.85 (IH, s) ; ESI MS m/z 230 [Cι3Hι5N30 + H] +; HPLC (Method A) >99% (AUC), tR = 12.1 min.
Reference Example 7 2 -Benzyl -IH-pyrrolo [2 , 3-c] pyridine
W-Benzyl-ΛT"— [ (7-chloro-lH-pyrrolo [2, 3-c] pyridin-2 — yl) (phenyl) methyl] amine dihydrochloride (103 mg, 286 μmol), ammonium formate (108 mg, 1.72 mmol) and palladium-on-carbon (30 mg, 10 mol % Pd) were combined in methanol (3 mL) . The reaction mixture was heated under reflux under an atmosphere of nitrogen for 2 h. The reaction mixture was cooled to room temperature . The catalyst was removed by filtration through a pad of diatomaceous earth and washed with methanol followed by methylene chloride. Evaporation of the solvents provided 102 mg of crude, off— white solid. Purification by chromatography (Si02; 93:7 methylene chloride /methanol) afforded 2-benzyl-lH- pyrrolo [2, 3-c] pyridine (41 mg, 194 μmol, 68%) as an off-white powder: mp 142-146°C; XH NMR (300 MHz, CD3OD) 5 4.17 (2H, s) , 6.29 (IH, s), 7.15-7.35 (5H, m) , 7.46 (IH, d, J = 5.1 Hz), 7.95 (IH, d, J = 5.1 Hz), 8.52 (IH, s) ; ESI MS m/z 209 [Cι4Hι2N2 + H]+; HPLC (Method A) 98.0% (AUC), tR - 15.5 min.
Figure imgf000079_0001
Phenyl (IH-pyrrolo [2 , 3-c] pyrridin-3-yl) methanone Phenyl (lH-pyrrolo[ 2, 3-c] pyridin-3-yl) methanone (379 mg, 78%) was prepared using phenyl (lff-pyrrolo [2, 3-c] pyridin-3- yl) methanol (Example 97) as a yellow solid following the procedure described for Reference Example 13: Rf 0.48 (90:10 methylene chloride /methanol) ; mp 218-220°C; XH NMR (300 MHz, DMSO-d_-) 57.55-7.58 (2H, m) , 7.62-7.65 (IH, m) , 7.81-7.83 (2H, m) , 8.09-8.10 (IH, d, J = 5.4 Hz), 8.19 (IH, s) , 8.33-8.34 (IH, d, J = 5.4 Hz), 8.88 (IH, s), 12.50 (IH, br s) ; ESI MS m/z 223 [C14HιoN20 + H]+; HPLC (Method A) 96.6% (AUC), tR = 13.2 min. Reference Example 9 tert-Butyl 3- (aminooxy)pyr--rolidine-l-carboxylate
A mixture of 3-hydrox:ypyrrolidine (2.0 g, 23 mmol), triethylamine (3.8 mL, 28 iriirioL) , di-tert-butyl dicarbonate (5.2 g, 24 mmol) and N, IV-dimethylaminopyridine (140 mg, 1.1 mmol) in CH2C12 (180 mL) was stirred at ambient temperature. After 5 h, the reaction mix-ture was diluted with H20 (50 mL) . The aqueous layer was separated and extracted with CH2C12 (25 mL) . The combined organic layers were washed with saturated NaCl (40 mL) , dried (Na2SC>4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 90:10 CH2Cl2/MeOH) gave tert-butyl 3-hydroxypyrrolidine-l- carboxylate (4.1 g, 95%) : 2H NMR (300 MHz, CDC13) 51.46 (9H, s), 1.92-2.04 (2H, s) , 2.11-2.17 (IH, s) , 3.30-3.49 (4H, s) , 4.44- 4.45 (IH, m) .
To an ice-cold solution of tert-butyl 3- ]m_ _ ^, ^ _
P&3zrό^^l-«y§-l-l( iτi^-lr^5 rboxyl te (1.0 g, 5.5 mmol), N- hydroxyphthalimide (0.90 g, 5.5 mmol) and triphenylphosphine (1.4 g, 5.5 mmol) in THF (30 mL) was added a solution of diethyl azodicarboxylate (0.96 mL, 6.1 mmol) in THF (5 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 3 days, most of the THF was removed under reduced pressure. The residue was partitioned between CH2C12 (40 mL) and H20 (30 mL) . The organic layer was separated and washed with saturated NaCl (20 mL) , dried (Na2S04) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 75:25 hexanes/EtOAc to 50:50 hexanes/EtOAc) gave tert-butyl 3- [ (1, 3-dioxo-l, 3-dihydro-2-7- isoindol-2-yl) oxy]pyrrolidine-l-carboxylate (0.96 g, 52%): 1H NMR (300 MHz, CDC13) 51.49 (9H, s) , 1.97-2.20 (IH, s), 2.25- 2.31 (IH, m) , 3.53-3.78 (4H, m) , 4.95-5.00 (IH, m) , 7.75-7.87 (4H, m) .
To an ice-cold solution of tert-butyl 3- [ (1, 3-dioxo-l, 3- dihydro-2H-isoindol-2-yl)oxy]pyrrolidine-l-carboxylate (0.96 g, 2.8 mmol) in CH2C12 (16 ml) and MeOH (4 mL) was added methylhydrazine (0.70 mL, 13 mmol) dropwise. The stirred reaction mixture was allowed to slowly warm to ambient temperature. After 2 h, the reaction mixture was concentrated under reduced pressure. To the residue was added CH2C12 (20 mL) and with the aid of sonication a solid formed and was collected by vacuum filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 75:25 hexanes/EtOAc to 25:75 he anes/EtOAc) to afford tert-butyl 3- (aminooxy)pyrrolidine-l-carboxylate (440 mg, 76%) : 1H NMR (500 MHz, CDC13) δ 1.46 (9H, s), 1.82-1.98 (IH, m) , 2.04-2.10 (IH, m) , 3.31-3.65 (4H, m) , 4.24-4.27 (IH, m) , 5.37. fcerfc-Butyl 4- (aminooxy)piperidine-l-carrboxylate Reaction of tert-butyl 4-hydroxypiperidine-l-carboxylate with N-hydroxyphthalimide following the procedure described for the preparation of Reference Example 9 gave tert-butyl 4- [ (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) oxy]piperidine-l- carboxylate (3.0 g, 72%) as a yellow oil: H NMR (500 MHz, CDC13) 5 1.46 (9H, s) , 1.82-1.85 (2H, m), 1.92-1.96 (2H, m) , 3.20-3.25 (2H, m) , 3.86-3.90 (2H, m) , 4.41-4.44 (IH, m) , 7.74- 7.78 (2H, m) , 7.82-7.86 (2H, ) .
Deprotection of tert-butyl 4-[(l, 3-dioxo-l, 3-dihydro-2H- isoindol-2-yl) oxy]piperidine-l-carboxyl-ate with methylhydrazine following the procedure described for the preparation of Reference Example 9 gave tert-butyl 4- (aminooxy)piperidine-l-carboxylate (1.3 g, 73%) as an amber oil: 1H NMR (500 MHz, CDC13) 5 1.47 (9H, s) , 1.48-1.54 (2H, m) , 1.86-1.88 (2H, m) , 3.04-3.10 (2H, m) , 3.66-3.69 (2H, m) , 4.20 (IH, br s) , 5.30 (2H, br s) .
Reference Example 11
tert-Butyl 3- (aminooxy)piperidine-l-car-boxylate
Reaction of tert-butyl 3-hydroxypiperidine-l-carboxylate with N-hydroxyphthalimide following the procedure described for the preparation of Reference Exampl e 9 gave tert-butyl 3- [ (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) oxy] piperidine-1- carboxylate (2.3 g, 57%) as a yellow oil: ^ ΝMR (500 MHz,
CDC13) δ 1.42 (9H, s) , 1.47-1.58 (IH, m) , 1.74-1.76 (IH, m) , 1.90-1.92 (IH, m) , 2.08-2.11 (IH, m) , 3.04-3.40 (2H, m) , 3.66-
Figure imgf000082_0001
(IH, m), 4.24-4.27 (IH, m) , 7.74-7.76 (2H, m) , 7.82-7.86 (2H, m) .
Deprotection of tert-butyl 3- [ (1, 3-dioxo —1, 3-dihydro-2H- isoindol-2-yl) oxy] piperidine-1-carboxylate wit-h methylhydrazine following the procedure descri-bed for the preparation of Reference Example 9 gave tert-koutyl 3- (aminooxy)piperidine-l-carboxylate (1.0 g, 73%) as an off- white, waxy solid: XE NMR (500 MHz, CDC13) δ 1-34-1.39 (IH, m) , 1.47 (9H, s), 1.69-1.76 (3H, m) , 3.12-3.26 (1.5H, m) , 3.45- 3.60 (3H, m) , 3.77-3.83 (0.5H, m) , 3.37-5.47 (2H, m) .
Reference Example 12 1- (Phenylsulfonyl) -IH-pyrrolo [2 , 3-c]pyridine
To a suspension of IH-pyrrolo [2, 3-c] pyridine (700 mg, 5.9 mmol) in tetrahydrofuran (14.0 mL) was added lithium diisopropylamide (2.9 mL of a 2 M solution in THF/heptane, 5.9 mmol) at -78°C. After 0.5 h, benzenesulfonyl chloride (0.79 mL, 6.2 mmol) was added dropwise. The mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was poured into 2% aq NaHC03 (30 mL) and extracted with EtOAc (2 x 25 mL) . The combined extracts were washed with H20 (20 mL) and saturated NaCl (20 mL) , dried (Na2S0 ) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 1:1 hexanes/EtOAc) gave 1- (phenylsulfonyl) -IH-pyrrolo [2, 3-c] pyridine (1.2 g, 80%): XH NMR (500 MHz, DMSO-de?) 5 6.94 (IH, d, J = 6.0 Hz), 7.59-7.66 (3H, m) , 7.70-7.75 (IH, ) , 8.07-8.10 (3H, m) , 8.38 (IH, d, J = 8.8 Hz), 9.23 (IH, s); ESI MS m/z 259 [Cι3Hι0N2O2S + H] + .
Reference Example 13
Figure imgf000083_0001
-IH-pyrrolo [2 , 3-c]pyr-idin-2- yl ] me thanone
To a solution of lithium diisopropylamide (1.2 mL of a 2 M solution in THF/heptane, 2.3 mmol) in THF (3 mL) was added a solution of 1- (phenylsulfonyl) -IH-pyrrolo [2, 3-c] pyridine (300 mg, 1.2 mmol) and N,N,N' , N'-tetramethylethylenediamine (0.18 mL, 1.2 mmol) in THF (5 mL) , dropwise at -25°C. After 0.5 h, a solution of benzaldehyde (0.24 mL, 2.3 mmol) in THF (6 mL) was added dropwise. After 1 h, the reaction mixture was warmed to 10°C and quenched by the addition of saturated NHC1 (5 mL) . The reaction mixture was diluted with H20 (20 iriL) and extracted with EtOAc (2 x 40 mL) . The combined extracts were dried (Na2S0) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 9:1 hexanes/EtOAc to EtOAc) gave phenyl [1- (phenylsulfonyl) -IH-pyrrolo [2, 3- c]pyridin-2-yl] methanol (155 mg, 37%) as a mixture of enantiomers: XH NMR (500 MHz, DMS0-d6) 5 6.36 (IH, d, J = 5.5 Hz), 6.43 (IH, d, J = 5.5 Hz), 6.75 (IH, s) , 7.32-7.36 (5H, m) , 7.53 (2H, dd, J = 8.4, 7.6 Hz), 7.59 (IH, d, J = 5.2 Hz), 7.66- 7.70 (IH, m) , 7.82-7.85 (2H, m) , 8.35 (IH, d, J = 5.2 Hz), 9.22 (IH, s); ESI MS m/z 365 [C20H16N2O3S + H]+; HPLC (Method A) 91.9% (AUC), tR = 16.5 min. A mixture of phenyl [1- (phenylsulfonyl) -lFf-pyrrolo [2, 3- c]pyridin-2-yl] methanol (2.6 g, 7.1 mmol) and Mn02 (9.3 g, 110 mmol) in THF (125 mL) was heated to reflux. After 20 h, the reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure. Purification by column chromatography (silica gel, CH2C12 to 99:1 CH2Cl2/MeOH) gave phenyl [1- (phenylsulfonyl ) -1H- pyrrolo [2, 3-c] pyridin~2-yl]methanone (1.7 g, 68%) as an off- white solid: mp 145-146°C; XH NMR (500 MHz, DI SO-dg) 57.32 (IH, 's ,
Figure imgf000084_0001
7.66-7.69 (2H, m) , 7.73-7.77 (3H, m) ,
7.93-7.95 (2H, m) , 8.07-8.09 (2H, m) , 8.50 (IH, d, J = -5.3 Hz), 9.35 (IH, s); ESI MS m/z 363 [C20Hι4N2O3S + H]+; HPLC (Method A) 99.0% (AUC), tR = 18.2 min.
Reference Example 14 terfc-Butyl [2- (aminooxy) ethyl]methylcarbamate A mixture of 2- (methylamino) ethanol (2.0 g, 27 mmol), triethylamine (4.4 ml, 33 mmol), di-tert-butyl dicarbonaize (6.1 g, 28 mmol) and 4-dimethylaminopyridine (160 mg, 1.3 mmol) in CH2C12 (200 mL) was stirred at ambient temperatu--re . After 17 h, the reaction mixture was diluted with H20 (50 L) . The aqueous layer was separated and extracted with CH2C12 (25 mL) . The combined organic layers were washed with saturated NaCl (25 mL) , dried (Na2S04) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 75:25 CH2Cl2/MeOH) gave tert-butyl (2- hydroxyethyl) ethylcarbamate (3.1 g, 66%) as a colorless oil: NMR (300 MHz, DMSO-d6) 51.38 (9H, s) , 2.80 (3H, br s) , 3.17 (2H, t, J = 8.8 Hz), 3.42-3.48 (2H, m) , 4.65 (IH, br s) .
To an ice-cold solution of tert-butyl (2- hydroxyethyl)methylcarbamate (3.0 g, 17 mmol), N- hydroxyphthalimide (2.8 g, 17 mmol) and triphenylphosphin-e (4.5 g, 17 mmol) in THF (90 L) was added a solution of diethyl azodicarboxylate (3.0 mL, 19 mmol) in THF (15 mL) dropwise. The stirred reaction mixture was allowed to wa-i-rm to ambient temperature. After 2 days, most of the THF was removed under reduced pressure. The residue was partitioned between CH2C12 (40 ml) and H20 (30 L) . The organic layer was separated and washed with saturated NaCl (20 ml) , dried ( a2S04) and- iffc f ■■ '"if" ,.■" it J ιtτ> f tut;;"' ,' ..K -if |i-ϊ' '""li •:"• , , .. . , , ,
« ©©n,cerϊ't-?ate '' nfde'r'' ;Λt e ιuced pressure. Purification by column chromatography (silica gel, 50:50 hexanes/EtOAc) gave tert- butyl [2-[ (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2- yl) oxy] ethyl] methylcarbamate (4.3 g, 79%) as a yellow oil: 1H NMR (300 MHz, CDC13) 51.46 (9H, s), 3.03 (3H, br s) , 3.62 (2H, br s), 4.34 (2H, br s), 7.74-7.85 (4H, m) .
To an ice-cold solution of tert-butyl [2- [ (1, 3-dioxo-l, 3- dihydro-2H-isoindol-2-yl) oxy] ethyl] methylcarbamate (4.3 g, 13 mmol) in CH2Cl2/MeOH (8:2, 90 mL) was added methylhydrazine (3.2 mL, 60 mmol) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 1.5 h, the reaction mixture was concentrated under reduced pressure. To the residue was added CH2C12 (35 mL) and the resulting white solid was collected by vacuum filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 50:50 hexanes/EtOAc to 35:65 hexanes/EtOAc) to afford tert- butyl [2- (aminooxy) ethyl] methylcarbamate (2.3 g, 90%) as a yellow oil: 1H NMR (500 MHz, CDC13) 5 1.46 (9H, s) , 1.82-1.98 (IH, m) , 2.88 (3H, br s) , 3.44-3.46 (2H, m) , 3.74 (2H, t, J = 5.3 Hz), 5.44-5.77 (2H, m) .
Reference Example 15 4- [ (Aminooxy) methyl] -IH-imidazole
To an ice-cold solution of 4- (hydroxymethyl) imidazole hydrochloride (2.0 g, 15 mmol), N-hydroxyphthalimide (2.4 g, 15 mmol) and triphenylphosphine (4.0 g, 15 mmol) in THF (65 mL) was added a solution of diethyl azodicarboxylate (2.6 mL, 16 mmol) in THF (10 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 18 h, the resultant precipitate was collected by vacuum filtration. The
Figure imgf000086_0001
"'between EtOAc (75 ml) and saturated NaHC03 (75 mL) . The aqueous layer was separated and extracted again with EtOAc (75 mL) . The combined organic layers were dried (Na2S04) and concentrated under reduced pressure. Purification by column chromatography (silica gel, CH2C12 to 90:10 CH2Cl2/MeOH) gave 2- (lH-imidazol-4-ylmethoxy) -1, 3- dihydro-2H-isoindole-l,3-dione (800 mg, 22%) as a yellow oil: XH NMR (300 MHz, DMSO~d6) δ5.03 (2H, s) , 7.30 (IH, s) , 7.55 (IH, s), 7.81-7.86 (4H, m) , 12.08 (IH, br s) .
Deprotection of 2- (lH-imidazol-4-ylmethoxy) -1, 3-dihydro- 2H-isoindole-l, 3-dione with methylhydrazine following the procedure described for Reference Example 14, except purification by column chromatography (silica gel, 98:2 CH2Cl2/MeOH to 90:10 CH2Cl2/MeOH) , gave 4- [ (aminooxy) methyl] -1H- imidazole (189 mg, 50%) as a colorless oil: XH NMR (300 MHz, DMSO-de) 5 4.45 (2H, s) , 5.98 (2H, br s) , 6.99 (IH, br s) , 7.57 (IH, s) , 11.96 (IH, br s) . Reference Example 16
2- [ (Aminooxy) methyl] -IH-imidazole
To an ice-cold solution of (lH-imidazol-2-yl) methanol hydrochloride (2.0 g, 15 mmol), N-hydroxyphthalimide (2.4 g, 15 mmol) and triphenylphosphine (4.0 g, 15 mmol) in THF (65 mL) was added a solution of diethyl azodicarboxylate (2.6 mL, 16 mmol) in THF (10 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 1 day, most of the THF was removed under reduced pressure. The residue was partitioned between CH2C12 (75 ml) and H20 (30 mL) . The organic layer was separated and washed with saturated ΝaHC03 (75 L) and saturated NaCl (20 ml) , dried (Na2S04) and concentrated
Figure imgf000087_0001
Purification by column chromatography (silica gel, CH2C12 to 95:5 CH2Cl2/MeOH) gave 2- (lH-imidazol-2- ylmethoxy) -1, 3-dihydro-2H-isoindole-l, 3-dione (240 mg, 6.5%) which was used directly in the next reaction.
Deprotection of 2- (lH-imidazol-2-ylmethoxy) -1, 3-dihydro- 2H-isoindole-l, 3-dione with methylhydrazine following the procedure described for the preparation of Reference Example 14, except purification by ion-exchange chromatography (SCX-2, 1:3 7 N NH4OH in MeOH/MeOH) , gave 2- [ (aminooxy)methyl] -1H- imidazole (51 mg, 45%) as an amber oil: XH NMR (300 MHz, DMSO- d6) 5 4.53 (2H, s), 6.95 (2H, s) .
Reference Example 17 tert-B tyl [2- (-aminooxy) ethyl] isopropylcarbamate
Reaction of 2- (isopropylamino) ethanol with di-tert-butyl dicarbonate following the procedure described for Reference Example 14, except purification by column chromatography (silica gel, CH2C12) , gave (2-hydroxyethyl) isopropylcarbamic acid tert-butyl ester (970 mg, 25%) as a colorless oil: -""H NMR (300 MHz, CDC13) δ 1.12 (6H, d, J = 6.8 Hz), 1.47 (9H, s) , 3.30-3.32 (2H, m) , 3.68-3.74 (2H, ) , 4.17 (IH, br s) .
Reaction of (2-hydroxyethyl) isopropylcarbamic acid tert- butyl ester with N-hydroxyphthalimide following the procedure described for Reference Example 14, except purification by column chromatography (silica gel, 75:25 hexanes/EtOAc to 50:50 hexanes/EtOAc) , gave tert-butyl [2- [ (1, 3-dioxo-l, 3- dihydro~2H-isoindol-2-yl) oxy] ethyl] isopropylcarbamate (960 mg, 57%) as a colorless oil: τE ΝMR (300 MHz, CDC13) 5 1.15-1.20 (6H, br s), 1.43 (9H, s) , 3.48-3.50 (2H, s) , 4.08-4.15 (IH, m) ,
Figure imgf000088_0001
Deprotection of tert-butyl [2- [ (1, 3-dioxo-l, 3-dihydro-2H- isoindol-2-yl) oxy] ethyl] isopropylcarbamate with methylhydrazine following the procedure described for Reference Example 14, except purification by column chromatography (silica gel, CH2C12 to 98:2 CH2Cl2/MeOH) , gave tert-butyl [2- (aminooxy) ethyl] isopropylcarbamate (422 mg, 72%) as a yellow oil: XE NMR (300 MHz, DMSO-d6) δ 1.07 (6H, d, J = 6.3 Hz), 1.39 (9H, s) , 3.15-3.21 (2H, m) , 3.54 (2H, t, J = 6.7 Hz), 3.8-4.15 (IH, m) , 6.00 (2H, br s) .
Reference Example 18 2- (Aminooxy) acetamide
Potassium carbonate (2.67g, 19.31 mmol) was added to a solution of _V~hydroxyphthalimide (3.0 g, 18.39 mmol) in anhydrous DMF (37 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 min and then at room temperature for 1 h. The reaction mixture was cooled to 0°C and 2-bromoacetamide (2.79 g, 20.23 mmol) was added. The reaction mixture was stirred at 0°C for 10 min and then at room temperature overnight. The reaction mixture was poured into rapidly stirring water and the precipitated solid was collected by filtration and dried to afford 2- [ (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2- yl) oxy] acetamide (2.0 g, 49%) as a yellow solid: λE NMR (300 MHz, CD3OD) 54.63 (2H, s) , 7.85-7.88 (4H, m) ; ESI MS m/z 221
Figure imgf000088_0002
Methylhydrazine (2.16 ml, 40.68 mmol) was added dropwise to a suspension of 2- [ (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2- yl) oxy] acetamide (2.0 g, 9.04 mmol) in MeOH/CH2Cl2 (2:8, 100 iH'iy! "iioέp ' h3" 1iέtτon mixture was stirred at 0°C for 10 min and then at room temperature for 6 h. The solvent was removed in vacuo. The solid was triturated with methylene chloride and filtered. The filtrate was concentrated and the solid obtained 5 was purified using SCX—2 to afford 2- (aminooxy) acetamide (220 mg, 27%) as a pale yellow solid: XE NMR (500 MHz, DMSO-d*) 53.90 (2H, s), 6.37 (2H, s), 7.18-7.34 (2H, br s) .
Reference Example 190 2- (Aminooxy) -N-methylacetamide
2- [ (1, 3-Dioxo-l, 3-dihydro-2H-isoindol-2-yl) oxy] -N- methylacetamide (470 mg, 11%) was prepared as a yellow solid5 following the procedure described for Reference Example 18 using 2-chloro-N-methylacetamide : λE NMR (300 MHz, CD3OD) 52.85 (3H, s), 4.69 (2H, s) , 7.80-7.88 (4H, m) .
2- (Aminooxy) -N-methylacetamide (147 mg, 71%) was prepared0 as a yellow solid from 2- [ (1, 3-dioxo-l, 3-dihydro-2H-isoindol- 2-yl) oxy] -N-methylacetamide following the procedure described for Reference Example 18: E ΝMR (300 MHz, DMS0-dff) 52.61-2.63 (3H, d, J = 4.7 Hz), 3.91 (2H, s) , 6.33 (2H, s), 7.71 (IH, br s) .5 Reference Example 20
2- (Aminooxy) -W-phenylacetamide θ 2- [ (1, 3-Dioxo-l, 3-dihydro-2H-isoindol-2-yl) oxy] -N- phenylacetamide (2.9 g, 53%) was prepared as a yellow solid following the procedure described for Reference Example 18 using 2-chloro-Z\7-phenylacetamide: XE ΝMR (300 MHz, CDC13) 54.89
Figure imgf000090_0001
t, J = 7.4 Hz), 7.35-7.40 (2H, m) , 7.75-7.93 (6H, m) , 9.69 (IH, br s) ; ESI MS m/z 297 [Cι6H12N2θ4 + + H] 2- (Aminooxy) -N-phenylacetamide (570 mg, 35%) was prepared as a yellow solid from 2- [ (1, 3-dioxo-l, 3-dihydro-2H-isoindol- 2-yl) oxy] -N-phenylacetamide following the procedure described for Reference Example 18: XE ΝMR (300 MHz, CDC13) δ4.29 (2H, s), 5.79 (2H, s), 7.10-7.16 (IH, m) , 7.31-7.37 (2H, m) , 7.55-7.58 (2H, m) , 8.08 (IH, br s) ; ESI MS m/z 167 [C8Hι0Ν2O2 + H] + .
Reference Example 21
7-Chloro-N- [2-hydroxy-l , 1-bis (hydroxymethyl) ethyl] -1H- pyrrolo [2 , 3-c] yridine-2-carboxamide
7-Chloro-N- [2-hydroxy-l, 1-bis (hydroxymethyl) ethyl] -1H- pyrrolo [2, 3-c]pyridine-2-carboxamide (11.3 mg, 7%) was prepared as an off-white solid following the procedure described for Example 2 using 2-amino-2- (hydroxymethyl) -1, 3- propanediol: mp 218-220°C; XE ΝMR (300 MHz, CD3OD) δ3.89 (6H, s), 7.22 (IH, s), 7.63 (IH, d, J = 5.6 Hz), 7.94 (IH, d, J = 5.6 Hz); ESI MS m/z 300 [Cι2Hι4ClΝ304 + H]+; HPLC (Method B) 97.5% (AUC), tR = 11.6 min.
Reference Example 22
[1- (Phenylsulfonyl) -IH-pyrrolo [2 ,3-c]pyridin-2-yl] (pyridin-4- yl) met-ttanol
[1- (Phenylsulfonyl) -IH-pyrrolo [2, 3-c]pyridin-2- yl] (pyridin-4-yl) methanol (269 mg, 48%) was prepared as a tan solid following the procedure described for Example 137 using
Figure imgf000091_0001
4-pyrιdme carboxaldehyde . Purification was achieved using Biotage chromatography (silica, 1 to 18% methanol in methylene chloride): XE NMR (500 MHz, CD3OD) δ 6.60 (IH, s), 6.77 (IH, s), 7.48-7.67 (6H, m) , 7.88-7.90 (2H, m) , 8.31-8.32 (IH, m) , 8.46-8.52 (2H, m) , 9.30 (IH, s) ; ESI MS m/z 366 [C19H15N303S + H]+.
Example 1 (7-Chloro-lH-pyrrolo [2,3-c]pyridin-2-yl) methanol
To a solution of ethyl 7-chloro-lH-pyrrolo [2, 3- c]pyridine-2-carboxylate (preparation described in Reference Example 1) (230 mg, 1.02 mmol) in tetrahydrofuran (4 mL) at 0°C under an atmosphere of nitrogen was added portionwise lithium aluminum hydride (94 mg, 2.0 mmol) . The reaction mixture was maintained at 0°C for 4 h then quenched by adding water (100 μL) , 15% aqueous sodium hydroxide (100 μL) , and water (250 μL) successively. The mixture was filtered through a pad of diatomaceous earth, washing well with ethyl acetate. Solvent evaporation provided 184 mg of crude yellow solid. Purification by column chromatography (silica gel, 60:40 hexanes/ethyl acetate) afforded (7-chloro-lH-pyrrolo[2, 3- c]pyridin-2-yl) methanol (157 mg, 0.860 mmol, 84%) as an off- white powder: Rf 0.30 (silica gel, 70:30 hexanes/ethyl acetate); mp 185-187°C; E NMR (300 MHz, CD3OD) δ4.94 (2H, s) , 6.56 (IH, s), 7.49 (IH, d, J = 5.5 Hz), 7.84 (IH, d, J = 5.5 Hz); ESI MS m/z 183 [C8H7C1N20 + H] +; HPLC (H20/CH3CN 100:0 to 0:100 over 20 min, hold for 10 min, 0.05% TFA added to solvents) 95.4% (AUC), tR = 11.1 min.
Example 2 w „,„ „ _ <( p„^ „
3'''-^Bfeiizyl^Υ^'^io o^l'i-^'ϊ-Yrrolo [2 ,3-c] yridine-2-carboxamide
A mixture of 7—chloro-lH-pyrrolo [2, 3-c]pyridine-2- carboxylic acid (Reference Example 1) (0.10 g, 0.51 mmol) and 1, 1' -carbonyldiimidazole (0.09 g, 0.53 mmol) in N,N- dimethylformamide (3.4 mL) was stirred at 50°C for 1 h. To the stirring solution was added benzylamine (0.11 mL, 1.02 mmol) and the reaction mixture was stirred at 65°C until the reaction was complete by TLC analysis. The crude reaction mixture was poured into rapidly stirring water, and extracted with ethyl acetate (3x) . The combined organic extracts were washed with water (3x) and saturated NH4C1, and dried over Na2S04. The organic extract was filtered and concentrated to provide N- benzyl-7-chloro-lH-pyrrolo [2, 3-c] pyridine-2-carboxamide (0.04 g, 0.14 mmol, 27%) as an off-white solid: mp 217-220°C; XH NMR (300 MHz, CDC13) δ .70 (2H, d, J = 5.7 Hz), 6.45-6.61 (IH, m) , 6.85 (IH, s), 7.31-7.39 (5H, m) , 7.47 (IH, d, J = 5.7 Hz), 8.06 (IH, d, J = 5.7 Hz), 9.55 (IH, br s) ; APCI MS m/z 286 [Cι5H12ClN30 + H]+; HPLC (Method A) >99% (AUC), tR = 16.3 min.
Example 3
7-Chloro-2- (4-morpholinylcarbonyl) -IH-pyrrolo [2 , 3-σ]pyridine 7-Chloro-2- (4-morpholinylcarbonyl) -IH-pyrrolo [2, 3- c]pyridine (70 mg, 50%) was prepared as an off-white solid following the procedure described for Example 2 using morpholine: mp 170-171°C; XE NMR (300 MHz, CDC13) δ3.73-3.93 (8H, m) , 6.78 (IH, d, J = 2.1 Hz), 7.48 (IH, d, J = 5.4 Hz), 8.07 (IH, d, J = 5.4 Hz), 9.55 (IH, br s) ; APCI MS m/z 266 [C12H12C1N302 + H]+; HPLC (Method A) >99% (AUC), tR = 11.7 min.
Example 4 7-Chloro-N- (2-pyridinyln.eth.3rl) -IH-pyrrolo [2 ,3-σ]pyridine-2- carboxamide 7-Chloro-N- (2-pyridinylmethyl) -IH-pyrrolo [2, 3-c]pyridine-
2-carboxamide (91 mg, 62%) was prepared as a yellow solid following the procedure described for Example 2 using 2- (aminomethyl) pyridine: mp 177-183°C; 1H ΝMR (300 MHz, CD30D) δ4.74 (2H, s), 7.26 (IH, s), 7.28-7.32 (IH, ) , 7.46 (IH, d) , 7.64 (IH, d, J = 5.7 Hz), 7.81-7.88 (IH, m) , 7.95 (IH, d, J = 5.7 Hz), 8.53 (IH, d) ; APCI MS m/z 287 [Cι4HnClΝ40 + H]+; HPLC (Method A) >99% (AUC), tR = 12.9 min.
Example 5
7-Chloro-N- (3-pyridinylmethγl) -IH-pyrrolo [2 , 3-σ]pyridine-2- carboxamide
7-Chloro-N- (3-pyridinylmethyl) -IH-pyrrolo [2, 3-c] pyridine- 2-carboxamide (49 mg, 33%) was prepared as a yellow solid following the procedure described for Example 2 using 3- picolylamine : mp 189-191°C; ^Η ΝMR (300 MHz, CD3OD) δ4.65 (2H, s), 7.20 (IH, d, J = 1.5 Hz) , 7.40-7.48 (IH, m) , 7.62 (IH, d, J = 5.7 Hz), 7.84-7.95 (2H, m) , 8.47 (IH, d) , 8.59 (IH, s) ; APCI MS m/z 287 [Cι4HuClΝ40 -+- H]+; HPLC (Method A) >99% (AUC), tR = 11.9 min .
Example 6
7-Chloro-iV- (4-pyridinylmethyl) -IH-pyrrolo [2 , 3 -c] yridine- 2- carboxamide
7-Chloro-N- (4-pyridinylmethyl) -IH-pyrrolo [2, 3-c]pyridine- i'''!'i*σ y©x'& 'ιi-l'e', (<*6§"> « -i 6%) was prepared as a yellow solid following the procedure described, for Example 2 using 4- (aminomethyl) pyridine : mp >340°C, no clear melt was observed; XH NMR (300 MHz, CD30D) δ4.67 (2H, s) , 7.22 (IH, s) , 7.44 (2H, d, J = 5.6 Hz), 7.63 (IH, d, J = 5.5 Hz), 7.94 (IH, d, J = 5.5 Hz), 8.48-8.50 (2H, m) ; APCI MS /z 287 [Cι4HnClN40 + H]+; HPLC (Method A) >99% (AUC), tR = 11.1 min.
Example 7
7-Chloro-iV- (2-furylmethyl) -IH-pyrrolo [2 , 3-c] pyridine-2- carboxa ide
7-Chloro-N- (2-furylmethyl) -IH-pyrrolo [2, 3-c] pyridine-2- carboxamide (64 mg, 45%) was prepared as a brown solid following the procedure described, for Example 2 using furfuryl amine: mp 205-209°C; XE MMR (300 MHz, CD3OD) δ4.60 (2H, s), 6.23-6.38 (2H, m) , 7.20 (IH, s) , 7.42-7.43 (IH, m) , 7.60 (IH, d, J = 5.5 Hz), 7.92 (IH, d, J = 5.5 Hz); APCI MS m/z 276 [Cι3Hι0ClΝ3O2 + H]+; HPLC (Method A) >99% (AUC), tR = 15.4 min.
Example 8
7-Chloro-JV- (2-thienylmethyl) -IH-pyrrolo [2 , 3-σ]pyridine-2- carboxamide
7-Chloro-N- (2-thienylmethyl ) -IH-pyrrolo [2, 3-c] pyridine-2- carboxamide (46 mg, 30%) was prepared as a yellow solid following the procedure described for Example 2 using 2- thiophenemethylamine: mp 179-181°C; 1H ΝMR (300 MHz, CD3OD) δ4.78 (2H, s), 6.89-6.99 (IH, m) , 7.07-7.09 (IH, m) , 7.19 (IH, s), 7.29-7.32 (IH, m) , 7.61 (IH, d, J = 5.5 Hz), 7.93 (IH, d, J = 5.5 Hz); APCI MS m/z 292 [Cι3Hι0ClΝ3OS + H] +; HPLC (Method A)
Figure imgf000095_0001
Example 9 N- [ (7-Chloro-lH-pyrrolo [2 ,3-c]pyridin-2-yl) methyl] -N- ethylamine hydrochloride
7-Chloro-lH-pyrrolo [2, 3-c]pyridine-2-carboxaldehyde (Example 138) (75 mg, 0.42 mmol) was dissolved in methanol (3 mL) . Ethylamine (0.23 mL, 2 M in tetrahydrofuran) was added. After 2 h, sodium borohydride (25 mg, 0.67 mmol) was added. After an additional 2 h, the reaction mixture was quenched by addition of 5% aqueous sodium bicarbonate. The reaction mixture was extracted with diethyl ether, dried (magnesium sulfate) , and evaporated to dryness (50 mg, 52% crude) . The crude material was dissolved in acetonitrile and treated with hydrochloric acid (0.24 mL, 1 M in diethyl ether) to give N- [ (7-chloro-lH-pyrrolo [2, 3-c] pyridin-2-yl ) methyl] -N-ethylamine hydrochloride (47 mg, 0.19 mmol, 42%) as an off-white powder: mp 242-245°C dec; XH ΝMR (300 MHz, CD3OD ) δl.40 (3H, t, J = 7.3 Hz), 3.24 (2H, q, J = 7.3 Hz), 4.57 (2H, s) , 7.09 (IH, s) , 7.92 (IH, d, J = 6.1 Hz), 8.1 (IH, d, J = 6.1 Hz); ESI MS m/z 210 [Cι0Hι2ClΝ3 + H]+; HPLC (H20/CH3CN 75:25 to 0:100 over 20 min, hold for 10 min) 94.5%, tR = 8.0 min.
Example 10
N- [ (7-Chloro-lH-pyrrolo [2 , 3-c]pyridin-2-yl)methyl] -N- methylamine hydrochloride
7-Chloro-lH-pyrrolo [2, 3-c] pyridine-2-carboxaldehyde (Example 138) (75 mg, 0.42 mmol) was dissolved in methanol (3 mL) . Methylamine (0.23 mL, 2 M in tetrahydrofuran) was added. P-lϊtfe>£
Figure imgf000096_0001
(25 mg, 0.67 mmol) was added. After an additional 2 h, the reaction mixture was quenched by addition of 5% aqueous sodium bicarbonate. Trie reaction mixture was extracted with diethyl ether, dried (magnesium sulfate) , and evaporated to dryness (29 mg, 32% crude) . The crude material was dissolved in acetonitrile and treated with hydrochloric acid (0. 15 mL, 1 M in diethyl ether) to give N- [ (7-c.hloro-lH-pyrrolo [2, 3-c] pyridin-2-yl) methyl] -N-methyl amine hydrochloride (21 mg, 9.3 μmol, 20%) as an off-white powder: mp 264-266°C dec; τ ΝMR (300 MHz, CD30D) δ2.85 (3H, s) , 4.57 (2H, s), 7.10 (IH, s), 7.97 (IH, d, J = 6.2 Hz), 8.15 (IH, d, J = 6.6 Hz); ESI MS m/z 196 [C9H10C1Ν3 + H] +; HPLC (H20/CH3CN 75:25 to 0:100 over 20 min, hold for 10 min) 88.2%, tR = 8.0 min.
Example 11
-V-Ben.zyl-W- [ (7-chloro-lH-pyrrolo [2 ,3-c]pyridin-2- yl) methyl] amine hydrochloride
7-Chloro-lH-pyrrolo [2, 3-c] pyridine-2-carboxaldehyde (Example 138) (102 mg, 0.565 mmol) was dissolved in methanol (2.5 mL) . Benzylamine (70 μL, 0.62 mmol) was added. After 2 h, sodium borohydride (35 mg, 0.90 mmol) was added. After an additional 2 h, the reaction mixture was quenched by addition of 5% aqueous sodium bicarbonate. The reaction mixture was extracted with diethyl ether, dried (magnesium sulfate) , and evaporated to dryness (124 mg, 81% crude) . The crude material was dissolved in acetonitrile and treated with hydrochloric acid (0.46 mL, 1 M in diethyl ether) to give ZV-benzyl-N- [ (7- chloro-lH-pyrrolo [2, 3-c] pyridin-2-yl)methyl] amine hydrochloride (107 mg, 0.347 mmol, 61%) as an off-white powder: p 201-204°C; XE ΝMR (300 MHz, CD30D) δ4.35 (2H, s) , ^ __ ^ Pl2^' X'jii§ i '$ $sβ$ « S) - 7.45-7.60 (5H, m) , 7.60 ( IH, d, J = 5.6 Hz), 7.94 (IH, d, J = 5.6 Hz); ESI MS m/z 272 [ Cι5H14ClN3 + H]+; HPLC (H20/CH3CN 90:10 to 0:100 over 20 min, hold, for 15 min, 0.05% TFA added to solvents) >99%, tR = 11.1 min. 5 Example 12
2- [ (4-Acetyl-l-piperazinyl) carbonyl] -7-chloro-lH-pyrrolo [2,3- σ] pyridine
10 2- [ (4-Acetyl-l-ρiperazinyl) carbonyl] -7-chloro-l-H- pyrrolo [2, 3-c] pyridine (20 mg, 12%) was prepared as an off- white solid following the procedure described for Example 2 using 1-acetylpiperazine: mp 179-184°C; NMR (300 MHz, CD3OD) 15 82.15 (3H, s), 3-65-3.87 (8H, m) , 6.92 (IH, s) , 7.63 (IH, d, J = 5.7 Hz), 7.95 (IH, d, J = 5.7 Hz); ESI MS m/z 307 [Cι4Hι5ClN402 + H]+; HPLC (Method A) >99% (AUC), tR = 11.6 min.
Example 13
20 7-Chloro-2- (l-py-crolidinylcarbonyl) -lH-pyrrolo[ 2, 3-c] yridine
7-Chloro-2— (1-pyrrolidinylcarbonyl) -IH-pyrrolo [2, 3- c] pyridine (79 mg, 60%) was prepared as an off-white solid 25 following the procedure described for Example 2 using pyrrolidine: mp 152-154°C; 1H NMR (300 MHz, CD30D) δl.98-2.07 (4H, m) , 3.65-3.69 (2H, m) , 3.82-3.86 (2H, m) , 7.08 (IH, s) , 7.64 (IH, d, J = 5.7 Hz), 7.94 (IH, d, J = 5.4 Hz); ESI MS m/z 250 [Cι2Hι2ClN30 + H]+; HPLC (Method A) 93.1% (AUC), tR = 14.4 30 min.
Example 14 P'f .Si'^c S^^-dil^oaSplioli-ciylcarbonyl) -IH-pyrrolo [2 , 3- σ] pyridine
7-Chloro-2- (4-thiomo-rpholinylcarbonyl) -IH-pyrrolo [2, 3— c] pyridine (76 mg, 54%) was prepared as an off-white solid following the procedure described for Example 2 using thiomorpholine : mp 62-72°C; Η NMR (300 MHz, CD30D) 62.67-2.81 (4H, m), 3.91-4.13 (4H, m) , 6.85 (IH, s) , 7.61 (IH, d, J = 5.4 Hz), 7.94 (IH, d, J = 5.7 Hz); ESI MS m/z 282 [Cι2Hχ2ClN3OS + H]+; HPLC (Method A) 94.5% (AUC), tR = 15.0 min.
Example 15
N- [ (7-Chloro-lH-pyrrolo [2 , 3-σ]pyridin-2-yl) methyl] -N- cyclopentylamine hydrochloa-ride
7-Chloro-lH-pyrrolo[-2, 3-c] pyridine-2-carboxaldehyde (Example 138) (75 mg, 0.42 mmol) and cyclopentylamine (45 μL-, 0.46 mmol) were dissolved n methanol (3 mL) . After 4 h, sodium borohydride (25 mg, 0.67 mmol) was added in one portion. After an additional 2 h, tre reaction mixture was quenched h>y addition of 2 N aqueous sodium hydroxide and extracted with diethyl ether. The organic layer was dried over sodium sulfate and evaporated. The residme was dissolved in acetonitrile and salted with 1 N ethereal hydrochloric acid. The precipitate was collected by filtration and crystallized from acetonitrile to give N- [ (7-chloro-lH-py-rrolo [2, 3-c] pyridin-2-yl) methyl] -2Ν7- cyclopentylamine hydrochlo-ride (35 mg, 30%) as a white solid: mp 241-244°C; Η NMR (300 MHz, CD3OD) δl .70-1.95 (6H, m) , 2.25 (2H, m) , 3.75 (IH, m) , 4.57 (2H, s) , 7.09 (IH, s) , 7.93 (IH, d, J = 6.0 Hz), 8.12 (IH, J = 6.0 Hz); ESI MS m/z 250 [C13HιSClN3 + H]+; HPLC (Method C) >99% (AUC), tR = 12.9 min. » -sxa-mple ■<«--. <™. <• * ™n~ »<«ι! -<-t( ^<«
-V- [ (7-Chloro-lH-pyrroLo [2 , 3-σ]pyridin-2-yl) methyl] -N- (2- furylmethyl) amine hydrochloride
N-[ (7-Chloro-lH-pyrrolo[2,3-c]pyridin-2-yl)methyl]-N-(2- furylmeth l) amine hydrochloride (56 mg, 41%) was prepared as an off-white powder following the procedure described for Example 15 using furfurylamine: mp 98-101°C; NMR (300 MHz, CD3OD) δ4.44 (2H, s) , 4.53 (2H, s) , 6.53 (IH, m) , 6.70 (IH, m) , 6.96 (IH, s), 7.68 (IH, ) , 7.76 (IH, d, J = 5.8 Hz), 8.03 (IH, J = 5.8 Hz); ESI MS /z 262 [Cι3H12ClN30 + H]+; HPLC (Method C) >99% (AUC), tR = 12.9 min. Example 17
N- [ ( 7 -Chloro- IH-pyrrolo [2 , 3-c]pyridin-2-yl) methyl] -N- [2- (4- morpholinyl) ethyl] amine hydrochloride N- [ (7-Chloro-lH-pyrrolo [2, 3-c] pyridin-2-yl) methyl] -N- [2- (4 -morpholinyl) ethyl] amine hydrochloride (22 mg, 16%) was prepared as an off-white powder following the procedure described for Example 15 using N- (2-aminoethyl)morρholine: mp 146-150°C; ESI MS m/z 295 [C14H19C1Ν40 + H] +; HPLC (Method C) >99% (AUC), tR = 11.1 min.
Example 18
N- [ (7-Chloro-lH-pyrrolo [2 ,3-c]pyridin-2-yl) methyl] -N- (2- pyridinylmethyl) amine hydrochloride
N- [ (7-Chloro-lH-pyrrolo [2, 3-c] pyridin-2-yl) methyl] -N- (2- pyridinylmethyl) amine hydrochloride (12 mg, 8%) was prepared as a white powder following the procedure described for "'"l-ata^l'MB^u^ mp 176-179°C; Η NMR (300 MHz, CD3OD) 84.46 (2H, s) , 4.59 ( 2H, s), 6.87 (IH, s) , 7.44 (2H, m) , 7.60 (IH, d, J = 5.5 Hz), 7.86 (IH, m) , 7.94 (IH, d, J = 5.5 Hz), 8.65 (IH, m) ; ESI MS rn/z 273 [Cι4Hι3ClN4 + H]+; HPLC (Method C) >99% (AUC), tR = 12.7 min.
Example 19
7-Chloro-2- [ (4-methyl-l-piperazinyl) ceirbonyl] -IH-pyrrolo [2 , 3- c] pyridine
7-Chloro-2- [ (4-methyl-l-piperaz nyl) carbonyl] -1H- pyrrolo [2, 3-c] pyridine (13.4 mg, 9%) -was prepared as a yellow solid following the procedure described for Example 2 using 1- methylpiperazine: mp 230-232°C; XH NMR (300 MHz, CD3OD) 82.34 (3H, s), 2.47-2.59 (4H, m) , 3.72-3.87 (4H, m) , 6.87 (IH, s) , 7.61 (IH, d, J = 5.4 Hz), 7.94 (IH, d_, J = 5.7 Hz); ESI MS m/z 279 [Ci3Hi5ClN40 + H]+; HPLC (Method B) 88.1% (AUC), tR = 10.9 min.
Example 20
7-Chloro-iV- (2-pyridinyl) -lH-pyrrolo[2 , 3-c]pyridine-2- carboxamide
7-Chloro-N- (2-pyridinyl) -lH-pyr-trolo [2, 3-c] pyridine-2- carboxamide (11.5 mg, 8%) was prepared as an off-white solid following the procedure described for Example 2 using 2- aminopyridine : mp 94-102°C; Η ΝMR (3O0 MHz, CD3OD) 87.16-7.46 (IH, m) , 7.67 (IH, s) , 7.81 (IH, d, CT = 5.6 Hz), 7.82-7.87 (IH, ) , 7.97 (IH, d, J = 5.6 Hz), 8.26-8.28 (IH, m) , 8.35-8.45 (IH, m) ; ESI MS m/z 273 [Cι3H9ClΝ40 + H] +; HPLC (Method B) >99% (AUC), tR = 13.4 min. £3^SP5 JL:t! -- ""J -If nifo
7-Chloro-W- (3-pyridinyl) -IH-pyrrolo [2 , -σ] pyridine-2- carboxamide
7-Chloro-N- (3-pyridinyl) -IH-pyrrolo [2, 3-c] pyridine-2- carboxamide (49 mg, 35%) was prepared as an off-white solid following the procedure described for Example 2 using 3- aminopyridine : mp >320°C (no melt was observed); Η ΝMR (300 MHz, CD30D) δ7.42-7.49 (2H, m) , 7.65-7.68 (IH, ) , 7.95-7.97 (IH, m) , 8.30-8.33 (2H, m) , 8.94-8.95 (IH, m) ; ESI MS m/z 273 [Cι3H9ClΝ40 + H]+; HPLC (Method B) >99% (AUC), tR = 12.2 min.
Example 22
7-Chloro-iV- (4-pyridinyl) -IH-pyrrolo [2 ,3-c]pyridine-2- carboxamide
7-Chloro-N- (4-pyridinyl) -IH-pyrrolo [2, 3-c] pyridine-2- carboxamide (24 mg, 17%) was prepared as an off-white solid following the procedure described for Example 2 using 4- aminopyridine : mp >320°C (no melt was observed); XH ΝMR (300 MHz, CD30D) δ7.46 (IH, s) , 7.68 (IH, d, J = 5.4 Hz), 7.87-7.89 (2H, m) , 7.97 (IH, d, J = 5.4 Hz), 8.45-8.47 (2H, m) ; ESI MS m/z 273 [Cι3H9ClΝ40 + H]+; HPLC (Method -B) 99.0% (AUC), tR = 12.4 min.
Example 23
l-Benzyl-4- [JV- [ (7-chloro-lH-pyrrolo[2 ,3-c]pyridin-2- yl) methyl] amino] piperidine hydrochloricie l-Benzyl-4- [N- [ (7-chloro-lH-pyrrolo [2, 3-c] pyridin-2-
Figure imgf000102_0001
hydrochloride (30 rag, 17%) was prepared as a white crystalline solid following the procedure described for Example 15 using l-benzyl-4-ami opiperidine : mp 295-310°C dec; NMR (300 MHz, CD3OD) δ2.07 C2H, m) , 2.46 (2H, m) , 3.16 (2H, m) , 3.50-3.70 (3H, ) , 4.35 (2Rr s), 4.54 (2H, s), 6.88 (IH, s), 7.45-7.65 (6H, m) , 7.95 (IH, d, J = 5.5 Hz); ESI MS m/z 355 [C20H23C1N4 + H]+; HPLC (Method D) >99% (AUC), tR = 12.6 min. Example 24
7-Chloro-2- (1-piperidinylmethyl) -IH-pyrrolo [2 , 3-σ]pyridine hydrochloride 7-Chloro-2- (1-piperidinylmethyl) -iH-pyrrrolo [2,3- c] pyridine hydrochloride (53 mg, 40%) was prepared as an off- white crystalline solid following the procedure described for Example 15 using piperidine: mp 240-244°C; XH NMR (300 MHz, CD30D) δl. 0-2.05 (6H, m) , 3.07 (2H, m) , 3.51 (2H, m) , 4.51 (2H, s), 6.91 (IH, s), 7.62 (IH, d, J = 5.6 Hz), 7.96 (IH, d, J = 5.6 Hz); ESI MS m/z 250 [C13Hι6ClN3 + H] +; HPLC (Method D) >99% (AUC) , tR = 11.9 min.
Example 25
W-Phenyl-2- [ [ [phenyl (IH-pyrrolo [2 ,3-c]pyridin—2- yl)methylene] amino] oxy] acetamide
N-Phenyl-2- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methylene] amino] oxy] acetamide (25 mg, 8%) was prepared using 2- (aminooxy) -N-phenylacetamide (Reference Example 20) as a white solid following the procedure described for Example 128: Rf 0.45 (90:10 methylene chloride/methanol) ; ESI MS m/z S^Ϊ^iy2IS I +' ]^:'"'!H;i> C (Method A) >99% (AUC) , tR = 17.7 min and 17.8 min.
Example 26
(7-Chloro-lH-pyrrolo [2 , 3-c]pyridin-2-yl) (phenyl) methanol
To a solution of 7-chloro-lH-pyrrolo [2, 3-c] pyridine-2- carboxaldehyde (Example 138) (1.0 g, 5.5 mmol) in THF ( 21.7 mL) was added 3.0 M phenylmagnesium bromide in Et20 (3.8 mL, 11.3 mmol) at -78°C under a nitrogen atmosphere. After stirring for ca. 2 h, additional 3.0 M phenylmagnesium b-tromide in Et20 (0.92 mL, 2.7 mmol) was added. The reaction mixtxαre was stirred for another 1.5 h. The reaction mixture was poured into a saturated NH4C1 solution and extracted with EtOAc (3x) . The combined organic extracts were washed with saturated NaCl, and dried over Na2S04. Filtration and concentration provided the crude material, which was purified by flash chromatogjraphy to provide (7-chloro-lH-pyrrolo [2, 3-c]pyridin-2- yl) (phenyl) methanol (0.97 g, 67%) as an off-white solid: XH
NMR (300 MHz, CD3OD) δ5.99 (IH, s) , 6.42 (IH, s) , 7.25-7-48 (6H, m) , 7.82 (IH, d, J = 5.4 Hz); ESI MS m/z 259 [Cι4HnClN20 -+ H]+; HPLC (Method A) >99% (AUC), tR = 13.8 min.
Example 27
N- (2-Pyridinylmethyl) -IH-pyrrolo [2 ,3-c]pyridine-2-carboxsιmide
7-Chloro-N- (2-pyridinylmethyl) -IH-pyrrolo [2, 3-c]py-t-:idine- 2-carboxamide (Example 4) (0.06 g, 0.21 mmol) in N,N- dimethylformamide (4.2 mL) was warmed to 60°C under a nitrogen atmosphere. To the stirring solution were added triethylamine (0.06 mL, 0.43 mmol) and palladium dichloride (spatula tip, «"',eβ'ia,i ^i^tø©UH ^'™(!a,'ά^' the reaction mixture was placed under a hydrogen atmosphere . The formation of palladium black was observed within 15 min. After stirring at 60°C for 2 h, the heating bath was removed and the reaction mixture was st irred at room temperature overnight under a hydrogen atmospher e . The crude reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with saturated NH4C1 and saturated NaCl, and dried over Na2S04. Filtration and concentration provided N- (2-pyridinylmet l) - IH-pyrrolo [2, 3-c]pyridine-2-carboxamide (0.015 g, 25%) a s an off-white solid: mp 230-236 C; 1H NMR (300 MHz, CD3OD) S4.73 (2H, s), 7.20 (IH, s), 7.31-7.35 (IH, m) , 7.46 (IH, d, J = 7.9 Hz), 7.67 (IH, d, J = 5.6 Hz), 7.79-7.83 (IH, m) , 8.12 ( IH, d, J = 5.6 Hz), 8.50-8.52 (IH, m) , 8.79 (IH, s) ; ESI MS m/z 253 [Cι4H12N40 + H]+; HPLC (Method A) 95.5% (AUC), tR = 16.7 min.
Example 28 N- (4-Pyridinylmethyl) -IH-pyrrolo [2 , 3-c]pyridine-2-carbox-amide
N- (4-Pyridinylmethyl) -IH-pyrrolo [2, 3-c] pyridine-2- carboxamide (10 mg, 30%) was prepared as a yellow solid following the procedure described for Example 27 using 7— chloro-N- (4-pyridinylmethyl) -IH-pyrrolo [2, 3-c] pyridine-2 — carboxamide (Example 6) : 1H ΝMR (300 MHz, CD3OD) δ4.66 (2H, s) , 7.18 (IH, s), 7.43-7.48 (2H, m) , 7.67-7.73 (IH, m) , 8.12—8.18 (IH, m) , 8.49-8.53 (2H, m) , 8.80 (IH, s) ; ESI MS m/z 253 [C14Hι2Ν40 + H]+; HPLC (Method A) 92.0% (AUC), tR = 16.2 min.
Example 29
(7-Chloro-lH-pyrrolo [2 ,3-c]pyridin-2-yl) (phenyl) methanon«= it'" A « ,•< A1 ',3 ζ.J ™.i> mtt- ,.tin '««. -™i> * A mixture of (7-chloro-lH-pyrrolo [2, 3-c]pyridin-2- yl) (phenyl)methanol (Example 26) (0.83 g, 3.2 mmol) and Mn02 (3.35 g, 38.5 mmol) in methylene chloride (64 mL) was stirred under a nitrogen atmosphere at room temperature overnight (20 h) . The crude reaction mixture was filtered through diatomaceous earth and rinsed with methylene chloride. Concentration afforded (7-chloro-lH-pyrrolo [2, 3-c]pyridin-2- yl) (phenyl) methanone (0.68 g, 82%) as an off-white solid: mp 152-153°C; Η NMR (300 MHz, CDC13) 87.18 (IH, d, J = 2.1 Hz), 7.55-7.71 (4H, m) , 7.99-8.05 (2H, m) , 8.11 (IH, d, J = 5.7 Hz), 9.55 (IH, br s) ; ESI MS m/z 257 [Cι4H9ClN20 + H]+; HPLC (Method A) >99% (AUC), tR = 25.0 min. Example 30
N- (3-Pyridinyl) -IH-pyrrolo [2 ,3-c]pyridine-2-carboxamide
N- (3-Pyridinyl) -IH-pyrrolo [2, 3-c] pyridine-2-carboxamide (10 mg, 60%) was prepared as an off-white solid following the procedure described for Example 27 using 7-chloro-N- (3- pyridinyl) -IH-pyrrolo [2, 3-c] pyridine-2-carboxamide (Example 21): mp 270-290°C; ΝMR (300 MHz, DMSO- 6) 87.43-7.48 (IH, m) , 7.58 (IH, d, J = 2.9 Hz), 7.90 (IH, d, J = 5.6 Hz), 8.22-8.25 (2H, m) , 8.36-8.40 (IH, m) , 8.94 (IH, s) , 8.99 (IH, s) , 10.79 (IH, d, J = 6.6 Hz), 12.83 (IH, br s) ; ESI MS m/z 239 [Cι3Hι0Ν4O + H]+; HPLC (Method A) 95.2% (AUC), tR = 16.1 min.
Example 31
Phenyl (iH-pyrrolo [2 , 3-σ]pyridin-2-yl) methanone O- (IH-imidazol- 2-ylmethyl) oxime dihydrochloride ic'it f '"!!-" ,.•' n !• if""' n ic;. .,>- -it -11 117" '""ft •« ιr ' iiini' ii ,. t «,ι> .„„. iι,-H ™II ,• mt(- „«- m-t- «*-• mfe Phenyl (IH-pyrrolo [2, 3-c]pyridin-2-yl)methanone 0- (1H- imidazol-2-ylmethyl) oxime dihydrochloride (79.5 mg, 51%) was prepared from 2- [ (aminooxy)methyl] -IH-imidazole (Reference Example 16) following the procedure described for Example 128, but without basic treatment, as a mixture of isomers (74.6:24.7 by HPLC analysis): NMR (500 MHz, DMSO- 6) δ 5.47 (0.6H, s), 5.61 (1.4H, s) , 6.72 (0.3H, s) , 7.08 (0.7H, s) , 7.50-7.57 (5H, m) , 7.73 (2H, m) , 8.10 (0.3H, d, J = 6.3 Hz), 8.19 (0.7H, d, J = 6.3 Hz), 8.31 (0.3H, d, J = 6.3 Hz), 8.37 (0.7H, d, J = 6.3 H) , 9.08 (0.3H, s) , 9.29 (0.7H, s) , 13.73 ( IH, br s ) , 15 . 07 ( 3H, br s ) ; ESI MS m/z 318 [Cι8H15N50 + H] +; HPLC (Method A) >99% (AUC ) , tR = 13 . 3 and 13 . 4 min . Example 32
(lH-Pyrrolo [2 ,3-σ]pyridin-2-yl) (thien-3-yl) methanone
[1- (Phenylsulfonyl) -IH-pyrrolo [2, 3-c] pyridin-2-yl] (thien- 3-yl) methanol (121 mg, 47%) was prepared as a tan solid following the procedure described for Example 137 using commercially available 3-thiophenecarboxaldehyde. Purification was achieved by Biotage chromatography (silica gel; 20 to 100% ethyl acetate in hexanes): mp 157-160°C dec; NMR (500 MHz, CD3OD) δ 6.66 (IH, br s) , 6.86 (IH, br s) , 7.08 (IH, m) , 7.29- 7.75 (8H, m) , 8.30 (IH, d, J = 5.3 Hz), 9.27 (IH, br s) ; ESI MS m/z 371 [Cι8Hι4N203S2 + H]+; HPLC (Method A) >99% (AUC), tR = 16.1 min. (lH-Pyrrolo[2, 3-c]pyridin-2-yl) (thien-3-yl) methanol (149 mg, 98%) was prepared as a tan solid following the procedure described for Example 137 from [1- (phenylsulfonyl) -1H- pyrrolo [2, 3-c]pyridin-2-yl] (thien-3-yl)methanol: Η NMR (500 k fa- •'cB3'Θ!Df δ "βΛr'fra, s), 6.39 (IH, S), 7.11-7.12 (IH, m) , 7.36-7.39 (2H, m) , 7.48-7.50 (IH, m) , 7.99-8.03 (IH, m) , 8.59 (IH, s) . (lH-Pyrrolo[2, 3-c]pyridin-2-yl) (thien-3-yl)methanone (90 mg, 61%) was prepared as a tan solid following the procedure described for Example 137 from (lH-pyrrolo[2, 3-c]pyridin-2- yl) (thien-3-yl) methanol: mp 178-181°C dec; NMR (300 MHz, CD3OD) δ 7.48 (IH, s) , 7.61-7.65 (IH, m) , 7.71-7.74 (IH, m) , 7.94-7.96 (IH, m) , 8.21 (IH, d, J = 6.0 Hz), 8.51-8.53 (IH, m) , 8.96 (IH, s); ESI MS m/z 229 [Cι2H8N2OS + H]+; HPLC (Method A) 96.2% (AUC), tR = 14.1 min.
Example 33
2- (1-Pyrrolidinylcarbonyl) -IH-pyrrolo [2 ,3-c]pyridine
2- (1-Pyrrolidinylcarbonyl) -IH-pyrrolo [2, 3-c] pyridine (22 mg, 46%) was prepared as an off-white solid following the procedure described for Example 27 using 7-chloro-2- (1- pyrrolidinylcarbonyl) -IH-pyrrolo [2, 3-c] pyridine (Example 13) and ethanol as a solvent: mp 260-275°C dec; 1H NMR (300 MHz, CD3OD) δl.98-2.10 (4H, m) , 3.66-3.71 (2H, m) , 3.89-3.94 (2H, m) , 7.10 (IH, s), 7.74 (IH, d, J = 5.4 Hz), 8.13 (IH, d, J = 5.7 Hz), 8.82 (IH, s); ESI MS m/z 216 [C12Hι3N30 + H]+; HPLC (Method A) 93.3% (AUC), tR = 10.3 min.
Example 34 iV-Benzyl-iV- [ (7-chloro-IH-pyrrolo [2 , 3-c]pyridin-2- yl) (phenyl) methyl] amine dihydrochloride
A mixture of (7-chloro-lH-pyrrolo [2, 3-c] pyridin-2-
Figure imgf000108_0001
29) (1.0 g, 3.9 mmol), molecular sieves and benzylamine (0.42 g, 3.90 mmol) in toluene (4.7 mL) was heated under reflux overnight (19 h) . The reaction mixture was hot filtered to remove the molecular sieves, and the sieves were rinsed with ethyl acetate. The filtrate was concentrated to provide the intermediate imine (1.3 g, 94%) as a viscous orange oil: ESI MS m/z 346 [C2ιHι6ClN3 + H] +.
The crude imine intermediate (1.3 g, 3.6 mmol) was dissolved in methanol (18.3 mL) , cooled to 0°C and placed under a nitrogen atmosphere, and sodium borohydride (0.14 g, 3.6 mmol) was carefully added. Upon complete addition of sodium borohydride, the ice/water bath was removed and the reaction mixture was stirred overnight (18 h) . The reaction mixture was quenched with water and concentrated to remove methanol. The residue was diluted with ethyl acetate, and the product was extracted with 2 N HCl (3x) . The combined extracts were washed with ethyl acetate. The acidic extracts were made basic (pH 10) with 6 N NaOH then extracted with ethyl acetate (3x) . The combined organic extracts were dried over Na2S0, filtered and concentrated to give a yellow foam. The crude foam was dissolved in methanol and ethereal HCl was added. This mixture was concentrated to dryness, and then triturated with ethyl acetate. The solid was collected by filtration to give N- benzyl-N- [ (7-chloro-lH-pyrrolo [2, 3-c] pyridin-2- yl) (phenyl)methyl] amine dihydrochloride (0.80 g, 52%) as an off-white solid: mp 170-185°C dec; ΝMR (300 MHz, CD3OD) 64.21-4.41 (2H, m) , 5.91 (IH, s) , 7.31 (IH, s), 7.45-7.71 (10H, m) , 7.97-8.14 (2H, m) ; ESI MS 348 [C2ιHι8ClΝ3 + H]+; HPLC (Method A) 88.3% (AUC), tR = 14.6 min.
Example 35 t"Jihey-llM"H*p E o'l .{§<iJ ]pyridin-2-yl)methanone
(7-Chloro-lH-pyrrolo [2, 3-c] pyridin-2-yl) (phenyl)methanone (Example 29) (1.09 g, 4.25 mmol), palladium(II) chloride (15.4 mg, 3 mol %) and triethylamine (1.3 mL) were combined in N,N~ dimethylformamide (25 mL) . The reaction mixture was heated at 60°C under an atmosphere of hydrogen for 8 h, then at room temperature for an additional 16 h. The reaction mixture was diluted with methylene chloride (25 mL) and filtered through a pad of diatomaceous earth. Evaporation of the solvents provided 1.3 g of crude orange solid. Purification by chromatography (Si02; 0-10% methanol in methylene chloride, 1400 ml) afforded phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (196 mg, 0.893 mmol, 21%) as an off-white solid: mp 245-247°C; ΝMR (300 MHz, CD3OD) δ 7.18 (IH, s) , 7.55-7.63 (2H, ) , 7.65-7.77 (2H, m) , 7.95-8.04 (2H, m) , 8.17 (IH, d, J = 5.7 Hz), 8.87 (IH, s) ; ESI MS m/z 223 [Cι4H10Ν2O + H]+; HPLC (Method A) >99% (AUC), tR = 13.4 min. Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl)methanone was prepared in an alternative method.
Phenyl [1- (phenylsulfonyl) -IH-pyrrolo [2, 3-c]pyridin-2- yl]methanone (Reference Example 13) (2.2 g, 6.1 mmol) and 10% aq NaOH (70 mL) in EtOH (135 mL) was heated to reflux. After 14 h, the mixture was concentrated under reduced pressure to remove most of the EtOH. The mixture was diluted with H20 (50 mL) and extracted with EtOAc (2 x 100 mL) . The combined extracts were washed with saturated NaCl (25 L) , dried (Na2S04) and concentrated under reduced pressure. Trituration in EtOAc/diethyl ether gave phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (1.14 g, 83%). « Exampl -36* ""* <• A ™# *-*■ A
3-Furyl (IH-pyrrolo [2 , 3-c] pyridin-2-yl) me thanone O- (2- aminoethyl) oxime dihydrochloride
3-Furyl (IH-pyrrolo [2, 3-c] pyridin-2-yl)methanone (Example 137) (63 mg, 0.30 mmol) and tert-butyl [2- (aminooxy) ethyl] carbamate (55 mg, 0.31 mmol) were combined in ethanol (5 mL) . The pH of the mixture was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the reaction mixture was refluxed for 12 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by Biotage chromatography (silica gel, 2 to 18% methanol in dichloromethane) produced tert-butyl 2- [ [ [ (3-furyl) (1H- pyrrolo [2, 3—c]pyridin-2-yl) methylene] amino] oxy] ethylcarbamate (50 mg, 45%) as a yellow solid. tert-Butyl 2- [ [ [ (3-furyl) (IH-pyrrolo [2, 3-c] pyridin-2- yl)methylene] amino] oxy] ethylcarbamate (50 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (5 mL) and the solution was stirred at room temperature for 1 h. The solvent was removed under vacuum. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated to an oil. Purification by column chromatography (silica gel, 95:5 dichloromethane; methanol followed by 89:9:1 dichloromethane: methanol: ammonium hydroxide) produced the amine as an oil. The amine (46 mg) was taken up in dichloromethane (3 mL) and cooled to 0°C. Ethereal hydrogen chloride (1 mL of a 1 M solution) was added dropwise and the reaction mixture was stirred for 45 min at ambient temperature. The solvent was removed under vacuum
Figure imgf000111_0001
Ja'i'-lried in a vacuum oven at 45°C for 12 h to give 3-furyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) me thanone 0-(2- aminoethyl) oxime dihydrochloride (18 mg, 51% yield) as a brown solid: NMR (500 MHz, CD3OD) 63.43-3.50 (2H, m) , 4.57-4.64 (2H, m) , 6.87 (0.6OH, s) , 6.96 (0.40H, s) , 7.23-7.31 (2H, m) , 7.66-7.73 (IH, m) , 7.87 (0.60H, s) , 8.15-8.37 (2.4H, m) , 9.06 (0.40H, s), 9.23 (0.60H,s); ESI MS m/z = 271 [Cι4Hι4N402 + H]+; HPLC (Method A) 93.4% (AUC), tR = 12.3 min. Example 37
7- (Dibenzylamino) -N- (3-pyridinylmethyl) -IH-pyrrolo [2 , 3- c] pyridine- 2 -carboxamide A mixture of ethyl 7- (dibenzylamino) -IH-pyrrolo [2, 3- c]pyridine-2-carboxylate (Reference Example 3) (634 mg, 1.64 mmol) and 3- (aminomethyl) pyridine (3.8 mL, 37 mmol) was heated neat at 100°C for 72 h under N2. The mixture was cooled to room temperature and diluted with dichloromethane (150 mL) and water (100 mL) . The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 50 mL) . The combined organic extracts were dried (Na2S04) , filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel, gradient 50-70% ethyl acetate/hexanes) to provide 7- (dibenzylamino) -N- (3- pyridinylmethyl) -IH-pyrrolo [2, 3-c] pyridine-2-carboxamide (364 mg, 49%) as an orange solid: Rf 0.08 (75:25 ethyl acetate/hexanes); mp 105-108°C; NMR (300 MHz, CDC13) 64.60 (2H, d, J = 6.0 Hz), 4.89 (4H, s), 6.50 (IH, t, J = 5.4 Hz), 6.71 (IH, s), 6.99 (IH, d, J = 5.6 Hz), 7.28-7.31 (2H, m) , 7.34-7.42 (9H, m) , 7.64 (IH, d, J = 7.8 Hz), 7.89 (IH, d, J = 5.6 Hz), 8.55 (2H, s) , 8.97 (IH, s); ESI MS m/z 448 [C28H25N50 + H]+; HPLC (Method A) >99% (AUC), tR = 13.02 min. CT US0S , ,I531
Example 38
7- (Dibenzylamino) -N- (2-thienylmethyl) -IH-pyrrolo [2 ,3- σ]pyridine-2-carboxamide
A mixture of ethyl 7- (dibenzylamino) -IH-pyrrolo [2, 3- c]pyridine-2-carboxylate (Reference Example 3) (634 mg, 1.64 mmol) and 2- (thienylmethyl ) amine (2.0 mL, 19 mmol) was heated neat at 100°C for 24 h under N2. The mixture was cooled to room temperature and diluted with dichloromethane (150 mL) and water (100 mL) . The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 50 mL) . The combined organic extracts were dried (Na2S0) , filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel, gradient 5-15% ethyl acetate/hexanes) to provide 7- (dibenzylamino) -N- (2- thienylmethyl) -IH-pyrrolo [2, 3-c]pyridine-2-carboxamide (22 mg, 3%) as a white solid: mp 152-154°C; ; Η NMR (300 MHz, CDC13) 64.76 (2H, d, J = 5.6 Hz), 4.88 (4H, s), 6.32 (IH, t, J = 5.1 Hz), 6.68 (IH, d, J = 1.9 Hz), 6.95-7.01 (3H, m) , 7.25-7.31 (4H, m) , 7.32-7.38 (7H, ) , 7.89 (IH, d, J = 5.6 Hz), 8.95 (IH, br s); ESI MS m/z 453 [C27H24N5OS + H]+; HPLC (Method A) >99% (AUC) , tR = 13.96 min.
Example 39
Phenyl (IH-pyrrolo [2 ,3-σ]py-cridin-2-yl) methanone oxime To a mixture of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (Example 35) (161 mg, 0.72 mmol) and hydroxylamine hydrochloride (100 mg, 1.45 mmol) in ethanol (3.6 mL) were added Li0H'H2O (120 mg, 2.16 mmol) and water (1.0
Figure imgf000113_0001
was heated under reflux until TLC analysis indicated consumption of the ketone. The mixture was concentrated to dryness. The residue was treated with water, and the residual solid was collected by filtration to give predominately one isomer of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone oxime (75.8 mg, 0.31 mmol, 44%) as a yellow solid. The aqueous filtrate was extracted with methylene chloride (3χ) . The combined extracts were washed with saturated NaCl, dried over Na2S04, filtered, and concentrated to give ca. 1:1 mixture of isomers of the oxime (72 mg, 0.30 mmol, 42%) as a yellow solid:
Isomer A: Η NMR (300 MHz, CDC13) 66.55 (IH, s) , 7.48-7.65 (7H, m) , 8.29 (IH, d, J= 5.4 Hz), 8.96 (IH, s) , 10.90 (IH, br s) .
Isomer B: mp 132-142°C; αH NMR (300 MHz, CDC13) δ6.24 (IH, s) , 7.34-7.63 (7H, m) , 8.90 (IH, d) , 9.89 (IH, br s) , 10.83 (IH, br s); ESI MS m/z 238 [CI4H 1SΓ30 + H]+; HPLC (Method A) >99% (AUC), tR = 14.93, 15.24 min.
Example 40
1-Phenyl-l- (IH-pyrrolo [2 , 3-σ] pyridin-2-yl) me hylamine dihydrochloride
To a solution of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone oxime (Example 39) (100 mg, 0.42 mmol) in THF (4.2 L) was added LiAlH4 (80 mg, 2.11 mmol) under a nitrogen atmosphere. The reaction mixture was heated to reflux and stirred until TLC analysis indicated the starting oxime was consumed. The reaction mixture was cooled to room temperature and water (0.80 L) was carefully added followed by 15% NaOH (0.80 mL) , and water (2.4 mL) . After stirring for 1 h, a wet
Figure imgf000114_0001
filterable solid. Consequently, solid
Na2S04 was added and the mixture was filtered through diatomaceous earth. The filtrate was concentrated to give an off-white foam (60 mg) . The crude material was dissolved in EtOAc (10 ml) and 2 N HCl in Et20 (0.70 mL) was added. The resulting precipitate was collected by filtration and rinsed with EtOAc and Et20 to give 1-phenyl-l- (IH-pyrrolo [2, 3- c]pyridin-2-yl)methylamine dihydrochloride (71 mg, 0.24 mmol, 57%) as an off-white solid: mp 240-250°C; NMR (300 MHz, CD30D) 66.09 (IH, s) , 7.22 (IH, s) , 7.53 (5H, br s) , 8.21 (IH, d, J = 6.4 Hz), 8.30 (IH, d, J = 6.5 Hz), 9.01 (IH, s) ; ESI MS m/z 224 [Cι4H13N3 + H]+; HPLC (Method A) 97.7% (AUC), tR = 11.76 min.
Example 41
7- (Dibenzylamino) -N- (4-pyridinylmethyl) -IH-pyrrolo [2 ,3- c]pyridine-2-carboxamide A mixture of 7- (dibenzylamino) -IH-pyrrolo [2, 3-c] pyridine-
2-carboxylic acid (Reference Example 4) (398 mg, 1.11 mmol), 4- (aminomethyl) pyridine (169 mg, 1.56 mmol), l-ethyl-3- dimethylaminopropylcarbodiimide (EDCI) (299 mg, 1.56 mmol), 1- hydroxybenzotriazole (HOBt) (211 mg, 1.56 mol) and N, N- dimethylformamide (5 mL) was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0:10 to 1:10 methanol/ethyl acetate) . Recrystallization from hexanes/ethyl acetate gave 7- (dibenzylamino) -N- (4-pyridinylmethyl) -IH-pyrrolo [2, 3- c]pyridine-2-carboxamide (419 mg, 84%) as colorless crystals:
Figure imgf000115_0001
acetate); mp 119-120°C; Η NMR (300 MHz, CDC13) 64.62 (2H, d, J = 6.0 Hz), 4.90 (4H, s) , 6.40-6.52 (IH, m) , 6.75 (IH, s) , 7.01 (IH, d, J = 5.6 Hz), 7.21 (2H, d, J = 5.9 Hz), 7.25-7.38 (10H, m) , 7.91 ( IH, d, J = 5.6 Hz), 8.57 (2H, d, J = 5.9 Hz), 8.98 (IH, br s); ESI MS m/z 448 [C28H25N50 + H]+; HPLC (Method A) >99% (AUC), tR = 15.7 min.
Example 42 7- (Benzylamino) -N- (4-pyridinylmethyl) -IH-pyrrolo [2 ,3- c]pyridine-2-carboxamide
Hydrogen (1 atm, balloon) was applied to a slurry of 7- (dibenzylamino) -N- (4-pyridinylmethyl) -IH-pyrrolo [2, 3- c]pyridine-2-carboxamide (Example 41) (69 mg, 0.15 mmol), 10% palladium on carbon (wet, 100 mg) and HCl (saturated solution in 2-propanol, 5 M, 0.5 mL) in ethanol (4.5 mL) at room temperature for 3 h. The slurry was filtered to remove the catalyst, and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The two layers were separated. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2:1 to 1:2 hexanes/ethyl acetate). Recrystallization from hexanes/ethyl acetate gave 7- (benzylamino) -N- (4-pyridinylmethyl) -IH-pyrrolo [2, 3-c] pyridine- 2-carboxamide (13.2 mg, 24%) as colorless crystals: Rf 0.42 (silica gel, 20:80 methanol/ethyl acetate); mp 199-200°C (recrystallized from hexanes/ethyl acetate) ; Η NMR (300 MHz, CD30D) 64.63 (2H, s) , 4.69 (2H, s) , 6.91 (IH, d, J = 6.0 Hz), 7.05 (IH, s), 7.22-7.43 (7H, m) , 7.55 ( IH, d, J = 6.0 Hz), 8.48 (2H, d, J = 6.0 Hz); ESI MS m/z 358 [C2ιHι9N50 + H]+; HPLC (Method A) >99% (AUC), tR = 13.2 min. Example 43
W- [Phenyl (IH-pyrrolo [2 , 3-σ]pyridin-2-yl) methyl] nicotinamide
To a solution of 1-phenyl-l- (IH-pyrrolo [2, 3-c]pyridin-2- yl)methylamine dihydrochloride (Example 40) (51 mg, 0.17 mmol), N,N-diisopropylethylamine (DIPEA) (0.15 mL, 0.85 mmol) and nicotinic acid (22 mg, 0.18 mmol) in methylene chloride (2.0 mL) was added l-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC-HCl) (30 mg, 0.20 mmol) followed by a catalytic amount of 4-dimethylaminopyridine (DMAP) . The reaction mixture was stirred at room temperature overnight (20 h) under a Ν2 atmosphere. TLC analysis showed the starting amine, therefore the reaction mixture was heated to reflux. After refluxing overnight, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and water. The organic layer was washed with water, 1 M citric acid, saturated NaHC03, and saturated NaCl. TLC analysis showed that the majority of desired product was extracted into the 1 M citric acid washing. The citric acid extracts were made basic with 15% NaOH solution and extracted with methylene chloride. The organic extracts were dried over Na2S04, filtered and concentrated to dryness. Trituration with Et20/CH2C12 (1:1) provided N- [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methyl] nicotinamide (18 mg, 32%) as a light yellow solid after drying: mp 178-188°C; NMR (300 MHz, CD3OD) 66.30 (IH, s), 6.67 (IH, s), 7.35-7.55 (7H, m) , 8.03 (IH, d, J = 5.5 Hz), 8.30-8.38 (IH, m) , 8.61 (IH, s) , 8.69-8.71 (IH, m) , 9.05-9.07 (IH, m) ; ESI MS m/z 329 [C20HιSNO + H] +; HPLC (Method A) >99% (AUC) tR = 13.3 min. EIxxaammppJle'<" 4'1 ,"" 11 » A «»-. J' «.-i* w*
lH-Pyrrolo[2 ,3-c] jρyridine-2-carboxaldehyde oxime To a solution of IH-pyrrolo [2, 3-c] pyridine-2- carboxaldehyde (0.83 g, 5.7 mmol) and hydroxylamine hydrochloride (0.49 g, 7.1 mmol) in ethanol (57 mL) , was added pyridine (0.57 mL, 7.1 mmol). After refluxing for 6.5 h, the reaction mixture "was cooled to room temperature and concentrated undex reduced pressure. The residue was dissolved in water, and extractions were attempted with EtOAc and CH2C12. However, the desired product remained in the aqueous layer. The aqueous layer was concentrated to give a solid residue that was triturated with EtOAc. The solid was collected by filtration to provide a mixture of oxime isomers of 1 H- pyrrolo [2, 3-c] pyridine-2-carboxaldehyde oxime (1.0 g, 111% theoretical yield) as a tan solid after drying: 1H NMR (300
MHz, CD3OD) major isomer 67.07 (IH, s) , 8.20-8.27 (2H, m) , 8.31 (IH, s) , 8.98 (IH, s) .
Example 45
[ [Phenyl (IH-pyrrolo [2 , 3-c]pyridin-2- yl ) methylene ] amino ] guanidine dihydrochloride
To a solution of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (Example 35) (0.15 g, 0.67 mmol) in ethanol (6.7 mL) were added aminoguanidine hydrochloride (0.09 g, 0.81 mmol) and 6 N HCl (0.56 mL) . The reaction mixture was heated to reflux under N2. After 3 h, heating was terminated and the reaction mixture was slowly cooled to room temperature overnight. The reaction mixture was concentrated to dryness. The residue was dissolved in water and washed with diethyl ether. The aqueoi s layer was made basic with 15% NaOH solution
Figure imgf000118_0001
acetate (2χ) . The organic extracts were combined and washed with water and saturated NaCl, and dried over Na2S04. Filtration and concentration provided the crude residue, which was dissolved in methanol. To the methanol solution was added 2 N HCl in Et20 (0.67 mL, 1.34 mmol) . The mixture was concentrated to dryness and the resulting solid was crystallized from EtOH/Et20 (9:1) to provide [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methylene] amino] guanidine dihydrochloride (0.22 g, 93%) as an off-white solid: mp 306-310°C; XE NMR (300 MHz, CD3OD) 66.71 (IH, s), 7.57-7.74 (5H, m) , 8.07 (IH, d, J = 6.5 Hz), 8.24 (IH, d, J = 6.4 Hz), 9.10 (IH,- s) ; ESI MS m/z 279 [Cι5Hι4N6 + H]+; HPLC (Method A) >99% (AUC) tR = 12.9 min. Example 46
[7- (Dibenzylamino) -lH-pyarrolo [2 ,3-c]pyridin-2- yl] (phenyl)methanol To a solution of 7— (dibenzylamino) -IH-pyrrolo [2, 3- c]pyridine-2-carboxaldehyde (Example 141) (1.7 g, 5.1 mmol) in tetrahydrofuran (25 mL) was added 3.0 M phenylmagnesium bromide in Et20 (2.0 mL, 6 mmol) dropwise at -78°C under a nitrogen atmosphere. After stirring for ca. 2 h, additional 3.0 M phenylmagnesium bromide in Et20 (2.0 mL, 6 mmol) was added. The reaction mixture was stirred for another 1.5 h warming to -15°C. The reaction mixture was poured into a saturated ammonium chloride solution, and extracted with ethyl acetate (3*) . The combined organic extracts were washed with saturated sodium chloride, and dried over sodium sulfate. Filtration and concentration provided the crude material, which was purified by Biotage chromatography (10-30% ethyl acetate in hexanes) to provide [7- (dibenzylamino) -1H- >h' ρy_|rόi'<-. p-y^te] p*sy-li-.M-fe-yl] (phenyl) methanol (1.32 g, 62%) as a yellow foam: mp 53-61°C; 1H NMR (500 MHz, CD3OD) 64.60 (4H, q, J = 23.2, 15.4 Hz), 5.95 (IH, s) , 6.25 (IH, s), 7.05 (IH, d, J = 5.7 Hz), 7.15-7.40 (15H, m) , 7.62 (IH, d, J = 5.7 Hz); ESI MS m/z 420 [C28H25N30 + H] +; HPLC (Method A) >99% (AUC), tR = 19.2 min.
Example 47 [7- (Dibenzylamino) -IH-pyrrolo[2 , 3—c]pyridin-2- yl] (phenyl) methanone
A mixture of [7- (dibenzylamino) -IH-pyrrolo [2, 3-c] pyridin- 2-yl] (phenyl)methanol (Example 46) (1.13 g, 2.69 mmol) and Mn02 (2.35 g, 27.0 mmol) in methylene chloride (75 mL) was stirred under a nitrogen atmosphere at room temperature overnight (17 h) . The crude reaction mixture was filtered through diatomaceous earth, rinsing with methylene chloride. The filtrate was concentrated to give a dark oil. Purification by Biotage chromatography (10-30% ethyl acetate in hexanes) provided [7- (dibenzylamino) -lH-pyrrrolo [2, 3-c] pyridin-2- yl] (phenyl)methanone as a yellow solid: mp 122-124°C; XH NMR (300 MHz, CD3OD) 64.76 (4H, s), 5.49 (IH, s) , 6.25 (IH, s) , 7.11(1H, s) 7.15-7.30 (10H, m) , 7.56-7.72 (4H, m) , 7.94-7.97 (2H, m) ; ESI MS m/z 418 [C28H23N30 + H]+; HPLC (Method A) >99% (AUC) , tR = 20.2 min.
Example 48 [5- (Dibenzylamino) -IH-pyrrolo [2 , 3— σ] pyr idin- 2-yl] methanol
To a solution of ethyl 5- (dibenzylamino) -IH-pyrrolo [2, 3- c]pyridine~2-carboxylate (Reference Example 5) (12.9 g, 33.6 ffi- fi ^Siff. (ϊfe#»S-ai''" ,nder a N2 atmosphere, was carefully added L1AIH4 (1.92 g, 50.5 mmol) portionwise. After stirring at room temperature for 2 h, TLC analysis showed the starting ester was consumed. The reaction mixture was carefully quenched with water (1.92 mL) , 15% NaOH (1.92 mL) , followed by more water (5.76 mL) and diluted with diethyl ether. After stirring for 5 h, the solid was removed by filtration through diatomaceous earth. The filtrate was concentrated to provide a dark oil (13.3 g) . The crude oil was purified by chromatography on silica gel to provide [5- (dibenzylamino) -1H- pyrrolo [2, 3-c] pyridin-2-yl] methanol (9.76 g, 84%) as a green foam: E NMR (300 MHz, CDC13) 64.72 (2H, s) , 4.78 (4H, s) , 6.04 (IH, s), 6.90 (IH, s), 7.20-7.30 (10H, m) , 8.34 (IH, s) , 8.63 (IH, br s); ESI MS m/z 344 [C22H2ιN30 + H]+; HPLC (Method A) >99% (AUC) tR = 17.7 min.
Example 49
N- [Phenyl (IH-pyrrolo [2 ,3-c]pyridin—2-yl)methyl] isonicotinamide
Using the procedure described for Example 43 with isonicotinic acid at room temperature, the reaction was stopped once 1-phenyl-l- (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylamine was consumed as judged by TLC analysis. Upon addition of water a solid precipitated. The solid was collected by filtration and dried to provide N- [phenyl (1H- pyrrolo [2, 3-c] pyridin-2-yl) methyl] isonicotinamide (58 mg, 44%) as an off-white solid: mp 182-192°C; XE ΝMR (300 MHz, CD3OD) 66.34 (IH, s), 6.67 (IH, s), 7.30-7.55 (7H, m) , 7.84-7.87 (2H, m) , 8.04 (IH, d, J = 5.7 Hz), 8.63 (IH, s), 8.69-8.71 (IH, m) ; ESI MS m/z 329 [C20Hι6Ν4O + H]+; HPLC (Method A) >99% (AUC) tR = 14.1 min. D £. £■£' ξp •Ψ l ""If -f
N- [Phenyl (IH-pyrrolo [2 , 3-c] pyridin-2-yl) methyl.] -2- pyridinecarboxamide
Using the procedure described for Example 43 with picolinic acid at room temperature, the reaction was stopped once 1-phenyl-l- (IH-pyrrolo [2, 3-c] pyridin-2-yl)methylamine was consumed as judged by TLC analysis. Purification by Biotage chromatography provided N- [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methyl] -2-pyridinecarboxamide (8 mg, 6%) as an off-white solid: mp 102-110°C; E ΝMR (300 MHz, CD3OD) 56.42 (IH, s) , 6.64 (IH, s), 7.36-7.62 (7H, m) , 7.98-8.03 (2H, m) , 8.13-8.16 (IH, m) , 8.59 (IH, s) , 8.63-8.67 (IH, m) ; ESI MS m/z 329 [C20Hι6Ν4O + H]+; HPLC (Method A) >99% (AUC) tR = 15.8 min.
Example 51
N- [Phenyl (IH-pyrrolo [2 , 3-c] pyridin-2-yl) methyl] benzamide
Using the procedure described for Example 43 with benzoic acid at room temperature, the reaction was stopped once 1- phenyl-1- (IH-pyrrolo [2, 3-c]pyridin-2-yl)methylamine was consumed as judged by TLC analysis. Upon addition of water a solid precipitated. The solid was collected by filtration and dried to provide N- [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methyl] benz amide (9 mg, 9%) as an off-white solid: mp 206- 208°C; XE NMR (300 MHz, CD3OD) 66.31 (IH, s), S .67 (IH, s) , 7.43-7.51 (9H, m) , 7.89-7.92 (2H, m) , 8.02 (IB, d, J = 5.6 Hz), 8.60 (IH, s); ESI MS m/z 328 [C2ιHι7N30 + H] +; HPLC (Method A) >99% (AUC) tR = 16.2 min. If"' ""if" S it I'd >f"ϊt if' ,-* "S "if IG_ '" "If
Phenyl (IH-pyrrolo [2 ,3-c]pyridin-2-yl)methanol To a solution of (7-chloro-lH-pyrrolo [2, 3-c]pyridin-2- yl) (phenyl)methanol (Example 26) (2.10 g, 8.12 mmol) a-nd ammonium formate (3.07 g, 48.7 mmol) in methanol (28 mL) was added 10% Pd/C (0.21 g) . The reaction mixture was refluxed for 1.5 h. TLC analysis showed the starting material was consumed. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated to dryness. The crude mixture was dissolved in EtOAc and water. The aqueous layer was extracted with EtOAc (2χ) and CH2C12. The combined orcjanic extracts were dried over Na2S04. After filtration and concentration, the crude material was purified by Biotage chromatography to provide phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanol (0.79 g, 43%) as an off-white solid: mp 178-180°C; 1H NMR (300 MHz, CD3OD) δ5.99 (IH, s) , 6.35 (IH, s) , 7-20-7.49 (6H, m) , 7.99 (IH, d, J = 5.6 Hz), 8.58 (IH, s) ; ESI MIS m/z 224 [Cι4Hι2N20 + H]+; HPLC (Method A) >99% (AUC) tR = 14.5 min.
Example 53
l- [5- (Dibenzylamino) -lH-pyrrolo [2 , 3-c] pyr idin- 2-yl] ettianol
To a solution of 5- (dibenzylamino) -IH-pyrrolo [2, 3- c]pyridine-2-carboxaldehyde (Example 139) (2.89 g, 8.4=6 mmol) in tetrahydrofuran (42 mL) was added 3.0 M methylmagnesium bromide in diethyl ether (7.05 mL, 21.2 mmol). The re ction mixture was stirred overnight (16 h) under a nitrogen atmosphere at room temperature . The reaction mixture -was poured into a stirring saturated NH4C1 solution. The layers were separated and the aqueous layer was extracted with EtOAc iP'jgxii) 'τ-i ,,*OTϊ--bϊ "1' organic extracts were dried over Na2S04. After filtration and concentration, a small amount of the desired product was obtained by trituration with CH2C12. Additional material was obtained by purification using Biotage chromatography on silica (eluting with Hex/EtOAc 90:10 to 0:100) to provide 1- [5- (dibenzylamino) -IH-pyrrolo [2, 3- c]pyridin-2-yl] ethanol (1.74 g, 57%) as an off-white solid: 1H NMR (300 MHz, CD3OD) 61.53 (3H, d, J = 6.6 Hz), 4.69 (4H, s) , 4.90-4.99 (IH, m) , 6.08 (IH, s) , 6.58 (IH, s) , 7.17-7.29 (10H, m) , 8.26 (IH, s) ; ESI MS m/z 358 [C23H23N30 + H]+; HPLC (Method A) 98.5% (AUC), tR = 18.2 min.
Example 54 [5- (Dibenzylamino) -lH-pyrrolo[2,3-c]pyridin-2- yl] (phenyl) methanol
Following the procedure described above for Example 53, using phenylmagnesium bromide, [5- (dibenzylamino) -1H- pyrrolo [2, 3-c] pyridin-2-yl] (phenyl) methanol was prepared (1.45 g, 42%) as a light red foam followed by purification by Biotage chromatography: XE NMR (300 MHz, CD3OD) 64.68 (4H, s), 5.87 (IH, s), 6.02 (IH, s) , 6.57 (IH, s) , 7.12-7.43 (15H, m) , 8.24 (IH, s); ESI m/z 420 [C28H25N30 + H]+; HPLC (Method A) >99% (AUC) , tR = 19.9 min.
Example 55
[5- (Dibenzylamino) -IH-pyrrolo [2 , 3-c]pyridin-2- yl] (phenyl) methanone
[5- (Dibenzylamino) -IH-pyrrolo [2, 3-c]pyridin-2- yl] (phenyl) methanol (Example 54) was oxidized using manganese jS^i'^^ I^'^ ^^-^dibenzylamino) -IH-pyrrolo [2, 3- c]pyridin-2-yl] (phenyl)methanone following the procedure described for Example 139 using methylene chloride as a solvent. Trituration of the crude material with Et20 provided [5- (dibenzylamino) -IH-pyrrolo [2, 3-c] pyridin-2- yl] (phenyl) methanone (220 mg, 44%) as a yellow solid: 1H NMR (300 MHz, CD3OD) 64.77 (4H, s) , 6.69 (IH, s) , 6.82 (IH, s) , 7.19-7.27 (10H, m) , 7.53-7.65 (3H, m) , 7.92-7.95 (2H, m) , 8.57 (IH, s); ESI MS m/z 418 [C28H23N30 + H]+; HPLC (Method A) >99% (AUC) , tR = 20.9 min.
Example 56
1- [5- (Dibenzylamino) -IH-pyrrolo [2 ,3-c]pyridin-2-yl]ethanone
1- [5- (Dibenzylamino) -IH-pyrrolo [2, 3-c]pyridin-2- yl] ethanol (Example 53) was oxidized using manganese dioxide to provide 1- [5- (dibenzylamino) -IH-pyrrolo [2, 3-c]pyridin-2- yl] ethanone following the procedure described for Example 139 using tetrahydrofuran as a solvent. Purification by Biotage chromatography provided 1- [5- (dibenzylamino) -IH-pyrrolo [2, 3- c]pyridin-2-yl] ethanone (200 mg, 40%) as a yellow solid: 1H NMR (300 MHz, CD3OD) 62.54 (3H, s), 4.76 (4H, s) , 6.67 (IH, s) , 6.97 (IH, s), 7.12-7.30 (10H, m) , 8.50 (IH, s) ; ESI m/z 356 [C23H21N30 + H]+; HPLC (Method A) >99% (AUC), tR = 18.8 min.
Example 57
(5-Amino-lH-pyrrolo [2 ,3-c]pyridin-2-yl) (phenyl)methanol
A mixture of [5- (dibenzylamino) -IH-pyrrolo [2, 3-c] pyridin- 2-yl] (phenyl)methanone (Example 55) (674 mg, 1.61 mmol), ammonium formate (2.04 g, 32.3 mmol) and 10% palladium on
Figure imgf000125_0001
in methanol (40.2 mL) and ethanol (40.2 mL) was heated under reflux for 1 h. The reaction mixture was filtered through diatomaceous earth to remove the catalyst. After concentration to dryness, the residue was treated with a small amount of methanol (ca. 3 mL) and a precipitate formed. The solid was filtered, rinsed with a small amount of methanol, and collected. Additional material was obtained from Biotage chromatography of the filtrate. This provided (5-amino-lH-pyrrolo [2, 3-c] pyridin-2- yl) (phenyl) methanol (119 mg, 32%) as a white solid: 1H NMR (300 MHz, DMSO- e) 65.81 (IH, s) , 5.94 (IH, s) , 6.44 (IH, s) , 7.27-7.53 (5H, m) , 8.06 (IH, s) , 8.20 (IH, s) , 10.9 (IH, br s); ESI MS m/z 240 [C14H13N30 + H]+; HPLC (Method A) 89.0% (AUC), tR = 14.0 min .
Example 58 fcerfc-Butyl [ [ [phenyl (IH-pyrrolo [2 , 3-σ] pyridin-2- yl) methylene] amino] oxy] acetate
A mixture of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methanone oxime (Example 39) (100 mg, 0.42 mmol) and sodium hydride (17 mg of a 60% in mineral oil, 0.43 mmol) in NrN- dimethylformamide (4 mL) was stirred for 0.5 h. tert-Butyl bromoacetate (60 μL, 0.41 mmol) was added dropwise and the reaction mixture was heated at 60°C for 3 h. After stirring at room temperature for 12 h, the reaction mixture was quenched with water (10 mL) and extracted with diethyl ether (3 x 15 mL) . The combined organic extracts were washed with water (1 25 mL) and brine (1 x 25 mL) , dried over sodium sulfate and concentrated to an oil. Purification by Biotage chromatography (1-10% methanol in methylene chloride) provided tert-butyl [ [ [phenyl (IH-pyrrolo [2, 3-c]pyridin-2-
Figure imgf000126_0001
as a tan solid: mp 47-52°C; XE NMR (500 MHz, CDC13) 6 1.46-1.61 (9H, m) , 4.63 (0.66 H, s) , 4.85 (1.33H, s), 6.37 (0.33H, s) , 6.53 (0.66H, s) , 7.26-7.62 (6H, m) , 8.23-8.28 (0.66H, m) , 8.84 (0.33H, br s) , 8.96 (IH, br s), 9.13 (0.33H, br s) , 11.04 (0.66H, br s) ; ESI MS m/z 352 [C20H2ιN3O3 + H]+; HPLC (Method A) 97.8 % (AUC), tR = 18.3 and 18.5 min .
Example 59
Phenyl (IH-pyrrolo [2 ,3-c]pyridin-2-yl) methanone O- [2- (dimethylamino) ethyl] oxime
Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- [2- (dimethylamino) ethyl] oxime was prepared as a yellow solid following the procedure described for Example 58 using commercially available dimethyl aminoethyl chloride : XE NMR (500 MHz, CD3OD) δ 2.99 (6H, s) , 3.31 (3H,s), 3.68-3.72 (2 H, m) , 7.07 (1 H, s), 7.47-7.63 (5 H, m) , 8.16-8.28 (2H, m) , 9.25 (IH, s); ESI MS m/z 309 [Cι8H20N4O + H] +; HPLC (Method A) 96.8 % (AUC) , tR = 13.3 min.
Example 60 terfc-Butyl 2- [ [ [phenyl (IH-pyrrolo [2 , 3-σ]pyridin-2- yl) methylene] amino] oxy] ethylcarbamate tert-Butyl 2- [ [ [phenyl (IH-pyrrolo [2, 3-c]pyridin-2- yl) methylene] amino] oxy] ethylcarbamate (a mixture of isomers) was prepared as an off white solid following the procedure described for Example 58 using Boc protected 2-aminoethyl chloride: mp 84-88°C; 1H NMR (300 MHz, CDC13) 6 1.46 (9H, br s) , 3.62-3.68 (2H,m), 4.37-4.40 (2 H, m) , 5.00-5.04 (IH, m) , 6.45
Figure imgf000127_0001
m) , 8.24 (IH, d, J = 5.5 Hz) , 9.15 (IH, s ) , 11 . 55 ( IH, br s ) ; ESI MS m/z 381 [ C2ιH24N403 + H] +; HPLC (Method A) 96 . 9 % (AUC) , tR = 18 . 5 min . Example 61
Phenyl (IH-pyrrolo [2 ,3-c]pyridin-2-yl) methanone O- (2- methoxyethyl) oxime Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl)methanone 0- (2- methoxyethyl) oxime was prepared as an orange oil following the procedure described for Example 58 using commercially available 2-chloroethyl methyl ether: 1H NMR (300 MHz, CDC13) δ 3.38 (0.6H, s), 3.54 (2.4H,s), 3.70-3.83 (2 H, m) , 4.35-4.55 (2H, m) , 6.38 (0.2H, s) , 6.53(0.8H, s) , 7.40-7.69 (6H, m) , 8.23-8.25 (1 H, m) , 8.86-8.91 (IH, m) , 9.25 (0.2H, br s) , 10.69 (0.8H, br s) ; ESI MS m/z 296 [Cι7Hι7N302 + H]+; HPLC (Method A) 90.5 % (AUC), tR = 16.4 and 16.6 min. Example 62 and Example 63
Phenyl (IH-pyrrolo [2 ,3-c]pyridin-2-yl)methanone semicarbazone
A mixture of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (Example 35) (108 mg, 0.49 mmol), semicarbazide hydrochloride (57 mg, 0.51 mmol) and potassium carbonate (58 mg, 0.42 mmol) in ethanol (3.0 mL) was refluxed under a nitrogen atmosphere overnight (14 h) . The reaction mixture was cooled to room temperature, water was added, and the reaction mixture was extracted with EtOAc (2χ). The combined organic extracts were dried over Na2S0. After filtration and concentration, the crude material was purified by Biotage chromatography to afford phenyl (IH-pyrrolo [2, 3-c] pyridin-2-
Figure imgf000128_0001
as two isomers, Example 62 (5.3 mg, 4%) and Example 63 (5.9 mg, 4%), as a yellow solid:
Example 62: R NMR (300 MHz, CD3OD) 66.87 (IH, s) , 7.39-7.42 (3H, m) , 7.61-7.64 (2H, m) , 7.72-7.74 (IH, m) , 8.15 (IH, d, J = 5.65 Hz), 8.75 (IH, s) ; ESI MS m/z 280 [C15H13N50 + H]+; HPLC (Method A) 92.1% (AUC), tR = 13.8 min.
Example 63: XH NMR (300 MHz, CD3OD) 66.21 (IH, s) , 7.45-7.50 (3H, m) , 7.62-7.65 (3H, m) , 8.04 (IH, d, J = 5.61 Hz), 8.69 (IH, s); ESI MS m/z 280 [C15H13N50 + H]+; HPLC (Method A) >99% (AUC) , tR = 13.8 min.
Example 64
[ [1- [5- (Dibenzylamino) -IH-pyrrolo [2 ,3-c]pyridin-2- yl] ethylidene] amino] guanidine dihydrochloride
A mixture of 1- [5- (dibenzylamino) -IH-pyrrolo [2, 3- c] pyridin-2-yl] ethanone (Example 56) (91 mg, 0.26 mmol), aminoguanidine hydrochloride (30 mg, 0.27 mmol) and 6 N HCl (0.22 ml) in ethanol (10 mL) was heated to reflux under a nitrogen atmosphere for 1.5 h. The reaction mixture was cooled to room temperature, and the desired product precipitated from the solution. The solid was collected by filtration and rinsed with ethanol. After drying, [ [1- [5- (dibenzylamino) -1H- pyxrolo [2, 3-c] pyridin-2-yl] ethylidene] amino] guanidine dihydrochloride (82 mg, 65%) was obtained as a yellow solid: ESI MS m/z 412 [C24H25N7 + H]+; HPLC (Method A) 94.9% (AUC), tR = 16.5 min.
Example 65 P^^fl' ^ ^iSl^la^ϊig)^-&-pyxrolo [2 ,3-σ]pyridin-2- yl] (phenyl)methylene] amino] guanidine dihydrochloride
A mixture of [5- (dibenzylamino) -IH-pyrrolo [2, 3-c] pyridin- 2-yl] (phenyl) methanone (Example 55) (129 mg, 0.31 mmol), aminoguanidine hydrochloride (36 mg, 0.32 mmol) and 6 N HCl (0.26 mL) in ethanol (10 mL) was heated to reflux under a nitrogen atmosphere for 2.5 h. TLC analysis showed the remaining ketone, therefore additional aminoguanidine hydrochloride (10 mg, 0.09 mmol) was added. The reaction mixture was refluxed until TLC analysis showed the reaction was completed (2 h) . After concentration to dryness, the crude material was triturated with EtOAc. The solid was collected by filtration and dried to provide [[ [5- (dibenzylamino) -1H- pyrrolo [2, 3-c] pyridin-2-yl] (phenyl)methylene] amino] guanidine dihydrochloride (60.6 mg, 36%) as a yellow solid: ESI MS m/z 474 [C29H27N7 + H]+; HPLC (Method A) 89.3% (AUC), tR = 17.5 min.
Example 66
[ [ [Phenyl (IH-pyrrolo [2 , 3-c] pyridin-2- yl) methylene] amino] oxy] acetic acid
[ [ [ Phenyl ( lH-pyrrolo [ 2 , 3-c] pyridin-2- yl) methylene] amino] oxy] acetic acid was prepared by treating tert-butyl [ [ [phenyl (IH-pyrrolo [2 , 3-c] pyridin-2- yl ) ethylene] amino] oxy] acetate (Example 58 ) ( 18 mg, 0 .05 mmol ) with trifluoroacetic acid ( 1 mL) as an off white solid after concentration : mp 68-73°C; ESI MS m/z 296 [Cι6H13N303 + H] +; HPLC (Method A) 98 . 9% (AUC) , tR = 15 . 7 min .
Example 67
Figure imgf000130_0001
aminoethyl) oxime hydrochloride
Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- (2- aminoethyl ) oxime hydrochloride was prepared by treating tert- butyl 2- [ [ [phenyl (IH-pyrrolo [2, 3-c]pyridin-2- yl) methylene] amino] oxy] ethylcarbamate (Example 60) with ethereal hydrogen chloride as an off-white solid (a mixture of isomers) : mp 176-184°C dec; XH NMR (500 MHz, CD3OD) 6 3.22 (2H, br s), 3.37 (2H, br s) , 4.44-4.81 (2H, m) , 6.68 (0.17 H, s) 7.00 (0.83 H, s), 7.37-7.54 (6H, m) , 7.97-8.20 (IH, m) , 8.96 (0.17 H, br s), 9.14 (0.83 H, br s) ; ESI MS m/z 281 [Cι6Hι6N40 + H]+; HPLC (Method A) 98.3% (AUC), tR = 13.0 and 13.2 min. Example 68
1- (IH-Pyrrolo[2 ,3-c]pyridin-2-yl) ethanol
To a solution of IH-pyrrolo [2, 3-c] pyridine-2- carboxaldehyde (0.80 g, 5.47 mmol) in THF (27.4 ml) was slowly added methylmagnesium chloride (22% by weight in THF, 5.0 mL, 15.3 mmol) at 0°C under a nitrogen atmosphere. The ice/water bath was removed, and the reaction mixture was stirred for 45 min. The reaction mixture was quenched with methanol and concentrated to dryness. The solid residue was treated with water (50 mL) and sonicated. The solids were filtered and collected, but they were shown to be undesired material. The water filtrate was concentrated to dryness, treated with 6 N HCl (2.55 mL) and concentrated to dryness again. The resulting orange solid was diluted with EtOAc and treated with saturated NaHC03. The aqueous layer was extracted with EtOAc (3χ) . The combined organic extracts were washed with saturated NaCl and dried over Na2S0. The organic extract was filtered and clinScer -iilS .' o ^© 'l 4 1 - ( 1 H-pyr r olo [ 2 , 3 - c] pyridin-2 - yl) ethanol (0.67 g, 75%) as a tan solid: XE NMR (300 MHz,
CD3OD) 61.59 (3H, d, J = 6.6 Hz), 5.05 (IH, q, J = 6.6 Hz), 6.41 (IH, s), 7.49-7.51 (IH, m) , 8.00 (IH, d, J = 5.6 Hz), 8.60 (IH, s); ESI MS m/z 163 [C9Hι0N2O + H]+; HPLC (Method A) 89.0% (AUC), tR = 9.34 min.
Example 69
Phenyl (IH-pyrrolo [2,3-c]pyridin-2-yl)methanone 0-[2-(4- morpholinyl) ethyl]oxime hydrochloride
A mixture of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone oxime (Example 39) (100 mg, 0.42 mmol) and sodium hydride (17 mg of 60% in mineral oil, 0.43 mmol) in N,N- dimethyl formamide (2 mL) was stirred under a nitrogen atmosphere for 0.5 h. A mixture of N- (2-chloroethyl)morpholine hydrochloride (80 mg, 0.43 mmol) and sodium hydride (17 mg of 60% in mineral oil, 0.43 mmol) in N^N-dimethylformamide was added and the reaction mixture was stirred at room temperature for 38 h. The reaction mixture was poured into stirring cold water (25 mL) and extracted with ethyl acetate (3 * 10 mL) . The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. Purification by Biotage chromatography (1 to 10% methanol in methylene chloride) produced an oil. The oil was dissolved in ethyl acetate (5 mL) and ethereal hydrogen chloride (0.45 mL of a 1 M solution in diethyl ether) was added. The reaction mixture was stirred for 1 h and the precipitate formed. The solvent was decanted and the solid was dried to give phenyl (1H- pyrrolo [2, 3-c] pyridin-2-yl)methanone 0- [2- (4- morpholinyl) ethyl] oxime hydrochloride, a mixture of isomers, as a pale yellow solid: ESI MS m/z 351 [C20H22Ν4O2 + H]+; HPLC
Figure imgf000132_0001
Example 70 1- (IH-Pyrrolo[2 ,3-σ]pyridin-2-yl) ethanone
To a solution of 1- (IH-pyrrolo [2, 3-c]pyridin-2-yl) ethanol (Example 68) (0.65 g, 4.0 mmol) in THF (80 mL) was added manganese dioxide (4.18 g, 48 mmol) . After stirring 2 h at room temperature, TLC analysis indicated that the reaction was completed. The reaction mixture was filtered through diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated and triturated with Et20 to provide 1-(1H- pyrrolo [2, 3-c] pyridin-2-yl) ethanone as an off-white solid: mp 236-242°C dec; XE NMR (300 MHz, CD3OD) 62.63 (3H, s) , 7.34 (IH, s), 7.70-7.73 (IH, m) , 8.13 ( IH, d, J = 5.7 Hz), 8.80 (IH, s) ; ESI MS m/z 161 [C9H8N20 + H]+; HPLC (Method A) 92.7% (AUC), tR = 7.75 min. Example 71
[ [1- (lH-Pyrrolo [2 ,3-σ]pyridin—2-yl) ethylidene] amino] guanidine dihydrochloride A mixture of 1- (IH-pyrrolo [2, 3-c] pyridin-2-yl) ethanone (Example 70) (90 mg, 0.56 mmol) and aminoguanidine hydrochloride (65 mg, 0.59 mmol) in ethanol (5.6 mL) and 6 N HCl (0.47 mL) was heated under reflux for 1.5 h. The reaction mixture was cooled to room temperature and the precipitate was filtered, rinsed with ethanol and diethyl ether, and dried under vacuum at 45°C to provide [ [1- (IH-pyrrolo [2, 3-c] pyridin- 2-yl) ethylidene] amino] guanidine dihydrochloride (138 mg, 86%) as a white solid: mp 314-318°C dec; XE NMR (300 MHz, CD3OD)
Figure imgf000133_0001
s ) , 8.10-8.27 (2H, m) , 9.04 (IH, s) ; ESI MS m/z 217 [Cι0H12N6 + H] +; HPLC (Method A) >99% (AUC ) , tR = 9 . 01 min . Example 72
1- (IH- yrrolo [2 ,3-c]pyridin-2-yl) ethanone oxime
To a solution of 1- (IH-pyrrolo [2, 3-c]pyridin-2- yl) ethanone (Example 70) (0.39 g, 2.42 mmol) and hydroxylamine •HCl (0.34 g, 4.84 mmol) in ethanol (12.1 mL) and water (3.4 ml) was added LiOH (0.31 g, 7.26 mmol) . The reaction mixture was refluxed for 1.0 h, and then the heat was removed. After concentration under reduced pressure, the residue was triturated with water. The solid was collected by filtration, rinsed with water and Et20, and dried under vacuum at 45°C to give 1- (IH-pyrrolo [2, 3-c] pyridin-2-yl) ethanone oxime (0.20 g, 47%) as a yellow solid: XE NMR (300 MHz, CD3OD) 62.26 (3H, s) , 6.78 (IH, s), 7.54-7.57 (IH, m) , 8.03 (IH, d, J = 5.6 Hz), 8.64 (IH, s); ESI MS m/z 176 [C9H9N30 + H]+; HPLC (Method A) >99% (AUC, isomeric ratio = 89.3:10.7), tR = 12.47 (major) and 12.25 (minor) .
Example 73
(5-Chloro-lH-pyrrolo [2 ,3-c]pyridin-2—yl) (phenyl) methanone
(5-Chloro-lH-pyrrolo [2, 3-c]pyridin-2-yl) (phenyl) methanol (Example 140) (105 mg, 0.41 mmol) was dissolved in methylene chloride (10 mL) . Manganese dioxide (358 mg, 4.1 mmol) was added and the reaction mixture was stirred for 60 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed several times with methylene >ciHi""'l"1o1 't.i''. Iα!ef <. Iiu"?Ti'H";i;e■•"f'Ji.l-ftfe F-Tfa""tKe-fti'"was concentrated to give a pmk solid.
Recrystallization from methylene chloride gave (5-chloro-lH- pyrrolo [2, 3-c] pyridin-2-yl) (phenyl)methanone (73 mg, 70%) as a white solid: mp 194-197°C; XE NMR (300 MHz, CDC13) 67.10 (IH, s), 7.51-7.75 (4H, m) , 8.01 (2H, m) , 8.79 (IH, s) , 9.57 (IH, br s ) ; ESI MS m/z 257 [Cι4H9ClN20 + H] +; HPLC (Method A) >99% (AUC) , tR = 21 . 5 min .
Example 74
[ [ (5-Chloro-lH-pyrrolo[2,3-c]pyridin-2- yl) (phenyl)methylene] amino] guanidine dihydrochloride
To a solution of (5-chloro-lH-pyrrolo [2, 3-c] pyridin-2- yl) (phenyl)methanone (Example 73) (65 mg, 0.25 mmol) in ethanol (5 mL) was added aminoguanidine hydrochloride (55 mg, 0.85 mmol) and 6 N HCl (0.2 mL) . The reaction mixture was heated to reflux under N2. After 2 h, heating was terminated and the reaction mixture was cooled to room temperature forming a white precipitate. The precipitate was collected by filtration and dried under vacuum to provide [ [ (5-chloro-lH- pyrrolo [2, 3-c]pyridin-2-yl) (phenyl)methylene] amino] guanidine dihydrochloride (78 mg, 100%) as a white solid: mp 274-278°C; XE NMR (300 MHz, CD30D) 6 6.62 (IH, s) , 7.49-7.58 (2H, m) , 7.68-7.79 (4H, ) , 8.04 (IH, s) , 8.98 (IH, s); ESI MS m/z 313 [Cι5Hι3ClN6 + H]+; HPLC (Method A) >99% (AUC) tR = 16.5 min.
Example 75
1- (lH-Pyrrolo [2 ,3-σ]pyridin-2-yl) ethylamine dihydrochloride
To a heterogeneous solution of 1- ( IH-pyrrolo [2 , 3- c] pyridin-2-yl) ethanone oxime (Example 72 ) ( 0 . 31 g, 1 . 75 mmol )
Figure imgf000135_0001
lithium aluminum hydride (0.33 g, 8.79 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was refluxed for 1 h and then quenched by careful addition of hydrated Na2S0 . Ethyl acetate was added and the reaction mixture was stirred overnight. The solid was filtered off and thoroughly rinsed with EtOAc and EtOH. The filtrate was concentrated to give a yellow oil. The crude residue was dissolved in EtOAc and EtOH (100 mL; 1:1) and 2 M HCl in Et20 was added (1.85 mL) . The precipitate was filtered off, rinsed with EtOAc and Et20, and dried to provide 1-(1H- pyrrolo [2, 3-c]pyridin-2-yl) ethylamine dihydrochloride (0.29 g, 72%) as a light orange solid: mp 289-292°C; XE NMR (300 MHz, CD3OD) 61.82 (3H, d, J = 6.9 Hz), 4.88-4.95 (IH, m) , 7.09 (IH, s), 8.17 (IH, d, J = 6.4 Hz), 8.29 (IH, d, J = 6.4 Hz), 9.13 (IH, s); ESI MS m/z 162 [C9HnN3 + H]+; HPLC (Method A) 97.7% (AUC) , £R = 6.50 min.
Example 76
tert-Butyl 3- [ [ [phenyl (IH-pyrrolo [2 , 3-c]pyridin-2- yl) methylene] amino] oxy]propylcarbamate
A mixture of 1- (IH-pyrrolo [2, 3-c] pyridin-2—yl) ethanone oxime (Example 72) (100 mg, 0.42 mmol) and sodium hydride (18 mg of a 60% in mineral oil, 0.45 mmol) in N,N- dimethylformamide (4 mL) was stirred for 0.5 h. N-Boc chloroprropylamine (86 mg, 0.44 mmol) was added dropwise and the reaction mixture was heated at 60°C for 3 h. After stirring at room temperature for 12 h, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 15 mL) . The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrrated to an oil. Purification by Biotage chromatography i -31 < <§!&§%—etϊlyi ^e te in hexanes) produced tert-butyl 3- [ [ [phenyl (IH—pyrrolo [2, 3-c]pyridin-2- yl) methylene] amino] oxy] propylcarbamate (76 mg, 46%) as a white solid: mp 52-58°C; ESI MS m/z 395 [C22H26N403 + H]+; HPLC (Method A) 98.6% (AUC), tR = 19.2 min.
Example 77
Phenyl (lH-pyarrolo [2 , 3-c]pyridin-2-yl) methanone O- (3- aminopropyl) oxime hydrochloride tert-Butyl 3- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] propylcarbamate (Example 76) (60 mg, 0.15 mmol) was dissolved in methylene chloride (4 mL) and trifluoroacetic acid (1 mL) was added-. The reaction mixture was stirred for 1 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate. Saturated sodium bicarbonate solution was added and the mixture was stirred for 10 min. The layers were separated and the aqueous layer extracted with ethyl acetate (2χ) . The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated to an oil. The oil was dissolved in ethyl acetate (4 mL) , 2 M ethereal hydrogen chloride (0.2 mL) was added and the precipitate formed. Removal of the solvents and drying under vacuum produced phenyl (IH-pyrrolo [2, 3— c] pyridin-2-yl) methanone 0- (3-aminopropyl) oxime hydrochloride, a mixture of isomers (39 mg, 71%) as an off-white solid: mp 168-174°C dec; XE NMR (500 MHz, CD30D) 62.02-2.31 (2H, m) , 2.98-3.27 (2H, ) , 4.47-4.59 (2H, m) , 6.75 (0.24H, s) 7.12 (0.76H, s), 7.47-7.59 (5H, m) , 8.05-8.27 (2H, m) , 8.96 (0.24H, s), 9.13 (0.76H, br s); ESI MS m/z 295 [C17Hι8N40 + H]+; HPLC (Method A) 91.5% (AUC), tR = 14.0 min. 2-Methyl-l- (lH-pyrrolo[2 ,3-c]pyridin-2-yl) -1-propanol lH-Pyrrolo[2, 3-c]pyridine-2-carboxaldehyde (125 mg, 0.86 mmol) was suspended in tetrahydrofuran (5 mL) at -30°C under a nitrogen atmosphere. Isopropylmagnesium bromide in diethyl ether (0.87 mL, 1.74 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature. After stirrin-g for ca. 3 h, the reaction mixture was cooled to -30°C and additional 2.0 M isopropylmagnesium bromide in diethyl ether (0.22 mL, 0.44 mmol) was added. The reaction mixture was stirred for another 1 h, while warming to room temperature . The reaction mixture was poured into a 2 : 1 solution of saturated ammonium chloride and water, and extracted with ethyl acetate (3*) . The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. The crude product was purified by Biotage chromatography (2 to 10% methanol in methylene chloride) to provide 2-methyl-l- (IH-pyrrolo [2, 3-c] pyridin-2-yl) -1-propanol (86 mg, 53%) as a white solid: mp 140-144°C; XH NMR (500 MHz, CD3OD) 60.99 (6H, m) , 2.01—2.25 (IH, m) , 4.57-4.65 (IH, m) , 6.38 (IH, s), 7.51 (IH, s) , 8.00 (IH, s) , 8.63 (lH,s); ESI MS m/z 191 [C11H14N2O + H]+; HPLC (Method A) >99% (AUC), tR = 13.1 min.
Example 79
3-Methyl-l- (IH-pyrrolo [2 ,3-σ]pyridin-2-yl) -1-butanol
3-Methyl-l- (IH-pyrrolo [2, 3-c] pyridin-2-yl) -1-butanol (101 mg, 58%) was prepared as an off-white solid following the procedure described for Example 78 using commercially FT. ψ '" "if" ,.'' if IE I!","' ."'It ΪC-" . ' ,- -f !!'"" ""'j' "j| r avail - ϊe'iHE «M' rsobu'tylmagnesium b-romide m diethyl ether: mp 182-189°C dec; i 1H NMR (300 MHz, CDC13) 60.97-1.00 (6H, m) , 1.72-1.89 (3H, m) , 5.03-5.07 (IH, m) , 6.35 (IH, s) , 7.44 (IH, d, J = 5.5 Hz), 8.16-88.18 (IH, dr J = 5.5 Hz), 8.62 (IH, s) ; ESI MS m/z 205 [Cι2Hι6N20 + H]+; HPLC (Method A) >99% (AUC), tR = 14.4 min.
Example 80 2 -Methyl- 1 - ( IH-pyrrolo [ 2 , 3 - σ] pyriciin- 2 -yl ) - 1 -propanone
2-Methyl-l- (IH-pyrrolo [2, 3-c] pyridin-2-yl) -1-propanol (Example 78) (75 mg, 0.39 mmol) was dissolved in methylene chloride (10 mL) . Manganese dioxide (343 mg, 3.94 mmol) was added and the reaction mixture was stirred for ca. 14 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed several times with hot methanol. The filtrate was concentrated to give a white solid. Drying under vacuum produced 2 -methyl- 1- (IH-pyrrolo [2, 3-c] pyridin-2- yl)-l-propanone (64 mg, 88%) as a white solid: mp 224-228°C; lE NMR (500 MHz, CD3OD) 61.26 (6H, d, J = 7.0 Hz), 3.45-3.62 (IH, m) , 7.37 (IH, s), 7.72-7.74 (IH, rti) , 8.14 (IH, d, J = 6.0 Hz), 8.82 (IH, s); ESI MS m/z 189 [CιιHι2 20 + H]+; HPLC (Method A) 95.4% (AUC), tR = 13.7 min.
Example 81
3-Methyl-l- (IH-pyrrolo [2 ,3-c]pyri iin-2-yl) -1-butanone 3-Methyl-l- (IH-pyrrolo [2, 3-c] pyridin-2-yl) -1-butanone (69 mg, 78%) was prepared as a yellow solid following the procedure described for Example 80 using 3-methyl-l- (IH- pyrrolo [2, 3-c]pyridin-2-yl) -1-butanol (Example 79): mp 215- ^iΪ8^C;^^ ^-'(9foθ'«MH ^,CD3θD) 61.03 (6H, d, J = 6.6 Hz), 2.22- 2.37 (IH, m) , 2.88-2.91 (2H, ) , 7.04 (IH, s) , 7.71-7.73 (IH, m) , 8.13 (IH, d, J = 5.7 Hz), 9.91 ( IH, s) ; ESI MS m/z 203 [Cι2Hι4N20 + H]+; HPLC (Method A) >99?s (AUC), tR = 15.0 min.
Example 82
N- [1- (lH-Pyrrolo [2 , 3-c] pyridin- 2-yl) ethyl] nicotinamide dihydrochloride
A mixture of 1- (IH-pyrrolo [2, 3-c] pyridin-2-yl) ethylamine dihydrochloride (Example 75) (74 mg 0.32 mmol), nicotinic acid (41 mg, 0.33 mmol), diisopropylethylamine (0.28 mL, 0.38 mmol), EDCI (73 mg, 0.38 mmol) and dimethylaminopyridine (catalytic amount) in methylene chloride (2.8 mL) was stirred under a nitrogen atmosphere overnighit (18 h) . The reaction mixture was diluted with EtOAc and extracted with 1 N HCl . The acidic extracts were washed with EtOAc, and then made basic with 15% NaOH. The aqueous layer was extracted with CH2C12 (3*) The combined extracts were dried over Na2S04. Filtration and concentration gave a crude yellow o l. Initial purification by Biotage chromatography (KP-NH silica) provided an impure product. The mixture was dissolved in EtOH and 2.0 M HCl in Et20 (0.34 mL) was added. The mixtu-ι-.e was concentrated and then crystallized from acetone/methanol (9:1) to provide N-[l- (IH-pyrrolo [2, 3-c] pyridin-2-yl) ethyl] nicotinamide dihydrochloride (12 mg, 11%) as a light yellow solid: 1H ΝMR (300 MHz, CD3OD) δ3.64 (3H, d, J = 7.1 Hz), 5.65 (IH, q, J = 7.0 Hz), 6.98 (IH, s) , 8.03-8.20 (3H, m) , 8.94-9.02 (3H, m) , 9.34 (IH, s); ESI MS m/z 267 [Cι5Hι4Ν40 + H] +; HPLC (Method A) >99% (AUC), tR = 9.19 min. t""tt ttmr' "."" it iliπ jϊ"(. '^'"' ,''■' "t! "it iϊTwft "ϊ"1
""Exaϋnpie^ "'83'* «™* <■' ""'" ™u" '""' ™' *
3-Phenyl-l- (IH-pyrrolo [2 , 3-c] pyridin-2-yl) propan-l-ol 3-Phenyl-l- (IH-pyrrolo [2, 3-c] pyridin-2 -yl) propan-1-ol (150 mg, 69%) was prepared as a white solid following the procedure described for Example 78 using commercially available 1 M phenethylmagnesium chloride in tetrahydrofuran: mp 162-166°C; ESI MS m/z 253 [C16Hι6N20 + H] +; HPLC (Method A) 98.9% (AUC), tR = 16.2 min.
Example 84
(lH-Pyrrolo [2 , 3-c] pyridin-2-yl) methylamine di_h.ydrochloride
Following the procedure described for Example 75, IH- pyrrolo [2, 3-c] pyridine-2-carboxaldehyde oxime (Example 44) was reduced to provide (IH-pyrrolo [2, 3-c] pyridin-2 -yl) methylamine dihydrochloride (1.0 g, 80%) as a tan solid: mp 302-303°C; """H NMR (300 MHz, CD3OD) 64.56 (2H, s) , 7.12 (IH, s), 8.16 (IH, d, J = 6.4 Hz), 8.28 (IH, d, J = 6.4 Hz), 9.16 ( H, s) ; ESI MS m/z 148 [C8H9N3 + H]+; HPLC (Method A) >99% (AUC), tR = 5.20 min.
Example 85
2-Phenyl-l- (IH-pyrrolo [2 ,3-c]pyridin-2-yl) ethsmol
2-Phenyl-l- (IH-pyrrolo [2, 3-c] pyridin-2-^1) ethanol (32 mg, 17%) was prepared as a yellow solid following the procedure described for Example 78 using commercially a/ailable 1 M benzylmagnesium chloride in diethyl ether: mp 169-172°C dec; XE NMR (500 MHz, CD3OD) 63.12-3.22 (2H, m) , 5.O8-5.10 (IH, m) , 6.35 (IH, s), 7.15-7.23 (5H, m) , 7.49 (IH, d, J = 5.5 Hz), •i"'rJ"" 'T' -' u " f 9*9*
Figure imgf000141_0001
) , 8 . 60 ( IH, s ) ; ESI MS m/z 239 [Cι5H14N20 + H] +; HPLC (Method A) 96 . 7 % (AUC) , s = 14 . 8 min .
Example 86 tert-Butyl [2- [ N- [1- (IH-pyrrolo [2 , 3-c] pyridin- 2- yl) ethyl] carbamoyl] ethyl] carbamate
A mixture of 1- (lH-pyrrolo[2, 3-c] pyridin -2-yl) ethylamine dihydrochloride (Example 75) (108 mg, 0.46 mmol), N-Boc-β- alanine (71 mg, 0.37 mmol), diisopropylethylamlne (0.31 mL, 1.85 mmol), EDCI (78 mg, 0.41 mmol) and HOBt (catalytic amount) in methylene chloride (2.2 mL) was sti red at room temperature under a nitrogen atmosphere overnight (22 h) . The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in CH2C12, washed with water and saturated ΝaHC03, and dried over Na2S04. Filtration and concentration provided tert-butyl [2- [N- [1 - (1H- pyrrolo [2, 3-c] pyridin-2-yl) ethyl] carbamoyl] ethyl] carbamate (70 mg, 58%) as a tan solid: XH NMR (500 MHz, CD30-D) 61.45 (9H, s) , 1.63 (3H, d) , 2.37-2.51 (2H, m) , 3.30-3.42 (2K, m) , 5.26-5.35 (IH, ) , 6.43 (IH, s) , 7.48-7.51 (IH, m) , 7.99-8.05 (IH, m) , 8.60 (IH, s); ESI MS m/z 333 [Cι7H24N403 + H]+; HPLC (Method A) 95.9% (AUC), tR = 14.39 min.
Example 87 tert-Butyl [ [ N- [1- (lH-pyrrolo [2 , 3-c] pyridin-2- yl) ethyl] carbamoyl] methyl] carbamate
Following the procedure described for Example 86, tert- butyl [ [N- [1- (IH-pyrrolo [2, 3-c] pyridin-2- yl) ethyl] carbamoyl] methyl] carbamate (0.15 g, quantitative) was ir'tt ij"'" "'if ,." i[ ii . ιτ.[ !!;;;," .. * --B »B tr,",""-,i( ••« prep'έ.t'ed™1,a«s"",'&' l'-L^h ,t«ye'-lιlow solid using N-Boc-glycme (81 mg, 0.46 mmol) : lE ΝMR (300 MHz, CD3OD) 61.45 (9H, s) , 1.61 (3H, d, J = 7.0 Hz), 3.75 (2H, s) , 5.33 (IH, q, J = 7.0 Hz), 6.45 (IH, s), 7.48-7.51 (IH, m) , 8.00 (IH, d, J = 5.6 Hz), 8.58 ( IH, s) ; ESI MS m/z 319 [Cι6H22Ν403 + H]+; HPLC (Method A) 97.5% (AUC), tR = 14.08 min.
Example 88 N- (lH-Pyrrolo [2 ,3-c]pyridin-2-ylmethyl) nicotinamide dihydrochloride
A mixture of (IH-pyrrolo [2, 3-c] pyridin-2-yl) methylamine dihydrochloride (Example 84) (110 mg, 0.50 mmol), nicotinic acid (62 mg, 0.50 mmol), diisopropylethylamme (0.44 mL, 2.5 mmol), EDCI (110 mg, 0.55 mmol) and HOBt (cat.) in methylene chloride (2.9 mL) and DMF (3 mL) was stirred at room temperature under a nitrogen atmosphere overnight (18 h ) . The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water. The water layer was concentrated to dryness. The residue was dissolved in ethanol (10 mL) and 2 N HCl in Et20 (10 mL) was added. Methanol (ca. 5 mL) was added to dissolve the majority of material. The remaining brown precipitate was filtered off and discarded. The filtrate was concentrated, and the resulting solid was triturated with EtOH (ca. 4 mL) , filtered, and dried to provide N- (IH-pyrrolo [2, 3-c] pyridin-2-ylmethyl) nicotinamide dihydrochloride (31 mg, 19%) as a tan solid: ^Η NMR (5O0 MHz, CD3OD) 64.99 (2H, s), 7.00 (IH, s) , 8.03 (IH, d, J = 6.0 Hz), 8.17-8.24 (3H, m) , 8.77 (IH, s) , 9.04-9.12 (3H, m) , 9.38 (IH, s); ESI MS m/z 253 [Cι4H12N40 + H]+; HPLC (Method A) >99% (AUC), tR = 7.78 min.
Figure imgf000143_0001
3-Phenyl-l- (lH-pyrrolo[2,3-c]pyridin-2-yl)propan-l-one 3-Phenyl-l- (IH-pyrrolo [2, 3-c] pyridin-2-yl) propan-1-one (98 mg, 72%) was prepared as a yellow solid following the procedure described for Example 80 using 3-phenyl-l- (IH- pyrrolo [2, 3-c]pyridin-2-yl)propan-l-ol (Example 83): mp 246- 250°C; E NMR (500 MHz, DMSO-d6) 63.00 (2H, t, J = 7.6 Hz), 3.87 (2H, t, J = 7.6 Hz), 7.16-7.19 (IH, m) , 7.25-7.32 (4H, ) , 7.43 (IH, s), 7.65 (IH, d, J = 5.5 Hz), 8.17 (IH, d, J = 5.5 Hz), 8.84 (IH, s), 12.18 (IH, s) ; ESI MS m/z 251 [Cι6Hι4N20 + H]+; HPLC (Method A) >99% (AUC), tR = 16.4 min. Example 90 tert-Butyl 3- [ [ [phenyl (IH-pyrrolo [2 ,3-c]pyridin-2- yl)methylene] amino] oxy]pyrrolidine-l-carboxylate To a mixture of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (Example 35) (90 mg, 0.40 mmol) and tert-butyl 3- (aminooxy)pyrrolidine-l-carboxylate (Reference Example 9) (82 mg, 0.40 mmol) in isopropanol (6 mL) was added 4 A molecular sieves. The pH of the solution was adjusted to pH 4-5 with glacial acetic acid. The reaction mixture was heated to reflux. After 3 days, the reaction mixture was cooled to ambient temperature. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. Purification by column chromatography (silica gel, 9.75:0.25 CH2Cl2/MeOH to 9.5:0.5 CH2Cl2/MeOH) followed by ion-exchange chromatography (SCX-2, 1:3 7 N NHOH in MeOH/MeOH) gave tert-butyl 3- [ [ [phenyl (IH-pyrrolo [2, 3- c]pyridin-2-yl)methylene] amino] oxy]pyrrolidine-l-carboxylate P'i'521'3 S&f ) ; l" "31 "ϊi±tture of isomers: mp 80-82°C; XH NMR (500 MHz, DMSO-d6) major isomer δ 1.37-1.39 (9H, m) , 2.08-2.10 (2H, m) , 3.13-3.17 (IH, m) , 3.31-3.50 (3H, m) , 4.92 (IH, br s), 6.23 (IH, s), 7.41-7.53 (6H, m) , 8.08 (IH, d, J = 5.4 Hz), 8.79 (IH, s), 11.85 (IH, s) ; ESI MS m/z 407 [C23H26N403 + H]+; HPLC (Method A) 85.8% (AUC), tR = 18.0 min.
Example 91 Phenyl (IH-pyrrolo [2,3-σ]pyridin-2-yl) methanone O-pyrrolidin-3- yloxime dihydrochloride
Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- pyrrolidin-3-yloxime dihydrochloride (12.3 mg, 33%) was prepared as an off-white amorphous solid from tert-butyl 3- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] pyrrolidine-1-carboxylate (Example 90) following the procedure described for Example 77, except 1:1 trifluoroacetic acid/CH2Cl2 was used: XE NMR (500 MHz, CD3OD) major isomer δ 0.94-0.92 (IH, m) , 2.33-2.35 (IH, m) , 3.26-3.27 (IH, m) , 3.33-3.34 (IH, m) , 3.45-3.46 (IH, m) , 3.58-3.60 (IH, m) , 3.70-3.72 (IH, m) , 5.23-5.24 (IH, m) , 6.78 (IH, s) , 7.53- 7.57 (5H, m) , 8.08 (IH, d, J = 6.4 Hz), 8.22 (IH, d, J = 6.5 Hz), 9.01 (IH, s); ESI MS m/z 307 [Cι8Hι8N40 + H]+; HPLC (Method A) 96.6% (AUC), tR = 12.6 min.
Example 92
[ [2-Methyl-1- (IH-pyrrolo [2 , 3-c]pyridin-2- yl)propylidene] amino] guanidine dihydrochloride
To a solution of 2-methyl-l- (lH-pyrrolo[2, 3-c] pyridin-2- yl) -1-propanone (Example 80) (100 mg, 0.53 mmol) in ethanol (5
Figure imgf000145_0001
hydrochloride (58 mg, 0.53 mmol) and 6 N HCl (0.2 mL) . The reaction mixture was heated to reflux under N2. After 2 h, heating was terminated and the reaction mixture was cooled to room temperature. Purification by column chromatography (silica gel, 5 to 20% methanol in methylene chloride) produced [ [2-methyl-l- (IH-pyrrolo [2, 3- c] pyridin-2-yl) propylidene] amino] guanidine dihydrochloride (28 mg, 26%) as a yellow solid: mp 242-245°C; XH NMR (500 MHz, CD3OD) 6 1.49 (6H, d, J = 7.1 Hz), 3.50-3.54 (IH, m) , 7.15 (IH, s), 7.72 (IH, d, J = 5.5 Hz), 8.11 (IH, d, J = 5.6 Hz), 8.77 (IH, s); ESI MS m/z 245 [Cι2H16N5 + H] +; HPLC (Method A) >99% (AUC) tR = 11.9 min.
Example 93
[ [3-Phenyl-l- (IH-pyrrolo [2,3-c]pyridin-2- yl) propylidene] amino] guanidine dihydrochloride
[ [3-Phenyl-l- (IH-pyrrolo [2, 3-c] pyridin-2- yl) propylidene] amino] guanidine dihydrochloride (18 mg, 22%) was prepared as a yellow solid following the procedure described for Example 92 from 3-phenyl-l- (lH-pyrrolo[2, 3- c]pyridin-2-yl)propan-l-one (Example 89) (60 mg, 0.24 mmol): αH NMR (500 MHz, CD30D) 6 3.00-3.04 (2H, m) , 3.19-3.22 (2H, m) , 7.03 (IH, s), 7.14-7.17 (IH, m) , 7.23-7.29 (4H, m) , 7.77 (IH, m) , 8.13 (IH, br s), 8.80 (IH, br s) ; ESI MS m/z 307 [Cι7Hι8N6 + H]+; HPLC (Method A) >99% (AUC) tR = 13.4 min.
Example 94
[ [3-Methyl-l- (lH-pyrrolo[2, 3-c]pyridin-2- yl) butylidene] amino] guanidine dihydrochloride
Figure imgf000146_0001
[2, 3-c] pyridin-2 - yl)butylidene] amino] guanidine dihydrochloride (27 mg, 34%) was prepared as a white solid following the procedure described for Example 92 from 3-methyl-l- (IH-pyrrolo [2, 3-c]pyridin-2- i yl) -1-butanone (Example 81) (54 mg,0.27 mmol) : mp 232-236°C; XE NMR (300 MHz, CD3OD) δ 1.06 (6H, d, J = 6.5 Hz), 2.14-2.23 (IH, m) , 2.86 (2H, d, J = 7.7 Hz), 7.40 (IH, s) , 8.13-8.25 (2H, m) , 9.06 (IH, s); ESI MS m/z 259 [Cι3H18N6 + H]+; HPLC (Method A) >99% (AUC) tR = 13.4 min.
Example 95
Phenyl (IH-pyrrolo[2 ,3-c]pyridin-2-yl)methanone O- (2- aminoethyl) oxime hydrochloride
One of the isomers of tert-butyl 2- [[ [phenyl (1H- pyrrolo [2, 3-c] pyridin-2-yl)methylene] amino] oxy] ethylcarbamate (Example 60) (81 mg, 0.21 mmol) was separated and dissolved in ethyl acetate (4 mL) . Trifluoroacetic acid (4 mL) was added and the reaction mixture was stirred for 14 h. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate. Saturated sodium bicarbonate solution was added to the stirring solution. After 15 min, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL) . The combined organic layers were washed with water and then brine, dried over sodium sulfate and the solvent was removed under vacuum to ca. 5 mL. Ethereal hydrogen chloride (0.9 mL of a 1 M solution) was added, and the solution was stirred under a nitrogen atmosphere. The solvent was removed under vacuum to give the isomerically pure phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- (2- aminoethyl) oxime hydrochloride (geometry of the oxime double bond was not defined) (25 mg, 78% yield) as a white solid: mp
Figure imgf000147_0001
MHz, CD3OD) 6 3.46 (2H, t, J = 5.1 Hz), 4.64 (2H, t, J = 5.1 Hz), 7.12 (IH, s) , 7.48-7.62 (5H, m) , 8.17 (IH, d, J = 6.5 Hz), 8.27 (IH, d, J = 6.5 Hz), 9.19 (IH, s) ; ESI MS m/z 281 [Cι6Hι6N4θ3 + H]+; HPLC (Method A) >99% (AUC) tR = 12.5 min.
Example 96
Phenyl (lH-pyrrolo [2 ,3-c]pyridin-2-yl) methanone O- (2- aminoethyl) oxime bis (hydrogen trifluoroacetate)
The other isomer of tert-butyl 2- [[ [phenyl (1H- pyrrolo [2, 3-c] pyridin-2-yl)methylene] amino] oxy] ethylcarbamate (Example 60) (27 mg, 0.07 mmol), containing a small amount of the isomer used in Example 95, was dissolved in methylene chloride (1 mL) . Trifluoroacetic acid (1 mL) was added and the reaction mixture was stirred for 3 h. The solvent was removed under vacuum. Preparative HPLC [Synergi column, 10 to 100% acetonitrile in water (0.05% TFA added)] produced phenyl(lH- pyrrolo [2, 3-c] pyridin-2-yl)methanone 0- (2-aminoethyl) oxime bis (hydrogen trifluoroacetate) as an off-white solid with a 84:16 isomeric ratio: 1H NMR (500 MHz, CD3OD) 6 3.40-3.44 (2H, m) , 4.51-4.54 (2H, m) , 6.79 (IH, s) , 7.56 (5H, s) , 8.06 (IH, d, J = 6.4 Hz), 8.20-8.22 (IH, m) , 8.98 (IH, s) ; ESI MS m/z 281 [C16H16N4θ3 + H]+; HPLC (Method A) 83.4% (AUC) tR = 13.0 min.
Example 97
Phenyl (IH-pyrrolo [2 , 3-σ]pyridin-3-yl) methanol
A mixture of IH-pyrrolo [2, 3-c] pyridine-3-carboxaldehyde (1O0 mg, 0.68 mmol) and THF (6.8 mL) was cooled to -40°C and phenylmagnesium chloride (0.68 mL, 1.36 mmol) was added. The Bfui? I?- i| α r.f'ji 'K"J: .■ -j; »u ic """* "if r -'eabtrόn"l'mτxτ:tι,e",(wai,sml'warmed to room temperature and refluxed for 1 h.. The reaction mixture was cooled to room temperature and quenched with saturated NH4C1 and then water was added. The aqueous layer was extracted with EtOAc (1*), dried (MgS0) and filtered, and the solvent was removed. The crude material was purified by Biotage chromatography (90:10 to 85:15 methylene chloride/methanol) to give phenyl (IH-pyrrolo [2, 3- c]pyridin-3-yl) methanol as a yellow solid (65.5 mg, 43%): Rf 0.11 (90:10 methylene chloride/methanol) ; XE NMR (300 MHz, CD30D) δ 6.09 (IH, s), 7.25-7.27 (IH, m) , 7.32-7.35 (3H, m) , 7.46-7.48 (3H, m) , 7.96-7.97 (IH, d, J = 5.6 Hz), 8.64 (IH, s ) ; ESI MS m/z 225 [Cι4H12N20+ H] +; Estimated Purity: >90% by XE NMR analysis . Example 98
(4-Meth.ylph.enyl) (lH-pyrrolo [2 ,3-c]pyridin-2-yl)methanol
IH-pyrrolo [2, 3-c] pyridine-2-carboxaldehyde (180 mg, 1.23 mmol) was dissolved in tetrahydrofuran (6 mL) under a nitrogen atmosphere. p-Tolylmagnesium bromide in tetrahydrofuran (2.48 mL, 2.48 mmol) was added dropwise. After stirring for 3 h, the reaction mixture was quenched by pouring into a 2:1 solution of saturated ammonium chloride and water, then extracted with ethyl acetate (2 20 mL) . The combined organic extracts were washed with water and then brine, dried over sodium sulfate, and concentrated to provide the crude material. Purification by Biotage chromotography (silica, 0 to 18% methanol in methylene chloride) to provide (4-methylphenyl) (1H- pyrrolo [2, 3-c] pyridin-2-yl)methanol (226 mg, 77%) as an off- white solid: mp 78-82°C; XH NMR (500 MHz, CD3OD) 62.32 (3H, s) , 5.95 (IH, s), 6.36 (IH, s) , 7.17 (2H, d, J = 7.9 Hz), 7.34 (2H, d, 8.0 Hz), 7.51 (IH, m) , 8.00 (IH, d, J = 5.6 Hz), 8.59 (IH,
Figure imgf000149_0001
+ H]+; HPLC (Method A) >99% (AUC), tR = 15.1 min.
Example 99
(4-Methoxyphenyl) (IH-pyrrolo [2 , 3-c] pyridin-2-yl) methanol
(4-Methoxyphenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanol (101 mg, 32%) was prepared as an off-white solid following the procedure described for Example 98 using commercially available 4-methoxyphenylmagnesium bromide in tetrahydrofuran: mp 183-185°C dec; E NMR (500 MHz, CD3OD) 63.78 (3H, s) , 5.94 (IH, s), 6.35 (IH, s), 6.90-6.92 (2H, ) , 7.35-7.38 (2H, m) , 7.48-7.50 (IH, m) , 7.95-8.00 (IH, m) , 8.59 (IH, s) ; ESI MS m/z 255 [Cι5H14N202 + H]+; HPLC (Method A) >99% (AUC), tR = 14.6 min.
Example 100 (4-Methylphenyl ) (IH-pyrrolo [2 , 3-c] pyridin-2-yl) methanone
(4-Methylphenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanol (Example 98) (225 mg, 0.94 mmol) was dissolved in methylene chloride (15 mL ) . Manganese dioxide (817 mg, 9.40 mmol) was added and the reaction mixture was stirred for ca. 14 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed several times with hot ethanol. The filtrate was concentrated to give a white solid. Drying under vacuum produced (4-methylphenyl) (IH-pyrrolo [2, 3-c]pyridin-2- yl)methanone (149 mg, 67%) as a white solid: mp 264-268°C dec; XH NMR (3O0 MHz, CD3OD) 62.47 (3H, s) , 7.18 (IH, s), 7.41 (2H, d, J = 7.9 Hz), 7.73-7.75 (IH, m) , 7.92 (2H, d, J = 8.1 Hz), 8.16 (IH, d, J = 5.6 Hz), 8.87 (IH, s) ; ESI MS m/z 237 [Cι5Hι2N20 + H]+; HPLC (Method A) 93.4% (AUC), tR = 15.9 min. SB±
Example 101
(4-Chlorophenyl) (IH-pyrrolo [2 ,3-c]pyridin-2-yl) methanol
(4-Chlorophenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanol (174 mg, 55%) was prepared as a white solid following the procedure described for Example 98 using commercially available 4-chlorophenylmagnesium bromide in diethyl ether: mp 176-180°C; XE NMR (500 MHz, CD3OD) 65.99 (IH, s) , 6.36 (IH, s) , 7.35-7.37 (2H, m) , 7.45-7.51 (3H, m) , 8.00 (IH, d, J = 5.6 Hz), 8.59 (IH, s); ESI MS m/z 259 [Cι Hn C1N20 + H]+; HPLC (Method A) 97.9% (AUC), tR = 15.5 min.
Example 102
(4-Methoxyphenyl) (IH-pyrrolo [2 , 3-c] pyridin-2-yl) methanone
(4-Methoxyphenyl ) ( IH-pyrrolo [2, 3-c] pyridin-2-yl ) ethanone (87 mg, 99%) was prepared as an off-white solid following the procedure described for Example 100 using (4- methoxyphenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanol (Example 99) and tetrahydrofuran as a solvent: mp 225-228°C; XE NMR (300 MHz, CD30D) 63.92 (3H, s) , 7.10-7.19 (3H, m) , 7.75-7.76 (IH, m) , 8.02-8.06 (2H, m) , 8.16 (IH, d, J = 5.6 Hz), 8.86 (IH, s) ; ESI MS m/z 253 [Cι5Hι2N202 + H]+; HPLC (Method A) >99% (AUC), tR = 15.3 min.
Example 103
(4-Chlorophenyl) (IH-pyrrolo [2 , 3-c]pyridin-2-yl) methanone
(4-Chlorophenyl) (IH-pyrrolo [2, 3-c] pyridin-2 -yl) methanone ^J" irø*''πi^,^?&f%,,)'''''^s!^-?^ fe.red as a yellow solid following the procedure described for Example 100 using (4-chlorophenyl) (1H- pyrrolo [2, 3-c] pyridin-2-yl) methanol (Example 101) and tetrahydrofuran as a solvent: mp 274-277°C dec; XE NMR (300 MHz, CD3OD) 67.21 (IH, s), 7.60-7.63 (2H, m) , 7.73-7.76 (IH, m) , 7.99-8.03 (2H, m) , 8.16 (IH, d, J = 5.6 Hz), 8.88 (IH, s) ; ESI MS m/z 257 [C14H9C1N20 + H] + ; HPLC (Method A) >99% (AUC), tR = 16.3 min . Example 104 and Example 105
Phenyl (IH-pyrrolo [2 ,3-c]pyaridin-2-yl) methanone O-piperidin-4- yloxime dihydrochloride A mixture of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (Example 35) (300 mg, 1.34 mmol) and tert-butyl 4- (aminooxy) piperidine-1-carboxylate (Reference Example 10) (289 mg, 1.34 mmol) in EtOH (30 mL) was adjusted to pH 4-5 with HCl (1.9 mL of a 1 N HCl solution in diethyl ether, 1.9 mmol) . The reaction mixture was heated to reflux. After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated NaHC03. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (Na2S04) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 98: 2 CH2Cl2/MeOH to 95: 5 CH2Cl2/MeOH) gave tert- butyl 4- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] piperidine-1-carboxylate (120 mg, 23%) as a white amorphous solid (geometry of the oxime double bond undefined) .
Isomer A (30 mg, 5%) : XE NMR (500 MHz, DMSO- s) 6 1.39 (9H, s) , 1.52-1.61 (2H, m) , 1.90-1.94 (2H, m) , 3.18-3.26 (2H, m) , 3.49-
Figure imgf000152_0001
(IH, m) , 6.19 (IH, s) , 7.44-7.64 (6H, m) , 7.97 (IH, d, J = 6.8 Hz) , 8.78 (IH, s) , 11.80 (IH, br s) .
Isomer B (175 mg, 31%) : XH NMR (500 MHz, DMSO-d5) 6 1.38 (9H, s), 1.70-1.77 (2H, m) , 1.98-2.02 (2H, m) , 3.10-3.12 (2H, m) , 3.72-3.75 (2H, m) , 4.43-4.46 (IH, m) , 6.76 (IH, s) , 7.45-7.62 (6H, m) , 8.13 (IH, d, J = 5.4 Hz), 8.86 (IH, s) , 11.51 (IH, br s) . Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone O- piperidin-4-yloxime dihydrochloride was prepared from tert- butyl 4- [ [ [phenyl (IH-pyrrolo [2, 3 — c] pyridin-2- yl) methylene] amino] oxy] piperidine-1-carboxylate (Isomer A) following the procedure described for Example 95 (24.9 mg, 98%) as a white solid (geometry of the oxime double bond undefined) .
Example 104: mp 240-245°C dec; XE NMR (500 MHz, DMSO-dg) δl.90-1.98 (2H, m) , 2.16-2.20 (2H, m) , 3.00-3.10 (4H, m) , 4.57- 4.61 (IH, m) , 6.69 (IH, s) , 7.53-7.58 (5H, m) , 8.07 (IH, d, J = 6.3 Hz), 8.30 (IH, d, J = 6.3 Hz), 8.88 (IH, br s) , 9.02 (IH, s), 9.18 (IH, br s), 13.06 (IH, s), 15.33 (IH, br s) ; ESI MS m/z 321 [Cι9H20N4O + H] +; HPLC (Method A) 99.0% (AUC), tR = 13.6 min.
Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- piperidin-4-yloxime dihydrochloride was prepared from tert- butyl 4- [ [ [phenyl (IH-pyrrolo [2, 3—c]pyridin-2- yl) methylene] amino] oxy] piperidine-1-carboxylate (Isomer B) following the procedure described for Example 95 (32.0 mg, 21%) as a white solid (isomer of Example 104, geometry of the oxime double bond undefined) . ^*^«3--φiy^δfe^*',π r4 )«ϊ^:l50C dec; XH NMR (500 MHz, DMSO-d6) δ 2.00-2.05 (2H, m) , 2.16-2.20 (2H, m) , 3.04-3.07 (2H, m) , 3.18- 3.22 (2H, m) , 4.58-4.61 (IH, m) , 7.17 (IH, s) , 7.48-7.56 (5H, m) , 8.19 (IH, d, J = 6.3 Hz), 8.35 (IH, d, J = 6.4 Hz), 8.89 5 (IH, br s), 9.02 (IH, br s) , 9.22 (IH, s) , 13.11 (IH, s) , 15.25 (IH, br s) ; ESI MS m/z 321 [C19H20N4O + H] +; HPLC (Method A) 94.1% (AUC), tR = 13.6 min.
Example 106 10 Phenyl (IH-pyrrolo [2 , 3-c]pyridin-2-yl) methanone O- [2- (isopropylamino) ethyl] oxime dihydrochloride
Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- [2- -25 (isopropylamino) ethyl] oxime dihydrochloride was prepared from tert-butyl [2- (aminooxy) ethyl] isopropylcarbamate (Reference Example 17) following the procedure described for Example 128 and Example 131 (318 mg, 33%) as a mixture of isomers (74.5:25.5 by HPLC analysis): E NMR (500 MHz,CD3OD) 6 1.31 20 (1.5H, d, J = 6.5 Hz), 1.37 (4.5H, d, J = 6.5 Hz), 3.32-3.36 (3H, ) , 4.61 (0.5H, t, J = 5.0 Hz), 4.70 (1.5H, t, J = 5.0 Hz), 6.78 (0.25H, s) , 7.06 (0.75H, s) , 7.48-7.63 (5H, m) , 8.07 (0.25H, d, J = 6.3 Hz), 8.17 (0.75H, d, J = 6.3 Hz), 8.23 (0.25, d, J = 6.3 Hz), 8.25 (0.75, d, J = 6.3 Hz), 9.04 (0.25H, 25 s), 9.27 (0.75H, s) ; ESI MS m/z 323 [Cα9H22N40 + H]+; HPLC (Method A) >99% (AUC), tR = 13.7 and 14.0 min.
Example 107 and Example 108
30 Phenyl (IH-pyrrolo [2 , 3-c]pyridin-2-yl) methanone O-piperidin-3- yloxime dihydrochloride tert-Butyl 3- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- f-'yi^met y^^ was prepared from phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone (Example 35) and tert-butyl 3- (aminooxy) piperidine-1-c-arboxylate (Reference Example 11) following the procedure described for Example 104 (geometry of the oxime double bond, undefined) .
Isomer A. (84 mg, 14%) : XE NMR (500 MHz, DMSO-d6) δ 1.06-1.49 (12H, m) , 1.74-1.88 (2H, m) , 2.94-3.03 (0.5H, m) , 2.49-2.50 (0.5H, rα) , 3.58-3.61 (IH, m) , 3.71-3.73 (0.5H, m) , 4.15-4.17 (0.5H, rα) , 4.29-4.30 (IH, m) , 6.24 (IH, s) , 7.45-7.49 (6H, m) , 8.08 (IH, d, J = 5.39 Hz), 8.79 (IH, s) , 11.83 (IH, s) .
Isomer B (170 mg, 30%) : XE NMR (500 MHz, DMSO-ds) δ 1.28-1.47 (9H, m), 1.67-1.74 (2H, m) , 1.94-1.98 (2H, m) , 3.31-3.80 (4H, m) , 4.30-4.32 (IH, m) , 5.87 (IH, s) , 6.83-6.86 (IH, m) , 7.47- 7.56 (5H, m) , 8.13 (IH, d, J = 5.5 Hz), 8.84 (IH, br s), 11.47 (IH, s).
Pb-enyl (IH-pyrrolo [2, 3-c] pyridin-2 -yl) methanone 0- piperidin-3-yloxime dihydrochloride was prepared from tert- butyl 3— [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2 - yl) methylene] amino] oxy] piperidine-1-carboxylate (Isomer A) following the procedure described for Example 95 (28.9 mg, 38%) as a white solid (geometry of the oxime double bond undefined) .
Example 107: mp 240-245°C dec; E NMR (500 MHz, DMSO-de) 61.75-1.78 (3H, m) , 1.98-2.02 (IH, m) , 2.99-3.07 (2H, ) , 3.46 (2H, br s), 4.57 (IH, br s) , 6.71 (IH, s), 7.55-7.65 (5H, m) , 8.08 (IH, d, J = 6.3 Hz), 8.30 (IH, d, J = 6.3 Hz), 8.92 (IH, br s), 9.05 (IH, s) , 9.58 (IH, br s) , 13.24 (IH, s) 15.21 (IH, br s); ESI MS m/z 321 [Cι9H20N4O + H]+; HPLC (Method A) 97.3% (AUC) , fcR = 13.8 min. Γ-II If" "Η"' .«' if if IE™ sF"t K~r .' -it "!I rc ""'$ ~'i
Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone O- piperidin— 3-yloxime dihydrochloride was prepared from tert- butyl 3-[ C [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] piperidine-1-carboxylate (Isomer B) following the procedure described for Example 95 (47.9 mg, 38%) as a white solid (isomer of Example 107, geometry of the oxime double bond undefined) . Example 108: mp 240-245°C dec; XE NMR (500 MHz, DMSO-d6) 61.66-1.69 (IH, m) , 1.90-1.98 (3H, m) , 2.99-3.01 (IH, m) , 3.03- 3.14 (IH, ) , 3.35-3.40 (IH, m) , 3.48-3.53 (IH, m) , 4.63 (IH, br s), 7.01 (IH, s), 7.49-7.59 (5H, m) , 8.09 (IH, d, J = 6.2 Hz), 8.32 (IH, d, J = 6.2 Hz), 9.16-9.29 (3H, m) , 13.20 (IH, br s), 15.11 (IH, br s) ; ESI MS m/z 321 [C19H20N4O + H]+; HPLC (Method A) 96.6% (AUC), tR = 13.9 min.
Example 109 and Example 110
Phenyl (IH— yrrolo[2 ,3-c]pyridin-2-yl)methanone O- [2- (tetrahydr:o-2H-pyran-2-yloxy) ethyl] oxime and phenyl (1H- pyrrolo [2 , 3-c]pyridin-2-yl)methanone O- (2-hydroxyethyl) oxime
To phenyl (IH-pyrrolo [2, 3-c]pyridin-2-yl) methanone oxime (Example 39) (200 mg, 0.84 mmol) in N, N-dimethylformamide (5 mL) was added ΝaH (40 mg, 60% dispersion in mineral oil, 1.0 mmol). After 45 min, 2- (2-bromoethoxy) tetrahydro-2H—pyran (0.13 mL, 0.88 mmol) was added and the mixture was heated to 60°C. After 15 h, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between H20 and EtOAc. Th-e aqueous layer was separated and extracted with EtOAc. Th-e combined organic layers were washed with H20 and saturated ΝaCl, dried (Νa2S0) and concentrated under reduced «"y-*ete--ufe,-*'^liϊfe*^"b-i, by column chromatography (silica gel, 95:5 CH2Cl2/MeOH) gave an impure brown oil (87.8 mg, 28%). Further purification by ion-exchange chromatography (SCX-2, 1:3 7 N NHOH in MeOH/MeOH) gave a mixture of phenyl (1H- pyrrolo[2, 3-c] pyridin-2-yl) methanone 0- [2- (tetrahydro-2H- pyran-2-yloxy) ethyl] oxime (Example 109) and phenyl (1H- pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- (2-hydroxyethyl) oxime (Example 110) . Separation was carried out by column chromatography (silica gel, 95:5 CH2Cl2/MeOH) .
Example 109 (12.3 mg) as an amber oil: XE NMR (500 MHz, DMSO- d6) 6 1.55-1.98 (6H, m) , 3.61-3.64 (IH, m) , 3.95-3.99 (2H, ) , 4.09-4.12 (IH, m) , 4.55-4.58 (2H, m) , 4.81-4.83 (IH, m) , 6.73 (IH, s), 7.48-7.55 (6H, rα) , 8.13 (IH, d, J = 5.5 Hz), 8.86 (IH, s), 11.68 (IH, s); ESI MS m/z 366 [C2ιH23N303 + H]+; HPLC (Method A) 85.8% (AUC), tR = 16.6 min.
Example 110 (33.2 mg) as a brown oil: XH NMR (500 MHz, DMSO-c-s) 6 3.77 (2H, d, J = 4.4 Hz), 4.30-4.32 (2H, m) , 4.86 (IH, br s), 6.68 (IH, s), 7.47-7.57 ( 6H, m) , 8.14 (IH, d, J = 5.5 Hz), 8.88 (IH, s), 11.68 (IH, br s) ; ESI MS m/z 282 [Cι6H15N302 + H]+; HPLC (Method A) 98.5% (AϋC) , tR = 14.5 min.
Example 111 ter t-Butyl 2- [ [ [phenyl (iJE-pyrrolo [2 , 3-c]pyridin-3- yl) methylene] amino] oxy] ethylcarbamate tert-Butyl 2- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-3- yl) methylene] amino] oxy] ethylcarbamate (429.2 mg, 89%) was prepared as a white foam using phenyl (IH-pyrrolo [2, 3- c] pyridin-3-yl) methanone (Reference Example 8) and tert-butyl [2- (aminooxy) ethyl] carbamate following the procedure described
Figure imgf000157_0001
( 90:10 methylene chloride /methanol) ; E NMR (300 MHz, CD30D) δl.38-1.39 (9H, s) , 3.40-3.44 (2H, m) , 3.17-3.20 (IH, t, J = 5.7 3Hz) , 3.26-3.28 (IH, t, J = 5.3 Hz), 6.50-6.80 (IH, m) , 7.30-7.50 (5H, m) , 7.86-8.32 (2H, m) , 8.76 5 (IH, s); ESI MS m/z 381 [C2ιH24N403+ H]+; HPLC (Method A) 96.8% (AUC) , tR = 17.7 min.
Example 112
l o Phenyl ( lH-pyrr olo [ 2 , 3 - σ] pyaridin- 3 -yl ) methanone O- ( 2 - aminoethyl) oxime
A mixture of tert-butyl 2- [ [ [phenyl (IH-pyrrolo [2, 3- c]pyridin-3-yl) methylene] a uino] oxy] ethylcarbamate (Example
15 111) (385.8 mg, 0.94 mmol) , trifluoroacetic acid (4 mL) and methylene chloride (2 mL) -was stirred at room temperature for 6 h. The solvent was removed in vacuo. The crude material was purified and free based using SCX-2 to give phenyl (1H- pyrrolo [2, 3-c]pyridin-3-yl )methanone 0- (2-aminoethyl) oxime
20 (220 mg, 84%) as an off-white foam: 1H NMR (500 MHz, CD3OD) 62.97-3.02 (2H, m) , 3.20-3.31 (2H, m) , 6.75-6.77 (0.6H, m) , 7.19 (0.4H, m), 7.40-7.49 (5H, m) , 7.91-7.92 (0.6H, ) , 8.07- 8.20 (1.5H, m) , 8.70-8.72 (IH, m) ; ESI MS m/z 281 [Cι6H16N0 + H]+; HPLC (Method A) >99% (AUC), Isomeric ratio 58:42, tR =
25 12.5 and 12.2 min.
Example 113 (3 ,4-Dichlorophenyl) (lH-pyαrrolo [2 ,3-c]pyridin-2-yl)methanol
30 (3, 4-Dichlorophenyl) (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanol (83 mg, 23%) was prepared as a white solid following the procedure de scribed for Example 98 using !rσ©ιt-hι6rtøialiy,''-ιvfei'lΛ-lliels"3, 4-dιchlorophenylmagnesιum bromide m tetrahydrofuran: mp 264-266°C dee *H NMR (500 MHz, CD3OD) 65.99 (IH, s), 6.13 (IH, s), 7.36-7.39 (IH, m) , 7.41-7.58 (2H, m) , 7.67 (IH, d, J = 1.9 Hz), 8.01 (IH, d, J = 5.6 Hz), 8.60(1H, s); ESI MS m/z 293 [C14H10 C12N20 + H]+; HPLC (Method A) >99% (AUC), tR = 16.5 min.
Example 114 [ [ henyl (IH-pyrrolo [2 ,3-c]pyridin-3- yl) methylene] amino] guanidine bis (hy"drogen trifluoroacetate)
[ [Phenyl (IH-pyrrolo [2, 3-c] pyr din-3- yl) methylene] amino] guanidine bis (hydrogen trifluoroacetate) (13.3 mg, 10%) was prepared as an off-white solid using phenyl (IH-pyrrolo [2, 3-c] pyridin-3-yl) methanone (Reference Example 8) following the procedure described for Example 74, except additional treatment with aqueous NaHC03 followed by trifluoroacetic acid: XE NMR (300 MHz, CD3OD) 67.48-7.51 (2H, m) , 7.68-7.72 (3H, m) , 8.01 (IH, s) 8.30-8.38 (2H, dd, J = 6.5, 16.5), 9.15 (IH, s); ESI MS m/z 279 [Cι5HιN6+ H]+; HPLC (Method A) 97.6% (AUC), tR = 11.8 min.
Example 115
Phenyl (IH-pyrrolo [2 ,3-c]pyridin-2 -γ1) methanone O-benzyloxime hydrochloride
A mixture of phenyl [1- (phenylsulfonyl) -IH-pyrrolo [2, 3- c]pyridin-2-yl] methanone (Reference Example 13) (200 mg, 0.55 mmol), O-benzylhydroxylamine hydrochloride (97 mg, 0.92 mmol) and pyridine (74 μL, 0.92 mmol) in 1,2-dichloroethane (8 mL) was heated at 60°C. After 24 h, saturated NH4C1 (10 mL) was adled
Figure imgf000159_0001
extracted with EtOAc (2 x 25 mL) . The combined extracts were washed with saturated NaCl (20 mL) , dried (Na2S04) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 1:1 hexanes/EtOAc) gave phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone O-benzyloxime hydrochloride (84 rng, 47%) as a mixture of isomers: mp 153-155°C; XE NMR (500 MHz, DMSO-d6) 6 5.35-5.40 (2H, m) , 6.66 (0.5H, s) , 7.12 (0.5H„ s), 7.34-7.56 (10H, m) , 8.07 (0.5H, d, J = 6.3 Hz), 8.19 (0.5H, d, J = 6.3 Hz), 8.29 (0.5H, d, J = 6.3 Hz), 8.34 (0.5H, cl, J = 6.3 Hz), 8.99 (0.5H, s), 9.17 (0.5H, s) , 13.04 (0.5H, s), 13.14 (0.5H, s), 15.14 (IH, br s) ; ESI MS m/z 328 [C2ιHι7N30 + H] +; HPLC (Method A) 98.3% (AUC), tR = 19.1 and 19.3 minx. Example 116 tert-Butyl 2- [ [ [ (4-chlorophenyl) (lH-pyrrolo[2 ,3-c]pyridin-2- yl)methylene] amino] oxy] ethylcarbamate tert-Butyl 2- [[[ (4-chlorophenyl) (lH-pyr-rolo [2, 3- c]pyridin-2-yl) methylene] amino] oxy] ethylcarbamate was prepared from (4-chlorophenyl) ( IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone (Example 103) and tert-butyl [2- (aminooxy) eth;yl] carbamate following the procedure described for Example 104. Purification by Biotage chromatography (silica., 2 to 15% methanol in methylene chloride) provided tert-butyl 2-[[[(4- chlorophenyl) (IH-pyrrolo [2, 3-c]pyridin-2- yl)methylene] amino] oxy] ethylcarbamate (geomet-ry of the oxime double bond undefined) .
Isomer A ( 81 mg, 53% ) as a white solid: mp 166-169°C; ^Η NMR ( 500 MHz CD3OD) δ 1 . 39 ( 9H, s ) , 3 . 42 (2H, t, J" = 5 . 5 Hz ) , 4 . 25 (2H, t, J = 5 . 6 Hz ) , 6 . 29 ( IH, s ) , 7 . 48-7 .58 ( 5H, m) , 8 . 05 ( IH, r.„ ,r-
*'&«
Figure imgf000160_0001
s); ESI MS m/-- 415 [C2ιH23ClN403 + H]+; HPLC (Method A) 85.4% (AUC), tR = 17.5 -min.
Isomer B (37 mg, 24%) as an oil: XE NMR (500 MHz CD3OD) 6 1.39 (9H, s), 3.52-3.55 (2H, m) , 4.35 (2H, t, J = 4.9 Hz), 6.58 (IH, s), 7.47-7.49 (2H, m) , 7.57-7.62 (3H, m) , 8.09 (IH, d, J = 5.6 Hz) , 8.93 (IH, s) .
Example 117 (Pyridin-2-yl) (IH-pyrrolo [2 ,3-σ]pyridin-2-y-l) methanol
A solution of diisopropylamine (0.43 rnL, 3.07 mmol) in tetrahydofuran (4 mL) was cooled to -78°C under a nitrogen atmosphere. n-Butyllithium (1.24 mL of a 2.5 M solution in hexanes) was added dropwise and the reaction mixture was stirred for 30 min at -78°C and then warmed to -30°C. A solution of 1- (phenylsulfonyl) -lH-pyrrolo[ 2, 3-c] pyridine (Reference Example 12) (400 mg, 1.55 mmol) -and NrN,N' ,Nr- tetramethylethylenediamine (0.24 mL, 1.59 mrnol) in tetrahydrofuran (4 mL) was added and the reaction mixture was stirred for 30 min. A solution of 2-pyridinecarboxaldehyde (0.30 mL, 3.14 mmol) in tetrahydrofuran (3 rnL) was added dropwise at -30°C. The reaction mixture was allowed to warm to ambient temperature over 1.5 h. Saturated ammonium chloride solution (7 mL) was added to quench the reaction mixture. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 * 25 mL) . The combined organic extracts were washed successively with water and brine, dried over sodium sulfate and concentrated to dryness. Purification by Biotage chromotography (silica, 2 to 18% methanol in methylene chloride) produced (pyridin-2-yl) (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanol (67 mg, 12%) as an off-white solid: mp 166-169°C;
Figure imgf000161_0001
δ 6.05 (IH, s) , 6.39 (IH, s) , 7.34- 7.36 (IH, m) , 7.50-7.52 (IH, m) , 7.72 (IH, d, J = 7.9 Hz), 7.87 (IH, d, J = 6.0 Hz), 8.00 (IH, d, J = 5.6 Hz), 8.52 (IH, d, J = 4.8 Hz), 8.62 (IH, s) ; ESI MS m/z 226 [Cι3HnN30 -1- H]+; HPLC (Method A) 98.9% (AUC), tR = 13.1 min.
Example 118
(4-Methylphenyl) (IH-pyrrolo [2,3-c]pyridin-2-yl) ethanone O- (2- aminoethyl) oxime bis (hydrogen trifluoroacetate)
(4-Methylphenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl)me thanone (Example 100) (130 mg, 0.55 mmol) and tert-butyl [2- (aminooxy) ethyl] carbamate (99 mg, 0.56 mmol) were combined in ethanol (8 mL) . The pH of the mixture was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the reaction mixture was refluxed for 14 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with- saturated sodium bicarbonate solution and then brine, d-ried over sodium sulfate, and concentrated to a solid. Puri-fication by column chromatography (silica gel, 75 to 100% ethyl acetate in hexanes) produced tert-butyl 2- [ [ [ (4-methylphenyl) (IH- pyrrolo [2, 3-c] pyridin-2-yl)methylene] amino] oxy] ethylcarbamate (geometry of the oxime double bond undefined) .
Isomer A (22 mg, 10%) as a white solid: E NMR (500 MHz CD3OD) 6 1.41 (9H, s), 3.11 (3H, s) , 3.51-3.53 (2H, m) , 4.32-4.34 (2H, m) , 6.61 (IH, s), 7.20-7.22 (2H, m) , 7.45-7.58 (3H, m) , 8.08 (IH, d, J= 5.6 Hz), 8.93 (IH, br s) .
Isomer B (24 mg, 11%) as a clear oil : XE NMR (300 MHz CD3OD) δ 1.40 (9H, s), 2.42 (3H, s) , 3.40-3.43 (2H, m) , 4.21-4.24 (2H, m) , 6.32 (IH, s) , 7.28-7.52 (5H, m) , 8.03 (IH, d, J= 5.6 Hz), tert-Butyl 2- [ [ [ (4-methylphenyl) (IH-pyrrolo [2, 3- c]pyridin-2-yl) methylene] amino] oxy] ethylcarbamate (Isomer A) (22 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (3 mL) at 0°C and the reaction mixture was stirred for 3 h. The solvent was removed under vacuum and the excess trifluoroacetic acid was co-evaporated with toluene (3 * 10 mL) . Drying in a vacuum oven at 50°C produced (4- methylphenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0-(2- aminoethyl) oxime bis (hydrogen trifluoroacetate) (22 mg, 71%) as an off-white solid (geometry of the oxime double bond undefined) .
Example 118: mp 179-182°C; E NMR (500 MHz, CD3OD) δ 2.42 (3H, s), 3.43 (2H, t, J = 5.1 Hz), 4.59 (2H, t, J = 5.1 Hz), 7.12 (IH, s), 7.31 (2H, d, J = 7.9 Hz), 7.49 (2H, d, J = 8.1 Hz), 8.15 (IH, d, J = 6.3 Hz), 8.26 (IH, d, J = 6.5 Hz), 9.11 (IH, s); ESI MS m/z 295 [Cι7Hι8N40 + H]+; HPLC (Method A) 98.4% (AUC) tR = 14.1 min.
Example 119 (4-Methylphenyl) (IH-pyrrolo [2 ,3-σ]pyridin-2-yl) methanone O- (2- aminoethyl) oxime bis (hydrogen trifluoroacetate) tert-Butyl 2- [[[ (4-methylphenyl) (IH-pyrrolo [2, 3- c] pyridin-2-yl) methylene] amino] oxy] ethylcarbamate (Example 118 j Isomer B) (22 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (3 mL) at 0°C and the reaction mixture was stirred for 4 h . The solvent was removed under vacuum and the excess trifluoroacetic acid was co-evaporated with toluene (3 * 10 _
*"ifc)V
Figure imgf000163_0001
oven at 60°C produced (4- methylphenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- (2- aminoethyl) oxime bis (hydrogen trifluoroacetate) (24 mg, 77%) as a tan solid (geometry of the oxime double bond undefined, isomer of Example 118) : mp 190-194°C; XH NMR (500 MHz, CD3OD) 6 2.44 (3H, s), 3.41 (2H, t, J = 5.0 Hz), 4.52 (2H, t, J = 5.0 Hz), 6.81 (IH, s), 7.37 (2H, d, J = 7.8 Hz), 7.47 (2H, d, J = 8.0 Hz), 8.06 (IH, d, J = 6.4 Hz), 8.21 (IH, d, J = 6.3 Hz), 8.98 (IH, s); ESI MS m/z 295 [Cι7Hι8N0 + H]+; HPLC (Method A) 96.9% (AUC) tR = 14.0 min.
Example 120 and Example 121
Phenyl (IH-pyrrolo [2 ,3-c]pyridin-2-yl) methanone O-methyloxime hydrochloride
Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- methyloxime hydrochloride was prepared from phenyl (IH- pyrrolo [2, 3-c] pyridin-2-yl) methanone (Example 35) and 0- methylhydroxylamine hydrochloride following the procedure described for Example 104 (geometry of the oxime double bond undefined) .
Example 120 (45.3 mg, 17%): mp 202-203°C; XH NMR (500 MHz, DMSO-d6) 64.11 (3H, s) , 7.03 (IH, s) , 7.48-7.56 (5H, m) , 8.17 (IH, d, J = 6.3 Hz), 8.34 (IH, d, J = 6.3 Hz), 9.19 (IH, s), 13.13 (IH, s), 15.30 (IH, br s) ; ESI MS m/z 252 [Cι5H13N30 + H] +; HPLC (Method A) 96.9% (AUC), tR = 16.6 min. Example 121 (geometry of the oxime double bond undefined, isomer of Example 120) (67.9 mg, 26%): mp 220-222°C; XE NMR (500 MHz, DMSO-ds) 64.05 (3H, s) , 6.65 (IH, s) , 7.48-7.56 (5H, m) , 8.07 (IH, d, J = 6.3 Hz), 8.29 (IH, d, J = 6.3 Hz), 8.99
Figure imgf000164_0001
15 .24 ( IH, br s ) ; ESI MS m/z 252 [Cι5H13N30 + H] +; HPLC (Method A) 98 . 3% (AUC) , tR = 16. 6 min . Example 122
(Pyridin-2-yl) (IH-pyrrolo [2 ,3-c]pyridin-2-yl) methanone
(Pyridin-2-yl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanol (Example 117) (55 mg, 0.24 mmol) was dissolved in tetrahydrofuran (4 mL) . Manganese dioxide (210 mg, 2.42 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed thoroughly with tetrahydrofuran. The organic filtrate was concentrated to a yellow solid. Drying under vacuum at 40°C produced (pyridin- 2-yl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone (60 mg, quant.): p 219-222°C; XE NMR (500 MHz, CD30D) δl . 66-1 . 16 (2H, m) , 7.85 (IH, m) , 8.04-8.08 (IH, m) , 8.14-8.21 (2H, m) , 8.82-8.43 (IH, m) , 8.92 (IH, s) ; ESI MS m/z = 224 [Cι3H9N30 + H]+; HPLC (Method A) 95.4% (AUC), tR = 13.1 min.
Example 123
(4-Methoxyphenyl) (IH-pyrrolo [2 , 3-c]pyridin-2-yl) methanone O- (2-aminoethyl) oxime bis (hydrogen trifluoroacetate) tert-Butyl 2- [ [ [ (4-methyloxyphenyl) (IH-pyrrolo [2, 3- c]pyridin-2-yl) methylene] amino] oxy] ethylcarbamate was prepared from (4-methoxyphenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone (Example 102) following the procedure described for Example 118. Isomeric separation by Biotage chromatography (silica gel, 3→10% methanol in methylene chloride) produced tert-butyl 2- [ [ [ (4-methyloxyphenyl) (IH-pyrrolo [2, 3-c]pyridin-2- ψ j.— . ■■■«■■ ." % |[ £"' irij cj -' -it -'t if.',; ""u- -jf ^±)metnγlen'e]''am--.riO t>xy'_"ethylcarbamate (geometry of the oxime double bond undefined) .
Isomer A (63 mg, 48%) as a yellow solid: XH NMR (500 MHz CD3OD) 6 1.41 (9H, s), 3.51-3.53 (2H, m) , 3.86 (3H, s) , 4.32-4.34 (2H, m) , 6.59 (IH, s), 7.00-7.02 (2H, m) , 7.50-7.59 (3H, m) , 8.08 (IH, d, J = 5.6 Hz), 8.92 (IH, s) .
Isomer B (20 mg, 15%) as an oil: XE NMR (500 MHz CD3OD) 6 1.40 (9H, s), 3.41-3.43 (2H, m) , 3.87 (3H, s) , 4.22-4.25 (2H, m) , 6.36 (IH, s), 7.02 (2H, d, J = 8.7 Hz)), 7.46-7.52 (3H, m) , 8.04 (IH, d, J = 5.6 Hz), 8.71 (IH, s) . tert-Butyl 2- [[[ (4-methyloxyphenyl) (IH-pyrrolo [2, 3- c] pyridin-2-yl) methylene] amino] oxy] ethylcarbamate (Isomer A) (58 mg, 0.14 mmol) was dissolved in 0°C trifluoroacetic acid (3 mL) and the reaction mixture was stirred for 3 h. The solvent was removed under vacuum and the excess trifluoroacetic acid was co-evaporated with toluene (3χ) . Preparative HPLC [synergi column, 10→100% acetonitrile in water (0.05% TFA added to eluents) over 35 min] produced (4-methoxyphenyl) (1H- pyrrolo [2, 3-c] pyridin-2-yl)methanone 0- (2-aminoethyl) oxime bis (hydrogen trifluoroacetate) (49 mg, 64%) as an off-white solid (geometry of the oxime double bond undefined) .
Example 123: mp 158-162°C; E NMR (500 MHz, CD3OD) 6 3.43 (2H, t, J = 5.1 Hz), 3.86 (3H, s) , 4.59 (2H, t, J = 5.1 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.14 (IH, s) , 7.53-7.55 (2H, m) , 8.17 (IH, d, J = 6.4 Hz), 8.26 (IH, d, J = 6.4 Hz), 9.11 (IH, s) ; ESI MS m/z 311 [C17Hι8N402 + H]+; HPLC (Method A) 96.5% (AUC), tR = 14.0 min. §; EX Sk^ S is ' * & s 3 i
(4-Methoxyphenγl) (IH-pyrrolo[2,3-c]pyridin-2-yl)methanone O- (2-aminoethyl) oxime dihydrochloride tert-Butyl 2- [[[ (4-methyloxyphenyl) (IH-pyrrolo [2, 3- c]pyridin-2-yl)methylene] amino] oxy] ethylcarbamate (Example 123, Isomer B) (22 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (3 mL) and the reaction mixture was stirred for 1.5 h. The solvent was removed under vacuum and the excess trifluoroacetic acid was co-evaporated with toluene (3χ) . The trifluoroacetic acid salt was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. The residue was dissolved in ethyl acetate and ethereal hydrogen chloride (2 ml of a 1 M solution) was added. After 2 h, the solvent was removed under vacuum to produce (4-methoxyphenyl) (IH-pyrrolo [2, 3-c] pyridin- 2-yl)methanone 0- (2-aminoethyl) oxime dihydrochloride (18 mg, 64%) as an off-white solid (geometry of the oxime double bond undefined, isomer of Example 123) : mp 178-184°C; XH NMR (500 MHz, CD3OD) δ 3.43 (2H, t, J = 5.1 Hz), 3.88 (3H, s), 4.53 (2H, t, J = 5.1 Hz), 6.85 (IH, s) , 7.07-7.10 (2H, m) , 7.56 (2H, d, J = 8.7Hz), 8.06-8.10 (IH, m) , 8.22 (IH, d, J = 6.3 Hz), 8.99 (IH, s); ESI MS m/z 311 [Cι7Hι8N402 + H]+; HPLC (Method A) 85.4% (AUC), Isomeric ratio 85:8, tR = 13.4 min.
Example 125 (4-Chlorophenyl) (IH-pyrrolo [2 ,3-σ]pyridin-2-yl) methanone O- (2- aminoethyl) oxime bis (hydrogen trifluoroacetate) tert-Butyl 2- [[[ (4-chlorophenyl) (IH-pyrrolo [2, 3- i * f<- ",|F" ■ a ifir1 Hiir .' -if •« ii-' ""Tι -s
«'?'} yfi'iτitA€^l),Λ;e,t&^--.'iτ:e] ammo] oxy] ethylcarbamate (Example 116, Isomer A) (22 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (3 mL) and the reaction mixture was stirred for 3 h. The solvent was removed under vacuum and the excess trifluoroacetic acid was co-evaporated with toluene (2 x 10 mL) . The residue was titurated with ethyl acetate to give (4- chlorophenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0-(2- aminoethyl) oxime bis (hydrogen trifluoroacetate) (18 mg, 46%) as a tan solid (geometry of the oxime double bond undefined) : E NMR (500 MHz, CD3OD) 6 3.41-3.45 (2H, m) , 4.62 (2H, t, J = 5.0 Hz), 7.12 (IH, s) , 7.50-7.62 (4H, m) , 8.17 (IH, d, J = 6.4 Hz), 8.28 (IH, d, J = 6.4 Hz), 9.17 (IH, s) ; ESI MS m/z 315 [CιSH15ClN40 + H]+; HPLC (Method A) 81.3% (AUC), Isomeric ratio 81:18, tR = 14.4 min.
Example 126
(4-Chlorophenyl) (IH-pyrrolo [2 ,3-σ]pyridin-2-yl)methanone O- (2- aminoethyl) oxime bis (hydrogen trifluoroacetate) tert-Butyl 2- [[[ (4-chlorophenyl) (IH-pyrrolo [2, 3- c]pyridin-2-yl) methylene] amino] oxy] ethylcarbamate (Example 116, Isomer B) (24 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (3 mL) at 0°C and the reaction mixture was stirred for 2 h. The solvent was removed under vacuum and the excess trifluoroacetic acid was co-evaporated with toluene (3 x 10 L) . Drying in a vacuum oven at 40°C produced (4- chlorophenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl)methanone 0-(2- aminoethyl) oxime bis (hydrogen trifluoroacetate) (28 mg, 88%) as a tan solid (geometry of the oxime double bond undefined, isomer of Example 125) : mp 146-150°C; XE NMR (500 MHz, CD3OD) δ 3.41 (2H, m) , 4.53 (2H, t, J = 5.0 Hz), 6.83 (IH, s) , 7.58 (4H, s), 8.09 (IH, d, J = 6.4 Hz), 8.23 (IH, d, J = 6.4 Hz),
Figure imgf000168_0001
•■,ΕϊiτB-fe aJ'-z' 315 [C1SH15C1N40 + H]+; HPLC (Method A) 93.9% (AUC), Isomeric ratio 94:4, tR = 14.2 min. Example 127 (3 ,4-Dichlorophenyl) (IH-pyrrolo [2 ,3-σ]pyridin-2-yl)methanone
(3, 4-Dichlorophenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl)methanone (99 mg, 45%) was prepared as a yellow solid following the procedure described for Example 100 using (3,4- dichlorophenyl) (IH-pyrrolo [2, 3-c] pyridin-2-yl)methanol (Example 113) and tetrahydrofuran as a solvent: mp 274-277°C dec; XE NMR (500 MHz, DMSO-d6) 67.24 (IH, s) , 7.70 (IH, d, J = 5.5 Hz), 7.87-7.95 (2H, m) , 8.14 (IH, d, J = 1.9 Hz), 8.22 (IH, d, J = 5.6 Hz), 8.93 (IH, s) , 12.50 (IH, s) ; ESI MS m/z 291 [Cι4H8Cl2N20 + H]+; HPLC (Method A) >99% (AUC), tR = 17.4 min.
Example 128 and Example 129 tert-Butyl methyl [2- [ [ [phenyl (IH-pyrrolo [2 ,3-c] yridin-2- yl)methylene] amino] oxy] ethyl] carbamate
A mixture of phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl)methanone (Example 35) (200 mg, 90 mmol) and tert-butyl [2- (aminooxy) ethyl] methylcarbamate (Reference Example 14) (180 mg, 94 mmol) in EtOH (20 mL) was adjusted to pH 4-5 with HCl (1.2 mL of a 1 N HCl solution in diethyl ether, 1.2 mmol). The reaction mixture was heated to reflux. After 15.5 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (25 mL) and washed with saturated NaHC03 (2 10 mL) . The combined organic layers were washed with saturated NaCl (10 mL) , dried (Na2S04) and concentrated under reduced pressure. Purification by column
Figure imgf000169_0001
99 : 1 CH2Cl2/MeOH to 95 : 5 CH2Cl2/MeOH) gave tert-butyl methyl [2- [ [ [phenyl ( IH-pyrrolo [2 , 3- c] pyridin-2 -yl) methylene] amino] oxy] ethyl] carbamate (geometry of the oxime double bond undefined) .
Example 128 (105 mg, 30%) as an off-white amorphous solid: 1H NMR (500 MHz, DMSO-ds) 61.27-1.38 (9H, m) , 2.79-2.86 (3H, m) , 3.58-3.62 (2H, m) , 4.39 (2H, s) , 6.60-6.68 (IH, m) , 7.48-7.55 (6H, m) , 8.13 (IH, d, J = 5.5 Hz), 8.87-8.91 (IH, m) , 11.75 (IH, br s); ESI MS m/z 395 [C22H2SN03 + H]+; HPLC (Method A) 98.1% (AUC), tR = 19.3 min.
Example 129 (40 mg, 11%) as an off-white amorphous solid: 1H NMR (500 MHz, DMS0-d&) δl.30-1.34 (9H, m) , 2.72-2.77 (3H, m) , 3.55 (2H, br s) , 4.26 (2H, t, J = 5.1 Hz), 6.20-6.22 (IH, m) , 7.44-7.50 (6H, m) , 8.08 (IH, d, J = 5.5 Hz), 8.79 (IH, s) , 11.78 (IH, br s) ; ESI MS m/z 395 [C22H2sN403 + H]+; HPLC (Method A) 94.9% (AUC), tR = 19.0 min Example 130
2- [ [ [Phenyl (IH-pyrrolo [2 ,3-σ]pyridin-2- yl)methylene] amino] oxy] acetamide I N HCl (0.67 mL, 0.67 mmol) was added to a solution of 2- (aminooxy) acetamide (Reference Example 18) (90.5 mg, 1.04 mmol) in EtOH (6.7 mL) followed by addition of phenyl (1H- pyrrolo [2, 3-c] pyridin-2-yl) methanone (Example 35) (150 mg, 0.67 mmol) . The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was free based using an SCX-2 and purified by Biotage chromatography to isolate 2- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- !p> fl"'" "!'" ,-''11 ϋ ' f'll '''"-; ' "if ~'-i C T't -if
^yϊ^ifie ftyϊ πβiami Hxyfacetamide (72.9 mg, 37%) as a white solid (single isomer, geometry of the oxime double bond undefined): Rf 0.13 (90:10 methylene chloride/methanol) ; XE NMR (500 MHz, DMSO-d6) 64.65 (2H, s) , 6.65 (IH, s) , 7.41-7.58 (8H, m) , 8.14-8.15 (IH, d, J = 5.5 Hz ), 8.89 (IH, s) , 12.01 (IH, br s); ESI MS m/z 295 [Cι6Hι4N402 + H]+; HPLC (Method A) 98.9% (AUC) , tR = 14.8 min.
Example 131
Phenyl (IH-pyrrolo [2 ,3-c]py idin-2-yl) methanone O- [2- (methylamino) ethyl] oxime dihydrochloride tert-Butyl methyl [2- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] ethyl] carbamate (Example 128) (100 mg, 0.25 mmol) in trifluoroacetic acid/CH2Cl2 (2:1, 5 mL) was stirred at ambient temperature. After 5 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2C12 (35 mL) and washed with saturated NaHC03 (20 mL) and saturated NaCl (20 mL) , dried (Na2S0) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 89:10:1 CH2Cl2/MeOH/NH4OH) . The obtained product was dissolved in EtOAc, an excess of 1 N HCl in Et20 was added and the mixture was concentrated under reduced pressure. The resulting solid was triturated with EtOAc and collected by vacuum filtration to give phenyl (1H- pyrrolo [2, 3-c] pyridin-2-yl ) methanone O- [2- (methylamino) ethyl] oxime dihydrochloride (46.8 mg, 51%) as an off-white solid (geometry of the oxime double bond undefined) : XE NMR (500 MHz, DMSO-dg) δ 2.63 (3H, s) , 3.39 (2H, br s) , 4.59 (2H, t, J = 4.5 Hz), 6.96 (IH, s) , 7.50-7.61 (5H, m) , 8.14 (IH, d, J = 6.3 Hz), 8.34 (IH, d, J = 6.3 Hz), 9.31-9.35 (3H, m) , 13.56 (IH, s), 15.28 (IH, br s) ; ESI MS m/z 295 [Cι7Hι8N40 + H] +; lf^ e 'tH'όd'',! )™,tlβ'Br6%'i>'tAUC) , tR = 13.5 min.
Example 132 Phenyl (IH-pyrrolo [2 ,3-c]pyridin-2-yl) m thanone O- [2- (methylamino) ethyl] oxime dihydrochloride
Phenyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- [2- (methylamino) ethyl] oxime dihydrochloride was prepared from tert-butyl methyl [2- [[ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] ethyl] carbamate (Example 129) following the procedure described for the Example 131 (21.4 mg, 86%) as an off-white amorphous solid (geometry of the oxime double bond undefined, isomer of Example 131) : 1H NMR (500 MHz, DMSO- d6) 6 2.60 (3H, s), 3.41 (2H, br s) , 4.50 (2H, t, J = 4.9 Hz), 6.68 (IH, s), 7.55-7.61 (5H, m) , 8.05 (IH, d, J = 6.3 Hz), 8.29 (IH, d, J = 6.3 Hz), 9.03-9.07 (3H, m) , 13.42 (IH, s) , 15.20 (IH, br s) ; ESI MS m/z 295 [Cι7Hι8N40 + H] +; HPLC (Method A) 95.8% (AUC), tR = 13.3 min.
Example 133
N-Methyl-2- [ [ [phenyl (IH-pyrrolo [2 , 3-c] yridin-2- yl) methylene] amino] oxy] acetamide
N-Methyl-2- [ [ [phenyl (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] acetamide (126 mg, 58%) was prepared using 2- (aminooxy) -N-methylacetamide (Reference Example 19) as an off-white foam following the procedure described for Example 130: Rf 0.31 (90:10 methylene chloride/methanol); XE ΝMR (300 MHz, CD3OD) 62.82 (3H, s), 4.78 (2H, s) , 6.66 (IH, s) , 7.42-7.62 (7H, m) , 8.09-8.11 (IH, d, J = 5.7 Hz), 8.84 (IH, s); ESI MS m/z 309 [Cι7H16Ν402 + H]+; HPLC (Method A) >99% (AUC) , ,,,„ --,., .„. ,.» . „ π ιj» , | ( y „u „„ ....... ™ >>tt l< B =* M 0'" ±ϊi':" ■* ■*■ ^ ^ «*■
Example 134
s (3 , 4-Dichlorophenyl) (IH-pyrrolo [2 , 3-σ] py:ridin-2-yl) methanone O— (2-aminoethyl) oxime bis (hydrogen trif lxαoroacetate)
(3, 4-Dichlorophenyl) (IH-pyrrolo [2, 3-c] pyridin-2- yl) methanone (Example 127) (92 mg, 0.32 mmol) and tert-butyl0 [2- (aminooxy) ethyl] carbamate (58 mg, 0.33 mmol) were combined in. ethanol (5 mL) . The pH was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the reaction mixture was refluxed for 14 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturateds sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by Biotage chromatography (silica gel, 97:3 CH2C12 :CH3OH) produced tert- bi tyl 2- [ [ [ (3, 4-dichlorophenyl) (IH-pyrrolo [2, 3-c] pyridin-2- yl) methylene] amino] oxy] ethylcarbamate (74 mg, 51%) as a yellow0 foam: 1H NMR (300 MHz CD3OD) 6 1.39 (9H, s) , 3.50-3.54 (2H, m) , 4.26-4.39 (2H, m) , 6.35 (0.35H, s) , 6.62 (0.65H, s) , 7.38-7.77 (4H, m) , 8.04-8.11 (IH, m) , 8.72 (0.35H, s), 8.93 (0.65H, s) ; ESI MS m/z 449 [C21H22C12N403 + H] + . 5 tert-Butyl 2- [[[ (3, 4-dichlorophenyl) (IH-pyrrolo [2, 3- c] pyridin-2-yl)methylene] amino] oxy] ethylcarbamate (72 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (3 mL) at 0°C and the reaction mixture was stirred for 3 . The solvent was removed under vacuum and the excess trifluoroacetic acid was0 co-evaporated with toluene (3 * 10 mL) . Drying in a vacuum oven at 50°C produced (3, 4-dichlorophenyl) (IH-pyrrolo [2, 3- c] pyridin-2 -yl) methanone 0- (2-aminoethyl) oxime bis (hydrogen trifluoroacetate) (48 mg, 52%) as a tan solid: mp 64-68°C; XH 111 iP> f" "T •" R rc «' l ill fli '! ' "ii "ϋ Fi "".. l •■»
(' lsfa-Rf S' 'b-ΗHz," CDs'OTf -"6X 3.43-3.45 (2H, m) , 4.54-4.64 (2H, m) , 6.85 (0.33H, s), 7.17 (0.67H, s) , 7.52-7.83 (3H, m) , 8.18-8.29 (2H, m) , 9.02 (0.33H, s) , 9.16 (0.67H, s) ; ESI MS m/z 349 [C16Hι4Cl2N40 + H]+; HPLC (Method A) 90.6% (AUC) tR = 14.6 min and 14.8 min, Isomeric ratio 30.9:59.7.
Example 135
Phenyl ( -IH-pyrrolo [2 , 3-c] yridin-2-yl) methanone O- (lH-imidazol- 4-ylmetJnyl) oxime dihydrochloride
Pt-enyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanone 0- (1H- imidazol-4-ylmethyl) oxime dihydrochloride was prepared from 4- [ (aminooxy) methyl] -IH- imidazole (Reference Example 15) following the procedure described for Example 128, but without basic t-reatment, (402 mg, 68%) as a mixture of isomers (64.5:34.7 by HPLC analysis) : XE NMR (500 MHz, DMSO-d6) 6 5.31 (0.7H, s), 5.44 (1.3H, s) , 6.67 (0.35H, s), 7.04 (0.65H, s) , 7.50-7.56 (5H, m) , 7.84 (0.65H, s) , 7.92 (0.35H, s) , 8.08 (0.35H, d, J = 6.3 Hz), 8.18 (0.65H, d, J = 6.3 Hz), 8.31 (0.35H, d, J = 6.3 Hz), 8.36 (0.65H, d, J = 6.3 Hz), 9.11 (0.35H, s), 9.16 (IH, s) , 9.30 (0.65H, s) , 13.48 (0.65H, s), 13.75 (O.35H, s), 15.07 (3H, br s) ; ESI MS m/z 318 [Cι8Hι5N50 + H]+; HPLC (Method A) >99% (AUC), tR = 13.4 and 13.6 min.
Example 136 (Pyridin-4-yl) (IH-pyrrolo [2 ,3-σ]pyridin-2-yl) methanone [ 1- (Phenylsulfonyl) -IH-pyrrolo [2, 3-c] pyridin-2- yl] (pyridin-4-yl) methanol (Reference Example 22, 217 mg, 0.59 mmol) was dissolved in ethanol (10 mL) . A 10% solution of sodium -hydroxide (6 mL) was added and the reaction mixture was
Figure imgf000174_0001
i .'o" ' urr d then stirred at ambient temperature for the wee-kend. The solvent was removed under vacuum. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated to give (pyridin-4-^ 1) (IH-pyrrolo [2, 3-c] pyridin-2-yl)methanone (air- oxidation p-roduct) (86 mg, 65%) as a yellow solid: XE NMR (500 MHz, CD3OD) 6 7.26 (IH, s) , 7.75-7.77 (IH, m) , 7.90-7.92 (2H, m) , 8.18 (IH, d, J = 5.6 Hz), 8.81-8.83 (2H, m) , 8.90 (IH, s) ; ESI MS m/z = 224 [Cι3H9N30 + H]+; HPLC (Method A) >99% (AUC), tR = 7.6 min.
Example 137
3-Furyl (IH-pyrrolo [2 , 3-c]pyridin-2-yl) methanone
A solution of diisopropylamine (0.43 mL, 3.07 mmol) in tetrahydofu-ran (4 mL) was cooled to -78°C under a nitrogen atmosphere. n-Butyllithium (1.24 mL of a 2.5 M solution in hexanes) was added dropwise and the reaction mixture was stirred for 30 minutes at -78°C and then warmed to —30°C. A solution of 1- (phenylsulfonyl) -IH-pyrrolo [2, 3-c] pyridine (Reference Example 12) (400 mg, 1.55 mmol) and N,N,N' ,Nf- tetramethylethylenediamine (0.24 mL, 1.59 mmol) in tetrahydrofi-iran (4 mL) was added and the reaction mixture was stirred for 45 minutes. A solution of 3-furfural (0.27 mL, 3.12 mmol) n tetrahydrofuran (3 mL) was added dropwise. The reaction mi-xture was allowed to warm to ambient temperature over 2 h. Saturated ammonium chloride solution (5 mL) was added to quench the reaction mixture . The reaction mixture was diluted with- water (10 mL) and extracted with ethyl acetate (3 x 25 mL) . The combined organic extracts were washed, successively with water and brine, dried over sodium sulfate and concentrated to dryness. Recrystallization from methanol jf^-t I 3^^-9fii'-^ptte&si ulfonyl) -IH-pyrrolo [2, 3-c] pyridin-2- yl]methanol (208 mg, 38%) as an off-white solid: mp 168-171°C; H NMR (500 MHz, DMS0-dβ) δ 6.24 (IH, d, J = 5.8 Hz), 6.40 (IH, d, J = 5.8 Hz), 6.48 (IH, d, J = 1.1 Hz), 6.84 (IH, s) , 7.55- 7.62 (5H, m) , 7.68-7.71 (IH, m) , 7.92-7.94 (2H, ) , 8.35 (IH, d, J = 5.2 Hz), 9.23 (IH, s) ; ESI MS m/z 355 [Cι8HιN204S + H]+; HPLC (Method A) >99% (AUC), tR = 15.4 min.
3-Furyl [1- (phenylsulfonyl) -IH-pyrrolo [2, 3-c] pyridin-2 - yl]methanol (186 mg, 0.51 mmol) was dissolved in ethanol (10 mL) . A 10% solution of sodium hydroxide (6 mL) was added and the reaction mixture was refluxed for 3 hours. The solvent was removed under vacuum. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated to give 3-furyl (IH-pyrrolo [2, 3- c]pyridin-2-yl) methanol (134 mg, quant.) as a yellow foam: XH NMR (500 MHz, DMSO-d6) δ 5.87 (IH, d, J = 4.7 Hz), 6.06 (IH, d, J = 4.9 Hz) , 6.29 (IH, s) , 6.49 (IH, s) , 7.42 (IH, d, J = 5.4 Hz), 7.60 (2H, s), 8.03 (IH, d, J = 5.4 Hz), 8.65 (IH, s) , 11.49 (IH, s) .
3-Furyl (IH-pyrrolo [2, 3-c] pyridin-2-yl) methanol (130 mg, 0.61 mmol) was dissolved in tetrahydrofuran (8 mL) . Manganese dioxide (530 mg, 6.10 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed thoroughly with ethyl acetate. The organic filtrate was concentrated to a tan solid. Drying under vacuum at 40°C produced 3-furyl (lH-pyrrrolo [2, 3-c] pyridin-2-yl) methanone (78 mg, 60%): mp 232-236°C dec; XH NMR (500 MHz, CD3OD) δ 7.00- 7.01 (IH, m) , 7.42 (IH, s) , 7.71-7.77 (2H, m) , 8.16 (IH, d, J = 5.6 Hz), 8.53 (IH, d, J = 0.8 Hz), 8.85 (IH, s) ; ESI MS /z = 213 [Cι2H8N202 + H]+; H.PLC (Method A) >99% (AUC), tR = 13.8 min. Example 138
7-Chloro-lH-pyrrolo[2 , 3-c]pyridine-2-carboxaldehyde
A mixture of (7-chloro-lH-pyrrolo [2, 3-c]pyridin-2- yl)methanol (Example 1) (2.81 g, 15.4 mmol), manganese (IV) oxide (16 g) and dichloromethane (250 mL) was stirred under an atmosphere of nitrogen for 16 h. The mixture was filtered through a pad of diatomaceous earth, washing generously with hot acetone. Evaporation of the solvents provided 7-chloro-lH- pyrrolo [2, 3-c] pyridine—2-carboxaldehyde (2.40 g, 13.3 mmol, 84%) as a mixture of aldehyde and aldehyde hydrate: 1H NMR (300 MHz, CD3OD) 65.79 (IH, s) , 6.65 (IH, s) , 7.44 (IH, s) , 7.53 (IH, d, J = 5.5 Hz), 7.72 (IH, d, J = 5.5 Hz), 7.85 (IH, d, J = 5.5 Hz), 7.99 ( IH, d, J = 5.5 Hz), 10.02 (IH, s) ; ESI MS m/z 181 [C8H5C1N20 + H] +.
Example 139
5- (Dibenzylamino) -IH-pyrrolo [2 ,3-c]pyridine-2-carboxaldehyde
A mixture of [5- (dibenzylamino) -IH-pyrrolo [2, 3-c] pyridin- 2-yl] methanol (Example 48) (9.74 g, 28.4 mmol) and manganese dioxide (24.6 g, 283.6 mmol) in methylene chloride (584 mL) was stirred at room temperature under a nitrogen atmosphere overnight (15 h) . The reaction mixture was filtered through diatomaceous earth to remove the manganese dioxide. Concentration of the filtrate provided the crude material as a dark solid. The crude material was purified by trituration with toluene to give 5 - (dibenzylamino) -IH-pyrrolo [2, 3- c]pyridine-2-carboxaldehyde (6.36 g, 65%) as an orange solid: XE NMR (300 MHz, CDCI3) 64.84 (4H, s) , 6.60 (IH, s) , 6.95 (IH, ue-' " " ,-■ a if iyT}»rr •■ -if iir"."""i .ii
' sT, (t7.^'^ 3'S TOH',^m!! " 8.63 (IH, s) , 9.75 (IH, br s) , 9.86 (IH, s) .
Example 140
(5-Chloro-lH-pyrrolo [2 ,3-c]pyridin-2-yl) (phenyl) methanol
Concentrated sulfuric acid (120 mL) was cooled in an ice bath at 0°C. 2-Amino-4-methylpyridi:r-e (25.0 g, 230 mmol) was added portionwise. A mixture of con-centrated sulfuric acid (18 mL) and concentrated nitric acid (17.5 mL) was added with addition funnel over 1 h, maintaining the temperature at 0°C. The reaction mixture was then warmed to room temperature over 4 h. After 15 h, the reaction mixtmre was heated at 60°C for 1 h, and then at 100°C for 1 h. The reaction mixture was poured over ice and adjusted to pH 4-5 with 6 N aqueous sodium hydroxide. The 3-regioisomer was removed by steam distillation (9.11 g, 26%). The remaining residue was extracted with methylene chloride and dried over sodium sulfate, and the solvent was evaporated. The dark yellow solid was crystallized from acetonitrile and methanol to give 2-amino-4-methyl-5- nitropyridine (9.53 g, 27%) as a da-t-rk yellow solid: """H NMR (300 MHz, CD3OD) 62.53 (3H, s) , 6.39 (IH, s) , 8.76 (IH, s) . Copper (II) chloride (10.01 g, 74.5 mmol) was dissolved in N, N-dimethylformamide (75 mL) and thie solution was warmed to 60°C. A solution of 2-amino-4-methyl-5-nitropyridine (9.50 g, 62.0 mmol) in N, N-dimethylformamide (145 mL) was added with addition funnel over 0.5 h. The reaction mixture was heated at 110°C for 16 h. The reaction mixture was cooled to room temperature and poured into 3 Ν aqueous hydrochloric acid (300 mL) , followed by extraction with diethyl ether. The organic extract was dried over sodium sulfate and adsorbed onto silica gel for purification by column chromatography (Si02, 20:3 ID' If"" " ii i;;;l li"'P l-I ,'" "Ii "if 8-7 ""ft -a . , ,
"hfecliήeSV tMy'r' -rf Ta'teH" 2-Chloro-4-methyl-5-nιtropyπdme was obtained as a yellow solid (2.10 g, 20%) : XE NMR (300 MHz, CD3OD) 62.63 (3H, s) , 7.60 (IH, s) , 8.96 ( IH, s) ; ESI MS m/z 173 [C6H5C1N202 + H]+.
Potassium ethoxide (1.17 g, 13.9 mmol) was suspended in diethyl ether (15 mL) . Diethyl oxalate (1.9 mL, 13.9 mmol) was added in one portion. 2-Chloro-4-methyl-5 -nitropyridine (2.40 g, 13.9 mmol) was added in one portion. The mixture was stirred 16 h. The solid was collected by filtration and washed generously with diethyl ether. Potassium (12.) -1- (2-chloro-5- nitropyridin-4-yl) -3-ethoxy-3-oxoprop-l-en-2-olate (2.86 g, 66%) was obtained as a dark brown powder: XE NMR (300 MHz, CD3OD) 61.33 (3H, t, J = 7.1 Hz), 4.20 (2H , q, J = 7.1 Hz), 6.67 (IH, s), 8.60 (IH, s) , 9.18 (IH, s) .
Potassium (1Z) -1- (2-chloro-5-nitrop\/ridin-4-yl) -3-ethoxy- 3-oxoprop-l-en-2-olate (2.86 g, 9.20 mmol) was dissolved in acetic acid (140 mL) and iron powder (2.11 g, 37.7 mmol) was added. The mixture was heated at 60°C for 6 h. The mixture was filtered through a pad of diatomaceous earrth and washed with water followed by ethanol. The filtrate was concentrated to dryness. The residue was dissolved in 1 : 1 methylene chloride/methanol, filtered through a bed of silica gel and washed with 1:1 ethyl acetate/methylene chloride until the filtrate was no longer UV-active. Concentration of the filtrate provided ethyl 5-chloro-lH-pyrrolo [2, 3-c] pyridine-2- carboxylate (0.39 g, 19%) as a brown solid: mp 170-175°C dec; XE NMR (300 MHz, CD30D) 61.42 (3H, t, J = 7.1 Hz), 4.44 (2H, q, J = 7.1 Hz), 7.17 (IH, s), 7.72 (IH, s) , 8.60 (IH, s) ; ESI MS m/z 225 [CιoH9ClN202 + H]+; HPLC (Method A) 94.9% (AUC), tR = 18.1 min.
Lithium aluminum hydride (105 mg, 2.11 mmol) was added in w t'rlέ pWicrf-s
Figure imgf000179_0001
of ethyl 5-chloro-lH-pyrrolo [2, 3- c]pyridine-2-carboxylate (410 mg, 1.83 mmol) in tetrahydrofuran (15 mL) under stirring at 0°C under a nitrogen atmosphere . The reaction mixture was warmed to room temperature and then heated to 60°C for 3 h. The reaction mixture was quenched by the gradual addition of hydrated sodium sulfate. The sodium sulfate was removed by filtration and washed thoroughly with tetrahydrofuran to give a yellow filtrate, which was concentrated to a brown solid. After sonication in diethyl ether for 20 minutes, the solid was collected by filtration and dried to give (5-chloro-lH- pyrrolo [2, 3-c] pyridin-2-yl) methanol (225 mg, 67%) as a brown solid: XH NMR (300 MHz, Acetone-ds) 64.52-4.89 (3H, m) , 6.38 (IH, s), 7.47 (IH, s), 8.49 (IH, s) , 10.88 (IH, br s) .
(5-Chloro-lH-pyrrolo [2, 3-c] pyridin-2-yl ) methanol (225 mg, 1.23 mmol) was dissolved in methylene chloride (25 mL) . Manganese dioxide (1.07g, 12.3 mmol) was added and the reaction mixture was stirred for 4 days. The reaction mixture was filtered through diatomaceous earth and tine filter cake was washed several times with hot ethyl acetate. The filtrate was concentrated to give 5-chloro-lH-pyrrolo [2, 3-c]pyridine-2- carboxaldehyde (156 mg, 70%) as a tan solid: E NMR (300 MHz, Acetone-d6) 67.43 (IH, s) , 7.80 (IH, s) , 8.77 (IH, s) , 10.08 (IH, s) , 11.49 (IH, br s) .
To a solution of 5-chloro-lH-pyrrolo [2, 3-c]pyridine-2- carboxaldehyde (156 mg, 0.86 mmol) in tetrahydrofuran (5 mL) was added 3.0 M phenylmagnesium bromide in diethyl ether (0.58 mL, 1.74 mmol) at -78°C under a nitrogen atmosphere. The reaction mixture was slowly warmed to -15°C. After stirring for ca. 5 h, additional 3.0 M phenylmagnesium bromide in diethyl ether (0.15 mL, 0.45 mmol) was added. The reaction ,m!--;,-tιirfe," 'dϊ'-l™§tifrfed"'fox" another 1 h, warming to 0°C. The reaction mixture was poured into a 2 : 1 solution of saturated ammonium chloride and water, and extracted with ethyl-, acetate (3χ) . The combined organic extracts were washed with water and brine, and dried over sodium sulfate. After filtration and concentration, the crude product was purified by Biotage chromatography (1 to 100% ethyl acetate in hexanes) to give (5-chloro-lH-pyrrolo [2, 3-c]pyridin-2-yl) (phenyl) metha-nol (109 mg, 49%) as a yellow foam: XE NMR (300 MHz, CDC13) δ6.06 (IH, s), 6.23 (IH, s), 7.33-7.61 (6H, m) , 8.49 (IH, s) , 8.S9 (IH, br s); ESI MS m/z 259 [Cι4HιXClN20 + H] +.
Example 141 1- (Dibenzylamino) -IH-pyrrolo [2 , 3-c]pyridine-2-carboxa_ldehyde
Ethyl 7- (dibenzylamino) -IH-pyrrolo [2, 3-c]ρyridine-2- carboxylate (Reference Example 3) (11.2 g, 29.0 mmol) was dissolved in tetrahydrofuran (150 mL) while stirring under N2 at 0°C. Lithium aluminum hydride (1.65 g, 43.4 mmol) was added in three portions, while monitoring the gas evolution and temperature. After the final addition, the reaction mixture was stirred at room temperature for 3 h and then heat ed at 60°C for 3 h. The reaction mixture was cooled to 0°C and qfuenched with freshly prepared hydrated sodium sulfate. The solid was removed by filtration and washed thoroughly with tetrahydrofuran. Concentration of the filtrate provided [7- (dibenzylamino) -IH-pyrrolo [2, 3-c] pyridin-2-yl] methanol (9.8 g, 99%) as a yellow solid: XE NMR (300 MHz, CDC13) 64.63 (2H, s) , 4.78 (4H, s), 6.26 (IH, s), 6.98 (IH, d, J = 5.54 Hz) _, 7.27- 7.38 (10H, m), 7.84 (IH, d, J = 5.7 Hz), 8.27 (IH, br s).
[ 7- (Dibenzylamino) -IH-pyrrolo [2 , 3-c] pyridin~2-yH] methanol f" "T it I!
"(3".0 'g,
Figure imgf000181_0001
in methylene chlonoLe (175 mL) . Manganese dioxide (8.0 g, 92 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The slurry was filtered through diatomaceous earth to reiti-ove the catalyst, and the filtrate was concentrated to a dark: oil. Purification by Biotage chromatography (10-30% ethyl acetate in hexanes) provided 7- (dibenzylamino) -IH-pyrrolo [2,3 - c]pyridine-2-carboxaldehyde (1.78 g, 60%) as a yellow- oil: XH NMR (300 MHz, CDC13) 64.89 (4H, s) , 7.06-7.12 (2H, ) r 7.27- 7.38 (10H, m) , 7.93 (IH, d, J = 5.7 Hz), 8.74 (IH, br s) , 9.77 (IH, s) .
Experimental Example 1 Determination of IKKβ inhibitory activity To a reaction solution (37.5 μl, 25 mM HEPES (pHH 7.5), 10 mM magnesium acetate) containing active IKKβ (10 ng) obtained in Reference Example 3A and 2.5 μg of IκBα substrate jorotein solution was added a test compound (2.5 μl) dissolved in DMSO, and the mixture was incubated at 30°C for 5 min. To the obtained mixture was added 10 μl of ATP solution (2.5 μM ATP, 0.01 μCi [γ-32P]ATP) and the mixture was allowed to react at 30°C for 60 min. Then 20% TCA solution (50 μl) was added thereto to stop the reaction. The reaction solution was left standing at 4°C for 20 min. and acid insoluble fraction was transferred to a GF/C filter (PACKARD JAPAN KK) using a cell harvester (PACKARD JAPAN KK) and washed with 250 mM ptiosphoric acid solution. The plate after washing was dried at --5°C for 60 min., 40 μl of MicroSinti 0 (PACKARD JAPAN KK) was added and the radioactivity was determined using TopCount (PACK- RD JAPAN KK) . The concentration (IC50) of the test compound neoessary for 50% inhibition of the amount of 32P uptake by the a.cid insoluble fraction was calculated using PRISM 3.0 (Gr-≡aphPad Software, Inc.). The results are shown in Table 1. Table 1 test compound IC50 (Example number) (μM) 91 1.7
Formulation Example 1 (Production of capsules) 1) Compound of Example 1 30 mg 2) Finely divided cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg
1), 2), 3) and 4) are admixed and filled into a gelatin capsule.
Formulation Example 2 (Production of tablets] 1) Compound of Example 1 30 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate --J----2 1000 tablets 140 g
The whole amounts of 1), 2) and 3) and 30 g of 4) are kneaded together with water and the mixture, after vacuum drying, is granulated. The granular mixture is admixed with 14 g of 4) and 1 g of 5) and the resulting mixture is tableted using a tableting machine, to give 1000 tablets each containing 30 mg of compound of Example 1.
The structural formulas of the compounds obtained in th. aforementioned Examples are shown in the following. Table 2
Figure imgf000183_0001
Table 3
Figure imgf000184_0001
Table 4
Figure imgf000185_0001
Table 5
Figure imgf000186_0001
Table 6
Figure imgf000187_0001
Table 7
Figure imgf000188_0001
Table 8
Figure imgf000189_0001
Table 9
Figure imgf000190_0001
Table 10
Figure imgf000191_0001
Table 11
Figure imgf000192_0001
Table 12
Figure imgf000193_0001
Table 13
Figure imgf000194_0001
" if " "if' mi!-' « "r""ϊrfdlstrial Applicability
The 6-azaindole compound of the present invention has a superior IκB kinase inhibitory activity, and is useful as a pharmaceutical agent such as an agent for preventing or treating diabetes and the like.

Claims

1. A compound represented by the formula
Figure imgf000196_0001
wherein
Figure imgf000196_0002
are the same or different and each is a hydrogen atom or a substituent; one of R4 and R5 is a hydrogen atom and the other is 1) a group represented by the formula: -C(=X)—R7 wherein X is N-O-R8 or N-NH-R9 wherein R8 and R.9 are the same or different and each is a hydrogen a-tom or a group bonded via a carbon atom, and R7 is a hydrogen atom or a substituent, 2) a group represented by the formula: -C(=0)—R10 wherein R10 is a hydrogen atom or a group bonded via a carbon atom; 3) a group represented by the formula: -CH(OH) -R10 wherein R10 is a hydrogen atom or a group bonded via a carbon atom; 4) a group represented by the formula: -C(=0)—NH- (CH2)n-Ar wherein n is 0, 1 or 2, and Ar is an aromatic group; 5) a group represented by the formula: -C(=0)—Het wherein Het is an optionally substituted heterocyclic group bonded via a nitrogen atom; or 6) a group represented by the formula: -CH(R12) -NR13R14 P , /
Figure imgf000197_0001
a hydrogen atom or a hydrocarbon group; R13 and R14 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acy-L group, or R13 and R14 form, together with the adjacen~t nitrogen atom, a nitrogen-containing heterocyclic group optionally having substituents (provided that the nitrogen-containing heterocyclic group is not an oxopyrrolidinyl group or an oxopiperazinyl group) except when R4 is a group represented by the formula : -C(=0)-R10 wherein R10 is as defined above, and R5 is a hydrogen atom; except tert-butyl 5- (benzyloxy) -3- (3-ethoxy-2-fluoro-l- hydroxy-3-oxopropyl) -IH-pyrrolo [2, 3-c]pyridine-l-carboxylate; [5- (benzyloxy) -IH-pyrrolo [2, 3-c] pyridin-3-yl]methanol; ethyl 3- (hydroxymethyl) -IH-pyrrolo [2, 3-c] pyridine-5- carboxylate; IH-pyrrolo [2, 3-c]pyridine-3-carbaldehyde oxime; ethyl 5-{ [5- (benzyloxy) -IH-pyrrolo [2, 3-c]pyridin-2- yl] carbonyl}-2, 4-dimethyl~lH-pyrrole-3-carboxylate; 5- (benzyloxy) -IH-pyrrolo [2, 3-c]pyridine-2-carbaldehyde; 5-methoxy-lH-pyrrolo [2, 3-c] pyridine-2-carbaldehyde; [5- (benzyloxy) -lH-pyrrolo[2, 3-c] pyridin-2-yl] methanol; (5-methoxy-lH-pyrrolo [2, 3-c] pyridin-2-yl) methanol; and [2- ( { [4- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) - 1, 3-thiazol-2-yl] amino} carbonyl) -5-methoxy-lH-pyrrolo [2, 3- c]pyridin-l-yl] acetic acid, or a salt thereof.
2 . A prodrug of the compound of claim 1 or a salt thereof.
3. The compound of claim 1, wherein one of R4 and R5 is a irfe r" '"§"' ,. " || |j j; |j" IC . •' -if -π r;-; ™; .• »»
"hy rogen atom'; "a:n'o-""thm,"other is a group represented by the formula: -C(=X)-R7 wherein X and R7 are as defined in claim 1
4. The compound of claim 1, wherein R4 is a hydrogen atom, and R5 is a group represented by the formula: -C(=0)-R10 wherein R10 is as defined in claim 1.
5. The compound of claim 1, wherein R1, R2 and R3 are each a hydrogen atom.
6. A pharmaceutical agent comprising a compound of claim 1 or a salt thereof or a prodrug thereof and a pharmacologically acceptable carrier.
7. A method for inhibiting IκB kinase in a mammal, which comprises administering an effective amount of a compound represented by the formula
Figure imgf000198_0001
wherein R1, R2, R3 and R6 are the same or different and each is a hydrogen atom or a substituent; one of R4' and R5' is a hydrogen atom and the other is 1) a group represented by the formula: -C(=X)-R7 wherein X is N-O-R8 or N-NH-R9 wherein R8 and R9 arre the same or different and each is a hydrogen atom or a group bonded via a carbon atom, and R7 is a f ** s 'y' ""Ji 'πy' o'δfeΗ"it'M" or a substituent, 2) a group represented by the formula: -C(=O)-R=L0 wherein R10 is a hydrogen atom or a group bonded- via a carbon atom; 3) a group represented by the formula: -CH (OH) -E10 wherein R10 is a hydrogen atom or a group bonded- via a carbon atom; 4) a group represented by the formula: ~C(=0)-NH- (CH2)n-Ar wherein n is 0, 1 or 2, and Ar is an aromatic group; 5) a group represented by the formula: -C (=0) -Het wherein Het is an optionally substituted heterocyclic group bonded via a nitrogen atom; or 6) a group represented by the formula: -CH(R12)- NR13'R14' wherein R12 is a hydrogen atom or a hydrocarbon group; R13' and R14' are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R13' and R14' form, toςgether with the adjacent nitrogen atom, a nitrogen- containing heterocyclic group optionally having substituents, or a salt thereof or a prodrug thereof to said mammal.
8. A method for preventing or treating diabetes in a mammal, which comprises administering an effective amount of a compound of claim 7 or a salt thereof or a prodrug thereo-f to said mammal.
9. A method for preventing or treating an inflammatory disease in a mammal, which comprises administering an effective amount of a compound of claim 7 or a salt thereof or a prodrug
Figure imgf000200_0001
10. An agent for inhibiting IκB kinase, which comprises a compound represented by the formula
Figure imgf000200_0002
wherein R1, R2, R3 and R6 are the same or different and each is a hydrogen atom or a substituent;0 one of R4' and R5' is a hydrogen atom and the other is 1) a group represented by the formula: -C(=X)-R7 wherein X is N-O-R8 or N-NH-R9 wherein R8 and R9 are the same or different and each is a hydrogen atom or5 a group bonded via a carbon atom, and R7 is a hydrogen atom or a substituent, 2) a group represented by the formula: -C(=0)-R10 wherein R10 is a hydrogen atom or a group bonded vi_a a carbon atom;0 3 ) a group represented by the formula: -CH(OH)-R10 wherein R10 is a hydrogen atom or a group bonded v-La a carbon atom; 4) a group represented by the formula: ~C(=0)-NH- (CH2)n-Ar wherein n is 0, 1 or 2, and Ar is an5 aromatic group; 5) a group represented by the formula: -C(=0)-Het wherein Het is an optionally substituted heterocyclic group bonded via a nitrogen atom; or Ui!""i||t- j"'1,' "gY'iϋρ rpresented by the formula: -CH(R1122,)- NR13'R14' wherein R12 is a hydrogen atom or a hydrocarbon group; R13' and R14' are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an opti-onally substituted heterocyclic group or an o>ptionally substituted acyl group, or R13' and R14' form, together with the adjacent nitrogen atom, a nitrogen- containing heterocyclic group optionaLly having substituents, or a salt thereof or a prodrug thereof.
11. An agent for preventing or treating diabetes , which comprises a compound of claim 10 or a salt thereof or a prodrug thereof.
12. An agent for preventing or treating an inflammatory disease, which comprises a compound of claim 10 or a salt thereof or a prodrug thereof.
13. Use of a compound represented by the formula
Figure imgf000201_0001
wherein
R1, R2, R3 and Rs are the same or different and each is a hydrogen atom or a substituent; one of R4' and R5' is a hydrogen atom and the other is m.ιp"" " ■ if p it-"
« IU * * -,mι
Figure imgf000202_0001
wherein X is N-O-R8 or N-NH-R9 wherein R8 and R9 are the same or different and each is a hydrogen atom or a group bonded via a carbon atom, and R7 is a hydrogen atom or a substituent, 2) a group represented by the formula: -C(=0)-R10 wherein R10 is a hydrogen atom or a group bonded via a carbon atom; 3) a group represented by the formula: -CH (OH)-R10 wherein R10 is a hydrogen atom or a group bonded via a carbon atom; 4) a group represented by the formula: -C(=0)-NH- (CH2)n-Ar wherein n is 0, 1 or 2, and Ar is an aromatic group; 5) a group represented by the formula: -C(=0)-Het wherein Het is an optionally substituted heterocyclic group bonded via a nitrogen atom; or 6) a group represented by the formula: -CH (R12)- NR13'R14' wherein R12 is a hydrogen atom or a hydrocarbon group; R13' and R14' are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R13' and R14' for-m, together with the adjacent nitrogen atom, a nitrogen- containing heterocyclic group optionally h-aving substituents, or a salt thereof or a prodrug thereof, for the prod-uction of an agent for inhibiting IκB kinase.
14. Use of a compound of claim 13 or a salt thereof or a prodrug thereof, for the production of an agent for preventing or treating diabetes.
15. Use of a compound of claim 13 or a salt thereof or a prodrug thereof, for the production of an agent for preventing or treating an inflammatory disease.
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JP2007531744A (en) 2007-11-08
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EP1732566A2 (en) 2006-12-20
US20080064715A1 (en) 2008-03-13
WO2005097129A3 (en) 2006-01-19

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