WO2012111995A1 - Oxime derivatives as gpr119 agonists - Google Patents

Oxime derivatives as gpr119 agonists Download PDF

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Publication number
WO2012111995A1
WO2012111995A1 PCT/KR2012/001185 KR2012001185W WO2012111995A1 WO 2012111995 A1 WO2012111995 A1 WO 2012111995A1 KR 2012001185 W KR2012001185 W KR 2012001185W WO 2012111995 A1 WO2012111995 A1 WO 2012111995A1
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Prior art keywords
phenyl
piperidin
difluoro
cyclohexyl
yloxyimino
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PCT/KR2012/001185
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French (fr)
Inventor
Young Kwan Kim
Hyun Woo Joo
Myoung Yeol KIM
Heui Sul Park
Tae Hee Lee
Hyo Shin Kwak
Dong Sup Shim
Eun Sil Choi
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Lg Life Sciences Ltd.
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Publication of WO2012111995A1 publication Critical patent/WO2012111995A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel oxime derivatives as GPR119 agonists, a method for preparing the same, a pharmaceutical composition comprising the same and use thereof.
  • a GPR119 agonist means a compound which can be effectively used for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis by stimulating the secretion of insulin in the pancreas and promoting GLP-1 and GIP formation in the gastrointestinal tract.
  • Diabetes is divided into two types ⁇ i.e., insulin-dependent type 1 diabetes and insulin-independent (insulin-resistant) type 2 diabetes which is found in 90% or more of diabetic patients.
  • sulfonlyureas act directly on the pancreas to secret insulin
  • metformin has the mechanism of action of preventing glucolysis in the liver.
  • Sulfonylureas have problems of decreasing the function of the pancreas and incurring hypoglycemia due to excessive secretion of insulin, and metformin causes gastroenteric disorders or renal toxicity.
  • Glitazones also have side effects of weight gain, serious heart failure, etc.
  • incretin-related drugs such as DPPIV inhibitors or Exenatide
  • DPPIV inhibitors which have recently entered the market
  • DPPIV inhibitors have a marginal effect
  • Galvus has a side effect of skin toxicity
  • Exenatide has a disadvantage in that it must be given by means of injection.
  • GPR119 agonists which are noted for possible treatment of type 2 diabetes, are known to have antidiabetic effects caused by the actions of (1) stimulating the secretion of insulin in the pancreas and (2) increasing incretin hormone in intestinal cells.
  • GPR119 agonists show antidiabetic effects by acting directly on ⁇ -cells in the pancreas to stimulate GSIS and acting on intestinal cells to stimulate the secretion of incretin hormones, GLP-1, GIP and PYY.
  • GLP-1 is known to act on ⁇ -cells in the pancreas to stimulate the secretion of insulin, and also to have an effect of various antidiabetics, anti-obesity, and prevention and treatment of osteoporosis, including a decrease of glucagon secretion after meals, a decrease of gastrointestinal activity, appetite loss, weight loss and proliferation of ⁇ -cells in the pancreas.
  • GPR119 agonists, which stimulate the secretion of incretin hormones are also expected to have the effects of incretin hormones.
  • GPR119 agonists are actively in progress.
  • patentability is mainly established in the center bridge structure binding left and right substituents and determining the orientation of the whole structure.
  • GPR119 agonist compounds having aromatic substituents are disclosed in WO 2007/003964, WO 2008/109702, WO 2008/076243 and WO 2008/085316.
  • the object of the present invention is to provide oxime derivatives as GPR119 agonists.
  • Another object of the present invention is to provide a method for preparing the oxime derivatives.
  • Still another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis which comprises as active components the oxime derivatives, and a method for preparing the composition.
  • a still further object of the present invention is to provide a method for preventing and treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis which use the oxime derivatives as active components.
  • the present invention provides oxime derivatives of Formula 1, or pharmaceutically acceptable salts or isomers thereof:
  • RA represents a partially or fully saturated 4- to 7-membered cycloalkyl
  • RB represents a partially or fully saturated 4- to 7-membered heterocycle, or a [5.5], [5.6], [5.7], [6.6] or [6.7] fused ring system consisting of two rings,
  • R1 and R2 represent independently hydrogen, halogen or alkyl
  • n an integer of 0 to 10 in each ring
  • A represents nitrogen or carbon
  • D represents carbon, nitrogen, oxygen or sulfur
  • R3, R4 and R5 are independently hydrogen or halogen, or represent in each case optionally substituted aryl, arylalkyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl or amine,
  • R3, R4 and R5 are connected together to form optionally substituted 3- to 7-membered cycloalkyl or heterocycle, or to form optionally substituted 5- or 6-membered aryl or heteroaryl,
  • E, F, G, H and I represent independently carbon, nitrogen, oxygen or sulfur to form 6-membered aryl or heteroaryl, or form optionally benzo-fused 5-membered aryl or heteroaryl excluding one of E, F, G, H and I,
  • n an integer of 0 to 5
  • R6 is hydrogen or halogen; or represents optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl or heteroarylalkyl; or represents hydroxy or amine optionally substituted by 1 or 2 alkyl or aryl, wherein two substituents of amine are connected together to form 3- to 7-membered heterocyclyl,
  • J represents optionally substituted C 1 -C 4 -alkylene or sulfonyl
  • R7 is hydrogen or halogen, or represents optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, and
  • Ar represents optionally substituted aryl or heteroaryl.
  • the compounds of Formula 1 according to the present invention can form pharmaceutically acceptable salts, which include acid-addition salts which are formed from inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicylic acid; or sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, which form non-toxic acid-addition salts including pharmaceutically acceptable anion.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid
  • organic acids such as tart
  • the pharmaceutically acceptable carboxylic acid salts include the salts with alkali metal or alkali earth metal such as lithium, sodium, potassium, calcium and magnesium; salts with amino acid such as lysine, arginine and guanidine; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine.
  • alkali metal or alkali earth metal such as lithium, sodium, potassium, calcium and magnesium
  • salts with amino acid such as lysine, arginine and guanidine
  • organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine.
  • the compounds of Formula 1 according to the present invention can be converted into their salts by conventional methods.
  • the compounds of Formula 1 according to the present invention can have an asymmetric carbon center and asymmetric axis or plane, they can exist as E- or Z-isomer, R- or S-isomer, racemic mixtures or diastereoisomer mixtures and each diastereoisomer, all of which are within the scope of the present invention.
  • the term “the compounds of Formula 1” is used to mean all the compounds of Formula 1, including the pharmaceutically acceptable salts and isomers thereof.
  • Halogen or halo means fluoride (F), chlorine (Cl), bromine (Br) or iodine (I).
  • Alkyl means straight or branched hydrocarbons which can include single bond, double bond or triple bond.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, acetylene, vinyl, trifluoromethyl and the like.
  • Cycloalkyl means partially or fully saturated single or fused ring hydrocarbons and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and the like.
  • Aryl means aromatic hydrocarbons and includes, but is not limited to, phenyl, naphthyl and the like.
  • Heteroaryl means aromatic hydrocarbons which form a single or fused ring including at least one hetero atom selected from N, O and S.
  • heteroaryl include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole, 1,2,3,4-tetrahydroisoquinolyl, thiazolopyridyl and the like.
  • Heterocyclyl means partially or fully saturated hydrocarbons which form a single or fused ring including at least one hetero atom selected from N, O and S.
  • heterocyclyl include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, imidazolinyl, piperazinyl, tetrahydrofuran, tetrahydrothiofuran and the like.
  • Arylalkyl and heteroarylalkyl mean groups which are formed by the combination of the above-mentioned aryl with alkyl and heteroaryl with alkyl. Examples include, but are not limited to, benzyl, thiophene methyl, pyrimidine methyl and the like.
  • alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl and heteroarylalkyl may be substituted by at least one group selected from the following groups: alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, oxo, cyano, halo, nitro, -OR, -OC(O)R, -OC(O)OR, SR, -S(O)R, -S(O) 2 R, -C(O)R, -C(O)OR, -C(S)R, -C(O)NRR, -NR 2 , -NRCHO, -NRC(O)R, -NRC(O)NRR, -C(S)NRR, -NRC(S)R, -NRC(S)NRR, -NRC(S)NRR
  • Preferable compounds of Formula 1 according to the present invention used as GPR119 agonists are those wherein A is nitrogen.
  • n, R3, R4, R5, R6 and R7 are as defined above.
  • K, L, M, Q and T represent independently carbon or nitrogen and form phenyl or 6-membered heteroaryl, or represent, when one of K, L, M, Q and T does not exist, 5-membered heteroaryl to which oxygen, nitrogen or sulfur may be added as a ring atom,
  • n an integer of 1 to 5
  • R8 is independently hydrogen, halogen, cyano or nitro, or represents in each case optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, amine, hydroxyl, acetylene or vinyl, or is selected from the following groups:
  • U is selected from carbon, nitrogen, oxygen, phosphorus and sulfur
  • n independently 1 or 2
  • n 1
  • n 0,
  • R9 represents hydrogen or optionally substituted hydroxyl, amine, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and
  • V represents carbon, nitrogen, oxygen or sulfur.
  • R10, R11 and R12 are independently hydrogen, halogen or carbamoyl, or represent optionally substituted hydroxyl, alkyl, amine, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two groups selected from R10, R11 and R12 may be connected to form a ring, and
  • Especially preferable compounds are those wherein Ar is selected from the following groups:
  • n an integer of 1 to 5
  • R8 is nitro, or represents optionally substituted hydroxyl, alkyl, acetylene, amine, heteroaryl or heterocyclyl, or is selected from the following groups:
  • n, R9, R10, R11 and R12 are as defined above.
  • RA is selected from the following groups:
  • RB is selected from the following groups:
  • R1 and R2 represent independently hydrogen or C 1 -C 6 -alkyl
  • n in each ring an integer of 0 to 9
  • A represents nitrogen
  • n an integer of 0 to 5
  • R3, R4 and R5 are independently hydrogen or halogen, or represent C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, C 5 -C 10 -aryl, C 5 -C 10 -aryl-C 1 -C 6 -alkyl, heterocyclyl or heterocyclyl-C 1 -C 6 -alkyl (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom); or R4 and R5 are connected to form C 3 -C 10 -cycloalkyl, or a partially of fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom; wherein each radical in the definition of R3, R4 and R5 can be optionally substituted by
  • R6 represents hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, C 1 -C 6 -alkoxy, C 5 -C 10 -aryl or di(C 1 -C 6 -alkyl)amine, and n represents 0 or 1,
  • R7 is hydrogen or halogen, or represents C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 5 -C 10 -aryl, or 5- or 6-membered heteroaryl including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, wherein each radical in the definition of R7 can be optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, C 1 -C 6 -alkoxycarbonyl and C 1 -C 6 -alkyl,
  • Ar is selected from the following groups:
  • n 1 or 2
  • R8 is nitro or hydroxy-C 1 -C 6 -alkyl, or represents amine optionally 1- or 2- substituted by C 1 -C 6 -alkylsulfonyl, partially or fully saturated 5- or 6-membered heterocyclyl which includes 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and is optionally substituted by oxo, or 5- or 6-membered heteroaryl which includes 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, or is selected from the following groups:
  • n 1 or 2
  • R9 represents amino, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamine, di(C 1 -C 6 -alkyl)amine, C 3 -C 10 -cycloalkylamine, C 5 -C 10 -arylamine, C 5 -C 10 -aryl-C 1 -C 6 -alkylamine, heterocyclyl or heterocyclyl-C 1 -C 6 -alkylamine (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom), wherein each radical in the definition of R9 is optionally substituted by at least one selected from halogen, hydroxyl, amine,
  • R10, R11 and R12 represent independently hydrogen, hydroxyl, halogen, carbamoyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, C 5 -C 10 -aryl, C 1 -C 6 -alkylamine, di(C 1 -C 6 -alkyl)amine, C 3 -C 10 -cycloalkylamine, C 5 -C 10 -arylamine or C 5 -C 10 -aryl-C 1 -C 6 -alkylamine, or represent heterocyclyl, heterocyclyl-C 1 -C 6 -
  • Representative compounds of Formula 1 according to the present invention include, but are not limited to, the following compounds:
  • butane-1-sulfonic acid (4- ⁇ 4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-amide;
  • the present invention also provides a method for preparing the compounds of Formula 1.
  • the method for preparing the compounds of Formula 1 is explained based on exemplary reactions in order to illustrate the present invention.
  • a person skilled in the art could prepare the compounds of Formula 1 by various methods based on the structure of Formula 1, and such methods should be interpreted to be within the scope of the present invention. That is, the compounds of Formula 1 may be prepared by the methods described herein or by combining various methods disclosed in the prior art, which should be interpreted to be within the scope of the present invention. Accordingly, a method for preparing the compounds of Formula 1 is not limited to the following methods.
  • RA, RB, Ar, A, B, R1, R2 and n are as described above,
  • X represents a leaving group, preferably halogen, methanesulfonate (-OMs) and the like.
  • reaction scheme 1 will be explained in detail.
  • Compound 4 is obtained by the reaction of Compound 2 with Compound 3 in the presence of a conventional base or an organometallic catalyst.
  • Compound 5 is obtained by a conventional reduction and deprotection reaction from Compound 4.
  • Compound 7 can be obtained from Compound 6 by the Mitsunobu reaction with N-hydroxyphthalimide.
  • Compound 8 is then obtained by reacting Compound 7 with a conventional amine deprotecting agent such as hydrazine or alkyl hydrazine.
  • the compound of Formula 1 is obtained by a conventional condensation reaction of the intermediates of Compounds 5 and 8.
  • the compounds of Formula 1 according to the present invention can be prepared by the following reaction.
  • RA, RB, Ar, A, B, R1, R2, n and X are as described above.
  • Compound 5 is reacted with hydroxylamine to yield oxime compound 5-1, and Mitsunobu reaction is then carried out with Compound 6 to yield Compound 1.
  • Compound 1 can be obtained by the reaction of oxime compound 5-1 with the intermediate compound 6-1 which is substituted by the leaving group X.
  • Exemplary bases include, but are not limited to, metallic base such as sodium hydride (NaH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (Cs 2 CO 3 ), sodium carbonate (Na 2 CO 3 ) and potassium carbonate (K 2 CO 3 ), and organic base such as diisopropylethylamine, triethylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
  • metallic base such as sodium hydride (NaH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (Cs 2 CO 3 ), sodium carbonate (Na 2 CO 3 ) and potassium carbonate (K 2 CO 3
  • organic base such as diisopropylethylamine, triethylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
  • Preferable solvents include, but are not limited to, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, ethanol, water, 1,2-dichloroethane, dimethylsulfoxide, ethylether, methyl tert-butylether, methylene chloride, chloroform and mixtures thereof.
  • the compounds of Formula 1 obtained by the above methods can be separated or purified from the reaction products by conventional methods such as recrystallization, ionospheresis, silica gel column chromatography or ion-exchange chromatography.
  • the compounds according to the present invention can be prepared by a variety of methods, which should be interpreted to be within the scope of the present invention.
  • the compounds of Formula 1 according to the present invention have the effect of GPR119 agonists. Accordingly, the present invention provides a pharmaceutical composition as GPR119 agonists comprising the compounds of Formula 1, pharmaceutically acceptable salts or isomers thereof as an active component.
  • Exemplary diseases which can be prevented or treated by the pharmaceutical composition according to the present invention as GPR119 agonists include, but are not limited to, diabetes, complications of diabetes, obesity, dyslipidemia, osteoporosis and the like.
  • the pharmaceutical composition of the present invention can be used to prevent or treat type 1 or type 2 diabetes, especially preferable to prevent or treat type 2 diabetes.
  • the present invention provides a composition for lowering blood glucose level comprising an effective amount of a compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof and a pharmaceutically acceptable carrier.
  • the present invention provides a method for preparing the composition for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis which comprises the step of mixing the compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof as an active component and a pharmaceutically acceptable carrier.
  • the “pharmaceutical composition” or the “composition for lowering blood glucose level” can include carriers, diluents, excipients or combinations thereof, in addition to the active component of the present invention. Accordingly, the pharmaceutical composition can include pharmaceutically acceptable carriers, diluents, excipients or combinations thereof as necessary.
  • the pharmaceutical composition facilitates the administration of compounds into the body. Various methods for administering the compounds include, but are not limited to, oral, injection, aerosol, parenteral and local administration.
  • carriers mean compounds that facilitate the addition of compounds into the cell or tissue.
  • dimethylsulfoxide is a conventional carrier facilitating the administration of compounds into the living cell or tissue.
  • diluents mean compounds that not only stabilize a biologically active form but are also diluted in solvent dissolving the compounds. Dissolved salts in buffer are used as diluents in this field.
  • a conventionally used buffer is a phosphate buffer saline copying salt form in body fluid. Since buffer solution can control the pH of the solution at low concentration, buffer diluents hardly modify the biological activity of compounds.
  • pharmaceutically acceptable means such property that does not impair the biological activity and physical property of compounds.
  • the compounds according to the present invention can be formulated as various pharmaceutically administered dosage forms.
  • an active component specifically, the compound of Formula 1 ⁇ , a pharmaceutically acceptable salt or isomer thereof is mixed with selected pharmaceutically acceptable carriers considering the dosage form to be prepared.
  • the pharmaceutical composition of the present invention can be formulated as injections, oral preparations and the like, as needed.
  • the compounds of the present invention can be formulated by conventional methods using known pharmaceutical carriers and excipients, and inserted into a unit or multi-unit containers.
  • the formulations may be solution, suspension or emulsion in oil or aqueous solvent and include conventional dispersing agents, suspending agents or stabilizing agents.
  • the compounds may be, for example, dry powder form which is dissolved in sterilized pyrogen-free water before use.
  • the compounds of the present invention can be formulated into suppositories by using a conventional suppository base such as cocoa butter or other glycerides.
  • Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are preferred. Tablets and pills are preferably enteric-coated.
  • Solid forms are manufactured by mixing the compounds of the present invention with at least one carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrating agents, binders and the like.
  • carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrating agents, binders and the like.
  • the compounds according to the present invention can be administered in combination with other drugs ⁇ for example, other antidiabetics, as required.
  • the dose of the compounds according to the present invention is determined by a physician’s prescription considering the patient’s body weight, age and disease condition.
  • a typical dose for adults is in the range of about 0.3 to 500 mg per day according to the frequency and intensity of administration.
  • a typical daily dose of intramuscular or intravenous administration for adults is in the range of about 1 to 300 mg per day which can be administered in divided unit dosage. Some patients need a higher daily dose.
  • the present invention also provides a method for preventing or treating diseases by using an effective amount of the compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof as an active component of GPR119 agonists.
  • Representative diseases to be treated by GPR119 agonists include, but are not limited to, metabolic disorders such as the above-mentioned diabetes, complications of diabetes, obesity, dyslipidemia, osteoporosis and the like.
  • treatment is used to mean deterring, delaying or ameliorating the progress of diseases in a subject exhibiting symptoms of diseases.
  • prevention is used to mean deterring, delaying or ameliorating the sign of diseases in a subject at risk of exhibiting symptoms of diseases, even if he or she does not exhibit the symptoms.
  • the oxime derivatives of Formula 1 according to the present invention stimulate the secretion of insulin in the pancreas and promote GLP-1, PYY and GIP formation in the gastrointestinal tract, and can accordingly be effectively used for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis.
  • M means molar concentration
  • N means normal concentration
  • the mixture was made vacuous by using a vacuum pump and purged with nitrogen. Under nitrogen gas, the mixture was refluxed at 80 °C for 16 hours. The reaction was terminated by adding water, filtered with celite, and washed with ethyl acetate, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography using 4:1 mixture solution of hexane and ethyl acetate to obtain the title compound (21.1 g, 85% yield).
  • Triphenylphosphine (4.17 g, 17.97 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to 0 °C. N,N-diisopropylazodicarboxylate (3 mL) was added dropwise and 4-hydroxy-piperidin-1-carboxylic acid tert-butyl ester (3 g, 14.9 mmol) was added thereto and the mixture was stirred for 30 minutes. Hydroxyphthalimide (2.46 g, 15.12 mmol) was added and the mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was distilled under reduced pressure to remove the solvent, and purified by column chromatography using 5:5:1 mixture solution of hexane, methylene chloride and ethyl acetate to obtain 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (3.11 g, 60% yield).
  • the obtained compound (3.11 g, 8.97 mmol) was dissolved in methylene chloride (50 mL) and cooled to 0 °C. Methylhydrazine (0.53 g, 11.67 mmol) was added and the mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was cooled to 0 °C and filtered under reduced pressure with methylene chloride to obtain the title compound (1.8 g, 92% yield).
  • the filtrate was distilled under reduced pressure, extracted with ethyl acetate, and washed with water and saturated aqueous solution of sodium chloride.
  • the organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure and purified by column chromatography using 4:1 ⁇ 1:1 mixture solution of hexane and ethyl acetate to obtain the title compound (80 mg, 88% yield).
  • Tetrahydrofuran (7.3 mL) was added to 4-[4-(1,4-dioxaspiro[4,5]decan-8-yloxyimino)cyclohexyl]-2,5-difluoroaniline (0.2 g, 0.5 mmol) obtained in Preparation Example 67 and cooled to 0 oC.
  • 6N HCl aqueous solution (1.5 mL) was added dropwise slowly and the mixture was stirred at room temperature. After confirming a completion of the reaction by TLC, sodium bicarbonate aqueous solution was used to adjust to pH 7, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the title compound (0.18 g, 99% yield).
  • Example 1 4-(4- ⁇ 2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester
  • 3-hydroxyazetidine hydrochloride (9.3 mg, 0.0857 mmol) and triethylamine (78 mg, 0.58 mmol) were added sequentially and stirred at room temperature for 10 minutes. Water was added to terminate the reaction, and then the mixture was washed with methylene chloride, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure and then separated by Prep-TLC using 1:1 mixture solution of methylene chloride and ethyl acetate to obtain the title compound (20 mg, 50% yield).
  • Example 8 4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
  • sodium borohydride (492 mg, 13.01 mmol) was added and dissolved into water at 0 oC, and stirred at room temperature for 3 hours. 1N hydrochloride aqueous solution was added thereto to terminate the reaction, and then the mixture was washed with ethyl acetate, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure and then separated by column chromatography using 2:1 mixture solution of hexane and ethyl acetate to obtain the title compound (90 mg, 84% yield).
  • Example 10 4-[4-(2,5-difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
  • Example 13 4-[4-(2,5-difluoro-4- ⁇ [(3-hydroxy-azetidine-1-carbonyl)-amino]-methyl ⁇ -phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester
  • Example 16 4- ⁇ 4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy ⁇ -piperidine-1-carboxylic acid isopropyl ester
  • Example 17 4-(4- ⁇ 2,5-difluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
  • Example 18 4-(4- ⁇ 4-[3-(2,3-dihydroxy-propyl)-ureido]-2,5-difluoro-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
  • Example 19 4-[4-(4-methanesulfonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
  • Example 20 4-(4- ⁇ 4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester
  • Example 21 4-(4- ⁇ 4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl ⁇ -cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
  • reaction mixture was distilled under reduced pressure to remove the solvent and then separated by Prep-TLC to obtain N-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-N-(methanesulfonyl)methanesulfonamide (18.3 mg, 67% yield).
  • Example 35 3-hydroxy-azetidine-1-carboxylic acid (3-fluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-amide
  • Example 36 1-(2,5-difluoro-4- ⁇ 4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-methoxy-ethyl)-urea
  • Example 40 ⁇ 2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl ⁇ -carbamic acid methyl ester
  • Example 39 A byproduct produced in Example 39 was purified to obtain the title compound (4.2 mg, 7% yield).
  • Example 42 ⁇ 4-[4-(1- benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5- difluoro-phenyl ⁇ -carbamic acid methyl ester
  • Example 45 1-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(3-hydroxy -2,2-dimethyl-propyl)-urea
  • Example 46 1-(2,5-difluoro-4- ⁇ 4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(3-hydroxy -2,2-dimethyl-propyl)-urea
  • Example 48 3-hydroxy-azetidine-1-carboxylic acid (2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-amide
  • Example 50 4-[4-(2,5-difluoro-4-guanidinocarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
  • Example 54 (4- ⁇ 4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-urea
  • Example 56 3-hydroxy-azetidine-1-carboxylic acid ⁇ 2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl ⁇ -amide
  • Example 57 1-(4- ⁇ 4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-3-(2-hydroxy-propyl)-urea
  • Example 58 1-(4- ⁇ 4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea
  • Example 59 1-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-ethoxy-ethyl)-urea
  • Example 60 1-(4- ⁇ 4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea
  • Example 61 1-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea
  • Example 62 ⁇ 2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl ⁇ -urea
  • Example 65 1-(2,3-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-hydroxy-propyl)-urea
  • Example 66 3-(4- ⁇ 4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -2,5-difluoro-phenyl)-1,1-dimethyl-urea
  • Example 69 1-(2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-methoxy-ethyl)-urea
  • Example 70 1-(2,5-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea
  • Example 72 1-(2,5-difluoro-4- ⁇ 4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(3-hydroxy-propyl)-urea
  • Example 73 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4- ⁇ 4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-amide
  • Example 74 1-(2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-hydroxy-ethyl)-urea
  • Example 75 1-(2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(3-hydroxy-propyl)-urea
  • Example 76 1-(2,6-difluoro-4- ⁇ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl ⁇ -phenyl)-3-(2-hydroxy-propyl)-urea

Abstract

The present invention relates to oxime derivatives, a method for preparing the same, a pharmaceutical composition comprising the same and use thereof. The oxime derivatives according to the present invention act as GPR119 agonists to stimulate the secretion of insulin and promote GLP-1 formation for preventing or treating type 2 diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis.

Description

OXIME DERIVATIVES AS GPR119 AGONISTS
The present invention relates to novel oxime derivatives as GPR119 agonists, a method for preparing the same, a pharmaceutical composition comprising the same and use thereof. Herein a GPR119 agonist means a compound which can be effectively used for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis by stimulating the secretion of insulin in the pancreas and promoting GLP-1 and GIP formation in the gastrointestinal tract.
Diabetes is divided into two types─i.e., insulin-dependent type 1 diabetes and insulin-independent (insulin-resistant) type 2 diabetes which is found in 90% or more of diabetic patients.
In insulin-resistant type 2 diabetic patients, internal insulin does not take effect completely so blood glucose should be controlled in another way, and an oral hypoglycemic agent is mostly used.
Currently, most antidiabetics control blood glucose by the mechanism of action to affect one target organ such as the liver, pancreas or muscle. For example, sulfonlyureas act directly on the pancreas to secret insulin, and metformin has the mechanism of action of preventing glucolysis in the liver. However, a single drug hardly accomplishes the expected effect in many cases and each drug also has its side effects. Sulfonylureas have problems of decreasing the function of the pancreas and incurring hypoglycemia due to excessive secretion of insulin, and metformin causes gastroenteric disorders or renal toxicity. Glitazones also have side effects of weight gain, serious heart failure, etc. Meanwhile, incretin-related drugs such as DPPIV inhibitors or Exenatide, which have recently entered the market, are noted as medicines for solving problems such as increase of glucagon production, gradual decrease of the β-cell function in the pancreas, incurrence of hypoglycemia, weight gain, etc. which cannot be solved by traditional antidiabetics. However, DPPIV inhibitors have a marginal effect, and it is especially reported that Galvus has a side effect of skin toxicity. Furthermore, Exenatide has a disadvantage in that it must be given by means of injection.
As described above, most conventional antidiabetics have various problems and side effects, and it is highly necessary to develop innovative antidiabetics which can be used for the treatment of diabetics effectively and safely.
GPR119 agonists, which are noted for possible treatment of type 2 diabetes, are known to have antidiabetic effects caused by the actions of (1) stimulating the secretion of insulin in the pancreas and (2) increasing incretin hormone in intestinal cells.
Accordingly, GPR119 agonists show antidiabetic effects by acting directly on β-cells in the pancreas to stimulate GSIS and acting on intestinal cells to stimulate the secretion of incretin hormones, GLP-1, GIP and PYY. GLP-1 is known to act on β-cells in the pancreas to stimulate the secretion of insulin, and also to have an effect of various antidiabetics, anti-obesity, and prevention and treatment of osteoporosis, including a decrease of glucagon secretion after meals, a decrease of gastrointestinal activity, appetite loss, weight loss and proliferation of β-cells in the pancreas. Accordingly, GPR119 agonists, which stimulate the secretion of incretin hormones, are also expected to have the effects of incretin hormones.
Considering the above, researches on GPR119 agonists are actively in progress. In the representative compounds presented as GPR119 agonists, patentability is mainly established in the center bridge structure binding left and right substituents and determining the orientation of the whole structure. GPR119 agonist compounds having aromatic substituents are disclosed in WO 2007/003964, WO 2008/109702, WO 2008/076243 and WO 2008/085316.
The object of the present invention is to provide oxime derivatives as GPR119 agonists.
Another object of the present invention is to provide a method for preparing the oxime derivatives.
Still another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis which comprises as active components the oxime derivatives, and a method for preparing the composition.
A still further object of the present invention is to provide a method for preventing and treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis which use the oxime derivatives as active components.
Therefore, the present invention provides oxime derivatives of Formula 1, or pharmaceutically acceptable salts or isomers thereof:
[Formula 1]
Figure PCTKR2012001185-appb-I000001
wherein,
RA represents a partially or fully saturated 4- to 7-membered cycloalkyl,
RB represents a partially or fully saturated 4- to 7-membered heterocycle, or a [5.5], [5.6], [5.7], [6.6] or [6.7] fused ring system consisting of two rings,
R1 and R2 represent independently hydrogen, halogen or alkyl,
n represents an integer of 0 to 10 in each ring,
A represents nitrogen or carbon,
B is selected from the following groups:
Figure PCTKR2012001185-appb-I000002
wherein,
D represents carbon, nitrogen, oxygen or sulfur,
R3, R4 and R5 are independently hydrogen or halogen, or represent in each case optionally substituted aryl, arylalkyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl or amine,
provided that, when D is oxygen or sulfur, both R3 and R4 do not exist,
when D is sulfur, R5 is not amine,
when D is nitrogen, R3 does not exist,
when D is carbon, two groups selected from R3, R4 and R5 are connected together to form optionally substituted 3- to 7-membered cycloalkyl or heterocycle, or to form optionally substituted 5- or 6-membered aryl or heteroaryl,
E, F, G, H and I represent independently carbon, nitrogen, oxygen or sulfur to form 6-membered aryl or heteroaryl, or form optionally benzo-fused 5-membered aryl or heteroaryl excluding one of E, F, G, H and I,
n represents an integer of 0 to 5,
R6 is hydrogen or halogen; or represents optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl or heteroarylalkyl; or represents hydroxy or amine optionally substituted by 1 or 2 alkyl or aryl, wherein two substituents of amine are connected together to form 3- to 7-membered heterocyclyl,
J represents optionally substituted C1-C4-alkylene or sulfonyl,
R7 is hydrogen or halogen, or represents optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, and
Ar represents optionally substituted aryl or heteroaryl.
The compounds of Formula 1 according to the present invention can form pharmaceutically acceptable salts, which include acid-addition salts which are formed from inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicylic acid; or sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, which form non-toxic acid-addition salts including pharmaceutically acceptable anion. For example, the pharmaceutically acceptable carboxylic acid salts include the salts with alkali metal or alkali earth metal such as lithium, sodium, potassium, calcium and magnesium; salts with amino acid such as lysine, arginine and guanidine; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine. The compounds of Formula 1 according to the present invention can be converted into their salts by conventional methods.
Furthermore, since the compounds of Formula 1 according to the present invention can have an asymmetric carbon center and asymmetric axis or plane, they can exist as E- or Z-isomer, R- or S-isomer, racemic mixtures or diastereoisomer mixtures and each diastereoisomer, all of which are within the scope of the present invention.
Herein, unless indicated otherwise, the term “the compounds of Formula 1” is used to mean all the compounds of Formula 1, including the pharmaceutically acceptable salts and isomers thereof.
The terms used herein are defined as follows.
Halogen or halo means fluoride (F), chlorine (Cl), bromine (Br) or iodine (I).
Alkyl means straight or branched hydrocarbons which can include single bond, double bond or triple bond. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, acetylene, vinyl, trifluoromethyl and the like.
Cycloalkyl means partially or fully saturated single or fused ring hydrocarbons and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and the like.
Aryl means aromatic hydrocarbons and includes, but is not limited to, phenyl, naphthyl and the like.
Heteroaryl means aromatic hydrocarbons which form a single or fused ring including at least one hetero atom selected from N, O and S. Examples of heteroaryl include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole, 1,2,3,4-tetrahydroisoquinolyl, thiazolopyridyl and the like.
Heterocyclyl means partially or fully saturated hydrocarbons which form a single or fused ring including at least one hetero atom selected from N, O and S. Examples of heterocyclyl include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, imidazolinyl, piperazinyl, tetrahydrofuran, tetrahydrothiofuran and the like.
Arylalkyl and heteroarylalkyl mean groups which are formed by the combination of the above-mentioned aryl with alkyl and heteroaryl with alkyl. Examples include, but are not limited to, benzyl, thiophene methyl, pyrimidine methyl and the like.
The above-mentioned amine, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl and heteroarylalkyl may be substituted by at least one group selected from the following groups: alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, oxo, cyano, halo, nitro, -OR, -OC(O)R, -OC(O)OR, SR, -S(O)R, -S(O)2R, -C(O)R, -C(O)OR, -C(S)R, -C(O)NRR, -NR2, -NRCHO, -NRC(O)R, -NRC(O)NRR, -C(S)NRR, -NRC(S)R, -NRC(S)NRR, wherein R is independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, and when two Rs are substituted, they may be connected to form cycloalkyl or heterocyclyl.
Preferable compounds of Formula 1 according to the present invention used as GPR119 agonists are those wherein A is nitrogen.
Other preferable compounds are those wherein B is selected from the following groups:
Figure PCTKR2012001185-appb-I000003
wherein n, R3, R4, R5, R6 and R7 are as defined above.
Still other preferable compounds are those wherein Ar represents the following formula:
Figure PCTKR2012001185-appb-I000004
wherein,
K, L, M, Q and T represent independently carbon or nitrogen and form phenyl or 6-membered heteroaryl, or represent, when one of K, L, M, Q and T does not exist, 5-membered heteroaryl to which oxygen, nitrogen or sulfur may be added as a ring atom,
n represents an integer of 1 to 5,
R8 is independently hydrogen, halogen, cyano or nitro, or represents in each case optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, amine, hydroxyl, acetylene or vinyl, or is selected from the following groups:
Figure PCTKR2012001185-appb-I000005
wherein,
U is selected from carbon, nitrogen, oxygen, phosphorus and sulfur,
when U is sulfur or phosphorus, n represents independently 1 or 2,
when U is carbon or nitrogen, n represents 1,
when U is oxygen, n represents 0,
R9 represents hydrogen or optionally substituted hydroxyl, amine, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and
V represents carbon, nitrogen, oxygen or sulfur.
R10, R11 and R12 are independently hydrogen, halogen or carbamoyl, or represent optionally substituted hydroxyl, alkyl, amine, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two groups selected from R10, R11 and R12 may be connected to form a ring, and
when V is oxygen or sulfur, R11 does not exist.
Especially preferable compounds are those wherein Ar is selected from the following groups:
Figure PCTKR2012001185-appb-I000006
wherein
n represents an integer of 1 to 5,
R8 is nitro, or represents optionally substituted hydroxyl, alkyl, acetylene, amine, heteroaryl or heterocyclyl, or is selected from the following groups:
Figure PCTKR2012001185-appb-I000007
wherein n, R9, R10, R11 and R12 are as defined above.
The most preferable compounds of Formula 1 according to the present invention are those wherein
RA is selected from the following groups:
Figure PCTKR2012001185-appb-I000008
RB is selected from the following groups:
Figure PCTKR2012001185-appb-I000009
wherein R1 and R2 represent independently hydrogen or C1-C6-alkyl,
n represents in each ring an integer of 0 to 9,
A represents nitrogen,
B is selected from the following groups:
Figure PCTKR2012001185-appb-I000010
wherein,
n represents an integer of 0 to 5,
R3, R4 and R5 are independently hydrogen or halogen, or represent C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C5-C10-aryl, C5-C10-aryl-C1-C6-alkyl, heterocyclyl or heterocyclyl-C1-C6-alkyl (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom); or R4 and R5 are connected to form C3-C10-cycloalkyl, or a partially of fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom; wherein each radical in the definition of R3, R4 and R5 can be optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, C1-C6-alkoxycarbonyl and C1-C6-alkyl,
R6 represents hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C1-C6-alkoxy, C5-C10-aryl or di(C1-C6-alkyl)amine, and n represents 0 or 1,
R7 is hydrogen or halogen, or represents C1-C6-alkyl, C3-C10-cycloalkyl, C5-C10-aryl, or 5- or 6-membered heteroaryl including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, wherein each radical in the definition of R7 can be optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, C1-C6-alkoxycarbonyl and C1-C6-alkyl,
Ar is selected from the following groups:
Figure PCTKR2012001185-appb-I000011
wherein,
n represents 1 or 2,
R8 is nitro or hydroxy-C1-C6-alkyl, or represents amine optionally 1- or 2- substituted by C1-C6-alkylsulfonyl, partially or fully saturated 5- or 6-membered heterocyclyl which includes 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and is optionally substituted by oxo, or 5- or 6-membered heteroaryl which includes 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, or is selected from the following groups:
Figure PCTKR2012001185-appb-I000012
wherein,
n represents 1 or 2,
R9 represents amino, hydroxyl, C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C1-C6-alkylamine, di(C1-C6-alkyl)amine, C3-C10-cycloalkylamine, C5-C10-arylamine, C5-C10-aryl-C1-C6-alkylamine, heterocyclyl or heterocyclyl-C1-C6-alkylamine (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom), wherein each radical in the definition of R9 is optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, carbamoyl and C1-C6-alkyl, and
R10, R11 and R12 represent independently hydrogen, hydroxyl, halogen, carbamoyl, C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C5-C10-aryl, C1-C6-alkylamine, di(C1-C6-alkyl)amine, C3-C10-cycloalkylamine, C5-C10-arylamine or C5-C10-aryl-C1-C6-alkylamine, or represent heterocyclyl, heterocyclyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkylamine (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom) or heteroarylalkyl (wherein, heteroaryl is a partially or fully saturated 3- to 10-membered aromatic ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom); or two groups selected from R10, R11 and R12 are connected to form C3-C10-cycloalkyl, 4- to 6-membered heteroaryl including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, or a partially or fully saturated 4- to 6-membered heterocyclyl including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, wherein each radical in the definition of R10, R11 and R12 is optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, azido, C3-C10-cycloalkyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyloxy and C1-C6-alkyl.
Representative compounds of Formula 1 according to the present invention include, but are not limited to, the following compounds:
4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester;
4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
3-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-1,1-dimethyl-urea;
3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-amide;
4-cyclopropyl-piperazine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea;
4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester;
4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[4-(2,5-difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester;
(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
3-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
4-[4-(2,5-difluoro-4-{[(3-hydroxy-azetidine-1-carbonyl)-amino]-methyl}-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[4-(2,5-difluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
4-{4-[2,5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester;
4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester;
4-(4-{2,5-difluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
4-(4-{4-[3-(2,3-dihydroxy-propyl)-ureido]-2,5-difluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
4-[4-(4-methanesulfonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester;
4-(4-{4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester;
4-(4-{4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimono]-cyclohexyl}-phenyl)-amide;
1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea;
(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1,1-dimethyl-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-hydroxymethyl-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2,3-dihydroxy-propyl)-urea;
N-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide;
1-(3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea;
(3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
3-hydroxy-azetidine-1-carboxylic acid (3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea;
N-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide;
{2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-urea;
{2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-carbamic acid methyl ester;
{4-[4-(1-benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5-difluoro-phenyl}-urea;
{4-[4-(1-benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5-difluoro-phenyl}-carbamic acid methyl ester;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-hydroxy-ethyl)-urea;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-2,2-dimethyl-propyl)-urea;
1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-2,2-dimethyl-propyl)-urea;
(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
3-hydroxy-azetidine-1-carboxylic acid (2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
butane-1-sulfonic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-amide;
4-[4-(2,5-difluoro-4-guanidinocarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester;
(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea;
(R)-3-fluoro-pyrrolidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-amide;
(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea;
(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea;
1-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
3-hydroxy-azetidine-1-carboxylic acid {2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl}-amide;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-hydroxy-propyl)-urea;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea;
1-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea;
{2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl}-urea;
(2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
1-(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
3-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-1,1-dimethyl-urea;
3-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
3-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea;
1-(2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea;
1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
4-[4-(2-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
4-(4-{2-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2-fluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2,5-difluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
(4-{4-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea;
1-(4-{4-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
(2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea;
(2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea;
(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-dicarbonimidic diamide;
1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
3-hydroxy-azetidin-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea;
1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-thiophen-2-ylmethyl-urea;
(2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
3-hydroxy-azetidine-1-carboxylic acid (2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
1-(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
1-(2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
3-hydroxy-azetidine-1-carboxylic acid (2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-amide;
(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-urea;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3-(2-hydroxy-propyl)-urea;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3-propyl-urea
4-[4-(3-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
(2,5-difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-urea;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(2-hydroxy-propyl)-urea;
3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-amide;
4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid ethyl ester;
4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid (2-fluoro-ethyl)-amide;
4-(5-hydroxymethyl-4-methyl-thiazol-2-yl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
3-hydoxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
4-(4-{3-fluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
1-(2,5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
3-hydoxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
[(S)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-(4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester;
4-{4-[(S)-2-amino-3-((S)-3-fluoro-pyrrolidin-1-yl)-3-oxo-propyl]-phenyl}-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-methyl-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-isopropyl-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea;
4-[4-(2-fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester;
4-[4-(3-fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester;
4-[4-(2,5-difluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester;
4-{4-[2,5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
4-{4-[4-(3,3-dimethyl-ureido)-2,5-difluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[(Z)-1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohex-1-enyl}-phenyl)-amide;
4-{4-[3-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
4-{4-[2-fluoro-4-(2-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
4-(4-{2-fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
4-{4-[4-(3,3-dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
4-(4-{3-fluoro-4-[3-(2-fluoro-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
3-(2-fluoro-4-{4-[1-(3,3,3-trifluoro-propyl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
3-{4-[4-(1-benzyl-piperidin-4-yloxyimino)-cyclohexyl]-2-fluoro-phenyl}-1,1-dimethyl-urea;
3-{2-fluoro-4-[4-(1-naphthalen-2-ylmethyl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-1,1-dimethyl-urea;
4-(4-{3-fluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
4-(4-{3-fluoro-4-[3-(2-fluoro-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
3-{4-[2-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-pyrrolidine-1-carboxylic acid phenyl ester;
4-(4-{3-fluoro-4-[3-(2-hydroxy-1-methyl-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
4-(4-{3-fluoro-4-[3-(2-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
4-(4-{3-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
4-{4-[3-fluoro-4-(3-methyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester;
4-{4-[3-fluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester;
4-{4-[4-(3,3-dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidin-yl-carboxylic acid isopropyl ester;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-methyl-urea;
1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(2-hydro-1-methyl-ethyl)-urea;
4-{4-[3-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidin-yl-carboxylic acid isopropyl ester;
4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea;
3-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea;
1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea;
(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea;
1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea;
3-hydroxy-azetidine-1-carboxylic acid (2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-((R)-2-hydroxy-1-methyl-ethyl)-urea;
1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-((S)-2-hydroxy-1-methyl-ethyl)-urea;
4-[4-(2,5-difluoro-4-ureido-phenyl)-cyclohexylideneaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester;
4-(2,5-difluoro-4-tetrazol-1-yl-phenyl)-cyclohexenone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
4-para-tolyl-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
4-naphthalen-2-yl-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
3-hydroxy-azetidine-1-carboxylic acid (3-methyl-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
3-hydroxy-azetidine-1-carboxylic acid (3-methoxy-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
1-(6-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-pyrimidin-3-yl)-3-propyl-urea; and
3-[4-(2-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester.
The terms and abbreviations used herein have their original meanings unless indicated otherwise.
The present invention also provides a method for preparing the compounds of Formula 1. Hereinafter, the method for preparing the compounds of Formula 1 is explained based on exemplary reactions in order to illustrate the present invention. However, a person skilled in the art could prepare the compounds of Formula 1 by various methods based on the structure of Formula 1, and such methods should be interpreted to be within the scope of the present invention. That is, the compounds of Formula 1 may be prepared by the methods described herein or by combining various methods disclosed in the prior art, which should be interpreted to be within the scope of the present invention. Accordingly, a method for preparing the compounds of Formula 1 is not limited to the following methods.
[Reaction scheme 1]
Figure PCTKR2012001185-appb-I000013
Figure PCTKR2012001185-appb-I000014
Figure PCTKR2012001185-appb-I000015
wherein,
RA, RB, Ar, A, B, R1, R2 and n are as described above,
X represents a leaving group, preferably halogen, methanesulfonate (-OMs) and the like.
Hereinafter, reaction scheme 1 will be explained in detail.
Compound 4 is obtained by the reaction of Compound 2 with Compound 3 in the presence of a conventional base or an organometallic catalyst. Compound 5 is obtained by a conventional reduction and deprotection reaction from Compound 4.
Compound 7 can be obtained from Compound 6 by the Mitsunobu reaction with N-hydroxyphthalimide. Compound 8 is then obtained by reacting Compound 7 with a conventional amine deprotecting agent such as hydrazine or alkyl hydrazine. The compound of Formula 1 is obtained by a conventional condensation reaction of the intermediates of Compounds 5 and 8.
Alternatively, the compounds of Formula 1 according to the present invention can be prepared by the following reaction.
[Reaction scheme 2]
Figure PCTKR2012001185-appb-I000016
Figure PCTKR2012001185-appb-I000017
Figure PCTKR2012001185-appb-I000018
wherein,
RA, RB, Ar, A, B, R1, R2, n and X are as described above.
Compound 5 is reacted with hydroxylamine to yield oxime compound 5-1, and Mitsunobu reaction is then carried out with Compound 6 to yield Compound 1. Alternatively, Compound 1 can be obtained by the reaction of oxime compound 5-1 with the intermediate compound 6-1 which is substituted by the leaving group X.
In the above reactions, conventional metallic base and organic base can be used. Exemplary bases include, but are not limited to, metallic base such as sodium hydride (NaH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3) and potassium carbonate (K2CO3), and organic base such as diisopropylethylamine, triethylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
The above reactions can be carried out in conventional solvents which do not have an adverse effect on the reactions. Preferable solvents include, but are not limited to, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, ethanol, water, 1,2-dichloroethane, dimethylsulfoxide, ethylether, methyl tert-butylether, methylene chloride, chloroform and mixtures thereof.
In the above reactions, unexplained compounds are known compounds or compounds easily obtainable from known compounds by known methods or similar methods.
The compounds of Formula 1 obtained by the above methods can be separated or purified from the reaction products by conventional methods such as recrystallization, ionospheresis, silica gel column chromatography or ion-exchange chromatography.
As described above, the compounds according to the present invention, starting materials or intermediates for the preparation thereof can be prepared by a variety of methods, which should be interpreted to be within the scope of the present invention.
The compounds of Formula 1 according to the present invention have the effect of GPR119 agonists. Accordingly, the present invention provides a pharmaceutical composition as GPR119 agonists comprising the compounds of Formula 1, pharmaceutically acceptable salts or isomers thereof as an active component.
Exemplary diseases which can be prevented or treated by the pharmaceutical composition according to the present invention as GPR119 agonists include, but are not limited to, diabetes, complications of diabetes, obesity, dyslipidemia, osteoporosis and the like. The pharmaceutical composition of the present invention can be used to prevent or treat type 1 or type 2 diabetes, especially preferable to prevent or treat type 2 diabetes. Specifically, the present invention provides a composition for lowering blood glucose level comprising an effective amount of a compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof and a pharmaceutically acceptable carrier.
In addition, the present invention provides a method for preparing the composition for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis which comprises the step of mixing the compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof as an active component and a pharmaceutically acceptable carrier.
According to the present invention, the “pharmaceutical composition” or the “composition for lowering blood glucose level” can include carriers, diluents, excipients or combinations thereof, in addition to the active component of the present invention. Accordingly, the pharmaceutical composition can include pharmaceutically acceptable carriers, diluents, excipients or combinations thereof as necessary. The pharmaceutical composition facilitates the administration of compounds into the body. Various methods for administering the compounds include, but are not limited to, oral, injection, aerosol, parenteral and local administration.
Herein, “carriers” mean compounds that facilitate the addition of compounds into the cell or tissue. For example, dimethylsulfoxide is a conventional carrier facilitating the administration of compounds into the living cell or tissue.
Herein, “diluents” mean compounds that not only stabilize a biologically active form but are also diluted in solvent dissolving the compounds. Dissolved salts in buffer are used as diluents in this field. A conventionally used buffer is a phosphate buffer saline copying salt form in body fluid. Since buffer solution can control the pH of the solution at low concentration, buffer diluents hardly modify the biological activity of compounds.
Herein, “pharmaceutically acceptable” means such property that does not impair the biological activity and physical property of compounds.
The compounds according to the present invention can be formulated as various pharmaceutically administered dosage forms. In the preparation of the pharmaceutical composition of the present invention, an active component─specifically, the compound of Formula 1─, a pharmaceutically acceptable salt or isomer thereof is mixed with selected pharmaceutically acceptable carriers considering the dosage form to be prepared. For example, the pharmaceutical composition of the present invention can be formulated as injections, oral preparations and the like, as needed.
The compounds of the present invention can be formulated by conventional methods using known pharmaceutical carriers and excipients, and inserted into a unit or multi-unit containers. The formulations may be solution, suspension or emulsion in oil or aqueous solvent and include conventional dispersing agents, suspending agents or stabilizing agents. In addition, the compounds may be, for example, dry powder form which is dissolved in sterilized pyrogen-free water before use. The compounds of the present invention can be formulated into suppositories by using a conventional suppository base such as cocoa butter or other glycerides. Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are preferred. Tablets and pills are preferably enteric-coated. Solid forms are manufactured by mixing the compounds of the present invention with at least one carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrating agents, binders and the like.
The compounds according to the present invention can be administered in combination with other drugs─for example, other antidiabetics, as required.
The dose of the compounds according to the present invention is determined by a physician’s prescription considering the patient’s body weight, age and disease condition. A typical dose for adults is in the range of about 0.3 to 500 mg per day according to the frequency and intensity of administration. A typical daily dose of intramuscular or intravenous administration for adults is in the range of about 1 to 300 mg per day which can be administered in divided unit dosage. Some patients need a higher daily dose.
The present invention also provides a method for preventing or treating diseases by using an effective amount of the compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof as an active component of GPR119 agonists. Representative diseases to be treated by GPR119 agonists include, but are not limited to, metabolic disorders such as the above-mentioned diabetes, complications of diabetes, obesity, dyslipidemia, osteoporosis and the like. Herein, the term “treatment” is used to mean deterring, delaying or ameliorating the progress of diseases in a subject exhibiting symptoms of diseases. The term “prevention” is used to mean deterring, delaying or ameliorating the sign of diseases in a subject at risk of exhibiting symptoms of diseases, even if he or she does not exhibit the symptoms.
The oxime derivatives of Formula 1 according to the present invention stimulate the secretion of insulin in the pancreas and promote GLP-1, PYY and GIP formation in the gastrointestinal tract, and can accordingly be effectively used for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis.
The present invention is explained in more detail by the following Examples. However, these Examples seek to illustrate the present invention only, and the scope of the present invention is not limited by them. Hereinafter, M means molar concentration and N means normal concentration.
Preparation Example 1: 8-(2,5-difluoro-4-nitro-phenyl)-1,4-dioxa-spiro[4.5]dec-7-ene
4-Bromo-2,5-difluoronitrobenzene (19.82 g, 83.28 mmol) was dissolved in 1,4-dioxane (410 mL) and then 8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (26 g, 99.88 mmol) was added thereto. After dichlorobis(triphenylphosphine) palladium(2) (2.9 g, 4.16 mmol) was added, 1.0M sodium carbonate (250 mL, 249.85 mmol) was added thereto. The mixture was made vacuous by using a vacuum pump and purged with nitrogen. Under nitrogen gas, the mixture was refluxed at 80 ℃ for 16 hours. The reaction was terminated by adding water, filtered with celite, and washed with ethyl acetate, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography using 4:1 mixture solution of hexane and ethyl acetate to obtain the title compound (21.1 g, 85% yield).
NMR: 1H-NMR(CDCl3) 7.81~7.77(1H, m), 7.24~7.00(1H, m), 6.11(1H, m), 4.03(4H, s), 2.64~2.61(2H, m), 2.52~2.51(2H, m), 1.92(2H, t)
Preparation Example 2: 4-(1,4-dioxa-spiro[4.5]dec-8-yl)-2,5-difluoro-phenylamine
8-(2,5-Difluoro-4-nitro-phenyl)-1,4-dioxa-spiro[4.5]dec-7-ene (21.1 g, 70.8 mmol) obtained in Preparation Example 1 was dissolved in ethyl acetate/methanol (8/2) (354 mL) and 10 % palladium on charcoal (3.5 g) was added thereto. The mixture was made vacuous by using a vacuum pump, and stirred under hydrogen gas for 12 hours. The mixture was celite-filtered by using ethyl acetate to obtain the title compound (18.9 g, 98% yield).
NMR: 1H-NMR(CDCl3) 6.88~6.83(1H, m), 6.47~6.42(1H, m), 3.97(4H, s), 3.67(2H, s), 2.79(1H, m), 1.83~1.75(4H, m), 1.74~1.65(4H, m)
Preparation Example 3: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone
4-(1,4-Dioxa-spiro[4.5]dec-8-yl)-2,5-difluoro-phenylamine (10 g, 37.13 mmol) obtained in Preparation Example 2 was dissolved in dichloromethane (50 mL), trifluoroacetic acid (30 mL) was added thereto at 0℃, and the mixture was stirred at room temperature for 5 hours. The solvent was removed from the mixture at reduced pressure, and the mixture was washed with ethyl acetate, water and saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography using 2:1 mixture solution of dichloromethane and ethyl acetate to obtain the title compound (7.9 g, 94% yield).
NMR: 1H-NMR(CDCl3) 6.83~6.78(1H, m), 6.50~6.45(1H, m), 3.73(2H, s), 3.25~3.18(1H, m), 2.60~2.55(4H, m), 2.27~2.10(2H, m), 1.90~1.80(2H, m)
Preparation Example 4: 4-aminooxy-piperidin-1-carboxylic acid tert-butyl ester
Triphenylphosphine (4.17 g, 17.97 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to 0 ℃. N,N-diisopropylazodicarboxylate (3 mL) was added dropwise and 4-hydroxy-piperidin-1-carboxylic acid tert-butyl ester (3 g, 14.9 mmol) was added thereto and the mixture was stirred for 30 minutes. Hydroxyphthalimide (2.46 g, 15.12 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and purified by column chromatography using 5:5:1 mixture solution of hexane, methylene chloride and ethyl acetate to obtain 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (3.11 g, 60% yield). The obtained compound (3.11 g, 8.97 mmol) was dissolved in methylene chloride (50 mL) and cooled to 0 ℃. Methylhydrazine (0.53 g, 11.67 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 ℃ and filtered under reduced pressure with methylene chloride to obtain the title compound (1.8 g, 92% yield).
NMR: 1H-NMR(CDCl3) 5.55~5.20(2H, br), 3.81~3.65(3H, m), 3.11~3.01(2H, m), 1.95~1.81(2H, m), 1.58~1.50(2H, m), 1.46(9H, s)
Preparation Example 5: 4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid tert-butyl ester
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (28 g, 78.49 mmol) obtained in Preparation Example 3 was dissolved in tetrahydrofuran/methanol/water (3/2/1) (400 mL), and 4-aminooxy-piperidin-1-carboxylic acid tert-butyl ester (17.82 g, 82.41 mmol) was added dropwise thereto and the mixture was stirred at room temperature for 2 hours. The solvent was removed from the mixture under reduced pressure, and the mixture was washed with ethyl acetate, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography using 2:1 mixture solution of dichloromethane and ethyl acetate to obtain the title compound (38.41 g, 87% yield).
NMR: 1H-NMR(CDCl3) 6.78~6.73(1H, m), 6.48~6.40(1H, m), 4.19(1H, m), 3.80~3.70(4H, m), 3.41~3.40(1H, m), 3.28~3.20(2H, m), 2.96(1H, m), 2.49~2.46(1H, m), 2.35~2.22(1H, m), 2.00~1.80(5H, m), 1.70~1.58(2H, m), 1.46(9H, s), 1.45~1.43(2H, m)
Preparation Example 6: O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine
4-Hydroxy-piperidine (2.0 g, 19.8 mmol), 2-chloro-5-methyl-pyrimidine (2.8 g, 19.38 mmol) and triethylamine (5.5 mL, 39.5 mmol) were dissolved in dimethylformamide (100 mL). The temperature was elevated to 100 ℃ and the mixture was stirred for 5 hours. The temperature was changed to room temperature, and water and ethyl acetate were added thereto. The mixture was extracted with ethyl acetate (100 mL) three times, concentrated by distilling under reduced pressure, and separated by column chromatography using 3:1 mixture solution of ethyl acetate and hexane to obtain 1-(5-methyl-pyrimidin-2-yl)-piperidin-4-ol (2.5 g, 65% yield). 1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-ol (2.5 g, 12.9 mmol) was then reacted according to the method of Preparation Example 4 to obtain the title compound (2.2 g, 82% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 5.33(2H, s), 4.32~4.22(2H, m), 3.83~3.74(1H, m), 3.37~3.27(2H, m), 2.11(3H, s), 2.03~1.94(2H, m), 1.62~1.50(2H, m)
Preparation Example 7: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (2.85 g, 7.93 mmol) obtained in Preparation Example 3 and O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (2.05 g, 9.51 mmol) were reacted in the same manner as in Preparation Example 5 to obtain the title compound (3.98 g, 90% yield).
NMR: 1H-NMR(CDCl3) 8.14(2H, m), 6.78~6.73(1H, m), 6.48~6.40(1H, m), 4.29(1H, m), 4.14~4.08(2H, m), 3.68(2H, s), 3.52~3.47(2H, m), 3.44~3.41(1H, m), 2.97(1H, m), 2.52~2.49(1H, m), 2.30~2.20(1H, m), 2.10(3H, s), 2.05~1.90(4H, m), 1.80~1.70(1H, m), 1.75~1.65(2H, m), 1.60~1.40(2H, m)
Preparation Example 8: O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine
5-Ethyl-2-chloro-pyrimidine (7.1 g, 50 mmol) and 4-hydroxypiperidine (5.05 g, 50 mmol) were reacted according to the method of Preparation Example 6 to obtain the title compound (7.77 g, 70% yield).
NMR: 1H-NMR(CDCl3) 8.11(2H, s), 5.31(2H, s), 4.24(2H, m), 3.74(1H, m), 3.28(2H, m), 2.42(2H, m), 1.94(2H, m), 1.53(2H, m), 1.14(3H, t)
Preparation Example 9: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (0.44 g, 2 mmol) obtained in Preparation Example 8 and 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone were reacted according to the method of Preparation Example 5 to obtain the title compound (0.81 g, 90% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 6.76(1H, m), 6.42(1H, m), 4.28(1H, m), 4.13(2H, m), 3.73(2H, s), 3.51(2H, m), 3.42(1H, d), 2.95(1H, t), 2.52~2.38(3H, m), 2.24(1H, m), 2.10~1.90(4H, m), 1.88(1H, m), 1.69(2H, m), 1.62~1.48(2H, m), 1.17(3H, t)
Preparation Example 10: 4-(4-amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
1-Chloro-2-fluoro-4-nitro-benzene (360 mg, 2.05 mmol) was subsequently reacted according to the methods of Preparation Examples 1, 2, 3 and 7 to obtain the title compound (580 mg, 61% overall yield of the four steps).
NMR: 1H-NMR(CDCl3) 8.15(2H, m), 6.94(1H, t), 6.42~6.34(2H, m), 4.29(1H, m), 4.14~4.08(2H, m), 3.68(2H, s), 3.52~3.47(2H, m), 3.44~3.41(1H, m), 2.97(1H, m), 2.52~2.49(1H, m), 2.30~2.20(1H, m), 2.10(3H, s), 2.05~1.90(4H, m), 1.80~1.70(1H, m), 1.75~1.65(2H, m), 1.60~1.40(2H, m)
Preparation Example 11: O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-hydroxylamine
4-Hydroxypiperidine (3.0 g, 29.7 mmol) was dissolved in methylene chloride (90 mL) and cooled to 0 ℃. Sodium bicarbonate (10.0 g, 119 mmol) was dissolved in water (30 mL) and added. After 30 minutes, cyanobromide (3.8 g, 35.6 mmol) was dissolved in methylene chloride (30 mL) and added. The temperature was elevated to room temperature and the mixture was stirred for 2 hours. Water was added to terminate the reaction and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to obtain 4-hydroxy-piperidin-1-carbonitrile (3.3 g, 88% yield).
4-Hydroxy-piperidin-1-carbonitrile (2.0 g, 15.9 mmol) and N-hydroxy-isobutyramidine (2.1 g, 20.6 mmol) were dissolved in ethyl acetate (53 mL), and 1N diethylether solution of zinc chloride (20.6 mL, 20.6 mmol) was added thereto slowly. The mixture was stirred for 15 minutes and diethylether was added thereto to obtain white solid. To the obtained solid, concentrated hydrochloric acid (5 mL) and ethanol (10 mL) were added and the mixture was refluxed for 1 hour. Ethanol was removed by distillation under reduced pressure and the mixture was neutralized by adding an aqueous solution of sodium carbonate thereto. After extracting with methylene chloride, the organic layer was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure. The mixture was separated by column chromatography using 1:1 mixture solution of ethyl acetate and hexane to obtain 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (1.0 g, 30%). 1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (1.0 g, 4.73 mmol) was reacted according to the method of Preparation Example 4 to obtain the title compound (0.89 g, 83% yield).
NMR: 1H-NMR(CDCl3) 3.99~3.89(3H, m), 3.40~3.34(2H, m), 2.92~2.84(1H, m), 1.99~1.92(2H, m), 1.67~1.59(2H, m), 1.56(2H, s), 1.28(6H, d)
Preparation Example 12: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (0.60 g, 2.7 mmol) obtained in Preparation Example 3 and O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-hydroxylamine (0.6 g, 2.7 mmol) obtained in Preparation Example 11 were reacted according to the method of Preparation Example 5 to obtain the title compound (1.1 g, 96% yield).
NMR: 1H-NMR(CDCl3) 6.81~6.73(1H, m), 6.47~6.42(1H, m), 4.32~4.26(1H, m), 3.81~3.68(4H, m), 3.54~3.48(2H, m), 3.41~3.35(1H, m), 2.96(1H, t), 2.91~2.83(1H, m), 2.52~2.47(1H, m), 2.28~2.20(1H, m), 2.05~1.91(4H, m), 1.90~1.75(3H, m), 1.61~1.54(2H, m), 1.28(6H, d)
Preparation Example 13: 1-thiazol-2-yl-piperidin-4-ol
2-Bromothiazole (1.0 g, 6.10 mmol) was dissolved in N,N-dimethylformamide (20 mL), piperidin-4-ol (925 mg, 9.15 mmol) and DBU (2.73 mL, 18.29 mmol) were added thereto, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography using 1:9 mixture solution of methanol and methylene chloride to obtain the title compound (240 mg, 24% yield).
NMR: 1H-NMR(CDCl3) 7.48(1H, d), 6.55(1H, d), 3.96(1H, m), 3.85(2H, m), 3.26(2H, m), 1.99(2H, m), 1.68(2H, m)
Preparation Example 14: 2-(1-thiazol-2-yl-piperidin-4-yloxy)-isoindol-1,3-dione
1-Thiazol-2-yl-piperidin-4-ol obtained in Preparation Example 13 (240 mg, 1.30 mmol) was dissolved in tetrahydrofuran (20 mL), and 2-hydroxy-isoindol-1,3-dione (2.34 mg, 1.43 mmol) and triphenylphosphine (410 mg, 1.56 mmol) were added thereto slowly.
At 0 ℃, diisopropyl azodicarboxylate (0.3 mL, 1.56 mmol) was added dropwise slowly and the mixture was stirred at room temperature for 3 days. The reaction mixture was distilled under reduced pressure to remove the solvent and separated by column chromatography using 1:2 mixture solution of ethyl acetate and hexane to obtain the title compound (460 mg, 107% yield).
NMR: 1H-NMR(CDCl3) 7.85(2H, m), 7.77(2H, m), 7.19(1H, d), 6.57(1H, d), 4.50(1H, m), 3.94(2H, m), 3.41(2H, m), 2.08(4H, m)
Preparation Example 15: O-(1-thiazol-2-yl-piperidin-4-yl)-hydroxylamine
2-(1-Thiazol-2-yl-piperidin-4-yloxy)-isoindol-1,3-dione obtained in Preparation Example 14 (460 mg, 1.40 mmol) was dissolved in methylene chloride (20 mL), hydrazine (0.1 mL, 2.09 mmol) was added thereto and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered and the filtrate was distilled under reduced pressure to obtain the title compound (20 mg, 72% yield). The obtained compound was then used in the next reaction without further purification.
Mass(EI) 200(M++1)
Preparation Example 16: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-(1-thiazol-2-yl-piperidin-4-yl)-oxime
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone obtained in Preparation Example 3 (200 mg, 1.03 mmol) and O-(1-thiazol-2-yl-piperidin-4-yl)-hydroxylamine obtained in Preparation Example 15 (256 mg, 1.03 mmol) were reacted according to a method similar with that of Preparation Example 7 to obtain the title compound (290 mg, 71% yield).
NMR: 1H-NMR(CDCl3) 7.18(1H, d), 6.77(1H, m), 6.55(1H, d), 6.45(1H, m), 4.31(1H, m), 3.73(4H, m), 3.40(3H, m), 2.98(1H, m), 2.53(1H, m), 2.24(1H, m), 2.06~1.95(4H, m), 1.85(3H, m), 1.64~1.46(2H, m)
Preparation Example 17: 4-hydroxy-piperidin-1-thiocarboxylic acid (2-bromo-phenyl)-amide
1-Bromo-2-isothiocyanato-benzene (500 mg, 2.34 mmol) was dissolved in methylene chloride (20 mL), piperidin-4-ol (283 mg, 2.80 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure to remove the solvent and separated by column chromatography using 1:9 mixture solution of methanol and methylene chloride to obtain the title compound (810 mg, 110% yield).
NMR: 1H-NMR(CDCl3) 7.63(1H, m), 7.57(1H, m), 7.30(1H, m), 7.18(1H, s), 7.02(1H, m), 4.16(2H, m), 4.06(1H, m), 3.71(2H, m), 1.97(2H, m), 1.69(2H, m)
Preparation Example 18: 1-benzothiazol-2-yl-piperidin-4-ol
The compound obtained in Preparation Example 17 (810 mg, 2.57 mmol) was dissolved in dimethoxyethane (20 mL). Copper iodide (24 mg, 0.13 mmol), 1,10-phenanthroline (46 mg, 0.26 mmol) and cesium carbonate (1.67 g, 5.14 mmol) were added thereto and the mixture was stirred at 70 ℃ for 3 hours. The reaction mixture was celite-filtered, the filtrate was distilled under reduced pressure to remove the solvent, and separated by column chromatography using ethyl acetate solution to obtain the title compound (550 mg, 91% yield).
NMR: 1H-NMR(CDCl3) 7.60(1H, m), 7.55(1H, m), 7.31(1H, m), 7.05(1H, m), 4.00(3H, m), 3.41(2H, m), 2.02(2H, m), 1.70(2H, m), 1.52(1H, d)
Preparation Example 19: 2-(1-benzothiazol-2-yl-piperidin-4-yloxy)-isoindol-1,3-dione
1-Benzothiazol-2-yl-piperidin-4-ol obtained in Preparation Example 18 (550 mg, 2.35 mmol) was reacted according to a method similar with that of Preparation Example 14 to obtain the unpurified title compound.
NMR: 1H-NMR(CDCl3) 7.87(2H, m), 7.78(2H, m), 7.61(1H, m), 7.56(1H, m), 7.31(1H, m), 7.08(1H, m), 4.55(1H, m), 4.06(2H, m), 3.60(2H, m), 2.11(4H, m)
Preparation Example 20: O-(1-benzothiazol-2-yl-piperidin-4-yl)-hydroxylamine
2-(1-Benzothiazol-2-yl-piperidin-4-yloxy)-isoindol-1,3-dione obtained in Preparation Example 19 was reacted according to a method similar with that of Preparation Example 15 to obtain the title compound (450 mg, 77% two-step yield).
NMR: 1H-NMR(CDCl3) 7.60(1H, m), 7.55(1H, m), 7.31(1H, m), 7.08(1H, m), 5.35(2H, m), 3.91~3.79(3H, m), 3.45(2H, m), 2.04(2H, m), 1.77(2H, m)
Preparation Example 21: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-(1-benzothiazol-2-yl-piperidin-4-yl)-oxime
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone obtained in Preparation Example 3 (204 mg, 1.03 mmol) and O-(1-benzothiazol-2-yl-piperidin-4-yl)-hydroxylamine obtained in Preparation Example 20 (226 mg, 1.03 mmol) were reacted according to a method similar with that of Preparation Example 7 to obtain the title compound (180 mg, 87% yield).
NMR: 1H-NMR(CDCl3) 7.60(1H, m), 7.53(1H, m), 7.31(1H, m), 7.08(1H, m), 6.80(1H, m), 6.48(1H, m), 4.36(1H, m), 3.84(2H, m), 3.70(2H, s), 3.55(2H, m), 3.43(1H, m), 2.98(1H, m), 2.53(1H, m), 2.24(1H, m), 2.09~1.95(4H, m), 1.88(3H, m), 1.64~1.49(2H, m)
Preparation Example 22: (4-bromo-2,6-difluoro-phenyl)-carbamic acid benzyl ester
4-bromo-2,6-difluoro-phenylamine (1 g, 4.80 mmol) was dissolved in tetrahydrofuran (15 mL) and sodium hydrogen carbonate (483 mg, 5.76 mmol) was added dropwise at 0 ℃. Benzyl chloroformate (800 mg, 5.76 mmol) was added dropwise and the mixture was stirred at room temperature for 12 hours. Water was added to terminate the reaction and the mixture was washed with diethylether, water and saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure and separated by column chromatography using 6:1 mixture solution of hexane and ethyl acetate to obtain the title compound (1.3 g, 81 % yield).
NMR: 1H-NMR(CDCl3) 7.39~7.34(5H, m), 7.17~7.13(2H, m), 6.07(1H, s), 5.21(2H, s)
Preparation Example 23: 4-(4-amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
(4-Bromo-2,6-difluoro-phenyl)-carbamic acid benzyl ester 489 mg, 1.43 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 7 to obtain the title compound (354 mg, 68% overall yield of the four steps).
NMR: 1H-NMR(CDCl3) 8.15(2H, m), 6.71~6.66(2H, m), 4.29(1H, m), 4.14~4.08(2H, m), 3.68(2H, s), 3.52~3.47(2H, m), 3.44~3.41(1H, m), 2.79(1H, m), 2.62~2.52(1H, m), 2.23~2.18(1H, m), 2.10(3H, s), 2.05~1.90(4H, m), 1.80~1.70(1H, m), 1.75~1.65(2H, m), 1.60~1.40(2H, m)
Preparation Example 24: 4-(4-amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
1-Chloro-2-fluoro-4-nitro-benzene 360 mg, 2.05 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 9 to obtain the title compound (570 mg, 67% overall yield of the four steps).
NMR: 1H-NMR(CDCl3) 8.17(2H, m), 6.94(1H, t), 6.42~6.34(2H, m), 4.29(1H, m), 4.14~4.08(2H, m), 3.68(2H, s), 3.52~3.47(2H, m), 3.44~3.41(1H, m), 2.97(1H, m), 2.52~2.40(3H, m), 2.30~2.20(1H, m), 2.07~1.90(4H, m), 1.90~1.80(1H, m), 1.75~1.65(2H, m), 1.60~1.40(2H, m), 1.18(3H, m)
Preparation Example 25: O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine
4-Hydroxy-piperidine (5.0 g, 49.3 mmol) and 2,5-dichloro-pyrimidine (7.2 g, 48.3 mmol) were reacted according to the method of Preparation Example 6 to obtain the title compound (5.5 g, 72% yield).
NMR: 1H-NMR(CDCl3) 8.20(2H, s), 5.33(2H, s), 4.24~4.17(2H, m), 3.83~3.76(1H, m), 3.41~3.32(2H, m), 2.01~1.92(2H, m), 1.62~1.53(2H, m)
Preparation Example 26: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-oxime
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (0.26 g, 1.1 mmol) obtained in Preparation Example 3 and O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine obtained in Preparation Example 25 were reacted according to the method of Preparation Example 5 to obtain the title compound (0.48 g, 96% yield).
NMR: 1H-NMR(CDCl3) 8.21(2H, s), 6.80~6.73(1H, m), 6.48~6.42(1H, m), 4.32~4.28(1H, m), 4.15~4.05(2H, m), 3.80~3.54(4H, m), 3.45~3.38(1H, m), 2.97(1H, t), 2.53~2.48(1H, m), 2.92~2.21(1H, m), 2.05~1.92(4H, m), 1.91~1.79(1H, m), 1.78~1.65(2H, m), 1.64~1.48(2H, m)
Preparation Example 27: 4-(4-amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-oxime
1-Chloro-2-fluoro-4-nitro-benzene (360 mg, 2.05 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 26 to obtain the title compound (530 mg, 62% overall yield of the four steps).
NMR: 1H-NMR(CDCl3) 8.21(2H, s), 6.96~6.93(1H, m), 6.41~6.30(2H, m), 4.30(1H, m), 4.15~4.05(2H, m), 3.70~3.51(4H, m), 3.40(1H, m), 3.00(1H, m), 2.55(1H, m), 2.35~2.25(1H, m), 2.10~1.90(4H, m), 1.95~1.85(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Preparation Example 28: O-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-hydroxylamine
5-Trifluoromethyl-2-chloro-pyridine (9.05 g, 50 mmol) and 4-hydroxypiperidine (5.05 g, 50 mmol) were reacted according to the method of Preparation Example 6 to obtain the title compound (8.71 g, 71% yield).
NMR: 1H-NMR(CDCl3) 8.37(1H, s), 7.60(1H, m), 6.65(1H, d), 5.33(2H, s), 4.02(2H, m), 3.81(1H, m), 3.36(2H, m), 1.98(2H, m), 1.64(2H, m)
Preparation Example 29: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-oxime
O-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-hydroxylamine (492 mg, 2 mmol) obtained in Preparation Example 28 was reacted according to the method of Preparation Example 5 to obtain the title compound (0.88 g, 94% yield).
NMR: 1H-NMR(CDCl3) 8.38(1H, s), 7.59(1H, m), 6.79(1H, m), 6.67(1H, d), 6.45(1H, m), 4.32(1H, m), 3.92(2H, m), 3.70(2H, s), 3.49(2H, m), 3.42(1H, d), 2,99(1H, t), 2.52(1H, d), 2.27(1H, m), 2.10~1.92(4H, m), 1.92~1.48(5H, m)
Preparation Example 30: 4-(4-amino-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
1-Chloro-4-nitro-benzene (200 mg, 1.269 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 7 to obtain the title compound (132 mg, 56% overall yield of the four steps).
NMR: 1H-NMR(CDCl3) 8.15(2H, m), 7.01~6.99(2H, m), 6.65~6.63(2H, m), 4.29(1H, m), 4.14~4.08(2H, m), 3.62~3.47(4H, m), 3.44~3.41(1H, m), 2.70(1H, m), 2.52~2.49(1H, m), 2.30~2.20(1H, m), 2.10(3H, s), 2.05~1.90(4H, m), 1.80~1.70(1H, m), 1.75~1.65(2H, m), 1.60~1.40(2H, m)
Preparation Example 31: 4-[4-(4-amino-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid tert-butyl ester
1-Chloro-4-nitro-benzene 200 mg, 1.269 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 5 to obtain the title compound (140 mg, 60% overall yield of the four steps).
NMR: 1H-NMR(CDCl3) 7.01~6.99(2H, m), 6.65~6.63(2H, m), 4.20(1H, m), 3.78~3.65(2H, m), 3.55(2H, m), 3.44~3.41(1H, m), 3.30~3.18(2H, m), 2.73(1H, m), 2.52~2.49(1H, m), 2.30~2.20(1H, m), 2.10~1.94(2H, m), 1.94~1.79(3H, m), 1.75~1.65(4H, m), 1.46(9H, s)
Preparation Example 32: 4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid isopropyl ester
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid tert-butyl ester (862 mg, 2.035 mmol) obtained in Preparation Example 5 was dissolved in dichloromethane (4 mL). 4N hydrochloric acid/1,4-dioxane solution (3 mL) was added dropwise thereto at 0 ℃ and the mixture was stirred at room temperature for 1 hour. The reaction mixture was distilled under reduced pressure and dried under high pressure. Dichloromethane (15 mL) was then added, isopropylchloroformate (800 mg, 0.800 mmol) was added dropwise at 0 ℃, triethylamine (1.4 mL, 13.85 mmol) was added, and the mixture was stirred and reacted for 10 minutes. Water was added to terminate the reaction, and the mixture was washed with ethyl acetate, water and saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure and separated by column chromatography using 2:1 mixture solution of hexane and ethyl acetate to obtain the title compound (500 mg, 65% yield).
NMR: 1H-NMR(CDCl3) 6.78~6.73(1H, m), 6.48~6.40(1H, m), 4.90(1H, m), 4.20(1H, m), 3.78~3.60(4H, m), 3.44~3.41(1H, m), 3.30~3.20(2H, m), 3.00(1H, m), 2.52~2.49(1H, m), 2.30~2.20(1H, m), 2.10~1.80(4H, m), 1.70~1.45(5H, m), 1.23(6H, d)
Preparation Example 33: 4-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-2,5-difluoro-benzoacid methyl ester
4-Bromo-2,5-difluoro-benzoacid methyl ester (152 mg, 0.735 mmol) and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (195 mg, 0.735 mmol) were reacted in the same manner as in Preparation Example 1 to obtain the title compound (117 mg, 51% yield).
NMR: 1H-NMR(CDCl3) 7.61~7.57(1H, m), 7.08~7.00(1H, m), 6.05(1H, m), 4.02(4H, s), 3.92(3H, s), 2.62(2H, m), 2.49(2H, m), 1.92(2H, t)
Preparation Example 34: 4-(1,4-dioxa-spiro[4.5]dec-8-yl)-2,5-difluoro-benzoacid methyl ester
4-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-2,5-difluoro-benzoacid methyl ester (91 mg, 0.293 mmol) obtained in Preparation Example 33 was reacted according to the method of Preparation Example 2 to obtain the title compound (90 mg, 99% yield).
NMR: 1H-NMR(CDCl3) 7.58~7.56(1H, m), 7.05~7.02(1H, m), 3.97(4H, s), 3.92(3H, s), 2.92(1H, m), 1.87~1.80(4H, m), 1.74~1.65(4H, m)
Preparation Example 35: 2,5-difluoro-4-(4-oxo-cyclohexyl)-benzoacid methyl ester
4-(1,4-Dioxa-spiro[4.5]dec-8-yl)-2,5-difluoro-benzoacid methyl ester (90 mg, 0.288 mmol) obtained in Preparation Example 34 was reacted in the same manner as in Preparation Example 3 to obtain the title compound (76 mg, 99% yield).
NMR: 1H-NMR(CDCl3) 7.64~7.60(1H, m), 7.02~6.98(1H, m), 3.93(3H, s), 3.11(1H, m), 2.56~2.53(4H, m), 2.23(2H, m), 1.97(2H, m)
Preparation Example 36: 4-[4-(4-carboxyl-2,5-difluoro-phenyl)-cyclohexylideneaminooxy-piperidin-1-carboxylic acid tert-butyl ester
4-[4-(2,5-Difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid tert-butyl ester (3.12 g, 6.673 mmol) obtained in Example 10 was added and dissolved in tetrahydrofuran/methanol/1N sodium hydroxide (1/1/1 ratio) solution (30 mL) at 0 ℃, and the mixture was stirred at room temperature for 1 hour and then distilled under reduced pressure. The aqueous layer was acidified with 1N aqueous solution of hydrochloric acid, extracted with ethyl acetate solution, and washed with brine. The organic layer was dried with magnesium sulfate, and then filtered and concentrated to obtain the title compound (2.95 g, 96% yield).
NMR: 1H-NMR(MeOD) 7.59~7.55(1H, m), 7.18~7.14(1H, m), 4.23(1H, m), 3.75~3.65(2H, m), 3.50~3.40(1H, m), 3.30~3.20(2H, m), 3.09(1H, m), 2.60~2.50(1H, m), 2.30~2.20(1H, m), 2.10~2.00(2H, m), 1.95~1.80(3H, m), 1.70~1.60(4H, m), 1.46(9H, s)
Preparation Example 37: O-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine
5-Propyl-2-chloro-pyrimidine (7.8 g, 50 mmol) and 4-hydroxypiperidine (5.05 g, 50 mmol) were reacted according to the method of Preparation Example 6 to obtain the title compound (7.68 g, 65% yield).
NMR: 1H-NMR(CDCl3) 8.13(2H, s), 5.32(2H, s), 4.29(2H, m), 3.79(1H, m), 3.33(2H, m), 2.39(2H, t), 1.99(2H, m), 1.62~1.50(4H, m), 0.93(3H, t)
Preparation Example 38: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
O-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (0.47 g, 2 mmol) obtained in Preparation Example 37 was reacted according to the method of Preparation Example 5 to obtain the title compound (0.86 g, 97% yield).
NMR: 1H-NMR(CDCl3) 8.13(2H, s), 6.78(1H, m), 6.44(1H, m), 4.29(1H, m), 4.14(2H, m), 3.71(2H, s), 3.52(2H, m), 3.41(1H, d), 2.98(1H, t), 2.51(1H, d), 2.38(2H, t), 2.17(1H, m), 2.10~1.91(4H, m), 1.88(1H, m), 1.69(2H, m), 1.63~1.44(4H, m), 0.91(3H, t)
Preparation Example 39: O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine
5-Fluoro-2-chloro-pyrimidine (6.6 g, 50 mmol) and 4-hydroxypiperidine (5.05 g, 50 mmol) were reacted according to the method of Preparation Example 6 to obtain the title compound (7.2 g, 68% yield). The obtained compound was used in the next reaction without further purification.
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 5.33(2H, s), 4.22(2H, m), 3.78(1H, m), 3.36(2H, m), 1.98(2H, m), 1.58(2H, m)
Preparation Example 40: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-oxime
O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (0.42 g, 2 mmol) obtained in Preparation Example 39 was reacted according to the method of Preparation Example 5 to obtain the title compound (0.79 g, 94% yield).
NMR: 1H-NMR(CDCl3) 8.17(2H, s), 6.78(1H, m), 6.45(1H, m), 4.29(1H, m), 4.10(2H, m), 3.69(2H, s), 3.54(2H, m), 3.42(1H, m), 3.00(1H, t), 2.52(1H, m), 2.26(1H, m), 2.06~1.90(4H, m), 1.89(1H, m), 1.71(2H, m), 1.66~1.48(2H, m)
Preparation Example 41: 4-{4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2,5-difluoro-phenyl]-cyclohexylideneaminooxy}-piperidin-1-carboxylic acid isopropyl ester
4-[4-(2,5-Difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid isopropyl ester (70 mg, 0.16 mmol) obtained in Example 9, phthalimide (26 mg, 0.18 mmol), diisopropylethylamine (35 ㎕, 0.18 mmol) and triphenylphosphine (47 mg, 0.18 mmol) were dissolved in tetrahydrofuran (5 mL) and the mixture was stirred at room temperature for 12 hours, and the reaction was terminated. The reaction mixture was washed with ethyl acetate and saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, and distilled under reduced pressure to obtain the title compound (120 mg) in unpurified state.
1H-NMR(400MHz, CDCl3); 7.90(2H, m), 7.77(2H, m), 7.02(1H, m), 6.90(1H, m), 4.92(1H, m), 4.88(2H, s), 4.24(1H, m), 3.71(2H, m), 3.46(1H, d), 3.30(2H, m), 3.05(1H, t), 2.50(1H, d), 2.24(1H, m), 2.05(5H, m), 1.65(4H, m), 1.27(6H, d)
Preparation Example 42: 4-[4-(4-aminomethyl-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid isopropyl ester
4-{4-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2,5-difluoro-phenyl]-cyclohexylideneaminooxy}-piperidin-1-carboxylic acid isopropyl ester (120 mg, 0.2 mmol) obtained in Preparation Example 41, hydrazine (52 ㎕, 1.0 mmol) and ethanol (1 mL) were stirred in dichloromethane solvent (1 mL) for 24 hours, and the reaction was terminated. The reaction mixture was washed with ethyl acetate and saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, and distilled under reduced pressure to obtain the title compound (88 mg) in unpurified state.
1H-NMR(400MHz, CDCl3); 7.05(1H, m), 6.88(1H, m), 4.92(1H, m), 4.22(1H, m), 3.85(2H, s), 3.71(2H, m), 3.45(1H, d), 3.28(2H, m), 3.08(1H, m), 2.54(1H, d), 2.26(1H, m), 2.05(1H, m), 1.89(4H, m), 1.65(4H, m), 1.26(6H, d)
Preparation Example 43: [(S)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-(4-iodo-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester
Commercially available (S)-2-tert-butoxycarbonylamino-3-(4-iodo-phenyl)-propionic acid (314 mg, 0.80 mmol) was dissolved in dichloromethane (15 mL). S-3-fluoro-pyrrolidine hydrochloride salt (111 mg, 0.88 mmol), EDC (231 mg, 1.20 mmol), HOBT (184 mg, 1.20 mmol) and diisopropylethylamine (277 mg, 2.14 mmol) were added thereto and the mixture was stirred at room temperature for 18 hours. After the reaction was terminated, saturated aqueous solution of NaHCO3 was added and the organic substances were extracted with EtOAc, dried with anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to obtain the title compound (363 mg, 98% yield).
1H-NMR(400MHz, CDCl3); δ 7.65(dd, 2H), 7.02(dd, 2H), 5.35(m, 1H), 5.19(d, 1H), 4.59(m, 1H), 3.89(m, 1H), 3.55~3.20(m, 2H), 3.00(m, 3H), 2.30(m, 1H), 2.05~1.60(m, 1H), 1.45(d, 9H)
Preparation Example 44: [(S)-1-[4-(1,4-dioxa-spiro[4,5]dec-8-yl)-benzyl]-2-((S)-3-fluoro-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester
As the starting material, [(S)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-(4-iodo-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (100 mg, 0.22 mmol) obtained in Preparation Example 43 was reacted subsequently according to the methods of Preparation Examples 1 and 2 to obtain the title compound (42 mg, 41% yield).
1H-NMR(400MHz, CDCl3); δ 7.12(m, 4H), 5.38(dd, 1H), 5.05(dd, 1H), 4.51(m, 1H), 3.96(s, 4H), 3.78(m, 1H), 3.45~3.26(m, 2H), 3.05~2.70(m, 3H), 2.50(m, 1H), 2.05(m, 2H), 1.90~1.60(m, 8H), 1.40(d, 9H)
Preparation Example 45: {(S)-2-((S)-3-fluoro-pyrrolidin-1-yl)-2-oxo-1-[4-(4-oxo-cyclohexyl)-benzyl]-ethyl}-carbamic acid tert-butyl ester
[(S)-1-[4-(1,4-dioxa-spiro[4,5]dec-8-yl)-benzyl]-2-((S)-3-fluoro-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (42 mg, 0.088 mmol) obtained in Preparation Example 44 was dissolved in tetrahydrofuran (2 mL), water (1 mL) and acetic acid (2 mL), and the mixture was stirred at 70 ℃ for 4 hours. After completing the reaction, the solvent was removed under reduced pressure, ethyl acetate was added and the inorganic substances were washed out with saturated sodium bicarbonate solution. The organic layer was dried with anhydrous magnesium sulfate and filtered to obtain the title compound (34 mg, 89% yield).
1H-NMR(400MHz, CDCl3); δ 7.20(m, 4H), 5.41(m, 1H), 5.13(dd, 1H), 4.60(m, 1H), 3.86(m, 1H), 3.70~3.30(m, 2H), 3.00(m, 4H), 2.53(m, 4H), 2.20(m, 3H), 2.10~1.75(m, 3H), 1.45(s, 9H)
Preparation Example 46: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid tert-butyl ester (235 mg, 0.56 mmol) obtained in Preparation Example 5 was dissolved in dichloromethane (4 mL). 4N hydrochloric acid/1,4-dioxane solution (3 mL) was added thereto at 0 ℃, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was distilled under reduced pressure and then dried under high pressure. The dried mixture was dissolved in dimethylformamide (5 mL). 2-Chloro-4-trifluoromethylpyrimidine (122 mg, 0.67 mmol) and triethylamine (169 mg, 1.67 mmol) were added thereto and reacted at 70 ℃ for 2 hours. Water was added to terminate the reaction, the organic substances were extracted with diethylether, and the organic layer was washed with saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate and filtered to obtain the title compound (220 mg, 84% yield).
1H-NMR(400MHz, CDCl3): δ 8.52(d, 1H), 6.83(dd, 1H), 6.76(d, 1H), 6.50(dd, 1H), 4.34(m, 1H), 4.21(m, 2H), 3.74(s, 2H), 3.68(m, 2H), 3.47(m, 1H), 3.03(m, 1H), 2.56(m, 1H), 2.30(td, 1H), 2.07(m, 4H), 1.91(td, 1H), 1.78(m, 2H), 1.60(m, 2H)
Preparation Example 47: 4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
4-Chloro-2-fluoro-1-nitrobenzene was reacted subsequently according to the methods of Preparation Examples 1, 2 and 3 to synthesize 4-(4-amino-3-fluoro-phenyl)-cyclohexanone. The synthesized compound (2.07 g, 10 mmol) and O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (2.22 g, 10 mmol) obtained in Preparation Example 8 were reacted according to the method of Preparation Example 5 to obtain the title compound (3.70 g, 90% yield).
NMR: 1H-NMR(CDCl3) 8.16(2H, s), 6.85(1H, d), 6.77(1H, d), 6.72(1H, t), 4.30(1H, m), 4.15(2H, m), 3.61(2H, s), 3.52(2H, m), 3.41(1H, d), 3.65(1H, t), 2.53~2.42(3H, m), 2.22(1H, m), 2.08~1.95(4H, m), 1.88(1H, m), 1.75~1.48(2H, m), 1.19(3H, t)
Preparation Example 48: 4-(4-amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
4-Bromo-2,3-difluoro-phenylamine (3.02 g, 14.51 mmol) was reacted subsequently according to the methods of Preparation Examples 22, 1, 2, 3 and 9 to obtain the title compound (504 mg, 43% overall yield of the five steps).
NMR: 1H-NMR(400MHz, CDCl3): 8.16(s, 2H), 6.70(t, 1H), 6.76(d, 1H), 4.30(m, 1H), 4.15(m, 2H), 3.71(s, 2H), 3.52(m, 2H), 3.42(m, 1H), 2.99(m, 1H), 2.51(m, 1H), 2.45(q, 2H), 2.25(td, 1H), 2.01(m, 4H), 1.86(td, 1H), 1.70(m, 2H), 1.56(m, 2H), 1.17(t, 3H)
Preparation Example 49: 4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
4-Chloro-2-fluoro-1-nitro-benzene (5.0 g, 28.2 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 7 to obtain the title compound (5.3 g, 47% overall yield of the four steps).
NMR: 1H-NMR(CDCl3) 8.15(s, 2H), 6.85(d, 1H), 6.82(d, 1H), 6.71(t, 1H), 4.31(m, 1H), 4.18(m, 2H), 3.61(s, 2H), 3.52(m, 2H), 3.39(m, 1H), 2.66(m, 1H), 2.49(m, 1H), 2.23(m, 1H), 2.05(s, 3H), 2.02(m, 4H), 1.86(m, 1H), 1.70(m, 2H), 1.56(m, 2H)
Preparation Example 50: 4-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-2,5-difluoro-phenylamine
8-(2,5-Difluoro-4-nitro-phenyl)-1,4-dioxa-spiro[4.5]dec-7-ene (102 mg, 0.34 mmol) was dissolved in tetrahydrofuran (1 mL), ethyl alcohol (1 mL) and water (1 mL). Iron (115 mg, 2.05 mmol) and ammonium chloride (110 mg, 2.05 mmol) were separately added thereto, and the mixture was heated to 90 ℃ and stirred for 2 hours. The reaction mixture was cooled to room temperature and filtered by using a celite pad, and washed with ethyl acetate. The filtrate was distilled under reduced pressure, extracted with ethyl acetate, and washed with water and saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure and purified by column chromatography using 4:1~1:1 mixture solution of hexane and ethyl acetate to obtain the title compound (80 mg, 88% yield).
NMR: 1H-NMR(CDCl3) 6.91~6.87(1H, m), 6.46~6.41(1H, m), 5.80(1H, m), 4.01(4H, s), 3.74(2H, s), 2.57(2H, m), 2.44(2H, m), 1.88(2H, m)
Preparation Example 51: 4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-cyclohexanecarboxylic acid ethyl ester
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (500 mg, 2.22 mmol) obtained in Preparation Example 3 and 4-aminooxy-cyclohexanecarboxylic acid ethyl ester (415 mg, 2.22 mmol) were reacted in the same manner as in Preparation Example 5 to obtain the title compound (880 mg, 100% yield).
NMR: 1H-NMR(CDCl3) 6.81~6.75(1H, m), 6.45(1H, m), 4.22(0.4H, m), 4.13(2.6H, m), 3.97(1H, m), 3.69(2H, m), 3.37(1H, m), 2.97(1H, m), 2.47(1H, m), 2.35~2.15(4H, m), 1.96(3H, m), 1.87~1.68(3H, m), 1.62~1.49(3H, m), 1.34(1H, m), 1.25(3H, m)
Preparation Example 52: 4-[4-(4-tert-butoxycarbonylamino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-cyclohexanecarboxylic acid ethyl ester
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-cyclohexanecarboxylic acid ethyl ester (880 mg, 2.23 mmol) obtained in Preparation Example 51 was dissolved in acetonitrile (50 mL). Boc2O (489 mg, 2.23 mmol) and DMAP (27 mg, 0.223 mmol) were added thereto slowly and the mixture was stirred at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and separated by column chromatography using 1:2 mixture solution of hexane and ethyl acetate to obtain the title compound (900 mg, 82% yield).
NMR: 1H-NMR(CDCl3) 6.88(2H, m), 4.25(0.3H, m), 4.14(2.7H, m), 3.98(1H, m), 3.45(1H, m), 3.08(1H, m), 2.51(1H, m), 2.39~2.15(3H, m), 2.04(4H, m), 1.87~1.72(3H, m), 1.56(2H, m), 1.44(10H, m), 1.24(1H, m), 1.24(3H, m)
Preparation Example 53: 4-[4-(4-tert-butoxycarbonylamino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-cyclohexanecarboxylic acid
4-[4-(4-Tert-butoxycarbonylamino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-cyclohexanecarboxylic acid ethyl ester (900 mg, 1.82 mmol) obtained in Preparation Example 52 was dissolved in tetrahydrofuran/water/methanol (5/3/1) (10 mL). Lithium hydroxide (15 mg, 3.64 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and separated by column chromatography using 1:9 mixture solution of methanol and methylene chloride to obtain the title compound (390 mg, 46% yield). The obtained compound was then used in the next reaction without further purification.
Mass(EI) 467(M++1)
Preparation Example 54: (2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-carbamic acid tert-butyl ester
4-[4-(4-Tert-butoxycarbonylamino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-cyclohexanecarboxylic acid (390 mg, 0.836 mmol) obtained in Preparation Example 53 was dissolved in methylene chloride (20 mL). N-hydroxy-isopropylamidine (102 mg, 1.00 mmol) and diisopropylcarbodiimide (0.157 mL, 1.00 mmol) were added thereto and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water, dried with anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The mixture was again dissolved in dimethylformamide (10 mL) and stirred under reflux at 150 ℃ for 3 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and separated by column chromatography using 1:2 mixture solution of ethyl acetate and hexane to obtain the title compound (85 mg, 19% yield).
NMR: 1H-NMR(CDCl3) 7.86(1H, m), 6.86(1H, m), 6.66(1H, s), 4.05(1H, m), 3.39(1H, m), 3.10~3.01(2H, m), 2.92(1H, m), 2.45(1H, m), 2.22(5H, m), 2.05(2H, m), 1.90(1H, m), 1.75(2H, m), 1.59(1H, m), 1.52~1.40(12H, m), 1.32(6H, d)
Preparation Example 55: (2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-carbamic acid tert-butyl ester
The title compound (77 mg, 17% yield), an isomer having slightly greater polarity, was obtained in the synthesis procedure of Preparation Example 54. The obtained compound was used in the next reaction without further purification.
Mass(EI) 533(M++1)
Preparation Example 56: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-oxime
(2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-carbamic acid tert-butyl ester (77 mg, 0.014 mmol) obtained in Preparation Example 55 was dissolved in methylene chloride (3 mL). Trifluoroacetic acid (3 mL) was added thereto and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure, and separated by column chromatography using 2:1 mixture solution of hexane and ethyl acetate to obtain the title compound (38 mg, 61% yield).
NMR: 1H-NMR(CDCl3) 6.79(1H, m), 6.45(1H, m), 4.30(1H, s), 3.70(2H, s), 3.43(1H, m), 3.05(1H, m), 2.96(2H, m), 2.48(1H, m), 2.23(1H, m), 2.03~1.87(9H, m), 1.72(2H, m), 1.60~1.49(2H, m), 1.33(6H, d)
Preparation Example 57: 4-(4-amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
4-Bromo-2,3-difluoro-phenylamine (3.02 g, 14.51 mmol) was reacted subsequently according to the methods of Preparation Examples 22, 1, 2, 3 and 7 to obtain the title compound (663 mg, 44% overall yield of the five steps).
NMR: 1H-NMR(CDCl3) 8.15(2H, m), 6.72~6.69(1H, m), 6.50~6.46(1H, m), 4.31(1H, m), 4.17~4.12(2H, m), 3.71(2H, s), 3.54~3.41(3H, m), 3.00(1H, m), 2.57~2.45(1H, m), 2.30~2.20(1H, m), 2.10(3H, s), 2.05~1.90(4H, m), 1.80~1.70(1H, m), 1.75~1.65(24H, m), 1.60~1.40(2H, m)
Preparation Example 58: 4-[4-(4-amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid isopropyl ester
1-Chloro-2-fluoro-4-nitro-benzene (0.20 g, 1.14 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3, 5 and 32 to obtain the title compound (0.15 g, 34% overall yield of the five steps).
NMR: 1H-NMR(CDCl3) 6.91(1H, t), 6.39(1H, d), 6.35(1H, d), 4.91(1H, m), 4.21(1H, m), 3.68(4H, s), 3.39(1H, m), 3.26(2H, m), 2.96(1H, t), 2.46(1H, m), 2.22(1H, m), 2.05~1.80(5H, m), 1.70~1.50(4H, m), 1.23(6H, d)
Preparation Example 59: 4-[4-(4-amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid isopropyl ester
4-Chloro-2-fluoro-1-nitro-benzene (1.0 g, 5.63 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3, 5 and 32 to obtain the title compound (0.78 g, 35% overall yield of the five steps).
NMR: 1H-NMR(CDCl3) 6.82(1H, d), 6.75(1H, d), 6.70(1H, t), 4.90(1H, m), 4.20(1H, m), 3.69(3H, s), 3.55(1H, s), 3.38(1H, m), 3.26(2H, m), 2.64(1H, m), 2.46(1H, m), 2.21(1H, m), 2.02(2H, m), 1.95~1.80(3H, m), 1.70~1.45(4H, m), 1.23(6H, d)
Preparation Example 60: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid tert-butyl ester (0.17 g, 0.40 mmol) obtained in Preparation Example 5 and 2-chloro-5-cyclopropyl-pyrimidine were reacted according to the method of Preparation Example 46 to obtain the title compound (0.12 g, 68% yield).
NMR: 1H-NMR (CDCl3) 8.10(2H, s), 6.79(1H, m), 6.46(1H, m), 4.30(1H, m), 4.15(2H, m), 3.69(2H, s), 3.52(2H, m), 3.43(1H, d), 2.99(1H, t), 2.51(1H, d), 2.26(1H, m), 2.00(4H, m), 1.85(2H, m), 1.76~1.46(4H, m), 0.89(2H, m), 0.57(2H, m)
Preparation Example 61: 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid tert-butyl ester (0.35 g, 0.83 mmol) obtained in Preparation Example 5 and 2-chloro-5-trifluoromethyl-pyrimidine were reacted according to the method of Preparation Example 46 to obtain the title compound (0.20 g, 51% yield).
NMR: 1H-NMR(CDCl3) 8.46(2H, s), 6.77(1H, m), 6.45(1H, m), 4.33(1H, m), 4.15(2H, m), 3.74(4H, m), 3.42(1H, m), 2.97(1H, t), 2.52(1H, d), 2.26(1H, m), 2.01(4H, m), 1.90(1H, m), 1.80(2H, m), 1.60(2H, m)
Preparation Example 62: 4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid phenyl ester
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid tert-butyl ester (0.12 g, 0.28 mmol) obtained in Preparation Example 5 and phenyl chloroformate were reacted according to the method of Preparation Example 32 to obtain the title compound (60 mg, 49% yield).
NMR: 1H-NMR(CDCl3) 7.37(2H, t), 7.18(1H, t), 7.11(2H, d), 6.78(1H, m), 6.47(1H, m), 4.30(1H, m), 3.86(1H, s), 3.78(1H, s), 3.70(2H, s), 3.53(1H, s), 3.48~3.38(2H, m), 2.98(1H, t), 2.52(1H, d), 2.27(1H, m), 2.08~1.95(4H, m), 1.88(1H, m), 1.78(2H, s), 1.65~1.58(2H, m)
Preparation Example 63: 3-[2-fluoro-4-(4-oxocyclohexyl)phenyl]-1,1-dimethylurea
4-Chloro-2-fluoro-1-nitrobenzene was reacted subsequently according to the methods of Preparation Examples 1, 2 and 3 to synthesize 4-(4-amino-3-fluorophenyl)cyclohexanone. To the synthesized compound (0.223 g, 1 mmol), dichloromethane (20 mL) was added. The reaction mixture was cooled to 0 ℃, and dimethylamine hydrochloride salt was used in the same method as in Example 1 to obtain the title compound (0.268g, 89% yield).
NMR: 1H-NMR(CDCl3) 8.04(1H, t), 6.99(1H, d), 6.93(1H, m), 6.48(1H, brs), 3.05(6H, s), 2.98(1H, m), 2.49(4H, m), 2.19(2H, m), 1.90(2H, m), 1.25(1H, m)
Preparation Example 64: 4-({4-[4-(dimethylcarbamoylamino)-3-fluoro-phenyl]cyclohexylidene}amino)oxypiperidin-1-carboxylic acid tert-butyl ester
3-[2-Fluoro-4-(4-oxocyclohexyl)phenyl]-1,1-dimethylurea (0.25 g, 0.9 mmol) obtained in Preparation Example 63 and 4-aminooxy-piperidin-1-carboxylic acid tert-butyl ester obtained in Preparation Example 4 were used in the same method as in Preparation Example 5 to synthesize the title compound (0.41 g, 96% yield).
NMR: 1H-NMR(CDCl3) 8.00(1H, t), 6.94(1H, m), 6.89(1H, m), 6.46(1H, m), 4.20(1H, m), 3.68(2H, m), 3.41(1H, m), 3.22(2H, m), 3.04(6H, s), 2.70(1H, m), 2.49(1H, m), 2.22(1H, m), 2.02(2H, m), 1.87(3H, m), 1.62(5H, m), 1.45(9H, s)
Preparation Example 65: 4-{[4-(4-amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidin-1-carboxylic acid tert-butyl ester
4-Chloro-2-fluoro-1-nitrobenzene was reacted subsequently according to the methods of Preparation Examples 1, 2 and 3 to synthesize 4-(4-amino-3-fluorophenyl)-cyclohexanone. The synthesized compound (0.452 g, 2.1 mmol) and 4-aminooxy-piperidin-1-carboxylic acid tert-butyl ester obtained in Preparation Example 4 were used in the same method as in Preparation Example 5 to obtain the title compound (0.8 g, 91% yield).
NMR: 1H-NMR(CDCl3) 6.82(2H, m), 6.73(1H, m), 4.20(1H, m), 3.65(2H, brs), 3.39(1H, m), 3.23(2H, m), 2.66(1H, m), 2.47(2H, m), 2.21(1H, m), 2.00(1H, m), 1.87(4H, m), 1.63(4H, m), 1.52(4H, m)
Preparation Example 66: 4-{[4-(4-amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidin-1-carboxylic acid isopropyl ester
4-{[4-(4-amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidine-1-carboxylic tert-butyl ester (0.8 g, 2 mmol) obtained in Preparation Example 65 was used in the same method as in Preparation Example 32 to obtain the title compound (0.36 g, 47% yield).
NMR: 1H-NMR(CDCl3) 6.82(1H, m), 6.76(1H, m), 6.71(1H, m), 4.90(1H, m), 4.21(1H, m), 3.69(2H, brs), 3.62(2H, m), 3.39(1H, m), 3.27(2H, m), 2.65(1H, m), 2.48(1H, m), 2.20(1H, m), 2.00(2H, m), 1.87(3H, m), 1.60(2H, m), 1.51(2H, m), 1.23(6H, d)
Preparation Example 67: 4-[4-(1,4-dioxaspiro[4,5]decan-8-yloxyimino)cyclohexyl]-2,5-difluoroaniline
4-(4-amino-2,5-difluorophenyl)-cyclohexanone (0.13 g, 0.57 mmol) obtained in Preparation Example 3 and O-(1,4-dioxaspiro[4.5]decan-8-yl)hydroxylamine (0.098 g, 0.57 mmol) were used in the same method as in Preparation Example 5 to obtain the title compound (0.2 g, 93% yield).
NMR: 1H-NMR(CDCl3) 6.77(1H, m), 6.45(1H, m), 4.17(1H, m), 3.95(4H, s), 3.68(2H, brs), 3.42(1H, m), 2.97(1H, m), 2.50(1H, m), 2.23(1H, m), 2.00(1H, m), 1.85(8H, m), 1.60(3H, m), 1.50(1H, m)
Preparation Example 68: 4-{[4-(4-amino-2,5-difluorophenyl)cyclohexylidene]amino}oxycyclohexanone
Tetrahydrofuran (7.3 mL) was added to 4-[4-(1,4-dioxaspiro[4,5]decan-8-yloxyimino)cyclohexyl]-2,5-difluoroaniline (0.2 g, 0.5 mmol) obtained in Preparation Example 67 and cooled to 0 ºC. To the reaction mixture, 6N HCl aqueous solution (1.5 mL) was added dropwise slowly and the mixture was stirred at room temperature. After confirming a completion of the reaction by TLC, sodium bicarbonate aqueous solution was used to adjust to pH 7, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain the title compound (0.18 g, 99% yield).
NMR: 1H-NMR(CDCl3) 6.78(1H, m), 6.46(1H, m), 4.43(1H, m), 3.71(2H, brs), 3.43(1H, m), 2.99(1H, m), 2.50(4H, m), 2.20(5H, m), 1.88(3H, m), 1.60(3H, m)
Preparation Example 69: 4-[4-(4-tert-butoxyiminocyclohexyloxy)iminocyclohexyl]2,5-difluoroaniline
4-{[4-(4-amino-2,5-difluorophenyl)cyclohexylidene]amino}oxycyclohexanone (0.18 g, 0.5 mmol) obtained in Preparation Example 68 and O-tert-butylhydroxy aminehydrochloride (0.06 g, 0.5mmol) were used in the same method as in Preparation Example 5 to obtain the title compound (0.12 g, 55% yield).
NMR: 1H-NMR(CDCl3) 6.73(1H, m), 6.45(1H, m), 4.28(1H, m), 3.69(2H, brs), 3.42(1H, m), 2.97(1H, m), 2.65(1H, m), 2.49(1H, m), 2.42(2H, m), 2.22(2H, m), 1.96(7H, m) 1.57(2H, m), 1.27(9H, m)
Preparation Example 70: 4-[4-(4-amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid phenyl ester
1-Chloro-2-fluoro-4-nitro-benzene (0.5 g, 2.9 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2 and 3 to obtain 4-(4-amino-2-fluoro-phenyl)-cyclohexanone. Said compound and 4-aminooxy-piperidine-1-carboxylic acid phenyl ester were used in the same method as in Preparation Example 5 to obtain the title compound (0.25 g, 21% yield).
NMR: 1H-NMR(CDCl3) 7.37(2H, t), 7.18(1H, t), 7.11(2H, d), 6.92(1H, t), 6.39(2H, m), 4.30(1H, m), 3.86(1H, s), 3.78(1H, s), 3.70(2H, s), 3.54(1H, s), 3.44(2H, m), 2.98(1H, t), 2.52(1H, d), 2.27(1H, m), 2.04(4H, m), 1.88(1H, m), 1.78(2H, s), 1.60(2H, m)
Preparation Example 71: 4-[4-(4-amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidin-1-carboxylic acid phenyl ester
4-Chloro-2-fluoro-1-nitrobenzene (0.5 g, 2.9 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2 and 3 to obtain 4-(4-amino-3-fluoro-phenyl)-cyclohexanone. Said compound and 4-aminooxy-piperidine-1-carboxylic acid phenyl ester were used in the same method as in Preparation Example 5 to obtain the title compound (0.32 g, 26% yield).
NMR: 1H-NMR(CDCl3) 7.37(2H, t), 7.18(1H, t), 7.11(2H, d), 6.82(1H, d), 6.75(1H, d), 6.68(1H, t), 4.31(1H, m), 3.86(1H, s), 3.78(1H, s), 3.71(2H, s), 3.54(1H, s), 3.43(2H, m), 2.98(1H, t), 2.52(1H, d), 2.27(1H, m), 2.06(4H, m), 1.90(1H, m), 1.77(2H, s), 1.65~1.50(2H, m)
Preparation Example 72: 4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime
4-chloro-2-fluoro-1-nitrobenzene was reacted subsequently according to the methods of Preparation Examples 1, 2 and 3 to synthesize 4-(4-amino-3-fluorophenyl)-cyclohexanone. The synthesized compound was reacted with O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-hydroxylamine (1.1 g, 4.8 mmol) obtained in Preparation Example 11 according to the method of Preparation Example 12 to obtain the title compound (1.7 g, 85% yield).
NMR: 1H-NMR(CDCl3) 6.85(1H, d), 6.77(1H, d), 6.70(1H, t), 4.32(1H, m), 3.80(4H, m), 3.53(2H, m), 3.41(1H, m), 2.96(1H, t), 2.92(1H, m), 2.52(1H, m), 2.28(1H, m), 2.05(4H, m), 1.90(3H, m), 1.61(2H, m), 1.28(6H, d)
Preparation Example 73: 3-aminooxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester
3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.31 g, 0.14 mmol) was reacted subsequently according to the methods of Preparation Examples 14, 32 and 15 to obtain the title compound (127 mg, 35% yield).
1H-NMR(CDCl3) 7.36(2H, t), 7.17(1H, t), 7.13(2H, d), 5.27(2H, s), 4.40(1H, s), 4.30(1H, s), 3.86(1H, s), 2.20~1.95(8H, m)
Preparation Example 74: 3-[4-(4-amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester
1-chloro-2-fluoro-4-nitro-benzene was reacted subsequently according to the methods of Preparation Examples 1, 2 and 3 to synthesize 4-(4-amino-2-fluorophenyl)-cyclohexanone. The synthesized compound was reacted with 3-aminooxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester (127 mg, 0.48 mmol) obtained in Preparation Example 73 according to the method of Preparation Example 12 to obtain the title compound (201 mg, 92% yield).
1H-NMR(CDCl3) 7.37(2H, t), 7.18(1H, t), 7.14(2H, d), 6.96(1H, t), 6.39(2H, m), 4.44(2H, s), 4.35(1H, s), 3.68(2H, s), 3.36(1H, d), 3.00(1H, t), 2.54(1H, d), 2.30~1.90(12H, m), 1.68(2H, m)
Preparation Example 75: 4-aminooxymethyl-piperidine-1-carboxylic acid tert-butyl ester
Piperidin-4-yl-methanol (15.4 g, 133.7 mmol) was reacted with di-tert-butyl dicarbonate (30.6 g, 140.0 mmol) according to the method of Preparation Example 6 to obtain the title compound (2.52 g, 90% yield).
NMR: 1H-NMR(CDCl3) 5.36(2H, s), 4.09~4.07(2H, m), 3.52(2H, d), 2.69(2H, m), 1.80(1H, m), 1.68(2H, m), 1.46(9H, s), 1.11(2H, m)
Preparation Example 76: 4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone (0.58 g, 2.61 mmol) obtained in Preparation Example 3 was reacted with 4-aminooxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.60 g, 2.61 mmol) obtained in Preparation Example 75 in the same manner as in Preparation Example 5 to obtain the title compound (1.00 g, 87% yield).
NMR: 1H-NMR(CDCl3) 6.78~6.73(1H, m), 6.48~6.40(1H, m), 4.19(2H, m), 3.90(2H, d), 3.80(2H, s), 3.41~3.40(1H, m), 3.00 (1H, m), 2.80(2H, m), 2.49~2.46(2H, m), 2.35~2.22(1H, m), 2.00~1.80(6H, m), 1.70~1.58(1H, m), 1.46(9H, s), 1.45~1.43(2H, m)
Example 1: 4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester
Figure PCTKR2012001185-appb-I000019
4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester (33 mg, 0.078 mmol) obtained in Preparation Example 5 was dissolved in methylene chloride (2 mL), and triethylamine (8.5 mg, 0.067 mmol) and triphosgene (16 mg, 0.054 mmol) were added thereto sequentially, and then the mixture was stirred at room temperature for 2 minutes. 3-hydroxyazetidine hydrochloride (9.3 mg, 0.0857 mmol) and triethylamine (78 mg, 0.58 mmol) were added sequentially and stirred at room temperature for 10 minutes. Water was added to terminate the reaction, and then the mixture was washed with methylene chloride, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure and then separated by Prep-TLC using 1:1 mixture solution of methylene chloride and ethyl acetate to obtain the title compound (20 mg, 50% yield).
NMR: 1H-NMR(CDCl3) 7.92~7.90(1H, m), 6.86~6.84(1H, m), 6.12(1H, s), 4.71(1H, m), 4.35~4.25(2H, m), 4.20(1H, m), 4.00~3.90(2H, m), 3.72~3.60(2H, m), 3.45~3.40(1H, m), 3.30~3.15(2H, m), 3.03(1H, m), 2.57(1H, d), 2.55~2.57(1H, m), 2.23(1H, m), 2.10~1.90(2H, m), 1.90~1.80(3H, m), 1.55~1.17(4H, m), 1.46(9H, s)
Example 2: 4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000020
4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (50 mg, 0.12 mmol) obtained in Preparation Example 32 was reacted with 3-hydroxyazetidine hydrochloride in the same manner as in Example 1 to obtain the title compound (38 mg, 61% yield).
NMR: 1H-NMR(CDCl3) 7.94~7.90(1H, m), 6.87~6.82(1H, m), 6.12(1H, s), 4.94~4.88(1H, m), 4.72(1H, s), 4.30(2H, t), 4.23~4.18(1H, m), 3.98~3.94(2H, m), 3.73~3.67(2H, m), 3.42~3.38(1H, m), 3.31~3.22(2H, m), 3.04(1H, t), 2.52(1H, d), 2.36(1H, s), 2.28~2.22(1H, m), 2.06~1.94(2H, m), 1.92~1.82(3H, m), 1.70~1.45(4H, m), 1.25(6H, d)
Example 3: 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000021
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (25.7 mg, 0.056 mmol) obtained in Preparation Example 7 was reacted with 3-hydroxyazetidine hydrochloride (10 mg, 0.085 mmol) in the same manner as in Example 1 to obtain the title compound (25 mg, 86% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.95~7.90(1H, m), 6.88~6.84(1H, m), 6.12(1H, s), 4.71(1H, m), 4.35~4.22(3H, m), 4.22~4.10(2H, m), 4.00~3.90(2H, m), 3.60~3.40(3H, m), 3.04(1H, m), 2.52(1H, d), 2.32~2.20(2H, m), 2.11(3H, s), 2.10~1.95(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 4: 3-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-1,1-dimethyl-urea
Figure PCTKR2012001185-appb-I000022
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (40 mg, 0.09 mmol) obtained in Preparation Example 9, dimethylamine hydrochloride (8.1 mg, 0.18 mmol), pyridine (5 μl, 0.07 mmol), diisopropylethylamine (94 μl, 0.54 mmol) and triphosgene (9 mg, 0.35 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (10 mg, 22% yield).
NMR: 1H-NMR(CDCl3): 8.22(2H, s), 7.96-7.91(1H, m), 6.88-6.65(1H, m), 6.58(1H, s), 4.31(1H, m), 4.19-4.13(2H, m), 3.55-3.53(2H, m), 3.52-3.50(1H, m), 3.03(6H, m), 2.51-2.43(3H, m), 2.27-2.26(2H, m), 2.03-2.01(4H, m), 1.99(1H, m), 1.72-1.30(4H, m), 1.20-1.17(3H, m)
Example 5: 3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-amide
Figure PCTKR2012001185-appb-I000023
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (12 mg, 0.028 mmol) obtained in Preparation Example 9, 3-hydroxyazetidine (6 mg, 0.056 mmol), diisopropylethylamine (10 μl, 0.056 mmol) and triphosgene (8 mg, 0.028 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (11.9 mg, 80% yield).
NMR: 1H-NMR(CDCl3): 8.16(2H, s), 7.92-7.89(1H, m), 6.87-6.84(1H, m), 6.13(1H, s), 4.70(1H, m), 4.31-4.27(3H, m), 4.20-4.00(2H, m), 3.77~3.71(2H, m), 3.53-3.50(3H, m), 3.10-3.03(1H, m), 2.85(1H, m), 2.45(3H, m), 2.25(1H, m), 2.01(4H, m), 1.87(1H, m), 1.71(2H, m), 1.68(2H, m), 1.17(3H, m)
Example 6: 4-cyclopropyl-piperazine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000024
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (26 mg, 0.057 mmol) obtained in Preparation Example 7 was reacted with 1-cyclopropyl-piperazine hydrochloride (14 mg, 0.086 mmol) in the same manner as in Example 1 to obtain the title compound (15 mg, 46% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.92~7.87(1H, m), 6.89~6.84(1H, m), 6.55(1H, s), 4.30(1H, m), 4.20~4.09(2H, m), 3.58~3.40(7H, m), 3.04(1H, m), 3.80~3.70(4H, m), 2.52(1H, d), 2.32~2.20(2H, m), 2.11(3H, s), 2.10~1.95(4H, m), 1.90~1.80(1H, m), 1.78~1.60(3H, m), 1.50~1.40(1H, m), 0.50~0.40(4H, m)
Example 7: (4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea
Figure PCTKR2012001185-appb-I000025
4-(4-amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (51 mg, 0.122 mmol) obtained in Preparation Example 27 was reacted with ammonium solution (1,4-dioxane 0.5M, 3 mL) in the same manner as in Example 1 to obtain the title compound (41 mg, 73% yield).
NMR: 1H-NMR(CDCl3) 8.21(2H, s), 7.18~7.08(2H, m), 6.96~6.93(1H, m), 6.47(1H, s), 4.67(2H, s), 4.30(1H, m), 4.15~4.05(2H, m), 3.60~3.40(3H, m), 3.05(1H, m), 2.55(1H, m), 2.35~2.25(1H, m), 2.10~1.90(4H, m), 1.95~1.85(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 8: 4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
Figure PCTKR2012001185-appb-I000026
4-[4-(2,5-difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.243 mmol) obtained in Example 10 was dissolved in tetrahydrofuran (3 mL), and 3-methyl-butyrylchloride (50 mg, 0.364 mmol) and triethylamine (36 mg, 0.364 mmol) were added thereto sequentially at 0 ºC, and stirred at room temperature for 10 minutes. After filtering the solid, sodium borohydride (492 mg, 13.01 mmol) was added and dissolved into water at 0 ºC, and stirred at room temperature for 3 hours. 1N hydrochloride aqueous solution was added thereto to terminate the reaction, and then the mixture was washed with ethyl acetate, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure and then separated by column chromatography using 2:1 mixture solution of hexane and ethyl acetate to obtain the title compound (90 mg, 84% yield).
NMR: 1H-NMR(CDCl3) 7.12~7.10(1H, m), 6.89~6.85(1H, m), 4.72(2H, d), 4.23(1H, m), 3.70~3.60(2H, m), 3.50~3.40(1H, m), 3.25~3.15(2H, m), 3.09(1H, m), 2.60~2.50(1H, m), 2.30~2.20(1H, m), 2.10~2.00(2H, m), 1.95~1.80(3H, m), 1.70~1.60(4H, m), 1.46(9H, s)
Example 9: 4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000027
4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester (85 mg, 0.193 mmol) obtained in Example 8 was reacted in the same manner as in Preparation Example 32 to obtain the title compound (75 mg, 92% yield).
NMR: 1H-NMR(CDCl3) 7.12~7.10(1H, m), 6.89~6.85(1H, m), 4.92(1H, m), 4.72(2H, d), 4.23(1H, m), 3.80~3.70(2H, m), 3.50~3.40(1H, m), 3.30~3.20(2H, m), 3.09(1H, m), 2.60~2.50(1H, m), 2.30~2.20(1H, m), 2.10~2.00(2H, m), 1.95~1.80(3H, m), 1.70~1.60(4H, m), 1.24(6H, d)
Example 10: 4-[4-(2,5-difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
Figure PCTKR2012001185-appb-I000028
2,5-difluoro-4-(4-oxo-cyclohexyl)-benzoic acid methyl ester (71 mg, 0.264 mmol) obtained in Preparation Example 35 was reacted in the same manner as in Preparation Example 5 to obtain the title compound (115 mg, 93% yield).
NMR: 1H-NMR(CDCl3) 7.61~7.52(1H, m), 6.99~6.95(1H, m), 4.22(1H, m), 3.92(3H, s), 3.75~3.65(2H, m), 3.50~3.40(1H, m), 3.30~3.20(2H, m), 3.09(1H, m), 2.60~2.50(1H, m), 2.30~2.20(1H, m), 2.10~2.00(2H, m), 1.95~1.80(3H, m), 1.70~1.60(4H, m), 1.46(9H, s)
Example 11: (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000029
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (50 mg, 0.11 mmol) obtained in Preparation Example 7 was reacted with ammoniumchloride (9 mg, 0.16 mmol) in the same manner as in Example 1 to obtain the title compound (30 mg, 54% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.87~7.83(1H, m), 7.00~6.86(1H, m), 6.49(1H, s), 4.63(2H, s), 4.30(1H, m), 4.20~4.10(2H, m), 3.60~3.40(3H, m), 3.04(1H, m), 2.52(1H, m), 2.32~2.20(1H, m), 2.11(3H, s), 2.10~1.95(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 12: 3-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea
Figure PCTKR2012001185-appb-I000030
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (50 mg, 0.11 mmol) obtained in Preparation Example 7 was reacted with dimethylamine hydrochloride (14 mg, 0.16 mmol) in the same manner as in Example 1 to obtain the title compound (54 mg, 93% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.96~7.91(1H, m), 6.88~6.84(1H, m), 6.53(1H, s), 4.30(1H, m), 4.20~4.10(2H, m), 3.58~3.40(3H, m), 3.10~3.00(7H, m), 2.52(1H, m), 2.32~2.20(1H, m), 2.11(3H, s), 2.10~1.95(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 13: 4-[4-(2,5-difluoro-4-{[(3-hydroxy-azetidine-1-carbonyl)-amino]-methyl}-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000031
4-[4-(4-aminomethyl-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (88 mg, 0.21 mmol) obtained in Preparation Example 42, diisopropylethylamine (74 μl, 0.42 mmol), triphosgene (62 mg, 0.21 mmol) and 3-hydroxyazetidine (46 mg, 0.42 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (15 mg, 14% yield).
NMR: 1H-NMR(CDCl3): 7.07-7.02(1H, m), 6.87-6.83(1H, m), 4.92-4.89(1H, m), 4.62-4.59(2H, m), 4.36(2H, d), 4.23-4.13(3H, m), 3.85-3.82(2H, m), 3.71(2H, m), 3.40(1H, d), 3.29-3.25(2H, m), 3.10(1H, t), 2.50(1H, d), 2.25(1H, m), 2.05(2H, m), 1.95-1.78(5H, m), 1.67-1.64(3H, m), 1.23(6H, d)
Example 14: 4-[4-(2,5-difluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000032
4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (113 mg, 0.275 mmol) obtained in Preparation Example 32 was reacted with ammonium chloride (22 mg, 0.41 mmol) in the same manner as in Example 1 to obtain the title compound (107 mg, 86% yield).
NMR: 1H-NMR(CDCl3) 7.90~7.86(1H, m), 6.88~6.84(1H, m), 4.92(1H, m), 4.84(2H, m), 4.21(1H, m), 3.78~3.60(2H, m), 3.44~3.41(1H, m), 3.30~3.20(2H, m), 3.00(1H, m), 2.50~2.40(1H, m), 2.30~2.20(1H, m), 2.10~1.90(2H, m), 1.90~1.80(3H, m), 1.65~1.45(4H, m), 1.23(6H, d)
Example 15: 4-{4-[2,5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000033
4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (51 mg, 0.124 mmol) obtained in Preparation Example 32 was reacted with propylamine (18 mg, 0.18 mmol) in the same manner as in Example 1 to obtain the title compound (54 mg, 88% yield).
NMR: 1H-NMR(CDCl3) 7.99~7.89(1H, m), 7.17(1H, s), 6.83~6.79(1H, m), 5.60(1H, s), 4.90(1H, m), 4.20(1H, m), 3.72~3.62(2H, m), 3.41~3.38(1H, m), 3.35~3.18(4H, m), 3.00(1H, m), 2.50~2.40(1H, m), 2.30~2.20(1H, m), 2.10~1.90(2H, m), 1.90~1.80(3H, m), 1.70~1.40(6H, m), 1.23(6H, d), 0.93(3H, t)
Example 16: 4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000034
4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (31 mg, 0.075 mmol) obtained in Preparation Example 32 was reacted with isopropylamine (10 mg, 0.15 mmol) in the same manner as in Example 1 to obtain the title compound (32 mg, 86% yield).
NMR: 1H-NMR(CDCl3) 7.91~7.87(1H, m), 6.87~6.82(1H, m), 6.28(1H, s), 4.92(1H, m), 4.45(1H, d), 4.20(1H, m), 4.00(1H, m), 3.78~3.68(2H, m), 3.44~3.41(1H, m), 3.30~3.20(2H, m), 3.07(1H, m), 2.55~2.45(1H, m), 2.35~2.25(1H, m), 2.10~1.88(5H, m), 1.75~1.60(4H, m), 1.30~1.15(12H, m)
Example 17: 4-(4-{2,5-difluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000035
4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (31 mg, 0.075 mmol) obtained in Preparation Example 32 was reacted with 2-hydroxyethylamine (15 mg, 0.15 mmol) in the same manner as in Example 1 to obtain the title compound (22 mg, 59% yield).
NMR: 1H-NMR(CDCl3) 7.87~7.83(1H, m), 6.88~6.84(1H, m), 6.71(1H, s), 5.13(1H, m), 4.92(1H, m), 4.22(1H, m), 3.85~3.62(4H, m), 3.49~3.38(3H, m), 3.30~3.20(2H, m), 3.07(1H, m), 2.55~2.45(1H, m), 2.32~2.20(2H, m), 2.10~1.88(5H, m), 1.70~1.60(4H, m), 1.23(6H, d)
Example 18: 4-(4-{4-[3-(2,3-dihydroxy-propyl)-ureido]-2,5-difluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000036
4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (31 mg, 0.075 mmol) obtained in Preparation Example 32 was reacted with 2,3-dihydroxypropylamine (10 mg, 0.15 mmol) in the same manner as in Example 1 to obtain the title compound (24 mg, 61% yield).
NMR: 1H-NMR(CDCl3) 7.85~7.80(1H, m), 6.89~6.85(1H, m), 6.70(1H, s), 5.22(1H, m), 4.91(1H, m), 4.22(1H, m), 3.90(1H, m), 3.80~3.62(4H, m), 3.51~3.40(3H, m), 3.30~3.20(2H, m), 3.07(1H, m), 2.55~2.45(1H, m), 2.30~2.20(1H, m), 2.10~1.88(5H, m), 1.70~1.60(4H, m), 1.23(6H, d)
Example 19: 4-[4-(4-methanesulfonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
Figure PCTKR2012001185-appb-I000037
1-chloro-4-methanesulfonyl-benzene (228 mg, 1.197 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 5 to obtain the title compound (80 mg, 4 steps total 16% yield).
NMR: 1H-NMR(CDCl3) 7.89~7.87(2H, m), 7.42~7.40(2H, m), 4.22(1H, m), 3.71~3.61(2H, m), 3.50~3.40(1H, m), 3.28~3.18(2H, m), 3.08(3H, s), 2.90~2.80(1H, m), 2.60~2.50(1H, m), 2.30~2.20(1H, m), 2.18~2.05(2H, m), 1.95~1.83(3H, m), 1.78~1.60(4H, m), 1.46(9H, s)
Example 20: 4-(4-{4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester
Figure PCTKR2012001185-appb-I000038
4-[4-(4-amino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester (18 mg, 0.05 mmol) obtained in Preparation Example 31 was reacted with 3-hydroxyazetidine hydrochloride (8 mg, 0.06 mmol) in the same manner as in Example 1 to obtain the title compound (20 mg, 90% yield).
NMR: 1H-NMR(CDCl3) 7.56~7.31(2H, m), 7.17~7.14(2H, m), 6.09(1H, s), 4.67(1H, m), 4.30~4.20(3H, m), 4.00~3.90(2H, m), 3.75~3.65(2H, m), 3.49~3.39(1H, m), 3.30~3.15(2H, m), 2.76(1H, m), 2.55~2.47(1H, m), 2.33~2.22(1H, m), 2.10~1.90(2H, m), 1.90~1.80(4H, m), 1.55~1.17(4H, m), 1.46(9H, s)
Example 21: 4-(4-{4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000039
4-[4-(4-amino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester (50 mg) obtained in Preparation Example 31 was reacted in the same manner as in Preparation Example 32 to synthesize 4-[4-(4-amino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester. The synthesized compound and 3-hydroxyazetidine hydrochloride were used in the same method as in Example 1 to obtain the title compound (37 mg, 2 steps total 60% yield).
NMR: 1H-NMR(CDCl3) 7.52~7.26(2H, m), 7.13~7.11(2H, m), 5.91(1H, s), 4.91(1H, m), 4.69(1H, m), 4.30~4.18(3H, m), 3.95~3.88(2H, m), 3.79~3.67(2H, m), 3.41~3.37(1H, m), 3.30~3.15(2H, m), 2.73(1H, m), 2.55~2.47(1H, m), 2.30~2.18(2H, m), 2.10~1.90(2H, m), 1.90~1.80(3H, m), 1.55~1.17(4H, m), 1.14(6H, d)
Example 22: 3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000040
4-(4-amino-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.05 mmol) obtained in Preparation Example 30 was reacted with 3-hydroxyazetidine hydrochloride (9 mg, 0.08 mmol) in the same manner as in Example 1 to obtain the title compound (20 mg, 80% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.52~7.26(2H, m), 7.13~7.11(2H, m), 5.90(1H, s), 4.70(1H, m), 4.34~4.25(3H, m), 4.21~4.10(2H, m), 3.95~3.90(2H, m), 3.65~3.40(3H, m), 2.71(1H, m), 2.52(1H, d), 2.30~2.20(1H, m), 2.10(3H, s), 2.10~1.94(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 23: 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000041
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime (10 mg, 0.02 mmol) obtained in Preparation Example 12 was reacted with 3-hydroxyazetidine hydrochloride in the same manner as in Example 1 to obtain the title compound (10 mg, 81% yield).
NMR: 1H-NMR(CDCl3) 7.92~7.88(1H, m), 7.89~7.83(1H, m), 6.14(1H, s), 4.70(1H, s), 4.32~4.28(3H, m), 3.99~3.94(2H, m), 3.80~3.73(2H, m), 3.55~3.48(2H, m), 3.45~3.37(1H, m), 3.03(1H, t), 2.92~2.84(1H, m), 2.77(1H, s), 2.52(1H, d), 2.28~2.22(1H, m), 2.08~1.92(4H, m), 1.91~1.78(3H, m), 1.68~1.45(2H, m), 1.25(6H, d)
Example 24: 1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000042
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime (10 mg, 0.02 mmol) obtained in Preparation Example 12 was reacted with 2-hydroxyethylamine in the same manner as in Example 1 to obtain the title compound (9 mg, 75% yield).
NMR: 1H-NMR(CDCl3) 7.88~7.82(1H, m), 7.92~7.82(2H, m), 5.29(1H, s), 4.32~4.28(1H, m), 3.82~3.75(4H, m), 3.54~3.47(2H, m), 3.47~3.38(3H, m), 3.04(1H, t), 2.92~2.85(1H, m), 2.52(1H, s), 2.28~2.22(1H, m), 2.08~1.94(4H, m), 1.92~1.79(3H, m), 1.68~1.47(2H, m), 1.28(6H, d)
Example 25: (2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000043
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime (10 mg, 0.02 mmol) obtained in Preparation Example 12 was reacted with ammonium solution (1,4-dioxane 0.5M) in the same manner as in Example 1 to obtain the title compound (5 mg, 45% yield).
NMR: 1H-NMR(CDCl3) 7.88~7.82(1H, m), 7.89~7.80(2H, m), 4.86(2H, s), 4.32~4.27(1H, m), 3.82~3.75(2H, m), 3.54~3.47(2H, m), 3.42(1H, d), 3.04(1H, t), 2.92~2.85(1H, m), 2.52(1H, s), 2.29~2.22(1H, m), 2.08~1.95(4H, m), 1.93~1.78(3H, m), 1.68~1.47(2H, m), 1.28(6H, d)
Example 26: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1,1-dimethyl-ethyl)-urea
Figure PCTKR2012001185-appb-I000044
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (21 mg, 0.05 mmol) obtained in Preparation Example 7 was reacted with 1,1-dimethyl-2-hydroxyethylamine (9 mg, 0.075 mmol) in the same manner as in Example 1 to obtain the title compound (10 mg, 38% yield).
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 7.82~7.78(1H, m), 6.87~6.83(1H, m), 6.46(1H, s), 4.73(1H, m), 4.29(1H, m), 4.18~4.10(2H, m), 3.87(1H, t), 3.65(2H, d), 3.52~3.40(3H, m), 3.05(1H, m), 2.52(1H, m), 2.25(1H, m), 2.10(3H, s), 2.10~1.90(4H, m), 1.90~1.80(1H, m), 1.72~1.60(2H, m), 1.50~1.40(2H, m), 1.33(6H, s)
Example 27: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000045
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (21 mg, 0.05 mmol) obtained in Preparation Example 7 was reacted with 2-hydroxypropylamine (6 mg, 0.075 mmol) in the same manner as in Example 1 to obtain the title compound (10 mg, 38% yield).
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 7.82~7.78(1H, m), 6.87~6.83(1H, m), 6.76(1H, s), 5.00(1H, m), 4.30(1H, m), 4.20~4.10(2H, m), 3.97~3.90(1H, m), 3.52~3.40(4H, m), 3.20~3.10(1H, m), 3.05(1H, m), 2.52(1H, m), 2.25(1H, m), 2.10(3H, s), 2.04(1H, d), 2.10~1.90(4H, m), 1.90~1.80(1H, m), 1.72~1.60(2H, m), 1.50~1.40(2H, m), 1.22(3H, d)
Example 28: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000046
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.048 mmol) obtained in Preparation Example 7 was reacted with 2-hydroxyethylamine (15 mg, 0.24 mmol) in the same manner as in Example 1 to obtain the title compound (14.6 mg, 60% yield).
1H-NMR(400MHz, CDCl3); δ 8.20(s, 2H), 7.88(dd, 1H), 6.91(dd, 1H), 6.76(br s, 1H), 5.18(t, 1H), 4.34(m, 1H), 4.20(m, 2H), 3.84(m, 2H), 3.56(m, 2H), 3.50(m, 3H), 3.09(t, 1H), 2.57(d, 1H), 2.31(m, 2H), 2.16(s, 3H), 2.04(m, 4H), 1.95(td, 1H), 1.74(m, 2H), 1.60(m, 2H)
Example 29: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000047
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.048 mmol) obtained in Preparation Example 7 was reacted with 3-amino-1-propanol (25 mg, 0.33 mmol) in the same manner as in Example 1 to obtain the title compound (18.1 mg, 73% yield).
1H-NMR(500MHz, CDCl3); δ 8.16(s, 2H), 7.83(dd, 1H), 6.85(dd, 1H), 6.47(br s, 1H), 5.02(t, 1H), 4.29(m, 1H), 4.14(m, 2H), 3.72(m, 2H), 3.50(m, 2H), 3.44(m, 3H), 3.04(t, 1H), 2.73(m, 1H), 2.52(d, 1H), 2.26(td, 1H), 2.11(s, 3H), 1.99(m, 4H), 1.87(td, 1H), 1.73(m, 4H), 1.55(m, 2H)
Example 30: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-hydroxymethyl-ethyl)-urea
Figure PCTKR2012001185-appb-I000048
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.07 mmol) obtained in Preparation Example 7 was reacted with 2-hydroxy-1-hydroxymethyl-ethylamine in the same manner as in Example 1 to obtain the title compound (5 mg, 13% yield).
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 7.84~7.80(1H, m), 7.21(1H, s), 6.84~6.78(1H, m), 6.12(1H, d), 4.32~4.25(1H, m), 4.18~4.10(2H, m), 3.92~3.78(5H, m), 3.53~3.47(2H, m), 3.43(1H, d), 3.02(1H, t), 2.52(1H, d), 2.29~2.21(1H, m), 2.10(3H, s), 2.05~1.92(4H, m), 1.91~1.82(1H, m), 1.72~1.50(6H, m)
Example 31: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2,3-dihydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000049
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.07 mmol) obtained in Preparation Example 7 was reacted with 2,3-dihydroxypropylamine in the same manner as in Example 1 to obtain the title compound (8 mg, 21% yield).
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 7.82~7.78(1H, m), 7.05(1H, s), 6.88~6.80(1H, m), 5.86(1H, d), 4.32~4.27(1H, m), 4.18~4.12(2H, m), 3.94~3.50(4H, m), 3.52~3.46(3H, m), 3.43(1H, d), 3.06(1H, t), 2.53(1H, d), 2.29~2.21(1H, m), 2.10(3H, s), 2.06~1.94(4H, m), 1.91~1.82(1H, m), 1.72~1.50(4H, m)
Example 32: N-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide
Figure PCTKR2012001185-appb-I000050
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.048 mmol) obtained in Preparation Example 7 was dissolved in dichloromethane (4 mL). Diisopropylethylamine (40 mg, 0.31 mmol) and methanesulfonylchloride (30 mg, 0.31 mmol) were added thereto, and the mixture was stirred for 18 hours. The reaction mixture was distilled under reduced pressure to remove the solvent and then separated by Prep-TLC to obtain N-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-N-(methanesulfonyl)methanesulfonamide (18.3 mg, 67% yield).
The obtained N-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-N-(methanesulfonyl)methanesulfonamide (17.3 mg, 0.030 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), and calciumhydroxide (20 mg, 0.36 mmol) was added thereto. Then, the mixture was stirred for 1 hour. The organic substance was extracted by adding water (20 mL) and ethylacetate (20 mL) thereto, and dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent. The residue was purified by Prep-TLC to obtain the title compound (10.9 mg, 73% yield).
1H-NMR(400MHz, CDCl3); δ 8.20(s, 2H), 7.35(dd, 1H), 7.02(dd, 1H), 6.51(br s, 1H), 4.35(m, 1H), 4.20(m, 2H), 3.53(m, 3H), 3.13(m, 1H), 3.09(s, 3H), 2.59(d, 1H), 2.32(td, 1H), 2.16(s, 3H), 2.02(m, 4H), 1.92(td, 1H), 1.73(m, 2H), 1.61(m, 2H)
Example 33: 1-(3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000051
4-(4-amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (53 mg, 0.133 mmol) obtained in Preparation Example 10 was reacted with 2-hydroxyethylamine (30 mg) in the same manner as in Example 1 to obtain the title compound (59 mg, 92% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.18~7.08(2H, m), 6.95~6.93(1H, m), 6.46(1H, s), 5.04(1H, m), 4.30(1H, m), 4.20~4.10(2H, m), 3.75~3.65(2H, m), 3.55~3.40(5H, m), 3.05(1H, m), 2.55(1H, m), 2.45~2.40(1H, m), 2.25(1H, m), 2.11(3H, s), 2.10~1.95(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 34: (3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000052
4-(4-amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (50 mg, 0.131 mmol) obtained in Preparation Example 10 was reacted with ammonium solution(1,4-dioxane 0.5M, 3 mL) in the same manner as in Example 1 to obtain the title compound (47 mg, 81% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.18~7.08(2H, m), 6.95~6.93(1H, m), 6.35(1H, s), 4.62(2H, s), 4.31(1H, m), 4.20~4.10(2H, m), 3.56~3.40(3H, m), 3.05(1H, m), 2.55(1H, m), 2.35~2.25(1H, m), 2.11(3H, s), 2.05~1.90(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 35: 3-hydroxy-azetidine-1-carboxylic acid (3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000053
4-(4-amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (50 mg, 0.131 mmol) obtained in Preparation Example 10 was reacted with 3-hydroxyazetidine hydrochloride (22 mg) in the same manner as in Example 1 to obtain the title compound (57 mg, 87% yield).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.28(1H, m), 7.09~7.07(1H, m), 7.00~6.95(1H, m), 5.94(1H, s), 4.71(1H, m), 4.32~4.22(3H, m), 4.19~4.10(2H, m), 3.98~3.90(2H, m), 3.56~3.40(3H, m), 3.05(1H, m), 2.55(1H, m), 2.20~2.20(1H, m), 2.11(3H, s), 2.08~1.95(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 36: 1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000054
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime (23 mg, 0.053 mmol) obtained in Preparation Example 12 was reacted with 2-methoxyethylamine (25 mg, 0.33 mmol) in the same manner as in Example 1 to obtain the title compound (23.0 mg, 81% yield).
1H-NMR(400MHz, CDCl3); δ 7.92(dd, 1H), 7.47(br s, 1H), 6.86(dd, 1H), 5.67(br s, 1H), 4.33(m, 1H), 3.82(m, 2H), 3.56(m, 4H), 3.48(m, 3H), 3.43(s, 3H), 3.07(t, 1H), 2.93(m, 1H), 2.54(d, 1H), 2.29(td, 1H), 2.05(m, 4H), 1.85(m, 3H), 1.56(m, 2H), 1.32(d, 6H)
Example 37: 1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000055
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime (22 mg, 0.051 mmol) obtained in Preparation Example 12 was reacted with 2-ethoxyethylamine (25 mg, 0.28 mmol) in the same manner as in Example 1 to obtain the title compound (19.0 mg, 68% yield).
1H-NMR(400MHz, CDCl3); δ 7.93(dd, 1H), 7.45(br s, 1H), 6.86(dd, 1H), 5.69(br s, 1H), 4.33(m, 1H), 3.81(m, 2H), 3.59(m, 6H), 3.48(m, 3H), 3.07(t, 1H), 2.92(m, 1H), 2.54(d, 1H), 2.29(td, 1H), 2.06(m, 4H), 1.88(m, 3H), 1.58(m, 2H), 1.32(d, 6H), 1.26(t, 3H)
Example 38: N-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide
Figure PCTKR2012001185-appb-I000056
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime (23 mg, 0.053 mmol) obtained in Preparation Example 12 was reacted in the same manner as in Example 32 to obtain the title compound (8.0 mg, 29% yield).
1H-NMR(400MHz, CDCl3); δ 7.32(dd, 1H), 6.96(dd, 1H), 6.47(br s, 1H), 4.29(m, 1H), 3.77(m, 2H), 3.51(m, 2H), 3.42(m, 1H), 3.08(m, 1H), 3.05(s, 3H), 2.88(m, 1H), 2.53(m, 1H), 2.27(td, 1H), 2.06(m, 1H), 2.00(m, 3H), 1.89(td, 1H), 1.82(m, 2H), 1.58(m, 2H), 1.28(d, 6H)
Example 39: {2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-urea
Figure PCTKR2012001185-appb-I000057
The compound obtained in Preparation Example 16 (50 mg, 0.123 mmol) was reacted with ammonium solution (1,4-dioxane 0.5M) according to a method similar with that of Example 1 to obtain the title compound (8 mg, 14% yield).
NMR: 1H-NMR(CDCl3) 7.88(1H, m), 7.19(1H, d), 6.88(1H, m), 6.55(2H, m), 4.66(2H, s), 4.28(1H, m), 3.71(2H, m), 3.40(3H, m), 3.05(1H, m), 2.54(1H, m), 2.25(1H, m), 2.06~1.92(4H, m), 1.88(3H, m), 1.62~1.49(2H, m)
Example 40: {2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-carbamic acid methyl ester
Figure PCTKR2012001185-appb-I000058
A byproduct produced in Example 39 was purified to obtain the title compound (4.2 mg, 7% yield).
NMR: 1H-NMR(CDCl3) 7.86(1H, m), 7.19(1H, d), 6.89(1H, m), 6.80(1H, s), 6.55(1H, d), 4.31(1H, m), 3.80(3H, s), 3.71(2H, m), 3.44(3H, m), 3.06(1H, m), 2.54(1H, m), 2.27(1H, m), 2.03(4H, m), 1.87(3H, m), 1.65~1.51(2H, m)
Example 41: {4-[4-(1-benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5-difluoro-phenyl}-urea
Figure PCTKR2012001185-appb-I000059
The compound (50 mg, 0.112mmol) obtained from Preparation Example 21 and ammonium solution (1, 4-dioxane 0.5M) were reacted in a similar manner as in Example 1 to obtain the title compound (6 mg, yield: 11%).
NMR: 1H-NMR(CDCl3) 7.86(1H, m), 7.58(2H, m), 7.28(1H, m), 7.06(1H, m), 6.87(1H, m), 6.75(1H, s), 4.77(2H, s), 4.34(1H, m), 3.82(2H, m), 3.55(2H, m), 3.44(1H, m), 3.05(1H, m), 2.54(1H, m), 2.26(1H, m), 2.05(4H, m), 1.88(3H, m), 1.60~1.50(2H, m)
Example 42: {4-[4-(1- benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5- difluoro-phenyl}-carbamic acid methyl ester
Figure PCTKR2012001185-appb-I000060
The title compound (4.6 mg, yield: 8%) was obtained from the purification of the byproduct produced from Example 41.
NMR: 1H-NMR(CDCl3) 7.84(1H, m), 7.55(2H, m), 7.29(1H, m), 7.06(1H, m), 6.87(1H, m), 6.79(1H, s), 4.34(1H, m), 3.80(5H, m), 3.56(2H, m), 3.41(1H, m), 3.06(1H, m), 2.51(1H, m), 2.26(1H, m), 2.05(4H, m), 1.89(3H, m), 1.69~1.48(2H, m)
Example 43: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-hydroxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000061
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (33 mg, 0.077 mmol) obtained from Preparation Example 9 and monoethanolamine (30 mg, 0.49 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (37.2 mg, yield: 94%).
1H-NMR(400MHz, CDCl3); δ 8.22(s, 2H), 7.89(dd, 1H), 6.91(br s, 1H), 6.90(dd s, 1H), 5.36(t, 1H), 4.34(m, 1H), 4.20(m, 2H), 3.84(m, 2H), 3.57(m, 2H), 3.50(m, 3H), 3.09(t, 1H), 2.55(d, 1H), 2.50(m, 3H), 2.31(td, 1H), 2.04(m, 4H), 1.92(td, 1H), 1.75(m, 2H), 1.52(m, 2H), 1.23(t, 3H)
Example 44: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000062
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained from Preparation Example 9 and 3-amino-1-propanol (30 mg, 0.40 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (33.2 mg, yield: 90%).
1H-NMR(400MHz, CDCl3); δ 8.22(s, 2H), 7.88(dd, 1H), 6.90(dd, 1H), 6.62(s, 1H), 5.18(t, 1H), 4.34(m, 1H), 4.20(m, 2H), 3.79(m, 2H), 3.54(m, 5H), 3.06(t, 1H), 2.83(m, 1H), 2.60(d, 1H), 2.51(q, 2H), 2.31(td, 1H), 2.05(m, 4H), 1.92(td, 1H), 1.75(m, 4H), 1.52(m, 2H), 1.23(t, 3H)
Example 45: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy -2,2-dimethyl-propyl)-urea
Figure PCTKR2012001185-appb-I000063
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (25 mg, 0.06 mmol) obtained from Preparation Example 7 and 3-hydroxy-2,2-dimetyl-propylamine were reacted in the same manner as in Example 1 to obtain the title compound (21 mg, yield: 64%).
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 7.84~7.80(1H, m), 6.88~6.82(1H, m), 6.72(1H, s), 5.21(1H, s), 4.32~4.26(1H, m), 4.18~4.12(2H, m), 3.53~3.48(2H, m), 3.43(1H, d), 3.27(2H, s), 3.12(2H, d), 3.04(1H, t), 2.53(1H, d), 2.30~2.22(1H, m), 2.11(3H, s), 2.08~1.95(4H, m), 1.91~1.82(1H, m), 1.72~1.63(2H, m), 1.55~1.47(2H, m), 0.89(6H, s)
Example 46: 1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy -2,2-dimethyl-propyl)-urea
Figure PCTKR2012001185-appb-I000064
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime (25 mg, 0.06 mmol) obtained from Preparation Example 12 and 3-hydroxy-2,2-dimetyl-propylamine were reacted in the same manner as in Example 1 to obtain the title compound (23 mg, yield: 71%).
NMR: 1H-NMR(CDCl3) 7.84~7.80(1H, m), 7.88~7.75(2H, m), 5.34(1H, s), 4.31~4.27(1H, m), 3.81~3.72(2H, m), 3.55~3.48(2H, m), 3.43(1H, d), 3.28(2H, d), 3.12(2H, d), 3.04(1H, t), 2.92~2.84(1H, m), 2.52(1H, d), 2.30~2.22(1H, m), 2.08~1.95(4H, s), 1.92~1.77(3H, m), 1.55~1.45(2H, m), 1.28(6H, d), 0.88(6H, s)
Example 47: (2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000065
4-(4-amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methylpyrimidine2-yl)-piperidin-4-yl]-oxime (51 mg, 0.121 mmol) obtained from Preparation Example 23 and ammonium solution (1, 4-dioxane 0.5M, 3mL) were reacted in the same manner as in Example 1 to obtain the title compound (45 mg, yield: 80%).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 6.83(2H, m), 5.81(1H, s), 4.66(2H, s), 4.30(1H, m), 4.20~4.10(2H, m), 3.55~3.40(3H, m), 2.85(1H, m), 2.65(1H, m), 2.30~2.20(1H, m), 2.15(3H, s), 2.10~1.95(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 48: 3-hydroxy-azetidine-1-carboxylic acid (2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000066
4-(4-amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methylpyrimidin-2-yl)-piperidin-4-yl]-oxime (51 mg, 0.121 mmol) obtained from Preparation Example 23 and 3-hydroxy-azetidine hydrochloride (20 mg) were reacted in the same manner as in Example 1 to obtain the title compound (45 mg, yield: 71%).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 6.83(2H, m), 5.46(1H, s), 4.71(1H, m), 4.35~4.25(3H, m), 4.20~4.10(2H, m), 4.00~3.90(2H, m), 3.55~3.40(3H, m), 2.71(1H, m), 2.65(1H, m), 2.30~2.20(2H, m), 2.15(3H, s), 2.10~1.95(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 49: butane-1-sulfone acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxylimino]-cyclohexyl}-2, 5-difluoro-phenyl)-amide
Figure PCTKR2012001185-appb-I000067
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (40 mg, 0.093 mmol) obtained from Preparation Example 9 with butanesulfonylchloride were reacted in the same manner as in Example 32 to obtain the title compound (25.0 mg, yield: 49%).
1H-NMR(400MHz, CDCl3); δ 8.23(s, 2H), 7.36(dd, 1H), 6.70(dd, 1H), 6.56(br s, 1H), 4.35(m, 1H), 4.19(m, 2H), 3.60(m, 2H), 3.49(d, 1H), 3.14(m, 3H), 2.60(d, 1H), 2.50(q, 2H), 2.31(td, 1H), 2.04(m, 4H), 1.95(m, 3H), 1.76(m, 2H), 1.52(m, 2H), 1.47(q, 2H), 1.23(t, 3H), 0.96(t, 3H)
Example 50: 4-[4-(2,5-difluoro-4-guanidinocarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester
Figure PCTKR2012001185-appb-I000068
4-[4-(4-carboxy-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.13 mmol) obtained from Preparation Example 36 was dissolved in dimethylformamide (5 mL). Triethylamine (78 mg, 0.77 mmol) and 1,1-carbonyldiimidazole (24 mg, 0.15 mmol) were added thereto and then the mixture were stirred for 2 hours. Guanidinehydrochloride (127 mg, 1.33 mmol) and triethylamine (150 mg, 1.48 mmol) were dissolved in dimethylformamide (4 mL) and added thereto and then the mixure was stirred for 2 hours. The reaction mixture was distilled under reduced pressure to remove the solvent and separated by Prep-TLC to obtain the title compound (22.2 mg, yield: 34%).
1H-NMR(400MHz, CDCl3); 7.62(dd, 1H), 6.93(dd, 1H), 6.74(br s, 2H), 4.25(m, 1H), 3.71(m, 2H), 3.47(d, 1H), 3.27(m, 2H), 3.13(m, 1H), 2.57(d, 1H), 2.30(td, 1H), 2.07(m, 2H), 1.92(m, 3H), 1.65(m, 4H), 1.50(s, 9H)
Example 51: (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea
Figure PCTKR2012001185-appb-I000069
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethylpyrimidin-2-yl)-piperidin-4-yl]-oxime (0.085 mg, 0.2 mmol) obtained from Preparation Example 9 and ammonium solution (1,4-dioxane 0.5M) were reacted in the same manner as in Example 1 to obtain the title compound.
NMR: 1H-NMR(CDCl3); δ 8.22(s, 2H), 7.86~7.91(dd, 1H), 6.89~6.94(dd, 1H), 6.72(s, NH, 1H), 4.80(s, NH2, 2H), 4.34~4.36(m, 1H), 4.17~4.23(m, 2H), 3.54~3.59(m, 2H), 3.46~3.50(dd, 1H), 3.08~3.12(t, 1H), 2.51~2.56(d, 1H), 2.47~2.51(t, 2H), 2.28~2.32(dt, 1H), 2.04~2.07(m, 4H), 1.88~1.95(dt, 1H) 1.18~1.77(m, 4H), 1.21~1.25(t, 3H)
Example 52: (R)-3-fluoro-pyrrolidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-amide
Figure PCTKR2012001185-appb-I000070
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained from Preparation Example 9 and S-(+)-3-fluoropyrrolidine hydrochloride (60 mg, 0.48 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (34.0 mg, yield: 89%).
1H-NMR(500MHz, CDCl3); δ 8.16(s, 2H), 7.96(dd, 1H), 6.86(dd, 1H), 6.36(s, 1H), 5.30(d, 1H), 4.30(m, 1H), 4.15(m, 2H), 3.84(dd, 1H), 3.64(m, 3H), 3.52(m, 2H), 3.43(d, 1H), 3.05(t, 1H), 2.52(d, 1H), 2.45(q, 2H), 2.38(m, 1H), 2.26(td, 1H), 2.15(m, 1H), 2.00(m, 4H), 1.87(td, 1H), 1.70(m, 2H), 1.53(m, 2H), 1.18(t, 3H)
Example 53: (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea
Figure PCTKR2012001185-appb-I000071
4-(4-amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (56 mg, 0.136 mmol) obtained from Preparation Example 24 and ammonium solution (1,4-dioxane 0.5M, 3 mL) were reacted in the same manner as in Example 1 to obtain the title compound (50 mg, yield: 81%).
NMR: 1H-NMR(CDCl3) 8.17(2H, s), 7.18~7.08(2H, m), 6.95~6.93(1H, m), 6.44(1H, s), 4.70(2H, s), 4.31(1H, m), 4.20~4.10(2H, m), 3.60~3.40(3H, m), 3.05(1H, m), 2.55~2.40(3H, m), 2.35~2.25(1H, m), 2.10~1.90(4H, m), 1.95~1.85(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m), 1.19(3H, t)
Example 54: (4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea
Figure PCTKR2012001185-appb-I000072
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.05 mmol) obtained from Preparation Example 26 and ammonium solution (1,4-dioxane 0.5M) were reacted in the same manner as in Example 1 to obtain the title compound (18 mg, yield: 82%).
NMR: 1H-NMR(CDCl3) 8.21(2H, s), 7.88~7.82(1H, m), 6.90~6.84(1H, m), 6.52(1H, s), 4.64(2H, s), 4.33~4.28(1H, m), 4.14~4.08(2H, m), 3.61~3.52(2H, m), 3.44(1H, d), 3.05(1H, t), 2.54(1H, t), 2.30~2.22(1H, m), 2.08~1.96(4H, m), 1.93~1.88(1H, m), 1.76~1.68(2H, m), 1.67~1.48(2H, m)
Example 55: 1-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000073
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.05 mmol) obtained from Preparation Example 26 and 3-hydroxypropylamine were reacted in the same manner as in Example 1 to obtain the title compound (19 mg, yield: 77%).
NMR: 1H-NMR(CDCl3) 8.21(2H, s), 7.88~7.82(1H, m), 6.88~6.82(1H, m), 6.53(1H, s), 5.11~5.06(1H, m), 4.33~4.28(1H, m), 4.14~4.08(2H, m), 3.74(2H, d), 3.62~3.52(2H, m), 3.48~3.40(3H, m), 3.04(1H, t), 2.76(1H, s), 2.53(1H, d), 2.31~2.21(1H, m), 2.08~1.96(4H, m), 1.93~1.88(1H, m), 1.76~1.66(4H, m), 1.67~1.46(2H, m)
Example 56: 3-hydroxy-azetidine-1-carboxylic acid {2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl}-amide
Figure PCTKR2012001185-appb-I000074
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-oxime (40 mg, 0.085 mmol) obtained from Preparation Example 29 and 3-hydroxyazetidine hydrochloride (60 mg, 0.55 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (16.0 mg, yield: 33%).
1H-NMR(400MHz, CDCl3); δ 8.43(s, 1H), 7.97(dd, 1H), 7.65(dd, 1H), 6.90(dd, 1H), 6.71(d, 1H), 6.17(d, 1H), 4.77(m, 1H), 4.37(m, 3H), 3.99(m, 4H), 3.52(m, 3H), 3.09(t, 1H), 2.57(d, 1H), 2.32(td, 1H), 2.26(d, 1H), 2.06(m, 4H), 1.92(td, 1H), 1.80(m, 2H), 1.52(m, 2H)
Example 57: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000075
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained from Preparation Example 9 and DL-1-amino-2-propanol (35 mg, 0.47 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (32.0 mg, yield: 86%).
1H-NMR(500MHz, CDCl3); δ 8.16(s, 2H), 7.83(dd, 1H), 6.85(dd s, 1H), 6.80(br s, 1H), 5.15(t, 1H), 4.30(m, 1H), 4.15(m, 2H), 3.97(m, 1H), 3.52(m, 2H), 3.44(m, 2H), 3.14(m, 1H), 3.04(t, 1H), 2.51(d, 1H), 2.45(q, 2H), 2.26(m, 2H), 2.00(m, 4H), 1.86(td, 1H), 1.70(m, 2H), 1.53(m, 2H), 1.23(d, 3H), 1.18(t, 3H)
Example 58: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000076
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained from Preparation Example 9 and 2-methoxyethylamine (35 mg, 0.48 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (29.5 mg, yield: 80%).
1H-NMR(500MHz, CDCl3); δ 8.17(s, 2H), 7.86(dd, 1H), 6.84(dd s, 1H), 5.10(t, 1H), 4.29(m, 1H), 4.15(m, 2H), 3.52(m, 4H), 3.43(m, 3H), 3.39(s, 3H), 3.02(t, 1H), 2.20(d, 1H), 2.45(q, 2H), 2.26(td, 1H), 2.00(m, 4H), 1.87(td, 1H), 1.69(m, 2H), 1.55(m, 2H), 1.13(d, 3H)
Example 59: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000077
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 7 and 2-ethoxyethylamine (35 mg, 0.39 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (31.0 mg, yield: 84%).
1H-NMR(500MHz, CDCl3); δ 8.14(s, 2H), 7.87(dd, 1H), 6.85(dd s, 1H), 5.07(m, 1H), 4.29(m, 1H), 4.15(m, 2H), 3.55(m, 4H), 3.51(m, 2H), 3.45(m, 3H), 3.02(t, 1H), 2.51(d, 1H), 2.26(td, 1H), 2.11(s, 3H), 1.99(m, 4H), 1.87(td, 1H), 1.69(m, 2H), 1.55(m, 2H), 1.22(d, 3H)
Example 60: 1-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000078
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.069 mmol) obtained from Preparation Example 26 and 2-methoxyethylamine (35 mg, 0.47 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (31.0 mg, yield: 84%).
1H-NMR(400MHz, CDCl3); δ 8.27(s, 2H), 7.92(dd, 1H), 7.10(br s, 1H), 6.89(dd s, 1H), 5.11(t, 1H), 4.35(m, 1H), 4.13(m, 2H), 3.63(m, 4H), 3.52(m, 3H), 3.45(s, 3H), 3.09(t, 1H), 2.57(m, 1H), 2.31(td, 1H), 2.05(m, 4H), 1.92(td, 1H), 1.76(m, 2H), 1.52(m, 2H)
Example 61: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea
Figure PCTKR2012001185-appb-I000079
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 7 and 2-(2-aminoethoxy)ethanol (40 mg, 0.38 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (28.0 mg, yield: 71%).
1H-NMR(400MHz, CDCl3); δ 8.20(s, 2H), 7.92(dd, 1H), 6.91(br s, 1H), 6.89(dd s, 1H), 5.32(m, 1H), 4.34(m, 1H), 4.18(m, 2H), 3.83(m, 2H), 3.68(m, 4H), 3.52(m, 5H), 3.09(t, 1H), 2.57(d, 1H), 2.30(td, 1H), 2.17(m, 1H), 2.16(s, 3H), 2.04(m, 4H), 1.92(td, 1H), 1.74(m, 2H), 1.53(m, 2H)
Example 62: {2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl}-urea
Figure PCTKR2012001185-appb-I000080
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-oxime (0.094 g, 0.2 mmol) obtained from Preparation Example 29 and ammonium solution (1,4-dioxane 0.5M) were reacted in the same manner as in Example 1 to obtain the title compound (yield: 72%).
1H-NMR(400MHz, CDCl3); δ 8.43(s, 1H), 7.83~7.91(dd, 1H), 7.63~7.66(dd, 1H), 6.81~6.93(dd, 1H), 6.77(s, NH, 1H), 6.70~6.73(d, 1H), 4.85(s, NH2, 2H), 4.36~4.38(m, 1H), 3.96~4.02(m, 2H), 3.45~3.55(m, 3H), 3.08~3.12(t, 1H), 2.53~2.55(d, 1H), 2.28~2.34(dt, 1H), 2.03~2.08(m, 4H), 1.88~1.93(dt, 1H) 1.30~1.83(m, 4H)
Example 63: (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000081
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (0.088 g, 0.2 mmol) obtained from Preparation Example 38 and ammonium solution (1,4-dioxane 0.5M) were reacted in the same manner as in Example 1 to obtain the title compound (yield: 80%).
1H-NMR(400MHz, CDCl3); δ 8.19(s, 2H), 7.87~7.91(dd, 1H), 6.89~6.94(dd, 1H), 6.71(s, NH, 1H), 4.78(s, NH2, 2H), 4.32~4.38(m, 1H), 4.17~4.23(m, 2H), 3.56~3.59(m, 2H), 3.46~3.50(m, 1H), 3.08~3.12(t, 1H), 2.56~2.58(d, 1H), 2.41~2.45(t, 2H), 2.22~2.34(dt, 1H), 2.03~2.11(m, 4H), 1.85~1.95(dt, 1H), 1.68~1.80(m, 2H), 1.50~1.80(m, 4H), 0.95~0.99(t, 3H)
Example 64: (2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000082
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (0.083 g, 0.2 mmol) obtained from Preparation Example 40 and ammonium solution (1,4-dioxane 0.5M) were reacted in the same manner as in Example 1 to obtain the title compound (yield: 78%).
1H-NMR(400MHz, CDCl3); δ 8.23(s, 2H), 7.87~7.92(dd, 1H), 6.90~6.94(dd, 1H), 6.56(s, NH, 1H), 4.68(s, NH2, 2H), 4.33~4.37(m, 1H), 4.10~4.22(m, 2H), 3.55~3.61(m, 2H), 3.46~3.50(d, 1H), 3.06~3.14(t, 1H), 2.56~2.60(d, 1H), 2.28~2.34(dt, 1H), 2.00~2.12(m, 4H), 1.90~1.98(dt, 1H), 1.50~1.80(m, 4H)
Example 65: 1-(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000083
4-(4-amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime obtained from Preparation Example 57 and 2-hydroxy-propylamine (50 mg, 0.13 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (40 mg, yield: 63%).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.70~7.66(1H, m), 6.91~6.87(1H, m), 6.89(1H, m), 5.30(1H, m), 4.30(1H, m), 4.20~4.10(2H, m), 4.00~3.90(1H, m), 3.50~3.40(4H, m), 3.20~3.00(2H, m), 2.55(1H, m), 2.32~2.22(1H, m), 2.10(3H, s), 2.05~1.90(4H, m), 1.90~1.80(1H, m), 1.72~1.60(3H, m), 1.50~1.40(1H, m), 1.22(3H, d)
Example 66: 3-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-1,1-dimethyl-urea
Figure PCTKR2012001185-appb-I000084
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.069 mmol) obtained from Preparation Example 26, dimethylamine hydrochloride (55 mg, 0.67 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (30 mg, yield: 86%).
1H-NMR(400MHz, CDCl3): δ 8.26(s, 2H), 7.98(dd, 1H), 6.90(dd, 1H), 6.57(s, 1H), 4.35(m, 1H), 4.15(m, 2H), 3.62(m, 2H), 3.47(m, 1H), 3.09(s, 6H), 3.09(m, 1H), 2.57(m, 1H), 2.31(td, 1H), 2.10(m, 4H), 1.92(td, 1H), 1.78(m, 2H), 1.60(m, 2H)
Example 67: 3-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea
Figure PCTKR2012001185-appb-I000085
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime (30 mg, 0.069 mmol) obtained from Preparation Example 12, dimethylamine hydrochloride (55 mg, 0.67 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (27.5 mg, yield: 79%).
1H-NMR(400MHz, CDCl3): δ 7.99(dd, 1H), 6.90(dd, 1H), 6.58(s, 1H), 4.33(m, 1H), 3.82(m, 2H), 3.56(m, 2H), 3.45(m, 1H), 3.09(s, 6H), 3.09(m, 1H), 2.93(m, 1H), 2.55(m, 1H), 2.30(td, 1H), 2.07(m, 4H), 1.89(m, 3H), 1.61(m, 2H), 1.33(d, 6H)
Example 68: 3-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea
Figure PCTKR2012001185-appb-I000086
4-(4-amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 23, dimethylamine hydrochloride (55 mg, 0.67 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (39 mg, yield: 83%).
1H-NMR(400MHz, CDCl3): δ 8.20(s, 2H), 6.83(d, 2H), 5.77(s, 1H), 4.34(m, 1H), 4.20(m, 2H), 3.54(m, 2H), 3.47(m, 1H), 3.10(s, 6H), 2.77(m, 1H), 2.57(m, 1H), 2.28(td, 1H), 2.16(s, 3H), 2.06(m, 4H), 1.90(td, 1H), 1.74(m, 2H), 1.61(m, 2H)
Example 69: 1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000087
4-(4-amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 23, 2-methoxyethylamine (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (31 mg, yield: 83%).
1H-NMR(400MHz, CDCl3): δ 8.20(s, 2H), 6.84(d, 2H), 5.08(t, 1H), 4.34(m, 1H), 4.20(m, 2H), 3.52(m, 7H), 3.43(s, 3H), 2.78(m, 1H), 2.58(m, 1H), 2.28(td, 1H), 2.16(s, 3H), 2.05(m, 4H), 1.90(td, 1H), 1.74(m, 2H), 1.62(m, 2H)
Example 70: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea
Figure PCTKR2012001185-appb-I000088
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 7, 2-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (30 mg, yield: 80%).
1H-NMR(500MHz, CDCl3): δ 8.14(s, 2H), 7.84(dd, 1H), 6.85(dd, 1H), 6.74(br s, 1H), 4.84(d, 1H), 4.29(m, 1H), 4.13(m, 2H), 3.98(m, 1H), 3.75(m, 1H), 3.58(dd, 1H), 3.50(m, 2H), 3.42(d, 1H), 3.04(t, 1H), 2.52(d, 1H), 2.46(s, 1H), 2.25(td, 1H), 2.11(s, 3H), 1.98(m, 4H), 1.86(td, 1H), 1.68(m, 2H), 1.55(m, 2H), 1.21(d, 3H)
Example 71: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea
Figure PCTKR2012001185-appb-I000089
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 7, 2.0 N methylamine tetrahydrofurane solution (0.5 mL, 1.0 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (24 mg, 0.081 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (29 mg, yield: 85%).
1H-NMR(500MHz, CDCl3): δ 8.14(s, 2H), 7.86(dd, 1H), 6.85(dd, 1H), 6.39(s, 1H), 4.66(m, 1H), 4.29(m, 1H), 4.14(m, 2H), 3.51(m, 2H), 3.41(d, 1H), 3.04(t, 1H), 2.87(d, 3H), 2.52(d, 1H), 2.26(td, 1H), 2.11(s, 3H), 1.99(m, 4H), 1.87(td, 1H), 1.70(m, 2H), 1.55(m, 2H)
Example 72: 1-(2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000090
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.068 mmol) obtained from Preparation Example 38, 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (24 mg, 0.081 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (27.5 mg, yield: 75%).
1H-NMR(500MHz, CDCl3): δ 8.14(s, 2H), 7.83(dd, 1H), 6.85(dd, 1H), 6.56(br s, 1H), 5.12(t, 1H), 4.30(m, 1H), 4.15(m, 2H), 3.73(m, 2H), 3.51(m, 2H), 3.44(m, 3H), 3.04(t, 1H), 2.83(s, 1H), 2.52(d, 1H), 2.38(t, 2H), 2.26(td, 1H), 2.01(m, 4H), 1.86(td, 1H), 1.72(m, 4H), 1.55(m, 4H), 0.92(t, 3H)
Example 73: 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000091
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.068 mmol) obtained from Preparation Example 38, azetidin-3-ol hydrochloride (55 mg, 0.50 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphosgene (23 mg, 0.078 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (28 mg, yield: 76%).
1H-NMR(500MHz, CDCl3): δ 8.14(s, 2H), 7.92(dd, 1H), 6.85(dd, 1H), 6.12(s, 1H), 4.72(m, 1H), 4.31(m, 3H), 4.15(m, 2H), 3.96(m, 2H), 3.51(m, 2H), 3.41(d, 1H), 3.04(t, 1H), 2.52(d, 1H), 2.38(t, 2H), 2.26(td, 1H), 2.20(s, 1H), 2.01(m, 4H), 1.86(td, 1H), 1.70(m, 2H), 1.54(m, 4H), 0.92(t, 3H)
Example 74: 1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000092
4-(4-amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained from Preparation Example 23 and 2-amino-1-ethanol (51 mg, 0.12 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (11.0 mg, yield: 18%).
NMR: 1H-NMR(MeOD) 8.21(2H, s), 7.02(2H, d), 6.36(1H, m), 4.80(1H, m), 4.30(1H, m), 4.15~4.05(3H, m), 3.50~3.40(3H, m), 3.30~3.20(1H, m), 3.15~3.05(3H, m), 2.80(1H, m), 2.40~2.30(1H, m), 2.30~2.19(1H, m), 2.07(3H, s), 2.00~1.80(5H, m), 1.65~1.45(4H, m)
Example 75: 1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000093
4-(4-amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 23, 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (29.5 mg, yield: 79%).
1H-NMR(400MHz, CDCl3): δ 8.20(s, 2H), 6.87(d, 2H), 5.56(s, 1H), 4.95(t, 1H), 4.35(m, 1H), 4.18(m, 2H), 3.76(m, 2H), 3.56(m, 2H), 3.50(m, 3H), 3.02(s, 1H), 2.79(m, 1H), 2.59(d, 1H), 2.29(td, 1H), 2.16(s, 3H), 2.04(m, 4H), 1.90(td, 1H), 1.74(m, 4H), 1.61(m, 2H)
Example 76: 1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000094
4-(4-amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 23, 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (29 mg, yield: 78%).
1H-NMR(400MHz, CDCl3): δ 8.20(s, 2H), 6.86(d, 2H), 6.10(br s, 1H), 5.13(t, 1H), 4.35(m, 1H), 4.20(m, 2H), 4.02(m, 1H), 3.52(m, 4H), 3.18(m, 1H), 2.79(m, 1H), 2.59(d, 1H), 2.50(s, 1H), 2.28(td, 1H), 2.16(s, 3H), 2.03(m, 4H), 1.92(td, 1H), 1.74(m, 2H), 1.61(m, 2H), 1.25(d, 3H)
Example 77: 4-[4-(2-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000095
4-[4-(4-amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (20 mg, 0.05 mmol) obtained from Preparation Example 58 and ammonium solution (1, 4-dioxane 0.5M) were reacted in the same manner as in Example 1 to obtain the title compound (18 mg, yield: 81%).
NMR: 1H-NMR(CDCl3) 7.17(2H, m), 7.07(1H, t), 6.96(1H, s), 4.90(3H, m), 4.23(1H, m), 3.70(2H, s), 3.41(1H, d), 3.28(2H, m), 3.03(1H, t), 2.51(1H, d), 2.26(1H, m), 2.04(2H, m), 1.87(3H, m), 1.68(4H, m), 1.24(6H, d)
Example 78: 4-(4-{2-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000096
4-[4-(4-amino-2-fluoro-phenyl)-cyclohexylidene aminooxy]-piperidine-1-carboxylic acid isopropyl ester (20 mg, 0.05 mmol) obtained from Preparation Example 58 and 3-hydroxypropylamine were reacted in the same manner as in Example 1 to obtain the title compound (15 mg, yield: 60%).
NMR: 1H-NMR(CDCl3) 7.18(2H, d), 7.04(1H, s), 6.9(1H, s), 5.47(1H, s), 4.91(1H, m), 4.22(1H, m), 3.70(4H, m), 3.40(3H, m), 3.28(2H, m), 3.02(1H, t), 2.61(2H, m), 2.50(1H, d), 2.26(1H, m), 2.04~1.80(5H, m), 1.71~1.50(4H, m), 1.24(6H, d)
Example 79: 4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2-fluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000097
4-[4-(4-amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (20 mg, 0.05 mmol) obtained from Preparation Example 58 and 2-ethoxyethylamine were reacted in the same manner as in Example 1 to obtain the title compound (19 mg, yield: 73%).
NMR: 1H-NMR(CDCl3) 7.30(1H, s), 7.20(1H, d), 7.04(1H, t), 6.94(1H, d), 5.37(1H, s), 4.91(1H, m), 4.22(1H, m), 3.70(2H, s), 3.54(4H, m), 3.42(3H, m), 3.27(2H, m), 3.03(1H, t), 2.50(1H, d), 2.26(1H, m), 2.05~1.96(2H, m), 1.94~1.82(3H, m), 1.70~1.52(4H, m), 1.24(9H, m)
Example 80: 4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2,5-difluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000098
4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (20 mg, 0.05 mmol) obtained from Preparation Example 32 32 and 2-ethoxyethylamine were reacted to obtain the title compound (18 mg, yield: 70%) according to the method described in Example 1.
NMR: 1H-NMR(CDCl3) 7.90(1H, m), 7.29(1H, bs), 6.84(1H, m), 5.56(1H, s), 4.91(1H, m), 4.21(1H, m), 3.70(2H, s), 3.55(4H, m), 3.45(3H, m), 3.27(2H, m), 3.03(1H, t), 2.50(1H, d), 2.26(1H, m), 2.06~1.80(5H, m), 1.70~1.45(4H, m), 1.26(9H, m)
Example 81: (4-{4-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea
Figure PCTKR2012001185-appb-I000099
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.05 mmol) obtained from Preparation Example 60 and ammonium solution (1, 4-dioxane 0.5M) were reacted to obtain the title compound (15 mg, yield: 68%) according to the method described in Example 1.
NMR: 1H-NMR(CDCl3) 8.11(2H, s), 7.85(1H, m), 6.87(2H, m), 4.84(2H, s), 4.30(1H, m), 4.12(2H, m), 3.51(2H, m), 3.45(1H, d), 3.10(1H, m), 3.04(1H, t), 2.53(1H, d), 2.26(1H, m), 1.98(4H, m), 1.87(1H, m), 1.76~1.45(4H, m), 0.89(2H, m), 0.57(2H, m)
Example 82: 1-(4-{4-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000100
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.05 mmol) obtained from Preparation Example 60 and 3-hydroxypropylamine were reacted to obtain the title compound (11 mg, yield: 45%) according to the method described in Example 1.
NMR: 1H-NMR(CDCl3) 8.10(2H, s), 7.83(1H, m), 6.84(2H, m), 5.52(1H, s), 4.29(1H, m), 4.12(2H, m), 3.72(2H, m), 3.51(2H, m), 3.43(3H, m), 3.03(1H, t), 2.65(1H, s), 2.52(1H, d), 2.27(1H, m), 1.97(4H, m), 1.86(1H, m), 1.76~1.45(7H, m), 0.89(2H, m), 0.57(2H, m)
Example 83: (2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000101
(2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-carbamic acid tert-butyl ester (85 mg, 0.16 mmol) obtained from Preparation Example 54 was dissolved in methylenechliride (2 mL). Trifluoroacetic acid (36 mL) was added thereto and then the mixture was stirred for 1 hour at room temperature. The reactant was distilled to remove the solvent under reduced pressure and dissolved in methylenechloride (5 mL). At 0 ℃, N,N-diisopropylethylamine (83 ㎕, 0.479 mmol) and triphosgene (47 mg, 0.16 mmol) were successively added thereto and the mixture was stirred for 10 minutes at room temperature. 0.5M dioxane ammonium solution (0.96 mL, 0.479 mmol) was added thereto and the mixture was stirred for 1 hour at room temperature. Water was added to terminate the reaction, the mixture was washed with methylenechloride solvent and water, saturated aqueous solution of sodium chloride. Organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure, and separated by Prep-TLC using the mixed solution of ethylacetate and hexane (1:1) to obtain the title compound (15 mg, yield: 20%).
NMR: 1H-NMR(CDCl3) 7.85(1H, m), 6.88(1H, m), 6.57(1H, s), 4.68(2H, s), 4.02(1H, m), 3.40(1H, m), 3.07(2H, m), 2.91(1H, m), 2.50(1H, m), 2.25(5H, m), 2.40(2H, m), 1.88(1H, m), 1.73(1H, m), 1.50(5H, m), 1.32(6H, d)
Example 84: (2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000102
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-oxime (38 mg, 0.088 mmol) obtained from Preparation Example 56 and ammonium solution (0.5 mL, 0.263 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (20 mg, yield: 29%) having larger polarity than its isomer, the title compound of Example 83.
NMR: 1H-NMR(CDCl3) 7.88(1H, m), 6.88(1H, m), 6.55(1H, s), 4.66(2H, s), 4.30(1H, m), 3.45(1H, m), 3.11~2.99(3H, m), 2.50(1H, m), 2.23(1H, m), 2.03~1.86(9H, m), 1.68(2H, m), 1.65~1.50(2H, m), 1.33(6H, d)
Example 85: (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-dicarbonimidic diamide
Figure PCTKR2012001185-appb-I000103
The title compound (390 mg, yield: 3%) was obtained as a byproduct during the synthesis of the title compounds of Example 11 using 4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (17 g, 40.92 mmol) obtained from Preparation Example 7 and ammonium solution (1,4-dioxane 0.5M, 245 mL).
NMR: 1H-NMR(CDCl3) 9.30(1H, s), 8.15(2H, s), 7.95(1H, m), 6.94(1H, m), 4.31(1H, m), 4.14(2H, m), 3.54~3.43(3H, m), 3.07(1H, m), 2.53(1H, m), 2.27(1H, m), 2.12(3H, s), 1.99(4H, m), 1.88(1H, m), 1.70~1.53(4H, m)
Example 86: 1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000104
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (32 mg, 0.076 mmol) obtained from Preparation Example 40, 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (23 mg, 0.078 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (34 mg, yield: 86%).
1H-NMR(500MHz, CDCl3): δ 8.18(s, 2H), 7.83(dd, 1H), 6.85(dd, 1H), 6.56(s, 1H), 5.12(t, 1H), 4.29(m, 1H), 4.09(m, 2H), 3.73(m, 2H), 3.53(m, 2H), 3.43(m, 3H), 3.04(t, 1H), 2.80(s, 1H), 2.52(d, 1H), 2.26(td, 1H), 2.00(m, 4H), 1.87(td, 1H), 1.74(m, 4H), 1.59(m, 2H)
Example 87: 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000105
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 40, azetidin-3-ol hydrochloride (56 mg, 0.51 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (33.6 mg, yield: 91%).
1H-NMR(500MHz, CDCl3): δ 8.18(s, 2H), 7.92(dd, 1H), 6.85(dd, 1H), 6.12(s, 1H), 4.72(s, 1H), 4.32(m, 3H), 4.10(m, 2H), 3.96(dd, 2H), 3.54(m, 2H), 3.42(d, 1H), 3.04(t, 1H), 2.52(d, 1H), 2.26(td, 1H), 2.19(s, 1H), 2.00(m, 4H), 1.87(td, 1H), 1.70(m, 2H), 1.55(m, 2H)
Example 88: 1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000106
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 40, 2-methoxy-ethylamine (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (28 mg, yield: 75%).
1H-NMR(500MHz, CDCl3): δ 8.18(s, 2H), 7.86(dd, 1H), 6.84(dd, 1H), 5.10(t, 1H), 4.29(m, 1H), 4.10(m, 2H), 3.53(m, 4H), 3.45(m, 3H), 3.40(s, 3H), 3.04(t, 1H), 2.51(d, 1H), 2.26(td, 1H), 2.00(m, 4H), 1.86(td, 1H), 1.70(m, 2H), 1.55(m, 2H)
Example 89: 1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea
Figure PCTKR2012001185-appb-I000107
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 40, isopropylamine (30 mg, 0.51 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (24 mg, yield: 94%).
1H-NMR(500MHz, CDCl3): δ 8.18(s, 2H), 7.88(dd, 1H), 6.84(dd, 1H), 6.27(s, 1H), 4.45(d, 1H), 4.29(m, 1H), 4.10(m, 2H), 3.97(m, 1H), 3.53(m, 2H), 3.42(d, 1H), 3.04(t, 1H), 2.51(d, 1H), 2.26(td, 1H), 2.01(m, 4H), 1.87(td, 1H), 1.70(m, 2H), 1.55(m, 2H), 1.20(d, 6H)
Example 90: 1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000108
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 40, 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (32 mg, yield: 86%).
1H-NMR(500MHz, DMSO): δ 8.51(s, 1H), 8.40(s, 2H), 7.91(dd, 1H), 7.14(dd, 1H), 6.74(t, 1H), 4.74(s, 1H), 4.20(m, 1H), 4.04(m, 2H), 3.41(m, 2H), 3.22(d, 2H), 3.09(m, 1H), 2.93(m, 2H), 2.34(m, 1H), 2.24(td, 1H), 1.88(m, 5H), 1.50(m, 4H), 1.00(d, 3H)
Example 91: 1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-thiophen-2-ylmethyl-urea
Figure PCTKR2012001185-appb-I000109
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained from Preparation Example 40, thiophen-2-ylmethyl-amine (35 mg, 0.31 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (35 mg, yield: 88%).
1H-NMR(500MHz, CDCl3): δ 8.18(s, 2H), 7.88(dd, 1H), 7.232(d, 1H), 7.00(d, 1H), 6.95(dd, 1H), 6.84(dd, 1H), 6.45(s, 1H), 5.06(t, 1H), 4.62(d, 2H), 4.29(m, 1H), 4.10(m, 2H), 3.53(m, 2H), 3.42(d, 1H), 3.04(t, 1H), 2.51(d, 1H), 2.25(td, 1H), 2.01(m, 4H), 1.88(td, 1H), 1.70(m, 2H), 1.58(m, 2H)
Example 92: (2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000110
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (100 mg, 0.25 mmol) obtained from Preparation Example 49 and ammonium solution (1,4-dioxane 0.5M) were reacted in the same manner as in Example 1 to obtain the title compound (100 mg, yield: 90%).
NMR: 1H-NMR(DMSO) 8.21(s, 2H), 7.97(t, 1H), 7.09(d, 1H), 6.97(d, 1H), 6.10(s, 2H), 4.23(m, 1H), 4.11(m, 2H), 3.43(m, 2H), 3.25(d, 1H), 2.74(t, 1H), 2.39(d, 1H), 2.27(m, 1H), 2.07(s, 3H), 1.91(m, 5H), 1.60(m, 4H)
Example 93: (2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000111
4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 57 and ammonium solution(1,4-dioxane 0.5M) (3 mL) were reacted in the same manner as in Example 1 to obtain the title compound (48 mg, yield 85%).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.69~7.66(1H, m), 6.93~6.89(1H, m), 6.46(1H, s), 4.68(2H, s), 4.30(1H, m), 4.20~4.10(2H, m), 3.60~3.40(3H, m), 3.10(1H, m), 2.60(1H, m), 2.32~2.20(1H, m), 2.15(3H, s), 2.10~1.95(4H, m), 1.91~1.81(1H, m), 1.75~1.62(3H, m), 1.50~1.40(1H, m)
Example 94: 3-hydroxy-azetidine-1-carboxylic acid (2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000112
4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 57 and 3-hydroxyazetidine hydrochloride (20 mg, 0.22 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (52 mg, yield 82%).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.82~7.78(1H, m), 6.94~6.89(1H, m), 6.09(1H, s), 4.73(1H, m), 4.35~4.22(3H, m), 4.22~4.10(2H, m), 4.00~3.90(2H, m), 3.58~3.40(3H, m), 3.04(1H, m), 2.52(1H, d), 2.32~2.20(1H, m), 2.20~2.15(1H, m), 2.11(3H, s), 2.10~1.95(4H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 95: 1-(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000113
4-(4-amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 57 and 3-amino-1-propanol (51 mg, 0.12 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (40 mg, yield 63%).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.67~7.60(1H, m), 6.90~6.85(1H, m), 6.39(1H, s), 5.02(1H, m), 4.30(1H, m), 4.15~4.05(2H, m), 3.80~3.70(2H, m), 3.55~3.40(5H, m), 3.06(1H, m), 2.52(1H, m), 2.58~2.49(1H, m), 2.30~2.20(1H, m), 2.11(3H, s), 2.10~1.95(4H, m), 1.90~1.80(1H, m), 1.80~1.60(6H, m)
Example 96: 1-(2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000114
4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained in Preparation Example 49, 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (25.4 mg, yield 67%).
1H-NMR(400MHz, CDCl3): δ 8.20(s, 2H), 7.85(t, 1H), 6.99(m, 2H), 6.41(s, 1H), 5.03(t, 1H), 4.34(m, 1H), 4.20(m, 2H), 3.76(q, 2H), 3.52(m, 5H), 3.02(t, 1H), 2.77(t, 1H), 2.57(d, 1H), 2.28(td, 1H), 2.16(s, 3H), 2.03(m, 4H), 1.91(td, 1H), 1.77(m, 4H), 1.60(m, 2H)
Example 97: 3-hydroxy-azetidine-1-carboxylic acid (2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000115
4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.072 mmol) obtained in Preparation Example 49, azetidin-3-ol hydrochloride (50 mg, 0.46 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (25.3 mg, yield 65%).
1H-NMR(400MHz, CDCl3): δ 8.19(s, 2H), 8.05(t, 1H), 7.00(d, 1H), 6.94(d, 1H), 6.14(s, 1H), 4.75(m, 1H), 4.35(m, 3H), 4.19(m, 2H), 4.00(dd, 2H), 3.55(m, 2H), 3.46(m, 1H), 2.76(m, 1H), 2.56(m, 1H), 2.27(m, 2H), 2.16(s, 3H), 2.03(m, 4H), 1.90(td, 1H), 1.72(m, 2H), 1.60(m, 2H)
Example 98: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000116
4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained in Preparation Example 48, 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (21 mg, 0.071 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (31.9 mg, yield 86%).
1H-NMR(400MHz, CDCl3): δ 8.22(s, 2H), 7.71(td, 1H), 6.94(td, 1H), 6.56(s, 1H), 5.16(t, 1H), 4.35(m, 1H), 4.20(m, 2H), 3.78(q, 2H), 3.55(m, 5H), 3.10(m, 1H), 2.87(s, 1H), 2.58(d, 1H), 2.50(q, 2H), 2.31(td, 1H), 2.07(m, 4H), 1.92(td, 1H), 1.76(m, 6H), 1.23(t, 3H)
Example 99: 3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-amide
Figure PCTKR2012001185-appb-I000117
4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained in Preparation Example 48, azetidin-3-ol hydrochloride (50 mg, 0.47 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (30.3 mg, yield 82%).
1H-NMR(400MHz, CDCl3): δ 8.21(s, 2H), 7.85(t, 1H), 6.93(t, 1H), 6.13(s, 1H), 4.77(m, 1H), 4.36(m, 3H), 4.20(m, 2H), 4.02(m, 2H), 3.55(m, 3H), 3.09(m, 1H), 2.58(d, 1H), 2.50(q, 2H), 2.30(m, 2H), 2.05(m, 4H), 1.92(td, 1H), 1.74(m, 4H), 1.23(t, 3H)
Example 100: (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-urea
Figure PCTKR2012001185-appb-I000118
4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained in Preparation Example 48, 0.5N ammonia dioxane solution (1.5 mL, 1.5 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (15.8 mg, yield 48%).
1H-NMR(400MHz, CDCl3): δ 8.22(s, 2H), 7.23(t, 1H), 6.96(t, 1H), 6.50(s, 1H), 4.70(s, 2H), 4.35(m, 1H), 4.20(m, 2H), 3.55(m, 3H), 3.11(m, 1H), 2.57(m, 1H), 2.50(q, 2H), 2.31(td, 1H), 2.04(m, 4H), 1.90(td, 1H), 1.74(m, 4H), 1.23(t, 3H)
Example 101: 1-(4-{4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3-(2-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000119
4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained in Preparation Example 48, 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (31.9 mg, yield 86%).
1H-NMR(400MHz, CDCl3): δ 8.22(s, 2H), 7.72(td, 1H), 6.94(td, 1H), 6.81(br s, 1H), 5.26(t, 1H), 4.35(m, 1H), 4.20(m, 2H), 4.03(m, 1H), 3.53(m, 4H), 3.20(m, 1H), 3.10(m, 1H), 2.58(d, 1H), 2.50(q, 2H), 2.37(d, 1H), 2.31(td, 1H), 2.06(m, 4H), 1.92(td, 1H), 1.73(m, 4H), 1.28(d, 3H), 1.23(t, 3H)
Example 102: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-propyl-urea
Figure PCTKR2012001185-appb-I000120
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (30 mg, 0.070 mmol) obtained in Preparation Example 9, propylamine hydrochloride (50 mg, 0.52 mmol), diisopropylethylamine (105 mg, 0.81 mmol) and triphosgene (21 mg, 0.071 mmol) were reacted in the same manner as in Example 1 to obtain the title compound 26.4 ㎎(yield 73%).
1H-NMR(400MHz, CDCl3): δ 8.22(s, 2H), 7.92(dd, 1H), 6.90(dd, 1H), 6.40(s, 1H), 4.71(t, 1H), 4.34(m, 1H), 4.20(m, 2H), 3.57(m, 2H), 3.47(d, 1H), 3.28(q, 2H), 3.09(t, 1H), 2.57(d, 1H), 2.50(q, 2H), 2.31(td, 1H), 2.04(m, 4H), 1.90(td, 1H), 1.75(m, 2H), 1.61(m, 4H), 1.23(t, 3H), 1.00(t, 3H)
Example 103: 4-[4-(3-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000121
4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (20 mg, 0.05 mmol) obtained in Preparation Example 59 and ammonium solution (1, 4-dioxane 0.5M) were reacted in the same manner as in Example 1 to obtain the title compound (20 mg, yield 90%).
NMR: 1H-NMR(CDCl3) 7.86(1H, t), 6.95(1H, d), 6.92(1H, d), 6.68(1H, s), 4.92(1H, m), 4.76(2H, s), 4.22(1H, m), 3.70(2H, m), 3.41(1H, d), 3.27(2H, m), 2.72(1H, t), 2.51(1H, d), 2.24(1H, m), 2.10~1.96(2H, m), 1.92~1.80(3H, m), 1.70~1.48(4H, m), 1.24(6H, d)
Example 104: (2,5-difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000122
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.04 mmol) obtained in Preparation Example 61 and ammonium solution (1,4-dioxane 0.5M) were reacted in the same manner as in Example 1 to obtain the title compound (16 mg, yield 73%).
NMR: 1H-NMR(CDCl3) 8.46(2H, s), 7.84(1H, m), 6.98(1H, s), 6.86(1H, m), 4.90(2H, s), 4.33(1H, m), 4.15(2H, m), 3.72(2H, m), 3.44(1H, d), 3.04(1H, t), 2.53(1H, d), 2.26(1H, m), 2.08~1.95(4H, m), 1.90(1H, m), 1.75(2H, m), 1.65~1.48(2H, m)
Example 105: (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-urea
Figure PCTKR2012001185-appb-I000123
4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (41 mg, 0.1 mmol) obtained in Preparation Example 47 and ammonium solution (1,4-dioxane 0.5M) (3 mL) were reacted in the same manner as in Example 1 to obtain the title compound (43 mg, yield 95%).
NMR: 1H-NMR(400MHz, CDCl3); δ 8.22(s, 2H), 7.85~7.89(t, 1H), 6.96~7.03(m, 2H), 6.51(s, NH, 1H), 4.70(s, NH2, 2H), 4.33~4.37(m, 1H), 4.12~4.21(m, 2H), 3.54~3.59(m, 2H), 3.46~3.49(d, 1H), 2.72 ~ 2.81(t, 1H), 2.56~2.60(d, 1H), 2.47~2.53(q, 2H), 2.22~2.32(dt, 1H), 2.00~2.12(m, 4H), 1.86~1.92(dt, 1H), 1.52 ~ 1.76(m, 4H), 1.21~1.25(t, 3H)
Example 106: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000124
4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (33 mg, 0.080 mmol) obtained in Preparation Example 47, 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (23 mg, 0.078 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (35 mg, yield 85%).
1H-NMR(500MHz, CDCl3): δ 8.16(s, 2H), 7.79(t, 1H), 6.95(d, 1H), 6.91(d, 1H), 6.40(s, 1H), 5.02(t, 1H), 4.30(m, 1H), 4.15(m, 2H), 3.71(m, 2H), 3.51(m, 2H), 3.43(m, 3H), 3.02(s, 1H), 2.72(t, 1H), 2.51(d, 1H), 2.45(q, 2H), 2.23(td, 1H), 2.01(m, 4H), 1.86(td, 1H), 1.71(m, 4H), 1.60(m, 2H), 1.18(t, 3H)
Example 107: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(2-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000125
4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (33 mg, 0.080 mmol) obtained in Preparation Example 47, 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (23 mg, 0.078 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (38 mg, yield 92%).
1H-NMR(500MHz, CDCl3): δ 8.16(s, 2H), 7.82(t, 1H), 7.00(d, 1H), 6.90(d, 1H), 6.62(s, 1H), 5.16(t, 1H), 4.30(m, 1H), 4.15(m, 2H), 3.97(m, 1H), 3.51(m, 2H), 3.43(m, 2H), 3.14(m, 1H), 2.71(t, 1H), 2.46(m, 4H), 2.23(td, 1H), 2.01(m, 4H), 1.85(td, 1H), 1.70(m, 2H), 1.58(m, 2H), 1.20(m, 6H)
Example 108: 3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-amide
Figure PCTKR2012001185-appb-I000126
4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (33 mg, 0.080 mmol) obtained in Preparation Example 47, azetidin-3-ol hydrochloride (50 mg, 0.47 mmol), diisopropylethylamine (113 mg, 0.87 mmol) and triphosgene (22 mg, 0.074 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (31 mg, yield 76%).
1H-NMR(500MHz, CDCl3): δ 8.16(s, 2H), 8.00(t, 1H), 6.93(d, 1H), 6.88(d, 1H), 6.09(s, 1H), 4.71(m, 1H), 4.29(m, 3H), 4.15(m, 2H), 3.95(dd, 2H), 3.52(m, 2H), 3.41(m, 1H), 2.71(t, 1H), 2.52(m, 1H), 2.45(q, 2H), 2.23(m, 2H), 2.20(m, 4H), 1.86(td, 1H), 1.69(m, 2H), 1.57(m, 2H), 1.19(m, 3H)
Example 109: 4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2012001185-appb-I000127
2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (3.02 g, 14.51 mmol) was sequentially reacted according to the methods of Preparation Examples 1, 2 and 3 to obtain 4-methyl-2-(4-oxo-cyclohexyl)-thiazole-5-carboxylic acid ethyl ester. Said compound and O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine were reacted in the same manner as in Preparation Example 5 to obtain the title compound (142 mg).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 4.37~4.20(3H, m), 4.19~4.10(2H, m), 3.52~3.45(2H, m), 3.40~3.30(1H, m), 3.19(1H, m), 2.70(3H, s), 2.67~2.57(1H, m), 2.35~2.21(3H, m), 2.11(3H, s), 2.05~1.95(3H, m), 1.85~1.60(4H, m), 1.36(3H, t)
Example 110: 4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid (2-fluoro-ethyl)-amide
Figure PCTKR2012001185-appb-I000128
4-Methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid ethyl ester (150 mg, 0.327 mmol) was reacted according to the method of Preparation Example 36 to obtain 4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid (26 mg, 0.065 mmol). Said compound was dissolved in N,N-dimethylformamide (2 mL), and EDC (15 mg, 0.0786 mmol), HOBT (11 mg, 0.0786 mmol), 2-fluoroethylamine (7.0 mg, 0.066 mmol) and triethylamine (0.03 mL, 0.24 mmol) were sequentially added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction solution was distilled under reduced pressure and extracted with ethyl acetate. The extracted solution was washed with water and a saturated aqueous solution of sodium chloride, and dried with magnesium sulfate. The organic layer was distilled under reduced pressure and purified by prep-TLC to obtain the title compound (17 mg).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 6.06(1H, m), 4.64(1H, t), 4.52(1H, t), 4.30(1H, m), 4.20~4.10(2H, m), 3.80~3.67(2H, m), 3.58~3.45(2H, m), 3.40~3.30(1H, m), 3.20(1H, m), 2.67(3H, s), 2.60~2.50(1H, m), 2.35~2.20(3H, m), 2.11(3H, s), 2.05~1.95(3H, m), 1.89~1.60(4H, m)
Example 111: 4-(5-hydroxymethyl-4-methyl-thiazol-2-yl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
Figure PCTKR2012001185-appb-I000129
4-Methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid ethyl ester (150 mg, 0.327 mmol) was sequentially reacted according to the methods of Preparation Example 36 and Example 8 to obtain the title compound (20 mg).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 4.94(2H, s), 4.30(1H, m), 4.19~4.10(2H, m), 3.55~3.45(2H, m), 3.40~3.30(1H, m), 3.19(1H, m), 2.67~2.57(1H, m), 2.28(3H, s), 2.32~2.15(3H, m), 2.11(3H, s), 2.05~1.95(3H, m), 1.85~1.60(5H, m)
Example 112: 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000130
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (20 mg, 0.04 mmol) obtained in Preparation Example 61 and 3-hydroxy-azetidine hydrochloride were reacted in the same manner as in Example 1 to obtain the title compound (15 mg, yield 62%).
NMR: 1H-NMR(CDCl3) 8.46(2H, s), 7.94(1H, m), 6.87(1H, m), 6.12(1H, s), 4.72(1H, m), 4.33(3H, m), 4.15(2H, m), 3.95(2H, m), 3.72(2H, m), 3.44(1H, m), 3.04(1H, t), 2.53(1H, d), 2.30~2.15(2H, m), 2.08~1.95(4H, m), 1.88(1H, m), 1.76(2H, m), 1.65~1.48(2H, m)
Example 113: 4-(4-{3-fluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000131
4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (20 mg, 0.05 mmol) obtained in Preparation Example 59 and 3-hydroxy-azetidine hydrochloride were reacted in the same manner as in Example 1 to obtain the title compound (21 mg, yield 84%).
NMR: 1H-NMR(CDCl3) 8.03(1H, t), 6.95(1H, d), 6.90(1H, d), 6.09(1H, s), 4.90(1H, m), 4.73(1H, m), 4.32(2H, t), 4.21(1H, m), 3.97(2H, m), 3.72(2H, m), 3.41(1H, m), 3.28(2H, m), 2.72(1H, m), 2.51(1H, m), 2.24(1H, m), 2.18(1H, d), 2.10~1.96(2H, m), 1.92~1.80(3H, m), 1.70~1.40(4H, m), 1.24(6H, d)
Example 114: 1-(2,5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000132
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (32 mg, 0.068 mmol) obtained in Preparation Example 46, 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (21 mg, 0.071 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (25.7 mg, yield 66%).
1H-NMR(400MHz, CDCl3): δ 8.52(s, 1H), 7.89(dd, 1H), 6.90(dd, 1H), 6.85(br s, 1H), 6.76(d, 1H), 5.23(t, 1H), 4.38(m, 1H), 4.21(m, 2H), 4.04(m, 1H), 3.70(m, 2H), 3.50(m, 2H), 3.19(m, 1H), 3.09(t, 1H), 2.58(d, 1H), 2.31(m, 1H), 2.05(m, 4H), 1.93(td, 1H), 1.79(m, 2H), 1.61(m, 2H), 1.28(d, 3H)
Example 115: 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000133
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (32 mg, 0.068 mmol) obtained in Preparation Example 46, azetidin-3-ol hydrochloride (45 mg, 0.41 mmol), diisopropylethylamine (113 mg, 0.87 mmol) and triphosgene (21 mg, 0.071 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (27 mg, yield 70%).
1H-NMR(400MHz, CDCl3): δ 8.52(s, 1H), 7.98(dd, 1H), 6.90(dd, 1H), 6.91(d, 1H), 6.17(s, 1H), 4.77(m, 1H), 4.36(m, 3H), 4.21(m, 2H), 4.01(dd, 2H), 3.71(m, 2H), 3.48(d, 1H), 3.10(t, 1H), 2.57(d, 1H), 2.31(td, 1H), 2.22(m, 1H), 2.05(m, 4H), 1.93(td, 1H), 1.79(m, 2H), 1.61(m, 2H)
Example 116: [(S)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-(4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester
Figure PCTKR2012001185-appb-I000134
{(S)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-2-oxo-1-[4-(4-oxo-cyclohexyl)-benzyl]-ethyl}-carbamic acid tert-butyl ester (34 mg, 0.079 mmol) obtained in Preparation Example 45 and O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine were reacted in the same manner as in Preparation Example 5 to obtain the title compound (44 mg, yield 90%).
1H-NMR(400MHz, CDCl3); δ 8.19(s, 2H), 7.07(m, 4H), 5.38(dd, 1H), 5.13(dd, 1H), 4.57(m, 1H), 4.34(m, 1H), 4.19(m, 2H), 3.84(m, 1H), 3.70~3.30(m, 5H), 3.10~2.70(m, 4H), 2.56(m, 1H), 2.29(m, 1H), 2.16(s, 3H), 2.12~2.00(m, 6H), 1.87(m, 1H), 1.80~1.50(m, 4H), 1.45(s, 9H)
Example 117: 4-{4-[(S)-2-amino-3-((S)-3-fluoro-pyrrolidin-1-yl)-3-oxo-propyl]-phenyl}-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
Figure PCTKR2012001185-appb-I000135
[(S)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-1-(4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (41.2 mg, 0.066 mmol) obtained in Example 116 was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added thereto, and the mixture was stirred at room temperature for 15 minutes. After completion of the reaction, the solvent was removed under reduced pressure. The residue was dissolved in a small amount of dichloromethane, and diethyl ether was added thereto. The resulting formed solid was filtered and dried to obtain the title compound (25 mg, yield 52%).
1H-NMR(400MHz, CDCl3); δ 8.20(s, 2H), 7.19(s, 4H), 5.08(dd, 1H), 4.40~4.15(m, 4H), 3.85(m, 1H), 3.57(m, 2H), 3.50~3.25(m, 5H), 3.10(m, 1H), 2.80~2.55(m, 4H), 2.26(m, 2H), 2.16(s, 3H), 2.04(m, 5H), 1.90(m, 2H), 1.80~1.50(m, 3H)
Example 118: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-methyl-urea
Figure PCTKR2012001185-appb-I000136
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (33 mg, 0.077 mmol) obtained in Preparation Example 9, 2.0 N methylamine tetrahydrofuran solution (0.8 mL, 1.6 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (23 mg, 0.078 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (25 mg, yield 67%).
1H-NMR(400MHz, CDCl3): δ 8.22(s, 2H), 7.91(dd, 1H), 6.90(dd, 1H), 6.41(s, 1H), 4.66(m, 1H), 4.35(m, 1H), 4.21(m, 2H), 3.57(m, 2H), 3.49(m, 1H), 3.09(m, 1H), 2.92(d, 3H), 2.51(m, 3H), 2.30(td, 1H), 2.05(m, 4H), 1.92(td, 1H), 1.75(m, 2H), 1.60(m, 2H), 1.23(t, 3H)
Example 119: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea
Figure PCTKR2012001185-appb-I000137
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (35 mg, 0.084 mmol) obtained in Preparation Example 7, propylamine (40 mg, 0.68 mmol), diisopropylethylamine (40 mg, 0.31 mmol) and triphosgene (25 mg, 0.084 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (33 mg, yield 78%).
1H-NMR(400MHz, CDCl3): δ 8.20(s, 2H), 7.92(dd, 1H), 6.90(dd, 1H), 6.42(s, 1H), 4.73(t, 1H), 4.34(m, 1H), 4.20(m, 2H), 3.55(m, 2H), 3.48(m, 1H), 3.28(q, 2H), 3.09(t, 1H), 2.57(d, 1H), 2.31(td, 1H), 2.16(s, 3H), 2.04(m, 4H), 1.92(td, 1H), 1.75(m, 2H), 1.61(m, 4H), 1.00(t, 3H)
Example 120: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-isopropyl-urea
Figure PCTKR2012001185-appb-I000138
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (35 mg, 0.081 mmol) obtained in Preparation Example 9, isopropylamine (40 mg, 0.68 mmol), diisopropylethylamine (40 mg, 0.31 mmol) and triphosgene (24 mg, 0.081 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (31 mg, yield 74%).
1H-NMR(400MHz, CDCl3): δ 8.22(s, 2H), 7.92(dd, 1H), 6.89(dd, 1H), 6.35(s, 1H), 4.51(d, 1H), 4.35(m, 1H), 4.19(m, 2H), 4.03(m, 1H), 3.57(m, 2H), 3.48(d, 1H), 3.09(t, 1H), 2.57(d, 1H), 2.50(q, 2H), 2.31(td, 1H), 2.04(m, 4H), 1.92(td, 1H), 1.75(m, 2H), 1.60(m, 2H), 1.24(m, 9H)
Example 121: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea
Figure PCTKR2012001185-appb-I000139
4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (35 mg, 0.084 mmol) obtained in Preparation Example 7, isopropylamine (40 mg, 0.68 mmol), diisopropylethylamine (40 mg, 0.31 mmol) and triphosgene (25 mg, 0.084 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (29 mg, yield 69%).
1H-NMR(400MHz, CDCl3): δ 8.20(s, 2H), 7.92(dd, 1H), 6.89(dd, 1H), 6.35(s, 1H), 4.52(d, 1H), 4.34(m, 1H), 4.19(m, 2H), 4.03(m, 1H), 3.56(m, 2H), 3.48(m, 1H), 3.09(t, 1H), 2.57(d, 1H), 2.30(td, 1H), 2.16(s, 3H), 2.05(m, 4H), 1.92(td, 1H), 1.75(m, 2H), 1.60(m, 2H), 1.25(d, 6H)
Example 122: 4-[4-(2-fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000140
1-Chloro-2-fluoro-4-nitro-benzene (0.20 g, 1.13 mmol) was sequentially reacted according to the methods of Preparation Examples 1, 2, 3 and 5 to obtain 4-[4-(4-amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester. Said compound and phenyl chloroformate were reacted in the same manner as in Preparation Example 32 to obtain the title compound (0.18 g, 29% overall yield of the five steps).
NMR: 1H-NMR(CDCl3) 7.42~7.30(5H, m), 7.25(1H, m), 7.20~7.08(6H, m), 7.06(1H, d), 6.94(1H, s), 4.30(1H, m), 3.88(1H, s), 3.78(1H, s), 3.54(1H, s), 3.46(2H, d), 3.08(1H, t), 2.54(1H, d), 2.30(1H, m), 2.10~1.98(4H, m), 1.91(1H, m), 1.78(2H, m), 1.74~1.55(2H, m)
Example 123: 4-[4-(3-fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000141
4-Chloro-2-fluoro-1-nitro-benzene (0.2 g, 1.13 mmol) was sequentially reacted according to the methods of Preparation Examples 1, 2, 3 and 5 to obtain 4-[4-(4-amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester. Said compound and phenyl chloroformate were reacted in the same manner as in Preparation Example 32 to obtain the title compound (0.16 g, 26% overall yield of the five steps).
NMR: 1H-NMR(CDCl3) 8.02(1H, s), 1.42~1.32(4H, m), 7.30~7.15(4H, m), 7.11(3H, d), 7.02(2H, m), 4.30(1H, m), 3.87(1H, s), 3.78(1H, s), 3.53(1H, s), 3.45(2H, d), 2.76(1H, t), 2.54(1H, d), 2.27(1H, m), 2.12~1.96(4H, m), 1.90(1H, m), 1.78(2H, s), 1.60~1.40(2H, m)
Example 124: 4-[4-(2,5-difluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000142
During the synthesis process of Preparation Example 62, the title compound (40 mg, yield 26%) was obtained as a by-product.
NMR: 1H-NMR(CDCl3) 7.42~7.32(6H, m), 7.28(1H, m), 7.20~7.12(4H, m), 7.11~7.05(2H, m), 4.30(1H, m), 3.87(1H, s), 3.78(1H, s), 3.57~3.38(3H, m), 3.14(1H, t), 2.57(1H, d), 2.31(1H, m), 2.14~2.04(2H, m), 2.00(2H, s), 1.92(1H, m), 1.78(2H, s), 1.71~1.56(2H, m)
Example 125: 4-{4-[2,5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000143
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester (15 mg, 0.03 mmol) obtained in Preparation Example 62 was reacted with propylamine in the same manner as in Example 1 to obtain the title compound (11 mg, yield 62%).
NMR: 1H-NMR(CDCl3) 7.90(1H, m), 7.34(2H, t), 7.20(1H, t), 7.10(2H, d), 6.85(1H, m), 6.68(1H, m), 4.91(1H, m), 4.29(1H, m), 3.87(1H, s), 3.78(1H, s), 3.53(1H, s), 3.44(2H, d), 3.15(2H, s), 3.05(1H, t), 2.53(1H, d), 2.28(1H, m), 2.10~1.95(4H, m), 1.90(1H, m), 1.79(2H, s), 1.70~1.45(4H, m), 0.92(3H, s)
Example 126: 4-{4-[4-(3,3-dimethyl-ureido)-2,5-difluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000144
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester (15 mg, 0.03 mmol) obtained in Preparation Example 62 was reacted with dimethylamine hydrochloride in the same manner as in Example 1 to obtain the title compound (10 mg, yield 57%).
NMR: 1H-NMR(CDCl3) 7.94(1H, m), 7.35(2H, t), 7.18(1H, t), 7.11(2H, d), 6.87(1H, m), 6.52(1H, s), 4.29(1H, m), 3.86(1H, s), 3.77(1H, s), 3.53(1H, s), 3.44(2H, d), 3.10~3.00(7H, m), 2.53(1H, d), 2.28(1H, m), 2.10~1.95(4H, m), 1.90(1H, m), 1.78(2H, s), 1.70~1.48(2H, m)
Example 127: 4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000145
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester (15 mg, 0.03 mmol) obtained in Preparation Example 62 was reacted with 3-hydroxyazetidine hydrochloride in the same manner as in Example 1 to obtain the title compound (12 mg, yield 65%).
NMR: 1H-NMR(CDCl3) 7.93(1H, m), 7.35(2H, t), 7.18(1H, t), 7.11(2H, d), 6.86(1H, m), 6.13(1H, s), 4.69(1H, m), 4.29(3H, m), 3.96(2H, m), 3.88(1H, s), 3.78(1H, s), 3.54(1H, s), 3.44(2H, d), 3.05(1H, t), 2.74(1H, d), 2.53(1H, d), 2.28(1H, m), 2.10~1.95(4H, m), 1.90(1H, m), 1.78(2H, s), 1.68~1.48(2H, m)
Example 128: 4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000146
4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester (15 mg, 0.03 mmol) obtained in Preparation Example 62 was reacted with isopropylamine in the same manner as in Example 1 to obtain the title compound (13 mg, yield 73%).
NMR: 1H-NMR(CDCl3) 7.92(1H, m), 7.34(2H, t), 7.18(1H, t), 7.10(2H, d), 6.83(1H, m), 6.65(1H, s), 4.84(1H, s), 4.29(1H, m), 3.94(2H, m), 3.77(1H, s), 3.54(1H, s), 3.44(2H, d), 3.04(1H, t), 2.52(1H, d), 2.26(1H, m), 2.10~1.95(4H, m), 1.90(1H, m), 1.79(2H, s), 1.68~1.48(2H, m), 1.14(6H, d)
Example 129: 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[(Z)-1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohex-1-enyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000147
4-Bromo-2,5-difluoronitrobenzene (1.5 g, 6.26 mmol) was sequentially reacted according to the methods of Preparation Examples 1, 50, 3 and 7 to give a compound. Said compound and 3-hydroxyazetidine hydrochloride (11 mg, 0.10 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (24 mg, yield 70%).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.97~7.92(1H, m), 6.93~6.90(1H, m), 6.17(1H, s), 6.00(0.3H, m), 5.90(0.7H, m), 4.71(1H, m), 4.35~4.22(3H, m), 4.20~4.10(2H, m), 4.00~3.90(2H, m), 3.59~3.41(2H, m), 3.20(1.3H, m), 3.04(0.7H, m), 2.75(1H, m), 2.65~2.50(4H, m), 2.11(3H, s), 2.10~1.95(2H, m), 1.80~1.70(2H, m)
Example 130: 4-{4-[3-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000148
4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester (70 mg, 0.16 mmol) obtained in Preparation Example 71 was reacted with propylamine in the same manner as in Example 1 to obtain the title compound (56 mg, yield 67%).
NMR: 1H-NMR(CDCl3) 7.89(1H, t), 7.35(2H, t), 7.10(1H, t), 7.09(2H, d), 6.96(1H, d), 6.91(1H, d), 6.46(1H, s), 4.84(1H, s), 4.32~4.27(1H, m), 3.87(1H, s), 3.78(1H, s), 3.53(1H, s), 3.43(2H, d), 3.19(2H, d), 2.72(1H, t), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.94(4H, m), 1.92~1.84(1H, m), 1.78(2H, s), 1.70~1.48(4H, m), 0.92(3H, t)
Example 131: 4-{4-[2-fluoro-4-(2-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000149
4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester (70 mg, 0.16 mmol) obtained in Preparation Example 70 was reacted with propylamine in the same manner as in Example 1 to obtain the title compound (62 mg, yield 74%).
NMR: 1H-NMR(CDCl3) 7.35(2H, t), 7.19(1H, t), 7.16~7.11(1H, m), 7.10(2H, d), 7.03(1H, d), 6.95~6.84(1H, m), 6.70(1H, d), 4.91(1H, s), 4.32~4.27(1H, m), 3.87(1H, s), 3.76(1H, s), 3.54(1H, s), 3.44(2H, d), 3.15(2H, s), 3.04(1H, t), 2.52(1H, d), 2.30~2.22(1H, m), 2.10~1.95(4H, m), 1.93~1.85(1H, m), 1.79(2H, s), 1.70~1.44(4H, m), 0.91(3H, t)
Example 132: 4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000150
4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester (70 mg, 0.16 mmol) obtained in Preparation Example 71 was reacted with 2-amino-1-ethanol in the same manner as in Example 1 to obtain the title compound (45 mg, yield 53%).
NMR: 1H-NMR(CDCl3) 7.85(1H, t), 7.35(2H, t), 7.19(1H, t), 7.11(2H, d), 6.97(1H, d), 6.91(1H, d), 6.79(1H, d), 5.34(1H, s), 4.32~4.27(1H, m), 3.87(1H, s), 3.80~3.70(3H, m), 3.53(1H, s), 3.47~3.35(4H, m), 2.78~2.62(2H, m), 2.53(1H, d), 2.28~2.19(1H, m), 2.10~1.94(4H, m), 1.92~1.84(1H, m), 1.78(2H, s), 1.68~1.50(2H, m)
Example 133: 4-(4-{2-fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000151
4-[4-(4-Amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester (70 mg, 0.16 mmol) obtained in Preparation Example 70 was reacted with 2-amino-1-ethanol in the same manner as in Example 1 to obtain the title compound (39 mg, yield 46%).
NMR: 1H-NMR(CDCl3) 7.35(2H, t), 7.20(1H, t), 7.18~7.11(1H, m), 7.10~7.03(3H, m), 6.95~6.86(1H, m), 6.85(1H, d), 5.22(1H, s), 4.32~4.27(1H, m), 3.87(1H, s), 3.82~3.70(3H, m), 3.54(1H, s), 3.48~3.34(4H, m), 3.05(1H, t), 2.73(1H, d), 2.53(1H, d), 2.30~2.22(1H, m), 2.09~1.96(4H, m), 1.93~1.85(1H, m), 1.79(2H, s), 1.71~1.52(2H, m)
Example 134: 4-{4-[4-(3,3-dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000152
3-[2-Fluoro-4-(4-oxocyclohexyl)phenyl]-1,1-dimethylurea (0.018 g, 0.06 mmol) obtained in Preparation Example 63 and 4-aminooxypiperidine-1-carboxylic acid phenyl ester (0.015 g, 0.06 mmol) were reacted in the same manner as in Preparation Example 5 to obtain the title compound (0.023 g, yield 72%).
NMR: 1H-NMR(CDCl3) 8.01(1H, t), 7.36(2H, t), 7.18(1H, t), 7.10(2H, d), 6.92(2H, m), 6.50(1H, m), 4.29(1H, m), 3.80(2H, m), 3.51(1H, m), 3.42(2H, m), 3.04(6H, s), 2.72(1H, m), 2.50(1H, m), 2.24(1H, m), 2.06(4H, m), 1.88(1H, m), 1.80(2H, m), 1.63(2H, m)
Example 135: 4-(4-{3-fluoro-4-[3-(2-fluoro-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000153
4-{[4-(4-Amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidine-1-carboxylic acid phenyl ester (0.049 g, 0.11 mmol) and 2-fluoroethylaminehydrochloride were reacted in the same manner as in Example 1 to obtain the title compound (0.04 g, yield 67%).
NMR: 1H-NMR(CDCl3) 7.83(1H, t), 7.35(2H, t), 7.19(1H, t), 7.11(2H, m), 6.97(1H, m), 6.93(1H, m), 6.30(1H, m), 4.98(1H, m), 4.59(2H, t), 4.50(2H, t), 4.23(1H, m), 3.85(2H, m), 3.63(1H, m), 3.57(1H, m), 3.55(1H, m), 3.43(2H, m), 2.74(1H, m), 2.53(1H, m), 2.25(1H, m), 2.04(4H, m), 1.89(1H, m), 1.80(2H, m), 1.65(2H, m)
Example 136: 3-(2-fluoro-4-{4-[1-(3,3,3-trifluoro-propyl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea
Figure PCTKR2012001185-appb-I000154
4-({4-[4-(Dimethylcarbamoylamino)-3-fluorophenyl]cyclohexylidene}amino)-oxypiperidine-1-carboxylic acid tert-butyl ester (0.05 g, 0.1 mmol) obtained in Preparation Example 64 was cooled to 0 ℃, 4N hydrochloric acid/1,4-dioxane (3 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure and dried under reduced pressure. Dichloroethane (1 mL) was added to the above unpurified reaction mixture, and then 3,3,3-trifluoropropanealdehyde (0.013 g, 0.1 mmol) and sodium triacetoxyborohydride (0.033 g, 0.15 mmol) were added thereto. A small amount of acetic acid was added dropwise to the reaction mixture, the pH was adjusted to 5, and stirred at room temperature. TLC was performed to confirm the termination of the reaction, 1N sodium hydroxide solution was added thereto, and the mixture was extracted using dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound (0.03 g, yield 60%).
NMR: 1H-NMR(CDCl3) 8.00(1H, t), 6.94(1H, m), 6.89(1H, m), 6.46(1H, m), 4.07(1H, m), 3.39(1H, m), 3.03(6H, s), 2.70(3H, m), 2.59(2H, m), 2.48(1H, m), 2.30(4H, m), 2.21(1H, m), 2.02(4H, m), 1.85(1H, m), 1.72(2H, m), 1.58(2H, m)
Example 137: 3-{4-[4-(1-benzyl-piperidin-4-yloxyimino)-cyclohexyl]-2-fluoro-phenyl}-1,1-dimethyl-urea
Figure PCTKR2012001185-appb-I000155
4-({4-[4-(dimethylcarbamoylamino)-3-fluorophenyl]cyclohexylidene}amino)-oxypiperidine-1-carboxylic acid tert-butyl ester (0.05 g, 0.1 mmol) obtained in Preparation Example 64 was reacted with benzaldehyde in the same manner as in Example 136 to obtain the title compound (0.03 g, yield 61%).
NMR: 1H-NMR(CDCl3) 8.00(1H, t), 7.32(5H, m), 6.94(1H, m), 6.87(1H, m), 6.46(1H, m), 4.11(1H, m), 3.61(2H, s), 3.36(1H, m), 3.03(6H, s), 2.72(3H, m), 2.48(1H, m), 2.35(1H, m), 2.20(1H, m), 2.02(5H, m), 1.83(3H, m), 1.58(2H, m)
Example 138: 3-{2-fluoro-4-[4-(1-naphthalen-2-ylmethyl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-1,1-dimethyl-urea
Figure PCTKR2012001185-appb-I000156
4-({4-[4-(dimethylcarbamoylamino)-3-fluorophenyl]cyclohexylidene}amino)-oxypiperidine-1-carboxylic acid tert-butyl ester (0.05 g, 0.1 mmol) obtained in Preparation Example 64 was reacted with naphthalene-2-carbaldehyde in the same manner as in Example 136 to obtain the title compound (0.023 g, yield 42%).
NMR: 1H-NMR(CDCl3) 8.00(1H, t), 7.83(3H, m), 7.76(1H, m), 7.51(1H, m), 7.46(2H, m), 6.95(1H, m), 6.89(1H, m), 6.48(1H, m), 4.13(1H, m), 3.72(2H, s), 3.38(1H, m), 3.04(6H, s), 2.73(2H, m), 2.48(1H, m), 2.37(1H, m), 2.20(1H, m), 2.00(4H, m), 1.83(2H, m), 1.60(2H, m), 1.26(3H, m)
Example 139: 4-(4-{3-fluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000157
4-{[4-(4-amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidine-1-carboxylic acid phenyl ester (0.039 g, 0.09 mmol) and 3-hydroxyazetidine hydrochloride were used in the same method as Example 1 to obtain the title compound (0.031 g, yield 64%).
NMR: 1H-NMR(CDCl3) 8.00(1H, t), 7.35(2H, t), 7.19(1H, t), 7.11(2H, d), 6.95(1H, m), 6.90(1H, m), 6.10(1H, m), 4.65(1H, m), 4.29(3H, m), 3.93(2H, m), 3.86(1H, m), 3.77(1H, m), 3.54(1H, m), 3.42(2H, m), 2.73(2H, m), 2.53(1H, m), 2.23(1H, m), 2.00(4H, m), 1.88(1H, m), 1.79(2H, m), 1.60(2H, m)
Example 140: 4-(4-{3-fluoro-4-[3-(2-fluoro-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000158
4-{[4-(4-amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidine-1-carboxylic acid isopropyl ester 0.06 g(0.15 mmol) obtained in Preparation Example 66 and 2-fluoroethylamine hydrochloride were used in the same method as Example 1 to obtain the title compound (0.05 g, yield 67%).
NMR: 1H-NMR(CDCl3) 7.86(1H, m), 6.94(2H, m), 6.61(1H, brs), 5.34(1H, brs), 4.91(1H, m), 4.57(1H, m), 4.48(1H, m), 4.22(1H, m), 3.70(2H, m), 3.61(1H, m), 3.56(1H, m), 3.40(1H, m) 3.28(2H, m), 2.72(1H, m), 2.50(1H, m), 2.22(1H, m), 2.00(2H, m), 1.87(3H, m), 1.60(4H, m), 1.24(6H, d)
Example 141: 4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000159
4-{[4-(4-amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidine-1-carboxylic acid isopropyl ester (0.06 g, 0.15 mmol) obtained in Preparation Example 66 and 2-hydroxyethylamine were used in the same method as Example 1 to obtain the title compound (0.04 g, yield 54%).
NMR: 1H-NMR(CDCl3) 7.84(1H, t), 6.95(1H, m), 6.93(1H, m), 6.57(1H, m), 5.19(1H, m), 4.92(1H, m), 4.48(1H, t), 4.22(1H, m), 3.79(2H, m), 3.70(2H, m), 3.65(1H, t), 3.45(2H, m), 3.40(1H, m), 3.28(1H, m), 2.72(1H, m), 2.50(2H, m), 2.23(1H, m), 2.05(1H, m), 2.01(1H, m), 3.87(3H, m), 1.64(2H, m), 1.25(6H, d)
Example 142: 3-{4-[2-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-pyrrolidine-1-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000160
1-chloro-2-fluoro-4-nitro-benzene was reacted subsequently according to the methods of Preparation Examples 1, 2 and 3 to synthesize 4-(4-amino-2-fluorophenyl)-cyclohexanone. 3-Aminooxy-pyrrolidine-1-carboxylic acid phenyl ester, which was obtained by the sequential reaction of 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester according to Preparation Examples 14, 32 and 15, was used in the same method as Preparation Example 5 to prepare 3-[4-(4-amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-pyrrolidine-1-carboxylic acid phenyl ester (0.02 g, 0.05 mmol). The synthesized compounds were used in the same method as Example 1 to obtain the title compound (0.008 g, yield 30%).
NMR: 1H-NMR(CDCl3) 7.53(2H, m), 7.25~7.00(4H, m), 7.00(1H, m), 6.88(1H, m), 6.60(1H, m), 4.88(2H, m), 3.90~3.50(4H, m), 3.41~3.40(1H, m), 3.10(2H, m), 3.00(1H, m), 2.49(1H, m), 2.35~2.22(2H, m), 2.10~1.80(3H, m), 1.80(1H, m), 1.70~1.46(4H, m), 0.95(3H, m)
Example 143: 4-(4-{3-fluoro-4-[3-(2-hydroxy-1-methyl-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000161
4-{[4-(4-amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidine-1-carboxylic acid isopropyl ester (0.1 g, 0.25 mmol) obtained in Preparation Example 66 and 2-amino-1-propanol were used in the same method as Example 1 to obtain the title compound (0.065 g, yield 51%).
NMR: 1H-NMR(CDCl3) 7.88(1H, t), 7.06(1H, s), 6.93(1H, m), 6.87(1H, m), 5.35(1H, d), 4.90(1H, m), 4.22(1H, m), 3.97(1H, m), 3.70(3H, m), 3.52(1H, m), 3.37(1H, m), 3.28(2H, m), 3.16(1H, m), 2.71(1H, m), 2.48(1H, m), 2.22(1H, m), 2.00(2H, m), 1.91(3H, m), 1.54(4H, m), 1.25(6H, d), 1.16(3H, d)
Example 144: 4-(4-{3-fluoro-4-[3-(2-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000162
4-{[4-(4-amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidine-1-carboxylic acid isopropyl ester (0.1 g, 0.25 mmol) obtained in Preparation Example 66 and DL-1-amino-2-propanol were used in the same method as Example 1 to obtain the title compound (0.11 g, yield 87%).
NMR: 1H-NMR(CDCl3) 7.84(1H, t), 6.95(1H, m), 6.92(1H, m), 6.58(1H, brs), 5.12(1H, m), 4.91(1H, m), 4.22(1H, m), 3.98(1H, m), 3.72(2H, m), 3.42(2H, m), 3.27(2H, m), 3.13(1H, m), 2.72(1H, m), 2.50(1H, m), 2.43(1H, m), 2.23(1H, m), 2.05(2H, m), 1.85(3H, m), 1.63(3H, m), 1.25(6H, d), 1.22(3H, d)
Example 145: 4-(4-{3-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000163
4-{[4-(4-amino-3-fluorophenyl)cyclohexylidene]amino}oxypiperidine-1-carboxylic acid isopropyl ester (0.1 g, 0.25 mmol) obtained in Preparation Example 66 and 3-amino-propan-1-ol were used in the same method as Example 1 to obtain the title compound (0.042 g, yield 33%).
NMR: 1H-NMR(CDCl3) 7.84(1H, t), 6.95(1H, m), 6.92(1H, m), 6.63(1H, brs), 5.28(1H, m), 4.91(1H, m), 4.22(1H, m), 3.70(4H, m), 3.43(3H, m), 3.28(2H, m), 3.13(1H, brs), 2.72(1H, m), 2.51(1H, m), 2.23(1H, m), 2.01(2H, m), 1.86(3H, m), 1.72(2H, m), 1.62(3H, m), 1.54(1H, m), 1.25(6H, d)
Example 146: 4-{4-[3-fluoro-4-(3-methyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000164
4-[4-(4-amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (0.1 g, 0.25 mmol) obtained in Preparation Example 59 and methylamine hydrochloride were used in the same method as Example 1 to obtain the title compound (0.078 g, yield 68%).
NMR: 1H-NMR(CDCl3) 7.85(1H, t), 6.94(1H, m), 6.92(1H, m), 6.20(1H, s), 4.91(1H, m), 4.55(1H, m), 4.22(1H, m), 3.70(2H, m), 3.43(1H, m), 3.26(2H, m), 2.86(3H, d), 2.72(1H, m), 2.51(1H, m), 2.22(1H, m), 2.01(2H, m), 1.86(3H, m), 1.62(3H, m), 1.54(1H, m), 1.22(6H, d)
Example 147: 4-{4-[3-fluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000165
4-[4-(4-amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (0.1 g, 0.25 mmol) obtained in Preparation Example 59 and isopropylamine were used in the same method as Example 1 to obtain the title compound (0.129 g, yield 99%).
NMR: 1H-NMR(CDCl3) 7.88(1H, t), 6.94(1H, m), 6.92(1H, m), 6.18(1H, s), 4.91(1H, m), 4.42(1H, m), 4.22(1H, m), 4.00(1H, m), 3.70(2H, m), 3.42(1H, m), 3.26(2H, m), 2.72(1H, m), 2.51(1H, m), 2.22(1H, m), 2.01(2H, m), 1.86(3H, m), 1.62(3H, m), 1.54(1H, m), 1.25(6H, d), 1.22(6H, d)
Example 148: 4-{4-[4-(3,3-dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidin-yl-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000166
4-[4-(4-amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (0.1 g, 0.25 mmol) obtained in Preparation Example 59 and dimethylamine hydrochloride were used in the same method as Example 1 to obtain the title compound (0.113 g, yield 95%).
NMR: 1H-NMR(CDCl3) 8.01(1H, t), 6.94(1H, m), 6.92(1H, m), 6.47(1H, s), 4.91(1H, m), 4.22(1H, m), 3.70(2H, m), 3.42(1H, m), 3.26(2H, m), 3.00(6H, s), 2.72(1H, m), 2.51(1H, m), 2.22(1H, m), 2.07(2H, m), 1.86(3H, m), 1.62(3H, m), 1.54(1H, m), 1.23(6H, d)
Example 149: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-methyl-urea
Figure PCTKR2012001185-appb-I000167
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (47 mg, 0.11 mmol) obtained in Preparation Example 47, 2.0 M methylamine tetrahydrofuran solution (0.5 mL, 1.0 mmol), diisopropylethylamine (70 mg, 0.54 mmol) and triphosgene (35 mg, 0.12 mmol) were reacted in the same method as Example 1 to obtain the title compound (42 mg, yield 78%).
1H-NMR(400MHz, DMSO): δ 8.26(s, 2H), 8.19(1H, s), 7.97(t, 1H), 7.08(d, 1H), 6.98(d, 1H), 6.40(m, 1H), 4.24(m, 1H), 4.12(m, 2H), 3.44(m, 2H), 3.26(m, 1H), 2.72(m, 1H), 2.65(d, 3H), 2.41(m, 3H), 2.26(td, 1H), 1.92(m, 5H), 1.51(m, 4H), 1.14(m, 3H)
Example 150: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(2-hydro-1-methyl-ethyl)-urea
Figure PCTKR2012001185-appb-I000168
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 47 (47 mg, 0.11 mmol), 2-amino-propan-1-ol (70 mg, 0.93 mmol), diisopropylethylamine (70 mg, 0.54 mmol) and triphosgene (35 mg, 0.12 mmol) were reacted in the same method as Example 1 to obtain the title compound (51 mg, yield 87%).
1H-NMR(400MHz, DMSO): δ 8.26(s, 2H), 8.19(1H, s), 7.80(t, 1H), 7.08(d, 1H), 6.97(d, 1H), 6.54(d, 1H), 4.79(m, t), 4.24(m, 1H), 4.12(m, 2H), 3.43(m, 4H), 3.26(m, 1H), 2.72(m, 1H), 2.41(m, 3H), 2.25(td, 1H), 1.91(m, 5H), 1.55(m, 4H), 1.14(m, 3H), 1.07(d, 3H)
Example 151: 4-{4-[3-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidin-yl-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000169
4-[4-(4-amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester obtained in Preparation Example 59 (0.1 g, 0.25 mmol) and isopropylamine were used in the same method as Example 1 to obtain the title compound (0.111 g, yield 91%).
NMR: 1H-NMR(CDCl3) 7.87(1H, t), 6.96(1H, m), 6.91(1H, m), 6.22(1H, s), 4.92(1H, m), 4.42(1H, m), 4.22(1H, m), 3.70(2H, m), 3.42(1H, m), 3.32~3.18(4H, m), 2.72(1H, m), 2.51(1H, m), 2.22(1H, m), 2.01(2H, m), 1.86(3H, m), 1.62(3H, m), 1.54(6H, m), 1.25(6H, d), 1.22(6H, d)
Example 152: 4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester
Figure PCTKR2012001185-appb-I000170
4-[4-(4-amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester obtained in Preparation Example 59 (0.15 g, 0.38 mmol) and 2-methylamino-ethanol were used in the same method as Example 1 to obtain the title compound (0.11 g, yield 58%).
NMR: 1H-NMR(CDCl3) 7.91(1H, t), 7.37(1H, s), 6.96(2H, m), 4.93(1H, m), 4.22(1H, m), 3.80(2H, m), 3.70(2H, m), 3.60(2H, m), 3.42(1H, m), 3.30(2H, m), 3.02(3H, s), 2.72(1H, m), 2.59(1H, s), 2.48(1H, m), 2.22(1H, m), 2.01(2H, m), 1.86(3H, m), 1.62(3H, m), 1.54(1H, m), 1.22(6H, d)
Example 153: 1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea
Figure PCTKR2012001185-appb-I000171
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted with propylamine in the same method as Example 1 to obtain the title compound (22 mg, yield 91%).
NMR: 1H-NMR(CDCl3) 7.88(1H, t), 6.95(1H, d), 6.91(1H, d), 6.34(1H, s), 4.75(1H, s), 4.32~4.27(1H, m), 3.81~3.74(2H, m), 3.54~3.48(2H, m), 3.37(1H, d), 3.23(2H, q), 2.92~2.83(1H, m), 2.72(1H, t), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.66~1.50(4H, m), 1.29(6H, d), 0.95(3H, t)
Example 154: 3-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea
Figure PCTKR2012001185-appb-I000172
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted with dimethylamine hydrochloride in the same method as Example 1 to obtain the title compound (18 mg, yield 77%).
NMR: 1H-NMR(CDCl3) 8.02(1H, t), 6.95(1H, d), 6.91(1H, d), 6.46(1H, s), 4.32~4.27(1H, m), 3.81~3.74(2H, m), 3.54~3.48(2H, m), 3.40(1H, d), 3.04(6H, s), 2.92~2.83(1H, m), 2.71(1H, t), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.68~1.50(2H, m), 1.29(6H, d)
Example 155: 1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea
Figure PCTKR2012001185-appb-I000173
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted with 2-methoxyethylamine in the same method as Example 1 to obtain the title compound (15 mg, yield 60%).
NMR: 1H-NMR(CDCl3) 7.92(1H, t), 6.95(1H, d), 6.91(1H, d), 6.86(1H, s), 5.09(1H, s), 4.32~4.27(1H, m), 3.82~3.75(2H, m), 3.52~3.36(10H, m), 2.92~2.83(1H, m), 2.72(1H, t), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.68~1.50(2H, m), 1.29(6H, d)
Example 156: 1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea
Figure PCTKR2012001185-appb-I000174
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted with isopropylamine in the same method as Example 1 to obtain the title compound (17 mg, yield 71%).
NMR: 1H-NMR(CDCl3) 7.89(1H, t), 6.95(1H, d), 6.90(1H, d), 6.31(1H, s), 4.55(1H, s), 4.32~4.27(1H, m), 4.02~3.95(1H, m), 3.81~3.74(2H, m), 3.55~3.48(2H, m), 3.40(1H, d), 2.92~2.83(1H, m), 2.71(1H, t), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.66~1.50(2H, m), 1.29(6H, d), 1.19(6H, d)
Example 157: (2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea
Figure PCTKR2012001185-appb-I000175
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted with 0.5N ammonia dioxane solution in the same method as Example 1 to obtain the title compound (19 mg, yield 86%).
NMR: 1H-NMR(CDCl3) 7.86(1H, t), 6.98(1H, d), 6.93(1H, d), 6.55(1H, s), 4.70(2H, s), 4.32~4.27(1H, m), 3.82~3.74(2H, m), 3.55~3.48(2H, m), 3.41(1H, d), 2.92~2.83(1H, m), 2.73(1H, t), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.66~1.50(2H, m), 1.29(6H, d)
Example 158: 1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea
Figure PCTKR2012001185-appb-I000176
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted with 2-amino-propan-1-ol in the same method as Example 1 to obtain the title compound 21 mg(yield 84%).
NMR: 1H-NMR(CDCl3) 7.86(1H, t), 6.97(1H, d), 6.92(1H, d), 6.63(1H, s), 4.88(1H, s), 4.32~4.27(1H, m), 4.03~3.95(1H, m), 3.81~3.71(3H, m), 3.60~3.48(3H, m), 3.41(1H, d), 2.92~2.83(1H, m), 2.76~2.65(2H, m), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.66~1.50(2H, m), 1.29(6H, d), 1.20(3H, d)
Example 159: 1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000177
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted with 2-hydroxy-propylamine in the same method as Example 1 to obtain the title compound (18 mg, yield 72%).
NMR: 1H-NMR(CDCl3) 7.86(1H, t), 6.97(1H, d), 6.92(1H, d), 6.77(1H, s), 5.31(1H, s), 4.32~4.27(1H, m), 4.01~3.94(1H, m), 3.82~3.73(2H, m), 3.55~3.48(2H, m), 3.47~3.38(2H, m), 3.18~3.10(1H, m), 2.92~2.83(1H, m), 2.72(1H, t), 2.58(1H, s), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.66~1.50(2H, m), 1.28(6H, d), 1.21(3H, d)
Example 160: 1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea
Figure PCTKR2012001185-appb-I000178
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted methylamine hydrochloride in the same method as Example 1 to obtain the title compound (15 mg, yield 66%).
NMR: 1H-NMR(CDCl3) 7.86(1H, t), 6.95(1H, d), 6.91(1H, d), 6.48(1H, s), 4.87(1H, s), 4.32~4.27(1H, m), 3.82~3.74(2H, m), 3.55~3.48(2H, m), 3.40(1H, d), 2.92~2.81(4H, m), 2.72(1H, t), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.66~1.50(2H, m), 1.28(6H, d)
Example 161: 3-hydroxy-azetidine-1-carboxylic acid (2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000179
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted with 3-hydroxy-azetidine hydrochloride in the same method as Example 1 to obtain the title compound (17 mg, yield 69%).
NMR: 1H-NMR(CDCl3) 8.03(1H, t), 6.95(1H, d), 6.91(1H, d), 6.09(1H, s), 4.74~4.70(1H, m), 4.33~4.27(3H, m), 3.99~3.94(2H, m), 3.81~3.74(2H, m), 3.55~3.48(2H, m), 3.40(1H, d), 2.92~2.81(1H, m), 2.72(1H, t), 2.52(1H, d), 2.28~2.19(2H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.66~1.50(2H, m), 1.29(6H, d)
Example 162: 1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea
Figure PCTKR2012001185-appb-I000180
4-(4-amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 72 (20 mg, 0.05 mmol) was reacted with 3-amino-propanol in the same method as Example 1 to obtain the title compound (14 mg, yield 56%).
NMR: 1H-NMR(CDCl3) 7.84(1H, t), 6.96(1H, d), 6.92(1H, d), 6.46(1H, s), 5.09(1H, s), 4.32~4.27(1H, m), 3.82~3.69(4H, m), 3.55~3.38(5H, m), 3.00(1H, s), 2.92~2.81(1H, m), 2.72(1H, t), 2.52(1H, d), 2.28~2.19(1H, m), 2.10~1.96(4H, m), 1.90~1.78(3H, m), 1.73~1.68(2H, m), 1.66~1.50(2H, m), 1.28(6H, d)
Example 163: 1-(6-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-pyrimidin-3-yl)-3-propyl-urea
Figure PCTKR2012001185-appb-I000181
2-bromo-5-nitro-pyrimidine (0.11 g, 0.58 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 7 to obtain 4-(5-amino-pyridin-2-yl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime. Said compound and propylamine were reacted according to the method of Example 1 to obtain the title compound (8 mg, yield 64%).
NMR: 1H-NMR(CDCl3) 8.29(1H, m), 8.15(2H, s), 7.92(1H, m), 7.12(1H, m), 6.76(1H, s), 4.94(1H, m), 4.30(1H, m), 4.15(2H, m), 3.51(2H, m), 3.40(1H, m), 3.20(2H, m), 2.90(1H, m), 2.50(1H, m), 2.26(1H, m), 2.11(3H, s), 2.08~1.95(3H, m), 1.90~1.80(3H, m), 1.78~1.60(2H, m), 1.50(2H, m), 1.40(2H, m), 0.90(3H, t)
Example 164: 3-[4-(2-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester
Figure PCTKR2012001185-appb-I000182
3-[4-(4-amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester obtained in Preparation Example 74 (30 mg, 0.07 mmol) was reacted with 0.5M ammonia in dioxane solution in the same method as Example 1 to obtain title compound (25 mg, yield 76%).
NMR: 1H-NMR(CDCl3) 8.19(1H, s), 7.37(3H, m), 7.14(4H, m), 6.07(1H, s), 4.44(2H, s), 4.35(1H, s), 3.84(2H, s), 3.37(1H, d), 3.07(1H, t), 2.55(1H, d), 2.30~1.90(12H, m), 1.71(2H, m)
Example 165: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-((R)-2-hydroxy-1-methyl-ethyl)-urea
Figure PCTKR2012001185-appb-I000183
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 7 (0.50 g, 1.2 mmol) and D-alaninol (0.18 g, 2.4 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (0.45 g, yield 72%).
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 7.84(1H, m), 6.93(1H, s), 6.85(1H, m), 5.05(1H, d), 4.30(1H, m), 4.13(2H, m), 3.97(1H, m), 3.74(1H, d), 3.53(3H, m), 3.43(1H, d), 3.03(1H, t), 2.68(1H, s), 2.53(1H, d), 2.27(1H, m), 2.10(3H, s), 1.98(4H, m), 1.87(1H, m), 1.66(4H, m), 1.22(3H, d)
Example 166: 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-((S)-2-hydroxy-1-methyl-ethyl)-urea
Figure PCTKR2012001185-appb-I000184
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 7 (0.50 g, 1.2 mmol) and L-alaninol 0.18 g(2.4 mmol) were reacted in the same manner as in Example 1 to obtain the title compound (0.48 g, yield 77%).
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 7.84(1H, m), 6.85(1H, m), 6.76(1H, s), 4.86(1H, d), 4.30(1H, m), 4.13(2H, m), 3.97(1H, m), 3.75(1H, d), 3.53(3H, m), 3.43(1H, d), 3.03(1H, t), 2.53(1H, d), 2.47(1H, s), 2.27(1H, m), 2.10(3H, s), 1.98(4H, m), 1.87(1H, m), 1.66(4H, m), 1.22(3H, d)
Example 167: 4-[4-(2,5-difluoro-4-ureido-phenyl)-cyclohexylidenaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester
Figure PCTKR2012001185-appb-I000185
4-[4-(4-amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example 76 (0.05 g, 0.11 mmol) and 0.5M ammonia in dioxane solution were reacted in the same method as Example 1 to obtain the title compound (0.01 g, yield 26%).
NMR: 1H-NMR(CDCl3) 7.87(1H, m), 6.88(1H, m), 5.55(1H, s), 4.63(2H, s), 4.10(2H, m), 3.90(2H, d), 3.41~3.40(1H, m), 3.00(1H, m), 2.80(2H, m), 2.49~2.46(2H, m), 2.35~2.22(1H, m), 2.00~1.80(6H, m), 1.70~1.58(1H, m), 1.46(9H, s), 1.45~1.43(2H, m)
Example 168: 4-(2,5-difluoro-4-tetrazol-1-yl-phenyl)-cyclohexenone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
Figure PCTKR2012001185-appb-I000186
4-(4-amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime obtained in Preparation Example 7 (0.11 g, 0.27 mmol) was dissolved in anhydrous acetic acid (0.3 mL), and sodium azide (54 mg, 0.83 mmol) and trimethoxymethane (88 mg, 0.83 mmol) were added thereto sequentially, and then the mixture was sttired at room temperature for 15 minutes. In addition, The mixture was sttired at 80 ℃ for 1 hour. The reaction mixture was distilled under reduced pressure, extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure to obtain the title compound (0.069 g, yield 53%).
NMR: 1H-NMR(CDCl3) 9.11(1H, m), 8.16(2H, s), 7.72(1H, m), 7.24(1H, m), 4.33(1H, m), 3.53~3.47(3H, m), 3.20(2H, t), 2.59(2H, t), 2.30(1H, t), 2.10(3H, s), 2.03~1.97(5H, m), 1.77~1.64(2H, m)
Example 169: 4-para-tolyl-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
Figure PCTKR2012001185-appb-I000187
1-bromo-4-methyl-benzene (0.08 g, 0.59 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 7 to obtain the title compound (123 mg, yield 50%).
NMR: 1H-NMR(CDCl3) 8.15(2H, s), 7.10(4H, m), 4.19~4.10(3H, m), 3.52~3.45(3H, m), 2.80(1H, m), 2.67~2.57(1H, m), 2.31(3H, s), 2.20(2H, m), 2.11(3H, s), 2.05~1.95(2H, m), 1.85~1.60(4H, m), 1.36(3H, t)
Example 170: 4- naphthalen-2-yl-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime
Figure PCTKR2012001185-appb-I000188
2-bromo-naphthalene (0.12 g, 0.59 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 7 to obtain the title compound (117 mg, yield 45%).
NMR: 1H-NMR(CDCl3) 8.16(2H, s), 7.80(3H, m), 7.64(1H, m), 7.50~7.30(3H, m), 4.33(1H, m), 4.18(2H, m), 3.52~3.45(3H, m), 2.94(1H, m), 2.60(1H, m), 2.32(1H, m), 2.11(3H, s), 2.05~1.95(2H, m), 1.85~1.60(2H, m), 1.36(3H, t)
Example 171: 3-hydroxy-azetidine-1-carboxylic acid (3-methyl-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000189
1-bromo-2-methyl-4-nitro-benzene (0.12 g, 0.57 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 7 to obtain 4-(4-amino-2-methyl-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime. Said compound and 3-hydroxy-azetidine hydrochloride were reacted according to the method of Example 1 to obtain the title compound (15 mg, yield 85%).
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 7.19~7.06(3H, m), 5.87(1H, s), 4.67(1H, m), 4.31~4.20(3H, m), 4.15(2H, m), 3.90(2H, m), 3.52~3.45(3H, m), 2.90(1H, m), 2.55(1H, m), 2.32(3H, s), 2.20~2.20(1H, m), 2.11(3H, s), 2.08~1.95(3H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Example 172: 3-hydroxy-azetidine-1-carboxylic acid (3-methoxy-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide
Figure PCTKR2012001185-appb-I000190
1-chloro-2-methoxy-4-nitro-benzene (0.10 g, 0.57 mmol) was reacted subsequently according to the methods of Preparation Examples 1, 2, 3 and 7 to obtain 4-(4-amino-2-methoxy-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime. Said compound and 3-hydroxy-azetidine hydrochloride were reacted according to the method of Example 1 to obtain the title compound (8 mg, yield 64%).
NMR: 1H-NMR(CDCl3) 8.14(2H, s), 7.28(1H, m), 7.00(1H, m), 6.65(1H, m), 5.92(1H, s), 4.76(1H, m), 4.28(3H, m), 4.15(2H, m), 3.92(2H, m), 3.82(3H, s), 3.51(2H, m), 3.40(1H, m), 3.12(1H, m), 2.50(1H, m), 2.26(1H, m), 2.11(3H, s), 2.08~1.95(3H, m), 1.90~1.80(1H, m), 1.78~1.60(2H, m), 1.50~1.40(2H, m)
Experimental Example 1: Measurement of activity of GPR agonist (cell-based assay)
HEK293 hGPR119-luciferase cells were dispensed into each well of a 96-well plate (3 × 104 cells/90 ㎕/well) and then incubated in a 5% CO2, 37℃ incubator for 18 hours. After the addition of 10 ㎕ of serially diluted GPR119 agonist to a final concentration of 1% DMSO, the cells were incubated in the 5% CO2, 37℃ incubator for 5 hours. 50 μl of Bright-Glo™ luciferase substrate (Promega) was added thereto, and then luminescence was measured with a luminometer (Molecular Devices).
Luminescence increased by the serially diluted agonist is calculated as a relative percent (%) value based on the luminescence represented by the treatment of 1% DMSO only. EC50 refers to the concentration of agonist which shows 50% of maximum luminescence increased by the treatment of agonist. The calculation of measurement was carried out by using statistical software (Prizm).
The agonistic effects of Example compounds on the receptor obtained by the above experiment are shown in the following Table 1 with EC50 unit (μM). Activity is denoted based on the following criteria:
A = 100 - 20 μM, B = 20 - 2 μM, C = 2 - 0.2 μM, D = 0.2 - 0.01 μM
Table 1
Figure PCTKR2012001185-appb-T000001

Claims (12)

  1. Oxime derivatives of Formula 1, or pharmaceutically acceptable salts or isomers thereof:
    [Formula 1]
    Figure PCTKR2012001185-appb-I000191
    wherein,
    RA represents a partially or fully saturated 4- to 7-membered cycloalkyl,
    RB represents a partially or fully saturated 4- to 7-membered heterocycle, or a [5.5], [5.6], [5.7], [6.6] or [6.7] fused ring system consisting of two rings,
    R1 and R2 represent independently hydrogen, halogen or alkyl,
    n represents an integer of 0 to 10 in each ring,
    A represents nitrogen or carbon,
    B is selected from the following groups:
    Figure PCTKR2012001185-appb-I000192
    wherein,
    D represents carbon, nitrogen, oxygen or sulfur,
    R3, R4 and R5 are independently hydrogen or halogen, or represent in each case optionally substituted aryl, arylalkyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl or amine,
    provided that, when D is oxygen or sulfur, both R3 and R4 do not exist,
    when D is sulfur, R5 is not amine,
    when D is nitrogen, R3 does not exist,
    when D is carbon, two groups selected from R3, R4 and R5 are connected together to form optionally substituted 3- to 7-membered cycloalkyl or heterocycle, or to form optionally substituted 5- or 6-membered aryl or heteroaryl,
    E, F, G, H and I represent independently carbon, nitrogen, oxygen or sulfur to form 6-membered aryl or heteroaryl, or form optionally benzo-fused 5-membered aryl or heteroaryl excluding one of E, F, G, H and I,
    n represents an integer of 0 to 5,
    R6 is hydrogen or halogen; or represents optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl or heteroarylalkyl; or represents hydroxy or amine optionally substituted by 1 or 2 alkyl or aryl, wherein two substituents of amine are connected together to form 3- to 7-membered heterocyclyl,
    J represents optionally substituted C1-C4-alkylene or sulfonyl,
    R7 is hydrogen or halogen, or represents optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, and
    Ar represents optionally substituted aryl or heteroaryl.
  2. The oxime derivatives, or pharmaceutically acceptable salts or isomers thereof according to Claim 1, wherein A is nitrogen.
  3. The oxime derivatives, or pharmaceutically acceptable salts or isomers thereof according to Claim 1, wherein B is selected from the following groups:
    Figure PCTKR2012001185-appb-I000193
    wherein n, R3, R4, R5, R6 and R7 are as defined in Claim 1.
  4. The oxime derivatives, or pharmaceutically acceptable salts or isomers thereof according to Claim 1, wherein Ar represents the following formula:
    Figure PCTKR2012001185-appb-I000194
    wherein,
    K, L, M, Q and T represent independently carbon or nitrogen and form phenyl or 6-membered heteroaryl, or represent, when one of K, L, M, Q and T does not exist, 5-membered heteroaryl to which oxygen, nitrogen or sulfur may be added as a ring atom,
    n represents an integer of 1 to 5,
    R8 is independently hydrogen, halogen, cyano or nitro, or represents in each case optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, amine, hydroxyl, acetylene or vinyl, or is selected from the following groups:
    Figure PCTKR2012001185-appb-I000195
    wherein,
    U is selected from carbon, nitrogen, oxygen, phosphorus and sulfur,
    when U is sulfur or phosphorus, n represents independently 1 or 2,
    when U is carbon or nitrogen, n represents 1,
    when U is oxygen, n represents 0,
    R9 represents hydrogen or optionally substituted hydroxyl, amine, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and
    V represents carbon, nitrogen, oxygen or sulfur.
    R10, R11 and R12 are independently hydrogen, halogen or carbamoyl, or represent optionally substituted hydroxyl, alkyl, amine, cycloalkyl, heterocyclyl, aryl or heteroaryl, or two groups selected from R10, R11 and R12 may be connected to form a ring, and
    when V is oxygen or sulfur, R11 does not exist.
  5. The oxime derivatives, or pharmaceutically acceptable salts or isomers thereof according to Claim 1, wherein Ar is selected from the following groups:
    Figure PCTKR2012001185-appb-I000196
    wherein
    n represents an integer of 1 to 5,
    R8 is nitro, or represents optionally substituted hydroxyl, alkyl, acetylene, amine, heteroaryl or heterocyclyl, or is selected from the following groups:
    Figure PCTKR2012001185-appb-I000197
    wherein n, R9, R10, R11 and R12 are as defined in Claim 4.
  6. The oxime derivatives, or pharmaceutically acceptable salts or isomers thereof according to Claim 1, wherein RA is selected from the following groups:
    Figure PCTKR2012001185-appb-I000198
    RB is selected from the following groups:
    Figure PCTKR2012001185-appb-I000199
    wherein R1 and R2 represent independently hydrogen or C1-C6-alkyl,
    n represents in each ring an integer of 0 to 9,
    A represents nitrogen,
    B is selected from the following groups:
    Figure PCTKR2012001185-appb-I000200
    wherein,
    n represents an integer of 0 to 5,
    R3, R4 and R5 are independently hydrogen or halogen, or represent C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C5-C10-aryl, C5-C10-aryl-C1-C6-alkyl, heterocyclyl or heterocyclyl-C1-C6-alkyl (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom); or R4 and R5 are connected to form C3-C10-cycloalkyl, or a partially of fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom; wherein each radical in the definition of R3, R4 and R5 can be optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, C1-C6-alkoxycarbonyl and C1-C6-alkyl,
    R6 represents hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C1-C6-alkoxy, C5-C10-aryl or di(C1-C6-alkyl)amine, and n represents 0 or 1,
    R7 is hydrogen or halogen, or represents C1-C6-alkyl, C3-C10-cycloalkyl, C5-C10-aryl, or 5- or 6-membered heteroaryl including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, wherein each radical in the definition of R7 can be optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, C1-C6-alkoxycarbonyl and C1-C6-alkyl,
    Ar is selected from the following groups:
    Figure PCTKR2012001185-appb-I000201
    wherein,
    n represents 1 or 2,
    R8 is nitro or hydroxy-C1-C6-alkyl, or represents amine optionally 1- or 2- substituted by C1-C6-alkylsulfonyl, partially or fully saturated 5- or 6-membered heterocyclyl which includes 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and is optionally substituted by oxo, or 5- or 6-membered heteroaryl which includes 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, or is selected from the following groups:
    Figure PCTKR2012001185-appb-I000202
    wherein,
    n represents 1 or 2,
    R9 represents amino, hydroxyl, C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C1-C6-alkylamine, di(C1-C6-alkyl)amine, C3-C10-cycloalkylamine, C5-C10-arylamine, C5-C10-aryl-C1-C6-alkylamine, heterocyclyl or heterocyclyl-C1-C6-alkylamine (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom), wherein each radical in the definition of R9 is optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, carbamoyl and C1-C6-alkyl, and
    R10, R11 and R12 represent independently hydrogen, hydroxyl, halogen, carbamoyl, C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C5-C10-aryl, C1-C6-alkylamine, di(C1-C6-alkyl)amine, C3-C10-cycloalkylamine, C5-C10-arylamine or C5-C10-aryl-C1-C6-alkylamine, or represent heterocyclyl, heterocyclyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkylamine (wherein, heterocyclyl is a partially or fully saturated 3- to 10-membered ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom) or heteroarylalkyl (wherein, heteroaryl is a partially or fully saturated 3- to 10-membered aromatic ring including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom); or two groups selected from R10, R11 and R12 are connected to form C3-C10-cycloalkyl, 4- to 6-membered heteroaryl including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, or a partially or fully saturated 4- to 6-membered heterocyclyl including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom, wherein each radical in the definition of R10, R11 and R12 is optionally substituted by at least one selected from halogen, hydroxyl, amine, oxo, carboxy, azido, C3-C10-cycloalkyl, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyloxy and C1-C6-alkyl.
  7. The oxime derivatives, or pharmaceutically acceptable salts or isomers thereof according to Claim 1, selected from the following compounds:
    4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester;
    4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    3-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-1,1-dimethyl-urea;
    3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-amide;
    4-cyclopropyl-piperazine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    (4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea;
    4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester;
    4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
    4-[4-(2,5-difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester;
    (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    3-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
    4-[4-(2,5-difluoro-4-{[(3-hydroxy-azetidine-1-carbonyl)-amino]-methyl}-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
    4-[4-(2,5-difluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
    4-{4-[2,5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester;
    4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester;
    4-(4-{2,5-difluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    4-(4-{4-[3-(2,3-dihydroxy-propyl)-ureido]-2,5-difluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    4-[4-(4-methanesulfonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester;
    4-(4-{4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester;
    4-(4-{4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimono]-cyclohexyl}-phenyl)-amide;
    1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea;
    (2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1,1-dimethyl-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-hydroxymethyl-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2,3-dihydroxy-propyl)-urea;
    N-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide;
    1-(3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea;
    (3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    3-hydroxy-azetidine-1-carboxylic acid (3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea;
    N-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide;
    {2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-urea;
    {2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-carbamic acid methyl ester;
    {4-[4-(1-benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5-difluoro-phenyl}-urea;
    {4-[4-(1-benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5-difluoro-phenyl}-carbamic acid methyl ester;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-hydroxy-ethyl)-urea;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-2,2-dimethyl-propyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-2,2-dimethyl-propyl)-urea;
    (2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    3-hydroxy-azetidine-1-carboxylic acid (2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    butane-1-sulfonic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-amide;
    4-[4-(2,5-difluoro-4-guanidinocarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester;
    (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea;
    (R)-3-fluoro-pyrrolidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-amide;
    (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea;
    (4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea;
    1-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
    3-hydroxy-azetidine-1-carboxylic acid {2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl}-amide;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-hydroxy-propyl)-urea;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea;
    1-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea;
    {2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yloxyimino)-cyclohexyl]-phenyl}-urea;
    (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    (2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    1-(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
    3-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-1,1-dimethyl-urea;
    3-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
    3-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
    1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea;
    1-(2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
    3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea;
    1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
    1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
    4-[4-(2-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
    4-(4-{2-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2-fluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2,5-difluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    (4-{4-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea;
    1-(4-{4-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
    (2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea;
    (2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea;
    (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-dicarbonimidic diamide;
    1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
    3-hydroxy-azetidin-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea;
    1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-thiophen-2-ylmethyl-urea;
    (2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    (2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    3-hydroxy-azetidine-1-carboxylic acid (2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    1-(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
    1-(2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
    3-hydroxy-azetidine-1-carboxylic acid (2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
    3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-amide;
    (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-urea;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3-(2-hydroxy-propyl)-urea;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3-propyl-urea;
    4-[4-(3-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester;
    (2,5-difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-urea;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(3-hydroxy-propyl)-urea;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(2-hydroxy-propyl)-urea;
    3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-amide;
    4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid ethyl ester;
    4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid (2-fluoro-ethyl)-amide;
    4-(5-hydroxymethyl-4-methyl-thiazol-2-yl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
    3-hydoxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    4-(4-{3-fluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    1-(2,5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
    3-hydoxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    [(S)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-(4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester;
    4-{4-[(S)-2-amino-3-((S)-3-fluoro-pyrrolidin-1-yl)-3-oxo-propyl]-phenyl}-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-methyl-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-isopropyl-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea;
    4-[4-(2-fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester;
    4-[4-(3-fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester;
    4-[4-(2,5-difluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester;
    4-{4-[2,5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
    4-{4-[4-(3,3-dimethyl-ureido)-2,5-difluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
    4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
    4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
    3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[(Z)-1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohex-1-enyl}-phenyl)-amide;
    4-{4-[3-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
    4-{4-[2-fluoro-4-(2-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
    4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
    4-(4-{2-fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
    4-{4-[4-(3,3-dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester;
    4-(4-{3-fluoro-4-[3-(2-fluoro-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
    3-(2-fluoro-4-{4-[1-(3,3,3-trifluoro-propyl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
    3-{4-[4-(1-benzyl-piperidin-4-yloxyimino)-cyclohexyl]-2-fluoro-phenyl}-1,1-dimethyl-urea;
    3-{2-fluoro-4-[4-(1-naphthalen-2-ylmethyl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-1,1-dimethyl-urea;
    4-(4-{3-fluoro-4-[(3-hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester;
    4-(4-{3-fluoro-4-[3-(2-fluoro-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    3-{4-[2-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-pyrrolidine-1-carboxylic acid phenyl ester;
    4-(4-{3-fluoro-4-[3-(2-hydroxy-1-methyl-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    4-(4-{3-fluoro-4-[3-(2-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    4-(4-{3-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    4-{4-[3-fluoro-4-(3-methyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester;
    4-{4-[3-fluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester;
    4-{4-[4-(3,3-dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidin-yl-carboxylic acid isopropyl ester;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-methyl-urea;
    1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(2-hydro-1-methyl-ethyl)-urea;
    4-{4-[3-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidin-yl-carboxylic acid isopropyl ester;
    4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester;
    1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea;
    3-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea;
    1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea;
    1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea;
    (2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea;
    1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea;
    1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea;
    1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea;
    3-hydroxy-azetidine-1-carboxylic acid (2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-((R)-2-hydroxy-1-methyl-ethyl)-urea;
    1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-((S)-2-hydroxy-1-methyl-ethyl)-urea;
    4-[4-(2,5-difluoro-4-ureido-phenyl)-cyclohexylideneaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester;
    4-(2,5-difluoro-4-tetrazol-1-yl-phenyl)-cyclohexenone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
    4-para-tolyl-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
    4-naphthalen-2-yl-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime;
    3-hydroxy-azetidine-1-carboxylic acid (3-methyl-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    3-hydroxy-azetidine-1-carboxylic acid (3-methoxy-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-amide;
    1-(6-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-pyrimidin-3-yl)-3-propyl-urea; and
    3-[4-(2-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester.
  8. A pharmaceutical composition as GPR119 agonists, comprising the oxime derivatives, pharmaceutically acceptable salts or isomers thereof according to Claim 1 and a pharmaceutically acceptable carrier.
  9. A pharmaceutical composition for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis, comprising the oxime derivatives, pharmaceutically acceptable salts or isomers thereof according to Claim 1 and a pharmaceutically acceptable carrier.
  10. The pharmaceutical composition according to Claim 9, wherein the diabetes is type 2 diabetes.
  11. A composition for lowering blood glucose level, comprising the oxime derivatives, pharmaceutically acceptable salts or isomers thereof according to Claim 1 and a pharmaceutically acceptable carrier.
  12. A method for preparing a composition for preventing or treating diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis, which comprises the step of mixing the oxime derivatives, pharmaceutically acceptable salts or isomers thereof according to Claim 1 with a pharmaceutically acceptable carrier.
PCT/KR2012/001185 2011-02-17 2012-02-16 Oxime derivatives as gpr119 agonists WO2012111995A1 (en)

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US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains

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CN106632302A (en) * 2016-12-15 2017-05-10 苏州汉德创宏生化科技有限公司 Synthesis method of 1-(thiazole-2-yl)piperidine-4-ol

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WO2004069852A1 (en) * 2003-02-04 2004-08-19 Syngenta Participations Ag Avermectins substituted in the 4” and 4’-positions having pesticidal properties
US20070173495A1 (en) * 2006-01-20 2007-07-26 Anandan Palani Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
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US20070173495A1 (en) * 2006-01-20 2007-07-26 Anandan Palani Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
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WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains

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