WO2020013646A1 - 피리미디논 유도체 화합물 및 이의 용도 - Google Patents

피리미디논 유도체 화합물 및 이의 용도 Download PDF

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WO2020013646A1
WO2020013646A1 PCT/KR2019/008609 KR2019008609W WO2020013646A1 WO 2020013646 A1 WO2020013646 A1 WO 2020013646A1 KR 2019008609 W KR2019008609 W KR 2019008609W WO 2020013646 A1 WO2020013646 A1 WO 2020013646A1
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Prior art keywords
methyl
oxadiazol
biphenyl
butyl
oxopyrimidin
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PCT/KR2019/008609
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English (en)
French (fr)
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김성헌
정원근
유병욱
김학도
양덕모
이성국
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보령제약 주식회사
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Publication of WO2020013646A1 publication Critical patent/WO2020013646A1/ko

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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to pyrimidinone derivative compounds and their use.
  • Hypertension is a chronic disease that has not yet been identified.
  • Essential hypertension primary hypertension
  • diabetes is one of metabolic diseases, its fatality is increased several times.
  • Angiotensin II produced by angiotensin converting enzyme from angiotensin I is known to increase blood pressure through angiotensin II receptors present in the vascular cell wall as cell membrane proteins.
  • angiotensin II antagonists have been used to treat hypertension caused by angiotensin.
  • drugs developed as oral administration angiotensin II antagonists include losartan, candesartan cilexetil, olmesartan medoxomil, telmisartan, pimasartan (fimasartan) and the like are known.
  • Diabetes causes problems in blood glucose control, which causes kidney disease, vascular disease, and the like, and is a life-threatening disease in severe cases by progressing to pressure sores, blindness, kidney failure, and the like.
  • TZD thiazolidinedione
  • the drug group known as TZD is a drug that targets PPAR ⁇ and restores blood glucose control ability by relieving insulin resistance in patients with abnormal blood glucose control.
  • the TZD family of drugs activates the nuclear receptor PPAR ⁇ , which is known to increase the expression of various genes such as fat metabolism and glucose metabolism. Because of this, unintended edema and obesity appear as side effects, and in order to reduce such side effects and obtain only the pharmacological effect of overcoming insulin resistance, development of partial activators, selective regulators, and the like have been attempted.
  • the present invention seeks to provide pyrimidinone derivative compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof that exhibit therapeutic activity in hypertension and / or diabetes.
  • the present invention is to provide a method for preparing the pyrimidinone derivative compound of the present invention.
  • the present invention also provides the use of the pyrimidinone derivative compound of the present invention.
  • the present invention provides a compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
  • X is or And ⁇ where X is If L 2 and Y are nothing (null) ⁇ ,
  • X 1 is N, O, S, CR 3 or NR 4 ,
  • X 2 is N, O, S or NR 4 ,
  • X 3 is N, O, S or CR 3 ,
  • X 4 is C or N
  • X 5 is O or S
  • Y is H, C 1 -C 6 alkyl, NR 5 R 6 , OR 7 , C 3 -C 7 cycloalkyl, C 5 -C 10 spiro ring, C 5 -C 10 bicyclic ring, 4-7 member Heterocycloalkyl, aryl or heteroaryl, wherein one or more H of said aryl or heteroaryl is C 1 -C 6 alkyl, NR 5 R 6 , OR 7 , May be substituted with halo or C 1 -C 6 haloalkyl ⁇ ,
  • R a1 , R a2 , R b1 and R b2 are each independently H, halo, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl,
  • R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 7 cycloalkyl,
  • R 3 and R 4 are each independently H, C 1 -C 6 alkyl or aryl
  • R 5 to R 8 are each independently H or C 1 -C 6 alkyl
  • L 1 is-(CH 2 ) m -wherein at least one H of-(CH 2 ) m -may be substituted with deuterium,
  • L 2 is-(CH 2 ) n -or And ⁇ wherein-(CH 2 ) n -and At least one H may be substituted with C 1 -C 6 alkyl ⁇ ,
  • n are each independently 0, 1, 2 or 3
  • p 1, 2, 3 or 4.
  • X is or And ⁇ where X is If L 2 and Y are nothing (null) ⁇ ,
  • X 1 is N, O, S, CR 3 or NR 4 ,
  • X 2 is N, O or NR 4 ,
  • X 3 is N, O or CR 3 ,
  • X 4 is C or N
  • X 5 is O
  • Y is C 1 -C 4 alkyl, NR 5 R 6 , OR 7 , C 3 -C 6 cycloalkyl, C 5 -C 10 spiro ring, C 5 -C 10 bicyclic ring, 4-6 membered heterocyclo Alkyl, aryl or heteroaryl, wherein one or more H of said aryl or heteroaryl is C 1 -C 4 alkyl, OR 7 , May be substituted with halo or C 1 -C 4 haloalkyl ⁇ ,
  • R a1 , R a2 , R b1 and R b2 are each independently H or C 1 -C 4 alkyl
  • R 1 and R 2 are each independently C 1 -C 4 alkyl
  • R 3 and R 4 are each independently H, C 1 -C 4 alkyl or aryl,
  • R 5 to R 8 are each independently H or C 1 -C 4 alkyl
  • L 1 is-(CH 2 ) m -wherein one or more H of-(CH 2 ) m -may be substituted with deuterium ⁇ ,
  • L 2 is-(CH 2 ) n -or And ⁇ wherein-(CH 2 ) n -and At least one H may be substituted with C 1 -C 4 alkyl ⁇ ,
  • n are each independently 0, 1 or 2
  • p 1 or 2.
  • X is , , , , , , , or And ⁇ where X is If L 2 and Y are nothing (null) ⁇ ,
  • Y is C 1 -C 4 alkyl, NR 5 R 6 , OR 7 , C 3 -C 6 cycloalkyl, C 5 -C 10 spiro ring, C 5 -C 10 bicyclic ring, piperidinyl, morphpoly Yl, tetrahydropyranyl, phenyl, naphthalenyl, pyridinyl or quinolinyl, wherein one or more H of said phenyl, naphthalenyl, pyridinyl or quinolinyl is C 1 -C 4 alkyl, OR 7 , May be substituted with F, Cl, Br or CF 3 ⁇ ,
  • R 1 and R 2 are each independently C 1 -C 4 alkyl
  • R 3 and R 4 are each independently H, C 1 -C 4 alkyl or aryl,
  • R 5 to R 8 are each independently H or C 1 -C 4 alkyl
  • L 1 is-(CH 2 ) m -wherein one or more H of-(CH 2 ) m -may be substituted with deuterium ⁇ ,
  • L 2 is-(CH 2 ) n -or And ⁇ wherein-(CH 2 ) n -and At least one H may be substituted with C 1 -C 4 alkyl ⁇ ,
  • n are each independently 0, 1 or 2
  • p 1 or 2.
  • the compound represented by Formula I may be a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is any one selected from the group consisting of the following compounds. have:
  • pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, for example, inorganic ionic salts, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, prepared from calcium, potassium, sodium and magnesium, Inorganic acid salts prepared with iodic acid, perchloric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid Organic acid salts prepared with acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid and the like; Sulfonic acid salts prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p
  • the compounds represented by formula (I) of the present invention may contain one or more asymmetric carbons and may therefore exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. have.
  • Such isomers can be separated by prior art, for example, compounds represented by the formula (I) by separation such as column chromatography or HPLC.
  • the stereoisomers of each of the compounds represented by Formula I can be stereospecifically synthesized using optically pure starting materials and / or reagents in known arrangements.
  • the present invention provides a process for preparing a compound represented by the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I) of the present invention, the optical isomer thereof or a pharmaceutically acceptable salt thereof may be prepared according to the route of Scheme 1 below.
  • a commercially available compound of Formula 1 and a compound of Formula 2 are used as starting materials to obtain a compound of Formula 3 through polymerization under basic conditions, and a cyclization reaction of the amidine compound of Formula 4 with Formula 5 To obtain a compound.
  • the compound of Formula 7 is obtained through a polymerization reaction using a compound of Formula 6 and a base, and the cyano group thereof is transformed into an oxadiazolone in a known manner to obtain a compound of Formula 11.
  • the compound of Formula I may be prepared by reacting with various oxime compounds, amidine compounds, or hydrazine compounds, and the like by cyclization.
  • the compound represented by the formula (I) of the present invention, the optical isomer thereof or a pharmaceutically acceptable salt thereof may be prepared according to the route of Schemes 2 to 9.
  • compositions comprising a compound of formula I, uses thereof and methods of treatment using the same
  • the present invention provides a pharmaceutical composition for treating or preventing hypertension or diabetes, comprising a compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the hypertension may be essential hypertension
  • the diabetes may be type 2 diabetes.
  • the compounds of the invention exhibit pharmacological activity against both hypertension and diabetes. Therefore, the pharmaceutical composition of the present invention can be usefully used to simultaneously treat or prevent hypertension and diabetes.
  • the pharmaceutical composition of the present invention may further include at least one pharmaceutically acceptable carrier in addition to the compound represented by the formula (I), the optical isomer thereof or the pharmaceutically acceptable salt thereof for administration.
  • Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, if necessary, with antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added.
  • compositions of the present invention may be patches, solutions, pills, capsules, granules, tablets, suppositories, and the like.
  • formulations may be prepared by conventional methods used in the art for formulation or by methods disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA, and formulated into various formulations depending on the individual disease or component. Can be.
  • composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease.
  • the daily dosage of the compound represented by the formula (I) of the present invention is about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and may be administered once to several times a day.
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicaments in addition to the compound represented by the formula (I), the optical isomer thereof or the pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating hypertension or diabetes, comprising administering to a mammal, including a human, a therapeutically effective amount of a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. do.
  • the hypertension may be essential hypertension
  • the diabetes may be type 2 diabetes.
  • a method of treating hypertension or diabetes comprising administering to a mammal, including a human, a therapeutically effective amount of a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof of the present invention.
  • a mammal including a human, a therapeutically effective amount of a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof of the present invention.
  • terapéuticaally effective amount refers to the amount of the compound represented by formula (I) effective for the treatment of hypertension or diabetes.
  • the method of treatment of the present invention includes not only treating the disease itself before the onset of the indication, but also inhibiting or avoiding the indication thereof by administering the compound represented by the formula (I).
  • the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dose will vary depending on the age, weight and response of the individual patient. Appropriate dosage regimens can be readily selected by those of ordinary skill in the art that naturally consider such factors.
  • the treatment method of the present invention may further comprise the administration of a therapeutically effective amount of an additional active agent which is helpful for treating a disease together with the compound represented by the formula (I), wherein the additional active agent is a compound of the formula (I) And synergistic or auxiliary effects.
  • the present invention also provides the use of a compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of hypertension or diabetes.
  • the compound represented by the formula (I) for the preparation of a medicament may be mixed with an acceptable adjuvant, diluent, carrier and the like, and may be prepared in a complex formulation with other active agents to have a synergistic action of the active ingredients.
  • the hypertension may be essential hypertension
  • the diabetes may be type 2 diabetes.
  • the compound represented by the formula (I), the optical isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of hypertension or diabetes may simultaneously treat hypertension and diabetes.
  • the pyrimidinone derivative compounds of the present invention exhibit therapeutic activity in hypertension and / or diabetes.
  • Example A-1 3- (4 '-((2-butyl-5-((3- (2-fluorophenyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (2-fluorophenyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Step 2 3- (4 '-((2-butyl-5-((3- (2-fluorophenyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2 -butyl-5-((3- (2-fluorophenyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2 Preparation of -yl) -1,2,4-oxadiazol-5 (4H) -one
  • Flask 2- (2-butyl-4-methyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) acetic acid (50 mg, 0.105 mmol) was added followed by 1 ml of pyridine. 15 mg of SOCl 2 was injected, followed by stirring at room temperature for 1 hour. The compound of step 1 prepared before (20 mg 0.126 mmol) was injected, followed by stirring at reflux for 12 hours.
  • Example A-2 to A-115 were synthesized using nitrile derivative compounds corresponding to each Example in a similar manner to Example A-1.
  • Example A-2 3- (4 '-((2-butyl-5-((3-cyclopropyl-1,2,4-oxadiazol-5-yl) methyl) -4-isopropyl-6 Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl -5-((3-cyclopropyl-1,2,4-oxadiazol-5-yl) methyl) -4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1, Preparation of 2,4-oxadiazol-5 (4H) -one
  • Example A-3 3- (4 '-((2-butyl-5-((3-cyclopropyl-1,2,4-oxodiazol-5-yl) methyl) -4-methyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 5-((3-cyclopropyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example A-4 3- (4 '-((2-butyl-5-((3-tert-butyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6 Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl -5-((3-tert-butyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl)- Preparation of 1,2,4-oxadiazol-5 (4H) -one
  • Example A-5 3- (4 '-((2-butyl-5-((3- (methoxymethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2 -butyl-5-((3- (methoxymethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl Preparation of) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-6 3- (4 '-((2-butyl-5-((3- (2-methoxyethyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (2-methoxyethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-7 3- (4 '-((2-butyl-5-((3-isopropyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 5-((3-isopropyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 , 4-oxadiazol-5 (4H) -one
  • Example A-8 3- (4 '-((2-butyl-5-((3- (dimethylamino) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2 -butyl-5-((3- (dimethylamino) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl Preparation of) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-9 3- (4 '-((2-butyl-5-((3-((dimethylamino) methyl) -1,2,4-oxadiazol-5-yl) methyl)- 4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((2-butyl-5-((3-((dimethylamino) methyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl Preparation of) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-10 3- (4 '-((2-butyl-5-((3- (diethylamino) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2 -butyl-5-((3- (diethylamino) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl Preparation of) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-11 3- (4 '-((2-butyl-5-((3-tert-butyl-1,2,4-oxadiazol-5-yl) methyl) -4-isopropyl- 6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2- butyl-5-((3-tert-butyl-1,2,4-oxadiazol-5-yl) methyl) -4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) Preparation of -1,2,4-oxadiazol-5 (4H) -one
  • Example A-12 3- (4 '-((2-butyl-5-((3- (2-methoxypropan-2-yl) -1,2,4-oxadiazol-5-yl) Methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((2-butyl-5-((3- (2-methoxypropan-2-yl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 ( Preparation of 6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-13 3- (4 '-((2-butyl-4-isopropyl-5-((3-methyl-1,2,4-oxadiazol-5-yl) methyl) -6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 4-isopropyl-5-((3-methyl-1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example A-14 3- (4 '-((2-butyl-4-methyl-5-((3-methyl-1,2,4-oxadiazol-5-yl) methyl) -6-ox Sopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-4 -methyl-5-((3-methyl-1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2, Preparation of 4-oxadiazol-5 (4H) -one
  • Example A-15 3- (4 '-((5-((3-benzyl-1,2,4-oxadiazol-5-yl) methyl) -2-butyl-4-methyl-6-jade Sopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3 -benzyl-1,2,4-oxadiazol-5-yl) methyl) -2-butyl-4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2, Preparation of 4-oxadiazol-5 (4H) -one
  • Example A-16 3- (4 '-((2-butyl-5-((3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-17 3- (4 '-((5-((3-benzyl-1,2,4-oxadiazol-5-yl) methyl) -2-butyl-4-isopropyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-(( 3-benzyl-1,2,4-oxadiazol-5-yl) methyl) -2-butyl-4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example A-18 3- (4 '-((2-butyl-5-((3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((2-butyl-5-((3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) Preparation of biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-19 3- (4 '-((2-butyl-4-methyl-5-((3- (1-methylcyclopropyl) -1,2,4-oxadiazol-5-yl) Methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-4-methyl-5-((3- (1-methylcyclopropyl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-20 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (spiro [2.2] pentan-1-yl) -1,2,4 -Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((2-butyl-4-methyl-6-oxo-5-((3- (spiro [2.2] pentan-1-yl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin Preparation of -1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-21 3- (4 '-((2-butyl-5-((3- (isopropoxymethyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-5-((3- (isopropoxymethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2- Preparation of yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-22 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (1-phenylcyclopropyl) -1,2,4-oxadiazole- 5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-4-methyl-6-oxo-5-((3- (1-phenylcyclopropyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-23 3- (4 '-((2-butyl-5-((3- (3-chloropyridin-2-yl) -1,2,4-oxadiazol-5-yl) methyl ) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((3- (3-chloropyridin-2-yl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-24 3- (4 '-((2-butyl-5-((3- (2-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (2-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-25 3- (4 '-((2-butyl-5-((3- (2-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((2-butyl-5-((3- (2-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) Preparation of biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-26 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (2-phenylpropan-2-yl) -1,2,4-oxa Diazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((2-butyl-4-methyl-6-oxo-5-((3- (2-phenylpropan-2-yl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-27 3- (4 '-((2-butyl-5-((3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl-d2) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((2-butyl-5-((3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl-d2) -4-methyl-6-oxopyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-28 3- (4 '-((2-butyl-5-((3-tert-butyl-1,2,4-oxadiazol-5-yl) methyl-d2) -4-methyl -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2 -butyl-5-((3-tert-butyl-1,2,4-oxadiazol-5-yl) methyl-d2) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2 Preparation of -yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-29 3- (4 '-((2-butyl-4-methyl-5-((3- (4-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl ) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-4-methyl-5-((3- (4-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-30 3- (4 '-((2-butyl-5-((3- (4-methoxybenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (4-methoxybenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-31 3- (4 '-((2-butyl-5-((3- (4-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-5-((3- (4-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-32 3- (4 '-((2-butyl-5-((3- (3-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (3-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-33 3- (4 '-((2-butyl-5-((3- (3,5-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl ) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((3- (3,5-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H)- Preparation of yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-34 3- (4 '-((5-((3-tert-butyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2 -Propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-(( 3-tert-butyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1 Preparation of 2,4-oxadiazol-5 (4H) -one
  • Example A-35 3- (4 '-((5-((3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6 -Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 5-((3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-36 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (piperidin-1-ylmethyl) -1,2,4-oxa Diazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((2-butyl-4-methyl-6-oxo-5-((3- (piperidin-1-ylmethyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H)- Preparation of yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-37 3- (4 '-((4-methyl-5-((3- (4-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl) -6- Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((4 -methyl-5-((3- (4-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2 Preparation of -yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-38 3- (4 '-((5-((3- (4-methoxybenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6 -Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 5-((3- (4-methoxybenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-39 3- (4 '-((5-((3- (4-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6- Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5 -((3- (4-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2 Preparation of -yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-40 3- (4 '-((5-((3- (3-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6 -Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 5-((3- (3-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-41 3- (4 '-((5-((3- (3,5-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((5-((3- (3,5-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-42 3- (4 '-((5-((3- (2,4-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((5-((3- (2,4-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-43 3- (4 '-((5-((3-cyclopentyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2- Propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3 -cyclopentyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2, Preparation of 4-oxadiazol-5 (4H) -one
  • Example A-44 3- (4 '-((5-((3- (cyclopentylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo 2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5- ((3- (cyclopentylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) Preparation of -1,2,4-oxadiazol-5 (4H) -one
  • Example A-45 3- (4 '-((5-((3- (cyclohexylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo 2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5- ((3- (cyclohexylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) Preparation of -1,2,4-oxadiazol-5 (4H) -one
  • Example A-46 3- (4 '-((2-butyl-5-((3- (2,4-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl ) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((3- (2,4-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H)- Preparation of yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-47 3- (4 '-((2-butyl-5-((3- (cyclohexylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2 -butyl-5-((3- (cyclohexylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl Preparation of) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-48 3- (4 '-((2-butyl-5-((3- (cyclopentylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2 -butyl-5-((3- (cyclopentylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl Preparation of) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-49 3- (4 '-((2-butyl-5-((3-cyclopentyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidine-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((3- cyclopentyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 Preparation of (4H) -one
  • Example A-50 3- (4 '-((5-((3- (cyclopropylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo 2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5- ((3- (cyclopropylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) Preparation of -1,2,4-oxadiazol-5 (4H) -one
  • Example A-51 3- (4 '-((5-((3- (2-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6- Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5 -((3- (2-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2 Preparation of -yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-52 3- (4 '-((5-((3- (3,4-Difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((5-((3- (3,4-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-53 3- (4 '-((5-((3- (2,5-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((5-((3- (2,5-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-54 3- (4 '-((5-((3- (2-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6 -Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 5-((3- (2-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-55 3- (4 '-((5-((3- (4-bromobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6 -Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 5-((3- (4-bromobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-56 3- (4 '-((5-((3- (3-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6- Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5 -((3- (3-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2 Preparation of -yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-57 3- (4 '-((5-((3- (2,6-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((5-((3- (2,6-dichlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-58 3- (4 '-((4-methyl-6-oxo-2-propyl-5-((3- (2,4,6-trifluorobenzyl) -1,2,4 -Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((4-methyl-6-oxo-2-propyl-5-((3- (2,4,6-trifluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 Preparation of (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-59 3- (4 '-((4-methyl-6-oxo-5-((3- (piperidin-1-yl) -1,2,4-oxadiazol-5- Yl) methyl) -2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((4-methyl-6-oxo-5-((3- (piperidin-1-yl) -1,2,4-oxadiazol-5-yl) methyl) -2-propylpyrimidin-1 (6H) -yl) Preparation of methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-60 3- (4 '-((5-((3-cyclohexyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2- Propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3 -cyclohexyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2, Preparation of 4-oxadiazol-5 (4H) -one
  • Example A-61 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (2- (trifluoromethyl) benzyl) -1,2,4- Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (2- (trifluoromethyl) benzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-62 3- (4 '-((2-butyl-4-methyl-5-((3- (2-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl ) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-4-methyl-5-((3- (2-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-63 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (3- (trifluoromethyl) benzyl) -1,2,4- Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (3- (trifluoromethyl) benzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-64 3- (4 '-((2-butyl-5-((3- (2,3-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl ) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((3- (2,3-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H)- Preparation of yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-65 3- (4 '-((4-methyl-6-oxo-5-((3- (piperidin-1-ylmethyl) -1,2,4-oxadiazole-5 -Yl) methyl) -2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((4-methyl-6-oxo-5-((3- (piperidin-1-ylmethyl) -1,2,4-oxadiazol-5-yl) methyl) -2-propylpyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-66 3- (4 '-((4-methyl-6-oxo-2-propyl-5-((3- (3- (trifluoromethyl) benzyl) -1,2,4- Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((4-methyl-6-oxo-2-propyl-5-((3- (3- (trifluoromethyl) benzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-67 3- (4 '-((4-methyl-6-oxo-2-propyl-5-((3- (4- (trifluoromethyl) benzyl) -1,2,4- Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((4-methyl-6-oxo-2-propyl-5-((3- (4- (trifluoromethyl) benzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-68 3- (4 '-((5-((3- (1- (4-fluorophenyl) cyclopropyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3- (1- (4-fluorophenyl) cyclopropyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin- Preparation of 1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-69 3- (4 '-((4-methyl-5-((3- (morpholinomethyl) -1,2,4-oxadiazol-5-yl) methyl) -6- Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((4 -methyl-5-((3- (morpholinomethyl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl Preparation of) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-70 3- (4 '-((4-methyl-6-oxo-5-((3- (1-phenylcyclobutyl) -1,2,4-oxadiazol-5-yl) Methyl) -2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 4-methyl-6-oxo-5-((3- (1-phenylcyclobutyl) -1,2,4-oxadiazol-5-yl) methyl) -2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-71 3- (4 '-((2-butyl-5-((3- (2,5-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl ) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((3- (2,5-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H)- Preparation of yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-72 3- (4 '-((2-butyl-5-((3- (2,6-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl ) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((3- (2,6-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H)- Preparation of yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-73 3- (4 '-((2-butyl-5-((3- (2-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-5-((3- (2-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-74 3- (4 '-((2-butyl-5-((3- (2,6-dichlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((2-butyl-5-((3- (2,6-dichlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-75 3- (4 '-((4-methyl-5-((3- (2-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl) -6- Oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((4 -methyl-5-((3- (2-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2 Preparation of -yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-76 3- (4 '-((5-((3- (2,3-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((5-((3- (2,3-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-77 3- (4 '-((5-((3- (2,6-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((5-((3- (2,6-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl Preparation of) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-78 3- (4 '-((5-((3- (3-chloro-5-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3- (3-chloro-5-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-79 3- (4 '-((5-((3- (4-bromobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -2-butyl-4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (5-((3- (4-bromobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -2-butyl-4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-80 3- (4 '-((2-butyl-5-((3- (3-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4- Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-5-((3- (3-chlorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-81 3- (4 '-((2-butyl-5-((3- (3,4-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl ) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((3- (3,4-difluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H)- Preparation of yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-82 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (4- (trifluoromethyl) benzyl) -1,2,4- Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (4- (trifluoromethyl) benzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-83 3- (4 '-((2-butyl-5-((3- (1- (4-fluorophenyl) cyclopropyl) -1,2,4-oxadiazol-5- Yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3 -(4 '-((2-butyl-5-((3- (1- (4-fluorophenyl) cyclopropyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin Preparation of -1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-84 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (1-phenylcyclobutyl) -1,2,4-oxadiazole- 5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-4-methyl-6-oxo-5-((3- (1-phenylcyclobutyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-85 3- (4 '-((4-methyl-6-oxo-2-propyl-5-((3- (2- (trifluoromethyl) benzyl) -1,2,4- Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((4-methyl-6-oxo-2-propyl-5-((3- (2- (trifluoromethyl) benzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-86 3- (4 '-((5-((3- (1- (3-fluorophenyl) cyclopropyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3- (1- (3-fluorophenyl) cyclopropyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin- 1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-87 3- (4 '-((5-((3- (2-chloro-4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3- (2-chloro-4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-88 3- (4 '-((4-methyl-6-oxo-2-propyl-5-((3- (3,4,5-trifluorobenzyl) -1,2,4 -Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((4-methyl-6-oxo-2-propyl-5-((3- (3,4,5-trifluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 Preparation of (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-89 3- (4 '-((2-butyl-4-methyl-5-((3- (morpholinomethyl) -1,2,4-oxadiazol-5-yl) methyl ) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-4-methyl-5-((3- (morpholinomethyl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2- Preparation of yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-90 3- (4 '-((2-butyl-4-methyl-5-((3- (3-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl ) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-4-methyl-5-((3- (3-methylbenzyl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl- Preparation of 2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-91 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (2,4,6-trifluorobenzyl) -1,2,4 -Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((2-butyl-4-methyl-6-oxo-5-((3- (2,4,6-trifluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 Preparation of (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-92 3- (4 '-((2-butyl-5-((3-cyclohexyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 5-((3-cyclohexyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example A-93 3- (4 '-((5-((3- (2-chloro-6-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3- (2-chloro-6-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-94 3- (4 '-((4-methyl-5-((3- (2-methylpentan-2-yl) -1,2,4-oxadiazol-5-yl) methyl l) -6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((4-methyl-5-((3- (2-methylpentan-2-yl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxo-2-propylpyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-95 3- (4 '-((2-butyl-5-((3- (3-chloro-5-fluorobenzyl) -1,2,4-oxadiazol-5-yl) Methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((2-butyl-5-((3- (3-chloro-5-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 ( Preparation of 6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-96 3- (4 '-((2-butyl-5-((3-cyclopropyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 5-((3-cyclopropyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example A-97 3- (4 '-((2-butyl-5-((3- (2-chloro-6-fluorobenzyl) -1,2,4-oxadiazol-5-yl) Methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((2-butyl-5-((3- (2-chloro-6-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 ( Preparation of 6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-98 3- (4 '-((2-butyl-5-((3- (2-chloro-4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) Methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((2-butyl-5-((3- (2-chloro-4-fluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 ( Preparation of 6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-99 3- (4 '-((2-butyl-4-methyl-5-((3- (2-methylpentan-2-yl) -1,2,4-oxadiazol-5) -Yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-4-methyl-5-((3- (2-methylpentan-2-yl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H Preparation of) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-100 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (3,4,5-trifluorobenzyl) -1,2,4 -Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((2-butyl-4-methyl-6-oxo-5-((3- (3,4,5-trifluorobenzyl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 Preparation of (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-101 3- (4 '-((5-((3- (1- (2-chlorophenyl) ethyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3- (1- (2-chlorophenyl) ethyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 ( Preparation of 6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-102 3- (4 '-((2-butyl-5-((3- (2-cyclohexylpropan-2-yl) -1,2,4-oxadiazol-5-yl) Methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((2-butyl-5-((3- (2-cyclohexylpropan-2-yl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 ( Preparation of 6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-103 3- (4 '-((2-butyl-5-((3- (2- (4-chloro-2-fluorophenyl) propan-2-yl) -1,2,4 -Oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazole- 5 (4H) -one 3- (4 '-((2-butyl-5-((3- (2- (4-chloro-2-fluorophenyl) propan-2-yl) -1,2,4-oxadiazol Preparation of -5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-104 3- (4 '-((2-butyl-5-((3- (2- (2-chloro-6-fluorophenyl) propan-2-yl) -1,2,4 -Oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazole- 5 (4H) -one 3- (4 '-((2-butyl-5-((3- (2- (2-chloro-6-fluorophenyl) propan-2-yl) -1,2,4-oxadiazol Preparation of -5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-105 3- (4 '-((2-butyl-5-((3- (3-methoxybenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (3-methoxybenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-106 3- (4 '-((2-butyl-5-((3- (2-methoxyphenyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (2-methoxyphenyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-107 3- (4 '-((2-butyl-5-((3- (2-methoxybenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (2-methoxybenzyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-108 3- (4 '-((2-butyl-4-methyl-5-((3- (naphthalen-2-yl) -1,2,4-oxadiazol-5-yl) Methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-4-methyl-5-((3- (naphthalen-2-yl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl Preparation of) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-109 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (tetrahydro-2H-pyran-4-yl) -1,2,4 -Oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- ( 4 '-((2-butyl-4-methyl-6-oxo-5-((3- (tetrahydro-2H-pyran-4-yl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin Preparation of -1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-110 3- (4 '-((2-butyl-5-((3- (1-ethylcyclopropyl) -1,2,4-oxadiazol-5-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((3- (1-ethylcyclopropyl) -1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-111 3- (4 '-((2-butyl-5-((3-cyclobutyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 5-((3-cyclobutyl-1,2,4-oxadiazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example A-112 3- (4 '-((5-((3- (bicyclo [2.2.1] heptan-2-yl) -1,2,4-oxadiazol-5-yl) methyl ) -2-butyl-4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((3- (bicyclo [2.2.1] heptan-2-yl) -1,2,4-oxadiazol-5-yl) methyl) -2-butyl-4-methyl Preparation of -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-113 3- (4 '-((2-butyl-4-methyl-5-((3- (1-methylcyclobutyl) -1,2,4-oxadiazol-5-yl) Methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-4-methyl-5-((3- (1-methylcyclobutyl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-114 3- (4 '-((2-butyl-4-methyl-5-((3- (naphthalen-1-yl) -1,2,4-oxadiazol-5-yl) Methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-4-methyl-5-((3- (naphthalen-1-yl) -1,2,4-oxadiazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl Preparation of) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example A-115 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((3- (quinolin-2-yl) -1,2,4-oxadiazole- 5-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-4-methyl-6-oxo-5-((3- (quinolin-2-yl) -1,2,4-oxadiazol-5-yl) methyl) pyrimidin-1 (6H) -yl) methyl Preparation of) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example B-1 3- (4 '-((2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6 Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl -5-((5-tert-butyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl)- Preparation of 1,2,4-oxadiazol-5 (4H) -one
  • Step 1 2- (2-butyl-4-methyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- (L) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) acetamide
  • 2- (2-butyl-4-methyl-6-oxo-1-((2 '-( Preparation of 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) acetamide
  • Step 2 2- (2-butyl-4-methyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- Yl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) acetonitrile 2- (2-butyl-4-methyl-6-oxo-1-((2'- Preparation of (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) acetonitrile
  • step 1 The compound prepared in step 1 (4.42 g) was dissolved in 25 mL of acetonitrile, and then POCl 3 (1.1 mL, 1.3 equiv) was added. The mixture was stirred at reflux for 18 hours and the resulting solid was removed by filtration. The filtrate was concentrated and dissolved in 50 mL of chloroform and washed with 50 ml of saturated NaHCO 3 . The aqueous layer was further extracted once with CHCl 3 (25 ml). The combined organic layers were washed with 20 ml of 1N HCl, dried over anhydrous MgSO 4 and filtered.
  • step 4 The compound prepared in step 4 (0.167 g) and K 2 CO 3 (0.107 g, 1.5 eq) were dissolved in 10 ml of toluene, followed by stirring under reflux for 3 hours.
  • the reaction mixture was concentrated under reduced pressure and purified by chromatography (silica, using 10% MeOH / CHCl 3 ) to afford 0.096 g (61% yield) of the title compound.
  • Examples B-2 to B-14 were synthesized using a carboxylic acid derivative compound corresponding to each Example in a similar manner to Example B-1.
  • Example B-2 3- (4 '-((2-butyl-4-methyl-5-((5- (1-methylcyclopropyl) -1,2,4-oxadiazol-3-yl) Methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-4-methyl-5-((5- (1-methylcyclopropyl) -1,2,4-oxadiazol-3-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example B-3 3- (4 '-((2-butyl-5-((5-cyclopropyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 5-((5-cyclopropyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example B-4 3- (4 '-((2-butyl-5-((5-isopropyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 5-((5-isopropyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example B-5 3- (4 '-((2-butyl-5-((5- (1- (4-chlorophenyl) cyclopropyl) -1,2,4-oxadiazol-3-yl ) Methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((5- (1- (4-chlorophenyl) cyclopropyl) -1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6-oxopyrimidin- Preparation of 1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example B-6 3- (4 '-((2-butyl-5-((5-cyclobutyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 5-((5-cyclobutyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example B-7 3- (4 '-((2-butyl-5-((5- (2-fluorophenyl) -1,2,4-oxadiazol-3-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((5- (2-fluorophenyl) -1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example B-8 3- (4 '-((2-butyl-5-((5- (2-fluorobenzyl) -1,2,4-oxadiazol-3-yl) methyl) -4 -Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (2-butyl-5-((5- (2-fluorobenzyl) -1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example B-9 4 '-((2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6-oxopy Rimidin-1 (6H) -yl) methyl) biphenyl-2-carboxylic acid 4 '-((2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl ) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-carboxylic acid
  • Example B-10 3-((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -2-butyl-5-((5-tert-butyl-1,2 , 4-oxadiazol-3-yl) methyl) -6-methylpyrimidin-4 (3H) -one (3-((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl Preparation of) -2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl) methyl) -6-methylpyrimidin-4 (3H) -one)
  • Example B-11 3-((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -2-butyl-5-((5- (2-fluorophenyl) -1,2,4-oxadiazol-3-yl) methyl) -6-methylpyrimidin-4 (3H) -one 3-((2 '-(1H-tetrazol-5-yl) biphenyl-4- Preparation of yl) methyl) -2-butyl-5-((5- (2-fluorophenyl) -1,2,4-oxadiazol-3-yl) methyl) -6-methylpyrimidin-4 (3H) -one
  • Example B-12 3-((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -2-butyl-5-((5- (4-methoxybenzyl) -1,2,4-oxadiazol-3-yl) methyl) -6-methylpyrimidin-4 (3H) -one 3-((2 '-(1H-tetrazol-5-yl) biphenyl-4- Preparation of yl) methyl) -2-butyl-5-((5- (4-methoxybenzyl) -1,2,4-oxadiazol-3-yl) methyl) -6-methylpyrimidin-4 (3H) -one
  • Example B-13 3-((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -2-butyl-5-((5- (4-chlorobenzyl)- 1,2,4-oxadiazol-3-yl) methyl) -6-methylpyrimidin-4 (3H) -one 3-((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl Preparation of) methyl) -2-butyl-5-((5- (4-chlorobenzyl) -1,2,4-oxadiazol-3-yl) methyl) -6-methylpyrimidin-4 (3H) -one
  • Example B-14 Methyl 4 ′-((2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl) methyl) -4-methyl-6-ox Sopyrimidin-1 (6H) -yl) methyl) biphenyl-2-carboxylate methyl 4 '-((2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3 Preparation of -yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-carboxylate
  • Example C-1 3- (4 '-((2-butyl-4-isopropyl-5-((5-methyl-1,3,4-oxadiazol-2-yl) methyl) -6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 4-isopropyl-5-((5-methyl-1,3,4-oxadiazol-2-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Step 1 2- (2-butyl-4-isopropyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3) -Yl) biphenyl-4-yl) methyl) -1,6-dihydropyridinin-5-yl) acetic acid 2- (2-butyl-4-isopropyl-6-oxo-1-((2 '-( Preparation of 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) acetic acid
  • Step 2 N'-acetyl-2- (2-butyl-4-isopropyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4- Oxadiazol-3-yl) biphenyl-4-yl) methyl) -1,6-dihydropyridinmin-5-yl) acetohydrazide N'-acetyl-2- (2-butyl-4-isopropyl -6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin- Preparation of 5-yl) acetohydrazide
  • Step 3 3- (4 ′-((2-butyl-4-isopropyl-5-((5-methyl-1,3,4-oxadiazol-2-yl) methyl) -6-oxopy Rimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-4- isopropyl-5-((5-methyl-1,3,4-oxadiazol-2-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4 Preparation of -oxadiazol-5 (4H) -one
  • step 2 The compound prepared in step 2 (0.02 g) was dissolved in 3 mL of toluene, and then POCl 3 (0.1 mL) was added dropwise. After stirring for 10 minutes at room temperature, the mixture was heated and stirred at 80 ° C. for 4 hours. 10 mL of ice water was added dropwise and diluted with 20 mL of ethyl acetate. After warming to room temperature, the mixture was washed with a saturated aqueous NaHCO 3 solution. The organic layer was dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. Purification by chromatography (99: 3 chloroform / methylalcohol) gave 8.5 mg (yield: 43%) of the title compound as an off-white solid.
  • Example C-2 to C-6 were synthesized using a hydrazide derivative compound corresponding to each Example in a similar manner to Example C-1.
  • Example C-2 3- (4 '-((2-butyl-4-isopropyl-5-((5- (4-methoxyphenyl) -1,3,4-oxadiazol-2-yl ) Methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((2-butyl-4-isopropyl-5-((5- (4-methoxyphenyl) -1,3,4-oxadiazol-2-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) Preparation of biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example C-3 3- (4 '-((2-butyl-4-isopropyl-5-((5- (3-methoxyphenyl) -1,3,4-oxadiazol-2-yl ) Methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((2-butyl-4-isopropyl-5-((5- (3-methoxyphenyl) -1,3,4-oxadiazol-2-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) Preparation of biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example C-4 3- (4 '-((2-butyl-5-((5-hydroxy-1,3,4-oxadiazol-2-yl) methyl) -4-isopropyl-6 Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl -5-((5-hydroxy-1,3,4-oxadiazol-2-yl) methyl) -4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1, Preparation of 2,4-oxadiazol-5 (4H) -one
  • Example C-5 3- (4 '-((2-butyl-5-((5- (dimethylamino) -1,3,4-oxadiazol-2-yl) methyl) -4-iso Propyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-5-((5- (dimethylamino) -1,3,4-oxadiazol-2-yl) methyl) -4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2- Preparation of yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example C-6 3- (4 '-((2-butyl-4-isopropyl-6-oxo-5-((5- (pyrrolidin-1-yl) -1,3,4-oxa Diazol-2-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((2-butyl-4-isopropyl-6-oxo-5-((5- (pyrrolidin-1-yl) -1,3,4-oxadiazol-2-yl) methyl) pyrimidin-1 (6H)- Preparation of yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example D-1 3- (4 '-((2-butyl-4-methyl-6-oxo-5-((5-phenyloxazol-2-yl) methyl) pyrimidine-1 (6H)- Yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-4-methyl-6-oxo-5- Of ((5-phenyloxazol-2-yl) methyl) pyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one Produce
  • step 1 The compound prepared in step 1 (0.095 g) was dissolved in 10 ml of acetonitrile, and then POCl 3 (0.03 ml, 2 eq) was added dropwise and stirred under reflux for 18 hours.
  • the reaction solution was concentrated under reduced pressure and dissolved in 25 ml of CHCl 3 . After washing with 25 ml of purified water, it was washed with 10 ml of saturated NaHCO 3 aqueous solution.
  • the organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The remaining organics were purified with silica and 5% MeOH / CHCl 3 to afford 0.060 g (yield: 65%) of the title compound.
  • Example D-2 3- (4 '-((5- (benzo [d] oxazol-2-ylmethyl) -2-butyl-4-isopropyl-6-oxopyrimidine-1 (6H) -Yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5- (benzo [d] oxazol-2-ylmethyl) Preparation of -2-butyl-4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example D-2 The compound of Example D-2 was synthesized using 1-aminophenol instead of 2-amino-1-phenylethanone in a similar manner to Example D-1.
  • Example D-3 3- (4 '-((5-((5-benzylisoxazol-3-yl) methyl) -2-butyl-4-methyl-6-oxopyrimidine-1 (6H) -Yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-((5-benzylisoxazol-3-yl) methyl ) -2-butyl-4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Flask 2- (2-butyl-4-methyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) acetic acid 5 g (10.5 mmol), (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexa 5.6 g (12.6 mmol) of fluorophosphate (BOP) was added, followed by the addition of 20 ml of methylene chloride, 4.4 ml (31.5 mmol) of triethylamine and 670 mg (11.0 mmol) of N, O-dimethylhydroxylamine, followed by mixture.
  • BOP fluorophosphate
  • Step 2 2- (2-butyl-4-methyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- Yl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) acetaldehyde 2- (2-butyl-4-methyl-6-oxo-1-((2 '-( Preparation of 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) acetaldehyde
  • Step 4 (Z) -2- (2-butyl-4-methyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadia) Zol-3-yl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) -N-hydroxyacetimidoyl chloride (Z) -2- (2-butyl-4 -methyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) -1,6- Preparation of dihydropyrimidin-5-yl) -N-hydroxyacetimidoyl chloride
  • Example D-4 3- (4 '-((2-butyl-5-((5-tert-butylisoxazol-3-yl) methyl) -4-methyl-6-oxopyrimidine-1 ( 6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5-((5-tert Preparation of -butylisoxazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example D-4 The compound of Example D-4 was synthesized using 3,3-dimethyl-1-butyne instead of 3-phenyl-1-propyne in a similar manner to Example D-3.
  • Example D-5 3- (4 '-((2-butyl-5-((5- (2-hydroxypropan-2-yl) isoxazol-3-yl) methyl) -4-methyl- 6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yll) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2 -butyl-5-((5- (2-hydroxypropan-2-yl) isoxazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) Preparation of -1,2,4-oxadiazol-5 (4H) -one
  • Example D-5 The compound of Example D-5 was synthesized using 2-methyl-3-butyn-2-ol instead of 3-phenyl-1-propyne in a similar manner to Example D-3.
  • Example D-6 3- (4 '-((2-butyl-5-((5- (1-hydroxyethyl) isoxazol-3-yl) methyl) -4-methyl-6-oxopy Rimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl-5- ((5- (1-hydroxyethyl) isoxazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol- Preparation of 5 (4H) -one
  • Example D-6 The compound of Example D-6 was synthesized using 3-butyn-2-ol instead of 3-phenyl-1-propyne in a similar manner to Example D-3.
  • Example E-1 3- (4 '-((2-butyl-4-methyl-5-((5-methyl-1,3,4-thiadiazol-2-yl) methyl) -6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 4-methyl-5-((5-methyl-1,3,4-thiadiazol-2-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example E-12 The compounds of Examples E-2 to E-12 were synthesized from the starting materials and the hydrazide derivatives corresponding to each Example in a similar manner to Example E-1.
  • Example E-2 3- (4 '-((2-butyl-5-((5-ethyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl-6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 5-((5-ethyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example E-3 3- (4 '-((2-butyl-5-((5-isopropyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl-6 Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl -5-((5-isopropyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1, Preparation of 2,4-oxadiazol-5 (4H) -one
  • Example E-4 3- (4 '-((2-butyl-5-((5-tert-butyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl- 6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2- butyl-5-((5-tert-butyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) Preparation of -1,2,4-oxadiazol-5 (4H) -one
  • Example E-5 3- (4 '-((4-methyl-5-((5- (1-methylcyclopropyl) -1,3,4-thiadiazol-2-yl) methyl)- 6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-( (4-methyl-5-((5- (1-methylcyclopropyl) -1,3,4-thiadiazol-2-yl) methyl) -6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl Preparation of -2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example E-6 3- (4 '-((5-((5-cyclopropyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl-6-oxo-2 -Propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5-(( 5-cyclopropyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2 Preparation of, 4-oxadiazol-5 (4H) -one
  • Example E-7 3- (4 '-((5-((5-tert-butyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl-6-oxo- 2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((5- ( (5-tert-butyl-1,3,4-thiadiazol-2-yl) methyl) -4-methyl-6-oxo-2-propylpyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl)- Preparation of 1,2,4-oxadiazol-5 (4H) -one
  • Example E-8 3- (4 '-((2-butyl-5-((5-tert-butyl-1,3,4-thiadiazol-2-yl) methyl) -4-isopropyl -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2 -butyl-5-((5-tert-butyl-1,3,4-thiadiazol-2-yl) methyl) -4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl Preparation of) -1,2,4-oxadiazol-5 (4H) -one
  • Example E-9 3- (4 '-((2-butyl-5-((5- (3-fluorophenyl) -1,3,4-thiadiazol-2-yl) methyl)- 4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 ' -((2-butyl-5-((5- (3-fluorophenyl) -1,3,4-thiadiazol-2-yl) methyl) -4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl Preparation of) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example E-10 3- (4 '-((2-butyl-4-isopropyl-5-((5-methyl-1,3,4-thiadiazol-2-yl) methyl) -6 Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl -4-isopropyl-5-((5-methyl-1,3,4-thiadiazol-2-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1, Preparation of 2,4-oxadiazol-5 (4H) -one
  • Example E-11 3- (4 '-((2-butyl-5-((5-ethyl-1,3,4-thiadiazol-2-yl) methyl) -4-isopropyl-6 Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl -5-((5-ethyl-1,3,4-thiadiazol-2-yl) methyl) -4-isopropyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1, Preparation of 2,4-oxadiazol-5 (4H) -one
  • Example E-12 3- (4 '-((2-butyl-4-isopropyl-5-((5-isopropyl-1,3,4-thiadiazol-2-yl) methyl)- 6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2- butyl-4-isopropyl-5-((5-isopropyl-1,3,4-thiadiazol-2-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1 Preparation of 2,4-oxadiazol-5 (4H) -one
  • Example F-1 3- (4 '-((2-butyl-5-((5- (4-fluorophenyl) -4H-1,2,4-triazol-3-yl) methyl)- 4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((2-butyl-5-((5- (4-fluorophenyl) -4H-1,2,4-triazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) Preparation of methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example F-2 3- (4 '-((2-butyl-5-((5- (2-fluorophenyl) -4H-1,2,4-triazol-3-yl) methyl)- 4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((2-butyl-5-((5- (2-fluorophenyl) -4H-1,2,4-triazol-3-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) Preparation of methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example F-3 3- (4 '-((2-butyl-4-methyl-5-((3-methyl-1H-1,2,4-triazol-5-yl) methyl) -6- Oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-((2-butyl- 4-methyl-5-((3-methyl-1H-1,2,4-triazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1 Preparation of 2,4-oxadiazol-5 (4H) -one
  • Example F-4 3- (4 '-((2-butyl-4-methyl-5-((3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl) methyl ) -6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-4-methyl-5-((3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl) methyl) -6-oxopyrimidin-1 (6H) -yl) methyl) Preparation of biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • the title compound was prepared in a similar manner to Example F-3 using phenylhydrazine instead of hydrazine.
  • Example F-5 3- (4 '-((2-butyl-5-((1-butyl-3-methyl-1H-1,2,4-triazol-5-yl) methyl) -4- Methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4 '-(( 2-butyl-5-((1-butyl-3-methyl-1H-1,2,4-triazol-5-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) Preparation of biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Example F-6 3- (4 '-((2-butyl-5-((1- (4-fluorobenzyl) -1H-1,2,3-triazol-4-yl) methyl)- 4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((2-butyl-5-((1- (4-fluorobenzyl) -1H-1,2,3-triazol-4-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) Preparation of methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Step 1 (4-((2-butyl-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl) methyl) -1H-1,2,3-triazole-1- Yl) methyl pivalate (4-((2-butyl-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl manufacture of pivalate
  • Step 2 (4-((2-butyl-1-((2'-cyanobiphenyl-4-yl) methyl) -4-methyl-6-oxo-1,6-dihydropyrimidine-5- Yl) methyl) -1H-1,2,3-triazol-1-yl) methyl pivalate (4-((2-butyl-1-((2'-cyanobiphenyl-4-yl) methyl) -4- Preparation of methyl-6-oxo-1,6-dihydropyrimidin-5-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl pivalate
  • Step 3 (Z)-(4-((2-butyl-1-((2 '-(N'-hydroxycarbamidoyl) biphenyl-4-yl) methyl) -4-methyl-6 -Oxo-1,6-dihydropyrimidin-5-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl pivalate (Z)-(4-((2-butyl- 1-((2 '-(N'-hydroxycarbamimidoyl) biphenyl-4-yl) methyl) -4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl) methyl) -1H-1,2,3 Preparation of -triazol-1-yl) methyl pivalate
  • Step 4 (Z)-(4-((2-butyl-4-methyl-6-oxo-1-((2 '-(N'-(phenoxycarbonyloxy) carbamimidoyl) biphenyl-4-yl) methyl)- 1,6-dihydropyrimidin-5-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl pivalate (Z)-(4-((2-butyl-4-methyl-6-oxo- 1-((2 '-(N'-(phenoxycarbonyloxy) carbamimidoyl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) methyl) -1H-1,2,3-triazol-1- Preparation of yl) methyl pivalate
  • Step 5 (4-((2-butyl-4-methyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-) 3-yl) biphenyl-4-yl) methyl) -1,6-dihydropyrimidin-5-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl pivalate (4 -((2-butyl-4-methyl-6-oxo-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl Preparation of) methyl) -1,6-dihydropyrimidin-5-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl pivalate
  • Example F-7 3- (4 '-((2-butyl-5-((1- (2-fluorobenzyl) -1H-1,2,3-triazol-4-yl) methyl)- 4-methyl-6-oxopyrimidin-1 (6H) -yl) methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one 3- (4'- ((2-butyl-5-((1- (2-fluorobenzyl) -1H-1,2,3-triazol-4-yl) methyl) -4-methyl-6-oxopyrimidin-1 (6H) -yl) Preparation of methyl) biphenyl-2-yl) -1,2,4-oxadiazol-5 (4H) -one
  • Cos-7 Fibroblast-like cell line derived from monkey kidney tissue
  • the cells were seeded in 3 x 10 4 cells / 250 ⁇ L / well in a 48 well plate and incubated for 24 hours at 37 °C, 5% CO 2 .
  • the hemihydrate activity concentration (EC 50 ) and the maximum activity (A max ) were measured by the following method.
  • CCM Cell Recovery Medium
  • CSM Compound Screening Medium

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Abstract

본 발명은 피리미디논 유도체, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염을 제공한다. 본 발명의 화합물은 고혈압 및/또는 당뇨병의 치료, 예방 또는 개선 활성을 나타낸다

Description

피리미디논 유도체 화합물 및 이의 용도
본 발명은 피리미디논 유도체 화합물 및 이의 용도에 관한 것이다.
고혈압은 만성 질환으로 아직까지 원인이 밝혀지지 않은 본태성 고혈압(1차성 고혈압)이 전체 환자의 90 %를 차지하며, 고혈압 상태가 지속될 경우 심장마비, 뇌졸중 등의 치명적인 질환이 발생할 가능성이 증가한다. 특히, 대사성 질환의 하나인 당뇨가 동반되는 경우 그 치명성은 수배가 증가하게 된다.
안지오텐신 I으로부터 안지오텐신 전환 효소에 의해 생성되는 안지오텐신 II는 세포막 단백질로서 혈관 세포벽에 존재하는 안지오텐신 II 수용체를 통해 혈압을 증가시킨다는 사실이 알려져 있다. 따라서, 안지오텐신 II 길항제는 안지오텐신에 의해 발생되는 고혈압을 치료하는데 사용되었다. 지금까지, 경구 투여 안지오텐신 II 길항제로서 개발된 약물로, 로사르탄(losartan), 칸데사르탄 실레세틸(candesartan cilexetil), 올메사르탄 메독소밀(olmesartan medoxomil), 텔미사르탄(telmisartan), 피마사르탄(fimasartan) 등이 알려져 있다.
한편, 당뇨병은 혈중 혈당 조절에 문제가 발생하며, 이로 인해 신장 질환, 혈관 질환 등이 발생하고 욕창, 실명, 신부전 등으로 진행하여 심한 경우 생명을 위협하는 질환이다.
TZD(티아졸리딘디온)로 알려진 약물군은 PPARγ를 타겟으로 하며, 혈당 조절 이상 환자에 대해 인슐린에 대한 저항성을 완화시킴으로서 혈당 조절 능력을 회복시켜 주는 약물이다. 이러한 TZD 계열의 약물은 핵 수용체인 PPARγ를 활성화시키는데, 이로 인해 지방대사, 당대사 등 다양한 유전자의 발현이 증가하게 된다고 알려져 있다. 이로 인해 의도하지 않게 부종이나 비만 등이 부작용으로 나타나며, 이러한 부작용을 줄이고 인슐린 내성 극복이라는 약리 효과만을 얻기 위해 부분 활성화제, 선택적 조절제 등의 개발이 시도되어 왔다.
고혈압과 당뇨가 동반되는 환자군을 치료하기 위하여, 고혈압과 당뇨를 동시에 치료할 수 있는 치료제의 개발이 진행된 적이 있으나, 실제 약물 개발까지 이루어지지는 못하였다. 이에 본 발명자들은 고혈압 치료와 함께 인슐린 저항성을 조절하는 약물을 개발하고자 하였다.
본 발명은 고혈압 및/또는 당뇨병의 치료 활성을 나타내는 피리미디논 유도체 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염을 제공하고자 한다.
또한, 본 발명은 본 발명의 피리미디논 유도체 화합물의 제조방법을 제공하고자 한다.
또한, 본 발명은 본 발명의 피리미디논 유도체 화합물의 용도를 제공하고자 한다.
본 발명자들은 고혈압 및/또는 당뇨병의 치료 활성을 나타내는 피리미디논 유도체 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염을 발견하고 본 발명을 완성하였다.
화학식 I의 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염
상기 목적에 따라 본 발명에서는, 하기 화학식 I 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염을 제공한다:
[화학식 I]
Figure PCTKR2019008609-appb-img-000001
상기 화학식 I 에서,
X 는
Figure PCTKR2019008609-appb-img-000002
또는
Figure PCTKR2019008609-appb-img-000003
이고 {여기서, X 가
Figure PCTKR2019008609-appb-img-000004
이면 L 2 및 Y 는 아무 것도 아님 (null)},
X 1 은 N, O, S, CR 3 또는 NR 4 이고,
X 2 는 N, O, S 또는 NR 4 이고,
X 3 는 N, O, S 또는 CR 3 이고,
X 4 는 C 또는 N 이고,
X 5 는 O 또는 S 이고,
X 6 는 N 이고,
Y 는 H, C 1-C 6 알킬, NR 5R 6, OR 7, C 3-C 7 시클로알킬, C 5-C 10 스파이로 고리, C 5-C 10 바이사이클릭 고리, 4-7원 헤테로시클로알킬, 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 C 1-C 6 알킬, NR 5R 6, OR 7, 할로 또는 C 1-C 6 할로알킬로 치환될 수 있음},
Z 는
Figure PCTKR2019008609-appb-img-000005
,
Figure PCTKR2019008609-appb-img-000006
또는 -(C=O)O-R 8 이고,
R a1, R a2, R b1 및 R b2 는 각각 독립적으로 H, 할로, C 1-C 6 알킬 또는 C 1-C 6 할로알킬이고,
R 1 및 R 2 는 각각 독립적으로 H, C 1-C 6 알킬, C 2-C 6 알케닐, C 2-C 6 알키닐 또는 C 3-C 7 시클로알킬이고,
R 3 및 R 4 는 각각 독립적으로 H, C 1-C 6 알킬 또는 아릴이고,
R 5 내지 R 8 은 각각 독립적으로 H 또는 C 1-C 6 알킬이고,
L 1 은 -(CH 2) m- 이고 여기서, 상기 -(CH 2) m- 의 하나 이상의 H 는 중수소로 치환될 수 있음,
L 2 는 -(CH 2) n- 또는
Figure PCTKR2019008609-appb-img-000007
이고 {여기서, 상기 -(CH 2) n- 및
Figure PCTKR2019008609-appb-img-000008
의 하나 이상의 H 는 C 1-C 6 알킬로 치환될 수 있음},
m 및 n 은 각각 독립적으로 0, 1, 2 또는 3 이고,
p 는 1, 2, 3 또는 4 이다.
또한, 본 발명의 일 구체예에 따르면, 상기 화학식 I 로 표시되는 화합물은,
X 는
Figure PCTKR2019008609-appb-img-000009
또는
Figure PCTKR2019008609-appb-img-000010
이고 {여기서, X 가
Figure PCTKR2019008609-appb-img-000011
이면 L 2 및 Y 는 아무 것도 아님 (null)},
X 1 은 N, O, S, CR 3 또는 NR 4 이고,
X 2 는 N, O 또는 NR 4 이고,
X 3 는 N, O 또는 CR 3 이고,
X 4 는 C 또는 N 이고,
X 5 는 O 이고,
X 6 는 N 이고,
Y 는 C 1-C 4 알킬, NR 5R 6, OR 7, C 3-C 6 시클로알킬, C 5-C 10 스파이로 고리, C 5-C 10 바이사이클릭 고리, 4-6원 헤테로시클로알킬, 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 C 1-C 4 알킬, OR 7, 할로 또는 C 1-C 4 할로알킬로 치환될 수 있음},
Z 는
Figure PCTKR2019008609-appb-img-000012
,
Figure PCTKR2019008609-appb-img-000013
또는 -(C=O)O-R 8 이고,
R a1, R a2, R b1 및 R b2 는 각각 독립적으로 H 또는 C 1-C 4 알킬이고,
R 1 및 R 2 는 각각 독립적으로 C 1-C 4 알킬이고,
R 3 및 R 4 는 각각 독립적으로 H, C 1- C 4 알킬 또는 아릴이고,
R 5 내지 R 8 은 각각 독립적으로 H 또는 C 1- C 4 알킬이고,
L 1 은 -(CH 2) m- 이고 {여기서, 상기 -(CH 2) m- 의 하나 이상의 H 는 중수소로 치환될 수 있음},
L 2 는 -(CH 2) n- 또는
Figure PCTKR2019008609-appb-img-000014
이고 {여기서, 상기 -(CH 2) n- 및
Figure PCTKR2019008609-appb-img-000015
의 하나 이상의 H 는 C 1-C 4 알킬로 치환될 수 있음},
m 및 n 은 각각 독립적으로 0, 1 또는 2 이고,
p 는 1 또는 2 이다.
X 는
Figure PCTKR2019008609-appb-img-000016
,
Figure PCTKR2019008609-appb-img-000017
,
Figure PCTKR2019008609-appb-img-000018
,
Figure PCTKR2019008609-appb-img-000019
,
Figure PCTKR2019008609-appb-img-000020
,
Figure PCTKR2019008609-appb-img-000021
,
Figure PCTKR2019008609-appb-img-000022
,
Figure PCTKR2019008609-appb-img-000023
,
Figure PCTKR2019008609-appb-img-000024
또는
Figure PCTKR2019008609-appb-img-000025
이고 {여기서, X 가
Figure PCTKR2019008609-appb-img-000026
이면 L 2 및 Y 는 아무 것도 아님 (null)},
Y 는 C 1-C 4 알킬, NR 5R 6, OR 7, C 3-C 6 시클로알킬, C 5-C 10 스파이로 고리, C 5-C 10 바이사이클릭 고리, 피페리디닐, 몰폴리닐, 테트라하이드로피라닐, 페닐, 나프탈레닐, 피리디닐 또는 퀴놀리닐이고 {여기서, 상기 페닐, 나프탈레닐, 피리디닐 또는 퀴놀리닐의 하나 이상의 H는 C 1-C 4 알킬, OR 7, F, Cl, Br 또는 CF 3로 치환될 수 있음},
Z 는
Figure PCTKR2019008609-appb-img-000027
,
Figure PCTKR2019008609-appb-img-000028
또는 -(C=O)O-R 8 이고,
R 1 및 R 2 는 각각 독립적으로 C 1-C 4 알킬이고,
R 3 및 R 4 는 각각 독립적으로 H, C 1-C 4 알킬 또는 아릴이고,
R 5 내지 R 8 은 각각 독립적으로 H 또는 C 1-C 4 알킬이고,
L 1 은 -(CH 2) m- 이고 {여기서, 상기 -(CH 2) m- 의 하나 이상의 H 는 중수소로 치환될 수 있음},
L 2 는 -(CH 2) n- 또는
Figure PCTKR2019008609-appb-img-000029
이고 {여기서, 상기 -(CH 2) n- 및
Figure PCTKR2019008609-appb-img-000030
의 하나 이상의 H 는 C 1-C 4 알킬로 치환될 수 있음},
m 및 n 은 각각 독립적으로 0, 1 또는 2 이고,
p 는 1 또는 2 이다.
또한, 본 발명의 구체예에 따르면, 상기 화학식 I 로 표시되는 화합물은, 하기 화합물들로 이루어진 군으로부터 선택된 어느 하나인 화학식 I 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염일 수 있다:
1) 3-(4'-((2-부틸-5-((3-(2-플루오로페닐)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
2) 3-(4'-((2-부틸-5-((3-사이클로프로필-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
3) 3-(4'-((2-부틸-5-((3-사이클로프로필-1,2,4-옥소다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
4) 3-(4'-((2-부틸-5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
5) 3-(4'-((2-부틸-5-((3-(메톡시메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
6) 3-(4'-((2-부틸-5-((3-(2-메톡시에틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-yl)-1,2,4-옥사다이아졸-5(4H)-온;
7) 3-(4'-((2-부틸-5-((3-이소프로필-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
8) 3-(4'-((2-부틸-5-((3-(다이메틸아미노)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
9) 3-(4'-((2-부틸-5-((3-((다이메틸아미노)메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
10) 3-(4'-((2-부틸-5-((3-(다이에틸아미노)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
11) 3-(4'-((2-부틸-5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
12) 3-(4'-((2-부틸-5-((3-(2-메톡시프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
13) 3-(4'-((2-부틸-4-이소프로필-5-((3-메틸-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
14) 3-(4'-((2-부틸-4-메틸-5-((3-메틸-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
15) 3-(4'-((5-((3-벤질-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
16) 3-(4'-((2-부틸-5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
17) 3-(4'-((5-((3-벤질-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
18) 3-(4'-((2-부틸-5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
19) 3-(4'-((2-부틸-4-메틸-5-((3-(1-메틸사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
20) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(스파이로[2.2]펜탄-1-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
21) 3-(4'-((2-부틸-5-((3-(이소프로폭시메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
22) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(1-페닐사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
23) 3-(4'-((2-부틸-5-((3-(3-클로로피리딘-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
24) 3-(4'-((2-부틸-5-((3-(2-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
25) 3-(4'-((2-부틸-5-((3-(2-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
26) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(2-페닐프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
27) 3-(4'-((2-부틸-5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸-d2)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
28) 3-(4'-((2-부틸-5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸-d2)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
29) 3-(4'-((2-부틸-4-메틸-5-((3-(4-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
30) 3-(4'-((2-부틸-5-((3-(4-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
31) 3-(4'-((2-부틸-5-((3-(4-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
32) 3-(4'-((2-부틸-5-((3-(3-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
33) 3-(4'-((2-부틸-5-((3-(3,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
34) 3-(4'-((5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
35) 3-(4'-((5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
36) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(피페리딘-1-일메틸)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
37) 3-(4'-((4-메틸-5-((3-(4-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
38) 3-(4'-((5-((3-(4-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
39) 3-(4'-((5-((3-(4-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
40) 3-(4'-((5-((3-(3-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
41) 3-(4'-((5-((3-(3,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
42) 3-(4'-((5-((3-(2,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
43) 3-(4'-((5-((3-사이클로펜틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
44) 3-(4'-((5-((3-(사이클로펜틸메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
45) 3-(4'-((5-((3-(사이클로헥실메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
46) 3-(4'-((2-부틸-5-((3-(2,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
47) 3-(4'-((2-부틸-5-((3-(사이클로헥실메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-yl)-1,2,4-옥사다이아졸-5(4H)-온;
48) 3-(4'-((2-부틸-5-((3-(사이클로펜틸메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
49) 3-(4'-((2-부틸-5-((3-사이클로펜틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
50) 3-(4'-((5-((3-(사이클로프로필메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
51) 3-(4'-((5-((3-(2-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
52) 3-(4'-((5-((3-(3,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
53) 3-(4'-((5-((3-(2,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
54) 3-(4'-((5-((3-(2-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
55) 3-(4'-((5-((3-(4-브로모벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
56) 3-(4'-((5-((3-(3-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
57) 3-(4'-((5-((3-(2,6-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
58) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(2,4,6-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
59) 3-(4'-((4-메틸-6-옥소-5-((3-(피페리딘-1-일)-1,2,4-옥사다이아졸-5-일)메틸)-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
60) 3-(4'-((5-((3-사이클로헥실-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
61) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(2-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
62) 3-(4'-((2-부틸-4-메틸-5-((3-(2-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
63) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(3-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
64) 3-(4'-((2-부틸-5-((3-(2,3-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
65) 3-(4'-((4-메틸-6-옥소-5-((3-(피페리딘-1-일메틸)-1,2,4-옥사다이아졸-5-일)메틸)-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
66) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(3-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
67) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(4-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
68) 3-(4'-((5-((3-(1-(4-플루오로페닐)사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
69) 3-(4'-((4-메틸-5-((3-(몰폴리노메틸)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
70) 3-(4'-((4-메틸-6-옥소-5-((3-(1-페닐사이클로부틸)-1,2,4-옥사다이아졸-5-일)메틸)-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
71) 3-(4'-((2-부틸-5-((3-(2,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
72) 3-(4'-((2-부틸-5-((3-(2,6-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
73) 3-(4'-((2-부틸-5-((3-(2-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
74) 3-(4'-((2-부틸-5-((3-(2,6-다이클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
75) 3-(4'-((4-메틸-5-((3-(2-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
76) 3-(4'-((5-((3-(2,3-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
77) 3-(4'-((5-((3-(2,6-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
78) 3-(4'-((5-((3-(3-클로로-5-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
79) 3-(4'-((5-((3-(4-브로모벤질)-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
80) 3-(4'-((2-부틸-5-((3-(3-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
81) 3-(4'-((2-부틸-5-((3-(3,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
82) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(4-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
83) 3-(4'-((2-부틸-5-((3-(1-(4-플루오로페닐)사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
84) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(1-페닐사이클로부틸)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
85) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(2-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
86) 3-(4'-((5-((3-(1-(3-플루오로페닐)사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
87) 3-(4'-((5-((3-(2-클로로-4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
88) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(3,4,5-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
89) 3-(4'-((2-부틸-4-메틸-5-((3-(몰폴리노메틸)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
90) 3-(4'-((2-부틸-4-메틸-5-((3-(3-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
91) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(2,4,6-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
92) 3-(4'-((2-부틸-5-((3-사이클로헥실-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
93) 3-(4'-((5-((3-(2-클로로-6-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
94) 3-(4'-((4-메틸-5-((3-(2-메틸펜탄-2-일)-1,2,4-옥사다이아졸-5-일)메틸l)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
95) 3-(4'-((2-부틸-5-((3-(3-클로로-5-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
96) 3-(4'-((2-부틸-5-((3-사이클로프로필-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
97) 3-(4'-((2-부틸-5-((3-(2-클로로-6-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
98) 3-(4'-((2-부틸-5-((3-(2-클로로-4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
99) 3-(4'-((2-부틸-4-메틸-5-((3-(2-메틸펜탄-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
100) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(3,4,5-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
101) 3-(4'-((5-((3-(1-(2-클로로페닐)에틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
102) 3-(4'-((2-부틸-5-((3-(2-사이클로헥실프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
103) 3-(4'-((2-부틸-5-((3-(2-(4-클로로-2-플루오로페닐)프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
104) 3-(4'-((2-부틸-5-((3-(2-(2-클로로-6-플루오로페닐)프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
105) 3-(4'-((2-부틸-5-((3-(3-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
106) 3-(4'-((2-부틸-5-((3-(2-메톡시페닐)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
107) 3-(4'-((2-부틸-5-((3-(2-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
108) 3-(4'-((2-부틸-4-메틸-5-((3-(나프탈렌-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
109) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(테트라하이드로-2H-피란-4-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
110) 3-(4'-((2-부틸-5-((3-(1-에틸사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
111) 3-(4'-((2-부틸-5-((3-사이클로부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
112) 3-(4'-((5-((3-(바이사이클로[2.2.1]헵탄-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
113) 3-(4'-((2-부틸-4-메틸-5-((3-(1-메틸사이클로부틸)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
114) 3-(4'-((2-부틸-4-메틸-5-((3-(나프탈렌-1-일)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
115) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(퀴놀린-2-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
116) 3-(4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
117) 3-(4'-((2-부틸-4-메틸-5-((5-(1-메틸사이클로프로필)-1,2,4-옥사다이아졸-3-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
118) 3-(4'-((2-부틸-5-((5-사이클로프로필-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
119) 3-(4'-((2-부틸-5-((5-이소프로필-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
120) 3-(4'-((2-부틸-5-((5-(1-(4-클로로페닐)사이클로프로필)-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
121) 3-(4'-((2-부틸-5-((5-사이클로부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
122) 3-(4'-((2-부틸-5-((5-(2-플루오로페닐)-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
123) 3-(4'-((2-부틸-5-((5-(2-플루오로벤질)-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
124) 4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-카르복실산;
125) 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온;
126) 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-(2-플루오로페닐)-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온;
127) 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-(4-메톡시벤질)-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온;
128) 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-(4-클로로벤질)-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온;
129) 메틸 4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-카르복실레이트;
130) 3-(4'-((2-부틸-4-이소프로필-5-((5-메틸-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
131) 3-(4'-((2-부틸-4-이소프로필-5-((5-(4-메톡시페닐)-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
132) 3-(4'-((2-부틸-4-이소프로필-5-((5-(3-메톡시페닐)-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
133) 3-(4'-((2-부틸-5-((5-하이드록시-1,3,4-옥사다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
134) 3-(4'-((2-부틸-5-((5-(다이메틸아미노)-1,3,4-옥사다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
135) 3-(4'-((2-부틸-4-이소프로필-6-옥소-5-((5-(피롤리딘-1-일)-1,3,4-옥사다이아졸-2-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
136) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((5-페닐옥사졸-2-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
137) 3-(4'-((5-(벤조[d]옥사졸-2-일메틸)-2-부틸-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
138) 3-(4'-((5-((5-벤질이소옥사졸-3-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
139) 3-(4'-((2-부틸-5-((5-터트-부틸이소옥사졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
140) 3-(4'-((2-부틸-5-((5-(2-하이드록시프로판-2-일)이소옥사졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일l)-1,2,4-옥사다이아졸-5(4H)-온;
141) 3-(4'-((2-부틸-5-((5-(1-하이드록시에틸)이소옥사졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
142) 3-(4'-((2-부틸-4-메틸-5-((5-메틸-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
143) 3-(4'-((2-부틸-5-((5-에틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
144) 3-(4'-((2-부틸-5-((5-이소프로필-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
145) 3-(4'-((2-부틸-5-((5-터트-부틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
146) 3-(4'-((4-메틸-5-((5-(1-메틸사이클로프로필)-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
147) 3-(4'-((5-((5-사이클로프로필-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
148) 3-(4'-((5-((5-터트-부틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
149) 3-(4'-((2-부틸-5-((5-터트-부틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
150) 3-(4'-((2-부틸-5-((5-(3-플루오로페닐)-1,3,4-싸이아다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
151) 3-(4'-((2-부틸-4-이소프로필-5-((5-메틸-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
152) 3-(4'-((2-부틸-5-((5-에틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
153) 3-(4'-((2-부틸-4-이소프로필-5-((5-이소프로필-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
154) 3-(4'-((2-부틸-5-((5-(4-플루오로페닐)-4H-1,2,4-트리아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
155) 3-(4'-((2-부틸-5-((5-(2-플루오로페닐)-4H-1,2,4-트리아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
156) 3-(4'-((2-부틸-4-메틸-5-((3-메틸-1H-1,2,4-트리아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
157) 3-(4'-((2-부틸-4-메틸-5-((3-메틸-1-페닐-1H-1,2,4-트리아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
158) 3-(4'-((2-부틸-5-((1-부틸-3-메틸-1H-1,2,4-트리아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
159) 3-(4'-((2-부틸-5-((1-(4-플루오로벤질)-1H-1,2,3-트리아졸-4-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온; 및
160) 3-(4'-((2-부틸-5-((1-(2-플루오로벤질)-1H-1,2,3-트리아졸-4-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온.
본 발명에서, 약제학적으로 허용가능한 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 포타슘, 소듐 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산 및 황산 등으로 제조된 무기산염; 아세트산, 트라이플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산 등으로 제조된 유기산염; 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산 등으로 제조된 설폰산염; 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염; 및 트리메틸아민, 트라이에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다.
본 발명의 화학식 I 로 표시되는 화합물은 1 개 이상의 비대칭 탄소를 함유할 수 있으며, 이에 따라 라세미체, 라세믹 혼합물, 단일의 에난티오머, 부분입체이성체 혼합물 및 각각의 부분입체이성체로서 존재할 수 있다. 이러한 이성질체는 종래기술, 예를 들어 화학식 I 로 표시된 화합물은 관 크로마토그래피 또는 HPLC 등의 분할에 의해 분리가 가능하다. 또는, 화학식 I 로 표시되는 화합물 각각의 입체 이성질체는 공지된 배열의 광학적으로 순수한 출발 물질 및/또는 시약을 사용하여 입체 특이적으로 합성할 수 있다.
화학식 I 화합물의 제조방법
본 발명은 화학식 I 로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염의 제조방법을 제공한다.
본 발명에 있어서, 본 발명의 화학식 I 로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염은 하기 반응식 1의 경로에 따라 제조할 수 있다.
[반응식 1]
Figure PCTKR2019008609-appb-img-000031
구체적으로, 상업적으로 구입가능한 화학식 1의 화합물 및 화학식 2의 화합물을 출발물질로 하여 염기 조건 하에 중합 반응을 통하여 화학식 3의 화합물을 얻고, 이와 화학식 4의 아미딘 화합물의 고리형성 반응을 통해 화학식 5의 화합물을 얻는다. 이를 화학식 6의 화합물과 염기를 이용한 중합반응을 통해 화학식 7의 화합물을 얻고 이의 시아노기를 공지된 방법으로 옥사다이아졸론으로 변형하여 화학식 11의 화합물을 얻는다. 화학식 11의 화합물을 가수분해한 뒤 여러가지 옥심화합물, 아미딘화합물 또는 히드라진화합물 등과 반응하고 고리화 반응을 통하여 화학식 I의 화합물을 제조할 수 있다.
보다 구체적으로, 본 발명의 화학식 I 로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염은 하기 반응식 2 내지 9의 경로에 따라 제조할 수 있다.
[반응식 2]
Figure PCTKR2019008609-appb-img-000032
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Figure PCTKR2019008609-appb-img-000033
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Figure PCTKR2019008609-appb-img-000034
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Figure PCTKR2019008609-appb-img-000035
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Figure PCTKR2019008609-appb-img-000036
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Figure PCTKR2019008609-appb-img-000037
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Figure PCTKR2019008609-appb-img-000038
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Figure PCTKR2019008609-appb-img-000039
화학식 I 화합물을 포함하는 조성물, 이의 용도 및 이를 이용한 치료방법
본 발명은 하기 화학식 I 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 고혈압 또는 당뇨병의 치료 또는 예방용 약학적 조성물을 제공한다.
[화학식 I]
Figure PCTKR2019008609-appb-img-000040
상기 화학식 I 은 위에서 정의한 바와 같다.
본 발명에 있어서, 상기 고혈압은 본태성 고혈압일 수 있고, 상기 당뇨병은 제2형 당뇨병일 수 있다.
본 발명의 일 구체예에 따르면, 본 발명의 화합물은 고혈압 및 당뇨병 모두에 대하여 약리활성을 나타낸다. 따라서, 본 발명의 약학적 조성물은 고혈압 및 당뇨병을 동시에 치료 또는 예방하기 위하여 유용하게 사용될 수 있다.
본 발명의 약학적 조성물은 투여를 위해서 상기 화학식 I 로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염 외에 추가로 약제학적으로 허용가능한 담체를 1 종 이상 더 포함할 수 있다. 약제학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 따라서, 본 발명의 조성물은 패치제, 액제, 환약, 캡슐, 과립, 정제, 좌제 등일 수 있다. 이들 제제는 당 분야에서 제제화에 사용되는 통상의 방법 또는 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA 에 개시되어 있는 방법으로 제조될 수 있으며 각 질환에 따라 또는 성분에 따라 다양한 제제로 제제화될 수 있다.
본 발명의 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양하다. 본 발명의 화학식 I 로 표시되는 화합물의 일일 투여량은 약 1 내지 1000 ㎎/㎏ 이고, 바람직하게는 5 내지 100 ㎎/㎏ 이며, 하루 일회 내지 수회에 나누어 투여할 수 있다.
본 발명의 상기 약학적 조성물은 상기 화학식 I 로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상 더 포함할 수 있다.
본 발명은 상기 화학식 I 로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염의 치료학적으로 유효한 양을 인간을 포함하는 포유류에 투여하는 단계를 포함하는, 고혈압 또는 당뇨병을 치료하는 방법을 제공한다.
본 발명에 있어서, 상기 고혈압은 본태성 고혈압일 수 있고, 상기 당뇨병은 제2형 당뇨병일 수 있다.
또한, 본 발명의 상기 화학식 I 로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염의 치료학적으로 유효한 양을 인간을 포함하는 포유류에 투여하는 단계를 포함하는, 고혈압 또는 당뇨병을 치료하는 방법은 고혈압과 당뇨병을 동시에 치료할 수 있다.
본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 고혈압 또는 당뇨병의 치료에 유효한 상기 화학식 I 로 표시되는 화합물의 양을 나타낸다.
본 발명의 치료방법은 상기 화학식 I 로 표시되는 화합물을 투여함으로써, 징후의 발현 전에 질병 그 자체를 다룰 뿐만 아니라, 이의 징후를 저해하거나 피하는 것을 또한 포함한다. 질환의 관리에 있어서, 특정 활성 성분의 예방적 또는 치료학적 용량은 질병 또는 상태의 본성(nature)과 심각도, 그리고 활성 성분이 투여되는 경로에 따라 다양할 것이다. 용량 및 용량의 빈도는 개별 환자의 연령, 체중 및 반응에 따라 다양할 것이다. 적합한 용량 용법은 이러한 인자를 당연히 고려하는 이 분야의 통상의 지식을 가진 자에 의해 쉽게 선택될 수 있다. 또한, 본 발명의 치료방법은 상기 화학식 I 로 표시되는 화합물과 함께 질환 치료에 도움이 되는 추가적인 활성 제제의 치료학적으로 유효한 양의 투여를 더 포함할 수 있으며, 추가적인 활성제제는 상기 화학식 I 의 화합물과 함께 시너지 효과 또는 보조적 효과를 나타낼 수 있다.
본 발명은 또한 고혈압 또는 당뇨병의 치료용 약제의 제조를 위한 상기 화학식 I 로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염의 용도를 제공하고자 한다. 약제의 제조를 위한 상기 화학식 I 로 표시되는 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다.
본 발명에 있어서, 상기 고혈압은 본태성 고혈압일 수 있고, 상기 당뇨병은 제2형 당뇨병일 수 있다.
본 발명에 있어서, 고혈압 또는 당뇨병의 치료용 약제의 제조를 위한 상기 화학식 I로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약제학적으로 허용가능한 염은 고혈압 및 당뇨병을 동시에 치료할 수 있다.
본 발명의 조성물, 용도, 치료방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.
본 발명의 피리미디논 유도체 화합물은 고혈압 및/또는 당뇨병의 치료 활성을 나타낸다.
이하, 하기 실시예 및 실험예를 들어 본 발명을 더욱 구체적으로 설명한다. 그러나 이들 실시예 및 실험예는 본 발명에 대한 이해를 돕기 위해 예시의 목적으로만 제공된 것일 뿐 본 발명의 범위가 하기 실시예 및 실험예에 의해 제한되는 것은 아니다.
실시예 A-1: 3-(4'-((2-부틸-5-((3-(2-플루오로페닐)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
[단계 1] (Z)-2-플루오로-N'-하이드록시벤즈이미드아마이드 (Z)-2-fluoro-N'-hydroxybenzimidamide의 제조
Figure PCTKR2019008609-appb-img-000041
플라스크에 NH 2OH.HCl (688 mg, 9.9 mmol), NaHCO 3 (832 mg, 9.9 mmol)을 넣고 정제수 5 ml를 주입 후 교반하였다. 2-플루오로 벤조나이트릴 (1 g, 8.26 mmol)을 에탄올 10 ml에 녹여서 플라스크에 주입한 후, 12 시간 동안 환류 교반하였다. 상온으로 냉각 후 반응액을 농축하였다. 에틸아세테이트 30 ml를 주입하고, 포화 NaHCO 3 30 ml로 세척하였다. MgSO 4로 건조하여 여과한 후, 여액을 농축하였다. 제조된 표제 화합물 (1.14 g)은 별도의 정제 없이 다음 반응에 사용하였다.
[단계 2] 3-(4'-((2-부틸-5-((3-(2-플루오로페닐)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000042
플라스크에 2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세트산 (50 mg, 0.105 mmol)을 넣은 후, 피리딘 1 ml를 넣었다. SOCl 2 15 mg를 주입한 후, 상온에서 1 시간 동안 교반하였다. 미리 준비된 단계 1의 화합물 (20 mg 0.126 mmol)을 주입한 후, 12 시간 동안 환류 교반하였다. 반응액을 농축한 후, 에틸아세테이트 20 ml를 넣고 정제수 20 ml와 brine 20 ml로 순차적으로 세척하였다. 무수 MgSO 4로 유기층을 건조하여 여과한 후, 여액을 농축하였다. Prep-LC (아세토나이트릴 20 내지 100 %, gradient)로 정제하여 표제 화합물 27mg을 수득하였다.
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.38 (2H, m), 1.67 (2H, m), 2.34 (3H, s), 2.67 (2H, t), 4.14 (2H, s), 5.26 (2H, s), 7.16-7.99 (12H, m)
<실시예 A-2 내지 A-115>
실시예 A-2 내지 A-115의 화합물은 실시예 A-1과 유사한 방법으로 각 실시예에 대응하는 나이트릴 유도체 화합물을 이용하여 합성하였다.
실시예 A-2: 3-(4'-((2-부틸-5-((3-사이클로프로필-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.97-1.01 (6H, m), 1.18 (6H, d), 1.43 (2H, m), 1.78 (2H, m), 2.05 (1H, m), 2.73 (2H, t), 3.01 (1H, m), 4.20 (2H, s), 5.31 (2H, s), 7.25-7.35 (4H, m), 7.43 (1H, d), 7.54 (1H, t), 7.61 (1H, t), 7.84 (1H, d)
실시예 A-3: 3-(4'-((2-부틸-5-((3-사이클로프로필-1,2,4-옥소다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.92 (3H, t), 0.98-1.02 (4H, m), 1.35-1.74 (4H, m), 1.99-2.04 (1H, m), 2.31 (3H, s), 2.69 (2H, t), 4.03 (2H, s), 5.28 (2H, s), 7.19-7.80 (8H, m)
실시예 A-4: 3-(4'-((2-부틸-5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-tert-butyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.33-1.43 (11H, m), 1.65-1.73 (2H, m), 2.30 (3H, s), 2.67 (2H, t), 4.05 (2H, s), 5,28 (2H, s), 7.18-7.78 (8H, m)
실시예 A-5: 3-(4'-((2-부틸-5-((3-(메톡시메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 1.33-1.71 (4H, m), 2.31 (3H, s), 2.66 (2H, t), 3.42 (3H, s), 4.08 (2H, s), 4.51 (2H, s), 5.24 (2H, s), 7.15-7.74 (8H, m)
실시예 A-6: 3-(4'-((2-부틸-5-((3-(2-메톡시에틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-yl)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 1.34-1.72 (4H, m), 2.31 (3H, s), 2.67 (2H, t), 2.95 (2H, t), 3.33 (3H, s), 3.73 (2H, t), 4.05 (2H, s), 5.26 (2H, s), 7.17-7.76 (8H, m)
실시예 A-7: 3-(4'-((2-부틸-5-((3-이소프로필-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-isopropyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one 의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.92 (3H, t), 1.30 (6H, d), 1.44-1.74 (4H, m), 2.32 (3H, s), 2.69 (2H, t), 3.00-3.07 (1H, m), 4.08 (2H, s), 5.28 (2H, s), 7.20-7.80 (8H, m)
실시예 A-8: 3-(4'-((2-부틸-5-((3-(다이메틸아미노)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(dimethylamino)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.34-1.72 (4H, m), 2.30 (3H, s), 2.66 (2H, t), 2.95 (6H, s), 3.91 (2H, s), 5.26 (2H, s), 7.18-7.77 (8H, m)
실시예 A-9: 3-(4'-((2-부틸-5-((3-((다이메틸아미노)메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-((dimethylamino)methyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.92 (3H, t), 1.36-1.76 (4H, m), 2.06 (6H, s), 2.41 (3H, s), 2.72 (2H, t), 3.38 (2H, s), 4.09 (2H, s), 5.23 (2H, s), 6.90-7.80 (8H, m)
실시예 A-10: 3-(4'-((2-부틸-5-((3-(다이에틸아미노)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(diethylamino)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.07 (3H, t), 1.30-1.69 (4H, m), 2.36 (3H, s), 2.63 (2H, t), 3.25-3.30 (4H, m), 3.93 (2H, s), 5.21 (2H, s), 6.93-7.67 (8H, m)
실시예 A-11: 3-(4'-((2-부틸-5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-tert-butyl-1,2,4-oxadiazol-5-yl)methyl)-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.18 (6H, d), 1.33-1.43 (11H, m), 1.65-2.05 (4H, m), 2.67 (2H, t), 3.01 (1H, m), 4.05 (2H, s), 5.27 (2H, s), 7.18-7.78 (8H, m)
실시예 A-12: 3-(4'-((2-부틸-5-((3-(2-메톡시프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-methoxypropan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, m), 1.23 (3H, d), 1.36 (5H, m), 1.72 (2H, m), 2.34 (3H, s), 2.71 (2H, t), 3.61 (2H, s), 3.74 (3H, s), 5.34 (2H, s), 7.20 (2H, d), 7.34 (2H, d), 7.44 (1H, q), 7.51 (1H, t), 7.62 (1H, t), 7.82 (1H, d)
실시예 A-13: 3-(4'-((2-부틸-4-이소프로필-5-((3-메틸-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-isopropyl-5-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.18 (6H, d), 1.32-1.43 (5H, m), 1.65-2.05 (4H, m), 2.67 (2H, t), 3.01 (1H, m), 4.05 (2H, s), 5,27 (2H, s), 7.18-7.78 (8H, m)
실시예 A-14: 3-(4'-((2-부틸-4-메틸-5-((3-메틸-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.32-1.43 (5H, m), 1.65-2.05 (4H, m), 2.67 (2H, t), 2.75 (3H, s), 4.05 (2H, s), 5,27 (2H, s), 7.18-7.78 (8H, m)
실시예 A-15: 3-(4'-((5-((3-벤질-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91-1.20 (3H, t), 1.38 (2H, m), 1.74 (2H, m), 2.75 (3H, s), 2.94 (1H, m), 3.98 (2H, s,), 4.07 (2H, s), 5.30 (2H, s), 6.53 (2H, t), 6.97-7.58 (11H, m),
실시예 A-16: 3-(4'-((2-부틸-5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91-1.20 (3H, t), 1.38 (2H, m), 1.74 (2H, m), 2.75 (3H, s), 2.94 (1H, m), 3.98 (2H, s,), 4.07 (2H, s), 5.30 (2H, s), 6.53 (2H, t), 6.97-7.31 (6H, m), 7.36 (1H, d), 7.45 (1H, q), 7.56 (1H, q), 7.62 (1H, d)
실시예 A-17: 3-(4'-((5-((3-벤질-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)-2-butyl-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91-1.10 (3H, t), 1.18 (6H, d), 1.38 (2H, m), 1.74 (2H, m), 2.70 (2H, t), 2.94 (1H, m), 3.98 (2H, s,), 4.07 (2H, s), 5.30 (2H, s), 6.54 (2H, t), 6.98-7.65 (10H, m)
실시예 A-18: 3-(4'-((2-부틸-5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91-1.05 (3H, t), 1.18 (6H, d), 1.38 (2H, m), 1.74 (2H, m), 2.70 (2H, t), 2.94 (1H, m), 3.98 (2H, s,), 4.07 (2H, s), 5.30 (2H, s), 6.54 (2H, t), 6.98-7.30 (6H, m), 7.36 (1H, d), 7.46 (1H, q), 7.57 (1H, q), 7.62 (1H, d)
실시예 A-19: 3-(4'-((2-부틸-4-메틸-5-((3-(1-메틸사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 0.98-1.25 (7H, m), 1.35-1.75 (4H, m), 2.31 (3H, s), 2.68 (2H, t, J=8Hz), 4.03 (2H, s), 5.23 (2H, s), 7.18-7.80 (8H, m)
실시예 A-20: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(스파이로[2.2]펜탄-1-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(spiro[2.2]pentan-1-yl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.75-0.79 (1H, m), 0.87-0.96 (6H, m), 1.31-1.69 (6H, m), 2.26 (3H, s), 2.35-2.38 (1H, m), 2.64 (2H, t), 4.00 (2H, s), 5.24 (2H, s), 7.13-7.71 (8H, m)
실시예 A-21: 3-(4'-((2-부틸-5-((3-(이소프로폭시메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(isopropoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.19 (6H, d), 1.32-1.70 (4H, m), 2.30 (3H, s), 2.66 (2H, t), 3.69-3.78 (1H, m), 4.07 (2H, s), 4.55 (2H, s), 5.24 (2H, s), 7.13-7.72 (8H, m)
실시예 A-22: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(1-페닐사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(1-phenylcyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.87 (3H, t), 1.26-1.65 (4H, m), 2.54 (3H, s), 2.62 (2H, t), 5.19 (2H, s), 6.91-7.95 (19H, m)
실시예 A-23: 3-(4'-((2-부틸-5-((3-(3-클로로피리딘-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(3-chloropyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91-1.15 (3H, t), 1.38 (2H, m), 1.74 (2H, m), 2.75 (3H, s), 2.94 (1H, m), 3.98 (2H, s,), 4.07 (2H, s), 5.30 (2H, s), 6.53 (2H, t), 6.97-7.31 (6H, m), 7.36 (1H, d), 7.45 (1H, q), 7.56 (1H, q), 7.62 (1H, d)
실시예 A-24: 3-(4'-((2-부틸-5-((3-(2-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 1.38 (2H, m), 1.69 (2H, m), 2.29 (3H, s), 2.68 (2H, m), 4.00 (2H, s), 4.15 (2H, s), 5.27 (2H, s), 6.96 (2H, m), 6.97-7.30 (6H, m), 7.37 (1H, d), 7.48 (1H, q), 7.60 (1H, q), 7.80 (1H, d)
실시예 A-25: 3-(4'-((2-부틸-5-((3-(2-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.92 (3H, t), 1.18 (6H, d), 1.38 (2H, m), 1.69 (2H, m), 2.68 (2H, m), 2.96 (1H, m), 4.00 (2H, s), 4.15 (2H, s), 5.27 (2H, s), 6.97 (2H, m), 6.97-7.30 (6H, m), 7.37 (1H, d), 7.48 (1H, q), 7.61 (1H, q), 7.80 (1H, d)
실시예 A-26: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(2-페닐프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(2-phenylpropan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.38 (2H, m), 1.64 (2H, m), 1.72 (6H, s), 2.20 (3H, s), 2.62 (2H, t), 3.97 (2H, s), 5.23 (2H, s), 7.12-7.28 (9H, m), 7.36 (1H, d), 7.44 (m, 1H), 7.53 (m, 1H), 7.67 (1H, d)
실시예 A-27: 3-(4'-((2-부틸-5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸-d2)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl-d2)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.40 (2H, m), 1.70 (2H, m), 2.30 (3H, s), 2.69 (2H, t), 3.99 (2H, s), 5.26 (2H, s), 6.94-7.79 (12H, m)
실시예 A-28: 3-(4'-((2-부틸-5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸-d2)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-tert-butyl-1,2,4-oxadiazol-5-yl)methyl-d2)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.32 (9H, s), 1.36 (2H, m), 1.66 (2H, m), 2.27 (3H, s), 2.64 (2H, m), 5.25 (2H, s), 7.14-7.72 (8H, m)
실시예 A-29: 3-(4'-((2-부틸-4-메틸-5-((3-(4-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-(4-methylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.30-1.68 (4H, m), 2.28 (6H, s), 2.63 (2H, t), 3.96 (2H, s), 4.03 (2H, s), 5.22 (2H, s), 7.08-7.61 (12H, m)
실시예 A-30: 3-(4'-((2-부틸-5-((3-(4-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.32-1.70 (4H, m), 2.27 (3H, s), 2.65 (2H, t), 3.73 (3H, s), 3.95 (2H, s), 4.01 (2H, s), 5.23 (2H, s), 6.78-7.71 (12H, m)
실시예 A-31: 3-(4'-((2-부틸-5-((3-(4-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.32-1.70 (4H, m), 2.27 (3H, s), 2.65 (2H, t), 3.97 (2H, s), 4.01 (2H, s), 5.23 (2H, s), 7.13-7.72 (12H, m)
실시예 A-32: 3-(4'-((2-부틸-5-((3-(3-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(3-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.31-1.70 (4H, m), 2.27 (3H, s), 2.65 (2H, t), 4.00 (2H, s), 4.01 (2H, s), 5.23 (2H, s), 6.88-7.71 (12H, m)
실시예 A-33: 3-(4'-((2-부틸-5-((3-(3,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.87 (3H, t), 1.29-1.68 (4H, m), 2.26 (3H, s), 2.63 (2H, t), 3.98 (2H, s), 4.01 (2H, s), 5.22 (2H, s), 6.62-7.68 (11H, m)
실시예 A-34: 3-(4'-((5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-tert-butyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.99 (3H, t), 1.33 (9H, s), 1.71-1.80 (2H, m), 2.31 (3H, s), 2.67 (2H, t), 4.08 (2H, s), 5.29 (2H, s), 7.19-7.80 (8H, m)
실시예 A-35: 3-(4'-((5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.97 (3H, t), 1.68-1.78 (2H, m), 2.28 (3H, s), 2.65 (2H, t), 3.99 (2H, s), 4.04 (2H, s), 5.25 (2H, s), 6.94-7.75 (12H, m)
실시예 A-36: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(피페리딘-1-일메틸)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(piperidin-1-ylmethyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 1.01 (3H, t), 1.49-2.72 (15H, m), 3.56-3.61 (4H, m), 4.13-4.20 (2H, m), 5.28 (2H, s), 7.20-7.80 (8H, m)
실시예 A-37: 3-(4'-((4-메틸-5-((3-(4-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-5-((3-(4-methylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.98 (3H, t), 1.69-1.78 (2H, m), 2.27-2.29 (6H, d), 2.65 (2H, t), 3.98 (2H, s), 4.04 (2H, s), 5.25 (2H, s), 7.08-7.76 (12H, m)
실시예 A-38: 3-(4'-((5-((3-(4-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.95 (3H, t), 1.65-1.75 (2H, m), 2.26 (3H, s), 2.62 (2H, t), 3.73 (3H, s), 3.94 (2H, s), 4.00 (2H, s), 5.22 (2H, s), 6.78-7.69 (12H, m)
실시예 A-39: 3-(4'-((5-((3-(4-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.98 (3H, t), 1.70-1.79 (2H, m), 2.30 (3H, s), 2.66 (2H, t), 3.99 (2H, s), 4.07 (2H, s), 5.26 (2H, s), 7.18-7.79 (12H, m)
실시예 A-40: 3-(4'-((5-((3-(3-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(3-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.95 (3H, t), 1.66-1.76 (2H, m), 2.27 (3H, s), 2.63 (2H, t), 4.01 (2H, s), 4.02 (2H, s), 5.23 (2H, s), 6.88-7.71 (12H, m)
실시예 A-41: 3-(4'-((5-((3-(3,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, t), 1.67-1.77 (2H, m), 2.29 (3H, s), 2.64 (2H, t), 3.99 (2H, s), 4.04 (2H, s), 5.20 (2H, s), 6.63-7.74 (11H, m)
실시예 A-42: 3-(4'-((5-((3-(2,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(2,4-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.97 (3H, t), 1.69-1.78 (2H, m), 2.29 (3H, s), 2.66 (2H, t), 4.02 (2H, s), 4.06 (2H, s), 5.26 (2H, s), 6.76-7.76 (11H, m)
실시예 A-43: 3-(4'-((5-((3-사이클로펜틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-cyclopentyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.97 (3H, t), 1.62-2.04 (10H, m), 2.29 (3H, s), 2.66 (2H, t), 3.10-3.18 (1H, m), 4.04 (2H, s), 5.26 (2H, s), 7.16-7.76 (8H, m)
실시예 A-44: 3-(4'-((5-((3-(사이클로펜틸메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(cyclopentylmethyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.97 (3H, t), 1.16-1.25 (2H, m), 1.46-1.79 (8H, m), 2.21-2.29 (4H, m), 2.63-2.67 (4H, m), 4.05 (2H, s), 5.26 (2H, s), 7.17-7.76 (8H, m)
실시예 A-45: 3-(4'-((5-((3-(사이클로헥실메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(cyclohexylmethyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.95-1.01 (5H, m), 1.11-1.26 (3H, m), 1.60-1.79 (8H, m), 2.29 (3H, s), 2.54 (2H, d), 2.64 (2H, t), 4.05 (2H, s), 5.26 (2H, s), 7.16-7.76 (8H, m)
실시예 A-46: 3-(4'-((2-부틸-5-((3-(2,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2,4-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.38 (2H, m), 1.68 (2H, m), 2.29 (3H, s), 2.68 (2H, m), 4.02 (2H, s), 4.06 (2H, s), 5.26 (2H, s), 6.78-6.81 (2H, m), 7.17-7.77 (9H, m)
실시예 A-47: 3-(4'-((2-부틸-5-((3-(사이클로헥실메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-yl)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(cyclohexylmethyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.38 (2H, m), 1.68 (2H, m), 2.30 (3H, s), 2.55 (2H, d), 2.68 (2H, m), 4.07 (2H, s), 5.27 (2H, s), 7.18-7.79 (8H,m)
실시예 A-48: 3-(4'-((2-부틸-5-((3-(사이클로펜틸메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(cyclopentylmethyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.21 (2H, m), 1.41 (2H, m), 1.45-1.80 (8H, m), 2.26 (1H, m), 2.30 (3H, s), 2.66 (2H, d), 2.68 (2H, s), 4.06 (2H, s), 5.27 (2H, s), 7.18-7.78 (8H, m)
실시예 A-49: 3-(4'-((2-부틸-5-((3-사이클로펜틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-cyclopentyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 1.39 (2H, m), 1.60-2.07 (10H, m), 2.30 (3H, s), 2.68 (2H, t), 3.15 (1H, m), 4.05 (2H, s), 5.27 (2H, s), 7.17-7.78 (8H, m)
실시예 A-50: 3-(4'-((5-((3-(사이클로프로필메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.20-0.24 (2H, m), 0.50-0.55 (2H, m), 0.98 (3H, t), 1.05-1.13 (1H, m), 1.70-1.79 (2H, m), 2.32 (3H, s), 2.58 (2H, d), 2.66 (2H, t), 4.06 (2H, s), 5.26 (2H, s), 7.17-7.77 (8H, m)
실시예 A-51: 3-(4'-((5-((3-(2-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(2-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 1.00 (3H, t), 1.71-1.81 (2H, m), 2.31 (3H, s), 2.68 (2H, t), 4.11 (2H, s), 4.17 (2H, s), 5.28 (2H, s), 7.17-7.82 (12H, m)
실시예 A-52: 3-(4'-((5-((3-(3,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(3,4-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, t), 1.68-1.77 (2H, m), 2.29 (3H, s), 2.65 (2H, t), 3.97 (2H, s), 4.04 (2H, s), 5.24 (2H, s), 6.98-7.74 (11H, m)
실시예 A-53: 3-(4'-((5-((3-(2,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(2,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.97 (3H, t), 1.69-1.78 (2H, m), 2.30 (3H, s), 2.66 (2H, t), 4.03 (2H, s), 4.06 (2H, s), 5.25 (2H, s), 6.86-7.76 (11H, m)
실시예 A-54: 3-(4'-((5-((3-(2-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(2-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 1.00 (3H, t), 1.75 (2H, m), 2.31 (3H, s), 2.67 (2H, t), 4.07 (2H, s), 4.09 (2H, s), 5.27 (2H, s), 7.05 (2H, m), 7.28 (4H, m), 7.30 (2H, m), 7.39 (1H, d), 7.49 (1H, m), 7.61 (1H, m), 7.80 (1H, d)
실시예 A-55: 3-(4'-((5-((3-(4-브로모벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(4-bromobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.99 (3H, t), 1.71-1.80 (2H, m), 2.30 (3H, s), 2.67 (2H, t), 3.97 (2H, s), 4.08 (2H, s), 5.27 (2H, s), 7.15-7.80 (12H, m)
실시예 A-56: 3-(4'-((5-((3-(3-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.95 (3H, t), 1.66-1.75 (2H, m), 2.27 (3H, s), 2.63 (2H, t), 3.98 (2H, s), 4.02 (2H, s), 5.22 (2H, s), 7.11-7.70 (12H, m)
실시예 A-57: 3-(4'-((5-((3-(2,6-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(2,6-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.95 (3H, t), 1.66-1.76 (2H, m), 2.27 (3H, s), 2.63 (2H, t), 4.01 (2H, s), 4.36 (2H, s), 5.23 (2H, s), 7.13-7.71 (11H, m)
실시예 A-58: 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(2,4,6-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-6-oxo-2-propyl-5-((3-(2,4,6-trifluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.94 (3H, t), 1.65-1.75 (2H, m), 2.26 (3H, s), 2.62 (2H, t), 4.00 (2H, s), 4.01 (2H, s), 5.22 (2H, s), 6.63-7.70 (10H, m)
실시예 A-59: 3-(4'-((4-메틸-6-옥소-5-((3-(피페리딘-1-일)-1,2,4-옥사다이아졸-5-일)메틸)-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-6-oxo-5-((3-(piperidin-1-yl)-1,2,4-oxadiazol-5-yl)methyl)-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 1.00 (3H, t), 1.58-1.81 (8H, m), 2.33 (3H, s), 2.68 (2H, t), 3.33-3.36 (4H, m), 3.96 (2H, s), 5.28 (2H, s), 7.20-7.82 (8H, m)
실시예 A-60: 3-(4'-((5-((3-사이클로헥실-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-cyclohexyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.99 (3H, t), 1.22-1.99 (12H, m), 2.32 (3H, s), 2.66-2.76 (3H, m), 4.08 (2H, s), 5.28 (2H, s), 7.19-7.80 (8H, m)
실시예 A-61: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(2-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(2-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.36 (2H, m), 1.66 (2H, m), 2.27 (3H, s), 2.65 (2H, t), 4.03 (2H, s), 4.22 (2H, s), 5.23 (2H, s), 7.13-7.70 (12H, m)
실시예 A-62: 3-(4'-((2-부틸-4-메틸-5-((3-(2-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-(2-methylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.36 (2H, m), 1.64 (2H, m), 2.25 (3H, s), 2.28 (3H, s), 2.64 (2H, t), 3.97 (2H, s), 3.99 (2H, s), 5.22 (2H, s), 7.03-7.68 (12H, m)
실시예 A-63: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(3-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.36 (2H, m), 1.66 (2H, m), 2.27 (3H, s), 2.65 (2H, t), 4.02 (2H, s), 4.07 (2H, s), 5.23 (2H, s), 7.13-7.70 (12H, m)
실시예 A-64: 3-(4'-((2-부틸-5-((3-(2,3-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2,3-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.36 (2H, m), 1.65 (2H, m), 2.27 (3H, s), 2.65 (2H, t), 4.02 (2H, s), 4.08 (2H, s), 5.23 (2H, s), 6.99-7.71 (11H, m)
실시예 A-65: 3-(4'-((4-메틸-6-옥소-5-((3-(피페리딘-1-일메틸)-1,2,4-옥사다이아졸-5-일)메틸)-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-6-oxo-5-((3-(piperidin-1-ylmethyl)-1,2,4-oxadiazol-5-yl)methyl)-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 1.01 (3H, t), 1.49-2.72 (15H, m), 3.56-3.61 (2H, m), 4.13-4.20 (5H, m), 5.28 (2H, s), 7.20-7.80 (8H, m)
실시예 A-66: 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(3-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-6-oxo-2-propyl-5-((3-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, t), 1.68-1.78 (2H, m), 2.28 (3H, s), 2.65 (2H, t), 4.04 (2H, s), 4.08 (2H, s), 5.24 (2H, s), 7.14-7.74 (12H, m)
실시예 A-67: 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(4-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-6-oxo-2-propyl-5-((3-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, t), 1.68-1.77 (2H, m), 2.29 (3H, s), 2.64 (2H, t, J=7.8Hz), 4.04 (2H, s), 4.07 (2H, s), 5.24 (2H, s), 7.14-7.73 (12H, m)
실시예 A-68: 3-(4'-((5-((3-(1-(4-플루오로페닐)사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(1-(4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 1.00 (3H, t), 1.55-1.58 (4H, m), 1.72-1.81 (2H, m), 2.31 (3H, s), 2.69 (2H, t), 4.05 (2H, s), 5.28 (2H, s), 6.93-7.82 (12H, m)
실시예 A-69: 3-(4'-((4-메틸-5-((3-(몰폴리노메틸)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-5-((3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.95 (3H, t), 1.67-1.77 (2H, m), 2.38 (3H, s), 2.46-2.64 (6H, m), 3.55-3.59 (6H, m), 4.09 (2H, s), 5.18 (2H, s), 6.88-7.62 (8H, m)
실시예 A-70: 3-(4'-((4-메틸-6-옥소-5-((3-(1-페닐사이클로부틸)-1,2,4-옥사다이아졸-5-일)메틸)-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-6-oxo-5-((3-(1-phenylcyclobutyl)-1,2,4-oxadiazol-5-yl)methyl)-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, t), 1.71-1.76 (2H, m), 1.86-1.94 (1H, m), 2.02-2.14 (1H, m), 2.30 (3H, s), 2.61-2.68 (4H, m), 2.79-2.86 (2H, m), 4.04 (2H, s), 5.23 (2H, s), 7.00-7.71 (13H, m)
실시예 A-71: 3-(4'-((2-부틸-5-((3-(2,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.35-1.74 (4H, m), 2.31 (3H, s), 2.69 (2H, t), 4.05 (2H, s), 4.10 (2H, s), 5.27 (2H, s), 6.86-7.80 (11H, m)
실시예 A-72: 3-(4'-((2-부틸-5-((3-(2,6-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.34-1.73 (4H, m), 2.29 (3H, s), 2.68 (2H, t), 4.05 (2H, s), 4.08 (2H, s), 5.26 (2H, s), 6.84-7.77 (11H, m)
실시예 A-73: 3-(4'-((2-부틸-5-((3-(2-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.34-1.73 (4H, m), 2.30 (3H, s), 2.69 (2H, t), 4.08 (2H, s), 4.17 (2H, s), 5.27 (2H, s), 7.17-7.78 (12H, m)
실시예 A-74: 3-(4'-((2-부틸-5-((3-(2,6-다이클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2,6-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 1.33-1.71 (4H, m), 2.28 (3H, s), 2.67 (2H, t), 4.03 (2H, s), 4.37 (2H, s), 5.25 (2H, s), 7.13-7.74 (11H, m)
실시예 A-75: 3-(4'-((4-메틸-5-((3-(2-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-5-((3-(2-methylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.87 (3H. t), 1.63 (2H, m), 2.21 (3H, s), 2.29 (3H, s), 2.49 (2H, t), 3.85 (2H, s), 3.98 (2H, s), 5.07 (2H, s), 6.82 (2H, d), 6.95 (3H, t), 7.07 (3H, m), 7.19 (2H, m), 7.34 (1H, m), 7.55 (1H, d)
실시예 A-76: 3-(4'-((5-((3-(2,3-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(2,3-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.98 (3H, t), 1.75 (2H, m), 2.30 (3H, s), 2.66 (2H, t), 4.07 (2H, s), 4.10 (2H, s), 5.26 (2H, s), 7.02 (3H, m), 7.18 (2H, m), 7.28 (2H, t), 7.38 (1H, t), 7.46 (1H, m), 7.46 (1H, m), 7.58 (1H, m), 7.60 (1H, d)
실시예 A-77: 3-(4'-((5-((3-(2,6-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(2,6-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.97 (3H, t), 1.73 (2H, m), 2.27 (3H, s), 2.64 (2H, m), 4.02 (2H, s), 4.08 (2H, s), 5.23 (2H, s), 6.88 (2H, t), 7.12 (2H, m), 7.20 (1H, m), 7.24 (2H, m), 7.29 (2H, m), 7.54 (1H, m), 7.59(1H, d)
실시예 A-78: 3-(4'-((5-((3-(3-클로로-5-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(3-chloro-5-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, t), 1.72 (2H, m), 2.30 (3H, s), 2.65 (2H, t), 3.99 (2H, s), 4.05 (2H, s), 5.25 (2H, s), 6.94 (2H, m), 7.08 (1H, s), 7.14 (2H, d), 7.27 (2H, m), 7.38 (1H, d), 7.46 (1H, t), 7.64 (1H, m), 7.72 (1H, d)
실시예 A-79: 3-(4'-((5-((3-(4-브로모벤질)-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(4-bromobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.31-1.69 (4H, m), 2.29 (3H, s), 2.64 (2H, t), 3.94 (2H, s), 4.03 (2H, s), 5.22 (2H, s), 7.07-7.66 (12H, m)
실시예 A-80: 3-(4'-((2-부틸-5-((3-(3-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.31-1.69 (4H, m), 2.28 (3H, s), 2.65 (2H, t), 3.98 (2H, s), 4.02 (2H, s), 5.22 (2H, s), 7.10-7.69 (12H, m)
실시예 A-81: 3-(4'-((2-부틸-5-((3-(3,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(3,4-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.88 (3H, t), 1.31-1.70 (4H, m), 2.28 (3H, s), 2.65 (2H, t), 3.96 (2H, s), 4.02 (2H, s), 5.23 (2H, s), 7.00-7.70 (11H, m)
실시예 A-82: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(4-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.36 (2H, m), 1.66 (2H, m), 2.28 (3H, s), 2.65 (2H, t), 4.03 (2H, s), 4.07 (2H, s), 5.24 (2H, s), 7.14-7.72 (12H, m)
실시예 A-83: 3-(4'-((2-부틸-5-((3-(1-(4-플루오로페닐)사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(1-(4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.29 (2H, m), 1.36 (2H, m), 1.54 (2H, m), 1.66 (2H, m), 2.28 (3H, s), 2.66 (2H, t), 3.98 (2H, s), 5.24 (2H, s), 6.95-7.73 (12H, m)
실시예 A-84: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(1-페닐사이클로부틸)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(1-phenylcyclobutyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.36 (2H, m), 1.66 (2H, m), 1.87-2.18 (2H, m), 2.62-2.70 (4H, m), 2.86 (2H, m), 3.96 (2H, s), 5.23 (2H, s), 7.12-7.68 (13H, m)
실시예 A-85: 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(2-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-6-oxo-2-propyl-5-((3-(2-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, t), 1.73 (2H, m), 2.28 (3H, s), 2.64 (2H, t), 4.05 (2H, s), 4.23 (2H, s), 5.25 (2H, s), 7.15 (2H, m), 7.27 (1H, m), 7.33 (1H, m), 7.38 (3H, m), 7.46 (2H, m), 7.60 (1H, t), 7.71 (1H, d), 7.74 (1H, d)
실시예 A-86: 3-(4'-((5-((3-(1-(3-플루오로페닐)사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(1-(3-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one
1H-NMR (400 MHz, CDCl 3): δ 0.97 (3H, t), 1.31-1.33 (2H, m), 1.55-1.57 (2H, m), 1.69-1.78 (2H, m), 2.29 (3H, s), 2.65 (2H, t), 4.01 (2H, s), 5.25 (2H, s), 6.90-7.75 (12H, m)
실시예 A-87: 3-(4'-((5-((3-(2-클로로-4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(2-chloro-4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.99 (3H, t), 1.71-1.80 (2H, m), 2.31 (3H, s), 2.68 (2H, t), 4.08 (2H, s), 4.12 (2H, s), 5.27 (2H, s), 6.89-7.79 (11H, m)
실시예 A-88: 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(3,4,5-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-6-oxo-2-propyl-5-((3-(3,4,5-trifluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, t), 1.68-1.77 (2H, m), 2.30 (3H, s), 2.65 (2H, t), 3.95 (2H, s), 4.05 (2H, s), 5.24 (22H, s), 6.88-7.74 (10H, m)
실시예 A-89: 3-(4'-((2-부틸-4-메틸-5-((3-(몰폴리노메틸)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.92 (3H, t), 1.40 (2H, m), 1.70 (2H, m), 2.36 (3H, s), 2.52 (4H, t), 2.69 (2H, t), 3.64 (4H, d), 3.66 (2H, s), 4.17 (2H, s), 5.29 (2H, s), 7.20 (2H, d), 7.31 (2H, d), 7.41 (1H, d), 7.50 (1H, t), 7.60 (1H, t), 7.78 (1H, d)
실시예 A-90: 3-(4'-((2-부틸-4-메틸-5-((3-(3-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-(3-methylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 1.40 (2H, m), 2.28 (3H, s), 2.68 (2H, t), 3.99 (2H, s), 4.05 (2H, s), 5.26 (2H, s), 7.10 (3H, m), 7.15 (3H, m), 7.36 (2H, m), 7.38 (1H, m), 7.58 (1H, t), 7.75 (1H, t), 7.77 (1H, t)
실시예 A-91: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(2,4,6-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(2,4,6-trifluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.36 (2H, m), 1.66 (2H, m), 2.27 (3H, s), 2.65 (2H, t), 4.02 (2H, s), 5.24 (2H, s), 6.67 (2H, t), 7.27 (2H, d), 7.38 (2H, d), 7.46 (1H, m), 7.56 (1H, t), 7.68 (1H, m), 7.70 (1H, d)
실시예 A-92: 3-(4'-((2-부틸-5-((3-사이클로헥실-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-cyclohexyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 1.26 (4H, m), 1.66 (10H, m), 2.04 (1H, m), 2.32 (3H, d), 2.65 (2H, t), 4.13 (2H, s), 5.28 (2H, s), 7.14 (2H, m), 7.28 (2H, d), 7.37 (1H, m), 7.42 (1H, m), 7.51 (1H, m), 7.69 (1H, d)
실시예 A-93: 3-(4'-((5-((3-(2-클로로-6-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(2-chloro-6-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.95 (3H, t), 1.66-1.75 (2H, m), 2.26 (3H, s), 2.63 (2H, t), 4.01 (2H, s), 4.19 (2H, s), 5.30 (2H, s), 6.96-7.71 (11H, m)
실시예 A-94: 3-(4'-((4-메틸-5-((3-(2-메틸펜탄-2-일)-1,2,4-옥사다이아졸-5-일)메틸l)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-5-((3-(2-methylpentan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.83 (3H, t), 0.96 (3H, t), 1.10-1.20 (2H, m), 1.29 (6H, s), 1.58-1.77 (4H, m), 2.27 (3H, s), 2.64 (2H, t), 4.04 (2H, s), 5.26 (2H, s), 7.15-7.75 (8H, m)
실시예 A-95: 3-(4'-((2-부틸-5-((3-(3-클로로-5-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(3-chloro-5-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.92 (3H, t), 1.72 (2H, m), 2.33 (3H, s), 2.72 (2H, t), 4.00 (2H, s), 4.09 (2H, s), 5.28 (2H, s), 6.91 (3H, m), 7.07 (1H, d), 7.19 (2H, d), 7.20 (1H, d), 7.38 (1H, d), 7.41 (1H, d), 7.49 (1H, t), 7.60 (1H, t), 7.78 (1H, d)
실시예 A-96: 3-(4'-((2-부틸-5-((3-사이클로프로필-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.22 (2H, m), 0.53 (2H, m), 0.88 (3H, t), 1.26 (1H, t), 1.35 (2H, m), 1.67 (2H, m), 2.30 (3H, s), 2.57 (2H, d), 2.66 (2H, t), 4.04 (2H, s), 5.25 (2H, s), 7.15 (2H, d), 7.28 (2H, d), 7.40 (1H, d), 7.47 (1H, t), 7.59 (1H, t), 7.71 (1H, d)
실시예 A-97: 3-(4'-((2-부틸-5-((3-(2-클로로-6-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-chloro-6-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.36 (2H, m), 1.69 (2H, m), 2.33 (3H, s), 2.64 (2H, s), 4.09 (2H, s), 4.22 (2H, s), 5.25 (2H, s), 7.00 (3H, m), 7.12 (2H, d), 7.20 (2H, m), 7.26 (2H, m), 7.44 (1H, t), 7.58 (1H, d)
실시예 A-98: 3-(4'-((2-부틸-5-((3-(2-클로로-4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-chloro-4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.39 (2H, m), 1.70 (2H, m), 2.32 (3H, s), 2.68 (2H, t), 4.10 (2H, s), 4.13 (2H, s), 5.28 (2H, s), 6.94 (2H, m), 7.15 (2H, m), 7.28 (3H, m), 7.48 (2H, d), 7.58 (1H, t), 7.78 (1H, d)
실시예 A-99: 3-(4'-((2-부틸-4-메틸-5-((3-(2-메틸펜탄-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-(2-methylpentan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (6H, m), 1.26 (1H, t), 1.38 (12H, m), 1.69 (2H, m), 2.29 (3H, s), 2.67 (2H, t), 4.14 (2H, s), 5.29 (2H, s), 7.22 (2H, d), 7.38 (2H, d), 7.40 (1H, d), 7.59 (1H, t), 7.61 (1H, t), 7.81 (1H, d)
실시예 A-100: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(3,4,5-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(3,4,5-trifluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.38 (1H, m), 1.66 (2H, m), 2.28 (3H, s), 2.67 (2H, t), 3.96 (2H, s), 4.06 (2H, s), 5.25 (2H, s), 6.92 (2H, m), 7.13 (2H, d), 7.26 (2H, m), 7.45 (1H, d), 7.57 (1H, t), 7.66 (1H, t), 7.68 (1H, d)
실시예 A-101: 3-(4'-((5-((3-(1-(2-클로로페닐)에틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(1-(2-chlorophenyl)ethyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.96 (3H, t), 1.63 (3H, d), 1.64-1.69 (2H, m), 2.28 (3H, s), 2.64 (2H, t), 4.07 (2H, s), 4.71-4.77 (1H, m), 5.25 (2H, s), 7.12-7.71 (12H, m)
실시예 A-102: 3-(4'-((2-부틸-5-((3-(2-사이클로헥실프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-cyclohexylpropan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 0.95-1.20 (5H, m), 1.24 (6H, s), 1.33-1.43 (2H, m), 1.48-1.51 (2H, m), 1.60-1.72 (6H, m), 2.27 (3H, s), 2.67 (2H, t), 4.06 (2H, s), 5.27 (2H, s), 7.17-7.77 (8H, m)
실시예 A-103: 3-(4'-((2-부틸-5-((3-(2-(4-클로로-2-플루오로페닐)프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-(4-chloro-2-fluorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.87 (3H, t), 1.29-1.67 (4H, m), 1.75 (6H, s), 2.20 (3H, s), 2.62 (2H, t), 4.01 (2H, s), 5.23 (2H, s), 6.94-7.68 (11H, m)
실시예 A-104: 3-(4'-((2-부틸-5-((3-(2-(2-클로로-6-플루오로페닐)프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-(2-chloro-6-fluorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.92 (3H, t), 1.36-1.45 (11H, m), 1.69-1.77 (2H, m), 2.46 (3H, s), 2.77 (2H, t), 5.33 (2H, s), 7.25-7.08 (8H, m)
실시예 A-105: 3-(4'-((2-부틸-5-((3-(3-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.90 (3H, t), 1.37 (2H, m), 1.68 (2H, m), 2.32 (3H, s), 2.65 (2H, t), 3.67 (3H, s), 4.02 (2H, s), 4.08 (2H, s), 5.28 (2H, s), 6.74 (1H, d), 6.87 (1H, s), 7.09 (1H, d), 7.14 (3H, m), 7.17 (1H, d), 7.19 (1H,s), 7.34 (3H, d), 7.49 (2H, t), 7.59 (1H, t), 7.79 (1H, d)
실시예 A-106: 3-(4'-((2-부틸-5-((3-(2-메톡시페닐)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.87 (3H, t), 1.33-1.68 (4H, m), 2.39 (3H, s), 2.65 (2H, t), 3.82 (3H, s), 4.14 (2H, s), 5.19 (2H, s), 6.90-7.83 (12H, m)
실시예 A-107: 3-(4'-((2-부틸-5-((3-(2-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(2-methoxybenzyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.87 (3H, t), 1.31-1.72 (4H, m), 2.34 (3H, s), 2.61 (2H, t), 3.70 (3H, s), 3.95 (2H, s), 4.02 (2H, s), 5.16 (2H, s), 6.77-7.65 (12H, m)
실시예 A-108: 3-(4'-((2-부틸-4-메틸-5-((3-(나프탈렌-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-(naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.87 (3H, t), 1.33-1.65 (4H, m), 2.39 (3H, s), 2.61 (2H, t), 4.15 (2H, s), 5.15 (2H, s), 6.97-7.99 (15H, m)
실시예 A-109: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(테트라하이드로-2H-피란-4-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(tetrahydro-2H-pyran-4-yl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.35-1.74 (4H, m), 1.80-1.90 (4H, m), 2.33 (3H, s), 2.69 (2H, t), 2.95-3.02 (1H, m), 3.45-3.51 (2H, m), 3.94-3.99 (2H, m), 4.08 (2H, s), 5.28 (2H, s), 7.18-7.76 (8H, m)
실시예 A-110: 3-(4'-((2-부틸-5-((3-(1-에틸사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-(1-ethylcyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.80-1.13 (10H, m), 1.34-1.43 (2H, m), 1.65-1.77 (4H, m), 2.30 (3H, s), 2.68 (2H, t), 4.02 (2H, s), 5.26 (2H, s), 7.15-7.77 (8H, m)
실시예 A-111: 3-(4'-((2-부틸-5-((3-사이클로부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.32-1.41 (2H, m), 1.63-1.70 (2H, m), 1.90-2.10 (2H, m), 2.28-2.35 (7H, m), 2.65 (2H, t, J=8Hz), 3.53-3.62 (1H, m), 4.03 (2H, s), 5.24 (2H, s), 7.14-7.72 (8H, m)
실시예 A-112: 3-(4'-((5-((3-(바이사이클로[2.2.1]헵탄-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((3-(bicyclo[2.2.1]heptan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.13-1.43 (5H, m), 1.45-1.72 (6H, m), 1.90 (1H, m), 2.28 (3H, s), 2.33 (1H, m), 2.45 (0.8H, m), 2.56 (0.2H, m), 2.66 (2H, t), 2.76 (0.8H, m), 3.10 (0.2H, m), 4.00 (1.5H, s), 4.03 (0.5H, s), 5.25 (2H, s), 7.14-7.80 (8H, m)
실시예 A-113: 3-(4'-((2-부틸-4-메틸-5-((3-(1-메틸사이클로부틸)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-(1-methylcyclobutyl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.89 (3H, t), 1.37 (2H, m), 1.52 (3H, s), 1.68 (2H, m), 1.90-2.10 (4H, m), 2.29 (3H, s), 2.50 (2H, m), 2.65 (2H, t), 4.03 (2H, s), 5.25 (2H, s), 7.14-7.80 (8H, m)
실시예 A-114: 3-(4'-((2-부틸-4-메틸-5-((3-(나프탈렌-1-일)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-(naphthalen-1-yl)-1,2,4-oxadiazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.83 (3H, t), 1.28 (2H, m), 1.58 (2H, m), 2.32 (3H, s), 2.56 (2H, t), 4.18 (2H, s), 5.19 (2H, s), 7.04 (2H, d), 7.15 (2H, m), 7.24 (2H, m), 7.48 (1H, t), 7.54 (4H, m), 7.85 (1H, d), 7.91 (1H, d), 8.17 (1H, d), 8.85 (1H, d)
실시예 A-115: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(퀴놀린-2-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400 MHz, CDCl 3): δ 0.91 (3H, t), 1.40 (2H, m), 1.80 (2H, m), 2.35 (3H, s), 2.69 (2H, t), 4.26 (2H, s), 5.28 (2H, s), 7.20 (2H, d), 7.27 (1H, d), 7.34 (2H, d), 7.46 (1H, t), 7.60 (2H, m), 7.65 (1H, t), 7.78 (1H, d), 7.84 (1H, d), 8.17 (2H, m), 8.29 (1H, d)
실시예 B-1: 3-(4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
[단계 1] 2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세트아마이드 2-(2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)acetamide의 제조
Figure PCTKR2019008609-appb-img-000043
에틸 2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세테이트 (5 g) 에 암모니아수 (6.9 mL, 10 eq)를 첨가한 후, 상온에서 18 시간 동안 교반하였다. 반응 용액에 H 2O 20 mL를 첨가하고, 생성된 슬러리를 여과하였다. 여과물을 45 ℃에서 열풍건조하여 표제 화합물 4.4 g (수율: 92%)을 얻었다.
[단계 2] 2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세토나이트릴 2-(2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)acetonitrile의 제조
Figure PCTKR2019008609-appb-img-000044
단계 1에서 제조된 화합물 (4.42 g)을 아세토나이트릴 25 mL에 녹인 후, POCl 3 (1.1 mL, 1.3 당량)를 첨가하였다. 18 시간 동안 환류 교반하고, 생성된 고체를 여과하여 제거하였다. 여액을 농축한 후 클로로포름 50 mL에 용해시키고, 포화 NaHCO 3 50ml를 사용하여 세척하였다. 수층을 CHCl 3 (25ml)로 1회 추가 추출하였다. 유기층을 모아 1N HCl 20 ml로 세척하고, 무수 MgSO 4로 건조 후 여과하였다. 감압농축 후 에틸아세테이트/헥산 = 16ml/24ml 첨가하고 가열하여 용해시켰다. 2 시간 동안 서서히 냉각하여 얻어진 고체 생성물을 여과 후 에틸아세테이트/헥산 = 1/2 (7ml)로 세척하였다. 얻어진 고체를 45 ℃에서 열풍건조하여 표제 화합물 2.78 g (수율: 65 %)을 수득하였다.
[단계 3] (Z)-2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)-N'-하이드록시아세트이미드아마이드 (Z)-2-(2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)-N'-hydroxyacetimidamide의 제조
Figure PCTKR2019008609-appb-img-000045
단계 2에서 제조된 화합물 (0.6 g)을 에탄올 (20 ml)에 녹인 후 하이드록실아민 (0.36 ml, 5 eq)을 첨가하였다. 18 시간 동안 환류 교반하고, 반응 혼합물을 감압 농축하였다. 크로마토그래피 (실리카, 10% MeOH/CHCl 3 사용)로 정제하여 표제 화합물 0.37 g (수율: 57 %)을 수득하였다.
[단계 4] (Z)-2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)-N'-(피발로일옥시)아세트이미드아마이드 (Z)-2-(2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)-N'-(pivaloyloxy)acetimidamide의 제조
Figure PCTKR2019008609-appb-img-000046
단계 3에서 제조된 화합물 (0.4 g), HOBt (0.25 g, 1.1 eq), EDCI (0.37 g, 1.15 eq), 터트-부틸 카르복실산 (0.22 g, 1.3 eq)를 메틸렌클로라이드 10 ml에 녹인 후, 트리에틸아민 (0.35 ml, 1.5 eq)을 적가하였다. 상온에서 18 시간 동안 교반 후, H 2O 10 ml를 첨가하고 메틸렌클로라이드 10 ml로 추출하였다. 유기층을 Brine 10 ml로 세척 후, 크로마토그래피 (실리카, 10% MeOH/CHCl 3 사용)로 정제하여 표제 화합물 0.167 g (수율: 31 %)을 수득하였다
[단계 5] 3-(4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000047
단계 4에서 제조된 화합물 (0.167 g)과 K 2CO 3 (0.107 g, 1.5 eq)를 톨루엔 10 ml에 녹인 후, 3 시간 동안 환류 교반하였다. 반응 혼합물을 감압 농축하고, 크로마토그래피 (실리카, 10% MeOH/CHCl 3 사용)로 정제하여 표제 화합물 0.096 g (수율: 61 %)을 수득하였다.
1H-NMR (400MHz, CDCl 3): δ 0.91 (3H, t), 1.35-1.44 (11H, m), 1.65-1.73 (2H, m), 2.32 (3H, s), 2.67 (2H, t), 3.93 (2H, s), 5.29 (2H, s), 7.21-8.57 (8H, m)
<실시예 B-2 내지 B-14>
실시예 B-2 내지 B-14의 화합물은 실시예 B-1과 유사한 방법으로 각 실시예에 대응하는 카르복실산 유도체 화합물을 이용하여 합성하였다.
실시예 B-2: 3-(4'-((2-부틸-4-메틸-5-((5-(1-메틸사이클로프로필)-1,2,4-옥사다이아졸-3-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.90 (3H, t), 0.95-0.98 (2H, m), 1.34-1.43 (4H, m), 1.51 (3H, s), 1.64-1.72 (2H, m), 2.66 (2H, t), 3.90 (2H, s), 5.28 (2H, s), 7.18-7.78 (8H, m)
실시예 B-3: 3-(4'-((2-부틸-5-((5-사이클로프로필-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.91 (3H, t), 1.15-1.20 (4H, m), 1.35-1.44 (2H, m), 1.66-1.73 (2H, m), 2.12-2.18 (1H, m), 2.31 (3H, s), 2.68 (2H, t), 3.89 (2H, s), 5.28 (2H, s), 7.21-7.81 (8H, m)
실시예 B-4: 3-(4'-((2-부틸-5-((5-이소프로필-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.91 (3H, t), 1.35-1.74 (8H, m), 1.65-1.72 (2H, m), 2.31 (3H, s), 2.67 (2H, t), 3.11-3.22 (1H, m), 3.92 (2H, s), 5.28 (2H, s), 7.20-7.79 (8H, m)
실시예 B-5: 3-(4'-((2-부틸-5-((5-(1-(4-클로로페닐)사이클로프로필)-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.89 (3H, t), 1.32-1.76 (8H, m), 2.26 (3H, s), 2.63 (2H, t), 3.82 (2H, s), 5.27 (2H, s), 7.15-7.73 (12H, m)
실시예 B-6: 3-(4'-((2-부틸-5-((5-사이클로부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-cyclobutyl-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): 0.90 (3H, t), 1.33-1.42 (2H, m), 1.63-1.71 (2H, m), 1.98-2.21 (2H, m), 2.30 (3H, s), 2.38-2.45 (4H, m), 2.65 (2H, t), 3.65-3.66 (1H, m), 3.90 (2H, s), 5.26 (2H, s), 7.18-7.76 (8H, m)
실시예 B-7: 3-(4'-((2-부틸-5-((5-(2-플루오로페닐)-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): 0.90 (3H, t), 1.33-1.43 (2H, m), 1.64-1.72 (2H, m), 2.34 (3H, s), 2.67 (2H, t), 4.01 (2H, s), 5.28 (2H, s), 7.19-8.08 (12H, m)
실시예 B-8: 3-(4'-((2-부틸-5-((5-(2-플루오로벤질)-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(2-fluorobenzyl)-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): 0.89 (3H, t), 1.32-1.70 (4H, m), 2.27 (3H, s), 2.64 (2H, t), 3.88 (2H, s), 4.21 (2H, s), 5.24 (2H, s), 7.04-7.72 (12H, m)
실시예 B-9: 4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-카르복실산 4'-((2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-carboxylic acid의 제조
1H-NMR (400MHz, CDCl 3): 0.84 (3H, t), 1.27-1.40 (11H, m), 1.55-1.63 (2H, m), 2.33 (3H, s), 2.65 (2H, t), 4.03 (2H, s), 5.34 (2H, s), 7.16-7.93 (8H, m)
실시예 B-10: 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온 (3-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl)-6-methylpyrimidin-4(3H)-one)의 제조
1H-NMR (400MHz, CDCl 3): 0.93 (3H, t), 1.38-1.47 (11H, m), 1.70-1.77 (2H, m), 2.35 (3H, s), 2.73 (2H, t), 3.98 (2H, s), 5.28 (2H, s), 7.19-8.13 (8H, m)
실시예 B-11: 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-(2-플루오로페닐)-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온 3-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-5-((5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-6-methylpyrimidin-4(3H)-one의 제조
1H-NMR (400MHz, CDCl 3): 0.89 (3H, t), 1.32-1.70 (4H, m), 2.34 (3H, s), 2.64 (2H, t), 4.03 (2H, s), 5.23 (2H, s), 7.06-8.04 (12H, m)
실시예 B-12: 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-(4-메톡시벤질)-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온 3-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-5-((5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)methyl)-6-methylpyrimidin-4(3H)-one의 제조
1H-NMR (400MHz, CDCl 3): 0.90 (3H, t), 1.33-1.72 (4H, m), 2.30 (3H, s), 2.67 (2H, t), 3.74 (3H, s), 3.92 (2H, s), 4.13 (2H, s), 5.18 (2H, s), 6.79-7.96 (12H, m)
실시예 B-13: 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-(4-클로로벤질)-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온 3-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-5-((5-(4-chlorobenzyl)-1,2,4-oxadiazol-3-yl)methyl)-6-methylpyrimidin-4(3H)-one의 제조
1H-NMR (400MHz, CDCl 3): 0.91 (3H, t), 1.35-1.74 (4H, m), 2.32 (3H, s), 2.70 (2H, t), 3.94 (2H, s), 4.19 (2H, s), 5.20 (2H, s), 6.89-8.01 (12H, m)
실시예 B-14: 메틸 4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-카르복실레이트 methyl 4'-((2-butyl-5-((5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-carboxylate의 제조
1H-NMR (400MHz, CDCl 3): 0.90 (3H, t), 1.33-1.71 (13H, m), 2.35 (3H, s), 2.68 (2H, t), 3.62 (2H, s), 4.04 (2H, s), 5.37 (2H, s), 7.20-7.83 (8H, m)
실시예 C-1: 3-(4'-((2-부틸-4-이소프로필-5-((5-메틸-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-isopropyl-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
[단계 1] 2-(2-부틸-4-이소프로필-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리디민-5-일)아세트산 2-(2-butyl-4-isopropyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)acetic acid의 제조
Figure PCTKR2019008609-appb-img-000048
플라스크에 메틸 2-(2-부틸-4-이소프로필-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세테이트 (5.9 g, 11.7 mmol)을 투입하고, 메틸알콜 50 mL를 주입하였다. 온도를 15 ℃ 이하로 유지하며 2.5N 수산화나트륨 수용액 10 mL를 적가하고, 15 시간 동안 실온 교반하였다. 실온 교반을 완료한 후 감압농축하고, 클로로포름 150 mL와 정제수 150 mL을 주입하였다. 2N 염산 수용액을 적가하여 pH를 3~4로 조절하고, 클로로포름층을 분리하였다. 분리한 클로로포름층을 정제수 150 mL로 세척하고, 마그네슘설페이트 1 g으로 건조한 후 여과하여 농축하였다. 잔사를 1:2 에틸아세테이트/n-헥산을 60 mL를 사용하여 미황색 고체의 표제 화합물 4.2 g (수율: 75.7 %)을 얻었다.
[단계 2] N'-아세틸-2-(2-부틸-4-이소프로필-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리디민-5-일)아세토하이드라자이드 N'-acetyl-2-(2-butyl-4-isopropyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)acetohydrazide의 제조
Figure PCTKR2019008609-appb-img-000049
플라스크에 단계 1에서 제조된 화합물 (140 mg, 0.2 mmol)을 투입하고, 클로로포름 5 mL를 주입하였다. 온도를 15 ℃ 이하로 유지하며 디메틸아미노프로필 에틸카보디이미드 염산염 (44 mg, 0.22 mmol), 하이드록시벤조트리아졸 (29.6 mg, 0.22 mmol), 아세틸하이드라자이드 (16.9 mg, 0.22 mmol)을 투입한 후, 트리에틸아민 (22 mg, 0.22 mmol)를 적가하고 15 시간 동안 실온 교반하였다. 클로로포름 15 mL와 정제수 15 mL을 가하여 유기층을 분리하였다. 분리한 유기층을 마그네슘설페이트 1 g으로 건조한 후 여과하고 농축하여 표제 화합물 95 mg (수율: 62.5 %)을 얻었다.
[단계 3] 3-(4'-((2-부틸-4-이소프로필-5-((5-메틸-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-isopropyl-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000050
단계 2에서 제조된 화합물 (0.02 g)을 톨루엔 3 mL에 녹인 후, POCl 3 (0.1 mL)를 적가하였다. 상온에서 10 분간 교반 후, 80 ℃에서 4 시간 동안 가열 교반하였다. 얼음물 10mL를 적가하고, 에틸아세테이트 20 mL로 희석하였다. 상온으로 승온시킨 후, NaHCO 3 포화 수용액으로 세척하였다. 유기층을 무수 Na 2SO 4로 건조하고 감압 농축하였다. 크로마토그래피 (99:3 클로로포름/메틸알콜)로 정제하여 미색 고체의 표제 화합물 8.5 mg (수율: 43 %)을 얻었다.
1H-NMR (400MHz, CDCl 3): δ 0.92 (m, 3H), 1.26 (d, 6H), 1.42 (m, 2H), 1.77 (m, 2H), 2.47 (s, 3H), 2.71 (t, 2H), 3.19 (q, 1H), 4.33 (s, 2H), 5.37 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.45 (d, 1H), 7.50 (m, 2H), 7.62 (t, 1H)
<실시예 C-2 내지 C-6>
실시예 C-2 내지 C-6의 화합물은 실시예 C-1과 유사한 방법으로 각 실시예에 상응하는 하이드라자이드 유도체 화합물을 이용하여 합성하였다.
실시예 C-2: 3-(4'-((2-부틸-4-이소프로필-5-((5-(4-메톡시페닐)-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-isopropyl-5-((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.94 (t, 3H), 1.24 (d, 6H), 1.38 (m, 2H), 1.75 (m, 2H), 2.72 (t, 2H), 3.33 (q, 1H), 3.70 (s, 3H), 3.81 (s, 2H), 5.40 (s, 2H), 7.04 (t, 1H), 7.23-7.35 (m, 3H), 7.45 (d, 2H), 7.52 (m, 3H), 7.50 (m, 2H), 7.72 (t, 1H)
실시예 C-3: 3-(4'-((2-부틸-4-이소프로필-5-((5-(3-메톡시페닐)-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-isopropyl-5-((5-(3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.91 (t, 3H), 1.24 (d, 6H), 1.39 (m, 2H), 1.78 (m, 2H), 2.71 (t, 2H), 3.33 (q, 1H), 3.67 (s, 3H), 3.94 (s, 2H), 5.31 (s, 2H), 6.94 (t, 2H), 7.21 (d, 2H), 7.23-7.35 (m, 4H), 7.45 (d, 2H), 7.79 (t, 2H)
실시예 C-4: 3-(4'-((2-부틸-5-((5-하이드록시-1,3,4-옥사다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-hydroxy-1,3,4-oxadiazol-2-yl)methyl)-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 1.26 (d, 6H), 1.42 (m, 2H), 1.77 (m, 2H), 2.46 (s, 1H), 2.70 (t, 2H), 3.20 (q, 1H), 4.33 (s, 2H), 5.37 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.45 (d, 1H), 7.50 (m, 2H), 7.62 (t, 1H)
실시예 C-5: 3-(4'-((2-부틸-5-((5-(다이메틸아미노)-1,3,4-옥사다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(dimethylamino)-1,3,4-oxadiazol-2-yl)methyl)-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 1.26 (d, 6H), 1.42 (m, 2H), 1.77 (m, 2H), 2.47 (s, 1H), 2.71 (t, 2H), 2.80-2.95 (6H, d), 3.19 (q, 1H), 4.33 (s, 2H), 5.37 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.45 (d, 1H), 7.50 (m, 2H), 7.62 (t, 1H)
실시예 C-6: 3-(4'-((2-부틸-4-이소프로필-6-옥소-5-((5-(피롤리딘-1-일)-1,3,4-옥사다이아졸-2-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-isopropyl-6-oxo-5-((5-(pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 1.26 (d, 6H), 1.42 (m, 2H), 1.50-1.85 (m, 6H), 2.47 (s, 1H), 2.71 (t, 2H), 2.80-2.95 (4H, m), 3.19 (q, 1H), 4.33 (s, 2H), 5.37 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.45 (d, 1H), 7.50 (m, 2H), 7.62 (t, 1H)
실시예 D-1: 3-(4'-((2-부틸-4-메틸-6-옥소-5-((5-페닐옥사졸-2-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((5-phenyloxazol-2-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
[단계 1] 2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)-N-(2-옥소-2-페닐에틸)아세트아마이드 2-(2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)-N-(2-oxo-2-phenylethyl)acetamide의 제조
Figure PCTKR2019008609-appb-img-000051
2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리디민-5-일)아세트산 (0.1g), HOBt (0.031 g, 1.1 eq), EDCI (0.046 g, 1.15 eq), 트리에틸아민 (0.088 ml, 3 eq), 2-아미노-1-페닐에타논 (0.047 g, 1.3 eq)을 메틸렌클로라이드 10 ml에 녹인 후, 상온에서 18 시간 동안 교반하였다. 메틸렌클로라이드 10 ml를 첨가 하고 정제수 10 ml로 세척하였다. 물층을 메틸렌클로라이드 10 ml로 추출하였다. 유기층을 모아 무수 MgSO 4로 건조, 여과 후 감압농축하였다. 남은 유기물을 실리카와 5% MeOH/CHCl 3로 정제하여 표제 화합물 0.095 g을 수득하였다.
[단계 2] 3-(4'-((2-부틸-4-메틸-6-옥소-5-((5-페닐옥사졸-2-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-6-oxo-5-((5-phenyloxazol-2-yl)methyl)pyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000052
단계 1에서 제조된 화합물 (0.095 g) 을 아세토나이트릴 10 ml에 녹인 후, POCl 3 (0.03 ml, 2 eq) 를 적가하고, 18 시간 동안 환류 교반하였다. 반응 용액을 감압 농축 후 CHCl 3 25 ml에 용해시켰다. 정제수 25 ml로 세척 후, 포화 NaHCO 3 수용액 10 ml로 세척하였다. 유기층을 MgSO 4 건조, 여과 후 감압 농축하였다. 남은 유기물을 실리카와 5% MeOH/CHCl 3로 정제하여 표제 화합물 0.060 g (수율: 65 %)을 수득하였다.
1H-NMR (400MHz, CDCl 3): δ 0.92 (3H, t), 1.37-1.76 (4H, m), 2.39 (3H, s), 2.71 (2H, t), 4.09 (2H, s), 5.31 (2H, s), 7.20-7.84 (14H, m)
실시예 D-2: 3-(4'-((5-(벤조[d]옥사졸-2-일메틸)-2-부틸-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-(benzo[d]oxazol-2-ylmethyl)-2-butyl-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
실시예 D-2의 화합물은 실시예 D-1과 유사한 방법으로 2-아미노-1-페닐에타논 대신 1-아미노페놀을 사용하여 합성하였다.
1H-NMR (400MHz, CDCl 3): δ 0.93 (3H, t), 1.24 (6H, d), 1.37-1.76 (4H, m), 2.71 (2H, t), 3.34 (1H, m), 4.09 (2H, s), 5.31(2H, s), 7.20-7.84 (12H, m)
실시예 D-3: 3-(4'-((5-((5-벤질이소옥사졸-3-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((5-benzylisoxazol-3-yl)methyl)-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
[단계 1] 2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)-N-메톡시-N-메틸아세트아마이드 2-(2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)-N-methoxy-N-methylacetamide의 제조
Figure PCTKR2019008609-appb-img-000053
플라스크에 2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세트산 5 g (10.5 mmol), (벤조트리아졸-1-일옥시)트리스(다이메틸아미노)포스포늄 헥사플루오로포스페이트 (BOP) 5.6 g (12.6 mmol)을 넣고, 메틸렌클로라이드 20 ml, 트리에틸아민 4.4 ml (31.5 mmol) 및 N,O-다이메틸하이드록실아민 670 mg (11.0 mmol)을 첨가 후, 혼합물을 12 시간 동안 상온에서 교반 후 감압 농축하였다. 남은 여액에 에틸아세테이트 100 ml를 넣고 포화 NH 4Cl 수용액과 brine으로 순차적으로 세척하였다. 무수 MgSO 4로 유기층을 건조하여 여과한 후, 여액을 농축하였다. 얻어진 표제 화합물은 별도의 정제 없이 다음 반응을 진행하였다 (수율: 100 %).
[단계 2] 2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세트알데하이드 2-(2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)acetaldehyde의 제조
Figure PCTKR2019008609-appb-img-000054
단계 1에서 제조된 화합물 4.8 g (10.5 mmol)에 THF 40 ml를 주입한 후, 질소 충전하였다. 반응액을 0 ℃로 냉각한 후 DIBAL-H 1.0 M THF 용액 10.5 mL (10.5 mmol)를 서서히 적가하였다. 0 ℃를 유지하면서 1 시간 동안 교반하였다. 반응액을 농축한 후, 에틸아세테이트 100 ml를 넣고 1N-HCl과 brine으로 순차적으로 세척하였다. 무수 MgSO 4로 유기층을 건조하여 여과한 후, 여액을 감압 농축하였다. silica 와 CHCl 3/MeOH=95/5)으로 분리 정제하여 표제 화합물 1.9 g을 수득하였다 (2 step 20%).
[단계 3] (E)-2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세트알데하이드 옥심 (E)-2-(2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)acetaldehyde oxime의 제조
Figure PCTKR2019008609-appb-img-000055
플라스크에 단계 2에서 제조된 화합물 400 mg (0.87 mmol)을 넣고, THF 7 ml, 정제수 4 ml를 넣은 후, NH 2OH 용액을 주입하였다. 12 시간 동안 상온에서 교반 후, 반응액을 감압 농축하였다. 여액에 에틸아세테이트 30 ml를 넣고 1N-HCl과 brine으로 순차적으로 세척하였다. 무수 MgSO 4로 유기층을 건조하여 여과한 후, 여액을 농축하였다. 실리카와 CHCl 3/MeOH=95/5로 정제하여 표제 화합물 150 mg (수율: 37 %)을 수득하였다.
[단계 4] (Z)-2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)-N-하이드록시아세트이미도일 클로라이드 (Z)-2-(2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)-N-hydroxyacetimidoyl chloride의 제조
Figure PCTKR2019008609-appb-img-000056
단계 3에서 제조된 화합물 30 mg (0.063 mmol)에 CHCl 3 3ml를 넣었다. 질소 충전 후 피리딘 100 mg (excess)을 주입하고, 1 시간 동안 환류 교반하였다. N-클로로숙신이미드 9.3 mg (0.07 mmol)을 넣고 2 시간 동안 환류 교반하였다. TLC, MS 를 사용하여 클로로화 반응을 확인한 후, 연속해서 다음 반응을 진행하였다.
[단계 5] 3-(4'-((5-((5-벤질이소옥사졸-3-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((5-benzylisoxazol-3-yl)methyl)-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000057
단계 4에서 제조된 화합물 반응액에 3-페닐-1-프로핀 8.2 mg을 넣었다. 12 시간 동안 환류교반 후, 반응 용액을 감압 농축하였다. 남은 여액에 CHCl 3 20 ml를 넣고 정제수로 세척하였다. 무수 MgSO 4로 유기층을 건조하여 여과한 후, 여액을 감압 농축하였다. Prep-HPLC (아세토나이트릴 20 내지 100 %, gradient)로 정제하여 표제 화합물 3.6 mg을 수득하였다.
1H-NMR (400MHz, CDCl 3): δ 0.90 (3H, t), 1.38 (2H, m), 1.66 (2H, s), 2.33 (3H, s), 2.65 (2H, t), 3.82 (2H, s), 4.00 (2H, s), 5.27 (2H, s), 5.83 (1H, s), 7.16-7.29 (9H, m), 7.39 (1H, d), 7.49 (1H, m), 7.60 (1H, m), 7.81 (1H, d)
실시예 D-4: 3-(4'-((2-부틸-5-((5-터트-부틸이소옥사졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-tert-butylisoxazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
실시예 D-4의 화합물은 실시예 D-3과 유사한 방법으로 3-페닐-1-프로핀 대신 3,3-다이메틸-1-부틴을 사용하여 합성하였다.
1H-NMR (400MHz, CDCl 3): δ 0.90 (3H, t), 1.33-1.42 (11H, m), 1.64-1.73 (2H, m), 2.31 (3H, s), 2.67 (2H, t), 4.05 (2H, s), 5,28 (2H, s), 7.17-7.78 (9H, m)
실시예 D-5: 3-(4'-((2-부틸-5-((5-(2-하이드록시프로판-2-일)이소옥사졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일l)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(2-hydroxypropan-2-yl)isoxazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
실시예 D-5의 화합물은 실시예 D-3과 유사한 방법으로 3-페닐-1-프로핀 대신 2-메틸-3-부틴-2-올을 사용하여 합성하였다.
1H-NMR (400 MHz, CDCl 3) δ 0.90 (3H, t), 1.38 (2H, m), 1.52 (6H, s), 1.68 (2H, m), 2.31 (3H, s), 2.67 (2H, t), 3.77 (2H, s), 5.24 (2H, s), 5.96 (1H, s), 7.15 (2H, d), 7.29 (2H, d), 7.41 (1H, d), 7.48 (1H, m), 7.61 (1H, m), 7.75 (1H, d)
실시예 D-6: 3-(4'-((2-부틸-5-((5-(1-하이드록시에틸)이소옥사졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(1-hydroxyethyl)isoxazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
실시예 D-6의 화합물은 실시예 D-3과 유사한 방법으로 3-페닐-1-프로핀 대신 3-부틴-2-올을 사용하여 합성하였다.
1H-NMR (400 MHz, CDCl 3) δ 0.90 (3H, t), 1.38 (2H, m), 1.48 (2H, d), 1.68 (2H, m), 2.31 (3H, s), 2.67 (2H, t), 3.77 (2H, s), 4.88 (1H, q), 5.24 (2H, s), 5.99 (1H, s), 7.14 (2H, d), 7.29 (2H, d), 7.41 (1H, d), 7.50 (1H, m), 7.61 (1H, m), 7.75 (1H, d)
실시예 E-1: 3-(4'-((2-부틸-4-메틸-5-((5-메틸-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000058
실시예 C-1의 단계 1 및 단계 2와 유사한 방법으로 제조된 N'-아세틸-2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리디민-5-일)아세토하이드라자이드 (35 mg, 0.045 mmol)를 플라스크에 투입하고 테트라하이드로퓨란 3 mL를 주입한 후, 로신 시약 (17 mg, 0.045 mmol)을 투입하였다. 4 시간 동안 환류 교반 후 감압 농축하여 용매를 제거하였다. 클로로포름 30 mL와 정제수 30 mL을 가하여 유기층을 분리하였다. 분리한 유기층을 정제수 30 mL로 세척하고, 마그네슘설페이트 0.1 g으로 건조한 후 여과하여 농축하였다. 잔사를 크로마토그래피 (99:3 클로로포름/메틸알콜)로 정제하여 미황색 고체의 표제 화합물 8.7 mg (수율: 36.7 %)을 얻었다.
1H-NMR (400MHz, CDCl 3): δ 0.89 (3H, t), 1.32-1.70 (4H, m), 2.39 (3H, s), 2.66-2.68 (5H, m), 4.20 (2H, s), 5.29 (2H, s), 7.14-7.76 (8H, m))
<실시예 E-2 내지 E-12>
실시예 E-2 내지 E-12의 화합물은 실시예 E-1과 유사한 방법으로 각 실시예에 대응되는 출발물질과 하이드라자이드 유도체로부터 합성하였다.
실시예 E-2: 3-(4'-((2-부틸-5-((5-에틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-ethyl-1,3,4-thiadiazol-2-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.88 (3H, t), 1.31-1.70 (7H, m), 2.38 (3H, s), 2.66 (2H, t), 2.99-3.04 (2H, m), 4.20 (2H, s), 5.29 (2H, s), 7.13-7.74 (8H, m)
실시예 E-3: 3-(4'-((2-부틸-5-((5-이소프로필-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-isopropyl-1,3,4-thiadiazol-2-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.90 (3H, t), 1.35-1.42 (8H, m), 1.64-1.71 (2H, m), 2.41 (3H, s), 2.69 (2H, t), 3.31-3.42 (1H, m), 4.23 (2H, s), 5.31 (2H, s), 7.17-7.77 (8H, m)
실시예 E-4: 3-(4'-((2-부틸-5-((5-터트-부틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-tert-butyl-1,3,4-thiadiazol-2-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.91 (3H, t), 1.36-1.42 (11H, m), 1.65-1.73 (2H, m), 2.42 (3H, s), 2.71 (2H, t), 4.24 (2H, s), 5.34 (2H, s), 6.82-7.78 (8H, m)
실시예 E-5: 3-(4'-((4-메틸-5-((5-(1-메틸사이클로프로필)-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((4-methyl-5-((5-(1-methylcyclopropyl)-1,3,4-thiadiazol-2-yl)methyl)-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.96 (5H, m), 1.24 (2H, t), 1.53 (3H, s), 1.74 (2H, m), 2.42 (3H, s), 2.65 (2H, t), 4.22 (2H, s), 5.32 (2H, s), 7.19 (2H, d), 7.29 (2H, d), 7.41 (1H, q), 7.49 (1H, t), 7.60 (1H, t), 7.80 (1H, d)
실시예 E-6: 3-(4'-((5-((5-사이클로프로필-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.96 (3H, t), 1.06 (2H, m), 1.16 (2H, m), 1.74 (2H, m), 2.33 (1H, m), 2.42 (3H, s), 2.68 (2H, t), 4.22 (2H, s), 5.33 (2H, s), 7.20 (2H, d), 7.31 (2H, d), 7.43 (1H, q), 7.51 (1H, t), 7.63 (1H, t), 7.80 (1H, d)
실시예 E-7: 3-(4'-((5-((5-터트-부틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((5-tert-butyl-1,3,4-thiadiazol-2-yl)methyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.96 (3H, m), 1.43 (9H, s), 1.74 (2H, m), 2.44 (3H, s), 2.65 (2H, t), 4.26 (2H, s), 5.33 (2H, s), 7.19 (2H, d), 7.31 (2H, d), 7.40 (1H, q), 7.52 (1H, t), 7.62 (1H, t), 7.79 (1H, d)
실시예 E-8: 3-(4'-((2-부틸-5-((5-터트-부틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-tert-butyl-1,3,4-thiadiazol-2-yl)methyl)-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.91 (3H, t), 1.20-1.40 (14H, m), 1.65-1.73 (2H, m), 2.71 (2H, t), 3.36 (q, 1H), 4.24 (2H, s), 5.34 (2H, s), 6.82-7.78 (8H, m)
실시예 E-9: 3-(4'-((2-부틸-5-((5-(3-플루오로페닐)-1,3,4-싸이아다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(3-fluorophenyl)-1,3,4-thiadiazol-2-yl)methyl)-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.91 (3H, t), 1.21 (6H, d), 1.41 (2H, m), 1.77 (2H, m), 2.73 (2H, t), 3.37 (1H, q), 4.40 (2H, s), 5.34 (2H, s), 7.14 (1H, t), 7.19 (2H, d), 7.33 (2H, d), 7.39 (2H, m), 7.45 (1H, t), 7.49 (1H, t), 7.61 (2H, t), 7.84 (1H, d)
실시예 E-10: 3-(4'-((2-부틸-4-이소프로필-5-((5-메틸-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-isopropyl-5-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.91 (3H, m), 1.17 (6H, d), 1.34 (2H, m), 1.75 (2H, m), 2.67 (5H, m), 3.30 (1H, q), 4.27 (2H, s), 5.30 (2H, s), 7.18 (2H, d), 7.31 (2H, d), 7.44 (1H, d), 7.50 (1H, t), 7.62 (1H, t), 7.80 (1H, d)
실시예 E-11: 3-(4'-((2-부틸-5-((5-에틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-ethyl-1,3,4-thiadiazol-2-yl)methyl)-4-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.92 (3H, m), 1.19 (6H, d), 1.34 (5H, m), 1.76 (2H, m), 2.70 (2H, t), 3.06 (2H, t), 3.35 (1H, q), 4.29 (2H, s), 5.31 (2H, s), 7.21 (2H, d), 7.34 (2H, d), 7.43 (1H, d), 7.53 (1H, t), 7.61 (1H, t), 7.81 (1H, d)
실시예 E-12: 3-(4'-((2-부틸-4-이소프로필-5-((5-이소프로필-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-isopropyl-5-((5-isopropyl-1,3,4-thiadiazol-2-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
1H-NMR (400MHz, CDCl 3): δ 0.92 (3H, m), 1.16 (6H, d), 1.36 (8H, m), 1.74 (2H, m), 2.70 (2H, t), 3.30 (1H, q), 3.39 (1H, q), 4.28 (2H, s), 5.30 (2H, s), 7.20 (2H, d), 7.30 (2H, d), 7.43 (1H, d), 7.52 (1H, t), 7.61 (1H, t), 7.78 (1H, d)
실시예 F-1: 3-(4'-((2-부틸-5-((5-(4-플루오로페닐)-4H-1,2,4-트리아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
[단계 1] 4-플루오로벤즈이미드아마이드 (4-fluorobenzimidamide)의 제조
Figure PCTKR2019008609-appb-img-000059
NH 4Cl (0.4 g, 1.01 eq)를 톨루엔에 첨가 후, 0 ℃로 냉각한 혼합물에 트리메틸 알루미늄 (3.7 6mL, 1.01 eq)를 첨가하였다. 상온에서 2 시간 동안 교반 후 4-플루오로벤조나이트릴 (1.0 g, 1 eq)을 첨가하였다. 80 ℃에서 16 시간 동안 교반한 후, 상온으로 냉각하였다. SiO 2, 메틸렌클로라이드 (10 mL)를 첨가한 후 상온에서 10 분간 교반하였다. 반응 혼합물을 셀라이트 필터를 통해 여과 후 MeOH (10 mL)로 세척하였다. 여과액을 농축 후 건조하여 표제 화합물 0.8 g을 얻어 다음 반응에 사용하였다.
[단계 2] 3-(4'-((2-부틸-5-((5-(4-플루오로페닐)-4H-1,2,4-트리아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000060
2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세트산 (0.2g)을 4-플루오로벤즈이미드아마이드 (0.20 g, 2.5 eq), HATU (0.18 g, 1.1 eq), DIPEA (0.22 ml, 3 eq) 와 함께 DMF 2 mL에 녹인 후, 상온에서 2 시간 동안 교반하였다. 반응 용액에 하이드라진 (0.04 ml, 1.5 eq)과 아세트산 (0.24 ml, 10 eq) 를 첨가하고 80 ℃에서 18 시간 동안 교반하였다. 상온으로 냉각하고 에틸아세테이트 (10 mL)로 희석한 후, 포화 NaHCO 3 수용액 (10 mL)으로 세척하였다. 무수 Na 2SO 4로 건조 후 농축하였다. 5% MeOH/CHCl 3와 실리카를 사용하여 정제하여 표제 화합물 0.029 g (수율: 11 %)을 수득하였다.
1H-NMR (400MHz, CDCl 3): δ 0.89 (3H, t), 1.32-1.73 (4H, m), 2.48 (3H, s), 2.69 (2H, t), 4.01 (2H, s), 5.29 (2H, s), 6.94-7.81 (12H, m)
실시예 F-2: 3-(4'-((2-부틸-5-((5-(2-플루오로페닐)-4H-1,2,4-트리아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
4-플루오로벤조나이트릴 대신 2-플루오로벤조나이트릴을 사용하여 실시예 F-1과 유사한 방법으로 합성하였다.
1H-NMR (400MHz, CDCl 3): δ 0.87 (3H, t), 1.30-1.69 (4H, m), 2.39 (3H, s), 2.65 (2H, t), 3.99 (2H, s), 5.25 (2H, s), 6.98-7.94 (12H, m)
실시예 F-3: 3-(4'-((2-부틸-4-메틸-5-((3-메틸-1H-1,2,4-트리아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-methyl-1H-1,2,4-triazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000061
2-(2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)아세트산 0.2 g, 아미딘 HCl 0.06 g (1.5 eq), HATU 0.176 g (1.1 eq), DIPEA 0.22 ml (3 eq)를 DMF 2ml 에 녹인 후 상온에서 3 시간 동안 교반하였다. 반응 용액에 50~60% 히드라진 수화물 0.04 ml (1.5 eq) 과 아세트산 0.24 ml (10 eq)를 첨가하고, 80 oC에서 3시간 동안 가열 교반하였다. 상온으로 냉각하고 에틸아세테이트 10 ml로 희석한 후, 포화 NaHCO 3 수용액으로 세척하였다. 무수 Na 2SO 4로 건조하고 농축한 뒤, Prep-HPLC (아세토니트릴 30 내지 100%, gradient)로 정제하여 표제 화합물 3.1 mg을 수득하였다.
1H-NMR (400MHz, CDCl 3): δ 0.91 (3H, t), 1.30-1.75 (4H, m), 2.14 (3H, s), 2.36 (3H, s), 2.65-2.74 (2H, m), 3.81 (2H, s), 5.24 (2H, s), 7.10-7.80 (8H, m)
실시예 F-4: 3-(4'-((2-부틸-4-메틸-5-((3-메틸-1-페닐-1H-1,2,4-트리아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-4-methyl-5-((3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl)methyl)-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
히드라진 대신 페닐히드라진을 사용하여 실시예 F-3과 유사한 방법으로 표제 화합물을 제조하였다.
1H-NMR (400MHz, CDCl 3): δ 0.89 (3H, t), 1.27-1.67 (4H, m), 2.18 (3H, s), 2.30 (3H, s), 2.59 (2H, t), 3.94 (2H, s), 5.18 (2H, s), 7.11-7.70 (13H, m)
실시예 F-5: 3-(4'-((2-부틸-5-((1-부틸-3-메틸-1H-1,2,4-트리아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((1-butyl-3-methyl-1H-1,2,4-triazol-5-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
히드라진 대신 부틸히드라진을 사용하여 실시예 F-3과 유사한 방법으로 표제 화합물을 제조하였다.
1H-NMR (400MHz, CDCl 3): δ 0.87-0.91 (6H, m), 1.22-1.72 (8H, m), 2.13 (3H, s), 2.37 (3H, s), 2.64 (2H, t), 3.89 (2H, s), 4.01 (2H, t), 5.25 (2H, s), 7.11-7.72 (8H, m)
실시예 F-6: 3-(4'-((2-부틸-5-((1-(4-플루오로벤질)-1H-1,2,3-트리아졸-4-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
[단계 1] (4-((2-부틸-4-메틸-6-옥소-1,6-다이하이드로피리미딘-5-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸 피발레이트 (4-((2-butyl-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate의 제조
Figure PCTKR2019008609-appb-img-000062
반응 용기에 아지도메틸 피발레이트 0.85 g (5.36 mmol)을 투입하고, 정제수 7.5 mL와 BuOH 7.5 mL을 투입한 후 교반하였다. 2-부틸-6-메틸-5-(프로프-2-이닐)피리미딘-4(3H)-온 1 g (4.90 mmol), CuSO 4 5H 2O 0.06 g (0.25 mmol) 및 소듐 아스코르베이트 0.29 g (1.47 mmol)를 순서대로 첨가한 후, 상온에서 24 시간 동안 교반하였다. 생성된 고체를 여과 후, 정제수 7.5 mL와 BuOH 7.5 mL의 혼합용매로 세척하였다. 여과물을 감압 건조하여 표제 화합물을 수득하였다.
[단계 2] (4-((2-부틸-1-((2'-시아노바이페닐-4-일)메틸)-4-메틸-6-옥소-1,6-다이하이드로피리미딘-5-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸 피발레이트 (4-((2-butyl-1-((2'-cyanobiphenyl-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate의 제조
Figure PCTKR2019008609-appb-img-000063
반응 용기에 단계 1에서 제조된 화합물 1.28 g (3.54 mmol)을 투입하고, 에틸아세테이트 11.5 mL와 DMF 1.3 mL를 가한 후 교반하였다. 4'-(브로모메틸)-[1,1'-바이페닐]-2-카보나이트릴 1.16 g (4.25 mmol)과 LiH 0.04 g (4.60 mmol)을 첨가 후, 80 ℃에서 24 시간 동안 교반하였다. 반응물을 농축 후, CHCl 3 10 mL와 정제수 10 mL를 첨가하였다. pH 7이 될 때까지 1N HCl을 첨가하였다. 유기층을 분리 후 수분을 제거하고 농축하였다. 컬럼 (에틸아세테이트:헥산=1:1, Rf: 0.3)을 통하여 분리하여 표제 화합물을 수득하였다.
[단계 3] (Z)-(4-((2-부틸-1-((2'-(N'-하이드록시카브아미미도일)바이페닐-4-일)메틸)-4-메틸-6-옥소-1,6-다이하이드로피리미딘-5-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸 피발레이트 (Z)-(4-((2-butyl-1-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate의 제조
Figure PCTKR2019008609-appb-img-000064
반응 용기에 NH 4OH.HCl 1.57 g (22.55 mmol)을 투입 후, DMSO 11 mL를 첨가하였다. NaHCO 3 2.74 g (32.63 mmol)을 첨가 후, 50 ℃에서 10 분간 교반하였다. 단계 2에서 제조된 화합물 1.39 g (2.51 mmol)을 DMSO 5mL에 용해 후 서서히 첨가하였다. 90 ℃에서 24 시간 동안 교반하였다. 상온에서 정제수 33 mL를 첨가 후 5 시간 동안 교반하였다. 고체 반응물을 여과하고 정제수 10 mL로 세척 후 감압 건조하였다. 수득물을 반응기에 넣고 에틸아세테이트 20 mL와 정제수 20 mL를 첨가 후 에틸아세테이트층을 수거하였다. 수분을 제거 후 농축하여 표제 화합물을 수득하였다.
[단계 4] (Z)-(4-((2-butyl-4-methyl-6-oxo-1-((2'-(N'-(phenoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (Z)-(4-((2-butyl-4-methyl-6-oxo-1-((2'-(N'-(phenoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate의 제조
Figure PCTKR2019008609-appb-img-000065
반응 용기에 단계 3에서 제조된 화합물 0.67 g (1.14 mmol)을 투입 후 CHCl 3 7 mL를 첨가하여 용해하였다. 0 ℃로 냉각 후 트리메틸아민 0.35 mL (2.52 mmol)을 첨가하였다. 페닐 클로로포르메이트 0.22 mL (1.71 mmol)을 첨가하고, 0 ℃에서 30 분 교반 후 상온에서 24 시간 동안 교반하였다. 정제수 10 mL를 첨가 후 유기층을 분리하였다. 수분을 제거 후 농축하여 표제 화합물을 수득하였다.
[단계 5] (4-((2-부틸-4-메틸-6-옥소-1-((2'-(5-옥소-4,5-다이하이드로-1,2,4-옥사다이아졸-3-일)바이페닐-4-일)메틸)-1,6-다이하이드로피리미딘-5-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸 피발레이트 (4-((2-butyl-4-methyl-6-oxo-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1,6-dihydropyrimidin-5-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate의 제조
Figure PCTKR2019008609-appb-img-000066
반응 용기에 단계 4에서 제조된 화합물 0.88 g (1.24 mmol)을 투입하고 톨루엔 6 mL를 첨가한 후, 110 ℃에서 24 시간 동안 교반하였다. 반응물을 농축후 에틸아세테이트 10 mL와 정제수 10 mL를 첨가 후 유기층을 분리하였다. 유기층의 수분을 제거 후 농축하였다. 에틸아세테이트 1.25 mL와 헥산 3.75 mL를 첨가 후, 상온에서 교반하였다. 고체 반응물을 여과 후 감압 건조하여 표제 화합물을 수득하였다.
[단계 6] 3-(4'-((5-((1H-1,2,3-트리아졸-4-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((5-((1H-1,2,3-triazol-4-yl)methyl)-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000067
반응 용기에 단계 5에서 제조된 화합물 0.58 g (0.95 mmol)을 투입 후 정제수 3 mL와 MeOH 3 mL 첨가하여 교반하였다. NaOH 0.83 g (2.09 mmol)을 첨가하고 24 시간 동안 상온에서 교반하였다. 농축 후 CHCl 3 10 mL와 정제수 10 mL를 첨가하고, pH 7이 될 때까지 1N HCl을 첨가하였다. 유기층을 분리 후 수분을 제거 후 농축하여 표제 화합물을 수득하였다.
[단계 7] 3-(4'-((2-부틸-5-((1-(4-플루오로벤질)-1H-1,2,3-트리아졸-4-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
Figure PCTKR2019008609-appb-img-000068
반응 용기에 단계 6에서 제조된 화합물 100 mg (0.20 mmol)을 투입 후, 에틸아세테이트 1 mL를 첨가하였다. K 2CO 3 30 mg (0.22 mmol)과 4-플루오로벤질클로라이드 31 mg (0.21 mmol)을 첨가 후, 78 ℃에서 24 시간 동안 교반하였다. 반응물을 농축 후 CHCl 3 10 mL와 정제수 10 mL를 첨가하였다. 유기층을 분리 후 수분을 제거하였다. 농축 후 컬럼으로 분리하여 (gradient H 2O:아세토나이트릴 = 9:1→0:10) 표제 화합물을 수득하였다.
1H-NMR (400 MHz, CDCl 3): δ 7.78 (d, 1H), 7.74 (t, 1H), 7.55 (t, 1H), 7.46 (m, 3H), 7.39 (m, 1H), 7.28 (m, 5H), 7.27 (m, 1H), 6.83 (d, 1H), 5.24 (s, 2H), 3.95 (s, 2H), 3.87 (s, 2H), 2.69 (t, 2H), 2.35 (s, 3H), 1.68 (m, 2H), 1.38 (m, 2H), 0.88 (t, 3H)
실시예 F-7: 3-(4'-((2-부틸-5-((1-(2-플루오로벤질)-1H-1,2,3-트리아졸-4-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온 3-(4'-((2-butyl-5-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one의 제조
4-플루오로벤질클로라이드 대신 2-플루오로벤질클로라이드를 사용하여 실시예 F-6과 동일한 방법으로 표제 화합물을 제조하였다.
1H-NMR (400 MHz, CDCl 3): δ 7.77 (d, 1H), 7.70 (t, 1H), 7.51 (t, 1H), 7.41 (m, 3H), 7.33 (m, 1H), 7.27 (m, 5H), 7.21 (m, 1H), 6.89 (d, 1H), 5.24 (s, 2H), 3.93 (s, 2H), 3.85 (s, 2H), 2.67 (t, 2H), 2.36 (s, 3H), 1.67 (m, 2H), 1.36 (m, 2H), 0.88 (t, 3H)
실시예 A-1 내지 A-115, 실시예 B-1 내지 B-14, 실시예 C-1 내지 C-6, 실시예 D-1 내지 D-6, 실시예 E-1 내지 E-12, 실시예 F-1 내지 F-7에서 제조한 본 발명의 화합물들의 구조는 다음 표 1에 정리된 바와 같다.
Figure PCTKR2019008609-appb-img-000069
Figure PCTKR2019008609-appb-img-000070
Figure PCTKR2019008609-appb-img-000071
Figure PCTKR2019008609-appb-img-000072
Figure PCTKR2019008609-appb-img-000073
Figure PCTKR2019008609-appb-img-000074
Figure PCTKR2019008609-appb-img-000075
Figure PCTKR2019008609-appb-img-000076
Figure PCTKR2019008609-appb-img-000077
Figure PCTKR2019008609-appb-img-000078
Figure PCTKR2019008609-appb-img-000079
Figure PCTKR2019008609-appb-img-000080
Figure PCTKR2019008609-appb-img-000081
Figure PCTKR2019008609-appb-img-000082
Figure PCTKR2019008609-appb-img-000083
Figure PCTKR2019008609-appb-img-000084
Figure PCTKR2019008609-appb-img-000085
Figure PCTKR2019008609-appb-img-000086
Figure PCTKR2019008609-appb-img-000087
Figure PCTKR2019008609-appb-img-000088
< 실험예 1> 피오글리타존 대비 활성도 측정
1. 실험 방법
- 사용 세포: Cos-7 (Fibroblast-like cell line derived from monkey kidney tissue)
- 사용 배지: Cos-7 cell_DMEM 10% FBS (DMEM : Invitrogen, #11995-065 or 073)
각 실시예의 화합물과 피오글리타존을 DMSO에 녹여 1 mM 농도의 용액을 제조한 후, 10 % FBS 배지로 희석하여 10 μM 농도의 용액으로 실험하였다.
[Day-1]
48 well plate에 세포를 3 X 10 4 cells / 250 μL / well 로 seeding 하고, 37 ℃, 5 % CO 2 에서 24 시간 동안 incubation 하였다.
[Day-2]
1) 상기 plate의 각 well을 PBS 0.5 mL로 2회 세척한 후, serum free media (DMEM) 250 μL씩 넣고 37 ℃, 5 % CO 2 incubator에 넣어 두었다.
2) 다음의 Mix 1과 Mix 2를 각각 제조한 뒤, Mix 1과 Mix 2를 잘 섞고 5분간 실온에 두었다.
- Mix 1
Figure PCTKR2019008609-appb-img-000089
- Mix 2
Figure PCTKR2019008609-appb-img-000090
- Lipofectamine 3000 (Invitrogen, #L3000008)
- Opti-MEM media (Invitrogen, #L31985-070)
3) incubator에 넣어둔 plate에 잘 섞인 Mix 1과 Mix 2 를 well당 25 μL씩 넣고, 37 ℃, 5 % CO 2 incubator에서 6 시간 동안 배양하였다.
4) 상기 plate의 배양액을 제거한 후 각 well당 각 실시예의 화합물 용액을 250 μL씩 넣고, 37 ℃, 5 % CO 2 incubator에서 20 시간 동안 배양하였다.
[Day-3]
1) 48 well plate를 PBS로 1회 세척한 후 각 well에 65 μL씩 passive Lysis Buffer(PLB)를 넣고, 15 분 동안 80 rpm으로 shaking 한 뒤, e-tube로 옮겨 4 ℃, 13000 rpm에서 1 분 동안 원심분리하였다.
2) 상층액 20 μL를 white well plate로 옮기고, Luciferase buffer 100 μL를 각 well에 넣고 Luminometer 기기로 Firefly activity를 측정하였다.
3) Renilla로 보정하여 Firefly activity를 산정한 후, DMSO를 기준으로 PPARγ 활성도를 측정하였다.
2. 실험 결과
실험예 1의 결과는 다음 표 2에 기재한 바와 같다.
실시예 활성도 (%) 실시예 활성도 (%)
A-2 88.9 A-3 70.6
A-4 165.5 A-5 84.5
A-6 92.5 A-7 150.0
A-8 76.9 A-10 135.5
A-12 103.5 A-14 100.0
A-15 92.5 A-16 121.0
A-17 91.5 A-18 140.0
A-19 89.5 A-21 114.5
A-23 146.5 A-24 146.5
A-25 150.0 A-27 122.0
A-28 172.0 A-32 91.0
A-33 76.5 A-34 147.0
A-40 73.5 A-41 79.5
A-42 128.0 A-43 105.5
A-46 130.5 A-48 94.5
A-49 130.5 A-50 103.5
A-51 136.5 A-53 123.5
A-54 140.0 A-56 123.5
A-57 153.5 A-58 143.5
A-60 93.5 A-61 113.5
A-62 133.5 A-64 120.0
A-68 73.5 A-70 93.5
A-71 90.0 A-72 130.0
A-73 110.0 A-74 130.0
A-75 126.5 A-76 73.5
A-77 130.0 A-78 70.0
A-79 43.5 A-80 93.5
A-83 116.5 A-84 144.0
A-85 123.5 A-86 135.5
A-87 144.0 A-90 206.0
A-91 160.0 A-92 88.0
A-93 175.0 A-94 142.5
A-96 122.5 A-97 150.0
A-98 106.5 A-99 94.0
A-102 94.0 A-104 73.5
A-105 103.0 A-106 76.5
A-107 173.5 B-1 129.0
B-2 96.5 B-3 73.5
B-4 116.5 B-6 80.5
B-7 75.0 B-8 140.5
B-10 76.5 D-3 75.0
D-4 134.0 D-6 75.0
E-4 82.0 E-8 90.0
< 실험예 2> 반수활성 농도(EC50) 및 최대활성 (Amax) 측정
1. 실험 방법
Indigo 사에서 공급하는 Human PPAR gamma Reporter assay (Indigo, #IB00101) 킷을 사용하여 다음과 같은 방법으로 반수활성 농도(EC 50)와 최대 활성(A max)을 측정하였다.
상기 킷에서 제공하는 reporter 세포가 담긴 튜브에 상기 킷에서 제공하는 Cell Recovery Medium(CRM) 10 mL을 넣은 후 37 ℃ 수조에서 10 분간 유지한 뒤, 500 μL를 취하여 reporter 세포 생존율을 측정하고, 상기 킷에서 제공하는 plate에 100 μL씩 분주 후 세포배양기에 1 시간 동안 넣어두었다.
상기 킷에서 제공하는 Compound Screening Medium(CSM) 20mL에 DMSO 20 μL를 넣어 0.1% DMSO in CSM 희석액을 만들고, 상기 희석액으로 각 실시예의 화합물을 희석하여 20, 10, 2.5, 0.625, 0.156, 0.039, 0.0009 μM 농도가 되도록 상기 plate에 처리하였다.
상기 plate를 37℃, 5% CO 2 배양기에서 22 내지 24 시간 동안 배양한 뒤, 상측액을 제거한 후 상기 킷에서 제공하는 Detection Substrate와 Detection Buffer를 1:1로 섞은 용액 100 μL를 각 well에 분주하고 5분 후 MDS사의 'SpectraMax L' Luminescence 장비로 흡광도를 측정하여 DMSO 값을 기준으로 보정한 후, A max 값 및 EC 50 값을 산출하였다.
2. 실험 결과
실험예 2의 결과는 다음 표 3에 기재한 바와 같다.
실시예 EC 50 (uM) A max (%) 실시예 EC 50 (uM) A max (%)
A-2 2.6 102.0 A-3 4.3 89.0
A-4 0.3 98.0 A-5 1.3 101.0
A-11 0.6 123.0 A-12 1.1 93.0
A-15 1.8 105.0 A-16 2.4 81.0
A-17 1.1 92.0 A-18 1.5 80.0
A-27 1.6 58.0 A-28 0.3 118.0
A-32 1.4 82.0 A-33 1.4 72.0
A-34 0.4 97.0 B-1 0.7 106.0
B-8 1.1 87.0 B-9 2.2 71.0
D-3 3.7 83.0 D-4 0.7 113.0
E-8 1.1 101.9 E-9 2.6 65.5

Claims (16)

  1. 하기 화학식 I 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염:
    [화학식 I]
    Figure PCTKR2019008609-appb-img-000091
    상기 화학식 I 에서,
    X 는
    Figure PCTKR2019008609-appb-img-000092
    또는
    Figure PCTKR2019008609-appb-img-000093
    이고 {여기서, X 가
    Figure PCTKR2019008609-appb-img-000094
    이면 L 2 및 Y 는 아무 것도 아님 (null)},
    X 1 은 N, O, S, CR 3 또는 NR 4 이고,
    X 2 는 N, O, S 또는 NR 4 이고,
    X 3 는 N, O, S 또는 CR 3 이고,
    X 4 는 C 또는 N 이고,
    X 5 는 O 또는 S 이고,
    X 6 는 N 이고,
    Y 는 H, C 1-C 6 알킬, NR 5R 6, OR 7, C 3-C 7 시클로알킬, C 5-C 10 스파이로 고리, C 5-C 10 바이사이클릭 고리, 4-7원 헤테로시클로알킬, 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 C 1-C 6 알킬, NR 5R 6, OR 7, 할로 또는 C 1-C 6 할로알킬로 치환될 수 있음},
    Z 는
    Figure PCTKR2019008609-appb-img-000095
    ,
    Figure PCTKR2019008609-appb-img-000096
    또는 -(C=O)O-R 8 이고,
    R a1, R a2, R b1 및 R b2 는 각각 독립적으로 H, 할로, C 1-C 6 알킬 또는 C 1-C 6 할로알킬이고,
    R 1 및 R 2 는 각각 독립적으로 H, C 1-C 6 알킬, C 2-C 6 알케닐, C 2-C 6 알키닐 또는 C 3-C 7 시클로알킬이고,
    R 3 및 R 4 는 각각 독립적으로 H, C 1-C 6 알킬 또는 아릴이고,
    R 5 내지 R 8 은 각각 독립적으로 H 또는 C 1-C 6 알킬이고,
    L 1 은 -(CH 2) m- 이고 {여기서, 상기 -(CH 2) m- 의 하나 이상의 H 는 중수소로 치환될 수 있음},
    L 2 는 -(CH 2) n- 또는
    Figure PCTKR2019008609-appb-img-000097
    이고 {여기서, 상기 -(CH 2) n- 및
    Figure PCTKR2019008609-appb-img-000098
    의 하나 이상의 H 는 C 1-C 6 알킬로 치환될 수 있음},
    m 및 n 은 각각 독립적으로 0, 1, 2 또는 3 이고,
    p 는 1, 2, 3 또는 4 이다.
  2. 제 1 항에 있어서,
    X 는
    Figure PCTKR2019008609-appb-img-000099
    또는
    Figure PCTKR2019008609-appb-img-000100
    이고 {여기서, X 가
    Figure PCTKR2019008609-appb-img-000101
    이면 L 2 및 Y 는 아무 것도 아님 (null)},
    X 1 은 N, O, S, CR 3 또는 NR 4 이고,
    X 2 는 N, O 또는 NR 4 이고,
    X 3 는 N, O 또는 CR 3 이고,
    X 4 는 C 또는 N 이고,
    X 5 는 O 이고,
    X 6 는 N 이고,
    Y 는 C 1-C 4 알킬, NR 5R 6, OR 7, C 3-C 6 시클로알킬, C 5-C 10 스파이로 고리, C 5-C 10 바이사이클릭 고리, 4-6원 헤테로시클로알킬, 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴의 하나 이상의 H는 C 1-C 4 알킬, OR 7, 할로 또는 C 1- C 4 할로알킬로 치환될 수 있음},
    Z 는
    Figure PCTKR2019008609-appb-img-000102
    ,
    Figure PCTKR2019008609-appb-img-000103
    또는 -(C=O)O-R 8 이고,
    R a1, R a2, R b1 및 R b2 는 각각 독립적으로 H 또는 C 1-C 4 알킬이고,
    R 1 및 R 2 는 각각 독립적으로 C 1-C 4 알킬이고,
    R 3 및 R 4 는 각각 독립적으로 H, C 1- C 4 알킬 또는 아릴이고,
    R 5 내지 R 8 은 각각 독립적으로 H 또는 C 1- C 4 알킬이고,
    L 1 은 -(CH 2) m- 이고 {여기서, 상기 -(CH 2) m- 의 하나 이상의 H 는 중수소로 치환될 수 있음},
    L 2 는 -(CH 2) n- 또는
    Figure PCTKR2019008609-appb-img-000104
    이고 {여기서, 상기 -(CH 2) n- 및
    Figure PCTKR2019008609-appb-img-000105
    의 하나 이상의 H 는 C 1- C 4 알킬로 치환될 수 있음},
    m 및 n 은 각각 독립적으로 0, 1 또는 2 이고,
    p 는 1 또는 2 인,
    화학식 I 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.
  3. 제 2 항에 있어서,
    X 는
    Figure PCTKR2019008609-appb-img-000106
    ,
    Figure PCTKR2019008609-appb-img-000107
    ,
    Figure PCTKR2019008609-appb-img-000108
    ,
    Figure PCTKR2019008609-appb-img-000109
    ,
    Figure PCTKR2019008609-appb-img-000110
    ,
    Figure PCTKR2019008609-appb-img-000111
    ,
    Figure PCTKR2019008609-appb-img-000112
    ,
    Figure PCTKR2019008609-appb-img-000113
    ,
    Figure PCTKR2019008609-appb-img-000114
    또는
    Figure PCTKR2019008609-appb-img-000115
    이고 {여기서, X 가
    Figure PCTKR2019008609-appb-img-000116
    이면 L 2 및 Y 는 아무 것도 아님 (null)},
    Y 는 C 1-C 4 알킬, NR 5R 6, OR 7, C 3-C 6 시클로알킬, C 5-C 10 스파이로 고리, C 5-C 10 바이사이클릭 고리, 피페리디닐, 몰폴리닐, 테트라하이드로피라닐, 페닐, 나프탈레닐, 피리디닐 또는 퀴놀리닐이고 {여기서, 상기 페닐, 나프탈레닐, 피리디닐 또는 퀴놀리닐의 하나 이상의 H는 C 1-C 4 알킬, OR 7, F, Cl, Br 또는 CF 3로 치환될 수 있음},
    Z 는
    Figure PCTKR2019008609-appb-img-000117
    ,
    Figure PCTKR2019008609-appb-img-000118
    또는 -(C=O)O-R 8 이고,
    R 1 및 R 2 는 각각 독립적으로 C 1-C 4 알킬이고,
    R 3 및 R 4 는 각각 독립적으로 H, C 1-C 4 알킬 또는 아릴이고,
    R 5 내지 R 8 은 각각 독립적으로 H 또는 C 1-C 4 알킬이고,
    L 1 은 -(CH 2) m- 이고 {여기서, 상기 -(CH 2) m- 의 하나 이상의 H 는 중수소로 치환될 수 있음},
    L 2 는 -(CH 2) n- 또는
    Figure PCTKR2019008609-appb-img-000119
    이고 {여기서, 상기 -(CH 2) n- 및
    Figure PCTKR2019008609-appb-img-000120
    의 하나 이상의 H 는 C 1-C 4 알킬로 치환될 수 있음},
    m 및 n 은 각각 독립적으로 0, 1 또는 2 이고,
    p 는 1 또는 2 인,
    화학식 I 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.
  4. 제 1 항에 있어서, 하기 화합물들로 이루어진 군으로부터 선택된 어느 하나인 화학식 I 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염:
    1) 3-(4'-((2-부틸-5-((3-(2-플루오로페닐)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    2) 3-(4'-((2-부틸-5-((3-사이클로프로필-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    3) 3-(4'-((2-부틸-5-((3-사이클로프로필-1,2,4-옥소다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    4) 3-(4'-((2-부틸-5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    5) 3-(4'-((2-부틸-5-((3-(메톡시메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    6) 3-(4'-((2-부틸-5-((3-(2-메톡시에틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-yl)-1,2,4-옥사다이아졸-5(4H)-온;
    7) 3-(4'-((2-부틸-5-((3-이소프로필-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    8) 3-(4'-((2-부틸-5-((3-(다이메틸아미노)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    9) 3-(4'-((2-부틸-5-((3-((다이메틸아미노)메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    10) 3-(4'-((2-부틸-5-((3-(다이에틸아미노)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    11) 3-(4'-((2-부틸-5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    12) 3-(4'-((2-부틸-5-((3-(2-메톡시프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    13) 3-(4'-((2-부틸-4-이소프로필-5-((3-메틸-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    14) 3-(4'-((2-부틸-4-메틸-5-((3-메틸-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    15) 3-(4'-((5-((3-벤질-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    16) 3-(4'-((2-부틸-5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    17) 3-(4'-((5-((3-벤질-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    18) 3-(4'-((2-부틸-5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    19) 3-(4'-((2-부틸-4-메틸-5-((3-(1-메틸사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    20) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(스파이로[2.2]펜탄-1-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    21) 3-(4'-((2-부틸-5-((3-(이소프로폭시메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    22) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(1-페닐사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    23) 3-(4'-((2-부틸-5-((3-(3-클로로피리딘-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    24) 3-(4'-((2-부틸-5-((3-(2-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    25) 3-(4'-((2-부틸-5-((3-(2-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    26) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(2-페닐프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    27) 3-(4'-((2-부틸-5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸-d2)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    28) 3-(4'-((2-부틸-5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸-d2)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    29) 3-(4'-((2-부틸-4-메틸-5-((3-(4-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    30) 3-(4'-((2-부틸-5-((3-(4-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    31) 3-(4'-((2-부틸-5-((3-(4-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    32) 3-(4'-((2-부틸-5-((3-(3-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    33) 3-(4'-((2-부틸-5-((3-(3,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    34) 3-(4'-((5-((3-터트-부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    35) 3-(4'-((5-((3-(4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    36) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(피페리딘-1-일메틸)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    37) 3-(4'-((4-메틸-5-((3-(4-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    38) 3-(4'-((5-((3-(4-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    39) 3-(4'-((5-((3-(4-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    40) 3-(4'-((5-((3-(3-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    41) 3-(4'-((5-((3-(3,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    42) 3-(4'-((5-((3-(2,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    43) 3-(4'-((5-((3-사이클로펜틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    44) 3-(4'-((5-((3-(사이클로펜틸메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    45) 3-(4'-((5-((3-(사이클로헥실메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    46) 3-(4'-((2-부틸-5-((3-(2,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    47) 3-(4'-((2-부틸-5-((3-(사이클로헥실메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-yl)-1,2,4-옥사다이아졸-5(4H)-온;
    48) 3-(4'-((2-부틸-5-((3-(사이클로펜틸메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    49) 3-(4'-((2-부틸-5-((3-사이클로펜틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    50) 3-(4'-((5-((3-(사이클로프로필메틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    51) 3-(4'-((5-((3-(2-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    52) 3-(4'-((5-((3-(3,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    53) 3-(4'-((5-((3-(2,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    54) 3-(4'-((5-((3-(2-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    55) 3-(4'-((5-((3-(4-브로모벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    56) 3-(4'-((5-((3-(3-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    57) 3-(4'-((5-((3-(2,6-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    58) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(2,4,6-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    59) 3-(4'-((4-메틸-6-옥소-5-((3-(피페리딘-1-일)-1,2,4-옥사다이아졸-5-일)메틸)-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    60) 3-(4'-((5-((3-사이클로헥실-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    61) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(2-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    62) 3-(4'-((2-부틸-4-메틸-5-((3-(2-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    63) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(3-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    64) 3-(4'-((2-부틸-5-((3-(2,3-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    65) 3-(4'-((4-메틸-6-옥소-5-((3-(피페리딘-1-일메틸)-1,2,4-옥사다이아졸-5-일)메틸)-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    66) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(3-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    67) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(4-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    68) 3-(4'-((5-((3-(1-(4-플루오로페닐)사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    69) 3-(4'-((4-메틸-5-((3-(몰폴리노메틸)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    70) 3-(4'-((4-메틸-6-옥소-5-((3-(1-페닐사이클로부틸)-1,2,4-옥사다이아졸-5-일)메틸)-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    71) 3-(4'-((2-부틸-5-((3-(2,5-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    72) 3-(4'-((2-부틸-5-((3-(2,6-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    73) 3-(4'-((2-부틸-5-((3-(2-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    74) 3-(4'-((2-부틸-5-((3-(2,6-다이클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    75) 3-(4'-((4-메틸-5-((3-(2-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    76) 3-(4'-((5-((3-(2,3-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    77) 3-(4'-((5-((3-(2,6-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    78) 3-(4'-((5-((3-(3-클로로-5-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    79) 3-(4'-((5-((3-(4-브로모벤질)-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    80) 3-(4'-((2-부틸-5-((3-(3-클로로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    81) 3-(4'-((2-부틸-5-((3-(3,4-다이플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    82) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(4-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    83) 3-(4'-((2-부틸-5-((3-(1-(4-플루오로페닐)사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    84) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(1-페닐사이클로부틸)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    85) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(2-(트리플루오로메틸)벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    86) 3-(4'-((5-((3-(1-(3-플루오로페닐)사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    87) 3-(4'-((5-((3-(2-클로로-4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    88) 3-(4'-((4-메틸-6-옥소-2-프로필-5-((3-(3,4,5-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    89) 3-(4'-((2-부틸-4-메틸-5-((3-(몰폴리노메틸)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    90) 3-(4'-((2-부틸-4-메틸-5-((3-(3-메틸벤질)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    91) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(2,4,6-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    92) 3-(4'-((2-부틸-5-((3-사이클로헥실-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    93) 3-(4'-((5-((3-(2-클로로-6-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    94) 3-(4'-((4-메틸-5-((3-(2-메틸펜탄-2-일)-1,2,4-옥사다이아졸-5-일)메틸l)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    95) 3-(4'-((2-부틸-5-((3-(3-클로로-5-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    96) 3-(4'-((2-부틸-5-((3-사이클로프로필-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    97) 3-(4'-((2-부틸-5-((3-(2-클로로-6-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    98) 3-(4'-((2-부틸-5-((3-(2-클로로-4-플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    99) 3-(4'-((2-부틸-4-메틸-5-((3-(2-메틸펜탄-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    100) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(3,4,5-트리플루오로벤질)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    101) 3-(4'-((5-((3-(1-(2-클로로페닐)에틸)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    102) 3-(4'-((2-부틸-5-((3-(2-사이클로헥실프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    103) 3-(4'-((2-부틸-5-((3-(2-(4-클로로-2-플루오로페닐)프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    104) 3-(4'-((2-부틸-5-((3-(2-(2-클로로-6-플루오로페닐)프로판-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    105) 3-(4'-((2-부틸-5-((3-(3-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    106) 3-(4'-((2-부틸-5-((3-(2-메톡시페닐)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    107) 3-(4'-((2-부틸-5-((3-(2-메톡시벤질)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    108) 3-(4'-((2-부틸-4-메틸-5-((3-(나프탈렌-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    109) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(테트라하이드로-2H-피란-4-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    110) 3-(4'-((2-부틸-5-((3-(1-에틸사이클로프로필)-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    111) 3-(4'-((2-부틸-5-((3-사이클로부틸-1,2,4-옥사다이아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    112) 3-(4'-((5-((3-(바이사이클로[2.2.1]헵탄-2-일)-1,2,4-옥사다이아졸-5-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    113) 3-(4'-((2-부틸-4-메틸-5-((3-(1-메틸사이클로부틸)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    114) 3-(4'-((2-부틸-4-메틸-5-((3-(나프탈렌-1-일)-1,2,4-옥사다이아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    115) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((3-(퀴놀린-2-일)-1,2,4-옥사다이아졸-5-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    116) 3-(4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    117) 3-(4'-((2-부틸-4-메틸-5-((5-(1-메틸사이클로프로필)-1,2,4-옥사다이아졸-3-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    118) 3-(4'-((2-부틸-5-((5-사이클로프로필-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    119) 3-(4'-((2-부틸-5-((5-이소프로필-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    120) 3-(4'-((2-부틸-5-((5-(1-(4-클로로페닐)사이클로프로필)-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    121) 3-(4'-((2-부틸-5-((5-사이클로부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    122) 3-(4'-((2-부틸-5-((5-(2-플루오로페닐)-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    123) 3-(4'-((2-부틸-5-((5-(2-플루오로벤질)-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    124) 4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-카르복실산;
    125) 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온;
    126) 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-(2-플루오로페닐)-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온;
    127) 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-(4-메톡시벤질)-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온;
    128) 3-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-2-부틸-5-((5-(4-클로로벤질)-1,2,4-옥사다이아졸-3-일)메틸)-6-메틸피리미딘-4(3H)-온;
    129) 메틸 4'-((2-부틸-5-((5-터트-부틸-1,2,4-옥사다이아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-카르복실레이트;
    130) 3-(4'-((2-부틸-4-이소프로필-5-((5-메틸-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    131) 3-(4'-((2-부틸-4-이소프로필-5-((5-(4-메톡시페닐)-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    132) 3-(4'-((2-부틸-4-이소프로필-5-((5-(3-메톡시페닐)-1,3,4-옥사다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    133) 3-(4'-((2-부틸-5-((5-하이드록시-1,3,4-옥사다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    134) 3-(4'-((2-부틸-5-((5-(다이메틸아미노)-1,3,4-옥사다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    135) 3-(4'-((2-부틸-4-이소프로필-6-옥소-5-((5-(피롤리딘-1-일)-1,3,4-옥사다이아졸-2-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    136) 3-(4'-((2-부틸-4-메틸-6-옥소-5-((5-페닐옥사졸-2-일)메틸)피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    137) 3-(4'-((5-(벤조[d]옥사졸-2-일메틸)-2-부틸-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    138) 3-(4'-((5-((5-벤질이소옥사졸-3-일)메틸)-2-부틸-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    139) 3-(4'-((2-부틸-5-((5-터트-부틸이소옥사졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    140) 3-(4'-((2-부틸-5-((5-(2-하이드록시프로판-2-일)이소옥사졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일l)-1,2,4-옥사다이아졸-5(4H)-온;
    141) 3-(4'-((2-부틸-5-((5-(1-하이드록시에틸)이소옥사졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    142) 3-(4'-((2-부틸-4-메틸-5-((5-메틸-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    143) 3-(4'-((2-부틸-5-((5-에틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    144) 3-(4'-((2-부틸-5-((5-이소프로필-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    145) 3-(4'-((2-부틸-5-((5-터트-부틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    146) 3-(4'-((4-메틸-5-((5-(1-메틸사이클로프로필)-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    147) 3-(4'-((5-((5-사이클로프로필-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    148) 3-(4'-((5-((5-터트-부틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-메틸-6-옥소-2-프로필피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    149) 3-(4'-((2-부틸-5-((5-터트-부틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    150) 3-(4'-((2-부틸-5-((5-(3-플루오로페닐)-1,3,4-싸이아다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    151) 3-(4'-((2-부틸-4-이소프로필-5-((5-메틸-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    152) 3-(4'-((2-부틸-5-((5-에틸-1,3,4-싸이아다이아졸-2-일)메틸)-4-이소프로필-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    153) 3-(4'-((2-부틸-4-이소프로필-5-((5-이소프로필-1,3,4-싸이아다이아졸-2-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    154) 3-(4'-((2-부틸-5-((5-(4-플루오로페닐)-4H-1,2,4-트리아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    155) 3-(4'-((2-부틸-5-((5-(2-플루오로페닐)-4H-1,2,4-트리아졸-3-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    156) 3-(4'-((2-부틸-4-메틸-5-((3-메틸-1H-1,2,4-트리아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    157) 3-(4'-((2-부틸-4-메틸-5-((3-메틸-1-페닐-1H-1,2,4-트리아졸-5-일)메틸)-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    158) 3-(4'-((2-부틸-5-((1-부틸-3-메틸-1H-1,2,4-트리아졸-5-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온;
    159) 3-(4'-((2-부틸-5-((1-(4-플루오로벤질)-1H-1,2,3-트리아졸-4-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온; 및
    160) 3-(4'-((2-부틸-5-((1-(2-플루오로벤질)-1H-1,2,3-트리아졸-4-일)메틸)-4-메틸-6-옥소피리미딘-1(6H)-일)메틸)바이페닐-2-일)-1,2,4-옥사다이아졸-5(4H)-온.
  5. 제 1 항 내지 제 4 항 중 어느 하나의 항의 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 고혈압 또는 당뇨병의 치료 또는 예방용 약학적 조성물.
  6. 제 5 항에 있어서, 상기 고혈압은 본태성 고혈압인 약학적 조성물.
  7. 제 5 항에 있어서, 상기 당뇨병은 제2형 당뇨병인 약학적 조성물.
  8. 제 5 항에 있어서, 고혈압 및 당뇨병을 동시에 치료 또는 예방하기 위한 약학적 조성물.
  9. 제1항 내지 제4항 중 어느 하나의 항의 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염의 치료학적으로 유효한 양을 투여하는 단계를 포함하는, 고혈압 또는 당뇨병을 치료하는 방법.
  10. 제9항에 있어서, 상기 고혈압은 본태성 고혈압인 치료방법.
  11. 제9항에 있어서, 상기 당뇨병은 제2형 당뇨병인 치료방법.
  12. 제9항에 있어서, 고혈압 및 당뇨병을 동시에 치료하는 방법.
  13. 고혈압 또는 당뇨병의 치료 또는 예방용 약제의 제조를 위한, 제1항 내지 제4항 중 어느 하나의 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염의 용도.
  14. 제13항에 있어서, 상기 고혈압은 본태성 고혈압인 염의 용도.
  15. 제13항에 있어서, 상기 당뇨병은 제2형 당뇨병인 염의 용도.
  16. 제13항에 있어서, 고혈압 및 당뇨병을 동시에 치료하기 위한 염의 용도.
PCT/KR2019/008609 2018-07-12 2019-07-11 피리미디논 유도체 화합물 및 이의 용도 WO2020013646A1 (ko)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5243054A (en) * 1991-06-27 1993-09-07 Takeda Chemical Industries, Ltd. Compound which is angiotensin ii antagonist
US5472967A (en) * 1991-02-20 1995-12-05 Synthelabo 4-pyrimidinone derivatives their preparation and their application in therapy
US5565464A (en) * 1991-08-02 1996-10-15 Istituto Luso Farmaco D'italia S.P.A. Compounds having angiotensine II antagonistic activity
WO2009133970A1 (en) * 2008-05-02 2009-11-05 Takeda Pharmaceutical Company Limited Crystalline compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5472967A (en) * 1991-02-20 1995-12-05 Synthelabo 4-pyrimidinone derivatives their preparation and their application in therapy
US5243054A (en) * 1991-06-27 1993-09-07 Takeda Chemical Industries, Ltd. Compound which is angiotensin ii antagonist
US5565464A (en) * 1991-08-02 1996-10-15 Istituto Luso Farmaco D'italia S.P.A. Compounds having angiotensine II antagonistic activity
WO2009133970A1 (en) * 2008-05-02 2009-11-05 Takeda Pharmaceutical Company Limited Crystalline compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHOUNG, W. ET AL.: "Discovery of BR 102375, a new class of non-TZD PPARy full agonist for the treatment of type 2 diabetes", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 29, no. 16, 19 June 2019 (2019-06-19), pages 2275 - 2282, XP085759059, DOI: 10.1016/j.bmcl.2019.06.027 *

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