WO2015167309A1 - Cyclohexene derivative, preparation method therefor, and pharmaceutical composition for preventing or treating metabolic diseases, containing same as active ingredient - Google Patents

Cyclohexene derivative, preparation method therefor, and pharmaceutical composition for preventing or treating metabolic diseases, containing same as active ingredient Download PDF

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Publication number
WO2015167309A1
WO2015167309A1 PCT/KR2015/004449 KR2015004449W WO2015167309A1 WO 2015167309 A1 WO2015167309 A1 WO 2015167309A1 KR 2015004449 W KR2015004449 W KR 2015004449W WO 2015167309 A1 WO2015167309 A1 WO 2015167309A1
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Prior art keywords
cyclohex
phenyl
enyl
piperidine
piperidin
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PCT/KR2015/004449
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French (fr)
Korean (ko)
Inventor
양진
김진웅
이한규
김재현
손창모
이규환
황정운
최형호
김대훈
이재걸
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현대약품 주식회사
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Priority claimed from KR1020150062119A external-priority patent/KR101651505B1/en
Application filed by 현대약품 주식회사 filed Critical 현대약품 주식회사
Priority to JP2016565405A priority Critical patent/JP6375539B2/en
Priority to CA2947552A priority patent/CA2947552C/en
Priority to CN201580033068.2A priority patent/CN106660955B/en
Priority to EP15786383.8A priority patent/EP3138834B1/en
Priority to US15/307,719 priority patent/US9758527B2/en
Publication of WO2015167309A1 publication Critical patent/WO2015167309A1/en

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to a cyclohexene derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or charging a metabolic disease using the same as an active ingredient.
  • Metabolic disease is a disease that occurs because metabolism of each organ of our body is not smooth, and it is a general term of disease caused by metabolic disorder caused by imbalance of in vivo sugar, lipid, protein, vitamin, mineral, and water.
  • metabolic diseases caused by weakened immunity and lack of nutrition. Most adult diseases are caused by malnutrition or lack of exercise due to poor food intake.
  • Typical metabolic diseases include obesity, type I diabetes, type ⁇ diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X. .
  • insulin resistance which is a hormone that sends glucose in the blood to the liver or muscles
  • insulin resistance which is a hormone that sends glucose in the blood to the liver or muscles
  • Diabetes a representative disease of the metabolic disease, is a serious metabolic disease suffered by more than 100 million people worldwide. In the United States, there are more than 12, 000, 000 diabetics and 600, 000 new cases are diagnosed each year. Diabetes etiology is not the same, but all people with diabetes commonly have excessive production of glucose by the liver and lack the ability to move the glucose into cells that use it as the main fuel of the body. People without diabetes rely on insulin hormones produced by the pancreas to move glucose from blood into cells in the body.
  • diabetes people with diabetes do not produce insulin or can not use the insulin they produce efficiently and thus cannot move glucose into their cells. As a result, glucose that remains incapable of moving into cells accumulates in the blood, causing a disease called hyperglycemia, and may cause serious health problems over time. Diabetes is also a syndrome that correlates with metabolic, vascular, and neuropathic factors. In general, metabolic syndromes characterized by hyperglycemia include changes in carbohydrate, fat and protein metabolism caused by lack of insulin secretion or markedly reduced or insulin, but the insulin is ineffective. Vascular syndrome consists of abnormalities in blood vessels that cause cardiovascular, retinal and renal complications. Abnormalities of the peripheral and autonomic nervous system are also part of the diabetes syndrome.
  • diabetes is associated with the development of kidney disease, eye disease and nervous system problems.
  • Cabin disease nephropathy
  • diabetes is also a cause of damage to the retina of the back of the eye and increases the risk of cataracts and glaucoma.
  • Type I diabetes also known as insulin dependent diabetes (IDDM)
  • IDDM insulin dependent diabetes
  • Type II diabetes also known as non-insulin dependent diabetes mellitus (NIDDM)
  • NIDDM non-insulin dependent diabetes mellitus
  • Type II diabetes may be characterized by a deficiency in insulin secretion or by insulin resistance, namely people with type II diabetes who have little or no insulin.
  • current treatments for diabetes include insulin 3 ⁇ 4, insulin secretagogues, glucose lowering effectors, activators of peroxysome proliferator-activated receptors (PPARs), and the like.
  • PPARs peroxysome proliferator-activated receptors
  • problems associated with currently available therapies including hypoglycemia, weight gain, decreased response to treatment over time, gastrointestinal problems and edema.
  • GPR-119CG protein-coupled receptor 119 is mainly expressed in the pancreas, small intestine, colon and adipose tissue.
  • GPCR G protein coupled receptors
  • GPR-119 receptors and isoforms are found in mammalian species including humans, mice, mice, hamsters, chimpanzees, rhesus macaques, cattle and dogs.
  • GPR-119 and expression in pancreatic ⁇ -cells Has the GPR-119 receptor It is known to have an effect on insulin secretion.
  • the activity of GPR-119 stimulates the cAMP single pathway, which increases the intracellular activity of cAMP (Cycl ic adenosine monophosphate) ⁇ cells in these cells.
  • cAMP Cycl ic adenosine monophosphate
  • GIP Gastr ic inhibitory polypeptide
  • GLP-1 Glucagon-ike peptide ⁇ 1
  • PYY Peptide YY
  • the same incretin is a gut hormone that strongly stimulates insulin secretion depending on blood sugar levels after a meal.
  • GPR-119 activators are effective for improving ⁇ -cell function and ⁇ -cell population. Activation of GPR-119 stimulates insulin secretion in a glucose-dependent manner in vitro and in vivo (rodent). The discovery of potent GPR-119 activators can lower plasma glucose and promote glycemic control without the risk of hypoglycemia.
  • Non-Patent Document 1 discloses that GPR-119 activation stimulates cAMP Cyclic adenosine monophosphate) to induce glucose-dependent glucagon-like peptide-1 (KGlucagon-like peptide-1, GLP-1) and insulin secretion. .
  • GLP-1 has been shown to mediate its action through GLP-1R, a specific G protein-binding receptor (GPCR), to regulate glucose homeostasis, to stimulate glucose-dependent insulin secretion, and to increase pancreatic beta cell mass. lost. GLP-1 has also been shown to slow down the rate of gastric emptying and promote satiety.
  • GPCR G protein-binding receptor
  • GLP ⁇ 1 peptide activator has a negative effect on efficacy due to lack of bioavailability during oral administration. Therefore, there is a need to develop a GPR-119 activator that not only has excellent oral bioavailability but also induces secretion of GLP-1 in the blood.
  • the GPR-119 activator disclosed in Patent Literatures 1-2 and Non-Patent Literature 2 causes acute food intake reduction and weight loss in rats after chronic administration. Proven.
  • Patent Document 3 as interest in triple-substituted heteroaryl derivatives increases, metabolic disease treatment using triple-substituted pyrimidine derivatives Independence
  • Patent Document 4 discloses a therapeutic agent for diabetes using an aryl, heteroaryl, or heterocyclyl derivative characterized by activating IC—GPCR2 or GPR-119 as a therapeutic agent for insulin resistance and related type I diabetes.
  • IC—GPCR2 or GPR-119 a therapeutic agent for insulin resistance and related type I diabetes.
  • no compound having a cyclohexene skeleton and its use for treating metabolic diseases are known.
  • the present inventors are studying an activator for GPR-119, the cyclohexene derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention is a GPR-119 (G protein-coupled receptor 119).
  • Activation increases the intracellular activity of Cyclic Adenosine Monophosphate (cAMP) and induces the release of GLP-1 (Glucagon-like peptide-1), a neuroendocrine protein, resulting in weight loss and hypoglycemic effects.
  • cAMP Cyclic Adenosine Monophosphate
  • GLP-1 Glucagon-like peptide-1
  • Pharmaceutical for the prevention or treatment of metabolic diseases such as diabetes mellitus, type I diabetes, type ⁇ diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X It was found useful as a composition and completed the present invention.
  • GPR-119 G protein-coupled receptor 119
  • the present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is a hetero atom selected from the group consisting of -H, -OH, d- K ⁇ straight or branched alkyl, straight or branched alkoxy of -10 , straight or branched alkoxycarbonyl of -10 , or N, 0 and S It is an unsubstituted or substituted 5-10 membered heteroaryl containing,
  • substituted 5-10 membered heteroaryl is 5-10 membered heteroaryl substituted with at least one linear or branched alkyl of ( ⁇ - ⁇ !;
  • R 2 is -H, -0H, halogen, ( ⁇ -10 Straight chain or branched alkyl of or straight chain or branched alkoxy of;
  • R 7 is —H, or d- 5 linear or branched alkyl
  • R 8 and R 9 may be linked with the nitrogen atom to which they are linked to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, 0 and S And
  • the substituent is a substituted 5-10 membered heterocycloalkyl, R 10 and R 11 are independently -H, or straight or branched chain alkyl of d- 5 , n, m and p are independently an integer of 1-10 ego;
  • R 4 is —H, unsubstituted or at least one —0H substituted ( ⁇ -10 straight or branched alkyl, or -10 straight or branched alkoxy;
  • Chloralkenyl or a line from the group consisting of N, 0 and S
  • R 12 , R 13 , R 14 and R 15 are independently —H or d- 5 , straight or branched alkyl
  • R 16 is —H, —0H, or ds straight or branched alkoxy
  • the fused 3-10 membered heterocycloalkyl is an unsubstituted 3-10 membered heterocycloalkyl fused with 6 to 10 aryl, and the substituted, substituted, or fused 3
  • substitutions and fusions can occur simultaneously;
  • the present invention as shown in the following reaction formula 1,
  • Step 2 Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 (Step 2);
  • Step 3 Preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 prepared in Step 2 with a base (Step 3); And. ⁇ .
  • Method of preparing a compound represented by the formula (1) comprising the step (4) to obtain a compound represented by the formula (1) by reacting the compound represented by the formula (7) and the compound represented by the formula (8) prepared in step 3 To provide.
  • R 1 , R 2 , R 3 , R 4 , ⁇ and ⁇ are as defined in Formula 1 above.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a G protein-coupled receptor 119 (GPR-119) activator containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • GPR-119 G protein-coupled receptor 119
  • the present invention provides a health functional food for preventing or improving metabolic well ring containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Cyclo nucene derivatives, optical isomers thereof, or pharmaceutically acceptable salts thereof according to the present invention activate GPR-119 (G protein-coupled receptor 119) to induce cAMP (Cyclic adenosine monophosphate).
  • GPR-119 G protein-coupled receptor 119
  • cAMP Cyclic adenosine monophosphate
  • Increasing intracellular activity and inducing the release of neuronal endocrine protein GLP-1 results in simultaneous weight loss and hypoglycemic effects.
  • Obesity, type I diabetes, type ⁇ diabetes It can be usefully used as a pharmaceutical composition for the prevention or treatment of metabolic diseases such as inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, X syndrome, etc. .
  • Figure 1 is a graph of the weight change of the compounds of Examples 48 and Comparative Examples 3, 4 according to the present invention to DIOCDiet-induced obesity rat model for 4 weeks (Fig. 1 "vehicle") Represents an untreated group of diet-induced obesity (DI0) models; “Lean” represents an untreated group of normal SD rat models, not the pathological model).
  • Figure 2 (A) is a compound of Example 48 and Comparative Example 3 according to the present invention
  • DIOCDiet-induced obesity is a graph evaluating the hypoglycemic efficacy according to the time change when glucose was administered 30 minutes after the administration of the compounds of Example 48 and Comparative Example 3 at the end of 4 weeks of administration to the rat model.
  • FIG. 2 (B) shows the administration of glucose 30 minutes after the administration of the compound of Example 119 at the end of 4 weeks of administration of the compound of Example 119 to the DK Diet-induced obesity rat It is a graph evaluating the hypoglycemic efficacy according to the time change.
  • GLP-1 Glucagon-ike peptide-1
  • the present invention provides a compound represented by the following formula (1), an optical isomer of ah, or a pharmaceutically acceptable salt thereof.
  • R 1 is a -H, -OH, a straight or branched chain alkoxycarbonyl of d- 10 straight or branched chain alkyl, d- 10 straight or branched chain alkoxy, and 10 of the, or a N, 0 and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more hetero atoms selected from the group consisting of,
  • substituted 5-10 membered heteroaryl is 5-10 membered heteroaryl substituted with at least one straight or branched chain alkyl of- ⁇ ;
  • R 2 is H, —0H, halogen, straight chain or branched alkyl of du), or straight chain or branched alkoxy of d- 10 ;
  • R 5 and R 6 are independently -H, Or straight or branched chain alkyl of d- 5 ,
  • R 7 is —H, or straight or branched chain alkyl of ds
  • R 8 and R 9 may be linked with the nitrogen atom to which they are linked to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, 0 and S
  • the substituent is a substituted 5-10 membered heterocycloalkyl, R 10 and R 11 are independently -H or d- 5 or straight or branched alkyl, and n, m and p are independently 1-10 An integer;
  • R 4 is unsubstituted or straight chained or branched alkyl of d- 10 substituted with one or more -0H, or straight chained or branched alkoxy of- ⁇ ;
  • R 3 and R 4 are unsubstituted 3-10 membered heterocycloalkenyl containing one or more heteroatoms selected from the group consisting of N, 0 and S connected with the nitrogen atom to which they are linked, or N, 0
  • R 12 , R 13 , R 14 and R 15 are independently —H or d- 5 , straight or branched alkyl, R 16 is —H, —0H, or straight or branched alkoxy of
  • the fused 3-10 membered heterocycloalkyl is a 3-10 membered heterocycloalkyl fused with an unsubstituted C 6-10 aryl, and the unsubstituted, substituted, or fused 3- 10-atomic heterocytheic cycle
  • substitution and fusion may occur simultaneously;
  • R 1 is an unsubstituted or substituted 5-10 membered heteroaryl containing at least one hetero atom selected from the group consisting of linear or branched alkoxycarbonyl of N, or N, 0 and S,
  • substituted 5-10 membered heteroaryl is ( 5-10 membered heteroaryl substituted with at least one straight or branched chain alkyl of ⁇ - ⁇ ;
  • R 2 is -H or halogen;
  • R 5 and R 6 are independently -H or )ego
  • R 7 is —H, or d- 5 linear or branched alkyl
  • R 8 and R 9 may be linked with the nitrogen atom to which they are linked to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, 0 and S And
  • the substituted 5-10 membered heterocycloalkyl is -CN and -COC ⁇ NR 10 !?
  • At least one substituent selected from the group consisting of 11 is substituted 5-10 membered heterocycloalkyl, wherein R 10 and R 11 are independently -H, n, m and p are independently an integer of 1-5 ;
  • R 4 is H or unsubstituted or substituted at least one -0H (: -10 straight or branched alkyl;
  • R 3 and R 4 is a group consisting of N, 0 and S connected with the nitrogen atom to which they are connected Unsubstituted, substituted, or fused containing one or more heteroatoms selected from the group consisting of one or more heteroatoms selected from the group consisting of one or more heteroatoms selected from the group consisting of N, 0 and S; (fused) 3-10 membered heterocycloalkyl, wherein the substituted 3-10 membered heterocycloalkyl is -
  • a 3-10 membered heterocycloalkyl substituted with one or more -Boc () is a 3-10 membered heterocycloalkyl substituted with a Spiro form.
  • R 12 , R 13 , 14 and R 15 are independently —H, or d— 5 straight or branched alkyl, R 16 is —0H, or d-5 is a straight or branched alkoxy, wherein wherein the fusion (fused) 3-10 membered heteroaryl cyclo alkyl is unsubstituted (: 6 - 10 aryl is fused, and the 3-10 membered heteroaryl cyclo alkyl, the unsubstituted, substituted, or fusion (fused) 3 For a -10 membered heterocycloalkyl, substitutions and fusions can occur simultaneously;
  • R 1 is Or and is -H or -F;
  • R 4 is -H, methyl, ethyl or HX
  • Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds.
  • (52) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (pyridin-1-yl) methanone;
  • (53) ((S) _3-fluoropyridin-1-yl) (4- (4-((l- (3 ⁇ isopropyl- 1,2,4-oxadiazole-5-yl) pi Ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
  • (161) (4- (4 ⁇ ((1- (5_ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) -3- Fluoropyridin-1-yl) methanone hydrochloride;
  • (162) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (pyridine—1 -Yl) methanone;
  • tert-butyl 4 ((4- (4- (ethyl (2-hydroxyethyl) carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1—carboxylate; (200) tert-butyl 4- ((4_ (4- (4- (2-hydroxyethyl) piperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1 -Carboxylate;
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy hydroxy alkanates And non-toxic organic acids such as alkanedioate aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-lluenesulfonic acid, tartaric acid and fumaric acid. .
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkan
  • These pharmaceutically nontoxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate , Succinate, suverate, sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate hydroxide Oxybenzoate, methoxybenzoate, phthalate, terephthalate , Benzenesulfonate, Tolu
  • the acid addition salt according to the present invention is produced by dissolving a compound represented by Chemical Formula 1 in a conventional method, for example, an organic solvent, such as methanol, ethanol, acetone, methylene chloride, acetonitrile, and adding an organic or inorganic acid.
  • the precipitate may be prepared by filtration, drying, or distillation under reduced pressure with a solvent and excess acid, and may be dried or prepared under an organic solvent.
  • the present invention includes not only the compound represented by Formula 1 and a pharmaceutically acceptable salt thereof, but also possible solvates, hydrates, optical isomers, and the like, which can be prepared therefrom.
  • the present invention as shown in the following reaction 1,
  • Step 2 Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 (Step 2);
  • Step 3 Preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 prepared in Step 2 with a base (Step 3); Method of preparing a compound represented by the formula (1) comprising the step (4) to obtain a compound represented by the formula (1) by reacting the compound represented by the formula (7) and the compound represented by the formula (8) prepared in step 3 To provide.
  • Step 1 is a step of obtaining a compound represented by Formula 4 by performing a coupling reaction between the compound represented by Formula 2 and the compound represented by Formula 3 to be.
  • dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM), toluene, acetonitrile, and the like may be used.
  • DMF dimethylformamide
  • DCM dichloromethane
  • toluene acetonitrile
  • acetonitrile acetonitrile
  • dimethylformamide (DMF) is used.
  • cesium carbonate (Cs 2 CO 3 ), potassium hydroxide (K0H), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and the like may be used as the base, and preferably cesium carbonate ( Cs 2 C0 3 ) can be used.
  • Step 2 is represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with the compound represented by Chemical Formula 5 under a base. It is a step of obtaining the compound. More specifically, a compound represented by Chemical Formula 6 is prepared by performing a Suzuki coupling reaction between the compound represented by Chemical Formula 4 prepared in Step 1 and the boronate compound represented by Chemical Formula 5. Step.
  • the reaction solvent is dioxane (Dioxane), ethanol, trihydric furan (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), die
  • cesium carbonate (Cs 2 CO 3 ), potassium hydroxide (K0H), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and the like may be used as the base, and preferably cesium carbonate ( Cs 2 C0 3 ) can be used.
  • Step 3 is a step of preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 prepared in Step 2 with a base. .
  • the reaction solvent is dioxane (Dioxane), ethane, trihydric furan (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF),
  • One or more organic solvents selected from the group consisting of dimethylacetamide (DMA), dimethyl sulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene and benzene can be used in combination with water. .
  • Cs 2 C0 3 cesium carbonate (Cs 2 C0 3 ), potassium hydroxide (K0H), a small hydroxide (NaOH), lithium hydroxide (LiOH) can be used, preferably lithium hydroxide Side (LiOH) can be used.
  • reaction temperature is preferably carried out between the boiling point of the solvent at 0 ° C, reaction time is not particularly limited, it is preferable to react for 0.5-10 hours.
  • Step 4 is a compound represented by Formula 7 prepared in Step 3 and the compound represented by Formula 8 to react with This is the step of obtaining compound. '
  • the reaction solvent is dioxane (dioxane), ethane, trihydric furan (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), ⁇
  • organic solvents selected from the group consisting of dimethylacetamide (DMA), dimethyl sulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene and benzene can be used in combination with water. .
  • the reaction temperature is preferably carried out between the boiling point of the solvent at 0 ° C, the reaction time is not particularly limited, it is preferable to react for 0.5-10 hours.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to the present invention activates G protein-coupled receptor 119 (GPR-119) to increase the intracellular activity of Cycl ic adenosine monophosphate (cAMP) ⁇ and the neuroendocrine protein GLP-1 (Ghicagon-like peptide).
  • the GPR-119 is a G-protein coupled receptor (GPCR) mainly expressed in pancreatic insulin secreting cells, and the GPR-119 expression profile has potential utility for the treatment of various metabolic diseases including obesity and diabetes.
  • GPCR G-protein coupled receptor
  • the present invention is a compound represented by the formula (1), its optical It provides a G protein-coupled receptor 119 (GPR-119) activator containing an isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound according to the present invention In the case of 4 weeks oral administration was confirmed to exhibit a steady weight loss effect (see Fig. 1 of Experimental Example 3), 30 minutes after administration of the compound according to the invention after the administration of 4 weeks, glucose As a result of oral administration of 2 g / kg and evaluation of hypoglycemic effect, the compound according to the present invention showed a remarkably excellent hypoglycemic effect (see FIG. 2 of Experimental Example 3), and the compound according to the present invention reduced weight and blood glucose during the administration period.
  • the lowering effect is exhibited at the same time.
  • the compound according to the present invention was shown to have an excellent effect of inducing GLP-1 secretion (Fig. 3 of Experimental Example 4 Reference).
  • the LD 50 value of the female ICR rat was confirmed to be more than 2g / kg, very low toxicity (See Experimental Example 5).
  • the cyclohexene derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention has an effect of promoting cAMP (Cycl ic adenosine monophosphate) by activating GPR-119 (G protein-coupled receptor 119). Not only is it excellent, but also has a weight loss and hypoglycemic effect, so obesity, type I diabetes, type ⁇ diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, and high cholesterol Like hypertension, dyslipidemia, X syndrome, etc. May be usefully used as a pharmaceutical composition for the prevention or treatment of metabolic diseases.
  • cAMP Cycl ic adenosine monophosphate
  • the compound represented by Formula 1 according to the present invention may be administered in various oral and parenteral dosage forms during clinical administration, and when formulated, commonly used fillers, extenders, binders, wetting agents, disintegrating agents, and system activation. It is prepared using diluents or excipients such as agents.
  • Solid formulations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which may comprise at least one excipient such as starch, calcium carbonate, sucrose ( sucrose) or lactose (lactose) or gelatin. In addition to simple excipients, lubricants such as magnesium styrate tals were also used.
  • Liquid preparations for oral administration include suspension 7- solution solutions, emulsions or syrups, and may include various excipients, such as lubricants, sweeteners, fragrances, and preservatives, in addition to commonly used diluents such as fire and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, current solvents, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and the current solvent propylene glycol, polyethylene glycol, a physical oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • a suppository base witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
  • the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, generally about 0.001-100 mg / kg / day Preferably 0.01-35. mg / kg / day.
  • Halogen-blended mixed cotton 3 ⁇ 4 when based on an adult patient weighing 70 kg, typically 0.07-7000 mg / day, preferably 0.7-2500 mg / day, judged by a physician or pharmacist Depending on the time interval, it may be administered once a day or divided into several times.
  • the present invention provides a health functional food for preventing or improving metabolic diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • ethyl 4- (trifluoromethylsulfonyloxy) cyclonux-3-enecarboxylate was dissolved in 1,4-dioxane 300 by stirring in a flask.
  • 41 g of bis (pinacholate) diboron, 9 g of tetrakis (triphenylphosphine) palladium, and 32 g of potassium acetate were added dropwise sequentially followed by stirring for 5 minutes. The temperature was slowly heated to 90 ° C and then stirred for 4 hours. After completion of reaction, the phase was quenched with silver, added with nucleic acid, and then filtered through a saltite.
  • Distilled water 300 was slowly added, extracted with 500 g of ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, concentrated and separated by silica column chromatography to prepare a title compound.
  • the title compound was prepared in the same manner as in ⁇ Preparation Example 17>, except that Ridine-1′carboxylate was used.
  • tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate instead of using tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate, tert ⁇ butyl 4- ( ⁇ Preparation 18>, except that (5- (4- (ethoxycarbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine-1-carboxylate was used. The same procedure was followed to prepare the title compound.
  • a title compound was prepared in the same manner as in ⁇ Example 8> except that a panol was used (amount: 220 mg I yield: 79%).
  • the title compound was prepared in the same manner as in ⁇ Example 17>, except that 1.3-propanediol was used (a yield 175 mg I yield: 79%).
  • Example 52 (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus -3-enyl) (pyridine- 1-yl) metabolic preparation
  • Example 65 Azetidin-1-yl (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) Preparation of Phenyl) cyclonux-3-enyl) methanone. .
  • Example 103 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) - ⁇ - (2 ⁇ 2, 2-trifluor Loethyl) cyclonux-3—encarboxamide
  • Example 112 4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Phenyl) -N- (2-morpholino-2-oxoethyl) cycle
  • Example 120 4- (3-fluoro-4-((1- (3-isopropyl—1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Phenyl) -N- (2-hydroxyethyl) cyclonucleose-3-
  • the title compound was prepared in the same manner as in ⁇ Example 80>, except that 2-aminoethanol was used instead of 2-amino-1,3-propanedi (yield 180 mg / Yield 76%).
  • ⁇ ⁇ R 400, CDC1 3 ): 7.11 (3H, m), 6.9K1H, m), 6.68 (1H, s) 6.60 (1 ⁇ , m), 6.07 (2 ⁇ , m), 5.43 (1 ⁇ , s), 4.60 (1H, d), 4.22 (2H, d), 4.11 (2H, m), 3.9K2H, d), 3.65 (1H, m), 3.49 (1H, m), 3.14 (2H m), 2.9K1H, m), 2.35-2.59 (6H, m) '1.83-2.21 (8H, m), 1.49 (2H, m), 1.3K6H, d).

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Abstract

The present invention relates to: a cyclohexene derivative; a preparation method therefor; and a pharmaceutical composition for preventing or treating metabolic diseases, containing the same as an active ingredient. The cyclohexene derivative according to the present invention increases the intracellular activity of cyclic adenosine monophosphate (cAMP) by activating G protein-coupled receptor 119 (GPR-119) and simultaneously exhibits weight loss and hypoglycemic effects by inducing the release of glucagon-like peptide-1 (GLP-1), which is a neuroendocrine protein, and thus can be useful as a pharmaceutical composition for preventing or treating metabolic diseases such as obesity, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.

Description

함것이Will
유의이  Significantly
【명세서】 【Specification】
【발명의 명칭】  [Name of invention]
싸이클로 핵센 유도체， 이의 제조방법 및 이를 유효성분 함유하는 대사성 질환의 예방 또는 치료용 약학적 조성물  Cyclo hackene derivatives, preparation method thereof and pharmaceutical composition for the prevention or treatment of metabolic diseases containing the active ingredient
【기술분야】 Technical Field
본 발명은 싸이클로 핵센 유도체 , 이의 광학 이성질체， 또는 약학적으로 허용가능한 염， 이의 제조방법 및 이를 유효성분으로 하는 대사성 질환의 예방 또는 차료용 약학적 조성물에 관한  The present invention relates to a cyclohexene derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or charging a metabolic disease using the same as an active ingredient.
【배경기술】 Background Art
대사성 질환이란 우리 몸의 각 기관의 신진대사가 원활하지 못 하기 때문에 나타나는 질병으로서， 생체 내 당질， 지질 , 단백질， 비타 민， 미네랄， 수분 등의 불균형에 의한 물질대사 장애로 발생하는 질환 의 총칭이며， 특히 성인병의 경우 99% 이상이 면역력 약화와 영양공급 결여로 발생 되는 대사질환이다. 대부분의 성인병의 경우 잘못된 음식 물 섭취에 의한 영양의 불균형 또는 운동부족 등으로 인하여 야기되어 진다. 대표적인 대사성 질환의 질병으로는 비만， I 형 당뇨병 , Π형 당뇨병， 부적합한 내당증， 인슐린 내성증， 고혈당증， 고지질혈증， 고 중성지방혈증， 고콜레스테를혈증， 이상지질혈증, X 증후군 등이 있다. 상기 대사성 질환으로 인하여 지방이 몸에 축적되는 경우， 혈액 내 포 도당을 간이나 근육에 보내는 호르몬인 인슐린이 제대로 생성되지 않 거나 기능이 저하되는 인슐린 저항성이 발생하고， 이로 인하여 혈당 증가 및 동맥경화가 유발되어 성인병이 발생하게 되는 원인이 된다. 상기 대사성 질환의 대표적인 질병인 당뇨병은 전 세계적으로 1 억 명이 넘는 사람들이 앓고 있는 심각한 대사성 질환이다. 미국에서 는， 12 , 000 , 000명 이상의 당뇨병 환자가 존재하며， 600 , 000명의 새로 운 환자가 매년 진단되고 있다. 당뇨병 병인은 동일하지 않지만， 당뇨 병을 앓는 모든 사람들은 공통적으로 간에 의해 글루코스가 과다 생성 되며， 상기 글루코스를 신체의 주요 연료로 사용하는 세포 내로 이동 시키는 능력이 없다. 당뇨병이 없는 사람들은 췌장에서 생성되는 인슐 린 호르몬에 의존하여， 글루코스를 혈액으로부터 신체의 세포 내로 이 동시킨다. 그러나， 당뇨병을 앓는 사람들은 인슐린을 생성하지 않거나 또는 그들이 생성하는 인슐린을 효율적으로 사용할 수 없으며， 이에 글루코스를 그들의 세포 내로 이동시킬 수 없다. 이에， 세포 내로 이 동하지 못하고 잔류하는 글루코스는 혈액 내에 축적되어 고혈당증이라 불리는 질병을 일으키고， 시간이 지남에 따라 심각한 건강 문제를 일 으킬 수 있다. 또한， 당뇨병은 대사성， 혈관, 및 신경병증 요소와 상호연관되 는 증후군이다. 일반적으로 고혈당증을 특징으로 하는 대사성 증후군 은 .인슐린 분비가 결여되었거나 현저히 감소되었으며 또는 인슐린은 있으나 인슐린이 효과를 나타내지 못하여 유발되는 탄수화물, 지방 및 단백질 대사의 변화를 포함한다. 혈관 증후군은 심혈관, 망막 및 신장 합병증올 유발하는 혈관의 이상으로 이루어진다. 말초 및 자율 신경계 의 이상 또한 당뇨병 증후군의 일부이다. 나아가， 당뇨병은 신장 질환， 안구 질환 및 신경계 문제의 발생에 연관성이 있다고 보고되어 왔다. 산장 질환 (신병증)은 신장의 "여과 메커니즘"이 손상되고， 단백질이 과량으로 소변 내로 새어 나가， 결국 신장이 약해지는 경우에 발생한 다. 또한， 당뇨병은 안구 후면의 망막에 손상을 유발하는 원인이며， 백내장 및 녹내장의 위험성을 증가시킨다. 보다 구체적으로， 당뇨병은 I형 및 II형의 2가지 임상 증후군으 로 분류할 수 있다. 인슐린 의존성 당뇨병 (IDDM)으로도 공지된 I형 당 뇨병은 인슐린을 생산하는 췌장 베타세포의 자가면역적인 파괴에 의해 비롯되며 외인성 인슐린의 정기적 투여를 필요로 한다. 비인슐린 의존 성 당뇨병 (NIDDM)으로도 공지된 II형 당뇨병은 혈당 수치를 적절하게 조절하는 능력이 상실됨으로 나타난다. Ιί형 당뇨병은 인슐린 분비에 서의 결함 또는 인슐린 저항 (insulin resistance) , 즉 인슐린이 거의 없거나 인슐린을 효과적으로 사용할 수 없는 II형 당뇨병을 앓는 사람 들에 의해 특징이 될 수 있다. 종래， 당뇨병에 대한 현재의 치료에는 인슐 ¾， 인슐린 분비촉진 제， 글루코스 저하 이펙터 (effector)， 퍼옥시좀 증식자-활성화된 수용 체 (PPAR)의 활성화제 등이 있다. 그러나, 저혈당 , 체중 증가， 시간 경 과에 따른 치료에 대한 반웅성 감소， 위장관 문제 및 부종을 포함하여， 현재 이용 가능한 치료법과 관련된 문제들이 있다. 이에 따른 더욱 효과적인 새로운 치료법을 시장에 도입하기 위 해 여러 영역을 목표로 연구가 이루어지고 있으며， 하나의 구체적인 표적이 GPR-119CG protein-coupled receptor 119)이다. GPR-119는 췌장， 소장， 결장 및 지방 조직에서 주로 발현되는Metabolic disease is a disease that occurs because metabolism of each organ of our body is not smooth, and it is a general term of disease caused by metabolic disorder caused by imbalance of in vivo sugar, lipid, protein, vitamin, mineral, and water. In particular, more than 99% of adult diseases are metabolic diseases caused by weakened immunity and lack of nutrition. Most adult diseases are caused by malnutrition or lack of exercise due to poor food intake. Typical metabolic diseases include obesity, type I diabetes, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X. . When fat accumulates in the body due to the metabolic disease, insulin resistance, which is a hormone that sends glucose in the blood to the liver or muscles, is not properly produced or functions are reduced, resulting in increased blood sugar and atherosclerosis. It is a cause of adult disease. Diabetes, a representative disease of the metabolic disease, is a serious metabolic disease suffered by more than 100 million people worldwide. In the United States, there are more than 12, 000, 000 diabetics and 600, 000 new cases are diagnosed each year. Diabetes etiology is not the same, but all people with diabetes commonly have excessive production of glucose by the liver and lack the ability to move the glucose into cells that use it as the main fuel of the body. People without diabetes rely on insulin hormones produced by the pancreas to move glucose from blood into cells in the body. However, people with diabetes do not produce insulin or can not use the insulin they produce efficiently and thus cannot move glucose into their cells. As a result, glucose that remains incapable of moving into cells accumulates in the blood, causing a disease called hyperglycemia, and may cause serious health problems over time. Diabetes is also a syndrome that correlates with metabolic, vascular, and neuropathic factors. In general, metabolic syndromes characterized by hyperglycemia include changes in carbohydrate, fat and protein metabolism caused by lack of insulin secretion or markedly reduced or insulin, but the insulin is ineffective. Vascular syndrome consists of abnormalities in blood vessels that cause cardiovascular, retinal and renal complications. Abnormalities of the peripheral and autonomic nervous system are also part of the diabetes syndrome. Furthermore, it has been reported that diabetes is associated with the development of kidney disease, eye disease and nervous system problems. Cabin disease (nephropathy) occurs when the "filtration mechanism" of the kidney is impaired, the protein leaks into the urine in excess, and eventually the kidney becomes weak. Diabetes is also a cause of damage to the retina of the back of the eye and increases the risk of cataracts and glaucoma. More specifically, diabetes can be classified into two clinical syndromes, type I and type II. Type I diabetes, also known as insulin dependent diabetes (IDDM), is caused by the autoimmune destruction of insulin producing pancreatic beta cells and requires regular administration of exogenous insulin. Type II diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM), appears to lack the ability to properly control blood glucose levels. Type II diabetes may be characterized by a deficiency in insulin secretion or by insulin resistance, namely people with type II diabetes who have little or no insulin. Conventionally, current treatments for diabetes include insulin ¾, insulin secretagogues, glucose lowering effectors, activators of peroxysome proliferator-activated receptors (PPARs), and the like. However, there are problems associated with currently available therapies, including hypoglycemia, weight gain, decreased response to treatment over time, gastrointestinal problems and edema. In order to introduce more effective new therapies into the market, research is being conducted in various areas, and one specific target is GPR-119CG protein-coupled receptor 119). GPR-119 is mainly expressed in the pancreas, small intestine, colon and adipose tissue.
G-단백질 결합 수용체 (G protein coupled recept o(GPCR) ) 중의 하나이 다. 리간드 혹은 길항근 (agonist)이 수용체에 결합 하게 되면 수용체 는 구조가 바뀌게 되고 G-단백질과 연결 되어 세포 또는 기관내의 2차 메신저의 반웅을 촉매하게 된다. It is one of the G protein coupled receptors (GPCR). When a ligand or an antagonist binds to a receptor, the receptor changes its structure and is linked to G-proteins to catalyze the reaction of secondary messengers in cells or organs.
GPR-119 수용체 및 이소폼 (isofornO은 사람， 쥐， 마우스， 햄스 터， 침팬지， 붉은털 원숭이 , 소 및 개를 포함하는 포유류 종에서 발견 된다 . 특히， 췌장의 β -세포에서 GPR-119와 발현은 GPR-119 수용체가 인술린 분비에 영향을 갖는 것으로 알려져 있다. GPR-119의 활성은， 이들 세포에서 2차 데신저인 cAMP(Cycl ic adenosine monophosphate)^ 세포 내 활성을 증가시키는 cAMP 단일 경로를 자극한다. cAMP의 자극 은 효소 또는 유전자 발현 등 많은 다양한 세포 반웅에 관여하게 되고， β—세포 내에서 cAMP(Cycl ic adenosine monophosphate)의 ^"극은 GPR- 119의 활성화를 통해 발생하게 된다. 또한 β _세포 내에서 GIP(Gastr i c inhibitory polypeptide) , GLP-l(Glucagon-l ike peptideᅳ 1)， PYY(Peptide YY) 등은 G-단백질 결합 수용체를 통해 인슐린 분비 작용을 일으킨다. 상기 GIP 및 GLP-1과 같은 인크레틴은 식사 후 혈당 치에 의존적으로 인슐린 분비를 강력하게 자극하는 장 호로몬이다. GPR-119 receptors and isoforms (isofornO are found in mammalian species including humans, mice, mice, hamsters, chimpanzees, rhesus macaques, cattle and dogs. In particular, GPR-119 and expression in pancreatic β-cells Has the GPR-119 receptor It is known to have an effect on insulin secretion. The activity of GPR-119 stimulates the cAMP single pathway, which increases the intracellular activity of cAMP (Cycl ic adenosine monophosphate) ^ cells in these cells. Stimulation of cAMP is involved in many different cell responses, such as enzyme or gene expression, and the ^ "polarity of cAMP (Cycl ic adenosine monophosphate) in β-cells is generated through activation of GPR-119. GIP (Gastr ic inhibitory polypeptide), GLP-1 (Glucagon-ike peptide ᅳ 1), PYY (Peptide YY), etc. cause insulin secretion through G-protein-coupled receptors. The same incretin is a gut hormone that strongly stimulates insulin secretion depending on blood sugar levels after a meal.
GPR-119 활성화제는 β -세포 기능 및 β -세포 집단에서의 개선 에 효과가 있다. GPR-119의 활성화는 시험관 내 및 생체 내 (설치류)에 서 글루코스—의존 방식으로 인슐린 분비를 자극한다. 강력한 GPR-119 활성화제의 발견은 혈장 글루코스를 저하시켜 저혈당증 위험 없이 혈 당 조절을 촉진시킬 수 있다. GPR-119 activators are effective for improving β-cell function and β-cell population. Activation of GPR-119 stimulates insulin secretion in a glucose-dependent manner in vitro and in vivo (rodent). The discovery of potent GPR-119 activators can lower plasma glucose and promote glycemic control without the risk of hypoglycemia.
최근에는， GPR-119 활성화제가 저혈당증의 위험 없이 당뇨병 설 치류에게서 혈당 수준을 효율적으로 저하시키는 것으로 나타났다. GPR-119 녹아웃 동물 (Knockout animal)들은 GPR-119 활성화제에 의해 유도된 인슐린， 및 인크레틴의 분비 모두가 GPR-119 수용체에 의존하 는 것으로 확인되었다. 또한， GPR-119 활성화제는 음식 섭취를 감소시 켜 스프라그 다우리 랫트 (Sprague Dawley rat)에서의 체중 저하를 유 발하는 것으로 나타났다. 비특허문헌 1은， GPR-119 활성화가 cAMP Cycl ic adenosine monophosphate)를 자극하여 글루코스 의존적인 글루카곤 -유사 펩티드- KGlucagon-like peptide-1, GLP-1) 및 인슐린 분비를 유도하는 내용 을 개시하고 있다. GLP-1은 특정 G 단백질 -결합 수용체 (GPCR)인 GLP- 1R을 통해 그의 작용을 매개하고 글루코스 항상성을 조절하고， 글루코 스-의존성 인슐린 분비를 자극하며， 췌장 베타 세포 질량을 증가시키 는 것으로 밝혀졌다. 또한, GLP-1은 위 배출의 속도를 감속시키고 포 만감을 촉진하는 것으로 밝학졌다.  Recently, GPR-119 activators have been shown to effectively lower blood glucose levels in diabetic installations without the risk of hypoglycemia. GPR-119 knockout animals were found to be dependent on the GPR-119 receptor for both insulin and incretin secretion induced by GPR-119 activators. GPR-119 activators have also been shown to reduce food intake, causing weight loss in Sprague Dawley rats. Non-Patent Document 1 discloses that GPR-119 activation stimulates cAMP Cyclic adenosine monophosphate) to induce glucose-dependent glucagon-like peptide-1 (KGlucagon-like peptide-1, GLP-1) and insulin secretion. . GLP-1 has been shown to mediate its action through GLP-1R, a specific G protein-binding receptor (GPCR), to regulate glucose homeostasis, to stimulate glucose-dependent insulin secretion, and to increase pancreatic beta cell mass. lost. GLP-1 has also been shown to slow down the rate of gastric emptying and promote satiety.
그러나， 현재 사용되고 있는 GLPᅳ 1 펩티드 활성화제는 경구 투 여시， 생체이용률이 부족하여 효능에 부정적인 영향을 미치고 있다. 따라서， 경구 생체이용률이 우수할 뿐 아니라 혈액에 GLP-1의 분비를 유도하는， GPR-119 활성화제를 개발이 요구되는 실정이다. 상기 연구결과의 일례로， 특허문헌 1-2 및 비특허문헌 2에 개시 되어 있는 GPR-119 활성화제는 랫트 (rat)에서， 만성투여 이후에 급성 음식 섭취의 감소를 일으키고, 체중을 감소시키는 것으로 입증되었다. 또한, 특허문헌 3에서는, 삼중치환된 해테로아릴 유도체에 대한 관심 이 높아지면서 , 삼중치환된 피리미딘 유도체를 이용한 대사질환 치료 는들지에된제 However, currently used GLP ᅳ 1 peptide activator has a negative effect on efficacy due to lack of bioavailability during oral administration. Therefore, there is a need to develop a GPR-119 activator that not only has excellent oral bioavailability but also induces secretion of GLP-1 in the blood. For example, the GPR-119 activator disclosed in Patent Literatures 1-2 and Non-Patent Literature 2 causes acute food intake reduction and weight loss in rats after chronic administration. Proven. In addition, in Patent Document 3, as interest in triple-substituted heteroaryl derivatives increases, metabolic disease treatment using triple-substituted pyrimidine derivatives Independence
4 를 개시하고 있다. 나아가， 특허문헌 4에서는， 인슐린 저항과 관련 I형 당뇨병에 대한 치료제로서 IC— GPCR2 또는 GPR-119를 활성화하 것을 특징으로 하는 아릴， 헤테로아릴 또는 헤테로사이클릴 유도체 을 이용한 당뇨병 치료제에 대하여 개시하고 있다 . 그러나， 현재까 싸이클로 핵센 골격을 갖는 화합물 및 이의 대사성 질환 치료 용도 대하여는 알려진 바가 없다. 이에， 본 발명자들은 GPR-119에 대한 활성화제를 연구하던 중， 본 발명에 따른 싸이클로 핵센 유도체， 이의 광학이성질체 , 또는 이꾀 약학적으로 허용가능한 염이 GPR-119(G protein-coupled receptor 119)를 활성화入]켜 cAMP(Cycl ic adenosine monophosphate)의 세포 내 활성을 증가시키고， 신경 내분비 단백질인 GLP-l(Glucagon-like peptide-1) 방출을 유도하여 체중감소 및 혈당강하 효과가 동시에 나타나므로， 비만, I형 당뇨병， Π형 당뇨병 , 부적합한 내당증, 인슐린 내성증, 고혈당증， 고지질혈증， 고중성지방혈증， 고콜레스테를혈증， 이상지질혈증， X 증후군 등과 같은 대사성 질환의 예방 또는 치료용 약학적 조성물로 유용함을 확인하고 본 발명을 완성하였다.  4 is disclosed. Furthermore, Patent Document 4 discloses a therapeutic agent for diabetes using an aryl, heteroaryl, or heterocyclyl derivative characterized by activating IC—GPCR2 or GPR-119 as a therapeutic agent for insulin resistance and related type I diabetes. . However, to date, no compound having a cyclohexene skeleton and its use for treating metabolic diseases are known. Accordingly, while the present inventors are studying an activator for GPR-119, the cyclohexene derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention is a GPR-119 (G protein-coupled receptor 119). Activation increases the intracellular activity of Cyclic Adenosine Monophosphate (cAMP) and induces the release of GLP-1 (Glucagon-like peptide-1), a neuroendocrine protein, resulting in weight loss and hypoglycemic effects. Pharmaceutical for the prevention or treatment of metabolic diseases such as diabetes mellitus, type I diabetes, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X It was found useful as a composition and completed the present invention.
【선행기술문헌】 Prior Art Documents
【특허문헌】  [Patent literature]
국제공개공보 제 2005/007647호  International Publication No. 2005/007647
국제공개공보 제 2005/007658호  International Publication No. 2005/007658
국제공개공보 제 2004/065380호  International Publication No. 2004/065380
국제공개공보 제 2008/083238호  International Publication No. 2008/083238
【비특허문헌】 [Non-patent literature]
• T. Soga et al . , Bi ochem . Biophy . Res . Commu . 326 , (2005) 744-751 . • T. Soga et al. , Bi ochem. Biophy. Res. Commu. 326, (2005) 744-751.
Overton, H.A. et al. , Cell metabolism, 3, (2006) , 167-175  Overton, H. A. et al. , Cell metabolism, 3, (2006), 167-175
【발명의 상세한 설명】 [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
본 발명의 목적은 싸이클로 핵센 유도체， 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다. 본 발명의 다른 목적은 상기 싸이클로 핵센 유도체의 제조방법 을 제공하는 것이다 . 본 발명의 또 다른 목적은 상기 싸이클로 핵센 유도체를 유효성 분으로 함유하는 대사성 질환의 예방 또는 치료용 약학적 조성물을 제 공하는 것이다. 본 발명의 다른 목적은 상기 싸이클로 핵센 유도체를 유효성분 으로 함유하는 GPR-119(G protein-coupled receptor 119) 활성화제를 제공하는 것이다. 본 발명꾀 또 다른 목적은 상기 싸이클로 핵센 유도체를 유효성분으로 함유하는 대사성 질환의 예방 또는 개선용 건강기능식품을 제공하는 것이다. It is an object of the present invention to provide cyclohexene derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof. It is another object of the present invention to provide a method for producing the cyclohexene derivative. Still another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of metabolic diseases containing the cyclohexene derivative as an active ingredient. Another object of the present invention is to provide a G protein-coupled receptor 119 (GPR-119) activator containing the cyclohexene derivative as an active ingredient. Another object of the present invention to provide a health functional food for the prevention or improvement of metabolic diseases containing the cyclo nucleene derivative as an active ingredient.
【기술적 해결방법】 Technical Solution
상기 목적을 달성하기 위하여， 본 발명은 하기 화학식 1로 표시 되는 화합물， 이의 광학 이성질체， 또는 아의 약학적으로 허용가능한 염을 제공한다.  In order to achieve the above object, the present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1]  [Formula 1]
Figure imgf000007_0001
Figure imgf000007_0001
상기 화학식 1에서，  In Chemical Formula 1,
R1은 -H, -OH, d-K^ 직쇄 또는 측쇄 알킬 , -10의 직쇄 또는 측쇄 알콕시， 의 직쇄 또는 측쇄 알콕시카보닐， 또는 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5-10원자 해테로아릴이고， R 1 is a hetero atom selected from the group consisting of -H, -OH, d- K ^ straight or branched alkyl, straight or branched alkoxy of -10 , straight or branched alkoxycarbonyl of -10 , or N, 0 and S It is an unsubstituted or substituted 5-10 membered heteroaryl containing,
여기서 , 상기 치환된 5-10원자 헤테로아릴은 (^-^！의 직쇄 또는 측쇄 알킬이 하나 이상 치환된 5-10원자 헤테로아릴이고; R2는 -H, -0H, 할로겐， (^-10의 직쇄 또는 측쇄 알킬， 또는 에 의 직쇄 또는 측쇄 알콕시이고; Wherein the substituted 5-10 membered heteroaryl is 5-10 membered heteroaryl substituted with at least one linear or branched alkyl of (^-^ ！; R 2 is -H, -0H, halogen, (^ -10 Straight chain or branched alkyl of or straight chain or branched alkoxy of;
R3는 비치환 또는 하나 이상의 -0H 또는 할로겐이 치환된 -^의 직쇄 또는 측쇄 알킬， 10의 직쇄 또는 측쇄 알콕시， d- o의 직쇄 또는 측쇄 알콕시 ( -10의 직쇄 또는 측쇄 알킬 , 비치환된 (：3-10의 싸이클로알킬， N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환된 5-10원자 해테로아릴 d-u)의 직 쇄 또는 측쇄 알킬， -(CH2)nNR5R6, -(CH2)mC(=0)0R7, 또는 - (CH2)pC(=0)NR8R9이고, R5 및 R6는 독립적으로 -H,
Figure imgf000008_0001
또는 d-5의 직쇄 또 는 측쇄 알킬이고, R 3 is unsubstituted or substituted with one or more -0H or halogen-^ straight or branched alkyl, 10 straight or branched alkoxy, d-o straight or branched alkoxy ( -10 or straight-chain or branched alkyl, unsubstituted straight-chain or branched alkyl of: - (310 of cyclo-alkyl, N, 0 and beach containing one or more heteroatoms selected from the group consisting of S ring of 5-10 atoms to interrogating aryl du), - (CH 2 ) n NR 5 R 6 ,-(CH 2 ) m C (= 0) 0R 7 , or-(CH 2 ) p C (= 0) NR 8 R 9 , R 5 and R 6 are independently -H,
Figure imgf000008_0001
Or straight or branched alkyl of d- 5 ,
R7은 -H， 또는 d-5의 직쇄 또는 측쇄 알킬이고， R 7 is —H, or d- 5 linear or branched alkyl,
R8 및 R9는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 및 S 로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하 는 비치환 또는 치환된 5-10원자 헤테로싸이클로알킬을 형성할 수 있 고， R 8 and R 9 may be linked with the nitrogen atom to which they are linked to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, 0 and S And
여기서， 상기 치환된 5-10원자 헤테로싸이클로알킬은 -CN, d-5 의 직쇄 또는 측쇄 알킬， 5의 직쇄 또는 측쇄 알콕시 및 ᅳ C(=0)NR10Rn로 이루어지는 군으로부터 선택되는 하나 이상의 치환기가 치환된 5— 10원자 헤테로싸이클로알킬이고， 상기 R10 및 R11은 독립적으 로 -H, 또는 d-5의 직쇄 또는 측쇄 알킬이고， n, m 및 p는 독립적으로 1-10의 정수이고; Wherein the substituted 5-10 membered heterocycloalkyl is one or more selected from the group consisting of -CN, straight or branched chain alkyl of d-5, straight or branched chain alkoxy of 5 and ᅳ C (= 0) NR 10 R n The substituent is a substituted 5-10 membered heterocycloalkyl, R 10 and R 11 are independently -H, or straight or branched chain alkyl of d- 5 , n, m and p are independently an integer of 1-10 ego;
R4는 -H, 비치환 또는 하나 이상의 -0H가 치환된 (^-10의 직쇄 또는 측쇄 알킬， 또는 -10의 직쇄 또는 측쇄 알콕시이고 ; R 4 is —H, unsubstituted or at least one —0H substituted (^ -10 straight or branched alkyl, or -10 straight or branched alkoxy;
이 C택 This C pick
이되상  Ideal
상기 R3 및 R4는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 상는의의 및 S로 이루어지는 군으로부터 선택되는 해테로 원자를 하나 이의상 포 함하는 비치환된 3-10원자 헤테로싸이클로알케닐， 또는 N, 0 및싸헤치 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하환이테는ᅳ 비치환， 치환, 또는 융합된 (fused) 3-10원자 헤테로싸이클로알킬을 형 성할 수 있고， 여기서， 상기 치환된 3-10원자 해테로싸이클로알킬은 -OH, -CN, =0， 할로겐， 비치환 또는 하나 이상의 -0H가 치환된 d-5의 직쇄 또는 측쇄 알킬， d— 5의 직쇄 또는 측쇄 알콕시， 비치환된 (：3-10의 싸이클로 알킬 의 직쇄 또는 측쇄 알킬， 비치환된 (：3-10의 싸이클로알킬 , N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환된 3-10원자 해테로싸이클로알킬， -C(=0)NR12R13, ― NR14R15, =NR16으로 이루어지는 군으로부터 선택되는 하나 R 3 and R 4 is an unsubstituted 3-10 membered heterocycloalkenyl containing one heterophasic heteroatomic selected from the group consisting of S and N in the N, 0 phase, connected with the nitrogen atom to which they are linked, Or an at least one hetero atom selected from the group consisting of N, 0 and sahech S, which may form an unsubstituted, substituted, or fused 3-10 membered heterocycloalkyl, wherein the substituted by 3-10 atoms Tero cyclo alkyl is -OH, -CN, = 0, halogen, unsubstituted or substituted one or more -0H the d-5 straight or branched alkyl, d- 5 straight or branched alkoxy , unsubstituted (: unsubstituted containing 10 cyclo-alkyl, N, 0, and one or more heteroatoms selected from the group consisting of S -: - 3 3 the 10-ring cyclo-alkyl of straight or branched chain alkyl, Beach ( 3-10 Atom heterocycloalkyl, -C (= 0) NR 12 R 13 ,-NR 14 R 15 , = NR 16
기가 치환되거나; 비치환된 (：6-10의 아릴이 융합된 (fused) The group is substituted; Unsubstituted (: 6 - 10 aryl fused with a (fused)
클로알케닐， 또는 N, 0 및 S로 이루어지는 군으로부터 선 Chloralkenyl, or a line from the group consisting of N, 0 and S
로 하나 이상 포함하는 비치환 또는 하나 Including one or more unsubstituted or
Boc(
Figure imgf000008_0002
)가 치환된 3-10원자 헤테로싸이클로알킬이 스피로 (Spiro) 형태로 치환된 3-10원자 해테로싸이클로알킬이고 , Boc (
Figure imgf000008_0002
Spiro substituted 3-10 membered heterocycloalkyl is spiro 3-10 membered heterocycloalkyl substituted in the form (Spiro),
상기 R12, R13, R14 및 R15는 독립적으로 -H, 또는 d-5의 직쇄 또 는 측쇄 알킬이고， 상기 R16은 -H, -0H， 또는 d-s의 직쇄 또는 측쇄 알콕시이고， 여기서 , 상기 융합된 (fused) 3-10원자 헤테로싸이클로알킬은 비 치환된 (：6-10의 아릴이 융합된 3-10원자 헤테로싸이클로알킬이고, 상기 바치환， 치환， 또는 융합된 (fused) 3-10원자 헤테로싸이클 로알킬에 있어서， 치환과 융합은 동시에 일어날 수 있고; R 12 , R 13 , R 14 and R 15 are independently —H or d- 5 , straight or branched alkyl, R 16 is —H, —0H, or ds straight or branched alkoxy, wherein , Wherein the fused 3-10 membered heterocycloalkyl is an unsubstituted 3-10 membered heterocycloalkyl fused with 6 to 10 aryl, and the substituted, substituted, or fused 3 For a -10 membered heterocycloalkyl, substitutions and fusions can occur simultaneously;
A 및 E는 독립작으로 -CH=, 또는 -N=이다. 또한， 본 발명은 하기 반웅식 1에 나타난 바와 같이 ， A and E are -CH = or -N = independently. In addition, the present invention, as shown in the following reaction formula 1,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반웅시켜 화학식 4로 표시되는 화합물을 제조하는 단계 (단계 1);  Preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3 (step 1);
상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반웅시켜 화학식 6으로 표시되는 화합물을 제 조하는 단계 (단계 2);  Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 (Step 2);
상기 단계 2에서 제조한 화학식 6으로 표시되는 화합물을 염기 와 반웅시켜 화학식 7로 표시되는 화합물을 제조하는 단계 (단계 3); 및 . ■ . Preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 prepared in Step 2 with a base (Step 3); And. ■ .
상기 단계 3에서 제조한 화학식 7로 표시되는 화합물과 화학식 8로 표시되는 화합물을 반웅시켜 화학식 1로 표시되는 화합물을 얻는 단계 (단계 4);를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방 법을 제공한다.  Method of preparing a compound represented by the formula (1) comprising the step (4) to obtain a compound represented by the formula (1) by reacting the compound represented by the formula (7) and the compound represented by the formula (8) prepared in step 3 To provide.
[반응식 1] Scheme 1
Figure imgf000010_0001
Figure imgf000010_0001
상기 반웅식 1에서 ,  In the reaction 1,
R1, R2, R3, R4, Α 및 Ε는 상기 화학식 1에서 정의한 바와 같다. 나아가， 본 발명은 상기 화학식 1로 표시되는 화합물， 이의 광 학 이성질체， 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함 유하는 대사성 질환의 예방 또는 치료용 약학적 조성물을 제공한다. 또한， 본 발명은 상기 화학식 1로 표시되는 화합물， 이의 광학 이성질체 , 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유 하는 GPR-119(G protein-coupled receptor 119) 활성화제를 제공한다 . 나아가， 본 발명은 상기 화학식 1로 표시되는 화합물 , 이의 광학 이성질체， 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 대사성 잘환의 예방 또는 개선용 건강기능식품을 제공한다. R 1 , R 2 , R 3 , R 4 , Α and Ε are as defined in Formula 1 above. Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also provides a G protein-coupled receptor 119 (GPR-119) activator containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the present invention provides a health functional food for preventing or improving metabolic well ring containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
【유리한 효과】 Advantageous Effects
본 발명에 따른 싸이클로 핵센 유도체， 이의 광학 이성질체， 또 는 이의 약학적으로 허용가능한 염은 GPR-119(G protein-coupled receptor 119)를 활성화시켜 cAMP(Cyclic adenosine monophosphate)의 세포 내 활성을 증가시키고, 신경 내분비 단백질인 GLP-l(Glucagon- 1 ike pept ide-1) 방출을 유도하여 체중감소 및 혈당강하 효과가 동시 에 나타나므로， 비만， I형 당뇨병， Π형 당뇨병， 부적합한 내당증， 인 슐린 내성증， 고혈당증， 고지질혈증， 고중성지방혈증， 고콜레스테를혈 증， 이상지질혈증， X 증후군 등과 같은 대사성 질환의 예방 또는 치료 용 약학적 조성물로 유용하게 사용할 수 있다. Cyclo nucene derivatives, optical isomers thereof, or pharmaceutically acceptable salts thereof according to the present invention activate GPR-119 (G protein-coupled receptor 119) to induce cAMP (Cyclic adenosine monophosphate). Increasing intracellular activity and inducing the release of neuronal endocrine protein GLP-1 (Glucagon-1 ike pept ide-1) results in simultaneous weight loss and hypoglycemic effects. Obesity, type I diabetes, type Π diabetes, It can be usefully used as a pharmaceutical composition for the prevention or treatment of metabolic diseases such as inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, X syndrome, etc. .
【도면의 간단한 설명】 [Brief Description of Drawings]
도 1은 본 발명에 따른 실시예 48 및 비교예 3, 4의 화합물을 DIOCDiet-induced obesity) 랫트 모델에 4주간 투여하며 체중변화를 측정한 그래프이다 (도 1에서 "무처리군 (vehicle)"은 고지방 식이 비만 랫트 모델 (diet-induced obesity, DI0)의 무처리군을 나타내고; "Lean"은 병태 모델이 아닌 정상 SD 랫트 모델의 무처리군을 나타낸 다 ).  Figure 1 is a graph of the weight change of the compounds of Examples 48 and Comparative Examples 3, 4 according to the present invention to DIOCDiet-induced obesity rat model for 4 weeks (Fig. 1 "vehicle") Represents an untreated group of diet-induced obesity (DI0) models; "Lean" represents an untreated group of normal SD rat models, not the pathological model).
도 2(A)는 본 발명에 따른 실시예 48 및 비교예 3의 화합물을 Figure 2 (A) is a compound of Example 48 and Comparative Example 3 according to the present invention
DIOCDiet-induced obesity) 랫트 모델에 4주간 투여가 종료되는 시점 에， 실시예 48 및 비교예 3의 화합물을 투여한 30분 후， 글루코스를 투여하였을 때 시간변화에 따른 혈당강하 효능을 평가한 그래프이다. 도 2(B)는 본 발명에 따른 실시예 119의 화합물을 DK Diet- induced obesity) 랫 ^ 모델에 4주간 투여가 종료되는 시점에 , 실시예 119의 화합물을 투여한 30분 후， 글루코스를 투여하였을 때 시간변화 에 따른 혈당강하 효능을 평가한 그래프이다. DIOCDiet-induced obesity is a graph evaluating the hypoglycemic efficacy according to the time change when glucose was administered 30 minutes after the administration of the compounds of Example 48 and Comparative Example 3 at the end of 4 weeks of administration to the rat model. . FIG. 2 (B) shows the administration of glucose 30 minutes after the administration of the compound of Example 119 at the end of 4 weeks of administration of the compound of Example 119 to the DK Diet-induced obesity rat It is a graph evaluating the hypoglycemic efficacy according to the time change.
도 3은 인간의 장 세포인 NCI-H716 세포에 본 발명에 따른 비교 예 1， 5 및 실시예 48를 처리하여 GLP-l(Glucagon-l ike pept ide-1)의 분비량올 나타낸 그래프이다.  3 is a graph showing the secretion amount of GLP-1 (Glucagon-ike peptide-1) by treating human intestinal cells NCI-H716 cells with Comparative Examples 1, 5 and 48 according to the present invention.
【발명의 실시를 위한 최선의 형태】 [Best form for implementation of the invention]
이하， 본 발명을 상세히 설명한다.  Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1 로 표시되는 화합물， 아의 광학 이성질체， 또는 이의 약학적으로 허용가능한 염을 제공한다.  The present invention provides a compound represented by the following formula (1), an optical isomer of ah, or a pharmaceutically acceptable salt thereof.
[화학식 1]  [Formula 1]
Figure imgf000011_0001
Figure imgf000011_0001
상기 화학식 1에서，  In Chemical Formula 1,
R1은 -H, -OH, d— 10의 직쇄 또는 측쇄 알킬， d-10의 직쇄 또는 측쇄 알콕시， 10의 직쇄 또는 측쇄 알콕시카보닐， 또는 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5-10원자 헤테로아릴이고 , R 1 is a -H, -OH, a straight or branched chain alkoxycarbonyl of d- 10 straight or branched chain alkyl, d- 10 straight or branched chain alkoxy, and 10 of the, or a N, 0 and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more hetero atoms selected from the group consisting of,
여기서 , 상기 치환된 5-10원자 헤테로아릴은 -^의 직쇄 또는 측쇄 알킬이 하나 이상 치환된 5-10원자 헤테로아릴이고;  Wherein the substituted 5-10 membered heteroaryl is 5-10 membered heteroaryl substituted with at least one straight or branched chain alkyl of-^;
R2는 H, -0H, 할로겐， d-u)의 직쇄 또는 측쇄 알킬， 또는 d-10 의 직쇄 또는 측쇄 알콕시이고; R 2 is H, —0H, halogen, straight chain or branched alkyl of du), or straight chain or branched alkoxy of d- 10 ;
R3는 -H, 비치환 또는 하나 이상의 -0H 또는 할로겐이 치환된 -^의 직쇄 또는 측쇄 알킬， d- 의 직쇄 또는 측쇄 알콕시， d-H)의 직쇄 또는 측쇄 알콕시 ( - 의 직쇄 또는 측쇄 알킬， 비치환된 (：3-10의 싸이클로알킬， N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환된 5-10원자 헤테로아릴 d-u)의 직 쇄 또는 측쇄 알킬， -(CH2)nNR5R6, -(CH2)mC(=0)0R7, 또는 - (CH2)PC(=0)NR8R9이고， R 3 is -H, unsubstituted or substituted at least one -0H or halogen-or straight chain or branched alkyl of-^, straight or branched chain alkoxy of d-, straight or branched chain alkoxy of (dH), straight or branched chain alkyl of- hwandoen: - straight-chain or branched alkyl of (310 of cyclo-alkyl, N, 0 and beach containing one or more heteroatoms selected from the group consisting of S-substituted 5 to 10-membered heteroaryl du), - (CH 2 ) n NR 5 R 6 ,-(CH 2 ) m C (= 0) 0R 7 , or-(CH 2 ) P C (= 0) NR 8 R 9 ,
R5 및 R6는 독립적으로 -H,
Figure imgf000012_0001
또는 d-5의 직쇄 또 는 측쇄 알킬이고， R 5 and R 6 are independently -H,
Figure imgf000012_0001
Or straight or branched chain alkyl of d- 5 ,
R7은 -H, 또는 d-s의 직쇄 또는 측쇄 알킬이고 R 7 is —H, or straight or branched chain alkyl of ds
R8 및 R9는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 및 S 로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하 는 비치환 또는 치환된 5-10원자 헤테로싸이클로알킬을 형성할 수 있 여기서， 상기 치환된 5-10원자 헤테로싸이클로알킬은 _CN, Ci-5 의 직쇄 또는 측쇄 알킬， d-5의 직쇄 또는 측쇄 알콕시 및 - C(=0)NR10Ru로 이루어지는 군으로부터 선택되는 하나 이상의 치환기가 치환된 5-10원자 헤테로싸이클로알킬이고， 상기 R10 및 R11은 독립적으 로 -H, 또는 d-5의 직쇄 또는 측쇄 알킬이 고 n, m 및 p는 독립적으로 1-10의 정수이고; R 8 and R 9 may be linked with the nitrogen atom to which they are linked to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, 0 and S Wherein the substituted 5-10 membered heterocycloalkyl is one selected from the group consisting of _CN, straight or branched chain alkyl of Ci-5, straight or branched chain alkoxy of d- 5 and -C (= 0) NR 10 R u The substituent is a substituted 5-10 membered heterocycloalkyl, R 10 and R 11 are independently -H or d- 5 or straight or branched alkyl, and n, m and p are independently 1-10 An integer;
R4는 비치환 또는 하나 이상의 -0H가 치환된 d-10의 직쇄 또는 측쇄 알킬， 또는 -^의 직쇄 또는 측쇄 알콕시이고 ; 상기 R3 및 R4는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포 함하는 비치환된 3-10원자 헤테로싸이클로알케닐， 또는 N, 0 및 로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환, 치환, 또는 융합된 (fused) 3-10원자 헤테로싸이클로알킬을 형 성할 수 있고， 여기서， 상기 치환된 3-10원자 헤테로싸이클로알킬은 -OH, -CN, =0， 할로겐， 비치환 또는 하나 이상의 -0H가 치환된 d-5의 직쇄 또는 측쇄 알킬， C— 5의 직쇄 또는 측쇄 알콕시， 비치환된 (：3-10의 싸이클로 알킬 의 직쇄 또는 측쇄 알킬， 비치환된 C3— 10의 싸이클로알킬 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환된 3-10원자 헤테로싸이클로알킬， -C(=0)NR12R13, - NR14R15, =NR16으로 이루어지는 군으로부터 선택되는 하나 이상의 치환 기가 치환되거나; 비치환된 (:6-10의 아릴이 융합된 (fused) (：5-10의 싸이 클로알케닐， 또는 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테 로 하나 이상 포함하는 비치환 또는 하나 이상의 - R 4 is unsubstituted or straight chained or branched alkyl of d- 10 substituted with one or more -0H, or straight chained or branched alkoxy of-^; R 3 and R 4 are unsubstituted 3-10 membered heterocycloalkenyl containing one or more heteroatoms selected from the group consisting of N, 0 and S connected with the nitrogen atom to which they are linked, or N, 0 And at least one hetero atom selected from the group consisting of Unsubstituted, substituted, or fused 3-10 membered heterocycloalkyl can be formed, wherein the substituted 3-10 membered heterocycloalkyl is -OH, -CN, = 0, halogen, unsubstituted or one or more -0H a straight-chain or branched alkoxy, Beach substituted d-5 straight or branched chain alkyl, C- 5 of the ring (3 - 10 cyclo alkyl, a straight or branched alkyl, unsubstituted C 3 - 10 Unsubstituted 3-10 membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, 0 and S, -C (= 0) NR 12 R 13 ,-NR 14 R 15 , = substituted groups are one or more substitution selected from the group consisting of NR 16, or; unsubstituted (: 6 - 10 aryl fusion (fused) (: 5 - 10 Cy claw alkenyl, or consisting of N, 0 and S Unsubstituted or containing at least one hetero group selected from the group Over me-
Boc(
Figure imgf000013_0001
)가 치환된 3-10원자 헤테로싸이클로알킬이 스피로 (Spiro) 형태로 치환된 3-10원자 해테로싸이클로알킬이고， Boc (
Figure imgf000013_0001
) Is substituted 3-10 membered heterocycloalkyl is a 3-10 membered heterocycloalkyl substituted in the form of Spiro,
상기 R12, R13, R14 및 R15는 독립적으로 -H, 또는 d-5의 직쇄 또 는 측쇄 알킬이고， 상기 R16은 -H, -0H, 또는 의 직쇄 또는 측쇄 알콕시이고, 여기서， 상기 융합된 (fused) 3-10원자 헤테로싸이클로알킬은 비 치환된 C6— 10의 아릴이 융합된 3-10원자 해테로싸이클로알킬이고, 상기 비치환， 치환， 또는 융합된 (fused) 3-10원자 헤테로싸싸원직이클 R 12 , R 13 , R 14 and R 15 are independently —H or d- 5 , straight or branched alkyl, R 16 is —H, —0H, or straight or branched alkoxy of The fused 3-10 membered heterocycloalkyl is a 3-10 membered heterocycloalkyl fused with an unsubstituted C 6-10 aryl, and the unsubstituted, substituted, or fused 3- 10-atomic heterocytheic cycle
,자쇄이 로알킬에 있어서， 치환과 융합은 동시에 일어날 수 있고 ;  In the case of a roalkyl chain, substitution and fusion may occur simultaneously;
A 및 E는 독립적으로 CH=, 또는 N=이다. 바람직하게는， A and E are independently CH =, or N =. Preferably,
R1은 의 직쇄 또는 측쇄 알콕시카보닐， 또는 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5-10원자 헤테로아릴이고， R 1 is an unsubstituted or substituted 5-10 membered heteroaryl containing at least one hetero atom selected from the group consisting of linear or branched alkoxycarbonyl of N, or N, 0 and S,
여기서， 상기 치환된 5-10원자 헤테로아릴은 (^-^의 직쇄 또는 측쇄 알킬이 하나 이상 치환된 5-10원자 헤테로아릴이고; R2는 -H 또는 할로겐이고; Wherein the substituted 5-10 membered heteroaryl is ( 5-10 membered heteroaryl substituted with at least one straight or branched chain alkyl of ^-^; R 2 is -H or halogen;
R3는 비치환 또는 하나 이상의 -0H 또는 할로겐이 치환된 의 직쇄 또는 측쇄 알킬， (^-10의 직쇄 또는 측쇄 알콕시 , (^-^의 또는 측쇄 알콕시 d- o의 직쇄 또는 측쇄 알킬， 비치환된 (：3-10의 클로알킬， N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 하나 이상 포함하는 비치환된 5-10원자 해테로아필 의 직쇄 또 측쇄 알킬， -(CH2)nNR5R6, -(CH2)mC(=0)0R7, 또는 -(CH2)pC(=0)NR8R9 고 , R 3 is unsubstituted or substituted with one or more -0H or halogen straight or branched chain alkyl of (^ -10 straight or branched chain alkoxy, (^-^ or branched alkoxy d-o straight or branched chain alkyl, unsubstituted a (3 - 10 of the claw-alkyl, N, 0 and heteroaryl is selected from the group consisting of S Straight or branched chain alkyl of unsubstituted 5-10 membered heteroafil containing one or more,-(CH 2 ) n NR 5 R 6 ,-(CH 2 ) m C (= 0) 0R 7 , or-(CH 2 ) p C (= 0) NR 8 R 9 High,
R5 및 R6는 독립적으로 -H 또는
Figure imgf000014_0001
)이고 R 5 and R 6 are independently -H or
Figure imgf000014_0001
)ego
R7은 -H， 또는 d-5의 직쇄 또는 측쇄 알킬이고， R 7 is —H, or d- 5 linear or branched alkyl,
R8 및 R9는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 및 S 로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하 는 비치환 또는 치환된 5-10원자 헤테로싸이클로알킬을 형성할 수 있 고， R 8 and R 9 may be linked with the nitrogen atom to which they are linked to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, 0 and S And
여기서， 상기 치환된 5-10원자 해테로싸이클로알킬은 -CN 및 - COC^NR10!?11로 이루어지는 군으로부터 선택되는 하나 이상의 치환기가 치환된 5-10원자 헤테로싸이클로알킬이고， 상기 R10 및 R11은 독립적으 로 -H이고, n, m 및 p는 독립적으로 1-5의 정수이고 ; R4는 H, 또는 비치환 또는 하나 이상의 -0H가 치환된 (： -10의 직쇄 또는 측쇄 알킬이고; 상기 R3 및 R4는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포 함하는 비치환된 3— 10원자 헤테로싸이클로알케닐， 또는 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환， 치환， 또는 융합된 (fused) 3-10원자 해테로싸이클로알킬을 형 성할 수 있고， 여기서， 상기 치환된 3-10원자 헤테로싸이클로알킬은 -OH, -CN,Herein, the substituted 5-10 membered heterocycloalkyl is -CN and -COC ^ NR 10 !? At least one substituent selected from the group consisting of 11 is substituted 5-10 membered heterocycloalkyl, wherein R 10 and R 11 are independently -H, n, m and p are independently an integer of 1-5 ; R 4 is H or unsubstituted or substituted at least one -0H (: -10 straight or branched alkyl; R 3 and R 4 is a group consisting of N, 0 and S connected with the nitrogen atom to which they are connected Unsubstituted, substituted, or fused containing one or more heteroatoms selected from the group consisting of one or more heteroatoms selected from the group consisting of one or more heteroatoms selected from the group consisting of N, 0 and S; (fused) 3-10 membered heterocycloalkyl, wherein the substituted 3-10 membered heterocycloalkyl is -OH, -CN,
=0， 할로겐 , 비치환 또는 하나 이상의 -0H가 치환된 d-5의 직쇄 또는 측쇄 알킬， 비치환된 (：3-10의 싸이클로알킬 d-5의 직쇄 또는 측쇄 알킬， 비치환된 (：3-10의 싸이클로알킬， N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환된 3-10원자 헤테 로싸이클로알킬， -C(=0)NR12R13, -NR14R15, =NR16으로 이루어지는 군으로 부터 선택되는 하나 이상의 치환기가 치환되거나; 비치환된 (：6-10의 아 릴이 융합된 (fused) C5— 10의 싸이클로알케닐， 또는 N, 0 및 S로 이루어 지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 O = 0, halogen, unsubstituted or at least one -0H a straight or branched chain alkyl, Beach substituted d- ring 5 (3-a 10 cyclo-alkyl d-5 straight or branched alkyl, unsubstituted (3 -Unsubstituted 3-10 membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of 10 cycloalkyl, N, 0 and S, -C (= 0) NR 12 R 13 , -NR 14 R 15, = optionally substituted with one or more substituents selected from the group as consisting of NR 16, or; unsubstituted (: 6 - 10 Ah reel fusion (fused) C 5 - 10 cyclo alkenyl, or a N, 0 And an unsubstituted at least one hetero atom selected from the group consisting of S. O
또는 하나 이상의 -Boc ( )가 치환된 3- 10원자 헤테로싸이클로 알킬이 스피로 (Spiro) 형태로 치환된 3-10원자 헤테로싸이클로알킬이 고, . Or a 3-10 membered heterocycloalkyl substituted with one or more -Boc () is a 3-10 membered heterocycloalkyl substituted with a Spiro form.
상기 R12, R13, 14 및 R15는 독립적으로 -H, 또는 d— 5의 직쇄 또 는 측쇄 알킬이고， 상기 R16은 -0H, 또는 d-5의 직쇄 또는 측쇄 알콕 시이고， 여기서， 상기 융합된 (fused) 3-10원자 헤테로싸이클로알킬은 비 치환된 (：6-10의 아릴이 융합된 ,3-10원자 헤테로싸이클로알킬이고, 상기 비치환, 치환, 또는 융합된 (fused) 3-10원자 헤테로싸이클 로알킬에 있어서， 치환과 융합은 동시에 일어날 수 있고; R 12 , R 13 , 14 and R 15 are independently —H, or d— 5 straight or branched alkyl, R 16 is —0H, or d-5 is a straight or branched alkoxy, wherein wherein the fusion (fused) 3-10 membered heteroaryl cyclo alkyl is unsubstituted (: 6 - 10 aryl is fused, and the 3-10 membered heteroaryl cyclo alkyl, the unsubstituted, substituted, or fusion (fused) 3 For a -10 membered heterocycloalkyl, substitutions and fusions can occur simultaneously;
A 및 E는 독립적으로 -CH=, 또는 -N=이다 더욱 바람직하 , A and E are independently —CH =, or —N =.
R1은
Figure imgf000015_0001
또는 이고 는 -H 또는 -F이고； R 1 is
Figure imgf000015_0001
Or and is -H or -F;
Figure imgf000015_0002
、/이고； R4는 -H, 메틸， 에틸 또는 H오 X이고，
Figure imgf000015_0002
,/ego; R 4 is -H, methyl, ethyl or HX,
3 및 R4는 이들이 연결된 질소 원자와 함께 3 and R 4 together with the nitrogen atom to which they are attached
Figure imgf000016_0001
Figure imgf000016_0001
Α 및 E는 독립적으로 -CH=, 또는 -N=이다. 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 바람직한 예로는 하기의 화합물들을 들 수 있다. A and E are independently -CH =, or -N =. Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds.
(1) tert-부틸 4-((4-(4-((R)-l-히드록시프로판 -2-일카바모일 ) 싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 ; (2) tert-부틸 4-((4-(4- (싸이클로프로필카바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트; (1) tert-butyl 4-((4- (4-((R) -l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1- Carboxylates; (2) tert-butyl 4-((4- (4- (cyclopropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(3) tert-부틸 4-((4-(4-(2,2-디플루오로에틸카바모일 )싸이클로 핵스 -1-엔일)페녹시 )메틸)피페리딘— 1-카 시레이트；  (3) tert-butyl 4-((4- (4- (2,2-difluoroethylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine— 1-carboxylate;
(4) tert-부틸 4-((4-(4-((R)-2,3-디히드록시프로필카바모일 )싸 아클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트 ;  (4) tert-Butyl 4-((4- (4-((R) -2,3-dihydroxypropylcarbamoyl) cycloclox-1-enyl) phenoxy) methyl) piperidine-1 Carboxylates;
(5) tert 부틸 4-((4-(4-((R)-3-히드록시피를리딘 -1—카보닐 )싸 이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트 ;  (5) tert butyl 4-((4- (4-((R) -3-hydroxypyridine-l-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine- 1-carboxylate;
(6) tert-부틸 4-((4-(4-((3-히드록시프로필 ) (메틸 )카바모일 )싸 이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트;  (6) tert-butyl 4-((4- (4-((3-hydroxypropyl) (methyl) carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Rate;
(7) tert-부틸 4— ((4-(4- (모르폴린 -4-카보닐)싸이클로핵스 -1-엔 일)페녹시 )메틸)피페리딘 -1-카복시레이트 ;  (7) tert-butyl 4— ((4- (4- (morpholine-4-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(8) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페라딘 -4-일 )메특시 )페 닐 )-N-((R)-l-히드록시프로판 -2-일 )싸이클로핵스 -3-엔카복스아마이드； (9) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페 닐 )-N— (3-히드록사프로필)싸이클로핵스 -3-엔카복스아마이드 ;  (8) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N-((R) -l-hydroxypropane -2-yl) cyclonux-3-encarboxamide; (9) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl ) -N— (3-hydroxyxapropyl) cyclonux-3-encarboxamide;
(10) tert 부틸 4-((6-(4-((R)-2,3—디히드록시프로필카바모일 ) 싸이클로핵스 -1-엔일)피리딘 -3-일옥시 )메틸)피페리딘 -1-카복시레이트； (10) tert butyl 4-((6- (4-((R) -2,3—dihydroxypropylcarbamoyl) cyclonux-1-enyl) pyridin-3-yloxy) methyl) piperidine- 1-carboxylate;
(11) tert-부틸 4-((6-(4-((S)_l-히드록시프로판 -2-일카바모일 ) 싸이클로핵스 -1-엔일 )피리딘 -3-일옥시 )메틸 )피페리딘 -1-카복시레이트；(11) tert-butyl 4-((6- (4-((S) _l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-3-yloxy) methyl) piperidine -1-carboxylate;
(12) N-((R)-2,3-디히드록시프로필 )— 4-(4-((1-(5-에틸피리미딘- 2-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이드；(12) N-((R) -2,3-dihydroxypropyl) — 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy ) Phenyl) cyclonux-3-enecarboxamide;
(13) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메록시 )페 닐 )싸이클로핵스 -3-엔일) (모폴리노)메타논 ; (13) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (morpholino) Metanon;
(14) tert-부틸 4-((6-(4-(1，3-디히드록시프로판 -2-일카바모일 ) 싸이클로핵스 -1—엔일 )피리딘 -3-일옥시 )메틸)피페리딘 -1-카복시레이트； (14) tert-butyl 4-((6- (4- (1,3-dihydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-3-yloxy) methyl) piperidine -1-carboxylate;
(15) N-(l,3-디히드록시프로판 -2-일 ) -4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스아마이드 ; (15) N- (l, 3-dihydroxypropan-2-yl) -4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy ) Phenyl) cyclonux-3-enecarboxamide;
(16) (4-(4-( (1-(5-에틸피리미딘 -2-일 )피페라딘 -4-일 )메록시 )페 닐 )싸이클로핵스 -3-엔일) ((R)-3-히드록시피를리딘 -1-일 )메타논 ;  (16) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((R)- 3-hydroxypyridin-1-yl) methanone;
(17) N-((R)-2,3-디히드록시프로필) -4-(4-( (1-(3-이소프로필 - 1， 2, 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔 카복스아마이드;  (17) N-((R) -2,3-dihydroxypropyl) -4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) pi Ferridin-4-yl) methoxy) phenyl) cyclonux-3-ene carboxamide;
(18) N-((S)-2,3-디히드록시프로필 ) -4-(4-((1-(3-이소프로필- 1,2 ,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔 f ό1- °1 H； (18) N-((S) -2,3-dihydroxypropyl) -4- (4-((1- (3-isopropyl- 1,2,4-oxadiazole-5-yl) pi Ferridin-4-yl) methoxy) phenyl) cyclonux-3-ene f ό 1- ° 1 H;
(19) N-((S)-1-히드록시프로판 -2-일 )-4-(4-( (1-(3-이소프로필 - (19) N-((S) -1-hydroxypropan-2-yl) -4- (4- ((1- (3-isopropyl-
1,2, 4-옥사디아졸 -5-일 )피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔 카복스아마이드; 1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-ene carboxamide;
(20) N-((R)-1-히드록시프로판 -2-일 ) -4-(4-((1-(3 이소프로필- (20) N-((R) -1-hydroxypropan-2-yl) -4- (4-((1- (3 isopropyl-)
1,2,4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )페닐)싸이클로핵스—3-엔 카복스아마이드; (21) 4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메톡시 )페 닐 )-N-(2-히드록시에틸 )-N-메틸싸이클로핵스 -3-엔카복스아마이드； 1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux—3-ene carboxamide; (21) 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (2-hydroxyethyl) -N- Methylcyclonux-3-enecarboxamide;
(22) N-(3-히 ^록시—2 ,2-디메틸프로필) -4-(4-( (1-(3-이소프로필 —1,2,4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )페닐)싸이클로핵스 -3- 엔카복스'아마이드； (22) N- (3-Hydroxy—2,2-dimethylpropyl) -4- (4-((1- (3-isopropyl —1,2,4-oxadiazol-5-yl) Ferridin-4-yl) methoxy) phenyl) cyclonux-3-encarbox 'amide;
(23) N-(l ,3-디히드록시프로판 -2-일 )-4-(4-( (1-(3-이소프로필- 1，2，4-옥사디아졸— 5-일 )피페리딘 -4-일)메록시 )페닐)싸이클로핵 스ᅳ 3-엔 카복스아마이드;  (23) N- (l, 3-dihydroxypropan-2-yl) -4- (4-((1- (3-isopropyl-1,2,4-oxadiazole- 5-yl) Ferridin-4-yl) methoxy) phenyl) cyclonuclear swim 3-ene carboxamide;
(24) tert-부틸 4-( (5-(4-( (S)_l_히드록시프로판 -2-일카바모일) 싸이클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트； (24) tert-butyl 4- ((5- (4- ((S) _l_hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine -1-carboxylate;
(25) tert-부틸 4-( ( 5-(4-( (R)-l-히드록시프로판 -2-일카바모일) 싸이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트；(25) tert-butyl 4- ((5- (4- ((R) -l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperi Din-1-carboxylate;
(26) tert-부틸 4-( (5-(4— ( (S)-2-히드록시프로필카바모일 )싸이 클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트； (26) tert-butyl 4- ((5- (4— ((S) -2-hydroxypropylcarbamoyl) cycloclox-1-enyl) pyridin-2-yloxy) methyl) piperidine-1 -Carboxylate;
(27) tert-부틸 4-( ( 5-( 4-( (R) -2-히드록시프로필카바모일 )싸이 클로핵스 -1-엔일)피리딘 -2—일옥시 )메틸)피페리딘 -1-카복시레이트 ;  (27) tert-butyl 4- ((5- (4- ((R) -2-hydroxypropylcarbamoyl) cycloclox-1-enyl) pyridine-2-yloxy) methyl) piperidine-1 Carboxylates;
(28) N-((R)-2-히드록시프로필) -4-(4-((1-(3-이소프로필 -1，2ᅳ4- 옥사디아졸 -5-일.)피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스 아마이드; (28) N-((R) -2-hydroxypropyl) -4- (4-((1- (3-isopropyl-1,2'4-oxadiazol-5-yl . ) Piperidine -4-yl) methoxy) phenyl) cyclonux-3-enecarboxamide;
(29) N-((S)-2—히드록시프로필 )-4-(4-((1-(3-이소프로필 -1，2，4- 옥사디아졸 -5-일)피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카복스 아마이드;  (29) N-((S) -2—hydroxypropyl) -4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine- 4-yl) methoxy) phenyl) cyclonux-3-enecarboxamide;
(30) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페 닐 )-N-((R)-2-히드록시프로필 )싸이클로핵스 -3-엔카복스아마이드;  (30) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N-((R) -2-hydroxypropyl ) Cyclonux-3-encarboxamide;
(31) N-(2—히드록시에틸 )-4-(4-( (1-(3_이소프로필 -1， 2，4-옥사디 아졸— 5—일)피페리딘 -4-일 )메특시 )페닐 )싸이클로핵스 -3-엔카복스아마이 드 ·  (31) N- (2—hydroxyethyl) -4- (4- ((1- (3_isopropyl-1, 2,4-oxadiazole— 5—yl) piperidin-4-yl) Mehsi)) phenyl) cyclonux-3-encarboxamide
(32) tert-부틸 4-( (5-(4-( (R)-2， 3-디히드록시프로필카바모일) 싸이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘— 1-카복시레이트； (32) tert-butyl 4- ((5- (4- ((R) -2, 3-dihydroxypropylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine — 1-carboxylate;
(33) tert-부틸 4-( (5-(4— ( (S)-2， 3-디히드록시프로필카바모일 ) 싸이클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸 )피페리딘— 1-카복시레이트；(33) tert-butyl 4- ((5- (4— ((S) -2, 3-dihydroxypropylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine — 1-carboxylate;
(34) ^(2-히드록시에틸)-4-(4-((1-(3-이소프로필-1，2,4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐) -N-메틸싸이클로핵스 -3-엔카복 스아마이드 ; (34) ^ (2-hydroxyethyl) -4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) meth Methoxy) phenyl) -N-methylcyclonux-3-enecarboxamide;
(35) N-에틸 -N-C2-히드록시에틸 )-4-(4-((1-(3-이소프로필- 1,2， 4-옥사디아졸 -5-일 )피페리딘— 4-일)메록시 )페닐)싸이클로핵스 -3-엔 카복스아마이드 '; (35) N-ethyl-N-C2-hydroxyethyl) -4- (4-((1- (3-isopropyl-1, 1,2, 4-oxadiazole-5-yl) piperidine— 4 -Yl) methoxy) phenyl) cyclonux-3-ene carboxamide ' ;
(36) N-((R)-1-히드록시프로판 -2-일 ) -4-(5-( (1-(3-이소프로필- 1,2， 4-옥사디아졸 -5-일 )피페리딘 -4-일)메톡시 )피리딘— 2-일 )싸이클로핵 스 -3-엔카복스아마이드;  (36) N-((R) -1-hydroxypropan-2-yl) -4- (5- ((1- (3-isopropyl-1, 1,2, 4-oxadiazole-5-yl) Piperidin-4-yl) methoxy) pyridine- 2-yl) cyclonux-3-encarboxamide;
(37) N-((S)-1—히드록시프로판 -2-일 ) -4-(5— ((1-(3-이소프로필- 1,2， 4ᅳ옥사디아졸 -5ᅳ일 )피페리딘 -4-일)메특시 )피리딘 -2-일)싸이클로핵 스 -3-엔카복스아마이드 ; (37) N-((S) -1—hydroxypropan-2-yl) -4- (5— ((1- (3-isopropyl- 1,2,4 ᅳ oxadiazole-5xyl) piperidin-4-yl) methoxy) pyridin-2-yl) cyclonucleus-3-encarboxamide;
(38) N-((R)-2-히드록시프로필 )-4-(5-( (1-(3ᅳ이소프로필 -1，2， 4- 옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )피리딘 -2-일 )싸이클로핵스 -3- 엔카복스아마이드 ;  (38) N-((R) -2-hydroxypropyl) -4- (5-((1- (3 ᅳ isopropyl-1,2,4-oxadiazole-5-yl) piperidine- 4-yl) methoxy) pyridin-2-yl) cyclonux-3-encarboxamide;
(39) N-((S)-2-히드록시프로필 )-4-(5-( (1-(3ᅳ이소프로필 -1，2， 4- 옥사디아졸— 5-일 )피페리딘 -4-일 )메록시 )피리딘 -2-일 )싸이클로핵스 -3- ¾ ^]- ^ ^ °> o] c ；  (39) N-((S) -2-hydroxypropyl) -4- (5- ((1- (3 ᅳ isopropyl-1,2,4-oxadiazole— 5-yl) piperidine- 4-yl) methoxy) pyridin-2-yl) cyclonux-3--3-¾ ^]-^^ °> o] c;
(40) N-((R)-2,3-디히드록시프로필 ) -4-(5— ((1ᅳ(3-이소프로필- 1,2，4ᅳ옥사디아졸 -5-일)피페리딘 -4-일)메록시 )피리딘 -2-일)싸이클로핵 스ᅳ 3-엔카복스아마이드;  (40) N-((R) -2,3-dihydroxypropyl) -4- (5— ((1 '(3-isopropyl- 1,2,4 oxadiazole-5-yl) Ferridin-4-yl) methoxy) pyridin-2-yl) cyclonuclear swab 3-encarboxamide;
(41) N-((S)-2,3-디히드록시프로필 ) -4-(5-((1ᅳ(3-이소프로필- 1,2,4ᅳ옥사디아졸 -5ᅳ일 )피페리딘 -4-일 )메특시 )피리딘 -2-일 )싸이클로핵 스 -3—엔카복스아마이드;  (41) N-((S) -2,3-dihydroxypropyl) -4- (5-((1 '(3-isopropyl- 1,2,4 ᅳ oxadiazole-5 -yl) piperi Din-4-yl) methoxy) pyridin-2-yl) cyclonucleus-3-encarboxamide;
(42) tert-부틸 4-((5-(4-((S)-3-히드록시피를리딘 -1-카보닐 )싸 이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트； (42) tert-butyl 4-((5- (4-((S) -3-hydroxypyridine-1-carbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl ) Piperidine-1-carboxylate;
(43) tertᅳ부틸 4_( ( 5-(4-( (R)-3-히드록시피를리딘 -1-카보닐)싸 이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트; (43) tert ᅳ butyl 4_ ((5- (4- ((R) -3-hydroxypyridine-1-carbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) Piperidine-1-carboxylate;
(44) tertᅳ부틸 4-( (2-플루오로 -4-(4-( ( S )-3ᅳ히드록시피를리딘- 1-카보닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (44) tert ᅳ butyl 4-((2-fluoro-4- (4-((S) -3 ᅳ hydroxypyridine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) Piperidine-1-carboxylate;
(45) tertᅳ부틸 4— ( (2-플루오로— 4-(4-( (R)-3-히드록시피를리딘- 1-카보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1—카복시레이트；(45) tert ᅳ butyl 4— ((2-fluoro— 4- (4- ((R) -3-hydroxypyridine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) Piperidine-1—carboxylate;
(46) N-(l,3-디히드록시프로판 -2-일 )-4-(5-( (1-(3 이소프로필- 1，2，4-옥사디아졸 -5-일 )피페리딘 -4—일 )메톡시 )피리딘 -2-일 )싸이클로핵 스ᅳ 3-엔카복스아마이드; (46) N- (l, 3-dihydroxypropan-2-yl) -4- (5- ((1- (3 isopropyl-1,2,4-oxadiazol-5-yl) piperi Din-4-yl) methoxy) pyridin-2-yl) cyclonuclear swab 3-encarboxamide;
(47) ^^-(3ᅳ히드록시-2,2-디메틸프로필)-4ᅳ(5ᅳ((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )피리딘 -2—일 )싸이클로 핵스 -3-엔카복스아마이드;  (47) ^^-(3, hydroxy-2,2-dimethylpropyl) -4 ᅳ (51-((1- (3-isopropyl-1,2,4-oxadiazole-5-yl) pi Ferridin-4-yl) methoxy) pyridine-2—yl) cyclonux-3-encarboxamide;
(48) ((R)-3-히드록시피를리딘 -1-일 ) (4-(4— ((1-(3-이소프로필- 1,2， 4-옥사디아졸 -5-일 )피페리딘 -4-일)메록시 )페닐)싸이클로핵스 -3-엔 일 )메타논 ;  (48) ((R) -3-hydroxypyridin-1-yl) (4- (4— ((1- (3-isopropyl-1, 1,2, 4-oxadiazole-5-yl) Piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(49) ((S)-3-히드록시피를리딘 -1-일 ) (4-(4-((1-(3-이소프로필- 1,2,4-옥사디아졸 -5-일 )피페리딘— 4-일)메톡시 )페닐 )싸이클로핵스 -3-엔 일 )메타논 ;  (49) ((S) -3-hydroxypyridin-1-yl) (4- (4-((1- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl) Piperidin- 4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(50) N-(2,2-디플루오로에틸) -4-(4-((1-(5-에틸피리미딘 -2-일 ) 피페리딘 -4-일 )메특시 )페닐 )싸이클로핵스 -3-엔카복스아마이드；  (50) N- (2,2-difluoroethyl) -4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclo Hacks-3-encarboxamide;
(51) N-(2,2-디플루오로에틸 )-4-(4-((l-C3-이소프로필— 1，2，4-옥 사디아졸 -5-일 )피페리딘ᅳ4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스아 마이드; (51) N- (2,2-difluoroethyl) -4- (4-((l-C3-isopropyl— 1,2,4-oxadiazole-5-yl) piperidine ᅳ 4- Mono) methoxy) phenyl) cyclonux-3-enecarboxamide;
(52) (4-(4-((1-(3-이소프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일) (피를리딘 -1-일 )메타논 ; (53) ((S)_3-플루오로피를리딘 -1-일 ) (4-(4-((l-(3ᅳ이소프로필- 1,2， 4-옥사디아졸 -5-일)피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3—엔 일 )메타논 ; (52) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (pyridin-1-yl) methanone; (53) ((S) _3-fluoropyridin-1-yl) (4- (4-((l- (3 ᅳ isopropyl- 1,2,4-oxadiazole-5-yl) pi Ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(54) (00-3-풀루오로피를리딘 -1-일 )(4-(4-((1-(3-이소프로필- 1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔 일 )메타논 ;  (00) (00-3-Pluoropyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole-5-yl)) Ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(55) (4-에틸피페라진 -1-일) (4-(4-((1-(5-에틸피리미딘 -2-일 )피 페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일)메타논;  (55) (4-ethylpiperazin-1-yl) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus -3-enyl) methanone;
(56) (4-(4-((1ᅳ(3-이소프로필-1,2,4ᅳ옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일 ) (피페리딘 -1-일 )메타논 ;  (56) (4- (4-((1 '(3-isopropyl-1,2,4'oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (piperidin-1-yl) methanone;
(57) tert-부틸 4— ( (2-플루오로— 4-( 4ᅳ( (S)-3-풀루오로피를리딘- 1-카보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트； (57) tert-butyl 4— ((2-fluoro— 4- (4 ᅳ ((S) -3-fluorofluoropyridine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl ) Piperidine-1-carboxylate;
(58) tert-부틸 4-( (2-플루오로 -4-(4ᅳ( (R)-3_플루오로괴를리딘- 1-카보닐)싸이클로핵스 - 1-엔일)페녹시 )메틸)피페리딘 - 1-카복시레이트; (58) tert-butyl 4- ((2-fluoro-4- (4 (((R) -3_fluorofluoride-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) Piperidine-1-carboxylate;
(59) tert-부틸 4-((2-플루오로 -4-(4-((S)-l-히드록시프로판 -2- 일카바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이 트；  (59) tert-butyl 4-((2-fluoro-4- (4-((S) -l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) pi Ferridine-1-carboxylate;
(60) tert-부틸 4-((2—플루오로 -4-(4ᅳ(00-1-히드록시프로판 -2- 일카바모일)싸이클로핵스 - 1 -엔일 )페녹시 )메틸)피페리딘 - 1 -카복시레이 트;  (60) tert-butyl 4-((2—fluoro-4- (4 ((00-1-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine Carboxylate;
(61) tert-부틸 4-((2ᅳ플루오로 -4-(4-((S)-2-히드록시프로필카 바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘ᅳ 1-카복시레이트； (61) tert-butyl 4-((2 (fluoro-4- (4-((S) -2-hydroxypropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine ᅳ 1-carboxylate;
(62) tert-부틸 4-( (2ᅳ플루오로 -4-(4-( (R)-2_히드록시프로필카 바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (63) tert-부틸 4-( (4-(4-( (S)-2， 3-디히드록시프로필카바모일) 싸이클로핵스 -1ᅳ엔일 ) -2-플루오로페녹시 )메틸)피페리딘 -1-카복시레이 트; (62) tert-butyl 4- ((2'fluoro-4- (4-((R) -2_hydroxypropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine- 1-carboxylate; (63) tert-butyl 4- ((4- (4- ((S) -2, 3-dihydroxypropylcarbamoyl) cyclonux-1-unenyl) -2-fluorophenoxy Methyl) piperidine-1-carboxylate;
(64) tert-부틸 4-( (4ᅳ( 4— ( (R)-2， 3 디히드록시프로필카바모일) 싸이클로핵스 -1ᅳ엔일 )-2-플루오로페녹시 )메틸)피페리딘 -1-카복시레이 트 ;  (64) tert-butyl 4- ((4 '(4— ((R) -2, 3 dihydroxypropyl carbamoyl) cyclonux-1' enyl) -2-fluorophenoxy) methyl) piperi Dine-1-carboxylate;
(65) 아제티딘 -1 일 (4— (4-((1-(3-이소프로필ᅳ 1，2，4-옥사디아졸- 5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔일 )메타논;  (65) Azetidine-1 day (4— (4-((1- (3-isopropyl1- 1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl ) Cyclonux-3-enyl) methanone;
(66) (4-(4-((1-(3-이소프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐 )싸이클로핵스 -3-엔일 ) (모폴리노)메타논 ;  (66) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (morpholino) methanone;
(67) tert-부틸 4-( (4-(4-( 1.3ᅳ디히드록시프로판 -2-일카바모일) 싸이클로핵스 -1-엔일 )-2-플루오로페녹시 )메틸)피페리딘 -1-카복시레이 트;  (67) tert-butyl 4- ((4- (4- (1.3 ᅳ dihydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) -2-fluorophenoxy) methyl) piperidine-1 Carboxylate;
(68) tert-부틸 4-((5-(4-(1，3-디히드록시프로판 -2-일카바모일 ) 싸이클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸 )피페리딘 -1-카복시레이트； (69) tert-부틸 4-( (2 플루오로 -4-(4- (모르폴린 -4—카보닐)싸이 클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1—카복시레이트；  (68) tert-butyl 4-((5- (4- (1,3-dihydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine -1-carboxylate; (69) tert-butyl 4- ((2 fluoro-4- (4- (morpholine-4-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine -1—carboxylate;
(70) tert-부틸 4-((5-(4- (모르폴린 -4-카보닐)싸이클로핵스 -1- 엔일)피리딘 -2-일옥시 )메틸 )피페리딘 -1-카복시레이트 ; (70) tert-butyl 4-((5- (4- (morpholine-4-carbonyl) cyclonux-1- Enyl) pyridin-2-yloxy) methyl) piperidine-1-carboxylate;
(71) tert-부틸 4-((2-플루오로 -4-(4- (싸이오모르폴린 -4ᅳ카보 닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트；  (71) tert-butyl 4-((2-fluoro-4- (4- (thiomorpholine-4 -carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Rate;
(72) tert-부틸 4-( ( 5-(4— (싸이오모르폴린 -4-카보닐)싸이클로핵 스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트 ;  (72) tert-Butyl 4- ((5- (4— (thiomorpholine-4-carbonyl) cyclonucleus-1-enyl) pyridin-2-yloxy) methyl) piperidine-1-carboxy Rate;
(73) tert-부틸 4-( ( 2-플루오로 -4-( 4- (싸이오모르폴린 -1， 1ᅳ디옥 사이드—4-카보닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시 레이트；  (73) tert-butyl 4- ((2-fluoro-4- (4- (thiomorpholine-1,1 dioxoxide—4-carbonyl) cyclonux-1-enyl) phenoxy) methyl) Piperidine-1-carboxylate;
(74) (4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔일) (싸이오모폴리노)메타논； (74) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (thiomorpholino) methanone;
(75) N-(2-플루오로에틸 )-4-(4-((1-(3-이소프로필 -1,2,4-옥사디 아졸 -5—일)피페리딘 -4-일)메특시 )페닐 )싸이클로핵스 -3-엔카복스아마이 드 ᅳ (75) N- (2-fluoroethyl) -4- (4-((1- (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) Mehsi)) phenyl) cyclonux-3-encarbox-amid de ᅳ
(76) tert-부틸 3— (4-(4-( ( 1-(3-이소프로필 -1， 2， 4-옥사디아졸- 5—일)피페리딘 -4-일)메톡시 )페닐) -N-메틸싸이클로핵스 -3—엔카복스아미 도)프로필카바메이트;  (76) tert-butyl 3— (4- (4- ((1- (3-isopropyl-1, 2, 4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl ) -N-methylcyclonux-3—encarboxamido) propylcarbamate;
(77) N-(3-아미노프로필)-4—(4—((l-(3-이소프로필-l,2，4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐 )-N-메틸싸이클로핵스 -3-엔카복 스아마이드;  (77) N- (3-aminopropyl) -4— (4 — ((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) ) Phenyl) -N-methylcyclonux-3-enecarboxamide;
(78) 4-(4-((1-(3-이소프로필— 1，2，4-옥사디아졸 -5-일 )피페리딘- (78) 4- (4-((1- (3-isopropyl— 1,2,4-oxadiazol-5-yl) piperidine-
4-일 )메톡시 )페닐 )-N-(2,2,2-트리플루오로에틸 )싸이클로핵스 -3-엔카복 스아마이드 ; 4-yl) methoxy) phenyl) -N- (2,2,2-trifluoroethyl) cyclonux-3-enecarboxamide;
(79) (4-에틸피페라진-1-일 )(4-(4-((1-(3-이소프로필-1，2，4-옥 사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔일)메타 논；  (79) (4-ethylpiperazin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine-4- Mono) methoxy) phenyl) cyclonux-3-enyl) methanone;
(80) N-(l,3-디히드록시프로판 -2-일 )-4-(3-플루오로 -4-((1-(3- 이소프로필 -1， 2 ,4-옥사디아졸 -5-일)피페리딘— 4-일)메톡시 )페닐)싸이클 로핵스—3-엔카복스아마이드;  (80) N- (l, 3-dihydroxypropan-2-yl) -4- (3-fluoro-4-((1- (3-isopropyl-1, 2,4-oxadiazole) 5-yl) piperidine—4-yl) methoxy) phenyl) cyclonux—3-encarboxamide;
(81) 4— (3-플루오로 -4-((1-(3-이소프로필 _1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메톡시 )페닐 )-N-(2-히드록시에틸 )— N-메틸싸이클로핵 스 -3-엔카복스아마이드;  (81) 4— (3-fluoro-4-((1- (3-isopropyl _1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl)- N- (2-hydroxyethyl) —N-methylcyclonux-3-enecarboxamide;
(82) tert-부틸 4-( (2-플루오로 -4-( 4-(3-히드록시 -2， 2-디메틸프 로필카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레 이트 ; .  (82) tert-Butyl 4- ((2-fluoro-4- (4- (3-hydroxy-2,2-dimethylpropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperi Dine-1-carboxylate; .
(83) 4-(3-플루오로 -4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메톡시 )페닐)— N-((S)_1-히드록시프로판 -2-일 )싸이클 로핵스 -3-엔카복스아마이드;  (83) 4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) — N-((S) _1-hydroxypropan-2-yl) cyclonux-3-encarboxamide;
(84) 4-(3-플루오로 -4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일)메록시 )페닐 )-N-((R)— 1-히드록시프로판 -2-일 )싸이클 로핵스 -3—엔카복스아마이드;  (84) 4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N-((R) — 1-hydroxypropan-2-yl) cyclonux-3-3-encarboxamide;
(85) tert-부틸 4-( (4-(4-(2 , 2-디플루오로에틸카바모일)싸이클 로핵스 -1-엔일 )-2-플루오로페녹시 )메틸)피페리딘 -1-카복시레이트； (86) tert-부틸 4-( ( 5-(4-(2， 2， 2-트리플루오로에틸카바모일 )싸 이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복사레이트 ; (85) tert-butyl 4- ((4- (4- (2,2-difluoroethylcarbamoyl) cyclonux-1-enyl) -2-fluorophenoxy) methyl) piperidine-1 -Carboxylate; (86) tert-butyl 4- ((5- (4- (2, 2, 2-trifluoroethylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine -1-carboxate;
(87) tert-부틸 4-( ( 5-(4-(2， 2-디플루오로에틸카바모일)싸이클 로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트 ;  (87) tert-butyl 4- ((5- (4- (2, 2-difluoroethylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine-1- Carboxylates;
(88) tert-부틸 4-((5-(4-(2-플루오로에틸카바모일)싸이클로핵 스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트 ;  (88) tert-butyl 4-((5- (4- (2-fluoroethylcarbamoyl) cyclonucleox-1-enyl) pyridin-2-yloxy) methyl) piperidine-1-carboxylate;
(89) (4ᅳ싸이클로프로필피페라진 -1-일 ) (4-(4-((1-(3-이소프로필 ᅳ 1,2,4-옥사디아졸 -5-일 )피페리 딘ᅳ 4-일 )메톡시 )페닐)싸이클로핵스 -3- 엔일 )메타논 ;  (89) (4'cyclopropylpiperazin-1-yl) (4- (4-((1- (3-isopropyl ᅳ 1,2,4-oxadiazol-5-yl) piperidine ᅳ 4 -Yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(90) tert-부틸 4-((5-(4-((R)-3-플루오로피를리딘 -1-카보닐 )싸 이클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트； (90) tert-butyl 4-((5- (4-((R) -3-fluoropyridine-1-carbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl ) Piperidine-1-carboxylate;
(91) tert-부틸 4-((5-(4-((S)— 3-플루오로피를리딘 -1-카보닐)싸 이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트; (91) tert-butyl 4-((5- (4-((S) — 3-fluoropyridine-1-carbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl ) Piperidine-1-carboxylate;
(92) 4-(3-플루오로-4-((1ᅳ(3-이소프로필-1ᅳ2,4-옥사디아졸 -5ᅳ 일)피페리딘 -4—일)메톡시 )페닐 )-N-(2,2,2-트리플루오로에틸)싸이클로 핵스 -3-엔카복스아마이드;  (92) 4- (3-fluoro-4-((1 '(3-isopropyl-1 ᅳ 2,4-oxadiazol-5 ᅳ yl) piperidin-4-yl) methoxy) phenyl) -N- (2,2,2-trifluoroethyl) cyclonux-3-enecarboxamide;
(93) N-(2,2-디플투오로에틸) -4— (3-플루오로 -4-((1-(3ᅳ이소프로 필 -1，2，4-옥사디아졸 -5-일)피페리딘— 4-일)메톡시 )페닐)싸이클로핵스- 3ᅳ엔카복스아마이드;  (93) N- (2,2-difluoroethyl) -4— (3-fluoro-4-((1- (3'isopropyl-1,2,4-oxadiazole-5) I) piperidine- 4-yl) methoxy) phenyl) cyclonux-3zenecarboxamide;
(94) 4-(3-플루오로 -4-((1ᅳ(3-이소프로필 -l，2,4-옥사디아졸-5- 일)피페리딘-4-일)메특시 )페닐 )-N-(2-플루오로에틸)싸이클로핵스 -3-엔 카복스아마이드;  (94) 4- (3-fluoro-4-((1 ′ (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N- (2-fluoroethyl) cyclonux-3-ene carboxamide;
(95) (4-(3-플루오로 -4-((1ᅳ(3ᅳ이소프로필ᅳ l,2，4-옥사디아졸-5- 일)피페리딘-4-일)메톡시 )페닐)싸이클로핵스-3-엔일) ( (S)-3-플루오로 피를리딘 -1-일 )메타논;  (95) (4- (3-fluoro-4-((1 '(3 ᅳ isopropyl ᅳ l, 2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl ) Cyclonux-3-enyl) ((S) -3-fluoro pyridin-1-yl) methanone;
(96) (4-(3-폴루오로 -4-((1-(3ᅳ이소프로필ᅳ 1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일) ((R)-3-플루오로 피롤리딘 _1-일 )메타논;  (96) (4- (3-Polouro-4-((1- (3 ᅳ isopropyl ᅳ 1,2,4-oxadiazole-5-yl) piperidin-4-yl) method) Phenyl) cyclonux-3-enyl) ((R) -3-fluoro pyrrolidin _1-yl) methanone;
(97) (4-(3-플루오로 -4-( (1-(3ᅳ이소프로필ᅳ1，2，4-옥사디아졸 -5- 일 )피페리딘 - 4 -일 )메록시 )페닐)싸이클로핵스 - 3 -엔일) (모폴리노)메타 논;  (97) (4- (3-fluoro-4-((1- (3 ᅳ isopropyl ᅳ 1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl ) Cyclonux-3-enyl) (morpholino) methanones;
(98) (4-(3-플루오로 -4-((1-(3ᅳ이 소프로필 -1，2,4-옥사디아졸— 5- 일 )피페리딘 -4-일 )메톡시 )페닐)싸아클로핵스 -3-엔일) (싸이오모폴리노) 메타논 ;  (98) (4- (3-fluoro-4-((1- (3bisisopropyl-1,2,4-oxadiazole— 5-yl) piperidin-4-yl) methoxy) Phenyl) cycloclox-3-enyl) (thiomorpholino) metanon;
(99) N-(2,2-디플루오로에틸) -4-(5-((1— (3-이소프로필 -1,2,4-옥 사디아졸 -5-일)피페리딘 -4-일)메록시 )피리딘 -2-일)싸이클로핵스 -3-엔 카복스아마이드;  (99) N- (2,2-difluoroethyl) -4- (5-((1— (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine-4 -Yl) methoxy) pyridin-2-yl) cyclonux-3-ene carboxamide;
(100) (4-(5-((1— (3-이소프로필 -1， 2，4-옥사디아졸— 5—일 )피페리 딘 -4-일 )메록시 )피리딘 -2-일 )싸이클로핵스 -3—엔일 ) (모폴리노)메타논;  (100) (4- (5-((1— (3-Isopropyl-1, 2,4-oxadiazol— 5—yl) piperidin-4-yl) methoxy) pyridin-2-yl) Cyclonux-3-enyl) (morpholino) methanone;
(101) ((R)-3-플루오로피를리딘 -1ᅳ일 ) (4-(5-((1-(3-이소프로필- (101) ((R) -3-fluoropyridin-1-yl) (4- (5-((1- (3-isopropyl-)
1,2， 4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )피리딘 -2ᅳ일 )싸이클로핵 스 -3-엔일)메타논 ; (102) ((S)-3-플루오로피를리딘 -1-일 ) (4-(5-((1-(3-이소프로필- 1，2,4-옥사디아졸 -5-일)피페리딘 -4ᅳ일 )메록시 )피리딘ᅳ 2-일 )싸이클로핵 스 -3-엔일)메타논 ; 1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) pyridin-2xyl) cyclonucleus-3-enyl) methanone; (102) ((S) -3-fluoropyridin-1-yl) (4- (5-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) Piperidin-4-ylyl) methoxy) pyridin-2-yl) cyclonux-3-enyl) methanone;
(103) 4-(4-( (1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페 닐 )-Ν-(2,2,2-트리플루오로에틸)싸이클로핵스 -3-엔카복스아마이드； (103) 4- (4- ((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -Ν- (2,2,2-trifluoro Ethyl) cyclonux-3-enecarboxamide;
(104) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘— 4ᅳ일 )메톡시 )페 닐 )-Ν-(2-플루오로에틸 )싸이클로핵스 -3-엔카복스아마이드； (104) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidine— 4 ᅳ yl) methoxy) phenyl) -Ν- (2-fluoroethyl) cyclonux-3 Encarboxamide;
(105) (2S)-1— (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 ) 메록시 )페닐 )싸이클로핵스 -3-엔카보닐)피를리딘 -2-카복스아마이드； (106) (2S)-l-(4-(4-((l-(5_에틸피리미딘 -2-일)파페리딘ᅳ 4-일 ) 메록시 )페닐 )싸이클로핵스 -3-엔카보닐 )피를리딘 -2-카르보니트릴；  (105) (2S) -1— (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarbonyl ) Pirridin-2-carboxamide; (106) (2S) -l- (4- (4-((l- (5_ethylpyrimidin-2-yl) paperidin-4-yl) meth) Hydroxy) phenyl) cyclonux-3-encarbonyl) pyridine-2-carbonitrile;
(107) tert-부틸 4-( (4-(4-( ( S)—2-카바모일피를라딘 -1—카보닐) 싸이클로핵스 -1-엔일 ) -2-플루오로페녹시 )메틸 )피페리딘 -1-카복시레이 트;  (107) tert-butyl 4- ((4- (4- ((S) —2-carbamoylpyridin-1-carbonyl) cyclonux-1-enyl) -2-fluorophenoxy) methyl) Piperidine-1-carboxylate;
(108) (2S)-l-(4-(3—플루오로ᅳ4-((1-(3-이소프로필 -1,2,4-옥사 디아졸 -5-일 )피페리딘 _4_일 )메톡시 )페닐 )싸이클로핵스 -3-엔카보닐)피 를리딘 -2-카복스아마이드; (108) (2S) -l- (4- (3—fluoro ᅳ 4-((1- (3-isopropyl-1,2,4-oxadiazol- 5 -yl) piperidine _ 4 _ Yl) methoxy) phenyl) cyclonux- 3 -encarbonyl) pyridine-2-carboxamide;
(109) (메틸 2-(4-(3-플루오로 -4-((1-(3-이소프로필 -1,2,4-옥사 디아졸 -5-일)피쩨리딘 -4ᅳ일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스아미 도)아세테이트 ;  (109) (Methyl 2- (4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piridin-4] yl) methoxy ) Phenyl) cyclonux-3-enecarboxamido) acetate;
(110) 에틸 3-(4-(3-플루오로 -4-((1-(3-이소프로필 -1，2，4-옥사 디아졸 -5-일)피페리딘 -4ᅳ일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스아미 도 )프로파노에이트;  (110) ethyl 3- (4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4 ylyl) methoxy ) Phenyl) cyclonux-3-enecarboxamido) propanoate;
(111) 3-(4-(3ᅳ폴루오로-4-((1-(3-이소프로필-1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카복스아미도)프 로파노익 엑시드;  (111) 3- (4- (3 ᅳ polouro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy ) Phenyl) cyclonux-3-encarboxamido) propanoic acid;
(112) 4-(3—플루오로ᅳ4-((1-(3-이소프로필 -1，2,4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메톡시 )페닐 )-N-(2-모플리노 -2-옥소에틸 )싸이클로핵 스一 3ᅳ엔카복스아마이드；  (112) 4- (3—fluoro ᅳ 4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N- (2-morpholin-2-oxoethyl) cyclonucleus syl 3 'carboxamide;
(113) 4-(3-플루오로ᅳ 4-((1-(3-이소프로필 _1，2，4-옥사디아졸 -5- 일)피페리딘 -4-일)메톡시 )페닐 )-N-(3-모폴리노 -3-옥소프로필 )싸이클로 핵스 -3-엔카복스아마이드;  (113) 4- (3-fluoro ᅳ 4-((1- (3-isopropyl _1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl)- N- (3-morpholino-3-oxopropyl) cyclonux-3-encarboxamide;
(114) tert-부틸 4-( (4-(4-( (S) -2-시아노피를리딘 -1-카보닐)싸 이클로핵스 -1-엔일 )ᅳ2-플루오로페녹시 )메틸)피페리딘 -1-카복시레이트； (115) (2S)-l- -(3-플루오로 -4-((1-(3-이소프로필 -1，2，4-옥사 디아졸 -5-일 )피페리딘 _4ᅳ일 )메록시 )페닐 )싸이클로핵스 -3_엔카보닐)피 를리딘 -2-카르보니트릴 ; (114) tert-butyl 4- ((4- (4- ((S) -2-cyanopyridine-1-carbonyl) cyclonux-1-enyl) ᅳ 2-fluorophenoxy) methyl ) Piperidine-1-carboxylate; (115) (2S) -l--(3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol- 5 ) yl) piperidin-4 _ euil) methoxy hydroxy) phenyl) cyclo haekseu - 3 _ Enka carbonyl) naphthyridine-2-carbonitrile of the blood;
(116) (2R)-l-(4-(3-플루오로 -4-( (1-(3-이소프로필 -1， 2， 4-옥사 디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카보닐)피 를리딘 -2-카복스아마이드;  (116) (2R) -l- (4- (3-fluoro-4-((1- (3-isopropyl-1, 2, 4-oxadiazol-5-yl) piperidine-4- Yl) methoxy) phenyl) cyclonux-3-encarbonyl) pyridine 2-carboxamide;
(117) (21?)-1-(4-(3ᅳ플루오로-4-((1-(3-이소프로필-1ᅳ2,4-옥사 디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스—3-엔카보닐)피 롤리딘 -2-카르보니트릴 ; (117) (21?)-1- (4- (3 ᅳ fluoro-4-((1- (3-isopropyl-1 ᅳ 2,4-oxadiazol-5-yl) piperidine-4 -Yl) methoxy) phenyl) cyclonux-3-encarbonyl) pi Rollidine-2-carbonitrile;
(118) (4-(4-( (1-(5-에틸피리미딘 -2ᅳ일 )피페리딘 -4-일 )메톡시 ) 페닐)싸이클로핵스 -3-엔일) ((R)_2- (히드록시메틸)피를리딘 -1-일 )메타 논;  (118) (4- (4- ((1- (5-ethylpyrimidin-2xyl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((R) _2- ( Hydroxymethyl) pyridin-1-yl) methanone;
(119) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐)싸이클로헥스 -3-엔일 ) ((S)-2- (히드록시메틸)피롤리딘 -1-일 )메타 논 ;  (119) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclohex-3-enyl) ((S) -2 -(Hydroxymethyl) pyrrolidin-1-yl) methanone;
(120) 4-(3—플루오로 -4ᅳ ((1-(3-이소프로필 -1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메톡시 )페닐 )-N-(2-히드록시에틸)싸이클로핵스ᅳ 3-엔 카복스아마이드;  (120) 4- (3—fluoro-4-4 ((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N- (2-hydroxyethyl) cyclonuclearscoop 3-ene carboxamide;
(121) (21^)-1-(2-(4-(3ᅳ플루오로-4-((1-(3-이소프로필-1，2，4-옥 사디아졸 -5-일 )피페리딘 -4—일)메록시 )페닐 )싸이클로핵스 -3-엔카복스아 미도)아세틸)피를리딘 -2-카복스아마이드；  (121) (21 ^)-1- (2- (4- (3 ᅳ fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperi Din-4-yl) methoxy) phenyl) cyclonux-3-encarboxamido) acetyl) pyridine-2-carboxamide;
(122) N-(2-((R)-2-시아노피롤리딘 -1-일 )— 2ᅳ옥소에틸 )— 4-(3-플 루오로 -4-((1-(3-이소프로필— 1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메 톡시 )페닐)싸이클로핵스 -3-엔카복스아마이드;  (122) N- (2-((R) -2-cyanopyrrolidin-1-yl) — 2oxoxoethyl) — 4- (3-fluoro-4-((1- (3-iso) Propyl— 1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide;
(123) (4-싸이클로프로필피페라진 -1-일) (4-(4-((1-(5-에틸피리 미딘 -2-일 )파페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일 )메타논 ;  (123) (4-cyclopropylpiperazin-1-yl) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclo Nux-3-enyl) methanone;
(124) (4- (싸이클로프로필메틸)피페라진 -1-일) (4-(4-((1-(5-에 틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔일 )메 타논;  (124) (4- (cyclopropylmethyl) piperazin-1-yl) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy ) Phenyl) cyclonux-3-enyl) methanone;
(125) tert 부틸 4-( (3-플루오로 -4-( 4-( ( S)-2-히드록시프로필카 바모일)싸이클로핵스— 1-엔일)페녹시 )메틸)피페리딘ᅳ 1-카복시레이트;  (125) tert butyl 4- ((3-fluoro-4- (4- ((S) -2-hydroxypropylcarbamoyl) cyclonucleus— 1-enyl) phenoxy) methyl) piperidine ᅳ 1 Carboxylates;
(126) tert-부틸 4-( (3ᅳ플루오로 -4-( 4-( (R)-2-히드록시프로필카 바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (126) tert-butyl 4- ((3'fluoro-4- (4-((R) -2-hydroxypropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine- 1-carboxylate;
(127) 4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메특시 )페 닐 )-N-((S)-l-히드록시프로판 -2-일 )싸이클로핵스 -3-엔카복스아마이드; (127) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N-((S) -l-hydroxypropane -2-yl) cyclonux-3-encarboxamide;
(128) N-((S)-2,3-디히드록시프로필) -4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3—엔카복스아마이드;  (128) N-((S) -2,3-dihydroxypropyl) -4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy ) Phenyl) cyclonux-3—encarboxamide;
(129) tert-부틸 4— ( ( 3-플루오로 -4- (4-( (R) -1-히드록시프로판- (129) tert-butyl 4— ((3-fluoro-4- (4- ((R) -1-hydroxypropane-
2-일카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레 이트 ; ' 2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate; '
(130) tert-부틸 4-( (3-플루오로 -4-(4-( (S)-l-히드록시프로판- 2 -일카바모일)싸이클로핵스 - 1 -엔일)페녹시 )메틸)피페리딘 - 1 -카복시레 이트;  (130) tert-butyl 4- ((3-fluoro-4- (4-((S) -l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) pi Ferridine-1 -carboxylate;
(131) tert-부틸 4-( (4-(4-( (R)-2， 3-디히드록시프로팔카바모일) 싸이클로핵스 -1-엔일) -3-플루오로페녹시 )메틸)피페리딘 -1-카복시레이 트；  (131) tert-butyl 4- ((4- (4- ((R) -2, 3-dihydroxypropalcarbamoyl) cyclonux-1-enyl) -3-fluorophenoxy) methyl) pi Ferridine-1-carboxylate;
(132) tert-부틸 4-( (4-(4-( (S)-2 , 3-디히드록시프로필카바모일) 싸이클로핵스 -1-엔일) -3-플루오로페녹시 )메틸 )피페리딘 -1-카복시레이 트；  (132) tert-butyl 4- ((4- (4- ((S) -2,3-dihydroxypropylcarbamoyl) cyclonux-1-enyl) -3-fluorophenoxy) methyl) piperi Dean-1-carboxylate;
(133) (2S)-1— (2-(4-(3-플루오로 -4-((1-(3-이소프로필 -1,2，4- 옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카복스 아미도)아세틸)피를리딘 -2-카복스아마이드; (133) (2S) -1— (2- (4- (3-fluoro-4-((1- (3-isopropyl-1,2,4- Oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarbox amido) acetyl) pyridine-2-carboxamide;
(134) (2S)-l-(3-(4-(3-플루오로 -4-( (1— (3-이소프로필 -1，2， 4-옥 사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스아 미도)프로파노일)피를리딘 -2-카복스아마이드;  (134) (2S) -l- (3- (4- (3-fluoro-4- ((1— (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidine -4-yl) methoxy) phenyl) cyclonux-3-encarboxamido) propanoyl) pyridine-2-carboxamide;
(135) (4-(4-((1-(5-에틸피리미딘— 2-일)파페리딘 -4-일 )메특시 ) 페닐)싸이클로핵스 -3-엔일) ((S)-3—히드록시피를리딘 -1-일 )메타논;  (135) (4- (4-((1- (5-ethylpyrimidin- 2-yl) paperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) -3 —Hydroxypyridin-1-yl) methanone;
(136) 4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘— 4-일 )메톡시 )페 닐 )-N-((S)-2-히드록시프로필 )싸이클로핵스 -3—엔카복스아마이드；  (136) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidine— 4-yl) methoxy) phenyl) -N-((S) -2-hydroxypropyl ) Cyclonux-3—encarboxamide;
(137) tert-부틸 4-( (4-(4- (싸이클로프로필카바모일)싸이클로핵 스 -1-엔일 )-3-플루오로페녹시 )메틸)피페리딘. -1-카복시레이트 ;  (137) tert-butyl 4- ((4- (4- (cyclopropylcarbamoyl) cyclonucleus-1-enyl) -3-fluorophenoxy) methyl) piperidine. -1-carboxylate;
(138) tert-부탈 4-( (3-플루오로— 4-(4— (2-플루오로에틸카바모 일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘— 1—카복시레이트 ;  (138) tert-butal 4- ((3-fluoro— 4- (4— (2-fluoroethylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine— 1—carboxylate ;
(139) N-(2-((S)-2-시아노피를리딘 -1-일 ) -2-옥소에틸) -4-(3-플 루오로— 4-((1— (3-이소프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일 )메 톡시 )페닐)싸이클로핵스 -3-엔카복스아마이드;  (139) N- (2-((S) -2-cyanopyridin-1-yl) -2-oxoethyl) -4- (3-fluoro- 4-((1— (3-iso Propyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide;
(140) N-(3-((S)-2-시아노피를리딘 -1-일 )— 3-옥소프로필 ) -4-(3- 플루오로-4-((1-(3-이소프로필-1,2，4-옥사디아졸 -5-일 )피페리딘 -4-일 ) 메톡시 )페닐)싸이클로핵스 -3-엔카복스아마이드;  (140) N- (3-((S) -2-cyanopyridin-1-yl) — 3-oxopropyl) -4- (3- fluoro-4-((1- (3-isopropyl -1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide;
(141) tert-부틸 4-( (4-(4-(2 , 2-디플루오로에틸카바모일)싸이클 로핵스 -1-엔일 )-3-플루오로페녹시 )메틸)피페리딘 -1-카복시레이트；  (141) tert-butyl 4- ((4- (4- (2,2-difluoroethylcarbamoyl) cyclonux-1-enyl) -3-fluorophenoxy) methyl) piperidine-1 -Carboxylate;
(142) tert-부틸 4-( (3-플루오로ᅳ4-( 4-( 2， 2， 2-트리플루오로에틸 카바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트； (142) tert-Butyl 4- ((3-fluoro ᅳ 4- (4- (2,2,2-trifluoroethyl carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine 1-carboxylate;
(143) ((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-( (1-(3-이소 프로필 -1,2,4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵 스— 3-엔일)메타논 ; (143) ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4- ((1- (3-isopropyl-1,2,4-oxadiazole-5- 1) piperidin-4-yl) methoxy) phenyl) cyclonuclear s—3-enyl) methanone;
(144) ((S)_3- (디메틸아미노)피를리딘 -1—일 ) (4-(4-((1-(3-이소 프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4—일 )메톡시 )페닐 )싸이클로핵 스 -3-엔일)메타논 ;  (144) ((S) _3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole-5-yl ) Piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(145) ((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(3-이소 프로필 -1,2， 4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )페닐 )싸이클로핵 스 -3-엔일)메타논 하이드로클로라이드;  (145) ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2, 4-oxadiazole-5- 1) piperidin-4-yl) methoxy) phenyl) cyclonucleox-3-enyl) methanone hydrochloride;
(146) ((S)— 3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(3-이소 프로필 -1,2,4-옥사디아졸 -5—일)피페리딘 -4—일)메툭시 )페닐 )싸이클로핵 스 -3-엔일)메타논 하이드로클로라이드;  (146) ((S) — 3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole-5-5) (I) piperidin-4-yl) methuxyl) phenyl) cyclonucleox-3-enyl) methanone hydrochloride;
(147) ((R)-2- (하이드록시메틸)피를리딘 -1-일) (4-(4-((1-(3-이 소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로 핵스 -3-엔일)메타논 ;  (147) ((R) -2- (hydroxymethyl) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole) 5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(148) ((S)_2- (하이드록시메틸)피를리딘 -1-일 ) (4-(4-( (1-(3-이 소프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일)메록시 )페닐 )싸이클로, 핵스 -3-엔일)메타논 ;  (148) ((S) _2- (hydroxymethyl) pyridin-1-yl) (4- (4- ((1- (3-isopropyl-1,2,4-oxadiazole-5) -Yl) piperidin-4-yl) methoxy) phenyl) cyclo, nucleus-3-enyl) methanone;
(149) ((R)-3- (하이드록시메틸 )피를리딘 -1-일 ) (4-(4-((1-(3-이 소프로필 -1,2, 4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )페닐 )싸이클로 핵스 -3-엔일)메타논 ; (149) ((R) -3- (hydroxymethyl) pyridin-1-yl) (4- (4-((1- (3- Sopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(150) ((S)-3- (하이드록시메틸)피를리딘 -1-일 ) (4-(4-((1-(3-이 소프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로 핵스 -3-엔일)메타논 ;  (150) ((S) -3- (hydroxymethyl) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole) 5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(151) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메록시 ) 페닐)싸이클로핵스 -3-엔일 ) ((R)-2- (하이드록시메틸)피롤리딘 -1-일 )메 타논 하이드로클로라이드;  (151) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((R) -2 (Hydroxymethyl) pyrrolidin-1-yl) methanone hydrochloride;
(152) (4-(4-((1-(5-에틸파리미딘 -2-일 )피페리딘 -4-일 )메특시 ) 페닐 )싸이클로핵스 -3-엔일 ) ((S)_3- (하이드록시메틸)피를리딘 -1-일)메 타논;  (152) (4- (4-((1- (5-ethylfarimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) _3- (Hydroxymethyl) pyridin-1-yl) methanone;
(153) (4-(4-((1— (5-에틸피리미딘 -2-일)피페리딘 -4-일)메톡시 ) 페닐)싸이클로핵스 -3-엔일) ((R)-3- (하이드록시메틸)피를리딘 -1-일 )메 타논;  (153) (4- (4-((1— (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((R) -3 (Hydroxymethyl) pyridin-1-yl) methanone;
(154) ((S)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(5-에틸 피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타 논;  (154) ((S) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (5-ethyl pyrimidin-2-yl) piperidin-4-yl ) Methoxy) phenyl) cyclonux-3-enyl) methanone;
(155) ((R)-3_ (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(5-에틸 피리미딘 -2—일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일 )메타 논；  (155) ((R) -3_ (dimethylamino) pyridin-1-yl) (4- (4-((1- (5-ethyl pyrimidin-2-yl) piperidin-4-yl) Methoxy) phenyl) cyclonux-3-enyl) methanone;
(156) ((S)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(5-에틸 피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타 논 하이드로클로라이드;  (156) ((S) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (5-ethyl pyrimidin-2-yl) piperidin-4-yl ) Methoxy) phenyl) cyclonux-3-enyl) methanone hydrochloride;
(157) ((R)-3- (디메틸아미노)피를리딘 -1ᅳ일 ) (4-(4-((1ᅳ(5ᅳ에틸 피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐)싸아클로핵스 -3-엔일)메타 논 하이드로클로라이드;  (157) ((R) -3- (dimethylamino) pyridin-1xyl) (4- (4-((1 ᅳ (5 ᅳ ethyl pyrimidin-2-yl) piperidin-4-yl) Methoxy) phenyl) cyclonux-3-enyl) methanone hydrochloride;
(158) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일) ((S)-3- (하아드록시메틸)피를리딘 -1-일 )메 타논 하이드로클로라이드;  (158) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) -3 (Hahydroxymethyl) pyridin-1-yl) methanone hydrochloride;
(159) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐 )싸이클로핵스 -3-엔일) ((R)_3- (하이드록시메틸)피률리딘 -1—일 )메 타논 하이드로클로라이드;  (159) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((R) _3- (Hydroxymethyl) pyrilidin-1-yl) methanone hydrochloride;
(160) (4ᅳ(4-((1-(5-에틸피리미딘— 2-일 )피페리딘 -4-일 )메톡시 ) 페닐)싸이클로핵스 -3-엔일) ((S)-3-플루오로피를리딘 -1-일 )메타논 ;  (160) (4 '(4-((1- (5-ethylpyrimidin- 2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) -3 -Fluoropyridin-1-yl) methanone;
(161) (4-(4ᅳ((1-(5_에틸피리미딘 -2-일)피떼리딘 -4-일)메톡시 ) 페닐 )싸이클로핵스 -3—엔일) ((S)-3-플루오로피를리딘 -1-일 )메타논 하이 드로클로라이드;  (161) (4- (4 ᅳ ((1- (5_ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) -3- Fluoropyridin-1-yl) methanone hydrochloride;
(162) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메특시 ) 페닐)싸이클로핵스 -3-엔일 ) (피를리딘— 1-일 )메타논 ;  (162) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (pyridine—1 -Yl) methanone;
(163) (4ᅳ(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐 )싸이클로핵스 -3-엔일) (피페리딘 -1-일 )메타논；  (163) (4 '(4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (piperidine-1 -Yl) methanone;
(164) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메톡시 ) 페닐 )싸이클로핵스 -3ᅳ엔일) (4-하이드록시피페리딘 -1-일)메타논 ; (164) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) Phenyl) cyclonux-3xenyl) (4-hydroxypiperidin-1-yl) methanone;
(165) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐)싸이클로핵스 -3-엔일) (4- (하이드록시메틸)피페리딘 -1-일 )메타논;  (165) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (4- (hydroxy Methyl) piperidin-1-yl) methanone;
(166) (4-(4-((1-(5-에틸파리미딘 -2-일 )피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일) (피를리딘 -1ᅳ일 )메타논 하이드로클로라이  (166) (4- (4-((1- (5-ethylparamidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (pyridine-1 Oil) Metanon Hydrochlory
(167) (4-(4-((1-(5-에틸피리미딘 2-일 )피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일) (피페리딘 -1-일)메타논 하이드로클로라이 드 * (167) (4- (4-((1- (5-ethylpyrimidin 2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (piperidine-1- (1) Methanone hydrochloride *
(168) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐 )싸이클로핵스ᅳ 3-엔일) (4-하이드록시피페리딘 -1-일 )메타논 하아드 로클로라이드;  (168) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleospent 3-enyl) (4-hydroxypi Ferridin-1-yl) methanone hadrochloride;
(169) (4-(4-((1-(5—에틸피리미딘 -2-일)피페리딘 -4-일)메톡시 ) 페닐 )싸이클로핵스ᅳ 3-엔일) (4- (하이드록시메틸)피페리딘 -1-일 )메타논 하이드로클로라이드; ,  (169) (4- (4-((1- (5—ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleospent 3-enyl) (4- (hydroxy Methyl) piperidin-1-yl) methanone hydrochloride; ,
(170) 아제티딘 1-일 (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘- 4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타논 ;  (170) Azetidin 1-yl (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) meta Paddy field;
(171) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘— 4-일)메톡시 ) 페닐 )싸이클로핵스ᅳ3-엔일) (3-하이드록시아제티딘 -1-일)메타논；  (171) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin- 4-yl) methoxy) phenyl) cyclonucleox-3-enyl) (3-hydroxyase Thidin-1-yl) methanone;
(172) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 ) 페닐 )싸이클로핵스ᅳ 3—엔일 ) (4-(2-하이드록시에틸)피페라진 -1-일 )메타 논;  (172) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleospent 3—enyl) (4- (2- Hydroxyethyl) piperazin-1-yl) methanone;
(173) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메톡시 ) 페닐 )싸이클로핵스ᅳ3-엔일 ) (4— (2-하이드록시에틸)피페리딘 -1-일 )메타 논;  (173) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleox-3-enyl) (4— (2- Hydroxyethyl) piperidin-1-yl) methanone;
(174) N-에톡시 -4ᅳ(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이드；  (174) N-ethoxy-4 '(4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enecarboxamide;
(175) N-에틸 -4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메 록시 )페닐 )-N-(2-하이드록시에틸 )싸이클로핵스 -3-엔카복스아마이드； (176) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페 닐 )-N-(2-하이드록시에틸 )싸이클로핵스 -3-엔카복스아마이드；  (175) N-ethyl-4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (2-hydroxyethyl) Cyclonux-3-encarboxamide; (176) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- ( 2-hydroxyethyl) cyclonux-3-enecarboxamide;
(177) 4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메톡시 )페 닐 )-N-(3-하이드록시 _2，2-디메틸프로필 )싸이클로핵스 -3ᅳ엔카복스아마 이드; ' (177) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (3-hydroxy _2,2-dimethyl Propyl) cyclonux-3 [3] encarboxamide; '
(178) 1— (4-(4-((1-(5—에틸피리미딘 -2-일 )파페리딘 -4-일 )메툭 시 )페닐 )싸이클로핵스 -3-엔카보닐 )피페리딘 -4-카복스아마이드；  (178) 1— (4- (4-((1- (5—ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) piperidine -4-carboxamide;
(179) 4-(4-((1-(5_에틸피리미딘 -2-일)피페리딘 -4-일)메특시 )페 닐 )-N-(3-메록시프로필)싸이클로핵스 -3-엔카복스아마이드;  (179) 4- (4-((1- (5_ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (3-methoxypropyl) cyclonucleus- 3-encarboxamide;
(180) 4— (4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페 닐 )-N— (퓨란 -2-일메틸 )싸이클로핵스 -3-엔카복스아마이드；  (180) 4— (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N— (furan-2-ylmethyl) cyclonucleus -3-encarboxamide;
(181) 4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4—일 )메록시 )페 닐 )-N,N 비스 (2-하이드록시에틸)싸이클로핵스 -3-엔카복스아마이드 ; (182) (4-하이드록시피페리딘 -1-일 ) (4-(4-((l-(3-이소프로필- 1,2 ,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔 일 )메타논 ; (181) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N, N bis (2-hydroxyethyl) cyclo Nuclears-3-encarboxamide; (182) (4-hydroxypiperidin-1-yl) (4- (4-((l- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl) piperidine- 4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(183) (4- (하이드록시메틸)피페리딘 -1-일) (4-(4-((1-(3-이소프 로필 -1， 2 ,4-옥사디아졸 -5-일 )파페리딘 -4-일 )메록시 )페닐)싸이클로핵스 (183) (4- (hydroxymethyl) piperidin-1-yl) (4- (4-((1- (3-isopropyl-1, 2,4-oxadiazole-5-yl) wave Ferridin-4-yl) methoxy) phenyl) cyclonux
-3-엔일 )메타논 ; -3-enyl) methanone;
(184) N-싸이클로프로필 -4-(4-((1-(3_이소프로필 -1，2，4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이 드■ .  (184) N-cyclopropyl-4- (4-((1- (3_isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) Cyclonux-3-encarboxamide ■.
(185) N-(3-하이드록시프로필) -4-(4-((1-(3-이소프로필 -1，2，4- 옥사디아졸 -5-일)피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스 아마이드;  (185) N- (3-hydroxypropyl) -4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) Methoxy) phenyl) cyclonux-3-enecarboxamide;
(186) (4-(2-하이드록시에틸)피페리딘 -1-일 )(4-(4-((1-(3-이소 프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵 스 -3-엔일 )메타논 ;  (186) (4- (2-hydroxyethyl) piperidin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole-5-yl ) Piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(187) (4-(2-하이드록시에틸 )피페라진 -1-일 ) (4-(4— ((1-(3-이소 프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵 스 -3—엔일)메타논 ;  (187) (4- (2-hydroxyethyl) piperazin-1-yl) (4- (4— ((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) Piperidin-4-yl) methoxy) phenyl) cyclonucleoside-3-enyl) methanone;
(188) 4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5—일)피페리딘 -4-일 )메톡시 )페닐 )-N- (메톡시메틸 )싸이클로핵스—3-엔카복스아마이드； (188) 4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N- (meth Methoxymethyl) cyclonux—3-encarboxamide;
(189) N-싸이클로프로필— 4-(4-((1-(5-에틸피리미딘— 2-일 )피페리 딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카복스아마이드; (189) N-cyclopropyl—4- (4-((1- (5-ethylpyrimidin- 2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide;
(190) tert-부틸 4-( (4-(4-(2—하이드록시에틸카바모일)싸이클로 핵스— 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；  (190) tert-butyl 4- ((4- (4- (2—hydroxyethylcarbamoyl) cyclonux- 1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(191) tert-부틸 4-( (4-(4-(3-하이드록시 -2 , 2-디메틸프로필카바 모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘— 1-카복시레이트 ;  (191) tert-butyl 4- ((4- (4- (3-hydroxy-2, 2-dimethylpropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine— 1-carboxylate ;
(192) tert-부틸 4-( (4-(4- (메톡시메틸카바모일)싸이클로핵스- 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；  (192) tert-butyl 4- ((4- (4- (methoxymethylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(193) tert-부틸 4-( (4— (4-(4- (피를리딘 -1-일 )피페리딘 -1-카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；  (193) tert-butyl 4- ((4— (4- (4- (4- (pyridin-1-yl) piperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperi Din-1-carboxylate;
(194) tert-부틸 4-( (4-( 4- (싸이클로부틸카바모일)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트 ;  (194) tert-butyl 4- ((4- (4- (cyclobutylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(195) tert-부틸 4-( ( 4-(4— (싸이클로펜틸카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 ;  (195) tert-butyl 4- ((4- (4— (cyclopentylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(196) tert-부틸 4-( (4-(4-(4-모폴리노피페리딘 -1-카보닐 )싸이 클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트;  (196) tert-butyl 4- ((4- (4- (4-morpholinopiperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate ;
(197) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페 닐 )-N-메톡시 -N-메틸싸이클로핵스 -3-엔카복스아마이드；  (197) 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N-methoxy-N-methylcyclonux-3 Encarboxamide;
(198) 4-(4-((1-(5-에틸피리미딘 -2ᅳ일 )피페리딘 -4-일 )메특시 )페 닐 ) -N-메톡시싸이클로핵스 -3-엔키^복스아마이드 ;  (198) 4- (4-((1- (5-ethylpyrimidin-2hexyl) piperidin-4-yl) methoxy) phenyl) -N-methoxycyclonux-3-enki ^ boxamide ;
(199) tert-부틸 4— ((4-(4- (에틸 (2-하이드록시에틸)카바모일)싸 이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1—카복시레이트； (200) tert-부틸 4-( (4_(4-(4-(2-하이드록시에틸)피페리딘 -1-카 보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；(199) tert-butyl 4— ((4- (4- (ethyl (2-hydroxyethyl) carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1—carboxylate; (200) tert-butyl 4- ((4_ (4- (4- (2-hydroxyethyl) piperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1 -Carboxylate;
(201) tert-부틸 4-( (4-(4—(4-( 2-하이드록시에틸)피페라진ᅳ 1-카 보닐)싸이클로핵스ᅳ 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (202) tert-부틸 4-( (4_(4- (피를리딘 -1-카보닐)싸이클로핵스 -1- 엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (201) tert-butyl 4- ((4- (4— (4- (2-hydroxyethyl) piperazin 1-carbonyl) cyclonuxion 1-enyl) phenoxy) methyl) piperidine-1 (202) tert-butyl 4- ((4_ (4- (pyridin-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(203) tert—부틸 4-( (4-(4-(4-에틸피페라진 -1-카보닐)싸이클로 핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；  (203) tert-butyl 4- ((4- (4- (4-ethylpiperazin-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(204) tert-부틸 4-( (4-(4- (피페리딘 -1-카보닐)싸이클로핵스— 1- 엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트;  (204) tert-butyl 4- ((4- (4- (piperidine-1-carbonyl) cyclonucleus— 1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(205) tert-부틸 4-( ( 4_(4— (3-에특시프로필카바모일)싸이클로핵 스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복사레이트;  (205) tert-butyl 4- ((4_ (4— (3-ethoxypropylcarbamoyl) cyclonucleus-1-enyl) phenoxy) methyl) piperidine-1-carboxate;
(206) tert-부탈 4-( (4-(4 (비스 (2-하이드록시에틸)카바모일)싸 이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘— 1-카복시레이트 ;  (206) tert-butal 4- ((4- (4 (bis (2-hydroxyethyl) carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine— 1-carboxylate;
(207) 1-(4ᅳ(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피폐 리딘 -4-일 )메톡시 )페닐)싸이클로핵스—3-엔카보닐)피페리딘 -4-카복스아 마이드; ' (207) 1- (4 ᅳ (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidindin-4-yl) methoxy) phenyl) cyclonucleus— 3-encarbonyl) piperidine-4-carboxamide; '
(208) (4-(4-((1-(3-이소프로필ᅳ 1，2，4-옥사디아졸 -5-일 )피페리 딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔일) ( 4- (파를리딘 -1-일 )피페리 딘— 1-일)메타논;  (208) (4- (4-((1- (3-isopropyl ᅳ 1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (4- (parridin-1-yl) piperidin— 1-yl) methanone;
(209) (4-(4-((1-(3-이소프로필ᅳ1，2,4-옥사디아졸-5-일 )피페리 딘 -4-일 )메록시 )페닐)싸이클로핵스—3-엔일) ( 4-모폴리노피페리딘— 1-일 ) 메타논 ;  (209) (4- (4-((1- (3-isopropyl ᅳ 1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus—3 -Enyl) (4-morpholinopiperidine— 1-yl) metanon;
(210) N-싸이클로펜틸 -4-(4— ((1-(3-이소프로필 -1，2，4-옥사디아 졸 -5-일)피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이  (210) N-cyclopentyl-4- (4— ((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) Cyclonus -3- encarbox arm
(211) N-싸이클로부틸 4-(4-((1-(3-이소프로필 -1，2，4-옥사디아 졸 -5-일)피페리딘 -4-일 )메특시 )페닐 )싸이클로핵스 -3-엔카복스아마이 드. (211) N-cyclobutyl 4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclo Hacks-3-encarboxamide.
(212) (3，4ᅳ디하이드로이소퀴놀린— 2(1H)-일 ) (4-(4— ((1-(3ᅳ이소 프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )페닐 )싸이클로핵 스 -3-엔일)메타논 ;  (212) (3,4 ᅳ dihydroisoquinoline—2 (1H) -yl) (4- (4 — ((1- (3 ᅳ isopropyl-1,2,4-oxadiazole-5-yl) Ferridin-4-yl) methoxy) phenyl) cyclonucleoside-3-enyl) methanone;
(213) (4-(4-((1-(3-이소프로필-1，2，4-옥사디아졸— 5-일 )피페리 딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔일) ( 1-메틸 -3， 4ᅳ디하이드로이 소퀴놀린 -2(1H)_일 )메타논;  (213) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol- 5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (1-methyl-3,4'dihydroisoquinolin-2 (1H) _yl) methanone;
(214) 이소인돌린ᅳ 2-일 (4-(4-((1-(3-이소프로필-1，2，4-옥사디아 졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일)메타논 ;  (214) isoindolin- 2-yl (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy ) Phenyl) cyclonux-3-enyl) methanone;
(215) 1，4'-바이피페리딘 -Γ-일 (4-(4-((1— (3-이소프로필 -1，2，4- 옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일 )메 타논;  (215) 1,4'-bipiperidin-Γ-yl (4- (4-((1— (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine- 4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(216) tert-부틸 4-( (4-(4-( 1 , 4 ' -바이피페리딘 -1 ' -카보닐)싸이 클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (217) (4-(4— ((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일) (3- (하이드록시이미노)피를리딘 -1-일 )메타 논； (216) tert-butyl 4- ((4- (4- (1, 4 '-bipiperidine -1' -carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1 Carboxylates; (217) (4- (4— ((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (3- (hydroxyi Mino) pyridin-1-yl) methanone;
(218) (4-(4-((1-(5-에틸피리미딘—2ᅳ일 )피페리딘 -4-일)메록시') 페닐)싸이클로핵스 -3-엔일) (4ᅳ (피를리딘 -1-일 )피페리딘 -1-일 )메타논 ; (218) (4- (4-((1- (5-ethylpyrimidin--2syl) piperidin-4-yl) methoxy ' ) phenyl) cyclonux-3-enyl) (4 Ridin-1-yl) piperidin-1-yl) methanone;
(219) 1，4'-바이피페리딘 -Γ-일 (4-(4-((1-(5-에틸피리미딘 -2- 일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타논 ;  (219) 1,4'-bipiperidin-Γ-yl (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) Cyclonux-3-enyl) methanone;
(220) (4-(4-((1 (5-에틸피리미딘 -2ᅳ일 )피페리딘— 4-일)메록시 ) 페닐 )싸이클로핵스 -3-엔일) (4ᅳ모폴리노피페리딘 -1-일 )메타논 ;  (220) (4- (4-((1 (5-ethylpyrimidin-2xyl) piperidin- 4-yl) methoxy) phenyl) cyclonux-3-enyl) (4'morpholinopiperidine- 1-yl) methanone;
(221) tert-부틸 4-( (4-(4- (퓨란 -2-일메틸카바모일 )싸이클로핵 스 -1—엔일)페녹시 )메틸)피페리딘 -1-카복시레이트;  (221) tert-butyl 4- ((4- (4- (furan-2-ylmethylcarbamoyl) cyclonuclear s-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(222) tert-부틸 4-( ( 4— ( 4- (메톡시카바모일 )싸이클로핵스 -1-엔 일 )페녹시 )메틸)피페리딘 -1-카복시레이트;  (222) tert-butyl 4- ((4— (4- (methoxycarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(223) tert-부틸 4-( (4ᅳ (4- (메특시 (메틸)카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복사레이트 ;  (223) tert-butyl 4- ((4 '(4- (methoxy (methyl) carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxate;
(224) tert—부틸 4-( ( 4-( 4-( 2， 5-디하이드로 -1H-피를 -1-카보닐) 싸이클로핵스— 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；  (224) tert-butyl 4- ((4- (4- (4- (2, 5-dihydro-1H-pyr-1-carbonyl) cyclonucleus— 1-enyl) phenoxy) methyl) piperidine-1 -Carboxylate;
(225) tert-부틸 4-( ( 4-(4-(4_하이드록시피페리딘 -1-카보닐)싸 이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1—카복시레이트 ;  (225) tert-butyl 4- ((4- (4- (4_hydroxypiperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1—carboxy Rate;
(226) tert-부틸 4-((4ᅳ(4-(4- (하아드록시메틸)피페리딘 -1ᅳ카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；  (226) tert-butyl 4-((4 '(4- (4- (hydroxyhydroxy)) piperidine-1'carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1 -Carboxylate;
(227) 1-(4— (4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록 시 )페닐)싸이클로핵스 -3-엔카보닐 )피페리딘 -4-카보나이트릴 ;  (227) 1- (4— (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) meroxy) phenyl) cyclonux-3-encarbonyl) piperidine -4-carbonitrile;
(228) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘—4-일)메특시 ) 페닐)싸이클로핵스 -3-엔일 ) (스피로 [인덴 -1,4'-피페리딘] -1'-일 )메타 논; ' (228) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (spiro [indene-1 , 4'-piperidine] -1'-yl) methanone; '
(229) (4-(4— ((1-(5-에틸피리끼딘 -2-일)피페리딘 -4-일)메록시 ) 페닐 )싸이클로핵스 -3-엔일) (1，4—디옥사 -8-아자스피로 [4.5]데칸 -8-일 ) 메타논 ;  (229) (4- (4— ((1- (5-ethylpyrikydin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (1,4-di Oxa-8-azaspiro [4.5] decane-8-yl) metanon;
(230) N-싸이클로펜틸 -4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 (230) N-cyclopentyl-4- (4-((1- (5-ethylpyrimidin-2-yl) piperidine
-4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이드； -4-yl) methoxy) phenyl) cyclonux-3-enecarboxamide;
(231) N-싸어클로부틸 -4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스아마이드；  (231) N-cyclochloro-4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide ;
(232) (3 ,4-디하이드로이소퀴놀린 -2(1H)-일 ) (4-(4-( (1-(5-에틸 피리미딘— 2-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔일)메타 논;  (232) (3,4-dihydroisoquinolin-2 (1H) -yl) (4- (4- ((1- (5-ethyl pyrimidin— 2-yl) piperidin-4-yl) meth Methoxy) phenyl) cyclonux-3-enyl) methanone;
(233) tert-부틸 4-( (4-(4-(5_하이드록시펜틸카바모일 )싸이클로 핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트;  (233) tert-butyl 4- ((4- (4- (5_hydroxypentylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(234) 4-(4-((1— (5-에틸피리미딘 -2-일)피페리딘— 4-일 )메록시 )페 닐 )-N-(5-하이드록시펜틸)싸이클로핵스—3-엔카복스아마이드 ;  (234) 4- (4-((1— (5-ethylpyrimidin-2-yl) piperidine— 4-yl) methoxy) phenyl) -N- (5-hydroxypentyl) cyclonucleus— 3-encarboxamide;
(235) (2, 5-디하이드로 -1H-피를 -1-일 ) (4-(4-((1-(5ᅳ에틸피리미 딘 -2-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3—엔일)메타논 ; (236) tert-부틸 4-( (4_(4-( (2-하이드록시에틸) (메틸)카바모일) 싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (235) (2, 5-dihydro-1H-pyr-1-yl) (4- (4-((1- (5 ᅳ ethylpyrimidin-2-yl) piperidin-4-yl) Methoxy) phenyl) cyclonux-3-enyl) methanone; (236) tert-butyl 4- ((4_ (4- ((2-hydroxyethyl) (methyl) carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(237) tert-부틸 4— ( (4-(4-( 1， 3_디하이드록시프로관 -2-일카바모 일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；  (237) tert-butyl 4— ((4- (4- (1,3_dihydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1 -Carboxylate;
(238) tert-부틸 4-( (4-(4-(3 하이드록시프로필카바모일)싸이클 로핵스 -1-엔일)페녹시 )메될)피페리딘— 1-카복시레이트；  (238) tert-butyl 4- ((4- (4- (3 hydroxypropylcarbamoyl) cyclonux-1-enyl) phenoxy) meryl) piperidine— 1-carboxylate;
(239) tert-부틸 4-( (4-(4-( 1， 2 , 3 , 4-테트라하이드로이소퀴놀린- 2ᅳ카보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트;  (239) tert-Butyl 4- ((4- (4- (4- (1,2,3,4-tetrahydroisoquinoline-2 닐 carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine- 1-carboxylate;
(240) tert-부틸 4-( (4— (4- (이소인돌린 -2-카보닐)싸이클로핵스- 1ᅳ엔일)페녹시 )메틸)피페리딘 -1-카복시레이트;  (240) tert-butyl 4- ((4— (4- (4- (isoindolin-2-carbonyl) cyclonux-1quinenyl) phenoxy) methyl) piperidine-1-carboxylate;
(241) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스ᅳ 3-엔일 ) (이소인돌린 -2-일 )메타는 ;  (241) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleospent 3-enyl) (isoindolin-2 -Day) meta;
(242) 4ᅳ (4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페 닐 )-N-(3-하이드록시프로필) -N-메틸싸이클로핵스 -3—엔카복스아마이드； (243) N-(3-하이드록시프로필) -4— (4-((1-(3—이소프로필 -1，2，4- 옥사디아졸 -5-일)피페리딘 -4-일 )메톡시 )페닐 )-N-메틸싸이클로핵스 -3— 엔카복스아마이드; ' (242) 4 '(4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (3-hydroxypropyl) -N- Methylcyclonux-3—encarboxamide; (243) N- (3-hydroxypropyl) -4— (4-((1- (3-isopropyl-1,2,4-oxadiazole-5- (I) piperidin-4-yl) methoxy) phenyl) -N-methylcyclonux-3—encarboxamide; '
(244) N- (퓨란 -2-일메틸 )-4-(4-((1-(3-이소프로필 -1， 2，4ᅳ옥사디 아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이 드; (244) N- (furan-2-ylmethyl) -4- (4-((1- (3-isopropyl-1,2,4oxadiazol-5-yl) piperidin-4-yl ) Methoxy) phenyl) cyclonux-3-enecarboxamide;
(245) N-(3-에록시프로필 )-4-(4-((1-(3-이소프로필 -1,2,4ᅳ옥사 디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마 이드 ;  (245) N- (3-ethoxypropyl) -4- (4-((1- (3-isopropyl-1,2,4oxadiazol-5-yl) piperidin-4-yl) Methoxy) phenyl) cyclonux-3-enecarboxamide;
(246) 4ᅳ(4-((1-(3ᅳ이소프로필-1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐) -N-메록시싸이클로핵스 -3—엔카복스아마이드;  (246) 4 '(4-((1- (3'isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N-methoxy Cyclonux-3—encarboxamide;
(247) 4ᅳ(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )-N-메톡시 -N-메틸싸이클로핵스 -3-엔카복스아마이 드 ·  (247) 4 '(4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N-methoxy -N-methylcyclonux-3-encarboxamide
(248) Ν,Ν-비스 (2ᅳ하이드록시에틸 )-4-(4-( (1-(3-이소프로필ᅳ 1， 2, 4-옥사디아졸 -5-일 )피페리딘 -4-일)메특시 )페닐 )싸이클로핵스 -3-엔 카복스아마이드;  (248) Ν, Ν-bis (2'hydroxyethyl) -4- (4-((1- (3-isopropyl ᅳ 1, 2, 4-oxadiazole-5-yl) piperidine-4 -Yl) methoxy) phenyl) cyclonux-3-ene carboxamide;
(249) 1-(4-(4-((1-(3ᅳ이소프로필-1,2，4-옥사디아졸-5-일 )피페 리딘 -4—일 )메톡시 )페닐)싸이클로핵스 -3-엔카보닐 )피페리딘 -4-카복스아 마이드; ■ (249) 1- (4- (4-((1- (3 ᅳ isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus- 3-encarbonyl) piperidine-4-carboxamide; ■
(250) 1-(4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록 시 )페닐)싸이클로핵스 -3-엔카보닐)피를리딘 -3-온 ;  (250) 1- (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) meroxy) phenyl) cyclonux-3-encarbonyl) pyridine 3-one;
(251) 1-(4-(4-((1-(3ᅳ이소프로필 -1， 2，4-옥사디아졸 -5-일 )피페 리딘 -4-일 )메특시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘 -4-카복스아 마이드;  (251) 1- (4- (4-((1- (3 ᅳ isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus- 3-encarbonyl) piperidine-4-carboxamide;
(252) 1-(4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피페 리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카보닐)피페리딘 -4-카복스아 마이드; (253) (Z)-(3, 3ᅳ비스 (하이드록시메틸) -4- (메톡시이미노)피를리 딘 -1-일 ) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘ᅳ 4-일 )메록시 )페닐) 싸이클로핵스 -3-엔일)메타논 ; (252) 1- (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus- 3-encarbonyl) piperidine-4-carboxamide; (253) (Z)-(3,3bisbis (hydroxymethyl) -4- (methoxyimino) pyridin-1-yl) (4- (4-((1- (5-ethylpyri) Midin-2-yl) piperidinyl 4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(254) (Z)-tert-부틸 6_(4-(4-( ( 1-(5-에틸피리미딘 -2-일 )피페리 딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3ᅳ엔카보닐) -8- (메톡시이미노) - (254) (Z) -tert-butyl 6_ (4- (4- ((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 Encarbonyl) -8- (methoxyimino)-
2,6-디아자스피로 [3.4]옥탄 -2-카복시레이트； 2,6-diazaspiro [3.4] octane-2-carboxylate;
(255) (Z)-(4— (4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡 시 )페닐 )싸이클로핵스 -3-엔일 ) (8- (메톡시이미노) -2，6—디아자스피로  (255) (Z)-(4— (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (8 -(Methoxyimino) -2,6-diazaspiro
[3.4]옥탄 -6—일 )메타논 하이드로클로라이드; [3.4] octane-6-yl) methanone hydrochloride;
(256) tert-부틸 4-( (4-(4— (4- (싸아클로프로필메틸)피페라진 -1- 카보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트； (256) tert-butyl 4- ((4- (4— (4- (4-cyclopropylmethyl) piperazin-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1- Carboxylate;
(257) tert-부틸 4-( ( 4— ( 4ᅳ ( 3 , 3—다플루오로피를리딘 -1-카보닐) 싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트 (257) tert-butyl 4- ((4— (4 ᅳ (3, 3—polyfluoropyridin-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1- Carboxylate
(258) (3,3-디플루오로피를리딘 -1-일 ) (4-(4-((1-(5-에틸피리미 딘 -2-일 )피페리딘 -4ᅳ일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타논;  (258) (3,3-difluoropyridin-1-yl) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4 ᅳ yl) methoxy ) Phenyl) cyclonux-3-enyl) methanone;
(259) (3,3-디플루오로피를리딘 -1-일 ) (4-(4-( (1ᅳ(3-이소프로필 - 1,2, 4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )페닐 )싸이클로핵스ᅳ 3—엔 일 )메타논 ;  (259) (3,3-difluoropyridin-1-yl) (4- (4-((1 ᅳ (3-isopropyl-1, 1,2,4-oxadiazole-5-yl) pi Ferridin-4-yl) methoxy) phenyl) cyclonucleosquax 3-enyl) methanone;
(260) N-(5-하이드록시펜틸) -4-(4-((1-(3-이소프로필 -1,2,4-옥 사디아졸 -5-일)피페리딘 -4—일)메특시 )페닐 )싸이클로핵스 -3-엔카복스아 마이드;  (260) N- (5-hydroxypentyl) -4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine-4-yl) Methiphenyl) phenyl) cyclonux-3-enecarboxamide;
(261) tert-부틸 4-( (4-(4-( 2， 2， 2-트리플루오로에틸카바모일 )싸 이클로핵스 -1—엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트;  (261) tert-butyl 4- ((4- (4- (2, 2, 2-trifluoroethylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Rate;
(262) tert-부틸 4-( (4-(4-(4-시아노싸이클로핵산카보닐)싸이클 로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트；  (262) tert-butyl 4- ((4- (4- (4-cyanocyclonucleocarbon)) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(263) tert-부틸 4-( (4-(4-( 1， 4-디옥사 -8-아자스피로 [4.5]데칸- 8-카보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트； (263) tert-butyl 4- ((4- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-carbonyl) cyclonux-1-enyl) phenoxy) methyl) pi Ferridine-1-carboxylate;
(264) tert-부틸 4-( (4-(4ᅳ (스피로 [인덴 -1， 4 ' -피페리딘] -1 ' -일 카보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트； (265) tert-부틸 4-( (4— (4ᅳ(3-옥소피를리딘 -1-카보닐)싸이클로 핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (264) tert-butyl 4- ((4- (4 ᅳ (spiro [indene-1,4'-piperidin] -1'-yl carbonyl) cyclonux-1-enyl) phenoxy) methyl) pi Ferridine-1-carboxylate; (265) tert-butyl 4- ((4— (4 ᅳ (3-oxopyridin-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperi Dine-1-carboxylate;
(266) 1-(4—(4-((1-(3-이소프로필-1，2,4ᅳ옥사디아졸—5-일 )피페 리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔카보닐 )피페리딘ᅳ 4-카보나이 트릴 ;  (266) 1- (4— (4-((1- (3-isopropyl-1,2,4oxoxadiazole—5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus- 3-encarbonyl) piperidine® 4-carbonitrile;
(267) (4-(4-((1-(3-이소프로필— 1，2，4-옥사디아졸 -5-일)피페리 딘ᅳ 4-일)메록시 )페닐)싸이클로핵스 -3-엔일 )(1,4ᅳ디옥사 -8-아자스피로 [4.5]데칸 -8-일 )메타논 ;. (267) (4- (4-((1- (3-isopropyl— 1,2,4-oxadiazol-5-yl) piperidinyl 4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (1,4 ᅳ dioxa-8-azaspiro [4.5] decane-8-yl) methanone; .
(268) (2ᅳ 3-디하이드로스피로 [인덴 -1,4' -피페리딘] -Γ-일 ) (4- (4ᅳ( (1-(3-이소프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일)메타논 ;  (268) (2'3-Dihydrospiro [indene-1,4'-piperidin] -Γ-yl) (4- (4 '((1- (3-isopropyl-1,2,4- Oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
(269) (3ᅳ (에특시이미노)피를리딘 -1-일) (4— (4-((1-(5-에틸피리 미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일)메타논 ; (270) tert-부틸 4-( (4-(4-(4- (메톡시이미노)피페리딘 -1-카보 닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트； (269) (3 '(ecoxyimino) pyridin-1-yl) (4— (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy ) Phenyl) cyclonux-3-enyl) methanone; (270) tert-butyl 4- ((4- (4- (4- (4- (methoxyimino) piperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1- Carboxylate;
(271) tert-부틸 4-( (4-(4-(4- (하이드록시이미노)피페리딘 -1-카 보닐)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트 ;  (271) tert-butyl 4- ((4- (4- (4- (hydroxyimino) piperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1- Carboxylates;
(272) tert-부틸 4-( ( 4-( 4-( 4-옥소피페리딘 -1-카보닐 )싸이클로 핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트；  (272) tert-butyl 4- ((4- (4- (4- (4-oxopiperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(273) tertᅳ부틸 4-( (4_(4-(3_ (메록시이미노)피를리딘 -1-카보 닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트；  (273) tert ᅳ butyl 4- ((4_ (4- (3_ (methoxyimino) pyridine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate ;
(274) 1-(4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘— 4-일 )메톡 시 )페닐)싸이클로핵스 -3-엔카보닐)피페리딘— 4-은 ;  (274) 1- (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidine- 4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) piperidine — 4-silver;
(275) 1-(4-(4-( (1-(3_이소프로필 -1， 2,4-옥사디아졸 -5-일 )피페 리딘 -4-일)메특시 )페닐 )싸이클로헥스 -3-엔카보닐 )피페리딘ᅳ 4ᅳ은 ；  (275) 1- (4- (4- ((1- (3_isopropyl-1, 2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclohex- 3-encarbonyl) piperidine® 4 ′ is;
(276) (4- (하이드록시이미노)피페리딘 -1-일 ) (4ᅳ (4-((1-(3-이소 프로필 -1，2，4-옥사디아졸 -5ᅳ일 )피페리딘 -4-일)메특시 )페닐 )싸이클로핵 스 -3-엔일)메타논 ;  (276) (4- (hydroxyimino) piperidin-1-yl) (4 ᅳ (4-((1- (3-isopropyl-1,2,4-oxadiazole-5 ᅳ yl) piperi) Din-4-yl) methoxy) phenyl) cyclonucleoside-3-enyl) methanone;
(277) (4ᅳ(4— ((1-(5—에틸피리미딘 -2-일)피페리 딘ᅳ 4-일 )메록시 ) 페닐 )싸이클로핵스 -3-엔일 ) (4- (하이드록시이미노)피페리딘 -1ᅳ일 )메타 논；  (277) (4 ᅳ (4— ((1- (5—ethylpyrimidin-2-yl) piperidinyl 4-yl) methoxy) phenyl) cyclonux-3-enyl) (4- (hydroxyi Mino) Piperidine-1syl) Metanon;
(278) (4-(4-((1-(3-이소프로필 -1,2,4-옥사디아졸 -5-일)피페리 딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일 ) (4- (메특시이미노)피페리딘 (278) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (4- (mepoxyimino) piperidine
-1-일 )메타논 ; -1-yl) methanone;
(279) (4ᅳ(4-((1-(3-이소프로필 -1，2ᅳ4-옥사디아졸 -5-일 )피페리 딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔일) (4- (메톡시이미노)피페리딘 -1-일 )메타논 ;  (279) (4 '(4-((1- (3-isopropyl-1,2'4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (4- (methoxyimino) piperidin-1-yl) methanone;
(280) tert-부틸 4-( (4-( 4-(3-옥소아제티딘 -1-카보닐 )싸이클로 핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；  (280) tert-butyl 4- ((4- (4- (3- (oxoazetidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate;
(281) tert-부틸 4-((4ᅳ(4-(3- (하이드록시이미노)아제티딘 -1-카 보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 ;  (281) tert-butyl 4-((4 ((4- (3- (hydroxyimino) azetidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Rate;
(282) tert-부틸 4ᅳ( (4-(4-(3- (메톡시이미노)아제티딘 -1-카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；  (282) tert-butyl 4 '((4- (4- (3- (methoxyimino) azetidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Rate;
(283) 1-(4-(4ᅳ((1ᅳ(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡 시 )페닐)싸이클로핵스 -3-엔카보닐)아제티딘 -3-온；  (283) 1- (4- (4 '((1' (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) azetidine- 3-on;
(284) 1-(4ᅳ(4-((1-(3-이소프로필-1，2，4-옥사디아졸-5-일 )피페 리딘 -4-일 )메특시 )페닐 )싸이클로핵스 -3-엔카보닐)아제티딘 -3—온；  (284) 1- (4 ᅳ (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus- 3-encarbonyl) azetidine-3—one;
(285) (3- (하이드록시이미노)아제티딘 -1-일 ) (4-(4-((1-(3-이소 프로필 -1,2, 4-옥사디아졸 -5-일)피페리딘 -4ᅳ일 )메톡시 )페닐)싸이클로핵 스 -3—엔일)메타논 ;  (285) (3- (hydroxyimino) azetidin-1-yl) (4- (4-((1- (3-isopropyl-1,2, 4-oxadiazole-5-yl) piperi Din-4 ylyl) methoxy) phenyl) cyclonucleoside-3-enyl) methanone;
(286) (4-(4-( (1-(3ᅳ이소프로필 -1， 2，4-옥사디아졸 -5-일 )피페리 딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일) (3- (메특시이미노)아제티딘 -1-일 )메타논 ;  (286) (4- (4- ((1- (3 ᅳ isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (3- (methoxyimino) azetidin-1-yl) methanone;
(287) (4-(4-((1-(5ᅳ에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐 )싸이클로핵스 -3-엔일 ) (3- (메록시이미노)아제티딘 -1-일 )메타논 ; (288) tert-부틸 4-( (4-(4_(3ᅳ하이드톡시아제티딘 -1-카보닐)싸 이클로핵스ᅳ 1 -엔일)페녹시 )메틸)피페리딘 - 1 -카복시레이트; 및 (287) (4- (4-((1- (5 ᅳ ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (3- (methoxy Mino) azetidin-1-yl) methanone; (288) tert-Butyl 4- ((4- (4_ (3_ (3 'hydroxyazetidine-1-carbonyl) cyclonucleosulf 1-enyl) phenoxy) methyl) piperidine-1-carboxylate ; And
(289) (3ᅳ하이드록시아제티딘 -1-일 ) (4-(4— ( (1-(3-이소프로필 - 1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔 일 )메타논 . 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며， 염으로는 약학적으로 허용 가능한 유리산 (free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산， 질산, 인산， 황산， 브름화수소산， 요드화수소산， 아질 산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트， 페닐-치환된 알카노에이트， 히드톡시 알카노에이트 및 알칸디오에이트 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산， 아세 트산， 안식향산， 구연산， 젖산， 말레인산， 글루콘산， 메탄설폰산， 4- 를루엔설폰산， 주석산， 푸마르산과 같은 유기산으로부터 얻었다. 이러 한 약학적으로 무독한 염류로는 설페이트, 피로설페이트， 바이설페이 트， 설파이트， 바이설파이트， 니트레이트， 포스페이트， 모노하이드로 겐 포스페이트， 디하이드로겐 포스페이트, 메타포스페이트 , 피로포스 페이트 클로라이드， 브로마이드， 아이오다이드 , 플루오라이드， 아세테 이트， 프로피오네이트 , 데카노에이트， 카프릴레이트， 아크릴레이트， 포메이트， 이소부티레이트, 카프레이트， 헵타노에이트， 프로피올레이 트， 옥살레이트， 말로네이트， 석시네이트， 수베레이트， 세바케이트， 푸마레이트， 말리에이트， 부틴 -1，4-디오에이트 , 핵산 -1,6-디오에이트， 벤조에이트， 클로로벤조에이트， 메틸벤조에이트， 디니트로 벤조에이트 히드록시벤조에이트， 메톡시벤조에이트， 프탈레이트， 테레프탈레이트, 벤젠설포네이트， 를루엔설포네이트， 클로로벤젠설포네이트， 크실렌설 포네이트， 페닐아세테이트， 페닐프로피오네이트， 페닐부티레이트， 시 트레이트, 락테이트， β -히드록시부티레이트， 글리콜레이트, 말레이트 타트레이트， 메탄설포네이트， 프로판설포네이트， 나프탈렌 -1-설포네이 트, 나프탈렌 -2-설포네이트 또는 만델레이트를 포함한다.  (289) (3'hydroxyazetidin-1-yl) (4- (4— ((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine-4 -Yl) methoxy) phenyl) cyclonux-3-enyl) methanone. The compound represented by Chemical Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy hydroxy alkanates And non-toxic organic acids such as alkanedioate aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-lluenesulfonic acid, tartaric acid and fumaric acid. . These pharmaceutically nontoxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate , Succinate, suverate, sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate hydroxide Oxybenzoate, methoxybenzoate, phthalate, terephthalate , Benzenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylene Sulfonate, Phenyl Acetate, Phenylpropionate, Phenylbutyrate, Citrate, Lactate, β-hydroxybutyrate, Glycolate, Maleate Tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법， 예를 들면 상기 화학 식 1로 표시되는 화합물을 유기용매， 예를 들면 메탄올 , 에탄올， 아세 톤， 메틸렌클로라이드, 아세토니트릴 등에 녹이고 유기산 또는 무기산 을 가하여 생성된 침전물을 여과， 건조하여 제조되거나， 용매와 과량 의 산올 감압 증류한 후 건조하거나 유기용매 하에서 제조할 수 있다. 또한， 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약 학적으로 허용하는 염뿐만 아니라， 이로부터 제조될 수 있는 가능한 용매화물， 수화물， 광학 이성질체 등을 모두 포함한다. 나아가， 본 발명은 하기 반웅식 1에 나타난 바와 같이，  The acid addition salt according to the present invention is produced by dissolving a compound represented by Chemical Formula 1 in a conventional method, for example, an organic solvent, such as methanol, ethanol, acetone, methylene chloride, acetonitrile, and adding an organic or inorganic acid. The precipitate may be prepared by filtration, drying, or distillation under reduced pressure with a solvent and excess acid, and may be dried or prepared under an organic solvent. In addition, the present invention includes not only the compound represented by Formula 1 and a pharmaceutically acceptable salt thereof, but also possible solvates, hydrates, optical isomers, and the like, which can be prepared therefrom. Furthermore, the present invention, as shown in the following reaction 1,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반웅시켜 화학식 4로 표시되는 화합물을 제조하는 단계 (단계 1); Compound represented by the formula (2) and compound represented by the formula (3) Reacting to prepare a compound represented by Chemical Formula 4 (Step 1);
단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반웅시켜 화학식 6으로 표시되는 화합물을 제 조하는 단계 (단계 2);  Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 (Step 2);
상기 단계 2에서 제조한 화학식 6으로 표시되는 화합물을 염기 와 반웅시켜 화학식 7로 표시되는 화합물을 제조하는 단계 (단계 3); 상기 단계 3에서 제조한 화학식 7로 표시되는 화합물과 화학식 8로 표시되는 화합물을 반웅시켜 화학식 1로 표시되는 화합물을 얻는 단계 (단계 4);를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방 법을 제공한다 .  Preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 prepared in Step 2 with a base (Step 3); Method of preparing a compound represented by the formula (1) comprising the step (4) to obtain a compound represented by the formula (1) by reacting the compound represented by the formula (7) and the compound represented by the formula (8) prepared in step 3 To provide.
Figure imgf000035_0001
Figure imgf000035_0001
상기 반웅식 1에서，  In the reaction form 1,
R1, R2, R3, R4, A 및 E는 상기 화학식 1에서 정의한 바와 같다. 이하, 본 발명에 따른 화학식 1로 표시되는 화합물의 제조방법 을 단계별로 상세히 설명한다 . 본 발명에 따른 화학식 1로 표시되는 화합물의 제조방법에 있어 서 , 상기 단계 1은 화학식 2로 표시되는 화합물과 화학식 3으로 표시 되는 화합물의 커플링 반웅을 수행하여 화학식 4로 표시되는 화합물을 얻는 단계이다. R 1 , R 2 , R 3 , R 4 , A and E are the same as defined in Chemical Formula 1. Hereinafter, a method for preparing a compound represented by Chemical Formula 1 according to the present invention will be described in detail step by step. In the method for preparing a compound represented by Formula 1 according to the present invention, Step 1 is a step of obtaining a compound represented by Formula 4 by performing a coupling reaction between the compound represented by Formula 2 and the compound represented by Formula 3 to be.
이때， 상기 반웅 용매로는 다이메틸포름아마이드 (DMF), 테트라 하이드로퓨란 (THF), 다이클로로메탄 (DCM)， 틀루엔， 아세토나이트릴 등 을 사용할 수 있고， 바람직하게는 다이메틸포름아마이드 (DMF)를 사용 할 수 있다.  In this case, as the reaction solvent, dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM), toluene, acetonitrile, and the like may be used. Preferably, dimethylformamide (DMF) is used. ) Can be used.
또한， 상기 염기로는 세슘카보네이트 (Cs2C03), 포타슘하이드록사 이드 (K0H)， 소듐하이드록사이드 (NaOH), 리튬하이드록사이드 (LiOH) 등 을 사용할 수 있으며， 바람직하게는 세슘 카보네이트 (Cs2C03)를 사용 할 수 있다. In addition, cesium carbonate (Cs 2 CO 3 ), potassium hydroxide (K0H), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and the like may be used as the base, and preferably cesium carbonate ( Cs 2 C0 3 ) can be used.
나아가， 반웅은도는 0°C에서 용매의 비등점 사이에서 수행하는 것이 바람직하고 , 반웅시간은 특별한 제약은 없으나， 0.5-10시간 동안 반응하는 것이 바람직하다 . 본 발명에 따른 화학식 1로 표시되는 화합물의 제조방법에 있어 서， 상기 단계 2은 상기 단계 1에서 제조한 화학식 4로 표시되는 화합 물과 화학식 5로 표시되는 화합물을 염기 하에서 반웅시켜 화학식 4로 표시되는 화합물을 얻는 단계이다. 보다 구체적으로는， 상기 단계 1에 서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 보로네 이트 화합물의 스즈키 커플링 반웅 (Suzuki coupling reaction)을 수행 하여 화학식 6으로 표시되는 화합물을 제조하는 단계이다. Furthermore, the reaction rate is preferably carried out between the boiling point of the solvent at 0 ° C, the reaction time is not particularly limited, it is preferable to react for 0.5-10 hours. In the method for preparing a compound represented by Chemical Formula 1 according to the present invention, Step 2 is represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with the compound represented by Chemical Formula 5 under a base. It is a step of obtaining the compound. More specifically, a compound represented by Chemical Formula 6 is prepared by performing a Suzuki coupling reaction between the compound represented by Chemical Formula 4 prepared in Step 1 and the boronate compound represented by Chemical Formula 5. Step.
이때， 상기 반웅 용매로는 디옥산 (Dioxane) , 에탄올, 트라하이 드로퓨란 (THF), 다이에틸에테르， 다이페닐에테르， 다이이소프로필에테 르 (DIPE), 다이메틸포름아마이드 (DMF)， 다이메틸아세트아마이드 (DMA), 다이메틸설폭사이드 (DMS0)， 다이클로로메탄 (DCM)， 클로로벤젠， 를루엔 : 벤젠으로 이루어지는 군으로부터 선택되는 1종 이상의 유기용매를 물 과 함께 흔합하여 사용할 수 있다. At this time, the reaction solvent is dioxane (Dioxane), ethanol, trihydric furan (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), die One or more organic solvents selected from the group consisting of methylacetamide (DMA), dimethylsulfoxide (DMS0), dichloromethane (DCM), chlorobenzene and toluene : benzene can be used in combination with water.
또한, 상기 염기로는 세슘카보네이트 (Cs2C03)， 포타슘하이드록사 이드 (K0H), 소듐하이드록사이드 (NaOH)， 리튬하이드록사이드 (LiOH) 등 을 사용할 수 있으며， 바람직하게는 세슘 카보네이트 (Cs2C03)를 사용 할 수 있다. In addition, cesium carbonate (Cs 2 CO 3 ), potassium hydroxide (K0H), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and the like may be used as the base, and preferably cesium carbonate ( Cs 2 C0 3 ) can be used.
나아가， 반웅온도는 0°C에서 용매의 비등점 사이에서 수행하는 것이 바람직하고， 반웅시간은 특별한 제약은 없으나， 0.5-10시간 동안 반웅하는 것이 바람직하다 . 본 발명에 따른 화학식 1로 표시되는 화합물의 제조방법에 있어 서， 상기 단계 3은 상기 단계 2에서 제조한 화학식 6으로 표시되는 화 합물을 염기와 반웅시켜 화학식 7로 표시되는 화합물을 제조하는 단계 이다. 이때 , 상기 반웅 용매로는 디옥산 (Dioxane)， 에탄을， 트라하이 드로퓨란 (THF) , 다이에틸에테르， 다이페닐에테르， 다이이소프로필에테 르 (DIPE) , 다이메틸포름아마이드 (DMF) , 다이메틸아세트아마이드 (DMA)， 다이메틸설폭사이드 (DMS0)， 다이클로로메탄 (DCM)， 클로로벤젠 , 를루엔， 벤젠으로 이루어지는 군으로부터 선택되는 1종 이상의 유기용매를 물 과 함깨 흔합하여 사용할 수 있다. Furthermore, the reaction temperature is preferably carried out between the boiling point of the solvent at 0 ° C, the reaction time is not particularly limited, it is preferable to react for 0.5-10 hours. In the method for preparing a compound represented by Chemical Formula 1 according to the present invention, Step 3 is a step of preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 prepared in Step 2 with a base. . At this time, the reaction solvent is dioxane (Dioxane), ethane, trihydric furan (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), One or more organic solvents selected from the group consisting of dimethylacetamide (DMA), dimethyl sulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene and benzene can be used in combination with water. .
또한， 상기 염기로는 세슘카보네이트 (Cs2C03)， 포타슘하이드록사 이드 (K0H) , 소듬하이드록사이드 (NaOH)， 리튬하이드록사이드 (LiOH) 둥 을 사용할 수 있으며 , 바람직하게는 리튬하이드록사이드 (LiOH)를 사용 할 수 있다. In addition, as the base, cesium carbonate (Cs 2 C0 3 ), potassium hydroxide (K0H), a small hydroxide (NaOH), lithium hydroxide (LiOH) can be used, preferably lithium hydroxide Side (LiOH) can be used.
나아가, 반웅온도는 0°C에서 용매의 비등점 사이에서 수행하는 것이 바람직하고， 반웅시간은 특별한 제약은 없으나 , 0.5-10시간 동안 반웅하는 것이 바람직하다. 본 발명에 따른.화학식 1로 표시되는 화합물의 제조방법에 있어 서， 상기 단계 4는 상기 단계 3에서 제조한 화학식 7로 표시되는 화합 물과 화학식 8로 표시되는 화합물을 반웅시켜 화학식 1로 표시되는 화 합물을 얻는 단계이다. ' Further, the reaction temperature is preferably carried out between the boiling point of the solvent at 0 ° C, reaction time is not particularly limited, it is preferable to react for 0.5-10 hours. In the method for producing a compound represented by Formula 1 according to the present invention, Step 4 is a compound represented by Formula 7 prepared in Step 3 and the compound represented by Formula 8 to react with This is the step of obtaining compound. '
이때， 상기 반웅 용매로는 디옥산 (Dioxane)， 에탄을， 트라하이 드로퓨란 (THF) , 다이에틸에테르， 다이페닐에테르， 다이이소프로필에테 르 (DIPE) , 다이메틸포름아마이드 (DMF)， 다이메틸아세트아마이드 (DMA) , 다이메틸설폭사이드 (DMS0)， 다이클로로메탄 (DCM)， 클로로벤젠， 를루엔， 벤젠으로 이루어지는 군으로부터 선택되는 ^종 이상의 유기용매를 물 과 함께 흔합하여 사용할 수 있다.  At this time, the reaction solvent is dioxane (dioxane), ethane, trihydric furan (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), ^ Or more organic solvents selected from the group consisting of dimethylacetamide (DMA), dimethyl sulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene and benzene can be used in combination with water. .
또한， 반웅온도는 0°C에서 용매의 비등점 사이에서 수행하는 것 이 바람직하고， 반응시간은 특별한 제약은 없으나, 0.5-10시간 동안 반웅하는 것이 바람직하다. 나아가， 본 발명은 상기 화학식 1로 표시되는 화합물， 이의 광 학 이성질체， 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함 유하는 대사성 질환의 예방 또는 치료용 약학적 조성물을 제공한다. 본 발명에 따른 약학적 조성물은 GPR-119(G protein-coupled receptor 119)를 활성화시켜 cAMP(Cycl ic adenosine monophosphate) ^ 세포 내 활성을 증가시키고， 신경 내분비 단쌕질인 GLP-l(Ghicagon- like peptide-1) 방출을 유도한다. 이때， 상기 GPR-119는 췌장의 인슐린 분비 세포에서 주로 발현 되는 G—단백질에 커플링된 수용체 (GPCR)로， GPR-119 발현 프로파일은 비만 및 당뇨병을 포함한 다양한 대사성 질환의 치료에 대하여 잠재적 유용성을 가진다. 또한， 본 발명은 상기 화학식 1로 표시되는 화합물， 이의 광학 이성질체 , 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유 하는 GPR-119(G protein-coupled receptor 119) 활성화제를 제공한다 . 이와 관련하여 본 발명에 따른 화합물의 GPR-119 수용체의 자극 으로 인한 cAMP 활성화 정도를 평가하기 위하여 실험을 수행한 결과， 본 발명에 따른 거의 대부분의 실시예 화합물이 200 ηΜ 이하의 낮은 농도에서 cAMP를 50% 활성화 (EC50)시키는 것으로 확인돠어 그 활성효 과가 우수한 것을 알 수 있었다 (실험예 1의 표 2 참조). 또한， 본 발명에 따른 화합물의 경구당 부하 실험을 수행한 결 과， 본 발명에 따른 모든 실시예 화합물은 종래에 알려진 GPR-119 활 성화제 (비교예 1 및 비교예 2)와 비교하여 혈당강하 효과가 우수한 것 으로 나타나 생체 내에서 GPR-119을 활성시키는 유효 효과가 상당히 뛰어난 것을 알 수 있었다 (실험예 2의 표 3 참조). 나아가， 본 발명에 따른 화학식 1로 표시되는 화합물， 이의 광 학 이성질체， 또는 이의 약학적으로 허용가능한 염의 체중감소 및 혈 당강하 효과를 동사에 평가하기 위한 실험을 수행한 결과， 본 발명에 따른 화합물의 경우 4주간의 경구투여 기간 동안 꾸준한 체중감소 효 과를 나타내는 것으로 확인되었고 (실험예 3의 도 1 참조)， 4주간의 투 여가 종료된 후 본 발명에 따른 화합물을 투여한 30분 후， 글루코스 2g/kg을 경구투여하고 혈당강하 효능을 평가한 결과 본 발명에 따른 화합물은 현저히 우수한 혈당강하 효과를 나타내어 (실험예 3의 도 2 참조)， 본 발명에 따른 화합물은 투여기간 동안 체중감소 및 혈당강하 효과를 동시에 나타내는 것올 알 수 있었다. 또한， 본 발명에 따른 화합물의 GLP-1의 분비유도 능력을 평가 하기 위한 실험을 수행한 결과， 본 발명에 따른 화합물은 GLP-1 분비 를 유도하는 효과가 우수한 것으로 나타났다 (실험예 4의 도 3 참조). 나아가， 본 발명에 따른 화합물의 백내장을 지닌 랫트 (Ihara's Cataract Rat , ICR)에 대한 급성 독성 실험을 수행한 결과， ICR 랫트 암컷의 LD50값은 2g/kg 이상으로 확인되어 독성이 매우 낮은 것을 알 수 있었다 (실험예 5 참조). 따라서， 본 발명에 따른 싸이클로 핵센 유도체， 이의 광학 이성 질체， 또는 이의 약학적으로 허용가능한 염은 GPR-119(G protein- coupled receptor 119)의 활성화게로 cAMP(Cycl ic adenosine monophosphate)를 촉진시키는 효과가 현저히 우수할 뿐만 아니라， 체 증감소 및 혈당강하 효과가 동시에 나타나므로， 비만， I형 당뇨병 , Π 형 당뇨병， 부적합한 내당증, 인슐린 내성증， 고혈당증， 고지질혈증， 고중성지방혈증， 고콜레스테를혈증， 이상지질혈증， X 증후군 등과 같 은 대사성 질환의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다. 본 발명에 따른 화학식 1로 표시돠는 화합물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며， 제제화할 경 우에는 보통 사용하는 충진제， 증량제， 결합제， 습윤제， 붕해제， 계 활성화제 등의 희석제 또는 부형제를 사용하여 제조된다. In addition, the reaction temperature is preferably carried out between the boiling point of the solvent at 0 ° C, the reaction time is not particularly limited, it is preferable to react for 0.5-10 hours. Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to the present invention activates G protein-coupled receptor 119 (GPR-119) to increase the intracellular activity of Cycl ic adenosine monophosphate (cAMP) ^ and the neuroendocrine protein GLP-1 (Ghicagon-like peptide). -1) induce release; At this time, the GPR-119 is a G-protein coupled receptor (GPCR) mainly expressed in pancreatic insulin secreting cells, and the GPR-119 expression profile has potential utility for the treatment of various metabolic diseases including obesity and diabetes. Have In addition, the present invention is a compound represented by the formula (1), its optical It provides a G protein-coupled receptor 119 (GPR-119) activator containing an isomer, or a pharmaceutically acceptable salt thereof as an active ingredient. In this regard, as a result of experiments to evaluate the degree of cAMP activation due to the stimulation of the GPR-119 receptor of the compound according to the present invention, almost all the examples of the compound according to the present invention cAMP at a low concentration of 200 ηΜ or less It was confirmed that 50% activation (EC 50 ), the activity effect was excellent (see Table 2 of Experimental Example 1). In addition, as a result of performing oral glucose loading test of the compound according to the present invention, all the example compounds according to the present invention are lowered in blood glucose compared with the known GPR-119 activator (Comparative Example 1 and Comparative Example 2) It was found that the effect was excellent, and the effective effect of activating GPR-119 in vivo was considerably excellent (see Table 3 of Experimental Example 2). Furthermore, as a result of performing experiments for evaluating the weight loss and hypoglycemic effect of the compound represented by the formula (1), the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention, the compound according to the present invention In the case of 4 weeks oral administration was confirmed to exhibit a steady weight loss effect (see Fig. 1 of Experimental Example 3), 30 minutes after administration of the compound according to the invention after the administration of 4 weeks, glucose As a result of oral administration of 2 g / kg and evaluation of hypoglycemic effect, the compound according to the present invention showed a remarkably excellent hypoglycemic effect (see FIG. 2 of Experimental Example 3), and the compound according to the present invention reduced weight and blood glucose during the administration period. It can be seen that the lowering effect is exhibited at the same time. In addition, as a result of the experiment to evaluate the secretion-inducing ability of GLP-1 of the compound according to the present invention, the compound according to the present invention was shown to have an excellent effect of inducing GLP-1 secretion (Fig. 3 of Experimental Example 4 Reference). Furthermore, as a result of conducting an acute toxicity test for the cataract rat (Ihara's Cataract Rat, ICR) of the compound according to the present invention, the LD 50 value of the female ICR rat was confirmed to be more than 2g / kg, very low toxicity (See Experimental Example 5). Therefore, the cyclohexene derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention has an effect of promoting cAMP (Cycl ic adenosine monophosphate) by activating GPR-119 (G protein-coupled receptor 119). Not only is it excellent, but also has a weight loss and hypoglycemic effect, so obesity, type I diabetes, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, and high cholesterol Like hypertension, dyslipidemia, X syndrome, etc. May be usefully used as a pharmaceutical composition for the prevention or treatment of metabolic diseases. The compound represented by Formula 1 according to the present invention may be administered in various oral and parenteral dosage forms during clinical administration, and when formulated, commonly used fillers, extenders, binders, wetting agents, disintegrating agents, and system activation. It is prepared using diluents or excipients such as agents.
경구투여를 위한 고형 제제에는 정제 , 환자， 산제， 과립제， 슐제， 트로키제 등이 포함되며， 이러한 고형 제제는 하나 이상의 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면， 전분， 탄산 슘， 수크로스 (sucrose) 또는 락토오스 ( lactose) 또는 젤라틴 등을 어 조제된다. 또한， 단순한 부형제 외에 마그네슘 스티레이트 탈 같은 윤활제들도 사용돤다. 경구 투여를 위한 액상 제제로는 현탁7 내용 액제， 유제 또는 시럽제 등이 해당되는데， 흔히 사용되는 단 희석제인 불 , 리퀴드 파라핀 이외에 여러 가지 부형제， 예를 들면 윤제， 감미제， 방향제， 보존제 등이 포함될 수 있다. Solid formulations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which may comprise at least one excipient such as starch, calcium carbonate, sucrose ( sucrose) or lactose (lactose) or gelatin. In addition to simple excipients, lubricants such as magnesium styrate tals were also used. Liquid preparations for oral administration include suspension 7- solution solutions, emulsions or syrups, and may include various excipients, such as lubricants, sweeteners, fragrances, and preservatives, in addition to commonly used diluents such as fire and liquid paraffin. have.
비경구 투여를 위한 제제에는 멸균된 수용액， 비수성용제， 현 용제 , 유제， 동결건조제제， 좌제 등이 포함된다. 비수성용제， 현 용제로는 프로필렌글리콜, 폴리에틸렌 글리콜， 올리브 오일과 같은 물성 기름， 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용 수 있다. 좌제의 기제로는 위텝솔 (witepsol)， 마크로골， 트원 (tween) 61， 카카오지 , 라우린지， 글리세를， 젤라틴 등이 사용될 수 있다.  Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, current solvents, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the current solvent, propylene glycol, polyethylene glycol, a physical oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As a suppository base, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
또한， 본 발명의 화합물의 인체에 대한 효과적인 투여량은 환자 의 나이， 몸무게， 성별 , 투여형태， 건강상태 및 질환 정도에 따라 달 라질 수 있으며， 일반적으로 약 0.001-100 mg/kg/일이며， 바람직하게 는 0.01-35. mg/kg/일이다. 몸무게가 70 kg인 성인 환자를 기준으로 할크습탁식될섞ᅵ순탁본칼면 ¾， 때 , 일반적으로 0.07-7000 mg/일이며， 바람직하게는 0.7-2500 mg /일이 며 , 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. 나아가， 본 발명은 상기 화학식 1로 표시되는 화합물， 이의 광 학 이성질체 , 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함 유하는 대사성 질환의 예방 또는 개선용 건강기능식품을 제공한다.  In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, generally about 0.001-100 mg / kg / day Preferably 0.01-35. mg / kg / day. Halogen-blended mixed cotton ¾, when based on an adult patient weighing 70 kg, typically 0.07-7000 mg / day, preferably 0.7-2500 mg / day, judged by a physician or pharmacist Depending on the time interval, it may be administered once a day or divided into several times. Furthermore, the present invention provides a health functional food for preventing or improving metabolic diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
【발명의 실시를 위한 형태】 [Form for implementation of invention]
이하， 본 발명을 실시예 및 실험예에 의하여 상세히 설명한다. 단， 하기 살시예 및 실험예는 본 발명을 예시하는 것일 뿐， 본 발명의 내용이 이에 한정되는 것은 아니다.  Hereinafter, the present invention will be described in detail by Examples and Experimental Examples. However, the following salsi examples and experimental examples are merely to illustrate the present invention, the content of the present invention is not limited thereto.
<제조예 1> 에틸 4- (트리플루오로메틸설포닐옥시)싸이클로핵스-Preparation Example 1 Ethyl 4- (trifluoromethylsulfonyloxy) cyclonucleus-
3-엔카복시레이트의 제조
Figure imgf000040_0001
Preparation of 3-Encarboxylate
Figure imgf000040_0001
질소 하에서 , 1000 1 플라스크에 LiHMDSaithium Hexa메틸 DiSi lazide) (1.0M in THF) 136/«를 THF 100/ ^에 교반하여 용해시킨다 온도를 5°C로 넁각한 후 에틸 -4—싸이클로핵사논 카복시레이트 17.8g 을 천천히 적가한 후 5분 동안 교반하였다. Ν,Ν-비스 (트라플루오로메 탄설포닐)아닐린 41g 을 천천히 적가한 후 2시간 동안 교반하였다. 반 웅 종결 후， 증류수 를 천천하 가하고 에틸 아세테이트 500 ^로 추출한 다음 브라인 100/^로 세척한 후， 무수황산마그네슘으로 건조하 고 농축 후 실리카 컬럼 크로마토그래피로 분리하여 표제 화합물을 제 조하였다. Under nitrogen, dissolve LiHMDSaithium Hexamethyl DiSi lazide) (1.0M in THF) 136 / «in THF 100 / ^ in a 1000 1 flask. Dissolve the temperature at 5 ° C, and then add ethyl-4—cyclonuxanon carboxylate. 17.8 g was slowly added dropwise and stirred for 5 minutes. 41 g of Ν, Ν-bis (trafluorome tansulfonyl) aniline was slowly added dropwise and stirred for 2 hours. After completion of reaction, distilled water was slowly added, extracted with 500 ^ ethyl acetate, washed with brine 100 / ^, dried over anhydrous magnesium sulfate, concentrated and separated by silica column chromatography to obtain the title compound.
XH 醒 R (400, CDCls) ： 3.69(3H, s) , 3.40(4H, m) , 3.20(1Η, m) , 2.57(2Η, d) , 2.48(3Η, m) , 2.27(2Η, d) , 1.47(9Η, s), 1.06 3H, d) . X H 醒 R (400, CDCls): 3.69 (3H, s), 3.40 (4H, m), 3.20 (1Η, m), 2.57 (2Η, d), 2.48 (3Η, m), 2.27 (2Η, d ), 1.47 (9Η, s), 1.06 3H, d).
<제조예 2> 에틸 4-(4，4，5，5-테트라메틸 -1，3，2-디옥사보로렌 -2- 일)싸 레이트의 제조 Preparation Example 2 Preparation of ethyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxabororen-2-yl) rate
Figure imgf000040_0002
Figure imgf000040_0002
질소 하에서， 플라스크에 에틸 4— (트리플루오로메틸설포 닐옥시 )싸이클로핵스 -3-엔카복시레이트 48.9g 을 1，4-디옥산 300 에 교반하여 용해시켰다. 비스 (피나콜레이트)디보론 41g, 테트라키스 (트 리페닐포스파인)팔라듐 9g, 포타슘 아세테이트 32g 을 순차적으로 적 가한 후 5분 동안 교반하였다. 온도를 서서히 90°C까지 가열 후 4시간 동안 교반 하였다. 반웅 종결 후, 상은으로 넁각 후 핵산 를 가 한 후 샐라이트 여과한다. 증류수 300 를 천천히 가하고 에틸 아세테 이트 500^로 추출한 다음 브라인 로 세척한 후， 무수황산마그네 슘으로 건조하고 농축 후 실리카 컬럼 크로마토그래피로 분리하여 표 제 화합물을 제조하였다. Under nitrogen, 48.9 g of ethyl 4- (trifluoromethylsulfonyloxy) cyclonux-3-enecarboxylate was dissolved in 1,4-dioxane 300 by stirring in a flask. 41 g of bis (pinacholate) diboron, 9 g of tetrakis (triphenylphosphine) palladium, and 32 g of potassium acetate were added dropwise sequentially followed by stirring for 5 minutes. The temperature was slowly heated to 90 ° C and then stirred for 4 hours. After completion of reaction, the phase was quenched with silver, added with nucleic acid, and then filtered through a saltite. Distilled water 300 was slowly added, extracted with 500 g of ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, concentrated and separated by silica column chromatography to prepare a title compound.
XH NMR (400, CDCls) ： 6.56(1H, s) , 4.16(3Η, q) , 2.52(1Η, m) , 2.40-2.0(6Η, m) , 1.63(2Η, m) , 1.29(15Η, m). X H NMR (400, CDCls): 6.56 (1H, s), 4.16 (3Η, q), 2.52 (1Η, m), 2.40-2.0 (6Η, m), 1.63 (2Η, m), 1.29 (15Η, m).
<제조예 3> (1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메탄을의 Preparation Example 3 (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methane
Figure imgf000040_0003
질소 하에서， 250 플라스크에 피페리딘 -4-메탄올 6.3g 을 DMF 100/^ 에 용해 시킨 후 교반하였다. Ν,Ν-디이소프로필에틸아민 13 를 적가한 후 2-클로로 -5ᅳ에틸피리미딘 5.2g 을 적가 하였다. 온도를 서 서히 60°C까지 가열 후 4시간 동안 교반 하였다. 반웅 종료 후 상온으 로 천천히 넁각 후， 증류수 를 천천히 가하고 에틸 아세테이트 로 추출한 다음 브라인 로 세척한 후, 무수황산마그네슘으로 건조하고 농축하여 표제 화합물을 제조하였다.
Figure imgf000040_0003
Under nitrogen, 6.3 g of piperidine-4-methanol was dissolved in DMF 100 / ^ in a 250 flask and stirred. N, N-diisopropylethylamine 13 was added dropwise, followed by dropwise addition of 5.2 g of 2-chloro-5'ethylpyrimidine. The temperature was slowly heated to 60 ° C. and then stirred for 4 hours. After the completion of reaction, the mixture was slowly cooled to room temperature, distilled water was slowly added, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated to prepare the title compound.
XH NMR (400, CDCls) ： 8.21(2H, s), 4.80(2H, d), 3.54(2H, d), 2.94(2H, m) , 2.48(2H, m) , 1.86(2H, d) , 1.81(1H, m) , 1.43(1H, s) , 1.26(2H, m)， 1.20(3H, m) . X H NMR (400, CDCls): 8.21 (2H, s), 4.80 (2H, d), 3.54 (2H, d), 2.94 (2H, m), 2.48 (2H, m), 1.86 (2H, d) , 1.81 (1H, m), 1.43 (1H, s), 1.26 (2H, m), 1.20 (3H, m).
<제조예 4> (1-C5-에틸피리미딘 -2-일)피페뫼딘 -4-일)메틸 메탄 설포네이트의 제조
Figure imgf000041_0001
Preparation Example 4 Preparation of (1-C5-ethylpyrimidin-2-yl) pipemodine-4-yl) methyl methane sulfonate
Figure imgf000041_0001
질소 하에서， 플라스크에 (1-(5-에틸피리미딘 -2-일 )피페 라딘 -4-일 )메탄올 11.4g 을 디클로로메탄 에 용해시킨 후 교반하 였다 . 트리에틸아민 를 적가한 후， 5°C에서 메탄설포닐 클로라이 드 를 천천히 적가 하였다. 30분 동안 교반한 후, 반웅이 종결되 면 증류수 를 천천히 가하고 디클로로메탄 로 추출한 다음 브 라인 로 세척한 후, 무수황산마그네슘으로 건조하고 농축 후， 디 에틸 에테르에서 표제 화합물을 고체 형태로 얻었다.Under nitrogen, 11.4 g of (1- (5-ethylpyrimidin-2-yl) piperazin-4-yl) methanol was dissolved in dichloromethane and stirred in the flask. After dropwise addition of triethylamine, methanesulfonyl chloride was slowly added dropwise at 5 ° C. After stirring for 30 minutes, when the reaction was completed, distilled water was slowly added, extracted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, concentrated, and the title compound was obtained in solid form in diethyl ether.
H 丽 R (400， CDCls) ： 8.18(2H, s), 4.77(2H, d) , 4.10(2H, d), 3.04(3H, s), 2.84(2H, m) , 2.46(2H, m) , 2.07(1H, m), 1.86(2H, d) , 1.27(2H, m) , 1.19(3H, m) .  H δ R (400, CDCls): 8.18 (2H, s), 4.77 (2H, d), 4.10 (2H, d), 3.04 (3H, s), 2.84 (2H, m), 2.46 (2H, m) , 2.07 (1H, m), 1.86 (2H, d), 1.27 (2H, m), 1.19 (3H, m).
<제조예 5> (l-(3-이소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘-Preparation Example 5 (l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine-
4-일 ) 4- days)
Figure imgf000041_0002
Figure imgf000041_0002
질소 하에서， 플라스크에 피페리딘 -4-메탄을 300g 을 AN(Acetonitri le)/water (400/400 / )에 넣고 교반하여 용해시키고 소 듐 바이카보네이트 330g 과 시아노겐 브로마이드 302g 을 넣고 12시간 이상 가열 환류하였다. 반웅이 완료되면 증류수 을 서서히 넣어 주고 MC 로 3회 추출하여 무수황산마그네슘으로 건조하고 농축하 였다. 잔사 (residue)를 에틸 아세테이트 에 넣고 교반하여 용 해시키고 N-히드록시ᅳ 2-메틸프로판이미드아마이드 175g 을 넣어주고 ΙΜ-Zinc 클로라이드 용액 를 서서히 적가한 후 12시간 이상 교 반하였다. 반웅이 완료되면 생성된 고체를 여과하고 디에틸 에테르 2000^로 세척하였다. 생성된 고체를 에탄올 1000 에 넣고 교반하여 용해시키고 4N-HC1 수용액 를 적가한 후 4시간 이상 가열 환류 하였다. 반웅이 완료되면 에탄올을 감압증류하여 제거하고 소듐 바이 카보네이트를 이용하여 pH를 염기로 만들고 에틸 아세테이트 1000/ 로 3회 추출하였다. 추출한 용액을 무수황산마그네슘으로 건조하고 농 축하여 표제 화합물을 제조하였다. Under nitrogen, add 300 g of piperidine-4-methane to the flask in AN (Acetonitrile) / water (400/400 /), dissolve, add 330 g of sodium bicarbonate and 302 g of cyanogen bromide and heat for at least 12 hours. It was refluxed. When the reaction was completed, distilled water was slowly added, extracted three times with MC, dried over anhydrous magnesium sulfate, and concentrated. The residue was added to ethyl acetate and stirred to After dissolving, 175 g of N-hydroxy ᅳ 2-methylpropaneimide was added thereto, and the solution was slowly added dropwise, followed by stirring for at least 12 hours. Upon completion of reaction, the resulting solid was filtered and washed with 2000 ^ diethyl ether. The resulting solid was added to ethanol 1000, stirred to dissolve, 4N-HC1 aqueous solution was added dropwise and heated to reflux for at least 4 hours. When the reaction was completed, ethanol was removed by distillation under reduced pressure, and the pH was made base using sodium bicarbonate, and extracted three times with ethyl acetate 1000 /. The extracted solution was dried over anhydrous magnesium sulfate and concentrated to give the title compound.
¾ NMR (400， CDC13) ： 4.24(2H, d), 3.86(2H, d) , 3.15(2H, m)， 2.9K1H, m) , 1.9K2H, m) , 1.48(2H, m) , 1.43(1H, m) , 1.32(6H, d). ¾ NMR (400, CDC1 3 ): 4.24 (2H, d), 3.86 (2H, d), 3.15 (2H, m), 2.9K1H, m), 1.9K2H, m), 1.48 (2H, m), 1.43 (1H, m), 1.32 (6H, d).
<제조예 6> (l-(3-이소프로필 -1,2, 4-옥사디아졸 -5-일)피페리딘-Production Example 6 (l- (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidine-
4-일)메틸 메탄설포네이트의 제조 Preparation of 4-yl) methyl methanesulfonate
Figure imgf000042_0001
Figure imgf000042_0001
(1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메탄올을 사용하는 대 신， (1ᅳ(3-이소프로필-1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메탄을을 사용하는 것을 제외하고, 상기 <제조예 4>와 동일한 방법으로 수행하 여 표제 화합물을 제조하였다.  Instead of using (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methanol, (1 '(3-isopropyl-1,2,4-oxadiazole-5- The title compound was prepared in the same manner as in <Preparation Example 4>, except that 1) piperidin-4-yl) methane was used.
XH NMR (400, CDC13) ： 4.24(2H, d), 3.86C2H, d) , 3.15(2H, m)， 3.04(3H, s) , 2.9K1H, m) 1.9K2H, m) , 1.48(2H, m), 1.32(6H, d) . X H NMR (400, CDC1 3 ): 4.24 (2H, d), 3.86C2H, d), 3.15 (2H, m), 3.04 (3H, s), 2.9K1H, m) 1.9K2H, m), 1.48 ( 2H, m), 1.32 (6H, d).
<제조예 7> tert-부틸 4- ((메틸설포닐옥시 )메틸)피페리딘 -1-카 복시레
Figure imgf000042_0002
Preparation Example 7 tert-Butyl 4- ((methylsulfonyloxy) methyl) piperidine-1-carboxyl
Figure imgf000042_0002
(1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메탄올을 사용하는 대 신， (tert-부틸 4- (히드록시메틸)피페리딘 -1-카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 4>와 동일한 방법으로 수행하여 표제 화 합물을 제조하였다.  Instead of using (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methanol, use (tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate Except that, the title compound was prepared in the same manner as in <Preparation Example 4>.
XH 丽 R (400， CDCls) ： 4.20-4.10(2H , m)， 4.04(2H, d)， 2.99(3H s) , 2.70(2H, m), 1.90(1H, m) , 1.70(2H, m) , 1.43(9H, s), 1.10(2H, m).  XH li R (400, CDCls): 4.20-4.10 (2H, m), 4.04 (2H, d), 2.99 (3H s), 2.70 (2H, m), 1.90 (1H, m), 1.70 (2H, m ), 1.43 (9H, s), 1.10 (2H, m).
<제조예 8> 2-(4-((4-브로모페녹시 )메틸)피페리딘 -1-일) -5-에틸 피리미딘의 제조
Figure imgf000043_0001
Preparation Example 8 Preparation of 2- (4-((4-bromophenoxy) methyl) piperidin-1-yl) -5-ethyl pyrimidine
Figure imgf000043_0001
질소 하에서， 1000 β 플라스크에 (1-(5-에틸피리미딘 -2-일 )피페 리딘 -4—일 )메틸 메탄설포네이트 50g 을 DMF 300 μϋ 에 용해시킨 후 교 반하였다. 세슘 카보네이트 110g 을 적가한 후 , 4-브로모페놀 30g 을 적가하였다. 60 °C 에서 5시간 동안 교반한 후 , 반웅이 종결되면 상은 으로 천천히 냉각하였다. 0°C에서 증류수 500 ^ 를 천천히 가하여 생 성되는 고체를 여과 후 건조하여 표제 화합물을 고체 형태로 얻었다. Under nitrogen, 50 g of (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methyl methanesulfonate was dissolved in DMF 300 µϋ and stirred in a 1000 β flask. After 110 g of cesium carbonate was added dropwise, 30 g of 4-bromophenol was added dropwise. After stirring for 5 hours at 60 ° C., the reaction was slowly cooled to the end of the reaction. Slowly adding 500 ^ distilled water at 0 ° C. The resulting solid was filtered and dried to give the title compound in the solid form.
!H NMR (400, CDCls) ： 8.2K2H, s) , 7.32(2H, d), 6.85(2H, d)， 4.80(2H, d) , 3.54(2H, d) , 2.94(2H, m) , 2.48(2H, m) , 1.86(2H, d) , 1.8K1H, m) , 1.26C2H, m) , 1.20(3H, m) . ! H NMR (400, CDCls): 8.2K2H, s), 7.32 (2H, d), 6.85 (2H, d), 4.80 (2H, d), 3.54 (2H, d), 2.94 (2H, m), 2.48 (2H, m), 1.86 (2H, d), 1.8K1H, m), 1.26C2H, m), 1.20 (3H, m).
<제조예 9> 5-(4-((4-브로모페녹시 )메틸)피페라딘 -1-일 ) -3-이소 프로필 - -옥사디아졸의 제조 Preparation Example 9 Preparation of 5- (4-((4-bromophenoxy) methyl) piperidin-1-yl) -3-isopropyl--oxadiazole
Figure imgf000043_0002
Figure imgf000043_0002
(1ᅳ(5-에틸피리미딘 -2-일 )피페리딘ᅳ 4-일 )메틸 메탄설포네이트를 사용하는 대신에， (1_(3-이소프로필 -1，2，4-옥사디아졸ᅳ 5-일 )피페리딘- 4-일 )메틸 메탄설포네이트를 사용하는 것을 제외하고， 상기 <제조예 8>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using (1 '(5-ethylpyrimidin-2-yl) piperidin'4-yl) methyl methanesulfonate, (1_ (3-isopropyl-1,2,4-oxadiazole ᅳ) The title compound was prepared in the same manner as in <Preparation Example 8>, except that 5-yl) piperidin-4-yl) methyl methanesulfonate was used.
¾ NMR (400, CDC13) ： 7.32(2H, d) , 6.85(2H, d) , 4.24(2Η, d) , 3.86(2Η, d) , 3.15(2Η. m)， 2.9K1H, m) , 1.9K2H, m) , 1.48(2Η, m) , 1.32(6Η, d) . ¾ NMR (400, CDC1 3 ): 7.32 (2H, d), 6.85 (2H, d), 4.24 (2Η, d), 3.86 (2Η, d), 3.15 (2Η. M), 2.9K1H, m), 1.9 K2H, m), 1.48 (2Η, m), 1.32 (6Η, d).
<제조예 10> tert-부틸 4-((4-브로모페녹시 )메틸)피페리딘 -1-카 복시레이트의 제조 Preparation Example 10 Preparation of tert-Butyl 4-((4-bromophenoxy) methyl) piperidine-1-carboxylate
Figure imgf000043_0003
(l-(5-에틸피리미딘 -2-일 )괴페리딘 -4—일 )메틸 메탄설포네이트를 사용하는 대신에， tert-부틸 4- ((메틸설포닐옥시 )메틸)피페리딘 -1-카 복시레이트를 사용하는 것을 제외하고ᅳ 상기 <제조예 8〉과 동일한 방 법으로 수행하여 표제 화합물을 제조하였다.
Figure imgf000043_0003
Instead of using (l- (5-ethylpyrimidin-2-yl) goperidin-4-yl) methyl methanesulfonate, tert-butyl 4-((methylsulfonyloxy) methyl) piperidine- The title compound was prepared in the same manner as in <Preparation Example 8>, except that 1-carboxylate was used.
XH NMR (400, CDCls) ： 7.32(2H, d )， 6.85(2H, d) , 4.15(2Η, d) 3.85(2Η, d) , 2.78(2Η, m)， 2.12(1Η, m) , 1.87(2Η, m)， 1.48(9Η, s) , 1.32(2Η, m . X H NMR (400, CDCls): 7.32 (2H, d), 6.85 (2H, d), 4.15 (2Η, d) 3.85 (2Η, d), 2.78 (2Η, m) ， 2.12 (1Η, m), 1.87 (2Η, m), 1.48 (9Η, s), 1.32 (2Η, m.
<제조예 11> tert-부틸 4-((6-브로모피리딘 -3-일옥시 )메틸)피페 리딘 Preparation Example 11 tert-Butyl 4-((6-bromopyridin-3-yloxy) methyl) piperidine
Figure imgf000044_0001
Figure imgf000044_0001
4-브로모페놀을 사용하는 대신에 2-브로모 -5-히드록시피리딘올 사용하고， (1— (5—에틸피리미딘ᅳ2-일 )피페리딘 -4ᅳ일 )메틸 메탄설포네이 트를 사용하는 대신에 tert-부틸 4- ((메틸설포닐옥시 )메틸)피페리딘- 1-카복시레이트를 사용하는 것을 제외하고, 상기 <제조예 8>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using 4-bromophenol, 2-bromo-5-hydroxypyridinol was used, and (1— (5—ethylpyrimidin- 2-yl) piperidin-4xyl) methyl methanesulfonate The title compound was prepared in the same manner as in <Preparation Example 8>, except that tert-butyl 4-((methylsulfonyloxy) methyl) piperidine-1-carboxylate was used instead of It was.
JH NMR (400， CDCI3) ： 8.2K1H, s) , 7.38(1H, d) , 7.15(1Η, d)， 4.15(2Η, d) , 3.85(2Η, d) , 2.78(2Η, m) , 2.12(1Η, m)， 1.87(2Η, m) , 1.48(9Η, s) , 1.32(2Η, m) . J H NMR (400, CDCI3): 8.2K1H, s), 7.38 (1H, d), 7.15 (1Η, d), 4.15 (2Η, d), 3.85 (2Η, d), 2.78 (2Η, m), 2.12 (1Η, m), 1.87 (2Η, m), 1.48 (9Η, s), 1.32 (2Η, m).
<제조예 12> tert-부틸 4-((5-브로모피리딘 -2-일옥시)메틸)피페 -1-카복시레이트의 제조 Preparation Example 12 Preparation of tert-Butyl 4-((5-bromopyridin-2-yloxy) methyl) pipet-1-carboxylate
Figure imgf000044_0002
Figure imgf000044_0002
질소 하에서， 플라스크에 (tert-부틸 4- (히드록시메틸)피 페리딘—1-카복시레이트 6.6g 을 DMF 100 에 녹여 교반하였다. 소듐 하이드라이드 1.85g 을 0°C에서 적가한 후 30분간 교반하였다. 이후， 2， 5-디브로모피리딘 8g 을 적가한 후 온도를 천천히 상온으로 을렸다. 4시간 후 0°C에서 증류수 를 천천히 적가한 후 생성된 고체를 여 과하여 건조하였다. 얻어진 고체를 핵산에서 재결정하여 표제 화합물 을 제조하였다.  Under nitrogen, 6.6 g of (tert-butyl 4- (hydroxymethyl) piperidine—1-carboxylate was dissolved in DMF 100 and stirred in a flask, and 1.85 g of sodium hydride was added dropwise at 0 ° C., followed by stirring for 30 minutes. Subsequently, 8 g of 2,5-dibromopyridine was added dropwise, and the temperature was slowly decreased to room temperature After 4 hours, distilled water was slowly added dropwise at 0 ° C., and the resulting solid was filtered and dried. Recrystallization from nucleic acid gave the title compound.
lR NMR (400, CDC 13 ) ： 8.14(1H, s) , 7.63(1H, d) , 6.7K1H, d) , 4.15(2H, d) , 3.85(2H, d) , 2.78(2H, m) , 2.12(1H, m) , 1.87(2H, m)， 1.48(9H, s), 1.32(2H, m) lR NMR (400, CDC 1 3 ): 8.14 (1H, s), 7.63 (1H, d), 6.7K1H, d), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m) , 2.12 (1H, m), 1.87 (2H, m), 1.48 (9H, s), 1.32 (2H, m)
<제조예 13> 5-(4-((6-클로로피리딘 -3-일옥시)메틸)피페리딘 -1- 일) -3- -1，2，4-옥사디아졸의 제조 Preparation Example 13 Preparation of 5- (4-((6-chloropyridin-3-yloxy) methyl) piperidin-1-yl) -3--1,2,4-oxadiazole
Figure imgf000045_0001
Figure imgf000045_0001
4-브로모페놀을 사용하는 대신에 2-클로로 -5-히드록시피리딘을 사용하고， (1-(5-에틸피리미딘—2-일 )피페리딘 -4-일 )메틸 메탄설포네이 트를 사용하는 대신에 (1-(3-이소프로필 -1，2，4-쇽사디아졸 -5-일)피페 리딘 -4-일)메틸 메탄설포네이트를 사용하는 것을 제외하고， 상기 <제 조예 8>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using 4-bromophenol, 2-chloro-5-hydroxypyridine was used, and (1- (5-ethylpyrimidin- 2-yl) piperidin-4-yl) methyl methanesulfonate Preparation Example except that (1- (3-isopropyl-1,2,4-xadiazol-5-yl) piperidin-4-yl) methyl methanesulfonate was used instead of 8> was carried out in the same manner as the title compound to prepare.
XH NMR (400， CDCI3) ： 8.2K1H, s) , 7.38(1H, d)， 7.15(1H, d) , 4.24(2H, d) , 3.86(2H, d) , 3.15(2H, m)， 2.9K1H, m)， 1.9K2H, m) , 1.48(2H, m) , 1.32(6H. d) . <제조예 14> tert-부틸 4-((4-브로모 -2-플루오로페녹시 )메틸)피 페리딘 -1-카복시레이트의 제조 X H NMR (400, CDCI 3 ): 8.2K1H, s), 7.38 (1H, d), 7.15 (1H, d), 4.24 (2H, d), 3.86 (2H, d), 3.15 (2H, m) , 2.9K1H, m), 1.9K2H, m), 1.48 (2H, m), 1.32 (6H.d). Preparation Example 14 Preparation of tert-Butyl 4-((4-bromo-2-fluorophenoxy) methyl) piperidine-1-carboxylate
Figure imgf000045_0002
Figure imgf000045_0002
4-브로모페놀을 사용하는 대신에 2-플루오로 -4—브로모페놀을 사 용하고， (1— (5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메틸 메탄설포네이트 를 사용하는 대신에 tert-부틸 4ᅳ ((메틸설포닐옥시 )메틸)피페리딘 -1- 카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 8〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using 4-bromophenol, use 2-fluoro-4—bromophenol, (1— (5-ethylpyrimidin-2-yl) piperidin-4-yl) methyl methanesulfo The title compound was prepared in the same manner as in <Preparation Example 8>, except that tert-butyl 4 ᅳ ((methylsulfonyloxy) methyl) piperidine-1-carboxylate was used instead of using Nate. Prepared.
XH NMR (400, CDC13) ： 7.13(1H, d)， 7.08(1H, d) , 6.89(1H, m)， 4.15(2H, d) , 3.85(2H, d) , 2.78(2H, m) , 2.12(lH, m)( 1.87(2H, m) , 1.48(9H, s)， 1.32(2H, m) . X H NMR (400, CDC1 3 ): 7.13 (1H, d), 7.08 (1H, d), 6.89 (1H, m), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m ), 2.12 (lH, m) ( 1.87 (2H, m), 1.48 (9H, s), 1.32 (2H, m).
<제조예 15> tert-부틸 4-((4-브로모 -3-플루오로페녹시 )메틸)피 페리딘 -1-카복시레이트의 제조
Figure imgf000046_0001
Preparation Example 15 Preparation of tert-Butyl 4-((4-bromo-3-fluorophenoxy) methyl) piperidine-1-carboxylate
Figure imgf000046_0001
4-브로모페놀을 사용하는 대신에 3-폴루오로 -4-브로모페놀을 사 용하고 , (1-(5-에틸피리미딘 -2-일 )피페리딘— 4-일 )메틸 메탄설포네이트 를 사용하는 대신에 tert-부틸 4ᅳ ((메틸설포닐옥시 )메틸)피페리딘 -1- 카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 8>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using 4-bromophenol, 3-polouro-4-bromophenol is used, and (1- (5-ethylpyrimidin-2-yl) piperidine—4-yl) methyl methane The title compound was prepared in the same manner as in <Preparation Example 8>, except that tert-butyl 4 ᅳ ((methylsulfonyloxy) methyl) piperidine-1-carboxylate was used instead of sulfonate. Was prepared.
XH 匪 R (400, CDC13) ： 7.13(111， m) , 6.65(1H, d) , 6.59(1Η, d) , 4.15(2Η, d), 3.85(2Η, d)， 2.78(2Η, m) , 2.12(1Η, m)， 1.87(2Η, m) , 1.48(9Η, s), 1.32(2Η, m) . X H 匪 R (400, CDC1 3 ): 7.13 (111 ， m), 6.65 (1H, d), 6.59 (1Η, d), 4.15 (2Η, d), 3.85 (2Η, d) ， 2.78 (2Η, m), 2.12 (1Η, m), 1.87 (2Η, m), 1.48 (9Η, s), 1.32 (2Η, m).
<제조예 16> 5-(4-((4-브로모 -2-플루오로페녹시 )메틸)피페리딘-Production Example 16 5- (4-((4-bromo-2-fluorophenoxy) methyl) piperidine-
1-일) 졸의 제조 1-day) preparation of sol
Figure imgf000046_0002
신에 2-플루오로 -4-브로모페놀을 사 용하고， (1-(5-에틸피리미딘 -2-일 )피페리딘 -4—일 )메틸 메탄설포네이트 를 사용하는 대신에 (1-(3-이소프로필 -1,2, 4—옥사디아졸— 5-일 )피페리 딘ᅳ 4-일 )메틸 메탄설포네이트를 사용하는 것을 제외하고， 상기 <제조 예 8>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.
Figure imgf000046_0002
Instead of using 2-fluoro-4-bromophenol in the scene and using (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methyl methanesulfonate (1 In the same manner as in <Preparation Example 8>, except that-(3-isopropyl-1,2, 4-oxadiazole- 5-yl) piperidinyl 4-yl) methyl methanesulfonate is used To give the title compound.
H NMR (400, CDC13) ： 7.13(1H, d)， 7.08(1H, d)， 6.89( 1H， m)H NMR (400, CDC1 3 ): 7.13 (1H, d), 7.08 (1H, d), 6.89 (1H, m)
4.24(2H, d) , 3.86(2H, d) , 3.15(2H, m) , 2.9K1H, m) , 1.9K2H, m) , 1.48(2H, m) , 1.32(6H, d) . 4.24 (2H, d), 3.86 (2H, d), 3.15 (2H, m), 2.9K1H, m), 1.9K2H, m), 1.48 (2H, m), 1.32 (6H, d).
<제조예 17> tert-부틸 4-((4-(4- (에록시카보닐)싸이클로핵스-Production Example 17 tert-Butyl 4-((4- (4- (ethoxycarbonyl) cyclonucleus-
1-에닐)페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 Preparation of 1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000047_0001
Figure imgf000047_0001
질소 하에서 500/^ 플라스크에 tert-부틸 4-( ( 4-브로모페녹시 ) 메틸)피페리딘 -1-카복시레이트 5g 을 디옥산 /물 /에탄을 (100^/20 /10 )에 녹여 교반하였다. 1,1—비스 (디페닐포스피노)페로센-팔라듐 ( Π ) 디클로라이드 550mg, 세슘 카보네이트 llg, 에틸 4-(4，4，5，5-테트라메 틸 1，3，2-디옥사보로렌 -2-일)싸이클로핵스 -3-엔카복시레이트 4.2g 을 순차적으로 적가하였다. 온도를 서서히 80°C 까지 가열한 후 5시간 동 안 교반하였다. 반웅 종결 후 상온으로 서서히 넁각한 뒤 ， 증류수 100 ^를 천천히 가하고 셀라이트 여과하였다. 여액을 에틸 아세테이트 300 ^로 추출한 다음 브라인 로 세척한 후， 무수황산마그네슘으 로 건조하고 농축 후 실리카 컬럼 크로마토그래피로 분리하여 표제 화 합물을 제조하였다. Dissolve 5 g of tert-butyl 4- ((4-bromophenoxy) methyl) piperidine-1-carboxylate in 500 / ^ flask under nitrogen in dioxane / water / ethane in (100 ^ / 20/10) Stirred. 1,1—bis (diphenylphosphino) ferrocene-palladium (Π) dichloride 550 mg, cesium carbonate llg, ethyl 4- (4,4,5,5-tetramethyl 1,3,2-dioxaborolene 2-yl) cyclonux-3-enecarboxylate 4.2 g was added dropwise sequentially. The temperature was slowly heated to 80 ° C. and stirred for 5 hours. After the reaction was completed, the solution was slowly cooled down to room temperature, and distilled water 100 ^ was slowly added thereto and filtered through Celite. The filtrate was extracted with ethyl acetate 300 ^, washed with brine, dried over anhydrous magnesium sulfate, concentrated and separated by silica column chromatography to prepare the title compound.
¾ NMR (400, CDC13) ： 7.32(2H, d) , 6.85(2H, d), 6.02(1Η, s) , 4.19(2Η, m) , 4.15(2Η, d) , 3.85(2Η, d) , 2.6K1H, m), 2.47(4Η, m) , 2.2Κ2Η, m) , 1.98(1Η, m)， 1.86(2Η, m) , 1.6K9H, s), 1.31(2Η, m) , 1.29(3Η, m) . ¾ NMR (400, CDC1 3 ): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1Η, s), 4.19 (2Η, m), 4.15 (2Η, d), 3.85 (2Η, d) , 2.6K1H, m), 2.47 (4Η, m), 2.2Κ2Η, m), 1.98 (1Η, m), 1.86 (2Η, m), 1.6K9H, s), 1.31 (2Η, m), 1.29 (3Η , m).
<제조예 18> 4-(4-((l-(tert-부톡시카보닐 )피페라딘 -4-일 )메특 시)페닐)싸이클로핵스 -3-엔카복실릭 엑시드의 제조 Preparation Example 18 Preparation of 4- (4-((l- (tert-butoxycarbonyl) piperazin-4-yl) methoxy) phenyl) cyclonux-3-enecarboxylic acid
Figure imgf000047_0002
Figure imgf000047_0002
질소 하에서 ， 250 플라스크에 tert-부틸 4-( (4-(4- (에록시카 보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 3.2g 을 THF7물 /에탄올 (100^/50/^/10^)에 녹여 교반하였다. 리튬 히드록 사이드 모노하이드레이트 2.4g을 적가한 후 상온에서 18시간 반웅시켰 다. 반웅 종결 후 농축된 HC1을 이용하여 pH를 1~2로 조절하였다 . 생 성된 고체를 여과 후 건조하여 원하는 표제 화합물을 제조하였다.  In nitrogen, 3.2 g of tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate was added to a 250 flask under THF7 water / It was dissolved in ethanol (100 ^ / 50 / ^ / 10 ^) and stirred. 2.4 g of lithium hydroxide monohydrate was added dropwise and reacted at room temperature for 18 hours. After completion of reaction, the pH was adjusted to 1-2 using concentrated HC1. The resulting solid was filtered and dried to give the desired title compound.
H NMR (400, CDCls) 7.32(2H, d) , 6.85(2Η, d), 6.02(1Η 4.15(2H, d) , 3.85(2H, d)， 2.6K1H, m)， 2.47(4H, m) , 2.21(2H 1.98(1H, m) , 1.86C2H, m) , 1.6K9H, s) , 1.3K2H, m) . H NMR (400, CDCls) 7.32 (2H, d), 6.85 (2Η, d), 6.02 (1Η 4.15 (2H, d), 3.85 (2H, d), 2.6K1H, m), 2.47 (4H, m), 2.21 (2H 1.98 (1H, m), 1.86C2H, m), 1.6K9H, s), 1.3 K 2 H, m).
<제조예 19> 에틸 4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4- 일)메 -3-엔카복시레이트의 제조 Preparation Example 19 Preparation of ethyl 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) me-3-enecarboxylate
Figure imgf000048_0001
Figure imgf000048_0001
tert—부틸 4-((4-브로모페녹시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에 2-(4-( (4-브로모페녹시 )메틸 )피페리딘 -1-일 )-5-에틸 피리미딘을 사용하는 것을 제외하고， 상기 <제조예 17>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다.  tert—Butyl 4-((4-bromophenoxy) methyl) piperidine-1-carboxylate Instead of using 2- (4-((4-bromophenoxy) methyl) piperidine-1 The title compound was prepared in the same manner as in <Preparation Example 17>, except that -yl) -5-ethyl pyrimidine was used.
^ NMR (400, CDCls) ： 8.21(2H, s) , 7.32(2H, d) 6.85(2H 6.02 1H, s) , 4.80C2H, d) , 4.19(2Η, m) , 3.54(2H, d) , 2.94(2H 2.6K1H, m) .2.48(2Η, m) , 2.47(4Η, m) , 2.2K2H, m) , 1.86(2H 1.8K1H, m) , 1.29(3Η, m) , 1.26(2Η, m), 1.20 3H, m) .  ^ NMR (400, CDCls): 8.21 (2H, s), 7.32 (2H, d) 6.85 (2H 6.02 1H, s), 4.80C2H, d), 4.19 (2Η, m), 3.54 (2H, d), 2.94 (2H 2.6K1H, m) .2.48 (2Η, m), 2.47 (4Η, m), 2.2K2H, m), 1.86 (2H 1.8K1H, m), 1.29 (3Η, m), 1.26 (2Η, m ), 1.20 3 H, m).
<제조예 20> 4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메 톡시)페닐)싸이클로핵스 -3-엔카복실릭 엑시드의 제조 Preparation Example 20 Preparation of 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enecarboxylic acid
Figure imgf000048_0002
Figure imgf000048_0002
tert-부틸 4-((4-(4ᅳ (에톡시카보닐)싸이클로핵스 -1-엔일)페녹 시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에， 에틸 4-(4-((1- (5-에틸피리미딘 -2-일)피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔 카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 18〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  tert-butyl 4-((4- (44- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate, instead of using ethyl 4- (4- (Preparation Example 18) except that ((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-ene carboxylate is used. The same procedure was followed to prepare the title compound.
¾ NMR (400， CDCls) ： 8.21(2H, s) , 7.32(2H, d) , 6.85(2Η, d)， 6.02(1Η, s), 4.80(2Η, d) , 3.54(2Η, d) , 2.94(2Η, m), 2.6K1H, m) ,2.48(2Η, m) , 2.47(4Η, m) , 2.21(2Η, m) , 1.86(2Η, d) , 1.81(1Η, m) , 1.26(2H, m) , 1.20(3H, m) . ¾ NMR (400, CDCls): 8.21 (2H, s), 7.32 (2H, d), 6.85 (2Η, d), 6.02 (1Η, s), 4.80 (2Η, d), 3.54 (2Η, d), 2.94 (2Η, m), 2.6K1H, m), 2.48 (2Η, m), 2.47 (4Η, m), 2.21 (2Η, m), 1.86 (2Η, d), 1.81 (1Η, m), 1.26 (2H, m), 1.20 (3H, m).
<제조예 21> 에틸 4-(4-((l-(3-이소프로필 -l，2,4-옥사디아졸-5- 일)피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복시레이트의 제조 Preparation Example 21 Ethyl 4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus Preparation of 3-encarboxylate
Figure imgf000049_0001
Figure imgf000049_0001
tert-부틸 4-((4—브로모페녹시 )메틸)피페리딘 -1—카복시레이트를 사용하는 대신에 , 5-(4-((4-브로모페녹시 )메틸) S 페리딘 -1-일 )— 3-이소 프로필 -1，2，4-옥사디아졸을 사용하는 것을 제외하고， 상기 <제조예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using tert-butyl 4-((4—bromophenoxy) methyl) piperidine-1—carboxylate, 5- (4-((4-bromophenoxy) methyl) S ferridine- 1-day) —The title compound was prepared in the same manner as in <Preparation Example 17>, except that 3-isopropyl-1,2,4-oxadiazole was used.
XH NMR (400, CDC13) ： 7.32(2H, d) , 6.85(2Η, d) , 6.02(1Η, s) ,XH NMR (400, CDC1 3 ): 7.32 (2H, d), 6.85 (2Η, d), 6.02 (1Η, s),
4.24(2Η, d), 4.19(2Η, m) , 3.86(2Η, d)， 3.15(2Η, m)， 2.9K1H, m) , 2.6K1H, m) , 2.47(4H, m)， 2.21(2H, m) , 1.91(2H, m) , 1.48(2H, m)， 1.32(6H, d)， 1.29(3H, m) . <제조예 22> 4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피 페리딘 복실릭 엑시드의 제조 4.24 (2Η, d), 4.19 (2Η, m), 3.86 (2Η, d) ， 3.15 (2Η, m) ， 2.9K1H, m), 2.6K1H, m), 2.47 (4H, m) ， 2.21 (2H , m), 1.91 (2H, m), 1.48 (2H, m), 1.32 (6H, d), 1.29 (3H, m). Production Example 22 Preparation of 4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine cycloxic acid
Figure imgf000049_0002
Figure imgf000049_0002
tert-부틸 4-( (4-(4- (에톡시카보닐)싸이클로핵스 -1-엔일 )페녹 시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에， 에틸 _4-(4-((1- (3-이소프로필 -1,2 ,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐 )싸 이클로핵스 -3-엔카복시레이트를 사용하는 것을 제외하고， 상기 <제조 예 18>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using tert-butyl 4- ((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate, ethyl 4- (4- ((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enecarboxylate using Except that, the title compound was prepared in the same manner as in <Preparation Example 18>.
¾ NMR (400， CDCls) ： 7.32(2H, d) , 6.85(2H, d), 6.02(1Η, s), 4.24(2Η, d) , 3.86(2Η, d), 3.15(2Η, m) , 2.9K1H, m) , 2.61(1Η, m)， 2.47(4H , m) , 2.21(2H, m) , 1.91(2H, m)， 1.48(2H, m) , 1.32(6H, ¾ NMR (400, CDCls): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1Η, s), 4.24 (2Η, d), 3.86 (2Η, d), 3.15 (2Η, m), 2.9K1H, m), 2.61 (1Η, m) ， 2.47 (4H, m), 2.21 (2H, m), 1.91 (2H, m), 1.48 (2H, m), 1.32 (6H,
<제조예 23> tert-부틸 4-((6-(4- (에톡시카보닐)싸이클로핵스-Production Example 23 tert-Butyl 4-((6- (4- (ethoxycarbonyl) cyclonucleus-
1-에닐)피리딘 -3-일옥시 )메틸)피페리딘ᅳ 1-카복시레이트의 제조 Preparation of 1-enyl) pyridin-3-yloxy) methyl) piperidine ᅳ 1-carboxylate
Figure imgf000050_0001
Figure imgf000050_0001
tert-부틸 4ᅳ ((4-브로모페녹시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에， tert-부틸 4-((5-브로모피리딘 -2-일옥시 )메틸)피페 리딘 -1-카복시레이트를 사용하는 것을 제외하고, 상기 <제조예 17〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  tert-butyl 4-((4-bromophenoxy) methyl) piperidine-1-carboxylate, instead of using tert-butyl 4-((5-bromopyridin-2-yloxy) methyl) The title compound was prepared in the same manner as in <Preparation Example 17>, except that Piperidine-1-carboxylate was used.
¾ 丽 R (400， CDCls) ： 8.2K1H, s) , 7.38(1H, d) , 7.15(1Η, d) , 6.02(1Η, s) , 4.19(2Η, ιη) , 4.15(2Η, d) , 3.85(2Η, d) , 2.78(2Η, m) , 2.6K1H, m) , 2.47(4Η, m) , 2.2Κ2Η, m) , 2.12(1Η, m), 1.87(2Η, m) , 1.48(9Η, s), 1.32(2Η, m) , 1.29(3Η, m) .  ¾ 丽 R (400, CDCls): 8.2K1H, s), 7.38 (1H, d), 7.15 (1Η, d), 6.02 (1Η, s), 4.19 (2Η, η), 4.15 (2Η, d), 3.85 (2Η, d), 2.78 (2Η, m), 2.6K1H, m), 2.47 (4Η, m), 2.2Κ2Η, m), 2.12 (1Η, m), 1.87 (2Η, m), 1.48 (9Η , s), 1.32 (2Η, m), 1.29 (3Η, m).
<제조예 24> 4-(5-((l-(tert-부톡시카보닐 )피페리딘 -4-일 )메록 시)피리딘 -2-일)싸이클로핵스—3-엔카복실릭 엑시드의 제조 Preparation 24 Preparation of 4- (5-((l- (tert-butoxycarbonyl) piperidin-4-yl) meroxy) pyridin-2-yl) cyclonux—3-encarboxylic acid
Figure imgf000050_0002
Figure imgf000050_0002
tert—부틸 4-((4-(4- (에록시카보닐)싸이클로핵스 -1-엔일)페녹 시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신 , tert-부틸 4ᅳ((6- (4- (에톡시카보닐 )싸이클로핵스 -1-엔일)피리딘 -3-일옥시 )메틸)피페리 딘 -1-카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 18>과 동 일한 방법으로 수행하여 표제 화합물을 제조하였다.  tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate, instead of using tert-butyl 4 ᅳ (( 6- (4- (ethoxycarbonyl) cyclonux-1-enyl) pyridin-3-yloxy) methyl) piperidine-1-carboxylate, except that The title compound was prepared by one method.
¾ 丽 R (400， CDCla) ： 8.21(1H, s), 7.38(1H, d), 7.15(1H, d)， ¾ リ R (400, CDCla): 8.21 (1H, s), 7.38 (1H, d), 7.15 (1H, d) ，
6.02(1H, s), 4.15(2H, d)， 3.85(2H, d)， 2.78(2H, m)， 2.6K1H, m) , 2.47(4H, m) , 2.21(2H, m), 2.12(1H, m)， 1.87(2H, m) , 1.48(9H, s) 1.32(2H, m) . 6.02 (1H, s), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m), 2.6K1H, m), 2.47 (4H, m), 2.21 (2H, m), 2.12 (1H, m), 1.87 (2H, m), 1.48 (9H, s) 1.32 (2H, m).
<제조예 25> 에틸 4-(5-((l-(3-이소프로필 -l，2,4-옥사디아졸-5- 일)피페리딘 -4-일)메특시 )피리딘 -2-일 )싸이클로핵스 -3-'엔카복시레이트 의 제조 Preparation 25 Ethyl 4- (5-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) pyridine-2- yl) Preparation of 3-cyclo haekseu "Enka diplopia rate
Figure imgf000051_0001
Figure imgf000051_0001
tert-부틸 4-((4-브로모페녹시 )메틸)피페리딘 -1-카복사레이트를 사용하는 대신에， 5-(4-((6-클로로피리딘— 3-일옥시 )메틸)피페리딘 -1- 일) -3—이소프로필 -1,2, 4-옥사다아졸을 사용하는 것을 제외하고， 상기 <제조예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using tert-butyl 4-((4-bromophenoxy) methyl) piperidine-1-carboxate, 5- (4-((6-chloropyridine- 3-yloxy) methyl) The title compound was prepared in the same manner as in <Preparation Example 17>, except that Piperidin-1-yl) -3—isopropyl-1,2,4-oxadaazole was used.
:H NMR (400, CDC13) ： 8.2K1H, s) , 7.38(1H, d), 7.15(1H, d) , 6.02(1H, s) , 4.24C2H, d) , 4.19(2H, m) , 3.86(2H, d)， 3.15(211， m) , 2.9K1H, m) , 2.6K1H, m)， 2.47(4H, m) , 2.21(2H, m) , 1.91(2H, m) , 1.48(2H, m) , 1.32(6H. d)， 1.29(3H, m) . : H NMR (400, CDC1 3 ): 8.2K1H, s), 7.38 (1H, d), 7.15 (1H, d), 6.02 (1H, s), 4.24C2H, d), 4.19 (2H, m), 3.86 (2H, d), 3.15 (211, m), 2.9K1H, m), 2.6K1H, m), 2.47 (4H, m), 2.21 (2H, m), 1.91 (2H, m), 1.48 (2H , m), 1.32 (6H.d), 1.29 (3H, m).
<제조예 26> 4-(5-((1-(3—이소프로필-1,2,4-옥사디아졸-5-일)피 페리딘 -4-일 )메톡시 )피리딘 -2-일 )싸이클로핵스 -3-엔카복실릭 엑시드의 쎄조 Production Example 26 4- (5-((1- (3—isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) pyridin-2-yl Sejo of cyclonux-3-encarboxyl acid
Figure imgf000051_0002
Figure imgf000051_0002
tert-부틸 4-((4-(4- (에록시카보닐)싸이클로핵스 -1-엔일 )페녹 시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에 , 에틸 4-(5-((1- (3-이소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )피리딘- 2-일 )싸이클로핵스 -3-엔카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 18>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다. ¾ NMR (400， CDCls) ： 8.21(1H, s) 7.38(1H, d), 7.15 1H, d) 6.02C1H, s) , 4.24C2H, d) , 3.86(2Η, d) 3.15(2H, m) , 2.9K1H, m) 2.6K1H, m) , 2.47(4Η, m) , 2.21(2Η, m) 1.9K2H, m) , 1.48(2H, m) 1.32C6H. d) . Instead of using tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate, ethyl 4- (5- ((1- (3-Isopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) pyridin-2-yl) cyclonux-3-enecarboxylate Except for using above The title compound was prepared in the same manner as in <Preparation Example 18>. ¾ NMR (400, CDCls): 8.21 (1H, s) 7.38 (1H, d), 7.15 1H, d) 6.02C1H, s), 4.24C2H, d), 3.86 (2Η, d) 3.15 (2H, m) , 2.9K1H, m) 2.6K1H, m), 2.47 (4Η, m), 2.21 (2Η, m) 1.9K2H, m), 1.48 (2H, m) 1.32C6H. d).
<제조예 27> tert-부틸 4-( (5-(4- (에톡시카보닐)싸이클로핵스-Production Example 27 tert-Butyl 4-((5- (4- (ethoxycarbonyl) cyclonucleus-
1-에닐)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트의 제조 Preparation of 1-enyl) pyridin-2-yloxy) methyl) piperidine-1-carboxylate
Figure imgf000052_0001
Figure imgf000052_0001
tert-부틸 4-((4-브로모페녹시 )메틸)피페리딘 -1-카복시레이 사용하는 대신에， tert-부틸 4-((5-브로모피리딘 -2-일옥시 )메틸)피페 리딘 -1ᅳ카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  tert-butyl 4-((4-bromophenoxy) methyl) piperidine-1-carboxylay Instead of using tert-butyl 4-((5-bromopyridin-2-yloxy) methyl) pipe The title compound was prepared in the same manner as in <Preparation Example 17>, except that Ridine-1′carboxylate was used.
匪 R (400， CDC13) 8.14(1H, s), 7.63(1H d) 6.7K1H匪 R (400, CDC1 3 ) 8.14 (1H, s), 7.63 (1H d) 6.7K1H
6.02(1Η, s), 4.19(2H, m) 4.15(2H, d) , 3.85(2H! d), 2.78(2H 2.6K1H, m), 2.47(4H, m) 2.2Κ2Η, m), 2.12(1H, m), 1.87(2H 1.48(9Η, s), 1.32(2H, m) 1.29(3Η, m) . 6.02 (1Η, s), 4.19 (2H, m) 4.15 (2H, d), 3.85 (2H ! D), 2.78 (2H 2.6K1H, m), 2.47 (4H, m) 2.2Κ2Η, m), 2.12 ( 1H, m), 1.87 (2H 1.48 (9Η, s), 1.32 (2H, m) 1.29 (3Η, m).
<제조예 28> 4-(6-((l-(tert-부특시카보닐 )피페리딘 -4-일 )메록 시)피리딘 -3-일)싸이클로핵스 -3-엔카복실릭 엑시드의 제조 Preparation 28 Preparation of 4- (6-((l- (tert-suboxycarbonyl) piperidin-4-yl) meroxy) pyridin-3-yl) cyclonux-3-enecarboxylic acid
Figure imgf000052_0002
Figure imgf000052_0002
tert-부틸 4-((4-(4- (에록시카보닐)싸이클로핵스 -1-엔일)페녹 시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에 , tertᅳ부틸 4- ((5-(4- (에톡시카보닐 )싸이클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸)피 페리딘 -1-카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 18> 과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate, tert ᅳ butyl 4- ( <Preparation 18>, except that (5- (4- (ethoxycarbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine-1-carboxylate was used. The same procedure was followed to prepare the title compound.
XH NMR (400, CDCI3) ： 8.14(1H, s), 7.63(1H, d) , 6.7K1H, d)， 6.02(1H, s) , 4.15(2H, d), 3.85(2H, d) , 2.78(2H, m) , 2.6K1H, m) , 2.47(4H, m) , 2.21(2H, m)， 2.12(1H, m)， 1.87(2H, m) ' 1.48(9H, s), 1.32(2H, m) . X H NMR (400, CDCI3): 8.14 (1H, s), 7.63 (1H, d), 6.7K1H, d), 6.02 (1H, s), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m), 2.6K1H, m), 2.47 (4H, m), 2.21 (2H, m), 2.12 ( 1 H, m), 1.87 (2 H, m) '1.48 (9 H, s), 1.32 (2 H, m).
<제조예 29> tert-부틸 4-((4-(4- (에특시카보닐 )싸이클로핵스-Production Example 29 tert-butyl 4-((4- (4- (epoxycarbonyl) cyclonucleus-
1-에닐) -2-플루오로페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 Preparation of 1-enyl) -2-fluorophenoxy) methyl) piperidine-1-carboxylate
Figure imgf000053_0001
Figure imgf000053_0001
tert-부틸 4-((4-브로모페녹시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에， tert 부틸 4-((4-브로모 -2-플루오로꽤녹시 )메틸 )피 페라딘 -1-카복시레이트를 사용하는 것올 제외하고 , 상기 <제조예 18> 과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using tert-butyl 4-((4-bromophenoxy) methyl) piperidine-1-carboxylate, tert butyl 4-((4-bromo-2-fluoroprettyoxy) methyl) Except for using piperadine-1-carboxylate, the title compound was prepared in the same manner as in <Preparation Example 18>.
XH NMR (400， CDC13) ： 7.13(1H, d) , 7.08(1H, d), 6.89(1Η, m) , 6.02(1Η, s), 4.19(2Η, m)， 4.15(2Η, d) , 3.85(2Η, d) , 2.78(2Η, m) , 2.6K1H, m) , 2.47(4Η, m) , 2.21(2Η, m) , 2.12(1Η, m), 1.87(2Η, m) , 1.48(9Η, s), 1.32(2Η, m)， 1.29(3Η, m) . X H NMR (400, CDC1 3 ): 7.13 (1H, d), 7.08 (1H, d), 6.89 (1Η, m), 6.02 (1Η, s), 4.19 (2Η, m), 4.15 (2Η, d ), 3.85 (2Η, d), 2.78 (2Η, m), 2.6K1H, m), 2.47 (4Η, m), 2.21 (2Η, m), 2.12 (1Η, m), 1.87 (2Η, m), 1.48 (9Η, s), 1.32 (2Η, m), 1.29 (3Η, m).
<제조예 30> 4-(4-((l-(tert-부톡시카보닐)피페리딘 -4-일)메톡 시 ) -3-풀루오로페닐)싸이클로핵스 -3-엔카복실릭 엑시드의 제조 Production Example 30 4- (4-((l- (tert-butoxycarbonyl) piperidin-4-yl) methoxy) -3-fluorofluorophenyl) cyclonux-3-enecarboxylic acid Manufacture
Figure imgf000053_0002
Figure imgf000053_0002
tert-부틸 4-((4-(4- (에톡시카보닐)싸이클로핵스 -1-엔일)페녹 시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에， tert-부틸 4ᅳ ((4-(4- (에록시카보닐 )싸이클로핵스 -1-엔일 ) -2ᅳ플루오로페녹시 )메틸) 피페리딘 -1-카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 18>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다. Instead of using tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate, tert-butyl 4 '( ( 4- ( 4- (ethoxycarbonyl) cyclonux-1-enyl) -2'fluorophenoxy) methyl) piperidine-1-carboxylate, except for using <Preparation Example 18> In the same manner as in the title compound was prepared.
XH NMR (400， CDCI3) :' 7.13(1H, d)， 7.08(1H, d) , 6.89(1H, m) , XH NMR (400, CDCI3): '7.13 (1H, d), 7.08 (1H, d), 6.89 (1H, m),
6.02(1H, s) , 4.15(2H, d) , 3.85(2H, d) , 2.78(2H, m)， 2.6K1H, m) , 2.47(4H, m) , 2.21(2H, m)， 2.12(1H, m) , 1.87(2H, m) , 1.48(9H; s) , 32(2H, m) 6.02 (1H, s), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m), 2.6K1H, m), 2.47 (4H, m), 2.21 (2H, m), 2.12 ( 1 H, m), 1.87 (2 H, m), 1.48 (9 H ; s), 32 (2H, m)
<제조예 31> 에틸 4-(3-플루오로 -4-((l-(3-이소프로필 -1，2,4-옥 사디아졸 -5-일)피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복시레 이트의 제조 Preparation Example 31 Ethyl 4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy Preparation of Phenyl Cyclonux-3-enecarboxylate
Figure imgf000054_0001
Figure imgf000054_0001
tert-부틸 4-((4-브로모페녹시 )메틸 )피페리딘 -1-카복시레이트를 사용하는 대신에， 5-(4-((4-브로모 -2-플루오로페녹시 )메틸)피페리딘- 1-일 ) -3-이소프로필 -1，2，4-옥사디아졸을 사용하는 것을 제외하고， 상 기 <제조예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였 다.  Instead of using tert-butyl 4-((4-bromophenoxy) methyl) piperidine-1-carboxylate, 5- (4-((4-bromo-2-fluorophenoxy) methyl ) The title compound was prepared in the same manner as in <Preparation Example 17>, except for using 1) 2-piperidin-1-yl) -3-isopropyl-1,2,4-oxadiazole. .
!H 蘭 R (400, CDCls) 7.13(1H, 7.08(1H, d), 6.89(1H, 6.02(1H, s) , 4.24(2Η, d) 4.19(2H, 3.86(2H, d) , 3.15(2H, 2.9K1H, m), 2.6K1H, m) 2.47(4H, 2.2K2H, m) , 1.9K2H, 1.48(2H, m) , 1.32(6H, d) 1.29(3H, ! H 蘭 R (400, CDCls) 7.13 (1H, 7.08 (1H, d), 6.89 (1H, 6.02 (1H, s), 4.24 (2Η, d) 4.19 (2H, 3.86 (2H, d), 3.15 (2H , 2.9K1H, m), 2.6K1H, m) 2.47 (4H, 2.2K2H, m), 1.9K2H, 1.48 (2H, m), 1.32 (6H, d) 1.29 (3H,
<제조예 32> 4-(3-플루오로-4-((1-(3-이소프로필-1,2,4-옥사디 아졸 -5-일)피페리딘 -4ᅳ일 )메특시 )페닐 )싸이클로핵스 -3-엔카복실릭 엑 시드의 제조 Production Example 32 4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4 ylyl) methoxy) phenyl Preparation of Cyclonux-3-Encarboxyl Acid
Figure imgf000054_0002
Figure imgf000054_0002
tert-부틸 4-((4-(4- (에록시카보닐 )싸이클로핵스 -1-엔일 )페녹 시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에， 에틸 4-(3-플루 오로 -4ᅳ((1-(3-이소프로필— 1，2，4—옥사디아졸 -5-일 )피페리딘 -4-일 )메특 시 )페닐)싸이클로핵스 -3-엔카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 18>과 동일한 방법으로 수행하여 표제 화합물을 제조하 였다. Instead of using tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate, ethyl 4- (3- Fluoro-4-4 ((1- (3-isopropyl— 1,2,4—oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enecarboxylate Except for using The title compound was prepared in the same manner as in <Preparation Example 18>.
¾ NMR (400， CDC13) ： 7.13(1H, d)， 7.08 1H, d)， 6.89C1H, m) , 6.02(1H, s) ,. 4.24(2Η, d) , 3.86(2Η, d) , 3.15(2H, m) , 2.9K1H, m)， 2.6K1H, m) , 2.47(4Η, m) , 2.21(2Η, m) , 1.9K2H, m) , 1.48(2Η, m) , 1.32(6Η, d) . ¾ NMR (400, CDC1 3 ): 7.13 (1H, d), 7.08 1H, d), 6.89C1H, m), 6.02 (1H, s) ,. 4.24 (2Η, d), 3.86 (2Η, d), 3.15 (2H, m), 2.9K1H, m), 2.6K1H, m), 2.47 (4Η, m), 2.21 (2Η, m), 1.9K2H, m), 1.48 (2Η, m), 1.32 (6Η, d).
<제조예 33> tert-부틸 4-((4-(4- (에록시카보닐)싸이클로핵스- 1一에닐 )-3-플루오로페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 Preparation Example 33 Preparation of tert-Butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1 unienyl) -3-fluorophenoxy) methyl) piperidine-1-carboxylate
Figure imgf000055_0001
Figure imgf000055_0001
tert-부틸 4-((4-브로모페녹시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에， tert-부틸 4-((4-브로모 -3-플루오로페녹시 )메틸)피 페리딘 -1-카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 17> 과 동일한 방법으로 수행하여 표제 화합물을 제조하였다.  Instead of using tert-butyl 4-((4-bromophenoxy) methyl) piperidine-1-carboxylate, tert-butyl 4-((4-bromo-3-fluorophenoxy) methyl The title compound was prepared in the same manner as in <Preparation Example 17>, except for using Pyriferridine-1-carboxylate.
¾ NMR (400， CDCls) ： 7.13(1H, m) , 6.65(1H, d) , 6.59(1Η, d)， 6.02(1Η, s), 4.19(2Η, m) , 4.15(2Η, d) , 3.85(2Η, d) , 2.78(2Η, m) , 2.6K1H, m) , 2.47(4Η, m) , 2.21(2Η, m) , 2.12(1Η, m) , 1.87(2Η, m) , 1.48(9Η, s) , 1.32(2Η, m) , 1.29(3Η, m) .  ¾ NMR (400, CDCls): 7.13 (1H, m), 6.65 (1H, d), 6.59 (1Η, d), 6.02 (1Η, s), 4.19 (2Η, m), 4.15 (2Η, d), 3.85 (2Η, d), 2.78 (2Η, m), 2.6K1H, m), 2.47 (4Η, m), 2.21 (2Η, m), 2.12 (1Η, m), 1.87 (2Η, m), 1.48 ( 9Η, s), 1.32 (2Η, m), 1.29 (3Η, m).
<제조예 34> 4-(4-((l-(tert-부톡시카보닐)피페리딘 -4-일)메톡 시 ) -2-플루오로페닐)싸이클로핵스 -3-엔카복실릭 엑시드의 제조 Preparation Example 34 of 4- (4-((l- (tert-butoxycarbonyl) piperidin-4-yl) methoxy) -2-fluorophenyl) cyclonux-3-enecarboxylic acid Produce
Figure imgf000055_0002
Figure imgf000055_0002
tertᅳ부틸 4-((4-(4- (에록시카보닐)싸이클로핵스 -1-엔일)페녹 시 )메털)피페리딘 -1-카복시레이트를 사용하는 대신에， tert-부틸 4ᅳ ((4-(4- (에록시카보닐)싸이클로핵스 -1-엔일 )-3-플루오로페녹시 )메틸) 피페리딘ᅳ 1-카복시레이트를 사용하는 것을 제외하고， 상기 <제조예 18〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다. NMR (400, CDCI3) 7.13 1H, m) , 6.65(1H 6.59 1H, 6.02(1H, s)， 4.15(2H, d) 3.85(2H, d) , 2.78(2H, 2.6K1H, 2.47(4H, m) , 2.21(2H/ m) 2.12(1H, m) , 1.87(2H, 1.48C9H, 1.32(2H, m) . ^ tert-Butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) metal) piperidine-1-carboxylate, instead of using tert-butyl 4 '( (4- (4- (Ethoxycarbonyl) cyclonux-1-enyl) -3 -fluorophenoxy) methyl) piperidine ᅳ 1-carboxylate, except for using <Preparation Example 18> In the same manner as in the title compound was prepared. NMR (400, CDCI3) 7.13 1H, m), 6.65 (1H 6.59 1H, 6.02 (1H, s), 4.15 (2H, d) 3.85 (2H, d), 2.78 (2H, 2.6K1H, 2.47 (4H, m ), 2.21 (2H / m) 2.12 (1H, m), 1.87 (2H, 1.48C9H, 1.32 (2H, m). ^
<실시예 1> tert-부틸 4-((4-(4-((R)-l-히드록시프로판 -2-일카 바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트의 제조 Example 1 tert-Butyl 4-((4- (4-((R) -l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine- Preparation of 1-carboxylate
Figure imgf000056_0001
Figure imgf000056_0001
질소 하에서， 100 ^ 플라스크에 4-(4-((l-(tert_부톡시카보닐) 피페리딘 -4-일)메특시 )페닐 )싸이클로핵스 -3-엔카복실릭 엑시드 200mg 를 DMF 2 id 에 녹여 교반하였다. EDCI 140mg, HOBt llOmg을 순차적으 로 적가한 후 10분간 추가작으로 교반하였다. (R)ᅳ 2-아미노 -1-프로판 올 72mg 을 적가한 후 상온에서 5시간 교반하였다. 반웅 종결 후， 증 류수 50 μί 를 0°C에서 천천히 가하고 생성되는 고체를 여과하여 건조 하여 원하는 흰색 고체화합물을 얻었다 (수득량 ： 167mg I 수율 ： 73%) 1 醒 R (400， CDCls) ： 7.31 (2H, d)， 6.85 (2H, d) , 6.05 (1H, s) , 5.75 (1H, d) 4.15 (3H, m)， 3.85 (2H, d) , 3.72 (1H, m) , 3.52 (1H, ni) , 2.78 (2H, m) , 2.50 (5H, m) , 2.12 (1H, m) , 1.95 (1H, m)， 1.88 (2H, m) , 1.52 (9H, s) ' 1.30 (2H, m)， 1.25 (3H, d) .  Under nitrogen, 200 mg of 4- (4-((l- (tert_butoxycarbonyl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxylic acid in a 100 ^ flask was added DMF 2 It was dissolved in id and stirred. EDCI 140mg, HOBt llOmg was added dropwise sequentially and stirred for a further 10 minutes. 72 mg of (R) '2-amino-1-propanol was added dropwise, followed by stirring at room temperature for 5 hours. After completion of reaction, 50 μί of distilled water was slowly added at 0 ° C, and the resulting solid was filtered and dried to obtain the desired white solid compound (yield: 167mg I yield: 73%) 1 醒 R (400, CDCls): 7.31 (2H, d), 6.85 (2H, d), 6.05 (1H, s), 5.75 (1H, d) 4.15 (3H, m), 3.85 (2H, d), 3.72 (1H, m), 3.52 (1H , ni), 2.78 (2H, m), 2.50 (5H, m), 2.12 (1H, m), 1.95 (1H, m), 1.88 (2H, m), 1.52 (9H, s) '1.30 (2H, m), 1.25 (3H, d).
<실사예 2> tert-부틸 4-((4-(4- (싸이클로프로필카바모일)싸 o 클로핵스 -1- )메틸)피페리딘 -1-카복시레이트의 제조 <Example 2> Preparation of tert-butyl 4-((4- (4- (cyclopropylcarbamoyl) cyloclonux-1-) methyl) piperidine-1-carboxylate
Figure imgf000056_0002
Figure imgf000056_0002
(R)-2-아미노 -1-프로판올을 사용하는 대신에， 싸이클로프로필 아민을 사용하는 것을 제외하고 , 상기 <실시예 1>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 180mg I 수율 ： 80%  The title compound was prepared in the same manner as in <Example 1>, except that instead of using (R) -2-amino-1-propanol, cyclopropyl amine was obtained (amount: 180 mg I). Yield ： 80%
¾ NMR (400， CDCI3) ： 7.31 (2H, d) , 6.86 (2H, d) , 6.05 (1Η, ， (3H, m)， 3.45 H, 1.52 (9H, s) , 28 에틸카바모일) 싸이 트의 제조 ¾ NMR (400, CDCI 3 ): 7.31 (2H, d), 6.86 (2H, d), 6.05 (1Η, ， (3H, m) ， 3.45 H, 1.52 (9H, s), 28 ethyl carbamoyl) site
Figure imgf000057_0001
Figure imgf000057_0001
(R)-2—아미노 -1-프로판올을 사용하는 대신에， 2，2-디플루오로에 틸아민을 사용하는 것을 제외하고, 상기 <실시예 1>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 ： 120mg I 수율 ： 72%) The title compound was obtained in the same manner as in <Example 1>, except that 2,2-difluoroethylamine was used instead of (R) -2—amino-1-propanol. (Quantity: 120 mg I yield: 72%)
¾ 丽 R (400， CDCls) ： 7.31 (2H, d) , 6.85 (2H, d) , 6.05 (1Η, s) , 5.87 (1H, m) , 4.15 (2H, m)， 3.85 (2H, d) , 3.68 (2H, m)， 2.78 (2H, m) , 2.50 (5H, m) , 2.12 (1H, m)， 1.85 (4H, m) , 1.52 (9H, s) , 1.30 (2H, m) . ¾ δ R (400, CDCls): 7.31 (2H, d), 6.85 (2H, d), 6.05 (1Η, s), 5.87 (1H, m), 4.15 (2H, m) ， 3.85 (2H, d) , 3.68 (2H, m), 2.78 (2H, m), 2.50 (5H, m), 2.12 (1H, m), 1.85 (4H, m), 1.52 (9H, s), 1.30 (2H, m).
<실시예 4> tert-부틸 4-((4-(4-((R)-2,3-디히드록시프로필카바 모일)싸이클로핵스ᅳ 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제 조 Example 4 tert-Butyl 4-((4- (4-((R) -2,3-dihydroxypropylcarbamoyl) cyclonucleosulf 1-enyl) phenoxy) methyl) piperidine-1 Preparation of carboxylates
Figure imgf000057_0002
Figure imgf000057_0002
(R)-2-아미노 -1-프로판올을 사용하는 대신에， (R)— 3-아미노- 1,2-프로판디올을 사용하는 것을 제외하고， 상기 <실시예 1>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 132mg I 수 율 ： 68%).  Instead of using (R) -2-amino-1-propanol, it was carried out in the same manner as in <Example 1>, except that (R)-3-amino-1, 1,2-propanediol was used. The title compound was prepared (yield: 132 mg I yield: 68%).
¾ 匪 R (400, CDC13) ： 7.32 (2H, d) , 6.82 (2H, d) , 6.04 (2H, s), .4.18 (2H, m) , 3.85 (3H, m)， 3.52 (4H, m) , 2.98 (2H, m)， 2.78 (2H, m) , 2.52 (5H, m) , 2.12 (1H, m) , 1.95 (1H, m) , 1.88 (2H, m) , 1.52 (9H, s) , 1.30 (2H, m.) . <실시예 5> tert-부틸 4-((4-(4-((R)-3-히드록시피를리딘 -1-카 보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 ~1-카복시레이트의 제 ¾ 匪 R (400, CDC1 3 ): 7.32 (2H, d), 6.82 (2H, d), 6.04 (2H, s), .4.18 (2H, m), 3.85 (3H, m), 3.52 (4H, m), 2.98 (2H, m), 2.78 (2H, m), 2.52 (5H, m), 2.12 (1H, m), 1.95 (1H, m), 1.88 (2H, m), 1.52 (9H, s ), 1.30 (2H, m.). Example 5 tert-Butyl 4-((4- (4-((R) -3-hydroxypyridine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine ~ 1-carboxylate
Figure imgf000058_0001
Figure imgf000058_0001
(R)-2-아미노— 1-프로판올을 사용하는 대신에， (R)-( + )_3-피를리 디놀올 사용하는 것을 제외하고， 상기 <실시예 1〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 : 130mg I 수율 ： 56%).  Instead of using (R) -2-amino— 1-propanol, the procedure was carried out in the same manner as in <Example 1>, except that (R)-(+) _ 3-pyridinolol was used. Compounds were prepared (yield: 130 mg I yield: 56%).
XH NMR (400, CDCls) ： 7.31 (2H, d) , 6.85 (2H, d)， 6.05 (1H, s) , 4.60 (1Η, d), 4.15 (2H, m) , 3.85 (2H, d) , 3.62 (4H, m) , 2.72 (3H, m) , 2.58 (3H, m) , 2.34 (1H, m) , 1.98 (8H, m) , 1.52 (9H, s) , 1.30 (2H, m) . X H NMR (400, CDCls): 7.31 (2H, d), 6.85 (2H, d), 6.05 (1H, s), 4.60 (1Η, d), 4.15 (2H, m), 3.85 (2H, d) , 3.62 (4H, m), 2.72 (3H, m), 2.58 (3H, m), 2.34 (1H, m), 1.98 (8H, m), 1.52 (9H, s), 1.30 (2H, m).
<실시예 6> tert-부틸 4-((4-(4-((3-히드록시프로필) (메틸)카바 모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제 Example 6 tert-Butyl 4-((4- (4-((3-hydroxypropyl) (methyl) carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Article of rate
Figure imgf000058_0002
Figure imgf000058_0002
00-2-아미노 -1-프로판을을 사용하는 대신에， 3- (메틸아미노) - 1-프로판올을 사용하는 것을 제외하고 , 상기 <실시예 1>과 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： HOmg / 수율 : 58%) .  Instead of using 00-2-amino-1-propane, the title compound was prepared by the same method as the <Example 1> except for using 3- (methylamino) -1-propanol. (Yield: HOmg / Yield: 58%).
¾ NMR (400, CDCls) ： 7.32 (2H, d)， 6.87 (2H, d)， 6.05 (1H, s), 4.18 (2H, m) , 3.95 ( 1H， m) , 3.82 (2H, m), 3.62 (2H, m) , 3.54 (2Η, m) . 3.12 (3Η, s) , 2.78 (3H, m) , 2.50 (3H, m), 2.32 (1H, m)， 1.95 (6H, m) , 1.78 (2H, m) , 1.52 (9H, s), 1.28 (2H, m) .  ¾ NMR (400, CDCls): 7.32 (2H, d), 6.87 (2H, d), 6.05 (1H, s), 4.18 (2H, m), 3.95 (1H, m), 3.82 (2H, m), 3.62 (2H, m), 3.54 (2Η, m). 3.12 (3Η, s), 2.78 (3H, m), 2.50 (3H, m), 2.32 (1H, m), 1.95 (6H, m), 1.78 (2H, m), 1.52 (9H, s), 1.28 (2H, m).
<실시예 7> tert-부틸 4-((4-(4- (모르폴린 -4-카보닐)싸이클로핵 스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트의 제조
Figure imgf000059_0001
Example 7 Preparation of tert-Butyl 4-((4- (4- (4- (morpholine-4-carbonyl) cyclonucleox-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000059_0001
(R)-2-아미노 -1-프로판올을 사용하는 대신에， 모르폴린을 사용 하는 것을 제외하고， 상기 <실시예 1>과 동일한 방법으로 수행하여 표 제 화합물을 제조하였다 (수득량 ： 200mg I 수율 ： 80%).  Instead of using (R) -2-amino-1-propanol, the title compound was prepared in the same manner as in <Example 1>, except that morpholine was used (amount: 200 mg I). Yield: 80%).
XH NMR (400, CDC13) ： 7.31 (2H, d) , 6.85 (2H, d)， 6.05 (1H, s) , 4.17 (2H, m) , 3.83 (2H, m) , 3.72 (4H, m) , 3.58 (4H, m)， 2.79 (3H, m) , 2.59 (3H, m) , 2.31 ( 1H， m) , 2.02 (3H, m) , 1.89 (2H, m) , 1.52 (9H, s) , 1.33 (2H, m) . XH NMR (400, CDC1 3 ): 7.31 (2H, d), 6.85 (2H, d), 6.05 (1H, s), 4.17 (2H, m), 3.83 (2H, m), 3.72 (4H, m) , 3.58 (4H, m), 2.79 (3H, m), 2.59 (3H, m), 2.31 (1H, m), 2.02 (3H, m), 1.89 (2H, m), 1.52 (9H, s), 1.33 (2 H, m).
<실시예 8> 4-(4-((l-(5—에틸피리미딘 -2-일)피페리딘 -4-일)메록 시 )폐닐) -N-((R)-1-히드록시프로판 -2-일 )싸이클로핵스 -3-엔카복스아마 이드 제조 Example 8 4- (4-((l- (5—ethylpyrimidin-2-yl) piperidin-4-yl) meroxy) pentyl) -N-((R) -1-hydroxy Propane-2-yl) cyclonux-3-encarboxamide preparation
Figure imgf000059_0002
Figure imgf000059_0002
질소 하에서，
Figure imgf000059_0003
플라스크에 4-(4-((1-(5-에틸피리미딘 -2- 일)피페리딘 -4-일)메록시 )페닐)싸이클로핵스 -3-엔카복실릭 엑시드Under nitrogen,
Figure imgf000059_0003
4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enecarboxylic acid in the flask
250mg 를 DMF 20^ 에 녹여 교반하였다. EDCI 140mg, HOBt HOmg 을 순차적으로 적가한 후 10분간 추가적으로 교반하였다 . (R)-2-아미노- 1-프로판올 0.1 을 적가한 후 상은에서 5시간 교반하였다. 반웅 종 결 후 증류수 50 μΐ 를 0°C에서 천천히 가하고 생성되는 고체를 여과 하여 건조하여 원하는 흰색 고체화합물을 얻었다 (수득량 ： 230mg I 수 율 ： 82%). 250 mg was dissolved in DMF 20 ^ and stirred. EDCI 140mg, HOBt HOmg were added dropwise sequentially followed by additional stirring for 10 minutes. 0.1 (R) -2-amino-1-propanol was added dropwise, followed by stirring for 5 hours at silver phase. After completion of reaction, 50 µl of distilled water was slowly added at 0 ° C., and the resulting solid was filtered and dried to obtain a desired white solid compound (yield: 230 mg I yield: 82%).
:H NMR (400， CDCls) ： 8.19 (2H, s), 7.31 (2H, d), 6.85 (2H, d) , 6.03 (1H, s) , 5.75 (1H, d) , 4.79 (2H, d) , 4.15 (1H, m)， 3.85 (2H, d) , 3.72 (1H, m) , 3.58 (1H, m)， 2.94 (2H, t), 2.82 (1H, m) , 2.48 (7H, m) , 2.14 (2H, m) , 1.88 (3H, m) , 1.38 (2H, m) , 1.23 (3H, t). : H NMR (400, CDCls): 8.19 (2H, s), 7.31 (2H, d), 6.85 (2H, d), 6.03 (1H, s), 5.75 (1H, d), 4.79 (2H, d) , 4.15 (1H, m), 3.85 (2H, d), 3.72 (1H, m), 3.58 (1H, m), 2.94 (2H, t), 2.82 (1H, m), 2.48 (7H, m), 2.14 (2H, m), 1.88 (3H, m), 1.38 (2H, m), 1.23 (3H, t).
<실시예 9> 4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메록 시)페닐) -N-(3-히드록시프로필)싸이클로핵스 -3-엔카복스아마이드의 제 조 ᅵ
Figure imgf000060_0001
Example 9 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) merok Phenyl) -N- (3-hydroxypropyl) cyclonux-3-encarboxamide
Figure imgf000060_0001
판올을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 220mg I 수율 ： 79%) .  A title compound was prepared in the same manner as in <Example 8> except that a panol was used (amount: 220 mg I yield: 79%).
lYi NMR (400, CDC13) ： 8.19 (2H, s) , 7.31 (2H, d) , 6.85 (2Η, d) , 6.05 (1H, s) , 5.95 (1H, t) , 4.75 (2H, d) , 3.85 (2H, d) , 3.68 (2H, m) , 3.48 (2H, m) , 3.14 (1H, m) , 2.94 (2H( m) , 2.42 (7H, m) , 2.12 (2H, m) , 1.98 (3H, m) , 1.72 (2H,m) , 1.38 (2H, m) , 1.21 (3H, t) . l Yi NMR (400, CDC1 3 ): 8.19 (2H, s), 7.31 (2H, d), 6.85 (2Η, d), 6.05 (1H, s), 5.95 (1H, t), 4.75 (2H, d) , 3.85 (2H, d), 3.68 (2H, m), 3.48 (2H, m), 3.14 (1H, m), 2.94 (2H ( m), 2.42 (7H, m), 2.12 (2H, m), 1.98 (3H, m), 1.72 (2H, m), 1.38 (2H, m), 1.21 (3H, t).
<실시예 10> tert-부틸 4-((6-(4-((R)-2,3-디히드록시프로필카 바모일)싸이클로핵스— 1-엔일)피리딘 -3-일옥시 )메틸)피페리딘 -1-카복시 레이트 Example 10 tert-Butyl 4-((6- (4-((R) -2,3-dihydroxypropylcarbamoyl) cyclonucleus— 1-enyl) pyridin-3-yloxy) methyl) Piperidine-1-carboxylate
Figure imgf000060_0002
Figure imgf000060_0002
4-(5-((l-(tert-부톡시카보닐)피페리딘ᅳ 4-일 )메록시 )피리딘 -2- 일)싸이클로핵스 -3-엔카복실릭 엑시드 200mg 를 DMF 25/ϋ 에 녹여 교 반하였다. EDCI 140mg, HOBt llOmg 을 순차적으로 적가한 후 10분간 추가적으로 교반하였다. (R)— 3-아미노 -1，2-프로판디을 을 적가 한 후 상온에서 3시간 교반하였다. 반웅 종결 후 증류수 50 를 0°C 에서 천천히 가하고 생성되는 고체를 여과하여 건조하여 원하는 흰색 고체화합물을 얻었다 (수득량 ： 160mg I 수율 ： 68%) .  200 mg of 4- (5-((l- (tert-butoxycarbonyl) piperidinyl 4-yl) methoxy) pyridin-2-yl) cyclonux-3-enecarboxylic acid in DMF 25 / dl Melted and stirred. EDCI 140mg, HOBt llOmg was added dropwise sequentially followed by additional stirring for 10 minutes. (R) — 3-amino-1,2-propanedi was added dropwise, followed by stirring at room temperature for 3 hours. After completion of reaction, distilled water 50 was slowly added at 0 ° C., and the resulting solid was filtered and dried to yield the desired white solid compound (yield: 160 mg I yield: 68%).
:H 匪 R (400， CDCls) ： 8.22 ( 1H， s) , 7.33 (1H, d) , 7.18 (1H, d) , 6.52 (1H, s) , 6.28 (1H, m) , 4.18 (2H, m) , 3.85 (2H, d) , 3.68 (1H, m) , 3.72 (3H, m) , 2.52 (4H, m) , 2.18 (1H, m) , 1.92 (4H, m) , 1.34 (9H, s)， 1.30 (2H, m) . <실시예 11> tert-부틸 4-((6-(4-((S)-l-히드록시프로판 -2-일카 바모일)싸이클로핵스 -1-엔일)피리딘 -3-일옥시 )메틸)피페리딘ᅳ 1-카복시 레이트 제조 : H 匪 R (400, CDCls): 8.22 (1H, s), 7.33 (1H, d), 7.18 (1H, d), 6.52 (1H, s), 6.28 (1H, m), 4.18 (2H, m ), 3.85 (2H, d), 3.68 (1H, m), 3.72 (3H, m), 2.52 (4H, m), 2.18 (1H, m), 1.92 (4H, m), 1.34 (9H, s) , 1.30 (2H, m). Example 11 tert-Butyl 4-((6- (4-((S) -l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-3-yloxy) methyl) Piperidine ᅳ 1-carboxylate preparation
Figure imgf000061_0001
Figure imgf000061_0001
(R)-3-아미노 -1，2-프로판디올을 사용하는 대신에 , (S)-2-아미노 -1-프로판올을 사용하는 것을 제외하고， 상기 <실시예 10>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 155mg I 수 율 ： 70%) · .  Instead of using (R) -3-amino-1,2-propanediol, except that (S) -2-amino-1-propanol is used, it is carried out in the same manner as in <Example 10> The title compound was prepared (yield 155 mg I yield: 70%).
XH NMR (400， CDCls) ： 8.24 ( 1H， s) , 7.33 (1H, d), 7.16 (1H( d), 6.54 (1H, s) , 5.78 (1H, m)， 4.18 (3H, m) , 3.87 (2H, d) , 3.64 (2H, m) , 2.72 (3H, m) ( 2.52 (4H, m) , 2.14 (1H, m) , 1.84 (4H m), 1.68 (1H, m) , 1.48 (9H, s), 1.31 (2H, m) , 1.20 (3H, d). X H NMR (400, CDCls): 8.24 (1H, s), 7.33 (1H, d), 7.16 (1H ( d), 6.54 (1H, s), 5.78 (1H, m), 4.18 (3H, m) , 3.87 (2H, d), 3.64 (2H, m), 2.72 (3H, m) ( 2.52 (4H, m), 2.14 (1H, m), 1.84 (4H m), 1.68 (1H, m), 1.48 (9H, s), 1.31 (2H, m), 1.20 (3H, d).
<실시예 12> N-((R)-2,3-디히드록시프로필) -4-(4-((l-(5-에틸피 리미딘 -2-일)피페리딘 -4-일)메록시 )페닐)싸이클로핵스 -3-엔카복스아마 이드의 제조 Example 12 N-((R) -2,3-dihydroxypropyl) -4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl Preparation of (methoxy) phenyl) cyclonux-3-encarboxamide
Figure imgf000061_0002
Figure imgf000061_0002
(R)-2-아미노 -1-프로판을을 사용하는 대신에， (R)-3-아미노- 1,2-프로판디올 을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일 한 방법으로 수행하껴 표제 화합물을 제조하였다 (수득량 ： 200mg / 수 율 ： 85%) .  In the same manner as in <Example 8>, except that (R) -3-amino-1, 1,2-propanediol is used instead of (R) -2-amino-1-propane. The title compound was prepared (yield: 200 mg / yield: 85%).
XH 丽 R (400, DMSO-de) ： 8.23 (2H, s) , 7.81 (1H, m) , 7.33 (2Η d) , 6.86 (2H, d) , 6.05 (1H, s) , 4.73 ( 1H , m) , 4.67 (2H, d) , 4.49 (1H, t) , 3.85 (2H, d) , 3.32 (4H, m) , 2.88 (2H, t) , 2.42 (7H, m) , 1.98 (5H, m) , 1.62 (2H, m) , 1.18 (4H, m) . X H δ R (400, DMSO-de): 8.23 (2H, s), 7.81 (1H, m), 7.33 (2Η d), 6.86 (2H, d), 6.05 (1H, s), 4.73 (1H, m), 4.67 (2H, d), 4.49 (1H, t), 3.85 (2H, d), 3.32 (4H, m), 2.88 (2H, t), 2.42 (7H, m), 1.98 (5H, m ), 1.62 (2H, m), 1.18 (4H, m).
<실시예 13> (4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메 톡시 )페닐)싸이클로핵스 -3-엔일) (모폴리노)메타논의 Example 13 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) meth Methoxy) phenyl) cyclonux-3-enyl) (morpholino) methanone
Figure imgf000062_0001
Figure imgf000062_0001
(R)-2-아미노 -1-프로판을을 사용하는 대신에 , 모르폴린을 사용 하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법으로 수행하여 표 제 화합물을 제조하였다 (수득량 ： 175mg I 수율 ： 65%).  Instead of using (R) -2-amino-1-propane, a title compound was prepared in the same manner as in <Example 8>, except that morpholine was used (amount: 175 mg). I yield: 65%).
!H NMR (400, CDCls) ： 8.19 (2H, s) , 7.33 (2H, d)， 6.87 (2H, d), 6.06 (1H, s), 4.80 (2H, d)， 3.85 (2H, d) , 3.72 (6H, d) , 3.58 (2H, m) , 2.96 (2H, t) , 2.78 (1H, m) , 2.52 (7H, m) , 2.28 (1H, m) , 1.98 (5H, m) , 1.38 (2H, m) , 1.21 (3H, t) . ! H NMR (400, CDCls): 8.19 (2H, s), 7.33 (2H, d), 6.87 (2H, d), 6.06 (1H, s), 4.80 (2H, d), 3.85 (2H, d), 3.72 (6H, d), 3.58 (2H, m), 2.96 (2H, t), 2.78 (1H, m), 2.52 (7H, m), 2.28 (1H, m), 1.98 (5H, m), 1.38 (2H, m), 1.21 (3H, t).
<실시예 14> tert-부틸 4-((6-(4-(1，3-디히드록시프로판 -2-일카 바모일 )싸이클로핵스 -1-엔일)피리딘 -3-일옥시 )메틸)피페리딘 -1-카복사 레이트 제조 Example 14 tert-Butyl 4-((6- (4- (1,3-dihydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-3-yloxy) methyl) pi Ferridine-1-carboxate Preparation
Figure imgf000062_0002
Figure imgf000062_0002
(R)-3-아미노 -1,2-프로판디올올 사용하는 대신에 ， 2-아미노- Instead of using (R) -3-amino-1,2-propanediolol, 2-amino-
1.3-프로판디올을 사용하는 것을 제외하고， 상가 <실시예 10〉과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 195mg / 수 율 ： 85%). Except for using 1.3-propanediol, the title compound was prepared in the same manner as in <Example 10> (yield: 195 mg / yield: 85%).
XH NMR (400， CDCI3) ： 8.22 (1H, s) , 7.32 (1H, d)， 7.16 (1H, d) , 6.49 (2H, m) , 4.17 (2H, m)， 4.03 (1H, m) , 3.89 (6H, m) , 2.76 (3H, m) , 2.52 (4H, m) , 2.15 (1H, m) , 1.99 (3H, m), 1.84 (2H, m), 1.67 (1H, m) , 1.48 (9H, s) , 1.34 (2H, m) . X H NMR (400, CDCI3): 8.22 (1H, s), 7.32 (1H, d), 7.16 (1H, d), 6.49 (2H, m), 4.17 (2H, m), 4.03 (1H, m) , 3.89 (6H, m), 2.76 (3H, m), 2.52 (4H, m), 2.15 (1H, m), 1.99 (3H, m), 1.84 (2H, m), 1.67 (1H, m), 1.48 (9 H, s), 1.34 (2 H, m).
<실시예 15> N-(l,3-디히드록시프로판 -2-일 ) -4-(4-((l-(5-에틸 피리미딘 -2-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카복스아 마이드의 제조 Example 15 N- (l, 3-dihydroxypropan-2-yl) -4- (4-((l- (5-ethyl pyrimidin-2-yl) piperidin-4-yl) Preparation of methoxy) phenyl) cyclonux-3-enecarboxamide
(R)-2-아미노 -1-프로판올을 사용하는 대신에， 2-아미노 -1.3-프 로판디올을 사용하는 것을 제외하고， 상기 <실사예 8>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 165mg I 수율 ： 72%) . The title compound was prepared in the same manner as in <Example 8>, except that 2-amino-1.3-propanediol was used instead of (R) -2-amino-1-propanol. (Yield: 165 mg I yield: 72%).
!H NMR (400, DMS0-d6) ： 8.22 (2H, s) , 7.50 (1H, d)， 7.33 (2H d), 6.88 (2H, d) , 4.63 (4H, m) , 3.84 (2H, d) , 3.73 (1H, m) , 2.86 (2H, t), 2.43 (2H, m) , 2.36 (2H, m) , 1.98 (5H, m) , 1.21 (7H, m) , 1.98 (5H, m) . ! H NMR (400, DMS0- d6 ): 8.22 (2H, s), 7.50 (1H, d), 7.33 (2H d), 6.88 (2H, d), 4.63 (4H, m), 3.84 (2H, d) , 3.73 (1H, m), 2.86 (2H, t), 2.43 (2H, m), 2.36 (2H, m), 1.98 (5H, m), 1.21 (7H, m), 1.98 (5H, m).
<실시예 16> (4-(4-((l-(5-에될피리미딘 -2-일 )피페리딘 -4-일 )메 톡시 )페닐)싸이클로핵스 -3-엔일) ((R)-3-히드록시피를리딘 -1-일)메타논 의 제조 Example 16 (4- (4-((l- (5-Elyylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((R Preparation of) -3-hydroxypyridin-1-yl) methanone
Figure imgf000063_0001
Figure imgf000063_0001
(R)-2-아미노 1-프로판올을 사용하는 대신에， (R)-( + )-3-피를리 디놀을 사용하는 것을 제외하고， 상기 <실시예 8〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 165mg / 수율 : 72%).  Instead of using (R) -2-amino 1-propanol, the procedure was carried out in the same manner as in <Example 8>, except that (R)-(+)-3-pyridinol was used. Compounds were prepared (yield: 165 mg / yield: 72%).
¾ 匪 R (400, CDCls) ： 8.19 (2H, s), 7.33 (2H, d) , 6.87 (2Ή, d) , 6.07 (1Η, s) , 4.80 (2H, d) , 4.55 (1H, d), 3.85 (2H, d) , 4.55 (5H, m) , 2.93 (2H, t) , 2.48 (8H, m)， 2.05 (7H, m) , 1.61 (2H, m)， 1.38 (2H, m) , 1.18 (3H, m) .  ¾ 匪 R (400, CDCls): 8.19 (2H, s), 7.33 (2H, d), 6.87 (2Ή, d), 6.07 (1Η, s), 4.80 (2H, d), 4.55 (1H, d) , 3.85 (2H, d), 4.55 (5H, m), 2.93 (2H, t), 2.48 (8H, m), 2.05 (7H, m), 1.61 (2H, m), 1.38 (2H, m), 1.18 (3 H, m).
<실시예 17> N-((R)-2,3-디히드록시프로필) -4-(4-((l-(3-이소프 로필 -1,2, 4-옥사디아졸 -5-일)피페리딘 -4-일 )메록시 )페닐)싸이클로핵스Example 17 N-((R) -2,3-dihydroxypropyl) -4- (4-((l- (3-isopropyl-1-, 2,4-oxadiazole-5-yl) ) Piperidin-4-yl) methoxy) phenyl) cyclonucleus
-3-엔카복스아마이드의 제조
Figure imgf000064_0001
Preparation of 3-encarboxamide
Figure imgf000064_0001
4-(4-((l-(3-이소프로필 -1,2, 4-옥사디아졸 -5-일)피페리딘 -4-일 ) 메특시.)페닐)싸이클로핵스 -3-엔카복실릭 액시드 200mg 를 DMF 25≠ 에 녹여 교반하였다. EDCI 140mg, HOBt HOmg 을 순차적으로 적가한 후 10분간 추가적으로 교반하였다. (R)-3-아미노 -1,2-프로판디올  4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) mesooxy.) Phenyl) cyclonux-3-enecarboxyl Rick acid 200 mg was dissolved in DMF 25 ≠ and stirred. EDCI 140mg, HOBt HOmg was added dropwise sequentially and further stirred for 10 minutes. (R) -3-amino-1,2-propanediol
을 적가한 후 상온에서 3시간 교반하였다. 반웅 종결 후 증류수 50 βί 를 0°C에서 천천히 가하고 생성되는 고체를 며과하여 건조하여 원하는 흰색 고체화합물을 얻었다 (수득량 ： I87mg I 수율 ： 83%). Was added dropwise and stirred at room temperature for 3 hours. After completion of reaction, 50 βί of distilled water was slowly added at 0 ° C., and the resulting solid was filtered and dried to obtain the desired white solid compound (yield: I87 mg I yield: 83%).
JH 丽 R (400, CDCls) ： 7.32 (2H, d) , 6.86 (2H, d) , 6.15 (1Η, t) , 6.03 (1H, s) , 4.23 (2H, d) , 3.85 (2H, d) , 3.80 (1H, m) , 3.58 (2H, m) , 3.48 (2H, m) , 3.14 (4H, m) , 2.92 (1H, m) , 2.49 (5H, m) , 2.09 (2H, m) , 1.94 (3H, m), 1.43 (2H, m)， 1.30 (6H, d) . J H δ R (400, CDCls): 7.32 (2H, d), 6.86 (2H, d), 6.15 (1Η, t), 6.03 (1H, s), 4.23 (2H, d), 3.85 (2H, d ), 3.80 (1H, m), 3.58 (2H, m), 3.48 (2H, m), 3.14 (4H, m), 2.92 (1H, m), 2.49 (5H, m), 2.09 (2H, m) , 1.94 (3H, m), 1.43 (2H, m), 1.30 (6H, d).
<실시예 18> N-((S)-2,3-디히드록시프로필) -4-(4-((l-(3-이소프 로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )페닐)싸이클로핵스Example 18 N-((S) -2,3-dihydroxypropyl) -4- (4-((l- (3-isopropyl-1-, 2,4-oxadiazole-5-yl) ) Piperidin-4-yl) methoxy) phenyl) cyclonucleus
-3-엔카복스아마이드의 제조 Preparation of 3-encarboxamide
Figure imgf000064_0002
Figure imgf000064_0002
(R)-3—아미노 -1,2-프로판디올을 사용하는 대신에， (S)— 3-아미노 -1,2-프로판디을을 사용하는 것을 제외하고， 상기 <실시예 17〉과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 155mg / 수 율 ： 70%) .  Instead of using (R) -3—amino-1,2-propanediol, the same as in <Example 17>, except that (S) — 3-amino-1,2-propanedi is used. The title compound was prepared by the method (yield: 155 mg / yield: 70%).
¾ 匪 R (400， CDCls) ： 7.32 (2H, d) , 6.83 (2H, d) , 6.21 (1Η, t) , 6.03 (1H, s) , 4.20 (2H, d) , 3.85 (2H, d) , 3.80 (1H, m) , 3.58 (2H, m) , 3.48 (2H, m)ᅳ 3.14 (4H, m) , 2.92 (1H, m)， 2.49 (5H, m)， 2.09 (2H, m) , 1.94 (3H, m), 1.43 (2H, m) , 1.30 (6H, d) . <실시예 19> N— ((S)-l-히드록시프로판 -2-일 ) -4-(4-((l-(3-이소 프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )페닐 )싸이클로핵 스 -3- ¾ 匪 R (400, CDCls): 7.32 (2H, d), 6.83 (2H, d), 6.21 (1Η, t), 6.03 (1H, s), 4.20 (2H, d), 3.85 (2H, d) , 3.80 (1H, m), 3.58 (2H, m), 3.48 (2H, m) ᅳ 3.14 (4H, m), 2.92 (1H, m), 2.49 (5H, m), 2.09 (2H, m), 1.94 (3H, m), 1.43 (2H, m), 1.30 (6H, d). Example 19 N — ((S) -l-hydroxypropan-2-yl) -4- (4-((l- (3-isopropyl-1,2,4-oxadiazole-5- 1) piperidin-4-yl) methoxy) phenyl) cyclonucleox-3-
Figure imgf000065_0001
Figure imgf000065_0001
(R)— 3-아미노 -1,2-프로판디올을 사용하는 대신에， (S)-2-아미노 -1-프로판을 을을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 130mg I 수 율 ： 62%).  (R) — The same method as in Example 17, except that instead of using 3-amino-1,2-propanediol, (S) -2-amino-1-propane is used. To give the title compound (yield: 130 mg I yield: 62%).
¾ 醒 R (400， CDCls) ： 7.33 (2H, d) , 6.84 (2H, d) , 6.04 (1Η, s) , 5.74 (1H, s) , 4.23 (2H, d), 4.14 (1H, s) , 3.84 (2H, d) , 3.73 (1H, m) , 3.69 (1H, m) , 3.14 (2H, m) , 2.91 (1H, m) , 2.53 (5H, m) , 2.08 (3H, m) , 1.94 (3H, m) , 1.47 (2H, m) , 1.30 (6H, d) , 1.20 (3H, m).  ¾ 醒 R (400, CDCls): 7.33 (2H, d), 6.84 (2H, d), 6.04 (1Η, s), 5.74 (1H, s), 4.23 (2H, d), 4.14 (1H, s) , 3.84 (2H, d), 3.73 (1H, m), 3.69 (1H, m), 3.14 (2H, m), 2.91 (1H, m), 2.53 (5H, m), 2.08 (3H, m), 1.94 (3H, m), 1.47 (2H, m), 1.30 (6H, d), 1.20 (3H, m).
<실시예 20> N-((R)-1-히드록시프로판 -2-일 ) -4-(4-((l-(3-이소 프로필 -1，2,4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵 스 -3- Example 20 N-((R) -1-hydroxypropan-2-yl) -4- (4-((l- (3-isopropyl-1,2,4-oxadiazole-5- 1) piperidin-4-yl) methoxy) phenyl) cyclonucleose-3-
Figure imgf000065_0002
Figure imgf000065_0002
00-3-아미노 -1,2-프로판디올을 사용하는 대신에 , (R)-2-아미노 -1-프로판올 을 사용하는 것을 제외하고， 상가 <실시예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 150mg I 수 율 ： 71%).  The title compound was carried out in the same manner as in <Example 17>, except that (R) -2-amino-1-propanol was used instead of 00-3-amino-1,2-propanediol. Was prepared (yield: 150 mg I yield: 71%).
ln NMR (400, CDCla) ： 7.33 (2H, d) , 6.84 (2H, d)， 6.04 (1H, s), 5.74 (1H, s), 4.23 (2H, d) , 4.14 ( 1Η , s), 3.84 (2H, d) , 3.73 (1H, m) , 3.69 (IE, m) , 3.14 (2H, m) , 2.91 (1H, m) , 2.53 (5H, m) , 2.08 (3H, m), 1.94 (3H, m) , 1.47 (2H, m), 1.30 (6H, d) , 1.20 (3Ή, m). ln NMR (400, CDCla): 7.33 (2H, d), 6.84 (2H, d), 6.04 (1H, s), 5.74 (1H, s), 4.23 (2H, d), 4.14 (1Η, s), 3.84 (2H, d), 3.73 (1H, m), 3.69 (IE, m), 3.14 (2H, m), 2.91 (1H, m), 2.53 (5H, m), 2.08 (3H, m), 1.94 (3H, m), 1.47 ( 2H, m), 1.30 (6H, d), 1.20 (3 Hz, m).
<실시예 21> 4ᅳ(4-((1-(5-에탈피리미딘 -2-일 )피페리딘 -4-일 )메 톡시 )페닐) -N-(2-히드록시에틸) -N-메틸싸이클로핵스 -3-엔카복스아마이 드의 제조 Example 21 4 ′ (4-((1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (2-hydroxyethyl)- Preparation of N-Methylcyclonux-3-Encarboxamide
Figure imgf000066_0001
Figure imgf000066_0001
(R)-2-아미노 -1—프로판을을 사용하는 대신에 , 2- (메틸아미노)에 탄을을 사용하는 것을 제외하고， 상기 <실시예 8〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 187mg I 수율 ： 81%) .  Preparation of the title compound in the same manner as in <Example 8>, except that instead of using (R) -2-amino-1—propane, carbon was used in 2- (methylamino). (Yield: 187 mg I yield: 81%).
^ NMR (400， CDCls) ： 8.19 (2H, s) , 7.34 (2H, d) , 6.87 (2Η, d), 6.07 (1H, s) , 4.80 (2H, d) , 3.85 (4H, m) , -3.63 (2H, m), 3.18 (3H, s) , 2.96 (2H, t) , 2.89 (1H, m), 2.48 (5H, m) , 2.06 (5H, m) , 1.38 (2H, m) , 1.21 (3H, m) .  ^ NMR (400, CDCls): 8.19 (2H, s), 7.34 (2H, d), 6.87 (2Η, d), 6.07 (1H, s), 4.80 (2H, d), 3.85 (4H, m), -3.63 (2H, m), 3.18 (3H, s), 2.96 (2H, t), 2.89 (1H, m), 2.48 (5H, m), 2.06 (5H, m), 1.38 (2H, m), 1.21 (3 H, m).
<실시예 22> N-(3-히드록시 -2，2-디메틸프로필 )-4-(4-((1-(3-이 소프로필 -1,2，4-옥사디아졸 -5-일 )피페리딘 -4-일)메록시 )페닐 )싸이클로 핵스 -3-엔카복스아마이드의 제 : Example 22 N- (3-hydroxy-2,2-dimethylpropyl) -4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl )) Piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide
Figure imgf000066_0002
Figure imgf000066_0002
(R)-3-아미노 -1,2-프로판디올을 사용하는 대신에， 3-아미노- 2，2-디메틸프로판 -1-올을 사용하는 것을 제외하고， 상기 <실시예 17> 과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 195mg / 수율 : 89%).  The same method as in <Example 17>, except that instead of using (R) -3-amino-1,2-propanediol, 3-amino-2,2-dimethylpropan-1-ol is used. The title compound was prepared by the yield (yield: 195 mg / yield: 89%).
lH 丽 R (400, MeOD) ： 7.65 (1H, s) , 7.31 (2H, d) , 6.85 (2Η, d) , 6.02 (1H, s), 4.18 (2H, d)， 3.87 (2H, d)， 3.15 (6H, m)， 2.86 (1H, m) , 2.46 (5H, m) , 2.04 (5H, m), 1.48 (2H, m) , 1.28 (6H, d)， 0.89. (6H, s) . lH R R (400, MeOD): 7.65 (1H, s), 7.31 (2H, d), 6.85 (2Η, d), 6.02 (1H, s), 4.18 (2H, d) ， 3.87 (2H, d) , 3.15 (6H, m), 2.86 (1H, m), 2.46 (5H, m), 2.04 (5H, m), 1.48 (2H, m), 1.28 (6H, d) ， 0.89. (6H, s).
<실시예 23> N-(l,3-디히드록시프로판 -2-일) -4-(4-((l-(3-이소 프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵 스 -3-엔카복스아마이드의 제조 Example 23 N- (l, 3-dihydroxypropan-2-yl) -4- (4-((l- (3-isopropyl-1,2,4-oxadiazole-5-yl Preparation of) Piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide
Figure imgf000067_0001
Figure imgf000067_0001
(R)-3-아미노 -1，2-프로판디올을 사용하는 대신에 : 2—아미노-Instead of using (R) -3-amino-1,2-propanediol : 2—amino-
1.3-프로판디올을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 175mg I 수 율 ： 79%). The title compound was prepared in the same manner as in <Example 17>, except that 1.3-propanediol was used (a yield 175 mg I yield: 79%).
XH 匪 R (400 MeOD) ： 7.27 (3H, d)， 6.85 (2H, d) , 6 (ΊΗ, s), 4.18 (2H, d) , 3.87 (6H, d), 3.18 (3H, m) , 2.86 (1Η, 2.46 (5H, m) , 2.04 (5Η m) , 1.48 (2H, m)， 1.28 (6H, d) . X H 匪 R (400 MeOD): 7.27 (3H, d), 6.85 (2H, d), 6 (ΊΗ, s), 4.18 (2H, d), 3.87 (6H, d), 3.18 (3H, m) , 2.86 (1Η, 2.46 (5H, m), 2.04 (5Η m), 1.48 (2H, m), 1.28 (6H, d).
<실시예 24> tert-부틸 4-((5-(4-((S)-l-히드록시프로판 -2-일카 바모일 )싸이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시 레이트의 제조 Example 24 tert-Butyl 4-((5- (4-((S) -l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) Preparation of Piperidine-1-carboxylate
Figure imgf000067_0002
Figure imgf000067_0002
4-(6—( (1-( tert 부톡시카보닐)피페리딘 -4-일 )메록시 )피리딘 -3- 이  4- (6— ((1- (tert butoxycarbonyl) piperidin-4-yl) methoxy) pyridine-3-i
Ξ )싸이클로핵스 -3-엔카복실릭 엑시드 300mg 를 DMF 25/ί, 에 녹여 교 반하였다. EDCI 210mg, HOBt 165mg 을 순차적으로 적가한 후 10분간 추가적으로 교반하였다. (S)-2-아미노 -1—프로판올 120mg 을 적가한 후 상은에서 5시간 교반하였다. 반웅 종결 후 증류수 50 를 0°C에서 천천히 가하고 생성되는 고체를 여과하여 건조하여 원하는 흰색 고체 화합물을 얻었다 (수득량 ： 235mg I 수을 ： 84%). 300 mg of cyclonux-3-encarboxylic acid was dissolved in DMF 25 / ί and stirred. EDCI 210mg, HOBt 165mg was added dropwise sequentially followed by additional stirring for 10 minutes. 120 mg of (S) -2-amino-1-propanol was added dropwise, followed by stirring for 5 hours at phase silver. After completion of reaction, distilled water 50 was slowly added at 0 ° C., and the resulting solid was filtered and dried to obtain the desired white solid compound (amount: 235 mg I water: 84%).
^ NMR (40으 CDC13) ： 8.14 (1H, s) , 7.62 (1H, d) , 6.70 (1Η, d) , 6.04 (1H, s) , 5.76. (1H, d) 4.16 (5H, m)， 4.15 (2H, m) , 2.79 (3H, m) , 2.50 (5H, m) , 2.13 (1H, m) , 1.98 (5H, m) , 1.48 (9H, s) , 1.30 (2H, m) , 1.20 (3H, d) . ^ NMR (40 CDC1 3 ): 8.14 (1H, s), 7.62 (1H, d), 6.70 (1Η, d), 6.04 (1 H, s), 5.76. (1H, d) 4.16 (5H, m), 4.15 (2H, m), 2.79 (3H, m), 2.50 (5H, m), 2.13 (1H, m), 1.98 (5H, m), 1.48 (9H , s), 1.30 (2H, m), 1.20 (3H, d).
<실시예 25> tert-부틸 4-((5-(4-((R)-l-히드록시프로판 -2-일카 바모일)싸이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시 레이트 제조 Example 25 tert-Butyl 4-((5- (4-((R) -l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) Piperidine-1-carboxylate Preparation
Figure imgf000068_0001
Figure imgf000068_0001
(S)-2-아미노 -1-프로판올을 사용하는 대신에， (R)-2-아미노 -1- 프로판을을 사용하는 것을 제외하고， 상기 <실시예 24>와 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： Orng I 수율 ： 62%) .  Instead of using (S) -2-amino-1-propanol, the title compound was carried out in the same manner as in <Example 24>, except that (R) -2-amino-1-propane was used. Was prepared (yield: Orng I yield: 62%).
!H NMR (400， CDCls) ： 8.14 (1H, s), 7.62 (1H, d) , 6.70 (1Η, d) , 6.04 (1H, s) , 5.76 (1H, d) 4.16 (5H, m), 4.15 (2H, m), 2.79 (3H, m) , 2.50 (5H, m) , 2.13 ( 1H ' m) , 1.98 (5H, m)， 1.48 (9H, s) , 1.30 (2H, m) , 1.20 (3H, d) . ! H NMR (400, CDCls): 8.14 (1H, s), 7.62 (1H, d), 6.70 (1Η, d), 6.04 (1H, s), 5.76 (1H, d) 4.16 (5H, m), 4.15 (2H, m), 2.79 (3H, m), 2.50 (5H, m), 2.13 (1H 'm), 1.98 (5H, m), 1.48 (9H, s), 1.30 (2H, m), 1.20 ( 3H, d).
<실시예 26> tert-부틸 4-((5-(4-((S)-2-히드록시프로필카바모 일)싸이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이 트의 제조 Example 26 tert-Butyl 4-((5- (4-((S) -2-hydroxypropylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine Production of -1-carboxylate
Figure imgf000068_0002
Figure imgf000068_0002
(S)-2-아미노— 1-프로판을을 사용하는 대신에， (S)-l-아미노 -2- 프로판올을 사용하는 것을 제외하고， 상기 <실시예 24>와 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 155mg I 수율 ： 67%) .  (S) -2-amino—Instead of using 1-propane, the title compound was carried out in the same manner as in <Example 24>, except that (S) -l-amino-2-propanol was used. Was prepared (yield: 155 mg I yield: 67%).
^ 匪 R (400, CDCls) ： 8.14 (1H, s) , 7.61 ( 1H， d) , 6.70 (1H, d) , 6.05 (2Η, s), 4.16 (4H, m) , 3.97 (1H, m) , 3.35 (2H, m)， 2.79 (2H, m) , 2.51 (6H, m)， 2.14 (1H, m) , 1.98 (4H, m)， 1.48 (9H, s) , 1.30 (2H, m) , 1.21 (3H, d) ^ 匪 R (400, CDCls): 8.14 (1H, s), 7.61 (1H, d), 6.70 (1H, d), 6.05 (2Η, s), 4.16 (4H, m), 3.97 (1H, m) , 3.35 (2H, m), 2.79 (2H, m), 2.51 (6H, m), 2.14 (1H, m), 1.98 (4H, m), 1.48 (9H, s), 1.30 (2H, m), 1.21 (3H, d)
<실시예 27> tert-부틸 4-((5-(4-((R)-2-히드록시프로필카바모 일 )싸이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이 트의 제조 Example 27 tert-Butyl 4-((5- (4-((R) -2-hydroxypropylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine Production of -1-carboxylate
Figure imgf000069_0001
Figure imgf000069_0001
(S)-2-아미노 -1ᅳ프로판올을 사용하는 대신에， (R)— 1-아미노 -2- 프로판올을 사용하는 ᅵ것을 제외하고， 상기 <실시예 24>와 동일한 방법 으로 수행하여 표제 화합물올 제조하였다 (수득량 ： 150mg / 수율 ： 65%) . Instead of using (S) -2-amino- 1′propanol , the title compound was carried out in the same manner as in <Example 24>, except that (R) — 1-amino-2-propanol was used. It was prepared (yield: 150 mg / yield: 65%).
LH 匪 R (400, CDCls) ： 8.14 (1H, s) , 7.61 (1H, d) , 6.70 ( 1Η , d) , 6.05 (2H, s) , 4.16 (4H, m) , 3.97 (1H, m)， 3.35 (2H, m) , 2.79 (2H, m) , 2.51 (6H, m) , 2.14 (1H, m) , 1.98 (4H, m) , 1.48 (9H, s), 1.30 (2H, ra) , 1.21 (3H, d) . L H 匪 R (400, CDCls): 8.14 (1H, s), 7.61 (1H, d), 6.70 (1Η, d), 6.05 (2H, s), 4.16 (4H, m), 3.97 (1H, m ), 3.35 (2H, m), 2.79 (2H, m), 2.51 (6H, m), 2.14 (1H, m), 1.98 (4H, m), 1.48 (9H, s), 1.30 (2H, ra) , 1.21 (3H, d).
<실시예 28> N-((R)-2-히드록시프로필) -4-(4-((l-(3-이소프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3- 엔카복스아마이드의 제조 Example 28 N-((R) -2-hydroxypropyl) -4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperi Preparation of din-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide
Figure imgf000069_0002
Figure imgf000069_0002
(R)-3-아미노ᅳ 1,2-프로판디을을 사용하는 대신에， (R)— 1-아미노 -2-프로판을을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： lOOmg I 수 율 ： 43%) .  Instead of using (R) -3-amino ᅳ 1,2-propanedi, it is carried out in the same manner as in <Example 17>, except that (R) — 1-amino-2-propane is used. The title compound was obtained (yield: 100 mg I yield: 43%).
¾ 匪 R (400， CDCls) ： 7.53 (2H, d) , 6.86 (2H, d), 6.04 (2H, s), 4.23 (1H, m) , 3.90 (2H, d)， 3.50 ( 1H , m) , 3.17 (3H, m) , 2.91 (1H, m) , 2.14 (2H, m) , 1.94 (3H, m) , 1.50 (2H, m) , 1.32 (6H, d) , 1.21 (3Η' d) ¾ 匪 R (400, CDCls): 7.53 (2H, d), 6.86 (2H, d), 6.04 (2H, s), 4.23 (1H, m), 3.90 (2H, d), 3.50 (1H, m) , 3.17 (3H, m), 2.91 (1H, m), 2.14 (2H, m), 1.94 (3H, m), 1.50 (2H, m), 1.32 (6H, d), 1.21 (3Η 'd)
<실시예 29> N-((S)-2-히드록시프로필) -4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3- 엔카복스아마이드의 제조 Example 29 N-((S) -2-hydroxypropyl) -4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperi Preparation of din-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide
Figure imgf000070_0001
Figure imgf000070_0001
(R)-3-아미노 -1， 2-프로판디올을 사용하는 대신에， (S)-l-아미노 -2-프로판을을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 3mg I 수 율 ： 62%).  (R) -3-amino-1, 2-propanediol, instead of using (S) -l-amino-2-propane, was carried out in the same manner as in Example 17 above To give the title compound (amount: 3 mg I yield: 62%).
JH NMR (400, CDCI3) ： 7.53 (2H, d)， 6.86 (2H, d) , 6.04 (2H, s), 4.23 (1H, m), 3.90 (2H, d) , 3.50 (1H, m)， 3.17 (3H, m) , 2.91 (1H, m) , 2.14 (2Η, m) , 1.94 (3H, m) , 1.50 (2H, m) , 1.32 (6H, d) , 1.21 (3H, d). J H NMR (400, CDCI3): 7.53 (2H, d), 6.86 (2H, d), 6.04 (2H, s), 4.23 (1H, m), 3.90 (2H, d), 3.50 (1H, m) , 3.17 (3H, m), 2.91 (1H, m), 2.14 (2Η, m), 1.94 (3H, m), 1.50 (2H, m), 1.32 (6H, d), 1.21 (3H, d).
<실시예 30> 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메 톡시 )페닐) -N-((R)-2-히드록시프로필 )싸이클로핵스 -3-엔카복스아마이 드의 제조 Example 30 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N-((R) -2-hydroxy Propyl) Production of Cyclonucles-3-Encarboxamide
Figure imgf000070_0002
Figure imgf000070_0002
(R)-2-아미노 -1-프로판올을 사용하는 대신에 , (R)-l-아미노 -2- 프로판올을 사용하는. 것을 제외하고， 상기 <실시예 8>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 180mg I 수율 ： 79%) . Instead of using (R) -2-amino-1-propanol, use (R) -l-amino-2-propanol . A title compound was prepared in the same manner as in <Example 8>, except that the yield: 180 mg I yield: 79%.
¾ NMR (400, CDCI3) ： 8.19 (2H, s) , 7.32 (2H, d) , 6.87 (2H, d) , 6.04 (2H, s), 4.80 (2H, d), 3.96 (1H, m) , 3.85 (2H, d) , 3.52 (1H, m) , 3.20 (1Η m), 2.92 (2H, t) , 2.53 (8H, m) , 2.13 (2H, m) , 1.96 (3H, m) , 1.38 (2H, m) , 1.28 (6H, m) . ¾ NMR (400, CDCI3): 8.19 (2H, s), 7.32 (2H, d), 6.87 (2H, d), 6.04 (2H, s), 4.80 (2H, d), 3.96 (1H, m), 3.85 (2H, d), 3.52 (1H, m), 3.20 (1Η m), 2.92 (2H, t), 2.53 (8H, m), 2.13 (2H, m), 1.96 (3H, m), 1.38 (2H, m), 1.28 (6H, m).
<실시예 31> N-(2-히드록시에틸 )-4-(4-((l-(3-이소프로필- 1,2,4-옥사디아졸 -5ᅳ일 )피페리딘 -4-일)메록시 )페닐 )싸아클로핵스 -3-엔 카복스아마이드의 제조 Example 31 N- (2-hydroxyethyl) -4- (4-((l- (3-isopropyl-1, 1,2,4-oxadiazole-5xyl) piperidin-4-yl Preparation of (methoxy) phenyl) cycloclox-3-enecarboxamide
Figure imgf000071_0001
Figure imgf000071_0001
00-3-아미노 -1,2-프로판다을을 사용하는 대신에 , 2-아미노에탄 올을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 22Omg I 수율 ： 94%).  The title compound was prepared in the same manner as in <Example 17>, except that 2-aminoethanol was used instead of 00-3-amino-1,2-propane. : 22 mg I yield: 94%).
LH 丽 R (400, CDCls) ： 7.33 (2H, d) , 6.86 (2H, d)， 6.07 (2H, m) , 4.23 (2Η, m) , 3.86 (2H, d) , 3.79 (1H, m) ,3.51 (1H, m) , 3.15 (2H, m), 2.95 (1H, m) , 2.51 (1H, m) , 2.46 (4H, m) , 2.06 (5H, m) , 1.50 (2H, m) , 1.30 (6H, d) . L H δ R (400, CDCls): 7.33 (2H, d), 6.86 (2H, d), 6.07 (2H, m), 4.23 (2Η, m), 3.86 (2H, d), 3.79 (1H, m ), 3.51 (1H, m), 3.15 (2H, m), 2.95 (1H, m), 2.51 (1H, m), 2.46 (4H, m), 2.06 (5H, m), 1.50 (2H, m) , 1.30 (6H, d).
<실시예 32> tert-부틸 4-((5-(4-((R)-2,3-디히드록시프로필카 바모일)싸이클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시 레이트의 제조 Example 32 tert-Butyl 4-((5- (4-((R) -2,3-dihydroxypropylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) Preparation of Piperidine-1-carboxylate
Figure imgf000071_0002
Figure imgf000071_0002
(S)-2-아미노 -1-프로판올을 사용하는 대신에， (R)-3-아미노— 1,2-프로판디올을 사용하는 것을 제외하고, 상기 <실시예 24〉와 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 176mg I 수 율 ： 80%).  Instead of using (S) -2-amino-1-propanol, it is carried out in the same manner as in <Example 24>, except that (R) -3-amino— 1,2-propanediol is used. To give the title compound (amount: 176 mg I yield: 80%).
JH 匪 R (400, CDCls) ： 8.14 (1H, s) , 7.62 (1H, d)， 6.71 (1H, d) , 6.06 (2Η, m) , 5.32 (5H, m) , 3.80 ( 1H , m) , 3.58 (2H, m) , 3.46 (2H, m) , 2.93 (1H, m) , 2.78 (2H, m) , 2.50 (5H, m) , 1.98 (5H, s), 1.49 (9H, m) , 1.27 (2H, m) . <실시예 33> tert-부틸 4-((5-(4-((S)-2,3-디히드록시프로필카 바모일 )싸이클로핵스 -1-엔일)피리딘 -2—일옥시 )메틸)피페리딘 -1-카복시 레이트의 제조 J H 匪 R (400, CDCls): 8.14 (1H, s), 7.62 (1H, d), 6.71 (1H, d), 6.06 (2Η, m), 5.32 (5H, m), 3.80 (1H, m ), 3.58 (2H, m), 3.46 (2H, m), 2.93 (1H, m), 2.78 (2H, m), 2.50 (5H, m), 1.98 (5H, s), 1.49 (9H, m) , 1.27 (2H, m). Example 33 tert-Butyl 4-((5- (4-((S) -2,3-dihydroxypropylcarbamoyl) cyclonux-1-enyl) pyridine-2-yloxy) methyl) Preparation of Piperidine-1-carboxylate
Figure imgf000072_0001
Figure imgf000072_0001
(S)_2-아미노 -1-프로판올을 사용하는 대신에， (S)-3-아미노- 1,2-프로판디올 을 사용하는 것을 제외하고， 상기 <실시예 24〉와 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 20Omg I 수 율 ： 87%).  Instead of using (S) _2-amino-1-propanol, it was carried out in the same manner as in <Example 24>, except that (S) -3-amino- 1,2-propanediol was used. The title compound was prepared (yield: 20Omg I yield: 87%).
XH 匪 R (400， CDCls) ： 8.14 (1H, s) , 7.62 (1H, d)， 6.71 (1H, d) , 6.06 (2Η, m) , 5.32 (5H, m) , 3.80 (1H, m)， 3.58 (2H, m) , 3.46 (2H, m) , 2.93 (1H, m) , 2.78 (2H, m) , 2.50 (5H, m) , 1.98 (5H, s), 1.49 (9H, m) , 1.27 (2H, m) . X H 匪 R (400, CDCls): 8.14 (1H, s), 7.62 (1H, d), 6.71 (1H, d), 6.06 (2Η, m), 5.32 (5H, m), 3.80 (1H, m ), 3.58 (2H, m), 3.46 (2H, m), 2.93 (1H, m), 2.78 (2H, m), 2.50 (5H, m), 1.98 (5H, s), 1.49 (9H, m) , 1.27 (2H, m).
<실시예 34> N-(2-히드록시에틸 )-4-(4-((l-(3-이소프로필- 1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일)메톡시 )페닐 )-N-메틸싸이클로핵 스 -3-엔카복스아마이드의 제조 Example 34 N- (2-hydroxyethyl) -4- (4-((l- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl) piperidine-4- Preparation of 1) methoxy) phenyl) -N-methylcyclonucleose-3-encarboxamide
Figure imgf000072_0002
Figure imgf000072_0002
(R)-3-아미노 -1,2-프로판디올을 사용하는 대신에， 2- (메틸아미 노)에탄올을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 190mg I 수율 ： 82%).  The title compound was carried out in the same manner as in <Example 17>, except that 2- (methylamino) ethanol was used instead of (R) -3-amino-1,2-propanediol. Was prepared (yield amount: 190 mg I yield: 82%).
¾ 丽 R (400， CDC13) ： 7.34 (2Hᅳ d) , 6.86 (2H, d) , 6.07 (2H, m) , 4.23 (2Η, m)， 3.86 (4H, m)， 3.63 (2H, m) , 3.18 (3Η, s) , 3.15 (2Η, m) , 2.92 (2Η, m)， 2.50 (4Η, m)， 2.03 (5H, m) , 1.92 (2H, m)， 1.30 (6H, m) . <실시예 35> N-에틸 -N-(2-히드록시에틸 )-4-(4-((l-(3-이소프로 필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스— 3-엔카복스아마이드의 제조 ¾ δ R (400, CDC1 3 ): 7.34 (2H ᅳ d), 6.86 (2H, d), 6.07 (2H, m), 4.23 (2Η, m), 3.86 (4H, m) ， 3.63 (2H, m ), 3.18 (3Η, s), 3.15 (2Η, m), 2.92 (2Η, m) ， 2.50 (4Η, m) ， 2.03 (5H, m), 1.92 (2H, m) ， 1.30 (6H, m) . Example 35 N-ethyl-N- (2-hydroxyethyl) -4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) pi Ferridin-4-yl) methoxy) phenyl) cyclonux—preparation of 3-encarboxamide
Figure imgf000073_0001
Figure imgf000073_0001
(R)-3-아미노 -1,2-프로판디올을 사용하는 대신에， 2- (에틸 1아미 노)에탄을을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 184mg I 수을 ： 80%) .  Instead of using (R) -3-amino-1,2-propanediol, it was carried out in the same manner as in <Example 17>, except that 2- (ethyl 1 amino) ethane was used. The title compound was prepared (yield: 184 mg I number: 80%).
^ 丽 R (400， CDC13) ： 7.34 (2H, d) , 6.87 (2H, d) , 6.08 (1Η, m) , 4.24 (2H, m) , 3.86 (4H, m) , 3.59 (2H, m) , 3.49 (2H, m), 3.11 (2H, m) , 2.94 ( 1H， m) , 2.59 (5H, m), 1.98 (5H, m) , 1.51 (2H, m)， 1.31 (6H, m) , 1.14 (3H, m). ^ R R (400, CDC1 3 ) ： 7.34 (2H, d), 6.87 (2H, d), 6.08 (1Η, m), 4.24 (2H, m), 3.86 (4H, m), 3.59 (2H, m ), 3.49 (2H, m), 3.11 (2H, m), 2.94 (1H, m), 2.59 (5H, m), 1.98 (5H, m), 1.51 (2H, m), 1.31 (6H, m) , 1.14 (3H, m).
<실시예 36> N-((R)-1—히드록시프로판 -2-일 ) -4-(5-((l-(3-이소 프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )피리딘 -2-일 )싸 이클로 — 3-엔카복스아마이드의 제조 Example 36 N-((R) -1—hydroxypropan-2-yl) -4- (5-((l- (3-isopropyl-1,2,4-oxadiazole-5- (I) piperidin-4-yl) methoxy) pyridin-2-yl) cyclo — Preparation of 3-encarboxamide
Figure imgf000073_0002
Figure imgf000073_0002
4-(5-((1-(3-이소프로필—1，2，4-옥사디아졸 -5-일)피페리딘 -4-일 ) 메톡시 )피리딘 -2-일)싸이클로핵스 -3-엔카복실릭 엑시드 300mg 를 DMF 25^ 에 녹여 교반하였다. EDCI 210mg, HOBt 165mg 을 순차적으로 적 가한 후 10분간 추가적으로 교반하였다. (FO-2-아미노 -1-프로판올 120mg 을 적가한 후 상온에서 5시간 교반하였다. 반웅 종결 후 증류수 50 μί 를 0°C에서 천천히 가하고 생성되는 고체를 여과하여 건조하여 원하는 흰색 고체화합물을 얻었다 (수득량 ： 280mg / 수율 ： 82%). 4- (5-((1- (3-isopropyl—1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) pyridin-2-yl) cyclonux-3 -300 mg of encarboxylic acid was dissolved in DMF 25 ^ and stirred. EDCI 210mg, HOBt 165mg was added dropwise sequentially and stirred for an additional 10 minutes. (120 mg of FO-2-amino-1-propanol was added dropwise and stirred at room temperature for 5 hours. After completion of reaction, 50 μί of distilled water was slowly added at 0 ° C, and the resulting solid was filtered and dried. The desired white solid compound was obtained (amount: 280 mg / yield: 82%).
XH NMR (400, CDC13) ： 8.25 (1H, s), 7.35 (1H, d) , 7.15 (1Η, d), 6.57 (1H, m) , 5.82 (1H, m) , 4.25 (2H, d), 4.13 (1H, m) , 3.90 (2H, d) , 3.70 (2H, m) , 3.14 (2H, m) , 2.94 (1H, m) , 2.53 (5H, m) , 2.03 (5H, m) , 1.50 (2H, m) , 1.32 (6H, d)， 1.20 (3H, d) . X H NMR (400, CDC1 3 ): 8.25 (1H, s), 7.35 (1H, d), 7.15 (1Η, d), 6.57 (1H, m), 5.82 (1H, m), 4.25 (2H, d ), 4.13 (1H, m), 3.90 (2H, d), 3.70 (2H, m), 3.14 (2H, m), 2.94 (1H, m), 2.53 (5H, m), 2.03 (5H, m) , 1.50 (2H, m), 1.32 (6H, d), 1.20 (3H, d).
<실시예 37> N-((S)-1-히드록시프로판 -2-일 ) -4-(5-((l-(3-이소 프로필 -1,2, 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )피리딘 -2-일 )싸 이클로 Example 37 N-((S) -1-hydroxypropan-2-yl) -4- (5-((l- (3-isopropyl-1,2, 4-oxadiazole-5- 1) piperidin-4-yl) methoxy) pyridin-2-yl) cyclo
Figure imgf000074_0001
Figure imgf000074_0001
(R)-2-아미노 -1-프로판올을 사용하는 대신에， (S)— 2-아미노 -1- 프로판을을 사용하는 것을 제외하고， 상기 <실시예 36>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 160mg I 수율 ： 70%) .  Instead of using (R) -2-amino-1-propanol, the title compound was carried out in the same manner as in <Example 36>, except that (S)-2-amino-1-propane was used. Was prepared (yield: 160 mg I yield: 70%).
XH NMR (400, CDCI3) ： 8.25 (1H, s), 7.35 (1H, d), 7.15 (1H, d) , 6.57 (1H, .m) , 5.82 (1H, m) , 4.25 (2H, d) , 4.13 (1H, m) , 3.90 (2H, d) , 3.70 (2H, m) , 3.14 (2H, m) , 2.94 (1H, m) , 2.53 (5H, m) , 2.03 (5H, m), 1.50 (2H, m)， 1.32 (6H, d)， 1.20 (3H, d) . X H NMR (400, CDCI 3 ): 8.25 (1H, s), 7.35 (1H, d), 7.15 (1H, d), 6.57 (1H, .m), 5.82 (1H, m), 4.25 (2H, d), 4.13 (1H, m), 3.90 (2H, d), 3.70 (2H, m), 3.14 (2H, m), 2.94 (1H, m), 2.53 (5H, m), 2.03 (5H, m ), 1.50 (2H, m), 1.32 (6H, d), 1.20 (3H, d).
<실시예 38> N-((R)-2—히드록시프로필) -4-(5-((l-(3-이소프로필Example 38 N-((R) -2—hydroxypropyl) -4- (5-((l- (3-isopropyl)
-1， 2， 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )피리딘 -2-일 )싸이클로 핵스 - 1, 2, 4-oxadiazole-5-yl) piperidin-4-yl) methoxy) pyridin-2-yl) cyclonucleus-
Figure imgf000074_0002
Figure imgf000074_0002
00-2-아미노 -1-프로판올을 사용하는 대신에 , (R)-l-아미노 -2- 프로판올을 사용하는 것을 제외하고, 상기 <실시예 36>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 180mg I 수율 ： 81%) . Instead of using 00-2-amino-1-propanol, (R) -l-amino-2- Except for using propanol, the title compound was prepared in the same manner as in <Example 36> (amount: 180 mg I yield: 81%).
:H NMR (400, CDCI3) ： 8.24 (1H, s) , 7.34 (1H, d)， 7.17 (1H, d) , 6.54 (1Η, m) , 6.12 (1H, m)， 4.25 (2H, d), 3.96 (1H, m) , 3.90 (2H, d), 3.51 (1H, m) , 3.16 (3H, m) , 2.93 (1H, m) , 2.51 (5H, m) , 2.03 (5H, m) , 1.49 (2H, m) ' 1.31 (6H, d) , 1.21 (3H, d) . : H NMR (400, CDCI 3 ): 8.24 (1H, s), 7.34 (1H, d), 7.17 (1H, d), 6.54 (1Η, m), 6.12 (1H, m), 4.25 (2H, d ), 3.96 (1H, m), 3.90 (2H, d), 3.51 (1H, m), 3.16 (3H, m), 2.93 (1H, m), 2.51 (5H, m), 2.03 (5H, m) , 1.49 (2H, m) '1.31 (6H, d), 1.21 (3H, d).
<실시예 39> N-((S)-2-히드록시프로필) -4-(5-((l-(3-아소프로필 -1,2，4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )피리딘 -2-일 )싸이클로 핵스 - Example 39 N-((S) -2-hydroxypropyl) -4- (5-((l- (3-asopropyl-1,2,4-oxadiazol-5-yl) piperi Din-4-yl) methoxy) pyridin-2-yl) cyclonux-
Figure imgf000075_0001
Figure imgf000075_0001
(R)-2-아미노 -1-프로판올을 사용하는 대신에， (S)-l-아미노 -2- 프로판올을 사용하는 것을 제외하고， 상기 <실시예 36>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 185mg / 수율 : 76%) .  Instead of using (R) -2-amino-1-propanol, the title compound was prepared in the same manner as in <Example 36>, except that (S) -l-amino-2-propanol was used. (Yield: 185 mg / yield: 76%).
XH NMR (400， CDCI3) ： 8.24 (1H, s), 7.34 (1H, d) , 7.17 ( 1H， d) , 6.54 (1H, m) , 6.12 (1H, m)， 4.25 (2H, d) , 3.96 (1H, m) , 3.90 (2H, d), 3.51 (1H, m) , 3.16 (3H, m) , 2.93 (1H, m), 2.51 (5H, m)， 2.03 (5H, m) , 1.49 (2H, m) , 1.31 (6H, d)， 1.21 (3H, d) . X H NMR (400, CDCI3): 8.24 (1H, s), 7.34 (1H, d), 7.17 (1H, d), 6.54 (1H, m), 6.12 (1H, m), 4.25 (2H, d) , 3.96 (1H, m), 3.90 (2H, d), 3.51 (1H, m), 3.16 (3H, m), 2.93 (1H, m), 2.51 (5H, m), 2.03 (5H, m), 1.49 (2H, m), 1.31 (6H, d), 1.21 (3H, d).
<실시예 40> N-((R)-2,3-디히드록시프로필) -4-(5-((l-(3-이소프 로필 -1,2,4-옥사디아졸ᅳ 5-일 )피페리딘 -4-일 )메록시 )피리딘 -2-일)싸이 클로핵스 -3ᅳ엔카복스아마이드의 제조 Example 40 N-((R) -2,3-dihydroxypropyl) -4- (5-((l- (3-isopropyl-1,2,4-oxadiazol ᅳ 5-yl Preparation of) Piperidin-4-yl) methoxy) pyridin-2-yl) cyclonux-3eneenecarboxamide
0 (R)-2-아미노 -1-프로판올을 사용하는 대신에， (R)-3-아미노- 1,2-프로판디올 을 사용하는 것을 제외하고， 상기 <실시예 36〉과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 160mg I 수 율 ： 기 ¾). 0 Instead of using (R) -2-amino-1-propanol, it was carried out in the same manner as in <Example 36>, except that (R) -3-amino- 1,2-propanediol was used. To give the title compound (yield: 160 mg I yield: groups ¾).
¾ NMR (400, CDC13) ： 8.24 (1H, s) , 7.34 (1H, d) , 7.17 (1H, d), 6.52 (1H, m) , 6.16 (1H, m)， 4.25 (2H, d) , 3.90 (2H, d) , 3.81 (1H, m) , 3.59 (3H, m)， 3.15 (3H, m) , 2.93 (1H, m) , 2.51 (5H, m) , 2.09 (5H, m) , 1.53 (2H, m) , 1.31 (6H, d) . ¾ NMR (400, CDC1 3 ): 8.24 (1H, s), 7.34 (1H, d), 7.17 (1H, d), 6.52 (1H, m), 6.16 (1H, m), 4.25 (2H, d) , 3.90 (2H, d), 3.81 (1H, m), 3.59 (3H, m), 3.15 (3H, m), 2.93 (1H, m), 2.51 (5H, m), 2.09 (5H, m), 1.53 (2 H, m), 1.31 (6 H, d).
<실시예 41> N-((S)-2,3-디히드록시프로필) -4-(5-((l-(3-이소프 로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4—일 )메록시 )피리딘 -2-일 )싸이 클로핵스 -3-엔카복스아마이드의 제조 Example 41 N-((S) -2,3-dihydroxypropyl) -4- (5-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) Preparation of 1) piperidin-4-yl) methoxy) pyridin-2-yl) cyclonux-3-encarboxamide
Figure imgf000076_0001
Figure imgf000076_0001
(R)-2-아미노 -1-프로판올을 사용하는 대신에， (S)-3-아미노ᅳ1，2- 프로판디올 을 사용하는 것을 제외하고， 상기 <실시예 36>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 176mg 수 율 ： 77%).  Instead of using (R) -2-amino-1-propanol, it was carried out in the same manner as in <Example 36>, except that (S) -3-amino ᅳ 1,2-propanediol was used. The title compound was prepared (yield 176 mg yield: 77%).
:H NMR (400， CDCls) ： 8.24 (1H, s), 7.34 (1H, d) , 7.17 (1Ή, d) , 6.52 (1H, m), 6.16 ( 1H , m) , 4.25 (2H, d) , 3.90 (2H, d) , 3.81 (1H, m), 3.59 (3H, m) , 3.15 (3H, m) , 2.93 (1H, m), 2.51 (5H, m) , 2.09 (5H, m) , 1.53 (2H, m)， 1.31 (6H, d). : H NMR (400, CDCls): 8.24 (1H, s), 7.34 (1H, d), 7.17 (1Ή, d), 6.52 (1H, m), 6.16 (1H, m), 4.25 (2H, d) , 3.90 (2H, d), 3.81 (1H, m), 3.59 (3H, m), 3.15 (3H, m), 2.93 (1H, m), 2.51 (5H, m), 2.09 (5H, m), 1.53 (2H, m), 1.31 (6H, d).
<실시예 42> tert-부틸 4-((5-(4-((S)-3-히드록시피를리딘 -1-카 보닐)싸이클로핵스ᅳ1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레 이트의 제조 Example 42 tert-Butyl 4-((5- (4-((S) -3-hydroxypyridine-1-carbonyl) cyclonucleoxen1-enyl) pyridin-2-yloxy) methyl Preparation of Piperidine-1-carboxylate
Figure imgf000076_0002
Figure imgf000076_0002
(S)-2-아미노 -1-프로판올을 사용하는 대신에 , (S)-(_)-3-피를리 디놀을 사용하는 것을 제의하고 , 상기 <실시예 24>와 동일한 ,방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 145mg I 수율 ： 65%). ln NMR (400， CDCls) ： 8.14 (1H, s) , 7.63 (1H, d) , 6.70 (1Η, d) , 6.07 (1H, s) , 4.58 ( 1H， d) , 4.16 (4H, m) , 3.76 (4H, m) , 2.75 (7H, m) , 1.98 (8H, m) , 1.52 (9H, m) , 1.29 (2H, m) . Instead of using (S) -2-amino-1-propanol, (S)-(_)-3-pyri Using the dinol was carried out, and the title compound was prepared in the same manner as in <Example 24> (amount: 145 mg I yield: 65%). ln NMR (400, CDCls): 8.14 (1H, s), 7.63 (1H, d), 6.70 (1Η, d), 6.07 (1H, s), 4.58 (1H, d), 4.16 (4H, m), 3.76 (4H, m), 2.75 (7H, m), 1.98 (8H, m), 1.52 (9H, m), 1.29 (2H, m).
<실시예 43> tert-부틸 4-((5-(4-((R)-3-히드록시피를리딘 -1-카 보닐)싸이클로핵스ᅳ1-엔일 )피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레 이트의 제조 ' Example 43 tert-Butyl 4-((5- (4-((R) -3-hydroxypyridine-1-carbonyl) cyclonucleoxen1-enyl) pyridin-2-yloxy) methyl Preparation of Piperidine-1-carboxylate ''
Figure imgf000077_0001
Figure imgf000077_0001
(S)-2-아미노 -1-프로판을을 사용하는 대신에， (R)-( + )-3-피를리 디놀을 사용하는 것을 제외하고， 상기 <실시예 24>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 162mg I 수율 : 70%). Instead of using (S) -2-amino-1-propane, it is carried out in the same manner as in <Example 24>, except that (R)-(+)-3-pyridinol is used. To give the title compound (amount: 162m g I yield: 70%).
¾ NMR (400， CDC13) ： 8.14 (1H, s) , 7.63 (1H, d)， 6.70 (1H, d), 6.07 (1H, s) , 4.58 (1H, d)， 4.16 (4H, m) , 3.76 (4H, m) , 2.75 (7H, m) , 1.98 (8H, m) , 1.52 (9H, m)， 1.29 (2H, m) . ¾ NMR (400, CDC1 3 ): 8.14 (1H, s), 7.63 (1H, d), 6.70 (1H, d), 6.07 (1H, s), 4.58 (1H, d), 4.16 (4H, m) , 3.76 (4H, m), 2.75 (7H, m), 1.98 (8H, m), 1.52 (9H, m), 1.29 (2H, m).
<실시예 44> tert-부틸 4-((2-플루오로 -4-(4-((S)-3-히드록시피 롤리딘 -1-카보닐)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시 레이트의 제조 Example 44 tert-Butyl 4-((2-fluoro-4- (4-((S) -3-hydroxypyrrolidine-1-carbonyl) cyclonux-1-enyl) phenoxy) Preparation of Methyl) piperidine-1-carboxylate
Figure imgf000077_0002
Figure imgf000077_0002
4-(4-((1-( tert-부톡시카보닐 )피페리딘 -4-일 )메톡시 )-3-플루오 로페닐)싸이클로핵스 -3-엔카복실릭 액시드 300mg 를 DMF 25^ 에 녹여 교반하였다. EDCI 210mg, HOBt 165mg 을 순차적으로 적가한 후 10분간 추가적으로 교반하였다. (S)_(— )-3-피를리디놀 lOOmg 을 적가한 후 상 온에서 12시간 교반하였다. 반웅 종결 후 증류수 50 i 를 0°C에서 천 천히 가하고 생성되는 고체를 여과하여 건조하여 원하는 흰색 고체화 합물을 얻었다 (수득량 ： 195 I 수율 ： 58%). XH 應 R (400, CDCls) ： 7.28 (2H, m) , 6.91 (1H, t), 6.10 (1H, s) , 4.58 (1H, d) , 4.16 (4H, m) , 3.88 (2H, d) , 3.69 (4H, m) , 2.75 (7Hᅳ m) , 1.98 (8H, m) , 1.52 (9H, m), 1.30 (2H, m) . 4- (4-((1- (tert-butoxycarbonyl) piperidin-4-yl) methoxy) -3-fluorophenyl) cyclonux-3-enecarboxylic acid 300mg in DMF 25 ^ It was dissolved in and stirred. EDCI 210mg, HOBt 165mg was added dropwise sequentially followed by additional stirring for 10 minutes. (S) _ (—)-3-pyridinol 100 mg was added dropwise and stirred at room temperature for 12 hours. After completion of reaction, distilled water 50 i was slowly added at 0 ° C., and the resulting solid was filtered and dried to obtain the desired white solid compound (amount: 195 I yield: 58%). X H 應 R (400, CDCls): 7.28 (2H, m), 6.91 (1H, t), 6.10 (1H, s), 4.58 (1H, d), 4.16 (4H, m), 3.88 (2H, d ), 3.69 (4H, m), 2.75 (7H ᅳ m), 1.98 (8H, m), 1.52 (9H, m), 1.30 (2H, m).
<실시예 45> tert-부틸 4-((2-플루오로 -4-(4-((R)-3-히드록시피 를리딘 -1-카보닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시 레이트의 제조 Example 45 tert-Butyl 4-((2-fluoro-4- (4-((R) -3-hydroxypyridine-1-carbonyl) cyclonux-1-enyl) phenoxy) Preparation of Methyl) piperidine-1-carboxylate
Figure imgf000078_0001
Figure imgf000078_0001
(S)-(-)-3-피를리디놀을 사용하는 대신에， (R)-( + )-3-피를리디 놀을 사용하는 것을 제외하고 , 상기 <실시예 44〉와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 120mg I 수율 ： 52%).  The same method as in <Example 44>, except that instead of using (S)-(-)-3-pyridinol, (R)-(+)-3-pyridinol is used. To give the title compound (amount: 120 mg I yield: 52%).
¾ 丽 R (400, CDCls) ： 7.28 (2H, m) , 6.91 (1H, t) , 6.10 (1H, s), 4.58 (1H, d) , 4.16 (4H, m)， 3.88 (2H, d) , 3.69 (4H, m) , 2.75 (7H, m) , 1.98 (8H, m) , 1.52 (9H, m), 1.30 (2H, m) .  ¾ δ R (400, CDCls): 7.28 (2H, m), 6.91 (1H, t), 6.10 (1H, s), 4.58 (1H, d), 4.16 (4H, m) ， 3.88 (2H, d) , 3.69 (4H, m), 2.75 (7H, m), 1.98 (8H, m), 1.52 (9H, m), 1.30 (2H, m).
<실시예 46> N-(l,3—디히드록시프로판 -2-일 ) -4-(5-((l-(3-이소 프로필 -1,2, 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )피리딘 -2-일 )싸 이클로 Example 46 N- (l, 3—dihydroxypropan-2-yl) -4- (5-((l- (3-isopropyl-1,2, 4-oxadiazole-5-yl ) Piperidin-4-yl) methoxy) pyridin-2-yl) cyclo
Figure imgf000078_0002
Figure imgf000078_0002
(R)-2-아미노 -1-프로판을올 사용하는 대신에， 2ᅳ아미노 -1，3-프 로판디올을 사용하는 것을 제외하고 , 상기 <실시예 36>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 185mg I 수율 ： 52%) .  Instead of using (R) -2-amino-1-propane, the title compound was carried out in the same manner as in <Example 36>, except that 2′amino-1,3-propanediol was used. Was prepared (yield amount: 185 mg I yield: 52%).
^ NMR (400, CDCls) ： 8.23 (1H, s) , 7.34 (1H, d), 7.16 (1H, d) , 6.48 (2H, m), 4.25 (2H, d)， 4.03 (1H, m) , 3.90 (2H, d) , 3.81 (4H, m) , 3.12 (2H, m)， 2.94 ( 1H， m) , 2.56 (1H, m) , 2.49 (5H, m) 2.11 (3H, m) , 1.98 (2H, m) , 1.45 (2H, m)， 1.30 (6H, d) - ^ NMR (400, CDCls): 8.23 (1H, s), 7.34 (1H, d), 7.16 (1H, d), 6.48 (2H, m), 4.25 (2H, d), 4.03 (1H, m), 3.90 (2H, d), 3.81 (4H, m), 3.12 (2H, m), 2.94 (1H, m), 2.56 (1H, m), 2.49 (5H, m) 2.11 (3H, m), 1.98 (2H, m), 1.45 (2H , m), 1.30 (6H, d)-
<실시예 47> N-(3-히드록시 -2,2-디메틸프로필 )-4-(5-((l-(3-o 소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일)메특시 )피리딘 -2-일 ) 싸이클로핵스—3-엔카복스아마이드의 제조 Example 47 N- (3-hydroxy-2,2-dimethylpropyl) -4- (5-((l- (3-o-sopropyl-1,2,4-oxadiazol-5-yl) ) Piperidin-4-yl) methoxy) pyridin-2-yl) cyclonux-3-encarboxamide
Figure imgf000079_0001
Figure imgf000079_0001
(R)-2-아미노 -1-프로판올을 사용하는 대신에， 3-아미노 2，2-디 메틸프로판 -1-올을 사용하는 것을 제외하고， 상기 <실시예 36〉과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 150mg I 수 율 ： 65%).  Instead of using (R) -2-amino-1-propanol, it was carried out in the same manner as in <Example 36>, except that 3-amino 2,2-dimethylpropan-1-ol was used. To give the title compound (yield: 150 mg I yield: 65%).
XH 匪 R (400, CDC13) ： 8.25 ( 1H , s), 7.34 ( 1H， d) , 7.17 (1H, d) , 6.55 (1Η, m) , 6.05 (1H, m) , 4.25 (2H, d), 3.90 (2H, d), 3.15 (6H, m) , 2.93 (1H, m) , 2.71 (1H, m) , 2.47 (4H, m) , 2.14 (2H, m) , 1.98 (3H, m) , 1.51 (2H, m) , 1.31 (6H, m) , 0.90 (6H, s) . X H 匪 R (400, CDC1 3 ): 8.25 (1H, s), 7.34 (1H, d), 7.17 (1H, d), 6.55 (1Η, m), 6.05 (1H, m), 4.25 (2H, d), 3.90 (2H, d), 3.15 (6H, m), 2.93 (1H, m), 2.71 (1H, m), 2.47 (4H, m), 2.14 (2H, m), 1.98 (3H, m ), 1.51 (2H, m), 1.31 (6H, m), 0.90 (6H, s).
<실시예 48> ((R)-3-히; £■톡시피를리딘 -1-일) (4-(4-((l-(3-이소 프로필 -1,2 ,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐 )싸이클로핵 스 -3-엔일)메타논의 제조 Example 48 ((R) -3-Hy; £ Toxypyridin-1-yl) (4- (4-((l- (3-isopropyl-1,2,4-oxadiazole) Preparation of -5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleox-3-enyl) methanone
Figure imgf000079_0002
Figure imgf000079_0002
(R)-3-아미노 -1，2-프로판디을을 사용하는 대신에， (R)-( + )-3-피 를리디놀을 사용하는 것을 제외하고， 상기 <실시예 17〉과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 175mg I 수율 ： 77%) .  The same method as in Example 17, except that (R)-(+)-3-pyridinol is used instead of (R) -3-amino-1,2-propanedi. The title compound was prepared by the yield (yield: 175 mg I yield: 77%).
¾ NMR (400， CDCls) ： 7.33 (2H, d), 6.86 (2H, d)， 6.07 (1H, m)， 4.53 (1H, m) , 4.23 (2H, d) , 3.85 (2H, d), 3.68 (4H, m) , 3 (2H, m) , 2.90 ( 1Ή m), 2.52 (6Η, m) , 1.99 (7H, m)， 1.43 (2H, 1.29 (6H, d) . ¾ NMR (400, CDCls): 7.33 (2H, d), 6.86 (2H, d), 6.07 (1H, m) ， 4.53 (1H, m), 4.23 (2H, d), 3.85 (2H, d), 3.68 (4H, m), 3 (2H, m), 2.90 (1Ή m), 2.52 (6Η, m) , 1.99 (7H, m), 1.43 (2H, 1.29 (6H, d).
<실시예 49> ((S)-3-히드록시피를리딘 -1-일 ) (4ᅳ(4-((1-(3-이소 프로필 -1,2 ,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵 스 -3-엔일 )메타논의 제조 Example 49 ((S) -3-hydroxypyridin-1-yl) (4 ′ (4-((1- (3-isopropyl-1,2,4-oxadiazole-5- Preparation of 1) piperidin-4-yl) methoxy) phenyl) cyclonucleox-3-enyl) methanone
Figure imgf000080_0001
Figure imgf000080_0001
(R)-3-아미노 -1,2-프로판디올을 사용하는 대신에， (S)-(-)-3-피 를리디놀을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 120mg I 수율 ： 52%) .  The same method as in Example 17, except that (S)-(-)-3-pyridinol is used instead of (R) -3-amino-1,2-propanediol. The title compound was prepared by the yield (yield: 120 mg I yield: 52%).
丽 R (400, CDC13) ： 7.33 (2H, d) , 6.86 (2H, d)， 6.07 (1H, m) , 4.53 (1Η, m) , 4.23 (2H, d)， 3.85 (2H, d) , 3.68 (4H, m) , 3.11 (2H, m) , 2.90 (1H, m) , 2.52 (6H, m) , 1.99 (7H, m), 1.43 (2H, m) , 1.29 (6H, d) . 丽 R (400, CDC1 3 ) ： 7.33 (2H, d), 6.86 (2H, d) ， 6.07 (1H, m), 4.53 (1Η, m), 4.23 (2H, d) ， 3.85 (2H, d) , 3.68 (4H, m), 3.11 (2H, m), 2.90 (1H, m), 2.52 (6H, m), 1.99 (7H, m), 1.43 (2H, m), 1.29 (6H, d).
<실시예 50> N-(2,2-디풀루오로에틸) -4-(4-((l-(5-에틸피리미딘Example 50 N- (2,2-difuluroethyl) -4- (4-((l- (5-ethylpyrimidine)
-2-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스아마이드의 제조 Preparation of 2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enecarboxamide
Figure imgf000080_0002
Figure imgf000080_0002
(R)-2-아미노 -1-프로판올을 사용하는 대신에， 2,2-디플루오로에 틸아민을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 ： 170mg / 수율 ： 74%) ¾ 丽 R (400, CDCls) ： 8.22 (2H, s) , 7.32 (2H, d)， 6.87 (2H, d) , 6.04 (1Η, s) , 5.91 (1.5H, m) , 5.88 (0.5H, t), 4.80 (2H, d) , 3.85 (2H, d) , 3.72 (2H, m) , 2.98 (2H, t) , 2.56 (8H, m) , 2.12 (2H m) , 1.94 (3H, m) , 1.41 (2H, m)， 1.21 (3H, t) . The title compound was prepared in the same manner as in <Example 8>, except that 2,2-difluoroethylamine was used instead of (R) -2-amino-1-propanol. Prepared (yield: 170 mg / yield: 74%) ¾ リ R (400, CDCls): 8.22 (2H, s), 7.32 (2H, d), 6.87 (2H, d), 6.04 (1Η, s), 5.91 (1.5H, m), 5.88 (0.5H, t), 4.80 (2H, d), 3.85 (2H, d), 3.72 (2H, m), 2.98 (2H, t), 2.56 (8H, m), 2.12 (2H m), 1.94 (3H, m), 1.41 (2H, m) ， 1.21 ( 3H, t).
<실시예 51> N-(2,2-디플루오로에틸) -4-(4-((l-(3-이소프로필- 1,2，4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔 카복스아마이드의 제조 Example 51 N- (2,2-difluoroethyl) -4- (4-((l- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl) piperidine Preparation of -4-yl) methoxy) phenyl) cyclonux-3-ene carboxamide
Figure imgf000081_0001
Figure imgf000081_0001
(R)-3-아미노 -1,2-프로판디올을 사용하는 대신에， 2,2-디플루오 로에틸아민 을 사용하는 것을 제외하고， 상기 <실시예 17〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 175mg I 수 율 ： 76%).  The title compound was carried out in the same manner as in <Example 17>, except that 2,2-difluoroethylamine was used instead of (R) -3-amino-1,2-propanediol. Was prepared (yield: 175 mg I yield: 76%).
XH NMR (400, CDC13) ： 7.33 (2H, d)， 6.86 (2H, d)， 6.04 (1H, m) , 5.88 (2H, m) , 4.23 (2Η, d) , 3.84 (2H, d) , 3.70 (2H, m) , 3.14 (2H, t) , 2.91 (1H, m) , 2.50 (5H, m) , 2.10 (2H, m) , 2.05 (3H, m) , 1.43 (2H, m) , 1.30 (6H, d) . X H NMR (400, CDC1 3 ): 7.33 (2H, d), 6.86 (2H, d), 6.04 (1H, m), 5.88 (2H, m), 4.23 (2Η, d), 3.84 (2H, d ), 3.70 (2H, m), 3.14 (2H, t), 2.91 (1H, m), 2.50 (5H, m), 2.10 (2H, m), 2.05 (3H, m), 1.43 (2H, m) , 1.30 (6H, d).
<실시예 52> (4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5-일) 피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일) (피를리딘— 1-일 )메타 논의 제조 Example 52 (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus -3-enyl) (pyridine- 1-yl) metabolic preparation
Figure imgf000081_0002
Figure imgf000081_0002
(R)-3-아미노 -1，2-프로판디올을 사용하는 대신에， 피를리딘을 사용하는 것을 제외하고, 상기 <실시예 17>과 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 ： 200mg / 수율 : 87%).  The title compound was prepared in the same manner as in <Example 17>, except that instead of using (R) -3-amino-1,2-propanediol, pyridine was used. Income: 200mg / yield: 87%).
XH 匪 R (400， CDCls) ： 7.34 (2H, d) , 6.86 (2H, d)， 6.07 ( 1H , m) , 4.24 (2H, d) , 3.84 (2H, d) , 3.53 (4H, m) , 3.08 (2H, m) , 2.91 (1H, m) , 2.34 (5H, m)， 1.98 (9H, m) , 1.47 (2H, m) , 1.25 (6H, d) . X H 匪 R (400, CDCls): 7.34 (2H, d), 6.86 (2H, d), 6.07 (1H, m), 4.24 (2H, d), 3.84 (2H, d), 3.53 (4H, m), 3.08 (2H, m), 2.91 (1H, m), 2.34 (5H, m) ， 1.98 (9H, m ), 1.47 (2H, m), 1.25 (6H, d).
<실시예 53> ((S)-3-플루오로피롤리딘 -1-일) (4-(4-((l-(3-이소 프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵 스 -3—엔일)메타논의 제조 Example 53 ((S) -3-fluoropyrrolidin-1-yl) (4- (4-((l- (3-isopropyl-1,2,4-oxadiazole-5) 1) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000082_0001
Figure imgf000082_0001
(R)-3—아미노 -1，2ᅳ프로판디올을 사용하는 대신에 (S)-3-플루오 로피를리딘 을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 175mg I 수 율 ： 76%) .  The title compound was carried out in the same manner as in <Example 17>, except that (S) -3-fluoropyridine was used instead of (R) -3—amino-1,2′propanediol. Was prepared (yield 175 mg I yield: 76%).
XH 匪 R (400, CDC13) ： 7.34 (2H, d)， 6.87 (2H, 5.36 (1H, m), 4.24 (2H, d) , 3.75 (6Η, m)， 3.14 (2H, t), 2.89 m), 2.50 (7H, m) , 2.00 (5H, m)， 1.50 (2H, m) , 1.30 (6H, d) . X H 匪 R (400, CDC1 3 ): 7.34 (2H, d), 6.87 (2H, 5.36 (1H, m), 4.24 (2H, d), 3.75 (6Η, m), 3.14 (2H, t), 2.89 m), 2.50 (7H, m), 2.00 (5H, m), 1.50 (2H, m), 1.30 (6H, d).
<실시예 54> ((R)-3-플루오로피를리딘 -1-일 ) (4-(4-((l-(3-이소 프로필 -1,2, 4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )페닐 )싸이클로핵 스ᅳ 3-엔일)메타논의 제조 Example 54 ((R) -3-fluoropyridin-1-yl) (4- (4-((l- (3-isopropyl-1,2, 4-oxadiazole-5) Preparation of 1) piperidin-4-yl) methoxy) phenyl) cyclonuclear swim 3-enyl) methanone
Figure imgf000082_0002
Figure imgf000082_0002
(R)-3-아미노 -1，2ᅳ프로판디올을 사용하는 대신에， (R)-3-플루오 로피를리딘 을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 175mg I 수 율 ： 77%).  Instead of using (R) -3-amino-1,2 ᅳ propanediol, the procedure was carried out in the same manner as in <Example 17>, except that (R) -3-fluoropyridine was used. Compounds were prepared (yield 175 mg I yield: 77%).
XH NMR (400， CDCh) ： 7.34 (2H, d), 6.87 (2H, d)， 5.36 ( 1H m) , 4.24 (2H, d) , 3.75 (6H, m), 3.14 (2H, t) , 2.89 (1H, m) , 2.50 (7H, m) , 2.00 (5H, m) , 1.50 (2H, m) , 1.30 (6H, d) . X H NMR (400, CDCh): 7.34 (2H, d), 6.87 (2H, d), 5.36 (1H m), 4.24 (2H, d), 3.75 (6H, m), 3.14 (2H, t), 2.89 (1H, m), 2.50 (7H, m), 2.00 (5H, m), 1.50 (2H, m ), 1.30 (6H, d).
<실시예 55> (4-에틸피페라진 -1-일) (4-(4-((l-(5-에틸피리미딘-Example 55 (4-ethylpiperazin-1-yl) (4- (4-((l- (5-ethylpyrimidine-))
2-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔일)메타논의 제조 Preparation of 2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000083_0001
Figure imgf000083_0001
00-2-아미노 -1-프로판올을 사용하는 대신에， 1-에틸 피페라진 올 사용하는 것올 제외하고， 상기 <실시예 8>과 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 ： 200mg I 수율 ： 87%).  Instead of using 00-2-amino-1-propanol, except for using 1-ethyl piperazine all, the title compound was prepared in the same manner as in <Example 8>, (yield: 200 mg I Yield: 87%).
XH NMR (400， CDC13) ： 8.19 (2H, s) , 7.32 (2H, d)， 6.87 (2H, d), 6.05 (1H, s) , 4.80 (2H, d), 3.76 (6H, m) , 2.50 (13H, m)ᅳ 1.99 (6H, m), 1.27 (8Ή, m) . XH NMR (400, CDC1 3 ): 8.19 (2H, s), 7.32 (2H, d), 6.87 (2H, d), 6.05 (1H, s), 4.80 (2H, d), 3.76 (6H, m) , 2.50 (13H, m) ᅳ 1.99 (6H, m), 1.27 (8 Ή, m).
<실시예 56> (4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5-일) 피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일 ) (피페리딘 - 1-일 )메타 논의 제조 Example 56 (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus 3-enyl) (piperidin-1-yl) metabolite preparation
Figure imgf000083_0002
Figure imgf000083_0002
(R)— 3-아미노 -1,2-프로판디올을 사용하는 대신에， 피페리딘을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 ： 170mg / 수율 ： 74%).  (R) —Instead of using 3-amino-1,2-propanediol, the title compound was prepared in the same manner as in <Example 17>, except that piperidine was used. Yield ： 170mg / yield ： 74%).
¾ NMR (400, CDCls) ： 7.34 (2H, d)， 6.86 (2H, d) , 6.07 ( 1H , m) , 4.23 (2Η, d) , 3.84 (2H, d)， 3.59 (4H, m) ' 3.11 (2H, t) , 2.84 (2H, m) , 2.49 (3H, m) , 2.31 ( 1H , m) , 1.98 (5H, m) , 1.67 (6H, m)， 1.44 (2H, m) , 1.30 (6H, d) .  ¾ NMR (400, CDCls): 7.34 (2H, d), 6.86 (2H, d), 6.07 (1H, m), 4.23 (2Η, d), 3.84 (2H, d), 3.59 (4H, m) ' 3.11 (2H, t), 2.84 (2H, m), 2.49 (3H, m), 2.31 (1H, m), 1.98 (5H, m), 1.67 (6H, m), 1.44 (2H, m), 1.30 (6H, d).
<실시예 57> tert-부틸 4-((2-플루오로 -4-(4-((S)-3-플루오로피 를리딘 -1-카보닐)싸이클로핵스 •1-엔일)페녹시 )메틸)피페리딘 -1-카복 ' 레이트의 제조 Example 57 tert-Butyl 4-((2-fluoro-4- (4-((S) -3-fluoropy) The preparation of naphthyridine-1-carbonyl) cyclo haekseu • 1- enyl) phenoxy) methyl) piperidine-1-kabok 'rate
Figure imgf000084_0001
Figure imgf000084_0001
(S)-(-)-3-피를리디놀을 사용하는 대신에， (S)-3-폴루오로피를 리딘을 사용하는 것을 제외하고， 상기 <샬시예 44>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 175mg I 수율 ： 76%). ιϋ NM (400， CDCls) ： 7.15 (2H, m)， 6.92 (1H, t), 6.10 (1H, s) , 5.23 (1Η, m) , 4.17 (2H, m) , 3.75 (6H, m) , 2.73 (3H, m) , 2.39 (5H, m) , 2.02 (6H, m)， 1.48 (9H, m) , 1.27 (2H, m). R)-3-플루오로피 를리딘 페리딘ᅳ 1-카복시 레이트  Instead of using (S)-(-)-3-pyridinol, (S) -3-polouropy is carried out in the same manner as in <Shalcy Example 44>, except that the use of ridine To give the title compound (amount: 175 mg I yield: 76%). ιϋ NM (400, CDCls): 7.15 (2H, m), 6.92 (1H, t), 6.10 (1H, s), 5.23 (1Η, m), 4.17 (2H, m), 3.75 (6H, m), 2.73 (3H, m), 2.39 (5H, m), 2.02 (6H, m), 1.48 (9H, m), 1.27 (2H, m). R) -3-fluoropyrrolidine ferridine® 1-carboxylate
Figure imgf000084_0002
Figure imgf000084_0002
(S)-(-)-3-피를리디놀을 사용하는 대신에， (R)-3-플루오로피를 리딘을 사용하는 것을 제외하고 , 상기 <실시예 44〉와 동일한 방법으로 수행하여 표제 화합물올 제조하였다 (수득량 ： 195mg / 수율 : 85%).  Instead of using (S)-(-)-3-pyridinol, (R) -3-fluoropy was carried out in the same manner as in <Example 44>, except for using ridine. The title compound was prepared (amount: 195 mg / yield: 85%).
JH NMR (400， CDCI3) ： 7.15 (2H, m)， 6.92 (1H, t), 6.10 (1H, s) , 5.23 (1H, m) , 4.17 (2H, m) , 3.75 (6H, m) , 2.73 (3H, m) , 2.39 (5H, m) , 2.02 (6H, m) , 1.48 (9H, m) , 1.27 (2H, m) . J H NMR (400, CDCI 3 ): 7.15 (2H, m), 6.92 (1H, t), 6.10 (1H, s), 5.23 (1H, m), 4.17 (2H, m), 3.75 (6H, m ), 2.73 (3H, m), 2.39 (5H, m), 2.02 (6H, m), 1.48 (9H, m), 1.27 (2H, m).
<실시예 59> tert-부틸 4-((2-플루오로 -4-(4-((S)-l-히드록시프 로판 -2-일카바모일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복 시레이트의 제조 Example 59 tert-Butyl 4-((2-fluoro-4- (4-((S) -l-hydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) Preparation of Methyl) piperidine-1-carboxylate
Figure imgf000085_0001
Figure imgf000085_0001
(S)-(-)-3-피를리디놀을 사용하는 대신에， (S)-2-아미노 -1-프로 판올을 사용하는 것올 제외하고， 상기 <실시예 44>와 동일한 방법으로 수횅하여 표제 화합물을 제조하였다 (수득량 ： 200mg / 수율 ： 87%).  Instead of using (S)-(-)-3-pyridinol, except for using (S) -2-amino-1-propanol, it was obtained in the same manner as in <Example 44>. To give the title compound (amount: 200 mg / yield: 87%).
匪 R (400， CDC13) ： 7.14 (2H, m) , 6.89 (1H, t), 6.06 (1H, s), 5.80 (1H, m) , 4.16 (3H, m) , 3.88 (2H. d) , 2.63 (2H, m) , 2.76 (2H, m) , 2.41 (6H, m) , 2.02 (5H, m) , 1.48 (9H, m) , 1.26 (5H, m) . 匪 R (400, CDC1 3 ): 7.14 (2H, m), 6.89 (1H, t), 6.06 (1H, s), 5.80 (1H, m), 4.16 (3H, m), 3.88 (2H.d) , 2.63 (2H, m), 2.76 (2H, m), 2.41 (6H, m), 2.02 (5H, m), 1.48 (9H, m), 1.26 (5H, m).
<실시예 60> tert-부틸 4-((2-플루오로 -4-(4-((R)-l-히드록사프 로판 -2-일카바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1ᅳ카복 시레 Example 60 tert-Butyl 4-((2-fluoro-4- (4-((R) -l-hydroxysapane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) Methyl) piperidine-1 ᅳ carboxyrene
Figure imgf000085_0002
Figure imgf000085_0002
(S)— (-)-3-피롤리디놀을 사용하는 대산에， (R)-2-아미노 -1ᅳ프로 판올을 사용하는 것을 제외하고， 상기 <실시예 44>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 174mg / 수율 : 75%).  (S) — In the same manner as in <Example 44>, except that (R) -2-amino-1vpropanol was used in the large acid using (-)-3-pyrrolidinol The title compound was prepared (yield: 174 mg / yield: 75%).
!H 匪 R (400, CDCls) ： 7.14 (2H, m)， 6.89 ( 1H , t) , 6.06 ( 1H , s), 5.80 (1H, m), 4.16 (3H, m) , 3.88 (2Η, d) , 2.63 (2Η, m) , 2.76 (2Η, m) , 2.41 (6Η, m)， 2.02 (5Η, m)， 1.48 (9H, m)， 1.26 (5H, m) . ! H 匪 R (400, CDCls): 7.14 (2H, m), 6.89 (1H, t), 6.06 (1H, s), 5.80 (1H, m), 4.16 (3H, m), 3.88 (2Η, d) , 2.63 (2Η, m), 2.76 (2Η, m), 2.41 (6Η, m), 2.02 (5Η, m), 1.48 (9H, m), 1.26 (5H, m).
<실시예 61> tert-부틸 4-((2-플루오로 -4-(4-((S)-2-히드록시프 로필카바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레 이트의 제조
Figure imgf000086_0001
Example 61 tert-Butyl 4-((2-fluoro-4- (4-((S) -2-hydroxypropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperi Preparation of Didine-1-carboxylate
Figure imgf000086_0001
(S)-(-)-3-피를리디놀을 사용하는 대신에， (S)— 1-아미노 -2ᅳ프로 판올을 사용하는 것을 제외하고， 상기 <실시예 44>와 동밀한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 120mg I 수율 ： 53%) .  In the same manner as in <Example 44>, except that (S)-1-amino-2vpropanol is used instead of (S)-(-)-3-pyridinol The title compound was obtained (yield: 120 mg I yield: 53%).
¾ 丽 R (400， CDC13) ： 7.14 (2H, m)， 6.89 (1H, t) , 6.07 (1H, s) , 4.15 (2Η, m) , 3.96 (1H, m)， 3.86 (2H, d) , 3.52 (1H, m) , 3.17 (1H, m) , 2.76 (2H, m) , 2.49 (6H, m) , 2.02 (5H, m) , 1.48 (9H, m)， 1.27 (5H, m) . ¾ 丽 R (400, CDC1 3 ): 7.14 (2H, m), 6.89 (1H, t), 6.07 (1H, s), 4.15 (2Η, m), 3.96 (1H, m), 3.86 (2H, d ), 3.52 (1H, m), 3.17 (1H, m), 2.76 (2H, m), 2.49 (6H, m), 2.02 (5H, m), 1.48 (9H, m), 1.27 (5H, m) .
<실시예 62> tert-부틸 4-((2-플루오로 -4-(4-((R)-2-히드록시프 로필카바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1—카복시레 이트의 제조 Example 62 tert-Butyl 4-((2-fluoro-4- (4-((R) -2-hydroxypropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperi Dean-1—Manufacture of Carboxylate
Figure imgf000086_0002
Figure imgf000086_0002
(S)-(-)-3-피를리디놀을 사용하는 대신에， (I -1-아미노 -2-프로 판올을 사용하는 것을 제외하고， 상기 <실시예 44>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량' ： 138mg I 수율 ： 6OT). Instead of using (S)-(-)-3-pyridinol, it was carried out in the same manner as in <Example 44>, except that (I-1-amino-2-propanol was used. the title compound (yield ': 138mg I yield: 6OT).
¾ 匪 R (400, CDCls) ： 7.14 (2H, m)， 6.89 (1H, t) , 6.07 (1H, s), 4.15 (2H, m) , 3.96 (1Η, m)， 3.86 (2H, d) , 3.52 (1H, m) , 3.17 (1H, m) , 2.76 (2Hᅳ m) , 2.49 (6H, m)， 2.02 (5H, m), 1.48 (9H, m)， 1.27 (5H, m) .  ¾ 匪 R (400, CDCls): 7.14 (2H, m), 6.89 (1H, t), 6.07 (1H, s), 4.15 (2H, m), 3.96 (1Η, m), 3.86 (2H, d) , 3.52 (1H, m), 3.17 (1H, m), 2.76 (2H ᅳ m), 2.49 (6H, m), 2.02 (5H, m), 1.48 (9H, m), 1.27 (5H, m).
<실시예 63> tert-부틸 4-((4-(4-((S)-2,3—디히드록시프로필카 바모일)싸이클로핵스 -1-엔일 )ᅳ2-플루오로페녹시 )메틸)피페리딘 -1-카복 시레이트의 제조 Example 63 tert-Butyl 4-((4- (4-((S) -2,3—dihydroxypropylcarbamoyl) cyclonux-1-enyl) ᅳ 2-fluorophenoxy) methyl Preparation of Piperidine-1-Carboxyrate
Figure imgf000087_0001
Figure imgf000087_0001
(S)-(-)-3-피롤리디놀을 사용하는 대신에， (S)-3-아미노 -1，2-프 로판디올을 사용하는 것을 제외하고， 상기 <실시예 44>와 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 185mg I 수율 ： 80%) .  The same method as in <Example 44>, except that (S) -3-amino-1,2-propanediol is used instead of (S)-(-)-3-pyrrolidinol The title compound was prepared by the yield (yield: 185 mg I yield: 80%).
¾ NMR (400, CDC13) ： 7.18 (2H, m) , 6.93 (1H, t) , 6.11 (2H, m), 4.21 (2H, m)， 3.91 (3H, m)， 3.61 (4H, m) , 3.03 (2H, m) , 2.83 (2H, m), 2.16 (5H, m) , 2.03 (6H, m) , 1.50 (9H, m)， 1.31 (2H, m) . ¾ NMR (400, CDC1 3 ): 7.18 (2H, m), 6.93 (1H, t), 6.11 (2H, m), 4.21 (2H, m), 3.91 (3H, m), 3.61 (4H, m) , 3.03 (2H, m), 2.83 (2H, m), 2.16 (5H, m), 2.03 (6H, m), 1.50 (9H, m), 1.31 (2H, m).
<실시예 64> tert-부틸 4-((4-(4-((R)-2,3-디히드록시프로필카 바모일)싸이클로핵스 -1-엔일 )-2-플루오로페녹시 )메틸)피페리딘 -1-카복 시레이 Example 64 tert-Butyl 4-((4- (4-((R) -2,3-dihydroxypropylcarbamoyl) cyclonux-1-enyl) -2-fluorophenoxy) methyl Piperidine-1-carboxyl
Figure imgf000087_0002
Figure imgf000087_0002
(S)-(-)-3-피를라디놀을 사용하는 대신에， (R)-3-아미노 -1,2-프 로판디올을 사용하는 것을 제외하고， 상기 <실시예 44>와 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 177mg I 수율 ： 77%) .  The same as in <Example 44> except that (R) -3-amino-1,2-propanediol is used instead of (S)-(-)-3-pyridinol The title compound was prepared by the method (yield: 177 mg I yield: 77%).
XH NMR (400, CDCls) ： 7.18 (2H, m) , 6.93 (1Η, t) , 6.11 (2H, m), 4.21 (2H, m) , 3.91 (3H, m) , 3.61 (4H, m) , 3.03 (2H, m) , 2.83 (2H, m) , 2.16 (5H, m)， 2.03 (6H, m) , 1.50 (9H, m) , 1.31 (2H, m) . X H NMR (400, CDCls): 7.18 (2H, m), 6.93 (1Η, t), 6.11 (2H, m), 4.21 (2H, m), 3.91 (3H, m), 3.61 (4H, m) , 3.03 (2H, m), 2.83 (2H, m), 2.16 (5H, m), 2.03 (6H, m), 1.50 (9H, m), 1.31 (2H, m).
<실시예 65> 아제티딘 -1-일 (4-(4-((l-(3-이소프로필 -1,2,4-옥사 디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일 )메타논 의 제조 . . Example 65 Azetidin-1-yl (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) Preparation of Phenyl) cyclonux-3-enyl) methanone. .
Figure imgf000088_0001
Figure imgf000088_0001
(R)-3-아미노 -1,2-프로판디올을 사용하는 대신에， 아제티딘올 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 ： 90mg / 수율 ： 40%).  Instead of using (R) -3-amino-1,2-propanediol, the title compound was prepared in the same manner as in <Example 17>, except that azetidinol was used. : 90mg / yield: 40%).
¾ 醒 R (400， CDCls) ： 7.34 (2H, d)， 6.85 (2H, d)， 6.06 (1H, m) , 4.24 (4H, m) , 4.07 (2H, m)， 3.84 (2H, m) , 3.11 (2Η, t), 2.91 (1H, m) , 2.50 (4H, m) , 2.31 (3H, m) , 1.97 (5H, m) , 1.47 (2H, m) , 1.31 (6H, m) .  ¾ 醒 R (400, CDCls): 7.34 (2H, d), 6.85 (2H, d), 6.06 (1H, m), 4.24 (4H, m), 4.07 (2H, m), 3.84 (2H, m) , 3.11 (2Η, t), 2.91 (1H, m), 2.50 (4H, m), 2.31 (3H, m), 1.97 (5H, m), 1.47 (2H, m), 1.31 (6H, m).
<실시예 66> (4-(4-((l-(3-이소프로필 -1， ,4-옥사디아졸 -5-일) 피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔일 )'(모폴리노)메타논의 제조 Example 66 (4- (4-((l- (3-isopropyl-1,, 4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus- Preparation of 3-enyl) ' (morpholino) methanone
Figure imgf000088_0002
대신에 , 모르폴린을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하 여 표제 화합.물을 제조하였다 (수득량 ： 190mg / 수율 : 83%) .
Figure imgf000088_0002
Instead, the title compound was prepared in the same manner as in <Example 17>, except that morpholine was used. Yield: 190 mg / yield: 83%.
!H 匪 R (400, CDCls) ： 7.33 (2H, d) , 6.84 (2H, d) , 6.06 (1Η, m) , 4.20 (2H, d)， 3.84 (2H, d), 3.72 (8H, m)， 3.11 (2H, t), 2.91 (1H, m) , 2.77 (1H, m) , 2.52 (3H, m) , 2.31 (1H, m) , 1.98 (5H, m) , 1.50 (2H, m) , 1.31 (6H, d). ! H 匪 R (400, CDCls): 7.33 (2H, d), 6.84 (2H, d), 6.06 (1Η, m), 4.20 (2H, d), 3.84 (2H, d), 3.72 (8H, m) , 3.11 (2H, t), 2.91 (1H, m), 2.77 (1H, m), 2.52 (3H, m), 2.31 (1H, m), 1.98 (5H, m), 1.50 (2H, m), 1.31 (6 H, d).
<실시예 67> tert-부틸 4-((4-(4-(l,3-디히드록시프로판 -2-일카 바모일 )싸이클로핵스 -1-엔일) -2-플루오로페녹시 )메틸)피페리딘 -1-카복 시레이트의 제조 Example 67 tert-Butyl 4-((4- (4- (l, 3-dihydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) -2-fluorophenoxy) methyl) Preparation of Piperidine-1-carboxylate
Figure imgf000089_0001
Figure imgf000089_0001
(S)-(-)-3ᅳ피를리디놀을 사용하는 대신에， 2-아미노 -1，3-프로판 디을을 사용하는 것을 제외하고， 상기 <실시예 44>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 115mg / 수율 ： 53%).  The title compound was carried out in the same manner as in <Example 44>, except that 2-amino-1,3-propanediol was used instead of (S)-(-)-3 ᅳ pyridinol. Was prepared (yield: 115 mg / yield: 53%).
¾ NMR (400, CDC13) ： 7.10 (2H, m)， 6.88 (1H, t) , 6.41 (1H, m) , 6.06 (1H, m) , 4.15 (2H, m)， 3.91 (7H, m) , 2.77 (3H, m) , 2.45 (6H, m) , 2.02 (4H, m) , 1.32 (9H, m) , 1.26 (2H, m) . ¾ NMR (400, CDC1 3 ): 7.10 (2H, m), 6.88 (1H, t), 6.41 (1H, m), 6.06 (1H, m), 4.15 (2H, m), 3.91 (7H, m) , 2.77 (3H, m), 2.45 (6H, m), 2.02 (4H, m), 1.32 (9H, m), 1.26 (2H, m).
<실시예 68> tert-부틸 4-((5-(4-(1，3_디히드록시프로판 -2-일카 바모일)싸이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시 레이트 제조 Example 68 tert-Butyl 4-((5- (4- (1,3_dihydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) pi Ferridine-1-carboxylate preparation
Figure imgf000089_0002
Figure imgf000089_0002
(S)-2-아미노 -1-프로판올을 사용하는 대신에， 2-아미노 -1，3-프 로판디올을 사용하는 것을 제외하고 , 상기 <실시예 24>와 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： U2mg I 수율 ： 63%) .  Instead of using (S) -2-amino-1-propanol, the title compound was prepared in the same manner as in <Example 24>, except that 2-amino-1,3-propanediol was used. (Yield: U2mg I Yield: 63%).
¾ 匪 R (400, CDCls) ： 8.14 (1H, s) , 7.61 (1H, d)， 6.70 (1H, d) , 6.40 (1Η, d), 6.04 (1H, s) , 4.16 (4H, m) , 4.01 (1H, m) , 3.90 (4H, m), 2.76 (4H, m) , 2.12 ( 1H , m )， 1.93 (2H, m) , 1.86 (2H, m) , 1.48 (9H, m)' 1.26 (2H, m) .  ¾ 匪 R (400, CDCls): 8.14 (1H, s), 7.61 (1H, d), 6.70 (1H, d), 6.40 (1Η, d), 6.04 (1H, s), 4.16 (4H, m) , 4.01 (1H, m), 3.90 (4H, m), 2.76 (4H, m), 2.12 (1H, m), 1.93 (2H, m), 1.86 (2H, m), 1.48 (9H, m) ' 1.26 (2 H, m).
<실시예 69> tert-부틸 4-((2-플루오로 -4-(4- (모르폴린 -4-카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제조
Figure imgf000090_0001
Example 69 tert-butyl 4-((2-fluoro-4- (4- (morpholine-4-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Manufacture of Rate
Figure imgf000090_0001
(S)-(-)-3-피롤리디놀을 사용하는 대신에， 모르폴린을 사용하는 것을 제외하고, 상기 <실시예 44>와 동일한 방법으로 수행하여 표제 화합물올 제조하였다 (수득량 ： 192mg I 수율 ： 83%).  Instead of using (S)-(-)-3-pyrrolidinol, the title compound was prepared in the same manner as in <Example 44>, except that morpholine was used (yield: 192 mg). I yield: 83%).
¾ 匪 R (400, CDC13) ： 7.14 (2H, m) ( 6.89 (1H, t)； 6.09 (1H, m) , 4.16 (2H, m), 3.88 (2H, d) , 3.69 (6Η, m) , 3.58 (2Η, m) , 2.78 (3Η, m) , 2.48 (4H, m) , 1.91 (5H, m) , 1.48 (9Ή, s), 1.28 (2H, m). ¾ 匪 R (400, CDC1 3 ) ： 7.14 (2H, m) ( 6.89 (1H, t); 6.09 (1H, m), 4.16 (2H, m), 3.88 (2H, d), 3.69 (6Η, m ), 3.58 (2Η, m), 2.78 (3Η, m), 2.48 (4H, m), 1.91 (5H, m), 1.48 (9 μs, s), 1.28 (2H, m).
<실시예 70> tert-부틸 4-((5-(4- (모르풀린 -4-카보닐)싸이클로 핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트의 제조 Example 70 tert-Butyl 4-((5- (4- (morphulin-4-carbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine-1-carboxylate Manufacture
Figure imgf000090_0002
Figure imgf000090_0002
(S)_2-아미노 -1-프로관올을 사용하는 대신에， 모르폴린을 사용 하는 것을 제외하고, 상기 <실시예 24>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 210mg I 수율 ： 91%).  The title compound was prepared in the same manner as in <Example 24>, except that morpholine was used instead of (S) _2-amino-1-proguanol (yield: 210 mg I yield). : 91%).
XH NMR (400, CDCls) ： 8.14 (1H, s) , 7.63 (1H, d)， 6.68 (1H, d) , 6.05 (1Η, s) , 4.15 (4H, m) , 3.71 (6H, m) , 3.58 (2H, m) , 2.77 (3H, m), 2.52 (3H, m)， 2.30 (1H, m), 1.98 (3H, m) , 1.84 (2H, d) , 1.48 (9H, s), 1.27 (2H, m) . X H NMR (400, CDCls): 8.14 (1H, s), 7.63 (1H, d), 6.68 (1H, d), 6.05 (1Η, s), 4.15 (4H, m), 3.71 (6H, m) , 3.58 (2H, m), 2.77 (3H, m), 2.52 (3H, m), 2.30 (1H, m), 1.98 (3H, m), 1.84 (2H, d), 1.48 (9H, s), 1.27 (2H, m).
<실시예 71> tert-부틸 4-((2-플루오로 -4-(4- (싸이오모르폴린-Example 71 tert-Butyl 4-((2-fluoro-4- (4- (thiomorpholine-)
4-카보닐 )싸이클로핵스ᅳ1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 의 제조 Preparation of 4-carbonyl) cyclonucleox-1-1-yl) phenoxy) methyl) piperidine-1-carboxylate
(S)-(-)— 3ᅳ피를리디놀을 사용하는 대신에 , 싸이오모르폴린을 사 용하는 것을 제외하고， 상기 <실시예 44〉와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 210mg / 수율 : 87%) .  The title compound was prepared in the same manner as in <Example 44>, except that thiomorpholine was used instead of (S)-(-) — 3Pypyridinol. Gain ： 210mg / Yield: 87%).
^ NMR (400, CDC13) ： 7.14 (2H, m) , 6.89 ( 1H , t) , 6.07 (1H, m) , 4.16 (2H, m) , 3.98 (1H, m) , 3.88 (5H, d), 2.79 (2H, m), 2.66 (4H, m) , 2.31 (3H, m) , 2.01 (1H, m) , 1.91 (5H, m) , 1.48 (9Ή, s), 1.26 (2H, m) · ^ NMR (400, CDC1 3 ): 7.14 (2H, m), 6.89 (1H, t), 6.07 (1H, m), 4.16 (2H, m), 3.98 (1H, m), 3.88 (5H, d) , 2.79 (2H, m), 2.66 (4H, m), 2.31 (3H, m), 2.01 (1H, m), 1.91 (5H, m), 1.48 (9Ή, s), 1.26 (2H, m)
<실시예 72> tert-부틸 4-((5-(4- (싸이오모르폴린 -4-카보닐)싸 이클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트의 제조 Example 72 tert-Butyl 4-((5- (4- (thiomorpholine-4-carbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine Preparation of 1-carboxylate
Figure imgf000091_0002
Figure imgf000091_0002
(S)-2-아미노 -1-프로판을을 사용하는 대신에， 싸이오모르폴린을 사용하는 것을 제외하고， 상기 <실시예 24>와 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 ： 180mg / 수율 : 79¾).  The title compound was prepared in the same manner as in <Example 24>, except that thiomorpholine was used instead of (S) -2-amino-1-propane. : 180mg / yield: 79¾).
¾ 匪 R (400， CDCls) ： 8.14 (1H, s) , 7.62 (1H, d)， 6.71 (1H, d), 6.06 (1H, s), 4.16 (4H, m)， 3.85 (4H, m), 2.78 (2H, m) , 2.67- (4H, m) , 2.55 (3H, m) , 2.31 (1H, m) , 1.99 (3H, m) , 1.84 (2H, d)， 1.48 (9H, s)， 1.27 (2H, m) .  ¾ 匪 R (400, CDCls): 8.14 (1H, s), 7.62 (1H, d), 6.71 (1H, d), 6.06 (1H, s), 4.16 (4H, m), 3.85 (4H, m) , 2.78 (2H, m), 2.67- (4H, m), 2.55 (3H, m), 2.31 (1H, m), 1.99 (3H, m), 1.84 (2H, d), 1.48 (9H, s) , 1.27 (2H, m).
<실시예 73> tert-부탈 4-((2-플루오로 -4-(4- (싸이오모르폴린- 1,1-디옥사이드 -4-카보닐)싸이클로핵스 -1ᅳ엔일 )페녹시 )메틸)피페리딘- 1-카복시레이트의 제조
Figure imgf000092_0001
Example 73 tert-Butal 4-((2-fluoro-4- (4- (thiomorpholine-1,1-dioxide-4-carbonyl) cyclonux-1-1-enyl) phenoxy) Preparation of Methyl) piperidine-1-carboxylate
Figure imgf000092_0001
tert-부틸 4-((2-플루오로 -4-(4- (싸이오모르폴린 -4-카보닐)싸이 클로핵스 -1-엔일 )페녹시 )메틸)괴페리딘— 1-카복시레이트 120mg 를 THF7 물 (50^/25^)에 녹여 교반하였다. 옥손 (Oxone) 360mg 을 적가한 후 30분간 교반하였다. 반응 종결 후 에틸아세테이트 150 로 추출한 다 음 브라인 100 μΐ 로 세척한 후， 무수황산마그네슘으로 건조하고 농축 후 실리카 컬럼 크로마토그래피로 분리하여 표제 화합물을 제조하였다 (수득량 ： lOOmg I 수율 ： 72%).  tert-butyl 4-((2-fluoro-4- (4- (thiomorpholine-4-carbonyl) cyclonux-1-enyl) phenoxy) methyl) goperidin— 1-carboxylate 120 mg Was dissolved in THF7 water (50 ^ / 25 ^) and stirred. 360 mg of Oxone was added dropwise and stirred for 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate 150, washed with 100 μΐ of brine, dried over anhydrous magnesium sulfate, concentrated and separated by silica column chromatography to obtain the title compound (amount: 100 mg yield: 72%).
!H 匪 R (400, CDCls) ： 7.14 (2H, m)， 6.90 (1H, t), 6.07 (1H, m) , 4.19 (6Η, m)， 3.89 (2H, d), 3.09 (4H, d), 2.77 (3H, m), 2.54 (3H, m) , 2.33 (1H, m) , 2.00 (3Hᅳ m), 1.87 (2H, m) , 1.48 (9H, s) , 1.27 (2H, m). ! H 匪 R (400, CDCls): 7.14 (2H, m), 6.90 (1H, t), 6.07 (1H, m), 4.19 (6Η, m), 3.89 (2H, d), 3.09 (4H, d) , 2.77 (3H, m), 2.54 (3H, m), 2.33 (1H, m), 2.00 (3H ᅳ m), 1.87 (2H, m), 1.48 (9H, s), 1.27 (2H, m).
<실시예 74> (4-(4-((1-(3-이소프로필-1,2,4-옥사디아졸-5-일) 피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔일 ) (싸이오모폴리노)메 타논의 제조 Example 74 (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus 3-enyl) Preparation of (thiomorpholino) methanone
Figure imgf000092_0002
Figure imgf000092_0002
(R)-3-아미노 -1,2-프로판디을을 사용하는 대신에 , 싸이오모르폴 린을 사용하는 것을 제외하고 , 상기 <실시예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 165mg I 수율 ： 63%). l NMR (400， CDCls) ： 7.33 (2H, d) , 6.84 (2H, d)， 6.05 ( 1H， s), 4.23 (2H, m) , 3.97 (6H, m), 3.08 (2H, t) , 2.91 (1Η, m) , 2.78 (2H, m) , 2.66 (4H, m) , 2.51 (2H, m) , 2.31 (1H, m) , 2.03 (5H, m) , 1.48 (2H, m) , 1.32 (6H, d) .  Instead of using (R) -3-amino-1,2-propanedi, the title compound was prepared in the same manner as in <Example 17>, except that thiomorpholine was used ( Yield: 165 mg I yield: 63%). NMR (400, CDCls): 7.33 (2H, d), 6.84 (2H, d), 6.05 (1H, s), 4.23 (2H, m), 3.97 (6H, m), 3.08 (2H, t) 2.91 (1Η, m), 2.78 (2H, m), 2.66 (4H, m), 2.51 (2H, m), 2.31 (1H, m), 2.03 (5H, m), 1.48 (2H, m), 1.32 (6H, d).
<실시예 75> N-(2-플루오로에틸 )-4-(4-((l-(3-이소프로필- 1,2, 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔 카복스아마이드의 제조 Example 75 N- (2-fluoroethyl) -4- (4-((l- (3-isopropyl-) Preparation of 1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-ene carboxamide
Figure imgf000093_0001
Figure imgf000093_0001
(R)-3-아미노 -1，2-프로판디을을 사용하는 대신에， 2-플루오로에 틸아민을 사용하는 것을 제외하고， 상기 <실사예 17>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 ： 174mg I 수율 ： 75%).  Instead of using (R) -3-amino-1,2-propanedi, the title compound was prepared in the same manner as in <Example 17>, except that 2-fluoroethylamine was used. (Yield: 174 mg I Yield: 75%).
¾ 丽 R (400， CDC13) ： 7.33 (2H, d)， 6.87 (2H, d)， 6.04 (2H, m) , 4.53 (1H, m)， 4.27 (2H, d) , 3.86 (2Η, d) , 3.66 (2H, m), 3.21 (8H, m) , 2.01 (5H, m) , 1.45 (1H, m) , 1.31 (6H, m) . ¾ リ R (400, CDC1 3 ): 7.33 (2H, d), 6.87 (2H, d), 6.04 (2H, m), 4.53 (1H, m), 4.27 (2H, d), 3.86 (2Η, d ), 3.66 (2H, m), 3.21 (8H, m), 2.01 (5H, m), 1.45 (1H, m), 1.31 (6H, m).
<실시예 76> tert-부틸 3-(4-(4-((l-(3-이소프로필 -1，2，4-옥사 디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )-N-메틸싸이클로핵스 -3-엔카 복스아미도)프로필카바메이트의 제조 Example 76 tert-Butyl 3- (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy (Phenyl) -N-methylcyclonux-3-enecarboxamido) propylcarbamate
BocHN씌 ^
Figure imgf000093_0002
BocHN write ^
Figure imgf000093_0002
(R)-3—아미노 1,2-프로판디을을 사용하는 대신에， tert-부틸 3- (메틸아미노)프로필카바메이트을 사용하는 것을 제외하고， 상기 <실시 예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득 량 ： 160mg / 수율 ： 53%) .  Instead of using (R) -3—amino 1,2-propanedi, tert-butyl 3- (methylamino) propylcarbamate was carried out in the same manner as in <Example 17>, except that The compound was prepared (amount: 160 mg / yield: 53%).
¾ NMR (400, CDC13) ： 7.34 (2H, d) , 6.86 (2H, d), 6.07 ( 1H， m), 5.01 (1H, m) , 4.21 (2H, d)， 3.86 (2H, d), 3.56 (2H, m) 3.33 (2H, m) , 3.11 (5H, m) , 2.93 (1H, m)， 2.80 (1H, m) , 2.51 (2H, m) , 2.98 (1H, m) , 2.01 (5H, m) , 1.48 (11H, m) , 1.32 (6H, d) . ¾ NMR (400, CDC1 3 ): 7.34 (2H, d), 6.86 (2H, d), 6.07 (1H, m), 5.01 (1H, m), 4.21 (2H, d), 3.86 (2H, d) , 3.56 (2H, m) 3.33 (2H, m), 3.11 (5H, m), 2.93 (1H, m), 2.80 (1H, m), 2.51 (2H, m), 2.98 (1H, m), 2.01 (5H, m), 1.48 (11H, m), 1.32 (6H, d).
<실시예 77> N-(3-아미노프로필 )-4-(4-((l-(3-이소프로필- 1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐) -N-메틸싸이클로핵 스 -3- Example 77 N- (3-aminopropyl) -4- (4-((l- (3-isopropyl-) 1,2-4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N-methylcyclonucleose-3-
Figure imgf000094_0001
Figure imgf000094_0001
tert-부틸 3ᅳ(4ᅳ(4-((1-(3ᅳ이소프로필 -1，2，4—옥사디아졸 -5-일 ) 피페리딘—4-일 )메록시 )페닐 )-N-메틸싸이클로핵스 -3-엔카복스아미도) 로필카바메이트 loomg 를 DCM 25^에 녹여 교반하였다 . 디옥산 2βί 용해된 4N-HC1을 적가한 후 상온에서 3시간 교반하였다. 반웅 종결 생성되는 고체를 여과한 후 DCM 50 로 씻어준 후 건조하여 원하는 색 고체화합물을 얻었다 (수득량 ： 30mg I 수율 ： 34%). tert-butyl 3 ′ (4 ᅳ (4-((1- (3 ᅳ isopropyl-1,2,4—oxadiazole-5-yl) piperidine— 4 -yl) methoxy) phenyl) -N -Methylcyclonux-3-encarboxamido) Lofilcarbamate loomg was dissolved in DCM 25 ^ and stirred. Dioxane 2βί dissolved 4N-HC1 was added dropwise and stirred at room temperature for 3 hours. Banung Termination The resulting solid was filtered, washed with DCM 50 and dried to give the desired colored solid compound (yield: 30 mg I yield: 34%).
χΥί 匪 R (400, DMS0) ： 7.34 (2Ή, d) , 6.86 (2H, d) , 6.07 (1H, m), 5.01 (1H, m) , 4.21 (2H, d) , 3.86 (2H, d) , 3.56 (2H, m) , 3.33 (2H, m) , 3.11 (5H, m) , 2.93 (1H, m)， 2.80 (1H, m)， 2.51 (2Hᅳ m)， 2.98 (1H, m), 2.01 (5H, m) , 1.48 (2H, m) , 1.32 (6H, d) .  χΥί 匪 R (400, DMS0): 7.34 (2H, d), 6.86 (2H, d), 6.07 (1H, m), 5.01 (1H, m), 4.21 (2H, d), 3.86 (2H, d) , 3.56 (2H, m), 3.33 (2H, m), 3.11 (5H, m), 2.93 (1H, m), 2.80 (1H, m), 2.51 (2H ᅳ m), 2.98 (1H, m), 2.01 (5H, m), 1.48 (2H, m), 1.32 (6H, d).
<실시예 78> 4-(4-((1-(3-이소프로필-1,2,4-옥사디아졸-5-일)피 페리딘 -4-일)메특시 )페닐) -N-(2,2, 2—트리플루오로에틸)싸이클로핵스- 3-엔카복스아마이드의 제조 Example 78 4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N- Preparation of (2,2,2-trifluoroethyl) cyclonux-3-encarboxamide
프후에흰  Phu White
Figure imgf000094_0002
Figure imgf000094_0002
(R)-3-아미노 -1，2-프로판디올을 사용하는 대신에， 2，2，2-트리플 루오로에틸 아민을 사용하는 것을 제외하고， 상기 <실시예 17〉과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 195mg I 수 율 ： 85%).  (R) -3-Amino-1,2-propanediol, instead of using 2,2,2-trifluoroethyl amine, but in the same manner as in Example 17 above The title compound was obtained (amount: 195 mg I yield: 85%).
¾ 匪 R (400, CDCls) ： 7.33 (2H, d) , 6.86 (2H, d) , 6.04 ( 1Η， m), 5.96 (1H, m) , 4.23 (2H, d) , 3.99 (2H, m) , 3.84 (2Hᅳ d) , 3.12 (2H, m), 2.92 (1H, m) , 2.48 (5H, m) , 2.01 (5H, m) , 1.46 (2H, m) , 1.29 (6H, d) . ¾ 匪 R (400, CDCls): 7.33 (2H, d), 6.86 (2H, d), 6.04 (1Η, m), 5.96 (1H, m), 4.23 (2H, d), 3.99 (2H, m) , 3.84 (2H ᅳ d), 3.12 (2H, m), 2.92 (1H, m), 2.48 (5H, m), 2.01 (5H, m), 1.46 (2H, m), 1.29 (6 H, d).
<실시예 79> (4-에틸피페라진 -1-일 ) (4-(4-((l-(3-이소프로필- 1，2,4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸아클로핵스 -3-엔 일)메타논의 제조 Example 79 (4-ethylpiperazin-1-yl) (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine Preparation of 4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000095_0001
Figure imgf000095_0001
(R)-3-아미노 -1,2-프로판디올을 사용하는 대신에， N-에틸피페라 진을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 150mg I 수율 ： 65%). xYi 丽 R (400， CDCls) ： 7.33 (2H, d)， 6.86 (2H, d) , 6.05 (1H, m) , 4.23 (2Η, d) , 3.85 (2H, d)， 3.70 (2H, m) . 3.59 (2H, m)， 3.08 (2H, t), 2.92 (1H, m) , 2.89 (1H, m) , 2.50 (9H, m), 2.24 (1H, m) , 1.98 (5H, m), 1.48 (2H, m) , 1.31 (6H, d) , 1.11 (3H, t) .  The title compound was prepared in the same manner as in <Example 17>, except that N-ethylpiperazine was used instead of (R) -3-amino-1,2-propanediol. (Yield: 150 mg I yield: 65%). x Yi Li R (400, CDCls): 7.33 (2H, d), 6.86 (2H, d), 6.05 (1H, m), 4.23 (2Η, d), 3.85 (2H, d) ， 3.70 (2H, m) . 3.59 (2H, m) ， 3.08 (2H, t), 2.92 (1H, m), 2.89 (1H, m), 2.50 (9H, m), 2.24 (1H, m), 1.98 (5H, m), 1.48 (2H, m), 1.31 (6H, d), 1.11 (3H, t).
<실시예 80> -(1，3-디히드록시프로판-2-일)-4-(3-플루오로-4- ((1-(3-이소프로필-1,2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페 닐)싸 Example 80-(1,3-dihydroxypropan-2-yl) -4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazole -5-yl) piperidin-4-yl) methoxy) phenyl) sa
Figure imgf000095_0002
Figure imgf000095_0002
4-(3-플루오로 -4-((1-(3ᅳ이소프로필 -1,2,4-옥사디아졸 -5-일 )피 페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3—엔카복살릭 엑시드 250mg 를 DMF 25 에 녹여 교반하였다. EDCI 200mg, HOBt 150mg 을 순차적으로 적가한 후 10분간 추가적으로 교반하였다. 2-아미노 -1,3-프로판디올 lOOmg 을 적가한 후 상온에서 12시간 교반하였다. 반웅 종결 후 증류 수 50 βί 를 0 °C에서 천천히 가하고 생성되는 고체를 여과하여 건조하 여 원하는 흰색 고체화합물올 얻었다 (수득량 ： 210mg I 수율 ： 71%).4- (3-fluoro-4-((1- (3 (isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux- 250 mg of 3—Encarboxic acid was dissolved in DMF 25 and stirred. EDCI 200mg, HOBt 150mg was added dropwise sequentially followed by additional stirring for 10 minutes. 100 mg of 2-amino-1,3-propanediol was added dropwise, followed by stirring at room temperature for 12 hours. After completion of reaction, distilled water 50 βί was slowly added at 0 ° C, and the resulting solid was filtered and dried. The desired white solid compound was obtained (amount: 210 mg I yield: 71%).
¾ NMR (400， CDCls) ： 7.14 (2H, m) , 6.91 (1H, t) , 6.37 (1H, m) , 6.07 (1H, m) , 4.24 (2H, d) , 4.01 ( 1H， m)， 3.91 (2H, m) , 3.81 (4H, m) , 3.15 (2Ή, t) , 2.94 (1H, m) , 2.64 (2H, m) , 2.50 (5H, m) , 2.14 (2H, m) , 1.92 (2H, d) , 1.88 (1H, m) , 1.45 (2H, m) , 1.30 (6H, d). ¾ NMR (400, CDCls): 7.14 (2H, m), 6.91 (1H, t), 6.37 (1H, m), 6.07 (1H, m), 4.24 (2H, d), 4.01 (1H, m) ， 3.91 (2H, m), 3.81 (4H, m), 3.15 (2Ή, t), 2.94 (1H, m), 2.64 (2H, m), 2.50 (5H, m), 2.14 (2H, m), 1.92 (2H, d), 1.88 (1H, m), 1.45 (2H, m), 1.30 (6H, d).
〈실시예 81> 4-(3-플루오로-4-((1-(3-이소프로필-1，2,4-옥사디 아졸 -5-일 )피페리딘—4-일 )메록시 )페닐 )-N-(2-히드록시에틸 )-N-메틸싸 이클로핵스 -3-엔카복스아마이드의 제조 Example 81 4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Preparation of Phenyl) -N- (2-hydroxyethyl) -N-methylcyclonux-3-enecarboxamide
Figure imgf000096_0001
Figure imgf000096_0001
2-아미노 -1， 3-프로판디올을 사용하는 대신에， 2- (메틸아미노)에 탄올을 사용하는 것을 제외하고， 상기 <실시예 80〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 168mg I 수율 ： 73%) .  The title compound was prepared in the same manner as in <Example 80>, except that, instead of using 2-amino-1,3-propanediol, using tanol in 2- (methylamino) Yield: 168mg I yield: 73%).
^ NMR (400, CDC13) ： 7.15 (1H, d)， 7.11(1H, d) , 6.9K1H, m)^ NMR (400, CDC1 3 ): 7.15 (1H, d), 7.11 (1H, d), 6.9K1H, m)
6.11 (1H, s) , 4.26 (2H, d), 3.94 (2H, d) , 3.84 (2H, m) , 3.61 (2H, m) , 3.21 (3H, s) , 3.16 (2H, m) , 3.05 (1H, s) , 2.91 (1H, m) , 2.87 (1H, m) , 2.25-2.61 (4H, m) , 1.85-2.19 (5H, m) , 1.43 (2H, m) , 1.30 (6H, d). 6.11 (1H, s), 4.26 (2H, d), 3.94 (2H, d), 3.84 (2H, m), 3.61 (2H, m), 3.21 (3H, s), 3.16 (2H, m), 3.05 (1H, s), 2.91 (1H, m), 2.87 (1H, m), 2.25-2.61 (4H, m), 1.85-2.19 (5H, m), 1.43 (2H, m), 1.30 (6H, d ).
<실시예 82> tertᅳ부틸 4-((2-플루오로 -4-(4-(3-히드록시 -2,2- 디메틸프로필카바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1- 카복시레이트의 제조 Example 82 tert ᅳ butyl 4-((2-fluoro-4- (4- (3-hydroxy-2,2-dimethylpropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) pi Preparation of Ferridine-1-carboxylate
Figure imgf000096_0002
Figure imgf000096_0002
(S)_(-)-3-피를리디놀을 사용하는 대신에 , 3-아미노 -2,2-디메틸 프로판 -1-올 을 사용하는 것을 제외하고， 상기 <실시예 44>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 150mg I 수 율 ： 65%). The same as in <Example 44>, except that instead of using (S) _ (-)-3-pyridinol, 3-amino-2,2-dimethyl propane-1-ol is used. The title compound was prepared by the method (yield: 150 mg I yield: 65%).
匪 R (400, CDC13) ： 7.15 (1H, d), 7.11(1H, d) , 6.9K1H, m) , 6.11 (1H, s) , 6.00 (1H, m) , 4.19 (2H, m) , 3.89 (3H, m) , 3.18 (4H, m) , 2.81 (2H, m) , 2.45-2.61 (5H, m) , 1.85-2.19 (4H, m) , 1.48 (9H, s) , 1.34 (2H, m) , 0.89 (6H, d) . 匪 R (400, CDC1 3 ): 7.15 (1H, d), 7.11 (1H, d), 6.9K1H, m), 6.11 (1H, s), 6.00 (1H, m), 4.19 (2H, m), 3.89 (3H, m), 3.18 (4H, m), 2.81 (2H, m), 2.45-2.61 (5H, m), 1.85-2.19 (4H, m), 1.48 (9H, s), 1.34 (2H, m), 0.89 (6H, d).
<실시예 83> 4-(3-플루오로 -4-((l-(3-이소프로필 -1，2，4-옥사디 아졸 -5-일)피페리딘— 4-일)메톡시 )페닐 )-N-((S)— 1—히드톡시프로판ᅳ 2ᅳ 일)싸이클로핵스ᅳ3ᅳ엔카복스아마이드의 제조 Example 83 4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin- 4-yl) methoxy) Preparation of Phenyl) -N-((S) — 1—hydroxytoxypropionate 2) yl) cyclonuxium 3′encarboxamide
Figure imgf000097_0001
Figure imgf000097_0001
2-아미노 -1，3-프로판디올을 사용하는 대신에 , (S)-2-아미노ᅳ1- 프로판을을 사용하는 것을 제외하고， 상기 <실시예 80>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 95mg I 수율 : 48%) .  Instead of using 2-amino-1,3-propanediol, the title compound was prepared in the same manner as in <Example 80>, except that (S) -2-amino ᅳ 1-propane was used. (Yield: 95 mg I Yield: 48%).
Έ 匪 R (400， CDC13)- ： 7.15 (1H, d) , 7.11(1H, d)， 6.9K1H, m)匪 匪 R (400, CDC1 3 )-： 7.15 (1H, d), 7.11 (1H, d), 6.9K1H, m)
6.11 (1H, s)ᅳ 5.71 (1Hᅳ d) , 4.25 (2H, d) , 4.16 (1H, m)， 3.92 (2H, d) , 3.65 (2H, m) , 3.16 (2H, m)， 2.91 (1H, m)， 2.35-2.61 (5H, m)，6.11 (1H, s) ᅳ 5.71 (1H ᅳ d), 4.25 (2H, d), 4.16 (1H, m), 3.92 (2H, d), 3.65 (2H, m), 3.16 (2H, m) ， 2.91 (1H, m) ， 2.35-2.61 (5H, m) ，
2.12 (2H, m) , 1.98 (2H, d) , 1.48 (2H, m)， 1.36(6H, d)， 1.2K3H, d) . 2.12 (2H, m), 1.98 (2H, d), 1.48 (2H, m), 1.36 (6H, d), 1.2K3H, d).
<실시예 84> 4-(3-플루오로-4-((1-(3-이소프로필-1，2,4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )-N-((R)-l-히드록시프로관 -2- 일)싸이클로핵스 -3-엔카복스아마이드의 제조
Figure imgf000098_0001
Example 84 4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Preparation of Phenyl) -N-((R) -l-hydroxypropane-2-yl) cyclonux-3-encarboxamide
Figure imgf000098_0001
2-아미노ᅳ1，3-프로판다올을 사용하는 대신에， (R)-2-아미노 -1- 프로판올을 사용하는 것을 제외하고， 상기 <실시예 80>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 120mg I 수율 ： 53%) .  The title compound was prepared in the same manner as in <Example 80>, except that (R) -2-amino-1-propanol was used instead of 2-amino ᅳ 1,3-propanedaol. (Yield: 120 mg I yield: 53%).
!H 匪 R (400， CDCls) ： 7.15 (1H, d) , 7.11(111， d)., 6.9K1H, m) ! H 匪 R (400, CDCls): 7.15 (1H, d), 7.11 (111, d)., 6.9K1H, m)
6.11 (1H, s) , 5.71 (1H, d) , 4.25 (2H, d) , 4.16 (1H, m) , 3.92 (2H, d) , 3.65 (2H, m) , 3.16 (2H, m)， 2.91 (1H, m), 2.35-2.61 (5H, m) ,6.11 (1H, s), 5.71 (1H, d), 4.25 (2H, d), 4.16 (1H, m), 3.92 (2H, d), 3.65 (2H, m), 3.16 (2H, m) ， 2.91 (1H, m), 2.35-2.61 (5H, m),
2.12 (2H, m), 1.98 (2H, d) , 1.48 (2H, m)， 1.36(6H, d)， 1.21(3H, d). 2.12 (2H, m), 1.98 (2H, d), 1.48 (2H, m), 1.36 (6H, d), 1.21 (3H, d).
<실시예 85> tert-부틸 4-((4ᅳ (4-(2，2-디플루오로에틸카바모일 ) 싸이클로핵스 -1-엔일)ᅳ 2-폴루오로페녹시 )메틸)피페리딘 -1-카복시레이 트의 제조 . Example 85 tert-Butyl 4-((4 '(4- (2,2-difluoroethylcarbamoyl) cyclonux-1-enyl) ᅳ 2-polorophenoxy) methyl) piperidine Preparation of -1-carboxylate.
Figure imgf000098_0002
Figure imgf000098_0002
(S)-(-)-3-피를라디놀을 사용하는 대신에， 2，2-디폴루오로에틸 아민을 사용하는 것을 제외하고， 상기 <실시예 44>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 150mg I 수율 ： 65%) .  The title compound was carried out in the same manner as in <Example 44>, except that 2,2-dipoloroethyl amine was used instead of (S)-(-)-3-pyridinol. Was prepared (yield: 150 mg I yield: 65%).
^ 丽 R (400, CDCls) : 7.15 (1H, d)， 7.11(1H, d) , 6.9K1H, m) 6.11 (1Η, s) , 5.88 (1H, m) , 5.85 (1H, m) , 4.16 (2H, m) , 3.87 ,(2H, d) , 3.69 (2H, m) , 2.77 (2H, m) , 2.35-2.61 (5H, m) , 2.12 (2H, m) , 2.02 (1H, m) , 1.89 (3H, m) , 1.46(9H, s), 1.25(3H, m) . ^ R (400, CDCls): 7.15 (1H, d), 7.11 (1H, d), 6.9K1H, m) 6.11 (1Η, s), 5.88 (1H, m), 5.85 (1H, m), 4.16 (2H, m), 3.87 , (2H, d), 3.69 (2H, m), 2.77 (2H, m), 2.35-2.61 (5H, m), 2.12 (2H, m), 2.02 (1H, m) , 1.89 (3H, m), 1.46 (9H, s), 1.25 (3H, m).
<실시예 86> tert-부틸 4-((5ᅳ(4-(2,2,2-트리를루오로에틸카바 모일)싸아클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸 )피페리딘 -1-카복시레 이트의 제조
Figure imgf000099_0001
Example 86 tert-Butyl 4-((5 '(4- (2,2,2-trifluoroethylcarbamoyl) cycloclox-1-enyl) pyridin-2-yloxy) methyl) pi Preparation of Ferridine-1-carboxylate
Figure imgf000099_0001
(S)-2-아미노 -1-프로판올을 사용하는 대신에， 2,2,2-트리플루오 로에탈아민 을 사용하는 것을 제외하고 , 상기 <실시예 24>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： llOmg I 수 율 ： 48%) .  Instead of using (S) -2-amino-1-propanol, the title compound was prepared in the same manner as in <Example 24>, except that 2,2,2-trifluoroethanolamine was used. (Yield: llOmg I Yield: 48%).
!H NMR (400, CDC13) ： 8.14 (1H, d)， 7.61(1H, d) , 6.70(1H, d) 6.05 1H, s) , 5.86 (1H, m) , 4.16 (4H, d) , 3.99 (2H, m) , 2.76 (2H, m) ,2.35-2.61 (5H, m) , 2.12 (1H, m) , 1.89 (2H, m) , 1.81(2H, d), 1.48(9H, s) , 1.33(2H, m) . ! H NMR (400, CDC1 3 ): 8.14 (1H, d), 7.61 (1H, d), 6.70 (1H, d) 6.05 1H, s), 5.86 (1H, m), 4.16 (4H, d), 3.99 (2H, m), 2.76 (2H, m), 2.35-2.61 (5H, m), 2.12 (1H, m), 1.89 (2H, m), 1.81 (2H, d), 1.48 (9H, s), 1.33 (2 H, m).
<실시예 87> tert-부될 4-((5-(4-(2,2-다플루오로에틸카바모일 ) 싸이클로핵스— 1-엔일)피리딘 -2-일옥시 )메틸 )피페리딘 -1-카복시레이트 의 제 Example 87 4-((5- (4- (2,2-difluoroethylcarbamoyl) cyclonucleus— 1-enyl) pyridin-2-yloxy) methyl) piperidine-1 -Made of carboxylate
Figure imgf000099_0002
Figure imgf000099_0002
(S)_2-아미노 -1-프로판올을 사용하는 대신에 , 2，2-디플루오로에 틸아민을 사용하는 것을 제외하고， 상기 <실시예 24>와 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 ： 150mg I 수율 : 65%).  Preparation of the title compound in the same manner as in <Example 24>, except that 2,2-difluoroethylamine was used instead of (S) _2-amino-1-propanol. (Yield: 150 mg I yield: 65%).
XH NMR (400, CDCI3) ： 8.14 (1H, d) , 7.6K1H, d)， 6.70(1H, d), 6.05 (1H, s), 5.88 (1H, m) , 5.85 (1H, m) , 4.16 (4H, (1)， 3.70 (2H, m) , 2.76 (2H, m) , 2.35-2.61 (5H, m)， 2.12 (1H, m) , 1.98 (2H, m)， 1.82 (2H, d) , 1.48(9H, s) , 1.29(3H, m) . X H NMR (400, CDCI3): 8.14 (1H, d), 7.6K1H, d), 6.70 (1H, d), 6.05 (1H, s), 5.88 (1H, m), 5.85 (1H, m), 4.16 (4H, 1), 3.70 (2H, m), 2.76 (2H, m), 2.35-2.61 (5H, m), 2.12 (1H, m), 1.98 (2H, m), 1.82 (2H, d ), 1.48 (9H, s), 1.29 (3H, m).
<실시예 88> tert-부틸 4-( (5-(4-(2-플루오로에틸카바모일)싸 o 클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘ᅳ 1ᅳ카복시레이트의 제 조
Figure imgf000100_0001
Example 88 tert-Butyl 4-((5- (4- (2-fluoroethylcarbamoyl) case o clonus-1-enyl) pyridin-2-yloxy) methyl) piperidine Preparation of Carboxylate
Figure imgf000100_0001
(S)-2-아미노 -1-프로판올을 사용하는 대신에 , 2-플루오로에틸아 민을 사용하는 것을 제외하고， 상기 <실시예 24>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 120mg I 수율 ： 52%).  Instead of using (S) -2-amino-1-propanol, the title compound was prepared in the same manner as in <Example 24>, except that 2-fluoroethylamine was used. Yield: 120 mg I yield: 52%).
!H 匪 R (400， CDCls) ： 8.14 (1H, d) , 7.6K1H, d)， 6.70C1H, d) 6.05 (1H, s) , 5.93 (1H, m) , 4.55 (2H, m) , 4.16 (4H, d) , 3,67 (2H, m) , 2.76 (2H, m) , 2.35-2.61 (5H, m) , 2.12 (1H, m) , 1.98 (2H, m)， 1.82 (2H, d) , 1.48(9H, s) , 1.29(3H, m) . ! H 匪 R (400, CDCls): 8.14 (1H, d), 7.6K1H, d), 6.70C1H, d) 6.05 (1H, s), 5.93 (1H, m), 4.55 (2H, m), 4.16 ( 4H, d), 3,67 (2H, m), 2.76 (2H, m), 2.35-2.61 (5H, m), 2.12 (1H, m), 1.98 (2H, m), 1.82 (2H, d) , 1.48 (9H, s), 1.29 (3H, m).
<실시예 89> (4-싸이클로프로필피페라진 -1-일 ) (4-(4-((l-(3-이 소프로 톡시 )페닐)싸이클로 핵스 -3 Example 89 (4-cyclopropylpiperazin-1-yl) (4- (4-((l- (3-isopropoxy) phenyl) cyclonux-3
Figure imgf000100_0002
Figure imgf000100_0002
(R)-3-아미노 -1,2-프로판디올을 사용하는 대신에， 싸이클로프로 필피페라진 을 사용하는 것을 제외하고， 상기 <실시예 17>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 210mg I 수 율 ： 87%),  The title compound was prepared in the same manner as in <Example 17>, except that instead of using (R) -3-amino-1,2-propanediol, cyclopropylpiperazine was used ( Yield: 210mg I yield: 87%),
XH NMR (400, CDCls) ： 7.32 (2H, d) , 6.85(2H, d) , 6.05(1Η, d) 4.22 (2Η, d) , 3.85 (2Η, d)， 3.66 (2Η, m)， 3.53 (2H, m), 3.12 (3H, m) , 2.81 (3H,. m) , 2.35-2.61 (8H, m), 1.91-2.14 (6H, m)， 1.68 (1H, m) , 1.48 (2H, m) , 1.32(6H, d), 1.15(1H, m), 0.48(4H, m) . X H NMR (400, CDCls): 7.32 (2H, d), 6.85 (2H, d), 6.05 (1Η, d) 4.22 (2Η, d), 3.85 (2Η, d) ， 3.66 (2Η, m) ， 3.53 (2H, m), 3.12 (3H, m), 2.81 (3H, .m), 2.35-2.61 (8H, m), 1.91-2.14 (6H, m), 1.68 (1H, m), 1.48 (2H , m), 1.32 (6H, d), 1.15 (1H, m), 0.48 (4H, m).
<실시예 90> tert-부틸 4-((5-(4-((R)-3-플루오로피를리딘 -1-카 보닐 )싸이클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸)피페리딘ᅳ 1-카복시레 이트의 제조
Figure imgf000101_0001
Example 90 tert-Butyl 4-((5- (4-((R) -3-fluoropyridine-1-carbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl Preparation of Piperidine ᅳ 1-carboxylate
Figure imgf000101_0001
(S)-2-아미노 -1-프로판올을 사용하는 대신에， (R)-3—플루오로피 를리딘을 사용하는 것을 제외하고 상기 <실시예 24〉와 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 ： 165mg / 수율 ： 72%).  Instead of using (S) -2-amino-1-propanol, the title compound was prepared in the same manner as in <Example 24>, except that (R) -3—fluoropyridine was used. (Quantity: 165 mg / yield: 72%).
XH NMR (400, CDCls) ： 8.15 (1H, s)ᅳ 7.63(1H, d), 6.70(1H, d) , 6.08 (1H, s ) , 5.31 (1H, m)， 4.16 (4H, m) , 3.53-4.01(2H , m) , 2.76 (2H, m) , 2.35-2.61 (5H, m) , 1.80-2.16 (6H, m )， 1.48(9H, s) , 1.29(3H, m) . <실시예 91> tert-부틸 4-((5-(4-((S)-3-플루오로피를리딘 -1-카 보닐)싸이클로헥스 - 1 -엔일)피리딘ᅳ 2 -일옥시 )메틸)피페리딘 - 1 -카복시레 이트의 제조 X H NMR (400, CDCls): 8.15 (1H, s) ᅳ 7.63 (1H, d), 6.70 (1H, d), 6.08 (1H, s), 5.31 (1H, m), 4.16 (4H, m) , 3.53-4.01 (2H, m), 2.76 (2H, m), 2.35-2.61 (5H, m), 1.80-2.16 (6H, m), 1.48 (9H, s), 1.29 (3H, m). Example 91 tert-Butyl 4-((5- (4-((S) -3-fluoropyridine-1-carbonyl) cyclohex-1-enyl) pyridinyl 2-yloxy) methyl Preparation of Piperidine-1-carboxylate
Figure imgf000101_0002
Figure imgf000101_0002
(S)-2-아미노 -1-프로판을을 사용하는 대신에， (S)-3-플루오로피 를리딘을 사용하는 것을 제외하고， 상기 <실시예 24〉와 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 ： 120mg I 수율 ： 53%).  Instead of using (S) -2-amino-1-propane, except for using (S) -3-fluoropyridine, the procedure was carried out in the same manner as in <Example 24>, and the title was Compounds were prepared (yield amount: 120 mg I yield: 53%).
^ NMR (400, CDCls) ： 8.15 (1H, s), 7.63(1H, d) , 6.70(1Η, d) , 6.08 (1Η, s) , 5.31 (1Η, m) , 4.16 (4Η, m) , 3.53-4.01 (2Η , m)， 2.76 (2Η, m) , 2.35-2.61 (5Η, m) , 1.80-2.16 (6Η, m) , 1.48(9Η, s) , 1.29(3Η, m) .  ^ NMR (400, CDCls): 8.15 (1H, s), 7.63 (1H, d), 6.70 (1Η, d), 6.08 (1Η, s), 5.31 (1Η, m), 4.16 (4Η, m), 3.53-4.01 (2Η, m), 2.76 (2Η, m), 2.35-2.61 (5Η, m), 1.80-2.16 (6Η, m), 1.48 (9Η, s), 1.29 (3Η, m).
<실시예 92> 4-(3-플루오로 -4-((1-(3-이소프로필 -1,2，4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐) -Ν-(2,2,2-트리플루오로에틸)싸 이클로핵스 -3ᅳ엔카복스아마이드의 제조
Figure imgf000102_0001
Example 92 4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Preparation of Phenyl) -Ν- (2,2,2-trifluoroethyl) cyclonux-3eneenecarboxamide
Figure imgf000102_0001
2-아미노 -1，3-프로판디올을 사용하는 대신에， 2，2，2-트리플루오 로에틸아민 을 사용하는 것을 제외하고， 상기 <실시예 80>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 140nig I 수 율 ： 62%).  The title compound was prepared in the same manner as in <Example 80>, except that 2,2,2-trifluoroethylamine was used instead of 2-amino-1,3-propanediol. (Yield: 140nig I yield: 62%).
¾ NMR (400， CDCls) ： 7.11 (2H, m)， 6.91(1H, m)， 6.07(1H, d) 5.80 (1H, m) , 4.22 (2H, d) , 3.99 (1H, m) , 3.92 (2H, d) , 3.12 (2H, m) , 2.92 (1H, m) , 2.35-2.61 (5H, m) , 1.83-2.21 (5H, m)， 1.48 (2H, m) , 1.32C6H, d) .  ¾ NMR (400, CDCls): 7.11 (2H, m), 6.91 (1H, m), 6.07 (1H, d) 5.80 (1H, m), 4.22 (2H, d), 3.99 (1H, m), 3.92 (2H, d), 3.12 (2H, m), 2.92 (1H, m), 2.35-2.61 (5H, m), 1.83-2.21 (5H, m), 1.48 (2H, m), 1.32C6H, d) .
<실시예 93> N-(2,2-디플루오로에틸) -4-(3-플루오로 -4-((l-(3- 이소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클 로핵스 Example 93 N- (2,2-difluoroethyl) -4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazole-5) 1) piperidin-4-yl) methoxy) phenyl) cyclonucleus
Figure imgf000102_0002
Figure imgf000102_0002
2-아미노 -1,3-프로판디올을 사용하는 대신에， 2, 2-디플루오로에 틸아민을 사용하는 것을 제외하고, 상기 <실시예 80>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 ： 110mg 7 수율 ： 49%).  Preparation of the title compound in the same manner as in <Example 80>, except that 2, 2-difluoroethylamine was used instead of 2-amino-1,3-propanediol. (Yield: 110 mg 7 yield: 49%).
:H 匪 R (400, CDC13) ： 7.11 (2H, m) , 6.91(1H, m)， 6.07(1H, d) , 5.89 (1Η, m) , 5.81 (1H, m) , 4.22(2H, d) , 3.99 (1H, m) , 3.69 (2H, m), 3.12 (2H, m) , 2.92 (1H, m) , 2.35-2.61 (5H, m) , 1.83-2.21 (5H, m) , 1.48 (2H, m) , 1.32(6H, d) . : H 匪 R (400, CDC1 3 ): 7.11 (2H, m), 6.91 (1H, m), 6.07 (1H, d), 5.89 (1Η, m), 5.81 (1H, m), 4.22 (2H, d), 3.99 (1H, m), 3.69 (2H, m), 3.12 (2H, m), 2.92 (1H, m), 2.35-2.61 (5H, m), 1.83-2.21 (5H, m), 1.48 (2H, m), 1.32 (6H, d).
<실시예 94> 4-(3-플루오로-4-((1-(3-이소프로필-1，2,4-옥사디 아졸 -5-일)피페리딘— 4-일)메톡시 )페닐 )-N-(2ᅳ플루오로에틸 )싸이클로핵 스 -3-엔카복스아마이드의 제조 Example 94 4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine- 4-yl) methoxy) Phenyl) -N- (2 ᅳ fluoroethyl) cyclonucleus -3- Production of Encarboxamide
Figure imgf000103_0001
Figure imgf000103_0001
2-아미노 -1,3-프로판디을을 사용하는 대신에， 폴루오로에틸아민 을 사용하는 것을 제외하고 상기 <실시예 80>과 동일한 방법으로 수 행하여 표제 화합물을 제조하였다 (수득량 ： 120mg / 수율 ： 53%).  Instead of using 2-amino-1,3-propanedi, the title compound was prepared in the same manner as in <Example 80> except for using poloroethylamine (yield: 120 mg / Yield: 53%).
¾ 丽 R (400， CDCls) ： 7.11 (2H, m) , 6.91(1H, m)， 6.07(1H, d) 5.94 (1H, s) , 4.55(2H, m) , 4.22 (2H, d)， 3.99 (1H, m), 3.63 (2H, m) , 3.12 (2H, m), 2.92 (1H, m) , 2.35-2.61 (5H, m) , 1.83-2.21 (5H, m) , 1.48 (2H, m) , 1.32(6H, d) .  ¾ δ R (400, CDCls): 7.11 (2H, m), 6.91 (1H, m), 6.07 (1H, d) 5.94 (1H, s), 4.55 (2H, m), 4.22 (2H, d) ， 3.99 (1H, m), 3.63 (2H, m), 3.12 (2H, m), 2.92 (1H, m), 2.35-2.61 (5H, m), 1.83-2.21 (5H, m), 1.48 (2H, m), 1.32 (6H, d).
<실시예 95> (4-(3-플루오로-4-((1-(3-이소프로필-1，2,4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일) ((S)-3-플 루오로피를리딘 -1-일)메타논의 제조 Example 95 (4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy Preparation of (phenyl) cyclonux-3-enyl) ((S) -3-fluoropyridin-1-yl) methanone
Figure imgf000103_0002
Figure imgf000103_0002
2-아미노 -1,3-프로판디올을 사용하는 대신에 , (S)— 3ᅳ플루오로피 를리딘을 사용하는 것을 제외하고， 상기 <실시예 80>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 ： 185mg / 수율 ： 78%).  Instead of using 2-amino-1,3-propanediol, the title compound was prepared in the same manner as in <Example 80>, except that (S) — 3′fluoropyrrolidine was used. It manufactured (amount: 185 mg / yield: 78%).
¾ 丽 R (400, CDCls) ： 7.11 (2H, m) , 6.91 ( 1H， ' m)， 6.10(1H, s) , 5.30 (1H, m), 4.22(2H, d) , 3.95 (2H, d) , 3.75 (4H, m) , 3.12 (2H, m) , 2.92 (1H, m) , 2.35-2.61 (5H, m) , 1.83-2.21 (5H, m) , 1.48 (2H, m) , 1.32(6H, d) . ¾ リ R (400, CDCls): 7.11 (2H, m), 6.91 (1H, ' m), 6.10 (1H, s), 5.30 (1H, m), 4.22 (2H, d), 3.95 (2H, d ), 3.75 (4H, m), 3.12 (2H, m), 2.92 (1H, m), 2.35-2.61 (5H, m), 1.83-2.21 (5H, m), 1.48 (2H, m), 1.32 ( 6H, d).
<실시예 96> (4-(3-플루오로-4-((1-(3-이소프로필-1，2,4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스ᅳ 3-엔일 ) ( (R)-3-플 루오로피를리딘 -1-일)메타논의 제조 Example 96 (4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy ) Phenyl) cyclonuclear swab 3-enyl) ((R) -3-ple Preparation of Luoropyridin-1-yl) methanone
Figure imgf000104_0001
Figure imgf000104_0001
2-아미노 -1，3-프로판디을을 사용하는 대신에， (R>-3-플루오로피 를리딘을 사용하는 것을 제외하고， 상기 <실시예 80>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 ： 150mg I 수율 ： 64%).  Instead of using 2-amino-1,3-propanedi, the title compound was prepared in the same manner as in <Example 80>, except that (R> -3-fluoropyridine was used. (Yield: 150 mg I Yield: 64%).
!H 匪 R (400, CDCls) ： 7.11 (2H, m)， 6.9K1H, m) , 6.10(1H, s) , 5.30 (1Η, m) , 4.22(2H, d) , 3,95 (2H, d)， 3.75 (4H, m)， 3.12 (2H, m) , 2.92 (1H, m) , 2.35-2.61 (5H, m) , 1.83-2.21 (5H, m)， 1.48 (2H,
Figure imgf000104_0002
 ! H 匪 R (400, CDCls): 7.11 (2H, m), 6.9K1H, m), 6.10 (1H, s), 5.30 (1Η, m), 4.22 (2H, d), 3,95 (2H, d ), 3.75 (4H, m), 3.12 (2H, m), 2.92 (1H, m), 2.35-2.61 (5H, m), 1.83-2.21 (5H, m), 1.48 (2H,
Figure imgf000104_0002
<실시예 97> (4-(3-플루오로 -4-((l-(3-이소프로필 -1，2，4-옥사디 아졸 -5-일)피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일 ) (모폴리 노)메타논의 제조 Example 97 (4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy Preparation of (phenyl) cyclonux-3-enyl) (morpholino) methanone
Figure imgf000104_0003
Figure imgf000104_0003
2—아미노 -1,3-프로판디올을 사용하는 대신에， 모르폴린을 사용 하는 것을 제외하고， 상기 <실시예 80>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 190mg I 수율 ： 83%).  The title compound was prepared in the same manner as in <Example 80>, except that morpholine was used instead of 2—amino-1,3-propanediol (yield: 190 mg I yield: 83%).
匪 R (400， CDCls) ： 7.11 (2H, m) , 6.91(1H, m)， 6.09(1H, s), 4.21 (2H, d), 3.9K2H, d) , 3.72 (6H, m) , 3.59 (2H, m) , 3.13 (2H, m) , 2.92 (1H, m) , 2.78(1H, m) , 2.35-2.61 (3H, m), 2.30 (1H, m) , 1.83-2.21 (5H, m) , 1.48 (2H, m) , 1.32(6H, d) .  匪 R (400, CDCls): 7.11 (2H, m), 6.91 (1H, m), 6.09 (1H, s), 4.21 (2H, d), 3.9K2H, d), 3.72 (6H, m), 3.59 (2H, m), 3.13 (2H, m), 2.92 (1H, m), 2.78 (1H, m), 2.35-2.61 (3H, m), 2.30 (1H, m), 1.83-2.21 (5H, m ), 1.48 (2H, m), 1.32 (6H, d).
<실시예 98> (4-(3-폴루오로 -4-((l-(3-이소프로필 -1，2，4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일) (싸이오모 폴리노)메타논의 제조 Example 98 (4- (3-Polouro-4-((l- (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) meth Methoxy) phenyl) cyclonux-3-enyl) (thiomo Preparation of Polyno) Methanone
Figure imgf000105_0001
Figure imgf000105_0001
2-아미노ᅳ 1， 3-프로판디올을 사용하는 대신에， 싸이오모르폴린을 사용하는 것을 제외하고， 상기 <실시예 80>과 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 ： 200mg I 수율 : 78%).  The title compound was prepared in the same manner as in <Example 80>, except that thiomorpholine was used instead of 2-amino ᅳ 1, 3-propanediol (yield: 200 mg). I yield: 78%).
XH NMR (400, CDCls) ： 7.11 (2H, m) , 6.9K1H, ni) , 6.09(1H, s) 4.21 (2Η, d) , 3.9K6H, m)， 3.13 (2Ή, m)， 2.92 (1H, m) , 2.78(1H, m) , 2.65(4H, m) , 2.35-2.61 (5H, m)， 1.83-2.21 (5H, m) , 1.48 (2H, m), 1.32(6H, d) . X H NMR (400, CDCls): 7.11 (2H, m), 6.9K1H, ni), 6.09 (1H, s) 4.21 (2Η, d), 3.9K6H, m) ， 3.13 (2Ή, m) ， 2.92 ( 1H, m), 2.78 (1H, m), 2.65 (4H, m), 2.35-2.61 (5H, m), 1.83-2.21 (5H, m), 1.48 (2H, m), 1.32 (6H, d) .
<실시예 99> Nᅳ (2,2-디플루오로에틸) -4-(5-((l-(3-이소프로필- 1,2, 4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )피리딘 -2-일 )싸이클로핵 스 -3-엔카복스아마이드의 제조 Example 99 N ′ (2,2-difluoroethyl) -4- (5-((l- (3-isopropyl-1, 1,2, 4-oxadiazole-5-yl) piperidine -4-yl) methoxy) pyridin-2-yl) cyclonucleose-3-encarboxamide
Figure imgf000105_0002
Figure imgf000105_0002
(R)-2-아미노 -1-프로판을을 사용하는 대신에 . 2，2-디플루오로에 틸아민을 사용하는 것을 쎄외하고, 상기 <실시예 36>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 : 165mg / 수율 : 기 ¾).  Instead of using (R) -2-amino-1-propane. Except for the use of 2,2-difluoro ethylamine, the title compound was prepared in the same manner as in <Example 36> (amount: 165 mg / yield: group ¾).
¾ 丽 R (400， CDC13) ： 8.25 (1H, d) , 7.34(1H, d)， 7.16(1H, d), 6.56 (1H, s) , 5.89 (1H, m)， 5.83 (1H, m) , 4.24 (2H, d) , 3.89(2H, d) ( 3.7K2H, m) , 3.12(2H, m) , 2.92(1H, m) , 2.75(1H, m) , 2.51(4H, m), 1.83-2.21 (5H, m) , 1.49 (2H, m) , 1.32(6H, d) . ¾ リ R (400, CDC1 3 ): 8.25 (1H, d), 7.34 (1H, d), 7.16 (1H, d), 6.56 (1H, s), 5.89 (1H, m), 5.83 (1H, m ), 4.24 (2H, d), 3.89 (2H, d) ( 3.7K2H, m), 3.12 (2H, m), 2.92 (1H, m), 2.75 (1H, m), 2.51 (4H, m), 1.83-2.21 (5H, m), 1.49 (2H, m), 1.32 (6H, d).
<실시예 100> (4-(5-((1-(3-이소프로필-1，2,4-옥사디아졸-5-일) 피페리딘 -4-일 )메록시 )피리딘 -2-일 )싸이클로핵스 -3-엔일) (모폴리노)메 타논의 Example 100 (4- (5-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) pyridine-2- Cyclonux-3-enyl) (morpholino) Tannon
Figure imgf000106_0001
Figure imgf000106_0001
(R)— 2-아미노 -1-프로판을을 사용하는 대신에， 모르폴린을 사용 하는 것을 제외하고， 상기 <실시예 36>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ： 200mg / 수율 : 87%).  (R) — The title compound was prepared in the same manner as in <Example 36>, except that morpholine was used instead of 2-amino-1-propane (yield: 200 mg / Yield 87%).
l\{ NMR.(400, CDC13) ： 8.25 (1H, d) , 7.34(1H, d) , 7.16(1Η, d) 6.56 (1H, s) , 4.24 (2H, d) , 3.90 (2H, d) , 3.72 (6H, m) , 3.58(211， m) , 3.12(2H, m)， 2.92(1H, m) , 2.78(2H, m) , 2.57(2H, m) , 2.37(1H, m) , 1.83-2.21 (5H, m)， 1.49 (2H, m) , 1.32(6H, d) . l \ {NMR. (400, CDC1 3 ): 8.25 (1H, d), 7.34 (1H, d), 7.16 (1Η, d) 6.56 (1H, s), 4.24 (2H, d), 3.90 (2H, d), 3.72 (6H, m), 3.58 (211, m), 3.12 (2H, m), 2.92 (1H, m), 2.78 (2H, m), 2.57 (2H, m), 2.37 (1H, m ), 1.83-2.21 (5H, m), 1.49 (2H, m), 1.32 (6H, d).
<실시예 101> (00-3-플루오로피를리딘 -1-일) (4-(5-((l-(3-이소 프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일 )메록시 )피리딘— 2-일)싸 이클로 -3-엔일)메타논의 제조 Example 101 (00-3-Fluoropyridin-1-yl) (4- (5-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) Preparation of piperidin-4-yl) methoxy) pyridine- 2-yl) cyclo-3-enyl) methanone
Figure imgf000106_0002
Figure imgf000106_0002
(R)-2-아미노 -1-프로판을을 사용하는 대신에， (R)-3-플루오로피 를리딘을 사용하는 것을 제외하고， 상기 <실시예 36>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 210mg I 수을 86%).  Instead of using (R) -2-amino-1-propane, the procedure was carried out in the same manner as in <Example 36>, except that (R) -3-fluoropyridine was used. Compounds were prepared (86% yield 210 mg I number).
XH 匪 R (400， CDCls) ： 8.25 (1H, d) , 7.34(1H, m) , 7.16(1Η, m) 6.58 (1Η, s), 5.30 (1H, m) , 4.23 (2H, d)， 3.55-3.99 (6H, m) , 3.12(2H, m) , 2.92(1H, m) , 2.25-2.83 (6H, m) , 1.83-2.21 (6H, m) , 1.49 (2H, m) , 1.3K6H, d) . X H 匪 R (400, CDCls): 8.25 (1H, d), 7.34 (1H, m), 7.16 (1Η, m) 6.58 (1Η, s), 5.30 (1H, m), 4.23 (2H, d) , 3.55-3.99 (6H, m), 3.12 (2H, m), 2.92 (1H, m), 2.25-2.83 (6H, m), 1.83-2.21 (6H, m), 1.49 (2H, m), 1.3 K6H, d).
<실시예 102> ((S)-3-플루오로피를리딘 -1-일) (4-(5-((l-(3-이소 프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )피리딘 -2-일 )싸 로핵스—3-엔일)메타논의 제조 Example 102 ((S) -3-fluoropyridin-1-yl) (4- (5-((l- (3-isopropyl-1,2,4-oxadiazole-5) (I) piperidin-4-yl) methoxy) pyridin-2-yl)) Preparation of RONUGX-3-enyl) methanone
Figure imgf000107_0001
Figure imgf000107_0001
(R)-2-아미노 -1—프로판올을 사용하 대신에， (S)-3-플루오로피 롤리딘을 사용하는 것을 제외하고 상기 <실시예 36>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 220mg I 수율 81%).  The title compound was prepared in the same manner as in Example 36, except for using (S) -3-fluoropyrrolidine instead of using (R) -2-amino-1—propanol. Prepared (yield 220 mg I yield 81%).
^ 匪 R (400， CDCls) 8.25 (1H, d) , 7.34(1H, m)， 7.16(1H, 6.58 (1H, s), 5.30 (1H, m) , 4.23 (2Η, d) , 3.55-3.99 (6Η, 3.12(2H, m) , 2.92(1Η, m) 2.25-2.83 (6Η, m) , 1.83-2.21 (6H, 1.49 (2Η, m) , 1.3K6H, d)  ^ 匪 R (400, CDCls) 8.25 (1H, d), 7.34 (1H, m), 7.16 (1H, 6.58 (1H, s), 5.30 (1H, m), 4.23 (2Η, d), 3.55-3.99 (6Η, 3.12 (2H, m), 2.92 (1Η, m) 2.25-2.83 (6Η, m), 1.83-2.21 (6H, 1.49 (2Η, m), 1.3K6H, d)
<실시예 103> 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메 톡시 )페닐) -Ν- (2ᅳ 2， 2-트리플루오로에틸 )싸이클로핵스 -3—엔카복스아마 이드의 Example 103 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -Ν- (2 ᅳ 2, 2-trifluor Loethyl) cyclonux-3—encarboxamide
Figure imgf000107_0002
Figure imgf000107_0002
(R)-2-아미노 -1-프로판올을 사용하는 대신에， 2，2，2-트리플루오 로에틸아민 을 사용하는 것을 제외하고， 상기 <실시예 8〉과 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 190mg I 수율 77%) The title compound was carried out in the same manner as in <Example 8>, except that 2,2,2-trifluoroethylamine was used instead of (R) -2-amino-1-propanol. Was prepared (yield 190 mg I yield 77%)
:H 匪 R (400, CDC13) ： 8.19 (2H, s) , 7.3K2H, d) , 6.86(2H, d) 6.03 (1Η, s) , 4.58 (1H, m) , 4.79 (2H, d), 3.99 (2H, m), 3.84(2H, d) , 2.96(2H, m) , 2.51 (7H, m) , 1.83-2.21 (5H, m) , 1.39 (2H, m)， 1.2K3H, m) . : H 匪 R (400, CDC1 3 ): 8.19 (2H, s), 7.3K2H, d), 6.86 (2H, d) 6.03 (1Η, s), 4.58 (1H, m), 4.79 (2H, d) , 3.99 (2H, m), 3.84 (2H, d), 2.96 (2H, m), 2.51 (7H, m), 1.83-2.21 (5H, m), 1.39 (2H, m), 1.2K3H, m) .
<실시예 104> 4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메 특시 )페닐) -N-(2ᅳ플루오로에틸)싸이클로핵스 -3-엔카복스아마이드의 제 조 Example 104 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (2 ᅳ fluoroethyl) cyclonucleus 3-Production of Encarboxamide
Figure imgf000108_0001
Figure imgf000108_0001
(R)-2—아미노 -1-프로판올을 사용하는 대신에， 플루오로에틸아민 을 사용하는 것을 제외하고， 상가 <실시예 8〉과 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 180mg I 수율 72%).  The title compound was prepared in the same manner as in <Example 8>, except that fluoroethylamine was used instead of (R) -2—amino-1-propanol (yield 180 mg I Yield 72%).
!H NMR (400, CDCls) ： 8.19 (2H, s) , 7.3K2H, d) , 6.86(2H, d) 6.03 (1Η, s) , 4.58 (1H, m)， 4.48 (1H, m) , 4.59 (1H, m) , 3.85 (2H, d) , 3.63(2H, m) , 2.96(2H, m) , 2.51 (7H, m) , 1.83-2.21 (5， m)， 1.39 (2H, m) , 1.2K3H, m) . ! H NMR (400, CDCls): 8.19 (2H, s), 7.3K2H, d), 6.86 (2H, d) 6.03 (1Η, s), 4.58 (1H, m), 4.48 (1H, m), 4.59 ( 1H, m), 3.85 (2H, d), 3.63 (2H, m), 2.96 (2H, m), 2.51 (7H, m), 1.83-2.21 (5, m), 1.39 (2H, m), 1.2 K 3 H, m).
<실시예 105> (2S)-l-(4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘Example 105 (2S) -l- (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidine
-4-일 )메특시 )페닐 )싸이클로핵스 -3-엔카보닐)피를리딘— 2-카복스아마이 드의 -4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) pyridine- of 2-carboxamide
Figure imgf000108_0002
Figure imgf000108_0002
(R)— 2-아미노 -1-프로판올을 사용하는 대신에， (S)-피를리딘 -2- 카복스아마이드를 사용하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 160mg I 수율 81%) .  (R) —Instead of using 2-amino-1-propanol, the procedure was carried out in the same manner as in <Example 8>, except that (S) -pyridine-2-carboxamide was used. Compounds were prepared (yield 160 mg I yield 81%).
:H NMR (400, CDCla) ： 8.21 (2H, s), 7.33(2H, d)， 6.86(2H, d) 6.06 (1H, s) , 5.32 ( 1H , s) , 4.79 (2H, d)， 4.67 (1H, d) , 3.85 (2H, d) , 3.68(1H, m) , 3.58(1H, m) , 2.95 (2H, m) , 2.74 (1H, m)， 2.27- 2.62 (7H, m) , 1.83-2.21 (10H, m) , 1.39 (2H, m)， 1.2K3H, m) . : H NMR (400, CDCla): 8.21 (2H, s), 7.33 (2H, d), 6.86 (2H, d) 6.06 (1H, s), 5.32 (1H, s), 4.79 (2H, d) ， 4.67 (1H, d), 3.85 (2H, d), 3.68 (1H, m), 3.58 (1H, m), 2.95 (2H, m), 2.74 (1H, m), 2.27-2.62 (7H, m) , 1.83-2.21 (10H, m), 1.39 (2H, m), 1.2K3H, m).
<실시예 106> (2S)-l-(4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘Example 106 (2S) -l- (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidine
-4-일)메특시 )페닐 )싸이클로핵스—3-엔카보닐)피를리딘 -2-카르보니트릴 의 제조
Figure imgf000109_0001
Preparation of -4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) pyridine-2-carbonitrile
Figure imgf000109_0001
(R)-2-아미노 -1-프로판올을 사용하는 대선에ᅳ (S)-피를리딘 -2- 카보나이트릴 하이드로클로라이드를 사용하는 것을 제외하고， 상기 < 실시예 8>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수 득량 220mg I 수율 83%).  Except for using (R) -2-amino-1-propanol, the same method as in <Example 8> was carried out except for using (S) -pyridine-2-carbonitrile hydrochloride. The title compound was prepared (yield 220 mg I yield 83%).
2H NMR (400, CDCls) ： 8.23 ( 2Ή , s)， 7.32(2H, d)， 6.86(2Ή, d) 6.06 (1H, s) , 4.79 (3H, m)， 3.85 (2Ή, d) , 3.75 (1H, m), 3.59 (1H, m) , 2.99C2H, m) , 2.4-2.71(7H, m)， 1.83-2.38 (10H, m) . 1.39 (2H, m) , 1.2K3H, m) . . 2 H NMR (400, CDCls): 8.23 (2Ή, s), 7.32 (2H, d), 6.86 (2Ή, d) 6.06 (1H, s), 4.79 (3H, m), 3.85 (2Ή, d), 3.75 (1H, m), 3.59 (1H, m), 2.99 C2H, m), 2.4-2.71 (7H, m), 1.83-2.38 (10H, m). 1.39 (2H, m), 1.2 K3H, m). .
<실시예 107> tert-부틸 4-( (4-(4-( (S)-2-카바모일피를리딘 -1- 카보닐)싸이클로핵스 -1—엔일) -2-플루오로페녹시 )메틸)피페리딘 -1-카복 시레이 Example 107 tert-butyl 4- ((4- (4-((S) -2-carbamoylpyridine-1-carbonyl) cyclonux-1-enyl) -2-fluorophenoxy) Methyl) piperidine-1-carboxy silane
Figure imgf000109_0002
(S) 피를리딘 -2-카복 스아마이드를 사용하는 것을 제외하고， 상기 <실시예 44〉와 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 210mg I 수율 82%) ¾ NMR (400, CDCls) ： 7.11 (3H, m)， 6.9K1H, m) , 6.09 (1H, s), 5.32 (1Hᅳ s), 4.67 (1H, d)， 4.17 (2H, d) , 3.88 (2H, d) , 3.62(2H, m) , 2.29-2.82 (5H, m) , 1.83-2.21 (8H, m)， 1.49 (9H, s) , 1.29(2H, m) .
Figure imgf000109_0002
(S) The title compound was prepared in the same manner as in <Example 44>, except for using pyridin-2-carboxyamide (yield 210 mg I yield 82%) ¾ NMR (400 , CDCls): 7.11 (3H, m), 6.9K1H, m), 6.09 (1H, s), 5.32 (1H ᅳ s), 4.67 (1H, d), 4.17 (2H, d), 3.88 (2H, d ), 3.62 (2H, m), 2.29-2.82 (5H, m), 1.83-2.21 (8H, m), 1.49 (9H, s), 1.29 (2H, m).
<실시예 108> (2S)-l-(4-(3-플루오로 -4-((l-(3-이소프로필- 1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔 카보닐)피를리딘ᅳ 2ᅳ카복스아마이드의 제조 Example 108 (2S) -l- (4- (3-fluoro-4-((l- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl) piperidine Preparation of 4-yl) methoxy) phenyl) cyclonux-3-ene carbonyl) pyridin ᅳ 2′carboxamide
2-아미노 -1，3-프로판디올을 사용하는 대신에， (S)-피를리딘 -2- 카복스아마이드를 사용하는 것을 제와하고, 상기 <실시예 80〉과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 180mg I 수율 79%) . Instead of using 2-amino-1,3-propanediol, (S) -pyridine-2-carboxamide was used, and was carried out in the same manner as in <Example 80>. The title compound was prepared (yield 180 mg I yield 79%).
!H NMR (400, CDCls) ： 7.11 (3H, m) , 6.9K1H, m) , 6.10 (1Η, s) , 5.32 (1H, s) , 4.67 (1H, d) , 4.22 (2H, d) , 3.92 (2H, d) , 3.62(2H, m) , 3.12(2H, m) , 2.91 ( 1H , m) , 2.29-2.82 (6H, m) , 1.83- 2.21 (7H, m) , 1.49 (2H, m) , 1.3K6H, d) . ! H NMR (400, CDCls): 7.11 (3H, m), 6.9K1H, m), 6.10 (1Η, s), 5.32 (1H, s), 4.67 (1H, d), 4.22 (2H, d), 3.92 (2H, d), 3.62 (2H, m), 3.12 (2H, m), 2.91 (1H, m), 2.29-2.82 (6H, m), 1.83-2.21 (7H, m), 1.49 (2H, m ), 1.3K6H, d).
<실시예 109> (메틸 2-(4-(3-플루오로 -4-((l-(3-이소프로필- 1，2，4-옥사디아졸 -5ᅳ일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3ᅳ엔 카복스아미도)아세테이트의 제조 Example 109 (methyl 2- (4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazole-5xyl)) piperidin-4-yl Preparation of (methoxy) phenyl) cyclonux-3 [3] -carboxamido) acetate
Figure imgf000110_0001
Figure imgf000110_0001
2—아미노 -1,3-프로판디을을 사용하는 대신에 , 메틸 2—아미노아 세테이트를 사용하는 것을 제외하고 , 상기 <실시예 80>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 850mg I 수율 83%) . Instead of using 2—amino-1,3-propanedi, the title compound was prepared in the same manner as in <Example 80>, except that methyl 2-aminoacetate was used. 850 mg I yield 83%).
Υί NMR (400, CDCI3) : 7.11 (2H, m)， 6.90(1H, m) , 6.08 (1H, s) , 4.21 (2H, d) , 4.11 (2H, d) , 3.91 (2H, d) , 3.80 (3H, s) , 3.12(2H, m) , 2.91 (1H, m) , 2.49 (5H, m) , 1.83-2.21 (5H, m) , 1.49 (2H, m) , 1.3K6H, d) .  Nί NMR (400, CDCI3): 7.11 (2H, m), 6.90 (1H, m), 6.08 (1H, s), 4.21 (2H, d), 4.11 (2H, d), 3.91 (2H, d), 3.80 (3H, s), 3.12 (2H, m), 2.91 (1H, m), 2.49 (5H, m), 1.83-2.21 (5H, m), 1.49 (2H, m), 1.3K6H, d).
<실시예 no 에틸 3-(4-(3-플루오로 -4-((l-(3-이소프로필- 1，2,4-옥사디아졸 -5-일)피페리딘— 4-일)메록시 )페닐 )싸이클로핵스 -3-엔 카복 Example no Ethyl 3- (4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine- 4-yl) Meoxy) phenyl) cyclonux-3-ene Kabok
Figure imgf000111_0001
Figure imgf000111_0001
2-아미노 -1,3-프로판디을을 사용하는 대신에， 에틸 3-아미노프 로파노에이트을 사용하는 것을 제외하고 , 상기 <실시예 80>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 940mg I 수율 86%) .  The title compound was prepared in the same manner as in <Example 80>, except that ethyl 3-aminopropanoate was used instead of 2-amino-1,3-propanedi. 940 mg I yield 86%).
- 丽 R (400, CDCls) ： 7.11 (2H, m)， 6.90(1H, m) , 6.08 (1Η, s) , 4.21 (4H, m) , 3.91 (2H, d) , 3.58 (2H, m) , 3.12(2H, m) , 2.91 (1H, m) , 2.58(2H, m) , 2.49 (5H, ra) , 1.83-2.21 (5H, m) , 1.49 (2H, m) , 1.3K6H, d) , 1.29C3H, m) .  -R R (400, CDCls): 7.11 (2H, m), 6.90 (1H, m), 6.08 (1Η, s), 4.21 (4H, m), 3.91 (2H, d), 3.58 (2H, m) , 3.12 (2H, m), 2.91 (1H, m), 2.58 (2H, m), 2.49 (5H, ra), 1.83-2.21 (5H, m), 1.49 (2H, m), 1.3K6H, d) , 1.29C3H, m).
<실시예 111> 3-(4-(3-플루오로 -4-((l-(3-이소프로필 -1，2，4-옥 사디아졸— 5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카복스아 Example 111 3- (4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol—5-yl) piperidin-4-yl) Meoxy) phenyl) cyclonux-3-encarbox
Figure imgf000111_0002
Figure imgf000111_0002
질소 하에서， 플라스크에 에틸 3-(4-(3-플루오로 -4-((1- Under nitrogen, the flask was placed in ethyl 3- (4- (3-fluoro-4-((1-
(3-이소프로필 -1,2,4-옥사디아졸— 5-일 )피페리딘 -4-일 )메톡시 )페닐)싸 이클로핵스 -3-엔카복스아미도)프로파노에이트 2000mg 을 THF7물 /에탄 올 (100 /50^/10/^)에 녹여 교반하였다. 리튬 하이드록사이드 모노하 이드레이트 1.4g 을 적가후 상은에서 18시간 반응시켰다. 반웅 종결 후 농축된 HC1을 사용하여 pH를 1~2로 조절하였다. 생성된 고체를 여 과 후 건조하여 원하는 표제 화합물을 제조하였다 (수득량 660mg I 수 율 88%). 2000 mg of (3-isopropyl-1,2,4-oxadiazole—5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxamido) propanoate THF7 was dissolved in water / ethanol (100/50 ^ / 10 / ^) and stirred. 1.4 g of lithium hydroxide monohydrate was added dropwise and reacted for 18 hours in phase silver. After completion of reaction, the pH was adjusted to 1-2 using concentrated HC1. The resulting solid was filtered and dried to afford the title compound (yield 660 mg I yield 88%).
H NMR (400， CDCls) (2H, m), 6.90 1H, m) , 6.08 ( 1H s), 4.21 (2H, m) , 3.91 (2H, d) , 3.58 (2Η, m) , 3.12(2H, m), 2.91 (1H, m) , 2.58(2H, m) , 2.49 (5H, m) , 1.83-2.21 (5H, m) , 1.49 (2H, m) , 1 :31(6H, d) . H NMR (400, CDCls) (2H, m), 6.90 1H, m), 6.08 (1H s), 4.21 (2H, m), 3.91 (2H, d), 3.58 (2Η, m), 3.12 (2H, m), 2.91 (1H, m), 2.58 (2H, m), 2.49 (5H, m), 1.83-2.21 (5H, m), 1.49 (2H, m), 1: 31 (6H, d).
<실시예 112> 4-(3-플루오로 -4-((l-(3-이소프로필 -1，2，4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐) -N-(2-모폴리노 -2-옥소에틸)싸 이클 Example 112 4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Phenyl) -N- (2-morpholino-2-oxoethyl) cycle
Figure imgf000112_0001
Figure imgf000112_0001
질소 하에서 , 플라스크에 2-(4-(3-플루오로ᅳ 4— ((1-(3_이 소프로필 -1,2,4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로 핵스 -3-엔카복스아미도)아세틱 엑시드 250mg 를 DMF 20,μί 에 녹여 교 반하였다. EDCI 140mg, HOBt llOmg 을 순차적으로 적가한 후 10분간 추가적으로 교반하였다. 모르폴린 0.1/ 을 적가한 후 상온에서 5시간 교반하였다. 반웅 종결 후 증류수 50 fd 를 0°C에서 천천히 가하고 생 성되는 고체를 여과하여 건조하여 원하는 흰색 고체화합물을 얻었다 (수득량 160mg I 수율 72%) . Under nitrogen, the flask was placed in 2- (4- (3-fluoro ᅳ 4— ((1- (3_isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl 250 mg of) methoxy) phenyl) cyclonux-3-encarboxamido) acetic acid was dissolved in DMF 20, μί and stirred. EDCI 140mg, HOBt llOmg was added dropwise sequentially followed by additional stirring for 10 minutes. Morpholine 0.1 / was added dropwise and stirred at room temperature for 5 hours. After completion of reaction, 50 fd of distilled water was slowly added at 0 ° C., and the solid produced was filtered and dried to obtain a desired white solid compound (yield 160 mg I yield 72%).
XH 匪 R (400, CDC13) ： 7.11 (2H, m)， 6.90(1H, m) , 6.71(1H, m)XH 匪 R (400, CDC1 3 ): 7.11 (2H, m), 6.90 (1H, m), 6.71 (1H, m)
6.07 (1Η, s) , 4.21 (2H, m)， 4.11(2H, d) , 3.91 (2H, d) , 3.7K6H, m) , 3.48 (2H, m) , 3.12(2H, m)， 2.91 (1H, m) , 2.49 (5H, m) , 1.83- 2.21 (5H, m) , 1.49 (2H, m)， 1.3K6H, d) . <실시예 113> 4-(3-플루오로 -4-((l-(3-이소프로필 -1，2，4-옥사디 아졸 -5-일)피페리딘 -4ᅳ일 )메록시 )페닐) -N-(3-모폴리노 -3-옥소프로필) 싸이클 -3-엔카복스아마이드의 제조 6.07 (1Η, s), 4.21 (2H, m), 4.11 (2H, d), 3.91 (2H, d), 3.7K6H, m), 3.48 (2H, m), 3.12 (2H, m) ， 2.91 ( 1H, m), 2.49 (5H, m), 1.83-2.21 (5H, m), 1.49 (2H, m), 1.3K6H, d). Example 113 4- (3-Fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4xyl) methoxy) phenyl Preparation of) -N- (3-morpholino-3-oxopropyl) cycle-3-encarboxamide
Figure imgf000112_0002
Figure imgf000112_0002
2-(4-(3-플루오로 -4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일 ) 피페리딘 -4-일)메록시 )페닐)싸이클로핵스 -3-엔카복스아미도)아세틱 액 시드를 사용하는 대신， 3ᅳ (4ᅳ(3-플루오로 -4-((1-(3-이소프로필 -1,2,4- 옥사디아졸 -5-일)피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스 아미도)프로파노익 엑시드를 사용하는 것을 제외하고， 상기 <실시예 112>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 155mg I 수율 74%) . 2- (4- (3-fluoro-4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) Instead of using cyclonux-3-encarboxamido) acetic acid, it is possible to use 3 ᅳ (4 ᅳ (3-fluoro-4-((1- (3-isopropyl-1,2,4- Same as <Example 112>, except that oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarbox amido) propanoic acid is used The title compound was prepared by the method (yield 155 mg I yield 74%).
:H NMR (400， CDC13) ： 7.11 (2H, m) , 6.90(1H, m) , 6.50(1Η, m) 6.06 (1Η, s) , 4.22 (2H, d) , 3.91 (2H, d) , 3.71(6H, m) , 3.48 (2H, m) , 3.12(2H, m) , 2.91 (1H, m) , 2.55(2H, m) , 2.49 (5H, m) , 1.83- 2.21 (5H, m) , 1.49 (2H, m) , 1.3K6H, d) . : H NMR (400, CDC1 3 ) ： 7.11 (2H, m), 6.90 (1H, m), 6.50 (1Η, m) 6.06 (1Η, s), 4.22 (2H, d), 3.91 (2H, d) , 3.71 (6H, m), 3.48 (2H, m), 3.12 (2H, m), 2.91 (1H, m), 2.55 (2H, m), 2.49 (5H, m), 1.83-2.21 (5H, m ), 1.49 (2H, m), 1.3K6H, d).
<실시예 114> tert-부틸 4-((4-(4-((S)-2-시아노피를리딘 -1-카 보닐)싸이클로핵스 -1-엔일 )-2ᅳ플루오로페녹시 )메틸)피페리딘 -1-카복시 레이트의 제조 Example 114 tert-Butyl 4-((4- (4-((S) -2-cyanopyridine-1-carbonyl) cyclonux-1-enyl) -2 ᅳ fluorophenoxy) methyl Preparation of Piperidine-1-carboxylate
Figure imgf000113_0001
Figure imgf000113_0001
(S)-(-)-3-피롤리디놀올 사용하는 대신에， (S)-피를리딘 -2-카보 나이트릴 하이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시 예 44〉와 동일한 방법으로 수행하여 표제 화합물올 제조하였다 (수득량 180mg I 수율 76%) .  The same method as in <Example 44>, except that instead of using (S)-(-)-3-pyrrolidinol, (S) -pyridine-2-carboniryl hydrochloride is used The title compound was prepared (yield 180 mg I yield 76%).
1H NMR (400, CDCI3) ： 7.11 (3H, m) , 6.91(1H, m) , 6.09 (1Η, s) , 4.67 (1H, d), 4.17 (2H, d) , 3.88 (2H, d) , 3.62(2H, m) , 2.29- 2.82 ( 5H , m) , 1.83-2.21 (8H, m) , 1.49 (9H, s) , 1.29(2H, m) . 1 H NMR (400, CDCI 3 ): 7.11 (3H, m), 6.91 (1H, m), 6.09 (1Η, s), 4.67 (1H, d), 4.17 (2H, d), 3.88 (2H, d ), 3.62 (2H, m), 2.29-2.82 (5H, m), 1.83-2.21 (8H, m), 1.49 (9H, s), 1.29 (2H, m).
<실시예 115> (2S)-l-(4-(3-플루오로 -4-((l-(3-이소프로필- 1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔 카보 -2-카르보니트릴의 제조 Example 115 (2S) -l- (4- (3-fluoro-4-((l- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl) piperidine Preparation of 4-yl) methoxy) phenyl) cyclonux-3-ene carbo-2-carbonitrile
Figure imgf000113_0002
Figure imgf000113_0002
2-아미노 -1，3ᅳ프로판디을을 사용하는 대신에， (S)-피를리딘 -2- 카보나이트릴 하이드로클로라이드를 사용하는 것을 제외하고， 상기 < 실시예 80>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수 득량 190mg I 수율 82%). Instead of using 2-amino-1,3′propanedi, (S) -pyridine-2- The title compound was prepared in the same manner as in <Example 80>, except that carbonitryl hydrochloride was used (a yield 190 mg I yield 82%).
l NMR (400， CDCls) ： 7.11 (3H, m) , 6.91(1H, m) , 6.10 (1Η, s), 4.67 (1H, d) , 4.22 (2H, d) , 3.92 (2H, d) , 3.62(2H, m) , 3.12(2H, m) , 2.91 (1H, m) , 2.29-2.82 (6H, m) , 1.83-2.21 (7H, m)， 1.49 (2H, m) , 1.3K6H, d).  NMR (400, CDCls): 7.11 (3H, m), 6.91 (1H, m), 6.10 (1Η, s), 4.67 (1H, d), 4.22 (2H, d), 3.92 (2H, d), 3.62 (2H, m), 3.12 (2H, m), 2.91 (1H, m), 2.29-2.82 (6H, m), 1.83-2.21 (7H, m), 1.49 (2H, m), 1.3K6H, d ).
<실시예 116> (2R)-l-(4-(3-플루오로 -4-((l-(3-이소프로필- 1，2，4-옥사디아졸 -5ᅳ일 )피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔 카보닐 -2—카 스아마이드의 제조 Example 116 (2R) -l- (4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol-5xyl)) piperidine-4 Preparation of -yl) methoxy) phenyl) cyclonux-3-ene carbonyl-2-carboxamide
Figure imgf000114_0001
Figure imgf000114_0001
2-아미노— 1,3-프로판디올을 사용하는 대신에， (R)-피를리딘 -2- 카복스아마이드를 사용하는 것을 제외하고， 상기 <실시예 80>과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 210mg / 수율 79%) .  Instead of using 2-amino— 1,3-propanediol, the procedure was carried out in the same manner as in <Example 80>, except that (R) -pyridine-2-carboxamide was used. Compounds were prepared (yield 210 mg / yield 79%).
匪 R (400, CDC13) ： 7.11 (3H, m)， 6.91(1H, m) , 6.10 (1H, s), 5.32 (1H, s) , 4.67 (1H, d)， 4.22 (2H, d) , 3.92 (2H, d), 3.62(2H, m) , 3.12(2H, m)， 2.91 (1H, m) , 2.29-2.82 (6H, m)， 1.83- 2.21 (7H, m) , 1.49 (2H, m) , 1.3K6H, d) . 匪 R (400, CDC1 3 ): 7.11 (3H, m), 6.91 (1H, m), 6.10 (1H, s), 5.32 (1H, s), 4.67 (1H, d), 4.22 (2H, d) , 3.92 (2H, d), 3.62 (2H, m), 3.12 (2H, m), 2.91 (1H, m), 2.29-2.82 (6H, m), 1.83-2.21 (7H, m), 1.49 (2H , m), 1.3K6H, d).
<실시예 117> (2R)-l-(4-(3-플루오로 -4-((l-(3-이소프로필- 1,2, 4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔 카보닐 )피를리딘 -2-카르보니트릴의 제조 Example 117 (2R) -l- (4- (3-fluoro-4-((l- (3-isopropyl- 1,2,4-oxadiazol-5-yl) piperidine Preparation of 4-yl) methoxy) phenyl) cyclonux-3-ene carbonyl) pyridine-2-carbonitrile
Figure imgf000115_0001
Figure imgf000115_0001
2-아미노 -1，3-프로판디올을 사용하는 대신에， (R)-피를라딘 -2- 카보나이트릴 하이드로클로라이드를 사용하는 것을 제외하고， 상기 < 실시예 80>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수 득량 165mg I 수율 73%).  Instead of using 2-amino-1,3-propanediol, (R) -pyrrardin-2-carbonitrile hydrochloride was carried out in the same manner as in <Example 80>, except that Compounds were prepared (yield 165 mg I yield 73%).
:H NMR (400， CDC 13 ) ： 7.11 (3H, m) , 6.9K1H, m) , 6.10 (1H, s), 4.67 (1H, d) , 4.22 (2H, d) , 3.92 (2H, d)， 3.62(2H, m)， 3.12(2H, m) , 2.91 (1H, m) , 2.29-2.82 (6H, m) , 1.83-2.21 (7H, m) , 1.49 (2H,— m)， 1.3K6H, d) . : H NMR (400, CDC 1 3 ): 7.11 (3H, m), 6.9K1H, m), 6.10 (1H, s), 4.67 (1H, d), 4.22 (2H, d), 3.92 (2H, d ), 3.62 (2H, m), 3.12 (2H, m), 2.91 (1H, m), 2.29-2.82 (6H, m), 1.83-2.21 (7H, m), 1.49 (2H, — m) ， 1.3 K6H, d).
<실시예 118> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메톡시 )페닐)싸이클로핵스 -3-엔일) ((R)-2- (히드록시메틸)피를리딘 -1- 일 )메 논의 제조 " Example 118 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((R) -2- (hydroxymethyl) pyridin-1-yl) methoxide manufacturing "
Figure imgf000115_0002
Figure imgf000115_0002
(R)-2-아미노 -1-프로판올을 사용하는 대신에 , (R)_피를리딘 -2- 일메탄을을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 240nig I 수율 86%).  Instead of using (R) -2-amino-1-propanol, the procedure was carried out in the same manner as in <Example 8>, except that (R) _pyridin-2-ylmethane was used for the title. Compounds were prepared (yield 240 nig I yield 86%).
JH 丽 R (400, CDCls) ： 8.19 (2H, s) , 7.32(1H, d) , 6.86 (1Η, d) , 6.06 (1H, s) , 5.19 (1H, m) , 4.88 (2H, d), 4.30(1H, m) , 3.85(2H, d) , 3.62 (4H, m)， 2.92 (2H, m) , 2.25-2.78(7H , m) , 1.83- 2.21 (9H, m) , 1.61 (1H, m) , 1.3K2H, m) , 1.22(3H, m) . J H δ R (400, CDCls): 8.19 (2H, s), 7.32 (1H, d), 6.86 (1Η, d), 6.06 (1H, s), 5.19 (1H, m), 4.88 (2H, d ), 4.30 (1H, m), 3.85 (2H, d), 3.62 (4H, m), 2.92 (2H, m), 2.25-2.78 (7H, m), 1.83-2.21 (9H, m), 1.61 ( 1 H, m), 1.3 K 2 H, m), 1.22 (3 H, m).
<실시예 119> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메톡시 )페닐)싸이클로핵스 -3-엔일) ((S)-2- (히드록시메틸)피를리딘 -1- 일 )메타논의 제조 Example 119 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) Preparation of -2- (hydroxymethyl) pyridin-1-yl) methanone
(R)-2-아미노 -1—프로판을을 사용하는 대신에 , (S)-피롤리딘 -2- 일메탄올을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 220mg I 수율 83%). Instead of using (R) -2-amino-1—propane, the procedure was carried out in the same manner as in <Example 8>, except that (S) -pyrrolidine-2-ylmethanol was used. Compounds were prepared (yield 220 mg I yield 83%).
^ NMR (400, CDC13) ： 8.19 (2H, s), 7.32(1H, d) , 6.86 (1Η, d) , 6.06 (1H, s), 5.19 (1H, m)， 4.88 (2H, d) , 4.30(1H, m) , 3.85(2H, d), 3.62 (4H, m) , 2.92 (2H, m) , 2.25-2.78( 7Ή , m) , 1.83- 2.21 (9H, m) , 1.61 (1H, m) , 1.3K2H, m) , 1.22(3H, m) . ^ NMR (400, CDC1 3 ): 8.19 (2H, s), 7.32 (1H, d), 6.86 (1Η, d), 6.06 (1H, s), 5.19 (1H, m), 4.88 (2H, d) , 4.30 (1H, m), 3.85 (2H, d), 3.62 (4H, m), 2.92 (2H, m), 2.25-2.78 (7Ή, m), 1.83-2.21 (9H, m), 1.61 (1H , m), 1.3K2H, m), 1.22 (3H, m).
<실시예 120> 4-(3-플루오로-4-((1-(3-이소프로필—1，2,4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 ) -N- ( 2-히드록시에틸 )싸이클로핵 스 -3- Example 120 4- (3-fluoro-4-((1- (3-isopropyl—1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Phenyl) -N- (2-hydroxyethyl) cyclonucleose-3-
Figure imgf000116_0001
Figure imgf000116_0001
2-아미노 -1，3-프로판디을을 사용하는 대신에， 2-아미노에탄올을 사용하는 것을 제외하고, 상기 <실시예 80〉과 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 180mg / 수율 76%).  The title compound was prepared in the same manner as in <Example 80>, except that 2-aminoethanol was used instead of 2-amino-1,3-propanedi (yield 180 mg / Yield 76%).
XH 丽 R (400, CDCls) ： 7.11 (3H, m)， 6.9K1H, m) , 6.05 (2H, m) , 4.19 (2Η, d) , 3.91 (2H, d) , 3.79 (2H, m) , 3.49(2H, m)， 3.12(2H, m) , 2.91 (1H, m)， 2.35-2.59 (6H, m) , 1.83-2.21 (5H, m) , 1.49 (2H, m) , 1.3K6H, d) . X H δ R (400, CDCls): 7.11 (3H, m), 6.9K1H, m), 6.05 (2H, m), 4.19 (2Η, d), 3.91 (2H, d), 3.79 (2H, m) , 3.49 (2H, m), 3.12 (2H, m), 2.91 (1H, m), 2.35-2.59 (6H, m), 1.83-2.21 (5H, m), 1.49 (2H, m), 1.3K6H, d).
<실시예 121> (2R)-l-(2-(4-(3-플루오로 -4-((l-(3-이소프로필- 1,2，4-옥사디아졸 -5-일 )피페리딘— 4-일 )메특시 )페닐)싸이클로핵스 -3-엔 카복스아미도)아세틸)피를리딘 -2-카복스아마이드의 제조 Example 121 (2R) -l- (2- (4- (3-fluoro-4-((l- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl)) blood Ferridine- 4-yl) methoxy) phenyl) cyclonux-3-enecarboxamido) acetyl) pyridine-2-carboxamide
Figure imgf000117_0001
Figure imgf000117_0001
모르폴린을 사용하는 대신에， (R)-피를리딘 -2-카복스아마이드를 사용하는 것을 제외하고, 상기 <실시예 112>와 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 160mg I 수율 74%) .  The title compound was prepared in the same manner as in <Example 112>, except that (R) -pyridine 2-carboxamide was used instead of morpholine (yield 160 mg I Yield 74%).
^ 匪 R (400, CDC13) ： 7.11 (3H, m) , 6.9K1H, m) , 6.68(1H, s) 6.60(1Η, m) , 6.07(2Η, m) , 5.43 (1Η, s) , 4.60 (1H, d) , 4.22 (2H, d) , 4.11(2H, m) , 3.9K2H, d) , 3.65 (1H, m)， 3.49 (1H, m)， 3.14(2H m) , 2.9K1H, m) , 2.35-2.59 (6H, m) ' 1.83-2.21 (8H, m)， 1.49 (2H, m) , 1.3K6H, d) . ^ 匪 R (400, CDC1 3 ): 7.11 (3H, m), 6.9K1H, m), 6.68 (1H, s) 6.60 (1Η, m), 6.07 (2Η, m), 5.43 (1Η, s), 4.60 (1H, d), 4.22 (2H, d), 4.11 (2H, m), 3.9K2H, d), 3.65 (1H, m), 3.49 (1H, m), 3.14 (2H m), 2.9K1H, m), 2.35-2.59 (6H, m) '1.83-2.21 (8H, m), 1.49 (2H, m), 1.3K6H, d).
<실시예 122> N-(2-((R)-2-시아노피롤리딘 -1-일 ) -2-옥소에틸) - 4-(3-플루오로 -4— ((1-(3-이소프로필ᅳ 1，2，4-옥사디아졸 -5-일 )피페리딘- 4-일 ) -3-엔카복스아마이드의 제조 Example 122 N- (2-((R) -2-Cyanopyrrolidin-1-yl) -2-oxoethyl)-4- (3-fluoro-4-((1- (3- Preparation of Isopropyl ᅳ 1,2,4-oxadiazole-5-yl) piperidine-4-yl) -3-encarboxamide
Figure imgf000117_0002
Figure imgf000117_0002
모르폴린을 사용하는 대신에 (R)-피를리딘 -2-카보나이트릴 하 이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 112>와 동 일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 190mg I 수 율 77%).  The title compound was prepared in the same manner as in <Example 112>, except that (R) -pyridine 2-carbonitrile hydrochloride was used instead of morpholine (yield yield). 190 mg I yield 77%).
XH NMR (400, CDCls) ： 7.11 (3H, m) , 6.91(1H, m) , 6.60(1H, m) 6.07(2Η, m) , 4.60 (1Η, d)， 4.22 (2H, d)， 4.11(2H, m)， 3.91(2H, d) 3.65 (1H, m) , 3.49 (1H, m)， 3.14(2H, m)， 2.9K1H, m) , 2.35-2.59 (6H, m) , 1.83-2.21 (8H, m) , 1.49 (2H, m)， 1.3K6H, d) . <실시예 123> (4-싸이클로프로필피쩨라진 -1-일) (4-(4-((l-(5-에 틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔일)메 타논의 제조 X H NMR (400, CDCls): 7.11 (3H, m), 6.91 (1H, m), 6.60 (1H, m) 6.07 (2Η, m), 4.60 (1Η, d), 4.22 (2H, d), 4.11 (2H, m) ， 3.91 (2H, d) 3.65 (1H, m), 3.49 (1H, m) ， 3.14 (2H, m) ， 2.9K1H, m), 2.35-2.59 (6H, m), 1.83 -2.21 (8H, m), 1.49 (2H, m), 1.3K6H, d). Example 123 (4-Cyclopropylpyrazin-1-yl) (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) Preparation of Phenyl) cyclonux-3-enyl) methanone
Figure imgf000118_0001
Figure imgf000118_0001
(R)-2-아마노 -1-프로판올을 사용하는 대신에 , 싸이클로프로필피 페라진을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법으 로 수행하여 표제 화합물을 제조하였다 (수득량 205mg I 수율 79%).  The title compound was prepared in the same manner as in <Example 8>, except that instead of using (R) -2-amano-1-propanol, cyclopropylpiperazine was used (amount of yield) 205 mg I yield 79%).
匪 R (400, CDCls) ： 8.19 (2H, s)， 7.32(2H d) , 6.86 (2H d) , 6.05 (1H, m), 4.79 ( 2Ή , d) , 3.85 (2H, d) 3.64(2H, m) 3.53(2H, m), 2.93 (2H, m) 2.80 (1H, m) , 2.55 (9H m) , 2.30 (1H m) , 2.0K5H, m) , 1.65(1H, m) , 1.33(2H, m) , 1.20(3H m) , 0.49 (4H m).  匪 R (400, CDCls): 8.19 (2H, s), 7.32 (2H d), 6.86 (2H d), 6.05 (1H, m), 4.79 (2Ή, d), 3.85 (2H, d) 3.64 (2H , m) 3.53 (2H, m), 2.93 (2H, m) 2.80 (1H, m), 2.55 (9H m), 2.30 (1H m), 2.0K5H, m), 1.65 (1H, m), 1.33 ( 2H, m), 1.20 (3H m), 0.49 (4H m).
<실시예 124> (4- (싸이클로프로필메틸)피페라진 -1-일 ) (4-(4- ( (1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스- 3-엔일 Example 124 (4- (Cyclopropylmethyl) piperazin-1-yl) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) meth Roxy) phenyl) cyclonux-3-enyl
Figure imgf000118_0002
Figure imgf000118_0002
(R)-2-아미노 -1-프로판을을 사용하는 대신에， 1- (싸이클로프로 필메틸)피페라진을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 185mg I 수율 77%)..  The title compound was carried out in the same manner as in <Example 8>, except that 1- (cyclopropylmethyl) piperazine was used instead of (R) -2-amino-1-propane. Was prepared (yield 185 mg I yield 77%).
XH 匪 R (400， CDCls) ： 8.19 (2H, s), 7.32(2H, d) , 6.86 (2Η, d), 6.05 (1Η, m), 4.79 (2H, d)， 3.85 (2H, d) , 3.64(2H, m)， X H 匪 R (400, CDCls): 8.19 (2H, s), 7.32 (2H, d), 6.86 (2Η, d), 6.05 (1Η, m), 4.79 (2H, d), 3.85 (2H, d ), 3.64 (2H, m) ，
3.53C2H, m) , 2.93 (2H, m) , 2.80 (1H, m)， 2.55 (9H, m) , 2.30 (3H, m) , 2.0K5H, m), 1.35(2H, m) , 1.20(3H, m) , 0.89 (1H, m) , 0.55 (2H m) , 0.14 (2H, m) . 3.53C2H, m), 2.93 (2H, m), 2.80 (1H, m), 2.55 (9H, m), 2.30 (3H, m), 2.0K5H, m), 1.35 (2H, m), 1.20 (3H , m), 0.89 (1H, m), 0.55 (2H m), 0.14 (2H, m).
<실시예 125> tert-부틸 4-((3-플루오로 -4-(4-((S)-2-히드록시 프로필카바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시 레이트 제조 Example 125 tert-Butyl 4-((3-fluoro-4- (4-((S) -2-hydroxypropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine -1-carboxy Rate manufacturing
Figure imgf000119_0001
Figure imgf000119_0001
4-(4-((1ᅳ (tert-부톡시카보닐 )피쩨리딘 -4-일 )메록시 )-2-플루오 로페닐)싸이클로핵스 -3-엔카복실릭 엑시드 300mg 를 DMF 25μΙ 에 녹여 교반하였다. EDCI 210mg, HOBt 165mg 을 순차적으로 적가한 후 10분간 추가적으로 교반하였다. (S)-l-아미노 -2-프로판올 120mg 을 적가한 후 상온에서 5시간 교반하였다. 반웅 종결 후 증류수 5Ό 를 0°C에서 천천히 가하고 생성되는 고체를 여과하여 건조하여 원하는 흰색 고체 화합물을 얻었다 (수득량 230mg I 수율 82%) .  4- (4-((1 '(tert-butoxycarbonyl) picridin-4-yl) methoxy) -2-fluorophenyl) cyclonux-3-encarboxylic acid 300mg dissolved in DMF 25μΙ and stirred It was. EDCI 210mg, HOBt 165mg was added dropwise sequentially followed by additional stirring for 10 minutes. 120 mg of (S) -l-amino-2-propanol was added dropwise, followed by stirring at room temperature for 5 hours. After completion of reaction, distilled water 5Ό was slowly added at 0 ° C, and the resulting solid was filtered and dried to obtain the desired white solid compound (yield 230mg I yield 82%).
¾ 匪 R (400, CDCls) ： 7.13 (1H, m) , 6.60(2H, m) , 6.11 (1Η, s) , 5.89 (1H, m) ' 4.17 (2H, s) , 3.96 (1H, s) , 3.79 (2H, d) , 3.51 (1H, m) , 3.19 (1H, m) , 2.78 (2H, m)， 2.63 (1H, s) , 2.48(5H, m) , 2.14 (1H, m) , 1.96 (2H, m) , 1.81 (2H, m) , 1.48 (9H, s) , 1.28(2H, m) , 1.21 (3H, d) .  ¾ 匪 R (400, CDCls): 7.13 (1H, m), 6.60 (2H, m), 6.11 (1Η, s), 5.89 (1H, m) '4.17 (2H, s), 3.96 (1H, s) , 3.79 (2H, d), 3.51 (1H, m), 3.19 (1H, m), 2.78 (2H, m), 2.63 (1H, s), 2.48 (5H, m), 2.14 (1H, m), 1.96 (2H, m), 1.81 (2H, m), 1.48 (9H, s), 1.28 (2H, m), 1.21 (3H, d).
<실시예 126> tert-부틸 4-((3-플루오로 -4-(4-((.R)-2-히드록시 프로필카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시 레이트의 제조 Example 126 tert-Butyl 4-((3-fluoro-4- (4-((. R) -2-hydroxy propylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperi Preparation of Dean-1 -Carboxylate
Figure imgf000119_0002
Figure imgf000119_0002
(S)-l-아미노 -2-프로판을을 사용하는 대신에 , (R)-l-아미노 -2- 프로판을을 사용하는 것을 제와하고, 상기 <실시예 125>와 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 210mg I 수율 80%) .  Instead of using (S) -l-amino-2-propane, using (R) -l-amino-2-propane was performed, and carried out in the same manner as in <Example 125>. The title compound was prepared (yield 210 mg I yield 80%).
XH 丽 R (400, CDC13) ： 7.13 (1H, m) , 6.60(2H, m) , 6.11 (1Η, s) , 5.89 (1H, m) , 4.17 (2H, s) , 3.96 (1H, s) , 3.79 (2H, d) , 3.51 (1H, m) , 3.19 (1H, m)， 2.78 (2H, m)， 2.63 (1H, s) , 2.48(5H, m) , 2.14 (1H, m) , 1.96 (2H, m) , 1.81 (2H, m) , 1.48 (9H, s) , 1.28(2H, m) , 1.21 (3H, d) . <실시예 127> 4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메 록시 )폐닐) -N-((S)-1-히드록시프로판 -2-일 )싸이클로핵스 -3-엔카복스아 마이드의 제조 X H δ R (400, CDC1 3 ): 7.13 (1H, m), 6.60 (2H, m), 6.11 (1Η, s), 5.89 (1H, m), 4.17 (2H, s), 3.96 (1H, s), 3.79 (2H, d), 3.51 (1H, m), 3.19 (1H, m), 2.78 (2H, m), 2.63 (1H, s), 2.48 (5H, m), 2.14 (1H, m ), 1.96 (2H, m), 1.81 (2H, m), 1.48 (9H, s), 1.28 (2H, m), 1.21 (3H, d). Example 127 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) hydroxy) phenyl) -N-((S) -1-hydroxy Preparation of propane-2-yl) cyclonux-3-encarboxamide
Figure imgf000120_0001
Figure imgf000120_0001
(R)-2-아미노 -1-프로판을을 사용하는 대신에 , (S)ᅳ 2-아미노 -1- 프로판올을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 170mg I 수율 771).  Instead of using (R) -2-amino-1-propane, (S) '2-amino-1-propanol was carried out in the same manner as in <Example 8>, except that the title compound was used. Was prepared (yield 170 mg I yield 771).
¾ NMR (400, CDCls) : 8.19 (2H, s), 7.3K2H, d) , 6.86 (2Η, d) , 6.04 (1Η, s), 5.73 (1H, d)， 4.79 (2H, d) , 4.15 (1H, m) , 3.84 (2H, d) , 3.72 (1H, m) , 3.57 (1H, m) , 2.92 (2H, m), 2.80 (1H, s) , 2.49 (7H, m), 2.11 (2H( m) , 1.91 (3Ή, m), 1.38 (2H, m) , 1.28(2H, m), 1.21 (3H, d) . ¾ NMR (400, CDCls): 8.19 (2H, s), 7.3K2H, d), 6.86 (2Η, d), 6.04 (1Η, s), 5.73 (1H, d) ， 4.79 (2H, d), 4.15 (1H, m), 3.84 (2H, d), 3.72 (1H, m), 3.57 (1H, m), 2.92 (2H, m), 2.80 (1H, s), 2.49 (7H, m), 2.11 ( 2H ( m), 1.91 (3 Hz, m), 1.38 (2H, m), 1.28 (2H, m), 1.21 (3H, d).
<실시예 128> N-((S)-2,3-디히드록시프로필) -4-(4-((l-(5-에틸 피리미딘 -2-일 )피페리딘 -4—일 )메톡시 )페닐)싸이클로핵스 -3-엔카복스아 마이드의 제조 Example 128 N-((S) -2,3-dihydroxypropyl) -4- (4-((l- (5-ethyl pyrimidin-2-yl) piperidin-4-yl) Preparation of methoxy) phenyl) cyclonux-3-enecarboxamide
Figure imgf000120_0002
Figure imgf000120_0002
00-2-아미노 -1-프로판을을 사용하는 대신에， (S)— 3-아미노- 1ᅳ 2-프로판디을 을 사용하는 것을 제외하고, 상기 <실시예 8>과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 180mg I 수율 74%) .  Instead of using 00-2-amino-1-propane, it was carried out in the same manner as in <Example 8>, except that (S)-3-amino-1 ′ 2-propanedi was used. The title compound was prepared (yield 180 mg I yield 74%).
¾ NMR (400， DMS0-d6) ： 8.23 (2H, s) , 7.85 (1H, t) , 7.33 (2H d), 6.88 (2H, d) , 6.05 ( 1H , s), 4.76 ( 1H， d) , 4.68 (2H, d) , 4.53 (1H, t) , 3.84 (2H, d) , 3.49 (1H, m) , 3.34 (2H, m) , 3.10 (2H, m) , 2.89 (2H, m) , 2.21 (7H, m) , 1.91 (2H,d) , 1.65 (1H, m) , 1.18 (5H, m). ¾ NMR (400, DMS0- d6 ): 8.23 (2H, s), 7.85 (1H, t), 7.33 (2H d), 6.88 (2H, d), 6.05 (1H, s), 4.76 (1H, d) , 4.68 (2H, d), 4.53 (1H, t), 3.84 (2H, d), 3.49 (1H, m), 3.34 (2H, m), 3.10 (2H, m), 2.89 (2H, m), 2.21 (7H, m), 1.91 (2H, d), 1.65 (1H, m), 1.18 (5H, m).
<실시예 129> tert-부틸 4-((3-플루오로 -4-(4-((R)-l-히드록시 프로판 -2-일카바모일 )싸이클로핵스 -1ᅳ엔일 )페녹시 )메틸)피페리딘 -1-카 복시레이트의 제조 Example 129 tert-butyl 4-((3-fluoro-4- (4-((R) -l-hydroxy) Preparation of propane-2-ylcarbamoyl) cyclonux-1-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000121_0001
Figure imgf000121_0001
(S)-l-아미노 -2-프로판을을 사용하는 대신에， (R)-2-아미노 -1- 프로판올올 사용하는 것을 제외하고， 상기 <실시예 125>와 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 180mg I 수율 80%) Instead of using (S) -l-amino-2-propane, except for using (R) -2-amino-1-propanolol, the procedure was carried out in the same manner as in <Example 125>, and the title was Compounds were prepared (yield 180 mg I yield 80%)
¾ 匪 R (400, CDC13) ： 7.15 (1H, t) , 6.64 (2H, m) , .5.89 (1Η, s) , 5.80 (1H, s), 4.15 (3H, m)， 3.79 (2H, d) , 3.59 (1H, d) , 3.45 (1H, m) , 2.87 (1H, s) , 2.75 (2H, m) , 2.48 (5H, m) , 1.94 (5H, m) , 1.48 (9H, s), 1.26 (5H, m) . ¾ 匪 R (400, CDC1 3 ): 7.15 (1H, t), 6.64 (2H, m), .5.89 (1Η, s), 5.80 (1H, s), 4.15 (3H, m), 3.79 (2H, d), 3.59 (1H, d), 3.45 (1H, m), 2.87 (1H, s), 2.75 (2H, m), 2.48 (5H, m), 1.94 (5H, m), 1.48 (9H, s ), 1.26 (5H, m).
<실시예 130> tert-부틸 4-((3-플루오로 -4-(4-((S)-l-히드록시 프로판 -2-일카바모일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카 복시레이트의 제조 Example 130 tert-Butyl 4-((3-fluoro-4- (4-((S) -l-hydroxy propane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl Preparation of Piperidine-1-carboxylate
Figure imgf000121_0002
Figure imgf000121_0002
(S)-l-아미노 -2-프로판올을 사용하는 대신에， (S)— 2-아미노 -1- 프로판을을 사용하는 것을 제외하고， 상기 <실시예 125>와 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 170mg I 수율 74%).  Instead of using (S) -l-amino-2-propanol, the procedure was carried out in the same manner as in <Example 125>, except that (S)-2-amino-1-propane was used. Compounds were prepared (yield 170 mg I yield 74%).
¾ NMR (400, CDC13) ： 7.15 (1H, t) , 6.62 (2H, m)， 5.89 (1H, s), 5.83 (1H, s)， 4.16 (3H, m) , 3.79 (2H, d) , 3.69 (1Η, d) , 2.95 (1H, m) , 2.76 (2H, m) , 2.49 (5H, m) , 1.98 (5H, m) , 1.49 (9H, s) , 1.26 (5H, m). 、 ¾ NMR (400, CDC1 3 ): 7.15 (1H, t), 6.62 (2H, m), 5.89 (1H, s), 5.83 (1H, s), 4.16 (3H, m), 3.79 (2H, d) , 3.69 (1Η, d), 2.95 (1H, m), 2.76 (2H, m), 2.49 (5H, m), 1.98 (5H, m), 1.49 (9H, s), 1.26 (5H, m). 、
<실시예 131> tert-부틸 4-((4-(4-((R)-2,3-디히드록시프로필카 바모일)싸이클로핵스 -1-엔일 )—3—플루오로페녹시 )메틸)피페리딘 -1-카복 시레이트의 제조 Example 131 tert-Butyl 4-((4- (4-((R) -2,3-dihydroxypropylcarbamoyl) cyclonux-1-enyl) —3—fluorophenoxy) methyl Preparation of Piperidine-1-Carboxyrate
Figure imgf000122_0001
Figure imgf000122_0001
(S)-l-아미노 -2-프로판올을 사용하는 대신에， (R)— 3-아미노- 1，2-프로판디올 을 사용하는 것을 제외하고， 상기 <실시예 125>와 동 일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 205mg I 수 율 81%). Instead of using (S) -l-amino-2-propanol, it is carried out in the same manner as in <Example 125>, except that (R)-3-amino-1,2-propanediol is used. The title compound was prepared (yield 205 mg I yield 81%).
!H NMR (400, CDCls) ： 7.13 (1H, 0， 6.63 (2H, m) , 6.55 ( 1H , m) , 5.88 (1Η, s) , 4.18 (3H, m) , 3.81 (3H, m) , 3.61 (4H, m) , 2.78 (2H, m) , 2.45 (5H, m) , 1.82 (7H, m) , 1.47 (9H, m) , 1.25 (2H, m) . ! H NMR (400, CDCls): 7.13 (1H, 0, 6.63 (2H, m), 6.55 (1H, m), 5.88 (1Η, s), 4.18 (3H, m), 3.81 (3H, m), 3.61 (4H, m), 2.78 (2H, m), 2.45 (5H, m), 1.82 (7H, m), 1.47 (9H, m), 1.25 (2H, m).
<실시예 132> tert-부틸 4-((4-(4-((S)-2,3-디히드록시프로필카 바모일 )싸이클로핵스 -1-엔일 )-3—플루오로페녹시 )메틸 )피페리던 -1ᅳ카복 시레이 Example 132 tert-Butyl 4-((4- (4-((S) -2,3-dihydroxypropylcarbamoyl) cyclonux-1-enyl) -3—fluorophenoxy) methyl Piperidon-1
Figure imgf000122_0002
Figure imgf000122_0002
(S)-l-아미노 -2—프로판을을 사용하는 대신에， (S)_3-아미노- 1,2-프로판디올 을 사용하는 것을 제외하고ᅳ 상기 <실시예 125>와 동 일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 165mg I 수 율 74%).  Instead of using (S) -l-amino-2-propane, except that (S) _3-amino- 1,2-propanediol is used ᅳ in the same manner as in Example 125 above. The title compound was prepared (yield 165 mg I yield 74%).
¾ NMR (400, CDC13) ： 7.13 (1H, t) , 6.63 (2H, m)， 6.55 (1H, m) , 5.88 (1H, s) , 4.18 (3H, m)， 3.81 (3H, m) , 3.61 (4H, m) , 2.78 (2H( m), 2.45 (5H, m)， 1.82 (7H, m) , 1.47 (9H, m) , 1.25 (2H, m) . ¾ NMR (400, CDC1 3 ): 7.13 (1H, t), 6.63 (2H, m), 6.55 (1H, m), 5.88 (1H, s), 4.18 (3H, m), 3.81 (3H, m) , 3.61 (4H, m), 2.78 (2H ( m), 2.45 (5H, m), 1.82 (7H, m), 1.47 (9H, m), 1.25 (2H, m).
<실시예 133> (2S)-l-(2-(4-(3-플루오로 -4-((l-(3-이소프로필- 1,2, 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔 카복스아미도)아세틸)피를리딘 -2-카복스아마이드의 제조 Example 133 (2S) -l- (2- (4- (3-fluoro-4-((l- (3-isopropyl-1, 1,2, 4-oxadiazol-5-yl)) blood Preparation of Ferridin-4-yl) methoxy) phenyl) cyclonux-3-ene carboxamido) acetyl) pyridine-2-carboxamide
Figure imgf000123_0001
Figure imgf000123_0001
모르폴린을 사용하는 대신에， (S)-피롤리딘 -2-카복스아마이드를 사용하는 것을 제외하고， 상기 <실시예 112>와 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 160mg / 수율 71%).  The title compound was prepared in the same manner as in <Example 112>, except that (S) -pyrrolidine-2-carboxamide was used instead of morpholine (yield 160 mg / Yield 71%).
l NMR (400, CDCls) ： 7.15 ( 1H， t)ᅳ 6.92 (1H, m)， 6.67 (1H, m) , 6.07 (1H, s) , 5.34 (1H, s) , 4.61 (1H, m) , 4.24 (2H, d), 4.11 (2H, m) , 3.92 (2H, d), 3.64 (1H, m) , 3.58 (1H, m)， 3.14 (2H, t), 2.91 (1H, m), 2.48 (6H, m) , 2.14 (4H, m) , 1.91 (3H, m) , 1.42 (2H, m) , 1.32 (6H, d) .  NMR (400, CDCls): 7.15 (1H, t) ᅳ 6.92 (1H, m), 6.67 (1H, m), 6.07 (1H, s), 5.34 (1H, s), 4.61 (1H, m), 4.24 (2H, d), 4.11 (2H, m), 3.92 (2H, d), 3.64 (1H, m), 3.58 (1H, m), 3.14 (2H, t), 2.91 (1H, m), 2.48 (6H, m), 2.14 (4H, m), 1.91 (3H, m), 1.42 (2H, m), 1.32 (6H, d).
<실시예 134> (2S)-l-(3-(4-(3-플루오로 -4-((l-(3-이소프로필- 1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔 카복스 도)프로파노일)피를리딘 -2-카복스아마이드의 제조 Example 134 (2S) -l- (3- (4- (3-fluoro-4-((l- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl)) blood Preparation of ferridin-4-yl) methoxy) phenyl) cyclonux-3-enecarbox degree) propanoyl) pyridine-2-carboxamide
Figure imgf000123_0002
Figure imgf000123_0002
3-(4-(3—플루오로-4ᅳ((1-(3-이소프로필-1，2，4-옥사디아졸-5-일 ) 피페리 딘ᅳ 4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스아미도)프로파노 익 엑시드와 (S)-파를리딘 -2-카복스아마이드를 사용하여， 상기 <실시 예 112>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득 량 210mg I 수율 80%).  3- (4- (3—fluoro-4 '((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidinyl 4-yl) methoxy) phenyl) Using the cyclonux-3-encarboxamido) propanoic acid and (S) -paridine-2-carboxamide, the title compound was prepared in the same manner as in <Example 112> ( Yield 210 mg I yield 80%).
!H NMR (400， CDC13) ： 7.15 (1H, t) , 6.92 (1H, m) , 6.67 (1H, m) , 6.07 (1H, s) , 5.34 (1H, s), 4.61 (1H, m) , 4.24 (2H, d) , 4.11 (2H, m), 3.92 (2H, d) , 3.64 (1H, m) , 3.58 (1H, m) , 3.14 (2H, t) , 2.91 (1H, m) , 2.54 (2H, m) , 2.48 (6H, m) , 2.14 (4H, m) , 1.91 (3H, m), 1.42 (2H, m) , 1.32 (6H, d) . <실시예 135> (4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일) 메톡시)페닐)싸이클로핵스 -3-엔일) ((S)-3-히드록시피를리딘 -1-일 )메타 논의 제조 ! H NMR (400, CDC1 3 ): 7.15 (1H, t), 6.92 (1H, m), 6.67 (1H, m), 6.07 (1H, s), 5.34 (1H, s), 4.61 (1H, m ), 4.24 (2H, d), 4.11 (2H, m), 3.92 (2H, d), 3.64 (1H, m), 3.58 (1H, m), 3.14 (2H, t), 2.91 (1H, m) , 2.54 (2H, m), 2.48 (6H, m), 2.14 (4H, m), 1.91 (3H, m), 1.42 (2H, m), 1.32 (6H, d). Example 135 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) 3-Hydroxypyridin-1-yl) metabolite preparation
Figure imgf000124_0001
Figure imgf000124_0001
(R)-2-아미노프로판— 1-을을 사용하는 대신에， (S)-( + )-3-피를리 디놀을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 22Omg I 수율 81%).  Instead of using (R) -2-aminopropane— 1-, the procedure was carried out in the same manner as in Example 8, except that (S)-(+)-3-pyridinol was used. To give the title compound (yield 22Omg I yield 81%).
^ NMR (400, CDC13) ： 8.19 (2H, s) , 7.33 (2H, d) , 6.87 (2Η, d) , 6.07 (1H, s), 4.80 (2H, d) , 4： 55 ( 1Ή , d), 3.85 (2H, d), 3.65 (4H, m), 2.94 (2H, t) , 2.4 & (7H, m) , 2.00 ( 7H , m)， 1.40 (2H, m) , 1.18 (3H, m) . ^ NMR (400, CDC1 3 ): 8.19 (2H, s), 7.33 (2H, d), 6.87 (2Η, d), 6.07 (1H, s), 4.80 (2H, d), 4: 55 (1Ή, d), 3.85 (2H, d), 3.65 (4H, m), 2.94 (2H, t), 2.4 & (7H, m), 2.00 (7H, m), 1.40 (2H, m), 1.18 (3H, m).
<실시예 136> 4-(4-((l-(5-에틸피리찌딘 -2-일 )피페리딘 -4-일 )메 특시 )페닐) N-((S)-2-히드록시프로필)싸이클로핵스 -3-엔카복스아마이 드의 Example 136 4- (4-((l- (5-ethylpyridindin-2-yl) piperidin-4-yl) methoxy) phenyl) N-((S) -2-hydroxypropyl Of cyclonux-3-encarboxamide
Figure imgf000124_0002
Figure imgf000124_0002
(R)-2—아머노 -1-프로판올을 사용하는 대신에， (S)-l-아미노 -2- 프로판올을 사용하는 것을 제외하고， 상기 <실시예 8>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 215mg I 수율 82%).  The title compound was carried out in the same manner as in <Example 8>, except that (S) -l-amino-2-propanol was used instead of (R) -2—amerno-1-propanol. Was prepared (yield 215 mg I yield 82%).
!H NMR (400, CDCls) ： 8.19 (2H, s), 7.32 (2H, d), 6.87 (2H, d) , 6.04 (2H, s), 4.80 (2H, d) , 3.96 (1H, m), 3.85 (2H, d) , 3.52 (1H, m), 3.14 (1H, m)， 2.9 & (2H, t) , 2.46 (8H, m) , 2.18 (2H, m) , 1.96 (3H, m) , 1.38 (2H, m) , 1.24 (6H, m) . ! H NMR (400, CDCls): 8.19 (2H, s), 7.32 (2H, d), 6.87 (2H, d), 6.04 (2H, s), 4.80 (2H, d), 3.96 (1H, m), 3.85 (2H, d), 3.52 (1H, m), 3.14 (1H, m), 2.9 & (2H, t), 2.46 (8H, m), 2.18 (2H, m), 1.96 (3H, m), 1.38 (2H, m), 1.24 (6H, m).
<실시예 137> tert-부틸 4-((4-(4- (싸이클로프로필카바모일)싸 이클로핵스 -1-엔일 )-3-플루오로페녹시 )메틸)피페리딘 -1-카복시레이트 의 제조 Example 137 tert-Butyl 4-((4- (4- (cyclopropylcarbamoyl) cyclonux-1-enyl) -3-fluorophenoxy) methyl) piperidine-1-carboxylate Manufacture
(S)-lᅳ아미노ᅳ 2-프로판올을 사용하는 대신에 , 싸이클로프로필아 만을 사용하는 것을 제외하고， 상기 <실시예 125>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 180mg I 수율 74%). Instead of using (S) -1-amino-2-propanol, the title compound was prepared in the same manner as in <Example 125>, except that cyclopropylaman was used (yield 180 mg I yield). 74%).
¾ 匪 R (400， CDC13) ： 7.14 (1H, t) , 6.64 (2H, m) , 5.88 (1H, s) , 5.74 (1H, s), 4.17 (2H, m) , 3.79 (2H, d) , 2.78 (3H, m) , 2.46 (5H, m) , 1.87. (5H, m)， 1.48 (9H, s), 1.28 (2H; m), 0.78 (2H, m) , 0.48 (2H, m) . <실시예 138> tert-부틸 4-((3-플루오로 -4-(4-(2-플루오로에틸 카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸 ')피페리딘 -1-카복시레이트 의 제 ¾ 匪 R (400, CDC1 3 ): 7.14 (1H, t), 6.64 (2H, m), 5.88 (1H, s), 5.74 (1H, s), 4.17 (2H, m), 3.79 (2H, d ), 2.78 (3H, m), 2.46 (5H, m), 1.87. (5H, m), 1.48 (9H, s), 1.28 (2H ; m), 0.78 (2H, m), 0.48 (2H, m). Example 138 tert-butyl 4-((3-fluoro-4- (4- (2-fluoroethyl carbamoyl) cyclonux-1-enyl) phenoxy) methyl ') piperidine-1- Carboxylate
Figure imgf000125_0001
Figure imgf000125_0001
(S)-l-아미노 -2-프로판올을 사용하는 대신에， 2-플루오로에틸아 민을 사용하는 것을 제외하고， 상기 <실시예 125>와 동일한 방법으로. 수행하여 표제 화합물을 제조하였다 (수득량 160mg I 수율 71%).  In the same manner as in <Example 125>, except that 2-fluoroethylamine is used instead of (S) -1-amino-2-propanol. The title compound was prepared (yield 160 mg I yield 71%).
¾ 丽 R (400， CDC13) ： 7.15 (1H, t) , 6.64 (2H, m)， 6.04 (1H, m) , 5.89 (1Η, s) ' 4.57 (2H, m) , 3.79 (2H, d) , 3.58 (2H, m) , 2.78 (2H, m), 2.54 (5H, m)， 1.92 (5H, m) , 1.48 (9H, s) , 1.28 (2H, m) . ¾ リ R (400, CDC1 3 ): 7.15 (1H, t), 6.64 (2H, m), 6.04 (1H, m), 5.89 (1Η, s) '4.57 (2H, m), 3.79 (2H, d ), 3.58 (2H, m), 2.78 (2H, m), 2.54 (5H, m), 1.92 (5H, m), 1.48 (9H, s), 1.28 (2H, m).
<실시예 139> N-(2-((S)-2-시아노피를리딘 -1-일) -2-옥소에틸) - 4-(3-플루오로ᅳ4-( (1-(3ᅳ이소프로필 -1，2，4—옥사디아졸 -5-일 )피페리딘ᅳ 4-일 )메톡시 )페닐)싸이클로핵스ᅳ 3-엔카복스아마이드의 제조 Example 139 N- (2-((S) -2-cyanopyridin-1-yl) -2-oxoethyl) -4- (3-fluoro ᅳ 4- ((1- (3 ') Preparation of isopropyl-1,2,4-oxadiazole-5-yl) piperidin4- 4-yl) methoxy) phenyl) cyclonucleox-3-encarboxamide
Figure imgf000126_0001
Figure imgf000126_0001
모르폴린을 사용하는 대신에， (S)—피를리딘 -2-카보나이트릴 하 이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 112>와 동 일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 190mg / 수 율 83%).  The title compound was prepared in the same manner as in <Example 112>, except that instead of using morpholine, (S) -pyridine 2-carbonitrile hydrochloride was used. Yield 190mg / yield 83%).
:H NMR (400， CDC13) ： 7.15 (1H, t) , 6.92 ( 1H， m)， 6.67 (1H, m) , 6.07 (1H, s), 4.61 (1H, m) , 4.24 (2Ή, d)， 4.11 (2H, m) , 3.92 (2H, d) , 3.64 (1H, m)， 3.58 (1H, m) , 3.14 (2H, t), 2.91 (1H, m)， 2.48 (6H, m) , 2.14 (4Ή, m) r 1.91 (3H, m), 1.42 (2H, m) , 1.32 (6H, d). : H NMR (400, CDC1 3 ): 7.15 (1H, t), 6.92 (1H, m), 6.67 (1H, m), 6.07 (1H, s), 4.61 (1H, m), 4.24 (2Ή, d ), 4.11 (2H, m), 3.92 (2H, d), 3.64 (1H, m), 3.58 (1H, m), 3.14 (2H, t), 2.91 (1H, m), 2.48 (6H, m) , 2.14 (4 Hz, m) r 1.91 (3H, m), 1.42 (2H, m), 1.32 (6H, d).
<실시예 140> N-(3-((S)-2-시아노피를리딘 -1-일) -3-옥소프로 필 ) -4-(3-플루오로ᅳ4-( (1-(3-이소프로필 -1, 2，4-옥사디아졸 -5-일 )피페 리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔카복스아마이드의 제조 Example 140 N- (3-((S) -2-cyanopyridin-1-yl) -3-oxopropyl) -4- (3-fluoro ᅳ 4- ((1- (3 Preparation of isopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide
Figure imgf000126_0002
Figure imgf000126_0002
3-(4-(3-플루오로 -4-((1-(3-이소프로필— 1，2,4-옥사디아졸 -5—일 ) 피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3—엔카복스아미도)프로파노 익 엑시드와 (S)-피를리딘 -2-카보나이트릴 하이드로클로라이드를 사용 하여 , 상기 <실시예 112>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 145mg I 수율 77%).  3- (4- (3-fluoro-4-((1- (3-isopropyl— 1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) Using the cyclonux-3-encarboxamido) propanoic acid and (S) -pyridine-2-carbonitrile hydrochloride, the title compound was prepared in the same manner as in <Example 112>. (Yield 145 mg I yield 77%).
ln NMR (400, CDCI3) ： 7.15 (1H, t), 6.92 ( 1H， m) , 6.67 (1H, m), 6.07 (1H, s), 4.61 (1H, m) , 4.24 (2H, d) , 4.11 (2H, m) , 3.92 (2H, d) , 3.64 (1H, m), 3： 58 (1H, m)， 3.14 (2H, t), 2.91 (1H, m) , 2.54 (2H, m) , 2.48 (6H,. m) , 2.14 (4H, m) , 1.91 (3H, m) , 1.42 (2H, m), 1.32 (6H, d) . <실시예 I4i> tert-부틸 4-((4-(4-(2，2-디플루오로에틸카바모 일)싸이클로핵스 -1-엔일) -3-플루오로페녹시 )메틸)피페리딘 -1-카복시레 이트의 제조 ln NMR (400, CDCI 3 ): 7.15 (1H, t), 6.92 (1H, m), 6.67 (1H, m), 6.07 (1H, s), 4.61 (1H, m), 4.24 (2H, d) , 4.11 (2H, m), 3.92 (2H, d), 3.64 (1H, m), 3: 58 (1H, m), 3.14 (2H, t), 2.91 (1H, m), 2.54 (2H, m ), 2.48 (6H, .m), 2.14 (4H, m), 1.91 (3H, m), 1.42 (2H, m), 1.32 (6H, d). Example I4i tert-Butyl 4-((4- (4- (2,2-difluoroethylcarbamoyl) cyclonux-1-enyl) -3-fluorophenoxy) methyl) piperidine Production of -1-carboxylate
Figure imgf000127_0001
Figure imgf000127_0001
(S)-l-아미노 -2-프로판올을 사용하는 대신에， 2，2-디플루오로에 틸아민을 사용하는 것을 제외하고， 상기 <실시예 125〉와 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 190mg / 수율 73%).  Preparation of the title compound in the same manner as in <Example 125>, except that 2,2-difluoroethylamine was used instead of (S) -l-amino-2-propanol. (Yield 190 mg / yield 73%).
XH 匪 R (400, CDCls) ： 7.15 (1H, t) , 6.64 (2H, m)， 6.04 (1H, m) , 5.89 (2Η, s), 4.28 ( 2H , m)， 3.79 (2H, d) , 3.70 (2H, m) , 2.78 (2H, m) , 2.54 (5H, m)， 1.92 (5M, m)， 1.48 (9H, s), 1.28 (2H, m) . X H 匪 R (400, CDCls): 7.15 (1H, t), 6.64 (2H, m), 6.04 (1H, m), 5.89 (2Η, s), 4.28 (2H, m), 3.79 (2H, d ), 3.70 (2H, m), 2.78 (2H, m), 2.54 (5H, m), 1.92 (5M, m), 1.48 (9H, s), 1.28 (2H, m).
<실시예 142> tert-부틸 4-((3-플루오로 -4-(4-(2，2,2-트뫼플루 오로에틸카바모일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘ᅳ 1-카복Example 142 tert-Butyl 4-((3-fluoro-4- (4- (2,2,2-tmefluuroethylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperi Dincheng 1-Carbox
Λ 레이트의 제조 Λ Rate Preparation
Figure imgf000127_0002
Figure imgf000127_0002
(S)-l-아미노 -2-프로판올을 사용하는 대신에， 플루오 로에틸아민 을 사용하는 것을 제외하고, 상기 <실入
Figure imgf000127_0003
동일한 방법 ^로 수행하여 표제 화합물을 제조하였다 (수득량 175mg I 수율 77%) Instead of using (S) -l-amino-2-propanol, except using fluoroethylamine, <
Figure imgf000127_0003
The title compound was prepared in the same manner ^ (yield 175 mg I yield 77%)
¾ 匪 R (400， CDCls) ： 7.15 (1H, t) , 6.64 (2H, m) , 6.04 (1H, m) , 5,89 (ΙΗ' s), 4.28 (2H, m) , 3.99 (1H, m) , 3.79 (2H d), 2.78 (2H, m) , 2.54 (5H, m) , 1.92 (5H, m) , 1.48 (9H, s) , 1.28 (2H, m) . <실시예 143> ((R)-3- (디메틸아미노)피롤리딘 -1-일) (4-(4-((l- ¾ 匪 R (400, CDCls): 7.15 (1H, t), 6.64 (2H, m), 6.04 (1H, m), 5,89 (ΙΗ 's), 4.28 (2H, m), 3.99 (1H, m), 3.79 (2H d), 2.78 (2H, m), 2.54 (5H, m), 1.92 (5H, m), 1.48 (9H, s), 1.28 (2H, m). Example 143 ((R) -3- (dimethylamino) pyrrolidin-1-yl) (4- (4-((l-
(3-이소프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4—일 )메툭시 )페닐)싸 이클로핵스— 3-엔일)메타논의 제조 Preparation of (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxyl) phenyl) cyclonux- 3-enyl) methanone
Figure imgf000128_0001
Figure imgf000128_0001
100 mL 플라스크에 4-(4-((l-(3-이소프로필ᅳ 1，2，4-옥사디아졸- 5-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔카복실릭 엑시드 400 mg을 DMF 30 mL 에 용해시키고， 질소환경 하에 교반하였다. TEA 0.4 mL, (R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드 215 mg을 순차적으로 적가한 후， 10분 동안 추가적으로 교반하였다. HATU(1- [비 스 (디메틸아미노)메틸렌] -1H-1,2,3-트리아졸 [4,5-b]피리디늄 3-옥 핵사플루오로포스페이트) 400 mg을 적가한 후， 상온에서 1시간 교 였다. 반웅 종결 후， 증류수 50 mL를 0°C에서 천천히 가하고 , 생 는 고체를 여과한 후， 건조하여 표제 화합물을 흰색 고체 형태로 하였다 (수득량 450mg I 수율 69%). In a 100 mL flask, 4- (4-((l- (3-isopropyl ᅳ 1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 400 mg of encarboxylic acid was dissolved in 30 mL of DMF and stirred under nitrogen. 0.4 mL of TEA, 215 mg of (R) -N, N-dimethylpyridin-3-amine hydrochloride were added dropwise sequentially followed by additional stirring for 10 minutes. After dropwise addition of 400 mg of HATU (1- [bis (dimethylamino) methylene] -1H-1,2,3-triazole [4,5-b] pyridinium 3-ox nucleofluorophosphate), at room temperature It was one hour school. After completion of reaction, 50 mL of distilled water was slowly added at 0 ° C., the produced solid was filtered and dried to give the title compound as a white solid (yield 450 mg I yield 69%).
^ NMR (400， CDCls) ： 7.32(2H, d) , 6.85(2H, d) , 6.02(1Η, s) 4.24(2Η, d) , 3.86(4Η, m) , 3.44(2Η, m) , 3.12(2Η, m) , 2.85(2Η, m) 2.69-1.85(19Η, m) , 1.47(2Η, m) , 1.32(6Η, d) .  ^ NMR (400, CDCls): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1Η, s) 4.24 (2Η, d), 3.86 (4Η, m), 3.44 (2Η, m), 3.12 (2Η, m), 2.85 (2Η, m) 2.69-1.85 (19Η, m), 1.47 (2Η, m), 1.32 (6Η, d).
<실시예 144> ((S)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1- 시반제성Example 144 ((S) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1- scavengers)
(3-이소프로필— 1,2,4-옥사디아졸— 5-일)피페리딘 -4-일)메록시 )페닐 )싸조하드되 이클로 -3ᅳ엔일)메타논의 제조 Preparation of (3-isopropyl— 1,2,4-oxadiazol— 5-yl) piperidin-4-yl) methoxy) phenyl) sazohard but cyclo-3-enyl) methanone
Figure imgf000128_0002
Figure imgf000128_0002
(R)-N,N-디메틸피를리딘— 3-아민 하이드로클로라이드를 사용하는 대신에 (S)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하 는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표 제 화합물을 제조하였다 (수득량 470mg I 수율 70%).  (R) -N, N-dimethylpyridine—except for using (S) -N, N-dimethylpyridin-3-amine hydrochloride instead of 3-amine hydrochloride, The title compound was prepared in the same manner as in <Example 143> (yield 470 mg I yield 70%).
ln NMR (400， CDCls) ： 7.32(2H, d) , 6.85(2H, d) , 6.02(1Η, s) , 4.24(2Η, d) , 3.86(4Η, m)， 3.44(2Η, m) , 3.12(2Η, m)， 2.85(2Η? m)， 2.69-1.85(19Η, m), 1.47(2Η, m)， 1.32(6H, d) . <실시예 145> ((R)-3- (디메틸아미노)피를리딘 -1-일) (4-(4-((1-ln NMR (400, CDCls): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1Η, s), 4.24 (2Η, d), 3.86 (4Η, m) ， 3.44 (2Η, m), 3.12 (2Η, m), 2.85 (2Η ? M), 2.69-1.85 (19Η, m), 1.47 (2Η, m), 1.32 (6H, d). Example 145 ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1-
(3-이소프로필 -1， 2 ,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸 (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) sa
-3ᅳ엔일)메타논 하이드로클로라이드의 제조  Preparation of 3-3-enyl) methanone hydrochloride
Figure imgf000129_0001
Figure imgf000129_0001
100 mL 플라스크에 (CR)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4- ((1-(3-아소프로필 -1，2,4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )페 닐)싸이클로핵스—3ᅳ엔일)메타논 150 mg올 디클로로메탄 20 mL에 용해 시킨 후， 질소환경 하에 교반하였다. 디옥산에 용해돤 4N-HC1 0.08 mL 를 적가한 후， 상은에서 3시간 동안 교반하였다. 용매를 제거한 후， 아세톤 30 mL를 천천히 적가하였다. 생성되는 고체를 여과한 후， 에틸 아세테이트 10 mL로 세척하고， 건조하여 표제 화합물을 흰색 고체 형 태로 제조하였다 (수득량 220mg I 수율 84%).  (CR) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole-5-) in a 100 mL flask 1) piperidin-4-yl) methoxy) phenyl) cyclonux-3xenyl) methanone 150 mgol was dissolved in 20 mL of dichloromethane and stirred under nitrogen. 0.08 mL of 4N-HC1 dissolved in dioxane was added dropwise, followed by stirring for 3 hours at silver. After removing the solvent, 30 mL of acetone was slowly added dropwise. The resulting solid was filtered off, washed with 10 mL of ethyl acetate and dried to give the title compound as a white solid (yield 220 mg I yield 84%).
匪 R (400， D20) ： 7.07(2H, d)， 6.55(2H, d)， 5.81 ( 1H， s )， 4.12-3.28 11H, m)， 2.93-2.62( 11H， m)， 2.44(2H, m) , 2.12(5Η, m)， 2.8K1H, m), 1.52(4H, m)， 1.08(6H, d)， 0.95(2H, s) . 匪 R (400, D 2 0): 7.07 (2H, d), 6.55 (2H, d), 5.81 (1H, s), 4.12-3.28 11H, m), 2.93-2.62 (11H, m), 2.44 ( 2H, m), 2.12 (5Η, m), 2.8K1H, m), 1.52 (4H, m), 1.08 (6H, d), 0.95 (2H, s).
<실시예 146> ((S)-3- (디메틸아미노)피를리딘 -1-일) (4-(4-((l-Example 146 ((S) -3- (dimethylamino) pyridin-1-yl) (4- (4-((l-
(3-이소프로필 -1,2,4-옥사디아졸 -5-일)피페리딘 -4ᅳ일)메록시 )페닐)싸 (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine-4xyl) methoxy) phenyl) sa
Figure imgf000129_0002
Figure imgf000129_0002
((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((l-(3-이소프로필- 1,2, 4-옥사디아졸 -5-일 )피페리딘 -4—일 )메록시 )페닐 )싸이클로핵스 -3-엔 일)메타논을 사용하는 대신에 ((S)-3- (디메틸아미노)피를리딘— 1- 일) (4-(4-((1-(3-이소프로필 -1,2,4-옥사디아졸 일)피페리딘 -4-일)메 특시 )페닐)싸이클로핵스ᅳ3-엔일)메타논을 사용하는 것을 제외하고 , 상 기 <실시예 145>와 동일한 방법으로 수행하여 표제 화합물을 제조 다 (수득량 210mg I 수율 83%). ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4-((l- (3-isopropyl-1, 1,2,4-oxadiazole-5-yl) pi ((S) -3- (dimethylamino) pyridin— 1-yl) (4- (instead of using ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone Except for using 4-((1- (3-isopropyl-1,2,4-oxadiazolyl) piperidin-4-yl) methic) phenyl) cyclonucleox-3-enyl) methanone , Award The title compound was prepared in the same manner as in <Example 145>, the yield 210 mg I yield 83%.
¾ 丽 R (400， D20) ： 7.07(2H, d)， 6.55(2H, d) , 5.8K1H, 4.12-3.28(11Η„ m)， 2.93-2.62( 11Η , m)， 2.44(2H, m)， 2.12(5H, 2.8K1H, m) , 1.52(4H, m) , 1.08(6H, d)， 0.95(2H, s) . ¾ リ R (400, D 2 0): 7.07 (2H, d), 6.55 (2H, d), 5.8K1H, 4.12-3.28 (11Η „m), 2.93-2.62 (11Η, m) ， 2.44 (2H, m), 2.12 (5H, 2.8K1H, m), 1.52 (4H, m), 1.08 (6H, d), 0.95 (2H, s).
<실시예 147> ((R)-2- (하이드록시메틸)피롤리딘 -1-일 ) (4-(4-Example 147 ((R) -2- (hydroxymethyl) pyrrolidin-1-yl) (4- (4-
((1-(3-이소프로필-1，2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페 닐 )싸 ((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) sa
로클로라이드를 사용하는 대신에
Figure imgf000130_0001
것을 제외하고， 상기 <실 시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수 득량 220mg / 수율 76%). Instead of using rochloride
Figure imgf000130_0001
Except that, the title compound was prepared in the same manner as in <Example 143> (amount 220 mg / yield 76%).
lE NMR (400， CDC13) 7.33(2H, d) , 6.86(2H, d) 6.06C1H, s) , 5.16(1H, m) 4.29(1H, m) , 4.22(2H, d) , 3.86(2H, d) 4.65(4H, m) , 3.13(2H, m) 2.9K1H, m), 2.77-2.28(5H, m) , 2.0Κ8Ή m) , 1.6K1H, m) , 1.46(2H m) , 1.32(6H, d). l NMR (400, CDC1 3 ) 7.33 (2H, d), 6.86 (2H, d) 6.06C1H, s), 5.16 (1H, m) 4.29 (1H, m), 4.22 (2H, d), 3.86 (2H , d) 4.65 (4H, m), 3.13 (2H, m) 2.9K1H, m), 2.77-2.28 (5H, m), 2.0Κ8Ή m), 1.6K1H, m), 1.46 (2H m), 1.32 ( 6H, d).
<실시예 148> ((S)-2- (하이드록시메틸)피를리딘 -1-일) (4-(4- ((1-(3-이소프로필-1， 2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페 닐 )싸이클로핵스 -3-엔일)메타논의 제조 Example 148 ((S) -2- (hydroxymethyl) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1, 2,4-oxadiazole) Preparation of -5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000130_0002
Figure imgf000130_0002
(R)-N,N-디메틸피를리딘— 3-아민 하이드로클로라이드를 사용하는 대신에 L-프를리놀 (L-Prolinol)을 사용하는 것을 제외하고， 상기 <실 시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수 득량 180mg I 수율. 74%) . (R) -N, N-dimethylpyridine—In the same manner as in <Example 143>, except that L-prolinol was used instead of 3-amine hydrochloride. To give the title compound (water Yield 180 mg I yield. 74%).
XH NMR (400， CDCls) 7.33(2H, d) 6.86C2H, d), 6.06 1H, s) , 5.16(1H, m) , 4.29(1H, m) 4.22(2H, d) , 3.86(2H, d) , 4.65(4H, m) , 3.13(2H, m) , 2.9K1H, m) 2.77-2.28(5H m) , 2.0K8H, m), 1.6K1H, m), 1.46(2H, m) , 1.32(6H d).  XH NMR (400, CDCls) 7.33 (2H, d) 6.86C2H, d), 6.06 1H, s), 5.16 (1H, m), 4.29 (1H, m) 4.22 (2H, d), 3.86 (2H, d ), 4.65 (4H, m), 3.13 (2H, m), 2.9K1H, m) 2.77-2.28 (5H m), 2.0K8H, m), 1.6K1H, m), 1.46 (2H, m), 1.32 ( 6H d).
<실시예 149> (00-3-(하이드록시메틸 )피를라딘-1-일 )(4-(4- ((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일 )메톡시 )페 닐)싸 -3-엔일)메타논의 제조 Example 149 (00-3- (hydroxymethyl) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole-5) Preparation of -yl) piperidin-4-yl) methoxy) phenyl) sa-3-enyl) methanone
Figure imgf000131_0001
Figure imgf000131_0001
(R)-N,N-디메틸피를리딘ᅳ3-아민 하이드로클로라이드를 사용하는 대신에 D-베타-프롤리놀 (D— beta-Prolinol)을 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하 였다 (수득량 175mg I 수율 77%).  Except for using D-beta-prolinol instead of (R) -N, N-dimethylpyridin ᅳ 3-amine hydrochloride, Example 143 above. The title compound was prepared in the same manner as the obtained (yield 175 mg I yield 77%).
¾ NMR (400, CDCls) ： 7.33(2H, d) , 6.86(2H, d) , 6.06(1Η, s) , ¾ NMR (400, CDCls): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1Η, s),
4.22(2Η, d), 3.86C2H, d) , 3.81-3.24(6Η , m) , 3.13(2Η, m) , 2.9K1H, m), 2.77-2.28(6Η, m) , 2.0Κ6Η, m)， 1.6K1H, m)， 1.46(2H„ m)， 1.32(6H, d) . <실시예 150> ((S)-3- (하이드록시메틸)피를리딘 -1-일) (4-(4一4.22 (2Η, d), 3.86C2H, d), 3.81-3.24 (6Η, m), 3.13 (2Η, m), 2.9K1H, m), 2.77-2.28 (6Η, m), 2.0Κ6Η, m) ， 1.6K1H, m), 1.46 (2H „m), 1.32 (6H, d). Example 150 ((S) -3- (hydroxymethyl) pyridin-1-yl) (4- (4 one
((1-(3-이소프로필 -1，2，4-옥사디아졸 -5—일 )피페리딘 -4-일 )메록시 )페 닐 )싸이클로핵스 -3-엔일)메타논의 제조 Preparation of ((1- (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000131_0002
Figure imgf000131_0002
(R)-N,N_디메틸피를리딘 -3-아민 하이드로클로과이드를 사용하는 대신에 L-베타-프를리놀 (L-beta-Prolinol)을 사용하는 것을 제외하고ᅳ 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하 였다 (수득량 210mg I 수율 74%). Except for using L-beta-prolinol instead of using (R) -N, N_dimethylpyridin-3-amine hydrochloride <Example 143 In the same manner as to prepare the title compound. (Yield 210 mg I yield 74%).
JH NMR (400， CDC13) ： 7.33(2H, d), 6.86(2H, d), 6.06(111， s), 4.22C2H, d) , 3.86(2H( d)， 3.81-3.24(6H , m)， 3.13(2H, m)， 2.9K1H, m) , 2.77-2.28(6H, m) , 2.0K6H, m) , 1.6K1H, m) , 1.46(2H, m) , 1.32(6H, d). J H NMR (400, CDC1 3 ): 7.33 (2H, d), 6.86 (2H, d), 6.06 (111, s), 4.22C2H, d), 3.86 (2H ( d), 3.81-3.24 (6H, m) ， 3.13 (2H, m) ， 2.9K1H, m), 2.77-2.28 (6H, m), 2.0K6H, m), 1.6K1H, m), 1.46 (2H, m), 1.32 (6H, d) .
<실시예 151> (4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일) 메특시 )페닐)싸이클로핵스 -3-엔일) ((R)-2— (하이드록시메틸)피를리딘- 1-일)메타논 하이드로클로라이드의 제조 Example 151 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) mesopropyl) phenyl) cyclonux-3-enyl) ((R) -2— Preparation of (hydroxymethyl) pyridin-1-yl) methanone hydrochloride
Figure imgf000132_0001
Figure imgf000132_0001
(00-3- (디메틸아미노)피롤리딘 -1-일.) (4-(4-((1-(3ᅳ이소프로필- (00-3- (dimethylamino) pyrrolidin-1-yl.) (4- (4-((1- (3'isopropyl-)
1,2， 4-윽사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔 일 )메타논을 사용하는 대신에 (4-(4-((1-(5-에틸피리미딘ᅳ2-일 )피페리 딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일) ( (R)-2- (하이드록시메틸 )피 롤리딘ᅳ 1-일 )메타논을 사용하는 것을 제외하고， 상기 <실시예 145>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 85mg I 수율 72%).. 1,2,4-xadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone instead of using (4- (4-(( 1- (5-ethyl-pyrimidin-eu 2- yl) piperidin-4-yl) methoxy hydroxymethyl) phenyl) cyclo haekseu-3-enyl) ((R) - 2 - (hydroxymethyl) pyrrolidin-1 eu Except for using -methanone, the title compound was prepared in the same manner as in <Example 145> (yield 85 mg I yield 72%).
XH 匪 R (400, CDCls) ： 8.4K2H, s) , 7.33(2H, d), 6.86(2H, d)， 6.06(1H, s) , 5.02(2H, d) , 4.29(1H, m) , 3.86(2H, d) , 3.79-3.24(6H , m) , 2.75-1.89(17H, m) , 1.65(1H, m), 1.35(2H, m)， 1.2K3H, m). X H 匪 R (400, CDCls): 8.4K2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.02 (2H, d), 4.29 (1H, m) , 3.86 (2H, d), 3.79-3.24 (6H, m), 2.75-1.89 (17H, m), 1.65 (1H, m), 1.35 (2H, m), 1.2K3H, m).
<실시예 152> (4-(4-((l-(5-에틸피리미딘 -2-일 )피떼리딘 -4-일 ) 메톡시 )페닐)싸이클로핵스 -3ᅳ엔일 ) ((S)-3- (하이드록시메틸)피를리딘- 1-일 ) Example 152 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3yenen) ((S) -3- (hydroxymethyl) pyridin-1-yl)
Figure imgf000132_0002
Figure imgf000132_0002
100 mL 플라스크에 4— (4-((1-(5_에틸피리미딘 -2-일 )피페리딘 -4- 일)메록시 )페닐)싸이클로핵스 -3-엔카복실릭 엑시드 300 mg을 DMF 30 mL에 용해시키고 질소환경 하에 교반하였다. TEA 0.2 mL , L-베타 -프를 리놀 110 mg을 순차적으로 적가한 후， 10분간 추가적으로 교반하였다. HATU 300 mg을 적가한 후， 상온에서 1시간 교반하였다. 반웅 종결 후， 증류수 50 mL를 0°C에서 천천히 가하고， 생성되는 고체를 여과한 후 건조하여 표제 화합물을 제조하였다 (수득량 230mg I 수을 74%). In a 100 mL flask, 300 mg of 4— (4-((1- (5_ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxylic acid DMF It was dissolved in 30 mL and stirred under nitrogen. 0.2 mL TEA, L-beta-pep Linol 110 mg was added dropwise sequentially followed by additional stirring for 10 minutes. 300 mg of HATU was added dropwise, followed by stirring at room temperature for 1 hour. After completion of reaction, 50 mL of distilled water was slowly added at 0 ° C., and the resulting solid was filtered and dried to obtain the title compound (yield 230 mg I water 74%).
XH 匪 R (400, CDC13) ： 8.18(2H, s) , 7.33(2H, d) , 6.86(2H( d) , 6.06(1H, s) , 4.78C2H, d) , 3.86(2H, d) , 3.79-3.24(6H , m) , 2.92(2H, m) , 2.77-2.28(8H, m)， 2.19-1.65( 10H , m) , 1.35(2H, m) , 1.2K3H, m) . X H 匪 R (400, CDC1 3 ): 8.18 (2H, s), 7.33 (2H, d), 6.86 (2H ( d), 6.06 (1H, s), 4.78C2H, d), 3.86 (2H, d ), 3.79-3.24 (6H, m), 2.92 (2H, m), 2.77-2.28 (8H, m), 2.19-1.65 (10H, m), 1.35 (2H, m), 1.2K3H, m).
<실시예 153> (4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일) 메록시 )페닐)싸이클로핵스ᅳ3-엔일) (CR)ᅳ 3- (하이드록시메틸)피를리딘- 1-일 ) 조 Example 153 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-3-enyl) (CR) 3- (hydroxymethyl) pyridin-1-yl) crude
Figure imgf000133_0001
Figure imgf000133_0001
L-베타 -프를리놀을 사용하는 대신에 D-베타 -프를리놀을 사용하 는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표 제 화합물을 제조하였다 (수득량 240mg I 수율 82%).  The title compound was prepared in the same manner as in <Example 152>, except that D-beta-prlinol was used instead of L-beta-prlinol (yield 240 mg I Yield 82%).
:H NMR (400， CDCls) ： 8.18(2H, s) , 7.33(2H, d) , 6.86(2H, d)， 6.06 1H, s) , 4.78 2H' d) , 3.86(2H, d) , 3.79-3.24(6H , m)， 2.92(2H, m) , 2.77-2.28(8H, m) , 2.19-1.65( lOH , ,m) , 1.3'5(2H, m) , 1.2K3H, m) . : H NMR (400, CDCls): 8.18 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 1H, s), 4.78 2H ' d), 3.86 (2H, d), 3.79 -3.24 (6H, m), 2.92 (2H, m), 2.77-2.28 (8H, m), 2.19-1.65 (lOH,, m), 1.3 ' 5 (2H, m), 1.2K3H, m).
<실시예 154> ((S)-3- (디메틸아미노)피롤리딘 -1-일) (4-(4-((l-Example 154 ((S) -3- (dimethylamino) pyrrolidin-1-yl) (4- (4-((l-
(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔 일 )메 (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) meth
Figure imgf000133_0002
Figure imgf000133_0002
L-베타ᅳ프를리놀을 사용하는 대신에 (S)-N,N-디메틸피를리딘 -3- 아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 470mg / 수율 80%).  The procedure was carried out in the same manner as in <Example 152>, except that (S) -N, N-dimethylpyridine-3-amine amine hydrochloride was used instead of L-betachamplinol. Compounds were prepared (yield 470 mg / yield 80%).
¾ NMR (400, CDC13) ： 8.18(2H, s) , 7.33(2H, d) , 6.86(2Η, d) , 6.06 1H, s), 4.78C2H, d)， 3.93-3.71(4H , m) , 3.59-3.18(2H , m) 2.92(2H, m), 2.86-2._41(7H , m) , 2.30(6H, s) , 2.22-1.71(8H , m) 1.35(2H, m) , 1.21(3H, m) . <실시예 155> ((R)-3- (디메틸아미노)피를리딘 -1-일) (4-(4-((l-¾ NMR (400, CDC1 3 ) ： 8.18 (2H, s), 7.33 (2H, d), 6.86 (2Η, d), 6.06 1H, s), 4.78 C2H, d), 3.93-3.71 (4H, m), 3.59-3.18 (2H, m) 2.92 (2H, m), 2.86-2._41 (7H, m), 2.30 (6H , s), 2.22-1.71 (8H, m) 1.35 (2H, m), 1.21 (3H, m). Example 155 ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4-((l-
( 5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔 일 )메타논의 제조 Preparation of (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000134_0001
Figure imgf000134_0001
L-베타 -프를리놀을 사용하는 대신에 (R)-N,N-디메틸피를리딘 -3- 아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 440mg I 수율 76%).  The procedure was carried out in the same manner as in <Example 152>, except that (R) -N, N-dimethylpyridin-3-amine amine hydrochloride was used instead of L-beta-prlinol. Compounds were prepared (yield 440 mg I yield 76%).
lE 画 R (400, CDCls) ： 8.18(2H, s), 7.33(2H, d) , 6.86(2H, d)， 6.06(111， s), 4.78(2H, d)， 3.93-3.71(4H , m) , 3.59-3.18(2H, m) , 2.92(2H, m) , 2.86-2.41(7H , m) , 2.30(6H, s), 2.22-1.71 (8H , m) , 1.35(2H, m) , 1.2K3H, m) .  l 画 R (400, CDCls): 8.18 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (111, s), 4.78 (2H, d), 3.93-3.71 (4H, m), 3.59-3.18 (2H, m), 2.92 (2H, m), 2.86-2.41 (7H, m), 2.30 (6H, s), 2.22-1.71 (8H, m), 1.35 (2H, m) , 1.2K3H, m).
<실시예 156> ((S)-3- (디메틸아미^ )피를리딘 -1-일 ).(4-(4-((1-Example 156 ((S) -3- (dimethylami ^) pyridin-1-yl). (4- (4-((1-
(5-에틸피리미딘 -2-일 )피페리딘 -4—일 )메톡시 )페닐)싸이클로핵스 -3-엔 일 )메타논 하이드로클로라이드의 제조 Preparation of (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone hydrochloride
Figure imgf000134_0002
Figure imgf000134_0002
((R)-3- (디메틸아미노)피를리딘 -1-일) (4-(4-((1-(3-이소프로필- 1，2，4-옥사디아졸 -5-일)피페리딘— 4-일)메록시 )페닐)싸이클로핵스 -3-엔 일)메타논을 사용하는 대신에 ((S)— 3- (디메틸아미노)피를리딘 -1- 일) (4-(4-((1-(5-에틸파리미딘— 2-일 )피페리딘 -4-일 )메록시 )페닐)싸이 클로핵스ᅳ 3ᅳ엔일)메타논을 사용하는 것을 제외하고， 상기 <실시예 145>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 180mg I 수율 76%). ¾ NMR (400， D20) ： 8.28(2H, s) , 7.33(2H, d) , 6.86(2H, d) , 6.06(1H, s), 4.3K1H, d) , 3.95-3.31(4H , m)， 3.14(2H, m) , 2.86(6H, s) , 2.72(1H, m), 2.53-1.87( 12H , m) , 1.63(1H, m), 1.31(2H, m) , 1.09C3H, m) . ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) pi Ferridin- 4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone ((S) — 3- (dimethylamino) pyridin-1-yl) (4- ( Except for using 4-((1- (5-ethylparimidine- 2-yl) piperidin-4-yl) methoxy) phenyl) cyclonusk ᅳ 3 ᅳ enyl) methanone, In the same manner as in Example 145>, the title compound was prepared (a yield 180 mg I yield 76%). ¾ NMR (400, D 2 0): 8.28 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.3K1H, d), 3.95-3.31 (4H, m), 3.14 (2H, m), 2.86 (6H, s), 2.72 (1H, m), 2.53-1.87 (12H, m), 1.63 (1H, m), 1.31 (2H, m), 1.09C3H, m).
<실시예 157> ((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((l-Example 157 ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4-((l-
(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스—3-엔 일)메 드로클로라이드의 제조 Preparation of (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methochloride
Figure imgf000135_0001
Figure imgf000135_0001
((R)-3- (디메틸아미노)피를리딘ᅳ1ᅳ일 ) (4-(4-( (1-(3-이소프로필ᅳ 1， 2, 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔 일)메타논올 사용하는 대신에 ((R)_3- (디메틸아미노)피를리딘 -1- 일) (4ᅳ(4-((1— (5ᅳ에틸피리미딘 -2-일)피페리딘 -4-일)메톡시 )페닐 )싸이 클로핵스 -3-엔일)메타논을 사용하는 것을 제외하고, 상기 <실시예 145>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 170mg / 수율 71%).  ((R) -3- (dimethylamino) pyridin ᅳ 1xyl) (4- (4- ((1- (3-isopropyl ᅳ 1, 2, 4-oxadiazol-5-yl) piperi Din-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanol ((R) _3- (dimethylamino) pyridin-1-yl) (4) (4- ( (1— (5'ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone, except for using <Example 145> The title compound was prepared in the same manner as the yield (170 mg / yield 71%).
¾ NMR (400， D20) ： 8.28(2H, s) , 7.33(2H, d) : 6.86(2H, d) , 6.06 1H, s) , 4.3K1H, d) , 3..95-3.31(4H , m), 3.14(2H m) , 2.86(6H, s), 2.72(1H, m) , 2.53-1.87( 12H , m), 1.63(1H, m) , 1.3K2H, m) , 1.09C3H, m) . ¾ NMR (400, D 2 0): 8.28 (2H, s), 7.33 (2H, d) : 6.86 (2H, d), 6.06 1H, s), 4.3K1H, d), 3..95-3.31 ( 4H, m), 3.14 (2H m), 2.86 (6H, s), 2.72 (1H, m), 2.53-1.87 (12H, m), 1.63 (1H, m), 1.3K2H, m), 1.09C3H, m).
<실시예 158> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메특시 )페닐)싸이클로핵스 -3-엔일) ((S)-3- (하이드록시메틸)피를리딘- 1-일)메타논 하이드로클로라이드의 제조 Example 158 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) mesospecific) phenyl) cyclonux-3-enyl) ((S) Preparation of 3- (hydroxymethyl) pyridin-1-yl) methanone hydrochloride
Figure imgf000135_0002
Figure imgf000135_0002
((R)-3ᅳ (디메틸아미노)피롤리딘 -1-일 ) (4-(4-((1-(3ᅳ이소프로필- 1,2,4-옥사디아졸— 5-일)피페리딘 -4-일)메록시 )페닐)싸이클로핵스—3-엔 일)메타논을 사용하는 대신에 (4-(4ᅳ((1ᅳ(5-에틸피리미딘 -2-일 )피페리 딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일) ((S)-3- (하이드록시메틸)피 를리딘 -1-일)메타논을 사용하는 것을 제외하고， 상기 <실시예 145>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 95mg I 수율 71%). ((R) -3 '(dimethylamino) pyrrolidin-1-yl) (4- (4-((1- (3'isopropyl- 1,2,4-oxadiazole- 5-yl) pi (4- (4 ((1 '(5-ethylpyrimidin-2-yl) piperi) instead of using ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone Dyn-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) -3- (hydroxymethyl) pyridin-1-yl) methanone, except that The title compound was prepared in the same manner as the Example 145> (yield 95 mg I yield 71%).
JH NMR (400， CDCls) ： 8.43(2H, s) , 7.33(2H, d) , 6.86C2H, d) , 6.06(1Η, s), 4.78C2H, d), 3.86(2Η, d)， 3.79-3.24(6Η , m) , 2.92(2Η, m), 2.77-2.28(8Η, m) , 2.19-1.65( 10H , m) , 1.35(2Η, m) , 1.21(3Η, m) . J H NMR (400, CDCls): 8.43 (2H, s), 7.33 (2H, d), 6.86C2H, d), 6.06 (1Η, s), 4.78C2H, d), 3.86 (2Η, d) ， 3.79 -3.24 (6Η, m), 2.92 (2Η, m), 2.77-2.28 (8Η, m), 2.19-1.65 (10H, m), 1.35 (2Η, m), 1.21 (3Η, m).
<실시예 159> (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메톡시 )페닐)싸이클로핵스 - 3 -엔일) (( R ) - 3 - (하이드록시메틸)피를리딘- 1-일 )메타논 하이드로클로라이드의 제조 Example 159 (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((R) Preparation of (hydroxymethyl) pyridin-1-yl) methanone hydrochloride
Figure imgf000136_0001
Figure imgf000136_0001
((R)-3- (디메틸아미노)피를리딘— 1-일 ) (4— (4-( (1-(3-이소프로필- 1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔 일 )메타논을 사용하는 대신에 (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리 딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3ᅳ엔일 ) ( (R)-3— (하이드록시메틸)피 를리딘ᅳ 1-일)메타논을 사용하는 것을 제외하고， 상기 <실시예 145>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 85mg I 수율 Ί2Λ) .  ((R) -3- (dimethylamino) pyridin— 1-yl) (4— (4- ((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) pi Instead of using ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone (4- (4-((1- (5-ethylpyrimidin-2-yl) piperi) Din-4-yl) methoxy) phenyl) cyclonux-3xenyl) (R) -3— (hydroxymethyl) pyridinyl 1-yl) methanone, except that < In the same manner as in Example 145>, the title compound was prepared (a yield 85 mg I yield: 2Λ).
¾ NMR (400, CDCls) ： 8.43(2H, s) , 7.33(2H, d) , 6.86(2H, d) , ¾ NMR (400, CDCls): 8.43 (2H, s), 7.33 (2H, d), 6.86 (2H, d),
6.06C1H, s) , 4.78(2H, d) , 3.86(2H, d) , 3.79-3.24( 6H , m)， 2.92(2H, m) , 2.77-2.28C8H, m) , 2.19— 1.65( 10H， m) , 1.35(2H, m)， 1.2K3H, m) 6.06C1H, s), 4.78 (2H, d), 3.86 (2H, d), 3.79-3.24 (6H, m), 2.92 (2H, m), 2.77-2.28C8H, m), 2.19— 1.65 (10H, m), 1.35 (2H, m) ， 1.2K3H, m)
<실시예 160> (4— (4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메록시 )페닐)싸이클로핵스 -3-엔일) ((S)-3-플루오로피를리딘 -1-일)메타 논의 제조 Example 160 (4— (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) 3-Fluoropyridin-1-yl) meta discussion preparation
Figure imgf000136_0002
Figure imgf000136_0002
L-베타 -프를리놀을 사용하는 대신에 (S)_3-플루오로피를리딘을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 195mg /. 수율 76%). (S) _3-fluoropyridine instead of using L-beta-prlinol Except for using, the title compound was prepared in the same manner as in <Example 152> (yield 195 mg /. Yield 76%).
¾ NMR (400， CDC13) ： 8.19(2H, s) , 7.33(2H, d) , 6.86(2Η, d)， 6.06(1Η, s), 5.3K1H, m)， 4.78(2H, d) , 4.01-3.51(6H , m) , 2.92(2H, m) , 2.77— 1.87(14H, m) , 1.35(2H, m) , 1.21(3H, m) . ¾ NMR (400, CDC1 3 ): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2Η, d), 6.06 (1Η, s), 5.3K1H, m), 4.78 (2H, d), 4.01-3.51 (6H, m), 2.92 (2H, m), 2.77— 1.87 (14H, m), 1.35 (2H, m), 1.21 (3H, m).
<실시예 161> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메톡시)페닐)싸이클로핵스 -3-엔일) ((S)-3-플루오로피를리딘— 1-일)메타 논 하이 로클로라이드의 제조 Example 161 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) Preparation of -3-fluoropyridin— 1-yl) methanone hydrochloride
Figure imgf000137_0001
Figure imgf000137_0001
((R)-3- (디메틸아미노)피롤리딘—1ᅳ일 ) (4-(4-( (1-(3-이소프로필 - 1,2，4-옥사다아졸 -5-일 )파페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔 일)메타논을 사용하는 대신에 (4-(4-((1-(5-에틸피리미딘ᅳ2-일)피페리 딘 -4-일)메톡시 )페닐)싸이클로핵스 -3ᅳ엔일) ((S)-3-플루오로피롤리딘- 1-일 )메타논을 사용하는 것을 제외하고， 상기 <실시예 145>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 105mg I 수율 73%) .  ((R) -3- (dimethylamino) pyrrolidin—1 ᅳ yl) (4- (4- ((1- (3-isopropyl-1,2,4-oxadazol-5-yl) paperi (4- (4-((1- (5-ethylpyrimidin ᅳ 2-yl) piperidine instead of using din-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone Except for using 4- (yl) methoxy) phenyl) cyclonux-3xenyl) ((S) -3-fluoropyrrolidin-l-yl) methanone, Example <145> The title compound was prepared in the same manner as the obtained yield (105 mg I yield 73%).
¾ 匪 R (400, CDC13) ： 8.4K2H, s), 7.33(2H, d) , 6.86(2Η, d) , 6.06 1H, s) , 5.3K1H, m) , 5.0Κ2Η, d) , 4.01-3.5K6H, m) , 2.92(2Η, m) , 2.77-1.87(14Η, m)， 1.35(2Η, m) , 1.2K3H, m) . ¾ 匪 R (400, CDC1 3 ): 8.4K2H, s), 7.33 (2H, d), 6.86 (2Η, d), 6.06 1H, s), 5.3K1H, m), 5.0Κ2Η, d), 4.01- 3.5K6H, m), 2.92 (2Η, m), 2.77-1.87 (14Η, m), 1.35 (2Η, m), 1.2K3H, m).
<실시예 162> (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메록시 )페닐)싸이클로핵스 -3-엔일) (피를리딘 -1-일 )메타논의 제조 Example 162 (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (pyridine -1-yl) Methanone Preparation
Figure imgf000137_0002
Figure imgf000137_0002
L-베타 -프를리놀을 사용하는 대신에 피를리딘을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합 물을 제조하였다 (수득량 250mg I 수을 84¾ .  The title compound was prepared in the same manner as in <Example 152>, except that pyridin was used instead of L-beta-prlinol (a yield of 250 mg I number was 84¾.
¾ NMR (400, CDCls) ： 8.19(2H, s) , 7.33(2H, d) , 6.86(2H, d)， 6.06C1H, s) , 4.78(2H, d) , 3.85(2H, d) , 3.52(4H, m) , 2.92(2H, m) , 2.71-2.28(7H, m) , 2.17-1.85(9H , m) , 1.35(2H, m)， 1.21(3H, m) . ¾ NMR (400, CDCls): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06C1H, s), 4.78 (2H, d), 3.85 (2H, d), 3.52 (4H, m), 2.92 (2H, m), 2.71-2.28 (7H, m), 2.17-1.85 (9H, m ), 1.35 (2H, m), 1.21 (3H, m).
<실시예 163> (4-(4— ((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메특시 )페닐)싸이클로핵스 -3-엔일) (피페리딘 -1-일 )메타논의 제조 Example 163 (4- (4 — ((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) mesospecific) phenyl) cyclonux-3-enyl) (piperidine -1-yl) Methanone Preparation
Figure imgf000138_0001
Figure imgf000138_0001
L-베타—프를리놀을 사용하는 대신에 피페리딘을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합 물을 제조하였다 (수득량 250mg I 수율 83%).  The title compound was prepared in the same manner as in <Example 152>, except that piperidine was used instead of L-beta-prlinol (yield 250 mg I yield 83%).
XH 匪 R (400, CDC13) ： 8.19(2H, s), 7.33(2H, d)， 6.86(2H, d)，XH 匪 R (400, CDC1 3 ): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d),
6.06(1H, s) , 4.78(2H, d)， 3.85(2H, d) , 3.67-3.52(4H , m)， 2.92(2H, m) , 2.80(1H, m) , 2.61-1.85( 11H , m) , 1.74-1.54(6H , m) , 1.35(2H , m) 1.2K3H, m) . <실시예 164> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메톡시 )페닐)싸이클로핵스 -3-엔일) (4-하이드록시피페리딘 -1-일)메타논 의 제조 6.06 (1H, s), 4.78 (2H, d), 3.85 (2H, d), 3.67-3.52 (4H, m), 2.92 (2H, m), 2.80 (1H, m), 2.61-1.85 (11H, m), 1.74-1.54 (6H, m), 1.35 (2H, m) 1.2K3H, m). Example 164 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (4-hydr Preparation of Roxypiperidin-1-yl) methanone
Figure imgf000138_0002
Figure imgf000138_0002
L-베타ᅳ프를리놀을 사용하는 대신에 4-하이드록시 피페리딘을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 15mg I 수율 77%).  The title compound was prepared in the same manner as in <Example 152>, except that 4-hydroxy piperidine was used instead of L-betachamplinol (yield 15 mg I yield 77 %).
¾ 丽 R (400, CDC13) ： 8.19(2H, s) , 7.33(2H, d) , 6.86(2H, d)， 6.06(1H, s) , 4.78C2H, d)ᅳ 4.18(1H, m) , 3.89(2H, m) , 3.85(2H, d), 3.28(2H, m) , 2.92(2H, m)， 2.80(1H, m) , 2.61-2.28( 6H , m) , 2.09(1H, m) , 1.98(6H, m)， 1.55(2H, m) , 1.35(2H, m) , 1.2K3H, m) . ¾ リ R (400, CDC1 3 ): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78C2H, d) ᅳ 4.18 (1H, m) , 3.89 (2H, m), 3.85 (2H, d), 3.28 (2H, m), 2.92 (2H, m), 2.80 (1H, m), 2.61-2.28 (6H, m), 2.09 (1H, m ), 1.98 (6H, m), 1.55 (2H, m), 1.35 (2H, m), 1.2K3H, m).
<실시예 165> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메록시 )페닐)싸이클로핵스 -3-엔일) (4- (하이드록시메틸)피페리딘 -1ᅳ일 ) 메타논의 제조 Example 165 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (4- ( Hydroxymethyl) piperidin-1syl) Preparation of metanon
Figure imgf000139_0001
Figure imgf000139_0001
L-베타 -프를리놀을 사용하는 대신에 4-피페리딘메탄올을 사용하 는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표 제 화합물을 제조하였다 (수득량 225mg I. 수율 75%).  The title compound was prepared in the same manner as in <Example 152>, except that 4-piperidinemethanol was used instead of L-beta-prlinol (yield 225 mg I. Yield 75%).
¾ 匪 R (400, CDC13) ： 8.19(2H, s) , 7.33(2H, d) , 6.86(2Η, d)， 6.06C1H, s) , 4.78C3H, m) , 4.Θ8(1Ή, d) , 3.85(2Η, d) , 3.55(2Η, m)， 3.09(1Η, m) , 2.92(2Η, m) , 2.81(1Η, m) , 2.65-2.28( 7Η , m)， 2.11(1Η, m) , 2.04-1.75(7Η, m) , 1.35(2Η, m) , 1.21(3Η, m) . ¾ 匪 R (400, CDC1 3 ): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2Η, d), 6.06C1H, s), 4.78C3H, m), 4.Θ8 (1Ή, d ), 3.85 (2Η, d), 3.55 (2Η, m) ， 3.09 (1Η, m), 2.92 (2Η, m), 2.81 (1Η, m), 2.65-2.28 (7Η, m) ， 2.11 (1Η, m), 2.04-1.75 (7Η, m), 1.35 (2Η, m), 1.21 (3Η, m).
<실시예 166> (4-(4-(( 1-( 5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메록시 )페닐)싸이클로핵스 -3-엔일) (피를리딘 -1-일 )메타논 하이드로클 로라이드의 제조 Example 166 (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (pyridine Preparation of -1-yl) methanone hydrochloride
Figure imgf000139_0002
Figure imgf000139_0002
((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(3-이소프로필- ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (3-isopropyl-
1,2,4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )페닐)싸이클로핵스 -3-엔 일)메타논을 사용하는 대신에 (4-(4-((1-(5-에틸피리미딘 -2-일)피페리 딘ᅳ 4-일 )메록시 )페닐)싸이클로핵스 -3-엔일) (피를리딘 -1-일 )메타논올 사용하는 것을 제외하고， 상기 <실시예 145>와 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 lOOmg I 수율 74%). 1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone instead of using (4- (4-(( 1- (5-ethylpyrimidin-2-yl) piperidinyl 4-yl) methoxy) phenyl) cyclonux-3-enyl) (pyridin-1-yl) methanol except that The title compound was prepared in the same manner as the <Example 145> (yield 100 mg yield 74%).
XH NMR (400， CDCI3) ： 8.4K2H, s) , 7.33(2Ή, d)， 6.86(2H; d) ,XH NMR (400, CDCI 3 ): 8.4K2H, s), 7.33 (2Hz, d), 6.86 (2H; d),
6.06(1H, s) , 5.03(2H, d) , 3.85(2H, d) , 3.52(4H, m), 2.92(2H, m)， 2.71-2.28(7H, m) , 2.17-1.85(9H , m) , 1.35(2H, m) , 1.21(3H, m) . <실시예 167> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메톡시 )페닐)싸이클로핵스 -3-엔일 ) (피페리딘ᅳ 1-일 )메타논 하이드로클 로라이드의 제조
Figure imgf000140_0001
6.06 (1H, s), 5.03 (2H, d), 3.85 (2H, d), 3.52 (4H, m), 2.92 (2H, m), 2.71-2.28 (7H, m), 2.17-1.85 (9H, m), 1.35 (2H, m), 1.21 (3H, m). Example 167 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (piperidine Preparation of 1-yl) methanone hydrochloride
Figure imgf000140_0001
((R)-3- (디메틸아미노)피롤리딘— 1-일) (4-(4-((l-(3-이소프로필- 1,2, 4-옥사디아졸 -5—일)피페리딘 -4-일)메록시 )페닐)싸이클로핵스 -3-엔 일)메타논을 사용하는 대신에 (4-(4-((1-(5ᅳ에틸피리미딘 -2-일)피페리 딘 -4-일 )메톡시 )페닐)싸이클로핵스—3-엔일) (피페리딘 -1—일 )메타논을 사용하는 것을 제외하고， 상기 <실시예 145〉와 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 85mg I 수율 71%).  ((R) -3- (dimethylamino) pyrrolidin— 1-yl) (4- (4-((l- (3-isopropyl-1, 1,2, 4-oxadiazole-5—yl) pi Instead of using ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone (4- (4-((1- (5) ethylpyrimidin-2-yl) piperi) The title compound was prepared in the same manner as in <Example 145>, except that din-4-yl) methoxy) phenyl) cyclonux-3-enyl) (piperidin-1-yl) methanone was used. Was prepared (yield 85 mg I yield 71%).
XH NMR (400, CDC13) ： 8.4K2H, s) , 7.33(2H, d) , 6.86(2Η, d) , 6.06(1Η, s), 5.03(2Η, d) , 3.85(211， d) , 3.67-3.52(4Η , m) , 2.92(2Η, m), 2.80(1Η, m) , 2.61-1.85( 11H , m) , 1.74-1.54(6Η, m) , 1.35(2Η, m) 1.2K3H, m) . X H NMR (400, CDC1 3 ): 8.4K2H, s), 7.33 (2H, d), 6.86 (2Η, d), 6.06 (1Η, s), 5.03 (2Η, d), 3.85 (211, d) , 3.67-3.52 (4Η, m), 2.92 (2Η, m), 2.80 (1Η, m), 2.61-1.85 (11H, m), 1.74-1.54 (6Η, m), 1.35 (2Η, m) 1.2K3H , m).
<실시예 168> (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메특시 )페닐)싸이클로핵스 -3—엔일) (4-하이드록시피쩨리딘— 1-일)메타논 하이드로를로라이드의 제조 Example 168 (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) mesospecific) phenyl) cyclonux-3-enyl) (4-hydr Oxypicuridine— Preparation of 1-yl) methanone hydrochloride
Figure imgf000140_0002
Figure imgf000140_0002
((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-( (1-(3-이소프로필- 1，2，4-옥사디아졸 -5—일 )파페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔 일)메타논을 사용하는 대신에 (4-(4-((1-(5-에틸피리미딘 -2-일)피페리 딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일 ) (4-하이드록시피페리딘— 1- 일)메타논을 사용하는 것을 제외하고， 상기 <실시예 145>와 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 85mg I 수율 77%). rH NMR (400, CDCI3) ： 8.4K2H, s) , 7.33(2H, d)， 6.86(2H, d)， 6.06(1H, s)ᅳ 5.03(2H, d) , 4.18 1H, m) , 3.89(2H, m) , 3.85(2H, d), 3.28(2H, m) , 2.92(2H, m) , 2.80(1H, m) , 2.61-2.28(6H, m) , 2.09(1H, m) , 1.98(6H, m)， 1.55(2H, m) , 1.35(2H, m) , 1.21(3H, m) .  ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole-5-yl) wave Instead of using ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone (4- (4-((1- (5-ethylpyrimidin-2-yl) piperi) Same method as in <Example 145>, except that din-4-yl) methoxy) phenyl) cyclonux-3-enyl) (4-hydroxypiperidin— 1-yl) methanone is used To give the title compound (yield 85 mg I yield 77%). rH NMR (400, CDCI3): 8.4K2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s) ᅳ 5.03 (2H, d), 4.18 1H, m), 3.89 ( 2H, m), 3.85 (2H, d), 3.28 (2H, m), 2.92 (2H, m), 2.80 (1H, m), 2.61-2.28 (6H, m), 2.09 (1H, m), 1.98 (6H, m), 1.55 (2H, m), 1.35 (2H, m), 1.21 (3H, m).
<실시예 169> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘— 4-일 ) 메록시)페닐)싸이클로핵스 - 3 -엔일) ( 4 - (하이드록시메틸)피페리딘 메타논 하이드로클로라이드의 제조 Example 169 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidine- 4-day) Preparation of methoxy) phenyl) cyclonux-3-enyl) (4-hydroxypropyl) piperidine metanon hydrochloride
Figure imgf000141_0001
Figure imgf000141_0001
((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(3—이소프로필- 1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )페닐)싸이클로핵스ᅳ 3-엔 일)메타논을 사용하는 대신에 (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리 딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일 ) ( 4- (하이드록시메틸)피페리 딘 -1-일 )메타논을 사용하는 것을 제외하고, 상기 <실사예 145>와 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 95mg I 수율 76%) .  ((R) -3- (dimethylamino) pyridin-1-yl) (4- (4-((1- (3—isopropyl-1,2,4-oxadiazol-5-yl) pi (4- (4-((1- (5-ethylpyrimidin-2-yl) piperi) instead of using ferridin-4-yl) methoxy) phenyl) cyclonucleosulf 3-enyl) methanone Dix-4-yl) methoxy) phenyl) cyclonux-3-enyl) (4- (hydroxymethyl) piperidin-1-yl) methanone, except that The title compound was prepared in the same manner (yield 95 mg I yield 76%).
¾ 匪 R (400， CDCls) ： 8.4K2.H, s) , 7.33(2Ή, d) , 6.86(2Η, d) , 6.06 1Hᅳ s), 5.03(2Ή, m) , 4.72(1Η, d) , 4.08(1Η, d) , 3.85(2Η, d) , 3.55C2H, m) , 3.09(1Η, ra) , 2.92(2Η, m)， 2.8K1H, m) , 2.65-2.28(7Η , m) , 2.1K1H, m) , 2.04-1.75( 7Η , m) , 1.35(2Η, m) , 1.21(3Η, m) .  ¾ 匪 R (400, CDCls): 8.4K2.H, s), 7.33 (2Ή, d), 6.86 (2Η, d), 6.06 1H ᅳ s), 5.03 (2Ή, m), 4.72 (1Η, d) , 4.08 (1Η, d), 3.85 (2Η, d), 3.55C2H, m), 3.09 (1Η, ra), 2.92 (2Η, m), 2.8K1H, m), 2.65-2.28 (7Η, m), 2.1 K1H, m), 2.04-1.75 (7Η, m), 1.35 (2Η, m), 1.21 (3Η, m).
<실시예 170> 아제티딘 -1-일 (4-(4-((1-(5-에틸피리미딘 -2-일 )피 페리 -4-일)메톡시 )페닐)싸이클로핵스 -3ᅳ엔일)메타논의 제조 Example 170 Azetidin-1-yl (4- (4-((1- (5-ethylpyrimidin-2-yl) piperid-4-yl) methoxy) phenyl) cyclonux-3yen (1) Manufacture of methanon
Figure imgf000141_0002
Figure imgf000141_0002
L-베타 -프롤리놀을 사용하는 대신에 아제티딘 (Azetidine)을 사 용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 180ing I 수율 76%).  The title compound was prepared in the same manner as in <Example 152>, except that Azetidine was used instead of L-beta-prolinol (yield 180ing I yield 76). %).
¾ 匪 R (400, CDCls) ： 8.19(2H, s) , 7.33(2H, d) , 6.86(2Η, d)， 6.06(1Η, s) , 4.78C3H, m)， 4.15(4H, m) , 3.85(2H, d) , 2.9K2H, m) , 2.61-1.8K14H, m) , 1.35(2H, m) , 1.21(3H, m) .  ¾ 匪 R (400, CDCls): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2Η, d), 6.06 (1Η, s), 4.78C3H, m), 4.15 (4H, m), 3.85 (2H, d), 2.9K2H, m), 2.61-1.8K14H, m), 1.35 (2H, m), 1.21 (3H, m).
<실시예 171> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메특시 )페닐 )싸이클로핵스 -3-엔일 ) (3-하이드록시아제티딘 -1-일 )메타논 의 제조 Example 171 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) mesospecific) phenyl) cyclonux-3-enyl) (3-hydric Preparation of Roxyazetidin-1-yl) methanone
Figure imgf000142_0001
Figure imgf000142_0001
L-베타 -프를리놀을 사용하는 대신에 3ᅳ하이드록시 아제티딘 (Azetidine)을 사용하는 것을 제외하고， 상기 <실시예 152〉와 동일한 방법으로 수행하여 표쎄 화합물을 제조하였다 (수득량 200mg I 수율 81%) .  A skin compound was prepared in the same manner as in <Example 152>, except that 3′hydroxy azetidine was used instead of L-beta-prlinol (yield 200 mg I Yield 81%).
!H 醒 R (400， CDCls) ： 8.19(2H, s) , 7.33(2H, d)， 6.86(2H, d) , 6.06(1H, s) , 4.78(2H, m) , 4.35(4H, m) , 3.85(2H, d) , 2.9K2H, m) , 2.71-1.8K13H, m) , 1.35(2H, m)， 1.21(3HS m) . ! H 醒 R (400, CDCls): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (2H, m), 4.35 (4H, m) , 3.85 (2H, d), 2.9K2H, m), 2.71-1.8K13H, m), 1.35 (2H, m), 1.21 (3H S m).
<실시예 172> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메록시 )페닐 )싸이클로핵스 -3-엔일 ) (4-(2-하이드록시에틸)피페라진 -1- 일 )메 Example 172 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (4- ( 2-hydroxyethyl) piperazin-1-yl) meth
Figure imgf000142_0002
Figure imgf000142_0002
L-베타 -프를리놀을 사용하는 대신에 4-하이드록시에틸피페라진 을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수 행하여 표제 화합물올 제조하였다 (수득량 220mg I 수율 79%).  The title compound was prepared in the same manner as in <Example 152>, except that 4-hydroxyethylpiperazine was used instead of L-beta-prlinol (yield 220 mg I yield 79 %).
XH 匪 R (400， CDC13) ： 8.19(2H, s) , 7.33(2H, d), 6.86(2H, d) , 6.06 1H, s) , 4.78C2H, m) , 3.85(2H, d) , 3.65(6H, m)， 2.9K2H, m)， 2.86-1.8K12H, m) , 1.35(2H, m) , 1.21(3H, m) . X H 匪 R (400, CDC1 3 ): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 1H, s), 4.78C2H, m), 3.85 (2H, d) , 3.65 (6H, m), 2.9K2H, m), 2.86-1.8K12H, m), 1.35 (2H, m), 1.21 (3H, m).
<실시예 173> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메록시 )페닐 )싸이클로핵스 -3-엔일 ) (4-(2-하이드록시에틸)피페리딘 -1- 일 )메타논의 제조 Example 173 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (4- ( Preparation of 2-hydroxyethyl) piperidin-1-yl) methanone
Figure imgf000143_0001
Figure imgf000143_0001
L-베타ᅳ프를리 사용하는 대신에 4-피페리딘 에탄올을 사용 하 것올 제외하고 기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 230mg , 수율 77%).  The title compound was prepared in the same manner as in <Example 152>, except that 4-piperidine ethanol was used instead of L-beta chopped (yield 230 mg, yield 77%).
¾ NMR (400, CDCls) ： 8.19(2H, s) 7.33(2H, d), 6.86(2H, d) , 6.06 1H, s) , 4.78(2Η, m)， 3.69(1H( d)' 3.99(1H, d) , 3.85(2H, d) , 3.75(2H, m) , 3.09(1H, m) , 2.9K2H, m) , 2.86-1.4K17H, m) , 1.35(2H m), 1.2K3H, m) . ¾ NMR (400, CDCls): 8.19 (2H, s) 7.33 (2H, d), 6.86 (2H, d), 6.06 1H, s), 4.78 (2Η, m), 3.69 (1H ( d) '3.99 ( 1H, d), 3.85 (2H, d), 3.75 (2H, m), 3.09 (1H, m), 2.9K2H, m), 2.86-1.4K17H, m), 1.35 (2H m), 1.2K3H, m .
<실시예 174> Nᅳ에톡시 -4-(4-((l-(5-에틸피리미딘 -2-일 )피페리 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카복스아마이드의 제조 Example 174 N-ethoxy-4- (4-((l- (5-ethylpyrimidin-2-yl) piperid-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide Manufacture
하동수 율이일
Figure imgf000143_0002
Hadong rate rate
Figure imgf000143_0002
L-베타 -프롤리놀을 사용하는 대신에 으에틸하이드록실아민 드로클로라이드를 사용하는 것을 제외하고 , 상기 <실시예 152>와 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 230mg / 81%) .  The title compound was prepared in the same manner as in <Example 152>, except that E-ethylhydroxylamine drawchloride was used instead of L-beta-prolinol (yield 230 mg / 81%). .
XH NMR (400, CDCI3) ： 8.19(2H, s) , 7.33(2H, d) , 6.86(2H, d)， 6.06(1H, s) , 4.78(2H, m) , 4.0K2H, m) , 3.85(2H, d) , 2.9K2H, m)， 2.71-1.8K12H, m) , 1.35(5H, m) , 1.2K3H, m) . X H NMR (400, CDCI3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (2H, m), 4.0K2H, m), 3.85 (2H, d), 2.9K2H, m), 2.71-1.8K12H, m), 1.35 (5H, m), 1.2K3H, m).
<실시예 175> N-에틸 -4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘-Example 175 N-ethyl-4- (4-((l- (5-ethylpyrimidin-2-yl) piperidine-
4-일)메특시 )페닐 )-N-(2-하이드록시에틸 )싸이클로핵스 -3-엔카복스아마 이드의 제조
Figure imgf000144_0001
Preparation of 4-yl) methoxy) phenyl) -N- (2-hydroxyethyl) cyclonux-3-enecarboxamide
Figure imgf000144_0001
L-베타 -프를리놀을 사용하는 대신에 2- (에틸아미노)에탄을을 사 용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하 여 표제 화합물올 제조하였다 (수득량 205mg I 수율 82%).  The title compound was prepared in the same manner as in <Example 152>, except that 2- (ethylamino) ethane was used instead of L-beta-prlinol (yield 205 mg). I yield 82%).
rH NMR (400， CDC13) ： 8.19(2H, s) , 7.33(2H, d)， 6.86(2H, d), 6.06 1H, s) , 4.78(2Η' m) , 3.85(4H, m) ' 3.71(1H, s), 3.52(4H, m) , 2.9K2H, m) , 2.81-1.8K12H, m)， 1.35(2Ή, m) , 1.2K6H, m) . rH NMR (400, CDC1 3 ): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 1H, s), 4.78 (2Η 'm), 3.85 (4H, m)' 3.71 (1H, s), 3.52 (4H, m), 2.9K2H, m), 2.81-1.8K12H, m), 1.35 (2Ή, m), 1.2K6H, m).
<실시예 176> 4-(4-((l-(5-에틸피리미딘 -2—일 )피페리딘 -4-일 )메 톡시 )페닐) -N-(2-하이드톡시에틸)싸이클로핵스 -3ᅳ엔카복스아마이드의 제조 Example 176 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (2-hydroxyethyl) cyclonucleus Preparation of -3 ᅳ encarboxamide
Figure imgf000144_0002
Figure imgf000144_0002
L-베타 -프를리놀을 사용하는 대신에 2-아미노에탄올을 사용하는 것을 제외하고, 상기 <실시예 152>와 동일한 방법으로 수행하여 '표제 화합물을 제조하였다 (수득량 260mg I 수율 85%). L- beta - except for using 2-aminoethanol instead of the program using a linoleate, and perform in the same manner as <Example 152> was prepared in the "title compound (Yield 260mg I 85% yield) .
XH NMR (400， CDCI3) ： 8.19(2H, s) , 7.33(2Η, d)， 6.86(2Η, d)， 6.06(2H, m) , 4.78(2H, m) , 3.85(2H, d)， 3.78(2H, m)， 3.51(2H, m) , 2.9K2H, m) , 2.48(7H, m)， 2 · 21-1.81(5H , m) , 1.35(2H, m) , 1.2K3H, m). X H NMR (400, CDCI 3 ): 8.19 (2H, s), 7.33 (2Η, d), 6.86 (2Η, d), 6.06 (2H, m), 4.78 (2H, m), 3.85 (2H, d ), 3.78 (2H, m), 3.51 (2H, m), 2.9K2H, m), 2.48 (7H, m), 2 · 21-1.81 (5H, m), 1.35 (2H, m), 1.2K3H, m).
<실시예 177> 4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메 톡시 )페닐) -Nᅳ (3-하이드록시 -2， 2-디메틸프로필)싸이클로핵스 -3-엔카복 스아마이드의 제조
Figure imgf000145_0001
Example 177 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N '(3-hydroxy-2,2 Preparation of -dimethylpropyl) cyclonux-3-enecarboxamide
Figure imgf000145_0001
L-베타 -프를리놀을 사용하는 대신에 3-아미노 -2, 2-디메틸프로판 올을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 265mg I 수율 85%).  The title compound was prepared in the same manner as in <Example 152>, except that 3-amino-2, 2-dimethylpropanol was used instead of L-beta-prlinol (yield yield). 265 mg I yield 85%).
:H 匪 R (400， CDCls) ： 8.19(2H, s), 7.33(2Ή, d), 6.86(2H, d)， 6.06C1H, s) , 5.98(1H, m) , 4.78(2H, m) , 3.85(2H, d) , 3.49(2H, m) , 3.16(4H, m) , 2.91(2H, m) , 2.48(7H, m) , 2.21-1.81 ( 5H , m) , 1.35(2H, m) ' 1.2K3H, m)， 0.89(6H, d) . : H 匪 R (400, CDCls): 8.19 (2H, s), 7.33 (2Ή, d), 6.86 (2H, d), 6.06C1H, s), 5.98 (1H, m), 4.78 (2H, m) , 3.85 (2H, d), 3.49 (2H, m), 3.16 (4H, m), 2.91 (2H, m), 2.48 (7H, m), 2.21-1.81 (5H, m), 1.35 (2H, m ) '1.2K3H, m), 0.89 (6H, d).
<실시예 178> l-(4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4- 일 )메톡시 )페닐 )싸이클로핵스 -3-엔카보닐 )파페리딘 -4-카복스아마이드 의 제조 Example 178 l- (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux- 3 -encarbonyl) wave Preparation of Ferridine- 4 -Carboxamide
Figure imgf000145_0002
Figure imgf000145_0002
L-베타 -프를리놀을 사용하는 대신에 이소니페코트아망이드 (Isonipecotamide)를 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물올 제조하였다 (수득량 240mg I 수율 79%).  The title compound was prepared in the same manner as in <Example 152>, except that Isonipecotamide was used instead of L-beta-prlinol (yield 240 mg I yield). 79%).
¾ 匪 R (400, CDCls) ： 8.19(2H, s) , 7.33(2H, d) , 6.86(2Η, d) , 6.06(1Η, s) , 5.39(2Η, m) , 4.78(2Η, m) , 4.68(1Η, m), 4.02(1Η, d) , 3.85(2Η, d), 3.65C6H, m)， 3.14(1Η, m) , 2.9Κ2Η, m) , 2.86-2.18(9Η, m), 2.15-1.59(13Η, m) , 1.35(2Η, m) , 1.21(3Η, m) .  ¾ 匪 R (400, CDCls): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2Η, d), 6.06 (1Η, s), 5.39 (2Η, m), 4.78 (2Η, m) , 4.68 (1Η, m), 4.02 (1Η, d), 3.85 (2Η, d), 3.65C6H, m), 3.14 (1Η, m), 2.9Κ2Η, m), 2.86-2.18 (9Η, m), 2.15-1.59 (13Η, m), 1.35 (2Η, m), 1.21 (3Η, m).
<실시예 179> 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메 록시 )페닐) -Ν-(3-메톡시프로필)싸이클로핵스 -3-엔카복스아마이드의 제 조
Figure imgf000146_0001
Example 179 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -Ν- (3-methoxypropyl) cyclonucleus 3-Production of Encarboxamide
Figure imgf000146_0001
Lᅳ베타 -프롤리놀을 사용하는 대신에 3-에특시프로필아민을 사용 하는 것을 제외하고， 상기 <실시예 152〉와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 240mg I 수율 78%).  The title compound was prepared in the same manner as in <Example 152>, except that 3-ethoxypropylamine was used instead of L-betabeta-prolinol (yield 240 mg I yield 78%). ).
丽 R (400, CDC13) ： 8.19(2H, s), 7.33(2H, d) , 6.86(2H, d), 6.3K1H, m), 6.06(1H, s) , 4.78(2H, m)， 3.85(2H, d) , 3.48(6H, m) , 2.9K2H, m) , 2.86-1.79(14H, m) , 1.35(2H, m) , 1.21(6Ή, m) . R R (400, CDC1 3 ): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.3K1H, m), 6.06 (1H, s), 4.78 (2H, m) ， 3.85 (2H, d), 3.48 (6H, m), 2.9K2H, m), 2.86-1.79 (14H, m), 1.35 (2H, m), 1.21 (6Ή, m).
<실시예 180> 4-(4-((l-(5—에틸피리미딘 -2-일)피페리딘 -4-일)메 특시 )페닐) -N- (퓨란 -2-알메틸)싸이클로핵스 -3-엔카복스아마이드의 제 조 Example 180 4- (4-((l- (5—ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (furan-2-almethyl) cyclo Manufacture of Hacks-3-encarboxamide
Figure imgf000146_0002
Figure imgf000146_0002
L-베타 -프를리놀을 사용하는 대신에 퍼퓨릴아민 (Furfurylamine) 을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수 행하여 표제 화합물을 제조하였다 (수득량 180mg / 수을 76%).  The title compound was prepared in the same manner as in <Example 152>, except that Furfurylamine was used instead of L-beta-furlinol (yield 180 mg / number 76% ).
¾ NMR (400, CDCls) ： 8.19(2H, s), 7.37(1H, s), 7.33(2H, d) , 6.86(2H, d) , 6.3K2H, m) , 6.06(1H, s), 5.89(1H, m) , 4.78(2H, m)， 4.5K2H, d), 3.85(2H, d) , 2.9K2H, m) , 2.59-1.81( 12H , m)， 1.35(2H m) , 1.2K3H, m) .  ¾ NMR (400, CDCls): 8.19 (2H, s), 7.37 (1H, s), 7.33 (2H, d), 6.86 (2H, d), 6.3K2H, m), 6.06 (1H, s), 5.89 (1H, m), 4.78 (2H, m), 4.5K2H, d), 3.85 (2H, d), 2.9K2H, m), 2.59-1.81 (12H, m), 1.35 (2H m), 1.2K3H, m).
<실시예 181> 4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메 톡시 )페닐 )-N,N-비스 (2-하이드록시에틸 )싸이클로핵스 -3-엔카복스아마 이드의 제조
Figure imgf000147_0001
Example 181 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N, N-bis (2-hydroxyethyl Preparation of cyclonux-3-encarboxamide
Figure imgf000147_0001
L-베타 -프를리놀을 사용하는 대신에 디에탄을아민을 사용하는 것을 제외하고， 상기 〈실시예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 185mg I 수율 77%).  The title compound was prepared in the same manner as in <Example 152>, except that diethan was used amine instead of L-beta-prlinol (yield 185 mg I yield 77%).
^ NMR (400， CDCls) ： 8.19(2H, s), 7.33(2H, d)， 6.86(2H, d) , 6.06C1H, s), 4.78(2H, m) , 3.88(6H, m)， 3.69(4H, m) , 3.15(2H, d)， 2.9K3H, m) , 2.59-1.83(llH, m)， 1.35(2H, m)， 1.21(3H, m) .  ^ NMR (400, CDCls): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06C1H, s), 4.78 (2H, m), 3.88 (6H, m) ， 3.69 (4H, m), 3.15 (2H, d), 2.9 K3H, m), 2.59-1.83 (llH, m), 1.35 (2H, m), 1.21 (3H, m).
<실시예 182> (4-하이드록시피페리딘 -1-일) (4-(4-((l-(3-이소프 로필 -1，2，4-옥사디아졸ᅳ 5ᅳ일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔 Example 182 (4-Hydroxypiperidin-1-yl) (4- (4-((l- (3-isopropyl -1,2,4-oxadiazol ᅳ 5 ᅳ yl) piperidine -4-yl) methoxy) phenyl) cyclonux-3-ene
Figure imgf000147_0002
Figure imgf000147_0002
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 4-하이드록시피페리딘을 사용하는 것을 제외하고, 상기 <실시 예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득 량 230mg / 수율 80%) .  The procedure was carried out in the same manner as in <Example 143>, except that 4-hydroxypiperidine was used instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride. Compounds were prepared (yield 230 mg / yield 80%).
^ NMR (400， CDCls) ： 7.33(2H, d) , 6.86(2H, d) , 6.06(1Η, s) , 5.16C1H, m) , 4.19(3Η, m)， 3.98(1Η, s), 3.85(3Η, m) , 3.21(4Η, m) , 2.88(2Η, m), 2.62-1.85( 11H , m) , 1.59(6Η, m) , 1.32(6Η, d) .  ^ NMR (400, CDCls): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1Η, s), 5.16C1H, m), 4.19 (3Η, m), 3.98 (1Η, s), 3.85 (3Η, m), 3.21 (4Η, m), 2.88 (2Η, m), 2.62-1.85 (11H, m), 1.59 (6Η, m), 1.32 (6Η, d).
<실시예 183> (4- (하이드톡시메틸)피페리딘 -1-일) (4-(4-((1-(3- 이소 Η로필 -1，2，4-옥사디아졸 -5-일 )피페리딘ᅳ 4ᅳ일 )메톡시 )페닐)싸이클 로핵스 -3-엔일)메타논의 제조
Figure imgf000148_0001
Example 183 (4- (Hydroxymethyl) piperidin-1-yl) (4- (4-((1- (3-isofluoropropyl-1,2,4-oxadiazole-5) Preparation of 1) piperidinyl 4xyl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000148_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 4-피페리딘 메탄올을 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 240mg I 수율 82%) .  The title compound was carried out in the same manner as in <Example 143>, except that 4-piperidine methanol was used instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride. Was prepared (yield 240 mg I yield 82%).
^ NMR (400, CDC13) ： 7.33(2H, d) , 6.86(2H, d) , 6.06(1Η, s) , 4.72(1Η, s) , 4.22(2Η, d) , 4.04(1Η, d) , 3.85(2Η, d) , 3.56(2Η, m) , 3.1K3H, m) , 2.88(2Η, m) , 2.62-1.75( 13H , m) , 1.45(3Η, m) , 1.32(6Η d). ^ NMR (400, CDC1 3 ): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1Η, s), 4.72 (1Η, s), 4.22 (2Η, d), 4.04 (1Η, d) , 3.85 (2Η, d), 3.56 (2Η, m), 3.1K3H, m), 2.88 (2Η, m), 2.62-1.75 (13H, m), 1.45 (3Η, m), 1.32 (6Η d).
<실시예 184> Ν-싸이클로프로필 -4-(4-((1-(3-이소프로필 -1,2,4- 옥사디아졸— 5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔카복스 아마이 Example 184 N-cyclopropyl-4- (4-((1- (3-isopropyl-1,2,4-oxadiazol- 5-yl) piperidin-4-yl) methoxy) Phenyl) cyclonux-3-encarbox flax
Figure imgf000148_0002
Figure imgf000148_0002
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 싸이클로프로필아민을 사용하는 것을 제외하고， 상기 <실시예 143〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 235mg / 수율 81%).  The title compound was prepared in the same manner as in <Example 143>, except that cyclopropylamine was used instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride. (Yield 235mg / Yield 81%).
:H NMR (400, CDCls) ： 7.33(2H, d), 6.86(2H, d), 6.06(1H, s) , 5.70C1H, s) , 4.2K2H, d) , 3.85(2H, d) , 3.11(2H, m) , 2.9K1H, m) , 2.76C1H, m) , 2.42(5H, m) , 1.98(5H, m)， 1.59(6H, m) , 1.32(6H, d) , 0.8K2H, m)， 0.5K2H, m) . : H NMR (400, CDCls): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.70C1H, s), 4.2K2H, d), 3.85 (2H, d), 3.11 (2H, m), 2.9K1H, m), 2.76C1H, m), 2.42 (5H, m), 1.98 (5H, m), 1.59 (6H, m), 1.32 (6H, d), 0.8K2H, m ), 0.5K2H, m).
<실시예 185> N-(3-하이드록시프로필) -4-(4-((l-(3-이소프로필- 1，2，4-옥사디아졸 -5-일)피페리딘— 4-일)메록시 )페닐)싸이클로핵스 -3ᅳ엔 카복스아마이드의 제조 수匪 m m m Example 185 N- (3-hydroxypropyl) -4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine—4- (I) methoxy) phenyl) cyclonux-3 ᅳ ene carboxamide 匪 mmm
Figure imgf000149_0001
Figure imgf000149_0001
(R)-N,N—디메틸피를리딘ᅳ 3—아민 하이드로클.로라이드를 사용하는 대신에 3-아미노프로판을을 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 (R) -N, N-Dimethylpyridine ᅳ 3-amine hydrochloride. Instead of using 3-aminopropane, except in the same manner as in <Example 143> The title compound was prepared (yield
220mg I 79%) . 220 mg I 79%).
(400， CDCls) ： 7.33C2H, (0， 6.86(2Ή, d), 6.Ό6(1Ή (400 ， CDCls) ： 7.33C2H, (0 ， 6.86 (2Ή, d), 6.Ό6 (1Ή
5.96(1H 4.2K2H, m) , 3.85(2Η, m)， 3.66(2Η, m) 3.48(2H5.96 (1H 4.2K2H, m), 3.85 (2Η, m), 3.66 (2Η, m) 3.48 (2H
3.20(1H; 3.11(2H, 2.89(1Η, m)， 2.48(5H, m) , 2.0K5H3.20 (1H ; 3.11 (2H, 2.89 (1Η, m), 2.48 (5H, m), 2.0K5H
1.71(2H: 1.59(6H, 1.32(6H, d) . 1.71 (2H : 1.59 (6H, 1.32 (6H, d)).
<실시예 186> (4-(2-하이드록시에틸)피페리딘 -1-일 ) (4-(4-((l-Example 186 (4- (2-hydroxyethyl) piperidin-1-yl) (4- (4-((l-
(3-이소프로필 -1，2，4—옥사디아졸 -5-일 )피페리딘ᅳ 4-일 )메톡시 )페닐 )싸 이클로핵스 -3-엔일)메타논의 제조 Preparation of (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidinyl 4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000149_0002
Figure imgf000149_0002
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 4-피페리딘 에탄을을 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 205mg / 수율 77%) .  The procedure was carried out in the same manner as in <Example 143>, except that 4-piperidine ethane was used instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride. Compounds were prepared (yield 205 mg / yield 77%).
- XH NMR (400, CDCls) ： 7.33(2H, d)， 6.86(2H, d) , 6.06(1Η, s) , 4.69(1H, d) , 4.2Κ2Η, m), 3.99(1Η, d) , 3.85(2Η, d)， 3.74(2Η, m) , 3.20(3Η, m) , 2.89(1Η, m) , 2.8K1H, m)， 2.64-2.24(5Η , m) , 2.12- 1.69(8Η, m) , 1.66(2Η, m) , 1.46(2Η, m) , 1.32(6Η, d) , 1.19(2Η, m) . -X H NMR (400, CDCls): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1Η, s), 4.69 (1H, d), 4.2Κ2Η, m), 3.99 (1Η, d) , 3.85 (2Η, d) ， 3.74 (2Η, m), 3.20 (3Η, m), 2.89 (1Η, m), 2.8K1H, m), 2.64-2.24 (5Η, m), 2.12- 1.69 (8Η, m), 1.66 (2Η, m), 1.46 (2Η, m), 1.32 (6Η, d), 1.19 (2Η, m).
<실시예 187> (4-(2-하이드록시에틸)피페라진 -1-일 ) (4-(4-((1- (3-이소프로필 _1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐)싸 이클로핵스— 3ᅳ엔일)메타논의 제조 Example 187 (4- (2-hydroxyethyl) piperazin-1-yl) (4- (4-((1- (3-isopropyl_1,2,4-oxadiazole-5-yl) ) Piperidin-4-yl) methoxy) phenyl) cyclonux- 3 ᅳ enyl) methanone
Figure imgf000150_0001
Figure imgf000150_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 4-하이드록시에틸 피페라진을 사용하는 것을 제외하고， 상기 < 실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 180mg I 수율 72%). The procedure was carried out in the same manner as in <Example 143>, except that 4-hydroxyethyl piperazine was used instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride. Compounds were prepared (yield 180 mg I yield 72%).
i NMR (400， CDC13) ： 7.33(2H, d), 6.86(2H, d) , 6.06(1H, s), 4.2K2H, m) , 3.85(2H, d)， 3.7K6H, m) , 3.12(2H, m) , 2.89(1H, m) , 2.81-2.24(12H, m) , 2.12-1.85(5H , m) , 1.46(2H, m), 1.32(6H, d) . i NMR (400, CDC1 3 ): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.2K2H, m), 3.85 (2H, d), 3.7K6H, m), 3.12 (2H, m), 2.89 (1H, m), 2.81-2.24 (12H, m), 2.12-1.85 (5H, m), 1.46 (2H, m), 1.32 (6H, d).
<실시예 188> 4-( 4- ( ( l- ( 3-이소프로필 -1 , 2， 4-옥사디아졸 -5-일 ) 피페리딘 -4-일)메록시 )페닐) -Ν- (메톡시메틸)싸이클로핵스—3-엔카복스 아마이 Example 188 4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -Ν- (Methoxymethyl) cyclonux-3-encarbox Amami
Figure imgf000150_0002
Figure imgf000150_0002
(R)-N,N-디메틸피를리딘 3-아민 하이드로클로라이드를 사용하는 대신에 0-에틸하이드톡실아민 하이드로클로라이드를 사용하는 것을 제 외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물 을 제조하였다 (수득량 170mg I 수율 71%) . .  (R) -N, N-dimethylpyridine 3-amine hydrochloride instead of using 0-ethyl hydroxyxylamine hydrochloride, except that it was carried out in the same manner as in <Example 143> The title compound was prepared (yield 170 mg I yield 71%). .
¾ NMR (400, CDCls) 8.14(1H, s) , 7.33(2Η, d) , 6.86(2Η, d)， 6.06(1Η, s) , 4.2Κ2Η, m) , 3.99(2Η, m)， 3.85(2Η, d), 3.12(2Η, m) , 2.89(1Η, m) , 2.62-2.28( 5Η , m), 2.14-1.87( 5Η , m)， 1.46(2Η, m) , 1.32(6Η, d) .  ¾ NMR (400, CDCls) 8.14 (1H, s), 7.33 (2Η, d), 6.86 (2Η, d), 6.06 (1Η, s), 4.2Κ2Η, m), 3.99 (2Η, m) ， 3.85 ( 2Η, d), 3.12 (2Η, m), 2.89 (1Η, m), 2.62-2.28 (5Η, m), 2.14-1.87 (5Η, m), 1.46 (2Η, m), 1.32 (6Η, d) .
<실시예 189> Ν-싸이클로프로필 -4-(4-((1-(5-에틸피리미딘 -2- 일)피페리딘 -4-일)메톡시 )페닐)싸이클로핵스ᅳ 3ᅳ엔카복스아마이드의 제 조 Example 189 N-cyclopropyl-4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleoss 3′encarbox Manufacture of amide
Figure imgf000151_0001
Figure imgf000151_0001
L-베타 -프를리놀을 사용하는 대신에 싸이클로프로필아민을 사용 하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 180mg / 수율 76%).  The title compound was prepared in the same manner as in <Example 152>, except that cyclopropylamine was used instead of L-beta-prlinol (yield 180 mg / yield 76%).
¾ NMR (400， CDCls) ： 8.19(2H, s) , 7.33(2H, d) , 6.86(2Η, d) , 6.06(1Η, s), 5.66 1H, s) , 4.78(3Η, m) , 3.85(2Η, d)， 2.91(2Η, m) , 2.76(1Η, s), 2.61-2.30(7Η, m) , 2.09(2Η, m) , 1.91(3Ή, m) , 1.35(2Η, m) , 1.2K3H, m) , 0.8Κ2Η, m) , 0.50(2Η, m) .  ¾ NMR (400, CDCls): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2Η, d), 6.06 (1Η, s), 5.66 1H, s), 4.78 (3Η, m), 3.85 (2Η, d), 2.91 (2Η, m), 2.76 (1Η, s), 2.61-2.30 (7Η, m), 2.09 (2Η, m), 1.91 (3Ή, m), 1.35 (2Η, m), 1.2K3H, m), 0.8Κ2Η, m), 0.50 (2Η, m).
<실시예 190> tert-부틸 4-((4-(4-(2-하이드록시에틸카바모일) 싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 - 1-카복시레이트의 제조 Example 190 Preparation of tert-Butyl 4-((4- (4- (2-hydroxyethylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000151_0002
툭시카보닐 )피페리딘 -4- 일)메특시 )페닐)싸이클로핵스 -3-엔카복실릭 엑시드 400 mg을 DMF 30 mL에 용해시킨 후， 질소환경 하 교반하였다. TEA 0.3 mL를 적가한 후， 2-아미노에탄을 90 mg을 순차적으로 적가하고， 10분 동안 추가적으로 교반하였다. HATU 400 mg을 적가한 후， 상은에서 1시간 동안 교반하였 다. 반웅 종결 후， 증류수 50 mL를 0°C에서 천천히 가하고， 생성되는 고체를 여과한 후， 건조하여 표제 화합물을 흰색 고체 형태로 제조하 였다 (수득량 190mg I 수율 77%).
Figure imgf000151_0002
400 mg of tuxicarbonyl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarboxylic acid was dissolved in 30 mL of DMF, followed by stirring under a nitrogen environment. After 0.3 mL of TEA was added dropwise, 90 mg of 2-aminoethane was added dropwise sequentially and further stirred for 10 minutes. After dropwise addition of 400 mg HATU, the mixture was stirred for 1 hour at silver. After completion of reaction, 50 mL of distilled water was slowly added at 0 ° C., the resulting solid was filtered and dried to give the title compound as a white solid (yield 190 mg I yield 77%).
XH NMR (400， CDCls) ： 7.33(2H, d) , 6.86(2Η, d) , 6.14(1Η, m) , 6.04(1Η, s) , 4.18(2Η, s), 3,79(4Η, m)， 3.48(2Η, m) , 2.75(3Η, m)， 2.48(5Η, m), 2.11(1Η, m)， 1.89(4Η, m)， 1.48(9H, s), 1.29(2H, m) . X H NMR (400, CDCls): 7.33 (2H, d), 6.86 (2Η, d), 6.14 (1Η, m), 6.04 (1Η, s), 4.18 (2Η, s), 3,79 (4Η, m) ， 3.48 (2Η, m) ， 2.75 (3Η, m) ， 2.48 (5Η, m) ， 2.11 (1Η, m) ， 1.89 (4Η, m) ， 1.48 (9H, s), 1.29 (2H, m .
<실시예 191> tert-부틸 4-((4-(4-(3-하이드록시 -2,2-디메틸프 로필카바모일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레 이트의 제조
Figure imgf000152_0001
Example 191 tert-Butyl 4-((4- (4- (3-hydroxy-2,2-dimethylpropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1 Preparation of Carboxylate
Figure imgf000152_0001
2-아미노에탄을을 사용하는 대신에 3-아미노 -2, 2-디메틸프로판 올을 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 230mg / 수율 84%) .  The title compound was prepared in the same manner as in <Example 190>, except that 3-amino-2, 2-dimethylpropanol was used instead of 2-aminoethane (yield 230 mg / Yield 84%).
^ NMR (400, CDCls) ： 7.33(2H, d) , 6.86(2H, d) , 6.04(1H, s) , 5.99(1H, m) , 4.18(2H, s) , 4.01(1H, m)ᅳ 3.80(2H, d) , 3.16(4H, m) , 2.75(2H, m) , 2.48(5H, m) , 2.11(1H, m) , 1.89(4H, m) , 1.48(9H, s) , 1.29(2H, m) , 0.89(6H, d) .  ^ NMR (400, CDCls): 7.33 (2H, d), 6.86 (2H, d), 6.04 (1H, s), 5.99 (1H, m), 4.18 (2H, s), 4.01 (1H, m) ᅳ 3.80 (2H, d), 3.16 (4H, m), 2.75 (2H, m), 2.48 (5H, m), 2.11 (1H, m), 1.89 (4H, m), 1.48 (9H, s), 1.29 (2H, m), 0.89 (6H, d).
<실시예 192> tert-부틸 4-( (4-(4- (메록시메틸카바모일)싸이클 로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 Example 192 Preparation of tert-butyl 4- ((4- (4- (methoxymethylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000152_0002
Figure imgf000152_0002
2-아미노에탄올을 사용하 하동수  Hadongsu using 2-aminoethanol
7ΰΓ 대신에 0-에틸하이드록실아민 0-ethylhydroxylamine instead of 7ΰΓ
율이일 드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 190>과 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 220nig I 81%) .  The title compound was prepared in the same manner as in <Example 190>, except that Yield chloride was used (yield 220 nig I 81%).
¾ 薩 (400, CDCls) 8.15(1Η 7.33(2H 6.86(2H 6.04C1H, s) , 4.18(2H, s) , 4.00C2H, 3.8K2H 3.48(2H 2.75(2H, m) , 2.48(5Η, m) , 2.1K1H, 1.89(4H: 1.48(9H 1.29(5H, m) . ¾ 400 (400, CDCls) 8.15 (1Η 7.33 (2H 6.86 (2H 6.04C1H, s), 4.18 (2H, s), 4.00C2H, 3.8K2H 3.48 (2H 2.75 (2H, m), 2.48 (5Η, m) , 2.1K1H, 1.89 (4H : 1.48 (9H 1.29 (5H, m)).
<실시예 193> tert-부틸 4-((4-(4-(4- (피를리딘 -1-일 )피페리딘- 1-카보닐)싸이 !■로핵스— 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 의 제조 Example 193 tert-butyl 4-((4- (4- (4- (pyridin-1-yl) piperidine-1-carbonyl) cy! ■ ronix- 1-enyl) phenoxy Preparation of Methyl) piperidine-1-carboxylate
2-아미노에탄올을 사용하는 대신에 4- (피를리딘 -1-일 )피페리딘 을 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수 행하여 표제 화합물을 제조하였다 (수득량 180mg / 수율 76%). The title compound was prepared in the same manner as in <Example 190>, except that 4- (pyridin-1-yl) piperidine was used instead of 2-aminoethanol (yield amount). 180 mg / yield 76%).
^ NMR (400, CDC13) ： 7.31 (3H, d)， 6.82 (2H, d), 6.04 ( 1H， s) , 4.59 (1H, s), 4.15 (2H, s), 3.95 (1H, d), 3.81 (1H, s), 3.09 (1H, m) , 2.75-2.48 (11H, m) , 2.29 (2H, d), 2.05-1.82 (11H, m)， 1.47 (11H, s) , 1.31 (2H, m) . ^ NMR (400, CDC1 3 ): 7.31 (3H, d), 6.82 (2H, d), 6.04 (1H, s), 4.59 (1H, s), 4.15 (2H, s), 3.95 (1H, d) , 3.81 (1H, s), 3.09 (1H, m), 2.75-2.48 (11H, m), 2.29 (2H, d), 2.05-1.82 (11H, m), 1.47 (11H, s), 1.31 (2H , m).
<실시예 194> tert-부틸 4-((4-(4- (싸이클로부틸카바모일 )싸이 클로핵 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 Example 194 Preparation of tert-Butyl 4-((4- (4- (cyclobutylcarbamoyl) cycloclonu-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000153_0001
Figure imgf000153_0001
2-아미노에탄올을 사용하는 대신에 싸이클로부틸아민 하이드로 클로라이드를 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 170mg I 수율 The title compound was prepared in the same manner as in <Example 190>, except that cyclobutylamine hydrochloride was used instead of 2-aminoethanol (yield 170 mg I yield).
71%) . 71%).
ιη 匪 R (400， CDC13) ： 7.32 (2H, d)， 6.85 (2H, d) , 6.04 (1H, m) , 5.69 (1Η, d) , 4.46 ( 1H , m)， 4.18 (2H, s), 3.82 (2H, d) , 2.75 (2H, t) , 2.44-2.34 (7H, m) , 2.12-1.71 (9H, m) , 1.48 (9H, s) , 1.29 (2H, m) . ιη 匪 R (400, CDC1 3 ): 7.32 (2H, d), 6.85 (2H, d), 6.04 (1H, m), 5.69 (1Η, d), 4.46 (1H, m) ， 4.18 (2H, s ), 3.82 (2H, d), 2.75 (2H, t), 2.44-2.34 (7H, m), 2.12-1.71 (9H, m), 1.48 (9H, s), 1.29 (2H, m).
<실시예 195> tert-부틸 4-((4-(4- (싸이클로펜틸카바모일)싸。' 클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 2-아미노에탄올을 사용하는 대신에 싸이클로펜틸아민을 사용하 는 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행하여 표 제 화합물을 제조하였다 (수득량 195mg I 수율 79%). Example 195 Preparation of tert-Butyl 4-((4- (4- (cyclopentylcarbamoyl). ' Clonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate A title compound was prepared in the same manner as in <Example 190>, except that cyclopentylamine was used instead of 2-aminoethanol (yield 195 mg I yield 79%).
!H 匪 R (400， CDCls) ： 7.31 (2H, d)， 6.85 (2H, d) , 6.04 ( 1H， m), 5.54 (1H, m), 4.30-4.18 (3H, m) , 3.81 (2H, d)， 2.81 (2H, m)， 2.56-2.32 (5H, m) , 2.10-1.58 (12H, m) , 1.48 (9Η, s) , 1.41-1.22 (4Η, m) . ! H 匪 R (400, CDCls): 7.31 (2H, d), 6.85 (2H, d), 6.04 (1H, m), 5.54 (1H, m), 4.30-4.18 (3H, m), 3.81 (2H, d), 2.81 (2H, m), 2.56-2.32 (5H, m), 2.10-1.58 (12H, m), 1.48 (9Η, s), 1.41-1.22 (4Η, m).
<실시예 196> tert-부틸 4-((4-(4-(4-모폴리노피페리딘 -1-카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 Example 196 tert-Butyl 4-((4- (4- (4-morpholinopiperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Manufacture of Rate
Figure imgf000154_0001
Figure imgf000154_0001
하는 것을 제외하고， 상기 <실시예 190〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 805mg I 수율 77%). A title compound was prepared in the same manner as in <Example 190>, except that 805 mg I yield 77%.
:H 丽 R (400， CDC13) ： 7.33 (2H, m)， 6.86 (2H, m) , 6.05 (1H, m) , 4.72 (1H, m) , 4.16-4.02 (3H, m) , 4.16-4.02 ( 3H , m) , 3.82-3.74 (6H, m) , 3.12 (1H, m) , 2.83-2.26 (13H, -m) , 1.98—1.82 (7H, m)， 1.48 (9H, s) , 1.33 (2H, m) . : H R R (400, CDC1 3 ): 7.33 (2H, m), 6.86 (2H, m), 6.05 (1H, m), 4.72 (1H, m), 4.16-4.02 (3H, m), 4.16- 4.02 (3H, m), 3.82-3.74 (6H, m), 3.12 (1H, m), 2.83-2.26 (13H, -m), 1.98—1.82 (7H, m), 1.48 (9H, s), 1.33 (2H, m).
<실시예 197> 4-(4-((l-(5-에틸피리미딘 -2—일 )피페리딘 -4-일 )메 흑시 ) -N-메록시 -N-메틸싸이클로핵스 -3-엔카복스아마이드의 제조 Example 197 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) -N-methoxy-N-methylcyclonux-3- Preparation of Encarboxamide
Figure imgf000154_0002
Figure imgf000154_0002
L-베타ᅳ프를리놀을 사용하는 대신에 Ν,Ο-디메틸하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 152〉와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 220mg I 수율 79%).  The title compound was prepared in the same manner as in <Example 152>, except that Ν, Ο-dimethylhydroxylamine hydrochloride was used instead of L-beta champlinol (yield 220 mg). I yield 79%).
¾ NMR (400， CDC13) ： 8.19 (2H, s), 7.34 (2H, m) , 6.88 (2Η, m) , 6.07 (1H, m), 4.80 (2H, m)， 3.85 (2H, d) , 3.74 (3H, s) , 3.24 (3H, s), 2.99-2.88 (3H, m)， 2.54-2.33 (6H, m) , 2.13-1.83 (5H, m) , 1.41 ( 2H, m) , 1.22 (3H, m) . ¾ NMR (400, CDC1 3 ): 8.19 (2H, s), 7.34 (2H, m), 6.88 (2Η, m), 6.07 (1H, m), 4.80 (2H, m), 3.85 (2H, d) , 3.74 (3H, s), 3.24 (3H, s), 2.99-2.88 (3H, m), 2.54-2.33 (6H, m), 2.13-1.83 (5H, m), 1.41 (2H, m), 1.22 (3H, m).
<실시예 198> 4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메 특시 )페닐) -N-메록시싸이클로핵스 -3-엔카복스아마이드의 제조 Example 198 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N-methoxycyclonux-3-encarbox Preparation of Amide
Figure imgf000155_0001
Figure imgf000155_0001
L-베타 -프를리놀을 사용하는 대신에 으메틸하이드록실아민 하이 드로클로라이드를 사용하는 것을 제외하고 , 상기 <실시예 152>와 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 240mg I 수율 83%) .  The title compound was prepared in the same manner as in <Example 152>, except that dimethylmethyl hydrochloride was used instead of L-beta-prlinol (yield 240 mg I Yield 83%).
¾ 丽 R (400, CDCls) ： 8.24 (2H, s) , 7.33 (2H, m) , 6.87 (2Η, m), 6.03 (1H, s), 4.80 (2H, m) , 3.84 (5H, m) , 2.96 (2Ή, m) , 2.57— 1.93 (13H, m) , 1.41 (2H, m) , 1.20 (3H, m) .  ¾ リ R (400, CDCls): 8.24 (2H, s), 7.33 (2H, m), 6.87 (2Η, m), 6.03 (1H, s), 4.80 (2H, m), 3.84 (5H, m) , 2.96 (2Ή, m), 2.57— 1.93 (13H, m), 1.41 (2H, m), 1.20 (3H, m).
<실시예 199> tert-부틸 4-((4-(4- (에틸 (2-하이드록시에틸)카바 모일 )싸이클로핵스 -1ᅳ엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트의 제 조 Example 199 tert-Butyl 4-((4- (4- (ethyl (2-hydroxyethyl) carbamoyl) cyclonux-1-1-enyl) phenoxy) methyl) piperidine-1-carboxylate Article of
Figure imgf000155_0002
Figure imgf000155_0002
2-아미노에탄을을 사용하는 대신에 2- (에틸아미노)에탄을을 사 용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 170mg I 수율 72%).  The title compound was prepared in the same manner as in <Example 190>, except that 2- (ethylamino) ethane was used instead of 2-aminoethane (yield 170 mg I yield). 72%).
¾ 匪 R (400, CDCls) ： 7.32 (2H, m)， 6.85 (2H, m)， 6.05 (1H, s) , 4.16 (2H, s) , 3,80 (3Η, m) , 3.73 (1H, m) , 3.57-3.44 (4H, m) , 2.87-1.71 (12H, m) , 1.47 (9H, s) , 1.31-1.13 (5H, m) .  ¾ 匪 R (400, CDCls): 7.32 (2H, m), 6.85 (2H, m), 6.05 (1H, s), 4.16 (2H, s), 3,80 (3Η, m), 3.73 (1H, m), 3.57-3.44 (4H, m), 2.87-1.71 (12H, m), 1.47 (9H, s), 1.31-1.13 (5H, m).
<실시예 200> tert-부틸 4-( (4-(4-(4-(2-하이드록시에틸)피페리 딘 -1-카보닐 )싸이클로핵스ᅳ1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이 트의 제조 Example 200 tert-Butyl 4- ((4- (4- (4- (2-hydroxyethyl) piperidine-1-carbonyl) cyclonucleoxen1-enyl) phenoxy) methyl) piperi Preparation of Dean-1-carboxylate
2-아미노에탄을을 사용하는 대신에 4-하이드록시에틸피페리딘을 사용하는 것을 제외하고， 상기 <실시예 190〉과 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 343mg / 수율 The title compound was prepared in the same manner as in <Example 190>, except that 4-hydroxyethylpiperidine was used instead of 2-aminoethane (yield 343 mg / yield).
¾ NMR (400， CDCb) ： 7.32 (2H, m) , 6.84 (2H, m) , 6.04 ( 1H , m) , 4.68 (1Η, m) , 4.16 (2H, s) , 3.99 ( 1H , m) , 3.81 (4H, m) , 3.09 ¾ NMR (400, CDCb): 7.32 (2H, m), 6.84 (2H, m), 6.04 (1H, m), 4.68 (1Η, m), 4.16 (2H, s), 3.99 (1H, m), 3.81 (4H, m), 3.09
(1H, m) , 2.78 (3H, m)., 2.60 (4H, m) , 2.29 (1H, m) , 1.97-1.47 (20H m) , 2.31 (4H, m) . (1H, m), 2.78 (3H, m)., 2.60 (4H, m), 2.29 (1H, m), 1.97-1.47 (20H m), 2.31 (4H, m).
<실시예 201> tert-부틸 4-( (4-(4-(4-(2-하이드록시에틸)피페라 진 -1-카보닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피쩨리딘 -1-카복시레이 트의 Example 201 tert-butyl 4- ((4- (4- (4- (2-hydroxyethyl) piperazin-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) pipiridine -1-carboxylate
Figure imgf000156_0001
록시에틸피페라진을 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 331mg I 수율 68%).
Figure imgf000156_0001
A title compound was prepared in the same manner as in <Example 190>, except that oxyethylpiperazine was used (a yield 331 mg I yield 68%).
:H NMR (400, CDCls) ： 7.32 (2H, m) , 6.85 (2H, m) , 6.04 (1H, m), 4.16 (2H, s) , 3.81-3.59 ( 8H, m) , 2.78-2.49 (14H, m)， 1.98- 1.84 (5H, m) , 1.47 (9H, s), 1.28 (2H, m) . : H NMR (400, CDCls): 7.32 (2H, m), 6.85 (2H, m), 6.04 (1H, m), 4.16 (2H, s), 3.81-3.59 (8H, m), 2.78-2.49 ( 14H, m), 1.98-1.84 (5H, m), 1.47 (9H, s), 1.28 (2H, m).
<실시예 202> tert-부틸 4-( (4— (4- (피를리딘 -1-카보닐)싸이클로 핵스 - 시레이트의 제조 Example 202 Preparation of Nucleus-Cyrate with tert-Butyl 4- ((4— (4- (pyridine-1-carbonyl) cyclo
Figure imgf000156_0002
Figure imgf000156_0002
2-아미노에탄올을 사용하는 대신에 피를리딘을 사용하는 것을 제외하고， 상기 <실시예 190〉과 동일한 방법으로 수행하여 표제 화합 물을 제조하였다 (수득량 357mg I 수율 74%). Instead of using 2-aminoethanol, using pyridine Except, the title compound was prepared in the same manner as in <Example 190> (yield 357 mg I yield 74%).
XH NMR (400, CDC13) ： 7.32 (2H, m) , 6.85 (2H, m), 6.06 ( 1H , m) , 4.16 (2H, s) , 3.81 (2H, m) , 3.54 (4H, m) , 2.75-2.28 (7H, m)， 2.00-1.81 (8H, m) , 1.48 (9H, s), 1.31 (2H, m) . X H NMR (400, CDC1 3 ): 7.32 (2H, m), 6.85 (2H, m), 6.06 (1H, m), 4.16 (2H, s), 3.81 (2H, m), 3.54 (4H, m ), 2.75-2.28 (7H, m), 2.00-1.81 (8H, m), 1.48 (9H, s), 1.31 (2H, m).
<실시예 203> tert-부틸 4-((4-(4-(4-에틸피페라진 -1-카보닐)싸 이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 Example 203 tert-Butyl 4-((4- (4- (4-ethylpiperazin-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Manufacture of Rate
Figure imgf000157_0001
Figure imgf000157_0001
것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 330mg I 수율 59%).  Except that, the title compound was prepared in the same manner as in <Example 190> (yield 330 mg I yield 59%).
NMR (400, CDC13) ： 7.32 (2H, m) ,6.85 (2H, m), 6.04 (1H, m) , 4.16 (2H, s) , 3.81-3.59 (6H, m) , 2.78 (3H, m) , 2.52-2.26 (10H m) , 1.98-1.81 (6H, m) , 1.47 (9H, s) , 1.31 (2H, m) , 1.141 (3H, m) . 피페리딘 -1-카보닐)싸이클로 핵스 - 시레이트의 제조 NMR (400, CDC1 3 ): 7.32 (2H, m), 6.85 (2H, m), 6.04 (1H, m), 4.16 (2H, s), 3.81-3.59 (6H, m), 2.78 (3H, m ), 2.52-2.26 (10H m), 1.98-1.81 (6H, m), 1.47 (9H, s), 1.31 (2H, m), 1.141 (3H, m). Preparation of piperidine-1-carbonyl) cyclonucleus-cirate
H을합 ),,  Sum H) ,,
Figure imgf000157_0002
Figure imgf000157_0002
22--아아미미노노에에탄탄을올을을 사용하는 대신에 피페리딘을 사용하는 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행하여 표제 물을 제조하였다 (수득량 345mg / 수율 67%).  22--The title was prepared in the same manner as in <Example 190>, except that amiminonoethane ethane was used instead of piperidine (yield 345 mg / yield 67). %).
¾ NMR (400, CDC13) ： 7.32 (2H, m) , 6.85 (2H, m)， 6.05 m) , 4.15 (2Η, s) , 3.81 (2H, m) , 3.62-3.49 (4H, m) , 2.79 (3H: ¾ NMR (400, CDC1 3 ): 7.32 (2H, m), 6.85 (2H, m), 6.05 m), 4.15 (2Η, s), 3.81 (2H, m), 3.62-3.49 (4H, m), 2.79 (3H :
2.52 (3H, m) , 2.31 (1H, m) , 1.98-1.58 (11H, m) , 1.47 (9H, 1.28 (2H, m) .  2.52 (3H, m), 2.31 (1H, m), 1.98-1.58 (11H, m), 1.47 (9H, 1.28 (2H, m).
<실시예 205> tert-부틸 4-((4-(4-(3-에록시프로필카바모일)싸 이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제조
Figure imgf000158_0001
Example 205 Preparation of tert-Butyl 4-((4- (4- (3-ethoxypropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000158_0001
2-아미노에탄올을 사용하는 대신에 3-에록시프로판 -1-아민을 사 용하는 것을 제외하고, 상기 <실시예 190>과 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 338mg I 수율 64%).  The title compound was prepared in the same manner as in <Example 190>, except that 3-ethoxypropane-1-amine was used instead of 2-aminoethanol (yield 338 mg I yield). 64%).
:H 薩 R (400, CDC13) ： 7.33 (2H, m) , 6.86 (2H, m)， 6.36 (1H, m) , 6.04 (1Η, m) , 4.17 (2H, s), 3.81 (2H, d) , 3.57-3.40 (6H, m)， 2.78 (2H, m) , 2.52-2.36 (5H, m) , 2.13 (1H, m)， 1.97 (1H, m) , 1.85-1.77 (5H, m) , 1.47 (9H, s) , 1.31—1.21 (5H, m) . : H 薩 R (400, CDC1 3 ) ： 7.33 (2H, m), 6.86 (2H, m), 6.36 (1H, m), 6.04 (1Η, m), 4.17 (2H, s), 3.81 (2H, d), 3.57-3.40 (6H, m), 2.78 (2H, m), 2.52-2.36 (5H, m), 2.13 (1H, m), 1.97 (1H, m), 1.85-1.77 (5H, m) , 1.47 (9H, s), 1.31—1.21 (5H, m).
<실시예 206> tert-부틸 4-((4-(4- (비스 (2-하이드록시에틸)카바 모일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제 조 Example 206 of tert-Butyl 4-((4- (4- (bis (2-hydroxyethyl) carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate Produce
Figure imgf000158_0002
탄올아민을 사용하는 것 을 제외하고, 상기 <실시예 190>과 동일한 방법으로 수행하여 표제 화 합물을 제조하였다 (수득량 351mg I 수율 70%).
Figure imgf000158_0002
Except for using a tanolamine, the title compound was prepared in the same manner as in <Example 190> (yield 351 mg I yield 70%).
:H NMR (400， CDCls) ： 7.32 (2H, m)， 6.86 (2H, m) , 6.05 ( 1H , m), 4.16 (2H, m) , 3.91 (2H, m) , 3.84 (4H, m) , 3.63 (4H, m) , 3.31 (2H, s) , 2.90-2.30 (7H, m) , 2.04-1.82 (5H, m) , 1.48 (9H, s) , 1.32 (2H, m) . : H NMR (400, CDCls): 7.32 (2H, m), 6.86 (2H, m), 6.05 (1H, m), 4.16 (2H, m), 3.91 (2H, m), 3.84 (4H, m) , 3.63 (4H, m), 3.31 (2H, s), 2.90-2.30 (7H, m), 2.04-1.82 (5H, m), 1.48 (9H, s), 1.32 (2H, m).
<실시예 207> l-(4-(4-((l-(3-이소프로필 -l,2，4-옥사디아졸-5- 일)피페리딘-4-일)메톡시 )페닐)싸이클로핵스 -3ᅳ엔카보닐)피페리딘 -4— 카복스아마이드의 제조 Example 207 l- (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) Preparation of Cyclonux-3′encarbonyl) piperidine-4—carboxamide
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 이소니페코트아마이드 (Isonipecotamide)를 사용하는 것을 제외 하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 142mg I 수율 53%) . Except for using (Isonipecotamide) instead of using (R) -N, N-dimethylpyridin-3-amine hydrochloride, the title was carried out in the same manner as in <Example 143> Compounds were prepared (yield 142 mg I yield 53%).
XH 丽 R (400， CDCls) ： 7.32 (2H, m) , 6.86 (2H, m) . 6.05 ( 1H， m) , 5.68 (2Η, m) , 4.67 (1Η, m) , 4.16-3.98 (3H, m) , 3.81 (2H, m) , 3.17 (1H, m), 2.89-2.40 (8H, m)， 1.99-1.63 (丽， m) , 1.47 (9Ή, m) 1.29 (2H, m) . X H Li R (400, CDCls): 7.32 (2H, m), 6.86 (2H, m). 6.05 (1H, m), 5.68 (2Η, m), 4.67 (1Η, m), 4.16-3.98 (3H, m), 3.81 (2H, m), 3.17 (1H, m), 2.89-2.40 (8H, m), 1.99-1.63 (丽 ， m), 1.47 (9Ή, m) 1.29 (2H, m).
<실시예 208> (4-(4-((1-(3-아소프로필-1，2,4-옥사디아졸-5-일) 피페리딘 -4-일)메록시 )페닐)싸이클로핵스 -3-엔일) (4- (괴를리딘— 1-일) 피페리 -1-일 )메타논의 제조 Example 208 (4- (4-((1- (3-Asopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus Preparation of (3-enyl) (4- (Golidin— 1-yl) piperi-1-yl) methanone
Figure imgf000159_0001
Figure imgf000159_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 4- (피를리딘- i -일)피페리딘을 사용하는 것을 제외하고， 상기 < 실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 159mg I 수율 51%). Except for using 4- (pyridin-i-yl) piperidine instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride, as described in Example 143 above. The title compound was prepared in the same manner as in (Yield 159 mg I yield 51%).
^ NMR (400, CDCls) ： 7.54 (2H, m)， 6.86 (2H, m) , 6.05 (1H, m) 4.67 (1H, m) , 4.23 (2H, m) , 4.05 (2H, m), 3.85 (2H, m) , 3.14 (3H, m) , 2.94-2.46 (12H, m) , 2.30 (1H, m) , 2.10-1.94 (12Hᅳ m), 1.62-1.51 (4H, m) , 1.31 (6H, d) .  ^ NMR (400, CDCls): 7.54 (2H, m), 6.86 (2H, m), 6.05 (1H, m) 4.67 (1H, m), 4.23 (2H, m), 4.05 (2H, m), 3.85 (2H, m), 3.14 (3H, m), 2.94-2.46 (12H, m), 2.30 (1H, m), 2.10-1.94 (12H ᅳ m), 1.62-1.51 (4H, m), 1.31 (6H , d).
<실시예 209> (4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5-일) 피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일 ) (4-모폴리노피페리딘 ᅳ 1ᅳ일 )메타논의 제조 Example 209 (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus Preparation of (3--3-yl) (4-morpholinopiperidine ᅳ 1 ᅳ yl) methanone
Figure imgf000160_0001
Figure imgf000160_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 4-모폴리노피페리딘을 사용하는 것을 제외하고 , 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물올 제조하였다 (수득량 155mg I 수율 58%) .  The procedure was carried out in the same manner as in <Example 143>, except that 4-morpholinopiperidine was used instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride, to give a title Compounds were prepared (yield 155 mg I yield 58%).
麗 R (400， CDCls) ： 7.33 (2H, m) , 6.86 (2H, m)， 6.05 (1H, m) , 4.75 (1Η, m), 4.23 (2H, m) , 4.02 (1H, m)， 3.85 (2H, d) , 3.52 (4H, m) , 3.14 (3H, m)， 2.97 (1H, s), 2.94-2.80 (3H, m)， 2.59-2.47 (9H, m) , 2.30 (1H, m) , 2.07-1.91 (7H, m) , 1.50 (4H, m) , 1.29 (6H, d).  麗 R (400, CDCls): 7.33 (2H, m), 6.86 (2H, m), 6.05 (1H, m), 4.75 (1Η, m), 4.23 (2H, m), 4.02 (1H, m) ， 3.85 (2H, d), 3.52 (4H, m), 3.14 (3H, m), 2.97 (1H, s), 2.94-2.80 (3H, m), 2.59-2.47 (9H, m), 2.30 (1H, m), 2.07-1.91 (7H, m), 1.50 (4H, m), 1.29 (6H, d).
<실시예 210> N-싸이클로펜틸 -4-(4-((l-(3-이소프로필 -1，2，4-옥 사디아졸 -5-일)피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔카복스아 마이드의 제조 Example 210 N-cyclopentyl-4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Preparation of Phenyl) cyclonux-3-encarboxamide
Figure imgf000160_0002
Figure imgf000160_0002
(R)-N,N—디메틸피롤리딘 -3-아민 하어드로클로라이드를 사용하는 대신에 싸이클로펜틸아민을 사용하는 것을 제외하고， 상기 <실시예 143〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 171mg I 수율 65%).  The title compound was prepared in the same manner as in <Example 143>, except that cyclopentylamine was used instead of (R) -N, N—dimethylpyrrolidine-3-amine hydrochloride. Prepared (yield 171 mg I yield 65%).
¾ NMR (400， CDCls) ： 7.33 (2H, m) , 6.86 (2H, m) , 6.04 (1Η, m) , 5.51 (1H, m) , 4.26-4.20 (3H, m), 3.85 (2H, d) , 3.14 (2H, m)， 2.92 (ΙΗ' m) , 2.46-2.37 (5H, m) , 2.06-1.94 (7H, m) , 1.68—1.61 (5H m) , 1.47-1.36 (4H, m) , 1.32 (6H, d) .  ¾ NMR (400, CDCls): 7.33 (2H, m), 6.86 (2H, m), 6.04 (1Η, m), 5.51 (1H, m), 4.26-4.20 (3H, m), 3.85 (2H, d ), 3.14 (2H, m) ， 2.92 (ΙΗ 'm), 2.46-2.37 (5H, m), 2.06-1.94 (7H, m), 1.68—1.61 (5H m), 1.47-1.36 (4H, m) , 1.32 (6H, d).
<실시예 211> N-싸이클로부틸 -4-(4-((l-(3-이소프로필 -1,2，4-옥 사디아졸 -5-일 )피페리딘 -4—일 )메톡시 )페닐 )싸이클로핵스 -3ᅳ엔카복스아 Example 211 N-cyclobutyl-4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Phenyl) cyclonux-3
Figure imgf000161_0001
Figure imgf000161_0001
(R)-N,N-디메틸피를리딘 -3-아민 하 o 드로클로라이드를 사용하는 대신에 싸이클로부틸아민 하이드로클로라 o 드를 사용하는 것을 제외하 고， 상기 <실시예 143〉과 동일한 방법으로 수행하여 표제 화합물을 제 조하였다 (수득량 170mg I 수율 63%) .  The same method as in <Example 143>, except that a cyclobutylamine hydrochlorate was used instead of (r) -N, N-dimethylpyridine-3-amine. To give the title compound (yield 170mg I yield 63%).
^ NMR (400, CDC13) ： 7.33 (2H, m)， 6.68 (2H, m) , 6.04 (1H, m), 5.71 (1H, m) , 4.45 (1Η, m) , 4.23 (2H, m) , 3.85 (2Ή, m)， 3.13 (2H, m) , 2.92 (1H, m)， 2.42-2.34 (7H, m) , 2.07-1.72 (9H, m) , 1.47 (2H, m) , 1.31 (6H, d) . ^ NMR (400, CDC1 3 ): 7.33 (2H, m), 6.68 (2H, m), 6.04 (1H, m), 5.71 (1H, m), 4.45 (1Η, m), 4.23 (2H, m) , 3.85 (2Ή, m), 3.13 (2H, m), 2.92 (1H, m), 2.42-2.34 (7H, m), 2.07-1.72 (9H, m), 1.47 (2H, m), 1.31 (6H , d).
<실시예 212> (3,4-디하이드로이소퀴놀린 -2(1Η)-일) (4-(4-((1-Example 212 (3,4-dihydroisoquinolin-2 (1Η) -yl) (4- (4-((1-
(3-이소프로필 -1， 2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸 이클로핵스 -3-엔일 )메타논의 제조 Preparation of (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000161_0002
Figure imgf000161_0002
(R)-N,N-디메틸피를리딘 -3—아민 하이드로클로라이드를 사용하는 대신에 1，2，3,4-테트라하이드로이소퀴놀린을 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물올 쎄조하 였다 (수득량 183mg / 수율 65%) .  Same as <Example 143>, except that 1,2,3,4-tetrahydroisoquinoline is used instead of (R) -N, N-dimethylpyridine-3-amine hydrochloride The title compound was washed out by the method (yield 183 mg / yield 65%).
1H NMR (400, CDC13) ： 7.32 (2H, m) , 7.23-7.12 (4H, m)， 6.87 (2H, m) , 6.08 (1Η， m)， 4.80-4.74 (2H, m)， 4.23 (2H, m) , 3.91-3.78 (4H, m) , 3.15 (2H, m)， 3.08-2.87 (4H, m) , 2.60 (3H, m) , 2.36 (1H, m) , 2.08-1.91 (5H, m)， 1.60 (2H, m), 1.31 (6H, d) .  1H NMR (400, CDC13): 7.32 (2H, m), 7.23-7.12 (4H, m), 6.87 (2H, m), 6.08 (1Η, m), 4.80-4.74 (2H, m), 4.23 (2H , m), 3.91-3.78 (4H, m), 3.15 (2H, m), 3.08-2.87 (4H, m), 2.60 (3H, m), 2.36 (1H, m), 2.08-1.91 (5H, m ), 1.60 (2H, m), 1.31 (6H, d).
<실시예 213> (4-(4-((1-(3-이소프로필-1,2,4-옥사디아졸-5-일) 피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3ᅳ엔일 ) ( 1-메틸 -3 , 4-디하이 Example 213 (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus -3 ᅳ enyl) (1-methyl-3, 4-dihi
동수대 Sisters
신율일 160 로이소퀴놀린 -2(1H)-일 )메타논의  Elongation of 160 lysoquinoline-2 (1H) -yl) methanone
Figure imgf000162_0001
Figure imgf000162_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 1-메틸 -1，2，3，4-테트라하이드로이소퀴놀린을 사용하는 것을 제 외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물 을 제조하였다 (수득량 174mg / 수을 60%).  Except for using 1-methyl-1,2,3,4-tetrahydroisoquinoline instead of using (R) -N, N-dimethylpyridin-3-amine hydrochloride, The title compound was prepared in the same manner as the Example 143> (the yield 174 mg / number 60%).
LH NMR (400, CDCls) ： 7.35 (2H, m) , 7.24-7.12 (4H, m) , 6.89 (2H, m) , 6.12 (1Η, m) , 5.74-5.16 (1H, m) , 4.79-3.56 (6H, m) , 3.15-1.90 (15H, m) , 1.62 (2H, m) , 1.51-1.40 (4H, m) , 1.31 (6H, d) . L H NMR (400, CDCls): 7.35 (2H, m), 7.24-7.12 (4H, m), 6.89 (2H, m), 6.12 (1Η, m), 5.74-5.16 (1H, m), 4.79- 3.56 (6H, m), 3.15-1.90 (15H, m), 1.62 (2H, m), 1.51-1.40 (4H, m), 1.31 (6H, d).
<실시예 214> 이소인돌린 -2-일 (4-(4-((l-(3-이소프로필 -1,2,4- 옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일 )메 타논의 제조 Example 214 isoindolin-2-yl (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) Preparation of methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000162_0002
Figure imgf000162_0002
(R)—N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 (R) —N, N-dimethylpyridin-3-amine hydrochloride using
]} 이소인돌린을 사용하는 것을 제외하고, 상기 <실시예 143>과 '} 방법으로 수행하쪄 표제 화합물을 제조하였다 (수득량 170mg I 69%) . ]} The title compound was prepared in the same manner as in <Example 143> and '} above except that isoindolin was obtained (yield 170 mg I 69%).
XH 匪 R (400, CDCI3) ： 7.33-7.28 (7H, m) , 6.88 (2Η, m) , 6.10 (1H, m) , 4.95 (4H, d) , 4.24 (2H, m) , 3.92 (2H, m) , 3.15 (2H, m) , 2.94 (1H, m) , 2.79 (1H, m) , 2.64-2.37 (4H, m) , 2.12-1.93 (5H, m), 1.51 (2H, m) , 1.31 (6H, d) . X H 匪 R (400, CDCI 3 ): 7.33-7.28 (7H, m), 6.88 (2Η, m), 6.10 (1H, m), 4.95 (4H, d), 4.24 (2H, m), 3.92 ( 2H, m), 3.15 (2H, m), 2.94 (1H, m), 2.79 (1H, m), 2.64-2.37 (4H, m), 2.12-1.93 (5H, m), 1.51 (2H, m) , 1.31 (6 H, d).
<실시예 215> 1,4'-바이피페리딘 -1'-일 (4-(4-((l-(3-이소프로필 -1,2, 4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 )페닐 )싸이클로핵스 -3- 엔일)메타논의 제조
Figure imgf000163_0001
Example 215 1,4'-bipiperidin-1'-yl (4- (4-((l- (3-isopropyl-1,2, 4-oxadiazole-5-yl) pi) Preparation of ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000163_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 1，4'-바이피페리딘올 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 165mg I 수율  Except for using 1,4'-bipiperidinol instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride, it was carried out in the same manner as in <Example 143> The title compound was prepared (yield 165 mg I yield)
¾ NMR (400, CDCls) ： 7.33 (2M, m)， 6.87 (2H, m) , 6.05 (1H, m), 4.78 (1H, m), 4.23 (2H, m)， 4.07 (1H, m) , 3.85 (2H, m) , 3.14 (3H, m), 2.94 (1H, m) , 2.79 (1H, m)， 2.56-2.25 (9H, m) , 2.07-1.40 (18H, m) , 1.31 (6H, d) .  ¾ NMR (400, CDCls): 7.33 (2M, m), 6.87 (2H, m), 6.05 (1H, m), 4.78 (1H, m), 4.23 (2H, m), 4.07 (1H, m), 3.85 (2H, m), 3.14 (3H, m), 2.94 (1H, m), 2.79 (1H, m), 2.56-2.25 (9H, m), 2.07-1.40 (18H, m), 1.31 (6H, d).
<실시예 216> tert-부틸 4-((4-(4-(1,4'-바이피페리딘 -1'-카보 닐 )싸 -카복시레이트의 제조 Example 216 Preparation of tert-butyl 4-((4- (4- (4- (1,4'-bipiperidine-l'-carbonyl) sa-carboxylate
Figure imgf000163_0002
Figure imgf000163_0002
2-아미노에탄을을 사용하는 대신에 1，4'-바이피페리딘을 사용하 는 것을 제외하고 , 상기 <실시예 190>과 동일한 방법으로 수행하여 표 제 화합물을 제조하였다 (수득량 168mg / 수율 75%).  The title compound was prepared in the same manner as in <Example 190>, except that 1,4'-bipiperidine was used instead of 2-aminoethane (yield 168 mg / Yield 75%).
¾ NMR (400, CDCls) ： 7.33 (2H, m)， 6.86 (2H, ηι) , 6.05 (1H, m) , 4.76 (1H, m)， 4.16-4.05 (3H, m)， 3.81 (2H, m)， 3.08 (1H, m) , 2.83 (3H, m) , 2.57-2.51 (9H, m) , 2.30 (1H, m) , 2.00-1.82 (7H, m) , 1.63 (4H, m) , 1.45 (13H, m) , 1.31 (2H, m) . ¾ NMR (400, CDCls): 7.33 (2H, m), 6.86 (2H, η ι), 6.05 (1H, m), 4.76 (1H, m), 4.16-4.05 (3H, m), 3.81 (2H, m) ， 3.08 (1H, m), 2.83 (3H, m), 2.57-2.51 (9H, m), 2.30 (1H, m), 2.00-1.82 (7H, m), 1.63 (4H, m), 1.45 (13H, m), 1.31 (2H, m).
<실시예 217> (4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일) 메톡시 )페닐)싸이클로핵스 -3-엔일) (3- (하이드록시이미노)피를리딘 -1- 일 )메타논의 제조
Figure imgf000164_0001
Example 217 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (3- ( Preparation of hydroxyimino) pyridin-1-yl) methanone
Figure imgf000164_0001
100 mL 플라스크에 1-(4-(4-((1-(3-이소프로필-1,2,4—옥사디아 졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리 딘 -4-카복스아마이드 600 mg을 THF/물 = 30 mL/10 mL에 용해시키고 질 소 하에 교반하였다. 소듬 바이카보네이트 200 mg을 적가한 후， 하이 드록실아민 하이드로클로라이드 170 mg을 순차적으로 적가하고， 상온 에서 3시간 동안 교반하였다. 반웅 종결 후， 갑압 증류하여 용매를 제 거하고， 증류수 50 mL를 0°C에서 천천히 가한 후， 생성되는 고체를 여 과하여 E-form 및 Z-form을 각각 3:1 비율의 흔합물 (Mixture)로 얻었 다 (수득량 485mg I 수율 68%). 1- (4- (4-((1- (3-isopropyl-1,2,4—oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclo in a 100 mL flask 600 mg of nux-3-encarbonyl) piperidine-4-carboxamide was dissolved in THF / water = 30 mL / 10 mL and stirred under nitrogen. 200 mg of a few bicarbonates were added dropwise, 170 mg of hydroxylamine hydrochloride was added dropwise sequentially, and stirred at room temperature for 3 hours. After completion of reaction, the solvent was distilled off under reduced pressure, 50 mL of distilled water was added slowly at 0 ° C., and the resulting solid was filtered to form an E-form and a Z-form in a 3: 1 ratio, respectively. Obtained (yield 485mg I yield 68%).
<실시예 218> (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메특시 )페닐)싸이클로핵스 -3-엔일) (4- (피를리딘 -1-일 )파페리딘— 1-일 ) Example 218 (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) mesospecific) phenyl) cyclonux-3-enyl) (4- ( Pyridin-1-yl) paperidin— 1-day)
Figure imgf000164_0002
Figure imgf000164_0002
L-베타ᅳ프를리놀을 사용하는 대신에 4- (피를리딘 -1-일 )피페리딘 을 사용하는 것을 제외하고 , 상기 <실시예 152>와 동일한 방법으로 수 행하여 표제 화합물을 제조하였다 (수득량 171mg I 수율 69%).  The title compound was prepared in the same manner as in <Example 152>, except that 4- (pyridin-1-yl) piperidine was used instead of L-betachamplinol. (Yield 171 mg I yield 69%).
¾ NMR (400, CDC13) ： 8.23 (2H, s) , 7.32 (2H, m)， 6.87 (2H, m) , 6.05 (1H, m) , 4.79 (2H, m) , 4.59 (1H, m) , 4.02 (1H, m) , 3.84 (2H, d) , 3.16 (1H, m), 2.95 (2H, m) , 2.82-2.94 (11H, m) , 2.29 (2H m) , 2.12-1.82 (11H, m) , 1.51 (2H, m) , 1.40 (2H, m) , 1.31 (3H, m) . ¾ NMR (400, CDC1 3 ): 8.23 (2H, s), 7.32 (2H, m), 6.87 (2H, m), 6.05 (1H, m), 4.79 (2H, m), 4.59 (1H, m) , 4.02 (1H, m), 3.84 (2H, d), 3.16 (1H, m), 2.95 (2H, m), 2.82-2.94 (11H, m), 2.29 (2H m), 2.12-1.82 (11H, m), 1.51 (2H, m), 1.40 (2H, m), 1.31 (3H, m).
<실시예 219> 1,4'-바이피페리딘 -Γ-일 (4-(4-((l-(5-에틸피리미 딘 -2-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일)메타논의 제 조 Example 219 1,4′-bipiperidin-Γ-yl (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy Preparation of (phenyl) cyclonux-3-enyl) methanone
Figure imgf000165_0001
Figure imgf000165_0001
L-베타 -프를리놀을 사용하는 대신에 1,4' -바이피페리딘을 사용 하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 180mg I 수율 77%).  The title compound was prepared in the same manner as in <Example 152>, except that 1,4'-bipiperidine was used instead of L-beta-prlinol (yield 180 mg I Yield 77%).
ln 丽 R (400， CDC13) ： 8.18 (2H, s), 7.33 (2H, m) , 6.87 (2H, m) , 6.05 (1H, m) , 4.79 (3H, m)， 4.05 (1H, m) , 3.84 (2H, d)， 3.08 (1H, m) , 2.95 (2Η, m), 2.83 (1H, m) , 2.58-2.44 (11H, m)， 2.30 ( 1H m) 2.12-1.87 (7H, m)， 1.61 (4H, m)， 1.52-1.30 (6H, m), 1.22 (3H, m) ln Li R (400, CDC1 3 ): 8.18 (2H, s), 7.33 (2H, m), 6.87 (2H, m), 6.05 (1H, m), 4.79 (3H, m), 4.05 (1H, m ), 3.84 (2H, d), 3.08 (1H, m), 2.95 (2Η, m), 2.83 (1H, m), 2.58-2.44 (11H, m), 2.30 (1H m) 2.12-1.87 (7H, m) ， 1.61 (4H, m) ， 1.52-1.30 (6H, m), 1.22 (3H, m)
<실시예 220> C4-(4— ( ( l-( 5 에틸피리미딘 2-일 )피페리딘 -4-일 ) 메록시 )페닐)싸이클로핵스—3-엔일) (4-모폴리노파페리딘 -1-일 )데타논의 제조 . Example 220 C4- (4— ((l- (5 ethylpyrimidin 2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (4-morpholinopaferri Preparation of din-1-yl) detanone.
Figure imgf000165_0002
Figure imgf000165_0002
L-베타 -프롤리놀을 사용하는 대신에 4-모폴리노피페리딘을 사용 하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 162mg I 수율 58%).  The title compound was prepared in the same manner as in <Example 152>, except that 4-morpholinopiperidine was used instead of L-beta-prolinol (yield 162 mg I yield 58 %).
XH 匪 R (400, CDCls) ： 8.18 (2H, s) , 7.33 (2H, m) , 6.87 (2Η, m) , 6.05 (1H, m) , 4.80-4.69 (3H, m) , 4.05 (1H, m) , 3.84 (2H, d) , 3.76 (4H, m) , 3.12 (1H, m) , 2.95 (2H, m)， 2.82 (1H, m) , 2.65-2.44 (11H, m) , 2.30 (1H, m) , 2.13 (1H, m) , 1.96-1.93 (7H, m) , 1.48- 1.30 (4H, m) , 1.22 (3H, m) . X H 匪 R (400, CDCls): 8.18 (2H, s), 7.33 (2H, m), 6.87 (2Η, m), 6.05 (1H, m), 4.80-4.69 (3H, m), 4.05 (1H , m), 3.84 (2H, d), 3.76 (4H, m), 3.12 (1H, m), 2.95 (2H, m), 2.82 (1H, m), 2.65-2.44 (11H, m), 2.30 ( 1H, m), 2.13 (1H, m), 1.96-1.93 (7H, m), 1.48-1.30 (4H, m), 1.22 (3H, m).
<실시예 221> tert-부틸 4-( (4-(4- (퓨란 -2-일메틸카바모일)싸이 클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 Example 221 Preparation of tert-butyl 4- ((4- (4- (furan-2-ylmethylcarbamoyl) cycloclox-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
2-아미노에탄올을 사용하는 대신에 퍼퓨릴아민 (Furfurylamine) 을 사용하는 것을 제외하고， 상기 <실시예 190〉과 동일한 방법으로 수 행하여 표제 화합물을 제조하였다 (수득량 168mg I 수율 70%). The title compound was prepared in the same manner as in <Example 190>, except that Perfurylamine was used instead of 2-aminoethanol (yield 168 mg I yield 70%).
XH NMR (400, CDCI3) ： 7.36 (1H, m)， 7.31 (2H, m) , 6.85 (2H, m) , 6.34 (1H, m)， 6.24 ( 1H , m) , 6.03 ( 1H， m)， 5.97 (1H, m) , 4.49 (2H, m) , 4.16 (2H, s), 3.81 (2H, m) , 2.97 (1H, m), 2.78 (2H, m) , 2.55-2.39 (5H, m) , 2.12 (1H, m) , 1.99-1.81 (4H, m) , 1.47 (9H, s) , 2.31 (2H, m) . X H NMR (400, CDCI 3 ): 7.36 (1H, m), 7.31 (2H, m), 6.85 (2H, m), 6.34 (1H, m), 6.24 (1H, m), 6.03 (1H, m ), 5.97 (1H, m), 4.49 (2H, m), 4.16 (2H, s), 3.81 (2H, m), 2.97 (1H, m), 2.78 (2H, m), 2.55-2.39 (5H, m), 2.12 (1H, m), 1.99-1.81 (4H, m), 1.47 (9H, s), 2.31 (2H, m).
<실시예 222> tert-부틸 4-((4-(4- (메톡시카바모일 )싸이클로핵 스-'卜엔일 )페녹시 )메틸 )꾀페리딘 -1-카복시레이트의 제조 Example 222 Preparation of tert-Butyl 4-((4- (4- (methoxycarbamoyl) cyclonucleoside- ' yenyl) phenoxy) methyl) guiperidine-1-carboxylate
동하수 율이일
Figure imgf000166_0001
0-메틸하이드록실아민 드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 190>과 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 166tng I 72%) . . East sewage rate
Figure imgf000166_0001
Except for using 0-methylhydroxylamine drawchloride, the title compound was prepared in the same manner as in <Example 190> above (yield 166tng I 72%). .
ΛΕ NMR (400， CDCI3) ： 8.24 ( 1H , m) , 7.33 (2Ηᅳ m) , 6.86 (2H, m) , 6.03 (1H, m) , 4.17 (2H, m) , 3.85-3.80 (5H, m) , 2.79 (2H, m) , 2.57-2.35 (5H, m)， 2.09 (1H, m) , 2.01-1.82 (4H, m) , 1.59 (1H, m)， 1.47 (9H, s), 1.32 (2H, m). Λ Ε NMR (400, CDCI 3 ): 8.24 (1H, m), 7.33 (2Η ᅳ m), 6.86 (2H, m), 6.03 (1H, m), 4.17 (2H, m), 3.85-3.80 (5H , m), 2.79 (2H, m), 2.57-2.35 (5H, m), 2.09 (1H, m), 2.01-1.82 (4H, m), 1.59 (1H, m), 1.47 (9H, s), 1.32 (2H, m).
<실시예 223> tert-부틸 4-((4-(4- (메톡시 (메틸 )카바모일 )싸 o 클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 동수하Example 223 Preparation of tert-Butyl 4-((4- (4- (methoxy (methyl) carbamoyl) sa o clonus-1-enyl) phenoxy) methyl) piperidine-1-carboxylate Equal
율일이 165
Figure imgf000167_0001
165 days
Figure imgf000167_0001
2-아미노에탄올을 사용하는 대신에 Ν,Ο-디메틸하이드록실아민 드로클로라이드를 사용하는 것을 제외하고 , 상기 <실시예 190>과 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 171mg I 74%).  The title compound was prepared in the same manner as in <Example 190>, except that Ν, Ο-dimethylhydroxylamine drop chloride was used instead of 2-aminoethanol (yield 171 mg I 74%). ).
¾ NMR (400， CDCI3) ： 7.34 (2H, m), 6.86 (2H, m), 6.07 (1H, m) , 4.16 (2H, s), 3.82 (2H, m)， 3.74 (3H, s) , 3.24 (3H, s) , 2.99- 2.73 (4H, m) , 2.52-2.33 (4H., m)， 2.07-1.82 (5H, m) , 1.47 (9H, s) , 2.33 (2H, m) . ¾ NMR (400, CDCI 3 ): 7.34 (2H, m), 6.86 (2H, m), 6.07 (1H, m), 4.16 (2H, s), 3.82 (2H, m), 3.74 (3H, s) , 3.24 (3H, s), 2.99-2.73 (4H, m), 2.52-2.33 (4H., M), 2.07-1.82 (5H, m), 1.47 (9H, s), 2.33 (2H, m).
<실시예 224> tert-부틸 4-((4-(4-(2，5-디하이드로 -1H-피를 -1 카보닐 )싸이클로핵스 -1-엔일 )페녹시 ) '메틸 )피페리딘 -1-카복시레이트의 제조 Example 224 tert-Butyl 4-((4- (4- (2,5-dihydro-1H-pyr-l carbonyl) cyclonux-1-enyl) phenoxy) ' methyl) piperidine Preparation of -1-carboxylate
Figure imgf000167_0002
Figure imgf000167_0002
2-아미노에탄을을 사용하는 대신에 2，5ᅳ디하이드로 -1H-피를을 사용하는 것을 제외하고, 상기 <실시예 190>과 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 167mg Ί 수율 63%) .  The title compound was prepared in the same manner as in <Example 190>, except that 2,5'dihydro-1H-py was used instead of 2-aminoethane (yield 167 mg Ί yield). 63%).
lR 丽 R (400, CDC13) ： 7.34 (2H, m) , 6.87 (2H, m) , 6.08 (1Η, m) , 5.93 (1H, m) , 5.85 (1H, m)， 4.37 (2H, m) , 4.60 (2H, m) , 4.17 (2H, s) , 3.82 (2H, d)， 3.53 (1H, m) , 2.79 (2H, m) , 2.66-2.47 (4H, m) , 2.36 (1H, m) , 2.05-1.82 (6H, m) , 1.47 (9H, s), 1.32 (2H, m) . l R R R (400, CDC1 3 ) ： 7.34 (2H, m), 6.87 (2H, m), 6.08 (1Η, m), 5.93 (1H, m), 5.85 (1H, m) ， 4.37 (2H, m ), 4.60 (2H, m), 4.17 (2H, s), 3.82 (2H, d), 3.53 (1H, m), 2.79 (2H, m), 2.66-2.47 (4H, m), 2.36 (1H, m), 2.05-1.82 (6H, m), 1.47 (9H, s), 1.32 (2H, m).
<실시예 225> tert-부틸 4-((4-(4-(4-하이드록시피페리딘 -1-카 보닐)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레아트의 제 조
Figure imgf000168_0001
이드록시피페리딘을 사 용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 174mg I 수율 70%). Example 225 tert-Butyl 4-((4- (4- (4-hydroxypiperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxy Manufacture of Leat
Figure imgf000168_0001
The title compound was prepared in the same manner as in <Example 190>, except that hydroxypiperidine was used (yield 174 mg I yield 70%).
¾ 匪 R (400， CDCls) ： 7.33 (2H, m) , 6.86 (2H, m) , 6.05 (1H, m) , 4.16 (3H, m) , 3.97 (1H, m) , 3.87-3.80 (3H, m) , 3.32-3.20 (2H, m) , 2.97-2.72 (4H, m), 2.54-2.47 (3H, m) , 2.31 (1H, m) , 2.01-2.56 (8H, m) , 1.56-1.51 (2H, m) , 1.47 (9Ή, s), 1.32 (2H, m) .  ¾ 匪 R (400, CDCls): 7.33 (2H, m), 6.86 (2H, m), 6.05 (1H, m), 4.16 (3H, m), 3.97 (1H, m), 3.87-3.80 (3H, m), 3.32-3.20 (2H, m), 2.97-2.72 (4H, m), 2.54-2.47 (3H, m), 2.31 (1H, m), 2.01-2.56 (8H, m), 1.56-1.51 ( 2H, m), 1.47 (9 μs, s), 1.32 (2H, m).
<실시예 226> tert-부틸 4-((4-(4-(4- (하이드록시메틸)피페리딘Example 226 tert-butyl 4-((4- (4- (4- (hydroxymethyl) piperidine
-1-카보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트 의 제조 Preparation of -1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000168_0002
딘메탄올을 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 167mg I 수율 65%).
Figure imgf000168_0002
A title compound was prepared in the same manner as in <Example 190> except that din methanol was used (a yield 167 mg I yield 65%).
!H NMR (400， CDCls) ： 7.33 (2Hᅳ m) , 6.86 (2H, m) , 6.05 (1Η, m), 4.73 (1H, m) , 4.16 (2H, s), 4.04 (1H, m) , 3.81 (2H, d) , 3.54 ! H NMR (400, CDCls): 7.33 (2H ᅳ m), 6.86 (2H, m), 6.05 (1Η, m), 4.73 (1H, m), 4.16 (2H, s), 4.04 (1H, m), 3.81 (2H, d), 3.54
(2H, m) , 3.07 (1H, m) , 2.80 (3H, m) , 2.59-2.46 (4H, m)， 2.30 (1H, m) , 2.00-1.70 (10H, m)， 1.47 (9H, m) , 1.31 (4H, m) . (2H, m), 3.07 (1H, m), 2.80 (3H, m), 2.59-2.46 (4H, m), 2.30 (1H, m), 2.00-1.70 (10H, m), 1.47 (9H, m ), 1.31 (4H, m).
<실시예 227> l-(4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4- 일)메록시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘 -4-카보나이트랄의 제조
Figure imgf000169_0001
Example 227 l- (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) pi Preparation of Ferridine-4-carbonitral
Figure imgf000169_0001
L-베타 -프를리놀을 사용하는 대신에 피페리딘— 4-카보나이트릴을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 165mg I 수율 62%).  The title compound was prepared in the same manner as in <Example 152>, except that piperidine- 4-carbonitrile was used instead of L-beta-prlinol (yield 165 mg I yield). 62%).
^ NMR (400, CDCls) ： 8.19 (2H, s) , 7.32 (2H, m) , 6.87 (2Η, m) , 6.04 (1H, m) , 4.80 (2H, m) , 3.85-3.55 (6H, m) , 2.95 (3H, m) , 2.82 (1H, m) , 2.58-2.44 (5H, m) , 2.28 ( 1Ή , m')， 2.11— 1.89 (·9Η, m) , 1.41 (2H, m) , 1.22 (3Ή, m) . ^ NMR (400, CDCls): 8.19 (2H, s), 7.32 (2H, m), 6.87 (2Η, m), 6.04 (1H, m), 4.80 (2H, m), 3.85-3.55 (6H, m ), 2.95 (3H, m), 2.82 (1H, m), 2.58-2.44 (5H, m), 2.28 (1Ή, m '), 2.11— 1.89 ( · 9Η, m), 1.41 (2H, m), 1.22 (3 Hz, m).
<실시예 228> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메특시 )페닐)싸이클로헥스 -3-엔일) (스꾀로 [인덴— 1，4'-피페리딘 Example 228 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) mesospecific) phenyl) cyclohex-3-enyl) Inden— 1，4'-piperidine
일 )메 조 Mezzo
동하수
Figure imgf000169_0002
East sewage
Figure imgf000169_0002
L-베타 -프를리놀을 사용하는 대신에 4-스파로인덴-피페리딘 이드로클로라이드를 사용하는 것을 제외하고 , 상기 <실시예 152>와 일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 183mg I 율 74%).  The title compound was prepared in the same manner as in <Example 152>, except that 4-sparodenene-piperidine idrochloride was used instead of L-beta-prlinol. Yield 183 mg I rate 74%).
¾ NMR (400， CDCls) ： 8.19 (2H, s), 7.37-7.22 (7H m) , 6.91- 6.83 (4H, m) , 6.08 (1H, m)， 4.80 (3H m), 4.13 (1H, m) 3.85 (2H, d) , 3.50 (1H, m) , 3.19-2.87 (4H, m) , 2.62-2.37 (6H, m) 2.10-1.93 (7H, m) , 1.48-1.31 (4H, m) , 1.23 (3H m).  ¾ NMR (400, CDCls): 8.19 (2H, s), 7.37-7.22 (7H m), 6.91-6.83 (4H, m), 6.08 (1H, m), 4.80 (3H m), 4.13 (1H, m ) 3.85 (2H, d), 3.50 (1H, m), 3.19-2.87 (4H, m), 2.62-2.37 (6H, m) 2.10-1.93 (7H, m), 1.48-1.31 (4H, m), 1.23 (3 H m).
<실시예 229> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메톡시 )페닐)싸이클로핵스 -3ᅳ엔일 )(1，4-디옥사 -8—아자스피로 [4.5]데칸 -8-일 )메타논의 제조
Figure imgf000170_0001
Example 229 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3phenylen) Preparation of 4-dioxa-8—azaspiro [4.5] decane-8-yl) methanone
Figure imgf000170_0001
Lᅳ베 타 -프를리놀을 사용하는 대신에 1,4-디옥사 -8-아자스피로 [4.5]데칸을 사용하는 것을 제외하고 , 상기 <실시예 152>와 동일한 방 법으로 수행하여 표제 화합물을 쩨조하였다 (수득량 175mg I 수율 69%).  The title compound was prepared in the same manner as in <Example 152>, except that 1,4-dioxa-8-azaspiro [4.5] decane was used instead of Lvinbeta-prlinol. Prepared (yield 175 mg I yield 69%).
¾ 匪 R (400, CDC13) ： 8.19 (2H, s) , 7.32 (2H, m) , 6.87 (2H, m) , 6.05 (1Η, m) , 4.80 (2H, m) , 4.01 (4H, s) . 3.84-3.63 (6H, m) , 2.95-2.82 (3H, m) , 2.58-2.46 (5H, m) , 2.31 (1H, m), 2.11-1.88 (5H, m) , 1.75-1.70 (5H, m)， 1.40 (2H, m) , 1.22 (3H, m) . ' ¾ 匪 R (400, CDC1 3 ): 8.19 (2H, s), 7.32 (2H, m), 6.87 (2H, m), 6.05 (1Η, m), 4.80 (2H, m), 4.01 (4H, s . 3.84-3.63 (6H, m), 2.95-2.82 (3H, m), 2.58-2.46 (5H, m), 2.31 (1H, m), 2.11-1.88 (5H, m), 1.75-1.70 (5H, m ), 1.40 (2H, m), 1.22 (3H, m). '
<실시예 230> N-싸이클로펜틸 -4-(4-((l-(5-에틸피리미딘 -2-일) 피페리 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이드의 제조 Example 230 N-cyclopentyl-4- (4-((l- (5-ethylpyrimidin-2-yl) piperid-4-yl) methoxy) phenyl) cyclonux-3-encarboxamide Manufacture
Figure imgf000170_0002
Figure imgf000170_0002
L-베타 -프를리놀을 사용하는 대신에 펜틸아민을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합 물을 제조하였다 (수득량 153mg I 수율 58%).  The title compound was prepared in the same manner as in <Example 152>, except that pentylamine was used instead of L-beta-prlinol (yield 153 mg I yield 58%).
¾ NMR (400, CDC13) ： 8.23 (2H, s) , 7.33 (2H, m)， 6.87 (2H, m) , 6.03 (1Ηᅳ m) . 5.55 (2H, m) , 4.79 (2H, d) , 4.26 (1H, m)， 3.84 (2H, d) , 2.95 (2H, m) , 2.50-2.36 (7H, m) , 2.09-1.92 (7H, m)， 1.68-1.61 (4H, m) , 1.40-1.33 (4H, m) , 2.12 (3H, m) . ¾ NMR (400, CDC1 3 ): 8.23 (2H, s), 7.33 (2H, m), 6.87 (2H, m), 6.03 (1Η ᅳ m). 5.55 (2H, m), 4.79 (2H, d), 4.26 (1H, m), 3.84 (2H, d), 2.95 (2H, m), 2.50-2.36 (7H, m), 2.09-1.92 (7H, m), 1.68-1.61 (4H, m), 1.40-1.33 (4H, m), 2.12 (3H, m).
<실시예 231> N-싸이클로부틸 -4-(4-((l-(5-에틸피리미딘 -2-일 ) 피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스ᅳ 3-엔카복스아마이드의 제조 Example 231 N-cyclobutyl-4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonuclearscap 3-encarbox Preparation of Amide
Figure imgf000171_0001
Figure imgf000171_0001
L-베타ᅳ프를리놀을 사용하는 대신에 싸이클로부틸아민 하이드로 클로라이드를 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 165mg / 수율 68%) .  The title compound was prepared in the same manner as in <Example 152>, except that cyclobutylamine hydrochloride was used instead of L-beta chopped linol (yield 165 mg / yield 68%). .
ln 麵 R (400, CDCls) ： 8.18 (2H, m) , 7.31 (2H, m) , 6.86 (2Η, m) , 6.04 (1H, m) , 5.74 (1H, m) , 4.79 (2Ή, d) , 4.47 ( IH , m) , 3.84 (2H, d) , 2.95 (2H,m) , 2.51-2.35 (9H, m) , 2.09—2.06 (2H, m) , 1.96— 1.80 (5H, m) , 1.75-1.69 (2H, m) , 1.39 (2H, m) , 1.22 (3H, m) .  ln 麵 R (400, CDCls): 8.18 (2H, m), 7.31 (2H, m), 6.86 (2Η, m), 6.04 (1H, m), 5.74 (1H, m), 4.79 (2Ή, d) , 4.47 (IH, m), 3.84 (2H, d), 2.95 (2H, m), 2.51-2.35 (9H, m), 2.09—2.06 (2H, m), 1.96— 1.80 (5H, m), 1.75 -1.69 (2H, m), 1.39 (2H, m), 1.22 (3H, m).
<실시예 232> (3,4-디하쩌드로이소퀴놀린-2(110-일)(4-(4-((1-Example 232 (3,4-Dihazardloquiquinolin-2 (110-yl) (4- (4-((1-
( 5-에틸피리미딘ᅳ 2-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔 (5-ethylpyrimidin- 2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-ene
Figure imgf000171_0002
Figure imgf000171_0002
L-베타ᅳ프를리놀을 사용하는 대신에 1，2，3,4-테트라하이드로이 소퀴놀린을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 173mg I 수율 69%) .  The title compound was prepared in the same manner as in <Example 152>, except that 1,2,3,4-tetrahydroisoquinoline was used instead of L-betachamplinol. Yield 173 mg I yield 69%).
:H 匪 R (400, CDC13) ： 8.19 (2H, m) , 7.34 (2H, m) , 7.24-7.12 : H 匪 R (400, CDC1 3 ): 8.19 (2H, m), 7.34 (2H, m), 7.24-7.12
(4Η, m) , 6.87 (2H, m) , 6.07 (1H, m) , 4.74-4.73 (4H, m)， 3.91-3.78 (4H, m), 2.97-2.89 (5H, m)， 2.60-2.44 (5H, m) , 2.36 (1H, m) , 2.13-1.93 (5H, m)， 1.41 (2H, m) , 1.24 (3H, m) . (4Η, m), 6.87 (2H, m), 6.07 (1H, m), 4.74-4.73 (4H, m), 3.91-3.78 (4H, m), 2.97-2.89 (5H, m), 2.60-2.44 (5H, m), 2.36 (1H, m), 2.13-1.93 (5H, m), 1.41 (2H, m), 1.24 (3H, m).
<실시예 233> tert-부틸 4-((4-(4-(5-하이드록시펜틸카바모일) 싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제조
Figure imgf000172_0001
Example 233 Preparation of tert-butyl 4-((4- (4- (5-hydroxypentylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000172_0001
2-아미노에탄올을 사용하는 대신에 5—아미노펜탄올을 사용하는 것을 제외하고, 상기 <실시예 190>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 ,166mg I 수율 67%).  The title compound was prepared in the same manner as in <Example 190>, except that 5-aminopentanol was used instead of 2-aminoethanol (yield, 166 mg I yield 67%).
¾ 薩 R (400, CDCls) ： 7.31 (2H, m) , 6.84 (2H, m) , 6.03 ( 1Η， m) , 5.73 (1H, m) , 4.15 (2H, s) , 3.81 (2H, d) , 3.66 (2H, m) , 3.32 (2H, m) , 2.97 (2H, d) , 2.78 (2H, m) , 2.50-2.38 (5H, m) , 2.09 (1H, m) , 1.96-1.73 (5H, m) , 1.58-1.52 (5H 1.47 (9Ή, s), 1.44-1.22 (5H. m) .  ¾ 薩 R (400, CDCls): 7.31 (2H, m), 6.84 (2H, m), 6.03 (1Η, m), 5.73 (1H, m), 4.15 (2H, s), 3.81 (2H, d) , 3.66 (2H, m), 3.32 (2H, m), 2.97 (2H, d), 2.78 (2H, m), 2.50-2.38 (5H, m), 2.09 (1H, m), 1.96-1.73 (5H , m), 1.58-1.52 (5H 1.47 (9 μs, s), 1.44-1.22 (5H. m).
<실시예 234> 4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메 록시 )페닐 )-N-(5-하이드톡시펜틸 )싸이클로핵스 -3 엔카복스아마이드의 제조 Example 234 4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (5-hydroxypentyl) cyclonucleus Preparation of -3 Encarboxamide
Figure imgf000172_0002
Figure imgf000172_0002
L-베타 -프롤리놀을 사용하는 대신에 5-아미노펜탄올을 사용하는 갓을 제외하고, 상기 <실시예 152〉와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 172mg I 수율 71%) .  The title compound was prepared in the same manner as in <Example 152>, except that Gad using 5-aminopentanol instead of L-beta-prolinol (yield 172 mg I yield 71%). .
XH NMR (400， CDC13) ： 8.18 (2H, s) , 7.32 (2H, m)， 6.86 (2H, m) , 6.03 (1Η, m) , 5.66 (1H, m) , 4.79 (2H, d) , 3.84 (2H, d) , 3.67 (2H, m), 3.33 (2H, m) , 2.95 (2H, m) , 2.50-2.38 (7H, m) , 2.09-1.87 (5H, m), 1.69-1.30 ( 1 Η , m) , 1.22 (3H, m) . X H NMR (400, CDC1 3 ): 8.18 (2H, s), 7.32 (2H, m), 6.86 (2H, m), 6.03 (1Η, m), 5.66 (1H, m), 4.79 (2H, d ), 3.84 (2H, d), 3.67 (2H, m), 3.33 (2H, m), 2.95 (2H, m), 2.50-2.38 (7H, m), 2.09-1.87 (5H, m), 1.69- 1.30 (1 Η, m), 1.22 (3H, m).
<실시예 235> (2,5-디하이드로 -1H-피롤 -1-일) (4-(4-((l-(5-에틸 피리미딘 -2-일 )피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔일)메타 논의 제조 Example 235 (2,5-dihydro-1H-pyrrol-1-yl) (4- (4-((l- (5-ethyl pyrimidin-2-yl) piperidin-4-yl) Methoxy) phenyl) cyclonux-3-enyl) meta discussion preparation
Figure imgf000173_0001
Figure imgf000173_0001
L-베타 -프를리놀을 사용하는 대신에 2,5-디하이드로-111-피를을 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 184mg I 수율 85%).  The title compound was prepared in the same manner as in <Example 152>, except that 2,5-dihydro-111-py was used instead of L-beta-prlinol (yield yield). 184 mg I yield 85%).
:H NMR (400， CDC13) ： 8.18 (2H, s) , 7.34 (2H, m) , 6.88 (2Η, m) , 6.08 (1H, m), 5.93-5.84 (2H, m) , 4.80 (2H, d) , 4.37 (3H, m) , 3.85 (2H, d) , 3.53 ( 1H , m)， 2.95 (2Ή, m) , 2.65-2.32 (7H, m) , 2.10-1.88 (6H, m) , 1.37 (2H, m) , 1.22 (3H, m) . : H NMR (400, CDC1 3 ) ： 8.18 (2H, s), 7.34 (2H, m), 6.88 (2Η, m), 6.08 (1H, m), 5.93-5.84 (2H, m), 4.80 (2H , d), 4.37 (3H, m), 3.85 (2H, d), 3.53 (1H, m), 2.95 (2Ή, m), 2.65-2.32 (7H, m), 2.10-1.88 (6H, m), 1.37 (2H, m), 1.22 (3H, m).
<실시예 236> tert-부틸 4-((4-(4-((2-하이드록시에틸) (메틸)카 바모일)싸이클로핵스 - 1-옌일)페녹시 )메틸 )피페리딘 - 1-카복시레이트의 . Example 236 tert-Butyl 4-((4- (4-((2-hydroxyethyl) (methyl) carbamoyl) cyclonux-1-jenyl) phenoxy) methyl) piperidine-1- Of carboxylate.
Figure imgf000173_0002
Figure imgf000173_0002
2-아미노에탄올을 사용하는 대신에 2- (메틸아미노)에탄올을 사 용하는 것을 제외하고 , 상기 <실시예 190〉과 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 162mg I 수율 64%).  The title compound was prepared in the same manner as in <Example 190>, except that 2- (methylamino) ethanol was used instead of 2-aminoethanol (yield 162 mg I yield 64%). ).
:H NMR (400， CDCI3) ： 7.33 (2H, m)， 6.86 (2H, m)， 6.07 (1H, m) , 4.16 (2Η, s), 3.84 (4H, m)， 3.63-3.57 (2H, m)， 3.18 (3H, s) , 2.83-2.73 (3H, m)， 2.54-2.46 (3H, m) , 2.36 (1H, m) , 2.03-1.82 (5H m) , 1.48 (9H, s) , 1.32 (2H, m) . : H NMR (400, CDCI 3 ) ： 7.33 (2H, m) ， 6.86 (2H, m) ， 6.07 (1H, m), 4.16 (2Η, s), 3.84 (4H, m) ， 3.63-3.57 (2H , m), 3.18 (3H, s), 2.83-2.73 (3H, m), 2.54-2.46 (3H, m), 2.36 (1H, m), 2.03-1.82 (5H m), 1.48 (9H, s) , 1.32 (2H, m).
<실시예 237> tert-부틸 4-((4-(4-(1，3-디하이드록시프로판 -2- 일카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘ᅳ 1-카복시레이 트의 제조 Example 237 tert-butyl 4-((4- (4- (1,3-dihydroxypropane-2-ylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine ᅳ 1 Preparation of carboxylates
퀴레 Curais
½이 172
Figure imgf000174_0001
½ is 172
Figure imgf000174_0001
2-아미노에탄올을 사용하는 대신에 2-아미노 -1,3ᅳ프로판디을을 사용하는 것을 제외하고， 상기 <실시예 190〉과 동일한 방법으로 수행 하여 표제 화합물을 제조하였다 (수득량 166tng I 수율 68%).  The title compound was prepared in the same manner as in <Example 190>, except that 2-amino-1,3′propanedi was used instead of 2-aminoethanol (yield 166tng I yield 68 %).
XH 丽 R (400, DMS0-d6) ： 7.50 (1H, d) , 7.35 (2H, m) , 6.88 (2Η m) , 6.04 (1H, m), 4.61 (2Η, m) , 4.03 (2H, m) , 3.9.7 (2H, m) , 3.82 (2H, d) , 3.74 (1H, m) , 3.41 (4H, m) , 2.72 ( 2Ή , m )， 2.44-2.19 (5H m), 1.92-1.89 (2H, m) , 1.74 (2Η, m) , 1.66 (1Η, m) , 1.39 (9H, s), 1.23 (2H, m) . X H δ R (400, DMS0- d6 ): 7.50 (1H, d), 7.35 (2H, m), 6.88 (2Η m), 6.04 (1H, m), 4.61 (2Η, m), 4.03 (2H, m), 3.9.7 (2H, m), 3.82 (2H, d), 3.74 (1H, m), 3.41 (4H, m), 2.72 (2Ή, m), 2.44-2.19 (5H m), 1.92- 1.89 (2H, m), 1.74 (2Η, m), 1.66 (1Η, m), 1.39 (9H, s), 1.23 (2H, m).
<실시예 238> t er t -부틸 4- ( ( 4-^4- ( 3 하이드록시프로필카바모 일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘— 1-카복시레이트의 제조 Example 238 Preparation of t er t -butyl 4- ((4- ^ 4- (3 hydroxypropylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine— Preparation of 1-carboxylate
Figure imgf000174_0002
노프로판을을 사용하 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수행하여 표 제 화합물을 제조하였다 (수득량 172mg I 수율 69%).
Figure imgf000174_0002
Except for using nopropane, the title compound was prepared in the same manner as in <Example 190> (yield 172mg I yield 69%).
¾ NMR (400， CDCls) ： 7.32 (2H, m) , 6.85 (2H, m)， 6.03 (2H, m )， 4.16 (2H, s)， 3.81 (2H, d) , 3.67 (2H, m) , 3.50 (2Η, m) , 3.27 (1H, m) , 2.78 (2Η, m) , 2.53-2.41 (5H, m)， 2.12 (1H, m) , 1.98-1.82 (氣 m) , 1.73 (2H, m) , 1.48 (9H, s) , 1.31 (2H, m) .  ¾ NMR (400, CDCls): 7.32 (2H, m), 6.85 (2H, m), 6.03 (2H, m), 4.16 (2H, s), 3.81 (2H, d), 3.67 (2H, m), 3.50 (2Η, m), 3.27 (1H, m), 2.78 (2Η, m), 2.53-2.41 (5H, m), 2.12 (1H, m), 1.98-1.82 (氣 m), 1.73 (2H, m ), 1.48 (9H, s), 1.31 (2H, m).
<실시예 239> tert-부틸 4-( (4-(4-( 1, 2, 3， 4-테트라하이드로이소 린 -2-카보넣 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시 의 쩨조 Example 239 tert-Butyl 4-((4- (4- (1,2,3,4-tetrahydroisolin-2-carboth) cyclonux-1-enyl) phenoxy) methyl) piperi Manufacture of Dean-1-carboxy
2-아미노에탄올을 사용하는 대신에 1,2 ,3,4-테트라하이드로이소 퀴놀린을 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 185mg I 수율 81%) . The title compound was prepared in the same manner as in <Example 190>, except that 1,2,3,4-tetrahydroisoquinoline was used instead of 2-aminoethanol (yield 185 mg I Yield 81%).
!H 蘭 R (400， CDC13) ： 7.35 (2H, ηι) , 7.25-7.12 (4H, m) , 6.86 (2H, m) , 6.07 (1H, m) 4.84 (2Η, m) , 4.18 (2H, s) , 3.91-3,78 (4H, m) , 2.97-2.88 (3Η, m) 2.79 (2H, m) , 2.60-2.50 (3H, m)， 2.33 (1H, m) , 2.06-1.93 (3H, m) 1.86 (2H, m) , 1.59 (1H, s) , 1.48 (9H, s) , 1.33 (2H, m) . ! H 蘭 R (400, CDC1 3 ): 7.35 (2H, ηι), 7.25-7.12 (4H, m), 6.86 (2H, m), 6.07 (1H, m) 4.84 (2Η, m), 4.18 (2H, s), 3.91-3,78 (4H, m), 2.97-2.88 (3Η, m) 2.79 (2H, m), 2.60-2.50 (3H, m), 2.33 (1H, m), 2.06-1.93 (3H , m) 1.86 (2H, m), 1.59 (1H, s), 1.48 (9H, s), 1.33 (2H, m).
<실시예 240> tert-부틸 4-((4-(4- (이소인돌린 -2-카보닐 )싸이클 로핵스 -1-엔일)페녹시 )메틸)피페리딘ᅳ 1-카복시레이트의 제조 Example 240 Preparation of tert-Butyl 4-((4- (4- (isoindoline-2-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine ᅳ 1-carboxylate
Figure imgf000175_0001
Figure imgf000175_0001
2-아미노에탄올을 사용하는 대신에 이소인돌린을 사용하는 것을 제외하고， 상기 <실사예 190>과 동일한 방법으로 수행하여 표제 화합 물을 제조하였다 (수득량 181mg I 수율 77%) .  Except for using isoindolin instead of 2-aminoethanol, the title compound was prepared in the same manner as in <Example 1>, (a yield 181 mg I yield 77%).
l\i 匪 R (400, CDCls) ： 7.36-7.29 (6H, m) , 6.88 (2H, m) , 6.10 l \ i 匪 R (400, CDCls): 7.36-7.29 (6H, m), 6.88 (2H, m), 6.10
(1H, m) , 4.95 (2H, s) , 4.86 (2H, s), 4.17 (2H, s) , 3.83 (2H, d) ,(1H, m), 4.95 (2H, s), 4.86 (2H, s), 4.17 (2H, s), 3.83 (2H, d),
2.82-2.73 (3H, m) , 2.63-2.37 (4H, m) , 2.12 (1H, m)， 2.02 (2H, m) ,2.82-2.73 (3H, m), 2.63-2.37 (4H, m), 2.12 (1H, m), 2.02 (2H, m),
1. & 6 (2H, m) , 1.64 (1H, s) , 1.48 (9H, s) , 1.33 (2H, m) . 1. & 6 (2H, m), 1.64 (1H, s), 1.48 (9H, s), 1.33 (2H, m).
<실시예 241> (4-(4-((l-(5-에틸피리미딘ᅳ 2-일 )피페리딘 -4-일 ) 메특시 )페닐)싸이클로핵스 -3-엔일) (이소인돌린 -2-일 )메타논의 제조
Figure imgf000176_0001
Example 241 (4- (4-((l- (5-ethylpyrimidin- 2-yl) piperidin-4-yl) mesospecific) phenyl) cyclonux-3-enyl) (isoindolin 2-yl) Methanone Preparation
Figure imgf000176_0001
L-베타 -프를리놀을 사용하는 대신에 이소인돌린을 사용하는 것 을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화 합물을 제조하였다 (수득량 180mg I 수율 76%).  A title compound was prepared in the same manner as in <Example 152>, except that isoindolin was used instead of L-beta-prlinol (yield 180 mg I yield 76%). .
2H NMR (400, CDCls) ： 8.19 (2H, s) , 7.64-7.23 (6H, m), 6.89 (2H, m), 6.10 (1H( m)， 4.95 (2H, s), 4.86 (2H, s), 4.80 (2H, d) , 3.86 (2H, d), 2.96 (2H, m) , 2/82 (1H, m) , 2.63-2.36 (6H, m) , 2.12-2.09 (2H, m) , 2.02-1.93 (3H, m) , 1.42-4.31 (2H, m) , 1.22 (3H m). 2 H NMR (400, CDCls): 8.19 (2H, s), 7.64-7.23 (6H, m), 6.89 (2H, m), 6.10 (1H ( m), 4.95 (2H, s), 4.86 (2H, s), 4.80 (2H, d), 3.86 (2H, d), 2.96 (2H, m), 2/82 (1H, m), 2.63-2.36 (6H, m), 2.12-2.09 (2H, m) , 2.02-1.93 (3H, m), 1.42-4.31 (2H, m), 1.22 (3H m).
<실시예 242> 4- ( 4- ( ( 1- ( 5-에틸꾀리미딘 -2-일 )피페리딘 -4-일 )메 톡시 )페닐 )-N-(3-하이드록시프로필) -N-메틸싸이클로핵스— 3-엔카복스아 마이드의 제조 Example 242 4- (4-((1- (5-ethylzirimidin-2-yl) piperidin-4-yl) methoxy) phenyl) -N- (3-hydroxypropyl)- N-Methylcyclonucleus—Preparation of 3-encarboxamide
Figure imgf000176_0002
Figure imgf000176_0002
L-베타 -프를리놀을 사용하는 대신에 3-메틸아미노프로판올을 사 용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방법으로 수행하 여 표제 화합물을 제조하였다 (수득량 175nig I 수율 73%).  The title compound was prepared in the same manner as in <Example 152>, except that 3-methylaminopropanol was used instead of L-beta-prlinol (yield 175 nig I yield 73 %).
¾ NMR (400, CDC13) ： 8.18 (2H, s) , 7.31 (2H, d) , 6.86 (2Η, d), 6.05 (1H, d), 4.76 (2H, d), 4.03 (1H, s), 3.84 (2H, d) , 3.58 (2H, t) , 3.50 (2H, s) , 3.09 (3H, s) , 2.96-2.80 (4H, m) , 2.88-2.82 (5H, m) , 2.55-2.44 (1H, m) , 2.10-2.00 (2H, m)， 1.99—1.89 (3H, m) , 1.75 (2H, m), 1.38-1.31 (2H, m) , 1.22 (3H, t). ¾ NMR (400, CDC1 3 ): 8.18 (2H, s), 7.31 (2H, d), 6.86 (2Η, d), 6.05 (1H, d), 4.76 (2H, d), 4.03 (1H, s) , 3.84 (2H, d), 3.58 (2H, t), 3.50 (2H, s), 3.09 (3H, s), 2.96-2.80 (4H, m), 2.88-2.82 (5H, m), 2.55-2.44 (1H, m), 2.10-2.00 (2H, m), 1.99—1.89 (3H, m), 1.75 (2H, m), 1.38-1.31 (2H, m), 1.22 (3H, t).
<실시예 243> N-(3-하이드록시프로필 ) -4-(4-((l-(3-이소프로필- 1,2,4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )-N-메틸싸이클로핵 스 -3-엔카복스아마이드의 제조 Example 243 N- (3-hydroxypropyl) -4- (4-((l- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl) piperidine-4- Preparation of 1) methoxy) phenyl) -N-methylcyclonucleose-3-encarboxamide
Figure imgf000177_0001
Figure imgf000177_0001
(R)ᅳ Ν,Ν-디메틸피를리딘 -3ᅳ아민 하이드로클로라이드를 사용하는 대신에 3—메틸아미노프로판올을 사용하는 것을 제외하고， 상기 <실시 예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득 량 174mg I 수율 71%). The title compound was prepared in the same manner as in <Example 143>, except that 3-methylaminopropanol was used instead of (R) 'N, Ν-dimethylpyridine-3'amine hydrochloride. Prepared (yield 174m g I yield 71%).
XH NMR (400, CDCI3) ： 7.31 (2H, d) , 6.84 (2Η, d) , 6.05 (1H, m) , 4.21 (2H, d) , 4.01 (1H, t) , 3.84 (2H, d) , 3.52 (2H, t), 3.50 (2H, m) , 3.11 (5H, m) , 2.90 (2H, m) , 2.55-2.48 (3H, m) , 2.34 (1H, m) , 2.06-1.90 (5H, m) , 1.73 (2H, m) , 1.47 (2H, m), 1.31 (6H, d) . X H NMR (400, CDCI3): 7.31 (2H, d), 6.84 (2Η, d), 6.05 (1H, m), 4.21 (2H, d), 4.01 (1H, t), 3.84 (2H, d) , 3.52 (2H, t), 3.50 (2H, m), 3.11 (5H, m), 2.90 (2H, m), 2.55-2.48 (3H, m), 2.34 (1H, m), 2.06-1.90 (5H , m), 1.73 (2H, m), 1.47 (2H, m), 1.31 (6H, d).
<실시예 244> N- (퓨란 -2-일메틸 )-4-(4-((l-(3-이소프로필- 1,2，4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로헥스 -3ᅳ엔 카복스아마이드의 제조 Example 244 N- (furan-2-ylmethyl) -4- (4-((l- (3-isopropyl-1, 1,2,4-oxadiazol-5-yl) piperidine-4 Preparation of -yl) methoxy) phenyl) cyclohex-3zene carboxamide
Figure imgf000177_0002
하는 대신에 퍼퓨릴아민 (Furfurylamine)을 사용하는 것을 제외하고， 상기 < 실시예 143>과 동일한 방법으로 수행하여 표제 화합물올 제조하였다 (수득량 159mg I 수율 62%) .
Figure imgf000177_0002
The title compound was prepared in the same manner as in <Example 143>, except that Perfurylamine was used instead (yield 159m g I yield 62%).
H NMR (400， CDC13) ： 7.37 (1H, s), 7.30 (2H, d)， 6.83 (2H, d) , 6.34 (1H, t), 6.25 (1H, d) , 6.03 (1H, s) , 5.88 (1H, t) , 4.48 (2H, d) , 4.21 (2H, d), 3.84 (2H, d), 3.10 (2H, t) , 2.90 (1H, m) , 2.46 (2H, m) , 2.06 (2H, m) , 1.89 (3H, m)， 1.49 (2H, m) , 1.31 (6H,, d). ' <실시예 245> N-(3-에록시프로필 )-4-(4-((l-(3-이소프로필-H NMR (400, CDC1 3 ): 7.37 (1H, s), 7.30 (2H, d), 6.83 (2H, d), 6.34 (1H, t), 6.25 (1H, d), 6.03 (1H, s) , 5.88 (1H, t), 4.48 (2H, d), 4.21 (2H, d), 3.84 (2H, d), 3.10 (2H, t), 2.90 (1H, m), 2.46 (2H, m), 2.06 (2H, m), 1.89 (3H, m), 1.49 (2H, m), 1.31 (6H ,, d). '<Example 245> N- (hydroxypropyl the 3-) -4- (4 - (( l- (3- isopropyl-
1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스—3-엔 카복 1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux—3-ene Kabok
Figure imgf000178_0001
Figure imgf000178_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이 \ 사용하는 대신에 3ᅳ에톡시프로필아민을 사용하는 것을 제외하고， 기 <실시예 (R) -N, N-dimethylpyridin-3-amine hydrochlory \ Except for using 3'ethoxypropylamine instead of using,
143>과 동일한 방 ！으로 수행하여 표제 화합물을 제조하였다 (수득량 167mg I 수율 64%) . 143>, to obtain the title compound (yield 167mg I yield 64%).
JH NMR (400， CDCls) ： 7.32 (2H, d) , 6.84 (2H, d), 6.33 (1H, t), 6.04 (1H, s), 4.21 (2H, d) , 3.84 (2H, d) , 3.55 (2H, t) , 3.47 (2H q) , 3.40 (2Η, q) , 3.11 (2H, m) , 2.90 (1H, m) , 2.52-2.36 (5H, m), 2.13-2.05 (2Η, m) , 1.97 (2H, d) , 1.85-1.77 (3H, m), 1.47 (2H, m), 1.31 (6Η, d) , 1.23 (3H, t) .  JH NMR (400, CDCls): 7.32 (2H, d), 6.84 (2H, d), 6.33 (1H, t), 6.04 (1H, s), 4.21 (2H, d), 3.84 (2H, d), 3.55 (2H, t), 3.47 (2H q), 3.40 (2Η, q), 3.11 (2H, m), 2.90 (1H, m), 2.52-2.36 (5H, m), 2.13-2.05 (2Η, m ), 1.97 (2H, d), 1.85-1.77 (3H, m), 1.47 (2H, m), 1.31 (6Η, d), 1.23 (3H, t).
<실시예 246> 4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5-일) 피페리딘 -4-일 )메록시 )페닐 )-Nᅳ메톡시싸이클로핵스 -3-엔카복스아마 0 드의 Example 246 4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) -N ᅳ me Toxycyclonux-3-encarbox flax 0 de
Figure imgf000178_0002
Figure imgf000178_0002
(R)ᅳ Ν,Ν-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 0-메틸하이드록실아민 하이드로클로라이드를 사용하는 것을 제 외하고， 상기 <실시예 143>과 동일한 방법으로 수행하껴 표제 화합물 을 제조하였다 (수득량 170mg I 수율 67%).  (R) ᅳ Performed in the same manner as in <Example 143>, except that 0-methylhydroxylamine hydrochloride was used instead of Ν, Ν-dimethylpyridine-3-amine hydrochloride. The title compound was prepared (yield 170 mg I yield 67%).
XH NMR (400, CDCls) ： 8.39 (1H, s), 7.30 (2H, d)， 6.83 (2H, d), 6.03 (1H, s) , 4.22 (2H, d) , 3.84 (2H, d) , 3.80 (3H, s) , 3.10 (2H, t) , 2.90 (1H, m) , 2.56-2.35 (5H, m) , 2.05 (2H, m) , 1.93 (2H, d) , 1.43 (2H, m) , 1.31 (6H, d) . X H NMR (400, CDCls): 8.39 (1H, s), 7.30 (2H, d), 6.83 (2H, d), 6.03 (1H, s), 4.22 (2H, d), 3.84 (2H, d) , 3.80 (3H, s), 3.10 (2H, t), 2.90 (1H, m), 2.56-2.35 (5H, m), 2.05 (2H, m), 1.93 (2H, d), 1.43 (2H, m ), 1.31 (6H, d).
〈실시예 247> 4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5-일) Example 247 4- (4-((l- (3-isopropyl-1,2,4-oxadiazole-5-yl)
수동대 Manual
신율일 177 피페리딘 -4-일 )메록시 )페닐) 메톡시 메틸싸이클로핵스ᅳ 3ᅳ엔카복스 아마이드의 제조  Preparation of elongation 177 piperidin-4-yl) methoxy) phenyl) methoxymethylcyclonucleosulfone 3′encarboxamide
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 Ν,Ο-디메틸하이드록실아민을 사용하는 것을 제외하고， 상기 < 실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 176mg I 수율 73%). Except for using Ν, Ο-dimethylhydroxylamine instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride, was carried out in the same manner as in <Example 143> The title compound was prepared (yield 176 mg I yield 73%).
匪 R (400, CDCls) ： 7.33 (2H, d) , 6.85 (2H, d) , 6.07 (1Η, d) , 4.21 (2H, d), 3.84 (2H, d) , 3.74 (3H, s) , 3.24 (3H, s) , 3.07 (2H, m) , 2.89 (1H, m) , 2.52-2.33 (4H, .m) , 2.04 (4H, m) , 1.97 (2H, d) , 1.83 (1H, m) , 1.46 (2H, m) , 1.30 (6H, s).  匪 R (400, CDCls): 7.33 (2H, d), 6.85 (2H, d), 6.07 (1Η, d), 4.21 (2H, d), 3.84 (2H, d), 3.74 (3H, s), 3.24 (3H, s), 3.07 (2H, m), 2.89 (1H, m), 2.52-2.33 (4H, .m), 2.04 (4H, m), 1.97 (2H, d), 1.83 (1H, m ), 1.46 (2H, m), 1.30 (6H, s).
<실시예 248> N,N-비스 (2-하이드록시에틸) -4-(4-((l-(3-이소프 로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이드의 제조 Example 248 N, N-bis (2-hydroxyethyl) -4- (4-((l- (3-isopropyl-1-, 2,4-oxadiazole-5-yl) piperidine Preparation of -4-yl) methoxy) phenyl) cyclonux-3-encarboxamide
0  0
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 에 디에탄올아민을 사용하는 것을 제외하고, 상기 <실시예 143>과 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 157mg I 55%) . The title compound was prepared in the same manner as in <Example 143>, except that edethanolamine using (R) -N, N-dimethylpyridin-3-amine hydrochloride was used ( Yield 157 mg I 55%).
TH NMR (400, CDCls) ： 7.31 (2H, d), 6.84 (2H, d) ' 6.05 (1H, d), 4.20 (2H, d) , 3.90 (2H, s), 3.84 (4H, m) , 3.60 (4H, m), 3.27 (2H, s) , 3.10 (4H, m), 2.92 (2H, m) , 2.50 (2H, m) , 2.30 (2H, m) , 2.05-1.87 (5H, m) , 1.44 (2H, m)， 1.30 (6H, d). T H NMR (400, CDCls): 7.31 (2H, d), 6.84 (2H, d) '6.05 (1H, d), 4.20 (2H, d), 3.90 (2H, s), 3.84 (4H, m) , 3.60 (4H, m), 3.27 (2H, s), 3.10 (4H, m), 2.92 (2H, m), 2.50 (2H, m), 2.30 (2H, m), 2.05-1.87 (5H, m ), 1.44 (2H, m), 1.30 (6H, d).
<실시예 249> l-(4-(4-((l-(3-이소프로필 -l,2,4-옥사디아졸-5- 일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔카보닐)피페리 딘ᅳ 4ᅳ 카복스아마이드의 제조 Example 249 l- (4- (4-((l- (3-isopropyl-1,2,4-oxadiazole-5-) Preparation of 1) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) piperidinepin 4′carboxamide
Figure imgf000180_0001
Figure imgf000180_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 이소니페코트아마이드 (Isonipecotamide)를 사용하는 것을 제외 하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 167mg I 수율ᅳ& 5%) .  Except for using (Isonipecotamide) instead of using (R) -N, N-dimethylpyridin-3-amine hydrochloride, the title was carried out in the same manner as in <Example 143> Compounds were prepared (yield 167 mg I yield ᅳ & 5%).
^ NMR (400, CDCls) ： 7.32 (2H, d)， 6.85 (2H, d)， 6.05 (1H, d) , 5.49 (1H, s) , 5.36 (1H, s) , 4.67 (1H, m) , 4.21 (2Η' d) , 4.04 (1Η, d) , 3.85 (2H, d) , 3.11 ( 2Ή , m) , 2.89 H, m)， 2.77-2.53 (2H, m) , 2.50-2.31 (4H, m) , 2.27 (1H, m) , 2.06—1.94 (7H, m) , 1.66 (2Ή, m)， 1.41 (2H, m)， 1.23 (6H, d) .  ^ NMR (400, CDCls): 7.32 (2H, d), 6.85 (2H, d), 6.05 (1H, d), 5.49 (1H, s), 5.36 (1H, s), 4.67 (1H, m), 4.21 (2Η 'd), 4.04 (1Η, d), 3.85 (2H, d), 3.11 (2Ή, m), 2.89 H, m), 2.77-2.53 (2H, m), 2.50-2.31 (4H, m ), 2.27 (1H, m), 2.06—1.94 (7H, m), 1.66 (2Ή, m), 1.41 (2H, m), 1.23 (6H, d).
<실시예 250> l-(4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4- 일)메톡시 )페닐)싸이클로핵스 -3-엔카보닐)피를뫼딘 -3-온의 제조 Example 250 l- (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) pi Preparation of tomodine-3-one
Figure imgf000180_0002
Figure imgf000180_0002
L-베타 -프롤리놀을 사용하는 대신에 피를리딘 -3-온 하이드로클 로라이드를 사용하는 것을 제외하고， 상기 <실시예 152〉와 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 188mg I 수율 81%) .  The title compound was prepared in the same manner as in <Example 152>, except that pyridin-3-one hydrochloride was used instead of L-beta-prolinol. Yield 188 mg I yield 81%).
^ NMR (400, CDCls) ： 8.19 (2H, s) , 7.31 (2H, m) , 6.86 (2Η, d) , 6.04 (1H, t ) , 4.77 (2H, d)， 3.99 (4H, m) , 3.83 (2H, d) , 2.92 (2H, t) , 2.75 (2H, t) , 2.66 (2H, t) , 2.57 (2H, m) , 2.48 (2H, q) , 2.36 (1H, m) , 2.10 (2H, m) , 1.95 (2H, d) , 1.40 (2H, m) , 1.28 (6H, d) .  ^ NMR (400, CDCls): 8.19 (2H, s), 7.31 (2H, m), 6.86 (2Η, d), 6.04 (1H, t), 4.77 (2H, d), 3.99 (4H, m), 3.83 (2H, d), 2.92 (2H, t), 2.75 (2H, t), 2.66 (2H, t), 2.57 (2H, m), 2.48 (2H, q), 2.36 (1H, m), 2.10 (2H, m), 1.95 (2H, d), 1.40 (2H, m), 1.28 (6H, d).
<실시예 251> l-(4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카보닐 )피페리딘 -4- 카복스 Example 251 l- (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) Cyclonux-3-encarbonyl) piperidine-4- Carbox
Figure imgf000181_0001
Figure imgf000181_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 피를리딘 -3—온 하이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하 였다 (수득량 177mg I 수율 65%).  Performed in the same manner as in <Example 143>, except that instead of using (R) -N, N-dimethylpyridin-3-amine hydrochloride, pyridin-3-one hydrochloride was used The title compound was obtained (a yield 177 mg I yield 65%).
!H 蘭 R (400， CDCls) ： 7.32 (2H, m) , 6.85 (2Ή, d)， 6.33 (1H, t) , 6.05 (1H, t) , 4.21 (2Ή, d) , 4.04-3.95 (4H, m) , 3.84 (2H, d)， 3.14 (2H, t) , 2.89 (1H, q) , 2.77 (2H, t) , 2.68 (2H, t) , 2.55 (3H, t) , 2.60-2.33 (3H, m) , 2.06 (3H, m) , 1.94 (2Ή, d) , 1.44 (2H, m) , 1.35 (6H, s) . ! H 蘭 R (400, CDCls): 7.32 (2H, m), 6.85 (2Ή, d), 6.33 (1H, t), 6.05 (1H, t), 4.21 (2Ή, d), 4.04-3.95 (4H, m), 3.84 (2H, d), 3.14 (2H, t), 2.89 (1H, q), 2.77 (2H, t), 2.68 (2H, t), 2.55 (3H, t), 2.60-2.33 (3H , m), 2.06 (3H, m), 1.94 (2 Hz, d), 1.44 (2H, m), 1.35 (6H, s).
<실시예 252> l-(4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘 -4— 카복스아마이드의 제조 Example 252 l- (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) Preparation of Cyclonux-3-encarbonyl) piperidine-4—carboxamide
Figure imgf000181_0002
Figure imgf000181_0002
하이드록살아민 하이드로클로라이드를 사용하는 대신에 0-메틸 하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고 , 상기 Except for using 0-methyl hydroxylamine hydrochloride instead of using hydroxylamine hydrochloride,
<실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 170mg I 수율 56%) . The title compound was prepared in the same manner as the <Example 217> (yield 170 mg I yield 56%).
XH 匪 R (400， CDCls) ： 7.32 (2H, d) , 6.86 (2H, d)， 6.05 (1H, s) , 4.23 (4H, m) , 3.91 (3Η, s) , 3.82-3.77 (4H, m) , 3.11 (2H, t) , 2.94 (2H, q) , 2.89-2.45 (5H, m)， 2.30 (1H, m) , 2.05-1.90 (5H, m)， 1.46 (2H, m) , 1.30 (6H, s) . X H 匪 R (400, CDCls): 7.32 (2H, d), 6.86 (2H, d), 6.05 (1H, s), 4.23 (4H, m), 3.91 (3Η, s), 3.82-3.77 (4H , m), 3.11 (2H, t), 2.94 (2H, q), 2.89-2.45 (5H, m), 2.30 (1H, m), 2.05-1.90 (5H, m), 1.46 (2H, m), 1.30 (6 H, s).
<실시예 253> (Z)-(3, 3-비스 (하이드록시메틸) -4- (메톡시이미노) 피를리딘 -1-일) (4-(4-((l-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메톡 시 )페 로핵스 -3-엔일)메타논와 제조 Example 253 (Z)-(3, 3-bis (hydroxymethyl) -4- (methoxyimino) Pyridin-1-yl) (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) feroxax-3-enyl) methanone Produce
Figure imgf000182_0001
Figure imgf000182_0001
L-베타—프를리놀을 사용하는 대신에 (Z)— 4，4-비스 (하이드록시메 틸 )피를리딘 -3-온 0-메틸 옥심을 사용하는 것을 제외하고， 상기 <실시 예 152>와 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득 량 190mg / 수율 79%).  Except for using (Z) -4,4-bis (hydroxymethyl) pyridin-3-one 0-methyl oxime instead of using L-beta-prlinol, as described in Example 152 above. The title compound was prepared in the same manner as> (yield 190 mg / yield 79%).
:H 丽 R (400, CDC13) ： 8.18 (2H, s) 7.30 (2H, d) , 6.85 (2Η, d) , 6.03 (1H, s), 4.77 (2H, d) , 4.32 (2H, d) , 3.92-3.67 (11H, m) , 2.91 (2H, t) , 2.80 (1H, s) , 2.70-2.46 (7H, m) , 2.32 (1H, m) , 2.09-1.88 (3H, m) , 1.36 (2Ή, m) , 1.19 (2Ή, t) . : H Li R (400, CDC1 3 ) ： 8.18 (2H, s) 7.30 (2H, d), 6.85 (2Η, d), 6.03 (1H, s), 4.77 (2H, d), 4.32 (2H, d ), 3.92-3.67 (11H, m), 2.91 (2H, t), 2.80 (1H, s), 2.70-2.46 (7H, m), 2.32 (1H, m), 2.09-1.88 (3H, m), 1.36 (2 Hz, m), 1.19 (2 Hz, t).
<실시예 254> (Z)-tert-부틸 6-(4-(4-((l-(5-에틸피리미딘 -2- 일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카보닐) -8- (메록시이 미노) - ᅳ디아자스피로 [3.4]옥탄— 2—카복시레이트의 제초 Example 254 (Z) -tert-butyl 6- (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus -3-encarbonyl) -8- (methoxyimino) -weeddiazaspiro [3.4] octane—2—carboxylate
Figure imgf000182_0002
Figure imgf000182_0002
L-베타 -프를리놀을 사용하는 대신에 (Z)-tert-부틸 8ᅳ (메록시이 미노) -2,6-디아자스피로 [3.4]옥탄 -2-카복시레이트를 사용하는 것을 제 외하고， 상기 <실시예 152>와 동일한 방법으로 수행하여 표제 화합물 을 제조하였다 (수득량 177mg I 수율 68%). ᅳ  Except for using (Z) -tert-butyl 8 부틸 (methoxyimino) -2,6-diazaspiro [3.4] octane-2-carboxylate instead of using L-beta-prlinol The title compound was prepared in the same manner as the <Example 152> (yield 177 mg I yield 68%). ᅳ
2H NMR (400, CDC13) ： 8.18 (2H, s) 7.29 (2H, d)， 6.85 (2H, d) , 6.03 (1Η, s) , 4.77 (2H, d) , 4.32 (2Η, d) , 4.20 (2H, m) , 3.95- 3.89 (7H, m)， 3.83 (2H, d) , 2.92 (2H, t) , 2.59-2.44 (6H, m) , 2.32 (1H, d) , 2.10 (1H, s) , 1.96 (氣 m) , 1.47 (9Η, s) , 1.36-1.28 (4Η, m)) . 2 H NMR (400, CDC1 3 ): 8.18 (2H, s) 7.29 (2H, d), 6.85 (2H, d), 6.03 (1Η, s), 4.77 (2H, d), 4.32 (2Η, d) , 4.20 (2H, m), 3.95-3.89 (7H, m), 3.83 (2H, d), 2.92 (2H, t), 2.59-2.44 (6H, m), 2.32 (1H, d), 2.10 (1H , s), 1.96 (氣 m), 1.47 (9Η, s), 1.36-1.28 (4Η, m)).
<실시예 255> (Ζ)-(4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4- 일 )메특시 )페닐)싸아클로핵스 -3-엔일 ) (8ᅳ (메톡시이미노) _2 6ᅳ디아자스 피로 [ 제조 Example 255 (vi)-(4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux- 3 -enyl ) ( 8 ᅳ (methoxyimino) _ 2 6 ᅳ diazasu Fatigue [Manufacture
Figure imgf000183_0001
Figure imgf000183_0001
100 mL 플라스크에 상가 <실시예 254>에서 제조한 (Z)-tert-부 틸 6ᅳ(4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메톡시 )페닐)싸 이클로핵스 -3-엔카보닐 )— 8- (메톡시이미노) -2, 6-디아자스피로 [3.4]옥탄 ᅳ 2-카복시레이트 150 mg을 에틸아세테이트 20 mL에 용해사킨 후， 질소 환경 하 교반하였다. 디옥산에 용해된 4N-HC1 0.08 mL를 적가한 후 , 상온에서 3시간 교반하였다. 생성되는 고체를 여과한 후， 에틸 아세테 이트 10 mL로 세척하고， 건조하여 표제 화합물을 흰색 고체 형태로 제 조하였다 (수득량 130mg I 수율 73%).  Add (Z) -tert-butyl 6 '(4- (4-((1- (5-ethylpyrimidin-2-yl) piperidine-4-) prepared in <Example 254> in a 100 mL flask. 1) methoxy) phenyl) cyclonux-3-encarbonyl) — 8- (methoxyimino) -2, 6-diazaspiro [3.4] octane ᅳ 2-carboxylate 150 mg in 20 mL ethyl acetate After dissolution, the mixture was stirred in a nitrogen environment. 0.08 mL of 4N-HC1 dissolved in dioxane was added dropwise, followed by stirring at room temperature for 3 hours. The resulting solid was filtered off, washed with 10 mL of ethyl acetate and dried to afford the title compound as a white solid (yield 130 mg I yield 73%).
^ NMR (400, MeGD) ： 8.50 (2Ή, s) , 7.34 (2H, d) , 6.87 (2Η, d) , 6.06 (1H, s) , 4.61 (2H, d)， 3.99 (3H, s) , 3.63 (8H, s) , 3.49 (2H, m) , 2.67 (2H, q) , 2.54 (1H, s) , 2.43 (1H, s) , 2.16 (3H, m) , 1.79 (1H, m) , 1.52 (2H, q) , 1.30 (4H, m) .  ^ NMR (400, MeGD): 8.50 (2Ή, s), 7.34 (2H, d), 6.87 (2Η, d), 6.06 (1H, s), 4.61 (2H, d) ， 3.99 (3H, s), 3.63 (8H, s), 3.49 (2H, m), 2.67 (2H, q), 2.54 (1H, s), 2.43 (1H, s), 2.16 (3H, m), 1.79 (1H, m), 1.52 (2H, q), 1.30 (4H, m).
<실시예 256> tert-부틸 4-(.(4-(4-(4- (싸이클로프로필메틸)피페 라진 -1-카보닐 )싸이클로핵스— 1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레 이트의 Example 256 tert-Butyl 4-(. (4- (4- (4- (cyclopropylmethyl) piperazin-1-carbonyl) cyclonucleus— 1-enyl) phenoxy) methyl) piperidine Of 1-carboxylate
Figure imgf000183_0002
Figure imgf000183_0002
2-아미노에탄을을 사용하는 대신에 1-싸이클로프로필메틸 피페 라진을 사용하는 것을 제외하고， 상기 <실시예 190〉과 동일한 방법으 로 수행하여 표제 화합물을 쩨조하였다 (수득량 168mg I 수을 71%).  The title compound was prepared in the same manner as in <Example 190>, except that 1-cyclopropylmethyl piperazine was used instead of 2-aminoethane (yield 168 mg I number 71% ).
XH 匪 R (400, CDCls) ： 7.32 (2H, d)， 6.84 (2H, d) , 6.05 (1H, d) , 4.17 (2Η, s), 3.82 (2H, d), 3.72 (2H, s) , 3.61 (2H, s) , 2.77 (3H, m) , 2.57-2.46 (7H, m) , 2.28 (3H, m)， 2.00-1.82 (5H, m) , 1.48 (9H, s) , 1.28 (2H, m) , 0.89 (1H, m) , 0.55 (2H, q) . 0.12 (2H, q) . X H 匪 R (400, CDCls): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.17 (2Η, s), 3.82 (2H, d), 3.72 (2H, s ), 3.61 (2H, s), 2.77 (3H, m), 2.57-2.46 (7H, m), 2.28 (3H, m), 2.00-1.82 (5H, m), 1.48 (9H, s), 1.28 ( 2H, m), 0.89 (1H, m), 0.55 (2H, q). 0.12 (2H, q).
<실시예 257> tert-부틸 4-((4-(4-(3，3-디플루오로피롤리딘 -1- 카보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리 딘ᅳ 1-카복시레이트의 제조 Example 257 tert-butyl 4-((4- (4- (3,3-difluoropyrrolidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine 1-carboxylate Produce
Figure imgf000184_0001
Figure imgf000184_0001
2-아미노에탄올을 사용하는 대신에 3，3-디플루오로피를리딘 하 이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 190〉과 동 일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 174mg I 수 율 76%) .  The title compound was prepared in the same manner as in <Example 190>, except that 3,3-difluoropyridine hydrochloride was used instead of 2-aminoethanol. 174 mg I yield 76%).
¾ 匪 R (400, CDC13) ： 7.30 (2H, d) , 6.84 (2H, d) , 6.05 ( 1Η , d) , 4.16 (2H, s) , 3.92-3.73 (2H, m) , 2.78 (2H, t) , 2.56 (1H, m)， 2.49-2.29 (6H, m) , 2.04-1.97 (3H, m) , 1.82 (2H, d), 1.47 (9H, s), 1.25 (2H, m) . ¾ 匪 R (400, CDC1 3 ): 7.30 (2H, d), 6.84 (2H, d), 6.05 (1Η, d), 4.16 (2H, s), 3.92-3.73 (2H, m), 2.78 (2H , t), 2.56 (1H, m), 2.49-2.29 (6H, m), 2.04-1.97 (3H, m), 1.82 (2H, d), 1.47 (9H, s), 1.25 (2H, m).
<실시예 258> (3,3-디폴루오-로꾀를리딘 1-일)(4-(4-((1 (5-에틸 피리미딘 -2-일)피페리딘 -4-일)메록시 )페닐)싸이클로핵스 -3-엔일)메타 논의 조 Example 258 (3,3-Dipoluo-rociridin 1-yl) (4- (4-((1 (5-ethyl pyrimidin-2-yl) piperidin-4-yl) methoxy ) Phenyl) cyclonux-3-enyl) meta discussion
Figure imgf000184_0002
Figure imgf000184_0002
Lᅳ베타 -프를리놀을 사용하는 대신에 3,3-디플루오로피 "리딘 하 이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 152>와 동 일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 175mg I 수 율. 73%) .  The title compound was prepared in the same manner as in <Example 152>, except that 3,3-difluoropyridine hydrochloride was used instead of L-Vbeta-prolinol. (Yield 175 mg I yield. 73%).
XH 匪 R (400, CDCls) ： 8.19 (2H, s) , 7.32 (2H, d)， 6.85 (2H, d) , 6.05 (1Η, d) , 4.77 (2H, d)， 3.92-3.74 (6H, m) , 2.92 (2H, m)， 2.56-2.32 (9H, m) , 2.11-1.88 (5H, m) , 1.37 (2H, m)， 1.22 (3H, t) . X H 匪 R (400, CDCls): 8.19 (2H, s), 7.32 (2H, d), 6.85 (2H, d), 6.05 (1Η, d), 4.77 (2H, d), 3.92-3.74 (6H , m), 2.92 (2H, m), 2.56-2.32 (9H, m), 2.11-1.88 (5H, m), 1.37 (2H, m), 1.22 (3H, t).
<실시예 259> (3,3-디플루오로피를리딘 -1-일) (4-(4-((l-(3-이소 프로필 -1,2,4—옥사디아졸 -5ᅳ일 )피페리딘 -4-일 )메특시 )페닐)싸이클로헥 스 -3-엔일)메타논의 제조
Figure imgf000185_0001
Example 259 (3,3-difluoropyridin-1-yl) (4- (4-((l- (3-isopropyl-1,2,4—oxadiazole-5xyl)) Preparation of piperidin-4-yl) methoxy) phenyl) cyclohex-3-enyl) methanone
Figure imgf000185_0001
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 3,3-디플루오로피를리딘 하이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합 물을 제조하였다 (수득량 182mg I 수율 77%).  Same as <Example 143>, except that 3,3-difluoropyridine hydrochloride is used instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride. Performed by the method to prepare the title compound (yield 182 mg I yield 77%).
XH NMR (400， CDC13) : 7.32 (2H, d), 6.84 (2H, d)， 6.05 ( 1H , d), 4.21 (2Η, d), 3.92-3.74 (6H, m), 3.11 (2H, m), 2.94 (1H, m) , 2.56-2.33 (7H, m) , 2.06-1.94 (5H, m) , 1.47 (2H, m)， 1.31 (6H, d) . X H NMR (400, CDC1 3 ): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.21 (2Η, d), 3.92-3.74 (6H, m), 3.11 (2H , m), 2.94 (1H, m), 2.56-2.33 (7H, m), 2.06-1.94 (5H, m), 1.47 (2H, m), 1.31 (6H, d).
<실시예 260> N- ( 5-하이드톡시펜틸 ) -4 (4- (( 1- (3-이소프로필 - 1， 2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔 카복스아마이드의 제조 Example 260 N- (5-hydroxypentyl) -4 (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl Preparation of methoxy) phenyl) cyclonux-3-enecarboxamide
Figure imgf000185_0002
Figure imgf000185_0002
(R)-N,N—디메탈피를리딘— 3—아민 하이드로클로라이드를 사용하는 대신에 5-아미노펜탄올을 사용하는 것을 제외하고， 상기 <실시예 143> 과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 185mg / 수율 78%).  The title compound was prepared in the same manner as in <Example 143>, except that 5-aminopentanol was used instead of (R) -N, N-dimetalpyridine- 3-amine hydrochloride. Prepared (yield 185 mg / yield 78%).
XH NMR (400, CDCI3) ： 7.30 (2H, d)， 6.84 (2H, d) , 6.04 (1Η, d) , 5.67 (1H, t), 4.19 (2H, d) , 3.85 (2H, d) , 3.65 (2H, t) , 3.31 (2H, q) , 3.07 (2H, m), 2.90 (1H, m) , 2.51-2.38 (5H, m) , 2.03 (2H, m) , 1.85 (3H, m) , 1.58 (5H, m) , 1.43 (5H, m) , 1.30 (6H, d) . X H NMR (400, CDCI 3 ): 7.30 (2H, d), 6.84 (2H, d), 6.04 (1Η, d), 5.67 (1H, t), 4.19 (2H, d), 3.85 (2H, d ), 3.65 (2H, t), 3.31 (2H, q), 3.07 (2H, m), 2.90 (1H, m), 2.51-2.38 (5H, m), 2.03 (2H, m), 1.85 (3H, m), 1.58 (5H, m), 1.43 (5H, m), 1.30 (6H, d).
<실시예 261> tert-부틸 4-((4-(4-(2，2，2-트리플루오로에틸카바 모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1ᅳ카복시레이트의 제 조
Figure imgf000186_0001
Example 261 tert-Butyl 4-((4- (4- (2,2,2-trifluoroethylcarbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1′carboxy Manufacture of Rate
Figure imgf000186_0001
2-아미노에탄올을 사용하는 대신에 2，2，2-트리플루오로에틸아민 을 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법으로 수 행하여 표제 화합물을 제조하였다 (수득 :량 164mg I 수율 70%) . The title compound was prepared in the same manner as in <Example 190>, except that 2,2,2-trifluoroethylamine was used instead of 2-aminoethanol (yield : amount 164 mg I Yield 70%).
XH NMR (400, CDCls) : 7.31 (2H, d) , 6.84 (2Η, d)， 6.03 (1H, d) , 5.90 (1H, t) , 4.17 (2H, s), 3.97 (2H, m)； 3.81 (2H, d) , 2.76 (2H, t) , 2.57-2.42 (5H, m) , 2.13-2.09 (1H, m) , 1.99-1.85 (2H, m) , 1.84 (2H, d) , 1.47 (9H, s) , 1,24 (2H, m) . X H NMR (400, CDCls): 7.31 (2H, d), 6.84 (2Η, d), 6.03 (1H, d), 5.90 (1H, t), 4.17 (2H, s), 3.97 (2H, m) 3.81 (2H, d), 2.76 (2H, t), 2.57-2.42 (5H, m), 2.13-2.09 (1H, m), 1.99-1.85 (2H, m), 1.84 (2H, d), 1.47 (9H, s), 1,24 (2H, m).
262> tert-부틸 4— ((4-(4-(4-시아노싸이클로핵산카보262> tert-butyl 4— ((4- (4- (4-cyanocyclonucleocarbon)
— 1-카복시레이트의 제조  — Preparation of 1-carboxylate
2ᅳ트리플루오로에틸아민 을 사
Figure imgf000186_0002
>과 동일한 방법으로 수 행하여 표제 화합물을 제조하였다 (수득량 165mg I 수율 67%). 2 ᅳ trifluoroethylamine
Figure imgf000186_0002
The title compound was prepared in the same manner as> (yield 165 mg I yield 67%).
¾ NMR (400, CDCls) ： 7.30 (2H, d) , 6.84 (2H, d) , 6.04 (1Η, s), 4.17 (2H, s), 3.87-3.76 (4H, m)， 3.63-3.50 (2H, m)， 2.93 ( 1H , m) , 2.82-2.73 (3H, m)， 2.73-2.47 (3H, m) , 2.28 (1H, m) , 1.97—1.82 (9H, m) , 1.47 (9H, s) , 1.23 (2H, m).  ¾ NMR (400, CDCls): 7.30 (2H, d), 6.84 (2H, d), 6.04 (1Η, s), 4.17 (2H, s), 3.87-3.76 (4H, m), 3.63-3.50 (2H , m), 2.93 (1H, m), 2.82-2.73 (3H, m), 2.73-2.47 (3H, m), 2.28 (1H, m), 1.97—1.82 (9H, m), 1.47 (9H, s ), 1.23 (2H, m).
<실시예 263> tert-부틸 4-((4-(4-(1，4-디옥사 -8-아자스파로 Example 263 tert-butyl 4-((4- (4- (1,4-dioxa-8-azaspiro)
[4.5]데칸 -8-카보닐)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카 복시레이트의 제조 [4.5] Decan-8-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000187_0001
Figure imgf000187_0001
2-아미노에탄올을 사용하는 대신에 1，4—디옥사— 8-아자스피로 [4.5]데칸을 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 177mg I 수율 74¾>) The title compound was prepared in the same manner as in <Example 190>, except that 1,4-dioxa-8-azaspiro [4.5] decane was used instead of 2-aminoethanol ( Yield 177 mg I yield 74¾>)
:H 麵 R (400, CDC13) ： 7.32 (2H, d) , 6.84 (2H, d)， 6.05 (1H, d) , 4.17 (2Η, s) , 4.ΌΚ4Η, s), 3.82—3.70 (4Ή, m) , 3.63 (2H, t) , 2.83-2.76 (3H, m) , 2.53—2.47 (2H, m) , 2.31 (1H, m), 2.02-1.90 (3H m)' 1.81 (2H, d), 1.73 (4H, m) 7 1.48 (9H, s) , 1.25 (2H, m) . <실시예 264> t er t -부될 4- ( ( 4- (4쪠꾀로 [인펜 -1， 4 ' 피페리 딘] - 1 ' -일카보닐)싸이클로핵스ᅳ 1 -엔일)페녹시 )메틸)피페리딘 - 1 -카복시 레이트 : H 麵 R (400, CDC1 3 ) ： 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.17 (2Η, s), 4.ΌΚ4Η, s), 3.82—3.70 ( 4 Ή, m), 3.63 (2H, t), 2.83-2.76 (3H, m), 2.53—2.47 (2H, m), 2.31 (1H, m), 2.02-1.90 (3H m) '1.81 (2H, d ), 1.73 (4H, m) 7 1.48 (9H, s), 1.25 (2H, m). <Example 264> t er t -4-((4- (4 -pipero- [enphen-1,4'piperidine] -1'-ylcarbonyl) cyclonucleossyl-enyl) phenoxy) methyl Piperidine-1 -carboxylate
Figure imgf000187_0002
Figure imgf000187_0002
2-아미노에탄을을 사용하는 대신에 2，3-디하이드로스피로 [인덴- 1，4'-피페리딘]을 사용하는 것을 제외하고， 상기 <실시예 190>과 동일 한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 183mg I 수율 75%) .  The procedure was carried out in the same manner as in <Example 190>, except that 2,3-dihydrospiro [indene-1,4'-piperidine] was used instead of 2-aminoethane. Compounds were prepared (yield 183 mg I yield 75%).
¾ 蘭 R (400， CDCls) ： 7.37-7.31 (4H, m) , 7.29-7.22 (2H, m) , 6.91 (1Η, dd) , 6.87-6.83 (3H, m) , 6.08 ( 1H， t) , 4.76 (2H, d)， 4.10 (3H, m) , 3.8K2H, d)， 3.47 (2H, t) , 3.05 (1H, t), 2.89 (1H, m) , 2.79 (2H, m) , 2.73-2.52 (3H, m) , 2.37 (1H, m)， 2.11-1.93 (5H, m) , 1.83 (2H, d) , 1.47-1.32 (11H, m) . 1.23 (2H, m) .  ¾ 蘭 R (400, CDCls): 7.37-7.31 (4H, m), 7.29-7.22 (2H, m), 6.91 (1Η, dd), 6.87-6.83 (3H, m), 6.08 (1H, t), 4.76 (2H, d), 4.10 (3H, m), 3.8K2H, d), 3.47 (2H, t), 3.05 (1H, t), 2.89 (1H, m), 2.79 (2H, m), 2.73- 2.52 (3H, m), 2.37 (1H, m), 2.11-1.93 (5H, m), 1.83 (2H, d), 1.47-1.32 (11H, m). 1.23 (2 H, m).
<실시예 265> tert-부틸 4-((4-(4-(3-옥소피를리딘 -1-카보닐 )싸 이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘ᅳ 1-카복시레이트의 제조 Example 265 tert-Butyl 4-((4- (4- (3-oxopyridine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine ᅳ 1- Preparation of Carboxylate
d 2시득 (대 d 2 acquisitions (large)
H 186 H 186
Figure imgf000188_0001
Figure imgf000188_0001
2-아미노에탄올을 사용하는 대신에 피롤리딘 -3-온 하이드로클로 라이드를 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법 으로 수행하여 표쩨 화합물을 제조하였다 <수득량 158mg I 수율 64%) .  A standard compound was prepared in the same manner as in <Example 190>, except that pyrrolidin-3-one hydrochloride was used instead of 2-aminoethanol <yield 158 mg I yield 64 %).
匪 R (400, CDCls) ： 7.32 (2H, d) , 6.84 (2H, d) , 6.06 (1Η, d), 4.17 (2H, s), 3.99 (4H, m)， 3.81 (2H, d) , 2.75 (5H, m)， 2.60- 2.42 (5H, m) , 2.33-2.30 (1H, m) , 2.06—1.94 (33H, m) , 1.89 (2H, d) 1.48 (9H, s)， 1.27 (2H, m) .  匪 R (400, CDCls): 7.32 (2H, d), 6.84 (2H, d), 6.06 (1Η, d), 4.17 (2H, s), 3.99 (4H, m), 3.81 (2H, d), 2.75 (5H, m), 2.60- 2.42 (5H, m), 2.33-2.30 (1H, m), 2.06—1.94 (33H, m), 1.89 (2H, d) 1.48 (9H, s), 1.27 (2H , m).
<실시예 266> l-(4-(4-((l-(3-이소프로필 -1,2,4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔카보닐)피페리딘 -4- 카보나이트릴의 제조 · Example 266 l- (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) Preparation of cyclonux-3-encarbonyl) piperidine-4-carbonitrile
Figure imgf000188_0002
Figure imgf000188_0002
(R)-N,N-디메틸피롤리딘 -3-아민 하이드로클로라이드를 사용하는 신에 피페리딘 -4-카보나이트릴을 사용하는 것을 제외하고， 상기 <실 예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수 량 174mg I 수율 70%).  (R) -N, N-dimethylpyrrolidin-3-amine was carried out in the same manner as in <Example 143>, except that piperidine-4-carbonitrile was used in the scene using hydrochloride The title compound was prepared (amount 174 mg I yield 70%).
XH 丽 R (400， CDC13) ： 7.31 (2H, d) , 6.86 (2H, d)， 6.05 (1H, ， 4.20 (2H, d) , 3.84-3.50 (6H, m) , 2.11 (2Η, m) , 2.93 (2H, m) , 78 (1H, m) , 2.52 (3H, m) , 2.28 (1H, m) , 2.05-1.89 (9H, m) , 1.43 m 29 (9H X H δ R (400, CDC1 3 ): 7.31 (2H, d), 6.86 (2H, d), 6.05 (1H,, 4.20 (2H, d), 3.84-3.50 (6H, m), 2.11 (2Η, m), 2.93 (2H, m), 78 (1H, m), 2.52 (3H, m), 2.28 (1H, m), 2.05-1.89 (9H, m), 1.43 m 29 (9H
<실시예 267> (4-(4-((1-(3-이소프로필 -1,2,4-옥사디아졸 -5-일) 피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔일 ) (1，4-디옥사 -8-아자 스피로 [4.5]데칸 -8-일 )메타논의 제조
Figure imgf000189_0001
Example 267 (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus 3-enyl) (1,4-dioxa-8-aza spiro [4.5] decane-8-yl) methanone
Figure imgf000189_0001
(R)-N,N-디쩨틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 1，4-디옥사 -8-아자스피로 [4.5]데칸을 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하 였다 (수득량 180mg I 수율 76%).  Except for using 1,4-dioxa-8-azaspiro [4.5] decane, instead of using (R) -N, N-dignitylpyridin-3-amine hydrochloride, Example <143 The title compound was prepared in the same manner as> (yield 180 mg I yield 76%).
JH NMR (400, CDCls) ： 7.32 (2H, d)， 6.84 (2H, d)， 6.05 (1H, d) , 4.20 (2H, d) , 4.01 (4Η, s) , 3.85 (2H, d) , 3.75 (2H, m) , 3.63 (2H, t), 3.11 (2H,m) , 2.94-2.83 (2H, m) , 2.51 (3Ή, m) , 2.31 (1H, m), 2.06-1.90 (5H, m)， 1.73 (4H, m)， 1.44 (2H, m) , 1.31 (6.H, d) . J H NMR (400, CDCls): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.20 (2H, d), 4.01 (4Η, s), 3.85 (2H, d) , 3.75 (2H, m), 3.63 (2H, t), 3.11 (2H, m), 2.94-2.83 (2H, m), 2.51 (3Ή, m), 2.31 (1H, m), 2.06-1.90 (5H , m), 1.73 (4H, m), 1.44 (2H, m), 1.31 (6.H, d).
<실시예 268> (2，3-디하이드로스피로 [인덴 -1，4'-피페리딘] -1'- 일) (4-(4-((1-(3_이소프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메 특시 )페닐)싸이클로핵스 -3-엔일 )메타논의 제조 Example 268 (2,3-dihydrospiro [indene-1,4'-piperidin] -1'-yl) (4- (4-((1- (3_isopropyl-1,2) , Preparation of 4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000189_0002
Figure imgf000189_0002
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 3-디하이드로스피로 [인덴 -1,4'-피페리딘]올 사용하는 것을 제 외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물 을 제조하였다 (수득량 194mg I 수율 82%).  Except for using (di) pyro [inden-1,4'-piperidin] ol instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride, the above < In the same manner as in Example 143>, the title compound was prepared (a yield 194 mg I yield 82%).
^ NMR (400, CDCls) ： 7.35-7.22 (8H, m) , 6.91-6.84 (4H, m)， 6.09 (1H, t) , 4.75 (1H, d)， 4.20 (2H, d) , 4.10 (1H, d)， 3.84 (2H, d) , 3.49 (1H, m) , 3.08 (3H, m), 2.89 (2H, m) , 2.62-2.34 (4H, m)， 2.19-1.94 (7H, m) , 1.46 (4H, m) , 1.31 (6H, d) .  ^ NMR (400, CDCls): 7.35-7.22 (8H, m), 6.91-6.84 (4H, m), 6.09 (1H, t), 4.75 (1H, d), 4.20 (2H, d), 4.10 (1H , d), 3.84 (2H, d), 3.49 (1H, m), 3.08 (3H, m), 2.89 (2H, m), 2.62-2.34 (4H, m), 2.19-1.94 (7H, m), 1.46 (4 H, m), 1.31 (6 H, d).
<실시예 269> (3- (에톡시이미노)피를리딘 -1—일 ) (4-(4-((l-(5-에 틸피리미딘 -2-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일 )메 타논의 제조 Example 269 (3- (ethoxyimino) pyridin-1-yl) (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl Manufacture) Methionone) Phenyl) cyclonux-3-enyl) Methanone
Figure imgf000190_0001
Figure imgf000190_0001
하이드록실아민 하이드로클로라이드를 사용하는 대신에 0-에틸 하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기 Except for using 0-ethyl hydroxylamine hydrochloride instead of using hydroxylamine hydrochloride,
<실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 177mg I 수율 71%). The title compound was prepared in the same manner as the <Example 217> (yield 177 mg g I yield 71%).
^ NMR (400, CDCls) ： 8.19 (2H, s), 7.32 (2H, d) , 6.86 (2Η, d) , 6.05 (1H, d) , 4.77 (2H, d)， 4.24 (2H, d), 4.12 (2H, m) , 3.85- 3.77 (4H, m) , 2.95 (3H, m) , 2.78-2.45 (7H, m) , 2.34 (1H, m) , 2.10-1.90 (5H, m) , 1.36 (2H, m) , 1.29 (3H, t), -1.20 (3H, t). ^ NMR (400, CDCls): 8.19 (2H, s), 7.32 (2H, d), 6.86 (2Η, d), 6.05 (1H, d), 4.77 (2H, d), 4.24 (2H, d), 4.12 (2H, m), 3.85-3.77 (4H, m), 2.95 (3H, m), 2.78-2.45 (7H, m), 2.34 (1H, m), 2.10-1.90 (5H, m), 1.36 ( 2H, m), 1.29 (3H, t), -1.20 (3H, t).
<실시예 270> tert-부틸 4-((4-(4-(4- (메록시이미노)피페리딘-Example 270 tert-butyl 4-((4- (4- (4- (methoxyimino) piperidine-)
1-카보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레 0 의 제 Preparation of 1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxyre 0
Figure imgf000190_0002
Figure imgf000190_0002
하이드록실아민 하이드로클로라이드를 사용하는 대신에 0-메틸 하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기 Except for using 0-methyl hydroxylamine hydrochloride instead of using hydroxylamine hydrochloride,
<실시예 217〉과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 173mg / 수율 75%). The title compound was prepared in the same manner as the <Example 217> (amount 173 mg / yield 75%).
JH NMR (400， CDCls) ： 7.30 (2H, d) , 6.84 (2Η, d) , 6.05 (1Η, d) , 4.17 (2H, s) , 3.86 (3H, s), 3.80-3.70 (6H, m) , 2.82-2.48 (10H, m) , 2.30 (1H, m) , 2.02-1.91 (3H, m) , 1.82 (2H, d) , 1.48 (9H, s) , 1.25 (2H, m) . J H NMR (400, CDCls): 7.30 (2H, d), 6.84 (2Η, d), 6.05 (1Η, d), 4.17 (2H, s), 3.86 (3H, s), 3.80-3.70 (6H, m), 2.82-2.48 (10H, m), 2.30 (1H, m), 2.02-1.91 (3H, m), 1.82 (2H, d), 1.48 (9H, s), 1.25 (2H, m).
<실시예 271> tert-부틸 4-((4-(4-(4- (하이드록시이미노)피페리 딘 -1-카보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이 트의 제조 O Example 271 tert-Butyl 4-((4- (4- (4- (hydroxyimino) piperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine Preparation of 1-carboxylate O
1-(4-(4-((1-(3-이소프로필 -1，2,4ᅳ옥사디아졸— 5—일 )피페리딘 -4- 일 )메톡시 )페닐)싸이클로핵스 -3-엔카보닐)피페리딘 -4-카복스아마이드 를 사용하는 대신에 tertᅳ부틸 4-((4-(4-(4-옥소피페리딘 -1-카보닐 )싸 이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트를 사용하는 것을 제외하고， 상기 <실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 161mg I 수율 66%).  1- (4- (4-((1- (3-isopropyl-1,2,4 ᅳ oxadiazole— 5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3- Instead of using encarbonyl) piperidine-4-carboxamide, tert ᅳ butyl 4-((4- (4- (4-oxopiperidine-1-carbonyl) cyclonux-1-enyl Except for using phenoxy) methyl) piperidine-1-carboxylate, the title compound was prepared in the same manner as in <Example 217> (yield 161 mg I yield 66%).
¾ NMR (400, CDCls) ： 7.32 (2H, d) , 6.84 (2H, d)， 6.05 (1H, d) , 4.16 (2H, s), 3.93-3.76 (6Η, m) , 2.83-2.73 (5H, m) , 2.66—2.41 (5H, m) , 2.30 (1H, m) , 2.04-1.91 (3H, m) , 1.82 (2H, d) , 1.48 (9H, s) , 1.22 (2H, m) .  ¾ NMR (400, CDCls): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.16 (2H, s), 3.93-3.76 (6Η, m), 2.83-2.73 (5H , m), 2.66—2.41 (5H, m), 2.30 (1H, m), 2.04-1.91 (3H, m), 1.82 (2H, d), 1.48 (9H, s), 1.22 (2H, m).
<실시예 272> tert-부틸 4-((4-(4-(4-옥소피페리딘 -1-카보닐 )싸 이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트의 제조 Example 272 tert-Butyl 4-((4- (4- (4-oxopiperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1- Preparation of Carboxylate
Figure imgf000191_0001
Figure imgf000191_0001
2-아미노에탄을을 사용하는 대신에 피페리딘 -4-온 하이드로클로 라ᄋ' 를 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 172mg I 수율 75%) The title compound was prepared in the same manner as in <Example 190>, except that Piperidin-4-one hydrochlorin ' was used instead of 2-aminoethane (yield 172 mg). I yield 75%)
¾ NMR (400, CDCls) ： 7 (2H, d) , 6.84 (2H, d) , 6.06 (1H, d) , 4.16 (2H, s), 3.99-3.87 m) , 2.89 (1H, m) , 2.85 (2H, m) , 2.61-2.56 (7H, m) , 2.35 (1Η, 2.07-1.98 (3H, m) , 1.84 (2H, d) , 1:48 (9Η' s) , 1.24 (2H, m) . <실시예 273> tert-부틸 4-( (4-(4-(3- (메톡시이미노)피를리딘-¾ NMR (400, CDCls): 7 (2H, d), 6.84 (2H, d), 6.06 (1H, d), 4.16 (2H, s), 3.99-3.87 m), 2.89 (1H, m), 2.85 (2H, m), 2.61-2.56 (7H, m), 2.35 (1Η, 2.07-1.98 (3H, m), 1.84 (2H, d), 1:48 (9Η 's), 1.24 (2H, m) Example 273 tert-Butyl 4-((4- (4- (3- (methoxyimino) pyridine-)
1-카보닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 의 제조 하이드록실아민 하이드로클로라이드를 사용하는 대신에 0-메틸 하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기Preparation of 1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate Except for using 0-methyl hydroxylamine hydrochloride instead of using hydroxylamine hydrochloride,
<실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 i68mg I 수율 69%). The title compound was prepared in the same manner as the <Example 217> (yield i68 mg I yield 69%).
¾ NMR (400, CDCls) ： 7.32 (2H, d) , 6.84 (2H, d)， 6.06 (1H, d), 4.26 (2H, d) , 4.16 (2Η, s) , 3.90 (3Η, s) , 3.77 (4Η, m) , 2.86- 2.49 (8Η, m), 2.32 (1Η, m) , 2.04-1.85 (5H, m)， 1.48 (9H, s) , 1.23 (2H, m) .  ¾ NMR (400, CDCls): 7.32 (2H, d), 6.84 (2H, d), 6.06 (1H, d), 4.26 (2H, d), 4.16 (2Η, s), 3.90 (3Η, s), 3.77 (4Η, m), 2.86-2.49 (8Η, m), 2.32 (1Η, m), 2.04-1.85 (5H, m), 1.48 (9H, s), 1.23 (2H, m).
<실시예 274> l-(4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4- 일)메 -3-엔카보닐)피페리딘 -4-온의 제조 Example 274 l- (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) me-3-encarbonyl) piperidin-4-one Manufacture
Figure imgf000192_0001
Figure imgf000192_0001
L-베타ᅳ프롤리놀을 사용하는 대신에 피페리딘 -4ᅳ은 하이드로클 로라이드를 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 180mg / 수율 77%).  Instead of using L-beta ᅳ prolinol, piperidine-4-was prepared in the same manner as in Example 152 above, except that hydrochloride was used to prepare the title compound. Yield 180mg / yield 77%).
¾ 匪 R (400, CDCls) ： 8.19 (2H, s) , 7.31 (2H, d)， 6.86 (2H, d) , 6.06 (1Η, d) , 4.76 (2H, d) , 3.96-3.83 (6H, m)， 2.96-2.89 (3H, m) , 2.61-2.45 (9H, m) , 2.36 (1H, m) , 2.11-2.03 (2H, m) , 1.95 (2H, d), 1.34 (2H, m) , 1.21 (3H, t) .  ¾ 匪 R (400, CDCls): 8.19 (2H, s), 7.31 (2H, d), 6.86 (2H, d), 6.06 (1Η, d), 4.76 (2H, d), 3.96-3.83 (6H, m), 2.96-2.89 (3H, m), 2.61-2.45 (9H, m), 2.36 (1H, m), 2.11-2.03 (2H, m), 1.95 (2H, d), 1.34 (2H, m) , 1.21 (3H, t).
<실시예 275> l-(4-(4-((l-(3-이소프로필 -l,2,4-옥사디아졸-5- 일)피페리딘-4-일)메톡시 )페닐)싸이클로핵스 -3-엔카보닐 )피페리딘 -4- 온의 제조
Figure imgf000193_0001
Example 275 l- (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) Preparation of Cyclonux-3-encarbonyl) piperidin-4-ones
Figure imgf000193_0001
(R)-N,N-디메틸피를리딘 -3ᅳ아민 하이드로클로라이드를 사용하는 대신에 피페리딘 -4-온 하이드로클로과이드를 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하 였다 (수득량 184mg I 수율 77%).  In the same manner as in <Example 143>, except that piperidine-4-one hydrochloride was used instead of (R) -N, N-dimethylpyridine-3 ᅳ amine hydrochloride. The title compound was obtained (yield 184 mg I yield 77%).
XH NMR (400, CDCls) ： 7.32 (2H, d) , 6.85 (2H, d)， 6.06 ( 1H , d), 4.21 (2H, d) , 3.98-3.84 (6Η, m)， 3.14 (2H, m) , 2.90 (2Η, m) , 2.61-2.53 (7Η, m)， 2.35 (1H, m) , 2.07-1.92 (5H, m) , 1.51 (2H, m) , 1.41 (6H, d) . X H NMR (400, CDCls): 7.32 (2H, d), 6.85 (2H, d), 6.06 (1H, d), 4.21 (2H, d), 3.98-3.84 (6Η, m), 3.14 (2H, m), 2.90 (2Η, m), 2.61-2.53 (7Η, m), 2.35 (1H, m), 2.07-1.92 (5H, m), 1.51 (2H, m), 1.41 (6H, d).
<실시예 276> (4- (하이드록시이미노)피페리딘 -1-일 ) (4-(4-((1-Example 276 (4- (hydroxyimino) piperidin-1-yl) (4- (4-((1-
(3-이소프로필 -1,2， 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸 이클로핵스 -3-엔일)메타논의 제조 Preparation of (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000193_0002
Figure imgf000193_0002
1-(4-(4-((1-(3ᅳ이소프로필ᅳ1，2， 4-옥사디아졸 -5-일 )피페리딘 -4- 일)메톡시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘— 4ᅳ카복스아마이드 를 사용하는 대신에 1ᅳ(4-(4-((1— (3-이소프로필 -1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔카보닐)피페리딘 -4- 온을 사용하는 것을 제외하고， 상기 <실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 183mg I 수율 76%).  1- (4- (4-((1- (3 ᅳ isopropyl ᅳ 1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3- Encarbonyl) piperidine—1 ᅳ (4- (4-((1— (3-isopropyl-1,2,4-oxadiazole-5-yl) piperi instead of using 4 ᅳ carboxamide) The title compound was prepared in the same manner as in <Example 217>, except that din-4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) piperidin-4-one was used. (Yield 183 mg I yield 76%).
!H 丽 R (400, CDC13) ： 7.51 (1H, m)， 7.31 (2H, d)， 6.86 (2H, d) , 6.06 (1H, d), 4.51 (2H, s), 3.84 (2H, d), 3.79-3.66 (4H, m) , 3.11 (2H, m) , 2.92 (2H, m) , 2.87 (2H, m) , 2.58-2.42 (5H, m) , 2.33 (1H, m) , 2.05 (2H, m) , 1.94 (3H, m) , 1.45 (2H, m)， 1.43 (9H, s) . ! H δ R (400, CDC1 3 ): 7.51 (1H, m), 7.31 (2H, d), 6.86 (2H, d), 6.06 (1H, d), 4.51 (2H, s), 3.84 (2H, d ), 3.79-3.66 (4H, m), 3.11 (2H, m), 2.92 (2H, m), 2.87 (2H, m), 2.58-2.42 (5H, m), 2.33 (1H, m), 2.05 ( 2H, m), 1.94 (3H, m), 1.45 (2H, m), 1.43 (9H, s).
<실시예 277> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메록시 )페닐)싸이클로핵스ᅳ 3-엔일) (4- (하이드록시이미노)피페리딘 -1- 일 )메 조 Example 277 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) Meoxy) phenyl) cyclonucleosulf 3-enyl) (4- (hydroxyimino) piperidin-1-yl) mezzo
Figure imgf000194_0001
Figure imgf000194_0001
1-(4-(4-((1-(3-이소프로필— 1，2，4ᅳ옥사디아졸 -5-일 )피페리딘 -4- 일 )메록시 )페닐)싸이클로핵스 -3-엔카보닐 )피페리딘 -4-카복스아마이드 를 사용하는 대신에 1-(4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4- 일 )메톡시 )페닐 )싸이클로핵스 -3-엔카보닐 )피페리딘— 4-온을 사용하는 것을 제외하고， 상기 <실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 166mg I 수율 65%).  1- (4- (4-((1- (3-isopropyl— 1,2,4 ， oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3- 1- (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy instead of using encarbonyl) piperidine-4-carboxamide ) Phenyl) cyclonux-3-encarbonyl) piperidine— except for using 4-one, the title compound was prepared in the same manner as in <Example 217> (yield 166 mg I yield 65% ).
¾ NMR (400, CDCls) ： 8.19 (2H, s) , 8.14 (lH,d) , 7.31 (2H, d) , 6.85 (2Η, d) , 6.05 (1Η, cl), 4.76 (2:H, d), 3.84-3.70 ( 6H , m) , 2.95 (2H, m) , 2.84 (1H, m) , 2.70 (2H, m) , 2.67-2.42 (7H, m) , 2.33 (1H, m) , 2.10-1.91 (5H, m) , 1.34 (2H, m)ᅳ 1.20 (3H, t) .  ¾ NMR (400, CDCls): 8.19 (2H, s), 8.14 (lH, d), 7.31 (2H, d), 6.85 (2Η, d), 6.05 (1Η, cl), 4.76 (2: H, d ), 3.84-3.70 (6H, m), 2.95 (2H, m), 2.84 (1H, m), 2.70 (2H, m), 2.67-2.42 (7H, m), 2.33 (1H, m), 2.10- 1.91 (5H, m), 1.34 (2H, m) ᅳ 1.20 (3H, t).
<실시예 278> (4-(4-((1-(3-이소프로필-1,2,4-옥사디아졸-5-일) 피페리딘 -4-일 )메톡시：)페닐 )싸이클로핵스 -3-엔일) (4- (메톡시이미노)피 페리딘 -1-일)메타논의 제조 Example 278 (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy:) phenyl) cyclo Preparation of nuclears-3-enyl) (4- (methoxyimino) piperidin-1-yl) methanone
Figure imgf000194_0002
Figure imgf000194_0002
하이드록실아민 하이드로클로라이드를 사용하는 대신에 0-메틸 하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고 , 상기 <실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 179mg I 수율 73%).  The title compound was prepared in the same manner as in <Example 217>, except that 0-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride (yield 179 mg I yield 73%) ).
XH NMR (400， CDCls) ： 7.32 (2H, d) , 6.85 (2Η, d), 6.05 (1H, d) , 4.21 (2H, d) , 3.86 (3H, s), 3.83-3.70 (5H, m) , 3.63 (1H, m) , 3.11 (2H, m) , 2.92 (2H, m) , 2.62-2.45 (7H, m) , 2.40 (1H, m) , 2.05-1.93 (5H, m), 1.44 (2H, m) , 1.29 (6H, d) . <실시예 279> (4-(4-((l-(3-이소프로필 -1,2,4-옥사디아졸 -5-일) 피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3ᅳ엔일 ) (4- (메톡시이미노 )피 페리딘 -1- 조 X H NMR (400, CDCls): 7.32 (2H, d), 6.85 (2Η, d), 6.05 (1H, d), 4.21 (2H, d), 3.86 (3H, s), 3.83-3.70 (5H, m), 3.63 (1H, m), 3.11 (2H, m), 2.92 (2H, m), 2.62-2.45 (7H, m), 2.40 (1H, m), 2.05-1.93 (5H, m), 1.44 (2H, m), 1.29 (6H, d). Example 279 (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus -3 ᅳ enyl) (4- (methoxyimino) piperidine-1-zo
Figure imgf000195_0001
Figure imgf000195_0001
하이드록실아민 하이드로클로라이드를 사용하는 대신에 0-메틸 하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 173mg I 수율 69%).  The title compound was prepared in the same manner as in <Example 217>, except that 0-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride (yield 173 mg I yield 69%) ).
!H 匪 R (400, CDCls) ： 8.19 (2H, s) , 7.31 (2H, d)， 6.85 (2H, d) ,6.05 (1H, d) , 4.77 (2H, d) , 3.87 (3H, s) , 3.85-3.70 (5H, m) , 3.63 (1H, m) , 2.95 (2H, m) , 2.88 (IH, m) , 2.65-2.39 (9H, m)， 2.40 (1H, m) , 2.00-1.93 (5H, m) , 1.33 (2H, m) , 1.18 (3H, t). ! H 匪 R (400, CDCls): 8.19 (2H, s), 7.31 (2H, d), 6.85 (2H, d), 6.05 (1H, d), 4.77 (2H, d), 3.87 (3H, s) , 3.85-3.70 (5H, m), 3.63 (1H, m), 2.95 (2H, m), 2.88 (IH, m), 2.65-2.39 (9H, m), 2.40 (1H, m), 2.00-1.93 (5H, m), 1.33 (2H, m), 1.18 (3H, t).
<실시예 280> tert-부틸 4-((4-(4-(3-옥소아제티딘 -1-카보닐)싸 이클로 복시레이트의 제조 Example 280 Preparation of tert-Butyl 4-((4- (4- (3-oxoazetidine-1-carbonyl) cyclocarboxylate
Figure imgf000195_0002
Figure imgf000195_0002
2-아미노에탄올을 사용하는 대신에 아제티딘 -3-온 하이드로클로 라이드를 사용하는 것을 제외하고， 상기 <실시예 190>과 동일한 방법 으로 수행하여 표제 화합물을 제조하였다 (수득량 172mg I 수율 75%).  The title compound was prepared in the same manner as in <Example 190>, except for using azetidine-3-one hydrochloride instead of 2-aminoethanol (yield 172 mg I yield 75%). ).
H NMR (400， CDCls) 7.32 (2H, d) , 6.84 (2Η, d)， 6.05 ( 1H d) , 4.85 (4H, d), 4.16 (2Hᅳ s), 3.81 (2H, d) , 2.78 (2Η, t) , 2.63- 2.37 (5Η, m) , 2.10-1.82 (5Η, m)， 1.48 (9H, s) , 1.24 (2Η, m) .  H NMR (400, CDCls) 7.32 (2H, d), 6.84 (2Η, d), 6.05 (1H d), 4.85 (4H, d), 4.16 (2H ᅳ s), 3.81 (2H, d), 2.78 ( 2Η, t), 2.63- 2.37 (5Η, m), 2.10-1.82 (5Η, m), 1.48 (9H, s), 1.24 (2Η, m).
<실시예 281> tert-부틸 4-((4-(4-(3- (하이드록시이미노)아제티 딘 -1-카보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이 트의 제조
Figure imgf000196_0001
Example 281 tert-Butyl 4-((4- (4- (3- (hydroxyimino) azetidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine Preparation of 1-carboxylate
Figure imgf000196_0001
l-(4-(4-((l-(3-이소프로필 -1,2，4—옥사디아졸 -5-일 )피페리딘 -4- 일 )메톡시 )페닐)싸이클로핵스 -3-엔카보닐)피페리딘 -4-카복스아마이드 를 사용하는 대신에 tert-부틸 4-((4-(4-(3-옥소아제티딘 -1-카보닐)싸 이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트를 사용하는 것을 제외하고, 상기 <실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 167mg 7 수율 66%).  l- (4- (4-((l- (3-isopropyl-1,2,4—oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3- Instead of using encarbonyl) piperidine-4-carboxamide tert-butyl 4-((4- (4- (3-oxoazetidine-1-carbonyl) cyclonux-1-enyl Except for using phenoxy) methyl) piperidine-1-carboxylate, the title compound was prepared in the same manner as in <Example 217> (yield 167 mg 7 yield 66%).
XH NMR (400, CDCls) ： 7. '80 (ΓΗ, s )， 7 · 31 (2H , d)， 6.84 (2H, d) , 6.04 (1H, d) , 4.89 (2Η, d) , 4.74 (2Ή, d) , 4.15 (2H, s), 3.87 (2H, d) , 2.76 (2H, t) , 2.58-2.29 (5H, m) , 2.06-1.82 (6H, m)， 1.48 (9H, s), 1.27 (2H, m). X H NMR (400, CDCls) : 7. '80 (ΓΗ, s), 7 · 31 (2H, d), 6.84 (2H, d), 6.04 (1H, d), 4.89 (2Η, d), 4.74 (2Ή, d), 4.15 (2H, s), 3.87 (2H, d), 2.76 (2H, t), 2.58-2.29 (5H, m), 2.06-1.82 (6H, m), 1.48 (9H, s ), 1.27 (2H, m).
<실시예 282> tert-부틸 4-((4-(4-(3- (메록시이미노)아제티딘-Example 282 tert-butyl 4-((4- (4- (3- (methoxyimino) azetidine-)
1-카보닐 )싸이클로핵스ᅳ 1ᅳ엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 의 제조 Preparation of 1-carbonyl) cyclonuclear swab 1 ᅳ enyl) phenoxy) methyl) piperidine-1-carboxylate
Figure imgf000196_0002
Figure imgf000196_0002
하이드록실아민 하이드로클로라이드를 사용하는 대신에 0—메틸 하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기 Except that 0-methyl hydroxylamine hydrochloride is used instead of hydroxylamine hydrochloride,
<실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 175mg I 수율 73%). The title compound was prepared in the same manner as the <Example 217> (a yield 175 mg I yield 73%).
XH NMR (400， CDC13) ： 7.32 (2H, d), 6.84 (2H, d)， 6.04 (1H, d) , 4.85 (2Η, m) , 4.69 (2H, d) , 4.17 (2H, s) , 3.91 (3H, s) , 3.82 (2H, d) , 2.76 (3H, m) , 2.53-2.47 (5H, m) , 2.29 (2H, m)， 2.09-1.82 (9H, m) , 1.48 (9H, s)， 1.27 (2H, m) . X H NMR (400, CDC13): 7.32 (2H, d), 6.84 (2H, d), 6.04 (1H, d), 4.85 (2Η, m), 4.69 (2H, d), 4.17 (2H, s) , 3.91 (3H, s), 3.82 (2H, d), 2.76 (3H, m), 2.53-2.47 (5H, m), 2.29 (2H, m), 2.09-1.82 (9H, m), 1.48 (9H , s), 1.27 (2H, m).
<실사예 283> l-(4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4- 일)메록시)페닐)싸이클로핵스 -3-엔카보닐)아제티딘ᅳ 3-은의 제조 <Example 283> l- (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) ase Preparation of Tidinjan 3-Silver
Figure imgf000197_0001
Figure imgf000197_0001
L-베타 -프롤리놀을 사용하는 대신에 아제티딘 -3-온 하이드로클 로라이드를 사용하는 것을 제외하고， 상기 <실시예 152>와 동일한 방 법으로 수행하여 표제 화합물을 제조하였다 (수득량 175mg I 수율 77%) The title compound was prepared in the same manner as in <Example 152>, except that azetidine-3-one hydrochloride was used instead of L-beta-prolinol (yield yield). 175mg I yield 77%)
!H NMR (400, CDC13) :8.19 (2H, s), 7.32 (2H, d) , 6.85 (2H, d) , 6.05 (1H, d), 5.02-4.76 (2H, m) , 3.85 (2H, d) , 2.95 (2H, m) , 2.63-2.59 (3H, m) , 2.58-2.48 (3H, m) , 2.36 (1Ή, m) , 2.11-2.06 (2H m) , 1.98-1.91 (3H, m) , 1.34 (2H, m)， 1.20 (3H, t) . ! H NMR (400, CDC13): 8.19 (2H, s), 7.32 (2H, d), 6.85 (2H, d), 6.05 (1H, d), 5.02-4.76 (2H, m), 3.85 (2H, d ), 2.95 (2H, m), 2.63-2.59 (3H, m), 2.58-2.48 (3H, m), 2.36 (1Ή, m), 2.11-2.06 (2H m), 1.98-1.91 (3H, m) , 1.34 (2H, m), 1.20 (3H, t).
<실시예 284> 1-(4-(4-((1-(3-이소프로필-1，2,4-옥사디아졸一5- 일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로훽스 -3-엔카보닐 )아제티딘 -3- 온의 제조 - Example 284 1- (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-1-5-yl) piperidin-4-yl) methoxy) phenyl) Preparation of Cyclox-3-encarbonyl) azetidin-3-one-
Figure imgf000197_0002
Figure imgf000197_0002
(R)-N,N-디메틸피를리딘 -3-아민 하이드로클로라이드를 사용하는 대신에 아제티딘ᅳ 3-온 하이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 143>과 동일한 방법으로 수행하여 표제 화합물을 제조하 였다 (수득량 180nig I 수을 75%).  Except for using azetidin- 3-one hydrochloride instead of (R) -N, N-dimethylpyridin-3-amine hydrochloride, it was carried out in the same manner as in <Example 143> The title compound was prepared (yield 180nig I number 75%).
JH NMR (400， CDCls) ： 7.32 (2H, d)， 6.85 (2H, d)， 6.06 (1H, d) , 4.88 (2H, s) , 4. 83 (2Η, s) , 4.21 (2Η, d) , 3.84 (2Η, d) , 3.12 (2Η, m) , 2.92 (1Η, m)， 2.63-2.53 (4H, m) , 2.38 (1H, m) , 2.07 (2H, m) , 1.97-2.91 (3H, m) , 1.44 (2H, m) , 1.41 (9H, d) . J H NMR (400, CDCls): 7.32 (2H, d), 6.85 (2H, d), 6.06 (1H, d), 4.88 (2H, s), 4. 83 (2Η, s), 4.21 (2Η, d), 3.84 (2Η, d), 3.12 (2Η, m), 2.92 (1Η, m), 2.63-2.53 (4H, m), 2.38 (1H, m), 2.07 (2H, m), 1.97-2.91 (3H, m), 1.44 (2H, m), 1.41 (9H, d).
<실시예 285> (3- (하이드톡시이미노)아제티딘 -1-일 ) (4-(4-((l-Example 285 (3- (hydroxyimino) azetidin-1-yl) (4- (4-((l-
(3-이소프로필 -1，2，4—옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸 이클로핵스 -3-엔일 )메타논의 제조 Preparation of (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
1-(4-(4-((1ᅳ(3-이소프로필-1，2，4-옥사디아졸 -5-일 )피페리딘 -4- 일)메톡시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘 -4-카복스아마이드 를 사용하는 대신에 1ᅳ(4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5- 일 )파페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카보닐)아제티딘 -3- 온을 사용하는 것을 제외하고， 상기 <실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 184mg I 수율 78%). 1- (4- (4-((1 ᅳ (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3- 1 ᅳ (4- (4-((1- (3-isopropyl-1,2,4-oxadiazole-5-yl) wave instead of using encarbonyl) piperidine-4-carboxamide The title compound was prepared in the same manner as in <Example 217>, except that ferridin-4-yl) methoxy) phenyl) cyclonux-3-encarbonyl) azetidin-3-one was used. (Yield 184 mg I Yield 78%).
XH NMR (400, CDCI3) ： 8.11 (1H, s) , 7.32 (2H, d) , 6.84 (2H, d) , 6.04 (1Η, d) , 4.87 (2H, d)， 4.75 (2H, d) , 4.21 (2H, d) , 3.84 (2H, d) , 3.11 (2H, m) , 2.93 (1H, m)， 2.58-2.42 (.4Ή, m) , 2.30 (1H, m), 2.09-2.02 (2Hᅳ m) , 1.97-1.89 (3H, m) , 1.43 (2H, m) , 1.30(6H, d). X H NMR (400, CDCI3): 8.11 (1H, s), 7.32 (2H, d), 6.84 (2H, d), 6.04 (1Η, d), 4.87 (2H, d), 4.75 (2H, d) , 4.21 (2H, d), 3.84 (2H, d), 3.11 (2H, m), 2.93 (1H, m), 2.58-2.42 (.4Ή, m), 2.30 (1H, m), 2.09-2.02 ( 2H ᅳ m), 1.97-1.89 (3H, m), 1.43 (2H, m), 1.30 (6H, d).
<실시예 286> (4-(4-((1-(3-이소프로필-1，2,4-옥사디아졸-5-일) 피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔일 ) (3- (메록시이미노)아 제티딘 - Example 286 (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus -3-enyl) (3- (methoxyimino) azetidine-
Figure imgf000198_0001
Figure imgf000198_0001
하이드록실아민 하이드로클로라이드를 사용하는 대신에 0-메틸 하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기 <실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 제조하였다 (수득량 178mg I 수율 71%) .  The title compound was prepared in the same manner as in <Example 217>, except that 0-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride (yield 178 mg I yield 71% .
:H 匪 R (400， CDCls) ： 7.32 (2H, d) , 6.84 (2H, d)， 4.85 (2H, m), 4.69 (2H, m)， 4.21 (2H, d)， 3.96 (3H, s), 3.84 (2H, d) , 3.11 (2H, m) , 2.89 (ΊΗ, m) , 2.59-5.47 (4Η, m) , 2.29 (1Η, m) , 2.07-1.89 (5H, m), 1.46 (2H, m) , 1.36 (6H, d) . <실시예 287> (4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메록시 )페닐)싸이클로핵스 -3-엔일) (3- (메톡시이미노)아제티딘 -1-일 )메 타논의 조 : H 匪 R (400, CDCls): 7.32 (2H, d), 6.84 (2H, d), 4.85 (2H, m), 4.69 (2H, m), 4.21 (2H, d), 3.96 (3H, s ), 3.84 (2H, d), 3.11 (2H, m), 2.89 (ΊΗ, m), 2.59-5.47 (4Η, m), 2.29 (1Η, m), 2.07-1.89 (5H, m), 1.46 ( 2H, m), 1.36 (6H, d). Example 287 (4- (4-((l- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (3- ( Methoxyimino) azetidin-1-yl) methanone
Figure imgf000199_0001
Figure imgf000199_0001
하이드록실아민 하이드로클로라이드를 사용하는 대신에 0-메틸 하이드록실아민 하이드로클로라이드를 사용하는 것을 제외하고， 상기 Except for using 0-methyl hydroxylamine hydrochloride instead of using hydroxylamine hydrochloride,
<실시예 217>과 동일한 방법으로 수행하여 표제 화합물을 체조하였다 (수득량 177mg I 수율 73%). The title compound was obtained in the same manner as in <Example 217> (yield 177 mg I yield 73%).
^ NMR (400, CDGls) ： 8.20 (2H,s) , 7.29 (2H, d) , 6.85 (2Η, d) , 6.04 (1H, d) , 4.85 (2H, s) , 4.79 (2Ή, d) , 4.72 (2H, d) , 3.96 (3H, s) , 3.84 (2H, d)， 2.92 (2H, m) , 2.55-2. 1 (6H, 'rti), 2.28 (1H, m) , 2.14-1.92 (5H, m) , 1.39 (2H, m) , 1.20 (3H, t) . .  ^ NMR (400, CDGls): 8.20 (2H, s), 7.29 (2H, d), 6.85 (2Η, d), 6.04 (1H, d), 4.85 (2H, s), 4.79 (2Ή, d), 4.72 (2H, d), 3.96 (3H, s), 3.84 (2H, d), 2.92 (2H, m), 2.55-2. 1 (6H, 'rti), 2.28 (1H, m), 2.14-1.92 (5H, m), 1.39 (2H, m), 1.20 (3H, t). .
<실시예 288> tert-부틸 4-((4-(4-(3-하이드록시아제티딘 -1-카 보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트의 제 조 Example 288 tert-Butyl 4-((4- (4- (3-hydroxyazetidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate Article of
Figure imgf000199_0002
Figure imgf000199_0002
1000 mL 플라스크에 tert-부틸 4-( (4— (4-(3-옥소아제티딘 -1-카 보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 470 mg을 THF 100 mL 에 교반하여 질소 하에 용해사켰다. 온도를 5°C로 넁 각한 후， 소듐보로하이드라아드(30< 111)01"01 (11"1(^) 80 mg 을 천천히 적가하고， 5분 동안 교반하였다. 반웅 종결 후 , 증류수 300 mL를 천천 히 가하고 에틸 아세테이트 500 mL로 추출한 후， 브라인 100 mL로 세 척하고， 무수황산마그네슘으로 건조한 후， 농축하고， 실리카 컬럼 크 로마토그래피로 분리하여 표제 화합물을 제조하였다 (수득량 432mg / 수율 71%). Tert-butyl 4- ((4— (4- (4- (3-oxoazetidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate in a 1000 mL flask 470 The mg was stirred in 100 mL of THF and dissolved in nitrogen. After cooling to 5 ° C., sodium borohydride (30 <111) 01 "01 (11" 1 (^) 80 mg was slowly added dropwise and stirred for 5 minutes. After completion of reaction, distilled water 300 mL was slowly added, extracted with 500 mL of ethyl acetate, washed with 100 mL of brine, dried over anhydrous magnesium sulfate, concentrated and separated by silica column chromatography to obtain the title compound (yield 432 mg / Yield 71%).
¾ NMR (400, CDC13) '· 7.30 (2H, d)， 6.84 (2H, d) , 6.03 ( 1Η , d), 4.71 (1H, m) , 4.42 (1H, t) , 4.28-4.07 (4H, m) , 3.92 (1H, dd) , 3.81 (2H, d) , 2.76 (2H, t) , 2.63 (1H, d)， 2.52-2.43 (4H, m) , 2.27 (1H, m) , 2.01-1.82 (5H, m) , 1.48 (9H, s), 1.26 (2H, m) . ¾ NMR (400, CDC1 3 ) ' 7.30 (2H, d), 6.84 (2H, d), 6.03 (1Η, d), 4.71 (1H, m), 4.42 (1H, t), 4.28-4.07 (4H , m), 3.92 (1H, dd), 3.81 (2H, d), 2.76 (2H, t), 2.63 (1H, d), 2.52-2.43 (4H, m), 2.27 (1H, m), 2.01-1.82 (5H, m), 1.48 (9H, s), 1.26 (2H, m).
<실시예 289> (3-하이드록시아제티딘 -1-일) (4-(4-((l-(3-이소프 로필 -1,2,4-옥사디아졸 -5ᅳ일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타논의 제조 Example 289 (3-Hydroxyazetidin-1-yl) (4- (4-((l- (3-isopropyl-1,2,4-oxadiazole-5xyl) piperidine) Preparation of 4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone
Figure imgf000200_0001
Figure imgf000200_0001
tert-부틸 4-((4-(4-(3-옥소아제티딘 -1-카보닐 )싸이클로핵스 -1- 엔일)페녹시 )메틸)피페리딘 -1-카복시레이트를 사용하는 대신에 1-(4- (4ᅳ((1-(3-이소프로필 _1，2，4-옥사디아졸ᅳ 5-일)피페리딘 -4-일)메특시 ) 페닐)싸이클로핵스 -3ᅳ엔카보닐)아제티던ᅳ3-은을 사용하는 것을 제외하 고， 상기 <실시예 288>과 동일한 방법으로 수행하여 표제 화합물을 제 조하였다 (수득량 402mg / 수율 66%).  Instead of using tert-butyl 4-((4- (4- (3-oxoazetidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate 1- (4- (4 ᅳ ((1- (3-isopropyl _1,2,4-oxadiazol ᅳ 5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3sene Except for using carbonyl) azetidon3-3-silver, the title compound was prepared in the same manner as the <Example 288> (yield 402 mg / yield 66%).
!H NMR (400, CDCls) ： 7.30 (2H, d) , 6.84 (2H, d)ᅳ 6.04 (1H, d) , 4.70 (1Η, m) , 4.43 (1H, t) , 4.30 (1H, dd) , 4.23 (2H, d)， 4.09 (1H, m), 3.92 (1H, dd) , 3.84 (2H, m) , 3.14 (2H, m) , 2.97 (2H, d) , 2.88 (1H, m), 2.55 ( 1H , m) , 2.53-2.43 (3H, m) , 2.27 (1H, m) , 2.07-2.02 (1H, m) , 1.94 (3H, m)， 1.84 (1H m)， 1.44 (2H, m)， 1.31 (6H, d). ! H NMR (400, CDCls): 7.30 (2H, d), 6.84 (2H, d) ᅳ 6.04 (1H, d), 4.70 (1Η, m), 4.43 (1H, t), 4.30 (1H, dd), 4.23 (2H, d), 4.09 (1H, m), 3.92 (1H, dd), 3.84 (2H, m), 3.14 (2H, m), 2.97 (2H, d), 2.88 (1H, m), 2.55 (1H, m), 2.53-2.43 (3H, m), 2.27 (1H, m), 2.07-2.02 (1H, m), 1.94 (3H, m), 1.84 (1H m), 1.44 (2H, m) , 1.31 (6H, d).
<비교예 1> Λ 2-플루오로 -4-메틸설포닐페닐) -5-나이트로 -6-[4-Comparative Example 1 Λ 2-Fluoro-4-methylsulfonylphenyl) -5-nitro-6- [4-
(3-프로판 -2-일— 1，2，4-옥사디아졸 -5-일)피페리딘 -1-일]피리미딘 -4-아 민 제조 (3-Propan-2-yl— 1,2,4-oxadiazol-5-yl) piperidin-1-yl] pyrimidine-4-amine
Figure imgf000200_0002
Figure imgf000200_0002
Λ 2-플루오로 -4-메틸설포닐페닐 ) 5-나이트로 -6-[4-(3ᅳ프로판- 2-일 -1 , 2， 4-옥사디아졸ᅳ5-일 )피페리딘 -1-일 ]피리미딘 -4-아민은 국제공 개특허 제 TO 2004/065380호에 공지된 방법으로 제조하였다. 비교예 2> 2-(4-메탄설포닐페닐) -5-({1-[3- (프로판 -2-일) - 1,2 ,4- -5-일]피페리딘 -4-일}메록시 )피리딘의 Λ 2-Fluoro-4-methylsulfonylphenyl) 5-nitro-6- [4- (3'propane- 2-yl-1,2,4-oxadiazol ᅳ 5-yl) piperidine- 1-yl] pyrimidin-4-amine was prepared by a method known from WO 2004/065380. Comparative Example 2> 2- (4-methanesulfonylphenyl) -5-({1- [3- (propane-2-yl)- 1,2,4--5-yl] piperidin-4-yl} methoxy) pyridine
Figure imgf000201_0001
Figure imgf000201_0001
2-(4-메탄설포닐페닐 )-5-({1-[3- (프로판 -2ᅳ일 )-1，2，4-옥사디아 졸 -5-일]피페리딘 -4-일}메록시 )피리딘은 국제공개특허 제 W0 2008/070692호에 공지된 방법으로 제조하였다.  2- (4-methanesulfonylphenyl) -5-({1- [3- (propane-2xyl) -1,2,4-oxadiazol-5-yl] piperidin-4-yl} meth Roxy) pyridine was prepared by a method known from WO 2008/070692.
：비교예 3> 메트포민 (Met form in)의 제조
Figure imgf000201_0002
Comparative Example 3 Preparation of Metformin
Figure imgf000201_0002
메트포민 (Metformin)은 국제공개특허 제 W0 2010/146604 A2호에 공지된 방법으로 제조하였다. tramine)의  Metformin was prepared by a method known from WO 2010/146604 A2. tramine
Figure imgf000201_0003
Figure imgf000201_0003
시부트라민 (Sibutramine)은 국제공개특허 제 W0 2002/083631 A1 호에 공지된 방법으로 제조하였다.  Sibutramine was prepared by a method known from WO 2002/083631 A1.
<비교예 5> 포스콜린 (Forskolin)의 제조 Comparative Example 5 Preparation of Forskolin
Figure imgf000202_0001
Figure imgf000202_0001
포스콜린 (Forskolin)은 국제공개특허 제 1991/017154 A1호에 지된 방법으로 제조하였다. 하기 표 1에 실시예 1-28 조한 화합물의 화학구조식을 정리하여 나타내었으며， -BQC는
Figure imgf000202_0002
. Forskolin was prepared by the method described in WO 1991/017154 A1. In Table 1 below, the chemical structural formulas of the prepared compounds of Examples 1-28 are summarized, and -B QC is
Figure imgf000202_0002
.
【표 1】 Table 1
Figure imgf000202_0003
Figure imgf000203_0001
Figure imgf000203_0002
60C.9l/ST0Z OAV
Figure imgf000204_0001
Figure imgf000202_0003
Figure imgf000203_0001
Figure imgf000203_0002
60C.9l / ST0Z OAV
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000205_0001
60C.9T/ST01 OAV
Figure imgf000206_0002
Figure imgf000206_0001
60C.9T / ST01 OAV
Figure imgf000206_0002
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000207_0001
60C.9T/ST01 OAV
Figure imgf000208_0001
60C.9T / ST01 OAV
Figure imgf000208_0001
90Z  90Z
60C.9l/ST0Z OAV 207 60C.9l / ST0Z OAV 207
Figure imgf000209_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000210_0001
60C/.91/S10Z ΟΛ\
Figure imgf000211_0001
60C / .91 / S10Z ΟΛ \
Figure imgf000211_0001
60Z 60Z
60CZ.91/S10Z OAV
Figure imgf000212_0001
60CZ.91 / S10Z OAV
Figure imgf000212_0001
60C.9l/ST0Z OAV 6S0//SS2M1:2/ 60ε/-9ϊ£ϊο OίAV 60C.9l / ST0Z OAV 6 S 0 // S S2M1 : 2 / 60ε / -9ϊ £ ϊο OίAV
Figure imgf000214_0001
Figure imgf000214_0001
^ttOO/SlOZHM/13d 60£.9l/≤lOZ OW
Figure imgf000215_0001
^ ttOO / SlOZHM / 13d 60 £ .9l / ≤lOZ OW
Figure imgf000215_0001
Figure imgf000216_0001
nz
Figure imgf000216_0001
nz
60C.9l/ST0Z OAV 60C.9l / ST0Z OAV
Figure imgf000217_0001
Figure imgf000217_0001
60C.9l/ST0Z OAV 60C.9l / ST0Z OAV
Figure imgf000218_0001
Figure imgf000218_0001
91Ζ  91Ζ
60fZ,9T/ST0Z OAV
Figure imgf000219_0001
60fZ, 9T / ST0Z OAV
Figure imgf000219_0001
LIZ  LIZ
60C.9l/ST0Z OAV 60C.9l / ST0Z OAV
Figure imgf000220_0001
Figure imgf000220_0001
21Z21Z
^7l700/SlOZaM/X3d 60C.9l/ST0Z OAV OAV/SSNP 60:/1£/2MSSS06 ^ 7 l 7 00 / SlOZaM / X3d 60C.9l / ST0Z OAV OAV / SSNP 60 : / 1 £ / 2M S SS 06
Figure imgf000221_0001
Figure imgf000221_0001
다성처베이 Daseong Chubei
자트화타음리 극를세날하에
Figure imgf000222_0001
Under the jaws
Figure imgf000222_0001
<실험예 1> cAMP 활성 평가 Experimental Example 1 cAMP Activity Evaluation
본 발명에 따른 싸이클로 핵센 유도체들의 cAMP Cyclic adenosine monophosphate) 활성화를 확인하기 위하여 하기와 같은 실 험을 수행하였다. 구체적으로 , GPR-119(G protein-coupled receptor 119)의 으로 인한 세포 내 cAMP(Cycl ic adenosine monophosphate) 활 측정하기 위하여， GPR-119를 함유하고 있는 햄스터에서 유래된 포인 HIT-T15 세포 (한국세포주은행 )를 사용하였다. 96-웰 플레 웰 당 60 ,000개의 HIT-T15 세포를 플레이팅하였다. 플레이팅한 상기 세포를， 다양한 농도의 본 발명에 따른 실시예 화합물을  In order to confirm the activation of cAMP Cyclic adenosine monophosphate) of the cyclohexene derivatives according to the present invention, the following experiment was performed. Specifically, to measure intracellular cAMP (Cycl ic adenosine monophosphate) activity caused by G protein-coupled receptor 119 (GPR-119), a HIT-T15 cell derived from a hamster containing GPR-119 (Korea cell line Bank). 60,000 HIT-T15 cells were plated per 96-well wells. Plated the cells, various concentrations of the example compounds according to the invention
고 1시간 동안 37°C에서 배양하였다. 이때， 처리되는 화합물은 0.0032 내지 10 μ M의 범위에서 6가지의 농도로 처리하였다. cAMP(Cyc 1 i c adenosine monophosphate) 활성은 Ci s Bio(Bedf ord MA)로부터의 cAMP 다이나믹 키트를 사용하여 제조자의 지시에 따라 측 정하였다. 세포를 용해하고 D2 표지된 cAMP 및 크립테이트 표지된 항 cAMP 항체를 사용하여 경쟁적 면역분석법에 의해 cAMP 수준을 측정하 였다. 형광은 플렉스 스테이션 (Flex Station, Molecular Devices)으로 판독하였다. D2와 크립테이트는 매우 근접했을 때 형광공명에너지전이 (FRET)를 나타냈으며， 665 nm/620 鍾의 형광비로 측정하였다. 세포 용 해물 내의 미표지된 cAMP는 크립테이트 표지된 항체에 대하여 D2 표지 된 cAMP와 경쟁하였다. 측정된 형광공명에너지전이 (FRET) 신호감소는 세포 내 cAMP 수준을 나타내므로， 화합물의 활성을 다이메틸설폭사이 드 (DMS0)의 양 조절을 통한 형광공명에너지전이 (FRET) 신호변화 정도 로 계산하였다. 계산된 EC50값을 하기 표 2에 나타내었다. Incubated at 37 ° C for 1 h. At this time, the treated compound is 0.0032 Six concentrations were treated in the range of from 10 μM. Cyc 1 ic adenosine monophosphate (cAMP) activity was measured according to the manufacturer's instructions using a cAMP dynamic kit from Ci s Bio (Bedf ord MA). Cells were lysed and cAMP levels were measured by competitive immunoassay using D2 labeled cAMP and cryptate labeled anti cAMP antibodies. Fluorescence was read by Flex Station (Molecular Devices). D2 and cryptate showed fluorescence resonance energy transfer (FRET) when very close, and were measured at a fluorescence ratio of 665 nm / 620 kV. Unlabeled cAMP in cell lysates competed with D2 labeled cAMP for cryptate labeled antibodies. Since the measured fluorescence resonance energy transduction (FRET) signal decrease represents the intracellular cAMP level, the activity of the compound was calculated as the degree of fluorescence resonance energy transfer (FRET) signal change by controlling the amount of dimethyl sulfoxide (DMS0). . The calculated EC 50 values are shown in Table 2 below.
【표 2】  Table 2
실시예 EC50 (nM) 실시예 EC50 (nM) Example EC 50 (nM) Example EC 50 (nM)
1 65 111 1500  1 65 111 1500
2 40 112 70  2 40 112 70
3 34 ' 113 68 3 34 '' 113 68
4 150 114 14  4 150 114 14
5 29 115 15  5 29 115 15
6 38 116 28  6 38 116 28
7 13 117 11  7 13 117 11
8 90 118 31  8 90 118 31
9 75 119 6.8  9 75 119 6.8
10 500 120 80  10 500 120 80
11 110 121 500  11 110 121 500
12 80 122 130  12 80 122 130
13 13 123 35  13 13 123 35
14 650 124 100  14 650 124 100
15 370 125 70  15 370 125 70
16 13 126 130  16 13 126 130
17 85 127 83  17 85 127 83
18 170 128 200  18 170 128 200
19 110 129 140  19 110 129 140
20 90 130 90  20 90 130 90
21 16 131 150  21 16 131 150
22 41 132 210  22 41 132 210
23 160 133 400
Figure imgf000224_0001
23 160 133 400
Figure imgf000224_0001
Figure imgf000225_0001
^7l700/SlOZaM/X3d 60C.9T/S10Z OAV
Figure imgf000225_0001
^ 7 l 7 00 / SlOZaM / X3d 60C.9T / S10Z OAV
Figure imgf000226_0001
Figure imgf000226_0001
½2  ½2
OO/SIOZaM/I d 60C.9l/ST0Z ΟΛ\ 상기 표 2에 나타낸 바와 같이， 본 발명에 따른 화합물들은 매우 낮 은 농도에서 cAMP를 활성화하는 것으로 나타났다 . 본 발명에 따른 화 합물 중 대부분의 화합물들은 200nM 이하의 EC50값을 갖는 것으로 나 타났으며， 보다 구체적으로는， 실시예 2， 3, 5-7， 13， 16， 21， 22, 34， 35, 44, 45， 48, 49， 53. 54, 56—58， 60, 61, 64-66, 69-74, 76, 77, 79, 81, 82， 84， 85， 89-91, 93, 95-98, 105-107, 114-119, 123, 135， 147-150, 152, 158-169, 172， 173, 175, 177, 181—183， 186， 195, 197， 199， 200, 202-204, 213, 217， 220, 223-229, 235， 236, 239， 242, 243, 247, 250-254, 256-259, 262-279, 286 및 289의 화합물들이 50nM 이하의 우수한 EC50값을 가지는 것으로 나타났다. 이로부터， 본 발명 에 따른 싸이클로 핵센 유도체는 GPRᅳ 119 수용체를 자극함으로써， cAMP를 활성화하는 효과가 우수한 것을 알 수 있다 . 따라서， 본 발명에 따른 싸이클로 핵센 유도체는 cAMP를 활성화 시키는 효과가 우수하므로, GPR-119를 활성화시킴으로써 비만， I형 당 뇨병， II형 당뇨병， 부적합한 내당증 , 인슐린 내성증， 고혈당증, 고지 질혈증， 고중성지방혈증， 고콜레스테를혈증， 이상지질혈증， X 증후군 등과 같은 대사성 질환의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다. OO / SIOZaM / I d 60C.9l / ST0Z ΟΛ \ As shown in Table 2, the compounds according to the present invention were found to activate cAMP at very low concentrations. Most of the compounds in the compounds according to the invention have been shown to have an EC 50 value of 200 nM or less, more specifically, Examples 2, 3, 5-7, 13, 16, 21, 22, 34, 35 , 44, 45, 48, 49, 53. 54, 56—58, 60, 61, 64-66, 69-74, 76, 77, 79, 81, 82, 84, 85, 89-91, 93, 95 -98, 105-107, 114-119, 123, 135, 147-150, 152, 158-169, 172, 173, 175, 177, 181—183, 186, 195, 197, 199, 200, 202-204 , 213, 217, 220, 223-229, 235, 236, 239, 242, 243, 247, 250-254, 256-259, 262-279, 286 and 289 have good EC 50 values below 50 nM Appeared. From this, it can be seen that the cyclohexene derivative according to the present invention has an excellent effect of activating cAMP by stimulating the GPR ᅳ 119 receptor. Therefore, the cyclohexene derivative according to the present invention has an excellent effect of activating cAMP, and by activating GPR-119, obesity, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, It can be usefully used as a pharmaceutical composition for the prevention or treatment of metabolic diseases such as hypertriglyceridemia, hypercholesterolemia, dyslipidemia, X syndrome and the like.
<실험예 2> 경구 당 부하 검사 (Oral Glucose Tolerance Test；Experimental Example 2 Oral Glucose Tolerance Test (Oral Glucose Tolerance Test;
OGTT) OGTT)
본 발명에 따른 싸이클로 핵센 유도체들의 생.체 내의 유효효과 를 평가하기 위하여 하기와 같은 실험을 수행하였다. 구체적으로 , 8 내지 10 주령의 수컷 고지방식 모델인 C57BL/6J(C57 black 6) 랫트를 이용하여 최소 7일간의 순화기간을 가 진 후에 건강한 개체만을 이용하여 경구 당 부하 검사를 수행하였다. 12-15시간 동안 절식시킨 후에 각 군당 5마리씩 무작위로 군 분리하고 , 본 발명에 따른 실시예 1， 14, 48, 69, 80， 118, 139, 147， 148， 169, 190, 199， 200, 204, 227， 277, 비교예 1 및 비교예 2의 화합물을 각 각 20 mg/kg 용량으로 투여하였다. 이때， 무처리군으로 부형제 (0.5%, Carboxy메틸 Celluluse, CMC)를 투여하였으며， 부형제와 함께 투여된 화합물의 투여량은 10 ml/kg으로 경구 투여하였다. 투여한 지 30분 후 에， 글루코스 (2 g/kg)를 10 ml/kg의 용량으로 경구 투여하였다. 혈당 은 아큐책 액티브 (Rosche diagnostic Co.)를 이용하여 측정하였으며， 측정시간은 글루코스를 투여한 시간을 기준으로 -30, 0， 20, 40, 60 및 120분에 미정맥을 천자하여 측정하였다. 그 결과를 하기 표 3에 나 타내었다.  In order to evaluate the effective effects in the living organisms of the cyclohexene derivatives according to the present invention, the following experiment was performed. Specifically, the oral glucose tolerance test was performed using only healthy subjects after at least 7 days of acclimation using C57BL / 6J (C57 black 6) rats, a male high-fat diet model of 8 to 10 weeks of age. After fasting for 12-15 hours, five dogs were randomly separated from each group, and Examples 1, 14, 48, 69, 80, 118, 139, 147, 148, 169, 190, 199, 200, The compounds of 204, 227, 277, Comparative Example 1 and Comparative Example 2 were administered at 20 mg / kg doses, respectively. At this time, the excipient (0.5%, Carboxymethyl Celluluse, CMC) was administered to the untreated group, the dose of the compound administered with the excipient was orally administered at 10 ml / kg. Thirty minutes after administration, glucose (2 g / kg) was orally administered at a dose of 10 ml / kg. Blood glucose was measured using Accusek Active Co., Ltd. (Rosche diagnostic Co.) and measurement time was measured by puncture of the microvenous veins at -30, 0, 20, 40, 60 and 120 minutes based on the time of glucose administration. The results are shown in Table 3 below.
5 【표 3】 5 Table 3
Figure imgf000228_0001
Figure imgf000228_0001
상기 표 3에서 , In Table 3 above,
AUC(Area Und e r t he c urve )는 혈당강하 정도를 나타낸다 상기 표 3에 나타낼 바와 같이 본 발명에 따른 ^성예 화합물 들은 무처리군 대비 평균 20.0%의 혈당강하 효과를 가지며 생체 내 유 효 효과가 우수한 것을 알 수 있다. 보다 구체적으로， 종래에 GPR-119 단백질 활성화제로 알려져 있는 비교예 1의 경우 13.5%, 비교예 2의 경우 15.3%의 혈당강하 효과가 있는 것으로 확인되지만， 본 발명에 따 른 실시예 화합물은 이보다 현저히 우수한 혈당강하 효과 (19.1% 이상) 가 있는 것으로 나타났다. - 따라서 , 본 발명에 따른 싸이클로 핵센 유도체는 GPR-119 단백 질을 활성시키는 효과가 뛰어나 이로 인한 인슐린 분비 촉진 효과가 우수하여 혈당강하 효과가 상당히 뛰어나므로 이를 유효성분으로 함유 하는 약학적 조성물은 비만， I 형 당뇨병， Π형 당뇨병 , 부적합한 내 당증， 인슐린 내성증, 고혈당증， 고지질혈증， 고중성지방혈증， 고콜레 스테를혈증， 이상지질혈증, X 증후군 등의 대사성 질환의 치료용 약학 적 조성물로 유용하게 사용될 수 있다.  AUC (Area Und hector urve) indicates the degree of hypoglycemic activity As shown in Table 3 above, the ^ star compounds according to the present invention have an average hypoglycemic effect of 20.0% compared to the untreated group and have an excellent in vivo effective effect. It can be seen that. More specifically, it was confirmed that the blood glucose lowering effect of 13.5% for Comparative Example 1 and 15.3% for Comparative Example 2, which is conventionally known as a GPR-119 protein activator, but the example compound according to the present invention is more remarkably. It has been shown to have an excellent hypoglycemic effect (more than 19.1%). Therefore, the cyclohexene derivative according to the present invention has an excellent effect of activating the GPR-119 protein, and thus an excellent effect of promoting insulin secretion, and thus has an excellent effect on lowering blood sugar, so that the pharmaceutical composition containing the same as an active ingredient is obese, It is a pharmaceutical composition for the treatment of metabolic diseases such as type I diabetes, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, X syndrome. It can be usefully used.
<실험예 3> DIOCDiet-induced obesity) 모델을 통한 체중감소 및 혈당강하 동시 효과 평가 본 발명에 따른 싸이클로 핵센 유도체의 체중감소 및 혈당강하 동시 효과를 평가하기 위하여 하기와 같은 실험을 수행하였다. 구체적으로， 약 4주령의 식이성 비만 모델 (diet-induced obesity)인 수컷 SD 랫트 (Sprague Dawley rat)에 약 10주간의 고지방 식이 (Lab. Diet co.)의 급여를 통해 고지방 식이 비만 랫트 모델 (diet-induced obesity, DI0)을 유도하였다. 고지방 식이를 거친 랫트 들 중 무작위로 선별하여 각각의 투여를 위한 군 분리 (n=8)를 실시하 였다. 군 분리가 완료된 DI0 랫트들에 각 군별로 비교예 3， 4 및 실 시예 48， 119를 4주간 투여하였다. Experimental Example 3 Evaluation of Simultaneous Weight Loss and Glucose Dropping Using DIOCDiet-induced Obesity Model In order to evaluate the simultaneous weight loss and hypoglycemic effect of the cyclohexene derivatives according to the present invention, the following experiment was performed. Specifically, high-fat dietary obese rats were fed a diet of obese rats (diet-induced obesity) of about 4 weeks in a 10-week diet of high-fat diet (Lab. Diet co.) To male SD rats (Sprague Dawley rats). diet-induced obesity (DI0) was induced. Randomly selected rats from the high fat diet were subjected to group separation (n = 8) for each administration. The group separated DI0 rats were administered Comparative Examples 3, 4 and Examples 48, 119 for 4 weeks in each group.
4주간의 투여 기간 중 1주 2회의 체중 측정을 수행하여 체중 변 화추이를 기록하였으며， 그 결과를 도 1에 나타내었고， 4주간의 투여 가 종료되는 시점에 0GTT(oral glucose tolerance test)를 통한 혈당 강하 효과를 하기의 방법으로 평가하였다. The weight change was recorded twice a week during the four-week administration period, and the results were shown in FIG. 1. The results are shown in FIG. 1, and at the end of the four-week administration, the 0 GTT (oral glucose tolerance test) was used. The hypoglycemic effect was evaluated by the following method.
구체적으로， 비교예 3(300 mg/kg) 및 실시예 48， 실시예 119(10 20， 50 mg/kg)의 화합물을 투여 30분 후， 글루코스 2 g/kg을 경구 투 여하였다. 혈당은 Accu-c'he-k active str ip(Roche diagnostic Co.)를 이용하여 측정하였으며 , 측정시간은 글루코스 투여 시기를 기준으로 하여 -30， 0, 20， 40， 60 및 120분에 미정맥을 천자하여 각각 측정하 였다. 각 시점의 혈당값을 근거로 한 결과의 각 군별 AUC(%)(area under curve)값을 산출하여 혈당강하 효능 여부를 평가하였으며 , 그 결과를 도 2(A) 및 도 2CB ᅵ 나타내었다. [도 2(A) ： 실시예 48， 도 2(B) ： 실시예 119]· 도 1은 본 발명에 따른 실시예 48 및 비교예 3, 4의 화합물을 DIO(Diet-induced obesity) 랫트 모델에 4추간 투여하며 체중변화를 측정한 그래프이다 (도 1에서 "무처리군 (vehicle)"은 고지방 식이 비만 랫트 모델 (diet-induced obesity, DI0)의 무처리군을 나타내고; "Lean"은 병태 모델이 아닌 정상 SD 랫트 모델의 무처리군을 나타낸 다). 도 2(A)는 본 발명에 따른 실시예 48 및 비교예 3의 화합물을 DKKDiet— induced obesity) 랫트 모델에 4주간 투여가 종료되는 시점 에， 실시예 48 및 비교예 3의 화합물을 투여한 30분 후， 글루코스를 투여하였을 때 시간변화에 따른 혈당강하 효능을 평가한 그래프이다. 도 2(B)는 본 발명에 따른 실시예 119의 화합물을 DKKDiet- induced obesity) 랫트 모델에 4주간 투여가 종료되는 시점에， 실시예 119의 화합물을 투여한 30분 후， 글루코스를 투여하였을 때 시간변화 에 따른 혈당강하 효능을 평가한 그래프이다. 체중감소 효과는 도 1에 나타난 바와 같이 , 본 발명에 따른 실 시예 48을 각각 10, 20， 50 mg/kg 투여한 경우， 비교예 3(300 mg/kg) 및 바교예 4(5 mg/kg)를 투여한 경우보다 높은 체중감소 효과가 나타 나는 것으로 확인되었다. 보다 구체적으로， 비교예 3(300 mg/kg) 및 비교예 4(5 mg/kg)의 경우， 경구 투여한 후 2주 동안 체중감소를 보였 지만， 2주 후 체중이 오히려 증가하는 것으로 나타났다. 반면에， 본 발명에 따른 실시예 48(10， 20， 50 mg/kg)의 경우， 경구 투여한 후 4 주 동안 지속적인 체중감소가 관찰되었다. 혈당강하 효과는 도 2(A)에 나타난 바와 같이 ， 본 발명에 따른 실시예 48을 각각 10， 20, 50 mg/kg 투여하였을 경우， 약 18-25%의 혈 당강하 효과가 나타나는 것으로 확인되었다. 보다 구체적으로， 비교예 3을 300 mg/kg 투여량으로 경구 투여한 경우， 약 22%의 혈당강하를 보 이지만， 본 발명에 따른 실시예 48을 50 mg/kg 경구 투여한 경우， 약 25%의 혈당강하 효과를 보임으로써 ， 비교예 3보다 현저히 우수한 혈당 강하 효과를 갖는 것으로 확인되았다. 또한， 도 2(B)에 나타난 바와 같이， 본 발명에 따른 실시예 119를 각각 10， 20， 50 mg/kg 투여하였 을 경우， 무처리군의 효과를 0으로 보았을 때 약 10-15%의 혈당강하 효과를 갖는 것으로 확인되었다. 따라서， 본 발명에 따른 싸이클로 핵센 유도체는 경구투여 기간 중 체중감소 및 혈당강하 효과가 우수할 뿐만 아니라， 이들 효과가 동 시에 발현되므로， 이를 휴효성분으로 함유하는 약학적 조성물은 비만， I 형 당뇨병， Π형 당뇨병， 부적합한 내당증， 인슐린 내성증， 고혈당 증， 고지질혈증， 고중성지방혈증， 고콜레스테를혈증， 이상지질혈증， X 증후군 등의 대사성 질환의 치료용 약학적 조성물로 유용하게 사용될 수 있다. Specifically, 30 minutes after administration of the compounds of Comparative Example 3 (300 mg / kg) and Example 48, Example 119 (10 20, 50 mg / kg), 2 g / kg of glucose was orally administered. Blood glucose was measured using Accu-c ' he-k active strip (Roche diagnostic Co.), and the measurement time was -30, 0, 20, 40, 60 and 120 minutes based on the timing of glucose administration. Was measured by measuring each. The AUC (%) (area under curve) value of each group of the results based on the blood glucose value at each time point was calculated to evaluate the hypoglycemic efficacy, and the results are shown in FIGS. 2 (A) and 2CB | Fig. 2 (A): Example 48, Fig. 2 (B): Example 119] Fig. 1 is a DIO (Diet-induced obesity) rat model of the compounds of Example 48 and Comparative Examples 3 and 4 according to the present invention. Is a graph measuring body weight change with administration at 4 weeks (in FIG. 1, "vehicle" represents a nonfat group of a high fat diet obesity rat model (diet-induced obesity, DI0); "Lean" is a condition Untreated group of normal SD rat model, not model). FIG. 2 (A) shows that the compound of Example 48 and Comparative Example 3 according to the present invention was administered to the DKKDiet-induced obesity rat model at the end of 4 weeks. Minutes later, when glucose was administered, it is a graph evaluating the hypoglycemic efficacy according to the time change. FIG. 2 (B) shows that when the compound of Example 119 according to the present invention was administered to the DKK Diet-induced obesity rat model at the end of 4 weeks, when glucose was administered 30 minutes after the administration of the compound of Example 119 It is a graph evaluating the effect of hypoglycemic activity over time. As shown in FIG. 1, when the Examples 48 according to the present invention were administered with 10, 20, and 50 mg / kg, Comparative Example 3 (300 mg / kg) and Baegyo 4 (5 mg / kg), respectively. ), The weight loss effect was higher than that of More specifically, in the case of Comparative Example 3 (300 mg / kg) and Comparative Example 4 (5 mg / kg), the weight was reduced for two weeks after oral administration, but after two weeks the weight was found to increase. On the other hand, in the case of Example 48 (10, 20, 50 mg / kg) according to the present invention, a continuous weight loss was observed for 4 weeks after oral administration. As shown in FIG. 2 (A), the hypoglycemic effect was confirmed to be about 18-25% of hypoglycemic effect when 10, 20, and 50 mg / kg of Example 48 were administered. . More specifically, when the oral administration of Comparative Example 3 at a 300 mg / kg dose shows a blood sugar drop of about 22%, when the oral administration of Example 48 according to the invention 50 mg / kg, about 25% By showing the hypoglycemic effect of, it was confirmed that it has a significantly lower hypoglycemic effect than Comparative Example 3. In addition, as shown in FIG. It was found to have a hypoglycemic effect. Therefore, the cyclohexene derivatives according to the present invention not only have excellent weight loss and hypoglycemic effects during the oral administration period, but because these effects are expressed at the same time, the pharmaceutical composition containing them as an active ingredient is obese, type I Useful as pharmaceutical composition for the treatment of metabolic diseases such as diabetes mellitus, Π diabetes mellitus, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, X syndrome Can be used.
<실험예 4> GLP-KGlucagon-like peptide一 1) 분비촉진 평가 본 발명에 따른 싸이클로 핵센 유도체의 GLP-1 분비촉진 효능을 평가하기 위하여 하기와 같은 실험을 수행하였다. 인간의 장 세포인 NCI-H716 세포를 12 웰에 1X106/웰로 플레이 팅 (plating) 하였다. 48시간 후， 무혈청 배지 (ser画 free media)로 2 시간 동안의 차단 (starvation)올 한 후에 DPP-I V(Dipept i dy 1 Peptidase-IV) 억제제인 시프타글립틴 (siptagl ipt in)과 비교예 1(1， 10, 30 μ M) , 비교예 5(10 μ Μ) 및 실시예 48(1， 10, 30 μ Μ)을 농도 별로 처리하였고 1시간 후에 상층액을 회수하여 분비된 GLP- KGlucagon-like peptide-1)의 양을 측정하였다. GLP-1 측정을 위하여 ELISA(enzyme-l inked immunosorbent assay) (Mi 11 i pore， EGLPᅳ 35K)를 사용하여 진행하였으며 분비된 GLP-1 양은 pM 단위로 나타내었다. 그 결과를 도 3에 나타내었다. 도 3은 인간의 장 세포인 NCI-H716 세포에 본 발명에 따른 비교 예 1， 5 및 실시예 48를 처리하여 GLP-l(Glucagon-like peptide-1)의 분비량을 나타낸 그래프이다. 도 3에 나타난 바와 같이， 본 발명에 따른 실시예 48올 각각 1， 10， 30 μΜ 농도로 처리하였을 경우， 약 340-470 ρΜ의 GLP-1이 분비되 는 것으로 확인되었다. 보다 구체적으로， 비교예 1과 실시예 48의 처 리 농도에 따른 GLP-1 분비량을 비교하였을 경우， 1， 10， 30μΜ의 처 리 군 모두에서 살시예 48이 비교예 1보다 우수한 GLP-1 분비를 유도 하는 것으로 나타났다. 따라서， 본 발명에 따른 싸이클로 핵센 유도체는 GPR-119의 활 성화에 따른 GLP-1의 분비를 유도하는 효능이 우수하므로， 이를 유효 성분으로 함유하는 약학적 조성물은 비만， I 형 당뇨병， Π형 당뇨병， 부적합한 내당증， 인슐린 내성증, 고혈당증， 고지질혈증， 고중성지방 혈증， i콜레스테를혈증， 이상지질혈증， X 증후군 등의 대사성 질환의 치료용 약학적 조성물로 유용.하게 사용될 수 었다. <실험예 5> 급성 득성 실험 <Experiment 4> GLP-KGlucagon-like peptide 一 1) Secretion promotion evaluation The following experiment was performed to evaluate the GLP-1 secretion promoting effect of the cyclohexene derivative according to the present invention. Human intestinal cells, NCI-H716 cells, were plated at 1 × 10 6 / well in 12 wells. 48 hours later, after 2 hours of starvation with serum free media, compared to diptagl ipt in, a DPP-I V (Dipept i dy 1 Peptidase-IV) inhibitor Example 1 (1, 10, 30 μΜ), Comparative Example 5 (10 μΜ) and Example 48 (1, 10, 30 μΜ) were treated according to the concentration and the supernatant was recovered after 1 hour to secrete GLP- The amount of KGlucagon-like peptide-1) was measured. GLP-1 was measured using an enzyme-l inked immunosorbent assay (ELISA) (Mi 11 i pore, EGLP ᅳ 35K) and the amount of secreted GLP-1 was expressed in pM. The results are shown in FIG. 3 is a graph showing the secretion amount of GLP-1 (Glucagon-like peptide-1) by treating NCI-H716 cells which are human intestinal cells with Comparative Examples 1, 5 and 48 according to the present invention. As shown in Figure 3, when treated with a concentration of 1, 10, 30 μM each of the Example 48 according to the present invention, it was confirmed that GLP-1 of about 340-470 ρΜ is secreted. More specifically, when comparing the amount of GLP-1 secretion according to the treatment concentration of Comparative Example 1 and Example 48, GLP-1 secretion in Salsal Example 48 is superior to Comparative Example 1 in all treatment groups of 1, 10, 30μΜ Appeared to induce. Therefore, the cyclohexene derivative according to the present invention has an excellent effect of inducing the secretion of GLP-1 according to the activation of GPR-119, and the pharmaceutical composition containing it as an active ingredient is obesity, type I diabetes, type Π diabetes mellitus. ， It can be useful as a pharmaceutical composition for the treatment of metabolic diseases such as inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, i-cholesterolemia, dyslipidemia, X syndrome. Experimental Example 5 Acute Beneficial Experiment
본 발명에 따른 싸이클로 핵센 유도체의 급성독성을 평가하기 위하여 하기와 같은 실험을 수행하였다. 생후 7주령된 백내장을 지닌 랫트 (Ihara's Cataract Rat , ICR) 암컷 5마리를 나라 바이오텍으로부터 공급받아 사육장에서 수용하며 일반 고형사료와 물을 주며 환경에 적웅시켰으며， 8주령이 되었을 때 실험을 수행하였다. 환경조건은 설정온도는 23 士 3°C , 습도는 55 士 15%, 조도는 150-300 Lux, 환기 횟수는 10-20 회 /시간， 조명시간은 12 시간 (명암주기 : 아침 8시 점등 -오후 8시 소등)으로 일정하게 유지하였 다. 사료는 방사선조사로 멸균한 실험동물용 고형사료 (5L79 Lab Diet , Purina Mi lis, Rich- mond , IN, USA)를 오리엔트 바이오로부터 공급받 아 자유롭게 섭취하도록 하고 , 물은 상수도수를 자외선 살균기 및 미 세여과장치로 소독한 후， 물병을 이용하여 자유롭게 섭취하도록 하였 다 . 물과 사료의 오염물질에 대한 검사는 (주)켐온의 관련 SOP에 따라 실시하였다. 본 발명에 따른 실시예 48 및 119에서 제조한 화합물을 각각 2000 mg/kg의 농도로 부형제 (1% PEG)에 희석하여 개체수 5마리에 랫트용 존대 (zonde)를 이용해서 시험물질을 하루에 한번， 위 내 투여 하고 시험기간 중에 1일 2회씩 동물의 일반상태， 중독증상 및 사망 유 무에 대해서 관찰하였다. 그 결과, 상기 ICR 랫트 암컷의 LD50(Lethal Dose 50 percent)값 은 2 g/kg 이상으로 확인되었으며， 이로부터， 본 발명에 따른 싸이클 In order to evaluate the acute toxicity of the cyclohexene derivatives according to the present invention, the following experiment was performed. Five female Ihara's Cataract Rat (ICR) rats, aged 7 weeks old, were supplied from Nara Biotech to livestock farms, fed with solid feed and water, and subjected to experiments at 8 weeks of age. . Environmental conditions are set at 23 ° C 3 ° C, humidity 55 ° C 15%, illuminance 150-300 Lux, ventilation frequency 10-20 times / hour, lighting time 12 hours (contrast cycle: lights up at 8 am- It was kept constant at 8 pm). Feed is freely fed from Orient Bio, a solid feed for laboratory animals sterilized by irradiation (5L79 Lab Diet, Purina Milis, Richmond, IN, USA). After sterilization with a filtration device, the water bottle was used for free intake. Water and feed contaminants were tested in accordance with the related SOP of Chem. The compounds prepared in Examples 48 and 119 according to the present invention were diluted in excipients (1% PEG) at a concentration of 2000 mg / kg, respectively, and the test substance was used once a day using a zone for rats in 5 populations. Intragastric administration was performed twice daily to observe the general condition, intoxication and death of the animals. As a result, the LD 50 (Lethal Dose 50 percent) value of the female ICR rat was confirmed to be 2 g / kg or more, from which the cycle according to the invention
성써고혈 230 Sexual hypertension 230
물증아혈, " Bloody blood , "
로 핵센 유도체는 독성이 매우 낮은 것을 알 수 있었다. 따라서， 본 발명에 따른 싸이클로 핵센 유도체는 GPR- 119를 활 성화하여 , cAMP를 촉진시키는 효과가 우수할 뿐만 아니라 세포독성이 인체에 안정도가 상당히 우수하므로， GPR- 119를 활성화시킴으로 만， I형 당뇨병， I I형 당뇨병， 부적합한 내당증, 인슐린 내성증， 당증， 고지질혈증， 고중성지방혈증， 고콜레스테를혈증， 이상지질 ， X 증후군 등과 같은 대사성 질환의 예방 또는 치료용 약학적 조 로 유용하게 사용할 수 있다. 한편， 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 목적 에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제쎄화 방 법을 예시한 것으로 본 발명이 이에 한정꾀는 것은 아니다. It was found that rho nucene derivatives have very low toxicity. Therefore, the cyclohexene derivative according to the present invention activates GPR-119, and not only has an excellent effect of promoting cAMP, but also cytotoxicity is very stable in the human body. ， Use as a pharmaceutical preparation for the prevention or treatment of metabolic diseases such as type II diabetes, inadequate glucose tolerance, insulin resistance, glucose, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, X syndrome, etc. Can be. On the other hand, the compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of preparation methods containing the compound represented by Chemical Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
<제제예 1> 약학적 제제의 제조 Preparation Example 1 Preparation of Pharmaceutical Formulation
1-1. 산제의 제조 .  1-1. Preparation of Powders.
화학식 1의 화합물 500 nig  500 nig of compound of Formula 1
유당 100 nig  Lactose 100 nig
탈크 10 nig 상기의 성분들을 흔합하고 기밀포에 충진하여 산제를 제조한다.  Talc 10 nig The above ingredients are mixed and filled in airtight cloth to prepare a powder.
1-2. 정제의 제조 1-2. Manufacture of tablets
화학식 1의 화합물 500 nig  500 nig of compound of Formula 1
옥수수전분 100 nig  Corn starch 100 nig
유당 100 nig  Lactose 100 nig
스테아린산 마그네슘 2 nig 상기의 성분들을 흔합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.  Magnesium stearate 2 nig After mixing the above components and tableting according to the conventional manufacturing method of the tablet to prepare a tablet.
1-3. 캅셀제의 제조 1-3. Manufacture of capsule
화학식 1의 화합물  Compound of Formula 1
옥수수전분  Corn starch
유당  Lactose
스테아린산 마그네슘 통상의 캡슐제 제조방법에 따라 상기의 성분을 흔합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.  Magnesium stearate According to the conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
-4. 주사제의 제조 화학식 1의 화합물 -4. Preparation of Injectables Compound of Formula 1
주사용 멸균 증류수 Sterile Distilled Water for Injection
H 조절제 통상의 주사제의 제조방법에 따라 1 앰플당 (2 me) 상기의 함량 로 제조한다.  H modifier According to the conventional method for preparing an injection, it is prepared in the amount described above (2 me) per ampule.
1-5. 액제의 제조 1-5. Preparation of liquid
화학식 1의 화합물 100 nig  100 nig of compound of Formula 1
이성화당 10 g  10 g of isomerized sugar
만니를 5 g  5 g of Manni
정제수 적량 통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 흔합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 로 조절한 후 갈색 병에 충진하여 멸균시켜 액체를 제조한다  Appropriate amount of purified water Dissolve each component by adding to the purified water according to the usual method of preparing a liquid solution, add a proper amount of lemon flavor, mix the above components, add purified water and adjust the whole to purified water, and then fill it in a brown bottle. Sterilize to prepare liquid
【산업상 이용가능성 ] 5 【Industrial Availability】 5
본 발명에 따른 싸이클로 핵센 유도체， 이의 광 o o적적학 이성질체， 또 는 아의 약학적으로 허용가능한 염은 GPR-119(G pr ^량량otein-coupled receptor 119)를 활성화시켜 cAMP(Cyclic. adenosine monophosphate)의 세포 내 활성을 증자시키교， 신경 내분비 단백질인 G:LP-l(Glucagon- 1 ike pept ide-1) 방출을 유도하여 체중감소 및 혈당강하 효과가 동시 에 나타나므로， 비만.， I형 당뇨병 , Π형 당.뇨병， 부적합한 내당증， 인 슐린 내성증, 고혈당증， 고지질혈증， 고중성지방 i증， 고콜레스테를혈 증， 이상지질혈증， X 증후군 등과 같은 대사성 질환의 예방 또는 치료 용 약학적 조성물로 유용할 수 있다.  Cyclo nucene derivatives according to the present invention, their optical oo-tepometric isomers, or pharmaceutically acceptable salts of children, can be activated by activating GPR-119 (G pr ^ o-otein-coupled receptor 119). Increasing the intracellular activity of the rat, inducing the release of the neuroendocrine protein G: LP-1 (Glucagon-1 ike pept ide-1), resulting in simultaneous weight loss and hypoglycemic effects, obesity. Pharmacology for the prevention or treatment of metabolic diseases such as diabetes mellitus, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X May be useful as a composition.

Claims

【청구의 범위】 [청구항 1】 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 , 또 이의 약학적으로 허용가능한 염 : [화학식 1] (상기 화학식 1에서 R1은 -H, -OH, Cno의 직쇄 또는 측쇄 알킬， (^-10의 직쇄 또는 측쇄 알콕시 , (^-10의 직쇄 또는 측쇄 알콕시카보닐， 또는 N, 0 및 ≤로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5-10원자 헤테로아릴이고， 여기서， 상기 치환된 5-10원자 헤테로아릴은 d-u)의 직쇄 또는 측쇄 알킬아 하나 이상 치환된 5-10원자 헤테로아릴이고; R2는 -0H, 할로겐， (^-^의 직쇄 또는 측쇄 알킬 , 또는 d-10 의 직쇄 또는 측쇄 알콕시이고 ; R3는 -H， 비치환 또는 하나 이상의 -0H 또는 할로겐이 치환된 d- 의 직쇄 또는 측쇄 알킬， -10의 직쇄 또는 측쇄 알콕시， -^의 직쇄 또는 측쇄 알콕시 (^-10의 직쇄 또는 측쇄 알킬， 비치환된 (：3-10의 싸이클로알킬， N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환된 5— 10원자 헤테로아릴 <： -10의 직 쇄 또는 측쇄 알킬， - CH2)nNR5R6, -(CH2)mC(=0)0R7, 또는 - (CH2)pC(=0)NR8R9이고， R5 및 R6는 독립적으로 -H, -Boc( , 또는 d-5의 직쇄 또 는 측쇄 알킬이고， R7은 -H, 또는 d-5의 직쇄 또는 측쇄 알킬이고， R8 및 R9는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 및 S 로 이루어기는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하 는 비치환 또는 치환된 5-10원자 헤테로싸이클로알킬을 형성할 수 있 여.기서， 상기 치환된 5-10원자 해테로싸이클로알킬은 -CN, d-5 의 직쇄 또는 측쇄 알킬 , d-5의 직쇄 또는 측쇄 알콕시 및 - C(=0)NR10Ru로 이루어지는 군으로부터 선택되는 하나 이상의 치환기가 치환된 5-10원자 헤테로싸이클로알킬이고， 상기 R10 및 R11은 독립적으 로 -H, 또는 d-5의 직쇄 또는 측쇄 알킬이고， n, m 및 p는 독립적으로 1-10의 정수이고; R4는 -H, 비치환 또는 하나 이상의 -擁가 치환된 의 직쇄 또는 측쇄 알킬， 또는 ( -10의 직쇄 또는 측쇄 알콕시이고 ; 상기 R3 및 R4는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 및 S로 이루어지는 군으로부터 선택되는 해테로 원자를 하나 어상 포 함하는 비치환된 3-10원자 헤테로싸이클로알케닐， 또는 N, 0. 및 S로 이루어지는 군으로부터 선택되는 해테로 원자를 하나 이상 포함하는 비치환， 치환， 또는 융합된 (fused) 3-10원자 헤테로싸이클로알킬을 형 성할 수 있고， 여기서， 상기 치환된 3-10원자 헤테로싸이클로알킬은 -OH, -CN, =0, 할로겐， 비치환 또는 하나 이상의 -0H가 치환된 d-5의 직쇄 또는 측쇄 알킬， 의 직쇄 또는 측쇄 알콕시， 비치환된 C3ᅳ 10의 싸이클로 알킬 의 직쇄 또는 측쇄 알킬， '비치환된 :(：3-10의 싸이클로알킬， N, 0 및 S로 이루어지는 군으로부터 선택되는 해테로 원자를 하나 이상 포함하는 비치환된 3- 10원자 혜테로싸이클로알 _¾， -C( =0 ) NR12R13， - NR14R15, =NR16으로 이루어지는 군으로부터 선택되는 하나 이상의 치환 기가 치환되거나; 비치환된 (：6-10의 아릴이 융합된 (fused) (：5-10의 싸이 클로알케닐， 또는 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테 로 나 이상 포함하는 비치환 또는 하나 이상의 - Boc( )가 치환된 3-10원자 헤테로싸이클로알킬이 스피로 (Spiro) 형태로 치환된 3-10원자 헤테로싸이클로알킬이고， 상기 R12, R13, R14 및 R15는 독립적으로 -H, 또는 d-5의 직쇄 또 는 측쇄 알킬이고， 상기 R16은 -H, -0H, 또는 d-5의 직쇄 또는 측쇄 알콕시이고， 여기서， 상기 융합된 (fused) 3-10원자 헤테로싸이클로알킬은 비 치환된 (：6-10의 아릴이 융합된 3-10원자 헤테로싸이클로알킬이고， 상기 비치환， 치환, 또는 융합된 (fused) 3-10원자 헤테로싸이클 로알킬에 있어서， 치환과 융합은 동시에 일어날 수 있고; A 및 E는 독립적으로 -CH=, 또는 -N=이다) 【청구항 2】 제 1항에 있어서， R1은 ( -^의 직쇄 또는 측쇄 알콕시카보닐， 또는 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5— 10원자 헤테로아릴이고， 여기서， 상기 치환된 5-10원자 헤테로아릴은 ( -^의 직쇄 또는 측쇄 알킬이 하나 이상 치환된 5— 10원자 헤테로아'렬이고； R2는 -H 또는 할로겐이고; R3는 비치환 또는 하나 이상의 -0H 또는 할로겐이 치환된 의 직쇄 또는 측쇄 알킬， d— 10의 직쇄 또는 측쇄 알콕시 , d-u)의 직쇄 또는 측쇄 알콕시 -10의 직쇄 또는 측쇄 알킬， 비차환된 (：3-10의 싸이 클로알킬， Nᅳ 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자 를 하나 이상 포함하는 비치환된 5-1Ό원자 헤퉤로아릴 직쇄 또 는 측쇄 알킬， -(CH2)nNR5R6, -(CH2)mC(=0)0R7, 또는 -(CH2)pC(=0)NR8R9 이고， 0 R5 및 R6는 독립적으로 -H 또는 -60(：( 우 )이고， R7은 -H, 또는 d-5의 직쇄 또는 측쇄 알킬이고， R8 및 R9는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 및 S 로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하 는 비치환 또는 치환된 5-10원자 헤테로싸이클로알킬을 형성할 수 있 고 , 여기서， 상기 치환된 5-10원자 헤테로싸이클로알킬은 -CN 및 - C(=0)NR10Rn로 이루어지는 군으로부터 선택되는 하나 아상의 치환기가 치환된 5-10원자 헤테로싸이클로알킬이고， 상기 R10 및 R11은 독립적으 로 -H이고， n, m 및 p는 독립적으로 1—5의 정수이고; R4는 -H, 또는 비치환 또는 하나 이상의 -0H가 치환된 d-u)의 직쇄 또는 측쇄 알킬이고; 상기 R3 및 R4는 이들이 연결된 질소 원자와 함께 연결되어 N, 0 및 S로 이루어지는 군으로부터 선택되는 해테로 원자를 하나 이상 포 함하는 비치환된 3-10원자 헤테로싸이클로알케닐， 또는 N, 0 및 S로 이루어지는 군으로부터 선택되는 헤테로 원자를 하나 이상 포함하는 비치환， 치환， 또는 융합된 (fused) 3-10원자 헤테로싸이클로알킬을 형 성할 수 있고， 여기서， 상기 치환된 3-10원자 헤테로싸이클로알킬은 -OH, -CN, =0， 할로겐， 비치환 또는 하나 이상의 -0H가 치환된 d-5의 직쇄 또는 측쇄 알킬 , 비치환된 (：3-10의 싸이클로알킬 C -5의 직쇄 또는 측쇄 알킬 , 비치환된 (：3-10의 싸이클로알킬， N, 0 및 S로 이루어지는 군으로부터 선택되는 해테로 원자를 하나 이상 포함하는 비치환된 3-10원자 헤테 로싸이클로알킬ᅳ C(=0)NR12R13, -NR14R15, =NR16으로 이루어지는 군으로 부터 선택되는 하나 이상의 치환기가 치환되거나; 비치환된 (：6-10의 아 릴이 융합된 (fused) (：5-10의 싸이클로알케닐， 또는 N, 0 및 S로 어루어 지는 군으로부터 선택되 헤테로 원자를 하나 이상 포함하는 비치환 또는 하나 이상의 —Bo c )가 치환된 3-10원자 헤테로싸이클로 알킬이 스피로 (Spiro) 형태로 치환된 3-10원자 헤테로싸이클로알킬이 상기 R12, R13, R14 및 R15는 독립적으로 -H 또 는 측쇄 알킬이고， 상기 R16은 -0H, 또는 d-5의 직쇄 쇄직 쇄 여기서， 상 7} 융합된 .Uused) .3-1.0원자 헤테로싸이클로알킬은 I알비 치환된 (6-10의 아릴이 융합된 3-10원자 헤테로싸이클로알킬이고， 또콕 상기 비치환， 치환， 또는 융합된 (fused) 3-10원자 해테로싸이클 로알킬에 있어서， 치환과 융합은 동시에 일어날 수 있고; A 및 E는 독립적으로 -CH=, 또는 =인 것을 특징으로 하는 상기 화학식 1로 표시되는 화합물 , 이의 광학 이성질체， 또는 이의 약학적으로 허용가능한 염 . [청구항 3】 R 또는 N^k^/이고； 는 -H 또는 -F이고; 、 또는 He f、이고 ; R4는 -H, 메틸 에틸 또는 Hcr^i이고， 기서 , 상기 R3 및 4는 이들이 연결된 질소 원자 함께 형성할 수 있고; A 및 E는 독립적으로 -CH=, 또는 =인 것을 특징으로 하는 상기 화학식 1로 표서되는 화합물 , 이의 광학 이성질체 , 또는 이의 약학적으로 허용가능한 염 . 【청구항 4】 제 1항에 있어서， 상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선 택되는 어느 하나인 것을 특징으로 하는 화합물， 이의 광학 이성질쎄 또는 이의 약학적으로 허용가능한 염 : 【Claims】 [Claim 1] A compound represented by the following Chemical Formula 1, an optical isomer thereof, and a pharmaceutically acceptable salt thereof: [Formula 1] (In Chemical Formula 1, R1 is a straight chain of -H, -OH, Cno) or branched alkyl, (^-10 straight or branched alkoxy, (^-10 straight or branched alkoxycarbonyl, or unsubstituted or substituted containing one or more heteroatoms selected from the group consisting of N, 0 and ≤ It is a 5-10 membered heteroaryl, wherein the substituted 5-10 membered heteroaryl is a 5-10 membered heteroaryl substituted with one or more straight or branched chain alkyl du); R2 is -0H, halogen, (^- ^ straight or branched alkyl, or d-10 straight or branched alkoxy; R3 is -H, unsubstituted or one or more -0H or halogen-substituted d- straight or branched alkyl, -10 straight or branched alkoxy. , -^ straight-chain or branched alkoxy (^-10 straight-chain or branched alkyl, unsubstituted (: 3-10 cycloalkyl, unsubstituted containing one or more heteroatoms selected from the group consisting of N, 0 and S) 5—10-atom heteroaryl <: -10 straight or branched alkyl, - CH2)nNR5R6, -(CH2)mC(=0)0R7, or - (CH2)pC(=0)NR8R9, and R5 and R6 is independently -H, -Boc(, or d-5 straight-chain or branched alkyl, R7 is -H, or d-5 straight-chain or branched alkyl, and R8 and R9 are connected together with the nitrogen atom to which they are connected. It is possible to form an unsubstituted or substituted 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, 0, and S. Here, the substituted 5-10 membered heterocycloalkyl may be formed. Cycloalkyl is a 5-10 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of -CN, d-5 straight or branched alkyl, d-5 straight or branched alkoxy, and -C(=0)NR10Ru. and R10 and R11 are independently -H, or d-5 straight or branched chain alkyl, and n, m and p are independently integers of 1-10; R4 is -H, unsubstituted or one or more -substituted straight or branched alkyl, or (-10 straight or branched alkoxy; R3 and R4 are connected together with the nitrogen atom to which they are connected to form N, 0 and S Unsubstituted 3-10 membered heterocycloalkenyl containing one or more heteroatoms selected from the group consisting of, or unsubstituted containing one or more heteroatoms selected from the group consisting of N, 0., and S. , may form a substituted or fused 3-10 member heterocycloalkyl, where the substituted 3-10 member heterocycloalkyl is -OH, -CN, =0, halogen, unsubstituted or one or -0H is substituted d-5 straight or branched alkyl, straight or branched alkoxy, unsubstituted C3-10 cycloalkyl, straight or branched alkyl, 'unsubstituted :(: 3-10 cycloalkyl, An unsubstituted 3-10 atom heterocycloal containing at least one heteroatom selected from the group consisting of N, 0 and S _¾, -C(=0) NR12R13, -NR14R15, =NR16 selected from the group consisting of One or more substituents are substituted; unsubstituted (: 6-10 aryl fused (: 5-10 cycloalkenyl), or a hetero group selected from the group consisting of N, 0 and S A 3-10 member heterocycloalkyl containing unsubstituted or one or more -Boc() substituted is a 3-10 member heterocycloalkyl substituted in Spiro form, and R12, R13, R14 and R15 are independent. is -H, or d-5 straight-chain or branched alkyl, and R16 is -H, -0H, or d-5 straight-chain or branched alkoxy, wherein the fused 3-10 atom heterocycle Alkyl is unsubstituted (: 3-10 membered heterocycloalkyl fused with 6-10 aryl, and in the unsubstituted, substituted, or fused 3-10 membered heterocycloalkyl, substituted and fused can occur simultaneously; A and E are independently -CH=, or -N=) [Claim 2] The method of claim 1, wherein R1 is (-^ linear or branched alkoxycarbonyl, or selected from the group consisting of N, 0, and S It is an unsubstituted or substituted 5-10-membered heteroaryl containing at least one heteroatom, wherein the substituted 5-10-membered heteroaryl is a 5-10-membered heteroaryl in which one or more straight-chain or branched-chain alkyls of -^ are substituted. heteroa'series; R2 is -H or halogen; R3 is unsubstituted or one or more -0H or halogen substituted straight or branched alkyl, d—10 straight or branched alkoxy, du) straight or branched alkoxy -10 linear or branched alkyl, unsubstituted (: 3-10 cycloalkyl, unsubstituted 5-1Ό atom heteroaryl straight chain containing one or more heteroatoms selected from the group consisting of Nᅳ 0 and S Or side chain alkyl, -(CH2)nNR5R6, -(CH2)mC(=0)0R7, or -(CH2)pC(=0)NR8R9, and 0 R5 and R6 are independently -H or -60(:( Right), R7 is -H, or d-5 straight-chain or branched alkyl, and R8 and R9 are connected together with the nitrogen atom to which they are connected and contain one or more heteroatoms selected from the group consisting of N, 0, and S. Can form an unsubstituted or substituted 5-10 membered heterocycloalkyl, wherein the substituted 5-10 membered heterocycloalkyl is one selected from the group consisting of -CN and -C(=0)NR10Rn. The substituents of the subphase are substituted 5-10 membered heterocycloalkyl, R10 and R11 are independently -H, n, m and p are independently integers of 1-5; R4 is -H, or unsubstituted or one or more -0H is substituted du) straight or branched alkyl; R3 and R4 are connected together with the nitrogen atom to which they are connected and contain one or more heteroatoms selected from the group consisting of N, 0 and S. Unsubstituted 3-10 membered heterocycloalkenyl, or unsubstituted, substituted, or fused 3-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, 0, and S. Can be formed, wherein the substituted 3-10 member heterocycloalkyl is -OH, -CN, = 0, halogen, unsubstituted or d-5 straight or branched chain alkyl substituted with one or more -0H, unsubstituted (: 3-10 cycloalkyl C -5 straight or branched chain alkyl, unsubstituted (: 3-10 cycloalkyl, N, 0 and S), which contains at least one hetero atom selected from the group consisting of substituted with one or more substituents selected from the group consisting of 3-10 atom heterocycloalkyl ᅳ C(=0)NR12R13, -NR14R15, and =NR16; Unsubstituted (:6-10 aryl fused (:5-10 cycloalkenyl), or unsubstituted containing one or more heteroatoms selected from the group consisting of N, 0, and S Or one or more —Bo c ) substituted 3-10 member heterocycloalkyl is substituted in Spiro form, and R12, R13, R14 and R15 are independently -H or side chain. alkyl, and R16 is -0H, or d-5 straight chain, where, phase 7} fused .Uused) .3-1.0 atom heterocycloalkyl is Ialbi substituted (6-10 aryl fused 3 -10-membered heterocycloalkyl, and in the unsubstituted, substituted, or fused 3-10 membered heterocycloalkyl, substitution and fusion may occur simultaneously; A and E are independently -CH A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that =, or =. [Claim 3] R or N^k^/; is -H or -F, and ; 、 or He f、; R4 is -H, methyl ethyl or Hcr^i, wherein R3 and 4 can form together the nitrogen atom to which they are connected; A and E are independently -CH=, or = A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. [Claim 4] The method of claim 1, wherein the compound represented by Formula 1 is selected from the group of compounds below. A compound characterized in that it is any one of the following: an optical isomer thereof or a pharmaceutically acceptable salt thereof:
(1) tert-부틸 4-((4-(4-((R)-l-히드록시프로판 -2-일카바모일 ) 싸이클로핵스 -1-엔일)페녹시^메틸)피페리딘 -1-카복시레이트; (1) tert-butyl 4-((4-(4-((R)-l-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy^methyl)piperidine-1- carboxylate;
(2) tert-부틸 4— ((4-(4- (싸이클로프로필카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸 ,)피페리딘 -1-카볶시레이트 ; (2) tert-butyl 4— ((4-(4- (cyclopropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl,)piperidine-1-carboxylate;
(3) tert-부틸 4-((4— (4— (2,2-디플루오로에틸카바모일 )싸이클로 핵스 -1-엔일)페녹시 )메틸 )피페리딘 -1-카복시레이트； (3) tert-butyl 4-((4— (4— (2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(4) tert-부틸 4-((4-(4-((R)-2,3-디히드록시프로필카바모일 )싸 이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 ; (4) tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohax-1-enyl)phenoxy)methyl)piperidine-1 -carboxylate;
(5) tert-부틸 4-((4-(4-((R)-3-히드록시피를리딘 -1-카보닐 )싸 이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (5) tert-butyl 4-((4-(4-((R)-3-hydroxypyrlidine -1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine -1-carboxylate;
(6) tert-부틸 4-((4-(4-((3-히드록시프로필 ) (메틸 )카바모일 )싸 이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (6) tert-butyl 4-((4-(4-((3-hydroxypropyl) (methyl)carbamoyl)cyclohax-1-enyl)phenoxy)methyl)piperidine-1-carboxy rate;
(7) tert-부틸 4-((4-(4- (모르폴린 -4—카보닐)싸이클로핵스 -1-엔 일)페녹시 )메틸)피페리딘 -1-카복시레이트; (7) tert-butyl 4-((4-(4- (morpholine-4—carbonyl)cyclohex-1-en yl)phenoxy)methyl)piperidine-1-carboxylate;
(8) 4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메특시 )페 닐 )-N— ((R)-l 히드록시프로판 -2—일 )싸이클로핵스 -3-엔카복스아마이드； (8) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N— ((R)-l hydroxypropane - 2—1) Cyclohex-3-encarboxamide;
(9) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리,딘 -4-일 )메톡시 )페 닐 )-N-(3-히드록시프로필)싸이클로핵스 -3-엔카복스아마이드； (9) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperi,din-4-yl)methoxy)phenyl)-N-(3-hydroxypropyl)cyclohex -3-Encarboxamide;
(10) tert-부틸 4-((6-(4-((R)-2,3-디히드록시프로필카바모일) 싸이클로핵스 -1-엔일)피리딘 -3-일옥시 )메틸)피페리딘 -1-카복시레이트； (10) tert-butyl 4-((6-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine -1-Carboxylate；
(11) tert-부틸 4— ((6-(4-((S)-l-히드록시프로판 -2-일카바모일) 싸이클로핵스 -1-엔일)피리딘 -3-일옥시 )메틸)피페리딘 -1 카복시레아트 ;(11) tert-butyl 4— ((6-(4-((S)-l-hydroxypropane-2-ylcarbamoyl) Cyclohax -1-enyl)pyridin-3-yloxy)methyl)piperidine-1 carboxyreat;
(12) N-((R)— 2，3-디히드록시프로필 ) -4-(4-((1— (5-에틸피리미딘- 2-일 )피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔카복스아마이드；(12) N-((R)— 2,3-dihydroxypropyl) -4-(4-((1— (5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy ) Phenyl ) Cyclohax -3-encarboxamide;
(13) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메톡시 )페 닐)싸이클로핵스 -3-엔일) (모폴리노)메타논; (13) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (morpholino) methanon;
(14) tert-부틸 4-((6-(4-(1，3-디히드록시프로판 -2-일카바모일 ) 싸이클로핵스 -1-엔일 )피리딘— 3-일옥시 )메틸)피페리딘 -1-카복시레이트； (14) tert-butyl 4-((6-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin—3-yloxy)methyl)piperidine -1-Carboxylate；
(15) N-(l,3-디히드록시프로판 -2-일 ) -4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메톡시 )페닐)싸이클로핵스—3-엔카복스아마이드； (15) N-(l,3-dihydroxypropan-2-yl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy ) phenyl) cyclohex—3-encarboxamide;
(16) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메특시 )페 닐 )싸이클로핵스 -3-엔일) ((R)-3_히드록시피를리딘 -1-일 )메타논 ; (16) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohax-3-enyl) ((R)- 3_hydroxypyrlidin-1-yl)methanone;
(17) N-((R)-2,3-디히드록시프로필 ) -4-(4-((1-(3-이소프로필- 1,2, 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스—3-엔 카복스아마이드; (17) N-((R)-2,3-dihydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazole-5-yl)p peridin -4-yl ) metaxi ) phenyl) cyclohex—3-ene carboxamide;
(18) N-((S)-2,3-디히드록시프로필 ) -4-(4-((1— (3-이소프로필- (18) N-((S)-2,3-dihydroxypropyl) -4-(4-((1— (3-isopropyl-
1,2， 4-옥사디아졸 -5-일 )피페리딘— 4-일)메록시 )페닐)싸이클로핵스 -3-엔 카복스아마이드; 1,2, 4-oxadiazole -5-yl)piperidine—4-yl)meroxy)phenyl)cyclohex-3-ene carboxamide;
(19) N-((S)-1-히드록시프로판 -2-일 ) -4-(4-((1-(3-이소프로필- 1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔 카복스아마이드; (19) N-((S)-1-hydroxypropan-2-yl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin -4-yl ) methoxy ) phenyl ) cyclohex -3-ene carboxamide;
(20) N-((R)-1-히드록시프로판 -2-일 )-4— (4-((1-(3-이소프로필- 1，2,4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐)싸이클로핵스—3-엔 카복스아마아드; (20) N-((R)-1-hydroxypropan-2-yl)-4— (4-((1-(3-isopropyl-1,2,4-oxadiazole-5-yl) piperidine -4-yl)methoxy)phenyl)cyclohex—3-ene carboxamide;
(21) 4-(4-((1-(5-에틸피리미딘 -2-일 )파페리딘 -4-일 )메톡시 )페 닐 ) -N- ( 2-히드록시에틸) -N-데틸싼이 로핵스 -.3-엔카복스아마이드； (21) 4-(4-((1-(5-ethylpyrimidin-2-yl)paperidin-4-yl)methoxy)phenyl)-N- (2-hydroxyethyl)-N- Detylsani loax -.3-encarboxamide;
(22) N-(3-히드록시 -2,2-디메틸프로필 )-4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3- 엔카복스아마이드 ; (22) N-(3-hydroxy-2,2-dimethylpropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperi din -4-yl) methoxy ) phenyl ) cyclohex -3- encarboxamide ;
(23) N-(lᅳ 3—디히드툭시프로판 -2-일 ) -4-(4-((1-(3-이소프로필- (23) N-(lᅳ 3—dihydrotuxypropane -2-yl) -4-(4-((1-(3-isopropyl-
1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔 카복스아마이드; 1,2,4-oxadiazole -5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-ene carboxamide;
(24) tert-부틸 4- ( ( 5- (4-( (S 히드록시프로판 -2-일카바모일) 싸이클로핵스— 1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트； (24) tert-butyl 4- ( ( 5- (4-( (S hydroxypropan -2-ylcarbamoyl) cyclohex— 1-enyl) pyridin -2-yloxy ) methyl) piperidine -1- Carboxylate;
(25). tert-부틸 4— ( ( 5-(4- ( (R) -1-히드록시프로판 -2-일카바모일) 싸이클로핵스 -1-엔일)피리딘—2-일옥시 )메틸)피페리딘 -1-카복시레이트；(25). tert-butyl 4— ( ( 5-(4- ( (R) -1-hydroxypropan -2-ylcarbamoyl) cyclohex -1-enyl) pyridin—2-yloxy ) methyl) piperidine -1 -Carboxylate；
(26) tert-부틸 4-( (5-(4-( (S)-2-히드록시프로필카바모일 )싸이 클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸 )피페리딘 -1-카복시레이트； (26) tert-butyl 4-( (5-(4-( (S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1 -Carboxylate；
(27) tert-부틸 4-( (5_(4— ( (R)-2-히드록시프로필카바모일 )싸이 클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸 )피페리딘— 1-카복시레이트； (27) tert-Butyl 4-( (5_(4— ( (R)-2-hydroxypropylcarbamoyl )cyclohex-1-enyl )pyridin-2-yloxy )methyl )piperidine— 1- Carboxylate;
(28) N-((R)-2-히드록시프로필 )-4-(4-((1-(3_이소프로필 -1,2,4- 옥사디아졸 -5-일 )피페리딘 -4_일 )메록시 )페닐 )싸이클로핵스—3-엔카복스 아마이드 ;' (28) N-((R)-2-hydroxypropyl)-4-(4-((1-(3_isopropyl-1,2,4-oxadiazole- 5 -yl)piperidine- 4 _ days )Meroxy )Phenyl )Cyclohax—3-encarbox Amide; '
(29) N-((S)-2-히드록시프로필) -4-(4-((1— (3-이소프로필 -1,2,4- 옥사디아졸— 5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스 아마이드; (29) N-((S)-2-hydroxypropyl) -4-(4-((1— (3-isopropyl -1,2,4- oxadiazole— 5-yl) piperidine - 4-yl ) meroxy ) phenyl ) cyclohex -3-encarbox amide;
(30) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페 닐 )-N-((R)-2-히드록시프로필 )싸이클로핵스 -3-엔카복스아마이드; (30) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((R)-2-hydroxypropyl )Cyclohax-3-encarboxamide;
(31) N- 2-히드록시에틸) -4-(4-((1-(3-이소프로필 _1，2,4-옥사디 아졸 -5-일)피페리딘— 4-일)메록시 )페닐)싸이클로핵스 -3-엔카복스아마이 (31) N- 2-hydroxyethyl) -4-(4-((1-(3-isopropyl_1，2,4-oxadiazole -5-yl)piperidine—4-yl)meroxy ) phenyl) cyclohex -3-encarboxamiy
(32) tert-부틸 4-((5-(4-((R)-2,3-디히드록시프로필카바모일) 싸이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트；(32) tert-butyl 4-((5-(4-((R)-2,3-dihydroxypropylcarbamoyl) cyclohex -1-enyl) pyridin -2-yloxy ) methyl) piperidine -1-Carboxylate；
(33) tert—부틸 4-( (5-(4-( (S)-2， 3-디히드록시프로필카바모일) 싸이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1—카복시레이트；(33) tert—butyl 4-( (5-(4-( (S)-2，3-dihydroxypropylcarbamoyl) cyclohex -1-enyl) pyridin -2-yloxy ) methyl) piperidine -1—carboxylate;
(34) N-(2-히드록시쎄틸 )-4-(4-((1-(3-이소프로필 -1,2,4-옥사디 아졸 -5-일)피페리딘 -4-일 )메특시 )페닐 )-N-메틸싸이클로핵스 -3-엔카복 스아마이드 ; (34) N-(2-hydroxycetyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl) Metaxi)phenyl)-N-methylcyclohex-3-enecarboxamide;
(35) N-에틸 -N-(2-히드록시에틸 )-4-(4-((1-(3-이소프로필- 1，2，4-옥사디아졸 -5-일 )피쩨리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3—엔 카복스아마이드; (35) N-ethyl -N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)phyzeridin-4 -yl )methoxy )phenyl)cyclohex -3—ene carboxamide;
(36) N-((R)-1-히드록시프로판 -2—일 ) -4-(5-((1-(3-이소프로필- (36) N-((R)-1-hydroxypropane -2—yl) -4-(5-((1-(3-isopropyl-
1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )피리딘 -2-일 )싸이클로핵 스 -3-엔카복스아마이드 ; 1,2,4-oxadiazol -5-yl ) piperidin -4-yl ) meroxy ) pyridin -2-yl ) cyclohex -3-encarboxamide ;
(37) N— ((S)-l-히드록시프로판 -2-일 )-4-(5-((1-(3-이소프로필- 1,2， 4-옥사디아졸 -5—일 )피페리딘 -4-일 )메톡시 )피리딘 -2-일 )싸이클로핵 스 -3-엔 ^!" 스0 !■口.1"01드; (37) N— ((S)-l-hydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2, 4-oxadiazole-5—yl) piperidin -4-yl ) methoxy ) pyridin -2-yl ) cyclohex -3-en ^!" s 0 ! ■口.1" 0 1d;
(38) N-((R)-2-히드록시프로필) -4-(5-((1— (3-이소프로필 -1，2，4- 옥사디아졸 -5-일)피페리딘 -4-일)메특시 )피리딘 -2-일 )싸이클로핵스 -3- 엔카복스아마이드; (38) N-((R)-2-hydroxypropyl) -4-(5-((1— (3-isopropyl -1,2,4-oxadiazol-5-yl)piperidine - 4-yl) metaxi) pyridin -2-yl) cyclohex -3- encarboxamide;
(39) N-((S)-2-히드록시프로필) -4-(5-((1-(3-이소프로필 -1，2，4- 옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )피리딘 -2-일)싸이클로핵스 -3— 엔카복스아마이드; (39) N-((S)-2-hydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine - 4-yl)methoxy)pyridin-2-yl)cyclohex-3—encarboxamide;
(40) N-((R)-2,3-디히드톡시프로필 ) -4-(5-((1-(3-이소프로필- 1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일)메톡시 )피리딘 -2—일 )싸이클로핵 스 -3-엔카복스아마이드; (40) N-((R)-2,3-dihydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)p Peridin-4-yl)methoxy)pyridin-2—yl)cyclohex-3-encarboxamide;
(41) N-((S)-2,3-디히드록시프로필 ) -4-(5— ((1-(3-이소프로필- (41) N-((S)-2,3-dihydroxypropyl) -4-(5— ((1-(3-isopropyl-
1，2，4ᅳ옥사디아졸 -5—일 )피페리딘 -4-일 )메특시 )피리딘 -2-일 )싸이클로핵 스 -3-엔카복스아마이드； 1,2,4-oxadiazole -5—yl ) piperidin -4-yl ) metaxi ) pyridin -2-yl ) cyclohex -3-encarboxamide;
(42) tert-부틸 4-( (5-(4-( (S)_3_히드록시피를리딘 -1-카보닐)싸 이클로핵스 -1-엔일 )피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트； (42) tert-butyl 4-( (5-(4-( (S)_3_hydroxypyrlidine -1-carbonyl) cyclohex -1-enyl) pyridin -2-yloxy) methyl) Piperidine-1-carboxylate;
(43) tert-부틸 4-( (5_(4-( (R)-3-히드록시피를리딘 -1-카보닐)싸 이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트；(43) tert-butyl 4-( (5_(4-( (R)-3-hydroxypyrlidine -1-carbonyl) cyclohex -1-enyl) pyridin -2-yloxy ) methyl) Piperidine-1-carboxylate;
(44) tert-부틸 4-( (2-플루오로 -4-( 4-( (S)-3-히드록시피를리딘- 1-카보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트；(44) tert-butyl 4-( (2-fluoro -4-( 4-( (S)-3-hydroxypyrlidine- 1-carbonyl ) cyclohex -1-enyl ) phenoxy ) methyl ) piperidine -1-carboxylate;
(45) tert-부틸 4- ( (2-플루오로ᅳ4-(4-( (R) -3—히드록시피롤리딘- 1-카보닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트；(45) tert-butyl 4- ( (2-fluoro ᅳ4-(4-( (R) -3—hydroxypyrrolidine- 1-carbonyl) cyclohex -1-enyl) phenoxy) methyl) Piperidine-1-carboxylate;
(46) N-(l,3-디히드록시프로관 -2-일 ) -4-(5-((1-(3-이소프로필- 1,2,4-옥사디아졸 -5—일)피페리딘 -4-일)메록시 )피리딘 -2-일 )싸이클로핵 스ᅳ 3—엔카복스아마이드； (46) N-(l,3-dihydroxypropyl-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazole-5—yl) piperidine -4-yl) meroxy ) pyridine -2-yl ) cyclohexyl sn 3—encarboxamide;
(47) N-(3-히드록시 -2ᅳ 2-디메틸프로필) -4-(5-( (1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )피리딘 -2-일 )싸이클로 핵스 -3-엔카복스아마이드; (47) N-(3-hydroxy-2ᅳ 2-dimethylpropyl)-4-(5-( (1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperi din-4-yl)methoxy)pyridin-2-yl)cyclohex-3-encarboxamide;
(48) ((R)-3-히드록시피를리딘 -1-일 ) (4-(4-((1ᅳ (3—이소프로필- (48) ((R)-3-hydroxypyrlidin -1-yl) (4-(4-((1ᅳ (3—isopropyl-
1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔 일 )메타논 ; 1,2,4-oxadiazol -5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-en yl)methanone;
(49) ((S)-3-히드록시피를리딘 -1-일 ) (4-(4-((1-(3—이소프로필- 1,2 ,4-옥사디아졸 -5-일 )피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔 일 )메타논 ; (49) ((S)-3-hydroxypyrlidin-1-yl) (4-(4-((1-(3—isopropyl-1,2,4-oxadiazole-5-yl) piperidin -4-yl)methoxy)phenyl)cyclohex-3-en yl)methanone;
(50) N-(2,2-디플루오로에틸 )-4-(4-( (1-(5-에틸피리미딘 -2-일 ) 피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이드； (50) N-(2,2-difluoroethyl)-4-(4-( (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclo Hax-3-encarboxamide;
(51) N-(2,2-디플루오로에틸) -4-(4-((1-(3-이소프로필 -1，2，4-옥 사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카복스아 마이드; ■ (51) N-(2,2-difluoroethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine-4 -1)meroxy)phenyl)cyclohex-3-encarboxamide; ■
(52) (4-(4-( (1-(3-이소프로필 -1ᅳ 2 ,4-옥사디아졸 -5—일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일 ) (피를리딘 -1-일 )메타논 ; (52) (4-(4-( (1-(3-isopropyl-1ᅳ 2,4-oxadiazol-5—yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -enyl) (pyrlidin -1-yl)methanone;
(53) ((S)-3-폴루오로피를리딘 -1-일 ) (4-(4-((1— (3-이소프로필- 1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일)메틈시 )페닐 )싸이클로핵스 -3-엔 일 )메타논 ; (53) ((S)-3-poluoropirlidin-1-yl) (4-(4-((1— (3-isopropyl-1,2,4-oxadiazole-5-yl) ) piperidin -4-yl) methymsey ) phenyl ) cyclohex -3-en yl ) methanone ;
(54) ((R)-3_플루오로피를리딘 -1-일 ) (4-(4-((1-(3_이소프로필ᅳ 1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3_엔 일 )메타논 ; (54) ((R)-3_fluoropyrlidin -1-yl) (4-(4-((1-(3_isopropylᅳ 1,2,4-oxadiazole -5-yl) piperidin -4-yl ) methoxy ) phenyl) cyclohex -3_en yl ) methanone ;
(55) (4-에틸피페라진 -1-일) (4-(4-((1-(5-에틸피리미딘 -2-일 )피 페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타논 ; (55) (4-ethylpiperazine -1-yl) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex -3-enyl)methanone;
(56) (4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일) (피페리딘 -1-일 )메타논 ; (56) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -enyl) (piperidine -1-yl)methanone;
(57) tert-부틸 4-( (2-플루오로 -4-(4-( (S)-3-플루오로피를리딘ᅳ 1-카보닐)싸이클로핵스 -1—엔일)페녹시 )메틸)피페리딘— 1-카복시레이트; (57) tert-butyl 4-( (2-fluoro-4-(4-( (S)-3-fluoropyrlidine ᅳ 1-carbonyl)cyclohex-1—enyl)phenoxy)methyl) Piperidine—1-carboxylate;
(58) tert-부틸 4-( ( 2-플루오로 -4-(4-( (R)-3-플루오로피를리딘ᅳ 1-카보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트； (58) tert-butyl 4-( ( 2-fluoro -4-(4-( (R)-3-fluoropyrlidine ᅳ 1-carbonyl ) cyclohex -1-enyl ) phenoxy ) methyl) Piperidine-1-carboxylate;
(59) tert-부틸 4-((2-플루오로 -4-(4-((S)-l-히드록시프로판 2- 일카바모일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이 트； (59) tert-butyl 4-((2-fluoro-4-(4-((S)-l-hydroxypropane 2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperi Dean-1-carboxylate;
(60) tertᅳ부틸 4-((2-플루오로 -4-(4-((R)-l-히드록시프로판 -2- 일카바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이 트; ' ■ (60) tert-butyl 4-((2-fluoro-4-(4-((R)-l-hydroxypropane-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)p Peridine -1-carboxylate crack; ' ■
(61) tert-부틸 4-((2-플루오로 -4-(4— ((S)_2-히드록시프로필카 바모일)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘— 1-카복시레이트； (61) tert-butyl 4-((2-fluoro-4-(4—((S)_2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine— 1 -Carboxylate；
(62) tert-부틸 4-((2-플루오로 -4-(4-((R)-2ᅳ히드록시프로필카 바모일)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 1-카복시레이트；(62) tert-butyl 4-((2-fluoro-4-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine 1 -Carboxylate；
(63) tert-부틸 4-( (4-(4-( ( S)-2， 3-디히드록시프로필카바모일) 싸이클로핵스 -1-엔일 )-2-플루오로페녹시 )메틸 )피페리딘 -1-카복시레이 트； (63) tert-butyl 4-( (4-(4-(( S)-2，3-dihydroxypropylcarbamoyl) cyclohex-1-enyl)-2-fluorophenoxy)methyl) piperi Dean-1-carboxylate;
(64) tert-부틸 4-( (4-(4-( (R)-2， 3-디히드록시프로필카바모일 ) 싸이클로핵스 -1-엔일 )-2-플루오로페녹시 )메틸)피페리딘 -1-카복시레이 트; ' (64) tert-butyl 4-( (4-(4-( (R)-2, 3-dihydroxypropylcarbamoyl) cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperi Dean-1-carboxylate; '
(65) 아제티딘 -1—일 (4-(4-((1-(3-이소프로필-1，2，4-옥사디아졸- 5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타논 ; (65) Azetidine -1—yl (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine-4-yl)methoxy) phenyl)cyclohex-3-enyl)methanone;
(66) (4-(4-((1-(3-이소프로필— 1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일)메특시 )페닐)싸이클로핵스 -3-엔일 ) (모폴리노)메타논; (66) (4-(4-((1-(3-isopropyl—1,2,4-oxadiazole -5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -enyl) (morpholino)methanone;
(67) tert-부틸 4-( (4-(4-( 1， 3-디히드록시프로판 -2-일카바모일) 싸이클로핵스 -1-엔일) -2-플루오로페녹시 )메틸)피페리딘 -1-카복시레이 트； (67) tert-butyl 4-( (4-(4-( 1, 3-dihydroxypropan -2-ylcarbamoyl) cyclohex -1-enyl) -2-fluorophenoxy ) methyl) piperi Dean-1-carboxylate;
(68) tert 부틸 4-( (5— (4-( 1， 3-디히드록시프로판 -2-일카바모일) 싸이클로핵스 -1—엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트; (68) tert Butyl 4-( (5— (4-( 1, 3-dihydroxypropan -2-ylcarbamoyl) cyclohex -1—enyl) pyridin -2-yloxy ) methyl) piperidine - 1-carboxylate;
(69) tert-부틸 4-( (2-플루오로 -4-(4- (모르폴린 -4-카보닐)싸이 클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (69) tert-butyl 4-( (2-fluoro-4-(4- (morpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate ；
(70) tert-부틸 4-((5-(4- (모르폴린 -4-카보닐)싸어클로핵스 -1- 엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1—카복시레이트; (70) tert-butyl 4-((5-(4- (morpholine-4-carbonyl)cyclohax-1-enyl)pyridin-2-yloxy)methyl)piperidine-1—carboxylate;
(71) tert-부틸 4-( ( 2-플루오로 -4- _ (싸이오모,르폴린 -4-카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (71) tert-butyl 4-((2-fluoro-4- _ (thiomo,lepoline-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate ；
(72) tert-부틸 4-( (5-(4- (싸이오모르폴린 -4-카보닐)싸이클로핵 스 -1-엔일 )피리딘 -2-일옥시 )메틸)피페리딘— 1-카복시레이트； (72) tert-Butyl 4-( (5-(4- (thiomorpholine-4-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine—1-carboxy Rate;
(73) tert-부틸 4-( (2-플루오로 -4-(4- (싸이오모르폴린— 1， 1-디옥 사이드 -4-카보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시 레이트; (73) tert-butyl 4-( (2-fluoro-4-(4- (thiomorpholine—1, 1-dioxide -4-carbonyl)cyclohex-1-enyl)phenoxy)methyl) piperidine-1-carboxylate;
(74) (4-(4-((1-(3-이소프로필-1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔일) (싸이오모폴리노)메타논； (74) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -enyl) (thiomorpholino) methanone；
(75) N-(2-플루오로에틸)-4-(4-((1-(3-이소프로필—1，2,4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔카복스아마이 (75) N-(2-fluoroethyl)-4-(4-((1-(3-isopropyl—1,2,4-oxadiazol-5-yl)piperidine-4-yl) Metaxi)phenyl)cyclohex-3-encarboxamii
(76) tert-부틸 3_(4-(4-( ( 1-(3-이소프로필 -1， 2， 4-옥사디아졸- 5-일)피페리딘 -4-일)메록시 )페닐 )-N-메틸싸이클로핵스 -3—엔카복스아미 도)프로필카바메이트; (76) tert-butyl 3_(4-(4-( ( 1-(3-isopropyl-1, 2, 4-oxadiazol-5-yl)piperidin-4-yl)meroxy)phenyl) -N-methylcyclohex-3—encarboxamido)propylcarbamate;
(77) N-(3—아미노프로필 )-4-(4-((1-(3-이소프로필— 1，2，4-옥사디 아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )-N-메틸싸이클로핵스 -3-엔카복 스아마이드 ; (77) N-(3—aminopropyl)-4-(4-((1-(3-isopropyl—1,2,4-oxadiazol-5-yl)piperidin-4-yl)mer Toxy )phenyl )-N-methylcyclohex -3-enecarboxamide ;
(78) 4-(4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피페리딘-(78) 4-(4-((l-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine-
4-일)메톡시 )페닐 )-N-(2,2,2-트리플루오로에틸)싸이클로핵스 -3-엔카복 스아마이드 ; 4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide;
(79) (4-에틸피페라진 -1-일 ) (4-(4-((1-(3—이소프로필 -1,2,4-옥 사디아졸— 5-일)피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔일)메타 (79) (4-ethylpiperazine -1-yl) (4-(4-((1-(3—isopropyl-1,2,4-oxadiazole—5-yl)piperidine-4- 1) meroxy ) phenyl ) cyclohex -3-enyl) meta
"논"， "rice paddy",
(80) . N-(l,3-디히드록시프로판 -2-일 ) -4-(3-플루오로 -4-((1-(3- 이소프로필 -1, 2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클 로핵스 -3-엔카복스아마이드; (80). N-(l,3-dihydroxypropan-2-yl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl ) piperidin -4-yl ) methoxy ) phenyl) cyclohex -3-encarboxamide;
(81) 4-(3-플루오로 -4-((1-(3—이소프로필 -1，2，4-옥사디아졸 -5- 일)피페리딘 -4-일 )메록시 )페닐 )-N-(2-히드록시에틸 )-N—메틸싸이클로핵 스 -3-엔카복스아마이드; (81) 4-(3-fluoro-4-((1-(3—isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)meroxy)phenyl) -N-(2-hydroxyethyl)-N—methylcyclohex-3-encarboxamide;
(82) tert-부틸 4-((2-플루오로 -4-(4ᅳ(3-히드록시 2，2-디메틸프 로필카바모일)싸이클로핵스 '엔일 )페녹시 ')메틸 )피페리딘 -1-카복시레 이트; (82) tert-butyl 4-((2-fluoro-4-(4ᅳ(3-hydroxy 2，2-dimethylpropylcarbamoyl)cyclohex ' enyl)phenoxy')methyl)piperidine - 1-carboxylate;
(83) 4-(3-플루오로 -4-((1-(3-이소프로필 -l，2,4—옥사디아졸-5- 일)피페리딘 -4—일 )메록시 )페닐 )-N-((S)-l_히드록시프로판 -2-일 )싸이클 로핵스 -3-엔카복스아마이 '드 ; (83) 4-(3-fluoro-4-((1-(3-isopropyl-l，2,4—oxadiazol-5-yl)piperidin-4—yl)meroxy)phenyl) -N-((S)-l_hydroxypropane -2-yl)cyclohex-3-encarboxamide ' de;
(84) 4-(3-플루오로 -4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5- 일)피페리딘 -4-일 )메특시 )페닐；) -N-((R)-1—히드록시프로판 -2-일 )싸이클 로핵스 -3-엔카복스아마이드; (84) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl; ) -N-((R)-1—hydroxypropane -2-yl )cyclohax -3-encarboxamide;
(85) tert-부틸 4-( (4-(4-(2， 2-디플루오로에틸카바모일)싸이클 로핵스— 1-엔일) -2-플루오로페녹시 )메틸)피페리딘— 1-카복시레이트 ; (85) tert-butyl 4-( (4-(4-(2, 2-difluoroethylcarbamoyl)cyclohex—1-enyl)-2-fluorophenoxy)methyl)piperidine—1 -carboxylate;
(86) tert-부틸 4-( (5-(4-(2， 2， 2-트리플루오로에틸카바모일)싸 이클로핵스 -1—엔일 )피 ¾딘 -2-일옥시 )데틸 λ피페 .리딘 -1-카복시레이트； (86) tert-butyl 4-( (5-(4-(2, 2, 2-trifluoroethylcarbamoyl) cyclohex -1—enyl) p ¾ din -2-yloxy ) decyl λ pipe .Ridine-1-carboxylate;
(87) tert 부틸 4— ( (5-(4-(2， 2-디플루오로에틸카바모일)싸이클 로핵스— 1-엔일 )피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트； (87) tert Butyl 4— ( (5-(4-(2, 2-difluoroethylcarbamoyl)cyclohex—1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxy Rate;
(88) tert-부틸 4-( (5-(4-(2-플루오로에틸카바모일)싸이클로핵 스 -1-엔일 )피리딘— 2-일옥시 )메틸 )피페리딘 -1-카복시레이트； (88) tert-butyl 4-( (5-(4-(2-fluoroethylcarbamoyl)cyclohex-1-enyl)pyridine—2-yloxy)methyl)piperidine-1-carboxylate;
(89) (4-싸이클로프로필피페라진— 1-일 ) (4-(4-((1-(3-이소프로필 (89) (4-cyclopropylpiperazine—1-yl) (4-(4-((1-(3-isopropyl)
— 1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3- 엔일)메타논 ; — 1,2,4-oxadiazol -5-yl ) piperidin -4-yl ) methoxy ) phenyl) cyclohex -3- enyl) methanone ;
(90) tert-부틸 4-((5-(4-((R)-3-플루오로피를리딘 -1-카보닐)싸 이클로핵스 -1—엔일 )피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트； (90) tert-butyl 4-((5-(4-((R)-3-fluoropyrlidin-1-carbonyl)cyclohex-1—enyl)pyridin-2-yloxy)methyl ) Piperidine-1-carboxylate;
(91) tert-부틸 4-((5-(4-((S)-3-플루오로피를리딘 -1-카보닐)싸 이클로핵스 -1-엔일)피리딘 -2-일옥시 )메틸)피페리딘 -1-카복시레이트; (91) tert-butyl 4-((5-(4-((S)-3-fluoropyrlidin-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl ) piperidine-1-carboxylate;
(92) 4-(3—플루오로 -4-((1-(3-이소프로필 -1,2,4—옥사디아졸— 5- 일)피페리딘 -4-일)메록시 )페닐 )-N-(2,2,2-트리플루오로에틸 )싸이클로 핵스 -3-엔카복스아마이드; (92) 4-(3—fluoro-4-((1-(3-isopropyl-1,2,4—oxadiazole— 5- yl)piperidin-4-yl)meroxy)phenyl) -N-(2,2,2-trifluoroethyl)cyclohex-3-encarboxamide;
(93) N-(2,2-디플루오로에틸) -4— (3-플루오로 -4-((1-(3-이소프로 필 -1,2,4-옥사디아졸 -5ᅳ일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스- (93) N-(2,2-difluoroethyl)-4— (3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazole-5-yl) piperidine -4-yl )meroxy )phenyl)cyclohex-
3ᅳ엔카복스아마이드; 3-encarboxamide;
(94) 4-(3-플루오로 -4-((l-(3-이소프로필 -1，2，4-옥사디아졸 -5- 일)피페리딘 -4-일 )메록시 )페닐 )-N-(2-플루오로에틸 )싸이클로핵스 -3-엔 카복스아마이드; . (94) 4-(3-fluoro-4-((l-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)meroxy)phenyl) -N-(2-fluoroethyl)cyclohex-3-ene carboxamide; .
(95) (4-(3-플루오로 -4-((1-(3ᅳ이소프로필 -1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일 ) ((S)-3-플루오로 피를리딘 -1-일)메타논; (95) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl )Cyclohax-3-enyl)((S)-3-fluoropyrlidin-1-yl)methanone;
(96) (4-(3-플루오로 -4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일) ((R)-3-플루오로 피를리딘 -1-일)메타논; (96) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl )Cyclohax-3-enyl)((R)-3-fluoropyrlidin-1-yl)methanone;
(97) (4-(3-플루오로 -4-((1-(3-이소프로필 -l,2，4-옥사디아졸-5- 일)피페리딘-4-일)메특시 )페닐)싸이클로핵스 -3-엔일) (모폴리노)메타 논; (97) (4-(3-fluoro-4-((1-(3-isopropyl-l,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl )Cyclohax-3-enyl)(morpholino)methanone;
(98) (4-(3-플루오로ᅳ 4-((1-(3-이소프로필 -1,2，4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일■) (싸이오모폴리노 ) 메타논 ; (98) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl )Cyclohax-3-enyl ■ ) (Thiomorpholino) Methanone;
(99) N-(2,2-디플루오로에틸 )— 4ᅳ(5-((1_(3-이소프로필 -1，2，4-옥 사디아졸 -5-일 )피페리딘 -4-일 )메특시 )피리딘 -2-일 )싸이클로핵스 -3-엔 카복스아마이드； (99) N-(2,2-difluoroethyl)—4ᅳ(5-((1_(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine-4- 1 ) Metaxi ) Pyridin -2-yl ) Cyclohax -3-ene carboxamide;
(100) (4-(5-( (1-(3-이소프로필 -1， 2，4-옥사디아졸 -5-일 )피페리 딘 -4-일 )메록시 )피리딘 -2-일 )싸이클로핵스 -3-엔일) (모폴리노)메타논 ; (100) (4-(5-( (1-(3-isopropyl-1, 2,4-oxadiazol-5-yl)piperidin-4-yl)meroxy)pyridin-2-yl) cyclohex-3-enyl) (morpholino)methanone;
(101) ((R)-3-플루오로피를리딘 -1-일 ) (4-(5-( (1— (3-이소프로필 - 1,2, 4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )피리딘— 2-일 )싸이클로핵 스 -3-엔일)메타논 ; (101) ((R)-3-fluoropyrlidin-1-yl) (4-(5-( (1— (3-isopropyl-1,2,4-oxadiazole-5-yl) piperidine -4-yl)meroxy )pyridine—2-yl)cyclohex-3-enyl)methanone ;
(102) ((S)-3-플루오로피를리딘 -1—일 ) (4-(5-((1-(3-이소프로필- 1,2，4-옥사디아졸 -5-일)피페리딘 -4-일)메톡시 )피의딘 -2-1 )싸이클로핵 스 -3-엔일)메타논 ; (102) ((S)-3-fluoropyrlidin-1—yl) (4-(5-((1-(3-isopropyl-1,2,4-oxadiazole-5-yl) piperidin -4-yl) methoxy ) piperidin -2-1 ) cyclohex -3-enyl) methanone ;
..
(103) 4-(4— ((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메톡시 )페 닐 )-N-(2,2,2-트리플루오로에틸 )싸이클로핵스 -3-엔카복스아마이드; (103) 4-(4— ((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoro ethyl)cyclohex-3-encarboxamide;
(104) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페 닐 )-N-(2-플루오로에틸 )싸이클로핵스 -3-엔카복스아마이드 ; (104) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-fluoroethyl)cyclohex - 3-encarboxamide;
(105) (2S)-l-(4-(4-((l-(5-에틸피라미딘 -2-일)피페리딘 -4-일 ) 메톡시 )페닐)싸이클로핵스 -3-엔카보닐)피를리딘 -2-카복스아마이드； (105) (2S)-l-(4-(4-((l-(5-ethylpyramidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-encarbonyl ) Pyrrhidine -2-carboxamide;
(106) (2S)-l-(4-(4-((l-(5-에틸피리미딘 2-일 )피페리딘 -4-일 ) 메록시 )페닐 )싸이클로핵스 -3-엔카보닐 )피를리딘 -2-카르보니트릴； (106) (2S)-l-(4-(4-((l-(5-ethylpyrimidin 2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-encarbonyl) Pyrrhidine-2-carbonitrile；
(107) tert-부틸 4-( (4-(4-( (S)-2-카바모일피를리딘 -1-카보닐) 싸이클로핵스 -1-엔일 )-2-플루오로페녹시 )메틸 )피페리딘 -1-카복시레이 트; ' ■ (107) tert-butyl 4-( (4-(4-( (S)-2-carbamoylpyrlidine -1-carbonyl) cyclohex -1-enyl)-2-fluorophenoxy) methyl) piperidine-1-carboxylate; ' ■
(108) (2S)-l-(4-(3-플루오로 -4-((1-(3-이소프로필 -1 ,2，4-옥사 디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카보닐)피 를리딘 -2-카복스아마이드; (108) (2S)-l-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine-4- 1)methoxy)phenyl)cyclohex-3-encarbonyl)pyrlidine-2-carboxamide;
(109) (메틸 2-(4-(3—플루오로 -4-((1— (3-이소프로필— 1，2，4-옥사 디아졸 -5-일)피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔카복스아미 도 )아세테이트; (109) (methyl 2-(4-(3—fluoro-4-((1— (3-isopropyl—1,2,4-oxadiazol-5-yl)piperidin-4-yl) meroxy ) phenyl ) cyclohex -3-encarboxyl group Figure ) Acetate;
(110) 에틸 3-(4-(3-플루오로 -4-((1-(3-이소프로필 -1,2,4-옥사 디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐 )싸이클로핵스 -3-엔카복스아미 도)프로파노에이트; (110) Ethyl 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)meteuk si ) phenyl ) cyclohex -3-encarboxamido) propanoate;
(111) 3-(4-(3-플루오로 -4-((1-(3_이소프로필 -1，2,4-옥사디아졸 (111) 3-(4-(3-fluoro-4-((1-(3_isopropyl-1,2,4-oxadiazole
-5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스아미도)프 로파노익 엑시드; -5-yl )piperidine -4-yl )meroxy )phenyl )cyclohex -3-encarboxamido)propanoic acid;
(112) 4-(3-플루오로 -4-((1-(3-이소프로필 -1,2,4-옥사디아졸 -5- 일 )피페리딘 -4-일 )메톡시 )페닐 )-N-(2-모폴리노 -2-옥소에틸 )싸이클로핵 스 -3ᅳ엔카복스아마이드; (112) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl) -N-(2-morpholino-2-oxoethyl)cyclohex-3-encarboxamide;
(113) 4-(3-플루오로 -4-((1ᅳ(3-이소프로필 -1，2，4-옥사디아졸 -5- 일)피페리딘 -4-일)메톡시 )페닐 )-N-(3-모폴리노 -3-옥소프로필)싸이클로 핵스— 3-엔ᅳ카복스아마이드; ― (113) 4-(3-fluoro-4-((1ᅳ(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl) -N-(3-morpholino-3-oxopropyl)cyclohex—3-ene-carboxamide; ―
(114) tert-부틸 4-( (4-(4-( (S)-2-시아노피를리딘 1-카보닐)싸 이클로핵스 -1-엔일) -2-플루오로페녹시 )메틸)피페리딘 -1—카복시레이트 ; (114) tert-butyl 4-( (4-(4-( (S)-2-cyanopyrlidine 1-carbonyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl) piperidine-1—carboxylate;
(115) (2S)— l-(4-(3-플루오로 -4-( (1-(3-이소프로필 -1， 2， 4-옥사 디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카보닐)피 를리딘 -2-카르보니트릴 ; (115) (2S)— l-(4-(3-fluoro-4-( (1-(3-isopropyl-1, 2, 4-oxadiazol-5-yl) piperidine-4- 1)methoxy)phenyl)cyclohex-3-encarbonyl)pyrlidine-2-carbonitrile;
(116) (2R)— 1-(4-(3ᅳ플루오로 -4-((1-(3-이소프로필 -1ᅳ 2,4-옥사 디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔카보닐)피 를리딘 -2-카복스아마이드; (116) (2R)— 1-(4-(3-fluoro-4-((1-(3-isopropyl-1-2,4-oxadiazole-5-yl)piperidine-4- 1)methoxy)phenyl)cyclohex-3-encarbonyl)pyrlidine-2-carboxamide;
(117) (21?)-1-(4-(3-플루오로—4-((1-(3-이소프로필-1，2,4-옥사 디아졸 -5-일 ')피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔카보닐 ')피 를리딘 -2-카르보니트릴 ; (117) (21?)-1-(4-(3-fluoro—4-((1-(3-isopropyl-1，2,4-oxadiazol-5-yl ')piperidine - 4-yl) metaxi) phenyl) cyclohax -3-enecarbonyl ') pyrlidine -2-carbonitrile;
(118) (4-(4-((1-(5-에틸피리미딘 -2-일 피페,리딘 -4-.일)데특시 ) 페닐)싸이클로핵스 -3-엔일) ((R)-2- (히드록시메틸)피를리딘 -1-일 )메타 '논; ' ' ' (118) (4-(4-((1-(5-ethylpyrimidin-2-yl pipe,ridin-4-.yl)detaxy)phenyl)cyclohex-3-enyl) ((R)-2 - (Hydroxymethyl)pyrlidin-1-yl)meta ' Non; '''
(119) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일) ((S)-2- (히드록시메틸)피를리딘— 1-일 )메타 논； (119) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) ((S)-2 - (Hydroxymethyl) pyrlidine— 1-yl) methanone;
(120) 4-(3-플루오로 -4-((1-(3_이소프로필 -1，2，4-옥사디아졸 -5- 일 )피페리딘— 4-일 )메톡시 )페닐) -^(2_히드록시에틸)싸이클로핵스 -3-엔 카복스아마이드; (120) 4-(3-fluoro-4-((1-(3_isopropyl-1,2,4-oxadiazol-5-yl)piperidine—4-yl)methoxy)phenyl) -^(2_hydroxyethyl)cyclohex -3-ene carboxamide;
(121) (2R)-1— (2-(4-(3-플루오로 -4-( (1-(3-이소프로필 -1ᅳ2，4-옥 사디아졸 -5-일 )피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔카복스아 미도)아세틸)피를리딘 -2-카복스아마이드; (121) (2R)-1— (2-(4-(3-fluoro-4-( (1-(3-isopropyl-1ᅳ2，4-oxadiazol-5-yl)piperidine -4-yl)methoxy)phenyl)cyclohex -3-encarboxamido)acetyl)pyrlidine -2-carboxamide;
(122) N-(2-((R)-2-시아노피를리딘 -1-일 )-2-옥소에틸 )-4-(3-플 루오로-4-( (1-(3-이소프로필 -1， 2， 4-옥사디아졸 -5-일 )피페리딘 -4—일 )메 록시 )페닐)싸이클로핵스 -3-엔카복스아마이드; ' (122) N-(2-((R)-2-cyanopyrlidin-1-yl)-2-oxoethyl)-4-(3-fluoro-4-( (1-(3-iso propyl -1, 2, 4-oxadiazol -5-yl ) piperidin -4—yl ) meroxy ) phenyl) cyclohex -3-encarboxamide; '
(123) (4-싸이클로프로필피페라진 -1-일 ) (4-(4-((1-(5ᅳ에틸피리 미딘 -2-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔일)메타논； (123) (4-cyclopropylpiperazine-1-yl) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclo Hax-3-enyl)methanone；
(124) (4- (싸이클로프로필메틸)피페라진 -1-일) (4-(4-((1-(5-에 틸피리미딘 -2-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일 )메 타논 ; (124) (4- (cyclopropylmethyl)piperazin-1-yl) (4-(4-((1-(5- Tylpyrimidin -2-yl ) Piperidin -4-yl ) Methoxy ) Phenyl) Cyclohax -3-enyl ) Methanone ;
(125) tert-부틸 4-( (3-플루오로 _4-(4-( (S)-2-히드록시프로필카 바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘- ;L-카복시레이트； (125) tert-butyl 4-( (3-fluoro_4-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-; L-carboxylate;
(126) tert-부틸 4-( (3-플루오로ᅳ4-( 4-( (R)-2-히드록시프로필카 바모일 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트；(126) tert-butyl 4-( (3-fluoro ᅳ4-( 4-( (R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine - 1-carboxylate;
(127) 4-(4-((1-(5-에틸피리미딘 -2ᅳ일)피페리딘 -4-일)메톡시 )페 닐 )-N-((S)-l-히드록시프로판 -2-일 )싸이클로핵스 -3-엔카복스아마이드; (127) 4-(4-((1-(5-ethylpyrimidin-2ᅳyl)piperidin-4-yl)methoxy)phenyl)-N-((S)-l-hydroxypropane - 2-day)cyclohex-3-encarboxamide;
(128) N-((S)-2,3-디히드톡시프로필 ) -4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메특시 )페닐 )싸이클로헥스 -3-엔카복스아마이드； (128) N-((S)-2,3-dihydroxypropyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy ) Phenyl ) Cyclohex -3-enecarboxamide;
(129) tert-부틸 4-( (3-플루오로 -4-(4-( (R) -1-히드록시프로판-(129) tert-butyl 4-( (3-fluoro -4-(4-( (R) -1-hydroxypropane-
2-일카바모일)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1—카복시레 이트; 2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1—carboxylate;
(130) tert-부틸 4-( ( 3-플루오로 -4- (4-( (S)-l-히드록시프로판- 2-일카바모일 )싸이클로핵스ᅳ1-엔일)페녹시 )메틸)피페리딘 -1-카복시레 이.트; (130) tert-butyl 4-( ( 3-fluoro -4- (4-( (S)-l-hydroxypropan- 2-ylcarbamoyl) cyclohexenyl) phenoxy) methyl) p Peridine-1-carboxylate;
(131) tert-부묄 4-( (4-(4-( (R)— 2 , 3-디히드록시프로필카바모일) 싸이클로핵스ᅳ1-엔일 )-3-플루오로쩨녹시 )메틸 )피페뫼딘 -1-카복시레이 (131) tert-bumen 4-( (4-(4-( (R)— 2, 3-dihydroxypropylcarbamoyl) cyclohexeu1-enyl)-3-fluoroxenoxy)methyl) pipemudine -1-carboxylate
■ 트; ' ■ ■ t; ' ■
(132) tert-부틸 4-( (4-(4-( ( S)-2， 3—디히드록시프로필카바모일) 싸이클로핵스 -1-엔일 )-3-풀루오로페녹시 )메틸)피페리딘 -1-카복시레이 트; ' (132) tert-butyl 4-( (4-(4-(( S)-2，3—dihydroxypropylcarbamoyl) cyclohex-1-enyl)-3-fluorophenoxy)methyl)p Peridine-1-carboxylate; '
(133) (2S)— 1— (2-(4-(3-플루오로 -4-((1-(3-이소프로필 -1，2，4- 옥사디아졸 -5-일 )피페리딘 -4-일)메특시 )페닐)싸이클로핵스 -3-엔카복스 아미도)아세틸)피를리딘 -2-카복스아마이드; (133) (2S)— 1— (2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazole-5-yl)piperidine -4-yl)methoxy)phenyl)cyclohex -3-encarbox amido)acetyl)pyrlidine -2-carboxamide;
(134) (2S)— 1-(3-(4-(3-플루오로 -4-( (1-(3-이소프로필 -1，2，4ᅳ옥 사디아졸 -5-일 )피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카복스아 미도)프로파노일)피를리딘 -2-카복스아마이드; (134) (2S)— 1-(3-(4-(3-fluoro-4-( (1-(3-isopropyl-1,2,4-oxadiazole-5-yl)piperidine - 4-yl)methoxy)phenyl)cyclohex-3-encarboxamido)propanoyl)pyrlidine-2-carboxamide;
(135) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메특시 ) 페닐)싸이클로핵스 -3-엔일 ) ((S)-3-히드록시피를리딘 -1-일)메타논 ; (135) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) ((S)-3 -hydroxypyrlidin -1-yl)methanone;
(136) 4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메톡시 )페 닐 ) -N-( (S)— 2-히드록시프로필 )싸이클로핵스 -3-엔카복스아마이드; (136) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-( (S)—2-hydroxypropyl )Cyclohax-3-encarboxamide;
(137) tert-부틸 4— ((4-(4- (싸이클로프로필카바모일 )싸이클로핵 스 -1-엔일 )-3-플루오로페녹시 )메틸 )피페리딘 -1-카복시레이트； (137) tert-butyl 4— ((4-(4- (cyclopropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate;
(138) tert-부틸 4-( (3-플루오로 -4-(4-(2-플루오로에틸카바모 일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (138) tert-butyl 4-( (3-fluoro-4-(4-(2-fluoroethylcarbamo yl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate ;
(139) N-(2-((S)-2-시아노피를리딘 -1-일 )-2-옥소에틸 )— 4-(3-플 루오로 -4-( (1-(3-이소프로필 -1， 2， 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메 톡시 )페닐)싸이클로핵스 -3-엔카복스아마이드； (139) N-(2-((S)-2-cyanopyrlidin-1-yl)-2-oxoethyl)—4-(3-fluoro-4-( (1-(3-iso Propyl -1, 2, 4-oxadiazol -5-yl) piperidin -4-yl) methoxy) phenyl) cyclohex -3-enecarboxamide;
(140) N-(3-((S)-2ᅳ시아노피를리딘— 1-일 ) -3-옥소프로필) -4-(3ᅳ 플루오로 -4-((1-(3-이소프로필ᅳ1，2，4—옥사디아졸 -5-일 )피페리딘 -4-일 ) 메록시 )페닐)싸이클로핵스 -3-엔카복스아마이드； (140) N-(3-((S)-2ᅳCyanopyrlidin—1-yl)-3-oxopropyl)-4-(3ᅳFluoro-4-((1-(3-iso Propylᅳ1,2,4—oxadiazol -5-yl )piperidine -4-yl )meroxy )phenyl)cyclohex -3-enecarboxamide；
(141) tert-부틸 4-( (4-(4-(2 , 2-디플루오로에틸카바모일)싸이클 로핵스 -1-엔일 )-3-플루오로페녹시 )메틸)피페리딘 -1-카복시레이트；(141) tert-butyl 4-( (4-(4-(2, 2-difluoroethylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1 -Carboxylate；
(142) tert-부틸 4-( (3-플루오로 -4-(4-(2 , 2， 2-트리폴루오로에틸 카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 ; (142) tert-butyl 4-( (3-fluoro-4-(4-(2, 2, 2-tripoluoroethyl carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine -1-carboxylate;
(143) ( )-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4— ( (1-(3—이소 프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )페닐 )싸이클로핵 스 -3-엔일)메타논； (143) ( )-3- (dimethylamino)pyrlidin-1-yl) (4-(4— ( (1-(3—isopropyl-1,2,4-oxadiazol-5-yl) piperidin -4-yl) meroxy ) phenyl ) cyclohex -3-enyl) methanone;
(144) ((S)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(3-이소 프로필 -1,2， 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵 스 -3-엔일)메타논 ; (144) ((S)-3- (dimethylamino) pyrlidin -1-yl) (4-(4-((1-(3-isopropyl -1,2, 4-oxadiazole -5- 1)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(145) ((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(3-이소 프로필 -1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일)메톡시 )페닐 )싸이클로핵 스 -3-엔일)메타논 하이드로클로라이드; (145) ((R)-3- (dimethylamino)pyrlidin-1-yl) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazole-5- 1)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride;
(146) ((S)-3- (디메틸아미노)피를리딘— 1-얼 ) (4-(4-((1-(3-이소 프로필 -1,2 ,4-옥사디아졸— 5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵 스 -3-엔일)메타논 하이드로클로라이드; (146) ((S)-3- (dimethylamino)pyrlidine—1-al) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazole—5- 1 ) piperidin -4-yl ) methoxy ) phenyl ) cyclohex -3-enyl) methanone hydrochloride;
(147) ((R)-2- (하이드록시메틸)피를리딘 -1-일 ) (4-(4-((1-(3-이 소프로필 -1,2,4-옥사디아졸 -5-일)피쩨리던 -4-일)메특시 )페닐 )싸이클로 핵스 -3-엔일)메타논 ; (147) ((R)-2- (hydroxymethyl)pyrlidin-1-yl) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazole- 5-yl) phychelidon -4-yl) metaxi) phenyl) cyclohax -3-enyl) methanone;
(148) ((S)-2- (하이드록시메틸)피를리딘 -1-일) (4-(4-((1-(3-이 소프로필 -1,2，4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )페닐 )싸이클로 핵스 -3-엔일)메타논; (148) ((S)-2- (hydroxymethyl) pyrlidin -1-yl) (4-(4-((1-(3-isopropyl -1,2,4-oxadiazole - 5-yl)piperidin -4-yl)meroxy)phenyl)cyclohex-3-enyl)methanone;
(149) ((R)-3- (하이드록시-메틸)피를리딘 -1-일) (4-(4-((1-(3-이 소프로필 -1， 2， 4-옥사디아졸 -5-일)피페리딘 4-일)메톡시 )페닐)싸이클로 핵스 -3-엔일)메타논 ; . (149) ((R)-3- (hydroxy-methyl) pyrlidin -1-yl) (4-(4-((1-(3-isopropyl-1, 2, 4-oxadiazole -5-yl) piperidine 4-yl) methoxy) phenyl) cyclohex -3-enyl) methanone; .
(150) ((S)-3- (하이드록시메틸)피를리딘 -1-일) (4-(4-((1-(3-이 소프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘— 4-일)메톡시 )페닐 )싸이클로 핵스 -3-엔일)메타논 ; (150) ((S)-3- (hydroxymethyl) pyrlidin -1-yl) (4-(4-((1-(3-isopropyl -1,2,4-oxadiazole - 5-yl)piperidine— 4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(151) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘— 4-일 )메톡시 ) 페닐 )싸이클로핵스 -3-엔일) ((R)_2- (하이드록시메틸)피를리딘 -1-일 )메 타논 하이드로클로라이드; (151) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidine— 4-yl)methoxy)phenyl)cyclohex-3-enyl) ((R)_2- (hydroxymethyl)pyrlidin-1-yl)methanone hydrochloride;
(152) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메특시 ) 페닐)싸이클로핵스 -3—엔일) ((S)-3— (하이드록시메틸)피를리딘 -1-일)메 타논 ; (152) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3—enyl) ((S)-3 — (hydroxymethyl)pyrlidin-1-yl)methanone;
(153) (4-(4-(( 1-(5-에틸피리미딘 -2—일)피페리딘 -4-일)메톡시 ) 페닐 )싸이클로핵스 -3-엔일) ((R)-3- (하이드록시메틸)피를리딘 -1-일 )메 타논; (153) (4-(4-(( 1-(5-ethylpyrimidin-2—yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) ((R)-3 - (hydroxymethyl)pyrlidin-1-yl)methanone;
(154) ((S)_3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(5-에틸 피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타 논； (154) ((S)_3- (dimethylamino)pyrlidin-1-yl) (4-(4-((1-(5-ethyl pyrimidin-2-yl)piperidin-4-yl) Methoxy )phenyl)cyclohex-3-enyl)methanone；
(155) ((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(5-에틸 피리미딘 -2-일 )피페리딘— 4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔일)메타 논; (155) ((R)-3- (dimethylamino)pyrlidin-1-yl) (4-(4-((1-(5-ethyl pyrimidin-2-yl)piperidine— 4-yl ) methoxy ) phenyl ) cyclohex -3-enyl) meta rice paddy;
(156) ((S)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-(( l-(5-에틸 피리미딘 -2-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔일)메타 논 하이드로클로라이드; (156) ((S)-3- (dimethylamino)pyrlidin-1-yl) (4-(4-(( l-(5-ethyl pyrimidin-2-yl)piperidin-4-yl )methoxy )phenyl )cyclohex-3-enyl)methanone hydrochloride;
(157) ((R)-3- (디메틸아미노)피를리딘 -1-일 ) (4-(4-((1-(5-에틸 피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일 )메타 논 하이드로클로라이드 ; (157) ((R)-3- (dimethylamino)pyrlidin-1-yl) (4-(4-((1-(5-ethyl pyrimidin-2-yl)piperidin-4-yl )methoxy )phenyl)cyclohex-3-enyl)methanone hydrochloride;
(158) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일 ) ( (S)— 3- (하이드록시메틸)피를리딘 -1-일 )메 타논 하이드로클로라이드; (158) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) ((S)— 3 - (hydroxymethyl)pyrlidin-1-yl)methanone hydrochloride;
(159) (4-(4-((1-(5-에틸꾀리미딘 -2-일)피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일) ((R)-3- (하이드록시메틸)피를리딘 -1-일 )메 타논 하이드로클로라이드; (159) (4-(4-((1-(5-ethylcoulimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) ((R)- 3- (hydroxymethyl)pyrlidin-1-yl)methanone hydrochloride;
(160) (4-(4-((1-(5-에틸피리머딘 -2-일)피페리딘 -4ᅳ일 )메톡시 ) 페닐)싸이클로핵스 -3-엔일 ) ((S)-3—플루오로피를리딘 -1-일 )메타논 ; (160) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4ᅳyl)methoxy)phenyl)cyclohex-3-enyl) ((S)-3— fluoropyrlidin-1-yl)methanone;
(161) (4-(4-((1-(5ᅳ에틸피리미딘 -2-일)피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일) ((S)-3-플루오로피를리딘 -1-일 )메타논 하이 드로클로라이드; (161) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) ((S)-3 -fluoropyrlidin-1-yl)methanone hydrochloride;
(162) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 ) 페닐 )싸이클로핵스 -3-엔일 ) (피를리딘 -1-일 )메타논 ; (162) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) (pyrlidine-1 -1) Methanone;
(163) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐)싸이클로핵스 -3-엔일) (피페리딘 -1-일 )메타논； (163) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (piperidine-1 -1) Methanone；
(164) (4-(4-((1-(5-에틸꾀리데딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐)싸이클로핵스 -3-엔일 )(4-하이드록시피페리딘 -1-일)메타논； (164) (4-(4-((1-(5-ethylcoalidedin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-hydroxyp Peridine-1-yl)methanone；
(165) (4-(4-(( 1-.(5—에틸피리미딘 -2-일)피페리딘 -4-일)메톡시 ) 페닐 )싸이클로핵스 -3-엔일 ) (4- (하이드록시메틸)피페리딘 -1—일 )메타논 ; (165) (4-(4-(( 1-.(5—ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (4- (hyde Roxymethyl)piperidine-1—yl)methanone;
(166) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일) (피를리딘 -1-일 )메타논 하이드로클로라이 드■ (166) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) (pyrlidine-1 -1) Methanone hydrochloride■
(167) (4— (4-(( 1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐 )싸이클로핵스 -3-엔일) (피페리딘 -1-일 )메타논 하이드로클로라이 드ᅳ (167) (4— (4-(( 1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (piperidine-1 -1) Methanone hydrochloride dr.
(168) (4-(4-((1-(5_에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐 )싸아클로핵스 -3-엔일 ) (4-하이드록시피페리딘 -1-일 )메타논 하이드 로클로라이드; (168) (4-(4-((1-(5_ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)thacyclohex-3-enyl) (4-hydroxy Cipiperidin-1-yl)methanone hydrochloride;
(169) (4-(4-((1-(5—에틸피리미딘 -2-일)피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일 ) (4- (하이드록시메틸)피페리딘 -1-일 )메타논 하이드로클로라이드; (169) (4-(4-((1-(5—ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) (4- (hydroxy methyl)piperidin-1-yl)methanone hydrochloride;
(170) 아제티딘 -1-일 (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘- 4-일)메록시 )페닐)싸이클로핵스 -3-엔일)메타논; (170) Azetidin-1-yl (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohax-3-enyl) methanon;
(171) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록시 ) 페닐 )싸이클로핵스 -3-엔일) (3-하이드톡시아제티딘 -1-일)메타논； (171) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) (3-hydroxy Zetidine -1-yl)methanone;
(172) (4ᅳ(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메특시 ) 페닐 )싸이클로핵스 -3-엔일) (4-(2-하이드록시에틸)피페라진 -1-일 )메타 논； (172) (4ᅳ(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohax-3-enyl) (4-(2- Hydroxyethyl)piperazine-1-yl)methanone；
(173) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메특시 ) 페닐 )싸이클로핵스 -3-엔일 ) (4-(2ᅳ하이드록시에틸)피페리딘 -1-일 )메타 논； (173) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (4-(2ᅳ Hydroxyethyl) piperidin-1-yl) methanone；
(174) N-에톡시 -4-(4-((1-(5ᅳ에틸피리미딘 -2-일 )피페리딘 -4-일 ) 메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이드； (174) N-ethoxy-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(175) N-에틸 -4-(4-((1ᅳ(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메 톡시 )페닐) -N-(2-하이드록시에틸 )싸이클로핵스 -3-엔카복스아마이드； (175) N-ethyl-4-(4-((1ᅳ(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl) Cyclohax -3-encarboxamide;
(176) 4-(4-((1-(5-에틸피리미딘 -2-일)피페리단 -4-일 )메톡시 )페 닐 ) -N-( 2-하이드톡시에틸)싸이클로핵스 -3-엔카복스아마이드; (176) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidan-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex- 3-encarboxamide;
(177) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페 닐 )-N-(3-하이드록시 -2, 2-디메틸프로필)싸이클로핵스 -3-엔카복스아마 이드; (177) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxy-2,2- Dimethylpropyl)cyclohex-3-encarboxamide;
(178) 1- (4- (4- ((1- (5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡 시 )페닐 )싸이클로핵스ᅳ3_엔카보닐 )피페리딘 -4-카복스아마이드； (178) 1- (4- (4- ((1- (5-ethylpyrimidin -2-yl ) piperidin -4-yl ) methoxy ) phenyl ) cyclohex eu 3_encarbonyl ) piperidine -4-carboxamide;
(179) 4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4—일 )메톡시 )페 닐 )-N-( 3-메특시프로필 )싸이클로핵스 -3-엔카복스마마이드； (179) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4—yl)methoxy)phenyl)-N-(3-methoxypropyl)cyclohex - 3-Encarboxamide;
(180) 4-(4-((1-(5-에틸피리미딘 -2ᅳ일 )피페리딘 -4-일 )메톡시 )페 닐 )-N- (퓨란 -2-일메틸 )싸이클로핵스 -3-엔카복스아마이드； (180) 4-(4-((1-(5-ethylpyrimidin-2ᅳyl)piperidin-4-yl)methoxy)phenyl)-N- (furan-2-ylmethyl)cyclohex - 3-Encarboxamide;
(181) 4-(4-((1-(5-에틸피리미딘 -2—일)피페리딘 -4-일)메톡시 )페 닐 )-N,N-비스 (2-하이드록시에틸)싸이클로핵스 -3-엔카복스아마이드； (181) 4-(4-((1-(5-ethylpyrimidin-2—yl)piperidin-4-yl)methoxy)phenyl)-N,N-bis(2-hydroxyethyl) Cyclohax -3-encarboxamide;
(182) (4-하이드록시피페리딘 -1-일 ) (4-(4-((1-(3-이소프로필- 1,2, 4ᅳ옥사디아졸 -5-일)피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔 일 )메타논 ; (182) (4-Hydroxypiperidin-1-yl) (4-(4-((1-(3-isopropyl-1,2, 4-oxadiazol-5-yl)piperidine - 4-yl)meroxy)phenyl)cyclohex-3-en yl)methanone;
(183) (4- (하이드톡시메틸)피페리딘 -1-일 ) (4— (4-( (1-(3-이소프 로필 -1， 2，4-옥사디아졸 -5-일)피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타논; (183) (4- (Hydroxymethyl) piperidin -1-yl) (4— (4-( (1-(3-isopropyl-1, 2, 4-oxadiazol-5-yl) p peridin -4-yl ) methoxy ) phenyl) cyclohax -3-enyl) methanone;
(184) N-싸이클로프로필 -4-(4-((1-(3-이소프로필 -1，2，4-옥사디 아졸 -5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이 (184) N-Cyclopropyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl) Cyclohax-3-encarboxamie
(185) N-(3-하이드록시프로필) -4-(4-((1-(3-이소프로필 -1,2,4- 옥사디아졸 -5-일 )피페리딘3-4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스 아마이드; (185) N-(3-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine 3-4 -yl ) meroxy ) phenyl ) cyclohex -3-encarbox amide;
(186) (4-(2-하이드톡시에틸)피페리딘 -1-일 ) (4-(4-((1-(3-이소 프로필 -1,2，4ᅳ옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵 스 -3-엔일)메타논 ; (186) (4-(2-hydroxyethyl)piperidin-1-yl) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl) )piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(187) (4— (2-하이드록시에틸 )피페라진 -1-일 ) (4-(4-((1-(3-이소 프로필 -1,2,4-옥사디아졸— 5-일)피페리딘 -4-일)메록시 )페닐 )싸이클로핵 스 -3-엔일)메타논; (187) (4— (2-hydroxyethyl)piperazine-1-yl) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazole—5-yl) piperidin -4-yl) meroxy ) phenyl ) cyclohex -3-enyl) methanone;
(188) 4-(4-( (1-(3-이소프로필 -1，2， 4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐) -N- (메톡시메틸)싸이클로핵스 -3-엔카복스아마이드; (188) 4-(4-( (1-(3-isopropyl-1，2， 4-oxadiazol-5-yl)piperidine -4-yl)methoxy)phenyl)-N- (methoxymethyl)cyclohex-3-enecarboxamide;
(189) N-싸이클로프로필 -4-(4-( (1-(5-에틸피리미딘 -2-일 )피페리 딘 -4—일 )메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마이드； (189) N-Cyclopropyl -4-(4-( (1-(5-ethylpyrimidin-2-yl)piperidin-4—yl)methoxy)phenyl)cyclohex-3-encarboxamide;
(190) tert-부틸 4-( (4_(4-(2-하이드록시에틸카바모일)싸이클로 핵스 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (190) tert-butyl 4-( (4_(4-(2-hydroxyethylcarbamoyl)cyclohex 1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(191) tert-부틸 4-( (4-(4-(3_하이드록시 -2 , 2-디메틸프로필카바 모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (191) tert-butyl 4-( (4-(4-(3_hydroxy-2, 2-dimethylpropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate ;
(192) tert-부틸 4-( (4-(4- (메톡시메틸카바모일)싸이클로핵스- 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레아트； (192) tert-butyl 4-( (4-(4- (methoxymethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(193) tert-부틸 4-( (4-(4-(4- (괴를리딘 -1-일)피페리딘 -1-카보 닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트； (193) tert-butyl 4-( (4-(4-(4- (görlidin-1-yl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperi Din-1-carboxylate;
(194) tert-부틸 4-( (4-(4- (싸이클로부틸카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (194) tert-butyl 4-( (4-(4- (cyclobutylcarbamoyl)cyclohax-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(195) tert-부틸 4-( (4-(4- (싸이클로펜틸카바모일)싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트； (195) tert-butyl 4-( (4-(4- (cyclopentylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(196) tert-부틸 4-( (4-(4-(4-모폴리노피페리딘 -1-카보닐)싸이 클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (196) tert-Butyl 4-( (4-(4-(4-morpholinopiperidine -1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate ；
(197) 4-(4-((1-(5-에틸피려미딘 -2-일)피페리딘 -4-일 )메톡시 )페 닐 )-N-데톡시 -N-메틸싸이클로핵스 -3-엔카복스아마이드； (197) 4-(4-((1-(5-ethylpyramidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-detoxy-N-methylcyclohex-3 -Encarboxamide；
(198) 4-(4-((1-(5-에틸피리미딘 2-일 )피페리딘— 4-일 )메톡시 )페 닐 ) -N-메특시싸이클로핵스 -3-엔카복스아마이드; (198) 4-(4-((1-(5-ethylpyrimidin 2-yl)piperidine—4-yl)methoxy)phenyl)-N-methoxycyclohex-3-encarboxamide;
(199) tert-부틸 4-( (4-( 4- (에틸 (2-하이드록시에틸)카바모일)싸 이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 ; (199) tert-butyl 4-( (4-( 4- (ethyl (2-hydroxyethyl)carbamoyl)cyclohax-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(200) tert-부틸 4-( (4-(4-(4-(2-하이드록시에틸)피페라딘 -1-카 보닐)싸이클로핵스 - 1-엔일)페녹시 )데틸)피페리딘 -1-카복시 .레이트； (200) tert-Butyl 4-( (4-(4-(4-(2-hydroxyethyl)piperadine -1-carbonyl)cyclohex -1-enyl)phenoxy)decyl)piperidine - 1-carboxylate;
(201) tert-부틸 4— ((4-(4-(4-(2-하이드록시에틸)피페라진 -1-카 보닐)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (201) tert-butyl 4— ((4-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1 -Carboxylate;
(202) tert-부틸 4-( (4-(4- (피를리딘 -1-카보닐)싸이클로핵스 -1- 엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (202) tert-butyl 4-( (4-(4- (pyrlidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(203) tert-부틸 4-( (4-(4_(4-에틸피페라진 -1-카보닐)싸이클로 핵스 -1-엔일)페녹시 )메틸)피페리딘— 1-카복시레이트； (203) tert-butyl 4-( (4-(4_(4-ethylpiperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine—1-carboxylate;
(204) tert-부틸 4-( (4-(4- (피페리딘 -1-카보닐)싸이클로핵스 - 1- 엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (204) tert-butyl 4-( (4-(4- (piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(205) tert-부틸 4— ( (4-(4-(3 에톡시프로필카바모일 )싸이클로핵 스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (205) tert-butyl 4— ( (4-(4-(3 ethoxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(206) tert-부틸 4-( (4ᅳ(4- (비스 (2-하이드록시에틸)카바모일)싸 이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트； (206) tert-butyl 4-( (4ᅳ(4- (bis (2-hydroxyethyl) carbamoyl) cyclohax -1-enyl) phenoxy) methyl) piperidine -1-carboxylate;
(207) 1-(4-(4-((1-(3ᅳ이 소프로필 -1，2，4-옥사디아졸 -5-일)피페 리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘 -4-카복스아 마이드 ; (207) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)meroxy)phenyl)cyclohex -3-encarbonyl)piperidine -4-carboxamide;
(208) (4-(4-((1-(3-이소프로필 -1， 2，4-옥사디아졸 -5-일 )피페리 딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일) (4- (피를리딘 -1-일 )피페리 딘 -1-일 )메타논 ; (208) (4-(4-((1-(3-isopropyl-1, 2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -enyl) (4- (pyrlidin -1-yl) piperi din -1-yl ) methanone ;
(209) (4-(4-((1-(3-이소프로필— 1，2，4-옥사디아졸 -5-일 )피페리 딘 -4-일)메록시 )페닐)싸이클로핵스 -3-엔일) (4-모폴리노피페리딘 -1-일 ) 메타논 ; (209) (4-(4-((1-(3-isopropyl—1,2,4-oxadiazol-5-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3 -enyl) (4-morpholinopiperidin -1-yl) methanone;
(210) N-싸이클로펜틸 -4— (4-((1-(3-이소프로필 -1，2，4-옥사디아 졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스아마이 드 ᅳ (210) N-cyclopentyl -4— (4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)meroxy)phenyl) Cyclohex-3-encarboxamide eu
(211) N-싸이클로부틸 -4-(4-((1-(3-이소프로필 -1， 2，4-옥사디아 졸 -5-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔카복스아마이 드 (211) N-Cyclobutyl-4-(4-((1-(3-isopropyl-1, 2,4-oxadiazol-5-yl)piperidin-4-yl)meroxy)phenyl) Cyclohex-3-encarboxamide
(212) (3 ,4-디하이드로이소퀴놀린 -2(1H)-일 ) (4-(4-( (1-(3-이소 프로필 -1,2 ,4-옥사디아졸 -5-일 )피페리딘 -4—일 )메톡시 )페닐)싸이클로핵 스 -3-엔일)메타논 ; (212) (3,4-dihydroisoquinolin-2(1H)-yl) (4-(4-( (1-(3-isopropyl-1,2,4-oxadiazol-5-yl) piperidine -4—yl )methoxy )phenyl)cyclohex-3-enyl)methanone ;
(213) (4-(4-( (1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일 )피페리 딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔일 ) (1-메틸 -3ᅳ 4-디하이드로이 소퀴놀린 -2(1H)-일)메타논 ; (213) (4-(4-( (1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -enyl) (1-methyl-3ᅳ 4-dihydroisoquinoline-2(1H)-yl)methanone;
(214) 이소인돌린 -2-일 (4-(4-((1-(3-어소프로필-1，2，4-옥사디아 졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로웩스 -3-엔일 )메타논 ; (214) Isoindolin-2-yl (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy ) Phenyl ) Cyclowex-3-enyl ) Methanone ;
(215) 1，4'-바이피페리딘 -Γ-일 (4-(4-((1-(3—이소프로필 -1,2,4- 옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔일)메 타논; (215) 1,4'-bipiperidine -Γ-yl (4-(4-((1-(3—isopropyl -1,2,4-oxadiazole -5-yl)piperidine - 4-yl)meroxy)phenyl)cyclohex-3-enyl)methanone;
(216) tert-부틸 4-((4-(4-(1，4'—바이피페리딘 -Γ-카보닐 )싸이 클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트； (216) tert-butyl 4-((4-(4-(1,4'—bipiperidine -Γ-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine -1- Carboxylate;
(217) (4— (4-( (1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐)싸이클로핵스 -3-엔일 ) (3- (하이드록시이미노)피를리딘 -1-일 )메타 논！ (217) (4— (4-( (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (3- (hydroxyy Mino)pyrlidin-1-yl)metanone!
(218) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 ) 페닐)싸이클로핵스 -3-엔일) (4- (피를리딘 -1-일 )피페리딘 -1-일 )메타논 ; (218) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (4- Ridin-1-yl)piperidin-1-yl)methanone;
(219) 1，4'-바이피페리딘 -Γ-일 (4-(4-((1-(5-에틸피리미딘 -2- 일 )피페라딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3—엔일)메타논 ; (219) 1,4'-bipiperidin -Γ-yl (4-(4-((1-(5-ethylpyrimidin-2-yl)piperadin-4-yl)methoxy)phenyl) cyclohex-3—enyl)methanone;
(220) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메록시 ) 페닐 )싸이클로핵스 -3-엔일 ) (4-모폴리노피페리딘 -1-일 )메타논 ; (220) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) (4-morpholinopy peridine-1-yl)methanone;
(221) tert-부틸 4-( (4-(4- (퓨란 -2-일메틸카바모일)싸이클로핵 스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (221) tert-butyl 4-( (4-(4- (furan-2-ylmethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(222) tert-부틸 4-( (4-(4- (메록시카바모일)싸이클로핵스 -1-엔 일)페녹시 )메틸)피페리딘 -1-카복시레이트 ; (222) tert-butyl 4-( (4-(4- (meroxycarbamoyl)cyclohex-1-en yl)phenoxy)methyl)piperidine-1-carboxylate;
(223) tert-부틸 4-( (4-(4- (메톡시 (메틸 )카바모일)싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (223) tert-butyl 4-( (4-(4- (methoxy (methyl) carbamoyl) cyclohex -1-enyl) phenoxy) methyl) piperidine -1-carboxylate;
(224) tert-부틸 4— ( (4_(4-(2， 5-디하이드로 -1H-피를 -1-카보닐) 싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (224) tert-butyl 4— ( (4_(4-(2， 5-dihydro -1H-pyrol -1-carbonyl) cyclohex -1-enyl) phenoxy ) methyl) piperidine -1- Carboxylate;
(225) tert-부틸 4_( (4-(4-(4-하이드록시피페리딘 -1-카보닐)싸 이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (225) tert-butyl 4_( (4-(4-(4-hydroxypiperidine -1-carbonyl) cyclohax -1-enyl) phenoxy ) methyl) piperidine -1-carboxylate ;
(226) tert-부틸 4-( (4-(4-(4- (하이드록시메틸)피페리딘— 1-카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (226) tert-Butyl 4-( (4-(4-(4- (hydroxymethyl)piperidine— 1-carbonyl )cyclohax -1-enyl)phenoxy )methyl)piperidine -1- Carboxylate;
(227) 1-(4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡 시 )페닐 )싸이클로핵스 -3-엔카보닐 )피페리딘 -4-카보나이트릴； (227) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidine-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine -4-Carbonitrile；
(228) (4-(4-(( 1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메록시 ) 페닐)싸이클로핵스 -3-엔일) (스피로 [인덴 -1 , 4 '-피페리딘] -1 일 )메타 논； (228) (4-(4-(( 1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) (spiro [indene-1 , 4 '-piperidine] -1 day) Methanone；
(229) (4-(4-((1-(5-에틸피리미딘—2-¾ )피페리딘— 4-일)메록시 ) 페닐 )싸이클로핵스 -3-엔일 )(1，4-디옥사-8-아자스피로[4.5]데칸 -8-일 ) 메타논 ; (229) (4-(4-((1-(5-ethylpyrimidine—2-¾ )piperidine—4-yl)meroxy )phenyl )cyclohex-3-enyl )(1,4-di oxa-8-azaspiro[4.5]decane-8-yl) methanone;
(230) N-싸이클로펜틸 -4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메록시 )페닐 )싸이클로핵스 -3-엔카복스아마이드； (230) N-Cyclopentyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enecarboxamide;
(231) N-싸이클로부틸 -4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡시 )페닐)싸미클로핵스 -3-엔카복스아마어드 ; (231) N-Cyclobutyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxama Erd ;
(232) (3,4-디하이드로이소퀴놀린 -2(1H)-일 ) (4-(4-((1-(5-에틸 피리미딘 -2-일 )피페리딘—4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일)메타 논； (232) (3,4-dihydroisoquinolin-2(1H)-yl) (4-(4-((1-(5-ethyl pyrimidin-2-yl)piperidin—4-yl) Toxy )phenyl)cyclohex-3-enyl)metanone；
(233) tert-부틸 4-( (4-,(4-( 5-하이드록시펜틸카바모일 )싸이클로 핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (233) tert-butyl 4-( (4- , (4-(5-hydroxypentylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(234) 4-(4-((1-(5-에틸피리미딘 -2—일)피페리딘 -4-일 )메톡시 )페 닐 )-N-(5-하이드록시펜틸)싸이클로핵스 -3-엔카복스아마이드; (234) 4-(4-((1-(5-ethylpyrimidin-2—yl)piperidin-4-yl)methoxy)phenyl)-N-(5-hydroxypentyl)cyclohex - 3-encarboxamide;
(235) (2 ,5-디하이드로 -1H-피를 -1-일 ) (4-(4-( (1— (5-에틸피리미 딘 -2-일 )피페리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3—엔일)메타논 ; (235) (2,5-dihydro-1H-pyrol-1-yl) (4-(4-( (1— (5-ethylpyrimidin-2-yl)piperidin-4-yl) methoxy )phenyl)cyclohex-3—enyl)methanone ;
(236) tert-부틸 4-( (4— (4-( ( 2-하이드록시에틸) (메틸)카바모일) 싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -,1-카복시레이트; (236) tert-butyl 4-( (4— (4-( ( 2-hydroxyethyl) (methyl) carbamoyl) cyclohex -1-enyl ) phenoxy ) methyl ) piperidine -, 1-carboxylate ;
(237) tert-부틸 4-( ( 4-( 4-( 1， 3-디하이드록시프로판 -2-일카바모 일 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (237) tert-butyl 4-( ( 4-( 4-( 1，3-dihydroxypropan -2-ylcarbamo yl ) cyclohex -1-enyl) phenoxy ) methyl) piperidine -1- Carboxylate;
(238) tert-부틸 4-( (4-(4-( 3-하이드록시프로필카바모일)싸이클 로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트 ; (238) tert-butyl 4-( (4-(4-(3-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(239) tert-부틸 4-( (4-(4-( 1ᅳ 2， 3 , 4-테트라하이드로이소퀴놀린- (239) tert-butyl 4-( (4-(4-( 1ᅳ 2, 3, 4-tetrahydroisoquinoline-
2-카보닐 )싸이클로핵스 -1-엔일)페녹시 )메틸 )피페리딘 -1-카복시레아트；2-carbonyl ) cyclohex -1-enyl) phenoxy ) methyl ) piperidine -1-carboxyreate;
(240) tert-부틸 4-( (4-(4- (이소인돌린 -2-카보닐)싸이클로핵스- 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (240) tert-butyl 4-( (4-(4- (isoindoline-2-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(241) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메록시 ) 페닐)싸이클로핵스 -3-엔일) (이소인돌린 -2-일)메타논; (241) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy)phenyl)cyclohex-3-enyl) (isoindoline-2 -1) methanone;
(242) 4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일)메톡시 )페 닐 ) -N- ( 3-하이드록시프로필) -N-메틸싸이클로핵스 -3-엔카복스아마이드; (242) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N- (3-hydroxypropyl)-N- Methylcyclohex-3-encarboxamide;
(243) N-(3-하이드록시프로필) -4-(4-((1-(3-이소프로필 -1，2，4- 옥사디아졸 -5-일)피페리딘 -4-일 )메톡시 )페닐 )-N-메틸싸이클로핵스 -3- 엔카복스아마이드; (243) N-(3-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl) methoxy )phenyl )-N-methylcyclohex -3- encarboxamide;
(244) N- (퓨란 -2-일메틸) -4-(4-((1-(3-이소프로필 -1,2ᅳ 4-옥사다 아졸 -5-일)피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔카복스아마이 (244) N- (furan-2-ylmethyl) -4-(4-((1-(3-isopropyl-1,2ᅳ 4-oxadazol-5-yl)piperidin-4-yl )methoxy )phenyl)cyclohex-3-encarboxamii
(245) N-(3-에록시프로필 )-4-(4-((1-(3-이소프로필 -1，2，4-옥사 디아졸ᅳ5-일)피페리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카복스아마 이드 ; (245) N-(3-eroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxa diazol-5-yl)piperidine-4-yl) methoxy ) phenyl ) cyclohex -3-encarboxamide ;
(246) 4-(4-((1-(3ᅳ이소프로필 -1，2，4—옥사디아졸 -5-일)피페리딘 (246) 4-(4-((1-(3-isopropyl-1，2，4—oxadiazole-5-yl)piperidine
-4-일 )메톡시 )페닐 )-Ν-메톡시싸이클로핵스 -3-엔카복스아마이드 ; -4-yl )methoxy )phenyl )-Ν-methoxycyclohex -3-enecarboxamide ;
(247) 4-(4-((1-(3-이소프로필— 1，2，4-옥사디아졸 -5—일 )피페리딘 -4-일 )메특시 )페닐 )-Ν-메톡시 -Ν-메틸싸이클로핵스 -3-엔카복스아마이 드 * (247) 4-(4-((1-(3-isopropyl— 1,2,4-oxadiazol -5—yl ) piperidin -4-yl ) methoxy ) phenyl )-Ν-methoxy -Ν-methylcyclohex-3-encarboxamide *
(248) Ν,Ν—비스 (2-하이드록시에털) -4-(4-((1-(3-이소프로필- (248) Ν,Ν—bis (2-hydroxyethyl) -4-(4-((1-(3-isopropyl-
1,2,4-옥사디아졸 -5-일 )피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔 카복스아마이드; 1,2,4-oxadiazol -5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-ene carboxamide;
(249) 1-(4-(4-((1-(3-,이소프로필 -1,2,4-옥사디아졸 -5-일)피페 리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘 -4-카복스아 마이드; (249) 1-(4-(4-((1-(3- , isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex -3-encarbonyl)piperidine -4-carboxamide;
(250) 1-(4-(4— ((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록 시 )페닐)싸이클로핵스 -3-엔카보닐)피를리딘 -3-은 ; (250) 1-(4-(4— ((1-(5-ethylpyrimidin -2-yl)piperidine-4-yl)meroxy)phenyl)cyclohex-3-encarbonyl)pyrlidine -3- is ;
(251) 1-(4-(4-((1-(3-이소프로필-1，2,4-옥사디아졸-5-일)피페 리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘 -4-카복스아 마이드； ' . (251) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex - 3-encarbonyl) piperidine -4-carboxamide; ' .
(252) 1ᅳ(4-(4-((1-(3-이소프로필 -1,2,4-옥사디아졸 -5-일 )피페 리딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘 -4-카복스아 마이드; (252) 1ᅳ(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex - 3-encarbonyl)piperidine-4-carboxamide;
(253) (Ζ)-(3, 3-비스 (하이드록시메틸) -4- (메톡시이미노)피를리 딘 -1-일) (4-(4— ((1-(5-에틸피리미딘 - -일)피페리딘 -4-일-)메특시 )페닐) 싸이클로핵스—3-엔일)메타논 ; (253) (Ζ)-(3, 3-bis (hydroxymethyl) -4- (methoxyimino) pyrlidin -1-yl) (4-(4— ((1-(5-ethylpyryl) Mydine - -yl)piperidine -4-yl-)methoxy )phenyl)cyclohex—3-enyl)methanone ;
(254) (Z)-tert-부틸 6_(4-(4-( ( 1-(5-에틸피리미딘 -2-일)피쩨리 딘 -4-일 )메록시 )페닐)싸이클로핵스 -3-엔카보닐) -8- (메톡시이미노) - 2，6-디아자스피로 [3.4]옥탄 -2-카복시레이트; (254) (Z)-tert-butyl 6_(4-(4-( ( 1-(5-ethylpyrimidin-2-yl)picheridin-4-yl)meroxy)phenyl)cyclohex-3- Encarbonyl) -8- (methoxyimino) - 2,6-diazaspiro [3.4] octane -2-carboxylate;
(255) (Z)-(4-(4-((l-(5-에틸피리미딘 -2-일 )피페리딘 -4-일)메톡 시 )페닐 )싸이클로핵스 -3-엔일 ) (8- (메톡시이미노) -2， 6_디아자스피로 (255) (Z)-(4-(4-((l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (8 - (methoxyimino) -2，6_diazaspiro
[3.4]옥탄 -6-일)메타논 하이드로클로라이드; [3.4]octane-6-yl)methanone hydrochloride;
(256) tert-부틸 4-( (4-(4-(4- (싸이클로프로필메틸)피페라진 -1- 카보닐)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트； (256) tert-butyl 4-( (4-(4-(4- (cyclopropylmethyl)piperazine -1- carbonyl)cyclohax -1-enyl)phenoxy)methyl)piperidine -1-carboxy Rate;
(257) tert-부틸 4-( (4-(4-(3， 3-디풀루오로피를리딘 -1-카보닐) 싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 (257) tert-butyl 4-( (4-(4-(3, 3-difluoropyrlidine -1-carbonyl) cyclohex -1-enyl) phenoxy ) methyl) piperidine -1- carboxylate
(258) (3,3-디플루오로피를리딘 -1-일) (4-(4-((1-(5-에틸피리미 딘 -2-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔일)메타논 ; (258) (3,3-difluoropyridin-1-yl) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)mer Toxy )phenyl )cyclohax -3-enyl)methanone ;
(259) (3,3-디플루오로피를리딘 -1-일 ) (4-(4-((1-(3-이소프로필- 1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔 일 )메타논 ; (259) (3,3-difluoropyrlidin-1-yl) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazole-5-yl)p peridin -4-yl ) metaxi ) phenyl) cyclohax -3-en yl ) methanone ;
(260) -N-(5-하이드록시펜틸) -4— (4-((1-(3-이소프로필 -1，2，4-옥 사디아졸 -5-일)피페리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔카복스아 마이드； : (260) -N-(5-hydroxypentyl) -4— (4-((1-(3-isopropyl -1,2,4-ox Cydiazol -5-yl) piperidin -4-yl) methoxy) phenyl) cyclohex -3-encarboxamide ;:
(261) tert-부틸 4-((4-(4-(2，2,2-트리플루오로에틸카바모일 )싸 이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트 ; (261) tert-butyl 4-((4-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohax-1-enyl)phenoxy)methyl)piperidine-1-carboxy rate ;
(262) tert-부틸 4-((4-(4-(4-시아노싸이클로핵산카보닐 )싸이클 로핵스 -1-엔일)페녹시 )메틸 )피페리딘 -1-카복시레이트； (262) tert-butyl 4-((4-(4-(4-cyanocyclonucleic acid carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(263) tert-부틸 4-( (4-(4-( 1 , 4-디옥사 -8-아자스피로 [4.5]데칸- 8-카보닐 )싸이클로핵스— 1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (263) tert-butyl 4-( (4-(4-( 1,4-dioxa-8-azaspiro [4.5]decane- 8-carbonyl)cyclohex—1-enyl)phenoxy)methyl)p Peridine -1-carboxylate;
(264) tert-부틸 4-( ( 4-( 4- (스피로 [인덴 -1， 4 ' -피페리딘] -Γ -일 카보닐)싸어클로핵스 -1-엔일)페녹시 )메틸)피쩨리딘 -1-카복시레이트; (264) tert-butyl 4-( ( 4-( 4- (spiro [indene -1, 4 '-piperidine] -Γ -yl carbonyl) cyclohex -1-enyl) phenoxy ) methyl) pice Lydine-1-carboxylate;
(265) tert-부틸 4-( (4-(4-(3-옥소피를리딘 -1-카보닐)싸이클로 핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트； (265) tert-butyl 4-( (4-(4-(3-oxopyrlidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(266) 1-(4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일 )피페 리딘 -4-일)메록시 )페닐)싸이클로핵스 -3-엔카보닐)피페리던 -4-카보나이 트릴 ; (266) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)meroxy)phenyl)cyclohex - 3-enecarbonyl) piperidone -4-carbonate trill;
(267) (4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일 )피페리 딘 -4-일)메톡시 )페닐 )싸이클로핵스 -3-엔얼) (1,4-디옥사 -8-아자스피로 [4.5]데칸 -8-일 )메타논 ; (267) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -ener) (1,4-dioxa -8-azaspiro [4.5] decane -8-yl) methanone;
(268) (2,3-디하이드로스피로 [인덴— 1，4'-피페리딘] -Γ-일 ) (4- (4-((1-(3_이소프로필 -1,2，4-옥사디아졸 -5-일)피페리딘 -4-일)메특시 ) 페닐 )싸이클로핵스 -3-엔일)메타논； (268) (2,3-dihydrospiro [indene—1,4'-piperidine] -Γ-yl) (4- (4-((1-(3_isopropyl -1,2,4- oxadiazol -5-yl) piperidin -4-yl) metaxy) phenyl) cyclohex -3-enyl) methanone;
(269) (3- (에톡시이미노)피를리딘 -1-일 ) (4-(4-((1-(5-에틸피리 미딘 -2-일 )피페리딘 -4-일 )메록시 )페닐 )싸이클로핵스 -3-엔일 )메타논； (269) (3- (ethoxyimino)pyrlidin-1-yl) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)meroxy ) Phenyl ) Cyclohax -3-enyl ) Methanone;
(270) tert-부틸 4-( (4-(4-(4- (메록시이미노)피페리딘ᅳ 1-카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피훼리딘—1_카복시레이트.; (270) tert-Butyl 4-( (4-(4-(4- (meroxyimino)piperidineᅳ 1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine—1_ Carboxylate . ;
(271) tert-부틸 4-((4-(4-(4- (하이드록시이미노)피페리딘 -1-카 보닐)싸이클로핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트； (271) tert-butyl 4-((4-(4-(4- (hydroxyimino)piperidine -1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1- Carboxylate;
(272) tert-부탈 4-( (4-(4-(4-옥소피페리딘 -1-카보닐)싸이클로 핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (272) tert-butal 4-( (4-(4-(4-oxopiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(273) tert-부틸 4-( (4-(4- (3- (메특시이미노)피를리딘— 1-카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메 -틸 )피페리딘 -1-카복시레이트； (273) tert-Butyl 4-( (4-(4- (3- (methoxyimino)pyrlidine— 1-carbonyl)cyclohex-1-enyl)phenoxy)methyl-thyl)piperidine - 1-carboxylate;
(274) 1— (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메록 시 )페닐 )싸이클로핵스 -3-엔카보닐)피페리딘 -4-온； (274) 1— (4-(4-((1-(5-ethylpyrimidin -2-yl)piperidine-4-yl)meroxy)phenyl)cyclohex-3-encarbonyl)piperidine -4-on；
(275) 1-(4-(4-((1-(3_이소프로필 -1,2,4-옥사디아졸 -5—일 )피페 리딘 -4-일)메톡시 )페닐)싸이클로핵스 -3-엔카보닐)피페리딘 -4-온； (275) 1-(4-(4-((1-(3_isopropyl-1,2,4-oxadiazol-5—yl)piperidin-4-yl)methoxy)phenyl)cyclohex - 3-encarbonyl) piperidine -4-one;
(276) (4- (하이드록시이미노)피페리딘 -1-일 ) (4-(4-((1-(3-이소 프로필 -1，2，4-옥사디아졸 -5-일)피페리딘 -4-일)메록시 )페닐)싸이클로핵 스 -3-엔일)메타논 ; (276) (4- (hydroxyimino) piperidin -1-yl) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)p peridin -4-yl) meroxy ) phenyl) cyclohex -3-enyl) methanone ;
(277) (4-(4-((1-(5-에틸피리미딘 -2-일)피페리딘 -4-일 )메톡시 ) 페닐)싸이클로핵스 -3-엔일 ) (4- (하이드록시이미노)피페리딘 -1-일 )메타 논; ' (277) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (4- (hydroxyy mino)piperidine-1-yl)methanone; '
(278) (4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피페리 딘 - 4 -일)메특시 )페닐)싸이클로핵스 - 3 -엔일) ( 4 - (메톡시이미노)피페리딘 (278) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperi Dean - 4 -yl)methoxy)phenyl)cyclohex -3 -enyl) ( 4 - (methoxyimino)piperidine
— 1-일 )메타논 ; — 1-day ) methanone ;
(279) (4-(4-((1-(3-이소프로필-1，2，4-옥사디아졸 -5-일 )피페리 딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔일) (4- (메록시이미노)피페리딘 -1-일 )메타논 ; (279) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -enyl) (4- (meroxyimino) piperidin -1-yl) methanone;
(280) tert-부틸 4-((4-(4-(3-옥소아제티딘 -1-카보닐)싸이클로 핵스 -1-엔일 )페녹시 )메틸)피페리딘 -1-카복시레이트; (280) tert-butyl 4-((4-(4-(3-oxoazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(281) tert 부틸 4-( (4-(4-(3- (하이드록시이미노)아제티딘 -1-카 보닐 )싸이클로핵스 -1-엔일 )페녹시 )메틸 )피페리딘 -1-카복시레이트； (281) tert Butyl 4-( (4-(4-(3- (hydroxyimino)azetidine -1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate ；
(282) tert-부틸 4-( (4-(4-(3_ (메톡시이미노)아제티딘 -1-카보 닐 )싸이클로핵스 -1-엔일)페녹시 )메틸)피페리딘 -1-카복시레이트; (282) tert-Butyl 4-( (4-(4-(3_ (methoxyimino)azetidine -1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate ;
(283) 1-(4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일 )메톡 시 )페닐)싸이클로핵스 -3-엔카보닐)아제티딘 -3-온; (283) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-encarbonyl)azetidine - 3-on;
(284) l-(4-(4-(U-(3-이소프로필 -1，2，4-옥사디아졸— 5-일 )피페 리딘 -4-일 )메톡시 )페닐)싸이클로핵스 -3-엔카보닐)아제티딘 -3-온； (284) l-(4-(4-(U-(3-isopropyl-1,2,4-oxadiazole—5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -encarbonyl)azetidine -3-one；
(285) (3- (하이드록시이미노)아제티딘 -1-일 ) (4-(4-((1-(3-이소 프로필 -1，2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메록시 )페닐)싸이클로핵 스 -3-엔일)메타논 ; (285) (3- (hydroxyimino)azetidin-1-yl) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperi din -4-yl ) meroxy ) phenyl) cyclohex -3-enyl) methanone ;
(286) (4-(4-((1-(3-이소프로필 -1，2，4-옥사디아졸 -5-일)피페리 딘 -4-일 )메특시 )페닐)싸이클로핵스 -3-엔일) (3- (메톡시이미노)아제티딘 (286) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3 -enyl) (3- (methoxyimino)azetidine
— 1-일 )메타논 ; — 1-day ) methanone ;
(287) (4-(4-((1-(5-에틸피리미딘 -2-일 )피페리딘 -4-일)메톡시 ) 페닐)싸이클로핵스 -3-엔일) (3-(메톡시이미노 )아제티딘 -1-일 )메타논 ; (287) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl) (3-(methoxyyl) Mino)azetidin-1-yl)methanone;
(288) tert-부틸 4-((4-(4— (3-하이드록시아제티딘 -1-카보닐)싸 이클로핵스 -1-엔일 )페녹시 )메틸 )피페 ^딘 -1-카복시레이트 ; 및 (288) tert-butyl 4-((4-(4— (3-hydroxyazetidine -1-carbonyl) cyclohax -1-enyl ) phenoxy ) methyl ) pipe ^dine -1-carboxylate ; and
(289) (3-하이드록시아제티딘 -1-일 ) (4-(4-((1-(3-이소프로필- 1ᅳ 2，4-옥사디아졸 -5-일 )피페리딘 -4-일 )메톡시 )페닐 )싸이클로핵스 -3-엔 일 )메타논 . [청구항 5】 (289) (3-Hydroxyazetidin-1-yl) (4-(4-((1-(3-isopropyl-1ᅳ 2,4-oxadiazol-5-yl)piperidine-4 - one ) methoxy ) phenyl ) cyclohex -3-en one ) methanone . [Claim 5]
하기 반웅식 1에 나타난 바와 같이， As shown in reaction equation 1 below,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반웅시켜 화학식 4로 표시되는 화합물올 제조하는 단계 (단계 1); Preparing a compound represented by Formula 4 by reacting a compound represented by Formula 2 and a compound represented by Formula 3 (Step 1);
상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반웅시켜 화학식 6으로 표시되는 화합물을 제 조하는 단계 (단계 2); Preparing a compound represented by Formula 6 by reacting the compound represented by Formula 4 and the compound represented by Formula 5 prepared in Step 1 (Step 2);
상기 단계 2에서 제조한 화학식 6으로 표시되는 화합물을 염기 와 반웅시켜 화학식 7로 표시되는 화합물을 제조하는 단계 (단계 3); 및 Preparing a compound represented by Formula 7 by reacting the compound represented by Formula 6 prepared in Step 2 with a base (Step 3); and
상기 단계 3에서 제조한 화학식 7로 표시되는 화합물과 화학식 Compound and formula represented by formula 7 prepared in step 3 above
8로 표시되는 화합물을 반웅시켜 화학식 1로 표시되는 화합물올 얻는 단계 (단계 4);를 포함하는 제 1항의 화학식 1로 표시되는 화합물의 제 조방법 : A step of reacting the compound represented by 8 to obtain a compound represented by Formula 1 (step 4); the first step of the compound represented by Formula 1 of claim 1, including; Method:
Figure imgf000257_0001
Figure imgf000257_0001
(상기 반웅식 1에서， (In reaction 1 above,
R1, R2, R3, R4, A 및 E는 제 1항의 화학식 1에서 정의한 바와 같다). R 1 , R 2 , R 3 , R 4 , A and E are as defined in Formula 1 of Clause 1).
【청구항 6】 【Claim 6】
제 5항에 있어서， In clause 5,
상기 단계 3의 염기는 세슘카보네미트 (Cs2C03), 포타슘하이드록 사이드 (K0H), 소듐하이드록사이드 (NaOH) '및 리튬하이드톡사이드 (LiOH) 로 이루어자는 군으로부터 선.택되는 어느 하나인 것을 특징으로 하는 제 1항의 화학식 1로 표시되는 화합물의 제조방법 . 【청구항 7】 The base in step 3 is selected from the group consisting of cesium carbonate (Cs 2 C0 3 ), potassium hydroxide (K0H), sodium hydroxide (NaOH) ', and lithium hydroxide (LiOH). A method for producing a compound represented by Formula 1 of claim 1, characterized in that: 【Claim 7】
제 1항의 화합물， 이의 광학 이성질체 , 또는 이의 약학적으로 허 용가능한 염을 유효성분으로 함유하는 대사성 질환의 예방 또는 치료 용 약학적 조성물 . 【청구항 8】 A pharmaceutical composition for the prevention or treatment of metabolic diseases containing the compound of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 【Claim 8】
제 7항에 있어서， In clause 7,
상기 화합물은 GPR-119(G protein-coupled receptor 119)를 활 성화시켜 cAMPCCyclic adenosine monophosphate)의 세포 내 활성을 증 가시키고， 신경 내분비 단백질인 GLP-l(Glucagon-l ike peptide-1) 방 출을 유도하는 것을 특징으로 하는 대사성 질환의 예방 또는 치료용 약학적 조성물 . 【청구항 9】 The compound activates GPR-119 (G protein-coupled receptor 119) to increase the intracellular activity of cAMPCCyclic adenosine monophosphate, and releases GLP-l (Glucagon-l ike peptide-1), a neuroendocrine protein. A pharmaceutical composition for preventing or treating metabolic diseases, which is characterized by inducing. 【Claim 9】
제 7항에 있어서 , . In clause 7, .
상기 대사성 질환은 비만, I 형 당뇨병， Π형 당뇨병 , 부적합한 내당증， 인슐린 내성증， 고혈당증， 고지질혈증， 고중성지방혈증， 고콜 레스테를혈증， 이상지질혈증 및 X 증후군으로 이루어진 군으로부터 선 택되는 어느 하나인 것을 특징으로 하는 대사성 질환의 예방 또는 치 료용 약학적 조성물. The metabolic disease is selected from the group consisting of obesity, type I diabetes, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X. A pharmaceutical composition for preventing or treating metabolic diseases, characterized in that it is one of the following.
[청구항 10】 [Claim 10]
제 1항의 화합물, 이의 광학 이성질체， 또는 이의 약학적으로 허 용가능한 염을 유효성분으로 함유하는 GPR-119(G protein-coupled receptor 119) 활성화제 . A GPR-119 (G protein-coupled receptor 119) activator containing the compound of claim 1, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.
【청구항 11】 【Claim 11】
제 1항의 화합물， 이의 광학 어성질체， 또는 이의 약학적으로 허 용가능한 염을 유효성분으로 함유하는 대사성 질환의 예방 또는 개선 용 건강기능식품. A health functional food for preventing or improving metabolic diseases containing the compound of claim 1, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.
【청구항 12】 【Claim 12】
제 11항에 있어서， In clause 11,
상기 대사성 질환은 비만， I 형 당뇨병， Π형 당뇨병 , 부적합한 내당 증， 인슐린 내성증， 고혈당증， 고지질혈증， 고중성지방혈증， 고콜레스 테를혈증, 이상지질혈증 및 X 증후군으로 이루어진 군으로부터 선택되 는 어느 하나인 것을 특징으로 하는 대사성 질환의 예방 또는 개선용 건강기능식품. The metabolic disease is selected from the group consisting of obesity, type I diabetes, type Π diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X. A health functional food for preventing or improving metabolic diseases, characterized in that it is one of the following:
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