# Patent

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

## 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.

## Background
This application is a U.S. National Stage Application under 35 U.S.C. §371 of International Patent Application No. PCT/KR2015/004449 filed 1 May 2015, which claims the benefit of priority to Korean Patent Application No. 10-2015-0062119 filed 30 Apr. 2015 and Korean Patent Application No. 10-2014-0053535 filed 2 May 2014, the disclosures of all of which are hereby incorporated by reference in their entireties. The International Application was published in Korean on 5 Nov. 2015 as WO 2015/167309.
TECHNICAL FIELD
The present invention relates to a cyclohexene derivative, or an optical isomer or pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating metabolic disease comprising the same as an active ingredient.
BACKGROUND ART
Metabolic diseases are disorders that are caused due to the abnormal metabolisms in separate organs from the human body, and thus include generic types of diseases caused by impaired metabolisms resulting from the in vivo imbalance of saccharides, lipids, proteins, vitamins, minerals, moisture, etc. In particular, metabolic diseases caused due to the weakening of immunity and the lack of nutrition supply account for over 99% of the adult diseases. Most adult diseases are caused by the nutritional imbalance caused by inadequate food intake, the lack of exercise, etc.
Representative examples of the metabolic diseases include obesity, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X, etc. When the metabolic diseases cause fat accumulation in the body, insulin resistance occurs in which insulin that is a hormone which moves glucose from the blood into the liver and muscles is not normally produced or its functions decline, thereby causing an increase in blood glucose level and arteriosclerosis, which leads to the onset of the adult diseases.
As a representative example of the metabolic diseases, diabetes mellitus is a serious metabolic disease from which over one hundred million people suffer all over the world. There are over 12,000,000 diabetic patients in the U.S. and approximately 600,000 new patients have been diagnosed with the diabetes mellitus each year. All people who do not have the same cause of diabetes but have suffered from the diabetes mellitus commonly produce an excessive amount of glucose in the liver, and have no activity to move glucose into cells in which the glucose is used as a main fuel for the body. People who do not suffer from diabetes mellitus depend on insulin hormones produced in the pancreas so that the glucose moves from the blood into cells of the body. However, people suffering from the diabetes neither produce insulin nor efficiently use the insulin produced thereby, and thus cannot move the glucose into their cells. Therefore, residual glucose that does not move into the cells may accumulate in blood, causing a disease referred to as hyperglycemia and leading to serious health problems over time.
Also, diabetes mellitus is a metabolic or vascular syndrome, or a syndrome associated with neuropathic factors. In general, the metabolic syndrome characterized by hyperglycemia include changes in carbohydrate, fat and protein metabolisms caused since insulin secretion is lacking or significantly decreased, or insulin exists but has no effects. The vascular syndrome results from abnormal blood vessels which cause cardiovascular, retinal and renal complications. Dysfunction in the peripheral and autonomic nervous systems is also a part of the diabetic syndrome. In addition, diabetes has been reported to be associated with the onset of renal disease, ocular disease and neurologic problems. The renal disease (nephropathy) develops when a “filtration mechanism” in the kidney is damaged, and an excessive amount of proteins leak into the urine, resulting in impaired kidney function. Also, diabetes mellitus is a provoking cause of inducing damage to the posterior retina of an eye, and increases the risk of developing cataract and glaucoma.
More specifically, the diabetes mellitus may be classified into two clinical syndromes; type 1 and 2 diabetes mellitus. Type 1 diabetes mellitus known as insulin-dependent diabetes mellitus (IDDM) is caused by autoimmune destruction of pancreatic β-cells producing insulin, and requires regular administration of exogenous insulin. Type 2 diabetes mellitus known as non-insulin-dependent diabetes mellitus (NIDDM) appears to develop due to its loss of an ability to properly regulate a blood glucose level. The type 2 diabetes mellitus is characterized by a disorder developed in people suffering from the type 2 diabetes mellitus who are deficient in insulin secretion or exhibit insulin resistance, that is, hardly have insulin or cannot effectively take use of insulin.
In the prior art, the current therapy against diabetes mellitus encompasses insulin, insulin secretagogues, glucose-lowering effectors, peroxisome proliferator-activated receptor (PPAR) activators, etc. However, there are problems associated with currently available therapies, including hypoglycaemia, weight gain, a decreased responsiveness to treatment over time, gastrointestinal dysfunction, and edema.
Accordingly, research has been conducted in various fields to introduce a more effective new therapy into the market. One specific target is G protein-coupled receptor 119 (GPR-119).
GPR-119 is one of G-protein-coupled receptors (GPCRs) that are mainly expressed in pancreatic, small intestinal, rectal and adipose tissues. When a ligand or agonist binds to the receptor, the receptor is structurally changed, and coupled to G-protein to catalyze reactions of secondary messengers in cells or organs.
GPR-119 receptors and isoforms thereof are found in mammalian species including humans, rats, mice, hamsters, chimpanzees, rhesus monkeys, cattle, and dogs. In particular, it is known that the expression of GPR-119 in pancreatic β-cells indicates that the GPR-119 receptors exert an effect on the insulin secretion. The activation of GPR-119 stimulates a cyclic adenosine monophosphate (cAMP) single pathway in which the intracellular activity of cAMP as a secondary messenger is enhanced in these cells. The stimulation of cAMP is involved in a variety of cellular reactions, such as expression of enzymes or genes, etc., and the stimulation of cAMP in the β-cells is induced through the activation of GPR-119. Also, gastric inhibitory polypeptides (GIPs), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and the like cause an insulin secretion action through the G-protein-coupled receptor in the β-cells. Incretins such as the GIP and GLP-1 are gut hormones that strongly stimulate the insulin secretion in a blood glucose level-dependent manner after meals.
GPR-119 activators are effective in improvements in β-cell functions and β-cell groups. The activation of GPR-119 stimulates the insulin secretion in vitro and in vivo (rodents) in a glucose-dependent manner. The finding of potent GPR-119 activators may reduce a level of plasma glucose to promote blood glucose control without the risk of developing hypoglycemia.
In recent years, it was shown that the GPR-119 activators efficiently reduce a blood glucose level in diabetic rodents without the risk of developing hypoglycemia. It was confirmed that the secretion of both insulin and incretin induced by the GPR-119 activators is dependent on the GPR-119 receptors in GPR-119-knockout animals. Also, it was shown that the GPR-119 activators induce weight loss in Sprague Dawley rats by reducing the food intake.
Non-patent document 1 discloses that the activation of GPR-119 induce cAMP to induce secretion of glucose-dependent glucagon-like peptide-1 (GLP-1) and insulin (T. Soga et al., Biochem. Biophy. Res. Commu. 326, (2005), 744-751). It was found that GLP-1 mediates its action through GLP-1R that is a certain G protein-coupled receptor (GPCR), regulates glucose homeostasis, stimulates glucose-dependent insulin secretion, and increases a mass of pancreatic β-cells. Also, it was found that GLP-1 slows down a gastric emptying rate and improves satiety.
However, the existing GLP-1 peptide activators have a negative effect on effectiveness due to deficiency in bioavailability when administered orally. Therefore, there is a demand for development of GPR-119 activators that exhibit excellent oral bioavailability and induce the secretion of GLP-1 into the blood as well.
As one example of the research results, it was proven that the GPR-119 activators disclosed in Patent Documents 1-2 and Non-patent Document 2 cause an acute decline in food intake after chronic administration, resulting in reduced body weight in rats. Also, Patent Document 3 discloses the therapeutic agents for treating metabolic diseases using trisubstituted pyrimidine derivatives with the growing interest in trisubstituted heteroaryl derivatives. Further, Patent Document 4 discloses the therapeutic agents for treating diabetes mellitus using aryl, heteroaryl or heterocyclyl derivatives, characterized in that the therapeutic agents activate IC-GPCR2 or GPR-119 as therapeutic agents for type 1 diabetes mellitus associated with insulin resistance. However, there are no known compounds having a cyclohexene backbone and use thereof for treating metabolic diseases.
Accordingly, the present inventors have conducted research on activators of GPR-119, and found that a cyclohexene derivative according to the present invention, or an optical isomer or pharmaceutically acceptable salt thereof activates G protein-coupled receptor 119 (GPR-119) to enhance the intracellular activity of cyclic adenosine monophosphate (cAMP), and induces the release of glucagon-like peptide-1 (GLP-1), which is a neuroendocrine protein, to simultaneously exhibit weight-loss and hypoglycemic effects, and thus is useful for pharmaceutical compositions 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. Therefore, the present invention has been completed based on these facts.
PRIOR ART DOCUMENT
Patent Document
1. WO 2005/007647
2. WO 2005/007658
3. WO 2004/065380
4. WO 2008/083238
Non-Patent Document
1. T. Soga et al., Biochem. Biophy. Res. Commu. 326, (2005), 744-751
2. Overton, H. A. et al., Cell metabolism, 3, (2006), 167-175
DISCLOSURE
Technical Problem
An aspect of the present invention may provide a cyclohexene derivative, or an optical isomer or pharmaceutically acceptable salt thereof.
Another aspect of the present invention may provide a method for preparing the cyclohexene derivative.
Still another aspect of the present invention may provide a pharmaceutical composition for preventing or treating metabolic diseases, which includes the cyclohexene derivative as an active ingredient.
Yet another aspect of the present invention may provide a G protein-coupled receptor 119 (GPR-119) activator including the cyclohexene derivative as an active ingredient.
Yet another aspect of the present invention may provide a health functional food for preventing or improving metabolic diseases, which includes the cyclohexene derivative as an active ingredient.
Technical Solution
To solve the above problems, the present invention provides a compound represented by the following Formula 1, or an optical isomer or pharmaceutically acceptable salt thereof.
[Formula 1]




In Formula 1, R1 is —H, —OH, a C1-10 linear or branched alkyl, a C1-10 linear or branched alkoxy, a C1-10 linear or branched alkoxycarbonyl, or an unsubstituted or substituted 5- to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heteroaryl is a 5- to 10-membered heteroaryl substituted with one or more C1-10 linear or branched alkyl;
R2 is —H, —OH, a halogen, a C1-10 linear or branched alkyl, or a C1-10 linear or branched alkoxy;
R3 is —H, a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH or a halogen, a C1-10 linear or branched alkoxy, a C1-10 linear or branched alkoxy C1-10 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 5- to 10-membered heteroaryl C1-10 linear or branched alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —(CH2)nNR5R6, —(CH2)mC(═O)OR7, or —(CH2)pC(═O)NR8R9, wherein:
R5 and R6 are each independently —H, -Boc




or a C1-5 linear or branched alkyl,

R7 is —H, or a C1-5 linear or branched alkyl, and
R8 and R9 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted or substituted 5- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heterocycloalkyl is a 5- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —CN, a C1-5 linear or branched alkyl, a C1-5 linear or branched alkoxy, and —C(═O)NR10R11, wherein R10 and R11 are each independently —H, or a C1-5 linear or branched alkyl;
n, m, and p are each independently an integer ranging from 1 to 10;
R4 is —H, a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH, or a C1-10 linear or branched alkoxy;
provided that R3 and R4 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted 3- to 10-membered heterocycloakenyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or an unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —OH, —CN, ═O, a halogen, a C1-5 linear or branched alkyl which is not substituted or substituted with one or more —OH, a C1-5 linear or branched alkoxy, an unsubstituted C3-10 cycloalkyl C1-5 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —C(═O)NR12R13, —NR14R15, and ═NR16; or substituted in a spiro fashion with a C5-10 cycloakenyl fused with an unsubstituted C6-10 aryl, or a 3- to 10-membered heterocycloalkyl which is not substituted or substituted with one or more -Boc




and contains one or more heteroatoms selected from the group consisting of N, O, and S,

R12, R13, R14, and R15 are each independently —H, or a C1-5 linear or branched alkyl, and R16 is —H, —OH, or a C1-5 linear or branched alkoxy,
provided that the fused 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl fused with an unsubstituted C6-10 aryl, and
the substitution and fusion may occur at the same time in the case of the unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl; and
A and E are each independently —CH═, or —N═.
Also, as shown in the following Scheme 1, the present invention provides a method for preparing the compound represented by Formula 1, which includes:
reacting a compound represented by Formula 2 with a compound represented by Formula 3 to prepare a compound represented by Formula 4 (Step 1);
reacting the compound represented by Formula 4 prepared in Step 1 with a compound represented by Formula 5 to prepare a compound represented by Formula 6 (Step 2);
reacting the compound represented by Formula 6 prepared in Step 2 with a base to prepare a compound represented by Formula 7 (Step 3); and
reacting the compound represented by Formula 7 prepared in Step 3 with a compound represented by Formula 8 to obtain the compound represented by Formula 1 (Step 4).




In Scheme 1, R1, R2, R3, R4, A, and E are as defined in Formula 1.
In addition, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, which includes the compound represented by Formula 1, or an optical isomer or pharmaceutically acceptable salt thereof as an active ingredient.
Also, the present invention provides a G protein-coupled receptor 119 (GPR-119) activator including the compound represented by Formula 1, or the optical isomer or pharmaceutically acceptable salt thereof as an active ingredient.
Further, the present invention provides a health functional food for preventing or improving metabolic diseases, which includes the compound represented by Formula 1, or the optical isomer or pharmaceutically acceptable salt thereof as an active ingredient.
Advantageous Effects
The cyclohexene derivative according to the present invention, or the optical isomer or pharmaceutically acceptable salt thereof activates G protein-coupled receptor 119 (GPR-119) to enhance the intracellular activity of cyclic adenosine monophosphate (cAMP), and simultaneously induces the release of glucagon-like peptide-1 (GLP-1), which is a neuroendocrine protein, to simultaneously exhibit weight-loss and hypoglycemic effects, and thus can be useful for pharmaceutical compositions 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, syndrome X, etc.



DESCRIPTION OF DRAWINGS
FIG. 1 is a graph determining the changes in weights of rats after compounds of Example 48 and Comparative Examples 3 and 4 according to the present invention are administered to a diet-induced obesity (DIO) rat model for 4 weeks (In FIG. 1, the term “untreated group (Vehicle)” represents an untreated group in a high-fat DIO rat model; and the term “Lean” represents an untreated group in a normal SD rat model rather than a disease model).
FIG. 2A is a graph for evaluating hypoglycemic effects over time when glucose is administered at the end of the 4-week period of administration of the compounds of Example 48 and Comparative Example 3 according to the present invention in the DIO rat model, and after 30 minutes of administration of the compounds of Example 48 and Comparative Example 3.
FIG. 2B is a graph for evaluating hypoglycemic effects over time when glucose is administered at the end of the 4-week period of administration of the compound of Example 119 according to the present invention in the DIO rat model, and after 30 minutes of administration of the compound of Example 119.
FIG. 3 is graphs plotted for amounts of secreted glucagon-like peptide-1 (GLP-1) when NCI-H716 cells that are human enterocytes are treated with the compounds of Comparative Examples 1 and 5 and Example 48 according to the present invention.



BEST MODE
Hereinafter, the present invention will be described in detail.
The present invention provides a compound represented by the following Formula 1, or an optical isomer or pharmaceutically acceptable salt thereof.




In Formula 1, R1 is —H, —OH, a C1-10 linear or branched alkyl, a C1-10 linear or branched alkoxy, a C1-10 linear or branched alkoxycarbonyl, or an unsubstituted or substituted 5- to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heteroaryl is a 5- to 10-membered heteroaryl substituted with one or more C1-10 linear or branched alkyl;
R2 is —H, —OH, a halogen, a C1-10 linear or branched alkyl, or a C1-10 linear or branched alkoxy;
R3 is —H, a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH or a halogen, a C1-10 linear or branched alkoxy, a C1-10 linear or branched alkoxy C1-10 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 5- to 10-membered heteroaryl C1-10 linear or branched alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —(CH2)nNR5R6, —(CH2)mC(═O)OR7, or —(CH2)pC(═O)NR8R9, wherein:
R5 and R6 are each independently —H, -Boc




or a C1-5 linear or branched alkyl,

R7 is —H, or a C1-5 linear or branched alkyl, and
R8 and R9 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted or substituted 5- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heterocycloalkyl is a 5- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —CN, a C1-5 linear or branched alkyl, a C1-5 linear or branched alkoxy, and —C(═O)NR10R11, and R10 and R11 are each independently —H, or a C1-5 linear or branched alkyl,
n, m, and p are each independently an integer ranging from 1 to 10;
R4 is —H, a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH, or a C1-10 linear or branched alkoxy;
provided that R3 and R4 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted 3- to 10-membered heterocycloakenyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or an unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —OH, —CN, ═O, a halogen, a C1-5 linear or branched alkyl which is not substituted or substituted with one or more —OH, a C1-5 linear or branched alkoxy, an unsubstituted C3-10 cycloalkyl C1-5 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —C(═O)NR12R13, —NR14R15, and ═NR16; or substituted in a spiro fashion with a C5-10 cycloakenyl fused with an unsubstituted C6-10 aryl, or a 3- to 10-membered heterocycloalkyl which is not substituted or substituted with one or more -Boc




and contains one or more heteroatoms selected from the group consisting of N, O, and S,

R12, R13, R14, and R15 are each independently —H, or a C1-5 linear or branched alkyl, and R16 is —H, —OH, or a C1-5 linear or branched alkoxy,
provided that the fused 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl fused with an unsubstituted C6-10 aryl, and
the substitution and fusion may occur at the same time in the case of the unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl; and
A and E are each independently —CH═, or —N═.
Preferably, R1 is a C1-10 linear or branched alkoxycarbonyl, or an unsubstituted or substituted 5- to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heteroaryl is a 5- to 10-membered heteroaryl substituted with one or more C1-10 linear or branched alkyl;
R2 is —H or a halogen;
R3 is a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH or a halogen, a C1-10 linear or branched alkoxy, a C1-10 linear or branched alkoxy C1-10 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 5- to 10-membered heteroaryl C1-10 linear or branched alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —(CH2)nNR5R6, —(CH2)mC(═O)OR7, or —(CH2)pC(═O)NR8R9, wherein:
R5 and R6 are each independently —H or -Boc




R7 is —H, or a C1-5 linear or branched alkyl, and
R8 and R9 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted or substituted 5- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heterocycloalkyl is a 5- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —CN and —C(═O)NR10R11, and R10 and R11 are each independently —H,
n, m, and p is each independently an integer ranging from 1 to 5;
R4 is —H, or a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH;
provided that R3 and R4 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted 3- to 10-membered heterocycloakenyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or an unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —OH, —CN, ═O, a halogen, a C1-5 linear or branched alkyl which is not substituted or substituted with one or more —OH, an unsubstituted C3-10 cycloalkyl C1-5 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —C(═O)NR12R13, —NR14R15, and ═NR16; or substituted in a spiro fashion with a C5-10 cycloakenyl fused with an unsubstituted C6-10 aryl, or a 3- to 10-membered heterocycloalkyl which is not substituted or substituted with one or more -Boc




and contains one or more heteroatoms selected from the group consisting of N, O, and S,

R12, R13, R14, and R15 are each independently —H, or a C1-5 linear or branched alkyl, and R16 is —OH, or a C1-5 linear or branched alkoxy,
provided that the fused 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl fused with an unsubstituted C6-10 aryl, and
the substitution and fusion may occur at the same time in the case of the unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl; and
A and E are each independently —CH═, or —N═.
More preferably,
R1 is




R2 is —H or —F;
R3 is







R4 is —H, methyl, ethyl, or




provided that R3 and R4 may be taken together with a nitrogen atom to which they are attached to form











and

A and E are each independently —CH═, or —N═.
Preferred examples of the compound represented by Formula 1 according to the present invention may include the following compounds:

    (1) tert-butyl 4-((4-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (2) tert-butyl 4-((4-(4-(cyclopropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (3) tert-butyl 4-((4-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (4) tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (5) tert-butyl 4-((4-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (6) tert-butyl 4-((4-(4-((3-hydroxypropyl)(methyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (7) tert-butyl 4-((4-(4-(morpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (8) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((R)-1-hydroxypropan-2-yl)cyclohex-3-enecarboxamide;
    (9) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxypropyl)cyclohex-3-enecarboxamide;
    (10) tert-butyl 4-((6-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;
    (11) tert-butyl 4-((6-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;
    (12) N-((R)-2,3-dihydroxypropyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (13) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(morpholino)methanone;
    (14) tert-butyl 4-((6-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;
    (15) N-(1,3-dihydroxypropan-2-yl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (16) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-hydroxypyrrolidin-1-yl)methanone;
    (17) N-((R)-2,3-dihydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (18) N-((S)-2,3-dihydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (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-enecarboxamide;
    (20) N-((R)-1-hydroxypropan-2-yl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (21) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)-N-methylcyclohex-3-enecarboxamide;
    (22) N-(3-hydroxy-2,2- dimethylpropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (23) N-(1,3-dihydroxypropan-2-yl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (24) tert-butyl 4-((5-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (25) tert-butyl 4-((5-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (26) tert-butyl 4-((5-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (27) tert-butyl 4-((5-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (28) N-((R)-2-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (29) N-((S)-2-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (30) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((R)-2-hydroxypropyl)cyclohex-3-enecarboxamide;
    (31) N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (32) tert-butyl 4-((5-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (33) tert-butyl 4-((5-(4-((S)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (34) N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamide;
    (35) N-ethyl-N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (36) N-((R)-1-hydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
    (37) N-((S)-1-hydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
    (38) N-((R)-2-hydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
    (39) N-((S)-2-hydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
    (40) N-((R)-2,3-dihydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
    (41) N-((S)-2,3-dihydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
    (42) tert-butyl 4-((5-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (43) tert-butyl 4-((5-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (44) tert-butyl 4-((2-fluoro-4-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (45) tert-butyl 4-((2-fluoro-4-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (46) N-(1,3-dihydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
    (47) N-(3-hydroxy-2,2-dimethylpropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
    (48) ((R)-3-hydroxypyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (49) ((S)-3-hydroxypyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (50) N-(2,2-difluoroethyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (51) N-(2,2-difluoroethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (52) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone;
    (53) ((S)-3-fluoropyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (54) ((R)-3-fluoropyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (55) (4-ethylpiperazin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (56) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone;
    (57) tert-butyl 4-((2-fluoro-4-(4-((S)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (58) tert-butyl 4-((2-fluoro-4-(4-((R)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (59) tert-butyl 4-((2-fluoro-4-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (60) tert-butyl 4-((2-fluoro-4-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (61) tert-butyl 4-((2-fluoro-4-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (62) tert-butyl 4-((2-fluoro-4-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (63) tert-butyl 4-((4-(4-((S)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (64) tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (65) azetidin-1-yl(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (66) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(morpholino)methanone;
    (67) tert-butyl 4-((4-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (68) tert-butyl 4-((5-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (69) tert-butyl 4-((2-fluoro-4-(4-(morpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (70) tert-butyl 4-((5-(4-(morpholine-4-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (71) tert-butyl 4-((2-fluoro-4-(4-(thiomorpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (72) tert-butyl 4-((5-(4-(thiomorpholine-4-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (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-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(thiomorpholino)methanone;
    (75) N-(2-fluoroethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (76) tert-butyl 3-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamido)propylcarbamate;
    (77) N-(3-aminopropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamide;
    (78) 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide;
    (79) (4-ethylpiperazin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (80) N-(1,3-dihydroxypropan-2-yl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (81) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)-N-methylcyclohex-3-enecarboxamide;
    (82) tert-butyl 4-((2-fluoro-4-(4-(3-hydroxy-2,2-dimethylpropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (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)cyclohex-3-enecarboxamide;
    (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)cyclohex-3-enecarboxamide;
    (85) tert-butyl 4-((4-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (86) tert-butyl 4-((5-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (87) tert-butyl 4-((5-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (88) tert-butyl 4-((5-(4-(2-fluoroethylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (89) (4-cyclopropylpiperazin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (90) tert-butyl 4-((5-(4-((R)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (91) tert-butyl 4-((5-(4-((S)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
    (92) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide;
    (93) N-(2,2-difluoroethyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (94) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-fluoroethyl)cyclohex-3-enecarboxamide;
    (95) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone;
    (96) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-fluoropyrrolidin-1-yl)methanone;
    (97) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(morpholino)methanone;
    (98) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(thiomorpholino)methanone;
    (99) N-(2,2-difluoroethyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
    (100) (4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enyl)(morpholino)methanone;
    (101) ((R)-3-fluoropyrrolidin-1-yl)(4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enyl)methanone;
    (102) ((S)-3-fluoropyrrolidin-1-yl)(4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enyl)methanone;
    (103) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide;
    (104) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-fluoroethyl)cyclohex-3-enecarboxamide;
    (105) (2 S)-1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carboxamide;
    (106) (2 S)-1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carbonitrile;
    (107) tert-butyl 4-((4-(4-((S)-2-carbamoylpyrrolidine-1-carbonyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (108) (2S)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carboxamide;
    (109) (methyl 2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetate;
    (110) ethyl 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoate;
    (111) 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoic acid;
    (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-enecarboxamide;
    (113) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-morpholino-3-oxopropyl)cyclohex-3-enecarboxamide;
    (114) tert-butyl 4-((4-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (115) (2S)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carbonitrile;
    (116) (2R)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carboxamide;
    (117) (2R)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carbonitrile;
    (118) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone;
    (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-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex-3-enecarboxamide;
    (121) (2R)-1-(2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetyl)pyrrolidine-2-carboxamide;
    (122) N-(2-((R)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (123) (4-cyclopropylpiperazin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (124) (4-(cyclopropylmethyl)piperazin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (125) tert-butyl 4-((3-fluoro-4-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (126) tert-butyl 4-((3-fluoro-4-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (127) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((S)-1-hydroxypropan-2-yl)cyclohex-3-enecarboxamide;
    (128) N-((S)-2,3-dihydroxypropyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (129) tert-butyl 4-((3-fluoro-4-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (130) tert-butyl 4-((3-fluoro-4-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (131) tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (132) tert-butyl 4-((4-(4-((S)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (133) (2S)-1-(2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetyl)pyrrolidine-2-carboxamide;
    (134) (2S)-1-(3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoyl)pyrrolidine-2-carboxamide;
    (135) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-hydroxypyrrolidin-1-yl)methanone;
    (136) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((S)-2-hydroxypropyl)cyclohex-3-enecarboxamide;
    (137) tert-butyl 4-((4-(4-(cyclopropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (138) tert-butyl 4-((3-fluoro-4-(4-(2-fluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (139) N-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (140) N-(3-((S)-2-cyanopyrrolidin-1-yl)-3-oxopropyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (141) tert-butyl 4-((4-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate;
    (142) tert-butyl 4-((3-fluoro-4-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (143) ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (144) ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (145) ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride;
    (146) ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride;
    (147) ((R)-2-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (148) ((S)-2-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (149) ((R)-3-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (150) ((S)-3-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (151) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone hydrochloride;
    (152) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone;
    (153) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone;
    (154) ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (155) ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (156) ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride;
    (157) ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride;
    (158) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone hydrochloride;
    (159) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone hydrochloride;
    (160) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone;
    (161) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone hydrochloride;
    (162) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone;
    (163) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone;
    (164) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-hydroxypiperidin-1-yl)methanone;
    (165) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;
    (166) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone hydrochloride;
    (167) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone hydrochloride;
    (168) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-hydroxypiperidin-1-yl)methanone hydrochloride;
    (169) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxymethyl)piperidin-1-yl)methanone hydrochloride;
    (170) azetidin-1-yl(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (171) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-hydroxyazetidin-1-yl)methanone;
    (172) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone;
    (173) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(2-hydroxyethyl)piperidin-1-yl)methanone;
    (174) N-ethoxy-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (175) N-ethyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex-3-enecarboxamide;
    (176) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex-3-enecarboxamide;
    (177) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxy-2,2-dimethylpropyl)cyclohex-3-enecarboxamide;
    (178) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
    (179) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-methoxypropyl)cyclohex-3-enecarboxamide;
    (180) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(furan-2-ylmethyl)cyclohex-3-enecarboxamide;
    (181) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N,N-bis(2-hydroxyethyl)cyclohex-3-enecarboxamide;
    (182) (4-hydroxypiperidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (183) (4-(hydroxymethyl)piperidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (184) N-cyclopropyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (185) N-(3-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (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-hydroxyethyl)piperazin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (188) 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(methoxymethyl)cyclohex-3-enecarboxamide;
    (189) N-cyclopropyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (190) tert-butyl 4-((4-(4-(2-hydroxyethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (191) tert-butyl 4-((4-(4-(3-hydroxy-2,2-dimethylpropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (192) tert-butyl 4-((4-(4-(methoxymethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (193) tert-butyl 4-((4-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (194) tert-butyl 4-((4-(4-(cyclobutylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (195) tert-butyl 4-((4-(4-(cyclopentylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (196) tert-butyl 4-((4-(4-(4-morpholinopiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (197) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxy-N-methylcyclohex-3-enecarboxamide;
    (198) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxycyclohex-3-enecarboxamide;
    (199) tert-butyl 4-((4-(4-(ethyl(2-hydroxyethyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (200) tert-butyl 4-((4-(4-(4-(2-hydroxyethyl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (201) tert-butyl 4-((4-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (202) tert-butyl 4-((4-(4-(pyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (203) tert-butyl 4-((4-(4-(4-ethylpiperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (204) tert-butyl 4-((4-(4-(piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (205) tert-butyl 4-((4-(4-(3-ethoxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (206) tert-butyl 4-((4-(4-(bis(2-hydroxyethyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (207) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
    (208) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;
    (209) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-morpholinopiperidin-1-yl)methanone;
    (210) N-cyclopentyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (211) N-cyclobutyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (212) (3,4-dihydroisoquinolin-2(1H)-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (213) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;
    (214) isoindolin-2-yl(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (215) 1,4′-bipiperidin-1′-yl(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (216) tert-butyl 4-((4-(4-(1,4′-bipiperidine-1′-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (217) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-(hydroxyimino)pyrrolidin-1-yl)methanone;
    (218) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;
    (219) 1,4′-bipiperidin-1′-yl(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (220) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-morpholinopiperidin-1-yl)methanone;
    (221) tert-butyl 4-((4-(4-(furan-2-ylmethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (222) tert-butyl 4-((4-(4-(methoxycarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (223) tert-butyl 4-((4-(4-(methoxy(methyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (224) tert-butyl 4-((4-(4-(2, 5-dihydro-1H-pyrrole-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (225) tert-butyl 4-((4-(4-(4-hydroxypiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (226) tert-butyl 4-((4-(4-(4-(hydroxymethyl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (227) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carbonitrile;
    (228) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(spiro[indene-1,4′-piperidin]-1′-yl)methanone;
    (229) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methanone;
    (230) N-cyclopentyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (231) N-cyclobutyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (232) (3,4-dihydroisoquinolin-2(1H)-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (233) tert-butyl 4-((4-(4-(5-hydroxypentylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (234) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(5-hydroxypentyl)cyclohex-3-enecarboxamide;
    (235) (2,5-dihydro-1H-pyrrol-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (236) tert-butyl 4-((4-(4-((2-hydroxyethyl)(methyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (237) tert-butyl 4-((4-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (238) tert-butyl 4-((4-(4-(3-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (239) tert-butyl 4-((4-(4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (240) tert-butyl 4-((4-(4-(isoindoline-2-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (241) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(isoindolin-2-yl)methanone;
    (242) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxypropyl)-N-methylcyclohex-3-enecarboxamide;
    (243) N-(3-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamide;
    (244) N-(furan-2-ylmethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (245) N-(3-ethoxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (246) 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxycyclohex-3-enecarboxamide;
    (247) 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxy-N-methylcyclohex-3-enecarboxamide;
    (248) N,N-bis(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (249) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
    (250) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidin-3-one;
    (251) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
    (252) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
    (253) (Z)-(3,3-bis(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (254) (Z)-tert-butyl 6-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3.4]octane-2-carboxylate;
    (255) (Z)-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(8-(methoxyimino)-2,6-diazaspiro[3.4]octan-6-yl)methanone hydrochloride;
    (256) tert-butyl 4-((4-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (257) tert-butyl 4-((4-(4-(3,3-difluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (258) (3,3-difluoropyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (259) (3,3-difluoropyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (260) N-(5-hydroxypentyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
    (261) tert-butyl 4-((4-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (262) tert-butyl 4-((4-(4-(4-cyanocyclohexanecarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (263) tert-butyl 4-((4-(4-(1,4-dioxa-8-azaspiro[4.5]decane-8-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (264) tert-butyl 4-((4-(4-(spiro[indene-1,4′-piperidin]-1′-ylcarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (265) tert-butyl 4-((4-(4-(3-oxopyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (266) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carbonitrile;
    (267) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methanone;
    (268) (2,3-dihydrospiro[indene-1,4′-piperidin]-1′-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (269) (3-(ethoxyimino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (270) tert-butyl 4-((4-(4-(4-(methoxyimino)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (271) tert-butyl 4-((4-(4-(4-(hydroxyimino)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (272) tert-butyl 4-((4-(4-(4-oxopiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (273) tert-butyl 4-((4-(4-(3-(methoxyimino)pyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (274) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidin-4-one;
    (275) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidin-4-one;
    (276) (4-(hydroxyimino)piperidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (277) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxyimino)piperidin-1-yl)methanone;
    (278) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(methoxyimino)piperidin-1-yl)methanone;
    (279) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(methoxyimino)piperidin-1-yl)methanone;
    (280) tert-butyl 4-((4-(4-(3-oxoazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (281) tert-butyl 4-((4-(4-(3-(hydroxyimino)azetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
    (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-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)azetidin-3-one;
    (284) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)azetidin-3-one;
    (285) (3-(hydroxyimino)azetidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
    (286) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-(methoxyimino)azetidin-1-yl)methanone;
    (287) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-(methoxyimino)azetidin-1-yl)methanone;
    (288) tert-butyl 4-((4-(4-(3-hydroxyazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate; and
    (289) (3-hydroxyazetidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;


The compound represented by Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. The acid addition salt may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid, or phosphorous acid, non-toxic organic acids such as aliphatic mono- and di-carboxylates, phenyl-substituted alkanoates, hydroxy alkanoates, and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. Such a pharmaceutically innocuous salt includes sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate.
The acid addition salt according to the present invention may be prepared using a conventional method, for example, prepared by dissolving the compound represented by Formula 1 in an organic solvent, for example, methanol, ethanol, acetone, methylenechloride, acetonitrile, etc., adding an organic or inorganic acid and filtering and drying the resulting precipitate, or by distilling a solvent and an excessive amount of an acid under reduced pressure and drying the resulting distillate, or prepared under an organic solvent.
In addition to the compound represented by Formula 1 and the pharmaceutically acceptable salt thereof, the present invention also encompasses all types of solvates, hydrates, optical isomers and the like which may be prepared from the compound of Formula 1 and the pharmaceutically acceptable salt thereof.
In addition, as shown in the following Scheme 1, the present invention provides a method for preparing the compound represented by Formula 1, which includes:
reacting a compound represented by Formula 2 with a compound represented by Formula 3 to prepare a compound represented by Formula 4 (Step 1);
reacting the compound represented by Formula 4 prepared in Step 1 with a compound represented by Formula 5 to prepare a compound represented by Formula 6 (Step 2);
reacting the compound represented by Formula 6 prepared in Step 2 with a base to prepare a compound represented by Formula 7 (Step 3); and
reacting the compound represented by Formula 7 prepared in Step 3 with a compound represented by Formula 8 to obtain the compound represented by Formula 1 (Step 4).




In Scheme 1, R1, R2, R3, R4, A, and E are as defined in Formula 1.
Hereinafter, respective steps of the method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.
In the method for preparing the compound represented by Formula 1 according to the present invention, Step 1 includes performing a coupling reaction between a compound represented by Formula 2 and a compound represented by Formula 3 to obtain a compound represented by Formula 4.
In this case, dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM), toluene, acetonitrile, and the like may be used as the reaction solvent. Preferably, dimethylformamide (DMF) may be used.
Also, cesium carbonate (Cs2CO3), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and the like may be used as the base. Preferably, cesium carbonate (Cs2CO3) may be used.
In addition, the reaction is preferably carried out at a reaction temperature ranging from 0° C. to a boiling point of a solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.
In the method for preparing the compound represented by Formula 1 according to the present invention, Step 2 includes reacting the compound represented by Formula 4 prepared in Step 1 with a compound represented by Formula 5 in the presence of a base to obtain a compound represented by Formula 6. More specifically, Step 2 includes performing a Suzuki coupling reaction between the compound represented by Formula 4 prepared in Step 1 and a boronate compound represented by Formula 5 to obtain a compound represented by Formula 6.
In this case, at least one organic solvent selected from the group consisting of dioxane, ethanol, tetrahydrofuran (THF), diethylether, diphenylether, diisopropylether (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dichloromethane (DCM), chlorobenzene, toluene, and benzene may be mixed with water to form a solvent mixture, which may be used as the reaction solvent.
Also, cesium carbonate (Cs2CO3), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and the like may be used as the base. Preferably, cesium carbonate (Cs2CO3) may be used.
In addition, the reaction is preferably carried out at a reaction temperature ranging from 0° C. to a boiling point of the solvent, and a reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.
In the method for preparing the compound represented by Formula 1 according to the present invention, Step 3 includes reacting the compound represented by Formula 6 prepared in Step 2 with a base to prepare a compound represented by Formula 7.
In this case, at least one organic solvent selected from the group consisting of dioxane, ethanol, tetrahydrofuran (THF), diethylether, diphenylether, diisopropylether (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dichloromethane (DCM), chlorobenzene, toluene, and benzene may be mixed with water to form a solvent mixture, which may be used as the reaction solvent.
Also, cesium carbonate (Cs2CO3), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and the like may be used as the base. Preferably, lithium hydroxide (LiOH) may be used.
In addition, the reaction is preferably carried out at a reaction temperature ranging from 0° C. to a boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.
In the method for preparing the compound represented by Formula 1 according to the present invention, Step 4 includes reacting the compound represented by Formula 7 prepared in Step 3 with a compound represented by Formula 8 to obtain the compound represented by Formula 1.
In this case, at least one organic solvent selected from the group consisting of dioxane, ethanol, tetrahydrofuran (THF), diethylether, diphenylether, diisopropylether (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dichloromethane (DCM), chlorobenzene, toluene, and benzene may be mixed with water to form a solvent mixture, which may be used as the reaction solvent.
Also, the reaction is preferably carried out at a reaction temperature ranging from 0° C. to a boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.
Also, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, which includes the compound represented by Formula 1 or the optical isomer or 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 enhance the intracellular activity of cyclic adenosine monophosphate (cAMP), and induces the release of glucagon-like peptide-1 (GLP-1) that is a neuroendocrine protein.
In this case, the GPR-119 is a G-protein-coupled receptor (GPCR) mainly expressed in insulin-secreting cells of the pancreas. Thus, a GPR-119 expression profile has potential usefulness in treating various metabolic diseases including obesity and diabetes.
Further, the present invention provides a GPR-119 activator including the compound represented by Formula 1 or the optical isomer or pharmaceutically acceptable salt thereof as an active ingredient.
In this regard, an experiment is performed to evaluate a level of cAMP activation in response to stimulation of the GPR-119 receptor by the compound according to the present invention. As a result, it is confirmed that almost all the example compounds according to the present invention activate cAMP by 50% (EC50) when present at a low concentration of 200 nM or less, indicating that the example compounds has an excellent effect of activation (see Table 2 for Experimental Example 1).
Also, an oral glucose tolerance test (OGTT) is performed on the compound according to the present invention. As a result, it is revealed that all the example compounds according to the present invention have a superior hypoglycemic effect, compared to GPR-119 activators (Comparative Examples 1 and 2) known in the prior art, and thus have a remarkably effective effect of activating GPR-119 in vivo (see Table 3 for Experimental Example 2).
In addition, an experiment is performed to simultaneously evaluate the weight-loss and hypoglycemic effects of the compound represented by Formula 1 according to the present invention or the optical isomer or pharmaceutically acceptable salt thereof. As a result, it is confirmed that the compound according to the present invention has a steady weight-loss effect for a 4-week period of oral administration (see FIG. 1 for Experimental Example 3). At the end of the 4-week administration, the compound according to the present invention is administered, and 2 g/kg of glucose is orally administered after 30 minutes so as to evaluate a hypoglycemic effect. As a result, it is revealed that the compound according to the present invention exhibits a remarkably excellent hypoglycemic effect (see FIG. 2 for Experimental Example 3). Accordingly, it can be seen that the compound according to the present invention simultaneously exhibits the weight-loss and hypoglycemic effects during the period of administration.
Additionally, an experiment is performed to evaluate an ability of the compound according to the present invention to induce secretion of GLP-1. As a result, it is revealed that the compound according to the present invention has an excellent effect of inducing the GLP-1 secretion (see FIG. 3 for Experimental Example 4).
Further, an acute toxicity test is performed on the compound according to the present invention in rats with cataract (Ihara's cataract rats; ICRs). As a result, it can be seen that the compound of the present invention has an LD50 value of 2 g/kg or more in female ICR rats, indicating that the compound exhibits very low toxicity (see Experimental Example 5).
Therefore, the cyclohexene derivative according to the present invention, or the optical isomer or pharmaceutically acceptable salt thereof has a very excellent effect of activating cAMP as a GPR-119 activator, and also simultaneously exhibits the weight-loss and hypoglycemic effects, and thus may be useful for 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, syndrome X, etc.
For clinical administration, the compound represented by Formula 1 according to the present invention may be administered in the form of various oral and parenteral formulations. When the compound is prepared into formulations, the formulations are prepared using a filler, an extender, a binder, a wetting agent, a disintegrating agent, a diluent or vehicle (e.g., a surfactant), etc.
Solid formulations for oral administration include tablets, pills, powders, granules, capsules, troche, and the like. In this case, the solid formulations are prepared by mixing one or more of the compounds of the present invention with one or more vehicles such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple vehicles, lubricants such as magnesium stearate and talc may also be used herein. Liquid formulations for oral administration include suspensions, solutions for internal use, emulsions, or syrups. In addition to simple diluents generally used herein, for example, water and liquid paraffin, the liquid formulations may include various vehicles, for example, wetting agents, sweetening agents, aromatics, preservatives, etc.
Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories, etc. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethylolate, and the like may be used as the non-aqueous solvents and suspensions. Witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol, gelatin, and the like may be used as base materials for suppositories.
Also, the effective dose of the compound according to the present invention administered into the human body may vary according to the age, weight and sex of a patient, a mode of administration, the general physical conditions, and the severity of a disease. In general, the daily dose of the compound is in a range of approximately 0.001 to 100 mg/kg, preferably in a range of 0.01 to 35 mg/kg. In the case of an adult patient weighing 70 kg, the dose of the compound according to the present invention is generally in a range of 0.07 to 7,000 mg/day, preferably in a range of 0.7 to 2,500 mg/day, and may also administered once a day or multiple times in divided doses at certain intervals by a medical judgment of a general physician or pharmacist.
Further, the present invention provides a health functional food for preventing or improving metabolic diseases, which includes the compound represented by Formula 1 or the optical isomer or pharmaceutically acceptable salt thereof as an active ingredient.
MODE FOR INVENTION
Hereinafter, the present invention will be described in detail with reference to examples and experimental examples thereof.
However, it should be understood that the examples and experimental examples are given by way of illustration of the present invention only, and are not intended to limit the scope of the present invention.
Preparative Example 1
Preparation of ethyl 4-(trifluoromethylsulfonyloxy)cyclohex-3-enecarboxylate




136 μl of lithium hexamethyldisilazide (LiHMDS) was dissolved in 100 μl of THF in a 1,000 μl flask while stirring under nitrogen. After the resulting mixture was cooled to a temperature of 5° C., 17.8 g of ethyl 4-oxocyclohexanecarboxylate was slowly added dropwise, and the mixture was then stirred for 5 minutes. 41 g of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide was slowly added dropwise, and then stirred for 2 hours. After the reaction was terminated, 300 μl of distilled water was slowly added, and the resulting mixture was extracted with 500 μl of ethyl acetate, washed with 100 μl of brine, dried with anhydrous magnesium sulfate, concentrated, and then isolated by silica column chromatography to obtain the title compound.
1H NMR (400, CDCl3): 3.69 (3H, s), 3.40 (4H, m), 3.20 (1H, m), 2.57 (2H, d), 2.48 (3H, m), 2.27 (2H, d), 1.47 (9H, s), 1.06 (3H, d)
Preparative Example 2
Preparation of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate




48.9 g of ethyl 4-(trifluoromethyl sulfonyloxy)cyclohex-3-enecarboxylate was dissolved in 300 μl of 1.4-dioxane in a 1,000 μl flask while stirring under nitrogen. 41 g of bis(pinacolate)diboron, 9 g of tetrakis(triphenylphosphine)palladium, and 32 g of potassium acetate were sequentially added dropwise thereto, and the resulting mixture was then stirred for 5 minutes. The mixture was gradually heated to a temperature of 90° C., and then stirred for 4 hours. After the reaction was terminated, the reaction mixture was cooled to room temperature. Then, 300 μl of hexane was added thereto, and filtered through celite. 300 μl of distilled water was slowly added thereto, and the reaction mixture was extracted with 500 μl of ethyl acetate, washed with 100 μl of brine, dried with anhydrous magnesium sulfate, concentrated, and then isolated by silica column chromatography to obtain the title compound.
1H NMR (400, CDCl3): 6.56 (1H, s), 4.16 (3H, q), 2.52 (1H, m), 2.40 (6H, m), 1.63 (2H, m), 1.29 (15H, m)
Preparative Example 3
Preparation of (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methanol




6.3 g of Piperidin-4-yl methanol was dissolved in 100 μl of DMF in a 250 μl flask, and then stirred under nitrogen. 13 μl of N,N-diisopropylethylamine was added dropwise thereto, and 5.2 g of 2-chloro-5-ethylpyrimidine was then added dropwise. The resulting mixture was gradually heated to a temperature of 60° C., and then stirred for 4 hours. After the reaction was terminated, the reaction mixture was slowly cooled to room temperature. Then, 100 μl of distilled water was slowly added thereto, and the reaction mixture was extracted with 300 μl of ethyl acetate, washed with 50 μl of brine, dried with anhydrous magnesium sulfate, and then concentrated to prepare the title compound.
1H NMR (400, CDCl3): 8.21 (2H, s), 4.80 (2H, d), 3.54 (2H, d), 2.94 (2H, m), 2.48 (2H, m), 1.86 (2H, m), 1.81 (1H, s), 1.26 (2H, m), 1.20 (3H, m)
Preparative Example 4
Preparation of (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate




11.4 g of (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methanol was dissolved in 100 μl of dichloromethane in a 250 μl flask, and then stirred under nitrogen. 10 μl of triethylamine was added dropwise thereto, 4.2 μl of methanesulfonyl chloride was slowly added dropwise at 5° C., and the resulting mixture was then stirred for 30 minutes. When the reaction was terminated, 50 μl of distilled water was slowly added, and the reaction mixture was extracted with 20 μl of dichloromethane, washed with 100 μl of brine, dried with anhydrous magnesium sulfate, and then concentrated to obtain the title compound as a solid from diethyl ether.
1H NMR (400, CDCl3): 8.18 (2H, s), 4.77 (2H, d), 4.10 (2H, d), 3.04 (3H, m), 2.84 (2H, m), 2.46 (2H, m), 2.07 (1H, m), 1.86 (2H, d), 1.27 (2H, m), 1.19 (3H, m)
Preparative Example 5
Preparation of (1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methanol




300 g of piperidin-4-yl methanol was added to an acetonitrile/water mixture (400 μl/400 μl), and dissolved in a 1,000 μl flask while stirring under nitrogen. 330 g of sodium bicarbonate and 302 g of cyanogen bromide were added thereto, and then heated at reflux for 12 hours or more. When the reaction was completed, 100 μl of distilled water was slowly added thereto, and the resulting reaction mixture was extracted three times with 100 μl of dichloromethane, dried with anhydrous magnesium sulfate, and then concentrated. Residues were added to 2,000 μl of ethyl acetate, dissolved while stirring. Then, 175 g of N-hydroxyisobutyramide was added thereto, and 1,700 μl of a 1 M zinc chloride solution was slowly added dropwise, and the resulting mixture was then stirred for 12 hours or more. When the reaction was terminated, the resulting solids were filtered, and washed with 2,000 μl of diethyl ether. The resulting solids were added to 1,000 μl of ethanol, and dissolved while stirring, and 1,000 μl of a 4 N HCl aqueous solution was added dropwise thereto, and then heated at reflux for 4 hours or more. When the reaction was completed, the resulting reaction mixture was distilled under reduced pressure to remove ethanol, and the pH of the reaction mixture was then made basic with sodium bicarbonate. Then, the mixture was extracted three times with 1,000 μl of ethyl acetate. The extracted solution was dried with anhydrous magnesium sulfate, concentrated, and then isolated by silica column chromatography to obtain the title compound.
1H NMR (400, CDCl3): 4.24 (2H, d), 3.86 (2H, d), 3.15 (2H, m), 2.91 (1H, m), 1.91 (2H, m), 1.48 (2H, m), 1.43 (1H, m), 1.32 (6H, d)
Preparative Example 6
Preparation of (1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate




The title compound was prepared in the same manner as in <Preparative Example 4>, except that (1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methanol was used instead of the (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate.
1H NMR (400, CDCl3): 4.24 (2H, d), 3.86 (2H, d), 3.15 (2H, m), 3.04 (3H, m), 2.91 (1H, m), 1.91 (2H, m), 1.48 (2H, m), 1.32 (6H, d)
Preparative Example 7
Preparation of tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Preparative Example 4>, except that tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate was used instead of the (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate.
1H NMR (400, CDCl3): 4.20 (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)
Preparative Example 8
Preparation of 2-(4-((4-bromophenoxy)methyl)piperidin-1-yl)-5-ethylpyrimidine




50 g of (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate was dissolved in 300 μl of DMF in a 1,000 μl flask, and then stirred under nitrogen. 110 g of cesium carbonate was added dropwise thereto, and 30 g of 4-bromophenol was also added dropwise. The resulting mixture was stirred at 60° C. for 5 hours. When the reaction was terminated, the mixture was slowly cooled to room temperature. Solids formed by slowly adding 500 μl of distilled water at 0° C. were filtered, and then dried to obtain the title compound as a solid.
1H NMR (400, CDCl3): 8.21 (2H, s), 7.32 (2H, d), 6.85 (2H, d), 4.80 (2H, d), 3.54 (2H, m), 2.48 (2H, m), 1.86 (2H, d), 1.81 (1H, m), 1.26 (2H, m), 1.20 (3H, m)
Preparative Example 9
Preparation of 5-(4-((4-bromophenoxy)methyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole




The title compound was prepared in the same manner as in <Preparative Example 8>, except that (1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate was used instead of the (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate.
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 4.24 (2H, d), 3.86 (2H, d), 3.15 (1H, m), 1.91 (2H, m), 1.48 (2H, m), 1.32 (6H, d)
Preparative Example 10
Preparation of tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Preparative Example 8>, except that tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate was used instead of the (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate.
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 4.15 (2H, d), 3.86 (2H, d), 2.78 (2H, m), 2.12 (1H, m), 1.87 (9H, s), 1.32 (2H, m)
Preparative Example 11
Preparation of tert-butyl 4-((6-bromopyridin-3-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Preparative Example 8>, except that tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate was used instead of the (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate, and 2-bromo-5-hydroxypyridine was used instead of the 4-bromophenol.
1H NMR (400, CDCl3): 8.21 (1H, s), 7.38 (1H, d), 7.15 (1H, 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)
Preparative Example 12
Preparation of tert-butyl 4-((5-bromopyridin-2-yloxy)methyl)piperidine-1-carboxylate




6.6 g of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate was dissolved in 100 μl of DMF in a 250 μl flask, and then stirred under nitrogen. 1.85 g of sodium hydride was added dropwise at 5° C., and the temperature was slowly raised to room temperature. After 4 hours, 50 μl of distilled water was slowly added at 0° C., and resulting solids were filtered and dried. The resulting solids were re-crystallized in hexane to obtain the title compound
1H NMR (400, CDCl3): 8.14 (1H, s), 7.63 (1H, d), 6.71 (1H, 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)
Preparative Example 13
Preparation of 5-(4-((6-chloropyridin-3-yloxy)methyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole




The title compound was prepared in the same manner as in <Preparative Example 8>, except that (1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate was used instead of the (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate, and 2-chloro-5-hydroxypyridine was used instead of the 4-bromophenol.
1H NMR (400, CDCl3): 8.21 (1H, s), 7.38 (1H, d), 7.15 (1H, d), 4.24 (2H, d), 3.86 (2H, d), 3.15 (2H, m), 2.91 (1H, m), 1.48 (2H, m), 1.32 (6H, d)
Preparative Example 14
Preparation of tert-butyl 4-((4-bromo-2-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Preparative Example 8>, except that tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate was used instead of the (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate, and 2-fluoro-4-bromophenol was used instead of the 4-bromophenol.
1H NMR (400, CDCl3): 7.13 (1H, s), 7.08 (1H, d), 6.89 (1H, m), 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)
Preparative Example 15
Preparation of tert-butyl 4-((4-bromo-3-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Preparative Example 8>, except that tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate was used instead of the (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate, and 3-fluoro-4-bromophenol was used instead of the 4-bromophenol.
1H NMR (400, CDCl3): 7.13 (1H, s), 6.65 (1H, d), 6.59 (1H, m), 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)
Preparative Example 16
Preparation of 5-(4-((4-bromo-2-fluorophenoxy)methyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole




The title compound was prepared in the same manner as in <Preparative Example 8>, except that (1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate was used instead of the (1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate, and 2-fluoro-4-bromophenol was used instead of the 4-bromophenol.
1H NMR (400, CDCl3): 7.13 (1H, s), 7.08 (1H, d), 6.89 (1H, m), 4.24 (2H, d), 3.86 (2H, d), 3.15 (2H, m), 2.91 (1H, m), 1.91 (2H, m), 1.48 (2H, s), 1.32 (6H, d)
Preparative Example 17
Preparation of tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




5 g of tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate was dissolved in a tetrahydrofuran/water/ethanol mixture (100 μl/20 μl/10 μl) in a 500 μl flask, and stirred under nitrogen. 550 mg of (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, 11 g of cesium carbonate, and 4.2 g of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate were sequentially added dropwise thereto. The resulting mixture was gradually heated to a temperature of 80° C., and then stirred for 5 hours. After the reaction was terminated, the reaction mixture was slowly cooled to room temperature, 100 μl of distilled water was slowly added thereto, and the reaction mixture was filtered through celite. The filtrate was extracted with 300 μl of ethyl acetate, washed with 100 μl of brine, dried with anhydrous magnesium sulfate, concentrated, and then isolated by silica column chromatography to prepare the title compound.
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1H, s), 4.10 (2H, m), 4.15 (2H, d), 3.85 (2H, d), 2.61 (1H, m), 2.47 (4H, m), 2.21 (2H, m), 1.98 (1H, m), 1.86 (2H, m), 1.61 (9H, s), 1.31 (2H, m), 1.20 (3H, m)
Preparative Example 18
Preparation of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid




3.2 g of tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate was dissolved in a tetrahydrofuran/water/ethanol mixture (100 μl/50 μl/10 μl) in a 250 μl flask, and stirred under nitrogen. 2.4 g of lithium hydroxide monohydrate was added dropwise thereto, and then reacted at room temperature for 18 hours. After the reaction was terminated, the pH of the resulting reaction mixture was adjusted to pH 1 to 2 using concentrated HCl. The resulting solids were filtered, and dried to prepare the desired title compound.
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1H, s), 4.15 (2H, m), 3.85 (2H, d), 2.61 (1H, m), 2.47 (4H, m), 2.21 (2H, m), 1.98 (1H, m), 1.86 (2H, m), 1.61 (9H, s), 1.31 (2H, m)
Preparative Example 19
Preparation of ethyl 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxylate




The title compound was prepared in the same manner as in <Preparative Example 17>, except that 2-(4-((4-bromophenoxy)methyl)piperidin-1-yl)-5-ethylpyrimidine was used instead of the tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 8.21 (2H, s), 7.32 (2H, d), 6.85 (2H, d), 6.02 (1H, s), 4.80 (2H, d), 4.19 (2H, m), 3.54 (2H, d), 2.94 (2H, m), 2.61 (1H, m), 2.48 (2H, m), 2.47 (4H, m), 2.21 (2H, m), 1.86 (2H, d), 1.81 (1H, m), 1.29 (3H, m), 1.26 (2H, m), 1.20 (3H, m)
Preparative Example 20
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid




The title compound was prepared in the same manner as in <Preparative Example 18>, except that ethyl 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxylate was used instead of the tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 8.21 (2H, s), 7.32 (2H, d), 6.85 (2H, d), 6.02 (1H, s), 4.80 (2H, d), 3.54 (2H, m), 2.94 (2H, m), 2.61 (1H, m), 2.48 (2H, m), 2.47 (4H, m), 2.21 (2H, m), 1.86 (2H, d), 1.81 (1H, m), 1.26 (2H, m), 1.20 (3H, m)
Preparative Example 21
Preparation of ethyl 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxylate




The title compound was prepared in the same manner as in <Preparative Example 17>, except that 5-(4-((4-bromophenoxy)methyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole was used instead of the tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1H, s), 4.24 (2H, d), 4.19 (2H, m), 3.86 (2H, d), 3.15 (2H, m), 2.91 (1H, m), 2.61 (1H, 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)
Preparative Example 22
Preparation of 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid




The title compound was prepared in the same manner as in <Preparative Example 18>, except that ethyl 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxylate was used instead of the tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1H, s), 4.24 (2H, d), 3.86 (2H, m), 3.15 (2H, m), 2.91 (1H, m), 2.61 (1H, m), 2.47 (4H, m), 2.21 (2H, m), 1.91 (2H, m), 1.48 (2H, m), 1.32 (6H, d)
Preparative Example 23
Preparation of tert-butyl 4-((6-(4-(ethoxycarbonyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Preparative Example 17>, except that tert-butyl 4-((6-bromopyridin-3-yloxy)methyl)piperidine-1-carboxylate was used instead of the tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 8.21 (1H, s), 7.38 (1H, d), 7.15 (1H, d), 6.02 (1H, s), 4.19 (2H, m), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m), 2.61 (1H, 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), 1.29 (3H, m)
Preparative Example 24
Preparation of 4-(5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxyilc acid




The title compound was prepared in the same manner as in <Preparative Example 18>, except that tert-butyl 4-((6-(4-(ethoxycarbonyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate was used instead of the tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 8.21 (1H, s), 7.38 (1H, d), 7.15 (1H, d), 6.02 (1H, s), 4.15 (2H, m), 3.85 (2H, d), 2.78 (2H, m), 2.61 (1H, 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)
Preparative Example 25
Preparation of ethyl 4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxylate




The title compound was prepared in the same manner as in <Preparative Example 17>, except that 5-(4-((6-chloropyridin-3-yloxy)methyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole was used instead of the tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 8.21 (1H, s), 7.38 (1H, d), 7.15 (1H, d), 6.02 (1H, s), 4.24 (2H, m), 4.19 (2H, m), 3.86 (2H, d), 3.15 (2H, m), 2.91 (1H, m), 2.61 (1H, 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)
Preparative Example 26
Preparation of 4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxyilc acid




The title compound was prepared in the same manner as in <Preparative Example 18>, except that 4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxyilc acid was used instead of the tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 8.21 (1H, s), 7.38 (1H, d), 7.15 (1H, d), 6.02 (1H, s), 4.24 (2H, d), 3.86 (2H, d), 3.15 (2H, m), 2.91 (1H, m), 2.61 (1H, m), 2.47 (4H, m), 2.21 (2H, m), 1.91 (2H, m), 1.48 (2H, m), 1.32 (6H, d)
Preparative Example 27
Preparation of tert-butyl 4-((5-(4-(ethoxycarbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Preparative Example 17>, except that tert-butyl 4-((5-bromopyridin-2-yloxy)methyl)piperidine-1-carboxylate was used instead of the tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 8.14 (1H, s), 7.63 (1H, d), 6.71 (1H, d), 6.02 (1H, s), 4.19 (2H, m), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m), 2.61 (1H, 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), 1.29 (3H, m)
Preparative Example 28
Preparation of 4-(6-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)pyridin-3-yl)cyclohex-3-enecarboxyilc acid




The title compound was prepared in the same manner as in <Preparative Example 18>, except that tert-butyl 4-((5-(4-(ethoxycarbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate was used instead of the tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 8.14 (1H, s), 7.63 (1H, d), 6.71 (1H, d), 6.02 (1H, s), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m), 2.61 (1H, 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)
Preparative Example 29
Preparation of tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Preparative Example 17>, except that tert-butyl 4-((4-bromo-2-fluorophenoxy)methyl)piperidine-1-carboxylate was used instead of the tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 7.13 (1H, d), 7.08 (1H, d), 6.89 (1H, m), 6.02 (1H, s), 4.19 (2H, m), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m), 2.61 (1H, 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), 1.29 (3H, m)
Preparative Example 30
Preparation of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-3-fluorophenyl)cyclohex-3-enecarboxyilc acid




The title compound was prepared in the same manner as in <Preparative Example 18>, except that tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate was used instead of the tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 7.13 (1H, d), 7.08 (1H, d), 6.89 (1H, m), 6.02 (1H, s), 4.15 (2H, m), 3.85 (2H, d), 2.78 (2H, m), 2.61 (1H, 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)
Preparative Example 31
Preparation of ethyl 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxylate




The title compound was prepared in the same manner as in <Preparative Example 17>, except that 5-(4-((4-bromo-2-fluorophenoxy)methyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole was used instead of the tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 7.13 (1H, d), 7.08 (1H, d), 6.89 (1H, m), 6.02 (1H, s), 4.24 (2H, d), 4.19 (2H, m), 3.86 (2H, d), 3.15 (2H, m), 2.91 (1H, m), 2.61 (1H, 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)
Preparative Example 32
Preparation of 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid




The title compound was prepared in the same manner as in <Preparative Example 18>, except that ethyl 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxylate was used instead of the tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 7.13 (1H, d), 7.08 (1H, d), 6.89 (1H, m), 6.02 (1H, s), 4.24 (2H, d), 3.86 (2H, d), 3.15 (2H, m), 2.91 (1H, m), 2.61 (1H, m), 2.47 (4H, m), 2.21 (2H, m), 1.91 (2H, m), 1.48 (2H, m), 1.32 (6H, d)
Preparative Example 33
Preparation of tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Preparative Example 17>, except that tert-butyl 4-((4-bromo-3-fluorophenoxy)methyl)piperidine-1-carboxylate was used instead of the tert-butyl 4-((4-bromophenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 7.13 (1H, m), 6.65 (1H, d), 6.59 (1H, d), 6.02 (1H, s), 4.19 (2H, m), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m), 2.61 (1H, 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), 1.29 (3H, m)
Preparative Example 34
Preparation of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-2-fluorophenyl)cyclohex-3-enecarboxyilc acid




The title compound was prepared in the same manner as in <Preparative Example 18>, except that tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate was used instead of the tert-butyl 4-((4-(4-(ethoxycarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate.
1H NMR (400, CDCl3): 7.13 (1H, m), 6.65 (1H, d), 6.59 (1H, d), 6.02 (1H, s), 4.15 (2H, d), 3.85 (2H, d), 2.78 (2H, m), 2.61 (1H, 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)
Example 1
Preparation of tert-butyl 4-((4-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




200 mg of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid was dissolved in 20 μl of DMF in a 100 μl flask, and stirred under nitrogen. 140 mg of EDCI and 110 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 72 mg of (R)-2-amino-1-propanol was added dropwise thereto, and the mixture was then stirred at room temperature for 5 hours. After the reaction was terminated, 50 μl of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 167 mg/Yield: 73%).
1H NMR (400, CDCl3): 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, m), 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)
Example 2
Preparation of tert-butyl 4-((4-(4-(cyclopropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 1>, except that cyclopropylamine is used instead of the (R)-2-amino-1-propanol (Amount obtained: 180 mg/Yield: 80%).
1H NMR (400, CDCl3): 7.31 (2H, d), 6.86 (2H, d), 6.05 (1H, s), 5.75 (1H, d), 4.15 (3H, m), 3.81 (2H, d), 2.78 (3H, m), 3.45 (5H, m), 2.08 (1H, m), 1.98 (1H, m), 1.82 (2H, m), 1.52 (9H, s), 1.28 (2H, m), 0.78 (2H, d), 0.55 (2H, d)
Example 3
Preparation of tert-butyl 4-((4-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 1>, except that 2,2-difluoroethylamine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 120 mg/Yield: 72%)
1H NMR (400, CDCl3): 7.31 (2H, d), 6.85 (2H, d), 6.05 (1H, 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)
Example 4
Preparation of tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 1>, except that (R)-3-amino-1,2-propanediol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 132 mg/Yield: 68%).
1H NMR (400, CDCl3): 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
Preparation of tert-butyl 4-((4-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 1>, except that (R)-(+)-3-pyrrolidinol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 130 mg/Yield: 56%).
1H NMR (400, CDCl3): 7.31 (2H, d), 6.85 (2H, d), 6.05 (1H, s), 4.60 (1H, 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)
Example 6
Preparation of tert-butyl 4-((4-(4-((3-hydroxypropyl)(methyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 1>, except that 3-(methylamino)-1-propanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 110 mg/Yield: 58%).
1H NMR (400, CDCl3): 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 (2H, m), 3.12 (3H, 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)
Example 7
Preparation of tert-butyl 4-((4-(4-(morpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 1>, except that morpholine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 200 mg/Yield: 80%).
1H NMR (400, CDCl3): 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).
Example 8
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((R)-1-hydroxypropan-2-yl)cyclohex-3-enecarboxamide




250 mg of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid was dissolved in 20 μl of DMF in a 100 μl flask, and stirred under nitrogen. 140 mg of EDCI and 110 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was additionally stirred for 10 minutes. 0.1 μl of (R)-2-amino-1-propanol was added dropwise thereto, and the mixture was then stirred at room temperature for 5 hours. After the reaction was terminated, 50 μl of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 230 mg/Yield: 82%).
1H NMR (400, CDCl3): 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)
Example 9
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxypropyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that 3-amino-1-propanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 220 mg/Yield: 79%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.31 (2H, d), 6.85 (2H, 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)
Example 10
Preparation of tert-butyl 4-((6-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate




200 mg of 4-(5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxyilc acid was dissolved in 25 μl of DMF, and stirred. 140 mg of EDCI and 110 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 0.15 μl of (R)-3-amino-1,2-propanediol was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. When the reaction was terminated, 50 μl of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 160 mg/Yield: 68%).
1H NMR (400, CDCl3): 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
Preparation of tert-butyl 4-((6-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 10>, except that (S)-2-amino-1-propanol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 155 mg/Yield: 70%).
1H NMR (400, CDCl3): 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)
Example 12
Preparation of N-((R)-2,3-dihydroxypropyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that (R)-3-amino-1,2-propanediol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 200 mg/Yield: 85%).
1H NMR (400, DMSO-d6): 8.23 (2H, s), 7.81 (1H, m), 7.33 (2H, 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)
Example 13
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(morpholino)methanone




The title compound was prepared in the same manner as in <Example 8>, except that morpholine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 175 mg/Yield: 65%).
1H NMR (400, CDCl3): 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)
Example 14
Preparation of tert-butyl 4-((6-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 10>, except that 2-amino-1.3-propanediol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 195 mg/Yield: 85%).
1H NMR (400, CDCl3): 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)
Example 15
Preparation of N-(1,3-dihydroxypropan-2-yl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that 2-amino-1.3-propanediol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 165 mg/Yield: 72%).
1H NMR (400, DMSO-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)
Example 16
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-hydroxypyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 8>, except that (R)-(+)-3-pyrrolidinol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 165 mg/Yield: 72%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.87 (2H, d), 6.07 (1H, 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)
Example 17
Preparation of N-((R)-2,3-dihydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




200 mg of 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid was dissolved in 25 μl of DMF, and stirred. 140 mg of EDCI and 110 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 0.15 μl of (R)-3-amino-1,2-propanediol was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. After the reaction was terminated, 50 μl of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 187 mg/Yield: 83%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.86 (2H, d), 6.15 (1H, 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)
Example 18
Preparation of N-((S)-2,3-dihydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that (S)-3-amino-1,2-propanediol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 155 mg/Yield: 70%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.83 (2H, d), 6.21 (1H, 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), 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
Preparation of N-((S)-1-hydroxypropan-2-yl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that (S)-2-amino-1-propanol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 130 mg/Yield: 62%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.84 (2H, d), 6.04 (1H, 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)
Example 20
Preparation of N-((R)-1-hydroxypropan-2-yl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that (R)-2-amino-1-propanol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 150 mg/Yield: 71%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.84 (2H, d), 6.04 (1H, 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)
Example 21
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)-N-methylcyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that 2-(methylamino)ethanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 187 mg/Yield: 81%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.34 (2H, d), 6.87 (2H, 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)
Example 22
Preparation of N-(3-hydroxy-2,2-dimethylpropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that 3-amino-2,2-dimethylpropan-1-ol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 195 mg/Yield: 89%).
1H NMR (400, MeOD): 7.65 (1H, s), 7.31 (2H, d), 6.85 (2H, 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)
Example 23
Preparation of N-(1,3-dihydroxypropan-2-yl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that 2-amino-1.3-propanediol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 175 mg/Yield: 79%).
1H NMR (400, MeOD): 7.27 (3H, d), 6.85 (2H, d), 6.02 (1H, s), 4.18 (2H, d), 3.87 (6H, d), 3.18 (3H, m), 2.86 (1H, m), 2.46 (5H, m), 2.04 (5H, m), 1.48 (2H, m), 1.28 (6H, d)
Example 24
Preparation of tert-butyl 4-((5-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




300 mg of 4-(6-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)pyridin-3-yl)cyclohex-3-enecarboxyilc acid was dissolved in 25 μl of DMF, and stirred. 210 mg of EDCI and 165 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 120 mg of (S)-2-amino-1-propanol was added dropwise thereto, and the mixture was stirred at room temperature for 5 hours. After the reaction was terminated, 50 μl of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 235 mg/Yield: 84%).
1H NMR (400, CDCl3): 8.14 (1H, s), 7.62 (1H, d), 6.70 (1H, 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)
Example 25
Preparation of tert-butyl 4-((5-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that (R)-2-amino-1-propanol was used instead of the (S)-2-amino-1-propanol (Amount obtained: 140 mg/Yield: 62%).
1H NMR (400, CDCl3): 8.14 (1H, s), 7.62 (1H, d), 6.70 (1H, 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)
Example 26
Preparation of tert-butyl 4-((5-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that (S)-1-amino-2-propanol was used instead of the (S)-2-amino-1-propanol (Amount obtained: 155 mg/Yield: 67%).
1H NMR (400, CDCl3): 8.14 (1H, s), 7.61 (1H, d), 6.70 (1H, 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, m), 1.21 (3H, d)
Example 27
Preparation of tert-butyl 4-((5-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that (R)-1-amino-2-propanol was used instead of the (S)-2-amino-1-propanol (Amount obtained: 150 mg/Yield: 65%).
1H NMR (400, CDCl3): 8.14 (1H, s), 7.61 (1H, d), 6.70 (1H, 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, m), 1.21 (3H, d)
Example 28
Preparation of N-((R)-2-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that (R)-1-amino-2-propanol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 100 mg/Yield: 43%).
1H NMR (400, CDCl3): 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 (3H, d)
Example 29
Preparation of N-((S)-2-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that (S)-1-amino-2-propanol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 143 mg/Yield: 62%).
1H NMR (400, CDCl3): 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 (3H, d)
Example 30
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((R)-2-hydroxypropyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that (R)-1-amino-2-propanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 180 mg/Yield: 79%).
1H NMR (400, CDCl3): 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 (1H, 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)
Example 31
Preparation of N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that 2-aminoethanol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 220 mg/Yield: 94%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.07 (2H, m), 4.23 (2H, 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)
Example 32
Preparation of tert-butyl 4-((5-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that (R)-3-amino-1,2-propanediol was used instead of the (S)-2-amino-1-propanol (Amount obtained: 176 mg/Yield: 80%).
1H NMR (400, CDCl3): 8.14 (1H, s), 7.62 (1H, d), 6.71 (1H, d), 6.06 (2H, 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
Preparation of tert-butyl 4-((5-(4-((S)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that (S)-3-amino-1,2-propanediol was used instead of the (S)-2-amino-1-propanol (Amount obtained: 200 mg/Yield: 87%).
1H NMR (400, CDCl3): 8.14 (1H, s), 7.62 (1H, d), 6.71 (1H, d), 6.06 (2H, 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 34
Preparation of N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that 2-(methylamino)ethanol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 190 mg/Yield: 82%).
1H NMR (400, CDCl3): 7.34 (2H, d), 6.86 (2H, d), 6.07 (2H, m), 4.23 (2H, m), 3.86 (4H, m), 3.63 (2H, m), 3.18 (3H, s), 3.15 (2H, m), 2.92 (2H, m), 2.50 (4H, m), 2.03 (5H, m), 1.92 (2H, m), 1.30 (6H, m)
Example 35
Preparation of N-ethyl-N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that 2-(ethyllamino)ethanol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 184 mg/Yield: 80%).
1H NMR (400, CDCl3): 7.34 (2H, d), 6.87 (2H, d), 6.08 (1H, 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)
Example 36
Preparation of N-((R)-1-hydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide




300 mg of 4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxyilc acid was dissolved in 25 μl of DMF, and stirred. 210 mg of EDCI and 165 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 120 mg of (R)-2-amino-1-propanol was added dropwise thereto, and the mixture was then stirred at room temperature for 5 hours. After the reaction was terminated, 50 μl of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 280 mg/Yield: 82%).
1H NMR (400, CDCl3): 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)
Example 37
Preparation of N-((S)-1-hydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 36>, except that (S)-2-amino-1-propanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 160 mg/Yield: 70%).
1H NMR (400, CDCl3): 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)
Example 38
Preparation of N-((R)-2-hydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 36>, except that (R)-1-amino-2-propanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 180 mg/Yield: 81%).
1H NMR (400, CDCl3): 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)
Example 39
Preparation of N-((S)-2-hydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 36>, except that (S)-1-amino-2-propanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 185 mg/Yield: 76%).
1H NMR (400, CDCl3): 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)
Example 40
Preparation of N-((R)-2,3-dihydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 36>, except that (R)-3-amino-1,2-propanediol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 160 mg/Yield: 71%).
1H NMR (400, CDCl3): 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)
Example 41
Preparation of N-((S)-2,3-dihydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 36>, except that (S)-3-amino-1,2-propanediol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 176 mg/Yield: 77%).
1H NMR (400, CDCl3): 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)
Example 42
Preparation of tert-butyl 4-((5-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that (S)-(−)-3-pyrrolidinol was used instead of the (S)-2-amino-1-propanol (Amount obtained: 145 mg/Yield: 65%).
1H NMR (400, CDCl3): 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)
Example 43
Preparation of tert-butyl 4-((5-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that (R)-(+)-3-pyrrolidinol was used instead of the (S)-2-amino-1-propanol (Amount obtained: 162 mg/Yield: 70%).
1H NMR (400, CDCl3): 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)
Example 44
Preparation of tert-butyl 4-((2-fluoro-4-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




300 mg of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-3-fluorophenyl)cyclohex-3-enecarboxyilc acid was dissolved in 25 μl of DMF, and stirred. 210 mg of EDCI and 165 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 100 mg of (S)-(−)-3-pyrrolidinol was added dropwise thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was terminated, 50 μl of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 195 mg/Yield: 58%).
1H NMR (400, CDCl3): 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)
Example 45
Preparation of tert-butyl 4-((2-fluoro-4-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (R)-(+)-3-pyrrolidinol was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 120 mg/Yield: 52%).
1H NMR (400, CDCl3): 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)
Example 46
Preparation of N-(1,3-dihydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 36>, except that 2-amino-1,3-propanediol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 185 mg/Yield: 52%).
1H NMR (400, CDCl3): 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)
Example 47
Preparation of N-(3-hydroxy-2,2-dimethylpropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 36>, except that 3-amino-2,2-dimethylpropan-1-ol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 150 mg/Yield: 65%).
1H NMR (400, CDCl3): 8.25 (1H, s), 7.34 (1H, d), 7.17 (1H, d), 6.55 (1H, 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)
Example 48
Preparation of ((R)-3-hydroxypyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 17>, except that (R)-(+)-3-pyrrolidinol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 175 mg/Yield: 77%).
1H NMR (400, CDCl3): 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), 3.11 (2H, m), 2.90 (1H, m), 2.52 (6H, m), 1.99 (7H, m), 1.43 (2H, m), 1.29 (6H, d)
Example 49
Preparation of ((S)-3-hydroxypyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 17>, except that (S)-(−)-3-pyrrolidinol was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 120 mg/Yield: 52%).
1H NMR (400, CDCl3): 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), 3.11 (2H, m), 2.90 (1H, m), 2.52 (6H, m), 1.99 (7H, m), 1.43 (2H, m), 1.29 (6H, d)
Example 50
Preparation of N-(2,2-difluoroethyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that 2,2-difluoroethylamine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 170 mg/Yield: 74%).
1H NMR (400, CDCl3): 8.22 (2H, s), 7.32 (2H, d), 6.87 (2H, d), 6.04 (1H, 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)
Example 51
Preparation of N-(2,2-difluoroethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that 2,2-difluoroethylamine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 175 mg/Yield: 76%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.04 (1H, m), 5.88 (2H, m), 4.23 (2H, 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)
Example 52
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 17>, except that pyrrolidine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 200 mg/Yield: 87%).
1H NMR (400, CDCl3): 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)
Example 53
Preparation of ((S)-3-fluoropyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 17>, except that (S)-3-fluoropyrrolidine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 175 mg/Yield: 76%).
1H NMR (400, CDCl3): 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)
Example 54
Preparation of ((R)-3-fluoropyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 17>, except that (R)-3-fluoropyrrolidine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 175 mg/Yield: 77%).
1H NMR (400, CDCl3): 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)
Example 55
Preparation of (4-ethylpiperazin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 8>, except that 1-ethyl piperazine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 200 mg/Yield: 87%).
1H NMR (400, CDCl3): 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), 1.99 (6H, m), 1.27 (8H, m)
Example 56
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 17>, except that piperidine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 170 mg/Yield: 74%).
1H NMR (400, CDCl3): 7.34 (2H, d), 6.86 (2H, d), 6.07 (1H, m), 4.23 (2H, 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)
Example 57
Preparation of tert-butyl 4-((2-fluoro-4-(4-((S)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (S)-3-fluoropyrrolidine was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 175 mg/Yield: 76%).
1H NMR (400, CDCl3): 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)
Example 58
Preparation of tert-butyl 4-((2-fluoro-4-(4-((R)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (R)-3-fluoropyrrolidine was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 195 mg/Yield: 85%).
1H NMR (400, CDCl3): 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)
Example 59
Preparation of tert-butyl 4-((2-fluoro-4-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (S)-2-amino-1-propanol was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 200 mg/Yield: 87%).
1H NMR (400, CDCl3): 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)
Example 60
Preparation of tert-butyl 4-((2-fluoro-4-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (R)-2-amino-1-propanol was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 174 mg/Yield: 75%).
1H NMR (400, CDCl3): 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)
Example 61
Preparation of tert-butyl 4-((2-fluoro-4-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (S)-1-amino-2-propanol was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 120 mg/Yield: 53%).
1H NMR (400, CDCl3): 7.14 (2H, m), 6.89 (1H, t), 6.07 (1H, s), 4.15 (2H, 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)
Example 62
Preparation of tert-butyl 4-((2-fluoro-4-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (R)-1-amino-2-propanol was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 139 mg/Yield: 60%).
1H NMR (400, CDCl3): 7.14 (2H, m), 6.89 (1H, t), 6.07 (1H, s), 4.15 (2H, 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)
Example 63
Preparation of tert-butyl 4-((4-(4-((S)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (S)-3-amino-1,2-propanediol was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 185 mg/Yield: 80%).
1H NMR (400, CDCl3): 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)
Example 64
Preparation of tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (R)-3-amino-1,2-propanediol was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 177 mg/Yield: 77%).
1H NMR (400, CDCl3): 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)
Example 65
Preparation of azetidin-1-yl(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 17>, except that azetidine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 90 mg/Yield: 40%).
1H NMR (400, CDCl3): 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 (2H, 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)
Example 66
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(morpholino)methanone




The title compound was prepared in the same manner as in <Example 17>, except that morpholine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 190 mg/Yield: 83%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.84 (2H, d), 6.06 (1H, 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)
Example 67
Preparation of tert-butyl 4-((4-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that 2-amino-1,3-propanediol was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 115 mg/Yield: 53%).
1H NMR (400, CDCl3): 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)
Example 68
Preparation of tert-butyl 4-((5-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that 2-amino-1,3-propanediol was used instead of the (S)-2-amino-1-propanol (Amount obtained: 142 mg/Yield: 63%).
1H NMR (400, CDCl3): 8.14 (1H, s), 7.61 (1H, d), 6.70 (1H, d), 6.40 (1H, 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).
Example 69
Preparation of tert-butyl 4-((2-fluoro-4-(4-(morpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that morpholine was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 192 mg/Yield: 83%).
1H NMR (400, CDCl3): 7.14 (2H, m), 6.89 (1H, t), 6.09 (1H, m), 4.16 (2H, m), 3.88 (2H, d), 3.69 (6H, m), 3.58 (2H, m), 2.78 (3H, m), 2.48 (4H, m), 1.91 (5H, m), 1.48 (9H, s), 1.28 (2H, m)
Example 70
Preparation of tert-butyl 4-((5-(4-(morpholine-4-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that morpholine was used instead of the (S)-2-amino-1-propanol (Amount obtained: 210 mg/Yield: 91%).
1H NMR (400, CDCl3): 8.14 (1H, s), 7.63 (1H, d), 6.68 (1H, d), 6.05 (1H, 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)
Example 71
Preparation of tert-butyl 4-((2-fluoro-4-(4-(thiomorpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that thiomorpholine was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 210 mg/Yield: 87%).
1H NMR (400, CDCl3): 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 (9H, s), 1.26 (2H, m)
Example 72
Preparation of tert-butyl 4-((5-(4-(thiomorpholine-4-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that thiomorpholine was used instead of the (S)-2-amino-1-propanol (Amount obtained: 180 mg/Yield: 79%).
1H NMR (400, CDCl3): 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)
Example 73
Preparation of tert-butyl 4-((2-fluoro-4-(4-(thiomorpholine-1,1-dioxide-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




120 mg of tert-butyl 4-((2-fluoro-4-(4-(thiomorpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate was dissolved in a THF/water mixture (50 μl/25 μl), and stirred. 360 mg of oxone was added dropwise thereto, and the resulting mixture was stirred for 30 minutes. After the reaction was terminated, the reaction mixture was extracted with 150 μl of ethyl acetate, washed with 100 μl of brine, dried with anhydrous magnesium sulfate, concentrated, and then isolated by silica column chromatography to prepare the title compound (Amount obtained: 100 mg/Yield: 72%).
1H NMR (400, CDCl3): 7.14 (2H, m), 6.90 (1H, t), 6.07 (1H, m), 4.19 (6H, m), 3.89 (2H, d), 3.09 (4H, d), 2.77 (3H, m), 2.54 (3H, m), 2.33 (1H, m), 2.00 (3H, m), 1.87 (2H, m), 1.48 (9H, s), 1.27 (2H, m)
Example 74
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(thiomorpholino)methanone




The title compound was prepared in the same manner as in <Example 17>, except that thiomorpholine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 165 mg/Yield: 63%).
1H NMR (400, CDCl3): 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 (1H, 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)
Example 75
Preparation of N-(2-fluoroethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that 2-fluoroethylamine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 174 mg/Yield: 75%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.87 (2H, d), 6.04 (2H, m), 4.53 (1H, m), 4.27 (2H, d), 3.86 (2H, d), 3.66 (2H, m), 3.21 (8H, m), 2.01 (5H, m), 1.45 (1H, m), 1.31 (6H, m)
Example 76
Preparation of tert-butyl 3-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamido)propylcarbamate




The title compound was prepared in the same manner as in <Example 17>, except that tert-butyl 3-(methylamino)propylcarbamate was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 160 mg/Yield: 53%).
1H NMR (400, CDCl3): 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)
Example 77
Preparation of N-(3-aminopropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamide




100 mg of tert-butyl 3-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamido)propylcarbamate was dissolved in 25 μl of DCM, and stirred. 4 N HCl dissolved in 2 μl of dioxane was added dropwise thereto, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was terminated, the resulting solids were filtered, washed with 50 μl of DCM, and then dried to obtain a desired compound as a white solid (Amount obtained: 30 mg/Yield: 34%).
1H NMR (400, DMSO): 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 (2H, m), 1.32 (6H, d)
Example 78
Preparation of 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 17>, except that 2,2,2-trifluoroethyl amine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 195 mg/Yield: 85%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.04 (1H, m), 5.96 (1H, m), 4.23 (2H, d), 3.99 (2H, m), 3.84 (2H, 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)
Example 79
Preparation of (4-ethylpiperazin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 17>, except that N-ethylpiperazine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 150 mg/Yield: 65%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.05 (1H, m), 4.23 (2H, 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)
Example 80
Preparation of N-(1,3-dihydroxypropan-2-yl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




250 mg of 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid was dissolved in 25 μl of DMF, and stirred. 200 mg of EDCI and 150 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 100 mg of 2-amino-1,3-propanediol was added dropwise thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was terminated, 50 μl of distilled water was slowly added as 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 210 mg/Yield: 71%).
1H NMR (400, CDCl3): 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 (2H, 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)
Example 81
Preparation of 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)-N-methylcyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 80>, except that 2-(methylamino)ethanol was used instead of the 2-amino-1,3-propanediol (Amount obtained: 169 mg/Yield: 73%).
1H NMR (400, CDCl3): 7.15 (1H, d), 7.11 (1H, d), 6.91 (1H, 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)
Example 82
Preparation of tert-butyl 4-((2-fluoro-4-(4-(3-hydroxy-2,2-dimethylpropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that 3-amino-2,2-dimethylpropan-1-ol was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 150 mg/Yield: 65%).
1H NMR (400, CDCl3): 7.15 (1H, d), 7.11 (1H, d), 6.91 (1H, 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)
Example 83
Preparation of 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-((S)-1-hydroxypropan-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 80>, except that (S)-2-amino-1-propanol was used instead of the 2-amino-1,3-propanediol (Amount obtained: 95 mg/Yield: 48%).
1H NMR (400, CDCl3): 7.15 (1H, d), 7.11 (1H, d), 6.91 (1H, 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)
Example 84
Preparation of 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-((R)-1-hydroxypropan-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 80>, except that (R)-2-amino-1-propanol was used instead of the 2-amino-1,3-propanediol (Amount obtained: 120 mg/Yield: 53%).
1H NMR (400, CDCl3): 7.15 (1H, d), 7.11 (1H, d), 6.91 (1H, 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)
Example 85
Preparation of tert-butyl 4-((4-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that 2,2-difluoroethylamine was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 150 mg/Yield: 65%).
1H NMR (400, CDCl3): 7.15 (1H, d), 7.11 (1H, d), 6.91 (1H, m), 6.11 (1H, 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)
Example 86
Preparation of tert-butyl 4-((5-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that 2,2,2-trifluoroethylamine was used instead of the (S)-2-amino-1-propanol (Amount obtained: 110 mg/Yield: 48%).
1H NMR (400, CDCl3): 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)
Example 87
Preparation of tert-butyl 4-((5-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that 2,2-difluoroethylamine was used instead of the (S)-2-amino-1-propanol (Amount obtained: 150 mg/Yield: 65%).
1H NMR (400, CDCl3): 8.14 (1H, d), 7.61 (1H, d), 6.70 (1H, d), 6.05 (1H, s), 5.88 (1H, m), 5.85 (1H, m), 4.16 (4H, d), 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)
Example 88
Preparation of tert-butyl 4-((5-(4-(2-fluoroethylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that 2-fluoroethylamine was used instead of the (S)-2-amino-1-propanol (Amount obtained: 120 mg/Yield: 52%).
1H NMR (400, CDCl3): 8.14 (1H, d), 7.61 (1H, d), 6.70 (1H, 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)
Example 89
Preparation of (4-cyclopropylpiperazin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 17>, except that cyclopropylpiperazine was used instead of the (R)-3-amino-1,2-propanediol (Amount obtained: 210 mg/Yield: 87%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.05 (1H, d), 4.22 (2H, d), 3.85 (2H, d), 3.66 (2H, 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)
Example 90
Preparation of tert-butyl 4-((5-(4-((R)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that (R)-3-fluoropyrrolidine was used instead of the (S)-2-amino-1-propanol (Amount obtained: 165 mg/Yield: 72%).
1H NMR (400, CDCl3): 8.15 (1H, s), 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
Preparation of tert-butyl 4-((5-(4-((S)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 24>, except that (S)-3-fluoropyrrolidine was used instead of the (S)-2-amino-1-propanol (Amount obtained: 120 mg/Yield: 53%).
1H NMR (400, CDCl3): 8.15 (1H, s), 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 92
Preparation of 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 80>, except that 2,2,2-trifluoroethylamine was used instead of the 2-amino-1,3-propanediol (Amount obtained: 140 mg/Yield: 62%).
1H NMR (400, CDCl3): 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), 1.32 (6H, d)
Example 93
Preparation of N-(2,2-difluoroethyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 80>, except that 2,2-difluoroethylamine was used instead of the 2-amino-1,3-propanediol (Amount obtained: 110 mg/Yield: 49%).
1H NMR (400, CDCl3): 7.11 (2H, m), 6.91 (1H, m), 6.07 (1H, d), 5.89 (1H, 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)
Example 94
Preparation of 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-fluoroethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 80>, except that fluoroethylamine was used instead of the 2-amino-1,3-propanediol (Amount obtained: 120 mg/Yield: 53%).
1H NMR (400, CDCl3): 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)
Example 95
Preparation of (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 80>, except that (S)-3-fluoropyrrolidine was used instead of the 2-amino-1,3-propanediol (Amount obtained: 185 mg/Yield: 78%).
1H NMR (400, CDCl3): 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)
Example 96
Preparation of (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-fluoropyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 80>, except that (R)-3-fluoropyrrolidine was used instead of the 2-amino-1,3-propanediol (Amount obtained: 150 mg/Yield: 64%).
1H NMR (400, CDCl3): 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)
Example 97
Preparation of (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(morpholino)methanone




The title compound was prepared in the same manner as in <Example 80>, except that morpholine was used instead of the 2-amino-1,3-propanediol (Amount obtained: 190 mg/Yield: 83%).
1H NMR (400, CDCl3): 7.11 (2H, m), 6.91 (1H, m), 6.09 (1H, s), 4.21 (2H, d), 3.91 (2H, 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)
Example 98
Preparation of (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(thiomorpholino)methanone




The title compound was prepared in the same manner as in <Example 80>, except that thiomorpholine was used instead of the 2-amino-1,3-propanediol (Amount obtained: 200 mg/Yield: 78%).
1H NMR (400, CDCl3): 7.11 (2H, m), 6.91 (1H, m), 6.09 (1H, s), 4.21 (2H, d), 3.91 (6H, m), 3.13 (2H, 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)
Example 99
Preparation of N-(2,2-difluoroethyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 36>, except that 2,2-difluoroethylamine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 165 mg/Yield: 71%).
1H NMR (400, CDCl3): 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), 3.71 (2H, 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)
Example 100
Preparation of (4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enyl)(morpholino)methanone




The title compound was prepared in the same manner as in <Example 36>, except that morpholine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 200 mg/Yield: 87%).
1H NMR (400, CDCl3): 8.25 (1H, d), 7.34 (1H, d), 7.16 (1H, d), 6.56 (1H, s), 4.24 (2H, d), 3.90 (2H, d), 3.72 (6H, m), 3.58 (2H, 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)
Example 101
Preparation of ((R)-3-fluoropyrrolidin-1-yl)(4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 36>, except that (R)-3-fluoropyrrolidine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 210 mg/Yield: 86%).
1H NMR (400, CDCl3): 8.25 (1H, d), 7.34 (1H, m), 7.16 (1H, m), 6.58 (1H, 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), 1.31 (6H, d)
Example 102
Preparation of ((S)-3-fluoropyrrolidin-1-yl)(4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 36>, except that (S)-3-fluoropyrrolidine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 220 mg/Yield: 81%).
1H NMR (400, CDCl3): 8.25 (1H, d), 7.34 (1H, m), 7.16 (1H, m), 6.58 (1H, 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), 1.31 (6H, d)
Example 103
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that 2,2,2-trifluoroethylamine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 190 mg/Yield: 77%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.31 (2H, d), 6.86 (2H, d), 6.03 (1H, 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), 1.21 (3H, m)
Example 104
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-fluoroethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that fluoroethylamine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 180 mg/Yield: 72%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.31 (2H, d), 6.86 (2H, d), 6.03 (1H, 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), 1.21 (3H, m)
Example 105
Preparation of (2S)-1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carboxamide




The title compound was prepared in the same manner as in <Example 8>, except that (S)-pyrrolidine-2-carboxamide was used instead of the (R)-2-amino-1-propanol (Amount obtained: 160 mg/Yield: 81%).
1H NMR (400, CDCl3): 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), 1.21 (3H, m)
Example 106
Preparation of (2S)-1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carbonitrile




The title compound was prepared in the same manner as in <Example 8>, except that (S)-pyrrolidine-2-carbonitrile hydrochloride was used instead of the (R)-2-amino-1-propanol (Amount obtained: 220 mg/Yield: 83%).
1H NMR (400, CDCl3): 8.23 (2H, s), 7.32 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.79 (3H, m), 3.85 (2H, d), 3.75 (1H, m), 3.59 (1H, m), 2.99 (2H, m), 2.4-2.71 (7H, m), 1.83-2.38 (10H, m), 1.39 (2H, m), 1.21 (3H, m)
Example 107
Preparation of tert-butyl 4-((4-(4-((S)-2-carbamoylpyrrolidine-1-carbonyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (S)-pyrrolidine-2-carboxamide was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 210 mg/Yield: 82%).
1H NMR (400, CDCl3): 7.11 (3H, m), 6.91 (1H, m), 6.09 (1H, s), 5.32 (1H, 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)
Example 108
Preparation of (2S)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carboxamide




The title compound was prepared in the same manner as in <Example 80>, except that (S)-pyrrolidine-2-carboxamide was used instead of the 2-amino-1,3-propanediol (Amount obtained: 180 mg/Yield: 79%).
1H NMR (400, CDCl3): 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), 1.31 (6H, d)
Example 109
Preparation of (methyl 2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetate




The title compound was prepared in the same manner as in <Example 80>, except that methyl 2-aminoacetate was used instead of the 2-amino-1,3-propanediol (Amount obtained: 850 mg/Yield: 83%).
1H NMR (400, CDCl3): 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), 1.31 (6H, d)
Example 110
Preparation of ethyl 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoate




The title compound was prepared in the same manner as in <Example 80>, except that ethyl 3-aminopropanoate was used instead of the 2-amino-1,3-propanediol (Amount obtained: 940 mg/Yield: 86%).
1H NMR (400, CDCl3): 7.11 (2H, m), 6.90 (1H, m), 6.08 (1H, 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, m), 1.83-2.21 (5H, m), 1.49 (2H, m), 1.31 (6H, d), 1.29 (3H, m)
Example 111
Preparation of 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoic acid




2,000 mg of ethyl 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoate was dissolved in a THF/water/ethanol mixture (100 μl/50 μl/10 μl) in a 500 μl flask, and stirred under nitrogen. 1.4 g of lithium hydroxide monohydrate was added dropwise thereto, and the resulting mixture was reacted at room temperature for 18 hours. After the reaction was terminated, the pH of the resulting reaction mixture was adjusted to pH 1 to 2 using concentrated HCl. The resulting solids were filtered, and dried to prepare the desired title compound (Amount obtained: 660 mg/Yield: 88%).
1H NMR (400, CDCl3): 7.11 (2H, m), 6.90 (1H, m), 6.08 (1H, s), 4.21 (2H, m), 3.91 (2H, d), 3.58 (2H, 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)
Example 112
Preparation of 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-enecarboxamide




250 mg of 2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetic acid was dissolved in 20 μl of DMF in a 100 μl flask, and stirred under nitrogen. 140 mg of EDCI and 110 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 0.1 μl of morpholine were added dropwise thereof, and the mixture was stirred at room temperature for 5 hours. After the reaction was terminated, 50 μl of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 160 mg/Yield: 72%).
1H NMR (400, CDCl3): 7.11 (2H, m), 6.90 (1H, m), 6.71 (1H, m), 6.07 (1H, s), 4.21 (2H, m), 4.11 (2H, d), 3.91 (2H, d), 3.71 (6H, 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), 1.31 (6H, d)
Example 113
Preparation of 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-morpholino-3-oxopropyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 112>, except that 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoic acid was used instead of the 2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetic acid (Amount obtained: 155 mg/Yield: 74%).
1H NMR (400, CDCl3): 7.11 (2H, m), 6.90 (1H, m), 6.50 (1H, m), 6.06 (1H, 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), 1.31 (6H, d)
Example 114
Preparation of tert-butyl 4-((4-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 44>, except that (S)-pyrrolidine-2-carbonitrile hydrochloride was used instead of the (S)-(−)-3-pyrrolidinol (Amount obtained: 180 mg/Yield: 76%).
1H NMR (400, CDCl3): 7.11 (3H, m), 6.91 (1H, m), 6.09 (1H, 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).
Example 115
Preparation of (2S)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carbonitrile




The title compound was prepared in the same manner as in <Example 80>, except that (S)-pyrrolidine-2-carbonitrile hydrochloride was used instead of the 2-amino-1,3-propanediol (Amount obtained: 190 mg/Yield: 82%).
1H NMR (400, CDCl3): 7.11 (3H, m), 6.91 (1H, 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), 1.31 (6H, d)
Example 116
Preparation of (2R)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carboxamide




The title compound was prepared in the same manner as in <Example 80>, except that (R)-pyrrolidine-2-carboxamide was used instead of the 2-amino-1,3-propanediol (Amount obtained: 210 mg/Yield: 79%).
1H NMR (400, CDCl3): 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), 1.31 (6H, d)
Example 117
Preparation of (2R)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carbonitrile




The title compound was prepared in the same manner as in <Example 80>, except that (R)-pyrrolidine-2-carbonitrile hydrochloride was used instead of the 2-amino-1,3-propanediol (Amount obtained: 165 mg/Yield: 73%).
1H NMR (400, CDCl3): 7.11 (3H, m), 6.91 (1H, 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), 1.31 (6H, d)
Example 118
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 8>, except that (R)-pyrrolidin-2-yl methanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 240 mg/Yield: 86%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.32 (1H, d), 6.86 (1H, 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), 1.31 (2H, m), 1.22 (3H, m)
Example 119
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 8>, except that (S)-pyrrolidin-2-yl methanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 220 mg/Yield: 83%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.32 (1H, d), 6.86 (1H, 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), 1.31 (2H, m), 1.22 (3H, m)
Example 120
Preparation of 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 80>, except that 2-aminoethanol was used instead of the 2-amino-1,3-propanediol (Amount obtained: 180 mg/Yield: 76%).
1H NMR (400, CDCl3): 7.11 (3H, m), 6.91 (1H, m), 6.05 (2H, m), 4.19 (2H, 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), 1.31 (6H, d)
Example 121
Preparation of (2R)-1-(2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetyl)pyrrolidine-2-carboxamide




The title compound was prepared in the same manner as in <Example 112>, except that (R)-pyrrolidine-2-carboxamide was used instead of the morpholine (Amount obtained: 160 mg/Yield: 74%).
1H NMR (400, CDCl3): 7.11 (3H, m), 6.91 (1H, m), 6.68 (1H, s), 6.60 (1H, m), 6.07 (2H, m), 5.43 (1H, s), 4.60 (1H, 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), 2.91 (1H, m), 2.35-2.59 (6H, m), 1.83-2.21 (8H, m), 1.49 (2H, m), 1.31 (6H, d)
Example 122
Preparation of N-(2-((R)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 112>, except that (R)-pyrrolidine-2-carbonitrile hydrochloride was used instead of the morpholine (Amount obtained: 190 mg/Yield: 77%).
1H NMR (400, CDCl3): 7.11 (3H, m), 6.91 (1H, m), 6.60 (1H, m), 6.07 (2H, m), 4.60 (1H, 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), 2.91 (1H, m), 2.35-2.59 (6H, m), 1.83-2.21 (8H, m), 1.49 (2H, m), 1.31 (6H, d)
Example 123
Preparation of (4-cyclopropylpiperazin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 8>, except that cyclopropylpiperazine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 205 mg/Yield: 79%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.32 (2H, d), 6.86 (2H, d), 6.05 (1H, m), 4.79 (2H, 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), 2.01 (5H, m), 1.65 (1H, m), 1.33 (2H, m), 1.20 (3H, m), 0.49 (4H, m)
Example 124
Preparation of (4-(cyclopropylmethyl)piperazin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 8>, except that 1-(cyclopropylmethyl)piperazine was used instead of the (R)-2-amino-1-propanol (Amount obtained: 185 mg/Yield: 77%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.32 (2H, d), 6.86 (2H, d), 6.05 (1H, m), 4.79 (2H, 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 (3H, m), 2.01 (5H, m), 1.35 (2H, m), 1.20 (3H, m), 0.89 (1H, m), 0.55 (2H, m), 0.14 (2H, m)
Example 125
Preparation of tert-butyl 4-((3-fluoro-4-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




300 mg of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-2-fluorophenyl)cyclohex-3-enecarboxyilc acid was dissolved in 25 μl of DMF, and stirred. 210 mg of EDCI and 165 mg of HOBt were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 120 mg of (S)-1-amino-2-propanol was added dropwise thereto, and the mixture was stirred at room temperature for 5 hours. After the reaction was terminated, 50 μl of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to obtain a desired compound as a white solid (Amount obtained: 230 mg/Yield: 82%).
1H NMR (400, CDCl3): 7.13 (1H, m), 6.60 (2H, m), 6.11 (1H, 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 126
Preparation of tert-butyl 4-((3-fluoro-4-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 125>, except that (R)-1-amino-2-propanol was used instead of the (S)-1-amino-2-propanol (Amount obtained: 210 mg/Yield: 80%).
1H NMR (400, CDCl3): 7.13 (1H, m), 6.60 (2H, m), 6.11 (1H, 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
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((S)-1-hydroxypropan-2-yl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that (S)-2-amino-1-propanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 170 mg/Yield: 77%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.31 (2H, d), 6.86 (2H, d), 6.04 (1H, 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 (3H, m), 1.38 (2H, m), 1.28 (2H, m), 1.21 (3H, d)
Example 128
Preparation of N-((S)-2,3-dihydroxypropyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that (S)-3-amino-1,2-propanediol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 180 mg/Yield: 74%).
1H NMR (400, DMSO-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)
Example 129
Preparation of tert-butyl 4-((3-fluoro-4-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 125>, except that (R)-2-amino-1-propanol was used instead of the (S)-1-amino-2-propanol (Amount obtained: 180 mg/Yield: 80%).
1H NMR (400, CDCl3): 7.15 (1H, t), 6.64 (2H, m), 5.89 (1H, 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)
Example 130
Preparation of tert-butyl 4-((3-fluoro-4-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 125>, except that (S)-2-amino-1-propanol was used instead of the (S)-1-amino-2-propanol (Amount obtained: 170 mg/Yield: 74%).
1H NMR (400, CDCl3): 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 (1H, 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)
Example 131
Preparation of tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 125>, except that (R)-3-amino-1,2-propanediol was used instead of the (S)-1-amino-2-propanol (Amount obtained: 205 mg/Yield: 81%).
1H NMR (400, CDCl3): 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)
Example 132
Preparation of tert-butyl 4-((4-(4-((S)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 125>, except that (S)-3-amino-1,2-propanediol was used instead of the (S)-1-amino-2-propanol (Amount obtained: 165 mg/Yield: 74%).
1H NMR (400, CDCl3): 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)
Example 133
Preparation of (2S)-1-(2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetyl)pyrrolidine-2-carboxamide




The title compound was prepared in the same manner as in <Example 112>, except that (S)-pyrrolidine-2-carboxamide was used instead of the morpholine (Amount obtained: 160 mg/Yield: 71%).
1H NMR (400, CDCl3): 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), 2.48 (6H, m), 2.14 (4H, m), 1.91 (3H, m), 1.42 (2H, m), 1.32 (6H, d)
Example 134
Preparation of (2S)-1-(3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoyl)pyrrolidine-2-carboxamide




The title compound was prepared in the same manner as in <Example 112> using 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoic acid and (S)-pyrrolidine-2-carboxamide (Amount obtained: 210 mg/Yield: 80%).
1H NMR (400, CDCl3): 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
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-hydroxypyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 8>, except that (S)-(+)-3-pyrrolidinol was used instead of the (R)-2-aminopropan-1-ol (Amount obtained: 220 mg/Yield: 81%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.87 (2H, d), 6.07 (1H, s), 4.80 (2H, d), 4.55 (1H, d), 3.85 (2H, d), 3.65 (4H, m), 2.94 (2H, t), 2.48 (7H, m), 2.00 (7H, m), 1.40 (2H, m), 1.18 (3H, m)
Example 136
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((S)-2-hydroxypropyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 8>, except that (S)-1-amino-2-propanol was used instead of the (R)-2-amino-1-propanol (Amount obtained: 215 mg/Yield: 82%).
1H NMR (400, CDCl3): 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), 2.96 (2H, t), 2.46 (8H, m), 2.18 (2H, m), 1.96 (3H, m), 1.38 (2H, m), 1.24 (6H, m)
Example 137
Preparation of tert-butyl 4-((4-(4-(cyclopropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 125>, except that cyclopropylamine was used instead of the (S)-1-amino-2-propanol (Amount obtained: 180 mg/Yield: 74%).
1H NMR (400, CDCl3): 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
Preparation of tert-butyl 4-((3-fluoro-4-(4-(2-fluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 125>, except that 2-fluoroethylamine was used instead of the (S)-1-amino-2-propanol (Amount obtained: 160 mg/Yield: 71%).
1H NMR (400, CDCl3): 7.15 (1H, t), 6.64 (2H, m), 6.04 (1H, m), 5.89 (1H, 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)
Example 139
Preparation of N-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 112>, except that (S)-pyrrolidine-2-carbonitrile hydrochloride was used instead of the morpholine (Amount obtained: 190 mg/Yield: 83%).
1H NMR (400, CDCl3): 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), 2.48 (6H, m), 2.14 (4H, m), 1.91 (3H, m), 1.42 (2H, m), 1.32 (6H, d)
Example 140
Preparation of N-(3-((S)-2-cyanopyrrolidin-1-yl)-3-oxopropyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 112> using 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoic acid and (S)-pyrrolidine-2-carbonitrile hydrochloride (Amount obtained: 145 mg/Yield: 77%).
1H NMR (400, CDCl3): 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 141
Preparation of tert-butyl 4-((4-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 125>, except that 2,2-difluoroethylamine was used instead of the (S)-1-amino-2-propanol (Amount obtained: 190 mg/Yield: 73%).
1H NMR (400, CDCl3): 7.15 (1H, t), 6.64 (2H, m), 6.04 (1H, m), 5.89 (2H, s), 4.28 (2H, m), 3.79 (2H, d), 3.70 (2H, m), 2.78 (2H, m), 2.54 (5H, m), 1.92 (5H, m), 1.48 (9H, s), 1.28 (2H, m)
Example 142
Preparation of tert-butyl 4-((3-fluoro-4-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 125>, except that 2,2,2-trifluoroethylamine was used instead of the (S)-1-amino-2-propanol (Amount obtained: 175 mg/Yield: 77%).
1H NMR (400, CDCl3): 7.15 (1H, t), 6.64 (2H, m), 6.04 (1H, m), 5.89 (1H, 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
Preparation of ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




400 mg of 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid was dissolved in 30 ml of DMF in a 100 ml flask, and stirred under a nitrogen atmosphere. 0.4 ml of TEA and 215 mg of (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 400 mg of HATU was added dropwise thereto, and the mixture was stirred at room temperature for an hour. After the reaction was terminated, 50 ml of distilled water was slowly added at 0° C., and the resulting solids were filtered, and dried to prepare the title compound as a white solid (Amount obtained: 450 mg/Yield: 69%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1H, s), 4.24 (2H, d), 3.86 (4H, m), 3.44 (2H, m), 3.12 (2H, m), 2.85 (2H, m), 2.69-1.85 (19H, m), 1.47 (2H, m), 1.32 (6H, d)
Example 144
Preparation of ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that (S)-N,N-dimethylpyrrolidine-3-amine hydrochloride was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 470 mg/Yield: 70%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.02 (1H, s), 4.24 (2H, d), 3.86 (4H, m), 3.44 (2H, m), 3.12 (2H, m), 2.85 (2H, m), 2.69-1.85 (19H, m), 1.47 (2H, m), 1.32 (6H, d)
Example 145
Preparation of ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride




150 mg of ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone was dissolved in 20 ml of dichloromethane in a 100 ml flask, and then stirred under a nitrogen atmosphere. 0.08 ml of 4 N HCl dissolved in dioxane was added dropwise thereto, and the resulting mixture was then stirred at room temperature for 3 hours. After the solvent were removed, 30 ml of acetone was slowly added dropwise. The resulting solids were filtered, washed with 10 ml of ethyl acetate, and then dried to prepare the title compound as a white solid (Amount obtained: 220 mg/Yield: 84%).
1H NMR (400, D2O): 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 (5H, m), 2.81 (1H, m), 1.52 (4H, m), 1.08 (6H, d), 0.95 (2H, s)
Example 146
Preparation of ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 210 mg/Yield: 83%).
1H NMR (400, D2O): 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 (5H, m), 2.81 (1H, m), 1.52 (4H, m), 1.08 (6H, d), 0.95 (2H, s)
Example 147
Preparation of ((R)-2-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that D-prolinol was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 220 mg/Yield: 76%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, 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), 2.91 (1H, m), 2.77-2.28 (5H, m), 2.01 (8H, m), 1.61 (1H, m), 1.46 (2H, m), 1.32 (6H, d)
Example 148
Preparation of ((S)-2-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that L-prolinol was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 180 mg/Yield: 74%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, 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), 2.91 (1H, m), 2.77-2.28 (5H, m), 2.01 (8H, m), 1.61 (1H, m), 1.46 (2H, m), 1.32 (6H, d)
Example 149
Preparation of ((R)-3-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that D-β-prolinol was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 175 mg/Yield: 77%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.22 (2H, d), 3.86 (2H, d), 3.81-3.24 (6H, m), 3.13 (2H, m), 2.91 (1H, m), 2.77-2.28 (6H, m), 2.01 (6H, m), 1.61 (1H, m), 1.46 (2H, m), 1.32 (6H, d)
Example 150
Preparation of ((S)-3-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that L-β-prolinol was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 210 mg/Yield: 74%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.22 (2H, d), 3.86 (2H, d), 3.81-3.24 (6H, m), 3.13 (2H, m), 2.91 (1H, m), 2.77-2.28 (6H, m), 2.01 (6H, m), 1.61 (1H, m), 1.46 (2H, m), 1.32 (6H, d)
Example 151
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 85 mg/Yield: 72%).
1H NMR (400, CDCl3): 8.41 (2H, 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), 1.21 (3H, m)
Example 152
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone




300 mg of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid was dissolved in 30 ml of DMF in a 100 ml flask, and stirred under a nitrogen atmosphere. 0.2 ml of TEA and 110 mg of L-β-prolinol were sequentially added dropwise thereto, and the resulting mixture was then additionally stirred for 10 minutes. 300 mg of HATU was added dropwise thereto, and the mixture was stirred at room temperature for an hour. After the reaction was terminated, 50 ml of distilled water was slowly added at 0° C., and the resulting solids were filtered, and then dried to prepare the title compound (Amount obtained: 230 mg/Yield: 74%).
1H NMR (400, CDCl3): 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 (10H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 153
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that D-β-prolinol was used instead of the L-β-prolinol (Amount obtained: 240 mg/Yield: 82%).
1H NMR (400, CDCl3): 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 (10H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 154
Preparation of ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that (S)-N,N-dimethylpyrrolidine-3-amine hydrochloride was used instead of the L-β-prolinol (Amount obtained: 470 mg/Yield: 80%).
1H NMR (400, CDCl3): 8.18 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, 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), 1.21 (3H, m)
Example 155
Preparation of ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride was used instead of the L-β-prolinol (Amount obtained: 440 mg/Yield: 76%).
1H NMR (400, CDCl3): 8.18 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, 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), 1.21 (3H, m)
Example 156
Preparation of ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 180 mg/Yield: 76%).
1H NMR (400, D2O): 8.28 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.31 (1H, 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), 1.09 (3H, m)
Example 157
Preparation of ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 170 mg/Yield: 71%).
1H NMR (400, D2O): 8.28 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.31 (1H, 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), 1.09 (3H, m)
Example 158
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 95 mg/Yield: 71%).
1H NMR (400, CDCl3): 8.43 (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 (10H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 159
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 85 mg/Yield: 73%).
1H NMR (400, CDCl3): 8.43 (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 (10H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 160
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that (S)-3-fluoropyrrolidine was used instead of the L-β-prolinol (Amount obtained: 195 mg/Yield: 76%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.31 (1H, 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)
Example 161
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 105 mg/Yield: 73%).
1H NMR (400, CDCl3): 8.41 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.31 (1H, m), 5.01 (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)
Example 162
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that pyrrolidine was used instead of the L-β-prolinol (Amount obtained: 250 mg/Yield: 84%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (2H, d), 3.85 (2H, d), 3.52 (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 163
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that piperidine was used instead of the L-β-prolinol (Amount obtained: 250 mg/Yield: 83%).
1H NMR (400, CDCl3): 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), 1.21 (3H, m)
Example 164
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-hydroxypiperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 4-hydroxy piperidine was used instead of the L-β-prolinol (Amount obtained: 215 mg/Yield: 77%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (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)
Example 165
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxymethyl)piperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 4-piperidinemethanol was used instead of the L-β-prolinol (Amount obtained: 225 mg/Yield: 75%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (3H, m), 4.08 (1H, d), 3.85 (2H, d), 3.55 (2H, m), 3.09 (1H, m), 2.92 (2H, m), 2.81 (1H, m), 2.65-2.28 (7H, m), 2.11 (1H, m), 2.04-1.75 (7H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 166
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 100 mg/Yield: 74%).
1H NMR (400, CDCl3): 8.41 (2H, s), 7.33 (2H, 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)
Example 167
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 85 mg/Yield: 71%).
1H NMR (400, CDCl3): 8.41 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.03 (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), 1.21 (3H, m)
Example 168
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-hydroxypiperidin-1-yl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-hydroxypiperidin-1-yl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 85 mg/Yield: 77%).
1H NMR (400, CDCl3): 8.41 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 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)
Example 169
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxymethyl)piperidin-1-yl)methanone hydrochloride




The title compound was prepared in the same manner as in <Example 145>, except that (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxymethyl)piperidin-1-yl)methanone was used instead of the ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone (Amount obtained: 95 mg/Yield: 76%).
1H NMR (400, CDCl3): 8.41 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.03 (2H, m), 4.72 (1H, d), 4.08 (1H, d), 3.85 (2H, d), 3.55 (2H, m), 3.09 (1H, m), 2.92 (2H, m), 2.81 (1H, m), 2.65-2.28 (7H, m), 2.11 (1H, m), 2.04-1.75 (7H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 170
Preparation of azetidin-1-yl(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that azetidine was used instead of the L-β-prolinol (Amount obtained: 180 mg/Yield: 76%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (3H, m), 4.15 (4H, m), 3.85 (2H, d), 2.91 (2H, m), 2.61-1.81 (14H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 171
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-hydroxyazetidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that azetidine was used instead of the L-β-prolinol (Amount obtained: 200 mg/Yield: 81%).
1H NMR (400, CDCl3): 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), 2.91 (2H, m), 2.71-1.81 (13H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 172
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 4-hydroxyethylpiperazine was used instead of the L-β-prolinol (Amount obtained: 220 mg/Yield: 79%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (2H, m), 3.85 (2H, d), 3.65 (6H, m), 2.91 (2H, m), 2.86-1.81 (12H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 173
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(2-hydroxyethyl)piperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 4-piperidine ethanol was used instead of the L-β-prolinol (Amount obtained: 230 mg/Yield: 77%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (2H, m), 3.69 (1H, d), 3.99 (1H, d), 3.85 (2H, d), 3.75 (2H, m), 3.09 (1H, m), 2.91 (2H, m), 2.86-1.41 (17H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 174
Preparation of N-ethoxy-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that O-ethylhydroxylamine hydrochloride was used instead of the L-β-prolinol (Amount obtained: 230 mg/Yield: 81%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (2H, m), 4.01 (2H, m), 3.85 (2H, d), 2.91 (2H, m), 2.71-1.81 (12H, m), 1.35 (5H, m), 1.21 (3H, m)
Example 175
Preparation of N-ethyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that 2-(ethylamino)ethanol was used instead of the L-β-prolinol (Amount obtained: 205 mg/Yield: 82%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (2H, m), 3.85 (4H, m), 3.71 (1H, s), 3.52 (4H, m), 2.91 (2H, m), 2.81-1.81 (12H, m), 1.35 (2H, m), 1.21 (6H, m)
Example 176
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that 2-aminoethanol was used instead of the L-β-prolinol (Amount obtained: 260 mg/Yield: 85%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (2H, m), 4.78 (2H, m), 3.85 (2H, d), 3.78 (2H, m), 3.51 (2H, m), 2.91 (2H, m), 2.48 (7H, m), 2.21-1.81 (5H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 177
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxy-2,2-dimethylpropyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that 3-amino-2,2-dimethylpropanol was used instead of the L-β-prolinol (Amount obtained: 265 mg/Yield: 85%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, 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), 1.21 (3H, m), 0.89 (6H, d)
Example 178
Preparation of 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide




The title compound was prepared in the same manner as in <Example 152>, except that isonipecotamide was used instead of the L-β-prolinol (Amount obtained: 240 mg/Yield: 79%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.39 (2H, m), 4.78 (2H, m), 4.68 (1H, m), 4.02 (1H, d), 3.85 (2H, d), 3.65 (6H, m), 3.14 (1H, m), 2.91 (2H, m), 2.86-2.18 (9H, m), 2.15-1.59 (13H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 179
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-methoxypropyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that 3-ethoxypropylamine was used instead of the L-β-prolinol (Amount obtained: 240 mg/Yield: 78%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.31 (1H, m), 6.06 (1H, s), 4.78 (2H, m), 3.85 (2H, d), 3.48 (6H, m), 2.91 (2H, m), 2.86-1.79 (14H, m), 1.35 (2H, m), 1.21 (6H, m)
Example 180
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(furan-2-ylmethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that furfurylamine was used instead of the L-β-prolinol (Amount obtained: 180 mg/Yield: 76%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.37 (1H, s), 7.33 (2H, d), 6.86 (2H, d), 6.31 (2H, m), 6.06 (1H, s), 5.89 (1H, m), 4.78 (2H, m), 4.51 (2H, d), 3.85 (2H, d), 2.91 (2H, m), 2.59-1.81 (12H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 181
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N,N-bis(2-hydroxyethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that diethanolamine was used instead of the L-β-prolinol (Amount obtained: 185 mg/Yield: 77%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.78 (2H, m), 3.88 (6H, m), 3.69 (4H, m), 3.15 (2H, d), 2.91 (3H, m), 2.59-1.83 (11H, m), 1.35 (2H, m), 1.21 (3H, m)
Example 182
Preparation of (4-hydroxypiperidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 4-hydroxypiperidine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 230 mg/Yield: 80%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.16 (1H, m), 4.19 (3H, m), 3.98 (1H, s), 3.85 (3H, m), 3.21 (4H, m), 2.88 (2H, m), 2.62-1.85 (11H, m), 1.59 (6H, m), 1.32 (6H, d)
Example 183
Preparation of (4-(hydroxymethyl)piperidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 4-piperidine methanol was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 240 mg/Yield: 82%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.72 (1H, s), 4.22 (2H, d), 4.04 (1H, d), 3.85 (2H, d), 3.56 (2H, m), 3.11 (3H, m), 2.88 (2H, m), 2.62-1.75 (13H, m), 1.45 (3H, m), 1.32 (6H, d)
Example 184
Preparation of N-cyclopropyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that cyclopropylamine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 235 mg/Yield: 81%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.70 (1H, s), 4.21 (2H, d), 3.85 (2H, d), 3.11 (2H, m), 2.91 (1H, m), 2.76 (1H, m), 2.42 (5H, m), 1.98 (5H, m), 1.59 (6H, m), 1.32 (6H, d), 0.81 (2H, m), 0.51 (2H, m)
Example 185
Preparation of N-(3-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that 3-aminopropanol was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 220 mg/Yield: 79%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.96 (1H, m), 4.21 (2H, m), 3.85 (2H, m), 3.66 (2H, m), 3.48 (2H, m), 3.20 (1H, m), 3.11 (2H, m) 2.89 (1H, m), 2.48 (5H, m), 2.01 (5H, m), 1.71 (2H, m), 1.59 (6H, m), 1.32 (6H, d)
Example 186
Preparation of (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




The title compound was prepared in the same manner as in <Example 143>, except that 4-piperidine ethanol was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 205 mg/Yield: 77%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.69 (1H, d), 4.21 (2H, m), 3.99 (1H, d), 3.85 (2H, d), 3.74 (2H, m), 3.20 (3H, m), 2.89 (1H, m), 2.81 (1H, m), 2.64-2.24 (5H, m), 2.12-1.69 (8H, m), 1.66 (2H, m), 1.46 (2H, m), 1.32 (6H, d), 1.19 (2H, m)
Example 187
Preparation of (4-(2-hydroxyethyl)piperazin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 4-hydroxyethyl piperazine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 180 mg/Yield: 72%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.21 (2H, m), 3.85 (2H, d), 3.71 (6H, 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)
Example 188
Preparation of 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(methoxymethyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that O-ethylhydroxylamine hydrochloride was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 170 mg/Yield: 71%).
1H NMR (400, CDCl3): 8.14 (1H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 4.21 (2H, m), 3.99 (2H, m), 3.85 (2H, d), 3.12 (2H, m), 2.89 (1H, m), 2.62-2.28 (5H, m), 2.14-1.87 (5H, m), 1.46 (2H, m), 1.32 (6H, d)
Example 189
Preparation of N-cyclopropyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that cyclopropylamine was used instead of the L-β-prolinol (Amount obtained: 180 mg/Yield: 76%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.33 (2H, d), 6.86 (2H, d), 6.06 (1H, s), 5.66 (1H, s), 4.78 (3H, m), 3.85 (2H, d), 2.91 (2H, m), 2.76 (1H, s), 2.61-2.30 (7H, m), 2.09 (2H, m), 1.91 (3H, m), 1.35 (2H, m), 1.21 (3H, m), 0.81 (2H, m), 0.50 (2H, m)
Example 190
Preparation of tert-butyl 4-((4-(4-(2-hydroxyethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




400 mg of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxyilc acid was dissolved in 30 ml of DMF in a 100 ml flask, and then stirred under a nitrogen atmosphere. 0.3 ml of TEA was added dropwise thereto, 90 mg of 2-aminoethanol was in turn added dropwise, and the resulting mixture was additionally stirred for 10 minutes. 400 mg of HATU was added dropwise thereto, and the mixture was stirred at room temperature for an hour. After the reaction was terminated, 50 ml of distilled water was slowly added at 0° C., and the resulting solids were filtered, and then dried to prepare the title compound as a white solid (Amount obtained: 190 mg/Yield: 77%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.14 (1H, m), 6.04 (1H, s), 4.18 (2H, s), 3.79 (4H, m), 3.48 (2H, m), 2.75 (3H, m), 2.48 (5H, m), 2.11 (1H, m), 1.89 (4H, m), 1.48 (9H, s), 1.29 (2H, m)
Example 191
Preparation of tert-butyl 4-((4-(4-(3-hydroxy-2,2-dimethylpropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 3-amino-2,2-dimethylpropanol was used instead of the 2-aminoethanol (Amount obtained: 230 mg/Yield: 84%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.86 (2H, d), 6.04 (1H, s), 5.99 (1H, m), 4.18 (2H, s), 4.01 (1H, m), 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)
Example 192
Preparation of tert-butyl 4-((4-(4-(methoxymethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that O-ethylhydroxylamine hydrochloride was used instead of the 2-aminoethanol (Amount obtained: 220 mg/Yield: 81%).
1H NMR (400, CDCl3): 8.15 (1H, s), 7.33 (2H, d), 6.86 (2H, d), 6.04 (1H, s), 4.18 (2H, s), 4.00 (2H, m), 3.81 (2H, m), 3.48 (2H, m), 2.75 (2H, m), 2.48 (5H, m), 2.11 (1H, m), 1.89 (4H, m), 1.48 (9H, s), 1.29 (5H, m)
Example 193
Preparation of tert-butyl 4-((4-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 4-(pyrrolidin-1-yl)piperidine was used instead of the 2-aminoethanol (Amount obtained: 180 mg/Yield: 76%).
1H NMR (400, CDCl3): 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)
Example 194
Preparation of tert-butyl 4-((4-(4-(cyclobutylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that cyclobutylamine hydrochloride was used instead of the 2-aminoethanol (Amount obtained: 170 mg/Yield: 71%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.04 (1H, m), 5.69 (1H, 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)
Example 195
Preparation of tert-butyl 4-((4-(4-(cyclopentylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that cyclopentylamine was used instead of the 2-aminoethanol (Amount obtained: 195 mg/Yield: 79%).
1H NMR (400, CDCl3): 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 (9H, s), 1.41-1.22 (4H, m)
Example 196
Preparation of tert-butyl 4-((4-(4-(4-morpholinopiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 4-morpholinopiperidine was used instead of the 2-aminoethanol (Amount obtained: 805 mg/Yield: 77%).
1H NMR (400, CDCl3): 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)
Example 197
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxy-N-methylcyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that N,O-dimethylhydroxylamine hydrochloride was used instead of the L-β-prolinol (Amount obtained: 220 mg/Yield: 79%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.34 (2H, m), 6.88 (2H, 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)
Example 198
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxycyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that O-methylhydroxylamine hydrochloride was used instead of the L-β-prolinol (Amount obtained: 240 mg/Yield: 83%).
1H NMR (400, CDCl3): 8.24 (2H, s), 7.33 (2H, m), 6.87 (2H, m), 6.03 (1H, s), 4.80 (2H, m), 3.84 (5H, m), 2.96 (2H, m), 2.57-1.93 (13H, m), 1.41 (2H, m), 1.20 (3H, m)
Example 199
Preparation of tert-butyl 4-((4-(4-(ethyl(2-hydroxyethyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 2-(ethylamino)ethanol was used instead of the 2-aminoethanol (Amount obtained: 170 mg/Yield: 72%).
1H NMR (400, CDCl3): 7.32 (2H, m), 6.85 (2H, m), 6.05 (1H, s), 4.16 (2H, s), 3.80 (3H, 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)
Example 200
Preparation of tert-butyl 4-((4-(4-(4-(2-hydroxyethyl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 4-hydroxyethylpiperidine was used instead of the 2-aminoethanol (Amount obtained: 343 mg/Yield: 71%).
1H NMR (400, CDCl3): 7.32 (2H, m), 6.84 (2H, m), 6.04 (1H, m), 4.68 (1H, 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)
Example 201
Preparation of tert-butyl 4-((4-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 1-hydroxyethylpiperazine was used instead of the 2-aminoethanol (Amount obtained: 331 mg/Yield: 68%).
1H NMR (400, CDCl3): 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)
Example 202
Preparation of tert-butyl 4-((4-(4-(pyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that pyrrolidine was used instead of the 2-aminoethanol (Amount obtained: 357 mg/Yield: 74%).
1H NMR (400, CDCl3): 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)
Example 203
Preparation of tert-butyl 4-((4-(4-(4-ethylpiperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 1-ethylpiperazine was used instead of the 2-aminoethanol (Amount obtained: 330 mg/Yield: 59%).
1H NMR (400, CDCl3): 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)
Example 204
Preparation of tert-butyl 4-((4-(4-(piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that piperidine was used instead of the 2-aminoethanol (Amount obtained: 345 mg/Yield: 67%).
1H NMR (400, CDCl3): 7.32 (2H, m), 6.85 (2H, m), 6.05 (1H, m), 4.15 (2H, s), 3.81 (2H, m), 3.62-3.49 (4H, m), 2.79 (3H, m), 2.52 (3H, m), 2.31 (1H, m), 1.98-1.58 (11H, m), 1.47 (9H, m), 1.28 (2H, m)
Example 205
Preparation of tert-butyl 4-((4-(4-(3-ethoxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 3-ethoxypropane-1-amine was used instead of the 2-aminoethanol (Amount obtained: 339 mg/Yield: 64%).
1H NMR (400, CDCl3): 7.33 (2H, m), 6.86 (2H, m), 6.36 (1H, m), 6.04 (1H, 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)
Example 206
Preparation of tert-butyl 4-((4-(4-(bis(2-hydroxyethyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that diethanolamine was used instead of the 2-aminoethanol (Amount obtained: 351 mg/Yield: 70%).
1H NMR (400, CDCl3): 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)
Example 207
Preparation of 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide




The title compound was prepared in the same manner as in <Example 143>, except that isonipecotamide was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 142 mg/Yield: 53%).
1H NMR (400, CDCl3): 7.32 (2H, m), 6.86 (2H, m), 6.05 (1H, m), 5.68 (2H, m), 4.67 (1H, 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 (10H, m), 1.47 (9H, m), 1.29 (2H, m)
Example 208
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 4-(pyrrolidin-1-yl)piperidine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 159 mg/Yield: 51%).
1H NMR (400, CDCl3): 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, m), 1.62-1.51 (4H, m), 1.31 (6H, d)
Example 209
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-morpholinopiperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 4-morpholinopiperidine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 155 mg/Yield: 58%).
1H NMR (400, CDCl3): 7.33 (2H, m), 6.86 (2H, m), 6.05 (1H, m), 4.75 (1H, 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)
Example 210
Preparation of N-cyclopentyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that cyclopentylamine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 171 mg/Yield: 65%).
1H NMR (400, CDCl3): 7.33 (2H, m), 6.86 (2H, m), 6.04 (1H, m), 5.51 (1H, m), 4.26-4.20 (3H, m), 3.85 (2H, d), 3.14 (2H, m), 2.92 (1H, 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)
Example 211
Preparation of N-cyclobutyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that cyclobutylamine hydrochloride was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 170 mg/Yield: 63%).
1H NMR (400, CDCl3): 7.33 (2H, m), 6.68 (2H, m), 6.04 (1H, m), 5.71 (1H, m), 4.45 (1H, m), 4.23 (2H, m), 3.85 (2H, 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)
Example 212
Preparation of (3,4-dihydroisoquinolin-2(1H)-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 1,2,3,4-tetrahydroisoquinoline was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 183 mg/Yield: 65%).
1H NMR (400, CDCl3): 7.32 (2H, m), 7.23-7.12 (4H, m), 6.87 (2H, m), 6.08 (1H, 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)
Example 213
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 1-methyl-1,2,3,4-tetrahydroisoquinoline was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 174 mg/Yield: 60%).
1H NMR (400, CDCl3): 7.35 (2H, m), 7.24-7.12 (4H, m), 6.89 (2H, m), 6.12 (1H, 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)
Example 214
Preparation of isoindolin-2-yl(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that isoindoline was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 170 mg/Yield: 69%).
1H NMR (400, CDCl3): 7.33-7.28 (7H, m), 6.88 (2H, 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)
Example 215
Preparation of 1,4′-bipiperidin-1′-yl(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 1,4′-bipiperidine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 165 mg/Yield: 71%).
1H NMR (400, CDCl3): 7.33 (2H, 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)
Example 216
Preparation of tert-butyl 4-((4-(4-(1,4′-bipiperidine-1′-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 1,4′-bipiperidine was used instead of the 2-aminoethanol (Amount obtained: 169 mg/Yield: 75%).
1H NMR (400, CDCl3): 7.33 (2H, m), 6.86 (2H, m), 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)
Example 217
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-(hydroxyimino)pyrrolidin-1-yl)methanone




600 mg of 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide was dissolved in a THF/water mixture (30 ml/10 ml) in a 100 ml flask, and stirred under nitrogen. 200 mg of sodium bicarbonate was added dropwise thereto, 170 mg of hydroxylamine hydrochloride was in turn added dropwise, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was terminated, the reaction mixture was distilled under reduced pressure to remove the solvent. Then, 50 ml of distilled water was slowly added thereto at 0° C., and the resulting solids were filtered to obtain a mixture including E and Z forms at a ratio of 3:1 (Amount obtained: 485 mg/Yield: 68%).
Example 218
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 4-(pyrrolidin-1-yl)piperidine was used instead of the L-β-prolinol (Amount obtained: 171 mg/Yield: 69%).
1H NMR (400, CDCl3): 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)
Example 219
Preparation of 1,4′-bipiperidin-1′-yl(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 1,4′-bipiperidine was used instead of the L-β-prolinol (Amount obtained: 180 mg/Yield: 77%).
1H NMR (400, CDCl3): 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 (2H, 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)
Example 220
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-morpholinopiperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 4-morpholinopiperidine was used instead of the L-β-prolinol (Amount obtained: 162 mg/Yield: 58%).
1H NMR (400, CDCl3): 8.18 (2H, s), 7.33 (2H, m), 6.87 (2H, 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)
Example 221
Preparation of tert-butyl 4-((4-(4-(furan-2-ylmethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that furfurylamine was used instead of the 2-aminoethanol (Amount obtained: 169 mg/Yield: 70%).
1H NMR (400, CDCl3): 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)
Example 222
Preparation of tert-butyl 4-((4-(4-(methoxycarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that O-methylhydroxylamine hydrochloride was used instead of the 2-aminoethanol (Amount obtained: 166 mg/Yield: 72%).
1H NMR (400, CDCl3): 8.24 (1H, m), 7.33 (2H, 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)
Example 223
Preparation of tert-butyl 4-((4-(4-(methoxy(methyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that N,O-dimethylhydroxylamine hydrochloride was used instead of the 2-aminoethanol (Amount obtained: 171 mg/Yield: 74%).
1H NMR (400, CDCl3): 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)
Example 224
Preparation of tert-butyl 4-((4-(4-(2,5-dihydro-1H-pyrrole-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 2,5-dihydro-1H-pyrrole was used instead of the 2-aminoethanol (Amount obtained: 167 mg/Yield: 63%).
1H NMR (400, CDCl3): 7.34 (2H, m), 6.87 (2H, m), 6.08 (1H, 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)
Example 225
Preparation of tert-butyl 4-((4-(4-(4-hydroxypiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 4-hydroxypiperidine was used instead of the 2-aminoethanol (Amount obtained: 174 mg/Yield: 70%).
1H NMR (400, CDCl3): 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 (9H, s), 1.32 (2H, m)
Example 226
Preparation of tert-butyl 4-((4-(4-(4-(hydroxymethyl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that piperidinemethanol was used instead of the 2-aminoethanol (Amount obtained: 167 mg/Yield: 65%).
1H NMR (400, CDCl3): 7.33 (2H, m), 6.86 (2H, m), 6.05 (1H, 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)
Example 227
Preparation of 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carbonitrile




The title compound was prepared in the same manner as in <Example 152>, except that piperidine-4-carbonitrile was used instead of the L-β-prolinol (Amount obtained: 165 mg/Yield: 62%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.32 (2H, m), 6.87 (2H, 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 (1H, m), 2.11-1.89 (9H, m), 1.41 (2H, m), 1.22 (3H, m)
Example 228
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(spiro[indene-1,4′-piperidin]-1′-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 4-spiroindene-piperidine hydrochloride was used instead of the L-β-prolinol (Amount obtained: 183 mg/Yield: 74%).
1H NMR (400, CDCl3): 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)
Example 229
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methanone




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 the L-β-prolinol (Amount obtained: 175 mg/Yield: 69%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.32 (2H, m), 6.87 (2H, m), 6.05 (1H, 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)
Example 230
Preparation of N-cyclopentyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that pentylamine was used instead of the L-β-prolinol (Amount obtained: 153 mg/Yield: 58%).
1H NMR (400, CDCl3): 8.23 (2H, s), 7.33 (2H, m), 6.87 (2H, m), 6.03 (1H, 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)
Example 231
Preparation of N-cyclobutyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that cyclobutylamine hydrochloride was used instead of the L-β-prolinol (Amount obtained: 165 mg/Yield: 68%).
1H NMR (400, CDCl3): 8.18 (2H, m), 7.31 (2H, m), 6.86 (2H, m), 6.04 (1H, m), 5.74 (1H, m), 4.79 (2H, d), 4.47 (1H, 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)
Example 232
Preparation of (3,4-dihydroisoquinolin-2(1H)-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 1,2,3,4-tetrahydroisoquinoline was used instead of the L-β-prolinol (Amount obtained: 173 mg/Yield: 69%).
1H NMR (400, CDCl3): 8.19 (2H, m), 7.34 (2H, m), 7.24-7.12 (4H, 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)
Example 233
Preparation of tert-butyl 4-((4-(4-(5-hydroxypentylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 5-aminopentanol was used instead of the 2-aminoethanol (Amount obtained: 166 mg/Yield: 67%).
1H NMR (400, CDCl3): 7.31 (2H, m), 6.84 (2H, m), 6.03 (1H, 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, m), 1.47 (9H, s), 1.44-1.22 (5H, m)
Example 234
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(5-hydroxypentyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that 5-aminopentanol was used instead of the L-β-prolinol (Amount obtained: 172 mg/Yield: 71%).
1H NMR (400, CDCl3): 8.18 (2H, s), 7.32 (2H, m), 6.86 (2H, m), 6.03 (1H, 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 (10H, m), 1.22 (3H, m)
Example 235
Preparation of (2,5-dihydro-1H-pyrrol-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 2,5-dihydro-1H-pyrrole was used instead of the L-β-prolinol (Amount obtained: 184 mg/Yield: 85%).
1H NMR (400, CDCl3): 8.18 (2H, s), 7.34 (2H, m), 6.88 (2H, 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 (2H, m), 2.65-2.32 (7H, m), 2.10-1.88 (6H, m), 1.37 (2H, m), 1.22 (3H, m)
Example 236
Preparation of tert-butyl 4-((4-(4-((2-hydroxyethyl)(methyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 2-(methylamino)ethanol was used instead of the 2-aminoethanol (Amount obtained: 162 mg/Yield: 64%).
1H NMR (400, CDCl3): 7.33 (2H, m), 6.86 (2H, m), 6.07 (1H, m), 4.16 (2H, 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)
Example 237
Preparation of tert-butyl 4-((4-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 2-amino-1,3-propanediol was used instead of the 2-aminoethanol (Amount obtained: 166 mg/Yield: 68%).
1H NMR (400, DMSO-d6): 7.50 (1H, d), 7.35 (2H, m), 6.88 (2H, m), 6.04 (1H, m), 4.61 (2H, m), 4.03 (2H, m), 3.97 (2H, m), 3.82 (2H, d), 3.74 (1H, m), 3.41 (4H, m), 2.72 (2H, m), 2.44-2.19 (5H, m), 1.92-1.89 (2H, m), 1.74 (2H, m), 1.66 (1H, m), 1.39 (9H, s), 1.23 (2H, m)
Example 238
Preparation of tert-butyl 4-((4-(4-(3-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 3-aminopropanol was used instead of the 2-aminoethanol (Amount obtained: 172 mg/Yield: 69%).
1H NMR (400, CDCl3): 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 (2H, m), 3.27 (1H, m), 2.78 (2H, m), 2.53-2.41 (5H, m), 2.12 (1H, m), 1.98-1.82 (4H, m), 1.73 (2H, m), 1.48 (9H, s), 1.31 (2H, m)
Example 239
Preparation of tert-butyl 4-((4-(4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 1,2,3,4-tetrahydroisoquinoline was used instead of the 2-aminoethanol (Amount obtained: 185 mg/Yield: 81%).
1H NMR (400, CDCl3): 7.35 (2H, m), 7.25-7.12 (4H, m), 6.86 (2H, m), 6.07 (1H, m), 4.84 (2H, m), 4.18 (2H, s), 3.91-3.78 (4H, m), 2.97-2.88 (3H, 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)
Example 240
Preparation of tert-butyl 4-((4-(4-(isoindoline-2-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that isoindoline was used instead of the 2-aminoethanol (Amount obtained: 181 mg/Yield: 77%).
1H NMR (400, CDCl3): 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), 2.82-2.73 (3H, m), 2.63-2.37 (4H, m), 2.12 (1H, m), 2.02 (2H, m), 1.86 (2H, m), 1.64 (1H, s), 1.48 (9H, s), 1.33 (2H, m)
Example 241
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(isoindolin-2-yl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that isoindoline was used instead of the L-β-prolinol (Amount obtained: 180 mg/Yield: 76%).
1H NMR (400, CDCl3): 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)
Example 242
Preparation of 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxypropyl)-N-methylcyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 152>, except that 3-methylaminopropanol was used instead of the L-β-prolinol (Amount obtained: 175 mg/Yield: 73%).
1H NMR (400, CDCl3): 8.18 (2H, s), 7.31 (2H, d), 6.86 (2H, 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)
Example 243
Preparation of N-(3-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that 3-methylaminopropanol was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 174 mg/Yield: 71%).
1H NMR (400, CDCl3): 7.31 (2H, d), 6.84 (2H, 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)
Example 244
Preparation of N-(furan-2-ylmethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that furfurylamine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 159 mg/Yield: 62%).
1H NMR (400, CDCl3): 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
Preparation of N-(3-ethoxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that 3-ethoxypropylamine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 167 mg/Yield: 64%).
1H NMR (400, CDCl3): 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 (2H, q), 3.11 (2H, m), 2.90 (1H, m), 2.52-2.36 (5H, m), 2.13-2.05 (2H, m), 1.97 (2H, d), 1.85-1.77 (3H, m), 1.47 (2H, m), 1.31 (6H, d), 1.23 (3H, t)
Example 246
Preparation of 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxycyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that O-methylhydroxylamine hydrochloride was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 170 mg/Yield: 67%).
1H NMR (400, CDCl3): 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)
Example 247
Preparation of 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxy-N-methylcyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that N,O-dimethylhydroxylamine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 176 mg/Yield: 73%).
1H NMR (400, CDCl3): 7.33 (2H, d), 6.85 (2H, d), 6.07 (1H, 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)
Example 248
Preparation of N,N-bis(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that diethanolamine was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 157 mg/Yield: 55%).
1H NMR (400, CDCl3): 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)
Example 249
Preparation of 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide




The title compound was prepared in the same manner as in <Example 143>, except that isonipecotamide was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 167 mg/Yield: 65%).
1H NMR (400, CDCl3): 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 (2H, d), 4.04 (1H, d), 3.85 (2H, d), 3.11 (2H, m), 2.89 (1H, 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 (2H, m), 1.41 (2H, m), 1.23 (6H, d)
Example 250
Preparation of 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidin-3-one




The title compound was prepared in the same manner as in <Example 152>, except that pyrrolidin-3-one hydrochloride was used instead of the L-β-prolinol (Amount obtained: 189 mg/Yield: 81%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.31 (2H, m), 6.86 (2H, 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)
Example 251
Preparation of 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide




The title compound was prepared in the same manner as in <Example 143>, except that pyrrolidin-3-one hydrochloride was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 177 mg/Yield: 65%).
1H NMR (400, CDCl3): 7.32 (2H, m), 6.85 (2H, d), 6.33 (1H, t), 6.05 (1H, t), 4.21 (2H, 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 (2H, d), 1.44 (2H, m), 1.35 (6H, s)
Example 252
Preparation of 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide




The title compound was prepared in the same manner as in <Example 217>, except that O-methylhydroxylamine hydrochloride was used instead of the hydroxylamine hydrochloride (Amount obtained: 170 mg/Yield: 56%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.86 (2H, d), 6.05 (1H, s), 4.23 (4H, m), 3.91 (3H, 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)
Example 253
Preparation of (Z)-(3,3-bis(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that (Z)-4,4-bis(hydroxymethyl)pyrrolidin-3-one O-methyl oxime was used instead of the L-β-prolinol (Amount obtained: 190 mg/Yield: 79%).
1H NMR (400, CDCl3): 8.18 (2H, s) 7.30 (2H, d), 6.85 (2H, 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 (2H, m), 1.19 (2H, t)
Example 254
Preparation of (Z)-tert-butyl 6-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3.4]octane-2-carboxylate




The title compound was prepared in the same manner as in <Example 152>, except that (Z)-tert-butyl 8-(methoxyimino)-2,6-diazaspiro[3.4]octane-2-carboxylate was used instead of the L-β-prolinol (Amount obtained: 177 mg/Yield: 68%).
1H NMR (400, CDCl3): 8.18 (2H, s) 7.29 (2H, d), 6.85 (2H, d), 6.03 (1H, s), 4.77 (2H, d), 4.32 (2H, 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 (4H, m), 1.47 (9H, s), 1.36-1.28 (4H, m))
Example 255
Preparation of (Z)-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(8-(methoxyimino)-2,6-diazaspiro[3.4]octan-6-yl)methanone hydrochloride




150 mg of the compound (Z)-tert-butyl 6-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3.4]octane-2-carboxylate prepared in <Example 254> was dissolved in 20 ml of ethyl acetate in a 100 ml flask, and then stirred under a nitrogen atmosphere. 0.08 ml of 4 N HCl dissolved in dioxane was added dropwise thereto, and the resulting mixture was then stirred at room temperature for 3 hours. The resulting solids were filtered, washed with 10 ml of ethyl acetate, and then dried to prepare the title compound as a white solid (Amount obtained: 130 mg/Yield: 73%).
1H NMR (400, MeOD): 8.50 (2H, s), 7.34 (2H, d), 6.87 (2H, 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)
Example 256
Preparation of tert-butyl 4-((4-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 1-cyclopropylmethyl piperazine was used instead of the 2-aminoethanol (Amount obtained: 169 mg/Yield: 71%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.17 (2H, 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)
Example 257
Preparation of tert-butyl 4-((4-(4-(3,3-difluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 3,3-difluoropyrrolidine hydrochloride was used instead of the 2-aminoethanol (Amount obtained: 174 mg/Yield: 76%).
1H NMR (400, CDCl3): 7.30 (2H, d), 6.84 (2H, d), 6.05 (1H, 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)
Example 258
Preparation of (3,3-difluoropyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 152>, except that 3,3-difluoropyrrolidine hydrochloride was used instead of the L-β-prolinol (Amount obtained: 175 mg/Yield: 73%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.32 (2H, d), 6.85 (2H, d), 6.05 (1H, 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)
Example 259
Preparation of (3,3-difluoropyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 3,3-difluoropyrrolidine hydrochloride was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 182 mg/Yield: 77%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.21 (2H, 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)
Example 260
Preparation of N-(5-hydroxypentyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide




The title compound was prepared in the same manner as in <Example 143>, except that 5-aminopentanol was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 185 mg/Yield: 78%).
1H NMR (400, CDCl3): 7.30 (2H, d), 6.84 (2H, d), 6.04 (1H, 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)
Example 261
Preparation of tert-butyl 4-((4-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 2,2,2-trifluoroethylamine was used instead of the 2-aminoethanol (Amount obtained: 164 mg/Yield: 70%).
1H NMR (400, CDCl3): 7.31 (2H, d), 6.84 (2H, 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)
Example 262
Preparation of tert-butyl 4-((4-(4-(4-cyanocyclohexanecarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 2,2,2-trifluoroethylamine was used instead of the 2-aminoethanol (Amount obtained: 165 mg/Yield: 67%).
1H NMR (400, CDCl3): 7.30 (2H, d), 6.84 (2H, d), 6.04 (1H, 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)
Example 263
Preparation of tert-butyl 4-((4-(4-(1,4-dioxa-8-azaspiro[4.5]decane-8-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




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 the 2-aminoethanol (Amount obtained: 177 mg/Yield: 74%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.17 (2H, s), 4.01 (4H, s), 3.82-3.70 (4H, 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), 1.48 (9H, s), 1.25 (2H, m)
Example 264
Preparation of tert-butyl 4-((4-(4-(spiro[indene-1,4′-piperidin]-1′-ylcarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that 2,3-dihydrospiro[indene-1,4′-piperidine] was used instead of the 2-aminoethanol (Amount obtained: 183 mg/Yield: 75%).
1H NMR (400, CDCl3): 7.37-7.31 (4H, m), 7.29-7.22 (2H, m), 6.91 (1H, dd), 6.87-6.83 (3H, m), 6.08 (1H, t), 4.76 (2H, d), 4.10 (3H, m), 3.81 (2H, 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)
Example 265
Preparation of tert-butyl 4-((4-(4-(3-oxopyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that pyrrolidin-3-one hydrochloride was used instead of the 2-aminoethanol (Amount obtained: 159 mg/Yield: 64%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.06 (1H, 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)
Example 266
Preparation of 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carbonitrile




The title compound was prepared in the same manner as in <Example 143>, except that piperidine-4-carbonitrile was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 174 mg/Yield: 70%).
1H NMR (400, CDCl3): 7.31 (2H, d), 6.86 (2H, d), 6.05 (1H, d), 4.20 (2H, d), 3.84-3.50 (6H, m), 2.11 (2H, m), 2.93 (2H, m), 2.78 (1H, m), 2.52 (3H, m), 2.28 (1H, m), 2.05-1.89 (9H, m), 1.43 (2H, m), 1.29 (9H, s)
Example 267
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 1,4-dioxa-8-azaspiro[4.5]decane was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 180 mg/Yield: 76%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.20 (2H, d), 4.01 (4H, 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 (3H, m), 2.31 (1H, m), 2.06-1.90 (5H, m), 1.73 (4H, m), 1.44 (2H, m), 1.31 (6H, d)
Example 268
Preparation of (2,3-dihydrospiro[indene-1,4′-piperidin]-1′-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 143>, except that 3-dihydrospiro[indene-1,4′-piperidine] was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 194 mg/Yield: 82%).
1H NMR (400, CDCl3): 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)
Example 269
Preparation of (3-(ethoxyimino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 217>, except that O-ethylhydroxylamine hydrochloride was used instead of the hydroxylamine hydrochloride (Amount obtained: 177 mg/Yield: 71%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.32 (2H, d), 6.86 (2H, 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)
Example 270
Preparation of tert-butyl 4-((4-(4-(4-(methoxyimino)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 217>, except that O-methylhydroxylamine hydrochloride was used instead of the hydroxylamine hydrochloride (Amount obtained: 173 mg/Yield: 75%).
1H NMR (400, CDCl3): 7.30 (2H, d), 6.84 (2H, d), 6.05 (1H, 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)
Example 271
Preparation of tert-butyl 4-((4-(4-(4-(hydroxyimino)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 217>, except that tert-butyl 4-((4-(4-(4-oxopiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate was used instead of the 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide (Amount obtained: 161 mg/Yield: 66%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.16 (2H, s), 3.93-3.76 (6H, 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)
Example 272
Preparation of tert-butyl 4-((4-(4-(4-oxopiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that piperidin-4-one hydrochloride was used instead of the 2-aminoethanol (Amount obtained: 172 mg/Yield: 75%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.06 (1H, d), 4.16 (2H, s), 3.99-3.87 (6H, m), 2.89 (1H, m), 2.85 (2H, m), 2.61-2.56 (7H, m), 2.35 (1H, m), 2.07-1.98 (3H, m), 1.84 (2H, d), 1.48 (9H, s), 1.24 (2H, m)
Example 273
Preparation of tert-butyl 4-((4-(4-(3-(methoxyimino)pyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 217>, except that O-methylhydroxylamine hydrochloride was used instead of the hydroxylamine hydrochloride (Amount obtained: 169 mg/Yield: 69%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.06 (1H, d), 4.26 (2H, d), 4.16 (2H, s), 3.90 (3H, s), 3.77 (4H, m), 2.86-2.49 (8H, m), 2.32 (1H, m), 2.04-1.85 (5H, m), 1.48 (9H, s), 1.23 (2H, m)
Example 274
Preparation of 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidin-4-one




The title compound was prepared in the same manner as in <Example 152>, except that piperidin-4-one hydrochloride was used instead of the L-β-prolinol (Amount obtained: 180 mg/Yield: 77%).
1H NMR (400, CDCl3): 8.19 (2H, s), 7.31 (2H, d), 6.86 (2H, d), 6.06 (1H, 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)
Example 275
Preparation of 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidin-4-one




The title compound was prepared in the same manner as in <Example 143>, except that piperidin-4-one hydrochloride was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 184 mg/Yield: 77%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.06 (1H, d), 4.21 (2H, d), 3.98-3.84 (6H, m), 3.14 (2H, m), 2.90 (2H, m), 2.61-2.53 (7H, m), 2.35 (1H, m), 2.07-1.92 (5H, m), 1.51 (2H, m), 1.41 (6H, d)
Example 276
Preparation of (4-(hydroxyimino)piperidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 217>, except that 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidin-4-one was used instead of the 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide (Amount obtained: 183 mg/Yield: 76%).
1H NMR (400, CDCl3): 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)
Example 277
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxyimino)piperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 217>, except that 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidin-4-one was used instead of the 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide (Amount obtained: 166 mg/Yield: 65%).
1H NMR (400, CDCl3): 8.19 (2H, s), 8.14 (1H, d), 7.31 (2H, d), 6.85 (2H, d), 6.05 (1H, d), 4.76 (2H, 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), 1.20 (3H, t)
Example 278
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(methoxyimino)piperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 217>, except that O-methylhydroxylamine hydrochloride was used instead of the hydroxylamine hydrochloride (Amount obtained: 179 mg/Yield: 73%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, 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
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(methoxyimino)piperidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 217>, except that O-methylhydroxylamine hydrochloride was used instead of the hydroxylamine hydrochloride (Amount obtained: 173 mg/Yield: 69%).
1H NMR (400, CDCl3): 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 (1H, 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)
Example 280
Preparation of tert-butyl 4-((4-(4-(3-oxoazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 190>, except that azetidin-3-one hydrochloride was used instead of the 2-aminoethanol (Amount obtained: 172 mg/Yield: 75%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.05 (1H, d), 4.85 (4H, d), 4.16 (2H, s), 3.81 (2H, d), 2.78 (2H, t), 2.63-2.37 (5H, m), 2.10-1.82 (5H, m), 1.48 (9H, s), 1.24 (2H, m)
Example 281
Preparation of tert-butyl 4-((4-(4-(3-(hydroxyimino)azetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 217>, except that tert-butyl 4-((4-(4-(3-oxoazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate was used instead of the 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide (Amount obtained: 167 mg/Yield: 66%).
1H NMR (400, CDCl3): 7.80 (1H, s), 7.31 (2H, d), 6.84 (2H, d), 6.04 (1H, d), 4.89 (2H, d), 4.74 (2H, 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)
Example 282
Preparation of tert-butyl 4-((4-(4-(3-(methoxyimino)azetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




The title compound was prepared in the same manner as in <Example 217>, except that O-methylhydroxylamine hydrochloride was used instead of the hydroxylamine hydrochloride (Amount obtained: 175 mg/Yield: 73%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.84 (2H, d), 6.04 (1H, d), 4.85 (2H, 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)
Example 283
Preparation of 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)azetidin-3-one




The title compound was prepared in the same manner as in <Example 152>, except that azetidin-3-one hydrochloride was used instead of the L-β-prolinol (Amount obtained: 175 mg/Yield: 77%).
1H NMR (400, CDCl3): 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 (1H, m), 2.11-2.06 (2H, m), 1.98-1.91 (3H, m), 1.34 (2H, m), 1.20 (3H, t)
Example 284
Preparation of 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)azetidin-3-one




The title compound was prepared in the same manner as in <Example 143>, except that azetidin-3-one hydrochloride was used instead of the (R)-N,N-dimethylpyrrolidine-3-amine hydrochloride (Amount obtained: 180 mg/Yield: 75%).
1H NMR (400, CDCl3): 7.32 (2H, d), 6.85 (2H, d), 6.06 (1H, d), 4.88 (2H, s), 4.83 (2H, s), 4.21 (2H, d), 3.84 (2H, d), 3.12 (2H, m), 2.92 (1H, 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)
Example 285
Preparation of (3-(hydroxyimino)azetidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 217>, except that 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)azetidin-3-one was used instead of the 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide (Amount obtained: 184 mg/Yield: 78%).
1H NMR (400, CDCl3): 8.11 (1H, s), 7.32 (2H, d), 6.84 (2H, d), 6.04 (1H, 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 (4H, m), 2.30 (1H, m), 2.09-2.02 (2H, m), 1.97-1.89 (3H, m), 1.43 (2H, m), 1.30 (6H, d)
Example 286
Preparation of (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-(methoxyimino)azetidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 217>, except that O-methylhydroxylamine hydrochloride was used instead of the hydroxylamine hydrochloride (Amount obtained: 179 mg/Yield: 71%).
1H NMR (400, CDCl3): 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 (1H, m), 2.59-5.47 (4H, m), 2.29 (1H, m), 2.07-1.89 (5H, m), 1.46 (2H, m), 1.36 (6H, d)
Example 287
Preparation of (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-(methoxyimino)azetidin-1-yl)methanone




The title compound was prepared in the same manner as in <Example 217>, except that O-methylhydroxylamine hydrochloride was used instead of the hydroxylamine hydrochloride (Amount obtained: 177 mg/Yield: 73%).
1H NMR (400, CDCl3): 8.20 (2H, s), 7.29 (2H, d), 6.85 (2H, d), 6.04 (1H, d), 4.85 (2H, s), 4.79 (2H, d), 4.72 (2H, d), 3.96 (3H, s), 3.84 (2H, d), 2.92 (2H, m), 2.55-2.41 (6H, m), 2.28 (1H, m), 2.14-1.92 (5H, m), 1.39 (2H, m), 1.20 (3H, t)
Example 288
Preparation of tert-butyl 4-((4-(4-(3-hydroxyazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate




470 mg of tert-butyl 4-((4-(4-(3-oxoazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate was dissolved in 100 ml of THF in a 1,000 ml flask while stirring under nitrogen. After the resulting mixture was cooled to a temperature of 5° C., 80 mg of sodium borohydride was slowly added dropwise, and the mixture was then stirred for 5 minutes. After the reaction was terminated, 300 ml of distilled water was slowly added thereto, and the mixture was extracted with 500 ml of ethyl acetate, washed with 100 ml of brine, dried with anhydrous magnesium sulfate, concentrated, and then isolated by silica column chromatography to prepare the title compound (Amount obtained: 432 mg/Yield: 71%).
1H NMR (400, CDCl3): 7.30 (2H, d), 6.84 (2H, d), 6.03 (1H, 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)
Example 289
Preparation of (3-hydroxyazetidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone




The title compound was prepared in the same manner as in <Example 288>, except that 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)azetidin-3-one was used instead of the tert-butyl 4-((4-(4-(3-oxoazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate (Amount obtained: 402 mg/Yield: 66%).
1H NMR (400, CDCl3): 7.30 (2H, d), 6.84 (2H, d), 6.04 (1H, d), 4.70 (1H, 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)
Comparative Example 1
Preparation of N-(2-fluoro-4-methylsulfonylphenyl)-5-nitro-6-[4-(3-propan-2-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]pyrimidine-4-amine




N-(2-fluoro-4-methyl sulfonylphenyl)-5-nitro-6-[4-(3-propan-2-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]pyrimidine-4-amine was prepared using a method known in International Publication No. WO 2004/065380.
Comparative Example 2
Preparation of 2-(4-methanesulfonylphenyl)-5-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}methoxy)pyridine




2-(4-Methanesulfonylphenyl)-5-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}methoxy)pyridine was prepared using a method known in International Publication No. WO 2008/070692.
Comparative Example 3
Preparation of Metformin




Metformin was prepared using a method known in International Publication No. WO 2010/146604 A2.
Comparative Example 4
Preparation of Sibutramine




Sibutramine was prepared using a method known in International Publication No. WO 2002/083631 A1.
Comparative Example 5
Preparation of Forskolin




Forskolin was prepared using a method known in International Publication No. WO 1991/017154 A1.
The chemical structures of the compounds prepared in Examples 1 to 466 are summarized and listed in the following Table 1. In Table 1, the group ‘-Boc’ is












TABLE 1





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Experimental Example 1
Evaluation of cAMP Activity
To check whether the cyclohexene derivatives according to the present invention activate cyclic adenosine monophosphate (cAMP), experiments were carried out, as follows.
Specifically, as hamster-derived β-cells containing G protein-coupled receptor 119 (GPR-119), HIT-T15 cells (Korean Cell Line Bank) were used to determine intracellular activation of cAMP in response to the stimulation of the GPR-119. The HIT-T15 cells were plated on a 96-well plate at 60,000 cells per well. On the next day of plating, the cells were treated with a varying concentration of each of the example compounds according to the present invention, and incubated at 37° C. for an hour. In this case, each of the treated compounds was used at six concentrations, ranging from 0.0032 to 10 M, to treat the cells.
The cyclic adenosine monophosphate (cAMP) activity was measured according to the manufacturer's instruction using a cAMP dynamic kit commercially available from Cis Bio Inc. (Bedford, Mass.). The cells were lysed, and a level of cAMP was determined by a competitive immunoassay using D2-labeled cAMP and a cryptate-labeled anti-cAMP antibody. Fluorescence was read in Flex Station (Molecular Devices). Fluorescence resonance energy transfer (FRET) was observed when D2 and cryptate were in close proximity, and then measured as a fluorescence ratio of 665 nm/620 nm. Unlabeled cAMP in the cell lysate competed with the D2-labeled cAMP against the cryptate-labeled antibody. Since a decrease in the measured intensity of the FRET signals represents a level of cAMP in the cells, the cAMP activities of the compounds are calculated as a change in FRET signals by adjusting an amount of dimethyl sulfoxide (DMSO). The calculated EC50 values are listed in the following Table 2.










TABLE 2







Examples
EC50 (nM)



















 1
65



 2
40



 3
34



 4
150



 5
29



 6
38



 7
13



 8
90



 9
75



 10
500



 11
110



 12
80



 13
13



 14
650



 15
370



 16
13



 17
85



 18
170



 19
110



 20
90



 21
16



 22
41



 23
160



 24
260



 25
210



 26
250



 27
310



 28
110



 29
95



 30
105



 31
260



 32
650



 33
600



 34
21



 35
22



 36
170



 37
300



 38
450



 39
350



 40
500



 41
650



 42
82



 43
85



 44
13



 45
25



 46
500



 47
150



 48
35



 49
26



 50
95



 51
66



 52
55



 53
21



 54
42



 55
100



 56
30



 57
8



 58
17



 59
78



 60
40



 61
45



 62
70



 63
110



 64
50



 65
41



 66
18



 67
60



 68
300



 69
7



 70
45



 71
5.4



 72
25



 73
11



 74
6.2



 75
210



 76
12



 77
12



 78
100



 79
49



 80
89



 81
9



 82
9



 83
75



 84
30



 85
18



 86
130



 87
70



 88
130



 89
21



 90
24



 91
28



 92
64



 93
50



 94
68



 95
16



 96
27



 97
8.4



 98
6.1



 99
160



100
95



101
110



102
52



103
75



104
70



105
43



106
22



107
35



108
55



109
190



110
110



111
1,500



112
70



113
68



114
14



115
15



116
28



117
11



118
31



119
6.8



120
80



121
500



122
130



123
35



124
100



125
70



126
130



127
83



128
200



129
140



130
90



131
150



132
210



133
400



134
350



135
30



136
62



137
60



138
100



139
130



140
120



141
75



142
85



147
6.9



148
13



149
23



150
19



152
36



158
25



159
20



160
14



161
6



162
27



163
7



164
16



165
7



166
22



167
14



168
17



169
9



172
38



173
18



175
7



177
38



181
24



182
27



183
12



186
17



195
28



197
18



199
8



200
23



202
24



203
37



204
9



213
24



217
30



220
40



223
25



224
38



225
22



226
14



227
6



228
8



229
11



235
24



236
14



239
22



242
21



243
30



247
16



250
12



251
22



252
17



253
9



254
10



256
32



257
8



258
10



259
10



262
7



263
9



264
18



265
32



266
12



267
21



268
17



269
35



270
12



271
13



272
33



273
11



274
27



275
28



276
29



277
20



278
18



279
29



286
37



289
32



Comparative
49



Example 2










As listed in Table 2, it was revealed that the compounds according to the present invention activated cAMP even at a very low concentration. It was revealed that most of the compounds according to the present invention had an EC50 value of 200 nM or less. More specifically, it was revealed that the compounds of Examples 2, 3, 5 to 7, 13, 16, 21, 22, 34, 35, 44, 45, 48, 49, 53, 54, 56 to 58, 60, 61, 64 to 66, 69 to 74, 76, 77, 79, 81, 82, 84, 85, 89 to 91, 93, 95 to 98, 105 to 107, 114 to 119, 123, 135, 147 to 150, 152, 158 to 169, 172, 173, 175, 177, 181-183, 186, 195, 197, 199, 200, 202 to 204, 213, 217, 220, 223 to 229, 235, 236, 239, 242, 243, 247, 250 to 254, 256 to 259, 262 to 279, 286 and 289 had a high EC50 value of 50 nM or less. From these results, it could be seen that the cyclohexene derivative according to the present invention had an excellent effect of activating cAMP by stimulating the GPR-119 receptor.
Therefore, the cyclohexene derivative according to the present invention activated GPR-119 since the cyclohexene derivative had an excellent effect of activating cAMP, and thus was able to be useful for pharmaceutical compositions 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.
Experimental Example 2
Oral Glucose Tolerance Test (OGTT)
To evaluate in vivo effective effects of the cyclohexene derivatives according to the present invention, experiments were carried out, as follows.
Specifically, male C57BL/6J (C57 black 6) rats (8 to 10 weeks old) in a high-fat diet model were acclimated for at least 7 days, and only healthy rat populations were selected and subjected to an oral glucose tolerance test (OGTT). The rats were fasted for 12 to 15 hours, and then randomly divided into groups with five rats per group. Thereafter, each of the compounds of Examples 1, 14, 48, 69, 80, 118, 139, 147, 148, 169, 190, 199, 200, 204, 227, and Comparative Examples 1 and 2 according to the present invention was administered to the rats at a dose of 20 mg/kg. In this case, a vehicle (0.5%, carboxymethyl cellulose (CMC)) was administered as an untreated group, and the dose of the compound administered together with the vehicle was orally administered at 10 ml/kg. After 30 minutes of administration, glucose (2 g/kg) was orally administered at a dose of 10 ml/kg. A blood glucose level was measured using an Accu-Chek Active Strip (Rosche Diagnostic Co.). In this case, the glucose level in blood collected via caudal venipuncture was measured at time points of −30, 0, 20, 40, 60, and 120 minutes after glucose administration. The results are listed in the following Table 3.










TABLE 3







Examples
% AUC









 1
28.5



 14
21.9



 48
21.2



 69
19.1



 80
19.7



118
23.5



139
25.4



147
23.3



148
22.6



169
21.7



190
20.9



199
20.9



200
24.0



204
24.0



227
26.8



277
19.8



Comparative Example 1
13.5



Comparative Example 2
15.3










In Table 3, the unit “% AUC (area under the curve)” represents a hypoglycemic level.
As listed in Table 3, it could be seen that the example compounds according to the present invention had 20% of a hypoglycemic effect on average and a high in vivo effective effect, compared to those in the untreated group. Also, it was revealed that the compounds of Comparative Examples 1 and 2 known as the GPR-119 protein activator in the art had a hypoglycemic effect of 13.5% and 15.3%, respectively, but that the example compounds according to the present invention had a superior hypoglycemic effect (over 19.1%) to the compounds of Comparative Examples 1 and 2.
Therefore, the cyclohexene derivative according to the present invention derivative had a very excellent hypoglycemic effect since the cyclohexene derivative had an excellent effect of activating a GPR-119 protein, thereby exhibiting an excellent effect of promoting insulin secretion. Accordingly, a pharmaceutical composition including the cyclohexene derivative as an active ingredient was able to 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, syndrome X, etc.
Experimental Example 3
Simultaneous Evaluation of Both Weight-loss and Hypoglycemic Effects in Diet-induced Obesity (DIO) Model
To simultaneously evaluate both the weight-loss and hypoglycemic effects of the cyclohexene derivative according to the present invention, experiments were carried out, as follows.
Specifically, male Sprague Dawley (SD) rats (approximately 4 weeks old) in a diet-induced obesity model were fed with a high-fat diet (Lab. Diet Co.) for approximately 10 weeks to induce high-fat diet-induced obesity (DIO). The rats undergoing the high-fat diet were randomly selected, and divided into groups (n=8) for respective administrations. The compounds of Comparative Examples 3 and 4 and Examples 48 and 119 were administered to the divided DIO rats each group for 4 weeks.
The weights of the DIO rats were measured twice a week during a period of administration of 4 weeks to record a change in the weights. The results are shown in FIG. 1. At the end of the 4-week period of administration, a hypoglycemic effect was evaluated using an oral glucose tolerance test (OGTT), as follows.
Specifically, each of the compounds of Comparative Example 3 (300 mg/kg) and Examples 48 and 119 (10, 20, 50 mg/kg) was administered, and 2 g/kg of glucose was orally administered after 30 minutes of the administration. A blood glucose level was determined using an Accu-Chek Active Strip (Roche diagnostic Co.). In this case, the glucose level in blood collected via caudal venipuncture was measured at time points of −30, 0, 20, 40, 60, and 120 minutes after glucose administration. Area-under-curve (AUC) values (%) of the respective groups were calculated from the results based on the blood glucose levels measured at the respective time points so as to evaluate the hypoglycemic effect. The results are shown in FIGS. 2A and 2B [FIG. 2A: Example 48, and FIG. 2B: Example 119].
FIG. 1 is a graph determining the changes in weights of rats after compounds of Example 48 and Comparative Examples 3 and 4 according to the present invention are administered to a diet-induced obesity (DIO) rat model for 4 weeks (In FIG. 1, the term “untreated group (Vehicle)” represents an untreated group in a high-fat DIO rat model; and the term “Lean” represents an untreated group in a normal SD rat model rather than a disease model).
FIG. 2A is a graph for evaluating hypoglycemic effects over time when glucose is administered at the end of the 4-week period of administration of the compounds of Example 48 and Comparative Example 3 according to the present invention in the DIO rat model, and after 30 minutes of administration of the compounds of Example 48 and Comparative Example 3.
FIG. 2B is a graph for evaluating hypoglycemic effects over time when glucose is administered at the end of the 4-week period of administration of the compound of Example 119 according to the present invention in the DIO rat model, and after 30 minutes of administration of the compound of Example 119.
As shown in FIG. 1, it was confirmed that the compound of Example 48 according to the present invention had a higher weight-loss effect when administered at a dose of 10, 20, and 50 mg/kg, compared to when the compounds of Comparative Examples 3 and 4 were administered at a dose of 300 mg/kg and 5 mg/kg, respectively. More specifically, it was revealed that the weight loss was observed for 2 weeks after oral administration of the compounds of Comparative Examples 3 and 4 (300 mg/kg and 5 mg/kg, respectively), but the weight rather increased after 2 weeks of the oral administration. On the other hand, it was revealed that the persistent weight loss was observed for 4 weeks after oral administration of the compound of Example 48 (10, 20, and 50 mg/kg) according to the present invention.
As shown in FIG. 2A, it was confirmed that the compound of Example 48 according to the present invention had a hypoglycemic effect of approximately 18 to 25% when administered at a dose of 10, 20, and 50 mg/kg. More specifically, it was revealed that the compound of Comparative Example 3 had a hypoglycemic effect of approximately 22% when orally administered at a dose of 300 mg/kg, and the compound of Example 48 according to the present invention had a hypoglycemic effect of approximately 25% when orally administered at a dose of 50 mg/kg, indicating that the compound of Example 48 had a remarkably superior hypoglycemic effect to that of Comparative Example 3. Also, as shown in FIG. 2B, when it was assumed that the hypoglycemic effect in the untreated group was 0, it was confirmed that the compound of Example 119 according to the present invention had a hypoglycemic effect of approximately 10 to 15% when administered at a dose of 10, 20, and 50 mg/kg.
Therefore, the cyclohexene derivative according to the present invention had excellent weight-loss and hypoglycemic effects during a period of oral administration, and these effects were also expressed at the same time. Accordingly, a pharmaceutical composition including the cyclohexene derivative as an active ingredient was able to be useful as a pharmaceutical composition for treating metabolic diseases such as obesity, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X, etc.
Experimental Example 4
Evaluation of Promotion of Glucagon-like Peptide-1 (GLP-1) Secretion
To evaluate an effect of the cyclohexene derivative according to the present invention on promotion of glucagon-like peptide-1 (GLP-1) secretion, experiments were carried out, as follows.
NCI-H716 cells that were human enterocytes were plated on 12 wells at 1×106 cells per well. After 48 hours, the cells were starved in serum-free media for 2 hours, and treated with a varying concentration of siptagliptin that was a dipeptidyl peptidase-IV (DPP-IV) inhibitor, and the compounds of Comparative Example 1 (1, 10, 30 μM), Comparative Example 5 (10 μM), Example 48 (1, 10, 30 μM), and Example 291 (1, 10, 30 μM). After an hour, supernatants are recovered to determine an amount of the secreted GLP-1 peptide. The GLP-1 measurement was performed using an enzyme-linked immunosorbent assay (ELISA; Millipore, EGLP-35K), and the amount of the secreted GLP-1 peptide was indicated by the unit “pM”. The results are shown in FIG. 3.
FIG. 3 is graph plotted for amounts of secreted GLP-1 when NCI-H716 cells that are human enterocytes are treated with the compounds of Comparative Examples 1 and 5 and Example 48 according to the present invention.
As shown in FIG. 3, it was confirmed that the GLP-1 was secreted at approximately 340 to 470 pM when the cells were treated with an increasing concentration (1, 10, and 30 μM) of the compound of Example 48 according to the present invention. More specifically, it was revealed that the compound of Example 48 induced GLP-1 secretion to a higher level than that of Comparative Example 1 in all the 1, 10 and 30 μM-treated groups when comparing the amounts of the GLP-1 secreted in response to the concentrations of the treated compounds of Comparative Example 1 and Example 48.
Therefore, the cyclohexene derivative according to the present invention had an excellent effect of inducing the GLP-1 secretion through activation of GPR-119. Accordingly, a pharmaceutical composition including the cyclohexene derivative as an active ingredient was able to be useful as a pharmaceutical composition for treating metabolic diseases such as obesity, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X, etc.
Experimental Example 5
Acute Toxicity Test
To evaluate acute toxicity of the cyclohexene derivative according to the present invention, experiments were carried out, as follows.
Five 7-week-old female Ihara's cataract rats (ICRs) were supplied by Nara Biotech Co. Ltd., housed in a breeding farm, and acclimated to new environments while being fed with general solid feeds and water. When the rats were 8 weeks old, experiments were carried out. Environmental conditions were maintained constant: a set temperature of 23±3° C., a humidity of 55±15%, an illuminance of 150 to 300 Lux, a ventilation rate of 10 to 20 times/hour, and a lighting time of 12 hours (light-dark cycle: lighting at 8 a.m. and lights-out at 8 p.m.). As the feeds, solid feeds for laboratory animals (5L79 Lab Diet, Purina Mills, Richmond, Ind., USA), which had been sterilized by exposure to radiation, were provided by Orientbio Inc. so that rats were allowed to freely consume the solid feeds. As the water, running water was disinfected using a UV sterilizer and an ultra-filtration system, and then provided o that rats were allowed to freely drink the water in a water bottle. Analyses of contaminants in the water and feeds were carried out according to the ChemOn Inc.'s standard operating procedure (SOP). Each of the compounds prepared in Examples 48 and 119 of the present invention was diluted to a concentration of 2,000 mg/kg in a vehicle (1% PEG), and the test chemicals were intragastrically administered once daily to each group of five rats using an oral zonde for rats, and the general conditions, toxic symptoms, and mortality of animals were observed twice a day during a test period.
As a result, it was confirmed that the lethal dose 50 percent (LD50) values of the female ICR rats were greater than or equal to 2 g/kg. From these result, it could be seen that the cyclohexene derivative according to the present invention had very low toxicity.
Therefore, the cyclohexene derivative according to the present invention had an excellent effect of promoting cAMP by activating GPR-119, and also exhibited very high safety to human bodies due to low cytotoxicity. Accordingly, the cyclohexene derivative according to the present invention activated the GPR-119, and thus was able to be useful for 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, syndrome X, etc.
Meanwhile, the compound represented by formula 1 according to the present invention can be formulated into several types depending on the desired purposes. The followings are representative preparative examples comprising the compound represented by formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
Preparative Examples 1
Preparation of Pharmaceutical Formulations
1-1: Preparation of Powder
















Compound of Formula 1
500 mg



Lactose
100 mg



Talc
 10 mg










The components are mixed, and filled in an airtight pack to prepare a powder.
1-2: Preparation of Tablet
















Compound of Formula 1
500 mg



Corn starch
100 mg



Lactose
100 mg



Magnesium stearate
 2 mg










The components were mixed, and tablet-pressed to prepare a tablet according to a conventional method of preparing a tablet.
1-3: Preparation of Capsule
















Compound of Formula 1
500 mg



Corn starch
100 mg



Lactose
100 mg



Magnesium stearate
 2 mg










The components were mixed, and filled in a gelatin capsule to prepare a capsule according to a conventional method of preparing a capsule.
1-4: Preparation of Injectable Solution
















Compound of Formula 1
500 mg



Sterile distilled water for injection
Proper amount



pH regulating agent
Proper amount










An injectable solution was prepared, according to a conventional method of preparing an injectable solution, so that one ampule (2 ml) contains the above-mentioned contents of the components.
1-5: Preparation of Solution
















Compound of Formula 1
100 mg



Isomerized sugar
 10 g



Mannitol
 5 g



Purified water
Proper amount










A solution was prepared according to a conventional method of preparing a solution by dissolving the respective components in purified water, adding a proper amount of a lemon flavor thereto, mixing all the components, adding purified water to the resulting mixture so that a final amount of the mixture was adjusted to 100 ml, putting the mixture into a brown vial, and sterilizing the mixture.
INDUSTRIAL APPLICABILITY
The cyclohexene derivative according to the present invention, or the optical isomer or pharmaceutically acceptable salt thereof activates G protein-coupled receptor 119 (GPR-119) to enhance the intracellular activity of cyclic adenosine monophosphate (cAMP), and simultaneously induces the release of glucagon-like peptide-1 (GLP-1), which is a neuroendocrine protein, to simultaneously exhibit weight-loss and hypoglycemic effects, and thus can be useful for pharmaceutical compositions 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, syndrome X, etc.

## Claims

1. A compound represented by the following Formula 1, or an isomer or pharmaceutically acceptable salt thereof:



wherein R1 is —H, —OH, a C1-10 linear or branched alkyl, a C1-10 linear or branched alkoxy, a C1-10 linear or branched alkoxycarbonyl, or an unsubstituted or substituted 5- to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heteroaryl is a 5- to 10-membered heteroaryl substituted with one or more C1-10 linear or branched alkyl;
R2 is —H, —OH, a halogen, a C1-10 linear or branched alkyl, or a C1-10 linear or branched alkoxy;
R3 is —H, a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH or a halogen, a C1-10 linear or branched alkoxy, a C1-10 linear or branched alkoxy C1-10 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 5- to 10-membered heteroaryl C1-10 linear or branched alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —(CH2)nNR5R6, —(CH2)mC(═O)OR7, or —(CH2)pC(═O)NR8R9, wherein:
R5 and R6 are each independently —H, -Boc




 or a C1-5 linear or branched alkyl,
R7 is —H, or a C1-5 linear or branched alkyl, and
R8 and R9 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted or substituted 5- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heterocycloalkyl is a 5- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —CN, a C1-5 linear or branched alkyl, a C1-5 linear or branched alkoxy, and —C(═O)NR10R11, wherein R10 and R11 are each independently —H, or a C1-5 linear or branched alkyl;
n, m, and p are each independently an integer ranging from 1 to 10;
R4 is —H, a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH, or a C1-10 linear or branched alkoxy;
provided that R3 and R4 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted 3- to 10-membered heterocycloakenyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or an unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —OH, —CN, ═O, a halogen, a C1-5 linear or branched alkyl which is not substituted or substituted with one or more —OH, a C1-5 linear or branched alkoxy, an unsubstituted C3-10 cycloalkyl C1-5 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —C(═O)NR12R13, —NR14R15, and ═NR16; or substituted in a spiro fashion with a C5-10 cycloakenyl fused with an unsubstituted C6-10 aryl, or a 3- to 10-membered heterocycloalkyl which is not substituted or substituted with one or more -Boc




 and contains one or more heteroatoms selected from the group consisting of N, O, and S,
R12, R13, R14, and R15 are each independently —H, or a C1-5 linear or branched alkyl, and R16 is —H, —OH, or a C1-5 linear or branched alkoxy,
provided that the fused 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl fused with an unsubstituted C6-10 aryl, and
the substitution and fusion may occur at the same time in the case of the unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl; and
A and E are each independently —CH═, or —N═.

2. The compound of Formula 1 or the isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is a C1-10 linear or branched alkoxycarbonyl, or an unsubstituted or substituted 5- to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heteroaryl is a 5- to 10-membered heteroaryl substituted with one or more C1-10 linear or branched alkyl;
R2 is —H or a halogen;
R3 is a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH or a halogen, a C1-10 linear or branched alkoxy, a C1-10 linear or branched alkoxy C1-10 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 5- to 10-membered heteroaryl C1-10 linear or branched alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —(CH2)nNR5R6, —(CH2)mC(═O)OR7, or —(CH2)pC(═O)NR8R9, wherein:
R5 and R6 are each independently —H or -Boc




R7 is —H, or a C1-5 linear or branched alkyl, and
R8 and R9 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted or substituted 5- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 5- to 10-membered heterocycloalkyl is a 5- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —CN and —C(═O)NR10R11, and R10 and R11 are each independently —H,
n, m, and p is each independently an integer ranging from 1 to 5;
R4 is —H, or a C1-10 linear or branched alkyl which is not substituted or substituted with one or more —OH;
provided that R3 and R4 may be taken together with a nitrogen atom to which they are attached to form an unsubstituted 3- to 10-membered heterocycloakenyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or an unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein:
the substituted 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of —OH, —CN, ═O, a halogen, a C1-5 linear or branched alkyl which is not substituted or substituted with one or more —OH, an unsubstituted C3-10 cycloalkyl C1-5 linear or branched alkyl, an unsubstituted C3-10 cycloalkyl, an unsubstituted 3- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, —C(═O)NR12R13, —NR14R15, and ═NR16; or substituted in a spiro fashion with a C5-10 cycloakenyl fused with an unsubstituted C6-10 aryl, or a 3- to 10-membered heterocycloalkyl which is not substituted or substituted with one or more -Boc




 and contains one or more heteroatoms selected from the group consisting of N, O, and S,
R12, R13, R14, and R15 are each independently —H, or a C1-5 linear or branched alkyl, and R16 is —OH, or a C1-5 linear or branched alkoxy,
provided that the fused 3- to 10-membered heterocycloalkyl is a 3- to 10-membered heterocycloalkyl fused with an unsubstituted C6-10 aryl, and
the substitution and fusion may occur at the same time in the case of the unsubstituted, substituted or fused 3- to 10-membered heterocycloalkyl; and
A and E are each independently —CH═, or —N═.

3. The compound of Formula 1 or the isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is



R2 is —H or —F;
R3 is







R4 is —H, methyl, ethyl, or




provided that R3 and R4 may be taken together with a nitrogen atom to which they are attached to form










 and
A and E are each independently —CH═, or —N═.

4. The compound of Formula 1 or the isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Formula 1 is the compound selected from the group consisting of:
(1) tert-butyl 4-((4-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(2) tert-butyl 4-((4-(4-(cyclopropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(3) tert-butyl 4-((4-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(4) tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(5) tert-butyl 4-((4-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(6) tert-butyl 4-((4-(4-((3-hydroxypropyl)(methyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(7) tert-butyl 4-((4-(4-(morpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(8) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((R)-1-hydroxypropan-2-yl)cyclohex-3-enecarboxamide;
(9) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxypropyl)cyclohex-3-enecarboxamide;
(10) tert-butyl 4-((6-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;
(11) tert-butyl 4-((6-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;
(12) N-((R)-2,3-dihydroxypropyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(13) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(morpholino)methanone;
(14) tert-butyl 4-((6-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;
(15) N-(1,3-dihydroxypropan-2-yl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(16) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-hydroxypyrrolidin-1-yl)methanone;
(17) N-((R)-2,3-dihydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(18) N-((S)-2,3-dihydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(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-enecarboxamide;
(20) N-((R)-1-hydroxypropan-2-yl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(21) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)-N-methylcyclohex-3-enecarboxamide;
(22) N-(3-hydroxy-2,2-dimethylpropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(23) N-(1,3-dihydroxypropan-2-yl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(24) tert-butyl 4-((5-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(25) tert-butyl 4-((5-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(26) tert-butyl 4-((5-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(27) tert-butyl 4-((5-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(28) N-((R)-2-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(29) N-((S)-2-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(30) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((R)-2-hydroxypropyl)cyclohex-3-enecarboxamide;
(31) N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(32) tert-butyl 4-((5-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(33) tert-butyl 4-((5-(4-((S)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(34) N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamide;
(35) N-ethyl-N-(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(36) N-((R)-1-hydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
(37) N-((S)-1-hydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
(38) N-((R)-2-hydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
(39) N-((S)-2-hydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
(40) N-((R)-2,3-dihydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
(41) N-((S)-2,3-dihydroxypropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
(42) tert-butyl 4-((5-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(43) tert-butyl 4-((5-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(44) tert-butyl 4-((2-fluoro-4-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(45) tert-butyl 4-((2-fluoro-4-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(46) N-(1,3-dihydroxypropan-2-yl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
(47) N-(3-hydroxy-2,2-dimethylpropyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
(48) ((R)-3-hydroxypyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(49) ((S)-3-hydroxypyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(50) N-(2,2-difluoroethyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(51) N-(2,2-difluoroethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(52) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone;
(53) ((S)-3-fluoropyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(54) ((R)-3-fluoropyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(55) (4-ethylpiperazin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(56) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone;
(57) tert-butyl 4-((2-fluoro-4-(4-((S)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(58) tert-butyl 4-((2-fluoro-4-(4-((R)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(59) tert-butyl 4-((2-fluoro-4-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(60) tert-butyl 4-((2-fluoro-4-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(61) tert-butyl 4-((2-fluoro-4-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(62) tert-butyl 4-((2-fluoro-4-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(63) tert-butyl 4-((4-(4-((S)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
(64) tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
(65) azetidin-1-yl(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(66) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(morpholino)methanone;
(67) tert-butyl 4-((4-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
(68) tert-butyl 4-((5-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(69) tert-butyl 4-((2-fluoro-4-(4-(morpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(70) tert-butyl 4-((5-(4-(morpholine-4-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(71) tert-butyl 4-((2-fluoro-4-(4-(thiomorpholine-4-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(72) tert-butyl 4-((5-(4-(thiomorpholine-4-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(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-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(thiomorpholino)methanone;
(75) N-(2-fluoroethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(76) tert-butyl 3-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamido)propylcarbamate;
(77) N-(3-aminopropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamide;
(78) 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide;
(79) (4-ethylpiperazin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(80) N-(1,3-dihydroxypropan-2-yl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(81) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)-N-methylcyclohex-3-enecarboxamide;
(82) tert-butyl 4-((2-fluoro-4-(4-(3-hydroxy-2,2-dimethylpropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(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)cyclohex-3-enecarboxamide;
(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)cyclohex-3-enecarboxamide;
(85) tert-butyl 4-((4-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
(86) tert-butyl 4-((5-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(87) tert-butyl 4-((5-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(88) tert-butyl 4-((5-(4-(2-fluoroethylcarbamoyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(89) (4-cyclopropylpiperazin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(90) tert-butyl 4-((5-(4-((R)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(91) tert-butyl 4-((5-(4-((S)-3-fluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;
(92) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide;
(93) N-(2,2-difluoroethyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(94) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-fluoroethyl)cyclohex-3-enecarboxamide;
(95) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone;
(96) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-fluoropyrrolidin-1-yl)methanone;
(97) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(morpholino)methanone;
(98) (4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(thiomorpholino)methanone;
(99) N-(2,2-difluoroethyl)-4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enecarboxamide;
(100) (4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enyl)(morpholino)methanone;
(101) ((R)-3-fluoropyrrolidin-1-yl)(4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enyl)methanone;
(102) ((S)-3-fluoropyrrolidin-1-yl)(4-(5-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)pyridin-2-yl)cyclohex-3-enyl)methanone;
(103) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2,2,2-trifluoroethyl)cyclohex-3-enecarboxamide;
(104) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-fluoroethyl)cyclohex-3-enecarboxamide;
(105) (2 S)-1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carboxamide;
(106) (2 S)-1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carbonitrile;
(107) tert-butyl 4-((4-(4-((S)-2-carbamoylpyrrolidine-1-carbonyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
(108) (2S)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carboxamide;
(109) (methyl 2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetate;
(110) ethyl 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoate;
(111) 3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoic acid;
(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-enecarboxamide;
(113) 4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-morpholino-3-oxopropyl)cyclohex-3-enecarboxamide;
(114) tert-butyl 4-((4-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-enyl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate;
(115) (2S)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carbonitrile;
(116) (2R)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carboxamide;
(117) (2R)-1-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidine-2-carbonitrile;
(118) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone;
(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-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex-3-enecarboxamide;
(121) (2R)-1-(2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetyl)pyrrolidine-2-carboxamide;
(122) N-(2-((R)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(123) (4-cyclopropylpiperazin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(124) (4-(cyclopropylmethyl)piperazin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(125) tert-butyl 4-((3-fluoro-4-(4-((S)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(126) tert-butyl 4-((3-fluoro-4-(4-((R)-2-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(127) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((S)-1-hydroxypropan-2-yl)cyclohex-3-enecarboxamide;
(128) N-((S)-2,3-dihydroxypropyl)-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(129) tert-butyl 4-((3-fluoro-4-(4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(130) tert-butyl 4-((3-fluoro-4-(4-((S)-1-hydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(131) tert-butyl 4-((4-(4-((R)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate;
(132) tert-butyl 4-((4-(4-((S)-2,3-dihydroxypropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate;
(133) (2S)-1-(2-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)acetyl)pyrrolidine-2-carboxamide;
(134) (2S)-1-(3-(4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamido)propanoyl)pyrrolidine-2-carboxamide;
(135) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-hydroxypyrrolidin-1-yl)methanone;
(136) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-((S)-2-hydroxypropyl)cyclohex-3-enecarboxamide;
(137) tert-butyl 4-((4-(4-(cyclopropylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate;
(138) tert-butyl 4-((3-fluoro-4-(4-(2-fluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(139) N-(2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(140) N-(3-((S)-2-cyanopyrrolidin-1-yl)-3-oxopropyl)-4-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(141) tert-butyl 4-((4-(4-(2,2-difluoroethylcarbamoyl)cyclohex-1-enyl)-3-fluorophenoxy)methyl)piperidine-1-carboxylate;
(142) tert-butyl 4-((3-fluoro-4-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(143) ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(144) ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(145) ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride;
(146) ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride;
(147) ((R)-2-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(148) ((S)-2-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(149) ((R)-3-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(150) ((S)-3-(hydroxymethyl)pyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(151) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone hydrochloride;
(152) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone;
(153) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone;
(154) ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(155) ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(156) ((S)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride;
(157) ((R)-3-(dimethylamino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone hydrochloride;
(158) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone hydrochloride;
(159) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methanone hydrochloride;
(160) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone;
(161) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)((S)-3-fluoropyrrolidin-1-yl)methanone hydrochloride;
(162) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone;
(163) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone;
(164) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-hydroxypiperidin-1-yl)methanone;
(165) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxymethyl)piperidin-1-yl)methanone;
(166) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone hydrochloride;
(167) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(piperidin-1-yl)methanone hydrochloride;
(168) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-hydroxypiperidin-1-yl)methanone hydrochloride;
(169) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxymethyl)piperidin-1-yl)methanone hydrochloride;
(170) azetidin-1-yl(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(171) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-hydroxyazetidin-1-yl)methanone;
(172) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone;
(173) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(2-hydroxyethyl)piperidin-1-yl)methanone;
(174) N-ethoxy-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(175) N-ethyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex-3-enecarboxamide;
(176) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(2-hydroxyethyl)cyclohex-3-enecarboxamide;
(177) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxy-2,2-dimethylpropyl)cyclohex-3-enecarboxamide;
(178) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
(179) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-methoxypropyl)cyclohex-3-enecarboxamide;
(180) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(furan-2-ylmethyl)cyclohex-3-enecarboxamide;
(181) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N,N-bis(2-hydroxyethyl)cyclohex-3-enecarboxamide;
(182) (4-hydroxypiperidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(183) (4-(hydroxymethyl)piperidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(184) N-cyclopropyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(185) N-(3-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(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-hydroxyethyl)piperazin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(188) 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-(methoxymethyl)cyclohex-3-enecarboxamide;
(189) N-cyclopropyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(190) tert-butyl 4-((4-(4-(2-hydroxyethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(191) tert-butyl 4-((4-(4-(3-hydroxy-2,2-dimethylpropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(192) tert-butyl 4-((4-(4-(methoxymethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(193) tert-butyl 4-((4-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(194) tert-butyl 4-((4-(4-(cyclobutylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(195) tert-butyl 4-((4-(4-(cyclopentylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(196) tert-butyl 4-((4-(4-(4-morpholinopiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(197) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxy-N-methylcyclohex-3-enecarboxamide;
(198) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxycyclohex-3-enecarboxamide;
(199) tert-butyl 4-((4-(4-(ethyl(2-hydroxyethyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(200) tert-butyl 4-((4-(4-(4-(2-hydroxyethyl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(201) tert-butyl 4-((4-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(202) tert-butyl 4-((4-(4-(pyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(203) tert-butyl 4-((4-(4-(4-ethylpiperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(204) tert-butyl 4-((4-(4-(piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(205) tert-butyl 4-((4-(4-(3-ethoxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(206) tert-butyl 4-((4-(4-(bis(2-hydroxyethyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(207) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
(208) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;
(209) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-morpholinopiperidin-1-yl)methanone;
(210) N-cyclopentyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(211) N-cyclobutyl-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(212) (3,4-dihydroisoquinolin-2(1H)-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(213) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;
(214) isoindolin-2-yl(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(215) 1,4′-bipiperidin-1′-yl(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(216) tert-butyl 4-((4-(4-(1,4′-bipiperidine-1′-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(217) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-(hydroxyimino)pyrrolidin-1-yl)methanone;
(218) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone;
(219) 1,4′-bipiperidin-1′-yl(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(220) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-morpholinopiperidin-1-yl)methanone;
(221) tert-butyl 4-((4-(4-(furan-2-ylmethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(222) tert-butyl 4-((4-(4-(methoxycarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(223) tert-butyl 4-((4-(4-(methoxy(methyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(224) tert-butyl 4-((4-(4-(2, 5-dihydro-1H-pyrrole-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(225) tert-butyl 4-((4-(4-(4-hydroxypiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(226) tert-butyl 4-((4-(4-(4-(hydroxymethyl)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(227) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carbonitrile;
(228) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(spiro[indene-1,4′-piperidin]-1′-yl)methanone;
(229) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methanone;
(230) N-cyclopentyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(231) N-cyclobutyl-4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(232) (3,4-dihydroisoquinolin-2(1H)-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(233) tert-butyl 4-((4-(4-(5-hydroxypentylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(234) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(5-hydroxypentyl)cyclohex-3-enecarboxamide;
(235) (2,5-dihydro-1H-pyrrol-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(236) tert-butyl 4-((4-(4-((2-hydroxyethyl)(methyl)carbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(237) tert-butyl 4-((4-(4-(1,3-dihydroxypropan-2-ylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(238) tert-butyl 4-((4-(4-(3-hydroxypropylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(239) tert-butyl 4-((4-(4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(240) tert-butyl 4-((4-(4-(isoindoline-2-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(241) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(isoindolin-2-yl)methanone;
(242) 4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-N-(3-hydroxypropyl)-N-methylcyclohex-3-enecarboxamide;
(243) N-(3-hydroxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methylcyclohex-3-enecarboxamide;
(244) N-(furan-2-ylmethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(245) N-(3-ethoxypropyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(246) 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxycyclohex-3-enecarboxamide;
(247) 4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)-N-methoxy-N-methylcyclohex-3-enecarboxamide;
(248) N,N-bis(2-hydroxyethyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(249) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
(250) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)pyrrolidin-3-one;
(251) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
(252) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carboxamide;
(253) (Z)-(3,3-bis(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(254) (Z)-tert-butyl 6-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3.4]octane-2-carboxylate;
(255) (Z)-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(8-(methoxyimino)-2,6-diazaspiro[3.4]octan-6-yl)methanone hydrochloride;
(256) tert-butyl 4-((4-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(257) tert-butyl 4-((4-(4-(3,3-difluoropyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(258) (3,3-difluoropyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(259) (3,3-difluoropyrrolidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(260) N-(5-hydroxypentyl)-4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarboxamide;
(261) tert-butyl 4-((4-(4-(2,2,2-trifluoroethylcarbamoyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(262) tert-butyl 4-((4-(4-(4-cyanocyclohexanecarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(263) tert-butyl 4-((4-(4-(1,4-dioxa-8-azaspiro[4.5]decane-8-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(264) tert-butyl 4-((4-(4-(spiro[indene-1,4′-piperidin]-1′-ylcarbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(265) tert-butyl 4-((4-(4-(3-oxopyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(266) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidine-4-carbonitrile;
(267) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methanone;
(268) (2,3-dihydrospiro[indene-1,4′-piperidin]-1′-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(269) (3-(ethoxyimino)pyrrolidin-1-yl)(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(270) tert-butyl 4-((4-(4-(4-(methoxyimino)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(271) tert-butyl 4-((4-(4-(4-(hydroxyimino)piperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(272) tert-butyl 4-((4-(4-(4-oxopiperidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(273) tert-butyl 4-((4-(4-(3-(methoxyimino)pyrrolidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(274) 1-(4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidin-4-one;
(275) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)piperidin-4-one;
(276) (4-(hydroxyimino)piperidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(277) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(hydroxyimino)piperidin-1-yl)methanone;
(278) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(methoxyimino)piperidin-1-yl)methanone;
(279) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(4-(methoxyimino)piperidin-1-yl)methanone;
(280) tert-butyl 4-((4-(4-(3-oxoazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(281) tert-butyl 4-((4-(4-(3-(hydroxyimino)azetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate;
(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-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)azetidin-3-one;
(284) 1-(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enecarbonyl)azetidin-3-one;
(285) (3-(hydroxyimino)azetidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone;
(286) (4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-(methoxyimino)azetidin-1-yl)methanone;
(287) (4-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)(3-(methoxyimino)azetidin-1-yl)methanone;
(288) tert-butyl 4-((4-(4-(3-hydroxyazetidine-1-carbonyl)cyclohex-1-enyl)phenoxy)methyl)piperidine-1-carboxylate; and
(289) (3-hydroxyazetidin-1-yl)(4-(4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy)phenyl)cyclohex-3-enyl)methanone.

5. A method for preparing the compound represented by Formula 1 defined in claim 1, which comprises, as shown in the following Scheme 1:
reacting a compound represented by Formula 2 with a compound represented by Formula 3 to prepare a compound represented by Formula 4 (Step 1);
reacting the compound represented by Formula 4 prepared in Step 1 with a compound represented by Formula 5 to prepare a compound represented by Formula 6 (Step 2);
reacting the compound represented by Formula 6 prepared in Step 2 with a base to prepare a compound represented by Formula 7 (Step 3); and
reacting the compound represented by Formula 7 prepared in Step 3 with a compound represented by Formula 8 to obtain the compound represented by Formula 1 (Step 4):




wherein R1, R2, R3, R4, A, and E are as defined in Formula 1 defined in claim 1.

6. The method according to claim 5, wherein the base in Step 3 is the one selected from the group consisting of cesium carbonate (Cs2CO3), potassium hydroxide (KOH), sodium hydroxide (NaOH), and lithium hydroxide (LiOH).

7. A pharmaceutical composition comprising the compound of claim 1, or the isomer or pharmaceutically acceptable salt thereof as an active ingredient.

8. A method of treating a metabolic disease comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 7 to a patient in need thereof, wherein the metabolic disease is selected from the group consisting of obesity, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X.