WO2012128582A2

WO2012128582A2 - A COMPOUND FOR INHIBITING HUMAN 11-β-HYDROXY STEROID DEHYDROGENASE TYPE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

Info

Publication number: WO2012128582A2
Application number: PCT/KR2012/002100
Authority: WO
Inventors: In Hee Lee; Chang Min Park; Se Hoan Kim; Hee Il Chae; Doo Hyeok PYEON; Myoung Hyeon SHIN; Jeong Un HWANG; Soon Young Moon; Tae Young Ha; So Youn Kim; Hyuk Joon Choi; Myoung Hyun YOO; Jong Chan Lee; Young Seok Kim; Jae Keol Rhee
Original assignee: Hyundai Pharm Co., Ltd.
Priority date: 2011-03-23
Filing date: 2012-03-23
Publication date: 2012-09-27
Also published as: WO2012128582A3

Abstract

The present invention relates to a novel compound, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for human-11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) comprising the same. The invention provides a compound, which has excellent activity and solubility and is more efficiently formulated and delivered, and a pharmaceutical composition for human-11-beta-hydroxysteroid dehydrogenase type 1 comprising the same.

Description

A COMPOUND FOR INHIBITING HUMAN 11-β-HYDROXY STEROID DEHYDROGENASE TYPE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

The present invention relates to a novel compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for inhibiting human 11-β-Hydroxy Steroid Dehydrogenase Type 1(11β-HSD1) comprising the same.

11-β-Hydroxy Steroid Dehydrogenase Type 1

A glucocorticoid (cortisol in human, corticosterone in rodents) is a reversely regulatory hormone, namely is against the action of insulin (Dallman MF, Strack AM, Akana SFetal., 1993; Front Neuroendocrinol 14, 303-347). It regulates the expression of liver enzymes associated with the gluconeogenesis, and increses the substrate supply by releasing amino acids from muscle (decrease of protein synthesis and increase of protein decomposition) and releasing glycerols from adipose tissue (increase of lipid decomposition). The glucocorticoid is also important in dividing a preadipocyte into mature adipocytes that can store triglycerids (Bujalska IJ et al., 1999; Endocrinology 140, 3188-3196). It can be important in disease status in which the glucocorticoid derived by "stress" as itself is associated with the central obesity that is a strong risk factor of type 2 diabetes, hypertension and cardiovascular disease (Bjorntorp P and Rosmond R, 2000; Int. J. Obesity 24, S80-S85).

The activity of glucocorticoid not only can be regulated by the secretion of cortisol, but also is regulated in tissue level according to the intracellular interconversion of inactive cortisone and active cortisol by 11β-Hydroxy Steroid Dehydrogenase, 11βHSD1 (that activates cortisone) and 11βHSD2 (that deactivates cortisol) (Sandeep TC and Walker BR, 2001 Trends in Endocrinol ＆ Metab. 12, 446-453). An isoform of 11β-Hydroxy Steroid Dehydrogenase Type 1(11βHSD1) is expressed in a liver, adpose tissues, a brain, lungs and other tissues of glucocorticoid, and is a potential target for treatment of numerous diseases that can be improved by the decrease of action of glucocorticoid, such as diabetes, obesity and age-related cognitive impairment (Seckl et al., 2001; Endocrinology 142, 1371-1376).

As a significant controller of efficacy of the local glucocorticoid the role of 11βHSD1 and accordingly the production of liver glucose had been also proven (Jamieson et al., 2000; J. Endocrinol., 165, 685-692). It was firstly represented by the treatment of carbene oxolone (that is a anti-ulcer drug inhibiting both 11βHSD1 and 2) that the mechanism of intracellular interconversion of inactive cortisone and active cortisol can be important in human (Walker BR et al., 1995; J. Clin. Endocrinol. Metab. 80, 3155-3159), and this implies that 11βHSD1 can decrease the tissue level of active glucocorticoid and thereby can regulate the effect of insulin, by increasing insulin sensitivity (Walker BR et al, 1995 J. Clin. Endocrinol. Metab. 80, 3155-3159). Also, recently a study on compounds having treatment effect of type 2 diabetes by inhibition of 11βHSD1 has been being implemented actively (Ji Seon Part et al., biological pharmacology, Anti-diabetic and anti-adipogenic effects of a novel selective 11βhydroxysteroid dehydrogenase type 1 inhibitor, 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), 2011; Sundbom M et al., Inhibition of 11beta HSD1 with the S-phenylethylaminothiazolone BVT116429 increases adiponectin concentrations and improves glucose homeostasis in diabetic KKAy mice, BMC Pharmacology 2008;　8:3 (12 February 2008); Clarence Hale et al., Chem Bio/Drug Des 2008;71:36-44; Clarence Hale et al., Diabetes, Obesity and Metabolism 11: 2009, 109-117; G. Hollis R. Huber, 2010; Diabetes, Obesity and Metabolism 13: 1-6, 2011: Clarence Hale et al., J. Med. Chem. 2010, 53, 4481-4487).

Clinically, Cushing's syndrome is associated with excess of cortisol, and this is associated with sugar tolerence, central obesity (which is caused by stimulation of differentiation of preadipocyte in depot), dyslipidemia and hypertension. Cushing's syndrome shows a number of obvious similarities with the metabolic syndrome. Although the metabolic syndrome is not generally associated with excessive levels of circulating cortisol (Jessop DS et al., 2001; J. Clin. Endocrinol. Metab. 86, 4109-4114), it is expected that the abnormally high activity of 11βHSD1 in tissue has the same effect. In obese people, although they have a level of plasma cortisol lower than or similar with lean control, the activity of 11βHSD1 of a subcutaneous fat was largely increased (Rask E et al. 2001; J. Clin. Endocrinol. Metab. 1418-1421). Moreover, a central fat associated with the metabolic syndrome represents much higher activity of 11βHSD1 than a subcutaneous fat (Bujalska IJ et al., 1997; Lancet 349, 1210-1213). Therefore, it is thought that there is a relationship between a glucocorticoid, 11βHSD1 and a metabolic syndrome.

11βHSD1 knock-out mice represent an attenuated glucocorticoid-derived activation of gluconeogenesis enzyme as a reaction to sugar concentration in plasma, which is meager and is reduced in response to stress or obesity (Kotelevtsev Y et al., 1997; Proc. Natl. Acad. Sci USA 94, 14924-14929), and this implies an usefulness of 11βHSD1 inhibition in output degradation of plasma sugar and liver sugar in type 2 diabetes. Moreover, these mice express an anti-arteriosclerotic lipoprotein profile, in which triglyceride decreases, HDL colesterol increases and apo-lipoprotein AI level increases (Morton NM et al., 2001; J. Biol. Chem. 276, 41293-41300). This phenotype is due to increase of expression in liver of PPARα and fat catabolic enzymes. Also, this implies an usefulness of 11βHSD1 inhibition in a treatment of dyslipedemia of metabolic syndrome.

The most obvious proof of relationship between a metabolic syndrome and 11βHSD1 is derived from a recent study on an excessive expression of 11βHSD1 of transgenic mouse (Masuzaki H et al., 2001; Science 294, 2166-2170). When it is expressed under the regulation of adipocyte-specific promoting genes, 11βHSD1 transgenic mouse shows corticosterone with high fat level, central obesity, insulin resistant diabetes, hyperlipidemia and sitomania. Most importantly, the increase of 11βHSD1 level in fat of this mouse is similar with that observed in diabetes object. The activity of 11βHSD1 in fat and corticosterone level in plasma were normal, but the corticosterone level in hepatic portal vein increased to 3 times. It is thought that this is a cause of metabolic effects in liver.

It is obvious that it is possible to imitate a complete metabolic syndrome in mouse by excessively expressing 11βHSD1 in fat only, similar with obese people.

The distribution of tissues of 11βHSD1 is widespread and is overlapped with the acceptor of glucocorticoid. Thus, the inhibition of 11βHSD1 can potentially counter the effect of glucocorticoid in numerous physiological/pathological roles. The 11βHSD1 is present in skeletal muscle of human, and the opposite action of glucocorticoid to assimilation effect of insulin which effects on protein conversion and glucose metabolism was widely disclosed (Whorwood CB et al., 2001; J. Clin. Endocrinol. Metab. 86, 2296-2308). Therefore, the skeletal muscle is an important target for the treatment of 11βHSD1-class.

*The glucocorticoid can also reduce the insulin secretion and degrade the effect of insulin resistance derived from glucocorticoid. Pancreatic islets can express 11βHSD1 and carbene oxolones can inhibit the effect of 11-dehydrocorticosterone on insulin release (Davani B et al., 2000; J. Biol. Chem. 275, 34841-34844). Thus, in the treatment of diabetes the treatment of 11βHSD1 inhibitor not only can act on insulin resistance at the tissue level, but also can increase the insulin secretion itself.

The skeletal development and bone action are also regulated by the action of glucocorticoid. The 11βHSD1 is present in human bone osteoclasts and osteoclasts and results of healthy volunteers treated with carbene oxolones show reduction in bone absorption without changes in markers of bone formation (Cooper MS et al. 2000; Bone 27, 375-381). In a bone the inhibition of activity of 11βHSD1 can be used as a protection mechanism in a treatment of osteoporosis.

The glucocorticoid can be also associated with an eye disease such as glaucoma. It was shown that the 11βHSD1 influences person's intraocular pressure and it can be expected that the inhibition of 11βHSD1 can reduce the increase of intraocular pressure associated with glaucoma (Rauz S et al., 2001; Investigative Opthalmology ＆ Visual Science 42, 2037-2042).

It was known that the stress and glucocorticoid influence cognitive function (de Quervain et al., 1998; Nature 394, 787-790). Because the 11βHSD1 regulates the degree of glucocorticoid action of brain, it is helpful in neurotoxin symptom (Rajan, V. et al., 1996; Neuroscience 16, 65-70; Seckl et al., 2000; Neuroendocrinol, 18, 49-99). If the 11βHSD1 of brain is inhibited on the basis of the known efficacy of glucocorticoid in brain, anxiety can be reduced (Tronche, F. et al., 1999; Nature Genetics, 23, 99-103). If the 11βHSD1 in human brain is inhibited, the reactivation of cortisone into cortisol can be inhibited, and the glucocorticoid-mediated effects, which is harmful to other aspects of survival of nerve and function of nerve, comprising cognitive impairment, depression and increased appetite are prevented.

It is shown that there is a definite relationship between the 11βHSD1 and the metabolic syndrome in both human and rodents. In obese patients with type 2 diabetes drugs that specifically inhibit 11βHSD1 will lower blood sugar by inhibiting the creation of hepatic glucose, reduce central obesity, improve phenotype of arteriosclerotic lipoprotein, lower blood pressure, and reduce insulin resistance. The effect of insulin in muscle will be improved and insulin secretion from beta cells of pancreatic islets can be increased.

At present two major recognized definitions of metabolic syndrome are present.

1) The definition of metabolic syndrome of adult treatment panel (ATP III 2001 JMA) indicates the presence when a patient has 3 or more symptoms of the following symptoms:

- For men a waist measurement of 40 inches (102 cm) or more, for women a waist measurement of 35 inches (88 cm) or more

- A triglyceride level in serum of 150 mg/dl(1.69 mmol/l) or more

- For men a HDL cholesterol level of less than 40 mg/dl(1.04 mmol/l), for women a HDL cholesterol level of less than 50 mg/dl(1.29 mmol/l)

- A blood pressure of 135/80 mm Hg or more and/or

- A blood sugar (serum glucose) of 110 mg/dl(6.1 mmol/l) or more.

2) WHO advisory body recommended the following definitions, but these do not imply causal relations and are presented as a practical definition in which there is room for improvement:

- A patient has one or more symptoms from among the following symptoms, namely glucose tolerance, impaired glucose tolerance (IGT) or diabetes and/or insulin resistance along with two or more from among the following items, namely,

- Increase in arterial pressure

- Increase in plasma triglycerides

- Central obesity

- Microalbuminuria.

The present invention provides a compound which has more excellent activity and solubility and is more efficient in formulation and transmission and a pharmaceutical composition for inhibiting human 11-β-Hydroxy Steroid Dehydrogenase Type 1 comprising the same for this.

The present invention provides a novel compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for inhibiting human 11-β-Hydroxy Steroid Dehydrogenase Type 1(11β-HSD1) comprising the same.

An embodiment of the present invention provides a compound represented by the following Chemical Formula 1 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

wherein

R' and R'' are each independently H or a C₁-C₃alkyl and may be taken together to form a 5- or 6-membered saturated or unsaturated ring;

X is any one selected from the group consisting of -NR₁R₂, -NHSO₂R₁, -C(O)OR₁, -NHC(O)R₁, -OC(O)R_1, -C(O)NR₁R₂, -NHC(O)NR₁R₂, and -C(O)NHNR₁R₂;

L is a bond or a C₁- C₃alkylene group, wherein each carbon atom constituting the C₁- C₃alkylene group may be independently substituted with one or more C₁- C₆ alkyl groups;

R₁ and R₂are each independently any one selected from the group consisting of hydrogen, -OH, a substituted or unsubstituted C₁- C₆ alkyl, a substituted or unsubstituted C₃- C₁₂ cycloalkyl, a substituted or unsubstituted C₆- C₁₂ aryl, and a substituted or unsubstituted C₅- C₁₂ heteroaryl having one or more ring heteroatoms selected from the group consisting of N, O and S;

R₁ and R₂may be taken together with the nitrogen atom to which they are attached to form a 5- to 8-membered saturated or unsaturated ring, wherein the saturated or unsaturated ring may be substituted with one or more groups selected from the group consisting of -OH, a C₁- C₆ alkoxy, a C₁- C₆ haloalkoxy, a substituted or unsubstituted C₁- C₆ alkyl, -NO₂, halo, -COOH, a -C₁- C₆ alkyloxycarbonyl, a C₆- C₁₀ aryl, -NH₂, a mono- or di- C₁- C₆ alkylamino, and a mono- or di- C₁- C₆ alkylcarbamoyl;

L‘ is a bond, -C(O)-, -C(O)O-, -C(O)NH-, -NHC(O)-, C₁- C₃alkylene, -SO₂-, C₁- C₃alkylene-C(O)-, or -C(O)-C₁- C₃alkylene, wherein each carbon atom constituting the C₁- C₃alkylene may be each independently substituted with one or more groups selected from the group consisting of C₁- C₆ alkyl, -CN, -COOH, and C₁- C₆ alkyloxycarbonyl;

P is any one selected from the group consisting of a substituted or unsubstituted C₁- C₆ alkyl, a substituted or unsubstituted C₃- C₁₂ cycloalkyl, a substituted or unsubstituted C₆- C₁₂ aryl, a substituted or unsubstituted C₅- C₁₂heteroaryl having one or more ring heteroatoms selected from the group consisting of N, O and S, a C₁- C₆ alkyloxycarbonyl, -COOH, and -NR₁R₂;

wherein when P is a C₆- C₁₂ aryl group in which two adjacent carbon atoms constituting the aryl group are each substituted with a C₁- C₆ alkyl group, carbon atoms constituting the alkyl group may be taken together to form a 5- or 6-membered saturated or unsaturated ring, wherein the ring may be substituted with one or more groups selected from the group consisting of -OH, C₁- C₆ alkoxy, C₁- C₆ haloalkoxy, C₁- C₆ alkyl, -NO₂, halo, -COOH, -C₁- C₆ alkyloxycarbonyl, C₆- C₁₀ aryl, -NH₂, mono or di C₁- C₆ alkylamino, and mono- or di- C₁- C₆ alkylcarbamoyl, and one or more of the carbon atoms constituting the ring may be substituted with one or more selected from the group consisting of N, O and S;

wherein when P is a C₃- C₁₂ cycloalkyl group in which two adjacent carbon atoms constituting the cycloalkyl group are each substituted with a C₁- C₆ alkyl group, carbon atoms constituting the alkyl group may be taken together to form a 5- or 6-membered saturated or unsaturated ring, wherein the ring may be substituted with one or more groups selected from the group consisting of -OH, C₁- C₆ alkoxy, C₁- C₆ haloalkoxy, C₁- C₆ alkyl, -NO₂, halo, -COOH, -C₁- C₆ alkyloxycarbonyl, C₆- C₁₀ aryl, -NH₂, mono- or di- C₁- C₆ alkylamino, and mono- or di- C₁- C₆ alkylcarbamoyl;

wherein said substituted C₁- C₆ alkyl, substituted C₃- C₁₂ cycloalkyl, substituted C₆- C₁₂ aryl and substituted C₅- C₁₂heteroaryl mean that said C₁- C₆ alkyl, C₃- C₁₂ cycloalkyl, C₆- C₁₂ aryl and C₅- C₁₂heteroaryl may be independently substituted with one or more groups selected from the group consisting of a C₁- C₆ alkyl which may be substituted with -CN, halo or -OH; a C₃- C₁₂ cycloalkyl; a C₂- C₆ alkenyl; a substituted or unsubstituted C₅- C₁₂heteroaryl having one or more ring heteroatom selected from the group consisting of N, O and S; a C₆- C₁₀ aryl; a C₁- C₆ alkylsulfonyl; a C₆- C₁₂ arylsulfonyl; a C₁- C₆ alkylthio; mercapto; -OH; a C₁- C₆ alkoxy; a C₁- C₆ haloalkoxy; -CN; -NO₂; halo; -COOH; -CHO; a -C₁- C₆ alkylcarbonyl; a -C₁- C₆ alkyloxycarbonyl; -NH₂; -CONH₂; a mono- or di- C₁- C₆ alkylamino; and a mono- or di- C₁- C₆ alkylcarbamoyl;

wherein one or more carbon atoms constituting the C₁- C₆ alkyl and the C₃- C₁₂ cycloalkyl may be substituted with one or more of N, O and S;

wherein alkyl or alkenyl in said C₁- C₆ alkyl, C₂- C₆ alkenyl, C₁- C₆ alkylsulfonyl, C₁- C₆ alkoxy, C₁- C₆ haloalkoxy, -C₁- C₆ alkylcarbonyl, -C₁- C₆ alkyloxycarbonyl, C₁- C₆ alkylamino and C₁- C₆ alkylcarbamoyl may be straight or branched-chain; and

wherein said C₃- C₁₂ cycloalkyl, C₆- C₁₂ aryl and C₅- C₁₂heteroaryl have a single ring or a multiple ring structure.

Further, an embodiment of the present invention provides a compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof characterized in that X is -C(O)NR₁R₂ and R₁ and R₂ are the same as defined above.

Also, an embodiment of the present invention provides a compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof characterized in that in the Chemical Formula 1 X is

, and the cycloalkyl moiety is substituted with one or more groups selected from the group consisting of a C₁- C₆ alkyl which may be substituted with -CN, halo or -OH; a C₃- C₁₂ cycloalkyl; a C₂- C₆ alkenyl; a substituted or unsubstituted C₅- C₁₂ heteroaryl having one or more ring heteroatoms selected from the group consisting of N, O and S; a C₆- C₁₀ aryl; a C₁- C₆ alkylsulfonyl; a C₆- C₁₂ arylsulfonyl; a C₁- C₆ alkylthio; mercapto; -OH; a C₁- C₆ alkoxy; a C₁- C₆ haloalkoxy; -CN; -NO₂; halo; -COOH; -CHO; a -C₁- C₆ alkylcarbonyl; a -C₁- C₆ alkyloxycarbonyl; -NH₂; -CONH₂; a mono- or di- C₁- C₆ alkylamino; and a mono- or di- C₁- C₆ alkylcarbamoyl.

Further, an embodiment of the present invention provides a compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof characterized in that the compound of the Chemical Formula 1 is any one selected from the group consisting of the following compounds.

Also, an embodiment of the present invention provides a compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof characterized in that the compound of the Chemical Formula 1 is any one selected from the group consisting of the following compounds.

Further, the present invention provides a pharmaceutical composition for inhibiting human 11-β-Hydroxy Steroid Dehydrogenase Type 1(11β-HSD1), comprising the compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof of the present invention as an active ingredient.

Further, the present invention provides a pharmaceutical composition for treating or preventing any one disease selected from the group consisting of hypertension, heart failure, renal failure, liver failure, peripheral vascular disease, coronary artery disease, myocardial infraction, hyderlipidemia, diabetes, hyperglycemia, obesity, ischemic heart disease, diabetic nephropathy, diabetic heart failure, dyslipidemia, stroke, arteriosclerosis, inflammation, adult respiratory distress syndrome, renal disease, Raynaud syndrome, obstructive pulmonary disease, interstitial pulmonary disease, asthma and arthritis, comprising the compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof of the present invention as an active ingredient.

Also, the present invention provides a pharmaceutical composition for treating or preventing any one disease selected from the group consisting of diabetes, metabolic syndrome, obesity, polycystic ovary syndrome, eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, hyderlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein level (HDL), high low-density lipoprotein level (LDL), hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, arteriosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, nerve disorder, muscle wasting, cognitive impairment, dementia, psoriasis, glaucoma, osteoporosis, viral infection, inflammatory disease, and immune disease, comprising the compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof of the present invention as an active ingredient.

It is intended that the term "compound" used in the present invention comprises not only a whole molecular specified, but also salt, prodrug conjugate, for example, ester and amide, and its pharmaceutically acceptable, pharmacological active derivatives comprising metabolites, hydrates, solvates and the like although it is not limited thereto.

It is intended that the term "composition" used in the present invention comprises not only a product including a specific ingredient in a specific amount, but also any product directly or indirectly produced by a combination of specific ingredients in a specific amount. The term "pharmaceutically acceptable" means that a carrier, a diluent, or an excipient should be harmonizable with other ingredient of dosage form, and not harmful to a consumer thereof.

The term "alkyl" used in the present invention means a saturated hydrocarbon radical, which can be linear or branched. This definition applies to both when the term is used alone, and when the term is used as a part of a compound term, such as "arylalkyl", "alkylamino" and the like. It is intended that in the present specification and claims all numerical ranges comprise an upper end and a lower end thereof.

The terms "cycloalkyl" and "cycloalkylene" represent a saturated hydrocarbon ring, and comprise noncyclic and polycyclic rings. Similarly, A cycloalkyl and cycloalkylene group having a hetero atom (for example, N, O or S) instead of carbon ring atom can be mentioned as "heterocycloalkyl" and "heterocycloalkylene", respectively. A part of the cycloalkyl and heterocycloalkyl can be also substituted or not be substituted with a halogen atom or another group, for example, nitro, alkyl, alkylamino, carboxyl, alkoxy, aryloxy and so on.

The term "halo" or "halogen" means fluorine, chlorine, bromine or iodine atom unless otherwise noted.

The term "hetero" represents a molecule, a coupler or a substituent, in which one or more than one of carbon atom is substituted with any one atom other than carbon, for example, nitrogen, oxygen, sulfur, phosphorus or silicon, generally nitrogen, oxygen or sulfur or more than one of noncarbon atom. Similarly, the term "heteroalkyl" represents a hetero atom-containing alkyl substituent, and the term "heterocyclic", "heterocycle" or "heterocyclyl" represents a hetero atom-containing or aromatic or nonaromatic cyclic substituent or group. The terms "heteroaryl" and "heteroaromatic" each represents a hetero atom-containing "aryl" and "aromatic" substituent. The terms "heterocyclic" and "heterocyclyl" comprise the terms "heteroaryl" and "heteroaromatic".

The term "substituted" represents that an atom or a group of atoms of any one compound is substituted with another atom or another group of atoms. For example, an atom or a group of atoms can be substituted with one or more than one of that from among the following substituents or groups: halo, nitro, C₁-C₈ alkyl, C₁-C₈ alkylamino, hydroxyC₁-C₈ alkyl, haloC₁-C₈ alkyl, carboxyl, hydroxyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyC₁-C₈ alkoxy, thioC₁-C₈ alkyl, aryl, aryloxy, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl C₁-C₈ alkyl, heteroaryl, arylC₁-C₈ alkyl, heteroarylC₁-C₈ alkyl, C₂-C₈ alkenyl including one or two double bond, C₂-C₈ alkynyl including one or two triple bond, C₄-C₈ alk(en)(yn)yl group, cyano, formyl, C₁-C₈ alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C₁-C₈ alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, C₁-C₈ alkylcarbonyl, C₁-C₈ dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylC₁-C₈ alkylaminocarbonyl, haloC₁-C₈ alkoxy, C₂-C₈ alkenyloxy, C₂-C₈ alkynyloxy, arylC₁-C₈ alkoxy, aminoC₁-C₈ alkyl, C₁-C₈ alkylaminoC₁-C₈ alkyl, C₁-C₈ dialkylaminoC₁-C₈ alkyl, arylaminoC₁-C₈ alkyl, amino, C₁-C₈ dialkylamino, arylamino, arylC₁-C₈ alkylamino, C₁-C₈ alkylcarbonylamino, arylcarbonylamino, azido, mercapto, C₁-C₈ alkylthio, arylthio, haloC₁-C₈ alkylthio, thiocyano, isothiocyano, C₁-C₈ alkylsulfinyl, C₁-C₈ alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, C₁-C₈ alkylaminosulfonyl, C₁-C₈ dialkylaminosulfonyl and arylaminosulfonyl.　 It is intended that when the term "substituted" is positioned before a possible substituent basis, the term applies to all members of such group.

The term "unsubstituted" means an original compound not substituted with any atom or group of atoms.

When the compound of the present invention, of which the effect was identified as described above is administered as a clinical purpose, a total daily dosage to be administered to host as a single dosage or a separate dosage is preferably 1 to 100 mg, particularly preferably 3 to 10 mg, per 1 kg body weight, but a specific dosage level for each patient can change according to a specific compound to be used, a body weight, a gender, a health status, a diet of patient, a time of administration, a method of administration of drug, an excretion rate, mixing drugs and a severity of disease and so on.

Although the compound of the present invention can be administered through any path depending on the purpose, injection and oral administration are preferable. An injectable formulation, for example a sterile injectable aqueous or oily suspension can be prepared by using a suitable dispersant, wetting agent or suspending agent according to the known technology. Solvents which can be used for this comprise water, Ringer's solution and isotonic NaCl solution, and a sterile fixed oil is also normally used as a solvent or a suspension medium. Any nonirritating fixed oil comprising mono-, di-glyceride can be also used for this purpose, and also a fatty acid such as oleic acid can be used in an injectable formulation.

Examples of a form of solid administration for oral administration comprise capsules, tablets, pills, powders and granules, and particularly capsules and tablets are useful. It is preferable to prepare tablets and pills into a form of long shell. The form of solid administration can be prepared by mixing the active compound of the Chemical Formula 1 according to the present invention with one or more inert diluent, such as sucrose, lactose, starch and so on, lubricants such as magnesium stearate, carriers such as disintegrants, binders and so on.

In using the compound of the present invention for treatment purpose, the present invention would be more specifically described with reference to the following examples and experimental examples. However, these examples and experimental examples are only for understanding of the present invention, but the scope of the present invention is not limited thereto at any sense.

The compound of the present invention and the pharmaceutical composition for inhibiting human 11-β-Hydroxy Steroid Dehydrogenase Type 1 comprising the same have excellent activity and solubility, and are more efficient in formulation and transmission.

All of the reagents used in Examples below were bought from Sigma-Aldrich, Fluka, and TCI, and ¹H NMR spectra were recorded with Bruker Biospin AVANCE II 400 (internal standard: tetramethyl silane).

[Example 1]

Preparation Example 1: Synthesis of N-(adamantane-2-yl)-4-benzylmorpholine-2-carboxamide (compound 108)

In a 1L flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105ml). In another vessel, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml), and this solution was added to the above mentioned 1L flask. The resultant mixture was stirred for 12 hours at room temperature, further added with toluene (205 ml), and cooled to -5℃. Then, the mixture was slowly added with t-BuOK (50.84g, 444 mmol) dissolved in THF (202 ml). The resultant mixture was stirred for 50 minutes while the temperature was maintained at -5℃. The resultant mixture was washed with salt water once, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, through column chromatography, 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %) was obtained.

¹H NMR (400 MHz, CDCl₃) δ7.39-7.28 (m, 5H), 4.62 (t, J = 3.6 Hz, 1H), 4.05 (m, 1H), 3.79 (dt, J = 3.6, 11.6 Hz, 1H), 3.59 (dd, J = 9.2, 25.2 Hz, 2H), 2.78 (dd, J = 3.6, 12.0 Hz, 1H), 2.66 (m, 1H), 2.58 (dd, J = 3.6, 12.0 Hz, 1H), 2.43 (m, 1H).

4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10℃. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10℃). The resultant solid compound was dried in a 60℃ oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).

¹H NMR (400 MHz, DMSO-d ₆) δ2.18 (bs, -COOH), 7.67-7.65 (m, 2H), 7.53-7.40 (m, 3H), 4.61 (d, J = 10.8 Hz, 1H), 4.39 (m, 2H), 4.05-4.94 (m, 2H), 3.43 (d, J = 12.0 Hz, 1H), 3.20-3.07 (m, 3H).

4-benzylmorpholine-2-carboxylic acid hydrochloride (162.0 mg, 0.63 mmol) was dissolved in CH₂Cl₂ (5 ml), added with EDCI (121 mg, 0.63 mmol) and DMAP (154 mg, 1.26 mmol), and stirred for 30 minutes. The resultant mixture was added with 2-adamantane amine (140.8 mg, 0.75 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H₂O, extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. Through vacuum distillation, the solvent was removed. The resultant mixture was purified by column chromatography so as to provide N-(adamantane-2-yl)-4-benzylmorpholine-2-carboxamide (207.7 mg, 0.59 mmol, 93 %).

H NMR (400 MHz, CDCl₃) δ 7.35-7.26 (m, 5H), 6.97 (d, J = 7.6 Hz, -CONH), 4.07-4.05 (m, 2H), 3.94 (dq, J = 1.2, 3.2, 11.2 Hz, 1H), 3.73 (m, 1H), 3.60 (d, J = 13.2 Hz, 1H), 3.50 (d, J = 12.8 Hz, 1H), 3.27 (d, J = 11.6 Hz, 1H), 2.69 (d, J = 11.2 Hz, 1H), 2.17 (td, J = 3.2, 11.2 Hz, 1H), 2.02 (t, J = 11.2 Hz, 1H), 1.93-1.64 (m, 14H).

Preparation Example 2: Synthesis of N-(adamantane-2-yl)morpholine-2-carboxamide

N-(adamantane-2-yl)-4-benzylmorpholine-2-carboxamide (500 mg, 1.41 mmol) was dissolved in EtOH (10 ml), and added with 10 % Pd/C (50mg). The resultant mixture was stirred under a hydrogen atmosphere for 12 hours, and filtered through celite to remove 10 % Pd/C. Then, N-(adamantane-2-yl)morpholine-2-carboxamide (279.7 mg, 1.25 mmol, 75 %) was obtained.

¹H NMR (400 MHz, CDCl₃) δ6.93 (t, J = 5.6 Hz, -NH), 4.05 (dd, J = 2.4, 10.4 Hz, 1H), 3.95 (m, 2H), 3.6 (m, 1H), 3.36 (dd, J = 2.8, 12.8 Hz, 1H), 2.88 (m, 2H), 2.67 (m, 1H), 1.83-1.74 (m, 12H), 1.66-1.62 (m, 2H).

Preparation Example 3: Synthesis of N-2-adamantyl-4-(4-fluoro-2-trifluorophenyl)morpholine-2-carboxyamide (compound 1)

N-2-adamantyl-morpholine-2-carboxyamide hydrochloride (100 mg, 0.33 mmol), 1-bromo-4-fluoro-2-trifluoro)benzene (80 mg, 0.33 mmol), BINAP (8 mg, 0.013 mmol), t-BuONa (64 mg, 0.66 mmol), and Pd₂(dba)₃ (6 mg, 0.007 mmol) were dissolved in toluene (1 ml), and stirred at 100℃ for 5 hours. After the reaction was completed, the resultant product was filtered through celite, and an organic layer was separated by Et₂O and EA. The organic layer was dried and filtered with MgSO₄. Then, the mixture was purified by column chromatography (EA/n-Hex = 1/4) so as to provide N-2-adamantyl-4-(4-fluoro-2-trifluorophenyl)morpholine-2-carboxyamide (15 mg, 0.035 mmol, 10 %).

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.32 (m, 2H), 7.28-7.22 (m, 1H), 7.02-7.00 (m, NH, 1H), 4.21-4.18 (m, 1H), 4.09-4.03 (m, 2H), 3.93-3.85 (m, 1H), 3.39-3.36 (m, 1H), 2.91-2.86 (m, 2H), 2.79-2.74 (m, 1H), 2.02-1.67 (m, 14H).

Preparation Example 4: Synthesis of N-2-adamantyl-4-(4-chlorophenyl)morpholine-2-carboxyamide (compound 2).

A desired compound was obtained in the same manner as described in Preparation Example 3 in Example 1 except that 1-bromo-4-chlorobenzene was used.

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.21 (m, 2H), 7.01-6.99 (m, NH, 1H), 6.90-6.87 (m, 2H), 4.17-4.07 (m, 3H), 3.97-3.92 (m, 1H), 3.87-3.80 (m, 1H), 3.40-3.37 (m, 1H), 2.88-2.81 (m, 1H), 2.66-2.60 (m, 1H), 1.95-1.76 (m, 12H), 1.68-1.65 (m, 2H).

Preparation Example 5: Synthesis of N-2-adamantyl-4-(2-chlorophenyl)morpholine-2-carboxyamide (compound 3)

A desired compound was obtained in the same manner as described in Preparation Example 3 in Example 1 except that 1-bromo-2-chlorobenzene was used.

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.37 (m, 1H), 7.24-7.22 (m, 1H), 7.05-6.99 (m, 3H), 4.26-4.23 (m, 1H), 4.10-4.06 (m, 2H), 3.99-3.92 (m, 1H), 3.73-3.70 (m, 1H), 3.34-3.30 (m, 1H), 2.82-2.79 (m, 1H), 2.75-2.70 (m, 1H), 1.96-1.66 (m, 14H).

Preparation Example 6: Synthesis of N-2-adamantyl-4-(4-fluorophenyl)morpholine-2-carboxyamide (compound 4)

A desired compound was obtained in the same manner as described in Preparation Example 3 in Example 1 except that 1-bromo-2-fluorobenzene was used.

¹H NMR (400 MHz, CDCl₃) δ 7.02-6.96 (m, NH, 3H), 6.95-6.90 (m, 2H), 4.19-4.09 (m, 3H), 3.92-3.83 (m, 2H), 3.35-3.31 (m, 1H), 2.88-2.81 (m, 1H), 2.65-2.60 (m, 1H), 1.96-1.77 (m, 12H), 1.69-1.66 (m, 2H).

Preparation Example 7: Synthesis of N-2-adamantyl-4-(4-trifluoromethylphenyl)morpholine-2-carboxyamide (compound 5)

A desired compound was obtained in the same manner as described in Preparation Example 3 in Example 1 except that 1-bromo-4-trifluoromethylbenzene was used.

¹H NMR (400 MHz, CDCl₃) δ7.53-7.51 (m, 2H), 7.02-6.98 (m, NH, 3H), 4.15-4.09 (m, 4H), 3.88-3.82 (m, 1H), 3.56-3.53 (m, 1H), 2.99-2.92 (m, 1H), 2.78-2.72 (m, 1H), 1.97-1.78 (m, 12H), 1.70-1.67 (m, 2H).

[Example 2]

Preparation Example 1: Synthesis of N-2-adamantyl-4-(2-phenyl-2-oxoethyl)morpholine-2-carboxyamide (compound 6)

¹H NMR (400 MHz, CDCl₃) δ7.35-7.26 (m, 5H), 6.97 (d, J = 7.6 Hz, -CONH), 4.07-4.05 (m, 2H), 3.94 (dq, J = 1.2, 3.2, 11.2 Hz, 1H), 3.73 (m, 1H), 3.60 (d, J = 13.2 Hz, 1H), 3.50 (d, J = 12.8 Hz, 1H), 3.27 (d, J = 11.6 Hz, 1H), 2.69 (d, J = 11.2 Hz, 1H), 2.17 (td, J = 3.2, 11.2 Hz, 1H), 2.02 (t, J = 11.2 Hz, 1H), 1.93-1.64 (m, 14H).

¹H NMR (400 MHz, CDCl₃) δ.93 (t, J = 5.6 Hz, -NH), 4.05 (dd, J = 2.4, 10.4 Hz, 1H), 3.95 (m, 2H), 3.6 (m, 1H), 3.36 (dd, J = 2.8, 12.8 Hz, 1H), 2.88 (m, 2H), 2.67 (m, 1H), 1.83-1.74 (m, 12H), 1.66-1.62 (m, 2H).

N-2-adamantyl-morpholine-2-carboxyamide hydrochloride (100 mg, 0.33 mmol), and 2-bromo-1-phenylethanone (99 mg, 0.5 mmol) were dissolved in DMF (1 ml), added with K₂CO₃ (92 mg, 0.66 mmol), and stirred at room temperature for 4 hours. After the reaction was completed, an organic layer was separated by H₂O and EA. The organic layer was dried and filtered with MgSO₄. Then, the mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-2-adamantyl-4-(2-phenyl-2-oxoethyl)morpholine-2-carboxyamide (30 mg, 0.08 mmol, 16 %).

¹H NMR (400 MHz, CDCl₃) δ 8.01-7.99 (m, 2H), 7.60-7.54 (m, 1H), 7.48-7.45 (m, 2H), 6.98-6.96 (m, NH, 1H), 4.16-4.13 (m, 1H), 4.06-4.04 (m, 1H), 3.97-3.93 (m, 2H), 3.83-3.72 (m, 2H), 3.36-3.34 (m, 1H), 2.88-2.85 (m, 1H), 2.40-2.34 (m, 1H), 2.30-2.24 (m, 1H), 1.92-1.63 (m, 14H).

Preparation Example 2: Synthesis of N-2-adamantyl-4-(2-(2-methoxyphenyl)-2-oxoethyl)morpholine-2-carboxyamide (compound 7)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 2-bromo-1-(2-methoxyphenyl)ethanone was used.

¹H NMR (400 MHz, CDCl₃) δ7.77-7.75 (m, 1H), 7.51-7.47 (m, 1H), 7.05-6.96 (m, 3H), 4.16-4.12 (m, 1H), 2.92-2.89 (m, 1H), 2.44-2.338 (m, 1H), 2.33-2.28 (m, 1H), 1.93-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 3: Synthesis of N-2-adamantyl-4-(2-(4-fluorophenyl)-2-oxoethyl)morpholine-2-carboxyamide (compound 8)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 2-bromo-1-(4-fluorophenyl)ethanone was used.

¹H NMR (400 MHz, CDCl₃) δ 8.09-8.04 (m, 2H), 7.17-7.11 (m, 2H), 6.98-6.94 (m, NH, 1H), 4.15-4.12 (m, 1H), 4.07-4.05 (m, 1H), 2.40-2.34 (m, 1H), 2.29-2.24 (m, 1H), 1.92-1.76 (m, 12H), 1.68-1.64 (m, 2H).

Preparation Example 4: Synthesis of N-2-adamantyl-4-(2-(3-nitrophenyl)-2-oxoethyl)morpholine-2-carboxyamide (compound 9)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 2-bromo-1-(3-nitrophenyl)ethanone was used.

¹H NMR (400 MHz, CDCl₃) δ8.98-8.91 (m, 1H), 8.46-8.44 (m, 1H), 8.39-8.35 (m, 1H), 7.72-7.68 (m, 1H), 6.97-6.95 (m, NH, 1H), 4.14-4.10 (m, 1H), 4.07-4.05 (m, 1H), 4.00-3.97 (m, 1H), 3.94-3.90 (m, 1H), 3.81-3.75 (m, 2H), 3.55-3.31 (m, 1H), 2.84-2.81 (m, 1H), 2.45-2.39 (m, 1H), 2.30-2.25 (m, 1H), 1.92-1.76 (m, 12H), 1.68-1.64 (m, 2H).

Preparation Example 5: Synthesis of N-2-adamantyl-4-(1-oxo-1-phenylpropane-2-yl)morpholine-2-carboxyamide (compound 10)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 2-bromo-1-phenylpropane-1-one was used.

¹H NMR (400 MHz, CDCl₃) δ 8.09-8.07 (m, 2H), 7.59-7.55 (m, 1H), 7.49-7.45 (m, 2H), 6.97-6.95 (m, NH 1H), 4.30-4.25 (m, 1H), 4.06-4.04 (m, 2H), 3.90-3.87 (m, 1H), 3.57-3.51 (m, 1H), 3.34-3.31 (m, 1H), 2.59-2.54 (m, 1H), 2.47-2.46 (m, 2H), 1.93-1.76 (m, 12H), 1.67-1.60 (m, 2H), 1.28-1.27 (m, 3H).

Preparation Example 6: Synthesis of N-2-adamantyl-ethyl-2-(2-(carbamoyl)morpholino)acetate (compound 70)

¹H NMR (400 MHz, CDCl₃)δ 6.97-6.95 (m, NH, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.14-4.09 (m, 1H), 4.07-4.04 (m, 1H), 3.99-3.95 (m, 1H), 3.83-3.77 (m, 1H), 3.33-3.22 (m, 3H), 2.84-2.81 (m, 1H), 2.48-2.41 (m, 1H), 2.28-2.22 (m, 1H), 1.93-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 7: Synthesis of N-2-adamantyl-ethyl-2-(2-(carbamoyl)morpholino)acetic acid (compound 71)

N-2-adamantyl-ethyl-2-(2-(carbamoyl)morpholino)acetate (100 mg, 0.29 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), and then was added with LiOH (61 mg, 1.45 mmol) dissolved in H₂O (1 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 2, and extracted with EA. The organic layer was dried and filtered with MgSO₄, and concentrated so as to provide N-2-adamantyl-ethyl-2-(2-(carbamoyl)morpholino)acetic acid (80 mg, 0.25 mmol, 86 %).

¹H NMR (400 MHz, DMSO-d ₆) δ12.10 (br, OH, 1H), 7.21-7.19 (m, NH, 1H), 4.02-3.95 (m, 1H), 3.90-3.83 (m, 2H), 3.62-3.57 (m, 1H), 3.18 (s, 2H), 3.01-2.98 (m, 1H), 2.71-2.68 (m, 1H), 2.35-2.31 (m, 1H), 2.22-2.16 (m, 1H), 1.81-1.69 (m, 12H), 1.56-1.53 (m, 2H).

Preparation Example 8: Synthesis of N-2-adamantyl-4-(2-(4-fluorophenylamino)-2-oxoethyl)morpholine-2-carboxyamide (compound 72)

N-2-adamantyl-ethyl-2-(2-(carbamoyl)morpholino)acetic acid (50 mg, 0.16 mmol) was dissolved in CH₂Cl₂ (1 ml), and added with BOP (70 mg, 0.16 mmol) and DIPEA (60 mg, 0.47 mmol), followed by stirring. The resultant mixture was added with 4-fluoroaniline (20 mg, 0.19 mmol), and stirred at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-2-adamantyl-4-(2-(4-fluorophenylamino)-2-oxoethyl)morpholine-2-carboxyamide (57 mg, 0.14 mmol, 88 %).

¹H NMR (400 MHz, CDCl₃) δ9.09 (br, NH, 1H), 7.65-7.54 (m, 2H), 7.07-7.03 (m, 2H), 6.98-6.96 (m, NH, 1H), 4.18-4.11 (m, 2H), 4.03-4.00 (m, 1H), 3.82-3.78 (m, 1H), 3.52-3.47 (m, 1H), 3.27-3.12 (m, 2H), 3.07-3.05 (m, 1H), 2.78-2.69 (m, 2H), 2.56-2.51 (m, 1H), 1.99-1.78 (m, 12H), 1.71-1.68 (m, 2H).

Preparation Example 9: Synthesis of N-2-adamantyl-ethyl-2-(2-(carbamoyl)morpholino)-2-methylpropanoate (compound 73)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that ethyl 2-bromo-2-methylpropanoate was used.

¹H NMR (400 MHz, CDCl₃) δ 7.28 (m, NH, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.07-4.05 (m, 1H), 4.01-3.94 (m, 2H), 3.71-3.65 (m, 1H), 3.36-3.32 (m, 1H), 2.79-2.76 (m, 1H), 2.48-2.42 (m, 1H), 2.29-2.23 (m, 1H), 1.93-1.76 (m, 12H), 1.35-1.34 (m, 6H), 1.29 (t, J = 7.2 Hz, 3H).

Preparation Example 10: Synthesis of N-2-adamantyl-4-(1-(2-chlorophenylamino)-2-methyl-1-oxopropane-2-yl)morpholine-2-carboxyamide (compound 74)

A desired compound was obtained in the same manner as described in Preparation Example 8 in Example 2 except that 2-chloroaniline was used.

¹H NMR (400 MHz, CDCl₃) δ9.24 (br, NH, 1H), 7.69 (m, 1H), 7.47-7.45 (m, 1H), 7.28-7.24 (m, 1H), 7.09-7.06 (m, 1H), 6.98-6.96 (m, NH, 1H), 4.13-4.11 (m, 2H), 4.05-4.02 (m, 1H), 3.77-3.73 (m, 1H), 3.22-3.19 (m, 1H), 2.60-2.45 (m, 3H), 1.96-1.78 (m, 12H), 1.71-1.68 (m, 2H), 1.35 (s, 3H), 1.29 (s, 3H).

Preparation Example 11: synthesis of N-2-adamantyl-4-(4-fluorophenethyl)morpholine-2-carboxamide (compound 78)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 1-(2-bromoethyl)-4-fluorobenzene was used.

¹H NMR (400 MHz, CDCl₃) δ7.17-7.16 (m, 2H), 6.99-6.98 (m, 2H+NH), 4.08-4.04 (m, 2H), 3.99-3.97 (m, 1H), 3.78-3.72 (m, 1H), 3.38-3.35 (m, 1H), 2.82-2.77 (m, 3H), 2.68-2.56 (m, 2H), 2.24-2.21 (m, 1H), 2.05-1.98 (m, 1H), 1.94-1.63 (m, 14H).

Preparation Example 12: Synthesis of N-2-adamantyl-4-phenethylmorpholine-2-carboxamide (compound 79)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that (2-bromoethyl)benzene was used.

¹H NMR (400 MHz, CDCl₃) δ7.32-7.28 (m, 2H), 7.23-7.20 (m, 3H), 7.00-6.98 (m, NH, 1H), 4.08-4.05 (m, 2H), 4.01-3.97 (m, 1H), 3.79-3.73 (m, 1H), 3.40-3.37 (m, 1H), 2.89-2.77 (m, 3H), 2.70-2.62 (m, 2H), 2.28-2.21 (m, 1H), 2.06-1.99 (m, 1H), 1.93-1.63 (m, 14H).

Preparation Example 13: Synthesis of N-2-adamantyl-4-(1-phenylpropane-2-yl)morpholine-2-carboxamide (compound 80)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that (2-bromopropyl)benzene was used.

¹H NMR (400 MHz, CDCl₃) δ 7.31-7.16 (m, 5H), 7.00-6.98 (m, NH, 1H), 4.11-3.97 (m, 3H), 3.74-3.68 (m, 1H), 3.28-3.23 (m, 1H), 3.01-2.97 (m, 1H), 2.87-2.84 (m, 1H), 2.72-2.65 (m, 1H), 2.57-2.39 (m, 2H), 2.32-2.27 (m, 1H), 1.94-1.60 (m, 14H), 0.99-0.95 (m, 3H).

Preparation Example 14: Synthesis of ethyl 2-(2-(2-(N-2-adamandylamino))morpholino)-2-phenylacetate(compound 81)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that ethyl 2-chloro-2-phenylacetate was used.

¹H NMR (400 MHz, CDCl₃) δ.45-7.32 (m, 5H), 6.96 (m, -NH-), 4.14-3.88 (m, 6H), 3.78-3.75 (m,1H), 3.37-3.12 (m, 1H), 2.82 (m, 1H), 2.5 (m, 1H), 2.22 (m, 1H), 1.91-1.63 (m, 14H), 1.23 (t, J = 7.2 Hz, 3H).

Preparation Example 15: Synthesis of ethyl 2-(2-(2-(N-2-adamandylamino))morpholino)-2-phenylacetic acid (compound 82)

A desired compound was obtained in the same manner as described in Preparation Example 7 in Example 2 except that ethyl 2-bromo-2-methylpropanoate was used.

¹H NMR (400 MHz, CD₃OD) δ7.53 (m, 2H), 7.36-7.29 (m, 3H), 4.23 (m,1H), 4.01 (m, 1H), 3.99-3.37 (m, 3H), 3.54 (m, 1H), 2.89 (m, 1H), 2.12 (m, 1H), 1.97-1.66 (m, 14H).

Preparation Example 16: Synthesis of N-2-adamantyl-4-(4-cyanobenzoyl)morpholine-2-carboxamide (compound 84)

N-2-adamantyl-morpholine-2-carboxyamide hydrochloride (245 mg, 0.816 mmol) was dissolved in CH₂Cl₂ (5 ml), and added with BOP (300 mg, 0.68 mmol) and DIPEA (264 mg, 2.04 mmol), followed by stirring. The resultant mixture was added with 4-cyanobenzoic acid (100 mg, 0.68 mmol), and stirred at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-2-adamantyl-4-(4-cyanobenzoyl)morpholine-2-carboxamide (140 mg, 0.35 mmol, 52 %).

¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 6.93-6.91 (m, NH, 1H), 4.49 (m, 1H), 4.16-3.94 (m, 4H), 3.72 (m, 1H), 3.16 (m, 2H), 1.89-1.77 (m, 12H), 1.69-1.65 (m, 2H).

Preparation Example 17: Synthesis of N-2-adamantyl-4-nitrophenyl-2-(carbamoyl)morpholine-4-carboxylicate (compound 85)

N-2-adamantyl-morpholine-2-carboxyamide hydrochloride (200 mg, 0.66 mmol) and 4-nitrophenyl carbonochloridate (133 mg, 0.66 mmol) were dissolved in DMF (10 ml), added with triethylamine (200 mg, 1.98 mmol) at 0℃, and stirred at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by H₂O and CH₂Cl₂, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-2-adamantyl-4-nitrophenyl-2-(carbamoyl)morpholine-4-carboxylicate (200 mg, 0.46 mmol, 70 %).

¹H NMR (400 MHz, CDCl₃) δ 8.30-8.26 (m, 2H), 7.38-7.32 (m, 2H), 6.98 (m, NH, 1H), 4.63-4.60 (m, 1H), 4.13-4.03 (m, 4H), 3.77-3.70 (m, 1H), 3.29-2.01 (m, 2H), 1.95-1.65 (m, 14H).

Preparation Example 18: Synthesis of N-2-adamantyl-4(1-(3,4-difluorophenyl)ethyl)morpholine-2-carboxyamide (compound 87)

1-(3,4-difluorophenyl)ethanone (1 g, 6.4 mmol) was dissolved in MeOH (20 ml), slowly added with NaBH₄ (363 mg, 9.6 mmol) at 0℃, and stirred at room temperature for 3 hours. After the reaction was completed, the organic layer was separated by EA and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:4) so as to provide 1-(3,4-difluorophenyl)ethanol (900 mg, 5.69 mmol, 90 %).

¹H NMR (400 MHz, CDCl₃) δ 7.28-6.76 (m, 3H), 4.91-4.88 (m, 1H), 1.91 (br, OH, 1H), 1.50-1.47 (m, 3H).

1-(3,4-difluorophenyl)ethanol (900 mg, 5.69 mmol) was dissolved in CH₂Cl₂ (15 ml), slowly added with SOCl₂ (1354 mg, 11.38 mmol), and stirred at room temperature for 12 hours. After the reaction was completed, the resultant mixture obtained through concentration was purified by column chromatography (EA/n-Hex = 1:5) so as to provide 4-(1-chloroethyl)-1,2-difluorobenzene (1 g, 5.66 mmol, 89 %).

¹H NMR (400 MHz, CDCl₃) δ 7.31-7.25 (m, 1H), 7.19-7.10 (m, 2H), 5.07-5.02 (m, 1H), 1.85-1.83 (m, 3H).

N-2-adamantyl-morpholine-2-carboxyamide (100 mg, 0.38 mmol) and 4-(1-chloroethyl)-1,2-difluorobenzene (201 mg, 1.14 mmol) were dissolved in DMF (1 ml), added with K₂CO₃ (158 mg, 1.14 mmol) and KI (189 mg, 1.14 mmol), and stirred at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by H₂O and EA, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-2-adamantyl-4(1-(3,4-difluorophenyl)ethyl)morpholine-2-carboxyamide (50 mg, 0.12 mmol, 33 %).

¹H NMR (400 MHz, CDCl₃) δ7.20-7.06 (m, 2H), 7.02-7.00 (m, 1H), 6.93-6.91 (m, NH, 1H), 4.08-3.96 (m, 3H), 3.75-3.70 (m, 1H), 3.45-3.39 (m, 1H), 3.10-3.06 (m, 1H), 2.79-2.76 (m, 1H), 2.24-2.17 (m, 1H), 1.97-1.75 (m, 13H), 1.66-1.63 (m, 2H), 1.35-1.33 (m, 3H).

Preparation Example 19: Synthesis of N-2-adamantyl-4-(1-(4-cyanophenyl)ethyl)morpholine-2-carboxyamide (compound 88)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-cyanoacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.61 (m, 2H), 7.47-7.43 (m, 2H), 6.98-6.90 (m, NH, 1H), 4.08-4.05 (m,1H), 4.02-3.96 (m, 2H), 3.89-3.38 (m, 3H), 3.07-2.79 (m, 1H), 2.47-1.97 (m, 2H), 1.94-1.75 (m, 12H), 1.66-1.63 (m, 2H), 1.37-1.36 (m, 3H).

Preparation Example 20: Synthesis of N-2-adamantyl-4-(1-(pyridine-2-yl)ethyl)morpholine-2-carboxyamide (compound 89)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 2-pyridineacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ8.57-8.55 (m, 1H), 7.69-7.64 (m, 1H), 7.41-7.38 (m, 1H), 7.19-7.15 (m, 1H), 6.99-6.91 (br, NH, 1H), 4.13-3.97 (m, 4H), 3.90-3.46 (m, 2H), 3.12-2.52 (m, 1H), 2.33-2.18 (m, 1H), 2.08-1.98 (m, 1H), 1.91-1.76 (m, 12H), 1.67-1.63 (m, 2H), 1.43-1.42 (m, 3H).

Preparation Example 21: Synthesis of N-2-adamantyl-4-(1-(pyridine-3-yl)ethyl)morpholine-2-carboxyamide (compound 90)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 3-pyridineacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 8.55-8.54 (m, 2H), 7.69-7.65 (m, 1H), 7.32-7.26 (m, 1H), 6.98-6.96(m, NH, 1H), 4.08-4.05 (m, 2H), 3.89-3.86 (m, 1H), 3.66-3.60 (m, 1H), 3.49-3.39 (m, 2H), 2.52-2.49 (m, 1H), 2.14-1.98 (m, 2H), 1.94-1.76 (m, 12H), 1.67-1.64 (m, 2H), 1.41-1.39 (m, 3H).

Preparation Example 22: Synthesis of N-2-adamantyl-4-(1-(pyridine-4-yl)ethyl)morpholine-2-carboxyamide (compound 91)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-pyridineacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ8.57-8.55 (m, 2H), 7.27-7.26 (m, 2H), 6.98-6.96 (m, NH, 1H), 4.09-4.05 (m, 2H), 3.90-3.86 (m, 1H), 3.68-3.62 (m, 1H), 3.46-3.42 (m, 1H), 3.39-3.34 (m, 1H), 2.52-2.49 (m, 1H), 2.12-2.05 (m, 1H), 2.03-1.97 (m, 1H), 1.94-1.76 (m, 12H), 1.72-1.64 (m, 2H), 1.37-1.36 (m, 3H).

Preparation Example 23: Synthesis of N-2-adamantyl-4-(1-(4-fluorophenyl)ethyl)morpholine-2-carboxyamide (compound 92)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-fluoroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ7.28-7.24 (m, 2H), 7.03-6.98 (m, 2H), 6.93-6.91 (m, NH, 1H), 4.08-3.85 (m, 3H), 3.76-3.59 (m, 1H), 3.48-3.43 (m, 1H), 3.37-3.10 (m, 1H), 2.80-2.50 (m, 1H), 2.22-1.96 (m, 1H), 1.94-1.61 (m, 15H), 1.38-1.35 (m, 3H).

Preparation Example 24: Synthesis of N-2-adamantyl-4-(cyano(phenyl)methyl)morpholine-2-carboxyamide (compound 93)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that benzoylcyanide was used.

¹H NMR (400 MHz, CDCl₃) δ7.56-7.54 (m, 2H), 7.46-7.38 (m, 3H), 6.99-6.96 (m, NH, 1H), 4.16-4.13 (m, 1H), 4.10-4.08 (m, 1H), 3.97-3.95 (m, 1H), 3.65-3.58 (m, 1H), 3.52-3.47 (m, 1H), 3.38-3.35 (m, 1H), 2.60-2.54 (m, 1H), 2.41-2.39 (m, 2H), 1.95-1.65 (m, 14H).

Preparation Example 25: Synthesis of N-2-adamantyl-4-(1-(4-cyanophenyl)propyl)morpholine-2-carboxyamide (compound 107)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-propionylbenzonitrile was used.

¹H NMR (400 MHz, CDCl₃) δ 7.64-7.60 (m, 2H), 7.41-7.33 (m, 2H), 6.95-6.88 (m, NH, 1H), 4.08-4.05 (m, 1H), 4.01-3.84 (m, 2H), 3.77-3.59 (m, 1H), 3.45-3.05 (m, 2H), 2.81-2.46 (m, 1H), 2.23-1.47 (m, 18H), 0.81-0.71 (m, 3H).

Preparation Example 26: Synthesis of N-2-adamantyl-4-((6-cyanopyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 96)

2-bromo-5-methylpyridine (5 g, 29.06 mmol) was dissolved in DMF (15 ml), and added with CuCN (5.2 g, 58.12 mmol), followed by reflux-stirring for 12 hours. After the reaction was completed, the organic layer was separated by ammonia water, NaCl, and CH₂Cl₂, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide 5-methylpicolinonitrile (400 mg) mixture.

2-bromo-5-methylpyridine (5 g, 29.06 mmol), benzoyl peroxide (410 mg, 1.692 mmol), and N-bromosuccinimide (3 g, 16.92 mmol) were dissolved in CCl₄ (50 ml), and reflux-stirred for 12 hours. After the reaction was completed, the organic layer was separated by H₂O and EA, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:4) so as to provide 5-(bromomethyl)picolinonitrile (500 mg) mixture.

N-2-adamantyl-morpholine-2-carboxyamide hydrochloride (382 mg, 1.27 mmol) and 5-(bromomethyl)picolinonitrile (500 mg, 2.54 mmol) were dissolved in DMF (10 ml), added with K₂CO₃(526 mg, 3.81 mmol) and KI (632 mg, 3.81 mmol), and stirred at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by H₂O and CH₂Cl₂, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-2-adamantyl-4-((6-cyanopyridine-3-yl)methyl)morpholine-2-carboxyamide (140 mg, 0.36 mmol, 28 %).

¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H),6.96-6.94 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.99-3.96 (m, 1H), 3.79-3.69 (m, 1H), 3.68-3.58 (m, 2H), 3.21-3.18 (m, 1H), 2.65-2.62 (m, 1H), 2.30-2.24 (m, 1H), 2.13-2.08 (m, 1H), 1.92-1.65 (m, 14H).

Preparation Example 27: Synthesis of N-2-adamantyl-4-(1-(4-chlorophenyl)ethyl)morpholine-2-carboxyamide (compound 161)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-chloroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ31-7.24 (m, 4H), 6.97 (br, -NH-), 4.08-4.04 (m, 2H), 3.88-3.84 (m, 1H), 3.65-3.59 (m, 1H), 3.48 (m, 1H), 3.36-3.31 (m, 1H), 2.53 (m, 1H), 2.04-1.64 (m, 14H), 1.36 (d, J = 6.8, 3H).

Preparation Example 28: Synthesis of N-2-adamantyl-4-(1-(6-bromopyridine-3-yl)ethyl)morpholine-2-carboxyamide (compound 162)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-bromo-3-pyridine acetone was used.

¹H NMR (400 MHz, CDCl₃) δ 8.31-8.29 (m, 1H), 7.68-7.54 (m, 1H), 7.47-7.23 (m, 1H), 6.97-6.91 (m, NH, 1H), 4.06-3.87 (m, 3H), 3.74-3.39 (m, 3H), 3.09-3.06 (m, 1H), 2.77-2.74 (m, 1H), 2.26-2.19 (m, 1H), 2.01-1.50 (m, 14H), 1.39-1.37 (m, 3H).

Preparation Example 29: Synthesis of N-2-adamantyl-4-(1-(6-cyanopyridine-3-yl)ethyl)morpholine-2-carboxyamide (compound 163)

¹H NMR (400 MHz, CDCl₃) δ8.31 (m, 1H), 7.68-7.65 (m, 1H), 7.32-7.30 (m, 1H), 6.97-6.95 (m, NH, 1H), 4.08-4.03 (m, 2H), 3.90-3.87 (m, 1H), 3.65-3.59 (m, 1H), 3.45-3.39 (m, 2H), 2.50-2.46 (m, 1H), 2.12-2.06 (m, 1H), 2.03-1.98 (m, 1H), 1.92-1.64 (m, 14H), 1.39-1.37 (m, 3H).

Preparation Example 30: Synthesis of N-2-adamantyl-4-((2-methoxypyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 160)

A desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 2-methoxy-3-pyridine aldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ8.09-8.07 (m, 1H), 7.67-7.65 (m, 1H), 6.98-6.96 (m, NH, 1H), 6.90-6.87 (m, 1H), 4.09-4.05 (m, 2H), 3.98-3.94 (m, 4H), 3.79-3.72 (m, 1H), 3.56-3.55 (m, 2H), 3.27-3.23 (m, 1H), 2.73-2.70 (m, 1H), 2.30-2.24 (m, 1H), 2.11-2.05 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

[Example 3]

Preparation Example 1: Synthesis of N-(adamantane-2-yl)-2-(4-benzylmorpholine-2-yl)acetamide (compound 109)

Epichlorohydrin (153g, 1653 mol) was added to N-benzylethanolamine (50 g, 331 mmol). The resultant mixture was stirred at 50℃ for 1 hour, and vacuum-distillated so as to remove the remaining epichlorohydrin. Then, c-H₂SO₄ (300 ml) was added thereto, followed by reflux for 2 hours. The resultant mixture was cooled to room temperature, and its acidity was adjusted to pH 14 through addition of 10N NaOH aqueous solution. Then, the resultant mixture was extracted (X3) with toluene, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide 4-benzyl-2-(chloromethyl)morpholine compound (18.7 g, 82.8 mmol, 25 %).

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.27 (m, 5H), 3.94 (ddd, J = 2.0, 3.2, 11.6 Hz, 1H), 3.83-3.79 (m, 1H), 3.74 (td, J = 2.4, 11.2 Hz, _1H), 3.56 (s, 2H), 3.54 (dd, J = 5.6, 11.2 Hz, 1H), 3.50 (dd, J = 5.2, 11.6 Hz, 1H), 2.86 (dt, J = 2.0, 11.2 Hz, 1H), 2.69 (dd, J = 1.6, 11.6 Hz, 1H), 2.24 (td, J = 3.2, 11.2 Hz, 1H), 2.05 (t, J = 10.4 Hz, 1H).

4-benzyl-2-(chloromethyl)morpholine (18.7 g, 82.8 mmol) was dissolved in DMF (150 ml), added with NaCN (4.87 g, 99.4 mmol) and tetrabutyl ammonium iodide (36.72 g, 99.4 mmol), and stirred under a reflux condition for 5 hours. Then, the resultant solution was cooled to 25℃, and added with H₂O. The resultant solution was extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide 2-(4-benzylmorpholine-2-yl)acetonitrile compound (15.2 g, 70.38 mmol, 85 %).

¹H NMR (400 MHz, CDCl₃) δ7.37-7.23 (m, 5H), 3.91 (ddd, J = 2.0, 3.2, 11.2 Hz, 1H), 3.86-3.81 (m, 1H), 3.72 (dt, J = 2.4, 11.2 Hz, 1H), 3.55 (dd, J = 12.8, 18.0 Hz, 2H), 2.83 (d, J = 11.2 Hz, 1H), 2.71 (d, J = 8.8 Hz, 1H), 2.54 (d, J = 5.6 Hz, 2H), 2.25 (dt, J = 3.2, 11.2 Hz, 1H), 2.05 (t, J = 10.4 Hz, 1H).

2-(4-benzylmorpholine-2-yl)acetonitrile (15.2 g, 70.38 mmol) was dissolved in MeOH (150 ml), and added with c-H₂SO₄ (30 ml) at 0℃. After the addition of c-H₂SO₄, the mixture was reflux-stirred for 12 hours. The resultant solution was added with 3N NaOH solution so that the acidity can be adjusted to PH 14. Then, the resultant solution was extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide methyl 2-(4-benzylmorpholine-2-yl)acetate compound (14.4 g, 57.71 mmol, 82 %).

¹H NMR (400 MHz, CDCl₃) δ7.35-7.26 (m, 5H), 4.03 (m, 1H), 3.86(ddd, J = 2.0, 3.2, 11.2 Hz, 1H), 3.75-3.70 (m, 4H), 3.54 (s, 1H), 2.81 (d, J = 11.2 Hz, 1H), 2.68 (d, J = 11.6 Hz, 1H), 2.54 (dd, J = 8.0, 15.2 Hz, 2H), 2.20 (m, 1H), 1.97 (d, J = 10.0 Hz, 1H)

Methyl 2-(4-benzylmorpholine-2-yl)acetate (500 mg, 2.00 mmol) was dissolved in 70% MeOH aqueous solution (10 ml), added with KOH (189 mg, 3.37 mmol), and stirred for 12 hours at room temperature. The resultant product was added with 2N HCl so that its acidity can be adjusted to pH 7. Then, vacuum distillation was carried out in such a manner that only 1ml of water remained. The resultant mixture was added with EtOH (10 ml), and the produced solid was removed through filtration, The filtrate was vacuum-distillated so as to provide 2-(4-benzylmorpholine-2-yl)acetic acid compound (418.8 mg, 1.78 mmol, 89 %).

¹H NMR (400 MHz, CDCl₃) δ7.37-7.30 (m, 5H), 4.13-4.05 (m, 1H), 3.91-3.88 (m, 1H), 3.83-3.77 (m, 1H), 3.74 (d, J = 12.8 Hz, 1H), 3.65 (d, J = 12.8 Hz, 1H), 3.01 (d, J = 11.6 Hz, 1H), 2.83(d, J = 11.2 Hz, 1H), 2.56 (dd, J = 7.2, 15.6 Hz, 1H), 2.45 (dd, J = 5.6, 17.2 Hz, 1H), 2.34 (td, J = 3.2, 11.2 Hz, 1H), 2.13 (t, J = 10.4 Hz, 1H).

2-(4-benzylmorpholine-2-yl)acetic acid (148.2 mg, 0.63 mmol) was dissolved in CH₂Cl₂ (4 ml), and added with EDCI (121 mg, 0.63 mmol) and DMAP (77 mg, 0.63 mmol), followed by stirring for 30 minutes. The resultant product was added with 2-adamantane amine hydrochloride (140.8 mg, 0.75 mmol), and stirred at room temperature for 5 hours. The resultant solution was added with H₂O, extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide N-(adamantane-2-yl)-2-(4-benzylmorpholine-2-yl)acetamide compound (169.5 mg, 0.46 mmol, 73 %).

¹H NMR (400 MHz, CDCl₃) δ7.35-7.25 (m, 5H), 7.00 (d, J = 8.0 Hz, -CONH), 4.06-4.04 (m, 1H), 3.94-3.87 (m, 2H), 3.75 (td, J = 2.4, 11.2 Hz, 1H), 3.51 (s, 2H), 2.76-2.69 (m, 2H), 2.41 (dd, J = 8.4, 15.6 Hz, 1H), 2.33 (dd, J = 5.6, 15.6 Hz, 1H), 2.20 (td, J = 3.2, 11.6 Hz, 1H), 1.98 (t, J = 10.8 Hz, 1H), 1.90-1.63 (m, 14H).

N-(adamantane-2-yl)-2-(4-benzylmorpholine-2-yl)acetamide (500 mg, 1.56 mmol) was dissolved in EtOH (10 ml), and added with 10 % Pd/C (50mg). The resultant mixture was stirred under a hydrogen atmosphere for 12 hours, and filtered through celite to remove 10 % Pd/C. Then, N-(adamantane-2-yl)-2-(morpholine-2-yl)acetamide (347.4 mg, 1.25 mmol, 80 %) was obtained.

¹H NMR (400 MHz, DMSO-d ₆) δ7.67 (d, J = 7.2 Hz, -CONH), 3.81 (d, J = 6.8 Hz, 1H), 3.68-3.60 (m, 2H), 3.40 (m, 1H), 2.74-2.53 (m, 3H), 2.36-2.28 (m, 2H), 2.15 (dd, J = 6.0, 18.0 Hz, 1H), 1.98-1.46 (m, 14H).

Preparation Example 2: Synthesis of N-2-adamantyl-2-(4-(3,4-difluorobenzyl)morpholine-2-yl)acetamide (compound 11)

N-2-adamantyl-2-(morpholine-2-yl)acetamide (50 mg, 0.18 mmol) and 3,4-difluorobenzaldehyde (25 mg, 0.18 mmol) were dissolved in DCE (1 ml), added with acetic acid (21 mg, 0.36 mmol), and stirred at room temperature for 10 minutes. Then, sodium triacetoxy borohydride (76 mg, 0.36 mmol) was added thereto, followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by H₂O and CH₂Cl₂, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:2) so as to provide N-2-adamantyl-2-(4-(3,4-difluorobenzyl)morpholine-2-yl)acetamide (48 mg, 0.12 mmol, 66 %).

¹H NMR (400 MHz, CDCl₃) δ7.21-7.17 (m, 1H), 7.16-7.08 (m, 1H), 7.04-7.03 (m, 1H), 6.93-6.91 (m, NH, 1H), 4.07-4.05 (m, 1H), 3.95-3.87 (m, 2H), 3.77-3.71 (m, 1H), 3.45 (s, 2H), 2.73-2.65 (m, 2H), 2.44-2.31 (m, 2H), 2.23-2.16 (m, 1H), 2.01-1.96 (m, 1H), 1.91-1.75 (m, 12H), 1.67-1.60 (m, 2H).

Preparation Example 3: Synthesis of N-2-adamantyl-2-(4-(pyridine-4-yl methyl)morpholine-2-yl)acetamide (compound 12)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-pyridinealdehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.54-8.53 (m, 2H), 7.27-7.25 (m, 2H), 6.91-6.89 (m, NH, 1H), 4.04-4.02 (m, 1H), 2.42-2.29(m, 2H), 2.24-2.17 (m, 1H), 2.03-1.98 (m, 1H), 1.88-1.72 (m, 12H), 1.64-1.60 (m, 2H).

Preparation Example 4: Synthesis of N-2-adamantyl-2-(4-(4-fluorobenzyl)morpholine-2-yl)acetamide (compound 13)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.26(m, 2H), 7.05-6.99 (m, 2H), 6.97-6.95 (m, NH, 1H), 4.06-4.04 (m, 1H), 3.95-3.86 (m, 2H), 3.76-3.70 (m, 1H), 3.47 (s, 2H), 2.73-2.66 (m, 2H), 2.44-2.31 (m, 2H), 2.21-2.15 (m, 1H), 2.00-1.94 (m, 1H), 1.90-1.75 (m, 12H), 1.66-1.63 (m, 2H).

Preparation Example 5: Synthesis of N-2-adamantyl-2-(4-(4-cyclohexylbenzyl)morpholine-2-yl)acetamide (compound 14)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that cyclohexanecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.05-7.03 (m, NH, 1H), 4.07-4.05 (m, 1H), 3.94-3.85 (m, 2H), 3.77-3.71 (m, 1H), 2.72-2.66 (m, 2H), 2.46-2.33 (m, 2H), 2.16-2.07 (m, 3H), 1.92-1.64 (m, 20H), 1.53-1.44 (m, 1H), 1.27-1.12 (m, 3H), 0.90-0.80 (m, 2H).

Preparation Example 6: Synthesis of N-2-adamantyl-2-(4-(4-nitrobenzyl)morpholine-2-yl)acetamide (compound 15)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-nitrobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H),6.87-6.85 (m, NH, 1H), 4.07-4.05 (m, 1H), 3.96-3.90 (m, 2H), 3.79-3.73 (m, 1H), 3.61 (s, 2H), 2.75-2.65 (m, 2H), 2.44-2.31 (m, 2H), 2.28-2.22 (m, 1H), 2.06-2.02 (m, 1H), 1.91-1.75 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 7: Synthesis of N-2-adamantyl-2-(4-(3-methylbenzyl)morpholine-2-yl)acetamide (compound 16)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-methylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.20 (m, 1H), 7.13-7.08 (m, 3H), 7.02-7.00 (m, NH, 1H), 4.06-4.04 (m, 1H), 3.94-3.88 (m, 2H), 3.79-3.72 (m, 1H), 3.48 (s, 2H), 2.76-2.69 (m, 2H), 2.44-2.31 (m, 5H), 2.22-2.16 (m, 1H), 1.99-1.94 (m, 1H), 1.90-1.75 (m, 12H), 1.66-1.63 (m, 2H).

Preparation Example 8: Synthesis of N-2-adamantyl-2-(4-(2-chlorobenzyl)morpholine-2-yl)acetamide (compound 17)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-chlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.47-7.45 (m, 1H), 7.38-7.36 (m, 1H), 7.28-7.19 (m, 2H), 6.98-6.96 (m, NH, 1H), 4.07-4.05 (m, 1H), 3.96-3.89 (m, 2H), 3.79-3.73 (m, 1H), 3.63 (s, 2H), 2.78-2.71 (m, 2H), 2.46-2.40 (m, 1H), 2.36-2.35 (m, 1H), 2.33-2.29 (m, 1H), 2.12-2.06 (m, 1H), 1.91-1.75 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 9: Synthesis of N-2-adamantyl-2-(4-(3-chlorobenzyl)morpholine-2-yl)acetamide (compound 18)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-chlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.19 (m, 4H), 6.96-6.95 (m, NH, 1H), 4.05-4.03 (m, 1H), 3.93-3.88 (m, 2H), 3.77-3.70 (m, 1H), 3.47 (s, 2H), 2.73-2.65 (m, 2H), 2.43-2.30 (m, 2H), 2.22-2.15 (m, 1H), 2.00-1.95 (m, 1H), 1.89-1.74 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 10: Synthesis of N-2-adamantyl-2-(4-(4-chlorobenzyl)morpholine-2-yl)acetamide (compound 19)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-chlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.28-7.26 (m, 4H), 6.95-6.93 (m, NH, 1H), 4.04-4.03 (m, 1H), 3.92-3.90 (m, 2H), 3.75-3.69 (m, 1H), 3.46 (s, 2H), 2.72-2.64 (m, 2H), 2.43-2.30 (m, 2H), 2.20-2.15 (m, 1H), 1.99-1.94 (m, 1H), 1.89-1.74 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 11: Synthesis of N-2-adamantyl-2-(4-(4-cyanobenzyl)morpholine-2-yl)acetamide (compound 20)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-cyanobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 6.8 Hz, 2H), 7.45 (d, J = 6.8 Hz, 2H),6.88 (m, NH, 1H), 4.04 (m, 1H), 3.90 (m, 2H), 3.76-3.70 (m, 1H), 3.54 (s, 2H), 2.71-2.62 (m, 2H), 2.42-2.30 (m, 2H), 2.24-2.19 (m, 1H), 2.03-1.98 (m, 1H), 1.89-1.74 (m, 12H), 1.65-1.62 (m, 2H).

[Example 4]

Preparation Example 1: Synthesis of 2-(4-(4-cyanobenzyl)morpholine-2-yl)-N-2-adamantyl-2-methylpropanamide (compound 21)

Methyl isobutyrate (500 mg, 4.9 mmol) was dissolved in THF (10 ml), and slowly added with 2M LDA (2.95 ml, 5.9 mmol) at -78℃. The temperature of the mixture was raised to 0℃, and then after 30-min stirring, it was lowered to -78℃. The resultant mixture was slowly added with N-Boc-2-aminoacetealdehyde (936 mg, 5.9 mmol) dissolved in THF (5 ml). The mixture was stirred at -78℃ for 3 hours, and the reaction was terminated through addition of H₂O. Then, the temperature was slowly raised to room temperature. The resultant mixture was extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide methyl 4-(t-butoxycarbonyl)amino)-3-hydroxy-2,2-dimethylbutanoate compound (768 mg, 2.94 mmol, 60 %).

¹H NMR (400 MHz, CDCl₃) δ4.98 (bs, -NH), 3.75-3.68 (m, 4H), 3.43 (m, 1H), 3.27 (d, J = 5.6 Hz, -OH), 3.03-2.96 (m, 1H), 1.49 (s, 9H), 1.28 (s, 3H), 1.23 (s, 3H).

Methyl 4-(t-butoxycarbonyl)amino)-3-hydroxy-2,2-dimethylbutanoate compound (768 mg, 2.94 mmol) was dissolved in ether (10 ml), and slowly added with 4N HCl in 1,4-dioxane (2.5 ml, 10 mmol). At room temperature, the mixture was stirred for 2 hours, and the solvent was removed through vacuum distillation. The resultant mixture was recrystallized in ether/MeOH so as to provide methyl 4-amino-3-hydroxy-2,2-dimethylbutanoate hydrochloride compound (552 mg, 2.79 mmol, 95 %).

¹H NMR (400 MHz, DMSO-d ₆) δ7.99 (bs, 3H, -NH₃), 5.71 (bs, -OH), 3.84 (m, 1H), 3.61 (s, 3H), 2.84 (m, 1H), 2.64 (m, 1H), 1.10 (s, 3H), 1.07 (s, 3H).

Methyl 4-amino-3-hydroxy-2,2-dimethylbutanoate hydrochloride compound (106.7 mg, 0.54 mmol) was dissolved in CH₂Cl₂ (4 ml), and added with 2-nitrobenzenesulfonyl chloride (119.7 mg, 0.54 mmol) and triethylamine (120.2 mg, 1.19 mmol), followed by stirring at room temperature for 3 hours. The resultant solution was added with H₂O, extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide methyl 3-hydroxy-2,2-dimethyl-4-(2-nitrophenylsulfonamido)butanoate (180.1 mg, 0.52 mmol, 94 %).

¹H NMR (400 MHz, CDCl₃) δ8.14-8.13 (m, 1H), 7.91-7.89 (m, 1H), 7.79-7.75 (m, 2H), 5.84 (d, J = 8.0 Hz, -NH), 3.78-3.74 (m, 1H), 3.71 (s, 3H), 3.41-3.35 (m, 1H), 3.12 (d, J = 6.0 Hz, -OH), 3.01-2.95 (m, 1H), 1.24 (s, 3H), 1.19 (s, 3H).

Methyl 3-hydroxy-2,2-dimethyl-4-(2-nitrophenylsulfonamido)butanoate (520 mg, 1.50 mmol) was dissolved in DMF (10 ml), and added with K₂CO₃ (415 mg, 3.00 mmol) and 1,2-dichloroethane (1.3 ml, 0.1.5 mmol), followed by stirring at room temperature for 12 hours. Then, the resultant mixture was cooled to 0℃, and added with 60% NaH (158 mg, 3.00 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H₂O, extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide methyl 2-methyl-2-(4-((2-nitrophenyl)sulfonyl)morpholine-2-yl)propanoate compound (407.7 mg, 1.10 mmol, 73 %).

¹H NMR (400 MHz, CDCl₃) δ8.00-7.97 (m, 1H), 7.78-7.70 (m, 2H), 7.67-7.64 (m, 1H), 3.87-3.95 (m, 1H), 3.73-3.60 (m, 7H), 2.89 (td, J = 3.2, 12.8 Hz, 1H), 2.80 (dd, J = 10.4, 11.6 Hz, 1H), 1.22 (s, 3H), 1.21 (s, 3H).

Methyl 2-methyl-2-(4-((2-nitrophenyl)sulfonyl)morpholine-2-yl)propanoate (141.5 mg, 0.38 mmol) was dissolved in THF (3 ml) and MeOH (3 ml), and added with LiOH (84.5 mg, 2.0 mmol) dissolved in H₂O (1 ml), followed by stirring at room temperature for 12 hours. The resultant solution was concentrated through vacuum distillation, acidified by the addition of 2N-HCl aqueous solution to pH 2, and extracted with CH₂Cl₂. The organic layer was dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, 2-methyl-2-(4-((2-nitrophenyl)sulfonyl)morpholine-2-yl)propanoic acid compound (129.4 mg, 0.36 mmol, 95 %) was obtained.

¹H NMR (400 MHz, DMSO-d ₆) δ12.43 (bs, -COOH), 8.05-8.00 (m, 2H), 7.94 (td, J = 1.6, 7.6 Hz, 1H), 7.88 (td, J = 1.6, 7.6 Hz, 1H), 3.95 (dd, J = 2.4, 11.2 Hz, 1H), 3.62-3.45 (m, 5H), 2.74-2.63 (m, 2H),

2-methyl-2-(4-((2-nitrophenyl)sulfonyl)morpholine-2-yl)propanoic acid (225.8 mg, 0.63 mmol) was dissolved in CH₂Cl₂ (5 ml), and added with EDCI (121 mg, 0.63 mmol) and DMAP (77 mg, 0.63 mmol), followed by stirring for 30 minutes. Then, the resultant product was added with 2-adamantane amine hydrochloride (140.8 mg, 0.75 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H₂O, extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide N-(adamantane-2-yl)-2-methyl-2-(4-((2-nitrophenyl)sulfonyl)morpholine-2-yl)propanamide compound (257.1 mg, 0.52 mmol, 83 %).

¹H NMR (400 MHz, CDCl₃) δ7.97 (dd, J = 1.6, 7.6 Hz, 1H), 7.77, 7.70 (m, 2H), 7.66-7.64 (m, 1H), 6.92 (d, J = 8.0 Hz, -CONH), 4.10-4.06 (m, 1H), 3.99 (m, 1H), 3.80-3.67 (m, 3H), 3.46 (dd, J = 2.4, 10.4 Hz, 1H), 2.95-2.88 (m, 1H), 2.72 (dd, J = 10.8, 12.4 Hz, 1H), 1.85-1.52 (m, 14H), 1.28 (s, 3H), 1.19 (s, 3H).

N-(adamantane-2-yl)-2-methyl-2-(4-((2-nitrophenyl)sulfonyl)morpholine-2-yl)propanamide (380 mg, 0.77 mmol) was dissolved in DMF (15 ml), and added with K₂CO₃ (213 mg, 1.54 mmol) and benzenethiol (238 ul, 2.32 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H₂O, extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was dissolved in 1,4-dioxane, and slowly added with 4N HCl in 1,4-dioxane (0.5 ml, 2 mmol). At room temperature, the mixture was stirred for 2 hours, and the solvent was removed through vacuum distillation. The resultant mixture was recrystallized in ether/MeOH so as to provide N-(adamantane-2-yl)-2-methyl-2-(morpholine-2-yl)propanamide hydrochloride compound (224 mg, 0.65 mmol, 85 %).

¹H NMR (400 MHz, DMSO-d ₆) δ9.45 (bs, -NH₂), 6.83 (d, J = 7.2 Hz, -CONH), 4.07-4.03 (m, 1H), 3.84-3.72 (m, 3H), 3.15 (m, 1H), 2.88 (m, 1H), 2.75 (m, 1H), 1.86-1.52 (m, 14H), 1.12 (s, 3H), 1.11 (s, 3H).

N-2-adamantyl-2-methyl-2-(morpholine-2-yl)propanamide hydro chloride (50 mg, 0.18 mmol) and 4-cyanobenzaldehyde(40 mg, 0.3 mmol) were dissolved in DCE (1 ml), and added with acetic acid (36 mg, 0.6 mmol), followed by stirring at room temperature for 10 minutes. The resultant mixture was added with sodium triacetoxy borohydride (127 mg, 0.6 mmol), and stirred at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by H₂O and CH₂Cl₂, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:2) so as to provide 2-(4-(4-cyanobenzyl)morpholine-2-yl)-N-2-adamantyl-2-methylpropanamide (54 mg, 0.12 mmol, 43 %).

¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H),4.05-4.03 (m, 1H), 4.00-3.97 (m, 1H), 3.74-3.68 (m, 1H), 3.61-3.58 (m, 1H), 3.52-3.45 (m, 2H), 2.85-2.82 (m, 1H), 2.63-2.60 (m, 1H), 2.18-2.12 (m, 1H), 2.05-2.00 (m, 1H), 1.88-1.73 (m, 12H), 1.67-1.64 (m, 2H), 1.26 (s, 3H), 1.11 (s, 3H).

[Example 5]

Preparation Example 1: Synthesis of N-2-adamantyl-4-(4-cyanobenzyl)morpholine-2-carboxyamide (compound 22)

¹H NMR (400 MHz, CDCl₃) δ7.61 (m, 2H), 7.46 (m, 2H), 6.95 (m, NH, 1H), 4.03-3.94 (m, 3H), 3.71 (m, 1H), 3.58-3.57 (m, 2H), 3.20-3.18 (m, 1H), 2.64-2.62 (m, 1H), 2.21 (m, 1H), 2.04 (m, 1H), 1.84-1.66 (m, 14H).

Preparation Example 2: Synthesis of N-2-adamantyl-4-(4-chlorobenzyl)morpholine-2-carboxyamide (compound 23)

¹H NMR (400 MHz, CDCl₃) δ7.32-7.25 (m, 4H), 6.97-6.95 (m, NH, 1H), 4.06-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.74-3.68 (m, 1H), 3.57-3.45 (m, 2H), 3.24-3.21 (m, 1H), 2.66-2.63 (m, 1H), 2.19-2.13 (m, 1H), 2.03-1.98 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 3: Synthesis of N-2-adamantyl-4-(3-chlorobenzyl)morpholine-2-carboxyamide (compound 24)

¹H NMR (400 MHz, CDCl₃) δ 7.34 (m, 1H), 7.26-7.25 (m, 2H), 7.23-7.19 (m, 1H), 6.97-6.95 (m, Nh, 1H), 4.08-4.04 (m, 2H), 3.97-3.94 (m, 1H), 3.76-3.70 (m, 1H), 3.57-3.45 (m, 2H), 3.25-3.22 (m, 1H), 2.68-2.65 (m, 1H), 2.21-2.15 (m, 1H), 2.04-1.99 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 4: Synthesis of N-2-adamantyl-4-(cyclohexanemethyl)morpholine-2-carboxyamide (compound 25)

¹H NMR (400 MHz, CDCl₃) δ6.97-6.95 (m, NH, 1H), 4.06-3.99 (m, 2H), 3.95-3.91 (m, 1H), 3.75-3.69 (m, 1H), 3.22-3.18 (m, 1H), 2.67-2.64 (m, 1H), 2.16-2.07 (m, 3H), 1.93-1.63 (m, 19H), 1.55-1.47 (m, 1H), 1.29-1.14 (m, 4H), 0.96-0.81 (m, 2H).

Preparation Example 5: Synthesis of N-2-adamantyl-4-(4-bromobenzyl)morpholine-2-carboxyamide (compound 26)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-bromobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H),6.96-6.95 (m, NH, 1H), 4.06-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.73-3.67 (m, 1H), 3.53-3.43 (m, 2H), 3.23-3.21 (m, 1H), 2.66-2.63 (m, 1H), 2.19-2.13 (m, 1H), 2.03-1.98 (m, 1H), 1.96-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 6: Synthesis of N-2-adamantyl-4-(naphthalene-2-yl methyl)morpholine-2-carboxyamide (compound 27)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-naphthaaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.83-7.81 (m, 3H), 7.73 (m, 1H), 7.51-7.47 (m, 3H), 6.98-6.97 (m, NH, 1H), 4.10-4.05 (m, 2H), 3.96-3.93 (m, 1H), 3.79-3.63 (m, 3H), 3.33-3.30 (m, 1H), 2.72-2.70 (m, 1H), 2.24-2.18 (m, 1H), 2.11-2.06 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 7: Synthesis of N-2-adamantyl-4-(4-morpholinebenzyl)morpholine-2-carboxyamide (compound 28)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-morpholinobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, J = 8.0 Hz, 2H), 6.97-6.95 (m, NH, 1H), 6.88 (d, J = 8.0 Hz, 2H),4.05-4.02 (m, 2H), 3.95-3.92 (m, 1H), 3.89-3.87 (m, 4H), 3.74-3.68 (m, 1H), 3.53-3.43 (m, 2H), 3.26-3.23 (m, 1H), 3.18-3.15 (m, 4H), 2.69-2.66 (m, 1H), 2.18-2.11 (m, 1H), 2.00-1.94 (m, 1H), 1.93-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 8: Synthesis of N-2-adamantyl-4-((6-methoxynaphthalene -2-yl)methyl)morpholine-2-carboxyamide (compound 29)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 6-methoxy-2-naphthabenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.72-7.70 (m, 2H), 7.65 (m, 1H), 7.46-7.44 (m, 1H), 7.16-7.14 (m, 2H), 6.98-6.98 (m, NH, 1H), 4.10-4.05 (m, 2H), 3.94 (m, 4H), 3.75-3.59 (m, 3H), 3.32-3.30 (m, 1H), 2.72-2.69 (m, 1H), 2.23-2.16 (m, 1H), 2.09-2.04 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.65 (m, 2H).

Preparation Example 9: Synthesis of N-2-adamantyl-4-(4-methylbenzyl)morpholine-2-carboxyamide (compound 30)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-methylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.20 (d, J = 7.6 Hz, 2H), 7.13 (d, J = 7.6 Hz, 2H), 6.97-6.95 (m, NH, 1H), 4.07-4.03 (m, 2H), 3.95-3.92 (m, 1H), 3.74-3.68 (m, 1H), 3.58-3.44 (m, 2H), 3.27-3.24 (m, 1H), 2.69-2.66 (m, 1H), 2.35 (s, 3H), 2.18-2.11 (m, 1H), 2.02-1.97 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 10: Synthesis of N-2-adamantyl-4-(4-(methylthio)benzyl)morpholine-2-carboxyamide (compound 31)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-(methylthio)benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.28-7.21 (m, 4H), 6.98-6.95 (m, NH, 1H), 4.06-4.03 (m, 2H), 3.95-3.92 (m, 1H), 3.74-3.68 (m, 1H), 3.56-3.44 (m, 2H), 3.25-3.22 (m, 1H), 2.68-2.65 (m, 1H), 2.49 (s, 3H), 2.18-2.12 (m, 1H), 2.02-1.97 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 11: Synthesis of N-2-adamantyl-4-(3-methylbenzyl)morpholine-2-carboxyamide (compound 32)

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.19 (m, 1H), 7.13-7.07 (m, 3H), 6.98-6.96 (m, NH, 1H), 4.80-4.04 (m, 2H), 3.96-3.93 (m, 1H), 3.76-3.70 (m, 1H), 3.57-3.45 (m, 2H), 3.28-3.25 (m, 1H), 2.71-2.68 (m, 1H), 2.36 (s, 3H), 2.19-2.13 (m, 1H), 2.02-1.97 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 12: Synthesis of N-2-adamantyl-4-(2-chlorobenzyl)morpholine-2-carboxyamide (compound 33)

¹H NMR (400 MHz, CDCl₃) δ7.48-7.46 (m, 1H), 7.37-7.35 (m, 1H), 7.28-7.19 (m, 2H), 6.98-6.96 (m, NH, 1H), 4.08-4.05 (m, 2H), 3.98-3.95 (m, 1H), 3.79-3.70 (m, 1H), 3.66 (s, 2H), 3.29-3.26 (m, 1H), 2.73-2.70 (m, 1H), 2.33-2.27 (m, 1H), 2.14-2.08 (m, 1H), 1.93-1.76 (m, 12H), 1.68-1.64 (m, 2H).

Preparation Example 13: Synthesis of N-2-adamantyl-4((6-methylpyridine-2-yl)methyl)morpholine-2-carboxyamide (compound 34)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 6-methyl-2-pyritincarboxyaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.57-7.54 (m, 1H), 7.26-7.24 (m, 1H), 7.05-7.03 (m, 1H), 6.97-6.95 (m, NH, 1H), 4.11-4.07 (m, 1H), 4.06-4.04 (m, 1H), 3.98-3.95 (m, 1H), 3.81-3.75 (m, 1H), 3.67 (m, 2H), 3.26-3.23 (m, 1H), 2.77-2.74 (m, 1H), 2.55 (s, 3H), 2.34-2.27 (m, 1H), 2.11-2.05 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 14: Synthesis of N-2-adamantyl-4(3-(trifluoromethyl)benzyl)morpholine-2-carboxyamide (compound 35)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-(trifluoromethyl)benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.59 (m, 1H), 7.55-7.53 (m, 2H), 7.47-7.43 (m, 1H), 6.97-6.95 (m, NH, 1H), 4.8-4.05 (m, 2H), 3.98-3.94 (m, 1H), 3.76-3.70 (m, 1H), 3.64-3.53 (m, 2H), 3.25-3.22 (m, 1H), 2.68-2.64 (m, 1H), 2.23-2.17 (m, 1H), 2.07-2.02 (m, 1H), 1.92-1.76 (m, 12H), 1.68-1.64 (m, 2H).

Preparation Example 15: Synthesis of N-2-adamantyl-4(4-(trifluoromethyl)benzyl)morpholine-2-carboxyamide (compound 36)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-(trifluoromethyl)benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.58 (m, 2H), 7.46 (m, 2H), 6.96 (m, NH, 1H_, 4.05 (m, 2H), 3.97-3.94 (m, 1H), 3.78-3.72 (m, 1H), 3.64-3.54 (m, 2H), 3.24-3.21 (m, 1H), 2.67-2.64 (m, 1H), 2.20 (m, 1H), 2.07-2.02 (m, 1H), 1.91-1.67 (m, 14H).

Preparation Example 16: Synthesis of N-2-adamantyl-4-(biphenyl-4-yl methyl)morpholine-2-carboxyamide (compound 37)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that biphenyl-4-carboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.61-7.55 (m, 4H), 7.47-7.34 (m, 5H), 6.99-6.97 (m, NH, 1H), 4.10-4.05 (m, 2H), 3.98-3.95 (m, 1H), 3.79-3.72 (m, 1H), 3.65-3.53 (m, 2H), 3.31-3.29 (m, 1H), 2.75-2.72 (m, 1H), 2.24-2.17 (m, 1H), 2.07-2.02 (m, 1H), 1.93-1.76 (m, 12H), 1.68-1.65 (m, 2H).

Preparation Example 17: Synthesis of methyl 4-((2-(N-2-adamantylcarbamoyl)morpholino)methyl)benzoate (compound 38)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that methyl 4-formylbenzoate was used.

¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.97-6.95 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.96-3.93 (m, 4H), 3.75-3.69 (m, 1H), 3.66-3.52 (m, 2H), 3.26-3.23 (m, 1H), 2.67-2.63 (m, 1H), 2.22-2.16 (m, 1H), 2.07-2.02 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 18: Synthesis of 4-((2-(N-2-adamantylcarbamoyl)morpholino)methyl)benzoic acid hydrochloride (compound 39)

A desired compound was obtained in the same manner as described in Preparation Example 7 in Example 2 except that methyl 4-formylbenzoate was used.

¹H NMR (400 MHz, DMSO-d ₆) δ 13.20 (br, NH, 1H), 11.75 (br, OH, 1H), 8.01-7.99 (m, 2H), 7.75-7.73 (m, 2H), 7.67-7.58 (m, NH, 1H), 4.44 (m, 3H), 4.10-3.82 (m, 3H), 3.24-2.94 (m, 4H), 1.91-1.68 (m, 12H), 1.53-1.49 (m, 2H).

Preparation Example 19: Synthesis of N-2-adamantyl-4-(4-fluorobenzyl)morpholine-2-carboxyamide (compound 40)

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.27 (m, 2H), 7.03-6.99 (m, 2H), 6.97-6.95 (m, NH, 1H), 4.06-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.74-3.68 (m, 1H), 3.56-3.45 (m, 2H), 3.25-3.22 (m, 1H), 2.67-2.64 (m, 1H), 2.19-2.13 (m, 1H), 2.02-1.97 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 20: Synthesis of 4-((1H-indole-5-yl)methyl)-N-2-adamantylmorpholine-2-carboxyamide (compound 41)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 1H-indole-5-carboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.47 (br, NH, 1H), 7.55 (s, 1H), 7.33-7.28 (m, 1H), 7.20-7.14 (m, 2H), 7.01-6.99 (m, NH, 1H), 6.52-6.51 (m, 1H), 4.10-4.06 (m, 2H), 3.95-3.91 (m, 1H), 3.75-3.69 (m, 2H), 3.61-3.58 (m, 1H), 3.34-3.31 (m, 1H), 2.74-2.71 (m, 1H), 2.21-2.15 (m, 1H), 2.08-2.02 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 21: Synthesis of N-2-adamantyl-4-((2,3-dihydrobenzo[b][1,4]dioxine-6-yl)methyl)morpholine-2-carboxyamide (compound 42)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2,3-dihydrobenzo[b][1,4]dioxine-6-carboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 6.97-6.95 (m, NH, 1H), 6.84-6.76 (m, 3H), 4.26 (s, 4H), 4.05-4.03 (m, 2H), 3.95-3.92 (m, 1H), 3.74-3.68 (m, 1H), 3.48-3.38 (m, 2H), 3.24-3.22 (m, 1H), 2.69-2.67 (m, 1H), 2.17-2.11 (m, 1H), 1.99-1.63 (m, 15H).

Preparation Example 22: Synthesis of N-2-adamantyl-4-((2-fluoropyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 43)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-fluoro-3-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.14-8.13 (m, 1H), 7.88-7.83 (m, 1H), 7.21-7.17 (m, 1H), 6.96-6.94 (m, NH, 1H), 4.06-4.03(m, 2H), 3.99-3.95 (m, 1H), 3.75-3.69 (m, 1H), 3.60 (s, 3H), 3.22-3.20 (m, 1H), 2.70-2.67 (m, 1H), 2.33-2.26 (m, 1H), 2.12-2.05 (m, 1H), 1.91-1.75 (m, 12H), 1.67-1.63 (m, 2H).

Preparation Example 23: Synthesis of N-2-adamantyl-4-((4-bromopyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 44)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-bromo-3-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ8.30 (m, 1H), 7.58-7.56 (m, 1H), 7.48-7.46 (m, 1H), 6.96-6.94 (m, NH, 1H), 4.05-4.02 (m, 2H), 3.98-3.94 (m, 1H), 3.73-3.67 (m, 1H), 3.57-3.45 (m, 2H), 3.22-3.19 (m, 1H), 2.64-2.62 (m, 1H), 2.23-2.17 (m, 1H), 2.08-2.03 (m, 1H), 1.92-1.76 (m, 12H), 1.68-1.64 (m, 2H).

Preparation Example 24: Synthesis of N-2-adamantyl-4-((5-bromopyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 45)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 5-bromo-3-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.63 (m, 1H), 8.46 (m, 1H), 7.86 (m, 1H), 6.97-6.95 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.99-3.96 (m, 1H), 3.76-3.70 (m, 1H), 3.59-3.48 (m, 2H), 3.24-3.21 (m, 1H), 2.66-2.64 (m, 1H), 2.25-2.22 (m, 1H), 2.09-2.03 (m, 1H), 1.92-1.76 (m, 12H), 1.68-1.65 (m, 2H).

Preparation Example 25: Synthesis of N-2-adamantyl-4-((2-bromopyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 46)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-bromo-3-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.30-8.28 (m, 1H), 7.83-7.81 (m, 1H), 7.30-7.27 (m, 1H), 6.98-6.96 (m, NH, 1H), 4.08-4.05 (m, 2H), 4.01-3.97 (m, 1H), 3.78-3.72 (m, 1H), 3.63 (s, 2H), 3.25-3.21 (m, 1H), 2.72-2.69 (m, 1H), 2.41-2.35 (m, 1H), 2.21-2.15 (m, 1H), 1.93-1.77 (m, 12H), 1.69-1.65 (m, 2H).

Preparation Example 26: Synthesis of N-2-adamantyl-4-((4-trifluoromethylpyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 47)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-trifluoromethyl-3-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.68 (m, 1H), 7.90-7.88 (m, 1H), 7.70-7.67 (m, 1H), 6.97-6.95 (m, NH, 1H), 4.15-4.05 (m, 2H), 4.00-3.96 (m, 1H), 3.76-3.58 (m, 3H), 3.24-3.20 (m, 1H), 2.66-2.63 (m, 1H), 2.29-2.22 (m, 1H), 2.13-2.08 (m, 1H), 1.92-1.77 (m, 12H), 1.68-1.65 (m, 2H).

Preparation Example 27: Synthesis of N-2-adamantyl-4-(pyridine-3-ylmethyl)morpholine-2-carboxyamide (compound 48)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.57-8.53 (m, 2H), 7.69-7.67 (m, 1H), 7.33-7.26 (m, 1H), 6.96-6.95 (m, NH, 1H), 4.06-4.04 (m, 2H), 3.97-3.94 (m, 1H), 3.74-3.68 (m, 1H), 3.62-3.50 (m, 2H), 3.25-3.22 (m, 1H), 2.67-2.64 (m, 1H), 2.23-2.17 (m, 1H), 2.08-2.03 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 28: Synthesis of N-2-adamantyl-4-(pyridine-4-ylmethyl)morpholine-2-carboxyamide (compound 49)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.57-8.56 (m, 2H), 7.29-7.27 (m, 2H), 6.96-6.94 (m, NH, 1H), 4.09-4.05 (m, 2H), 3.98-3.95 (m, 1H), 3.77-3.71 (m, 1H), 3.61-3.48 (m, 2H), 3.24-3.22 (m, 1H), 2.67-2.63 (m, 1H), 2.25-2.19 (m, 1H), 2.10-2.04 (m, 1H), 1.92-1.76 (m, 12H), 1.68-1.65 (m, 2H).

Preparation Example 29: Synthesis of N-2-adamantyl-4-(pyridine-2-ylmethyl)morpholine-2-carboxyamide (compound 50)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ8.59-8.57 (m, 1H), 7.72-7.65 (m, 1H), 7.44-7.42 (m, 1H), 7.25-7.17 (m, 1H), 6.97-6.95 (m, NH, 1H), 4.12-4.08 (m, 1H), 4.06-4.04 (m, 1H), 3.98-3.95 (m, 1H), 3.82-3.76 (m, 1H), 3.71 (s, 2H), 3.27-3.24 (m, 1H), 2.76-2.73 (m, 1H), 2.35-2.29 (m, 1H), 2.13-2.07 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 30: Synthesis of 4-((1H-pyrrole-2-yl)methyl)-N-2-adamantylmorpholine-2-carboxyamide (compound 51)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 1H-pyrrole-2-carboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ8.45 (br, NH, 1H), 6.97-6.95 (m, NH, 1H), 6.78-6.76 (m, 1H), 6.14-6.12 (m, 1H), 6.04 (m, 1H), 4.07-4.02 (m, 2H), 3.98-3.93 (m, 1H), 3.72-3.65 (m, 1H), 3.63-3.60 (m, 1H), 3.50-3.47 (m, 1H), 3.23-3.20 (m, 1H), 2.66-2.63 (m, 1H0, 2.19-2.12 (m, 1H), 2.10-2.05 (m, 1H), 1.93-1.76 (m, 12H), 1.68-1.64 (m, 2H).

Preparation Example 31: Synthesis of N-2-adamantyl-4-((6-methoxypyridine-2-yl)methyl)morpholine-2-carboxyamide (compound 52)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 6-methoxypicolinealdehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.53 (m, 1H), 7.01-6.96 (m, 2H), 6.63-6.61 (m, 1H), 4.11-4.05 (m, 2H), 3.98-3.95 (m, 1H), 3.92 (s, 3H), 3.80-3.74 (m, 1H), 3.64-3.63 (m, 2H), 3.34-3.31 (m, 1H), 2.80-2.78 (m, 1H), 2.37-2.31 (m, 1H), 2.16-2.10 (m, 1H), 1.93-1.76 (m, 12H), 1.67-1.63 (m, 2H).

Preparation Example 32: Synthesis of N-2-adamantyl-4-((6-methoxypyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 53)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-methoxy-3-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (m, 1H), 7.59-7.56 (m, 1H), 6.96-6.94 (m, NH, 1H), 6.74-6.72 (m, 1H), 4.06-4.01 (m, 2H), 3.96-3.94 (m, 4H), 3.72-3.66 (m, 1H), 3.53-3.41 (m, 2H), 3.24-3.21 (m, 1H), 2.66-2.63 (m, 1H), 2.19-2.13 (m, 1H), 2.03-1.98 (m, 1H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 33: Synthesis of N-2-adamantyl-4-((1-methyl-1H-pyrrole-2-yl) methyl)morpholine-2-carboxyamide (compound 54)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 1-methyl-1H-pyrrole-2-carboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ6.97-6.95 (m, NH, 1H), 6.60-6.59 (m, 1H), 6.02-5.99 (m, 2H), 4.06-4.04 (m, 1H), 4.02-3.99 (m, 1H), 3.93-3.91 (m, 1H), 3.65 (s, 3H), 3.65-3.59 (m, 1H), 3.56-3.53 (m, 1H), 3.38-3.35 (m, 1H), 3.26-3.23 (m, 1H), 2.64-2.62 (m, 1H), 2.10-1.97 (m, 2H), 1.92-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 34: Synthesis of N-2-adamantyl-4-((3-bromopyridine-4-yl)methyl)morpholine-2-carboxyamide (compound 55)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-bromoisonicotinaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ8.68 (m, 1H), 8.50-8.49 (m, 1H), 7.50-7.48 (m, 1H), 6.98-6.96 (m, NH, 1H), 4.13-4.05 (m, 2H), 4.01-3.98 (m, 1H), 3.80-3.74 (m, 1H), 3.63 (s, 2H), 3.25-3.22 (m, 1H), 2.71-2.68 (m, 1H), 2.39-2.33 (m, 1H), 2.21-2.16 (m, 1H), 1.93-1.77 (m, 12H), 1.68-1.65 (m, 2H).

Preparation Example 35: Synthesis of N-2-adamantyl-4-((3-methylpyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 56)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-methyl-3-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.41-8.40 (m, 1H), 7.57-7.54 (m, 1H), 7.19-7.12 (m, 1H), 6.96-6.94 (m, NH, 1H), 4.15-4.02 (m, 2H), 3.96-3.92 (m, 1H), 3.78-3.67 (m, 1H), 3.57-3.46 (m, 2H), 3.24-3.19 (m, 1H), 2.67-2.63 (m, 1H), 2.56 (s, 3H), 2.21-2.13 (m, 1H), 2.05-2.00 (m, 1H), 1.92-1.76 (m, 12H), 1.69-1.64 (m, 2H).

Preparation Example 36: Synthesis of N-2-adamantyl-4-(3-cyanobenzyl)morpholine-2-carboxyamide (compound 57)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-cyanobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.66 (s, 1H), 7.59-7.57 (m, 2H), 7.46-7.42 (m, 1H), 6.97-6.95 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.99-3.95 (m, 1H), 3.76-3.70 (m, 1H), 3.60-3.51 (m, 2H), 3.22-3.19 (m, 1H), 2.66-2.63 (m, 1H), 2.25-2.19 (m, 1H), 2.07-2.01 (m, 1H), 1.92-1.65 (m, 14H).

Preparation Example 37: Synthesis of N-2-adamantyl-4-((4,6-dichloropyrimidine-5-yl)methyl)morpholine-2-carboxyamide (compound 58)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4,6-dichloropyrimidine-5-carboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ8.44 (s, 1H), 7.02-6.97 (m, NH, 1H), 4.76-4.68 (m, 2H), 4.53-4.49 (m, 1H), 4.16-4.07 (m, 3H), 3.85-3.79 (m, 1H), 3.40-3.33 (m, 1H), 3.30-3.27 (m, 1H), 2.69-2.66 (m, 1H), 1.95-1.77 (m, 12H), 1.70-1.67 (m, 2H).

Preparation Example 38: Synthesis of N-2-adamantyl-4-((3-methylpyridine-2-yl) methyl)morpholine-2-carboxyamide (compound 59)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-methylpicolinealdehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J = 4.0 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.12 (dd, J = 7.2 Hz, 4.0 Hz, 1H), 6.97-6.95 (m, NH, 1H), 4.05-4.02 (m, 2H), 3.94-3.91 (m, 1H), 3.76-3.61 (m, 3H), 3.22-3.19 (m, 1H), 2.67-2.64 (m, 1H), 2.42 (s, 3H), 2.33-2.26 (m, 1H), 2.15-2.10 (m, 1H), 1.92-1.65 (m, 14H).

Preparation Example 39: Synthesis of N-2-adamantyl-4-(2-cyanobenzyl)morpholine-2-carboxyamide (compound 60)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-cyanobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.67-7.65 (m, 1H), 7.59-7.54 (m, 2H), 7.40-7.36 (m, 1H), 6.97-6.95 (m, NH, 1H), 4.06-4.02 (m, 2H), 3.99-3.96 (m, 1H), 3.82-3.73 (m, 2H), 3.70-3.66 (m, 1H), 3.19-3.17 (m, 1H), 2.75-2.73 (m, 1H), 2.40-2.34 (m, 1H), 2.12-2.06 (m, 1H), 1.92-1.76 (m, 12H), 1.68-1.64 (m, 2H).

Preparation Example 40: Synthesis of N-2-adamantyl-4-(3-chlorobenzyl)morpholine-2-carboxyamide hydrochloride (compound 61)

N-2-adamantyl-4-(3-chlorobenzyl)morpholine-2-carboxyamide (100 mg, 0.25 mmol) was dissolved in DCM (30 ml), and added with 1,4-dioxane (11 mg, 0.3 mmol) including 4M HCl dissolved therein, followed by stirring at room temperature for 4 hours. After the reaction was completed, the solid was caught by DCM and EA. Then, through filtering, N-2-adamantyl-4-(3-chlorobenzyl)morpholine-2-carboxyamide hydrochloride (109 mg, 0.16 mmol, 82%) was obtained.

¹H NMR (400 MHz, CDCl₃) δ 13.87 (m, 1H), 7.73-7.71 (m, 1H), 7.55 (m, 1H), 7.48-7.42 (m, 2H), 6.79-6.77 (m, NH, 1H), 4.89-4.86 (m, 1H), 4.63-4.57 (m, 1H), 4.22-4.11 (m, 3H), 4.04-4.02 (m, 1H), 3.85-3.83 (m, 1H), 3.40-3.37 (m, 1H), 2.81 (m, 1H), 2.67 (m, 1H), 1.91-1.63 (m, 14H).

Preparation Example 41: Synthesis of N-2-adamantyl-4-((6-chloropyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 62)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-chloro-3-pyridinecarboaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 6.95 (m, NH, 1H), 4.05-4.02 (m, 2H), 3.98-3.94 (m, 1H), 3.73-3.67 (m, 1H), 3.59-3.47 (m, 2H), 3.22-3.19 (m, 1H), 2.65-2.62 (m, 1H), 2.24-2.17 (m, 1H), 2.08-2.03 (m, 1H), 1.92-1.63 (m, 14H).

Preparation Example 42: Synthesis of N-2-adamantyl-4-(4-carbamoylbenzyl)morpholine-2-carboxyamide (compound 106)

N-2-adamantyl-4-(4-cyanobenzyl)morpholine-2-carboxyamide (100 mg, 0.26 mmol) was dissolved in t-BuOH (1.5 ml), and added with KOH (74 mg, 1.32 mmol), followed by reflux-stirring for 12 hours. After the reaction was completed, the organic layer was separated by NaCl and EA, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (CH₂Cl₂/MeOH = 9/1) so as to provide N-2-adamantyl-4-(4-carbamoylbenzyl)morpholine-2-carboxyamide (40 mg, 38%).

¹H NMR (400 MHz, CDCl₃) δ 7.82-7.80 (m, 2H), 7.54-7.51 (m, 2H), 7.02-6.92 (m, NH, 1H), 6.24-6.18 (m, NH, 1H), 5.85-5.81 (m, NH, 1H), 4.26-4.24 (m, 1H), 4.06-4.00 (m, 3H), 3.77 (m, 2H), 3.41-3.38 (m, 1H), 2.88-2.86 (m, 1H), 2.37 (m, 1H), 2.20 (m, 1H), 1.92-1.57 (m, 14H).

Preparation Example 43: Synthesis of N-2-adamantyl-4-(3,4-difluorobenzyl)morpholine-2-carboxyamide (compound 155)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3,4-difluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.18 (m, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H, -NH-), 3.97 (m, 2H), 3.95 (m, 1H), 3.73 (m, 1H), 3.49 (q, J = 13.2 Hz, 2H), 3.21 (m, 1H), 2.65 (m, 1H), 2.17 (m, 1H), 2.01 (t, J = 11.2 Hz, 1H), 1.93-1.76 (m, 12H), 1.67-1.64 (m, 2H).

Preparation Example 44: Synthesis of N-2-adamantyl-4-(4-nitrobenzyl)morpholine-2-carboxyamide (compound 156)

¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J= 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.4 Hz, 1H, -NH-), 3.99 (m, 2H), 3.95 (m, 1H), 3.76 (m, 1H), 3.72 (q, J = 13.2 Hz, 2H), 3.21 (m, 1H), 2.65 (m, 1H), 2.24 (m, 1H), 2.07 (m, 1H), 1.93-1.76 (m, 12H), 1.68-1.65 (m, 2H).

Preparation Example 45: Synthesis of N-2-adamantyl-4-(2-fluorobenzyl)morpholine-2-carboxyamide (compound 157)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.41-7.37 (m, 1H), 7.29-7.24 (m, 1H), 7.15-7.10 (m, 1H), 7.07-7.02 (m, 1H), 6.96 (br, -NH-), 4.07-3.94 (m, 3H), 3.76-3.70 (m, 1H), 3.29-3.25 (m, 1H), 2.73-2.70 (m, 1H), 2.29-2.22 (m, 1H), 2.06 (t, J = 11.2 Hz, 1H), 1.93-1.62 (m, 14H).

Preparation Example 46: Synthesis of N-2-adamantyl-4-(3-fluorobenzyl)morpholine-2-carboxyamide (compound 158)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.34-7.25 (m, 1H), 7.10-7.06 (m, 2H), 6.98-6.93 (m, 1H, -NH-), 4.07-4.04 (m, 2H), 3.97-3.93 (m, 1H), 3.76-3.70 (m, 1H), 3.55 (m, 2H), 3.26-3.22 (m,1H), 2.69-2.65 (m, 1H), 2.21-1.99 (m, 2H), 1.93-1.64 (m, 14H)

Preparation Example 47: Synthesis of N-2-adamantyl-4-(4-trifluoromethoxybenzyl)morpholine-2-carboxyamide (compound 159)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-trifluoromethoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.37 (d, J = 2.4 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, -NH-), 4.07-3.94 (m, 3H), 3.78-3.69 (m, 1H), 3.54 (m, 2H), 3.25-3.22 (m, 1H), 2.68-2.65 (m, 1H), 2.22-1.99 (m, 2H), 1.93-1,65 (m, 14H).

[Example 6]

Preparation Example 1: Synthesis of N-cyclohexyl-4-(4-fluorobenzyl)morpholine-2-carboxyamide (compound 63)

¹H NMR (400 MHz, DMSO-d ₆) δ 2.18 (bs, -COOH), 7.67-7.65 (m, 2H), 7.53-7.40 (m, 3H), 4.61 (d, J = 10.8 Hz, 1H), 4.39 (m, 2H), 4.05-4.94 (m, 2H), 3.43 (d, J = 12.0 Hz, 1H), 3.20-3.07 (m, 3H).

4-benzylmorpholine-2-carboxylic acid hydrochloride (162.0 mg, 0.63 mmol) was dissolved in CH₂Cl₂ (5 ml), added with EDCI (121 mg, 0.63 mmol) and DMAP (154 mg, 1.26 mmol), and stirred for 30 minutes. The resultant mixture was added with cyclohexaneamine (86 ul, 0.75 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H₂O, extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. Through vacuum distillation, the solvent was removed. The resultant mixture was purified by column chromatography so as to provide 4-benzyl-N-cyclohexylmorpholine-2-carboxamide (172.4 mg, 0.57 mmol, 90 %).

¹H NMR (400 MHz, CDCl₃) δ7.56 (m, 5H),6.45 (d, J = 8.0 Hz, -CONH), 4.04 (dd, J = 2.8, 10.8 Hz, 1H), 3.91 (ddd, J = 1.2, 3.2, 11.2 Hz, 1H), 3.82-3.68 (m, 2H), 3.60 (d, J = 12.8 Hz, 1H), 3.50 (d, J = 12.8 Hz, 1H), 3.26 (td, J = 2.0, 11.2 Hz, 1H), 2.68 (dd, J = 1.2, 11.6 Hz, 1H), 2.15 (dt, J = 3.2, 11.6 Hz, 1H), 2.00 (t, J = 11.2 Hz, 1H), 1.90 (m, 2H), 1.72 (td, J = 3.6, 12.8 Hz, 1H), 1.64-1.60 (m, 1H), 1.43-1.32 (m, 2H), 1.23-1.10 (m, 3H).

4-benzyl-N-cyclohexylmorpholine-2-carboxamide compound (7.0 g, 23.3 mmol) was dissolved in 1,2-dichloroethane (30 ml), and added with 1-chloroethyl chloroformate (10.2g, 70.1 mmol) at 0℃. After the addition, the mixture was stirred for 24 hours under reflux. Then, through vacuum distillation, the solvent was removed. The resultant reaction intermediate was dissolved in MeOH (50 ml), and stirred again for 24 hours under reflux. Then, through vacuum distillation, the solvent was removed. The resultant mixture was recrystallized in an ether/MeOH condition so as to provide N-cyclohexylmorpholine-2-carboxamide hydrochloride compound (4.1 g, 16.3 mmol, 70 %).

¹H NMR (400 MHz, DMSO-d ₆) δ9.49 (bs, -NH₂), 7.83 (bs, -CONH), 4.24 (dd, J = 2.4, 6.8 Hz, 1H), 4.02 (m, 1H), 3.82 (td, J = 2.4, 12.0 Hz, 1H), 3.55 (m, 1H), 3.34 (m, 1H), 3.17 (d, J = 10.8 Hz, 1H), 3.00 (td, J = 4.0, 12.0 Hz, 1H), 2.92 (dd, J = 11.2, 12.8 Hz, 1H), 1.68 (m, 4H), 1.56 (m, 1H), 1.24 (m, 4H), 1.08 (m, 1H).

¹H NMR (400 MHz, CDCl₃) δ7.30-7.26 (m, 2H), 7.03-6.98 (m, 2H), 6.44-6.43 (m, NH, 1H), 4.03-3.99 (m, 1H), 3.93-3.89 (m, 1H), 3.82-3.66 (m, 2H), 3.55-3.44 (m, 2H), 3.24-3.20 (m, 1H), 2.66-2.63 (m, 1H), 2.17-2.11 (m, 1H), 2.01-1.95 (m, 1H), 1.90-1.89 (m, 2H), 1.75-1.70 (m, 2H), 1.65-1.60 (m, 1H), 1.43-1.32 (m, 2H), 1.24-1.13 (m, 3H).

Preparation Example 2: Synthesis of N-cyclohexyl-4-(3-fluorobenzyl)morpholine-2-carboxyamide (compound 64)

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.25 (m, 1H), 7.09-7.05 (m, 2H), 6.98-6.93 (m, 1H), 6.45-6.43 (m, NH, 1H), 4.04-4.01 (m, 1H), 3.93-3.91 (m, 1H), 3.81-3.67 (m, 2H), 3.58-3.47 (m, 2H), 3.24-3.21 (m, 1H), 2.67-2.64 (m, 1H0, 2.19-2.13 (m, 1H), 2.03-1.97 (m, 1H), 1.90 (m, 2H), 1.74-1.70 (m, 2H), 1.64-1.61 (m, 1H), 1.42-1.33 (m, 2H), 1.22-1.14 (m, 3H).

Preparation Example 3: Synthesis of N-cyclohexyl-4-(2-fluorobenzyl)morpholine-2-carboxyamide (compound 65)

¹H NMR (400 MHz, CDCl₃) δ7.39-7.36 (m, 1H), 7.29-7.23 (m, 1H), 7.14-7.10 (m, 1H), 7.06-7.01 (m, 1H), 6.44-6.43 (m, NH, 1H), 4.04-4.00 (m, 1H), 3.94-3.90 (m, 1H), 3.82-3.68 (m, 2H), 3.66-3.59 (m, 2H), 3.27-3.23 (m, 1H), 2.72-2.68 (m, 1H), 2.27-2.20 (m, 1H), 2.07-2.01 (m, 1H), 1.91-1.89 (m, 2H), 1.75-1.70 (m, 2H), 1.65-1.60 (m, 1H), 1.43-1.33 (m, 2H), 1.26-1.16 (m, 3H).

[Example 7]

Preparation Example 1: Synthesis of 4-((2-(3-hydroxy-8-azabicyclo[3.2.1]octane-8-carbonyl)morpholino)methyl)benzonitrile (compound 66)

4-benzylmorpholine-2-carboxylic acid hydrochloride (162.0 mg, 0.63 mmol) was dissolved in CH₂Cl₂ (5 ml), added with EDCI (121 mg, 0.63 mmol) and DMAP (154 mg, 1.26 mmol), and stirred for 30 minutes. The resultant mixture was added with nortropine (95.4 mg, 0.75 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H₂O, extracted (X3) with CH₂Cl₂, and dried and filtered with MgSO₄. Through vacuum distillation, the solvent was removed. The resultant mixture was purified by column chromatography so as to provide (4-benzylmorpholine-2-yl)(3-hydroxy-8-azabicyclo[3.2.1]ontane-8-yl)methanone (152.0 mg, 0.46 mmol, 73 %).

¹H NMR (400 MHz, CDCl₃) δ.39-7.23 (m, 5H), 4.65 (m, 1H), 4.48-4.11 (m, 3H), 3.97-3.93 (m, 1H), 3.74-3.67 (m, 1H), 3.60-3.50 (m, 2H), 2.94-2.86 (m, 1H), 2.71-2.68 (m, 1H), 2.42-1.62 (m, 10H).

(4-benzylmorpholine-2-yl)(3-hydroxy-8-azabicyclo[3.2.1]ontane-8-yl)methanone compound (7.0 g, 21.2 mmol) was dissolved in 1,2-dichloroethane (50 ml), and added with 1-chloroethyl chloroformate (9.1g, 63.4 mmol) at 0℃. After the addition, the mixture was stirred for 24 hours under reflux. Then, through vacuum distillation, the solvent was removed. The resultant reaction intermediate was dissolved in MeOH (50 ml), and stirred again for 24 hours under reflux. Then, through vacuum distillation, the solvent was removed. The resultant mixture was recrystallized in an ether/MeOH condition so as to provide (3-hydroxy-8-azabicyclo[3.2.1]octane-8-yl)(morpholine-2-yl)methanone hydrochloride compound (3.4 g, 12.3 mmol, 58 %).

¹H NMR (400 MHz, DMSO-d ₆) δ9.61 (bs, -NH₂), 4.71 (s, 1H), 4.56 (m, 1H), 4.43-4.22 (m, 2H), 3.91 (m, 3H), 3.37-2.99 (m, 4H), 2.25-2.10 (m, 2H), 2.00-1.60 (m, 6H).

¹H NMR (400 MHz, CDCl₃) δ 7.65-7.63 (m, 2H), 7.53 (m, 2H), 4.65 (m, 1H), 4.26-4.08 (m, 3H), 3.99-3.96 (m, 1H), 3.80-3.69 (m, 3H), 2.93 (m, 1H), 2.74 (m, 1H), 2.52-1.98 (m, 6H), 1.87-1.73 (m, 3H).

[Example 8]

Preparation Example 1: Synthesis of 4-benzyl-N-((2S,4S)-1,7,7-trimethylbicyclo [2.2.1]heptane-2-yl)morpholine-2-carboxyamide (compound 67)

¹H NMR (400 MHz, CDCl₃) δ 7.39-7.28 (m, 5H), 4.62 (t, J = 3.6 Hz, 1H), 4.05 (m, 1H), 3.79 (dt, J = 3.6, 11.6 Hz, 1H), 3.59 (dd, J = 9.2, 25.2 Hz, 2H), 2.78 (dd, J = 3.6, 12.0 Hz, 1H), 2.66 (m, 1H), 2.58 (dd, J = 3.6, 12.0 Hz, 1H), 2.43 (m, 1H).

4-benzylmorpholine-2-carboxylic acid hydrochloride (100 mg, 0.39 mmol) was dissolved in CH₂Cl₂ (2 ml), and added with BOP (173 mg, 0.39 mmol) and DIPEA (152 mg, 1.17 mmol), followed by stirring. The resultant mixture was added with (2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-amine (66 mg, 0.429 mmol), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide 4-benzyl-N-((2S,4S)-1,7,7-trimethylbicyclo [2.2.1]heptane-2-yl)morpholine-2-carboxyamide (57 mg, 0.16 mmol, 50 %).

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.24 (m, 5H), 6.62-6.60 (m, NH, 1H), 4.27-4.21 (m, 1H), 4.09-4.05 (m, 1H), 3.96-3.93 (m, 1H), 3.75-3.69 (m, 1H), 3.62-3.58 (m, 1H), 3.52-3.48 (m, 1H), 3.29-3.24 (m, 1H), 2.70-2.67 (m, 1H), 2.39-2.31 (m, 1H), 2.21-2.14 (m, 1H), 2.04-1.99 (m, 1H), 1.83-1.73 (m, 1H), 1.70-1.67 (m, 1H), 1.55-1.48 (m, 1H), 1.44-1.36 (m, 1H), 1.32-1.22 (m, 2H), 1.97 (m, 3H), 1.90 (m, 3H), 0.81 (m, 3H).

Preparation Example 2: Synthesis of N-[3-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (compound 68)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 7 except that 1-adamantylamine-3-ol was used.

¹H NMR (400 MHz, CDCl₃) δ7.34-7.24 (m, 5H), 6.34 (br, NH, 1H), 3.96-3.89 (m, 2H), 3.72-3.66 (m, 1H), 3.60-3.57 (m, 1H), 3.52-3.48 (m, 2H), 3.24-3.20 (m, 1H), 2.68-2.65 (m, 1H), 2.28 (m, 2H), 2.18-2.11 (m, 1H), 2.01-1.91 (m, 7H), 1.70 (m, 4H), 1.64-1.49 (m, 2H).

Preparation Example 3: Synthesis of N-[5-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (compound 97)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 7 except that 2-adamantylamine-5-ol was used.

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.28 (m, 5H), 6.86-6.84 (m, NH, 1H), 4.08-4.01 (m, 2H), 3.95-3.92 (m, 1H), 3.75-3.69 (m, 1H), 3.64-3.57 (m, 1H), 3.54-3.48 (m, 1H), 3.27-3.24 (m, 1H), 2.70-2.67 (m, 1H), 2.19-2.13 (m, 4H), 2.03-1.96 (m, 1H), 1.91-1.88 (m, 2H), 1.78-1.73 (m, 7H), 1.54-1.51 (m, 2H).

Preparation Example 4: Synthesis of N-[5-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (compound 98)

N-[5-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (120 mg, 0.33 mmol) was dissolved in EtOH (1 ml), added with 5% Pd/C (24 mg), and stirred at room temperature for 12 hours under a H₂(g) atmosphere. After the reaction was completed, the resultant product was subjected to celite filtration, and concentration so as to provide N-[5-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide mixture (50 mg, 0.18 mmol, 54 %).

N-[5-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide (50 mg, 0.18 mmol) and 4-cyanobenzaldehyde (24 mg, 0.18 mmol) were dissolved in dichloroethane (1 ml), and added with acetic acid (21 mg, 0.36 mmol), followed by stirring at room temperature for 10 minutes. The resultant mixture was added with sodium triacetoxy borohydride (76 mg, 0.36 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 5:1) so as to provide N-[5-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (35 mg, 0.09 mmol, 50 %).

¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H),6.89-6.84 (m, NH, 1H), 4.07-3.94 (m, 3H), 3.76-3.70 (m, 1H), 3.64-3.54 (m, 2H), 3.22-3.19 (m, 1H), 2.66-2.63 (m, 1H), 2.25-2.00 (m, 5H), 1.91-1.88 (m, 1H), 1.78-1.72 (m, 8H), 1.55-1.51 (m, 2H).

Preparation Example 5: Synthesis of adamantyl 4-benzylmorpholine-2-carboxylate (compound 86)

4-benzylmorpholine-2-carboxylic acid hydrochloride (100 mg, 0.39 mmol) was dissolved in CH₂Cl₂ (3 ml), and added with EDCI (150 mg, 0.78 mmol) and DMAP (95 mg, 0.78 mmol), followed by stirring. The resultant mixture was added with 2-adamantanol (60 mg, 0.39 mmol), followed by reflux-stirring for 3 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide adamantyl 4-benzylmorpholine-2-carboxylate (76 mg, 0.21 mmol, 55 %).

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.26 (m, 5H), 4.30-4.27 (m, 1H), 4.08-4.03 (m, 1H), 3.89 (m, 1H), 3.73-3.68 (m, 1H), 3.62-3.59 (m, 1H), 3.50-3.47 (m, 1H), 2.99-2.96 (m, 1H), 2.57-2.48 (m, 2H), 2.35-2.30 (m, 1H), 2.10-1.50 (m, 14H).

[Example 9]

Preparation Example 1: Synthesis of N-2-adamantyl-4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxyamide (compound 69)

2-aminophenol (1 g, 9.16 mmol) and ethyl 2,3-dibromopropanoate (4.76 g, 18.32 mmol) were dissolved in acetone (40 ml), and added with K₂CO₃(2.53 g, 18.32 mmol), followed by reflux-stirring for 12 hours. After the reaction was completed, the organic layer was separated by H₂O and EA, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:3) so as to provide ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (980 mg, 4.73 mmol, 51 %).

¹H NMR (400 MHz, CDCl₃) δ6.95-6.93 (m, 1H), 6.82-6.78 (m, 1H), 6.63-6.61 (m, 1H), 4.82-4.80 (m, 1H), 4.31-4.21 (m, 2H), 3.78 (br, NH, 1H), 3.64-3.56 (m, 2H), 1.27 (m, 3H).

Ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (414 mg, 2 mmol) and 4-fluorobenzaldehyde (250 mg, 2 mmol) were dissolved in DCE (5 ml), and added with acetic acid (240 mg, 4 mmol), followed by stirring at room temperature for 10 minutes. The resultant mixture was added with sodium triacetoxy borohydride (848 mg, 4 mmol), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by H₂O and CH₂Cl₂, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:3) so as to provide ethyl 4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (510 mg, 1.62 mmol, 80 %).

¹H NMR (400 MHz, CDCl₃) δ 7.27-7.23 (m, 2H), 7.06-6.98 (m, 3H), 6.85-6.81(m, 1H), 6.76-6.72 (m, 1H), 6.68-6.66 (m, 1H), 4.86-4.84 (m, 1H), 4.50-4.46 (m, 1H), 4.34-4.17 (m, 3H), 3.52-3.51 (m, 2H), 1.28-1.24 (m, 3H).

Ethyl 4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (500 mg, 1.59 mmol) was dissolved in THF (5 ml) and MeOH (5 ml), and then was added with LiOH (334 mg, 7.95 mmol) dissolved in H₂O (5 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 2, and extracted with EA. The organic layer was dried and filtered with MgSO₄, and concentrated so as to provide 4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (400 mg, 1.39 mmol, 87 %). The mixture was subjected to the following reaction.

4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (200 mg, 0.7 mmol) was dissolved in CH₂Cl₂ (5 ml), and added with BOP (308 mg, 0.7 mmol) and DIPEA (270 mg, 2.09 mmol), followed by stirring. The resultant mixture was added with 2-adamantaneamine hydrochloride (145 mg, 0.7 mmol), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:3) so as to provide N-2-adamantyl-4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxyamide (280 mg, 0.66 mmol, 95 %).

¹H NMR (400 MHz, CDCl₃) δ 7.28-7.24 (m, 2H), 7.03-6.94 (m, 4H), 6.86-6.81 (m, 1H), 6.72-6.69 (m, 1H), 6.66-6.64 (m, 1H), 4.76-4.74 (m, 2H), 4.41 (s, 3H), 4.09-4.07 (m, 1H), 3.66-3.62 (m, 1H), 3.57-3.52 (m, 1H), 1.95-1.65 (m, 12H), 1.50-1.39 (m, 2H).

[Example 10]

Preparation Example 1: Synthesis of N-2-adamantyl-ethyl-2-(2-(2-(amino)-2-oxoethyl)morpholino)-2-methylpropanoate (compound 75)

Epichlorohydrin (153g, 1653 mol) was added with N-benzylethanolamine (50 g, 331 mmol). The mixture was stirred at 50℃ for 1 hour, and vacuum-distillated so as to remove the remaining epichlorohydrin. Then, c-H₂SO₄ (300 ml) was added thereto, followed by reflux for 2 hours. The resultant mixture was cooled to room temperature, and its acidity was adjusted to pH 14 through addition of 10N NaOH aqueous solution. Then, the resultant mixture was extracted (X3) with toluene, and dried and filtered with MgSO₄. After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide 4-benzyl-2-(chloromethyl)morpholine compound (18.7 g, 82.8 mmol, 25 %).

Methyl 2-(4-belzylmorpholine-2-yl)acetate (500 mg, 2.00 mmol) was dissolved in 70% MeOH aqueous solution (10 ml), and added with KOH (189 mg, 3.37 mmol), followed by stirring for 12 hours at room temperature. The resultant mixture was added with 2N HCl so that its acidity can be adjusted to pH 7. Then, vacuum distillation was carried out in such a manner that only 1ml of water remained. The resultant mixture was added with EtOH (10 ml), and the produced solid was removed through filtration, The filtrate was vacuum-distillated so as to provide 2-(4-benzylmorpholine-2-yl)acetic acid compound (418.8 mg, 1.78 mmol, 89 %).

¹H NMR (400 MHz, CDCl₃) δ 6.99-6.97 (m, NH, 1H), 4.18 (q, J = 7.2 Hz, 2H), 4.06-4.04 (m, 1H), 9.96-3.93 (m, 1H), 3.89-3.83 (m, 1H), 3.75-3.68 (m, 1H), 2.84-2.77 (m, 2H), 2.49-2.32 (m, 3H), 2.25-2.20 (m, 1H), 1.91-1.75 (m, 12H), 1.67-1.63 (m, 2H), 1.32 (m, 6H), 1.29 (t, J = 7.2 Hz, 3H).

Preparation Example 2: Synthesis of ethyl 2-(2-(2-(N-2-adamandylamino)-2-oxoethyl)morpholino)-2-phenylacetate(compound 76)

N-2-adamantyl-2-(morpholine-2-yl)acetamide (100 mg, 0.36 mmol) and ethyl 2-bromo-2-phenylacetate (216 mg, 1.08 mmol) were dissolved in DMF (1 ml), and added with K₂CO₃(149 mg, 1.08 mmol) and KI (180 mg, 1.08 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by H₂O and EA, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide ethyl2-(2-(2-(N-2-adamandylamino)-2-oxoethyl)morpholino)-2-phenylacetate (100 mg, 0.22 mmol, 63 %).

¹H NMR (400 MHz, CDCl₃) δ 7.44-7.41 (m, 2H), 7.38-7.31 (m, 3H), 6.97-6.90 (m, NH, 1H), 4.24-3.73 (m, 8H), 2.85-2.82 (m, 1H), 2.60-2.57 (m, 1H), 2.46-2.12 (m, 3H), 1.95-1.59 (m, 14H), 1.24-1.20 (m, 3H).

Preparation Example 3: Synthesis of ethyl 2-(2-(2-(N-2-adamandylamino)-2-oxoethyl)morpholino)-2-phenyl acetic acid (compound 77)

¹H NMR (400 MHz, MeOH-d₄) δ 7.57-7.54 (m, 2H), 7.44-7.43 (m, 3H), 4.10-4.02 (m, 2H), 3.94-3.87 (m, 2H), 3.63-3.61 (m, 1H), 2.97-2.92 (m, 1H), 2.78-2.75 (m, 1H), 2.54-2.44 (m, 2H), 2.31-2.26 (m, 1H), 1.95-1.55 (m, 15H).

Preparation Example 4: Synthesis of 2-(4-(1-(4-cyanophenyl)ethyl)morpholine-2-yl)-N-2-adamantylacetamide (compound 94)

¹H NMR (400 MHz, CDCl₃) δ7.64-7.62 (m, 2H), 7.46-7.44 (m, 2H), 6.92-6.81 (m, NH, 1H), 4.07-3.92 (m, 2H), 3.86-3.63 (m, 2H), 3.42-3.38 (m, 1H), 2.95-2.86 (m, 1H), 2.53-2.41 (m, 2H), 2.40-2.19 (m, 2H), 2.13-1.98 (m,1H), 1.91-1.63 (m, 14H), 1.34-1.33 (m, 3H).

Preparation Example 5: Synthesis of N-2-adamantyl-2-(4-(1-(pyridine-4-yl)ethyl)morpholine-2-yl)acetamide (compound 95)

A desired compound was obtained in the same manner as described in Preparation Example 7 in Example 2 except that 4-pyridineacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 8.57-8.56 (m, 2H), 7.28-7.27 (m, 2H), 6.94-6.55 (m, NH, 1H), 4.07-6.65 (m, 5H), 3.41-3.34 (m, 1H), 2.92-2.83 (m, 1H), 2.44-1.96 (m, 4H), 1.94-1.64 (m, 14H), 1.35-1.33 (m, 3H).

[Example 11]

Preparation Example 1: Synthesis of 4-benzyl-N-2-adamantyl-5-methylmorpholine-2-carboxamide (compound 83)

2-aminopropane-1-ol (100 mg, 1.33 mmol) and ethyl benzylbromide (114 mg, 0.665 mmol) were dissolved in acetonitrile (4 ml), and stirred at room temperature for 4 hours. After the reaction was completed, the organic layer was separated by H₂O and EA, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (MeOH/CH₂Cl₂ = 1:9) so as to provide 2-(benzylamino)propane-1-ol (89 mg, 0.54 mmol, 81 %).

¹H NMR (400 MHz, CDCl₃) δ 7.64-7.62 (m, 2H), 7.43-7.36 (m, 3H), 6.00 (br, NH, OH, 2H), 4.35-4.32 (m, 1H), 4.08-4.05 (m, 1H), 3.81-3.69 (m, 2H), 3.29-3.22 (m, 1H), 1.37-1.36 (m, 3H).

2-(benzylamino)propane-1-ol (500 mg, 3.03 mmol) and ethyl 2,3-dibromopropanoate (945 mg, 3.64 mmol) were dissolved in acetone (10 ml), and added with K₂CO₃ (838 mg, 6.06 mmol), followed by reflux-stirring for 12 hours. After the reaction was completed, the organic layer was separated by H₂O and EA, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide ethyl 4-benzyl-5-methylmorpholine-2-carboxylate mixture.

¹H NMR (400 MHz, CDCl₃) δ 7.39-7.25 (m, 5H), 4.27-2.74 (m, 10H), 1.31-1.23 (m, 3H), 0.99-0.97 (m, 3H).

Ethyl 4-benzyl-5-methylmorpholine-2-carboxylate (500 mg, 1.9 mmol) was dissolved in THF (3 ml) and MeOH (3 ml), and added with LiOH (399 mg, 9.5 mmol) dissolved in H₂O (3 ml), followed by stirring at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 2, and extracted with EA. The organic layer was dried and filtered with MgSO₄, and concentrated so as to provide 4-benzyl-5-methylmorpholine-2-carboxylic acid mixture.

4-benzyl-5-methylmorpholine-2-carboxylic acid mixture was dissolved in CH₂Cl₂ (1 ml), and added with EDCI (1.09 g, 5.7 mmol) and DMAP (232 mg, 1.9 mmol), followed by stirring. The resultant mixture was added with 2-adamantaneamine hydrochloride (357 mg, 1.9 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-2-adamantyl-4-(2-(4-fluorophenylamino)-2-oxoethyl)morpholine-2-carboxyamide (50 mg).

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.23 (m, 5H), 6.92-6.90 (m, NH, 1H), 4.12-4.09(m, 1H), 4.02-3.99 (m, 2H), 3.85-3.81 (m, 1H), 3.43-3.34 (m, 1H), 3.19-3.15 (m, 2H), 2.45-2.40 (m, 1H), 2.00-1.97 (m, 1H), 1.91-1.75 (m, 12H), 1.66-1.63 (m, 2H), 1.11-1.10 (m, 3H).

[Example 12]

Preparation Example 1: Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (compound 99)

4-oxo-adamantane-1-carboxyacid (10 g, 51.5 mmol) was dissolved in 7N NH₃ in MeOH (50 ml), and added with 10% Pd/C (1 g, 10%), followed by stirring under a hydrogen gas atmosphere for 12 hours. After the reaction was completed, the resultant product was added with H₂O and filtered so as to provide 4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0℃, MeOH (85 ml) was added with AcCl (16.08 g, 204.85 mmol), and at room temperature, 4-amino-adamantane-1-carboxyacid (8.0 g, 40.97 mmol) was added thereto, followed by stirring at 45℃ for 12 hours. After the reaction was completed, the produced solid was filtered by using acetonitrile so as to provide 4-amino-adamantane-1-carboxy acid (8.17 g, 41.8 mmol, 81%).

¹H NMR (400 MHz, CDCl₃) δ8.61 (m, 3H), 3.68 (s, 3H), 3.50 (s, 1H), 2.34-1.64 (m, 13H).

4-benzylmorpholine-2-carboxylic acid hydrochloride (100 mg, 0.39 mmol) was dissolved in CH₂Cl₂ (3 ml), and added with BOP (173 mg, 0.39 mmol) and DIPEA (152 mg, 1.17 mmol), followed by stirring. The resultant mixture was added with methyl 4-aminoadamantane-1-carboxylate (82 mg, 0.39 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (120 mg, 0.29 mmol, 75 %).

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.25 (m, 5H), 6.93-6.87 (m, NH, 1H), 4.08-4.00 (m, 2H), 3.96-3.93 (m, 1H), 3.75-3.68 (m, 4H), 3.61-3.58 (m, 1H), 3.52-3.49 (m, 1H), 3.27-3.24 (m, 1H), 2.70-2.67 (m, 1H), 2.20-2.13 (m, 1H), 2.05-1.95 (m, 7H), 1.91-1.90 (m, 3H), 1.82-1.79 (m, 3H), 1.62-1.59 (m, 1H).

Preparation Example 2: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (compound 100)

Synthesis of N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide

N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), and then was added with LiOH (50 mg, 1.2 mmol) dissolved in H₂O (1 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄ so as to provide N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide mixture(70 mg).

Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide

N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (70 mg, 0.176 mmol) was dissolved in CH₂Cl₂ (2 ml), and added with EDCI (68 mg, 0.35 mmol) and HOBt (46 mg, 0.26 mmol), followed by stirring. Then, an ammonium hydroxide solution (1.88 ml) was added thereto, followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9) so as to provide N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (25 mg, 0.06 mmol, 35 %).

¹H NMR (400 MHz, CDCl₃) δ 7.67-7.28 (m, 5H), 6.94-6.92 (m, NH, 1H), 5.78-5.56 (m, NH₂, 2H), 4.12-4.09 (m, 1H), 4.01-3.93 (m, 2H), 3.77-3.72 (m, 1H), 3.65-3.50 (m, 2H), 3.31-3.29 (m, 1H), 2.78-2.75 (m, 1H), 2.23 (m, 1H), 2.04-1.79 (m, 12H), 1.61-1.58 (m, 2H).

[Example 13]

Preparation Example 1: Synthesis of N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (compound 103)

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

¹H NMR (400 MHz, CDCl₃) δ 8.61 (m, 3H), 3.68 (s, 3H), 3.50 (s, 1H), 2.34-1.64 (m, 13H).

N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (200 mg, 0.49 mmol) was dissolved in EtOH (10 ml), added with 5% Pd/C (40 mg), and stirred at room temperature for 5 hours under a H₂(g) atmosphere. After the reaction was completed, the resultant product was subjected to celite filtration, and concentration so as to provide N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide mixture(100 mg, 0.31 mmol, 63 %).

N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide (100 mg, 0.31 mmol) and 4-cyanobenzaldehyde (41 mg, 0.31 mmol) were dissolved in dichloroethane (2 ml), and added with acetic acid (37 mg, 0.62 mmol), followed by stirring at room temperature for 10 minutes. Then, sodium triacetoxy borohydride (131 mg, 0.62 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by H₂O and CH₂Cl₂, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 5:1) so as to provide N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (41 mg, 0.09 mmol, 30 %).

¹H NMR (400 MHz, CDCl₃) δ7.65-7.62 (m, 2H), 7.47-7.45 (m, 2H), 6.92-6.86 (m, NH, 1H), 4.29-3.81 (m, 3H), 3.75-3.49 (m, 5H), 3.22-2.63 (m, 1H), 2.56-2.19 (m, 2H), 2.12-1.40 (m, 14H).

N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (40 mg, 0.09 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), added with LiOH (11 mg, 0.27 mmol) dissolved in H₂O (1 ml) and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄so as to provide N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide mixture(20 mg).

¹H NMR (400 MHz, DMSO-d ₆) δ11.99 (br, OH, 1H), 7.85-7.80 (m, 2H), 7.54-7.52 (m, 2H), 7.22-7.18 (m, NH, 1H), 4.04-3.94 (m, 2H), 3.78-3.73 (m, 1H), 3.64-3.51 (m, 3H), 2.87-2.85 (m, 1H), 2.64-2.61 (m, 1H), 2.21-2.15 (m, 1H), 2.04-1.98 (m, 1H), 1.91-1.61 (m, 13H).

Preparation Example 2: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (compound 104)

N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (20 mg, 0.047 mmol) was dissolved in CH₂Cl₂ (1 ml), and added with EDCI (18 mg, 0.094 mmol) and HOBt (11 mg, 0.071 mmol), followed by stirring. The resultant mixture was added with ammonium hydroxide solution (0.6 ml), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O , and dried and filtered with MgSO₄, The resultant mixture was purified by column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9) so as to provide N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (10 mg, 0.02 mmol, 50 %).

¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.93-6.87 (m, NH, 1H), 5.56 (m, NH, 1H), 5.32 (m, NH, 1H), 4.08-4.04 (m, 2H), 4.01-3.96 (m, 1H), 3.77-3.68 (m, 1H), 3.64-3.55 (m, 2H), 3.22-3.17 (m, 1H), 2.66-2.62 (m, 1H), 2.26-2.19 (m, 1H), 2.09-1.74 (m, 14H).

Preparation Example 3: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-fluorobenzyl)morpholine-2-carboxyamide (compound 110)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.29-7.28 (m, 2H), 7.03-6.99 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.60 (m, NH, 1H), 5.29 (m, NH, 1H), 4.04 (m, 2H), 3.96-3.95 (m, 1H), 3.72-3.69 (m, 1H), 3.56-3.46 (m, 2H), 3.24-3.21 (m, 1H), 2.68-2.66 (m, 1H), 2.17-2.16 (m, 1H), 2.08-1.82 (m, 12H), 1.62 (m, 2H).

Preparation Example 4: Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((6-chloropyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 111)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 4-chloro-3-pyridinealdehyde was used.

¹H NMR (400 MHz, CDCl₃)δ8.31-8.30 (m, 1H), 7.68-7.65 (m, 1H), 7.33-7.32 (m, 1H), 6.91-6.85 (m, NH, 1H), 4.03-3.99 (m, 2H), 3.98-3.94 (m, 1H), 3.73-3.67 (m, 4H), 3.58-3.47 (m, 2H), 3.21-3.17 (m, 1H), 2.65-2.62 (m, 1H), 2.23-2.17 (m, 1H), 2.08-1.73 (m, 12H), 1.63-1.59 (m, 2H).

Preparation Example 5: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((6-chloropyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 112)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-chloro-3-pyridinealdehyde was used.

¹H NMR (400 MHz, CDCl₃)δ8.33-8.32 (m, 1H), 7.68-7.66 (m, 1H), 7.37-7.25 (m, 1H), 6.92-6.90 (m, NH, 1H), 5.60(m, NH, 1H), 5.28 (m, NH, 1H), 4.05-3.96 (m, 3H), 3.74-3.68 (m, 1H), 3.58-3.48 (m, 2H), 3.21-3.19 (m, 1H), 2.65-2.63 (m, 1H), 2.21-2.18 (m, 12H), 1.63-1.61 (m, 2H).

Preparation Example 6: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyano-3-fluorobenzyl)morpholine-2-carboxyamide (compound 113)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-fluoro-4cyanobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.61-7.57 (m, 1H), 7.26-7.23 (m, 1H), 7.02-6.97 (m, 1H), 6.93-6.87 (m, NH, 1H), 5.59 (m, NH, 1H), 5.28 (m, NH, 1H), 4.09-3.95 (m, 3H), 3.78-3.72 (m, 1H), 3.63-3.54 (m, 2H), 3.23-3.16 (m, 1H), 2.67-2.64 (m, 1H), 2.28-2.22 (m, 1H), 2.10-1.82 (m, 12H), 1.65-1.60 (m, 2H).

Preparation Example 7: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(3-bromo-4fluorobenzyl)morpholine-2-carboxyamide (compound 147)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-bromo-4-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.54-7.52 (m, 1H), 7.25-7.22 (m, 1H), 7.12-7.02 (m, 1H), 6.93-6.87 (m, NH, 1H), 5.59 (m, NH, 1H), 5.32 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.98-3.95 (m, 1H), 3.76-3.68 (m, 1H), 3.53-3.42 (m, 2H), 3.22-3.18 (m, 1H), 2.67-2.64 (m, 1H), 2.21-2.15 (m, 1H), 2.07-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 8: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((6-bromopyridine-3-yl)methyl)morpholine-2-carboxyamide (compound 114)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-bromo-3-pyridinealdehyde was used.

¹H NMR (400 MHz, CDCl₃)δ8.30 (m, 1H), 7.58-7.54 (m, 1H), 7.48-7.46 (m, 1H), 6.92-6.86 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.06-4.01 (m, 2H), 3.98-3.95 (m, 1H), 3.74-3.65 (m, 1H), 3.57-3.46 (m, 2H), 3.22-3.17 (m, 1H), 2.65-2.62 (m, 1H), 2.24-2.18 (m, 1H), 2.09-1.75 (m, 12H), 1.65-1.61 (m, 2H).

Preparation Example 9: Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((6-methoxypyridine-2-yl)methyl)morpholine-2-carboxyamide (compound 115)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 5-methoxy-6-pyridinealdehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.58-7.53 (m, 1H), 7.02-6.98 (m, 1H), 6.93-6.91 (m, NH, 1H), 6.65-6.61 (m, 1H), 4.16-3.89 (m, 6H), 3.77-3.75 (m, 1H), 3.71-3.63 (m, 5H), 3.33 (m, 1H), 2.80-2.78 (m, 1H), 2.36-2.31 (m, 1H), 2.14-1.83 (m, 12H), 1.64 (m, 2H).

Preparation Example 10: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((6-methoxypyridine-2-yl)methyl)morpholine-2-carboxyamide (compound 116)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 5-methoxy-6-pyridinealdehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.57-7.53 (m, 1H), 7.02-6.99 (m, 1H), 6.94-6.88 (m, NH, 1H), 6.64-6.61 (m, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.09-4.02 (m, 2H), 3.99-3.96 (m, 1H), 3.93 (s, 3H), 3.82-3.75 (m, 1H), 3.64 (s, 2H), 3.34-3.30 (m, 1H), 2.81-2.78 (m, 1H), 2.38-2.31 (m, 1H), 2.15-1.82 (m, 12H), 1.64-1.62 (m, 2H).

Preparation Example 11: Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(3-chlorobenzyl)morpholine-2-carboxyamide (compound 117)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 3-chlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.35-7.21 (m, 4H), 6.93-6.91 (m, NH, 1H), 4.07-3.97 (m, 3H), 3.78-3.67 (m, 4H), 3.58-3.46 (m, 2H), 3.23 (m, 1H), 2.68-2.66 (m, 1H), 2.20-2.15 (m, 1H), 2.02-1.83 (m, 12H), 1.60 (m, 2H).

Preparation Example 12: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(3-chlorobenzyl)morpholine-2-carboxyamide (compound 118)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-chlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.34 (s, 1H), 7.28-7.19 (m, 3H), 6.93-6.88 (m, NH, 1H), 5.59 (m, NH, 1H), 5.32 (m, NH, 1H), 4.13-4.03 (m, 2H), 3.98-3.94 (m, 1H), 3.76-3.68 (m, 1H), 3.57-3.46 (m, 2H), 3.24-3.20 (m, 1H), 2.69-2.66 (m, 1H), 2.22-2.15 (m, 1H), 2.09-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 13: Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-methoxybenzyl)morpholine-2-carboxyamide (compound 119)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 4-methoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ7.22 (d, J = 8.8 Hz, 2H), 6.93-6.91 (m, NH, 1H), 6.86 (d, J =8.8 Hz, 2H), 4.03-4.00 (m, 2H), 3.96-3.92 (m, 1H), 3.82 (s, 3H), 3.76-3.68 (m, 4H), 3.54-3.41 (m, 2H), 3.25-3.22 (m, 1H), 2.69-2.66 (m, 1H), 2.17-2.11 (m, 1H), 2.07-1.79 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 14: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-methoxybenzyl)morpholine-2-carboxyamide (compound 120)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-methoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.23 (d, J = 8.4 Hz, 2H), 6.94-6.92 (m, NH, 1H), 6.87 (d, J = 8.4 Hz, 2H), 5.59 (m, NH, 1H), 5.26 (m, NH, 1H), 4.06-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.82 (s, 3H), 3.72-3.68 (m, 1H), 3.56-3.42 (m, 2H), 3.25-3.22 (m, 1H), 2.69-2.66 (m, 1H), 2.18-2.14 (m, 1H), 2.07-1.82 (m, 12H), 1.64-1.62 (m, 2H).

Preparation Example 15: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((6-methylpyridine-2-yl)methyl)morpholine-2-carboxyamide (compound 121)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 5-methyl-6pyridinealdehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.56-7.51 (m, 1H), 7.26-7.23 (m, 1H), 7.06-7.04 (m, 1H), 6.94-6.88 (m, NH, 1H), 5.60 (m, NH, 1H), 5.27 (m, NH, 1H), 4.03-3.93 (m, 3H), 3.83-3.76 (m, 1H), 3.75-3.63 (m, 2H), 3.26-3.22 (m, 1H), 2.77-2.75 (m, 1H), 2.56 (m, 3H), 2.34-2.27 (m, 1H), 2.10-1.73 (m, 12H), 1.64-1.61 (m, 2H).

Preparation Example 16: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-chlorobenzyl)morpholine-2-carboxyamide (compound 122)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-chlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.47-7.45 (m, 1H), 7.37-7.35 (m, 1H), 7.23-7.19 (m, 2H), 6.94-6.88 (m, NH, 1H), 5.64-5.57 (m, NH, 2H), 4.08-3.95 (m, 3H), 3.82-3.61 (m, 3H), 3.27-3.24 (m, 1H), 2.74-2.71 (m,1H), 2.32-2.27 (m, 1H), 2.13-1.78 (m, 12H), 1.64-1.61 (m, 2H).

Preparation Example 17: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(3-chloro-4-fluorobenzyl)morpholine-2-carboxyamide (compound 123)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-chloro-4-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.38-7.37 (m, 1H), 7.19-7.16 (m, 1H), 7.11-7.06 (m, 1H), 6.93-6.87 (m, NH, 1H), 5.66 (m, NH, 2H), 4.05-3.94 (m, 3H), 3.74-3.67 (m, 1H), 3.52-3.43 (m, 2H), 3.21-3.18 (m, 1H), 2.67-2.64 (m, 1H), 2.21-2.14 (m, 1H), 2.06-1.80 (m, 12H), 1.63-1.60 (m, 2H).

Preparation Example 18: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-methylbenzyl)morpholine-2-carboxyamide (compound 124)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-methylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.21-7.18 (m, 2H), 7.14-7.12 (m, 2H), 6.93-6.87 (m,NH, 1H), 5.87-5.69 (m, NH, 2H), 4.05-4.02 (m, 2H), 3.94-3.92 (m, 1H), 3.73-3.66 (m, 1H), 3.56-3.44 (m, 2H), 3.24-3.21 (m, 1H), 2.69-2.66 (m, 1H), 2.34 (s, 3H), 2.17-2.14 (m, 1H), 2.05-1.81 (m, 12H), 1.63-1.59 (m, 2H).

Preparation Example 19: Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-nitrobenzyl)morpholine-2-carboxyamide (compound 125)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 4-nitrobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ8.26-8.16 (m, 2H), 7.58-7.49 (m, 2H), 6.92-6.90 (m, NH, 1H), 4.08-3.96 (m, 3H), 3.76-3.59 (m, 6H), 3.23-3.20 (m, 1H), 2.67-2.65 (m, 1H), 2.26-2.21 (m, 1H), 2.02-1.82 (m, 1H), 1.64-1.61 (m, 2H).

Preparation Example 20: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-nitrobenzyl)morpholine-2-carboxyamide (compound 126)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-nitrobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ 8.20 (d, J = 8.8 Hz, 2H), 7.52 (d, J =8.8 Hz, 2H), 6.93-6.87 (m, NH, 1H), 5.63 (m, Nh, 1H), 5.47 (m, NH, 1H), 4.07-3.96 (m, 3H), 3.75-3.59 (m, 3H), 3.25-3.18 (m, 1H), 2.67-2.64 (m, 1H), 2.28-2.19 (m, 1H), 2.08-1.70 (m, 14H).

Preparation Example 21: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(pyridine-4-ylmethyl)morpholine-2-carboxyamide (compound 127)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 4-pyridinealdehyde was used.

¹H NMR (400 MHz, CDCl₃)δ8.58-8.56 (m, 2H), 7.39-7.27 (m, 2H), 6.89 (m, NH, 1H), 5.64 (m, NH, 1H), 5.43 (m, NH, 1H), 4.06-3.95 (m, 3H), 3.74-3.68 (m, 1H), 3.58-3.48 (m, 2H), 3.21-3.18 (m, 1H), 2.66-2.63 (m, 1H), 2.24-1.63 (m, 14H).

Preparation Example 22: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-nitrobenzyl)morpholine-2-carboxyamide (compound 128)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-nitrobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.85-7.83 (m, 1H), 7.60-7.53 (m, 2H), 7.45-7.41 (m, 1H), 6.91-6.85 (m, NH, 1H), 5.59 (m, NH, 1H), 5.32 (m, NH, 1H), 4.03-3.94 (m, 4H), 3.74-3.65 (m, 2H), 3.12-3.09 (m, 1H), 2.68-2.64 (m, 1H), 2.35-2.27 (m, 1H), 2011-1.79(m, 14H).

Preparation Example 23: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-aminobenzyl)morpholine-2-carboxyamide (compound 129)

N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-nitrobenzyl)morpholine-2-carboxyamide (40 mg 0.09 mmol) was dissolved in ethanol (3 ml), added with, Pd/C 5% (12 mg, 30%), and stirred under a hydrogen gas atmosphere. After the reaction was completed, the resultant product was subjected to filtration, and concentration so as to provide N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-aminobenzyl)morpholine-2-carboxyamide (30 mg, 0.07 mmol, 81%).

¹H NMR (400 MHz, CDCl₃)δ7.13-7.09 (m, 1H), 6.98-6.97 (m, 1H), 6.93-6.87 (m, NH, 1H), 6.69-6.65 (m, 2H), 5.60 (m, NH, 1H), 5.23 (m, NH, 1H), 4.61 (m, NH, 1H), 4.06-3.95 (m, 3H), 3.69-3.56 (m, 2H), 3.52-3.47 (m, 1H), 3.26-3.22 (m, 1H), 2.70-2.67 (m, 1H), 2.19-1.74 (m, 12H), 1.65-1.59 (m, 2H).

Preparation Example 24: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(isoquinoline-5-ylmethyl)morpholine-2-carboxyamide (compound 130)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that isoquinoline-5-aldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ9.28 (m, 1H), 8.58-8.57 (m, 1H), 8.09-8.07 (m, 1H), 7.94-7.92 (m, 1H), 7.63-7.61 (m, 1H), 7.56-7.52 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.58 (m, NH, 1H), 5.22 (m, NH, 1H), 4.08-3.87 (m, 5H), 3.71-3.66 (m, 1H), 3.31-3.28 (m, 1H), 2.70-2.67 (m, 1H), 2.30-2.23 (m, 1H), 2.12-1.82 (m, 12H), 1.65 (m, 2H).

Preparation Example 25: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-trifluoromethylbenzyl)morpholine-2-carboxyamide (compound 133)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-trifluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.80-7.78 (m, 1H), 7.65-7.63 (m, 1H), 7.55-7.52 (m, 1H), 7.38-7.34 (m, 1H), 6.94-6.89 (m, NH, 1H), 5.59 (m, NH, 1H), 5.25 (m, NH, 1H), 4.10-3.96 (m, 3H), 3.78-3.66 (m, 3H), 3.24-3.20 (m, 1H), 2.69-2.66 (m, 1H), 2.32-2.22 (m, 1H), 2.11-1.76 (m, 12H), 1.65-1.60 (m, 2H).

Preparation Example 26: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2,4,6-trifluorobenzyl)morpholine-2-carboxyamide (compound 134)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2,4,6-trifluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ6.91-6.85 (m, NH, 1H), 6.70-6.66 (m, 2H), 5.59 (m, NH, 1H), 5.24 (m, NH, 1H), 4.06-3.94 (m, 3H), 3.74-3.66 (m, 3H), 3.23-3.21 (m, 1H), 2.72-2.69 (m, 1H), 2.29-2.24 (m, 1H), 2.11-1.73 (m, 12H), 1.64-1.60 (m, 2H).

Preparation Example 27: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-methylbenzyl)morpholine-2-carboxyamide (compound 141)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-methylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.23-7.21 (m, 1H), 7.19-7.12 (m, 3H), 6.94-6.88 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.06-4.00 (m, 2H), 3.95-3.92 (m, 1H), 3.70-3.62 (m, 1H), 3.58-3.54 (m, 1H), 3.45-3.42 (m, 1H), 3.26-3.21 (m, 1H), 2.66-2.63 (m, 1H), 2.38 (s, 3H), 2.20-2.14 (m, 1H), 2.09-1.74 (m, 12H), 1.65-1.61 (m, 2H).

Preparation Example 28: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-fluorobenzyl)morpholine-2-carboxyamide (compound 142)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.38-7.35 (m, 1H), 7.29-7.27 (m, 1H), 7.13-7.01 (m, 2H), 6.92-6.88 (m, NH, 1H), 5.60 (m, NH, 1H), 5.26 (m, NH, 1H), 4.04-3.93 (m, 3H), 3.75-3.70 (m, 1H), 3.64-3.62 (m, 2H), 3.25 (m, 1H), 2.72-2.70 (m, 1H), 2.26-2.21 (m, 1H), 2.08-1.84 (m, 12H), 1.61-1.59 (m, 2H).

Preparation Example 29: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-cyanobenzyl)morpholine-2-carboxyamide (compound 143)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-cyanobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.67-7.66 (m, 1H), 7.61-7.54 (m, 2H), 7.40-7.37 (m, 1H), 6.93-6.87 (m, NH, 1H), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.05-3.97 (m, 3H), 3.82-3.66 (m, 3H), 3.18-3.15 (m, 1H), 2.76-2.73 (m, 1H), 2.41-2.34 (m, 1H), 2.11-1.76 (m, 12H), 1.65-1.63 (m, 2H).

Preparation Example 30: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-bromo-2-fluorobenzyl)morpholine-2-carboxyamide (compound 144)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-fluoro-4-bromobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.33-7.20 (m, 3H), 6.92-6.86 (m, NH, 1H), 5.60 (m, NH, 1H), 5.37 (m, NH, 1H), 4.05-4.00 (m, 2H), 3.97-3.94 (m, 1H), 3.75-3.66 (m,1H), 3.62-3.52 (m, 2H), 3.22-3.18 (m, 1H), 2.70-2.67 (m, 1H), 2.27-2.21 (m, 1H), 2.11-1.74 (m, 12H), 1.64-1.61 (m, 2H).

Preparation Example 31: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-bromo-4-hydroxybenzyl)morpholine-2-carboxyamide (compound 145)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-bromo-4-hydroxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.43 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.4Hz, 2.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.93-6.87 (m, OH, NH, 2H), 5.59 (m, NH, 1H), 5.20 (m, NH, 1H), 4.07-4.01 (m, 2H), 3.97-3.94 (m, 1H), 3.75-3.67 (m, 1H), 3.50-3.40 (m, 2H), 3.23-3.19 (m, 1H), 2.68-2.66 (m, 1H), 2.19-2.13 (m, 1H), 2.07-1.79 (m, 12H), 1.64-1.58 (m, 2H).

Preparation Example 32: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2,4,6-methylbenzyl)morpholine-2-carboxyamide (compound 146)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2,4,6-trimethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ6.94-6.89 (m, NH, 1H), 6.84 (s, 2H), 5.59 (m, NH, 1H), 5.23 (m, NH, 1H), 4.06-4.02 (m, 1H), 3.99-3.94 (m, 1H), 3.89-3.87 (m, 1H), 3.62-3.57 (m, 1H), 3.54-3.43 (m, 2H), 3.21-3.19 (m, 1H), 2.59-2.57 (m, 1H), 2.40-2.16 (m, 10H), 2.11-1.77 (m, 12H), 1.64-1.54 (m, 2H).

Preparation Example 33: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(3-fluorobenzyl)morpholine-2-carboxyamide (compound 153)

A desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃)δ7.31-7.26 (m, 1H), 7.10-7.06 (m, 2H), 7.02-6.88 (m, 2H), 5.60 (m, NH, 1H), 5.36 (m, NH, 1H), 4.09-3.94 (m, 3H), 3.77-3.68 (m, 1H), 3.59-3.49 (m, 2H), 3.25 (m, 1H), 2.70-2.67 (m, 1H), 2.22-2.15 (m, 1H), 2.10-1.74 (m, 12H), 1.65-1.61 (m, 2H).

[Example 14]

Preparation Example 1: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-phenylethyl)morpholine-2-carboxyamide (compound 102)

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

4-benzylmorpholine-2-carboxylic acid hydrochloride (100 mg, 0.39 mmol) was dissolved in CH₂Cl₂ (3 ml), and added with BOP (173 mg, 0.39 mmol) and DIPEA (152 mg, 1.17 mmol), followed by stirring. The resultant mixture was added with methyl 4-aminoadamantane-1-carboxylate (82 mg, 0.39 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. . The resultant mixture was purified by column chromatography(EA/n-Hex = 1:1) so as to provide N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (120 mg, 0.29 mmol, 75 %).

Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide

Acetophenone (1 g, 8.32 mmol) was dissolved in MeOH (30 ml), and slowly added with NaBH₄(472 mg, 12.48 mmol) at 0℃, followed by stirring for 5 hours at room temperature. After the reaction was completed, the organic layer was separated by EA and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:4) so as to provide 1-phenylethanol (840 mg, 6.87 mmol, 82 %).

¹H NMR (400 MHz, CDCl₃) δ7.44-7.35 (m, 4H), 7.32-7.29 (m, 1H), 4.94-4.92 (m, 1H), 1.82 (br, OH, 1H), 1.53-1.52 (m, 3H).

1-phenylethanol (840 mg, 6.87 mmol) was dissolved in CH₂Cl₂ (10 ml), and slowly added with SOCl₂ (2.6 g, 13.74 mmol), followed by stirring at room temperature for 5 hours. After the reaction was completed, the resultant mixture was concentrated and purified by column chromatography (EA/n-Hex = 1:4) so as to provide (1-chloroethyl)benzene mixture (840 mg, 5.97 mmol, 87 %).

¹H NMR (400 MHz, CDCl₃) δ7.39-7.29 (m, 5H), 5.15-5.09 (m, 1H), 1.89-1.87 (m, 3H).

Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-phenylethyl)morpholine-2-carboxyamide (compound 101)

N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide (300 mg, 0.836 mmol) and (1-chloroethyl)benzene (235 mg, 1.672 mmol) were dissolved in DMF (5 ml), and added with K₂CO₃ (347 mg, 2.508 mmol) and KI (416 mg, 2.508 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by H₂O and EA, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-phenylethyl)morpholine-2-carboxyamide (520 mg, 1.22 mmol, 73 %).

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.28 (m, 5H), 6.93-6.89 (m, NH, 1H), 4.15-3.98 (m, 3H), 3.87-3.58 (m, 4H), 3.50 (m, 1H), 3.55-3.16 (m, 1H), 2.82-2.55 (m, 1H), 2.23-2.17 (m, 1H), 2.06-1.59 (m, 14H), 1.40 (m, 3H).

N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-phenylethyl)morpholine-2-carboxyamide (520 mg, 1.22 mmol) was dissolved in THF (5 ml) and MeOH (5 ml), added with LiOH (256 mg, 6.1 mmol) dissolved in H₂O (5 ml), and stirred at room temperature for 4 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄ so as to provide N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-phenylethyl)morpholine-2-carboxyamide mixture(542 mg).

N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (542 mg, 1.31 mmol) was dissolved in CH₂Cl₂ (15 ml), and added with EDCI (502 mg, 2.62 mmol) and HOBt (401 mg, 2.62 mmol), followed by stirring. The resultant mixture was added with ammonium hydroxide solution (6 ml), followed by stirring at room temperature for 4 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9) so as to provide N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (390 mg, 0.94 mmol, 72 %).

¹H NMR (400 MHz, CDCl₃) δ7.30-7.27 (m, 5H), 6.91 (m, NH, 1H), 5.60 (m, NH, 1H), 5.34 (m, NH, 1H), 4.06-3.84 (m, 3H), 3.76-3.60 (m, 1H), 3.49-3.48 (m, 1H), 3.35-3.13 (m, 1H), 2.82-2.56 (m, 1H),2.22-2.16 (m, 1H), 2.08-1.82 (m, 12H), 1.63 (m, 2H), 1.40 (m, 3H).

Preparation Example 2: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(4-cyanophenyl)ethyl)morpholine-2-carboxamide (compound 105)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 4-cyanoacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.64-7.62 (m, 2H), 7.47-7.43 (m, 2H), 6.94-6.84 (m, NH, 1H), 5.59 (m, NH, 1H), 5.29 (m, NH, 1H), 4.09-3.87 (m, 3H), 3.77-3.66 (m, 1H), 3.52-3.39 (m, 2H), 3.06-2.81 (m, 1H), 2.48-2.19 (m, 1H), 2.10-1.76 (m, 15H), 1.38-1.36 (m, 3H).

Preparation Example 3: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(4-trifluoromethoxyphenyl)ethyl)morpholine-2-carboxamide (compound 131)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 4-trifluoromethoxyacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.35-7.32 (m, 2H), 7.18-7.16 (m, 2H), 6.95-6.80 (m, NH, 1H), 5.58 (m, NH, 1H), 5.24 (m, NH, 1H), 4.09-3.89 (m, 3H), 3.74-3.61 (m, 1H), 3.50-3.45 (m, 1H), 3.38-3.09 (m, 1H), 2.83-2.50 (m, 1H), 2.21-1.74 (m, 13H), 1.63-1.59 (m, 2H), 1.38-1.36 (m, 3H).

Preparation Example 4: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(4-trifluoromethylphenyl)ethyl)morpholine-2-carboxamide (compound 132)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 4-trifluoromethylacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.62-7.58 (m, 2H), 7.46-7.42 (m, 2H), 6.94-6.83 (m, NH, 1H), 5.59 (m, NH, 1H), 5.32 (m, NH, 1H), 4.10-3.86 (m, 3H), 3.75-3.61 (m, 1H), 3.61-3.47 (m, 1H), 3.47-3.07 (m, 1H), 2.85-2.49 (m, 1H), 2.22-1.73 (m, 13H), 1.62 (m, 2H), 1.39-1.37 (m, 3H).

Preparation Example 5: Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(2-methylphenyl)ethyl)morpholine-2-carboxamide (compound 135)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 2-methylacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.46-7.38 (m, 1H), 7.20-7.12 (m, 3H), 6.96-6.89 (m, NH, 1H), 4.09-3.82 (m, 3H), 3.72-3.11 (m, 6H), 2.82-2.53 (m, 1H), 2.36 (s, 3H), 2.31-1.78 (m, 13H), 1.62-1.58 (m, 2H), 1.33-1.30 (m, 3H).

Preparation Example 6: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(2-methylphenyl)ethyl)morpholine-2-carboxamide (compound 136)

¹H NMR (400 MHz, CDCl₃)δ7.46-7.39 (m, 1H), 7.23-7.16 (m, 1H), 7.15-7.12 (m, 2H), 6.97-6.90 (m, NH, 1H), 5.61 (m, NH, 1H), 5.32 (m, NH, 1H), 4.08-3.83 (m, 3H), 3.72-3.67 (m, 1H), 3.66-3.10 (m, 1H), 2.83-2.53 (m, 1H), 2.36 (s, 3H), 2.27-1.81 (m, 13H), 1.62-1.60 (m, 2H), 1.33-1.28 (m, 3H).

Preparation Example 7: Synthesis of N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(2-chlorophenyl)ethyl)morpholine-2-carboxamide (compound 137)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 2-chloroacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.59-7.57 (m, 1H), 7.35-7.33 (m, 1H), 7.28-7.25 (m, 1H), 7.19-7.15 (m, 1H), 6.96-6.94 (m, NH, 1H), 4.09-4.07 (m, 2H), 3.91-3.84 (m, 2H), 3.68 (s, 3H), 3.65-3.55(m, 2H), 2.53-2.50 (m, 1H), 2.13-1.80 (m, 13H), 1.64-1.59 (m, 2H), 1.33-1.31 (m, 3H).

Preparation Example 8: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(2-chlorophenyl)ethyl)morpholine-2-carboxamide (compound 138)

¹H NMR (400 MHz, CDCl₃)δ7.59-7.53 (m, 1H), 7.36-7.32 (m, 1H), 7.27-7.23 (m, 1H), 7.20-7.15 (m, 1H), 6.97-6.88 (m, NH, 1H), 5.60 (m, NH, 1H), 5.23 (m, NH, 1H), 4.10-4.04 (m, 1H), 4.02-3.84 (m, 3H), 3.80-3.60 (m, 1H), 3.57-3.07 (m, 1H), 3.00-2.50 (m, 1H), 2.29-1.80 (m, 13H), 1.65-1.60 (m, 2H), 1.33-1.31 (m, 3H).

Preparation Example 9: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(3-trifluoromethylphenyl)ethyl)morpholine-2-carboxamide (compound 139)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 3-trifluoromethylacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.57-7.52 (m, 3H), 7.47-7.43 (m, 1H), 6.95-6.88 (m, NH, 1H), 5.59 (m, NH, 1H), 5.25 (m, NH, 1H), 4.10-4.07 (m, 1H), 4.02-3.86 (m, 2H), 3.78-3.61 (m, 1H), 3.54-3.08 (m, 2H), 2.83-2.49 (m, 1H), 2.25-1.82 (m, 13H), 1.64-1.60 (m, 2H), 1.40-1.38 (m, 3H).

Preparation Example 10: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(4-methoxyphenyl)ethyl)morpholine-2-carboxamide (compound 140)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 4-methoxyacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.23-7.19 (m, 2H), 6.94-6.83 (m, NH, 3H), 4.09-4.06 (m, 1H), 4.03-3.59 (m, 6H), 3.47-3.44 (m, 1H), 3.35-3.12 (m, 1H), 2.81-2.54 (m, 1H), 2.21-1.81 (m, 13H), 1.63-1.59 (m, 2H), 1.39-1.36 (m, 3H).

Preparation Example 11: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(2-fluorophenyl)ethyl)morpholine-2-carboxamide (compound 148)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 2-fluoroacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.46-7.36 (m, 1H), 7.26-7.20 (m, 1H), 7.17-7.11 (m, 1H), 7.07-7.00 (m, 1H), 6.95-6.83 (m, NH, 1H), 5.61 (m, NH, 1H), 5.32 (m, NH, 1H), 4.10-3.93 (m, 3H), 3.89-3.71 (m, 2H), 3.67-3.47 (m, 1H), 3.19-2.88 (m, 1H), 2.60-1.58 (m, 15H), 1.44-1.38 (m, 3H).

Preparation Example 12: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(2-methoxyphenyl)ethyl)morpholine-2-carboxamide (compound 149)

¹H NMR (400 MHz, CDCl₃)δ7.48-7.38 (m, 1H), 7.24-7.17 (m, 1H), 6.99-6.86 (m, 2H+NH), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.11-3.90 (m, 3H), 3.87-3.72 (m, 5H), 3.67-3.15 (m, 2H), 2.95-2.58 (m, 1H), 2.22-1.73 (m, 12H), 1.64-1.53 (m, 2H), 1.34-1.31 (m, 3H).

Preparation Example 13: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(2-trifluoromethylphenyl)ethyl)morpholine-2-carboxamide (compound 150)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 2-trifluoromethylacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.87-7.83 (m, 1H), 7.63-7.53 (m, 2H), 7.36-7.30 (m, 1H), 7.02-6.83 (m, NH, 1H),5.59 (m, NH, 1H), 5.28 (m, NH, 1H), 4.10-3.89 (m, 3H), 3.83-3.77 (m, 1H), 3.74-3.65 (m, 2H), 3.62-3.06 (m, 1H), 2.92-2.34 (m, 1H), 2.27-1.73 (m, 12H), 1.66-1.60 (m, 2H), 1.34-1.31 (m, 3H).

Preparation Example 14: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(3-methylphenyl)ethyl)morpholine-2-carboxamide (compound 151)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 3-methylacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.22-7.19 (m, 1H), 7.11-7.07 (m, 3H), 6.95-6.84 (m, NH, 1H), 5.59 (m, NH, 1H), 5.29 (m, NH, 1H), 4.10-3.85 (m, 4H), 3.78-3.61 (m, 1H), 3.50-3.41 (m, 1H), 3.33-3.12 (m, 1H), 2.84-2.55 (m, 1H), 2.36 (s, 3H), 2.22-1.73 (m, 12H), 1.61 (m, 2H), 1.39-1.38 (m, 3H).

Preparation Example 15: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(2,6-difluorophenyl)ethyl)morpholine-2-carboxamide (compound 152)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 2,6-difluoroacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.26-7.15 (m, NH, 1H), 6.95-6.80 (m, 3H), 5.59 (m, NH, 1H), 5.26 (m, NH, 1H), 4.10-3.65 (m, 5H), 3.42-3.28 (m, 1H), 2.87-2.72 (m, 1H), 2.23-1.56 (m, 18H).

Preparation Example 16: Synthesis of N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-(3-fluorophenyl)ethyl)morpholine-2-carboxamide (compound 154)

A desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 3-fluoroacetophenone was used.

¹H NMR (400 MHz, CDCl₃)δ7.30-7.25 (m, 1H), 7.12-7.02 (m, 2H), 6.97-6.84 (m, 2H), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.09-3.61 (m, 4H), 3.48-3.08 (m, 2H), 2.83-2.53 (m, 1H), 2.23-1.63 (m, 15H), 1.38-1.36 (m, 3H).

[Example 15]

Preparation Example 1: Synthesis of N-((4-adamantane-1-carbonyl)morpholine-2-yl)methyl-3-chloro-2-methylbenzenesulfonamide(compound 164)

Into a 50mL-1-neck-rbf, 4-benzyl-2-(chloromethyl)morpholine (1 g, 4.43 mmol) and potassium phthalimide (1.65 g, 8.91 mmol) were charged, and were dissolved in dimethylformamide(3ml). K₂CO₃(1.23 g, 8.90 mmol) was charged thereto, and the mixture was heated to 120℃, followed by stirring overnight. After the completion of the reaction was monitored with TLC, the resultant product was cooled to room temperature, and slowly added with water (3 ml) to produce a solid. The product was stirred for 1 hour, and filtered. The produced solid was washed with water, and dried in a 60℃ oven so as to provide 2-(4-benzylmorpholine-2-yl)methylphthalimide (1.35 g, 90.6 %). The dried mixture was directly used in the following reaction.

Into a 50mL-1-neck-rbf, 2-(4-benzylmorpholine-2-yl)methylphthalimide (1.3 g, 3.87 mmol) and hydrazine hydrate(0.38 g, 7.6 mmol) were charged, and EtOH (13 ml) was charged thereto. The mixture was heated to 80℃, followed by stirring for 4 hours. After the completion of the reaction was monitored with TLC, the resultant solution was cooled to room temperature, and inorganic matters were separated by filtration. The filtrate was vacuum-concentrated, added with 10% NaOH solution (10 m), and extracted with methylenechloride(20 ml) twice. The extracted organic layer was completely collected, dried with MgSO₄, and filtered. The filtrate was vacuum-concentrated to produce a solid. The produced solid was dried in a 60℃ oven so as to (4-benzylmorpholine-2-yl)methanamine (550 mg, 69 %). The dried mixture was directly used in the following reaction.

Into a 25mL-1-neck-rbf, (4-benzylmorpholine-2-yl)methanamine (483 mg, 2.34 mmol) was charged, and dissolved in methylenechloride (3 ml). 3-chloro-2-methylbenzene-1-sulfonyl chloride (633 mg, 2.812 mmol) was charged thereto, and the resultant solution was cooled to 0℃. Triethylamine (0.391 ml, 2.812 mmol) was charged thereto, and the mixture was heated to room temperature, followed by stirring for 1 hour. After the completion of the reaction was monitored with TLC, the reaction was terminated with addition of water (3 ml). The organic layer was separated, washed with Brine (3 ml), dried with MgSO₄, and filtered. The filtrate was vacuum-concentrated, and purified by column chromatography so as to provide methyl N-((4-benzylmorpholine-2-yl)methyl)-3-chloro-2-methylbenzenesulfonamide (550 mg, 59.5 %).

¹H NMR (400 MHz, CDCl₃) δ7.91-7.93 (dd, 1H), 7.59-7.61 (dd, , 1H), 4.98-5.00 (m, 1H), 3.81-3.84 (dt, 1H), 3.55-3.61 (m, 2H), 3.04-3.10 (m, 1H), 2.83-2.91 (m, 1H), 2.71 (s, 3H), 2.55-2.67 (m, 2H), 2.11-2.20 (m, 1H), 1.83-1.88 (t, 1H).

Preparation Example 2: Synthesis of N-((4-adamantane-1-carbonyl)morpholine-2-yl)methyl-3-chloro-2-methylbenzenesulfonamide (compound 165)

Into a 50mL-1-neck-rbf, N-((4-benzylmorpholine-2-yl)methyl)-3-chloro-2-methylbenzenesulfonamide (498 mg, 1.26 mmol) was charged, and dissolved in ethanol (7.5 ml). 5% Pd/C (55 mg) was charged thereto in driblets, and H₂ gas was charged into a reactor by using a balloon. After the completion of the reaction was monitored with TLC, the resultant solution was filtered through celite. The filtrate was vacuum-concentrated to produce a solid. The produced solid was dried in a 60℃ oven so as to provide 3-chloro-2-methyl-N-(morpholine-2-ylmethyl)benzenesulfonamide (350 mg, 91 %). The dried mixture was directly used in the following reaction.

Into a 50mL-1-neck-rbf, 3-chloro-2-methyl-N-(morpholine-2-ylmethyl)benzenesulfonamide (50 mg, 0.164 mmol) was charged, and dissolved in methylenechloride (2 ml). BOP(72.55 mg, 0.164 mmol) and 1-adamantanecarboxylic acid (29.57 mg, 0.164 mmol) were charged thereto, methylenechloride (2 ml) was charged thereto, and DIPEA (0.057 ml, 0.327 mmol) was charged thereto, followed by stirring at room temperature overnight. After the completion of the reaction was monitored with TLC, the reaction was terminated with addition of water (4 ml). The organic layer was separated, washed with Brine (4 ml), dried with MgSO₄, and filtered. The filtrate was vacuum-concentrated, and purified by column chromatography so as to provide N-((4-adamantane-1-carbonyl)morpholine-2-yl)methyl-3-chloro-2-methylbenzenesulfonamide (20 mg, 26 %).

¹H NMR (400 MHz, CDCl₃) δ7.98-8.00 (dd, 1H), 7.47-7.51 (m, 1H), 7.33-7.36 (m, 1H), 4.94-4.97 (m, 1H), 4.26-4.33 (t, 2H), 3.86-3.89(m, 1H), 3.41-3.47 (m, 2H), 3.38-3.47 (m, 2H), 3.10-3.16(m, 1H), 2.88-3.02 (m, 2H). 2.71-2.74 (m, 1H), 2.57(s, 3H), 1.69-2.07 (m, 15H)

[Example 16]

Preparation Example 1: Synthesis of (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide

¹H NMR (400 MHz, DMSO-d ₆) δ 12.18 (bs, -COOH), 7.67-7.65 (m, 2H), 7.53-7.40 (m, 3H), 4.61 (d, J = 10.8 Hz, 1H), 4.39 (m, 2H), 4.05-4.94 (m, 2H), 3.43 (d, J = 12.0 Hz, 1H), 3.20-3.07 (m, 3H).

4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4 g, 15.52 mmol) was dissolved in MeOH (200 ml), and slowly added with H₂SO₄ (4 ml), followed by stirring for 12 hours under reflux. After the reaction was completed, the resultant mixture was concentrated and purified by column chromatography (EA/n-Hex = 1:1) so as to provide 4-benzylmorpholine-2-carboxy ester compound (3.4 g, 14.15 mmol, 93 %).

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.28 (m, 5H), 4.28-4.25 (m, 1H), 4.05-3.96 (m, 1H), 3.76-3.70 (m, 4H), 3.60-3.52 (m, 2H), 3.00-2.97 (m, 1H), 2.65-2.62 (m, 1H), 2.38-2.30 (m, 2H).

4-benzylmorpholine-2-carboxy ester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂0 (2000 ml), and added with Candida rugasa (0.9 g), followed by stirring for 12 hours. After the reaction was completed, a water layer was separated. Through concentration, (S)-4-benzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %) was obtained.

4-oxo-adamantane-1-carboxyacid (10 g, 51.5 mmol) was dissolved in 7N NH₃ in MeOH (50 ml), and added with 10% Pd/C (1 g, 10%), followed by stirring under hydrogen gas atmosphere for 12 hours. After the reaction was completed, the resultant product was added with H₂O and filtered so as to provide (E)-4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0℃, MeOH (85 ml) was added with AcCl (16.08 g, 204.85 mmol), and at room temperature, (E)-4-amino-adamantane-1-carboxyacid (8.0 g, 40.97 mmol) was added thereto, followed by stirring at 45℃ for 12 hours. After the reaction was completed, the produced solid was filtered by using acetonitrile so as to provide (E)-4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).

Synthesis of (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)4-benzyl)morpholine-2-carboxyamide

(S)-4-benzylmorpholine-2-carboxylic acid hydrochloride (100 mg, 0.39 mmol) was dissolved in CH₂Cl₂ (3 ml), and added with BOP (173 mg, 0.39 mmol) and DIPEA (152 mg, 1.17 mmol), followed by stirring. The resultant mixture was added with (E)-methyl 4-aminoadamantane-1-carboxylate (82 mg, 0.39 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)4-benzyl)morpholine-2-carboxyamide (120 mg, 0.29 mmol, 75 %).

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.24 (m, 5H), 6.93-6.91 (m, NH, 1H), 4.08-4.03 (m, 2H), 3.98-3.92 (m, 1H), 3.78-3.68 (m, 4H), 3.64-3.47 (m, 2H), 3.28-3.22 (m, 1H), 2.70-2.67 (m, 1H), 2.20-2.14 (m, 1H), 2.06-1.79 (m, 12H), 1.63-1.60 (m, 2H).

Synthesis of (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), added with LiOH (50 mg, 1.2 mmol) dissolved in H₂O (1 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄ so as to provide (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide mixture(70 mg).

Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide (compound 166)

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide mixture (70 mg, 0.176 mmol) was dissolved in CH₂Cl₂ (2 ml), and added with EDCI (68 mg, 0.35 mmol) and HOBt (46 mg, 0.26 mmol), followed by stirring. The resultant mixture was added with ammonium hydroxide solution (1.88 ml), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9) so as to provide (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide (25 mg, 0.06 mmol, 35 %).

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.25 (m, 5H), 6.90-6.88 (m, NH, 1H), 5.60 (m, NH, 1H), 5.26 (m, NH, 1H), 4.07-4.01 (m, 2H), 3.97-3.93 (m, 1H), 3.74-3.67 (m, 1H), 3.61-3.49 (m, 2H), 3.26-3.23 (m, 1H), 2.70-2.67 (m, 1H), 2.20-2.06 (m, 4H), 1.99-1.97 (m, 2H), 1.89-1.74 (m, 8H).

[Example 17]

4-benzylmorpholine-2-carboxy ester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂0 (2000 ml), and added with Candida rugasa (0.9 g), followed by stirring for 12 hours. After the reaction was completed, the water layer was separated. Through concentration, (S)-4-benzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %) was obtained.

4-oxo-adamantane-1-carboxyacid (10 g, 51.5 mmol) was dissolved in 7N NH₃ in MeOH (50 ml), and added with 10% Pd/C (1 g, 10%), followed by stirring under a hydrogen gas atmosphere for 12 hours. After the reaction was completed, the resultant product was added with H₂O and filtered so as to provide (Z)-4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0℃, MeOH (85 ml) was added with AcCl (16.08 g, 204.85 mmol), and at room temperature, (E)-4-amino-adamantane-1-carboxyacid (8.0 g, 40.97 mmol) was added thereto, followed by stirring at 45℃ for 12 hours. After the reaction was completed, the produced solid was filtered by using acetonitrile so as to provide (Z)-4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).

Synthesis of (Z)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)4-benzyl)morpholine-2-carboxyamide

(S)-4-benzylmorpholine-2-carboxylic acid hydrochloride (100 mg, 0.39 mmol) was dissolved in CH₂Cl₂ (3 ml), and added with BOP (173 mg, 0.39 mmol) and DIPEA (152 mg, 1.17 mmol), followed by stirring. The resultant mixture was added with (Z)-methyl 4-aminoadamantane-1-carboxylate (82 mg, 0.39 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide (Z)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)4-benzyl)morpholine-2-carboxyamide (120 mg, 0.29 mmol, 75 %).

Synthesis of (Z)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide

(Z)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), added with LiOH (50 mg, 1.2 mmol) dissolved in H₂O (1 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄ so as to provide (Z)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide mixture(70 mg).

Synthesis of (Z)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide (compound 167)

(Z)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide mixture (70 mg, 0.176 mmol) was dissolved in CH₂Cl₂ (2 ml), and added with EDCI (68 mg, 0.35 mmol) and HOBt (46 mg, 0.26 mmol), followed by stirring. The resultant mixture was added with ammonium hydroxide solution (1.88 ml), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9) so as to provide (Z)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide (25 mg, 0.06 mmol, 35 %).

[Example 18]

Preparation Example 1: Synthesis of (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide

4-benzylmorpholine-2-carboxy ester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂0 (2000 ml), and added with Candida rugasa (1.5 g), followed by stirring for 12 hours. After the reaction was completed, an organic layer was separated. Through concentration, (R)-4-benzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %) was obtained.

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.13 (m, 5H), 4.25-4.23 (m, 1H), 4.00-3.95 (m, 1H), 3.73 (s, 3H), 3.71-3.64 (m, 1H), 3.55 (s, 2H), 2.89-2.85 (m, 1H), 2.63-2.60 (m, 1H), 2.38-2.26 (m, 2H).

(R)-4-benzylmorpholine-2-carboxyester (5g, 21.25 mmol) was dissolved in THF (20 ml) and MeOH (20 ml), added with LiOH (2.6 g, 63.75 mmol) dissolved in H₂O (20 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄ so as to provide (R)-4-benzylmorpholine-2-carboxylic acid hydrochloride compound mixture (4.5 g).

4-oxo-adamantane-1-carboxyacid (10 g, 51.5 mmol) was dissolved in 7N NH₃ in MeOH (50 ml), and added with 10% Pd/C (1 g, 10%), followed by stirring under a hydrogen gas atmosphere for 12 hours. After the reaction was completed, the resultant product was added with H₂O and filtered so as to provide (E)-4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

(R)-4-benzylmorpholine-2-carboxylic acid hydrochloride (219 mg, 0.96 mmol) was dissolved in CH₂Cl₂ (3 ml), and added with BOP (424 mg, 0.96 mmol) and DIPEA (372 mg, 2.88 mmol), followed by stirring. The resultant mixture was added with (E)-methyl 4-aminoadamantane-1-carboxylate (200 mg, 0.96 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol, 25 %).

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.25 (m, 5H), 6.93-6.91 (m, NH, 1H), 4.08-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.76-3.68 (m, 4H), 3.61-3.58 (m, 1H), 3.52-3.49 (m, 1H), 3.27-3.25 (m, 1H), 2.70-2.68 (m, 1H), 2.20-2.14 (m, 1H), 2.10-1.79 (m, 12H), 1.63-1.60 (m, 2H).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), added with LiOH (50 mg, 1.2 mmol) dissolved in H₂O (1 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄, so as to provide (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide mixture(70 mg).

Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (compound 168)

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (70 mg, 0.176 mmol) was dissolved in CH₂Cl₂ (2 ml), and added with EDCI (68 mg, 0.35 mmol) and HOBt (46 mg, 0.26 mmol), followed by stirring. The resultant mixture was added with ammonium hydroxide solution (1.88 ml), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9) so as to provide (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (25 mg, 0.06 mmol, 35 %).

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.28 (m, 5H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.24 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.97-3.93 (m, 1H), 3.76-3.70 (m, 1H), 3.61-3.49 (m, 2H), 3.27-3.25 (m, 1H), 2.71-2.68 (m, 1H), 2.21-2.14 (m, 1H), 2.07-1.82 (m, 11H), 1.64-1.61 (m, 2H).

[Example 19]

Preparation Example 1: Synthesis of (E)-N-[5-(methylaminecarboxy)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide

(R)-4-benzylmorpholine-2-carboxyester (5g, 21.25 mmol) was dissolved in THF (20 ml) and MeOH (20 ml), added with LiOH (2.6 g, 63.75 mmol) dissolved in H₂O (20 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄, so as to provide (R)-4-benzylmorpholine-2-carboxylic acid hydrochloride compound mixture (4.5 g).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0℃ or less, MeOH (85 ml) was added with AcCl (16.08 g, 204.85 mmol), and at room temperature, (E)-4-amino-adamantane-1-carboxyacid (8.0 g, 40.97 mmol) was added thereto, followed by stirring at 45℃ or less for 12 hours. After the reaction was completed, the produced solid was filtered by using acetonitrile so as to provide (E)-4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), added with LiOH (50 mg, 1.2 mmol) dissolved in H₂O (1 ml), stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄ so as to provide (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide mixture(70 mg).

Synthesis of (E)-N-[5-(methylaminecarboxy)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide (compound 178)

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide mixture (100 mg, 0.25 mmol) was dissolved in CH₂Cl₂ (2 ml), and added with EDCI (68 mg, 0.35 mmol) and HOBt (46 mg, 0.26 mmol), followed by stirring. The resultant mixture was added with NHCH₃ solution (0.5 ml), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9) so as to provide (E)-N-[5-(methylaminecarboxy)tricyclo[3,3,1,13,7]dec-2-yl]-4-((S)-4-benzyl)morpholine-2-carboxyamide (25 mg, 0.06 mmol, 35 %).

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.25 (m, 5H), 6.90-6.88 (m, NH, 1H), 5.60 (m, NH, 1H), 4.07-4.01 (m, 2H), 3.97-3.93 (m, 1H), 3.74-3.67 (m, 1H), 3.61-3.49 (m, 2H), 2.35 (s, 3H), 3.26-3.23 (m, 1H), 2.70-2.67 (m, 1H), 2.20-2.06 (m, 4H), 1.99-1.97 (m, 2H), 1.89-1.74 (m, 8H).

[Example 20]

Preparation Example 1: Synthesis of (E)-N-[5-(cyanide)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

Synthesis of (E)-N-[5-(cyanide)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (compound 226)

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (300 mg, 0.75 mmol) was dissolved in pyridine (2 ml), and added with methanesulfonylchloride (343 mg, 3 mmol), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide (E)-N-[5-(cyanide)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (25 mg, 0.06 mmol, 35 %).

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.28 (m, 5H), 6.94-6.92 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.99-3.93 (m, 1H), 3.76-3.70 (m, 1H), 3.61-3.49 (m, 2H), 3.27-3.25 (m, 1H), 2.71-2.68 (m, 1H), 2.21-2.14 (m, 1H), 2.07-1.82 (m, 11H), 1.64-1.61 (m, 2H).

[Example 21]

4-benzylmorpholine-2-carboxy ester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂0 (2000 ml), and added with Candida rugasa (1.5 g), followed by stirring for 12 hours. After the reaction was completed, the organic layer was separated. Through concentration, (R)-4-benzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %) was obtained.

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0℃, MeOH (85 ml) was added with AcCl (16.08 g, 204.85 mmol), and at room temperature, (Z)-4-amino-adamantane-1-carboxyacid (8.0 g, 40.97 mmol) was added thereto, followed by stirring at 45℃ for 12 hours. After the reaction was completed, the produced solid was filtered by using acetonitrile so as to provide (Z)-4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).

(R)-4-benzylmorpholine-2-carboxylic acid hydrochloride (219 mg, 0.96 mmol) was dissolved in CH₂Cl₂ (3 ml), and added with BOP (424 mg, 0.96 mmol) and DIPEA (372 mg, 2.88 mmol), followed by stirring. The resultant mixture was added with (Z)-methyl 4-aminoadamantane-1-carboxylate (200 mg, 0.96 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide (Z)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide(100 mg, 0.24 mmol, 25 %).

(Z)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), added with LiOH (50 mg, 1.2 mmol) dissolved in H₂O (1 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2N-HCl to pH 5, and extracted with EA. The organic layer was dried and filtered with MgSO₄, so as to provide (Z)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide mixture(70 mg).

Synthesis of (Z)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (compound 169)

(Z)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (70 mg, 0.176 mmol) was dissolved in CH₂Cl₂ (2 ml), and added with EDCI (68 mg, 0.35 mmol) and HOBt (46 mg, 0.26 mmol), followed by stirring. The resultant mixture was added with ammonium hydroxide solution (1.88 ml), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH₂Cl₂ and H₂O, and dried and filtered with MgSO₄. The resultant mixture was purified by column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9) so as to provide (Z)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (25 mg, 0.06 mmol, 35 %).

[Example 22]

Preparation Example 1: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide (compound 172)

In a 1-liter flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105 ml). In another flask, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml), and the solution was added to the above 1-liter flask. The reaction mixture was stirred at room temperature for 12 hours, and toluene (205 ml) was added thereto, after which the reaction mixture was cooled to -5 ℃. A solution of t-BuOK (50.84 g, 444 mmol) in THF (202 ml) was added slowly to the flask containing the reaction mixture cooled to -5 ℃. Then, the reaction mixture was stirred at -5 ℃ for 50 minutes, washed once with brine and dried with MgSO₄and filtered. The filtrate was distilled under reduced pressure to remove the solvent, and the residue was separated by column chromatography, thereby obtaining a 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %).

4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), and the solution was refluxed for 2.5 hours and cooled to -10 ℃. The produced solid was filtered and washed with acetone (300 ml) cooled to -10 ℃. The resulting solid compound was dried in an oven at 60 ℃, thereby obtaining a 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).

The 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4 g, 15.52 mmol) was dissolved in MeOH (200 ml), and H₂SO₄ (4 ml) was added slowly thereto, and the mixture was stirred under reflux for 12 hours. After completion of the reaction, the solution was concentrated and subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining a 4-benzylmorpholine-2-carboxyester compound (3.4 g, 14.15 mmol, 93 %).

The 4-benzylmorpholine-2-carboxyester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂O (2000 ml), and Candida rugasa (1.5 g) was added thereto, followed by stirring for 12 hours. After completion of the reaction, the organic layer was isolated and concentrated, thereby obtaining a (R)-4-benzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %).

(R)-4-benzylmorpholine-2-carboxyester (5 g, 21.25 mmol) was dissolved in THF (20 ml) and MeOH (20 ml) and added to a solution of LiOH (2.6 g, 63.75 mmol) in H₂O (20 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with ethyl acetate (EA). The organic layer was dried with MgSO₄ and filtered, thereby obtaining a (R)-4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4.5 g).

4-oxo-adamantane-1-carboxylic acid (10 g, 51.5 mmol) was dissolved in a solution of 7N NH₃ in MeOH (50 ml), and 10% Pd/C (1 g, 10%) was added thereto. The mixture solution was stirred for 12 hours under a hydrogen gas atmosphere. After completion of the reaction, H₂O was added to the reaction solution, followed by filtration, thereby obtaining (E)-4-amino-adamantane-1-carboxylic acid (8.17 g, 41.8 mmol, 81%).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0 ℃, AcCl (16.08 g, 204.85 mmol) was added to MeOH (85 ml), and then (E)-4-amino-adamantane-1-carboxylic acid (8.0 g, 40.97 mmol) was added thereto at room temperature, followed by stirring at 45 ℃ for 12 hours. After completion of the reaction, the produced solid was filtered using acetonitrile, thereby obtaining (E)-4-amino-adamantane-1-carboxylic acid (8.17 g, 41.8 mmol, 81%).

(R)-4-benzylmorpholine-2-carboxylic acid hydrochloride (219 mg, 0.96 mmol) was dissolved in CH₂Cl₂ (3 ml), and BOP (424 mg, 0.96 mmol) and DIPEA (372 mg, 2.88 mmol) were added thereto, followed by stirring. Then, (E)-methyl 4-aminoadamantane-1-carboxylate (200 mg, 0.96 mmol) was added to the stirred solution, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄ and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol, 25 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (200 mg, 0.49 mmol) was dissolved in EtOH (10 ml), and 5% Pd/C (40 mg) was added thereto, followed by stirring at room temperature under a hydrogen gas atmosphere for 5 hours. After completion of the reaction, the solution was filtered through celite and concentrated, thereby obtaining a (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide compound (100 mg, 0.31 mmol, 63 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide (100 mg, 0.31 mmol) and 4-cyanobenzaldehyde (41 mg, 0.31 mmol) were dissolved in dichloroethane (2 ml), and acetic acid (37 mg, 0.62 mmol) was added thereto. The mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using H₂O and CH₂Cl₂, and the separated organic layer was dried with MgSO₄ and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 5:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide (41 mg, 0.09 mmol, 30 %).

¹H NMR (400 MHz, CDCl₃) δ 7.64-7.62 (m, 2H), 7.47-7.45 (m, 2H), 6.92-6.90 (m, NH, 1H), 4.07-4.02 (m, 2H), 3.98-3.95 (m, 1H), 3.76-3.69 (m, 1H), 3.68 (s, 3H), 3.64-3.54 (m, 1H), 3.22-3.19 (m, 1H), 2.66-2.63 (m, 1H), 2.25-2.19 (m, 1H), 2.07-1.79 (m, 12H), 1.63-1.59 (m, 1H).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide (40 mg, 0.09 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), and a solution of LiOH (11 mg, 0.27 mmol) in H₂O (1 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with ethyl acetate (EA). Then, the organic layer was dried with MgSO₄and filtered, thereby obtaining a (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide compound (20 mg).

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide (20 mg, 0.047 mmol) was dissolved in CH₂Cl₂ (1 ml), and EDCI (18 mg, 0.094 mmol) and HOBt (11 mg, 0.071 mmol) were added thereto, followed by stirring. Then, an ammonium hydroxide solution (0.6 ml) was added thereto, followed by stirring at room temperature for 5 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9), thereby obtaining (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide (10 mg, 0.02 mmol, 50 %).

¹H NMR (400 MHz, CDCl₃) δ 7.64-7.62 (m, 2H), 7.47-7.45 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.29 (m, NH, 1H), 4.08-4.03 (m, 2H), 3.99-3.96 (m, 1H), 3.77-3.70 (m, 1H), 3.64-3.55 (m, 2H), 3.22-3.19 (m, 1H), 2.67-2.64 (m, 1H), 2.26-2.19 (m, 1H), 2.07-1.62 (m, 14H).

Preparation Example 2: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-cyanobenzyl)morpholine-2-carboxyamide (compound 225)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-cyanobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, 1H), 7.59-7.57 (m, 2H), 7.46-7.42 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.60 (m, NH, 1H), 5.38 (m, NH, 1H), 4.08-4.03 (m, 2H), 3.99-3.94 (m, 1H), 3.77-3.71 (m, 1H), 3.61-3.52 (m, 2H), 3.21-3.18 (m, 1H), 2.67-2.64 (m, 1H), 2.26-2.19 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 3: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-cyanobenzyl)morpholine-2-carboxyamide (compound 199)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-cyanobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (m, 1H), 7.60-7.54 (m, 2H), 7.41-7.36 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.32 (m, NH, 1H), 4.06-4.03 (m, 2H), 4.00-3.96 (m, 1H), 3.82-3.66 (m, 3H), 3.19-3.15 (m, 1H), 2.77-2.74 (m, 1H), 2.41-2.34 (m, 1H), 2.12-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 4: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-chlorobenzyl)morpholine-2-carboxyamide (compound 170)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-chlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.48-7.45 (m, 1H), 7.38-7.35 (m, 1H), 7.27-7.19 (m, 2H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.26 (m, NH, 1H), 4.09-4.04 (m, 2H), 3.99-3.95 (m, 1H), 3.77-3.71 (m, 1H), 3.67 (m, 2H), 3.28-3.25 (m, 1H), 2.75-2.71 (m, 1H), 2.34-2.27 (m, 1H), 2.10-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 5: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-bromobenzyl)morpholine-2-carboxyamide (compound 171)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-bromobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.54 (m, 1H), 7.47-7.45 (m, 1H), 7.31-7.27 (m, 1H), 7.16-7.11 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.09-4.04 (m, 2H), 3.99-3.95 (m, 1H), 3.77-3.71 (m, 1H), 3.65 (s, 2H), 3.28-3.24 (m, 1H), 2.75-2.71 (m, 1H), 2.35-2.28 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 6: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-fluorobenzyl)morpholine-2-carboxyamide (compound 208)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.27 (m, 2H), 7.04-6.99 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.24 (m, NH, 1H), 4.07-4.03 (m, 2H), 3.98-3.93 (m, 1H), 3.75-3.69 (m, 1H), 3.56-3.46 (m, 2H), 3.25-3.21 (m, 1H), 2.68-2.65 (m, 1H), 2.20-2.13 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 7: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-fluorobenzyl)morpholine-2-carboxyamide (compound 198)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.31-7.26 (m, 1H), 7.10-7.06 (m, 2H), 6.99-6.92 (m, 2H), 5.59 (m, NH, 1H), 5.30 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.98-3.95 (m, 1H), 3.76-3.71 (m, 1H), 3.59-3.48 (m, 2H), 3.25-3.22 (m, 1H), 2.70-2.67 (m, 1H), 2.22-2.16 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 8: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-fluorobenzyl)morpholine-2-carboxyamide (compound 197)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.42-7.38 (m, 1H), 7.29-7.24 (m, 1H), 7.14-7.10 (m, 1H), 7.07-7.02 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.25 (m, NH, 1H), 4.06-4.04 (m, 2H), 3.98-3.94 (m, 1H), 3.76-3.70 (m, 1H), 3.63 (s, 2H), 3.28-3.24 (m, 1H), 2.74-2.71 (m, 1H), 2.29-2.22 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 9: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-chlorobenzyl)morpholine-2-carboxyamide (compound 218)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-chlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.25 (m, 4H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.31 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.97-3.93 (m, 1H), 3.75-3.69 (m, 1H), 3.57-3.46 (m, 2H), 3.24-3.20 (m, 1H), 2.68-2.65 (m, 1H), 2.20-2.14 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 10: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-chlorobenzyl)morpholine-2-carboxyamide (compound 219)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-chlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.34 (m, 1H), 7.27-7.24 (m, 2H), 7.23-7.19(m, 1H), 6.93-6.91 (m, NH, 1H), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.06-4.04 (m, 2H), 3.98-3.94 (m, 1H), 3.77-3.70 (m, 1H), 3.57-3.46 (m, 2H), 3.24-3.21 (m, 1H), 2.69-2.66 (m, 1H), 2.22-2.15 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 11: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-bromobenzyl)morpholine-2-carboxyamide (compound 217)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-bromobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.47-7.44 (m, 2H), 7.22-7.19 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.21 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.97-3.94 (m, 1H), 3.72-3.71 (m, 1H), 3.56-3.44 (m, 2H), 3.24-3.21 (m, 1H), 2.68-2.65 (m, 1H), 2.20-2.17 (m, 1H), 2.08-1.58 (m, 14H).

Preparation Example 12: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-bromobenzyl)morpholine-2-carboxyamide (compound 200)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-bromobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.49 (m, 1H), 7.42-7.39 (m, 1H), 7.26-7.18 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.32 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.98-3.94 (m, 1H), 3.76-3.70 (m, 1H), 3.56-3.45 (m, 2H), 3.25-3.21 (m, 1H), 2.69-2.66 (m, 1H), 2.21-2.15 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 13: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-methylbenzyl)morpholine-2-carboxyamide (compound 183)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-methylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.20 (m, 1H), 7.13-7.08 (m, 3H), 6.94-6.92 (m, NH, 1H), 5.58 (m, NH, 1H), 5.24 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.97-3.93 (m, 1H), 3.76-3.70 (m, 1H), 3.57-3.46 (m, 2H), 3.27-3.24 (m, 1H), 2.72-2.68 (m, 1H), 2.36 (s, 3H), 2.20-2.13 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 14: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-methylbenzyl)morpholine-2-carboxyamide (compound 184)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-methylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.12 (m, 4H), 6.94-6.92 (m, NH, 1H), 5.58 (m, NH, 1H), 5.23 (m, NH, 1H), 4.06-4.02 (m, 2H), 3.95-3.91 (m, 1H), 3.70-3.64 (m, 1H), 3.58-3.42 (m, 2H), 3.26-3.22 (m, 1H), 2.67-2.63 (m, 1H), 2.38 (s, 3H), 2.20-2.14 (m, 1H), 2.09-1.62 (m, 14H).

Preparation Example 15: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-trifluoromethylbenzyl)morpholine-2-carboxyamide (compound 206)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-trifluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.60-7.58 (m, 2H), 7.47-7.45 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.57 (m, NH, 1H), 5.22 (m, NH, 1H), 4.09-4.04 (m, 2H), 3.98-3.95 (m, 1H), 3.77-3.70 (m, 1H), 3.65-3.55 (m, 2H), 3.24-3.21 (m, 1H), 2.68-2.65 (m, 1H), 2.24-2.17 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 16: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-trifluoromethylbenzyl)morpholine-2-carboxyamide (compound 205)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-trifluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.59 (m, 1H), 7.55-7.53 (m, 2H), 7.47-7.43 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.34 (m, NH, 1H), 4.09-4.04 (m, 2H), 3.98-3.95 (m, 1H), 3.77-3.71 (m, 1H), 3.64-3.54 (m, 2H), 3.25-3.21 (m, 1H), 2.69-2.66 (m, 1H), 2.24-2.17 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 17: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-trifluoromethylbenzyl)morpholine-2-carboxyamide (compound 204)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-trifluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.80-7.78 (m, 1H), 7.65-7.63 (m, 1H), 7.55-7.52 (m, 1H), 7.38-7.34 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.29 (m, NH, 1H), 4.09-4.04 (m, 2H), 3.98-3.95 (m, 1H), 3.78-3.70 (m, 3H), 3.24-3.20 (m, 1H), 2.69-2.66 (m, 1H), 2.32-2.26 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 18: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-trifluoromethoxybenzyl)morpholine-2-carboxyamide (compound 203)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-trifluoromethoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.34 (m, 2H), 7.19-7.17 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.25 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.98-3.95 (m, 1H), 3.76-3.70 (m, 1H), 3.59-3.49 (m, 2H), 3.25-3.22 (m, 1H), 2.69-2.66 (m, 1H), 2.22-2.15 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 19: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-trifluoromethoxybenzyl)morpholine-2-carboxyamide (compound 181)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-trifluoromethoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.33 (m, 1H), 7.27-7.25 (m, 1H), 7.21 (m, 1H), 7.14-7.12 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.24 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.98-3.95 (m, 1H), 3.77-3.70 (m, 1H), 3.62-3.50 (m, 2H), 3.26-3.22 (m, 1H), 2.69-2.66 (m, 1H), 2.22-2.16 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 20: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-trifluoromethoxybenzyl)morpholine-2-carboxyamide (compound 194)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-trifluoromethoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.55-7.53 (m, 1H), 7.34-7.23 (m, 3H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.98-3.94 (m, 1H), 3.76-3.70 (m, 1H), 3.62 (s, 2H), 3.25-3.21 (m, 1H), 2.70-2.67 (m, 1H), 2.29-2.23 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 21: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-ethylbenzyl)morpholine-2-carboxyamide (compound 190)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-ethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.20 (m, 3H), 7.16-7.12 (m, 1H), 6.95-6.93 (m, NH, 1H), 5.60 (m, NH, 1H), 5.24 (m, NH, 1H), 4.06-4.02 (m, 2H), 3.95-3.91 (m, 1H), 3.70-3.63 (m, 1H), 3.62-3.42 (m, 2H), 3.28-3.24 (m, 1H), 2.75 (q, J = 7.6 Hz, 2H), 2.67-2.63 (m, 1H), 2.19-2.12 (m, 1H), 2.09-1.83 (m, 12H), 1.65-1.59 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H).

Preparation Example 22: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-difluoromethoxybenzyl)morpholine-2-carboxyamide (compound 196)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-difluoromethoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.42-7.40 (m, 1H), 7.33-7.29 (m, 1H), 7.23-7.19 (m, 1H), 7.16-7.14 (m, 1H), 6.93-6.91 (m, NH, 1H), 6.75-6.28 (m, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.05-3.95 (m, 3H), 3.76-3.67 (m, 1H), 3.63-3.52 (m, 2H), 3.23-3.19 (m, 1H), 2.75-2.72 (m, 1H), 2.33-2.26 (m, 1H), 2.09-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 23: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-difluoromethoxybenzyl)morpholine-2-carboxyamide (compound 233)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-difluoromethoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.31 (m, 2H), 7.09-7.07 (m, 2H), 6.93-6.91 (m, NH, 1H), 6.70-6.33 (m, 1H), 5.60 (m, NH, 1H), 5.30 (m, NH, 1H), 4.07-4.03 (m, 2H), 3.98-3.94 (m, 1H), 3.75-3.69 (m, 1H), 3.56-3.48 (m, 2H), 3.24-3.20 (m, 1H), 2.69-2.66 (m, 1H), 2.21-2.15 (m, 1H), 2.09-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 24: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methoxybenzyl)morpholine-2-carboxyamide (compound 210)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-methoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.21 (m, 2H), 7.02 (m, NH, 1H), 6.94-6.85 (m, 2H), 5.59 (m, NH, 1H), 5.28 (m, NH, 1H), 3.96-3.95 (m, 2H), 3.94-3.93 (m, 1H), 3.82(s, 3H) 3.75-3.71 (m, 1H), 3.55-3.41 (m, 2H), 3.25-3.22 (m, 1H), 2.69-2.67 (m, 1H), 2.19-2.15 (m, 1H), 2.14-1.61 (m, 14H).

Preparation Example 25: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,3-dimethylbenzyl)morpholine-2-carboxyamide (compound 191)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,3-dimethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.11-7.08 (m, 1H), 7.07-7.01 (m, 2H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.29 (m, NH, 1H), 4.06-4.01 (m, 2H), 3.95-3.91 (m, 1H), 3.69-3.63 (m, 1H), 3.59-3.41 (m, 2H), 3.26-3.22 (m, 1H), 2.66-2.63 (m, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.19-2.12 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 26: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,4-dimethylbenzyl)morpholine-2-carboxyamide (compound 228)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,4-dimethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.10-7.08 (m, 1H), 6.99 (m, 1H), 6.96-6.92 (m, 2H), 5.61 (m, NH, 1H), 5.40 (m, NH, 1H), 4.06-4.00 (m, 2H), 3.94-3.90 (m, 1H), 3.69-3.63 (m, 1H), 3.54-3.38 (m, 2H), 3.24-3.21 (m, 1H), 2.66-2.63 (m, 1H), 2.34 (s, 3H), 2.31 (s, 3H), 2.18-2.11 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 27: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,6-dimethylbenzyl)morpholine-2-carboxyamide (compound 182)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,6-dimethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.10-7.06 (m, 1H), 7.02-7.00 (m, 2H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.28 (m, NH, 1H), 4.06-4.04 (m, 1H), 4.00-3.97 (m, 1H), 3.93-3.89 (m, 1H), 3.63-3.58 (m, 1H), 3.57-3.49 (m, 2H), 3.23-3.19 (m, 1H), 2.60-2.57 (m, 1H), 2.39 (s, 6H), 2.28-2.22 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 28: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-fluoro-4-cyanobenzyl)morpholine-2-carboxyamide (compound 207)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-fluoro-4-cyanobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.60-7.50 (m, 1H), 7.26-7.23 (m, 2H), 7.02-6.97 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.40 (m, NH, 1H), 4.09-4.04 (m, 2H), 4.02-3.97 (m, 1H), 3.78-3.71 (m, 1H), 3.63-3.51 (m, 3H), 3.22-3.17 (m, 1H), 2.67-2.64 (m, 1H), 2.28-2.19 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 29: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-fluoro-4-bromobenzyl)morpholine-2-carboxyamide (compound 209)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-fluoro-4-bromobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.22 (m, 3H), 6.92-6.90 (m, NH, 1H), 5.61 (m, NH, 1H), 5.40 (m, NH, 1H), 4.02-3.99 (m, 2H), 3.98-3.94 (m, 1H), 3.75-3.68 (m, 1H), 3.57 (m, 1H), 3.23-3.19 (m, 1H), 2.70-2.67 (m, 1H), 2.28-2.21 (m, 1H), 2.07-1.61 (m, 14H).

Preparation Example 30: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-fluoro-2-methylbenzyl)morpholine-2-carboxyamide (compound 223)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-fluoro-2-methylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.18-7.14 (m, 1H), 6.94-6.92 (m, NH, 1H), 6.90-6.79 (m, 2H), 5.59 (m, NH, 1H), 5.31 (m, NH, 1H), 4.06-4.00 (m, 2H), 3.96-3.92 (m, 1H), 3.69-3.63 (m, 1H), 3.52-3.38 (m, 2H), 3.23-3.19 (m, 1H), 2.64-2.61 (m, 1H), 2.37 (s, 3H), 2.19-2.13 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 31: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-bromo-2-methoxybenzyl)morpholine-2-carboxyamide (compound 227)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-bromo-2-methoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.21 (m, 1H), 7.09-7.07 (m, 1H), 7.01 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.24 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.96-3.93 (m, 1H), 3.82 (m, 3H), 3.76-3.70 (m, 1H), 3.59-3.50 (m, 2H), 3.25-3.22 (m, 1H), 2.72-2.69 (m, 1H), 2.25-2.20 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 32: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,3-difluorobenzyl)morpholine-2-carboxyamide (compound 188)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,3-difluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.16-7.13 (m, 1H), 7.11-7.05 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.21 (m, NH, 1H), 4.07-4.03 (m, 2H), 3.98-3.95 (m, 1H), 3.76-3.70 (m, 1H), 3.65 (s, 2H), 3.25-3.22 (m, 1H), 2.73-2.70 (m, 1H), 2.30-2.24 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 33: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,6-difluorobenzyl)morpholine-2-carboxyamide (compound 187)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,6-difluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.23 (m, 1H), 6.93-6.87 (m, 3H), 5.59 (m, NH, 1H), 5.29 (m, NH, 1H), 4.06-4.01 (m, 2H), 3.97-3.93 (m, 1H), 3.75-3.67 (m, 3H), 3.28-3.25 (m, 1H), 2.75-2.73 (m, 1H), 2.33-2.26 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 34: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,4-difluorobenzyl)morpholine-2-carboxyamide (compound 224)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,4-difluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.32 (m, NH, 1H), 6.93-6.78 (m, 3H), 5.59 (m, NH, 1H), 5.32 (m, NH, 1H), 4.06-4.05 (m, 2H), 4.03-4.02 (m, 1H), 3.98-3.70 (m, 1H), 3.59 (m, 2H), 3.24-3.21 (m, 1H), 2.72-2.68 (m, 1H), 2.27-2.40 (m, 1H), 2.07-1.27 (m, 14H).

Preparation Example 35: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,4-ditrifluoromethylbenzyl)morpholine-2-carboxyamide (compound 221)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,4-ditrifluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.01-7.99 (m, 1H), 7.90 (m, 1H), 7.82-7.80 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.37 (m, NH, 1H), 4.10-3.97 (m, 3H), 3.79-3.73 (m, 3H), 3.21-3.17 (m, 1H), 2.68-2.65 (m, 1H), 2.37-2.31 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 36: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-trifluoromethyl-4-fluorobenzyl)morpholine-2-carboxyamide (compound 232)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-trifluoromethyl-4-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.79-7.76 (m, 1H), 7.36-7.34 (m, 1H), 7.26-7.21 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.33 (m, NH, 1H), 4.08-4.03 (m, 2H), 3.99-3.96 (m, 1H), 3.76-3.70 (m, 1H), 3.66 (m, 2H), 3.21-3.18 (m, 1H), 2.67-2.64 (m, 1H), 2.32-2.25 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 37: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-trifluoromethyl-6-fluorobenzyl)morpholine-2-carboxyamide (compound 222)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-trifluoromethyl-6-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.49 (m, 1H), 7.43-7.37 (m, 1H), 7.27-7.24 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.30 (m, NH, 1H), 4.05-4.03 (m, 1H), 3.99-3.92 (m, 2H), 3.72 (m, 2H), 3.69-3.63 (m, 1H), 3.19-3.16 (m, 1H), 2.68-2.65 (m, 1H), 2.37-2.31 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 38: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,3-dichlorobenzyl)morpholine-2-carboxyamide (compound 189)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,3-dichlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.41-7.39 (m, 2H), 7.22-7.18 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.08-4.04 (m, 2H), 4.00-3.96 (m, 1H), 3.77-3.71 (m, 1H), 3.68 (s, 2H), 3.26-3.22 (m, 1H), 2.74-2.71 (m, 1H), 2.35-2.29 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 39: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-chloro-6-fluorobenzyl)morpholine-2-carboxyamide (compound 195)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-chloro-6-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.20 (m, 2H), 7.02-6.97 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.04-3.99 (m, 2H), 3.96-3.92 (m, 1H), 3.77-3.66 (m, 3H), 3.28-3.26 (m, 1H), 2.75-2.72 (m, 1H), 2.39-2.32 (m, 1H), 2.08-1.61 (m, 14H).

Preparation Example 40: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,4,6-trifluorobenzyl)morpholine-2-carboxyamide (compound 220)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,4,6-trifluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 6.91-6.89 (m, NH, 1H), 6.70-6.66 (m, 2H), 5.59 (m, NH, 1H), 5.30 (m, NH, 1H), 4.03-3.94 (m, 3H), 3.74-3.67 (m, 3H), 3.25-3.22 (m, 1H), 3.72-3.70 (m, 1H), 2.30-2.24 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 41: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2,6-difluorobenzyl)morpholine-2-carboxyamide (compound 229)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-cyano-2,6-difluorobenzaldehyde was used.

¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.82 (m, 1H), 7.64-7.62 (m, 1H), 7.21-7.19 (m, NH, 1H), 7.00 (m, NH, 1H), 6.75 (m, NH, 1H), 3.94-3.88 (m, 3H), 3.79-3.77 (m, 1H), 3.67 (m, 2H), 3.56-3.51 (m, 1H), 2.90-2.86 (m, 1H), 2.65-2.62 (m, 1H), 2.23-2.17 (m, 1H), 2.06-2.01 (m, 1H), 1.86-1.40 (m, 12H).

Preparation Example 42: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2-fluorobenzyl)morpholine-2-carboxyamide (compound 230)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-cyano-2-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.61-7.57 (m, 1H), 7.47-7.45 (m, 1H), 7.37-7.33 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.60 (m, NH, 1H), 5.35 (m, NH, 1H), 4.06-4.04 (m, 2H), 4.00-3.97 (m, 1H), 3.77-3.71 (m, 1H), 3.66 (m, 2H), 3.22-3.18 (m, 1H), 2.70-2.67 (m, 1H), 2.33-2.27 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 43: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,4-dichlorobenzyl)morpholine-2-carboxyamide (compound 234)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,4-dichlorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.43-7.39 (m, 2H), 7.28-7.23 (m, 1H), 6.93-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.98-3.96 (m, 1H), 3.75-3.70 (m, 1H), 3.62 (s, 2H), 3.24-3.21 (m, 1H), 2.71-2.68 (m, 1H), 2.32-2.27 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 44: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-chloro-5-trifluoromethylbenzyl)morpholine-2-carboxyamide (compound 235)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-chloro-5-trifluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.78 (m, 1H), 7.54-7.46 (m, 2H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.23 (m, NH, 1H), 4.11-4.04 (m, 2H), 4.00-3.97 (m, 1H), 3.79-3.65 (m, 3H), 3.26-3.23 (m, 1H), 2.71-2.68 (m, 1H), 2.36-2.30 (m, 1H), 2.20-2.14 (m, 1H), 2.10-1.61 (m, 13H).

Preparation Example 45: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-fluoro-3-trifluoromethylbenzyl)morpholine-2-carboxyamide (compound 236)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-fluoro-3-trifluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.52 (m, 2H), 7.19-7.14 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.99-3.96 (m, 1H), 3.76-3.70 (m, 1H), 3.58-3.49 (m, 2H), 3.22-3.19 (m, 1H), 2.67-2.64 (m, 1H), 2.24-2.18 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 46: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-fluoro-2-bromobenzyl)morpholine-2-carboxyamide (compound 237)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-fluoro-2-bromobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.45-7.42 (m, 1H), 7.32-7.28 (m, 1H), 7.05-7.00 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.61 (m, NH, 1H), 5.43 (m, NH, 1H), 4.06-4.04 (m, 2H), 3.98-3.96 (m, 1H), 3.76-3.70 (m, 1H), 3.60 (s, 2H), 3.24-3.21 (m, 1H), 2.71-2.68 (m, 1H), 2.34-2.27 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 47: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-5-fluoro-3-trifluoromethylbenzyl)morpholine-2-carboxyamide (compound 238)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 5-fluoro-3-trifluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.38 (m, 1H), 7.31-7.30 (m, 1H), 7.25-7.23 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.61 (m, NH, 1H), 5.39 (m, NH, 1H), 4.09-4.03 (m, 2H), 4.00-3.96 (m, 1H), 3.78-3.72 (m, 1H), 3.63-3.53 (m, 2H), 3.23-3.19 (m, 1H), 2.68-2.65 (m, 1H), 2.26-2.19 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 48: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methoxy-2-trifluoromethylbenzyl)morpholine-2-carboxyamide (compound 239)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-methoxy-2-trifluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.65-7.63 (m, 1H), 7.16-7.15 (m, 1H), 7.06-7.03 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.61 (m, NH, 1H), 5.34 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.97-3.95 (m, 1H), 3.85 (s, 3H), 3.75-3.69 (m, 1H), 3.62 (m, 2H), 3.21-3.18 (m, 1H), 2.67-2.65 (m, 1H), 2.28-2.22 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 49: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-fluoro-4-trifluoromethylbenzyl)morpholine-2-carboxyamide (compound 240)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-fluoro-4-trifluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.58-7.54 (m, 1H), 7.42-7.40 (m, 1H), 7.33-7.31 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.60 (m, NH, 1H), 5.33 (m, NH, 1H), 4.07-4.03 (m, 2H), 3.99-3.95 (m, 1H), 3.77-3.70 (m, 1H), 3.66 (s, 2H), 3.24-3.20 (m, 1H), 2.72-2.69 (m, 1H), 2.32-2.25 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 50: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3,5-difluorobenzyl)morpholine-2-carboxyamide (compound 241)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3,5-difluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 6.93-6.86 (m, 3H), 6.74-6.68 (m, 1H), 5.61 (m, NH, 1H), 5.35 (m, NH, 1H), 4.08-4.03 (m, 2H), 3.99-3.95 (m, 1H), 3.77-3.71 (m, 1H), 3.56-3.46 (m, 2H), 3.23-3.19 (m, 1H), 2.69-2.66 (m, 1H), 2.23-2.17 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 51: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-bromo-2,6-difluorobenzyl)morpholine-2-carboxyamide (compound 244)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-bromo-2,6-difluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.13-7.08 (m, 2H), 6.90-6.88 (m, NH, 1H), 5.60 (m, NH, 1H), 5.34 (m, NH, 1H), 4.05-3.99 (m, 2H), 3.97-3.93 (m, 1H), 3.73-3.67 (m, 3H), 3.24-3.21 (m, 1H), 2.72-2.69 (m, 1H), 2.30-2.24 (m, 1H), 2.06-2.01 (m, 1H), 1.86-1.40 (m, 13H).

Preparation Example 52: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-hydroxybenzyl)morpholine-2-carboxyamide (compound 245)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-hydroxylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.12-7.09 (m, 2H), 6.98-6.86 (m, NH, 1H), 6.72-6.69 (m, 2H), 5.69 (m, NH, 1H), 5.39 (m, NH, 1H), 4.07-4.02 (m, 2H), 3.99-3.95 (m, 1H), 3.79-3.73 (m, 1H), 3.56-3.53 (m, 1H), 3.51 (m, OH, 1H), 3.40-3.37 (m, 1H), 3.24-3.21 (m, 1H), 2.78-2.75 (m, 1H), 2.26-2.19 (m, 1H), 2.08-1.60 (m, 14H).

Preparation Example 53: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,2-difluoro-1,3-dioxalebenzyl)morpholine-2-carboxyamide (compound 256)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,2-difluoro-1,3-benzodioxale-5-carboxyaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.11 (m, 1H), 6.99 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.29 (m, NH, 1H), 4.06-4.03 (m, 2H), 3.98-3.95 (m, 1H), 3.75-3.69 (m, 1H), 3.55-3.47 (m, 2H), 3.23-3.19 (m, 1H), 2.68-2.66 (m, 1H), 2.22-2.15 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 54: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-(6-bromopyridin-3-yl)methyl)morpholine-2-carboxyamide (compound 257)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-bromo-3-pyridine aldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.32-8.30 (m, 1H), 7.59-7.56 (m, 1H), 7.48-7.46 (m, 1H), 6.92-6.90 (m, NH, 1H), 5.59 (m, NH, 1H), 5.29 (m, NH, 1H), 4.07-4.03 (m, 2H), 3.99-3.98 (m, 1H), 3.74-3.68 (m, 1H), 3.57-3.54 (m, 2H), 3.22-3.18 (m, 1H), 2.66-2.63 (m, 1H), 2.24-2.18 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.63 (m, 2H).

Preparation Example 55: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-(4-trifluoromethylpyridin-3-yl)methyl)morpholine-2-carboxyamide (compound 258)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-trifluoromethyl-3-pyridine aldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 8.68 (m, 1H), 7.90-7.88 (m, 1H), 7.69-7.67 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.23 (m, NH, 1H), 4.09-4.04 (m, 2H), 4.00-3.97 (m, 1H), 3.77-3.63 (m, 3H), 3.23-3.21 (m, 1H), 2.68-2.66 (m, 1H), 2.29-2.23 (m, 1H), 2.13-1.82 (m, 12H), 1.66-1.62 (m, 2H).

Preparation Example 56: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-sulfonylmethylbenzyl)morpholine-2-carboxyamide (compound 259)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-sulfonylmethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.92-7.90 (m, 2H), 7.57-7.54 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.27 (m, NH, 1H), 4.08-4.03 (m, 2H), 4.01-3.97 (m, 1H), 3.79-3.72 (m, 1H), 3.67-3.58 (m, 2H), 3.22-3.18 (m, 1H), 3.08 (s, 3H), 2.71-2.68 (m, 1H), 2.29-2.23 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 57: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-tert-butyloxybenzyl)morpholine-2-carboxyamide (compound 265)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-tert-butyloxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.21-7.19 (m, 2H), 6.97-6.94 (m, 2H), 6.93-6.92 (m, NH, 1H), 5.58 (m, NH, 1H), 5.32 (m, NH, 1H), 4.15-4.04 (m, 2H), 3.97-3.94 (m, 1H), 3.77-3.70 (m, 1H), 3.56-3.45 (m, 2H), 3.29-3.26 (m, 1H), 2.71-2.68 (m, 1H), 2.19-2.13 (m, 1H), 2.10-1.82 (m, 12H), 1.65-1.62 (m, 2H). 1.36 (m, 9H)

Preparation Example 58: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(1,1,2,2,-tetrafluoroethoxy)benzyl)morpholine-2-carboxyamide (compound 260)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-(1,1,2,2-tetrafluoroethoxy)benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.32 (m, 2H), 7.18-6.91 (m, 2H), 6.93-6.91 (m, NH, 1H), 6.06-5.78 (m, 1H), 5.58 (m, NH, 1H), 5.28 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.98-3.94 (m, 1H), 3.76-3.70 (m, 1H), 3.59-3.48 (m, 2H), 3.26-3.22 (m, 1H), 2.69-2.66 (m, 1H), 2.22-2.15 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 59: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-trifluoromethylthiobenzyl)morpholine-2-carboxyamide (compound 261)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-trifluoromethylthiobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.63-7.61 (m, 2H), 7.41-7.39 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.20 (m, NH, 1H), 4.09-4.04 (m, 2H), 3.99-3.96 (m, 1H), 3.77-3.72 (m, 1H), 3.71-3.52 (m, 2H), 3.23-3.22 (m, 1H), 2.70-2.67 (m, 1H), 2.24-2.18 (m, 1H), 2.10-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 60: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-acetylbenzyl)morpholine-2-carboxyamide (compound 301)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-acetylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.94-7.92 (m, 2H), 7.44-7.42 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.32 (m, NH, 1H), 4.09-4.03 (m, 2H), 3.98-3.95 (m, 1H), 3.77-3.71 (m, 1H), 3.65-3.55 (m, 2H), 3.25-3.21 (m, 1H), 2.69-2.66 (m, 1H), 2.62 (s, 3H), 2.24-2.18 (m, 1H), 2.10-1.61 (m, 14H).

Preparation Example 61: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylethanolbenzyl)morpholine-2-carboxyamide (compound 255)

(E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-acetylbenzyl)morpholine-2-carboxyamide (compound 301) (30 mg, 0.068 mmol) was dissolved in MeOH (3 ml), and NaBH₄ (3.9 mg, 0.102 mmol) was added thereto, followed by stirring at room temperature for 4 hours. After completion of the reaction, the organic layer was separated using EA and H₂O, and the separated organic layer was dried with MgSO₄and filtered, thereby obtaining (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylethanolbenzyl)morpholine-2-carboxyamide (28 mg, 0.052 mmol, 93 %).

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.35 (m, 2H), 7.32-7.30 (m, 2H), 6.92-6.90 (m, NH, 1H), 5.77 (m, NH, 1H), 5.01 (m, NH, 1H), 4.92-4.90 (m, OH, 1H), 4.04-4.01 (m, 2H), 3.98-3.95 (m, 1H), 3.76-3.71 (m, 1H), 3.59-3.48 (m, 2H), 3.17-3.14 (m, 1H), 2.74-2.71 (m, 1H), 2.24-2.18 (m, 1H), 2.10-1.61 (m, 14H), 1.52-1.50 (m, 3H).

Preparation Example 62: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylthiobenzyl)morpholine-2-carboxyamide (compound 267)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-methylthiobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.21 (m, 4H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.21 (m, NH, 1H), 4.10-4.04 (m, 2H), 3.97-3.93 (m, 1H), 3.75-3.69 (m, 1H), 3.57-3.46 (m, 2H), 3.25-3.22 (m, 1H), 2.70-2.67 (m, 1H), 2.50 (m, 3H), 2.20-2.13 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.61 (m, 2H).

Preparation Example 63: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-dimethylaminobenzyl)morpholine-2-carboxyamide (compound 268)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-dimethylaminobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.18-7.16 (m, 2H), 6.94-6.92 (m, NH, 1H), 6.73-6.69 (m, 2H), 5.59 (m, NH, 1H), 5.22 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.95-3.92 (m, 1H), 3.75-3.68 (m, 1H), 3.54-3.41 (m, 2H), 3.27-3.24 (m, 1H), 2.95 (m, 6H), 2.71-2.68 (m, 1H), 2.17-1.82 (m, 13H), 1.64 (m, 2H).

Preparation Example 64: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-bromo-4-fluorobenzyl)morpholine-2-carboxyamide (compound 269)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-bromo-4-fluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.55-7.53 (m, 1H), 7.26-7.22 (m, 1H), 7.10-7,02 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.25 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.99-3.95 (m, 1H), 3.76-3.70 (m, 1H), 3.54-3.44 (m, 2H), 3.23-3.20 (m, 1H), 2.68-2.64 (m, 1H), 2.22-2.15 (m, 1H), 2.10-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 65: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-methoxy-4-hydroxybenzyl)morpholine-2-carboxyamide (compound 271)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-methoxy-4-hydroxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 6.94-6.92 (m, NH, 1H), 6.87-6.84 (m, 2H), 6.79-6.76 (m, 1H), 5.59 (m, NH, 1H), 5.23 (m, NH, 1H), 4.09-4.05 (m, 2H), 3.97-3.94 (m, 1H),3.91 (m, 3H), 3.75-3.68 (m, 1H), 3.54-3.41 (m, 2H), 3.26-3.24 (m, 1H), 2.71-2.68 (m, 1H), 2.20-1.82 (m, 13H), 1.65-1.60 (m, 2H).

Preparation Example 66: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methoxy-3-hydroxybenzyl)morpholine-2-carboxyamide (compound 272)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-methoxy-3-hydroxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 6.94 (m, NH, 1H), 6.92-6.91 (m, 1H), 6.82-6.77 (m, 2H), 5.61 (m, NH, 1H), 5.28 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.96-3.93 (m, 1H),3.90 (m, 3H), 3.75-3.70 (m, 1H), 3.51-3.41 (m, 2H), 3.25-3.22 (m, 1H), 2.71-2.68 (m, 1H), 2.18-1.82 (m, 13H), 1.64-1.61 (m, 2H).

Preparation Example 67: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(2-hydroxyethoxy)benzyl)morpholine-2-carboxyamide (compound 273)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-(2-hydroxyethoxy)benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.23 (m, 2H), 6.94-6.91 (m, NH, 1H), 6.90-6.87 (m, 2H), 5.61 (m, NH, 1H), 5.24 (m, NH, 1H), 4.11-4.10 (m, 2H), 4.09-4.03 (m, 2H), 4.00-3.93 (m, 3H), 3.75-3.69 (m, 1H), 3.54-3.45 (m, 2H), 3.25-3.22 (m, 1H), 2.70-2.67 (m, 1H), 2.20-1.82 (m, 13H), 1.67-1.64 (m, 2H).

Preparation Example 68: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylcyanobenzyl)morpholine-2-carboxyamide (compound 278)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-methylcyanobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.23 (m, 4H), 6.93 (m, NH, 1H), 5.58 (m, NH, 1H), 5.22 (m, NH, 1H), 4.14-4.05 (m, 2H), 3.98-3.95 (m, 1H), 3.76-3.71 (m, 3H), 3.60-3.51 (m, 2H), 3.24-3.22 (m, 1H), 2.69-2.67 (m, 1H), 2.22-1.82 (m, 13H), 1.65-1.62 (m, 2H).

Preparation Example 69: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylbenzyl)morpholine-2-carboxyamide (compound 279)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-methylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.21-7.13 (m, 4H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.31 (m, NH, 1H), 4.06-4.04 (m, 2H), 3.96-3.93 (m, 1H), 3.75-3.69 (m, 1H), 3.58-3.46 (m, 2H), 3.26-3.24 (m, 1H), 2.70-2.67 (m, 1H), 2.35 (m, 3H), 2.19-1.82 (m, 13H), 1.65-1.61 (m, 2H).

Preparation Example 70: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(2-isopropyl)benzyl)morpholine-2-carboxyamide (compound 280)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-(2-isopropyl)benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.18 (m, 4H), 6.94-6.92 (m, NH, 1H), 5.60 (m, NH, 1H), 5.48 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.97-3.93 (m, 1H), 3.77-3.71 (m, 1H), 3.56-3.48 (m, 2H), 3.27-3.24 (m, 1H), 2.94-2.88 (m, 1H), 2.73-2.70 (m, 1H), 2.21-1.82 (m, 13H), 1.64-1.61 (m, 2H), 1.27-1.25 (m, 6H).

Preparation Example 71: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-tert-butylbenzyl)morpholine-2-carboxyamide (compound 281)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-tert-butylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.33 (m, 2H), 7.26-7.23 (m, 2H), 6.94-6.92 (m, NH, 1H), 5.58 (m, NH, 1H), 5.29 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.97-3.94 (m, 1H), 3.77-3.71 (m, 1H), 3.56-3.48 (m, 2H), 3.27-3.24 (m, 1H), 2.73-2.71 (m, 1H), 2.21-1.82 (m, 13H), 1.65-1.57 (m, 2H), 1.33 (m, 9H).

Preparation Example 72: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyclohexylmethyl)morpholine-2-carboxyamide (compound 282)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that cyclohexanebenzaldehyde was used.

¹H NMR (400 MHz, DMSO-d ₆) δ 7.17 (d, J = 7.6 Hz, NH, 1H), 6.99 (bs, NH, 1H), 6.73 (bs, NH, 1H), 3.93 (m, 2H), 3.79 (m, 1H), 3.57 (m, 1H), 2.87 (m, 1H), 2.62 (m, 1H), 2.09 (m, 2H), 2.01 (m, 1H), 1.89-1.64 (m, 17H), 1.48 (m, 2H), 1.17 (m, 4H), 0.82 (m, 2H).

Preparation Example 73: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methoxy-3-difluoromethoxybenzyl)morpholine-2-carboxylamide (compound 286)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-difluoromethoxy benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.11-7.09 (m, 1H), 6.99-6.98 (m, 2H), 6.94-6.92 (m, NH, 1H), 6.88-6.85 (m, 1H), 6.73-6.36 (m, 1H), 5.58 (m, NH, 1H), 5.37 (m, NH, 1H), 4.09-4.04 (m, 2H), 3.98-3.96 (m, 1H), 3.90 (s, 3H), 3.77-3.70 (m, 1H), 3.56-3.46 (m, 2H), 3.25-3.22 (m, 1H), 2.71-2.68 (m, 1H), 2.22-2.15 (m, 1H), 2.11-2.09 (m, 10H), 1.85-1.82 (m, 2H), 1.65-1.62 (m, 2H).

Preparation Example 74: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-difluoromethoxy-3-methoxybenzyl)morpholine-2-carboxyamide (compound 285)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-difluoromethoxy-3-methoxy benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.11-7.09 (m, 1H), 6.99-6.98 (m, 2H), 6.94-6.92 (m, NH, 1H), 6.88-6.85 (m, 1H), 6.73-6.36 (m, 1H), 5.59 (m, NH, 1H), 5.46 (m, NH, 1H), 4.09-4.04 (m, 2H), 3.99-3.95 (m, 1H), 3.90 (s, 3H), 3.77-3.70 (m, 1H), 3.56-3.46 (m, 2H), 3.25-3.22 (m, 1H), 2.71-2.68 (m, 1H), 2.22-2.15 (m, 1H), 2.11-2.09 (m, 10H), 1.85-1.82 (m, 2H), 1.65-1.62 (m, 2H).

Preparation Example 75: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4,4-tetrazole benzyl)morpholine-2-carboxyamide (compound 288)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-tetrazole benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (m, 2H), 7.58-7.56 (m, 2H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.22 (m, NH, 1H), 4.09-4.04 (m, 2H), 4.01-3.98 (m, 1H), 3.79-3.73 (m, 1H), 3.63 (m, 2H), 3.25-3.22 (m, 1H), 2.73-2.70 (m, 1H), 2.29-2.24 (m, 1H), 2.10-1.93 (m, 10H), 1.85-1.82 (m, 2H), 1.65-1.62 (m, 2H).

Preparation Example 76: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3,4-difluorobenzyl)morpholine-2-carboxyamide (compound 290)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3,4-difluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.21-7.02 (m, 3H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.26 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.98-3.94 (m, 1H), 3.76-3.69 (m, 1H), 3.53-3.44 (m, 2H), 3.23-3.19 (m, 1H), 2.68-2.64 (m, 1H), 2.22-2.15 (m, 1H), 2.09-1.93 (m, 10H), 1.85-1.82 (m, 2H), 1.65-1.62 (m, 2H).

Preparation Example 77: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-fluoroethoxybenzyl)morpholine-2-carboxyamide (compound 296)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-fluoroethoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.23 (m, 2H), 6.93-6.87 (m, 3H), 5.58 (m, NH, 1H), 5.21 (m, NH, 1H), 4.84-4.82 (m, 1H), 4.72-4.70 (m, 1H), 4.27-4.25 (m, 1H), 4.22-4.20 (m, 1H), 4.08-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.75-3.68 (m, 1H), 3.55-3.44 (m, 2H), 3.25-3.22 (m, 1H), 2.69-2.66 (m, 1H), 2.18-2.12 (m, 1H), 2.09-1.93 (m, 10H), 1.85-1.82 (m, 2H), 1.65-1.62 (m, 2H).

Preparation Example 78: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2,3-dihydrobenzo[1,4]dioxin-6-yl)morpholine-2-carboxyamide (compound 289)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2,3-dihydrobenzo[1,4]dioxin-6-ylaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 6.93-6.91 (m, NH, 1H), 6.85-6.76 (m, 3H), 5.58 (m, NH, 1H), 5.20 (m, NH, 1H), 4.27 (m, 4H), 4.07-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.76-3.69 (m, 1H), 3.48-3.40 (m, 2H), 3.25-3.22 (m, 1H), 2.71-2.69 (m, 1H), 2.18-1.82 (m, 13H), 1.65-1.61 (m, 2H).

Preparation Example 79: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-(1-fluoroethyl)benzyl)morpholine-2-carboxyamide (compound 291)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 1-fluoroethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.25 (m, 4H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.23 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.97-3.94 (m, 1H), 3.76-3.70 (m, 1H), 3.57-3.51 (m, 2H), 3.26-3.23 (m, 1H), 2.71-2.68 (m, 1H), 2.21-2.16 (m, 1H), 2.09-1.82 (m, 12H), 1.64-1.61 (m, 2H).

Preparation Example 80: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-(3-difluoromethoxy)benzyl)morpholine-2-carboxyamide (compound 292)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3-difluoromethoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.28 (m, 1H), 7.18-7.16 (m, 1H), 7.12 (m, 1H), 7.04-7.02 (m, 1H), 6.94-6.92 (m, NH, 1H), 6.73-6.35 (m, 1H), 5.59 (m, NH, 1H), 5.23 (m, NH, 1H), 4.09-4.04 (m, 2H), 3.98-3.95 (m, 1H), 3.77-3.71 (m, 1H), 3.60-3.49 (m, 2H), 3.24-3.21 (m, 1H), 2.70-2.67 (m, 1H), 2.23-2.17 (m, 1H), 2.09-1.82 (m, 12H), 1.65-1.61 (m, 2H).

Preparation Example 81: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-(benzo[d][1,3]dioxyl-5-ylmethyl)benzyl)morpholine-2-carboxyamide (compound 293)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that benzo[d][1,3]dioxyl-5-ylmethyl benzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 6.94-6.92 (m, NH, 1H), 6.86 (m, 1H), 6.77-6.72 (m, 2H), 5.96 (m, 2H), 5.58 (m, NH, 1H), 5.19 (m, NH, 1H), 4.08-4.03 (m, 2H), 3.97-3.94 (m, 1H), 3.75-3.68 (m, 1H), 3.50-3.42 (m, 2H), 3.24-3.22 (m, 1H), 2.71-2.68 (m, 1H), 2.20-1.82 (m, 13H), 1.65-1.62 (m, 2H).

Preparation Example 82: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-(4-hydroxymethyl)benzyl)morpholine-2-carboxyamide (compound 294)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-hydroxymethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.28 (m, 4H), 6.93-6.91 (m, NH, 1H), 5.72 (m, NH, 1H), 5.05 (m, NH, 1H), 4.71-4.70 (m, 2H), 4.05-4.02 (m, 2H), 3.98-3.94 (m, 1H), 3.77-3.70 (m, 1H), 3.59-3.51 (m, 2H), 3.20-3.17 (m, 1H), 2.73-2.70 (m, 1H), 2.24-2.22 (m, 1H), 2.20-1.81 (m, 12H), 1.64-1.58 (m, 2H).

Preparation Example 83: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-(4-fluoromethyl)benzyl)morpholine-2-carboxyamide (compound 295)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 4-fluoromethylbenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.28 (m, 4H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.44 (m, 2H), 5.29 (m, NH, 1H), 4.08-4.04 (m, 2H), 3.97-3.93 (m, 1H), 3.76-3.70 (m, 1H), 3.63-3.51 (m, 2H), 3.26-3.22 (m, 1H), 2.70-2.67 (m, 1H), 2.22-2.15 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 84: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-((1,3-difluoropropan-2-yl)oxo)benzyl)morpholine-2-carboxyamide (compound 297)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that (1,3-difluoropropan-2-yl)oxobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.28-7.24 (m, 2H), 6.96-6.93 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.22 (m, NH, 1H), 4.75-4.63 (m, 5H), 4.06-4.03 (m, 2H), 3.97-3.94 (m, 1H), 3.76-3.70 (m, 1H), 3.53-3.46 (m, 2H), 3.25-3.22 (m, 1H), 2.71-2.68 (m, 1H), 2.20-2.14 (m, 1H), 2.07-1.82 (m, 12H), 1.65-1.58 (m, 2H).

Preparation Example 85: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-(3,4,5-trifluoro)benzyl)morpholine-2-carboxyamide (compound 299)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 3,4,5-trifluorobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.00-6.95 (m, 2H), 6.92-6.90 (m, NH, 1H), 5.58 (m, NH, 1H), 5.26 (m, NH, 1H), 4.08-4.04 (m, 2H), 4.00-3.95 (m, 1H), 3.76-3.68 (m, 1H), 3.51-3.43 (m, 2H), 3.21-3.18 (m, 1H), 2.67-2.64 (m, 1H), 2.24-2.18 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.62 (m, 2H).

Preparation Example 86: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(2-fluoro-2-methylethoxybenzyl))morpholine-2-carboxyamide (compound 298)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 22, except that 2-fluoro-2-methylethoxybenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.23 (m, 2H), 6.93-6.90 (m, NH, 1H), 6.89-6.87 (m, 2H), 6.25-5.96 (m, 1H), 5.58 (m, NH, 1H), 5.22 (m, NH, 1H), 4.23-4.16 (m, 2H) 4.06-4.03 (m, 2H), 3.97-3.93 (m, 1H), 3.75-3.68 (m, 1H), 3.54-3.45 (m, 2H), 3.24-3.21 (m, 1H), 2.69-2.66 (m, 1H), 2.20-2.13 (m, 1H), 2.08-1.82 (m, 15H), 1.65-1.61 (m, 2H).

Preparation Example 87: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(methylisoethoxybenzyl))morpholine-2-carboxyamide (compound 300)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 3, except that 4-ethoxymethylisobenzaldehyde was used.

¹H NMR (400 MHz, CDCl₃) δ 7.14-7.12 (m, 2H), 6.97-6.95 (m, NH, 1H), 6.74-6.71 (m, 2H), 5.61 (m, NH, 1H), 5.24 (m, NH, 1H), 4.07-4.06 (m, 2H) 3.98-3.95(m, 1H), 3.78-3.73 (m, 1H), 3.54-3.40 (m, 2H), 3.25-3.22 (m, 1H), 2.96-2.73 (m, 1H), 2.23-2.18 (m, 1H), 2.08-1.82 (m, 12H), 1.64-1.61 (m, 2H).

[Example 23]

Preparation Example 1: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-ethoxybenzyl)morpholine-2-carboxyamide

In a 1-liter flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105ml). In another flask, N-benzylethanolamine (66.5 g, 440 mmol) was dissolvled in toluene (35 ml), and the solution was added to the above 1-liter flask. The reaction mixture was stirred at room temperature, and toluene (205 ml) was added thereto, after which the reaction mixture was cooled to -5 ℃. A solution of t-BuOK (50.84 g, 444 mmol) in THF (202 ml) was added to the flask containing the mixture cooled to -5 ℃. The resulting mixture was stirred at -5 ℃ for 50 minutes, and then the stirred mixture was washed once with brine, after which it was dried with MgSO₄and filtered. The filtrate was distilled under reduced pressure to remove the solvent, and the residue was separated by column chromatography, thereby obtaining a 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %).

4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in a 6N HCl aqueous solution (600 mL) and refluxed for 2.5 hours, followed by cooling to -10 ℃. The produced solid was filtered, and then washed with acetone (300 ml) cooled to -10 ℃. The resulting solid compound was dried in an oven at 60 ℃, thereby obtaining a 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).

The 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4 g, 15.52 mmol) was dissolved in MeOH (200 ml), and H₂SO₄ (4 ml) was added slowly thereto, after which the mixture was stirred under reflux for 12 hours. After completion of the reaction, the mixture was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining a 4-benzylmorpholine-2-carboxyester compound (3.4 g, 14.15 mmol, 93 %).

The 4-benzylmorpholine-2-carboxyester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂0 (2000 ml), and Candida rugasa (1.5 g) was added thereto, followed by stirring for 12 hours. After completion of the reaction, the organic layer was separated and concentrated, thereby obtaining a (R)-4-nenzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %).

(R)-4-benzylmorpholine-2-carboxyester (5g, 21.25 mmol) was dissolved in THF (20 ml) and MeOH (20 ml), and a solution of LiOH (2.6 g, 63.75 mmol) in H₂O (20 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. Then, the organic layer was dried with MgSO₄and filtered, thereby obtaining a (R)-4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4.5 g).

4-oxo-adamantane-1-carboxylic acid (10 g, 51.5 mmol) was dissolved in a solution of 7N NH₃ in MeOH (50 ml), and 10% Pd/C (1 g, 10%) was added thereto, followed by stirring under a hydrogen gas atmosphere for 12 hours. After completion of the reaction, H₂O was added to the reaction solution, followed by filtration, thereby obtaining (E)-4-amino-adamantane-1-carboxylic acid (8.17 g, 41.8 mmol, 81%).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0 ℃, AcCl (16.08 g, 204.85 mmol) was added to MeOH (85 ml), after which (E)-4-amino-adamantane-1-carboxylic acid (8.0 g, 40.97 mmol) was added thereto at room temperature, followed by stirring at 45 ℃ for 12 hours. After completion of the reaction, the produced solid was filtered using acetonitrile, thereby obtaining (E)-4-amino-adamantane-1-carboxylic acid (8.17 g, 41.8 mmol, 81%).

(R)-4-benzylmorpholine-2-carboxylic acid hydrochloride (219 mg, 0.96 mmol) was dissolved in CH₂Cl₂ (3 ml), and BOP (424 mg, 0.96 mmol) and DIPEA (372 mg, 2.88 mmol) were added thereto, followed by stirring. Then, (E)-methyl 4-aminoadamantane-1-carboxylate (200 mg, 0.96 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol, 25 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxylamide (200 mg, 0.49 mmol) was dissolved in EtOH (10 ml), and 5% Pd/C (40 mg) was added thereto, followed by stirring at room temperature under a hydrogen gas atmosphere for 5 hours. After completion of the reaction, the solution was filtered through celite and concentrated, thereby obtaining a (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide compound (100 mg, 0.31 mmol, 63 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide (300 mg, 0.93 mmol) and 4-hydroxybenzaldehyde (113 mg, 0.93 mmol) were dissolved in dichloroethane (3 ml), and acetic acid (111 mg, 1.86 mmol) was added thereto. Then, the mixture was stirred at room temperature for 10 minutes, and sodium triacetoxyborohydride (394 mg, 1.86 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using H₂O and CH₂Cl₂, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 5:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-hydroxylbenzyl)morpholine-2-carboxyamide (290 mg, 0.67 mmol, 72 %).

¹H NMR (400 MHz, CDCl₃) δ 7.13-7.09 (m, 2H), 6.98-6.96 (m, NH, 1H), 6.70-6.67 (m, 2H), 4.08-4.02 (m, 2H), 3.99-3.95 (m, 1H), 3.79-3.73 (m, 1H), 3.67 (s, 3H), 3.55-3.37 (m, 2H), 3.26-3.23 (m, 1H), 2.78-2.75 (m, 1H), 2.78-2.75 (m, 1H), 2.25-2.19 (m, 1H), 2.06-1.79 (m, 12H), 1.63-1.60 (m, 2H).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-hydroxylbenzyl)morpholine-2-carboxyamide (200 mg, 0.46 mmol), ethyl iodide (143 mg, 0.92 mmol) and K₂CO₃(127 mg, 0.92 mmol) were dissolved in dimethylformamide (2 ml), and then stirred at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using H₂O and EA, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-ethoxybenzyl)morpholine-2-carboxyamide (157 mg, 0.34 mmol, 74 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-ethoxybenzyl)morpholine-2-carboxyamide (157 mg, 0.34 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), and a solution of LiOH (71 mg, 1.7 mmol) in H₂O (1 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. Then, the organic layer was dried with MgSO₄and filtered, thereby obtaining a (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-ethoxybenzyl)morpholine-2-carboxyamide compound (125 mg).

Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-ethoxybenzyl)morpholine-2-carboxyamide (compound 262)

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-ethoxybenzyl)morpholine-2-carboxyamide (125 mg, 0.28 mmol) was dissolved in CH₂Cl₂ (1 ml), and EDCI (107 mg, 0.56 mmol) and HOBt (86 mg, 0.56 mmol) were added thereto, followed by stirring. Then, an ammonium hydroxide solution (3 ml) was added thereto, followed by stirring at room temperature for 5 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9), thereby obtaining (E)-N-[5-(aminocarbonyl)tricyclo [3,3,1,13,7]dec-2-yl]-4-((R)-4-ethoxybenbyl)morpholine-2-carboxyamide (84 mg, 0.19 mmol, 68 %).

¹H NMR (400 MHz, CDCl₃) δ 7.22-7.19 (m, 2H), 6.93-6.91 (m, NH, 1H), 6.87-6.83 (m, 2H), 5.58 (m, NH, 1H), 5.25 (m, NH, 1H), 4.06-4.01 (m, 5H), 3.96-3.92 (m, 1H), 3.74-3.68 (m, 1H), 3.55-3.43 (m, 2H), 3.26-3.23 (m, 1H), 2.69-2.67 (m, 1H), 2.19-1.61 (m, 15H).

Preparation Example 2: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-isopropylbenzyl)morpholine-2-carboxyamide (compound 263)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 23, except that 2-iodopropane was used.

¹H NMR (400 MHz, CDCl₃) δ 7.21-7.18 (m, 2H), 6.93-6.91 (m, NH, 1H), 6.86-6.82 (m, 2H), 5.57 (m, NH, 1H), 5.23 (m, NH, 1H), 4.57-4.51 (m, 1H), 4.07-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.75-3.69 (m, 1H), 3.53-3.43 (m, 2H), 3.26-3.23 (m, 1H), 2.70-2.67 (m, 1H), 2.24-2.12 (m, 1H), 2.10-1.61 (m, 15H), 1.35-1.34 (m, 6H).

Preparation Example 3: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(1-oxo-2-methylpropylbenzyl))morpholine-2-carboxyamide (compound 264)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 23, except that 1-iodo-2-methylpropane was used.

¹H NMR (400 MHz, CDCl₃) δ 7.22-7.19 (m, 2H), 6.93-6.91 (m, NH, 1H), 6.87-6.83 (m, 2H), 5.57 (m, NH, 1H), 5.24 (m, NH, 1H), 4.06-4.03 (m, 2H), 3.96-3.92 (m, 1H), 3.79-3.68 (m, 3H), 3.55-3.43 (m, 2H), 3.26-3.22 (m, 1H), 2.69-2.66 (m, 1H), 2.19-1.61 (m, 17H), 1.05-1.03 (m, 6H).

Preparation Example 4: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(1,1,1-trifluoro-2-ethoxybenzyl))morpholine-2-carboxyamide (compound 266)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 23, except that 1,1,1-trifluoro-2-iodoethane was used

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.30 (m, 2H), 7.17-7.15 (m, 1H), 7.09-7.02 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.07-4.04 (m, 2H), 3.97-3.94 (m, 1H), 3.75-3.66 (m, 2H), 3.59-3.47 (m, 2H), 3.26-3.22 (m, 1H), 2.69-2.66 (m, 1H), 2.20-2.14 (m, 1H), 2.10-1.98 (m, 9H), 1.93 (m, 2H), 1.85-1.82 (m, 2H), 1.65-1.59 (m, 2H).

Preparation Example 5: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylsulfide ethoxybenzyl)morpholine-2-carboxyamide (compound 275)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 23, except that chloromethylmethylsulfide was used.

¹H NMR (400 MHz, CDCl₃) δ 7.16-7.14 (m, 2H), 6.96-6.94 (m, NH, 1H), 6.77-6.73 (m, 2H), 5.60 (m, NH, 1H), 5.21 (m, NH, 1H), 3.98-3.95 (m, 2H), 3.9 (m, 1H), 3.76-3.69 (m, 1H), 3.56-3.34 (m, 7H), 3.25-3.22 (m, 1H), 2.74-2.71 (m, 1H), 2.22-1.82 (m, 13H), 1.51-1.48 (m, 2H).

Preparation Example 6: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(2,2-difluoroethoxybenzyl))molpholine-2-carboxyamide (compound 277)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 23, except that iodo-2-methyl difluoride was used.

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.23 (m, 2H), 6.93-6.90 (m, NH, 1H), 6.89-6.87 (m, 2H), 6.25-5.96 (m, 1H), 5.58 (m, NH, 1H), 5.22 (m, NH, 1H), 4.23-4.16 (m, 2H) 4.06-4.03 (m, 2H), 3.97-3.93 (m, 1H), 3.75-3.68 (m, 1H), 3.54-3.45 (m, 2H), 3.24-3.21 (m, 1H), 2.69-2.66 (m, 1H), 2.20-2.13 (m, 1H), 2.08-1.82 (m, 12H), 1.65-1.61 (m, 2H).

[Example 24]

Preparation Example 1: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2-chlorobenzyl)morpholine-2-carboxyamide (compound 246)

In a 1-liter flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105 ml). In another flask, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml), and the solution was added to the above 1-liter flask. The reaction mixture was stirred at room temperature for 12 hours, and toluene (205 ml) was added thereto, followed by cooling to -5 ℃. A solution of t-BuOK (50.84g, 444 mmol) in THF (202 ml) was added to the flask containing the mixture cooled to -5 ℃. The resulting mixture was stirred at -5 ℃ for 50 minutes, after which it was washed once with brine, dried with MgSO₄ and filtered. The filtrate was distilled under reduced pressure to remove the solvent, and the residue was separated by column chromatography, thereby obtaining a 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %).

4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in a 6N HCl aqueous solution (600 mL) and refluxed for 2.5 hours, followed by cooling to -10 ℃. The produced solid was filtered and then washed with acetone (300 ml) cooled to -10 ℃. The solid compound thus obtained was dried in an oven at 60 ℃, thereby obtaining a 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).

The 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4 g, 15.52 mmol) was dissolved in MeOH (200 ml), and H₂SO₄ (4 ml) was added slowly thereto, after which the mixture was stirred under reflux for 12 hours. After completion of the reaction, the mixture was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining 4-benzylmorpholine-2-carboxyester compound (3.4 g, 14.15 mmol, 93 %).

The 4-benzylmorpholine-2-carboxyester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂0 (2000 ml), and Candida rugasa (1.5 g) was added thereto, followed by stirring for 12 hours. After completion of the reaction, the organic layer was separated and concentrated, thereby obtaining a (R)-4-benzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %).

(R)-4-benzylmorpholine-2-carboxyester (5 g, 21.25 mmol) was dissolved in THF (20 ml) and MeOH (20 ml), and a solution of LiOH (2.6 g, 63.75 mmol) in H₂O (20 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. The organic layer was dried with MgSO₄and filtered, thereby obtaining a (R)-4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4.5 g).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

(R)-4-benzylmorpholine-2-carboxylic acid hydrochloride (219 mg, 0.96 mmol) was dissolved in CH₂Cl₂ (3 ml), and BOP (424 mg, 0.96 mmol) and DIPEA (372 mg, 2.88 mmol) was added thereto, followed by stirring. Then, (E)-methyl 4-aminoadamantane-1-carboxylate (200 mg, 0.96 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol, 25 %).

3-chloro-4-methylbenzonitrile (2 g, 13.2 mmol) was dissolved in carbon tetrachloride (20 ml), and N-bromosuccinimide (3.5 g, 19.8 mmol) and 2,2-azo-bis-isobutyronitrile (216 mg, 1.32 mmol) were added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄ and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:9), thereby obtaining 2-chloro-4-cyanobenzyl bromide (1.2 g, 5.2 mmol, 40 %).

¹H NMR (400 MHz, CDCl₃) δ 7.72 (s, 2H), 7.28 (s, 1H), 4.59 (s, 2H).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide (300 mg, 0.93 mmol) and 4-cyano-2-chlorobenzyl bromide (643 mg, 2.79 mmol) were dissolved in dimethylformamide (2 ml), and then stirred at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using H₂O and EA, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2-chlorobenzyl)morpholine-2-carboxyamide (240 mg, 0.5 mmol, 55 %).

¹H NMR (400 MHz, CDCl₃) δ 7.69-7.67 (m, 2H), 7.58-7.55 (m, 1H), 6.93-6.91 (m, NH, 1H), 4.09-3.97 (m, 3H), 3.79-3.72 (m, 1H), 3.69 (s, 2H), 3.68 (s, 3H), 3.22-3.19 (m, 1H), 2.71-2.68 (m, 1H), 2.39-2.33 (m, 1H), 2.18-2.13 (m, 1H), 2.10-1.60 (m, 13H).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2-chlorobenzyl)morpholine-2-carboxyamide (240 mg, 0.5 mmol) was dissolvled in THF (5 ml) and MeOH (5 ml), and a solution of LiOH (105 mg, 2.5 mmol) in H₂O (5 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. Then, the organic layer was dried with MgSO₄and filtered, thereby obtaining a (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2-chlorobenzyl)morpholine-2-carboxyamide compound (180 mg).

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2-chlorobenzyl)morpholine-2-carboxyamide (180 mg, 0.39 mmol) was dissolved in CH₂Cl₂ (3 ml), and EDCI (119 mg, 0.78 mmol) and HOBt (119 mg, 0.78 mmol) were added thereto, followed by stirring. Then, an ammonium hydroxide solution (3 ml) was added to the stirred mixture, followed by stirring at room temperature for 5 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9), thereby obtaining (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2-chlorobenzyl)morpholine-2-carboxyamide (100 mg, 0.21 mmol, 56 %).

¹H NMR (400 MHz, CDCl₃) δ 8.04-7.67 (m, 2H), 7.60-7.55 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.34 (m, NH, 1H), 4.09-4.04 (m, 2H), 4.01-3.96 (m, 1H), 3.79-3.73 (m, 1H), 3.70-3.69 (m, 2H), 3.22-3.19 (m, 1H), 2.70-2.68 (m, 1H), 2.39-2.33 (m, 1H), 2.18-1.62 (m, 14H).

Preparation Example 2: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2-bromobenzyl)morpholine-2-carboxyamide (compound 247)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 24, except that 3-bromo-4-methylbenzonitrile was used.

¹H NMR (400 MHz, CDCl₃) δ 7.85 (m, 1H), 7.67-7.59 (m, 2H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.28 (m, NH, 1H), 4.09-3.98 (m, 3H), 3.79-3.73 (m, 1H), 3.67 (m, 2H), 3.22-3.20 (m, 1H), 2.71-2.68 (m, 1H), 2.41-2.34 (m, 1H), 2.20-2.14 (m, 1H), 2.08-1.62 (m, 13H).

Preparation Example 3: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-3-cyano-2-bromobenzyl)morpholine-2-carboxyamide (compound 248)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 24, except that 2-bromo-3-methylbenzonitrile was used.

¹H NMR (400 MHz, CDCl₃) δ 7.74-7.72 (m, 1H), 7.61-7.59 (m, 1H), 7.44-7.41 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.58 (m, NH, 1H), 5.27 (m, NH, 1H), 4.09-3.98 (m, 3H), 3.78-3.72 (m, 1H), 3.68-3.67 (m, 2H), 3.22-3.19 (m, 1H), 2.71-2.68 (m, 1H), 2.41-2.34 (m, 1H), 2.18-2.12 (m, 1H), 2.08-1.62 (m, 13H).

Preparation Example 4: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-2-bromo-5-cyanobenzyl)morpholine-2-carboxyamide (compound 249)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 24, except that 4-bromo-3-methylbenzonitrile was used.

¹H NMR (400 MHz, CDCl₃) δ 8.10-7.78 (m, 1H), 7.69-7.63 (m, 1H), 7.43-7.41 (m, 1H), 6.94-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.28 (m, NH, 1H), 4.10-3.98 (m, 3H), 3.81-3.72 (m, 1H), 3.68-3.67 (m, 2H), 3.26-3.20 (m, 1H), 2.73-2.68 (m, 1H), 2.39-2.33 (m, 1H), 2.20-2.15 (m, 1H), 2.08-1.62 (m, 13H).

Preparation Example 5: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-3-bromobenzyl)morpholine-2-carboxyamide (compound 250)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 24, except that 2-bromo-4-methylbenzonitrile was used.

¹H NMR (400 MHz, CDCl₃) δ 7.70 (m, 1H), 7.63-7.61 (m, 1H), 7.42-7.40 (m, 1H), 6.92-6.92 (m, NH, 1H), 5.58 (m, NH, 1H), 5.25 (m, NH, 1H), 4.09-4.03 (m, 2H), 4.00-3.98 (m, 1H), 3.78-3.71 (m, 1H), 3.61-3.52 (m, 2H), 3.20-3.17 (m, 1H), 2.66-2.63 (m, 1H), 2.28-2.21 (m, 1H), 2.08-1.62 (m, 14H).

Preparation Example 6: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyano-2-trifluoromethylbenzyl)morpholine-2-carboxylamide (compound 254)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 24, except that 3-trifluoromethyl-4-methylbenzonitrile was used.

¹H NMR (400 MHz, CDCl₃) δ 8.05-8.03 (m, 1H), 7.94 (m, 1H), 7.86-7.83 (m, 1H), 6.93-6.91 (m, NH, 1H), 5.59 (m, NH, 1H), 5.36 (m, NH, 1H), 3.09-3.80 (m, 3H), 3.80-3.73 (m, 3H), 3.19-3.16 (m, 1H), 2.67-2.64 (m, 1H), 2.39-2.33 (m, 1H), 2.17-2.12 (m, 1H), 2.08-1.62 (m, 13H).

[Example 25]

Preparation Example 1: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo [3,3,1,13,7]dec-2-yl]-4-((R)-1-phenylethyl)morpholine-2-carboxyamide

In a 1-liter flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105 ml). In another flask, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml), and then the solution was added to the above 1-liter flask. The reaction mixture was stirred at room temperature for 12 hours, and toluene (205 ml) was added thereto, after which the reaction mixture was cooled to -5 ℃. A t-BuOK (50.84 g, 444 mmol) in THF (202 ml) was added slowly to the flask containing the reaction mixture cooled to -5 ℃. The resulting mixture was stirred at -5 ℃ for 50 minutes, washed once with brine, dried with MgSO₄and filtered. The filtrate was distilled under reduced pressure to remove the solvent, and the residue was separated by column chromatography, thereby obtaining a 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %).

4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in a 6N HCl aqueous solution (600 mL), and then refluxed for 2.5 hours, followed by cooling to -10 ℃. The produced solid was filtered, and then washed with acetone (300 ml) cooled to -10 ℃. The solid compound thus obtained was dried in an oven at 60 ℃, thereby obtaining a 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).

The 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4 g, 15.52 mmol) was dissolved in MeOH (200 ml), and H₂SO₄ (4 ml) was added slowly thereto, followed by stirring under reflux for 12 hours. After completion of the reaction, the solution was concentrated and then subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining a 4-benzylmorpholine-2-carboxyester compound (3.4 g, 14.15 mmol, 93 %).

(R)-4-benzylmorpholine-2-carboxyester (5 g, 21.25 mmol) was dissolved in THF (20 ml) and MeOH (20 ml), and a solution of LiOH (2.6 g, 63.75 mmol) in H₂O (20 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. Then, the organic layer was dried with MgSO₄ and filtered, thereby obtaining a (R)-4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4.5 g).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0 ℃ or below, AcCl (16.08 g, 204.85 mmol) was added to MeOH (85 ml), and then (E)-4-amino-adamantane-1-carboxylic acid (8.0 g, 40.97 mmol) was added thereto at room temperature, followed by stirring at 45 ℃ or below for 12 hours. After completion of the reaction, the produced solid was filtered using acetonitrile, thereby obtaining (E)-4-amino-adamantane-1-carboxylic acid (8.17 g, 41.8 mmol, 81%).

(R)-4-benzylmorpholine-2-carboxylic acid hydrochloride (219 mg, 0.96 mmol) was dissolved in CH₂Cl₂ (3 ml), and BOP (424 mg, 0.96 mmol) and DIPEA (372 mg, 2.88 mmol) were added thereto, followed by stirring. Then, (E)-mehtyl 4-aminoadamantane-1-carboxylate (200 mg, 0.96 mmol) was added to the stirred mixture, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol, 25 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (200 mg, 0.49 mmol) was dissolvled in EtOH (10 ml), and 5% Pd/C (40 mg) was added thereto, followed by stirring at room temperature under a hydrogen gas atmosphere for 5 hours. After completion of the reaction, the solution was filtered through celite and concentrated, thereby obtaining a (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide compound (100 mg, 0.31 mmol, 63 %).

Synthesis of 1-phenolethanol

Acetophenone (1 g, 8.32 mmol) was dissolved in MeOH (30 ml), and NaBH₄ (472 mg, 12.48 mmol) was added slowly thereto at 0 ℃, followed by stirring at room temperature for 5 hours. After completion of the reaction, the organic layer was separated using EA and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:4), thereby obtaining 1-phenylethanol (840 mg, 6.87 mmol, 82 %).

¹H NMR (400 MHz, CDCl₃) δ 7.44-7.35 (m, 4H), 7.32-7.29 (m, 1H), 4.94-4.92 (m, 1H), 1.82 (br, OH, 1H), 1.53-1.52 (m, 3H).

Synthesis of (1-chloroethyl)benzene

1-phenylethanol (840 mg, 6.87 mmol) was dissolved in CH₂Cl₂ (10 ml), and SOCl₂ (2.6 g, 13.74 mmol) was added slowly thereto, followed by stirring at room temperature for 5 hours. After completion of the reaction, the solution was concentrated and then subjected to column chromatography (EA/n-Hex = 1:4), thereby obtaining a (1-chloroethyl)benzene compound (840 mg, 5.97 mmol, 87 %).

¹H NMR (400 MHz, CDCl₃) δ 7.39-7.29 (m, 5H), 5.15-5.09 (m, 1H), 1.89-1.87 (m, 3H).

Synthesis of (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-phenylethyl)morpholine-2-carboxyamide

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide (300 mg, 0.836 mmol) and (1-chloroethyl)benzene (235 mg, 1.672 mmol) were dissolved in DMF (5 ml), and K₂CO₃ (347 mg, 2.508 mmol) and KI (416 mg, 2.508 mmol) were added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using H₂O and EA, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining (3E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-phenylethyl)morpholine-2-carboxyamide (520 mg, 1.22 mmol, 73 %).

Synthesis of (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-phenylethyl)morpholine-2-carboxyamide

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-phenylethyl)morpholine-2-carboxyamide (520 mg, 1.22 mmol) was dissolved in THF (5 ml) and MeOH (5 ml), and a solution of LiOH (256 mg, 6.1 mmol) in H₂O (5 ml) was added thereto, followed by stirring at room temperature for 4 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. Then, the organic layer was dried with MgSO₄and filtered, thereby obtaining a (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-phenylethyl)morpholine-2-carboxyamide compound (542 mg).

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-phenylethyl)morpholine-2-carboxyamide (542 mg, 1.31 mmol) was dissolved in CH₂Cl₂ (15 ml), and EDCI (502 mg, 2.62 mmol) and HOBt (401 mg, 2.62 mmol) were added thereto, followed by stirring. Then, an ammonium hydroxide solution (6 ml) was added to the stirred mixture, followed by stirring at room temperature for 4 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9), thereby obtaining (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-phenylethyl)morpholine-2-carboxyamide (compound 173) (390 mg, 0.94 mmol, 72 %).

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.23 (m, 5H), 6.95-6.88 (m, NH, 1H), 5.60 (m, NH, 1H), 5.29 (m, NH, 1H), 4.10-4.06 (m, 1H), 4.01-3.84 (m, 2H), 3.78-3.61 (m, 1H), 3.51-3.45 (m, 1H), 3.37-3.13 (m, 1H), 2.83-2.53 (m, 1H), 2.24-1.78 (m, 13H), 1.63-1.59 (m, 2H), 1.41-1.38 (m, 3H).

Preparation Example 2: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(2-methylphenyl)ethyl)morpholine-2-carboxyamide (compound 175)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 2-methylacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.46-7.39 (m, 1H), 7.21-7.12 (m, 3H), 6.97-6.90 (m, NH, 1H), 5.58 (m, NH, 1H), 5.22 (m, NH, 1H), 4.09-3.97 (m, 3H), 3.86-3.11 (m, 4H), 2.83-2.53 (m, 1H), 2.36 (s, 3H), 2.27-1.80 (m, 13H), 1.63-1.59 (m, 2H), 1.33-1.27 (m, 3H).

Preparation Example 3: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(3-methylphenyl)ethyl)morpholine-2-carboxyamide (compound 193)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 3-methylacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.19 (m, 1H), 7.11-7.02 (m, 3H), 6.95-6.88 (m, NH, 1H), 5.59 (m, NH, 1H), 5.23 (m, NH, 1H), 4.10-3.85 (m, 3H), 3.78-3.61 (m, 1H), 3.50-3.42 (m, 1H), 3.33-3.14 (m, 1H), 2.84-2.55 (m, 1H), 2.36 (s, 3H), 2.23-1.80 (m, 13H), 1.63-1.59 (m, 2H), 1.40-1.37 (m, 3H).

Preparation Example 4: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(2-chlorophenyl)ethyl)morpholine-2-carboxyamide (compound 174)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 2-chloroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.59-7.53 (m, 1H), 7.35-7.32 (m, 1H), 7.29-7.24 (m, 1H), 7.20-7.15 (m, 1H), 6.97-6.88 (m, NH, 1H), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.11-4.07 (m, 1H), 4.05-3.95 (m, 2H), 3.91-3.84 (m, 1H), 3.80-3.59 (m, 1H), 3.58-3.07 (m, 1H), 3.00-2.50 (m, 1H), 2.29-1.79 (m, 13H), 1.63-1.59 (m, 2H), 1.33-1.31 (m, 3H).

Preparation Example 5: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(3-chlorophenyl)ethyl)morpholine-2-carboxyamide (compound 215)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 3-chloroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.24-7.17 (m, 4H), 6.95-6.89 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.09-3.98 (m, 2H), 3.87-3.86 (m, 1H), 3.77-3.64 (m, 1H), 3.48-3.33 (m, 2H), 3.12-3.09 (m, 1H), 2.83-2.53 (m, 1H), 2.22-1.56 (m, 14H), 1.38-1.35 (m, 3H).

Preparation Example 6: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(4-chlorophenyl)ethyl)morpholine-2-carboxyamide (compound 213)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 4-chloroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.31-7.22 (m, 4H), 6.94-6.87 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.08-3.97 (m, 2H), 3.89-3.86 (m, 1H), 3.73-3.62 (m, 1H), 3.47-3.33 (m, 2H), 3.11-3.09 (m, 1H), 2.82-2.51 (m, 1H), 2.20-1.58 (m, 14H), 1.38-1.35 (m, 3H).

Preparation Example 7: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(2-fluorophenyl)ethyl)morpholine-2-carboxyamide (compound 176)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 2-fluoroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.44-7.38 (m, 1H), 7.28-7.23 (m, 1H), 7.14 (m, 1H), 7.13 (m, 1H), 6.93-6.88 (m, NH, 1H), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.07 (m, 1H), 3.99-3.61 (m, 4H), 3.51-3.16 (m, 1H), 2.91-2.57 (m, 1H), 2.24-1.79 (m, 13H), 1.63-1.59 (m, 2H), 1.39 (m, 3H).

Preparation Example 8: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(3-fluorophenyl)ethyl)morpholine-2-carboxyamide (compound 192)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 3-fluoroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.29-7.25 (m, 1H), 7.09-7.02 (m, 2H), 6.97-6.88 (m, 2H), 5.59 (m, NH, 1H), 5.35 (m, NH, 1H), 4.01-3.86 (m, 1H), 3.77-3.61 (m, 1H), 3.48-3.43 (m, 1H), 3.38-3.10 (m, 1H), 2.83-2.53 (m, 1H), 2.24-1.81 (m, 13H), 1.63-1.59 (m, 2H), 1.38-1.36 (m, 3H).

Preparation Example 9: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(4-fluorophenyl)ethyl)morpholine-2-carboxyamide (compound 214)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 4-fluoroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.24 (m, 2H), 7.04-6.99 (m, 2H), 6.94-6.88 (m, NH, 1H), 5.58 (m, NH, 1H), 5.22 (m, NH, 1H), 4.08-3.97 (m, 2H), 3.89-3.86 (m, 1H), 3.66-3.45 (m, 1H), 3.36-3.34 (m, 2H), 2.98-2.91 (m, 1H), 2.54-2.51 (m, 1H), 2.11-1.58 (m, 14H), 1.38-1.35 (m, 3H).

Preparation Example 10: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(2,6-difluorophenyl)ethyl)morpholine-2-carboxyamide (compound 177)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 2,6-difluoroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.26-7.18 (m, 1H), 6.90-6.85 (m, 3H), 5.58 (m, NH, 1H), 5.26 (m, NH, 1H), 4.09-3.91 (m, 4H), 3.80-3.64 (m, 1H), 3.42-3.28 (m, 1H), 2.87-2.72 (m, 1H), 2.21-1.77 (m, 13H), 1.62-1.56 (m, 5H).

Preparation Example 11: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(2-bromophenyl)ethyl)morpholine-2-carboxyamide (compound 179)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 2-bromoacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.59-7.51 (m, 2H), 7.33-7.29 (m, 1H), 7.12-7.07 (m, 1H), 6.97-6.88 (m, NH, 1H), 5.58 (m, NH, 1H), 5.27 (m, NH, 1H), 4.11-4.04 (m, 1H), 4.02-3.81 (m, 3H), 3.80-3.59 (m, 1H), 3.57-3.06 (m, 1H), 3.00-2.49 (m, 1H), 2.30-1.80 (m, 13H), 1.63-1.60 (m, 2H), 1.32-1.30 (m, 3H).

Preparation Example 12: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(3-bromophenyl)ethyl)morpholine-2-carboxyamide (compound 180)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 3-bromoacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.47-7.45 (m, 1H), 7.40-7.37 (m, 1H), 7.26-7.17 (m, 2H), 6.94-6.88 (m, NH, 1H), 5.59 (m, NH, 1H), 5.30 (m, NH, 1H), 4.10-4.06 (m, 1H), 4.02-3.86 (m, 2H), 3.77-3.61 (m, 1H), 3.47-3.41 (m, 1H), 3.34-3.09 (m, 1H), 2.82-2.52 (m, 1H), 2.24-1.81 (m, 13H), 1.64-1.61 (m, 2H), 1.37-1.35 (m, 3H).

Preparation Example 13: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(4-bromophenyl)ethyl)morpholine-2-carboxyamide (compound 231)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 4-bromoacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.46-7.43 (m, 2H), 7.23-7.16 (m, 2H), 6.94-6.87 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.07-3.85 (m, 3H), 3.76-3.59 (m, 1H), 3.47-3.41 (m, 1H), 3.55-3.08 (m, 1H), 2.81-2.50 (m, 1H), 2.22-1.81 (m, 13H), 1.64-1.60 (m, 2H), 1.37-1.34 (m, 3H).

Preparation Example 14: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(4-trifluoromethoxyphenyl)ethyl)morpholine-2-carboxyamide (compound 185)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 4-trifluoromethoxyacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.31 (m, 2H), 7.18-7.16 (m, 2H), 6.95-6.88 (m, NH, 1H), 5.59 (m, NH, 1H), 5.27 (m, NH, 1H), 4.07-4.01 (m, 1H), 4.00-3.86 (m, 2H), 3.77-3.60 (m, 1H), 3.49-3.45 (m, 1H), 3.39-3.09 (m, 1H), 2.83-2.50 (m, 1H), 2.24-1.81 (m, 13H), 1.64-1.60 (m, 2H), 1.37-1.36 (m, 3H).

Preparation Example 15: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(3-trifluoromethylphenyl)ethyl)morpholine-2-carboxyamide (compound 186)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 3-trifluoromethylacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.52 (m, 3H), 7.47-7.43 (m, 1H), 6.95-6.88 (m, NH, 1H), 5.59 (m, NH, 1H), 5.28 (m, NH, 1H), 4.07-3.86 (m, 3H), 3.77-3.61 (m, 1H), 3.53-3.46 (m, 1H), 3.44-3.08 (m, 1H), 2.83-2.49 (m, 1H), 2.23-1.82 (m, 13H), 1.65-1.60 (m, 2H), 1.40-1.38 (m, 3H).

Preparation Example 16: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(4-trifluoromethylphenyl)ethyl)morpholine-2-carboxyamide (compound 211)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 4-trifluoromethylacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.60-7.58 (m, 2H), 7.46-7.43 (m, 1H), 6.95-6.93 (m, NH, 1H), 5.58 (m, NH, 1H), 5.21 (m, NH, 1H), 4.10-4.06 (m, 2H), 4.02-3.98 (m, 1H), 3.89-3.86 (m, 1H), 3.67-3.61 (m, 1H), 3.52-3.39 (m, 2H), 2.52-2.49 (m, 1H), 2.09 -1.58 (m, 14H), 1.40-1.38 (m, 3H).

Preparation Example 17: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(2,6-dichlorophenyl)ethyl)morpholine-2-carboxyamide (compound 201)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 2,6-dichloroacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.26 (m, 2H), 7.12-7.07 (m, 2H),6.97-6.90 (m, NH, 1H), 5.61 (m, NH, 1H), 5.43 (m, NH, 1H), 4.24-3.96 (m, 4H), 3.85-3.75 (m, 1H), 3.66-3.04 (m, 1H), 2.89-2.34 (m, 1H), 2.24-1.81 (m, 13H), 1.65-1.50 (m, 2H), 1.53-1.49 (m, 3H).

Preparation Example 18: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(2,4-dimethylphenyl)ethyl)morpholine-2-carboxyamide (compound 216)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 2,4-dimethylacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.23 (m, 1H), 7.02-6.96 (m, 2H), 6.92-6.90 (m, NH, 1H), 5.59 (m, NH, 1H), 5.25 (m, NH, 1H), 4.08-3.96 (m, 2H), 3.83-3.82 (m, 1H), 3.69-3.50 (m, 3H), 3.13-3.10 (m, 1H), 2.83-2.54 (m, 1H), 2.33-2.30 (m, 6H), 2.23-1.61 (m, 14H), 1.32-1.30 (m, 3H).

Preparation Example 19: (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(2-fluoro-4-methoxyphenyl)ethyl)morpholine-2-carboxyamide (compound 212)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 2-fluoro-4-methoxyacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 6.94-6.87 (m, NH, 1H), 6.72-6.68 (m, 1H), 6.61-6.57 (m, 1H), 5.59 (m, NH, 1H), 5.23 (m, NH, 1H), 4.08-3.96 (m, 2H), 3.91-3.81 (m, 1H), 3.08 (m, 3H), 3.78-3.68 (m, 1H), 3.68-3.44 (m, 2H), 3.47-3.15 (m, 1H), 2.86-2.58 (m, 1H), 2.20-1.61 (m, 14H), 1.41-1.38 (m, 3H).

Preparation Example 20: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(4-cyanophenyl)ethyl)morpholine-2-carboxyamide (compound 202)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 4-cyanoacetophenone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.64-7.62 (m, 2H), 7.47-7.43 (m, 2H), 6.94-6.87 (m, NH, 1H), 5.59 (m, NH, 1H), 5.39 (m, NH, 1H), 4.10-4.05 (m, 1H), 4.02-3.86 (m, 2H), 3.77-3.61 (m, 1H), 3.51-3.03 (m, 2H), 2.84-2.45 (m, 1H), 2.25-1.77 (m, 13H), 1.64-1.60 (m, 2H), 1.37-1.36 (m, 3H).

Preparation Example 21: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(R)-1-(4-(1,2,3,4-tetrahydro-1-naphthane))morpholine-2-carboxyamide (compound 242)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 1,2,3,4-tetrahydro-1-naphthanol was used.

¹H NMR (400 MHz, CDCl₃) δ 7.70-7.63 (m, 1H), 7.16-7.14 (m, 2H), 7.08-7.05 (m, 1H), 6.97-6.91 (m, NH, 1H), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.16-4.07 (m, 1H), 4.09-3.62 (m, 4H), 3.24-2.98 (m, 1H), 2.80-2.15 (m, 5H), 2.19-1.16 (m, 17H).

Preparation Example 22: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(R)-1-(4-indane)molpholine-2-carboxyamide (compound 243)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that hydroxyindane was used.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.33 (m, 1H), 7.24-7.18 (m, 3H), 6.94-6.90 (m, NH, 1H), 5.60 (m, NH, 1H), 5.32 (m, NH, 1H), 4.42-4.32 (m, 1H), 4.12-3.90 (m, 3H), 3.80-3.64 (m, 1H), 3.27-3.01 (m, 1H), 3.00-2.79 (m, 2H), 2.72-2.47 (m, 1H), 2.42-2.39 (m, 1H), 2.34-2.17 (m, 1H), 2.13-1.60 (m, 15H).

Preparation Example 23: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(R)-1-(4-(3,3-dimethyl-1-indane))morpholine-2-carboxyamide (compound 253)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 3,3-dimethyl-1-indanone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.31 (m, 1H), 7.26-7.14 (m, 3H), 6.95-6.92 (m, NH, 1H), 5.59 (m, NH, 1H), 5.25 (m, NH, 1H), 4.50-4.44 (m, 1H), 4.15-3.92 (m, 3H), 3.81-3.68 (m, 1H), 3.31-3.01 (m, 1H), 2.78-2.14 (m, 2H), 2.10-1.60 (m, 16H), 1.38-1.37 (m, 3H), 1.19 (m, 3H).

Preparation Example 24: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(4-(5-fluoro-1-indane))morpholine-2-carboxyamide (compound 251)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 5-fluoro-1-indanone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.27 (m, 1H), 6.92-6.88 (m, 3H), 5.58 (m, NH, 1H), 5.21 (m, NH, 1H), 4.34-4.28 (m, 1H), 4.10-3.91 (m, 3H), 3.76-3.62 (m, 1H), 3.26-3.21 (m, 1H), 2.96-2.79 (m, 3H), 2.72-2.49 (m, 1H), 2.40-2.38 (m, 1H), 2.34-1.60 (m, 16H).

Preparation Example 25: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(R)-1-(4-(5-bromo-1-indane))morpholine-2-carboxyamide (compound 252)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 5-bromo-1-indanone was used.

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.33 (m, 2H), 7.23-7.21 (m, 1H), 6.93-6.88 (m, NH, 1H), 5.58 (m, NH, 1H), 5.23 (m, NH, 1H), 4.35-4.28 (m, 1H), 4.10-3.91-3.64 (m, 5H), 3.25-2.89 (m, 2H), 2.85-2.36 (m, 3H), 2.33-2.17 (m, 1H), 2.13-1.81 (m, 12H), 1.64-1.59 (m, 2H).

Preparation Example 26: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-1-(4-difluoromethoxyphenyl)ethyl)morpholine-2-carboxyamide (compound 287)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 25, except that 4-difluoromethoxyacetophenone was used.

¹H NMR (400 MHz, CDCl₃) 7.57-7.48 (m, 1H), 7.28-7.23 (m, 2H), 7.13-7.08 (m, 1H), 6.95-6.88 (m, -CONH), 6.73-6.33 (m, 1H), 5.63 (bs, -CONH₂), 4.03-3.86 (m, 1H), 3.86-3.62 (m, 2H), 3.43-2.52 (m, 2H), 2.22-1.59 (m, 18H), 1.36-1.26 (m, 3H)

[Example 26]

Preparation Example 1: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-aminocarbonylbenzyl)morpholine-2-carboxyamide

In a 1-liter flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105ml). In another flask, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml), and the solution was added to the above 1-liter flask. The reaction mixture was stirred at room temperature for 12 hours, and toluene (205 ml) was added thereto, followed by cooling to -5 ℃. A solution of t-BuOK (50.84g, 444 mmol) in THF (202 ml) was added slowly to the flask containing the mixture cooled to -5 ℃. Then, the reaction mixture was stirred at -5 ℃ for 50 minutes, washed once with brine, dried with MgSO₄and filtered. The solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography, thereby obtaining a 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %).

4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in a 6N HCl aqueous solution (600 mL) and then refluxed for 2.5 hours, followed by cooling to -10 ℃. The produced solid was filtered, and then washed with acetone (300 ml) cooled to -10 ℃. The solid compound thus obtained was dried in an oven at 60 ℃, thereby obtaining a 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).

The 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4 g, 15.52 mmol) was dissolved in MeOH (200 ml), and H₂SO₄ (4 ml) was added slowly thereto, followed by stirring under reflux for 12 hours. After completion of the reaction, the mixture was concentrated and then subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining a 4-benzylmorpholine-2-carboxyester compound (3.4 g, 14.15 mmol, 93 %).

The 4-benzylmorpholine-2-carboxyester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂O (2000 ml), and Candida rugasa (1.5 g) was added thereto, followed by stirring for 12 hours. After completion of the reaction, the organic layer was separated and concentrated, thereby obtaining a (R)-4-benzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0 ℃, AcCl (16.08 g, 204.85 mmol) was added to MeOH (85 ml), and then (E)-4-amino-adamantane-1-carboxylic acid (8.0 g, 40.97 mmol) was added thereto at room temperature, followed by stirring at 45 ℃ for 12 hours. After completion of the reaction, the formed solid was filtered using acetonitrile, thereby obtaining (E)-4-amino-adamantane-1-carboxylic acid (8.17 g, 41.8 mmol, 81%).

(R)-4-benzylmorpholine-2-carboxylic acid hydrochloride (219 mg, 0.96 mmol) was dissolved in CH₂Cl₂ (3 ml), and BOP (424 mg, 0.96 mmol) and DIPEA (372 mg, 2.88 mmol) were added thereto, followed by stirring. Then, (E)-methyl 4-aminoadamantane-1-carboxylate (200 mg, 0.96 mmol) was added to the stirred mixture, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol, 25 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (200 mg, 0.49 mmol) was dissolved in EtOH (10 ml), and 5% Pd/C (40 mg) was added thereto, followed by stirring at room temperature under a hydrogen gas atmosphere for 5 hours. After completion of the reaction, the solution was filtered through celite, followed by concentration, thereby obtaining a (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide compound (100 mg, 0.31 mmol, 63 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide (100 mg, 0.31 mmol) and 4-cyanobenzaldehyde (41 mg, 0.31 mmol) were dissolved in dichloroethane (2 ml), and acetic acid (37 mg, 0.62 mmol) was added thereto, followed by stirring at room temperature for 10 minutes. Then, sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added to the stirred mixture, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using H₂O and CH₂Cl₂, and the separated organic layer was dried with MgSO₄ and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 5:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide (41 mg, 0.09 mmol, 30 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide (40 mg, 0.09 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), and a solution of LiOH (11 mg, 0.27 mmol) in H₂O (1 ml) was added thereto, after which the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. Then, the organic layer was dried with MgSO₄and filtered, thereby obtaining a (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide compound (20 mg).

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide (20 mg, 0.047 mmol) was dissolved in CH₂Cl₂ (1 ml), and EDCI (18 mg, 0.094 mmol) and HOBt (11 mg, 0.071 mmol) were added, followed by stirring. Then, an ammonium hydroxide solution (0.6 ml) was added to the stirred mixture, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄ and filtered. The filtrate was subjected to column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9), thereby obtaining (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-cyanobenzyl)morpholine-2-carboxyamide (10 mg, 0.02 mmol, 50 %).

(E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-nitrilebenzene)morpholine-2-carboxyamide (400 mg, 0.94 mmol) was dissolved in ethanol (10 ml), and NaOH (150 mg, 3.78 mmol) was added thereto, followed by stirring under reflux for 12 hours. After completion of the reaction, the mixture was subjected to column chromatography (MC/MeOH = 1:10), thereby obtaining a (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-aminocarbonylbenzyl)morpholine-2-carboxyamide compound (compound 274) (157 mg, 0.36 mmol, 38 %).

¹H NMR (400 MHz, DMSO-d ₆) δ 7.96 (bs, NH, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.35 (bs, NH, 1H), 7.18 (d, J = 7.6 Hz, NH, 1H), 7.01 (bs, NH, 1H), 6.76 (bs, NH, 1H), 3.98 (m, 2H), 3.78 (m, 1H), 3.57 (m, 3H), 2.86 (m, 1H), 2.55 (m, 1H), 2.18 (m, 1H), 1.96 (m, 1H), 1.95-1.73 (m, 11H), 1.44 (m, 2H).

[Example 27]

Preparation Example 1: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-trifluoromethoxyphenyl)morpholine-2-carboxyamide

In a 1-liter flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105 ml). In another flask, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml), and the solution was added to the above 1-liter flask. The reaction mixture was stirred at room temperature for 12 hours, and toluene (205 ml) was added thereto, followed by cooling to -5 ℃. A solution of t-BuOK (50.84g, 444 mmol) in THF (202 ml) was added slowly to the flask containing the reaction mixture cooled to -5 ℃. The resulting mixture was stirred at -5 ℃ for 50 minutes, after which the reaction mixture was washed once with brine, dried with MgSO₄and filtered. The solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography, thereby obtaining a 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %).

4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in a 6N HCl aqueous solution (600 mL), and then refluxed for 2.5 hours, followed by cooling to -10 ℃. The produced solid was filtered and then washed with acetone (300 ml) cooled to -10 ℃. The solid compound thus obtained was dried in an oven at 60 ℃, thereby obtaining a 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).

The 4-benzylmorpholine-2-carbxylic acid hydrochloride compound (4 g, 15.52 mmol) was dissolved in MeOH (200 ml), and H₂SO₄ (4 ml) was added slowly thereto, followed by stirring under reflux for 12 hours. After completion of the reaction, the mixture was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining 4-benzylmorpholine-2-carboxyester compound (3.4 g, 14.15 mmol, 93 %).

The 4-benzylmorpholine-2-carboxy ester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂O (2000 ml), and Candida rugasa (1.5 g) was added thereto, followed by stirring for 12 hours. After completion of the reaction, the organic layer and separated and concentrated, thereby obtaining a (R)-4-benzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %).

4-oxo-adamantane-1-carboxylic acid (10 g, 51.5 mmol) was dissolved in a solution of 7N NH₃ in MeOH (50 ml), and 10% Pd/C (1 g, 10%) was added thereto, followed by stirring under a hydrogen gas atmosphere for 12 hours. After completion of the reaction, H₂O was added to the mixture, followed by filtration, thereby obtaining (E)-4-amino-adamantane-1-carboxylic acid (8.17 g, 41.8 mmol, 81%).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (200 mg, 0.49 mmol) was dissolved in EtOH (10 ml), and 5% Pd/C (40 mg) was added thereto, followed by stirring at room temperature under a hydrogen gas atmosphere for 5 hours. After completion of the reaction, the mixture was filtered and then concentrated, thereby obtaining a (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide compound (100 mg, 0.31 mmol, 63 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide (500mg, 1.55 mmol) and 1-bromo-4-(trifluoromethoxy)benzene (395 mg, 1.55 mmol) were dissolved in toluene (10 ml), and Pd₂(dba)₃(28 mg, 0.031 mmol), BINAP (38 mg, 0.062 mmol) and t-BuONa (298 mg, 3.10 mmol) were added thereto, followed by stirring at 100 ℃ for 5 hours. After completion of the reaction, the mixture was filtered through celite using ether, and the filtrate was dried with MgSO₄ and filtered. Then, the filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(trifluoromethoxy)phenyl)morpholine-2-carboxyamide (145 mg, 0.30 mmol, 19 %).

¹H NMR (400 MHz, CDCl₃) δ 7.15 (m, 2H), 6.98 (m, NH, 1H), 6.96 (m, 2H), 4.17 (m, 2H), 4.08 (m, 1H), 3.98 (m, 1H), 3.87 (m, 1H), 3.69 (s, 3H), 3.42 (m, 1H), 2.89 (m, 1H), 2.67 (m, 1H), 2.07-1.82 (m, 11H), 1.64 (m, 2H).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(trifluoromethoxy)phenyl)morpholine-2-carboxyamide (145 mg, 0.30 mmol) was dissolved in THF (5 ml) and MeOH (5 ml), and a solution of LiOH (21 mg, 0.90 mmol) in H₂O (2 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. Then, the organic layer was dried with MgSO₄, thereby obtaining a (E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(trifluoromethoxy)phenyl)morpholine-2-carboxyamide compound (0.135 mg, 0.28 mmol, 96%).

¹H NMR (400 MHz, DMSO-d ₆) δ 12.12 (bs, -COOH), 7.39 (d, J = 7.6 Hz, NH, 1H), 7.24 (m, 2H), 7.04 (m, 2H), 4.14 (m, 1H), 4.07 (m, 1H), 3.83 (m, 1H), 3.73 (m, 2H), 3.52 (m, 1H), 2.79 (m, 1H), 2.69 (m, 1H), 1.99-1.79 (m, 11H), 1.48 (m, 2H).

(E)-N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(trifluoromethoxy)phenyl)morpholine-2-carboxyamide (164 mg, 0.35 mmol) was dissolved in CH₂Cl₂ (8 ml), and EDCI (134 mg, 0.70 mmol) and HOBt (94 mg, 0.70 mmol) were added thereto, followed by stirring. Then, an ammonium hydroxide solution (4 ml) was added to the stirred mixture, followed by stirring at room temperature for 5 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (MeOH/CH₂Cl₂ = 20/1), thereby obtaining (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(trifluoromethoxy)phenyl)morpholine-2-carboxyamide (compound 284) (120 mg, 0.256 mmol, 74 %).

¹H NMR (400 MHz, DMSO-d ₆) δ 7.36 (d, J = 7.2 Hz, NH, 1H), 7.22 (m, 2H), 7.04 (m, 2H), 6.95 (bs, NH, 1H), 6.74 (bs, NH, 1H), 4.16 (m, 1H), 4.06 (m, 1H), 3.85 (m, 1H), 3.73 (m, 2H), 3.59 (m, 1H), 2.83 (m, 1H), 2.68 (m, 1H), 1.92-1.76 (m, 11H), 1.45 (m, 2H).

Preparation Example 2: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-(trifluoromethyl)phenyl)morpholine-2-carboxyamide (compound 283)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 27, except that 1-bromo-4-(trifluoromethyl)benzene was used.

¹H NMR (400 MHz, DMSO-d ₆) δ 7.54 (m, 2H), 7.39 (d, J = 7.6 Hz, NH, 1H), 7.09 (m, 2H), 7.01 (bs, NH, 1H), 6.74 (bs, NH, 1H), 4.16 (m, 1H), 4.08 (m, 1H), 3.83 (m, 2H), 3.71 (m, 2H), 2.91 (m, 1H), 2.81 (m, 1H), 1.92-1.76 (m, 11H), 1.46 (m, 2H).

[Example 28]

Preparation Example 1: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylbenzyl)morpholine-2-carboxyamide

In a 1-liter flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105ml). In another flask, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml), and the solution was added to the above 1-liter flask. The reaction mixture was stirred at room temperature for 12 hours, and then toluene (205 ml) was added thereto, after which the reaction mixture was cooled to -5 ℃. A solution of t-BuOK (50.84g, 444 mmol) in THF (202 ml) was added slowly to the flask containing the mixture cooled to -5 ℃. Then, the reaction mixture was stirred at -5 ℃ for 50 minutes, after which it was washed once with brine, dried with MgSO₄and filtered. The solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography, thereby obtaining a 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %).

The 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (4 g, 15.52 mmol) was dissolved in MeOH (200 ml), and H₂SO₄ (4 ml) was added slowly thereto, after which the mixture was stirred under reflux for 12 hours. After completion of the reaction, the mixture was concentrated and then subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining a 4-benzylmorpholine-2-carboxy ester compound (3.4 g, 14.15 mmol, 93 %).

The 4-benzylmorpholine-2-carboxy ester compound (50 g, 0.21 mol) was dissolved in t-BuOMe-H₂O (2000 ml), and Candida rugasa (1.5 g) was added thereto, followed by stirring for 12 hours. After completion of the reaction, the organic layer was separated and concentrated, thereby obtaining a (R)-4-benzylmorpholine-2-carboxyester compound (23 g, 0.09 mmol, 93 %).

(R)-4-benzylmorpholine-2-carboxyester (5 g, 21.25 mmol) was dissolved in THF (20 ml) and MeOH (20 ml), and a solution of LiOH (2.6 g, 63.75 mmol) in H₂O (20 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. Then, the organic layer was dried with MgSO₄ and filtered, thereby obtaining a (R)-4-benzylmorphopline-2-carboxylic acid hydrochloride compound (4.5 g).

4-oxo-adamantane-1-carboxylic acid (10 g, 51.5 mmol) was dissolved in a solution of 7N NH₃ in MeOH (50 ml), and 10% Pd/C (1 g, 10%) was added thereto, after which the mixture was stirred under a hydrogen gas atmosphere for 12 hours. After completion of the reaction, H₂O was added to the mixture, followed by filtration, thereby obtaining (E)-4-amino-adamantane-1-carboxylic acid (8.17 g, 41.8 mmol, 81%).

¹H NMR (400 MHz, D₂O) δ 3.36 (m, 1H), 2.03-1.53 (m, 13H).

At 0 ℃, AcCl (16.08 g, 204.85 mmol) was added to MeOH (85 ml), and then (E)-4-amino-adamantane-1-carboxylic acid (8.0 g, 40.97 mmol) was added thereto at room temperature, after which the mixture was stirred at 45 ℃ for 12 hours. After completion of the reaction, the solid was filtered using acetonitrile, thereby obtaining (E)-4-amino-adamantane-1-carboxylic acid (8.17 g, 41.8 mmol, 81%).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-benzyl)morpholine-2-carboxyamide (200 mg, 0.49 mmol) was dissolved in EtOH (10 ml), and 5% Pd/C (40 mg) was added thereto, followed by stirring at room temperature under a hydrogen gas atmosphere for 5 hours. After completion of the reaction, the mixture was filtered through celite and concentrated, thereby obtaining a (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide compound (100 mg, 0.31 mmol, 63 %).

(E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-(R)-morpholine-2-carboxyamide (300 mg, 0.93 mmol) and 2-bromoethylbenzene (516mg, 2.79 mmol) were dissolved in dimethylformamide (2 ml), and then stirred at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using H₂O and EA, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining a (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylbenzene)morpholine-2-carboxyamide compound (345mg, 0.81 mmol, 87 %).

The (E)-N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylbenzene)morpholine-2-carboxyamide compound (40 mg, 0.09 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), and a solution of LiOH (11 mg, 0.27 mmol) in H₂O (1 ml) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was adjusted to a pH of 5 with 2N-HCl and extracted with EA. Then, the organic layer was dried with MgSO₄and filtered, thereby obtaining a (E)-N-[5-(hydroxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylbenzyl)morpholine-2-carboxyamide compound (20 mg).

The (E)-N-[5-(hydroxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylbenzyl)morpholine-2-carboxyamide compound (20 mg, 0.049 mmol) was dissolved in CH₂Cl₂ (1 ml), and EDCI (19 mg, 0.098 mmol) and HOBt (15 mg, 0.098 mmol) were added thereto, followed by stirring. Then, an ammonium hydroxide solution (0.6 ml) was added to the stirred mixture, followed by stirring at room temperature for 5 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtered. The filtrate was subjected to column chromatography (MeOH/n-Hex/CH₂Cl₂ = 0.5:0.5:9), thereby obtaining (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-methylbenzyl)morpholine-2-carboxyamide (compound 270) (10 mg, 0.02 mmol, 50 %).

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.30 (m, 2H), 7.24-7.21 (m, 3H), 6.96-6.94 (m, NH, 1H), 5.59 (m, NH, 1H), 5.22 (m, NH, 1H), 4.10-4.06 (m, 2H), 4.02-3.98 (m, 1H), 3.80-3.74 (m, 1H), 3.40-3.37 (m, 1H), 2.91-2.79 (m, 3H), 2.71-2.61 (m, 2H), 2.29-2.22 (m, 1H), 2.10-1.84 (m, 12H), 1.66-1.62 (m, 2H).

Preparation Example 2: Synthesis of (E)-N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-((R)-4-ethyl)morpholine-2-carboxyamide (compound 276)

The title compound could be obtained in the same manner as Preparation Example 1 of Examples 28, except that iodoethane was used.

¹H NMR (400 MHz, CDCl₃) δ 6.95-6.93 (m, NH, 1H), 5.54 (m, NH, 1H), 5.22 (m, NH, 1H), 4.15-4.04 (m, 2H), 4.01-3.97 (m, 1H), 3.32-3.30 (m, 1H), 2.79-2.75 (m, 1H), 2.50-2.40 (m, 2H), 2.25-1.77 (m, 13H), 1.65-1.60 (m, 2H), 1.14-1.11 (m, 3H).

[Example 29]

Preparation Example 1: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((2,6-dichlorophenyl)sulfonyl)morpholine-2-carboxamide (compound 302)

In a 1-liter flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105 ml). In another flask, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml), and the solution was added to the above 1-liter flask. The reaction mixture was stirred at room temperature for 12 hours, and then toluene (205 ml) was added thereto, after which the reaction mixture was cooled to -5 ℃. A solution of t-BuOK (50.84g, 444 mmol) in THF (202 ml) was added slowly to the flask containing the mixture cooled to -5 ℃. The reaction mixture was stirred at -5 ℃ for 50 minutes, after which it was washed once with brine, dried with MgSO₄and filtered. The solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography, thereby obtaining a 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %).

¹H NMR (400 MHz, DMSO-d ₆) δ12.18 (bs, -COOH), 7.67-7.65 (m, 2H), 7.53-7.40 (m, 3H), 4.61 (d, J = 10.8 Hz, 1H), 4.39 (m, 2H), 4.05-4.94 (m, 2H), 3.43 (d, J = 12.0 Hz, 1H), 3.20-3.07 (m, 3H).

4-benzylmorpholine-2-carboxylic acid hydrochloride (100 mg, 0.39 mmol) was dissolved in CH₂Cl₂ (3 ml), and BOP (173 mg, 0.39 mmol) and DIPEA (152 mg, 1.17 mmol) were added thereto, followed by stirring. Then, methyl 4-aminoadamantane-1-carboxylate (82 mg, 0.39 mmol) was added to the stirred mixture, followed by stirring at room temperature for 12 hours. After completion of the reaction, the organic layer was separated using CH₂Cl₂and H₂O, and the separated organic layer was dried with MgSO₄and filtrated. The filtrate was subjected to column chromatography (EA/n-Hex = 1:1), thereby obtaining methyl 4-(4-benzylmorpholine-2-carboxamido)adamantane-1-carboxylate (120 mg, 0.29 mmol, 75 %).

Methyl 4-(4-benzylmorpholine-2-carboxamido)adamantane-1-carboxylate (200 mg, 0.49 mmol) was dissolved in EtOH (10 ml), and 5% Pd/C (40 mg) was added thereto, after which the mixture was stirred at room temperature under a hydrogen gas atmosphere for 5 hours. After completion of the reaction, the mixture was filtered through celite and concentrated, thereby obtaining a methyl 4-(morpholine-2-carboxamido)adamantane-1-carboxylate compound (100 mg, 0.31 mmol, 63 %).

The methyl 4-(morpholine-2-carboxamido)adamantine-1-carboxylate compound (174.0 mg, 0.54 mmol) was dissolved in CH₂Cl₂ (4 ml), and 2,6-dichlorobenzenesulfonyl chloride (132.6 mg, 0.54 mmol) and triethylamine (120.2 mg, 1.19 mmol) were added thereto, followed by stirring at room temperature for 3 hours. H₂O was added to the reaction solution, which was then extracted three times with CH₂Cl₂. The extract was dried with MgSO₄, filtered and distilled under reduced pressure to remove the solvent. The residue was separated by column chromatography, thereby obtaining a methyl 4-(4-((2,6-dichlorophenyl)sulfonyl)morpholine-2-carboxamido)adamantane-1-carboxylate compound (243.9 mg, 0.46 mmol, 85 %).

¹H NMR (400 MHz, CDCl₃) δ7.53-7.48 (m, 2H), 7.39-7.33 (m, 1H), 6.92 (br, -CONH), 4.15-4.00 (m, 4H), 3.85-3.63 (m, 5H), 3.13-3.06 (m, 1H), 2.90-2.84 (m, 1H), 2.07-1.54 (m, 13H).

4-(4-((2,6-dichlorophenyl)sulfonyl)morpholine-2-carboxamido)adamantane-1-carboxylate (222.5 mg, 0.43 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), and a solution of LiOH (123 mg, 2.92 mmol) in H₂O (1.5 ml) was added thereto, followed by stirring at room temperature for 12 hours. The reaction solution was concentrated by distillation under reduced pressure, and the concentrate was adjusted to a pH of 2 by addition of 2N-HCl aqueous solution, followed by extraction with CH₂Cl₂. The organic layer was dried with MgSO₄, filtered and distilled under reduced pressure to remove the solvent, thereby obtaining a 4-((3-chloro-2-methylphenyl)sulfonyl)morpholine-2-carboxylic acid compound.

The 4-(4-((2,6-dichlorophenyl)sulfonyl)morpholine-2-carboxamido)adamantane-1-carboxylic acid compound was dissolved in CH₂Cl₂ (5 ml), and EDCI (164.9 mg, 0.86 mmol) and HOBT (116 mg, 0.86 mmol) were added thereto, followed by stirring for 30 minutes. Then, a 30% NH₄OH aqueous solution (1 ml) was added to the stirred mixture, followed by stirring at room temperature for 12 hours. H₂O was added to the reaction solution, which was then extracted three times with CH₂Cl₂, and the extract was dried with MgSO₄, filtered, and distilled under reduced pressure to remove the solvent. The residue was separated by column chromatography, thereby obtaining N-(5-carbamoyladamantan-2-yl)-4-((2,6-dichlorophenyl)sulfonyl)morpholine-2-carboxamide (compound 303) (144.3 mg, 0.28 mmol, 65 %).

¹H NMR (400 MHz, DMSO-d ₆) δ7.72-, 7.60 (m, 3H), 7.45 (br, -CONH), 7.03, 6.77 (br, -CONH₂), 4.07-4.00 (m, 2H), 3.78-3.76 (m, 2H), 3.61-3.55 (m, 2H), 3.06-3.00 (m, 1H), 2.94-2.88 (m, 1H), 1.94-1.41 (m, 13H).

Preparation Example 2: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-(m-torylsulfonyl)morpholine-2-carboxamide (compound 303)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2-methylbenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.57-7.44 (m, 4H, -CONH), 7.01, 7.76 (br, -CONH₂), 4.13-4.10 (m, 1H), 4.04-3.97 (m, 1H), 3.79-3.77 (m, 1H), 3.64-3.59 (m, 2H), 3.45-3.40 (m, 1H), 2.43-2.31 (m, 4H), 2.26-2.09 (m, 1H), 1.88-1.39 (m, 13H).

Preparation Example 3: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((2-chlorophenyl)sulfonyl)morpholine-2-carboxamide (compound 304)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2-chlorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ8.00-7.98 (m, 1H), 7.75-7.69 (m, 2H), 7.61-7.57 (m, 1H), 7.48-7.41 (br, -CONH), 7.03, 6.75 (br, -CONH₂), 4.07-4.00 (m, 2H), 3.79 (m, 1H), 3.69 (m, 1H), 3.61-3.35 (m, 5H), 2.88-2.82 (m, 1H), 2.76-2.70 (m, 1H), 1.90-1.41 (m, 13H).

Preparation Example 4: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((4-fluoro-2-methylphenyl)sulfonyl)morpholine-2-carboxamide (compound 305)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 4-fluoro-2-methylbenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.89 (dd, J = 5.6, 8.8 Hz, 1H), 7.46-7.39 (m, 1H, -CONH), 7.32-7.27 (m, 1H), 7.04, 6.78 (br, -CONH₂), 4.09-3.99 (m, 2H), 3.79-3.77 (m, 1H), 3.62-3.50 (m, 3H), 2.76-2.57 (m, 5H), 1.88-1.41 (m, 13H).

Preparation Example 5: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((4-chlorophenyl)sulfonyl)morpholine-2-carboxamide (compound 306)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 4-chlorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.81-7.71 (m, 4H), 7.45 (br, -CONH), 7.02, 6.76 (br, -CONH₂), 4.14, 4.10 (m, 1H),4.04-3.97 (m, 1H), 3.79-3.77 (m, 1H), 3.64-3.59(m, 2H), 3.46-3.40 (m, 1H), 2.41-2.23 (m, 2H), 1.87-1.40 (m, 13H).

Preparation Example 6: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((2-cyanophenyl)sulfonyl)morpholine-2-carboxamide (compound 307)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2-cyanobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ8.21-8.18 (m, 1H), 8.05-7.91 (m, 3H), 7.18 (br, -CHNH), 7.02, 6.77 (br, -CONH₂), 4.14-4.02 (m, 2H), 3.79-3.53 (m, 4H), 2.73-2.55 (m, 2H), 1.88-1.40 (m, 13H).

Preparation Example 7: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((2-fluorophenyl)sulfonyl)morpholine-2-carboxamide (compound 308)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2-fluorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.83-7.78 (m, 2H), 7.56-7.44 (m, 2H, -CONH), 7.04, 6.78 (br, -CONH₂), 4.13-4.09 (m, 1H), 4.03-4.00 (m, 1H), 3.79-3.78 (m, 1H), 3.69-3.58 (m, 2H), 3.51-3.48 (m, 1H), 2.64-2.41 (m, 2H), 1.87-1.40 (m, 13H).

Preparation Example 8: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((3-chloro-2-fluorophenyl)sulfonyl)morpholine-2-carboxamide (compound 309)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 3-chloro-2-fluorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.97-7.87 (m, 1H), 7.78-7.69 (m, 1H), 7.49-7.34 (m, 1H, -CONH), 7.03, 6.77 (br, -CONH₂), 4.14-3.98 (m, 2H), 3.84-3.46 (m, 4H), 2.74-2.58 (m, 2H), 1.99-1.40 (m, 13H).

Preparation Example 9: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((2,6-difluorophenyl)sulfonyl)morpholine-2-carboxamide (compound 310)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2,6-difluorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.69-7.60 (m, 1H), 7.53-6.90 (m, 2H, -CONH), 6.90, 6.76 (-CONH₂), 4.10, 3.93 (m, 2H), 3.81-3.71 (m, 2H), 3.66-3.52 (m, 2H), 2.80-2.55 (m, 2H), 1.88-1.45 (m, 13H).

Preparation Example 10: Synthesis of N-(5-carbomoyladamantan-2-yl)-4-((3-chlorophenyl)sulfonyl)morpholine-2-carboxamide (compound 311)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 3-chlorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.87-7.69 (m, 4H), 7.47 (br, -CONH), 7.01, 6.76 (br, -CONH₂), 4.14-4.11 (m, 1H), 4.02-3.98 (m, 1H), 3.79-3.78 (m, 1H), 3.65-3.59 (m, 2H), 3.49-3.46 (m, 1H), 2.43 (td, J = 3.2, 11.2 Hz, 1H), 2.31 (t, J = 10.8 Hz, 1H), 1.88-1.40 (m, 13H).

Preparation Example 11: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((3-chloro-2-methylphenyl)sulfonyl)morpholine-2-carboxamide (compound 312)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 3-chloro-2-methylbenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.87, 7.81 (m, 2H), 7.50-7.45 (t, J = 8.0 Hz, 1H), 7.45-7.38 (br, -CONH), 7.03, 6.73 (br, -CONH₂), 4.11-4.074 (m, 1H), 4.04-4.01 (m, 1H), 3.79(m, 1H), 2.79-2.70 (m, 1H), 2.61 (s, 3H), 1.93-1.43 (m, 13H).

Preparation Example 12: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-(phenylsulfonyl)morpholine-2-carboxamide (compound 313)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that benzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.79-7.66 (m, 5H), 7.48 (br, -CONH), 7.01, 6.76 (br, -CONH₂), 4.13-4.10 (m, 1H), 4.05-3.97 (m, 1H), 3.78-3.70 (m, 1H), 3.64-3.59 (m, 2H), 3.46-3.44 (m, 1H), 2.36-2.29 (m, 1H), 2.22-2.16 (m, 1H), 1.87-1.39 (m, 13H).

Preparation Example 13: Synthesis of 4-((4-bromo-2-fluorophenyl)sulfonyl)-N-(5-carbamoyladamantan-2-yl)morpholine-2-carboxamide (compound 314)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 4-bromo-2-fluorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.95-7.50 (m, 2H), 7.44-7.32 (m, 1H, -CONH), 7.02, 6.77 (br, -CONH₂), 4.11-3.97 (m, 1H), 3.79 (m, 1H), 3.66-3.46 (m, 4H), 2.83-2.76 (m, 1H), 2.68-2.59 (m, 1H), 1.87-1.41 (m, 13H).

Preparation Example 14: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((2,5-dichlorophenyl)sulfonyl)morpholine-2-carboxamide (compound 315)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2,5-dichlorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.96 (d, J = 2.4 Hz, 1H), 7.83-7.76 (m, 1H), 7.42 (d, J = 7.2 Hz, -CONH), 6.59, 6.73 (br, -CONH₂), 4.07-3.99 (m, 2H), 3.79-3.72 (m, 2H), 3.60-3.55 (m, 2H), 2.94-2.82 (m, 2H), 1.90-1.41 (m, 13H).

Preparation Example 15: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((3-fluorophenyl)sulfonyl)morpholine-2-carboxamide (compound 316)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 3-fluorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ8.02 (dd, J = 2.4, 7.2 Hz, 1H), 7.92 (dd, J = 2.0, 7.2 Hz, 1H), 7.66-7.58 (m, 2H), 7.41 (d, J = 7.6 Hz, -CONH), 6.99, 6.73 (br, -CONH₂), 4.07-4.00 (m, 2H), 3.79-3.78 (m, 1H), 3.72-3.69 (m, 1H), 3.62-3.51 (m, 2H), 2.89 (td, J = 3.2, 12.4 Hz, 1H), 2.78 (dd, J = 2.0, 8.0 Hz, 1H), 1.87-1.41 (m, 13H).

Preparation Example 16: Synthesis of 4-((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)-N-(5-carbamoyladamantan-2-yl)morpholine-2-carboxamide (compound 317)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2-bromo-5-(trifluoromethyl)benzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ8.20-8.16 (m, 2H, 8.01-7.99 (m, 1H), 7.46 (br, -CONH), 7.01-6.76 (br, -CONH₂), 4.08-3.99 (m, 2H), 3.79-3.74 (m, 2H), 3.62-3.54 (m, 2H), 3.02-2.89 (m, 2H), 1.91-1.41 (m, 13H).

Preparation Example 17: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((2,5-difluorophenyl)sulfonyl)morpholine-2-carboxamide (compound 318)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2,5-difluorobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.72-7.59 (m, 3H), 7.46 (br, -CONH), 7.01-6.75 (br, -CONH₂), 4.13-4.10 (m, 1H), 4.06-3.98 (m, 1H), 3.80-3.78 (m1, H), 3.71-3.69 (m, 1H), 3.64-3.58 (m, 1H), 3.53-3.50 (m, 1H), 2.74-2.69 (m, 1H), 2.63-2.58 (m, 1H), 1.88-1.41 (m, 13H).

Preparation Example 18: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((2-fluoro-5-methylphenyl)sulfonyl)morpholine-2-carboxamide (compound 319)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2-fluoro-5-methylbenzenesulfonyl chloride was used.

¹H NMR (400 MHz, DMSO-d ₆) δ7.59-7.58 (m, 2H), 7.49-7.38 (m, 1H, -CONH), 7.03, 6.76 (br, -CONH₂), 4.11-4.09 (m, 1H), 4.06-4.00 (m, 1H), 3.80-3.78 (m, 1H), 3.68-3.59 (m, 2H), 3.49 (d, J = 12.4 Hz, 1H), 2.64-2.58 (m, 1H), 2.50-2.38 (m, 4H), 1.88-1.41 (m, 13H).

Preparation Example 19: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-((2-(trifluoromethoxy)phenyl)sulfonyl)morpholine-2-carboxamide (compound 320)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2-(trifluoromethoxy)benzenesulfonyl chloride was used.

¹H NMR (400 MHz, CDCl₃) δ8.05-8.02 (m, 1H), 7.69-7.64 (m, 1H), 7.42-7.33 (m, 3H), 6.81 (br, -CONH), 5.61, 5.44 (br, -CONH₂), 4.15-4.40 (m, 4H), 3.84-3.72 (m, 2H), 2.95-2.88 (m, 1H), 2.57-2.51 (m, 1H), 2.07-1.60 (m, 13H).

Preparation Example 20: Synthesis of 4-((3-bromophenyl)sulfonyl)-N-(5-carbamoyladamantan-2-yl)morpholine-2-carboxamide (compound 321)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 3-bromobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, CDCl₃) δ7.92 (m, 1H), 7.78-7.76 (m, 1H), 7.74-7.70 (m, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.78 (br, -CONH), 5.60, 5.44 (br, -CONH₂), 4.16-4.02 (m, 4H), 3.81-3.76 (m, 1H), 3.68-3.65 (m, 1H), 2.53-2.57 (m, 1H), 2.08-1.58 (m, 13H).

Preparation Example 21: Synthesis of 4-((2-bromophenyl)sulfonyl)-N-(5-carbomoyladamantan-2-yl)morpholine-2-carboxamide (compound 322)

The title compound could be obtained in the same manner as Preparation Example 1 of Example 29, except that 2-bromobenzenesulfonyl chloride was used.

¹H NMR (400 MHz, CDCl₃) δ8.15 (m, 1H), 7.78 (dd, J = 1.2, 7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.85 (br, -CONH), 5.60, 5.38 (br, -CONH₂), 4.15-3.99 (m, 4H), 3.82-3.75 (m, 2H), 3.09-3.02 (m, 1H), 2.78-2.70 (m, 1H), 2.07-1.61 (m, 13H).

Preparation Example 22: Synthesis of N-(5-carbamoyladamantan-2-yl)-4-(o-torylsulfonyl)morpholine-2-carboxamide (compound 323)

¹H NMR (400 MHz, DMSO-d ₆) δ7.82-7.80 (m, 1H), 7.63-7.59 (m, 1H), 7.49-7.40 (m, 2H,-CONH), 7.00, 6.75 (br, -CONH₂), 4.09-3.99 (m, 2H), 3.79-3.77 (m, 1H), 3.62-3.55 (m, 2H), 3.43-3.34 (m, 1H), 2.73-2.68 (m, 1H), 2.61-2.55 (m, 4H), 1.89-1.41 (m, 13H).

[Example 30] Enzymatic activity assay for human/mouse 11β-HSD1

Enzymatic activity for human 11β-HSD1 was determined in a 10 μl final volume of an assay mixture containing 20 mM Tris, 5 mM EDTA buffer (pH 6.0), 200 uM NADPH, a test compound, 100 ug/ml human/mouse liver microsome, and 160 nM cortisone (Sigma) as a substrate. After incubation for 2 hours at 37 ℃, 5 μl of europium cryptate-labeled anti-cortisol antibody and 5 μl of d2-labeled cortisol were added. After further incubation for 2 hours at room temperature, the homogeneous time-resolved fluorescence (HTRF, Cisbio) signal was measured. The cortisol production was quantified by a standard curve generated with several known concentrations of cortisol in each assay.

The amount of cortisol production without the test compound served as a control, and the percent inhibition by the test compound at each concentration was calculated. The IC50 value of the compound for 11β-HSD1 was obtained using the inhibition curve generated by plotting the percent inhibition versus the concentration of test compound. The results of the assay are shown in Table 1.

[Table 1]

*

[Example 31: Cell-based enzymatic activity assay for human/mouse 11β-HSD1

CHO cells transfected stably with human/mouse 11β-HSD1 cDNA were plated at a density of 2x10⁴cells/well in a 96-well plate with a phenol red-free RPMI medium (Wellgene) containing 100 μl of 10% FBS, 100 ug/ml penicillin, 100 ug/ml streptomycin and 12 ug/ml puromycin (12 ug/ml), and were then cultured at 37 ℃ overnight. 17 hours after plating of the cells, 160 nM cortisone (Sigma) was added to culture medium, after which the cells were cultured at 37 ℃ for 3 hours in the presence or absence of a test compound diluted to various concentrations. 10 μl of the supernatant of the culture medium was transferred into a 384-well plate, and 5 μl of cryptate-labeled anti-cortisol antibody and 5 μl of d2-labeled cortisol were added to each well. The cells were further cultured at room temperature for 2 hours, and then the homogeneous time-resolved fluorescence (HTRF, Cisbio) signal was measured. The cortisol production was quantified by a standard curve generated with several known concentrations of cortisol in each assay.

[Example 32] Evaluation of 11b-HSD2inhibition

CHO cells were plated at a density of 2x10⁴ cells/well in a 96-well plate with a phenol red-free RPMI medium (Wellgene) containing 100 μl of 10% FBS, 100 ug/ml penicillin and 100 ug/ml streptomycin. A plasmid (Origene, SC122552) expressing human 11β-HSD2 in a pCMV6-XL5 vector was transfected into the CHO cells using FuGENE6 reagent (Promega, E2311). 24 hours after the transfection, the transfected cells were incubated with 50 nM cortisol (Sigma) in the presence or absence of various concentrations of the test compound. The next day (after 24 hours), the supernatant was collected and the amount of competitive cortisol was determined by HTRF (Cisbio, 62CO2PEB) assay.

Compounds 102, 122, 123, 168, 172, 173, 185, 203 and 233 showed an inhibition of 30% or less at a concentration of 10 uM, and compounds 306 and 302 each showed an inhibition of 2.81 % and 30.51% at a concentration of 10 uM.

[Example 33] Glucocorticoid receptor competitive binding assay

In order to examine the selective inhibitory ability of a 11β-HSD1 inhibitor, a competitive binding assay between the 11β-HSD1 inhibitor and a glucocorticoid ligand was performed using LanthaScreen^® TR-FRET Glucocorticoid Receptor Competitive Binding Assay (Invitrogen, PV6040). A test compound was dissolved in DMSO (Sigma, 276855) so as to reach 100 times the final concentration (10 uM). Then, using complete nuclear receptor buffer F (1x stabilizing peptide, 5 mM DTT, nuclear receptor buffer F), the test compound was diluted 2-fold and 4-fold, Fluormone^TM GS1 green was diluted 4-fold to 20 nM, 4X GR-LBD was diluted 4-fold to 4 nM, and Tb anti-GST antibody was diluted to 8 nM.

In a 96-well plate, 30 μl of 2-fold-diluted test compound, 15 μl of 4-fold-diluted Fluormone^TM GS1 Green, and 15 μl of 4-fold-diluted GR-LBD/Tb anti-GST antibody were mixed with each other to a final volume of 60 μl, followed by incubation for 1 hour. In a positive control, dexamethasone (Sigma, D1756) known as a ligand of glucocorticoid receptor was used instead of the test compound, and in a maximum activity control, DMSO was used instead of the test compound. In a negative control, DMSO was used instead of the test compound, and Complete Nuclear Receptor Buffer F was used instead of Fluormone^TM GS1 Green. 20 μl was dispensed into each well of a 384-well white plate, and then the fluorescence value was read using a Time-Resolved program in Flexstation3 under the following set conditions: excitation = 332 nm, emission = 515 nm/486 nm, delay time = 100 μs, and integration time = 1500 μs. Based on the obtained value, the 515 nm/486 nm value was calculated, and the negative control value was subtracted from the calculated value. The degree of glucocorticoid receptor binding of the test compound was expressed as the percentage of the activity value of test compound relative to 100% for the maximum activity control.

As a result, compounds 100, 104, 105, 172, 173, 185, 203, 233, 261, 302 and 312 showed an activity value of 90% or higher, suggesting that these compounds did not bind to the glucocorticoid receptor.

[Example 34] In vitro enzymatic activity assay for mouse 11β-HSD1

C57BL/6N mice were fasted for 12 hours prior to the experiment, but had free access to water. Only healthy animals showing no abnormalities during quarantine and acclimation and after fasting were selected, and a test compound was administered into the stomach of the mice by a sonde. 2 hours after administration of the test compound, the animals were subjected to cervical dislocation, after which the abdominal cavity was open, and the left lobe of the liver and the subcutaneous fat opposite to the inguinal region were extracted. The extracted organs were washed with saline, and the blood and the hair were removed. The edge portion (10-30 mg) of the liver and the middle portion (50-100 mg) of the subcutaneous fat were sectioned with a blade and transferred into a 48-well plate containing 500 μl PBS (cold state). 500 μl of the tissue placed in the plate was transferred into each well of a 48-well plate with a phenol red-free DMEM medium (Wellgene) containing 1 uM cortisone and 100 nM NADPH, and was then allowed to react at 37 ℃ for 3 hours. 300 μl of the reaction solution in the plate was transferred into a 1.5-ml tube and stored at -20 ℃.

The quantitative assay of cortisol in the reaction solution was performed using cortisol EIA (Assay Design, 900-071). 100 μl of each of a test sample (diluted to 1/20) and a cortisol standard was added to the 96-well plate coated with a primary antibody, and 50 μl of each of a cortisol conjugate and anti-cortisol EIA antibody was added to the plate, after which they were allowed to react at room temperature for 2 hours in an orbital shaker. Then, the wells were evacuated by upsetting the plate, after which each well was washed three times with 400 μl of a washing buffer. 200 μl of the substrate solution pNpp was added to each well and allowed to react at room temperature for 1 hour. Then, 50 μl of sodium triphosphate was added to each well to stop the reaction, and the absorbance at a wavelength of 405 nm was measured. The quantitative value of cortisol in the test samples was determined by interpolation from a standard curve plotted by the cortisol standard. The percentage of inhibition was calculated relative to a control that was a sample collected from an animal which was not administered with the test compound.

Compounds 100, 102, 105, 113, 118, 122, 123, 128, 131, 168, 171, 172, 176, 177, 181, 185, 203, 233, 266, 263, 277, 302, 304, 306, 307, 312 and 321 were evaluated by the in vitro enzymatic activity assay as described above. As a result, most of the compounds showed an inhibition of 70% or higher against 11b-HSD1 enzyme in the liver and the subcutaneous fat, and compounds 302, 306 and 312 showed an inhibition of 60% or higher against 11b-HSD1 enzyme in the liver and the subcutaneous fat.

Claims

A compound represented by the following Chemical Formula 1 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

wherein

R' and R'' are each independently H or a C₁-C₃alkyl and may be taken together to form a 5- or 6-membered saturated or unsaturated ring;

X is any one selected from the group consisting of -NR₁R₂, -NHSO₂R₁, -C(O)OR₁, -NHC(O)R₁, -OC(O)R_1, -C(O)NR₁R₂, -NHC(O)NR₁R₂, and -C(O)NHNR₁R₂;

L is a bond or a C₁- C₃alkylene group, wherein each carbon atom constituting the C₁- C₃alkylene group may be independently substituted with one or more C₁- C₆ alkyl groups;

R₁ and R₂are each independently any one selected from the group consisting of hydrogen, -OH, a substituted or unsubstituted C₁- C₆ alkyl, a substituted or unsubstituted C₃- C₁₂ cycloalkyl, a substituted or unsubstituted C₆- C₁₂ aryl, and a substituted or unsubstituted C₅- C₁₂ heteroaryl having one or more ring heteroatoms selected from the group consisting of N, O and S;

R₁ and R₂may be taken together with the nitrogen atom to which they are attached to form a 5- to 8-membered saturated or unsaturated ring, wherein the saturated or unsaturated ring may be substituted with one or more groups selected from the group consisting of -OH, a C₁- C₆ alkoxy, a C₁- C₆ haloalkoxy, a substituted or unsubstituted C₁- C₆ alkyl, -NO₂, halo, -COOH, a -C₁- C₆ alkyloxycarbonyl, a C₆- C₁₀ aryl, -NH₂, a mono- or di- C₁- C₆ alkylamino, and a mono- or di- C₁- C₆ alkylcarbamoyl;

L‘ is a bond, -C(O)-, -C(O)O-, -C(O)NH-, -NHC(O)-, C₁- C₃alkylene, -SO₂-, C₁- C₃alkylene-C(O)-, or -C(O)-C₁- C₃alkylene, wherein each carbon atom constituting the C₁- C₃alkylene may be each independently substituted with one or more groups selected from the group consisting of C₁- C₆ alkyl, -CN, -COOH, and C₁- C₆ alkyloxycarbonyl;

P is any one selected from the group consisting of a substituted or unsubstituted C₁- C₆ alkyl, a substituted or unsubstituted C₃- C₁₂ cycloalkyl, a substituted or unsubstituted C₆- C₁₂ aryl, a substituted or unsubstituted C₅- C₁₂heteroaryl having one or more ring heteroatoms selected from the group consisting of N, O and S, a C₁- C₆ alkyloxycarbonyl, -COOH, and -NR₁R₂;

wherein when P is a C₆- C₁₂ aryl group in which two adjacent carbon atoms constituting the aryl group are each substituted with a C₁- C₆ alkyl group, carbon atoms constituting the alkyl group may be taken together to form a 5- or 6-membered saturated or unsaturated ring, wherein the ring may be substituted with one or more groups selected from the group consisting of -OH, C₁- C₆ alkoxy, C₁- C₆ haloalkoxy, C₁- C₆ alkyl, -NO₂, halo, -COOH, -C₁- C₆ alkyloxycarbonyl, C₆- C₁₀ aryl, -NH₂, mono or di C₁- C₆ alkylamino, and mono- or di- C₁- C₆ alkylcarbamoyl, and one or more of the carbon atoms constituting the ring may be substituted with one or more selected from the group consisting of N, O and S;

wherein when P is a C₃- C₁₂ cycloalkyl group in which two adjacent carbon atoms constituting the cycloalkyl group are each substituted with a C₁- C₆ alkyl group, carbon atoms constituting the alkyl group may be taken together to form a 5- or 6-membered saturated or unsaturated ring, wherein the ring may be substituted with one or more groups selected from the group consisting of -OH, C₁- C₆ alkoxy, C₁- C₆ haloalkoxy, C₁- C₆ alkyl, -NO₂, halo, -COOH, -C₁- C₆ alkyloxycarbonyl, C₆- C₁₀ aryl, -NH₂, mono- or di- C₁- C₆ alkylamino, and mono- or di- C₁- C₆ alkylcarbamoyl;

wherein said substituted C₁- C₆ alkyl, substituted C₃- C₁₂ cycloalkyl, substituted C₆- C₁₂ aryl and substituted C₅- C₁₂heteroaryl mean that said C₁- C₆ alkyl, C₃- C₁₂ cycloalkyl, C₆- C₁₂ aryl and C₅- C₁₂heteroaryl may be independently substituted with one or more groups selected from the group consisting of a C₁- C₆ alkyl which may be substituted with -CN, halo or -OH; a C₃- C₁₂ cycloalkyl; a C₂- C₆ alkenyl; a substituted or unsubstituted C₅- C₁₂heteroaryl having one or more ring heteroatom selected from the group consisting of N, O and S; a C₆- C₁₀ aryl; a C₁- C₆ alkylsulfonyl; a C₆- C₁₂ arylsulfonyl; a C₁- C₆ alkylthio; mercapto; -OH; a C₁- C₆ alkoxy; a C₁- C₆ haloalkoxy; -CN; -NO₂; halo; -COOH; -CHO; a -C₁- C₆ alkylcarbonyl; a -C₁- C₆ alkyloxycarbonyl; -NH₂; -CONH₂; a mono- or di- C₁- C₆ alkylamino; and a mono- or di- C₁- C₆ alkylcarbamoyl;

wherein one or more carbon atoms constituting the C₁- C₆ alkyl and the C₃- C₁₂ cycloalkyl may be substituted with one or more of N, O and S;

wherein alkyl or alkenyl in said C₁- C₆ alkyl, C₂- C₆ alkenyl, C₁- C₆ alkylsulfonyl, C₁- C₆ alkoxy, C₁- C₆ haloalkoxy, -C₁- C₆ alkylcarbonyl, -C₁- C₆ alkyloxycarbonyl, C₁- C₆ alkylamino and C₁- C₆ alkylcarbamoyl may be straight or branched-chain; and

wherein said C₃- C₁₂ cycloalkyl, C₆- C₁₂ aryl and C₅- C₁₂heteroaryl have a single ring or a multiple ring structure.
The compound, stereoisomer or salt according to claim 1, wherein X is -C(O)NR₁R₂, wherein R₁ and R₂are as defined in claim 1.
The compound, stereoisomer or salt according to claim 1, wherein X is
, wherein the cycloalkyl moiety is substituted with one or more groups selected from the group consisting of a C₁- C₆ alkyl which may be substituted with -CN, halo or -OH; a C₃- C₁₂ cycloalkyl; a C₂- C₆ alkenyl; a substituted or unsubstituted C₅- C₁₂ heteroaryl having one or more ring heteroatoms selected from the group consisting of N, O and S; a C₆- C₁₀ aryl; a C₁- C₆ alkylsulfonyl; a C₆- C₁₂ arylsulfonyl; a C₁- C₆ alkylthio; mercapto; -OH; a C₁- C₆ alkoxy; a C₁- C₆ haloalkoxy; -CN; -NO₂; halo; -COOH; -CHO; a -C₁- C₆ alkylcarbonyl; a -C₁- C₆ alkyloxycarbonyl; -NH₂; -CONH₂; a mono- or di- C₁- C₆ alkylamino; and a mono- or di- C₁- C₆ alkylcarbamoyl.
The compound, stereoisomer or salt according to claim 1, wherein the compound of Chemical Formula 1 is any one selected from the group consisting of the following compounds:
The compound, stereoisomer or salt according to claim 1, wherein the compound of Chemical Formula 1 is any one selected from the group consisting of the following compounds:
A pharmaceutical composition for inhibiting human-11-beta-hydroxysteroid dehydrogenase type 1, comprising, as an active ingredient, the compound, stereoisomer or salt according to any one of claims 1 to 5.
A pharmaceutical composition for treating or preventing any one disease selected from the group consisting of hypertension, heart failure, renal failure, liver failure, peripheral vascular disease, coronary artery disease, myocardial infraction, hyderlipidemia, diabetes, hyperglycemia, obesity, ischemic heart disease, diabetic nephropathy, diabetic heart failure, dyslipidemia, stroke, arteriosclerosis, inflammation, adult respiratory distress syndrome, renal disease, Raynaud syndrome, obstructive pulmonary disease, interstitial pulmonary disease, asthma and arthritis, the pharmaceutical composition comprising, as an active ingredient, the compound, stereoisomer or salt according to any one of claims 1 to 5.
A pharmaceutical composition for treating or preventing any one disease selected from the group consisting of diabetes, metabolic syndrome, obesity, polycystic ovary syndrome, eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, hyderlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein level (HDL), high low-density lipoprotein level (LDL), hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, arteriosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, nerve disorder, muscle wasting, cognitive impairment, dementia, psoriasis, glaucoma, osteoporosis, viral infection, inflammatory disease, and immune disease, the pharmaceutical composition comprising, as an active ingredient, the compound, stereoisomer or salt according to any one of claims 1 to 5.