BACKGROUND ART Five receptor subtypes have been cloned and characterized in the melanocortin family. These G-protein coupled receptors (GPCR) stimulate the cAMP signal transduction pathway in many different tissues, mediating a wide range of physiological functions. The melanocortin 1 receptor (MC1R) is mainly expressed in melanocytes, monocytes and mast cells and mediates pigmentation of the hair and skin and blocking inflammation. MC2R is expressed in adipocytes and adrenal cells and mediates steroidogenesis in the adrenal gland. MC3R is present in the brain, hyphothalamus, heart, gut and placenta and has been associated with energy homeostasis and inflammation. MC4R is uniquely expressed in the brain and control feeding behavior, energy homeostasis and erectile function. MC4R knock out mice revealed the phenotype of hyperphasia and obesity. MC5R is found in a wide range of tissues and is considered to have a role in the exocrine gland system.

With the plethora of physiological functions of melanocortin receptors, a large number of compounds have been designed and synthesized in search for potent agonists and antagonists.

Early examples are synthetic peptides and peptide analogues that have been identified based on endogenous agonists such as a-MSH. These peptide agonists have been used to characterize the function of these receptors. NDP-aMSH is a highly potent and nonselective agonist of MC1R, 3R, 4R and 5R and has been reported to attenuate food intake and body weight gain in rat models. A cyclic heptapeptide MT-II is an agonist with a similar non-selective profile and its therapeutic use has proven in clinical trials for the treatment of erectile dysfunction. HP-228, a peptide analogue with similar affinity for all four receptors, was in clinical trials for the treatment of pain and inflammation associated with surgery.

Several small molecule agonists for the melanocortin receptors have been disclosed with most of activity in drug discovery aiming at MC4R agonists for the treatment of obesity, sexual dysfunction or inflammation. For example, the Merck research group has disclosed a series of potent and selective MC4R agonists, one of which demonstrated its great effect on augmenting erectile response in mice (J Med.

Chez. 2002, 45, 4849). The Chiron research group has disclosed a series of guanidine compounds as agonists that have hyphophasic and anti-obesity effects in the ob/ob mouse model (WO 02/18327). On the other hand, the Bristol-Myers Squibb group has disclosed a highly potent selective MC1R agonist, which showed efficacy in an acute mouse model of inflammation (J. Med. Chers. 2003, 46, 1123).

In view of the unresolved deficiencies of the various pharmaceutical compounds as discussed above, there is continuing need for in the arts for small molecule MCR agonists and pharmacological compositions that have improved phannacological profiles. It is therefore an object of the present invention to provide novel compounds that are useful for the treatment of obesity, diabetes, sexual dysfunction and inflammation.

DISCLOSURE OF THE INVENTION The present invention relates to a compound of the following formula 1, and pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof. in which R1 represents hydrogen, -(CH2)p-R6, -(CH2)p-CO-R6, -(CH2)p-SO2-R6, or -CO-(CH2)p-R6, wherein p represents independently 0,1, 2, or 3, R6 represents C1-C10-alkyl, C3-C8-cycloalkyl, heterocycle, aryl, heteroaryl, amino, or hydroxyl, each of which is unsubstituted or mono-to polysubstituted by substituents from the group consisting of Cl-C6-alkyl, halogen, amino, Cl-C6-alkylamino, di (Cl-C6-alkyl) amino, hydroxy, C1- C8-alkoxy, trifluoromethoxy, Ci-Ce-alkylcarbonyl, arylcarbonyl, Cl-C6- alkoxycarbonyl, carbamoyl, Cl-C6-alkylsulfonyl, arylsulfonyl, carboxy, cyano, and oxo, hydrogen atom in -(CH2)p- group can be replaced by R6 as defined above, R2 represents hydrogen, Cl-C8-alkyl, or C3-C7-cycloalkyl, R2 and R1 together with the atom to which they attached, may form 4-or 8- membered single ring or two rings which may be interrupted by heteroatom from the group consisting of by O, S, and N-(C1-C4-alkyl), R3 represents -C1-C8-alkyl, -(CH2)q-C3-cycloalkyl, -(CH2) q-phenyl, or- (CH2) q-heteroaryl, each of which is unsubstituted or mono-to tri-substituted by substituents from the group consisting of Cl-C6-alkyl, halogen, amino, Cl-C6-alkylamino, di (C1-C6-alkyl) amino, hydroxy, Cl-C8-alkoxy, C1-C6- alkylcarbonyl, arylcarbonyl, C1-C6-alkoxycarbonyl, carbamoyl, C1-C6- alkylsulfonyl, arylsulfonyl, carboxy, cyano, and oxo, wherein q represents independently 0,1, 2, or 3, R4 represents phenyl, cyclohexyl, or NR7R8, wherein R7 and R8 independently of one another represent C1-C6-alkyl,- (CH2) q-C3- C7-cycloalkyl,-(CH2) q-phenyl, or-(CH2) q-heteroaryl (wherin q is as defined above), or together with the nitrogen atom to which they attached, may form 4-or 8-membered single ring or two rings which may contain O, S, or N-(Cl-C4-alkyl), and these radicals are unsubstituted or mono-to poly-substituted by substituents from the group consisting of Cl-C6-alkyl, halogen, amino, C1-C6-alkylamino, di (Cl-C6-alkyl) amino, hydroxy, C1-C8-alkoxy, trifluoromethoxy, C1-C6- alkylcarbonyl, arylcarbonyl, Cl-C6-alkoxycarbonyl, carbamoyl, C1-C6- alkylsulfonyl, arylsulfonyl, carboxy, cyano, and oxo R5 represents- (CH2) o R9, -(CH2)o-COR9, or - (CH2) o-C (O) N (R9) (Rlo), wherein o represents independently 0,1, 2, or 3, R9 andRl° independently of one another represent hydrogen, amino, hydroxy, Cl-C6-alkyl, Cl-C6-alkoxy, C3-C7-cycloalkyl, phenyl, heterocycle, or heteroaryl, and these radicals except for hydrogen are unsubstituted or substituted by one to three substituents from the group consisting of C1-C6- alkyl, halogen, amino, Cl-C6-alkylamino, di (Cl-C6-alkyl) amino, hydroxy, Cl-C8-alkoxy, trifluoromethoxy, Cl-C6-alkylcarbonyl, arylcarbonyl, C1-C6- alkoxycarbonyl, carbamoyl, Cl-C6-alkylsulfonyl, arylsulfonyl, C3-C6- cycloalkyl C2-C8-alkanoyl, Cl-C6-alkylsulfamoyl, carboxy, cyano, and oxo, or R9 and Rl° together with the nitrogen atom to which they attached, may form 4-or 8-membered single ring or two rings which may contain O, S, or N- (Cl-C4-alkyl).

In the radical definitions of the compound of formula (1) according to the present invention, the term"alkyl"means straight-chain or branched hydrocarbon radical when used alone or in combination with hetroatoms such"alkyloxy." The term"cycloalkyl"represents unsaturated aliphatic ring including cyclohexyl.

The term"aryl"represents aromatic group including phenyl, naphthyl, etc.

The term"heteroaryl"includes 1 to 2 heteroatom (s) from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and represents aromatic 3-to 6- membered ring which can be fused with benzo or C3-Cs-cycloalkyl. Examples of monocyclic heteroaryl are, but are not limited to, thiazole, oxazole, thiophene, furane, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and similar group to them. Examples of acyclic heteroaryl are, but are not limited to, indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, furopyridine, and similar group to them.

The term"heterocycle"includes 1 to 2 heteroatom (s) from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and represents saturated 3-to 6- membered ring which can be fused with benzo or C3-C8-cycloalkyl. Its examples are, but are not limited to, piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and similar group to them.

Preferred compounds among the compounds of formula (1) above are those wherein i) R1 represents hydrogen, -(CH2)p-R6, -(CH2)p-CO-R6, or -(CH2)p-SO2-R6, wherein p is as defined above, preferably, Rl represents hydrogen, or- (CH2) p-R6, wherein p is as defined above, ii) Rl represents-CO-(CH2) p-R6, wherein p is as defined above, iii) W represents hydrogen, or Cl-C6-alkyl, iv) R3 represents- (CH2) q-C3-C7-cycloalkyl,- (CH2) q-phenyl, or- (CH2) q- heteroaryl, each of which is unsubstituted or mono-to tri-substituted by substituents from the group consisting of halogen, cyano, carboxy, hydroxy, Cl-C4-alkyl, C1-C8- alkoxy, amino, Cl-C4-alkylamino, and di (Cl-C4-alkyl) amino, wherin q is as defined above, preferably, R3 represents-CH2-cyclohexyl or CH2-phenyl, each of which is unsubstituted or mono-to tri-substituted by substituents from the group consisting of halogen, cyano, hydroxy, Cl-C4-alkoxy, trifluoromethoxy, and Cl-C4-alkyl, v) R4 represents phenyl, cyclohexyl, C1-C4-alkylamino, di (Cl-C4-alkyl) amino, pyrrolidinyl, piperidinyl, or azepinyl, wherein Cl-C4-alkyl, pyrrolidinyl, piperidinyl or azepinyl is unsubstituted or mono-to tri-substituted by substituents from the group consisting of halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, amino, Cl-C4-alkylamino, and di (Cl-C4-alkyl) amino, vi) R5 represents C1-C6-alkyl, -(CH2)o-heteroaryl, -(CH2)o-heterocycle, -CO2R9,- C(O)N(R9)(R10), -(CH2)o-OR11, -(CH2)o-NHR11, or -(CH2)o-N(R11)(R12), wherein heteroary is unsubstituted or mono-to tri-substituted by substituents from the group consisting of hydroxy, Ci-C4-alkyl, C1-C4-alkoxy, amino, C1-C4-alkylamino, di (Cl-C4- alkyl) amino, and oxo, wherin R9 and Rl° are as defined above, R11 and R12 independently of one another represent Cl-C6-alkyl, C3-C6-cycloalkyl, C2-C8-alkanoyl, Cl-C6-alkylsulfonyl, Cl-C6-alkylsulfamoyl, or arylsulfonyl, and o is as defined above, preferably, R5 represents -(CH2)0-1-heteroaryl, -(CH2)0-1-heterocycle, -C(O)N(R9)(R10), - (CH2)o-OR11, -(CH2)0-1-NHR11, or -(CH2)-0-1-N(R11)(R12), wherein R9, R10, R11 and R12 are defined above.

Representative compounds of formula 1 according to the present invention include the compounds listed in the following Table 1.

Table 1 Ri Rz R3 * Ra s H H 4-CI-Bn R c-Hex C (O) NH (t-Bu) H H 4-CI-Bn R c-Hex C (O) N (Me) (i-Pr) H H 4-CI-Bn R c-Hex C (O) N (Me) 2 H H 4-CI-Bn S c-Hex C (O) N (Me) 2 H H 4-Cl-Bn R c-Hex C (O) NH (CH2-c-Hex) H H 4-CI-Bn R c-Hex C (O) (Pyd-l-yl) H H 4-CI-Bn R c-Hex C (0) (1, 2, 3-Trz-1-yl) H H 4-CI-Bn R c-Hex C (0) (1, 3-Imz-l-yl) H H Bn R c-Hex C (O) NH (t-Bu) H H 4-Br-Bn R c-Hex C (O) NH (t-Bu) H H 4-MeO-Bn R c-Hex C (O) NH (t-Bu) H H 3, 4-diCl-Bn R c-Hex C (O) N (Me) 2 H H 4-F-Bn R c-Hex C (O) N (Me) Z H H 4-HO-Bn R c-Hex C (O) N (Me) 2 H H 4-CI-Ph R, S c-Hex C (O) N (Me) 2 H H (c-Hex)-CH2 R c-Hex C [-O-CH2C (Me) 2-N=] H H (c-Hex)-CH2 S c-Hex ^H2-(1, 2, 4-Trz-l-yl) H H Ph- (CH2) 2 R c-Hex C (O) NH (t-Bu) H H (indol-2-yl)-CH2 R c-Hex C (O) NH (t-Bu) H H 3-NH2- (CH2) 3 R c-Hex C (O) NH (t-Bu) H H NH2C (O)-CH2 R c-Hex C (O) NH (t-Bu) H H i-Bu R c-Hex C (O) NH (t-Bu) H H 4-CI-Bn R c-Hex C (-0-CH2CH2-N=) Table 1 (continued) H H 4-Cl-Bn R c-Hex C [-O-CH2C (Me) 2-N=] H H 4~CI-Bn R c-Hex C [-S-CH2CH2-N=] H H 4-Cl-Bn R c-Hex CHO H H 4-C1-Bn R c-Hex C (O) OMe H H 4-Cl-Bn R c-Hex C (O) (i-Bu) H H 4-Cl-Bn R c-Hex (C (O) (1-OH-i-Bu) H H 4-Cl-Bn R c-Hex N (Me) 2 H H 4-Cl-Bn R c-Hex NHAc H H Bn R c-Hex C (-O-CH2CH2-N=) H H 4-Cl-Bn R c-Hex CH2OSOzMe H H 4-Cl-Bn R c-Hex CH20SO2 (i-Pr) H H 4-CI-Bn R c-Hex CH2NSO2Me H H 4-Cl-Bn R c-Hex CHzNHAc H H 4-Cl-Bn R c-Hex CHZN (Me) 2 H H 4-Cl-Bn R c-Hex CH2N (c-Hex) [C (O) (i-Bu)] H H 4-Cl-Bn R c-Hex CH2N (c-Hax) (Me) H H 4-Cl-Bn R c-Hex CH2- (1, 2, 3-Trz-l-yl) H H 4-CI-Bn R c-Hex CH2-(1, 2, 4-Trz-1-yi H H 4-Cl-Bn R c-Hex (1, 3-Imz-1-yl)-CHz H H 4-Cl-Bn R c-Hex (Tez-l-yl)-CH2 H H 4-Cl-Bn R c-Hex CH2N [-C (0) OCH2C (Me) 2-] H H 4-Cl-Bn S c-Hex oH2-(1, 2, 4-Trz-l-yl) J Table 1 (continued) H 4-CI-Bn R c-Hex C (O) NHC (Me) 2CH2NH2 H H 4-CI-Bn R c-Hex C (O) NHCH2CH2NH2 H H 4-C1-Bn R c-Hex C (O) NHCH2CH2CH2NH2 H 4-CI-Bn R c-Hex C (o) NHCH2CH2CH2CH2NH2 H 4-CI-Bn R c-Hex C (O)-O-CH2CH2NH2 H 4-CI-Bn R c-Hex C (O) N (Me) CH2CH2NH2 H 4-CI-Bn R c-Hex C (O) NHCH2CH2N (Me) 2 H 4-CI-Bn R c-Hex C (O) NHCH2CH2N (Et) 2 H 4-CI-Bn R c-Hex C (O) NHC (Me) 2CH20H H H 4-C1-Bn R c-Hex C (O) NHCH (Me) CH20H H 4-CI-Bn R c-Hex C (O) NHCH2CH20H H H 4-C I-Bn R c-Hex C (O) NHCH2CH2CH20H H 4-CI-Bn c-Hex C (O) N (Me) CH2CH2CH20Me H H 4-CI-Bn R c-Hex C (O) N (Me) CH2CH20H H 4-CI-Bn R c-Hex C (O) N (Me) CH2CH20Me H H 4-CI-Bn R c-Hex C (O) NHCH2CH20Me H 4-CI-Bn R c-Hex C (O) N [-CH2CH (OH) CH2-] H 4-CI-Bn R c-Hex C (0) N [-CH2CH (OMe) CH2-] H H 4-CI-Bn R c-Hex C (O) N [-CH2CH (NH2) CH2-] H H 4-CI-Bn R c-Hex C (0) N {-CH2CH [ (R)-OH] CH2CH2-} H 4-CI-Bn R c-Hex C (0) N [-CH2CH2CH (OH) CH2CH2-] H H 4-CI-Bn R c-Hex C (0) N [-CH2CH2CH (OMe) CH2CH2-] H 4-C1-Bn R c-Hex C (0) N [-CH2CH2CH (OAc) CH2CH2-] Table 1 (continued) H H 4-Cl-Bn R c-Hex C (O) N {-CH2CH [ (R)-NH2] CH2CH2-} H H 4-Cl-Bn R c-Hex C (O) N {-CH2CH [ (S)-NH2] CH2CH2-} H H 4-Ct-Bn R c-Hex C (O) N [-CH2CH2CH (NH2) CH2CH2-] H H 4-Cl-Bn R c-Hex C (O) N (-CH2CH2NHCH2CH2-) H H 4-CI-Bn R c-Hex C (0) N [-CH2CH2N (Me) CH2CH2-I H H 4-CI-Bn R c-Hex C (O) NH-(S)-CH (-CH2NHCH2CH2-) H H 4-Cl-Bn R c-Hex C (O) NH- (R)-CH (-CH2NHCH2CH2-) H H 4-Cl-Bn R c-Hex C (O) N (-CH2CH20CH2CH2-) H H 4-Cl-Bn R c-Hex C (O) NHCH (CH20H) 2 H H 4-Cl-Bn R c-Hex C (O) N (CH2CH20H) 2 H H 4-Cl-Bn R c-Hex C (O) N [-CH2C (0) CH2-] H H 4-CI-Bn R c-Hex C (0) N [-CH2CH2C (O) CH2CH2-] Me Me 4-Cl-Bn R c-Hex C (O) N (Me) CH2CH20H Me Me 4-Cl-Bn R c-Hex C (O) NHCH2CH2NH2 Gly H 4-Cl-Bn R c-Hex C (O) NHCH2CH20H Gly H 4-Cl-Bn R c-Hex C (O) NHCH2CH2OMe NH2C (O) CH2 H 4-Cl-Bn R c-Hex C (O) NHCH2CH20H CH (CH2NHCH2CH2) H 4-CI-Bn R c-Hex C (O) NHCH2CH20H Table 1 (continued) Me H 4-Cl-Bn R c-Hex C (O) NH (t-Bu) Me H 4-CI-Bn R c-Hex CH2-(1, 2, 4-Trz-1-yl) Me H 4-CI-Bn R c-Hex C (-0-CHzC (Me) 2-N=) Me H 4-Cl-Bn R c-Hex C (O) N (Me) 2 Me Me 4-Cl-Bn R c-Hex C (O) N (Me) 2 Me Me 4-CI-Bn R c-Hex CH2-(1, 2, 4-Trz-l-yl) Me Me 4-CI-Bn R c-Hex C (O) NH (t-Bu) Ac H 4-CI-Bn R c-Hex C (O) N (Me) 2 Ac H 4-Cl-Bn R c-Hex CH2-(1, 2, 4-Trz-1-yl MeS02 H 4-Cl-Bn R c-Hex C (0) N (Me) MeO2C-CH2 H 4-CI-Bn R c-Hex C (0) NH (t-Bu) MeO2c-cH2 H 4-Cl-Bn R c-Hex CH2- (1, 2, 4-Trz-1-yl) HOzC-CH2 H 4-CI-Bn R c-Hex C (0) NH (t-Bu) (Me) 2NC (O) H, 4-CI-Bn R c-Hex C (O) N (Me) (Me) 2NC (O)-CH2 H 4-Cl-Bn R c-Hex H2-(1, 2, 4-Trz-l-yl) Gly H 4-Cl-Bn R c-Hex C (0) N (Me) 2 Gly H 4-Cl-Bn R c-Hex (-O-CH2CH2-N=) Gly H 4-Cl-Bn R c-Hex CH2- (1, 2, 4-Tra-1-yl) N-diMe-Gly H 4-CI-Bn R c-Hex C (O) N (Me) 2 (R) Ala H 4-CI-Bn R c-Hex C (O) N (Me) 2 (R) His H 4-Cl-Bn R c-Hex C (O) N (Me) 2 (S) His H 4-Cl-Bn R c-Hex C (O) N (Me) 2 (S) His H 4-CI-Bn R c-Hex CH2- (1, 2, 4-Tra-1-yl) Table 1 (continued) __ i N-Me- (S) His H 4-Cl-Bn R c-Hex CH2-(1, 2, 4-Trz-1-yl) N-Ac- (S) His H 4-CI-Bn R c-Hex CH2-(1, 2, 4-Trz-l-yl) N-BOC- (S) His H 4-CI-Bn R c-Hex CH2- (1, 2, 4-Trz-l-yl) N- (n-Pr) C (0)- (S) His H 4-Cl-Bn R c-Hex CH2-(1, 2, 4-Trz-l-yl) N-Ph (CH2) 4C (O)- H 4-Cl-Bn R c-Hex CH2-(1, 2, 4-Trz-1-yl) (S) His (S) Phe H 4-Cl-Bn R c-Hex C (O) N (Me) Z (R) Pro H 4-Cl-Bn R c-Hex C (O) N (Me) a (R) Pro H 4-Cl-Bn R c-Hex C (O) NH (t-Bu) (R) Pro H 4-Cl-Bn R c-Hex C (-O-CH2CH2-N=) (R) Pro H 4-Cl-Bn R c-Hex Chez- (1, 2, 4-Trz-1-yl) (R) Pro H 4-Cl-Bn R c-Hex CHZN [-C (O) OCH2C (Me) 271 N-Me- (R) Pro H 4-Cl-Bn R c-Hex CH2-(1, 2, 4-Trz-l-yl) N-Me- (R) Pro H 4-Cl-Bn R c-Hex C (O) N (Me) Z N-Me- (R) Pro H 4-Cl-Bn R c-Hex C [-0-CH2C (Me) 2-N=] N-Me- (R) Pro H 4-Cl-Bn R c-Hex CH2N [-C (O) OCH2C (Me) 2-] (S) Pro H 4-Cl-Bn R c-Hex C [-O-CH2C (Me) 2-N=] (R) Pid-2-CO H 4-Cl-Bn R c-Hex C (O) N (Me) 2 (R) Pid-2-CO H 4-Cl-Bn R c-Hex C [-O-CH2C (Me) 2-N=] (R) Pid-2-CO H 4-Cl-Bn R c-Hex CH2-(1, 2, 4-Trz-1-yl) (R) Pid-2-CO H 4-Cl-Bn R c-Hex CH2N [-C (0) OCH2C (Me) 2-] 1-Me- (R) Pid-2-CO H 4-Cl-Bn R c-Hex C [-O-CH2C (Me) 2-N=] 1-Me- (R) Pid-2-CO H 4-Cl-Bn R c-Hex CH2N [-C (O) OCHZC (Me) 2-] Table 1 (continued) (S) Pid-2-CO H 4-CI-Bn R c-Hex C (O) N (Me) z (S) Pid-2-CO H 4-CI-Bn R c-Hex C [-O-CH2C (Me) 2-N=l H, Ny H 4-CI-Bn R c-Hex C (CH2CH2-N=) o H, N H 4-CI-Bn R c-Hex CH2-(1, 2, 4-Trz-1-yl) o H H 4-C I-Bn R c-Hex C (O) N (Me) 2 . 0 H 4-Cl-Bn R c-Hex Chia- (1, 2, 4-Trz-1-yl) N I. 0 HO-CH2-C (O) H 4-CI-Bn R c-Hex C (O) N (Me) 2 HO-CH2-C (O) H 4-C1-Bn R c-Hex C (-0-CH2CH2-N=) H 4-C1-Bn R c-Hex C (O) N (Me) 2 o 0 H N H 4-C 1-Bn R c-Hex C (-O-CH2CH2-N=) _ H 4-CI-Bn R c-Hex C (O) NH (t-Bu) (2R) Pyd-2-CH2 H 4-CI-Bn R c-Hex C (O) N (Me) 2 (2R) Pyd-2-CH2 H 4-CI-Bn R c-Hex C [-O-CH2C (Me) 2-N=] (2R) Pyd-2-CH2 H 4-CI-Bn R c-Hex CH2- (1, 2, 4-Trz-1-yl) (2R) Pyd-2-CH2 H 4-CI-Bn R c-Hex'CH2N [-C (O) OCH2C (Me) 2-] (2R) Pyd-2-CH2 H 4-C1-Bn R c-Hex C (O) NH (t-Bu) (2R) Pyd-2-CH2 Me 4-CI-Bn R c-Hex C (0) N (Me) 2 (2R) Pyd-2-CH2 Me 4-Cl-Bn R c-Hex (+CH2CH2-N=) Table 1 (continued) (2R)-l-Me-Pyd-2-CH2 H 4-CI-Bn R c-Hex C (O) NH (t-Bu) (2R)-l-Me-Pyd-2-CH2 H 4-Cl-Bn R c-Hex C (O) N (Me) 2 (2R)-l-Me-Pyd-2-CH2 Me 4-CI-Bn R c-Hex C (O) N (Me) z (2R)-l-Ac-Pyd-2-CH2 H 4-CI-Bn R c-Hex C (O) N (Me) 2 (2R)-l-Ac-Pyd-2-CH2 H 4-CI-Bn R c-Hex CH2-(1, 2, 4-Trz-1-yl) (2R)-l-Ms-PYd-2-CH2 H 4-CI-Bn R c-Hex C (O) N (Me) 2 (2S) Pyd-2-CH2 H 4-CI-Bn R c-Hex C (O) N (Me) 2 (2S)-l-Me-PYd-2-cH2 H 4-CI-Bn R c-Hex CH2-(1, 2, 4-Trz-1-yl) (R) Pid-2-CH2 H 4-CI-Bn R c-Hex C (O) N (Me) 2 (R) Pid-2-CH2 H 4-CI-Bn R c-Hex C (-O-CH2CH2-N=) (S) Pid-2-CH2 H 4-Cl-Bn R c-Hex C (O) N (Me) 2 NH2- (CH2) 2 H 4-CI-Bn R c-Hex C (O) N (Me) 2 NH2- (CH2) 2 H 4-CI-Bn R c-Hex C (-O-CH2CH2-N=) NH2- (CH2) 2 H 4-Cl-Bn R c-Hex C (O) NH (t-Bu) NH2- (CH2) 2 Me 4-CI-Bn R c-Hex C (O) NH (t-Bu) NH2- (CH2) 2 H 4-CI-Bn R c-Hex CH2N [-C (O) OCH2C (Me) 2-] (Me) NH- (CH2) 2 Me 4-CI-Bn R c-Hex C (O) NH (t-Bu) (Me) NH- (CH2) 2 H 4-Cl-Bn R c-Hex C (O) NH (t-Bu) (Ac) NH- (CH2) 2 H 4-Cl-Bn R c-Hex C (O) NH (t-Bu) (Me) NH- (CH2) 2 H 4-Cl-Bn R c-Hex CH2N [-C (O) OCH2CH2-] (Me) NH- (CH2) 2 H 4-CI-Bn R c-Hex C [-O-CH2C (Me) 2-N=] (Me) NH- (CH2) 2 Me 4-Cl-Bn R c-Hex C (O) N (Me) 2 (Me) 2N- (CH2) 2 H 4-CI-Bn R c-Hex C (O) N (Me) 2 Table 1 (continued) (Me) 2N- (CH2) 2 H 4-Cl-Bn R c-Hex C (0) NH (t-8u) (Me) 2N- (CH2) 2 H 4-Cl-Bn R c-Hex C (-O-CH2CH2-N=) (Me02N- (CHz) 2 H 4-Cl-Bn R c-Hex H2-(1, 2, 4-Trz-1-Yl) --N H 4-Cl-Bn R c-Hex C (0) N (Me) 2 HO- (CH2) 2 H 4-Cl-Bn R c-Hex C (O) N (Me) z (Me) 2N- (CH2) 2 H 4-Cl-Bn R c-Hex CH2N [-C (0) OCH2C (Me) 2-] (Me) 2N- (CH2) 2 Me 4-Cl-Bn R c-Hex C (O) N (Me) 2 H 4-Cl-Bn R c-Hex C (O) N (Me) 2 H 4-Cl-Bn R c-Hex C (O) N (Me) 2 1-Pyd- (CH2) 2 H 4-Cl-Bn R c-Hex C (O) N (Me) 2 1-Me-3-Pyd- (CH2) 2 H 4-Cl-Bn R c-Hex C (O) N (Me) 2 H H 4-Cl-Bn R c-Hex C (O) N (Me) 2 H'4-Cl-Bn R c-Hex C (O) N (Me) z Me 4-Cl-Bn R c-Hex C (O) N (Me) 2 (3R) Pyd-3-yl H 4-Cl-Bn R c-Hex C (O) N (Me) 2 (3R) Pyd-3-yl H 4-Cl-Bn R c-Hex C (O) NHCH2CH20H Pid-3-yl H 4-Cl-Bn R c-Hex C (O) N (Me) 2 H H 4-Cl-Bn R. Pid-1-yl C (O) NH (t-Bu) H H 4-Cl-Bn R Pid-1-yl C (O) NH (i-Bu) H H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 H H 4-Cl-Bn R Pid-1-yl C (O) (Pyd-1-yl) H H 4-Cl-Bn R Pid-l-yl C (0) (1, 2, 3-Trz-1-yl) Table 1 (continued) H H 4-Cl-Bn R Pid-1-yl C (0) (1, 3-lmz-1-yl) H H Bn R Pid-1-yl C (O) NH (t-Bu) H H 4-Br-Bn R Pid-1-yl C (O) NH (t-Bu) H H 4-Cl-Bn R Pid-1-yl C (-O-CH2CH2-N=) H H 4-Cl-Bn R Pid-1-yl C (O) N (Me) Z H H 4-Cl-Bn R Pid-1-yl C (O) CH (OH) (i-Pr) H H 4-Cl-Bn R Pid-1-yl CH2N (Me) z Me H 4-Cl-Bn R Pid-l-yl C (O) N (Me) a Me H 4-Cl-Bn R Pid-1-yl C [-O-CH2C (Me) 2-N=] Me Me 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 Ac H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 MeS02 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 NHZC (O)-CH2 H 4-Cl-Bn R Pid-1-yl C (-O-CH2CH2-N=) Gly H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 Gly H 4-Cl-Bn R. Pid-1-yl C (-O-CH2CH2-N=) (S) His H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 N-Ac- (S) His H 4-Cl-Bn R Pid-1-yl C [-O-CH2C (Me) 2-N=] (R) His H 4-Cl-Bn R Pid-1-yl C [-O-CH2C (Me) 2-N=] (R) Pro H 4-Cl-Bn R Pid-1-yl C (O) N (Me) Z (R) Pro H 4-Cl-Bn R Pid-1-yl C (-O-CH2CH2-N=) N-Me- (R) Pro H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 N-Me- (R) Pro H 4-Cl-Bn R Pid-1-yl C [-0-CH2C (Me) 2-N=] (S) Pro H 4-Cl-Bn Pid-1-yl C [-0-CH2C (Me) 2-N=] (R) Pid-2-CO H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 Table 1 (continued) (R) Pid-2-00 H 4-Cl-Bn R Pid-1-yl C (-0-CH2CH2-N=) 1-Me- (R) Pip H 4-Cl-Bn R Pid-1-yl C [-O-CH2C (Me) 2-N=] (R) Tic H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 HO-CH2-C (O) H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 MeO2C-CH2 H 4-Cl-Bn R Pid-1-yl C (O) NH (t-Bu) HNY H 4-Cl-Bn R Pid-1-yl C (O) N (Me) o 0 (2R) Pyd-2-CH2 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) (2R) Pyd-2-CH2 H 4-Cl-Bn R Pid-1-yl C [-0-CH2C (Me) 2-N=] (2R) Pyd-2-CHz Me 4-Cl-Bn R Pid-1-yl C (O) N (Me) z (2R) Pyd-2-CH2 Me 4-Cl-Bn R Pid-1-yl C (-0-CHzCH2-N=) (2R)-l-Me-Pyd-2-CH2 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 (2R)-l-Me-Pyd-2-CH2 H 4-Cl-Bn R id-1-yl C (O) NH (t-Bu) (2R)-l-Me-Pyd-2-CH2 H 4-Cl-Bn R id-1-yl C (-0-CH2CH2-N=) (2R)-l-Ac-Pyd-2-CH2 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 (2R)-l-Ms-Pyd-2-CH2 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 (2S) Pyd-2-CH2 H 4-Cl-Bn R id-1-yl C (O) N (Me) z (2S) Pyd-2-CH2 H 4-Cl-Bn R Pid-1-yl C (-0-CH2CH2-N=) (2R) Pid-2-CH2 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 (2R) Pid-2-CH2 Me 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 (2R)-l-Me-Pid-2-CH2 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) (2S) Pid-2-CH2 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) z NH2- (CH2) 2 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 (Me) NH- (CH2) 2 e 4-Cl-Bn R Pid-1-yl C [-0-CH2C (Me) 2-N=] Table 1 (continued) (Me) 2N-(CH2) 2 H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 (Me) 2N- (CH2) 2 H 4-Cl-Bn R Pid-1-yl C (O) NH (t-Bu) (Me) 2N-(CH2) 2 4-Cl-Bn R Pid-l-y F (-O-CH2CH2-N=) (Me) 2N- (CH2) 2 Me 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 (Me) 2N- (CH2) 2 Me 4-Cl-Bn R Pid-1-yl C [-0-CH2C (Me) 2-N=] (Ac) NH- (CH2) z 4-CI-Bn R Pid-1-yl C (O) N (Me) 2 1-Pyd-(CH2) 2 4-Cl-Bn R Pid-1-yl C [-0-CH2C (Me) 2-N=] H 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 (3S) Pyd-3-yl Me 4-Cl-Bn R Pid-1-yl C (O) N (Me) 2 H H 4-Cl-Bn R N [-CH2 (CH2) 4CH2-] C (O) N (Me) H H 4-Cl-Bn R N [-CH2 (CH2) 4CH2-] C (O) NH (t-Bu) H H 4-Cl-Bn R N (Me) C (O) N (Me) z H H 4-Cl-Bn R N (Me) Z C (O) NH (t-Bu) H H 4-Cl-Bn R NH (i-Bu) C (O) N (Me) 2 H H 4-Cl-Bn R NH (c-Hex) C (O) N (Me) z H H 4-Cl-Bn R NH (c-Hex) C (O) NH (t-Bu) H H 4-Cl-Bn R NH (c-Pen) C (O) N (Me) 2 H H 4-Cl-Bn R NH (Bn) C (O) N (Me) z H H 4-Cl-Bn R N (Me) [(c-hex) ~CH2] C (O) N (Me) 2 H H 4-Cl-Bn R Pyd-1-yl C (O) N (Me) 2 H H 4-Cl-Bn R Pyd-1-yl C (O) NH (t-Bu) H H 4-Cl-Bn R CH2-Pid C (O) N (Me) z H H 4-Cl-Bn R CH2-Pid C (O) NH (t-Bu) Table 1 (continued) Ac H 4-Cl-Bn R NH (c-Hex) C (O) N (Me) 2 MeSO2 H 4-Cl-Bn R N (Me) Z C (O) NH (t-Bu) (Me) 2NC (0)-CH2 H 4-Cl-Bn R N (Et) z C (O) N (Me) Z (S) His H 4-Cl-Bn R N (Et) Z C (O) N (Me) 2 (S) His H 4-Cl-Bn R NH (c-Hex) C (O) NH (t-Bu) (R) Pro H 4-Cl-Bn R Pyd-1-yl C (O) N (Me) a (R) Pro H 4-Cl-Bn R Pyd-l-yl C (O) NH (t-Bu) (R) Pid-2-CO H 4-Cl-Bn R Pyd-1-yl C (O) N (Me) 2 (S) Pid-2-CO H 4-Cl-Bn R N (Me) 2 C (O) NH (t-Bu) (Me) 2NCH2CH2 H 4-Cl-Bn R c-Hex C (O) NHCH2CH2NH2 (Me) 2NCH2CH2 H 4-CI-Bn R c-Hex C (O) N (Me) CH2CH2NH2 (Me) 2NCH ? (Me) 2NCH2CH2 H 4-CI-Bn R c-Hex C (O) NH [(R)-pyd-3-yl] (Me) 2NCH2CH2-H 4-Cl-Bn R c-Hex C (O) NHCH2CH20H (Me) 2NCH2CH2 H 4-Cl-Bn R c-Hex C (O) N (Me) CH2CH20Me (Me) 2NCH2CH2 H 4-Cl-Bn R c-Hex C (O) NHCH2CH2CH2OMe (Me) 2NCH2CH2 H 4-Cl-Bn R c-Hex C (0) N [-CH2CH2CH (OMe) CH2CHr] (Me) 2NCH2CH2 H 4-Cl-Bn R c-Hex C (O) NHCH2CH (OH) CH20H (Me) 2NCH2CH2 H 4-Cl-Bn R c-Hex C (O) N (-CH2CH20CH2CHz) (Me) 2NCH2CH2 H 4-Cl-Bn R c-Hex C (O) N (CH2CH20H) 2 (Me) 2NCH2CH2 H 4-CI-Bn R c-Hex C (-OCH2CH2N=) (Me) 2NCH2CH2 H 4-Cl-Bn R c-Hex C (O) NHCH2CH2NH2 The compound according to the present invention also can form pharmaceutically acceptable salts. These pharmaceutically acceptable salts include acid forming non-toxic acid addition salt containing pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; organic carboxylic acid such as tartaric, formic, citric, acetic, trichloroacetic, trifluoroacetic, gluconic, benzoic, lactic, fumaric, maleic, and the like; acid-addition salts formed by sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-tolunesulfonic acid or naphthalenesulfonic acid, and the like ; preferably, acid-addition salts formed by sulfuric acid, methansulfonic acid or hydrohalic acid, and the like. The compound of formula 1 according to the present invention can be converted to its salts by customary method.

Also, the compound according to the present invention can have asymmetric carbon center, and so can be present as R or S isomeric forms, racemates, diasteromeric mixtures, and individual diasteromers. The present invention encompasses all these isomeric forms and mixtures.

The compound according to the present invention can be prepared according to the procedures in the following Reaction Schemes 1-7. In the following Schemes, compounds (3), (6), (10), (11), (12), (14), (18), (20) and (31) represent representative compounds of formula 1.

Compounds of formula (3) can be prepared by coupling a protected amino acid of formula (1) (wherein P represents protecting group, such as BOC, Cbz, Fmoc, etc.) with a piperidine derivative of formula (2) according to general amide coupling conditions, as illustrated in Scheme 1. Protected amino acid derivatives (1) are either commercially available or may be prepared by literature methods (Williams, R. M., Synthesis of Optically Active a-Amino Acids, Pergamon Press: Oxford, 1989).

Similarly, piperidine derivatives (2) can be prepared from commercially available compounds described in literature (WO 00/14930).

Scheme 1 R3 3 P OH R4 i) amide coupling R4 + H-N P N I I R5 ii) deprotection H 0 H 0 (1) (2) (3) Compounds of formula (6) (Rl = Ac, Ms, etc. ) can be prepared by coupling amino acid derivatives (5) with piperidine derivatives (2) as illustrated in Scheme 2.

Alkyl, acyl, or sulfonyl substituted amino acid derivatives (4) can be converted to amino acid derivatives (5) by hydrolysis in the presence of base.

Scheme 2 Ru 3 3 3 i/n. _, _/ R4 R \ sR5 H>N OMe i) acylation R pH 2) N N N H p ii) hydrolysis M H J, ii) hydrolysis J, U"0 n L n \ (4) (5) (6) Compounds formula (10), (11), and (12) [R2 = H, R'= C (O)-containing group] can be prepared by coupling protected amino acid derivatives (7), (8), or (9) with compounds formula (3) prepared in the Reaction Scheme 1, as shown in Scheme 3. Cy in compound (8) represents pyrrolidine, azetidine, aziridine, piperidine, etc.. Protected amino acid derivatives (7), (8) and (9) are commercially available or can be prepared by protection reaction from available amino acids.

Scheme 3 H R3 R P'**'N OH N R4 H O R6H 0 (7) R5 (10) 1) H\N N\__/'\R4 H O 3 s H lOl R 1 Rs ruz Cy H Cy H O (8) ii) deprotection ) H O s Rs n P OH tiN N ^, TR4 H O H O (9) (12) Compounds of formula (14) can be prepared through reductive amination of compounds of formula (3) prepared in Scheme 1 and protected amino aldehydes of formula (13), as shown in Scheme 4. As a reducing agent for reductive amination, NaHB (OAc) 3 or NaBH3CN may be used, and DCE, DMF, methanol, DCM, etc. may be used as solvent, but the reaction reagent and solvent are not limited to these. Protected amino aldehydes (13) can be prepared by known methods such as reductive reaction of thioesters or oxidation of amino alcohols from commercially available amino acid, but not limited to them.

Scheme 4 3 3 Rs i) reductive N RS amination Cy H O i i) deprotect ion CY O Cy (13) (3) (14) Compounds of formula (18), (19) and (20) can be prepared as shown in the following Scheme 5. Nitrobenzenesulfonyl protected intermediates of formula (15) can be converted to the compounds of formula (17) by alkylation or reductive amination (Tetrahedron Lett., 1995, 36, 6373-6374). In protected compounds of formula (16), Q represents aminoalkyl or alkylated aminoalkyl, and X represents halogen. Compounds of formula (19) can be prepared through reductive amination of compounds of formula (17) and then converted into the compounds of formula (20) by alkylation.

Scheme 5 So2XC 0 rus 0 0 SN \__/R H 0 (15) zu P-Q-X (16) ii) desulfonylation 3 3 . deprotection R4 N R H M (17) (18) reductive amination R3 Ru Rs 5 P-QN XC R i) alkylation R QN XC Rs Rs iii) deprotection R 0 (19) (20) 4,4-Disubstituted piperidine derivatives (21) can be prepared from acid derivatives that known in literature (WO 00/14930) and converted to the oxazoline- substituted compounds of formula (23). Coupling piperidine derivatives (21) with amino alcohols gives the intermediate of formula (22). The compound (22) can be converted to compounds (23) by cyclization using phosgene and then deprotection.

Scheme 6 p p I I N coupling reaction i) cyclization N ii) deprotection II R R 0 (21) (22) (23) 4-Piperidine substituted piperidine derivatives can be prepared as illustrated in Scheme 7. Piperidinecarboxylic acids of formula (24) can be prepared from commercially available 4-amino-piperidine carboxylic acids or 4-piperidinone and converted to compounds of formula (25) through amide coupling. Cyclization of the compounds of formula (25) carried out through reductive amination using dialdehyde, or alkylation reaction using dihaloalkanes, gives the 4-piperidine substituted piperidine derivatives (26). Compounds (28) can be prepared by the same manner as in the preparation of compounds of formula (23) from compounds of formula (24), and converted into compound of formula (29) through cyclization.

Scheme 7 P P I N i) coupling reaction R i) cyclization Qi ii) deprotection HN NR ii) deprotection N R I-'R R (24) (25) (26) 1 P P N f) i) cyclization i) cyclization Q, N N 'i) deprotection H, ii) deprotection N N N (27) (28) (29) Compounds of formula (31) can be prepared as illustrated in Scheme 8.

Amide coupling of compounds of formula (3) with 4-cyclohexyl-4- piperidinecarboxylicacid can give compounds of formula (30) which can be converted to compounds of formula (31) through amide coupling and deprotection.

Scheme 8 . 3 3 Ut I N N N o ii) acid chloride N - II ii) deprotection N _J - ; H 0 « H 0 0 H 0 0 R (30) (31) It is preferable to carry out each step of the above methods in conventional solvents which do not have significant deleterious effect to the reaction, and particularly preferable to use one or more kinds selected from the group consisting of, but not limited to, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, and chloroform.

Deprotection reaction can be carried out in the presence of strong acid such as hydrochloric acid, trifluoroacetic acid, etc. , in the presence of amine base such as triethylamine, diisopropylethylamine, etc. , or by hydrogenation. Specific reaction conditions are described in T. W. Green & G. M. Wuts Protective Groups in Organic Synthesis, Chapter 7, pp 309-405.

Known coupling agents usable in coupling reaction are, but are not limited to, carbodiimides such as dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC), 1, 1'-dicarbonyldiimidazole (CDI), etc. which are used in a mixture with 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT); bis- (2-oxo-3-oxazolidinyl)-phosphinic acid chloride (BOP-C1), diphenylphosphorylazide (DPPA), 0- (7-Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyl- uronium hexafluorophosphate (HATU), O-Benzotriazol-1-yl-N, N, N', N'-tetramethyl- uronium hexafluorophosphate (HBTU), etc.

General separation of mixtures is conducted by column chromatography, and in case of final compound, separation can be done by recrystallization or normal or reverse HPLC (Waters, Delta Pack, 300x50 mm I. D. , C18 5 um, 100A). When recrystallization or HPLC is used for purification, the compound can be obtained in the form of trifluoroacetic acid salt. Hydrochloric acid salt can be obtained by using ion exchange resin.

After the above reactions according to the present invention are completed, products can be separated and purified by customary work-up methods, for example, chromatography, recrystallization, etc.

The compounds of the present invention have potent agonistic effect against melanocortin receptors, and so the present invention provides a melanocortin receptor agonistic composition comprising the compound of formula 1 as active ingredients together with pharmaceutically acceptable carrier. In particular, the composition according to the present invention has potent effect for the prevention and treatment of, but not limited to, diabetes, erectile dysfunction, obesity, and inflammation.

When the compounds according to the present invention are administered for clinical purpose, a preferable daily dose would be within the range of 0. 01-10 mg/kg body weight as unitary dosage or separated dosage. However, a dosage level specific to individual patients can be varied, depending upon specific compound to be used, weight, sex, health condition, diet, administration time and method of drug, excretion rate, drug mixing, and severity of disease condition.

Any route depending on purpose can administer the compounds according to the present invention. Injection, and oral and nasal administration are preferred, but administration may be made through dermal, intraperitoneal, retroperitoneal, and rectal route.

Injectable preparation, for example, aqueous or oily suspension for sterile injection, can be prepared according to known method by using proper dispersants, wetting agents, or suspending agents. Solvents usable for this purpose are water, ringer's solution, and isotonic NaCI solution, and sterilized fixed oil is conventionally used as solvent or suspending media, too. Any non-irritable fixed oil including mono-, di-glyceride can be used for this purpose, and aliphatic acid such as oleic acid can be used for injectable preparation.

Solid dosage forms for oral administrations are capsules, tablets, pills, powders and granules, and in particular, capsules and tablets are useful. Capsules and tablets are preferable to be prepared as enteric coating. Solid dosage forms can be prepared by mixing compound (1) according to the present invention with one or more inert diluents such as sucrose, lactose, starch, etc. , and carriers, for example, lubricants like magnesium stearate, disintegrants, binding agents, etc.

Abbreviations used in the above Description, and the following Preparations and Examples are as follows: Ac acetyl BOC tert-butoxycarbonyl Bn benzyl Bu butyl CBZ (Cbz) benzyloxycarbonyl c-Hep cycloheptyl c-Hex cyclohexyl c-Pen cyclopentyl DCC dicyclohexylcarbodiimide DCE dichloroethane DCM dichloromethane Dic decahydroisoquioline-3-carboxylic acid DIPEA diisopropylethyamine DMAP 4-dimethylaminopyridine DMF N, N-dimethylformamide DMSO dimethylsulfoxide EDC 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide HC1 Fmoc 9-fluorenylmethoxycarbonyl Hex hexane HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography i-Bu isobutyl iPr isopropyl Imz imidazole LAH lithiumaluminium hydride Ms methansulfonyl Ph phenyl Phe phenylalanine Pid piperidine Pro proline Pyd pyrrolidine TEA triethylamine Tez tetrazole TFA trifluoroacetic acid THF tetrahydrofuran Tic 1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid TPAP tetrapropylamonium peruthenate Trz triazole The following Preparations further illustrate preparation of intermediates needed for synthesis of the compound according to the present invention.

Intermediate 1: 4-Cyclohexyl-4-(t-butylcarbamoyl) piperidine Step A: 1-BOC-4-Cyclohexyl-4- (t-butylcarbamoyl) piperidine To a solution of 4-cyclohexyl-4-piperidine carboxylic acid (311 mg, 1 mmol) in DMF (3 mL) were added DIPEA (0.348 mL, 2 mmol), EDC (600 mg, 1.3 mmol), HOBT (230 mg, 1.5 mmol), and t-butyl amine (0.137 mL, 1.3 mmol). After the reaction mixture was stirred at rt for 6 h, DMF was distilled off ira vacuo, and the residue was diluted with a saturated aqueous NaHC03 solution. The organic material was extracted with EtOAc and washed with an aqueous NaHC03 solution and 1N HC1. The extracts were dried over MgS04, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/n-Hex = 1/1) to give the title compound (350 mg, 94 %).

MS [M+H] = 367 (M+1).

Step B: 4-Cyclohexyl-4- (t-butylcarbamoyl) piperidine l-BOC-4-Cyclohexyl-4-(t-butylcarbamoyl) piperidine, prepared in Step A, (300 mg, 0. 818 mmol) was dissolved in DCM (2 mL), and then TFA (2 mL) was added dropwise. The reaction mixture was stirred at rt for 30 min. and concentrated ill vacuo to give the title compound (235 mg, 90%) as a TFA salt.

MS [M+H] = 267 (M+1).

Intermediates 2-8: The following Intermediates listed in Table 2 were prepared from 4-cyclohexyl- 4-piperidinecarboxylic acid and amine derivatives using the same procedure described in Intermediate 1.

Table 2 O xD1 N H-N HN ~9 D2 Inter. D1 Dz MS (M+1) 2 Me Me 239 3 H i-Pr 253 4 H Pr 253 5 Me Et 253 6 H Ph 287 7 Pyd 265 8 1, 2, 4-Trz-1-yl 263 Intermediate 9: 4-Cyclohexyl-4- [ (4, 4-dimethyl) oxazolin-2-yl] piperidine Step A: 1-BOC-4-Cyclohexyl-4-piperidine carboxyl chloride To a solution of 4-cyclohexyl-4-piperidine carboxylic acid (3.11 g, 10 mmol) in DCM (30 mL) was added oxalyl chloride (1.40 g, 11 mmol) and the reaction mixture was stirred at rt for 3 h. After the solvent was distilled off in vacuo, the residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/4) to give the title compound (3.06 g, 94 %).

MS [M+H] = 307 (M+1).

Step B: 1-BOC-4-Cyclohexyl-4- [ (2-hydroxy-1, 1-dimethyl) ethylcarbamoyl] piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4-piperidine carboxyl chloride and 2-amino-2-methyl-1-propanol using the same procedure as Step A of Intermediate 1.

MS [M+H] = 383 (M+1).

Step C: 1-BOC-4-Cyclohexyl-4- [ (4, 4-dimethyl) oxazolin-2-yl] piperidine To a solution of 1-BOC-4-cyclohexyl-4- [ (2-hydroxy-1, 1-dimethyl) ethyl- carbamoyl] piperidine, prepared in Step B, (3.82 mg, 1 mmol) in DCM (5 mL) were added DIPEA (0.348 mL, 2 mmol), DMAP (25 mg, 0.2 mmol), and phosgene (2. 5M solution in toluene, 2 mL). After being stirred at rt for 2 h, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc/n-Hex = 2/1) to give the title compound (328 mg, 90%).

MS [M+H] = 365 (M+1).

Step D: 4-Cyclohexyl-4- [ (4, 4-dimethyl) oxazolin-2-yl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [ (4, 4-dimethyl) - oxazolin-2-yl] piperidine prepared in Step C according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 265 (M+1).

Intermediate 10: 4-Cyclohexyl-4- (oxazolin-2-yl) piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-piperidine carboxyl chloride according to the same procedure as Intermediate 9.

MS [M+H] = 237 (M+1).

Intermediate 11: 4-Cyclohexyl-4- [ (4, 4-dimethyl) thiooxazolin-2-yl] piperidine Step A: 1-BOC-4-Cyclohexyl-4- [ (4, 4-dimethyl) thiooxazolin-2-yl] piperidine To a solution of 1-BOC-4-Cyclohexyl-4- [ (4, 4-dimethyl) oxazolin-2- yl] piperidine, prepared in Step C of Intermediate 9, (382 mg, 1 mmol) in toluene (30 mL) was added Laewsson's reagent (330 mg, 3 mmol). After the reaction mixture was stirred at 120 °C for 2 h, the precipitate was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM/MeOH = 19/1) to give the title compound (304 mg, 80%).

MS [M+H] = 381 (M+1).

Step B: 4-Cyclohexyl-4- [ (4, 4-dimethyl) thiooxazolin-2-yl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [ (4, 4- dimethyl) thiooxazolin-2-yl] piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] =281 (M+1).

Intermediate 12: 4-Cyclohexyl-4- (thiooxazolin-2-yl) piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [ (2- hydroxyethyl) carbamoyl] piperidine according to the same procedure as Intermediate 11.

MS [M+H] = 253 (M+1).

Intermediate 13: Methyl 4-cyclohexyl-4-piperidinecarboxylate Step A: Methyl l-BOC-4-cyclohexyl-4-piperidinecarboxylate To a solution of 1-BOC-4-cyclohexyl-4-piperidinecarboxylic acid (311 mg, 1 mmol) in DMF (5 mL) was added K2CO3 (414 mg, 3 mmol) and methyl iodide (0.183 mL, 1.2 mmol). After the reaction was stirred at room temperature for 3 h, the reaction mixture was concentrated in vacuo, and the residue was diluted with an aqueous 1N HC1 solution. The organic material was extracted with EtOAc and the organic extracts were dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/10) to give the title compound (109 mg, 95%).

MS [M+H] = 326 (M+1).

Step B: Methyl 4-cyclohexyl-4-piperidinecarboxylate The title compound was obtained from 1-BOC-4-cyclohexyl-4-piperidine carboxylate prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 226 (M+1).

Intermediate 14: 1-BOC-4-Cyclohexyl-4-piperidinemethanol To a solution of methyl 1-BOC-4-cyclohexyl-4-piperidine carboxylate (3.25 g, 10 mmol), prepared in Step A of Intermediate 13, in THF (30 mL) was added LAH (759 mg, 20 mmol) at 0 C, and then the reaction mixture was warmed to rt. After the reaction was stirred at rt for 2 h, the reaction mixture was cooled at 0°C and was quenched by slow adding of water. When no further gas evolution occurred, the organic layer was extracted with EtOAc, and the organic extracts were dried over MgS04 and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/1) to give the title compound.

MS [M+H] = 298 (M+1).

Intermediate 15: 1-BOC-4-Cyclohexyl-4-piperidinealdehyde l-BOC-4-Cyclohexyl-4-piperidinemethanol prepared in Intermediate 14 was dissolved in DCM (10 mL). After the reaction temperature was cooled to 0°C, 4- methylmorpholine-N-oxide (351 mg, 3 mmol) and TPAP (25 mg) were added dropwise, and the reaction mixture was stirred at rt for 3 h. The precipitate was filtered through Florisil and Celite, and the filtrate was dried over MgS04 and concentrated in vacuo to give the title compound.

MS [M+H] = 296 (M+1).

Intermediate 16: 4-Cyclohexyl-4-[(1-hydroxy)isobutyl]piperidine Step A: 1-BOC-4-Cyclohexyl-4- [ (1-hydroxy) isobutyl] piperidine l-BOC-4-cyclohexyl-4-piperidine aldehyde prepared in Intermediate 15 (295 mg, 1 mmol) was placed in a two-neck round-bottomed flask and 5 mL of THF was added dropwise. The reaction mixture was cooled at 0°C and isopropylmagnesium chloride (2. 5M solution in hexane, 1 mL) was added dropwise. After 30 min. , the reaction mixture was warmed to rt and stirred for additional 3 h. The reaction was quenched with a saturated aqueous NH4C1 solution, and the organic material was extracted with EtOAc. The combined organic solution was dried over MgS04, and concentrated in vacuo. The residue was purified by column chromatography (eluent : EtOAc/n-Hex = 1/2) to give the title compound.

MS [M+H] = 340 (M+1).

Step B: 4-Cyclohexyl-4-[(1-hydroxy) isobutyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-[(1- hydroxy) isobutyl] piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 240 (M+1).

Intermediate 17: 4-Cyclohexyl-4- (isobutyryl) piperidine Step A: 1-BOC-4-Cyclohexyl-4- (isobutyryl) piperidine l-BOC-4-Cyclohexyl-4- [ (l-hydroxy) isobutyl] piperidine prepared in Step A of Intermediate 16 (200 mg, 0.59 mmol) was placed in a two-neck round bottomed flask and oxalyl chloride (0.052 mL, 0.590 mmol) was added dropwise. The reaction mixture was cooled to-78 °C, and DMSO (0.042 mL) was added dropwise keeping the temperature below-50 °C. After the reaction mixture was stirred for 30 min. , TEA (0.248 mL, 2 mmol) was added dropwise to the solution and, the reaction mixture was warmed to rt. The reaction was diluted with a saturated aqueous NH4Cl solution and the organic layer was extracted with DCM, The extracts were dried over MgS04, filtrated, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/2) to give the title compound (177 mg, 89%).

MS [M+H] = 338 (M+1).

Step B: 4-Cyclohexyl-4- (isobutyryl) piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4- (isobutryl) piperidine prepared in Step A of Intermediate 17 according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 238 (M+1).

Intermediate 18: 4-Cyclohexyl-4- [ (4, 4-dimethyloxazolidin-2-one-3-yl) methyl]- piperidine Step A: 1-BOC-4-Cyclohexyl-4- {N-[(2-hydroxy-1, 1-dimethyl) ethyl] imino} piperidine To a solution of l-BOC-4-cyclohexyl-4-piperidine aldehyde, prepared in Intermediate 15, (590 mg, 2 mmol) and 2-hydroxy-1, 1-dimethylethylamine (178 mg, 2 mmol) in toluene (10 mL) was added acetic acid (0.05 mL). The reaction mixture was refluxed using Dean Stark apparatus at 90°C for 8 h to remove water formed. The reaction mixture was concentrated in vacuo and the residue was dissolved in acetic acid.

Put02 was added to the solution and the rection mixture was stirred under hydrogen for 12 hr. The reaction mixture was filtered through Celite and concentrated in vacuo to give the title compound.

MS [M+H] = 367 (M+1).

Step B : 1-BOC-4-Cyclohexyl-4- [ (4, 4-dimethyloxazolidin-2-one-3-yl) methyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- {N-[(2-hydroxy- l, l-dimethyl) ethyl] imino} piperidine prepared in Step A according to the same procedure as Step C of Intermediate 9.

MS [M+H] = 395 (M+1).

Step C: 4-Cyclohexyl-4- [ (4, 4-dimethyloxazolidin-2-one-3-yl) methyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [ (4, 4- dimethyloxazolidin-2-one-3-yl) methyl] piperidine prepared in Step B according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 295 (M+1).

Intermediate 19: 4-Cyclohexyl-4-[(oxazolidin-2-one-3-yl) methyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-piperidine aldehyde prepared in Intermediate 15 according to the same procedure as Intermediate 18.

MS [M+H] = 267 (M+1).

Intermediate 20: 4-Cyclohexyl-4-[(N-methoxy) iminyl] piperidine Step A: 1-BOC-4-Cyclohexyl-4- [ (N-methoxy) iminyl] piperidine 1-BOC-4-Cyclohexyl-4-piperidine aldehyde, prepared in Intermediate 15, (295 mg, 1 mmol) and methoxyamine (94 mg, 2 mmol) were dissolved in toluene (10 mL), and acetic acid (1-2 drops) was added dropwide to the solution. The reaction mixture was refluxed using Dean Stark apparatus at 90 °C for 8 h. The reaction mixture was quenched with a saturated aqueous NH4C1 solution and the organic layer was extracted with EtOAc. The combined organic solution was dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 9/1) to give the title compound.

MS [M+H] = 325 (M+1).

Step B: 4-Cyclohexyl-4- [ (N-methoxy) iminyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [ (N- methoxy) iminyl] piperidine prepared in the above Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 225 (M+1).

Intermediate 21: 4-Cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine Step A: 1-BOC-4-Cyclohexyl-[(methanesulfonyloxy) methyl] piperidine To a solution of 1-BOC-4-cyclohexyl-4-piperidine methanol prepared in Intermediate 14 (2.97 g, 10 mmol) in DCM (60 mL) was added TEA (2.8 mL, 20 mmol) and methansulfonyl chloride (3.11 mL, 20 mmol). After lh, a saturated aqueous NH4C1 solution was added, and the organic material was extracted with DCM followed by EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo.

The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/9) to give the title compound (1.55 g, 95%).

MS [M+H] = 323 (M+1).

Step B: 4-Cyclohexyl-4-[(methanesulfonyloxy) methyl] piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4- [(methanesulfonyloxy) methyl] piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 276 (M+1).

Intermediate 22: 1,2, 3-Triazole-l-carboxyl chloride 1,2, 3-Triazole (207 mg, 3 mmol) and DMAP (366 mg, 3 mmol) were dissolved in DCM (10 mL), and phosgene (25% solution in toluene, 3 mL) was added dropwise to the solution. After the reaction mixture was stirred at rt for 30 min. , the precipitate was filtered, and the filtrate was concentrated in vacuo to give the title compound.

MS [M+H] = 132 (M+1).

Intermediate 23: 1,2, 4-Triazole-l-carboxyl chloride The title compound was obtained from 1,2, 4-Triazole according to the same procedure as Intermediate 22.

MS [M+H] = 132 (M+l) Intermediate 24: 1, 3-Imidazole-l-carboxyl chloride The title compound was obtained from 1, 3-hnidazole according to the same procedure as Intermediate 22.

MS [M+H] = 131 (M+1) Intermediate 25: 1-BOC-4-Cyclohexyl-4-(aminomethyl) piperidine Step A: 1-BOC-4-Cyclohexyl-4- (azidomethyl) piperidine To a solution of l-BOC-4-cyclohexyl-4-[(methanesulfonyl) methyl] piperidine prepared in Intermediate 21 (1. 88 g, 5 mmol) in DMF (20 mL) was added sodium azide, and the reaction mixture was warmed to 90 °C for 4 h. After DMF was distilled off in vacuo, the residue was diluted with water, and the organic material was extracted with EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/15) to give the title compound (1. 55 g, 96%).

MS [M+H] = 323 (M+1) Step B: 1-BOC-4-Cyclohexyl-4- (aminomethyl) piperidine To a solution of 1-BOC-4-cyclohexyl-4- (azidomethyl) piperidine prepared in Step A (1.0 g, 3.10 mmol) in methanol was added Pd/C (200 mg), and the reaction mixture was stirred under H2 for 12 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound.

MS [M+H] = 297 (M+1) Intermediate 26: 4-Cyclohexyl-4-{ [(cyclohexylmethyl) amino] methyl} piperidine Step A: 1-BOC-4-Cyclohexyl-4- [ (cyclohexylamino) methyl] piperidine To a solution of l-BOC-4-cyclohexyl-4-(aminomethyl) piperidine prepared in Intermediate 25 (296 mg, 1 mmol) and cyclohexanone (98.3 mg, 1.0 mmol) in DCE (5 mL) was added NaBH (OAc) 3 (678 mg, 3.2 mmol) slowly. After the reaction mixture was stirred at rt for 4 h, a saturated aqueous NaHC03 solution was added, and the organic layer was extracted with DCM. The extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: MeOH/EtOAc/n-Hex = 1/4/4) to give the title compound.

MS [M+H] = 379 (M+1) Step B : 1-BOC-4-Cyclohexyl-4- {[(cyclohexylmethyl) amino] methyl} piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [(cyclohexylamino) methyl] piperidine prepared in Step A and formalin according to the same procedure as Step A of Intermediate 1.

MS [M+H] = 393 (M+1) Step C: 4-CycloheXyl-4-{[(cyclohexylmethyl) amino] methyl} piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- {[(cyclohexylmethyl) amino] methyl} piperidine prepared in Step B according to the same procedure as Step B.

MS [M+H] = 293 (M+1) Intermediates 27-37: The following intermediates listed in the following Table 3 were prepared from 1-BOC-4-cyclohexyl-4-piperidinemethanol, 1-BOC-4-cyclohexyl-4- (ainino-methyl)- piperidine and 1-BOC-4-cyclohexyl-4-[(cyclohexylamino) methyl] piperidine using the same procedure described in Intermediate 21.

Table 3 xD1 H-N \ D2 ( :, 3 Inter. X D1 D2 MS (M+1) 27 0 S02 (i-Pr)-304 28 0 SOzPh-338 29 N Ac H 238 30 N S02Me H 275 Table 3 (continued) 31 N S02 (i-Pr) H 304 32 N C (0) N (Me) 2 H 268 33 N S02N (Me) 2 H 304 34 N C (0) (i-Pr) c-Hex 349 35 N C (0) (1, 2, 3-Trz-1-yl) H 292 36 N C (0) (1, 2, 4-Trz-1-yl) H 292 37 N C (0) (1, 3-Imz-1-yl) H 291 Intermediate 38: 4-Cyclohexyl-4- [ (1, 2, 4-triazol-1-yl) methyl] piperidine Step A: 1-BOC-4-Cyclohexyl-4- [ (1, 2, 4-triazol-1-yl) methyl] piperidine To a solution of 1-BOC-4-cyclohexyl-4- [ (methanesulfonyloxy) methyl] piperidine (375 mg, 1 mmol) in DMF (10 mL) was added Na-1, 2,4-triazole (273 mg, 3 mmol), and the solution was stirred at 90-100°C for 12 h. After DMF was distilled off in vacuo, the reaction mixture was quenched wirh a saturated aqueous NH4C1 solution, and the organic material was extracted with EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent : acetone/DCM = 3/1) to give the title compound (313 mg, 90%).

MS [M+H] = 349 (M+1) Step B: 4-Cyclohexyl-4- [ (1, 2, 4-triazol-1-yl) methyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-[(1, 2,4-triazol- 1-yl) methyl] piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 249 (M+1) Intermediate 39: 4-Cyclohexyl-4- [ (1, 2, 3-triazol-1-yl)methyl]piperidine Step A: 1-BOC-4-Cyclohexyl-4- [ (1, 2, 3-triazol-1-yl) methyl] piperidine To a solution of l-BOC-4-cyclohexyl-4-[(methanesulfonyloxy) methyl] - piperidine (375 mg, 1 mmol) and 1,2, 3-triazol (205 mg, 3 mmol) in DMF (10 mL) was added sodium isopentoxide (220 mg, 2 mmol), and the reaction mixture was stirred at 90-100°C for 12 h. After DMF was distilled off in vacuo, a saturated aqueous NH4C1 solution. The organic material was extracted with EtOAc, and the extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: acetone/DCM = 3/1) to give the title compound (292 mg, 84%).

MS [M+H] = 349 (M+1) Step B: 4-Cyclohexyl-4- [ (1, 2, 3-triazol-1-yl) methyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [ (1, 2,3-triazol- 1-yl) methyl] piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 249 (M+1) Intermediate 40: 4-Cyclohexyl-4- [ (tetrazol-1-yl) methyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [(methanesulfonyloxy) methyl] piperidine and tetrazole according to the same procedure as Intermediate 39.

MS [M+H] = 250 (M+1) Intermediate 41: 4-Cyclohexyl-4-{ [(1-methyl)tetrazol-5-yl]methyl}piperidine Step A: l-BOC-4-Cyclohexyl-4-(cyanomethyl) piperidine 1-BOC-4-Cyclohexyl-4- [ (methanesulfonyloxy) methyl] piperidine (375 mg, 1 mmol) and sodium cyanide (153 mg, 3 mmol) were dissolved in DMF (5 mL), and the mixture was stirred 100°C for 24 h. The reaction mixture was quenched with an aqueous 1N HC1 solution, and the organic material was extracted with EtOAc. The extracts were washed with saturated aqueous NaHC03 solution, dried over MgS04, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/3) to give the title compound.

MS [M+H] = 306 (M+1) Step B : 1-BOC-4-Cyclohexyl-4-f [ (1-methyl) tetrazol-5-yl] methyl} piperidine To a solution of l-BOC-4-Cyclohexyl-4-(cyanomethyl) piperidin, e prepared in Step A, (250 mg, 0.82 mmol) in DMF (5 mL) were added sodium azide (195 mg, 3 mmol) and NH4C1 (132 mg, 3 mmol), and the mixture was stirred at 90°C for 24 h.

The reaction mixture was diluted with water, and the organic material was extracted with EtOAc. The extracts were washed with a 1N HC1 solution, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: aceton/DCM = 3/1) to give the title compound.

MS [M+H] = 350 (M+1) Step C: 4-CycloheXyl-4-{[(1-methyl) tetrazol-5-yl] methyl} piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4-{[(1- methyl) tetrazol-5-yl] methyl} piperidine prepared in Step B according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 250 (M+1) Intermediate 42: 4-Cyclohexyl-4-[(2-pyrrolidinon-1-yl) methyl] piperidine Step A: 1-BOC-4-Cyclohexyl-4-[(2-pyrrolidinon-1-yl) methyl] piperidine NaH (60% in mineral oil, 60 mg, 1.5 mmol) was placed in a 50-mL two-neck round-bottomed flask, filled in nitrogen, and THF (5 mL) was added. The reaction solution was cooled at 0°C in an ice-water bath, and a solution of 2-pyrrolidinone (102 mg, 1.2 mmol) in THF (1 mL) was slowly added. After the reaction mixture was stirred at 0°C for 30 min. , a solution of 1-BOC-4-cyclohexyl-4-[(methanesulfonyloxy)- methyl]} piperidine (375 mg, 1 mmol) in THF (1 mL) was slowly added. After 30 minuets, the reaction mixture was warmed to rt, and stirred for additional 5 h. The reaction mixture was quenched with a saturated aqueous NH4C1 solution, and the organic material was extracted with EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (255 mg, 70 %).

MS [M+H] = 365 (M+1) Step B: 4-Cyclohexyl-4- [ (2-pyrrolidinon-1-yl) methyl] piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4-[(2- pyrrolidinon-1-yl) methyl] piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 265 (M+1) Intermediate 43: 4-Cyclohexyl-4-[(dimethylamino) methyl] piperidine Step A: 1-BOC-4-Cyclohexyl-4-[(dimethylamino) methyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- (aminomethyl)- piperidine and formaline according to the same procedure as Intermediate 26.

MS [M+H] = 325 (M+1) Step B: 4-Cyclohexyl-4-[(dimethylamino) methyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-[(dimethyl- amino) methyl) piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 225 (M+1) Intermediate 44: 4-Cyclohexyl-4-{[methyl (cyclohexyl) amino] methyl} piperidine Step A: 1-BOC-4-Cyclohexyl-4- { [methyl (cyclohexyl) amino] methyl} piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-f [ (cyclohexyl)- amino] methyl} piperidine and formaline according to the same procedure as Intermediate 26.

MS [M+H] = 393 (M+1) Step B : 4-Cyclohexyl-4- [ (methyl (cyclohexyl) amino) methyl] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-{[methyl- (cyclohexyl) amino] methyl} piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 293 (M+1) Intermediate 45: 1-BOC-4-Cyclohexyl-4-aminopiperidine Step A: 1-BOC-4-Cyclohexyl-4-[(benzyloxycarbonyl) amino] piperidine To a solution of l-BOC-4-cyclohexyl-4-piperidinecarboxylic acid (3.1 g, 10 mmol) and TEA (2.8 ml, 20 mmol) in THF (30 mL) was added DPPA (diphenyl phosphoryl azide) (2.6 g, 12 mmol), and the reaction mixture was stirred at 70°C for 24 h. After THF was distilled off in vacuo, Toluene (10 mL) and benzyl alcohol (1.5 mL) were added dropwide, and the reaction mixture was stirred at 100°C. After 24h, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/5) to give the title compound.

MS [M+H] = 417 (M+1) Step B : 1-BOC-4-Cyclohexyl-4-aminopiperidine To a solution of 1-BOC-4-cyclohexyl-4- [benzyloxycarbonyl] amino] piperidine, prepared in Step A, (2.1 g, 5 mmol) in MeOH (30 mL) was added Pd/C (200 mg). The reaction mixture was stirred under H2 at rt for 12 hr. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound.

MS [M+H] = 283 (M+1) Intermediate 46: 4-Cyclohexyl-4- (dimethylamino) piperidine Step A: l-BOC-4-Cyclohexyl-4-(dimethylamino) piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-aminopiperidine prepared in Step B of Intermediate 45 and formaline according to the same procedure as Intermediate 26.

MS [M+H] = 311 (M+1) Step B: 4-Cyclohexyl-4- (dimethylamino) piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- (dimethyl- amino) piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 211 (M+1) Intermediate 47: 4-Cyclohexyl-4- (acetylamino) piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-aminopiperidine and acetic acid according to the same procedure as Intermediate 1.

MS [M+H] = 225 (M+1) Intermediate 48: 4-Cyclohexyl-4- [isopropyl (methyl) amino] piperidine Step A: 1-BOC-4-Cyclohexyl-4-[(isopropyl) amino] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4-aminopiperidine and acetone according to the same procedure as Step A in Intermediate 26.

MS [M+H] = 325 (M+1) Step B: 1-BOC-4-Cyclohexyl-4- [isopropyl (methyl) amino] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [ (isopropyl)- amino] piperidine and formaline according to the same procedure as step A in Intermediate 26.

MS [M+H] = 339 (M+1) Step C: 4-Cyclohexyl-4- [isopropyl (methyl) amino] piperidine The title compound was obtained from 1-BOC-4-cyclohexyl-4- [isopropyl- (methyl) amino] piperidine according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 239 (M+1) Intermediate 49: (2R)-N-Methanesulfonyl- (4-chlorophenyl) alanine Step A: (2R)-N-Methanesulfonyl- (4-chlorophenyl) alanine methyl ester To a solution of (2R)- (4-chlorophenyl) alanine methyl ester (213mg, 1.00 mmol) in DCM (5 mL) was added TEA (280 mL, 2.00 mmol) and methansulfonyl chloride at 0°C. After 30 minutes, DCM was distilled off in vacuo, and the residue was diluted with EtOAc, and then washed with 1N HC1. The organic solution was dried over MgS04 and concentrated in vacuo, and the residue was purified by column chromatography (eluent: MeOH/CHCl3 = 1/25) to give the title compound (280 mg, 96. 1 %).

MS [M+H] = 292 (M+1) Step B: (2R)-N-Metlianesulfonyl- (4-chlorophenyl) alanine To a solution of (2R)-N-methanesulfonyl- (4-chlorophenyl) alanine methyl ester, prepared in Step A, (590 mg, 2 mmol) in H20/MeOH (5 ml, 1/1) was added LiOH (70.0 mg, 2.00 mmol). After the reaction mixture was stirred at rt for 3 h, the reaction solution was concentrated in vacuo and diluted with a aqueous 1N HC1. The organic material was extracted with EtOAc, and the extracs were concentrated in vacuo to give the title compound (179 mg, 94.3 %).

MS [M+H] = 278 (M+1) Intermediate 50: (2R)-N-Acetyl- (4-chlorophenyl) alanine The title compound was obtained from (2R)- (4-chlorophenyl) alanine methylester and acetic anhydride according to the same procedure as Intermediate 49.

MS [M+H] = 240 (M+1) Intermediate 51: (2R)-N-Dimethylcarbamoyl- (4-chlorophenyl) alanine The title compound was obtained from (2R)- (4-chlorophenyl) alanine methyl ester and chlorodimethylcarbamate according to the same procedure as Intermediate 49.

MS [M+H] = 269 (M+1) Intermediate 52: (2R)-N-Boc-Prolinecarboxyaldehyde Step A: (2R) -N-Boc-Prolinethioester To a solution of DCC (2. 55 g, 12.4 mmol), DMAP (100 mg), and EtSH (0.71 g, 11.1 mmol) DCM (30 mL) was added a solution of (2R)-N-Boc-proline (3.00 g, 9.52 mmol) in DCM (30 mL). After the reaction mixture was stirred at rt for 30 min. , the precipitate was filtered off through Celite. The filtrate was dried over MgS04 and concentrated in vacuo, and the residue was purified by column chromatography (eluent : EtOAc/Hex = 1/4) to give the title compound (2.34 g, 95.2%).

MS [M+H] = 260 (M+1) Step B: (2R) -N-Boc-Prolinecarboxyaldehyde To a solution of (2R)-N-Boc-Proline thioester, prepared in Step A, (15.0 g, 6.5 mmol) in acetone was added triethylsilane (5.39 g, 46.3 mmol) and Pd/C (100 mg) at 0°C. When the bubbling was not generated any more, the reaction mixture was warmed to rt and stirred for 30 min. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (1.43 g, 93.2%).

MS [M+H] = 200 (M+1) Intermediate 53: (2R)-N-Methyl-prolinecarboxyaldehyde Step A: (2R) -N-Methyl-proline methyl ester To a solution of (2R)-Proline methylester (1.20 g, 10.0 mmol) and formalin (37 % in H2O, 1.12 mL, 15.0 mmol) in DMF (30 mL) was added NaBH (OAc) 3 (4.20 g, 20.0 mmol). After being stirred for 12h, the reaction mixture was concentrated in vacuo, and the residue was diluted with NaHC03 (30 mL). The organic material was extracted with EtOAc, and the extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 4/1) to give the title compound.

MS [M+H] = 144 (M+1) Step B : (2R)-N-Methyl-prolinecarboxyaldehyde The title compound was obtained from (2R)-N-Methyl-proline methyl ester prepared in Step A according to the same procedure as Step B of Intermediate 49 and Intermediate 52.

MS [M+H] =114 (M+1) Intermediates 54-62 : The following intermediates listed in the following Table 4 were obtained from amino acid methyl ester using the same procedure described in Intermediate 26, or Intermediate 49 and Intermediate 52.

Table 4 zon H N * NON X O Inter. X n * MS (M+1) 54 Me 1 S 114 55 Ac 1 R 142 56 S02Me 1 R 178 57 C (0) N (Me) 2 1 R 171 58 Bu 1 R 156 59 Me 2 S 128 60 Me 2 R 128 61 Ac 2 R 156 62 S02Me 2 R 192 Intermediate 63: 1-BOC-Aziridine-2-carboxylic acid Step A: Methyl 1-benzyl-2-aziridinecarboxylate To a solution of methyl-2, 3-dibromopropiolate (92.50 g, 10.0 mmol) and K2C03 (4.10 g, 3.00 mmol) in acetonitrile (30 mL) was added dropwise benzyl amine (1.20 mL, 11 mmol), and the reaction mixture was stirred at rt for 4 h. The reaction mixture was quenched with a saturated aqueous NH4CL solution, and the organic material was extracted with EtOAc (50 mL x 3). The extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 2/1) to give the title compound (1.62 g, 85.0%).

MS [M+H] = 192 (M+1) Step B: Methyl l-BOC-2-aziridinecarboxylate.

To a solution of methyl l-benzyl-2-aziridinecarboxylate prepared in Step A (1.00 g, 5.23 mmol) and di-t-butyldicarbonate (1.34 g, 5.75 mmol) in MeOH (20 mL) was added Pd/C (300 mg). After being stirred under H2 at rt for 24 h, the reaction mixture was filtered through Celite, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 2/1) to give the title compound (985 mg, 91.0%).

MS [M+H] = 202 (M+1) Step C: l-BOC-2-Aziridinecarboxylic acid The title compound was obtained from Methyl 1-BOC-2-aziridinecarboxylate prepared in Step B according to the same procedure as Step B of Intermediate 49.

MS [M+H] = 188 (M+l) Intermediate 64: 1-BOC-2-Aziridinecarboxyaldehyde The title compound was obtained from 1-BOC-aziridine-2-carboxylic acid according to the same procedure as Intermediate 52.

MS [M+H] = 172 (M+l) Intermediate 65: Methyl 1-BOC-4-amino-4-piperidinecarboxylate To a solution of l-BOC-4-amino-4-piperidinecarboxylic acid (2.00 g, 8.2 mol) in MeOH (300 mL) and DCM (300 mL) was added diazomethane slowly until the reaction solution became to pale yellow. The reaction mixture was stirred at room temperature for additional 30 min. and concentrated in vacuo to give the title compound.

MS [M+H] = 393 (M+1) Intermediate 66: 1-BOC-4-(Cbz) Amino-4-piperidinecarboxylic acid To a solution of methyl l-BOC-4-amino-4-piperidinecarboxylate (1.29 g, 5 mol), prepared in Intermediate 65, in water (10 mL) and dioxane (10 mL) were added Na2C03 (IN water solution, 10 mL) and CbzCl (1.5 mL, 10 mmol). After the reaction mixture was stirred at room temperature for 6 h, the solvent was distilled off in vacuo, and the residue was diluted with IN HCI. The organic material was extracted with EtOAc, and the extracts were dried over MgS04, filtered, and concentrated to give the title compound.

MS [M+H] = 379 (M+1) Intermediate 67: 4- (Piperidin-1-yl)-4- (dimethylcarbamoyl) piperidine Step A: 1-BOC-4- (Cbz-Amino)-4- (dimethylcarbamoyl) piperidine The title compound was obtained from 1-BOC-4- (Cbz) aminopiperidine carboxylic acid and dimethylamine according to the same procedure as Step A of Intermediate 1.

MS [M+H] = 406 (M+1) Step B: 1-BOC-4-Amino-4- (dimethylcarbamoyl) piperidine The title compound was obtained from 1-BOC-4- (Cbz) amino-4- (dimethyl- carbamoyl) piperidine prepared in Step A according to the same procedure as Step B of Intermediate 45.

MS [M+H] = 272 (M+1) Step C: l-BOC-4-(Piperidin-l-yl)-4-(dimethylcarbamoyl) piperidine To a solution of l-BOC-4-amino-4-(dimethylcarbamoyl) piperidine, prepared in Step B, (1.35 g, 5 mmol) in DMF (15 mL) was added glutaraldehyde (25% in water, 6 mL) and NaBH (OAc) 3 (2.1 g, 10 mmol). After being stirred at rt for 4h, the reaction mixture was concentrated in vacuo, and the residue was diluted with saturated a aqueous NaHC03 solution. The organic material was extracted with EtOAc, and the extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent : EtOAc/n-Hex = 2/1) to give the title compound (1.51 g, 91.0%).

MS [M+H] = 340 (M+1) Step D: 4- (Piperidin-1-yl)-4- (dimethylcarbamoyl) piperidine The title compound was obtained from 1-BOC-4- (piperidin-1-yl)-4- (dimethylcarbamoyl) piperidine prepared in Step C according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 240 (M+1) Intermediates 68-76: The following intermediates listed in Table 5 were prepared from 1-BOC-4- (Cbz) aminopiperidine using the same procedure described inIntermediate 67.

Table 5 0 Dol H-N z Inter. MS (M+1) 68 NH (c-Hex) 292 69 NH (t-Bu) 268 70 NH (i-Pr) 254 71 NH (Pr) 254 72 N (Me) (Et) 254 73 NHPh 288 74 Pyd-1-yl 266 75 Imz-1-yl 263 76 1, 2, 4-Trz-1-yl 264 Intermediate 77: 4- (Piperidin-1-yl)-4- [4, 4- (dimethyl) oxazolin-2-yl] piperidine Step A: 1-BOC-4- (Cbz) Amino-4- {[(2-hydroxy-1,1-dimethyl) ethyl] carbamoyl} piperidine The title compound was obtained from l-BOC-4- (Cbz) amino-4-piperidine carboxylic acid and 2-amino-2-methyl-1-propanol according to the same procedure as Step A of Intermediate 1.

MS [M+H] = 450 (M+1) Step B: 1-BOC-4- (Cbz) Amino-4- [4, 4- (dimethyl) oxazolin-2-yl] piperidine The title compound was obtained from l-BOC-4-(Cbz) amino-4-{[(2-hydroxy- 1, l-dimethyl) ethyl] carbamoyl} piperidine prepared in Step A according to the same procedure as Step C of Intermediate 9.

MS [M+H] = 432 (M+1) Step C: 1-BOC-4-Amino-4- [4, 4- (dimethyl) oxazolin-2-yl] piperidine The title compound was obtained from 1-BOC-4- (Cbz) amino-4- [4, 4- (dimethyl) oxazolin-2-yl] piperidine prepared in Step B according to the same procedure as Step B of Intermediate 45.

MS [M+H] = 298 (M+1) Step D : 1-BOC-4- (Piperidin-1-yl)-4- [4, 4- (dimethyl) oxazolin-2-yl] piperidine The title compound was obtained from 1-BOC-4-amino-4- [4, 4- (dimethyl) oxazolin-2-yl] piperidine prepared in Step C according to the same procedure as Step C of Intermediate 67.

MS [M+H] = 366 (M+1) Step E : 4- (Piperidin-1-yl)-4- [4, 4- (dimethyl) oxazolin-2-yl] piperidine The title compound was obtained from 1-BOC-4- (piperidin-1-yl)-4- [4, 4- (dimethyl) oxazolin-2-yl) piperidine prepared in Step D according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 266 (M+1) Intermediate 78: 4- (Piperidin-1-yl)-4- (oxazolin-2-yl) piperidine The title compound was obtained from 1-BOC-4- (Cbz) amino-4-piperidine carboxylic acid and aminoethanol according to the same procedure as Intermediate 77.

MS [M+H] = 238 (M+1) Intermediate 79: Methyl 4- (piperidin-1-yl)-4-piperidinecarboxylate Step A: Methyl 1-BOC-4- (piperidin-1-yl)-4-piperidinecarboxylate The title compound was obtained from methyl l-BOC-4-amino-4-piperidine carboxylate according to the same procedure as Step C of Intermediate 67.

MS [M+H] = 327 (M+1) Step B: Methyl 4- (piperidin-1-yl)-4-piperidinecarboxylate The title compound was obtained from Methyl l-BOC-4-(piperidin-l-yl)-4- piperidinecarboxylate prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 227 (M+l) Intermediate 80: 1-BOC-4- (Piperidin-1-yl)-4- (hydroxymethyl) piperidine The title compound was obtained from Methyl 1-BOC-4- (piperidin-1-yl)-4- piperidinecarboxylate according to the same procedure as Intermediate 14.

MS [M+H] = 299 (M+1) Intermediate 81: 1-BOC-4- (Piperidin-1-yl)-4-piperidinecarboxyaldehyde The title compound was obtained from 1-BOC-4- (piperidin-1-yl)-4- (hydroxymethyl) piperidine according to the same procedure as Intermediate 15.

MS [M+H] = 297 (M+l) Intermediate 82: 4- (Piperidin-1-yl)-4- [ (1-hydroxy) isobutyl] piperidine The title compound was obtained from 1-BOC-4- (piperidin-1-yl)-4- piperidinecarboxylate and isopropyl magnesium bromide according to the same procedure as Intermediate 16.

MS [M+H] = 241 (M+1) Intermediate 83: 4- (Piperidin-1-yl)-4- (isobutyryl) piperidine The title compound was obtained from 4- (piperidin-1-yl)-4- [ (1- hydroxy) isobutyl] piperidine according to the same procedure as Intermediate 17.

MS [M+H] = 239 (M+1) Intermediate 84: 4- (Pyrrolidin-1-yl)-4- (dimethylcarbamoyl) piperidine Step A: 1-BOC-4-(pyrrolidin-1-yl)-4-(dimethylcarbamoyl) piperidine To a solution of l-BOC-4-amino-4-(dimethylcarbamoyl) piperidine (542 mg, 2 mmol) in DMF (10 mL) were added TEA (0.560 mL, 4 mmol) and dibromobutane (473 mg, 1.1 mmol) and the reaction mixture was stirred at 80-90°C for 12 h. After DMF was distilled off in vacuo, the residue was diluted with a saturated aqueous NaHC03 solution, and the organic material was extracted with EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 3/1) to give the title compound (520 mg, 80.0%).

MS [M+H] = 326 (M+1) Step B: 4- (Pyrrolidin-1-yl)-4- (dimethylcarbamoyl) piperidine The title compound was obtained from l-BOC-4-(pyrrolidin-l-yl)-4-(dimethyl- carbamoyl) piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.

MS [M+H] = 226 (M+l) Intermediates 85-97: The following Intermediates listed in Table 6 were obtained from 1-BOC-4- (Cbz) amino-4-piperidinecarboxylic acid using the same procedure described in Intermediate 67 or 84.

Table 6 0/du N H-N \D2 N-D3 D4 Inter. D1 Dz D3 D¢ MS (M+1) 85 Me Me Me Me 200 86 Me Me Et Et 228 87 Me Me H i-Pr 214 88 Me Me H Bn 248 89 Me Me H (c-Hex) 242 90 Me Me H (c-Pen) 228 91 Me Me H (c-Hex)-CH2 268 92 t-Bu H Me Me 228 Table 6 (continued) 93 t-Bu H Et Et 256 94 t-Bu H H (c-Hex)-CH2 296 95 Me Me- (CH2) 4- 254 96 Me Me- (CH2) 6-282 97 t-Bu H H c-Pen 254 Intermediate 98: Phthaliminoethyl amine Step A: 2-Phthalimino-l-BOC-aminoethane To a solution of commercially available N-BOC-ethylenediamine (1.6 g, 10 mmol) and TEA (2.8 mL, 20 mmol) in DCM (30 mL) was added phthalic anhydride (1.63 g, 11 mmol). After being stirred at rt for 4 h, the reaction mixture was quenched with a aqueous IN HC1 solution, and the organic material was was extracted with EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/4) to give the title compound (1.60 g, 84.0%).

MS [M+H] = 291 (M+1) Step B: Phthaliminoethyl amine To a solution of 2-phthalimino-1-BOC-aminoethane prepared in Step A (1.0 g, 3.43 mmol) in DCM (5 mL) was added TFA (5 mL) at rt for 30 min. The reaction mixture was concentrated to give the title compound.

MS [M+H] = 191 (M+1) Intermediate 99: 2-Phthalimino-1-(methyl) aminoethane Step A: 2-Phthalimino-1- [methyl (BOC) amino] ethane To a solution of NaH (80 mg, 60% in mineral oil, 2 mmol) in THF (3 mL) was added 2-Phthalimino-l-BOC-aminoethane prepared in Step A of Intermediate 98 (291 mg, 1 mmol) at 0°C. After 30 min, methyl iodide (74. 5, uL, 1.2 mmol) in THF (1 mL) was added slowly at 0 °C and the reaction mixture was stirred at rt 12 h. The reaction mixture was quenched a saturated aqueous NH4Cl solution and diluted with EtOAc, and the organic layer was extracted with EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/5) to give the title compound (198 mg, 64%).

MS [M+H] = 305 (M+1) Step B: 2-Phthalimino-l-(methyl) aminoethane The title compound was obtained from 2-phthalimino-1-methyl (N-BOC) - aminoethane prepared in Step A according to the same procedure as Step B of Intermediate 98.

MS [M+H] = 205 (M+1) Intermediate 100: (3S)-1-(2-Nitrobenzene) sulfonyl-3-aminopyrrolidine Step A: (3S)-l- (2-Nitrobenzene) sulfonyl-3-BOC-aminopyrrolidine To a solution of 3-BOC-aminopyrrolidine (372 mg, 2 mmol) in DCM (10 mL), were added TEA (0.56 mL, 4 mmol) and (2-nitrobenzene) sulfonyl chloride (487. 4 mg, 2.2 mmol), and the reaction mixture was stirred at rt for 12 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, the organic material was extracted with EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo.

The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/7) to give the title compound (697 mg, 94%).

MS [M+H] = 372 (M+1) Step B: (3S)-1- (2-Nitrobenzene) sulfonyl-3-aminopyrrolidine The title compound was obtained from (3S)-1-(2-nitrobenzene) sulfonyl-3- (BOC) aminopyrrolidine prepared in Step A according to the same procedure as Step B of Intermediate 98.

MS [M+H] = 272 (M+1) The present invention is illustrated by the following examples. However, the scopes of the invention are not limited to these examples.

Examples Example 1: (2R)-2-Amino-N- [4-Cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide TFA Step A: (2R)-2- (BOC-Amino)-N- [4-Cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide To a solution of 4-cyclohexyl-4-(t-butylcarbamoyl) piperidine (HCl salt, 917 mg, 3. 30 mmol) in DMF (30 mL) were added DIPEA (1. 15 mL, 6.70 mmol), EDC (845 mg, 4.30 mmol), HOBT (668 mg, 5.00 mmol), and (2R)-N-BOC- (4-chlorophenyl) alanine, and the reaction mixture was stirred at rt for 12 h. After DMF was distilled off under reduced pressure, the residue was poured into EtOAc, and subsequently washed with a saturated aqueous NaHC03 solution and an aqueous 1N HCl solution. The organic solution was dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 2/1) to give the title compound (1.58 g, 93.9%).

MS [M+H] = 520 (M+1) Step B: (2R)-2-Amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide TFA To a solution of (2R)-2- (BOC) amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)- piperidin-1-yl]-3- (4-chlorophenyl) propionamide, prepared in Step A, (1.00 g, 1.93 mmol) in DCM (7 mL) was added TFA (7 mL). After being stirred at rt for 30 min. , the reaction solution was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (TFA salt, 979 mg, 95. 1%).

MS [M+H] = 420 (M+1) Example 2: (2R)-2- { [ (2R)-Pyrrolidin-2-yl] carbonyl} amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-l-yt]-3- (4-ch ! orophenyl) propionamide TFA Step A: (2R)-2-{[(2R)-l-(BOC) pyrrolidin-2-yl] carbonyl} amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide To a solution of (2R)-2-amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin- 1-yl]-3- (4-chlorophenyl) propionamide, prepared in Example 1, (TFA salt, 100 mg, 0. 188 mmol) in DMF (3 mL) were added DIPEA (66.1 mL, 0. 381 mmol), EDC (48.7 mg, 0.252 mmol), HOBT (43.6 mg, 0.322 mmol), and (2R) -N-BOC-proline (40.9 mg, 0.190 mmol), and the reaction mixture was stirred at rt for 12 h. After DMF was distilled off in vacuo, the residue was poured into EtOAc, and subsequently washed with a saturated aqueous NaHC03 solution and an aqueous 1N HCl solution. The organic solution was dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 2/1) to give the title compound (107 g, 90.8%).

MS [M+H] = 617 (M+1) Step B: (2R)-2- { [ (2R)-Pyrrolidin-2-yl] carbonyl} amino-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide TFA To a solution of (2R)-2-f [ (2R)-1- (BOC) pyrrolidin-2-yl] carbonyl} amino-N- [4- cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide, prepared in Step A, (50.0 mg, 0.081 mmol) in DCM (2 mL) was added TFA (2 mL), and the reaction mixture was stirred at rt for 1 h. The reaction solution was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (TFA salt, 50.0 mg, 98.2%).

MS [M+H] = 516 (M+1) Example 3: (2R)-2- { [ (2R)-Pyrrolidin-2-yl] methyl} amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA Step A: (2R)-2- { [ (2R)-l- (BOC) Pyrrolidin-2-yl] methyl} amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide To a solution of (2R)-2-amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin- 1-yl]-3- (4-chlorophenyl) propionamide, prepared in Example 1 (TFA salt, 100 mg, 0.191 mmol), and (2R) -N-BOC-proline carboxyaldehyde (37.9 mg, 0. 191 mmol) in DCE (5 mL) was added NaBH (OAc) 3 (80.0 mg, 0.380 mmol). After being stirred at rt for 4 h, the reaction mixture was quenched with a saturated aqueous NaHCO3. The organic material was extracted with DCM followed by EtOAc, and the extracts were dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: DCM/MeOH = 9/1) to give the title compound (109 mg, 95. 0%).

MS [M+H] = 603 (M+1) Step B: (2R)-2-f [ (2R)-Pyrrolidin-2-yl] methyl} amino-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA The title compound was obtained from (2R)-2-{[(2R)-l-(BOC) pyrrolidin-2- yl] methyl} amino-N- [4-Cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Example 1 according to the same procedure as Step B of Example 1.

MS [M+H] = 503 (M+1).

Example 4: (2R)-2-1 [ (2R)-I- (Methyl) pyrrolidin-2-yl] methyl}} amino-N- [4-cyclo- hexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA The title compound was obtained from (2R)-2-{[(2R)-l-(BOC) pyrrolidin-2- yl] methyl} amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-l-yl]-3- (4- chlorophenyl) propionamide and formaline according to the same procedure as Example 3.

MS [M+H] = 545 (M+1).

Example 5 : (2R)-2- (Dimethyl) amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)- piperidin-1-yl]-3- (4-chlorophenyl) propionamide TFA The title compound was obtained from (2R)-2-amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3-(4-chlorophenyl)propionamide (TFA salt) prepared in Example 1 and formaline according to the same procedure as Example 3.

MS [M+H] = 476 (M+1).

Example 6: (2R)-2- [1- (Methyl) azetidin-3-yl] amino-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidin-l-yl]-3-(4-chlorophenyl) propionamide 2TFA Step A: (2R)-2- [1- (BOC) Azetidin-3-yl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)- piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2-amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide (TFA salt) prepared in Example 1 and fonnaline according to the same procedure as Step A of Example 3.

MS [M+H] = 603 (M+l).

Step B: (2R)-2- {Fmoc [1- (BOC) azetidin-3-yl]} amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2- [l- (BOC) azetidin-3-yl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide prepared in Step A and Fmoc chloride according to the same procedure as Step A of Intermediate 98.

MS [M+H] = 825 (M+1). <BR> <BR> <P>Step C: (2R)-2- [Fmoc (Azetidin-3-yl) ] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)- piperidin-1-yl]-3- (4-chlorophenyl) propionamide TFA.

The title compound was obtained from (2R)-2-{Fmoc [l-(BOC) azetidin-3- yl]} amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) pipcridin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step B according to the same procedure as Step B of Example 1.

MS [M+H] = 725 (M+1).

Step D: (2R)-2- [Fmoc (l-Methylazetidin-3-yl)] amino-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2- [Fmoc (azetidin-3-yl) ] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide TFA prepared in Step C and formaline according to the same procedure as Step A of Example 3.

MS [M+H] = 739 (M+1).

Step E: (2R)-2- [l- (Methyl) azetidin-3-yl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)]- piperidin-1-yl}-3- (4-chlorophenyl) propionamide 2TFA (2R)-2- {Fmoc [1- (Methyl) azetidin-3-yl]} amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-l-yl]-3- (4-chlorophenyl) propionamide, prepared in Step D, (71.1 mg, 1 mmol) was desolved in 50% piperidine/DMF solution (2 mL), and the mixture was stirred at rt for 30 min. The reaction solution was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (TFA salt, 52 mg, 73.5%).

MS [M+H] = 517 (M+1).

Examples 7-186: The following compounds listed in Table 7 were synthesized from piperidine derivatives prepared in Intermediates using the same procedure described in Examples 1-6.

Table 7 Example Rl RZ R3 * R5 n MS (M+1) 7 H H 4-Cl-Bn R C (O) NH (i-Pr) 1 434 8 H H 4-CI-Bn R C (O) N (Me) 2 1 420 9 H H 4-CI-Bn S C (O) N (Me) 2 1 420 C (O) N (Me) (c-Hex) 10 H H 4-CI-Bn R 1 488 11 H H 4-Cl-Bn R C (O) (Pyd-1-yl) 1 456 12 H H 4-C1-Bn R C (-OCH2CH2N=) 1 418 13 H H 4-Cl-Bn R C [-OCH2C (Me) 2N=) 1 446 14 H H 4-Cl-Bn R C [-SCH2C (Me) 2N=) 1 434 15 H H 4-Cl-Bn R CHO 1 377 16 H H 4-Cl-Bn R C (O) OMe 1 407 17 H H 4-Cl-Bn R C (O) (iPr) 1 419 18 H H 4-Cl-Bn R CH (OH) (i-Pr) 1 420 19 H H 4-Cl-Bn R N (Me) 2 1 392 20 H H 4-CI-Bn R NHAc 1 406 21 H H 4-Cl-Bn R CH20SO2Me 1 457 22 H H 4-Cl-Bn R CH2SO2 (i-Pr) 1 485 23 H H 4-CI-Bn R CH2502NH2 1 456 24 H 4-CI-Bn R CHzNHAc 1 420 25 H H 4-CI-Bn R CHzN (Me) 2 2 406 26 H H 4-CI-Bn R CH2N (c-Hex) (i-bu) 1 530 27 H H 4-CI-Bn R CH2N (c-Hex) (Me) 2 474 28 H H 4-Cl-Bn R CH2 (1, 2, 3-Trz-1-yl) 1 432 Table 7 (continued) 29 H H 4-Cl-Bn R C (0) (1, 2, 4-Trz-1-yl) 1 444 30 H H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 432 31 H H 4-Cl-Bn S CH2 (1, 2, 4-trz-1-yl) 1 432 32 H H 4-Cl-Bn R CHz (1, 3-Imz-1-yl) 2 431 33 H H 4-CI-Bn R C (0) (1, 3-Imz-1-yl) 2 443 34 H H 4-Cl-Bn R CH2 (Tez-1-yl) 1 433 35 H H 4-CI-Bn R CH2N [-C (0) OCH2C (Me) 2-] 1 460 36 H H Bn R C (O) NH (t-Bu) 1 414 37 H H Bn R C (-OCH2CH2N=) 1 384 38 H H 4-Br-Bn R C (O) NH (t-Bu) 1 493 39 H H 4-MeO-Bn R C (O) NH (t-Bu) 1 444 40 H H 3, 4-diCl-Bn R C (O) N (Me) 2 1 454 41 H H 4-F-Bn R C (O) N (Me) 2 1 404 42 H H 4-OH-Bn R C (O) N (Me) 2 1 402 43 H H 4-Cl-Ph R, S C (O) N (Me) 2 1 406 44 H H (c-Hex)-CH2 R C [-OCH2C (Me) 2N=] 1 418 45 H H (c-Hex)-CH2 R CH2 (1, 2, 4-trz-1-yl) 1 400 46 H H Ph- (CH2) 2 R C (O) NH (t-Bu) 1 428 47 H H (indol-2-yl)-CH2 R C (O) NH (t-Bu) 2 455 48 H H i-Bu R C (O) NH (t-Bu) 1 380 49 H H 3-NH2- (CH2) 3 R C (O) NH (t-Bu) 2 381 50 H H NH2C (0)-CH2 R C (O) NH (t-Bu) 1 381 51 Me Me 4-Cl-Bn R C (O) N (Me) 2 1 448 52 Me Me 4-CI-Bn R CH2 (1, 2, 4-trz-1-yl) 1 460 Table 7 (continued) 53 Ac H 4-CI-Bn R C (O) N (Me) z 0 462 54 Ac H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 0 474 55 MeSOz H 4-CI-Bn R C (O) N (Me) 2 0 498 56 (Me) 2NC (O) H 4-Cl-Bn R C (O) N (Me) 2 0 491 57 (Me) 2NC (O)-CH2 H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 505 58 Gly H 4-Cl-Bn R C (O) N (Me) 2 1 477 59 Gly H 4-Cl-Bn R C (-OCH2CH2N=) 1 475 60 Gly H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 487 61 N-diMe-Gly H 4-Cl-Bn R C (O) N (Me) 2 1 505 62 (R) Ala H 4-Cl-Bn R C (O) N (Me) 2 1 491 63 (R) His H 4-Cl-Bn R C (O) N (Me) 2 2 557 64 (S) His H 4-Cl-Bn R C (O) N (Me) z 2 557 65 (S) His H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 2 568 66 N-Me- (S) His H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 2 630 67 N-Ac- (S) His H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 658 68 N-BOC- (S) His H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 716 N- [PrC (0)]- 69 H 4-Cl-Bn R CH2 (1, 2, 4-trz-l-yl) 1 686 (S) His ? 0 N- [Ph (CHZ) QC (0)]- (S) His H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 776 71 (S) Phe H 4-Cl-Bn R C (O) N (Me) 2 1 567 72 (R) Pro H 4-Cl-Bn R C (O) N (Me) 2 1 517 73 (R) Pro H 4-Cl-Bn R C (-OCH2CH2N=) 1 515 74 (R) Pro H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 527 75 (R) Pro H 4-Cl-Bn R CHzN [-C (O) OCH2C (Me) 2-] 1 573 Table 7 (continued) 76 N-Me- (R) Pro H 4-Cl-Bn R C (O) N (Me) 2 1 531 77 N-Me- (R) Pro H 4-Ct-Bn R C [-OCHZC (Me) zN=] 1 557 78 N-Me- (R) Pro H 4-CI-Bn R CH2N [-C (O) OCH2C (Me) 2-] 1 587 79 N-Me- (R) Pro H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 541 80 (S) Pro H 4-Cl-Bn R 4C [-OCH2C (Me) 2N=] 1 543 81 (R) Pid-2-CO H 4-Cl-Bn R C (O) N (Me) 2 1 531 82 (R) Pid-2-CO H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 1 531 83 (R) Pid-2-CO H 4-CI-Bn R CH2 (1, 2, 4-Trz-1-yl) 1 541 84 (R) Pid-2-CO H 4-Cl-Bn R CH2N [-C (O) OCH2C (Me) 2-] 1 553 1-Me- (R) Pid-2- 85 H 4-Cl-Bn R CH2N [-C (O) OCH2C (Me) 2-] 1 567 CO 1-Me-(R) Pid-2- 86 H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 1 545 CO 87 (S) Pid-2-CO H 4-Cl-Bn R C (O) N (Me) 2 1 531 88 (S) Pid-2-CO H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 1 531 89 H, NV H 4-Cl-Bn R C (-OCH2CH2N=) 1 501 0 90 HxN H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 513 91 H 4-Cl-Bn R C (O) N (Me) 2 1 545 HzN I 0 92 HNQIR H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 555 han 0 Table 7 (continued) 93 HO-CHrC (O) H 4-CI-Bn R C (O) N (Me) Z 0 478 94 HO-CH2-C (O) H 4-Cl-Bn R C (-OCH2CH2N=) 0 478 95 HN H 4-Cl-Bn R C (O) N (Me) 2 1 489 0 96 (S H 4-Cl-Bn R C (O) N (Me) 2 1 532 lir 97 (2R) Pyd-2-CH2 H 4-CI-Bn R C (O) N (Me) 2 2 503 98 (2R) Pyd-2-CH2 H 4-CI-Bn R C [-OCH2C (Me) 2N=] 2 529 99 (2R) Pyd-2-CH2 H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 2 513 100 (2R) Pyd-2-CH2 H 4-Cl-Bn R CH2N [-C (O) OCH2C (Me) 2-] 2 559 101 (2R) Pyd-2-CH2 Me 4-CI-Bn R C (O) N (Me) 2 2 517 102 (2R) Pyd-2-CH2 Me 4-Cl-Bn R C (-OCH2CH2N=) 2 515 (2R)-1-Me-Pyd 103 H 4-Cl-Bn R C (O) N (Me) 2 2 531 -2-CH2 (2R)-1-Me-Pyd 104 Me. 4-CI-Bn R C (O) N (Me) 2 2 545 - 2-CHz (2R)-1-Ac-Pyd 105 H 4-Cl-Bn R C (0) N (Me) 2 1 559 - 2-CHO (2R)-1-Ac-Pyd 106 H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 555 - 2-CH2 (2R)-1-Ms-Pyd 107 H 4-Cl-Bn R C (O) N (Me) 2 1 581 - 2-CH2 108 (2S) Pyd-2-CH2 H 4-Cl-Bn R C (O) N (Me) 2 1 517 (2S)-1-Me-Pyd 109 H 4-C. 1-Bn R C (O) N (Me) 2 1 531 -2-CH2 Table 7 (continued) 110 (2R) Pid-2-CH2 H 4-Cl-Bn R C (O) N (Me) 2 2 531 111 (2R) Pid-2-CHz H 4-Cl-Bn R C (-OCH2CH2N=) 2 514 112 (2S) Pid-2-CH2 H 4-Cl-Bn R C (O) N (Me) 2 2 531 113 H 4-Cl-Bn R C (O) N (Me) 2 2 475 HNw _ _ l l 4 A H 4-Cl-Bn R C (O) N (Me) 2 2 475 HNsr _ 115 H 4-Cl-Bn R C (O) N (Me) 2 2 501 N l l 6 Me 4-Cl-Bn R C (O) N (Me) 2 2 489 HNS _ 117 Pid-3-ylH 4-Cl-Bn R C (O) N (Me) 2 2 503 Table 7 (continued) 3 N R JANO R5 R2 01. R2 ° nTFA Example R1 Ra R3 * R5 n MS (M+1) 118 H H 4-Cl-Bn R CONH (t-Bu) 2 449 119 H H 4-Cl-Bn R C (0) NH (i-Bu) 2 435 120 H H 4-Cl-Bn R C (O) N (Me) 2 2 421 121 H H 4-Cl-Bn R C (O) (Pyd-1-yl) 2 447 122 H H 4-Cl-Bn R C (0) (1, 2, 3-Trz-1-yl) 2 445 123 H H 4-Cl-Bn R C (O) (1, 3-Imz-1-yl) 3 444 124 H H 4-Cl-Bn R C (-OCH2CH2N=) 2 419 125 H H 4-Cl-Bn R C (O) N (Me) 2 2 408 126 H H 4-Cl-Bn R C (0) CH (OH) (i-Pr) 2 413 127 H H 4-Cl-Bn R CHZN (Me) 2 2 406 128 H H Bn R CONH (t-Bu) 2 415 129 H H 4-Br-Bn R CONH (t-Bu) 2 494 130 Me Me 4-Cl-Bn R C (O) N (Me) a 2 449 131 Ac H 4-Cl-Bn R C (O) N (Me) 2 1 463 132 MeSOz H 4-Cl-Bn R C (O) N (Me) 2 1 499 133 (Me) 2NC (0)-CH2 H 4-Cl-Bn R C (-OCH2CH2N=) 2 511 134 Gly H 4-Cl-Bn R C (O) N (Me) z 2 478 135 Gly H 4-Cl-Bn R C (-OCH2CH2N=) 2 476 136 (S) His H 4-Cl-Bn R C (0) N (Me) 2 3 607 Table 7 (continued) 137 N-Ac- (S) His H 4-Cl-Bn R C (O) N (Me) 2 2 649 138 (R) His H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 3 584 139 (R) Pro H 4-Cl-Bn R C (O) N (Me) 2 2 518 140 (R) Pro H 4-Cl-Bn R C (-OCH2CH2N=) 2 516 141 N-Me- (R) Pro H 4-Cl-Bn R C (O) N (Me) 2 2 532 142 N-Me- (R) Pro H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 2 544 143 (S) Pro H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 2 544 144 (R) Pid-2-CO H 4-Cl-Bn R C (O) N (Me) 2 2 532 145 (R) Pid-2-CO H 4-Cl-Bn R C (-OCH2CH2N=) 2 530 146 1-Me-(R) Pid-2-CO H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 2 572 147 (R) Tic H 4-Cl-Bn R C (0) N (Me) 2 2 580 148 HO-CH2-C (O) H 4-Cl-Bn R C (O) N (Me) 2 1 479 149 < H 4-CI-Bn R C (O) N (Me) 2 2 490 150 (2R) Pyd-2-CH2 H 4-Cl-Bn R C (O) N (Me) 2 3 504 151 (2R) Pyd-2-CH2 H 4-CI-Bn R C [-OCH2C (Me) 2N=] 3 572 152 (2R) Pyd-2-CH2 Me 4-Cl-Bn R C (O) N (Me) 2 3 518 153 (2R) Pyd-2-CH2 Me 4-Cl-Bn R C (-OCH2CH2N=) 3 516 (2R)-1-Me-Pyd-2- 154 H 4-Cl-Bn. R C (O) N (Me) 2 3 518 CH2 (2R)-1-Me-Pyd-2- 155 H 4-Cl-Bn R CONH (t-Bu) 3 546 CH2 (2R)-1-Me-Pyd-2- 156 H 4-Cl-Bn R C (-OCH2CH2N=) 3 530 CH2 Table 7 (continued) (2R)-l-Ac-Pyd-2- 157 H 4-CI-Bn R C (O) N (Me) 2 2 546 CH2 (2R)-1-Ms-Pyd-2- 158 H 4-CI-Bn R C (O) N (Me) 2 2 582 CH2 159 (2S) Pyd-2-CH2 H 4-Cl-Bn R C (O) N (Me) 2 3 504 160 (2S) Pyd-2-CH2. H 4-Cl-Bn R C (-OCH2CH2N=) 3 502 161 (2R) Pid-2-CH2 H 4-Cl-Bn R C (O) N (Me) 2 3 518 162 (2R) Pid-2-CH2 Me 4-Cl-Bn R C (O) N (Me) 2 3 532 (2R)-1-Me-Pid-2- 163 H 4-Cl-Bn R C (O) N (Me) 2 3 532 CH2 164 (2S) Pid-2-CH2 H 4-Cl-Bn R C (O) N (Me) 2 3 518 165 H 4-Cl-Bn R C (O) N (Me) 2 3 476 166 3-Pid-1-yl H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 3 530 167 3-Pid-1-yl H 4-Cl-Bn R C (-OCH2CH2N=) 3 502 Table 7 (continued) Example R1 R7 R8 n MS(M+1) 168 H Me Me 2 381 169 H i-Bu H 2 409 170 H c-Hex H 2 435 171 H c-Pen H 2 421 172 H Bn H 2 443 173 H (c-Hex)-CH2 Me 2 463 174 H- (CH2) 4- 2 407 175 H -(CH2)6- 2 435 176 Ac c-Hex H 1 477 177 (Me) 2C (0)-CH2- Et Et 2 494 178 His Et Et 3 546 179 (D) Pro -(CH2)4- 2 504 180 (D) Pid-2-CO- (CH2) 4- 2 518 Table 7 (continued) Example R1 R3 * R7 Rs n MS (M+1) 181 H 4-CI-Bn R Me Me 2 409 182 H 4-CI-Bn R c-Hex H 2 477 183 H 4-Cl-Bn R -(CH2)4- 2 435 184 H 4-Cl-Bn R -(CH2)6- 2 449 185 (L) His 4-CI-Bn R c-Hex H 3 600 186 (D) Pro 4-Cl-Bn R-(CH2) 4-2 532 Example 187: (2R)-2-Amino-N- [4-cyclohexyl-4- (aminoethylcarbamoyl) piperidin-1- yl]-3- (4-chlorophenyl) propionamide 2HCl Step A: (2R)-2- (BOC) Amino-N- (4-cyclohexyl-4-carboxypiperidin-1-yl)-3- (4-chloro- phenyl) propionamide The title compound was obtained from (2R)-N-BOC- (4-chlorophenyl) alanine and 4-cyclohexyl-4-carboxypiperidin-l-yl according to the same procedure as Step A of Example 1.

MS [M+H] = 493 (M+l).

Step B: (2R)-2-(BOC)Amino-N-(4-cyclohexyl-4-chlorocarbonylpiperidin- 1-yl)-3-(4- chlorophenyl) propionamide To a solution of (2R)-2- (BOC) Amino-N- (4-cyclohexyl-4-carboxypiperidin-l- yl)-3- (4-chlorophenyl) propionamide, prepared in Step A, (1. 0 g, 2.03 mmol) in DCM (10 mL) were added oxaly chloride (0.26 mL, 3.10 mmol) and catalytic amounts of DMF, and the reaction mixture was stirred at 0 °C for 30 min. The reaction solution was removed in vacuo, and the residue was purified by column chromatography (eluent : EtOAc/Hex = 1/1) to give the title compound (705 mg, 68%).

MS [M+H] = 511 (M+1) Step C: (2R)-2- (BOC) Amino-N- [4-cyclohexyl-4- (aminoethylcarbamoyl) piperidin-l- yl]-3- (4-clilorophenyl) propionamide To a solution of (2R)-2- (BOC) Amino-N- (4-cyclohexyl-4-chlorocarbonyl- piperidin-1-yl)-3- (4-chlorophenyl) propionamide, prepared in Step B, (511 mg, 1. 0 mmol) in DCM (5 mL) were added TEA (0.28 mL, 2.0 mmol) and a solution of N (BOC)-ethylene diamine (90 mg, 1.5 mmol) in DCM (0.5 mL), and the reaction mixture was stirred at rt for 2 h. The reaction solution was concentrated in vacuo, the residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (578 mg, 91%).

MS [M+H] = 635 (M+l) Step D: (2R)-2-Amino-N- [4-cyclohexyl-4- (aminoethylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide 2TFA The title compound was obtained from (2R)-2- (BOC) amino-N- [4-cyclohexyl- 4- (aminoetliylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide prepared in Step C according to the same procedure as Step B of Example 1.

MS [M+H] = 435 (M+l).

Step E: (2R)-2-Amino-N- [4-cyclohexyl-4- (aminoethylcarbamoyl) piperidin-l-yl]-3- (4- chlorophenyl) propionamide 2HCl The title compound was obtained from (2R)-2-amino-N- [4-cyclohexyl-4- (aminoethylcarbamoyl) piperidin-l-yl]-3-(4-chlorophenyl) propionamide (2TFA salt) prepared in Step D in methanol, and passed through HCl-substituted ion exchange resin.

MS [M+H] = 435 (M+l).

Example 188: (2R)-2- (Dimethylamino)-N- [4-cyclohexyl-4- (aminoethylcarbamoyl)- piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2HC1 Step A: (2R)-2- (BOC) Amino-N- [4-cyclohexyl-4- (phthaliminoethylcarbamoyl)- piperidin-l-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2- (BOC) Amino-N- [4-cyclohexyl- 4- (chlorocarbonyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide prepared in Step B of Example 187 and 2-phthalimino-l-aminoethanol prepared in Intermediate 98 according to the same procedure as Step C of Example 187.

MS [M+H] = 665 (M+l).

Step B: (2R)-2-Amino-N- [4-cyclohexyl-4- (phthaliminoethylcarbamoyl) piperidin-l-yl]- 3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2- (BOC) amino-N- [4-cyclohexyl-4- (phthaliminoetliylcarbamoyl)-piperidin-l-yl]-3- (4-chlorophenyl) propionamide prepared in Step A according to the same procedure as Step B of Example 1.

MS [M+H] = 565 (M+l).

Step C: (2R)-2- (Dimethyl) amino-N- [4-cyclohexyl-4- (phthaliminoethylcarbamoyl)- piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2-amino-N- [4-cyclohexyl-4- (phthaliminoethylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide prepared in Step B according to the same procedure as Example 3.

MS [M+H] = 593 (M+l).

Step D: (2R)-2- (Dimethyl) amino-N- [4-cyclohexyl-4- (aminoethylcarbamoyl) piperidin- 1-yl]-3- (4-chlorophenyl) propionamide 2TFA To a solution of (2R)-2- (dimethyl) amino-N- [4-Cyclohexyl-4- (phthaliminoethyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide, prepared in Step C, (200 mg, 0.34 mmol) in MeOH (5 mL) was added hydrazine (0. 10 mL, 3.64 mmol), and the reaction mixture was stirred at rt for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (TFA salt, 111 mg, 57.0%).

MS [M+H] = 463 (M+1) Step E: (2R)-2- (Dimethyl) amino-N- [4-cyclohexyl-4- (aminoethylcarbamoyl) piperidin-1- yl]-3- (4-chlorophenyl) propionamide 2HC1 The title compound was obtained from (2R)-2- (Dimethyl) amino-N- [4- cyclohexyl-4- (aminoethylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide 2TFA prepared in Step D according to the same procedure as Step E of Example 187.

MS [M+H] = 463 (M+l).

Examples 189-225: The following compounds listed in Table 8 were synthesized from reaction piperidin-1-yl derivatives prepared in Intermediates using the same procedure descried in Examples 187 and 188.

Table 8 Example R1 R2 R4 n MS (M+1) 189 H H NHC (Me) 2CH2NH2 2 463 190 H H NHCH2CH2CH2NH2 2 449 191 H H NHCH2CH2CH2CH2NH2 2 463 192 H H OCH2CH2NH2 2 436 193 H H N (Me) CH2CH2NH2 2 449 194 H H NHCH2CH2N (Me) 2 2 463 195 H H NHCH2CH2N (Et) 2 2 491 196 H H'NHC (Me) 2CH20H 1 464 197 H H NHCH (Me) CH20H 1 450 198 H H NHCH2CH20H 1 436 199 H H NHCH2CH2CH20H 1 450 200 H H N (Me) CH2CH2CH20Me 478 201 H H N (Me) CH2CH20H 1 450 202 H H N (Me) CH2CH20Me 1 464 203 H H NHCH2CH20Me 1 450 204 H H N [-CH2CH (OH) CH2-] 1 448 205 H H N [-CH2CH (OMe) CH2-]. 1 462 Table 8 (continued) 206 H H N [-CH2CH ((S)-OH) CH2CH2-] 1 462 207 H H N [-CH2CH2CH (OH) CH2CH2-] 1 476 208 H H N [-CH2CH2CH (OMe) CH2CH2-] 1 490 209 H H N [-CH2CH2CH (OAc) CH2CH2-] 1 518 210 H H N [-CH2CH ((R)-NH2) CH2CH2-] 2 461 211 H H N [-CH2CH ((S)-NH2) CH2CH2-] 2 461 212 H H N [-CHzCH2CH (NH2) CH2CH2-] 2 475 213 H H N (-CH2CH2NCH2CHz-) 2 461 214 H H N [-CH2CH2N (Me) CH2CH2-] 2 475 215 H H (R)-NHC (-CH2NHCH2CH2-) 2 461 216 H H (S)-NHC (-CH2NHCH2CH2-) 2 461 217 H H (S)-NHC (-CH2N (Me) CH2CH2-) 2 475 218 H H N (CH2CH20Me) 2 1 508 219 H H N (-CH2CH20CH2CH2-) 1 462 220 H H NHCH (CH20H) 2 1 466 221 H H N (CH2CH20H) 2 1 480 222 Me Me N (Me) CH2CH20H 1 478 223 Gly H NHCH2CH20H 1 493 224 Gly H NHCH2CHZOMe 1 507 225 HtO-H NHCH2CH20H 1 505 Example 226: (2R)-2-Amino-N- [4-cyclohexyl-4- (3-oxo-azetidin-1-yl) piperidin-l- yl]-3- (4-chlorophenyl) propionamide 2HC1 Step A: (2R)-2-Amino-N- [4-cyclohexyl-4- (3-oxo-azetidin-1-yl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide 2TFA To a solution of (2R)-2- (BOC) amino-N- [4-cyclohexyl-4- (3-hydroxyazetidin-l- yl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide, prepared in Example 204, (200 mg, 0.45 mmol) in DCM (5 mL) was added Dess-Martin reagent (3.0 mL, 15 wt% in DCM, 10 mmol). After being stirred at rt for 12 h, the reaction mixture was quenched with a saturated aqueous Na2S203 solution, and the precipitate was filtered. The filtrate was dried over MgS04, concentrated in vacuo, the residue was purified by HPLC to give the title compound (TFA salt, 203 mg, 81. 0%).

MS [M+H] = 446 (M+l) Step B: (2R)-2-Amino-N- [4-cyclohexyl-4- (3-oxo-azetidin-1-yl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide 2HC1 The title compound was obtained from (2R)-2-amino-N- [4-cyclohexyl-4- (3- oxoazetidin-1-yl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide2TFA prepared in Step A according to the same procedure as Step E of Example 187.

MS [M+H] = 446 (M+1).

Example 227: (2R)-2-Amino-N- [4-cyclohexyl-4- (4-oxo-piperidin-1-yl) piperidin-l- yl]-3- (4-chlorophenyl) propionamide 2HCl The title compound was obtained from (2R)-2-amino-N- [4-cyclohexyl-4- (4- hydroxyazetidin-l-yl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2HC1 prepared in Example 207 according to the same procedure as Example 226.

MS [M+H] = 474 (M+1). <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>Example 228: (2R) -2- [2- (Dimethyl) aminoethyl] amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA Step A: (2R)-2- [ (2-nitrobenzene) sulfonyl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)- piperidin-l-yl-3- (4-chlorophenyl) propionamide To a solution of (2R)-2-Amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin- 1-yl]-3- (4-chlorophenyl) propionamide, prepared in Example 1 (519 mg, 1 mmol), in DMF (10 mL) were added TEA (280 mL, 2 mmol) and (2-nitrobenzene)- sulfonylchloride (222 mg, 1.00 mmol). After being stirred at rt for 4 h, the reaction mixture was quenched with an aqueous NH4Cl solution, and the organic material was extracted with DCM followed by EtOAc. The extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (570 mg, 90%).

MS [M+H] = 633 (M+1) Step B: (2R)-2- (2-Nitrobenzene) sulfonyl [2- (dimethyl) aminoethyl]} amino-N- [4-cyclo- hexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide To a solution of (2R)-2- [ (2-nitrobenzene) sulfonyl] amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide, prepared in Step A, (500 mg, 0.79 mmol) in DMF (5 mL) were added K2C03 (280 mg, 2 mmol) and 2- (dimethylamino) ethyl chloride (HCl salt, 125.9 mg, 1 mmol). After being stirred at rt for 12 h, the reaction mixture was concentrated in vacuo, and the residue was dilueted with a saturated aqueous NH4Cl solution. The organic material was extracted with EtOAc, and the extracts were dried over MgS04, filtered, and concentrated in vacuo.

The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (511 mg, 92%).

MS [M+H] = 703 (M+l) Step C: (2R)-2- [2- (dimetliyl) aminoethyl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)- piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA To a solution of (2R)-2-{(2-nitrobenzene) sulfonyl [2-(dimetllyl) aminoethyl]}- amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl)- propionamide, prepared in Step B, (500 mg, 0.71 mmol) in DMF (3 mL) were added K2CO3 (300 mg, 2 mmol) and thiobenzene (210 mL, 0.429 mmol). After being stirred at rt for 2 hr, the reaction mixture was concentrated ira vacuo, and the residue was diluted with water. The organic material was extracted with EtOAc, the extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by HPLC to give the title compound (TFA salt, 477 mg, 90%).

MS [M+H] = 520 (M+1) Example 229: (2R) -2- [2- (Methyl) aminoethyl] amino-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA Step A: (2R) -2- { (2-Nitrobenzene) sulfbnyl [2- (BOC) aminoethyl]} amino-N- [4-cyclo- hexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2- [ (2-nitrobenzene) sulfonyl] - amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step A of Example 228 and N-BOC- aminoethyl bromide according to the same procedure as Step B of Example 228.

MS [M+H] = 727 (M+1).

Step B: (2R)-2- {(2-Nitrobenzene) sulfonyl [2-(N-methyl-N-BOC-amino) ethyl]} amino- N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2-{(2-nitrobenzene) sulfonyl [2- (BOC) aminoethyl] lamino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step A and iodomethane according to the same procedure as Step B of Example 228.

MS [M+H] = 740 (M+1).

Step C: (2R)-2- {2- [Methyl (BOC) amino] ethyl]} amino-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2-{(2-nitrobenzene) sulfonyl [2-(N- methyl-N-BOC-amino) ethyl]} amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-l- yl]-3- (4-chlorophenyl) propionamide prepared in Step B according to the same procedure as Step C of Example 228.

MS [M+H] = 606 (M+1).

Step D: (2R)-2- [2- (Methyl) aminoethyl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)- piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA The title compound was obtained from (2R)-2- 2- [Methyl (BOC) amino] - ethyl} amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step C according to the same procedure as Step B of Example 1.

MS [M+H] = 506 (M+1).

Example 230: (2R)-2- (2-Aminoethyl) amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)- piperidin-l-yl]-3- (4-chlorophenyl) propionamide 2TFA Step A: (2R)-2- [2- (BOC) Aminoethyl] amino-N-{[4-cyclohexyl-4-(t-butylcarbamoyl)]- piperidin-1-yl}-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2-{(2-nitrobenzene) sulfonyl [2- (BOC) aminoethyl]} amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step A of Example 229 according to the same procedure as Step C of Example 228.

MS [M+H] = 563 (M+1).

Step B: (2R)-2- (2-Aminoethyl) amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin- 1-yl]-3- (4-chlorophenyl) propionamide 2TFA The title compound was obtained from (2R)-2-[2-(BOC) aminoethyl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide prepared in Step A according to the same procedure as Step B of Example 1.

MS [M+H] = 463 (M+1).

Example 231: (2R)-2- [2- (Acetylamino) ethyl] amino-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide TFA The title compound was obtained from acetylaminoethyl bromide according to the same procedure as Example 228.

MS [M+H] = 505 (M+1).

Example 232: (2R)-2-fMethyl [2- (methyl) aminoethyl] amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA <BR> <BR> Step A: (2R)-2- {Methyl [2- (BOC) aminoethyl] } amino-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2- [2- (BOC) aminoethyl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide prepared in Step A of Example 230 according to the same procedure as Step A of Example 3.

MS [M+H] = 577 (M+1). Step B: (2R)-2- {Methyl [2- [methyl (BOC) amino] ethyl]}-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained fiom (2R)-2-{Methyl [2-(BOC) aminoethyl]}- amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step A according to the same procedure as Step A of Intermediate 42.

MS [M+H] = 591 (M+1).

Step C: (2R)-2-fMethyl [2- (methyl) aminoethyl]}-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA The title compound was obtained from (2R) -2- {Methyl [2- [methyl (BOC) - amino] ethyl]}-N- [4-cyclohexyl-4- (t-butylcarbamoyl)] piperidin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step B according to the same procedure as Step B of Example 1.

MS [M+H] = 491 (M+1).

Example 233: (2R)-2- {Methyl [2- (amino) ethyl]} amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) ] piperidin-l-yl]-3- (4-chlorophenyl) propionamide 2TFA The title compound was obtained from (2R)-2- {Methyl [2-(BOC) amino- etliyl]} amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step A of Example 232 according to the same procedure as Step B of Example 1.

MS [M+H] = 477 (M+1).

Example 234: (2R)-2- (Methyl) amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl)- piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA Step A: (2R)-2- {Methyl [ (2-nitrobenzene) sufonyl]} amino-N- [4-cyclohexyl-4- (t-butyl- carbamoyl) piperidine-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2-[(2-nitrobenzene) sulfonyl]- amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step A of Example 228 according to the same procedure as Step B of Preparation 228.

MS [M+H] = 619 (M+1). Step B : (2R)-2- (Methyl) amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidine-1-yl]-3- (4-chlorophenyl) propionamide 2TFA The title compound was obtained from (2R)-2- {Methyl [(2-nitrobenzene)- sufonyl]} amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidine-1-yl]-3- (4- chlorophenyl) propionamide prepared in Step A according to the same procedure as Step C of Preparation 228.

MS [M+H] = 434 (M+1).

Examples 235-269: The compounds listed in the following Table 9 were synthesized from piperidine derivatives prepared in Intermediates using the same procedure described in Example 228-234.

Table 9 Ex. R'R2 R3 R, n MS (Mtl) 235 Me H 4-CI-Bn R C (O) N (Me) z 1 434 236 Me H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 1 460 237 Me H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 490 238 MeO2C-CH2 H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 1 502 239 MeO2C-CH2 H 4-Cl-Bn R C (O) NH (t-Bu) 1 520 240 NH2- (CH2) 2 H 4-Cl-Bn R C (O) N (Me) 2 2 463 241 NH2- (CH2) 2 H 4-CI-Bn R C [-OCH2CH2N= 2 461 242 NH2- (CH2) 2 H 4-Cl-Bn R CHzN [-C (O) OCH2C (Me) 2-] 2 519 243 MeNH- (CH2) 2 H 4-Cl-Bn R C [-OCH2CH2N=] 2 505 244 MeNH- (CH2) 2 H 4-CI-Bn R C [-OCH2C (Me) 2N=] 2 503 245 MeNH- (CH2) 2 Me 4-CI-Bn R C (O) N (Me) 2 2 491 246 (Me) 2N- (CH2) 2 H 4-Cl-Bn R C (O) N (Me) 2 2 491 247 (Me) 2N- (CH2) 2 H 4-CI-Bn R C [-OCH2CH2N=] 2 489 248 (Me) 2N- (CH2) 2 H 4-Cl-Bn R CH2 (1, 2, 4-trz-1-yl) 2 501 249-N H 4-Cl-Bn R C (O) N (Me) 2 2 489 Table 9 (continued) 250 HO- (CH2) 2 H 4-CI-Bn R C (0) N (Me) a 2 464 251 (Me) 2N- (CH2) 2 H 4-CI-Bn R CH2N [-C (O) OCH2C (Me) 2-] 2 547 252 (Me) 2N- (CH2) 2 Me 4-Cl-Bn R C (O) N (Me) 2 2 505 253 CNN/Y H 4-Cl-Bn R C (O) N (Me) 2 2 489 254 1-Pyd- (CH2) 2 H 4-CI-Bn R C (O) N (Me) 2 2 517 255 1-Me-3-Pyd-H 4-Cl-Bn R C (O) N (Me) 2 2 503 (CH2) 2 256 (3R) Pyd H 4-C 1-Bn R C (O) N (Me) 2 2 489 -3-yl- I I Table 9 (continued) Example Rl-R3-R5 N MS (M+1) 257 Me H 4-C1-Bn R C (O) N (Me) 2 435 258 Me H 4-C 1-Bn R C [-OCH2C (Me) 2N=] 2 460 259 MeO2C-CH2 H 4-CI-Bn R C (0) NH (t-Bu) 1 520 260 NH2- (CH2) 2 H 4-Cl-Bn R C (O) N (Me) 2 3 464 261 (Me) NH- (CH2) 2 Me 4-CI-Bn R C [-OCH2C (Me) 2N=] 3 503 262 (Me) 2N- (CH2) 2 H 4-Cl-Bn R C (O) N (Me) 2 3 492 263 (Me) 2N- (CH2) Z H 4-Cl-Bn R C [-OCH2CH2N=] 3 489 264 (Me) 2N- (CH2) 2 H 4-Cl-Bn R C (O) NH (t-Bu) 3 455 265 (Me)'2N-(CH2) 2 Me 4-CI-Bn R C (O) N (Me) 2 3 506 266 (Me) 2N-(CH2) 2 Me 4-Cl-Bn R C [-OCH2C (Me) 2N=] 3 531 267 (Ac) NH- (CH2) 2 H 4-Cl-Bn R C (O) N (Me) 2 2 506 268 1-Pyd-(CH2) 2 H 4-Cl-Bn R C [-OCH2C (Me) 2N=] 3 544 (3S) Pyd 269 Me 4-CI-Bn R C (O) N (Me) 2 3 484 - 3-yl Example 270: (2R)-2- [2- (Dimethyl) aminoethyl] amino-N- [4-cyclohexyl-4- (amino- ethylcarbamoyl) piperidin-l-yl]-3-(4-chlorophenyl) propionamide 2HCl Step A: (2R)-2- [2- (Dimethyl) aminoethyl] amino-N- [4-cyclohexyl-4- (phthaliminoethyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2-amino-N- [4-cyclohexyl-4- (phthaliminoethylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide prepared in Step B of Example 188 according to the same procedure as Example 228.

MS [M+H] = 636 (M+1).

Step B: (2R)-2- [2- (Dimethyl) aminoethyl] amino-N- [4-cyclohexyl-4- (aminoethyl- carbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide 2TFA The title compound was obtained from (2R)-2- [2- (dimethyl) aminoethyl] amino- N- { [4-cyclohexyl-4-(phthaliminoethylcarbamoyl)] piperidin-1-yl}-3-(4-chlorophenyl) prepared in Step A according to the same procedures as Steps D and E of Example 188.

MS [M+H] = 506 (M+1).

Examples 271-280: The compounds listed in the following Table 10 were synthesized from r piperidine derivatives prepared in Intermediates using the same procedure described in Example 187 and 270.

Table 10 Ex. R'R 2 R n MS (M+l) 271 (Me) 2N- (CH2) 2 H 4-Cl-Bn R N (Me) CH2CH2NH2 2 520 272 (Me) 2N- (CH2) 2 H 4-Cl-Bn R NHC (-CH2NHCH2CH2-) 2 532 273 (Me) 2N- (CH2) 2 H 4-CI-Bn R NHCH2CH20H 2. 507 274 (Me) 2N- (CH2) 2 H 4-CI-Bn R N (Me) CHzCH20Me 2 535 275 (Me) 2N- (CH2) 2 H 4-C I-Bn R NHCH2CH2CH20Me 2 535 276 (Me) 2N- (CH2) 2 H 4-Cl-Bn R N (-CH2CH2CH (OMe) CH2CH2-) 2 561 277 (Me) 2N- (CH2) 2 H 4-CI-Bn R N (-CH2CH20CH2CH2-) 2 533 278 (Me) 2N- (CH2) 2 H 4-CI-Bn R N (CH2CH20H) 2 2 551 279 (Me) 2N-(CH2) 2 H 4-CI-Bn R NHCH2CH (OH) CH20H 2 537 280 NH2C (O)-CH2 H 4-Cl-Bn R NHCH2CH20H 2 493 Example 281: (2R)-2- (Carboxymethyl) amino-N- [4-cyclohexyl-4- (t- butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl) propionamide The title compound was obtained from (2R)-2- [ (methoxycarbonyl)- methyl] amino-N- [4-cyclohexyl-4- (t-butylcarbamoyl) piperidin-1-yl]-3- (4-chlorophenyl)- propionamide prepared in Example 259 according to the same procedure as Step B of Preparation 49.

MS [M+H] = 506 (M+1).

Biological Assays A. Binding Assay The membrane fraction binding assay was used to identify competitive inhibitors of l25I-NDP-MSH binding to cloned human MCRs expressed in HEK cells.

Cell lines expressing human melanocortin receptor 4 (MC4R) were grown in 0150 mm culture dishes in DMEM (GIBCO-BRL) supplemented with 10% FBS, 200 ug/ml Geneticin (GIBCO-BRL), and antibiotics (penicillin and streptomycin) (GIBCO- BRL) in an atmosphere of 6 % COz at 37°C. When the cells were fully grown, the cells were washed once with 10 ml of Ca++, Mg++ free DPBS. The cells were incubated with 8 ml of Ca++, Mg"-+ free DPBS for 15-30 min at 37 °C until the cells were easily detached by triturating with pipette. The cells were harvested into 50 ml of conical tubes, and spun at 1500 rpm for 5 min. The supernatant was discarded, and the cells were resuspended in 8 ml of Ca++, Mg++ free DPBS, and spun at 1500 rpm for 5 min. The supernatant was discarded, and pellets were resuspended in 3 ml of membrane preparation buffer (50 mM Tris, pH 7. 2-7. 4,4 ug/ml Leupeptin; 10 uM Phosphoramidon; 40 ug/ml Bacitracin; 5 ug/ml Aprotinin; 10 mM Pefabloc). The pellets were homogenized with dounce homogenizer (Bellco with type"B"glass pestle) using 10-12 strokes. The homogenate was centrifuged (Beckman XL-100K Ultracentrifuge, Rotor 45 Ti, 50 ml centrifuge tube) at 40,000 rpm (100,000 X g) for 30 min at 4 ° C. The pellets were resuspended in 20 ml of membrane preparation buffer, and protein was determined by BCA assay kit (PIERCE). Aliquots were placed in tubes and stored at-80 ° C.

Membrane fraction was diluted with membrane binding buffer to make final 600 ug/ml, and 50 ul of membrane fraction containing 30 ug of membrane protein was added onto each well of 96-well assay plate. 25 ul of test compounds or 20 uM unlabelled NDP-MSH (to make the final concentration at 5 uM) diluted with membrane binding buffer was added onto each well of 96-well assay plate. 25 ul of 0.4 nM l25I- NDP-MSH [NEN, Cat. # NEX352 (50 uCi), ti/2 = 60 days] diluted with membrane binding buffer was added onto each well to make the final concentration of 0.1 nM.

The resulting mixture was incubated for 2 hours at room temperature. The reaction mixture was filtered with 96 well GF/C filter plate (Unifilter GF/CTM, Packard) presoaked with 0.1 % polyethleneimine for 30 min. The filter plate was washed 3 times with 200 ul of washing buffer (50 mM Tris pH 7.2 ; 20 mM NaCI) under vacuum at 8"Hg. The filter was dried for 15 min at room temperature, and the bottom was sealed. 40 ul of Packard Microscint-20 was added to each well. The top was sealed, and the radioactivity was quantitated in a Packard Topcount Microplate Scintillation Counter. The ICso was defined as the concentration of test compound that results in the half maximal inhibition of 125I-NDP-MSH binding to cloned human MCRs. The ICso values obtained in the competition assay were converted to affinity constants (Ki values).

B. Functional Assay 1. Luciferase Assay.

Cell lines expressing human melanocortin receptor 4 (MC4R) were dissociated from tissue culture dishes by rinsing with Ca++, Mg free DPBS, treated with 1 X Trypsin/EDTA solution for 1 min at 37 ° C, and resuspended with DMEM (GIBCO- BRL) supplemented with 10% FBS. The cells were counted and diluted with DMEM supplemented with 10% FBS and 200 ug/ml of Geneticin to 5 X 105 cells/ml. 90 ul of cell suspension was plated onto each well of 96-well black and clear bottom culture plates (Costar). After the incubation for 24 hours in the atmosphere of 6 % C02 at 37 ° C, 10ul of NDP-MSH and test compounds diluted in DMSO were added to each well.

The final DMSO concentration was 1 %. After 4 hours of incubation in the atmosphere of 6 % C02 at 37 ° C, 50 ul of Bright-Glo (Promega) was added to each well.

Luciferase activity was measured by using L-Max luminometer (Molecular Device).

The amount of luciferase activity induced by treatment with NDP-MSH was defined as 100 % to obtain the relative efficacy of test compounds. The EC o. 5 MSH was defined as the concentration of test compounds that results in half maximal activity of NDP-- MSH. The ECso was defined as the concentration of test compound that results in half maximal activity of its own.

2. cAMP Accumulation Assay.

The membrane fraction cAMP assay was used to identify MC4R agonist compounds.

Cell lines expressing human melanocortin receptor 4 (MC4R) were grown in 0150 mm culture dishes in DMEM (GIBCO-BRL) supplemented with 10% FBS, 200 ug/ml Geneticin (GIBCO-BRL), and antibiotics (penicillin and streptomycin) (GIBCO- BRL) in an atmosphere of 6 % C02 at 37 ° C. When the cells were fully grown, the cells were washed once with 10 ml of Ca++, Mg++ free DPBS. The cells were incubated with 8 ml of Ca++, Mg++ free DPBS for 15-30 min at 37 ° C until the cells were easily detached by triturating with pipette. The cells were harvested into 50 ml of conical tubes, and spun at 1500 rpm for 5 min. The supernatant was discarded, and the cells were resuspended in 8 ml of Ca++, Mg++ free DPBS, and spun at 1500 rpm for 5 min. The supernatant was discarded, and the pellets were resuspended in 3 ml of membrane preparation buffer (lOmM Tris pH 7.4 ; 0.32M sucrose; 4ug/ml leupeptin; lOuM phosphoramidon ; 40ug/ml bacitracin; 5ug/ml aprotinin). The pellets were homogenized with dounce homogenizer (Bellco with type"B"glass pestle) using 20 strokes. The homogenate was centrifuged at 1300Xg at 4°C for 10 min. The supematants were collected, and the pellets were resuspended in membrane preparation buffer, and homogenization and centrifugation were repeated. All of the supernatants were collected and centrifuged at 40,000 rpm (Beckman XL-100K Ultracentrifuge, Rotor 45 Ti, 50 ml centrifuge tube) at 4°C for 15 minutes. The pellets were resuspended in membrane preparation buffer, and protein was determined by BCA assay kit (PIERCE). Aliquots were placed in tubes and stored at-80 ° C.

20 ul of NDP-MSH or test compounds diluted in DMSO were added onto each well of 96well V-plate. 20 ul of 750ug/ml membrane fraction in MP buffer was added onto each well. After the reaction was performed at room temperature for 15 min, cAMP was measured using cAMP (3H) assay Kit (Amersham, cat. No. TRK 432).

The amount of cAMP produced by the treatment with test compound was compared to that produced in the response to NDP-MSH which was defined as 100 % agonist. The EC50 was defined as the concentration of test compound that results in half maximal activity of its own.

As can be seen from the above results, the compounds according to the present invention showed agonistic efficacy and binding affinity to each MCR. In particular, the compounds according to the present invention showed excellent agonistic efficacy and binding affinity to the MCR4. i. e. , 0.005 uM-10 aM ofECso value and 0. 01 M- 50 uM ofICso value. For example, the compounds of examples 1, 2 and 3 showed 0.005 uM-0. 5 aM ofECso value, and 0. 111M-0. 5, uM of IC50 value, against MCR4.

C. In vivo food intake models 1. Hypophasic effects in fasted mice Hypophasic effects of melanocortinergic ligands are determined by using the food-deprived mouse model (male ddY mice). The animals are individually housed.

One day before treatment, the animals are grouped (7-10 animals/group), based on their basal daily food intakes, and then their food is removed for 20 hr fasting before treatment. In the morning of the test day, each animal receives the administration of vehicle or test substance via oral gavage, and 1 hr after, food is re-supplied. Food intakes after the food-supply are measured for the first 1 hr period.

2. Effects on nocturnal food intake Effects on nocturnal food intake are determined in male ICR mice. The animals are housed individually, and are grouped (7-10 animals/group) based on their basal daily food intakes. Each animal receives the administration of vehicle or test substance via oral gavage 1 hr before starting the dark phase, and food is removed. Food is resupplied lhr after the administration, and food intakes are measured at 1,2, 4, 8, 24 hr after the food is supplied.

3. Effects on food intake and body weight change in ob/ob mice Effects on food intake and body weight change are determined in male 8 wks old ob/ob mice. The animals are housed individually, and are grouped (7-10 animals/group) based on their basal body weights. Each animal receives the administration of vehicle or test substance via oral gavage once a day for 14 days.

Food intakes and body weigh changes are measured daily.

4. Effects on food intake and body weight change in diet-induced obese (DIO) mice Effects on food intake and body weight change are determined in male DIO mice. The DIO mice are prepared by feeding C57BL/6 mice on high fat diet for more than 8 weeks. The DIO animals are housed individually, and are grouped (7-10 animals/group) based on their basal body weights. Each animal receives the administration of vehicle or test substance via oral gavage once a day for 14 days.

Food intakes and body weigh changes are measured daily.

D. Anti-inflammatory effects in an acute inflammation model Anti-inflammatory effects are determined as the effects on crystal-induced Polymorphonuclear Neutrophil (PMN) recruitment. Each Balb/c mouse receives the administration of vehicle or test substance via oral gavage. One hour after the vehicle or drug treatment, the animals receive 3 mg of mono-sodium urea crystals in 0.5 ml of PBS (pH 7.4) buffer (time = 0) by the intraperitoneal injection. At 6 hrs after the crystal injection, the animals are euthanized by C02 exposure, and then their peritoneal cavities are washed with 3 ml of PBS buffer. Aliquots of the lavage fluids are stained with Turk's solution (0.01% crystal violet in 3% acetic acid), and the number of cells are counted by using a hemacytometer and a light microscope. PMNs are counted as many as (1 ~ 10) x 1 o6 per mouse. Data are presented as 106 PMN per mouse.

E. Erectile effects The erectile effect of the test substance is determined by counting the number of erection of male Sprague Dawley rats. Each animal receives the administration of vehicle or test substance via oral gavage 30 min before the test session, and then is placed in a 2-liter glass beaker. The beakers are located on an observation box designed for the ventral view of the animals. The number of erection is counted by observing the posture of the animals (hip constriction, hip thrust, tiptoe posture) for 1 hr.