# Patent

## Title
Melanocortin receptor agonists

## Abstract

The present invention relates a compound of formula 1, and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof effective as agonist of melanocortin receptor, and an agonistic composition of melanocortin receptor comprising the same as active ingredient.

## Background
TECHNICAL FIELD
The present invention relates to a compound of the following formula 1, pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof effective as an agonist for melanocortin receptor.




in which
R1, R2, R3, R4, R5, n and m are defined as described below.
BACKGROUND ART
Five subtypes of receptors 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. Melanocortin 1 receptor (MC1R) is mainly expressed in melanocytes, monocytes, and mast cells, to mediate pigmentation of the hair and skin and to block inflammation. MC2R is expressed in adipocytes and adrenal cells, to mediate 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 controls 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 play a role for the exocrine gland system.
With a 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 on the basis of endogenous agonist such as αMSH. These peptide agonists have been used to characterize the function of these receptors. NDP-αMSH 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 been 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 discovered to have significant activity in drug trials to search MC4R agonists for the treatment of obesity, sexual dysfunction or inflamation. For example, the Merck research group has discovered a series of potent and selective MC4R agonists, one of which demonstrated significant effect for augmenting erectile response in mice (J. Med. Chem. 2002, 45, 4849). The Chiron research group has discovered a series of guanidine compounds as agonists that have hyphophasic activity and thus anti-obesity effect in the ob/ob mouse model (WO 02/18327). On the other hand, the Bristol-Myers Squibb group has discovered a highly potent selective MC 1R agonist, which showed efficacy in an acute mouse model of inflammation (J. Med. Chem. 2003, 46, 1123).
In view of the unresolved deficiencies of the various pharmaceutical compounds as discussed above, there is continuing need in the art for small molecule MCR agonists and pharmacological compositions that have improved pharmacological 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.
Specifically, the present invention provides a compound of formula 1 having agonistic effect against MCRs, in particular selective agonistic effect against MCR4, and pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof.
Another object of the present invention is to provide a melanocortin receptor agonistic composition comprising the compound of formula 1, and pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof, 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 diabetes, erectile dysfunction, obesity, 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

m and n each independently represents 1 or 2,

R1 reperesents

hydrogen,
—(CH2)p—R6,
—(CH2)p—CO—(CH2)p—R6,
—(CH2)p—CO—(CH2)p—CH(R6)(R10), or
—(CH2)p—SO2—(CH2)p—R6,
wherein
p independently represent 0, 1, 2, or 3,
R6 represents C1-C10-alkyl, C1-C8-alkoxy, C3-C8-cycloalkyl, heterocycle, aryl, heteroaryl, amino, or hydroxy, in each of which is unsubstituted or mono- or poly-substituted by one or more substituents selected from the group consisting of C1-C10-alkyl, C1-C10-dialkyl, C3-C13-cycloalkyl, C3-C13-dicycloalkyl, C3-C13-tricycloalkyl, perhalo-C1-C8-alkyl, aryl, heteroaryl, heterocycle, hydroxy, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkoxy, trifluoromethoxy, aryl-C1-C8-alkyloxy, aryloxy, oxo, mercapto, C1-C8-alkylcarbonyl, C1-C8-alkoxycarbonyl, C1-C8-alkylsulfonyl, arylsulfonyl, C1-C8-alkylthio, arylthio, cyano, formyl, halogen, carbonyl, thiocarbonyl, C3-C8-cycloalkylcarbonyl, arylcarbonyl, ar-C1-C8-alkyl, ar-C1-C8-alkylcarbonyl, ar-C1-C8-alkylsulfonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, carbamoyl, C1-C8-alkylcarbamoyl, di(C1-C8-alkyl)carbamoyl, O-sulfoneamido, N-sulfonamido, carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, trihalomethanesulfonyl, amino, C1-C6-alkylamino, di(C1-C6-alkyl)amino, and protective derivatives thereof,
R10 represents heterocycle, or represents amino or hydroxy, in each of which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R7,
wherein,
R7 represents halogen, amino, C1-C6-alkylamino, di(C1-C6-alkyl)amino, hydroxy, C1-C8-alkoxy, trifluoromethoxy, C1-C6-alkylcarbonyl, carboxy, C1-C8-alkyl, mercapto, C1-C10-alkylthio, phenoxy, C1-C8-alkoxycarbonyl, arylcarbonyl, carbamoyl, C1-C6-alkylsulfonyl, arylsulfonyl, cyano or oxo,
R6 and R10 may form 5- or 6-membered single ring together with the atoms to which they attached,
hydrogen atom in —(CH2)p— group can be replaced by R6,
R1 represents
hydrogen,
C1-C8-alkyl which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R7,
C3-C7-cycloalkyl, or
—CO—(CH2)p—R6,
R1 and R2 together with the atoms to which they attached, may form 4- or 8-membered single ring or two ring which can contain heteroatom selected from the group consisting of O, S and N—(C1-C4-alkyl),
R3 and R4 each independently represents
hydrogen,
C1-C8-alkyl,
—(CH2)p—C3-C8-cycloalkyl,
—(CH2)p—C6-C10-aryl,
—(CH2)p-heteroaryl, or
—(CH2)p-heterocycle,
wherein, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl, in each of which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R7,
R5 represents
hydrogen,
C1-C6-alkyl,
—(CH2)p—CO—R8,
—(CH2)p—C(O)N(R8)(R9),
—(CH2)p—C(S)N(R8)(R9),
—(CH2)p—SO2—N(R8)(R9), or
—(CH2)p—SO2—R8,
wherein,
R8 and R9 each independently represents
hydrogen,
C1-C8-alkyl,
C1-C6-alkoxy,
C1-C6-alkylthio,
C3-C7-cycloalkyl,
C3-C7-cycloalkenyl,
heterocycle,
aryl, or
heteroaryl,
wherein
alkyl, cycloalkyl, or aryl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R7, C3-C8-cycloalkyl, heterocycle, hydroxy-C1-C8-alkyl, halogen-C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, amino-C1-C8-alkyl, C3-C8-cycloalkyloxy, ar-C1-C8-alkyloxy, aryloxy, arylthio, formyl, C1-C8-alkylcarbamoyl, di(C1-C8-alkyl)carbamoyl, C1-C8-alkylcarbonyloxy, C1-C8-alkoxy-C1-C8-alkoxy, C3-C8-cycloalkylcarbonyl, ar-C1-C8-alkylcarbonyl, C2-C8-alkanoyloxy, C3-C8-cycloalkylcarbonyloxy, arylcarbonyloxy which is unsubstituted or substituted by halogen, ar-C1-C8-alkylcarbonyloxy, C1-C8-alkoxyimino, ar-C1-C8-alkylsulfonyl, and C1-C8-alkylsulfonyloxy,
heterocycle, cycloalkenyl, or heteroaryl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R7, and hydroxy-C1-C8-alkyl,
R4 and R5 together with the atoms to which they attached, may form 4- or 8-membered single ring or two ring which can contain heteroatom selected from the group consisting of O, S and N—(C1-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 6- to 10-membered 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-C8-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, pyrimnidine, 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 4- to 8-membered ring which can be fused with benzo or C3-C8-cycloalkyl, and which is saturated or has 1 or 2 of double bond. 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, —CO—(CH2)p—R6, —(CH2)p—CO—(CH2)p—CH(R6)(R10), or —SO2—(CH2)p—R6,
R6 represents C1-C10-alkyl, C1-C8-cycloalkyl, heterocycle, aryl, or heteroaryl, or represent amino or hydroxy,
hydrogen atom in —(CH2)p— group can be replaced by R6,
wherein
C1-C10-alkyl, C1-C8-cycloalkyl, heterocycle, aryl, or heteroaryl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R7,
amino or hydroxy is unsubstituted or mono- or di-substituted by the substituents selected from the group consisting of C1-C10-alkyl, ar-C1-C8-alkyl, C3-C8-cycloalkyl, C2-C8-alkylcarbonyl, C3-C8-cycloalkylcarbonyl, arylcarbonyl, ar-C1-C8-alkylcarbonyl, C1-C8-alkoxycarbonyl, carbamoyl, di(C1-C8-alkylcarbamoyl, C1-C8-alkylsulfonyl, arylsulfonyl, and ar-C1-C8-alkylsulfonyl,
R10 is defined as the above description,
R6 and R10 may form 5- or 6-membered single ring together with the atoms to which they attached,
preferably, R1 represents hydrogen, —(CH2)p—R6, —(CH2)p—CO—R6, —CO—(CH2)p—R6 or —(CH2)p—CO—(CH2)p—CH(R6)(R10),
more preferably, R1 represents hydrogen, —R6 or —CO—CH(R6)(R10),
R10 represents heterocycle, or represents amino or hydroxy, in each of which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R7,
R6 and R10 may form 5- or 6-membered single ring together with the atoms to which they attached,
ii) R2 represents hydrogen or C1-C6-alkyl,
iii) R3 represents C1-C8-alkyl, —(CH2)p—C3-C7-cycloalkyl, —(CH2)p-phenyl, or —(CH2)p-heteroaryl, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of R7,
preferably, R3 represents —CH2-cyclohexyl or —CH2-phenyl, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of halogen, cyano, hydroxy, C1-C8-alkoxy, trifluoromethoxy and C1-C4-alkyl,
more preferably, R3 represents —CH2-phenyl, in which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of chloro, bromo, cyano, hydroxy, methoxy and metyhl,
iv) R4 represents C1-C8-alkyl, or represent C3-C8-cycloalkyl, phenyl, heteroaryl, or heterocycle, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of R7,
preferably, R4 represents C3-C8-cycloalkyl or phenyl,
more preferably, R4 represents cyclohexyl, cylcoheptyl or cylcopentyl, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of methyl, ethyl, t-butyl, hydroxy and oxo, or represent phenyl unsubstituted or mono- to tri-substituted by substituents from the group consisting of fluoro, chloro, methoxy and methyl,
v) R5 represents hydrogen, C1-C6-alkyl, —(CH2)p—CO—R8, —(CH2)p—C(O)N(R5)9), or —(CH2)p—SO2—R8,
preferably, R5 represents —CO—R8 or —C(O)N(R8)(R9),
more preferably, R8 and R9 each independently represents hydrogen, methoxy, amino, C1-C8-alkyl, C3-C6-cycloalkyl, C5-C6-cycloalkenyl, heterocycle, or phenyl,
wherein, C1-C8-alkyl or C3-C6-cycloalkyl is unsubstituted or mono-substituted by the substituents selected from the group consisting of methyl, hydroxy, amino, C1-C4-alkoxy, phenoxy, benzyloxy, fluoro, phenylsulfoxy, acetyl, methoxymethylalkoxy, carboxy, formyl, methoxycarbonyl, dimethylcarbamoyl, carboxy, phenylcarbonyloxy, methoxycarbonyl, difluorophenylcarbonyloxy, dimethylphenylcarbonyloxy, cyclohexylcarbonyloxy, arylcarbonyloxy, and oxo,
C5-C6-cycloalkenyl represents cyclopentyl or cyclohexyl substituted by hydroxy or amino,
heterocycle or phenyl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of hydroxy, methyl, amino, nitrobenzenesulfonyl, and oxo.
vi) R1 represents hydrogen, —R6 or —CO—CH(R6)(R10),
R10 represents heterocycle, or represents-amino or hydroxy, in each of which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R7,
R6 and R10 may form 5- or 6-membered single ring together with the atoms to which they attached,
R3 represents —CH2-phenyl, in which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of chloro, bromo, cyano, hydroxy, methoxy and metyhl,
R4 represents cyclohexyl, cylcoheptyl or cylcopentyl, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of methyl, ethyl, t-butyl, hydroxy and oxo, or represent phenyl unsubstituted or mono- to tri-substituted by substituents from the group consisting of fluoro, chloro, methoxy and methyl,
R5 represents —CO—R8 or —C(O)N(R6)(R9),
R8 and R9 each independently represents hydrogen, methoxy, amino, C1-C8-alkyl, C3-C6-cycloalkyl, C5-C6-cycloalkenyl, heterocycle, or phenyl,
wherein, C1-C8-alkyl or C3-C6-cycloalkyl is unsubstituted or mono-substituted by the substituents selected from the group consisting of methyl, hydroxy, amino, C1-C4-alkoxy, phenoxy, benzyloxy, fluoro, phenylsulfoxy, acetyl, methoxymethylalkoxy, carboxy, formyl, methoxycarbonyl, dimethylcarbamoyl, carboxy, phenylcarbonyloxy, methoxycarbonyl, difluorophenylcarbonyloxy, dimethylphenylcarbonyloxy, cyclohexylcarbonyloxy, arylcarbonyloxy, and oxo,
C5-C6-cycloalkenyl represents cyclopentyl or cyclohexyl substituted by hydroxy or amino,
heterocycle or phenyl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of hydroxy, methyl, amino, nitrobenzenesulfonyl, and oxo.
Representative compounds of formula 1 according to the present invention include the compounds listed in the following Table 1.















TABLE 1





R1
R2
R3
*1
n
m
R4
*2
R5







H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)OMe


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)N(Me)2


H
H
4-Cl-Bn
R
2
1
c-Hex
S
SO2Me


H
H
4-Cl-Bn
R
2
1
c-Hex
S
CH2C(O)OMe


H
H
4-CI-Bn
R
2
1
c-Hex
S
SO2NH2


H
H
4-Cl-Bn
R
2
1
c-Hex
S
Gly


H
H
4-Cl-Bn
R
2
1
c-Hex
S
CH2C(O)N(Me)2


H
H
4-Cl-Bn
R
2
1
c-Hex
S
CH2SO2Me


H
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)C(Me)3


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[(R)—CH(Me)CH2OH]


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2OH


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH2)2—OH


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)—(CH2OH)2


H
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OMe


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OBn


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(—(CH2)4—)CH2OH


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH2)3O-(2,4-diMe—Ph)


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)CH2OAc


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C[—(CH2)2—]CH2OH


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)NH(Pr)


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)NHEt


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)NH(Bu)


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)(3-HO—Ph)


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)(4-HO—Ph)


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[2-(CH2OH)-1-(c-penten)-1-yl]


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[2-(CH2OH)-1-(c-hexen)-1-yl]


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[1-Nos-Pid-4-yl]


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[Pid-4-yl]


H
H
4-Cl-Bn
R
2
1
c-Pen
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
c-Hep
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
i-Pr
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
c-Hex-CH2
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
c-Pen
R
C(O)CH(Me)2


H
H
4-Cl-Bn
S
2
1
c-Hex
S
C(O)CH(Me)2


H
H
Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Br-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
4-Br-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-MeO-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
4-MeO-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


H
H
3,4-diCl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
4-F-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
4-F-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Me-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-HO-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
(c-Hex)-CH2
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
(indol-2-yl)-CH2
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
i-Bu
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
NH2C(O)CH2—
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
2,3-diF—Ph
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
2,4-diF—Ph
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
2,3-diF—Ph
R
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
2,4-diF—Ph
R
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)NH(CH2)4NH2


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)NH(CH2)3NH2


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)NH(CH2)2NH2


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)NH(CH2)2OH


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)NH(CH2)2OMe


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[(3S)-3-(OH)-Pyd-1-yl]


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[(2S)-2-(HOCH2)-Pyd-1-yl]


H
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)C(Me)CH2OH


H
H
4-Cl-Bn
R
2
1
2,3-diF—Ph
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
3,5-diMe—Ph
R,S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
2,3-diF-ph
R,S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-Me—Ph
R,S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-trans-Me-c-Hex
S
C(Q)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-cis-Me-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-t-Bu-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4,4-diF-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-F-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-trans-Et-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-cis-Et-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-oxo-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-OH-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
Spiro[2.5]octane
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-Pid-1-yl
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
4-Ph-c-Hex
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
Ph
R,S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
2-adamantyl
S
C(O)C(Me)2CH2OH


H
H
4-F-Bn
R
2
1
c-Hex
S
C(O)[(R)—CH(Me)CH2OH]


H
H
4-Cl-Bn
R
2
1
4-trans-Me-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


H
H
4-Cl-Bn
R
2
1
4-cis-Me-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


H
H
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[C(OH)(i-Pr)]


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[CH2C(Me)2—OH]


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)(—(CH2)2—)C(O)OH


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)(—(CH2)2—)C(O)OMe


H
H
4-Cl-Bn
R
2
1
Pid-4-yl
S
C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
1
c-Hex
S
2-(CH2OH)-1-(c-peten)1-yl


H
H
4-Cl-Bn
R
2
1
c-Hex
S
2-(CH2OH)-1-(c-hexen)1-yl


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)N[(CH)2OH]2


H
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)N[(CH)3OH]2


Me
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


Me
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
4-trans-Me-c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
4-cis-Me-c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
4-t-Bu-c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
4,4-diF-c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
Spiro[2.5]octane
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
4-F-c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
4-trans-Et-c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
4-cis-Et-c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
4-trans-Me-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


Me
H
4-Cl-Bn
R
2
1
4-cis-Me-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


Me
H
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


Me
H
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(—CH2CH2)CH2OH


Me
H
Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-F-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Me-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-MeO-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


i-Pr
H
4-Cl-Bn
R
2
1
4-trans-Me-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


i-Pr
H
4-Cl-Bn
R
2
1
4-cis-Me-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


i-Pr
H
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


i-Pen
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


Me
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


Me
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


Me
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


Me
Me
4-Cl-Bn
R
2
1
4-trans-Me-c-Hex
S
C(O)C(Me)2CH2OH


Me
Me
4-Cl-Bn
R
2
1
4-cis-Me-c-Hex
S
C(O)C(Me)2CH2OH


Me
Me
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(O)C(Me)2CH2OH


Me
Me
4-Cl-Bn
R
2
1
4-trans-Et-c-Hex
S
C(O)C(Me)2CH2OH


Me
Me
4-Cl-Bn
R
2
1
4-cis-Et-c-Hex
S
C(O)C(Me)2CH2OH


Me
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)(CH2—OH)2


Me
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH2—OMe)


Me
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH2—OMOM)


i-Pr
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[(R)—CH(Me)CH2OH]


Me
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[(R)—CH(Me)CH2OH]


Me
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[C(Me)(CH2—OH)2]


Me
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)(—CH2OC(O)OCH2—)


Me
Me
4-Cl-Bn
R
2
1
4-trans-Me-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


Me
Me
4-Cl-Bn
R
2
1
4-cis-Me-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


Me
Me
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(O)[C(Me)(CH2—OH)2]


Me
Me
Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH2—OH)


Me
Me
4-F-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH2—OH)


Me
Me
4-Me-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH2—OH)


Me
Me
4-MeO-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH2—OH)


Me
Me
4-MeO-Bn
R
2
1
4-t-Bu-c-Hex
S
C(O)C(Me)2(CH2—OH)


Et
Et
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


i-Pr
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH














—(CH2)5—
4-MeO-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH















MeO—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


HO(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


Ac
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


MeSO2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(iPr)C(O)
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


EtC(O)
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


Gly
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[(R)—CH(Me)CH2OH]


Gly
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


HO(CH2)3C(O)
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


(Me)2N-Gly
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


i-Bu
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH














—(CH2)4—
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


—(CH2)5—
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH















NH2—(CH2)4
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


HOCH2C(Me)2C(O)
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


imidazol-2-yl
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


imidazol-4-yl
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


HO(CH2)4
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


PrC(O)
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


Pyd-3-yl
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


(S)Pyd-2-CH2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


MeOC(O)CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


DTic
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


NH2—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


(Me)HN—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


(S)Pyd-2-CH2
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[2-(CH2OH)-1-(c-penten)-1-yl]


(Me)2NC(O)—CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


NH2C(O)—CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


MeO2C—CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


HO2C—CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


Gly
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


N—Me-Gly
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


N-diMe-Gly
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


N—Ac-Gly
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


N-Ms-Gly
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Ala
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


β-Ala
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


β-Ala
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


N—Me-β-Ala
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


N-diMe-β-Ala
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


NH2(CH2)4
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)Ala
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)His
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)His
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


N-Me-(S)His
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


N-Ac-(S)His
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


N-Ac-(S)His
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


N-Ms-(S)His
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)His
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)Phe
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Phe
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Pro
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Pro
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


N—Me-(R)Pro
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


(S)Pro
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Pid-2-CO
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Pid-2-CO
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


N—Me-(R)Pid-2-CO
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


N—Ac-(R)Pid-2-CO
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)Pid-2-CO
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Tic
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Tic
H
Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)Tic
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)CH(Me)2


cis-Dic
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 


HO—CH2—C(O)
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 


HO—C(O)CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


HO—C(O)CH2
HO—C(O)CH2
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


MeOC(O)CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
1
2,3-diF—Ph
R
C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
1
2,4-diF—Ph
R
C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
1
c-Pen
S
C(O)CH(Me)2


(R)Pyd-2-CH2
H
Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Pyd-2-CH2
H
(c-Hex)-CH2—
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Pyd-2-CH2
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)-1-Me-Pyd-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)-1-Me-Pyd-2-CH2
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)-1-Ac-Pyd-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)Pyd-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)-1-Me-Pyd-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)Pid-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)-1-Me-Pid-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(R)-1-Me-Pid-2-CH2
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)Pid-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(S)-1-Me-Pid-2-CH2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


NH2—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


NH2—(CH2)2
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(Me)N—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(Me)N—(CH2)2
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(Me)N—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)CH(Me)2


(Me)N—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
R
C(O)C(Me)3


(Me)2N—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(Me)2N—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)3


(Me)2N—(CH2)2
H
Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(Me)2N—(CH2)2
H
(c-Hex)-CH2—
R
2
1
c-Hex
S
C(O)CH(Me)2


(Me)2N—(CH2)2
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(Me)N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)CH2OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)(CH2—OH)2


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2[CH2—N(Me)2]


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2—OMe


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH2—OMOM)


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2—OBn


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2[CH2—O(i-Bu)]


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2—OPh


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2—SPh


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2—OCOPh


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2[CH2—OCO(c-Hex)]


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2—OCOBn


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2CH2—OCOBu


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2[CH2—OCO(i-Pr)]


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2[CH2—OCO(2,5diF—Ph)]


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2OAc


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[2-(HOCH2)-1-(c-penten)-1-yl]


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)[(3S)-3-(OH)-Pyd-1-yl]


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CHO)


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)C(Me)2(CH═N—OMe)


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
2,3-diF—Ph
S
C(O)C(Me)2(CH2—OH)


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
2,3-diF—Ph
S
C(O)N(Me)2


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
4-cis-Mec-Hex
S
C(O)C(Me)2CH2OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
1
4,4-diMe-c-Hex
S
C(O)C(Me)2CH2OH


AcNH—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(Et)2N—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


[Me(Et)]N—(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 


(R)Pyd-3-yl
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2






H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


 


Pid-4-yl
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


Pid-4-yl
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


1-Me-Pid-4-yl
Me
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


(Me)2N—CH═
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
1
c-Hex
S
C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)C(Me)3


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)OMe


H
H
4-Cl-Bn
R
2
2
c-Hex

CH2C(O)OMe


H
H
4-Cl-Bn
R
2
2
c-Hex

CH2C(O)N(Me)2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)2


H
H
4-Cl-Bn
R
2
2
c-Hex

Gly


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)NH(i-Pr)


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(i-Pr)


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)NH(Bu)


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(Bu)


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)NH(c-Hex)


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)NHPh


H
H
4-Cl-Bn
R
2
2
c-Hex

C(S)NH(Et)


H
H
4-Cl-Bn
R
2
2
c-Hex

C(S)N(Me)(Et)


H
H
4-Cl-Bn
R
2
2
c-Hex

SO2Me


H
H
4-Cl-Bn
R
2
2
c-Pen

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
c-Hep

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
2-MeO-Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
3-MeO-Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
2-Cl-Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
2-F-Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
3-F-Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
4-F-Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
2,4-diF—Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
2,5-diF—Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
2,6-diF—Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
3,4-diF—Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
2-F-4-MeO-Ph

C(O)CH(Me)2


H
H
4-Cl-Bn
S
2
2
c-Hex

C(O)CH(Me)2


H
H
4-Br-Bn
R
2
2
c-Hex

C(O)CH(Me)2


H
H
3,4-diCl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


H
H
4-F-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


H
H
4-HO-Bn
R
2
2
c-Hex

C(O)CH(Me)2


H
H
4-MeO-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


H
H
(c-Hex)-CH2
R
2
2
c-Hex

C(O)CH(Me)2


H
H
3,4-diCl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


H
H
4-F-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


H
H
4-HO-Bn
R
2
2
c-Hex

C(O)CH(Me)2


H
H
4-MeO-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


H
H
(c-Hex)-CH2
R
2
2
c-Hex

C(O)CH(Me)2


H
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)N(Me)(CH2)2OH


H
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)N(Me)(CH2)2OMe


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)CH2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[2-(CH2OH)-1-(c-penten)-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[2-(CH2OH)-1-(c-hexen)-1-yl]


H
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(n-Pr)(CH2)2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(c-Pr)(CH2)2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OMe


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)NH(CH2)2OMe


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OMe


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe]2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)OMe


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)[C(Me)2CH2NH2]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2F


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2F


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)3OH]2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)3OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)3OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F]2


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OMe


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OH


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3F


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(n-Pr)(CH2)2OH


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(c-Pr)(CH2)2OH


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OMe


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2F


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2F


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)3OH


H
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F]2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(3S)-3-(OH)-Pyd-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(3R)-3-(OH)-Pyd-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(2R)-2-(HOCH2)-Pyd-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(2S)-2-(HOCH2)-Pyd-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(3R)-3-amino-Pyd-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(3S)-3-amino-Pyd-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(3R)-3-(OH)-Pid-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(3S)-3-(OH)-Pid-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[4-(OH)-Pid-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[4-amino-Pid-1-yl]


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)(—(CH2)2—)C(O)OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)(—(CH2)2—)C(O)OMe


H
H
4-Cl-Bn
R
2
2
4-cis-Me-c-Hex

C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
2
4-trans-Me-c-Hex

C(O)C(Me)2CH2OH


H
H
4-Cl-Bn
R
2
2
4-diMe-c-Hex

C(O)(—(CH2)2—)C(O)OMe


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3F


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)2


H
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)[C(O)(Me)2CH2OH]


Me
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


Me
H
4-Cl-Bn
R
2
2
c-Hex

C(O)C(Me)3


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)2


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N(c-Pr)(CH2)2OH


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OH


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OMe


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OMe


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3F


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


Me
Me
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)3OH


Me
Me
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)2


Me
Me
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


Me
Me
4-F-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


Me
Me
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


Me
Me
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OMe


Me
Me
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


MeO2C—CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


HO2C—CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


N-diMe-Gly
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Ala
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


β-Ala
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


N-diMe-β-Ala
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(S)His
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Pro
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


N-Me-(R)Pro
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Tic
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


MeO2C—CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


HO2C—CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


N-diMe-Gly
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Ala
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


β-Ala
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


N-diMe-β-Ala
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(S)His
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Pro
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


N-Me-(R)Pro
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Tic
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)C(Me)3


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,4-diF—Ph

C(O)CH(Me)2


(S)Pyd-2-CH2
H
4-F-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


(2R,4S)-4F-Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


(S)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(S)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


(R)Pyd-2-CH2—
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)C(Me)2CH2OH


(R)Pyd-2-CH2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)C(Me)2CH2OH


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OH


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(n-Pr)(CH2)2OH


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)OMe


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)[C(Me)2CH2NH2]


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe]2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(c-Pr)(CH2)2OH


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(3S)-3-(OH)-Pyd-1-yl]


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(2R)-2-(HOCH2)-Pyd-1-yl]


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[4-(OH)-Pid-1-yl]


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(3R)-3-(OH)-Pid-1-yl]


(R)Pyd-2-CH2
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)2


(R)Pyd-2-CH2
H
4-F-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


(R)Pyd-2-CH2
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


(R)Pyd-2-CH2
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OMe


(R)Pyd-2-CH2
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


(R)Pyd-2-CH2
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


(R)Pyd-2-CH2
H
4-F-Bn
R
2
2
c-Hex

C(O)[(3S)-3-(OH)-Pyd-1-yl]


(R)Pyd-2-CH2
H
4-F-Bn
R
2
2
c-Hex

C(O)[(2R)-2-(HOCH2)-Pyd-1-yl]


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

N(Me)[C(Me)2CH2OH]


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)2


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(c-Pr)(CH2)2OH


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OH


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OMe


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OMe


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)3OH


1-Pyd-(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)2


1-Pyd-(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


1-Pyd-(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


1-Pyd-(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


1-Pyd-(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OMe


1-Pyd-(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3F


(R)-3-BnO-1-pyd-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3F


(S)-3-BnO-1-pyd-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


(i-Pr)(Me)N—(CH2)2
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3F


NH2—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


(Me)NH—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)C(Me)3


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,4-diF—Ph

C(O)CH(Me)2


(S)Pyd-2-CH2
H
4-F-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


(2R,4S)-4F-Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


(S)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(S)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)CH(Me)2


(S)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,4-diF—Ph

C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)N(Me)(CH2)2OH


(R)Pyd-2-CH2
H
4-Cl-Bn
R
2
2
2,3-diF—Ph

C(O)N(Me)(CH2)2OMe


(R)-1-Me-Pid-2-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(S)-1-Me-Pid-3-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)-1-Me-Pid-3-CH2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Pyd-3-yl
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(R)Pyd-3-yl
H
Bn
R
2
2
c-Hex

C(O)CH(Me)2


(S)Pyd-3-yl
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)2


(S)Pyd-3-yl
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OH


(S)Pyd-3-yl
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


2-oxo-1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


2-oxo-1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


3-OH-1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3F


3-OH-1-Pyd-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)2


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(c-Pr)(CH2)2OH


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OH


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OMe


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OMe


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)3OH


(i-Pr)HN—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)2


(i-Pr)HN—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


(i-Pr)HN—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


(i-Pr)HN—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


(i-Pr)HN—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OMe


(i-Pr)HN—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)2


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)2OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(c-Pr)(CH2)2OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(i-Pr)(CH2)2OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2OMe](CH2)2OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2OH]2


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2F](CH2)2OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Me)(CH2)2OMe


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2F](CH2)2OMe


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)3F


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)2F


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)3OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2OMe](CH2)3OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N(Et)2


(S)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N(Et)(CH2)2OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N(i-Pr)(CH2)2OH


(S)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N[(CH2)2OH]2


(S)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N[(CH2)2F](CH2)2OMe


(S)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N(Et)(CH2)3OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)2


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)2OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(c-Pr)(CH2)2OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(i-Pr)(CH2)2OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2OMe](CH2)2OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2OH]2


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2F](CH2)2OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Me)(CH2)2OMe


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2F](CH2)2OMe


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)3F


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)2F


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)3OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2OMe](CH2)3OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N(Et)2


(R)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N(Et)(CH2)2OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N(i-Pr)(CH2)2OH


(R)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N[(CH2)2OH]2


(R)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N[(CH2)2F](CH2)2OMe


(R)-3-OH-Pyd-1-(CH2)2
H
4-F-Bn
R
2
2
c-Hex

N(Et)(CH2)3OH


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)2


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)2OH


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N(c-Pr)(CH2)2OH


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N(i-Pr)(CH2)2OH


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2OMe](CH2)2OH


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2OH]2


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2F](CH2)2OH


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N(Me)(CH2)2OMe


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2F](CH2)2OMe


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)3F


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)2F


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)2OH


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N(Et)(CH2)3OH


2-oxo-1-pyd--(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

N[(CH2)2OMe](CH2)3OH


2-oxo-1-pyd--(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

N(Et)2


2-oxo-1-pyd--(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

N(Et)(CH2)2OH


2-oxo-1-pyd--(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

N(i-Pr)(CH2)2OH


2-oxo-1-pyd--(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

N[(CH2)2OH]2


2-oxo-1-pyd--(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

N[(CH2)2F](CH2)2OMe


2-oxo-1-pyd--(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

N(Et)(CH2)3OH


Mor-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(c-Pr)(CH2)2OH


Mor-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


Mor-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C O)N[(CH2)2OMe]2


Mor-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


Mor-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OH


Mor-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2OMe


Mor-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OMe


Mor-(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


Mor-(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2OH


Mor-(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


Mor-(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OH]2


NH2—(CH2)2
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)CH(Me)2


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)OMe


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2—OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(n-Pr)(CH2)2—OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2—OH]2


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2—OMe]2


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)[(2R)-2-(HOCH2)-Pyd-1-yl]


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)(4-amino-Pid-1-yl)


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2—OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Me)(CH2)2—OMe


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)2


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OH


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


(Me)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Me)OMe


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2—OH


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(n-Pr)(CH2)2—OH


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2—OH]2


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2—OMe]2


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OH


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


(Me)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


(Et)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


(Et)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2—OH


(Et)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(n-Pr)(CH2)2—OH


(Et)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2—OH]2


(Et)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2—OMe]2


(Et)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


(Et)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


(Et)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N[(CH2)2F](CH2)2OH


(Et)2N—(CH2)2—
H
4-Cl-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2F


(Et)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)3OH


(Et)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(Et)(CH2)2—OH


(Et)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(n-Pr)(CH2)2—OH


(Et)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2—OH]2


(Et)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2—OMe]2


(Et)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N(i-Pr)(CH2)2OH


(Et)2N—(CH2)2—
H
4-F-Bn
R
2
2
c-Hex

C(O)N[(CH2)2OMe](CH2)2OH


H
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


H
H
4-Cl-Bn
R
1
1
c-Hex

C(O)C(Me)3


H
H
4-Cl-Bn
R
1
1
c-Hex

C(O)OMe


H
H
4-Cl-Bn
R
1
1
c-Hex

C(O)N(Me)2


H
H
4-Cl-Bn
R
1
1
c-Hex

S(O)2Me


H
H
4-Cl-Bn
R
1
1
c-Pen

C(O)CH(Me)2


H
H
4-Cl-Bn
R
1
1
c-Hep

C(O)CH(Me)2


H
H
4-Cl-Bn
R
1
1
i-Pr

C(O)CH(Me)2


H
H
4-Cl-Bn
R
1
1
(c-Hex)Me

C(O)CH(Me)2


H
H
4-Cl-Bn
R
1
1
2-Me-(c-Hex)

C(O)CH(Me)2


H
H
4-Cl-Bn
R
1
1
i-Bu

C(O)CH(Me)2


MeO2C—CH2
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


HO2C—CH2
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


Gly
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


N-diMe-Gly
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(S)His
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


N-BOC-(S)His
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(R)Pro
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


N-Me-(R)Pro
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(S)Pro
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(R)Pid-2-CO
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


N—Me-(R)Pid-2-CO
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(R)Tic
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(R)Pyd-2-CH2
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


Pyd-1-(CH2)2
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(R)-1-Me-Pid-2-CH2
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(Me)2N—(CH2)2
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(R)-Pid-2-CH2
H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2


(Me)2N—(CH2)2
H
4-Cl-Bn
R
1
1
c-Hex

C(O)C(Me)3






H
4-Cl-Bn
R
1
1
c-Hex

C(O)CH(Me)2









The compounds 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-toluenesulfonic acid or naphthalenesulfonic acid, and the like; preferably, acid-addition salts formed by sulfuric acid, methansulfonic acid or hydrohalic acid, and the like. The compounds of formula 1 according to the present invention can be converted to its salts by customary method.
Also, the compounds according to the present invention can have asymmetric carbon center, and so can be present as R or S isomeric forms, racemates, diastereomeric mixtures, and individual diasteromers. The present invention encompasses all these isomeric forms and mixtures.
The compounds according to the present invention can be prepared according to the procedures explained in the following Schemes 1-9. In the following Schemes, compounds of general formula (3), (6), (11), (12), (13), (14), (17), (18), (22), (24), (40) and (43) represent representative compounds of formula 1.
Compounds of formula (3) can be prepared by coupling protected amino acids (1) (P represents protecting groups, such as BOC, Cbz, Fmoc, etc.) with substituted amino-cyclic amine derivatives (2) (cyclic amine represent pyrrolidine, piperidine, or azetidine) under standard peptide coupling conditions, as illustrated in Scheme 1. The protected amino acids (1), starting materials, are either commercially available or may be prepared by known methods (Williams, R. M., Synthesis of Optically Active a-Amino Acids, Pergamon Press: Oxford, 1989). Similarly, the amino-cyclic amine derivatives (2) can be prepared following literature methods described for analogous compounds.




Compounds of formula (6) may be prepared by coupling N-substituted amino acid derivatives (5) with amino-cyclic amine derivatives (2), as illustrated in Scheme 2. Alkyl, acyl, or sulfonyl substituted amino acid derivatives (5) can be converted to amino acid derivatives (6) by hydrolysis in the presence of base.




Compounds of formula (10), (11), (12), and (14) may be prepared by coupling protected amino acid derivatives (7), (8), (9), and (10) with the compounds of formula (3) as shown in Scheme 3 [Cy in compound (8) represents pyrrolidine, azetidine, aziridine, piperidine, etc.]. Protected amino acid derivatives (7), (8) and (9) are either commercially available or can be prepared by general protection reaction from various amino acids.




In the above Reaction Scheme 3, R6′ is same as defined above in R6, and R represents alkyl or protected aminoalkyl.
Alkylated amine compounds of formula (17) or (18) can be prepared through reductive amination of protected amino aldehydes of formula (15) with compounds of formula (3) prepared in Scheme 1, as shown in Scheme 4. As a reducing agent in the reductive amination, NaHB(OAc)3 or NaBH3CN may be used, and DCE, DMF, methanol, DCM, etc. may be used as a solvent, but the reaction reagents and solvents are not limited to these. The protected amino aldehydes (15) is either commercially available or can be prepared by known methods such as reduction of thioesters or oxidation of amino alcohols. Compounds of formula (16) are general alkyl aldehydes, amino aldehydes or hydroxy aldehydes whose amino or alcohol group is either substituted or protected. These compounds are either commercially available or can be prepared by protection reaction. Mono- or di-substituted compounds (18) can be prepared by reductive amination and deprotection.




Compounds of formula (22), (23) and (24) can be prepared as shown in the following Scheme 5. Nitrobenzenesulfonyl protected intermediates of formula (19) can be converted to the compounds of formula (21) by alkylation or reductive amination (Tetrahedron Lett., 1995, 36, 6373-6374). In compounds of formula (20) such as dimethylaminoethylchloride or N-BOC-2-aminoethyl-chloride, Q represents aminoalkyl or alkylated aminoalkyl, and X represents halogen. Compounds of formula (23) can be prepared through reductive amination of compounds of formula (21) and then converted into the compounds of formula (24) by alkylation.




3-Disubstituted amino pyrrolidine derivatives (30) can be prepared as illustrated in Scheme 6. Compound (26) prepared from the commercially available compound (25) can be converted to compounds of formula (28) by reductive amination. Compounds of formula (30) can be prepared by acylation, amide coupling, or alkylation of compounds formula (28), and removing cbz group. Compounds of formula (30) can also be prepared from compound (31) using the similar method illustrated in Scheme 7.




In the above reaction scheme, compound (29) represents alkylhalide, substituted alkylhalide, carboxylic acid, or acid chloride; and R6 is the same as defined above; and X represents OH, Br, Cl, etc.
4-Disubstituted piperidine derivatives (35) can be prepared as illustrated in Scheme 7. Compounds of formula (34) can be prepared by introducing various amine groups into compound (32) by reductive amination. Amino piperidine derivatives (35) can be prepared by acylation, amide coupling reaction, or akylation of compounds of formula (34), and deprotection.




Azetidine derivatives can be prepared by the method illustrated in Scheme 8. Coupling of protected amino acid derivatives (1) with 3-azetidinol gives compounds of formula (37) which can then be converted into carbonyl compounds of formula (38). Compounds of formula (40) can be prepared from compounds of formula (38) via reductive amination, acylation, amide coupling, and alkylation.




Urea derivatives can be prepared by the method illustrated in Scheme 9. Coupling of protected amino acid derivatives (1) with cyclic amine derivatives (41) produces compounds of formula (42). Compounds of formula (42) can be converted to urea derivatives (43) by phosgene-mediated amide coupling.




In the above reaction scheme, NRR′ represents substituted or unsubstituted amino group among the definition of R7, R8, or R9.
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—Cl), diphenylphosphorylazide (DPPA), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium 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, 300×50 mm I.D., C18 5 μm, 100 A). 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 NaCl 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
    Bn benzyl
    Bu butyl
    CBZ(Cbz) benzyloxycarbonyl
    BOC(Boc) tert-butoxycarbonyl
    Fmoc 9-fluorenylmethoxycarbonyl
    c-Hep cycloheptyl
    c-Hex cyclohexyl
    c-Pr: cyclopropyl
    c-Pen cyclopentyl
    DAST Diethylaminosulfur trifluoride
    DCC dicyclohexylcarbodiimide
    DCE dichloroethane
    DCM dichloromethane
    DEAD diethylazodicarboxylate
    Dic decahydroisoquioline-3-carboxylic acid
    DIPEA diisopropylethylamine
    DMAP 4-dimethylaminopyridine
    DMF N,N-dinethylformamide
    DMSO Dimethylsulfoxide
    DTic (D)-1,2,3,4-tetrahydriosoquinoline-3-carboxylic
    EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl
    Gly Glycine
    Hex hexane
    HOBt 1-hydroxybenzotriazole
    HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium
    hexafluorophosphate
    i-Bu isobutyl
    i-Pr isopropyl
    Mor Morpholine
    MOM Methoxymethyl
    Nos 2-Nitrobenzene sulfonyl
    Ph phenyl
    Phe phenylalanine
    Pid piperidine
    Pro proline
    Pyd pyrrolidine
    TEA triethylamine
    TFA trifluoroacetic acid
    TH:F Tetrahydrofuran
    Tic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid


The following Intermediates further illustrate preparation of intermediates needed for synthesis of the compounds according to the present invention.
Intermediate 1: (3S)-1-Cbz-3-aminopyrrolidine
Step A: (3S)-1-Cbz-3-(N-BOC-amino)pyrrolidine
To a solution of (3S)-1-Cbz-3-(N-BOC-amino)pyrrolidine (5.00 g, 26.9 mmol) and TEA (7.54 mL, 53.8 mmol) in DCM (6 mL) was added CbzCl (5.50 g, 29.6 mmol) at rt. After 4 h, a saturated aqueous NH4Cl solution was added and the reaction mixture was extracted with DCM followed by EtOAc. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc/Hex=1/2) to give the title compound (9.06 g, 96.1%).
MS [M+H]=321 (M+1)
Step B: (3S)-1-Cbz-3-amino-pyrrolidine
The product of Step A, (3S)-1-Cbz-3-(N-BOC-amino)pyrrolidine, (5.26 g, 16.4 mmol) was dissolved in EtOAc (50 mL) and treated with a saturated HCl in EtOAc (15 mL). After the reaction mixture was stirred at rt for 30 min., the volatiles were removed to provide the title compound (4.11 g, 98.1%) as a colorless solid. The crude product was used without further purification.
MS [M+1]=221 (M+1)
Intermediate 2: (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine
To a solution of (3S)-1-Cbz-3-aminopyrrolidine (4.11 g, 16.0 mmol) and cyclohexanone (2.36 g, 24.0 mmol) in DCE (50 mL) was slowly added NaBH(OAc)3 (6.78 g, 32.0 mmol) at rt. The reaction mixture was quenched after 4 h using a saturated aqueous NaHCO3 solution and extracted with DCM followed by EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc/Hex=2/1) to give the title compound (4.79 g, 98.1%).
MS [M+1]=303 (M+1)
Intermediate 3: 4,4-Dimethyl-cyclohexan-1-one
4,4-Dimethyl-cyclohexene-1-one (5 g, 52 mmol) and n-pentane (50 mL) were placed in a hydrogen reaction vessel and Pd/C (300 mg) was added. The hydrogen reaction vessel was purged three times with hydrogen and subsequently pressurized with hydrogen (25 psi). After shaking in a Parr hydrogenator for 30 min., the reaction mixture was filtered though Celite and the filtrate concentrated in vacuo to give the title compound.
MS[M+H]=127 (M+1)
Intermediate 4: 1-BOC-4-piperidone
To a solution of 4-piperidone (10 g, 100 mmol) and TEA (28.0 mL, 20 mmol) in DCM (2.00 l) was added di-t-butyldicarbonate (30 g, 150 mmol) at rt. After 4 h, the reaction mixture was concentrated in vacuo and the residue was diluted with 1N HCl (500 mL). The reaction mixture was extracted with EtOAc, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/15) to give the title compound (19.1 g, 96.5%).
MS[M+H]=200 (M+1)
Intermediate 5: Spiro[2,5]octanone
Step A: 4,4-Methylene-1,1-ethyleneketal-4-spiro[2,5]octane
To a solution of DMSO (80 mL), filled with nitrogen, was added NaH (2.3 g, 58 mmol), and the reaction mixture was heated at 50-60° C. When the reaction solution turned light green, MeP (Ph)3Br (21.2 g, 60 mmol) was added, and the reaction solution was cooled to rt and stirred for 1 h. Cyclohexanedione monoethyleneketal (5.64 g, 36 mmol) was slowly added, and then the reaction mixture was heated to 40° C. and stirred for additional 2 h. The reaction solution was cooled to rt and a solution of diethyl ether/ice-water was added. The organic solution extracted with Et2O was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/5) to give the title compound (4.51 g, 82%).
MS[M+H]=155 (M+1)
Step B: spiro[2,5]octanone
To a solution of 4,4-methylene-1,1-ethyleneketal-4-spiro[2,5]octane (4.5 g, 30 mmol), prepared by Step A, in Et2O was added CH2I2 (12.0 mL, 150 mmol) and Zn—Cu (12.3 g, 48 mmol). The mixture was stirred at rt for 12 h, filtered, and diluted with 1N HCl solution. The organic material was extracted with diethyl ether, dried over MgSO4 and then concentrated in vacuo to give the title compound. The crude product was used without further purification.
Intermediates 6 ̃35
The compounds below were prepared following the procedure described in Intermediate 2 using commercially available amines, carbonyl compounds, amine compound prepared in Intermediate 1, and carbonyl compounds prepared in Intermediates 4, and 5.
















 












Intermediate
P
n
R4
*
MS (M + 1)















6
BOC
1
c-Hex
S
303


7
Cbz
1
c-Hex
R
303


8
Cbz
1
c-Pen
S
289


9
Cbz
1
c-Hep
S
317


10
Cbz
1
i-Pr
S
263


11
Cbz
1
(c-Hex)-CH2—
S
317


12
Cbz
1
Ph
R,S
297


13
Cbz
1
4-Me—Ph
R,S
311


14
Cbz
1
3,5-diMe—Ph
R,S
325


15
Cbz
1
2-Adamantyl
S
355


16
Cbz
1
4-cis-Me-(c-Hex)
S
317


17
Cbz
1
4-trans-Me-(c-Hex)
S
317


18
Cbz
1
4,4-di-Me-(c-Hex)
S
331


19
Cbz
1
4-t-Bu-(c-Hex)
S
359


20
Cbz
1
4-cis-Et-(c-Hex)
S
331


21
Cbz
1
4-trans-Et-(c-Hex)
S
331


22
Cbz
1
N—BOC-Pip-4-yl
S
404


23
Cbz
1
4,4-ethyleneketal-(c-Hex)
S
361


24
Cbz
1
Spiro[2,5]octan-1-yl
S
329


25
Cbz
1
4-Ph-c-Hex
S
379


26
BOC
2
c-Hex

283


27
BOC
2
c-Pen

269


28
BOC
2
c-Hep

297


29
BOC
2
i-Pr

243


30
BOC
2
(c-Hex)-CH2—

297


31
BOC
2
i-Bu

257


32
BOC
2
2-Me-c-Hex

297


33
BOC
2
4,4-diMe-c-Hex

311


34
BOC
2
4-trans-Me-c-Hex

297


35
BOC
2
4-cis-Me-c-Hex

297









Intermediate 36: (3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine
Step A: (3S)-1-Cbz-3-[cyclohexyl(isobutyryl)amino]pyrrolidine
To a solution of (3S)-1-Cbz-3-(cyclohexylamino)pyrolidine (4.75 g, 15.1 mmol) and TEA (4.26 mL, 30.2 mmol) in DCM (50 mL) was added dropwise isobutyryl chloride (1.15 mL, 60.3 mmol). The reaction mixture was stirred at rt for 12 h and quenched with 1N HCl solution. The organic material was extracted with DCM (50 mL×2) followed by EtOAc (50 mL×2), and the extracts were washed with a saline, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/3) to give the title compound (5.40 g, 96.7%).
MS[M+H]=372 (M+1)
Step B; (3)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine
To a solution of (3S)-1-cbz-3-[cyclohexyl(isobutyryl)amino]pyrrolidine (5.00 g, 13.4 mmol), prepared in Step A, in Dioxane (40 mL) was added dropwise Pd/C (250 mg) at rt. After 12 h, the reaction mixture was filtered though Celite and the filtrate concentrated in vacuo to give the title compound as an oil (3.14 g, 98.5%).
MS[M+H]=239 (M+1)
Intermediates 37-61
The compounds below were prepared following the procedure described in Intermediate 36 or a step B of Intermediate 1 using acylchlorides or carbonyl compounds.
















 












Intermediates
*
n
R4
R5
MS (M + 1)





37
S
1
C(O)C(Me)3
c-Hex
253


38
S
1
C(O)Me
c-Hex
227


39
S
1
S(O)2Me
c-Hex
247


40
S
1
C(O)N(Me)2
c-Hex
240


41
S
1
C(O)CH(Me)2
c-Pen
225


42
S
1
C(O)CH(Me)2
c-Hep
253


43
S
1
C(O)CH(Me)2
i-Pr
199


44
S
1
C(O)CH(Me)2
(c-Hex)-CH2—
253


45
R
1
C(O)CH(Me)2
c-Hex
238


46
R
1
C(O)C(Me)3
c-Hex
253


47
R
1
C(O)N(Me)2
c-Hex
240


48
R
1
C(O)CH(Me)2
c-Pen
225


49

2
C(O)CH(Me)2
c-Hex
253


50

2
C(O)C(Me)3
c-Hex
267


51

2
C(O)OMe
c-Hex
241


52

2
S(O)2Me
c-Hex
261


53

2
C(O)N(Me)2
c-Hex
254


54

2
Et
c-Hex
210


55

2
i-Bu
c-Hex
238


56

2
C(O)CH(Me)2
c-Pen
239


57

2
C(O)CH(Me)2
c-Hep
267


58

2
C(O)CH(Me)2
i-Pr
212


59

2
C(O)CH(Me)2
(c-Hex)-CH2—
267


60

2
C(O)CH(Me)2
i-Bu
226


61

2
C(O)N(Me)2
2-Me-c-Hex
267









Intermediate 62: (3S)-1-benzyl-3-[(2,4-difluorophenyl)amino]pyrrolidine
To a solution of (3S)-1-benzyl-3-aminopyrrolidine (0.20 g, 1.1 mmol), tris-(2,4-difluorophenyl)bismuth (0.64 g, 1.2 mmol), and TEA (0.280 mL, 2 mmol) in DCM (5 mL) was added Cu(OAc)2 (0.21 g, 1.2 mmol). After being stirred at rt for 24 h, the reaction solution was concentrated in vacuo, and the residue was purified by column chomatography (MeOH/CHCl3=1/25) to give the title compound (150 mg, 46.0%).
MS[M+H]=289 (M+1)
Intermediate 63: (3S)-1-benzyl-3-[isobutyryl(2,4-difluorophenyl)amino]pyrrolidine
To a solution of (3S)-1-benzyl-3-[(2,4-difluorophenyl)amino]pyrrolidine (150 mg, 0.52 mmol) and DMAP (6 mg, 0.05 mmol) in pyridine (7 mL) was added isobutyryl chloride (0.16 mL, 1.5 mmol) at 0° C. After being stirred at 60° C. for 18 h, the reaction mixture was quenched with an aqueous NaH(CO)3 solution and extracted with EtOAc. The extracts were concentrated in vacuo, the reside was purified by column chomatography (MeOH/CHCl3=1/25) to give the title compound (160 mg, 86.0%).
MS[M+H]=359 (M+1)
Intermediate 64: (3S)-3-[(isobutyryl(2,4-difluorophenyl)amino)pyrrolidine
To a solution of (3S)-1-benzyl-3-[isobutyryl(2,4-difluorophenyl)amino]pyrrolidine in 1N HCl and an aqueous EtOH solution was added Pd/C, and the reaction mixture was stirred at rt for 3 days under hydrogen. The reaction mixture was filtered though Celite, and the filtrate concentrated in vacuo. The crude product was recrystalized from EtOAc to give the title compound (99 mg, 73%) as a colorless prism.
MS[M+H]=269 (M+1)
Intermediate 65: (3S)-3-[(isobutyryl(2,5-difluorophenyl)amino)pyrrolidine
The title compound was prepared following the procedure described in Intermediates 63 and 64 using (3S)-1-benzyl-3-[(2,5-difluorophenyl)amino]pyrrolidine.
MS[M+H]=269 (M+1)
Intermediate 66: (3S)-3-[(isobutyryl(3,4-difluorophenyl)amino)pyrrolidine
The title compound was prepared following the procedure described in Intermediates 63 and 64 using (3S)-1-benzyl-3-[(3,4-difluorophenyl)amino]pyrrolidine.
MS[M+H]=269 (M+1)
Intermediate 67: 1-hydroxymethyl-1-cyclopentanecarboxylic acid
Cyclopentanecarboxylic acid (1.10 g, 10.0 mmol) was placed in a round-bottomed bottomed flask, filled with nitrogen, and 30 mL of THF (30 mL) was added. The solution was cooled to −78° C., and LDA (8.8 mL, 2.5 m in hexane) was added dropwise. After being stirred for 30 min., the solution was bubbled by nitrogen stream containing formaldehyde gas (formaldehyde gas was in situ generated by thermal degradation of anhydrouse paraformaldehyde at 160° C.). When the reaction solution turned light yellow, the reaction mixture was quenched with a saturated aqueous NH4Cl solution at −78° C., and the organic material was extracted with EtOAc. The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound.
MS[M+H]=145 (M+1)
Intermediate 68: 2,2-dimethyl-3-methoxypropionic acid
Step A: 2,2-dimethyl-3-methoxypropionic acid ethyl ester
To a solution of 2,2-dimethyl-3-hydroxypropionic acid ethyl ester (1.3 g, 10.0 mmol) in CH3CN (30 mL) was added Ag2O (11.5 g, 50.0 mmol) and methyl iodide (0.56 mL, 11 mmol). The reaction mixture was stirred at rt for 12 h and quenched with a saturated aqueous NH4Cl. The mixture was filtered though Celite, the filtrate concentrated in vacuo, and the residue was purified by column chromatography (EtOAc/Hex=1/10) to give the title compound (1.34 g, 91.2%).
MS[M+H]=147 (M+1)
Step B: 2,2-dimethyl-3-methoxypropionic acid
To a solution of 2,2-dimethyl-3-methoxypropionic acid ethyl ester (1.17 g, 8.00 mmol) in an aqueous MeOH solution (MeOH/H2O=1/1, 24 mL) was added LiOH (560 mg, 16.0 mmol) at rt. After the rection mixture was stirred for 30 min., the solvent was removed in vacuo, and the residue was diluted with 1N HCl and EtOAc. The organic layer extracted with EtOAc, and the organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was used without further purification.
MS[M+H]=133 (M+1)
Intermediate 69: 2,2-dimethyl-3-benzyloxypropionic acid
The title compound was prepared following the procedure described in Intermediate 68 using 2,2-dimethyl-3-hydroxypropionic acid ethyl ester and benzyl chloride.
MS[M+H]=209 (M+1)
Intermediate 70: 1-BOC-piperidine-4-carboxylic acid
To a solution of piperidine-4-carboxylic acid (1.29 g, 10.0 mmol) in water was added NaOH (800 mg, 20.0 mmol). When the reaction solution was clear, (BOC)2O (2.5 g, 11.0 mmol) was added, and the reaction mixture was stirred at rt for 12 h. The solvent was removed in vacuo, and the residue was diluted with 1N HCl and EtOAc. The organic layer was extracted with EtOAc, and the organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The product was used without further purification.
MS[M+]=230 (+1)
Intermediate 71: (2R)-2-methyl-3-acetyloxypropionic acid
To a solution of (2R)-2-methyl-3-hydroxypropionic acid (10.0 g, 100 mmol) in pyridine (30 mL) as added acetyl chloride(11.8 g, 15.0 mmol) at 0° C., and the reaction mixture was warmed to rt. After being stirried for 3 h, the reaction mixture was quenched with 1N HCl (30 mL), and the pH of the solution was adjusted to 3-4. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl at 4-5 times, dried over MgSO4, filtered, and concentrated to give the title compound (11.4 g, 95.0%).
MS[M+H]=147 (M+1)
Intermediates 72-80
The compounds below were prepared following the procedure described in Intermediate 71 using various hydroxy carboxylic acid compounds.
















 











Intermediate
R
R′
R′′
MS (M + 1)





72
Me
Me
OAc
147


73
Me
Me
CH2OAc
161


74
Me
Me
(CH2)2OAc
175


75
Me
Me
(CH2)3OAc
189


76
Me
CH2—OAc
CH2OAc
218










77
—(CH2)3—
CH2OAc
187


78
—(CH2)2—
CH2OAc
159









79
2-(AcOCH2)-1-cyclopenten-1-yl
185


80
2-(AcOCH2)-1-cyclohexen-1-yl
199









Intermediate 81: (3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine
Step A: 2,2-dimethyl-3-acetyloxypropionyl chloride
Intermediate 73, 2,2-dimethyl-3-acetyloxypropionic acid (11.76 g, 80 mmol) was dissolved in benzene (100 mL), and the reaction solution was cooled to 0° C. Oxalyl chloride (15.0 g, 120 mmol) was added dropwise. After being stirred for 3 h, the solvent was removed in vacuo, and the residue was distilled in vacuo to give the title compound.
MS[M+H]=179 (M+1)
Step B: (3S)-1-Cbz-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine
To the mixture of (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine (3.0 g, 10 mmol), TEA (15 mL), and DMAP (1.25 g, 10 mmol) in THF (15 mL) was added 2,2-dimethyl-3-acetyloxypropionyl chloride (3.58 g, 20 mmol) prepared in Step A. After the reaction mixture was refluxed for 48 h (90-110° C.), the solvent was removed, and the residue was diluted with an aqueous NaHCO3 solution was added to the residue. The organic material was extracted with EtOAc, and the extracts were washed by 1N HCl, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (2.80 g, 62.9%).
MS[M+H]=445 (M+1)
Step C: (3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine
To a solution of (3S)-1-Cbz-3-[cyclohexyl (acetyloxypivaloyl)amino]pyrrolidine (1.00 g, 2.25 mmol), prepared in Step B, in dioxane (10 mL) was added portionwise Pd/C (200 mg), and the mixture was stirred for 12 h under hydrogen. The reaction solution was filtered though Celite and the filtratae concentrated to give the title compound (657 mg, 84%).
MS[M+H]=311 (M+1)
Intermediates 82-125
The compounds below were prepared following the procedure described in Intermediate 81 or Step B of Intermediate 1 using commercially available carboxylic acid or carboxylic acid prepared in Intermediates 67-80, and amine compounds prepared in Intermediates 2, 6 and 6 ̃35.
















 














Intermediate
n
*
R
R′
R′′
R4
MS (M + 1)

















82
1
S
H
OH
i-Pr
c-Hex
311


83
1
S
H
H
C(Me)2OH
c-Hex
269


84
1
S
H
Me
CH2—OAc
c-Hex
297


85
1
S
Me
Me
OAc
c-Hex
297


86
1
S
Me
Me
(CH2)2—OAc
c-Hex
325


87
1
S
Me
Me
(CH2)3—OAc
c-Hex
339


88
1
S
Me
Me
CH2—OAc
4-cis-Me-c-Hex
325


89
1
S
Me
Me
CH2—OAc
4-trans-Me-(c-Hex)
325


90
1
S
Me
Me
CH2—OAc
4,4-di-Me-(c-Hex)
339


91
1
S
Me
Me
CH2—OAc
4-t-Bu-(c-Hex)
367


92
1
S
Me
Me
CH2—OAc
4-cis-Et-(c-Hex)
339


93
1
S
Me
Me
CH2—OAc
4-trans-Et-(c-Hex)
339


94
1
S
Me
Me
CH2—OAc
Spiro[2.5]octan-1-yl
337


95
1
S
Me
Me
CH2—OAc
4-Ph-c-Hex
387


96
1
S
Me
Me
CH2—OAc




369


 


97
1
S
Me
CH2—OAc
CH2—OAc
4-cis-Me-(c-Hex)
383


98
1
S
Me
CH2—OAc
CH2—OAc
4-trans-Me-(c-Hex)
383


99
1
S
Me
CH2—OAc
CH2—OAc
4,4-di-Me-(c-Hex)
397


100
1
S
Me
CH2—OAc
CH2—OAc
c-Hex
369


101
1
S
Me
Me
CH2—OMe
c-Hex
283


102

S
Me
Me
CH2—OBn
c-Hex
359


103
1
S
Me
Me
(CH2)3—O-(2,4-diMe)Ph
c-Hex
401













104
1
S
—(CH2)4—
CH2—OAc
c-Hex
337


105
1
S
—(CH2)2—
CH2—OAc
c-Hex
309


106
1
S
—(CH2)2—
CO2Et
c-Hex
309













107
1
S
H
1-BOC-Pid-4-yl
c-Hex
380


108
1
S
H
1-(Nos)-Pid-4-yl
c-Hex
465












109
1
S
3-OH—Ph
c-Hex
289


110
1
S
2-(AcOCH2)-1-cyclopenten-1-yl
c-Hex
335


111
1
S
2-(AcOCH2)-1-cyclohexen-1-yl
c-Hex
349














112
1
R
Me
Me
CH2—OAc
c-Hex
311


113
1
R,S
Me
Me
CH2—OAc
c-Hex
311


114
1
S
Me
Me
CH2—OAc
2,3-diF—Ph
341


115
1
R,S
Me
Me
CH2—OAc
2,3-diF—Ph
341


116
1
R,S
Me
Me
CH2—OAc
3,5-diMe-ph
333


117
1
R,S
Me
Me
CH2—OAc
4-Me—Ph
319


118
1
R,S
Me
Me
CH2—OAc
Ph
305


119
1
S
Me
Me
CH2—OAc
2-Adamantyl
363


120
2
S
Me
CH2—OAc
CH2—OAc
4-cis-Me-(c-Hex)
397


121
2
S
Me
CH2—OAc
CH2—OAc
4-trans-Me-(c-Hex)
397


122
2
S
Me
CH2—OAc
CH2—OAc
4,4-di-Me-(c-Hex)
411


123
2
S
Me
Me
CH2—OAc
c-Hex
325












124
2
S
2-(AcOCH2)-1-cyclopenten-1-yl
c-Hex
349


125
2
S
2-(AcOCH2)-1-cyclohexen-1-y1
c-Hex
363









Intermediate 126: (3S)-3-[acetyloxypivaloyl(4,4-diF-cyclohexyl)amino]pyrrolidine
Step A: (3S)-1-cbz-3-[acetyloxypivaloyl (4-oxo-cyclohexyl)amino]pyrrolidine
Intermediate 96, (3S)-1-cbz-3-[acetyloxypivaloyl(4,4-ethyleneketal-cyclohexyl)amino]pyrrolidine (1.86 g, 5.16 mmol) was dissolved in THF (5 mL), and 3N HCl (5 mL) was added. The reaction solution was stirred at 50° C. for 12 h and neutralized by addition of a saturated aqueous 1N NaOH solution. The organic material was extracted with EtOAc and the extracts were dried over MgSO4, concentrated in vacuo, and purified by column chomatography (EtOAc/Hex=1/1) to give the title compound (1.40 g, 85.7%).
MS[M+H]=459 (M+1)
Step B: (3)-1-cbz-3-[acetyloxypivaloyl(4,4-difluoro-cyclohexyl)amino]pyrrolidine
The product of Step A, (3S)-1-cbz-3-[acetyloxypivaloyl(4-oxo-cyclohexyl)amino]pyrrolidine (1.40 g, 4.42 mmol) was dissolved in DCM (15 mL), and DAST (1.42 g, 8.84 mmol) was added at −78° C., and the reaction mixture was warmed to rt. After being stirred for 24 h, the reaction mixture was quenched with a saturated aquenous NaHCO3 solution w and extracted with DCM. The extracts were dried over MgSO4 and concentrated in vacuo, and the residue purified by column chomatography (EtOAc/Hex=2/1) to give the title compound (500 mg, 33.5%).
MS[M+H]=481 (N+1)
Step C: 3-[acetyloxypivaloyl(4,4-diF-cyclohexyl)amino]pyrrolidine
The title compound was prepared following the procedure described in Intermediate 64 using the product of Step B, (3S)-1-cbz-3-[acetyloxypivaloyl (4,4-diF-cyclohexyl)amino]pyrrolidine.
MS[M+1]=347 (M+1)
Intermediate 127: (3S)-3-[acetyloxypivaloyl(4-F-cyclohexyl)amino]pyrrolidine
Step A: (3S)-1-cbz-3-[acetyloxypivaloyl(4-hydroxycyclohexyl)amino]pyrrolidine
The product of Step A of Intermediate 126, (3S)-1-cbz-3-[acetyloxypivaloyl (4-oxo-cyclohexyl)amino]pyrrolidine (1.60 g, 3.49 mmol) was dissolved in THF (15 mL), and NaBH4 (172 mg, 4.19 mmol) was added at rt. After being stirred for 12 h, the reaction mixture was quenched with water, and the organic material was extracted with EtOAc. The extracts were dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/1) to give the title compound (1.481 mg, 92.1%).
MS[M+H]=461 (M+1)
Step B: (3S)-1-cbz-3-[acetyloxypivaloyl(4-fluorocyclohexyl)amino]pyrrolidine
The title compound was prepared following the procedure described in Step B of Intermediate 126 using the product of Step A, (3S)-1-cbz-3-[acetyloxypivaloyl(4-hydroxy-cyclohexyl)amino]pyrrolidine.
MS[M+H]=463 (+1)
Step C: (3S)-3-[acetyloxypivaloyl(4-fluorocyclohexyl)amino]pyrrolidine
The title compound was prepared following the procedure described in Intermediate 64 using the product of Step B, (3S)-1-cbz-3-[acetyloxypivaloyl(4-fluoro-cyclohexyl)amino]pyrrolidine.
MS[M+1]=329 (M+1)
Intermediate 128: methyl 2-[(3S)-3-pyrrolidinyl(cyclohexyl)amino]acetate
Step A: methyl 2-[(3S)-1-Cbz-3-pyrolidinyl(cyclohexyl)amino]acetate
NaH (60% in mineral oil, 52.0 mg, 1.30 mmol) was placed in a round-bottom flask, filled with nitrogen, and then THF (10 mL) was added. A solution of (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine (302 mg, 1.00 mmol) prepared in Intermediate 2 in THF was added dropwise at 0° C., and the reaction mixture was stirred for 30 min until no further gas evolution occurred, followed by slow addition of methyl bromoacetate. After 4 h, the reaction, mixture was quenched with water and extracted with EtOAc. The extracts were dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (227 mg, 90.0%).
MS[M+H]=375 (M+1)
Step B: methyl 2-[(3S)-3-pyrrolidinyl(cyclohexyl)amino]acetate
The title compound was prepared following the procedure described in Step B of Intermediate 3 using the product of Step A, methyl 2-[(3S)-1-Cbz-pyrrolidin-3-yl (cyclohexyl) amino]acetate.
MS[M+H]=241 (M+1)
Intermediate 129: (3S)-3-{cyclohexyl[(N-BOC)aminoacetyl]amino}pyrrolidine
Step A: A: (3S)-1-Cbz-3-{cyclohexyl[(N-BOC)aminoacetyl]amino}pyrrolidine
To a solution of (3S)-1-Cbz-3-{cyclohexylamino}pyrrolidine (3.0 g, 10.0 mmol), prepared in Intermediate 2, in DMF (30 mL) were added DIPEA (3.50 mL, 20.0 mmol), HBTU (4.88 g, 13 mmol), BOC-Gly (1.92 g, 11 mmol). After the mixture was stirred at rt for 4 h, the solvent was removed in vacuo, and the residue was diluted with an aqueous NaHCO3. The organic material was extracted with EtOAc, and the organic extracts were washed with 1N HCl, dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/3) to give the title compound (4.63 g, 92.0%).
MS[M+H]=474 (M+1)
Step B: (3S)-3-{cyclohexyl[(N-BOC)aminoacetyl]amino}pyrrolidine
The title compound was prepared following the procedure described in Step B of Intermediate 3 using the product of Step A, (3S)-1-Cbz-3-{cyclohexyl[(N-BOC)aminoacetyl]amino}pyrrolidine.
MS[M+H]=340 (M+1)
Intermediates 130 ̃134
The compounds below were prepared following the procedure described in Intermediate 36 or 129 using commercially available carboxylic acid and amine compounds prepared in Intermediates 6 ̃35.
















 









Intermediate
R
MS (M + 1)





130
CH2NH(BOC)
354


131
CH2CH2NH(BOC)
368


132
CH2C(O)OMe
297


133
CH2OH
255


134
(CH2)2—OC(O)—CF3
365









Intermediate 135: (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine
Step A: (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine methyl ester
To a solution of (2R)-4-chlorophenylalanine methylester (213 mg, 1.00 mmol) in DCM (5 mL) was added dropwise TEA (280 μl, 2.00 mmol) and then methanesulfonylchloride (100 μl, 1.3 mmol) at 0° C. After 30 min, the reaction mixture was quenched with water and extracted with DCM and EtOAc. The organic solution was washed with 1N HCl, dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (MeOH/CHCl3=1/25) to give the title compound (280 mg, 96.1%).
MS[M+H]=292 (M+1)
Step B: (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine
To a solution of (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine methylester, prepared in Step A, in water/methanol (5 mL, 1/1) was added portionwise LiOH (70.0 mg, 2.00 mmol). After being stirred at rt for 3 h, the reaction mixture was concentrated, and the residue was diluted with 1N HCl solution. The organic material was extracted with EtOAc, the extracts were concentrated in vacuo to give the title compound (179 mg, 94.3%).
MS[M+H]=277 (M+1)
Intermediate 136: (2R)-N-acetyl-(4-chlorobenzyl)alanine
The title compound was prepared following the procedure described in Intermediate 135 using anhydrous (2R)-4-chlorophenylalanine methylester.
MS[M+H]=278 (M+1)
Intermediate 137: (2R)-N-[(N,N-dimethyl)carbamoyl]-(4-chlorobenzyl)alanine
The title compound was prepared following the procedure described in Intermediate 135 using (2R)-4-chlorophenylalanine methylester and chlorodimethyl carbamate.
MS[M+H]=278 (M+1)
Intermediate 138: (2R)-N-BOC-prolinal
Step A: (2R)-N-BOC-proline ethylthioester
To a solution of DCC (2.55 g, 12.4 mmol), DMAP (100 mg), and EtSH (0.71 g, 11.1 mmol) in DCM was added dropwise a solution of (2R)-N-BOC-proline (3.00 g, 9.52 mmol) in DCM (30 mL). The reaction mixture was stirred at rt for 30 min, and filtered though Celite. The filtrate was dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (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-prolinal
To a solution of (2R)-N-BOC-proline ethylthioester, prepared in Step A, in acetone were added dropwise triethylsilane (5.39 g, 46.3 mmol) and Pd/C (100 mg) at 0° C. When no further gas evolution occurred, the reaction mixture was warmed to rt and then stirred for additional 30 min. The reaction solution was filtered though Celite, the filtrate concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (1.43 g, 93.2%).
MS[M+H]=200 (M+1)
Intermediate 138: (2R)-N-methylprolinal
Step A: (2R)-N-methylproline methyl ester
(2R)-proline methylester (1.20 g, 10.0 mmol) was dissolve in DMF (30 mL), and formalin (37% in water, 1.12 mL, 15.0 mmol) and NaBH (OAc)3 (4.20 g, 20.0 mmol) were added portionwise. After 12 h, the reaction material was concentrated in vacuo, and the residue was diluted with NaHCO3 (30 mL). The organic material was extracted with EtOAc, and the organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=4/1) to give the title compound (1.33 g, 93.0%).
MS[M+H]=144 (M+1)
Step B: (2R)-N-methylprolinal
The title compound was prepared following the procedure described in Step of Intermediate 135 using methyl (2R)-N-methyl-proline methylester prepared in Step A.
MS[M+H]=114 (M+1)
Intermediates 140 ̃148
The compounds below were prepared following the procedure described in Intermediates 138 and 139 using various amino acid derivatives.
















 











Intermediate
X
n
*
MS (M + 1)





140
Me
1
S
114


141
Ac
1
R
142


142
S(O)2Me
1
R
178


143
C(O)N(Me)2
1
R
171


144
n-Bu
1
R
156


145
Me
2
S
128


146
Me
2
R
128


147
Ac
2
R
156


148
S(O)2Me
2
R
192









Intermediate 149: 1-BOC-2-aziridinecarboxylic acid
Step A: Methyl 1-benzyl-2-aziridinecarboxylate
To a solution of methyl 2,3-dibromopropionate (92.50 g, 10.0 mmol) and K2CO3 (4.10 g 30.0 mmol) in acetonitrile (30 mL) was added dropwise benzylamine (1.20 mL, 11 mmol). After being stirred at rt for 4 h, and the reaction mixture was quenched with a saturated aqueous NH4Cl solution. The organic material was extracted with EtOAc, the extracts dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex 2/1) to give the title compound (1.62 g, 85%).
MS[M+H]=192 (M+1)
Step b: Methyl 1-BOC-2-aziridine carboxylate
To a solution of methyl 1-benzyl-2-aziridinecarboxylate (1.00 g, 5.23 mmol) and di-t-butyl-dicarbonate (1.34 g, 5.75 mmol), prepared in Step A, in methanol (20 mL) was added portionwise Pd/C (300 mg). The mixture was stirred at rt under hydrogen for 24 h and filtered though Celite. The filtrate was concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=2/1) to give the title compound (985 mg, 91.0%).
MS[M+H]=202 (+1)
Step C: 1-BOC-aziridine-2-carboxylic acid
The title compound was prepared following the procedure described in Step B of Intermediate 135 using methyl 1-BOC-2-aziridinecarboxylate prepared in Step B.
MS[+H]=188 (M+1)
Intermediate 150: 1-BOC-aziridine-2-carboxaldehyde
The title compound was prepared following the procedure described in Intermediate 138 using 1-BOC-aziridine-2-carboxylic acid.
MS[M+H]=172(M+1)
Intermediate 151: 2-ethylamino-1-acetyloxyethane
Step A: 2-(BOC)amino-1-acetyloxyethane
To a solution of 2-(BOC)aminoethanol (3.2 g, 20.0 mmol) in DCM (60 mL) were added TEA (5.6 mL, 40.0 mL) and acetyl chloride (3.36 mL, 30 mmol) at 0° C. After the reaction solution was stirred for 2 h, the solvent was removed, and the residue dissolved in water. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/10) to give the title compound (3.2 g, 80%).
MS[M+H]=204(M+1)
Step B: 2-amino-1-acetyloxyethane
2-(BOC)amino-1-acetyloxyethane (3.00 g, 15.0 mmol), prepared in Step A, was dissolved in DCM (15.0 mL), and TFA (15.0 mL) was added. After being stirred 30 min, the reaction mixture was concentrated in vacuo to give the title compound. The product was used without further purification.
MS[M+H]=104(M+1)
Step C: 2-[(2-nitrobenzene)sulfonyl]amino-1-acetyloxyethane
To a solution of 2-amino-1-acetyloxyethane (1.00 g, 10.0 mmol), prepared in Step B (1.00 g, 10.0 mmol) and Et3N (2.80 mL, 20 mmol) in DCM (30 mL) was added dropwise (2-nitrobenzene)sulfonyl chloride (2.43 g, 22 mmol). After being stirred at rt for 4 h, the reaction mixture was quenched with water and extracted with EtOAc. The extracts were washed with 1N HCl, dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (2.72 g, 94.0%).
MS[M+1]=289(M+1)
Step D: 2-{ethyl[(2-nitrobenzene)sulfonyl]}amino-1-acetyloxyethane
To a solution of 2-[(2-nitrobenzene)sulfonyl]amino-1-acetyloxyethane prepared in Step C (1.45 g, 5.00 mmol) and P(Ph)3 (1.3 g, 5 mmol) in THF (15 mL) were added ethanol (0.40 mL, 15 mmol) and DEAD (0.32 mL, 10.0 mmol). After being stirred for 12 h, the solvent was removed and the residue was purified by column chromatography (eluent: EtOAc/Hex=1/5) to give the title compound (1.40 g, 80%).
MS[M+1]=317(M+1)
Step E: 2-ethylyamino-1-acetyloxyethane
To a solution of 2-{ethyl[(2-nitrobenzene)sulfonyl]}amino-1-acetyloxyethane (634 mg, 2.00 mmol) prepared in Step D in DMF (10 mL) were added K2CO3 (540 mg, 4 mmol) and mercaptobenzene (330 mg, 1.5 mmol). The reaction mixture was stirred at rt for 1 h, concentrated in vacuo, and diluted with water. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound.
MS[M+H]=132(M+1)
Intermediate 152-157
The compounds below were prepared following the procedure described in Intermediates 151 using commercially available aminoalcohol or (N-BOC)aminoethanol.
















 












Intermediate
R
R′
R′′
R′′′
MS (M + 1)





152
Pr
Ac
H
H
146


153
Et
Me
H
H
104


154
c-Pr
Ac
H
H
144


155
CH2CH2OMe
Ac
H
H
162


156
Me
Ac
Me
Me
146


157
CH2CH2OMe
Me
H
H
134









Intermediate 158: (2R)-2-(BOC)amino-N-{4-[cyclohexyl(hydroxyethylcarbamoyl)amino]piperidine-1-yl}-3-(4-chlorophenyl)propionamide
Step A; 4-[cyclohexyl)amino]piperidine
The title compound was prepared following the procedure described in Step A of Intermediate 1 using 1-BOC-4-[(cyclohexyl)amino]piperidine prepared in Intermediate 26.
MS[M+H]=183(M+1)
Step B; (2R)-2-(BOC)amino-N-[4-(cyclohexylamino)piperidine-1-yl]-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Intermediate 129 using (2R)-2-(BOC)amino-3-(4-chlorophenyl)propionic acid and 4-[(cyclohexyl)amino]piperidine.
MS[M+H]=464(M+1)
Step C: N-cyclohexyl[(2R)-2-(BOC)amino-3-(4-chlorophenyl)-1-oxo]piperidine-4-yl}carbamoyl chloride
To a solution of (2R)-2-(BOC)amino-N-[4-(cyclohexylamino)poperidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Step B (4.63 g, 10 mmol) in DCM (30 mL) was added phosgene (25% in toluene, 12.6 mL, 30 mmol). After the reaction solution was stirred at rt for 4 h, the solvent was removed, and the residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (4.58 g, 87%).
MS[M+H]=526(M+1)
Step D: (2R)-2-(BOC)amino-N-{(4-[cyclohexyl(hydroxyethylcarbamoyl)amino]piperidine-1-yl)-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step B of Intermediate 81 using N-cyclohexyl[(2R)-2-(BOC)amino-3-(4-chlorophenyl)-1-oxo]piperidine-4-yl}carbamoyl chloride.
MS[M+H]=551(M+1)
Intermediate 59-190
The compounds below were prepared following the procedure described in Intermediates 158 using commercially available aminoalcohols or amine compounds prepared in Intermediate 6-35.
















 













Intermediate
R
R′
R4
n
*
MS (M+ 1





159
H
CH2(CH2)3NH(BOC)
c-Hex
1
S
664


160
H
CH2(CH2)2NH(BOC)
c-Hex
1
S
650


161
H
CH2CH2NH(BOC)
c-Hex
1
S
636


162
H
CH2CH2OH
c-Hex
1
S
537


163
CH2CH2OH
CH2CH2OH
c-Hex
1
S
581


164
H
CH2CH2OMe
c-Hex
1
S
551












165
3(S)-hydroxy-Pyd-1-yl
c-Hex
1
S
563


166
2(S)-hydroxymethyl-Pyd-1-yl
c-Hex
1
S
577













167
Me
CH2CH2OH
c-Hex
2

565


168
Et
CH2CH2OH
c-Hex
2

579


169
Pr
CH2CH2OH
c-Hex
2

593


170
c-Pr
CH2CH2OH
c-Hex
2

591


171
CH2CH2OMe
CH2CH2OH
c-Hex
2

609


172
Me
CH2CH2OMe
c-Hex
2

579


173
Et
CH2CH2OMe
c-Hex
2

593


174
CH2CH2OMe
CH2CH2OMe
c-Hex
2

623


175
Me
Et
c-Hex
2

563


176
Me
OMe
c-Hex
2

551


177
Me
C(Me)2CH2OH
c-Hex
2

593


178
Me
CH2CH2OH
2,3-diF—Ph
2

593


179
Me
CH2CH2OMe
2,3-diF—Ph
2

609


180
CH2CH2F
CH2CH2OMe
c-Hex
2

611












181
3(R)-hydroxy-Pyd-1-yl
c-Hex
2

577


182
3(S)-hydroxy-Pyd-1-yl
c-Hex
2

577


183
(2R)-hydroxymethyl-Pyd-1-yl
c-Hex
2

591


184
(2S)-hydroxymethyl-Pyd-1-yl
c-Hex
2

591


185
(3S)-N-BOC-amino-Pyd-1-yl
c-Hex
2

576


186
(3R)-N-BOC-amino-Pyd-1-yl
c-Hex
2

576


187
(3R)-hydroxy-Pid-1-yl
c-Hex
2

591


188
(3S)-hydroxy-Pid-1-yl
c-Hex
2

591


189
4-hydroxy-Pid-1-yl
c-Hex
2

591


190
4-N-BOC-amino-Pid-1-yl
c-Hex
2

590









Intermediate 191: 4-[cyclohexyl(isopropylcarbamoyl)amino]piperidine
Step A: 1-BOC-4-[cyclohexyl(isopropylcarbamoyl)amino]piperidine
To a solution of 1-BOC-4-cyclohexylamino)piperidine (282 mg, 1.00 mmol) in DCM (3 mL) was added isopropyl isocyanate (108 μl, 1.10 mmol). After being stirred at rt for 30 min, the reaction solution was concentrated in vacuo, and the residue was purified by column chomatography (eluent: EtOAc/Hex=1/5) to give the title compound (354 mg, 94.0%).
MS[M+H]=368(M+1)
Step B: 4-[cyclohexyl(N-isopropylcarbamoyl)amino]piperidine
The title compound was prepared following the procedure described in Step B of Intermediate 1 using 1-BOC-4-[cyclohexyl(N-isopropylcarbamoyl)amino]piperidine.
MS[M+H]=268(M+1)
Intermediate 192: 4-{cyclohexyl[methyl(isopropyl)carbamoyl]amino}piperidine
Step A: 1-BOC-4-{cyclohexyl[methyl(isopropyl)carbamoyl]amino}piperidine
The title compound was prepared following the procedure described in Step A of Intermediate 128 using 1-BOC-4-[cyclohexyl(isopropylcarbamoyl)amino]piperidine.
MS[M+H]=382(M+1)
Step B: 4-{cyclohexyl[methyl(isopropyl)carbamoyl]amino}piperidine
The title compound was prepared following the procedure described in Step B of Intermediate 1 using 1-BOC-4-{cyclohexyl[methyl(isopropyl)carbamoyl]amino}piperidine.
MS[M+H]=282(M+1)
Intermediate 193-198
The compounds below were prepared following the procedure described in Intermediates 128 or Step A of Intermediate 191 using 1-BOC-4-(cyclohexylamino)piperidine and isocyanates or isothiocyanates.
















 











Intermediate
X
R9
R10
MS (M + 1)





193
O
H
n-Bu
281


194
O
H
c-Hex
307


195
O
H
Ph
301


196
O
Me
n-Bu
295


197
S
H
Et
275


198
S
Me
Et
289









Intermediate 199: methyl[cyclohexyl(piperidin-4-yl)amino]acetate
Step A; methyl{cyclohexyl[1-(BOC)piperidin-4-yl]amino}acetate
The title compound was prepared following the procedure described in Step A of Intermediate 128 using 1-BOC-4-(cyclohexylamino)poperidine.
MS[M+H]=355(M+1)
Step B: methyl[cyclohexyl(piperidin-4-yl)amino]acetate
The title compound was prepared following the procedure described in Step B of Intermediate 1 using methyl{cyclohexyl[1-(BOC)piperidin-4-yl]amino}acetate prepared in Step A.
MS[M+H]=255(M+1)
Intermediate 200: (2R)-2-(BOC)amino-N-(3-hydroxyazetidine-1-yl)-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Intermediate 129 using (2R)-1-BOC-(4-chlorophenyl)alanine and 3-hydroxyazetidine (Syn. Lett., 1991, 783.).
MS[M+H]=355(M+1)
Intermediate 201: (2R)-2-(BOC)amino-N-(3-oxo-azetidine-1-yl)-3-(4-chlorophenyl)propionamide
(2R)-2-(BOC)Amino-N-(3-hydroxyazetidine-1-yl)-3-(4-chlorophenyl)propionamide (3.54 g, 10 mmol) was placed in a round-bottomed flask, filled with nitrogen, and DCM (30 mL) and oxalyl chloride (872 μl, 10 mmol) were added. The mixture was cooled to −78-C, and DMSO (709 μl, 10 mmol) was added. The reaction solution was stirred for 3 h keeping the temperature below −50° C. The reaction mixture was quenched by addition of TEA and warmed to rt. The reaction solution was diluted with a saturated aqueous NH4Cl solution, and the organic material was extracted with EtOAc. The extracts was dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (2.88 g, 84%).
MS[M+H]=353(M+1)
Intermediate 202: (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Intermediate 2 using (2R)-2-(BOC-amino)-N-(3-oxo-azetidine-1-yl)-3-(4-chlorophenyl)propionamide prepared in Intermediate 201 and cyclohexylamines.
MS[M+H]=437(M+1)
Intermediate 203: (2R)-2-(BOC)amino-N-{3-[cyclohexyl(isobutyryl)amino]azetidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Intermediate 36 using (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Intermediate 202 and isobutyrylchloride.
MS[M+H]=507(M+1)
Intermediate 204-217
The compounds below were prepared following the procedure described in Intermediates 201 and 203 using (2R)-2-(BOC)amino-N-(3-hydroxyazetidine-1-yl)-3-(4-chlorophenyl)propionamide prepared in Intermediate 200.
















 












Intermediate
R3
*
R4
R5
MS (M + 1)





204
4-Cl-Bn
R
C(O)C(Me)3
c-Hex
520


205
4-Cl-Bn
R
C(O)OMe
c-Hex
494


206
4-Cl-Bn
R
S(O)2Me
c-Hex
515


207
4-Cl-Bn
R
C(O)N(Me)2
c-Hex
507


208
4-Cl-Bn
R
C(O)CH(Me)2
c-Pen
492


209
4-Cl-Bn
R
C(O)CH(Me)2
c-Hep
520


210
4-Cl-Bn
R
C(O)CH(Me)2
i-Pr
466


211
4-Cl-Bn
R
C(O)CH(Me)2
i-Bu
480


212
4-Cl-Bn
R
C(O)CH(Me)2
(c-Hex)-CH2—
520


213
4-Cl-Bn
R
C(O)CH(Me)2
2-Me-c-Hex
520


214
Bn
R
C(O)CH(Me)2
c-Hex
472


215
Bn
R
C(O)CH(Me)2
c-Hex
486


216
Bn
R
C(O)C(Me)3
c-Hex
500


217
(c-Hex)-CH2—
R
C(O)CH(Me)2
c-Hex
478









Intermediate 218: (2R)-2-(BOC)amino-N-{3-[cyclohexyl(methoxycarbonyl)amino]azetidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Intermediate 135 using (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Intermediate 202 and methyl bromoacetate.
MS[M+H]=508(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-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide.TFA
Step A: (2R)-2-(BOC-amino)-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
To a solution of (3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine (HCl salt, 917 mg, 3.30 mmol) in DMF (30 mL) were added DIPEA (1.15 mL, 6.70 mmol), (2R)-N-BOC-(4-chlorophenyl)alanine (1.00 mg, 3.30 mmol), HOBT (668 mg, 5.00 mmol), and EDC (845 mg, 4.30 mmol). After being stirred at rt for 12 h, the reaction solution was concentrated in vacuo, and the residue was diluted with a saturated NaHCO3 solution and EtOAc. The organic layer was extracted with EtOAc and subsequently washed with a saturated aqueous NaHCO3 solution, water and an aqueous 1N HCl solution. The organic solution was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/2) to give the title compound (1.58 g, 93.9%).
MS[M+H]=520(M+1)
Step B: (2R)-2-amino-N-{(3R)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide.TFA
(2R)-2-(BOC-amino)-N-{(3R)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step A, (1.00 g, 1.93 mmol) was dissolved in DCM (7 mL), and TFA (7 mL) was added dropwise. After the solution was stirred at rt for 1 h, the solvent was removed 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)-pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide.2TFA
Step A: (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA, prepared in Example 1, (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). After the reaction mixture was stirred at rt for 12 h, DMF was removed in vacuo, and the residue was diluted with a saturated aqueous NaHCO3 solution and EtOAc. The organic layer was extracted with EtOAc and subsequently washed with a saturated aqueous NaHCO3 solution, water and an aqueous 1N HCl solution. The organic solution was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=2/1) to give the title compound (107 g, 90.8%).
MS [M+H]=617 (+1)
Step B: (2R)-2-{[(2R)-pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
To a solution of (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-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). After the reaction solution was stirred at rt for 30 min. the solvent was removed in vacuo, and the residue was purified by HPLC to give the title compound (50.0 mg, 98.2%).
MS[M+H]=517(M+1)
Example 3
(2R)-2-{[(2R)-pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
Step A: (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Example 1, (TFA salt, 100 mg, 0.191 mmol) and (2R)-N-BOC-proline carboxyaldehyde (39.6 mg, 0.2 mmol) in DCE (3 mL) was added and NaBH(OAc)3 (96 mg, 4 mmol) at rt. After being stirred 4 h, the reaction mixture was quenched with a saturated aqueous NaHCO3 solution, and the organic material was extracted with DCM followed by EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chomatography (eluent: DCM/MeOH=9/1) to give the title compound (107 mg, 90.80%).
MS [M+H]=603 (M+1)
Step B: (2R)-2-{[(2R)-pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
To a solution of (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide(50 mg, 0.0831 mmol), prepared in Step A, in DCM (2 mL) was added TFA (2 mL). After being 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 (58.8 mg, 97.1%).
MS[M+H]=517(M+1)
Example 4
(2R)-2-{methyl[((2R)-pyrrolidine-2-yl)methyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
The title compound was prepared following the procedure described in Example 3 using (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B of Example 3 and formaline.
MS[M+H]=531(M+1)
Example 5
(2R)-(dimethyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
The title compound was prepared following the procedure described in Example 3 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TEA prepared in Example 1 and formaline.
MS[M+H]=449(M+1)
Example 6
(2R)-2-[1-(methyl)azetidine-3-yl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
Step A: (2R)-2-[1-(BOC)azetidine-3-yl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Example 1 and BOC-3-oxo-azetidine.
MS[M+H]=575(M+1)
Step B: (2R)-2-{Fmoc[1-(BOC)azetidine-3-yl]}amino-N-f{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Intermediate 1 using (2R)-2-[1-(BOC)azetidine-3-yl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared Step A.
MS[M+H]=797(M+1)
Step C: (2R)-2-[Fmoc(azetidine-3-yl)]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-{Fmoc[1-(BOC)azetidine-3-yl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B
MS[M+H]=697(M+1)
Step D: (2R)-2-{Fmoc[1-(methyl)azetidine-3-yl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-[Fmoc(azetidine-3-yl)]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared Step C.
MS[M+H]=711(M+1)
Step E: (2R)-2-[1-(methyl)azetidine-3-yl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
(2R)-2-{Fmoc[1-(methyl)azetidine-3-yl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step D (71.1 mg, 1 mmol) was dissolved in 50% of piperidine-DMF (2 mL). After being stirred 30 min., the reaction mixture was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (52 mg, 73.5%).
MS[M+H]=489(M+1)
Example 7-186
The compounds below were prepared following the procedure described in Example 1-6 using pyrrolidine, piperidine, or azetidine derivatives prepared in the above Intermediates.
















 
















Exm.
R1
R2
R3
*1
R4
*2
R5
n
MS (M + 1)



















7
H
H
4-Cl-Bn
R
c-Hex
S
C(O)C(Me)3
1
434


8
H
H
4-Cl-Bn
R
c-Hex
S
C(O)OMe
1
408


9
H
H
4-Cl-Bn
R
c-Hex
S
C(O)N(Me)2
1
421


10
H
H
4-Cl-Bn
R
c-Hex
S
SO2Me
1
428


11
H
H
4-Cl-Bn
R
c-Hex
S
CH2C(O)OMe
1
422


12
H
H
4-Cl-Bn
R
c-Hex
S
SO2NH2
1
429


13
H
H
4-Cl-Bn
R
c-Hex
S
Gly
2
409


14
H
H
4-Cl-Bn
R
c-Hex
S
CH2C(O)N(Me)2
2
435


15
H
H
4-Cl-Bn
R
c-Hex
S
CH2SO2Me
1
442


16
H
H
4-Cl-Bn
R
c-Hex
R
C(O)CH(Me)2
1
420


17
H
H
4-Cl-Bn
R
c-Hex
R
C(O)C(Me)3
1
434


18
H
H
4-Cl-Bn
R
c-Pen
S
C(O)CH(Me)2
1
406


19
H
H
4-Cl-Bn
R
c-Hep
S
C(O)CH(Me)2
1
434


20
H
H
4-Cl-Bn
R
i-Pr
S
C(O)CH(Me)2
1
480


21
H
H
4-Cl-Bn
R
(c-Hex)-CH2
S
C(O)CH(Me)2
1
434


22
H
H
4-Cl-Bn
R
4,4-diMe-c-Hex
S
C(O)CH(Me)2
1
448


23
H
H
4-Cl-Bn
R
c-Pen
R
C(O)CH(Me)2
1
406


24
H
H
4-Cl-Bn
S
c-Hex
S
C(O)CH(Me)2
1
420


25
H
H
Bn
R
c-Hex
S
C(O)CH(Me)2
1
386


26
H
H
4-Br-Bn
R
c-Hex
S
C(O)CH(Me)2
1
465


27
H
H
4-MeO-Bn
R
c-Hex
S
C(O)CH(Me)2
1
416


28
H
H
3,4-diCl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
454


29
H
H
4-F-Bn
R
c-Hex
S
C(O)CH(Me)2
1
404


30
H
H
4-HO-Bn
R
c-Hex
S
C(O)CH(Me)2
1
402


31
H
H
(c-Hex)-CH2
R
c-Hex
S
C(O)CH(Me)2
1
392


32
H
H
(indol-2-yl)-CH2
R
c-Hex
S
C(O)CH(Me)2
2
425


33
H
H
i-Bu
R
c-Hex
S
C(O)CH(Me)2
1
352


34
H
H
NH2C(O)CH2
R
c-Hex
S
C(O)CH(Me)2
1
353


35
H
H
4-Cl-Bn
R
2,3-diF—Ph
S
C(O)CH(Me)2
1
450


36
H
H
4-Cl-Bn
R
2,4-diF—Ph
S
C(O)CH(Me)2
1
450


37
H
H
4-Cl-Bn
R
2,3-diF—Ph
R
C(O)CH(Me)2
1
450


38
H
H
4-Cl-Bn
R
2,4-diF—Ph
R
C(O)CH(Me)2
1
450


39
Me
Me
4-Cl-Bn
R
c-Hex
S
C(O)C(Me)3
1
465


40
Ac
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
0
462


41
MeSO2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
0
498


42
(Me)2NC(O)—CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
505


43
Gly
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
477


44
H2NC(O)—CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
477


45
N-diMe-Gly
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
505


46
N-Ac-Gly
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
0
519


47
N-Ms-Gly
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
0
555


48
(R)Ala
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
491


49
β-Ala
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
491


50
β-Ala
H
4-Cl-Bn
R
c-Hex
S
C(O)C(Me)3
1
505


51
N-diMe-β-Ala
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
533


52
4-amino-Bu
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
0
505


53
(S)Ala
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
491


54
(S)His
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
606


55
N—Me-(S)His
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
620


56
N—Ac-(S)His
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
648


57
N—Ac-(S)His
H
4-Cl-Bn
R
c-Hex
S
C(O)C(Me)3
1
662


58
N—Ms-(S)His
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
684


59
(R)His
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
606


60
(S)Phe
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
567


61
(R)Phe
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
567


62
(R)Pro
H
4-Cl-Bn
R
c-Hex
S
C(O)C(Me)3
1
531


63
N—Me-(R)Pro
H
4-Cl-Bn
R
c-Hex
S
C(O)C(Me)3
1
545


64
(S)Pro
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
517


65
(R)Pid-2-CO
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
531


66
(R)Pid-2-CO
H
4-Cl-Bn
R
c-Hex
S
C(O)C(Me)3
1
545


67
1-Me-(R)Pid-2-CO
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
545


68
1-Ac-(R)Pid-2-CO
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
0
573


69
(S)Pid-2-CO
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
531


70
(R)Tic
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
579


71
(R)Tic
H
Bn
R
c-Hex
S
C(O)CH(Me)2
1
545


72
(S)Tic
H
4-Cl-Bn
R
c-Hex
R
C(O)CH(Me)2
1
579


73
cis-Dic
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
583


74




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
503


 


75




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
545


 


76




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
570


 


77




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
574


 


78




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
546


 


79




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
560


 


80




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
504


 


81




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
532


 


82
HO—CH2—C(O)
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
0
478


83




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
489


 


84
(R)Pyd-2-CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)C(Me)3
2
517


85
(R)Pyd-2-CH2
H
4-Cl-Bn
R
c-Hex
R
C(O)CH(Me)2
2
503


86
(R)Pyd-2-CH2
H
4-Cl-Bn
R
2,3-diF—Ph
R
C(O)CH(Me)2
2
533


87
(R)Pyd-2-CH2
H
4-Cl-Bn
R
2,4-DiF—Ph
R
C(O)CH(Me)2
2
533


88
(R)Pyd-2-CH2
H
4-Cl-Bn
R
c-Pen
S
C(O)CH(Me)2
2
589


89
(R)Pyd-2-CH2
H
Bn
R
c-Hex
S
C(O)CH(Me)2
2
569


90
(R)Pyd-2-CH2
H
(c-Hex)-CH2—
R
c-Hex
S
C(O)CH(Me)2
2
475


91
(R)-1-Ac-Pyd-2-CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
1
545


92
(S)Pyd-2-CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
503


93
(S)Pyd-2-CH2
Me
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
517


94
(S)-1-Me-Pyd-2-CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
517


95
(R)Pid-2-CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
517


96
(R)-1-Me-Pid-2-CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
531


97
(R)-1-Me-Pid-2-CH2
Me
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
559


98
(S)Pid-2-CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
517


99
(S)-1-Me-Pid-2-CH2
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
531


100




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
475


 


101




H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
475


 


102
1-Me-Pid-4-yl
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
503


103
Pid-4-yl
H
4-Cl-Bn
R
c-Hex
S
C(O)CH(Me)2
2
503


104
Pid-4-yl
Me
4-Cl-Bn
R
c-Hex
S
C(O)C(Me)2
2
517

























 























MS


Exm.
R1
R2
R3
*
R4
R5
n
(M + 1)


















105
H
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
434


106
H
H
4-Cl-Bn
R
c-Hex
C(O)C(Me)3
1
448


107
H
H
4-Cl-Bn
R
c-Hex
C(O)OMe
1
422


108
H
H
4-Cl-Bn
R
c-Hex
C(O)N(Me)2
1
435


109
H
H
4-Cl-Bn
R
c-Hex
CH2C(O)OMe
2
436


110
H
H
4-Cl-Bn
R
c-Hex
Gly
1
423


111
H
H
4-Cl-Bn
R
c-Hex
CH2C(O)N(Me)2
2
449


112
H
H
4-Cl-Bn
R
c-Hex
C(O)NH(i-Pr)
1
449


113
H
H
4-Cl-Bn
R
c-Hex
C(O)N(i-Pr)(Me)
1
463


114
H
H
4-Cl-Bn
R
c-Hex
C(O)N(Bu)
1
463


115
H
H
4-Cl-Bn
R
c-Hex
C(O)N(Bu)(Me)
1
477


116
H
H
4-Cl-Bn
R
c-Hex
C(O)N(c-Hex)
1
489


117
H
H
4-Cl-Bn
R
c-Hex
C(O)N(Ph)
1
485


118
H
H
4-Cl-Bn
R
c-Hex
C(S)N(Et)
1
451


119
H
H
4-Cl-Bn
R
c-Hex
C(S)N(Et)(Me)
1
465


120
H
H
4-Cl-Bn
R
c-Hex
S(O)2Me
1
456


121
H
H
4-Cl-Bn
R
c-Pen
C(O)CH(Me)2
1
420


122
H
H
4-Cl-Bn
R
c-Hep
C(O)CH(Me)2
1
448


123
H
H
4-Cl-Bn
R
ph
C(O)CH(Me)2
1
428


124
H
H
4-Cl-Bn
R
2-MeO—Ph
C(O)CH(Me)2
1
458


125
H
H
4-Cl-Bn
R
3-MeO—Ph
C(O)CH(Me)2
1
458


126
H
H
4-Cl-Bn
R
2-Cl—Ph
C(O)CH(Me)2
1
462


127
H
H
4-Cl-Bn
R
2-F—Ph
C(O)CH(Me)2
1
446


128
H
H
4-Cl-Bn
R
3-F—Ph
C(O)CH(Me)2
1
446


129
H
H
4-Cl-Bn
R
4-F—Ph
C(O)CH(Me)2
1
446


130
H
H
4-Cl-Bn
R
2,3-diF—Ph
C(O)CH(Me)2
1
464


131
H
H
4-Cl-Bn
R
2,4-diF—Ph
C(O)CH(Me)2
1
464


132
H
H
4-Cl-Bn
R
2,5-diF—Ph
C(O)CH(Me)2
1
464


133
H
H
4-Cl-Bn
R
2,6-diF—Ph
C(O)CH(Me)2
1
464


134
H
H
4-Cl-Bn
R
3,4-diF—Ph
C(O)CH(Me)2
1
464


135
H
H
4-Cl-Bn
R
2-F-4-MeO—Ph
C(O)CH(Me)2
1
476


136
H
H
4-Cl-Bn
S
c-Hex
C(O)CH(Me)2
1
434


137
H
H
4-Br-Bn
R
c-Hex
C(O)CH(Me)2
1
479


138
H
H
3,4-di-F-Bn
R
c-Hex
C(O)CH(Me)2
1
468


139
H
H
4-F-Bn
R
2,3-diF—Ph
C(O)CH(Me)2
1
448


140
H
H
4-HO-Bn
R
c-Hex
C(O)CH(Me)2
1
416


141
H
H
4-MeO-Bn
R
2,3-diF—Ph
C(O)CH(Me)2
1
448


142
H
H
(c-Hex)-CH2
R
c-Hex
C(O)CH(Me)2
1
406


143
N-diMe-Gly
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
519


144
(R)Ala
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
505


145
β-Ala
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
519


146
N-diMe-β-Ala
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
547


147
(S)His
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
620


148
(R)Pro
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
531


149
N—Me-(R)Pro
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
617


150
(R)Tic
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
591


151
(R)Pyd-2-CH2
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
517


152
(R)Pyd-2-CH2
H
4-Cl-Bn
R
c-Hex
C(O)C(Me)3
2
531


153
(R)Pyd-2-CH2
H
4-Cl-Bn
R
2,3-diF—Ph
C(O)CH(Me)2
2
547


154
(R)Pyd-2-CH2
H
4-Cl-Bn
R
2,4-diF—Ph
C(O)CH(Me)2
2
547


155
(S)Pyd-2-CH2
H
4-F-Bn
R
2,3-diF—Ph
C(O)CH(Me)2
2
547


156
(2R, 4S)-4F-Pyd-2-CH2
H
4-Cl-Bn
R
2,3-diF—Ph
C(O)CH(Me)2
2
554


157
(S)Pyd-2-CH2
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
517


158
(S)Pyd-2-CH2
H
4-Cl-Bn
R
2,3-diF—Ph
C(O)CH(Me)2
2
547


159
(S)Pyd-2-CH2
H
4-Cl-Bn
R
2,4-diF—Ph
C(O)CH(Me)2
2
547


160
(R)-1-Me-Pid-2-CH2
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
545


161
(R)-1-Me-Pid-3-CH2
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
545

























 















Example
R1
R2
R3
*
R4
R5
n
MS (M + 1)





162
H
H
4-Cl-Bn

c-Hex
C(O)CH(Me)2
1
406


163
H
H
4-Cl-Bn
R
c-Hex
C(O)C(Me)3
1
420


164
H
H
4-Cl-Bn
R
c-Hex
C(O)OMe
1
394


165
H
H
4-Cl-Bn
R
c-Hex
C(O)N(Me)2
1
407


166
H
H
4-Cl-Bn
R
c-Hex
S(O)2Me
1
414


167
H
H
4-Cl-Bn
R
c-Pen
C(O)CH(Me)2
1
392


168
H
H
4-Cl-Bn
R
c-Hep
C(O)CH(Me)2
1
420


169
H
H
4-Cl-Bn
R
i-Pr
C(O)CH(Me)2
1
466


170
H
H
4-Cl-Bn
R
(c-Hex)-CH2
C(O)CH(Me)2
1
420


171
H
H
4-Cl-Bn
R
2-Me-(c-Hex)
C(O)CH(Me)2
1
420


172
H
H
4-Cl-Bn
R
i-Bu
C(O)CH(Me)2
1
480


173
Gly
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
463


174
N-diMe-Gly
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
505


175
(S)His
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
592


176
N—BOC-(S)His
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
692


177
(R)Pro
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
503


178
N—Me-(R)Pro
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
517


179
(S)Pro
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
503


180
(R)Pid-2-CO
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
517


181
N—Me-(R)Pid-2-CO
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
531


182
(R)Tic
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
1
565


183




H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
489


 


184
(R)Pyd-2-CH2
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
589


185
(R)-1-Me-Pid-2-CH2
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
631


186
(R)Pid-2-CH2
H
4-Cl-Bn
R
c-Hex
C(O)CH(Me)2
2
617









Example 187
(2R)-2-amino-N-{(3S)-3-{[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
Step A: (2R)-2-(BOC)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Example 1 using 3(S)-3-{cyclohexyl[(2R)-2-methyl-3-acetyloxypropionyl]amino}pyrrolidine.
MS[M+H]=520(M+1)
Step B: (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
To a solution of (2R)-2-(BOC)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step A, in DCM (7 mL) was added TFA (7 mL). After being stirred at rt for 1 h, the reaction mixture was concentrated iii vacuo to give the title compound. The product was used without further purification.
MS[M+1]=420(M+1)
Step C: (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-propionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA, prepared in Step B, (592 mg, 1.00 mmol) in MeOH/H2O=1/1, 10 mL) was added LiOH (70 mg, 2.00 mmol) portionwise. After the reaction mixture was stirred at rt for 30 min., the solvent was removed in vacuo, and the residue was dilute with a saturatd aqueous NaHCO3 solution. The organic material was extracted with EtOAc, and the extracts were dried over MgSO4 and concentrated in vacu. The residue was purified by HPLC to give the title compound (495 mg, 90.0%).
MS[M+1]=420(M+1)
Step D: (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
(2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in the above Step C was dissolved in methanol, and passed though HCl-substituted ion exchange resin to give the title compound.
MS[M+1]=420(M+1)
Example 188
(2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
Step A: (2R)-2-[(BOC)aminoacetyl]amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Example 1 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B of Example 187 and N-BOC-Gly.
MS[M+H]=635(M+1)
Step B: (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step B of Example 187 using (2R)-2-[(BOC)aminoacetyl]amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A.
MS[M+H]=535(M+1)
Step C: (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B.
MS[M+H]=493(M+1)
Step D: (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step C.
MS[M+H]=493(M+1)
Example 189
(2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
Step A: (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA, prepared in Step B of Example 187, (592 mg, 1.00 mmol) and formaline (0.72 mL, 10.0 mmol) in DCE (3 mL) was added NaBH(OAc)3 (460 mg, 2.00 mmol). After the being stirred at rt for 4 h, the reaction mixture was quenched with an aqueous NaHCO3 solution and extracted with DCM followed by EtOAc. The extracts were dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (eluent: DCM/MeOH=9/1) to give the title compound (512 mg, 90.0%).
MS[M+H]=563(M+1)
Step B: (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in the above Step A.
MS[M+H]=521(M+1)
Step C: (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in the above Step B.
MS[M+H]=521(M+1)
Example 190-293
The compounds below were prepared following the procedure described in Example 187-189 using pyrrolidine and piperidine derivatives prepared in the above Intermediates.
















 

























MS


Exm.
R1
R2
Y
R4
R5′
*
n
x
[M + 1]





190
H
H
Cl
c-Hex
C(Me)2CH2OH
S
1
1
464


191
H
H
Cl
c-Hex
C(Me)2OH
S
1
1
436


192
H
H
Cl
c-Hex
C(Me)2(CH2)2OH
S
1
1
478


193
H
H
Cl
c-Hex
C(Me)(CH2OH)2
S
1
1
466


194
H
H
Cl
c-Hex
C(Me)2CH2OH
R
1
1
464


195
H
H
Cl
c-Hex
C(Me)2CH2OMe
S
1
1
464


196
H
H
Cl
c-Hex
C(Me)2CH2OBn
S
1
1
540


197
H
H
Cl
c-Hex
C(—(CH2)4—)CH2OH
S
1
1
464


198
H
H
Cl
c-Hex
C(Me)2(CH2)3O-(2,4-diMe—Ph)
S
1
1
582


199
H
H
Cl
c-Hex
C(Me)CH2OAc
S
1
1
478


200
H
H
Cl
c-Hex
C(—(CH2)2—)C(O)OH
S
1
1
461


201
H
H
Cl
c-Hex
N(n-Pr)
S
1
2
450


202
H
H
Cl
c-Hex
N(Et)
S
1
2
436


203
H
H
Cl
c-Hex
N(n-Bu)
S
1
2
464


204
H
H
Cl
c-Hex
3-OH—Ph
S
1
1
470


205
H
H
Cl
c-Hex
4-OH—Ph
S
1
1
470


206
H
H
Cl
c-Hex
2-(CH2OH)-1-(c-penten)-1-yl
S
1
1
474


207
H
H
Cl
c-Hex
2-(CH2OH)-1-(c-Hexen)-1-yl
S
1
1
488


208
H
H
Cl
c-Hex
1-Nos-Pid-4-yl
S
1
1
646


209
H
H
Cl
c-Hex
Pid-4-yl
S
1
2
461


210
H
H
Cl
c-Hex
C(OH)(i-Pr)
S
1
1
449


211
H
H
Cl
c-Hex
CH2C(Me)2OH
S
1
1
449


 


212
H
H
Cl
c-Hex




S
1
1
475


 


213
H
H
Cl
c-Hex




S
1
1
447


 


214
H
H
H
c-Hex
C(Me)2CH2OH
S
1
1
415


215
H
H
F
c-Hex
C(Me)2CH2OH
S
1
1
433


216
H
H
Me
c-Hex
C(Me)2CH2OH
S
1
1
429


217
H
H
MeO
c-Hex
C(Me)2CH2OH
S
1
1
445


218
Me
Me
Cl
c-Hex
C(Me)2CH2OH
S
1
1
478


219
Me
Me
Cl
c-Hex
C(Me)(CH2OH)2
S
1
1
494


 


220
Me
Me
Cl
c-Hex




S
1
1
520


 


221
Me
Me
H
c-Hex
C(Me)2CH2OH
S
1
1
443


222
Me
Me
F
c-Hex
C(Me)2CH2OH
S
1
1
461


223
Me
Me
Me
c-Hex
C(Me)2CH2OH
S
1
1
457


224
Me
Me
MeO
c-Hex
C(Me)2CH2OH
S
1
1
473


225
Et
Et
Cl
c-Hex
C(Me)2CH2OH
S
1
1
506


226
iPr
H
Cl
c-Hex
C(Me)2CH2OH
S
1
1
492















227
—(CH2)5—
Cl
c-Hex
C(Me)2CH2OH
S
1
1
518
















228
HOCH2C(Me)2C(O)
H
Cl
c-Hex
C(Me)2CH2OH
S
1
0
550


229
Imidazol-2-yl
H
Cl
c-Hex
C(Me)2CH2OH
S
1
2
530


230
Imidazol-4-yl
H
Cl
c-Hex
C(Me)2CH2OH
S
1
2
530


231
(i-Pr)C(O)
H
Cl
c-Hex
C(Me)2CH2OH
S
1
0
520


232
Gly
H
Cl
c-Hex
C(Me)CH2OH
S
1
1
507


233
NH2—(CH2)4
H
Cl
c-Hex
C(Me)2CH2OH
S
1
1
535


234
N-diMe-Gly
H
Cl
c-Hex
C(Me)2CH2OH
S
1
1
535


235
HO—(CH2)3—C(O)
H
Cl
c-Hex
C(Me)2CH2OH
S
1
0
536


236
EtC(O)
H
Cl
c-Hex
C(Me)2CH2OH
S
1
0
506


237
Pyd-3-yl
H
Cl
c-Hex
C(Me)2CH2OH
S
1
2
519


238
(S)Pyd-2-CH2—
H
Cl
c-Hex
C(Me)2CH2OH
S
1
2
533


239
MeOC(O)CH2
H
Cl
c-Hex
C(Me)2CH2OH
S
1
0
522


240
DTic
H
Cl
c-Hex
C(Me)2CH2OH
S
1
1
609


241
NH2—(CH2)2
H
Cl
c-Hex
C(Me)2CH2OH
S
1
2
493


242
(Me)NH—(CH2)2
H
Cl
c-Hex
C(Me)2CH2OH
S
1
2
507


243
Pyd-2-CH2—
H
Cl
c-Hex
2-(CH2OH)-1-(c-Penen)-1-yl
S
1
2
557


244
H
H
Cl
4-cis-Me-c-Hex
C(Me)2CH2OH
S
1
1
464


245
H
H
Cl
4-trans-Me-c-Hex
C(Me)2CH2OH
S
1
1
464


246
H
H
Cl
4-t-Bu-c-Hex
C(Me)2CH2OH
S
1
1
506


247
H
H
Cl
4-Ph-c-Hex
C(Me)2CH2OH
S
1
1
526


248
H
H
Cl
4,4-diMe-c-Hex
C(Me)2CH2OH
S
1
1
478


249
H
H
Cl
Pid-4-yl
C(Me)2CH2OH
S
1
2
451


250
H
H
Cl
4-oxo-c-Hex
C(Me)2CH2OH
S
1
1
464


251
H
H
Cl
4,4-diF-c-Hex
C(Me)2CH2OH
S
1
1
486


252
H
H
Cl
4-OH-c-Hex
C(Me)2CH2OH
S
1
1
466


253
H
H
Cl
4-F-c-Hex
C(Me)2CH2OH
S
1
1
468


254
H
H
Cl
Spiro[2,5]octane
C(Me)2CH2OH
S
1
1
476


255
H
H
Cl
4-cis-Et-c-Hex
C(Me)2CH2OH
S
1
1
478


256
H
H
Cl
4-trans-Et-c-Hex
C(Me)2CH2OH
S
1
1
478


257
H
H
Cl
4-cis-Me-c-Hex
C(Me)(CH2OH)2
S
1
1
480


258
H
H
Cl
4-trans-Me-c-Hex
C(Me)(CH2OH)2
S
1
1
480


259
H
H
Cl
4,4-diMe-c-Hex
C(Me)(CH2OH)2
S
1
1
494


270
Me
Me
Cl
4-cis-Me-c-Hex
C(Me)2CH2OH
S
1
1
492


271
Me
Me
Cl
4-trans-Me-c-Hex
C(Me)2CH2OH
S
1
1
492


272
Me
Me
Cl
4-t-Bu-c-Hex
C(Me)2CH2OH
S
1
1
534


273
Me
Me
Cl
4,4-diMe-c-Hex
C(Me)2CH2OH
S
1
1
514


274
Me
Me
Cl
4-cis-Et-c-Hex
C(Me)2CH2OH
S
1
1
506


275
Me
Me
Cl
4-trans-Et-c-Hex
C(Me)2CH2OH
S
1
1
506


276
Me
Me
Cl
4-cis-Me-c-Hex
C(Me)(CH2OH)2
S
1
1
508


277
Me
Me
Cl
4-trans-Me-c-Hex
C(Me)(CH2OH)2
S
1
1
508


278
Me
Me
Cl
4,4-diMe-c-Hex
C(Me)(CH2OH)2
S
1
1
522


279
H
H
Cl
2,3-diF—Ph
C(Me)2CH2OH
S
1
1
480


280
H
H
Cl
3,5-DiMe—Ph
C(Me)2CH2OH
R,S
1
1
472


281
H
H
Cl
2,5-diF—Ph
C(Me)2CH2OH
R,S
1
1
480


282
H
H
Cl
4-Me—Ph
C(Me)2CH2OH
R,S
1
1
458


283
H
H
Cl
Ph
C(Me)2CH2OH
R,S
1
1
444


284
H
H
Cl
2-Adamantyl
C(Me)2CH2OH
S
1
1
472


285
H
H
Cl
c-Hex
C(Me)2CH2OH
R
2
1
464


286
H
H
Cl
c-Hex
C(Me)(CH2OH)2
R
2
1
479


287
H
H
Cl
c-Hex
2-(CH2OH)-1-(c-penten)-1-yl
S
2
1
488


288
H
H
Cl
c-Hex
2-(CH2OH)-1-(c-hexen)-1-yl
S
2
1
502


289
H
H
Cl
4-cis-Me-c-Hex
C(Me)2CH2OH
S
2
2
477


290
H
H
Cl
4,4-diMe-c-Hex
C(Me)2CH2OH
S
2
2
591


291
H
H
Cl
4-trans-Me-c-Hex
C(Me)2CH2OH
S
2
2
493


292
(R)Pyd-2-CH2—
H
Cl
2,3-diF—Ph
C(Me)2CH2OH
S
2
2
576


293
(R)Pyd-2-CH2—
H
Cl
c-Hex
C(Me)2CH2OH
S
2
2
546









Example 294
(2R)-2-[isopropyl(methyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
Step A: (2R)-2-[isopropyl(methyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step A of Example 189 using (2R)-2-(isopropyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrroridine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Example 226 (purified by HPLC).
MS[M+H]=492(M+1)
Step B: (2R)-2-[isopropyl(methyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[isopropyl(methyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine 1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step A.
MS[M+H]=492(M+1)
Example 295
(2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
Step A: (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Example 190, (492 mg, 1.00 mmol) in acetonitrile (5 mL) were added DIEA (0.435 mL, 2.50 mmol) was added dropwise and methylbromoacetate (0.085 mL, 1.00 mmol). After the reaction mixture was stirred at 60° C. for 4 h, the solvent was removed in vacuo, and the residue was diluted with an aqueous NaHCO3 solution. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO4, and concentrated in vacuo to give the title compound. The product was used without further purification.
MS[M+H]=564(M+1)
Step B: (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step A.
MS[M+H]=508(M+1)
Step C: (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step B.
MS[M+H]=508(M+1)
Example 296
(2R)-2-[di(hydroxyacetyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
The title compound was prepared following the procedure described in Example 295 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide. MS[M+H]=566(M+1)
Example 297
(2R)-2-amino-N-{(3S)-3-[cyclohexyl(4-aminobutylcarbamoyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl
Step A: (2R)-2-amino-N-{(3S)-3-[cyclohexyl(4-aminobutylcarbamoyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
The title compound was prepared following the procedure described in Step B of Example 187 using (3S)-3-[cyclohexyl[4-(BOC)aminobutylcarbamoyl]amino]pyrrolidine prepared in Intermediate 159.
MS[M+H]=549(M+1)
Step B: (2R)-2-amino-N-{(3S)-3-[cyclohexyl(4-aminobutylcarbamoyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl
The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(4-aminobutylcarbamoyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA prepared in Step A.
MS[M+H]=549(M+1)
Example 298-357
The compounds below were prepared following the procedure described in Example 189 and 297 using pyrrolidine and piperidine derivatives prepared in the above Intermediates.
















 





















MS


Exm.
R1
R4
R5′
*
n
x
[M + 1]





298
H
c-Hex
N—(CH2)3—NH2
S
1
2
450


299
H
c-Hex
N—(CH2)2—NH2
S
1
2
436


300
H
c-Hex
N—(CH2)2—OH
S
1
1
437


301
H
c-Hex
N—(CH2)2—OMe
S
1
1
451


302
H
c-Hex
(3S)-3-(OH)-Pyd-1-yl
S
1
1
463


303
H
c-Hex
(2S)-2-(HOCH2)-Pyd-1-yl
S
1
1
477


304
H
c-Hex
N[(CH2)2OH]2
S
1
1
495


305
H
c-Hex
N[(CH2)3OH]2
S
1
1
523


306
H
c-Hex
N(Me)(CH2)2OH

2
1
465


307
H
c-Hex
N(Et)(CH2)2OH

2
1
479


308
H
c-Hex
N(Et)(CH2)3OH

2
1
493


309
H
c-Hex
N(Et)(CH2)2F

2
1
481


310
H
c-Hex
N(Et)(CH2)3F

2
1
495


311
H
c-Hex
N(n-Pr)(CH2)2OH

2
1
493


312
H
c-Hex
N(c-Pr)(CH2)2OH

2
1
491


313
H
c-Hex
N(i-Pr)(CH2)2OH

2
1
493


314
H
c-Hex
N[(CH2)2OMe](CH2)2OH

2
1
509


315
H
c-Hex
N[(CH2)2F](CH2)2OH

2
1
497


316
H
c-Hex
N(Me)(CH2)2OMe

2
1
479


317
H
c-Hex
N(H)(CH2)2OMe

2
1
465


318
H
c-Hex
N(Et)(CH2)2OMe

2
1
493


319
H
c-Hex
N[(CH2)2OMe]2

2
1
523


320
H
c-Hex
N(c-Pen)[(CH2)2OMe]

2
1
533


321
H
c-Hex
N(Et)2

2
1
463


322
H
c-Hex
N(Me)OMe

2
1
451


323
H
c-Hex
N(Me)[C(O)(Me)2CH2OH]

2
1
493


324
H
c-Hex
N[(CH2)2OMe][(CH2)2F]

2
1
511


325
H
c-Hex
(3S)-3-(OH)-Pyd-1-yl

2
1
477


326
H
c-Hex
(3R)-3-(OH)-Pyd-1-yl

2
1
477


327
H
c-Hex
(2R)-2-(HOCH2)-Pyd-1-yl

2
1
491


328
H
c-Hex
(2S)-2-(HOCH2)-Pyd-1-yl

2
1
491


329
H
c-Hex
(3R)-3-amino-Pyd-1-yl

2
1
476


330
H
c-Hex
(3S)-3-amino-Pyd-1-yl

2
1
476


331
H
c-Hex
(3R)-3-(OH)-Pid-1-yl

2
1
491


332
H
c-Hex
(3S)-3-(OH)-Pid-1-yl

2
1
491


333
H
c-Hex
4-(OH)-Pid-1-yl

2
1
491


334
H
c-Hex
4-amino-Pid-1-yl

2
1
490


335
(R)Pyd-2-CH2
c-Hex
N(n-Pr)(CH2)2OH

2
2
576


336
(R)Pyd-2-CH2
c-Hex
N[(CH2)2OH]2

2
2
578


337
(R)Pyd-2-CH2
c-Hex
N(Me)OMe

2
2
534


338
(R)Pyd-2-CH2
c-Hex
N(Me)[C(Me)2CH2OH]

2
2
562


339
(R)Pyd-2-CH2
c-Hex
N(Et)(CH2)2OH

2
2
576


340
(R)Pyd-2-CH2
c-Hex
N[(CH2)2OMe]2

2
2
620


341
(R)Pyd-2-CH2
c-Hex
N(c-Pr)(CH2)2OH

2
2
588


342
(R)Pyd-2-CH2
c-Hex
(3S)-3-(OH)-Pyd-1-yl

2
2
560


343
(R)Pyd-2-CH2
c-Hex
(2R)-2-(HOCH2)-Pyd-1-yl

2
2
574


344
(R)Pyd-2-CH2
c-Hex
4-(OH)-Pid-1-yl

2
2
574


345
(R)Pyd-2-CH2
c-Hex
(3R)-3-(OH)-Pid-1-yl

2
2
574


346
(S)Pyd-3-yl
c-Hex
N[Et]2

2
2
532


347
(S)Pyd-3-yl
c-Hex
N(Me)(CH2)2OH

2
2
548


348
NH2—(CH2)2—
c-Hex
N[(CH2)2OH]2

2
2
552


349
(Me)NH—(CH2)2
c-Hex
N[(CH2)2OH]2

2
2
566


350
(i-Pr)NH—(CH2)2—
c-Hex
N(Et)(CH2)2OH

2
2
564


351
Mor-(CH2)2
c-Hex
N(c-Pr)(CH2)2OH

2
2
604


352
Mor-(CH2)2
c-Hex
N(Et)(CH2)2OH

2
2
592


353
Mor-(CH2)2
c-Hex
N[(CH2)2OMe]2

2
2
636


354
H
2,3-diF—Ph
N(Me)(CH2)2OH

2
1
495


355
H
2,3-diF—Ph
N(Me)(CH2)2OMe

2
1
495


356
(R)Pyd-2-CH2
2,3-diF—Ph
N(Me)(CH2)2OH

2
2
578


357
(R)Pyd-2-CH2
2,3-diF—Ph
N(Me)(CH2)2OMe

2
2
592









Example 358
(2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
Step A: (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA, prepared in Example 1 (420 mg, 1 mmol), in DM F (10 mL) were added TEA (280 μl, 2 mmol) and (2-nitrobenzene)sulfonylchloride (222 mg, 1.00 mmol). After the being stirred at rt for 4 h, the reaction mixture was quenched with a saturated aqueous NH4Cl solution and was extracted with DCM followed by EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (568 mg, 94.0%).
MS[M+H]=585(M+1)
Step B: (2R)-2-{(2-nitrobenzene)sulfonyl[2-(dimethylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
To a solution of (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide(200 mg. 0.331 mmol), prepared in Step A, in DMF (3 mL) were added K2CO3 and 2-(dimethylamino)ethyl chloride (HCl salts, 73.9 mg, 0.533 mmol). After being stirred at rt for 24 h, the reaction mixture was concentrated in vacuo, and the residue was diluted a saturated aqueous NH4Cl solution. The organic material was extracted with EtOAc, and the extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (205 mg, 92.0%).
MS[M+H]=585(M+1)
Step C: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
To a solution of (2R)-2-{(2-nitrobenzene)sulfonyl[2-(dimethylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide (100 mg, 0.148 mmol), prepared in Step B, in DMF (3 mL) were added K2CO3 (61.3 mg, 0.429 mmol) and thiobenzene (45.6 μl, 0.429 mmol). After being stirred at rt for 2 h, the reaction mixture was concentrated in vacuo to remove DMF, and the residue was diluted with water. The organic material was extracted with EtOAc, and the extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by HPLC to give the title compound (89 mg, 84.0%).
MS[M+H]=470(M+1)
Example 359
(2R)-2-[2-(methylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
Step A: (2R)-2-{(2-nitrobenzene)sulfonyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step B of Example 358 using (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 358 and N-BOC-aminoethylbromide.
MS[M+H]=642(M+1)
Step B: ((2R)-2-{(2-nitroenzene)sulfonyl[2-(methyl(BOC)amino)ethyl]}amino-N-{(3S)-3-[(cyclohexyl(isobutyryl)amino)pyrrolidine-1-yl]-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Example 128 using (2R)-2-{(2-nitrobenzene)sulfonyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in the above Step A and methyliodide.
MS[M+H]=657(M+1)
Step C: (2R)-2-{2-[methyl(BOC)amino]ethyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step C of Example 358 using (2R)-2-{[2-BOC(methyl)amino]ethyl(2-nitrobenzenesulfonyl)}amino-N-{(3S)-3-[(cyclohexyl(isobutyryl)amino)pyrrolidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Step B.
MS[M+H]=657(M+1)
Step D: (2R)-2-[2-(methylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-{2-[methyl(BOC)amino]ethyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step C.
MS[M+H]=657(M+1)
Example 360
(2R)-2-(2-aminoethyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
Step A: (2R)-2-[2-(BOC)aminoethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step C of Example 358 using (2R)-2-{(2-nitrobenzene)sulfonyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 359.
MS[M+H]=563(M+1)
Step B: (2R)-2-(2-aminoethyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-[2-(BOC)aminoethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A.
MS[M+H]=463(M+1)
Example 361
(2R)-2-[2-(acetylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Example 358 using acetylaminoethyl bromide.
MS[M+H]=505(M+1)
Example 362
(2R)-2-{methyl[2-(methylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
Step A: (2R)-2-{methyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-[2-(BOC)aminoethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 360 and formaline.
MS[M+H]=577(M+1)
Step B: (2R)-2-{methyl[2-(methyl(BOC)amino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Example 128 using (2R)-2-{methyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in the above Step A and methyliodide.
MS[M+H]=591(M+1)
Step C: (2R)-2-{methyl[2-(methylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-{methyl[2-[methyl(BOC)amino]ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B.
MS[M+H]=491(M+1)
Example 363
(2R)-2-{methyl[2-(amino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-{methyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 362.
MS[M+H]=477(M+1)
Example 364
(2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
Step A: (2R)-2-{methyl[(2-nitrobenzene)sulfonyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step B of Example 358 using (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(isopropyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 358 and methyliodide.
MS[M+H]=619(M+1)
Step B: (2R)-(methyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step Cof Example 358 using (2R)-2-{methyl[(2-nitrobenzene)sulfonyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A.
MS[M+H]=434(M+1)
Example 365-388
The compounds below were prepared following the procedure described in Example 358 and 364 using piperidine derivatives prepared in the above Intermediates.
















 























MS


Example
R1
R2
R3
*1
*2
R4
n
(M + 1)





365
MeO2C—CH2
H
4-Cl-Bn
R
S
C(O)CH(Me)2
2
492


366
N-Me-Gly
H
4-Cl-Bn
R
S
C(O)CH(Me)2
1
491


367
N-Me-β-Ala
H
4-Cl-Bn
R
S
C(O)CH(Me)2
1
505


368
(Me)NH—(CH2)2
H
4-Cl-Bn
R
R
C(O)CH(Me)2
2
477


369
(Me)2N—(CH2)2
H
4-Cl-Bn
R
S
C(O)C(Me)3
2
505


370
(Me)2N—(CH2)2
H
Bn
R
S
C(O)CH(Me)2
2
457


371
(Me)2N—(CH2)2
H
(c-Hex)-CH2—
R
S
C(O)CH(Me)2
2
463


372
(Me)2N—(CH2)2
Me
4-Cl-Bn
R
S
C(O)CH(Me)2
2
484


373
(Et)2N—(CH2)2
H
4-Cl-Bn
R
S
C(O)CH(Me)2
2
519


374
[Me(Et)]N—(CH2)2
H
4-Cl-Bn
R
S
C(O)CH(Me)2
2
505


375
(aziridine-1-yl)-(CH2)2
H
4-Cl-Bn
R
S
C(O)CH(Me)2
2
489


376
(3R)Pyd-3-yl
H
4-Cl-Bn
R
S
C(O)CH(Me)2
2
489


377
(azetidine-2-yl)-CO
H
4-Cl-Bn
R
S
C(O)CH(Me)2
2
503


378
Pyd-1-(CH2)2
H
4-Cl-Bn
R
S
C(O)CH(Me)2
2
517

























 














Example
R1
R2
R3
*
R4
n
MS (M + 1)





379
Me
H
4-Cl-Bn
R
C(O)CH(Me)2
1
448


380
MeO2C—CH2
H
4-Cl-Bn
R
C(O)CH(Me)2
1
506


381
NH2—(CH2)2
H
4-Cl-Bn
R
C(O)CH(Me)2
2
477


382
(Me)2N—(CH2)2
H
4-Cl-Bn
R
C(O)CH(Me)2
2
505


383
(3R)Pyd-3-yl
H
4-Cl-Bn
R
C(O)CH(Me)2
2
503


384
(3R)Pyd-3-yl
H
Bn
R
C(O)CH(Me)2
2
489

























 














Example
R1
R2
R3
*
R4
n
MS (M + 1)





385
MeO2C—CH2
H
4-Cl-Bn
R
C(O)CH(Me)2
1
478


386
(Me)2N—(CH2)2
H
4-Cl-Bn
R
C(O)CH(Me)2
2
505


387
(Me)2N—(CH2)2
H
4-Cl-Bn
R
C(O)C(Me)3
2
519


388
Pyd-1-(CH2)2
H
4-Cl-Bn
R
C(O)CH(Me)2
2
503









Example 389
(2R)-2-[(dimethylamino)methylene]amino-N-{(3S)-3-{[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
(2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA (51.4 mg, 0.1 mmol) and dimethylformamide dimethoxyformat (0.24 mg, 0.2 mmol) were dissolved in methanol (5 mL). After the reaction mixture was stirred at rt for 1 h, the solvent was distilled out in vacuo to remove, the residue was purified by HPLC to give the title compound (46 mg, 99%).
MS[M+H]=477 (M+1)
Example 390
(2R)-2-(carboxymethyl)amino-N-{(3S)-3-{[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step B of Example 135 using Example 365.
MS[M+H]=478 (M+1)
Example 391
(2R)-2-(carboxymethyl)amino-N-{4-[cyclohexyl(isobutyryl)amino]piperidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step B of Example 135 using Example 380.
MS[M+H]=492 (M+1)
Example 392
(2R)-2-(carboxymethyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]azetidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
The title compound was prepared following the procedure described in Step B of Example 135 using Example 385.
MS[M+H]=464 (M+1)
Example 393
(2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-yl}-3-(4-chlorophenyl)propionamide 2HCl
Step A: (2R)-2-[(2-nitrobenzene)sulfonyl]amino-3-(4-chlorophenyl)propionic acid methylester
The title compound was prepared following the procedure described in Step C of Example 151 using p-chlorophenylalanine methylester.
MS[M+H]=399(M+1)
Step B: (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-3-(4-chlorophenyl)propionic acid methylester
To a solution of (2R)-2-[(2-nitrobenzene)sulfonyl]amino-3-(4-chlorophenyl)propionic acid methylester (1 g, 2.51 mmol), prepared in Step A, in DMF (10 mL) were added K2CO3 (678 mg, 5.00 mmol) and methyliodide (427 mg, 3.01 mmol). After the reaction solution was stirred at rt for 12 h, the solvent was concentrated in vacuo, and the residue was diluted with aqueous 1n HCl solution. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (932 mg, 90.0%).
MS[M+H]=413(M+1)
Step C: (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-3-(4-chlorophenyl)propionic acid
The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-3-(4-chlorophenyl)propionic acid methyl ester prepared in Step B.
MS[M+H]=399(M+1)
Step D: (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Example 188 using (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-3-(4-chlorophenyl)propionic acid prepared in Step B and (3S)-3-N-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine prepared in Intermediate 81.
MS[M+H]=521(M+1)
Step E: (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
To a solution of (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step D, (691 mg, 1.00 mmol) in DMF (5 mL) were added K2CO3 (270 mg, 2.00 mmol) and mercaptobenzene (0.154 mL, 1.5 mmol), and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was diluted with aqueous 1N HCl solution. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO4, and concentrated in vacuo to give the title compound. This product was used without further purification.
MS[M+H]=506(M+1)
Step F: (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step E.
MS[M+H]=464(M+1)
Step G: (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl
The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA prepared in Step F.
MS[M+H]=464(M+1)
Example 394
(2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl
Step A: (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step A of Example 358 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Example 190 and 2-nitrobenzenesulfonylchloride.
MS[M+H]=677(M+1)
Step B: (2R)-2-{(2-nitrobenzene)sulfonyl[2-(dimethylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl) propionamide
The title compound was prepared following the procedure described in Step B of Example 358 using (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl) propionamide prepared in Step A and dimethylaminoethylchloride.
MS[M+H]=748(M+1)
Step C: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide
The title compound was prepared following the procedure described in Step C of Example 358 using (2R)-2-{(2-nitrobenzene)sulfonyl[2-(dimethylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl) propionamide prepared in Step B.
MS[M+H]=565(M+1)
Step D: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
The title compound was prepared following the procedure described in Step B of Example 187 using (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl) propionamide prepared in Step C.
MS[M+H]=521(M+1)
Step E: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl
The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA prepared in Step D.
MS[M+H]=521(M+1)
Example 395-463
The compounds below were prepared following the procedure described in Example 394 using pyrrolidine or piperidine derivatives prepared in the above Intermediates.
















 

























MS


Exm.
R1
R2
X
R4
R5′
*
n
x
[M + 1]





395
Me
H
Cl
c-Hex
C(Me)(CH2OH)2
S
1
1
480


396
Me
H
Cl
c-Hex
C(Me)2CH2OMe
S
1
1
478


397
Me
H
Cl
c-Hex
C(Me)2CH2OMOM
S
1
1
508


 


398
Me
H
Cl
c-Hex




S
1
1
462


 


399
Me
H
Cl
4-cis-Me-c-Hex
C(Me)2CH2OH
S
1
1
478


400
Me
H
Cl
4-trans-Me-c-Hex
C(Me)2CH2OH
S
1
1
478


401
Me
H
Cl
4-diMe-c-Hex
C(Me)2CH2OH
S
1
1
492


402
Me
H
Cl
4-t-Bu-c-Hex
C(Me)2CH2OH
S
1
1
520


403
Me
H
Cl
4,4-diF-c-Hex
C(Me)2CH2OH
S
1
1
500


404
Me
H
Cl
Spiro[2.5]octane
C(Me)2CH2OH
S
1
1
490


405
Me
H
Cl
4-F-c-Hex
C(Me)2CH2OH
S
1
1
482


406
Me
H
Cl
4-cis-Et-c-Hex
C(Me)2CH2OH
S
1
1
492


407
Me
H
Cl
4-trans-Et-c-Hex
C(Me)2CH2OH
S
1
1
492


408
Me
H
Cl
4-cis-Me-c-Hex
C(Me)(CH2OH)2
S
1
1
494


409
Me
H
Cl
4-trans-Me-c-Hex
C(Me)(CH2OH)2
S
1
1
494


410
Me
H
Cl
4-diMe-c-Hex
C(Me)(CH2OH)2
S
1
1
508


411
Me
H
H
c-Hex
C(Me)2CH2OH
S
1
1
430


412
Me
H
F
c-Hex
C(Me)2CH2OH
S
1
1
448


413
Me
H
Me
c-Hex
C(Me)2CH2OH
S
1
1
444


414
Me
H
OMe
c-Hex
C(Me)2CH2OH
S
1
1
460


415
i-Pr
H
Cl
4-cis-Me-c-Hex
C(Me)2CH2OH
S
1
1
506


416
i-Pr
H
Cl
4,4-diMe-c-Hex
C(Me)2CH2OH
S
1
1
520


417
i-Pr
H
Cl
4,4-diF-c-Hex
C(Me)2CH2OH
S
1
1
528















418
—(CH2)4—
Cl
c-Hex
C(Me)2CH2OH
S
1
1
520


419
—(CH2)5—
Cl
c-Hex
C(Me)2CH2OH
S
1
1
534
















420
i-Pen
H
Cl
c-Hex
C(Me)2CH2OH
S
1
1
520


421
MeO—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OH
S
1
1
508


422
HO—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OH
S
1
1
494


423
(Me)2N—(CH2)2—
H
Cl
4-cis-Me-c-Hex
C(Me)2CH2OH
S
1
2
535


424
(Me)2N—(CH2)2—
H
Cl
4,4-diMe-c-Hex
C(Me)2CH2OH
S
1
2
549


425
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)(CH2OH)2
S
1
2
537


426
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2N(Me)
S
1
3
548


427
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OMe
S
1
2
535


428
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OMOM
S
1
2
565


429
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OBn
S
1
2
611


430
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2O(i-Bu)
S
1
2
577


431
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OPh
S
1
2
597


432
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2SPh
S
1
2
613


433
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OCOPh
S
1
2
625


434
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OCO(c-Hex)
S
1
2
631


435
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OCOBn
S
1
2
639


436
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OCOBu
S
1
2
605


437
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OCO(i-Pr)
S
1
2
591


438
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2CH2OCO(2,5- diF—Ph)
S
1
2
661


439
(Me)2N—(CH2)2—
H
Cl
c-Hex
C(Me)2OAc
S
1
2
563


440
(Me)2N—(CH2)2—
H
Cl
c-Hex
2-(HOCH2)-1-(c-penten)-1-yl
S
1
2
545


441
(Me)2N—(CH2)2—
H
Cl
c-Hex
(3S)-3-(OH)-Pyd-1-yl
S
1
2
534


442
(Me)2N—(CH2)2—
H
Cl
2,3-diF—Ph
C(Me)2CH2OH
S
1
2
566


443
(Me)2N—(CH2)2—
H
Cl
2,3-diF—Ph
N(Me)2
S
1
2
580


444
(Me)2N—(CH2)2—
H
Cl
c-Hex
N(Me)OMe

2
2
522


445
(Me)2N—(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)2F

2
2
552


446
(Me)2N—(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)3F

2
2
566


447
(Me)2N—(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)3OH

2
2
564


448
(Me)2N—(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)2OH

2
2
550


449
(Me)2N—(CH2)2—
H
Cl
c-Hex
N(n-Pr)(CH2)2OH

2
2
564


450
(Me)2N—(CH2)2—
H
Cl
c-Hex
N(i-Pr)(CH2)2OH

2
2
564


451
(Me)2N—(CH2)2—
H
Cl
c-Hex
N[(CH2)2OH]2

2
2
566


452
(Me)2N—(CH2)2—
H
Cl
c-Hex
N[(CH2)2OMe]2

2
2
594


453
(Me)2N—(CH2)2—
H
Cl
c-Hex
(2R)-2-(HOCH2)-Pyd-1-yl

2
2
562


454
(Me)2N—(CH2)2—
H
Cl
c-Hex
4-amino-Pid-1-yl

2
2
561


455
(Me)2N—(CH2)2—
H
Cl
c-Hex
N(Me)(CH2)2OH

2
2
536


456
(Me)2N—(CH2)2—
H
Cl
c-Hex
N(Me)(CH2)2OMe

2
2
550


457
(Et)2N—(CH2)2—
H
Cl
c-Hex
N(i-Pr)(CH2)2OH

2
2
592


458
(Et)2N—(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)2OH

2
2
578


459
1-pyd-(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)2F

2
2
578


460
1-pyd-(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)3F

2
2
592


461
(R)-3-OBn-1-Pyd-(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)3F

2
1
698


462
(R)-3-OBn-1-Pyd-(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)2OH

2
1
682


463
[Me(i-Pr)]N—(CH2)2—
H
Cl
c-Hex
N(Et)(CH2)3F

2
2
594









Example 464
(2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl
Step A: (2R)-2-[2-(diethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA
To a solution of (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl, prepared in Example 394, (521 mg, 1 mmol) in DCM (5 mL) was added Dess-Martin reagent (4M in THF, 0.5 mL). After the reaction mixture was stirred at rt for 12 h, an aqueous Na2S2O3 solution was added portionwise, and the aqueous NaHCO3 solution was added when the reaction solution is clear. The organic layer was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound (610 mg, 85.1%).
MS[M+H]=519(M+1)
Step B: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl
The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA prepared in Step A.
MS[M+H]=519(M+1)
Example 465
(2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((methoxyimino)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
Step A: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((1-methoxyimino)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA
To a solution of (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl, prepared in Example 464, (704 mg, 1.00 mmol) in pyridine (5 mL) was methoxyamine (HCl salts, 167 mg, 2.00 mmol). After the reaction mixture was stirred at rt for 12 h, the solvent was removed in vacuo, and the residue was diluted with a saturated aqueous NaHCO3 solution. The organic material was extracted with EtOAc, and the extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound (500 mg, 91.2%).
MS[M+H]=617(M+1)
Step B: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((1-methoxyimino)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl
The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((1-methoxyimino)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step A.
MS[M+H]=617(M+1)
Biological Assays
A. Binding Assay
The membrane fraction binding assay was used to identify competitive inhibitors of 125I-NDP- -MSH binding to cloned human MCRs expressed in HEK cells.
Cell lines expressing human melanocortin receptor 4 (MC4R) were grown in Φ150 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% CO2 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×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 125I-NDP- -MSH [NEN, Cat. # NEX352 (50 uCi), t1/2=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 h at rt. 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 NaCl) under vacuo at 8 “Hg. The filter was dried for 15 min at rt, and the bottom was sealed. 40 ul of Packard MicroscintTM-20 was added to each well. The top was sealed, and the radioactivity was quantitated in a Packard Topcount Microplate Scintillation Counter. The IC50 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 IC50 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× 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 5×105 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 h in the atmosphere of 6% CO2 at 37° C., 10 ul of NDP- -MSH and test compounds diluted in DMSO were added to each well. The final DMSO concentration was 1%. After 4 h of incubation in the atmosphere of 6% CO2 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 EC0.5 MSH was defined as the concentration of test compounds that results in half maximal activity of NDP- -MSH. The EC50 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 Φ150 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% CO2 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 (10 mM Tris pH 7.4; 0.32M sucrose; 4 ug/ml leupeptin; 10 uM phosphoramidon; 40 ug/ml bacitracin; 5 ug/ml aprotinin). The pellets were homogenized with dounce homogenizer (Bellco with type “B” glass pestle) using 20 strokes. The homogenate was centrifuged at 1300×g at 4° C. for 10 min. The supernatants 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 min. 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 96 well V-plate. 20 ul of 750 ug/ml membrane fraction in MP buffer was added onto each well. After the reaction was performed at rt 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 μM-10 μM of EC50 value and 0.01 μM-50 μM of IC50 value. For example, the compounds of examples 1, 2 and 3 showed 0.005 μM-0.5 μM of EC50 value, and 0.1 μM-0.5 μM 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 h 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 h after, food is re-supplied. Food intakes after the food-supply are measured for the first 1 h 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 h before starting the dark phase, and food is removed. Food is resupplied 1 h after the administration, and food intakes are measured at 1, 2, 4, 8, 24 h 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) rec met. 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 (H 7.4) buffer (time=0) by the intraperitoneal injection. At 6 hs after the crystal injection, the animals are euthanized by CO2 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)×106 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 thust, tiptoe posture) for 1 h.

## Claims

1. A compound of the following formula (1):



in which m and n each independently represents 2,
R1 represents
hydrogen;
heterocycle which is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and which is unsubstituted, or mono- or polysubstituted by substituents selected from halogen and C1-C10-alkyl;
—(CH2)1-3—R6, wherein R6 is selected from the group consisting of hydrogen, C1-C10-alkyl, C1-C8-alkoxy, heterocycle, hydroxy, C1-C8-alkoxylcarbonyl, carboxy, amino, C1-C10-alkylamino, di(C1-C10-alkyl)amino, and C1-C8-alkylcarbonylamino, wherein heterocycle is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and is substituted by one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C1-C10-alkyl, C1-C8-alkylcarbonyl and C6-C10-aryloxy;
glycine, alanine, histidine, phenylalanine or proline, wherein one or more hydrogen atoms on nitrogen atom are unsubstituted or substituted by a substituent selected from the group consisting of C1-C10-alkyl, C1-C8-alkylcarbonyl, C1-C8-alkoxycarbonyl and C1-C8-alkylsulfonyl; or
—SO2—C1-C3-alkyl,
R2 represents
hydrogen;
C1-C8-alkyl;
—CO—(CH2)1-3-hydroxy; or
—CH2—CO-hydroxy,
R3 represents
C1-C8-alkyl which is unsubstituted, or mono- or polysubstituted by substituents selected from C1-C8-alkyl and carbamoyl;
—(CH2)1-3—C3-C8-cycloalkyl; or
—(CH2)0-3—C6-C10-aryl which is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of halogen, hydroxy, C1-C8-alkoxy and C1-C8-alkyl,
R4 represents
C1-C8-alkyl;
—(CH2)1-3—C3-C8-cycloalkyl;
C3-C8-cycloalkyl which is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of halogen, C1-C8-alkyl and C6-C10-aryl;
or
heterocycle which is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring,
R5 represents
carbonyl substituted by a substituent selected from the group consisting of C1-C8-alkyl, C1-C6 alkoxy, C3-C7-cycloalkyl, heterocycle and C6-C10-aryl unsubstituted or substituted by hydroxyl, wherein alkyl is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino, hydroxy, C1-C8-alkoxy, C6-C10-ar-C1-C8-alkyloxy, C1-C8-alkyl C6-C10-aryloxy, C6-C10-aryloxy, C6-C10-arylthio, formyl, C2-C8-alkanoyloxy, C3-C8-cycloalkylcarbonyloxy, C6-C10-arylcarbonyloxy unsubstituted or substituted by halogen, C6-C10-ar-C1-C8-alkylcarbonyloxy; cycloalkyl is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of hydroxycarbonyl, C1-C8-alkoxycarbonyl, hydroxyl-C1-C8alkyl, and wherein heterocycle is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and is unsubstituted, or mono- or polysubstituted by the substituents selected from the group consisting of hydroxy, hydroxyC1-C8-alkyl, amino and 2-nitrobenzenesulfonyl;
—(CH2)1-3—C(═O)—C1-C6-alkoxy;
carbamoyl which is mono- or polysubstituted by substituents selected from the group consisting of hydrogen, C1-C8-alkyl, C1-C6-alkoxy, C3-C7-cycloalkyl, C6-C10-aryl and C1-C8-alkylcarbonyl substituted by hydroxy, wherein alkyl is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of halogen, hydroxy, amino and C1-C8-alkoxy;
—(CH2)1-3—C(═O)N(C1-C8-alkyl)(C1-C8-alkyl);
—C(═S)N(H)(C1-C8-alkyl) or —C(═S)N(H)(C1-C8-alkyl)(C1-C8-alkyl); or
—SO2—NH2 or —(CH2)0-3—SO2—C1-C8alkyl,
wherein heterocycle can be fused with benzo or C3-C8-cycloalkyl, and which is saturated or has 1 or 2 double bond, or
a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.

2. The compound according to claim 1, wherein
R1 represents
hydrogen; or
—(CH2)1-3—R6, wherein R6 selected from the group consisting of hydrogen, C1-C10-alkyl, C1-C8-alkoxy, heterocycle, hydroxy, C1-C8-alkoxylcarbonyl, carboxy, amino, C1-C10-alkylamino, di(C1-C10-alkyl)amino, and C1-C8-alkylcarbonylamino, wherein heterocycle is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and is substituted by one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C1-C10-alkyl, C1-C8-alkylcarbonyl and C6-C10-aryloxy; or
a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.

3. The compound according to claim 1, wherein
R2 represents hydrogen or C1-C6-alkyl, or
a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.

4. The compound according to claim 1, wherein
R3 represents —CH2-phenyl which is unsubstituted or mono- to tri-substituted by substituents selected from the group consisting of chloro, bromo, hydroxy, methoxy and methyl, or
a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.

5. The compound according to claim 1, wherein
R4 represents C3-C8-cycloalkyl which is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of halogen, C1-C8-alkyl and C6-C10-aryl, or
a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.

6. The compound according to claim 1, wherein
R5 represents carbonyl substituted by the substituent selected from the group consisting of C1-C8-alkyl, C1-C6-alkoxy, C3-C7-cycloalkyl, heterocycle and C6-C10-aryl unsubstituted or substituted by hydroxyl, wherein alkyl is unsubstituted, or mono- or polysubstituted by the substituents selected from the group consisting of amino, C1-C6-alkylamino, di(C1-C6-alkyl)amino, hydroxy, C1-C8-alkoxy, C6-C10-ar C1-C8-alkyloxy, C1-C8-alkyl C6-C10-aryloxy, C6-C10-aryloxy, C6-C10-arylthio, formyl, C2-C8-alkanoyloxy, C3-C8-cycloalkylcarbonyloxy, C6-C10-arylcarbonyloxy unsubstituted or substituted by halogen, C6-C10-ar-C1-C8-alkylcarbonyloxy; cycloalkyl is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of hydroxycarbonyl, C1-C8-alkoxycarbonyl, hydroxyl-C1-C8-alkyl, and wherein heterocycle is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and is unsubstituted, or mono- or polysubstituted by the substituents selected from the group consisting of hydroxy, hydroxyC1-C8-alkyl, amino and 2-nitrobenzenesulfonyl, or
a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.

7. An agonistic composition of melanocortin receptor comprising the compound of formula (1), or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof as defined in claim 1 together with a pharmaceutically acceptable carrier.