Description MELANOCORTIN RECEPTOR AGONISTS Technical Field [1] The present invention relates to a compound of the following formula 1, pharma- ceutical!}' acceptable salt or isomer thereof effective as an agonist for melanocortin receptor: .2] F*5 (1) [4] wherein R1, R2, R3, R" and R5 are as defined below. [5] The present invention also relates to a process for preparing a compound of the above formula I. [6] The present invention also relates to a melanocortin receptor agonistic composition comprising a compound of the above formula 1 as active ingredient, in particular, a composition for the prevention and treatment of obesity, diabetes, inflammation or erectile dysfunction. 171 Background Art [8] 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 phys¬iological functions. Melanocortin 1 receptor (MC(R) is mainly expressed in melanocytes, raonocyles, 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, hy¬pothalamus, 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. [9] [10] 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 us MSI I. These peptide agonists have been used to characterize the function of these receptors. NBP-MSH is a highly potent and nonselective agonist of MCI R, 3R, 4R and 5R, and has been reported to attenuate food intake and body weight gain in rat models. A cyclic hep-lapeptidc MT-TI 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. [HI [ 12] Small molecule agonists for the melanocortin receptors have been reported to have significant activity in drug trials for the treatment of obesity, sexual dysfunction or in-flamation. For example, a series of potent and selective MC4R agonists has been identified, one of which demonstrated significant effect for augmenting erectile response En mice (/. Med. Chem. 2002, 45, 4849). A number of MC4R agonists have also been identified, which displayed hyphophasic activity and anti-obesity effect in the rat model (Btoorg. Med. Chem. Utt. 2005,15,171, Bioorg. Med. Chem. Utt. 2005, 15, 3430, Bioorg. Med. Chem. Utt. 2005, 15, 3501). A highly potent and selective MC1R agonist has been discovered, which showed efficacy in an acute mouse model of inflammation (J. Med. Chem. 2003, 46, 1123). In addition, a variety of small molecules as MCR agonists have been described in the patent applications (WO 01/55109, WO 01/70337, WO 01/70708, WO 02/018327, WO 02/059095, WO 02/059107, WO 02/059117, WO 02/059108, WO 02/081443, WO 02/085925, WO 02/15909, WO 02/067869, WO 02/068387, WO 02/068388, WO 03/009847, WO 03/009850, WO 2004/087159, WO 2004/078716, WO 2004/078717, WO 2005/040109, WO 2005/047251, WO 2005/077935, WO 2005/077935, WO 20067019787, WO 2006/020277, WO 2007/041052, WO 2007/041061, WO 2007/047496, WO 2006/072393, WO 2007/015157, WO 2007/015162). [13] [14] 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. [151 Disclosure of Invention Technical Solution {16] The present invention provides a compound of formula 1 having agonistic effect against MCRs, in particular, selective agonistic effect against MC4R, pharmaceutically [33] R and R may combine each other lo form single ring or two rings, or further comprise oxygen atom or sulfur atom, [34] wherein, alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl is unsubstituted or substituted with a subsliluent selected from the group consisting of methyl, triflu- oromclbyl, hydroxy, hydroxyimino, amino, acetylamino, (C -C -alkyl)amino and (C -C 4-aIkyI)(C-C^aIkyl)aTnino, [35] RJ represents C -C -cycloalkyl, C -C -aryl, heteroaryl or fieterocyclc, [36] wherein, C -C -aryl or heteroaryl is unsubstituted or mono- or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, C -C -alkyl, trU fluoromethyl, C -C -alkoxy and amino, 1 4 [37] cycloalkyl or heterocycle is unsubstituted or mono- or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, C -C -alkyl, triflu- 1 4 oromethyl, C -C -alkoxy and oxo, 1 4 [38] R5 represents hydrogen, C -C -alkyl, -C(0)-Rn, C -C -alkylsulfonyl, C -C - 16 16 6 10 arylsulfonyl, [25] R1 represents hydrogen, amidino, C -C -alkylarnidino, C -C -alkanoylamidino, C -C -alkyl, C -C -cycloalkyl, C -C -aryl, heterocycle, heteroaryi, C -C -alkylcarbonyl, C - 3 7 6 10 16 3 C -cycloalkylcarbonyl, C -C -alkoxycarbonyl, C -C -aryl-C -C -alkoxycarbonyl, SO -C -C -alkyl, -C(0>N(R*)(RS or -C(S>-N(R6)(R ), [26] wherein, [27] R6 and R7 each independently represents hydrogen, C -C -alky! or C -C -cycloalkyl, 16 ^7 [28] alkyl, cycloalkyl, heterocycle, aryl or heteroaryi is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, amino, C -C -alkyl, trifluoromethyl, hydroxy, C -C -alkoxy and oxo, [29] R2 represents C -C -aryl or heteroaryi, each of which is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of halogen, hydroxy, C -C -alkyl, C -C -alkoxy, cyano and amino, [30] R3 represents hydrogen, cyano, C -C -alkyl, C -C -cycloalkyl, C -C -alkenyl, monocyclic heterocycle, monocyclic heteroaryi, -C(0)-R or -C(S)-R , [31 ] wherein, R8 represents hydroxy, C -C -alkyl, C -C -alkyloxy or N(R9KR10), [32] K9 and R10 each independently represents hydrogen, C -C -alkyl, C -C -cycloalkyl, C J 6 3 7 1 -C -alkyloxy, phenyl or heteroaryi, or 4 to 6-mernbered ring which can be fused with benzo or C -C -cycloalkyl. Examples of monocyclic heteroaryl are, but not limited to, thiazole, oxazole, tbiopbene, furarje, pyrrole, imidazole, isoxazole, pyrazolc, triazolc, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and similar group thereto. Examples of bicyclic heteroaryl arc, but not limited to, indole, benzolhiophene, benzofuran, benz-imidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinolinc, purine, furopyridinc, and similar group thereto. [48] The term "heterocycle" includes 1 to 2 heleroatom(s) from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and represents 4- to 8-tnembered ring which can be fused with benzo or C -C -cycloalkyl, and which is saturated or has 1 or 2 of double bond. Its examples are, but are not limited to, piperidine, morpholine, (hi-amorphoJine, pyrrolidine, imidazolidine, letrahydrofuran, piperazine, and similar group thereto. [49] [50] Preferred compounds among the compounds of formula 1 above are those wherein [51] i) R represents hydrogen, amidino, C -C -alkylamidino, C -C -alkanoylamidino, C - 14 1 4 1 C -alkyl, C -C -cycloalkyl, phenyl, monocyclic lieterocycle, monocyclic heteroaryl, C 6 3 7 1 -C -alkylcarbonyl, trifluoroacetyl, C -C -alkoxycarbonyl, C -C -aryl-C -C -alkoxycarbonyl, -SO -C -C -alkyl, carbamoyl, C -C -alkylcarbamoyl, (C -C -alkyl)(C - 2 14 16 1 & 1 C -alkyl)carbamoyI, thiocarbamoyl, C -C -alkylthiocarbamoyl or (C -C -alkyl)(C -C -alkyl)thiocarbamoyI, [52] more preferably, R1 represents hydrogen, amidino, methylamidino, ethylamidino, acetylamidino, methyl, ethyl, trifluoroethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxazolynyl, imidazolynyl, thiazolynyl, piperidinyl, telrahydropyranyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridinyl, acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, pivaloyl, r.ietfioxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, methylsulfonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, trifluoroethylcarbamoyl, propylcarbamoyl, iso-propylcarbamoyl, butyl carbamoyl, t-butylcarbamoyl, thiocarbamoyl, methylthio-carbamoyl, ethylthiocarbamoyl or methylethylcarbamoyl, [531 [54] ii) R3 represents phenyl unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of F, CI and methyl, [55] more preferably, R3 represents phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methyIphenyl or 2,4-difluorophenyl, [56] [57] iii) R3 represents hydrogen, cyano, C -C -alkyl, C -C -alkenyl, -CH C(CH ) CH OH, \ 4 2 4 ? 3 3 2 oxazolyl, thiazolyl, oxazolynyl, thiazolynyl, carboxy, C -C -alkylcarbonyl, C -C - alkyloxycarbonyl, carbamoyl, thiocarbamoyl, C -C -alkylcarbamoyl, (C -C -alkyl)(C - T 4 I A } C -alkyl)carbamoyl, (C -C -alkyl)(C -C -a I kyloxy Carbamoyl, C -C -alkylthtocarbamo)'] or(C -C -alkyJ)(C -C -alkyOtbiocarbamoyl, phenylcarbamoyl, bet-eroarylcarbamoyl, azetidinecarbonyl, pyrTolidinecarbonyl, piperidinecarboTiyl or mor-pbolinecarbonyl, [58] wherein, alkyl is unsubstituted or substituted with a substituent selected from the group consisting of hydroxy, hydroxyimino, amino, (C -C -alkyl)amino and (C -C -alkyl)(C -C -alkyl)amino, [59] more preferably, R represents hydrogen, cyano, methyl, ethyl, propyl, ally!, - CHNOH, hydroxymethyl, -CH(CH )OH, aminomethyl, dimethylaminomethyl, oxazolyl, thiazolyl, oxazolynyl, thiazolynyl, carboxy, acetyl, propanoyl, methoxycarbonyl, elhoxycarbonyl, isopropoxycarbonyl, t-buloxycarbonyl, carbamoyl, thiocarbamoyl, ethylcarbamoyl, t-butylcarbamoyl, dimethylcarbamoyl, methylelhyl-carbamoyl, methylmethoxycarbamoyl, dimethyl thiocarbamoyl, phenylcarbamoyl, het-eroarylcarbamoyl, -C(0)NH(CH ) NIT , azelidinecarbonyl, pyrrol idinecarbonyl, piperidinecarbonyl or morpholinecarbonyl. T60] [61] iv) R represents C -C -cycloalkyl or monocyclic heterocycle unsubstituted or mono- A 7 or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, C -C -alkyl, trifluoromethy I, C -C -alkoxy and oxo; or phenyl or monocyclic heteroaryl unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of halogen, hydroxy, C -C -alkyl, trifluoromethyl, C -C -alkoxy and ] i 4 4 amino, 62] more preferably, R represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methyIcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4-trifluoromethyIcyclohexyl, 3,4-tetramethylcyclopentyI, tetrahydropyranyl, pyridinyl, N-methylpyridinyl or phenyl, 63] wherein, phenyl is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of F, CI, methyl and methoxy. 64] 651 v) R5 represents hydrogen, C -C -alkyl, trifluoromethyl, C -C -alkylcarbonyl, triflu- 15 16 oroacetyl, acryloyl, methacryloyl, C -C -cycloalkylcarbonyl, C-€. - 3 8 3 8 cycloalkenylcarbonyl, carbamoyl, C -C -alkylcarbamoyl, (C -C -alkyl)(C -C - 14 14 14 alky])carbamoyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, benzoyl, hy-droxybenzoyl, aminobenzoyl, monocyclic heteroarylcarbonyl, helerocyclecarbonyl, benzyl, -Cl-I -monocyclic heteroaryl, or -CU -C -C -cycloalkyl, 2 2 J 8 66] more preferably, R represents hydrogen, methyl, ethyl, propyl, isobutyl, hy- droxyethyl, -CH C(CH \CU OH, -CU C(CH ) CH(CH )OH, -CH CH NHCCO)^, aminoethyl, acetyl, trifluoroacetyl, hydro xyacciyl, merboxyacefy], ethoxyacelyl, propionyl, ethoxy propionyl, isobulyryl, cyanoisobulyryl, hydroxyisobutyryl, car-bamoylisobutyryl, 3,3-dimethylbutanoyl, pivaloyl, ftuoropivaloyl, difluoropivaloyl, hydroxypivaloyl, mercaptopivaloyl, dihydroxypivaloyl, melhoxypivaloyl, ethoxypivaloyl, aminopivaloyl, dimethylaminopivaloyl, hydroxyiminopivaloyl, acelylisobutyryl, -C(0)C(CII ) CH(CH )OH, -C(0)C(CH ) C(C1I ) OH, acryloyl, 3 2 3 3 3 12 meihacryloyl, cyclopentaneearbonyl, eyclohexylenccarbonyl, carbamoyl, dimelhyl-carbamoyl, methanesulfonylcarbonyl, benzoyl, thiopenecarbonyl, fufoyl, oxa-zolecarbonyl, thiazolecarbonyl, imidazolecarbonyl, pyrazolecarbonyl, letrahy-drofuroyl, dihydrofuroyl, tetrahydropyrancarbonyl, morpholinecarbonyl, methanesulfonyl, benzyl, furanmethyl, thiazolemethyl or imidazolemethyl. [67] [68] The compounds according to the present invention also can form pharmaceutically acceptable salts. These pharmaceutically acceptable salts include acid-addition salts formed by acid which contains pharmaceutically acceptable anion to form non-toxic acid addition salt, 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; sulfonic acid such as methanesulfonic acid, benzenestdfonic acid, p-toluenesulfonic acid or naphthale-nesulfonic acid, and the like; and more preferably acid-addition salts formed by sulfuric acid, methansuifonic acid or hydrohalic acid, and the like. The compounds of formula 1 according to the present invention can be converted to its salts by con¬ventional method. [69] 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. [70] [71 ] Also, the present invention relates to a process for preparing the compound of formula 1 comprising amide coupling a compound of formula 2 with a compound of formula 3: f72] O ,73] [74] R' HN NT R5 ,R' RLN [75] [76] (3) [77] [78] [79] [80] (1) wherein, R , R", R , R4 and R' are as defined above. Also, the present invention relates lo a process for preparing the compound of formula 1 comprising amide coupling a compound of formula 2' with a compound of formula 3 to form a compound of formula 1': and deprotecting the compound of formula 1': O P-N on P-N [81] [82] (21) (!') R"LN [83] [84] ? F F? F? (I) [85] wherein, R represents hydrogen, f 86] R , R', R and R arc as defined above, fS7] P represent amino protecting groups, preferably l-butoxycarbonyl (Boc), benzy- loxycarbonyl (Cbz) or fluorenylmethnxycarhonyl (Fmoc). W) [89] Also, the present invention relates to a process for preparing the compound of formula 1 comprising deprotecting the compound of formula 1! in the above process followed by (i) amide coupling with C -C -alkyl-CO H, or (ii) reacting with 1 6 2 isocyanate, C -C -aikyl isocyanate, isothiocyanateorC -C -alkylisolhiocyanate: 14 14 [90] [91] R!-N [92] [93] (!') 0) [94] wherein, R represents C -C -alkylcarbonyl, carbamoyl, thiocarbamoyl, C -C - alkylcarbamoyl or C -C -thiocarbamoyl, I 4 [95] wherein, aikyl is unsubstituted or substituted with a substituent selected from the group consisting of halogen, amino, C -C -aikyl, trifiuoromethyl, hydroxy, C -C - 14 I 4 alkoxy and oxo; [96] R2, R3, R4 and R5 are as defined above. i97] [98] It is preferable to carry out each step of the above processes 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, dimcthylacetamide, tetrahydrofuran, methylene chloride, and chloroform. [99] Deprotection reaction for amino groups can be carried out in the presence of strong add such as hydrochloric acid (I IC1), trifluoroacetic acid (TFA), etc., in the presence of amine base such as triethylaminc, diisopropylethylamine (DIl'HA), etc., or by hy- drogenalion. Specific reaction conditions are described in T. W. Green & G. M. Wilis Protective Groups in Organic Synthesis, Chapter 7, pp 309-405. [100] Known coupling agents usable in coupling reaction are, but are not limited to, car- bodiimides such as dicyclohexykarbodijmide (DCC), l~(3-dimethylaminopropyI)-3-ethylcarbodiirnide (EDC), l,l'-dicarbonyldiimidazole (CDf), etc. which are used in a mixture with 1 -hydroxybenzotriazole (HOBT) or f-hydroxy-7-azabenzotriazoIe (HOAT); bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride (BOP-C1), diphenyiphosphorylazide (DPPA), N- rdimethylamino-lH'l12,3-lriazoI[4,5-b]pyridine-l-ylmetliyIene]-N-methylmethaneami num (HATU), etc. [101] Tlie compounds of formula 1 prepared by the process of the present invention can be converted to its safts by conventional method. [102] After the above reactions according to the process of the present invention are completed, products can be separated and purified by conventional work-up methods, for example, chromatography, recrystallization, etc. [103] [104] The compounds of (he 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. [ 105] 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 ~ lOmg/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. [106] Any route depending on purpose can administer the compounds according to the present invention. Injection, and oral and nasal administration are preferred, but admin¬ istration may be made through dermal, intraperitoneal, retroperitoneal, and rectal route. [107] 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 diis purpose are water, ringer's solution, and isotonic NaCl solution, and sterilized fixed oit 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. ["108] Solid dosage forms for oral administrations are capsules, tamets, puis, powders ana granules, and in particular, capsules and (ablets are useful. Tablets and pills are pieferable to be prepared as enteric coaling. Solid dosage forms can be prepared by mixing the compounds of formula 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, disintegranls, binding agents, etc. [109] [110] Representative compounds of formula I according to the present invention include the following listed compounds: fill] [112] (45)-1 - {[(35,4/?)-1 -fetf-bu!yl-4-(2,4-dinuorophenyl)pyrro!idine-3-yl]carbonyl} -4-[(4, 4-dimethylcyclohexyl)(2,2-drmethylpropanoyi)arnino]-W,A'-dimethyl-L-prolineamide [113] [114] (4.9)-1 - {[(35,4/?> l-tert-butyI-4-(4-chlorophenyI)pyrrolidine-3-yl]carbonyl }-4- {(4,4- dimethylcyclohexyI)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-A',W-ethyImethyl-L-pr olineamide [115] [116] (AS)-1 - {[OSA^ l-^rf-buryl-4-(4-chlorophenyl)pyrroIidine-3-yl]carbonyI }-4- {(4,4- dimethyIcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-A'-ethyl-L-prolineami de [117] [118] (45)-l-{r(35,4/?)-l-^rt-butyl-4-(2,4-dinuoraphenyI)pyrrolidine-3-yl]carbonyl]^-[(4, 4-dimethylcycIohexyl)(3-hydroxy-2,2dimethylpropanoyl)aniinol-A'-ethyl-A'-methyMJ- prolineamide [119] [ 120] (AS)-1 - [ [(35,4/?)-1 -fert-butyl-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}-4-[(4,4-d ifluorocyclohexyl)(2,2-dimethylpropanoyl)amino]-A/,A/-dimethyl-L-proIineamide [121] [ 122] (AS)-1 - {[(3S,4/?)-l -/£rf-butyl-4-(4-chlorophenyI)pyrrolidine-3-yl]carbonyl ]-4-[(4,4-d ifluorocyclohexyl)(2,2-dimethylpropanoyl)amino]-//-ethyl-L-prolineamide [123] [ 124] (45)-1 - [ [(35,4/0-4-(4-chlorophenyI)-1 -meuiylpyrroUdine-3-yl]carbonyl) -4-[(2,2-dim ethylpropanoyl)(cis-4-mcthylcycIohexyI)amino]-L-prolineamide [125] [126] NT-[(3S)-l-([(3S,4R)-l-t-butyl-4-(4-chlorophenyl)pyrTolidine-3-yl]carbonyl]pyrTolidi ne-3-yll-N-(4,4-dimethylcyclohexyI)-3-hydroxy-2,2-dimethylpropaneamide [127] [ 128] N-[(3S)-l-[ [(3S.4R)-! -l-bulyM-(4-chlomphenyl)pym>lidine-3-yl]carbony!} pyrrolidi ne-3-yll-N-(4,4'dimethylcyclo!ioxyl)-2,2-dimeihy]propancamide [129] [130] (45)-l-{f(35,4/?)-l-rcr/-butyI-4-(2,4-dinuorophcnyi)pyrrolidme-3-y1]carbonyl}-4-[(4, 4-dinielhyicyclohexyl)(melhylsulfon5'l)amiTio]-Af,A'-dimeihyl-L-proliiieamide [131] [132] N-[(3S)-! - {[(3S,4R)-1 -t-butyl-4-(4-chIorophenyl)pyn«lidine-3-yl]carbonyl Jpyrrolidi ne-3-yl](4,4-dimethyIcyclohexyI)amino}-2,2-dimeUiylpropane-l-ol [133] [ 134] <35> 1 - {[(35",4/?)-1 ^cn-butyl-4-(4-chlorophcnyl)pyrrolidine-3-yI]carboiiyI} -A'-isabut yl^A'-(cis-4-methylcyclohexyl)pyn-olidine-3-amine [135] [ 136] (45> 1 - [ f (3S,4/?H -fert-buty ]-4-(4-chlorophenyl)pyiro1idiiie-3-yI]carboriyl) -4-[(cw-4 -mcthylcycl ohex yl)(telrahydro-2//-pyran-4-y lcarbonyl)amino]-L-prolineamide [137] [ 138] (45)-1 - {[(3S,4K)-1 -/eft-butyl-4-(2,4-difluorophenylpyrTGlidine-3-yl]carbonyI }-4-f (4, 4-iiimelhyIcyclohexyl)(3-thicnylcarbonyI)amino]-IJ-prolineamide [139] f 140] (45)-1 - {[(35,4/?)-1 -/e^butyl-4-(2,4-difluorophenyI)pyrTolidine-3-yl]carbonyl ] -4-[(4, 4-di methyl cyclohexyl)(isobutyryl)amino]-A',A'-dimethyl-L-proIineaniide [141] [ 142] (45)-1 - [ [(35,4«)- l-(ert-butyl-4-(4-chlorophenyl)pyrrolidine-3-y1]carbonyl} -4-f(4,4-d imethyIcycIohexyI)(2,2,-dimethylpropanoyl)amino]-iV,A'-dimethyi-L-prolineainide ri43] [144] (45)-l-[[(35',4/;)-l-rert-butyJ-4-(2,4-difluoropheny1)pyiTolidine-3"yl]carbonyl}^-[(2, 2J-dimelhylpropanoyl)(c/i,-4-melhylcyclohexyI)amino]-/V,W-dimethyl-L-prolineamide [145] [146] (45)-l-[[(35,4/?)-l-(ert-buty]-4-(2,4^difluorophenyl)pyrroUdine-3-yl]carbony|)^-[(4, 4-dimethylcyclohexyl)(2,2,-dimethylpropanoyl)amino]-W-ethyl-L-prolinearaide [147] [148] (45)-l-{[(35,,4fi)-l-(ert-butyl-4-(2,4-difluorophenyI)pym)lLdiiie-3-yl]carbonyl}^-[(4, 4-dimethylcyclohexyl)(2,2,-dimethylpropanoyl)araino]-W-ethyl-A'-methyl - L-prolineamide ri49] f 150] (45)-1 - {f (35,4W>1 -(crt-buty1-4-(2,4-dinuorophenyl)pyiTolidine-3-yl]carbonyI }-4-[(4, 4-dimethylcyclohexyl)(2,2,-diTnethylpropanoyi)amino]-A/-isopropyl-L-prolineamide [151] [152] Af-[(3.S,,55)-5-(a7£tidine-l-ylcarboiiyl)-l-{((3S,4ff)-l^er/-butyl-4-(2,4-dinuorophenyl )pyrroHdine-3-yIlcarbonyl}pyrrolidiiie-3-yI]-A'-(4,4-dimeUiy|cyclohcxyl)-2,2-dimethyl propaneamide [153] [154] (4.V)-1-[f(35,4/?J-l-(en-butyl-4-(2,'1-difluorophenyl)pyrro1idiiie-3-yncarbonyI}^-((2, 5-d ihydrofuran-3-yJcarbonyI)(4,4-()imelhyfcyc/ohcxyl)amino]-A', A'—dimethyl-L-proltn eamide [155] [ 156] (45)-1 - {[(35,4fl> 1 ^rt-bulyl-4-(4-chloropheny!)pyrTOHdine-3-yllcarbonyl} -4-f (4,4-d imethyIcyclohexyl)(3-hydroxy-2,2,-dimcthylpropaiioyI)aniino]-A/,W-diinethyl-L-proliii eamide [157] [158] (4S,)-l-{[(35,4ff)-l-(crt-butyl-4<2,4-dinuorophenyl)pyrToHdine-3-yncarboiiyl}^[(4, 4-dimethyIcycIohexyI)[(2S)-tetrahydrofiiran-2-y[carbonyI]amino]-/V,/V-dimethyI-L-proI ineamide [159] [ f 60] (45)-1 - [ {QSARy 1 -/erl-butyl-4-(2,4'dinuurophenyl)pyrTo!idine-3-yl]carbonyl ] -4-[(4, 4-difluorocyclohexy!)(3-hydroxy-2,2,-dimethylpropanoyl)amino]-A',A'-dimethy1-L-pro! ineamide [161] [162] (41?)-1-{[(3.S',4/?)-K(eft-butyl-4-(2,4-diniioraphenyl)pyrrolidine-3-yl]carbonyl]-4-[(4, 4-dimethylcyclohexyl){3-hydroxy-2,2,-dimethyIpropanoyl)amino]-Af-ethyl-A/-methyl-L -prolineamide n63] [164] (45)-l-{[(35!4R)-l-fert-butyM-(4-chIorophenyl)pyrrolidine-3-y]lcarbonyl}-4-[(4,4-d Jinelhylcyc]ohexyJ)(3-furoyl)amiTio]-A',A'-dimethyl-L-proHneamide [165] [ 166] (45)-1 -[ [(35,4ff)-1 ~/ert-butyi-4-(2,4-difluorophenyl)pyrrulidine-3-yncarbony]} -4-[(4, 4-dimethyicyclohexyl)(3-furoyi)amino]~A'-ethyl-Af-methyl-L-proIineamide [167] [ 168] N-[(3S)-1 -{[(3S,4rt)-1 -tert-bMyI-4-(4-chlorophenyl)pyrrolidiiie-3-yl]carbonyl ] pyrrol idine-3-yn~A'-r(4,4-difIuorocycfohexy0(3-hydroxy-2,2-dimethyIpropanoyl)arnfrio]-A'-e thyl-ALmethyI-L-pralineamide [169] f 170] (45)-1 - [ [(35,4/?)-1 -/ert-butyl-4-(2,4-dinuorophenyl)pyTTolidine-3-yl]carbonyl} -4-f (4, 4-dimethylcyclohexy])[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-W-ethyl-//-methyl-L -prolineamide [171] [172] (45)-1-{[(35,4/?)-l-^n-buty1-4-(4-ch!orophenyl)pyiTolidine-3-yl]carbonyl)^-[(4,4-d inuorocyctohexyl)(^,2,-diniethyipropa.noyl)iiniinohAr-elhy(-Af-mclhyl-L-proIiiieaniide |H3] [ 174] (AS)-1 - (f (3£,4K}-1 -fett-butyl-4-(4-cl)InropheTiyl)pyiroli(liiit;-3-yl]carbonyI }-W-elhyI- 4-f(3-hydroxy-2,2,-dimethylpropaiioyl)- r.is-4- me(hylcydohexylaniino]-/V-methyl-L-pr olineamide [1751 [1761 W-[(3X,5S)-1-{[(35,4R)-l-fcrt-butyM-(4-chlorophenyl)pyrToIidiFie-3-yllcarbonyll'5- (J'ethyl(methy()aniino]carbonyI)pyiTot(dine-3-yiI-(V-(4I4-dimelhylcyclohexyl)-2,2-dim ethylpropaneamide [1771 [I7S] ^-f(35',51Vl-f[(35',4«>l-lert-bulyl-4-(4-ciilorophenyl)pyrro(idiiie-3-yiIcarbony[]-5-( pyiTolidine-l-ylcarbonyl)pyrrolidine-3-yI]-A'-(4,4-dinuorocyclohexyl)-2,2-dimethylprQ paneatnide [179] f 180) (4,S> J - {\(3SARyi -tert-bufyl-4-(4-chlorophenyl)pynt>Jidine-3-yJ]carbonyi }-]-N-erby] -A'-methyl-4-{spiro[2,51oct-6-yI[(2S)-tctrahydrofuran-2-ylcarbonyl]amino)-L-prolinea mide [181] [1821 A'-[(35,55-l-{[(35,4K)-l-rer(-butyl-4 (4-cblorophenyl)pyrTolidine-3-yl]carbonyl)-5-( moq)holme-4-ylcarbonyl)pyiTolidine-3-yl]-W-(4,4-diinethylcyclohexyl)acetamide [t83] [184] (45) l-jf(35,4fl)-l-Krt-butyI-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl)-4-[(4,4-d imethy!cyclohexyl)r(2R)-tetrahydrofuran-2-ylcarboiiyl]amiTio]-/V-ethyl-W-methyl-L-pr olineamide [185] [186] (45)-l~([(35,4«)-l-(ert-bulyl-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl)^-[(4,4-d imethylcyclohexyl)(3-hydroxy-2,2,-dimelhyIpropanoyl)amino]-A/-ethyI-L-prolineamid e [187] [ 188] (4S)-1 - [ [(3S,4R> 1 -tert-bulyI-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl M-[(4,4-d imethylcyclohexyl)(2,2,-dimethyIpropanoyf)aminol-A'-phenyI-L-proIineamide [189] [190] (25J-W-[(35)-l-{[(3S,4/?)-U(erf'butyl-4-(4-chlorophenyl)pyn-otidine-3-yllcarbonyl)p yrrolidine-3-yI]-W-(4,4-dimethylcyclohexyl)tetrahydrofuran-2-carboxamide [192] Ar-[(3S)-l-{[(3S,4K)-l-^rt-butyI-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}pyrTol idine-3-yl]-2-methyl-W-[ci.j-4-(trif!uoromethyl)cycIohexyl]propaneaniide f!93] f!94] (2S>Atf(35}-l-{f(35,4«)-!-f«rr-hutyM-C2,4-difluorophenyI)pyiToIidiiie-3~yncarbtmy 0pyn'oHdinc-3-yl'|-JV-(4,4-diniethylcyc:lnht;xyI)telratiydrofuraii-2-carhoxamide [195] [196] N-[(3S)-\- [ \(3S,AR)-1 -terf-butyl- -4-(2,4-dinuorophenyl)pynolidine-3-yllcaibonyl }py n-o{idma-3-y(J-Ar-(4,4»dimethyfcyc[ohexyi)tetrahydrofuran-3-carboxamide [197] [I9S] A'-f(3,S')-l-(f(35,,4ff)-I-^rt-butyI-4-(2,4-diftuorophenyI)pyrrolidiiie-3-yI]carbony[ipy rrolidine-3-yl]-A'-(4,4-di methyl cyclohexyl)-3-hydroxy-2,2-dimelhylpropaneamide fI99J [200] A'-[(3,S>1 -{\(3SAR)-1 -fert-butyI-4-(4-chloropheiiy1)pyiralidine-3-yl]caiboiiyl Jpyrrol id(ne-3-ylI-A/-cyc(ohep(yl-3-hydroxy-2,2-dime(hylpropaneamide r2on [202] (4^-l-{f(3,?,4/?>l-Wrt~butyM-(4-chIoropIienyf)pyrTOlidine-3-yl]carbanyl)^-{(4,4- dimethyIcycIohexyl)[(raethylsulfonyl)amino}-A'-ethyl-A/-methyl-L-prolineamide [203] [204] (35)-l-{[(35',4«)-l-/ert-buty]-4-(4-chIoroPhenyl)pym)lidine-3-yl]carbonyI}-N-(4,4-di me(hy[cycJohexyl)-A'-3-fuiylpyrroIidifte3-anirne [205] [206] A'-[(3i-,55)-)-{[(3A,,4ffM-refr-!)UtyJ-4-(4-chloTOpheny0pyrralrdine-3-yI]carbonyl]-5-(4,5-dihydro-l,3-oxazole-2-yl)pyiTolidine-3-yl]-A7-(4,4-diniethyIcyclohexyl)-2,2-dimet hylpropaneamide [207] [208] Ar- {(3S,5S)-1 - {[(3S,4R)~ 1 -fcrt-biityM^(4-cbloropheny0pyrrolidine-3-yl]carbonyI (-5-f(dimethylamino)carbonothionyllpyrroUdiiie-3-yl)-Ar'(4,4-dirnethylcyc]ohexyI)-2-meth ylpropaneamide [209] [210] A74(35',5y?)-l-{[(3i',4y?)-l-fen'-butyI-4^2,4-difluorophenyI)pyrrolrdine-3-y(]carbonyf }-5-(l,3-thiazoIe-2-yl)pyrrolidine-3-yl]-A'-(4,4-dimethylcyclohexyl)-2,2-diTnethylpropa neamide [211] [2 t2] N-t(3S,5S)-l-{ [(3SAR)-1 -^rt-butyM~(4-chlorophenyJ)pyrrolidine-3-yJ]carbonyI }-5- (hydroxymethyI)pyirolidine'3-yn-A/-(4,4-diroethylcycIohexyl)-2,2-dimethylpropaneam Ide [213] [214] N-[(3S,5S)-1 - { [(3S,4R)-1 -tert-batyt-4-(4-chlovaphenyl)pytTalidine-3-yUcarbonyl )-5- methyl pyrrol idine-3-y 11^(4,4-dimethylcyclohexy I)- 2,2-dimethylpropaneam ide [215] [216] A'-{(3S,5S)"l-{r(3S',4ff)-l-/er(~biityl-4-(2,4-diniiorophenyl)pyrTolidine-3-yl]carbonyl }--">-r(E)-(hydroxyimino)methyl]pyn-olidine-3-yl]-W-(4,4-dimelhyIcyc!ohexyl)-2,?.-dim ethylpropaneamide [2171 [218] W-[(3S,5.V)-5-(aminoethyl)-]-{[(35,4K)-l-/erT-bulyl-4-(2,4-difluorophenyl)pyrralidin e-3-yl]carbonyl)pytTolidine-3-yn/V-(4,4-dinielhylcyc[ohexyl)-2,2'dimethylpropaneani ide [219] [220] A'-[(3>5!55)-5-[(acetylamino)mcthyl]-l-{[(3S,4R)-l-/ert-bulyl-4-(2,4-dichIorophenyl) pyrrolidine-3-yl]carbonyl}pyrrolidinc-3-yl]-/V-C4,4-dimelhylcyclohexyI)-2,2-dimethyip rnpaneamide [2211 [222] ^tOS^^-l-lKS^RJ-l-Zert-bulyM^^-dichlorophenyOpyrrolidine-S-yllcarbonyl }-5-[(dimethy]amino)methyl]pyjTo]idine-3-yI)-]-A'-(4,4-din)ethylcyc]ohexyl)-2,2-dime Ihylpropaneamide [223] [2241 N-r(3S,55)-l-{[(3.?,4^)-l-/ert-bLityl-4-(2,4-dinuoropheiiyl)pyrroIidine-3-yllcarbony1] -5-cyaiiopyrTolidine-3-yl]-2,2-dimethyl-A'-(cis-4-inethylcyclohexyl)propaneamide [225] [226] ^-[(3S,5i?)-5-acetyl-l-{[(3.9,4/;)-l-/er(-butyM-(4-chloropheny1)pyrroIidine-3-yl]carb onyl}pyrrolidine-3-yl]-A'-(4,4-dimethylcyclohexyl)-2,2-dimethylpropaneaniide [227] [228] W-[(3.9)-l-[[(35,4ff)-l-fert-butyl-4H:4-chlorophenyl)pyrTolidiiie-3-yl]carbonyl]-5-(l- hydroxyrnelhyJ)pyn-olidine-3-yl]-A'-(4,4-dimethy(cyclohexyl)-2,2-dimethyJpropaneami de [229] [230] (4S)-4-[acetyl(4,4-dimethylcyclohexyl)amino]-N'(2-aminoethyl>l - {[(3S,4tf)-1 -tert-b utyl-4-(2,4-difluorophenyl)pyiTolidine-3-y!]carbonyl}-L-proHneamide [231] [232] methyl(45)-l-([(35',4K)-l-/1er(butyl-4~(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}^l- [(4,4-dimethylcycIohexyl)(2,2-dimethyIpropanoyl)amino]-IJ-prolinate [233] [234] (45)-l-{[(35',4J?)-l^rt'butyl-4-(4-chIorophenyI)pyrrolidine-3-yl]carboiiyl}-4-[(4,4-d imeihyIcyc[ohexyO(2,2-dimelhylpropanoylI)amino]-L-pro(ine [235] [236] W-[(35,5^)-5-(ammocart>othionyl-l-[[(35,4fi)-l-rert-butyl-4-(2,4-difluorophenyl)pyr rolidine-3-yl]carbonyl)pyrrolidine-3-ytl-Af-(4,4-dimethylcyclohexyl)-2,2-dimethylprop aneamide [237] [238] A'-K35,5K>N{[(3S,4ff)-l-^rt-buly1-4-(2t4-dinuorophenyl)pyrrolidine-3-y]|caibonyl }-5-[(dimethylamino)cavbonothionyllpyrrolidiTie-3-yl}-A''(4,4-diniethylcycIohexyl)-2, 2-dimelhylpropaneamide [239] [240] JV-r(35,5ff>^{fC3,?,4/?)-I-reri-buty[-4^2,4-dinuorophenyI)pyrro[idine-3-y[Icarbony[ }-5-propionyJpyrroJidine-3-yI]-A'-(4,4-diniethylcyclohexyJ)-2,2-d(fnethylpropanean]ide f2411 [242] JV-[(3,9,55J-l-{[(35,4R)-l-fert-bulyl-4-(4-cl]]orophenyl)pyTrolidiiie-3-yl]carbonyl}-5' propionylpyrrolidine-3-yl]-//-(4,4-dLfluorocycIohexyi)-2,2-dimelhylpropaneamide [243] [244] N-{(3S)-l-{i(3S,4R)-l -^n-butyI-4-(4-cliloropheny[)pyrroIidine-3-yncarbony(}pyTTo[ idine-3-yl]-A/-(4,4-di7nethylcydohex3'0-2,2-dimethyJmalonajnide [245] [246] A'-[(35)-l-{[(3S,4/e)-l-lcrl-bulyl-4-(4-chloropheny0pyrro1idine-3-yl]carbonyl}pyrroi idine-3-yl]-A'-(4,4-diniethy!cydohexy0-3-methoxy'2,2-dimethylpropaneaniide [2471 [248] (3E)-A'-f(3^-I-{r(3i'!4ffM-fcO-buiyi-4-(4-chIorophenyI)pyrrofidine-3-yncarbonyI)p yrrol idine-3-yl ]-Ar-(4,4-dimethylcycIohexyl)-3 -(hydroxy i mino)-2,2-di methyl propanea mide [M9] [250] ^[(S^l^rtSS^^l-fe^-bulyl^^-chlorophcny^pyrTOlidine-S-yllcarbonyllpyiTol tdine-S-yll-A'^^-dimethylcycIohexyU-S-hydroxy^^-dimethylbutaneamide [251] T252] A'-[(35)-l-{((35,4^}-l-/£^butyl-4-(4-chiorophenyI)pyn-olidi7ie-3-yHcarbonyl}pyfToI idine~3-yl]-A'-(4,4-dimethylcyclohexyl)-2,2-diniethyl-3-oxobutaneaniide [253] [254] ^[(SS^-l-ttCSS^RVl-rert-butyl^^-chlorophenylJpyrrolidine-S-yllcarbonyllpyrrol idine-3-yl]-A'-(4!4-dimethylcyclohexyl)-3-hydroxy-2,2,3-trimethylbutanearnide [255] [256] Af-[(35)^-[f(35,4^)-l-^^butyl-4-(4-ch!orophenyI)pyrToJidine-3-yI]carbonyl)pyrro] idine-3-yl]-A'-(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethylpropaneamide [257] [258] A'-[{35)-l-{[(3SJ4i?)-l-tert-bulyI-4-(4-chlorophenyl)pymilidine-3-yl]carbonyl}pyrrol idine-3-yl]-Ar-(4,4-dimethylcyclohexyI)-3,3-dinuoro-2,2-dimethyipropaneamide [259] [260] Ar-f(35)-]-f[(35,4^)~]-/£rt-bu(y)-4-(4-ch]orophenyl)pyrro!idine-3-y]]carbonyJ}pyrrol idine-3-yl]-Ar-[(4,4-difluorocyclohexyl)(3-melhoxy-2,2-dimethylpropanoyl)aminol-A'-e thyl-Af-methyl-L-nroliiieaTnide [2611 [262] (4.f)-4-|'(3-amino-2,2-dimethylpropanoyl)(4,4-(iinie(hylcyclohexyl)aiTiLTioVi-{[(35,4 fi)-I-^rt-butyl-4-(2,4-dinuorophenyl)pytTolidinc-3-yl]caiboiiyIj-A',A'-dimcthyl-L-proli neamide [263] [264] (4.S)-K{r(3.S,,4^)-)-(e/(-buly]-4-(4-chloropheny!)pyrraIidine-3-yl]carbonyiH-{[3-(di methy[aTnino)-2,2-dimelhy(propanoyI](4,4-dimelhyIcycIohexyI)amino[-MAf-dimelhyl-L-prolineamide [265] [266] AI-{(35J5^>-l-j[(3SJ4A>l-fert-butyl-4-(4-chloroplienyl)pyrTolidiiie-3-yl]carbonyl)-5- [(dimethy!amino)carbony1]pynrolidine-3-yl}-A'-(4,4-dimcthylcycIohexyl)-2,2-diTnethyI malonamide [267] [268] 5<3-{r(3W^-l-{r(3,S,4^)-l-/ert-butyl^2,4^muon>pheny])pyirolidinfr3-yl]ca^ nylj-5-([ethyJ(Tnethyl)amino]carbonyl|pyrTolidine-3-yI](4,4-dimethyIcyclohexyl)amin o}-2,2-dimethyl-3-oxopropyl)ethanethioate [269] [270] (4S)-l-{[(35,4«)-l-Wr/-butyl-4-(2,4-dtfluorophenyl)pyrrolidine-3-yl]carbonyl}^-[(4, 4-dimelhylcyclohexyl)(3'mercapto-2,2-diniethyIpropanoyl)amino]-Ar-ethy1-iV-methyl-L-prolineamide [271] [272] <4^-]-[f(35,4^)-]-/m-butyM-(4-ch]orophenyl)pym>]idme-3-y]]carbony]}^4(4,4-d ifiuoracyclohexyl)(3-melhoxy-2,2,-dimelhylprapanoyl)amino]-/V^V-diinediyl-L-proline amide [273] [2741 <45)-U[[(35,4W)-l-le^-bulyl^4-(4-chlorophenyI)pyrrolidine-3-yI]carbonyl}-4-[(4,4-d ifl uorocydohex y])(3-et hox y-2,2,-dimelby3propaiioyl)ami no]-A'-efhy]-^N-methyl-L-proH neamide [275] [276] (4S)-l-{[(3S,4«)-l-(err-butyl-4-(4-chIorophenyl)pyrTOHdine-3-yl]carbonyI}^-[(2,4-d ifluorophenyl)(2,2-dimethylpropanoyl)amino]-A',N-dimethyI-L-prolineamide [277] [278] (4S)-l-([(35,4/e>l-(ert-butyl-4-(4^chlorophenyl)pyrrolidine-3-yI]carbonyI}^-[(2,2r dimethylpropanoyl) (4-melhoxyphenyI)aminoJ-A/,A/-dimethyI-L-prolineamide T279] [280] (41V)-J-([(35,4K)-l-rert-butyI-4-(4-chlorophenyl)pyrrolidine-3-yllcarbonyl}^-{(2,2,- dimethylpropanoyl) [4-(trifluoromethyl)phcnyl]amino}- W,/V-dimethyl-L-prolineamide [281] [2H2] (45)-]-ffCay,4y?)-J-Wtt-butyl-4-(4-chIorophcnyOpyrTOlidine-3-yllcarbonyI]-4-f(2(2,- dimcthylpropanoyl) (4-melhylphenyl)amino'j- A^W-dimelhyl-L-profineamide (283] 1284] C45)-l-(f(35,4ff)-1-tert-4nityl-4-(4-chlorophenyl)pyrTOlidine-3-yl]carbonyl 1-4-1(2,4-- di fIuoropheny[)f(2S)-tetrahydrofuran-2-yIt;arboiiyl]aniiri(>l-A'-A'-dinicthyt-L-prolmeaiTii de f285] [2861 (45)-l-{[(3^4RH-(4-chlorophenyl)pynolidine-3-yllcarbonyl]-4-[(4,4-diinethylcycl ohexyI)(2,2-dimelhy]propanoyl)aminol-A',A'-dimethyi-L-prolineainide [287] [288] (IS^-W-fta^-l-trfa^RH^-chlorophenylJpyiTolidtne-S-yflcarbonylJpyiTolidine-S- yl ] -JV-(4,4-dimethylcycl ohexyl)tetrahydrofuran-2-carboxami de [289] [290] A'-r(3y)-l-{[(35,4R)-4-(4-chlorophenyl)pyrTOlidine ~3-y1]carbonyl|pyrrolidine-3-yl]- W-(cj^-4-niethylcyclohexyl)3-furairiide [291] [292] A'-[(3^)-U{[(35,4K>4-(4^ch]orophenyl)pyrroIidme-3-yl]carbonyl]pyrralidine-3-yl]- A'~(cri'-4-methylcyc]ohexyI)-2,5-dihydrofuran-3-cart)oxamide [293] [294] (4S)-AM-[f(3S,4rt>4 -(4-chlorophcnyI)pyrrolidme-3-yllcarbonyt]-4-[(2,2,-dimethylp ropanoyl)(c«-4-raethylcyclohexyl)amiTiol-D-prolineamide [295] [296] A/-[(35)-l-{[(35,4^)-4-(4-chJorophenyl)pyrToIidine-3-yllcarbonyl]-5-(l-hydroxymet by])pyrrol idine-3-yl]-A/-(4,4-dimethy]cy clobexy l)-2,2-di methy)propaneamide [297] [298] (4^-J-[[(35',4^>]-(am(nocarbony)M-(4-chJoropheijyl)pyirolidine-3--yncarix)nyl}-4 -[(4]4-dimethy1cyclohexyl)(2,2-dimelhylpropanoyl)ainino]-Af,W-diniethyl-L-proHneami de [2991 [300] (3ff,4y)-3-(4-chIoropheny0-4-(((3^-3-[(4,4-dime(hylcycrohexyI)(3-hydraxy-2,2-dim ethylpropanoyl)amino]pyrroIidine-1 -yl} carbonyl)pyrrolidine-1 -carboxamide POI] [302] (3/?,45)-3-(4-chloropheny!)-4-({(35)-3-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropa noyl)armno] pyrrolidine-1 -yl ] carbonyl)pyrrolidine-1 -carboxamide [303] [304] (4S)-l-({[(35,4K)-4-(4-chlorophenyl)-l-(ethylamino)carbonyI]pyiTolidine-3-yi]carbo nyl)-4-[(4,4-dimelhylcyclohexyl)(2,2-dimethylpropanoyl)arntno]-//,jV-dirnethyl-L-pro]i neamide |305] [306] N-[(3S)-l-(r(3S,4R)-4-(4-c!iIorophlinyr)-l-[(etliylamino)carbonolhionyIlpyiT()|Jdine- 3-yl]carbonyl}pyn-olidine-3-y]]-N-(4,'1-dii]iioracyclohexyl)-3-hydroxy-2,2-diiriethylpr opaneamidc [307] [308] (3/e,4,S>3-(4-chlorophenyl)-4-()(35)-3-f(4,4-dimethylcycIohexylJ(3-hydroxy-2,2-dim ethylpropanoyl)amino]pyrrolidine-l-yl}carbonyI)- W-elhylpyrrolidine-l-carboxamide [309] [310] (3W,45)-3-(4-chlorophcnyI)-4-({(35)-34(4,4-dime(hy(cyclohexy!)(2,2-dimethylpropa noy!)amino]pyrrolidine-l-yI}carbonyI)- A'-ediylpyrrolidine-I-carboxamide [311] [312] (3/f,45)-3-(4-cl]lorophenyl)-4-(((3^-3-[(2,4-difluQrophcnyl)(2,2-dimelhylpropatioyl) amino]pyrrolidine-]-yl]carbonyl)-A/ethylpyrrolidine-l-carboxamide [313] [314] (3^,45)-3-(4-chlorophenyl>A/-ethyl-4-(j(35)-3-[isobutyryI(fi>4-methylcyclQhexyl)a Tnino]pyrro!idine-l-yl}carbonyl)-A/-methyIpyrToIidine-l-carboxaniide [315] [316] (45)-l-({[(3.9,4fi)-l-acctyM-(4-chloropheiiyl)pyrrolidiiic-3-yI]carbonyl}-4-[(4,4-dim ethylcyclohexyl)(2,2-dimethylpropanoyI)amino]-A',A'-dimelhyl-L-prolineamide [317] [318] A/-[(3S)-l-[[(35',4A,)-4-(4-chlorophenyl)-l-isobulyrylpyiToIidine-3-yi]carbonyl}pyiTO ]idine-3-yI]-A/-(4,4-dimelhylcyclohexyl)-2,2-dimelhylprapaneamide [319] [320] (4S)-l-{[(35,4fi)-4-(4-chlorophenyl)-l-isobutyrylpyrrolidine-3-y11carbonyl]-4-r{4,4- dime(hyIcyclohexyl)(212-diinethylpropanoyl)ajnino]-L-proliiieamide [321] [322] (45)-1 -({[(3S,4i?)-4-(4-chlorophenyl) 1 -cyclopropylpyrrolidine-3-yl]carbonyl }-4-[(4, 4-dimethylcyclohexyl)(2,2-dimethylpropaTioyl)amino]-A',A'-dimethyl-L-prolineamide [323] [324] (45)-l-([(3S',4K)-4-(4-chlorophenyl)-l-(tetrahydro-2//-pyran-4-yl)pyrrolidine-3-yl]ca rbonyl} -A- {(4>4-dimethylcyclohexyl)[(25)-tetrahydroftiran-2-ylcart)onyl]amino ] -AAeth yl-W-mcthyl-L-prolineamide [325] [326] M-[(35)-l-([(35,4/f)-4-(4-chIorophenyl)-l-(2,2,2-trifluoroethyi)pyn-olidine-3-yl]carb onyl}pyrrolidine-3-yl]-A'-(4,4-dimethylcyc]ohexyI)-2,2-dimethylpropaneamide [327] [328] (4,S)-l-{[(35,4^)-4-(2,4-dinuoropheiiyl)-l-isobulyryIpyrTolidine-3-yl]carbonyl}-4-[(4 ,4-dimethylcyclohexyl)(3-hydroxy-2,2-diTnethyIpropaTioyl)amino]-A',A'-dimeIhyM.-pro lineamide [329] [330] (4.S0-l-{r(3>9,4/?)-4<4-chlorophenylj-l-cycIobutylpyrTolidint;-3-yncai-bonyl}-4-[(4,4-dimethylcycIohcxyl)(3-hydroxy-2,2-dinielliyIpropanoyl)aminoj-A/,A'-dimethyl-L-prolin camide [331] [332] (45)-l-{f(3.^4/?)-1-cyclopei)tyl-4-(2,4-difIuorophenyl)pym)lidine-3-yl]caibonyl]-4-[ (4,4-dimelhylcyclohexyl)(2,2-dimelby]propanoyl)amino]-A'1A'-dimelbyl-L-pro1ijieamid e [333] [334] A/-{(3^,5.9)-1-{[(3S,4/;)-4-(2,4-difiuoropheTiyI)-l-isobutyryipyrTolidine-3-yl]carbonyl }-5-[(dimethylamino)carbono(hiolpyrrolidinc-3-yI)-//-(4,4-diTnethylcyclohexyl)-2,2-di methylpropaneami de [335] 1336] A'-[(3S)-J-{r(3S,4R)-4-(4-chloraphenyl)-^(methyIsuIfonyI)pyrro/idine-3-y/]carbonyl }pyrrolidine-3-yl]-2-methyl-N-(cis-4-inethylcyclohexyl)propaneamide [337] [338] (3R,4S)-3-(4-ch1orophenyl)-4-([(3S)-3-[(cis-4-methylcyclohexyl)(2-methylpropanoy I )aminol pyrrol idine-1 -yl JcarbonylJ-N-^^^-lrifluoroethyOpyrroIidine-1 -carboxamide [339] [340] (3/?,4S)-3-(4-cWoropheny1)-4-({(35)-3-[(4,4-dimethyIcyc]ohexyI)(2,2-dimethyIpropa noyl)aniino]pyrrolidine-l-yl}carbonyl)-A/-(2,2,2-trifluoromethyl)pyrrolidine-l-carboxa mide [3411 T342] melbyJ(3R,4S)-3-(4-cblorophenyl)-4-([(3S)-3-f{4,4-dijnelhylcycl»bexyl)(3-bydroxy- 2,2-dimethylpropanoyl)ainino]pyn'olidine-l-yl}carbonyl)pyrrolidine-l-carboxylate F343J [344J /V-[(3S)-l-{[(3S,4R)-l-[amino(imino)methyl]-4-(4-chlorophenyl)pyrrolidine-3-yI]car bonyI}pyrroIidine-3-yl]-2-nielhyl-N-(cis-4-methylcyclohexyl)propaneamide [345J [346] Ar-[(3S)-l-({(3S,4R)^-(4-chlorophenyl)-I'[(ethylamino)(imino)melhyl]pynx>lidine-3 -yl]carbony[)pyrrolidine-3-yl]2-methyl-N-(cis-4-niethylcyclohexyI)propaneamide [347] [348] 7V-[(3S)-l-([(3S,4R)-l-[(acetylaiTiino)(imino)methyl]-4-(4-chloropheny0pyn-olidme- 3-yl]carbonyl}pyrro!idiiie-3-yl]-2-melhyl-N-(cis-4-methylcycIohexyl)propaiieamide f349] [350] A'-[(3S)-K{f(3S,4R)^-(4-chlorophenyl)-l-phenylpyrrolidine-3-yl]carbonyl}pyiTolidi ne-3-yl]-N-(4,4-dimethylcyclohexyl)-propaneamide [351] [3521 NJQSy 1 -{r(3S,4«)-4-(4-ch(orc)p[iei)y[)-1 -pyridinc-2-yipyno[idinc-3-yi]carbonyl }py iTolidine-3-yll-2,2-diTnethyl-N~(c(.f-4-melliyIcycIohexyI)propaneamide [3531 [3541 Af-[(19)-l-{[(3X,4K)-4-(4-chlorophcnyl)-I-(4,5-dihydro-l/MmidazoIe-2^yl)pyn-olidiii c-3-yllcarbonyl}pyrrolidiiie-3'yl]-A'-(4,4-diTnethylcyclohexyl)-3-h3'droxy-2,2-diTnethyl proparieamide [355] [356] N-[(3S)-1 - [ [(3S,4R)-4-(4-chlorophenyl)-1 <4,5-dihydro- lH-imidazole-2-yl)pyrrolidi ne-3-yl]carbonyl}pyrrolidine-3-yll-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2'dime)h ylpropancamide. [357] [358] The present invention is described in more detail by the exemplified compounds in the following Examples, but the scopes of the invention are not be construed to be limited thereby in any manner. [359] Abbreviations used in the following Preparation Examples and Examples are as follows: [360] Ac: acetyl [361] AcOH: acetic acid [362] Bn: benzyl [363] n-Bu n-butyl [364] t-Bu: t-butyl [365] BOP: (benzotriazol-1 -yl-oxy)tris(dimclhylamino-)phosphontum hexafluorophosphate f366] Bu: bmyl [367} CBZ(Cbz): benzyloxycarbonyl [368] BOC(Boc): t-buloxycarbonyl [369] CDI: N,IsT-carbonyldiimidazole [370] c-Hex: cyclohexyl [371] c-Bu cyclobutyl [372] c-Pen: cyclopentyl [373] c-Pr: cyclopropyl [374] DAST: diethylaminosulfur trifluoride [375] DCC: dicyclohexylcarbodiimide [376] DCE: dichloroethane [377] DCM: dichloromeihane [378] diMe dimethyl [379] diF: difluoro [380] DIPEA: diisopropylethylamine J3S1] DMAP; 4-dime(hy?aminopyridine [382] DMF: N,N-di methyl form amide [383] DMSO: dimetbylsulfoxide [384] DPPA: diphenylphosphorylazide [385] EDC: ] -(3-dimelhylaminopropyl)-3-elhy]carbodiimide hydrochloride [386] EDTA: ethylenediaminetetraacetic acid [387] Et: ethyl [388] EtOAc: elhylacelale [389] Et O: diethylether [390] Emoc: 9-fluorenylmelhoxycarbonyl [391] Hex: norma) hexane [392] HATU: N-f(dimethylamiiio)(3II-l,2,3-tnazo]o[4,5-b]pyridine-3-yloxy) methylene] - N-methylenemethaneammonium hexafluorophosphate [393] HOAT: l-hydroxy-7-azabenzotriazole [394] HOBT: hydroxybenzotriazole [395] HBTU: 2-(lH-bcnzotriazole-l-yl)4,l,3,3-letramethy]uronium hexafluoro [396] phosphate (397] i-Pr: isopropyl [398] i-Bu:isobutyl [399] KOCN: potassium cyanate [400] K CO : potassium carbonate [401] LiBH : lithium borohydride [402] Me: methyl [4031 MeOH methanol [404] MTBE: methyl t-bulyl ether [405] MgSO : magnesium sulfate 4 [406] NaBH : sodium borohydride 4 f407] NaBH(OAc) : sodium triacetoxyborohydride [408] NaOtBu: sodium t-butoxide [409] NaOI I: sodium hydroxide [410] NaN : sodium azide [411] NaH : sodium hydride [412] Pyr: pyridine [413] Ph: phenyl [4141 Pr: propyl [415] TBAF: tetrabutylammonium fluoride [416] TEA: triethylamine [417] TFA: trifluoroacetic acid |418] HI 9] J4201 T42I] {422} [423] [424] [4251 TFAA: trifluoroacclic anhydride Tin7: telrahydrofuran MJu: t-butyl The compounds of (lie present invention can be prepared according to the following procedures (Schemes A, B, C, D, E, etc.). Scheme A P1--. F"--_N-\ MaBH(OAc). n x + ketone — —' Int. A3 DCE SlepAl Inf. AS if P*=H/propyl/ allyl, go to Step A 5 toLAL NH= P'=CO,CH,,H, propyl. ally! O. OH J L HNR' HBTU DIEA \ O Step A3 DMF StepA4 Int. Afl Int. A 7 intte R* DMF Step A6 Int. A1Q R1 = fSu , Me lnt=intermediat'e [426] [4271 [4281 [429] [430] mi] The Intermediate Al compounds can be prepared as follows: Preparation Example Al-1: methyl (2S,4S)-l-Boc-4-aminopyrrolidine-2-carboxylate Step A: (4RVl-Boc-4-hydroxy-L-proIine To a solution of (4R)-hydroxy-L-proline (5.08 g, 38.77 mmol) in IN NaOH (40 ml) and 1,4-dioxanc (40 ml) was added dropwise di-t-butyl dicarbortate (9.3 g, 42.6 mmol) at 0°C. The reaction mixture was stirred al rt for 8 h, concentrated in vacuo, acidified wilh IN HCl, and extracted with EtOAc. The organic extracts were washed with brine. dried over Mg.SO , filtered, and concentrated in vacuo to give the title compound (8.8 g, 99 %). |432] MSIM+HJ =232(M+]) 1433] [434] Step B: methyl (2S.4RVl-Boc^-hydroxypyrro]idine-2-carboxy1ate [435] To a solution of (4R)-l-Boc-4-hydroxy-L-proline (8 g, 34.63 mmol) prepared in Step A in DMF was added K CO (14 g, lOlmmol) and methyliodide (2.6 ml, 51.9 mmol). The reaction mixture was stirred at rl for 5 h, concentrated in vacuo, and extracted with EtOAc. The organic extracts were washed with water and brine, dried over MgSO , filtered, and concentrated in vacuo to give the title compound (8.0 g, 95 %). [436] MS[M+H] =246(M+1) [437] [438] Step C: methyl (2S.4RVl-Roc-4-ffmRthvlsulfnnynoxylpyrrnlidine-2-carboxylate T439] To a solution of methyl (2S,4R)-l-Boc-4-hydroxypynT>lidine-2-carboxylale (8 g, 32.65 mmol) prepared in Step B in DCM was added dropwise TEA (11.99 ml, 81.56 mmol) and methanesulfonyl chloride (3.77 ml, 48.9 mmol) at 0°C. After the reaction mixture was stirred at rt for 3 h, the organic extracts were washed with a saturated NalICO aqueous solution, IN HC1 and brine, dried over MgSO , filtered, and con¬centrated in vacuo to give the title compound (9.4 g, 90 %). [440] MSfM+II] = 324(M+1) [441] [442] Step D: methyl (2S.4SM-Boc-4-azidopyrrolidine-2-carbosylate [443] To a solution of methyl (2S,4R)-l-Boc-4-[(methylsulfonyl)oxy] pyrrolidbie- 2-carboxylate (9 g, 27.86 mmol) prepared in Step C in DMF was added NaN (2.7 g, 41.79 mmol), and stirred at 90°C for 10 h. The reaction mixture was concentrated in vacuo, extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by column chro¬ matography (eluent, EtOAc/IIex = 1/4) to give the title compound (6 g, 80 %). [444] MS[M+H1 =271(M+1) T445] [446] Step E: methyl f2S.4S)-l-Boc-4-a^inopyrro[jdine-2-cajboxytate [447J To a solution of methyl (2S,4SH-Boc-4-azidopyrrolidine-2-carboxylate (6 g, 22.22 mmof) prepared in Step D in dioxane (10 mL) was added Pd/C (800 mg). The reaction mixture was stirred under hydrogen condition for 24 h, filtered through Celitc, and (he filtrate was concentrated in vacuo to give (he title compound as an oil (5.34 g, 98.5 %). [448] MS[M+H] = 245(M+I) [449] [450] Preparation Example Al-2: methyl (2S,4R)-1-Boc-4-aminopyrn)lidine-2-carhoxylatc [451 ] The title compound was prepared according to the procedure described in Preparation Example Al-I using (4S)-hydroxy-L-proliiie. 1452] MSfM+H] = 245(M+1) [453] (454] Preparation Example Al-3: methyl (2R,4S)-l-Boc-4-aminopyrrolidine-2-carhoxyIate [455] The title compound was prepared according to the procedure described in Preparation Example A1 -1 using (4R)-hydroxy-D-proJine. [456] MS[M+m =245(M+1) [457] [458] Preparation Example Al-4: (2S,4S)-l-Boc-2-aUy!4-aminopyrrolidine [459] Step A: f2S.4RM-Boc-2-aHvl-44ivdroxypyrroridine (460] (3R)-I-BOC-3-hydroxypyrroIidine (1 g, 5.34 mmol) was dissolved in diethylether (50ml), and filled with nitrogen. The reaction mixture was cooled to -78°C, N,N,N',N'-tetramethylethylenediamine (620 mg, 5.34 mmol) was added, and sec-butyllithium (1.4M cyclohexane solution 4.45 ml, 6.23 mmol) was slowly added. After being stirred for 30 min at the same temperature, dimethylsulfale (1.44 g, 10.68 mmol) was dissolved in diethylether (10 ml). The reaction solution was slowly heated to rt, diluted with water (12 ml), and extracted with diethylether. The organic extracts were dried over MgSO , and the residue was purified by column chromatography (eluent, 4 EtOAc/Hex = 1/4) to give the title compound (840 mg, 70 %). [464] MSfM+H] = 228(M+1) [462] [463] Step B: (2S.4S)-l-Boc-2-anvl-4-azidoPvrroiidine [464] The title compound was prepared according to the procedure described in Steps C~¥) of Preparation Example A1-1 using (2S,4S)-l-Boc-2-allyi-4-hydroxypyrroHdme prepared in Sfep A. [465] MS[M+H] =253(M+1) [466] [467] Step C: (2S.4RU -Boc-2-aHvl-4-aminoDvrrolidine [468] To a solution of (2S,4R)-l-Boc-2-allyi-4-azidopyrrolidine (450 mg, 1.78 mmol) prepared in Step B in THF was added dropwise trimethylphosphin (135 mg, 1.78 mmol). After the reaction mixture was stirred at rt for 5 h, water (0.03 ml) was added, and stirred for additional 20 min. The reaction mixture was concentrated in vacuo, extracted with EtOAc, washed with water and brine, and concentrated in vacuo. The residue was purified by column chromatography(eluent, MeOH/DCM - 1/9) to give the title compound (280 mg, 70 %). [469] MSfM+IH =227(M+1) [470] [471] Preparation Example Al-5 : (2S,4S)-l-Jloc-2-propyl-4-aminopyrrou'dine (472] To a solution of (2S,4S)-I-Boc-2-a(lyI-4-aminopyrrolidine (450 mg, 1.78 mmol) prepared in Preparation Example A1-4 in dioxane (5 mL) was added PoVC (40 mg). The reaction mixture was stirred under hydrogen condition for 24 h, filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound as an oil (390 mg, 98.5 %). [473] MSfM+IIj =229(M+1) (474] [475] Preparation Example Al-6: (2R,4S)-l-Boc-2-propyI-4-aminopyrroIidine (476] The title compound was prepared according to the procedure described in Preparation Example Al-5 using (2R,4R)-l-Boc-2-a!fyl-4-hydroxypyrrolidine as starting material. [477] MS[M+II] = 229(M+1) [478] [479] The Intermediate A2 compounds can be prepared as follows: [480] [481] Preparation Example A2-1:4,4 -dimethyl-cycitohexanone [482] 4,4-Dimethyl-cyclohexene-l-one (5 g, 40.3 mmol) and n-pentane (15 ml) were placed in a hydrogen reaction vessel, and Pd/C (500 mg) was added. The hydrogen reaction vessel was pressurized with hydrogen (25 psi), and reacted for 30 min. After the reaction finished, the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound (5 g, 98 %). [483] MSfM+H] = 127(M+1) [4S4] [485] Preparation Example A2-2: 4-trifluoromethylcyclotaexanone [486] Step A: 4-trifluoromethyl-cyclohexanol [487] 4-Hydroxybenzotrifluoride (5 g, 30.8 mmol) was placed in a hydrogen reaction vessel, dissolved in acetic acid (15 ml), and Pt O (500 mg) was added. The hydrogen reaction vessel was pressurized with hydrogen (50 psi), and reacted for 16 b. After the reaction finished, the reaction mixture was filtered through Celite, and to the filtrate was added I N-NaOIi, extracted with diethylelher, dried over MgSO , and concentrated 4 in vacuo at rt to give the title compound (4.5 g, 87 %). [488] MS[M+H] = 169(M+1) [4891 [490] Step R: 4-lrifluoromethylcyclohexanone [491] To a solution of 4-Trifluoromethylcyclohexanol (4.5 g, 26.7 mmol) in DCM (100 ml) was added Dess-Martin periodinane (I 3.6 g, 32 mmol), and stirred at rt for 2 h. After the reaction finished, the reaction mixture was concentrated in vacuo, sodium thiosulfate aqueous solution and dielhylethcr were added and stirred at rt for 30 min, and extracted with diethylether. The organic layer was dried over MgSO , concentrated in vacuo at rt to give the tide compound (4.2 g, 94.6 %). (4921 MS[M+H1 = 167(M+1) [493] 1494] Preparation Example A2-3:4,4-difluoro cyclohexanone [495] Step A: 8.8-difiuoro-l ,4-dioxospiro(4.51decane [496] To a solution of commercially available 1,4-cyclohexanedione-mono-ethylene ketal (25 g, 160 mmol) in DCM (500 ml) was added dropwise DAST (52 g , 2.0 mmol) at 0°C. The reaction mixture was slowly heated up to rt, and stirred until the reaction finished. After confirming that all the reaction mixture was disappeared, the reaction solution was added to a saturated NaHCO aqueous solution (700 ml) to finish the reaction, and extracted with DCM. The organic extracts were washed with a saturated NaHCO aqueous solution and brine, dried over MgSO, filtered, and concentrated in 3 4 vacuo. The obtained residue was used in the next reaction without further purification. K97] [49SJ Step B: 4.4-difluoro cyclohexanone [499] The product of Step A, 8,8-difluoro-1,4-dioxospiro[4.5]decane was dissolved in acetone (90 ml) and 3N HC1 (900 ml), and stirred until the reaction finished. Then, the reaction mixture was extracted with DCM, washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The obtained residue was used in the next reaction without further purification. (5001 [501 ] Preparation Example A2-4: spiro[2,5]octane-6-one [502] Step A: 4.4-methylene-l.l-ethyleneketal-4-spiro[2.51octane [S03] To a solution of DMSO (15 ml.), filled with nitrogen, was added Nal[(60 % suspension in mineral oil, 0.42 g, 10.50 mmol), and the reaction mixture was stirred at 50-60°C for 2 h, methykriphenylphosphonium bromide (MeP(Ph) Br) (3.76 g, 10.50 mmol) was added, and stirred at rt for 1 h. Cyclohexanedione monoethylenekctal (1 g, 6.40 mmol) was added, and stirred at 40*^ for 2 h. The reaction solution was cooled to rt, an ice water was added, and extracted with Et O. The organic extracts were dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by column 4 chromatography (eluent, EtOAc/Hex = 1/5) to give the title compound (0.74 g, 74.95 %). [504] [505] Step B: spiro(2.51octane-6-one [506] The product of Step A, 4,4-methylene-1,1 ~ethyleneketal-4-spiro[2,5]octane (0.74 g. 4.80 mmol) and diiodomethane (1.93 raL, 24.0(1 mmol) were placed in Et O (45 ml.), Zn-Cu (1.96 g, 30 mmol) was added, and refluxed for 12 h. Tlie reaction solution was cooled tort, diiodomeihane (1.93 ml., 24.00 mmol) and Zn-Cu (1.96 g, 30 mmol) were added again, and refluxed for 20 h. The reaction solution was cooled to rt, filtered, and washed with Ht O. To the filtrate was added 1M HCI (100 mL), reacted at rt for 1 h, and cxlracled Tor four (4) times with Rt O. The organic extracts were dried over MgSO , filtered, and concentrated in vacuo (0.28 g, 46.99 %). [507] f50S] The Intermediate A4 compounds can be prepared as follows: [509] [510] Preparation Example A4-1: 2,2-dimethyl-3-acetyioxypropionyl chloride [511] Step A: 2.2-dimethyl-3-acctyloxypropionic acid [512] 2,2-Dimethyl-3-hydroxypropionicacid (11.8g, 100 mmol) was dissolved in pyridine (30 mL), and the reaction solution was cooled to0°C. Acetyl chloride (11.8 g, 15.0 mmol) was slowed added dropwise, the temperature was increased to rt, and the reaction solution was stirred at rt for 3 h. After the reaction finished, IN HCI (30 mL) was added, pH adjusted to 3-4, the reaction mixture was extracted with EtOAc. The organic extracts were washed with 1N HCI for 4-5 times, dried over MgSO , con- 4 centrated in vacuo to give the title compound (15.2 g, 95.0 %). [513] MS[M+H] = 161(M+1) [514] [515] Step B: 2.2-dimethyL3-acetyioxypropionvl chloride [516] The product of Step A, 2,2-dimethyI-3-acetyloxypropionic acid (11.76 g, 80 mmo!) was dissolved in benzene (100 mL), the reaction solution was cooled 0°C, oxalyl chloride (15.0 g, 120 mmol) was slowly added dropwise. After 3 h, the solvent was removed in vacuo, and distilled in vacuo to give the title compound. [517] MSfM+H] = 179(M+1) [518] [519] Preparation Example A4-2: 2,5-dihydrofuran-3-carboxyl chloride [520] Step A: t-butyl 4-oxotetrahydrofuran-3-carboxylic acid [521] Sodium hydride (55% suspension in mineral oil, 0.5 g, 11.46 mmol) was placed in anhydride Et O (8 mL), and stirred, and ethyl glycolate (0.9 mL, 9.61 mmol) was added dropwise at rt. The reaction solution was stirred for 1 h, concentrated in vacuo, and t-butyl acrylate (1.68 mL, 11.46 mmol) in anhydride DMSO (8 mL) was added at 0-5°C. The reaction solution was stirred for 15 min at 0-5DC, stirred at rt for additional 1 h, and filtered. At 0-5°C, the filtrate was placed in a sulfuric acid solution (5 %, 5.6 mL), and extracted with lit O for 3 times. The organic extracts were washed with brine, dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent, KtOAc/IIex = ]/5) to give the title compound (0.95 g, 53. II %). [5221 [523] Step B: 1-butyl 4-hydroxytetrahydrpfuran-3-carboxylate [524] The product of Step A, tert-butyl 4-oxotctrahydrofuran-3-carboxylate (0.95 g, 5.10 mmol) was placed in isopropyl alcohol (14 mL) at 0-5°C, NaBH (77 mg, 2.04 mmol} 4 was added, and stirred for 2 h. NaBII (77 mg, 2.04 mmol) was added again, and stirred at rt for 1 h, NaBH (39 mg, 1.02 mmol) was added, and stirred for 30 min. The 4 reaction mixture was treated with Rl O to dilute, washed with brine, and extracted with Et O twice. The organic layer was collected, extracted with a NaHCO aqueous solution, dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent, EtOAc/Hex = 1/3) to give the title compound (0.83 g, 86.56 %). [525] [526] Step C: t-butyl 2.5-dihydroftiran-3Tcar|x)xylate [527] The product of Step B, t-butyl 4-hydroxytetrahydrofuran-3-carboxylate (0.83 g, 4.41 mmol) and PPh3 (1.74 g, 6.63 mmol) were placed in THF (5 mL), the solution was cooled to 0-5oC, and DIAD (1.13 mL, 5.74 mmol) was added dropwise. After reacting at rt for 12 h, the reaction mixture was filtered, washed with a solution of EtOAc/Hsx = 1/4, and the filtrate concentrated in vacuo The residue was purified by column chro¬matography (eluent, EtOAc/Hex = 1/7) to give the title compound (0.39 g, 51.34 %). [528] [529] Step D: 2.5-dihydrcfuran-3-carboxylic acid [530] To a solution of t-butyl 2,5-dihydrofuran-3-carboxylate (0.39g, 2.29mmol) prepared in Step C in DCM (2mL) was added TFA (6mL), and stirred at rt for 12 h. The reaction solution was concentrated in vacuo, the residue was treated with n-Hexane, stirred at rt for 30 min, and filtered to give the title compound (0.19g, 72.3%). [531] [532] Step E: 2.5-dihvdrofuran-3-carboxvl chloride [533] The product of Step D, 2,5-dihydrofuran-3-carboxylic acid (0.19.g, 1.66 mmol) was dissolved in benzene (3 mL), the reaction solution was cooled to 0°C, and oxalyl chloride (0.4 g, 3.32mmol) was slowly added dropwise. After 3 h, the solvent was removed in vacuo, and distilled in vacuo to give the title compound. [534] [535] Preparation Example A4-3: 2-cyano-2-methylpropanoyl chloride [536] To a solution of commercially available ethyl-2-cyano-2-methylpropanoate (3.5g, 24.8mmol) in methanol (10 ml) was added LiOH (900mg, 37.2mmot) and water (0.5ml), and reacted at rt for 1 h. After the reaction finished, the solvent was con- [537] [538] |539] [540] [541] centra ted in vacuo, 1N-HC1 (50m!) was added, and extracted with ElOAc. The extracted organic layer was dried over MgSO , concentrated in vacuo to give 4 2-cyano-2-methylpropionic acid (2.67g, 95%). This compound (2.5g, 22mmol) was dissolved in DCM (7 ml), and reacted according to the procedure described in Step B of Preparation Example A4-1 to give the title compound (2.5g, 86.3%). MS[M+H] = 132(M+1) Preparation Example A4-4-9 The acyichlondes in the following table were prepared according to the procedure described in Preparation Example A4-1 or A4-3 using commercially available carboxylic acid. o CI R5 [542] [543] Table 1 [Table 1] Preparation Example R* MS(M + 1) Preparation Example R* MS(M+I) A-1-4 '-6 1 j.i A4-5 H 0 - '' ns A4-6 149 A4-7 147 A4-8 H o ' 135 A4-9 ^ Q 131 [544] [545] [546] [547] [548] [549] Preparation Example A9-1: (3S,4R)-l-t-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxyllicacid The title compound was prepared according to the procedure described in WO 2004/09126. Preparation Example A9-2-7 The compounds in the following table were prepared according to the procedure described in Preparation Example A9-1 using commercially available alpha-halo ketone compounds. ,550] H02C N A / R2 rs5u [552] Table 2 [Table 21 Preparation Example A R1' M-H A 9-2 I-Bu 4 CI 282 A 9- 3 <-Bu 4-Me 262 A9-4 l-Bu 4-F 266 A9-6 Me A-CI 240 A9-7 Me 2,4-diF 242 [553] [554] [555] T556] [557] [558] [559] [560] Preparation Example A9-8: (3S,4R)-l-Boc-4-(2,4-dffluoroprienyI)pyrroHdine-3-carboxylicacid Step A: f4R)-4-f2,4-difluorophenyl1pvrrolidine-3-carbonitriie To a solution of (4R)-1 -t-butyl-4-(2,4-difluorophenyl)pyirolidine-3-carbonitrile (4g, 15.15mmol) prepared according to the procedure described in WO 2004/09126 in DCE (10 ml) was added dropwise 1-chloroethyl chloroformate (2.45ml, 22.68mmol) at 0°C. The reaction solution was heated to 70°C, and maintaining this temperature, l.8-bis(dimethylamino)naphthaIene (4.87g, 22.72mmol) in DCE (10 ml) was added dropwise for 2 Ii. After the reaction finished, methanol (10 ml) was added, and maintaining the temperature, the reaction mixture was stirred for additional 1 h, con¬centrated in vacuo, and the next reaction was carried out without further purification. MSfM+l]=209(M+l) Step B; f4R)-l-BOC-4-(2.4-difluorophenvl)pyiTolidine-3-carhonitrile To a solution of (4R)-4-(2,4-difluorophenyl)pyirolidine-3-carbonitrile prepared in Step A, DMAP (1.8g, 15.15mmol) and TEA (5.56ml, 15.15mmol) in DCM (10 ml) was added dropwise di-l butyl dicarbonate (4.9g, 22.7mmol) at 0°C. The reaction mixture was stirred at rt for 8 h, concentrated in vacuo, and extracted with EtOAc. The organic extracts were washed with 1 N-HCl and brine, dried over MgSO , concentrated 4 in vacuo, and purified by column chromatography (eluent: EtOAc/lfex = 1/6) to give the title compound (3.3g, total of Step A and B: 72%). MS[M+II]=3D9(M+I) [562] [563] Step C: r3S.4RVl-Boc-4-(?..4-dinuornphenvl)pvTTolidine-3-carbnxylic acid [564] 1 o a solution of (4R)-]-BOC-4-(2,4»difluorophenyl)pyn"otidine-3-carbonitrile (3.3g, 10.6mmol) prepared in Step B in ethanol (10 ml) was added 6N NaOH solution (5 ml), and stirred at 70°C for 4 h. After the reaction finished, the solvent was removed, the reaction mixture diluted with ether, the organic solution was sufficiently acidified with 6N HC1, and washed. The organic solution was washed with brine, dried over MgSO , and concentrated in vacuo to give the title compound (3.43g, 99.0%). [565] MS[M+1] = 328(M+1) [566] [567] Preparation Example A9-9-11 [568] The compounds in the following tabfe were prepared according (o (he procedure described in Preparation Example A9-8 using phenylpyrrolidine-3-caibonitrile in¬termediates obtained in Preparation Example A9-2-4. [569] H02C N boc [570] [571] Table 3 [Table 3] Preparation Example R2 MH A9-9 4-CI 326 A9-I0 4-Me 306 A9-U 4-F 310 [572] [573] The Examples synthesized by the procedure of Scheme A are as follows. [574] [575] Example Al: (4S )-l-{[(3S ,4 R )-l- tert - butyl-4-(2,4-difluoropheny])pyrrr»Iidine-3-yl]carbonyI}-4-[(4,4-dimethylcyclohex}l )(2^2-dimethylpropanQyI)aniino]- N, N -dimethyl-L-prolineamidc HC1 salt [576] 0 °. N SH N 0 N- - F / F -y- IICI [577] f5783 Step A: mfilhvl-f25.4SVl-BOC-4-fM,4-dimethvlcvclohexvnaminn] pyrrolidine-2-carboxylalp. f579] To methyl (2S,4S)-l-Boc-4-aminopyrroIidine-2-carboxylate (1.07 g, 4.38 mmol) and dimethylcyclohexanone (0.66g, 5.25 mmol) in DCE (20 mL) was added dropwise NaBIIfOAc^ (1.39 g, 6.57 mmol) at rt. The reaction mixture was stirred at it for 4 h, a saturated NaHCO aqueous solution was added, and extracted with DCM (50 ml. X 2) and EtOAc. The organic extracts were washed with brine, dried over MgSO , filtered, and concentrated in vacuo. The obtained residue was purified by column chro¬matography (eluent, ElOAc/Hex = 1/2) to give the title compound (1.16 g, 75 %). [580] MS[M+H] = 355(M+1) T581] [582] StenB: l-BOC-2-methvl-(2^ .4,9 )-4-r(4,4-dimethvlcvclohexvn('2.2-dimethylpropanovI)aminolpvnrolidine-2-carboxylate [583] To a solution of methyl (2S,4S)-l-BOC-4-[(4,4-dimethylcyclohexyl)amino] pyrrolidine-2-carboxylate (1.01 g, 2.84 mmol) prepared in Step A in DCE (5 mL) was added dropwise TEA (5 mL) and DMAP (0.34 g, 2.84 mmol), and added commercially available pivaloyl chloride (1.01 g, 8.52 mmol). The reaction solution was heated to 90°C, and stirred for 24 h. After the reaction finished, the solvent was removed in vacuo, the residue treated with a saturated NaHCO aqueous solution, and extracted with EtOAc. The organic extracts were washed with IN HCI, dried over MgS04, con¬centrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex = 1/4) to give the title compound (1.02 g, 82 %). [584] MSfM+H] = 439(M+1) [585] [586] Step C: (4 S 1-l-BQC-4-ff4.4-dimethylcvclohexvn(?.-2-dimethvlnropanovnaminol - [ ,-proline [587] To a solution of 1-BOC 2-methyl (25,45 )_4_ [(4,4-di methylcyclohexyl)(2,2-d i methy lpropanoyl)ami no] pyrrolidine-2-carboxy late (1.02 g, 2.32 mmol) prepared in Step B in methanol (7 ml) and water (7 ml) was added LiOH (O.I5g , 6.99 mrnol). The reaction mixture was stirred at rt for 3 h, concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO, and concentrated in vacuo to give (he title compound (0 93g 95 %). f588] MSfM+IT] =425(M+1) [589] i-S90] Stenjj: BOC(2 S A S )-2-rrdimethvlamino)carbony|] - 4-f(4.4-dimethvlcvclohexvlV2.?,-dimethylpropanovDamiiiol pyrrolidine [591 ] To a solution of (4S )-l-ROC-4-[(4,4-dimethylcyclohexyl)(2,2-l-BOC-4-{(4,4-dimethylcyclohexyl)[(2£ )-tetrahydrofuran-2-ylcarbonyl]amino]-L-proIine (0.96 g, 2.2 mmol) prepared in Step B and commercially available N-methylethylamine (0.92g, 93 %). [619] MS[M+H] =480(M+1) [620] [621] Step D: (4 S )^-ff4.4-dimethvlcvclohexyl)(tetrahvdrofuran-2-ylcarbnnvnaniino1- N - ethyl- W-methvl-L-prolineamide [622] To a solution of BOC-(2S,4S)-4- {(4,4- dimethylcyclohexyl)[(25 )-tetrahydrofuran-2-ylcarbonyI]amino ] -2- {[ethyl(methyl)amino]carbonyl) pyrrolidine (0.92 g, 2.0 mmol) prepared in Step C in DCM (1 (1) was added dropwise 4M MCI (1 D). The reaction mixture was stirred at rt for 1 h, and concentrated in vacuo. The residue was concentrated in vacuo to give the title compound (750mg, 99.9 %). [623] MS [M+H] = 380(M+1) [624] [625] Step F: (4 S V1-f f(3 S .4 K V\-tert -butyl-4-f4-chlorophenyl>pyrrolidine-3-vll carbonyI}-4-{f4.4-dimethylcyclohexyl)ff2S)-tetrahy(|rofuran-2-ylcarhonvnaminol-A^. Af-elhylmethvl-L-prolineamide HCI salt [626] To a solution of (45 )-4-f(44_(jjiriemyiCyCi0hexyl)(tetraliydrofuran-2-ylcarbonyl)amino]-A'-ethy!-A^-methyl- L-prolineamide (0.76 g, 2.0 mmol) prepared in Step D in DMF (5 0) was added dropwise DIPEA (0.95 ff, 5.5 mmol). Then, (he product of Preparation Example A9-2, (3S,4R)-)-f-bufyM-(4-ch/orophen3'J)pyrroIidiiie'3-carboxy[ic acid (0.56 g, 2.0 mmol) was added dropwise followed by UJiTU (0.76g, 2.0 mmol). The reaction mixture was stirred at rt for 2 h, (he solution was concentrated i'« vacuo. The residue was diluted with EtOAc, and washed with a saturated aqueous NaHCO solution and water The organic solution was dried over MgSO , concentrated itx vacuo, and the residue was 4 purified by HPLC to give TFA salt of the compound (1.09 g, 85%). This compound was treated according to the procedure described in Step G of Example Al to give the title compound. [627] MS[M+H] = 643(M+1) [628] IN NMR (400 MHz, CDC13) 7.51 (d, 210, 7.33 (d, 211), 4.68 (t, 1H), 4.48 (t, 111), 4.40-4.21 (m, 1H), 4.03-3.90 (m, 3H), 3.90-3.81 (m, 2H), 3.80-3.70 (m, 2H), 3.66-3.46 (m, 3IT), 3.45-3.12 (m, 3H), 2.97 (d, 311), 2.86-2.62 (m, 1H), 2.41-2.28 (m, 1H), 2.13-1.82 (m, 4H), 1.64-1.40 (m, 4H), 1.52 (s, 9H), 1.40-1.22 (m, 2H), 1.26 (t, 3H), 1.20-1.08 (m, 210,0.97 (s, 310, 0.94 (s, 311) [629] [630] Example A3: (4S )-l-tf{3 S ,4 R )-l- tert - b«tyl-4-(4-chIorophenyl)pyrrol(dinc-3-yI]cartjonyI) -4-{ (4,4-dimefliylcyclofteieyl)[<2 S)-fetrahydrofiiran-2-yIcarbonyl]arnino]-A7 -ethyl-L-prolineamide HCl salt [631] O 0 .... NH "A-N' N " 1 - _. I 0 1 "" ; i> __ N"\ H / C(' —rj' HCl [632] [633] Step A: l-BQC-(2 S A S )-4-f('4.4-dimcthylcyclohexvl)rf2 S ^-letrahydrofi]ran-2-ylcarhonynaminol~2-[fethylaminoV.arhonvl)nvrrolidine [6341 The title compound was prepared according to the procedure described in Step D of Example Al, using (4S)-l-BOC 4-[(4,4-dimethylcyclohexyl)[(25)- tetrahydrofuran- 2-ylcarbonyllamino}-L-proline (0.96 g, 2.2 mmol) prepared in Step B of Example A2 and commercially available elhylamine (0.95g, 93 %). [635] MSfM+10 =466 (M+l) [636] [637] Step B: (4 S )-44(4.4-dimethv)cvclohexvl)l'letrahvdroruran-2-vlcarbonvnamino)- N ethyl -L-prolineamide [638] To a solution of I-BOC-(25,4S)-4-[(4,4-dimelhyIcyclohexyl)[(25 )-telrahydrofuraTi-2-ylcarbonyl]amino}-2-f(tithyliimiTio)carbonyl}pyn-nlidine(0.95g, 2.0 mmol) prepared in Step A in DCM (I (I) was added dropwise 4M IICI (i LI). The reaction mixture was stirred at n for 1 h, and concentrated in vacuo. The residue was concentrated in vacuo to give the title compound (730mg, 99.9 %). 1639] MS[M+H] = 366(M-( I) [640] [641] Step C: (4 S )-l-f fC3 S A R U- ten -butvl-4-(4-chloronhenvnnvrrolidine-3-vn carhonyl)-4-((4.4-dimethvlcvclohexvn[(2S)-tetrahvdrofuran-2-vlcarbonvllamino)-A' -ethyl-L-prolineamideHCI salt [642] To a solution of (45 )-44(4,4-dimethyIcyclohexylXtetrdhydrofuran'2-ylcarbonyl)amino]-A'-ethy]-L-pro!ine amide (0.73 g, 2.0 mmol) prepared in Step B in DMF (5 Q) was added dropwise DIPEA (0.95 0,5.5 mmol). Then, the product of Preparation Example A9-2, (3S,4R)-l-t-b\)tyl-4-(4-dichlorophenyl)pyiToHdine-3-carboxylic acid (0.56 g, 2.0 mmol) was added dropwise followed by 1IBTU (0.76g, 2.0 mmol). The reaction mixture was stirred at rt for 2 h, and the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with a saturated aqueous NaIIC03 solution and water. The organic solution was dried over MgSO , concentrated in vacuo , and the residue was purified by IIPLC to give TFA salt o the compound (1.06 g, 85%). This compound was treated according to the procedure described in Step G of Example Al to give the title compound. [643] MS[M+H1 = 629(M+1) [644] III NMR (400 MHz. CDC13) 7.55 (d, 2H), 7.33 (d, 2H), 4.51-4.43 (m. IH), 4.26 (t. !H), 4.06-3.98 (m, HO, 3.97-3.56 (m, 7H), 3.49-3.02 (m, 4H), 2.83-2.74 (m, IH), 2.49-2.38 (m. IH), 2.32-2.22 (m, IH), 2.21-2.11 (m, IH), 2.02-1.82 (m, 4H), 1.61-1.15 (m, 811), 1 -49 (s, 9H), 1.10 (t, 3H), 0.93 (s, 3H), 0.91 (s, 3H) [645] [646] Example A4: (4.S')-l-{[(35,4ff )-l-tcrt - butyl-4-(4-ch!orophenyl)pyrrolidine-3-yl]carbonyl].4-[(4,4-dimethylcyclohexyl)(3- hydroxy-2>dimethylpropanoyl)amino]- JV -ethyl- JV -methyl-L-prolineamide UCl salt 1647) O ° N O Cl HC1 OH [648] f649! Step A: 1 -boc>2-methvK2 SAS V4-f B-tacetvloxvV^-dimemvlpropanoyll f4,4Hiimetliylcyc1ohexynamirin>pyiTpjidme:2-carboxyla^ [650] To a solution of methy!-(2S,4S)-l-BOC-4-[(4,4-dimethylcyclohexyl)amino] pyrrol id ine-2-carboxy late (1.01 g, 2.84 nimol) prepared in Step A of Example A1 in DCE (5 ml) was added dropwise TEA (5 mL) and DMAP (0.34 g, 2.84 mmol). Then, the product of Preparation Example A4-1, 2,2-dimethyl-3-acetyloxypropionyl chloride (1.01 g, 5.68 mmol) was added. The reaction solution was heated to 90°C, and stirred for 48 h. After the reaction finished, the solvent was removed in vacuo, to the residue was added a saturated aqueous NaHCO solution, and extracted with ElOAc. The organic extracts were washed with IN HC1, dried over MgSO , concentrated in vacuo, 4 and purified by column chromatography (eluent: EtOAc/Hex = 1/4) to give the title compound (0.88 g, 63 %). [651] MS[M+H] = 497(M+1) [652] [653] StepB:(4S Vl-BOC-4-ff4.4-dimethylcvc1ohexyl'H'3-hvdroxy-2.2-dimethvlpropanovnamino1-L-pr oiine [654] To a solution of l-BOC-2'methyl-(25,45)^-[[3-(acetyloxy)-2,2-dimethylpropanoyl] (4,4-dimethylcyclohexy!)amino}pyrrolidine-2-carboxylate (1.02 g, 2.05 mmol) prepared in Step A in methanol (10 ml) and water (10 ml), was added NaOH (246 mg, 6.15 mmol), and stirred for 12 h. After the reaction finished, the reaction solution was concentrated in vacuo, acidified with IN HC1, and extracted with EtOAc. The organic extracts were washed with IN IIC1, dried MgSO , and concentrated in vacuo to give the title compound (0.85g, 95 %). [655] MSfM+Hl = 441(M+1) [656] [657] Step C: BOC-C2 S A S )-4-rf4.4-dimelhvlcvclohexyl¥3-hydroxv-2.2~dimethylpropanoyl1aminol-2-([ethyl(me lhyl)amino]carbonyl Ipyrrolidine 1658] The title compound was prepared according lo ihe procedure described in Step D of Example Al using (4,? )-l-BOC-4-[(4,4-dimethy]cyc1ohexy])(3-hydroxy-2J2-dimelhylpmpanoyl)aniino]4^pr oline (0.85 g, 1.94 mmol) prepared in Slep B and commercially available N-methylethy famine (0.86g, 93 %). [659] MSfM+H] =482(M+1) [660] [661] Slep D: (4 S )-4-ff4.4-dimethvlcvclohexvnG-hydroxy-2,2-dimethvlpropanovnamino 1- W-ethyl- A/-methyl-L-prolineamide [662] The title compound was prepared according to the procedure described in Step E of Example Al using BOC-(2S,4S )-4-[(4,4-dimelhylcycIol]exyi)(3-hydroxy-2,2-diinethyIpropaiioyl)amino]-2-{[ethyl(me thyl)amino]carbonyl]pyrrolidine (0.86 g, 1.8 mmol) prepared in Step C (0.68 g, 99.9 %). [663] MS[M+H] == 382(M+1) [664] [665] Step E: (4 S V1-IU3 S .4 R VI- ten -butyl-4-f4-chlorophenvnpvn-oIidine-3-vn caroonyH-4-[(4,4-dimethylcyclohexyl)('3-hydroxy-2.2-dimethvlpropanoynamino]- N - ethyl- N -metliyl-L-prolineamide HO SftU [666] TFA salt of the compound was prepared according to the procedure described in Step G of Example Al using (4S )^-[(4i4_dimethylcycIohexyl)(3-hydroxy-2,2-diinethylpropanoyl)aniino]-A7-ethyl-Ar-m ethyl-L-prolineamide (0.68 g, 2.0 mmol) prepared in Step D (1 g, 89%). This compound was treated according to the procedure described in Step G of Example A1 to give the title compound. [667] MS[M+H] = 645(M+1) [668] IHNMR (400MHz, CDCI3)7.62(d,2H), 7.3l(d, 211), 4.68(t, lH),4.36-4.19(m, IH), 3.96-3.79(m, 3H), 3.77-3.52(m, 4H), 3.43-3.08(m, 611), 2.94(s, 3H), 2.74-2.62(m, IH), 2.11-1.97(m, IH), l.67-l.36(m, 1411), 1.35-1.15(m, 9H), U0(t, 3H), 0.95(s, 3H), 0.92(s, 3H) [669] [670] Example A5: (4 S )-l-{[(3 S ,4 R )-1- tert - butyl-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}-4-[(4,4-dinuorocycloheKyl)(2^ -dimethylpropanoyl)amino]- N, N -dimethyl-L-prolineamide IICI sail f671] 0 ° -N VN 0 N - F HCI [672] f673] Step A: 2-Tnethvl-aS.4SVl-HOC-4-Fi'4 4 -difluorocvdohexyllaminol pyrrolidine- carhoxvlatft [674] To a solution of 4,4-DifIuoro cyclohexanone prepared in Preparation Example A2-3, and methyl (2S,4S)-l-Boc^-aminopyrro!idine-2-carboxylate (29g, I20mmol) prepared in Preparation Example All in DCE was added NaBH(OAc) (37g, 180mmol), and stirred at it for 6 h. After the reaction finished, the solvent was concentrated in vacuo, NaNCO aqueous solution was added, extracted with EtOAc, and the organic layer was dried over MgSO , concentrated i/i vacuo. The residue was purified by column chro- 4 matography (eluent: EtOAc/Hex = 1/4) to isolate 2-methyl-(2S,4S)-l-BOC-44(4 -fluorocyclohex-3-ene-l-yi)amino]pyrrolidine-carboxylate, whereby to give the title compound (23g, 55%). [6751 MS[M+H] = 363 (M+l) [676] [677] Step B: 1 -BOC 2-methvl (2 S A S )^-r(-4J4_jjfjuoroCyC[0|ieXy|)l'2,2Klimethylpnjpanoy[)amino]pyrrolidine-2-r-arhoxvlate [678] The title compound was prepared according to the procedure described in Step B of Example Al using 2-methyl-(2S,4S)-l-BOC-4-[(4 ,4 -difluorocyclohexyl)amino] pyrrol idine-carboxylate (1.03 g, 2.84 mmol) prepared in Step A (1.02 g, 82 %). [679] MS[M+H] = 447(M+1) [680] [681] Sten C: (A S Vl-BOC-4-rr4,4-difluorocvclohexvlV?.2-dimethvlpropannvnaminQl - L-proline [682] The title compound was prepared according to the procedure described in Step C of Example Al using 1 -BOC 2 methyl (25,45 )-4-[(4,4-difluorocyclohexyl)(2,2-dimethy!propanoyl)amino]pyrrolidine-2-carboxylate (1.02 g, 2.32 mmol) prepared in Step B (0.95g, 95 %). [683] MS[M+H] = 433(M+1) [684] [685] Step D: BOC-C2 S .4 S V4-rf4.4-difluorocvclohexyl¥2.2-dimethvlproDannvnamino1 - 2-[(dimethvlamino^carhonvll pyrrolidine [686] The title compound was prepared according to the procedure described in Step D of Example Al using (4S )-l-BOC-4-[(4,4-difluorocyclohexylJ(2,2-dimelhylpropanoyl)amino]-L-proline(0.95 g, 2.2 mmol) prepared in Step C (0.93 g, 93 %). [687] MS[M+II]=460(M+1) [688] [689] Step E: (4 S V4-tf4.4- dinuorocyclohexviy2,2-dimelbv1propanovr)amino1- AT. N - dimethyl-L-prolineamide [690] The title compound was prepared according to the procedure described in Step E of Example A1 using BQC-QS.4S )^-[(4,4-difluorocyclohexyI)(2,2^imelhyIpropanoyl}amino]-2-[(dirnethyIamino)carbo nylpyrrolidine (0.93 g, 2.0 mmol) prepared in Step D (7I0mg, 99.9 %). [691] MS[M+H] = 360(M+1) [692] [6931 Step F: (4 S Vl-f ff3 S A R Y\-tert -butvI-4-f4-chlorophenvnPviTo1idine-3-vn carbonyl J^-rM^-difluorocvclohexvn^^-dimelhylpropanovnamino]- N. N - dimethyl -I^-prolineamide HC1 fraU [694] The title compound was prepared according to the procedure described in Step F~G of Example Al, using (4S)-4-[(4,4-difluorocyc!ohexyl)(2,2- dimethylpropanoyI)amino] -A^W-dimethyl-L-proIineamide (0.70 g, 2.0 mmol) prepared in Step E and (3S,4R)-l-t-bulyl-4-(4-dich1orophenyl)pyrrolidine-3'Carboxylic acid prepared in Preparation Example A9-2 (1.06 g, 85%). [695] MS[M+H] = 623(M+1) [696] IH NMR (400MHz, CDC13) 7.60(d, 211), 7.31 (d, 2H), 4.69(t, IH), 4.33-4.n(m, IH), 4.00-3.51(m, 6H), 3.37-3.08(m, 3H), 2.99(d, 611), 2.45-1.96(m, 5H), 1.90-l-56(m, 5H), 1.4*(s,9H), 1.21(s,9H) [6971 [698] ExampleAfi: (4 S )-l-{[(3 S ,4 R )-l-tert - bi!fyl-4-(4-chIorophenyl)pyrrolidine-3-yl]carbonyI}-4-[(4>4-dinuorocyclohexyI)(2,2 -dimethylpropanoy])amino]-Ar-ethyl-L-prolmeamide HC1 salt [699] o N ■■ CI F " I- IICI ROO] I7011 Step A: B0C-C2 .V .4 .9 >-4-rf4.4-dif1iiorocvclohexvl¥2.2-dimethvInrop;inovl^minnl - 2-ffethylaminolcarbonvPpvrrolidine [702] The title compound was prepared according to the procedure described in Slep D of Example AI using (4S )-l-BOC^-[(4,4-difIuorocyclohexyl){2,2-dimethylpropanoyl)aminol-L-proIine(0.95 g, 2.2 mmol) prepared in Step C of Example A5 and commercially available elhylamine (0.93 g, 93 %). [703] MS[M+H] =460(M+1) [704] [705] Slep B: (4 S V4-ff4.4- difluorocvcloriexynf2.2- dimelhvlpropanoynaminol- N - ethyl-L-prolineamide [706] The title compound was prepared according to the procedure described in Step E of Example Al using BOC-(2S,4S )-4-[(4,4-difluorocyclohexyl)(2,2-dimethylpropaiioyl)amino]-2-[(ethylamino)carbonyn pyrrolidine (0.93 g, 2.0 mmol) prepared in Step A (710mg, 99.9 %). [707] MSfM+H] = 360(M+1) [708] [709] StepC:f4SVl-fff3S.4RVl-tert-butvM-r4-chlorophenvnpvrrolidine-3-vll carbonyl)-4-[(4.4-difiuorocyclohexvl'l(2.2-dimethylpropanovl>aminQl-N-ethvI-L-pron neamide IICI salt [710] The title compound was prepared according to the procedure described in Step F-G of Example AI, using (45)^f-[(4,4HiifluorocyclohexyI)(2,2- dimethyIpropanoyl)amino] -Af-ethyl-L-prolineamide (0.70 g, 2.0 mmol) prepared in Step B and (3S,4R)-l-t-butyI-4-(4-dichlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (1.06 g, 85 %). [711] MS [M+II] = 623(M+1) [712] 1H NMR (400MHz, CDC13) 7.56(d, 2H), 7.35(d, 2H), 4.26(t, III), 4.04-3.57(m, 611), 3.57-3.40(m, 1H), 3.40-3.05(m, 3H), 2.70-2.50(m, III), 2.43-2.15(m, 3H), 1.95-1.22(m, 8H), 1.49(s, 9H), 1.22(8, 9H), l.ll(t, 3H) [713] [714] Example A7: (4S )-l-{[(35,4fi )-4-(4-chIorophenyl)-l-methylpyrrolidinc-3-yl] carbonyl]-4-[(2,2-dimctliylpropanoyl)(cis-4-methylcycloliexyl)amino]-L-prolinea midc 11 CI salt [7'5' 0 ° NH, 0 N / Cl' / HCi I7* V Step A: 3-BOC 2-melhyig .9.4 ,9 V4-ffcis-4-metbvlcvc>obcxvnammnl pyrrolidine- 2-carboxylate [718] To a solution of methyl (2S,4S)-l-Boc^-arrunopyrroHdine-2-carboxyIale (1.07 g, 4.38 mmol) prepared in Preparation Example Al-1 and 4-melhyIcyclohexanone in DCE (30 ml) was added dropwise NaBN(OAc) (1.39 g, 6.57 mmol) at rt. The reaction mixture was stirred at rl for 4 h, a saturated NaHCO aqueous solution was added, and extracted with DCM (50 mL X 2) and EtOAc. The organic extracts were washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent, ElOAc/Hex = 1/2) to isolate cis and trans compounds, whereby to give the title compound (0.84 g, 57%). [719] MS[M+II] =341 (M+l) [720] [721] Step B: 1-BOC 2-methyl(2 S A S M-rf2.2-dimethvipropanovl¥cis-4- methyi-cyclohexyl)amino1pyrrolidine-2-carboxylate [722] The title compound was prepared according to the procedure described in Step B of Example Al using 1-BOC 2-methyl(25,45)-4-Kcis-4-methylcyclohexyl)amino] pyrrolidine-2-carboxylate (0.84 g, 2.49 mmol) prepared in Step A (0.92 g, 87 %). [723] MSfM+H] = 425(M+1) [724] [725] Step C: (4 S Vl-BOC-4-rf2.2-dimethylpropanovl¥cis-4-methvlcyclohexvnaminol - L-proline [726] The title compound was prepared according to the procedure described in Step C of Example Al using 1-BOC 2-methy((25',45)^-[(2,2-dimethylprapanoyl)(cis-4- methyl- cyclohexyl)amino]pyrrolidine-2-carboxylate (0.92 g, 2.16 mmol) prepared in Step B (0.84 g, 95%). [727] MSfM+H] =411(M+1) [7281 [729] Step D: BOC-(2 S A S )-2(arninocarbonyl)-4-[(2.2-dimethylpropanoyl)(cis-4-rnethylcyclohexynaminolpyiToli dine [730] To a solution of (4S)-1 -BOC-4-[(2,2-dimelhyIpropanoyI)(cis-4- methyl- cyclohexyl)amino]-L-prolinc (0.83g, 2.05 mmol) prepared in Step C in TrlF was added dropwise TE A (0.32ml, 2.27 mmol). Then, cthylchloroformate (0.24 g, 2.27 mmol) was slowly added dropwise at 0"C, and the reaction solution was stirred at the same temperature for 1 h. 2A% Ammonia water (1 equivalent) was slowly added dropwise af 0°C, and stirred at the same temperature for additional 1 h. After the reaction finished, the reaction mixture was concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO , concentrated in vacuo, 4 and purified by column chromatography (eluent: EtOAc/Ilex = 2/1) to give the title compound (0.62 g, 74 %). [731] MS[M+H]=410(M+1) [732] [733] Step E; ("4 S V4-rC2.2-dimethylpropanoyl¥cis-4-methylcvclohexvnaminol L- prolineamide [734] The title compound was prepared according to the procedure described in Step E of Example Al using BOC-(2S,4S )-2(aminocarbonyI)-4-[(2,2-dimethylpropanoyl)(cis-4-methylcyclohexyl)amino]pyiTo]! dine (0.62 g, 1.53 mmol) prepared in Step D (0.45 g, 95 %). [735] MS[M+H] = 310(M+1) [736] [737] StepF:(4y)-l-fr(3^.4/?M-(4-ch[orophenvn-l-methvlpyn-olidine-3-vn caihonvlM-f(2.2^imethylpropanovU(cis^-inethylcvctohexvUaminol-L-prolineamide HC1 salt [738] The title compound was prepared according to the procedure described in Step F~G of Example A1, using (4S)-4-[(2,2-dimelhyIpropanoyi)(ris-4-melhylcyclohexyl)amino] L-prolineamide (0.45 g, 1.45 mmol) prepared in Step E and (3S,4R)-l-t-methyl-4-<4-chIorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-6 (0.67 g, 88 %). [739] MS[M+H] = 531(M+1) [740] 1H NMR (400 MHz, CDC13) 7.51 (d, 2H), 7.33 (d, 2H), 4.69 (t, 1H), 4.35-4.22 (m, 2H), 3.95-3.90 (m, 2H), 3.81-3.69 (m, 1H), 3.67-3.54 (in, 211), 3.42-3.29 (m, 2H), 3.22-3.11 (m, 1H), 2.82-2.68 (m, 1H), 2.68-2.56 (m, 3H), 2.19-1.97 (m, 1H), 1.61-1.39 (m, 5U), 1.31-1.15 (m, 4H), 1.22 (s, 910, 0.90 (d, 3H) P4H [742] Example A8:N-[(3S)-I-{[(3S,4R)-l-t-botyl-4-(4-chlorophcnyl)pyrrolidine-3-yl] carbonyl}pyrrolidine-3-yI]-N-(4,4-dimethylcycIohexyl)-3-hydroxy-2,2-dimethylpr opaneamidc HC1 salt 17431 O u N J N O CI 1ICI OH [7441 r7451 Step A: OSVl-Boc-3-r(4,4-dimethvlcyclohexylkminoloviTolidine [746] To a solution of 4,4-dimelhylcyclohexanone (3.8g, 30mmo1) in DCM (200 ml) was added commercially obtained (3S)-l-Hoc-3-aminopyrrolidine (5.6 g, 30 mmol), and NaBH(OAc) (12.7g, 60mmol) was added, and stirred at rt for 6 h. After the reaction finished, the solvent was concentrated in vacuo, a NalICO aqueous solution was added, and extracted with EtOAc. The organic layer was dried over MgSO , con¬centrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex - 2/1) to give the title compound (8.4g, 94.5%). [747] MS[M+H] = 297 -Z2-diinelhy1- N-ff3 S Vpyrrolidine-3-yn propaneamide [769] The title compound %vas prepared according to the procedure described in Step E of Example A1 using (3S)-l-Roc-3-[(4,4-dimelhyIcyclohexyl){2,2-dimethyIpropanoyI)amino]pyrrolidine (460mg, 1.22mmoI) prepared in Step A (0.33g, 97%). [770] MS[M+H1 = 281(M+1) [771] [772] StcpC:N4f3S)-l-(fr3S.4RVl-l-hutvl-4-f4-ch1orophenynPyrrolidine-3-vl] carhonyllpyrrolidine-S-yn-N-M^-dimethylcyclohexyn^^-dimethylprop^neamide UC\ sail [773] The title compound was prepared according to the procedure described in Step F~G of Example Al, using //-(4,4-dimethylcyclohexyI)-2,2-dimethyl-A'-[(3S' )-pyrrolidine-3-yl]propaneamide (300 mg, 1.06mmol) prepared in Step B and (3S,4R)-I-t'hutyI-4-(4-chIorophenyl)pyrroiidine-3-carboxyIic acid prepared in Preparation Example A9-2 (510mg, 90%). [774] MSfM+IT] = 544(M+1) [775] III NMR (400MHz, CDC13) 7.58-7.47(m, 2H), 7.37-7.30(m, 2IT), 3.92-3.48(m, 7IJ). 3.47-3.22(m, 3H), 2.77-2.69(m, 1H), 2.53-2.33(m, III), I.78-1.57(TTI, 811), 1.52-1.38(m, 10H), 1.32-1.20(m, 1011), 0.94(s, 3H), 0.92(s, 311) [776] [777] ExampleA10:(4.V)-l-{[(35',4/f)-l-(crt - butyl-'l-Ca^-dinuorophenyOpyrroUdine-a-ylJcarbony/J-^-^^-dimethylcydoheKyl )(melhy]sulfonyI)amino]- N, N -dimethyl-L-proIineamide HC1 salt [778] Q 0 / F :' ;>V° F :"- HC1 [779] [780] Step A: methyl f2S.4S)-l-BOC-4-[r4.4-dimethvlcvclohexvlVmelhvlsulfonvl)amino1 pyrToHdine-2-carboxylate [781] To a solution of methyl (2S,4S)-[-BOC-4-[(4,4'dimelhy]cyc]ohexyl)amiiio] pyrrol idine-2-carboxy I ate (2.37 g, 6.7mmoi) prepared in Step A of Example AI in DCM (10ml) was added TEA (1.36g, 13.4mmol), slowly added dropwise methancsul-fonylchloride (104mg, 0.91mmol) at 0°C, and stirred at it for 30 min. After the reaction finished, the solvent was concentrated in vacuo, the residue was extracted with water and EtOAc. The organic layer was dried over MgSO , concentrated in vacuo, and A purified by column chromatography (elucnt: EtOAc/IIex = 1/1) to give the title compound (2.08 g, 72%). [782] MS[M+H) = 433 [(3S)-l-(r(3S,4K)-l.^butyJ-4<4-chloropheny0pyrrolidine-3-ylJ carbonyI}pyrroIidine-3-yi](4,4-dime(hylcyclohexyI)amino}-2,2-diineHiyIpropanc-l -ol 11(1 salt [802] O / N a HCl OH [803] [804] Step A: (3S)-l-Boc-3-[(4.4-dimethylcyclohexvl)(3-hvdroxy-2.2-dimelhylpropyl)amino1pyrroii dine [805] To a solution of (3S)-l-Boc-3-[(4,4-dimethyIcyc!ohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amfno]pyr ralidine (210mg, 0.53mmol) prepared in Step B of Example A8 in THF was added dropwise borane-methylsulfide complex (in THF, 2.0M, 0.4ml, 0.8mmol), and stirred at 80°C for 3 h. After the reaction finished, the solvent was concentrated in vacuo, water added, extracted with EtOAc. The organic layer was dried over MgSO , con¬centrated in vacuo, and purified by column chromatography (eluent: DCM/MeOII = 9/1) to give the title compound (140mg, 75%). [806] MSfM+H] = 382 (M+l) [807] [808] StepB:m(3S)-l-U<3SARU-t-bMvl-4-(4-dilomphenvl)ovrtvlidine-3-vll carbonyl}pvTTolidine-3-vllf'l,4-dimelhyIcvclohexvl1aTniTiol-2.2-dimethvlproDane-l-ol HCl salt [809] The title compound was prepared according to the procedure described in Step E~G of Example Al using (3S)-l-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethyIpropyl)amino]pyrron dine (14Gmg, 0.36mmol) prepared in Step A (156mg, 78%). [810] MS[M+H1=546(M+1) 18111 IH NMR (500MHz, CDCI3) 7.55-7.48(m, 211), 7.36-7.28(m, 211), 3.95-3.l5(m, 1 HI), 2.85-2.78(m, III), 2.58-2.38(m, 211), 2.28-2.08(m, 211), 1.85-1.53(m, 7H), 1.53-1.35(m, 1 OH), 1.32-1.14(m, 8H), 0.94(s, 310, 0.91(s, 311) [8121 1813] FjrampleA12:(3S)-l-U(3£,4ff)-1-ferf - bu(yl-4-(4-chlorophcnyI)pyrrolidine-3-yl]carbonyl|- A' -isobutyl- A7 - (cis-4-melhyIcyelohexyl)pyrrolidine-3-aminc IIC1 salt [814] [8151 [8161 Step A: f3SVI-Boc-3-lisobmyIfcis-4-methylcyclohexvOamino1pyiTolidine [817] Commercially obtained (3S)-3-Boc-3-aminopyrrolidine (5.6g, 30mmol) was reacted according to the procedure described in Step A of Example A7 to give (3S)-l-Boc-3-cis-(4'-methylcyclohexyl)aminopyrrolidine. Then, the title compound was prepared from this compound and isobutyl aldehyde via reductive amination as described in Step A of Example Al. [818] MS[M+Ifl=339(M+l) [819] [820] Step B: (3 SV1-JU3 SA R VI- fgrt-butvl-4-r4-chlorophenyl)pvrrolidiTie-3-V_ll carbonyl}- N -isobutyl- N-(cis-4-methylcyclohexyl)pyrrolidine-3-amine HCI salt [821] The title compound was prepared according lo the procedure described in Steps E,F,G of Example Al using (3SVl-Boc-3-[isobutyKcis-4-methyIcyclohexyl)arnino] pyrrolidine (lOOmg, 0.30mmol) prepared in Step A (115mg, 78%). [822] MSfM+H] = 502 (M+l) [823] IH NMR (400MHz, CDC13) 7.59-7.48(m, 2H), 7.35-7.28(m, 2H), 3.91-3.47(m, 7H), 3.47-3.22(m, 3H), 2.80-2.69(m, 211), 2.53-2.33(m, IH), 1.78-1.57(m, 8H), 1.52-1.38(m, 11H), 1.28-1.18(m, 7H), 0.95(d, 3H) [824] [825] Example A13-172 [826] The following Examples were prepared according to the procedure described in Example A1~A7,A9, using appropriate compounds among Preparation Example Al, A2, A4, A9 and commercially available amine. A120 l-Ru 4-CI II -l.l-diMf-i--llc.\ r 1 s 1 56S AI:I t I hi 4 CI I II 4.-l-iilNk-c-Hl.>\ i s >28 A122 I-BJ 4-CI H eis-4-.Me-t-l k\ Clf, T S 488 A123 I-Bu 4-CI 1( 4.4-iliMc-i-ilM i - s 554 0 1 V A124 1-Bu 4-CI H 4.J-(liM,'i-Hcx -n. s 554 AJ25 l-Bn 4-CI 11 4,4-diMe-c-Hex >' S s 571 A126 r B.i 4-CI M 4,4-diMc-t-lles CHjOCHs s 532 A!27 t-Bu 4-CI H ■U-diMe-c-l [ex CIliOCHjCH ! s 546 AI2S l-Gu 4-CI II 4,4-diMe-o-Htx C(Cli,).OH s 546 A129 t-Bu 4-CI H cis-4-Mi'-oHcx ciiicn. s 5112 A1 30 l-llu 4-CI II [ cis-4-Me-c-lkx CH.OCH, S 518 AI3I l-EJn t-Uu 4-CI II | tii-4-Me-c-He\ i-Bu s 530 AI32 4-CI li cis-4-Me-c-Hcx cydopcnt} 1 s 542 A133 I-Bu 4-CI i H ' cis-4-Me-c-llex s 540 A134 1-I3u 4-CI H cis-4-Me-c-Hex s 556 AI35 I-Bu 4-CI II cis-4-Me-c-llex C(CHi|2CH. OH s 546 A116 AI37 AI3K 1-B.i 4-CI H cii-4-Me-c-Hex C(C(l;k CH(CH,)OH s 5(i{] l-Ru 4-CI II cib-4-Mc-c-ltex CfCHil.CfC fl,);OH s >74 t-Bu 4-CI H ' cii-4-Mt-c-Jlex =.30 5J2 A 142 '■ I-BLI ll.:ll.-, 1 ML'C- I Li IBII t-Rii A 14 J A 14 1 I-Ru 2,4-di[" H T|,51]LI--1-ML--(- Ikx CVdlJpt^llyl >1 "" " - - 6 l-Hu 4-CI II H CfCHO.CIl, Oli s s 5IK 514 A14? 1 fiu 4-CI C(Cllj),CH. Oil A 146 I-Bu 4-CI H 4,4-diF-c H»x CH(CH,>:. s 538 AM? l-Bu 4 CI 11 li 4,4-diF-c-Hex l-Bu £ 5 552 A! 48 t-llu 4-CI 4,4.diF-c-Hex II o-1 566 A149 t-Bu 4-CI 11 4,4-dil--c Hex S 566 A I5fi L-Bu 4 CI - 4.4-diF-c-Hex en, 510 AI5I i-Bu l-Bu l-Bu 4-CI 4-CI l( Cis-J-Ci ;-c-!lev a\t< n,); £ 570 A152 A153 H Os-d-CKc-Hex [-Bu l-Bu S S 5S4 4-CI II TJJII^-4-CFJ-L" Hex 584 A154 AI55 i-Bu l-Bu 2,4-diF II 4.4-diM<.-i-Hc\ CH(C:H;,); S •- 5 32 2.4-diF 11 4.4-diMe-c-Itex 4.4-diMc-c-Hcx i-Bu s 546 A156 I-Bu 2.4-diK 11 ^6 s 55H A 157 t-Bu 2,4-d.F 11 4,4-diMe-c-Hex 6-*' s 560 A158 i flu 2.4-diK H 4,4-diMe-c-Hex '*-6 s s — 560 A159 i-Bu 2.4 diF H ■1.4-diMe-t-Hex (XCHJIJCHJ OH 562 A16H [-Bu 2.4-diF H 4,4-diMe-c-Hfiii CHICHJOCH ;CH, s 562 AI61 i-Bu 2,4-diF H ds-4-Me-c-llcx r-Bu s 532 [845] A 162 A 161 1 i-Hn t-iiu 2,l-dd H u\ 4 V1c-c-He4.4-diF-c-He.s 4 4-dil-c-lkx 'o' '■(CHS), s S 1 1 1 yl2 2.4-dif: H A 16! t-Bu 2.-I diF 11 OH H o -' ai(ciii). s s - 570 A165 A166 l-Hu t-Hu 2.4-dih 11 4.4-di[:-c-Hc\ S6K 4-1' H Cii-l-Me-c-Nux s 5111) 524 A167 AI68 l-Bu 4-Me H 4,4-dilHe-c-Hex l-Bu s s t-Ru 4-C1 II cjdofeutyl OH 504 546 516 A169 1 Bu Me 4-C! H cycli)liepl>l C(CH,),CHi OH s A 17(1 ■1-CI H 4.4-diVle-c-Hex H o- -' s A171 Mc •l-CI H ■f.J-diMe-c-Hex '■ o CH.OH s s _._- 516 A172 t-Bu I •1 CI H 4,4-diMe-c-H«x 518 j [846] [847] [848] [849] [850] [851] [852] [853] 854] (A44) (TFA salt) III NMR (500MHz, CDCI3) 7.60-7.52(m, IH), 6.92-6.85(m, III), 6.82-6.74(m, IH), 4.72(t, IH), 4.23^.10 (m, 2H), 4.06-3.93 (m, 2H), 3.74-3.40 (m, 5H), 3.35-3.25 (m, IH), 2.99 (s, 310, 2.95 (s, 311), 2.81-2.66 (m, 2H), 2.17-2.06 (m, III), 1.68-1.14{m, 6H), 1.44 (s, 9H), 1.14-1.00 (m, 2H). 1.07 (dd, 611), 0.95 (s, 3H), 0.92 (s, 3H) (A50) (TFA salt) IH NMR (500 MHz, CDC13) 7.61-7.54 (m, IH), 6.92-6.86 (m, IH), 6.81-6.75 (m, IH), 4.71 (t, IH), 4.25-4.07 (m, 2H), 4.04-3.93 (m, 2H), 3.84-3.71 (m, IH), 3.70-3.55 (m, 2H), 3.55-3.45 (m, IH), 3.45-3.35 (m, IH), 3.35-3.25 (m, 1T0, 3.11 (s, 6H), 2.81-2.70 (m, IH), 2.01-1.90 (m, IH), 1.60-1.39 (in, 5H), 1.44 (s. 9H), 1.28-1.13 (m. 4H), 1.21 (s, 9H), 0.97 (d, 3H) (A52) GIC1 salt) IH NMR (400 MHz, CDC13) 8.10-8.04 (m, IH), 6.97-6.93 (m, HO, 6.79-6.74 (m, IH), 4.70 (t, 111), 4.35-4.22 (m, 2H), 3.95-3.40 (m, 2H), 3.81-3.69 (m, HI), 3.67-3.54 (m, 2H), 3.42-3.29 (m, 211), 3.26-3.11 (m, 3H). 2.82-2.68 (m, IH), 2.19-1.97 (m, IH), 1.61-1.39 (m,4H), 1.49 (s, 9H), 1.32-1.15 (m, 711), 1-22 (s, 9H), 0.95 (s, 3H),0.91 (s, 3H) 855] [8561 (A53) (I1C1 sail) [857] HI NMR (400 MHz, CDCI3)R.in-8.04(ni, IH), 6.97-6.93 (m, III), 6.79-6.74 (m, III), 4.70 (I, IH), 4.35-4.22 (m, 2H), 3.95-3.40 (m, 2H), 3.81-3.69 (m, III), 3.67-3.54 (m, 2)1), 3.42-3.29 (m, 211), 3.26-3. J1 (in, 311), 2.99 (s, 3H), 2.82-2.68 (m, IH), 2.19-1.97 (m, IH), 1.61-1.39 (m, 411). 1.49 (s, 9H), 1.32-1.15 (m, 7H), 1.22 (s, 9H), 0.95 (s,3H), 0.91 (s,3I0 [858] [859] (A54) (HO salt) [860] IH NMR (400 MHz, CDC13) 8.10-8.04 (m, IH), 6.97-6.93 (m, III), 6.79-6.74 (m, IH), 4.70 (1, IH), 4.35-4.22 (m, 2H), 3.98-3.93 (m, IH), 3.95-3.81 (m, 2H), 3.81-3.69 (m, IH), 3.67-3.54 (m, 211), 3.42-3.29 (m, 2H), 3.26-3.11 (m, IH), 2.82-2.68 (m, IH), 2.19-3.97 (m, IH), 1.61-1.39 (m, 4H), 1.49 (s,9H), 1.34-1.15 (m, 1011), 1.22 (s,9H), 0.95 (s, 3H), 0.91 (s, 3TI) [861] T862] (A55) (HCI salt) [863] III NMR (400 MHz, CDC13) 8.10-8.04 (m, IH), 6.97-6.93 (m, Hi), 6.79-6.74 (m, IH), 4.70 (t, IH), 4.35-4.22 (m, 2H), 3.97-3.81 (m, 6H), 3.81-3.69 (m, IH), 3.67-3.54 (m, 2H), 3.42-3.29 (m, 2I{), 3.22-3.11 (m, IH), 2.82-2.68 (m, HI), 2.35-2.20 (m, 2H), 2.19-1.97 (m, HI), 1.61-1.39 (m, 411), 1.49 (s, 9H), 1.31-1.15 (m, 4H), 1.22 (s, 9H), 0.95 (s,3H), 0.91 (s,3H) [864] [865] (A60) (HCI salt) [866] IH NMR (400 MHz, CDC13) 8.14-8.00 (m, IH), 7.03-6.91 (m, IH), 6.83-6.72 (m, IH), 5.94 (s, IH), 4.89-4.66 (m, 5H), 4.30^.12 (m, 2H), 4.12-3.99 (m, IH), 3.99-3.88 (m, IH), 3.74-3.47 (m, 414), 3.42-3.26 (m, 2H), 3.00 (s, 3H), 2.95 (s, 3H), 2.76-2.52 (m, III), 2.24-2.09 (m, IH), 1.57-1.34 (m, 4H), 1.49 (s, 9H), 1.34-1.16 (ra, 4H), 0.93 (s, 3H), 0.90 (s, 3H) [867] [868] A62) (HCI salt) [869] HI NMR (400MHz, CDCI3) 7.62(d, 2H), 7.31(d, 2H), 4.70(t, IH), 4.36-4.19(m, IH), 3.97-3.80(m, 3H), 3.78-3.64(m, 2H). 3.63-3.52(m, 2H), 3.39-3.2J s s 571 AISO t-Bu 4-CI 4,4-diMe-c-Hex i'li s 564 AI8I I-Ru 4-CI 4.4-diMe-c-Hex 0 s 554 AI82 1-Bu 4-CI Cis-4-Me-c-Hex CH3GH s 5' s s 557 AI8S l-Bu 4-CI H Cis-4-Me-c-Hex \ s 540 [921] [922] Scheme H [923] o "' NO o 0 S •-J R3 —- \ o a W Inl. A9 HBTU "' D1EA ——*- \ o R' p DMF IM. B2 Inl B1 "' R. InLAS P'=C01CHl Int=intermediate 924] 925] The preparation process of the Inermediate B1 compounds, and the Bxamples synthesized by the procedure of Scheme B are as follows. 926] [927] Kxamplc HI: N-[(3 S,5 S)~]-{[(3iS A H)-\-tcrt - b«tyl-4-(4-chIorophenyl)pyrrolidine-3-yl]carbonyl}-S-(4,5-dihy(iro-l,3-oxazo[c-2-y ])pyrro!idine-3-yI]- A' -(4,4-dimethyIcyciohexyl)-2,2-dimethyIpropancamide IIC1 salt [928] I 0 ,. N V" N """ N'I TV ->-;° " - - - " ■■ \ A- -. CI >■■ • HC1 [929] [930] Step A: (2S.4SVl-Boc-2-f rf2-hydmxyelhyl)amino1 caTbonvl)-4-fdimethvlpropanoyK4.4-diTTiethylcycloheJtyl'iaminolpyrrolidine [9311 The title compound was prepared according to the procedure described in Step D of Example A1 using (4S )-l-BOC-4-[(4,4-difluorocyclohexyI)(2,2-dimethylpropanoyl)amino]-L-proline (410 mg, 0.9 mmol) prepared in Step C of Example Al and hydroxy ethyl amine (273 mg, 65%). [932] MSfM+H] =468 (M+l) [933] [934] SlepB: (2SAS)-l-Boc-2-|'4,5-dihvdro-1.3-oxa2ole-2-yh-4-[dimethyipropanoylf4,4-dimelhylcy clohexynaminolpyrrolidine [935] The product of Step A, (2S.4S)-1 -Boc-2- {f (2-hydroxyethyl)amino] carbonyl]-4-[dimethylpropanQyl(4,4-dimethylcyclohexyl)amino]pyTTolidine(410mg, 0.58 mmol) together with DMAP (70.7 mg, 0.58 mmol) and DIPEA (0.39 ml, 2.32 mmol) were dissolved in toluene (3 ml), and phosgene (20% in toluene, 0.31 ml, 0.87 mmol) was added dropwise. After the reaction solution was stirred at 30~40°C for 48 h, the solution was concentrated in vacuo. The residue was diluted with BtOAc, and washed with a saturated NaHCO aqueous solution, water and IN HC1. The organic solution was dried over MgSO , concentrated in vacuo, and the residue was purified by 4 column chromatography (eluent: F.tOAc) to give the title compound (160mg, 62 %). [936] MS[M+H] =450(M+I) [937] [938] Step C: N-U3 S .5 S 1-1-f f(3 S A R VI- ten - butvl-4-(4-chiorophenvl)pviTolidine-3-vl1carbonvl|-5-(4.5-dihydro-1.3-oxazole-2-vnp vn-olidine-3-yll- .V-^.4-dtmethvIf:vc1ohesylV2,2-dJmfthylprop.ineajnideHCl salt [939] The title compound was prepared according to the procedure described in Step Ii-G of Example A1 using (2S,4S)4-Boc-2-(4,5-dihydro-l,3-oxa7.ole-2-yI)-4-[dimethyIpropaiioyl(4,4-dimethylcy clohexyl)amino]pyrrolidine (lOOmg, 0.2 mmol) prepared in Step B (95 mg, %1%). [940] MS[M+lTj = 613(MM) [941] III NMR (400 MIIz, CDC13) 7.36 (d, 2H), 7.29 (d, 2H), 4.35-4.22 (m, 2H), 3.95-3.90 (m,2H), 3.80-3.51 (m,6H), 3.42-3.29 (m, 2H), 3.22-3.11 (m, III), 2.82-2.68 (m. Ill), 2.194.97 (m, III), 1.61-1.39 (in, 6H), 1.49 (s,9H), 1.31-1.15 (m, 4H), 1.22 (s, 9H). 0.95 (s, 3H), 0.91 (s, 311) [942] [943] ExampleB2:AT.{(3SI5^)-l-{[(35,^^)-l-fert - butyI-4-(4-cWorophenyl)p5Trolidine-3-yl]carbonyI}-5-[(dimethylamino)carbonoth ionyl]pyrrolidine-3-yl}- iV -(4,4-dimethylcyclohexyl)-2-methylpropaneamide TFA salt [944] S, / .--N ■ N' ■-. ■--/ I. / r% W° ct' —r--'' TFA [945] [946] Step A: 1 -BOC-2-methylf2 S AS V4-ff4,4-dimethy1cvc1nhexvl>(isohiityrynamino1 pyrrolidine-2-carboxvlale [947] The title compound was prepared according to the procedure described in Step B of Example Al, using methyl-(2S,4S)-l-BOC-4-[(4,4-dimetIiylcyclohexyl)amino] pyrrol id ine-2-carboxylate (lg , 2.82 mmol) prepared in Step A of Example Al and isobutyryl chloride (1.1 g, 93 %). [948] MS[M+H] =425(M+1) [949] [950] StepB: (4 ,S')-l-BOC-4-[l'4,4-dimeihyicyclohexylVisobutyrvl)arninol-L-proJing [951] The title compound was prepared according to the procedure described in Step C of Example Al using 1-BOC- 2-methyl(IS AS )-4-[(4>4-dimethylcyclohexyl)(isobulyry!)amrno]pyiTolidine-2-carboxylate (1.1 g, 2.62 mmol) prepared in Step A (1.0 g, 93 %). [952] MS[M+H] =4U(M+1) substitute sheet [953] f954) Step C: R0C-f2 S A S V24(din1elhylarnino)carbonyIl - 4-f("4.4-dimelhylcyct()hexviyisobL]lvrynaTninq1pyn-plidine [955] The title compound was prepared according to the procedure described in Step D of Example A! using (4^-l-BOC-4-[(4,4-dimemylcycIohexyl)(isobutyryl)amino] - I.-proline (1.0 g, 2.43 mmol) prepared in Step B (0.97 g, 92%). [956] MSfM+Hl =438(M+1) [957] [958] Step D: BOC (2 S A S )-2-[(dimethvlamino)carbonothionvil - 4-[f4.4-dimethvlcvclohexyl)fisobutvrvnaminolpvrrolidine [959] To a solution of BOC-(2,S,4S)-2-f(dimemylamino)carbonyl] - 4-[(4,4-dimelhylcyclohcxylXisobutyryl)amino]pyrrolidine(615 mg, 1.41 mmol) prepared in Step C in benzene (3 ml) was added Lawson s reagents (570 mg, 1.47 mmol). The reaction solution was heated to 80°C, and stirred for 1 h. After the reaction finished, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with brine. The organic solution was dried over MgSO , concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc:Hex = 1/2) to give the title compound (409 mg, 64 %). [960] MSfM+Ii] =454(M+1) [961] [962] Step E: JV-((3 S .5 S V5-rfdimethYlaminokaroonothiony11pyrrolidine-3-vll- N - (4.4-dimethylcyclohexyl)-2-methylpropanearnide [963] The title compound was prepared according to the procedure described in Step E of Example Al using BOC (2£,4^-2-[(dimethylamino)carbonothionyl] -4-[(4,4-dimethyIcycIohexyl)(isobutyryI)ami no]pyrrolidine (50mg, 0.11 mmol) prepared in Step D (38 mg, 98%). [964] MS[M+II] = 354 (M+l) [965] [966] Step F: N-iB S .5 S)-!-(Fi3 S A R )-l- tert - butyl-4-(4-chlorophenyl)pyrrolidine-3-vncarhonvll-5-[(dimethylamino)carbonothionvl lpyrrolidine-3-yl}- /V-(4,4-dimethylcycIohexvl)-2-methylpropaneamideTFA salt [967] The title compound was prepared according to the procedure described in Step F of Example Al using A'-[(35,,519)-5-[(dimethyIamino)carbonolhionyl)pyrTolidine-3-yl}-A'-(4,4-dimeIhylcycIohexyi)-2-methylpropaneamide (38 mg, 0.10 mmol) prepared in Step E and (3S,4R)-l-t-butyI-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (55 mg, 89%). [968] MS[M+H] =617(M+1) [969] III NMR (500MHz, CDC13) 7.55-7.50(m, 1H), 6.92-6.85(m, III), 6.82-6.75(m, 1H), 5.02-4.95(t, 11I), 4.20-4.08(rn, H 0, 4.0S-3.90(m, 2H), 3.68-3.26(m, 511), 3.46(s, 311), 3.31 (s, 310, 3.15-2.88(m, 311), 2.79-2.68(m, 1 IT), 2.20-2.00(m. 1II), 1.75-1,60(m, 111), 1.60-1.52(m. Ill), 1.52-1.38(m,4H), 1.44(s,9Ii), l.38-1.25(m, 2H), 1.10(dd, 611), 0.94(s, 311), 0.92(s, 310 [970] [971 ] Example B3: N-1(3 S$R )-I-{[(3S ,4 /? )-l- tert - hiity]-4-(2(4-(JifluoroplienyI)pyrro[idine-3-yI]carbonyl}-5-(13-lhia7oIe-2.yl)pyrroli dine-3-yl]- N -(4,4-dimelhyIcydohexyl)-2,2-dimethylpropaneamide HC1 salt f9?2] s- j 0 N I. -■ F-r,.. 0 > M-v ' , /'' - ■■ '. F —7 '-HC1 T9731 [9741 Step A: ROC (2 K A S V2-(aminocarbonothionylV4rr4.4- dimethvlcvclo hexvlV2.2-dimethyIpropanoyl)amino pyrrolidine (9751 The title compoiind was prepared according to the procedure described in Step A~C of Example Al and Step D of Example B2, using methyl (2R,4S)-l-Boc-4-aminopyrTolidine-2-carboxyIate prepared in Preparation Example A1-3 as starting material (880 mg, 2 mmol). [9761 MS[M+III = 440 (M+1) [977] [978] Step B: BOC (2 R A S V4-K4A- dimethyIcyclohexynf2.2- dimethvlpropanovnamino l-2-(l,3-thia7:ole-2-yBpyrT0lidine [979] To a solution of BOC (2K,4S)-2-(aminocarbonothionyl)-4-[(4,4- dimethyl- cyclohexyl)(2,2-dimethyIpropanoyl)amino pyrrolidine (880 mg, 2 mmol) prepared in Step A in dimethoxyelhane (JO ml) was added 50 wt% chloroacetaldehyde (0.38 ml, 3 mmol) and NalICO (504 mg, 6 mmol), and stirred at it for 2 h. After the reaction finished, the reaction solution was concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with water and brine, dried over MgSO , con-c;ntrated in vacuo, and the residue was purifed by column chromatography (eluent: IitOAc:Hex = 1/1). This compound (510 mg, 1.24 mmol) was dissolved in pyridine (0.9 ml, 11.1 mmol), and TFAA (1.0 g, 4.96 mmol) was added dropwise at 0°C. At the same temperature, the solution was stirred for 1.5 h, concentrated in vacuo, and extracted with EtOAc. The organic extracts were washed with 0.5N HC1 solution and brine, dried over MgSO , and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtO Ac/Hex = 2/1) to give the title compound (249 mg, 51.0%). [980] MS[M+JI]=464(M+I) [981] [982] Step C: N -(4,4- dimcthvlcvclohcxvn-2.2-dimethvU N 4(3 S .5 R )-5-( 1,3-thiazole-2-vllpymilidine-3- vllpropaneamide [983] Tlie title compound was prepared according to the procedure described in Step H of Example Al using BOC (2R,4S )-4-[(4,4-dimethylcyclohexyI)(2,2-dimethyIpropanoyl)amino]-2-(l,3-thia7cle-2-yl)pyiT olidine (80mg, 0.17 mmol) prepared in Step B (60mg, 98%). T984] MSfM+H] = 364 (M+l) [985] [986] Step D: AM(3 S .5 R Vl-tfG S A R U-tert - batyl-4-(2,4-diflpomphgnyUpyTrolidin&-3-yncarhonyU-5-(1.3-lhia7-ole.-2-yt^pyTToltdin e-3-yl]- A^-(4.4-djniethvlcyclnhexyn-2.2-dimethvlpropaneaniide HC1 salt [987] The title compound was prepared according to the procedure described in Step F,G of Example A1 using A/-(4,4- dimethylcyclohexyl)-2,2-dimethyl-A'-[(3S,5# )-5-(l ,3-thiazole-2-yl)pyrroIidine-3- yl]propaneamide (60 mg, 0.16 mmol) prepared in Step C (55 mg, 89%). [988] MS[M+H] = 629(M+1) [989] 1HNMR (400 MHz, CDC13) 8.10-8.04 (m, 1H), 7.92-7.86 (m, III), 7.21-7.15 (m, 1H), 6.97-6.93 (m, 1H), 6.79-6.74 (m, 1H), 4.94 (t, 1H), 4.35-4.22 (m, 2H), 3.95-3.90 (m, 211), 3.81-3.69 (m, IH), 3.67-3.54 (m, 211), 3.42-3.29 (m, 2H), 3.22-3.11 (m, IH), 2.82-2.68(m, IH), 2.19-1.97 (m, IH), 1.61-1.39 (m, 4H), 1.49 (s,9H), 1.31-1.15(m, 4H), 1.22 (s, 9H), 0.95 (s, 3H), 0.91 (s, 3H) [990] [991] Example B4: TV-[(3 S,5 SH-U^ A*,4/?)-l-terf - butyI-4-(4-ehIorophenyl)pyrroIidme-3-yl]carbonyl}-5-(hydroxymethyl)pyrrolidine -3-yI]- N -(4,4-dimethylcyclohexyl)-2,2-dimethylpropaneamidc TFA salt [992] , o . OH r\ -,N ° ci TFA [993] [994] Step A: BOC (2 S A S )-4-lf4,4-dimeihylcyclohexyni'2.2-d)methvlDroDaTiovnainmt)l - 2-(hydroxvinethy0pvrTolidiTie [995] To a solution of l-B0O2-methyl-(2S,4S )-4'[(4,4-dimethyleyclohcxyl)(2,2-dimethytpropanoyl)amino]pyrrolidina-2-carboKylate (1.18 g, 2.71 mmol) prepared in Step B of Example A) in TlIFOOml) was added LiBH (177 mg, 8.13 mmol). The solution was stirred at 70°C for 2 h, concentrated in vacuo, and extracted with HtOAc. The organic extracts were washed with a saturated NaHCO aqueous solution and brine, dried over MgSO , and concentrated in vacuo to give the title compound (0.88 g, 81 %). [996] MS[M+H] = 411 (M+l) [9971 [9981 Step B: Ar-(4.4-dimahylcyclohexyIV N-\(3 S .5 S V5-("hvdroxymethyl'lpyrTolidine-3-yl]~2,2-di methyl propaneamide [999] The title compound was prepared according to the procedure described in Step E of Example A1 using BOC (2S.45 )-4-[(4,4-dimethylcycIohexyl)(2,2-dimethylpropanoyl)amino)-2-(hydroxyinethyl)pyrro lidine (120mg, 0.29 mmol) prepared in Step A ( 89mg, 98%). [ 1000] MS fM+H] « 311 (M-t 1) noon [1002] step C; AT-K3 ,S ,5 S)-f.-{rf3 S A * .H- ten - hutvi-4-(4-chIorophenyl)pyrrolidine-3-yl [carbon yH-5-(hydroxvmethvOpytTolidine-3-y 11- A,-(4,4-dimethytcycloriexyn-2.2 1-2-fhvdroxvrnethy ^pyrrolidine f 1011] The title compound (1.11 g) was prepared according to the procedure described in Step A-Cof Example A1 and Step A of Example B4, using methyl (2R.4S)-1 -Boc-4-aminopyrroIidine-2-carboxylate prepared in Preparation Example Al-3 as starting material. [10121 MS[M+II]=411(M+1) [1013] HOT4] Step B: BOC- (2 R A S 1-4-K4.4- dimethvlcyclohexviy2.2-dimethvlprnpannynamino l-2-f[(methvlsulfonyl)oxylTriethynpvrrolidine f 10151 The title compound was prepared according to the procedure described in Step C of Preparation Example Al-1 A using BOC- (2RAS )-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)aminol-2-(hydroxymethyl)pyrro lidine (LI I g, 2.71 mmo?) prepared in Step A (1.1 g, 85%). [1016] MSfM+II] = 489 (M+l) [1017] [1018] Step C: BOC- (2 R A S V4-ff4.4-dimethvlcvclohexvl¥2.2-dimetrivloropanovnaminol -2methylpyrrolidine [1019] To a solution of BOC- (IRAS )^_[(4i4-dimethyIcyclohexyl)(2,2-dimethylpropanoyl)aminol-2-{[(methylsulfonyl)oxy ]methy]}pyrrolidine (580 mg, 1.19 mmol) prepared in Step B in THF (5 ml) was added dropwise LiBH (77mg, 3.57 mmol) at 70°C. The solution was stirred at 70°C for 5 h, 4 concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with a saturated NaHCO aqueous solution and brine, dried over MgSO , and con¬centrated in vacuo. The residue was purifed by column chromatography (eluent: EtOAc:IIex = 1/4) to give the title compound (258 mg, 53 %). [1020] MS[M+H1 = 395CM+1) [1021] [ 1022] Step D: /V-f4.4-dimethvlcydnhexvlV2.2-dimethyl- N-\(3 S .5 S V5-methylpyrrolidine-3-ynpropanearnide [1023] The title compound was prepared according to (he procedure described in Step R of Example Al using BOC- (2R,4S')-4~\(4,4- dimelhyl- cyc]ohexylX2,2-dime(hyJpropanoyl)arnmoJ-2me[hyfpyiToIidine (50mg, 0.12 mmotj prepared in Step C (36mg, 98%). [1024] MSfM+I-H = 295(M+1) [1025] T1026] Steo E: N-U3S.5 S VMK3 S A R VI- tert - butyl-4-(4-chlorophenvnDvrrolidiTie-3-vI1camonvlV5-methvlpyrrolidine-3-yl]- N -f4,4-dimelhvlcvclohexvlV2.2-dimethvipropaneamide TFA salt [1027] The title compound was prepared according to the procedure described in Step F of Example Al, using AK4,4-dimethylcyclohexyl)-2,2-dimethyl-W-|"(3.aininn1 - 2-[fEV(hvdroxvimino)methyl1pvrTolidine [1039] To a solution of (2S,4S)-I-Boc-4-f(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-2-formylp yrrolidine (312 mg, 0.88 mmol) prepared in Step A in methanol (5 ml) and TEA (0.64 ml, 4.4 mmol) was added hydroxylamine hydrochloride (305 mg, 4.4 mmol), and stirred at rt for 2 h. After the reaction finished, the solution was concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with water and brine, dried over MgSO , and concentrated in vacuo. The residue was purified fay column A chromatography (cluent: EtOAc:Hex = 1/2) to give the title compound (208 mg, 67%). [1040] MSfM+H] =424(M+1) f!041] [1042] StepC: JV-r4.4-dimethvlcvclohexyl) -^-ff3 .■J.S.yVS-rC EVOiydroxvimino^methvll pyrrolidine-3-yl|-2.2-dimethylpropaneamide [1043] The title compound was prepared according to the procedure described in Step H of Example A1 using BOC (25,45 )-4_[(4i4_dimethyIcyclohexyl)(2,2-dimethylpropanoyl)amino]-24(E)-(hydroxyimino)m ethy]]pyrrolidine (2O0mg, 0.47 mmol) prepared in Step B (150mg, 98%). [1044] MSfM+Hl =324(M+1) [1045] [1046] SicnD: N-U3S.5 S)-\-U(3S.4 RVUtert - butyl-4-(2.4-difluoronhenvl)pvrrol id ine-3-vncarbonvn-5-rfE)-fhvdroxvimino)methvl1 pvrroHdine-3-vn-//-f4.4-dimethvlcvclohexvlV2.2-dimethvlprODanearriideHCIsalt [1047] The title compound was prepared according to the procedure described in Step F,G of Example Al using W-(4,4-dimethylcyclohexyl)-W-{(3S,55)-5-[(£ )-(hydroxyimino)methyl]pyrrolidine-3-yl}-2,2-dimethy]propaneamide (150 mg, 0.46 mmol) prepared in Step C (144 mg, 90%). [1048] MS[M+TI] = 589(M+1) [1049] 1H NMR (500 MHz, CDC13) 8.06-8.01 (m, 111), 7.36-7.30 (m, 111), 6.97-6.93 (m, 1H), 6.79-6.74 (m, 1H), 4.34-4.25 (m, 1H), 3.82-3.69 (m, 3H), 3.69-3.44 (m, 3H), 3.19-3.10 (m, 2H), 3.08-2.98 (m, 111), 2.88 (d, 1H), 2.34-2.25 (m, III), 2.13-2.03 (m, 1H), 1.61-1.37 (m,4H), 1.45 (s,9H), 1.36-1.17 (m,4H), 1.23 (s,9H), 0-94 (s,3H), 0.90 (s, 3H) [1050] V t, U'l. two [1051] EvamplcB7:Ar-[(3^)5 5)-5-faminoethyI)-I-{f(35)4^)-i-tert' - butyI-4-(2,4-dinnnrophenyI)pyrrolidine-3-yl]carbonyI}pyrroIidine-3-yI]-A' -(4,4-dimothyIcycIohexy])-2,2-diniethylpropaneamide TFA salt ■N T "M TFA [1053] [1054] Step A: C2S.4SVl-BOC-2-raminomethyn4-ri'4.4-dimethylcvc1ohexyl>f2.2-dimethylpri>panovn aminolpvrrolidine [1055] The title compound was prepared according to the procedure described in Step C-E of Preparation Example Al-1 using BOC (25,45 )-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-2--(hydToxymelhyl)pyrro lidine (2g g, 4.87 mmol) prepared in Step A of Example B4(l -69 g, 85%). [1056] MS[M+H] = 410 (M+l) [1057] [1058] Step B: f2S.4SV1-BOC-2-f f rfhenzvloxytcarbonvll amino}methvl>4-[f4,4-dimethvlcyclohexvI)f2,2-dimethvlpropanoyBarnino1pvrrolidine [1059] To a solution of (2S,4S)-l-BOC-2l-tat -butyM^l^-dichlorophenyOpyrrolidine-S-yllcarbonylJpyrrolidine-a-yl]-^ - (4,4-dimethylcyclohexyl)-2,2-dimcthylpropaneamide TFA salt IW76] 0 N r N - ci 4- . ' TFA [1077] H07S] Step A: t2S.4SVl-BOC-?-riaceiy1aniiiinlniftlhyll ^f^.^-dirnethylcyciohexvn^.^^firnethylpropanoyr^amitiolpvrrolidine [1079] To a solution of (2S,4S)-l-BOC-2-(aminomethyl)4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl) amino]pyrrolidine (500 mg, 1.21 mmol) prepared in Step A of Example B7 in DMF was added dropwise acetic acid (80 mg, 1.3 mmol), HBTU(490 mg, 1.28 mmol) and DIPEA (0.56 ml, 3.22 mmol) in order. After the reaction mixture was stirred at rt for 5 h, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with a saturated NalfCO aqueous solution, water and IN HC1. The organic solution was dried over MgSO , and concentrated in vacuo. The residue was purified 4 by column chromatography (eluent: EtOAc:Hex = 1/2) to give the title compound (508 mg, 93 %). [1080] MSrM+H] = 452(M+1) [1081] [1082] Step B: N-U3 S .5 S >5-r(acetvlaminolmethvnpvrrolidine-3-vn- N - (4,4-di methyl CYclohexyl)-2,2-dimethylpropaneamide [1083] The title compound was prepared according to the procedure described in Step E of Example Al using (2S,4S)-l-BOC-2-[(acety!amino)methyl] 4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]pyrrolidine(100mg, 0.22 mmol) prepared in Step A (75mg, 98%). [10S4] MSfM+H] = 352(M+1) [1085] [1086] Step C: N-K3S JSV5-r(arety1*mimlmethyn - l-{[f3S.4R)-l-tert-butvl-4-f2.4-dichlorophenvl1pyrrolidine-3-yllcarbQnyl}pyrrolidine- 3-yll-N-(4.4-dimethylcvclohexyn-2.2-dimethylpropaneamide TFA salt [1087] The title compound was prepared according to the procedure described in Step F of Example Al, using N-{(3S,5S)-5-[(acetylamino)rnethyl]pyrrolidine-3-yl}-N- (4,4-dimethylcyclohexyl)-2,2-dimethyIpropaneamide (75 mg, 0.21 mmol) prepared in Step B and (3S,4R)-l-t-butyl-4-(4-chlorophenyl)pyrrolidine-3-carhoxylic acid prepared in Preparation Example A9-2 (] 13 ing, 89%). M08S] MS[M+in=615(M+1) 1)089} 1)1 NMR (500 MHz, CDC13) 7.41 (d, 211), 7.30 (d, 210, 4.34-4.24 (m, 2H), 3.82-3.69 (m, 3H), 3,69-3.54 (m, 211), 3.42-3.27 (m, 2H), 3.19-3.10 (m, 2H), 3.08-2.98 (m, III), 2.88 (d, 1H), 2.34-2.25 (in, III), 2.13-2.03 (m, IH), 2.08 (s, 3H), 1.61-1.37 (m,4II), 1.45 (s, 911), 1.36-1.17 (m, 411), 3.23 (s, 9TF), 0.94 (s, 311), 0.90 (s, 311) [1090] [1091] ExampleB9zN-[(3S£S)-l-[[(3S,4RH-tert - butyI-4-(2,4-dichlorophcnyl)pyrrolidme-3-yl]carbonyl)-S-f(dimethylamino)mcthyl ]pyrroIidine-3-yl}-]- N -(4,4-dimethyIcydohexyl)-2^-dimcfhylpropaneamide IIC1 salt [1092] 0 N HC1 [1093] [1094] Step A: f2S.4S)-l-Boc 2-lfdimethvlamino)methvll - 44f4.4-dimethylcyc1ohexylY2.2wlimefoylpropanoyl)aminolpyrrolidine [1095] The title compound was prepared according to the procedure described in Step A of Example Al, using (2S,4S)-l-ROC-2-(arnrnornethyl)4-f(4,4-dirnethylcyclohexyI)(2,2-dimethylpropafioyl) amino]pyrrolidine (440 rag, 1 mmol) prepared in Step A of Example B7 and formaldehyde via reductive aminalion (300 mg, 70%). [1096] MSfM+H] = 438 (M+l) [1097] [1098] Step B: N -U3 S .5 S )-5-[(dimethv(aminolmethvnpyrrolidine-3-y( 1- V - (4.4-dimelhylcyclohexyl'l-2.2-dirpcthylpropaneamide [1099] The title compound was prepared according to the procedure described in Step E of Example Al using (2S,4S)-J-Boc-2-[(dimethyIamino)methyl] - 4-[(4,4-dimethylcyclohexyl)(2,2,-dimethylpropanoyl)amino]pyrroIidine(100mg, 0.22 mmol) prepared in Step A (75mg, 98%). [1100] MS[M+H] = 338(M+1) [1101] [1102] Step C: JV-IY3 S ,5 S )-U(jG S A R 1-1- ten - bt]tvl-4-f2.4-dichlorophenyl)pviTolidine-3-yl]carhonyll-5-[(dimethylamino1methvnpvr rnlidine-3-vn-]- N-(4.4-dimetbvlcvclnhexvn-2,?-dimethvlpropanearnide HCI salt [1 103] The (illc compound was prepared according to (he procedure described in Step F,G of Example Al using N-K3S,55y5-[(dimeUiylammo)mcthyllpyrrolidine-3-yl}-W-(4,4-dimethylcyclohexy1)-2,2-dimelfiyIpropancamide (75 mg, 0.21 mmol) prepared in StepR (IBmg, 89%). [1104] MSFM+H]=603(M+1) [1105] 1II NMR (500 MHz, CDCI3) 8.05-7.90 (m, III), 6.97-6.93(m, III), 6.79-6.74(m, HI), 4.67-1.48 (m, 1H), 3.84-3.69 (m, 4H), 3.69-3.54 (m, 211), 3.19-3.10 (m, 2H), 3.08-2.97 (m, 110, 2.88-2.58 (m, 311), 2.34-2.27 (m, IH), 2.25 (s, 3H), 2.23 (s, 3U), 2.13-2.03 (m, IH), 1.61-1.37 (m, 411), 1.45 (s, 9H), 1.36-1.17 (m, 4H), 1.23 (s, 9H), 6.94 (s, 3H), 0.90 (s, 311) [1106] [1107] Example B10: N-[Q S ,5 S )-l-{[0 S ,4 R W-tert - hutyl-4-(2,4-difluorophenyl)pyrroHdine-3-yl]carbonyl}-5-cyanopyrrolidine-3-yl]-2 ,2-dimcthyI- iV -(cis-4-methylcyclohexyl)propaneamide HCI salt [1108] , O CN w i ; '. ■'/ /""■'■/ F }■--' [ HCI [1109] [11101 Step A: 1-BOQ (2S.4SV2-cyaTio-4-rf2.2-dimethvlprtipanovn(cis-4-methvlcyclQhexynainiiin1pvn-olidin S [1111] To a solution of BOC-(ZS,4S )"2(aminocarbonyl)-4-[(2,2-dimethylpropanoyl)(cis^-melhylcyclohexyl)amino]pyrroli dine (576 mg, 1.41 mmol) prepared in Step D of Example A7 in DCM (5 ml) was added dropwise TFAA (0.2 ml, 1.41 mmol), and the solution was stirred at rt for 2 h. After the reaction finished, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with brine. The organic solution was dried over MgSO , and concentrated in vacuo. The residue was purified by column chra- 4 matography (eluent: EtOAc:IIex = 1/2) to give the title compound (514 mg, 93 %). [1112] MS[M+1I] = 392 (M+l) [H13] 11114] Step B: N -ff3 S .5 S V5-cvannpymilidine-3-yl1-2.2-dimethvl- N -< cis - 4-methylcvclohexyOpropaneamide f 1115] The litle compound was prepared according to the procedure described in Step E of Example Al using 1-BOC (2S,4S)-2-cyano-4-[(2,2-dimethylpropanoyl)(cis-4-meihylcycIohexyI)aminolpyrrolidin e (50mg, 0.13 mmol) prepared in Step A (37mg, 98%). 11116] MS[M+II] = 292(M+1) [1117] flH8] StepC: N-U3 S .5 S )-l-{\(3 SARVUtert - butvl-4-(2,4-difluorophenvBpvrTolidine-3-yncarbonvl)-5-cvanopyrrolidine-3-y)]-2.2-d imelhyl- N -(cis-4-methylcvclohexvOpropancarnide J JCI salt f 1119] The title compound was prepared according to the procedure described in Step F,G of Example Al using A,-[(35',5S)-5-cyanopyrroIidine'3-yI]-2,2-dimethyl-A'-(cw - 4-methylcycIohexy!)propaneamide (37 mg, 0.12 mmol) prepared in Step B (58 mg, 89%). [11201 MS[M+H] = 557(M+1) [1121] 1H NMR (400 MHz, CDC13) 8.10-8.04 (m, 1H), 6.97-6.93 (m, 1H), 6.79-6.74 (m, III), 4.76 (t, III), 4.35-4.22 (m, 211), 3.95-3.90 (m, 2H), 3.81-3.69 (m, 1H), 3.67-3.54 (m, 2H), 3.42-3.29 (m, 2H), 3.22-3.11 (m, 1H), 2.82-2.68 (m, 1H), 2.28-2.10 (m, III), 1.61-1.39 (m, 5H). 1.49 (s, 9H), 1.31-1.15 (m, 411), 1.22 (s, 911), 0.86 (d, 311) [1122] [11231 ExampleB11:W-[(3S,5/f)-5-acetyM-{[(3£,4« H-tert - biityl-4-(4-ch]orophenyl)pyrrolidine-3-yl]carbonyl}pyrTolidine-3-yl]-A' - (4,4-dimethyJcycJohexyl)-2,2-dim ethyl propaneamlde TFA salt [11241 Q 0< _ [11251 [11261 [1127J [1128] [1129] Cl' --)--TFA StepA:f4,<.1-l-BOC-4-[r4.4-dimethylcvclohexvnr2.2-dimethvlpropaTiovnainino1- D-proline The title compound was prepared according to the procedure described in Step A-C of Example Al using Preparation Example Al-3 as starting material. Step B: BOC (2RAS )-44t4.4-dimethvlcvclohexvl)(2,2-dimethvlDropanovnamino] -2- {[methoxv(methyl)anii no] carbon yl }pyrrolidine [1130] To a solution of (4S )-l-BOC-4-f(4,4-dimetiiyIcycloliexylJ(2,2-dimelh>'lprapaiioyI)amino]-D-proIine (1.08g, 2.57 mmol) prepared in Step A in DMT (10 0) was added dropwise DIPEA (1.15 D, 6.70 mmol), and N,0-dimethyl hydroxy lamine hydrochloride (292 mg, 3 mmol) and ITBTU (1.1 g, 3 mmol) were added dropwise in order. After the reaction mixture was stirred at rt for 1 h, the solution was concentraied in vacuo. The residue was diluted with EtOAc, and washed with a saturated NalICO aqueous solution, water and IN HCI. The organic solution was dried over MgSO , and concentrated in vacuo. The 4 residue was purified by column chromatography (eiuent: EtOAcrllex = 3/1) to give the title compound (600 mg, 50 %). [1131] MS[M+H]=468(M+1) ri i32i [1133] StepC: 1-BOC-f2 R A S U2-ace^yI-4-^(4,4-dimethylcyclohexy^(2.2-dimethylp^opanoyl1amino1pylTolidiT^e [ 1134] To a solution of BOC {2RAS )-4-[(4,4-dimefhy]cycJohexyJ)(2,2-dimethy]propanDy]>amino}-2-)[methoxy(methyl)am ino]carbonyl}pyrrolidine (670 mg, 1.44 mmol) prepared in Step B in THE (5 ml) was added methylmagnesium bromide 3M in ether solution (1.2 ml, 3.66 mmol), and the solution was stirred for 3 h. After the reaction finished, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with water and brine. The organic solution was dried over MgSO , and concentrated in vacuo. The residue was 4 purified by column chromatography (eluent: EtOAc:Hex = 3/1) to give the title compound (280 mg, 46 %). [1135] MSfM+H] =423(M+1) [1136] [1137] Step D: N -ff3 S .5 R )-5-acelvlnvrrolidine-3-vll- N - f4,4-dirnethv1cvclohexvl)-2.2-dimethvlpropaneamide [1138] The title compound was prepared according to the procedure described in Step E of Example Al using 1-BOC-(2fl,4£ )-2-acetyM-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)aminolpyrroliduie (200mg, 0.47 mmol) prepared in Step C (149mg, 98%). [11391 MS[M+H] = 323(M+1) [1140] [1141] Step E: N- |T3S.5R>-5-acetyl-1 - f fi 3S.4R)-1 -tert-butvl^-M-chloroDhenvDpvn-olidine-S-vllcarbonv 1 )pyrrolidine-3-yll-N-(4,4-dimethylcvclohexvlV2.2-dimethylpropaneamide TFA salt [1142] The title compound was prepared according to the procedure described in Step F of Example Al, using A'-[(3S,5/?)-5-acetylpyrrolidine-3-yll-W- (4,4-dimelhylcycIohexyl)-2,2-dimelhylpropanearnide (149 nig,, 0.46 mmol) prepared in Step D and (3S,4R)-)-(-butyM-(4-cfiIorophenyl)pyrTolidine-3-carbnxylic acid prepared in Preparation Example A9-2 (230 mg, 89%). ri 143] MSfM+H] = 587(M+1) [1144] HI NMR (500 MHz, CDC13) 7.44-7.37 (m, 2H), 7.36-7.28 (m, 2H), 4.8QA74 (m, 1H), 4.01-3.26 (m, 1 OH), 2.81-2.71 (m, 1H), 2.64 (t, 1H), 2.11 (s, 3H), 1.70-1.13 (m, 811), 1.45 (s, 911), 1.20 (s, 911), 0.93 (s, 3H), 0.91 (s, 3H) [1145] [1146] EsampleB12:JV-[(35)-l-{K3S,4fi)-l-rerf - buryM-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}-5-(l-hydrosymethyl)pyiToIidi ne-3-yl]- N -(4,4-dimcthykyclohexyJ)-2,2-dimethylpropaneamide TFA salt [U47] Q 0 !! "' N ^'N ■■'". [1148] [1149] [1150] [1151] [1152] [1153] fl!541 [1155] [1156] CI ..--:---TFA Step A: 1-boc - f4 S V4-f(4.4-dimethykyclohexylX2,2-diTnetbylprQpanoyl^airdnol -2-H -hydroxymethvDpyrrolidine To a solution of 1 -BOC~(2R,4S )-2-acetyl-4-[(4,4-dimethyIcyclohexy!)(2,2-dimethylpropanoyl)amino]pyrroIidine(270 mg, 0.66 mmol) prepared in Step C of ExampleBli in methanol (5 ml) was added NaBH (49.9 mg, 1.32 mmol). The solution was stirred at rt for 2 h, concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO , and concentrated in vacuo to give the title compound (225 mg, 80 %). MS[M+II]=425(M+1) Step B : A/-C4.4-dimethvlcvclohexyl)- JV-ff3 S )-5-("Khvdroxyethvl)pvn-olidine-3-vl] -2.2-dimethylpropaneamide The title compound was prepared according to the procedure described in Step E of Example Al using l-boc-(4S )-4-[(4j4-dimethylcycIohexyl)(2J2-dimethyIpropanoyl)aminol-2-(l-hydroxymethyl)pyr rolidine (1 OOmg, 0.23 mmol) prepared in Step A (75mg, 98%). MS[M+H]=325(M+1) Hi 57) Step C: N -[(3 S VI -11 f 3 S ,4 R VI - fgrf -hutvM-f4-chloropr.envl"lpyrrolidme-3-vl1 carhoiivll-5-n-hv(lroxvnietriyl)pyrrg_lidine-3-vn- N - C4.4-dimethvicvclohexviV2.2-dimethylpropaneamide TFA salt 11158] The title compound was prepared according to the procedure described in Step F of Example A ], using // (4,4-dimelhylcyclohexyI)-A'-[(35' )-5-(VhydroxyethyI)pyrrolidine-3-yl]-2,2-dimethylpropaneamide (75 mg, 0.22 mmol) prepared in Step B and (3S,4R)-l-t-butyl-4-(4-chloraphenyl)pyrrolidine-3-carboxylic acid prepared in Preparaiion Example A9-2 (113 mg, 88%). [1159] MS[M+H] =588(M+1) [1160] 1H NMR (400 MH?., CDC13) 7.49-7.21 (m, 4H), 4.30-3.24 (m, 1IH), 3.17-3.04 (m, 1H), 2.46-2.29 (m, 1II), 2.06-1.92 (m, 1H), 1.72-1.04 (m, 8H), 1.45 (s, 911), I -21 (s, 9H), 1.18 (d, 3H), 0.93 (s. 3H), 0.90 (s, 311) [1161] Hi 62] ExampleB13: (4S)-4-[acctyl(4,4-dimethylcycloheryl)amino]-JV - (2-aminoe(hyl)-l-{[(3 S ,4 R )-l- tert -butyM-(2,4-difluorophenyI)pyrrolidine-3-yI] carbonyl]-L-prr>lineamide TFA salt ni63] 0 o H . \ .J NH, V_-/ N,° .-■) I TFA [1164] [1165] Step A: 1-BOC (2 S A S V4-facetyir4.4-dimethylcyclohexynaminol -2-{[(2-f[(benzyloxy)carbonynaminn}ethyl)amino1carbonyl (pyrrolidine [1166] MethyI-(2S,4S)-I-BOC-4-[(4,4-dimethyIcyclohexyl)amino]pyrrolidine-2-carboKylate (1.77 g , 5 mmol) prepared in Step A of Example A1 and acetyl chloride were reacted according to the procedure described in Step B-C of Example Al, and then reacted according to the procedure described in Step D of Example Al using CBZ-ethyJamine to give the title compound (1.5 g,55%). [1167] MS[M+H] = 559(M+1) [1168] [1169] Step B; (4 S )-4 [acetyl(414-dimethvlcvclohexyI)aTnino1- N -(2-U(benzyloxy)carboovnaminolethylVl-U(3 S A R VI- tert -butyl-4-<,2.4-difluorophenyl)pyrrolidine-3-vncarbonvll-L-prolineamide [1170] The title compound was prepared according to the procedure described in Step E~F of Example A1 using 1 -BOC (2S,,4.9)-4-[acetyl(4,4-dimelhyIcyciohexyl)amino] - 2-{[(2-{f(benzyloxyJcarbonyl];iinino)clhyI)amino]carbonyI}pyrrolidine (560 mg, 1 mmol) prepared in Step A (0.56 g, 78%). [11711 MS [M+H] = 724(M+1) [1172] [1173] Step C: 4 S V4-facetylf4.4-dimethvlcvrtohexvnaminol - W-^-aminoethvlVl -1 \(3 S .4 R >-l- tgrf-butyl-4-f2.4-difluorophenvnpyrrolidine-3-vncarbonyl)'L-prolineamide TFA salt [1174] The title compound was prepared according to the procedure described in Step E of Preparation Example Al-1 using (4it)-4-racctyl(4,4-dimethylcycIohexyI)amino]-//- (2- {[(benzyIoxy)carbnnyl [amino} ethyl)-1 - {[(35,4/?)-1 -tert-butyl-4~(2,4-difluoropheny1 )pyrrolidine-3-yHcarbonyl}-L-prolineamide (100 mg, 0.13 mmol) prepared in Step B and purification via HPLC (65 mg, 80%). [11751 MS[M+H1 = 590(M+1) [1176] lHNMR(500MHzJCDCI3) 7.71-7.61 (m, III),6.99-6.79 (m,2H), 4.67-4.48 (m, IH), 4.22-3.94 (m, 2H), 3.94-3.84 (m, III), 3.83-3.00 (m, 11H), 2.59-2.29 (m, 2H), 1.99 (d, 3H), 1.69-1.17 (m, 811), 1-43 (s, 9H), 0.94 (s, 3H), 0.91 (s, 3H) [1177] [1178] ExanipleB14: methyl (4 S)-1-{[(3S,4 R)-l-tert - butyI-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyI}-4-[(4,4-dimethylcyclohexyI)(2, 2-dimethylpropanoyl)amino]-L-prolinate IIC1 salt H179] 0 O. \ ^ J a' -f--' ' ' HCI [1180] [1181] The title compound was prepared according to the procedure described in StepE~G of Example Al using l-BOC-2-methy1-(2S,4£ )-4-f(4,4-dimethylcyc[ohexyI)(2,2-dimethylpropanoyl)amino]pyrrolidine-2-carboxylate (200 mg, 0.45 mmol) prepared in Step B of Example Al ( 230mg, 87%). [1182] MS[M+H] = 602(M+1) [1183] IH NMR (500 MHz, CDC13) 7.57 (d, 2H). 7.32 (d, 2H), 4.45 (t, IH), 4.05-3.94 (m, HI), 3.89-3.54 (m, 6H), 3.72 (s, 3H), 3.39-3.21 (m, 2H), 3.04-2.95 (m, IH), 2.74-2.62 (m, IH), 2.15-2.05 (m, IH), 1.54-1.35 (m, 4H), 1.48 (s,9H), 1.27-1.12 (m, 4H), 1.19 (s, 911), 0.93 (s, 311), 0.90 (s, 311) [1184] 11185] Example 1115: (4 S )-l-{[(3 S ,4 K )-l- tert - biityl-4-(4-clilorophenyl)pyrrolidine-3-yl]carbonyl]-4-[(4,4-dimethylcyclohexyl)(2, 2-dimcthylpropanoyll)aminoH.-p ratine TFA salt i' •- - ' I / r, ...>t° TFA [1187] fl 188] The title compound was prepared according to the procedure described in Step C of Example A1 using methyl (45)-1 -{f(3£,4fl)-1 -ten - butyl-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyI)(2,2-d imethylpropanoyl)amino]-L-prolinate TFA salt prepared in Example B14 (230mg, 82%). [11891 MSfM+H]=588(M+l) [1190] IH NMR (500MHz, CDCI3) 7.38(d, 2H), 7.30(d, 2H), 4.37(t, IH), 4.10-3.56(m, 8H), 3.36-3.18(m, 2H), 2.5I-2.42(m, HI), 2.40-2.30(m, IH), 1.61-1.37(m, 5H), l-50(s, 9H), 1.32-1.08(m, 3H), 1.22(s, 9H), 0.94(s, 3H), 0.90(s, 3H) H1911 T1192] ExampleB16~41 [1193] The following Examples were prepared according to the procedure described in Example B1-15, using the intermediates which are prepared in a series of Example A by the reactions between appropriate compounds among Preparation Example Al, A2, A4, A9 and appropriate amines. r 1194i o -J. R, ' N / R3 N R* " \* O N , [1195] [1196] Table 7 I Table 7] Sample UK. HI7 IMS i-Hu r-Bu R- R' K1 -J-ft Me c-lfc* 2,4-diF 2,-1-dif ftSJNH. cllc I Bu f(S>NH2 civl-Mt-c-lks RI9 l-flii 2,4 -dlF Cil.OH oHex H20 l-Bu 2,4-diF 2,4-diF L'H-Olf (.is-4-Me-t-llex B2I l-Bu ■ N, '/ OH c-Hcx B22 l-l)u 2,4-diF -fJ. |- OH 1 cis-4-Me-<:-Hex ft- Mr Mc X 0 Me l-Bu Mc 1-Bu MS (MT ■IKK 535 dft*. 506 562 519 575 [1197] B23 r-Ru ] 2.4-dJF cis-4-Me-c-Hex C1KCH,), R 603 B24 i-Ru I-BII 4-CI 4-C1 1 cis-4-Me-c-Hex tH(ril,), s 5X5 Fi25 CKjNH. c-Hex Mc S S s s 505 H26 i-Bu 2,4-dil' CH,N(CH,)j c-He* Me 533 B27 i-Hn 2,4-diF Ac c is-4-Me-''-Hex l-llll S R 5113 B2S B29 l-Bu 2,4-tiiF C(S)NT(, cis-4-Me-c-Hex l-Bu S R 591 t-»ti 4-CI CXS>NH, cii-<-Me-c-[lex l-Bu s R 589 B30 l-Bu 2,4-diF C(S)N(CH,). 4,4-diMe-c-iIex T-Bi| s S 633 B31 l-Hu 2,4-dif CH;OH ■1,4-JiMe-t-KcJ. Ci^CH,}, s s 562 B32 l-Bu 2.4 diF fN'OH M-diMc-c-Hcx CUfCll,). s R 575 ["1198] B51 B33 i-Uu t llu i-I'.n 2.4-Jit' >.4-drt; 2.4-dir N OH t A< Ac -t-l-LdMi'-t-Hti 4 4 JiMs-c-lle;, 4 4-riiM^-c-lkx CH{CH5), s <.~< {'lljirili); ~i I>~) R35 l-liu s s r>SX Bid 4-CI <-(S)N(t.'H,b 4.4-JiMe-c-lfcx 4 J-diMc-c-Hex l-[)U Ml 602 B3? i-Tlu 2,-1-dil-' fisimcn,1)? t\0)fil l-fiu s - ms i-llu r-[)u 2,4-diF 4 4-diMc-oHex i-Bu s H39 aoji-i 4,4 diF-c-He* t-fiu s - 608 (i29 590 G40 r-Hu 1-13 u 4-U S ,-N 1 4,4-JiMe-c-Hex 1-Bu s R41 2.-1 -diF C(0|NH(CH;)j 4,4-diMt-c-He\ CH> s [1199] [1200] [1201] Scheme C p< RJ R> N-f R* H Rs R^ H~^ Rl-N 7" O Int. A9 R2 HBTU DIEA DMF ,i N R-' " *' in(. C2 RJ N-^" R* [1202] [1203] [1204] one of Int. AS int. CI Int. -Intermediate Example CI: N -[(3S )-l-{[(3 S ,4 R )-l- terf -butyl-4-(4-chIorophenyl)pyrro!idine-3-yl]carbonyl]pyrrolidinc-3-yl]-/V -(4,4-dimethyIcycInhexyl)-2,2-dimethylmaloneamide TFA salt o 7---N 1 N /' .,' N 0 \ ° CI NH TFA [12051 [1206] Step A: (3SV1 -Boc-rr2-cyano-2-methylpropanoyl"lf4.4-7dimethv1cvclohexvnamiTio] pyrrolidine [1207] The title compound was prepared according to the procedure described in Step B of Example Al, using (3S)-l-Boc-3-[(4,4-dimethyleydohexyl)amino]pyrrolidine (1.5g, 5mmoI) prepared in Slop A of Example AS and 2-cyano-2-methylpropanoyl chloride (2g, 15mmol) prepared in Preparalion Example A4-3 (1.5g, 76.6%). [ 1208] MS[M+H] = 392 (M+1) [1209] [1210] Step B; GSVl-Boc-3-f('3-amiiio-2.2-dimethvl-3-oxopropanoyl)f4,4-dimethvlcvc]ohexyl)arnino Invrrolidine 11211] To a solution of (3S)-l-Boc-[(2-cyano-2-rnethylpiopanoyI)(4,4-dimethylcyclohexyl)amino]pyrrolidme (900mg, 2.3mmol) prepared in Step A in methanol (10 ml) was added lON-NaOH (5ml), and the solution was stirred at 80°C for 2 h. After the reaction finished, the solvent was concentrated in vacuo, diluted with water, and extracted with EtOAc. The extracted organic layer was dried over MgSO , concentrated in vacuo, and purified by 4 column chromatography (eluent: ElOAc/Hex - 3/1) to give the title compound (828mg, 88%). [1212] MS[M+H1=410(M+1) [1213] [1214] StepC:^-(,4.4-dimethvlcyclohexvlV2.2-dimelhyl-Af-rf3 5)-pvn-olidine-3-v)l maloneamide [1215] The title compound was prepared according to the procedure described in Step E of Example Al using (3S)-l-Boc-3-[(3-amino-2,2-dimethyl-3-oxopropanoyl)(4,4-dimethylcyclohexyI)amino lpyrrolidine (192mg, 0.47 mmol) prepared in Step B (142mg, 98%). [1216] MS[M+ITI = 310(M+1) [1217] [1218] Step D: N -f(3 S)-1 -f \(3 S A R VI - tert -butyl-4-f4-chlorophenynpvrrolidine-3-yH carfaonvllpyrrolidine-l-yll- Ar-f4,4-dimethylcyclohexyl)-2.2-dimethylma1oneamide TEA salt [1219] The title compound was prepared according to the procedure described in Step F of Example Al, using W^^-dimethylcyclohexyO^^-dimethyl-W-tCS^-pyiTolidine-S-yn maloneamide (142 mg, 0.46 mmol) prepared in Step C and (3S,4R)-l-t-butyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (234 mg, 89%). [1220] MS[M+II1 = 573(M+1) [1221] HINMR(500MHz,CDC13)7.29-7.25(m,4H),4.58-4.50(m, HI), 4.34-4.26(m, 111), 4.20-4.14(m, HI), 4.04-3.96(m, 111), 3.84-3.75(m, 1H), 3.69-3.60(m, IH), 3.55-3.40(m, 2H), 3.40-3.32(m, 111), 3.19-3.10(m, 2H), 2.96-2.87(m, 1H), 2.28-2.17(m, III), 1.87-!.78(m, III), 1.72-l..i6(m, 211), 1.53-1.38(m, 3H), 1.43(s,9H), 1.40(s,3H), l.36-l.21(m,31l), l.30(s, 311), (l.RQ(s, 3II),0.87(s, 3TI) [1222] [ 1223] Example C2: N -|(3S )-l-{[(3S A R )-l- tcrt - hutyl-4-(4-chlorophenyI)pyrrolidine-3-yI]carbonyl]pyrroIidine-3-yl]-A' -(4,4-dimethylcyclohcxyl)-3-mcthoxy-2(2-dinietliyipropaneaniideTFA salt [1224] , 0 '' N f N '*- ' I / / \ "N,° ' K { ^a ; ■' ■■ OMe TEA [1225] [12261 Step A: GSVI-Boc-3-(r3- ' N r H o .'/ /""{ \ ,-N-OH a -;- • • TTCI 1241] 1242] Step A: f3SVl-Boc-3-f('4.4-dimethylcyclohexyl¥2.2-dimethyl-3-oxopropanoynaminnlpvrrolid ine 1243] To a solution of (3S)-l-Boc-3-[(4,4-dimethyIcyclohexy!)(3-hydroxy-2,2-dimethylpropanoyl)amuio]pyr rolidine (1.05g, 2.7mmol) prepared in Step B of Example A8 in DCM was added Dess-Martinperiodinane(1.35g, 3.17mmoI), and stirred at it for 2h. After the reaction finished, the solvent was concentrated in vacuo, sodium thiosulfate aqueous solution and EtOAc were added and stirred at rt for 30 min, and extracted with EtOAc. The organic layer was dried over MgSO , concentrated in vacuo at rt, and purified by 4 column chromatography (eluent: EtOAc/Hex = 1/3) to give the title compound (960mg, 90%). 1244] MS[M+II] = 395 (M+l) 1245] 1246] StepD: l-Boc-OS )-3-|f4.4-dimelhylcvr.lohexvlY2,2-dimethyl-3^xopropanoyl)amino]pviTolidine 11247] To a solution of (3S)-l-Boc-3-[(4,4-dimethyfcyclohexyl)C2,2-dimethyl-3-oxopropanoyi)amiTio]pyn-oIid ine (250mg, 0.63mmol) prepared in Step A in methanol (5 ml) was added hydroxyam-moniumchloride (49mg, l.27mmoi) and TEA (127mg, 1.26mmol), and the solution was stirred at 80°C for 1 h. After the reaction finished, the solvent was concentrated in vacuo, diluled with water (20ml), and extracted with EtOAc. The organic layer was washed with 1 N-HC1, dried over MgSO , concentrated in vacuo, and purified by A column chromatography (eluent: EtOAc/Hex - 1/2) to give the title compound (206mg, 80%). [1248] MS[M+11]=410(M+1) T1249] [1250] Step C: (3 ff V AT -M.4 dimethvlcvclohexyiy3-(hydroxyiminoV2,2-dimetrivl- N -If3 S )-pyrrolidine-3-yl1prop;meamide [1251] The title compound was prepared according to the procedure described in Step E of Example Al using \-Bac-0S )-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxopropanoyI)amino]pyrrolidine (I92mg, 0.47 mmol) prepared in Step B (142mg, 98%). [1252] MSfM+Hl = 310(M+1) [1253] [1254] StepD: (3 EVN-UlSU-mSARVUtert - butvl-4-(4-chIorophenyl)pyiTolidine-3-yllcarbonyl)pytTolidine-3-vn- N -(4.4-dimethvlcyclohexvl)-3-(hvdroxyimino)-2.2-dimethylpropaneamideHCl salt f 1255] The title compound was prepared according to the procedure described in Step F,G of Example A1, using (3E)-N - (4,4-dimethylcyclohexyl)-3-(hydroxy imino)-2,2-dimethyI-ALr(35)-pyrrolidine-3-yl]pro paneamide (142 mg, 0.46 mmol) prepared in Step C and (3S,4R)-l-t-butyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (234 mg, 89%). [1256] MS[M+H] = 573(M+1) [1257] 1H NMR (400MHz, CDC13) 7.45-7.39(m, 2H), 7.37-7.30(m, 2H), 6.72(s, 1H), 4.12-3.52(m, 7H), 3.40-3.19(m, 3H), 2.77-2.69(m, 1H), 2.53-2.33(m, 1H), 1.78-1.57(m, 8H), 1.55-1.41 (m, I0H), 1.35-1.22(m, 7H), 0.94(s, 3H), 0.92(s, 3H) [1258] [1259] Example C4: N-[(3 S )-l-{[(3 S AR)-l- tert - hutyl-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}pyrrolidine-3-yl]-A7 -(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylbutaneamideIICI salt [1260] o 1 -N ^ N '- ■' ! / . N ,° '•• // , \ OH CI HC1 [1261] [1262] Step A: GSVl-Boc-S-f^^-dirnethylcycloheKvnfB-hydroxy^^-dimelhylbutanoyDaminojpyrro lidine [1263] To a solution of (3S)-l-Boc-3-[(4,4-dimethylcycJohexyI)(2,2-dimethyl-3-oxopropanoyI)aniino]pyrrolid ine (250mg, 0.63mmol) prepared in Step A of Example C3 in TIIF was slowly added dropwise methylmagnesium bromide (in diethylether, 3.0M, 0.25ml, 0.76mmol) at O^C, and the solution was stirred at rt for 2 h. After the reaction finished, to the solution was added 1N-HC1 at 0°C, and extracted with EtOAc. The organic layer was dried over MgSO , concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/IIex = 1 /2) to give the title compound (238mg, 92%). [1264] MSrM+H] =425 (M+l) [1265] [1266] Sten ft: N -(4.4^imethvlcvclohexvlV3-hydroxy-2.2-dimethvl- N -1(3 S )-pyrrolidine-3-yHbutaneamide [1267] The title compound was prepared according to the procedure described in Step E of Example Al using (3S)-l-Doc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethyIbutanoyl)amino]pyrTO lidine (lOOmg, 0.23 mmol) prepared in Step A (73mg, 98%). [1268] MS[M+H] = 325 (M+l) [1269] [1270] Step C: N-\(3 S)-\-i\(3 S .4 RV\- tert -butv]-4-<4-ch]otophenvhpvrroiidme-3-\\] carbonyl)pyrrolidine-3-yn- N -(4.4-dimethylcyclohexyn-3-hydroxy-2.2-dimethylbutaneamideHCIsalt [ 1271 ] The title compound was prepared according to the procedure described in Step F,G of Example A1, using A^-(4,4-dimethylcyclohexyI)-3-hydroxy-2,2-dimethyl-A'-[(35' )-pyrroIidine-3-yl]butaneamide (73 mg, 0.23 mmol) prepared in Step B and (3S,4R)-l-t-butyl-4-(4-chforophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (232 mg, 89%). [1272] MS[M+H]=574(M+0 [1273] 1H NMK (400MHz, CDCI3) 7.58-7.48(m, 211), 7.37-7.29(m, 211), 3.92-3.48(m, 7H), 3.47-3.22(m,4Il),2.77-2.69(m, 111), 2.53-2.33(m, IH), 1.80-1.55(m, 811), l.52-1.38(m, lOIQ, 1.32-1.20(m, 1011), 0.94(s, 3H), 0.92(s, 311) [12741 [12751 Kxamplc C5-.N-YQ S)-i-{[(3 S,4 It )-1-tert - butyI-4-(4-chlorophenyl)pyrrolidine-3-yl)carbonyl]pyrrolidine-3-yl]- TV - (*,4-dimc(hylcyclohcxyI)-2,2-dimcthyl-3-oxobuLaneamide HCI salt [1276] 4 o ■\ • ^ N r N - O / ii N \ o /" \ \ CI ■ 7"" 1 HCI [1277] [1278] SteoA:GSVl-Boc-3-r(4.4-dimethvlcyclohexvl)f2.2-dimethvl-3-oxobutanoyl)aTnino1 pyrrolidine [1279] To a solution of (3S)-l-Boc-3'[(4,4'dimethylcycIohexyI)(3-hydroxy-2,2-dimelhylbulanoyl)amino]pyrTo Iidine(150mg, 0.36mmol) prepared in Step A of Example C4 in DCM was added Dess-Martin periodinane (230mg, 0.54mmol), and stirred at rt for 2 h. After the reaction finished, the solvent was concentrated in vacuo, sodium thiosulfate aqueous solution and EtOAc were added and stirred at rt for 30 min, and extracted with EtOAc. The organic layer was dried over MgSO , concentrated in vacuo at rt, and purified by 4 column chromatography (eluenl: EtOAc/Hex = 1/3) to give the title compound (132mg, 90%). [1280] MS[M+H] =409 (M+l) [1281] [1282] Step B : Af-f4.4-dimethvlcvclohexvlV2-2-dimethvl-3-oxo- N-\(3 S Vpvrrolidine-3-vl [ 1283] The title compound was prepared according to the procedure described in Step E of Example Al using (3S)-1 -B oc-3- [(4,4-dimethylcyclohexy l)(2,2-dimethy 1-3-oxobutanoy l)amino] pyrrolidin e (50mg, 0.12 mmol) prepared in Step A ( 36mg, 98%). [1284] MS[M+H] = 309(M+1) [1285] [1286] StenC: N-\G S )-l-f [(3 S A R )-l- ten -butvl-4-C4-chlorophenvl)Dvn-olidine-3-vll carbonvl )pvrrolidine-3-vn- N - (4.4-flim^hvlcyc)ohexvl)-2,2- ■ \"\ CI i - ( HCI [1293] [1294] Step A: f3S)-l-Boc~3-ff4,4-dimelhvlcvclohexvl)f3-hvdroxv-2.2.3-trimethylbutanovnamino1pv rrolidine [1295] To a solution of (3S>l-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimelhyl-3-oxobutanoy])amino]pyiTolidin e (1 OOmg, 0.25mmol) prepared in Step A of Example C5 in TI fp was slowly added dropwise methylmagnesium bromide (in diethylether, 3.0M, 0.1ml, 0.3mmol) at 0°C, and the solution was stirred at rt for 2 h. After the reaction finished, to the solution was added 1N-HC1 at 0X1, and extracted with EtOAc. The organic layer was dried over MgSO , concentrated in vacuo, and purified by column chromatography (eluent: 4 EtOAc/Hex = 1/3) to give the title compound (97mg, 92%). [1296] MS[M+II]=425(M+1) [1297] [12981 StepB:N-r4.4^dimethvlcyclohexvlV3-hvdroxv-2.2.3-lrimethvl-M-fG^ Vpyrrol idine-3-vl Ibulancamide [1299] The title compound was prepared according to the procedure described in Step E of Example Al using (3S)-l-B()c--3-rC4,4-dirnclhylcyclohexyl)(3-hydroxy-2,2,3-trimethyIbulanoyl)aminolpy rrolidinc (80mg, 0.19 mmol) prepared in Step A (60.5 mg, 98%). [13001 MSrM+Hl = 325(M+l) [13011 [130?.] StenC:^-K3S)-l-U(3^.4^>-l-fert-butyl-4-f4-chlorophenyl)pvrrolidine-3-vll carbonvl)pvrrolidine-3-vlV N - f4,4-dimetbvlcvcloliexvl)-3-hvdroxv-2,23-trimelhylbutaneamideHCI salt [1303] Trie title compound was prepared according to the procedure described in Step F,G of Hxample Al, using /V-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2,3'trimethyl'A/'[(35 )-pyrrolidine-3-yI]bulaneamide (62 mg, 0.19 mmol) prepared in Step B and (3S,4R)-l-t-butyI-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (99 mg, 89%). [1304] MSfM+H] = 588 (M+l) [1305] 111 NMR (400MlIz, CDC13) 7.60-7.49(m, 211), 7.39-7.30(m, 211), 3.93-3.48(m, 7H), 3.47-3.21(m, 311), 2.77-2.69(m, IH), 2.53-2.33(m, III), 1.80-1.55(m, 811), 1.52-1.38(m, 10H), 1.34-1.21(m, 1311), 0.94(s, 3H), 0.92(s, 3H) [1306] [1307] Example C7: JV-[(35')-l-{[(3*,4 R )-l- tert ■ bntyl-4-(4-chlorophenyl)pyrrolidine-3-yI]carbonyl}pyrrolidine-3-yl]-A/ -(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethylpropaneamide IIC1 salt [13081 , 9 ".-' "N f* H • \ ; o N - ,; \ \ . CI ' F HCI [1309] [13101 Step A: r3SVl-Boc-3-fM.4-dimethvlcyclohexvnr3-f1noro-2.2-dimethylpropanoynaminolpvrrol idine [1311] To a solution of (3S)-l-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyr rolidine (300mg, 0.76mmol) prepared in Step B of Example A8 in DCM was added TEA (192mg, 1.9mmol), slowly added dropwise methanesulfonylchloride (104mg, 0.91mmol) at 0°C, and the solution was heated to it, and stirred for 1 h. After the reaction finished, the solvent was concentrated in vacuo, and washed with water and litOAc. The organic layer was dried over MgSO , concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Ilex = 1/2) to give (3S)-l-Boc-3-[(4,4-dimethylcyc]ohexyl){2,2-dimelhyl-3-r(methyIsulfonyl)oxy]propan oyl]ammo]pyrrolidine(250mg, 75%). A solution of this compound (200mg, 0.42rnmol) in TI IF was added dropwise TB AF (in TIIF, 1 .OM 0.5ml, O.Smmol), and the solution was stirred at 80°C for 3 h. After the reaction finished, the solvent was concentrated in vacuo, and extracted with 1N-HCI and ElOAc. The organic layer was dried over MgSO , concentrated in vacuo, and purified by column chromatography 4 (eluent: FtOAc/Hex = 1/4) to give the title compound (147mg, 89%). [1312] MS[M+H]=399(M+1) [1313] [1314] StepB: ^-C4.4-dimeHiylcyclohexyn-3-fluoro-2.2--l-tert-bu tyl-4-(2,4-difluorophenyl)pyrroIidine-3-yl]carbonyl}-Af,A'-dimethyI-L-prolineamide (217mg, 0.28 mmol) prepared in Step E and purification via YfPlXZ ( 160 mg, 91%). [13921 MSfM+H] = 632(M+1) [1393] 1H NMR (400 MIIz, CDC13) 8.10-8.04 (m, III), 6.97-6.93 (m, 1H), 6.79-6.74 (m, 1IT), 4.70 (t, III), 4.35-4.22 (m, 211), 3.95-3.90 (m, 211), 3.81-3.69 (m, 1H), 3.67-3.54 (m, 2H), 3.42-3.29 (m, 211), 3.22-3.11 (m, III), 2.99 (s, 3H), 2.95 (s, 3H), 2.92-2.70 (m, 311), 2.19-1.97 (m, 1H), 1.61-1.39 (m, 411), 1.49 (s, 911), 1.31-1.15 (m, 4H), 1.27 (s, 611), 0.95 (s, 3H), 0.91 (s, 311) [13941 [1395] Example CU: (4S)-1-[[(3S,4R)-l-tert - butyI-4-(4-chlorophcnyl)pyrrolidinc-3-yl]carbonyI}-4-{[3-(dimcthyIamioo)-2,2-di methylpropanoyl ](4,4-dimethylcycloliexyl)amino}- W, JV -dimethyl-L-proIineamidc HC1 salt f1396l o °,.N' vv- N- 0 CI --\- ' N - IICI [1397] [1398] Step A: l-BOC(2 S A S 1-2-rfdimethylaminofcarbonvn - 4-{f3-fdijnelhylamino)-2.2-dimethyipropanoyni'4.4-dimethylcyclohexyl)amino)pyjToli dine [1399] The liderompound was prepared according To the procedure described in Step A of Example A1 using l-BOC-(2S,4S )-4-[(3-amino-2,2-dimelhy]propanoyl)(4,4-dimelhylcycIohexyl)amino]-2-[(dimediylam ino)carbonyl]pyrrolidine (142 mg, 0.3 mniol) prepared in Step B of Example CIO and formaldehyde (105 mg, 71%). [1400] MS[M+JI] =495(M+1) [1401] [1402] StepB:C4,yV4-lf3^diTnethvlaminoV2.2-dimethvlpropanovl] (4,4-dimelhylcyclohexyl)amino)-/y. W-dimethyl-L-prolineamide [1403] The title compound was prepared according to the procedure described in Step E of Example AI using 1 -BOC(2,?,4S)-2-[(dimelhylamino)carbonyl] -4-{[3~(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}pyrroli dine (105mg, 0.21 mmol) prepared in Step A (82mg, 98%). [1404] MS[M+H] = 395(M+1) [1405] [1406] StepC:(4S)-l-frGS.4R)-l-tert^hutvM-(,4-chlorophenynpytTolidine-3-vn carbonyl)-4-{[3-(dimethylaminoV2,2-dimeUiylpropanoyl](4,4-dimethylcyclohexynam ino]-N.N-dimethyl-L-protineamide HCI sal; [ 1407] The title compound was prepared according to the procedure described in Step F,G of Example Al, using (4S)-4-{[3-(dimethyIamino)-2,2-dimethylpropanoyl] (4,4-dimethylcyclohexyl)aminoJ-A?,A'-dimemyl-L-prolineamide (82 mg, 0.18 mmol) prepared in Step B and (3S,4R)-l-t-bmyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (105 mg, 89%). [1408] MS[M+H] =658(M+1) [1409] 1H NMR (400 MIIz, CDC13) 7.50 (d, 2H), 7.32 (d, 2H), 4.70 (t, IH), 4.35^.22 (m, 2H), 3.95-3.90 (m, 2H), 3.81-3.69 (m, IH), 3.67-3.54 (m, 2H), 3.42-3.29 (m, 2H), 3.22-3.11 (m, 1H), 2.99 (s, 3H), 2.95 (s, 3H), 2.88-2.55 (m, 3H), 2.30-2.01 (m, 7H), 1.61-1.39 (m,4H), 1.49 (s, 9H), 1.31-1.15 (m, 4H), 1.27 (s, 6H), 0.95 (s, 3H), 0.91 (s, 310 [1410] [1411] Example C12-.N -{(3 S,5S)-1-{[(3S, 4 R)-\-tert - butyl-4-(4-chlorophenyI)pyrrolidine-3-yl]carbonyl}-S-[(dimethylamino)carbonyl] pyrrolidine-3-yl}- A' -(4,4-dimethylcyc]ohexyl)-2,2-dimethylmaIoneamide TFA salt N ° ■ : , .o CI NH, TFA [1413] [1414] StenA: 1-BOC-C2 S A S V4-('('2-cyano-2-methvlpropanovnf4.4-dtmethvlcyclohexy1'>amino1-2-rfdimefhylaiiiino) carbonyllpvrrolidine f 1415] Tlie title compound was prepared according to the procedure described in Step B-D of Example A1, using methy!-(2S,4S>-l-BOC-4-[(4,4-dimethylcyclohexyl)amino] pyrrolidine-2-carboxylate(1.77g, 5mmol) prepared in Step A of Example A1 and 2-cyano-2-methylpropanoyl chloride prepared in Preparation Example A4-3 as starting materials (1.3g, 56%). [1416] MSfM+II] = 463 (M+l) [1417] r 1418] StepB: UBOC-(2SAS V4-rf3-amino-2.2-dimelhyl-3-oxopropanoyl1C4.4-dimethvlcvclohexyl1amino]-2-[fdime IhylaminokarbonvllpviTolidine [1419] To a solution of 1-BOC-(25,45)- 4-[(2-cyano-2-methylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)c arbonyl]pyrrolidine (1.06 g, 2.3mmol) prepared in Step A in methanol (10 ml) was added lON-NaOH (5 ml), and stirred at 80°C for 2 h. After the reaction finished, the solvent was concentrated in vacuo, diluted with water, and extracted with EtOAc. The extracted organic layer was dried over MgSO , concentrated in vacuo, and purified by 4 column chromatography (eluent: ElOAc/Hex = 3/1) to give the title compound (970 mg, 88%). [1420] MS1M+H1 =481 (M+l) 11421] [1422] StepC: N-{(?, S .5 S l54idimethvlaminotearbonvllpvrrolidine-3-vll- N - (4.4-dimethyIcyclohexyl)-2t2-dimethylmaloneamide [1423] The title compound was prepared according to the procedure described in Step E of Example Al using l-BOC-(2S,4S )-4-[(3-amino-2,2-dimethyl-3-oxopropanoyl)(4,4-dimethylcyclohexyl)amino]'2-[(dime thyIaminn)carbonynpyrrolidine (226mg, 0.47 mmol) prepared in Step B (166mg, 98%). [1424] MS[M+II] =381 (M+l) [1425] [1426] Sten D: N-U3 S .5 S Vl-f TB S A R V\~tert - butyl-4-f4-chlorophenvnpvrrondine-3-yl]carbonyl}-54<'dirnetlivlarnirio)carboriYl1pyrro lidine-3-vl]- N-f4,4-dimethyIcvclohexylV2.2-dimerhv1maloneamideTFA salt [1427] The title compound was prepared according to the procedure described in Step F of Example A!, using W-{(35,5,S)-5-[(dimethy!amino)carbonyl]pyrrolidine-3-yl}-Af-(4,4-dimethylcycIohexyl)-2,2-dimethylmaIoneamide (166 mg, 0.53 mmol) prepared in Step C and (3S,4R)-]-t-butyI-4-(4-ch!orophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (273 mg, 89%). 1428] MS[M+H] = 644 (M+l) 1429] IH NMR (500 MHz, CDCB) 7.36 (d, 2H), 7.29 (d. 211), 4.60 (t, IH), 4.38-4.25 (ra, IH), 4.25^.14 (m, IH), 3.92-3.78 (m, IH), 3.72-3.27 (ra, 6H), 3.19-3.12 (m, IH), 2.98 (d, 311), 2.94 (d, 3H), 2.85-2.68 (m, IH), 2.13-1.99 (m, IH), 1.62-1.11 (m, 8H), 1.43 (s, 911), 1.39 (s, 3H), 1.33 (s, 3H), 0.90 (s, 3H),0.87 (s, 3H) 1430] 1431] Example C13:S-(3-{[_(3S£Syi~[[(3S,4R H~tcrt - butyl-4-(2,4-difluorophenyl)pyrrolidine-3-yl]carbonyl}-5-{[ethyI(methyl)amiDo]ca rbonyI}pyrroIidine-3-yl](4,4-dimethylcyclohexyl)amino)-2,2-dimethyI-3-oxopropy I) ethanelhioate HCI salt 1432] _ O / /-H__f N -y \.. f. HCl 1433] 1434] Step A: 1 -BOC-f2 S AS V4-(r3-facetylthio)-2.2-dimethvlpropanovn (4.4-dimethvlcvc]ohexvl)amino]-2-frethvlfmetbyl)aminolcarborivn pyrrolidine 1435] The product of Step C of Example A4, BOC-(2S,45 )-4-[(4,4-dimethylcyc!ohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-2-[[ethyI(me lhyl)amino]carbonyl}pyrrolidine (lg, 2.1mmol) was reacted according to the procedure described in Step C of Preparation Example Al-1 to give l-BOC-(25,4S )-4-[(4,4-dimethylcyclohexyl)[2,2-dimethyl-3-[(methyIsulfonyl)oxy]propanoyl} amino ]-2~[[ethyl(rnethyl)arnino]carbonyl) pyrrolidine (0.72g,61%). This compound (200mg, 0.36mmol) and potassium thioacetate (41 lmg, 3.6mmol) was dissolved in rnetlianol substitute sheet (3.6ml,), and the solution was stirred for 8 h. After the reaction finished, the solution was concentrated in vacuo, and extracted with ElOAc. The organic extracts were washed with water, dried over MgSO , and concentrated in vacuo to give the title compound (0.14g, 76 %). [14361 MSfM+H] =540 (M+l) T1437] [14381 StenR: S-(3-(\<3 S .5 S ll-([(3 SAR U- tert - butvl-4-f2,4-difluorophcnvnpvrrolidine-3-vncarbonvl)-5-(rethvirmelhvnamino1carbo nvnpyiTolidine-3-yn(4.4>dimetlwlcyclohesvl)amino)-2.2-dimethvl-3-oxoprop,vl'l ethanethioate HCI salt [1439] The title compound was prepared according to the procedure described in StepR-G of Example Al using l-BOC-(2S,45j-4-((3-(acetylthia)-2,2-dimethylpropanoyll (4,4-dimethylcyclohexyl)amino)-2-([elhyl(niethyl)aminolcarbonyl}pyrrolidine (lOOmg, 0.19mmol) prepared in Step A (60mg, 44%). [1440] MSfM+H] = 705 (M+l) [14411 IH NMR (400 MHz, CDC13) 8.10-8.03 (m, IH), 6.96-6.93 (m, IH), 6.79-6.74 (m, IH), 4.70 (t, IH), 4.35-4.22 (m, 2H), 3.95-3.40 (m, 2H), 3.81-3.69 (m, IH), 3.67-3.54 (m, 210, 3.42-3.29 (m, 2H), 3.26-3.10 (m, 3H), 2.99 (s, 3H), 2.82-2.63 (m, 3H), 2.19-1.97 (m, 111), 1.61-1.39 (m, 411), 1.49 (s, 9H), 1.32-1.15 (m, 7H), 1.27 (s, 6H), 0.95 (s, 311), 0.91 (s, 3H) [1442] [1443] Example CU: (4S)-1-{[(3S,4R)A-tert - butyl-4-(2,4-dinuorophenyI)pyrrolidine-3-yI]carbonyl)-4-[(4,4-dimethylcyclohexyI )(3-mercapto-2^-dimethyIpropanoyl)amino]-jV-cthyl-Af-methyl-L-prolineamide HCI sail [1444] ^ ? o^r- ■ ■ ■', \ V-. F' ) - ' ■ S , ° [1445] H446] HCI To a solution of £-(3-{K3S,5S)-Hf(3S,4fl)-I-tert -butyl-4-(2,4-dinuorophenyl)pyrroIidine'3-yl]carbonyI]-5-{[elhyl(methyl)amino]carbo nyl}pyrTolidine-3-y\l(4,4-dirnethylcyclohexyl)amino}-2,2-dimethyl-3-oxopropyl) ethanethioate (32mg, 0.045mmol) prepared in Example CI3 in methanol/water (5:1, ImL) was added potassiourhcarbonate (38mg, 0.28mmol), and the solution was stirred for 5 h. The methanol in the reaction solution was concentrated in vacuo, purified by prep-TLC without further process, and treated according to the procedure described in Step G of Example Al to give the compound (7mg, 23%). f!4471 MS[M+II]=663(M+1) [ 14481 in NMR (400 MHz, CDCI3) 8.10-8.03 (m, III), 6.96-6.93 (m, IH), 6.79-6.74 (m, 111), 4.70(1, IH), 4.35-4.22 (m, 2H), 3.95-3.40 (m, 2H), 3.81-3.69 (m, III), 3.67-3.54 (m, 2H), 3.42-3.29 (m, 2H), 3.26-3.07 (m, 511), 2.99 (s, 3H), 2.82-2.30 (m, 4H), 2.19-1.97 (m, III), 1.61-1.39 (m,4H), 1.49(s,9H), 1.32-1.15 (m, 7H), 1.27 (s,6H), 0.95 (s,3H), 0.91 (s, 3H) [14491 [1450] Example C1S-25 [1451] The following Examples were prepared according to the procedure described in Example CI ~14, using the intermediates which are prepared in a series of Example A by the reactions between appropriate compounds among Preparation Example Al, A2, A4, A9 and appropriate amines. [14521 R1 —N R? [14531 [1454] Table 8 o R3 J 1 j N \ / ( * O \ N- - --■ Ij / ■I R4 R5 {Table 8] Kxamplc CIS P.1 t-Bn t-Bu R* Rr RJ 4,4-diMe-c-llex Rv * s 11 MS (Mi i) 561 2,4 -diP H CfCH^CHjNH, CI6 4-CI 4-CI II 4,4-diMe-c-hkx N(CH,)2 s 531 CI7 CIS L-Bu II 4,4-diMe-c-Hex CHJCHIOCIIJCHJ b 561) t-Gu 4-CI H 4,4-diMe-c-llex C{CH03CH2OCII: en, S 588 CI9 t-Bu 4-C\ H cis-4-Me-c-IIex QCH^CfOJCH, S 558 C20 I-Rn 4-CI H cis-4-Me-c-Hex C(CH3);CH(=NOH) S 559 C2! t-Bu 4-CI H cis-4-Me-c-Hex C(CII3)2CH2F S 548 C22 t-Bu 4-CI H cJs-4-Me-c-Hex C(CII,)2CtO)NH, s 559 C23 t-Bu 2,4-diF II cis-4-Me-c-Hcx C(CH,)jC("0)NH2 s 561 CIA t-Bu 4-Ct C(0)N( Clbh 4,4-diF-c-Hex C(CH3)2CH2OCH3 s s 653 C25 t-Bu 4-CI C(0)N MeGi j 4.4-diF-c-Hex C(CH,);CU.O CHJCHJ s s 681 [1455] [1456] [1457] Scheme D n lntA9 R» R> R1 -N' HBTU DIE A R1--M \ O R' Int. PI Int. ■ Intermediate V 0 M R* OMF R! Int. D2 [1458] [1459] [1460] [1461] The preparation process of the Inermediate Dl compounds, and the Examples synthesized by the procedure of Scheme D are as follows. Example Dl:(4£)-l-{[(35,4 17 )-l-feit -butyl-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}-4-[(2,4-dinuorophenyl)(2^-di methylpropanoyl)amino]- N, N -dimethyl-L-prolineamide TFA salt IH62] o 0 « F F ' TFA [1463] [1464] Step A: f2S.4S>-l-Boc^-azidopynnlidine-2-carboxvlic caid [1465] To a solution of methyl (2S,4S)-l-Boc^-azidopyirolidine-2-carboxylate(10 g, 37 mmol) prepared in Step D of Preparation Example Al-1 in methanol (100 ml) and water (100 ml) was added 1J01I (2.5g, 111 mmol). The solution was stirred al rt for 3 h, concentrated in vacuo, acidified with IN NCI, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO , and concentrated in vacuo 4 to give the title compound (9.5 g, 95 %). [1466] MS[M+II] = 257(M+1) [1467] f I46S] StepB: (2S.4SVl-Boc-4-a7.idof(dimelhYlamino)carbonvllpvrrolidine [1469] To a solution of (2S,4S)-l -Boc-4-azidopyrrolidine-2-carboxyJic acid (9.5 g, 35 mmol) prepared in Step A in DMF (30 U) was added dropwise DIPEA (1.15 0, 6.70 mmol), and added dropwise 2M dimethylamine-THF solution (26.3ml, 52.5mmoI), HOBT (7g, 52.5 mmol) and EDC (10.2 g, 52.5 mmol) in order. The reaction mixture was stirred at rt for 12 h, and concentrated in vacuo. The residue was diluted with EtOAc, and washed with a saturated NalICO aqueous solution, water and IN HC1. The organic solution was dried over MgSO , concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc:Hex = 1/2) to give the title compound (9.1g, 93 %). [1470] MS[M+II1 = 284(M+1) [1471] [1472] Step C: f2S.4SV 1 -Boc-4-amino[fdimethylamino)carhonyllpyrrolidine [1473] Toasolulion of (2S,4S)'l-Boc-4-azido[(dimethylamino)carbonyl]pyrrolidine(9g, 32 mmol) prepared in Step B in dioxane (30 mL) was added dropwise Pd/C (900 mg). The reaction mixture was stirred under hydrogen condition for 24 h, filtered through Celite, and concentrated in vacuo to give the title compound as an oil (8.1 g, 98.5 %). r 1474] MS [M+I I] = 258(M+1) [1475] [1476] StepD:f2S.4SVl-noc-4-[f2.4-ilinuorophenvnaminol-2rfdimethvlamino)carbonvn pyrrolidine [ 1477] To a solution of (2S,4S)-1 -Boc-4-ami no [(di met hylamino)carbonyll pyrrolidine (8 g, 31.5mmoI) prepared in Step C in toluene (100 ml) was added sodium t-butoxidc (3.46 g, 36 mmol), 2-(di-l-rjuiylphosphmo)bi phenyl (800 mg, 2.68 mmol), tris(dihen7ylideneacetone)dipalladium(0)(1.6 g, 1.79 mmol) and l-bromo-2,4-difluorobenzene (6.94 g, 36 mmol), and the solution was stirred at 110°C for 10 h. After the reaction finished, the solution was fdtered through Celite, and extracted with water and EtOAc. The organic layer was dried over MgSO , con- 4 centrated in vacuo, and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give the title compound (1.5 g, 78%). [1478] MS[M+H] = 370 (M+l) [1479] [1480] Step E: (4 S VIA \(3 SAR VI - ten ^butyl-4-f4-chlorophenvnpyrTolidine-3-vl] carbonyl)-4-f(24-difluorophenyW2.2-dimethylpropanoyl)amino1- N.N - dimethyl-L-prolineamide TFA salt ri481] The title compound was prepared according to the procedure described in Step B, E, F, G of Example Al using (2S,4S)-l-Boc-4-[(2,4-difluorophenyl)amino] - 2f (dimethylamino)carbonyllpyrrolidine (0.5 g, 1.34 mmol) prepared in Step D as starting materia! (0.46 g, 55%). [1482] MSIM+Ti]=617(M+l) [1483] 1HNMR (500 MHz, CDC13) 7.57 (d, 211), 7.41 (d, 2H), 7.35-7.14 (m, 1IT), 7.13-7.00 (m, III), 6.99-6.89 (m, 1H), 4.82-4.71 (m, 1H), 4.61-4.53 (m, 1H), 3.92-3.49 (m, 511), 3.29-3.20 (m, 1H), 3.14-2.85 (m, 211), 3.04 (d, 3H), 2.93 (d, 3H), 2.59-2.42 (m, 1H), 2.21-2.10 (m, 1H), 1.40 (s, 9H), 0.97 (s, 9Ii) [1484] [1485] Example D2-39 [1486] The following Examples were prepared according to the procedure described in Example Dl, using the intermediates which are prepared in a series of Example A by the reactions between appropriate compounds among Preparation Example Al, A2, N A4, A9 and appropriate amines. [1487] 0 R* R, —N / \ * N O [1488] R2 R3 [14891 Table 9 (Table 9] Kiam[i!e R1 R- R1' H' CH(CH3): ■ -- "Mb " (M + l) D2 03 04 I Bu 4-C! H 2,4-diP-Pli i >"i2 i-Bu i-Bu 4-CI 4-C1 U II 2,4diF-Pli 2,4-diF-Ph [-Bu cr3 s s 546 — 556 Di i-Bu 4-CI 11 2-K-Ph CH[CH2); s 5(4 06 i-ltn 4-CI H H 2.3-itiF-Ph f'HK'H,), s 53? [17 i-Bu 2.4-diF 2.4-diF-Ph ClllClh); s 534 08 i-Bu 4-CI II 2-F-Pli l-Bu s 52R m 010 i-ltn 4-CI II 2,3-diF-Ph t-Bu s 546 i-Bu 4-CI 11 3.4-diF-Pli Miu s 546 DM l-Bu 4-CI II 3,5-diF-Ph tUu s s -- - 546 D12 1113 t-Bu t-Bu 4-CI 4-CI H 4-CI-Ph t-Bu 544 H 3-CI-Ph i-Bu s 544 DM I-Bu 4-CI H ■J-Me-Pli l-Bu t-Bu s s 524 015 t-Ru 4-CI H 3-Me-Ph 524 016 I-Bu 4-CI H I-Bu R 5M DI7 I-Bu 4-CI H >- s t-Bu R 517 DIH I-Bu 2,4-diF H l-Bu R 519 D19 1-Bu 4-CI H 2.4-ilif-Ph CH(CH,|; R 532 D20 I-Bu 4-CI H 2,4di]-Ph i-Bu R 546 021 t-Bu 4-CI H 2.4-diF-Ph ,7 V. <■ ■; o' R S 556 022 1-Bu 4-CI H Ph t-ISu 510 023 I-Bu 4-CI C(0)NH. 2.4-diF-Ph CH[CH,); S S 575 024 t-Ru 4-CI C(0)NH. 4-CI Ph CH(CHj); s S 573 1.125 l-Bu 2,4-diF CIOINJCH,); 2,4-dil-"-Ph l-Bu ?; s 619 1)26 l-Bu 4-CI r<(»N(CH,); 2,4-diF-Ph CHICH,); s s 603 1127 r-Bu 4-n C(0)N(CH.V 4-OMc-Ph [-Bu s s 611 617 D28 t-Bu 4 CI C(0)N(CH,)_ 2,4-diF-Ph i-Bu R S s 1)29 i-Du 4-CI CfOmOl,): 4-rp,-pf) I-Bu 650 [14911 [110 1 flu J-CI C(OiN«:Hi), 2.4-HiM'li l-Hu T R S s f>n 1)11 rn: i-iiu -U"l A n 4-Cll,-l'h 2.4-dif-Pli I-Hn ■ _ 6ii 1)31 l-Hii an C(O|N(CH0: 4-CI-Ph H b -' S s s s 621 0)4 [)3S l>3(. l-FJu i-flu 4-Cl C(0)N(CH,); 2.4-diF-Ph b '' s 627 627 2,4-diF-Ph x--6 ! Bu 4-Cl a())N(CH,); 2:4-diF-Pli H s 631 D37 t-Bu 4-Cl C(0)N(CH5), 2,4-diF-Ph 1 s s s 631 ms i-Hu 4-CI C(0)N(CH;); CUi-(2,1-diF-Phl t-Bu s 631 039 l-Rii 4-Cl H 2,4-diF-Ph R rm [14921 [1493] Scheme K [1494] v R3 ,Ni R' UN N ^ V- 0 ,^ RS R' R3 0 -N I '"' ) _/i Rs /nf. dIO Jn(. fi?, tot. CZ, inf. o; at P=floc /fit.= Intermediate [1495] [1496] Example El-1: (45)-l-{[{35,4 ff )-4-(4-chlorophenyl)pyrrolidine-3-yl] carbonyl}-4-[(4,4-dimethylcyc1ohexyl)(2^-dimethy]propanoy])amino]- N, W dimethyl-L-prolineamidc ri497i _ o ,; N- Cl [14981 f 14991 -Step A 1-BOC- (3 R A S V3-f4-chlorophenvn-^-f(f2S,4SV24('diTTiethvlainino)carboTiyll-4-K4,4-dimethvlcvcloh exyl)(2.2-d]"methvlpropanoyl)aminolpyrrolidine-l-yllcarbonvnpvrrolidine [15001 The title compound was prepared according to the procedure described in Step F of Example Al, using (45)-4-[(4,4-(iimethylcyclohexyI)(2,2-dunethylpropanoy[)amino]-A' ,A,-dimethyIl~L-pro!ineamide(350mg, 1 .Gmmol) prepared in Step E of Example Al and (3S,4R)-l-(tert-buloxycarbonyl)-4-(4-chlorophenyI)pyrrolidine-3-carboxyIicacid prepared in Preparation Example A9-9 (593 mg, 90%). [1501] MS[M+ir| = 659(M+l) [1502] [1503] Step B: (A S V1 - T \(3 S A R V4-f4^hloniDhenvl^yrrolidine-3-yn carbonyl}-4-[f4.4-dimethylcyclohexyn(2.2-dimethylpropanoyl1amino1- N. N -dimethy[-L-prolineamide [ 1504] 1 -BOC- (3tf,4£)-3-(4-chloropbenyl)-4-({(2S,4S)-2-[(dimelhylamino)carbonyI] - 4-f(4,4-dimethylcyclohexyl)(2,2-dimethyIpropanoyl)aminolpyrrolidine-l-yl}carbonyl) pyrrolidine (100 mg, 0.15mmol) prepared in Step A was treated according to the procedure described in Step Eof Example Al, and purified by HPLC. ThisTFA salt of the compound was basified with IN NaOH, and extracted with EtOAc. The organic layer was dried over MgSO , and concentrated in vacuo to give the title compound (75 4 mg, 90%). [1505] MS[M+H] = 559(M+1) [15061 IH NMR (500 MHz, CDC13) 7.30 (d, 2H), 7.24 (d, 2H), 4.71 (t, IH), 4.29-4.19 (m, IH), 3.78-3.60 (m, br, 2H), 3.45-3.19 (m, 4H), 3.59-3.50 (m, IH), 3.06 (s, 3H), 2.96 (s, 3H), 2.96-2.74 (m, 2H), 2.50-2.41 (m, IH), 2.09-1.95 (m, IH), 1.63-1.04 (m, 8H), 1.18 (s, 9H), 0.95 (s, 3H), 0.92 (s, 3H) [1507] [1508] Example E1-2-S8 [1509] The following Examples were prepared according to the procedure described in Example E1 -1, using the intermediates which are prepared in a series of Example A,B,C,D by the reactions between appropriate compounds among Preparation Example Al, A2, A4, A9 and appropriate amines. [1510] o R* 11 ' * o N R4 ri5in [15121 Table 10 [Table 10] Ev ample IV R2 R' R' R1 »» IMtll 16(1 ~474 " EI-? li i'i' H H Ti-CI 11 Cn-l-Me-c-llcv cmnij, CH(CH;), ..... HI-3 4-C1 II __ 4,4-diMe-c-IUv 4.4-JiMe-oilex s £1-5 4 CI l-Hu s -138 4-CI H 4.4-diMe-c-Hex V li VL 0 498 r-i 6 11 4-CI 11 4.4-d.Me-c-htex ciijOCHjCii, CF3 490 El-7 II 4-CI II 4 4-diMe-c-Hex 500 '499 El-8 11 4-CI H 4.4-diMc-c-llex C(CHi),CN C(CH3)jCH,F Et-9 11 4-CI 11 4,4-diMe-c-Mo. 506 £1-10 11 4-CI H 4.4-diMe-c-Hex c(cri,),cn;ocii; Cll, 532 HIM II li 4 CI 4-CI M II 4.4-diMe-c-Hex b—' 502 El -12 4.4-diMd-c-Hex -o 5fl2 Bl-13 H H 4-CI 4-CI H H c-is-4-Me-c-Hex l-Hu 47-1 EI-I4 cis-4 Me-i-llex 0 434 ei-15 II 4-CI !1 Lis-4-Me-c-Mtx QCH,), CH(CH,)OII s 504 [15131 E.I-16 F7T? t-i-i'T" Fl'"if Tl-22~ Fl-23 4-CI Tci ~4~ci ~~4-~Cl 4-CI rr CK-4 Mi-C-IL-M ti!.-4-Mc-7-hk-cis-4 Mt-c-lle\ CK-4-Me-r-lli?> 4.4-dif-c -llc>; 4.4-iiii'"-c-lk> 4.4-il~iP-i-Hi.'cis-4-Mt'-c-Hex t'i'CHi)jC'(rH,ljCi t'(CH;),f'{0)CU, C(CII3|;[/(0)NH. l-Bu_ CF,~ """ -O ill? ">(T"i ~~5"iW is" ~496 SOS ■IKft El-24 4-CI 4.4 dil'-c Ik-* 510 Q ' tl-25 2,4-diF 4.4-diMc-c-Hox 500 El -26 El-27 4-CI 4-CI CONH. Pi cis-4-Mc-c-tlcs. c-Hcx t-Bu Mc sn 460 El-28 4-CI 502 F.I-29 4-C) "allyF 1-BLI 500 El-30 2.4-diF C(0)NH3 cii-4 -Me-c-Hev — O 533 [15141 1-1-31 El 32 il II 4-CI 4-CI C(OlNH; C(0)NH, CIS-4 Me-c-Hex cii-4-Me-c-Hc* H 0—' S s 531 '•- o s s 527 El-33 II 4-CI C(0)NII, 4.4-diMe-c-Hex H o-< s s 545 I! 1-34 1! 2.4-diF QOlNHEl cts-4-Me-oHex t-Bu s s 547 n-35 P.I-36 El-37 id H 4-CI 4-CI C(0)NHl-B" \ cis-4-Mis-c-Hcsi c-Hen 1-Bu s R 573 Me s H 501 II 4-C) S ,N 1 cis-4-Mc-c-Hex CHfCHj), s R 541 El IS II 4-CI CHjNHi 4,4-diMe-c-Hex l-Bn s S 517 El-39 il 4-CI CH.N(CII,|; 4,4-diMe-c-I tex t-Bu s S 545 El 40 II 4-CI <:N c-Hev Me s R 443 EI-41 H 4-CI CM cis-4-Me-c-Hex f-Bu s R 491 FJ-42 II 4-CI Ac c-Hri Me s R 460 EI-43 11 2,4-tliF Ac cis-4-Me-t-Mc\ l-!3u s R 5IB HI-44 ■1-CI AL 4.4-diMe-c Hi:v 1-Eiu s R 530 |I3 1S| 1.14 5 It H ■i-n C!i> i.ii 519 "T-i- 5IS 52" h"1 -4o "hi-js '" niTjy" " 7i-5~[f~ 4-CI H H " M " II ■i-n j-rt C'tOlNIIEl cis-'i-Mi-c-lkx 2,4-rtiF "To -1 -C| C(0)NH; ci^-4-Me-c-Hex t-Bu r(0)N(rnn>j C(0)NHj cis-4-Me-c-Hex (-l)ii S 1-1 -S1 cis-t-Mc-c-HirK i-Hu S s R. R R L! -y> II ■i-Ci cis^-Me-c-Hc* "-o bi-S3 II -1 CI C(0>NH, cis 4-Me-c-Hex i-Bu 517 FI-54 FT-??"" It "IT 2,4-d* C(0)N(CH3)j 4,4-diMe-t-Hex 1-Bu s S 561 2.4-diF C(S)N(CH3)i C{0)N(CHjl, 4.4-diMe-c-Hcx T-Bll CH(CH0i C(CH3)iCH3OH s S S 5?' 1 LI-56 ii 4-CI 2.4-diF-Pli 547 "ioT- RI--57 Examf u 4-CI It 4,4-diMe-c-Hex s [1516] [1517] ilef 12-1: (< isn-m S,4R )-l-(aminocarbonyI)-4-(4-chIorophenyl)pyrroIidine-3-yl]carbonyl}-4-[(4,4-dimeth ylcyclohcxyl)(2,2-diniethylpropanoy])amino]- A', JV -dimethyl -L-prolineamide [1518] o 0 o H.N 0 N \._. CI [1519] [15201 [1521] [1522] (1523] [15241 To a solution of (4S)-l-[[(3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-yl] carbonyl}-4-[(4,4-dimelhylcyclohexyI)(2,2-dimethylpropanoyl)amino]-A^,N-dimethyl-L-prolineamide (84 mg, 0.15 mmol) prepared in Example Ell in DMF was added dropwise KOCN (24 mg, 0.3 mmol) and a catalytic amount of acetic acid. The reaction mixture was stirred at rt for 1 h, extracted with EtOAc, washed with excessive amount of water and brine, and the organic solution was dried over MgSCK The residue was purified by HPLC to give the title compound. MS[M+H] = 602(M+1) llf NMR (500 MTIz, CDCI3) 7.30 (d, 2H), 7.24 (d, 2H), 4.71 (t, Hi), 4.29-4.19 (m, HI), 4.05-3.77 (m, 4H), 3.76-3.60 (m, 2H), 3.59-3.50 (m, IH), 3.06 (s, 311), 2.96 (s, 3H), 2.99-2.71 (m, 211), 2.50-2.40 (m, IH), 2.09-1.95 (m, IH), 1.63-1.04 (m, 8H), 1.18 (s, 9H), 0.95 (s, 3H), 0.94 (s, 311) Example E2-2-25 [1525] The following Examples were prepared according to the procedure described in Example E2-1, using the intermediates which are prepared in a series of Example A,B,C,n> by the reactions between appropriate compounds among Preparation Example Al, A2, A4, A9 and appropriate amines. R8 O ii [1526] R1 N N T1527] 1528] R3 Table 11 [Table 11] R4 O N ■ (' R5 Example R1 R2' R! R' R5 1 MS (M-ll L2-2 NH,C{0) 4-CI II j 4.4-diMe-c-ltex C(CH3);CH, OH s 547 r-:2-3 NHjCfO) 4 CI II 4.4-diMe-c-Hcx 1-Bll s -- ^ i 1 E2-t NtlX(O) 4-CI K 4.4-diMe-c-IIex CHfCHjfe 517 545 E2-5 4-CI K 4,4-diMe-c-Efcx 0 ' s E2-fi NHjCfO) 4-CI II 4,4-diMe-c-Hcx s 545 E2-7 NH,C(0) 4-CI Ii 4.4-diMc-c-Hex C(CHJXCH, OHIJ s 563 e:2-s NHjC(O) 4-CI H cis-4-Me-c-Hex CH(CH,)2 s 503 R2-9 NU,C(0) 4-CI H cis-4-Me-c-Hex l-Bu s 517 E2-I0 NHiC(O) 4-CI H cis-4-Me-<-l lex -r s SOI E2-I1 NH.C(O) J-CI H cis-4-Me-c-Heji CfCHjKCH, OH); s 549 E2-I2 NH,C(0) 2.4-diE H 4.4-diMe-c-Hex t-Bu s 535 E2-13 NII;C(0) 2.4-diE II 4.4-diMe-c-He* H o—' s 547 f15291 EM4 Nt 1,Q01 4 -a 4-a~~ O0)NH7~ cii-4-Me-c-]L-x i-Bu * 5uU . ~>4 f, F2-15 ~F2-~KT~' E2-17 F2-IS NJI;r(6) MM.an] i]i-4-Me-c-H=\ 4.1-iJiMc-c-Hex OffCH-.), s s x .4 -d i r l-Hu ■ — s ^ s 574 2,4-c!il aOiNH. Ui-4-Me-c-Hck, — '-- d H O -' NH3t"((l) 4-CI rtOlNH. cfs 4 Me-c-lleii F.2-19 NHjCtO) 2.4-diF C(0)NH, cis-4-Me-c-He\ -<1 ' O s s s 572 604 E2-20 NH,C(0) 2,4-iliF rfO)N(C tis 4-Me-c-Hex *-0 E2-2I NH.C(O) 4-Cl C(0)N{C 4,4-diMe-c-He\ ■ o n)6 E2-22 NH;C(0) 4-CI C{0)NH{ CH.):NH, us-^-Me-c-Hes: t-Bu s s 603 E2-23 NH.C(0) 2.4-diF C(0)NH{ CHJ),NHJ cis-4-Me-c-Hex t-Bu 605 E2-24 NH_>C(p) 2,4-diP C(0)NH( CHJJJNH; 4,4-diMc-c-Ht>. t-Bu ■ s 633 F.3-25 NHjC(S) 2,-1-diK C(0)N{C 4,4-cliMe-oHex t-Bu s 620 [1530] [1531] Example E3-1: (4 S )-l-({[(3 S A R )-4-(4-ch1orophenyI)-l-(ethylamino)carbony] ]pyrrolidine-3-yl}carboayI)-4-[(4,4~dimethyIcyclohexy))(2^-dimethyIpropanoyI)a mino]- N, N -dimefhyl-L-prolinearmde [1532] / o w /- N — N o ■J O N N O N^ [1533] [1534] [1535] [1536] To a solution of (4S)-l-{[(3S,4/?)-4-(4-chlorophenyI)pynoHdine-3-yl] carbonyl]-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-/v')/V-dimethyl-L-proIineamide (84 mg, 0.15 mmol) prepared in Example El-1 and TEA (0.04 ml, 0.3 mmol) in DCM, was added dropwise ethylisocyanate (16 mg, 0.22 mmol). The reaction mixture was stirred at rt for 1 h, extracted with EtOAc, washed with excessive amount of water and brine, and the organic solution was dried overMgSO . The residue was purifed by IfPLC to give the title compound. MS[M+H]=630(M+1) IH NMR (500 MHz, CDC13) 7.28 (d, 2H), 7.23 (d, 2H), 4.71 (t, IH), 4.26-4.13 (m, HI), 4.08-3.98 (m. 111), 3.87-3.62 (m, br, 311), 3.58-3.37 (m, br, 3H), 3.37-3.21 (m, 3H), 3.10-2.96 (m, 111), 3.05 (s, 311), 2.94 (s, 311), 2.74-2.60 (m, III), 2.09-1.98 (m, 1H), 1.63-1.04 (m, 811), 1.18 (s, 911), 1.14 (t, 311), 0.95 (s, 3H), 0.93 (s, 3H) [15371 {1538] Example E3-2: N- r(3S)-l-{r(3S,4R)-4-(4-chlorophenyl)-l-[(ethylamino)carbonothioyl]pyrrolidine-3-yl]carbonyl]pyrroIidine-3-yl]-N-(4,4-difluorocycIohexyl)-3-hydroxy-2,2-dimethy!p ropaneamide o [1539] O s ■ J \\_ / N I I / - N \..l »-/ o / A ( / [1540] [1541] To a solution of N- [(3S)-I-{[(3S,4R)^-(4-chIorophenyl)pyiroIidine-3-yl)-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropaneamide (93mg, 0.15mmol) prepared in Example El-57 and TEA (0.04 ml, 0.3 mmol) in DCM, was added dropwise ethylisocyanate (19mg, 0.22mmol). The reaction mixture was stirred at it for 1 h, extracted with EtOAc, washed with excessive amount of water and brine, and the organic solution was dried over MgSO . The residue was purifed by HPLC to give the title compound (74,4mg, 84%). [1542] MS[M+II] = 591(M+1) [ 1543] 1H NMR (500MHz, CDC13) 7.55-7.48(m, 2H), 7.36-7.28(m, 2H), 3.95-3.20(m, 12H), 3.12-2.89 (m,4H), 1.86-1.68(m, ITT), 1.67-1.53(m, 611), 1.52-1.14(m, 9H), 0.94(s, 311), 0.91(s, 3H), 0.88 (t, 311) [1544] [1545] Example E3-3-37 [1546] The following Examples were prepared according to the procedure described in Example E3-1.2, using the intermediates which are prepared in a series of Example A,B,C,D by the reactions between appropriate compounds among Preparation Example Al, A2, A4, A9 and appropriate amines. r15471 Ri _N / R? fJ 5481 M549] Table 12 (Table 12] o RT N ; R4 O R? Kvpmple R1 RJ IT K* R' * t * MS (MM) F.3-3 fclNHC(O) 4-cr 4-CI II ■M-diMe-c-Hex C(CHj);CH ;OH -!- 575 133-4 HNHC(O) 11 4,4-di Met-Hex CHICHJI, 545 E3-5 EINHQO) 4 -CI II 4,4-diMe-c-Hex H o- ■' 573 E3-6 EtNIIC cis-4-Me-c-Hex l-Bu s s 620 E3-31 ElNUC(S) 2,4-dil- C(0)N(CH,), cis-4-Me-c-Hex t-Bu s s 634 E3-32 MeNEIC(S) 4-CI C(0)N(CH;). 4,4-diMe-c-Hex t-Bu s s 632 E3-33 EiNHC(S) 4-CI C(0)N(CM;), cis-4-Me-c-Hex t-Bu s s 632 bj-34 ElNHC(O) 2,4-diF C(0)N(CII,). 4,4-diMe-c-Hex l-Bu s s 632 E3-35 EtNHC(S) 2,4-diF C(0)N(CHi)i 4,4-diMe-c-Hex t-Bu s s 648 E3-36 ElNHC(O) 2,4-diF CfONICH,), 4,4-diMe-c-Hex C(CH3).CH ,OH s s 64 8 E3-37 ElNHr(O) 4-CI C(0)N(CH3), 4,4-diMe-c-Hex C(CH3)2CH >OH s s 646 [1552] [15531 Example E4-1: (4 S )-l-({[(3 S ,4 R )-l-acctyl-4-(4-chlorophcnyI)pyrrolidine-3-yl] carbonyI]-4-[(4,4-dimethylcycIohexyI)(2^-dimethylpropanoyl)amino]- N, N - dimethyl-L-proIineamidc [15541 o J, 0 J o - N 0 Cl N- 115551 [ 1556] The title compound was prepared according to the procedure described in Step F of Example Al using (4S)-l-{[(3.S\4tf)-4-(4-dik>rophenyI)pyrrolidine-3-yl] carbonyl}-4-[(4,4-dimelhylcyclohexyl)(2,2-dimethylpropanoyl)amino]-A',A'-dimelhyl-L-prolineamide (84 mg,, 0.15 mmol) prepared in Example El-1 and AcOH via amide coupling reaction. [1557] MS[M+H]=601(M+1) [1558] IH NMR (500 MHz, CDCI3) 7.30 (d, 211), 7.24 (d, 2H), 4.71 (t, IH), 4.29-4.19 (m, IH), 4.16^1.09 (m, IH), 4.03-3.79 (m, br, 311), 3.78-3.60 (m, br, 211), 3.59-3.50 (m, IH), 3.37-3.29 (m, IH), 3.06 (s, 3H), 2.96 (s, 3H), 2.91-2.69 (m, br, 211), 2.14 (s, 311), 2.09-1.95 (m, IH), 1.63-1.04 (m, 811), 1.18 (s, 9H), 0.95 (s, 3H), 0.94 (s, 3H) [1559] [15601 Example E4-2-14 [1561] The following Examples were prepared according to the procedure described in Example E4-1, using the intermediates which are prepared in a series of Example A,B,C,D by the reactions between appropriate compounds among Preparation Example Al, A2, A4, A9 and appropriate amines. Ri N o [1562] 0 FF 0 r>, / ■ 1 / ■<• N i! RZ RS [1563] [1564] Table 13 [Table 131 Example R1 W R' RJ Ry * ** MS (M-H) VA-2 Ac 4-CI H 4,4-iljMe-c-Hex c(cn,)2c HjOH S 546 E4-J Ac 4 CI [] 4,4-diMe-c-Hex CH(CM3)2 s 516 E4-4 At 4-CI II 4,4-diMe-c-Hex CfCH,), s 530 E4-5 Ac 4-CI II 4,4-diMe-c-llex H o ■-' s 544 E4-6 Ac 4-CI H cis-4-Me-c-llex so2CH, s 538 E4-7 (CH^CHC(0) 4-CI H 4T4-diMe-t-Hex C(CH,)j s 558 E4-8 (CHjfeCHCfO) 4-CI II 4,4-diMe-c-Hex H o-1 s 572 G4-9 CFjC(O) 4-CI H 4,4-diMe-c-Hex C(CH3)3 s 584 E4-I0 Ac 4-CI C(0)NH; cis-4-Me-c-Hex t-Bu s s 559 E4-II CH(CH3),C(0) 4-CI C(0)NH. cis-4-Me-c-Hex CHCCHJJJ s s 573 E4-12 CH;,CH,C(0) 4-CI C{0)NH, cis-4-Me-c-Hex CIKCHiJj s s 559 E4-13 t-BuCCO) 4-CI C(0)NH, cis-4-Me-c-Hex CH(CH3), s s 587 E4-I4 CH(CH,);C(0) 4-CI C(0)NH; 4,4-diMe-c-Hex l-Bu s s 601 [1565] [1566] Example E5-1: (4 S )-l-({[(3 S ,4 R )-4-(4-chlorophenyl)l-cyclopropyIpyrrolidine-3-y]]carbonyl}-4-[(4,4-diinethyIcycl ohexyl)(2,2-dimethylpropanoyl)aniino]- N, N -dimethyl-E-proIineamide HCl salt [1567] 0 0 -N N' 0 CI [1568] [1569] HCl To a solution of (45)-1 - {[(3S,4fl)-4-(4-chloropheny!)pyrrolidine-3-yl] carbonyl)-4-[(4,4-dimethylcyclohexyl)(2,2-diinethyIpropanoyl)amiiio]-A',/V-dimethy[- L-prolineamide (100 mg, 0.18 mmol) prepared in Example El-1 in DCE (5 ml) was added 1-ethoxycyclopropoxytrimethylsilane (47 mg, 0.27 mmol) and sodium- cyanohomhydride (23 nig, ().36 mmol), added a calalylic amount of acetic acid, and the solution was stirred at 80UC for 2 h. After the reaction finished, the solvent was concentrated in vacuo, and extracted with a saturated NaliCO aqueous solution and ElOAc. The organic solution was dried over MgSO , concentrated in vacuo, and the residue was purified by HPLC. This TFA sail of the compound was treated according to the procedure described in Step G of Example Al to give the title compound. [1570] MSfM+II] = 599(M+I) [1571] IH NMR (400 MHz, CDC13) 7.57 (d, 2H), 7.32 (d, 2H), 4.70 (t, IH), 4.35-4.22 (m, 211), 3.95-3.90 (m, 2H), 3.81-3.69 (m, IH), 3.67-3.54 (m, 2H), 3.42-3.29 (m, 2H), 3.22-3.11 (m, III), 2.99 (s, 3H), 2.95 (s, 3H), 2.82-2.68 (in, IH), 2.15-1.79 (m, 2H), 1.61-1.39 (m, 411), 1.31-1.15 (m, 4H), 1.22 (s, 9H), 0.95 (s, 311), 0.91 (s, 311), 0.82-0.65 (m, 4H), [1572] [1573] ExampleE5-2: (4S)-l-{[(35,4/?)-4-(4-chIorophenyl)-l-(tetrahydro-2H -pyran-4-yI)pyrrolidine-3-yl]carbonyl]-4-{(4,4-dimethylcyclohexyl)[(2S )-tc(rahydrofuran-2-ylcarbonyl]amino]- N -ethyl- N -methyl-L-prolineamide HC1 salt [15741 o o I . N O - N w ■l" CI O 'V H / }° HC1 [1575] [1576] (45)-4-[(4,4-dimethylcyclohexyl)(letrahydrofuran-2-ylcarbonyl)amino]-A'-ethyl-W-m ethyl-L-prolineamide (100mg,0.26 mmol) prepared in Step D of Example A2 and (3S,4R)-l-(tert-butoxycarbonyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylicacid prepared in Preparation Example A9-9 were reacted according to the procedure described in Step F of Example A1, and then according to that in Step E of Example A1. This compound was reacted with tetrahydro-4H-pyran-4-one via reductive amination as described in Step A of Example Al, and purified by HPLC. This TFA salt of the compound was treated according to the procedure described in Step G of Example Al to give the title compound (139 mg, 80%). [1577] MS[M+H] =671(M+1) [1578] III NMR (500 MHz, CDCI3) 7.66-7.52 (m, 2H), 7.37-7.27 (m, 2H), 4.73-4.62 (m, IH), 4.52-4.39 (m, III), 4.32-4.16 (m, IH), 4.15-3.69 (m, br, 10H), 3.59-3.12 (m, br, 1011), 3.00-2.88 (m, 3H), 2.23-2.80 (m, br, 811), 1.65-1.04 (m, I IH), 0.98-0.86 (m, 6H) 11579] [15801 Example E5-3-21 f (581] The following Examples were prepared according to the procedure described in Example E5-1,2, using (he intermediates which are prepared in a series of Example A,R,C,D by the reactions between appropriate compounds among Preparation Example Al, A2, A4, A9 and appropriate amines. H582] Q R* - J /- R' — N / y \* O 31 41 Table 14 [Table 141 Example R1 Rr R1' R4 R5' * • • MS F.5-3 c-Pr 4-ci 11 4,4-diMe-c-Hex c(CHj)jCn, OH S 544 E5-4 n-Bu 4-a 11 cis-4-Me-c-Hex CH(CHj)2 s 516 E5-5 i-Pr 4-CI H 4,4-diMe-c-Hex t-Bu s ?3() 115-6 CF,C II. 4-CI H 4,4-diMe-c-Hex t-Bu s 570 E5-7 c-Pr 4-Cl 11 4,4-diMe-c-Hex CH(CII,>, s 514 R5-8 c-Pr 4-CI II 4,d-diMe-c-!lev t-Bu s 528 E5-9 c-Bu 4-CI II cis-4-Me-c-Hex t-Bu s 528 E5-W c-Pen 4-CI U cis-4-Me-c-Hex ai(CHih_ s 52S E5-11 i-Pr 2,4-diF aowaiih 4,4-diF-c-Hex t-Bu s s 611 G5-12 i-Pr 2,4-diF C(OMCH-,)2 4,4-diMe-c-Hex C(CH3)iCH, OH s s 619 629 E5-13 c-Bu 4-CI C(0)N(CH,), 4,4-diMe-c-Hex C(CH;),CH3 OH s s E5-M c-Pen 4-CI C(0)N(CH3)2 4,4-diMe-c-Hex C(CHi).CH2 OH s s 643 E5-Li c-Pr 2,4-diF C(0)N(CH3)2 4,4-diMe-c-Hex l-Bu s s 601 E5-16 c-Pen 2,4-diF QONtCH,)! 4,4-diMe-c-lIex 1-Bu s s 629 ES-17 j C-Pl 2,4-diF QOWCthh 4,4-diMe-c-Hex CU(CUi)2 s s 5S7 E5-I8 c-Pen 4-CI C(0)N(CH,), 4,4-diMe-c-Hex i-Bu s s 627 E5-19 i-Pr 2,4-diF C(0)N(CH3)2 4,4-diMe-c-Ikx t-Bu s s 603 E5-20 c-Pr 2,4-diF: C(S)N(CH,)2 4,4-diMe-c-Hex t-Bu s s 617 E5-21 i-Pr 2,4-dil' C(S)N(CH,)2 4,4-diMe-c-Hex t-Bu s s 619 [15861 Example E6: N- |(3S)-l-[|(3S,4U)-4-(4-chlorophenyl)-l-(methylsnlfonyl)pyrroIidine-3-y]]c^rhonyl) pyrroM-din(!-3-yl]-2-m(!tIiy[-N-(cis-4-mefhylcyclohexyl)propancamide [1587] O O O s II N ^ N O N 4 / a [1588] [1589] To a solution of N-[(3S)-l-jf(3S,4R)-4-(4-cliforophenyl)pyrTolidine-3-yl]- N-(cis-4-methylcyclohexyl)-2-methyIpropaneamide TFA salt (124mg, 0.2mmol) prepared in Example El -2 in DCM (3ml) was added TEA (50mg, 0.5mmol), and added methanesulfonylchloride (27.4mg, 0.24mmol) at 0°C, and stirred at rt for 30 min. After the reaction finished, the solvent was concentrated in vacuo, the residue extracted with water and EtOAc, and the organic layer was dried over MgSO . The residue was purified by HPEC to give the title compound (82.8mg, 77%). [1590] MS[M+H] = 538(M+1) [1591] IH NMR (400MHz, CDC13) 7.40-7.10(m, 4H), 3.87-3.50(m, 6H), 3.47-3.21(m, 3H), 2.84(s, 311), 2.80-2.69(m, 2H), 2.60-2.33(m, 211), 1.78-1.57(m, 8H), 1.50-1.21(m, 9H), 0.95(d, 3H) [1592] [1593] Example E7-I: (3R,4S)-3-(4-chlorophcnyl)-4-({(3S)-3-[(cis^-methylcyclohexyl)(2-methy!propano y!)ammo]pyrrolidlne-l-yl]carbonyl)-N-(2^,2-trifIuoroeOiyl)pyrrolidine-l-carboxa mide [1594] o o N i / a [1595] [1596] To a solution of phosgene (148mg, 1.5mmol) and TEA (30mg, 0.3mmol) in DCM (5ml) was slowly added dropwise N- [(3S)-l-([(3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-yl)-N-(cis-4-methylcyclohexyl)-2-methylpropaneamide TFA salt(90mg, 0.15mmol) prepared in Example El-2, and stirred at rt for 30 min, and concentrated in vacuo to remove phosgene. To the residue [1597] [15981 [1599] [1600] [1601] f16021 was added DCM (5ml) and TEA (30mg, 0.3mmol), and added dropwise 2,2,2-lrifhinroetriylamine (20mg, 0.2mmo!), and stirred at rt for 1 h. After the reaction finished, the solvent was concentrated in vacuo, and the residue was extracted with EtOAc and water, and dried over MgSO . The residue was purified by IIPLC to give the title compound (53.4mg, 67%). MS[M+ir] = 585(M+l) III NMR (500MHz, CDCB) 7.35-7.28 (m, 2H), 7.22-7.1 l(m, 211), 4.06-3.93(m, HI), 3.91-3.71(m, 5H), 3.70-3.46(m, 5H), 3.44-3.I0(m, 411), 2.86-2.66(m, 2H), 2.55-2.45(m, 1H), 2.02- 1.92(m, IH), 1.79-1.56(m, 5H), 1.51-1.39(m, 2H), 1.10-1.03(4 6TT), 1.02-0.96(m,3H) Example E7-2-3 The following Rxamples were prepared according to the procedure described in Example E7-1, using the intermediates which are prepared in a series of Example A,B,C,D by the reactions between appropriate compounds among Preparation Example AI, A2, A4, A9 and appropriate amines. O R1 N N 'i R1 N- O [1603] [1604] Table 15 [Table 15] [Example R' Rr RJ * MS (M+l) ~E?1H CF3CH,NHC(0) 4-Cl 4,4-diMe-c-Hex s 1 613 E7-3 CF,CH,NHC(0) 4-CI cis-J-Me-c-Hex s 599 [E605] [1606] Example E8-1: methyl (3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethyIcyclohexyl)(3-hydroxy-2,2.di methylpropanoyOaminolpyrrolidine-l-ylJcarbonylJpyrrobdine-l-carboxylate [16071 ° o II a in N / N 9 N '. a i neosi [1609] To a solution of N-[(3SH-[[(3S,4R))-4-(4-chIorophenyl)pyrrolidine-3-yll - N-(4,4-dimethylcycIohexyl)-3-hydroxy-2,2-dimethylpropaneamide (93mg, 0.15mmoI) prepared in Example El-57 and TEA (0.04ml, 0.3mmol) in DCM, was added dropwise methylchloroformate (20mg, 0.22mmol). The reaction mixture was stirred at rt for 1 h, extracted with EtOAc, washed with excessive amount of water and brine, and the organic solution was dried over MgSO . The residue was purified by HPLC to give the A title compound (76mg, 90%). [16101 MS[M+H] = 562(M+1) [16111 1HNMR (500MHz, CDC13) 7.30-7.15(m, 411), 4.00-3.33(m, 1311), 3.32-3.22(m, IH), 3.21-3.1 l(m, !H), 2.78-2.68(m, 0.6H), 2.61-2.51(m, 0.6H), 2.51-2.40(m, 0.4H), 1.98-1.89(m, 0.4H), 1.86-1.68(m, III), 1.67-1.35(m, 7H), 1.32-1.14(m, 8H), 0.93(s, 611) [16121 [16131 Example E8-2-5 f 16141 The following Examples were prepared according to the procedure described in Example E8-1, using the intermediates which are prepared in a series of Example A,B,C,D by the reactions between appropriate compounds among Preparation Example A1, A2, A4, A9 and appropriate amines. [1615] O R1 N \...l N R4 a N -," [1616] [1617] Table 16 [Table. 161 KJ' * MS (Wl) cn(aij)j s 532 t-Bu s 532 CiKOith s 532 ClKCHJj s 594 K\ ample R1 RJ E8-2 l-B-3 MeOC{0) 4,-1-diMc-c-l-iex MeOQO) cis-4-Me-c-!lcx EM ElOCfO) cis-4-W-£-ikx 1 E8-5 Phfll,OC(0) cis-4-Me-c-Hex [1618] [1619] Example E9: N-f(3S)-l-{[(3S,4R)-l-[andno(lmIao)methyl] -4-(4K;hlorophcnyI)pyrrolidine-3-yl]carbonyl]pyrrolidine-3-yl]-2-mcthyl-N-(cis-4-methyIcyclohexyl)propaneamide TFA salt [1620] HjN NH N \. O J o N CI / TFA [1621] T1622] [1623] [1624] f!625] [1626] To a solution of N-[(3S)-l-{[(3S,4R)-4-(4-ch1orophenyl)pyrrolidinc-3-yl] -N-(cis-4-methylcyclohexyl)~2-methylpropaneamide (248mg, 0.4mmoJ) prepared in Example Rl-2 in THF (5ml) was added N,N -bis-Boc-l-guanylpyrazole (186mg, 0.6mmol), and stirred at it for 12 h. After the reaction finished, the solvent was con-cenlrated in vacuo, the residue was extracted with water and EfOAc, and the organic layer was dried over MgSO , DCM (3ml) was added, TFA (1ml) was added, and stirred at 40°C for 10 h. The solvent was concentrated in vacuo, and the residue was purified by HPLC to give the titJe compound (190mg, 77%). MS[M+1I] = 502(M+1) ilT NMR (500MHz, CDC13) 7.34-7.28 (m, 2H), 7.25-7.23(m, IH), 7.15-7.11(m, IH), 4.06-3.93(m, IH), 3.91-3.71-4-f4-chlorophenyn-l-cyanopyrTolidine-3-vn carhonyl]pyrrolidine-3-yH2-melhvl-^l-fcis-4-methvlcvclohexynpropaneqjnide [1630] To a solution of N-[(3S)-l-{[(3S,4R)^-(4-chlorophenyl)pyrTolidine-3-yl] - N-(cis-4-methylcycIohexyl)-2-methylpropaneamide (120mg, 0.21mmol) prepared in Example El-2 in ethanol (5 ml) was added cyanogen bromide (33mg, 0.31mmol) and NaHCO (88mg, 1,05mmol), and stirred at rt for 1 h. The reaction solution was con¬centrated in vacuo, extracted with water and EtOAc, and the organic layer was dried over MgSQ . The organic solution was concentrated to give the title compound, which 4 was used in next step without further purificaton. [16311 MS[M+H1 = 485(M+1) [1632] [16331 StenB:N4f3SVl-rff3S.4RV444^hkM^henvlVl-rfethvlaminoViminohneUivn pyrrolidine-^-yllcarbonvnpviTolidine^-yll^-melhvl-N'fcis^-methvIcvclohexy^prop aneamide TFA salt [ 1634] To a solution of the compound of Step A in hexafluoroisopropanol (2 ml) was added TEA (Iml) and excessive amount of ethylamine hydrochloride, and heated to 70CC The reaction solution was stirred for 5 h, concentrated in vacuo, and purified by HPLC to give the title compound (98.7mg, 73%). [1635] MSfM+H] = 530(M+1) [1636] IH NMR (500MHz, CDC13) 7.35-7.28 (m, 2H), 7.25-7.22(m, IH), 7.15 7.U(m, III), 4.06 3.93(m, IH), 3.91-3.71(m, 5H). 3.70-3.46(m, 3H), 3.44-3.10(m, 611), 2.86-2.66(rn, 2H), 2.55-2.45(m, IH), 2.02-1.92(m, IH), 1.79-I.56(m, 511), 1.51-1.39(m,2H), 1.35-1.23(m, 3H), 1.10-1.03(m, 6H), 1.02-0.96(m, 3H) [16371 [1638] Example Ell: N-[(3S)-l-{[(3S,4R)-l-[(acetylamino)(imino)methyl] - 4-(4-chlorophcnyl)pyrrolidine-3-yl]carbonyl}pyrrolidine-3-yl>2-methyl-N-(cis4- methylcyclohcxyl)propancamide [1639] ON 0 N N ^ N H „__■ O N { i i / [1640] [1641] To a solution of N-[(3S)-I-|[(3S,4R)-Hamino(imino)methyll - 4-(4-chlorophenyl)pyrTolidine-3-yl]carbonyl}pyiTolidine-3-yl]-2-methyl-N-(cis-4-mcth ylcyclohexyl)propaneamide TFA salt (185mg, 0.3mmol) prepared in Example E9 in DCM (3 ml) was added acetic acid anhydride (46mg, 0.45mmol) and TEA (71mg, 0.7mmol), and stirred at rt for 6 h. After the reaction finished, the solvent was con¬centrated in vacuo, extracted with water and RtOAc, and the organic layer was dried over MgSO . The organic solution was concentrated in vacuo, and purified by HPLC to give the title compound (139mg, 85%). [1642] MS[M+H] =544(M+1) [1643] IHNMR (500MHz, CDCI3) 7.38-7.I0(m, 4H), 4.2I-4.05(m, IH), 3.95~3.57(m, 3H), 3.56-3.42(m, 211), 3.40-3.04(m, 3H), 2.75-2.62(m, IH), 2.54-2.40N(R*XR7) or -C(S)-N(R*)(R7), wherein, R andR each independently represents hydrogen, C-C -alkyl or C -C - cycloalkyl, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, amino, C -C -alkyl, trifluoromethyl, hydroxy, C -C -alkoxy and oxo, l A 14 R represents C-C -aryl or heteroaryl, each of which is unsubstituted or mono- 6 10 or di-substiluted with a substituent selected from the group consisting of halogen, hydroxy, C -C -alkyl, C -C -alkoxy, cyano and amino, R3 represents hydrogen, cyano, C -C -alkyl, C -C -cycloalkyl, C -C -alkenyl, monocyclic heterocycle, monocyclic heteroaryl, -C(0)-R or -C(S)-R , wherein, RK represents hydroxy, C -C -alkyl, C -C -alkyloxy or N(R )(R °), 1 4 14 R and R each independently represents hydrogen, C -C -alkyl, C -C - 16 3 7 cycloalkyl, C -C -alkyloxy, phenyl or heteroaryl, R9 and R10 may combine each other to form single ring or two rings, or further comprise oxygen atom or sulfur atom, wherein, alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl is unsubstituted or substituted with a substituent selected from the group consisting of methyl, triflu¬oromethyl, hydroxy, hydroxyimino, amino, acetylamino, (C -C -alkyI)aminoand (C -C -alkyl)(C -C -alkyl)amino, 14 14 R4 represents C -C -cycloalkyl, C -C -aryl, heteroaryl or heterocycle, wherein, C -C -aryl or heteroaryl is unsubstituted or mono- or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, C -C - 1 4 alkyl, frifluonimethyl, C -C -alkoxy and amino, I A cycloalkyl or heterocycle is unsubstituted or mono- or poly-substi luted with a substiluenl selected from the group consisting of halogen, hydroxy, C -C -alkyl, trifluoromethyl, C -C -alkoxy and oxo, R represents hydrogen, C C -alkyl, -C(0)-Rn, C -C -alkylsulfony], C -C - 16 16 6 10 arylsulfonyi, -(CH ) -C -C -aryl, -(CII ) -hcteroaryl or -(CH ) -C -C -cycloalkyl, I P 6 10 2p 2 p 3 8 wherein, p represents 1 or 2, R" represents C -C -alkyl, C -C -alkenyl, C -C -cycloalkyl, C -C -cycloalkenyl, amino, C -C -alkylamino, (C -C -a!kyl)(C -C -alkyljamino, C -C -aryl, heteroaryl, or heterocycle, wherein, alkyl is unsubstituted or substituted with one or more suhstituents inde¬pendently selected from the group consisting of halogen, hydroxy, mercapto, C -C -alkoxy, C -C -alkylcarboxy, amino, dimethylamino, C -C - 4 13 14 alkylcarbonylamino, cyano, carbamoyl, dimethylcarbamoyl, hydroxyimino and oxo, aryl or heteroaryl is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of halogen, hydroxy, C ~C -alkyl, triflu¬oromethyl, C -C -alkoxy and amino, cycloalkyl, cycloalkenyl or heterocycle is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, C -C -alkyl, trifluoromethyl, C -C -alkoxy and oxo. 14 14 The compound of claim 1, wherein R' represents hydrogen, amidino, C -C -alkyiamidino, C -C -alkanoylamidino, C 14 14 -C -alkyl, C -C -cycloalkyl, phenyl, monocyclic heterocycle, monocyclic 16 3 7 heteroaryl, C -C -alkylcarbonyl, trifluoroacetyl, C -C -alkoxycarbonyl, C -C -aryl-C -C -alkoxycarbonyl, -SO -C -C -alkyl, carbamoyl, C -C -alkylcarbamoyl, 14 2 14 16 (C -C -alkyl)(C -C -alkyl)carbamoyl, thiocarbamoyl, C -C -alkylthiocarbamoyl 16 16 16 or (C -C -alkyl)(C -C -alkyl)thiocarbamoyl, wherein, alkyl is unsubstitued or substituted with trifluoromethyl, pharmaceutically acceptable salt or isomer thereof. The compound of claim 2, wherein R1 represents hydrogen, amidino, methylamidino, ethyJamidino, acetylamidino, methyl, ethyl, trifluoroemyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cy- clopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxazolynyl, imi- dazolynyl, thiazolynyl, piperidinyl, telrahydropyranyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridinyl, acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, pivaloyl, methoxycarbonyl, ethoxycarbonyl, benzy- loxycarbonyl, methylsulfonyl, carbamoyl, methy[carbamoyl, ethylcarbamoyl, tri- flunroelhy [carbamoyl, propylcarbarnoyl, isopropylcarbamoyl, butylcarbamoyl, t- butylcarbamoyl, thiocarbamoyl, methyllhiocarbamnyl, elhyllhiocarbamoyl or methyiethylcarbamoyl, pharmaceutically acceptable salt or isomer thereof. f4] The compound of claim 1, wherein R" represents phenyl unsubslituted or mono- or di-substituted with a substituent selecled from the group consisting of F, CI and methyl, pharmaceutical ly acceptable salt or isomer thereof. f5] The compound of claim 4, wherein R represents phenyl, 4-lluorophcnyl, 4-chIorophenyl, 4-methyiphenyl or 2,4-di fluoropheny I, pharmaceuttcally acceptable salt or isomer thereof. [6] The compound of claim 1, wherein R3 represents hydrogen, cyano, C -C -alkyl, C -C -alkenyi, -CH C(CH ) CH OH, oxazolyl, thiazolyl, oxazolynyl, thiazolynyl, carboxy, C -C -alkylcarbony], C -C -alkyloxycarbonyl, carbamoyl, thiocarbamoyl, C -C -alkylcarbamoyl, (C -C - ■ 4 14 alkyl)(C -C -alkyI)carbamoyl, (C C -alkyl)(C -C -alkyloxy)carbamoyl, C -C -alkylthiocarbamoyl or (C -C -alkyl)(C -C -alkyl)thiocarbamoyl, phenyl- 14 14 carbamoyl, heteroarylcarbamoyl, azetidinecarbonyl, pyrrolidinecarbonyl, piperidinecarbonyl or morpholinecarbonyl, wherein alkyl is unsubstituted or substituted with a substituent selected from the group consisting of hydroxy, hydroxyimino, amino, (C -C -alkyl)amino and (C -C -alkyl)(C -C -alkyI)amino, 4 1 4 pharmaceutically acceptable salt or isomer thereof. [7] The compound of claim 6, wherein R3 represents hydrogen, cyano, methyl, ethyl, propyl, allyl, -CltNOH, hy-droxymethyl, -CH(CH )OII, aminomethyl, dimethylaminomethyl, oxazolyl, thiazolyl, oxazolynyl, thiazolynyl, carboxy, acetyl, propanoyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, carbamoyl, thio¬carbamoyl, ethylcarbamoyl, t-butylcarbamoyl, dimelhylcarbamoyl, methyiethyl¬carbamoyl, methylmethoxycarbamoyl, dimethylthiocarbamoyl, phenyl-carbamoyl, heteroarylcarbamoyl, -C(0)NH(CH ) NH , azetidinecarbonyl, pyrro¬lidinecarbonyl, piperidinecarbonyl or morpholinecarbonyl, pharmaceutically acceptable salt or isomer thereof. [8] The compound of claim 1, wherein R4 represents C -C -cycloalkyl or monocyclic heterocycle unsubstituted or mono- or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, C -C -alkyl, trifluoromcthyl, C -C -alkoxy and oxo; or phenyl or monocyclic heteroaryl unsubstituted or mono- or di-substiluted with a substituent selected from the group consisting of halogen, hydroxy, C -C -alkyl, I 4 trifluoromelhyl, C -C -alkoxy and amino, pharmaceutically acceptable salt or isomer thereof. The compound of claim 8, wherein R4 represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-melhylcyclohexyl,4,4-dimethylcycIohexyI,4,4-difluorocyclohexyl, 4-lrifiuoromelhylcyclohexyl, 3,4-letramethylcyclopenlyl, tetrahydropyranyl, pyridinyl, N-methylpyridinyl or phenyl, wherein, phenyl is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of F, CI, methyl and methoxy, pharmaceutical ly acceptable sail or isomer thereof. The compound of claim 1, wherein R5 represents hydrogen, C -C -alkyl, -CO-R11, C -C -alkylsulfonyl, -CI I^-C -C - aryl, -CH -heteroaryl or -CH -C -C -cycloalkyi, wherein, R represents C -C -alkyl, difluoromethyl, trifluoromethyl, C -C - alkenyl, C -C -cycloalkyi, C -C -cycloalkenyl, amino, C -C -alkylamino or (C -C -alkyI)(C -C -alkyl)amino, phenyl, monocyclic heteroaryl, or monocyclic 4 1 4 heterocycle, wherein, alkyl is unsubstituted or substituted with one or more substituents inde¬pendently selected from the group consisting of halogen, hydroxy, mercapto, C -C -alkoxy, acetoxy, amino, acetylamino, cyano, carbamoyl, dimethylcarbamoyl, 4 hydroxytmino and oxo phenyl or heteroaryl is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of F, hydroxy, methyl, trifluoromethyl, methoxy and amino, cycloalkyi, cycloalkenyl or heterocycle is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of C -C -alkyl, 1 4 C -C -alkoxy and oxo, pharmaceutical ly acceptable salt or isomer thereof. The compound of claim 10, wherein Rs represents hydrogen, C -C -alkyl, trifluoromethyl, C -C -alkylcarbonyl, triflu- oroacetyl, acryloyl, methacryloyl, C -C -cycloalkylcarbonyl, C -C - cycloalkenylcarbonyl, carbamoyl, C -C -alkylcarbamoyl, (C -C -alkyl)(C -C^ - alkyOcarbamoyl, melhanesulfonyl, elhanesulfonyl, propanesulfonyl, benzoyl, hy- droxybenzoyl, aminobenzoyl, monocyclic heteroarylcarbonyl, heterocy- clecarbonyl, benzyl, -CH -monocyclic heteroaryl, or -CH -C -C -cycloalkyi, wherein C -C -alkyl, or C -C -alkylcarbonyl is unsubstitued or mono- or di- subsfilued wild a substiluent selected from the group consisting nf 1% hydroxy, mercaplo, melhoxy, ethoxy, acetoxy, amino, melhylcarbonylamino, cyano, carbamoyl, hydroxyimino and oxo, pharmaceutical^ acceptable salt or isomer thereof. The compound of claim 11, wherein R represents hydrogen, methyl, ethyl, propyl, isobutyl, hydroxyethyl, -CII C(CH3)2CirOII, -CH C(CH ) CH(CH )ON, -CII CU NHC(0)CH , aminoethyl, acetyl, trifluoroacctyl, hydroxyacetyl, melhoxyacelyl, ethoxyacetyl, propionyl, ethoxypropionyl, isobiityryl, cyanoisobulyryl, hydroxyisobulyryl, car¬bamoyl isobutyryl, 3,3-dimelhylbutanoyl, pivaloyl, fluoropivaloyl, difluo-ropivaloyl, hydroxypivaloyl, mercaptopivaloyl, dihydroxypivaloyl, melhoxypivaloyl, ethoxypivaloyl, aminopivaloyl, dimethylaminopivaloyl, hy-droxyiminopivaloyl, acetylisobutyryl, -C(0)C(CH ) CH(CH )OH, -C(0)C(CH ) C(CH ) OH, acryloyl, methacryloyl, cyclopentanecarbonyl, cyclo-hexylenecarbonyl, carbamoyl, dimethylcarbamoyi, methanesulfonylcarbonyl, benzoyl, thiopenecarbonyl, furoyl, oxazolecarbonyl, thiazolecarbonyl, imida-zolecarbonyl, pyrazolccarbonyl, tetrahydrofuroyl, dihydrofuroyl, tetrahydropy-rancarbonyl, morpholinecarbonyl, methanesulfonyl, benzyl, furanmethyl, thia-zolemethyl or imidazolemetfiyl, pharmaceutical^ acceptable salt or isomer thereof. The compound of claim 1, wherein R represents hydrogen, amidino, methylamidino, ethylamidino, acetylamidino, methyl, ethyl, trifluoroethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cy-clopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxazolynyl, imi-dazolynyl, thiazolynyl, piperidinyl, telrahydropyranyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridinyl, acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, pivaloyl, methoxycarbonyl, ethoxycarbonyl, ben7.y-loxycarbonyl, methylsulfonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, tri-fluoroethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, thiocarbamoyl, methylthiocarbamoyl, ethylthiocarbamoyl or methylethylcarbamoyl, R represents phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methyIphenyl or 2,4-difluorophenyl, R represents hydrogen, cyano, methyl, ethyl, propyl, allyl,-CHNOH, hy-droxymethyl, -CH(CH )OH, aminomelhyl, dimethylaminomethyl, oxazolyl, thiazolyl, oxazolynyl, thiazolynyl, carboxy, acetyl, propanoyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, carbamoyl, thio¬carbamoyl, ethylcarbamoyl, t-butylcarbamoyl, dimethylcarbamoyi, methylethyl- carbamoyl, melhylmethoxycarbamoyl, dimethyl!hiocarbamoyI, phenyl-carbamoyl, heteroarylcarbamoy], -C(0)NH(CH ) Nil , azelidinecarbonyl, pyrro-lidinecarbonyl, piperidinccarbonyl or morpholinecarbonyl, R represents cyclobutyl, cyclopenlyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4-trifluoromethylcyclohexyl, 3,4-tetramethyIcyclopentyl, tetrahydropyranyl, pyridinyl, N-methy[pyridinyl or phenyl, wherein, phenyl is unsubsliluted or mono- or di-substituted with a substituent selected from the group consisting of F, CI, methyl and methoxy, RS hydrogen, methyl, ethyl, propyl, isobutyf, hydroxyethyl, -CH C(CH ) CH OH, -CH C(CH ) CII(CII )OH, -CII CH NHC(0)CII, aminoethyl, acetyl, triflu- 232 3 2 2 3 oroacetyl, hydroxyacetyl, methoxyacelyl, ethoxyacetyl, propionyl, ethoxypropionyl, isobutyryl, cyanoisobutyryl, hydroxyisobutyryl, car-bamoylisobutyryl, 3,3-dimethyIbutanoyl, pivaloyl, fluoropivaloyl, difluo-ropivaloyl, hydroxypivaloyl, mercaptopivaloyl, dihydroxypivaloyl, methoxypivaloyl, ethoxypivaloyl, aminopivaloyl, dimethylaminopivaloyl, hy-droxyiminopivaloyl, acetylisobutyryl, -C(0)C(CH )2CH(CHs)OH, -C(0)C(CUJ2 C(CH ) OH, acryloyl, methacryloyl, cyclopentanecarbonyl, cyclo-hexylenecarbonyl, carbaraoyl, dimethylcarbamoyl, methanesulfonylcarbonyl, benzoyl, thiopenecarbonyl, furoyl, oxazolecarbonyl, thiazolecarbonyl, imida-zolecarbonyl, pyrazofecarbonyl, tetrahydrofuroyl, dihydrofuroyl, tetrahydropy-rancarbonyl, morpholinecarbonyl, methanesulfonyl, benzyl, furanmethyl, thia-zolemethyl or imidazolemethyl, pharmaceutically acceptable salt or isomer thereof. The compound of claim 13, which is selected from the following group: (45)-l-([(35,4fi)-l-/ert-butyl^(2,4-difluorophenyl)pyn-olidine-3-yl]carbonyl}-4 -[(4,4-duriethylcyclohexyl)(2,2-dimethylpropanoyl)aminol-MA'-dirnethyl-L-proIi neamide (4S)-l-{f(3S,4fl)-l-/ert-butyl-4-(4-chlorophenyl)pyrrolidme-3-yl]carbonyl}^l-{( 4,4-dimethylcyclohexyl)f(2S)-tetrahydrofuran-2-yIcarbonyl]amino}-A'',/l/-ethylm ethyl-L-prolineam i de (45)-l-{[(35,4«)-1-fert-butyl-4-(4-chlorophenyl)pyrroHdine-3-yl]carbonyl}-4-{( 4,4-dimethylcyclohexy!)[(2S)-tetrahydrofuran-2-ylcarbonynamino)-A'-ethyi-L-p rolineamide (45)-l-([(35,4R)-I-rer(-butyi-4-(2,4-difluorophenyl)pyrTolidine-3-yl]carbonyl)-4 -f(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-A'-ethyl-A' -methyl -L-prolineamide (4.^)-l-{f(3.?,4ff)-l-(frt-butyl-4-(4-chlorophenyl)pyrrolidine-3-yllcarbonyl}-4-[(4 .4-dinunrocycI(ihexyl)(?.,2-dimethy]pmpanoyl)amino]-Af^-dimethyl-I^prolinea niide (4tS)-l-{f(35,4/i)-l-/ert-butyM-(4-chlort)phenyl)pyrrolidine-3-yl]carbonyl}-4-[C4 ,4-difiuorocyclohcxyl)(2,2-dimelhy[propanoyI)amiiiol-A'-ethyI-IJ-proIiiieamide (4^-K{f(3.9,4fi)-4-(4-chlorophenyI)-l-melhylpyrroIidiiie-3-yl]carbonyI}-4-f(2,2 -dimethyIpn)panoyl)(cis-4-methylcyclohexy])amino]-L-prolineamide N-f(3S)-l-{[(3S,4R)-l-t-butyl-4-(4-chlorophenyf)pyrrolidine-3-yl]carbonyl}pyrT olidine-3-y1]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimelhylpropaneamide N-f(3S)-l-{[(3S,4R>M-butyl-4-(4-chloropheny])pyrrolidine-3-yncarbonyl|pyrT olidme-3-yi]-N-(4,4-diniethy1cyclohexyI)-2,2-dimethylpropaneamide (4S)-1 -{f(35,4fi)-1 -fert-butyI-4-(2,4-difluoropheny0pyrrolidine-3-yncari)onyl }-4 - f (4,4-dimelhy I cyclohexyl)(melhyIsul fonyI)amino] -JV.W-dimethyl-L-prolineamid e N-[(3S)-l-{[(3S,4R)-1-l-buty]-4-(4-ch]oropheny1)pynralidine-3-yl]carbonyl}pyrr olidine-3-yl](4,4-dimelhylcyclohexyI)amino|-2,2-dimetiiylpropane-l-ol (35)-l-{f(35,4R)-I-/ert-butyM-(4-ch]oropbenyI)pyrrolidine-3-y]lcarbonyl)-A'-is obutyl-W-(cis-4-methyIcyclohexyl)pyrroIidine-3-amine (45)-l-{[(35,4«)-1-/fir/-butyM-(4-chloropheny1)pyrrotidine-3-yncarbony]}-4-[(c w-4-methyIcyclohexyl)(tetrahydro-2//-pyran-4-ylcarbonyl)amino]-L-prolineami de (45)-l-{[(35,4/e)-l-fcrt-butyl-4-(214-difluorophenylpyrrolidine-3-yl]carbonyl}-4- f(4,4-dimethy1cyclohexyl)(3-thienylcarbonyl)amino]-L-prolineamide (45)-l-{[(35,4^)-l-/ert-butyI-4-(2,4-difluorophenyl)pyrroUdine-3-yllcarbonyl}-4 -f(4,4-dimethylcyclohexyl)(isobutyryl)aminol~N,iV:-dimelhyl-L-prolineaniide (45)-]-{f(35,4/f)-1-/er/-butyl-4-(4-chlorophenyl)pyrro!idine-3-yl]carbonyl}-4-[(4 ,4-dimethylcyclohexyl)(2,2rdimeUiylpropanoyI)amino]-W^-dimethyl-L-proline amide (45)-l-([(3S',4/?)-I-^rt-butyl-4-(2,4-difluorophenyl)pyiTolidine-3-yl]caibonyl}-4 -[(2,2,-dimethylpropanoyl)-<:i5-4-methylcycIohexyl)amino]-A',W-dimethyl-L-prol ineamide (45)-l-{r(35,4W)-l-rert-butyl-4-(2,4-difluoropheny])pyrrolidine-3-yllcarbonyl)-4 -[(4,4-dimethylcyclohexyI)(212,-dimethy[propanoyl)aminol-W-ethyl-L-proHneam ide (45)-1-{f(35,4i?)-1-^r/-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-yl]carbonyl}-4 -f(4,4-dimethylcyclohexyl)(2,2,-dimelhylpropaiioyl)aitiino]-W-ethyl-Af-methyl - L-prol ineamide (4S)-l-{[(35,4K)-l-fer/-butyM-(2,4-difluorophenyl)pyn-olidine-3-yllcarbonyl)-4 -r(4,4-dimelhylcyclohexyl)(2,2,-dimethylpropanoyl)amino]-A'-isopropyl-L-prolin eamide AH(3£5.V)-.'Hazelidine-1 -ylcarbonyl)-1 - [ \(3S,4R)-1 -^r/-bulyM-(2,4-difluoroph enyl)pyrro)idine-3-yl]carbonyl} pyrrol idine-3-yl]-A'-(4,4-dimethyIcyclohexyl)-2,2 -dimethylpropaneamide (4S)-l-{|(3.9,4ff)-l-^rt-butyM-(2,4-difluorophenyI)pyrrolidine-3-yIlcarbonyl}-4 -[(2,5-dihydrofuran-3-ylcarbonyl)(4,4-dimetliy!cyclohexyl)amiiio]-A',A'-dimelhy I-L-prolineamide (45)1- {[(35,4/?)-1 -/ert-butyl-4-(4-chlorophenyl)pyrrolidine-3-yllcarbonyl J-4-[(4 ,4-dimethyicyc!ohexyl)(3-hydroxy-2,2,-dimethylpropanoyI)ami no] -N,N-d\ methyl -L-prolineamide (45)-K(r(3>S'14K)-l-/ert-butyl-4-(2,4-difluorophenyl)pyiTolidine-3-yl]carbonyl|-4 -[(4,4-dirnelIiylcyclohexyI)[(2S)-letrdliydrofuran-2-ylcarbonyIlamino]-A7,A'-dimet hyl-L-prolineamide (45)-l-{r(3i',4K)-l-/ert-butyM-(2,4-difluorophenyl)pyrTolidine-3-yIlcarbonyl}-4 -[(4,4-difluorocyclohexyl)(3-hydroxy-2,2,-dimethylpropanoyl)ainmo]-A'JV-dimel hyl-L-prolineamide (45)-l -{[(35,4/?)-1 -/ert-butyl-4-(2,4-dinuorophenyl)pyrrotidine-3-yl]caibonyl }-4 -f(4,4-dimethylcyclohexyl)(3-hydroxy-2,2,-dimelhylpropanoyl)amino]-A'-ethyl-A' -methyl-L-prolineamide (45)-1 - {f (35,4V?)-1 -/ert-butyl-4-(4-ch!nrophenyl)pyrrolidine-3-yl]carbonyI) -4-[(4 ,4-dimethylcyclohexyl)(3-furoyl)aminol-A/A-dimethyl-L-prolineamide (45)1- {[(35,4/?)-1 -rert-butyl-4-(2,4-difluoropheny])pyrrolidine-3-yllcarbonyl) -4 -[(4,4-dimethylcyclohexylX3-ruroyl)aniino]-Af-ethyl-//-methy1-L-pnjlineamide 7V-[(35)-1 - {[(35,4/?)-1 -rert-butyM-(4-chlorophenyl)pyrro]idine-3-yllcarbonyl Jpy rrolidine-3-yll-A'-[(4,4-difluorocyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)a mino]-ALethyl-A/-methyl-L-prolineamidc (45)-] - {[(35,4/?)-1 -(er/-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-yl]carbonyl} -4 -[(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-A'-ethyl-W -methyl-L-proIineamide (45)-l-{[(314-methylcyclohexylaminol-A'-me thyl-L-prolineamide /V-f(35,55)-l-{f(35,4/?>l-/«rt-butyl-4-(4-chlorophenyl)pynrolidine-3-yllcarbonyl }-5-{[ethyl(melhyl)aminolcarbonyl)pyrrolidine-3-yl]-A'-(4,4-dimethylcyclohexyI )-2,2-dimethylpropaneamide A'-|(31V,.S,S'--l-(f(3lV,4/?)-1-/crr-bi][yl-4-(4-chlorophenyI)pyn-olidine-3-yncarbonyI) -5-(pyrrolidiiic-NyIcarbonyl)pyrrolidine-3-y]]-/V-(4,4-dinuorocyclobexyl)-2,2-di melhylpropaneamide (45)1 -{f(35,4/?)-1 -/ert-butyl^-(4-chlorophenyI)pyiTo]idine-3-yl]carbonyl }-l-/V- elhyI-A'-melhyl-4-{spirof2,5]Qct-6-ylf(2S)-tetrahydrofuraii-2-yIcarbonynamino|-L-prolineamide A,4(35,55-l-{[(35,4/?)-1-rer/-buly]-4^(4-chlorophenyl)pyrro]idinc^3-yI]carbonyl} -5-(morphoIine-4-ylcarbonyl)pyrTo]idine-3-yl]'A'-(4,4-dimelhyIcycIohexyl)aceta mide (45)-] - [ [(35,4tf)-1 -/ert-butyl-4-(4-chloropbenyl)pyrroIidine-3-yl]carbonyl} -4-[(4 ,4-d imethylcyclohexy 1 )r(2R )-tetrahydroftjraii-2-ylcarbony I ]amino'I-W-ethyl-A'-me thyl-L-prolineamide (45)-l-[[(35,4R)-l-(ert-butyM-(4-chIorophenyl)pyrro]idine-3-yncarbonyl}-4-[(4 ,4-dimethyIcyclohexyl)(3-hydroxy-2,2,-dimemylpropanoy0ainino]-N-ethy1-L-pr olineamide (45)-l-{f(35,4^)-l-/ert-butyl-4-(4-chlorophenyI)pyrrolidine-3-y]lcarbonyl}^-[(4 ,4-dimelhylcycIohexylX2,2,-dimethylpropanoyl)amino]-A'-phenyI-L-prolineamid e (2S)-N-[(3S)-1 - {R35,4tf)-1 -te^butyM-(4-chlorophenyl)pyrrolidine-3-yl]carbon yl}pyrrolidine-3-yll-A'-(4,4-dimefhylcyciohexyl)tetrahydrofuran-2-carboxamide N-[(3S)-1 - {[(35,4/?)- l-/ert-butyl-4-(4-chlorophenyl)pyrroIidine-3-yl]carbony] }py rrolidine-3-yll-2-methyl-A'-rcw-4-(trifluoromethyl)cyclohexyl]propaneainide QS)-N-\(3S)-1 - ([(35,4* )-I -fc>rf-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-y]]car bonyl}pyrTolidine-3-yl]-W-(4,4-dimethylcyclohexyI)tetrahydrofuran-2-carboxami de W-[(35)-l-[r(35,4K)-l-/m-butyl-4-(2,4-difluorophenyI)pyiroIidme-3-yI]carboiiyl |pyrrolidine-3-yll-W-(4,4-dimethy]cyclohexyl)tetrahydrofuran-3-carboxamide W-[(35)-l-{f(35,4i?)-l-fcrt-buty!-4-(2I4-difluorophenyl)pyn-alidine-3-yl]carbonyl }pyrrolidine-3-yn-A/-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanea mide N-[QS)-1 - {f (35,4/?)-1 -tert-butyM-(4-ch1orophenyl)pyrrolidine-3-yl]carbonyI} py rrolidine-3-yl]A''Cycloheptyl-3-hydroxy-2,2-diinethylpropaneamide (^-l-IKSS^^-l-tert-butyM^-chlorophenyOpyrrolidine-S-yllcarbonylJ^-lt 4,4-dimethylcyclohexyl)r(metbylsulfonyl)amino}-A'-ethyl-/V-methyl-L-prolinea mide (3S)-l-{f(3S,4j?)-1-fcrf-butyM-(4-chlorophenyI)pyrTolidme-3-yncarbonyl}-A'-(4 ,4-dimethy!cyclohexyl)-A/-3-fiiiylpyrrolidine3-amine N-r(3.S,,S.9)-l-{[(35,4/?)-l-^rt-butyI-4-(4-chlorophenyl)pyrro]idine-3-yncarbonyl }-5-(4,5-dihydro-l,3-oxa7ole-2-yl)pyrmIidine-3-yl]-W-(4J4-dimethy]cycIohexyl}- 2,2-dimethyIpropaneamide W-[(35,5^-l-{K3S,4«>l-tert-bulyl-4-(4-chlorophenyl)pyrrolidine-3-yl]cart»nyl }-5-[(dimethylamino)carbonothionynpyrrolidine-3-yl)-A'-(4,4-dimethyIcyclohex yl)-2-methylpropaneamide A'-f(3i',5K)-l-i[(35,4^)-1-^^bulyl-4-(2,4-difluorophenyI)pyrrolidine~3-yl]carbo nyI}-5-(l,3-thia7ole'2-y0pyrrolidine-3-yl]-W-(4,4-dimethyIcyc]ohexyI)-2,2-dime thylpropaneamide /^[(S^SSJ-l-tfO^^-l-fcrt-bulyl^^-chlorophenyOpyrrolidine^-yllcarbony] )-5-(hydroxymethyl)pyrrolidine-3-yll-W-(4,4-dimethy1cyclohexyl)-2,2-dimethyIp ropaneamide /V-[(35,,55)-l-{[(35,4/?)-l-ren-butyl-4-(4-chloropheny1)pynrolidiiie-3-yncarbony] }-5-methylpyrrolidine-3-yl]-A'-(4,4-dimethylcyclohexyl)-2,2-diinethylpropaneain ide W-{(35,5.S)-l-{[(35,4W)-l-rm-butyl-4-(2,4-difliiorophenyl)pyrTo1idine-3-yl]carix) nyI]-5-[(E)-(hydroxyimino)melhyllpyrroIidine-3-yl}-Af-(4,4-diniethylcycIohexyl )-2,2-dimethy[propaneamide W-[(35,55)-5-(aniinoethyl)-l-{f(3S,4ff)-l-lert-butyl-4-(2,4-difluorophenyl)pyrroli dine-3-yl]caTtoonyl}pyrrolidine-3-yn-A'-(4,4-diniethylcyc]ohexyl)-2,2-dimethylpr opaneamide W-r(35,55>5-r(acetylamino)melhyI]-l-(r(35,4ff)-l-/ert-butyM-(2,4-dichlorophe nyl)pyrrolidine-3-y11carbonyIJpyiro1idine-3-yl]-W-(4,4-dimethy]cyclohexyl)-2,2- dimethylpropaneamide A'-[(35,55)-l-{[(31S',4^)-l-/ert-butyl-4-(2,4-dich]orophenyl)pyn:olidine-3-yllcarbo nyIJ-5-f(dimelhylamino)methyl]pyrrolidine-3-yl}-]-A'-(4,4-dimethylcyclohexyl)- 2,2-dimethylpropaneamide N-[(3S,5S)-1- {[(35,4fi> 1 -/ert-butyI-4-(2,4-difluorophenyl)pyrrolidine-3-yl]carbo nyl} -5-cyanopyrrolidine-3-yl] -2,2-di methyl-W-(cis-4-methy lcyclohexyl)propanea mide W-r(35,5/e)-5-acetyl-l-{f(3S,4/f)-l-/ert-butyl-4-(4-chlorophenyl)pyrToIidine-3-yI] carbonyl}pyrTOlidine-3-y]l-/^-(4,4-dimethylcyclohexyl)-2,2-dimethylpropaiieami de N-[(5S)-1 - (r(3S,4ff)-1 -rert-butyl-4-(4-chlorophenyl}pyrrolidine-3-yllcarbonyI} -5 -(l-hydroxymethyl)pyn-olidine-3-yll-W-(4,4-dimethylcyc1ohexyl)-2,2-dimethylpr opaneamide (45)^-facetyt(4,4-dimethy]cyclohexyl)ammo]-A^-(2-aminoelhyI)-l-{f(35,4K)-l-r ert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-yl]carbonyl}-L-prolineamide merhy](4.9)-1-{((3.9,4^)-1-^rt-butyl-4-(4-ch1orophenyl)pyiTolidme-3-yncarbonyl }-4-|(4,4-dimethylcyc!ohexyfK2,2-dimethy]propanoyl)amino]-I,-prolinate (4A>l-{ f(3.V,4W)-l-/er/-biityl-4-(4-c!ilorophcnyl)pyiTolidine-3-yl]carbonyl}-4-f(4 ,4-dimethylcycIoliexyI)(2,2'dimelhylpropanoyll)ainino]-L-proline A,-f(3i',5^)-5-(aminocarbothionyl-l-(((35,4fi)-l-fert-butyl-4-(2,4-difluorophenyl )pyrrolidine-3-yl]carbonyl)pyrrolidiiic-3-y]]-A'-(4,4-dimethyIcyc]ohexy])-2,2-di melhylpropaneaniide A'-f(3515/f>l-{f(35,4^)-l-/ert-butyI-4-(2,4-difluorophenyl)pyrrolidiiie-3-yl]carb onyl}-5-f(dimethylamino)carbonoIhionynpyrrolidine-3-yl}-/V-(4,4-diniethylcycl ohexyl)-2,2-dimethylpropaneamidc W-f(35,5/;>]-{[(35,4ff)-l-fert4jutyl-4-(2,4-difluoTOpheny])pyiToIidine-3-yl]carbo nyl}-5-propionylpyrroIidine-3-yl]-A'-(4,4-dimethy]cyclohexyl)-2,2-dimethylprop aneamide A'-[(35,55'>l-{[(3S,4^)-l-Krt-butyl-4-(4-chIorophenyl)pyrrolidine-3-yl]carbonyl }-5-propionylpyiTolidine-3-yl]-Ar-(4,4-difluorocyclohexy1)-2,2-dimelhylpropanea mide N-[(3S)-l-fl(3S,4R)4-tert-butyl-4-(4-chlorophenyl)pynoIidiTie-3-yl]caibonyl}py rroIidine-3-yl]-A'-(4,4-dimeUiylcyclohexyl)-2,2-dimelhylnialonan]ide W-[(3lS)-l-{f(3S,4^)-l-^rt-buty]-4-(4-chlorophenyl)pyrrolidine-3-yI]carbonyl}py iroIidine-3-yn-/V-(4,4-dimethylcyclohexyl)-3-methoxy-2,2-dimethy[propaneaniid e (3ZT)-A'-f(35)-l-{r(35',4^)-l-^rr-butyl-4-(4-chloropheny])pyrroHdine-3-yl]carbon y1}pyrro1idine-3-yIl-//-(4,4-dimethylcyclohexyI)-3-(hydroxyimmo)-2,2-dimethyl propaneamide //-[(3.ST|-l-{[(35,4^)-l-fcrt-butyl-4-(4-ch1oropheny0pyrrolidine-3-yl]carbonyI}py rrolidme-3-yl]-Af-(4)4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylbutaneamide A'-f(35)-l-{[(3S,4J?)-l-(ert-butyI-4-(4-chlorophenyI)pyrrolidine-3-yl]carbonyl}py iroIidiiie-3-yl]-A'-(4,4-dimelhylcyclohexyl)-2,2-diinethyI-3-oxobutaneamide W-[(35)-l-{[(3S,4W)-l-fert-butyl-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}py rTolidine-3-yl]^-(4,4-dimethyicyclohexyl)-3-hydroxy-2,2,3-trimethylbutaneami de A'-[(35)-l-{[(35,47;)-l-fert-butyl-4-(4-chlorophenyl)pyrTolidine-3-y]]carbonyl}py rTolidine-3-yl]-A'-(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethylpropaneamide //-[(3^-l-{f(35,4ff)-l-/ert-butyl'4-(4-chlorophenyl)pyrrolidiiie-3-yI]carbonyl}py rro1idine-3-yl]-A'-(4,4-dimethylcycIohexyl)-3,3-dif|lloro-2.2-din!ethylpropaneaini de A'-[(31?)'I-{[(35,4/?)-l-fert-butyl-4-(4-chtorophenyl)pyrTolidine-3-yncarbonyl}py rrolidine-3-yll-A'-[(4,4-difluorocyclohexy))(3-methoxy-2,2-dimethylpropanoyl)a minol-ZZ-ethyl-A'-Tnethyl-L-proIineamide (4.V)-4-[(3-amino-2,2-dime[fiyfpropaiioyl)(4,4-dimelhylcyclohexyl)ainiiio]-l-([(3 5,4W)-l-tert-buty]-4-(2,4-difluoropheny])pynoIidine-3-yllcartK)nyl}-W^-dimeth yl-L-prol ineamide (4,S,)-l-{|"(3S',4«)-1-^rt-bulyl-4-(4-chlorophenyl)pyiTolidinc-3-yl]carbonyl}^}-{f 3-(dimelhylamin<))-2,2-dimetbylpropanoyll(4,4-dimethylcyc[ohexyl)amino}-A',A' -d i met hy 1 -I ,-prol ineamide A'-{(35,5^)-l-{f(35,4/f)-l-fcrt-butyI-4-(4^;hlorophenyl)pyrTolidine-3-yl]carbonyf }-5-E(dimelhylaniino)cart)onyl]pyrrolidine-3-yI)-Af-(4,4-dimelhylcyclohexyl)-2,2 -d imethy Imalonamide 5-(3-{ [(35,55)-1 - {[(35,4*)- i -te^butyI-4-(2,4-difluorophenyl)pyrrolidine-3-yI]c arbonylJ-5-{[ethyl(metiiyl)amino]carbonyl}pyiToIidin&-3-yl](4,4-diiTiethylcycIoh exyl)amino]-2,2-dimethyI-3-oxopropyI)ethanethioate (45)-l-{[(35,4R)-l-fert-buty!-4-(2,4-difluorophenyI)pyiToIidine-3-y!]cari>onyI}-4 '[(4,4-dimethylcyclohexyl)(3-mercaplo-2,2-dimethyIpropanoyl)amino]-A'-ethyl- W-methyl-L-prol ineamide (45)-l-{[(35,4R)-l-feri-butyM-(4-chlnrophenyl)pyiToIidine-3-yI]caiboTiyn^-[(4 ,4-dinuorocyclohexyl)(3-melhoxy-2,2,-dimelhylpropaiioyl)amino]-^V,A'-dimethyl -L-prolineamide (45)-l-([(35,4ff)-1-Krt-bulyl-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl)-4-[(4 ,4-difluorocyclohexyl)(3-ethoxy-2,2,-dimethylpropanoyl)amino]-W-ethyl-A'-meth yl-L-prol ineamide (4S)-l-{[(35,4fi)-1-ten-butyl-4-(4-chlorophenyI)pyn-olidine-3-yl]carbonyIJ-4-[(2 ,4-difluorophenyl)(2,2-dimethylpropanoyI)amino]-M^/-dimethyl-L-proIineamide (45)-l-([(35,4ff)-l-(ert-butyM-(4-chlorophenyl)pyrrolidine-3-y]]carbonylJ^l-[(2 ,2,-dimethylpropanoyJ) (4-methoxyphenyl)amino]- N,N- dimethyl-L-prolineamide (45)-l-([(3S,4K)-l-tert-butyl-4-(4-chlorophenyl)pyfroIidine-3-yllcarbonyl}^-{( 2,2,-dimethylpropanoy1)[4-(trifluoromethyl)phenyl]amino}-A^,/l/-dimethyl-L-prol ineamide (45)-l-{[(35,4fi)-l-rcr^butyl-4-(4-chloropheny1)pyn-o]idine-3-yllcarbonyI]-4-r(2 ,2,-dimethy!propanoy1)(4-methylphenyl)amino]-A',A'-dimethy1-L-pro]!neamide (45)-l-{[(35,4^)-l-(ert-butyl-4-(4-chlorophenyl)pyrTolidine-3-yl]carbonyl|^-{( 2,4'difluorophenyi)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-A'-A'-dimethyl-L- prolineamide (45)-l-{[(35)4^)_4-(4H:hlorophenyI)pyrrolidine-3-yl]carbony]}-4-[(4,4-dimelhyI cyclohexyl)(2,2-dimethylpropanoyl)amino]-M^dimethyl-L-prolineamide (25)-A'-f(35)-l-{[(35,4K)-4-(4-chloropheny])pyrrolidine-3-yl]carbonyl}pyrrolidin e-3-yl]-A'-(4,4-di methyl eye I ohexyl)telrahydrofuran-2-carbox amide A'-[(3,S')-l-{|(35,4^)-4-(4-chlomphenyl)pyn-olidine-3-yncarbonyl}pyrTolidiiie-3-y1>N-(m-4-methylcyc1ohexyl)3-ftiramide W4(3S)-l-{r(3,S,4/0^<4^Iiloropheiiyl)pyiTOlidine-3-yllcarbony1}pyrrolidine-3- yIVA'-(c/>4-methylcycIohexyl)-2,5-d)hydrofuran-3-carboxajnide (AS)-N-\ '{f(31S',4A>)-4-(4-chIoropheiiyl)pyrTolidine-3-yI]carbonyI}-4-[(2,2,-dimet hylpropanoyl)(a"s4-methyfcyclohexyOamino]-D-proliiieaTmde N-[(3S)-1 - {f(35,4fl)-4-(4-chIorophenyl)pyrrolidine-3-yIlcarbonyl} -5-( 1 -hydroxy methyI)pyrrolidine-3-y]]-A'-(4,4-diniethylcyclohexyI)-2,2-dimelhyIprop3neamide (45)-l-{f(3.V,4fi)-l-(aminocarbonyI)-4-(4-chloroph(;nyl)pyrToIidine-3-yncarbony ]]-4-[(4,4-dimethylcyclohcxy[)(2,2-dimethylprQpanoyl)amino]'W,W-dimethyl-L- prolineamide (3^,4^-3-(4-chIoraphenyl)-4-({(35)-3-[(4,4-diniethykyc]ohexyl)(3-hydroxy-2,2 -dimethylpropanoyl)amino)pyrrolidine-l'yl}cart)onyl)pyrrolidine-l-carboxamide (3ff,45)-3-(4-chlorophenyI)-4-({(35)-3-f(4,4-dimelhyIcyclohexy])(2,2-dimethylpr opanoyl)amino]pyiTolidine-l-yl}carbonyl)pyiTolidine-1-carboxamide (45)-l-({[(3S,4^)-4-(4-chIorophenyl)-l-(elhylainino)carbonyl]pyn-olidiiie-3-yl}c arbonyl)-4-f(4,4-dimethylcycIohexyl)(2,2-dimethylpropanoyl)amino]-A',A'-dimel hyl-L-proIineamide N-r(3S)-I-{[(3S,4R)-4-(4chloropheiiy[)-l-[(ethylamino)carboiiothiony[]pyrrolid ine-3-yl]carbonyl}pyiToIidme-3-yl]-N-(4,4-difluorocycIohexyl)-3-hydroxy-2,2-di methylpropaneamide (3^,45)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyc1ohexyl)(3-hydroxy-2,2 -dimelhylpropanoyl)amino]pyiTo]idine-1 -yl }carix}nyl)-A'-ethylpyrrolidine-1 -carb oxamide (3/?,45)-3-(4-chlomphenyl)-4-({(3S)-3-[(4,4-dimethy]cyclohexyI)(2,2-dimelhyIpr opajioyOaniinojpyrrolidine-l-yllcarbonyO-^-ethylpyfrolidine-l-caitMjxaniide (3ff,45)-3-(4-chloropheny1)-4-(({35)-3-[(2,4-difluo!ophenyl)(2,2-dimethylpropan oyl)amino]pyrToHdine-l-yIIcarbonyl)-Af-ethy]pyrroIidme'l-carboxamide (3«,45)-3-(4-chlornphenyl)-A'-ethyl-4-({(35)-3-[isobutyryI(cK-4-methylcycIohex yI)amino]pyrroIidine"I-yl}carbonyl)-Ar-melhylpyrrolidine-l-carboxamide (4S)-1 -(t [(3S,4R)-1 -acetyl-4-(4'Chlorophenyl)pyiTolidme-3-yl]carbonyl) -4-[(4,4-dimeUiylcyc1ohexyl)(2,2-dimethylpropanoyl)amino]-/^,^-dimethyl-L-pro1ineami de Af-f(35)-l-{f(35,4/f)-4-(4-chlorophenyl)-l-isobutyrylpyrroHdme-3-y]]carbonyl}p yrrolidine-3-yl]-iV-(4J4-dimelhylcyclohexyl)-2J2-dimethylpropaneamide (4^)4-{[(3^,4R)-4-(4-chlorophenyl)-l-isobutyry]pyrrolidine-3-yl]carbonyl}-4-rC 4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyI)aminol-L-prolineamide (4.?)-I-({r(3.5,4ff)-4-(4-chlorophenyI)1-cyclopropyipyTTolidine'3-yl]carbonylH- r(4!4-dimelhyIcyc]ohcxyl)(?.,2-dimelhylpropanoyl)aini!iol-A',W-dimethyl-L-proIi neamide (45>!^[(3S,4^)-4-(4-chlorophenyl)-l-(tetrahydro-2//-pyran^l-yl)pyrrolidine-3-yllcarbony]}-4-{(4,4-dimelhy]cycIohexy[)f(ZS)-tetrahydrofuran-2-yIcarbonyIlam inoJ-A'-cUiyl-A'-melhyl-L-prolineaTriide A'-[(31S>l-{f(35,4/?)-4-(4-chIoropheny])-l-(2,2,2-trifluoroethyl)pyn-oIidine-3-yl]c arbonyl}pyrrolidine-3-yll-A'-(4,4-dimethylcycIohexyI)-2,2-dimethylpropaiicamid e (4i)-l-([(3S,4fi)-4-(2,4-difiuorophenyI)-l-isobuiyryIpyiTolidine-3-yI]carbonyl)- 4-f(4,4-dimethylcyclobexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-A'^/-dim ethyl-L-prol ineam ide (45)-l-{[(35,4fi)-4-(4-chloropbenyl)-l-cyclobutyIpyrrolidine-3-yllcarbonyl}-4-[( 4,4-dimethylcycIohexyl)(3'hydroxy-2,2-dimethylpropanoyl)amino]-A^,M-dimethy 1-L-prol ineamide (45)-l-{[(35,4i?)-]-cycIopenlyl-4-(2,4-difluorophenyl)pyrTolidine-3-yl]carbonyl} -4-[(4,4-dimethylcyclohexyl)(2,2-diinethylpropanoyI)aminol-Af,A/Ldimethyl-L-pr olineamide At{(35,55)-l-(f(35,4iO^(2,4^ifluorophenyl)-l-isobutyiy1pym)Hdiiie-3-yncaib onyl}-5-r(dimediyIamino)cari>onothio]pyrrolidine'3-yl}-AL(4,4-dimeU:ytcyclohe xyl)-2,2-dimethylpropaneamide W-[(3S)-l-{f(3S,4R>4^(4-chlorophenyl)-l-(methyIsulfonyI)pyiroIidine-3-y11caib onyl]pyrrolidine-3-yll-2-methyl-N-(cis-4-methylcyclohexyl)propaneamide (3R,4S>-3-(4-chloropheny1)-4-({(3S)-3-[(cis-4-methylcyclohexyIX2-methylpropa noyl)aminolpyrroIidine-1 -yl }carbonyl)-N-(2,2,2-trifluoroethyl)pyrroIidine-1 -car boxamide (3/e,45)-3-(4-chloropheny!)'4-({(31V)-3-f(4,4-diroethylcyclohexyI)(2,2-dimethylpr opanoy1)amino]pyrrolidine-1 -yl ]carbonyI)-AH2,2,2-trifluoromethyl)pyrrolidine-1-carboxamide methyI(3R,4S)-3-(4-chlorophenyI)-4-({(3S)-3-[(4,4-dimethy1cyclohexyl}(3-hydr oxy-2,2-dimethy[propanoyl)amino]pyirolidine-l-yl}caibonyl)pyrrolidine-l-carb oxylate N-[(3S)-1 - {f(3S,4R)-l -famino(imino)methyl]^-(4-ch1orophenyl)pyrrolidiiie-3-yl ]carbonyl}pyrrolidine-3-y[l'2-methyl-N-(cis-4-methylcyclohexyl)propaneamide //-[(3S)-l-()(3S,4R)-4-(4-chlorophenyl)-l-[(ethyIamJnoXiniino)methyllpyrrolidi ne^3-yl}carboiiy])pyrrolidine-3-yl]2-methyl-N-(cis-4-methyIcyclohexyl)propane amide W-[(3S)-I-{[(3S,4R)-l-[(acetylamino)(imino)methy]]-4-(4-chIorophenyl)pyrTo]id ine-3'yncarbonyl}pytTolidine-3-yll-2-methyl-N-(cis-4-inethy1cyc1ohexyl)propan eamide A'-r(3S)-]-(j;(3.S,4R)-4-(4-chIorophenyl)-Kphenylpyrrolidine-3-yncarbonyl}pyn- olidinc-3-yll-N-(4,4-dimethylcyclohexyl)-propancamide A'-[(35)-l-{r(3i',4^)-4-(4-chlorophenyl)-l-pyridine-2-ylpyrrolidine-3-yncarbonyl }pyrrolidiiie-3-yll-2,2'dimethyl-A'-(cis-4-nieihylcyclohexyI)propaneamide N-K3S)-l-{K3S,4R)-4-C4-chlorophenyl)-l-(4,5-dihydro-U/-imida7.ole-2-yl)pyiTo Iidine-3-yl]carfaonyl}pyrrolJdine-3-yl]-A'-(4,4'dimethyIcyc1ohexy1)-3-hydroxy-2, 2-dimethylpropaneamide N-f(3S)-l-{[(3S,4R)-4-(4-ch1oropheny])-l-(4,5-dihydro-lH-imidazo1e~2-yl)pyn-o lidine-3-yl]cafbonyl}pyrrolidine-3-yIl-N-(4,4-dimediylcycIohexyl)-3-hydroxy-2, 2-dimethylpropaneamide, pharmaceutical ly acceptable salt or isomer thereof. i 5] A melanocortin receptor agonistic composition comprising the compound of formula 1 as defined in Claim 1, pharmaceutical ly acceptable salt or isomer thereof as active ingredient, together with pharmaceutically acceptable carrier. 16] The composition of claim 15 for the prevention and treatment of obesity. 17] The composition of claim 15 for the prevention and treatment of diabetes. [ 8] The composition of claim 15 for the prevention and treatment of inflammation. [9] The composition of claim 15 for the prevention and treatment of erectile dysfunction.