JP4265993B2 - Novel carboxylic acid derivatives - Google Patents

Description

  The present invention provides a general formula

(Wherein R ¹ is a substituted alkyl group, a substituted alkenyl group, a substituted amino group, a substituted alkoxy group, a substituted alkylthio group, a substituted carbamoyl group, a substituted sulfonamide group or a substituted amide group, and ring A is saturated with 5 to 7 carbon atoms. A cyclic alkyl group or a saturated heterocyclic group having 3 to 6 carbon atoms containing a hetero atom, R ² is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic hydrocarbon group, or a substituted or unsubstituted heterocyclic group; A cyclic group, R ³ is a hydrogen atom, a group represented by the general formula R ⁴ O—, or a group represented by the general formula R ⁵ (R ⁶ ) N—, wherein R ⁴ is a hydrogen atom, substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, R ⁵ and R ⁶ are the same or different hydrogen atom, a substituted or unsubstituted alkyl group Aromatic substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted heterocyclic group.) Relates to useful carboxylic acid derivatives for the production of cyclic amide derivative represented by the. In addition to osteoporosis, hypercalcemia, Paget's disease and other bone diseases, this cyclic amide derivative and a medicine containing this cyclic amide derivative as an active ingredient are used to treat arthritis and rheumatism caused by increased bone resorption. Useful as a drug or prophylactic.

  With the rapid progress of the aging social phenomenon in recent years, the incidence of senile diseases has increased with age and has become a major social problem. In particular, the number of bone disease patients has been steadily increasing. Among them, the number of osteoporosis patients is estimated to be 5 million in 1990 and 10 million in 2000. In addition, more than 80,000 cases of femoral fractures annually are the second leading cause of “bedridden elderly” and the number is expected to increase to 200,000 in 2000.

  On the other hand, osteoporosis in postmenopausal women is also a serious problem, and osteoporosis is recognized in about 13% of women over 40 years old, and also in about 60% of women over 60 years old. In postmenopausal women, increased bone resorption caused by hormonal imbalance and aging is closely related to the onset and progression of bone disease. Inhibitors are used. However, currently used calcitonin preparations, estrogen preparations, vitamin K preparations, bisphosphonate preparations and other drugs having a bone resorption inhibitory action have problems in terms of their therapeutic effects, sustainability, side effects, compliance, etc. Development of a bone resorption inhibitor that can be a more effective therapeutic agent or preventive agent for osteoporosis is desired.

  Bone is a vast store of calcium in vivo, calcium in bone is in equilibrium with calcium in blood, and the transfer of calcium from bone to blood, or from blood to bone, is always occurring, Such movement of calcium between bone and blood is carried out by a dynamic balance between bone formation and bone resorption.

  In the process of bone resorption, activated osteoclasts elute bone minerals such as calcium and simultaneously decompose bone organic substances such as collagen. Recent studies have shown that cysteine proteases secreted from osteoclasts are involved in bone resorption by degrading collagen.

  In lysosomes of osteoclasts, cysteine proteases such as cathepsin B, cathepsin H, cathepsin L, and cathepsin S are present, and it has been reported that inhibitors against these cysteine proteases have an effect of inhibiting bone resorption (for example, (Refer nonpatent literature 1-3 and patent literature 1-4.).

  In addition, recently, human cathepsin K localized in osteoclasts has been isolated and found to be expressed more in osteoclasts than other cathepsins (see, for example, Non-Patent Documents 4 and 5). ). Furthermore, it has been found that the cathepsin K gene is mutated in dwarfism patients who have abnormal bone resorption (see, for example, Non-Patent Document 6). Thus, cathepsin K has attracted attention as a major cysteine protease involved in bone resorption, and expectations for a cathepsin K inhibitor as a bone resorption inhibitor are increasing.

  Until now, as a compound which has cathepsin K inhibitory action, an aldehyde derivative or an epoxy succinic acid derivative (for example, refer nonpatent literature 7 and 8), a vinyl sulfonic acid derivative (for example, refer nonpatent literature 9 and 10). However, these derivatives have low selectivity and are known to strongly inhibit not only cathepsin K but also cysteine proteases such as cathepsin B, cathepsin H, cathepsin L, cathepsin S, and calpain. (For example, refer nonpatent literature 11-14.).

  Furthermore, as cathepsin K is attracting attention as described above, studies such as X-ray crystallographic analysis of cathepsin K and an inhibitor (for example, see Non-Patent Documents 9 and 15) become active, and cathepsin is selectively performed. Compounds having a K inhibitory action (see, for example, Non-Patent Documents 16-18 and Patent Document 5) are also known. Also, the catalytic active site of cathepsin K has been clarified, and a method for inhibiting cathepsin K using a compound that interacts with this active site has been disclosed (for example, see Patent Document 6).

“Biochem. J.” 192, 365 (1993) "Biochem. Biophys. Res. Commun." 125, 441 (1984) "FEBS Lett." 321, 247 (1993) "Biochem. Biophys. Res. Commun." 206, 89 (1995) "J. Biol. Chem." 271, 12511 (1996) `` Science '' 273, 1236 (1997) “J. Biol. Chem.” 271, 2126 (1996) "Biol. Phrm. Bull." 19, p. 1026 (1996) `` Nature Structural Biology '', p. 105 (1997) “J. Med. Chem.” 38, 3139 (1995) `` J. Enzyme Inhibition '', p. 13, 13 (1989) Biochem. Biophys. Res. Commun., 153, 1201 (1988) `` J. Biochem. '' 87, 39 (1980) `` J. Biochem. '' 88, 1805 (1980) `` Nature Stractural Biology '' 4, p. 109 (1997) "Proc. Natl. Acad. Sci. USA" 94, 14249 (1997) `` J. Am. Chem. Soc. '' 120, 9114 (1998) `` J. Med. Chem. '' 41, 3563 (1998) JP-A-8-92193 JP-A-8-41043 Japanese Patent Laid-Open No. 7-101924 Japanese Patent Application Laid-Open No. 5-155664 International Publication No. 98/01133 Pamphlet International Publication No. 97/16177 Pamphlet

  Thus, compounds that inhibit cathepsin K have attracted attention as bone resorption inhibitors, and many derivatives have been reported, but have not yet been put into practical use as therapeutic agents for metabolic bone diseases. Here, considering the characteristics desired as a therapeutic agent, it can include therapeutic effects, sustainability, safety, availability of oral administration, etc. It is particularly important to show an effect on administration.

  Accordingly, an object of the present invention is to provide a compound represented by the formula (I), which is a novel compound that exhibits potent and selective cathepsin K inhibitory action and can be an effective bone resorption inhibitor when administered orally. It is an object to provide a carboxylic acid derivative useful for the production thereof.

  As a result of intensive studies to develop a compound that exhibits selective cathepsin K inhibitory action and is effective even when administered orally, the present inventors have found that in the above general formula (I) having a non-natural amino acid structure not found in conventional inhibitors. The present inventors have found a cyclic amide derivative represented by the present invention and found a carboxylic acid derivative useful for the production of the cyclic amide derivative.

  That is, the present invention has the following formula:

It is related with the carboxylic acid derivative shown by these.

  The cyclic amide derivative represented by the general formula (I) showed a strong inhibitory action in the cathepsin K inhibitory activity measurement test, and was also shown to have high efficacy by oral administration.

  The cyclic amide derivative represented by the general formula (I) is, for example, a compound that can be produced according to the following reaction formula.

(Wherein A, R ¹ , R ² and R ³ are the same as above)

  (First Step) In this step, the cyclic carboxylic acid derivative represented by the general formula (II) and the amino alcohol derivative represented by the general formula (III) are reacted to form the general formula (IV). It is the process of manufacturing the alcohol derivative represented. The cyclic carboxylic acid derivative represented by the general formula (II), which is a raw material in this step, is a compound that can be easily produced from commercially available raw material compounds (see the following Reference Examples and Examples). The amino alcohol derivative represented by the general formula (III) can be produced from the corresponding amino aldehyde derivative according to the method described in J. Med. Chem., 37, 2918-2929 (1994). This aminoaldehyde derivative can be produced by a known method (Tetrahedron Lettrers, 33, 5029-5032 (1992); Chem. Pharm. Bull., 30, 1921-1924 (1982); Synthesis 1990, 1173-1176 1983, 676-678; Tetrahedron Letters, 33, 1347-1350 (1992); Chem. Rev., 89, 149-164 (1992)).

In the cyclic carboxylic acid derivative represented by the general formula (II), R ¹ represents a substituted alkyl group, a substituted alkenyl group, a substituted amino group, a substituted alkoxy group, a substituted alkylthio group, a substituted carbamoyl group, a substituted sulfonamido group or a substituted amide. Group, ring A represents a 5- to 7-membered saturated cyclic alkyl group or a 5- to 7-membered saturated heterocyclic group containing an oxygen atom, sulfur atom or nitrogen atom, and ring A may further have a substituent. Good.

The alkyl group of R ¹ may be any of a linear, branched or cyclic alkyl group having about 1 to 12 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, or a 1-methylethyl group. , Cyclopropyl group, n-butyl group, 2-methylpropyl group, 1-methylpropyl group, 1,1-dimethylethyl group, cyclobutyl group, n-pentyl group, 3-methylbutyl group, cyclopentyl group, 2,2- Dimethylpropyl group, 1-methylcyclobutyl group, cyclobutylmethyl group, n-hexyl group, 4-methylpentyl group, cyclohexyl group, 1-methylcyclopentyl group, cyclopentylmethyl group, (1-methylcyclobutyl) methyl group, n-heptyl group, 5-methylhexyl group, 4,4-dimethylpentyl group, cycloheptyl group, cyclohexylmethyl group, (1- Methylcyclopentyl) methyl group, n-octyl group, 6-methylheptyl group, 5,5-dimethylhexyl group, (1-methylcyclohexyl) methyl group, n-nonyl group, 7-methyloctyl group, 6,6-dimethyl Heptyl group, n-decyl group, 8-methylnonyl group, 7,7-dimethyloctyl group, n-undecyl group, 9-methyldecyl group, 8,8-dimethylnonyl group, n-dodecyl group, 10-methylundecyl group , 9,9-dimethyldecyl group and the like.

  Examples of the substituent for the alkyl group include, for example, a hydroxyl group, an oxo group, a halogen atom such as chlorine, bromine, iodine, and fluorine, a substituted or unsubstituted linear or branched chain having about 2 to 6 carbon atoms. Or a cyclic alkenyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, a nitro group, a substituted or unsubstituted amino group, a trifluoromethyl group, a substituted or unsubstituted sulfonyl group, Examples include substituted alkoxy groups, substituted alkylthio groups, substituted aryloxy groups, substituted arylthio groups, acyl groups, alkoxycarbonyl groups, substituted carbamoyl groups, mercapto groups, and cyano groups.

  Here, examples of the substituted or unsubstituted aromatic hydrocarbon group exemplified as the substituent of the alkyl group include a phenyl group, a methylphenyl group, a methoxyphenyl group, a nitrophenyl group, a fluorophenyl group, a chlorophenyl group, and a bromophenyl group. Examples of the substituted or unsubstituted heterocyclic group such as a group, 3,4-dimethoxyphenyl group, and 3,4-methylenedioxyphenyl group include tetrahydrofuran-2-yl group and 1,3-dioxolan-2-yl group Examples of substituted amino groups such as benzodioxolan-2-yl group, 1,3-dioxan-2-yl group, 3,4-dihydro-2H-pyran-6-yl group include methylamino group, N, N -Dimethylamino group, butylamino group, N, N-dibutylamino group, 2,2-dimethylethylamino group, cyclohexylamino group, Enylamino group, methylphenylamino group, fluorophenylamino group, chlorophenylamino group, nitrophenylamino group, N, N-diphenylamino group, naphthylamino group, 3,4-dimethoxyphenylamino group, N-methyl-N-phenyl Amino group, N-methyl-N-naphthylamino group, pyridylamino group, furylamino group, thienylamino group, quinolylamino group, isoquinolylamino group, phenylmethylamino group, fluorophenylmethylamino group, chlorophenylmethylamino group, nitro Examples thereof include a phenylmethylamino group, a naphthylmethylamino group, a 3,4-dimethoxyphenylmethylamino group, and a 3,4-methylenedioxyphenylmethylamino group.

  Examples of the substituted sulfonyl group include methylsulfonyl group, butylsulfonyl group, 2,2-dimethylethylsulfonyl group, cyclohexylsulfonyl group, phenylsulfonyl group, methylphenylsulfonyl group, fluorophenylsulfonyl group, chlorophenylsulfonyl group, and nitrophenyl. Sulfonyl group, naphthylsulfonyl group, 3,4-dimethoxyphenylsulfonyl group, 3,4-methylenedioxyphenylsulfonyl group, pyridylsulfonyl group, furylsulfonyl group, thienylsulfonyl group, quinolylsulfonyl group, isoquinolylsulfonyl group, Phenylmethylsulfonyl group, fluorophenylmethylsulfonyl group, chlorophenylmethylsulfonyl group, nitrophenylmethylsulfonyl group, naphthylmethylsulfonyl group, 3,4- Examples of substituted alkoxy groups such as methoxyphenylmethylsulfonyl group and 3,4-methylenedioxyphenylmethylsulfonyl group include methyloxy group, butyloxy group, 2,2-dimethylethyloxy group, cyclohexyloxy and the like, substituted aryloxy groups As, phenyloxy group, methylphenyloxy group, fluorophenyloxy group, chlorophenyloxy group, nitrophenyloxy group, naphthyloxy group, 3,4-dimethoxyphenyloxy group, 3,4-methylenedioxyphenyloxy group, Pyridyloxy, furyloxy, thienyloxy, quinolyloxy, isoquinolyloxy, nitrophenylmethyloxy, naphthylmethyloxy, 3,4-dimethoxyphenyloxy, 3,4-methylenedioxypheny It can be a methyl group and the like.

  Furthermore, examples of the substituted alkylthio group include a methylthio group, a butylthio group, a 2,2-dimethylethylthio group, and a cyclohexylthio group. Examples of the substituted arylthio group include a phenylthio group, a methylphenylthio group, a fluorophenylthio group, and a chlorophenyl group. Thio group, nitrophenylthio group, naphthylthio group, 3,4-dimethoxyphenylthio group, 3,4-methylenedioxyphenylthio group, pyridylthio group, furylthio group, thienylthio group, quinolylthio group, isoquinolylthio group, phenylmethylthio group, Fluorophenylmethylthio group, chlorophenylmethylthio group, nitrophenylmethylthio group, naphthylmethylthio group, 3,4-dimethoxyphenylmethylthio group, 3,4-methylenedioxyphenylmethylthio group, etc., substituted carbamo Examples of the group include N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, N-butylcarbamoyl group, N, N-dibutylcarbamoyl group, N- (2,2-dimethylethyl) carbamoyl group, and N-cyclohexyl. Carbamoyl group, N-phenylcarbamoyl group, N- (methylphenyl) carbamoyl group, N- (fluorophenyl) carbamoyl group, N- (chlorophenyl) carbamoyl group, N- (nitrophenyl) carbamoyl group, N, N-diphenylcarbamoyl Group, N-naphthylcarbamoyl group, N- (3,4-dimethoxyphenyl) carbamoyl group, N- (3,4-methylenedioxyphenyl) carbamoyl group, N-methyl-N-phenylcarbamoyl group, N-methyl- N-naphthylcarbamoyl group, N-naphthylcarba Yl group, N-pyridylcarbamoyl group, N-furylcarbamoyl group, N-thienylcarbamoyl group, N-quinolylcarbamoyl group, N-isoquinolylcarbamoyl group, N- (phenylmethyl) carbamoyl group, N- (fluorophenyl) Methyl) carbamoyl group, N- (chlorophenylmethyl) carbamoyl group, N- (nitrophenylmethyl) carbamoyl group, N- (naphthylmethyl) carbamoyl group, N- (3,4-dimethoxyphenylmethyl) carbamoyl group, N- ( And 3,4-methylenedioxyphenylmethyl) carbamoyl group.

The alkenyl group for R ¹ may be any of linear, branched or cyclic alkenyl groups having about 2 to 6 carbon atoms, such as 1-methyl-1-propenyl group, 1-methyl-2- Propenyl group, 2-methyl-2-propenyl group, ethenyl group, 1-methylethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 2-pentenyl group, 1-pentenyl group, Examples include 1,3-butanedienyl group, 1-hexenyl group, 2-hexenyl group, 1,3-pentadienyl group, 1,3-hexadienyl group and the like.

  Examples of the substituent for the alkenyl group include the same substituent as the substituent for the alkyl group.

The substituted amino group of R ¹ refers to a secondary amino group or a tertiary amino group substituted with various substituents, and these substituents include substituted or unsubstituted alkyl groups, substituted or Examples thereof include an unsubstituted alkenyl group, a substituted or unsubstituted aromatic hydrocarbon group, and a substituted or unsubstituted heterocyclic group.

Examples of the substituted or unsubstituted alkyl group and the substituted or unsubstituted alkenyl group include the same groups as those exemplified for R ¹ above. The substituted or unsubstituted aromatic hydrocarbon group is monocyclic or polycyclic, and further represents an aromatic hydrocarbon group which may have one or more various substituents on the ring. For example, phenyl group, methylphenyl group, dimethylphenyl group, methoxyphenyl group, 2,3-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 2,3-methylenedioxyphenyl Group, 3,4-methylenedioxyphenyl group, nitrophenyl group, dinitrophenyl group, chlorophenyl group, dichlorophenyl group, bromophenyl group, dibromophenyl group, iodophenyl group, fluorophenyl group, 2,3-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, trifluoromethylphenyl group, 3-phenyl Kishifeniru group, 4-phenoxyphenyl group, 4- (1-naphthoxy) phenyl group, 4-acetaminophenyl group, 1-naphthyl group, and 2-naphthyl group.

  Furthermore, the substituted or unsubstituted heterocyclic group is a 5-membered or 6-membered ring group containing at least one hetero atom such as a nitrogen atom, a sulfur atom, or an oxygen atom as a ring constituent atom. It may be condensed and may further have one or more substituents on the ring. Examples of the heterocyclic group include pyridyl group, furyl group, thienyl group, indolyl group, quinolyl group, isoquinolyl group, benzofuranyl group, benzothienyl group, imidazolyl group, benzimidazolyl group, thiazolyl group, oxazolyl group, pyrazolyl group, pyrimidyl group. Group, pyrimidinyl group, dioxanyl group, thiazolidinyl group, imidazolidinyl group, 2-oxotetrahydrofuran-3-yl group, benzothiazolyl group, quinazoline group, hexahydro-2-azenopin-3-yl group, morpholino group, thiamorpholino group, pyrrolidino group Piperidino group, piperazino group, perhydro-4-azepin-1-yl group, perhydro-4-azaazepin-1-yl group, 4-acetylpiperazino group, 4-methoxycarbonylpiperazino group, 4-ethoxycarbonyl Pipette Dino group, 4- (2-methyl-2-propyloxycarbonyl) piperazino group, 4-methylsulfonylpiperazino group, 4-methoxypiperidino group, 4-ethoxycarbonylpiperidino group, 4- (2- A methyl-2-propyloxycarbonyl) piperidino group, a 1-benzoyl-piperidin-4-yl group, and the like.

  The alkoxy group is an alkyl-substituted oxy group having an alkyl moiety of about 1 to 6 carbon atoms, such as a methoxy group, ethoxy group, n-propoxy group, 1-methylethoxy group, n-butoxy group, 2- Examples thereof include a methylpropoxy group, a 1-methylpropoxy group, a 2-methyl-2-propoxy group, an n-pentyloxy group, a 3-methylbutoxy group, an n-hexyloxy group, and a 4-methylpentoxy group.

  The substituted alkoxy group is an alkoxy group in which the alkoxy group is substituted with various substituents, and examples of the substituent include the same groups as the substituents on the alkyl group.

  The alkylthio group is an alkyl-substituted thio group having an alkyl portion of about 1 to 6 carbon atoms, such as a methylthio group, an ethylthio group, an n-propylthio group, a 1-methylethylthio group, an n-butylthio group, 2 -Methylpropylthio group, 1-methylpropylthio group, 2-methyl-2-propylthio group, n-pentylthio group, 3-methylbutylthio group, n-hexylthio group, 4-methylpentylthio group, etc. it can.

  The substituted alkylthio group is an alkylthio group in which the alkylthio group is substituted with various substituents, and examples of the substituent include the same groups as the substituents on the alkyl group.

The substituted carbamoyl group refers to a group represented by the formula R ⁷ —NHCO— in which various substituents are substituted on the nitrogen atom of the carbamoyl bond group, and the substituent R ⁷ substituted on the nitrogen atom is the above-mentioned substituent R ⁷ Substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted amino groups, substituted or unsubstituted aromatic hydrocarbon groups, substituted or unsubstituted heterocyclic groups, and the like. .

The substituted sulfonamide group refers to a group represented by the formula R ⁸ —SO ₂ NH— in which various substituents are substituted on the sulfur atom of the sulfonamide bonding group, and the substituent R substituted on the sulfur atom here. ⁸ includes the above-described substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted amino group, substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted heterocyclic group, and the like. Can be mentioned.

The substituted amide group refers to a group represented by the formula R ⁹ —CONH— in which various substituents are substituted on the carbon atom of the amide bond group. Here, the substituent R ⁹ substituted on the carbon atom is the above-described substituent R ^9. Substituted or unsubstituted alkyl group, substituted alkoxy group, phenoxy group, 1-naphthyloxy group, 2-naphthyloxy group, substituted or unsubstituted alkenyl group, substituted or unsubstituted amino group, substituted or unsubstituted aromatic An aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, and the like.

  Furthermore, the ring A is a C5-C7 saturated cyclic alkyl group or a C3-C6 saturated heterocyclic group containing a hetero atom. Examples of the saturated cyclic alkyl group having 5 to 7 carbon atoms include groups derived from cyclopentane, cyclohexane, cycloheptane and the like. Examples of the saturated heterocyclic group having 3 to 6 carbon atoms containing a hetero atom include groups derived from pyrrolidine, piperidine, perhydroazepine, oxolane, oxane, oxepane, thiolane, thiane, thiepan and the like. Examples of the hetero atom include an oxygen atom, a sulfur atom, and a nitrogen atom. Moreover, the C3-C6 saturated heterocyclic group containing a hetero atom can also be condensed with a benzene ring. The saturated cyclic alkyl group having 5 to 7 carbon atoms or the saturated heterocyclic group having 4 to 6 carbon atoms including a hetero atom may have a substituent, and examples of the substituent include a hydroxyl group, a chlorine atom, and a bromine atom. , Halogen atoms such as iodine atom and fluorine atom, substituted or unsubstituted alkyl group, substituted or unsubstituted aromatic hydrocarbon group such as phenyl group, methylphenyl group and naphthyl group, thienyl group, furyl group, pyridyl group, etc. Substituted or unsubstituted heterocyclic group, nitro group, substituted or unsubstituted amino group, trifluoromethyl group, substituted or unsubstituted sulfonyl group, substituted alkoxy group, substituted alkylthio group, acyl group, alkoxycarbonyl group, substituted A carbonyl group, a mercapto group, a cyano group, etc. can be mentioned.

Examples of the cyclic carboxylic acid derivative represented by the general formula (II) include the following compounds.
1- [N- (phenylmethoxycarbonyl) amino] cyclohexanecarboxylic acid, 1- [N- (phenyloxycarbonyl) amino] cyclohexanecarboxylic acid, 1- [N- (2-methylpropyloxycarbonyl) amino] cyclohexanecarboxylic acid 1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxylic acid, 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid, 1- [N- [1- ( Methoxycarbonyl) piperidine-4-carbonyl] amino] cyclohexanecarboxylic acid, 1-phenylsulfonylmethylcyclohexanecarboxylic acid, 1- [N- [4- (2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] amino ] Cyclohexanecarboxylic 1- [N- [4- (methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid, 1- [N- (4-acetyl-piperazine-1-carbonyl) amino] cyclohexanecarboxylic acid,

1- [N- (phenylsulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- (piperazine-1-carbonyl) amino] cyclohexanecarboxylic acid, 1- [N- (morpholine-4-sulfonyl) amino] cyclohexanecarboxylic acid 1- [N- (4-acetylpiperazine-1-sulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- (piperazine-1-sulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- (4-methylpiperazine) -1-carbonyl) amino] cyclohexanecarboxylic acid, 1- [N- (4-phenylpiperazine-1-carbonyl) amino] cyclohexanecarboxylic acid, 1- [N- (4-methylpiperazine-1-sulfonyl) amino] cyclohexane Carboxylic acid, 1- [N- (4-phenylpiperazine-1 Sulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- (4-methoxyphenylsulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- (4-nitrophenylsulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- ( 4-acetaminophenylsulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- (pyridine-3-sulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- (quinoline-5-sulfonyl) amino] cyclohexanecarboxylic acid, 1 -[N- (4-dimethylaminophenylsulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- (5-acetoaminonaphthyl-2-sulfonyl) amino] cyclohexanecarboxylic acid, 1- [N- (5-dimethylamino) Naphthyl-2-sulfonyl) amino] B hexane carboxylic acid, 1 - [(morpholin-4-sulfonyl) methyl] cyclohexanecarboxylic acid, 1 - [(4-acetyl-piperazine-1-sulfonyl) methyl] cyclohexanecarboxylic acid,

1- [N-[(4-ethoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid, 1- [N-[(4-methylsulfonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid, [N-[(4-isobutyryl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid, 1- [N- (thiamorpholine-4-carbonyl) amino] cyclohexanecarboxylic acid, 1- [N-[(4-ethoxy Carbonyl) piperidine-1-carbonyl] amino] cyclohexanecarboxylic acid, 1- [N-[(4-acetyl) perhydro-4-azaazepine-1-carbonyl] amino] cyclohexanecarboxylic acid, 1- [N-[(4- Methoxy) piperidine-1-carbonyl] amino] cyclohexanecarboxylic acid 1- [N- [N, N-bis (2-methoxyethyl) amino-1-carbonyl] amino] cyclohexanecarboxylic acid, 1- [N-[[N- (2-methoxyethyl) -N-methyl] amino -1-carbonyl] amino] cyclohexanecarboxylic acid.

On the other hand, in the amino alcohol derivative represented by the general formula (III), R ² is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group. R ³ is a hydrogen atom, a group represented by R ⁴ O— or a group represented by R ⁵ (R ⁶ ) N—, wherein R ⁴ is a hydrogen atom, substituted or unsubstituted alkyl A group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, etc., and R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted group Aromatic hydrocarbon groups, substituted or unsubstituted heterocyclic groups, and the like. The alkyl group, aromatic hydrocarbon group and heterocyclic group in this amino alcohol derivative are the same as those exemplified for the cyclic carboxylic acid derivative represented by the general formula (II).

Examples of the amino alcohol derivative represented by the general formula (III) include the following compounds.
(2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide, (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-5- (methylthio) pentanamide, (2RS, 3S ) -N-cyclopentyl-3-amino-2-hydroxybutanamide, (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-4-methylpentanamide, (2RS, 3S) -3-amino- 2-hydroxyheptanamide, (2RS, 3S) -N-cyclopentylmethyl-3-amino-2-hydroxyheptanamide, (2RS, 3S) -N- (1-methyl-cyclopentylmethyl) -3-amino-2- Hydroxyheptanamide, (2RS, 3S) -N-2,2-dimethylpropyl-3-amino-2-hydride Carboxymethyl heptanamide, (2RS, 3S)-N-cyclobutyl-3-amino-2-hydroxy-5- (methylthio) pentaamide,

(2RS, 3S) -N-cyclohexyl-3-amino-2-hydroxy-5- (methylthio) pentanamide, (2RS, 3S) -N-cyclopentylmethyl-3-amino-2-hydroxy-5- (methylthio) Pentanamide, (2RS, 3S) -N- (1-methyl-cyclopentylmethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide, (2RS, 3S) -N-2,2-dimethylpropyl -3-amino-2-hydroxy-5- (methylthio) pentanamide, (2RS, 3S) -N-cyclopentylmethyl-3-amino-2-hydroxy-4-methylpentanamide, (2RS, 3S) -N- (1-methyl-cyclopentylmethyl) -3-amino-2-hydroxy-4-methylpentanamide, (2RS, 3S) N-2,2-dimethylpropyl-3-amino-2-hydroxy-4-methylpentanamide, (2RS, 3S) -N-cyclobutyl-3-amino-2-hydroxy-5-methylhexanamide, (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-5-methylhexanamide, (2RS, 3S) -N-cyclohexyl-3-amino-2-hydroxy-5-methylhexanamide, (2RS, 3S) -N-cyclopentylmethyl-3-amino-2-hydroxy-5-methylhexanamide, (2RS, 3S) -N- (1-methyl-cyclopentylmethyl) -3-amino-2-hydroxy-5-methylhexanamide , (2RS, 3S) -N-2,2-dimethylpropyl-3-amino-2-hydroxy-5-methylhexane (2RS, 3S) -N-cyclobutyl-3-amino-2-hydroxy-4-phenylbutanamide, (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-4-phenylbutanamide, (2RS, 3S) -N-cyclohexyl-3-amino-2-hydroxy-4-phenylbutanamide, (2RS, 3S) -N-cyclopentylmethyl-3-amino-2-hydroxy-4-phenylbutanamide, ( 2RS, 3S) -N- (1-methyl-cyclopentylmethyl) -3-amino-2-hydroxy-4-phenylbutanamide, (2RS, 3S) -N-2,2-dimethylpropyl-3-amino-2 -Hydroxy-4-phenylbutanamide.

  The reaction of the amino alcohol derivative represented by the general formula (III) and the cyclic carboxylic acid derivative represented by the general formula (II) in this step is preferably performed in the presence of a condensing agent. For example, carbodiimide reagents such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, and isopropylcarbodiimide can be used. The condensing agent used in this step is 1 to 3 equivalents relative to the cyclic carboxylic acid derivative represented by the general formula (II) or the aminoalcohol derivative represented by the general formula (III), in order to produce with good yield. Is preferably used in an amount of 1.5 to 2 equivalents. The reaction is preferably carried out in an inert solvent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane, etc. Ethers, amides such as dimethylformamide and dimethylacetamide, dimethylsulfoxide, acetonitrile and the like can be used alone or in combination. The reaction usually proceeds at -50 ° C to reflux temperature under normal pressure, but it is preferably performed at -10 ° C to 30 ° C in order to carry out with good yield. The cyclic carboxylic acid derivative represented by the general formula (II) in this step can be subjected to this reaction after converting the carboxyl group to various reactive derivatives.

(Step 2) In this step, the alcohol represented by the general formula (IV) is obtained by reacting the hydroxycarboxylic acid derivative represented by the general formula (V) with the compound represented by the general formula (VI). A derivative is produced. The hydroxycarboxylic acid derivative represented by the general formula (V), which is a raw material compound in this step, is a compound that is easily produced from a commercially available raw material compound (see the following reference example). In addition, the compound represented by the general formula (VI), which is another raw material, is a compound represented by the general formula R ⁴ —OH or R ⁵ (R ⁶ ) NH (wherein R ⁴ , R ⁵ And R ⁶ is as defined above. These alcohol compounds, phenol compounds, amine compounds and the like are readily available compounds.

  This step is a condensation reaction, and the first step can be carried out using the same condensing agent and the same reaction solvent and reaction conditions.

  (Third Step) In this step, the cyclic amide represented by the general formula (I) is obtained by oxidizing the alcohol derivative represented by the general formula (IV) produced in the first step or the second step. This is a process for producing a derivative. As an oxidation reaction used in this step, for example, an active dimethyl sulfoxide oxidation method can be used. As the oxidizing agent, dimethyl sulfoxide is used, and an activator such as dicyclohexylcarbodiimide, phosphorus pentoxide, pyridine-sulfur trioxide complex, oxalyl oxide, acetic anhydride, trifluoroacetic acid or the like is used in combination. The activator can be used in an amount of 1 to 12 equivalents based on the alcohol derivative represented by the general formula (IV). The reaction is preferably carried out in a solvent. For example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like can be used, but an excessive amount of dimethylsulfoxide used as an oxidizing agent can be used as a solvent. . The reaction can be carried out at -78 ° C to 30 ° C.

Moreover, the compound represented by the following general formula (Ia) in which R ³ is an alkoxy group obtained in the third step is, for example, a carboxylic acid derivative represented by the following general formula (Ib) by hydrolysis. Then, various compounds of the cyclic amide derivative represented by the general formula (I) can be further produced. The reaction formula is shown below.

(Wherein R ¹ , R ² and A are the same as above, and R ³¹ is an alkoxy group.)

  The cyclic amide derivative represented by the general formula (I) produced according to the above method can form a known acid addition salt or basic salt when administered to a human as a medicine, for example. Examples of acid addition salts include inorganic salts (eg hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or organic acids (eg acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid, etc.), basic salts And pharmacologically acceptable salts such as sodium salt, potassium salt and ammonium salt.

  When these compounds or pharmacologically acceptable salts thereof are administered to humans as pharmaceuticals, the effective amount varies depending on the level of effective activity, the age of the patient, the symptoms of the target disease, etc. It is 0.01-100 mg per kg body weight, preferably 0.1-50 mg.

  When the cyclic amide derivative represented by the general formula (I) is administered for the purpose of treatment, the cyclic amide derivative or one of its salts as an active ingredient, which is a pharmaceutically acceptable carrier, for example, It is used as a pharmaceutical composition blended with organic or inorganic solid or liquid excipients suitable for oral as well as parenteral, external use or inhalation. These pharmaceutical compositions can take the form of capsules, tablets, dragees, granules, solutions, suspensions, emulsions and the like. If necessary, auxiliaries, stabilizers, lubricants, emulsifiers, buffers or other conventional additives can be added to these formulations.

Hereinafter, the present invention will be described in more detail with reference examples, examples and examples.
Reference Example 1 1- [N- (Phenylmethoxycarbonyl) amino] cyclohexanecarboxylic acid

  28.6 g (0.2 mol) of 1-aminocyclohexanecarboxylic acid was dissolved in 2N aqueous sodium hydroxide solution (110 ml) and stirred under ice cooling with 2N aqueous sodium hydroxide solution (120 ml) and phenylmethyl chlorocarbonate (41 g, 0.24 mol) was slowly added dropwise. After 1 hour, after returning to room temperature and stirring overnight, the reaction solution was placed in a separatory funnel, washed with ether to remove excess phenylmethyl chlorocarbonate, acidified with 10% hydrochloric acid under ice-cooling, extracted with ethyl acetate and saturated. After washing with brine, it was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained crystals were washed with ether to obtain 37.2 g (yield 67%) of the title 1- [N- (phenylmethoxycarbonyl) amino] cyclohexanecarboxylic acid.

1H-NMR (CDCl ₃ , δ): 1.23-1.39 (7H, m), 1.39-1.51 (2H, m), 1.57-1.70 (3H, m), 1.79-1.97 (2H, m), 1.98-2.13 ( 2H, m), 5.01 (1H, s), 5.12 (2H, s), 7.26-7.39 (5H, m)

Reference Example 2 1- [N- (Phenyloxycarbonyl) amino] cyclohexanecarboxylic acid

  In the same manner as in Reference Example 1, using 3.29 g of 1-aminocyclohexanecarboxylic acid and 3.62 g of phenyl chlorocarbonate instead of phenylmethyl chlorocarbonate of Reference Example 1, the title 1- [N- (phenyloxycarbonyl) amino] The cyclohexanecarboxylic acid compound 2.2g (yield 36%) was obtained.

1H-NMR (CDCl ₃ , δ): 1.30-1.40 (1H, m), 1.40-1.60 (2H, m), 1.60-1.80 (3H, m), 1.90-2.00 (2H, m), 2.10-2.20 ( 2H, m), 5.20 (1H, br-s), 7.00-7.40 (5H, m)

Reference Example 3 1- [N- (2-Methylpropyloxycarbonyl) amino] cyclohexanecarboxylic acid

  In the same manner as in Reference Example 1, using 1.93 g of 1-aminocyclohexanecarboxylic acid and 3.73 g of 2-methylpropyl chlorocarbonate instead of phenylmethyl chlorocarbonate of Reference Example 1, the title 1- [N- (2-methyl Propyloxycarbonyl) amino] cyclohexanecarboxylic acid (3.37 g, yield 50%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.90 (6H, d, J = 5Hz), 1.20-1.40 (1H, m), 1.40-1.55 (2H, m), 1.60-1.70 (3H, m), 1.80- 2.00 (3H, m), 2.00-2.10 (2H, m), 3.85 (2H, d, J = 7Hz), 5.90 (1H, br-s)

Reference Example 4 1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxylic acid

  2.74 g (16.5 mmol) of 3,4-methylenedioxybenzoic acid was dissolved in anhydrous dichloromethane and then ice-cooled. Then, 4.62 ml (33.0 mmol) of triethylamine, 2.53 g of 1-hydroxybenzotriazole hydrate (16 0.5 mmol), 3.57 g (17.3 mmol) of N, N′-dicyclohexylcarbodiimide and 3.20 g (16.5 mmol) of ethyl 1-aminocyclohexanecarboxylate / hydrochloride in order, and gradually raising the temperature to room temperature Stir for 18 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, and insolubles were filtered off. The ethyl acetate solution was washed successively with 1N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1- [N- (3,4 -Methylenedioxyphenylcarbonyl) amino] 5.21 g of ethyl cyclohexanecarboxylate was obtained.

  Next, 5.21 g of the ethyl 1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxylate was dissolved in ethanol, and 16 ml of 1N sodium hydroxide aqueous solution was added dropwise. After heating under reflux for 18 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in water and washed with ether. The aqueous layer was adjusted to pH 2 by adding 4N hydrochloric acid, extracted with ethyl acetate, and washed with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3.18 g (yield 68%) of the title 1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxylic acid.

1H-NMR (δ, CD ₃ OD): 1.30-1.70 (6H, m), 1.85-1.98 (2H, m), 2.14-2.25 (2H, m), 6.02 (2H, s), 6.87 (1H, d , J = 8Hz), 7.28 (1H, d, J = 2Hz), 7.40 (1H, dd, J = 8Hz, 2Hz)

Reference Example 5 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid

  In the same manner as in Reference Example 4, using 1.36 g (21 mmol) of 1-aminocyclohexanecarboxylic acid ethyl ester of hydrochloric acid and 3.15 g (21 mmol) of morpholinecarbonyl chloride, the title 1- [N- (morpholine-4-carbonyl) amino There was obtained 1.8 g (yield 33%) of cyclohexanecarboxylic acid.

1H-NMR (δ, CDCl ₃ ): 1.30-1.50 (3H, m), 1.60-1.80 (3H, m), 1.90-2.15 (4H, m), 3.26-3.50 (4H, m), 3.60-3.80 ( 4H, m), 4.49 (1H, s)

Reference Example 6 1- [N- [1- (2-Methyl-2-propyloxycarbonyl) piperidine-4-carbonyl] amino] cyclohexanecarboxylic acid

  In the same manner as in Reference Example 4, instead of 3,4-methylenedioxybenzoic acid, 6.87 g of 1- (2-methyl-2-propyloxycarbonyl) piperidine-4-carboxylic acid was used and the title 1- [N- [1- (2-Methyl-2-propyloxycarbonyl) piperidine-4-carbonyl] amino] cyclohexanecarboxylic acid (3.8 g, yield 70%) was obtained.

1H-NMR (CDCl ₃ , δ): 1.30-1.40 (3H, m), 1.50 (9H, m), 1.55-1.88 (5H, m), 1.80-2.00 (4H, m), 2.00-2.10 (2H, m), 2.36 (1H, tt, J = 11, 3Hz), 2.60-2.80 (2H, m), 4.00-4.30 (2H, m), 5.60 (1H, s)

Example 1 1-Phenylsulfonylmethylcyclohexanecarboxylic acid

  Under a nitrogen stream, 1.85 ml (13.2 mmol) of diisopropylamine in anhydrous tetrahydrofuran was cooled in a dry ice-acetone bath, and then 7.23 ml (12 mmol) of a hexane solution of n-butyllithium was added dropwise. After completion of the dropwise addition, the reaction solution was returned to room temperature and stirred for 1 hour, and then cooled again in a dry ice-acetone bath, and an anhydrous tetrahydrofuran solution of 1.56 g (10.0 mmol) of ethyl cyclohexanecarboxylate was added dropwise. After stirring for 30 minutes, an anhydrous tetrahydrofuran solution of 1.34 ml (10 mmol) of chloromethylphenyl sulfide was added dropwise, and the mixture was stirred for 18 hours while gradually raising the temperature to room temperature. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate, and the ethyl acetate layer was further washed successively with 1N-hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate and saturated brine. This organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.79 g of ethyl 1-phenylsulfinylmethylcyclohexanecarboxylate.

  Next, 1.28 g (4.60 mmol) of ethyl 1-phenylsulfinylmethylcyclohexanecarboxylate is dissolved in 3 ml of acetic acid, 1.78 ml of 30% hydrogen peroxide solution is gradually added, heated under reflux for 30 minutes, and then poured into ice water. The mixture was extracted with ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.43 g of ethyl 1-phenylsulfonylmethylcyclohexanecarboxylate.

  Further, 1.43 g (4.6 mmol) of ethyl 1-phenylsulfonylmethylcyclohexanecarboxylate and 1.52 g (23.0 mmol) of potassium hydroxide were dissolved in a 90% ethanol aqueous solution and heated under reflux for 18 hours. After concentration under reduced pressure, the resulting residue was dissolved in water and washed with ether. The aqueous layer was adjusted to pH 2 by adding 4N hydrochloric acid, extracted with ethyl acetate, and washed with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.22 g (yield 60%) of the title 1-phenylsulfonylmethylcyclohexanecarboxylic acid.

1H-NMR (δ, CDCl ₃ ): 1.35-1.68 (4H, m), 1.68-1.80 (2H, m), 2.02-2.15 (2H, m), 3.56 (2H, s), 7.52-7.70 (3H, m), 7.90-8.00 (2H, m)

Reference Example 7 1- [N- [4- (2-Methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid

  It was synthesized with reference to the method of literature (Tetrahedron Letters, Vol 35, 839-842, 1994). 15.78 g (84.7 mmol) of 1- (t-butoxycarbonylamino) piperazine, 6.85 ml (84.7 mmol) of pyridine and 15.1 ml (84.7 mmol) of diisopropylethylamine were dissolved in 200 ml of anhydrous toluene and −10 ° C. Carbon dioxide gas was introduced at 1 hour (1 hour). The reaction solution was added to a toluene (80 ml) solution of thionyl chloride 10.6 ml (84.7 mmol) cooled to −10 ° C. and stirred for 1 hour. The reaction solution was added to 0.1N hydrochloric acid, and the toluene layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with hexane to obtain 13.7 g of 4- (2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl chloride.

  Next, 6.39 g (25.71 mmol) of the synthesized 4- (t-butoxycarbonylamino) piperazine-1-carbonyl chloride, 5 g (21.43 mmol) of aminocyclohexanecarboxylic acid benzyl ester, and 3.58 ml (25.71 mol) of triethylamine. ) Was dissolved in 100 ml of anhydrous tetrahydrofuran and stirred at 50 ° C. for 18 hours. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate / 1N hydrochloric acid, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 7 g of 1- [N- [4- (2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester.

  Further, 4.3 g (9.65 mmol) of 1- [N- [4- (2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester was dissolved in 200 ml of ethanol. 400 mg of 10% palladium carbon was suspended and stirred for 15 hours under a hydrogen stream. Insoluble matter was removed by Celite filtration, and the filtrate was concentrated under reduced pressure to give the title 1- [N- [4- (2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid 3 Obtained .25 g (45% yield).

1H-NMR (CD ₃ OD, δ): 1.30-1.40 (1H, m), 1.46 (9H, s), 1.50-1.70 (6H, m), 1.75-1.90 (2H, m), 2.00-2.10 (2H , m), 3.3-3.5 (8H, m)

Reference Example 8 1- [N- [4- (methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid

  1- [N- [4- (2-Methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 2.5 g (5.6 mmol) synthesized in Reference Example 7 was added to ethyl acetate. Then, 14 ml (56 mmol) of 4N hydrogen chloride-ethyl acetate solution was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, dissolved in 1N hydrochloric acid, and washed with ethyl acetate. The aqueous layer was separated, sodium carbonate was added to adjust the pH to 9, and the mixture was extracted 3 times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.7 g of 1- [N- (piperazine-1-carbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester.

  Next, 0.98 g (2.83 mmol) of 1- [N- (piperazine-1-carbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester and 0.39 ml (2.83 mmol) of triethylamine were dissolved in 20 ml of anhydrous methylene chloride, At 0 ° C., 0.21 ml (2.83 mmol) of methyl chlorocarbonate was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was washed successively with 1N hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title 1- [N- [4- (methoxycarbonyl) piperazine-1-carbonyl]. Amino] 1.12 g of cyclohexanecarboxylic acid phenylmethyl ester was obtained.

  Further, 1.12 g (2.77 mmol) of 1- [N- [4- (methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester was used and the title 1- [ 0.8 g (yield 78%) of N- [4- (methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid was obtained.

1H-NMR (CDCl ₃ , δ): 1.30-1.50 (3H, m), 1.60-1.70 (3H, m), 1.80-1.90 (2H, m), 2.00-2.10 (2H, m), 3.40-3.50 ( 4H, m), 3.50-3.60 (4H, m), 3.75 (3H, s), 5.15 (2H, s)

Reference Example 9 1- [N- (4-acetylpiperazine-1-carbonyl) amino] cyclohexanecarboxylic acid

  In the method according to Reference Example 8, 1.32 g of acetic anhydride was used instead of methyl chlorocarbonate, and 2.3 g of the title 1- [N- (4-acetylpiperazine-1-carbonyl) amino] cyclohexanecarboxylic acid (yield 59%) )

1H-NMR (CD ₃ SOCD ₃ , δ): 1.10-1.20 (1H, m), 1.40-1.70 (7H, m), 1.90-2.10 (5H, m), 3.20-3.50 (8H, m), 6.37 ( 1H, s)

Reference Example 10 (2RS, 3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide

  40 g (200 mmol) of (S) -2- [N- (2-methyl-2-propyloxycarbonyl) amino] hexanal was dissolved in 300 ml of anhydrous methylene chloride, and 34 g (400 mmol) of acetone cyanohydrin and 12.1 g of triethylamine ( 120 mmol) was added and stirred overnight. The reaction solution was concentrated under reduced pressure, 300 ml of ether was added to the residue, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 38.7 g of (2RS, 3S) -2-hydroxy-3- [N- (2-methyl-2-propyloxycarbonyl) amino] heptanenitrile.

  Next, 133 ml of concentrated hydrochloric acid was added to a dioxane solution (260 ml) of 38.7 g (160 mmol) of (2RS, 3S) -2-hydroxy-3- [N- (2-methyl-2-propyloxycarbonyl) amino] heptanenitrile. And stirred under reflux conditions. After 3 hours, the reaction solution was concentrated under reduced pressure, 100 ml of distilled water and 100 ml of dioxane were added to the residue, and a dioxane solution (100 ml) of 70 g (319 mmol) of di-tert-butylcarboxylate was added dropwise to the mixed solution at 0 ° C. After completion of the dropwise addition, the reaction solution was returned to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, distilled water was added to the residue, and the mixture was washed with ether. The organic layer was extracted with 1N aqueous sodium hydroxide solution, and this aqueous layer was combined with the previous aqueous layer. The combined aqueous layer was adjusted to about pH 2 with potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with 50% brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. (2RS, 3S) -2-hydroxy-3- [N- (2-methyl-2-propyloxycarbonyl) amino] heptanecarboxylic acid 36.2 g was obtained.

  Further, the above (2RS, 3S) -2-hydroxy-3- [N- (2-methyl-2-propyloxycarbonyl) amino] heptanecarboxylic acid 1.32 g (5 mmol), tert-butylamine 0.37 g (5 mmol) And 1-hydroxybenzotriazole 0.81 g (6 mmol) in 50 ml of anhydrous methylene chloride, followed by 1.15 g (6 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at 0 ° C. under a nitrogen stream. Was added. Thereafter, the reaction solution was returned to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 100 ml of ethyl acetate, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (2RS, 3S) -N- (2-methyl-2-propyl) -2-hydroxy-3- [N- (2-methyl-2-propyloxycarbonyl) amino] 0.74 g (47% yield) of heptane amide was obtained.

  Furthermore, 0.74 g of (2RS, 3S) -N- (2-methyl-2-propyl) -2-hydroxy-3- [N- (2-methyl-2-propyloxycarbonyl) amino] heptanamide ( 2.33 mmol) was dissolved in 50 ml of 4N hydrogen chloride-ethyl acetate solution and allowed to stand. After 2 hours, the reaction solution was concentrated under reduced pressure, and 100 ml of distilled water was added to the residue and washed with ether. The aqueous layer was adjusted to about pH 9 with potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.27 g (yield 15%) of the title (2RS, 3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide. Obtained.

1H-NMR (CDCl ₃ , δ): 0.89-0.92 (3H, m), 1.21-1.44 (4H, m), 1.37 (9H, s), 1.58-1.63 (2H, m), 3.05 (1 / 2H, s), 3.31-3.34 (1 / 2H, m), 3.70 (1 / 2H, d, J = 3Hz), 3.76 (1 / 2H, d, J = 5Hz), 7.06 (1 / 2H, s), 7.35 (1 / 2H, s)

Reference Example 11 (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide

  In the same manner as in Reference Example 10, using 2.70 g of cyclopentylamine instead of t-butylamine, 6.22 g of the title (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide (yield 55%) )

1H-NMR (CDCl ₃ , δ): 0.90 (3 / 2H, t, J = 7Hz), 0.91 (3 / 2H, t, J = 7Hz), 1.22-1.48 (7H, m), 1.53-1.74 (5H , m), 1.92-2.03 (2H, m), 3.04-3.13 (1 / 2H, m), 3.30-3.35 (1 / 2H, m), 3.78 (1 / 2H, d, J = 3Hz), 3.88 ( 1 / 2H, d, J = 5Hz), 4.16-4.25 (1H, m), 7.11 (1 / 2H, d, J = 7Hz), 7.42 (1 / 2H, d, J = 7Hz)

Reference Example 12 (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-5- (methylthio) pentanamide

  In the method according to Reference Example 11, instead of (S) -2- [N- (2-methyl-2-propyloxycarbonyl) amino] hexanal, (S) -2- [N- (2-methyl-2- Propyloxycarbonyl) amino] -4- (methylthio) butanal (7.53 g) was used to give the title (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-5- (methylthio) pentanamide (3.22 g) 42%).

1H-NMR (CDCl ₃ , δ): 1.34-1.47 (2H, m), 1.54-1.75 (5H, m), 1.91-2.05 (3H, m), 2.10 (3 / 2H, s), 2.11 (3 / 2H, s), 2.52-2.69 (2H, m), 3.13-3.20 (1 / 2H, m), 3.40-3.46 (1 / 2H, m), 3.81 (1 / 2H, d, J = 3Hz), 3.83 (1 / 2H, d, J = 5Hz), 4.16-4.26 (1H, m), 7.09 (1 / 2H, d, J = 7Hz), 7.43 (1 / 2H, d, J = 7Hz)

Reference Example 13 (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxybutanamide

  In the method according to Reference Example 11, instead of (S) -2- [N- (2-methyl-2-propyloxycarbonyl) amino] hexanal, (S) -2- [N- (2-methyl-2- Propyloxycarbonyl) amino] propanal (14.33 g) was used to obtain 6.95 g (45% yield) of the title (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxybutanamide.

1H-NMR (CDCl ₃ , δ): 1.05 (3 / 2H, d, J = 7Hz), 1.15 (3 / 2H, d, J = 7Hz), 1.35-1.50 (2H, m), 1.55-1.76 (4H , m), 1.90-2.10 (2H, m), 3.31-3.41 (1 / 2H, m), 3.48-3.52 (1 / 2H, m), 3.74 (1 / 2H, d, J = 3Hz), 3.87 ( 1 / 2H, d, J = 5Hz), 4.13-4.29 (1H, m), 7.18 (1 / 2H, d, J = 8Hz), 7.25 (1 / 2H, d, J = 8Hz)

Reference Example 14 (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-4-methylpentanamide

  In a method according to Reference Example 10, instead of (S) -2- [N- (2-methyl-2-propyloxycarbonyl) amino] hexanal, (S) -2- [N- (2-methyl-2- Propyloxycarbonyl) amino] -4-methylbutanal (20.13 g) was used to give the title (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-4-methylpentanamide (4.71 g, yield 22%). )

1H-NMR (CDCl ₃ , δ): 0.87 (3H, d, J = 7Hz), 0.94 (3H, d, J = 7Hz), 1.30-2.10 (7H, m), 2.12-2.28 (1 / 2H, m ), 2.60-2.67 (1 / 2H, m), 3.09 (1H, dd, J = 7Hz, 2Hz), 3.70 (1 / 2H, d, J = 8Hz), 3.91 (1H, d, J = 2Hz), 4.15-4.28 (3 / 2H, m), 6.87 (1 / 2H, br-s), 8.37 (1 / 2H, br-s)

Reference Example 15 (2RS, 3S) -3-amino-2-hydroxyheptanamide

  (S) -2- [N- (2-phenylmethoxycarbonyl) amino instead of (S) -2- [N- (2-methyl-2-propyloxycarbonyl) amino] hexanal by a method according to Reference Example 10. Using 27.4 g of hexanal, 27.7 g of (2RS, 3S)-[3- (N-phenylmethoxycarbonyl) amino] -2-hydroxyheptanenitrile was obtained.

  Next, 20.1 g (72.9 mmol) of the (2RS, 3S)-[3- (N-phenylmethoxycarbonyl) amino] -2-hydroxyheptanenitrile was dissolved in a mixed solvent of dimethyl sulfoxide and ethanol, and the mixture was cooled with ice. A 1N aqueous sodium hydroxide solution (73.6 ml) and then a 30% aqueous hydrogen peroxide solution (15 ml) were added dropwise, followed by stirring for 1 hour. The reaction mixture was poured into ethyl acetate, washed successively with 1N hydrochloric acid, saturated sodium hydrogen carbonate, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crystals were washed with a mixed solvent of ether-hexane to obtain 17.57 g of the title (2RS, 3S)-[3- (N-phenylmethoxycarbonyl) amino] -2-hydroxyheptanamide.

  Further, 17.6 mg (59.7 mmol) of the (2RS, 3S)-[3- (N-phenylmethoxycarbonyl) amino] -2-hydroxyheptanamide was dissolved in methanol, and 10% palladium-activated carbon (1. 7 g) was added and stirred for 2 days at 40 ° C. under a hydrogen stream. 10% Palladium-activated carbon was removed by Celite filtration, and the filtrate was concentrated under reduced pressure to obtain 7.82 g (yield 67%) of the title (2RS, 3S) -3-amino-2-hydroxyheptanamide.

1H-NMR (CDCl ₃ , δ): 0.91 (3H, t, J = 5 Hz), 1.10-1.82 (6H, m), 2.96-3.08 (1H, m), 3.87 (1H, d, J = 6 Hz), 5.62 (1H, br-s), 7.50 (1H, br-s)

Reference Example 16 (2RS, 3S) -2-hydroxy-3- [N- [1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarbonyl] amino] heptanoic acid

  13.2 g (50 mmol) of (2RS, 3S) -2-hydroxy-3- [N- (2-methyl-2-propyloxycarbonyl) amino] heptanoic acid obtained in Reference Example 10 and 6.3 g of sodium bicarbonate ( 75 ml) of dimethylformamide in 100 ml was added with 9.4 g (55 mmol) of benzylformamide in 20 ml of dimethylformamide and stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed twice with water and then once with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then the solvent was distilled off under reduced pressure to obtain (2RS, 3S) -2-hydroxy-3- [N- (2-methyl-2-propyloxycarbonyl) amino] phenyl methyl heptanoate. A crude product of the ester was obtained. To the obtained (2RS, 3S) -2-hydroxy-3- [N- (2-methyl-2-propyloxycarbonyl) amino] heptanoic acid phenylmethyl ester was added 100 ml of 4N-hydrochloric acid / ethyl acetate at room temperature. After being left for 1 hour, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water and washed twice with diethyl ether. The aqueous layer was basified with sodium carbonate and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 9.3 g of (2RS, 3S) -3-amino-2-hydroxyheptanoic acid phenylmethyl ester. .

  Then, under ice cooling, 9.3 g (37 mmol) of (2RS, 3S) -3-amino-2-hydroxyheptanoic acid phenylmethyl ester and 1- [N- (morpholine-4-carbonyl) amino obtained in Reference Example 5 were used. ] 8.5 g (45 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in a solution of 9.5 g (37 mmol) of cyclohexanecarboxylic acid and 6.0 g (45 mmol) of 1-hydroxybenzotriazole in 100 ml of methylene chloride And then stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate and reduced pressure. The solvent was distilled off under. The residue was purified by silica gel column chromatography, and (2RS, 3S) -2-hydroxy-3- [N- [1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarbonyl] amino] heptanoic acid 16.8 g of phenylmethyl ester was obtained.

  Further, 16.8 g (34 mmol) of (2RS, 3S) -2-hydroxy-3- [N- [1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarbonyl] amino] heptanoic acid phenylmethyl ester To 100 ml of methanol, 1.5 g of 10% palladium carbon was added and stirred at room temperature for 2 hours under a hydrogen atmosphere. After filtering the insoluble matter in the reaction solution, the filtrate was concentrated under reduced pressure to give the title (2RS, 3S) -2-hydroxy-3- [N- [1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarbonyl. 13.6 g (yield 68%) of amino] heptanoic acid were obtained.

1H-NMR (CDCl ₃ , δ): 0.90 (3H, t, J = 7 Hz), 1.16-1.43 (8H, m), 1.51-2.19 (8H, m), 3.33-3.45 (4H, m), 3.64- 3.74 (4H, m), 4.11-4.29 (1H, m), 4.30-4.40 (1H, m), 4.88 (1 / 2H, br-s), 5.07 (1 / 2H, br-s), 6.65 (1 / 2H, d, J = 7Hz), 7.31 (1 / 2H, d, J = 7Hz)

Reference Example 17 (2RS, 3S) -3-Amino-2-hydroxyheptanoic acid methyl ester

  In the same manner as in the synthesis method of (2RS, 3S) -3-amino-2-hydroxyheptanoic acid phenylmethyl ester of Reference Example 16, using 579 mg of methyl iodide instead of benzyl bromide, the title (2RS, 3S) -3 -683 mg (yield 91%) of amino-2-hydroxyheptanoic acid methyl ester was obtained.

1H-NMR (CDCl ₃ , δ): 0.85-0.96 (3H, m), 1.24-1.50 (6H, m), 3.01-3.09 (1H, m), 3.80 (3 / 2H, s), 3.81 (3 / 2H, s), 4.09 (1 / 2H, d, J = 2Hz), 4.17 (1 / 2H, d, J = 4Hz)

Reference Example 18 1- [N- (Phenylsulfonyl) amino] cyclohexanecarboxylic acid

  Using a method according to Reference Example 5 and using 3.52 g of benzenesulfonyl chloride instead of 4-morpholinecarbonyl chloride, 3.04 g of the title 1- [N- (phenylsulfonyl) amino] cyclohexanecarboxylic acid was obtained (yield 54%). Obtained.

1H-NMR (CDCl ₃ , δ): 1.09-1.49 (6H, m), 1.81-1.96 (4H, m), 4.97 (1H, s), 7.46-7.61 (3H, m), 7.90 (2H, dd, (J = 8Hz, 2Hz)

Example 1 N-[(S) -1,2-dioxo-1-N- (2-methyl-2-propyl) amino-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexane Carboxamide

  1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid 0.26 g (1.26 mmol), (3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptane 0.27 g (1.26 mmol) of amide and 0.24 g (1.5 mmol) of 1-hydroxybenzotriazole were dissolved in 15 ml of anhydrous methylene chloride, followed by 1-ethyl-3- (3-dimethyl) at 0 ° C. under a nitrogen stream. Aminopropyl) carbodiimide 0.29 g (1.5 mmol) was added. Thereafter, the reaction solution was returned to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 100 ml of ethyl acetate, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated by silica gel column chromatography, and N-[(S) -2-hydroxy-1- [N- (2-methyl-2-propyl) amino] -1-oxo-3-heptyl] -1- [ N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 0.35 g was obtained.

1H-NMR (CDCl ₃ , δ): 0.86-0.89 (3H, m), 1.24-1.31 (6H, m), 1.35 (9H, s), 1.50-2.11 (10H, m), 3.31-3.41 (4H, m), 3.69-3.71 (4H, m), 3.92-3.99 (1H, m), 4.09-4.16 (1H, m), 4.67 (1 / 2H, s), 4.79 (1 / 2H, s), 5.12 ( 1 / 2H, d, J = 6Hz), 5.27 (1 / 2H, s), 6.67 (1 / 2H, s), 6.82 (1H, s), 7.16 (1 / 2H, d, J = 7Hz)

  N-[(S) -2-hydroxy-1- [N- (2-methyl-2-propyl) amino] -1-oxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) ) Amino] cyclohexanecarboxamide (0.35 g, 0.78 mmol) was added with 5 ml of anhydrous dimethyl sulfoxide, 0.47 g (4.68 mmol) of triethylamine and 5 ml of anhydrous methylene chloride, followed by sulfur trioxide at 0 ° C. under a nitrogen stream. An anhydrous dimethyl sulfoxide solution (3 ml) of 0.75 g (4.6 mmol) of pyridine complex salt was added dropwise. After completion of the dropwise addition, the reaction solution was returned to room temperature and stirred. After 2 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ether was added to the residue and stirred. After 3 hours, the crystals were collected by filtration to give the title N-[(S) -1,2-dioxo-1-N- (2-methyl-2-propyl) amino-3-heptyl] -1- [N- (morpholine 0.17 g (yield 29%) of -4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.26-1.42 (15H, m), 1.61-1.65 (5H, m), 1.86-2.13 (5H, m), 3.39 ( 4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.45 (1H, s), 5.18 (1H, ddd, J = 4Hz, 7Hz, 9Hz), 6.73 (1H, s), 7.88 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3328, 2931, 1662, 1641, 1517
Rf value: Thin layer chromatography (TLC) analysis was performed under the following conditions. The Rf values shown in the following examples were also measured under the same conditions.
Used TLC plates: Merck HPTLC plates RP-18 F254s
Developing solvent used: Acetonitrile: Water = 7: 3
Rf value: 0.52

Example 2 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  (2RS, 3S) -N—synthesized in Reference Example 11 in place of (2RS, 3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide by a method according to Example 1. Using 0.45 g of cyclopentyl-3-amino-2-hydroxyheptanamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- 0.54 g (yield 58%) of (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7H), 1.20-1.55 (9H, m), 1.55-1.80 (8H, m), 1.80-2.08 (5H, m), 2.08- 2.18 (2H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.10-4.21 (1H, m), 4.46 (1H, s), 5.15-5.25 (1H , m), 6.81 (1H, d, J = 7Hz), 7.92 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3340, 2864, 1840, 1812, 1364
Rf value: 0.56

Example 3 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (phenylmethoxycarbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 2, 555 mg of 1- [N- (phenylmethoxycarbonyl) aminocyclohexanecarboxylic acid obtained in Reference Example 1 was used instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid. N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (phenylmethoxycarbonyl) amino] cyclohexanecarboxamide 721 mg (yield 74%) Got.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.22-1.51 (9H, m), 1.52-1.76 (9H, m), 1.82-2.10 (6H, m), 4.10- 4.22 (1H, m), 4.92 (1H, s), 5.11 (2H, s), 5.16-5.24 (1H, m), 6.79 (1H, br-s), 7.23-7.42 (6H, m)
IR (ν, KBr, cm ⁻¹ ): 3344, 1648
Rf value: 0.26

Example 4 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxamide

  1- [N- (3,4-methylenedioxyphenylcarbonyl) amino obtained in Reference Example 4 was used instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid in the same manner as in Example 2. ] Using 583 mg of cyclohexanecarboxylic acid, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (3,4-methylenedioxyphenyl) Carbonyl) amino] cyclohexanecarboxamide 489 mg (yield 49%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.23-1.54 (9H, m), 1.56-1.74 (9H, m), 1.92-2.05 (4H, m), 2.21- 2.30 (2H, m), 4.08-4.17 (1H, m), 5.18-5.24 (1H, m), 5.95 (1H, s), 6.04 (2H, s), 6.79 (1H, d, J = 8Hz), 6.85 (1H, d, J = 8Hz), 7.26 (1H, d, J = 2Hz), 7.31 (1H, dd, J = 8Hz, 2Hz), 7.82 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 1652
Rf value: 0.38

Example 5 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexane Carboxamide

  1- [N- [4- (methoxycarbonyl) piperazine-1-carbonyl synthesized in Reference Example 8 instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by a method according to Example 1 ] Using N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-methoxycarbonyl)] using 244 mg of amino] cyclohexanecarboxylic acid 168 mg (32% yield) of piperazine-1-carbonyl] amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-1.52 (8H, m), 1.52-1.80 (10H, m), 1.80-2.10 (6H, m), 3.30- 3.45 (4H, m), 3.53 (4H, br-s), 3.73 (3H, s), 4.10-4.20 (1H, m), 4.49 (1H, s), 5.16-5.20 (1H, m), 6.81 ( 1H, d, J = 8Hz), 7.86 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3684, 3300, 1656, 1374
Rf value: 0.55

Example 6 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-acetyl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide

  1- [N- (4-acetylpiperazine-1-carbonyl) synthesized in Reference Example 9 in place of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid in Example 2 by a method according to Example 2 The title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-acetyl)] using 0.32 g of amino] cyclohexanecarboxylic acid Piperazine-1-carbonyl] amino] cyclohexanecarboxamide 0.26 g (yield 50%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.20-2.10 (24H, m), 2.12 (3H, s), 3.35-3.45 (2H, m), 3.45-3.60 ( 4H, m), 3.62-3.72 (2H, m), 4.10-4.20 (1H, m), 4.50 (1H, s), 5.15-5.21 (1H, m), 6.81 (1H, d, J = 7Hz), 7.78 (1H, d, J = 7Hz)
Rf value: 0.63

Example 7 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5- (methylthio) -3-pentyl] -1- [N-[(4-methoxycarbonyl) piperazine-1 -Carbonyl] amino] cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 synthesized in Reference Example 12 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 5 Using 384 mg of -hydroxy-5- (methylthio) pentanamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5- (methylthio) -3-pentyl] -1- 166 mg (yield 21%) of [N-[(4-methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 1.25-1.50 (6H, m), 1.55-1.78 (6H, m), 1.84-2.18 (7H, m), 2.04 (3H, s), 2.30-2.42 (1H, m), 2.50-2.60 (2H, m), 3.32-3.42 (4H, m), 3.53 (4H, br-s), 3.73 (3H, s), 4.10-4.21 (1H, m), 4.50 (1H, s), 5.20-5.28 (1H, m), 6.80 (1H, d, J = 8Hz), 7.93 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3356, 2332, 1870, 1472, 1374
Rf value: 0.60

Example 8 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5- (methylthio) -3-pentyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexane Carboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 synthesized in Reference Example 12 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 1 Using 370 mg of -hydroxy-5- (methylthio) pentanamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5- (methylthio) -3-pentyl] -1- 360 mg (yield 50%) of [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 1.25-1.55 (6H, m), 1.55-1.82 (6H, m), 1.82-2.20 (7H, m), 2.05 (3H, s), 2.31-2.42 (1H, m), 2.52-2.61 (2H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.10-4.22 (1H, m), 4.52 (1H, s), 5.20-5.28 (1H, m), 6.81 (1H, d, J = 8Hz), 7.97 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3728, 2332, 1730, 1338, 1224
Rf value: 0.67

Example 9 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methylthio-3-pentyl] -1- [N- (phenylmethoxycarbonyl) amino] cyclohexanecarboxamide

  1- [N- (Phenylmethoxycarbonyl) amino] synthesized in Reference Example 1 instead of 1- [N- [4- (methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid by a method according to Example 7 Using 832 mg of cyclohexanecarboxylic acid, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methylthio-3-pentyl] -1- [N- (phenylmethoxycarbonyl) amino 200 mg (yield 29%) of cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 1.31-1.48 (5H, m), 1.61-1.72 (7H, m), 1.86-2.10 (10H, m), 2.30-2.41 (1H, m), 2.51 (2H, s), 4.12-4.19 (1H, m), 4.96 (1H, s), 5.11 (2H, s), 5.24 (1H, d, J = 5Hz), 6.78 (1H, d, J = 6Hz), 7.33- 7.45 (6H, m)
IR (ν, KBr, cm ⁻¹ ): 3326, 1693, 1660, 1517
Rf value: 0.36

Example 10 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methylthio-3-pentyl] -1- [N- (3,4-methylenedioxyphenylcarbonyl) amino ] Cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 obtained in Reference Example 12 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 4. Using 246 mg of -hydroxy-5- (methylthio) pentanamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methylthio-3-pentyl] -1- [N 118 mg (yield 23%) of-(3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 1.31-1.76 (12H, m), 1.91-2.17 (5H, m), 2.03 (3H, s), 2.20-2.41 (3H, m), 2.56 (2H, t, J = 7Hz), 4.09-4.19 (1H, m), 5.24-5.31 (1H, m), 5.99 (1H, s), 6.05 (2H, s), 6.79 (1H, d, J = 7Hz), 6.85 ( 1H, d, J = 8Hz), 7.26 (1H, d, J = 2Hz), 7.31 (1H, dd, J = 8Hz, 2Hz), 7.90 (1H, d, J = 7Hz)
IR (ν, KBr, cm ^-1 ): 3320, 1660
Rf value: 0.49

Example 11 N-[(S) -1- [N- (cyclopentyl) amino] -1,2-dioxo-5-methylthio-3-pentyl] -1- [N- (phenyloxycarbonyl) amino] cyclohexanecarboxamide

  1- [N- [Phenyloxycarbonyl) amino] synthesized in Reference Example 2 in place of 1- [N- [4- (methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid by a method according to Example 7 Using 263 mg of cyclohexanecarboxylic acid, the title N-[(S) -1- [N- (cyclopentyl) amino] -1,2-dioxo-5-methylthio-3-pentyl] -1- [N- (phenyloxycarbonyl) ) Amino] cyclohexanecarboxamide 160 mg (yield 34%) was obtained.

1H-NMR (CDCl ₃ , δ): 1.34-1.70 (12H, m), 1.89-2.16 (10H, m), 2.35-2.39 (1H, m), 2.53 (2H, t, J = 7Hz), 4.12- 4.17 (1H, m), 5.24-5.27 (2H, m), 6.79 (1H, d, J = 8Hz), 7.14-7.22 (3H, m), 7.34-7.38 (2H, m), 7.53 (1H, d , J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3305, 2937, 1727, 1658, 1530, 1490, 1454, 1251, 1201, 1162
Rf value: 0.38

Example 12 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methylthio-3-pentyl] -1- [N- (2-methylpropyloxycarbonyl) amino] cyclohexanecarboxamide

  1- [N- (2-methylpropyloxycarbonyl) obtained in Reference Example 3 was used instead of 1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxylic acid in the same manner as in Example 10. The title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methylthio-3-pentyl] -1- [N- (2-methyl) was obtained using 243 mg of amino] cyclohexanecarboxylic acid. Propyloxycarbonyl) amino] cyclohexanecarboxamide 133 mg (yield 28%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.93 (6H, d, J = 7Hz), 1.13-1.51 (5H, m), 1.55-1.76 (7H, m), 1.81-2.17 (8H, m), 2.05 ( 3H, s), 2.31-2.42 (1H, m), 2.54 (2H, t, J = 7Hz), 3.85 (2H, d, J = 7Hz), 4.12-4.23 (1H, m), 4.85 (1H, s ), 5.23-5.30 (1H, m), 6.79 (1H, d, J = 7Hz), 7.52 (1H, br-s)
IR (ν, KBr, cm ^-1 ): 3344, 1658
Rf value: 0.31

Example 13 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-butyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 synthesized in Reference Example 13 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 1 -N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-butyl] -1- [N- (morpholine-4-carbonyl) amino] using 373 mg of hydroxybutanamide 163 mg (39% yield) of cyclohexane carboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 1.14-1.50 (3H, m), 1.44 (3H, d, J = 7Hz), 1.45-1.80 (10H, m), 1.80-2.15 (5H, m), 3.33- 3.42 (4H, m), 3.62-3.80 (4H, m), 4.07-4.23 (1H, m), 4.44 (1H, s), 5.16-5.27 (1H, m), 6.81 (1H, d, J = 8Hz ), 7.81 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3756, 3356, 2364, 1740, 1336
Rf value: 0.76

Example 14 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-butyl] -1- [N- (3,4-methylenedioxycarbonyl) amino] cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 synthesized in Reference Example 13 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 4 -N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-butyl] -1- [N- (3,4-methylenedioxycarbonyl) using 373 mg of hydroxybutanamide ) Amino] cyclohexanecarboxamide 97 mg (yield 21%) was obtained.

1H-NMR (CDCl ₃ , δ): 1.24-1.52 (4H, m), 1.45 (3H, d, J = 7Hz), 1.53-1.78 (8H, m), 1.90-2.05 (4H, m), 2.20- 2.30 (2H, m), 4.09-4.20 (1H, m), 5.20-5.30 (1H, m), 5.94 (1H, s), 6.05 (2H, s), 6.79 (1H, d, J = 8Hz), 6.85 (1H, d, J = 8Hz), 7.28 (1H, d, J = 2Hz), 7.31 (1H, dd, J = 8Hz, 2Hz), 7.76 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3756, 3076, 2356, 1730, 1358
Rf value: 0.60

Example 15 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  (2RS, 3S) -N synthesized in Reference Example 14 instead of (2RS, 3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide by a method according to Example 1 Using 268 mg of -cyclopentyl-3-amino-2-hydroxy-4-methylpentanamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl ] 253 mg (yield 56%) of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.84 (3H, d, J = 7Hz), 1.01 (3H, d, J = 7Hz), 1.28-1.50 (5H, m), 1.55-1.76 (7H, m), 1.86-2.18 (6H, m), 2.35-2.48 (1H, m), 3.39 (4H, t, J = 5Hz), 3.72 (5H, t, J = 5Hz), 4.10-4.22 (1H, m), 4.45 (1H, s), 5.15 (1H, dd, J = 8Hz, 8Hz), 6.82 (1H, d, J = 8Hz), 8.03 (1H, d, J = 8Hz)
IR (ν, KBr, cm ⁻¹ ): 3808, 2860, 1730, 1454, 1394, 1338, 1300
Rf value: 0.56

Example 16 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl] -1- [N- (3,4-methylenedioxyphenylcarbonyl) amino ] Cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 synthesized in Reference Example 14 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 4 Using 268 mg of -hydroxy-4-methylpentanamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl] -1- [N- ( 3,4-Methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxamide (82 mg, 17% yield) was obtained.

1H-NMR (CDCl ₃ , δ): 0.83 (3H, d, J = 7 Hz), 1.01 (3H, d, J = 7 Hz), 1.30-1.52 (5H, m), 1.52-1.77 (7H, m), 1.90-2.05 (4H, m), 2.22-2.31 (2H, m), 2.38-2.48 (1H, m), 4.07-4.16 (1H, m), 5.18 (1H, dd, J = 8Hz, 8Hz), 5.94 (1H, s), 6.05 (2H, s), 6.80 (1H, d, J = 8Hz), 6.86 (1H, d, J = 8Hz), 7.27 (1H, d, J = 8Hz), 7.31 (1H, dd, J = 8Hz, 2Hz), 7.92 (1H, d, J = 8Hz)
IR (ν, KBr, cm ⁻¹ ): 3404, 2872, 2248, 1726, 1608, 1392, 1360
Rf value: 0.37

Example 17 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl] -1- [N-[(4-methoxycarbonyl) piperazine-1-carbonyl Amino] cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 synthesized in Reference Example 14 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 5 Using 268 mg of -hydroxy-4-methylpentanamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl] -1- [N- [ There was obtained 279 mg (yield 55%) of (4-methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.83 (3H, d, J = 7Hz), 1.01 (3H, d, J = 7Hz), 1.25-1.48 (5H, m), 1.45-1.76 (7H, m), 1.87-2.20 (6H, m), 2.34-2.45 (1H, m), 3.34-3.47 (4H, m), 3.53 (4H, br-s), 3.73 (3H, s), 4.10-4.20 (1H, m ), 4.46 (1H, s), 5.15 (1H, dd, J = 8Hz, 8Hz), 6.81 (1H, d, J = 8Hz), 7.96 (1H, d, J = 8Hz)
IR (ν, KBr, cm ⁻¹ ): 3804, 3420, 2868, 1408, 1374, 1288, 1192
Rf value: 0.53

Example 18 N-[(S) -1-Amino-1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

例１に準ずる方法で（２ＲＳ，３Ｓ）−Ｎ−（２−メチル−２−プロピル）−３−アミノ−２−ヒドロキシヘプタンアミドの代わりに、参考例１５で合成した（２ＲＳ，３Ｓ）−３−アミノ−２−ヒドロキシヘプタンアミド０．７７ｇを用いて標記Ｎ−〔（Ｓ）−１−アミノ−１，２−ジオキソ−３−ヘプチル〕−１−〔Ｎ−（モルホリン−４−カルボニル）アミノ〕シクロヘキサンカルボキサミド０．９８ｇ（収率５１％）を得た。

(2RS, 3S) -3 synthesized in Reference Example 15 in place of (2RS, 3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide by a method according to Example 1 Using 0.77 g of amino-2-hydroxyheptanamide, the title N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino ] 0.98 g (51% yield) of cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-1.45 (7H, m), 1.57-1.80 (4H, m), 1.80-2.00 (3H, m), 2.02- 2.18 (2H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.49 (1H, s), 5.10-5.18 (1H, m), 5.54 (1H, s ), 6.76 (1H, s), 7.98 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3356, 2936, 1696, 1670, 1650, 1524, 1258
Rf value: 0.87

Example 19 N-[(S) -1-Amino-1,2-dioxo-3-heptyl] -1- [N- (phenylmethoxycarbonyl) amino] cyclohexanecarboxamide

  (2RS, 3S) -3-amino-2-hydroxyheptanamide synthesized in Reference Example 15 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 3 Using 0.64 g, 0.7 g (yield 66) of the title N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- [N- (phenylmethoxycarbonyl) amino] cyclohexanecarboxamide %).

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.20-1.50 (7H, m), 1.50-1.70 (4H, m), 1.80-1.98 (3H, m), 1.98- 2.12 (2H, m), 4.95 (1H, s), 5.11 (2H, s), 5.11-5.22 (1H, m), 5.45 (1H, s), 6.71 (1H, s), 7.20-7.45 (6H, m)
IR (ν, KBr, cm ⁻¹ ): 3448, 3304, 2936, 1722, 1678, 1530, 1248
Rf value: 0.57

Example 20 N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxamide

  (2RS, 3S) -3-amino-2-hydroxyheptanamide synthesized in Reference Example 15 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 4 Using 0.64 g, the title N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxamide 0 Obtained .79 g (45% yield).

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.20-1.55 (7H, m), 1.60-1.80 (4H, m), 1.85-2.10 (3H, m), 2.18- 2.35 (2H, m), 5.12-5.22 (1H, m), 5.42 (1H, s), 5.96 (1H, s), 6.05 (2H, s), 6.72 (1H, s), 6.85 (1H, d, J = 8Hz), 7.27 (1H, s), 7.30 (1H, dd, J = 8Hz, 2Hz), 7.89 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3320, 2936, 1658, 1486, 1260, 1038
Rf value: 0.70

Example 21 N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- (phenylsulfonylmethyl) cyclohexanecarboxamide

  Example 1 using 1.12 g of 1- (phenylsulfonylmethyl) cyclohexanecarboxylic acid instead of 1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxylic acid in the same manner as in Example 18. Yielded 1.05 g (yield 62%) of the title N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- (phenylsulfonylmethyl) cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.90 (3H, t, J = 7 Hz), 1.20-1.70 (10H, m), 1.70-1.95 (3H, m), 1.95-2.10 (3H, m), 3.47 ( 2H, s), 5.15-5.25 (1H, m), 5.60 (1H, s), 6.80 (1H, s), 6.82 (1H, d, J = 7Hz), 7.53 (2H, t, J = 8Hz), 7.62 (1H, t, J = 7Hz), 7.89 (2H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3352, 2936, 1698, 1520, 1308, 1150, 600
Rf value: 0.64

Example 22 N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- [N-[(2-methyl-2-propyloxycarbonyl) piperidine-4-carbonyl] amino] cyclohexane Carboxamide

  1- [N- [1-[(2-methyl-2) synthesized in Reference Example 6 in place of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid in Example 1 was prepared in the same manner as in Example 1. -Propyloxycarbonyl) piperidine-4-carbonyl] amino] cyclohexanecarboxylic acid, 1.06 g, and (2RS, 3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide. Instead, the title N-[(S) -1-amino-1,2-dioxo-3-heptyl was synthesized using 0.48 g of (2RS, 3S) -3-amino-2-hydroxyheptanamide synthesized in Reference Example 15. ] 1- [N-[(2-Methyl-2-propyloxycarbonyl) piperidine-4-carbonyl] amino] cyclohexanecarboxamide (yield 49) ) Was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-1.50 (6H, m), 1.46 (9H, s), 1.60-1.80 (7H, m), 1.80-2.00 ( 5H, m), 2.10-2.20 (2H, m), 2.30 (1H, tt, J = 11, 3Hz), 2.70-2.90 (2H, m), 4.10-4.30 (2H, m), 5.10-5.20 (1H , m), 5.43 (1H, s), 5.47 (1H, br-s), 6.73 (1H, br-s), 7.77 (1H, d, J = 5Hz)
IR (ν, KBr, cm ⁻¹ ): 3448, 3316, 2940, 2860, 1670, 1528, 1172
Rf value: 0.62

Example 23 N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- [N- [4- (2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] amino ] Cyclohexanecarboxamide

  1- [N- [4- (2-Methyl-2-) synthesized in Reference Example 8 in place of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid in Example 1 was prepared in the same manner as Example 1. Propyloxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid 1.06 g, instead of (2RS, 3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide Using 0.43 g of (2RS, 3S) -3-amino-2-hydroxyheptanamide synthesized in Reference Example 15, the title N-[(S) -1-amino-1,2-dioxo-3-heptyl] 0.92 g of -1- [N- [4- (2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide (yield 6 %) Was obtained.

1H-NMR (CDCl ₃ , δ): 0.85 (3H, t, J = 7Hz), 1.20-1.50 (6H, m), 1.47 (9H, s), 1.58-1.70 (5H, m), 1.80-2.00 ( 3H, m), 2.00-2.20 (2H, m), 3.30-3.40 (4H, m), 3.40-3.60 (4H, m), 4.49 (1H, s), 5.09-5.14 (1H, m), 5.48 ( 1H, br-s), 6.75 (1H, br-s), 7.97 (1H, d, J = 5Hz)
IR (ν, KBr, cm ⁻¹ ): 3330, 2936, 1686, 1522, 1464, 1254, 1234, 1170
Rf value: 0.63

Example 24 N-[(S) -1,2-dioxo-1-methoxy-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  (2RS, 3S) -3 synthesized in Reference Example 17 instead of (2RS, 3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide by a method according to Example 1 Using 1.02 g of methyl amino-2-hydroxyheptanoate, the title N-[(S) -1,2-dioxo-1-methoxy-3-heptyl] -1- [N- (morpholine-4-carbonyl ) Amino] cyclohexanecarboxamide 0.83 g (yield 35%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.82-0.98 (3H, m), 1.20-1.45 (7H, m), 1.50-1.70 (4H, m), 1.80-2.00 (3H, m), 2.00-2.18 ( 2H, m), 3.38 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 3.88 (3H, s), 4.44 (1H, s), 4.95-5.04 (1H, m), 7.97 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3312, 2928, 1736, 1650, 1630, 1536, 1260

Example 25 N-[(S) -1-oxo-1-carboxy-2-hexyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  N-[(S) -1,2-dioxy-1-methoxy-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 77 mg (0.19 mmol) synthesized in Example 24 was added. After dissolving in methanol and adding 0.4 ml of 1N sodium hydroxide aqueous solution and stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in water, neutralized with 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 52 mg of the title N-[(S) -1-oxo-1-carboxy-2-hexyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide. (Yield 70%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.80-0.98 (3H, m), 1.20-1.50 (7H, m), 1.50-1.80 (4H, m), 1.80-2.00 (3H, m), 2.00-2.20 ( 2H, m), 3.40 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.00-5.00 (1H, br-s), 4.65 (1H, s), 4.85-5.00 (1H , m), 8.00 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3388, 2932, 1644, 1528, 1260

Example 26 N-[(S) -1,2-dioxo-1- [N- (3-pyrazolyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  Under ice cooling, 795 mg (2 mmol) of N-[(S) -1-carboxy-1-oxo-2-hexyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide obtained in Example 25, To a solution of 166 mg (2 mmol) of 3-aminopyrazole and 324 mg (2.4 mmol) of 1-hydroxybenzotriazole in 20 ml of methylene chloride was added 460 mg (2.4 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. Thereafter, the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate and reduced pressure. The solvent was distilled off under. The residue was purified by silica gel column chromatography, and the title N-[(S) -1,2-dioxo-1- [N- (3-pyrazolyl) amino] -3-heptyl] -1- [N- 218 mg (yield 26%) of (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.23-1.78 (10H, m), 1.82-2.17 (6H, m), 3.32-3.44 (4H, m), 3.62- 3.76 (4H, m), 4.55-4.64 (1H, m), 4.75 (1H, s), 6.31 (1H, br-s), 6.64 (1H, br-s), 7.41 (1H, d, J = 2Hz ), 10.20 (1H, s)
IR (ν, KBr, cm ^-1 ): 3296, 1652
Rf value: 0.78

Example 27 N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- [N- (piperazine-1-carbonyl) amino] cyclohexanecarboxamide

  N-[(3S) -1,2-dioxo-1-amino-3-heptyl] -1-[[4- (2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] synthesized in Example 23 Amino] cyclohexanecarboxamide 0.45 g (0.9 mmol) was dissolved in 5 ml of methanol, 190 mg (1 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 50 ° C. for 4 hours. The reaction mixture was concentrated, and the residue was dissolved in 1N hydrochloric acid and washed with ethyl acetate. Potassium carbonate was added to the aqueous layer to adjust the pH to 10, followed by extraction with chloroform three times. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title N-[(S) -1-amino-1,2-dioxo-3-heptyl] -1- [N- (piperazine-1-carbonyl) 0.088 g (24% yield) of amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.90 (3H, t, J = 7Hz), 1.20-2.20 (16H, m), 2.80-3.00 (4H, m), 3.30-3.40 (4H, m), 4.60- 4.70 (1H, m), 4.76 (1H, s), 5.33 (1H, br-s), 5.56 (1H, br-s), 8.30 (1H, m)
IR (ν, KBr, cm ⁻¹ ): 3396, 2936, 1680, 1654, 1539, 1260

Example 28 N-[(S) -1- [N- (3-chlorophenylmethyl) amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  799 mg (2 mmol) of (2RS, 3S) -2-hydroxy-3- [N- [1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarbonyl] amino] heptanoic acid obtained in Reference Example 16 under ice cooling ), 3-chlorobenzylamine 283 mg (2 mmol) and 1-hydroxybenzotriazole 324 mg (2.4 mmol) in methylene chloride 20 ml solution 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 460 mg (2.4 mmol) And then stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate and reduced pressure. The solvent was distilled off under. The residue was purified by silica gel column chromatography, and N-[(2RS, 3S) -1- [N- (3-chlorophenylmethyl) amino] -2-hydroxy-1-oxo-3-heptyl] -1 -[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 876 mg was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.23-2.05 (16H, m), 3.28-3.38 (4H, m), 3.64-3.71 (4H, m), 3.92- 4.01 (1 / 2H, m), 4.10-4.20 (1H, m), 4.33-4.49 (5 / 2H, m), 4.59 (1 / 2H, s), 4.66 (1 / 2H, s), 5.09 (1 / 2H, d, J = 6Hz), 5.23 (1 / 2H, d, J = 6Hz), 6.61 (1 / 2H, d, J = 8Hz), 6.75 (1 / 2H, d, J = 8Hz), 7.14 -7.29 (4H, m), 7.33 (1 / 2H, t, J = 7Hz), 7.61 (1 / 2H, t, J = 7Hz)

  Then, under ice cooling, the N-[(2RS, 3S) -2-hydroxy-1- [N- (3-chlorophenylmethyl) amino] -1-oxo-3-heptyl] -1- [N- (morpholine- 4-carbonyl) amino] cyclohexanecarboxamide 876 mg (1.68 mmol) and triethylamine 1.02 g (10.1 mmol) in dimethyl sulfoxide 10 ml and methylene chloride 10 ml mixed solution of sulfur trioxide pyridine complex 1.61 g (1.68 mmol) Dimethyl sulfoxide 5 ml solution was added and stirred for 2 hours. The reaction mixture was poured into ice water, ethyl acetate was added, and the mixture was washed twice with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Was distilled off. The residue was purified by silica gel column chromatography, and the title N-[(S) -1- [N- (3-chlorophenylmethyl) amino] -1,2-dioxo-3-heptyl] -1- [N -(Morpholine-4-carbonyl) amino] cyclohexanecarboxamide (546 mg, yield 52%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.21-1.42 (6H, m), 1.54-1.74 (5H, m), 1.82-2.18 (5H, m), 3.37 ( 4H, t, J = 5Hz), 3.65-3.74 (4H, m), 4.43 (1H, s), 4.45 (2H, d, J = 6Hz), 5.11-5.16 (1H, m), 7.13-7.30 (5H , m), 8.01 (1H, d, J = 7Hz)
IR (ν, KBr, cm ^-1 ): 3328, 1660
Rf value: 0.56

Example 29 N-[(S) -1,2-dioxo-1- [N- (3-fluorophenylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexane Carboxamide

  In the same manner as in Example 28, using 250 mg of 3-fluorobenzylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (3-fluorophenylmethyl) Amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (597 mg, yield 59%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.23-1.42 (6H, m), 1.57-1.74 (5H, m), 1.82-2.13 (5H, m), 3.37 ( 4H, t, J = 5Hz), 3.65-3.73 (4H, m), 4.43 (1H, s), 4.47 (2H, d, J = 6Hz), 5.09-5.16 (1H, m), 6.94-7.03 (2H , m), 7.05 (1H, d, J = 7Hz), 7.21 (1H, t, J = 6Hz), 7.25-7.34 (1H, m), 8.02 (1H, 6Hz)
IR (ν, KBr, cm ^-1 ): 3320, 1658
Rf value: 0.62

Example 30 N-[(S) -1,2-dioxo-1- [N- (3-nitrophenylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexane Carboxamide

  In the same manner as in Example 28, using 377 mg of 3-nitrobenzylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (3-nitrophenylmethyl) Amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 571 mg (yield 54%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.22-1.42 (6H, m), 1.55-1.72 (5H, m), 1.82-2.13 (5H, m), 3.38 ( 4H, t, J = 5Hz), 3.64-3.73 (4H, m), 4.46 (1H, s), 4.58 (2H, d, J = 6Hz), 5.05-5.14 (1H, m), 7.38 (1H, t , J = 6Hz), 7.53 (1H, t, J = 8Hz), 7.64 (1H, d, J = 8Hz), 8.05 (1H, d, J = 6Hz), 8.12-8.18 (2H, m)
IR (ν, KBr, cm ^-1 ): 3340, 1658
Rf value: 0.63

Example 31 N-[(S) -1- (N-methylamino) -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  The title N-[(S) -1- (N-methylamino) -1,2-dioxo-3-heptyl]-using 0.06 g of methylamine instead of 3-chlorobenzylamine in the same manner as in Example 28 0.28 g (yield 38%) of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-1.45 (7Hz, m), 1.55-1.80 (4H, m), 1.80-2.02 (3H, m), 2.02- 2.18 (2H, m), 2.88 (3H, d, J = 5Hz), 3.38 (3H, d, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.46 (1H, s), 5.12-5.22 (1H, m), 6.90 (1H, d, J = 4Hz), 7.95 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3352, 2936, 1664, 1532, 1258, 1116
Rf value: 0.71

Example 32 N-[(S) -1- (N-2-propylamino) -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 95 mg of isopropylamine instead of 3-chlorobenzylamine, the title N-[(S) -1- (N-2-propylamino) -1,2-dioxo-3-heptyl]- 220 mg (yield 50%) of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20 (6H, d, J = 7Hz), 1.24-1.45 (6H, m), 1.58-1.70 (5H, m), 1.85-2.02 (2H, m), 3.39 (4H, t, J = 5Hz), 3.88-3.98 (4H, m), 3.98-4.10 (1H, m), 4.47 (1H, s), 5.17-5.22 (1H , m), 6.70 (1H, d, J = 8Hz), 7.91 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3760, 2324, 2232, 1730, 1336
Rf value: 0.66

Example 33 N-[(S) -1- (N-cyclohexylamino) -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 157 mg of cyclohexylamine instead of 3-chlorobenzylamine, the title N-[(S) -1- (N-cyclohexylamino) -1,2-dioxo-3-heptyl] -1- 199 mg (yield 42%) of [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.11-1.44 (12H, m), 1.56-1.78 (7H, m), 1.85-2.03 (5H, m), 2.06- 2.16 (2H, m), 3.39 (4H, t, J = 5Hz), 3.66-3.80 (5H, m), 4.44 (1H, s), 5.19-5.23 (1H, m), 6.75 (1H, d, J = 8Hz), 7.91 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3672, 3344, 1996, 1732, 1374
Rf value: 0.51

Example 34 N-[(S) -1- (N-phenylamino) -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  The title N-[(S) -1- (N-phenylamino) -1,2-dioxo-3-heptyl] -1 using 0.17 g of aniline instead of 3-chlorobenzylamine in the same manner as in Example 28 There was obtained 0.33 g (yield 37%) of-[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.82-0.98 (3H, m), 1.23-1.45 (7H, m), 1.50-1.80 (4H, m), 1.80-2.18 (5H, m), 3.36 (4H, t, J = 5Hz), 3.70 (4H, t, J = 5Hz), 4.44 (1H, s), 5.20-5.30 (1H, m), 7.17 (1H, t, J = 8Hz), 7.36 (2H, td , J = 7Hz, 2Hz), 7.63 (2H, dd, J = 8Hz, 1Hz), 8.07 (1H, d, J = 6Hz), 8.64 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3320, 2932, 1684, 1648, 1628, 1536, 1448, 1260, 1116, 760
Rf value: 0.54

Example 35 N-[(S) -1- (N-morpholine-4-amino) -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 163 mg of N-aminomorpholine instead of 3-chlorobenzylamine, the title N-[(S) -1- (N-morpholine-4-amino) -1,2-dioxo-3- 82 mg (17% yield) of heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.21-1.43 (7H, m), 1.51-1.70 (4H, m), 1.84-2.15 (5H.m), 2.80- 2.92 (4H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 3.81 (4H, t, J = 5Hz), 4.43 (1H, s), 5.08-5.18 (1H, m), 7.61 (1H, s), 7.95 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3340, 2364, 1730, 1454, 1306, 1172
Rf value: 0.77

Example 36 N-[(S) -1,2-dioxo-1- [N- (3-methoxyphenylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexane Carboxamide

  In the same manner as in Example 28, using 1.1 g of 3-methoxyphenylmethylamine instead of 3-chloro-phenylmethylamine, the title N-[(S) -1,2-dioxo-1- [N- (3- There were obtained 735 mg (yield 36%) of methoxyphenylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.26-1.40 (7H, m), 1.65-1.71 (4H, m), 1.85-2.11 (5H, m), 3.37 ( 4H, t, J = 5Hz), 3.70 (4H, t, J = 5Hz), 3.80 (3H, s), 4.45 (1H, s), 4.45 (2H, d, J = 6Hz), 5.14 (1H, ddd , J = 5Hz, 7Hz, 8Hz), 6.42-6.87 (3H, m), 7.15 (1H, t, J = 6Hz), 7.22-7.25 (1H, m), 7.99 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3322, 2931, 1685, 1648, 1529, 1454, 1257, 1112
Rf value: 0.61

Example 37 N-[(S) -1,2-dioxo-1- [N- (2-thiazolyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 0.7 g of 2-aminothiazole instead of 3-chlorophenylmethylamine of Example 28, the title N-[(S) -1,2-dioxo-1- [N- (2-thiazolyl) was used. ) Amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 0.18 g (13% yield) was obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 6Hz), 1.20-2.00 (16H, m), 3.30-3.50 (4H, m), 3.70-3.80 (4H, m), 4.40 ( 1H, s), 5.15-5.20 (1H, m), 7.08 (1H, d, J = 3Hz), 7.55 (1H, d, J = 3Hz), 8.22 (1H, d, J = 5Hz), 10.20-10.40 (1H, br-s)
IR (ν, KBr, cm ⁻¹ ): 3356, 2936, 2864, 1650, 1536, 1258, 1112
Rf value: 0.64

Example 38 N-[(S) -1,2-dioxo-1- [N- (phenylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 536 mg of phenylmethylamine instead of 3-chloro-phenylmethylamine, the title N-[(S) -1,2-dioxo-1- [N- (phenylmethyl) amino] -3 -Heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 900 mg (yield 38%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.87-0.91 (3H, m), 1.24-1.42 (5H, m), 1.63-1.71 (7H, m), 1.85-2.17 (4H, m), 3.37 (4H, t, J = 5Hz), 3.70 (4H, t, J = 5 Hz), 4.44 (1H, s), 4.46 (2H, dd, J = 3Hz, 6Hz), 5.16 (1H, ddd, J = 5Hz, 7Hz , 8Hz), 7.16-7.20 (1H, m), 7.27-7.36 (5H, m), 7.96 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3317, 2929, 2857, 1658, 1513, 1454, 1253
Rf value: 0.58

Example 39 N-[(S) -1,2-dioxo-1- [N- (tetrahydro-2-furylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] Cyclohexane carboxamide

  In the same manner as in Example 28, using 202 mg of tetrahydrofurfurylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (tetrahydro-2-furylmethyl) amino] ] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (510 mg, yield 53%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.22-1.44 (7H, m), 1.47-1.70 (5H, m), 1.83-2.06 (8H, m), 3.21- 3.28 (1H, m), 3.34-3.43 (4H, m), 3.49-3.58 (1H, m), 3.66-3.79 (5H, m), 3.83-3.90 (1H, m), 3.93-4.03 (1H, m ), 4.46 (1H, s), 5.18-5.25 (1H, m), 7.17 (1H, br-s), 7.93 (1H, t, J = 7Hz)
IR (ν, KBr, cm ^-1 ): 3324, 1670
Rf value: 0.67

Example 40 N-[(S) -1,2-dioxo-1- [N- (2-oxo-tetrahydro-3-furyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 364 mg of α-amino-γ-butyrolactone instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (2-oxo- 341 mg (36% yield) of tetrahydro-3-furyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.22-1.46 (6H, m), 1.53-1.67 (4H, m), 1.77-1.98 (4H, m), 2.03- 2.39 (3H, m), 2.71-2.83 (1H, m), 3.32-3.42 (4H, m), 3.66-3.74 (4H, m), 4.26-4.35 (1H, m), 4.42-4.63 (3H, m ), 4.88-5.04 (1H, m), 7.23-7.33 (1H, m), 8.21 (1 / 2H, d, J = 7Hz), 8.31 (1 / 2H, d, J = 7Hz)
IR (ν, KBr, cm ^-1 ): 3360, 1666
Rf value: 0.80

Example 41 N-[(S) -1- [N- (cyclopentylmethyl) amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 399 mg of cyclopentylmethylamine instead of 3-chloro-phenylmethylamine, the title N-[(S) -1- [N- (cyclopentylmethyl) amino] -1,2-dioxo-3 -Heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 190 mg (yield 20%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 5Hz), 1.17-1.42 (10H, m), 1.50-1.80 (8H, m), 1.86-2.12 (7H, m), 3.22 ( 2H, dd, J = 6Hz, 7Hz), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.45 (1H, s), 5.17 (1H, ddd, J = 5Hz, 7Hz, 8Hz), 6.91 (1H, br-s), 7.92 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3328, 2953, 1656, 1525
Rf value: 0.46

Example 42 N-[(S) -1- [N- (1-Methyl-cyclopentyl) amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexane Carboxamide

  In the same manner as in Example 28, using 452.8 mg of 1-methyl-cyclopentylamine instead of 3-chloro-phenylmethylamine, the title N-[(S) -1- [N- (1-methyl-cyclopentyl) amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (228 mg, yield 23%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 5Hz), 1.26-1.41 (9H, m), 1.42 (3H, s), 1.60-1.72 (9H, s), 1.86-2.12 ( 6H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.46 (1H, s), 5.17 (1H, ddd, J = 5Hz, 7Hz, 8Hz), 6.79 (1H, s), 7.89 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3313, 2958, 2933, 1656, 1521, 1255
Rf value: 0.42

Example 43 N-[(S) -1,2-dioxo-1- [N- (1-indanyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 533 mg of 1-aminoindan instead of 3-chloro-phenylmethylamine, the title N-[(S) -1,2-dioxo-1- [N- (1-indanyl) amino] -3-mg of heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained (yield 28%).

1H-NMR (CDCl ₃ , δ): 0.88-0.92 (3H, m), 1.21-1.42 (7H, m), 1.62-1.73 (5H, m), 1.84-2.09 (5H, m), 2.56-2.65 ( 1H, m), 2.86-3.00 (1H, m), 3.01-3.06 (1H, m), 3.37-3.40 (4H, m), 3.68-3.72 (4H, m), 4.46 (1H, s), 5.22- 5.29 (1H, m), 5.39-5.47 (1H, m), 7.07 (1H, d, J = 8Hz), 7.19-7.31 (4H, m), 7.94 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3317, 2929, 1654, 1525, 1255
Rf value: 0.46

Example 44 N-[(S) -1,2-dioxo-1- [N- (2-indanyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 533 mg of 2-aminoindane instead of 3-chloro-phenylmethylamine, the title N-[(S) -1,2-dioxo-1- [N- (2-indanyl) amino] -3-mg of heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained (33% yield).

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.25-1.66 (11H, m), 1.85-2.21 (5H, m), 2.85 (2H, dt, J = 5Hz, 16Hz ), 3.29-3.39 (6H, m), 3.71 (4H, t, J = 5Hz), 4.44 (1H, s), 4.68-4.72 (1H, m), 5.18 (1H, ddd, J = 5Hz, 7Hz, 9Hz), 7.07 (1H, d, J = 9 Hz), 7.16-7.23 (4H, m), 7.92 (1H, d, J = 7Hz)
IR (ν, KBr, cm ^-1 ): 3311, 2933, 1652
Rf value: 0.47

Example 45 N-[(S) -1- [N- (cyclobutyl) amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 284 mg of cyclobutylamine instead of 3-chloro-phenylmethylamine, the title N-[(S) -1- [N- (cyclobutyl) amino] -1,2-dioxo-3-heptyl was used. ] 440 mg (yield 24%) of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.21-1.54 (7H, m), 1.62-1.81 (7H, m), 1.86-2.11 (6H, m), 2.31- 2.39 (2H, m), 3.37-3.42 (4H, m), 3.71-3.73 (4H, m), 4.30-4.39 (1H, m), 4.45 (1H, s), 5.14 (1H, ddd, J = 5Hz , 7Hz, 8Hz), 7.00 (1H, d, J = 7Hz), 7.91 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3330, 2933, 1649, 1527, 1257
Rf value: 0.60

Example 46 N-[(S) -1,2-dioxo-1- [N- (3-pyridyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 376 mg of 3-aminopyridine instead of 3-chloro-phenylmethylamine, the title N-[(S) -1,2-dioxo-1- [N- (3-pyridyl) amino] There was obtained 30 mg (yield 2%) of -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.90 (3H, t, J = 7Hz), 1.24-1.30 (5H, m), 1.32-1.74 (6H, m), 1.85-2.11 (5H, m), 3.36- 3.38 (4H, m), 3.69-3.72 (4H, m), 4.51 (1H, s), 5.17 (1H, ddd, J = 5Hz, 6Hz, 9Hz), 7.32 (1H, dd, J = 5Hz, 8Hz) , 8.15 (1H, d, J = 6Hz), 8.21 (1H, ddd, J = 1Hz, 3Hz, 8Hz), 8.41 (1H, dd, J = 1Hz, 5Hz), 8.72 (1H, d, J = 3Hz) , 8.79 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3052, 2300, 1674, 1628, 1276
Rf value: 0.67

Example 47 N-[(S) -1,2-dioxo-1- [N- (furylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 389 mg of furylmethylamine instead of 3-chloro-phenylmethylamine, the title N-[(S) -1,2-dioxo-1- [N- (furylmethyl) amino] -3 -Heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (375 mg, yield 20%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.86-0.90 (3H, m), 1.24-1.42 (6H, m), 1.63-1.71 (3H, m), 1.83-2.11 (7H, m), 3.38 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz), 4.46 (2H, dd, J = 1Hz, 6Hz), 4.52 (1H, s), 5.15 (1H, ddd, J = 5Hz, 7Hz, 9Hz), 6.26 (1H, dd, J = 1Hz, 3Hz), 6.32 (1H, dd, J = 2Hz, 3 Hz), 7.20 (1H, t, J = 6Hz), 7.35 (1H, dd, J = 1Hz , 2Hz), 7.93 (1H, d, J = 7Hz)
IR (ν, KBr, cm ^-1 ): 3376, 1658
Rf value: 0.67

Example 48 N-[(S) -1- (N, N-dimethylamino) -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 0.009 g of dimethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1- (N, N-dimethylamino) -1,2-dioxo-3-heptyl ] 0.33 g (39% yield) of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.25-1.45 (7H, m), 1.59-1.73 (3H, m), 1.73-1.95 (3H, m), 1.98- 2.15 (3H, m), 2.94 (3H, s), 3.00 (3H, s), 3.37 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz), 4.48 (1H, s), 4.50-4.58 (1H, s), 7.53 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 2932, 1666, 1642, 1522, 1260, 1124
Rf value: 0.69

Example 49 N-[(S) -1,2-dioxo-1- [N- (1-methyl-cyclopentylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] Cyclohexane carboxamide

  In the same manner as in Example 28, using 453 mg of 1-methyl-cyclopentylmethylamine instead of 3-chloro-phenylmethylamine, the title N-[(S) -1,2-dioxo-1- [N- (1-methyl -Cyclopentylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 430 mg (yield 22%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.86-0.90 (3H, m), 0.98 (3H, s), 1.31-1.45 (12H, m), 1.59-1.70 (7H, m), 1.86-1.97 (3H, m), 2.09-2.12 (2H, m), 3.19 (2H, dd, J = 5Hz, 6Hz), 3.39 (4H, t, J = 5Hz), 4.45 (1H, s), 5.18 (1H, ddd, J = 5Hz, 7Hz, 8Hz), 6.94 (1H, br-s), 7.94 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3368, 2932, 1676, 1662, 1612, 1538
Rf value: 0.36

Example 50 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (phenylsulfonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 2, 567 mg of 1- [N- (phenylsulfonyl) amino] cyclohexanecarboxylic acid obtained in Reference Example 18 was used instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid. 786 mg (yield 80%) of the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (phenylsulfonyl) amino] cyclohexanecarboxamide. Obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.09-1.53 (12H, m), 1.57-1.77 (5H, m), 1.78-2.05 (7H, m), 4.13- 4.23 (1H, m), 5.10 (1H, dt, J = 8Hz, 5Hz), 5.17 (1H, s), 6.86 (1H, d, J = 8Hz), 7.06 (1H, d, J = 7Hz), 7.45 -7.58 (3H, m), 7.88 (2H, dd, J = 8Hz, 2Hz)
IR (ν, KBr, cm ⁻¹ ): 3360, 1666
Rf value: 0.32

Reference Example 19 (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-5-methylhexanamide

  Instead of (S) -2- [N- (2-methyl-2-propyloxycarbonyl) amino] hexanal in the same manner as in Reference Example 10, (S) -2- [N- (2-methyl-2- Propyloxycarbonyl) amino] -4-methylpentanal (18.64 g) was used to give 6.72 g (34% yield) of the title (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxy-5-methylhexanamide. )

1H-NMR (CDCl ₃ , δ): 0.88 (3 / 2H, d, J = 7 Hz), 0.93 (4H, d, J = 7 Hz), 0.96 (1 / 2H, d, J = 7 Hz), 1.20-1.48 (4H, m), 1.65-1.73 (5H, m), 1.93-2.04 (2H, m), 3.19-3.25 (0.4H, m), 3.22-3.29 (0.6H, m), 3.76 (0.6H, d , J = 3Hz), 3.93 (0.4H, d, J = 5Hz), 4.16-4.25 (1H, m), 7.11 (0.6H, d, J = 8Hz), 7.29 (0.4H, d, J = 8Hz)

Reference Example 20 1- [N- (4-Methoxybenzenesulfonyl) amino] cyclohexanecarboxylic acid

  8.1 g (20 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester / p-toluenesulfonate was added to 50 ml of water, and 4.1 g (20 mmol) of 4-methoxybenzenesulfonyl chloride and 50 ml of ethyl acetate were added while stirring. Stir at room temperature. After completion of the reaction, the reaction solution was transferred to a separatory funnel, the aqueous layer was removed, and the organic layer was washed successively with 10% aqueous potassium hydrogen sulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were stirred in ether overnight to obtain 4.36 g of 1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester.

  Subsequently, 1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxylic acid was used instead of 1- [N- (3,4-methylenedioxyphenylcarbonyl) amino] cyclohexanecarboxylic acid ethyl ester by the method according to Reference Example 4. 450 mg (yield 26%) of the title 1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxylic acid was obtained using 1.0 g (2.5 mmol) of acid phenylmethyl ester.

1H-NMR (CDCl ₃ , δ): 1.26-1.89 (10H, m), 3.88 (3H, s), 4.78 (1H, s), 6.95-7.00 (2H, m), 7.82-7.89 (2H, m)

Reference Example 21 1- [N- (4-Nitrobenzenesulfonyl) amino] cyclohexanecarboxylic acid

  In accordance with Reference Example 20, 4.4 g of 4-nitrobenzenesulfonyl chloride was used instead of 4-methoxybenzenesulfonyl chloride, and 6.1 g of the title 1- [N- (4-nitrobenzenesulfonyl) amino] cyclohexanecarboxylic acid (yield) 72.9%).

1H-NMR (CDCl ₃ , δ): 1.23-1.35 (4H, m), 1.47-1.49 (2H, m), 1.80-2.05 (4H, m), 8.06-8.08 (2H, m), 8.32-8.36 ( 2H, m)

Reference Example 22 (2RS, 3S) -N-cyclopentylmethyl-3-amino-2-hydroxy-5-methylhexanamide

  In the same manner as in Reference Example 19, 496 mg of cyclopentylmethylamine was used instead of cyclopentylamine, and 603 mg of the title (2RS, 3S) -N-cyclopentylmethyl-3-amino-2-hydroxy-5-methylhexanamide (yield 58%) )

1H-NMR (CDCl ₃ , δ): 0.89-0.96 (6H, m), 1.15-1.37 (3H, m), 1.49-1.79 (8H, m), 2.00-2.07 (1H, m), 3.10-3.32 ( 2H, m), 3.84 (1H, br-s), 4.06-4.81 (1 / 2H, m), 4.15-4.18 (1 / 2H, m), 5.16 (1 / 2H, d, J = 6Hz), 5.23 (1 / 2H, br-s), 6.89 (1 / 2H, br-s), 6.95 (1 / 2H, br-s)

Reference Example 23 1- [N- (Quinolin-8-sulfonyl) amino] cyclohexanecarboxylic acid

  In accordance with the method of Reference Example 20, 4.5 g of quinoline-8-sulfonyl chloride was used instead of 4-nitrobenzenesulfonyl chloride, and 4.9 g of the title 1- [N- (quinoline-8-sulfonyl) amino] cyclohexanecarboxylic acid was obtained. Rate 57.7%).

1H-NMR (CDCl ₃ , δ): 1.08-1.24 (4H, m), 1.33-1.37 (2H, m), 1.85-1.86 (4H, m), 7.54 (1H, dd, J = 4Hz, 8Hz), 7.69 (1H, d, J = 8Hz), 8.01 (1H, dd, J = 2Hz, 8Hz), 8.26 (1H, dd, J = 1Hz, 8Hz), 8.31 (1H, dd, J = 1Hz, 8Hz), 9.01 (1H, dd, J = 2Hz, 4Hz)

Reference Example 24 1- [N- (morpholine-4-sulfonyl) amino] cyclohexanecarboxylic acid

  A methylene chloride solution of sulfuryl chloride (12 ml, 0.15 mol) was cooled in an ice-water bath, and a solution of triethylamine (21 ml, 0.15 mol) and morpholine (13 ml, 0.15 mol) in methylene chloride was added dropwise over 1 hour. After stirring for 2 hours, the reaction solution was washed with cold 0.1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 20.54 g of morpholine-4-sulfonyl chloride.

  Subsequently, according to the method according to Reference Example 7, using 3.65 g of the above morpholine-4-sulfonyl chloride instead of 4- (t-butoxycarbonylamino) piperazine-1-carbonyl chloride, the title 1- [N- (morpholine-4- Sulfonyl) amino] cyclohexanecarboxylic acid 0.98 g (yield 16%) was obtained.

1H-NMR (CDCl ₃ , δ): 1.30-1.42 (1H, m), 1.58-1.62 (5H, m), 1.90-2.00 (4H, m), 3.23 (4H, t, J = 5Hz), 3.73 ( 4H, t, J = 5Hz), 4.62 (1H, s)

Reference Example 25 1- [N-[(4-acetylpiperazine-1-sulfonyl)] amino] cyclohexanecarboxylic acid

  In the same manner as in Reference Example 24, using 1.53 g of the title 1- [N-[(4-acetylpiperazine-1-sulfonyl)] amino] cyclohexanecarboxylic acid using 5.53 g of 1-acetylpiperazinesulfonyl chloride instead of morpholine ( Yield 23%).

1H-NMR (CDCl ₃ , δ): 1.30-1.40 (1H, m), 1.48-1.70 (5H, m), 1.80-2.00 (4H, m), 2.10 (3H, s), 3.18 (2H, t, J = 7Hz), 3.23 (2H, t, J = 7Hz), 3.52 (2H, t, J = 7Hz), 3.66 (2H, t, J = 7Hz), 6.14 (1H, s)

Reference Example 26 1- [N- (Pyridin-3-sulfonyl) amino] cyclohexanecarboxylic acid

  In the same manner as in Reference Example 20, 1.74 g of the title 1- [N- (pyridine-3-sulfonyl) amino] cyclohexanecarboxylic acid was obtained using 2.74 g of pyridine-3-sulfonyl chloride instead of 4-nitrobenzenesulfonyl chloride. 28%).

1H-NMR (DMSO-d ₆ , δ): 1.18-1.40 (4H, m), 1.44-1.54 (2H, m), 1.70-1.72 (4H, m), 7.54 (1H, dd, J = 5Hz, 8Hz ), 8.16 (1H, dd, J = 2Hz, 8Hz), 8.75 (1H, dd, J = 1Hz, 5Hz), 8.94 (1H, d, J = 2Hz)

Reference Example 27 (2RS, 3S) -2-hydroxy-3- [N- [1- [N- (4-acetylpiperazine-1-carbonyl) amino] cyclohexanecarbonyl] amino] heptanoic acid

  1- [N- (4-acetylpiperazine-1-carbonyl) amino] synthesized in Reference Example 9 instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by a method according to Reference Example 16 Using 595 mg of cyclohexanecarboxylic acid, the title (2RS, 3S) -2-hydroxy-3- [N- [1- [N- (4-acetylpiperazine-1-carbonyl) amino] cyclohexanecarbonyl] amino] heptanoic acid 0 g (99% yield) was obtained.

1H-NMR (d-DMSO, δ): 0.80-0.89 (3H, m), 1.18-1.72 (16H, m), 1.92-2.03 (3H, s), 3.29-4.19 (11H, m), 6.29 (1 / 2H, s), 6.31 (1 / 2H, s), 7.15-7.50 (1H, m)

Reference Example 28 1- [N- (4-acetylaminobenzenesulfonyl) amino] cyclohexanecarboxylic acid

  1- [N- (4-acetylaminobenzenesulfonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester using 11.7 g of 4-acetylaminobenzenesulfonyl chloride in place of 4-methoxybenzenesulfonyl chloride by the method according to Reference Example 20. 11.5 g was synthesized.

  Instead of 1- [N- [4- (2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester by the method according to Reference Example 7, the 1- [N- ( 4-acetylaminobenzenesulfonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester was used in an amount of 8.7 g (yield 97%) of the title 1- [N- (4-acetylaminobenzenesulfonyl) amino] cyclohexanecarboxylic acid. Obtained.

1H-NMR (CDCl ₃ , δ): 1.13-1.31 (6H, m), 1.61-1.66 (2H, m), 1.76-1.80 (2H, m), 2.08 (3H, s), 7.68-7.73 (5H, m), 10.29 (1H, s)

Example 51 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  (2RS, 3S) -N synthesized in Reference Example 19 in place of (2RS, 3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide by a method according to Example 1. Using N-cyclopentyl-3-amino-2-hydroxy-5-methylhexanamide 571 mg, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexyl ]-[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 689 mg (yield 59%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.94 (3H, d, J = 7Hz), 0.99 (3H, d, J = 7Hz), 1.28-1.80 (14H, m), 1.86-2.15 (7H, m), 3.38 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.10-4.21 (1H, m), 4.42 (1H, s), 5.19-5.25 (1H, m), 6.80 (1H , d, J = 8Hz), 7.90 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3840, 2360, 1732, 1334, 1150, 1072, 1016
Rf value: 0.54

Example 52 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N-[(4-methoxycarbonyl) piperazine-1-carbonyl Amino] cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 synthesized in Reference Example 19 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 5. Using 343 mg of -hydroxy-5-methylhexaneamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexane] -1- [N- [ There was obtained 416 mg (yield 53%) of (4-methoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.93 (3H, d, J = 7 Hz), 0.99 (3H, d, J = 7 Hz), 1.23-1.50 (6H, m), 1.55 -1.78 (8H, m), 1.83-2.14 (7H, m), 3.37-3.45 (4H, m), 3.53 (4H, br-s), 3.73 (3H, s), 4.10-4.21 (1H, m), 4.44 (1H, s), 5.19-5.25 (1H, m), 6.80 (1H, d, J = 8Hz), 7.84 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3392, 2872, 1372, 1286, 1192, 1172, 1118
Rf value: 0.54

Example 53 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxamide

  1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxylic acid synthesized in Reference Example 20 in place of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by a method according to Example 2. Using 450 mg of the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxamide 407 mg ( Yield 56%).

1H-NMR (CDCl ₃ , δ): 0.87-0.92 (3H, m), 1.24-1.52 (13H, m), 1.65-1.76 (4H, m), 1.85-2.05 (7H, m), 4.23 (3H, s), 4.98 (1H, s), 4.16-4.21 (1H, m), 5.08 (1H, ddd, J = 5Hz, 8Hz, 13Hz), 6.85 (1H, d, J = 8Hz), 6.93 (2H, dd , J = 2Hz, 7Hz), 7.04 (1H, d, J = 7Hz), 7.80 (2H, dd, J = 2Hz, 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3330, 2954, 1664, 1498, 1455, 1328, 1259, 1149
Rf value: 0.34

Example 54 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-nitrobenzenesulfonyl) amino] cyclohexanecarboxamide

In the same manner as in Example 53, 463 mg of 1- [N- (4-nitrobenzenesulfonyl) amino] cyclohexanecarboxylic acid synthesized in Reference Example 21 instead of 1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxylic acid 266 mg (yield) of the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-nitrobenzenesulfonyl) amino] cyclohexanecarboxamide 30%).

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7 Hz), 1.22-1.39 (6H, m), 1.44-1.51 (5H, m), 1.62-1.72 (5H, m), 1.85- 2.05 (8H, m), 4.15-4.24 (1H, m), 5.11 (1H, ddd, J = 5Hz, 8Hz, 13Hz), 6.10 (1H, s), 6.92 (1H, d, J = 8Hz), 7.13 (1H, d, J = 8Hz), 8.10 (2H, d, J = 9Hz), 8.33 (2H, d, J = 9Hz)
IR (ν, KBr, cm ⁻¹ ): 3347, 2954, 1664, 1531, 1349, 1168
Rf value: 0.34

Example 55 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl] -1- [N-[(4-acetyl) piperazine-1-carbonyl] Amino] cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 synthesized in Reference Example 14 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 6. Using 321 mg of -hydroxy-4-methylpentanamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl] -1- [N- [ 190 mg (yield 26%) of (4-acetyl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.84 (3H, d, J = 7Hz), 1.01 (3H, d, J = 7Hz), 1.28-1.50 (6H, m), 1.66-1.75 (5H, m), 1.86-2.20 (7H, m), 2.13 (3H, s), 2.35-2.45 (1H, m), 3.37-3.51 (2H, m), 3.47-3.53 (4H, m), 3.65-3.71 (2H, m ), 4.08-4.20 (1H, m), 4.51 (1H, s), 5.15 (1H, dd, J = 8Hz, 8Hz), 6.82 (1H, d, J = 8Hz), 7.90 (1H, d, J = (8Hz)
IR (ν, KBr, cm ⁻¹ ): 3856, 3760, 2108, 1730, 1468, 1374, 1200
Rf value: 0.67

Example 56 N-[(S) -1- (N-cyclopentylmethylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N- (4-acetylpiperazine-1-carbonyl) amino ] Cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentylmethyl-3-amino- synthesized in Reference Example 22 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 6. Using 343 mg of 2-hydroxy-5-methylhexanamide, the title N-[(S) -1- (N-cyclopentylmethylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N 304 mg (yield 47%) of-(4-acetylpiperazine-1-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.93 (3H, d, J = 6 Hz), 0.98 (3H, d, J = 6 Hz), 1.15-1.43 (6H, m), 1.52-1.77 (10H, m), 1.84-1.92 (2H, m), 2.02-2.10 (3H, m), 2.13 (3H, s), 3.10-3.16 (1H, m), 3.20-3.24 (2H, m), 3.38-3.40 (2H, m ), 3.50 (4H, d, J = 2Hz), 3.67-3.70 (2H, m), 4.53 (1H, s), 5.19-5.24 (1H, m), 6.93 (1H, t, J = 5Hz), 7.78 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3343, 2950, 1654, 1631, 1251
Rf value: 0.56

Example 57 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (quinoline-8-sulfonyl) amino] cyclohexanecarboxamide

  1- [N- (quinoline-8-sulfonyl) amino] cyclohexanecarboxylic acid synthesized in Reference Example 23 in place of 1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxylic acid by a method according to Example 53 669 mg of the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (quinoline-8-sulfonyl) amino] cyclohexanecarboxamide (520 mg) Yield 48%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.91 (3H, t, J = 7Hz), 1.24-1.49 (9H, m), 1.58-1.74 (7H, m), 1.86-2.08 (8H, m), 4.17- 4.22 (1H, m), 5.24-5.30 (1H, m), 6.86 (1H, d, J = 8Hz), 7.09 (1H, s), 7.32 (1H, d, J = 7Hz), 7.59-7.66 (2H , m), 8.05 (1H, d, J = 7Hz), 8.31-8.36 (2H, m), 9.09 (1H, dd, J = 2Hz, 4Hz)
IR (ν, KBr, cm ⁻¹ ): 3340, 3266, 2954, 2935, 2857, 1679, 1644, 1508, 1324, 1170, 1143
Rf value: 0.53

Example 58 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N-[(4-acetyl) piperazine-1-carbonyl] Amino] cyclohexanecarboxamide

  (2RS, 3S) -N-cyclopentyl-3-amino-2 synthesized in Reference Example 19 in place of (2RS, 3S) -N-cyclopentyl-3-amino-2-hydroxyheptanamide by a method according to Example 6. Using 343 mg of -hydroxy-5-methylhexanamide, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N- [ There was obtained 345 mg (44% yield) of (4-acetyl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.94 (3H, d, J = 7 Hz), 0.97 (3H, d, J = 7 Hz), 1.25-1.57 (6H, m), 1.58-1.80 (8H, m), 1.85-2.20 (7H, m), 2.13 (3H, s), 3.37-3.41 (2H, m), 3.47-3.51 (4H, m), 3.66-3.70 (2H, m), 4.10-4.20 (1H, m ), 4.52 (1H, s), 5.19-5.25 (1H, m), 6.82 (1H, d, J = 8Hz), 7.78 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3904, 1730, 1370, 1286, 1202, 1172, 1104
Rf value: 0.62

Example 59 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-sulfonyl) amino] cyclohexanecarboxamide

  1- [N- (morpholine-4-sulfonyl) amino synthesized in Reference Example 24 in place of 1- [N- [4- (morpholine-4-carbonyl)] amino] cyclohexanecarboxylic acid by a method according to Example 2. ] Using 0.49 g of cyclohexanecarboxylic acid, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-sulfonyl) 0.64 g (yield 76%) of amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7H), 1.20-1.50 (8H, m), 1.58-1.80 (9H, m), 1.90-2.10 (7H, m), 3.22 ( 4H, t, J = 4Hz), 3.72 (4H, t, J = 4Hz), 4.14-4.20 (1H, m), 4.54 (1H, s), 5.21-5.26 (1H, m), 6.82 (1H, d , J = 8Hz), 6.93 (1H, d, J = 8Hz)
IR (ν, KBr, cm ⁻¹ ): 3336, 3270, 2956, 2931, 2861, 1725, 1671, 1521, 1454
Rf value: 0.47

Example 60 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N- (morpholine-4-sulfonyl) amino] cyclohexanecarboxamide

  1- [N- (morpholine-4-sulfonyl) amino] cyclohexanecarboxylic acid synthesized in Reference Example 24 in place of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by a method according to Example 51 Using 0.49 g, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N- (morpholine-4-sulfonyl) 0.63 g (74% yield) of amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.95 (3H, d, J = 6H), 1.01 (3H, d, J = 6H), 1.20-1.80 (15H, m), 1.90-2.10 (6H, m), 3.22 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.10-4.20 (1H, m), 4.51 (1H, s), 5.20-5.30 (1H, m), 6.82 (1H , d, J = 7Hz), 6.86 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3394, 3340, 3261, 2958, 2865, 1725, 1671, 1523, 1454
Rf value: 0.48

Example 61 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-acetylpiperazine-1-sulfonyl) amino] cyclohexanecarboxamide

  1- [N- (4-acetylpiperazine-1-sulfonyl) amino] synthesized in Reference Example 25 in place of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by a method according to Example 59 Using 0.5 g of cyclohexanecarboxylic acid, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-acetylpiperazine-1- Sulfonyl) amino] cyclohexanecarboxamide 0.35 g (43% yield) was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7H), 1.31-1.80 (17H, m), 1.88-2.10 (7H, m), 2.11 (3H, s), 3.20-3.30 ( 4H, m), 3.50-3.57 (2H, m), 3.60-3.70 (2H, m), 4.10-4.20 (1H, m), 4.70 (1H, s), 5.20-5.25 (1H, m), 6.86 ( 1H, d, J = 8Hz), 6.91 (1H, d, J = 8Hz)
IR (ν, KBr, cm ⁻¹ ): 3334, 3266, 2956, 2933, 2867, 1727, 1668, 1646, 1525, 1450
Rf value: 0.60

Example 62 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N- (4-acetylpiperazine-1-sulfonyl) amino] Cyclohexane carboxamide

  1- [N- (4-acetylpiperazine-1-synthesized in Reference Example 25 in place of 1- [N- [4- (morpholine-4-carbonyl)] amino] cyclohexanecarboxylic acid by a method according to Example 60 (Sulfonyl) amino] cyclohexanecarboxylic acid 0.5 g was used to prepare the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-5-methyl-3-hexyl] -1- [N- 0.41 g (yield 50%) of (4-acetylpiperazine-1-sulfonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.95 (3H, d, J = 6H), 1.00 (3H, d, J = 6H), 1.30-2.10 (21H, m), 2.11 (3H, s), 3.20- 3.30 (4H, m), 3.50-3.57 (2H, m), 3.60-3.70 (2H, m), 4.10-4.20 (1H, m), 4.51 (1H, s), 5.20-5.30 (1H, m), 6.84 (1H, d, J = 8Hz), 6.87 (1H, d, J = 8Hz)
IR (ν, KBr, cm ⁻¹ ): 3340, 3266, 2956, 2869, 1727, 1671, 1641, 1521, 1430
Rf value: 0.61

Example 63 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl] -1- [N- (4-acetylpiperazine-1-sulfonyl) amino] Cyclohexane carboxamide

  1- [N- (4-acetylpiperazine-1-synthesized in Reference Example 25 in place of 1- [N- [4- (morpholine-4-carbonyl)] amino] cyclohexanecarboxylic acid by a method according to Example 15. (Sulfonyl) amino] cyclohexanecarboxylic acid 0.5 g is used to prepare the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-4-methyl-3-pentyl] -1- [N- 0.41 g (yield 50%) of (4-acetylpiperazine-1-sulfonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, d, J = 7H), 1.01 (3H, d, J = 7H), 1.30-1.80 (12H, m), 1.90-2.05 (6H, m), 2.11 (3H, s), 2.36-2.43 (1H, m), 3.20-3.25 (4H, m), 3.46-3.51 (2H, m), 3.60-3.70 (2H, m), 4.13-4.18 (1H, m ), 4.64 (1H, s), 5.12-5.15 (1H, m), 6.86 (1H, d, J = 8Hz), 7.00 (1H, d, J = 8Hz)
IR (ν, KBr, cm ⁻¹ ): 3384, 3261, 2958, 2865, 1737, 1670, 1633, 1536, 1508, 1450
Rf value: 0.63

Example 64 N-[(S) -1- [N- (2,2-dimethyl-propyl) amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino ] Cyclohexanecarboxamide

  In the same manner as in Example 28, using 174 mg of neopentylamine instead of 3-chlorobenzylamine, the title N-[(S) -1- [N- (2,2-dimethyl-propyl) amino] -1,2 -Dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (367 mg, yield 38%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.88-0.90 (3H, m), 0.92 (9H, s), 1.08-1.42 (7H, m), 1.65-1.71 (4H, m), 1.86-1.99 (3H, m), 2.00-2.12 (2H, m), 3.04-3.15 (2H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.46 (1H, s), 5.18 (1H, ddd, J = 5Hz, 7Hz, 8Hz), 6.96 (1H, t, J = 6Hz), 7.95 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3340, 2958, 2929, 1677, 1608, 1531, 1261, 1116
Rf value: 0.48

Example 65 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (pyridine-3-sulfonyl) amino] cyclohexanecarboxamide

  1- [N- (Pyridin-3-sulfonyl) amino] cyclohexanecarboxylic acid synthesized in Reference Example 26 in place of 1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxylic acid by a method according to Example 53 Using 1.1 g, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (pyridine-3-sulfonyl) amino] cyclohexanecarboxamide 248 mg (yield 13%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.86-0.93 (3H, m), 1.26-1.36 (7H, m), 1.47-1.51 (5H, m), 1.60-1.72 (5H, m), 1.84-2.06 ( 7H, m), 4.19-4.23 (1H, m), 4.98-5.04 (1H, m), 5.50 (1H, s), 6.93 (1H, d, J = 8Hz), 7.01 (1H, dt, J = 2Hz , 8Hz), 7.43 (1H, ddd, J = 1Hz, 5Hz, 8Hz), 8.15 (1H, dt, J = 2Hz, 8Hz), 8.75 (1H, dt, J = 2Hz, 5Hz), 9.06 (1H, d , J = 2Hz)
IR (ν, KBr, cm ⁻¹ ): 3355, 2956, 1668, 1525, 1170
Rf value: 0.48

Example 66 N-[(S) -1- (N-cyclopentylmethylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-acetylpiperazine-1-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, instead of (2RS, 3S) -2-hydroxy-3- [N- [1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarbonyl] amino] heptanoic acid, Reference Example 27 881 mg of (2RS, 3S) -2-hydroxy-3- [N- [1- [N- (4-acetylpiperazine-1-carbonyl) amino] cyclohexanecarbonyl] amino] heptanoic acid synthesized in 1 Using 496 mg of cyclopentylmethylamine instead of benzylamine, the title N-[(S) -1- (N-cyclopentylmethylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-acetyl Piperazine-1-carbonyl) amino] cyclohexanecarboxamide 64 mg (yield 11%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.86-0.90 (3H, m), 1.17-1.44 (9H, m), 1.53-1.77 (8H, m), 1.86-2.14 (10H, m), 3.22 (2H, dd, J = 6Hz, 7Hz), 3.34-3.41 (2H, m), 3.45-3.51 (5H, m), 3.67-3.70 (2H, m), 4.52 (1H, s), 5.17-5.22 (1H, m ), 6.90 (1H, t, J = 6Hz), 7.79 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3353, 2952, 1629, 1529, 1444, 1250
Rf value: 0.51

Example 67 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-acetylaminobenzene-1-sulfonyl) amino] cyclohexanecarboxamide

  1- [N- (4-acetylaminobenzenesulfonyl) amino] cyclohexanecarbon synthesized in Reference Example 28 in place of 1- [N- (4-methoxybenzenesulfonyl) amino] cyclohexanecarboxylic acid by a method according to Example 53 Using 511 mg of acid, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (4-acetylaminobenzene-1-sulfonyl) amino 526 mg (yield 63%) of cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.85-0.87 (3H, m), 1.24-1.35 (7H, m), 1.46-1.60 (5H, m), 1.63-2.05 (12H, m), 2.23 (3H, s), 4.11-4.21 (1H, m), 4.90-4.95 (1H, m), 5.00 (1H, s), 6.98 (1H, d, J = 8Hz), 7.08 (1H, d, J = 8Hz), 7.55 (1H, s), 7.61 (2H, d, J = 9Hz), 7.78 (2H, dd, J = 2Hz, 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3334, 2952, 1656, 1592, 1531, 1402, 1324, 1151, 1095
Rf value: 0.58

Example 68 N-[(S) -1,2-dioxo-1- [N- (1-hydroxycyclohexylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexane Carboxamide

  In the same manner as in Example 28, using 258 mg of 1-hydroxycyclohexylmethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (1-hydroxycyclohexylmethyl) ) Amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield 18%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.26-1.44 (11H, m), 1.52-1.71 (9H, m), 1.84-1.97 (3H, m), 2.04- 2.11 (3H, m), 3.30 (2H, d, J = 6Hz), 3.38 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz), 4.48 (1H, s), 5.06-5.11 (1H, m), 7.18 (1H, bs), 7.90 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 2931, 1664, 1631, 1529
Rf value: 0.65

Example 69 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-ethoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexane Carboxamide

  1- [N-[(4-ethoxycarbonyl) piperazine synthesized by a method according to Reference Example 7 instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by the method according to Example 2 The title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4- Ethoxycarbonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide 767 mg (yield 48%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-1.51 (12H, m), 1.55-1.73 (8H, m), 1.82-2.04 (5H, m), 2.05- 2.14 (2H, m), 3.37-3.42 (4H, m), 3.51-3.53 (4H, m), 4.13-4.19 (3H, m), 4.48 (1H, s), 5.18 (1H, ddd, J = 12Hz , 7Hz, 5Hz), 6.81 (1H, d, J = 8Hz), 7.88 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3299, 2931, 1650, 1523
Rf value: 0.49

Example 70 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-methylsulfonyl) piperazine-1-carbonyl] amino] cyclohexane Carboxamide

  1- [N-[(4-methylsulfonyl) piperazine-synthesized by the method according to Reference Example 7 instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by the method according to Example 2 1-Carbonyl] amino] cyclohexanecarboxylic acid 667 mg was used to give the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4- 791 mg (yield 73%) of methylsulfonyl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.23-1.50 (8H, m), 1.58-1.80 (9H, m), 1.83-2.18 (7H, m), 3.10 ( 3H, s), 3.26 (4H, t, J = 5Hz), 3.54 (4H, t, J = 5Hz), 4.11-4.21 (1H, m), 4.54 (1H, s), 5.19 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 6.80 (1H, d, J = 8Hz), 7.71 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3318, 2954, 2933, 1654, 1529
Rf value: 0.62

Example 71 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-isobutyryl) piperazine-1-carbonyl] amino] cyclohexanecarboxamide

  1-[[((4-Isobutyryl) piperazine-1-carbonyl] synthesized by the method according to Reference Example 7 instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by the method according to Example 2 ] Using amino acid 416 mg of cyclohexanecarboxylic acid, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1-N-[(4-isobutyryl) piperazine- There was obtained 349 mg (yield 51%) of 1-carbonyl] amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.14 (6H, d, J = 9Hz), 1.21-2.18 (24H, m), 2.78-2.82 (1H, m), 3.30-3.70 (8H, m), 4.10-4.20 (1H, m), 4.48 (1H, s), 5.18 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 6.79 (1H, d, J = 8Hz) , 7.81 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 3266, 2960, 2861, 1733, 1666, 1614
Rf value: 0.54

Example 72 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (thiamorpholine-4-carbonyl) amino] cyclohexanecarboxamide

  1- [N- (thiamorpholine-4-carbonyl) amino synthesized by a method according to Reference Example 5 instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid ] Using 348 mg of cyclohexanecarboxylic acid, the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- (thiamorpholine-4-carbonyl) amino 333 mg (yield 53%) of cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-2.20 (24H, m), 2.60-2.70 (4H, m), 3.65-3.80 (4H, m), 4.05- 4.10 (1H, m), 4.42 (1H, s), 5.18 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 6.79 (1H, d, J = 8Hz), 7.94 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3320, 2952, 2933, 2856, 1727, 1648, 1623, 1517
Rf value: 0.41

Example 73 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-ethoxycarbonyl) piperidine-1-carbonyl] amino] cyclohexane Carboxamide

  1- [N-[(4-ethoxycarbonyl) piperidine-synthesized by the method according to Reference Example 7 instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by the method according to Example 2 1-Carbonyl] amino] cyclohexanecarboxylic acid 979 mg of the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4- There were obtained 815 mg (yield 50%) of ethoxycarbonyl) piperidine-1-carbonyl] amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.26 (3H, t, J = 7Hz), 1.21-2.18 (28H, m), 2.50 (1H, tt, J = 10Hz , 4Hz), 2.90-3.05 (2H, m), 3.80-3.95 (2H, m), 4.05-4.12 (3H, m), 4.44 (1H, s), 5.19 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 6.85 (1H, d, J = 9Hz), 8.04 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3372, 2954, 2859, 1731, 1656, 1544
Rf value: 0.38

Example 74 N-[(S) -1,2-dioxo-1- [N- (2-oxo-2-phenylethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 257 mg of 2-aminoacetophenone hydrochloride and 304 mg of triethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (2- 364 mg (47% yield) of oxo-2-phenylethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.26-1.43 (6H, m), 1.57-1.71 (5H, m), 1.85-2.18 (5H, m), 3.36- 3.42 (4H, m), 3.68-3.74 (4H, m), 4.46 (1H, s), 4.73 (1H, dd, J = 16Hz, 5Hz), 4.84 (1H, dd, J = 16Hz, 5Hz), 5.22 -5.28 (1H, m), 7.52 (2H, t, J = 8Hz), 7.64 (1H, t, J = 8Hz), 7.87 (1H, t, J = 5Hz), 7.97 (2H, d, J = 8Hz) ), 7.98 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3288, 2929, 2857, 1677, 1629
Rf value: 0.61

Example 75 N-[(S) -1,2-dioxo-1- [N-[(2-methyl-1,3-benzodioxolan-2-yl) methyl] amino] -3-heptyl] -1- [ N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

In the same manner as in Example 28, using 248 mg of 1- (2-methyl-1,3-dioxolan-2-yl) methanamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo -1- [N-[(2-Methyl-1,3-benzodioxolan-2-yl) methyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 464 mg (Yield 57%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.22-1.42 (6H, m), 1.56-1.68 (5H, m), 1.65 (3H, s), 1.61-1.94 ( 3H, m), 2.03-2.13 (2H, m), 3.37 (4H, t, J = 5Hz), 3.64 (1H, dd, J = 12Hz, 6Hz), 3.71 (4H, t, J = 5Hz), 3.78 (1H, dd, J = 12Hz, 6Hz), 4.41 (1H, s), 5.15-5.22 (1H, m), 6.73-6.82 (4H, m), 7.54 (1H, t, J = 5Hz), 7.94 ( (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3315, 2931, 2857, 1666, 1639
Rf value: 0.50

Example 76 N-[(S) -1,2-dioxo-1- [N-[(2-phenyl-1,3-dioxolan-2-yl) methyl] amino] -3-heptyl] -1- [N -(Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 269 mg of 1- (2-phenyl-1,3-dioxolan-2-yl) methanamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo -1- [N-[(2-phenyl-1,3-dioxolan-2-yl) methyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (553 mg) Yield 66%).

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.21-1.42 (6H, m), 1.55-1.71 (5H, m), 1.83-1.97 (3H, m), 2.04- 2.15 (2H, m), 3.38 (4H, t, J = 5Hz), 3.61 (1H, dd, J = 14Hz, 6Hz), 3.70 (1H, dd, J = 14Hz, 6Hz), 3.72 (4H, t, J = 5Hz), 3.79-3.89 (2H, m), 4.00-4.10 (2H, m), 4.44 (1H, s), 5.12-5.18 (1H, m), 7.15 (1H, t, J = 5Hz), 7.31-7.38 (3H, m), 7.45-7.56 (2H, m), 7.93 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3313, 2954, 2931, 1689, 1650
Rf value: 0.50

Example 77 N-[(S) -1- [N- (2,2-dimethoxyethyl) amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] Cyclohexane carboxamide

  In the same manner as in Example 28, using 158 mg of 2,2-dimethoxyethanamine instead of 3-chlorobenzylamine, the title N-[(S) -1- [N- (2,2-dimethoxyethyl) amino]- 391 mg (yield 54%) of 1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.23-1.42 (6H, m), 1.57-1.69 (5H, m), 1.83-2.15 (5H, m), 3.35- 3.51 (2H, m), 3.39 (4H, t, J = 5Hz), 3.40 (6H, s), 3.72 (4H, t, J = 5Hz), 4.40 (1H, t, J = 6Hz), 4.44 (1H , s), 5.16-5.24 (1H, m), 7.03 (1H, t, J = 5Hz), 7.94 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 2931, 2857, 1675, 1631
Rf value: 0.74

Example 78 N-[(S) -1,2-dioxo-1- [N-[(1,3-dioxolan-2-yl) methyl] amino] -3-heptyl] -1- [N- (morpholine- 4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 155 mg of 1- (1,3-dioxolan-2-yl) methanamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [ 352 mg (yield 49%) of N-[(1,3-dioxolan-2-yl) methyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained. .

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.22-1.44 (6H, m), 1.57-1.69 (5H, m), 1.82-2.15 (5H, m), 3.39 ( 4H, t, J = 5Hz), 3.52 (2H, dd, J = 6Hz, 4Hz), 3.72 (4H, t, J = 5Hz), 3.85-4.04 (4H, m), 4.45 (1H, s), 5.00 (1H, t, J = 4Hz), 5.13-5.20 (1H, m), 7.06 (1H, t, J = 6Hz), 7.95 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3320, 2931, 2857, 1677, 1648
Rf value: 0.77

Example 79 N-[(S) -1- [N-[(2-methyl-1,3-dioxolan-2-yl) methyl] amino] -1,2-dioxo-3-heptyl] -1- [N -(Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 179 mg of 1- (2-methyl-1,3-dioxolan-2-yl) methanamine instead of 3-chlorobenzylamine, the title N-[(S) -1- [N- [(2-Methyl-1,3-dioxolan-2-yl) methyl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (447 mg) Yield 60%).

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.22-1.42 (6H, m), 1.33 (3H, s), 1.50-1.71 (5H, m), 1.82-2.15 ( 5H, m), 3.39 (4H, t, J = 5Hz), 3.39-3.49 (2H, m), 3.72 (4H, t, J = 5Hz), 3.93-4.02 (4H, m), 4.43 (1H, s ), 5.15-5.22 (1H, m), 7.06 (1H, t, J = 5Hz), 7.96 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3428, 2929, 2857, 1660
Rf value: 0.72

Example 80 N-[(S) -1,2-dioxo-1-N-[(S)-(1-phenylethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 164 mg of (S) -1-phenylethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1-N-[(S)- 601 mg (yield 80%) of (1-phenylethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.24-1.45 (8H, m), 1.53 (3H, d, J = 7Hz), 1.58-1.70 (4H, m), 1.80-1.91 (2H, m), 2.02-2.14 (2H, m), 3.22-3.38 (4H, m), 3.68-3.72 (4H, m), 4.47 (1H, s), 5.03-5.07 (1H, m ), 5.12 (1H, ddd, J = 12Hz, 8Hz, 5Hz), 7.10 (1H, d, J = 8Hz), 7.27-7.35 (5H, m), 7.95 (1H, d, J = 8Hz)
IR (ν, KBr, cm ⁻¹ ): 3376, 2931, 1654, 1546, 1511
Rf value: 0.54

Example 81 N-[(S) -1,2-dioxo-1-N-[(R)-(1-phenylethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 164 mg of (R) -1-phenylethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1-N-[(R)- 587 mg (yield 78%) of (1-phenylethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.86 (3H, t, J = 7Hz), 1.13-1.45 (8H, m), 1.53 (3H, d, J = 7Hz), 1.55 (4H, m), 1.80- 2.00 (2H, m), 2.02-2.18 (2H, m), 3.35-3.38 (4H, m), 3.68-3.72 (4H, m), 4.47 (1H, s), 5.04-5.08 (1H, m), 5.12 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 7.11 (1H, d, J = 8Hz), 7.25-7.37 (5H, m), 7.93 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3367, 3307, 1650, 1550, 1511
Rf value: 0.54

Example 82 N-[(S) -1,2-dioxo-1- [N-3-pentylamino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 131 mg of 3-pentylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-3-pentylamino] -3- Heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 330 mg (yield 46%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.86-0.91 (9H, m), 1.20-1.57 (13H, m), 1.64-1.74 (2H, m), 1.80-2.02 (3H, m), 2.16-2.17 ( 2H, m), 3.34 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.45 (1H, m), 5.19-5.24 (1H, m), 6.59 (1H, d, J = 9Hz), 7.93 (1H, d, J = 7Hz)
IR (ν, KBr, cm ^-1 ): 3316, 1654, 1513
Rf value: 0.51

Example 83 N-[(S) -1,2-dioxo-1- [N- (2-methylphenyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 161 mg of 2-methylaniline instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (2-methylphenyl) amino] 445 mg (yield 59%) of -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.90 (3H, t, J = 7 Hz), 1.30-1.42 (6H, m), 1.62-1.76 (6H, m), 1.87-2.17 (5H, m), 2.32 ( 3H, s), 3.37 (4H, t, J = 5Hz), 3.69 (4H, t, J = 5Hz), 5.24-5.29 (1H, m), 7.10 (1H, dt, J = 7Hz, 1Hz), 7.20 (1H, d, J = 7Hz), 7.23 (1H, d, J = 8Hz), 8.07 (2H, d, J = 8Hz), 8.64 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3386, 2929, 1685, 1643, 1527, 1457, 1255
Rf value: 0.52

Example 84 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-acetyl) perhydro-4-azaazepine-1-carbonyl] Amino] cyclohexanecarboxamide

  1- [N-[(4-acetyl) perhydro-4] synthesized by a method according to Reference Example 7 in place of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by the method according to Example 2 -Azaazepine-1-carbonyl] amino] cyclohexanecarboxylic acid was used in 622 mg of the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- [ 502 mg (yield 47%) of (4-acetyl) perhydro-4-azaazepine-1-carbonyl] amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-2.20 (29H, m), 3.40-3.80 (8H, m), 4.10-4.20 (1H, m), 4.44 ( 1H, s), 5.18-5.23 (1H, m), 6.85 (1 / 2H, d, J = 8Hz), 6.88 (1 / 2H, d, J = 8Hz), 7.86 (1 / 2H, d, J = 7Hz), 7.95 (1 / 2H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3397, 3363, 2954, 2935, 1664, 1629, 1527
Rf value: 0.62

Example 85 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-methoxy) piperidine-1-carbonyl] amino] cyclohexanecarboxamide

  1- [N-[(4-methoxy) piperidine-1 synthesized by a method according to Reference Example 7 instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by the method according to Example 2 -Carbonyl] amino] cyclohexanecarboxylic acid 568 mg of the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[(4-methoxy ) Piperidine-1-carbonyl] amino] cyclohexanecarboxamide was obtained 512 mg (51% yield).

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.20-2.18 (28H, m), 3.10-3.25 (2H, m), 3.36 (3H, s), 3.34-3.42 ( 1H, m), 3.60-3.70 (2H, m), 4.10-4.20 (1H, m), 4.45 (1H, s), 5.18 (1H, ddd, J = 11Hz, 7Hz, 4Hz), 6.80 (1H, d , J = 7Hz), 8.10 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3330, 2935, 1658, 1625, 1517
Rf value: 0.47

Example 86 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N- [N, N-bis (2-methoxyethyl) amino-1- Carbonyl] amino] cyclohexanecarboxamide

  1- [N- [N, N-Bis (2-) synthesized by the method according to Reference Example 5 instead of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by the method according to Example 2. Methoxyethyl) amino-1-carbonyl] amino] cyclohexanecarboxylic acid 604 mg was used to give the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N 456 mg (43% yield) of [N, N-bis (2-methoxyethyl) amino-1-carbonyl] amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.20-2.10 (24H, m), 3.63 (3H, s), 3.69 (3H, s), 3.50-3.60 (8H, m), 4.10-4.20 (1H, m), 5.19 (1H, ddd, J = 11Hz, 7Hz, 4Hz), 6.23 (1H, s), 6.80 (1H, d, J = 8Hz), 7.97 (1H, d , J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3361, 3257, 2952, 2859, 1724, 1646, 1517
Rf value: 0.36

Example 87 N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1- [N-[[N- (2-methoxyethyl) -N-methyl] amino -1-carbonyl] amino] cyclohexanecarboxamide

  1- [N-[[N- (2-methoxyethyl) synthesized by the method according to Reference Example 5 in place of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid by the method according to Example 2. ) -N-methyl] amino-1-carbonyl] amino] cyclohexanecarboxylic acid was used to give the title N-[(S) -1- (N-cyclopentylamino) -1,2-dioxo-3-heptyl] -1 496 mg (yield 52%) of-[N-[[N- (2-methoxyethyl) -N-methyl] amino-1-carbonyl] amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-2.20 (24H, m), 2.93 (3H, s), 3.40 (3H, s), 3.45 (2H, t, J = 4Hz), 3.56 (2H, t, J = 4Hz), 4.10-4.20 (1H, m), 5.17 (1H, ddd, J = 12Hz, 7Hz, 4Hz), 5.72 (3H, br-s), 6.82 (1H, d, J = 8Hz), 8.03 (1H, d, J = 7H)
IR (ν, KBr, cm ⁻¹ ): 3347, 3257, 2952, 2857, 1725, 1646, 1523
Rf value: 0.43

Example 88 N-[(S) -1,2-dioxo-1- [N-[(S) -1-oxo-1-methoxy-3-methyl-2-butyl] amino] -3-heptyl] -1 -[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, 251 mg of L-valine methyl ester hydrochloride and 304 mg of triethylamine were used instead of 3-chlorobenzylamine, and the title N-[(S) -1,2-dioxo-1- [N-[( S) -1-oxo-1-methoxy-3-methyl-2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 325 mg (43% yield) Got.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 0.92 (3H, d, J = 7Hz), 0.94 (3H, d, J = 7Hz), 1.23-1.43 (6H, m ), 1.56-1.69 (5H, m), 1.84-2.27 (6H, m), 3.38 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 3.76 (3H, s), 4.43 (1H, s), 4.49 (1H, dd, J = 9Hz, 5Hz), 5.18-5.24 (1H, m), 7.33 (1H, d, J = 9Hz), 8.00 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 2958, 2933, 1685, 1648
Rf value: 0.57

Example 89 N-[(S) -1- [N-[(3,4-dihydro-2H-pyran-6-yl) methyl] amino] -1,2-dioxo-3-heptyl] -1- [N -(Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 170 mg of 1- (3,4-dihydro-2H-pyran-6-yl) methanamine instead of 3-chlorobenzylamine, the title N-[(S) -1- [N- [(3,4-Dihydro-2H-pyran-6-yl) methyl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 256 mg ( Yield 29%).

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.22-1.44 (6H, m), 1.54-1.70 (5H, m), 1.75-2.15 (9H, m), 3.38 ( 4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 3.80 (2H, d, J = 5Hz), 4.00 (2H, t, J = 5Hz), 4.43 (1H, s), 4.72 (1H, t, J = 4Hz), 5.14-5.21 (1H, m), 7.05 (1H, t, J = 5Hz), 7.94 (1H, d, J = 6Hz)
IR (ν, KBr, cm ^-1 ): 3318, 2931, 2856, 1668
Rf value: 0.58

Example 90 N-[(S) -1- [N-[(2-cyclohexyl-2-oxo) ethyl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4- Carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 215 mg of 2-amino-1-cyclohexylethanol instead of 3-chlorobenzylamine, the title N-[(S) -1- [N-[(2-cyclohexyl-2-oxo) There were obtained 470 mg (yield 60%) of [ethyl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.08-1.45 (12H, m), 1.54-1.71 (5H, m), 1.74-1.98 (7H, m), 2.02- 2.17 (2H, m), 2.37-2.46 (1H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.16 (1H, dd, J = 20Hz, 5Hz) , 4.24 (1H, dd, J = 20Hz, 5Hz), 4.27 (1H, s), 5.18-5.25 (1H, m), 7.57 (1H, t, J = 5Hz), 7.96 (1H, d, J = 6Hz )
IR (ν, KBr, cm ⁻¹ ): 3320, 2931, 2856, 1685, 1648
Rf value: 0.49

Example 91 N-[(S) -1,2-dioxo-1- [N- (1-methoxycyclohexylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexane Carboxamide

  In the same manner as in Example 28, using 340 mg of 1-methoxycyclohexylmethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (1-methoxycyclohexylmethyl) ) Amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained in an amount of 310 mg (yield 39%).

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.24-1.34 (16H, m), 1.48-1.55 (3H, m), 1.64-1.67 (5H, m), 1.89- 1.97 (2H, m), 2.04-2.13 (2H, m), 3.17 (3H, s), 3.38 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.42 (1H, s ), 5.22-5.27 (1H, m), 7.03 (1H, bs), 7.91 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3413, 2933, 1675, 1629, 1523
Rf value: 0.68

Example 92 N-[(S) -1,2-dioxo-1- [N-[(RS) -2-oxocyclohexyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 173 mg of trans-2-aminocyclohexanol instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-[(RS)- There were obtained 508 mg (yield 69%) of 2-oxocyclohexyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7 Hz), 1.22-1.47 (8H, m), 1.55-2.00 (10H, m), 2.03-2.20 (3H, m), 2.35- 2.70 (3H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.36-4.47 (1H, m), 4.46 (1H, s), 5.20-5.29 (1H , m), 7.69 (1 / 2H, d, J = 7Hz), 7.76 (1 / 2H, d, J = 6Hz), 7.89 (1 / 2H, d, J = 7Hz), 7.93 (1 / 2H, d , J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 2931, 2859, 1675, 1643
Rf value: 0.68

Example 93 N-[(S) -1,2-dioxo-1-N-[[(R, S) -4-methyl-1-oxo-1- [N- (phenylmethyl) amino] -2-pentyl ] Amino] -3-pentyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 330 mg of DL-N-benzylleucinamide instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1-N-[[(R, S ) -4-Methyl-1-oxo-1- [N- (phenylmethyl) amino] -2-pentyl] amino] -3-pentyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 503 mg (yield 56%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 0.92 (3 / 2H, d, J = 6Jz), 0.94 (3 / 2H, d, J = 6Hz), 1.21-1.42 (8H, m), 1.53-1.97 (9H, m), 1.98-2.16 (2H, m), 3.36 (4H, t, J = 5Hz), 3.69 (4H, t, J = 5Hz), 4.20-4.51 ( 1H, m), 4.42 (2H, d, J = 6Hz), 4.61 (1 / 2H, s), 4.66 (1 / 2H, s), 5.00-5.03 (1H, m), 5.92-6.10 (1H, m ), 7.10 (1 / 2H, dd, J = 6Hz, 6Hz), 7.12 (1 / 2H, dd, J = 6Hz, 6Hz), 7.87 (1 / 2H, d, J = 6Hz), 8.07 (1 / 2H , d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3315, 2956, 2933, 1654, 1527
Rf value: 0.53

Example 94 N-[(S) -1,2-dioxo-1-N-[(RS) -phenylsulfonyl-5-methylthio-1-penten-3-yl] amino-3-heptyl] -1- [N -(Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 407 mg of (2RS) -1-phenylsulfonyl-3-amino-5-methylthio-3-pentene instead of 3-chlorobenzylamine, the title N-[(S) -1,2 -Dioxo-1-N-[(RS) -phenylsulfonyl-5-methylthio-1-penten-3-yl] amino-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 478 mg (yield 49%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3 / 2H, t, J = 7Hz), 0.90 (3 / 2H, t, J = 7Hz), 1.22-1.51 (9H, m), 1.52-1.78 (6H , m), 1.80-2.28 (3H, m), 2.05 (3 / 2H, s), 2.09 (3 / 2H, s), 2.43-2.60 (2H, m), 3.41 (4H, t, J = 5Hz) , 3.71 (4H, t, J = 5Hz), 4.62-4.69 (1H, m), 4.73-4.85 (1H, m), 4.78 (1H, s), 6.48 (1 / 2H, d, J = 15Hz), 6.59 (1 / 2H, d, J = 15Hz), 6.89-6.98 (2H, m), 7.52-7.70 (3H, m), 7.59 (1 / 2H, d, J = 8Hz), 7.85 (1 / 2H, d, J = 8Hz), 7.86 (1H, d, J = 8Hz), 8.38 (1 / 2H, d, J = 6Hz), 8.54 (1 / 2H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3384, 2954, 2927, 1671, 1634, 1523
Rf value: 0.57

Example 95 N-[(S) -1,2-dioxo-1-N-[[(RS) -4-methyl-1-oxo-1- (phenylmethyl) oxy-2-pentyl] amino] -3- Pentyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 332 mg of DL-leucine benzyl ester instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1-N-[[(RS) -4- 550 mg (61% yield) of methyl-1-oxo-1- (phenylmethyl) oxy-2-pentyl] amino] -3-pentyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide Obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 0.91 (3H, d, J = 6Hz), 0.92 (3H, d, J = 6Hz), 1.21-1.42 (8H, m ), 1.52-1.72 (6H, m), 1.83-2.00 (3H, m), 2.02-2.18 (2H, m), 3.38 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz) , 4.43 (1H, s), 4.60-4.68 (1H, m), 5.14-5.22 (1H, m), 5.17 (2H, s), 7.21 (1 / 2H, d, J = 9Hz), 7.23 (1 / 2H, d, J = 9Hz), 7.31-7.40 (5H, m), 7.96 (1 / 2H, d, J = 6Hz), 7.97 (1 / 2H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3357, 2958, 1675, 1631, 1523
Rf value: 0.34

Example 96 N-[(S) -1- [N-[(2-methyl-1,3-dioxan-2-yl) methyl] amino-1,2-dioxo-3-heptyl] -1- [N- (Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 197 mg of 1- (2-methyl-1,3-dioxane-2-yl) methanamine instead of 3-chlorobenzylamine, the title N-[(S) -1- [N [(2-Methyl-1,3-dioxan-2-yl) methyl] amino-1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield) 59%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.22-1.41 (6H, m), 1.43-1.70 (6H, m), 1.83-2.16 (6H, m), 3.39 ( 4H, t, J = 5Hz), 3.44 (2H, d, J = 5Hz), 3.72 (4H, t, J = 5Hz), 3.83-3.99 (4H, m), 4.44 (1H, s), 5.20-5.25 (1H, m), 7.15 (1H, t, J = 6Hz), 7.94 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3351, 2933, 2861, 1677
Rf value: 0.74

Example 97 N-[(S) -1- [N-[[2- (1,1-dimethylethyl) -1,3-dioxolan-2-yl] methyl] amino] -1,2-dioxo-3- Heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 239 mg of 1- [2- (1,1-dimethylethyl) -1,3-dioxolan-2-yl] methanamine instead of 3-chlorobenzylamine, the title N-[(S ) -1- [N-[[2- (1,1-dimethylethyl) -1,3-dioxolan-2-yl] methyl] amino] -1,2-dioxo-3-heptyl] -1- [N -(Morpholine-4-carbonyl) amino] cyclohexanecarboxamide 603 mg (yield 75%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 0.98 (9H, s), 1.23-1.42 (6H, m), 1.56-1.70 (5H, m), 1.83-2.17 ( 5H, m), 3.38 (4H, t, J = 5Hz), 3,53 (1H, dd, J = 14Hz, 6Hz), 3.61 (1H, dd, J = 14Hz, 6Hz), 3.71 (4H, t, J = 5Hz), 3.94-4.04 (4H, m), 4.43 (1H, s), 5.12-5.19 (1H, m), 7.00 (1H, t, J = 5Hz), 7.97 (1H, d, J = 7Hz )
IR (ν, KBr, cm ^-1 ): 3311, 2952, 2933, 1660
Rf value: 0.45

Example 98 N-[(S) -1- [N-[(2,5,5-trimethyl-1,3-dioxan-2-yl) methyl] amino] -1,2-dioxo-3-heptyl]- 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, except for using 251 mg of 1- (2,5,5-trimethyl-1,3-dioxan-2-yl) methanamine instead of 3-chlorobenzylamine, -[N-[(2,5,5-trimethyl-1,3-dioxan-2-yl) methyl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4- Carbonyl) amino] cyclohexanecarboxamide 546 mg (yield 68%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.82 (3H, s), 0.88 (3H, t, J = 7Hz), 1.23-1.43 (6H, m), 1.38 (3H, s), 1.57-1.70 (5H, m), 1.83-2.16 (5H, m), 3.36-3.51 (4H, m), 3.38 (4H, t, J = 5Hz), 3.61 (2H, d, J = 11Hz), 3.72 (4H, t, J = 7Hz), 4.45 (1H, s), 5.21-5.27 (1H, m), 7.21 (1H, t, J = 5Hz), 7.91 (1H, d, J = 6Hz)
IR (ν, KBr, cm ^-1 ): 3347, 2954, 2857, 1677
Rf value: 0.51

Example 99 N-[(S) -1,2-dioxo-1- [N- (4-phenoxyphenyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 277 mg of 4-phenoxyaniline instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (4-phenoxyphenyl) amino] There was obtained 170 mg (yield 19%) of -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.20-2.20 (16H, m), 3.35-3.42 (4H, m), 3.60-3.80 (4H, m), 4.43 ( 1H, s), 5.25 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 6.95-7.05 (4H, m), 7.06-7.15 (1H, m), 7.30-7.40 (2H, m), 7.55-7.65 (2H, m), 8.07 (1H, d, J = 7Hz), 8.64 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3318, 3264, 2929, 2856, 1666, 1637, 1508
Rf value: 0.31

Example 100 N-[(S) -1,2-dioxo-1- [N- (1-benzoyl-4-piperidino) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino ] Cyclohexanecarboxamide

  In the same manner as in Example 28, but using 306 mg of 4-amino-1-benzoylpiperazine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (1-benzoyl) 356 mg (yield 40%) of -4-piperidino) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-2.20 (20H, m), 2.90-3.30 (2H, m), 3.30-3.42 (4H, m), 3.60- 3.90 (5H, m), 3.95-4.05 (1H, m), 4.44 (1H, s), 4.50-4.80 (1H, m), 5.18 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 6.85 (1H , d, J = 8Hz), 7.30-7.42 (5H, m), 7.96 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3355, 2929, 2857, 1670, 1619, 1527
Rf value: 0.66

Example 101 N-[(S) -1,2-dioxo-1- [N- (4-oxo-1-cyclohexyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino ] Cyclohexanecarboxamide

  In the same manner as in Example 28, using 230 mg of 4-aminocyclohexanol instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (4-oxo-1- There were obtained 101 mg (yield 13%) of (cyclohexyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.85-1.00 (3H, m), 1.30-1.42 (7H, m), 1.60-2.00 (10H, m), 2.00-2.30 (3H, m), 2.40-2.55 ( 4H, m), 3.30-3.45 (4H, m), 3.65-3.80 (4H, m), 4.10-4.20 (1H, m), 4.47 (1H, s), 5.18 (1H, ddd, J = 12Hz, 7Hz , 5Hz), 6.92 (1H, d, J = 8Hz), 7.99 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 2934, 2857, 1718, 1662, 1629, 1529
Rf value: 0.75

Example 102 N-[(S) -1- [N- (3,3-dimethyl-2-oxo-butyl) amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4 -Carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 176 mg of 1-amino-3,3-dimethyl-2-butanol instead of 3-chlorobenzylamine, the title N-[(S) -1- [N- (3,3- 422 mg (57% yield) of dimethyl-2-oxo-butyl) amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7 Hz), 1.21 (9H, s), 1.22-1.43 (6H, m), 1.55-1.69 (5H, m), 1.82-2.15 ( 5H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.26 (1H, dd, J = 16Hz, 5Hz), 4.35 (1H, dd, J = 16Hz, 5Hz), 4.45 (1H, s), 5.21-5.27 (1H, m), 7.62 (1H, t, J = 5Hz), 7.95 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3374, 2933, 2857, 1683, 1643
Rf value: 0.60

Example 103 N-[(S) -1,2-dioxo-1- [N- [2- (phenylsulfonyl) ethyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino ] Cyclohexanecarboxamide

  In the same manner as in Example 28, using 278 mg of 2- (phenylsulfonyl) ethanamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- [2- (phenyl Sulfonyl) ethyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 256 mg (yield 30%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.21-1.43 (7H, m), 1.53-1.69 (4H, m), 1.83-2.16 (5H, m), 3.29- 3.41 (6H, m), 3.69-3.77 (6H, m), 4.44 (1H, s), 5.11-5.17 (1H, m), 7.45 (1H, t, J = 5Hz), 7.60 (2H, t, J = 8Hz), 7.69 (1H, t, J = 8Hz), 7.89-7.97 (3H, m)
IR (ν, KBr, cm ⁻¹ ): 3394, 2929, 2857, 1675, 1643
Rf value: 0.68

Example 104 N-[(S) -1,2-dioxo-1- [N- (2-oxo-3-phenylpropyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 454 mg of (2RS) -2-hydroxy-3-phenylpropylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- 200 mg (yield 25%) of (2-oxo-3-phenylpropyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.24-1.38 (7H, m), 1.60-1.64 (4H, m), 1.83-1.93 (3H, m), 2.05- 2.12 (2H, m), 3.36 (4H, t, J = 5Hz), 3.69 (4H, t, J = 5Hz), 3.76 (2H, s), 4.17 (2H, ddd, J = 5Hz, 20Hz, 25Hz) , 4.43 (1H, s), 5.12-5.18 (1H, m), 7.21-7.32 (5H, m), 7.49 (1H, t, J = 5Hz), 7.79 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3318, 2931, 1685, 1644, 1529
Rf value: 0.63

Example 105 N-[(S) -1,2-dioxo-1- [N- (2-oxo-4-phenylbutyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 496 mg of (2RS) -2-hydroxy-4-phenylbutylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- There was obtained 235 mg (yield 29%) of (2-oxo-4-phenylbutyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.29-1.45 (8H, m), 1.60-1.65 (3H, m), 1.86-1.94 (3H, m), 2.03- 2.13 (2H, m), 2.80 (2H, t, J = 7Hz), 2.95 (2H, t, J = 7Hz), 3.38 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz) , 4.07 (2H, ddd, J = 5Hz, 20Hz, 35Hz), 4.43 (1H, s), 5.16-5.21 (1H, m), 7.16-7.29 (5H, m), 7.52 (1H, t, J = 5Hz ), 7.97 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3382, 2927, 1675, 1527
Rf value: 0.59

Example 106 N-[(S) -1,2-dioxo-1- [N- (2-methyl-2-phenoxypropyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 600 mg of 2-methyl-2-phenoxypropylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (2-methyl -2-Phenoxypropyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (241 mg, 22% yield) was obtained.

1H-NMR (CDCl ₃ , δ): 0.86 (3H, t, J = 7Hz), 1.26 (6H, d, J = 2Hz), 1.30-1.43 (7H, m), 1.64-1.72 (4H, m), 1.86-2.01 (3H, m), 2.09-2.11 (2H, m), 3.39 (4H, t, J = 5Hz), 3.49 (2H, dd, J = 2Hz, 6Hz), 3.72 (4H, t, J = 5Hz), 4.44 (1H, s), 5.23-5.28 (1H, m), 6.94-6.96 (2H, m), 7.09-7.12 (1H, s), 7.27-7.30 (2H, m), 7.41 (1H, t, J = 6Hz), 7.97 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3330, 2931, 1689, 1648, 1527
Rf value: 0.44

Example 107 N-[(S) -1,2-dioxo-1- [N-[(R) -2-oxocyclohexyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 173 mg of (1R, 2R) -2-aminocyclohexanol instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- [ 280 mg (yield 38%) of (R) -2-oxocyclohexyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.22-1.47 (8H, m), 1.55-1.99 (10H, m), 2.03-2.20 (3H, m), 2.35- 2.69 (3H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.40-4.46 (1H, m), 4.46 (1H, s), 5.22-5.29 (1H , m), 7.69 (1H, d, J = 7Hz), 7.89 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3392, 2931, 2859, 1675, 1629
Rf value: 0.68

Example 108 N-[(S) -1,2-dioxo-1- [N-[(S) -2-oxocyclohexyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 173 mg of (1S, 2S) -2-aminocyclohexanol instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- [ There was obtained 236 mg (yield 32%) of (S) -2-oxocyclohexyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.23-1.46 (8H, m), 1.56-2.00 (10H, m), 2.03-2.20 (3H, m), 2.36- 2.70 (3H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.36-4.47 (1H, m), 4.46 (1H, s), 5.20-5.25 (1H , m), 7.76 (1H, d, J = 6Hz), 7.93 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3380, 2931, 2859, 1675, 1629
Rf value: 0.66

Example 109 N-[(3S) -1,2-dioxo-1- [N-[(1RS) -2-oxo-1-cyclohexyl] amino] -5-methyl-3-hexyl] -1- [N- (Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  (2RS, 3S) -N-[(1R2R, 1S2S) -2-hydroxycyclohexyl] using 3.7 g of (1R2R, 1S2S) -2-aminocyclohexanol instead of cyclopentylamine in the same manner as in Reference Example 19. 910 mg (yield 7%) of -3-amino-2-hydroxy-5-methylhexamide was obtained. Then, in the same manner as in Example 1, instead of (3S) -N- (2-methyl-2-propyl) -3-amino-2-hydroxyheptanamide, the above (2RS, 3S) -N-[(1R2R, 1S2S ) -2-Hydroxycyclohexyl] -3-amino-2-hydroxy-5-methylhexamide 910 mg was used and the title N-[(3S) -1,2-dioxo-1- [N-[(1RS) -2- 395 mg (22% yield) of oxo-1-cyclohexyl] amino] -5-methyl-3-hexyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.93 (3H, t, J = 8 Hz), 0.98 (3H, t, J = 8 Hz), 1.20-2.20 (19H, m), 2.30-2.45 (1H, m), 2.50-2.70 (1H, m), 3.38 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz), 4.19-4.30 (2H, m), 5.20-5.35 (1H, m), 7.69 (1 / 2H, d, J = 6Hz), 7.76 (1 / 2H, d, J = 6Hz), 7.90 (1 / 2H, d, J = 7Hz), 7.94 (1 / 2H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3378, 2937, 2861, 1725, 1675, 1648, 1523
Rf value: 0.68

Example 110 N-[(S) -1,2-dioxo-1- [N-[(S) -3-methyl-1-oxo-1- (phenylmethoxy) -2-butyl] amino] -3-heptyl ] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 223 mg of L-valine benzyl ester instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-[(S) -3- 217 mg (34% yield) of methyl-1-oxo-1- (phenylmethoxy) -2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained. It was.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 0.88 (6H, dd, J = 14Hz, 7Hz), 1.30-1.41 (8H, m), 1.52-1.67 (4H, m ), 1.82-2.00 (3H, m), 2.04-2.13 (2H, m), 2.14-2.26 (1H, m), 3.38 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz) , 4.43 (1H, s), 4.52 (1H, dd, J = 9Hz, 5Hz), 5.14-5.24 (3H, m), 7.32-7.39 (6H, m), 7.98 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 2960, 2931, 1741, 1675, 1629, 1523
Rf value: 0.39

Example 111 N-[(S) -1- [N-[(R) -1-oxo-1-methoxy-3-methyl-2-butyl] amino] -1,2-dioxo-3-heptyl] -1 -[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 262 mg of D-valine methyl ester instead of 3-chlorobenzylamine, the title N-[(S) -1- [N-[(R) -1-oxo-1-methoxy- There were obtained 472 mg (yield 46%) of 3-methyl-2-butyl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 0.90-0.96 (6H, m), 1.21-1.39 (7H, m), 1.57-1.65 (5H, m), 1.89- 1.97 (2H, m), 2.11-2.16 (2H, m), 2.17-2.24 (1H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 3.76 (3H , s), 4.44 (1H, s), 4.49 (1H, dd, J = 9Hz, 5Hz), 5.18-5.23 (1H, m), 7.31 (1H, d, J = 10Hz), 7.96 (1H, d, (J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3355, 2960, 2933, 1745, 1677, 1643, 1517, 1257
Rf value: 0.60

Example 112 N-[(S) -1,2-dioxo-1- [N-[(R) -2-oxo-2-methoxy-1-phenylethyl] amino] -3-heptyl] -1- [N -(Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 323 mg of D-phenylglycine methyl ester instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-[(R) -2 There was obtained 490 mg (yield 45%) of -oxo-2-methoxy-1-phenylethyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 8Hz), 1.30-1.38 (7H, m), 1.61-1.66 (3H, m), 1.81-2.09 (6H, m), 3.36 ( 4H, t, J = 5Hz), 3.70 (4H, t, J = 5Hz), 3.74 (3H, s), 4.40 (1H, s), 5.08-5.15 (1H, m), 5.50 (1H, d, J = 8Hz), 7.34-7.36 (5H, m), 7.76 (1H, d, J = 7Hz), 7.97 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3430, 3293, 2954, 2931, 1735, 1666, 1525
Rf value: 0.60

Example 113 N-[(S) -1,2-dioxo-1- [N-[(R) -2-oxocyclopentyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 152 mg of (1R, 2R) -2-aminocyclopentanol instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- There was obtained 266 mg (yield 37%) of [(R) -2-oxocyclopentyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.23-1.45 (7H, m), 1.58-1.72 (5H, m), 1.82-1.99 (4H, m), 2.03- 2.31 (4H, m), 2.39-2.49 (1H, m), 2.60-2.68 (1H, m), 3.38 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz), 4.12-4.21 (1H, m), 4.50 (1H, s), 5.12-5.17 (1H, m), 7.14 (1H, d, J = 7Hz), 8.02 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 2929, 2857, 1675, 1648
Rf value: 0.71

Example 114 N-[(S) -1,2-dioxo-1- [N-[(S) -2-oxocyclopentyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the method according to Example 28, using 152 mg of (1S, 2S) -2-aminocyclopentanol instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- 230 mg (yield 32%) of [(S) -2-oxocyclopentyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.23-1.46 (7H, m), 1.54-1.99 (9H, m), 2.03-2.33 (4H, m), 2.40- 2.49 (1H, m), 2.57-2.64 (1H, m), 3.89 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.01-4.09 (1H, m), 4.51 (1H , s), 5.08-5.15 (1H, m), 7.18 (1H, d, J = 7Hz), 8.05 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3316, 2931, 2857, 1677, 1648
Rf value: 0.70

Example 115 N-[(S) -1,2-dioxo-1- [N-[(S) -3-methyl-1-oxo-1- [N- (phenylmethyl) amino] -2-butyl] amino ] -3-Heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 128 mg of LN-benzylvalinamide instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-[(S)- 161 mg of 3-methyl-1-oxo-1- [N- (phenylmethyl) amino] -2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide ( Yield 45%).

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 0.94 (6H, dd, J = 19Hz, 7Hz), 1.24-1.33 (7H, m), 1.60-1.80 (5H, m ), 1.81-2.11 (4H, m), 2.42 (1H, dt, J = 19Hz, 7Hz), 3.36 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz), 4.27 (1H, dd, J = 9Hz, 5Hz), 4.38 (1H, s), 4.43 (2H, d, J = 6Hz), 5.06-5.11 (1H, m), 6.73 (1H, t, J = 6Hz), 7.22-7.35 (6H, m), 8.06 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3399, 1648, 1529
Rf value: 0.57

Example 116 N-[(S) -1,2-dioxo-1- [N-[(S) -3-methyl-1-oxo-1- [N- (1,1-dimethylethyl) amino] -2 -Butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 143 mg of LN-tert-butylvalinamide instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-[(S ) -3-Methyl-1-oxo-1- [N- (1,1-dimethylethyl) amino] -2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) 154 mg (34% yield) of amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 0.92 (6H, dd, J = 12Hz, 7Hz), 1.24-1.34 (7H, m), 1.35 (9H, s), 1.58-1.70 (3H, m), 1.87-2.00 (3H, m), 2.04-2.22 (3H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.02 (1H, dd, J = 9Hz, 6Hz), 4.43 (1H, s), 5.20-5.26 (1H, m), 5.61 (1H, s), 7.35 (1H, d, J = 9Hz), 7.94 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3322, 2962, 2933, 1677, 1643, 1531, 1255
Rf value: 0.55

Example 117 N-[(S) -1,2-dioxo-1- [N- [4- (ethoxycarbonylmethylene) cyclohexane-1-yl] amino] -3-heptyl] -1- [N- (morpholine- 4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 361 mg of 4- (ethoxycarbonylmethylene) cyclohexylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- [4- 250 mg (22% yield) of (ethoxycarbonylmethylene) cyclohexane-1-yl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.27 (3H, t, J = 7Hz), 1.20-2.40 (21H, m), 3.38 (4H, t, J = 5Hz ), 3.71 (4H, t, J = 5Hz), 3.90-4.10 (1H, m), 4.15 (2H, qd, J = 12Hz, 7Hz), 4.43 (1H, s), 5.19 (1H, ddd, J = 13Hz, 9Hz, 4Hz), 5.66 (1H, s), 6.78 (1H, d, J = 8Hz), 7.95 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3328, 2935, 2856, 1712, 1681, 1646, 1527
Rf value: 0.51

Example 118 N-[(S) -1,2-dioxo-1- [N- (1,4-dioxaspiro [4,5] decan-8-yl) amino] -3-heptyl] -1- [N- (Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 314 mg of 8-amino-1,4-dioxaspiro [4,5] decane instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (1,4-dioxaspiro [4,5] decan-8-yl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield 33%) )

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.20-2.20 (24H, m), 3.38 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz ), 3.94 (4H, s), 4.45 (1H, s), 5.20 (1H, ddd, J = 12Hz, 7Hz, 4Hz), 6.78 (1H, d, J = 8Hz), 7.92 (1H, d, J = (7Hz)
IR (ν, KBr, cm ⁻¹ ): 3345, 2937, 2857, 1729, 1685, 1648, 1525
Rf value: 0.68

Example 119 N-[(S) -1- [N-[(S) -Hexahydro-2-azepin-3-yl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine -4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 192 mg of (S) -3-aminohexahydro-2-azepinone instead of 3-chlorobenzylamine, the title N-[(S) -1- [N-[(S)- Hexahydro-2-azepin-3-yl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield 12%) was obtained. .

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.22-1.73 (13H, m), 1.75-2.18 (9H, m), 3.20-3.31 (2H, m), 3.39 ( 4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.43-4.50 (1H, m), 4.48 (1H, s), 5.24-5.31 (1H, m), 6.02 (1H, t , J = 5Hz), 7.86 (1H, d, J = 7Hz), 8.16 (1H, d, J = 6Hz)
IR (ν, KBr, cm ^-1 ): 3355, 2931, 2857, 1658
Rf value: 0.76

Example 120 N-[(S) -1,2-dioxo-1- [N-[(2S, 3S) -1-oxo-1-methoxy-3-methyl-2-hexyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

In the same manner as in Example 28, using 363 mg of L-isoleucine methyl ester hydrochloride and 403 mg of triethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-[( 2S, 3S) -1-Oxo-1-methoxy-3-methyl-2-hexyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield 36) %).

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 0.91 (3H, d, J = 7Hz), 0.92 (3H, t, J = 7Hz), 1.20-1.50 (9H, m ), 1.62-1.70 (3H, m), 1.85-2.00 (4H, m), 2.07-2.13 (3H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz) , 3.75 (3H, s), 4.44 (1H, s), 4.52 (1H, dd, J = 9Hz, 5Hz), 5.18-5.23 (1H, m), 7.33 (1H, d, J = 9Hz), 7.99 ( (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 2958, 2931, 1743, 1648, 1525
Rf value: 0.55

Example 121 N-[(S) -1,2-dioxo-1- [N-[(S) -2-oxo-2-methoxy-1-phenylethyl] amino] -3-heptyl] -1- [N -(Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

In the same manner as in Example 28, but using 330 mg of L-phenylglycine methyl ester instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-[(S) -2 There were obtained 531 mg (yield 49%) of -oxo-2-methoxy-1-phenylethyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.84 (3H, t, J = 7 Hz), 1.21-1.42 (8H, m), 1.50-1.68 (3H, m), 1.81-1.95 (3H, m), 2.01- 2.16 (2H, m), 3.35 (4H, t, J = 5), 3.70 (4H, t, J = 5Hz), 3.74 (3H, s), 4.40 (1H, s), 5.07-5.15 (1H, m ), 5.50 (1H, d, J = 7Hz), 7.34-7.38 (5H, m), 7.83 (1H, d, J = 8Hz), 7.96 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3380, 1654, 1511
Rf value: 0.61

Example 122 N-[(S) -1,2-dioxo-1- [N-[(S) -1-oxo-1-methoxy-3,3-dimethyl-2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 400 mg of L-tert leucine methyl ester instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-[(S) -1 445 mg (43% yield) of -oxo-1-methoxy-3,3-dimethyl-2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide It was.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 0.98 (9H, s), 1.22-1.42 (7H, m), 1.62-1.69 (4H, m), 1.86-1.95 ( 3H, m), 2.06-2.10 (2H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 3.74 (3H, s), 4.40 (1H, d, J = 10Hz), 4.44 (1H, s), 5.20-5.25 (1H, m), 7.39 (1H, d, J = 10Hz), 8.00 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3332, 2956, 2933, 1741, 1691, 1648, 1521
Rf value: 0.55

Example 123 N-[(S) -1- [N-[(S) -3-Methyl-1-oxo-1-phenyl-2-butyl] amino] -1,2-dioxo-3-heptyl] -1 -[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 269 mg of (1RS, 2S) -2-amino-3-methyl-1-phenyl-1-butanol instead of 3-chlorobenzylamine, the title N-[(S) -1- [N-[(S) -3-Methyl-1-oxo-1-phenyl-2-butyl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) 400 mg (yield 48%) of amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.79 (3H, d, J = 7Hz), 0.88 (3H, t, J = 7Hz), 1.01 (3H, d, J = 7Hz), 1.23-1.44 (6H, m ), 1.54-1.73 (5H, m), 1.83-2.30 (6H, m), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.43 (1H, s), 5.23 -5.30 (1H, m), 5.51 (1H, dd, J = 9Hz, 4Hz), 7.49 (2H, t, J = 8Hz), 7.62 (1H, t, J = 8Hz), 7.69 (1H, d, J = 8Hz), 7.95-8.03 (3H, m)
IR (ν, KBr, cm ⁻¹ ): 3332, 2931, 2857, 1675, 1648
Rf value: 0.43

Example 124 N-[(S) -1,2-dioxo-1- [N-[[2- (2-propyl) -1,3-dioxolan-2-yl] methyl] amino] -3-heptyl]- 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 194 mg of 1- [2- (2-propyl) -1,3-dioxolan-2-yl] methanamine instead of 3-chlorobenzylamine, the title N-[(S) -1 , 2-Dioxo-1- [N-[[2- (2-propyl) -1,3-dioxolan-2-yl] methyl] amino] -3-heptyl] -1- [N- (morpholine-4- Carbonyl) amino] cyclohexanecarboxamide 368 mg (yield 47%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 0.95 (6H, d, J = 7Hz), 1.24-1.42 (6H, m), 1.53-1.70 (5H, m), 1.83-2.15 (6H, m), 3.39 (4H, t, J = 5Hz), 3.41-3.53 (2H, m), 3.72 (4H, t, J = 5Hz), 3.94-4.03 (4H, m), 4.43 (1H, s), 5.14-5.21 (1H, m), 6.99 (1H, t, J = 5Hz), 7.95 (1H, d, J = 7Hz)
IR (ν, KBr, cm ^-1 ): 3320, 2952, 2857, 1658
Rf value: 0.57

Example 125 N-[(S) -1- [N-[(S) -4-methyl-2-oxo-3-pentyl] amino] -1,2-dioxo-3-heptyl] -1- [N- (Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, but using 176 mg of (2RS, 3S) -3-amino-4-methyl-2-pentanol instead of 3-chlorobenzylamine, the title N-[(S) -1- [N- [(S) -4-Methyl-2-oxo-3-pentyl] amino] -1,2-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield) 62%).

1H-NMR (CDCl ₃ , δ): 0.83 (3H, d, J = 7Hz), 0.87 (3H, t, J = 7Hz), 0.99 (3H, d, J = 7Hz), 1.21-1.43 (6H, m ), 1.50-1.72 (5H, m), 1.82-2.33 (6H, m), 2.23 (3H, s), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.45 (1H, s), 4.56 (1H, dd, J = 9Hz, 5Hz), 5.19-5.24 (1H, m), 7.42 (1H, d, J = 9Hz), 7.99 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3336, 2932, 2860, 1668
Rf value: 0.64

Example 126 N-[(S) -1- [N-[(S) -2-Methyl-1- (2-methyl-1,3-dioxolan-2-yl) propyl] amino] -1,2-dioxo -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 239 mg of (S) -2-methyl-1- (2-methyl-1,3-dioxolan-2-yl) propanamine instead of 3-chlorobenzylamine, the title N- [ (S) -1- [N-[(S) -2-Methyl-1- (2-methyl-1,3-dioxolan-2-yl) propyl] amino] -1,2-dioxo-3-heptyl] 478 mg (yield 59%) of -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.83-0.96 (9H, m), 1.22-1.43 (6H, m), 1.32 (3H, s), 1.5 6-1.75 (5H, m), 1.82-2.17 (6H , m), 3.38 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 3.84-4.07 (5H, m), 4.44 (1H, s), 5.17-5.26 (1H, m) , 6.97 (1H, d, J = 6Hz), 7.96 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3424, 2936, 2864, 1664
Rf value: 0.51

Example 127 N-[(S) -1,2-dioxo-1- [N- (4-methoxyphenyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 369 mg of 4-methoxyaniline instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (4-methoxyphenyl) amino] There were obtained 493 mg (yield 49%) of -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.20-2.20 (16H, m), 3.35-3.40 (4H, m), 3.70-3.80 (4H, m), 3.80 ( 3H, s), 4.44 (1H, s), 5.25 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 6.89 (2H, ddd, J = 9Hz, 6Hz, 3Hz), 7.53 (2H, ddd, J = 9Hz, 6Hz, 3Hz), 8.04 (1H, d, J = 7Hz), 8.57 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3320, 2936, 2860, 1728, 1666, 1642, 1514
Rf value: 0.59

Example 128 N-[(S) -1- [N- (4-fluorophenyl) amino] -1,3-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 167 mg of 4-fluoroaniline instead of 3-chlorobenzylamine, the title N-[(S) -1- [N- (4-fluorophenyl) amino] -1,3-dioxo was used. There was obtained 363 mg (yield 49%) of -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.90 (3H, t, J = 7Hz), 1.25-1.44 (6H, m), 1.53-1.77 (5H, m), 1.83-2.15 (5H, m), 3.37 ( 4H, t, J = 5Hz), 3.70 (4H, t, J = 5Hz), 4.43 (1H, s), 5.19-5.26 (1H, m), 7.01-7.08 (2H, m), 7.56-7.64 (2H , m), 8.09 (1H, d, J = 6Hz), 8.64 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3332, 2936, 2864, 1668, 1644
Rf value: 0.53

Example 129 N-[(S) -1- [N- (3,5-difluorophenyl) amino] -1,3-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] Cyclohexane carboxamide

  In the same manner as in Example 28, using 194 mg of 3,5-difluoroaniline instead of 3-chlorobenzylamine, the title N-[(S) -1- [N- (3,5-difluorophenyl) amino] -1 , 3-dioxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (43% yield).

1H-NMR (CDCl ₃ , δ): 0.90 (3H, t, J = 7Hz), 1.28-1.44 (6H, m), 1.58-1.78 (5H, m), 1.83-2.17 (5H, m), 3.37 ( 4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz), 4.42 (1H, s), 5.12-5.19 (1H, m), 6.58-6.66 (1H, m), 7.21-7.30 (2H , m), 8.17 (1H, d, J = 6Hz), 8.73 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3336, 2932, 2864, 1678, 1642
Rf value: 0.44

Example 130 N-[(S) -1,2-dioxo-1- [N-[(S) -2-methyl-1-oxo-1- (N-phenylamino) -2-butyl] amino] -3 -Heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 461 mg of LN-phenylvalinamide instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N-[(S)- 291 mg of 2-methyl-1-oxo-1- (N-phenylamino) -2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield 25 %).

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.01 (6H, dd, J = 16Hz, 7Hz), 1.06-1.35 (7H, m), 1.58-1.75 (4H, m ), 1.78-2.10 (4H, m), 2.48 (1H, q, J = 6Hz), 3.34 (4H, t, J = 5Hz), 3.67 (4H, t, J = 5Hz), 4.37 (1H, dd, J = 9Hz, 6Hz), 4.41 (1H, s), 4.98-5.03 (1H, s), 7.09 (1H, t, J = 8Hz), 7.25-7.28 (5H, m), 7.57 (1H, d, J = 8Hz), 8.04 (1H, d, J = 6Hz), 8.14 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3320, 2936, 1604, 1448
Rf value: 0.53

Example 131 N-[(S) -1,2-dioxo-1- [N- (3,4-methylenedioxyphenylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 1.13 g of 3,4-methylenedioxyphenylmethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- 1.1 g (yield 42%) of (3,4-methylenedioxyphenylmethyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.23-1.42 (7H, m), 1.58-1.75 (4H, m), 1.81-2.06 (3H, m), 2.08- 2.11 (2H, m), 3.37 (4H, t, J = 5Hz), 3.71 (4H, t, J = 5Hz), 4.36 (2H, d, J = 6Hz), 4.44 (1H, s), 5.13-5.21 (1H, m), 5.94 (2H, s), 6.74-6.76 (3H, m), 7.11 (1H, bs), 7.99 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3076, 2860, 1724, 1516, 1494
Rf value: 0.63

Example 132 N-[(S) -1,2-dioxo-1- [N-[(S) -1-methylamino-2-methyl-1-oxo-2-butyl] amino] -3-heptyl]- 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 867 mg of LN-methylvalinamide hydrochloride and 607 mg of triethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- [(S) -1-Methylamino-2-methyl-1-oxo-2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield) 10%).

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 0.91 (3H, d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 1.34-1.38 (7H, m ), 1.64-1.73 (6H, m), 1.80-1.93 (3H, m), 2.04-2.15 (2H, m), 2.39 (1H, dq, J = 7Hz, 6Hz), 2.78-2.84 (1H, m) , 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 4.24 (1H, dd, J = 10Hz, 6Hz), 4.54 (1H, s), 5.08 (1H, dt, J = 8Hz, 6Hz), 6.49 (1H, d, J = 5Hz), 7.25 (1H, d, J = 10Hz), 8.06 (1H, d, J = 6Hz)
IR (ν, KBr, cm ^-1 ): 3311, 2960, 2931, 1654, 1517
Rf value: 0.78

Example 133 N-[(3S) -1,2-dioxo-1- [N-[(1RS) -1-methoxy-3-methyl-2-butyl] amino] -3-heptyl] -1- [N- (Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 569 mg of (1RS) -1- (methoxymethyl) -2-methylpropyl] amine instead of 3-chlorobenzylamine, the title N-[(3S) -1,2-dioxo- 1- [N-[(1RS) -1-methoxy-3-methyl-2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield) 33%).

1H-NMR (CDCl ₃ , δ): 0.80-1.10 (9H, m), 1.20-2.20 (17H, m), 3.15-3.25 (1H, m), 3.32 (3H, s), 3.30-3.50 (4H, m), 3.50-3.60 (1H, m), 3.70-3.85 (5H, m), 4.49 (1H, s), 5.18-5.22 (1 / 2H, m), 5.23-5.28 (1 / 2H, m), 7.01 (1 / 2H, d, J = 6Hz), 7.04 (1 / 2H, d, J = 6Hz), 7.91 (1 / 2H, d, J = 7Hz), 7.94 (1 / 2H, d, J = 7Hz )
IR (ν, KBr, cm ⁻¹ ): 3328, 2964, 2864, 1728, 1664, 1532
Rf value: 0.56

Example 134 N-[(3S) -1,2-dioxo-1- [N-[(1RS) -1-phenoxy-3-methyl-2-butyl] amino] -3-heptyl] -1- [N- (Morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 520 mg of (1RS) -1- (phenoxymethyl) -2-methylpropyl] amine instead of 3-chlorobenzylamine, the title N-[(3S) -1,2-dioxo- 1- [N-[(1RS) -1-phenoxy-3-methyl-2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield) 27%).

1H-NMR (CDCl ₃ , δ): 0.80-1.00 (9H, m), 1.20-2.20 (17H, m), 3.36-3.40 (4H, m), 3.70 (4H, t, J = 4Hz), 3.90- 4.05 (2H, m), 4.05-4.15 (1H, m), 4.18 (1 / 2H, s), 4.29 (1 / 2H, s), 5.19-5.27 (1H, m), 6.88 (2H, t, J = 6Hz), 6.89 (1H, t, J = 7Hz), 7.15 (1 / 2H, d, J = 9Hz), 7.17 (1 / 2H, d, J = 9Hz), 7.29 (2H, d, J = 7Hz ), 7.94 (1 / 2H, d, J = 7Hz), 7.96 (1 / 2H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3316, 2960, 2864, 1726, 1658, 1602,1588
Rf value: 0.36

Example 135 N-[(S) -1,2-dioxo-1- [N- (3,4-methylenedioxyphenyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) Amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 548 mg of 3,4-methylenedioxyaniline instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (3,4 447 mg (43% yield) of -methylenedioxyphenyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide were obtained.

1H-NMR (CDCl ₃ , δ): 0.89 (3H, t, J = 7Hz), 1.20-2.20 (16H, m), 3.30-3.40 (4H, m), 3.70 (4H, t, J = 5Hz), 4.44 (1H, s), 5.22 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 5.97 (2H, s), 6.77 (1H, d, J = 8Hz), 6.94 (1H, dd, J = 8Hz, 2Hz), 7.34 (1H, d, J = 2Hz), 8.06 (1H, d, J = 6Hz), 8.56 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3324, 2932, 2864, 1728, 1668, 1644, 1506
Rf value: 0.60

Example 136 N-[(S) -1,2-dioxo-1- [N- (2-benzothiazolyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 600 mg of 2-aminobenzothiazole instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (2-benzothiazolyl) amino] 192 mg (yield 18%) of -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide was obtained.

1H-NMR (CDCl ₃ , δ): 0.82 (3H, t, J = 7Hz), 1.10-2.20 (16H, m), 3.20-3.40 (4H, m), 3.50-3.80 (4H, m), 4.75 ( 1 / 2H, s), 4.82 (1 / 2H, s), 5.05-5.15 (1 / 2H, m), 6.10-6.20 (1 / 2H, m), 7.20-7.42 (2H, m), 7.70-7.80 (2H, m), 8.20 (1H, d, J = 8Hz)
IR (ν, KBr, cm ⁻¹ ): 3388, 2936, 2860, 1642, 1604, 1536
Rf value: 0.53

Example 137 N-[(3S) -1,2-dioxo-1- [N-[(1S) -1-oxo-1-methoxy-3-phenyl-2-propyl] amino] -3-heptyl] -1 -[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, 862 mg of L-phenylalanine methyl ester hydrochloride and 404 mg of triethylamine were used instead of 3-chlorobenzylamine, and the title N-[(3S) -1,2-dioxo-1- [N-[( 1S) -1-oxo-1-methoxy-3-phenyl-2-propyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 513 mg (yield 46%) Got.

1H-NMR (CDCl ₃ , δ): 0.80-0.95 (3H, m), 1.20-2.10 (16H, m), 3.08 (1H, dd, J = 14Hz, 7Hz), 3.20 (1H, dd, J = 14Hz , 6Hz), 3.37 (4H, t, J = 4Hz), 3.70 (4H, t, J = 4Hz), 3.73 (3H, s), 4.42 (1H, s), 4.80-4.86 (1H, m), 5.16 -5.20 (1H, m), 7.08 (1H, d, J = 8Hz), 7.20-7.35 (5H, m), 7.96 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3400, 2936, 2860, 1748, 1672, 1530
Rf value: 0.53

Example 138 N-[(3S) -1,2-dioxo-1- [N-[(R) -1-oxo-1-methoxy-3-methylthio-2-propyl] amino] -3-heptyl] -1 -[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 742 mg of LS-methylcysteine methyl ester hydrochloride and 404 mg of triethylamine instead of 3-chlorobenzylamine, the title N-[(3S) -1,2-dioxo-1- [N -[(R) -1-Oxo-1-methoxy-3-methylthio-2-propyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield) 35%).

1H-NMR (CDCl ₃ , δ): 0.87 (3H, t, J = 7Hz), 1.20-2.20 (16H, m), 2.11 (3H, s), 2.94 (1H, dd, J = 14Hz, 6Hz), 3.02 (1H, dd, J = 14Hz, 5Hz), 3.39 (4H, t, J = 5Hz), 3.72 (4H, t, J = 5Hz), 3.79 (3H, s), 4.43 (1H, s), 4.75 -4.79 (1H, m), 5.19-5.24 (1H, m), 7.56 (1H, d, J = 8Hz), 7.99 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3352, 2932, 2864, 1748, 1662, 1524
Rf value: 0.66

Example 139 N-[(3S) -1,2-dioxo-1- [N-[(S) -1,4-dioxo-1,4-dimethoxy-2-butyl] amino] -3-heptyl] -1 -[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 988 mg of L-aspartic acid dimethyl ester hydrochloride and 505 mg of triethylamine instead of 3-chlorobenzylamine, the title N-[(3S) -1,2-dioxo-1- [N- [ (S) -1,4-dioxo-1,4-dimethoxy-2-butyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide 469 mg (43% yield) )

1H-NMR (CDCl ₃ , δ): 0.80-0.90 (3H, m), 1.20-2.20 (16H, m), 2.87 (1H, dd, J = 17Hz, 5Hz), 3.06 (1H, dd, J = 17Hz , 5Hz), 3.39 (4H, t, J = 5Hz), 3.65-3.80 (4H, m), 3.69 (3H, s), 3.77 (3H, s), 4.84 (1H, s), 4.75-4.92 (1H , m), 5.15-5.26 (1H, m), 7.72 (1H, d, J = 8Hz), 7.99 (1H, d, J = 6Hz)
IR (ν, KBr, cm ⁻¹ ): 3380, 2965, 2859, 1741, 1675, 1629, 1523
Rf value: 0.73

Example 140 N-[(S) -1,2-dioxo-1- [N- [2- (3,4-methylenedioxyphenyl) ethyl] amino] -3-heptyl] -1- [N- (morpholine -4-carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 660 mg of 3,4-methylenedioxyphenylethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- [2- There were obtained 469 mg (yield 46%) of (3,4-methylenedioxyphenyl) ethyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide.

1H-NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7Hz), 1.20-2.20 (16H, m), 2.75 (2H, td, J = 7Hz, 2Hz), 3.37 (4H, t, J = 5Hz), 3.42-3.60 (2H, m), 3.71 (4H, t, J = 5Hz), 4.42 (1H, s), 5.17 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 5.93 (2H, s), 6.63 (1H, dd, J = 8Hz, 2Hz), 6.67 (1H, d, J = 2Hz), 6.74 (1H, d, J = 2Hz), 6.89 (1H, t, J = 6Hz), 7.94 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3392, 2931, 2859, 1708, 1654, 1621, 1533
Rf value: 0.56

Example 141 N-[(S) -1,2-dioxo-1- [N- (3,4-dimethoxyphenyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] Cyclohexane carboxamide

  In the same manner as in Example 28, using 612 mg of 3,4-dimethoxyaniline instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- (3,4-dimethoxy) was used. Phenyl) amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (270 mg, yield 25%) was obtained.

1H-NMR (CDCl ₃ , δ): 0.87-0.92 (3H, m), 1.20-2.20 (16H, m), 3.36-3.83 (4H, m), 3.70 (4H, t, J = 4Hz), 3.87 ( 3H, s), 3.90 (3H, s), 4.46 (1H, s), 5.26 (1H, ddd, J = 12Hz, 7Hz, 5Hz), 6.83 (1H, d, J = 8Hz), 7.04 (1H, dd , J = 8Hz, 3Hz), 7.42 (1H, d, 3Hz), 8.07 (1H, d, J = 7Hz), 8.60 (1H, s)
IR (ν, KBr, cm ⁻¹ ): 3374, 2931, 2857, 1725, 1662, 1608, 1515
Rf value: 0.63

Example 142 N-[(S) -1,2-dioxo-1- [N- [2- (3,4-dimethoxyphenyl) ethyl] amino] -3-heptyl] -1- [N- (morpholine-4 -Carbonyl) amino] cyclohexanecarboxamide

  In the same manner as in Example 28, using 905 mg of 3,4-dimethoxyphenylethylamine instead of 3-chlorobenzylamine, the title N-[(S) -1,2-dioxo-1- [N- [2- (3 , 4-dimethoxyphenyl) ethyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (yield 53%).

1H-NMR (CDCl ₃ , δ): 0.86-0.89 (3H, m), 1.20-2.20 (16H, m), 2.78 (2H, td, J = 7Hz, 2Hz), 3.37 (4H, t, J = 5Hz ), 3.53 (2H, td, J = 7Hz, 6Hz), 3.71 (4H, t, J = 5Hz), 3.86 (3H, s), 3.87 (3H, s), 4.42 (1H, s), 5.17 (1H , ddd, J = 11Hz, 7Hz, 5Hz), 6.70 (1H, d, J = 2Hz), 6.73 (1H, dd, J = 8Hz, 2Hz), 6.81 (1H, d, J = 2Hz), 6.92 (1H , t, J = 6Hz), 7.95 (1H, d, J = 7Hz)
IR (ν, KBr, cm ⁻¹ ): 3328, 2929, 2857, 1725, 1664, 1617, 1517
Rf value: 0.66

Test Example 1 Measurement of Cathepsin K Inhibitory Activity Cathepsin K was expressed as a proenzyme in a cell culture medium by a baculovirus expression system using insect cells Sf21, and an active enzyme was prepared by incubation at 40 ° C. for 2 hours. (Tezuka et al., J. Biol. Chem., 269, 1106-1109 (1994)). Cathepsin K activity was measured by degradation of the fluorescent substrate Cbz-Gly-Pro-Arg-MCA according to the method of Aibe et al. (Biol. Pharm. Bull., 1026-1031 (1996)). That is, the degradation of 20 μM Cbz-Gly-Pro-Arg-MCA by cathepsin K was measured in 100 mM potassium potassium phosphate, 1 mM EDTA, 8 mM Cystein, pH 6.0. The reaction was carried out at 37 ° C. for 30 minutes, stopped by adding carpeptin 2 × 10 ⁻⁵ M, and the fluorescence intensity at an excitation wavelength of 370 nm and a measurement wavelength of 460 nm was measured. The cathepsin K inhibition of the compounds was examined using the above reaction system. Table 1 shows the cathepsin K inhibitory activity of the example compounds.

Test Example 2 Measurement of Bone Resorption Inhibitory Action Male mice (23 to 25 g, 8 per group) were raised on a low calcium diet (0.1% calcium diet) for 7 days. After fasting overnight, the compound of the examples shown in Table 2 was orally administered at a dose of 100 mg / kg body weight, and the serum calcium concentration 4 hours after administration was measured by the methylxylenol blue method (Biochem Biophys Res Commun 125, 441-447 ( 1984); FEBS 321, 247-250 (1993)). The serum calcium reduction rate was determined in comparison with the control group. The results are shown in Table 2.

Test Example 3 Test on Osteoporosis Model The rat ovariectomy model is an experimental model of human postmenopausal osteoporosis, and the action of the inventive compounds on this model was examined. The ovaries on both sides of 24-week-old female rats (Crj: CD (SD) IGS) were removed, and 100 mg / kg of the example compound shown in Table 3 was orally administered twice a day for 12 weeks from the next day. Urine was collected for 24 hours using a metabolic cage. After the final administration, the left femur was removed, muscles and connective tissue were removed, and the volume was measured. The volume was dried at 180 ° C. for 4 hours, and the dry weight was measured. Bone density was calculated from dry weight and volume. Similarly, the cervical bone strength of the right femur extracted was measured with a bone strength measuring machine (TK-252C, Muromachi Machine). Urinary deoxypyridinoline (Dpy) is measured by HPLC-fluorescence method according to the method of Ruud A. et al. (J Chromatogr B 703, 37-44 (1997)) and converted to urinary creatinine (Cre) concentration did. The effects on these measurement items were compared with those of the compound non-administered group. A normal group was provided separately.

  The results for the bone density, bone strength and bone resorption markers of the compounds are shown in Table 3. Example compounds are useful for osteoporosis because they decreased urinary Dpy, a bone resorption marker increased by ovariectomy, and suppressed bone density and bone strength.

As described above, the present invention provides a carboxylic acid derivative useful for producing a cyclic amide derivative having cathepsin K inhibitory activity. This cyclic amide derivative showed high activity and highly selective cathepsin K inhibitory action, and bone resorption inhibitory action after oral administration. Therefore, in addition to bone diseases such as osteoporosis, hypercalcemia, and Paget's disease, it is useful for the prevention and treatment of osteoarthritis and rheumatism caused by increased bone resorption, and its contribution to medical care is great. It is a thing.

Claims (1)

Following formula

A carboxylic acid derivative represented by