JP4008019B1 - Cycloalkylcarbonyl amino acid ester derivative and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a cycloalkylcarbonylamino acid ester derivative which is a raw material intermediate of a novel cycloalkanecarboxamide derivative having a selective cathepsin K inhibitory action and a method for producing the same.
[Solution]
A cycloalkylcarbonylamino acid ester derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.
[Chemical 1]

[Wherein R ¹ and R ² represent an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group, a heterocyclic group, etc., R ⁸ represents an alkyl group having 1 to 6 carbon atoms, and ring A represents a carbon number. Represents a 5, 6 or 7 cyclic alkylidene group; ]
[Selection figure] None

Description

  The present invention relates to a novel cycloalkylcarbonyl amino acid ester, a salt thereof, and a process for producing them. More specifically, the present invention relates to a novel cycloalkylcarbonyl useful as a raw material intermediate for producing a cycloalkanecarboxamide derivative having an action of selectively inhibiting cathepsin K, which is a main cysteine protease particularly involved in bone resorption. The present invention relates to amino acid ester derivatives and pharmaceutically acceptable salts thereof, and methods for producing them.

  In recent years, with the rapid progress toward an aging society, the number of patients with senile diseases, especially bone diseases, has been increasing. Among them, osteoporosis, which is common among women, especially postmenopausal women, has become a major problem. Yes. Increased bone resorption caused by hormonal imbalance and aging in postmenopausal women is closely related to the onset and progression of bone disease. The agent is used. However, currently used calcitonin preparations, estrogen preparations, vitamin K preparations, bisphosphonate preparations and other drugs with bone resorption inhibitory effects have problems such as their therapeutic effects, immediate effects, side effects, and compliance, and are more effective. Development of a bone resorption inhibitor that can be a highly therapeutic or preventive agent for osteoporosis is desired.

In the living body, calcium in the bone and calcium concentration in the blood are in an equilibrium relationship, and there is always a movement of calcium between the bone and the blood. Such movement of calcium between the bone and the blood It is driven by the dynamic transition between formation and bone resorption. In the process of bone resorption, activated osteoclasts elute bone minerals such as calcium, and at the same time, cysteine protease secreted from osteoclasts promotes bone resorption by degrading bone organic substances such as collagen. It is known that Cysteine proteases such as cathepsin B, cathepsin H, cathepsin L, cathepsin S and the like are present in osteoclast lysosomes, but human cathepsin K localized in osteoclasts was isolated in 1995. More than cathepsins were found to be expressed in osteoclasts (Biochem. Biophys. Res. Commun., 206, p. 89 (1995); J.
Biol. Chem., 271, 12511 (1996)). Furthermore, it has been found that the cathepsin K gene is mutated in dwarfism patients who develop abnormal bone resorption (Science, 273, p. 1236 (1997)).

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. So far, compounds having cathepsin K inhibitory activity include aldehyde derivatives, epoxy succinic acid derivatives (J. Biol. Chem., 271, 2126 (1996); Biol.
Pharm. Bull., 19, 1026 (1996)), or vinyl sulfonic acid derivatives (NatureStructural Biology, 4, 105 (1997); J, Med. Chem., 38,
3139 (1995)), but these derivatives have low selectivity and are known to strongly inhibit not only cathepsin K but also other cysteine proteases (J. Enzyme Inhibition, 3, 13 (1989); Biochem.
Biophys. Res. Commun., 153, 1201 (1988); J. Biochem.,
87, 39 (1980); J. Biochem., 88, 1805 (1980)).

Furthermore, as cathepsin K is attracting attention as described above, X-ray crystallographic analysis of cathepsin K and inhibitors (Nature
Structural Biology, 4, 105 (1997); Nature Structural
Biology, 4, 109 (1997)) is also active, and compounds having a selective inhibitory effect on cathepsin K are also known (Proc. Natl. Acad. Sci. USA., 94, 142, 49 ( 1997); WO9801133;
J. Am. Chem. Soc., 120. 9. 114 (1998); J. Med. Chem.,
41, 3563 (1998); JP 2000-204071; Bioorg.
Med. Chem., 14, 4333 (2004); Bioorg. Med. Chem., 14,
4897 (2004)). In WO971677, the catalytic active site of cathepsin K is clarified, and a method for inhibiting cathepsin K using a compound that interacts with this active site is disclosed.

Furthermore, although there is no description of inhibition against cathepsin K, various protease inhibitors are disclosed as aldehyde derivatives in JP-A-2-256654, JP-A-2-268145 and the like.
Proc. Natl. Acad. Sci. USA., 94, 142, 49 (1997) J. Am. Chem. Soc., 120. 9. 114 (1998) J. Med. Chem., 41, 3563 (1998) Bioorg. Med. Chem., 14, 4333 (2004) (Bioorg. Med. Chem., 14, 4897 (2004)) WO9801133 WO971677 JP2000-204071 JP 2-256654 JP-A-2-268145

  As described above, compounds that inhibit cathepsin K have attracted attention as bone resorption inhibitors, and many derivatives have been reported, but they have not yet been put to practical use as therapeutic agents for metabolic bone diseases. As a result of intensive studies on a novel compound having a potent and selective cathepsin K inhibitory effect, the present inventors have found a novel cycloalkylcarbonylaminoaldehyde derivative represented by a specific structural formula represented by the formula (XII) described later However, it has been found that it selectively inhibits cathepsin K as compared with aldehyde derivatives conventionally known as protease inhibitors. An object of the present invention is to provide a novel cycloalkylcarbonylamino acid ester derivative which is a raw material compound useful for producing the cycloalkylcarbonylaminoaldehyde derivative and a method for producing the same.

The present invention is a raw material compound for producing a cycloalkylcarbonylaminoaldehyde derivative represented by the following formula (XII) having selective inhibitory properties against cathepsin K, represented by the formula (I) having an unnatural amino acid structure. The present invention relates to a cycloalkyl carbonyl amino acid ester derivative, a pharmaceutically acceptable salt thereof, and a method for producing the same as described in 1 to 9 below.

  1. A cycloalkylcarbonylamino acid ester derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic ring. A group represented by a group, R ⁴ O—, a group represented by R ⁵ S—, or a group represented by R ⁶ (R ⁷ ) N— (R ⁴ , R ⁵ , R ⁶ , R ⁷ are Independently, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, Wherein R ⁶ and R ⁷ may be combined to form a ring; and R ² is a primary or secondary substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, substituted or Unsubstituted alkynyl group, substituted or unsubstituted aromatic hydrocarbon group Or a substituted or unsubstituted heterocyclic group; ring A is a 7 cyclic alkylidene group was 6 or atoms; R ⁸ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms; wherein , R ² is a carbamoylmethyl group or a hydroxymethyl group, R ⁸ is not a t-butyl group, and R ² is a benzyl group, a 2,2-dimethylpropyl group, a 2-propyl group, or a 1-hydroxy group. When it is an ethyl group, R ⁸ is not a benzyl group, and R ² is a 1,1-dimethylethyl group, a benzyl group, a 2- (methylthio) ethyl group, a 2-methylpropyl group, p-hydroxyphenylmethyl. If a group or a methyl group, R ⁸ is a methyl group rather than,
The substituents of the alkyl group in R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently a hydroxyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, Ring group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo Group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group (except when R ¹ is an alkyl group), alkoxycarbonylamino group and Rx (Ry) N Groups (Rx and Ry are each independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, Group, a group selected from an aromatic hydrocarbon group or heterocyclic group),
Substituents for the alkenyl group, alkynyl group, aromatic hydrocarbon group or heterocyclic group in R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently a hydroxyl group, an alkyl group, an alkenyl group, Alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, Amide group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfonamide group, mercapto group, alkoxycarbonylamino group and Rx (Ry) N Groups (Rx and Ry are each independently a hydrogen atom, an alkyl group, Nyl group, alkynyl group, aromatic hydrocarbon group or heterocyclic group). ]

2. In the formula (I), in R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ , the alkyl group is a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, and the alkenyl group is A linear, branched or cyclic alkenyl group having 2 to 12 carbon atoms, an alkynyl group is a linear, branched or cyclic alkynyl group having 2 to 12 carbon atoms, and an aromatic hydrocarbon group is carbon A monocyclic or polycyclic aromatic hydrocarbon group of formula 6-18, wherein the heterocyclic group has at least one nitrogen atom, oxygen atom or sulfur atom as a ring-constituting atom. 2. The cycloalkyl carbonyl amino acid ester derivative or the pharmaceutically acceptable salt thereof according to the above item 1, which is

3 . A cycloalkylcarbonylamino acid ester derivative represented by the formula (I ′) or a pharmaceutically acceptable salt thereof.

[Wherein R ¹ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic ring; A group represented by R ⁴ O—, a group represented by R ⁵ S— or a group represented by R ⁶ (R ⁷ ) N— (R ⁴ , R ⁵ , R ⁶ , R ⁷ are Independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, Wherein R ⁶ and R ⁷ may be combined to form a ring); R ² ′ is an alkyl group represented by Ra (Rb) CH— (Ra and Rb are each independently Hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted aromatic hydrocarbon Or a substituted or unsubstituted heterocyclic group), a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group ; ring a is a 7 cyclic alkylidene group was 6 or atoms; R ⁸ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms;

R ¹ alkenyl group, alkynyl group, aromatic hydrocarbon group and R ² ′, R ⁴ , R ⁵ , R ⁶ and R ⁷ alkenyl group, alkynyl group, aromatic hydrocarbon group and heterocyclic group substituents Each independently a hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl Group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfonamide group, Mercapto group, alkoxycarbonylamino group, Rx (Ry) N group (Rx, R each y is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group.
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Ra and Rb are each independently substituted with a hydroxyl group, an alkenyl group, an alkynyl group, a halogen atom, an aromatic hydrocarbon group or a heterocyclic group. , Alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, Sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfonamide group, mercapto group, alkoxycarbonylamino group and Rx (Ry) N group (Rx and Ry are each independently a hydrogen atom, alkyl group) An alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group. A group selected from to),

The substituents on the alkyl group of R ¹ are each independently a hydroxyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy Group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfone An amide group, a mercapto group and an Rx (Ry) N group (Rx and Ry each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group; A group selected from:
The substituent of the heterocyclic group of R ¹ is a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, an aromatic hydrocarbon group, a heterocyclic group, an alkoxy group, a guanidino group, an alkylthio group, an aryloxy group, an arylthio group Sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group and Rx (Ry) N group (Rx and Ry each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group),

The substituents of the aromatic hydrocarbon group or heterocyclic group of Ra and Rb are each independently a hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, guanidino group, alkylthio group. Group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group , Acyloxy group, azide group, sulfonamide group, mercapto group, alkoxycarbonylamino group and Rx (Ry) N group (Rx and Ry are each independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, aromatic hydrocarbon Represents a group or a heterocyclic group),
Here, R ⁴ and R ⁸ are not each a t-butyl group, and R ² ′, R ⁴ and R ⁸ are not simultaneously a benzyl group.

4 . A cycloalkylcarbonylamino acid ester derivative represented by the formula (I ″) or a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ ′ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, A cyclic group, a group represented by R ⁵ S— or a group represented by R ⁶ (R ⁷ ) N— (R ⁵ , R ⁶ and R ⁷ are each independently a substituted or unsubstituted alkyl group, A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, wherein R ⁶ and R ⁷ are combined; R ² ′ is an alkyl group represented by Ra (Rb) CH— (Ra and Rb are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted group, which may form a ring) Or unsubstituted aromatic hydrocarbon group or substituted or unsubstituted A heterocyclic group), a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group; ring A is the number of carbon atoms 6 or is an 7 cyclic alkylidene group; R ⁸ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms,

R ¹ ′ alkenyl group, alkynyl group and aromatic hydrocarbon group and R ² ′, R ⁵ , R ⁶ and R ⁷ alkenyl group, alkynyl group, aromatic hydrocarbon group and heterocyclic group substituents, respectively, Independently, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, Sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group , Alkoxycarbonylamino group and Rx (Ry) N group (Rx, Ry Each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group),
R ⁵ , R ⁶ , R ⁷ , R ⁸ , Ra and Rb are each independently substituted with a hydroxyl group, an alkenyl group, an alkynyl group, a halogen atom, an aromatic hydrocarbon group, a heterocyclic group, or an alkoxy group. Guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, Sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group, alkoxycarbonylamino group and Rx (Ry) N group (Rx and Ry are each independently a hydrogen atom, alkyl group, alkenyl group) Represents an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group Is a group selected from,

The substituent of the alkyl group of R ¹ ′ is a hydroxyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio Group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfonamide group, Mercapto group and Rx (Ry) N group (Rx and Ry each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group, provided that they simultaneously become a hydrogen atom. Is a group selected from
The substituent of the heterocyclic group of R ¹ ′ is a hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, aryloxy group, arylthio Group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group and Rx (Ry) N group (Rx and Ry each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group)].

5 . In formula (I ′) or (I ″), in R ¹ or R ¹ ′, R ⁴ , R ⁵ , R ⁶ , R ⁷ , Ra, Rb, Rx and Ry, the alkyl group has 1 to 12 carbon atoms A linear, branched or cyclic alkyl group, which is an aromatic hydrocarbon in R ¹ or R ¹ ′, R ² ′, R ⁴ , R ⁵ , R ⁶ , R ⁷ , Ra, Rb, Rx and Ry The group is a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 18 carbon atoms, and the heterocyclic group is a 3- to 7-membered ring containing at least one nitrogen atom, oxygen atom or sulfur atom as a ring constituent atom It is a heterocyclic group, and R ¹ or R ¹ ′, R ² ′, R ⁴ , R ⁵ , R ⁶ , R ⁷ , Rx and Ry have an alkenyl group having 2 to 12 carbon atoms in a straight chain, branched or cyclic form And the alkynyl group is a linear, branched or cyclic alkynyl group having 2 to 12 carbon atoms. Cycloalkyl carbonyl amino acid ester derivative or a pharmaceutically acceptable salt thereof according to the above 3 or 4, wherein.

6 . In the formula (I), (I ′) or (I ″), R ² or R ² ′ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic hydrocarbon group, or a substituted or unsubstituted complex. 6. The cycloalkyl carbonyl amino acid ester derivative or the pharmaceutically acceptable salt thereof according to any one of 1 to 5 above, which is a cyclic group.

7 . In formula (I), (I ′) or (I ″), a substituted or unsubstituted alkyl group represented by R ² or R ² ′ or an alkyl group represented by Ra (Rb) CH— (Ra, Rb is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group), a substituted or unsubstituted alkenyl group, substituted Or an unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group is derived from an α-amino acid, and the α-amino acid is alanine, arginine, asparagine, Aspartic acid, isoasparagine, γ-carboxyglutamic acid, cysteine, cystine, glutamine, glutamic acid, histidine, homoarginine, homocysteine, homocystin, pho Serine, homophenylalanine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, phenylalanine, phenylglycine, serine, threonine, tryptophan, tyrosine, valine, 3,4-dihydroxyphenylalanine, allylglycine, neopentylglycine, arosleonine The cycloalkyl carbonyl amino acid ester according to any one of 1 to 5 above, which is an α-amino acid selected from lysine, homolysine, naphthylalanine, α-aminoadipic acid, thienylglycine, pyridylalanine, and cyclohexylalanine A derivative or a pharmaceutically acceptable salt thereof. 0027

8 . In formula (I), (I ′) or (I ″), R ¹ or R ¹ ′ is a substituted or unsubstituted 3- to 7-membered ring containing at least one nitrogen atom, oxygen atom or sulfur atom as a ring-constituting atom. A substituted heterocyclic group or a substituted aromatic hydrocarbon group, R ² or R ² ′ is an alkyl group having 1 to 4 carbon atoms, R ⁸ is an alkyl group having 1 to 6 carbon atoms, and ring A is The cycloalkyl carbonyl amino acid ester derivative or the pharmaceutically acceptable salt thereof according to any one of 1 to 7 above, which is a cyclohexylidene group.

9 . A carboxylic acid derivative represented by the following formula (VI) or an oxazolone derivative represented by the formula (I _O ) is reacted with an amino acid ester derivative represented by the formula (IX). A method for producing an alkylcarbonylamino acid ester derivative.

(In the formula, R ¹ , R ² , R ⁸ and ring A have the same meanings as in Section 1).

  The novel cycloalkylcarbonylaminoaldehyde derivative derived from the novel cycloalkylcarbonylamino acid ester derivative of the present invention has a high activity and a highly selective cathepsin K inhibitory activity. Therefore, the compound of the present invention is used for osteoporosis, hypercalcemia, Pechet's disease, bone resorption disease, osteogenesis failure, osteoarthritis, rheumatoid arthritis, Klinefelter syndrome, hereditary hyperphosphataseemia, Charcot neuroarthropathy It is useful as an intermediate for drugs for the prevention and treatment of mastocytosis, Gaucher disease, cancer metastasis, multiple myeloma and the like, and its contribution to medical care is great.

The cycloalkyl carbonyl amino acid ester derivative of the present invention is a compound represented by the formula (I), (I ′) or (I ″) and a pharmaceutically acceptable salt thereof. ¹ or R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group, and a heterocyclic group included in the group represented by Ra and Rb Specific examples include the following groups.

  The alkyl group may be any of a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, a 2-propyl group, a cyclopropyl group, n-butyl group, 2-methylpropyl group, 2-butyl 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-dimethylheptyl group, Examples thereof include an n-decyl group, an 8-methylnonyl group, an n-dodecayl group, a 10-methylundecacyl group, and a 9,9-dimethyldecacil group.

The substituent R ⁸ of the compound represented by the formula (I), (I ′) or (I ″) is, in the above examples, an alkyl group having 1 to 6 carbon atoms or an alkyl substituted with the following substituent It is a group.
The alkenyl group may be any of linear, branched or cyclic alkenyl groups having 2 to 12 carbon atoms, such as vinyl group, 1-propenyl group, 2-propenyl group, 1-methylethenyl group, 1- Methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 2-pentenyl group, A 1-pentenyl group, 1-hexenyl group, 2-hexenyl group and the like can be mentioned.

  The alkynyl group may be linear, branched or cyclic having 2 to 12 carbon atoms, and may have a substituent, such as an ethynyl group, a 1-propynyl group, or a 2-propynyl group. , 2-butynyl group and the like.

The aromatic hydrocarbon group may be monocyclic or polycyclic having 6 to 18 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, and an anthranyl group.
The heterocyclic group is a 3- to 7-membered ring group containing at least one hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom as a ring-constituting atom, and these are heterocycles, aliphatic rings or aromatic rings. May form a spiro ring, for example, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl Groups, indolyl groups, benzofuranyl groups, benzimidazolyl groups, benzoxazolyl groups, quinolyl groups, isoquinolyl groups, pyrrolidinyl groups, piperidinyl groups, piperazinyl groups, morpholinyl groups, indolinyl groups, benzodioxolyl groups, etc. . A furanyl group or a morpholinyl group is preferable.

  Examples of the substituent that the alkyl group may have include a hydroxyl group, an alkenyl group, an alkynyl group, a halogen atom, an aromatic hydrocarbon group, a heterocyclic group, an alkoxy group, a guanidino group, an alkylthio group, an alkoxycarbonyl group, and an aryloxy group. Group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide Group, sulfonamide group, mercapto group, alkoxycarbonylamino group, Rx (Ry) N group (Rx and Ry are each independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, aromatic hydrocarbon group or heterocyclic group. A group selected from the group consisting of

  Furthermore, the substituent that the alkenyl group, alkynyl group, aromatic hydrocarbon group, and heterocyclic group may have is a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, an aromatic hydrocarbon group, a heterocyclic group. , Alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, Sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfonamide group, mercapto group, alkoxycarbonylamino group, Rx (Ry) N group (Rx and Ry are each independently a hydrogen atom, alkyl group) Alkenyl group, alkynyl group, aromatic hydrocarbon group or It includes groups selected from a heterocyclic group).

Here, when R ² is a carbamoylmethyl group or a hydroxymethyl group, R ⁸ is not a t-butyl group, and R ² is a benzyl group, a 2,2-dimethylpropyl group, a 2-propyl group, or 1 When it is a -hydroxyethyl group, R ⁸ is not a benzyl group, and R ² is a 1,1-dimethylethyl group, a benzyl group, a 2- (methylthio) ethyl group, a 2-methylpropyl group, p-hydroxy When it is phenylmethyl or a methyl group, R ⁸ is not a methyl group.
Here, Rx, Ry, and the alkyl group, alkenyl group, alkynyl group, aromatic hydrocarbon group, and heterocyclic group as the substituent are R ¹ or R ¹ ′, R ² or R ² ′, R ^4. , R ⁵ , R ⁶ , and R ⁷ are included. In addition, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, and an alkoxycarbonylamino group as a substituent are the same as the alkyl group having 1 to 12 carbon atoms. This is the same as the aromatic hydrocarbon group of formula 6-18.
Examples of guanidino group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carbamoyl group, sulfamoyl group, acyloxy group, sulfonamido group, alkoxycarbonylamino group as substituents are as follows: Shown in

(In the groups exemplified above, R ^{9 to} R ¹² , R ^{17 to} R ²¹ , R ^{23 to} R ²⁵ , R ²⁸ and R ³⁰ are hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, R ¹³ , R ¹⁴ , R ²² , R ²⁶ , R ²⁷ , R ²⁹ are substituted or unsubstituted alkynyl groups, substituted or unsubstituted aromatic hydrocarbon groups, or substituted or unsubstituted heterocyclic groups. or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group, .R ¹⁵ and R ¹⁶ represent a substituted or unsubstituted heterocyclic group Represents a substituted or unsubstituted heterocyclic group.
In addition, as the substituents of these substituted alkyl groups, substituted alkenyl groups, substituted alkynyl groups, substituted aromatic hydrocarbon groups, and substituted heterocyclic groups, those similar to the substituents of these groups in R ¹ of the above item 3 can be used. Can be mentioned. )

Formula of the present invention (I), in cycloalkylcarbonyl amino acid ester derivative represented by (I ') or (I''), ring A is a shea Kurohekishiriden group or cycloheptylidene group, preferably a cyclohexylidene group It is.
In formula (I), (I ′) or (I ″), R ¹ is a 3- to 7-membered heterocyclic group or substituted aromatic group containing at least one nitrogen atom, oxygen atom or sulfur atom as a ring-constituting atom. Preferred is a compound which is a hydrocarbon group, R ² or R ² ′ is an alkyl group having 1 to 4 carbon atoms, R ⁸ is an alkyl group having 1 to 6 carbon atoms, and ring A is a cyclohexylidene group. .

  When the cycloalkyl carbonyl amino acid ester derivative represented by the formula (I) of the present invention has a basic moiety in the molecule, it can form a salt with an inorganic acid or an organic acid. Examples of the inorganic acid include hydrochloric acid, Examples include sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and the like. Examples of organic acids include acetic acid, propionic acid, benzoic acid, succinic acid, malonic acid, succinic acid, phthalic acid, glycolic acid, lactic acid, glyceric acid, malic acid, tartaric acid, gallic acid, citric acid, maleic acid, Examples thereof include fumaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like.

  Furthermore, when an acidic moiety is present in the molecule of the cycloalkylcarbonylamino acid ester derivative, an alkali metal such as lithium, sodium or potassium, an alkaline earth metal such as magnesium or calcium, a salt such as an aluminum salt or zinc salt is formed. be able to. Further, a salt can also be formed with an organic base. Examples of the organic base include primary amines such as methylamine, ethylamine, and aniline, secondary amines such as diethylamine, pyrrolidine, piperidine, morpholine, piperazine, and dicyclohexylamine, trimethylamine, Examples thereof include tertiary amines such as triethylamine, N, N-diisopropylethylamine, pyridine, and ammonia.

  Production examples of the cycloalkylcarbonylamino acid ester derivative represented by the formula (I) and the cycloalkylcarbonylaminoaldehyde derivative represented by the formula (XII) of the present invention are shown below.

(Wherein R ¹ , R ² , R ⁸ and ring A are as defined in formula (I) above, R ³ represents a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and X is Represents a hydroxyl group or a leaving group.)

1st step This step condenses the amino acid represented by the formula (II) and the carboxylic acid derivative represented by the formula (IV) to produce the cycloalkyl carboxylic acid derivative represented by the formula (VI). It is a process. Examples of carboxylic acid derivatives that can be used include acid halides, active esters, and acid anhydrides. Moreover, this process can add and react by adding a base as needed. As the base, for example, pyridine, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and the like are used. Can do.
In carrying out this step, it is preferably carried out in a solvent, such as methylene chloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, An organic solvent such as dimethoxyethane and water can be used, and a mixed solvent of an organic solvent and water can be used as necessary. The reaction temperature is usually in the range of −30 ° C. to 200 ° C., preferably in the range of −15 ° C. to 100 ° C.

Second Step In this step, the cycloalkyl ester represented by the formula (V) is subjected to a condensation reaction between the amino acid ester represented by the formula (III) and the carboxylic acid or carboxylic acid derivative represented by the formula (IV). This is a process for producing a derivative. Examples of carboxylic acid derivatives that can be used include acid halides, active esters, and acid anhydrides. Moreover, this process can react by adding a condensing agent and a base as needed. As the condensing agent, for example, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diisopropylcarbodiimide, carbonyldiimidazole and the like can be used.
Here, an activator such as 1-hydroxybenzotriazole may be added as necessary. As the base, for example, pyridine, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like can be used.

  In carrying out this step, it is preferably carried out in a solvent, such as methylene chloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, An organic solvent such as dimethoxyethane and water can be used, and a mixed solvent of an organic solvent and water can be used as necessary. The reaction temperature is usually in the range of −30 ° C. to 200 ° C., preferably in the range of −15 ° C. to 100 ° C.

Third Step This step is a step for producing the compound of the formula (VI) by hydrolyzing the cycloalkyl ester derivative represented by the formula (V) or a hydrogenation reaction by catalytic reduction using a metal catalyst. Hydrolysis can be performed in the presence of acid and base. As the acid, for example, hydrochloric acid, sulfuric acid, nitric acid, acetic acid and the like can be used. As the base, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like can be used. This step is preferably carried out in water or a mixed solvent of an organic solvent and water. As the organic solvent, for example, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dimethoxyethane, or the like can be used. The reaction temperature is usually in the range of −20 ° C. to 200 ° C., preferably 0 ° C. to 180 ° C. As a metal catalyst for the catalytic hydrogenation reaction, for example, platinum, palladium, nickel, rhodium, ruthenium, copper or the like can be used. In carrying out this step, it is preferably carried out in a solvent, and for example, methanol, ethanol, isopropyl alcohol, isopropyl ether, tetrahydrofuran, benzene, toluene, xylene, dimethylformamide, dioxane, water and the like can be used. The reaction temperature is usually in the range of −50 ° C. to 200 ° C., preferably 10 ° C. to 100 ° C.

Examples of the carboxylic acid or carboxylic acid derivative represented by the formula (IV) include the following compounds.
Carboxylic acid: acetic acid, isobutyric acid, acrylic acid, propionic acid, cyclohexanecarboxylic acid, benzoic acid, cinnamic acid, 2-furancarboxylic acid, nicotinic acid, tetrahydrofuran-2-carboxylic acid, 1-acetyl-piperidine-2-carboxylic acid 2-pyrrolecarboxylic acid, 5-indolecarboxylic acid halide: acetyl chloride, benzoyl chloride, pivaloyl chloride, 2-furancarbonyl chloride, 4-morpholinecarbonyl chloride, 2-thiophenecarbonyl chloride active ester: 1-acetyl Imidazole, benzoic acid p-nitrophenyl ester, benzoic acid N-hydroxysuccinimide ester, benzoic acid 1-hydroxybenzotriazole ester anhydride: acid anhydride of benzoic acid and methyl carbonate, benzoic acid and isobutyric carbonate Acid anhydride with an acid anhydride with benzoic acid and pivalic acid, acid anhydride with benzoic acid and methanesulfonic acid.

Examples of the cycloalkyl carboxylic acid derivative represented by the formula (VI) include the following compounds.
1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[(1-oxo-3-phenylpropyl) amino] cyclohexanecarboxylic acid, 1- (benzoylamino) cyclohexanecarboxylic acid, 1-[(4-biphenylcarbonyl) ) Amino] cyclohexanecarboxylic acid, 1-[(2-naphthylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[(1-naphthylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[[[(RS) -2,3- Tetrahydrobenzofuran-2-yl] carbonyl] amino] cyclohexanecarboxylic acid, 1-[(2-furanylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid, 1- [ [(E) -3- (2-furanyl) -1-oxo-2-propenyl] amino] cyclohexane Xanthcarboxylic acid, 1-[(2-benzofuranylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[(cyclohexylcarbonyl) amino] cyclohexanecarboxylic acid,

1-[(6-Benzothiazolylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[[(6-hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid, 1-[(2-thienylcarbonyl) amino] Cyclohexanecarboxylic acid, 1-[(2-pyridinylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[(3-thienylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[[(3-ethoxy-2-thienyl) carbonyl ] Amino] cyclohexanecarboxylic acid, 1-[[(S) -1-oxo-2-phenylpropyl] amino] cyclohexanecarboxylic acid, 1-[(2-pyrazinylcarbonyl) amino] cyclohexanecarboxylic acid, 1- [ [(5-Methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid, 1-[[(4-methoxyphenyl) calcyl Nyl] amino] cyclohexanecarboxylic acid, 1-[[(3-methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid, 1-[[(3-methyl-2-furanyl) carbonyl] amino] cyclohexanecarboxylic acid, 1-[(3-pyridinylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[[(1-methyl-1H-pyrrol-2-yl) carbonyl] amino] cyclohexanecarboxylic acid, 1-[((R)- 1-oxo-2-phenylpropyl) amino] cyclohexanecarboxylic acid, 1-[(1H-indol-5-ylcarbonyl) amino] cyclohexanecarboxylic acid,

1-[(1-Cyclopentenylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[(4-pyridinylcarbonyl) amino] cyclohexanecarboxylic acid, 1-[[(1H-pyrrol-2-yl) carbonyl] amino] Cyclohexanecarboxylic, 1-[[(6-hydroxy-2-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid, 1-[[(2-hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid, 1-[[( 6-hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid, 1-[[[1- (2-propoxycarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid, 1-[[[1- (Ethoxycarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid, 1-[[[1- (2-furanyl) Rubonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid, 1-[[[(2-furanylcarbonyl) amino] acetyl] amino] cyclohexanecarboxylic acid, 1-[[(benzoylamino) acetyl] amino] Cyclohexanecarboxylic acid, 1-[[(2-oxo-2H-pyran-5-yl) carbonyl] amino] cyclohexanecarboxylic acid, 1-[(4-fluorobenzoyl) amino] cyclohexanecarboxylic acid, 1-[[[4 -(4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid, 1-[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid hydrochloride,

[[(2,3-dihydro-2-oxo-5-benzoxazole) carbonyl] amino] cyclohexanecarboxylic acid, [[(2,3-dihydro-1,4-benzodioxin-6-yl) carbonyl] amino ] Cyclohexanecarboxylic acid, [[(2,4-dioxo-3-thiazolidinenyl) acetyl] amino] cyclohexanecarboxylic acid, [(1-oxo-3-phenyl-2-propenyl) amino] cyclohexanecarboxylic acid, [[1 -Oxo-3- (2-chlorophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (4-chlorophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo -3- (dichlorophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (2-bromophenyl) -2 Propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (4-bromophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (dibromophenyl) -2-propenyl] Amino] cyclohexanecarboxylic acid, [[(1-oxo-3- (2-fluorophenyl) -2-propenyl) amino] cyclohexanecarboxylic acid,

[[1-oxo-3- (2-iodophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[oxo-3- (4-fluorophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[ Oxo-3- (difluorophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (4-iodophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo- 3- (Diiodophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[oxo-3- (trifluorophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (2 -Methylphenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (3-methylphenyl) -2-propenyl Amino] cyclohexanecarboxylic acid, [[1-oxo-3- (4-methylphenyl) -2-propenyl] amino] cyclohexanecarboxylic acid,
[[1-oxo-3- (dimethylphenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (2-methoxyphenyl) -2-propenyl] amino] cyclohexanecarboxylic acid,

[[1-oxo-3- (4-methoxyphenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (dimethoxyphenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[ 1-oxo-3- (nitrophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid,
[[1-oxo-3- (dinitrophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[oxo-3- (acetaminophenyl) -2-propenyl] amino] cyclohexanecarboxylic acid,
[[1-oxo-3- (2-pyridinyl) -2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3-cyclohexyl-2-propenyl] amino] cyclohexanecarboxylic acid, [[1-oxo- 3-cyclopentyl-2-propenyl] amino] cyclohexanecarboxylic acid, [(1-oxo-3-phenyl-2-propynyl) amino] cyclohexanecarboxylic acid, [[1-oxo-3- (fluorophenyl) -2-propynyl ] Amino] cyclohexanecarboxylic acid, [[1-oxo-3- (chlorophenyl) -2-propynyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (bromophenyl) -2-propynyl] amino] cyclohexanecarboxylic Acid, [[1-oxo-3- (iodophenyl) -2-propynyl] amino] cyclohexanecarboxylic acid,

[[1-oxo-3- (difluorophenyl) -2-propynyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (dibromophenyl) -2-propynyl] amino] cyclohexanecarboxylic acid, [[1- Oxo-3- (diiodophenyl) -2-propynyl] amino] cyclohexanecarboxylic acid, [[1-oxo-3- (trifluorophenyl) -2-propynyl] amino] cyclohexanecarboxylic acid, [(1-oxo- 3-cyclohexyl-2-propynyl) amino] cyclohexanecarboxylic acid, [(1-oxo-3-cyclopentyl-2-propynyl) amino] cyclohexanecarboxylic acid, [[3- (2-furanyl) -1-oxo-2- Propynyl] amino] cyclohexanecarboxylic acid, 1-[[[4- (4-propylpiperazin-1-yl) phenyl] carboni ] Amino] cyclohexanecarboxylic acid acetate, 1-[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid hydrobromide, 1-[[[4- (4 -Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid benzenesulfonate, 1-[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid toluenesulfone Acid salt, 1-[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid phthalate, 1-[[[4- (4-propylpiperazin-1-yl) Phenyl] carbonyl] amino] cyclohexanecarboxylic acid fumarate, 1-[[[4- (4-propylpiperazine-1- Yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid citrate and the like.

Fourth Step This step is a step for producing an oxazolone derivative represented by the formula (I 2 _{O 3} ) by ring-closing the cycloalkyl carboxylic acid derivative represented by the formula (VI) by a dehydration reaction.
The dehydration reaction in this step is preferably performed in the presence of a condensing agent, a halogenating agent, an acid, an acid anhydride, an acid chloride and the like. Examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diisopropylcarbodiimide, carbonyldiimidazole, and the like can be used. As the halogenating agent, for example, chlorine, bromine, iodine, phosphorus pentachloride, thionyl chloride, oxalyl chloride, thionyl bromide and the like can be used. As the acid, for example, acetic acid, sulfuric acid, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid and the like can be used. Examples of the acid anhydride include acetic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, and the like. Examples of the acid chloride include acetyl chloride, pivaloyl chloride, methanesulfonyl chloride, toluenesulfonyl chloride, methyl chloroformate, ethyl chloroformate, propyl chloroformate, and isobutyl chloroformate.

Moreover, this process can also react by adding a base as needed. As the base, for example, pyridine, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like can be used.
In carrying out this step, it is preferably carried out in a solvent, such as methylene chloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, Dimethoxyethane or the like can be used.
The reaction temperature is usually in the range of −30 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.

Step 5 In this step, the oxazolone derivative represented by the formula (I 2 _{O 3} ) is reacted with the amino acid derivative represented by the formula (VII) to produce a cycloalkylcarbonyl amino acid derivative represented by the formula (X). It is a process to do.
This step can be carried out in the presence of a base without solvent or in a solvent. Examples of the solvent include methylene chloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, Diethyl ether, diisopropyl ether, dimethoxyethane, dimethyl sulfoxide, methanol, ethanol, 2-propanol and the like can be used. Examples of the base include pyridine, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and the like. Can be used.
The reaction temperature is usually in the range of −30 ° C. to 200 ° C., preferably in the range of 20 ° C. to 200 ° C.

Step 6 This step is a step of producing a cycloalkylcarbonylamino alcohol derivative represented by the above formula (XI). In this step, a method using the cycloalkyl carboxylic acid derivative represented by the formula (VI) as a starting material (step 6-A) and a method using the oxazolone derivative represented by the formula (I _O ) (first step) The cycloalkylcarbonylaminoalcohol derivative represented by the formula (XI) can be produced by the two types of methods in Step 6-B).

Step 6-A In this step, the cycloalkyl represented by the formula (XI) is obtained by condensing the cycloalkylcarboxylic acid derivative represented by the formula (VI) and the amino alcohol derivative represented by the formula (VIII). This is a process for producing a carbonylamino alcohol derivative.
As the condensing agent in this step, for example, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diisopropylcarbodiimide, carbonyldiimidazole and the like can be used. Here, an activator such as 1-hydroxybenzotriazole or N-hydroxysuccinimide may be added as necessary.
Moreover, this process can also be condensed by the mixed acid anhydride method with an acid chloride in the presence of a base. As the acid chloride, for example, pivaloyl chloride, isobutyl chloroformate, methyl chloroformate, ethyl chloroformate, methanesulfonyl chloride, toluenesulfonyl chloride and the like can be used. As the base, for example, pyridine, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, N-methylmorpholine and the like can be used.

In carrying out this step, it is preferably carried out in a solvent, such as methylene chloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, Dimethoxyethane or the like can be used.
The reaction temperature is usually in the range of −30 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.

Step 6-B In this step, the oxazolone derivative represented by the formula (I 2 _{O 3} ) is reacted with the amino alcohol derivative represented by the formula (VIII) to produce a cycloalkylcarbonylamino represented by the formula (XI). This is a process for producing an alcohol derivative.
This step can be performed without a solvent or in a solvent. Examples of the solvent include methylene chloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl. Ether, dimethoxyethane, dimethyl sulfoxide, methanol, ethanol, 2-propanol and the like can be used. In this step, a base can be added as necessary. As the base, for example, pyridine, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, N-methylmorpholine and the like can be used. The reaction temperature is usually in the range of −30 ° C. to 200 ° C., preferably in the range of 20 ° C. to 200 ° C.

Seventh Step This step is a step for producing the cycloalkylcarbonylamino acid ester derivative of the present invention represented by the formula (I). In this step, a method using the cycloalkyl carboxylic acid derivative represented by the formula (VI) as a starting material (step 7-A) and a method using the oxazolone derivative represented by the formula (I _O ) (first step). The cycloalkyl carbonyl amino acid ester derivative represented by the formula (I) can be produced by the two types of methods of Step 7-B).

Step 7-A In this step, the cycloalkyl represented by the formula (I) is condensed with the cycloalkyl carboxylic acid derivative represented by the formula (VI) and the amino acid ester derivative represented by the formula (IX). This is a process for producing a carbonyl amino acid ester derivative.
As the condensing agent in this step, for example, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diisopropylcarbodiimide, carbonyldiimidazole and the like can be used. Here, an activator such as 1-hydroxybenzotriazole or N-hydroxysuccinimide may be added as necessary.
Moreover, this process can also be condensed by the mixed acid anhydride method with an acid chloride in the presence of a base.
As the acid chloride, for example, pivaloyl chloride, isobutyl chloroformate, methyl chloroformate, ethyl chloroformate, methanesulfonyl chloride, toluenesulfonyl chloride and the like can be used. As the base, for example, pyridine, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, N-methylmorpholine and the like can be used.
In carrying out this step, it is preferably carried out in a solvent, such as methylene chloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, Dimethoxyethane or the like can be used.
The reaction temperature is usually in the range of −30 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.

Step 7-B In this step, the oxazolone derivative represented by the formula (I 2 _{O 3} ) is reacted with the amino acid ester derivative represented by the formula (IX) to produce a cycloalkylcarbonyl amino acid represented by the formula (I). This is a process for producing an ester derivative.
This step can be performed without a solvent or in a solvent. Examples of the solvent include methylene chloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl. Ether, dimethoxyethane, dimethyl sulfoxide, methanol, ethanol, 2-propanol and the like can be used. In this step, a base can be added as necessary. As the base, for example, pyridine, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, N-methylmorpholine and the like can be used. The reaction temperature is usually in the range of −30 ° C. to 200 ° C., preferably in the range of 20 ° C. to 200 ° C.

Examples of the oxazolone derivative represented by the formula (I ₀ ) include the following compounds.
2-Phenylmethyl-3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2-phenylethyl-3-oxa-1-azaspiro [4.5] dec-1-ene- 4-one, 2- (4-biphenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (2-naphthyl) -3-oxa-1-azaspiro [ 4.5] dec-1-en-4-one, 2-[(RS) -2,3-tetrahydrobenzofuran-2-yl] -3-oxa-1-azaspiro [4.5] dec-1-ene -4-one, 2- (6-benzothiazolyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (2-thienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (1,3-benzoxol-5-yl)- 3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (2-benzofuranyl) -3-oxa-1-azaspiro [4.5] dec-1-ene-4- ON, 2- (2-pyridinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (3-ethoxy-2-thienyl) -3-oxa-1- Azaspiro [4.5] dec-1-en-4-one, 2- (2-pyrazinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (5 -Methylisoxazol-4-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2-cyclopentyl-3-oxa-1-azaspiro [4.5] dec- 1-en-4-one, 2- (5-methyl-2-thienyl) -3-oxa-1-azaspiro [4 .5] dec-1-en-4-one,

2- (4-Methoxyphenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (3-methyl-2-furanyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (1-methyl-1H-pyrrol-2-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4 -One, 2- (1H-indol-5-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (1-cyclopentenyl) -3-oxa- 1-azaspiro [4.5] dec-1-en-4-one, 2- (6-hydroxy-2-pyridinyl) -3-oxa-1-azaspiro [4.5] dec-1-ene-4- ON, 2- [2- (Furanyl) ethyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-o 2- [1-[(2-propoxy) carbonyl] piperidin-4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [1- (ethoxy Carbonyl) piperidin-4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [1- (2-furanylcarbonyl) piperidin-4-yl]- 3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2-[(2-furanylcarbonyl) amino] methyl] -3-oxa-1-azaspiro [4.5] dec -1-en-4-one, 2-[(benzoylamino) methyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (4-fluorophenyl)- 3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2-[[4-[(1-p Pyr) piperazin-1-yl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (2-furyl) -3-oxa-1-azaspiro [4] .5] dec-1-en-4-one, 2-cyclohexyl-3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (2-propyl) -3-oxa -1-Azaspiro [4.5] dec-1-en-4-one, 2- (1-acetyl-piperidin-4-yl) -3-oxa-1-azaspiro [4.5] dec-1-ene -4-one,

2- [4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [ 4- [2- [4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4- (2- [1,4-bipiperidine] -1′-yl-4-thiazolyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4- [2- [4- (1,1-dimethylethyl) -1-piperazinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4- ON, 2-([1,1′-biphenyl] -3-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [ -(4-pyridinyl) -4-thiazolyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (4-aminophenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4- (4-morpholinyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (5-Bromo-2-thienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4-[(4-methyl-1-piperazinyl) carbonyl ] Phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl] -3-oxa- 1-azaspiro [4.5] dec-1-en-4-one, 2- [4- (dimethylamino) phenyl] -3 Oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (4-ethynylphenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 2- [4 ′-(dimethylamino) [1,1′-biphenyl] -4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [ 4- (4-Methyl-1-piperazinyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4 ′-(1-piperazinyl) [1, 1′-biphenyl] -4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one,

2- [4 ′-[[1- (2-hydroxyethyl) -4-piperidinyl] oxy] [1,1′-biphenyl] -4-yl] -3-oxa-1-azaspiro [4.5] dec -1-en-4-one, 2- [4 ′-[(1-methyl-4-piperidinyl) oxy] [1,1′-biphenyl] -4-yl] -3-oxa-1-azaspiro [4 .5] dec-1-en-4-one, 2- [4 ′-[methyl (1-methyl-3-pyrrolidinyl) amino] [1,1′-biphenyl] -4-yl] -3-oxa- 1-azaspiro [4.5] dec-1-en-4-one, 2- [4 ′-[4- (1,1-dimethylethyl) -1-piperidinyl] [1,1′-biphenyl] -4 -Yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4 ′-(1-piperazinylsulfonyl) [1,1′- Phenyl] -4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4 ′-(4-fluoro-4-piperidinyl) [1,1 ′ -Biphenyl] -4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4 '-[[4- (2,2,2-trifluoro) Ethyl) -1-piperazinyl] sulfonyl] [1,1′-biphenyl] -4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4 ′ -[(1-Methyl-3-piperidinyl) oxy] [1,1′-biphenyl] -4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2 -[4 '-[[1- (2-methoxyethyl) -4-piperidinyl] oxy] [1,1'-biphenyl] -4-yl]]-3-oxa-1-azas Russia [4.5] dec-1-en-4-one

2- [4 ′-[[(2S) -1-methyl-2-pyrrolidinyl] methoxy] [1,1′-biphenyl] -4-yl] -3-oxa-1-azaspiro [4.5] dec- 1-en-4-one, 2- [4 ′-[4-[(1,1-dimethylethyl) amino] -1-piperidinyl] [1,1′-biphenyl] -4-yl] -3-oxa -1-Azaspiro [4.5] dec-1-en-4-one, 2- [4 ′-(5-isoxazolyl) [1,1′-biphenyl] -4-yl] -3-oxa-1- Azaspiro [4.5] dec-1-en-4-one, 2- [4- [2- (4-morpholinylmethyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4. 5] dec-1-en-4-one, 2- [4- [2- [3- (dimethylamino) -1-pyrrolidinyl] -4-thiazolyl] phenyl] -3-oxa- 1-azaspiro [4.5] dec-1-en-4-one, 2- [4- [2- (4-methyl-1-piperazinylmethyl) -4-thiazolyl] phenyl] -3-oxa- 1-azaspiro [4.5] dec-1-en-4-one, 2- [4- [2- (1,4-dimethyl-4-piperidinyl) -4-thiazolyl] phenyl] -3-oxa-1 -Azaspiro [4.5] dec-1-en-4-one, 2- [4- [2- (1-methyl-4-piperidinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [ 4.5] dec-1-en-4-one, 2- [4- [2-[(3R) -3-amino-1-pyrrolidinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4- [2- (4-piperidinyloxy) -4-thiazolyl] phenyl] -3 Oxa-1-azaspiro [4.5] dec-1-en-4-one,

2- [4- [2- (4-morpholinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4- [2 -[4-[(1-methylethyl) amino] -1-piperidinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4- [2- [Methyl (4-methyl-1-piperazinyl) amino] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2 -[4- [2- [4- [Methyl (1-methylethyl) amino] -1-piperidinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-ene -4-one, 2- [4- [2- [4- (tetrahydro-2H-pyran-4-yl) -1-piperazinyl] -4-thiazo Ryl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4- [2- [4- (2-methoxyethyl) -1-piperazinyl]- 4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [3- (4-morpholinyl) -1-propynyl] -3-oxa-1 -Azaspiro [4.5] dec-1-en-4-one, 2-cycloheptyl-3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4- ( 4-morpholinylmethyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2-cyclopropyl-3-oxa-1-azaspiro [4.5] dec -1-en-4-one, 2- [2- (diethylamino) ethyl] -3-oxa-1-azaspiro [4.5] dec-1 -En-4-one, 2- [4-[(dimethylamino) methyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (2-benzo Thienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (1-methyl-4-piperazinyl) -3-oxa-1-azaspiro [4.5] dec -1-en-4-one, 2- [2- (1-piperazinyl) ethyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [3- ( Trifluoromethyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4- (trifluoromethoxy) phenyl] -3-oxa-1-azaspiro [ 4.5] dec-1-en-4-one

2- [4- (trifluoromethyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [2- (trifluoromethyl) phenyl] -3- Oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [3- (trifluoromethoxy) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-ene -4-one, 2- (4-pyridinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (3-fluorophenyl) -3-oxa-1- Azaspiro [4.5] dec-1-en-4-one, 2- (2-fluorophenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [ 2- (Trifluoromethoxy) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-e -4-one, 2- (3-methylphenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [4-[(methoxymethylamino) methyl] phenyl ] -3-Oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (3-methoxyphenyl) -3-oxa-1-azaspiro [4.5] dec-1-ene -4-one, 2- (4-chlorophenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

2- (4-Cyanophenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [3- (4-morpholinylmethyl) phenyl] -3-oxa -1-azaspiro [4.5] dec-1-en-4-one, 2- (phenoxymethyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (2-Chlorophenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (2-thienylmethyl) -3-oxa-1-azaspiro [4.5] dec -1-ene-4-one, 2- (2-methylphenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (4-hydroxyphenyl) -3 -Oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- [3-[(dimethylamino) methyl Phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 2- (4-methyl-1,2,3-thiadiazol-5-yl) -3-oxa-1 -Azaspiro [4.5] dec-1-en-4-one, 2- (2,5-dimethyl-3-furanyl) -3-oxa-1-azaspiro [4.5] dec-1-ene-4 -ON etc.

Moreover, as an amino acid ester derivative represented by the said formula (IX), the following compounds can be mentioned, for example.
Alanine methyl ester, ^Nω -p-toluenesulfonyl-arginine ethyl ester, asparagine t-butyl ester, aspartic acid α-benzyl ester, aspartic acid dimethyl ester, isoasparagine ethyl ester, γ-carboxyglutamic acid dibenzyl ester, cysteine ethyl ester , S-benzylcysteine methyl ester, cystine dimethyl ester, glutamine ethyl ester, glutamic acid di-t-butyl ester, histidine methyl ester, homoarginine ethyl ester, homocysteine methyl ester, homocystine diethyl ester, homoserine benzyl ester, homophenylalanine methyl ester , Isoleucine t-butyl ester, leucine cyclohexyl ester, N ^epsilon - carbobenzoxy - lysine methyl ester, methionine ethyl ester, norleucine isopropyl ester, t-leucine butyl ester, norvaline methyl ester, N ^[delta] - carbobenzoxy - ornithine benzyl ester, phenylalanine t-butyl ester, phenylglycine 3-pentyl Ester, serine ethyl ester, threonine benzyl ester, tryptophan methyl ester, tyrosine ethyl ester, valine cyclopentyl ester, 3,4-dihydroxyphenylalanine ethyl ester, allyl glycine methyl ester, neopentyl glycine t-butyl ester, arosleonine benzyl ester, homolysine Methyl ester, naphthylalanine ethyl ester, α-amino adipic acid t Butyl ester, thienyl glycine methyl ester, pyridyl alanine benzyl ester, cyclohexyl alanine t- butyl ester.

Step 8 In this step, the cycloalkylcarbonylamino acid derivative represented by the formula (XI) is activated by the mixed acid anhydride method, followed by a reduction reaction, and the cycloalkylcarbonylamino alcohol derivative represented by the formula (XI). Is a process of manufacturing.
Examples of the acid chloride used in the mixed acid anhydride formation reaction in this step include pivaloyl chloride, isobutyl chloroformate, methyl chloroformate, ethyl chloroformate, methanesulfonyl chloride, toluenesulfonyl chloride, and the like. As the base, for example, pyridine, triethylamine, N, N-diisopropylethylamine, 4- (dimethylamino) pyridine, N-methylmorpholine and the like can be used.
The reaction is preferably carried out in a solvent such as methylene chloride, chloroform, dichloroethane, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dimethoxyethane and the like. be able to.
The reaction temperature is usually in the range of −50 ° C. to 200 ° C., preferably in the range of −20 ° C. to 50 ° C.
As the reducing agent used in this step, for example, sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, dihydro-bis (2-methoxyethoxy) sodium aluminate (Red-Al) and the like can be used. .

In carrying out this step, it is preferably carried out in a solvent, such as methylene chloride, chloroform, dichloroethane, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dimethoxyethane, ethanol, 2-propanol or water can be used.
The reaction temperature is usually in the range of −30 ° C. to 200 ° C., preferably in the range of −20 ° C. to 80 ° C.

Ninth Step This step is a step of reducing the cycloalkyl carbonyl amino acid ester derivative represented by the formula (I) to produce the cycloalkyl carbonyl amino alcohol derivative represented by the formula (XI).
As the reducing agent used in this step, for example, sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, Red-Al, or the like can be used.
In carrying out this step, it is preferably carried out in a solvent, such as methylene chloride, chloroform, dichloroethane, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dimethoxyethane, etc. be able to.
The reaction temperature is usually in the range of −100 ° C. to 200 ° C., preferably in the range of −80 ° C. to 100 ° C.

Step 10 This step is a step for producing a cycloalkylcarbonylaminoaldehyde derivative represented by the formula (XII) by oxidizing the cycloalkylcarbonylaminoalcohol derivative represented by the formula (XII).
For the oxidation reaction used in this step, activated DMSO (dimethyl sulfoxide) oxidation can be used. As the electrophilic activation reagent used here, for example, dicyclohexylcarbodiimide, phosphorus pentoxide, pyridine-sulfur trioxide complex, acetic anhydride, mercury (II) acetate, oxalyl chloride and the like can be used. In this step, a hydrogen donor such as phosphoric acid, trifluoroacetic acid, dichloroacetic acid, pyridine-phosphoric acid, pyridine-trifluoroacetic acid can be added as necessary. Triethylamine, N, N An amine such as diisopropylethylamine or N-methylmorpholine can also be added.
This step can be carried out in dimethyl sulfoxide, and a solvent such as methylene chloride, chloroform, dichloroethane, toluene, acetone, tetrahydrofuran or the like can be added as necessary.
The reaction temperature is usually in the range of −80 ° C. to 200 ° C., preferably in the range of −40 ° C. to 40 ° C.

Further, in this step, an active species having a structure similar to that of the activated DMSO reaction can be prepared from a sulfide and a halogenating agent to carry out an oxidation reaction. For example, dimethyl sulfide or methylphenyl sulfide can be used as the sulfide used in this step. As the halogenating agent, N-chlorosuccinimide or chlorine can be used.
In this step, amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) can be added as necessary. .
This step is preferably performed in a solvent, and examples of the solvent include methylene chloride, chloroform, dichloroethane, toluene, tetrahydrofuran and the like.
The reaction temperature is usually in the range of −80 ° C. to 200 ° C., preferably in the range of −40 ° C. to 40 ° C.

Moreover, this process can also be oxidized using a high-valent iodine compound reagent.
Examples of the high-valent iodine compound used in this step include Dess-Martin reagent (1,1,1-Tris (acetoxy) -1,1-dihydro1,2-benziodoxol-3- (1H) -one) and IBX ( 1-hydroxy-1,2-benziodoxol-3- (1H) -1-oxide) and the like can be used.
In this step, a base such as pyridine or sodium hydrogencarbonate can be added as necessary.
This step is preferably performed in a solvent. Examples of the solvent include methylene chloride, chloroform, dichloroethane, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, and the like.
The reaction temperature is in the range of −20 ° C. to 200 ° C., preferably in the range of 0 ° C. to 40 ° C.

Moreover, this process can also use oxidation (Oppenauer oxidation) by an aluminum alkoxide and a hydrogen acceptor. As the aluminum alkoxide, for example, aluminum isopropoxide, aluminum t-butoxide, or the like can be used.
As the hydrogen acceptor, for example, benzoquinone, benzophenone, acetone, cyclohexanone, benzaldehyde and the like can be used.
This step is preferably performed in a solvent, and as the solvent, for example, benzene, toluene, xylene and the like can be used.
The reaction temperature can be advanced in the range of -20 ° C to 200 ° C, preferably in the range of 0 ° C to 150 ° C.

In this step, an oxidation reaction with tetrapropylammonium pearlate (TPAP) can also be used.
As the oxidizing agent, N-methylmorpholine-N-oxide or molecular oxygen can be used.
This step is preferably performed in a solvent, and as the solvent, for example, methylene chloride, acetonitrile, toluene or the like can be used.
In this step, molecular sieves can be added as necessary.
The reaction temperature is in the range of −20 ° C. to 200 ° C., preferably in the range of 0 ° C. to 40 ° C.

In this step, an oxidation reaction with 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) or a derivative thereof can also be used.
As the oxidizing agent, hypochlorite, bromite, N-chlorosuccinimide and the like can be used.
This step is preferably performed in a solvent, and examples of the solvent include dimethyl sulfoxide, N, N-dimethylformamide, methylene chloride, acetonitrile, toluene, ethyl acetate and the like.
Moreover, this process can also add sodium bromide and water as needed.
The reaction temperature is in the range of −20 ° C. to 200 ° C., preferably in the range of 0 ° C. to 40 ° C.

Specific examples of the cycloalkylcarbonylamino acid ester derivative represented by the general formula (I) of the present invention include the following compounds.
N-[[1-[[(Phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valine methyl ester, N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L- Norleucine ethyl ester, N-[[1-[(2-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valine benzyl ester, N-[[1-[(4-morpholinylcarbonyl) amino] cyclohexyl] Carbonyl] -L-norleucine t-butyl ester, N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-methionine ethyl ester, N-[[1-[(2-furanyl) Carbonyl) amino] cyclohexyl] carbonyl] -L-phenylalanine benzyl ester, N-[[1-[(4-morpholinylcarb) Nyl) amino] cyclohexyl] carbonyl] -L-tryptonephan methyl ester, N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-tyrosine propyl ester, N-[[1- [(2-Furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycine 2-propyl ester, N-[[1-[(4-morpholinylcarbonyl) amino] cyclohexyl] carbonyl] -L-histidine butyl Ester, N-[[1-[[(Phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-pyridylglycine t-butyl ester, N-[[1- (acetamido) cyclohexyl] carbonyl] -L-valine methyl Esters, N-[[1-[[(phenylmethylthio) carbonyl] amino] cyclohexyl] cal Nyl] -L-valine benzyl ester, N-[[1-[(1-oxo-3phenyl-2-propenyl) amino] cyclohexyl] carbonyl] -L-valine ethyl ester, N-[[1-[(1 -Oxo-3phenyl-2-propynyl) amino] cyclohexyl] carbonyl] -L-valine benzyl ester, N-[[1-[(1-oxo-3phenyl-2-propynyl) amino] cyclohexyl] carbonyl] -L Allyl glycine t-butyl ester,

N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycine methyl ester, N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L -Methionine methyl ester, N-[[1-[[[4-[(dimethylamino) methyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycine methyl ester, N-[[1-[[[ 4-[(Dimethylamino) methyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methionine methyl ester, N-[[1-[[[4- [2- (4-methyl-1-piperazinyl)- 4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methionine methyl ester, N-[[1- [ [4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycine methyl ester, N-[[1-[[[4- [ 2- [4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methionine methyl ester, N-[[1-[[[4- [2 -[4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycine methyl ester and the like.

  The cycloalkylbonylaminoaldehyde derivative derived from the cycloalkylcarbonylamino acid ester derivative represented by the formula (I) of the present invention has high activity and high selective inhibitory activity against cathepsin K, as is apparent from the test examples described later. However, since it has a selective inhibitory action on cathepsin K, it is expected to be used as a drug useful for the prevention and treatment of osteoporosis, hypercalcemia, osteoarthritis, rheumatism, etc. .

Hereinafter, the present invention will be described in more detail with reference examples and examples. However, the present invention is not limited to these examples as long as the gist thereof is not exceeded.
% Means% by weight unless otherwise specified.
In addition, synthesis examples of the cycloalkyl carboxylic acid represented by the formula (VI) and the ester thereof, which are intermediates for producing the cycloalkyl carbonyl amino acid ester derivative of the present invention, and an oxazolone represented by the formula (I 2 _{O 3} ) Synthesis examples of derivatives and synthesis examples of cycloalkylcarbonylamino acid derivatives, cycloalkylcarbonylamino alcohol derivatives, and cycloalkylcarbonylaminoaldehyde derivatives represented by (X), (XI), and (XII) are shown as reference examples.

Reference example 1
1-[(Phenylacetyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

To a solution of 1-aminocyclohexanecarboxylic acid phenylmethyl ester 2.33 g (10 mmol) in tetrahydrofuran 100 ml was added triethylamine 1.21 g (12 mmol), and 1.55 g (10 mmol) of phenylacetyl chloride was added dropwise with ice cooling, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain 3.21 g (91%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.10-1.23 (3H,
m), 1.50-1.58 (3H, m), 1.74-1.80 (2H, m), 1.95-1.98 (2H, m), 3.57 (2H, s), 5.12 (2H,
s), 5.48 (1H, br-s), 7.24-7.38 (10H, m)

Reference example 2
1-[(Phenylacetyl) amino] cyclohexanecarboxylic acid

1-[(Phenylacetyl) amino] cyclohexanecarboxylic acid phenylmethyl ester 2.69 g (9.1 mmol) obtained in Reference Example 1 was dissolved in 100 ml of methanol, 300 mg of 10% palladium carbon was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. . After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain 1.96 g (98%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.01-1.10 (2H,
m), 1.18-1.26 (1H, m), 1.49-1.59 (3H, m), 1.75-1.82 (2H, m), 1.97-2.00 (2H, m),
3.66 (2H, s), 5.67 (1H, br-s), 7.29-7.34 (3H, m), 7.37-7.40 (2H, m)

Reference example 3
1-[(1-oxo-3-phenylpropyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

By the method according to Reference Example 1, 1.47 g (10 mmol) of 3-phenylpropionyl chloride was used instead of phenylacetyl chloride to obtain 3.47 g (95%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.19-1.26 (3H,
m), 1.50-1.61 (3H, m), 1.78-1.84 (2H, m), 1.96-2.05 (2H, m), 2.50 (2H, t, J = 7Hz),
2.93 (2H, t, J = 7Hz), 5.13 (2H, s), 5.45 (1H, br-s), 7.18-7.21 (4H, m),
7.26-7.37 (6H, m)

Reference example 4
1-[(1-oxo-3-phenylpropyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 2, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid phenylmethyl ester, 1.47 g of 1-[(1-oxo-3-phenylpropyl) amino] cyclohexanecarboxylic acid phenylmethyl ester ( 9.5 mmol) was used to give 2.35 g (90%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.16-1.25 (3H,
m), 1.48-1.51 (1H, m), 1.52-1.62 (2H, m), 1.84-1.97 (4H, m), 2.62 (2H, t, J = 7Hz),
3.00 (2H, t, J = 7Hz), 5.43 (1H, br-s), 7.21-7.26 (3H, m), 7.29-7.33 (2H, m)

Reference Example 5
1- (Benzoylamino) cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 1, 1.39 g (10 mmol) of benzoyl chloride was used instead of phenylacetyl chloride to obtain 3.39 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.33-1.40 (1H,
m), 1.45-1.54 (2H, m), 1.62-1.76 (3H, m), 1.93-1.99 (2H, m), 2.19-2.22 (2H, m),
5.17 (2H, s), 6.25 (1H, br-s), 7.25-7.32 (4H, m), 7.41-7.45 (3H, m), 7.49-7.52 (1H,
m), 7.75-7.77 (2H, m)

Reference Example 6
1- (Benzoylamino) cyclohexanecarboxylic acid

In the same manner as in Reference Example 2, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid phenylmethyl ester, 1.39 g (10 mmol) of 1- (benzoylamino) cyclohexanecarboxylic acid phenylmethyl ester was used to give 2.44 g of the title compound. (99%) was obtained.
1H-NMR (CDCl ₃ , δ): 1.38-1.55 (3H,
m), 1.67-1.71 (1H, m), 1.75-1.79 (2H, m), 1.98-2.04 (2H, m), 2.24-2.27 (2H, m),
6.26 (1H, br-s), 7.46 (1H, td, J = 7Hz, 1Hz), 7.48 (1H, td, J = 7Hz, 1Hz), 7.57 (1H,
td, 7Hz, 1Hz), 7.79-7.82 (2H, m)

Reference Example 7
1-[(4-Biphenylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

To a solution of 1-aminocyclohexanecarboxylic acid phenylmethyl ester 2.33 g (10 mmol), 1-hydroxybenzotriazole 1.68 g (11 mmol) and 4-biphenylcarboxylic acid 3.23 g (10 mmol) in 120 ml of methylene chloride was added 1-ethyl hydrochloride under ice-cooling. -3- (3-Dimethylaminopropyl) carbodiimide (2.11 g, 11 mmol) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, saturated brine, and dried over anhydrous sodium sulfate. did. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain 3.51 g (85%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.38-1.41 (1H,
m), 1.51-1.61 (2H, m), 1.66-1.80 (3H, m), 1.95-2.05 (2H, m), 2.23-2.31 (2H, m),
5.20 (2H, s), 6.38 (1H, br-s), 7.24-7.34 (7H, m), 7.55-7.60 (2H, m), 7.81 (1H, dd,
J = 8Hz, 1Hz), 7.87-7.91 (3H, m), 8.26 (1H, d, J = 1Hz)

Reference Example 8
1-[(4-Biphenylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 2, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid phenylmethyl ester, 3.51 g (8.5 mmol) of 1-[(4-biphenylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester was used. Used to give 2.75 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.37-1.48 (1H,
m), 1.48-1.60 (2H, m), 1.66-1.73 (1H, m), 1.73-1.82 (2H, m), 2.00-2.10 (2H, m),
2.27-2.35 (2H, m), 6.32 (1H, br-s), 7.39-7.43 (1H, m), 7.46-7.49 (2H, m),
7.61-7.66 (2H, m), 7.68-7.70 (2H, m), 7.87-7.89 (2H, m)

Reference Example 9
1-[(2-Naphtylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 7, 1.28 g (7.4 mmol) of 2-naphthoic acid was used instead of 4-biphenylcarboxylic acid to obtain 2.12 g (74%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.32-1.41 (1H,
m), 1.48-1.61 (2H, m), 1.64-1.78 (3H, m), 1.95-2.01 (2H, m), 2.21-2.24 (2H, m),
5.19 (2H, s), 6.27 (1H, br-s), 7.27-7.36 (3H, m), 7.40 (1H, td, J = 7Hz, 1Hz),
7.46-7.49 (2H, m), 7.61-7.63 (2H, m), 7.65-7.67 (2H, m), 7.83-7.85 (2H, m)

Reference Example 10
1-[(2-Naphtylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 2, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid phenylmethyl ester, 2.12 g (5.5 mmol) of 1-[(2-naphthylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester was used. Used to obtain 1.63 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.41-1.45 (1H,
m), 1.52-1.60 (2H, m), 1.70-1.74 (1H, m), 1.77-1.82 (2H, m), 2.03-2.09 (2H, m),
2.29-2.32 (2H, m), 6.41 (1H, br-s), 7.56-7.63 (2H, m), 7.83 (1H, dd, J = 8Hz, 2Hz),
7.89-7.96 (3H, m), 8.33 (1H, s)

Reference Example 11
1-[(1-Naphtylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

By the method according to Reference Example 7, 1.87 g (10 mmol) of 1-naphthoic acid was used instead of 4-biphenylcarboxylic acid to obtain 3.87 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.31-1.42 (1H,
m), 1.45-1.60 (2H, m), 1.65-1.71 (1H, m), 1.71-1.80 (2H, m), 1.98-2.05 (2H, m),
2.24-2.32 (2H, m), 5.26 (2H, s), 6.10 (1H, br-s), 7.32-7.37 (3H, m), 7.40-7.45 (4H,
m), 7.48-7.52 (1H, m), 7.57 (1H, dd, J = 7Hz, 1Hz), 7.85 (1H, dd, J = 7Hz, 1Hz),
7.91 (1H, dd, J = 7Hz, 1Hz), 8.25 (1H, dd, J = 7Hz, 1Hz)

Reference Example 12
1-[(2-Benzofuranylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 7, 12.22 g (75.4 mmol) of benzofuran-2-carboxylic acid was used instead of 4-biphenylcarboxylic acid to obtain 21.3 g (75%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.26-1.42 (1H,
m), 1.50-1.61 (2H, m), 1.64-1.77 (3H, m), 1.95-2.04 (2H, m), 2.21-2.28 (2H, m),
5.19 (2H, s), 6.77 (1H, br-s), 7.25-7.34 (6H, m), 7.44 (1H, td, J = 8Hz, 2Hz),
7.52 (1H, dd, J = 8Hz, 2Hz), 7.57 (1H, dd, J = 8Hz, 2Hz), 7.68 (1H, dd, J = 8Hz, 2Hz)

Reference Example 13
1-[[[(RS) -2,3-Tetrahydrobenzofuran-2-yl] carbonyl] amino] cyclohexanecarboxylic acid

To a solution of 1-[(2-benzofuranylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester 15 g (40 mmol) in 2-propanol 300 m, 10% palladium carbon 1.5 g was added and stirred at 60 ° C. for 20 hours in a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain 11.57 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.07-1.19 (1H,
m), 1.21-1.36 (2H, m), 1.50-1.63 (2H, m), 1.65-1.71 (1H, m), 1.80-1.88 (1H, m),
1.89-1.95 (1H, m), 2.04-2.15 (2H, m), 3.42 (1H, dd, J = 17Hz, 7Hz), 3.60 (1H, dd,
J = 17Hz, 7Hz), 5.18 (1H, dd, J = 7Hz, 7Hz), 6.84 (1H, br-s), 6.91 (1H, d, J = 8Hz),
6.96 (1H, dd, J = 8Hz, 1Hz), 7.18 (1H, td, J = 8Hz, 1Hz), 7.22 (1H, dd, J = 8Hz, 1Hz)

Reference Example 14
1-[(2-furanylcarbonyl) amino] cyclohexanecarboxylic acid

71.6 g (0.5 mol) of 1-aminocyclohexanecarboxylic acid was added to a 250 ml aqueous solution of 20 g (0.5 mol) of sodium hydroxide and stirred at 80 ° C. for 2 hours. The mixture was cooled with ice-water, and 71.8 g (0.2 mol) of 2-furancarbonyl chloride and 100 ml of an aqueous solution of 24 g (0.6 mol) of sodium hydroxide were simultaneously added over about 1 hour. The reaction was slowly warmed to room temperature and stirred overnight. After 80 ml of ethyl acetate was added to the reaction solution and stirred for 1 hour, insoluble matters were removed by filtration. The aqueous layer was separated, and 49 ml of concentrated hydrochloric acid was added under ice cooling. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 112.6 g (95%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.35-1.41 (1H,
m), 1.48-1.53 (2H, m), 1.64-1.67 (1H, m), 1.71-1.76 (2H, m), 1.96-2.02 (2H, m),
2.20-2.24 (2H, m), 6.48 (1H, br-s), 6.55 (1H, dd, J = 4Hz, 2Hz), 7.19 (1H, dd, J = 4Hz,
1Hz), 7.50 (1H, dd, J = 2Hz, 1Hz)

Reference Example 15
1-[(3-Furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

To a solution of 98.8 g (500 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 84.2 g (550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of 3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 ml of methylene chloride. Under ice-cooling, 105 g (550 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added. After stirring overnight at room temperature, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained crystals were washed with diisopropyl ether to obtain 114 g (91%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.34-1.40 (1H,
m), 1.43-1.44 (2H, m), 1.62-1.73 (3H, m), 1.90-1.96 (2H, m), 2.10-2.14 (2H, m),
3.73 (3H, s), 5.87 (1H, br-s), 6.23 (1H, dd, J = 2Hz, 1Hz), 7.44 (1H, dd, J = 2Hz, 1Hz),
7.94 (1H, dd, J = 2Hz, 1Hz)

Reference Example 16
1-[(3-Furanylcarbonyl) amino] cyclohexanecarboxylic acid

To a solution of 75.4 g (300 mmol) of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester in 450 ml of tetrahydrofuran was added 450 ml of 2N aqueous sodium hydroxide solution, and the mixture was heated to reflux for 3 hours. After ether was added to the reaction solution for washing, the aqueous layer was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 68.8 g (97%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.37-1.50 (3H,
m), 1.58-1.64 (1H, m), 1.68-1.80 (2H, m), 1.98-2.05 (2H, m), 2.14-2.23 (2H, m),
5.87 (1H, s), 6.63 (1H, d, J = 2Hz), 7.49 (1H, d, J = 2Hz), 8.00 (1H, s)

Reference Example 17
1-[[((E) -3- (2-furanyl) -1-oxo-2-propenyl] amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 80 g (362 mmol) of 2-furanacrylic acid was used instead of 3-furancarboxylic acid to obtain 89 g (89%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.29-1.39 (1H,
m), 1.40-1.51 (2H, m), 1.58-1.71 (3H, m), 1.88-1.95 (2H, m), 2.05-2.14 (2H, m),
3.73 (3H, s), 5.67 (1H, br-s), 6.35 (1H, d, J = 16Hz), 6.45 (1H, dd, J = 3Hz, 2Hz), 6.54 (1H, d, J = 3Hz) , 7.37 (1H, d,
J = 16Hz), 7.40 (1H, d, J = 2Hz)

Reference Example 18
1-[[(E) -3- (2-furanyl) -1-oxo-2-propenyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[[(E) -3- (2-furanyl) -1-oxo-2- Propenyl] amino] cyclohexanecarboxylic acid methyl ester 44.9 g (162 mmol) was used to give 37.5 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.32-1.85 (6H,
m), 1.96-2.05 (2H, m), 2.15-2.18 (2H, m), 5.66 (1H, br-s), 6.36 (1H, d, J = 15Hz),
6.49 (1H, dd, J = 3Hz, 2Hz), 6.64 (1H, d, J = 3Hz), 7.48 (1H, d, J = 15Hz), 7.49 (1H, d,
J = 2Hz)

Reference Example 19
1-[(2-Benzofuranylcarbonyl) amino] cyclohexanecarboxylic acid ethyl ester

In the same manner as in Reference Example 15, 1-aminocyclohexanecarboxylic acid ethyl ester hydrochloride (3.11 g, 15 mmol) was used instead of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, and benzofuran- The title compound (3.80 g, 80%) was obtained using 2.43 g (15 mmol) of 2-carboxylic acid.
1H-NMR (CDCl ₃ , δ): 1.26 (3H,
t, J = 7Hz), 1.33-1.42 (1H, m), 1.50-1.62 (2H, m), 1.65-1.78 (3H, m), 1.94-2.02 (2H,
m), 2.19-227 (2H, m), 4.21 (2H, q, J = 7Hz), 6.75 (1H, br-s), 7.30 (1H, td, J = 8Hz,
1Hz), 7.43 (1H, td, J = 8Hz, 1Hz), 7.45 (1H, d, J = 1Hz), 7.53 (1H, dd, J = 8Hz, 1Hz),
7.67 (1H, dd, J = 8Hz, 1Hz)

Reference Example 20
1-[(2-Benzofuranylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, 1-[(2-benzofuranylcarbonyl) amino] cyclohexanecarboxylic acid ethyl ester instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester 3.80 g (12 mmol ) To give 3.42 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.35-1.44 (1H,
m), 1.50-1.62 (2H, m), 1.65-1.73 (1H, m), 1.74-1.82 (2H, m), 2.00-2.08 (2H, m),
2.25-2.33 (2H, m), 6.77 (1H, br-s), 7.32 (1H, td, J = 8Hz, 1Hz), 7.46 (1H, td, J = 8Hz,
1Hz), 7.53 (1H, d, J = 1Hz), 7.55 (1H, dd, J = 8Hz, 1Hz), 7.70 (1H, dd, J = 8Hz, 1Hz)

Reference Example 21
1-[(Cyclohexylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

By the method according to Reference Example 7, 4.77 g (46%) of the title compound was obtained using 3.85 g (30 mmol) of cyclohexanecarboxylic acid instead of 4-biphenylcarboxylic acid.
1H-NMR (CDCl ₃ , δ): 1.17-1.45 (8H,
m), 1.59-1.77 (4H, m), 1.73-1.88 (6H, m), 2.03-2.11 (3H, m), 5.12 (2H, s), 5.55 (1H,
br-s), 7.23-7.36 (5H, m)

Reference Example 22
1-[(Cyclohexylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 2, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[(cyclohexylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester (5.62 g, 16.3 mmol) was used. 4.15 g (quantitative) of the title compound were obtained.
1H-NMR (CDCl ₃ , δ): 1.18-1.50 (8H,
m), 1.60-1.76 (4H, m), 1.78-1.95 (6H, m), 2.06-2.14 (2H, m), 2.16-2.23 (1H, m),
5.58 (1H, br-s)

Reference Example 23
1-[(6-Benzothiazolylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 7, 1.58 g (62%) of the title compound was obtained using 1.15 g (6.4 mmol) of benzothiazole-6-carboxylic acid instead of 4-biphenylcarboxylic acid.
1H-NMR (CDCl ₃ , δ): 1.35-1.43 (1H,
m), 1.49-1.60 (2H, m), 1.61-1.78 (3H, m), 1.96-2.06 (2H, m), 2.20-2.27 (2H, m),
5.19 (2H, s), 6.30 (1H, br-s), 7.28-7.75 (5H, m), 7.86 (1H, dd, J = 7Hz, 2Hz),
8.17 (1H, dd, J = 7Hz, 1Hz), 8.41 (1H, dd, J = 2Hz, 1Hz), 9.12 (1H, s)

Reference Example 24
1-[(6-Benzothiazolylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[(6-benzothiazolylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester 1.18 g (30 mmol) was used to give 0.77 g (84%) of the title compound.
1H-NMR (CD ₃ OD, δ): 1.38-1.46 (1H,
m), 1.60-1.76 (5H, m), 1.91-2.01 (2H, m), 2.21-2.28 (2H, m), 7.98 (1H, dd, J = 7Hz,
2Hz), 8.12 (1H, dd, J = 7Hz, 1Hz), 8.54 (1H, dd, J = 2Hz, 1Hz), 9.37 (1H, s)

Reference Example 25
1-[[((6-Hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

By the method according to Reference Example 7, 139 mg (1.0 mmol) of 6-hydroxy-3-pyridinecarboxylic acid was used instead of cyclohexanecarboxylic acid to obtain 222 mg (62%) of the title compound.
1H-NMR (CDCl ₃ , δ):
1.30-1.40 (1H, m), 1.42-1.54 (2H, m), 1.62-1.73 (3H, m), 1.91-1.98 (2H.m),
2.13-2.20 (2H, m), 5.17 (2H, s), 6.22 (1H, s), 6.54 (1H, d, J = 10Hz), 7.26-7.35 (5H,
m), 7.76 (1H, dd, J = 10Hz, 3Hz), 7.93 (1H, d, J = 3Hz)

Reference Example 26
1-[[(6-Hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid

In the method according to Reference Example 2, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[(6-hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 760 mg (2.2 mmol) was used to give 565 mg (quantitative) of the title compound.
1H-NMR (CD ₃ OD, δ): 1.21-1.30 (1H,
m), 1.43-1.54 (5H, m), 1.67-1.74 (2H, m), 2.03-2.09 (2H, m), 6.33 (1H, d, J = 9Hz),
7.84 (1H, dd, J = 9Hz, 3Hz), 8.05 (1H, d, J = 3Hz)

Reference Example 27
1-[(2-Thienylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 14, 57.6 g (51%) of the title compound was obtained using 100 g (680 mmol) of 2-thiophenecarbonyl chloride instead of 2-furancarbonyl chloride.
1H-NMR (CDCl ₃ , δ): 1.35-1.54 (3H,
m), 1.65-1.80 (3H, m), 1.98-2.05 (2H, m), 2.21-2.27 (2H, m), 6.06 (1H, br-s),
7.13 (1H, dd, J = 5Hz, 3Hz), 7.57 (1H, dd, J = 5Hz, 1Hz), 7.59 (1H, dd, J = 3Hz, 1Hz)

Reference Example 28
1-[(2-Pyridinylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 370 mg (3 mmol) of 2-pyridinecarboxylic acid was used instead of 3-furancarboxylic acid to obtain 600 mg (76%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.31-1.42 (1H,
m), 1.51-1.73 (5H, m), 1.95 (2H, td, J = 13Hz, 4Hz), 1.99-2.08 (2H, m), 3.73 (3H, s),
7.44 (1H, ddd, J = 8Hz, 5Hz, 2Hz), 7.84 (1H, dd, J = 8Hz, 2Hz), 8.16 (1H, d, J = 8Hz),
8.33 (1H, s), 8.57 (1H, dd, J = 5Hz, 2Hz)

Reference Example 29
1-[(2-Pyridinylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 539 mg (2 mmol) of 1-[(2-pyridinylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester Was used to obtain 479 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.32-1.41 (1H,
m), 1.48-1.57 (2H, m), 1.62-1.78 (3H, m), 1.98 (2H, m), 2.25-2.35 (2H, m), 7.50 (1H,
ddd, J = 8Hz, 5Hz, 2Hz), 7.89 (1H, dd, J = 8Hz, 2Hz), 8.19 (1H, d, J = 8Hz), 8.59 (1H,
s), 8.60 (1H, dd, J = 5Hz, 2Hz)

Reference Example 30
1-[(3-Thienylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 384 mg (3 mmol) of 3-thiophenecarboxylic acid was used instead of 3-furancarboxylic acid to obtain 759 mg (95%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.32-1.41 (1H,
m), 1.42-1.55 (2H, m), 1.61-1.75 (3H, m), 1.90-1.99 (2H, m), 2.11-2.18 (2H, m),
3.74 (3H, s), 6.26 (1H, br-s), 7.35 (1H, dd, J = 5Hz, 2Hz), 7.39 (1H, dd, J = 5Hz,
2Hz), 7.88 (1H, dd, J = 3Hz, 2Hz)

Reference Example 31
1-[(3-Thienylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 759 mg (2.8 mmol) of 1-[(3-thienylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester was used. Used to give 692 mg (96%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.24-1.32 (1H,
m), 1.45-1.55 (5H, m), 1.72-1.78 (2H, m), 2.05-2.12 (2H, m), 7.50 (1H, dd, J = 5Hz,
2Hz), 7.57 (1H, dd, J = 5Hz, 2Hz), 7.96 (1H, br-s), 8.21 (1H, dd, J = 3Hz, 2Hz)

Reference Example 32
1-[[(3-Ethoxy-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid

1-aminocyclohexanecarboxylic acid methyl ester hydrochloride 581 mg (3 mmol), 1-hydroxybenzotriazole 482 mg (3.1 mmol), 3-ethoxy-2-thiophenecarboxylic acid 517 mg (3 mmol) and diisopropylethylamine 1.16 g (9 mmol) in methylene chloride To a 10 ml solution was added 633 mg (3.3 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride under ice cooling. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, washed with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and dried over anhydrous sodium sulfate. did. After distilling off the solvent under reduced pressure, diisopropyl ether was added to the residue and stirred overnight, and the crystals were collected by filtration. Next, the obtained crystals were dissolved in 3 ml of tetrahydrofuran, 2.8 ml of 2N-NaOH aqueous solution was added, and the mixture was heated to reflux for 3 hours. Ether was added to the reaction solution, and the aqueous layer was separated. The separated aqueous layer was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 656 mg (73%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.29-1.40 (1H,
m), 1.43-1.54 (2H, m), 1.50 (3H, t, J = 7Hz), 1.62-1.76 (3H, m), 1.90-2.00 (2H, m),
2.22-2.30 (2H, m), 4.30 (2H, q, J = 7Hz), 6.87 (1H, d, J = 6Hz), 7.49 (1H, d, J = 6Hz),
7.60 (1H, s)

Reference Example 33
1-[[(S) -1-Oxo-2-phenylpropyl] amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 451 mg (3 mmol) of (S)-(+)-2-phenylpropionic acid was used instead of 3-furancarboxylic acid to obtain 601 mg (69%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.06-1.22 (2H,
m), 1.48-1.61 (7H, m), 1.71-1.77 (2H, m), 1.90-1.96 (2H, m), 3.60 (1H, q, 7Hz),
3.67 (3H, s), 5.40 (1H, br-s), 7.27-7.39 (5H, m)

Reference Example 34
1-[[(S) -1-oxo-2-phenylpropyl] amino] cyclohexanecarboxylic acid

1-[[(S) -1-oxo-2-phenylpropyl] amino] cyclohexanecarboxylic acid instead of methyl ester of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid by a method according to Reference Example 16. Using 608 mg (2.1 mmol) of the methyl ester gave 366 mg (63%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.08-1.21 (2H,
m), 1.28-1.47 (7H, m), 1.53-1.62 (2H, m), 1.93 (2H, br-s), 3.79 (1H, q, J = 7Hz),
7.18-7.21 (1H, m), 7.27-7.33 (4H, m), 7.90 (1H, s), 12.00 (1H, s)

Reference Example 35
1-[(2-Pyrazinylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, 372 mg (3 mmol) of 2-pyrazinecarboxylic acid was used instead of 3-furancarboxylic acid to obtain 476 mg (60%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.35-1.40 (1H,
m), 1.47-1.59 (2H, m), 1.65-1.75 (3H, m), 1.94-2.00 (2H, m), 2.18-2.29 (2H, m),
3.75 (3H, s), 8.03 (1H, s), 8.55 (1H, dd, J = 3Hz, 1Hz), 8.77 (1H, d, J = 3Hz),
9.38 (1H, d, J = 1Hz)

Reference Example 36
1-[(2-Pyrazinylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[(2-pyrazinylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester 476 mg (1.8 mmol ) To give 356 mg (79%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.28-1.59 (6H,
m), 1.79 (2H, td, J = 12Hz, 4Hz), 2.10-2.19 (2H, m), 8.35 (1H, s), 8.75 (1H, d,
J = 2Hz), 8.89 (1H, d, J = 2Hz), 9.14 (1H, d, J = 2Hz), 12.42 (1H, s)

Reference Example 37
1-[[(5-Methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 427 mg (3 mmol) of 5-methyl-2-thiophenecarboxylic acid was used instead of 3-furancarboxylic acid to obtain 812 mg (96%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.36-1.72 (6H,
m), 1.92 (2H, td, J = 13Hz, 4Hz), 2.11-2.19 (2H, m), 2.51 (3H, s), 3,73 (3H, s),
5.95 (1H, s), 6.74 (1H, d, J = 4Hz), 7.34 (1H, d, J = 4Hz)

Reference Example 38
1-[[(5-Methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid

1-[[(5-Methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester by the method according to Reference Example 16. Using 812 mg (2.9 mmol), 771 mg (99%) of the title compound was obtained.
1H-NMR (DMSO-d ₆ , δ): 1.21-1.38 (1H,
m), 1.52 (5H, br-s), 1.68-1.80 (2H, m), 2.01-2.12 (2H, m), 2.46 (3H, s), 6.84 (1H,
d, J = 4Hz), 7.70 (1H, s), 8.02 (1H, s)

Reference Example 39
1-[[(4-Methoxyphenyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 1, 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester 581 mg (3 mmol), 4-methoxybenzoyl chloride 512 mg (3 mmol) instead of phenylacetyl chloride To give 619 mg (71%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.32-1.41 (1H,
m), 1.49-1.74 (5H, m), 1.94 (2H, td, J = 13Hz, 4Hz), 2.12-2.22 (2H, m), 3.73 (3H, s),
3.85 (3H, s), 6.16 (1H, br-s), 6.92 (2H, dd, J = 7Hz, 2Hz), 7.76 (2H, dd, J = 7Hz, 2Hz)

Reference Example 40
1-[[(4-Methoxyphenyl) carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[[(4-methoxyphenyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester 619 mg (2.1 mg mmol) to give 552 mg (94%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.22-1.38 (1H,
m), 1.51-1.60 (5H, br-s), 1.65-1.79 (2H, m), 2.04-2.19 (2H, m), 3.81 (3H, s),
6.98 (2H, d, J = 9Hz), 7.83 (2H, d, J = 9Hz), 8.04 (1H, s), 12.3 (1H, br-s)

Reference Example 41
1-[[(3-Methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 1, instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride 581 mg (3 mmol), instead of phenylacetyl chloride 3-methyl-2-thiophenecarbonyl chloride 482 mg (3 mmol) was used to obtain 394 mg (47%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.32-1.42 (1H,
m), 1.49-1.53 (2H, m), 1.70-1.72 (3H, m), 1.92 (2H, td, J = 12Hz, 4Hz),
2.11-2.22 (2H, m), 2.36 (3H, s), 3.74 (3H, s), 6.33 (1H, d, J = 2Hz), 6.44 (1H, br-s),
7.30 (1H, d, J = 2Hz)

Reference Example 42
1-[[(3-Methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid

1-[[(3-Methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester by a method according to Reference Example 16. Using 394 mg (1.4 mmol), 330 mg (88%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.36-1.53 (3H,
m), 1.68-1.78 (3H, m), 1.96-2.05 (2H, m), 1.99-2.08 (2H, m), 2.55 (3H, s), 5.91 (1H,
s), 6.94 (1H, d, J = 5Hz), 7.35 (1H, d J = 5Hz)

Reference Example 43
1-[[(3-Methyl-2-furanyl) carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 32, 756 mg (6 mmol) of 3-methyl-2-furancarboxylic acid was used instead of 3-ethoxy-2-thiophenecarboxylic acid to obtain 902 mg (59%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.20-1.38 (1H,
m), 1.40-1.59 (5H, m), 1.70-1.80 (2H, m), 2.02-2.18 (2H, m), 2.25 (3H, s), 6.50 (1H,
d, J = 1Hz), 7.67 (1H, s), 7.68 (1H, d, J = 1Hz)

Reference Example 44
1-[(3-Pyridinylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, 370 mg (3 mmol) of 3-pyridinecarboxylic acid was used instead of 3-furancarboxylic acid to obtain 539 mg (68%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.32-1.42 (1H,
m), 1.45-1.55 (2H, m), 1.62-1.78 (3H, m), 1.92-2.01 (2H, m), 2.12-2.21 (2H, m),
3.75 (3H, s), 6.27 (1H, s), 7.40 (1H, dd, J = 8Hz, 5Hz), 8.12 (1H, d, J = 8Hz),
8.74 (1H, d, J = 5Hz), 9.00 (1H, s)

Reference Example 45
1-[(3-Pyridinylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[(3-pyridinylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester 539 mg (2 mmol) Was used to obtain 508 mg (quantitative) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.22-1.35 (1H,
m), 1.49-1.62 (5H, m), 1.69-1.82 (2H, m), 2.09-2.17 (2H, m), 7.50 (1H, dd, J = 8Hz,
5Hz), 8.16 (1H, d, J = 8Hz), 8.44 (1H, s), 8.71 (1H, d, J = 5Hz), 8.97 (1H, s),
12.24 (1H, br-s)

Reference Example 46
1-[[(1-Methyl-1H-pyrrol-2-yl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 375 mg (3 mmol) of 1-methyl-2-pyrrolecarboxylic acid was used instead of 3-furancarboxylic acid to obtain 320 mg (40%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.28-1.40 (1H,
m), 1.44-1.55 (2H, m), 1.61-1.74 (3H, m), 1.86-1.95 (2H, m), 2.05-2.16 (2H, m),
3.73 (3H, s), 3.89 (3H, s), 5.97 (1H, s), 6.09 (1H, dd, J = 4Hz, 3Hz), 6.59 (1H, dd,
J = 4Hz, 2Hz), 6.71 (1H, dd, J = 3Hz, 2Hz)

Reference Example 47
1-[[(1-Methyl-1H-pyrrol-2-yl) carbonyl] amino] cyclohexanecarboxylic acid

1-[[(1-Methyl-1H-pyrrol-2-yl) carbonyl] amino] cyclohexane instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester by the method according to Reference Example 16. The title compound 187 mg (62%) was obtained using 320 mg (1.2 mmol) of carboxylic acid methyl ester.
1H-NMR (CDCl ₃ , δ): 1.31-1.53 (3H,
m), 1.62-1.79 (3H, m), 1.91-2.02 (2H, m), 2.18-2.24 (2H, m), 3.93 (3H, s), 5.92 (1H,
s), 6.14 (1H, dd, J = 4Hz, 3Hz), 6.68 (1H, dd, J = 4Hz, 2Hz), 6.81 (1H, dd, J = 3Hz,
(2Hz)

Reference Example 48
1-[((R) -1-oxo-2-phenylpropyl) amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, 435 mg (50%) of the title compound was obtained using 451 mg (3 mmol) of (R)-(−)-2-phenylpropionic acid instead of 3-furancarboxylic acid.
1H-NMR (CDCl ₃ , δ): 1.03-1.22 (3H,
m), 1.48-1.62 (6H, m), 1.88-2.00 (2H, m), 3.60 (3H, q, J = 7Hz), 3.68 (3H, s),
5.40 (1H, br-s), 7.27-7.39 (5H, m)

Reference Example 49
1-[((R) -1-oxo-2-phenylpropyl) amino] cyclohexanecarboxylic acid

1-[((R) -1-oxo-2-phenylpropyl) amino] cyclohexanecarboxylic acid instead of methyl ester of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid by a method according to Reference Example 16. Using 435 mg (1.5 mmol) of methyl ester, 349 mg (84%) of the title compound was obtained.
1H-NMR (DMSO-d ₆ , δ): 1.15-1.23 (2H,
m), 1.29 (3H, d, J = 7Hz), 1.35-1.53 (4H, m), 1.53-1.63 (2H, m), 1.91 (2H, br-s), 3.78 (1H,
q, J = 7Hz), 7.18-7.20 (1H, m), 7.21-7.32 (4H, m), 7.90 (1H, s), 12.00 (1H, s)

Reference Example 50
1-[(1H-Indol-5-ylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, 483 mg (3 mmol) of indole-5-carboxylic acid was used in place of 3-furancarboxylic acid to obtain 766 mg (85%) of the title compound.
1H-NMR (DMSO-d ₆ , δ):
1.16-1.33 (1H, m), 1.54-1.63 (5H, m), 1.75-1.80 (2H, m), 2.04-2.18 (2H, m),
3.33 (3H, s), 6.52-6.56 (1H, m), 7.40 (1H, s), 7.41-7.44 (1H, m), 7.60 (1H, dd,
J = 9Hz, 2Hz), 8.14 (1H, d, J = 2Hz), 8.18 (1H, s), 11.32 (1H, s)

Reference Example 51
1-[(1H-Indol-5-ylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[(1H-indol-5-ylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester 766 mg ( 2.6 mmol) was used to give 561 mg (77%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.22-1.38 (1H,
m), 1.55-1.62 (5H, m), 1.63-1.79 (2H, m), 2.10-2.22 (2H, m), 6.54 (1H, d, J = 3Hz),
7.40-7.43 (2H, m), 7.60 (1H, dd, J = 3Hz, 1Hz), 8.03 (1H, s), 8.14 (1H, s), 11.31 (1H,
s), 12.04 (1H, s)

Reference Example 52
1-[(1-Cyclopentenylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, 336 mg (3 mmol) of 1-cyclopentenecarboxylic acid was used instead of 3-furancarboxylic acid to obtain 717 mg (95%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.34-1.44 (2H,
m), 1.60-1.70 (4H, m), 1.87 (2H, td, J = 9Hz, 4Hz), 1.99-2.09 (4H, m), 2.49 (2H, m),
2.58 (2H, m), 3.72 (3H, s), 5.75 (1H, br-s), 6.55 (1H, t, J = 2Hz)

Reference Example 53
1-[(1-Cyclopentenylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[(1-cyclopentenylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester 717 (2.9 mmol) To give 588 mg (87%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.24 (1H,
d, J = 8Hz), 1.40-1.50 (5H, m), 1.67 (2H, td, J = 10Hz, 9Hz), 1.81-1.89 (2H, m),
1.91-2.09 (2H, m), 2.40-2.50 (4H, m), 6.53 (1H, t, J = 3Hz), 7.46 (1H, s), 12.03 (1H,
s)

Reference Example 54
1-[(4-Pyridinylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, the title compound 609 mg (77%) was obtained using 370 mg (3 mmol) of 4-pyridinecarboxylic acid instead of 3-furancarboxylic acid.
1H-NMR (CDCl ₃ , δ): 1.32-1.53 (3H,
m), 1.62-1.77 (3H, m), 1.92-2.03 (2H, m), 2.13-2.21 (2H, m), 3.75 (3H, s), 6.29 (1H, br-s), 7.62 (2H, dd, J = 5Hz, 2Hz), 8.76 (2H, dd, J = 5Hz, 2Hz)

Reference Example 55
1-[(4-Pyridinylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[(4-pyridinylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester 609 (2.3 mmol ) To give 522 mg (97%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.22-1.33 (1H,
m), 1.46-1.59 (5H, m), 1.70-1.80 (2H, m), 2.09-2.15 (2H, m), 7.73 (2H, dd, J = 5Hz,
2Hz), 8.51 (1H, s), 8.72 (2H, dd, J = 5Hz, 2Hz)

Reference Example 56
1-[(1H-pyrrol-2-ylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 278 mg (2.5 mmol) of 2-pyrrolecarboxylic acid was used instead of 3-furancarboxylic acid to obtain 534 mg (85%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.32-1.45 (2H,
m), 1.45-1.53 (2H, m), 1.62-1.72 (2H, m), 1.93 (2H td, J = 13Hz, 4Hz), 2.08-2.19 (2H,
m), 3.70 (3H, s), 6.05 (1H, br-s), 6.23-6.25 (1H, m), 6.61 (1H, d, J = 2Hz), 6.94 (1H,
d, J = 2Hz)

Reference Example 57
1-[(1H-pyrrol-2-ylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[[(1H-pyrrol-2-yl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester Using 500 mg (2 mmol) gave 338 mg (71%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.20-1.31 (1H,
m), 1.52 (5H, br-s), 1.70-1.80 (2H, m), 2.04-2.18 (2H, m), 6.08 (1H, dd, J = 4Hz,
2Hz), 6.85-6.89 (2H, m), 7.59 (1H, s), 11.39 (1H, s), 12.09 (1H, br-s)

Reference Example 58
1-[[(6-Hydroxy-2-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, 1.32 g (47%) of the title compound was obtained using 1.39 g (10 mmol) of 6-hydroxy-2-pyridinecarboxylic acid instead of 3-furancarboxylic acid.
1H-NMR (CDCl ₃ , δ): 1.30-1.42 (1H,
m), 1.65 (5H, m), 1.96 (2H, td, J = 12Hz, 4Hz), 2.10-2.21 (2H, m), 3.73 (3H, s),
6.71 (1H, d, J = 9Hz), 7.20 (1H, d, J = 7Hz), 7.62 (1H, dd, J = 9Hz, 7Hz), 8.00 (1H, s)

Reference Example 59
1-[[(6-Hydroxy-2-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[[(6-hydroxy-2-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester 1.32 mg (4.7 mmol) was used to give 1.16 g (88%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.39-1.50 (1H,
m), 1.39-1.50 (2H, m), 1.51-1.63 (3H, m), 1.70-1.82 (2H, m), 2.01-2.12 (2H, d, m),
6.78 (1H, d, J = 8Hz), 7.32 (1H, br-s), 7.74 (1H, t, J = 8Hz), 8.18 (1H, s)

Reference Example 60
1-[[(2-Hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 697 mg (25%) of the title compound was obtained using 1.39 g (10 mmol) of 2-hydroxynicotinic acid instead of 3-furancarboxylic acid.
1H-NMR (CDCl ₃ , δ): 1.24-1.38 (1H,
m), 1.50-1.62 (2H, m), 1.64-1.74 (3H, m), 1.82-1.93 (2H, m), 2.15-2.24 (2H, m),
3.74 (3H, s), 6.53 (1H, t, J = 7Hz), 7.49 (1H, d, J = 7Hz), 8.57 (1H, d, J = 7Hz),
10.04 (1H, s)

Reference Example 61
1-[[(2-Hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid

1-[[(2-Hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester by the method according to Reference Example 16. 698 mg (2.5 mmol) was used to give 580 mg (83%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.21-1.31 (1H,
m), 1.38-1.41 (2H, m), 1.59 (3H, d, J = 10Hz), 1.67-1.72 (2H, m), 1.98-2.04 (2H, m),
6.49 (1H, t, J = 7Hz), 7.73 (1H, br-s), 8.28 (1H, d, J = 7Hz), 10.21 (1H, s), 12.19 (1H,
s), 12.53 (1H, br-s)

Reference Example 62
1-[[(6-Hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester

By a method according to Reference Example 15, 1.39 g (10 mmol) of 6-hydroxynicotinic acid was used instead of 3-furancarboxylic acid to obtain 869 mg (31%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.30-1.41 (1H,
m), 1.43-1.58 (2H, m), 1.61-1.75 (3H, m), 1.89-1.99 (2H, m), 2.11-2.19 (2H, m),
3.74 (3H, s), 6.43 (1H, s), 6.53 (1H, d, J = 10Hz), 7.82 (1H, dd, J = 10Hz, 2Hz),
8.05 (1H, d, J = 2Hz)

Reference Example 63
1-[[(6-Hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[[(6-hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester 869 mg (3.1 mmol) was used to give 818 mg (94%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.19-1.31 (1H,
m), 1.42-1.57 (5H, m), 1.67-1.78 (2H, m), 2.01-2.11 (2H, m), 6.34 (1H, d, J = 10Hz),
7.84 (1H, dd, J = 10Hz, 2Hz), 7.95 (1H, s), 8.05 (1H, d, J = 2Hz), 11.90-12.18 (2H, m)

Reference Example 64
1-[[1-Oxo-3- (2-furanyl) propyl] amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 478 mg (57%) of the title compound was obtained using 420 mg (3 mmol) of 3- (2-furyl) propionic acid instead of 3-furancarboxylic acid.
1H-NMR (CDCl ₃ , δ): 1.25-1.38 (3H,
m), 1.57-1.65 (3H, m), 1.78-1.85 (2H, m), 1.96-2.01 (2H, m), 2.56 (2H, t, J = 7Hz),
2.98 (2H, t, J = 7Hz), 3.69 (3H, s), 5.56 (1H, br-s), 6.06 (1H, dd, J = 3Hz, 2Hz),
6.29 (1H, dd, J = 3Hz, 2Hz), 7.31 (1H, dd, J = 3Hz, 2Hz)

Reference Example 65
1-[[[1- (2-propoxycarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

979 mg (92%) of the title compound was obtained by a method according to Reference Example 15 using 646 mg (3 mmol) of 1- (2-propoxycarbonyl) nipecotic acid instead of 3-furancarboxylic acid.
1H-NMR (CDCl ₃ , δ): 1.24 (6H,
d, J = 6Hz), 1.25-1.44 (3H, m), 1.56-1.70 (5H, m), 1.79-1.90 (4H, m), 1.98-2.07 (2H,
m), 2.26-2.34 (1H, m), 2.75-2.88 (2H, m), 3.69 (3H, s), 4.17 (2H, br-s),
4.86-4.96 (1H, m), 5.58 (1H, s)

Reference Example 66
1-[[[1- (2-propoxycarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[[[1- (2-propoxycarbonyl) piperidin-4-yl] carbonyl] amino was used. Using 979 mg (2.76 mmol) of cyclohexanecarboxylic acid methyl ester, 940 mg (quantitative) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.23-1.28 (7H,
m), 1.34-1.39 (3H, m), 1.62-1.71 (6H, m), 1.85-1.91 (4H, m), 2.05-2.09 (2H, m),
2.33-2.36 (1H, m), 2.74-2.84 (2H, m), 4.21 (1H, br-s), 4.91 (1H, q, J = 7Hz),
5.67 (1H, s)

Reference Example 67
1-[[[1- (Ethoxycarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, 604 mg (3 mmol) of 1-ethoxycarbonylnipecotic acid was used instead of 3-furancarboxylic acid to obtain 976 mg (95%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.26 (3H,
t, J = 7Hz), 1.25-1.42 (3H, m), 1.55-1.70 (3H, m), 1.81-1.86 (4H, m), 2.01-2.05 (3H,
m), 2.26-2.32 (1H, m), 2.80-2.89 (2H, m), 3.69 (3H, s), 4.08-4.23 (3H, m), 4.13 (2H,
q, J = 7Hz), 5.54 (1H, br-s)

Reference Example 68
1-[[[1- (Ethoxycarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[[[1- (ethoxycarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexane Using 976 mg (2.87 mmol) of carboxylic acid methyl ester, 935 mg (quantitative) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.25 (3H,
t, J = 7Hz), 1.30-1.42 (3H, m), 1.62-1.72 (5H, m), 1.85-1.91 (4H, m), 2.06-2.09 (2H,
m), 2.34-2.39 (1H, m), 2.79-2.90 (2H, m), 4.10-4.25 (3H, m), 4.13 (2H, q, J = 7Hz),
5.69 (1H, s)

Reference Example 69
1-[[[1- (2-Furanylcarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, 670 mg (3 mmol) of 1- (2-furanylcarbonyl) piperidine-4-carboxylic acid was used instead of 3-furancarboxylic acid to obtain 910 mg (80%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.30-1.43 (3H,
m), 1.53-1.69 (3H, m), 1.74-1.90 (4H, m), 1.91-2.05 (4H, m), 2.43-2.48 (1H, m),
2.89-3.21 (2H, m), 3.79 (3H, s), 4.40-4.56 (2H, m), 5.58 (1H, br-s), 6.47 (1H, dd,
J = 3Hz, 1Hz), 6.95 (1H, dd, J = 3Hz, 1Hz), 7.48 (1H, dd, J = 3Hz, 1Hz)

Reference Example 70
1-[[[1- (2-Furanylcarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[[[1- (2-furanylcarbonyl) piperidin-4-yl] carbonyl] Amino] cyclohexanecarboxylic acid methyl ester 910 mg (2.4 mmol) was used to give 196 mg (23%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.17-1.25 (1H,
m), 1.40-1.58 (7H, m), 1.58-1.62 (2H, m), 1.73-1.76 (2H, m), 1.93-1.96 (2H, m),
2.51-2.61 (1H, m), 2.80-3.11 (2H, m), 4.22-4.33 (2H, m), 6.61 (1H, dd, J = 3Hz, 1Hz),
6.95 (1H, dd, J = 3Hz, 1Hz), 7.78 (1H, s), 7.82 (1H, dd, J = 3Hz, 1Hz)

Reference Example 71
1-[[[[(2-Furanylcarbonyl) amino] acetyl] amino] cyclohexanecarboxylic acid methyl ester

By a method according to Reference Example 15, 507 mg (3 mmol) of N- (2-furanylcarbonyl) glycine was used instead of 3-furancarboxylic acid to obtain 781 mg (88%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.22-1.38 (1H,
m), 1.39-1.50 (2H, m), 1.58-1.69 (3H, m), 1.85 (2H, td, J = 9Hz, 4Hz), 2.02-2.10 (2H,
m), 3.70 (3H, s), 4.15 (2H, d, J = 6Hz), 6.51 (1H, dd, J = 2Hz, 1Hz), 6.67 (1H, s),
7.13 (2H, m), 7.47 (1H, dd, J = 2Hz, 1Hz)

Reference Example 72
1-[[[[(2-Furanylcarbonyl) amino] acetyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of methyl 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, methyl 1-[[[(2-furanylcarbonyl) amino] acetyl] amino] cyclohexanecarboxylic acid Ester 781 mg (2.7 mmol) was used to give 320 mg (41%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.12-1.25 (1H,
m), 1.39-1.58 (5H, m), 1.64 (2H, td, J = 13Hz, 4Hz), 1.90-2.02 (2H, m), 3.88 (2H, d,
J = 6Hz), 6.62 (1H, dd, J = 3Hz, 1Hz), 7.13 (1H, dd, J = 3Hz, 1Hz), 7.84 (1H, d, J = 1Hz),
7.87 (1H, s), 8.38 (1H, d, J = 6Hz)

Reference Example 73
1-[[(Benzoylamino) acetyl] amino] cyclohexanecarboxylic acid methyl ester

By the method according to Reference Example 15, 538 mg (3 mmol) of N-benzoylglycine was used instead of 3-furancarboxylic acid to obtain 812 mg (81%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.23-1.38 (1H,
m), 1.48 (2H, td, J = 9Hz, 4Hz), 1.58-1.71 (3H, m), 1.84 (2H, dt, J = 9Hz, 4Hz),
2.02-2.10 (2H, m), 3.70 (3H, s), 4.21 (2H, d, J = 7Hz), 7.08 (1H, br-s),
7.26-7.46 (3H, m), 7.54 (1H, td, J = 8Hz, 1Hz), 7.84 (2H, dd, J = 8Hz, 1Hz)

Reference Example 74
1-[[(Benzoylamino) acetyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 16, instead of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester, 1-[[(benzoylamino) acetyl] amino] cyclohexanecarboxylic acid methyl ester 812 mg (2.4 mmol) To give 724 mg (93%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.09-1.67 (8H,
m), 1.96 (2H, d, J = 11Hz), 3.93 (2H, d, J = 6Hz), 7.47 (2H, td, J = 6Hz, 1Hz),
7.52-7.55 (1H, m), 7.86-7.89 (3H, m), 8.64 (1H, t, J = 6Hz)

Reference Example 75
1-[[(2-Furanylmethoxy) carbonyl] amino] cyclohexylsancarboxylic acid methyl ester

To a solution of 65.48 g (0.3 mol) of di-t-butyl dicarbonate in 300 ml of anhydrous toluene was added 3.67 g (30 mmol) of dimethylaminopyridine, and the mixture was stirred at room temperature for 15 minutes. To the reaction solution was added a solution of 47.17 g (0.3 mol) of 1-aminocyclohexanecarboxylic acid methyl ester in anhydrous toluene, and the mixture was stirred at room temperature for 1 hour. Further, 60.71 g (0.6 mol) of triethylamine and 44.1 g (0.45 mol) of furfuryl alcohol were added, followed by heating under reflux for 3 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure. The obtained residue was pulverized in a mortar and stirred in a mixed solution of 5 ml of hydrochloric acid and 3 l of water for 18 hours. The obtained crystals were collected by filtration to obtain 74.37 g (88%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.23-1.36 (1H,
m), 1.38-1.51 (2H, m), 1.55-1.65 (3H, m), 1.80-1.88 (2H, m), 1.93-2.04 (2H, m),
3.71 (3H, br-s), 4.93 (1H, br-s), 5.04 (2H, s), 6.36 (1H, dd, J = 3Hz, 2Hz), 6.41 (1H,
d, J = 3Hz), 7.43 (1H, d, J = 2Hz)

Reference Example 76
1-[[(2-Furanylmethoxy) carbonyl] amino] cyclohexylsancarboxylic acid

1-[[(2-Furanylmethoxy) carbonyl] amino] cyclohexylsancarboxylic acid methyl ester 28.13 (0.1 mol) was added to a mixed solution of 150 ml of 2N sodium hydroxide aqueous solution and 200 ml of tetrahydrofuran, and heated to reflux for 18 hours. After distilling off the solvent, water was added to the residue and washed with diethyl ether. The aqueous layer was acidified with potassium hydrogen sulfate, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue and stirred for 18 hours. The obtained crystals were collected by filtration to obtain 19.89 g (74%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.24-1.37 (1H,
m), 1.38-1.52 (2H, m), 1.59-1.71 (3H, m), 1.82-1.93 (2H, m), 1.99-2.12 (2H, m),
4.99 (1H, br-s), 5.07 (2H, s), 6.37 (1H, dd, J = 3Hz, 2Hz), 6.42 (1H, d, J = 3Hz),
7.43 (1H, d, J = 2Hz)

Reference Example 77
1-[[(4-Phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

Add methylene chloride solution of N, N-dimethylaminopyridine 366 mg (3 mmol) and 1-aminocyclohexanecarboxylic acid phenylmethyl ester 6.99 g (30 mmol) to a solution of di-t-butyl dicarbonate 6.55 g (30 mmol) in methylene chloride 150 ml. After stirring at room temperature for 30 minutes, a methylene chloride solution of 6.07 g (60 mmol) of triethylamine and 5.11 g (33 mmol) of 1-phenylpiperazine was added and stirred overnight at room temperature. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystals were washed with diethyl ether to obtain 8.88 g (70%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.25-1.37 (1H,
m), 1.42-1.51 (2H, m), 1.50-1.69 (3H, m), 1.82-1.91 (2H, m), 2.03-2.10 (2H, m),
3.17 (4H, t, J = 5Hz), 3.54 (4H, t, J = 5Hz), 4.60 (1H, br-s), 5.15 (2H, s), 6.89-6.94 (3H,
m), 7.26-7.35 (7H, m)

Reference Example 78
1-[[(4-Phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid

1-[[(4-Phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 8.88 g (21 mmol) obtained in Reference Example 77 was dissolved in methanol 200 ml, 10% palladium carbon 900 mg was added, and hydrogen atmosphere was added. Stir at room temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain 6.96 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.22-1.30 (1H,
m), 1.36-1.42 (2H, m), 1.50-2.05 (5H, m), 2.06-2.14 (2H, m), 3.24 (4H, t, J = 5Hz),
4.61 (4H, t, J = 5Hz), 4.51 (1H, br-s), 6.92-6.95 (2H, m), 7.28-7.32 (3H, m)

Reference Example 79
1-[[[4- (2-Pyridinyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

By the method according to Reference Example 77, 7.33 g (87%) of the title compound was obtained using 3.43 g (21 mmol) of 1- (2-pyridinyl) piperazine instead of 1-phenylpiperazine.
1H-NMR (CDCl ₃ , δ): 1.26-1.35 (1H,
m), 1.42-1.53 (2H, m), 1.60-1.68 (3H, m), 1.83-1.92 (2H, m), 2.02-2.10 (2H, m),
3.52 (4H, t, J = 5Hz), 3.57 (4H, t, J = 5Hz), 4.58 (1H, br-s), 5.15 (2H, s), 6.63 (1H,
d, J = 8Hz), 6.67 (1H, td, J = 8Hz, 1Hz), 7.25-7.34 (5H, m), 7.51 (1H, td, J = 8Hz,
1Hz), 8.20 (1H, dd, J = 8Hz, 1Hz)

Reference Example 80
1-[[[4- (2-Pyridinyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[[4- (2-pyridinyl) -1-piperazinyl [7] Carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 7.33 g (17.4 mmol) was used to give 5.75 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.30-1.43 (2H,
m), 1.60-1.72 (4H, m), 1.89-1.99 (2H, m), 2.06-2.13 (2H, m), 3.61 (4H, t, J = 5Hz),
3.66 (4H, t, J = 5Hz), 4.61 (1H, br-s), 6.65 (1H, dd, J = 8Hz, 1Hz), 6.69 (1H, td,
J = 8Hz, 1Hz), 7.52 (1H, td, J = 8Hz, 1Hz), 8.20 (1H, dd, J = 8Hz, 1Hz)

Reference Example 81
1-[[[4- (4-Fluorophenyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 77, 1.48 g (51%) of the title compound was obtained using 3.78 g (21 mmol) of 1- (4-fluorophenyl) piperazine instead of 1-phenylpiperazine.
1H-NMR (CDCl ₃ , δ): 1.22-1.35 (1H,
m), 1.40-1.51 (2H, m), 1.55-1.70 (3H, m), 1.85-1.93 (2H, m), 2.02-2.09 (2H, m),
3.07 (4H, t, J = 5Hz), 3.53 (4H, t, J = 5Hz), 4.60 (1H, br-s), 5.15 (2H, s), 6.87 (2H,
ddd, J = 9Hz, 6Hz, 2Hz), 6.98 (2H, ddd, J = 9Hz, 6Hz, 2Hz), 7.25-7.35 (5H, m)

Reference Example 82
1-[[[4- (4-Fluorophenyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[[4- (4-fluorophenyl) -1- Piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 4.48 g (10 mmol) was used to give 3.56 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.31-1.43 (3H,
m), 1.60-1.75 (3H, m), 1.89-2.01 (2H, m), 2.05-2.13 (2H, m), 3.14 (4H, t, J = 5Hz),
3.61 (4H, t, J = 5Hz), 4.55 (1H, br-s), 6.89 (2H, ddd, J = 8Hz, 5Hz, 2Hz), 6.99 (2H,
ddd, J = 8Hz, 5Hz, 2Hz)

Reference Example 83
1-[[[4- [3- (Trifluoromethyl) phenyl] -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 77, 4.83 g (21 mmol) of 1- [3- (trifluoromethyl) phenyl] piperazine was used instead of 1-phenylpiperazine to obtain 7.54 g (77%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.23-1.37 (1H,
m), 1.42-1.53 (2H, m), 1.59-1.70 (3H, m), 1.85-1.94 (2H, m), 2.02-2.10 (2H, m),
3.21 (4H, t, J = 5Hz), 3.55 (4H, t, J = 5Hz), 4.60 (1H, br-s), 5.15 (2H, s), 7.05 (1H,
dd, J = 8Hz, 2Hz), 7.09 (1H, s), 7.12 (1H, dd, J = 8Hz, 2Hz), 7.25-7.40 (6H, m)

Reference Example 84
1-[[[4- [3- (trifluoromethyl) phenyl] -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[[4- [3- (trifluoromethyl) phenyl ] -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 7.54 g (15.4 mmol) was used to give 5.92 g (96%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.36-1.44 (2H,
m), 1.60-1.75 (4H, m), 1.91-2.00 (2H, m), 2.05-2.14 (2H, m), 3.30 (4H, t, J = 5Hz),
3.63 (4H, t, J = 5Hz), 4.63 (1H, br-s), 7.07 (1H, d, J = 8Hz), 7.11 (1H, s), 7.15 (1H,
d, J = 8Hz), 7.38 (1H, t, J = 8Hz)

Reference Example 85
1-[[(4-Cyclohexyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

By the method according to Reference Example 77, 3.21 g (50%) of the title compound was obtained using 2.66 g (15.8 mmol) of 1- (cyclohexyl) piperazine instead of 1-phenylpiperazine.
1H-NMR (CDCl ₃ , δ): 1.22-1.45 (3H,
m), 1.39-1.50 (3H, m), 1.51-1.67 (6H, m), 1.89-1.90 (6H, m), 2.01-2.07 (2H, m),
2.22-2.30 (1H, m), 2.54 (4H, t, J = 5Hz), 3.38 (4H, t, J = 5Hz), 4.53 (1H, br-s),
5.14 (2H, s), 7.25-7.34 (5H, m)

Reference Example 86
1-[[(4-Cyclohexyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid

1-[[((4-Cyclohexyl-1-piperazinyl) carbonyl] amino instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester by a method according to Reference Example 78 ] By using 3.21 g (7.5 mmol) of cyclohexanecarboxylic acid phenylmethyl ester, 2.53 g (quantitative) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.05-1.19 (1H,
m), 1.10-1.19 (2H, m), 1,20-1.32 (2H, m), 1.58-1.97 (13H, m), 2.03-2.12 (2H, m),
2.35-2.44 (1H, m), 2.67 (4H, t, J = 5Hz), 3.48 (4H, t, J = 5Hz), 4.59 (1H, br-s)

Reference Example 87
1-[[(4-Benzoyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

In a solution of 2.03 g (9.3 mmol) of di-tert-butyl dicarbonate in 60 ml of methylene chloride, 114 mg (0.9 mmol) of N, N-dimethylaminopyridine and 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in methylene chloride After adding the solution and stirring at room temperature for 30 minutes, a methylene chloride solution of 1.88 g (18.6 mmol) of triethylamine and 1.86 g (9.8 mmol) of 1- (benzoyl) piperazine was added and stirred overnight at room temperature. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystals were washed with diethyl ether to obtain 3.60 g (86%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.26-1.38 (1H,
m), 1.39-1.50 (2H, m), 1.53-1.68 (3H, m), 1.85-1.93 (2H, m), 2.02-2.08 (2H, m),
3.28-3.57 (6H, m), 3.66-3.85 (2H, m), 4.57 (1H, br-s), 5.15 (2H, s), 7.31-7.39 (4H,
m), 7.40-7.48 (6H, m)

Reference Example 88
1-[[(4-Benzoyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[(4-benzoyl-1-piperazinyl) carbonyl] amino was used. Using 2.60 g (8 mmol) of cyclohexanecarboxylic acid phenylmethyl ester, 2.88 g (quantitative) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.34-1.42 (2H,
m), 1.59-1.74 (2H, m), 1.85-2.10 (6H, m), 3.42-3.58 (6H, m), 3.70-3.87 (2H, m),
4.60 (1H, br-s), 7.39-7.47 (5H, m)

Reference Example 89
1-[[[4- (Phenylmethyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester

In the same manner as in Reference Example 77, 5.82 g (33 mmol) of 4- (phenylmethyl) piperazine was used instead of 1-phenylpiperazine, and ethyl 1-aminocyclohexanecarboxylate was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester. Using 5.14 g (30 mmol) of the ester, 7.62 g (68%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.24 (3H,
t, J = 7Hz), 1.24-1.39 (1H, m), 1.40-1.49 (2H, m), 1.55-1.64 (3H, m), 1.80-1.89 (2H,
m), 1.97-2.04 (2H, m), 2.44 (4H, t, J = 5Hz), 3.39 (4H, t, J = 5Hz), 3.52 (2H, s),
4.17 (2H, q, J = 7Hz), 4.50 (1H, br-s), 7.23-7.30 (1H, m), 7.30-7.37 (4H, m)

Reference Example 90
1-[[[4- (Phenylmethyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid

To a solution of 1-[[(4-phenylmethyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid ethyl ester (7.62 g, 20 mmol) in ethanol (300 ml) was added 1N aqueous sodium hydroxide solution (600 ml), and the mixture was heated to reflux for 2 hours. After ether was added to the reaction solution for washing, the aqueous layer was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.90 g (42%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.28-1.38 (2H,
m), 1.60-1.71 (4H, m), 1.88-1.98 (2H, m), 2.01-2.10 (2H, m), 2.49 (4H, t, J = 5Hz),
3.45 (4H, t, J = 5Hz), 3.55 (2H, s), 4.43 (1H, br-s), 7.24-7.34 (5H, m)

Reference Example 91
1-[[4- (1-Oxo-3-phenylpropyl] -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 87, 1.40 g (11 mmol) of 1- (1-oxo-3-phenylpropyl) piperazine was used instead of 1- (benzoyl) piperazine to obtain 3.53 g (74%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.22-1.39 (1H,
m), 1.40-1.49 (2H, m), 1.58-1.67 (3H, m), 1.84-1.93 (2H, m), 2.00-2.07 (2H, m),
2.62 (2H, t, J = 6Hz), 2.98 (2H, t, J = 6Hz), 3.25-3.33 (6H, m), 3.59-3.65 (2H, m),
4.52 (1H, br-s), 5.14 (2H, br-s), 7.18-7.23 (4H, m), 7.28-7.34 (6H, m)

Reference Example 92
1-[[[4- (1-Oxo-3-phenylpropyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[[4- (1-oxo-3-phenylpropyl ) -1-Piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 3.53 g (7.4 mmol) was used to give 2.87 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.28-1.53 (3H,
m), 1.57-1.70 (3H, m), 1.84-1.97 (2H, m), 2.00-2.08 (2H, m), 2.63 (2H, t, J = 6Hz),
2.98 (2H, m, J = 6Hz), 3.33-3.41 (6H, m), 3.67-3.71 (2H, m), 4.78 (1H, br-s),
7.18-7.25 (3H, m), 7.27-7.34 (2H, m)

Reference Example 93
1-[[[4- (Phenylacetyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

By the method according to Reference Example 87, 1.39 g (87%) of the title compound was obtained using 1.23 g (6 mmol) of 1- (phenylacetyl) piperazine instead of 1- (1-oxo-3-phenylpropyl) piperazine. .
1H-NMR (CDCl ₃ , δ): 1.22-1.36 (1H,
m), 1.37-2.06 (2H, m), 1.55-1.66 (3H, m), 1.83-1.92 (2H, m), 1.98-2.03 (2H, m),
3.20 (2H, t, J = 5Hz), 3.31 (2H, t, J = 5Hz), 3.41 (2H, t, J = 5Hz), 3.63 (2H, t, J = 5Hz),
3.74 (2H, s), 4.49 (1H, br-s), 5.12 (2H, s), 7.24-7.32 (10H, m)

Reference Example 94
1-[[[4- (Phenylacetyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[[4- (phenylacetyl) -1-piperazinyl] Carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 2.39 g (5.2 mmol) was used to give 1.94 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.29-1.39 (3H,
m), 1.58-1.70 (3H, m), 1.86-1.96 (2H, m), 1.99-2.07 (2H, m), 3.26 (2H, t, J = 5Hz),
3.38 (2H, t, J = 5Hz), 3.50 (2H, t, J = 5Hz), 3.72 (2H, t, J = 5Hz), 3.76 (2H, s), 4.50 (1H,
br-s), 7.23-7.30 (3H, m), 7.30-7.35 (2H, m)

Reference Example 95
1-[(1-Piperidinylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 87, 1.34 g (15.8 mmol) of piperidine was used instead of 1- (1-oxo-3-phenylpropyl) piperazine to obtain 4.59 g (89%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.22-1.34 (1H,
m), 1.40-1.65 (11H, m), 1.82-1.90 (2H, m), 2.02-2.08 (2H, m), 3.32 (4H, t, J = 5Hz),
4.53 (1H, br-s), 5.14 (2H, s), 7.29-7.35 (5H, m)

Reference Example 96
1-[(1-Piperidinylcarbonyl) amino] cyclohexanecarboxylic acid

1-[[(4-Phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid 1-[(1-piperidinylcarbonyl) amino] cyclohexanecarboxylic acid instead of phenylmethyl ester by the method according to Reference Example 78 Using 4.59 g (12 mmol) of phenyl methyl ester, 3.05 g (quantitative) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.30-1.41 (4H,
m), 1.56-1.70 (8H, m), 1.85-1.96 (2H, m), 2.05-2.13 (2H, m), 3.89 (4H, t, J = 5Hz),
4.51 (1H, br-s)

Reference Example 97
1-[(1-Pyrrolidinylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

By a method according to Reference Example 87, 3.22 g (65%) of the title compound was obtained using 1.12 g (15.8 mmol) of pyrrolidine instead of 1- (1-oxo-3-phenylpropyl) piperazine.
1H-NMR (CDCl ₃ , δ): 1.23-1.33 (1H,
m), 1.42-1.51 (2H, m), 1.51-1.68 (3H, m), 1.82-1.95 (2H, m), 1.89 (4H, t, J = 7Hz),
2.02-2.10 (2H, m), 3.35 (4H, t, J = 7Hz), 4.33 (1H, br-s), 5.16 (2H, s),
7.26-7.36 (5H, m)

Reference Example 98
1-[(1-Pyrrolidinylcarbonyl) amino] cyclohexanecarboxylic acid

1-[[(4-Phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid 1-[(1-pyrrolidinylcarbonyl) amino] cyclohexanecarboxylic acid instead of phenylmethyl ester by the method according to Reference Example 78 Using 3.23 g (9.8 mmol) of phenyl methyl ester, 2.35 g (quantitative) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.29-1.42 (3H,
m), 1.58-1.72 (3H, m), 1.88-2.00 (6H, m), 2.05-2.14 (2H, m), 3.40 (4H, t, J = 6Hz),
4.34 (1H, br-s)

Reference Example 99
1-[[(2-Oxo-1-piperidinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

To a solution of 3.27 g (15 mmol) of di-t-butyl dicarbonate in 60 ml of toluene was added a toluene solution of 183 mg (1.5 mmol) of N, N-dimethylaminopyridine and 3.50 g (15 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester at room temperature. After stirring for 30 minutes, 3.04 g (30 mmol) of triethylamine, 1.83 g (15 mmol) of N, N-dimethylaminopyridine and 1.56 g (15.8 mmol) of 2-piperidone were added and heated under reflux overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 4.10 g (76%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.21-1.30 (1H,
m), 1.42-1.53 (2H, m), 1.61-1.69 (3H, m), 1.78-1.90 (6H, m), 2.06-2.15 (2H, m),
2.54 (2H, t, J = 6Hz), 3.73 (2H, t, J = 6Hz), 5.16 (2H, s), 7.27-7.35 (5H, m), 9.85 (1H,
br-s)

Reference Example 100
1-[[(2-Oxo-1-piperidinyl) carbonyl] amino] cyclohexanecarboxylic acid

1-[[(1- (2-Oxo-1-piperidinyl) carbonyl] instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester by a method according to Reference Example 78 Amino] cyclohexanecarboxylic acid phenylmethyl ester 4.10 g (11.4 mmol) was used to give 2.95 g (96%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.24-1.35 (1H,
m), 1.45-1.64 (2H, m), 1.50-1.71 (3H, m), 1.82-1.92 (6H, m), 2.12-2.16 (2H, m),
2.58 (2H, t, J = 6Hz), 3.80 (2H, t, J = 6Hz), 9.96 (1H, br-s)

Reference Example 101
1-[(1,4-Dioxa-8-azaspiro [4.5] dec-8-ylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 87, 3.00 g (21 mmol) of 1,4-dioxa-8-azaspiro [4.5] decane was used instead of 1- (benzoyl) piperazine to obtain 5.70 g (71%) of the title compound. It was.
1H-NMR (CDCl ₃ , δ): 1.23-1.34 (1H,
m), 1.40-1.48 (2H, m), 1.59-1.67 (3H, m), 1.69 (4H, t, J = 6Hz), 1.84-1.93 (2H, m),
2.00-2.08 (2H, m), 3.47 (4H, t, J = 6Hz), 3.98 (4H, s), 4.59 (1H, br-s), 5.14 (2H, s),
7.27-7.36 (5H, m)

Reference Example 102
1-[(1,4-Dioxa-8-azaspiro [4.5] dec-8-ylcarbonyl) amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[(1,4-dioxa-8-azaspiro [4. 5) Dec-8-ylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester 5.70 g (14.2 mmol) was used to give 4.38 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.30-1.42 (3H,
m), 1.60-1.77 (3H, m), 1.75 (4H, t, J = 6Hz), 1.88-2.01 (2H, m), 2.05-2.14 (2H, m),
3.54 (4H, t, J = 6Hz), 3.99 (4H, s), 4.55 (1H, br-s)

Reference Example 103
1-[[[(1,3-Dioxolan-2-ylmethyl) methylamino] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

By the method according to Reference Example 87, 6.05 g (80%) of the title compound was obtained using 2-[(methylamino) methyl] -1,3-dioxolane 2.46 (21 mmol) instead of 1- (benzoyl) piperazine. .
1H-NMR (CDCl ₃ , δ): 1.22-1.34 (1H,
m), 1.39-1.50 (2H, m), 1.59-1.68 (2H, m), 1.68-1.74 (3H, m), 1.82-1.91 (2H, m),
2.00-2.08 (2H, m), 3.44-3.50 (4H, m), 3.98 (4H, s), 4.59 (1H, br-s), 5.14 (2H, s),
7.27-7.36 (5H, m)

Reference Example 104
1-[[[(1,3-Dioxolan-2-ylmethyl) methylamino] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[[(1,3-dioxolan-2-ylmethyl) Methylamino] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 6.05 g (16 mmol) was used to give 4.45 g (97%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.30-1.41 (3H,
m), 1.60-1.75 (5H, m), 1.88-1.97 (2H, m), 2.04-2.13 (2H, m), 3.48-3.59 (4H, m),
3.99 (4H, s), 4.53 (1H, br-s)

Reference Example 105
1-[[(1,3-Dihydro-2H-isoindol-2-yl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 87, 5.95 g (79%) of the title compound was obtained using isoindoline 2.50 (21 mmol) instead of 1- (benzoyl) piperazine.
1H-NMR (CDCl ₃ , δ): 1.23-1.38 (1H,
m), 1.45-1.70 (5H, m), 1.89-1.97 (2H, m), 2.07-2.16 (2H, m), 4.48 (1H, br-s),
4.73 (4H, s), 5.17 (2H, s), 7.25-7.31 (7H, m), 7.31-7.36 (2H, m)

Reference Example 106
1-[[(1,3-Dihydro-2H-isoindol-2-yl) carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[(1,3-dihydro-2H-isoindole- Using 2.95 g (15.8 mmol) of 2-yl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 3.09 g (68%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.23-1.30 (1H,
m), 1.35-1.48 (2H, m), 1.59-1.76 (3H, m), 1.96-2.05 (2H, m), 2.10-2.17 (2H, m),
4.40 (1H, br-s), 4.78 (4H, br-s), 7.24-7.35 (4H, m)

Reference Example 107
1-[[(2-oxo-1-imidazolidinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

To a solution of 1.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 1.04 g (10 mmol) of triethylamine in 100 ml of chloroform was added 1.38 g (9.3 mmol) of 2-oxo-1-imidazolidinecarbonyl chloride, and 4 Stir for days. The reaction solution was washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with diethyl ether to obtain 2.64 g (82%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.22-1.31 (1H,
m), 1.44-1.54 (2H, m), 1.60-1.68 (3H, m), 1.81-1.88 (2H, m), 2.08-2.16 (2H, m),
3.48 (2H, t, J = 7Hz), 3.93 (2H, t, J = 7Hz), 4.75 (1H, br-s), 5.17 (2H, s),
7.26-7.36 (5H, m), 8.45 (1H, br-s)

Reference Example 108
1-[[(2-Oxo-1-imidazolidinyl) carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[(2-oxo-1-imidazolidinyl) carbonyl] Amino] cyclohexanecarboxylic acid phenylmethyl ester (2.64 g, 7.6 mmol) was used to give 1.95 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.23-1.38 (1H,
m), 1.41-1.70 (5H, m), 1.83-1.92 (2H, m), 2.11-2.20 (2H, m), 3.54 (2H, t, J = 8Hz),
4.01 (2H, t, J = 8Hz), 4.92 (1H, br-s), 8.53 (1H, br-s)

Reference Example 109
1-[[(3-Methyl-2-oxo-1-imidazolidinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

1-[[(2-Oxo-1-imidazolidinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 1.50 g (4.3 mmol), potassium carbonate 1.78 g (12.9 mmol) in 100 ml of acetonitrile 1.83 g (12.9 mmol) was added and heated to reflux overnight. The reaction mixture was concentrated, ethyl acetate was added, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain 710 mg (50%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.21-1.30 (1H,
m), 1.42-1.56 (2H, m), 1.61-1.69 (3H, m), 1.79-1.88 (2H, m), 2.08-2.17 (2H, m),
2.86 (3H, s), 3.40 (2H, t, J = 8Hz), 3.81 (2H, t, J = 8Hz), 5.17 (2H, s), 7.30-7.36 (5H,
m), 8.55 (1H, br-s)

Reference Example 110
1-[[(3-Methyl-2-oxo-1-imidazolidinyl) carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 78, instead of 1-[[(4-phenyl-1-piperazinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1-[[(3-methyl-2-oxo-1- 710 mg (2 mmol) of imidazolidinyl) carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester gave 539 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.23-1.33 (1H,
m), 1.42-1.53 (2H, m), 1.61-1.70 (3H, m), 1.82-1.89 (2H, m), 2.11-2.20 (2H, m),
2.89 (3H, s), 3.46 (2H, dd, J = 10Hz, 8Hz), 3.91 (2H, dd, J = 10Hz, 8Hz), 8.66 (1H,
br-s)

Reference Example 111
1-[[(2,5-Dihydro-1H-pyrrol-1-yl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 77, instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, 472 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester and 3,5-dihydropyrrole 311 mg instead of 1-phenylpiperazine (4.5 mmol) was used to give 698 mg (92%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.23-1.38 (1H,
m), 1.42-1.53 (2H, m), 1.53-1.69 (3H, m), 1.82-1.92 (2H, m), 2.01-2.10 (2H, m),
3.73 (3H, s), 4.18 (4H, s), 4.31 (1H, s), 5.82 (2H, s)

Reference Example 112
1-[[(2,5-Dihydro-1H-pyrrol-1-yl) carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 90, instead of 1-[[[4- (phenylmethyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester, 1-[[(2,5-dihydro-1H- Using 698 mg (2.8 mmol) of pyrrol-1-yl) carbonyl] amino] cyclohexanecarboxylic acid methyl ester, 453 mg (69%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.34-1.73 (6H,
m), 1.92-2.22 (2H, m), 2.24-2.36 (2H, m), 4.23 (5H, br-s), 5.87 (2H, br-s)

Reference Example 113
1-[(1H-pyrrol-1-ylcarbonyl) amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 77, instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, 1 g (6.36 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester and 512 mmol (7.6 mmol) of pyrrole instead of 1-phenylpiperazine To give 1.52 g (95%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.36-1.57 (3H,
m), 1.65-1.74 (3H, m), 1.91-2.02 (2H, m), 2.08-2.19 (2H, m), 3.74 (3H, s), 5.58 (1H,
s), 6.28 (2H, dd, J = 2Hz, 1Hz), 7.19 (2H, dd, J = 2Hz, 1Hz)

Reference Example 114
1-[(1H-pyrrol-1-ylcarbonyl) amino] cyclohexanecarboxylic acid

In the method according to Reference Example 90, instead of 1-[[[4- (phenylmethyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester, 1-[[(1H-pyrrol-1-yl) Carbonyl] amino] cyclohexanecarboxylic acid methyl ester 1.52 g (6 mmol) was used to give 839 mg (58%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.15-1.61 (4H,
m), 1.69-1.81 (2H, m), 1.83-1.98 (2H, m), 2.08-2.19 (2H, m), 6.12 (2H, s), 6.21 (1H,
d, J = 2Hz), 7.42 (2H, d, J = 2Hz), 7.88 (1H, dr-s)

Reference Example 115
1-[(3-Thiazolidinylcarbonyl) amino] cyclohexanecarboxylic acid

To a solution of 1.39 mg (6.36 mmol) of di-t-butyl dicarbonate in 10 ml of methylene chloride was added a solution of 78 mg (0.6 mmol) of N, N-dimethylaminopyridine and 1 g (6.36 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester in methylene chloride. After stirring at room temperature for 30 minutes, a methylene chloride solution of 1.29 g (12.7 mmol) of triethylamine and 680 mg (7.6 mmol) of thiazolidine was added and stirred overnight at room temperature. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, tetrahydrofuran and 1N aqueous sodium hydroxide solution were added to the residue, and the mixture was heated to reflux for 3 hours. After ether was added to the reaction solution for washing, the aqueous layer was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.1 g (66%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.08-1.25 (1H,
m), 1.36-1.69 (6H, m), 1.82-2.01 (3H, m), 2.93 (2H, t, J = 7Hz), 3.59 (2H, t, J = 7Hz),
4.43 (2H, s), 6.44 (1H, s), 11.99 (1H, br-s)

Reference Example 116
1-[[[((2-Furanylmethyl) methylamino] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 77, instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, 2.83 g (18 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester and (2-furanylmethyl) methyl instead of 1-phenylpiperazine The title compound 4.27g (78%) was obtained using 2.18g (18mmol) of the amine.
1H-NMR (CDCl ₃ , δ): 1.25-1.47 (3H,
m), 1.57-1.68 (3H, m), 1.80-1.85 (2H, m), 1.97-2.20 (2H, m), 2.94 (3H, s), 3.71 (3H,
s), 4.42 (2H, s), 4.74 (1H, s), 6.24 (1H, dd, J = 3Hz, 1Hz), 6.34 (1H, dd, J = 3Hz,
J = 3Hz, 2Hz), 7.37 (1H, dd, J = 2Hz, 1Hz)

Reference Example 117
1-[[[[(2-Furanylmethyl) methylamino] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 90, instead of 1-[[[4- (phenylmethyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester, 1-[[[(2-furanylmethyl) methylamino] Carbonyl] amino] cyclohexanecarboxylic acid methyl ester 4.27 g (14 mmol) was used to give 3.47 g (84%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.12-1.23 (1H,
m), 1.38-1.52 (5H, m), 1.58-1.64 (2H, m), 1.80-2.22 (2H, m), 2.81 (3H, s), 4.42 (2H,
s), 6.03 (1H, s), 6.24 (1H, dd, J = 3Hz, 1Hz), 6.40 (1H, dd, J = 3Hz, 2Hz), 7.57 (1H,
(dd, J = 2Hz, 1Hz)

Reference Example 118
1-[[(Methylphenylamino) carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 77, instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, 472 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester and 643 mg (6 mmol of N-methylaniline instead of 1-phenylpiperazine) ) To give 834 mg (96%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.12-1.28 (2H,
m), 1.48-1.62 (4H, m), 1.64-1.70 (2H, m), 1.90-1.98 (2H, m), 3.25 (3H, s), 3.74 (3H,
s), 4.49 (1H, s), 7.26-7.36 (3H, m), 7.43-7.46 (2H, m)

Reference Example 119
1-[[(Methylphenylamino) carbonyl] amino] cyclohexanecarboxylic acid

1-[[[(4- (Phenylmethyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester instead of 1-[[(methylphenylamino) carbonyl] amino] cyclohexane in accordance with Reference Example 90 The title compound 464 mg (59%) was obtained using 834 mg (2.87 mmol) of carboxylic acid methyl ester.
1H-NMR (CDCl ₃ , δ): 0.96-1.05 (2H,
m), 1.19-1.30 (1H, m), 1.50-1.60 (3H, m), 1.70-1.81 (2H, m), 1.96-2.02 (2H, m),
3.31 (3H, s), 4.30 (1H, s), 7.26-7.33 (2H, m), 7.44 (1H, t, J = 9Hz), 7.51 (2H, t,
(J = 9Hz)

Reference Example 120
1-[[[Methyl (phenylmethyl) amino] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 77, instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, 2.83 g (18 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester and N-methylbenzylamine 2.18 instead of 1-phenylpiperazine Using g (18 mmol) gave 4.27 g (78%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.20-1.38 (3H,
m), 1.50-1.63 (3H, m), 1.78-1.85 (2H, m), 1.97-2.03 (2H, m), 2.94 (3H, s), 3.73 (3H,
s), 4.49 (2H, s), 4.51 (1H, s), 7.25-7.30 (3H, m), 7.35 (2H, dt, J = 8Hz, 1Hz)

Reference Example 121
1-[[[Methyl (phenylmethyl) amino] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 90, instead of 1-[[[4- (phenylmethyl) -1-piperazinyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester, 1-[[[methyl (phenylmethyl) amino] carbonyl] Using 4.27 g (14 mmol) of amino] cyclohexanecarboxylic acid methyl ester, 3.54 g (86%) of the title compound was obtained.
1H-NMR (DMSO-d ₆ , δ): 1.16-2.04 (1H,
m), 1.39-1.47 (5H, m), 1.58-1.65 (2H, m), 1.97-2.22 (2H, m), 2.79 (3H, s), 4.44 (2H,
s), 6.00 (1H, s), 7.21-7.34 (5H, m)

Reference Example 122
1-[[(2-oxo-2H-pyran-5-yl) carbonyl] amino] cyclohexanecarboxylic acid

20 ml of a dimethylformamide solution of 2.37 g (10 mmol) of 5-coumarincarboxylic acid N-hydroxysuccinimide ester, 1.43 g (10 mmol) of 1-aminocyclohexanecarboxylic acid and 3.04 g (30 mmol) of triethylamine was stirred overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 10% aqueous potassium hydrogen sulfate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.42 g (60%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 1.30-1.44 (3H,
m), 1.44-1.63 (3H, m), 1.95-2.09 (4H, m), 5.26 (1H, d, J = 9Hz), 7.62 (1H, d, J = 9Hz),
8.28 (1H, d, J = 15Hz), 9.68 (1H, d, J = 15Hz)

Reference Example 123
1-[(4-Fluorobenzoyl) amino] cyclohexanecarboxylic acid

  Under ice-cooling, a mixed solution of 22.6 g (15.8 mmol) of 1-aminocyclohexanecarboxylic acid and 25.0 g (23.7 mmol) of sodium carbonate in 100 ml of ether and 300 ml of water was mixed with 30 ml of ether of 25.0 g (15.8 mmol) of 4-fluorobenzoyl chloride. The solution was added dropwise and stirred overnight at room temperature. After the ether layer was separated, the aqueous layer was neutralized with concentrated hydrochloric acid under ice cooling, and the precipitated crystals were collected by filtration to obtain 27.7 g (66%) of the title compound.

Reference Example 124
1-[[[4- (4-Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

In the same manner as in Reference Example 1, 1.79 g (46%) of the title compound was obtained using 2.36 g (8.44 mmol) of 4- (4-propylpiperazin-1-yl) benzoic acid hydrochloride instead of phenylacetyl chloride. .
1H-NMR (CDCl ₃ , δ): 0.94 (3H,
t, J = 7Hz), 1.28-1.40 (1H, m), 1.45-1.61 (4H, m), 1.61-1.72 (3H, m), 1.90-1.98 (2H,
m), 2.15-2.23 (2H, m), 2.36 (1H, t, J = 6Hz), 2.37 (1H, t, J = 6Hz), 2.59 (4H, t,
J = 5Hz), 3.31 (4H, t, J = 5Hz), 5.16 (2H, s), 6.13 (1H, br-s), 6.89 (2H, d, J = 8Hz),
7.25-7.33 (5H, m), 7.68 (2H, d, J = 8Hz)

Reference Example 125
1-[[[4- (4-Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid

1-[[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexane instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid phenylmethyl ester by the method according to Reference Example 2. The use of 1.79 g (3.86 mmol) of carboxylic acid phenylmethyl ester gave 1.43 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.95 (3H,
t, J = 8Hz), 1.39-1.61 (3H, m), 1.65-1.78 (4H, m), 1.94-2.03 (3H, m), 2.21-2.41 (2H,
m), 2.45-2.54 (2H, m), 2.65-2.70 (4H, m), 3.27-3.35 (4H, m), 6.06 (1H, br-s),
6.85 (2H, d, J = 8Hz), 7.65 (2H, d, J = 8Hz)

Reference Example 126
1-[[[4- (4-Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

In the same manner as in Reference Example 15, using 1.00 g (3.57 mmol) of 4- (4-propylpiperazin-1-yl) benzoic acid hydrochloride instead of 3-furancarboxylic acid, 602 g (44%) of the title compound was obtained. It was.
1H-NMR (CDCl ₃ , δ): 0.94 (3H,
t, J = 8Hz), 1.31-1.40 (1H, m), 1.44-1.58 (4H, m), 1.62-1.74 (3H, m), 1.88-1.96 (2H,
m), 2.11-2.19 (2H, m), 2.36 (1H, t, J = 6Hz), 2.37 (1H, t, J = 6Hz), 2.59 (4H, t,
J = 5Hz), 3.30 (4H, t, J = 5Hz), 3.72 (3H, s), 6.12 (1H, br-s), 6.89 (2H, dd, J = 2Hz,
7Hz), 7.69 (2H, dd, J = 2Hz, 7Hz)

Reference Example 127
1-[[[4- (4-Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester hydrochloride

1-[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester (120 mg, 0.31 mmol) in ethyl acetate (10 ml) and 1 ml of 4N hydrochloric acid / ethyl acetate solution were added to room temperature. And stirred for 30 minutes. The precipitated crystals were collected by filtration to obtain 87 mg (66%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 0.91 (3H,
t, J = 8Hz), 1.21-1.35 (1H, m), 1.47-1.62 (5H, m), 1.70-1.81 (4H, m), 2.02-2.10 (2H,
m), 3.01-3.14 (4H, m), 3.15-3.28 (2H, m), 3.50-3.58 (2H, m), 3.82-4.02 (5H, m),
7.04 (2H, dd, J = 2Hz, 7Hz), 7.79 (2H, dd, J = 2Hz, 7Hz), 8.11 (1H, s)

Reference Example 128
1-[[[4- (4-Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid hydrochloride

To 600 mg (1.55 mmol) of 1-[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester was added 3 ml of 4N hydrochloric acid, and the mixture was heated to reflux for 6 hours. After cooling to room temperature, the precipitated crystals were collected by filtration to obtain 258 mg (41%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.05 (3H,
t, J = 7Hz), 1.31-1.43 (1H, m), 1.45-1.56 (2H, m), 1.64-1.78 (3H, m), 1.90-2.02 (4H,
m), 2.16-2.25 (2H, m), 2.95-3.28 (5H, m), 3.60-3.75 (4H, m), 3.78-3.89 (2H, m),
6.65 (1H, br-s), 6.92 (2H, d, J = 8Hz), 7.97 (2H, d, J = 8Hz)

Reference Example 129
1-[[[4- (4-Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester

According to the method of Reference Example 15, 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride 741 mg (3.57 mmol) and 3-furancarboxylic acid instead of 4- (4- By using 1.00 g (3.57 mmol) of propylpiperazin-1-yl) benzoic acid hydrochloride, 928 mg (65%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 0.94 (3H,
t, J = 8Hz), 1.24 (3H, t, J = 7Hz), 1.30-1.41 (1H, m), 1.43-1.71 (7H., m),
1.88-1.97 (2H, m), 2.10-2.20 (2H, m), 2.36 (1H, t, J = 6Hz), 2.37 (1H, t, J = 6Hz),
3.31 (4H, t, J = 5Hz), 4.18 (4H, t, J = 5Hz), 4.20 (2H, q, J = 7Hz), 6.10 (1H, br-s),
6.89 (2H, dd, J = 2Hz, 8Hz), 7.69 (2H, dd, J = 2Hz, 8Hz)

Reference Example 130
1-[[[4- (4-Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester hydrochloride

In the same manner as in Reference Example 127, instead of 1-[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester, 1-[[[4- (4-propyl Piperazine-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester 120 mg (0.3 mmol) was used to give 114 mg (87%) of the title compound.
1H-NMR (DMSO-d ₆ , δ): 0.93 (3H,
t, J = 8Hz), 1.11 (3H, t, J = 7Hz), 1.23-1.32 (1H, m), 1.45-1.55 (5H, m),
1.68-1.80 (4H, m), 2.02-2.10 (2H, m), 3.03-3.18 (6H, m), 3.51-3.62 (2H, m),
3.95-4.04 (2H, m), 4.02 (2H, q, J = 7Hz), 7.04 (2H, d, J = 8Hz), 7.78 (2H, d, J = 8Hz),
8.10 (1H, s)

Reference Example 131
1-[[[4- (4-Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid hydrochloride

In the same manner as in Reference Example 128, instead of 1-[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester, 1-[[[4- (4-propyl Piperazine-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid ethyl ester 800 mg (1.99 mmol) was used to give 197 mg (24%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.05 (3H,
t, J = 7Hz), 1.31-1.43 (1H, m), 1.45-1.56 (2H, m), 1.64-1.78 (3H, m), 1.90-2.02 (4H,
m), 2.16-2.25 (2H, m), 2.95-3.28 (5H, m), 3.60-3.75 (4H, m), 3.78-3.89 (2H, m),
6.65 (1H, br-s), 6.92 (2H, d, J = 8Hz), 7.97 (2H, d, J = 8Hz)

Reference Example 132
2- (Phenylmethyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

To a 20 ml methylene chloride solution of 784 mg (3 mmol) of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid obtained in Reference Example 2 was added 633 mg (3.3 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. added. After stirring at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. did. The solvent was distilled off under reduced pressure to obtain 625 mg (86%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.48-1.51 (1H,
m), 1.56-1.70 (3H, m), 1.70-1.79 (6H, m), 3.79 (2H, s), 7.28-7.36 (5H, m)

Reference Example 133
2- (2-Phenylethyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

The title compound was prepared by a method analogous to that of Reference Example 132, using 826 mg (3 mmol) of 1-[(1-oxo-3-phenylpropyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. 764 mg (99%) was obtained.
1H-NMR (CDCl ₃ , δ): 1.47-1.55 (4H,
m), 1.57-1.78 (6H, m), 2.79 (2H, t, J = 7Hz), 3.02 (2H, t, J = 7Hz), 7.20-7.23 (3H, m),
7.28-7.31 (2H, m)

Reference Example 134
2-Phenyl-3-oxa-1-azaspiro [4.5] dec-1-en-4-one

By the method according to Reference Example 132, 742 mg (3 mmol) of 1-[(benzoyl) amino] cyclohexanecarboxylic acid was used instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid to obtain 633 mg (92%) of the title compound. It was.
1H-NMR (CDCl ₃ , δ): 1.52-1.58 (1H,
m), 1.63-1.78 (3H, m), 1.79-1.89 (6H, m), 7.47 (1H, td, J = 7Hz, 1Hz), 7.49 (1H, td,
J = 7Hz, 1Hz), 7.56 (1H, td, J = 7Hz, 1Hz), 8.02 (2H, m)

Reference Example 135
2- (4-Biphenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

914 mg (quantitative) of the title compound using 970 mg (3 mmol) of 1-[(4-biphenylcarbonyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid in the same manner as in Reference Example 132 )
1H-NMR (CDCl ₃ , δ): 1.52 (2H,
m), 1.63-1.71 (1H, m), 1.72-1.80 (2H, m), 1.81-1.90 (5H, m), 7.39-7.42 (1H, m),
7.47-7.50 (2H, m), 7.63 (1H, dd, J = 7Hz, 1Hz), 7.65 (1H, dd, J = 7Hz, 1Hz), 7.71 (1H,
d, J = 7Hz, 1Hz), 7.72 (1H, dd, J = 7Hz, 1Hz), 8.07 (1H, dd, J = 7Hz, 1Hz), 8.08 (1H,
(dd, J = 7Hz, 1Hz)

Reference Example 136
2- (2-Naphthyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[(2-naphthylcarbonyl) amino] cyclohexanecarboxylic acid 595 mg (2 mmol) was used, and the title compound 562 mg (quantitative) )
1H-NMR (CDCl ₃ , δ): 1.54-1.68 (1H,
m), 1.69-1.76 (1H, m), 1.78-1.94 (8H, m), 7.26-7.62 (2H, m), 7.89 (1H, d, J = 8Hz),
7.92 (1H, dd, J = 8Hz, 1Hz), 7.95 (1H, dd, J = 8Hz, 1Hz), 8.09 (1H, dd, J = 8Hz, 1Hz),
8.49 (1H, d, J = 1Hz)

Reference Example 137
2- (1-Naphtyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

Dissolve 1.35 g (3.5 mmol) of 1-[(1-naphthylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester obtained in Reference Example 11 in 50 ml of methanol, add 150 mg of 10% palladium carbon, and at room temperature under a hydrogen atmosphere. Stir overnight. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 30 ml of methylene chloride, and 633 mg (3.3 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added. After stirring at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. did. The solvent was distilled off under reduced pressure to obtain 738 mg (88%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.50-1.68 (3H,
m), 1.70-2.00 (7H, m), 7.53-7.60 (2H, m), 7.67 (1H, td, 7Hz, 1Hz), 7.92 (1H, dd,
J = 7Hz, 1Hz), 8.03 (1H, d, J = 7Hz), 8.17 (1H, dd, J = 7Hz, 1Hz), 9.33 (1H, dd, J = 7Hz,
1Hz)

Reference Example 138
2-[(RS) -2,3-Tetrahydrobenzofuran-2-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

1-[[[((RS) -2,3-tetrahydrobenzofuran-2-yl] carbonyl] amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid by the method according to Reference Example 132
868 mg (3 mmol) was used to give 686 mg (87%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.43-1.82 (10H,
m), 3.56 (2H, d, J = 9Hz), 5.46 (1 / 2H, d, J = 10Hz), 5.48 (1 / 2H, d, J = 10Hz), 6.89 (1H, td, 8Hz, 1Hz) , 6.93 (1H, dd, H = 8Hz, 1Hz), 7.16 (1H, td,
J = 8Hz, 1Hz), 7.21 (1H, dd, J = 8Hz, 1Hz)

Reference Example 139
2- (2-Furanyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, using 53.2 g (224 mmol) of 1-[(2-furanylcarbonyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 49.8 g of the title compound (Quantitative) was obtained.
1H-NMR (CDCl ₃ , δ): 1.53-1.57 (1H,
m), 1.66-1.86 (9H, m), 6.58 (1H, dd, J = 4Hz, 2Hz), 7.09 (1H, dd, J = 4Hz, 1Hz),
7.65 (1H, dd, J = 2Hz, 1Hz)

Reference Example 140
2- (3-Furanyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, the title compound 4.02 was prepared by using 4.48 g (18.9 mmol) of 1-[(3-furanylcarbonyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. g (97%) was obtained.
1H-NMR (CDCl ₃ , δ): 1.54-1.57 (1H,
m), 1.63-1.86 (9H, m), 6.86 (1H, dd, J = 2Hz, 1Hz), 7.51 (1H, t, J = 2Hz), 7.99 (1H,
(dd, J = 2Hz, 1Hz)

Reference Example 141
2- [2- (2-Furanyl) ethenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

Instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[[(E) -3- (2-furanyl) -1-oxo-2-propenyl] amino] cyclohexane was prepared according to the method of Reference Example 132. Using 10.0 g (38 mmol) of carboxylic acid, 8.92 g (96%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.26-1.54 (2H,
m), 1.66-1.84 (8H, m), 6.48 (1H, dd, J = 2Hz, 1Hz), 6.53 (1H, d, J = 16Hz), 6.60 (1H,
d, J = 2Hz), 7.22 (1H, d, J = 16Hz), 7.51 (1H, dd, J = 2Hz, 1Hz)

Reference Example 142
2-Cyclohexyl-3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, except that 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid was used instead of 1-[(cyclohexylcarbonyl) amino] cyclohexanecarboxylic acid 4.15 g (16.3 mmol), 3.75 g (98 %).
1H-NMR (CDCl ₃ , δ): 1.24-1.38 (3H,
m), 1.44-1.56 (3H, m), 1.56-1.63 (3H, m), 1.63-1.84 (9H, m), 1.92-2.00 (2H, m),
2.43-2.49 (1H, m)

Reference Example 143
2- (6-Benzothiazolyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, the title compound was used by using 365 mg (1.2 mmol) of 1-[(6-benzothiazolylcarbonyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. 287 mg (83%) was obtained.
1H-NMR (CDCl ₃ , δ): 1.53-1.62 (4H,
m), 1.68-1.79 (2H, m), 1.81-1.92 (4H, m), 8.19 (1H, dd, J = 9Hz, 2Hz), 8.22 (1H, dd,
J = 9Hz, 1Hz), 8.65 (1H, dd, J = 2Hz, 1Hz), 9.15 (1H, s)

Reference Example 144
2- (2-Thienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 5.0 g (20 mmol) of 1-[(2-thienylcarbonyl) amino] cyclohexanecarboxylic acid was used, and 4.46 g ( 96%).
1H-NMR (CDCl ₃ , δ): 1.51-1.59 (1H,
m), 1.61-1.69 (1H, m), 1.71-1.88 (8H, m), 7.14 (1H, dd, J = 5Hz, 4Hz), 7.57 (1H, dd,
J = 5Hz, 1Hz), 7.70 (1H, dd J = 4Hz, 1Hz)

Reference Example 145
2- (2-Furanyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

To a solution of 10 g (42 mmol) of 1-[(2-furanylcarbonyl) amino] cyclohexanecarboxylic acid obtained in Reference Example 14 and 6.1 ml (44 mmol) of triethylamine in tetrahydrofuran (80 ml) was added 6.0 g (44 mmol) of isobutyl chloroformate. The solution was added dropwise and stirred at room temperature for 1 hour. The precipitated crystals were removed by filtration, and the filtrate was concentrated. The obtained crystals were washed with water to obtain 8.95 g (97%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.53-1.57 (1H,
m), 1.66-1.86 (9H, m), 6.58 (1H, dd, J = 4Hz, 2Hz), 7.09 (1H, dd, J = 4Hz, 1Hz),
7.65 (1H, dd, J = 2Hz, 1Hz)

Reference Example 146
2- (1,3-Benzodioxol-5-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the method according to Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 5.8 g of 1-[[(1,3-benzodioxole) -5-carbonyl] amino] cyclohexanecarboxylic acid ( 20 mmol) was used to obtain 4.9 g (90%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.51-1.57 (1H,
m), 1.63-1.75 (3H, m), 1.76-1.88 (6H, m), 6.05 (2H, s), 6.87 (1H, d, J = 8Hz),
7.46 (1H, d, J = 2Hz), 7.55 (1H, dd, J = 8Hz, 2Hz)

Reference Example 147
2- (2-Benzofuranyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, the title compound 3.4 was obtained using 3.8 g (13 mmol) of 1-[[(2-benzofuranyl) carbonyl] amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. g (96%) was obtained.
1H-NMR (CDCl ₃ , δ): 1.51-1.74 (2H,
m), 1.78-1.94 (8H, m), 7.33 (1H, ddd, J = 8Hz, 7Hz, 1Hz), 7.44 (1H, d, J = 1Hz),
7.46 (1H, ddd, J = 8Hz, 7Hz, 1Hz), 7.63 (1H, ddd, J = 8Hz, 2Hz, 1Hz), 7.70 (1H, ddd,
(J = 8Hz, 2Hz, 1Hz)

Reference Example 148
2- (2-Pyridinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, using 511 mg (2 mmol) of 1-[(2-pyridinylcarbonyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 405 mg of the title compound ( 85%).
1H-NMR (CDCl ₃ , δ): 1.54-1.77 (3H,
m), 1.78-1.92 (7H, m), 7.62 (1H, ddd, J = 7Hz, 5Hz, 2Hz), 7.87 (1H, dt, J = 7Hz, 2Hz),
8.04 (1H, dd, J = 5Hz, 2Hz), 8.82 (1H, dd, J = 5Hz, 2Hz)

Reference Example 149
2- (3-Thienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, using 253 mg (1 mmol) of 1-[(3-thienylcarbonyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 234 mg (quantitative) )
1H-NMR (CDCl ₃ , δ): 1.52-1.87 (10H,
m), 7.40 (1H, dd, J = 5Hz, 3Hz), 7.60 (1H, dd, J = 5Hz, 1Hz), 8.00 (1H, dd, J = 3Hz,
1Hz)

Reference Example 150
2- (3-Ethoxy-2-thienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[[(3-ethoxy-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid 327 mg (1 mmol) was used. This gave 307 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.46 (3H,
t, J = 7Hz), 1.49-1.84 (10H, m), 4.22 (2H, q, J = 7Hz), 6.86 (1H, d, J = 6Hz), 7.42 (1H,
d, J = 6Hz)

Reference Example 151
2- [2-[(S) -1-Phenylethyl]]-3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, 275 mg (1 mmol) of 1-[[(S) -1-oxo-2-phenylpropyl] amino] cyclohexanecarboxylic acid was used instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. Used to give 257 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.51-1.78 (13H,
m), 3.89 (1H, q, J = 7Hz), 7.26-7.35 (5H, m)

Reference Example 152
2- (2-Pyrazinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, 249 mg (1 mmol) of 1-[(2-pyrazinylcarbonyl) amino] cyclohexanecarboxylic acid was used instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, and 231 mg of the title compound ( Quantitative).
1H-NMR (CDCl ₃ , δ): 1.56-1.93 (10H,
m), 8.78 (2H, m), 9.28 (1H, t, J = 3Hz)

Reference Example 153
2- (5-Methylisoxazol-4-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

To 3 ml of thionyl chloride was added 1 g (7.87 mmol) of 5-methylisoxazole-4-carboxylic acid and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was added to a solution of 1.13 g (7.87 mmol) of 1-aminocyclohexanecarboxylic acid and 6.6 g (79 mmol) of sodium hydrogencarbonate in 30 ml of toluene and 30 ml of water. After stirring overnight at room temperature, the toluene layer was separated. The aqueous layer was neutralized with potassium hydrogen sulfate and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, methylene chloride was added, and 332 mg (1.73 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added under ice cooling. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, saturated brine, and dried over anhydrous sodium sulfate. did. The solvent was distilled off under reduced pressure to obtain 295 mg (16%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.50-1.59 (1H,
m), 1.64-1.72 (2H, m), 1.76-1.83 (7H, m), 2.75 (3H, s), 8.55 (1H, s)

Reference Example 154
2-Cyclopentyl-3-oxa-1-azaspiro [4.5] dec-1-en-4-one

To a solution of 2.16 g (15 mmol) of 1-aminocyclohexanecarboxylic acid and 4.8 g (45 mmol) of sodium carbonate in 50 ml of ethyl acetate and 50 ml of water, 1.98 g (15 mmol) of cyclopentanecarbonyl chloride was added under ice cooling. After stirring overnight at room temperature, ethyl acetate was added, and the mixture was washed with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate, and then saturated brine. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, methylene chloride was added, and 1.59 g (8.3 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added under ice cooling. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, saturated brine, and dried over anhydrous sodium sulfate. did. The solvent was distilled off under reduced pressure to obtain 1.41 g (42%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.53-1.65 (5H,
m), 1.67-1.76 (4H, m), 1.86-1.95 (8H, m), 2.80-2.89 (2H, m)

Reference Example 155
2- (5-Methyl-2-thienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, 294 mg (1.1 mmol) of 1-[[(5-methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid was used instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. This gave 273 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.53-1.62 (3H,
m), 1.71-1.84 (7H, m), 2.55 (3H, s), 6.79 (1H, d, J = 3Hz), 7.50 (1H, d, J = 3Hz)

Reference Example 156
2- (4-Methoxyphenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

The title compound was prepared by a method analogous to that of Reference Example 132, using 305 mg (1.1 mmol) of 1-[[(4-methoxyphenyl) carbonyl] amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. 288 mg (90%) was obtained.
1H-NMR (CDCl ₃ , δ): 1.51-1.60 (1H,
m), 1.61-1.73 (3H, m), 1.76-1.90 (6H, m), 3.87 (3H, s), 6.96 (2H, dd, J = 7Hz, 2Hz),
7.94 (2H, dd, J = 7Hz, 2Hz)

Reference Example 157
2- (3-Methyl-2-thienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, 1-[[(3-methyl-2-thienyl) carbonyl] amino] cyclohexanecarboxylic acid 249 mg (1.1 mmol) was used instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. This gave 249 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.50-1.60 (1H,
m), 1.65-1.78 (3H, m), 1.78-1.90 (6H, m), 2.58 (3H, s), 6.95 (1H, d, J = 5Hz),
7.42 (1H, d, J = 5Hz)

Reference Example 158
2- (3-Methyl-2-furanyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In accordance with the method according to Reference Example 132, 902 mg (3.59 mmol) of 1-[[(3-methyl-2-furanyl) carbonyl] amino] cyclohexanecarboxylic acid was used instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. This gave 233 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.48-1.61 (1H,
m), 1.62-1.89 (9H, m), 2.36 (3H, s), 6.40 (1H, d, J = 1Hz), 7.52 (1H, d, J = 1Hz)

Reference Example 159
2- (3-Pyridinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, using 523 mg (2.11 mmol) of 1-[(3-pyridinylcarbonyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 486 mg of the title compound (Quantitative) was obtained.
1H-NMR (CDCl ₃ , δ): 1.50-1.90 (10H,
m), 7.42 (1H, dd, J = 8Hz, 5Hz), 8.27 (1H, d, J = 8Hz), 8.78 (1H, d, J = 5Hz), 9.00 (1H,
s)

Reference Example 160
2- (1-Methyl-1H-pyrrol-2-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[[(1-methyl-1H-pyrrol-2-yl) carbonyl] amino] cyclohexanecarboxylic acid 187 mg (0.75 mmol) to give 172 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.44-1.85 (10H,
m), 3.40 (3H, s), 6.18 (1H, dd, J = 4Hz, 3Hz), 6.82-6.86 (2H, m)

Reference Example 161
2-[(R) -1-Phenylethyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[((R) -1-oxo-2-phenylpropyl) amino] cyclohexanecarboxylic acid 303 mg (1.1 mmol) To give 257 mg (90%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.45-1.65 (7H,
m), 1.67-1.80 (6H, m), 3.89 (1H, q, J = 7Hz), 7.26-7.34 (5H, m)

Reference Example 162
2- (1H-Indol-5-ylcarbonyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, using 329 mg (1.2 mmol) of 1-[(1H-indol-5-ylcarbonyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid 258 mg (80%) of compound were obtained.
1H-NMR (CDCl ₃ , δ): 1.56-1.89 (10H,
m), 6.65 (1H, dd, J = 3Hz, 2Hz), 7.26-7.36 (1H, m), 7.46 (1H, d, J = 9Hz), 7.88 (1H,
dd, J = 9Hz, 2Hz), 8.32 (1H, s), 8.35 (1H, br-s)

Reference Example 163
2- (1-Cyclopentenylcarbonyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, 219 mg (quantitative determination) of the title compound was carried out using 237 mg (1 mmol) of 1-[(1-cyclopentenylcarbonyl) amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. Obtained).
1H-NMR (CDCl ₃ , δ): 1.53-1.82 (10H,
m), 1.99-2.10 (2H, m), 2.55-2.69 (2H, m), 2.69-2.80 (2H, m), 6.65-6.67 (1H, m)

Reference Example 164
2- (4-Pyridinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, but using 1-[(4-pyridinylcarbonyl) amino] cyclohexanecarboxylic acid 552 mg (2.2 mmol) instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, the title compound 450 mg (88%) was obtained.
1H-NMR (CDCl ₃ , δ): 1.50-1.92 (10H,
m), 7.85 (2H, dd, J = 5Hz, 2Hz), 8.80 (2H, dd, J = 5Hz, 2Hz)

Reference Example 165
2- (1H-pyrrol-2-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the method according to Reference Example 132, 200 mg (0.85 mmol) of 1-[[(1H-pyrrol-2-yl) carbonyl] amino] cyclohexanecarboxylic acid was used instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. This gave 184 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.51-1.65 (1H,
m), 1.65-1.86 (9H, m), 6.32 (1H, dd, J = 4Hz, 2Hz), 6.87 (1H, dd, J = 4Hz, 2Hz),
7.01 (1H, dd, J = 4Hz, 2Hz), 9.37 (1H, br-s)

Reference Example 166
2- (6-Hydroxy-2-pyridinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the method according to Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 278 mg (1 mmol) of 1-[[(6-hydroxy-2-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid was used. 250 mg (97%) of the title compound were obtained.
1H-NMR (CDCl ₃ , δ): 1.52 (1H,
m), 1.78 (9H, m), 6.85-6.79 (2H, m), 7.50 (1H, dd, J = 9Hz, 7Hz)

Reference Example 167
2- (2-Hydroxy-3-pyridinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the method according to Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[[(2-hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid 278 mg (1 mmol) was used. This gave 257 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.04-2.21 (10H,
m), 6.40-6.50 (1H, m), 7.69-7.82 (1H, m), 8.28-8.35 (1H, m)

Reference Example 168
2- (6-Hydroxy-3-pyridinyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[[(6-hydroxy-3-pyridinyl) carbonyl] amino] cyclohexanecarboxylic acid 278 mg (1 mmol) was used. This gave 257 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.45-1.86 (10H,
m), 6.66 (1H, d, J = 10Hz), 8.02 (1H, d, J = 2Hz), 8.05 (1H, dd, J = 10Hz, 2Hz)

Reference Example 169
2- [2- (2-Furanyl) ethyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

To a solution of 1-[[1-oxo-3- (2-furanyl) propyl] amino] cyclohexanecarboxylic acid methyl ester 478 mg (1.7 mmol) obtained in Reference Example 64 in 2 ml of tetrahydrofuran was added 1.7 ml of 2N-NaOH aqueous solution. Heated to reflux for 3 hours. Ether was added to the reaction solution and washed. The separated aqueous layer was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Subsequently, 10 ml of the residual methylene chloride and 377 mg (1.82 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, ethyl acetate was added, washed with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 198 mg (47%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.43-1.60 (4H,
m), 1.60-1.80 (6H, m), 2.84 (2H, t, J = 7Hz), 3.05 (2H, t, J = 7Hz), 6.06 (1H, dd,
J = 2Hz, 1Hz), 6.27 (1H, dd, J = 2Hz, 1Hz), 7.31 (1H, dd, J = 2Hz, 1Hz)

Reference Example 170
2- [1-[(2-propoxy) carbonyl] piperidin-4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[[[1- (2-propoxycarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid 940 mg (2.76 mmol) was used to give 818 mg (92%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.24 (6H,
d, J = 6Hz), 1.44-1.79 (12H, m), 1.90-1.98 (2H, m), 2.62-2.69 (1H, m), 2.89-2.99 (2H,
m), 4.03-4.19 (2H, m), 4.88-4.97 (1H, m)

Reference Example 171
2- [1- (Ethoxycarbonyl) piperidin-4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[[[1- (ethoxycarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid 935 mg (2.86 mmol) to give 730 mg (83%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.26 (3H,
t, J = 7Hz), 1.45-1.80 (12H, m), 1.92-1.99 (2H, m), 2.62-2.70 (1H, m), 2.90-3.03 (2H,
m), 4.03-4.20 (4H, m)

Reference Example 172
2- [1- (2-Furanylcarbonyl) piperidin-4-yl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

1-[[[1- (2-Furanylcarbonyl) piperidin-4-yl] carbonyl] amino] cyclohexanecarboxylic acid instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid by the method according to Reference Example 132 196 mg (0.56 mmol) was used to give 185 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.49-1.68 (5H,
m), 1.68-1.80 (5H, m), 1.80-1.92 (2H, m), 2.03-2.10 (2H, m), 2.75-2.83 (1H, m),
3.05-3.31 (2H, m), 4.28-4.40 (2H, m), 6.48 (1H, dd, J = 3Hz, 1Hz), 7.00 (1H, dd,
J = 3Hz, 1Hz), 7.48 (1H, dd, J = 3Hz, 1Hz)

Reference Example 173
2-[[(2-Furanylcarbonyl) amino] methyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the method according to Reference Example 132, 249 mg (1 mmol) of 1-[[[(2-furanylcarbonyl) amino] acetyl] amino] cyclohexanecarboxylic acid was used instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid. This gave 276 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.50-1.80 (10H,
m), 4.45 (2H, d, J = 6Hz), 6.53 (1H, dd, J = 3Hz, 1Hz), 6.90 (1H, br-s), 7.18 (1H, ddd,
J = 3Hz, 2Hz, 1Hz), 7.50 (1H, dd, J = 2Hz, 1Hz)

Reference Example 174
2-[(Benzoylamino) methyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 132, instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid, 1-[[(benzoylamino) acetyl] amino] cyclohexanecarboxylic acid 724 mg (2.26 mmol) was used, and 631 mg of the title compound ( 97%).
1H-NMR (CDCl ₃ , δ): 1.48-1.58 (1H,
m), 1.63-1.80 (9H, m), 4.49 (2H, d, J = 5Hz), 6.76 (1H, br-s), 7.48 (2H, m), 7.55 (1H,
m), 7.83 (2H, m)

Reference Example 175
2- (4-Fluorophenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

A suspension of 13.3 g (50 mmol) of 1-[(4-fluorobenzoyl) amino] cyclohexanecarboxylic acid in 30 ml of acetic anhydride was stirred at 100 ° C. for 30 minutes, and then the reaction solution was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 8.5 g (69%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.49-1.60 (1H,
m), 1.63-1.90 (9H, m), 7.13-7.20 (2H, m), 8.00-8.05 (2H, m)

Reference Example 176
2- [4- (4-Propylpiperazin-1-yl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

1-[[[4- (4-Propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid 1.43 instead of 1-[(phenylacetyl) amino] cyclohexanecarboxylic acid by a method according to Reference Example 132 Using g (3.86 mmol), 1.33 g (98%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 0.94 (3H,
t, J = 8Hz), 1.50-1.61 (3H, m), 1.61-1.69 (1H, m), 1.69-1.76 (2H, m), 1.79-1.84 (6H,
m), 2.35 (1H, t, J = 6Hz), 2.36 (1H, t, J = 6Hz), 2.59 (4H, t, J = 5Hz), 3.35 (4H, t,
J = 5Hz), 6.91 (2H, dd, J = 2Hz, 7Hz), 7.86 (2H, dd, J = 2Hz, 7Hz)

Reference Example 177
2- [4- (4-Propylpiperazin-1-yl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one hydrochloride

After stirring a suspension of 1-[[[4- (4-propylpiperazin-1-yl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid hydrochloride 631 mg (1.54 mmol) in acetic anhydride at 100 ° C. for 1 hour, The reaction solution was concentrated under reduced pressure. Toluene was added to the resulting residue and distilled off under reduced pressure three times, and acetic anhydride was removed azeotropically to obtain 500 mg (83%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.05 (3H,
t, J = 8Hz), 1.50-1.87 (10H, m), 1.95-2.06 (2H, m), 2.86-3.01, (4H, m),
3.59-3.68 (2H, m), 3.79-3.90 (4H, m), 6.91 (2H, dd, 2Hz, 7Hz), 7.91 (2H, dd, J = 2Hz,
(7Hz)

Reference Example 178
N-[[1-[[(Phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol

A solution of 555 mg (2 mmol) of 1-[[(phenylmethoxy) carbonyl] amino] cyclohexylsancarboxylic acid, 322 mg (2.1 mmol) of 1-hydroxybenzotriazole and 206 mg (2 mmol) of L-valinol in 20 ml of methylene chloride under ice cooling. After adding 422 mg (2.2 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 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. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 662 mg (91%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.87 (3H,
d, J = 7Hz), 0.92 (3H, d, J = 7Hz), 1.28-1.46 (3H, m), 1.52-1.70 (3H, m), 1.73-1.82 (1H,
m), 1.85-2.03 (4H, m), 2.76 (1H, br-s), 3.42-4.47 (1H, m), 3.65-3.74 (2H, m),
5.02-5.16 (3H, m), 6.36 (1H, d, J = 8Hz), 7.30-7.40 (5H, m)

Reference Example 179
N-[[1-[[(Phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-norleucinol

By a method according to Reference Example 178, 350 mg (75%) of the title compound was obtained using 234 mg (2 mmol) of L-norleucinol instead of L-valinol.
1H-NMR (CDCl ₃ , δ): 0.88 (3H,
t, J = 7Hz), 1.23-1.52 (9H, m), 1.58-1.70 (3H, m), 1.83-2.04 (4H, m), 2.83 (1H,
br-s), 3.34-3.40 (1H, m), 3.70 (1H, br-s), 3.89 (1H, br-s), 5.02-5.13 (3H, m),
6.26 (1H, d, J = 8Hz), 7.31-7.40 (5H, m)

Reference Example 180
N-[[1-[(2-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valinol

To a solution of 3.71 g (16.9 mmol) of 2- (2-furanyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one in 100 ml of toluene, 8.81 ml of N, N-diisopropylethylamine ( 50.6 mmol) and 2.09 g (20.2 mmol) of L-valinol in 10 mL of methylene chloride were added and heated to reflux for 14 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. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and stirred overnight. The obtained crystals were collected by filtration to obtain 4.06 g (74.7%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.93 (3H,
d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 1.32-1.56 (3H, m), 1.58-1.76 (3H, m), 1.80-1.90 (1H,
m), 1.96-2.08 (2H, m), 2.14-2.24 (2H, m), 3.00-3.06 (1H, m), 3.52-3.58 (1H, m),
3.68-3.78 (2H, m), 6.49 (1H, s), 6.53 (1H, dd, J = 4Hz, 2Hz), 6.75-6.77 (1H, m),
7.14 (1H, dd, J = 4Hz, 1Hz), 7.49 (1H, dd, J = 2Hz, 1Hz)

Reference Example 181
N-[[1-[(2-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valinol

Under an argon atmosphere, 2 ml of tetrahydrofuran in a solution of 200 mg (0.59 mmol) of N-[[1-[(2-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valine and 60 mg (0.59 mmol) of triethylamine was added to 72 mg of isopropyl chlorocarbonate. (0.59 mmol) was added under ice cooling. After stirring at 0 ° C. for 2 hours, the reaction solution was filtered, poured into a solution of sodium borohydride 45 mg (1.2 mmol) in 1 ml of water, and stirred overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained crystals were washed with ether to obtain 30 mg (16%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.93 (3H,
d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 1.32-1.56 (3H, m), 1.58-1.76 (3H, m),
1.80-1.90 (1H, m), 1.96-2.08 (2H, m), 2.14-2.24 (2H, m), 3.00-3.06 (1H, m),
3.52-3.58 (1H, m), 3.68-3.78 (2H, m), 6.49 (1H, s), 6.53 (1H, dd, J = 4Hz, 2Hz),
6.75-6.77 (1H, m), 7.14 (1H, dd, J = 4Hz, 1Hz), 7.49 (1H, dd, J = 2Hz, 1Hz)

Reference Example 182
N-[[1-[(2-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valinol

Under an argon atmosphere, 31 mg (0.82 mmol) of lithium aluminum hydride was added to 1 ml of diethyl ether in the flask. Under ice zero, 1 ml of a tetrahydrofuran solution of 0.3 g (0.82 mmol) of the above compound was added to the flask and stirred for 1.5 hours. Ice water was added to the reaction solution. Ethyl acetate was added, and the mixture was washed successively with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crystals were washed with ether to obtain 155 mg (60%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.93 (3H,
d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 1.32-1.56 (3H, m), 1.58-1.76 (3H, m),
1.80-1.90 (1H, m), 1.96-2.08 (2H, m), 2.14-2.24 (2H, m), 3.00-3.06 (1H, m),
3.52-3.58 (1H, m), 3.68-3.78 (2H, m), 6.49 (1H, s), 6.53 (1H, dd, J = 4Hz, 2Hz),
6.75-6.77 (1H, m), 7.14 (1H, dd, J = 4Hz, 1Hz), 7.49 (1H, dd, J = 2Hz, 1Hz)

Reference Example 183
N-[[1-[(4-morpholinylcarbonyl) amino] cyclohexyl] carbonyl] -L-norleucinol

In the same manner as in Reference Example 179, 513 mg (2 mmol) of 1-[(4-morpholinylcarbonyl) amino] cyclohexanecarboxylic acid was used instead of 1-[[(phenylmethoxy) carbonyl] amino] cyclohexylsancarboxylic acid. This gave 215 mg (30%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.89 (3H,
t, J = 7Hz), 1.26-1.56 (9H, m), 1.60-1.73 (3H, m), 1.85-2.05 (4H, m), 3.33-3.43 (5H,
m), 3.54 (1H, t, J = 7Hz), 3.66-3.73 (4H, m), 3.76-3.82 (1H, m), 3.83-3.93 (1H, m),
4.64 (1H, br-s), 6.35 (1H, d, J = 8Hz)

Reference Example 184
N- [N-[(phenylmethoxy) carbonyl] -L-leucyl] -L-valinol

In the same manner as in Reference Example 178, N-[(phenylmethoxy) carbonyl] -L-leucine was used instead of 1-[[(phenylmethoxy) carbonyl] amino] cyclohexylanecarboxylic acid, and 659 mg (94% )
1H-NMR (CDCl ₃ , δ): 0.83-0.99 (12H,
m), 1.46-1.74 (3H, m), 1.78-1.90 (1H, m), 2.42 (1H, br-s), 3.57-3.72 (3H, m),
4.10-4.17 (1H, m), 5.04-5.17 (3H, m), 6.22 (1H, d, J = 7Hz), 7.27-7.39 (5H, m)

Reference Example 185
N- [N-[(phenylmethoxy) carbonyl] -L-leucyl] -L-norleucinol

In the same manner as in Reference Example 178, N-[(phenylmethoxy) carbonyl] -L-leucine was used instead of L-valinol instead of 1-[[(phenylmethoxy) carbonyl] amino] cyclohexylanecarboxylic acid. Using norleucinol, 421 mg (58%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 0.88 (3H,
t, J = 7Hz), 0.95 (6H, d, J = 7Hz), 1.23-2.72 (9H, m), 2.44 (1H, br-s), 3.47-3.71 (2H,
m), 3.89 (1H, br-s), 4.10-4.17 (1H, m), 5.08-5.16 (3H, m), 6.10 (1H, d, J = 6Hz),
7.31-7.39 (5H, m)

Reference Example 186
N- [N- (4-morpholinylcarbonyl) -L-leucyl] -L-norleucinol

To a solution of N- [N-[(phenylmethoxy) carbonyl] -L-leucyl] -L-norleucinol 700 mg (2 mmol) obtained in Reference Example 185 in 10 ml of methanol, 70 mg of 10% palladium carbon was added, and room temperature under a hydrogen atmosphere. Stir overnight. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. To the residue were added 20 ml of methylene chloride and 404 mg (4 mmol) of triethylamine. To this mixture was added a solution of 299 mg (2 mmol) of 4-morpholinecarbonyl chloride in 3 ml of methylene chloride under ice cooling. The reaction solution was returned to room temperature and stirred overnight. The reaction mixture was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed by adding ether to give 488 mg (71%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.89 (3H,
t, J = 7Hz), 0.94 (3H, d, J = 7Hz), 0.96 (3H, d, J = 7Hz), 1.23-1.37 (4H, m),
1.43-1.72 (5H, m), 2.67 (1H, br-s), 3.31-3.44 (4H, m), 3.52-3.60 (1H, m), 3.65-3.73 (5H,
m), 3.82-3.89 (1H, m), 4.24-4.32 (1H, m), 4.82 (1H, d, J = 8Hz), 6.31 (1H, d, J = 8Hz)

Reference Example 187
N- [N- (2-furanylcarbonyl) -L-leucyl] -L-valinol

To a solution of 350 mg (1 mmol) of N- [N-[(phenylmethoxy) carbonyl] -L-leucyl] -L-valinol obtained in Reference Example 184 in 10 ml of methanol was added 30 mg of 10% palladium carbon, and room temperature under a hydrogen atmosphere. Stir overnight. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. To the residue, 10 ml of ethyl acetate, 10 ml of water and 159 mg (1.5 mmol) of sodium carbonate were added.
To this mixture was added a solution of 2-furancarbonyl chloride 131 mg (1 mmol) in ethyl acetate 3 ml under ice cooling. The reaction solution was returned to room temperature and stirred overnight. The aqueous layer of the reaction solution was separated and extracted with ethyl acetate. The organic layers were combined, washed with 10% potassium hydrogen sulfate and then saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue, and the crystals were washed to obtain 268 mg (86%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.91 (3H,
t, J = 7Hz), 0.93 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 0.99 (3H, t, J = 7Hz),
1.65-1.94 (4H, m), 2.47 (1H, t, J = 5Hz), 3.63-3.74 (3H, m), 4.54-4.62 (1H, m),
6.42 (1H, d, J = 7Hz), 6.52 (1H, dd, J = 4Hz, 2Hz), 6.68 (1H, d, J = 8Hz), 7.14 (1H, dd,
J = 4Hz, 1Hz), 7.47 (1H, dd, J = 2Hz, 1Hz)

Example 1
N-[[1-[(2-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valine ethyl ester

Flask containing 5 g (27 mmol) of L-valine ethyl ester hydrochloride and 5 g (22.8 mmol) of 2- (2-furanyl) -3-oxa-1-azaspiro [4,5] dec-1-en-4-one 30 ml of dimethylformamide was added. Next, 3.53 g (27.4 mmol) of diisopropylethylamine was added and stirred for 3 days. After evaporating the solvent under reduced pressure, ethyl acetate was added, washed successively with 10% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain 8.3 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.89 (3H,
d, J = 7Hz), 0.94 (3H, d, J = 7Hz), 1.25 (3H, t, J = 7Hz), 1.35-1.70 (6H, m),
1.98-2.01 (2H, m), 2.19-2.23 (2H, m), 2.31-2.39 (1H, m), 4.11-4.19 (2H, m),
4.49 (1H, dd, J = 9Hz, 5Hz), 6.34 (1H, s), 6.53 (1H, dd, J = 3Hz, 1Hz), 7.15 (1H, dd,
J = 3Hz, 1Hz), 7.48 (1H, dd, J = 2Hz, 1Hz), 7.58 (1H, d, J = 9Hz)

Reference Example 188
N-[[1-[(2-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valine

N-methylmorpholine was added to 1.0 g (9.1 mmol) of L-valine and 2.0 g (9.1 mmol) of 2- (2-furanyl) -3-oxa-1-azaspiro [4,5] dec-1-en-4-one. 10ml was added and it stirred under heating-refluxing overnight. Under reduced pressure, the reaction solution was distilled off, ethyl acetate was added, washed with 10% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 384 mg (12.5%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.93 (3H,
d, J = 7Hz), 0.97 (3H, d, J = 7Hz), 1.33-1.48 (3H, m), 1.64-1.73 (3H, m), 1.98 (2H, dt,
J = 14Hz, 4Hz), 2.22-2.30 (3H, m), 4.46 (1H, m), 6.43 (1H, s), 6.53 (1H, dd, J = 3Hz,
2Hz), 7.17 (1H, dd, J = 3Hz, 1Hz), 7.48 (1H, dd, J = 2Hz, 1Hz), 7.55 (1H, d, J = 8Hz)

Reference Example 189
N-[[1-[[(Phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinal

Under argon gas atmosphere, 1.22 g (9.44 mmol) of N, N-diisopropylethylamine was added dropwise to 10 ml of anhydrous dimethylsulfoxide and 5 ml of anhydrous methylene chloride solution of 1.50 g (9.44 mmol) of sulfur trioxide pyridine complex under ice-cooling, and 15 Stir for minutes. Further, under ice cooling, a solution of 570 mg (1.57 mmol) of N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol in 3 ml of anhydrous dimethyl sulfoxide was added to the reaction mixture, and Stir for 2 hours. The reaction solution was poured into ice-water and extracted twice with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 20 ml of diisopropyl ether was added to the residue and stirred at room temperature for 18 hours. The obtained crystals were collected by filtration to obtain 435 mg (77%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.88 (3H,
d, J = 7Hz), 0.97 (3H, d, J = 7Hz), 1.22-1.44 (3H, m), 1.59-1.70 (3H, m),
1.85-2.15 (4H, m), 2.22-2.34 (1H, m), 4.48 (1H, s), 4.96 (1H, s), 5.11 (2H, s),
7.10-7.41 (6H, m), 9.59 (1H, s)

Reference Example 190
N-[[1-[[(Phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-norleucinal

In the same manner as in Reference Example 189, instead of N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol, N-[[1-[[(phenylmethoxy) carbonyl] amino [Cyclohexyl] carbonyl] -L-norleucinol 465 mg (1.24 mmol) was used to give 350 mg (75%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.88 (3H,
d, J = 7Hz), 1.19-1.43 (7H, m), 1.51-1.70 (4H, m), 1.82-2.13 (5H, m), 4.42 (1H,
br-s), 4.95 (1H, s), 5.10 (2H, s), 7.10 (1H, br-s), 7.29-7.42 (5H, m), 9.53 (1H, s)

Reference Example 191
N-[[1-[(2-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valinal

Instead of N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol, N-[[1-[(2-furanylcarbonyl) amino] was prepared according to the method of Reference Example 189. [Cyclohexyl] carbonyl] -L-valinol (3.50 g, 10.9 mmol) was used to give 3.14 g (90.3%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.94 (3H,
d, J = 7Hz), 1.01 (3H, d, J = 7Hz), 1.30-1.40 (1H, m), 1.41-1.54 (2H, m),
1.62-1.76 (3H, m), 1.95-2.04 (2H, m), 2.20-2.26 (1H, m), 2.28-2.36 (2H, m),
4.44 (1H, dd, J = 8Hz, 5Hz,), 6.38 (1H, br-s), 6.54 (1H, dd, J = 4Hz, 2Hz), 7.15 (1H,
dd, J = 4Hz, 1Hz), 7.49 (1H, dd, J = 2Hz, 1Hz), 7.68 (1H, d, J = 8Hz), 9.60 (1H, s)

Reference Example 192
N-[[1-[(4-morpholinylcarbonyl) amino] cyclohexyl] carbonyl] -L-norleucinal

In the same manner as in Reference Example 189, instead of N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol, N-[[1-[(4-morpholinylcarbonyl) Amino] cyclohexyl] carbonyl] -L-norleucinol 205 mg (0.58 mmol) was used to give 125 mg (61%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.89 (3H,
t, J = 7Hz), 1.23-1.42 (7H, m), 1.52-1.71 (4H, m), 1.83-1.98 (3H, m), 2.05-2.18 (2H,
m), 3.34-3.42 (4H, m), 3.65-3.76 (4H, m), 4.37 (1H, dt, J = 7Hz, 7Hz), 4.48 (1H, s),
7.81 (1H, d, J = 7Hz), 9.55 (1H, s)

Reference Example 193
N- [N-[(phenylmethoxy) carbonyl] -L-leucyl] -L-valinal

In the same manner as in Reference Example 189, instead of N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol, N- [N-[(phenylmethoxy) carbonyl] -L- Leucyl] -L-valinol 280 mg (0.8 mmol) was used to give 278 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.83-1.01 (12H,
m), 1.48-1.59 (1H, m), 1.62-1.74 (2H, m), 2.28-2.37 (1H, m), 4.19-4.28 (1H, m),
4.51-4.56 (1H, m), 5.05-5.17 (3H, m), 6.51 (1H, d, J = 7Hz), 7.27-7.39 (5H, m),
9.64 (1H, s)

Reference Example 194
N- [N-[(phenylmethoxy) carbonyl] -L-leucyl] -L-norleucine

In the same manner as in Reference Example 189, instead of N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol, N- [N-[(phenylmethoxy) carbonyl] -L- Leucyl] -L-norleucinol 253 mg (0.7 mmol) was used to give 195 mg (78%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.89 (3H,
t, J = 7Hz), 0.95 (6H, d, J = 7Hz), 1.22-1.39 (4H, m), 1.47-1.72 (4H, m),
1.83-1.97 (1H, m), 4.19-4.26 (1H, m), 4.45-4.53 (1H, m), 5.08-5.17 (3H, m),
6.46 (1H, br-s), 7.29-7.39 (5H, m), 9.57 (1H, s)

Reference Example 195
N- [N- (4-morpholinylcarbonyl) -L-leucyl] -L-norleucine

In the same manner as in Reference Example 189, instead of N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol, N- [N- (4-morpholinylcarbonyl) -L -Leucyl] -L-norleucinol 473 mg (1.4 mmol) was used to obtain 315 mg (67%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.90 (3H,
t, J = 7Hz), 0.96 (3H, d, J = 6Hz), 0.97 (3H, d, J = 6Hz), 1.23-1.39 (4H, m),
1.50-1.76 (4H, m), 1.85-1.96 (1H, m), 3.32-3.43 (4H, m), 3.63-3.72 (4H, m),
4.37-4.46 (2H, m), 4.86 (1H, d, J = 8Hz), 6.69 (1H, d, J = 7Hz), 9.56 (1H, s)

Reference Example 196
N- [N- (2-furanylcarbonyl) -L-leucyl] -L-valinal

In the same manner as in Reference Example 189, instead of N-[[1-[[(phenylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol, N- [N- (2-furanylcarbonyl) -L- Leucyl] -L-valinol 256 mg (0.8 mmol) was used to give 175 mg (72%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.90-1.02 (12H,
m), 1.64-1.82 (3H, m), 2.29-2.36 (1H, m), 4.52 (1H, dd, J = 8Hz, 5Hz), 4.67 (1H, td,
J = 8Hz, 6Hz), 6.51 (1H, dd, J = 4Hz, 2Hz), 6.67-6.73 (2H, m), 7.14 (1H, dd, J = 4Hz,
1Hz), 7.46 (1H, dd, J = 2Hz, 1Hz), 9.65 (1H, s)

Reference Example 197
1-[(2-Benzothienylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

Under ice-cooling, a solution of 2-benzothiophenecarboxylic acid 5 g (28 mmol), 1-aminocyclohexanecarboxylic acid phenylmethyl ester 6.5 g (28 mmol) and 1-hydroxybenzotriazole 4.5 g (29 mmol) in methylene chloride solution was diluted with 1-ethyl hydrochloride. 5.9 g (31 mmol) of -3- (3-dimethylaminopropyl) carbodiimide was added. After stirring at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was stirred overnight. The crystals were collected by filtration and dried by heating under reduced pressure to obtain 10 g (91%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.25-1.78 (6H, m),
1.93-2.05 (2H, m), 2.12-2.25 (2H, m), 5.18 (2H, s), 6.24 (1H, s), 7.20-7.38 (5H, m),
7.38-7.51 (2H, m), 7.77 (1H, s), 7.80-7.91 (2H, m)

Reference Example 198
1-[(2-Benzothienylcarbonyl) amino] cyclohexanecarboxylic acid

To a 20 ml tetrahydrofuran solution of 10 g (24 mmol) of 1-[(2-benzothienylcarbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester was added 42 ml of 2N aqueous sodium hydroxide solution, and the mixture was heated to reflux for 3 days. After ether was added to the reaction solution for washing, the aqueous layer was neutralized with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain 6.1 g (80%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.H 31-1.85 (6H, m),
1.91-2.08 (2H, m), 2.21-2.35 (2H, m), 6.22 (1H, s), 7.38-7.53 (2H, m), 7.80-7.93 (3,
m)

Reference Example 199
2- (2-Benzothienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

To a solution of 1-[(2-benzothienylcarbonyl) amino] cyclohexanecarboxylic acid 5 g (16 mmol) in 50 ml of methylene chloride was added 4.1 g (21 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed successively with water, 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.5 g (75%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.45-1.98 (10H, m),
7.38-7.51 (2H, m), 7.80-7.91 (2H, m), 7.93 (1H, s)

Reference Example 200
1-[[[4- (Chloromethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

Under ice cooling, 4- (chloromethyl) benzoic acid 8.8 g (52 mmol), 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride 10 g (52 mmol), triethylamine 15 g (152 mmol), and 1-hydroxybenzotriazole 8.63 g (56 mmol) To a methylene chloride solution, 9.96 g (52 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added. After stirring at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 8.5 g (53%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.25-1.73 (6H, m),
1.83-2.00 (2H, m), 2.08-2.21 (2H, m), 3.71 (3H, s), 5.56 (2H, s), 6.30 (1H, s),
7.44 (2H, dd, J = 8Hz, 2Hz), 7.75 (2H, dd, J = 8Hz, 2Hz)

Reference Example 201
1-[[[4- (Hydroxymethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

Under ice cooling, hydrochloric acid 1 was added to a solution of 5- (hydroxymethyl) benzoic acid 5 g (33 mmol), 1-aminocyclohexanecarboxylic acid phenylmethyl ester 7.7 g (33 mmol) and 1-hydroxybenzotriazole 5.29 g (35 mmol) in methylene chloride. -6.94 g (36 mmol) of ethyl-3- (3-dimethylaminopropyl) carbodiimide was added. After stirring at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 6.83 g (56%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.23-1.79 (6H, m),
1.82-2.23 (4H, m), 4.73 (2H, m), 5.16 (2H, s), 6.25 (1H, s), 7.20-7.32 (5H, m),
7.32-7.43 (2H, m), 7.62-7.79 (2H, m)

Reference Example 202
1-[[[4-[(Dimethylamino) methyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

To 4.5 g (14.5 mmol) of 1-[[[4- (chloromethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester was added 30 ml of 40% aqueous dimethylamine solution, and the mixture was heated to reflux for 3 hours. The reaction solution was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue and stirred overnight, and the precipitated solid was collected by filtration to obtain 2.3 g (50%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.30-2.19 (10H, m), 2.24 (6H,
s), 3.46 (2H, s), 3.76 (3H, s), 6.22 (1H, s), 7.38 (2H, d, J = 9Hz), 7.73 (2H, d,
(J = 9Hz)

Reference Example 203
1-[[[4-[(Dimethylamino) methyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

Under ice-cooling, 1-[[[4- (hydroxymethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 3 g (8 mmol) and triethylamine 2.46 g (24 mmol) in methylene chloride solution 1 g (9 mmol) of methanesulfonyl chloride Was dripped. After stirring for 1 hour at room temperature, 20 ml of 2N dimethylamine tetrahydrofuran solution was added and stirred overnight. The reaction mixture was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 700 mg (22%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.30-2.01 (9H, m),
2.12-2.28 (1H, m), 2.24 (6H, s), 3.46 (2H, s), 5.17 (2H, s), 6.25 (1H, s),
7.21-7.32 (5H, m), 7.37 (2H, dd, J = 9Hz, 2Hz), 7.10 (2H, dd, J = 9Hz, 2Hz)

Reference Example 204
2- [4-[(Dimethylamino) methyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

1-[[[4-[(Dimethylamino) methyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester 1.85 g (5.8 mmol) in 29 ml tetrahydrofuran solution was added 2N sodium hydroxide aqueous solution 29 ml and heated to reflux overnight. . After neutralizing with concentrated hydrochloric acid, the reaction solution was distilled off under reduced pressure. To the residue, 30 ml of methylene chloride, 1.76 g (17 mmol) of triethylamine and 1.67 g (8.7 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added and stirred for 1 hour. The reaction solution was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.33 g (80%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.50-1.88 (10H, m), 2.25 (6H,
s), 3.48 (2H, s), 7.43 (2H, dd, J = 9Hz, 2Hz), 7.96 (2H, dd, J = 9Hz, 2Hz)

Reference Example 205
2- [4-[(Dimethylamino) methyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

1-[[[4-[(Dimethylamino) methyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid Phenylmethyl ester 100 mg (0.25 mmol) in 1 ml tetrahydrofuran solution was added 2N aqueous sodium hydroxide solution 0.7 ml and heated to reflux overnight. did. After neutralizing with concentrated hydrochloric acid, the reaction solution was distilled off under reduced pressure. To the residue, 3 ml of methylene chloride, 126 mg (1.25 mmol) of triethylamine and 96 mg (0.5 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added and stirred for 1 hour. The reaction solution was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 52 mg (68%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.50-1.88 (10H, m), 2.25 (6H,
s), 3.48 (2H, s), 7.43 (2H, dd, J = 9Hz, 2Hz), 7.96 (2H, dd, J = 9Hz, 2Hz)

Reference Example 206
1-[[[4- (4-morpholinylmethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

Under ice-cooling, 1-[[[4- (hydroxymethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester 1.83 g (5 mmol) and triethylamine 1.52 g (15 mmol) in methylene chloride solution were dissolved in 628 mg (5.5 mg) of methanesulfonyl chloride. mmol) was added dropwise. After stirring at room temperature for 1 hour, 5 ml of morpholine was added and stirred overnight. The reaction mixture was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1 g (57%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.25-1.79 (6H, m),
1.89-2.03 (2H, m), 2.15-2.29 (2H, m), 2.43 (4H, t, J = 5Hz), 3.53 (2H, s), 3.70 (4H,
t, J = 5Hz), 5.17 (2H, s), 6.21 (1H, s), 7.21-7.38 (5H, m), 7.39 (2H, d, J = 8Hz),
7.71 (2H, d, J = 8Hz)

Reference Example 207
1-[[[4- (4-morpholinylmethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

30 ml of morpholine was added to 4 g (13 mmol) of 1-[[[4- (chloromethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester, and the mixture was heated to reflux for 1 hour. The reaction solution was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration to obtain 3.8 g (83%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.28-1.80 (6H, m),
1.80-1.99 (2H, m), 2.11-2.21 (2H, m), 2.38-2.49 (4H, m), 3.54 (2H, s),
3.63-3.74 (4H, m), 3.73 (3H, s), 6.22 (1H, s), 7.41 (2H, d, J = 8Hz), 7.73 (2H, d,
(J = 8Hz)

Reference Example 208
2- [4- (4-morpholinylmethyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

1-[[[4- (4-Morpholinylmethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester 2.07 g (5.7 mmol) in 18 ml tetrahydrofuran solution was added 18 ml of 2N sodium hydroxide aqueous solution and heated under reflux overnight. did. After neutralizing with concentrated hydrochloric acid, the reaction solution was distilled off under reduced pressure. To the residue, 30 ml of methylene chloride, 1.74 g (17 mmol) of triethylamine and 1.65 g (8.6 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added and stirred for 1 hour. The reaction solution was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.27 g (60%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.42-1.80 (10H, m), 2.44 (4H,
t, J = 5Hz), 3.56 (2H, s), 3.71 (4H, t, J = 5Hz), 7.45 (2H, d, J = 8Hz), 7.96 (2H, d,
(J = 8Hz)

Reference Example 209
2- [4- (4-morpholinylmethyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

1-[[[4- (4-Morpholinylmethyl) phenyl] carbonyl] amino] cyclohexanecarboxylic acid Phenylmethyl ester 300 mg (0.69 mmol) in 2 ml tetrahydrofuran solution was added 2N 2N aqueous sodium hydroxide solution and heated to reflux overnight. did. After neutralizing with concentrated hydrochloric acid, the reaction solution was distilled off under reduced pressure. To the residue, 3 ml of methylene chloride, 698 mg (6.9 mmol) of triethylamine and 264 mg (1.38 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added and stirred for 1 hour. The reaction solution was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 191 mg (80%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.42-1.80 (10H, m), 2.44 (4H,
t, J = 5Hz), 3.56 (2H, s), 3.71 (4H, t, J = 5Hz), 7.45 (2H, d, J = 8Hz), 7.96 (2H, d,
(J = 8Hz)

Reference Example 210
1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester

Under ice-cooling, 4- [2- (4-methyl-1-piperazinyl) -4-thiazolyl] benzoic acid benzoate 8.84 g (23.0 mmol), 1-hydroxybenzotriazole 4.19 g (27.6 mmol) and 1-amino Cyclohexanecarboxylic acid phenylmethyl ester (6.44 g, 27.6 mmol) and N, N-diisopropylethylamine (11.9 g, 92 mmol) in dimethylformamide (120 m) were added to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.29 g, 374 mmol). ) Was added. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, the mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, ether was added to the residue, and the crystals were washed to obtain 11.8 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.30-1.42 (1H,
m), 1.45-1.61 (2H, m), 1.62-1.75 (3H, m), 1.91-2.01 (2H, m), 2.18-2.24 (2H, m),
2.37 (3H, s), 2.56 (4H, t, J = 5Hz), 3.59 (4H, t, J = 5Hz), 5.18 (2H, s), 6.23 (1H,
br-s), 6.88 (1H, s), 7.25-7.34 (5H, m), 7.76 (2H, dd, J = 8Hz, 2Hz), 7.90 (2H, dd,
(J = 8Hz, 2Hz)

Reference Example 211
1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid

1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid Phenylmethyl ester 11.8 g (23.0 mmol) in tetrahydrofuran 120 ml solution with 2N hydroxylation A sodium aqueous solution (35 ml) was added, and the mixture was heated to reflux for 15 hours. Ether was added to the reaction solution to separate the aqueous layer. The separated aqueous layer was neutralized with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration to obtain 6.60 g (67%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.28-1.38 (1H,
m), 1.40-1.51 (2H, m), 1.58-1.73 (3H, m), 1.85-2.00 (2H, m), 2.10-2.21 (2H, m),
2.47 (3H, s), 2.66-2.75 (4H, m), 3.54-4.04 (4H, m), 6.38 (1H, br-s), 6.83 (1H, s),
7.69 (2H, d, J = 8Hz), 7.76 (2H, d, J = 8Hz)

Reference Example 212
2- [4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

1-[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid 910 mg (2.1 mmol) in dimethylformamide 20 ml solution with 1-ethyl-3 HCl -450 mg (2.5 mmol) of-(3-dimethylaminopropyl) carbodiimide was added. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, the mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 577 mg (67%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.51-1.62 (1H,
m), 1.62-1.71 (1H, m), 1.71-1.78 (2H, m), 1.78-1.90 (6H, m), 2.37 (3H, s), 2.56 (4H,
t, J = 5Hz), 3.60 (4H, t, J = 5Hz), 6.92 (1H, s), 7.94 (2H, d, J = 8Hz), 8.00 (2H, d,
(J = 8Hz)

Reference Example 213
4-[[2- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] benzoic acid odorate

A solution of 2.47 g (16.9 mmol) of 4- (4-morpholinyl) piperidine-1-thiocarboxamide and 4.08 g (16.9 mmol) of 4- (bromoacetyl) benzoic acid in 150 ml of ethanol was heated to reflux for 2 hours and then allowed to cool to room temperature. did. After 150 ml of ether was added to the reaction solution and stirred overnight at 4 ° C., the precipitated crystals were collected by filtration to obtain 4.64 g (95%) of the title compound.
1H-NMR (DMSO-d6, δ): 1.68-1.80 (2H,
m), 2.17-2.25 (2H, m), 3.07-3.20 (4H, m), 3.21-3.63 (5H, m), 3.64-3.78 (1H, m),
3.98-4.10 (1H, m), 4.10-4.18 (2H, m), 7.51 (1H, s), 7.95-7.99 (4H, m)

Reference Example 214
1-[[[4- [2- [4- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester

4- [2- [4- (4-morpholinyl) -1 instead of 4- [2- (4-methyl-1-piperazinyl) -4-thiazolyl] benzoic acid odorate by a method according to Reference Example 210 Using -piperazinyl] -4-thiazolyl] benzoic acid bromide 4.50 g (9.90 mmol) and 1.57 g (9.90 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester This gave 5.08 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.32-1.42 (1H,
m), 1.45-1.74 (7H, m), 1.93-2.01 (4H, m), 2.14-2.21 (2H, m), 2.41-2.50 (1H, m),
2.58 (4H, t, J = 5Hz), 3.07 (2H, dd, J = 13Hz, 13Hz), 3.73 (4H, t, J = 5Hz), 3.74 (3H,
s), 4.13 (2H, d, J = 13Hz), 6.25 (1H, br-s), 6.86 (1H, s), 7.78 (2H, dd, J = 8Hz, 2Hz),
7.90 (2H, dd, J = 8Hz, 2Hz)

Reference Example 215
1-[[[4- [2- [4- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid

In the same manner as in Reference Example 211, instead of 1-[[[4- [2- (4-methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid phenylmethyl ester, 1- [ Using 5.08 g (9.90 mmol) of [[4- [2- [4- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid methyl ester, 4.93 g ( Quantitative).
1H-NMR (CDCl ₃ , δ): 1.32-1.45 (1H,
m), 1.46-1.60 (2H, m), 1.61-1.77 (5H, m), 1.90-2.03 (4H, m), 2.15-2.25 (2H, m),
2.44-2.52 (1H, m), 2.62 (4H, t, J = 5Hz), 3.08 (2H, dd, J = 13Hz, 13Hz), 3.78 (4H, t,
J = 5Hz), 4.14 (2H, d, J = 13Hz), 6.70 (1H, br-s), 6.88 (1H, s), 7.79 (2H, d, J = 8Hz),
7.90 (2H, d, J = 8Hz)

Reference Example 216
2- [4- [2- [4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one

In the same manner as in Reference Example 212, instead of 1-[[[4- [2- (4-methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid, 1-[[[4 -[2- [4- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexanecarboxylic acid 4.93 (9.90 mmol) was used to give 3.00 g (63%) of the title compound. .
1H-NMR (CDCl ₃ , δ): 1.50-1.61 (1H,
m), 1.61-1.71 (3H, m), 1.71-1.79 (2H, m), 1.79-1.89 (5H, m), 1.91-2.00 (2H, m),
2.40-2.48 (1H, m), 2.59 (4H, t, J = 5Hz), 3.09 (2H, d, J = 12Hz), 3.74 (4H, t, J = 5Hz),
4.13 (2H, d, J = 12Hz), 6.90 (1H, s), 7.96 (2H, dd, J = 7Hz, 2Hz), 8.00 (2H, dd, J = 7Hz,
(2Hz)

Reference Example 217
N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycinol

L-phenylglycinol in a solution of 500 mg (1.75 mmol) of 2- (2-benzothienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one in 3 ml of N, N-dimethylformamide 288 mg (2 mmol) was added and stirred overnight. Slowly water was added and the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain 730 mg (98%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.29-1.80 (6H, m),
1.91-2.12 (2H, m), 2.19-2.38 (2H, m), 2.91 (1H, br-s), 3.73-3.83 (1H, m),
3.89-4.02 (1H, m), 5.07-5.20 (1H, m), 6.26 (1H, s), 7.20-7.49 (8H, m), 7.83 (1H, s),
7.84-7.92 (2H, m)

Reference Example 218
N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycinal

Under ice-cooling, N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycinol 100 mg (0.23 mmol) in 5 ml of methylene chloride was added to 585 mg (1.38 mmol) of Dess-Martin periodinane. ) Was added and stirred for 1 hour. At the same temperature, 10 ml of ethyl acetate and 10 ml of saturated aqueous sodium bicarbonate were added to the reaction solution. Sodium thiosulfate was added until the solution became clear and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration to obtain 55 mg (57%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.21-1.80 (6H, m),
1.83-2.18 (2H, m), 2.23-2.40 (2H, m), 5.51 (1H, d, J = 5Hz), 6.10 (1H, s),
7.21-7.52 (7H, m), 7.83 (1H, s), 7.84-7.96 (2H, m), 8.18 (1H, d, J = 5Hz), 9.55 (1H,
s)

Reference Example 219
N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-methioninol

2- (2-benzothienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 500 mg (1.75 mmol) in 3 ml of N, N-dimethylformamide in 284 mg of L-methioninol ( 2.1 mmol) was added and stirred overnight. Slowly water was added and the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain 722 mg (98%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.31-2.29 (16H, m),
2.45-2.63 (1H, m), 3.06 (1H, br-s), 3.45-3.61 (1H, m), 3.73-3.82 (1H, m),
3.97-4.05 (1H, m), 6.29 (1H, s), 6.85 (1H, br-s), 7.38-7.50 (2H, m), 7.82 (1H, s),
7.83-7.90 (2H, m)

Reference Example 220
N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-methioninal

Under an argon gas atmosphere, 245 mg (1.9 mmol) of N, N-diisopropylethylamine was added dropwise to a solution of 297 mg (1.9 mmol) of sulfur trioxide pyridine complex in 10 ml of anhydrous dimethyl sulfoxide and 5 ml of anhydrous methylene chloride under ice cooling, followed by stirring for 15 minutes. did. Further, 100 mg (0.23 mmol) of N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-methioninol was added to the reaction solution under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into ice-water and extracted twice with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 20 ml of diisopropyl ether was added to the residue and stirred at room temperature for 18 hours. The obtained crystals were collected by filtration to give the title compound quantitatively.
_{1H-NMR (CDCl 3, δ} ): 1.36-1.80 (9H, m),
1.91-2.09 (5H, m), 2.20-2.35 (2H, m), 2.50-2.63 (1H, m), 4.43-4.59 (1H, m),
6.19 (1H, s), 7.38-7.52 (2H, m), 7.67 (1H, d, J = 7Hz), 7.71 (1H, s), 7.80-7.89 (2H,
m), 9.61 (1H, s)

Reference Example 221
N-[[1-[[[4- (4-morpholinylmethyl) phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycinol

2- [4- (4-morpholinylmethyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 100 mg (0.29 mmol) in 3 ml N, N-dimethylformamide solution To this was added 44 mg (0.32 mmol) of L-phenylglycinol and stirred overnight. Slowly water was added and the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain 46 mg (34%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.25-1.80 (6H, m),
1.92-2.10 (2H, m), 2.18-2.32 (2H, m), 2.37-2.50 (4H, m), 2.99 (1H, br-s), 3.55 (2H,
s), 3.62-3.71 (4H, m), 3.71-3.83 (1H, m), 3.91-4.02 (1H, m), 5.05-5.18 (1H, m),
6.24 (1H, s), 7.17-7.37 (6H, m), 7.44 (2H, d, J = 8Hz), 7.73 (2H, d, J = 8Hz)

Reference Example 222
N-[[1-[[[4- (4-morpholinylmethyl) phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycinal

Under ice-cooling, N-[[1-[[[4- (4-morpholinylmethyl) phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycinol 46 mg (0.1 mmol) in 5 ml methylene chloride solution 254 mg (0.6 mmol) of Dess-Martin periodinane was added and stirred for 1 hour. At the same temperature, 10 ml of ethyl acetate and 10 ml of saturated aqueous sodium bicarbonate were added to the reaction solution. Sodium thiosulfate was added until the solution became clear and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration to obtain 30 mg (60%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.20-2.37 (10H, m),
2.37-2.60 (4H, m), 3.55 (2H, s), 3.61-3.80 (4H, m), 5.49 (1H, d, J = 6Hz), 6.16 (1H,
s), 7.20-7.58 (7H, m), 7.75 (2H, d, J = 8Hz), 8.27 (1H, d, J = 6Hz), 9.54 (1H, s)

Reference Example 223
N-[[1-[[[4- (4-morpholinylmethyl) phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninol

2- [4- (4-morpholinylmethyl) phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 100 mg (0.29 mmol) in 3 ml N, N-dimethylformamide solution L-methioninol 43 mg (0.32 mmol) was added thereto and stirred overnight. Slowly water was added and the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain 65 mg (49%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.31-2.23 (15H, m),
2.35-2.45 (4H, m), 2.45-2.62 (2H, m), 3.12 (1H, br-s), 3.40-3.60 (3H, m),
3.60-3.82 (5H, m), 3.95-4.05 (1H, m), 6.28 (1H, s), 6.80 (1H, d, J = 8Hz), 7.43 (2H,
d, J = 8Hz), 7.72 (2H, d, J = 8Hz)

Reference Example 224
N-[[1-[[[4- (4-morpholinylmethyl) phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninal

Under ice cooling, N-[[1-[[[4- (4-morpholinylmethyl) phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninol (65 mg, 0.14 mmol) was added to a 5 ml methylene chloride solution. Martin periodinane (356 mg, 0.84 mmol) was added and the mixture was stirred for 1 hour. At the same temperature, 10 ml of ethyl acetate and 10 ml of saturated aqueous sodium bicarbonate were added to the reaction solution. Sodium thiosulfate was added until the solution became clear and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 55 mg (85%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.20-2.80 (21H, m), 3.56 (2H,
s), 3.60-3.81 (4H, m), 4.40-4.58 (1H, m), 5.12 (1H, d, J = 7Hz), 6.18 (1H, s),
7.44 (2H, d, J = 8Hz), 7.73 (2H, d, J = 8Hz), 9.59 (1H, s)

Reference Example 225
N-[[1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninol

2- [4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 250 mg (0.68 mmol) ) In 20 ml of dimethylformamide was added 100 mg (0.74 mmol) of L-methioninol. After stirring at 80 ° C. for 15 hours, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, diisopropyl ether was added to the residue, and the crystals were washed to obtain 319 mg (86%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.37-1.61 (3H,
m), 1.65-1.80 (3H, m), 1.80-1.86 (2H, m), 1.96-2.05 (2H, m), 2.07 (3H, s),
2.15-2.29 (2H, m), 2.37 (3H, s), 2.51-2.60 (2H, m), 2.56 (4H, t, J = 5Hz),
3.14-3.21 (1H, m), 3.50-3.56 (1H, m), 3.59 (4H, t, J = 5Hz), 3.77-3.84 (1H, m),
4.00-4.06 (1H, m), 6.30 (1H, br-s), 6.85 (1H, d, J = 7Hz), 6.90 (1H, s), 7.76 (2H, dd,
J = 8Hz, 2Hz), 7.92 (2H, dd, J = 8Hz, 2Hz)

Reference Example 226
N-[[1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninal

Under an argon gas atmosphere, 453 mg (3.5 mmol) of N, N-diisopropylethylamine was added dropwise to 10 ml anhydrous dimethyl sulfoxide and 5 ml anhydrous methylene chloride solution of 658 mg (3.5 mmol) of sulfur trioxide pyridine complex under ice-cooling and stirred for 15 minutes. did. Furthermore, N-[[1-[[[4- [2- (4-methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninol 319 mg (0.58) was cooled with ice. mmol) in 3 ml of anhydrous dimethyl sulfoxide was added to the reaction solution and stirred at the same temperature for 2 hours. The reaction solution was poured into ice-water and extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 20 ml of diisopropyl ether was added to the residue and stirred at room temperature for 18 hours. The obtained crystals were collected by filtration to give 203 mg (64%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.36-1.78 (6H,
m), 1.98-2.08 (3H, m), 2.02 (3H, s), 2.21-2.57 (3H, m), 2.38 (3H, s), 2.55 (4H, t,
J = 5Hz), 2.56 (2H, m), 3.61 (4H, t, J = 5Hz), 4.49 (1H, dt, J = 8Hz, 5Hz), 6.17 (1H,
br-s), 6.90 (1H, s), 7.78 (2H, d, J = 8Hz), 7.84 (1H, d, J = 8Hz), 7.92 (2H, d, J = 8Hz),
9.62 (1H, s)

Reference Example 227
N-[[1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycinol

In the same manner as in Reference Example 225, 96 mg (0.7 mmol) of L-phenylglycinol was used instead of L-methioninol to obtain 220 mg (57%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.34-1.43 (1H,
m), 1.42-1.61 (2H, m), 1.61-1.79 (3H, m), 1.96-2.10 (2H, m), 2.20-2.29 (1H, m),
2.30-2.36 (1H, m), 2.37 (3H, s), 2.56 (4H, t, J = 5Hz), 3.01-3.08 (1H, m), 3.60 (4H,
t, J = 5Hz), 3.76-3.85 (1H, m), 3.92-4.01 (1H, m), 5.09-5.15 (1H, m), 6.27 (1H,
br-s), 6.90 (1H, s), 7.24-7.30 (3H, m), 7.31-7.36 (2H, m), 7.37 (1H, d, J = 7Hz),
7.78 (2H, d, J = 8Hz), 7.92 (2H, d, J = 8Hz)

Reference Example 228
N-[[1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycinal

Under an argon gas atmosphere, 310 mg (2.4 mmol) of N, N-diisopropylethylamine was added dropwise to a solution of 382 mg (2.4 mmol) of sulfur trioxide pyridine complex in 10 ml of anhydrous dimethyl sulfoxide and 5 ml of anhydrous methylene chloride under ice cooling, followed by stirring for 15 minutes. did. Further, under ice cooling, N-[[1-[[[4- [2- (4-methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycinol 220 mg A solution of (0.4 mmol) in anhydrous dimethyl sulfoxide (3 ml) was added to the reaction solution and stirred at the same temperature for 30 minutes. After completion of the reaction, 200 ml of water was added to the reaction solution under ice cooling, followed by stirring at room temperature for 3 hours. The precipitated crystals were washed again with diethyl ether to obtain 67 mg (31%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.35-1.82 (6H,
m), 2.25-2.39 (2H, m), 2.50-2.59 (1H, m), 2.62 (3H, s), 2.75 (4H, t, J = 5Hz),
3.06-3.15 (1H, m), 3.72 (4H, t, J = 5Hz), 5.51 (1H, d, J = 6Hz), 6.16 (1H, br-s),
6.91 (1H, s), 7.21-7.38 (5H, m), 7.38 (1H, d, J = 6Hz), 7.79 (2H, d, J = 8Hz), 7.92 (2H,
d, J = 8Hz), 9.56 (1H, s)

Reference Example 229
N-[[1-[[[4- [2- [4- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninol

2- [4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-ene was prepared according to the method of Reference Example 225. 2- [4- [2- [4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec- instead of -4-one Using 481-mg (1.00 mmol) of 1-en-4-one, 501 mg (81%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.35-1.80 (7H,
m), 1.81-1.89 (2H, m), 1.92-2.09 (4H, m), 2.07 (3H, s), 2.15-2.23 (3H, m),
2.41-2.49 (1H, m), 2.54 (2H, t, J = 6Hz), 2.57 (4H, t, J = 5Hz), 3.08 (2H, dd, J = 13Hz,
13Hz), 3.18 (1H, t, J = 7Hz), 3.50-3.58 (1H, m), 3.74 (4H, t, J = 5Hz), 3.77-3.85 (1H,
m), 4.00-4.08 (1H, m), 4.12 (2H, d, J = 13Hz), 6.30 (1H, br-s), 6.83 (1H, d, J = 8Hz),
6.88 (1H, s), 7.77 (2H, d, J = 8Hz), 7.96 (2H, d, J = 8Hz)

Reference Example 230
N-[[1-[[[4- [2- [4- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninal

N-[[1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninol was prepared in the same manner as in Reference Example 226. N-[[1-[[[4- [2-[(4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninol 501 mg (0.81 mmol) to give 100 mg (20%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.36-1.56 (3H,
m), 1.61-1.79 (6H, m), 1.93-2.07 (5H, m), 2.02 (3H, s), 2.04-2.15 (2H, m),
2.40 (2.49 (1H, m), 2.45 (2H, t, J = 6Hz), 2.58 (4H, t, J = 5Hz), 3.08 (2H, dd, J = 12Hz,
12Hz), 3.74 (4H, t, J = 5Hz), 4.12 (2H, d, J = 12Hz), 4.49 (1H, dd, J = 8Hz, 5Hz,),
6.15 (1H, br-s), 6.88 (1H, s), 7.78 (2H, d J = 8Hz), 7.85 (1H, d, J = 8Hz), 7.93 (2H, d,
J = 8Hz), 9.62 (1H, s)

Reference Example 231
N-[[1-[[[4- [2- [4- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycinol

2- [4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-ene was prepared according to the method of Reference Example 225. 2- [4- [2- [4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec- instead of -4-one Using 481-mg (1.00 mmol) of 1-en-4-one and 137 mg (1.00 mmol) of L-phenylglycinol instead of L-methioninol, 324 mg (52%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.32-1.78 (9H,
m), 1.95-2.11 (4H, m), 2.20-2.27 (1H, m), 2.29-2.36 (1H, m), 2.40-2.49 (1H, m)
2.59 (4H, t, J = 5Hz), 3.09 (2H, dd, J = 13Hz, 13Hz), 3.74 (4H, t, J = 5Hz),
3.78-3.82 (1H, m), 3.96-4.00 (1H, m), 4.12 (2H, d, J = 13Hz), 5.09-5.14 (1H, m),
6.28 (1H, br-s), 6.88 (1H, s), 7.25-7.30 (1H, m) 7.30-7.35 (4H, m), 7.78 (1H, d,
J = 8Hz), 7.78 (2H, dd, J = 7Hz, 2Hz), 7.92 (2H, dd, J = 7Hz, 2Hz)

Reference Example 232
N-[[1-[[[4- [2- [4- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycinal

N-[[1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methioninol was prepared in the same manner as in Reference Example 226. N-[[1-[[[4- [2- [4- (4-morpholinyl) -1-piperazinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenyl Using 324 mg (0.52 mmol) of ricinol, 128 mg (40%) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 1.30-1.85 (8H,
m), 1.92-2.13 (4H, m), 2.25-2.50 (3H, m), 2.59 (4H, t, J = 5Hz), 3.08 (2H, dd,
J = 12Hz, 12Hz), 3.74 (4H, t, J = 5Hz), 4.13 (2H, d, J = 12Hz), 5.51 (1H, d, J = 6Hz),
6.14 (1H, br-s), 6.88 (1H, s), 7.30-7.41 (5H, m), 7.79 (2H, d, J = 8Hz), 7.93 (2H, d,
J = 8Hz), 8.34 (1H, d, J = 6Hz), 9.56 (1H, s)

Example 2
N-[[1-[(2-Benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycine methyl ester

L-phenylglycine methyl ester hydrochloride 423 mg (2 mmol) and 2- (2-benzothienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 500 mg (1.75 mmol) in toluene To 10 ml suspension, 679 mg (5.3 mmol) of diisopropylethylamine was added and heated to reflux overnight. After evaporating the solvent under reduced pressure, ethyl acetate was added, washed with 10% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, diethyl ether was added and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 670 mg (91%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.25-1.80 (6H, m),
1.90-2.08 (2H, m), 2.23-2.40 (2H, m), 3.69 (3H, s), 5.53 (1H, d, J = 7Hz), 6.10 (1H,
s), 7.23-7.49 (7H, m), 7.81 (1H, s), 7.83-7.91 (2H, m), 8.13 (1H, d, J = 7Hz)

Example 3
N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-methionine methyl ester

L-methionine methyl ester hydrochloride 419 mg (2 mmol) and 2- (2-benzothienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 500 mg (1.75 mmol) in toluene 10 ml To the suspension was added 679 mg (5.3 mmol) of diisopropylethylamine, and the mixture was heated to reflux overnight. After evaporating the solvent under reduced pressure, ethyl acetate was added, washed with 10% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, diethyl ether was added and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 678 mg (86%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.30-1.81 (8H, m),
1.95-2.09 (5H, m), 2.11-2.39 (2H, m), 2.43-2.61 (2H, m), 3.71 (3H, s),
4.61-4.73 (1H, m), 6.16 (1H, s), 7.38-7.45 (2H, m), 7.59 (1H, d, J = 8Hz), 7.80 (1H,
s), 7.82-7.90 (2H, m)

Example 4
N-[[1-[[[4-[(Dimethylamino) methyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycine methyl ester

L-phenylglycine methyl ester hydrochloride 85 mg (0.42 mmol) and 2- [4-[(dimethylamino) methyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one To a suspension of 100 mg (0.35 mmol) in 3 ml toluene was added 129 mg (1 mmol) of diisopropylethylamine, and the mixture was heated to reflux overnight. After evaporating the solvent under reduced pressure, ethyl acetate was added, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, diethyl ether was added and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 62 mg (39%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.27-1.80 (7H, m),
1.83-2.09 (2H, m), 2.18-2.39 (1H, m), 2.25 (6H, s), 3.47 (2H, s), 3.69 (3H, s),
5.53 (1H, d, J = 7Hz), 6.07 (1H, s), 7.10-7.25 (7H, m), 7.73 (2H, d, J = 8Hz), 8.28 (1H,
d, J = 7Hz)

Example 5
N-[[1-[[[4-[(Dimethylamino) methyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methionine methyl ester

L-methionine methyl ester hydrochloride 84 mg (0.42 mmol) and 2- [4-[(dimethylamino) methyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 100 mg To a 3 ml toluene suspension of (0.35 mmol), 129 mg (1 mmol) of diisopropylethylamine was added and heated to reflux overnight. After evaporating the solvent under reduced pressure, ethyl acetate was added, washed with saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, diethyl ether was added and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 93 mg (59%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.29-1.58 (4H, m),
1.58-1.79 (4H, m), 1.92-2.35 (7H, m), 2.25 (6H, s), 2.43-2.59 (2H, m), 3.47 (2H, s),
3.71 (3H, s), 4.61-4.72 (1H, m), 6.10 (1H, s), 7.41 (2H, d, J = 8Hz), 7.69 (1H, d,
J = 8Hz), 7.73 (2H, d, J = 8Hz)

Example 6
N-[[1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methionine methyl ester

2- [4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 411 mg (1.00 mmol) ) And N, N-diisopropylethylamine 258 mg (2.00 mmol) in dimethylformamide 20 ml was added L-methionine methyl ester hydrochloride 200 mg (1.00 mmol). After stirring at 80 ° C. for 15 hours, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain 191 mg (33%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.33-1.60 (3H,
m), 1.63-1.78 (3H, m), 1.97-2.05 (3H, m), 2.05 (3H, s), 2.15-2.35 (3H, m), 2.37 (3H,
s), 2,50-2.58 (2H, m), 2.56 (4H, t, J = 5Hz), 3.59 (4H, t, J = 5Hz), 3.71 (3H, s),
4.69 (1H, dt, J = 7Hz, 5Hz), 6.13 (1H, br-s), 6.90 (1H, s), 7.72 (1H, d, J = 7Hz),
7.78 (2H, dd, J = 8Hz, 2Hz), 7.92 (2H, dd, J = 8Hz, 2Hz)

Example 7
N-[[1-[[[4- [2- (4-Methyl-1-piperazinyl) -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycine methyl ester

In the same manner as in Example 6, L-phenylglycine methyl ester hydrochloride 202 mg (1.00 mmol) was used instead of L-methionine methyl ester hydrochloride to give 156 mg (24%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.25-1.41 (1H,
m), 1.41-1.55 (2H, m), 1.60-1.76 (3H, m), 1.94-2.05 (2H, m), 2.25-2.40 (2H, m),
2.37 (3H, s), 2.56 (4H, t, J = 5Hz), 3.59 (4H, t, J = 5Hz), 3.69 (3H, s), 5.54 (1H, d,
J = 7Hz), 6.08 (1H, br-s), 6.89 (1H, s), 7.26-7.35 (3H, m), 7.38-7.41 (2H, m),
7.78 (2H, d, J = 8Hz), 7.92 (2H, d, J = 8Hz), 8.29 (1H, d, J = 7Hz)

Example 8
N-[[1-[[[4- [2- [4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-methionine methyl ester

In a manner analogous to Example 6, 2- [4- [2- (4-methyl-1-piperazinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-ene 2- [4- [2- [4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec- instead of -4-one Using 481 mg (1.00 mmol) of 1-en-4-one, 439 mg (68%) of the title compound were obtained.
1H-NMR (CDCl ₃ , δ): 1.31-1.79 (8H,
m), 1.92-2.05 (5H, m), 2.05 (3H, s), 2.15-2.34 (3H, m), 2.40-2.49 (1H, m), 2.53 (2H,
t, J = 7Hz), 2.59 (4H, t, J = 5Hz), 3.08 (2H, dd, J = 12Hz, 12Hz), 3.71 (3H, s),
3.74 (4H, t, J = 5Hz), 4.13 (2H, d, J = 12Hz), 4.69 (1H, dt, J = 8Hz, 5Hz), 6.12 (1H,
br-s), 6.88 (1H, s), 7.72 (1H, d, J = 8Hz), 7.78 (2H, d, J = 8Hz), 7.92 (2H, d, J = 8Hz)

Example 9
N-[[1-[[[4- [2- [4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycine methyl ester

In a manner analogous to Example 6, 2- [4- [2- (4-methyl-1-piperazinyl) -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec-1-ene 2- [4- [2- [4- (4-morpholinyl) -1-piperidinyl] -4-thiazolyl] phenyl] -3-oxa-1-azaspiro [4.5] dec- instead of -4-one Using 1-en-4-one 481 mg (1.00 mmol) and L-methionine methyl ester hydrochloride instead of L-phenylglycine methyl ester hydrochloride 202 mg (1.00 mmol), the title compound 156 mg (24%) was obtained. .
1H-NMR (CDCl ₃ , δ): 1.30-1.41 (1H,
m), 1.42-1.60 (3H, m), 1.61-1.77 (4H, m), 1.92-2.08 (4H, m), 2.25-2.37 (2H, m),
2.40-2.49 (1H, m), 2.59 (4H, t, J = 5Hz), 3.08 (2H, dd, J = 12Hz, 12Hz), 3.69 (3H, s),
3.74 (4H, t, J = 5Hz), 4.12 (2H, d, J = 12H), 5.54 (1H, d, J = 7Hz), 6.07 (1H, br-s),
6.87 (1H, s), 7.26-7.36 (3H, m), 7.37-7.42 (2H, m), 7.77 (2H, d, J = 8Hz), 7.91 (2H,
d, J = 8Hz), 8.30 (1H, d, J = 8Hz)

Reference Example 233
N-[[1-[(2-Benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycine

N-methylmorpholine was added to 530 mg (3.5 mmol) of L-phenylglycine and 500 mg (1.75 mmol) of 2- (2-benzothienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one. 10ml was added and it stirred under heating-refluxing overnight. The reaction solution was distilled off under reduced pressure, 10% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted 3 times with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resulting residue and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 259 mg (34%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.25-1.80 (6H, m),
1.83-2.03 (2H, m), 2.12-2.40 (2H, m), 4.47 (1H, d, J = 5Hz), 6.11 (1H, s),
7.18-7.55 (8H, m), 7.79 (1H, s), 7.80-7.91 (2H, m)

Reference Example 234
N-[[1-[(2-Benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-methionine

L-methionine 522 mg (3.5 mmol) and 2- (2-benzothienyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 500 mg (1.75 mmol) and 10 ml of N-methylmorpholine Was added and stirred overnight under reflux with heating. The reaction solution was distilled off under reduced pressure, 10% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted 3 times with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resulting residue and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 170 mg (22%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.21-2.99 (17H, m),
4.51-4.68 (1H, m), 6.42 (1H, s), 6.75-6.85 (1H, m), 7.32-7.50 (2H, m), 7.74-7.98 (3H,
m)

Reference Example 235
N-[[[1-[(1H-pyrrol-2-yl) carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycine

To 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2- (1H-pyrrol-2-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one -Add 10 ml of methylmorpholine and stir overnight under reflux with heating. The reaction solution was distilled off under reduced pressure, 10% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted 3 times with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 120 mg (17%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.18-2.08 (9H, m),
2.18-2.30 (1H, m), 5.63 (1H, d, J = 7Hz), 6.16-6.23 (1H, m), 6.25 (1H, s),
6.61-6.83 (2H, m), 7.17-7.35 (3H, m), 7.41 (2H, d, J = 8Hz), 7.83 (1H, d, J = 7Hz),
10.92 (1H, s)

Reference Example 236
N-[[[1-[(1H-pyrrol-2-yl) carbonyl] amino] cyclohexyl] carbonyl] -L-methionine

L-methionine 575 mg (3.9 mmol) and 2- (1H-pyrrol-2-yl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one 500 mg (1.9 mmol) were mixed with N- 10 ml of methylmorpholine was added, and the mixture was stirred overnight with heating under reflux. The reaction solution was distilled off under reduced pressure, 10% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted 3 times with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Ethyl acetate was added to the resulting residue and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 503 mg (72%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.20-2.33 (15H, m),
2.42-2.61 (2H, m), 4.58-4.72 (1H, m), 6.21 (1H, dd, J = 5Hz, 3Hz), 6.28 (1H, s),
6.69 (1H, d, J = 3Hz), 6.78 (1H, d, J = 5Hz), 7.29 (1H, d, J = 8Hz)

Reference Example 237
N-[[[1-[(4-Methoxyphenyl) carbonyl] amino] cyclohexyl] carbonyl] -L-phenylglycine

N-methylmorpholine was added to 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2- (4-methoxyphenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one. 10ml was added and it stirred under heating-refluxing overnight. The reaction solution was distilled off under reduced pressure, 10% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted 3 times with methylene chloride. The obtained organic layer was dried over anhydrous sodium hydrogen sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 92 mg (22%) of the title compound.
_{1H-NMR (CDCl 3, δ} ): 1.25-1.58 (3H, m),
1.60-1.81 (3H, m), 1.85-2.05 (2H, m), 2.17-2.39 (2H, m), 3.86 (3H, s), 4.45 (1H, d,
J = 6Hz), 6.01 (1H, s), 6.82-7.00 (3H, m), 7.19-7.38 (4H, m), 7.57-7.83 (3H, m)

Reference Example 238
N-[[1-[[(4-Methoxyphenyl) carbonyl] amino] cyclohexyl] carbonyl] -L-methionine

To 298 mg (2 mmol) of L-methionine and 259 mg (1 mmol) of 2- (4-methoxyphenyl) -3-oxa-1-azaspiro [4.5] dec-1-en-4-one, 10 ml of N-methylmorpholine was added. The mixture was stirred overnight under heating and reflux. The reaction solution was distilled off under reduced pressure, 10% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted 3 times with methylene chloride. The obtained organic layer was dried over anhydrous sodium hydrogen sulfate, and the solvent was removed under reduced pressure. Ethyl acetate was added to the resulting residue and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 52 mg (13%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.20-2.62 (17H, m), 3.86 (3H,
s), 4.56-4.71 (1H, m), 6.27 (1H, s), 6.95 (2H, d, J = 9Hz), 7.75 (2H, d, J = 9Hz),
7.86 (1H, d, J = 8Hz)

Reference Example 239
N-[[1-[[(E) -3- (2-furanyl) -1-oxo-2-propenyl] amino] cyclohexyl] carbonyl]
-L-methionine

2-[(E) -2- (2-furanyl) ethenyl] -3-oxo-1-azaspiro [4.5] dec-1-en-4-one 491 mg (2 mmol) and L-methionine 597 mg (4 mmol) Of N-methylmorpholine in 20 ml was heated to reflux for 15 hours. Ethyl acetate and water were added to the reaction solution, and the mixture was acidified with concentrated hydrochloric acid. The organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain 74 mg mg (9%) of the title compound.
1H-NMR (CDCl ₃ , δ): 1.24-1.48 (3H,
m), 1.59-1.71 (3H, m), 1.87-1.98 (2H, m), 2.00-2.25 (4H, m), 2.05 (3H, s),
2.51-2.63 (2H, m), 4.63 (1H, dt, J = 8Hz, 5H), 6.00 (1H, br-s), 6.40 (1H, d, J = 15Hz),
6.46 (1H, dd, J = 3Hz, 2Hz), 6.59 (1H, d, J = 3Hz), 7.40 (1H, d, J = 15Hz), 7.45 (1H, d,
J = 2Hz), 7.76 (1H, d, J = 8Hz)

Reference Example 240
N-[[1-[[(2-furanylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol

In the same manner as in Reference Example 197, 1-[[((2-furanylmethoxy) carbonyl] amino] cyclohexanecarboxylic acid 2.00 instead of 2-benzothiophenecarboxylic acid
Substituting g (7.48 mmol) and 1-aminocyclohexanecarboxylic acid phenylmethyl ester with 772 mg (7.48 mmol) of L-valinol to give 2.67 g (quantitative) of the title compound.
Was used to obtain 2.64 g (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.90 (3H,
d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 1.29-1.46 (3H, m), 1.56-1.72 (3H, m),
1.78-1.85 (1H, m), 1.88-1.96 (2H, m), 1.96-2.06 (2H, m), 2.75-2.90 (1H, br-s),
3.48-3.55 (1H, m), 3.68-3.78 (2H, m), 5.06 (1H, br-s), 5.00 (1H, d, J = 13Hz),
5.10 (1H, d, J = 13Hz), 6.35 (1H, br-s), 6.37 (1H, dd, J = 3Hz, 2Hz), 6.43 (1H, dd,
J = 3Hz, 1Hz), 7.43 (1H, dd, J = 2Hz, 1Hz)

Reference Example 241
N-[[1-[[(2-furanylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinal

In the same manner as in Reference Example 218, instead of N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycinol, N-[[1-[[ Using 2.67 g of (2-furanylmethoxy) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol, 2.08 g (83.7%, 2 steps) of the title compound was obtained.
1H-NMR (CDCl ₃ , δ): 0.92 (3H,
d, J = 7Hz), 1.00 (3H, d, J = 7Hz), 1.26-1.46 (3H, m), 1.52-1.70 (3H, m),
1.86-1.96 (2H, m), 1.96-2.04 (1H, m), 2.05-2.14 (1H, m), 2.28-2.36 (1H, m),
4.46-4.52 (1H, m), 4.92-4.99 (1H, br-s), 5.04 (1H, d, J = 13Hz), 5.09 (1H, d,
J = 13Hz), 6.36 (1H, dd, J = 3Hz, 2Hz), 6.41 (1H, d, J = 3Hz), 7.04-7.16 (1H, m),
7.42 (1H, d, J = 2Hz), 9.61 (1H, s)

Reference Example 242
N-[[1-[[(E) -3- (2-furanyl) -1-oxo-2-propenyl] amino] cyclohexyl] carbonyl] -L-valinol

L-valinol 252 mg (2.45 mmol) and 2-[(E) -2- (2-furanyl) ethenyl] -3-oxo-1-azaspiro [4.5] dec-1-en-4-one 500 mg DIPEA 1.07 ml (6.12 mmol) was added to a toluene 15 ml solution of (2.04 mmol), and the mixture was stirred for 4 days while heating under reflux. The reaction solution was distilled off under reduced pressure and purified by silica gel chromatography to obtain 481 mg (67.7%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.93 (3H,
d, J = 7Hz), 0.95 (3H, d, J = 7Hz), 1.34-1.52 (3H, m), 1.60-1.74 (3H, m),
1.80-1.88 (1H, m), 1.94-2.06 (2H, m), 2.08-2.18 (2H, m), 3.16-3.21 (1H, m),
3.51-3.57 (1H, m), 3.68-3.78 (2H, m), 5.72 (1H, br-s), 6.35 (1H, d, 15Hz), 6.47 (1H,
dd, J = 3Hz, 2Hz), 6.58 (1H, dd, J = 3Hz, 1Hz), 6.73 (1H, br-d, J = 9Hz), 7.41 (1H, d,
J = 15Hz), 7.46 (1H, dd, J = 2Hz, 1Hz)

Reference Example 243
N-[[1-[[(E) -3- (2-furanyl) -1-oxo-2-propenyl] amino] cyclohexyl] carbonyl] -L-valinal

In the same manner as in Reference Example 218, instead of N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycinol, N-[[1-[[(E)- 3- (2-furanyl) -1-oxo-2-propenyl] amino] cyclohexyl] carbonyl] -L-valinol 481
449 mg (93.9%) of the title compound was obtained using mg (1.38 mmol).
1H-NMR (CDCl ₃ , δ): 0.95 (3H,
d, J = 7Hz), 1.01 (3H, d, J = 7Hz), 1.30-1.74 (6H, m), 1.92-2.02 (2H, m),
2.14-2.22 (1H, m), 2.22-2.30 (1H, m), 2.28-2.36 (1H, m), 4.42 (1H, ddd, J = 8Hz, 5Hz,
1Hz), 5.55 (1H, br-s), 6.38 (1H, d, J = 15Hz), 6.47 (1H, dd, J = 3Hz, 2Hz), 6.58 (1H, d,
J = 3Hz, 1Hz), 7.42 (1H, d, J = 15Hz), 7.46 (1H, dd, J = 2Hz, 1Hz), 7.83 (1H, d, J = 8Hz),
9.59 (1H, d, 1Hz)

Reference Example 244
N-[[1-[(3-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valinol

L-valinol 124 mg (1.20 mmol) and 2- (3-furanyl) -3-oxo-1-azaspiro [4.5] dec-1-en-4-one 222 mg (1.00 mmol) in toluene 10 ml DIPEA 0.52 ml (3.01 mmol) was added to the mixture, and the mixture was stirred with heating under reflux for 4 days. The reaction solution was distilled off under reduced pressure and purified by silica gel chromatography to obtain 340 mg (quantitative) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.93 (3H,
d, J = 7Hz), 0.96 (3H, d, J = 7Hz), 1.35-1.54 (3H, m), 1.56-1.76 (3H, m), 1.82-1.90 (1H,
m), 1.96-2.06 (2H, m), 2.13-2.20 (2H, m), 3.05 (1H, br-s), 3.54-3.59 (1H, m),
3.69-3.78 (2H, m), 5.88 (1H, br-s), 6.60 (1H, dd, J = 2Hz, 1Hz), 6.80 (1H, br-d,
J = 8Hz), 7.46 (1H, dd, J = 2Hz, 2Hz), 7.96 (1H, dd, J = 2Hz, 1Hz)

Reference Example 245
N-[[1-[(3-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valinal

In the same manner as in Reference Example 218, instead of N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycinol, N-[[1-[( Using 340 mg of 3-furanylcarbonyl) amino] cyclohexyl] carbonyl] -L-valinol, 282 g (87.6%, 2 steps) of the title compound was obtained.
1H-NMR (CDCl3, δ): 0.95 (3H, d,
J = 7Hz), 1.02 (3H, d, J = 7Hz), 1.32-1.52 (3H, m), 1.60-1.76 (3H, m), 1.95-2.06 (2H,
m), 2.18-2.24 (1H, m), 2.26-2.36 (2H, m), 4.46 (1H, ddd, J = 8Hz, 5Hz, 1Hz),
5.74 (1H, br-s), 6.62 (1H, dd, J = 2Hz, 1Hz), 7.47 (1H, dd, J = 2Hz, 1Hz), 7.71 (1H, d,
J = 8Hz), 7.97 (1H, dd, J = 1Hz, 1Hz), 9.61 (1H, d, J = 1Hz)

Reference Example 246
N-[[1-[[(4-Methoxyphenyl) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol

L-valinol 252 mg (2.45 mmol) ethyl acetate
2- (4-Methoxyphenyl) -3-oxo-1-azaspiro [4.5] dec-1-en-4-one 260 in 5 ml solution
mg (1.00 mmol) was added, and the mixture was stirred at room temperature for 4 days. The reaction solution was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 243.5 mg (66.7%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.93 (3H,
d, J = 7Hz), 0.96 (3H, d, J = 7Hz), 1.36-1.80 (7H, m), 1.80-1.88 (1H, m),
1.98-2.10 (2H, m), 2.16-2.26 (2H, m), 3.55 (1H, dd, J = 11Hz, 6Hz), 3.69-3.74 (1H,
m), 3.77 (1H, dd, J = 11Hz, 3Hz), 3.86 (3H, s), 6.17 (1H, br-s), 6.84 (1H, br-d,
J = 9Hz), 6.95 (2H, dd, J = 7Hz, 2Hz), 7.74 (2H, dd, J = 7Hz, 2Hz)

Reference Example 247
N-[[1-[[(4-Methoxyphenyl) carbonyl] amino] cyclohexyl] carbonyl] -L-valinal

In the same manner as in Reference Example 218, instead of N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycinol, N-[[1-[[(4-methoxy Phenyl) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol 243 mg (0.67 mmol) was used to give 240 mg (98.9%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.95 (3H,
d, J = 7Hz), 1.02 (3H, d, J = 7Hz), 1.34-1.54 (3H, m), 1.63-1.78 (3H, m),
1.96-2.05 (2H, m), 2.24-2.37 (3H, m), 3.87 (3H, s), 4.43 (1H, ddd, J = 8Hz, 5Hz,
1Hz), 6.03 (1H, br-s), 6.96 (2H, dd, J = 7Hz, 2Hz), 7.75 (2H, dd, J = 7Hz, 2Hz),
7.87 (1H, d, J = 8Hz), 9.60 (1H, s)

Reference Example 248
N-[[1-[[(1H-pyrrol-2-yl) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol

L-valinol 252 mg (2.45 mmol) ethyl acetate
2- (1H-pyrrol-2-yl) -3-oxo-1-azaspiro [4.5] dec-1-en-4-one 220 in 5 ml solution
mg (1.01 mmol) was added, and the mixture was stirred at room temperature for 4 days. The reaction solution was distilled off under reduced pressure and purified by silica gel chromatography to obtain 247 mg (76.4%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.93 (3H,
d, J = 7Hz), 0.94 (3H, d, J = 7Hz), 1.34-1.52 (3H, m), 1.62-2.14 (8H, m),
2.16-2.22 (1H, m), 3.51 (1H, dd, J = 12Hz, 7Hz), 3.69-3.76 (2H, m), 6.03 (1H, br-s),
6.27 (1H, ddd, J = 4Hz, 3Hz, 3Hz), 6.60-6.66 (2H, m), 6.97 (1H, ddd, J = 3Hz, 3Hz,
1Hz), 9.48 (1H, br-s)

Reference Example 249
N-[[1-[[(1H-pyrrol-2-yl) carbonyl] amino] cyclohexyl] carbonyl] -L-valinal

In the same manner as in Reference Example 218, instead of N-[[1-[(2-benzothienylcarbonyl) amino] cyclohexyl] carbonyl] -L-phenylglycinol, N-[[1-[[(1H-pyrrole) -2-yl) carbonyl] amino] cyclohexyl] carbonyl] -L-valinol 247 mg (0.77 mmol) was used to give 217 mg (88.2%) of the title compound.
1H-NMR (CDCl ₃ , δ): 0.93 (3H,
d, J = 7Hz), 1.00 (3H, d, J = 7Hz), 1.32-1.52 (3H, m), 1.60-1.76 (3H, m),
1.94-2.03 (2H, m), 2.18-2.25 (1H, m), 2.26-2.34 (2H, m), 4.45 (1H, dd, J = 8Hz, 5Hz),
5.84 (1H, br-s), 6.28 (1H, ddd, J = 4Hz, 3Hz, 3Hz), 6.63 (1H, ddd, J = 4Hz, 3Hz, 1Hz),
6.96 (1H, ddd, J = 3Hz, 3Hz, 1Hz), 7.75 (1H, br-d, J = 8Hz), 9.33 (1H, br-s), 9.59 (1H,
s)

Test Example 1 Measurement of Cathepsin K Inhibitory Activity Cathepsin K is expressed as a proenzyme in a cell culture medium using a baculovirus expression system using insect cells Sf21 and incubated at 40 ° C. for 1 hour to produce an active enzyme. ¹⁾ . Cathepsin K activity was measured by degradation of the fluorescent substrate Z-Gly-Pro-Arg-MCA (Peptide Institute) according to Aibe et al. Method ²⁾ . That is, degradation of 20 mM Z-Gly-Pro-Arg-MCA by cathepsin K was measured in 100 mM potassium potassium phosphate, 1 mM EDTA, 8 mM Cysteine, pH 6.0. The reaction was carried out at 37 ° C. for 30 minutes and stopped by adding carpeptin 2 × 10 ⁻⁵ M. After stopping the reaction, excitation wavelength 355
The fluorescence intensity at 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 50% inhibitory concentration of Reference Example compounds against cathepsin K.

Test Example 2 Human cathepsin B (Calbiochem) was used for measurement and measurement of cathepsin B inhibitory activity. According to the method ^{3) of} Barrett et al., Measurement was performed by decomposing the fluorescent substrate Z-Arg-Arg-MCA (Peptide Institute). That is, 20 with cathepsin B in 100 mM potassium sodium phosphate, 1 mM EDTA, 8 mM Cysteine, 0.005% Brij35, pH 6.0
The degradation of mM Z-Arg-Arg-MCA was measured. The reaction is carried out at 30 ° C. for 30 minutes, and calpeptin 2 × 10 ⁻⁵
Stopped by adding M. After stopping the reaction, the fluorescence intensity at an excitation wavelength of 355 nm and a measurement wavelength of 460 nm was measured. The cathepsin B inhibition of the compound was examined using the above reaction system. Table 1 shows the 50% inhibitory concentration of the reference compound against cathepsin B.

Test Example 3 Measurement of cathepsin L inhibitory activity Human cathepsin L (Calbiochem) was used for measurement. According to the method ^{3) of} Barrett et al., Measurement was performed by decomposing the fluorescent substrate Z-Phe-Arg-MCA (Peptide Institute). That is, 100 mM sodium acetate, 5 mM EDTA, 4 mM Urea, 8
Degradation of 20 mM Z-Phe-Arg-MCA by cathepsin L was measured in mM Cysteine, 0.005% Brij35, pH 5.5. The reaction was carried out at 30 ° C. for 30 minutes and was stopped by adding carpeptin 2 × 10 ⁻⁵ M. After stopping the reaction, excitation wavelength 355
The fluorescence intensity at a measurement wavelength of 460 nm was measured. The cathepsin L inhibition of the compound was examined using the above reaction system. Table 1 shows the 50% inhibitory concentration of the reference example compound against cathepsin L.
References ・ Tezuka et al., J. Biol. Chem., 269, 1106-1109 (1994)
・ Aibe et al., Biol. Pharm. Bull., 19, 1026-1031 (1996)
・ Barrett, AJ & Kirschke, H. Methods Enzymol. 80,
535-561 (1981)

Claims (9)

A cycloalkylcarbonylamino acid ester derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.
[Wherein, R ¹ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic ring. A group represented by a group, R ⁴ O—, a group represented by R ⁵ S—, or a group represented by R ⁶ (R ⁷ ) N— (R ⁴ , R ⁵ , R ⁶ , R ⁷ are Independently, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, Wherein R ⁶ and R ⁷ may be combined to form a ring; and R ² is a primary or secondary substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, substituted or Unsubstituted alkynyl group, substituted or unsubstituted aromatic hydrocarbon group Or a substituted or unsubstituted heterocyclic group; ring A is a 7 cyclic alkylidene group was 6 or atoms; R ⁸ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms; wherein , R ² is a carbamoylmethyl group or a hydroxymethyl group, R ⁸ is not a t-butyl group, and R ² is a benzyl group, a 2,2-dimethylpropyl group, a 2-propyl group, or a 1-hydroxy group. When it is an ethyl group, R ⁸ is not a benzyl group, and R ² is a 1,1-dimethylethyl group, a benzyl group, a 2- (methylthio) ethyl group, a 2-methylpropyl group, p-hydroxyphenylmethyl. If a group or a methyl group, R ⁸ is a methyl group rather than,
The substituents of the alkyl group in R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently a hydroxyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, Ring group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo Group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group (except when R ¹ is an alkyl group), alkoxycarbonylamino group and Rx (Ry) N Groups (Rx and Ry are each independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, Group, a group selected from an aromatic hydrocarbon group or heterocyclic group),
Substituents for the alkenyl group, alkynyl group, aromatic hydrocarbon group or heterocyclic group in R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently a hydroxyl group, an alkyl group, an alkenyl group, Alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, Amide group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfonamide group, mercapto group, alkoxycarbonylamino group and Rx (Ry) N Groups (Rx and Ry are each independently a hydrogen atom, an alkyl group, Nyl group, alkynyl group, aromatic hydrocarbon group or heterocyclic group). ] In the formula (I), in R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ , the alkyl group is a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, and the alkenyl group is A linear, branched or cyclic alkenyl group having 2 to 12 carbon atoms, an alkynyl group is a linear, branched or cyclic alkynyl group having 2 to 12 carbon atoms, and an aromatic hydrocarbon group is carbon A monocyclic or polycyclic aromatic hydrocarbon group of formula 6-18, wherein the heterocyclic group has at least one nitrogen atom, oxygen atom or sulfur atom as a ring-constituting atom. The cycloalkyl carbonyl amino acid ester derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein A cycloalkylcarbonylamino acid ester derivative represented by the formula (I ′) or a pharmaceutically acceptable salt thereof.
[Wherein R ¹ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic ring; A group represented by R ⁴ O—, a group represented by R ⁵ S— or a group represented by R ⁶ (R ⁷ ) N— (R ⁴ , R ⁵ , R ⁶ , R ⁷ are Independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, Wherein R ⁶ and R ⁷ may be combined to form a ring); R ² ′ is an alkyl group represented by Ra (Rb) CH— (Ra and Rb are each independently Hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted aromatic hydrocarbon Or a substituted or unsubstituted heterocyclic group), a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group ; ring a is a 7 cyclic alkylidene group was 6 or atoms; R ⁸ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms;
R ¹ alkenyl group, alkynyl group, aromatic hydrocarbon group and R ² ′, R ⁴ , R ⁵ , R ⁶ and R ⁷ alkenyl group, alkynyl group, aromatic hydrocarbon group and heterocyclic group substituents Each independently a hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl Group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfonamide group, Mercapto group, alkoxycarbonylamino group, Rx (Ry) N group (Rx and Ry are Each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group),
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Ra and Rb are each independently substituted with a hydroxyl group, an alkenyl group, an alkynyl group, a halogen atom, an aromatic hydrocarbon group or a heterocyclic group. , Alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, Sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfonamide group, mercapto group, alkoxycarbonylamino group and Rx (Ry) N group (Rx and Ry are each independently hydrogen atom, alkyl group) Represents an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group) Is an al chosen based on,
R ¹ alkyl group substituents are each independently a hydroxyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy Group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfone An amide group, a mercapto group and an Rx (Ry) N group (Rx and Ry each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group, provided that the hydrogen atom and A group selected from:
The substituent of the heterocyclic group of R ¹ is a hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, aryloxy group, arylthio group Sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group and Rx (Ry) N group (Rx and Ry each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group),
The substituents of the aromatic hydrocarbon group or heterocyclic group of Ra and Rb are each independently a hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, guanidino group, alkylthio group. Group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group , Acyloxy group, azide group, sulfonamide group, mercapto group, alkoxycarbonylamino group and Rx (Ry) N group (Rx and Ry are each independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, aromatic hydrocarbon Represents a group or a heterocyclic group),
Here, R ⁴ and R ⁸ are not each a t-butyl group, and R ² ′, R ⁴ and R ⁸ are not simultaneously a benzyl group. A cycloalkylcarbonylamino acid ester derivative represented by the formula (I ″) or a pharmaceutically acceptable salt thereof.
[Wherein, R ¹ ′ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, A cyclic group, a group represented by R ⁵ S— or a group represented by R ⁶ (R ⁷ ) N— (R ⁵ , R ⁶ and R ⁷ are each independently a substituted or unsubstituted alkyl group, A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, wherein R ⁶ and R ⁷ are combined; R ² ′ is an alkyl group represented by Ra (Rb) CH— (Ra and Rb are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted group, which may form a ring) Or unsubstituted aromatic hydrocarbon group or substituted or unsubstituted A heterocyclic group), a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group; ring A is the number of carbon atoms 6 or is an 7 cyclic alkylidene group; R ⁸ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms,
R ¹ ′ alkenyl group, alkynyl group and aromatic hydrocarbon group, and R ² ′, R ⁵ , R ⁶ and R ⁷ alkenyl group, alkynyl group, aromatic hydrocarbon group and heterocyclic group substituents, respectively, Independently, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, Sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group , Alkoxycarbonylamino group and Rx (Ry) N group (Rx and Ry are It is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a group selected from an aromatic hydrocarbon group or heterocyclic group),
R ⁵ , R ⁶ , R ⁷ , R ⁸ , Ra, and Rb are each independently substituted with a hydroxyl group, an alkenyl group, an alkynyl group, a halogen atom, an aromatic hydrocarbon group, a heterocyclic group, or an alkoxy group. Guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amide group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, Sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group, alkoxycarbonylamino group and Rx (Ry) N group (Rx and Ry are each independently a hydrogen atom, alkyl group, alkenyl group) Represents an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group) A Bareru group,
The substituent of the alkyl group of R ¹ ′ is a hydroxyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio Group, acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azide group, sulfonamide group, Mercapto group and Rx (Ry) N group (Rx and Ry each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group, provided that they simultaneously become a hydrogen atom. Is a group selected from
The substituent of the heterocyclic group of R ¹ ′ is a hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidino group, alkylthio group, aryloxy group, arylthio Group, sulfonyl group, heterocyclyloxy group, heterocyclylthio group, ureido group, carboxyl group, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group, azido group, sulfonamide group, mercapto group and Rx (Ry) N group (Rx and Ry each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group or a heterocyclic group)]. In formula (I ′) or (I ″), in R ¹ or R ¹ ′, R ⁴ , R ⁵ , R ⁶ , R ⁷ , Ra, Rb, Rx and Ry, the alkyl group has 1 to 12 carbon atoms A linear, branched or cyclic alkyl group, which is an aromatic hydrocarbon in R ¹ or R ¹ ′, R ² ′, R ⁴ , R ⁵ , R ⁶ , R ⁷ , Ra, Rb, Rx and Ry The group is a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 18 carbon atoms, and the heterocyclic group is a 3- to 7-membered ring containing at least one nitrogen atom, oxygen atom or sulfur atom as a ring constituent atom It is a heterocyclic group, and R ¹ or R ¹ ′, R ² ′, R ⁴ , R ⁵ , R ⁶ , R ⁷ , Rx and Ry have an alkenyl group having 2 to 12 carbon atoms in a straight chain, branched or cyclic form And the alkynyl group is a linear, branched or cyclic alkynyl group having 2 to 12 carbon atoms. Cycloalkyl carbonyl amino acid ester derivative or a pharmaceutically acceptable salt thereof according to claim 3 or 4. In the formula (I), (I ′) or (I ″), R ² or R ² ′ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic hydrocarbon group, or a substituted or unsubstituted complex. A cycloalkylcarbonylamino acid ester derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 , which is a cyclic group. In formula (I), (I ′) or (I ″), a substituted or unsubstituted alkyl group represented by R ² or R ² ′ or an alkyl group represented by Ra (Rb) CH— (Ra, Rb is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group), a substituted or unsubstituted alkenyl group, substituted Or an unsubstituted alkynyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group is derived from an α-amino acid, and the α-amino acid is alanine, arginine, asparagine, Aspartic acid, isoasparagine, γ-carboxyglutamic acid, cysteine, cystine, glutamine, glutamic acid, histidine, homoarginine, homocysteine, homocystin, pho Serine, homophenylalanine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, phenylalanine, phenylglycine, serine, threonine, tryptophan, tyrosine, valine, 3,4-dihydroxyphenylalanine, allylglycine, neopentylglycine, arosleonine The cycloalkyl carbonyl amino acid according to any one of claims 1 to 5 , which is an α-amino acid selected from lysine, homolysine, naphthylalanine, α-aminoadipic acid, thienylglycine, pyridylalanine, and cyclohexylalanine. An ester derivative or a pharmaceutically acceptable salt thereof. In formula (I), (I ′) or (I ″), R ¹ or R ¹ ′ is a substituted or unsubstituted 3- to 7-membered ring containing at least one nitrogen atom, oxygen atom or sulfur atom as a ring-constituting atom. A substituted heterocyclic group or a substituted aromatic hydrocarbon group, R ² or R ² ′ is an alkyl group having 1 to 4 carbon atoms, R ⁸ is an alkyl group having 1 to 6 carbon atoms, and ring A is It is a cyclohexylidene group, The cycloalkyl carbonyl amino acid ester derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 . A carboxylic acid derivative represented by the following formula (VI) or an oxazolone derivative represented by the formula (I _O ) is reacted with an amino acid ester derivative represented by the formula (IX). A method for producing an alkylcarbonylamino acid ester derivative.
(Wherein R ¹ , R ² , R ⁸ and ring A have the same meanings as in claim 1).