JP2004035574A - Aliphatic nitrogenous five-membered ring compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new aliphatic nitrogenous five-membered ring compound having excellent dipeptidyl peptidase IV (DPPIV) inhibitory action and its pharmacologically permissible salts, and to provide a method for producing the compound. <P>SOLUTION: The aliphatic nitrogenous five-membered ring compound is represented by formula [1] [wherein, A is CH<SB>2</SB>or S; R<SP>1</SP>is H, a lower alkyl, a hydroxy lower alkyl or a lower alkoxy lower alkyl; X is N(R<SP>3</SP>) or O; R<SP>3</SP>is H or a lower alkyl; and R<SP>2</SP>is (1) a (substituted) cyclic group or (2) a (substituted) amino]. <P>COPYRIGHT: (C)2004,JPO

Description

The present invention relates to a novel aliphatic nitrogen-containing five-membered ring compound having an excellent inhibitory activity against dipeptidyl peptidase IV (DPPIV) and useful as a medicament.

Dipeptidyl peptidase IV (DPPIV) is a serine protease that specifically hydrolyzes the dipeptide Xaa-Pro or Xaa-Ala (Xaa may be any amino acid) from the N-terminus of the polypeptide chain. .

There are various reports on the role of DPPIV (also referred to as CD26) in vivo and its relationship with diseases (Non-patent Documents 1 to 4).

GLP-1 (glucagon-like peptide 1) is a peptide hormone having a function of amplifying insulin secretion mainly in a glucose-dependent manner, and is mainly secreted after eating from the lower small intestine and acts on the pancreas. There are also reports suggesting that GLP-1 has an antifeedant effect. DPPIV hydrolyzes and inactivates this GLP-1 and produces a peptide that acts as an antagonist of GLP-1.
A substance that inhibits the enzyme activity of DPPIV enhances the action of endogenous GLP-1 through its inhibitory action, thereby increasing the insulin secretory response to an oral glucose load and improving impaired glucose tolerance. I do.

Therefore, DPPIV inhibitors are considered to be useful for prevention and treatment of diabetes (particularly type 2 diabetes) and the like. Also, other diseases induced or exacerbated by impaired glucose tolerance (eg, hyperglycemia (eg, postprandial hyperglycemia), hyperinsulinemia, diabetic complications (eg, renal disorder, neuropathy), abnormal lipid metabolism, For obesity and the like). Furthermore, it is also expected to be effective in preventing and treating diseases (eg, overeating, obesity, etc.) which are expected to be improved by enhancing the antifeedant effect of GLP-1.

Ｄ In addition, the expression of DPPIV (CD26) present on the surface of T cells in immune system cells is induced by activation of T cells, and plays an important role in T cell activation and proliferation. It is known that blocking DPPIV (CD26) with an antibody or an inhibitor suppresses T cell activation. In addition, there is an interest in the relationship between the present enzyme and a disease state in diseases of abnormal collagen metabolism and abnormal immune. For example, the DPPIV (CD26) positive rate of peripheral blood T cells is increasing in rheumatic patients, and high DPPIV activity is detected in urine of nephritis patients. In addition, DPPIV (CD26) is thought to play an important role in the entry of HIV into lymphocytes.

Therefore, substances that inhibit DPPIV (CD26) also prevent autoimmune diseases (eg, arthritis, rheumatoid arthritis), osteoporosis, acquired immunodeficiency syndrome (AIDS), and rejection of transplanted organs and tissues. Or a therapeutic effect is expected.

On the other hand, Patent Documents 1 and 2 disclose 2-cyanopyrrolidine derivatives having a DPPIV inhibitory action as compounds having a DPPIV inhibitory action.

Holst et al., Diabetes, 47, 1663-1670, 1998

Augustyns et al., Current Medicinal Chemistry, Vol. 6, pp. 311-327, 1999. Meester et al., Immunol. Today, Vol. 20, pp. 367-375, 1999 Fleicher et al., Immunol. Today, Vol. 15, pp. 180-184, 1994. International Publication Patent WO98 / 19998 International Patent Publication WO00 / 34241

The present invention provides a novel aliphatic nitrogen-containing five-membered ring compound having an excellent DPPIV inhibitory action.

解決 In order to solve the problems, the present inventors have conducted intensive studies and, as a result, have found a novel aliphatic nitrogen-containing five-membered ring compound having DPPIV inhibitory activity, and completed the present invention.

{That is, the present invention relates to a compound represented by the general formula [I]:

(In the formula, A is -CH ₂ - or an -S-,
R ¹ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group,
X is ^{-N (R 3) -, -} O-, or -CO- represent,
R ³ represents a hydrogen atom or a lower alkyl group;
R ² is (1) an optionally substituted cyclic group, wherein the cyclic group moiety is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic hydrocarbon group. Represents a group which is a cyclic heterocyclic group or (2) an amino group which may be substituted. )
Or a pharmacologically acceptable salt thereof.

目的 The target compound [I] of the present invention may have optical isomers based on asymmetric carbon, and the present invention includes any of these optical isomers and also includes a mixture thereof. In addition, there are isomers (cis or trans) based on the relative position of the substituent with respect to the reference plane of the cyclic group, and the present invention includes any of these isomers and also includes a mixture thereof.

In the present invention, examples of the lower alkyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkoxy group, and lower alkylamino group include straight-chain or branched-chain ones having 1 to 6 carbon atoms. 1-4. Examples of the lower alkanoyl group and lower alkanoylamino group include linear or branched ones having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms. The lower cycloalkyl group and the lower cycloalkenyl group include those having 3 to 8 carbon atoms, especially those having 3 to 6 carbon atoms. Examples of the lower alkylene group include linear or branched ones having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. Examples of the lower alkenyl group and the lower alkenylene group include those having 2 to 7 carbon atoms, particularly those having 2 to 5 carbon atoms. Further, examples of the halogen atom include fluorine, chlorine, bromine and iodine.

目的 The target compound [I] of the present invention or a pharmaceutically acceptable salt thereof has an excellent inhibitory action on the enzyme activity of DPPIV. In particular, it has an excellent inhibitory effect on human DPPIV. It also shows high selectivity for DPPIV (ie, type IV dipeptidyl peptidase) among various serine proteases (eg, plasmin, thrombin, prolyl endopeptidase, trypsin, dipeptidyl peptidase II, etc.). In addition, the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof improves the insulin secretory response to an oral glucose load through its DPPIV inhibitory action.

In the target compound [I] of the present invention, specific examples of the hydrogen atom or lower alkyl group represented by R ³ include a hydrogen atom and a methyl group. Of these, a hydrogen atom is more preferred.

In the compound [I] of the present invention, specific examples of the “hydrogen atom, lower alkyl group, hydroxy lower alkyl group or lower alkoxy lower alkyl group” represented by R ¹ include, for example, a hydrogen atom, a methyl group, a hydroxymethyl And a methoxymethyl group. Of these, a hydrogen atom is preferred.

In the compound [I] of the present invention, the cyclic group portion of the “optionally substituted cyclic group” represented by R ² includes:
(I) a monocyclic, bicyclic or tricyclic hydrocarbon group and (ii) a monocyclic, bicyclic or tricyclic heterocyclic group.

Examples of the monocyclic, bicyclic or tricyclic hydrocarbon group include those having 3 to 15 carbon atoms, which may be partially or wholly saturated.

{Examples of the monocyclic hydrocarbon group include those having 3 to 7 carbon atoms, and specific examples include a phenyl group, a cyclohexyl group, a cyclopentyl group, a cyclobutyl group, and a cyclopropyl group.

Examples of the bicyclic hydrocarbon group include those having 9 to 11 carbon atoms, and specifically, an indanyl group, an indenyl group, a naphthyl group, a tetrahydronaphthyl group, and some or all of these groups are saturated. And a cyclic group.

As the tricyclic hydrocarbon group, those having 12 to 15 carbon atoms are preferable, and specific examples thereof include a fluorenyl group, an anthryl group, a phenanthryl group, and a cyclic group in which some or all of these groups are saturated. No.

The monocyclic, bicyclic or tricyclic heterocyclic group includes, for example, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, even if a part or all of the hetero atoms are saturated. A good example is a monocyclic, bicyclic or tricyclic heterocyclic group.

The monocyclic heterocyclic group is a heterocyclic group containing one or two hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and is a heterocyclic group having a saturated or unsaturated 5- to 7-membered ring. Ring group, specifically,
Pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxolanyl group, thiolanyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, furyl group, oxazolyl group, isoxazolyl group, oxaziazolyl group , Thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group , A perhydroazepinyl group, a perhydrothiazepinyl group, and a cyclic group partially or wholly saturated with these groups.

The bicyclic heterocyclic group is a heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and includes two saturated or unsaturated 5- to 7-membered rings. Heterocyclic group obtained by condensation, specifically,
Indolinyl group, isoindolinyl group, indolyl group, indazolyl group, isoindolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group,
Benzodioxolanyl group, benzothienyl group, benzofuryl group, thienopyridyl group, thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, quinazolinyl group, phthalazinyl group, cinnolinyl group, chromanyl group, Examples include an isochromanyl group, a naphthyridinyl group, and a cyclic group partially or wholly saturated with these groups.

The tricyclic heterocyclic group is a heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and has three saturated or unsaturated 5- to 7-membered rings. Heterocyclic group obtained by condensation, specifically,
Examples include a benzooxolanopyrimidinyl group, a β-carbolinyl group, a carbazolyl group, a phenothiazinyl group, a phenoxazinyl group, and a cyclic group in which some or all of these groups are saturated.

Of these cyclic groups (monocyclic, bicyclic or tricyclic hydrocarbon groups or monocyclic, bicyclic or tricyclic heterocyclic groups),
"(I) a monocyclic hydrocarbon group having 3 to 7 carbon atoms,
(Ii) a bicyclic hydrocarbon group having 9 to 11 carbon atoms,
(Iii) a monocyclic heterocyclic group containing one or two hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or
(Iv) Bicyclic heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and formed by condensing two 5- to 7-membered rings "
Are preferred, and specific examples of such a group include:
`` Phenyl group, cyclohexyl group, cyclopentyl group, cyclobutyl group, cyclopropyl group, indanyl group, indenyl group, naphthyl group, tetrahydronaphthyl, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxolanyl group, thiolanyl group, pyrrolinyl group, imidazolinyl Group, pyrazolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, furyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, piperidyl group, piperazinyl group, Morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group, Hydroazepinyl group, perhydrothiazepinyl group, indolinyl group, isoindolinyl group, indolyl group, indazolyl group, isoindolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, benzodioxolanyl group, benzothienyl group, benzofuryl group, thienopyridyl group , Thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, quinazolinyl group, phthalazinyl group, cinnolinyl group, chromanyl group, isochromanyl group, naphthyridinyl group, and some or all of these are saturated And the like cyclic group ”.

Among them, more preferred specific examples include:
"Phenyl group, cyclohexyl group, pyrrolidinyl group, tetrazolyl group,
Furyl, thienyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, perhydroazepinyl, indolinyl, isoindolinyl, benzothienyl, Thienopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, and a cyclic group in which some or all of these are saturated '' and the like.
`` A pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a pyridyl group, a pyrimidinyl group, an indolinyl group, an isoindolinyl group, a pyrrolopyridyl group, a dihydropyrrolopyridyl group, and a cyclic system in which some or all of these are saturated And the like ”.

Among these, particularly preferred specific examples include:
"1-pyrrolidinyl group, 1-piperidyl group, 1-piperazinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 2-pyridyl group, 2-pyrimidinyl group, 2-isoindolinyl group, 1-indolinyl group, and 2,3- Dihydro-1H-pyrrolo [3,4-b] pyridin-2-yl group and the like ".

The “optionally substituted cyclic group (monocyclic, bicyclic or tricyclic hydrocarbon group or monocyclic, bicyclic or tricyclic heterocyclic group)” represented by R ² is unsubstituted , But may have 1 to 3 identical or different substituents.
The substituent in the cyclic group is not particularly limited, but specific examples include a substituent selected from the following “group A substituents”, among which “A ′ group substituent” is more preferable.

In the target compound [I] of the present invention, the “optionally substituted amino group” represented by R ² may be unsubstituted, but may have the same or different one or two substituents. It may have an amino group (mono- or di-substituted amino group).
The substituent in the amino group is not particularly limited, but specific examples include a substituent selected from the following “group B substituents”, of which “group B ′ substituent” is more preferable.

As the “optionally substituted amino group” represented by R ² , a substituted amino group (mono- or di-substituted amino group) is preferable, and more specifically,
The same or different 1 selected from the group consisting of lower alkyl groups (eg, methyl group, ethyl group, isopropyl group, and butyl group), lower cycloalkyl groups, lower alkoxy-substituted lower alkyl groups, pyrimidinyl groups, thiazolyl groups and thiadiazolyl groups; And an amino group substituted with two substituents ". this house,
"(I) an amino group disubstituted with the same or different substituent (s) selected from a lower alkyl group (such as a methyl group, an ethyl group, an isopropyl group and a butyl group), a lower cycloalkyl group and a lower alkoxy-substituted lower alkyl group; Or (ii) an amino group mono-substituted with a substituent selected from a pyrimidinyl group, a thiazolyl group and a thiadiazolyl group,
“Amino groups di-substituted with the same or different substituents selected from lower alkyl groups (eg, methyl group, ethyl group, isopropyl group, butyl group), lower cycloalkyl groups and lower alkoxy-substituted lower alkyl groups” are particularly preferred. .

---- Group A substituent: -------------------------
Group A substituents include the following:
A halogen atom (Cl, F, Br, etc.); a cyano group; a nitro group; an oxo group; a hydroxyl group; a carboxy group; an oxydyl group; an amino group; a carbamoyl group; an aminosulfonyl group; a lower alkyl group; ;
Lower alkoxycarbonyl group; lower alkoxy-substituted lower alkanoyl group;
Lower alkoxycarbonyl-substituted lower alkoxy group;
Lower alkoxycarbonyl-substituted lower alkoxycarbonyl group;
Lower alkylthio group (lower alkylsulfanyl group);
Lower alkylsulfonyl group;
A di-lower alkylamino-substituted lower alkoxy group;
A di-lower alkylaminocarbonyloxy group;

A lower alkyl group substituted with a group selected from an amino group, a carbamoyl group, a halogen atom, a hydroxy group, a carboxy group, a lower alkoxy group, and a mono- or di-substituted amino group; Although it is not limited, specific examples include the substituents of Group C described below. ];

Mono- or di-substituted amino group and mono- or di-substituted carbamoyl group [Substituents in the substituted amino group or substituted carbamoyl group are not particularly limited, and specific examples thereof include the substituents in Group C described below. ];

A substituted or unsubstituted lower cycloalkyl group,
Substituted or unsubstituted lower cycloalkyl-CO-,
A substituted or unsubstituted lower cycloalkyl-lower alkyl group,
A substituted or unsubstituted phenyl group,
Substituted or unsubstituted phenyl-O-,
Substituted or unsubstituted phenyl-CO-,
A substituted or unsubstituted phenyl-lower alkyl group,
A substituted or unsubstituted phenyl-O-lower alkyl group,
A substituted or unsubstituted phenylsulfonyl group,
A substituted or unsubstituted phenyl lower alkoxy group,
A substituted or unsubstituted phenyl lower alkoxycarbonyl group,
A substituted or unsubstituted lower cycloalkenyl group (such as a cyclobutenyl group),
A substituted or unsubstituted bicyclic heterocyclic group,
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group,
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group -O-,
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group -CO-,
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group -CO-lower alkyl group; and
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-lower alkyl group

(Substituted lower cycloalkyl group portion, substituted phenyl group portion, substituted lower cycloalkenyl group portion, substituted bicyclic heterocyclic group portion, or substituted monocyclic 5- to 6-membered heterocyclic group, all substituents are particularly Although not limited, specifically, for example,
Examples include a halogen atom (Cl, F, Br, etc.), a cyano group, a nitro group, an oxo group, and substituents of the group C substituent described below.
Examples of the monocyclic 5 to 6-membered heterocyclic group moiety include a monocyclic 5 to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, Specifically, piperidyl group, piperazinyl group, morpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group,
A thiazolyl group, a thiadiazolyl group and a thienyl group.
In addition, the bicyclic heterocyclic group moiety includes a bicyclic heterocyclic ring containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and formed by condensing two 5- to 6-membered rings. And an isoindolinyl group and an indolinyl group. ].
-------------------------------------------------- -----------

--- A 'group substituent (particularly preferable group A substituent): ---------------
More preferred Group A substituents include:
A halogen atom (Cl 2 or the like); a cyano group; a nitro group; an oxo group; a carbamoyl group; a lower alkyl group; a lower alkoxy group; a lower alkanoyl group;
Lower alkoxy-substituted lower alkyl group,
A mono- or di-substituted amino group (such as a lower cycloalkylcarbonyl-substituted amino group), a mono- or di-substituted carbamoyl group (such as a phenyl-substituted carbamoyl group),
Lower cycloalkyl-CO-,
A substituted or unsubstituted phenyl group (phenyl group, halophenyl group, etc.),
Substituted or unsubstituted phenyl-lower alkyl groups (phenyl lower alkyl groups, halophenyl lower alkyl groups, etc.),
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group (such as a thienyl group),
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -O- (pyrimidinyloxy group, halopyrimidinyloxy group, etc.),
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -CO- (pyridylcarbonyl group, thienylcarbonyl group, etc.).
(In the above, the monocyclic 5- to 6-membered heterocyclic group moiety includes a monocyclic 5- to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. And specific examples include a pyridyl group, a pyrimidinyl group, and a thienyl group.)
-------------------------------------------------- ------------

------- B group substituent: -------------------------------------- -----
Group B substituents include:
Lower alkyl groups; lower alkoxy-substituted lower alkyl groups; lower alkoxycarbonyl-substituted lower alkyl groups;
A hydroxy lower alkyl group; a carboxy lower alkyl group;

A substituted or unsubstituted lower cycloalkyl group,
A substituted or unsubstituted lower cycloalkyl-lower alkyl group,
A substituted or unsubstituted phenyl group,
A substituted or unsubstituted phenyl-lower alkyl group,
A substituted or unsubstituted bicyclic hydrocarbon group,
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group,
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group-lower alkyl group, and
A substituted or unsubstituted bicyclic heterocyclic group-lower alkyl group (substituted lower cycloalkyl group, substituted phenyl group, substituted bicyclic hydrocarbon group, substituted monocyclic 5- to 6-membered heterocyclic group, or The substituent in the substituted bicyclic heterocyclic group moiety is not particularly limited, and specific examples include a substituent of the group C substituent described below.
Examples of the bicyclic hydrocarbon group portion include a bicyclic hydrocarbon group having 9 to 11 carbon atoms, and specific examples include an indanyl group.
Examples of the monocyclic 5- to 6-membered heterocyclic group include a monocyclic 5- to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. ,In particular,
Piperidyl group, piperazinyl group, morpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, thiadiazolyl group and thienyl group. Can be
In addition, the bicyclic heterocyclic group moiety is formed by condensing two saturated or unsaturated 5- or 6-membered rings containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples include a heterocyclic group, and specific examples include a benzodioxolanyl group. ].
-------------------------------------------------- ----

------- B 'group substituent (more preferable B group substituent): --------
More preferred Group B substituents include:
Lower alkyl groups (such as methyl group, ethyl group, isopropyl group and butyl group), lower cycloalkyl group, lower alkoxy-substituted lower alkyl group, pyrimidinyl group, thiazolyl group and thiadiazolyl group.

Particularly preferred Group B substituents include:
In the case where R ² is a disubstituted amino group,
A lower alkyl group (such as a methyl group, an ethyl group, an isopropyl group, or a butyl group), a lower cycloalkyl group, a lower alkoxy-substituted lower alkyl group; and when R ² is a monosubstituted amino group,
Pyrimidinyl, thiazolyl and thiadiazolyl groups.
-------------------------------------------------- ---------

------- C group substituent: -------------------------------------- -
Group C substituents include:
A lower alkyl group; a hydroxy lower alkyl group, a lower alkanoyl group; a lower cycloalkylcarbonyl group; a lower alkoxy group; a lower alkoxycarbonyl group; a lower alkylsulfonyl group; a di-lower alkyl-substituted carbamoyl group; a di-lower alkylamino-substituted lower alkanoyl group; A substituted or unsubstituted phenyl group,
Substituted or unsubstituted phenyl-O-,
Substituted or unsubstituted phenyl-CO-,
A substituted or unsubstituted phenyl lower alkanoyl group,
A substituted or unsubstituted phenyl lower alkyl group,
A substituted or unsubstituted phenyl lower alkoxy group,
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group,
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -O- (pyridyloxy group and the like),
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -CO- (pyridylcarbonyl group, etc.)
And a substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-substituted amino group (eg, pyridylamino group)
[Substituents in the substituted phenyl group portion or the substituted monocyclic 5- to 6-membered heterocyclic group portion are not particularly limited, but specific examples include a halogen atom (Cl, F, Br, etc.), a cyano group, a nitro Group, oxo group,
Examples include a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, and a lower alkoxycarbonyl group.
Examples of the monocyclic 5 to 6-membered heterocyclic group moiety include a monocyclic 5 to 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, Specifically, piperidyl group, piperazinyl group, morpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, thiadiazolyl group and And a thienyl group. ]
-------------------------------------------------- -----------
In the target compound [I] of the present invention, R ² when X is —N (R ³ ) — or —O— is preferably an optionally substituted cyclic group. Can be

In the target compound [I] of the present invention, when X is —CO—, R ² is a group represented by the formula:

Suitable examples include (1) an optionally substituted monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group and (2) an optionally substituted amino group.

Further, in the target compound [I] of the present invention,
Of the two types of cis-trans isomers having the cyclohexyl ring as a reference plane in the structure [I], the trans-isomeric compound is more preferable in that a higher DPPIV inhibitory activity can be obtained. That is, in the target compound [I] of the present invention, the following partial structure

Or a pharmaceutically acceptable salt thereof is preferred.
In particular, in the compound in which the group X is -CO-, the superiority of the trans form is remarkable.

As one compound group of the compounds of the present invention, among the compounds [I],
R ² is (1) a cyclic group which may have 1 to 3 identical or different substituents selected from Group A substituents, wherein the cyclic group portion is (i) a monocyclic group, One or two identical or different substituents selected from a bicyclic or tricyclic hydrocarbon group or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) a group B substituent Examples of the compound include an amino group having a group. (Compound group 1)

As another compound group, in the compound [I] or the compound group 1, R ² is
(1) a cyclic group which may be substituted, wherein the cyclic group portion is selected from the following (i) to (iv): (i) a monocyclic hydrocarbon group having 3 to 7 carbon atoms ,
(Ii) a bicyclic hydrocarbon group having 9 to 11 carbon atoms,
(Iii) a monocyclic heterocyclic group containing one or two hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; and (iv) one to three selected from a nitrogen atom, an oxygen atom and a sulfur atom A bicyclic heterocyclic group comprising two or more fused 5- to 7-membered rings; or (2) a substituted amino group;
(Compound Group 2).

Further, in the compound group 2, R ² is
(1) An optionally substituted cyclic group, wherein the cyclic group portion is
Phenyl group, cyclohexyl group, cyclopentyl group, cyclobutyl group, cyclopropyl group, indanyl group, indenyl group, naphthyl group, tetrahydronaphthyl, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxolanyl group, thiolanyl group, pyrrolinyl group, imidazolinyl group , Pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, piperidyl, piperazinyl, morpholinyl Group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group, par Droazepinyl, perhydrothiazepinyl, indolinyl, isoindolinyl, indolyl, indazolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzodioxolanyl, benzothienyl, benzofuryl, thienopyridyl , Thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, quinazolinyl group, phthalazinyl group, cinnolinyl group, chromanyl group, isochromanyl group, naphthyridinyl group, and some or all of these are saturated Or (2) a substituted amino group. (Compound group 3)

In the compound group 3, as a more preferred compound group, R ² is
(1) An optionally substituted cyclic group, wherein the cyclic group portion is
Phenyl group, cyclohexyl group, pyrrolidinyl group, tetrazolyl group,
Furyl, thienyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, perhydroazepinyl, indolinyl, isoindolinyl, benzothienyl, benzothienyl, Or (2) a group selected from the group consisting of a thienopyridyl group, a pyrrolopyridyl group, a dihydropyrrolopyridyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, and a cyclic group in which some or all of these groups are saturated; And b) a compound that is a substituted amino group. (Compound group 4)

Further, in compound group 4, as a more preferred compound group, R ² is
(1) An optionally substituted cyclic group, wherein the cyclic group portion is
Pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, indolinyl group, isoindolinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, and cyclic groups in which some or all of these are saturated A compound selected from the group consisting of: and (2) a substituted amino group. (Compound group 5)

Further, among the compound [I], as another more preferred compound group, R ² is
(1) a cyclic group which may have 1 to 3 identical or different substituents selected from A ′ group substituents, wherein the cyclic group portion is
Pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, indolinyl group, isoindolinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, and cyclic groups in which some or all of these are saturated Or (2) an amino group substituted with one or two same or different substituents selected from the group B 'substituents. (Compound group 6)

Further, in compound [I] or each of compound groups 1, 2, 3, 4, 5 and 6 above, R ² when X is —N (R ³ ) — or —O— may be substituted. A group of compounds that are good cyclic groups are mentioned. (Compound group 7)

Further, in the compound [I] or each of the compound groups 1, 2, 3, 4, 5, and 6, when X is —CO—, R ² is a group represented by the formula:

And (2) a compound group which is an optionally substituted monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group or (2) an optionally substituted amino group. (Compound group 8)

Further, among the compound [I] or the respective compound groups 1, 2, 3, 4, 5, 6, 7 or 8, more preferred compound groups include:
X is -CO- or -O-, A is -CH ₂ -, compound group;
X is -CO- or -O-, A is -CH ₂ -, group of compounds ^{R 1} is a hydrogen atom;
X is -CO-, A is -CH ₂ -, group of compounds ^{R 1} is a hydrogen atom;
X is -CO-, A is -CH ₂ -, ^{R 1} is hydrogen atom, ^{R 2} is is an optionally substituted cyclic group compounds;
X is -CO-, A is -CH ₂ -, ^{R 1} is hydrogen atom, group of compounds ^{R 2} is an amino group substituted;
A group of compounds wherein X is -CO- or -O- and A is -S-;
A group of compounds wherein X is -CO- or -O-, A is -S-, and R ¹ is a hydrogen atom;
A group of compounds wherein X is -CO-, A is -S-, and R ¹ is a hydrogen atom;
A group of compounds wherein X is -CO-, A is -S-, R ¹ is a hydrogen atom, and R ² is an optionally substituted cyclic group;
A compound group wherein X is -CO-, A is -S-, R ¹ is a hydrogen atom, and R ² is a substituted amino group; and the like.

Furthermore, in each of the above compound groups, as a more preferred compound group,
The following partial structure

And a compound group having the formula:

Further, among the compound [I], preferred specific compounds include the following compounds;
(S) -2-cyano-1- [trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (5-cyano-2-pyridyloxy) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (5-bromo-2-pyrimidinyloxy) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano 1- [trans-4- (5-pyrimidinylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano 1- [trans-4- (N-ethyl-N-methoxyethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (N-ethyl-N-isopropylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (N-methyl-N-butylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4-[(S) -2-methoxymethylpyrrolidin-1-ylcarbonyl] cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (3-carbamoylpiperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (3-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (2-isoindolinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- [4- (3-pyridylcarbonyl) piperazin-1-ylcarbonyl] cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (3-thenoyl) piperazin-1-ylcarbonyl] cyclohexylamino} acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (4-chlorophenyl) piperazin-1-ylcarbonyl] cyclohexylamino} acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (cis-2,6-dimethylmorpholinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (5-nitro-2-isoindolinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (piperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-carbamoylpiperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (1-pyrrolidinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-cyclopropylcarbonylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-propionylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (1-indolinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (2,3-dihydro-1H-pyrrolo [3,4-b] pyridin-2-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- [4- (2-pyrimidinyloxy) piperidinocarbonyl] cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (5-bromo-2-pyrimidinyloxy) piperidinocarbonyl] cyclohexylamino} acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (cis-3,5-dimethyl-4-benzylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-cyclohexylcarbonylaminopiperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (N-phenylcarbamoyl) piperazin-1-ylcarbonyl] cyclohexylamino} acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-ethoxycarbonylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (2-thienyl) piperidinocarbonyl] cyclohexylamino} acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (1,1-dioxoperhydro-1,4-thiazin-4-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;

(R) -4-cyano-3- [trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylthiazolidine;
(R) -4-cyano-3- [trans-4- (5-cyano-2-pyridyloxy) cyclohexylamino] acetylthiazolidine;
(R) -4-cyano-3- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylthiazolidine;
(R) -4-cyano-3- [trans-4- (2-isoindolinylcarbonyl) cyclohexylamino] acetylthiazolidine;
(R) -4-cyano-3- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylthiazolidine; and (R) -4-cyano-3- [trans-4- (pyrrolidinylcarbonyl) cyclohexylamino] Acetylthiazolidine.

目的 The target compound [I] of the present invention or a pharmaceutically acceptable salt thereof has an excellent inhibitory action on the enzyme activity of DPPIV. In particular, it has an excellent inhibitory effect on human DPPIV. It also shows high selectivity for DPPIV (ie, type IV dipeptidyl peptidase) among various serine proteases (eg, plasmin, thrombin, prolyl endopeptidase, trypsin, dipeptidyl peptidase II, etc.). In addition, the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof improves the insulin secretory response to an oral glucose load through its DPPIV inhibitory action.

Therefore, the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof can improve the disease state by inhibiting DPPIV-related diseases (disease mediated by DPPIV), that is, by inhibiting the enzyme activity of DPPIV. It is useful as a prophylactic or therapeutic drug for potential diseases.

Such diseases include, for example, diabetes (eg, type 1 diabetes, type 2 diabetes, etc.), hyperglycemia (eg, postprandial hyperglycemia, etc.), hyperinsulinemia, diabetic complications (eg, renal disorder, neuropathy, etc.) ), Obesity, overeating, dyslipidemia (eg, hyperlipidemia such as hypertriglyceridemia), autoimmune diseases (eg, arthritis, rheumatoid arthritis, etc.), osteoporosis, acquired immunodeficiency syndrome (AIDS), Examples include rejection of transplanted organs and tissues. The target compound [I] of the present invention or a pharmaceutically acceptable salt thereof is particularly useful as an agent for preventing or treating diabetes (particularly type 2 diabetes).

The compound of the present invention has low toxicity and high safety when used as a pharmaceutical compound. In addition, it shows excellent pharmacokinetic properties [bioavailability, in vitro metabolic stability (stability in human liver homogenate), P450 inhibitory activity, protein binding, etc.].

The DPPIV inhibitory effect of the compound of the present invention and the drug effect based thereon (antiglycemic effect, insulin secretory response improving effect on glucose load, etc.) are known or equivalent thereto (WO98 / 19998; WO00 / 34241; Holst et al., Diabetes). Augustin et al., Current Medicinal Chemistry, Vol. 6, pp. 311-327, 1999; Meester et al., Immunol. Today, Vol. 20, pp. 367-375. Fleicher et al., Immunol. Today, Vol. 15, pp. 180-184, 1994).

目的 The target compound [I] of the present invention can be used for pharmaceutical use in free form or in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of compound [I] include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citric acid Salts, organic salts such as methanesulfonate, benzenesulfonate, tosylate or maleate, and the like. When the compound has a substituent such as a carboxyl group, a salt with a base (for example, an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt) is used.

目的 The target compound [I] of the present invention or a salt thereof includes any of its inner salts and adducts, solvates and hydrates thereof.

The target compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and may be administered in the form of tablets, granules, capsules, powders, injections, inhalants and the like. It can be used as a conventional pharmaceutical preparation. For example, the compound of the present invention is used together with an activator or diluent such as a binder, a disintegrant, a bulking agent, a filler, a lubricant, and the like, which are acceptable in general medicaments, and formulated and used by an ordinary method. be able to.

The dose of the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method, age, weight and condition of the patient, but is usually about 0.01 to 300 mg / kg per day. In particular, it is preferably about 0.1 to 30 mg / kg.

目的 The target compound [I] of the present invention can be produced by the following [Method A] to [Method B], but is not limited thereto.

[Method A]
The target compound [I] of the present invention has the general formula [II]

(In the formula, Z ¹ represents a reactive residue, and other symbols have the same meanings as described above.)
And a compound represented by the general formula [III]

(Wherein the symbols have the same meanings as described above.)
And a salt thereof, if desired, and converting the product into a pharmaceutically acceptable salt, if desired.

塩 As the salt of the compound [III], for example, a salt with an inorganic acid such as a hydrochloride or a sulfate or an inorganic base such as an alkali metal salt or an alkaline earth metal salt can be used.

As the reactive residue of Z ^1, halogen atom, lower alkylsulfonyloxy group, but the reactive residue conventional such arylsulfonyloxy group can be suitably used, especially a halogen atom.

反 応 The reaction of compound [II] with compound [III] or a salt thereof can be carried out in the presence or absence of a deoxidizing agent in a suitable solvent or without a solvent.

The solvent may be any solvent that does not adversely affect the reaction, for example, acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride , Dichloroethane, chloroform or a mixed solvent thereof can be used as appropriate.

The present reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.

Examples of the deoxidizing agent include inorganic bases (eg, alkali metal hydride such as sodium hydride, alkali metal carbonate such as sodium carbonate and potassium carbonate, alkali metal alkoxide such as sodium methoxide, alkali metal such as sodium, sodium hydroxide , Potassium hydroxide or the like, an alkali metal hydroxide or the like) or an organic base (eg, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.) can be suitably used.

[Method B]
Further, among the target compounds [I] of the present invention,
General formula [Ia]

(Wherein, R ²¹ is a formula

(1) an optionally substituted monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group or (2) an optionally substituted amino group, and other symbols have the same meanings as described above. Having. )
The compound represented by the general formula [IV]

(In the formula, R ⁴ represents a protecting group for an amino group, and other symbols have the same meanings as described above.)
Or a salt thereof represented by the general formula [V]
R ²¹ -H
Or a salt thereof, to give a compound of the general formula [VI]

(Wherein the symbols have the same meanings as described above.)
Or a salt thereof, and the amino-protecting group (R ⁴ ) of the product is further removed, and if desired, the product can be converted into a pharmaceutically acceptable salt to produce the compound.

塩 As the salts of the compounds [IV] to [VI], for example, salts with inorganic acids such as hydrochlorides and sulfates or salts with inorganic bases such as alkali metal salts and alkaline earth metal salts can be used.

Examples of the protecting group for the amino group of R ⁴ include a conventional amino group protecting group such as a t-butoxycarbonyl group, a benzyloxycarbonyl group, a trifluoroacetyl group, a chloroacetyl group, and a 9-fluorenylmethyloxycarbonyl group. Can also be suitably used.

反 応 The reaction of compound [IV] or a salt thereof with compound [V] or a salt thereof can be carried out in the presence or absence of a condensing agent, in a suitable solvent or without a solvent.

The solvent may be any solvent that does not adversely affect the reaction, for example, acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride, dichloroethane, Chloroform or a mixed solvent thereof can be used as appropriate.

The present reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.

As the condensing agent, O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate, DCC (dicyclohexylcarbodiimide), EDC (1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide), chloroformates (eg, ethyl chloroformate, isobutyl chloroformate), carbonyldiimidazole, and the like can be suitably used.

In order to promote the reaction, a base (such as sodium carbonate, sodium hydrogencarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, etc.) and , 1-hydroxybenzotriazole, 1-hydroxysuccinimide, and other additives can also be added to the condensing agent.

The subsequent removal of the amino group-protecting group (R ⁴ ) of the compound [VI] can be carried out by a conventional method. For example, it can be carried out by acid treatment, base treatment or catalytic reduction in a suitable solvent or without a solvent. it can.

The solvent may be any solvent that does not adversely affect the reaction, for example, methanol, ethanol, isopropyl alcohol, propyl alcohol, dioxane, methylene chloride, chloroform, dichloroethane, ether, tetrahydrofuran, ethyl acetate, toluene or a mixed solvent thereof. It can be used as appropriate.
This reaction suitably proceeds at −78 to 80 ° C., particularly at 0 ° C. to room temperature.

As the diacid, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid can be suitably used.

Examples of the base include inorganic bases (eg, alkali metal hydride such as sodium hydride, alkali metal carbonate such as sodium carbonate and potassium carbonate, alkali metal alkoxide such as sodium methoxide, alkali metal such as sodium, sodium hydroxide, water An alkali metal hydroxide such as potassium oxide or the like or an organic base (eg, triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, piperidine, dimethylaniline, dimethylaminopyridine, etc.) can be preferably used.

The catalytic reduction reaction can be carried out in a hydrogen atmosphere by suitably using palladium carbon, palladium hydroxide carbon, platinum oxide, Raney nickel or the like.

原料 The starting compound [II] of the present invention can be produced, for example, according to the methods described in International Patent Publication Nos. WO 98/19998, WO 00/34241, and Reference Examples (Reference Examples 1 and 2) described later.

{For example, the compound [II] has the general formula [10]

(Wherein the symbols have the same meanings as described above.)
And a compound represented by the general formula [11]:
Z ² —CH ₂ CO—Z ³ [11]
(Wherein, Z ² and Z ³ are the same or different and represent reactive residues.)
Is reacted in the presence of a deoxidizing agent (for example, triethylamine or the like) to give a compound of the general formula [12]

(Wherein the symbols have the same meanings as described above.)
Can be obtained by further treating the product with a dehydrating agent (for example, phosphorus oxychloride, trifluoroacetic anhydride, etc.) by a conventional method.

As the reactive residue of Z ² or Z ^3, the same conventional reactive residue as that of Z ¹ can be suitably used.

Specifically, the starting compound [III] can be produced, for example, in the same manner as described in Reference Examples (Reference Examples 3 to 14) described later.

For example, the compound [III] in which X is —N (R ³ ) — or —O— is represented by the general formula [13]

(In the formula, V ¹ represents —NH (R ³ ) — or a hydroxy group, and other symbols have the same meanings as described above.)
And a protected amino group thereof or a salt thereof, and a compound represented by the general formula [14]:
R ² -Z ⁴ [14]
(In the formula, Z ⁴ represents a reactive residue, and other symbols have the same meanings as described above.)
Is reacted with or without a deoxidizing agent (for example, an organic base such as triethylamine and diisopropylethylamine, an inorganic base such as sodium hydride and potassium carbonate), and if necessary, an amino group Can be produced by deprotecting the protecting group by a conventional method.

As the amino-protecting group, any of the same conventional protecting groups as those described above for R ⁴ can be suitably used.

As the reactive residue of Z ^4, it can be suitably used reactive residues similar conventional to the Z ^1.

For example, X is -CO-, and R ² is of the formula

The compound [III] which is a group represented by the general formula [15]

(Wherein, V ² represents —COOH, and other symbols have the same meanings as described above.)
A compound represented by the formula, an amino-protected form thereof or a salt thereof,
General formula [16]
R ²² -H [16]
(Wherein, R ²² is represented by the formula

(1) an optionally substituted monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group or (2) an optionally substituted amino group, which is cyclic or linear together with a hydrogen atom Forms an amine. )
And a salt thereof in the presence of a condensing agent (such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) and, if necessary, remove the amino-protecting group by a conventional method. It can be manufactured by protecting.

Alternatively, the compound [III] wherein X is -CO- is
General formula [17]

(In the formula, Z ⁵ represents a reactive residue, and other symbols have the same meanings as described above.)
A compound represented by the formula, an amino-protected form thereof or a salt thereof,
General formula [18]
R ² -Sn (R ⁵ ) ₃ [18]
(In the formula, R ⁵ represents a lower alkyl group, and other symbols have the same meanings as described above.)
Can be obtained by reacting with a compound represented by the following formula in the presence of a palladium catalyst (for example, dichlorobis (triphenylphosphine) palladium or the like).

As the amino-protecting group, any of the same conventional protecting groups as those described above for R ⁴ can be suitably used. As the reactive residue of Z ^5, it can be suitably used reactive residues similar conventional to the Z ^1.

Alternatively, compound [III] in which X is —N (R ³ ) — is represented by general formula [19]

(Wherein the symbols have the same meanings as described above.)
And a protected amino group or a salt thereof represented by the general formula [20]:
R ² -V ³ [20]
(In the formula, V ³ represents —N (R ³ ) H, and other symbols have the same meanings as described above.)
Can be produced by reacting with a compound represented by the formula (1) in the presence of a reducing agent (such as sodium triacetoxyborohydride) and, if necessary, deprotecting an amino-protecting group by a conventional method.

As the amino-protecting group, any of the same conventional protecting groups as those described above for R ⁴ can be suitably used.

Starting compounds [10] to [20] can be produced by a known method or a method described in Reference Examples described later. When the trans-form starting material compound [III] having a cyclohexane ring as a reference plane is obtained, a trans-form starting cyclohexane compound (compounds [13], [15], [17], etc.) may be used.

In addition, for example, as shown in the following figure, the starting compound [IV] is produced in the same manner as in the method described in Examples (Examples 3-1 (1) to (3)) or according to the method. be able to. (In the figure, Z ⁶ represents a reactive residue, R ⁴ represents an amino group protecting group, and other symbols have the same meaning as described above.)
As the reactive residue of Z ^6, it can be suitably used reactive residues similar conventional to the Z ^1.

The compound [I] of the present invention or its starting compound produced as described above is isolated or purified as it is or as a salt thereof. The salt can be produced by subjecting it to a commonly used salt-forming treatment. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.

In the compound of the present invention, optical isomers such as a racemate, an optically active substance and a diastereomer may exist alone or as a mixture. Stereochemically pure isomers can be derived by using stereochemically pure starting compounds or by separating optical isomers by a general racemic resolution method. The mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography.

Hereinafter, the present invention will be described in more detail with reference to Examples, but these Examples do not limit the present invention.

Example 1a-1
100 mg of (S) -1-bromoacetyl-2-cyanopyrrolidine (Reference Example 1) and N- (5-nitro-2-pyridyl) -trans-1,4-cyclohexanediamine (Reference Example 3-1) Stir 327 mg of acetonitrile-methanol solution at room temperature for 15 hours. Water is added to the reaction mixture and extracted with chloroform. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by diol column chromatography [solvent: 0-10% methanol-chloroform] to obtain an oil. This was dissolved in 0.5 ml of ethyl acetate-0.5 ml of chloroform, 1.0 ml of 2N hydrochloric acid-ether and then 2 ml of ether were added, and the deposited precipitate was collected by filtration, washed with ether, and washed with (S) -2-cyano-1- [Trans-4- (5-Nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine dihydrochloride (Table 1a, Example 1a-1) is obtained.

Examples 1a-2 to 1d-152
Using (S) -1-bromoacetyl-2-cyanopyrrolidine and the corresponding starting compound, treatment was conducted in the same manner as in Example 1a-1, and the following Tables 1a to 1d (Examples 1a-2 to 1a-89, 1b -1 to 1b-71, 1c-1 to 1c-52, 1d-1 to 152).
(The corresponding starting compound is obtained by the same method as in Reference Examples described later, a known method, or a method combining them.)
However, the compound of Example 1d-77 can be obtained by using trans-4- (1-piperazinylcarbonyl) cyclohexylamine as a raw material.

Also, the compound of Example 1c-39 {(ie, (S) -2-cyano-1- {trans-4-[(N-carboxymethyl-N-methylamino) carbonyl] cyclohexylamino} acetylpyrrolidine.hydrochloride) Is the compound of Example 1c-38 {(ie, (S) -2-cyano-1- {trans-4-[(N-tert-butoxycarbonylmethyl-N-methylamino) carbonyl] cyclohexylamino} acetylpyrrolidine) Is treated with trifluoroacetic acid and then treated with hydrochloric acid.

Further, the compound of Example 1d-14 (that is, (S) -2-cyano-1- [trans-4- (1-piperazinylcarbonyl) cyclohexylamino] acetylpyrrolidine dihydrochloride) was prepared in Example 1d- A free form of the compound of No. 70 ((S) -2-cyano-1- [trans-4- (4-benzyloxycarbonyl-1-piperazinylcarbonyl) cyclohexylamino] acetylpyrrolidine) is treated with trimethylsilyl iodide. can get.

Examples 2-1 to 2-2
(1) 4-tert-butoxycarbonylamino-4-methylcyclohexanone (compound of Reference Example 6-1 (3)) 600 mg, sodium triacetoxyborohydride 783 mg, 3-cyanoaniline 343 mg, acetic acid 159 mg, and dichloroethane 6 ml Is stirred at room temperature for 16 hours. After dilution with a saturated aqueous solution of sodium bicarbonate, the mixture is extracted with chloroform. The extract is dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography [solvent: hexane-ethyl acetate (4: 1) → (1: 1)] to give N-tert-butoxycarbonyl-1-methyl-c-4- (3-cyano This gives 304 mg of -phenylamino) -r-1-cyclohexylamine and 292 mg of N-tert-butoxycarbonyl-1-methyl-t-4- (3-cyano-phenylamino) -r-1-cyclohexylamine.

(2) 243 mg of N-tert-butoxycarbonyl-1-methyl-c-4- (3-cyano-phenylamino) -r-1-cyclohexylamine obtained in (1) above was added to 2 ml of 4N hydrochloric acid / dioxane and 2 ml of ethanol. Is stirred at room temperature for 15 hours.
After concentration of the reaction solution, 320 mg of (S) -1-bromoacetyl-2-cyanopyrrolidine, 0.6 ml of triethylamine, 3.5 ml of acetonitrile and 1 ml of methanol are added to the residue, and the mixture is stirred at room temperature for 15 hours. After dilution with a saturated aqueous solution of sodium bicarbonate, the mixture is extracted with chloroform. The extract is dried over sodium sulfate and the solvent is distilled off under reduced pressure. 154 mg of a compound obtained by purifying the residue by silica gel column chromatography [solvent: chloroform-methanol (50: 1)] is treated with hydrochloric acid to give (S) -2-cyano-1- [1-methyl-c- 4- (3-Cyano-phenylamino) -r-1-cyclohexylamino] acetylpyrrolidine dihydrochloride (Table 2, Example 2-1) is obtained.

(3) Using N-tert-butoxycarbonyl-1-methyl-t-4- (3-cyano-phenylamino) -r-1-cyclohexylamine obtained in the above (1) and treating in the same manner as in (2) To give (S) -2-cyano-1- [1-methyl-c-4- (3-cyano-phenylamino) -r-1-cyclohexylamino] acetylpyrrolidine dihydrochloride (Table 2 Examples 2-2) is obtained.

Examples 2-3 to 2-8
Using the corresponding starting compounds, the compounds were treated in the same manner as in Examples 2-1 to 2-2 to obtain the compounds of Examples 2-3 to 2-8 in Table 2.

Example 3-1

{(1) 5.0 g of trans-4-ethoxycarbonylcyclohexylamine hydrochloride} is dissolved in water, alkalified by adding potassium carbonate, and extracted with chloroform. The extract is washed with brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. A mixture of the residue, 5.1 g of p-toluenesulfonic acid monohydrate and 50 ml of allyl alcohol is heated under reflux for 48 hours. After the reaction solution is concentrated, it is diluted with chloroform. The chloroform solution is washed with an aqueous solution of potassium carbonate, water, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography [solvent: chloroform-methanol-aqueous ammonia (500: 10: 1)] to obtain 3.29 g of trans-4- (2-propenyloxycarbonyl) cyclohexylamine.

(2) A mixture of 507 mg of the compound obtained in the above (1), 400 mg of (S) -1-bromoacetyl-2-cyanopyrrolidine, 714 mg of N, N-diisopropylethylamine, and 4 ml of acetonitrile is stirred at 50 ° C. for 12 hours. After cooling to room temperature, 476 mg of N, N-diisopropylethylamine and then 4 ml of a solution of 803 mg of di-tert-butyldicarbonate in 4 ml of acetonitrile are added, and the mixture is stirred at room temperature for 3 hours. After the reaction solution is concentrated, it is diluted with ethyl acetate. The ethyl acetate solution is washed with a 10% aqueous solution of citric acid, water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography [solvent: chloroform-methanol- (100: 1)] to give (S) -2-cyano-1- [N-tert-butoxycarbonyl-trans-4- (2 658 mg of [-propenyloxycarbonyl) cyclohexylamino] acetylpyrrolidine are obtained.

(3) A mixture of the compound (600 mg) obtained in the above (2), 165 mg of tetrakis (triphenylphosphine) palladium, 271 mg of ammonium formate, and 6 ml of dioxane is stirred at 50 ° C. for 1 hour. After cooling, the reaction mixture is poured into water and extracted with chloroform. The extract is washed with brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography [solvent: chloroform-methanol (50: 1)] to give (S) -2-cyano-1- (N-tert-butoxycarbonyl-trans-4-carboxycyclohexylamino). ) 394 mg of acetylpyrrolidine are obtained.

(4) N, N- of 150 mg of the compound obtained in the above (3), 64 mg of 2-aminomethylpyridine, 114 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and 80 mg of 1-hydroxybenzotriazole The 2 ml solution of dimethylformamide is stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is extracted with chloroform. The extract is washed with brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 3 ml of acetonitrile, 1 ml of a solution of 118 mg of trimethylsilyl iodide in acetonitrile is added dropwise under ice cooling, and the mixture is stirred at room temperature for 30 minutes. Methanol and water are added to the reaction mixture, the mixture is stirred for a while, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The extract is washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by diol chromatography [solvent: chloroform] to give an oily substance. This was dissolved in ethyl acetate (1 ml), 1N hydrochloric acid-ether (0.5 ml) and then ether (2 ml) were added, and the deposited precipitate was washed with ether and washed with (S) -2-cyano-1- [trans-4- (2-pyridyl). Methylaminocarbonyl) cyclohexylamino] acetylpyrrolidine dihydrochloride (Table 3, Example 3-1) (106 mg) is obtained.

Examples 3-2 to 3-12
Using (S) -2-cyano-1- (N-tert-butoxycarbonyl-trans-4-carboxycyclohexylamino) acetylpyrrolidine (the compound of item (3) of Example 3-1) and a corresponding starting compound, By treating in the same manner as in item (4) of Example 3-1, the compounds of Examples 3-2 to 3-12 in Table 3 are obtained.

Examples 4-1 to 4-32
(R) -3-chloroacetyl-4-cyanothiazolidine (the compound of Reference Example 2 described later) 100 mg and N- (5-nitro-2-pyridyl) -trans-1,4-cyclohexanediamine 372 mg acetonitrile 2 ml -Stir a 1 ml solution of methanol at room temperature for 15 hours. Water is added to the reaction mixture and extracted with chloroform. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by diol column chromatography [solvent: 0-5% methanol-chloroform] to obtain an oil. This was dissolved in 0.5 ml of ethyl acetate-0.5 ml of chloroform, 1.0 ml of 2N hydrochloric acid-ether and then 2 ml of ether were added, and the deposited precipitate was collected by filtration and washed with ether to give (R) -4-cyano-3. 173 mg of-[trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylthiazolidine dihydrochloride (Table 4, Example 4-1) are obtained.

Also, using the corresponding starting compounds, the compounds of Examples 4-2 to 4-32 in Table 4 are obtained in the same manner as described above.

Reference Example 1
According to the method described in the literature (WO98 / 19998), (S) -1-bromoacetyl-2-cyanopyrrolidine is obtained by reacting L-prolinamide (commercially available) and bromoacetyl bromide, followed by a dehydration reaction.

Reference Example 2
L-thioprolinamide hydrochloride is synthesized according to the method described in the literature (Ashworth et al., Bioorg. Med. Chem. Lett., Vol. 6, pp. 2745-2748, 1996). To a solution of 5.00 g of the obtained L-thioprolinamide hydrochloride and 8.67 ml of triethylamine in 150 ml of dichloromethane is added 2.36 ml of chloroacetyl chloride under ice cooling, and the mixture is stirred at the same temperature for 1 hour. A solution of pyridine (4.8 ml) and trifluoroacetic anhydride (8.4 ml) in dichloromethane is added to the reaction solution, and the mixture is further stirred at room temperature for 1 hour. The reaction solution was washed with a 10% HCl aqueous solution and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.The residue was crystallized from ether to give (R) -3-chloroacetyl-4-cyanothiazolidine (4.82 g). Obtained as tan crystals.

Reference Examples 3-1 to 3-40
A solution of 5-nitro-2-chloropyridine (2.50 g) and trans-1,4-cyclohexanediamine (5.40 g) in ethanol (15 ml) -tetrahydrofuran (10 ml) is stirred at room temperature for 5 days. The precipitate is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol-concentrated aqueous ammonia (20: 4: 1)), crystallized from ethyl acetate, and N- (5-nitro-2-pyridyl) -trans-1 , 4-Cyclohexanediamine (Reference Example 3-1 in Table 5) is obtained.
Further, the corresponding raw material compounds were used and treated in the same manner as described above to obtain the compounds of Reference Examples 3-2 to 3-40 in Table 5.

Reference Examples 3-41 to 3-44
A solution of 4-nitrofluorobenzene (1.69 g) and trans-1,4-cyclohexanediamine (4.1 g) in N, N-dimethylacetamide (30 ml) is stirred at 144 ° C. for 3 days. After cooling, a saturated aqueous solution of potassium carbonate was added to the reaction solution, the reaction mixture was extracted with ethyl acetate, the extract was dried over potassium carbonate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel flash column chromatography [solvent: chloroform-methanol-ammonia (90: 10: 1)], the solvent is distilled off, and trans-N- (4-nitrophenyl) -1,4-cyclohexane is removed. The diamine (Table 5 Reference Example 3-41) (2.31 g) is obtained.
In addition, compounds of Reference Examples 3-42 to 3-44 in Table 5 are obtained in the same manner using the corresponding raw material compounds.

Reference Examples 3-45 to 3-47
A solution of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine (1.23 g), 2-chloro-3-nitropyridine 1-oxide (1.0 g) and dimethylaminopyridine (700 mg) in ethanol (25 mL) is heated to reflux in an argon atmosphere for 2 hours. .
After cooling, the reaction solution is concentrated under reduced pressure, the residue is dissolved in chloroform, washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The obtained residue is purified by silica gel flash column chromatography [solvent: chloroform-methanol (30: 1)] to obtain a red powder. The obtained compound is dissolved in 5 mL of trifluoroacetic acid and stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography [solvent: aqueous ammonia saturated chloroform-methanol (10: 1)], and N- (3-nitropyridin-1-oxide-2-yl) was purified. 110 mg of -trans-1,4-cyclohexanediamine (Reference Example 3-45 in Table 5) is obtained.

In addition, by using the corresponding starting compounds and treating in the same manner, the compounds of Reference Examples 3-46 to 3-47 in Table 5 are obtained.

Reference Examples 3-48 to 3-49
168 mg of N-tert-butoxycarbonyl-trans-4-[(6-chloro-3-pyridazinyl) amino] cyclohexylamine (Reference Example 3-46) and 0.5 ml of triethylamine are mixed in a mixed solvent of 5 ml of ethanol and 4 ml of tetrahydrofuran. Dissolve. 50 mg of 10% palladium carbon is added, and the mixture is stirred at room temperature for 1 day under a hydrogen atmosphere at normal pressure. After filtering off the catalyst, the solvent is distilled off and the residue is stirred in 2 ml of trifluoroacetic acid for 3 hours. The solvent was distilled off, a 10% aqueous sodium hydroxide solution was added to the residue, extracted with chloroform, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain trans-4- (pyridazin-3-ylamino) cyclohexyl. 61 mg of the amine (Table 5 Reference Example 3-48) is obtained.

By treating the corresponding starting compound (Reference Example 3-47) in the same manner,
Table 5 Reference Example The compound of 3-49 is obtained.

Reference Examples 3-50 to 3-58
In the same manner as in Reference Example 9-50 or Reference Example 9-55, compounds in Table 5 Reference Examples 3-50 to 3-58 are obtained.

Reference Example 3-59
4-Chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester and N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine were treated with ethanol in the presence of dimethylaminopyridine in the same manner as in Reference Example 3-49. To give N-tert-butoxycarbonyl-trans-4- (5-ethoxycarbonyl-2-phenyl-4-pyrimidinylamino) cyclohexylamine.
This compound was treated in the same manner as in (1) and (2) of Reference Example 9-56 to give trans-4- (5-morpholinocarbonyl-2-phenyl-4-pyrimidinylamino) cyclohexylamine (Table 5). Reference Example 3-59) is obtained.

Reference example 4
(1) To a suspension of trans-4-aminocyclohexanol (10 g) in tetrahydrofuran (150 ml) was added triethylamine (15 ml), and a solution of 2-chloro-5-nitropyridine in tetrahydrofuran (50 ml) was added under ice-cooling. Stir for 18 hours. Water is added to the reaction mixture and extracted with chloroform. The extract is washed with brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (2: 1)] to obtain 8.52 g of trans-4- (5-nitro-2-pyridylamino) cyclohexanol.

(2) To a solution of 1.0 g of the compound obtained in (1) above in 10 ml of dichloromethane was added 1.8 ml of triethylamine, and 0.65 ml of methanesulfonyl chloride was further added under ice-cooling, followed by stirring for 1 hour. To the reaction mixture is added a saturated aqueous solution of sodium bicarbonate, and the mixture is extracted with chloroform. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. To a solution of the residue in 10 ml of dimethylformamide is added 1.37 g of sodium azide, and the mixture is stirred at 50 ° C. for 3 days. After cooling, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (1: 5)] to obtain 758 mg of cis-4-azido-N- (5-nitro-2-pyridyl) cyclohexylamine. .

(3) A solution of 640 mg of the compound obtained in the above (2) and 704 mg of triphenylphosphine in 10 ml of tetrahydrofuran and 1 ml of water is stirred at room temperature for 2 days. The reaction mixture was concentrated, and the residue was purified by flash column chromatography on silica gel [solvent: ethyl acetate-methanol (10: 1)] to give N- (5-nitro-2-pyridyl) -cis-1,4-. 531 mg of cyclohexanediamine (the compound of Reference Example 4 in Table 5) is obtained.

Reference Examples 5-1 to 5-6
(1) 60.0 g of trans-4-tert-butoxycarbonylaminocyclohexyl methanesulfonate and 20.1 g of sodium azide are suspended in 600 mL of dimethylformamide and stirred at 90 ° C. for 6 hours. Pour the reaction mixture into water and extract with ethyl acetate. The extract was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 47.9 g of cis-4-azido-N- (tert-butoxycarbonyl) cyclohexylamine.

(2) 500 mg of the compound obtained in the above (1) and 100 mg of palladium-carbon (wet) are suspended in 8 mL of tetrahydrofuran, and the mixture is vigorously stirred under a hydrogen atmosphere at room temperature for 1.5 hours. On the way, hydrogen in the system is replaced twice. The insoluble matter is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform-methanol (20: 1) followed by chloroform-methanol-aqueous ammonia (100: 10: 1)) to give N-tert-butoxycarbonyl-cis-1,4. -395 mg of cyclohexanediamine are obtained.

(3) A suspension of 2.0 g of the compound obtained in (2), 1.63 g of 2-chloro-3-nitropyridine, and 1.95 mL of diisopropylethylamine in 10 mL of 2-propanol is stirred at 80 ° C. for 1 day. After the reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform followed by chloroform-ethyl acetate (7: 1)). Hydrochloric acid-dioxane was added to the ethanol suspension of the obtained compound, and the mixture was stirred at room temperature for 18 hours. The precipitate was collected by filtration, and N- (3-nitro-2-pyridyl) -cis-1,4-cyclohexanediamine was collected. 2.15 g of dihydrochloride (Table 5 Reference Example 5-1) is obtained.

In addition, compounds of Reference Examples 5-2 to 5-6 in Table 5 are obtained in the same manner using the corresponding starting compounds.

Reference Example 6-1

(1) According to the method described in the literature (JP83-118577), methyl 1,4-dioxaspiro [4.5] decane-8-carboxylate is reacted with methyliodide in the presence of LDA (lithium diisopropylamide) to give 8-methyl-1, Methyl 4-dioxaspiro [4.5] decane-8-carboxylate (compound (1) in the above figure) is obtained.
[The starting compounds were synthesized according to the methods described in Rosemmund et al. (Chem. Ber., 1975, 108, 1871-1895) and Black et al. (Synthesis, 1981, 829). Used. ]
(2) A mixture of 3.80 g of the compound obtained in (1) above, 3.55 g of sodium hydroxide, 16 mL of methanol, and 25 mL of water is heated under reflux for 2 hours. The reaction solution is ice-cooled, adjusted to pH 5 with 2N hydrochloric acid and a 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give 8-methyl-1,4-dioxaspiro [4.5] decane-8-carboxylic acid (the compound shown in the above figure). (2)) 3.46 g are obtained.

(3) A mixture of 16.19 g of the compound obtained in the above (2), 24.51 g of diphenylphosphoryl azide, 9.00 g of triethylamine, and 160 mL of toluene is heated under reflux for 2.5 hours. The reaction solution is ice-cooled, washed with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. 9.55 g of potassium tert-butoxide is gradually added to a solution of the obtained compound in 100 mL of dimethylacetamide under ice-cooling, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice water, and the precipitated crystals are collected by filtration, washed with water and dried. To a solution of the obtained compound in 100 mL of tetrahydrofuran is added 100 mL of an aqueous solution of 30.87 g of p-toluenesulfonic acid hydrate, and the mixture is stirred at room temperature for 16 hours. After dilution with a saturated aqueous solution of sodium hydrogen carbonate, the mixture is extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 10.41 g of 4-tert-butoxycarbonylamino-4-methylcyclohexanone (compound (3) in the above figure). obtain.

(4) A mixture of 10.41 g of the compound obtained in the above (3), 11.01 g of sodium triacetoxyborohydride, 5.10 mL of benzylamine, and 150 mL of methylene chloride is stirred at room temperature for 16 hours. After dilution with a saturated aqueous solution of sodium hydrogen carbonate, the mixture is extracted with ethyl acetate. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. To a solution of the obtained compound in 15 mL of methanol, 3.32 g of p-toluenesulfonic acid hydrate and then 160 mL of ether are added. The precipitate was collected by filtration, washed with ether, and dried. N-benzyl-t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine.p-toluenesulfonate (the compound (4 )) 7.49 g are obtained.

(5) A mixture of 16.63 g of the compound obtained in the above (4), 5.0 g of 10% palladium on carbon, and 400 mL of methanol is stirred under a hydrogen atmosphere (1 atm) for 24 hours. The 10% palladium on carbon is removed by filtration, and the filtrate is concentrated. The obtained residue was dissolved in a mixture of 50 mL of a 10% aqueous sodium hydroxide solution and 300 mL of ether, and the ether layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
6.87 g of t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (compound (5) in the above figure) is obtained.

(6) The filtrate obtained in the step (4) is treated with an aqueous sodium hydroxide solution and extracted with chloroform. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to NH-silica gel column chromatography (solvent: hexane-ethyl acetate (30: 1 → 3: 1)) to give N-benzyl-c-4-tert-butoxycarbonylamino-4-methyl-r- 1-cyclohexylamine is obtained. Then, this is treated in the same manner as in the above (5) to obtain c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (compound (6) in the above figure).

Reference Example 6-2
In the same manner as in (1) to (5) or (6) of Reference Example 6-1 except that benzyloxymethyl chloride is used in place of methyl iodide in the step (1) of Reference Example 6-1, t- 4-tert-butoxycarbonylamino-4-hydroxylmethyl-r-1-cyclohexylamine or c-4-tert-butoxycarbonylamino-4-hydroxylmethyl-r-1-cyclohexylamine is obtained.

Further, except that methoxymethyl chloride was used in place of methyl iodide in the step (1) of Reference Example 6-1 in the same manner as in the items (1) to (5) or (6) of Reference Example 6-1; There is obtained t-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclohexylamine or c-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclohexylamine.

Reference Examples 7-1 to 7-18
t-4-tert-Butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (compound obtained in the item (5) of Reference Example 6-1) 1.70 g, 2-chloropyrimidine 2.04 g, diisopropylethylamine 3.24 A mixture of mL and 13 mL of 2-propanol is heated to reflux for 12 hours. After cooling, dilute the reaction with water and extract with ethyl acetate. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [solvent: ethyl acetate-hexane (30:70 50:50)]. The obtained compound is dissolved in dioxane (4 mL), 4N hydrochloric acid-dioxane (10 mL) is added, and the mixture is stirred for 8 hours. The reaction solution is diluted with ether, and the precipitated crystals are collected by filtration and washed with ether. The obtained crystals are dissolved in water, saturated with potassium carbonate, and extracted with chloroform. The extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and 587 mg of 1-methyl-t-4- (2-pyrimidinylamino) -r-1-cyclohexylamine (Reference Example 7-1 in Table 5) was added. obtain.
In addition, compounds of Reference Examples 7-2 to 7-5 in Table 5 are obtained in the same manner using the corresponding starting compounds.

Further, using c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compound obtained in the item (6) of Reference Example 6-1) and the corresponding starting compound, The compounds of Reference Examples 7-6 to 7-9 in Table 5 are obtained.

Further, using t- or c-4-tert-butoxycarbonylamino-4-hydroxylmethyl-r-1-cyclohexylamine (Reference Example 6-2) and the corresponding raw material compounds, similarly, -10 to 7-18 are obtained.

Reference Examples 7-19 to 7-23
4-tert-butoxycarbonylamino-4-methylcyclohexanone (compound (3) of Reference Example 6-1) and the corresponding starting compound (amine compound) were allowed to stand at room temperature for 16 hours in the presence of sodium triacetoxyborohydride. After stirring and reacting, the mixture is subjected to an acid treatment to remove the protecting group (t-butoxycarbonyl group), thereby obtaining the compounds of Reference Examples 7-19 to 7-23 in Table 5.

Reference Examples 8-1 to 8-4
(1) To a solution of 16.93 g of 4- (tert-butoxycarbonylamino) cyclohexanone and 10.55 ml of N-methylbenzylamine in 160 ml of methylene chloride, 19.08 g of sodium triacetoxyborohydride was added under ice cooling, followed by stirring at room temperature for 14 hours. I do. Dilute the reaction with aqueous sodium bicarbonate and extract with ethyl acetate. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is suspended in hexane and collected by filtration. The mother liquor was concentrated, the residue was purified by NH-silica gel chromatography, [solvent: hexane-ethyl acetate (97: 3-83: 17)], and the residue was suspended in hexane and collected by filtration. And 13.55 g of N'-benzyl-N-tert-butoxycarbonyl-N'-methyl-trans-1,4-cyclohexanediamine.
A suspension of 13.53 g of this compound and 2.00 g of palladium hydroxide-carbon in methanol is subjected to catalytic hydrogenation at normal pressure and room temperature for 5 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to obtain 9.93 g of N-tert-butoxycarbonyl-N'-methyl-trans-1,4-cyclohexanediamine.

(2) Using the compound obtained in the above item (1) and the corresponding raw material compound (chloride), the reaction was carried out by heating and refluxing for 12 hours in the presence of diisopropylethylamine in 2-propanol in the same manner as in Reference Example 7-1. The obtained compound is acid-treated with hydrochloric acid and neutralized with potassium carbonate to obtain compounds of Reference Examples 8-1 to 8-4 in Table 5.

Reference Examples 9-1 to 9-45
To a solution of 10.0 g of trans-4- (tert-butoxycarbonylamino) cyclohexanol and 7.35 g of 2-chloro-5-nitropyridine in 150 mL of tetrahydrofuran, 2.04 g of 60% sodium hydride was gradually added, and further 30 mL of dimethyl sulfoxide was added. Thereafter, the mixture is stirred at room temperature for one day. Pour the reaction mixture into water and extract with chloroform. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [solvent: chloroform alone to chloroform-ethyl acetate (20: 1)], and the obtained powder crystals were suspended in a mixed solution of ethyl acetate-hexane and collected by filtration. 12.20 g of -1-tert-butoxycarbonylamino-4- (5-nitro-2-pyridyloxy) cyclohexane are obtained. To a suspension of 800 mg of this compound in 10 ml of ethanol is added a 2 N hydrochloric acid-dioxane 2 ml solution, and the mixture is stirred at room temperature for 18 hours. The precipitate is collected by filtration to obtain 568 mg of trans-4- (5-nitro-2-pyridyloxy) cyclohexylamine hydrochloride (Reference Example 9-1 in Table 6).
Also, using the corresponding starting compounds, the compounds of Reference Examples 9-2 to 9-45 in Table 6 are obtained in the same manner as described above.

Reference Examples 9-46 to 9-47
To a suspension of 1.00 g of trans-4-aminocyclohexanol hydrochloride in 10 ml of tetrahydrofuran is added 60% sodium hydride, and the mixture is heated under reflux for 1 hour. After cooling to room temperature, 2-chloropyrimidine is added slowly and stirred at room temperature for 6 hours. The reaction mixture is poured into ice-cold water and extracted with chloroform. The extract is washed with brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography (solvent: ethyl acetate-hexane (1: 4) to chloroform only) to give trans-4- (2-pyrimidinyloxy) cyclohexylamine (Table 6 Reference Examples 9-46). ) To get 788 mg.
Using the corresponding starting compounds, the compounds of Reference Examples 9-47 in Table 6 were obtained in the same manner as described above.

Reference Example 9-48
Trans-1-tert-butoxycarbonylamino-4- (3-nitro-2-pyridyloxy) cyclohexane is obtained in the same manner as in Reference Example 9-1. Then, a suspension of 3.35 g of this compound in 30 ml of ethanol is stirred at 50 ° C., and 155 mg of palladium-carbon (dry) and further 1.6 ml of hydrazine monohydrate are added. After stirring the reaction mixture for 10 minutes, the remaining 185 mg of palladium-carbon is added and heated to reflux for 40 minutes. After cooling the reaction mixture to room temperature, insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. The obtained residue was crystallized from ethanol-water (1: 1), and the crystals were collected by filtration to give 2.58 g of trans-1-tert-butoxycarbonylamino-4- (3-amino-2-pyridyloxy) cyclohexane. Get. Then, hydrochloric acid-dioxane is added to an ethanol solution of this compound, followed by acid treatment to obtain trans-4- (3-amino-2-pyridyloxy) cyclohexylamine hydrochloride (Reference Example 9-48 in Table 6).

Reference Example 9-49
By using trans-4- (tert-butoxycarbonylamino) cyclohexanol and the corresponding starting compound and treating in the same manner as in Reference Example 9-1, trans-4- (5-ethoxycarbonyl-2-methylthiopyrimidine-4- (Iloxy) cyclohexylamine hydrochloride is obtained. The hydrochloride compound is converted to an aqueous solution, treated with potassium carbonate, and extracted with chloroform to obtain its free form (Table 6 Reference Examples 9-49).

Reference Examples 9-50 to 9-54
2.75 g of N-tert-butoxycarbonyl-trans-4- (5-ethoxycarbonyl-2-methylthiopyrimidin-4-yloxy) cyclohexylamine (the compound before deprotection (hydrochloric acid-dioxane treatment) in Reference Example 9-49) was added. Dissolve in 50 mL of chloroform, add 1.73 g of 75% -metachloroperbenzoic acid, and stir at room temperature for 30 minutes. Next, 1.14 g of dimethylamine hydrochloride and 2.79 mL of triethylamine are added, and the mixture is further stirred for 5 hours. After adding a saturated aqueous solution of sodium hydrogen carbonate to the reaction solution and stirring, the chloroform layer is separated, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel flash chromatography [solvent: hexane-chloroform (50:50 100: 0)] to give N-tert-butoxycarbonyl-trans-4- [5-ethoxycarbonyl-2- (dimethylamino). 2.74 g of [pyrimidin-4-yloxy] cyclohexylamine are obtained.
This compound is treated with hydrochloric acid-dioxane to deprotect, then neutralized with potassium carbonate,
trans-4- [5-ethoxycarbonyl-2- (dimethylamino) pyrimidin-4-yloxy] cyclohexylamine (Table 6 Reference Examples 9-50) is obtained.
Further, the compounds of Reference Examples 9-51 to 9-54 in Table 6 are obtained in the same manner as described above.

Reference Examples 9-55 to 9-57
(1) N-tert-butoxycarbonyl-trans-4- [5-ethoxycarbonyl-2- (dimethylamino) pyrimidin-4-yloxy] cyclohexylamine (compound before deprotection treatment in Reference Example 9-50) 2.675 g Is dissolved in 15 mL of ethanol, 3.27 mL of a 3N aqueous solution of sodium hydroxide is added at room temperature, and the mixture is stirred overnight. After diluting the reaction solution with water, citric acid is added until the solution becomes neutral. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give 2.015 g of N-tert-butoxycarbonyl-trans-4- [5-carboxy-2- (dimethylamino) pyrimidin-4-yloxy] cyclohexylamine. obtain.

(2) Using the compound obtained in the above (1) as a raw material, it is reacted with the raw material amine compound in the same manner as in Reference Example 11-1. The obtained compound (hydrochloride) is converted to an aqueous solution, treated with potassium carbonate, and extracted with chloroform to obtain a free form.
Thus, the compounds of Reference Examples 9-55 to 9-57 in Table 6 are obtained.

Reference Examples 9-58 to 9-64
(1) To a solution of oxalyl chloride (0.526 ml) in methylene chloride (10 ml), slowly add dropwise DMSO (0.494 ml) at -78 ° C under an argon gas atmosphere. Fifteen minutes after the completion of the dropwise addition, 30 ml of a suspension of trans-4-tert-butoxycarbonylaminocyclohexanol in methylene chloride was added dropwise, and 30 minutes later, 2.52 ml of triethylamine was added, and the mixture was added at -78 ° C for 30 minutes and at 0 ° C for 15 minutes. Stir for a minute. Aqueous sodium bicarbonate solution is added to the reaction solution, and the mixture is extracted with chloroform. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure, and the obtained residue is suspended in a mixed solvent of hexane and isopropyl ether, and filtered to obtain 0.903 g of 4- (tert-butoxycarbonylamino) cyclohexanone.

(2) To a solution of 33.05 g of the compound obtained in the above (1) in 350 ml of toluene was added dropwise 313 ml of a 1.0 M solution of diisobutylaluminum hydride in toluene at -78 ° C, and the mixture was stirred at the same temperature for 4 hours. After the excess reagent is decomposed by dropping 33 ml of methanol, 100 ml of water is added and the mixture is stirred for 1 hour, and the insoluble precipitate is removed by filtration. Separate the organic layer of the filtrate and dry over sodium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is suspended under heating in a mixed solvent of chloroform and isopropyl ether, and insolubles are removed by filtration. After concentrating the filtrate, the same operation is performed with isopropyl ether. The obtained filtrate is concentrated, and the residue is purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (1: 2-1: 1)], and the obtained colorless crystals are heated and suspended in a hexane-isopropyl ether mixed solvent. After filtration at 0 ° C., 6.95 g of cis-4-tert-butoxycarbonylaminocyclohexanol was obtained.

(3) Using the cis-4-tert-butoxycarbonylaminocyclohexanol and the corresponding starting compound obtained above, the compounds of Table 6 Reference Examples 9-58 to 9-64 are obtained in the same manner as in Reference Example 9-1. .

Reference Example 10-1
(1) A mixture of 9.13 g of 4-tert-butoxycarbonylamino-4-methylcyclohexanone, 3.05 g of sodium borohydride and 100 mL of isopropyl alcohol is stirred at room temperature for 1 hour. The reaction solution is diluted with a saturated aqueous ammonium chloride solution under ice-cooling, and extracted with ethyl acetate. The obtained extract was washed with water and saturated saline, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to give t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol. 9.20 g of a mixture of C.sub.4 and c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol are obtained.

(2) A mixture of 9.20 g of the compound obtained in the above (1), 8.26 g of p-methoxybenzoic acid chloride, 5.93 g of dimethylaminopyridine and 100 mL of methylene chloride is heated under reflux for 20 hours. After cooling, the reaction solution is washed with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid, water and saturated saline, dried over sodium sulfate, and the solvent is distilled off. The residue is crystallized from n-hexane to obtain 0.68 g of c-4-tert-butoxycarbonylamino-4-methyl-O- (4-methoxyphenylcarbonyl) -r-1-cyclohexanol (cis compound). .
Further, the residue was purified by silica gel column chromatography [solvent: ethyl acetate / n-hexane (1/10)], and the compound (cis compound) and t-4-tert-butoxycarbonylamino-4-methyl- 3.50 g of a mixture (1: 5) of O- (4-methoxyphenylcarbonyl) -r-1-cyclohexanol (trans compound) is obtained.

(3) A mixture of 10.68 g of the cis compound obtained in the above (2), 6.10 g of sodium hydroxide, 150 mL of methanol and 120 mL of water is heated at an external temperature of 75 ° C. for 1 hour. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give c-4-tert-butoxycarbonylamino-4-methyl-r-1. 6.61 g of cyclohexanol are obtained.

(4) Using 3.50 g of a mixture (1: 5) of the cis and trans forms obtained in the above (2) and treating in the same manner as in the above (3), t-4-tert-butoxycarbonylamino-4 1.77 g of -methyl-r-1-cyclohexanol are obtained.

Reference Examples 10-2 to 10-8
Table 6 was prepared in the same manner as in Reference Example 9-1 using t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol (Reference Example 10-1 (4)) and the corresponding starting compounds. The compounds of Reference Examples 10-2 to 10-3 are obtained. Similarly, using c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol (Reference Example 10-1 (3)), Table 6 Reference Examples 10-4 to 10-. 8 are obtained.

Reference Examples 11-1 to 11-38 and 12-1 to 12-96
trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid 500 mg and N-methyl-benzylamine 250 mg, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 434 mg, 1-hydroxybenzotriazole A mixture of 306 mg and 5 mL of N, N-dimethylformamide is stirred at room temperature for 15 hours. The reaction solution is made alkaline by adding an aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 691 mg of N-benzyl-trans-4-tert-butoxycarbonylamino-N-methylcyclohexanecarboxamide. A mixture of 670 mg of this compound, 5 mL of 4N-hydrochloric acid-dioxane, and 5 mL of dioxane is stirred at room temperature for 12 hours. The reaction mixture is concentrated to obtain 585 mg of trans-4-amino-N-benzyl-N-methylcyclohexanecarboxamide hydrochloride (Reference Example 11-1 in Table 7).

Table 7 and Table 8 Reference Examples 11-2 to 11- in the same manner as described above using the corresponding raw material amine compounds (chain amine compounds or cyclic secondary amine compounds such as piperidine compounds and piperazine compounds). 38 and compounds of 12-1 to 12-96 are obtained.
(However, the free compound can be obtained by saturating an aqueous solution of a hydrochloride compound with potassium carbonate, extracting with chloroform, drying the extract with sodium sulfate, and distilling off the solvent under reduced pressure.)
[The raw material amine compound (piperidine compound, piperazine compound, etc.) is a compound synthesized by Reference Examples 15-1 to 15-11 described later, a known method, or a combination thereof. ]

Reference Example 12-97
(1) 4.5 g of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid, 2.29 g of thiomorpholine, 3.90 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2.74 g of 1-hydroxybenzotriazole, And a mixture of 30 mL of N, N-dimethylformamide at room temperature for 4 hours.
The reaction solution is made alkaline by adding an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is suspended in diisopropyl ether, and the deposited precipitate is collected by filtration to obtain N-tert-butoxycarbonyl-trans-4- (4-thiomorpholinylcarbonyl) cyclohexylamine.

(2) To a solution of 5.4 g of the compound obtained in the above (1) in 50 ml of chloroform is added 8.9 g of 75% -metachloroperbenzoic acid under ice cooling, and the mixture is stirred at room temperature for 1 hour. The reaction solution is made alkaline by adding an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract is washed with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is suspended in diisopropyl ether, and the deposited precipitate is collected by filtration.
Next, this compound is suspended in 25 mL of dioxane, a 4N hydrochloric acid-dioxane solution (25 mL) is added, and the mixture is stirred at room temperature for 16 hours. Ether is added to the reaction solution, and the deposited precipitate is collected by filtration and dissolved in water. After adding potassium carbonate to make the mixture alkaline, the mixture is extracted with chloroform. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue was suspended in diisopropyl ether, and the deposited precipitate was collected by filtration to obtain trans-4- (1,1-dioxo-4-thiomorpholinylcarbonyl) cyclohexylamine (Reference Example 12-97 in Table 8). .

Reference Examples 13-1 to 13-7
4.0 ml of thionyl chloride and 0.3 ml of N, N-dimethylformamide are added to a suspension of 5.07 g of trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid in 50 ml of methylene chloride, and the mixture is stirred at room temperature for 1 hour.
500 mg of the solid obtained by concentrating the reaction solution under reduced pressure is added to a solution of 207 mg of ice-cooled 2-aminopyrimidine and 0.4 ml of triethylamine in 8 ml of methylene chloride. After stirring at room temperature for 2 hours, water is added to the reaction solution, and the mixture is extracted with chloroform. The residue obtained by concentrating the extract under reduced pressure was purified by silica gel column chromatography [solvent: chloroform-methanol (50: 1)] to give N-benzyloxycarbonyl-trans-4-[(pyrimidin-2-ylamino). ) Carbonyl] cyclohexylamine 240 mg is obtained.
This compound is subjected to a deprotection treatment to obtain trans-4-[(pyrimidin-2-ylamino) carbonyl] cyclohexylamine (Reference Example 13-1 in Table 8).
Further, the corresponding raw material compound was used in place of 2-aminopyrimidine, and the same treatment as above was carried out to obtain the compounds of Reference Examples 13-2 to 13-7 in Table 8.

Deprotection is performed as follows using acetic acid hydrobromide. That is, the compound is stirred at 50 ° C. for 4 hours in 3 ml of a 30% hydrogen bromide acetic acid solution. 30 ml of diisopropyl ether is added to the reaction solution, and the precipitate is collected by filtration to obtain a hydrobromide salt of the deprotected compound. The hydrobromide is converted into an aqueous solution, saturated with potassium carbonate, and extracted with chloroform to obtain a free form.

However, the deprotection of the compound of Reference Example 13-2 is performed as follows using palladium carbon. That is, a 10% palladium carbon catalyst and ammonium formate are added to a methanol-tetrahydrofuran suspension of the compound, and the mixture is heated under reflux. The insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure.

Reference Examples 13-8 to 13-16
Under an argon atmosphere, a mixture of 1.0 g of trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid chloride, 1.92 g of tributylphenyltin, 61 mg of dichlorobis (triphenylphosphine) palladium, and 10 mL of dioxane is heated and stirred at 110 ° C. for 12 hours. . After cooling, the reaction solution is concentrated by a centrifugal concentrator, and the residue is dissolved in tetrahydrofuran and concentrated to dryness with 5 g of silica gel. The obtained residue is purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (1: 2) (1: 1)] to obtain 883 mg of N-benzyloxycarbonyl-trans-4-benzoylcyclohexylamine.
870 mg of this compound is stirred at room temperature for 2 hours together with 1.0 g of trimethylsilyl iodide and 5 mL of chloroform under an argon atmosphere. After confirming the disappearance of the raw materials by TLC, 0.17 mL of methanol and 5 mL of diethyl ether are added to the reaction solution, and the mixture is stirred at room temperature for 3 days. The precipitate obtained is collected by filtration, washed with anhydrous diethyl ether and dried to obtain 830 mg of trans-4-benzoylcyclohexylamine (Reference Example 13-8 in Table 8).
In the same manner as described above, the compounds of Reference Examples 13-9 to 13-16 in Table 8 are obtained.

Reference Example 13-17
(1) trans-4-methoxycarbonylcyclohexane-1-carboxylic acid chloride is obtained from 5 g of trans-4-methoxycarbonylcyclohexane-1-carboxylic acid and oxalyl chloride. 7.58 g of morpholine is added dropwise to the methylene chloride 50 mL solution under ice cooling, and the mixture is stirred for 2 hours. The reaction solution is poured into a 10% aqueous citric acid solution, extracted with chloroform, dried over magnesium sulfate, and the solvent is removed under reduced pressure. The residue was purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (1: 1) to ethyl acetate-chloroform (1: 1)], crystallized from hexane, and trans-1-methoxycarbonyl-4- ( 6.49 g of morpholinocarbonyl) cyclohexane are obtained.

(2) In an argon atmosphere, 40 g (0.024 mol) of LDA (lithium diisopropylamide) in hexane-tetrahydrofuran (3: 5) prepared at the time of use was added at −78 ° C. to 2.0 g of the compound obtained in the above item (1). Of tetrahydrofuran was added dropwise, and the mixture was heated and stirred at -30 ° C over 2 hours. The reaction solution is cooled again to -78 ° C, reacted with 1.46 mL of methyl iodide, heated to ice temperature, added with water, and extracted with ethyl acetate. The extract is washed sequentially with a 10% aqueous citric acid solution, water and saturated saline, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue was purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (1: 2) to (1: 1)], and a mixture of 1-methoxycarbonyl-1-methyl-4- (morpholinocarbonyl) cyclohexane isomers I get 1.47g. The mixture is stirred at room temperature for 12 hours in a mixture of 158 mg of sodium hydroxide, 1 mL of ethanol and 1 mL of water. The reaction solution is extracted with diethyl ether, the extract is washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is recrystallized from a mixed solvent of diethyl ether-hexane to obtain 592 mg of a single isomer of 1-methoxycarbonyl-1-methyl-4- (morpholinocarbonyl) cyclohexane.

(3) 546 mg of the compound (single isomer) obtained in the above item (2) is heated and stirred at 110 ° C. for 2 hours in a mixture of 251 mg of sodium hydroxide, 5 mL of methanol and 10 mL of water. After cooling, the reaction solution is adjusted to pH 3 with 10% hydrochloric acid, extracted three times with chloroform, dried with magnesium sulfate, and the solvent is removed under reduced pressure. A solution of 479 mg of the obtained compound (carboxylic acid), 550 mg of diphenylphosphonyl azide and 216 mg of benzyl alcohol in 5 mL of toluene is heated and stirred for 12 hours. After cooling, a 10% aqueous solution of citric acid was added to the reaction solution, the toluene layer was separated, washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue is purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (1: 2) to (1: 1)] to give N-benzyloxycarbonyl-1-methyl-4- (morpholinocarbonyl) cyclohexylamine 387 mg are obtained. This compound is treated with trimethylsilyl iodide and deprotected to obtain 1-methyl-4- (morpholinocarbonyl) cyclohexylamine (Reference Example 13-17 in Table 8).

Reference Examples 13-18 to 13-21
Trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and piperazine were treated in the same manner as in Reference Example 11-1, to give N-tert-butoxycarbonyl-trans-4- (1-piperazinylcarbonyl) cyclohexyl. Obtain the amine.
Methyl chlorocarbonate is added dropwise to a mixed solution of 400 mg of this compound, 260 mg of triethylamine and 8 mL of methylene chloride under ice cooling, and the mixture is stirred at room temperature overnight. The reaction solution is washed sequentially with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was suspended in isopropyl ether, and the resulting precipitate was collected by filtration to give N-tert-butoxycarbonyl-trans-4- (4-methoxycarbonyl-1-piperazinylcarbonyl) cyclohexylamine (410 mg). obtain.
This compound was deprotected under acidic conditions according to a conventional method, and further returned to basicity, to give trans-4- (4-methoxycarbonyl-1-piperazinylcarbonyl) cyclohexylamine (Table 8 Reference Examples 13-18). obtain.
Also, in the same manner as described above, the compounds of Reference Examples 13-19 to 13-21 in Table 8 are obtained.

Reference Example 13-22
A mixture of 623 mg of N-tert-butoxycarbonyl-trans-4- (piperazinocarbonyl) cyclohexylamine, 340 mg of 3,4-diethoxy-3-cyclobutene-1,2-dione and 5 ml of ethanol was added at room temperature for 2.5 days. Stir for a day. The residue obtained by concentrating the reaction solution under reduced pressure is purified by silica gel column chromatography (solvent: chloroform-methanol (50: 1)), and then powdered with ether. This compound was deprotected by treatment with hydrochloric acid-dioxane, and trans-4- [4- (4-ethoxy-1,2-dioxo-3-cyclobuten-3-yl) piperazinylcarbonyl] cyclohexylamine (Table 8) Reference Example 13-22) is obtained.

Reference Example 13-23
(1) A mixture of 1101 mg of N-benzyloxycarbonylpiperazine, 1,131 mg of 3,4-dibutoxy-3-cyclobutene-1,2-dione and 5 ml of ethanol is stirred at room temperature for 25 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (19: 1)),
1570 mg of 1-benzyloxycarbonyl-4- (4-butoxy-1,2-dioxo-3-cyclobuten-3-yl) -piperazine are obtained.
This compound was deprotected by treating with palladium carbon under a hydrogen atmosphere in the presence of 3 ml of 10% hydrochloric acid to give 4- (4-butoxy-1,2-dioxo-3-cyclobuten-3-yl) -piperazine. obtain.

(2) The compound obtained in the above (1) is reacted with trans- (4-benzyloxycarbonylamino) cyclohexanecarboxylic acid chloride in methylene chloride in the presence of triethylamine to give N-benzyloxycarbonyl-trans-4. -[4- (4-Butoxy-1,2-dioxo-3-cyclobuten-3-yl) piperazinocarbonyl] cyclohexylamine is obtained.

(3) By reacting the compound obtained in the above (2) with dimethylamine hydrochloride in ethanol in the presence of triethylamine, N-benzyloxycarbonyl-trans-4- [4- (4-dimethylamino-1 , 2-dioxo-3-cyclobuten-3-yl) piperazinylcarbonyl] cyclohexylamine. This compound is deprotected by treatment with trimethylsilane iodide, and trans-4- [4- (4-dimethylamino-1,2-dioxo-3-cyclobuten-3-yl) piperazinylcarbonyl] cyclohexylamine (Table 8 Reference Examples 13-23) is obtained.

Reference Examples 13-24
N-benzyloxycarbonyl-trans-4-[(5-hydroxymethyl-2-isoindolinyl) carbonyl] cyclohexylamine Triethylamine 0.15 ml, methanesulfonyl chloride in a suspension of 0.31 g of tetrahydrofuran-methylene chloride 10 ml under ice-cooling Add 0.07 ml and stir for 1 hour under ice cooling. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. 5 ml of dimethylformamide and 0.25 ml of morpholine are added to the residue, and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (solvent: chloroform-methanol = 100: 1). This compound is treated with palladium carbon under a hydrogen atmosphere to obtain trans-4-[(5-morpholinomethyl-2-isoindolinyl) carbonyl] cyclohexylamine (Reference Example 13-24 in Table 8).

Reference Examples 13-25 to 13-29
(1) 20 g of manganese dioxide was added to a solution of 4.0 g of N-benzyloxycarbonyl-trans-4-[(5-hydroxymethyl-2-isoindolinyl) carbonyl] cyclohexylamine in 120 ml of chloroform, and the mixture was stirred at room temperature for 4 hours. Manganese dioxide is filtered off through celite and the solvent is distilled off under reduced pressure. The residue is suspended in hexane-ethyl acetate, and the crystals are collected by filtration to obtain N-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl) carbonyl] cyclohexylamine.

(2) 2.75 g of the compound obtained in the above (1) and 110 ml of ethanol are added to an aqueous solution of 3.35 g of silver nitrate under ice cooling, and an aqueous solution of 2.61 g of potassium hydroxide is added dropwise. The mixture was stirred for 1 hour under ice cooling, filtered off through celite, and the solvent was distilled off under reduced pressure. To the residue is added 50 ml of 1N aqueous hydrochloric acid and extracted with chloroform. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue was suspended in hexane-ether, and the crystals were collected by filtration.
N-benzyloxycarbonyl-trans-4-[(5-carboxy-2isoindolinyl) carbonyl] cyclohexylamine is obtained.

(3) Using the compound obtained in the above (2) and condensing with the starting amine compound in the same manner as in Reference Example 11-1, by treating with palladium carbon under a hydrogen atmosphere,
trans-4-[(5-Dimethylaminocarbonyl-2-isoindolinyl) carbonyl] cyclohexylamine (Table 8 Reference Example 13-25) is obtained.
Similarly, the compounds of Reference Examples 13-26 to 13-29 in Table 8 are obtained.

Reference Examples 13-30 to 13-33
(1) N-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl) carbonyl] cyclohexylamine (Compound obtained in (1) of Reference Example 13-25) A suspension of 3.0 g of acetonitrile in 25 ml was used. 2.6 g of tert-butyl carbamate, 3.5 ml of triethylsilane and 1.15 ml of trifluoroacetic acid are added to the suspension, and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and extracted with chloroform. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue is suspended in hexane-ethyl acetate, and the crystals are collected by filtration to obtain N-benzyloxycarbonyl-trans-4-[(5-tert-butoxycarbonylaminomethyl-2-isoindolinyl) carbonyl] cyclohexylamine.

(2) The compound obtained in the above (1) is treated with palladium carbon under a hydrogen atmosphere to give trans-4-[(5-tert-butoxycarbonylaminomethyl-2-isoindolinyl) carbonyl] cyclohexylamine {(table 8 Reference Example 13-30) is obtained.

(3) The compound obtained in the above (1) is treated with 4N hydrochloric acid-dioxane to give N-benzyloxycarbonyl-trans-4-[(5-aminomethyl-2-isoindolinyl) carbonyl] cyclohexylamine.hydrochloride Get.

(4) To a solution of 0.5 g of the compound (hydrochloride) obtained in (3) above in 5 ml of methylene chloride-pyridine is added 0.25 ml of cyclopropanecarbonyl chloride, and the mixture is stirred at room temperature for 4 hours. Dilute hydrochloric acid is added to the reaction mixture, and the mixture is extracted with chloroform. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (solvent: chloroform-methanol = 50: 1) to obtain a crystal. This compound is treated with palladium carbon under a hydrogen atmosphere to obtain trans-4-[(5-cyclopropylcarbonylaminomethyl-2-isoindolinyl) carbonyl] cyclohexylamine (Reference Example 13-31 in Table 8).
Similarly, the compounds of Reference Examples 13-32 to 13-33 in Table 8 are obtained.

Reference Example 13-34
(1) N-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl) carbonyl] cyclohexylamine (Compound obtained in (1) of Reference Example 13-25) A solution of 0.3 g of 3 ml of formic acid Then, 0.08 g of hydroxylamine hydrochloride and 0.09 g of sodium formate are added, and the mixture is heated under reflux for 3 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue was purified by NH silica gel chromatography (solvent: chloroform-ethyl acetate = 50: 1), and the resulting compound was treated with trimethylsilane iodide to give trans-4-[(5-cyano-2-isoindolinyl) carbonyl]. Cyclohexylamine hydroiodide (Table 8 Reference Examples 13-34) is obtained.

Reference Examples 13-35 to 13-46
(1) N-benzyloxycarbonyl-trans-4-[(6-nitro-1-indolinyl) carbonyl] cyclohexylamine (Compound before deprotection obtained by the same method as in Reference Example 13-1) 6.08 g of water 17.33 g of stannous chloride is added to a suspension of ethanol (120 ml of ethanol + 1.2 ml of water), and the mixture is refluxed for 4.5 hours under an argon atmosphere. The reaction mixture is adjusted to pH 9-10 by adding a 10% aqueous sodium hydroxide solution, diluted with chloroform (300 ml), dried over magnesium sulfate, and filtered to remove insolubles. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (2: 1)) to give N-benzyloxycarbonyl-trans-4-[(6-amino- 4.72 g of 1-indolinyl) carbonyl] cyclohexylamine are obtained.

(2) To a solution of 396 mg of the compound obtained in (1) above in 10 ml of methylene chloride is added 0.12 ml of pyridine and 0.104 ml of acetic anhydride at room temperature, and the mixture is stirred for 5 hours. The reaction mixture is added with 5% hydrochloric acid and extracted with chloroform. The extract layer is sequentially washed with water and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (1: 1)).
This compound is treated with palladium carbon and deprotected to obtain trans-4-[(6-acetylamino-1-indolinyl) carbonyl] cyclohexylamine (Reference Example 13-35 in Table 8).
Similarly, the compounds of Reference Examples 13-36 to 13-37 in Table 8 are obtained.

(3) To a solution of 400 mg of the compound obtained in the above (1) in 10 ml of pyridine is added 0.085 ml of methanesulfonyl chloride at room temperature, and the mixture is stirred for 5 hours. The residue obtained by concentrating the reaction solution under reduced pressure is dissolved in chloroform, washed successively with 5% hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (2: 1)).
This compound is treated with palladium carbon and deprotected to give trans-4-[(6-methylsulfonylamino-1-indolinyl) carbonyl] cyclohexylamine (Reference Example 13-38 in Table 8).

(4) 403 mg of the compound obtained in the above (1), 169 mg of N, N-dimethylglycine hydrochloride, 243 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, 1-hydroxybenzotriazole A solution of 173 mg and 0.181 ml of triethylamine in 15 ml of N, N-dimethylformamide is stirred at room temperature for 5 hours. The residue obtained by concentrating the reaction solution under reduced pressure is dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (solvent: chloroform-methanol (50: 1)).
This compound is treated with palladium carbon and deprotected to obtain trans-4-{[6- (dimethylamino) methylcarbonyl-1-indolinyl] carbonyl} cyclohexylamine (Reference Example 13-39 in Table 8). .

(5) To a suspension of 402 mg of the compound obtained in (1) above in 10 ml of acetonitrile, 0.8 ml of a 37% aqueous solution of formalin and 635 mg of sodium triacetoxyborohydride are added at room temperature and stirred for 1.5 hours. Dilute the reaction with water and extract with ethyl acetate. The extract layer is washed successively with water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (2: 1)). This compound is treated with palladium on carbon and deprotected to obtain trans-4-[(6-dimethylamino-1-indolinyl) carbonyl] cyclohexylamine (Table 8 Reference Example 13-40).

(6) except that N-benzyloxycarbonyl-trans-4-[(5-nitro-1-indolinyl) carbonyl] cyclohexylamine (a compound obtained by the same method as in Reference Example 13-1) was used as a starting material, In the same manner as in the above (1) to (5), the compounds of Reference Examples 13-41 to 13-46 in Table 8 are obtained.

Reference Examples 13-47 to 13-52
N-benzyloxycarbonyl-trans-4-[(5-hydroxy-1-indolinyl) carbonyl] cyclohexylamine (Compound obtained by the same method as in Reference Example 13-1)
To a 400 mg solution of N, N-dimethylformamide in 5 ml, 451 mg of potassium carbonate and 238 mg of 2- (dimethylamino) ethyl chloride hydrochloride are added, and the mixture is stirred at 50 ° C. for 19 hours. The chloroform solution of the residue obtained by concentrating the reaction solution under reduced pressure is washed with water, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (solvent: chloroform-methanol (30: 1)).
This compound is added to a suspension of methanol (10 ml) -tetrahydrofuran (10 ml), 10% palladium on carbon catalyst (100 mg) and ammonium formate (920 mg) are added, and the mixture is heated under reflux for 17 hours. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to give trans-4-{[5- (2-dimethylaminoethyl) oxy-1-indolinyl] carbonyl} cyclohexylamine (Reference Example 13-47 in Table 8). get mg.
Also, in the same manner as above, the compounds of Reference Examples 13-48 to 13-52 in Table 8 are obtained.

Reference Examples 14-1 to 14-16
cis-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid 400 mg, 4-hydroxypiperidine 216 mg, 1-hydroxybenzotriazole 244 mg, O-benzotriazol-1-yl-N, N, N ', N' A mixture of -686 mg of tetramethyluronium hexafluorophosphate, 398 μl of N-methylmorpholine and 11 ml of N, N-dimethylformamide is stirred at room temperature for 14 hours. Water is added to the reaction solution, and extracted with ethyl acetate. The extract is washed with a 10% aqueous citric acid solution, water and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is dissolved in dioxane (5 ml), 4N hydrochloric acid-dioxane (6 ml) is added, and the mixture is stirred at room temperature for 12 hours. The reaction solution is concentrated, methanol is added to the residue, and the mixture is concentrated under reduced pressure. Then, ether was added to the residue and the mixture was concentrated under reduced pressure to obtain cis-4- (4-hydroxypiperidinocarbonyl) cyclohexylamine hydrochloride (Reference Example 14-1 in Table 8).
Further, the corresponding raw material compounds were used and treated in the same manner as described above to obtain the compounds of Reference Examples 14-2 to 14-16 in Table 8. (However, the free compound is obtained by saturating an aqueous solution of the hydrochloride compound with potassium carbonate, extracting with chloroform, drying the extract with sodium sulfate, and distilling off the solvent under reduced pressure.)

Reference Example 15-1
To a solution of N- (tert-butoxycarbonyl) piperazine (1.0 g) in dimethylformamide (7 ml), add potassium carbonate (742 mg) and further butyl iodide (1.09 g), and stir at room temperature for 15 hours to react. Yields N-tert-butoxycarbonyl-N-butylpiperazine. This is treated with hydrochloric acid to give N-butylpiperazine dihydrochloride.
Similarly, N-isopropylpiperazine dihydrochloride is obtained.

Reference Example 15-2
Dimethylamine hydrochloride (430 mg) was added to a solution of 4- (tert-butoxycarbonyl) piperidone (1.0 g) in methylene chloride (10 ml), and further, under ice-cooling, triethylamine (0.84 ml) and triacetoxyborohydride (1.17 g). Is added, and the mixture is stirred and reacted at room temperature for 3 hours to obtain N-tert-butoxycarbonyl-4-dimethylaminopiperidine. This is treated with hydrochloric acid to give 4- (dimethylamino) piperidine dihydrochloride.

Reference Example 15-3
To a solution of N-formylpiperazine (5.08 g) and cyclohexanecarboxaldehyde (7.50 g) in methylene chloride (50 ml) is added sodium triacetoxyborohydride (10.51 g) under ice-cooling, and the mixture is stirred and reacted at room temperature for 18 hours. Thus, 1-formyl-4-cyclohexylmethylpiperazine is obtained, which is treated with hydrochloric acid to give 1- (cyclohexylmethyl) piperazine hydrochloride.

Reference Example 15-4
60% sodium hydride (0.232 g) was gradually added to a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (0.900 g) and 2-chloropyrimidine (0.666 g) in tetrahydrofuran (4.5 ml), and after 2 hours, Dimethyl sulfoxide (1.0 ml) was added and the mixture was stirred and reacted at room temperature for 1 day to obtain 1-tert-butoxycarbonyl-4- (2-pyrimidinyloxy) piperidine. This compound is treated with hydrochloric acid to give 4- (2-pyrimidinyloxy) piperidine hydrochloride. Similarly, the following compound is obtained.
4- (5-cyano-2-pyridyloxy) piperidine hydrochloride 4- (5-bromo-2-pyrimidinyloxy) piperidine hydrochloride 4- (p-nitrophenoxy) piperidine hydrochloride

Reference Example 15-5
N- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (700 mg), morpholine (319 μL), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (702 mg), 1-hydroxybenzotriazole (495 mg) and a mixture of N, N-dimethylformamide (9 ml) were stirred and reacted at room temperature for 16 hours, and the compound obtained was treated with hydrochloric acid to give 4- (morpholinocarbonyl) piperidine. Obtain the hydrochloride salt.
The following compounds are obtained in the same manner as described above.
4- (diethylaminocarbonyl) piperidine / hydrochloride 4- (N-methyl-N-benzylaminocarbonyl) piperidine / hydrochloride 4- (p-chlorophenylaminocarbonyl) piperidine / hydrochloride

Reference Example 15-6
4-amino-1- (tert-butoxycarbonyl) piperidine (700 mg), benzoic acid (512 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (804 mg), 1-hydroxybenzotriazole (567 mg) and a mixture of N, N-dimethylformamide (10 ml) were reacted by stirring at room temperature for 16 hours. The compound obtained was acid-treated with hydrochloric acid to give 4- (benzoylamino) piperidine. Obtain the hydrochloride salt.
The following compounds are obtained in the same manner as described above.
4- (2-pyridylcarbonylamino) piperidine hydrochloride
4- (cyclohexylcarbonylamino) piperidine hydrochloride

Reference Example 15-7
A solution of N- (tert-butoxycarbonyl) piperazine (700 mg), N-methyl-N-phenylcarbamoyl chloride (700 mg), and triethylamine (1.05 mL) in acetonitrile (7 mL) is stirred and reacted at room temperature for 15 hours. By doing
The resulting compound is treated with hydrochloric acid to give 1- (N-methyl-N-phenylaminocarbonyl) piperazine hydrochloride.

Reference Example 15-8
Methanesulfonyl chloride (3.65 ml) was added to a solution of N-formylpiperazine (5.08 g) and triethylamine (6.85 ml) in methylene chloride (50 ml) under ice-cooling, and the mixture was stirred at room temperature for 18 hours to react. Formyl-4-methanesulfonylpiperazine is obtained. This compound is acid-treated with hydrochloric acid to obtain 1-methanesulfonylpiperazine hydrochloride. Also, 1- (phenylsulfonyl) piperazine hydrochloride is obtained in the same manner using the corresponding starting compound.

Reference Example 15-9
To a solution of 0.99 g of 2-tert-butoxycarbonyl-5- (hydroxymethyl) isoindoline in 10 ml of tetrahydrofuran are added 0.84 ml of triethylamine and 0.37 ml of methanesulfonyl chloride under ice cooling, and the mixture is stirred for 1 hour under ice cooling. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. 20 ml of ethanol and 1.02 ml of diisopropylethylamine are added to the residue, and the mixture is heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, and the residue is extracted with ethyl acetate and 5% aqueous hydrochloric acid. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (solvent: hexane-ethyl acetate = 4: 1) to obtain an oil. It is dissolved in 5 ml of dioxane, 8 ml of 4N hydrochloric acid-dioxane is added, and the mixture is stirred at room temperature. 20 ml of ether was added, and the resulting precipitate was collected by filtration and washed with ether to obtain 5- (ethoxymethyl) isoindoline hydrochloride.
The following compounds are obtained in the same manner as described above.
5- (methoxymethyl) isoindoline hydrochloride
5- (isopropyloxymethyl) isoindoline hydrochloride

Reference Example 15-10
To a solution of 0.72 g of 5-amino-2-tert-butoxycarbonylisoindoline in 8 ml of methylene chloride are added 0.85 ml of triethylamine and 0.35 ml of methyl chlorocarbonate, and the mixture is stirred at room temperature for 5 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. After the extract is dried over sodium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (solvent: chloroform-ethyl acetate = 2: 1) to obtain an oil. It is dissolved in 5 ml of dioxane, 8 ml of 4N hydrochloric acid-dioxane is added, and the mixture is stirred at room temperature. 20 ml of ether was added, and the resulting precipitate was collected by filtration and washed with ether to give 5- (methoxycarbonylamino) isoindoline hydrochloride.
The following compounds are obtained in the same manner as described above.
5- (acetylamino) isoindoline hydrochloride

Reference Example 15-11
Using 2-tert-butoxycarbonyl-5-aminoisoindoline (a compound obtained in the same manner as in WO 00/23428) and dimethylglycine as raw materials, the reaction was carried out in the same manner as in Reference Example 11-1 to give 5- (dimethyl). Aminomethylcarbonylamino) isoindoline is obtained.

The following Tables 1a to 1d and Tables 2 to 8 show the chemical structural formulas and physical properties of the compounds of the above Examples and Reference Examples.
(In the table, “Me” represents a methyl group. In the table, MS · APCI (m / z) represents a mass spectrometry value (atmospheric pressure chemical ionization mass spectrum).)

Claims (15)

General formula (I)

(In the formula, A is -CH ₂ - or an -S-,
R ¹ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group,
X is -N ^{(R 3)} - or an -O-,
R ³ represents a hydrogen atom or a lower alkyl group;
R ² is (1) an optionally substituted cyclic group, wherein the cyclic group moiety is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic hydrocarbon group. Represents a group which is a cyclic heterocyclic group, or (2) an amino group which may be substituted. )
Or a pharmacologically acceptable salt thereof. A is -CH ₂ -,
X is -N ^{(R 3)} - or -O-, and
R ³ is a lower alkyl group;
The compound according to claim 1, wherein R ² is an optionally substituted cyclic group, wherein the cyclic group moiety is a monocyclic, bicyclic or tricyclic heterocyclic group. The compound according to claim 1, wherein A is -S-. R ² is
(1) A cyclic group optionally having 1 to 3 identical or different substituents selected from the following group A substituents, wherein the cyclic group portion is (i) a monocyclic or bicyclic ring Or a tricyclic hydrocarbon group or (ii) a group that is a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) one or two identical or different substituents selected from the following group B substituents The compound according to claim 1, which is an amino group optionally having a group.
Group A substituent:
A halogen atom, a cyano group, a nitro group, an oxo group, a hydroxy group, a carboxy group, an oxydyl group, an amino group, a carbamoyl group, an aminosulfonyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group;
Lower alkoxycarbonyl group; lower alkoxy-substituted lower alkanoyl group;
Lower alkoxycarbonyl-substituted lower alkoxy group;
Lower alkoxycarbonyl-substituted lower alkoxycarbonyl group;
Lower alkylthio group; lower alkylsulfonyl group; di-lower alkylamino-substituted lower alkoxy group; di-lower alkylaminocarbonyloxy group;
A lower alkyl group substituted with a group selected from an amino group, a carbamoyl group, a halogen atom, a hydroxy group, a carboxy group, a lower alkoxy group and a mono- or di-substituted amino group;
A mono- or di-substituted amino group; a mono- or di-substituted carbamoyl group;
A substituted or unsubstituted lower cycloalkyl group;
Substituted or unsubstituted lower cycloalkyl-CO-;
A substituted or unsubstituted lower cycloalkyl-lower alkyl group;
A substituted or unsubstituted phenyl group;
Substituted or unsubstituted phenyl-O-;
Substituted or unsubstituted phenyl-CO-;
A substituted or unsubstituted phenyl-lower alkyl group;
A substituted or unsubstituted phenyl-O-lower alkyl group;
A substituted or unsubstituted phenylsulfonyl group;
A substituted or unsubstituted phenyl lower alkoxy group;
A substituted or unsubstituted phenyl lower alkoxycarbonyl group;
A substituted or unsubstituted lower cycloalkenyl group;
A substituted or unsubstituted bicyclic heterocyclic group;
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group;
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group -O-;
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -CO-;
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group-CO-lower alkyl group; and a substituted or unsubstituted monocyclic 5-6 membered heterocyclic group-lower alkyl group.
Group B substituent:
A lower alkyl group; a lower alkoxy-substituted lower alkyl group; a lower alkoxycarbonyl-substituted lower alkyl group; a hydroxy lower alkyl group; a carboxy lower alkyl group;
A substituted or unsubstituted lower cycloalkyl group;
A substituted or unsubstituted lower cycloalkyl-lower alkyl group;
A substituted or unsubstituted phenyl group;
A substituted or unsubstituted phenyl-lower alkyl group;
A substituted or unsubstituted bicyclic hydrocarbon group;
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group;
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-lower alkyl group; and a substituted or unsubstituted bicyclic heterocyclic group-lower alkyl group. When the "substituent selected from the group A substituent" is a mono- or di-substituted amino lower alkyl group, a mono- or di-substituted amino group or a mono- or di-substituted carbamoyl group, the substituent of the substituent is the following C Those selected from group substituents;
"Substituent selected from group A substituent" is a substituted lower cycloalkyl group, a substituted lower cycloalkyl-CO-, a substituted lower cycloalkyl-lower alkyl group, a substituted phenyl group, a substituted phenyl-O-, a substituted phenyl- CO-, substituted phenyl-lower alkyl group, substituted phenyl-O-lower alkyl group, substituted phenylsulfonyl group, substituted phenyl lower alkoxy group, substituted phenyl lower alkoxycarbonyl group, substituted lower cycloalkenyl group, substituted bicyclic heterocyclic group A substituted monocyclic 5-6 membered heterocyclic group, a substituted monocyclic 5-6 membered heterocyclic group -O-, a substituted monocyclic 5-6 membered heterocyclic group -CO-, a substituted monocyclic 5-6 When it is a membered heterocyclic group -CO-lower alkyl group or a substituted monocyclic 5-6 membered heterocyclic group-lower alkyl group, the substituent of the substituent is a halogen atom, a cyano group, a nitro group. Oxo group, and is one selected from the following group C substituent;
The “substituent selected from the group B substituents” is a substituted lower cycloalkyl group, a substituted lower cycloalkyl-lower alkyl group, a substituted phenyl group, a substituted phenyl-lower alkyl group, a substituted bicyclic hydrocarbon group, a substituted monocyclic group. When it is a cyclic 5- to 6-membered heterocyclic group, a substituted monocyclic 5- to 6-membered heterocyclic group-lower alkyl group or a substituted bicyclic heterocyclic group-lower alkyl group, the substituent of the substituent is 3. The compound according to claim 2, which is selected from Group C substituents.
Group C substituent:
A lower alkyl group; a hydroxy lower alkyl group, a lower alkanoyl group; a lower cycloalkylcarbonyl group; a lower alkoxy group; a lower alkoxycarbonyl group; a lower alkylsulfonyl group; a di-lower alkyl-substituted carbamoyl group; a di-lower alkylamino-substituted lower alkanoyl group;
A substituted or unsubstituted phenyl group;
Substituted or unsubstituted phenyl-O-;
Substituted or unsubstituted phenyl-CO-;
A substituted or unsubstituted phenyl lower alkanoyl group;
A substituted or unsubstituted phenyl lower alkyl group;
A substituted or unsubstituted phenyl lower alkoxy group;
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group;
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group -O-;
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group -CO-; and
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-substituted amino group;
(In the group C substituent, the substituent of the substituted phenyl group or the substituted monocyclic 5- to 6-membered heterocyclic group is a halogen atom, a cyano group, a nitro group, an oxo group,
A lower alkyl group, a lower alkoxy group, a lower alkanoyl group, and a lower alkoxycarbonyl group). R ² is
(1) a cyclic group which may be substituted, wherein the cyclic group portion is selected from the following (i) to (iv): (i) a monocyclic hydrocarbon group having 3 to 7 carbon atoms ,
(Ii) a bicyclic hydrocarbon group having 9 to 11 carbon atoms,
(Iii) a monocyclic heterocyclic group containing one or two hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; and (iv) one to three selected from a nitrogen atom, an oxygen atom and a sulfur atom A bicyclic heterocyclic group comprising two or more fused 5- to 7-membered rings; or (2) a substituted amino group;
The compound according to any one of claims 1 to 4, wherein R ² is
(1) An optionally substituted cyclic group, wherein the cyclic group portion is
Phenyl group, cyclohexyl group, cyclopentyl group, cyclobutyl group, cyclopropyl group, indanyl group, indenyl group, naphthyl group, tetrahydronaphthyl, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxolanyl group, thiolanyl group, pyrrolinyl group, imidazolinyl group , Pyrazolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group,
Furyl, oxazolyl, isoxazolyl, oxadiazolyl,
Thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group,
Piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, tetrahydropyridyl, dihydropyridazinyl, perhydroazepinyl, perhydrothiazepinyl Group, indolinyl group, isoindolinyl group, indolyl group, indazolyl group, isoindolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, benzodioxolanyl group, benzothienyl group, benzofuryl group, thienopyridyl group, thiazolopyridyl group, pyrrolopyridyl group , Dihydropyrrolopyridyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, chromanyl, isochromanyl, naphthyridinyl, Is or (2) substituted amino groups; beauty or some of these or all is a group selected from cyclic groups are saturated
A compound according to any one of claims 1 to 4. R ² is
(1) An optionally substituted cyclic group, wherein the cyclic group portion is
Phenyl group, cyclohexyl group, pyrrolidinyl group, tetrazolyl group,
Furyl, thienyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, perhydroazepinyl, indolinyl, isoindolinyl, benzothienyl, (2) a group selected from the group consisting of a thienopyridyl group, a pyrrolopyridyl group, a dihydropyrrolopyridyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, and a cyclic group in which some or all of these groups are saturated; ) Is a substituted amino group
A compound according to any one of claims 1 to 4. R ² is
(1) An optionally substituted cyclic group, wherein the cyclic group portion is
Pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, indolinyl group, isoindolinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, and cyclic groups in which some or all of these are saturated A group selected from the group consisting of; or (2) a substituted amino group
A compound according to any one of claims 1 to 4. R ² is
(1) a cyclic group optionally having 1 to 3 identical or different substituents selected from the following A ′ group substituents, wherein the cyclic group portion is
Pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, indolinyl group, isoindolinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, and cyclic groups in which some or all of these are saturated Or (2) an amino group substituted with one or two identical or different substituents selected from the following group B 'substituents: A compound according to any one of the preceding claims.

A 'group substituent:
Halogen atom, cyano group, nitro group, oxo group, carbamoyl group, lower alkyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group, lower alkoxy-substituted lower alkyl group, mono- or di-substituted amino group, mono- or di-substitution Carbamoyl group,
Lower cycloalkyl-CO-,
A substituted or unsubstituted phenyl group,
A substituted or unsubstituted phenyl-lower alkyl group,
A substituted or unsubstituted monocyclic 5-6 membered heterocyclic group,
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -O- and a substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -CO-.
B 'group substituent:
Lower alkyl group, lower cycloalkyl group, lower alkoxy-substituted lower alkyl group, pyrimidinyl group, thiazolyl group and thiadiazolyl group. The compound according to any one of claims 1 to 10, wherein X is —O— and A is —CH ₂ —. The compound according to claim ¹ , wherein X is —O—, A is —CH ₂ —, and R ¹ is a hydrogen atom. The following partial structure

The compound according to any one of claims 1 to 11, having the formula: A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:
(S) -2-cyano-1- [trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (5-cyano-2-pyridyloxy) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (5-bromo-2-pyrimidinyloxy) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (3-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine;
(R) -4-cyano-3- [trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylthiazolidine;
(R) -4-cyano-3- [trans-4- (5-cyano-2-pyridyloxy) cyclohexylamino] acetylthiazolidine. General formula [II]

(In the formula, A is -CH ₂ - or an -S-, ^{Z 1} represents a reactive residue.)
And a compound represented by the general formula [III]

(Wherein, R ¹ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group;
X is -N ^{(R 3)} - or an -O-,
R ³ represents a hydrogen atom or a lower alkyl group;
R ² is (1) an optionally substituted cyclic group, wherein the cyclic group moiety is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or Represents a group which is a tricyclic heterocyclic group or (2) an amino group which may be substituted. )
Wherein the compound represented by the general formula (I) is reacted with a compound or a salt thereof, if desired, to obtain a pharmaceutically acceptable salt of the product.

(Wherein the symbols have the same meanings as described above.)
Or a pharmaceutically acceptable salt thereof.