JP2002371042A - Dimamine compound, method for producing the same and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a diamine compound useful for the treatment of acquired immune deficiency, cancer, or the like, based on CXCR4 antagonistic action. SOLUTION: The diamine compound is a compound expressed by formula (I) (R<1> and R<2> are each H or an alkyl; A is a (substituted) cyclic group; X is a bond or an alkylene or an alkenylene group bonded to A optionally through a heteroatom; Y is S, O, C(=O)-N(R<15> ) (R<15> is H or a (substituted) alkyl), SO2 -N(R<16> ) (R<16> is H or a (substxtuted) alkyl), C(=O)-O, SO, SO2 , or N(R<17> ) (R<17> is H or a (substituted) alkyl); A-X-Y may form a (substituted) heterocyclic group; (1) is 2-6; (m) is 2-4; and (n) is O-8) (when Y is -N(R<17> ), A is a (substituted) aromatic heterocyclic group) or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a diamine compound based on CXCR4 antagonism, which is useful for treating acquired immunodeficiency syndrome, cancer and the like, a method for producing the diamine compound, and a use thereof.

[0002]

2. Description of the Related Art In recent years, HIV (human immunodeficiency virus) protease inhibitors have been developed as a treatment for AIDS (acquired immunodeficiency syndrome) and can be combined with two HIV reverse transcriptase inhibitors conventionally used. Has significantly improved the treatment of AIDS. CD4 has long been known as a receptor for HIV entry into target cells, but recently, macrophage-tropic H
It is called CCR5 as the second receptor for IV and CXCR4 as the second receptor for T cells.
Transmembrane and G protein-coupled chemokine receptors have been found, respectively, and these chemokine receptors are thought to play an essential role in the establishment and transmission of HIV infection. HIV isolated during the asymptomatic stage of the infected person is tropic for macrophages using CCR5, but from one year to two years before the infected person develops AIDS, it becomes tropic for T cells using CXCR4. It has been found that it changes. On the other hand, recently, it has been reported that the expression of CXCR4 is enhanced in breast cancer and the like, and that the expression of its ligand CXCR12 or SDF-1α is enhanced in organs to which metastasis (lymph node, lung, liver and bone) has been performed. (Nature, No. 41)
0, paragraphs 50-56).

At present, as chemokine receptor antagonists, aromatic urea derivatives (J. Biol. Chem., 1998, 273,
10095-10098.), Benzdiazepine derivatives (JP-A-9-24)
9570), cyclam derivative (Nat.Med., 1998, 4, 72-7
7.), spiropiperidine derivative (WO98 / 25604, 25605,), acridine derivative (WO98 / 30218), xanthene derivative (WO98 / 045)
54), haloperidol derivatives (J. Biol. Chem., 1998, 273, 156).
87-15692., WO98 / 24325, 02151.), benzazosin compounds (JP-A-9-25572), benzimidazole derivatives (WO98 /
06703), piperazine and diazepine derivatives (WO 97/4432
9), 3-substituted piperidine derivative (JP-A-9-249566), 4
Position-substituted piperidine derivatives (WO99 / 04794), substituted pyrrolidine derivatives (WO99 / 09984, WO99 / 38514) and the like are known,
To date, there have been no examples in which CXCR4 antagonists have been developed as therapeutic agents for AIDS and cancer.

[0004]

The conventional AIDS therapeutic agent is not yet sufficient for eradication of AIDS, and there is a need for the development of a new anti-AIDS drug based on another mechanism of action. Among them, CXCR4 antagonists are AID
It is expected to be a new anti-HIV drug that has the effect of preventing the onset of S or preventing the progression of the disease state after the onset and has a therapeutic effect, and is also expected to be a promising therapeutic drug as an anticancer drug having an antimetastatic effect. Anti-AIDS based on CXCR4 antagonism
In order to search for drugs and anticancer drugs, it is necessary to obtain a CXCR4-expressing cell line by cloning the CXCR4 gene from a human tissue-derived cDNA library, ligating it to an animal cell expression vector, and introducing it into animal cells. is there. This transformed cell line is then used to generate the natural ligand C
A compound that strongly inhibits the binding of the XC chemokine SDF-1α to CXCR4 must be screened. However, there is no report of a low-molecular compound having the antagonistic activity and having a molecular weight of 500 or less.

[0005]

Means for Solving the Problems As a result of intensive studies, the present inventors have synthesized for the first time a compound represented by the following general formula (I) or a salt thereof having a chemical structure characteristic in a diamine structure. (I) or a salt thereof exhibits unexpectedly excellent CXCR4 antagonism based on its specific chemical structure, and is a prophylactic / therapeutic agent for HIV infection of human peripheral blood mononuclear cells, particularly AIDS, and an anti-metastasis. The present inventors have found that they are useful as medicaments such as anticancer drugs having an effect, and that they have excellent properties as medicaments such as oral absorption, and based on this, the present invention has been completed. That is, the present invention provides the following formula [1]:

Embedded image[Wherein, R¹And R^TwoIs a hydrogen atom or alk
A represents a cyclic group which may be substituted, and X represents a bond.
May be attached to A by hand or via a heteroatom;
A alkylene group or an alkenylene group, and Y is (1) sulfur source
, (2) oxygen atom, (3) -C (= O) -N (R¹⁵)-(R¹⁵Is a hydrogen atom
Or an optionally substituted alkyl group), (4)-
SO_Two-N (R¹⁶)-(R¹⁶Is a hydrogen atom or even if it is substituted
Good alkyl group), (5) -C (= O) -O-, (6) -SO-, (7)
-SO_Two-Or (8) -N (R¹⁷)-(R¹⁷Is a hydrogen atom or substitution
Represents an optionally substituted alkyl group), and AX-
The group represented by Y- forms an optionally substituted heterocyclic group.
Where l is an integer from 2 to 6 and m is 2 to
And n represents an integer of 0 to 8. However
And Y is -N (R¹⁷)-, A represents an optionally substituted fragrance
Represents a group heterocyclic group. Or a salt thereof,
[2] R¹And R^TwoAre each independently a hydrogen atom or
C_1-6A is 1 to 5 alkyl groups represented by (1) (i) halogen.
C which may be replaced_1-6Alkoxy group, (ii) halogen
And 1 to 3 substituents selected from carbamoyl
C that may be_6-14Aryloxy group, (iii) halo
Gen atom, (iv) C_3-8Cycloalkyl group, (v) amino group,
(vi) (a) carbamoyl, (b) C_1-6Alkylsulfonyl,
(c) C_1-6Alkyl, (d) mono or di (C_1-6Archi
Ru) C which may be substituted by 1 or 2 amino
_1-6A substituent selected from alkyl and (e) benzoyl
An amino group substituted by 1 or 2 with (vii) C_1-6Al
Carbamoy optionally substituted by 1 or 2 kills
Group, (viii) formyl group, (ix) C_2-6Alkanoyl group,
(x) C_1-6A substituent selected from alkyl and halogen
1 to 5 optionally substituted C_6-14Aryl group, (xi)
C_6-14Aryl-carbonyl group, (xii) C_7-13Aralki
Ru-carbonyl group, (xiii) hydroxyl group, (xiv) C_2-5Alkano
Yloxy group, (xv) C_7-13Aralkyl-carbonyloxy
(Xvi) nitro group, (xvii) C_1-6Alkyl or 1
Is a sulfamoyl group which may be substituted two times, (xvii
i) C_1-6C optionally substituted with 1 to 3 alkyl (s)
_6-14An arylthio group, (xix) -N = N-Ar (Ar is C
_6-14Represents an aryl group), (xx) cyano
Group, (xxi) amidino group, (xxii) carboxyl group, (xxiii)
C_1-4Alkoxycarbonyl group, (xxiv) C_1-6Alkyl
O group, (xxv) C_1-6Alkylsulfinyl group, (xxvi) C
_1-6Alkylsulfonyl group, (xxvii) C_6-14Arylchi
Oh, (xxviii) C_6-14Arylsulfinyl group, (xxix) C
_6-14An arylsulfonyl group, and (xxx) C_1-6Archi
Le, C_1-6Alkoxy, halogen, oxo, thioxo
And C_{1 -6}1 to 5 substituents selected from alkylthio
Or a 5- or 6-membered heterocyclic group optionally substituted with
6-membered heterocyclic ring or fused ring group with benzene ring:
C which may be substituted with 1 to 5 substituents_1-6
Alkyl group, (2) (i) 1 to 5 halogen-substituted,
Good C_1-6Alkoxy group, (ii) halogen and carba
Even if substituted with 1 to 3 substituents selected from moyl
Good C_6-14Aryloxy group, (iii) halogen atom, (i
v) C_3-8Cycloalkyl group, (v) amino group, (vi) (a)
Bamoyl, (b) C_1-6Alkylsulfonyl, (c) C_1-6Al
Kill, (d) mono or di (C_1-6Alkyl) amino with 1
Or two optionally substituted C_1-6Alkyl
And (e) 1 or 2 with a substituent selected from benzoyl
(Vii) C-substituted amino group_1-6Alkyl or 1
Is a carbamoyl group which may be substituted two times, (viii)
Lumil group, (ix) C_2-6Alkanoyl group, (x) C_1-6Archi
1 to 5 substituents selected from the group consisting of
C that may be_6-14Aryl group, (xi) C_6-14Aryl
-Carbonyl group, (xii) C_7-13Aralkyl-carbonyl
Group, (xiii) hydroxyl group, (xiv) C_2-5Alkanoyloxy group,
(xv) C_7-13Aralkyl-carbonyloxy group, (xvi)
Toro group, (xvii) C_1-61 or 2 substituted with alkyl
An optionally substituted sulfamoyl group, (xviii) C_1-6Archi
Optionally substituted with 1 to 3 carbon atoms_6-14Arylthio
Group, (xix) -N = N-Ar (Ar is C_6-14Aryl group
(Xx) cyano group, (xxi) amidino
Group, (xxii) carboxyl group, (xxiii) C_1-4Alkoxyka
Rubonyl group, (xxiv) C_1-6Alkylthio group, (xxv) C_1-6
Alkylsulfinyl group, (xxvi) C_1-6Alkylsulfo
Nyl group, (xxvii) C_6-14Arylthio, (xxviii) C_6-14
Arylsulfinyl group, (xxix) C_6-14Arylsulfo
Nil group, and (xxx) C_1-6Alkyl, C_1-6Alkoki
Si, halogen, oxo, thioxo and C_{1 -6}Alkyl
Even if substituted with 1 to 5 substituents selected from thio
A good 5- to 6-membered heterocyclic group or its 5- to 6-membered heterocyclic group or
Is a condensed ring group with a benzene ring: 1 to 5 positions selected from
C optionally substituted with a substituent_2-6Alkenyl group, (3)
(i) C optionally substituted with 1 to 5 halogens_1-6Al
Oxy group, (ii) selected from halogen and carbamoyl
Which may be substituted by 1 to 3 substituents_6-14Ally
Loxy group, (iii) halogen atom, (iv) C_3-8Cycloal
Kill group, (v) amino group, (vi) (a) carbamoyl, (b) C_1-6
Alkylsulfonyl, (c) C_1-6Alkyl, (d) mono-if
Kuhaji (C_1-61 or 2 substituted with alkyl) amino
C that may be_1-6Alkyl, and (e) benzoyl
Amino substituted with one or two substituents selected from
Group, (vii) C_1-6Substituted with one or two alkyl groups
Carbamoyl group, (viii) formyl group, (ix) C
_2-6Alkanoyl group, (x) C_1-6Alkyl and halogen
C may be substituted with 1 to 5 substituent (s) selected from
_6-14Aryl group, (xi) C_6-14An aryl-carbonyl group,
(xii) C_7-13Aralkyl-carbonyl group, (xiii) hydroxyl
Group, (xiv) C_2-5Alkanoyloxy group, (xv) C_7-13Ara
Alkyl-carbonyloxy group, (xvi) nitro group, (xvii)
C_1-61 or 2 may be substituted with alkyl
A sulfamoyl group, (xviii) C_1-6Place 1 to 3 with alkyl
C which may be replaced_6-14Arylthio group, (xix) -N
= N-Ar (Ar is C_6-14Represents an aryl group)
Group, (xx) cyano group, (xxi) amidino group, (xxii)
Boxyl group, (xxiii) C_1-4An alkoxycarbonyl group, (x
xiv) C_1-6Alkylthio group, (xxv) C_1-6Alkylsulf
Ynyl group, (xxvi) C_1-6Alkylsulfonyl group, (xxvii)
C_6-14Arylthio, (xxviii) C_6-14Aryl sulfy
Nyl group, (xxix) C_6-14An arylsulfonyl group, and (x
xx) C_1-6Alkyl, C_1-6Alkoxy, halogen, oki
So, thioxo and C_{1 -6}1 selected from alkylthio
5 to 6-membered heterocyclic ring optionally substituted with up to 5 substituents
Of a group or its 5- or 6-membered heterocyclic or benzene ring
Condensed group: substituted with 1 to 5 substituents selected from
May be C_2-6Alkynyl group, (4) (i) halogen with 1 to 5
C optionally substituted_1-6Alkoxy group, (ii) halo
1 to 3 substituents selected from gen and carbamoyl
Optionally substituted C_6-14Aryloxy group, (iii)
Halogen atom, (iv) 1 to 5 halogen atoms are substituted
Good C_1-6Alkyl group, (v) C_3-8Cycloalkyl group,
(vi) amino group, (vii) (a) carbamoyl, (b) C_1-6Archi
Rusulfonyl, (c) C_1-6Alkyl and (d) mono or
Is di (C_1-6Alkyl or amino substituted with 1 or 2
C that may be_1-61 with a substituent selected from alkyl
Or two substituted amino groups, (viii) C_1-6Archi
Carbamoyl optionally substituted by 1 or 2
Group, (ix) formyl group, (x) C_2-6Alkanoyl group, (xi) C
_6-14Aryl group, (xii) C_6-14Aryl-carbonyl
Group, (xiii) C_7-13Aralkyl-carbonyl group, (xiv) water
Acid group, (xv) C_2-5Alkanoyloxy group, (xvi) C_7-13A
Aralkyl-carbonyloxy group, (xvii) nitro group, (xvi
ii) C_1-6May be substituted with 1 or 2 alkyl groups
Sulfamoyl group, (xix) C_1-6Place 1 to 3 with alkyl
C which may be replaced_6-14Arylthio group, (xx) -N =
N-Ar (Ar is C_6-14Represents an aryl group)
Group, (xxi) cyano group, (xxii) amidino group, (xxiii)
Boxyl group, (xxiv) C_1-4Alkoxycarbonyl group, (xx
v) C_1-6Alkylthio group, (xxvi) C_1-6Alkylsulfi
Nyl group, (xxvii) C_1-6Alkylsulfonyl group, (xxviii)
C_6-14Arylthio, (xxix) C_6-14Arylsulfini
Group, (xxx) C_6-14Arylsulfonyl group, and (xxx
i) C_1-6Alkyl, C_1-6Alkoxy, halogen, oki
So, thioxo and C _1-61 selected from alkylthio
5 to 6-membered heterocyclic ring optionally substituted with up to 5 substituents
Of a group or its 5- or 6-membered heterocyclic or benzene ring
Condensed group: substituted with 1 to 5 substituents selected from
May be C_6-14Aryl group, (5) (i) 1 to 5 halogens
Optionally substituted C_1-6Alkoxy group, (ii) halogen
1-3 substituents selected from carbamoyl and carbamoyl
C which may be replaced_6-14Aryloxy group, (iii) c
A halogen atom, (iv) 1 to 5 halogen atoms
Good C_1-6Alkyl group, (v) C_3-8Cycloalkyl group, (v
i) amino group, (vii) (a) carbamoyl, (b) C_1-6Alkyl
Sulfonyl, (c) C_1-6Alkyl and (d) mono or
J (C_1-6Alkyl or amino substituted by 1 or 2
May be C_1-6One of the substituents selected from alkyl
Or two substituted amino groups, (viii) C_1-6Alkyl
May be substituted with one or two carbamoyls
Group, (ix) formyl group, (x) C_2-6Alkanoyl group, (xi) C
_6-14Aryl group, (xii) C_6-14Aryl-carbonyl
Group, (xiii) C_7-13Aralkyl-carbonyl group, (xiv) water
Acid group, (xv) C_2-5Alkanoyloxy group, (xvi) C_7-13A
Aralkyl-carbonyloxy group, (xvii) nitro group, (xvi
ii) C_1-6May be substituted with 1 or 2 alkyl groups
Sulfamoyl group, (xix) C_1-6Place 1 to 3 with alkyl
C which may be replaced_6-14Arylthio group, (xx) -N =
N-Ar (Ar is C_6-14Represents an aryl group)
Group, (xxi) cyano group, (xxii) amidino group, (xxiii)
Boxyl group, (xxiv) C_1-4Alkoxycarbonyl group, (xx
v) C_1-6Alkylthio group, (xxvi) C_1-6Alkylsulfi
Nyl group, (xxvii) C_1-6Alkylsulfonyl group, (xxviii)
C_6-14Arylthio, (xxix) C_6-14Arylsulfini
Group, (xxx) C_6-14Arylsulfonyl group, and (xxx
i) C_1-6Alkyl, C_1-6Alkoxy, halogen, oki
So, thioxo and C _1-61 selected from alkylthio
5 to 6-membered heterocyclic ring optionally substituted with up to 5 substituents
Of a group or its 5- or 6-membered heterocyclic or benzene ring
Meridyl group: each substituted with 1 to 5 substituents selected from
C that may be_3-7Cycloalkyl group or C_3-6
Cycloalkenyl group, (6) (i) 1 to 5 substituents with halogen
C that may be_1-6Alkyl, (ii) C_1-6Alkoki
(Iii) halogen, (iv) oxo, (v) thioxo and (v
i) C_1-6With 1 to 5 substituents selected from alkylthio
5- or 6-membered heterocyclic group which may be substituted or
6-membered heterocyclic ring or fused ring group with benzene ring, (7) (i)
Logen and C_6-141 to 5 positions selected from aryl
C optionally substituted with a substituent_1-6Alkyl group, (ii) C
_1-6C 1-5 optionally substituted with alkyl_6-14A
Reel group, (iii) formyl group, (iv) C_2-6Alkanoyl
Group, (v) C_6-14Aryl-carbonyl group, (vi) C_1-6Al
Killsulfonyl group, (vii) C_1-6Substitute 1-3 with alkyl
C that may be_6-14An arylsulfonyl group, and
(viii) C optionally substituted by 1 to 3 halogens_1-6
An alkoxy-carbonyl group, and (ix) C_1-6Alkyl
Or one or two of which may be substituted with formyl
Substituted with one or two substituents selected from a midino group
An optionally substituted amino group (where two substituents
Together with the atom, C_1-6Alkyl group, C_7-10Aral
Kill group and C_6-101 to 3 selected from aryl groups
3- to 8-membered cyclic amino group which may be substituted with a substituent
(8) (i) halogen and C_6-14Ants
Even when substituted with 1 to 5 substituents selected from
Good C_1-6Alkyl group, (ii) C_1-6Alkyl 1-5 places
C which may be replaced_6-14Aryl group, (iii) formyl
Group, (iv) C_2-6Alkanoyl group, (v) C_6-14Aryl-ka
Rubonyl group, (vi) C_1-6Alkylsulfonyl group, (vii) C
_1-6C optionally substituted with 1 to 3 alkyl (s)_6-14A
1 to 3 reelsulfonyl groups and (viii) halogen
Optionally substituted C_1-6Alkoxy-carbonyl group
Substituted with one or two substituents selected from
Amidino group, (9) (i) halogen and C_6-14Ally
May be substituted with 1 to 5 substituents selected from
C_1-6Alkyl group, (ii) C_1-6Substitute 1 to 5 with alkyl
C that may be_6-14Aryl group, (iii) formyl
Group, (iv) C_2-6Alkanoyl group, (v) C_6-14Aryl-ka
Rubonyl group, (vi) C_1-6Alkylsulfonyl group, (vii) C
_1-6C optionally substituted with 1 to 3 alkyl (s)_6-14A
1 to 3 reelsulfonyl groups and (viii) halogen
Optionally substituted C_1-6Alkoxy-carbonyl group
A hydroxyl group which may be substituted with a substituent selected from (1)
0) (i) halogen and C_6-141 selected from aryl
C optionally substituted with 5 substituents_1-6Alkyl
Group, (ii) C_1-61 to 5 alkyl groups may be substituted
C_6-14Aryl group, (iii) formyl group, (iv) C_2-6Al
Canoyl group, (v) C_6-14Aryl-carbonyl group, (vi)
C_1-6Alkylsulfonyl group, (vii) C_1-61 with alkyl
Up to 3 optionally substituted C_6-14Arylsulfonyl
Group, and (viii) even if substituted with 1 to 3 halogens
Good C_1-6Substitution selected from alkoxy-carbonyl group
A thiol group which may be substituted with a group, (11) (i)
A xyl group, (ii) C_1-6An alkoxy-carbonyl group, (iii)
 (a) hydroxyl group, (b) C_1-6Alkyl group, mono- or di-
C_1-6C substituted with 1 to 3 alkylamino_1-6Archi
Group, mono- or di-C_3-6Cycloalkylamino
Substituted with one to three C_1-6Alkyl group, formyl, C
_2-6One if selected from alkanoyl and benzoyl
Or an amino group optionally substituted with two substituents,
(c) halogen atom, (d) nitro, (e) cyano, (f) 1 to 5
C optionally substituted with halogen_1-6Alkyl group,
And (g) optionally substituted with 1 to 5 halogens
C_1-6Substituted with 1 to 3 substituents selected from alkoxy groups
C which may be replaced_6-10Aryloxy-carbonyl
And (iv) (a) hydroxyl, (b) C_1-6Alkyl group, mono
-Or di-C_1-61-3 substituted with alkylamino
C_1-6Alkyl group, mono- or di-C_3-6Cyclo
C substituted with 1 to 3 alkylamino_1-6Alkyl
Group, formyl, C_2-6Alkanoyl and benzoyl?
Even if it is substituted with one or two substituents selected from
Good amino group, (c) halogen atom, (d) nitro, (e) shea
No, (f) C optionally substituted with 1 to 5 halogens
_1-6Alkyl group, and (g) substituted with 1 to 5 halogens.
C that may be_1-61-3 selected from alkoxy groups
C which may be substituted with_7-10Aralquilo
Esterified selected from xy-carbonyl groups,
Carboxyl group, (12) (i) (a) hydroxyl group, (b) C_1-6A
Alkyl group, mono- or di-C_1-6With alkylamino
1-3 substituted C_1-6Alkyl groups, mono- or
Di-C_3-61-3 substituted by cycloalkylamino
C_1-6Alkyl group, formyl, C_2-6Alkanoyl and
Substituted with one or two substituents selected from benzoyl
Optionally substituted amino group, (c) halogen atom, (d) nitro
B, (e) cyano, and (f) substituted with 1 to 5 halogens
C that may be_1-61 to 1 selected from an alkoxy group
C optionally substituted with three substituents_1-6Alkyl
Group, (ii) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono-if
Kuha-C_1-6C substituted with 1 to 3 alkylamino
_1-6Alkyl group, mono- or di-C_3-6Cycloalkyl
C substituted with 1 to 3 amino acids_1-6Alkyl group, phor
Mill, C_2-6Selected from alkanoyl and benzoyl
Amino which may be substituted with one or two substituents
Group, (c) halogen atom, (d) nitro, (e) cyano, (f) 1
C optionally substituted with up to 5 halogens_1-6Archi
And (g) substituted with 1 to 5 halogens.
Good C_1-61-3 substitutions selected from alkoxy groups
C optionally substituted with a group_3-6A cycloalkyl group, (ii
i) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono- or di-
-C_1-6C substituted with 1 to 3 alkylamino_1-6Al
Kill group, mono- or di-C_3-6Cycloalkylamide
C substituted 1 to 3 times_1-6Alkyl group, formyl,
C_2-6Also one selected from alkanoyl and benzoyl
Or an amino group optionally substituted with two substituents,
(c) halogen atom, (d) nitro, (e) cyano, (f) 1 to 5
C optionally substituted with halogen_1-6Alkyl group,
And (g) optionally substituted with 1 to 5 halogens
C_1-6Substituted with 1 to 3 substituents selected from alkoxy groups
C which may be replaced_6-10Aryl group, (iv) (a) hydroxyl
Group, (b) C_1-6Alkyl group, mono- or di-C_1-6A
C substituted with 1 to 3 alkylamino_1-6Alkyl group,
Mono- or Di-C_3-61 to cycloalkylamino
Three substituted C_1-6Alkyl group, formyl, C_2-6Al
One or two selected from canoyl and benzoyl
An amino group optionally substituted with a substituent of
Atom, (d) nitro, (e) cyano, (f) 1 to 5 halogen
C optionally substituted with_1-6An alkyl group, and (g)
C optionally substituted with 1 to 5 halogens_1-6Al
Substituted with 1 to 3 substituents selected from a oxy group
May be C_7-10An aralkyl group, and (v) (a) a hydroxyl group,
(b) C_1-6Alkyl group, mono- or di-C_1-6Archi
C substituted with 1 to 3 amino acids_1-6Alkyl group, mono
-Or di-C_3-61 to 3 cycloalkylamino
Replaced C_1-6Alkyl group, formyl, C_2-6Alkano
One or two positions selected from yl and benzoyl
An amino group which may be substituted with a substituent, (c) a halogen atom
(D) nitro, (e) cyano, (f) 1 to 5 halogens
Optionally substituted C_1-6An alkyl group, and (g) 1
C optionally substituted with 5 halogens_1-6Alkoki
Even when substituted with 1 to 3 substituents selected from
A good 5- to 6-membered heterocyclic group or its 5- to 6-membered heterocyclic group or
Is one or two selected from a condensed ring group with a benzene ring
A carbamoyl group (two
Together with the adjacent nitrogen atom form C_1-6A
Alkyl group, C_7-10Aralkyl group and C_6-10Aryl group
May be substituted with 1 to 3 substituents selected from
(A 3- to 8-membered cyclic amino group may be formed), (13) (i)
(a) hydroxyl group, (b) C_1-6Alkyl group, mono- or di-
C_1-6C substituted with 1 to 3 alkylamino_1-6Archi
Group, mono- or di-C_3-6Cycloalkylamino
Substituted with one to three C_1-6Alkyl group, formyl, C
_2-6One if selected from alkanoyl and benzoyl
Or an amino group optionally substituted with two substituents,
(c) a halogen atom, (d) nitro, (e) cyano, and (f) 1
C optionally substituted with up to 5 halogens_1-6Arco
Substituted with 1 to 3 substituents selected from xy groups,
Good C_1-6Alkyl group, (ii) (a) hydroxyl group, (b) C_1-6A
Alkyl group, mono- or di-C_1-6With alkylamino
1-3 substituted C_1-6Alkyl groups, mono- or
Di-C_3-61-3 substituted by cycloalkylamino
C_1-6Alkyl group, formyl, C_2-6Alkanoyl and
Substituted with one or two substituents selected from benzoyl
Optionally substituted amino group, (c) halogen atom, (d) nitro
B) (e) cyano, (f) substituted with 1 to 5 halogens.
May be C_1-6An alkyl group, and (g) 1 to 5 halogen
C optionally substituted with_1-6Choose from alkoxy groups
C optionally substituted with 1 to 3 substituents_3-6Shi
Chloroalkyl group, (iii) (a) hydroxyl group, (b) C_1-6Alkyl
Group, mono- or di-C_1-61-3 with alkylamino
Replaced C_1-6Alkyl group, mono- or di-C
_3-6C substituted with 1 to 3 cycloalkylamino_1-6A
Alkyl group, formyl, C_2-6Alkanoyl and benzo
Substituted with one or two substituents selected from yl
Optionally amino group, (c) halogen atom, (d) nitro,
(e) cyano, (f) even when substituted with 1 to 5 halogens
Good C_1-6An alkyl group, and (g) 1 to 5 halogens
Optionally substituted C_1-6Selected from alkoxy groups
C optionally substituted with 1 to 3 substituents_6-10Ally
(Iv) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono-
Or Di-C_1-61-3 substituted with alkylamino
C_1-6Alkyl group, mono- or di-C_3-6Cycloal
C substituted with 1 to 3 alkylamino_1-6Alkyl group, e
Lumil, C_2-6Choose from alkanoyl and benzoyl
A which may be substituted with one or two substituents
Amino group, (c) halogen atom, (d) nitro, (e) cyano, (f)
C optionally substituted with 1 to 5 halogens_1-6Al
A alkyl group, and (g) substituted with 1 to 5 halogens.
May be C_1-61 to 3 positions selected from alkoxy groups
C optionally substituted with a substituent_7-10Aralkyl groups and
(V) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono- or
Is Di-C_1-6C substituted with 1 to 3 alkylamino_1-6
Alkyl group, mono- or di-C_3-6Cycloalkyl
C substituted with 1 to 3 amino groups_1-6Alkyl group, holmi
Le, C_2-6Selected from alkanoyl and benzoyl
Amino optionally substituted with one or two substituents
Group, (c) halogen atom, (d) nitro, (e) cyano, (f) 1
C optionally substituted with 5 halogens_1-6Alkyl
And (g) even if substituted with 1 to 5 halogens
Good C_1-61 to 3 substituents selected from alkoxy groups
Or a 5- or 6-membered heterocyclic group optionally substituted with
Selected from a 6-membered heterocyclic ring or a condensed ring group with a benzene ring
Which may be substituted with one or two substituents
Ocarbamoyl group (where two substituents are
Together, C_1-6Alkyl group, C_7-10Aralkyl group
And C_6-101 to 3 substituents selected from aryl groups
Forms a 3- to 8-membered cyclic amino group which may be substituted with
(14) halogen atom, (15) cyano group, (16)
Nitro group, (17) (i) (a) hydroxyl group, (b) C_1-6Alkyl group, mo
No- or di-C_1-6Substitute 1-3 with alkylamino
Done C_1-6Alkyl group, mono- or di-C_3-6Shiku
C substituted with 1-3 alkylamino_1-6Alkyl
Group, formyl, C_2-6Alkanoyl and benzoyl?
Even if it is substituted with one or two substituents selected from
Good amino group, (c) halogen atom, (d) nitro, (e) shea
And (f) even when substituted with 1 to 5 halogens
Good C_1-61 to 3 substituents selected from alkoxy groups
C optionally substituted with_1-6Alkyl group, (ii) (a) water
Acid group, (b) C_1-6Alkyl group, mono- or di-C_1-6
C substituted with 1 to 3 alkylamino_1-6Alkyl
Group, mono- or di-C_3-6With cycloalkylamino
1-3 substituted C_1-6Alkyl group, formyl, C_2-6
One selected from alkanoyl and benzoyl or
An amino group optionally substituted with two substituents, (c)
A halogen atom, (d) nitro, (e) cyano, (f) 1-5
C optionally substituted with a logen_1-6Alkyl group and
And (g) C optionally substituted with 1 to 5 halogens_1-6
Substituted with 1 to 3 substituents selected from an alkoxy group
May be C_3-6Cycloalkyl group, (iii) (a) hydroxyl
Group, (b) C_1-6Alkyl group, mono- or di-C_1-6A
C substituted with 1 to 3 alkylamino_1-6Alkyl group,
Mono- or Di-C_3-61 to cycloalkylamino
Three substituted C_1-6Alkyl group, formyl, C_2-6Al
One or two selected from canoyl and benzoyl
An amino group optionally substituted with a substituent of
Atom, (d) nitro, (e) cyano, (f) 1 to 5 halogen
C optionally substituted with_1-6An alkyl group, and (g)
C optionally substituted with 1 to 5 halogens_1-6Al
Substituted with 1 to 3 substituents selected from a oxy group
May be C_6-10Aryl group, (iv) (a) hydroxyl group, (b) C_1-6
Alkyl group, mono- or di-C_1-6Alkylamino
Substituted with one to three C_1-6Alkyl groups, mono- or
Is Di-C_3-61-3 substituted with cycloalkylamino
C_1-6Alkyl group, formyl, C_2-6Alkanoyl and
And one or two substituents selected from benzoyl
Optionally substituted amino group, (c) halogen atom, (d)
Toro, (e) cyano, (f) substituted with 1 to 5 halogens
May be C_1-6An alkyl group, and (g) 1 to 5 halo
C optionally substituted with gen_1-6Select from alkoxy groups
C which may be substituted with 1 to 3 substituents_7-10
Aralkyl group, and (v) (a) hydroxyl group, (b) C_1-6Archi
Group, mono- or di-C_1-61 to alkylamino
Three substituted C_1-6Alkyl group, mono- or di-
C_3-6C substituted with 1 to 3 cycloalkylamino_1-6
Alkyl group, formyl, C_2-6Alkanoyl and ben
Substituted with one or two substituents selected from zoyl
Optionally an amino group, (c) a halogen atom, (d) nitro,
(e) cyano, (f) even when substituted with 1 to 5 halogens
Good C_1-6An alkyl group, and (g) 1 to 5 halogens
Optionally substituted C_1-6Selected from alkoxy groups
5 to 6-membered heterocyclic group which may be substituted by 1 to 3 substituents
A cyclic group or a 5- or 6-membered heterocyclic or benzene ring
A sulfonyl group bonded to a sulfonyl group
Acyl group derived from fonic acid, (18) hydrogen atom, or (i) (a) water
Acid group, (b) C_1-6Alkyl group, mono- or di-C_1-6
C substituted with 1 to 3 alkylamino_1-6Alkyl
Group, mono- or di-C_3-6With cycloalkylamino
1-3 substituted C_1-6Alkyl group, formyl, C_2-6
One selected from alkanoyl and benzoyl or
An amino group optionally substituted with two substituents, (c)
A halogen atom, (d) nitro, (e) cyano, and (f) 1-5
C optionally substituted with two halogens_1-6Alkoxy
May be substituted with 1 to 3 substituents selected from
C_1-6Alkyl group, (ii) (a) hydroxyl group, (b) C_1-6Archi
Group, mono- or di-C_1-61 to alkylamino
Three substituted C_1-6Alkyl group, mono- or di-
C_3-6C substituted with 1 to 3 cycloalkylamino_1-6
Alkyl group, formyl, C_2-6Alkanoyl and ben
Substituted with one or two substituents selected from zoyl
Optionally an amino group, (c) a halogen atom, (d) nitro,
(e) cyano, (f) even when substituted with 1 to 5 halogens
Good C_1-6An alkyl group, and (g) 1 to 5 halogens
Optionally substituted C_1-6Selected from alkoxy groups
C optionally substituted with 1 to 3 substituents_3-6Cyclo
Alkyl group, (iii) (a) hydroxyl group, (b) C_1-6Alkyl group,
Mono- or Di-C_1-6Place 1 to 3 with alkylamino
Transformed C_1-6Alkyl group, mono- or di-C_3-6Shi
C substituted with 1 to 3 cycloalkylamino_1-6Archi
Group, formyl, C_2-6Alkanoyl and benzoyl
Substituted with one or two substituents selected from
Amino group, (c) halogen atom, (d) nitro, (e)
Ano, (f) optionally substituted with 1 to 5 halogens
C_1-6Substituted with an alkyl group and (g) 1 to 5 halogens
C that may be_1-61 to 1 selected from an alkoxy group
C optionally substituted with three substituents_6-10Aryl
Group, (iv) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono-if
Kuha-C_1-6C substituted with 1 to 3 alkylamino
_1-6Alkyl group, mono- or di-C_3-6Cycloalkyl
C substituted with 1 to 3 amino acids_1-6Alkyl group, phor
Mill, C_2-6Selected from alkanoyl and benzoyl
Amino which may be substituted with one or two substituents
Group, (c) halogen atom, (d) nitro, (e) cyano, (f) 1
C optionally substituted with up to 5 halogens_1-6Archi
And (g) substituted with 1 to 5 halogens.
Good C_1-61-3 substitutions selected from alkoxy groups
C optionally substituted with a group_7-10An aralkyl group, and
(v) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono- or
Di-C_1-6C substituted with 1 to 3 alkylamino_1-6A
Alkyl group, mono- or di-C_3-6Cycloalkylua
C substituted with 1 to 3 amino acids_1-6Alkyl group, holmi
Le, C_2-6Selected from alkanoyl and benzoyl
Amino optionally substituted with one or two substituents
Group, (c) halogen atom, (d) nitro, (e) cyano, (f) 1
C optionally substituted with 5 halogens_1-6Alkyl
And (g) even if substituted with 1 to 5 halogens
Good C_1-61 to 3 substituents selected from alkoxy groups
Or a 5- or 6-membered heterocyclic group optionally substituted with
Selected from a 6-membered heterocyclic ring or a condensed ring group with a benzene ring
Derived from a carboxylic acid in which the group
Group, (19) oxo group, (20) thioxo group, and (21) sulfo group.
Each with 1 to 5 substituents selected from a famoyl group
Optionally substituted (1) C_6-14No aryl group, (2) 5
6-membered aromatic monocyclic heterocyclic group or 8-12-membered aromatic condensed
Heterocyclic group, (3) C_3-9Cycloalkyl group, 1-indani
Group, 2-indanyl group, C_3-6Also cycloalkenyl groups
Or C_4-6Cycloalkanedienyl group, or (4) 3-
X represents a cyclic group selected from an 8-membered non-aromatic heterocyclic group;
Bonded to A by hand or through an oxygen or sulfur atom
May be, C _1-6Alkylene group or C_2-6Alkenelle
Group, Y is (1) sulfur atom, (2) oxygen atom, (3) -C (= O) -N
(R¹⁵)-(R¹⁵Is substituted with 1 to 3 hydrogen atoms or halogens
C that may be_1-6Alkyl group), (4) -SO_Two-N
(R¹⁶)-(R¹⁶Is substituted with 1 to 3 hydrogen atoms or halogens
C that may be_1-6Alkyl group), (5) -C (= O)
-O-, (6) -SO-, (7) -SO_Two-Or (8) -N (R¹⁷)-(R¹⁷Is
1 to 3 hydrogen atoms or halogens may be substituted
C_1-6Represents an alkyl group), and represented by A-X-Y-.
May be carried by the cyclic group represented by A.
1 to 5 substituents may be substituted with the same substituents as
5 to 8 membered heterocyclic group or 5 to 8 membered heterocyclic ring and ben
A condensed heterocyclic ring obtained by condensing 1 to 3 rings selected from a zen ring
L may be an integer from 2 to 6, and m may be
An integer from 2 to 4 and n is an integer from 0 to 8
The compound according to the above [1], [3] R¹And R^TwoBut each is water
The compound according to the above [1], which is an elemental atom or a methyl group,
[4] X is a bond, CH_Two, CH_TwoCH_TwoCH_Two, SC
H_Two, SCH_TwoCH_TwoOr [1] wherein CH = CH
[5] X is a bond or CH_TwoBefore
The compound according to the above [1], wherein [6] Y is -C (= O) -N (R¹⁵)-(R
¹⁵Is as defined in the above [1]) or -SO_Two-N
(R¹⁶)-(R¹⁶Is the same as defined in the above [1])
The compound of the above-mentioned [1], wherein [7] l is 3, 4 or 5
The compound of the above-mentioned [1], wherein [8] m is 2 or 3
The compound according to the above [1], which is

[9] The compound according to [1], wherein n is an integer of 2 to 5, [10] the compound according to [1], wherein l is 4, m is 2, and n is 3.
[11] R ¹ and R ² are each a hydrogen atom or C _1-6
A represents an alkyl group

Embedded image A cyclic group having a bond in a ring selected from the group consisting of (1) (i) a halogen atom, (ii) an amino group, (iii) an amino group substituted by one or two benzoyl groups, and ( iv)
A substituent selected from C _1-6 alkyl and halogen;
A C _1-6 alkyl group _optionally substituted with 1 to 5 substituents selected from an optionally substituted C _6-14 aryl group, (2) (i) a halogen atom, and ( ii) optionally have been 1-5 substituted with a halogen substituted with 1 to 5 substituents, also selected from optionally C _1-6 alkyl group C _6-14
Aryl group, (3) 1-3 optionally substituted with 1 to 5 halogen-substituted C _1-6 alkyl,
A 6-membered heterocyclic group, (4) an amino group optionally substituted with one or two substituents selected from a C _1-6 alkyl group and a C _2-6 alkanoyl group, (5) (i) halogen Or an optionally substituted C _1-6 alkyl group or (ii) C
_6-14 hydroxyl group _optionally substituted with an aryl group, (6) (i)
C _{1-6 optionally} substituted with 1 to 3 C _6-14 aryl
An alkyl group, or (ii) a thiol group optionally substituted with 1 to 5 C _6-14 aryl groups optionally substituted with C _1-6 alkyl, (7) C _3-6 cycloalkylamino- C
_1-6 alkylamino -C _1-6 alkyl carbamoyl group which may be substituted with a group, (8) halogen atoms, (9) a halogen 1-3 optionally substituted by C _1-6 alkyl atoms -
Carbonyl group, (10) benzoyl group (11) oxo group, and
(12) A C _1-6 alkylene group or C ₂ which may be respectively substituted with 1 to 5 substituents selected from a sulfamoyl group, and X may be bonded to A via a bond or a sulfur atom. _-6 alkenylene group, Y is (1) a sulfur atom, (2) an oxygen atom, (3) -C (= O ) -N (R 15) - and (R ¹⁵ is a hydrogen atom or a C _{1 -6} alkyl group _{shown), (4) -SO 2 -N} (R 16) - (R 16 represents a hydrogen atom or a C _1-6 alkyl group), (5) -C (= O) -O -, (6) - S
O—, (7) —SO ₂ —, or (8) —N (R ¹⁷ ) — (R ¹⁷ represents a hydrogen atom or a C _1-6 alkyl group), and is represented by AXY—. Groups are (i) a C _1-6 alkyl group and (ii)
(a) 1 to 5 substituents selected from halogen and (b) C _1-6 alkyl group, which are substituted with 1 to 3 substituents selected from C _6-14 aryl group which may be substituted. May

Embedded image And may form a heterocyclic group selected from
Wherein m is an integer from 2 to 4 and n is an integer from 0 to 8,
2] a prodrug of the compound of the above-mentioned [1] or a salt thereof, [13] a formula:

Embedded image [Wherein, R ¹ and R ² each represent a hydrogen atom or an alkyl group, A represents an optionally substituted cyclic group, X represents a bond, or an alkylene which may be bound to A via a hetero atom. A group or an alkenylene group, Y is (1) a sulfur atom, (2) an oxygen atom, (3) -C (= O) -N (R ¹⁵ )-(R ¹⁵ is a hydrogen atom or an optionally substituted alkyl Represents a group), (4)-
SO ₂ -N (R ¹⁶ )-(R ¹⁶ represents a hydrogen atom or an optionally substituted alkyl group), (5) -C (= O) -O-, (6) -SO-, (7 )
-SO ₂ - or ^{(8) -N (R 17)} , - (R 17 represents a hydrogen atom or an optionally substituted alkyl group) indicates, A-X-
The group represented by Y- may form an optionally substituted heterocyclic group, l is an integer from 2 to 6, m is an integer from 2 to 4, and n is an integer from 0 to 8. A compound represented by the formula (1) or a salt thereof, or a prodrug thereof; (14) a composition according to the above (13), which is a chemokine receptor antagonist; and (15) a chemokine receptor. The composition according to [14], which is CXCR4; [16] the composition according to [13], which is an agent for preventing or treating HIV infectious disease; The composition of [18] A
The composition according to the above [13], which is an agent for suppressing the progression of IDS pathology, [19] The composition comprising a combination with one or more agents selected from a protease inhibitor, a reverse transcriptase inhibitor and a CCR5 antagonist 16] The composition described in [2]
0] The composition according to the above [19], wherein the reverse transcriptase inhibitor is one or more selected from zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, nevirapine, delavirdine and efavirenz; The composition according to the above [19], wherein the agent is one or more selected from saquinavir, ritonavir, indinavir and nelfinavir, [22] the anticancer agent having an anti-metastatic effect,
3] The composition according to the above, [23] Formula (1):

Embedded image [Wherein, R ³ represents a carboxyl group, a sulfo group or a reactive derivative thereof, a leaving group or a formyl group, and the other symbols have the same meanings as described in the above [1].] :

Embedded image Wherein the R ⁴ is an amino group or a substituted amino group, a hydroxyl group or a thiol group, R ⁵ and R ⁶ are each a hydrogen atom, a protecting group of an alkyl group or an amino group, and other symbols the [1] Or a salt thereof, or a compound represented by the formula (2): AXR ⁴ (II ′) wherein each symbol is as defined above. And a salt thereof or a compound represented by the formula:

Embedded image Wherein each symbol in the formula has the same meaning as described above, and the amino-protecting group is removed if desired.

Embedded image [The symbols in the formula are as defined in the above [1].] A method for producing a compound represented by the formula (1):

Embedded image [Wherein R ⁷ represents a protecting group for a hydrogen atom, an alkyl group or an amino group, and other symbols have the same meanings as described in the above [1]] or a salt thereof and a compound represented by the formula:

Embedded image [In the formula, R ⁸ represents a formyl group or a leaving group, R ⁹ represents a protecting group for a hydrogen atom, an alkyl group or an amino group, and other symbols have the same meanings as described in the above [1].] Reacting with a compound or a salt thereof, or a compound represented by formula (2): AXY- (CH ₂ ) ₁ -R ⁸ (IV ′) wherein each symbol is as defined above, or a compound thereof Salt and formula:

Embedded image Wherein each symbol in the formula is as defined above, or a salt thereof, and if necessary, the amino-protecting group is removed.

Embedded image [The symbols in the formula have the same meanings as described in the above [1]] or a method for producing a salt thereof, [25] Formula: AX-NH ₂ (XIX) [The symbols in the formula are the aforementioned [1] ] Or a salt thereof represented by the formula:

Embedded image [Wherein, R ⁵ and R ⁶ each represent a hydrogen atom, an alkyl group or an amino group protecting group, and the other symbols are those of the above [1].
A compound of the formula: or a salt thereof, and optionally removing an amino-protecting group.

Embedded image [The symbols in the formula have the same meanings as described in the above [1]].

In the present specification, the formula:

Embedded image (Wherein, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group, A represents an optionally substituted cyclic group,
X represents an alkylene group or alkenylene group which may be bonded to A via a bond or a hetero atom, and Y represents (1)
Sulfur atom, (2) an oxygen atom, (3) -C (= O ) -N (R 15) - (R 15 represents an alkyl group which may optionally be a hydrogen atom or a substituent), (4) -SO ₂ -N (R ¹⁶ )-(R ¹⁶ represents a hydrogen atom or an optionally substituted alkyl group), (5) -C (= O) -O-,
(6) —SO—, (7) —SO ₂ —, or (8) —N (R ¹⁷ ) — (R ¹⁷ represents a hydrogen atom or an optionally substituted alkyl group), and AX The group represented by -Y- may form a heterocyclic group which may be substituted, l is an integer from 2 to 6, m is an integer from 2 to 4, and n is 0 to 8 The compound represented by the following (hereinafter, an integer is shown) may be abbreviated as compound (I).

[0007] The "alkyl group" represented by R ¹ and R ² is a C, such as methyl, ethyl, n-propyl, isopropyl, etc.
_Examples thereof include a _1-6 alkyl group, among which a C _1-3 alkyl group is preferable. R ¹ or R ² is particularly preferably a hydrogen atom or a methyl group.

The cyclic group of the "optionally substituted cyclic group" represented by A includes an aromatic hydrocarbon ring group, an aromatic heterocyclic group, a non-aromatic hydrocarbon ring group and a non-aromatic heterocyclic group. And the like. Examples of the aromatic hydrocarbon ring group include C _6-14 such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, 4-indanyl and 5-indanyl.
Aryl groups and the like are preferable, and phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl) and the like are particularly preferable.

Examples of the aromatic heterocyclic group include aromatic monocyclic heterocyclic groups (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2 1,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1.2 5- or 6-membered aromatic monocyclic heterocyclic groups such as 1,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl) and aromatic condensed heterocyclic groups [eg benzofuranyl, isobenzofuranyl, benzothienyl] , Indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzo Oxazolyl, 1,2
-Benzisoxazolyl, benzothiazolyl, 1,2
-Benzoisothiazolyl, 1H-benzotriazolyl,
Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,
Purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ] pyridinyl Pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,
4- triazolo [4,3- a] pyridyl, 1,2,4-triazolo [4,3- b] pyridazinyl, 1,4B- diazacycloalkyl pent [cd] indenyl, 5-thia-1,8-b An 8- to 12-membered aromatic condensed heterocyclic group such as diazaacenaphthylenyl (preferably, a heterocyclic group in which the 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring or A heterocyclic group in which two identical or different heterocyclic rings selected from a 5- or 6-membered aromatic monocyclic heterocyclic group are condensed)]
And the like.

The non-aromatic hydrocarbon ring group includes, for example, a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group and a cycloalkanedienyl group. Preferably it is a cycloalkyl group. Examples of the cycloalkyl group include C _3-9 cycloalkyl (preferably C _3-8 cycloalkyl and the like) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl, and 1-indanyl; Condensed rings such as 2-indanyl are exemplified. Examples of the cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, And C _3-6 cycloalkenyl groups such as cyclopenten-1-yl. As the cycloalkanedienyl group,
For example, 2,4-cyclopentanedien-1-yl, 2,4
- cyclohexane-dien-1-yl, and the like C _4-6 cycloalkanedienyl group such as 2,5-cyclohexane-dien-1-yl.

Examples of the non-aromatic heterocyclic group include 3- to 8-membered (preferably 5- to 5-membered) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like.
6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group).

The “substituent” of the cyclic group in the “optionally substituted cyclic group” includes, for example, an optionally substituted alkyl group, an optionally substituted alkenyl group,
An optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted cycloalkyl group or cycloalkenyl group, an optionally substituted heterocyclic group, an optionally substituted amino group An optionally substituted amidino group, an optionally substituted hydroxyl group,
Optionally substituted thiol group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group,
Halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.
Preferred are chlorine, bromine, etc.), cyano group, nitro group, acyl group derived from sulfonic acid, acyl group derived from carboxylic acid, and the like.
From 5 to 5 (preferably 1 to 3) may be substituted.

As a substituent, "optionally substituted
Examples of the alkyl group in the "alkyl group" include, for example, methyl
, Ethyl, n-propyl, isopropyl, n-butyl
, Isobutyl, sec-butyl, tert-butyl, n-
Methyl, isopentyl, neopentyl, 1-methylpro
Pill, n-hexyl, isohexyl, 1,1-dimethyl
Butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl
C such as 3,3-dimethylpropyl_1-6Alkyl etc.
I can do it. Here, as the substituent of the alkyl group, (i)
Lower alkoxy group optionally substituted with halogen (eg,
For example, C such as methoxy, ethoxy, propoxy, etc._1-6Arco
Xy groups such as fluoromethoxy, difluoromethoxy
Si, trifluoromethoxy, 1,1-difluoroethoxy
Si, 2,2-difluoroethoxy, 3,3-difluoro
Propoxy, 2,2,3,3,3-pentafluoropro
Halogen-substituted C such as epoxy_1-6Alkoxy group, preferred
Or halogen-substituted C_1-4Alkoxy group), (ii) halogen
(Eg, fluorine, chlorine, bromine, iodine) and carbamo
1 to 3 substituents selected from yl
C _6-14Aryloxy (e.g., phenoxy, 4-f
Fluorophenoxy, 2-carbamoylphenoxy, etc.),
(iii) halogen atoms (for example, fluorine, chlorine, bromine, iodine
Element, etc.), (iv) C_3-8Cycloalkyl groups (eg, cycloalkyl
Propyl, cyclobutyl, cyclopentyl, cyclohexyl
Sil, cycloheptyl, etc.), (v) amino group, (vi) substitution
Amino group [for example, (a) carbamoyl, (b) C_1-6Alkyl
Sulfonyl (eg, methylsulfonyl, ethylsulfonyl
Etc.), (c) C_1-6Alkyl (eg, methyl, ethyl, pro
Pill), (d) mono or di (C_1-6Alkyl)
C which may be substituted by 1 or 2_1-6Archi
(Eg, ethylaminopropyl), (e) benzoyl
Mono- or di-substituted amino groups (di-substituted amino groups)
As the amino group, for example, dimethylamino, diethylamino,
N-methyl-N-methylsulfonylamino, dimethyls
Rufonylamino and the like. )], (Vii) C_1-6A
Alkyl (eg, methyl, ethyl, n-propyl, isopro
Pill, n-butyl, isobutyl, sec-butyl, tert-
Butyl, etc.)
Rubamoyl group (for example, butylcarbamoyl and the like), (v
iii) formyl, (ix) C_2-6Alkanoyl groups (for example,
Cetyl, propionyl, butyryl, etc.), (x) C_1-6Al
Killing groups (eg, methyl, ethyl) and halogens (eg,
1 to 1 substituents selected from nitrogen, chlorine, bromine and iodine).
5 optionally substituted C_6-14Aryl groups (eg,
Phenyl, naphthyl, etc.), (xi) C_6-14Aryl-cal
Bonyl groups (eg, benzoyl, naphthoyl, etc.), (x
ii) C_7-13Aralkyl-carbonyl groups (e.g., benzyl
C such as carbonyl, naphthylmethylcarbonyl, etc. _6-14
Aryl-C_1-2Alkyl-carbonyl, etc.), (xiii)
Hydroxyl group, (xiv) C_2-5Alkanoyloxy groups (for example, ace
Tyloxy, propionyloxybutyryloxy
Etc.), (xv) C_7-13Aralkyl-carbonyloxy (eg,
C such as benzylcarbonyloxy_6-14Aryl-C
_1-2Alkyl-carbonyloxy, etc.), (xvi) nitro
Group, (xvii) C_1-6Substituted one or two times with alkyl
A sulfamoyl group (eg, unsubstituted sulfamoyl group)
Other groups such as methylsulfamoyl), (xviii)
C_1-6C optionally substituted with 1 to 3 alkyl (s)_6-14
Arylthio group (for example, phenylthio, 4-methylphenyl
Nilthio etc.), (xix) -N = N-Ar (Ar is phenyl
Such as C_6-14An aryl group), (xx)
Ano group, (xxi) amidino group, (xxii) carboxyl group, (xx
iii) C_1-4Alkoxy-carbonyl group (eg, methoxy
Rubonyl, ethoxycarbonyl, t-butoxycarboni
Etc.), (xxiv) C_1-6Alkylthio (eg, methylthio,
Ethylthio), (xxv) C_1-6Alkylsulfinyl
(Eg, methylsulfinyl, ethylsulfinyl, etc.),
(xxvi) C_1-6Alkylsulfonyl (eg, methylsulfonyl
, Ethylsulfonyl, etc.), (xxvii) C_6-14Arylchi
E (eg, phenylthio, etc.), (xxviii) C_{6-1 Four}Aryls
Rufinyl (eg, phenylsulfinyl, etc.), (xxix) C
_6-14Arylsulfonyl (eg, phenylsulfonyl
Etc.), (xxx) C_1-6Alkyl (eg, methyl, ethyl, pro
Pill etc.), C_1-6Alkoxy (eg, methoxy, ethoxy
Etc.), halogens (eg, fluorine, chlorine, bromine, iodine),
Oxo, thioxo and C_1-6Alkylthio (eg, meth
1 to 5 substituents selected from the group consisting of
A heterocyclic group which may be substituted with (for example, pyridyl,
Such as enyl, tetrazolyl, and morpholinoxazole
5-6 membered heterocyclic group or a 5-6 membered heterocyclic or
And a condensed ring group with a benzene ring).
The substituent has 1 to 5 (preferably 1 or
(2) may be substituted.

Examples of the alkenyl group in the “optionally substituted alkenyl group” as the substituent include vinyl, allyl, isopropenyl, 2-methylallyl,
-Propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-
Butenyl, 2-methyl-2-butenyl, 3-methyl-2
- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl C _{2 -6} alkenyl group and the like. Here, as the substituent of the alkenyl group, the aforementioned “optionally substituted alkyl group”
And the same number of the same substituents as described above.

Examples of the alkynyl group in the “optionally substituted alkynyl group” as a substituent include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2
-Pentynyl, 3-pentynyl, 4-pentynyl, 1-
And C _2-6 alkynyl groups such as hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. Here, examples of the substituent of the alkynyl group include the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl group”.

As a substituent, "optionally substituted
Examples of the aryl group in the "reel group" include phenyl
Le, naphthyl, anthryl, phenanthryl, acenaph
C such as tyrenyl_6-14And an aryl group. here
In the substituent of the aryl group, (i) substituted with halogen
Lower alkoxy group which may be (for example, methoxy,
C such as ethoxy and propoxy_1-6An alkoxy group, for example
Fluoromethoxy, difluoromethoxy, trifluoro
Methoxy, 1,1-difluoroethoxy, 2,2-diph
Fluoroethoxy, 3,3-difluoropropoxy, 2,
Halo such as 2,3,3,3-pentafluoropropoxy
Gen substitution C_1-6Alkoxy group, preferably halogen substitution
C_1-4Alkoxy group, etc.), (ii) halogen (eg, fluorine,
Selected from chlorine, bromine, iodine) and carbamoyl
C that may be substituted with 1 to 3 substituent (s)_6-14Aryl
Oxy (for example, phenoxy, 4-fluorophenoxy)
, 2-carbamoylphenoxy, etc.), (iii) halogen
Atoms (eg, fluorine, chlorine, bromine, iodine, etc.);
C optionally substituted with 1 to 5 logens_1-6Alkyl
Groups (eg, unsubstituted lower radicals such as methyl, ethyl, propyl, etc.)
Alkyl group, preferably C_{1- 6}Alkyl group; for example, fluoro
Romethyl, difluoromethyl, trifluoromethyl,
1,1-difluoroethyl, 2,2-difluoroethyl
, 3,3-difluoropropyl, 2,2,3,3,3
-Halogen-substituted C such as pentafluoropropyl _1-6A
Alkyl group, preferably halogen-substituted C_1-4Alkyl group
Etc.), (v) C_3-8Cycloalkyl groups (eg, cyclopro
Pill, cyclobutyl, cyclopentyl, cyclohexyl
, Cycloheptyl, etc.), (vi) amino group, (vii) substitution
Amino group [for example, (a) carbamoyl, (b) C_1-6Alkyl
Sulfonyl (eg, methylsulfonyl, ethylsulfonyl
Etc.), (c) C_1-6Alkyl (eg, methyl, ethyl, pro
Pill), (d) mono or di (C_1-6Alkyl)
C which may be substituted by 1 or 2_1-6Archi
(Eg, ethylaminopropyl), (e) benzoyl
Mono- or di-substituted amino groups (di-substituted amino groups)
As the amino group, for example, dimethylamino, diethylamino,
N-methyl-N-methylsulfonylamino, dimethyls
Rufonylamino and the like. )], (Viii) C_1-6
Alkyl (eg, methyl, ethyl, n-propyl, isop
Ropyl, n-butyl, isobutyl, sec-butyl, tert
-Butyl or the like)
A carbamoyl group (eg, butylcarbamoyl and the like),
(ix) formyl, (x) C_2-6Alkanoyl groups (for example, ace
Tyl, propionyl, butyryl, etc.), (xi) C_1-6Al
Killing groups (eg, methyl, ethyl) and halogens (eg,
1 to 1 substituents selected from nitrogen, chlorine, bromine and iodine).
5 optionally substituted C_6-14Aryl groups (eg,
Phenyl, naphthyl, etc.), (xii) C_6-14Aryl-ka
Rubonyl group (for example, benzoyl, naphthoyl, etc.),
(xiii) C_7-13Aralkyl-carbonyl groups (e.g., benzene
C such as zircarbonyl, naphthylmethylcarbonyl, etc.
_6-14Aryl-C_1-2Alkyl-carbonyl, etc.), (xi
v) hydroxyl group, (xv) C_2-5Alkanoyloxy groups (e.g.
Cetyloxy, propionyloxybutyryloxy
Etc.), (xvi) C_{7-1 Three}Aralkyl-carbonyloxy
(Eg, C such as benzylcarbonyloxy)_6-14Aryl
-C_1-2Alkyl-carbonyloxy, etc.), (xvii)
Toro group, (xviii) C_1-61 or 2 substituted with alkyl
An optionally substituted sulfamoyl group (eg, an unsubstituted sulfoyl group)
Other than an amoyl group such as methylsulfamoyl), (xi
x) C_1-6C optionally substituted with 1 to 3 alkyl (s)
_6-14Arylthio group (for example, phenylthio, 4-methyl
Phenylthio etc.), (xx) -N = N-Ar (Ar is phenyl
C such as_6-14A group represented by an aryl group), (xx
i) cyano group, (xxii) amidino group, (xxiii) carboxyl
Group, (xxiv) C_1-4Alkoxy-carbonyl group (eg, meth
Xoxycarbonyl, ethoxycarbonyl, t-butoxyca
Rubonil etc.), (xxv) C_1-6Alkylthio (eg, methylthio
E, ethylthio, etc.), (xxvi) C_1-6Alkylsulfi
Nil (eg, methylsulfinyl, ethylsulfinyl
Etc.), (xxvii) C_1-6Alkylsulfonyl (eg, methyls
Ruphonyl, ethylsulfonyl, etc.), (xxviii) C _6-14Ants
Thio (eg, phenylthio, etc.), (xxix) C_6-14Ally
Rusulfinyl (eg, phenylsulfinyl, etc.), (xx
x) C_6-14Arylsulfonyl (eg, phenylsulfonyl
Etc.), (xxxi) C_1-6Alkyl (eg, methyl, ethyl,
Ropil etc.), C_1-6Alkoxy (eg, methoxy, ethoxy,
Etc.), halogen (eg, fluorine, chlorine, bromine, iodine)
Element), oxo, thioxo and C_1-6Alkylthio
(Eg, 1-5 selected from methylthio, ethylthio, etc.)
Heterocyclic groups which may be substituted with
Lysyl, thienyl, tetrazolyl, morpholinoxazo
5- or 6-membered heterocyclic group or a 5- or 6-membered heterocyclic group such as ril
Or a condensed ring group with a benzene ring).
These optional substituents have 1 to 5 (preferably
Or 1 to 3, more preferably 1 or 2)
You may.

As the cycloalkyl group in the “optionally substituted cycloalkyl group” as a substituent,
For example, a C _3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be mentioned. Here, examples of the substituent of the cycloalkyl group include the same number of the same substituents as in the above-mentioned “optionally substituted aryl group”. Examples of the cycloalkenyl group in the “optionally substituted cycloalkenyl group” as a substituent include C _3-6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. Here, as the substituent of the optionally substituted cycloalkenyl group, the same number of the same substituents as in the above-mentioned “optionally substituted aryl group” can be mentioned.

The heterocyclic group in the “optionally substituted heterocyclic group” as a substituent includes, for example, pyridyl,
Examples thereof include a 5- to 6-membered heterocyclic group such as thienyl, tetrazolyl, and morpholinoxazolyl, or a 5- to 6-membered heterocyclic ring or a condensed ring group with a benzene ring. Examples of the substituent of the heterocyclic group include C _1-6 alkyl (eg, methyl) which may be substituted with 1 to 5 (preferably 1 to 3) halogens (eg, fluorine, chlorine, bromine, iodine). , Ethyl, propyl, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, fluorine, chlorine, bromine, iodine),
Oxo, thioxo and C _1-6 alkylthio (eg, methylthio, ethylthio, etc.) and the like. The substituent may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions.

Examples of the substituent of the amino group in the “amino group which may be substituted” as the substituent include, for example,
(i) halogen (fluorine, chlorine, bromine, iodine) and C
Lower alkyl groups which may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from _6-14 aryl (eg, phenyl) (eg, methyl, ethyl, propyl,
(C _1-6 alkyl group such as isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), (ii) 1 to 5 (preferably 1 to 3) C _1-6 alkyl A good C _6-14 aryl group (eg, phenyl, 4-methylphenyl, etc.), (iii) an acyl group (eg, formyl group, C _2-6 alkanoyl group (eg, acetyl, propionyl, pivaloyl, etc.), C _{6- 14 Even when} substituted with 1 to 3 aryl-carbonyl groups (eg, benzoyl, etc.), C _1-6 alkylsulfonyl groups (eg, methylsulfonyl, etc.), C _1-6 alkyl (eg, methyl, ethyl, etc.) Good C _{6-1 4} arylsulfonyl group (eg, paratoluenesulfonyl, etc.), halogen (eg, fluorine, chlorine, bromine,
C _1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 carbon atoms (iodine) (for example, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloro) Ethoxycarbonyl, etc.), etc.), and (iv) further substituted with C _1-6 alkyl (eg, methyl, ethyl, etc.) or an amidino group which may be substituted one or two times with formyl. You may. The number of the substituents is one or two. In addition, two substituents on an amino group together with an adjacent nitrogen atom form a C _1-6 alkyl group (eg, methyl, ethyl, etc.) or a C _7-10 aralkyl group (eg, benzyl, phenethyl, etc.). Phenyl-C _1-4
An alkyl group or the like and a C _6-10 aryl group (eg, phenyl or the like) to form a 3- to 8-membered cyclic amino group which may be substituted with 1 to 3 substituents. Examples of such a cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino,
Piperazinyl and a lower alkyl group at the 4-position (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.),
Aralkyl groups (for example, C _7-10 such as benzyl and phenethyl);
Aralkyl group, etc.), aryl group (for example, phenyl, 1-
Examples thereof include a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino such as 1-piperazinyl which may have a C _6-10 aryl group such as naphthyl and 2-naphthyl.

As a substituent, "optionally substituted
Examples of the substituent of the amidino group in the "midino group" include:
(I) halogen (fluorine, chlorine, bromine, iodine) and
And C_{6-1 Four}1 to 5 selected from aryl (eg, phenyl)
(Preferably 1 to 3) substituents
Good lower alkyl groups (eg methyl, ethyl, propyl
Isopropyl, butyl, isobutyl, t-butyl,
C such as pentyl and hexyl _1-6Alkyl group, etc.), (ii) C
_1-6Substituted with 1 to 5 (preferably 1 to 3) alkyl
C that may be_6-14Aryl groups (eg, phenyl,
4-methylphenyl), (iii) acyl group [for example,
Formyl group, C_2-6Alkanoyl group (eg, acetyl,
Propionyl, pivaloyl, etc.), C_6-14Aryl-ka
Rubonyl group (eg, benzoyl, etc.), C_1-6Alkyls
A rufonyl group (eg, methylsulfonyl, etc.), C_1-6Al
1 to 3 substituents (eg, methyl, ethyl, etc.)
May be C_{6 -14}Arylsulfonyl group (eg, paratolue
Sulfonyl, etc.), halogen (eg, fluorine, chlorine, odor
Optionally substituted with 1 to 3 carbon atoms_1-6A
Alkoxy-carbonyl group (e.g. trifluoromethoxy
Carbonyl, 2,2,2-trifluoroethoxycarbo
Nil, trichloromethoxycarbonyl, 2,2,2-to
Lichloroethoxycarbonyl etc.) etc.
You. The number of the substituents is one or two.

Examples of the substituent of the hydroxyl group in the “optionally substituted hydroxyl group” as the substituent include the same substituents as those of the above-mentioned “optionally substituted amidino group”.

As the substituent of the thiol group in the “optionally substituted thiol group (mercapto group)” as the substituent, the above-mentioned “optionally substituted amidino group”
And the same substituents as mentioned above.

The "carboxyl group which may be esterified" as a substituent includes, in addition to a free carboxyl group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group and the like. As the "lower alkoxycarbonyl group",
For example, C _1-6 such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, etc. Examples thereof include an alkoxy-carbonyl group and the like, and among them, a C _1-3 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl is preferable. As the “aryloxycarbonyl group”, for example, a C _6-10 aryloxy-carbonyl group such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like are preferable. As the “aralkyloxycarbonyl group”, for example, a C _7-10 aralkyloxy-carbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably a C _6-10 aryl-C _1-4 alkoxy-carbonyl and the like) are preferable. . The “aryloxycarbonyl group” and “aralkyloxycarbonyl group” may have a substituent, for example, (a)
A hydroxyl group, (b) an optionally substituted amino group [the amino group is, for example, a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t
-C _1-6 alkyl group such as butyl, pentyl, hexyl, etc.), mono- or di-C _1-6 alkylamino
To three substituted C _1-6 alkyl group (e.g., methylamino ethyl, dimethylaminoethyl group, etc.), mono - or di -C _3-6 C which is 1-3 substituted cycloalkyl amino _{1- 6} alkyl group (e.g., cyclohexyl aminoethyl group), an acyl group [(e.g., formyl; acetyl, propionyl, C _2-6 alkanoyl pivaloyl, benzoyl, etc.) have one or two such as a substituent Is also good. ], (C) halogen atom (for example, fluorine, chlorine, bromine, iodine), (d) nitro group, (e) cyano group, (f) 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine) A lower alkyl group which may be substituted with (for example, C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like)
An alkyl group, etc.), (g) a lower alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy) which may be substituted by 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine).
C such as t-butoxy, pentyloxy and hexyloxy
_1-6 alkoxy group etc.). These substituents may be the same or different from one to three (preferably 1 or 2
Is preferably substituted.

The “optionally substituted carbamoyl group” as a substituent includes, in addition to unsubstituted carbamoyl,
N-monosubstituted carbamoyl groups and N, N-disubstituted carbamoyl groups are exemplified. As the substituent for the carbamoyl group, for example, a lower alkyl group (eg, methyl, ethyl,
C _1-6 alkyl groups such as propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.),
Cycloalkyl groups (eg, C _3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aryl groups (eg, C _6-10 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, etc.), aralkyl Groups (eg, C _7-10 aralkyl groups such as benzyl and phenethyl, preferably phenyl-C _1-4 alkyl groups); heterocyclic groups (eg, 5- to 6-membered heterocyclic groups such as pyridyl, thienyl, tetrazolyl, and morpholinoxazolyl). Ring group or a 5- to 6-membered heterocyclic ring or a condensed ring group with a benzene ring, etc.]. The number of the substituents is one or two. The lower alkyl group, cycloalkyl group, aryl group, aralkyl group, and heterocyclic group may have a substituent. Examples of the substituent on the lower alkyl group include (a) a hydroxyl group and (b) an optionally substituted amino group (the amino group is, for example, a lower alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl,
a C _1-6 alkyl group such as t-butyl, pentyl, hexyl, etc.), mono- or di-C _1-6 alkylamino,
To three substituted C _1-6 alkyl group (e.g., methylamino ethyl, dimethylaminoethyl group, etc.), mono - or di -C _3-6 C which is 1-3 substituted cycloalkyl amino _{1- 6 or} an alkyl group (eg, cyclohexylaminoethyl group, etc.), an acyl group (eg, C _2-6 alkanoyl, benzoyl, etc. such as formyl, acetyl, propionyl, pivaloyl, etc.) as a substituent. Is also good. ], (C) halogen atom (for example, fluorine, chlorine, bromine, iodine), (d) nitro group, (e) cyano group, (f) 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine) A lower alkoxy group which may be substituted with (for example, methoxy, ethoxy, propoxy, isopropoxy,
Butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy, and other C _1-6 alkoxy groups). These substituents may be the same or different
(Preferably 1 or 2). Examples of the substituent on the cycloalkyl group, aryl group, aralkyl group or heterocyclic group include (a) a hydroxyl group,
(b) optionally substituted amino group [the amino group is, for example, a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
Pentyl, and the like C _1-6 alkyl groups hexyl), mono- - or di -C _1-6 alkylamino with 1-3 substituted C _1-6 alkyl group (e.g., methylamino ethyl, dimethylaminoethyl Group), mono- or di-C
A C _1-6 alkyl group substituted with 1 to 3 _3-6 cycloalkylamino (eg, cyclohexylaminoethyl group and the like), an acyl group (eg, formyl, acetyl, propionyl,
And one or two such as C _2-6 alkanoyl such as pivaloyl and benzoyl) as a substituent. ],
(c) substituted with a halogen atom (eg, fluorine, chlorine, bromine, iodine), (d) nitro group, (e) cyano group, (f) with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine) Lower alkyl groups which may be substituted (eg, methyl,
Substituted ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, and the like C _1-6 alkyl groups hexyl), at (g) 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) And a lower alkoxy group (for example, C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy, etc.). These substituents are preferably the same or different and are substituted with 1 to 3 (preferably 1 or 2). “N-monosubstituted carbamoyl group” means a carbamoyl group having one substituent on a nitrogen atom, and examples of the substituent include the above-mentioned substituents. “N, N-disubstituted carbamoyl group” means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is the above-mentioned “N-monosubstituted carbamoyl group”. The same as the group,
Other examples include, for example, lower alkyl groups (eg, C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.),
A C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
_{A 7-10} aralkyl group (for example, benzyl, phenethyl and the like, preferably a phenyl-C _1-4 alkyl group and the like) and the like are preferable. In addition, two substituents on the carbamoyl group are combined with an adjacent nitrogen atom to form one to three substituents selected from a C _1-6 alkyl group, a C _7-10 aralkyl group and a C _6-10 aryl group. A 3- to 8-membered cyclic amino group which may be substituted with a group may be formed. Examples of the cyclic aminocarbamoyl group include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and a lower alkyl group at the 4-position (eg, methyl, ethyl, C _1-6 alkyl groups such as propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc., aralkyl groups (eg, C _7-10 aralkyl groups such as benzyl and phenethyl), and aryl groups (eg, phenyl, 1- 3 to 8 members (preferably 5 to 6 members) such as 1-piperazinylcarbonyl which may have a C _6-10 aryl group such as naphthyl and 2-naphthyl, etc.
Cyclic amino-carbonyl and the like.

Examples of the substituent of the “optionally substituted thiocarbamoyl group” as the substituent include the same substituents as those of the aforementioned “optionally substituted carbamoyl group”.

Examples of the “acyl group derived from sulfonic acid” as a substituent include those in which the above-mentioned “N-monosubstituted carbamoyl group” having one substituent on a nitrogen atom is bonded to sulfonyl. Preferably, acyl such as C _1-6 alkylsulfonyl such as methanesulfonyl and ethanesulfonyl is used.

Examples of the “acyl group derived from carboxylic acid” as the substituent include those in which a carbonyl is bonded to a hydrogen atom or a substituent having one of the above “N-monosubstituted carbamoyl groups” on the nitrogen atom. Among them, preferred are acyl such as C _2-6 alkanoyl such as formyl, acetyl, trifluoroacetyl, propionyl and pivaloyl, and benzoyl.

Examples of the substituent of the cyclic group in A include an alkyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted (eg, a thiazolyl group, an isoxazolyl group, a pyrazolyl group). Group, tetrazolyl group, etc.), optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted thiol group, optionally substituted carbamoyl group, halogen atom, acyl derived from carboxylic acid Groups, oxo and sulfamoyl groups are preferred.

X is A via a bond or a heteroatom.
Represents an alkylene group or an alkenylene group which may be bonded to. Examples of the hetero atom include a nitrogen atom, an oxygen atom and a sulfur atom. An oxygen atom or a sulfur atom is preferred, and a sulfur atom is particularly preferred. The alkylene group is preferably a linear or cyclic alkylene group having 1 to 6 carbon atoms, for example, methylene, methylmethylene,
Dimethylmethylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, cyclopropylene, 1,2-cyclobutylene, 1,
3-cyclobutylene, cyclopentylene, 1,3-cyclopentylene, cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene and the like are used. Among the above, a linear alkylene group having 1 to 3 carbon atoms is preferable. The alkenylene group preferably represents a linear, branched or cyclic alkenylene group having 2 to 6 carbon atoms, for example, vinylene, propenylene, 1-propene-
1,2-ylene, 2-propene-1,2-ylene, butenylene (eg, 1-butene-1,4-ylene, 2-butene-1,4-ylene, etc.), pentenylene (eg, 1-pentene- 1,5-ylene, 2-pentene-1,5-ylene, etc., hexenylene (eg, 1-hexene-1,6-ylene, 2-hexene-1,6-ylene, 3-hexene-)
1,6-ylene and the like, cyclopropenylene (eg, 1-
Cyclopropene-1,2-ylene, 2-cyclopropene-1,2-ylene, etc., cyclobutenylene (eg, 1-
Cyclobutene-1,2-ylene, 1-cyclobutene1,
3-ylene, 2-cyclobutene-1,2-ylene, 3-
Cyclobuten-1,2-ylene, etc.), cyclopentenylene (eg, 1-cyclopenten-1,2-ylene, 1-
Cyclopentene-1,3-ylene, 2-cyclopentene-1,2-ylene, 3-cyclopentene-1,2-ylene, 3-cyclopentene-1,3-ylene, 4-cyclopentene-1,3-ylene, etc.), Cyclohexenylene (eg, 1-cyclohexene-1,2-ylene, 1-cyclohexene-1,3-ylene, 1-cyclohexene-
1,4-ylene, 2-cyclohexene-1,2-ylene, 2-cyclohexene-1,4-ylene, 3-cyclohexene-1,2-ylene, 3-cyclohexene-1,
3-ylene, 4-cyclohexene-1,2-ylene, 4
-Cyclohexene-1,3-ylene and the like are used. Among them, a linear alkenylene group having 2 or 3 carbon atoms is preferable. X is a bond, -CH ₂ -,-(C
H ₂ ) ₂ -,-(CH ₂ ) _3- , -SCH _2- , -S (CH ₂ ) _2- , -CH = CH- are preferable, and a bond, -CH ₂ -,-(CH ₂ ) ₃ -, -SCH _2- , -S (CH ₂ ) _2- ,
-CH = CH- are more preferred, especially a bond or -CH ₂ - are preferred.

The “optionally substituted alkyl group” for R ¹⁵ , R ¹⁶ and R ¹⁷ is exemplified as the substituent of the cyclic group in the “optionally substituted cyclic group” for A. "Alkyl group which may be substituted"
And the same. Among them, a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) is preferable, and an unsubstituted C _1-3 alkyl group is particularly preferable.
Alkyl groups (eg, methyl, ethyl, etc.) are preferred. As Y, among the above, -C (= O) -N (R ¹⁵ )-(R ¹⁵ has the same meaning as described above), -SO ₂ -N (R ¹⁶ )-(R ¹⁶ is as defined above) Is preferable), and -N (R ¹⁷ )-(R ¹⁷ has the same meaning as described above) is preferable, and particularly, -C (= O) -N (R ¹⁵ )-or -SO ₂ -N (R ¹⁶ ) is preferable. -Is preferred. It is preferred that the bond on the left be bonded to X and the bond on the right be bonded to -N (R ¹ )-. Here, when Y is -N (R ¹⁷ )-,
A is preferably an aromatic heterocyclic group which may be substituted. As the heterocyclic group which may be formed by the group represented by A-X-Y-, 1 to 5 substituents may be substituted with the same substituents as those which the cyclic group represented by A may have. A 5- to 8-membered heterocyclic group which may be optionally substituted or a condensed heterocyclic group in which 1 to 3 rings selected from a 5- to 8-membered heterocyclic ring and a benzene ring are condensed are preferred. As the heterocyclic group,

Embedded image A condensed ring group containing 1 to 5 heteroatoms (eg, a nitrogen atom, an oxygen atom, a sulfur atom, etc.) and condensed with three heterocyclic groups is preferable. Oxo is preferred as the substituent for the heterocyclic group.

L is preferably 3, 4 or 5. m is preferably 2 or 3. n is preferably an integer from 2 to 5. It is particularly preferred that l is 4, m is 2, and n is 3.

Preferred embodiments of the compound of the present invention are shown below. R ¹ and R ² each independently represent a hydrogen atom or C
A is a _1-6 alkyl group,

Embedded image A cyclic group having a bond in a ring selected from the group consisting of (1) (i) a halogen atom, (ii) an amino group, (iii) an amino group substituted by one or two benzoyl groups, and ( iv)
A substituent selected from C _1-6 alkyl and halogen;
A C _1-6 alkyl group _optionally substituted with 1 to 5 substituents selected from an optionally substituted C _6-14 aryl group, (2) (i) a halogen atom, and ( ii) optionally have been 1-5 substituted with a halogen substituted with 1 to 5 substituents, also selected from optionally C _1-6 alkyl group C _6-14
Aryl group, (3) 1-3 optionally substituted with 1 to 5 halogen-substituted C _1-6 alkyl,
A 6-membered heterocyclic group, (4) an amino group optionally substituted with one or two substituents selected from a C _1-6 alkyl group and a C _2-6 alkanoyl group, (5) (i) halogen Or an optionally substituted C _1-6 alkyl group or (ii) C
_6-14 hydroxyl group _optionally substituted with an aryl group, (6) (i)
C _{1-6 optionally} substituted with 1 to 3 C _6-14 aryl
An alkyl group, or (ii) a thiol group optionally substituted with 1 to 5 C _6-14 aryl groups optionally substituted with C _1-6 alkyl, (7) C _3-6 cycloalkylamino- C
_1-6 alkylamino -C _1-6 alkyl carbamoyl group which may be substituted with a group, (8) halogen atoms, (9) a halogen 1-3 optionally substituted by C _1-6 alkyl atoms -
Carbonyl group, (10) benzoyl group (11) oxo group, and
(12) A C _1-6 alkylene group or C ₂ which may be respectively substituted with 1 to 5 substituents selected from a sulfamoyl group, and X may be bonded to A via a bond or a sulfur atom. _-6 alkenylene group, Y is (1) a sulfur atom, (2) an oxygen atom, (3) -C (= O ) -N (R 15) - and (R ¹⁵ is a hydrogen atom or a C _{1 -6} alkyl group _{shown), (4) -SO 2 -N} (R 16) - (R 16 represents a hydrogen atom or a C _1-6 alkyl group), (5) -C (= O) -O -, (6) - S
O—, (7) —SO ₂ —, or (8) —N (R ¹⁷ ) — (R ¹⁷ represents a hydrogen atom or a C _1-6 alkyl group), and is represented by AXY—. Groups are (i) a C _1-6 alkyl group and (ii)
(a) 1 to 5 substituents selected from halogen and (b) C _1-6 alkyl group, which are substituted with 1 to 3 substituents selected from C _6-14 aryl group which may be substituted. May

Embedded image And may form a heterocyclic group selected from
A compound in which m is an integer from 2 to 4, and n is an integer from 0 to 8.

The "reactive derivative" in the "reactive derivative of carboxyl group and sulfo group" for R ³ includes, for example, acid halide, acid azide, acid anhydride, mixed acid anhydride, active amide, active ester, It is a reactive derivative such as an active thioester. Examples of the acid halide include acid chloride, sulfonyl chloride, and sulfonyl bromide, and examples of the mixed acid anhydride include mono-C _1-6 alkyl carbonate mixed acid anhydrides (eg, monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monoisobutyl carbonate, monoisobutyl carbonate, etc.). tert-butyl carbonate, monobenzyl carbonate, mono (p-nitrobenzyl) carbonate or monoallyl carbonate mixed anhydride, etc., C _1-6 aliphatic carboxylic acid mixed anhydride [eg acetic acid, trichloroacetic acid, cyanoacetic acid, propion Acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid or acetoacetic acid mixed anhydride), _C7-12 aromatic carboxylic acid mixed anhydride (for example, benzoic acid, p-toluic acid, p-
Chlorobenzoic acid mixed acid anhydride, etc.), and organic sulfonic acid mixed acid anhydride (eg, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid mixed acid anhydride). Amides with nitrogen heterocyclic compounds (for example, acid amides such as pyrazole, imidazole and benzotriazole; these nitrogen-containing heterocyclic compounds may be C _1-6 alkyl groups (eg, methyl, ethyl, etc.), C _1-6 alkoxy groups (E.g.,
Methoxy, ethoxy, etc.), halogen atoms (eg, fluorine,
Chlorine, bromine, etc.), an oxo group, a thioxo group, a C _1-6 alkylthio group (eg, methylthio, ethylthio, etc.). ].

As the active ester, all those used for this purpose in the field of β-lactam and peptide synthesis can be used. For example, organophosphates (eg, diethoxyphosphate, diphenoxyphosphate, etc.) as well as p-nitroester Phenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester,
1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazole ester, 1-
And hydroxy-1H-2-pyridone esters. As the active thioester, an ester with an aromatic heterocyclic thiol compound [for example, 2-pyridylthiol ester, 2-benzothiazolylthiol ester, etc., and these heterocycles are a C _1-6 alkyl group (eg, methyl,
Substituted with a C _1-6 alkoxy group (eg, methoxy, ethoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, etc.), a C _1-6 alkylthio group (eg, methylthio, ethylthio, etc.) May be. ]. As the leaving group represented by R ³ , a halogen atom (eg,
A chlorine atom, a bromine atom, an iodine atom, an alkylsulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.) or an arylsulfonyloxy group (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.).

Examples of the "alkyl group" represented by R ⁵ , R ⁶ , R ⁷ and R ⁹ include C _1-3 alkyl groups such as methyl, ethyl, n-propyl and isopropyl. R ⁵ , R ⁶ ,
Examples of the “protecting group for amino group” represented by R ⁷ and R ⁹ include, for example, formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl,
Protecting groups of the type that form amides such as acetoacetyl and o-nitrophenylacetyl or tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, benzhydryloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 1-methyl-1- (4-biphenyl) ethoxycarbonyl, 9-fluorenyl Methoxycarbonyl, 9-
Protecting groups of the type forming carbamates such as anthrylmethoxycarbonyl, isonicotinyloxycarbonyl, 1-adamantyloxycarbonyl and the like, and trityl, phthaloyl and the like can be mentioned. As the leaving group for R ⁸ , those similar to the “leaving group” for R ³ described above can be mentioned.

As the salt of the compound represented by the formula (I) of the present invention, an acid addition salt such as an inorganic acid salt (eg, hydrochloride,
Sulfates, hydrobromides, phosphates, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate,
Tartrate, lactate, oxalate, methanesulfonate, p-
Salts with bases (eg, alkali metal salts such as potassium, sodium, and lithium salts, alkaline earth metal salts such as calcium and magnesium salts, ammonium salts, and trimethylamine salts). Salts with organic bases such as triethylamine salt, tert-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt and quinoline salt).

The compound represented by the general formula (I) or a salt thereof may be a hydrate. Hereinafter, the compound including the salt and the hydrate is referred to as the compound (I). The prodrug of compound (I) is converted into C by in vivo reaction with an enzyme or gastric acid.
It refers to a compound that converts to a compound (I) having an XCR4 inhibitory action. Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated). ,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,
Compound (I) such as a tert-butylated compound);
When has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated) ,
When the compound (I) has a carboxyl group, a compound in which the carboxyl group is esterified or amidated (eg, the carboxyl group of the compound (I) is ethyl ester , Phenylesterification, carboxymethylesterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification, phthalidylesterification, (5-methyl-2-oxo-1,3- Dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound and the like); These compounds can be produced by a method known per se. The prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, pp. 163-198, Molecular Design. It may be. The prodrug of compound (I) may be itself or a pharmacologically acceptable salt. Such salts include, when the prodrug of compound (I) has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, zinc, Transition metals such as iron and copper), organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, organic amines such as N, N'-dibenzylethylenediamine, arginine , Lysine, or basic amino acids such as ornithine, etc.).

When the prodrug of the compound (I) has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid,
Nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid), aspartic acid, glutamic acid, and other acidic amino acids. Compound (I)
May be any of hydrates and non-hydrates. Compound (I) of the present invention is an isotope (eg,
³ H, ¹⁴ C, ³⁵ S, etc.). Compound (I) may have one or more asymmetric carbons in the molecule.
Either arrangement is encompassed by the present invention. Formulas (II)-(V)
In the compound represented by the formula (1), a compound having a basic group or an acidic group can form a salt with an acid addition salt or a salt with a base, respectively. Examples of the acid addition salt and the salt with a base include those similar to the salts of the compound represented by the formula (I). Compounds represented by the following formulas (II) to (V), including their salts, are represented by compounds (II) to (V), respectively.
(V).

Compound (I) is produced, for example, by the method shown in the following (A) or (B). (A) Equation (1):

Embedded image (Wherein each symbol is as defined above) or a salt thereof and a compound represented by the formula:

Embedded image (Each symbol in the formula is as defined above) or a salt thereof, or (2) Formula: AXR ⁴ (II ′) (each symbol in the formula) Is as defined above) or a salt thereof and a compound represented by the formula:

Embedded image (Wherein each symbol has the same meaning as described above), and then (3) the compound (I) can be produced by removing (3) an amino-protecting group, if desired. As the solvent in the present production method, for example, an ether solvent (eg, ethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, etc.), a halogen solvent (eg, dichloromethane,
Dichloroethane, chloroform, etc.), aromatic solvents (eg, toluene, chlorobenzene, xylene, etc.), acetonitrile, N, N-dimethylformylamide (DM
F), acetone, methyl ethyl ketone, dimethyl sulfoxide (DMSO), water and the like can be used alone or as a mixture thereof. This reaction usually involves the compound (II
Alternatively, the reaction is carried out by reacting 1 to 5 equivalents, preferably 1 to 3 equivalents of compound (III or III ') with II'). The reaction temperature is from -20 ° C to 50 ° C,
The temperature is preferably from 0 ° C to room temperature (20 to 25 ° C), and the reaction time is usually from 5 minutes to 100 hours.

(B) Equation (1):

Embedded image (Wherein each symbol is as defined above) or a salt thereof and a compound represented by the formula:

Embedded image (Wherein each symbol has the same meaning as described above), or a compound represented by the formula (2): AXY- (CH ₂ ) ₁ -R ⁸ (IV ′) Wherein each symbol is as defined above) or a salt thereof and a compound represented by the formula:

Embedded image (Wherein each symbol has the same meaning as described above) or a compound thereof by reacting the compound (I)
Can be manufactured. (However, when R ⁸ is a formyl group, m is m-1 and 1 is 1-1) Examples of the solvent in the present production method include ether solvents (eg, ethyl ether, diisopropyl ether, Dimethoxyethane, tetrahydrofuran, dioxane, etc.), halogen-based solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), aromatic solvents (eg, toluene, chlorobenzene, xylene, etc.), acetonitrile, N, N-dimethylformylamide (DMF) , Acetone, methyl ethyl ketone, dimethyl sulfoxide (D
MSO), water and the like can be used alone or as a mixture thereof. This reaction usually involves the compound (II or I
The reaction is carried out by reacting 1 to 5 equivalents, preferably 1 to 3 equivalents of compound (III or III ') with I'). The reaction temperature is from -20C to 50C, preferably from 0C to room temperature (20 to 25C), and the reaction time is usually from 5 minutes to 100 hours.

A more specific production method is described below. Y is -C of Preparation 1 Compound (I) (= O) -NR 15 -, -SO 2 -N
R ¹⁶ — (R ¹⁵ and R ¹⁶ are each a hydrogen atom or an optionally substituted alkyl group) or —C (＝ O) —O
When-, compound (I) can be produced by reacting compound (VI) with compound (VII) as shown in the following formula.

Embedded image (Wherein, R ¹⁰ is a carboxyl group, a sulfo group or a reactive derivative thereof, R ¹¹ is an amino group or a substituted amino group [amino which may be substituted with a lower alkyl group (eg, a methyl group, an ethyl group, etc.) Group] or a hydroxyl group, and the other symbols are as defined above.) This reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include ether solvents (eg, ethyl ether, diisopropyl ether, dimethoxyethane,
Tetrahydrofuran, dioxane, etc.), halogen-based solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), aromatic solvents (eg, toluene, chlorobenzene, xylene, etc.), acetonitrile, N, N-dimethylformylamide (DMF), acetone, Methyl ethyl ketone, dimethyl sulfoxide (DMSO), water and the like can be used alone or in combination. Among them, acetonitrile, dichloromethane, chloroform,
Tetrahydrofuran and the like are preferred. This reaction is generally carried out by reacting compound (VI) with 1 to 5 equivalents, preferably 1 to 3 equivalents of compound (VII). The reaction temperature is from -20C to 50C, preferably from 0C to room temperature (20 to 25C), and the reaction time is usually from 5 minutes to 100 hours. In addition, in this reaction, by allowing a base to coexist, the reaction sometimes proceeds more smoothly. As the base, both inorganic bases and organic bases are effective. Examples of inorganic bases include hydroxides, hydrides, carbonates, bicarbonates, and organic acid salts of alkali metals and alkaline earth metals, among which potassium carbonate,
Sodium carbonate, sodium hydroxide, potassium hydroxide,
Sodium bicarbonate and potassium bicarbonate are preferred. Tertiary amines such as triethylamine are preferred as the organic base. Examples of the reactive derivative include an acid anhydride, an acid halide (for example, acid chloride and acid bromide), an active ester and the like, and among them, an acid halide is preferable. The amount of the base to be used is generally 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (VII).

In the case of acylation from a carboxylic acid, 1 to 1.5 equivalents of compound (VII) and 1 equivalent of compound (VII) are used in an inert solvent (eg, a halogen solvent, acetonitrile, tetrahydrofuran, etc.). And 1 to 1.5 equivalents of dicyclohexylcarbodiimide (DC
The reaction is carried out in the presence of a dehydrating condensing agent such as C). This reaction is usually performed at room temperature (20 to 25 ° C), and the reaction time is 0.5 to 24 hours. When R ⁵ and R ⁶ are amino-protecting groups, a method known in the art (for example, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS
According to the method described in the second edition, pages 309-405, published by JOHN WILEY), they can be removed and the compound (I) can be produced.

Production method 2 Y of compound (I) is -S-, -O-, -N (R ¹⁷ )-(R
¹⁷ represents a hydrogen atom or an alkyl group which may be substituted, when the compound (VI
Compound (I) can be produced by reacting II) with compound (IX).

Embedded image (Wherein, R ¹² represents a halogen atom (eg, chlorine atom, bromine atom, iodine atom, etc.), an alkylsulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.) or an arylsulfonyloxy group (eg, benzenesulfonyloxy group) , P-toluenesulfonyloxy, etc.), R ¹³ is a thiol group, hydroxyl group, amino group or substituted amino group [lower alkyl group (eg, methyl group, ethyl group, etc.) or acyl group (eg, acetyl group) , An amino group which may be substituted with a group such as a propionyl group, etc.), and other symbols are as defined above.) This reaction is usually carried out in the presence of a base in a solvent inert to the reaction. Done. Examples of the solvent include ether solvents (eg, ethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), and aromatic solvents (eg, toluene, Chlorobenzene, xylene, etc.), acetonitrile, N, N-dimethylformylamide (DMF), acetone, methyl ethyl ketone, dimethyl sulfoxide (D
MSO), water and the like can be used alone or as a mixture thereof. Among them, acetonitrile, DMF and the like are preferable. This reaction is generally carried out by reacting compound (VIII) with 1 to 5 equivalents, preferably 1 to 3 equivalents of compound (IX). The reaction temperature is from -20C to 50C, preferably from 0C to room temperature (20 to 25C), and the reaction time is usually from 5 minutes to 100 hours. As the base, both inorganic bases and organic bases are effective. Examples of inorganic bases include hydroxides, hydrides, carbonates, bicarbonates, and organic acid salts of alkali metals and alkaline earth metals. Among them, potassium carbonate, sodium carbonate, sodium hydroxide, hydroxide Potassium, sodium bicarbonate and potassium bicarbonate are preferred. Tertiary amines such as triethylamine are preferred as the organic base. The amount of the base to be used is generally 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (VIII). When R ⁵ and R ⁶ are amino-protecting groups, a method known in the art (for example, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS
According to the method described in the second edition, pages 309-405, published by JOHN WILEY), they can be removed and compound (I) can be produced. When R ¹³ is an amino group, the reaction product of compound (VIII) and compound (IX) is reacted with a large excess (10-50 equivalents) of formaldehyde in acetic acid at 100 ° C. A and a nitrogen atom formed a ring structure via a methylene group by removing the protecting group of the amino group by a generally known method according to (I ′)
It is also possible to get

Production method 3 When Y of compound (I) is -N (R ¹⁷ )-(R ¹⁷ represents a hydrogen atom or an optionally substituted alkyl group), the reduced amino group of an amine and an aldehyde is used. Utilizing a compound (X) and a compound (X)
Compound (I) can be produced by reacting with (I).

Embedded image (Wherein X ′ is a bond or methylene, and R ¹⁴ is an amino group or a substituted amino group [lower alkyl group (eg,
An amino group which may be substituted with a methyl group, an ethyl group, etc.), and other symbols are as defined above. This reaction is usually performed in a solvent inert to the reaction (for example, an alcohol, an ether or a mixed solvent thereof) in the presence of a reducing agent. Examples of the reducing agent include sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. The amount of the reducing agent to be used is generally 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound (X). The reaction temperature is -20 to 50C, preferably 0C to
Room temperature (20-25 ° C), reaction time 0.5-24
Time. In the case of the catalytic reduction method, a catalytic amount of Raney nickel, platinum oxide, metal palladium, metal contact such as palladium-carbon and the like in an inert solvent (eg, an alcoholic solvent such as methanol, ethanol, isopropanol, t-butanol) at room temperature (20-25 ° C) to 1
It is obtained by reacting at 00 ° C. and a hydrogen pressure of 1 to 100 atm for 1 to 48 hours. When R ⁵ and R ⁶ are amino-protecting groups, a method known in the art (for example, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS
According to the method described in the second edition, pages 309-405, published by JOHN WILEY), they can be removed and compound (I) can be produced.

Production Method 4 As shown below, compound (I) can be produced by subjecting compound (XII) and compound (XIII) to a reductive amination reaction of amines and aldehydes.

Embedded image (Wherein each symbol has the same meaning as described above.) This reaction can be carried out according to Production method 3.

Production Method 5 As shown below, compound (I) can be produced by reacting compound (XIV) with compound (XV).

Embedded image (Wherein the symbols have the same meanings as described above.) This reaction can be carried out according to Production method 2.

Production method 6 As shown below, compound (I) can be produced by subjecting compound (XVI) and compound (XVII) to a reductive amination reaction of amines and aldehydes.

Embedded image (In the formula, R ¹⁸ represents a hydrogen atom or an optionally substituted alkyl group or amino group-protecting group, and other symbols are as defined above.) This reaction is carried out according to Production method 3. be able to.

Production method 7 As shown below, compound (XVIII) and compound (XVII)
Compound (I) can be produced by reacting

Embedded image (Wherein the symbols have the same meanings as described above.) This reaction can be carried out according to Production method 2.

Production method 8 As shown below, compound (I) can be produced by performing a reductive amination reaction of amines and aldehydes using compound (XIX) and compound (XX).

Embedded image (Wherein the symbols have the same meanings as described above.) This reaction can be carried out according to Production method 2. The reaction product of compound (XIX) and compound (XX) was treated in acetic acid with a large excess (10-50 equivalents) of formaldehyde at 100 ° C.
After reacting with A, it is also possible to obtain (I ′) in which A and a nitrogen atom form a ring structure via a methylene group by removing the protecting group of the amino group by a generally known method as necessary. is there.

Production method 9 In compound (I), when A is an aromatic hydrocarbon ring group or an aromatic heterocyclic group, X is a bond, and Y is an oxygen atom, Compound (I) can be produced by reacting (XXI) with compound (XXII).

Embedded image (In the formula, each symbol has the same meaning as described above.) This production method utilizes the Mitsunobu reaction carried out in the coexistence of diethylazodicarboxylate and triphenylphosphine. Ether solvents that are usually inert to the reaction (eg, ethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, etc.)
Done in The amount of diethylazodicarboxylate and triphenylphosphine to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to (XXI). The reaction temperature is -20 to 50C, preferably 0C to room temperature (20 to 2C).
5 ° C). When R ⁵ and R ⁶ are protecting groups for an amino group, a method known in the art (for example, PROTECTIVE GROUPS
IN ORGANIC SYNTHESIS 2nd edition, pages 309-405, JOH
According to the method described in N WILEY, they can be removed, and the compound (I) can be produced.

In the production methods 1 to 9, when the reaction product contains a primary or secondary amine, an aldehyde such as formaldehyde, acetaldehyde and propionaldehyde is used and the reductive amination reaction described in the production method 3 is carried out. By performing N-methylation, N-ethylation and N-
N-alkylation such as propylation can be performed. When an amino group protected by an amino-protecting group is present in the cyclic group A, if necessary, a generally known method (for example, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS)
According to the method described in the second edition, pages 309-405, published by JOHN WILEY), it can be removed and the compound (I) can be produced. Compound (I) or a salt thereof thus obtained can be separated by a known separation means (eg,
Concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc.) to isolate and purify from the reaction mixture.

Typical production methods of the starting compounds (II) to (V) required for the production of the compound (I) are shown below.

The starting compound (II) of the compound (I) is, for example,
In the case of 1,7b-diazacyclopent [cd] indene-4-carboxylic acid, trifluoroacetic anhydride is added to imidazo [1,2-a] pyridine-5-acetate (XXIII) in the presence of an organic base. , 7b-diazacyclopent [cd] obtained by the action of acetic acid, perfluoropropionic anhydride, chloroacetyl chloride or ethyl oxalyl chloride
By hydrolyzing methyl indene-4-carboxylate (XXIV), the corresponding compound (XXV) can be produced. This reaction is usually performed in a solvent inert to the reaction (eg, a halogen-based solvent such as dichloromethane, dichloroethane, and chloroform) in the presence of an organic base (eg, triethylamine, pyridine, 4-dimethylaminopyridine). The amount of the acid anhydride, acid chloride and organic base to be used is generally 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound (XXIII). The reaction temperature is -20 to 100C, preferably 25 to 70C, and the reaction time is 0.5 to 24.
Time.

Embedded image (Wherein R ¹⁹ represents a trifluoromethyl group, a trichloromethyl group, a pentafluoroethyl group or an ethoxycarbonyl group). 5 if it is a carboxylic acid
-Compound (XXVII) is synthesized from chloromethylimidazo [1,2-a] pyridine (XXVI) by the method described above and hydrolyzed in concentrated sulfuric acid to give the compound (XXXV).
III) can be manufactured.

Embedded image

When R ⁸ of the starting compound (V) of the compound (I) is, for example, a formyl group, the amino alcohol (XXI
X) and the amino group of the compound obtained by the reductive amination reaction of cycloalkanone (XXX) (according to Production Method 3) with a known method (for example, PROTECTIVE GROUPS IN ORGANIC SYN).
The corresponding compound (XXXI) can be prepared by protecting the compound with a hydroxyl group to an aldehyde after protection by the method described in THESIS Second Edition, pages 309-405, published by JOHN WILEY).
The amino-protecting group in this production method is preferably a tert-butoxycarbonyl group or a benzyloxycarbonyl group. Examples of the oxidation method include a method using pyridinium chlorochromate and the like, and a DMSO oxidation method using a combination of dimethyl sulfoxide and acetic anhydride, oxalyl chloride, trifluoroacetic anhydride (Mancuso, AJ
J. Org. Chem., 43, 2480 (1978)).

Embedded image (Wherein, R ²⁰ is a protecting group for an amino group, and other symbols are as defined above)

The starting compound (V ') of the compound (I) is obtained by a reductive amination reaction of an alkyldiamine (XXXII) having one amino group protected with cycloalkanone (XXX) (according to the production method 3). The amino-protecting group can be produced by a known method (for example, PROTECTI
VE GROUPS IN ORGANIC SYNTHESIS 2nd edition, 309-4
05, published by JOHN WILEY). When m = 2, the compound is also synthesized by performing a reductive amination reaction between aminoacetonitrile (XXXIII) and cycloalkanone (XXX), and then reducing the nitrile group with lithium aluminum hydride or the like. It is possible.

Embedded image

When R ⁴ is a hydroxyl group in the starting compound (III) of the compound (I), the compound (XXXV) is subjected to a reductive amination reaction (according to the production method 3) between the compound (XXXI) and the amino alcohol (XXXIV). ) Can be manufactured. In addition, the terminal hydroxyl group is determined by Gabriel's amine synthesis method (Gabriel).
el, S. Ber., 20, 2224 (1887)), and can be converted to an amino group to produce compound (XXXVI).

Embedded image (In the formula, R ²⁰ , R ²³ , and R ²⁴ represent a hydrogen atom, a lower alkyl group (eg, a methyl group, an ethyl group, or the like) or an amino-protecting group, and other symbols have the same meanings as described above.)

The starting compound of compound (I) (IV or I
In V ′), when the cyclic group A is, for example, 1,4,7b-triazacyclopenta [cd] indene-2 (1H) -one or 1,4,7b-triazacyclopenta [cd] indene Can be prepared by a known method (for example, the method described in JP-A-8-81467). Also, the cyclic group A
Is 2,3,4,5-tetrahydro-1H-3-benzazepine, for example, when 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride and ammonia or alkylamine (eg, , A methylamine, an ethylamine, etc.) to obtain a sulfonamide (XXXVII) from a dihalogenoalkyl (eg, 1-bromo-3-chloropropane, 1-bromo-
The compound (XXXVIII) can be produced by alkylation with 4-chlorobutane or the like. Also,
The halogen (R ²⁷ ) of the compound (XXXVIII) can be converted to an amino group by applying the amine synthesis method of Gabriel (Gabriel, S. Ber., 20, 2224 (1887)), and the compound (XXXIX)
Can be manufactured.

Embedded image (Where R ²⁵ is a trifluoroacetyl group or a benzoyl group, R ²⁶ is a hydrogen atom or a lower alkyl group (eg, a methyl group, an ethyl group, etc.), and R ²⁷ is a halogen (eg, a chlorine atom, a bromine atom, etc.) ) And other symbols have the same meanings as above.)

Since the compound (I) of the present invention has a particularly strong CXCR4 antagonistic action such as a chemokine receptor antagonistic action, it can be used as a preventive / therapeutic agent for various HIV infections, for example, AIDS, or as a disease progression of AIDS in humans. As an inhibitor or as a preventive or therapeutic agent for cancer
Alternatively, it is used as a pharmaceutical composition such as an anticancer agent having an antimetastatic effect. For example, the compound (I) of the present invention may be sugar-coated tablets, capsules, elixirs,
It can be used orally as a microcapsule, sustained release or the like, or parenterally in the form of an injection such as a sterile solution or suspension with water or other pharmaceutically acceptable liquids. For example, known carriers physiologically recognized compound (I) of the present invention, flavors, excipients, vehicles,
It can be manufactured by mixing with preservatives, stabilizers, binders and the like in the unit dosage form generally required for the practice of formulations. The amount of the active ingredient in these preparations is such that a proper dosage in the specified range can be obtained. The usual content of the compound (I) of the present invention or a salt thereof in the pharmaceutical composition of the present invention is about 0.01 to 100% by weight of the whole composition (preferably about 0.1 to 0.1% by weight).
To 90% by weight).

Examples of additives that can be mixed with tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth, gum arabic, excipients such as crystalline cellulose, corn starch, gelatin, alginic acid. For example, a leavening agent such as sucrose, a lubricant such as magnesium stearate, a sweetening agent such as sucrose, lactose or saccharin, a flavoring agent such as peppermint, reddish oil or cherry and the like are used. When the preparation unit form is a capsule, the above type of material can further contain a liquid carrier such as oil and fat. Sterile compositions for injection can be formulated according to normal pharmaceutical practice such as dissolving or suspending the active substance in vehicles such as water for injection, and naturally occurring vegetable oils such as sesame oil, coconut oil and the like. As the aqueous solution for injection, for example, physiological saline, isotonic solution containing glucose and other adjuvants (for example, D-sorbitol, D-mannitol, sodium chloride, and the like) and the like are used. For example, alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate)
80 ^TM , HCO-50) and the like. As the oily liquid, for example, sesame oil, soybean oil and the like are used, and may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol.

The prophylactic / therapeutic agents include, for example, buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, For example, human serum albumin, polyethylene glycol, etc.), preservatives (eg,
Benzyl alcohol, phenol, etc.), antioxidants and the like. The prepared injection is usually filled in a suitable ampoule. Since the preparation obtained in this way is safe and has low toxicity, for example, humans and mammals (for example, rats, mice, rabbits, sheep, pigs, cows,
Cats, dogs, monkeys, etc.). The dose of the compound (I) of the present invention varies depending on the administration subject, target organ, symptoms, administration method, and the like. In the case of oral administration, for example, in an HIV-infected patient (as 60 kg), it is generally used. About 0.1 to 100 mg, preferably about 1.0 to 50 mg, more preferably about 1.0 to 20 mg per day. In the case of parenteral administration, the single dose varies depending on the administration subject, target organ, symptoms, administration method, etc., for example, usually in the form of injection, for example, HIV infection patients (as 60 kg) , About 0.01 per day
It is convenient to administer about -30 mg, preferably about 0.1-20 mg, more preferably about 0.1-10 mg by intravenous injection. In the case of other animals, the amount can be administered in terms of 60 kg.

The compound (I) of the present invention can be used as a prophylactic / therapeutic agent for other HIV infections (in particular, a prophylactic / therapeutic agent for AIDS).
Alternatively, it may be used in combination with another anticancer drug. In this case, these drugs are separately or simultaneously mixed and formulated with pharmacologically acceptable carriers, excipients, binders, diluents and the like, and formulated for prevention and treatment of HIV infection. It can be administered orally or parenterally as a pharmaceutical composition. When the drugs are separately formulated, the separately formulated ones can be mixed and administered using a diluent at the time of use.However, the individually formulated separately can be administered simultaneously or with a time lag. And may be separately administered to the same subject. A kit product (for example, an ampoule containing an individual drug in powder form and 2
Injection kits containing diluents for mixing and dissolving more than one drug at the time of use, etc.) Kit products (e.g., tablets containing individual drugs in the same or separate bags,
If necessary, a column for describing the time for administering the drug was provided.
Tablet kits for administering more than one kind of tablets at the same time or separately at different times are also included in the pharmaceutical composition of the present invention.

Specific examples of other preventive / therapeutic agents for HIV infection which can be used in combination with the compound (I) of the present invention include zidovudine, didanosine, zalcitabine and zalcitabine. Nevirapine, nevirapine (nevirpine)
Delavirdine, efavirenz (efavi)
renz), loviride, immunocal (immunoca)
l), non-nucleic acid reverse transcriptase inhibitors such as oltipraz (including drugs having an antioxidant effect such as immunocal and oltipraz); saquinavir, ritonavir (ritona)
vir), indinavir (indinavir), nelfinavir (nelfinavir), amprenavir (amprenavir), parinavir (palinavir), lacinavir (lasinavir) and the like; and the like.

Specific examples of other anticancer drugs used in combination with the compound (I) of the present invention include melphalan, carmustine, lomustine, dacarbazine,
Cisplatin, carboplatin (carbopl)
alkylating agents such as atin); methotrexate (methot)
rexate), azacitidine (azacytidine), cytarabine (cytarabine), fluorouracil (fluorouracil),
Antimetabolites such as mercaptopurine and thioguanine; tamoxifen (t
amoxifen), hormone antagonists such as flutamide, leuprolide, and the like.

The compound (I) of the present invention may be, for example, a protease inhibitor or a reverse transcriptase inhibitor (eg, a nucleic acid-based reverse transcriptase inhibitor, a non-nucleic acid-based reverse transcriptase inhibitor), or the like. Antagonists of CCR5 which is a second receptor for M cell-directed HIV-1 (eg, N, N-dimethyl-N- [4-[[[2-
(4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-yl] carbonyl] amino] benzyl] tetrahydro-2H-pyran-4-aminium chloride) The above (preferably 2 to 5, more preferably 2 to 3) agents can be used in combination. Furthermore, it can also be used in combination with an antibody against the HIV-1 surface antigen or an HIV-1 vaccine.

Reverse transcriptase inhibitors such as nucleic acid reverse transcriptase inhibitors include zidovudine, didanosine, zalcitabine, lamivudine, stavudine,
Abacavir (abacavir) and the like are preferred, and examples of the non-nucleic acid reverse transcriptase inhibitor include nevirapine, delavirdine, and efavirenz (efavire).
nz) and the like, and examples of the protease inhibitor include saquinavir, ritonavir,
Indinavir, nelfinavir
vir) and the like are preferred.

[0066]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in more detail with reference to Examples, Reference Examples and Experimental Examples. However, these are merely examples and do not limit the present invention in any way. In addition, the room temperature in the text indicates a temperature of 20 to 25 ° C.

[0067]

EXAMPLES Reference Example 1 Cyclohexyl (2-hydroxyethyl) carbamic acid tert
-Butyl cyclohexyl (2-hydroxyethyl) amine (70g) in ethanol solution (500ml) in di-tert-butyl dicarbonate (107g)
Was added and the mixture was stirred at room temperature (20 to 25 ° C) for 2 hours, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1),
The title compound was obtained as a colorless syrup (115 g). ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.90 (10H, m), 1.47 (9H, s),
3.20-3.40 (2H, m), 3.60-3.90 (3H, m).

Reference Example 2 Cyclohexyl (2-oxoethyl) carbamic acid tert-butyl oxalyl chloride (9.8 ml) in dichloromethane solution (50 ml)
ml) in a dry ice-acetone bath to -78 ° C, and dimethyl sulfoxide (14.6ml) in dichloromethane
(30 ml) was added dropwise over 30 minutes. After completion of the dropwise addition, the mixture was stirred for 30 minutes, and cyclohexyl of Reference Example 1 (2-hydroxyethyl)
Tert-butyl carbamate (25g) in dichloromethane
(50 ml) was added dropwise over 30 minutes. After completion of the dropwise addition, the mixture was stirred for 30 minutes, triethylamine (43 ml) was added, and the reaction solution was heated to room temperature (20 to 25 ° C). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate-water, and the organic layer was washed sequentially with a 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound as a pale yellow syrup (23.9 g). As obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.90 (10H, m), 1.43 (9H, s),
3.70-3.90 (3H, m), 9.50 (1H, s).

Reference Example 3 tert-butyl 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl (4-hydroxybutyl) carbamate tert-butyl cyclohexyl (2-oxoethyl) carbamate of Reference Example 2 (22 g) After stirring a solution of 4-aminobutanol (20 g) in methanol (500 ml) at room temperature for 2 hours, sodium triacetoxyborohydride (39 g) was added and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was extracted with diethyl ether-water, and the organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. Dissolve the residue in tetrahydrofuran (50 ml) -water (50 ml), di-tert-butyl dicarbonate (22 g) and sodium hydrogen carbonate (25 g)
Was added and stirred for 18 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a colorless solid (26 g). ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.90 (14H, m), 1.47 (18H, br
s), 3.10-3.40 (6H, m), 3.60-3.75 (2H, m), 3.80-4.00
(1H, m).

Reference Example 4 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl [4- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butyl] carbamic acid tert-butyl reference example
Methanesulfonyl chloride (7.2 g)
g) was added and the mixture was stirred at room temperature for 1 hour and filtered. The filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate-water.
The extract was washed sequentially with an aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dimethylformamide (100 ml), potassium phthalimide (13.4 g) was added, and the reaction solution was stirred at 100 ° C. for 1 hour and concentrated under reduced pressure. The residue was extracted with ethyl acetate-water, and the organic layer was washed successively with a 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give the title compound as a colorless syrup (24 g). ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.90 (14H, m), 1.40-1.47 (1
8H, br), 3.05-3.35 (6H, m), 3.71 (2H, t, J = 6.6H
z), 3.80-4.00 (1H, m), 7.70-7.78 (2H, m), 7.82-7.9
0 (2H, m).

Reference Example 5 tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] of Reference Example 4 Ethyl [4- (1,3-dioxo-1,3-dihydro-2H-
Hydrazine monohydrate (6.6 g) was added to an ethanol solution (200 ml) of tert-butyl isoindol-2-yl) butyl] carbamate (24 g), and the mixture was refluxed for 1 hour. After allowing to cool at room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with diethyl ether-water. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound as a colorless solid (16 g). ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.00 (14H, m), 1.47 (18H, br
s), 2.65-2.85 (2H, m), 3.10-3.35 (6H, m), 3.80-4.00
(1H, m).

Reference Example 6 tert-butyl 4-[(3-nitrobenzoyl) amino] butyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate 3-nitrobenzoic acid (512 mg) 4-aminobutyl of Example 5
{2-[(tert-Butoxycarbonyl) (cyclohexyl) amino] ethyl} tert-butylcarbamate (1.22 g) and 1-hydroxybenzotriazole (563 mg) in acetonitrile (30 ml) were added to 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (589 mg) was added, and the mixture was stirred at room temperature for 3 days. After the reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water, and the organic layer was washed successively with a 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a colorless syrup (1.1 g). ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.90 (14H, m), 1.45 (9H, s),
1.49 (9H, s), 3.05-3.35 (6H, m), 3.40-3.70 (2H,
m), 3.80-4.00 (1H, m), 7.61 (1H, t, J = 8.0Hz), 8.
20-8.40 (2H, m), 8.76 (1H, s).

Reference Example 7 tert-butyl 4-[(3-aminobenzoyl) amino] butyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate 4-[(3- Nitrobenzoyl) amino] butyl {2-
[(tert-butoxycarbonyl) (cyclohexyl) amino]
To a methanol solution (20 ml) of tert-butyl ethyl} carbamate (1.0 g) was added 10% palladium carbon (100 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours, and then the reaction solution was filtered.
The filtrate was concentrated under reduced pressure to give the title compound as a pale yellow syrup (840 m
g). ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.90 (14H, m), 1.45 (18H, b
r), 3.00-3.60 (9H, m), 6.90-7.00 (1H, m), 7.10-7.45
(3H, m).

Reference Example 8 tert-butyl 4- [benzyl (methyl) amino] butyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate 2-[(tert-butoxycarbonyl) of Reference Example 3 ) (Cyclohexyl) amino] ethyl (4-hydroxybutyl) carbamic acid
rt-butyl (568mg) solution in tetrahydrofuran (10ml)
To the mixture was added methanesulfonyl chloride (172 mg) and triethylamine (166 mg), and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water, and the organic layer was extracted with 5 parts.
The solution was washed sequentially with a 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dimethylformamide (10 ml), and benzylmethylamine (250 mg) and potassium carbonate (284 mg) were added.
For 18 hours. The reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water, and the organic layer was washed sequentially with a 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give the title compound as a colorless syrup (300 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.90 (14H, m), 1.46 (18H, br
s), 2.17 (3H, s), 2.38 (2H, t, J = 7.4Hz), 3.05-3.3
0 (7H, m), 3.47 (2H, s), 7.20-7.35 (5H, m).

Reference Example 9 4- (methylamino) butyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamic acid tert-
Butyl 4- [benzyl (methyl) amino] butyl {2-[(tert
-Butoxycarbonyl) (cyclohexyl) amino] ethyl}
Tert-Butyl carbamic acid (290 mg) in methanol (10 ml)
The residue was dissolved in water (2 ml) -acetic acid (34 mg), 20% palladium hydroxide on carbon (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was extracted with diethyl ether-saturated aqueous sodium hydrogen carbonate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound as a colorless syrup (210 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.90 (14H, m), 1.47 (18H, br
s), 2.42 (3H, s), 2.58 (2H, t, J = 7.0Hz), 3.05-3.3
5 (7H, m).

Reference Example 10 3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3
-Benzazepine-7-sulfonyl chloride 1-liter autoclave o-xylylene dicyanide (50 g), 2-
Butanol (500 ml) and Raney-Ni (wet, 55 g) were charged,
Hydrogen was absorbed at a hydrogen pressure of 9 kg / cm ² and 65 ° C. On the way, 5kg / cm ²
Was added, hydrogen was added to 9 kg / cm ² . After about 2 hours, confirm that hydrogen absorption has stopped.
The temperature was raised to 30 ° C. The mixture was stirred for 3 hours from when the temperature reached 130 ° C. After returning to room temperature, the catalyst was removed by filtration, washed with ethanol, and the filtrates were combined and concentrated under reduced pressure. Add ethanol to the residue,
Concentrated hydrochloric acid (30 ml) was added. Crystals crystallized out immediately. The solvent was distilled off under reduced pressure, and isopropanol (100 ml) and acetone (140 ml) were added to the residue. The mixture was stirred at room temperature for 30 minutes and under ice-cooling for 30 minutes, and collected by filtration. After washing with acetone, drying under reduced pressure, 2,3,
Crude crystals of 4,5-tetrahydro-1H-3-benzazepine hydrochloride
(43.7 g) was obtained. To a mixture of the crude crystals (42.4 g), triethylamine (70.7 ml) and tetrahydrofuran (450 ml) was added dropwise a solution of trifluoroacetic anhydride (31.9 ml) in tetrahydrofuran (50 ml) under ice-cooling. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline,
After drying, it was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 2: 1) to give 3- (trifluoroacetyl) -2,3,3 as pale yellow crystals.
4,5-Tetrahydro-1H-3-benzazepine (38.0 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.94-3.03 (4H, m), 3.65-3.82 (4H,
m), 7.10-7.22 (4H, m). Chlorosulfonic acid (17 ml) in 1,2-dichloroethane (15 ml)
To the solution was added a solution of 3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (17.2 g) in 1,2-dichloroethane (15 ml) under ice-cooling. 1,2-dichloroethane (30
ml) and stirred at 80 ° C. for 3 hours. After allowing to cool, the mixture was poured into ice and stirred. The mixture was extracted with ether, and the extract was washed with saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and crystallized from a mixture of isopropyl ether and hexane to give the title compound (15.9 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.06-3.18 (4H, m), 3.70-3.88 (4H,
m), 7.37-7.47 (1H, m), 7.81-7.92 (2H, m).

Reference Example 11 N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide 3- (trifluoroacetyl) obtained in Reference Example 10. ) -2,3,4,5-Tetrahydro-1H-3-benzazepine-7-sulfonyl chloride (7.11 g) in ethyl acetate (80 ml), 40% methylamine methanol solution (4.00 ml) under ice-cooling Added and stirred for 5 minutes. 1N Hydrochloric acid (10 ml) was added to make the mixture weakly acidic. Ethyl acetate was added, and the mixture was washed with water and saturated saline, dried and concentrated.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 2) to give the title compound (5.08 g) as a colorless syrup. ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H, d, J = 5.4 Hz), 3.00-3.12
(4H, m), 3.68-3.86 (4H, m), 4.41 (1H, q, J = 5.4Hz),
7.25-7.35 (1H, m), 7.68-7.76 (2H, m).

Reference Example 12 N- (4-Chlorobutyl) -N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide The obtained N-methyl-3- (trifluoroacetyl) -2,
3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide (5.58 g), 1-bromo-4-chlorobutane (2.29 ml),
Potassium carbonate (4.59 g), acetonitrile (72 ml), N, N-
A mixture of dimethylformamide (8 ml) was stirred at 80 ° C. overnight. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added,
The extract was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to give the title compound (5.86 g) as a pale yellow-green syrup. ¹ H-NMR (CDCl ₃ ) δ: 1.63-1.95 (4H, m), 2.74 (3H, s),
3.00-3.12 (6H, m), 3.60 (2H, t, J = 6.3Hz), 3.67-3.8
5 (4H, m), 7.26-7.36 (1H, m), 7.55-7.64 (2H, m).

Reference Example 13 N- (4-aminobutyl) -3-benzoyl-N-methyl-2,3,4,5-
Tetrahydro-1H-3-benzazepine-7-sulfonamide
Hydrochloride N-methyl-3- (trifluoroacetyl)-obtained in Reference Example 11
2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfo
Hydroxylation in methanol (40 ml) solution of amide (4.42 g)
Sodium (10 ml) was added and stirred for 30 minutes. 1N hydrochloric acid (1
0 ml) and methanol was distilled off under reduced pressure. 10% carbonate
Thorium water (20 ml), ethyl acetate (50 ml), benzoyl chloride
(1.74 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Deposited
The crystals were collected by filtration, washed with water and ethyl acetate-ether,
Colored crystals of 3-benzoyl-N-methyl-2,3,4,5-tetrahydro
-1H-3-benzazepine-7-sulfonamide (1.38 g) was obtained.
Was. ¹H-NMR (CDCl_Three) δ: 2.68 (3H, d, J = 5.4Hz), 2.80-
3.25 (4H, m), 3.40-4.10 (4H, m), 4.30-4.45 (1H,
m), 7.20-7.90 (8H, m) .3-Benzoyl-N-methyl-2,3,4,5-tetrahydro-1H-3-beta
Ndazepine-7-sulfonamide (3.73 g), N- (4-bromo
(Butyl) phthalimide (3.67 g), potassium carbonate (3.04 g)
g), acetonitrile (50 ml), N, N-dimethylformamide
(5 ml) was stirred at 70 ° C. for one day. Ethyl acetate
The mixture was washed with water and saturated saline, dried, and concentrated. Residue
To silica gel column chromatography (hexane: vinegar)
Ethyl acid = 1: 1 → 0: 1) to give a colorless amorph
Vacuum-like 3-benzoyl-N- [4- (1,3-dioxo-1,3-dihydrogen
B-2H-isoindol-2-yl) butyl] -N-methyl-2,3,
4,5-tetrahydro-1H-3-benzazepine-7-sulfone
The mid (5.12 g) was obtained.¹ H-NMR (CDCl_Three) δ: 1.50-1.85 (4H, m), 2.73 (3H, s),
2.80-3.20 (6H, m), 3.45-3.65 (2H, m), 3.72 (2H, d,
 J = 6.8Hz), 3.78-4.00 (2H, m), 7.35-7.65 (8H, m), 7.
68-7.77 (2H, m), 7.79-7.88 (2H, m) .3-Benzoyl-N- [4- (1,3-dioxo-1,3-dihydro-2H-i
Soindol-2-yl) butyl] -N-methyl-2,3,4,5-tetra
Lahydro-1H-3-benzazepine-7-sulfonamide (5.07
 g) in ethanol (50 ml) -tetrahydrofuran (10 ml)
And hydrazine monohydrate (0.60 ml) was added, and the mixture was heated to 70 ° C.
For 3 hours. Add hydrazine monohydrate (0.40 ml)
Then, the mixture was further stirred at 70 ° C. for 1 hour. After cooling, the reaction solution is filtered.
Then, the solvent was distilled off under reduced pressure. Add 1N hydrochloric acid to the residue and add vinegar
After washing with a mixed solution of ethyl acetate and ether, 1N
It was made alkaline with thorium and extracted with ethyl acetate.
The extract was washed with brine, dried and concentrated. Obtained
Ethanol and 4N hydrochloric acid / ethyl acetate were added to the oily product
Then, the mixture was concentrated under reduced pressure to give the title compound as a pale yellow amorphous compound.
(3.68 g) was obtained.¹ H-NMR (DMSO-d₆) δ: 1.57 (4H, brs), 2.64 (3H, s),
2.70-3.20 (8H, m), 3.30-3.90 (4H, m), 7.30-7.70 (8
H, m), 7.97 (3H, br).

[0080] Reference Example 14 N ¹ - cyclohexyl-1,2-diamine dihydrochloride N-(2-aminoethyl) carbamic acid tert- butyl (1.60
g), cyclohexanone (982 mg) and acetic acid (0.57 ml) in tetrahydrofuran (30 ml) were added with sodium triacetoxyborohydride (3.18 g) and stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and 10%
The extract was washed with aqueous sodium carbonate and saturated saline, dried and concentrated. Ethanol (4 ml) and 4N hydrochloric acid / ethyl acetate (14
ml) and concentrated hydrochloric acid (2 ml), and the mixture was stirred at room temperature for 2 hours.
After the reaction solution was concentrated under reduced pressure, the precipitated crystals were concentrated in ethanol.
After washing with a mixture of ethyl acetate, the title compound (1.5%) was obtained as colorless crystals.
0 g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.50 (5H, m), 1.50-1.85 (3
H, m), 1.96-2.12 (2H, m), 2.94-3.14 (1H, m), 3.20
(4H, s), 8.00-9.80 (5H, br).

Reference Example 15 N ¹ -cycloheptyl-N ¹ -methyl-1,2-ethylenediamine aminoacetonitrile sulfate (2.10 g) and sodium acetate
(1.64 g) was dissolved in water (5 ml), and dried under reduced pressure. Tetrahydrofuran (50 ml), cycloheptanone (2.24 g),
Then sodium triacetoxyborohydride (4.24 g)
Was added and stirred at room temperature for 2 hours. After sodium triacetoxyborohydride (2.12 g) was added and the mixture was further stirred at room temperature for 1 hour, formalin (4.50 ml) was added. After stirring for 20 minutes, sodium triacetoxyborohydride (5.09 g) was added, and the mixture was further stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and concentrated. The residue was subjected to basic silica gel column chromatography (hexane: ethyl acetate = 5: 1 →
2: 1) to give [cycloheptyl (methyl) amino] acetonitrile (2.59 g) as a colorless oil. Lithium aluminum hydride (887 mg) was added to tetrahydrofuran (10 m
l) -Ethanol (30 ml) was suspended, and a solution of [cycloheptyl (methyl) amino] acetonitrile (2.59 g) in tetrahydrofuran (20 ml) was added dropwise. After stirring at room temperature for 30 minutes, water (0.9 ml), 10% aqueous sodium hydroxide (0.9 ml), water
(2.7 ml) was added carefully in order. After stirring for a while, insolubles were removed with celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.64 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.00 (12H, m), 2.20 (3H, s),
2.43 (2H, t, J = 6.0Hz), 2.46-2.65 (1H, m), 2.71 (2
(H, t, J = 6.0Hz).

REFERENCE EXAMPLE 16 N ¹ -cycloheptyl-1,2-ethylenediamine dihydrochloride In the same manner as in Reference Example 14, using cycloheptanone instead of cyclohexanone, colorless crystals of N ¹ -cycloheptyl-1, 2-Ethylenediamine dihydrochloride was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.90 (10H, m), 1.95-2.15
(2H, m), 3.20 (4H, s), 3.10-3.30 (1H, m), 8.00-9.80
(5H, br).

Reference Example 17 tert-butyl 4-aminobutyl {2- [cyclohexyl (methyl) amino] ethyl} carbamate In the same manner as in Example 15, using cyclohexanone instead of cycloheptanone, a colorless oil N ¹ -Cyclohexyl-N ¹ -methyl-1,2-ethylenediamine was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.90 (10H, m), 2.24 (3H, s),
2.20-2.45 (1H, m), 2.48 (2H, t, J = 6.1Hz), 2.73 (2
H, t, J = 6.1Hz) .N ¹ -cyclohexyl-N ¹ -methyl-1,2-ethylenediamine
(1.56 g), N- (4-bromobutyl) phthalimide (2.82
g), potassium carbonate (2.76 g), N, N-dimethylformamide
(30 ml) of the mixture was stirred at 60 ° C. for 1 hour. Subsequently, di-tert-butyl dicarbonate (2.62 g) was added, and the mixture was stirred overnight at room temperature.
The reaction solution was concentrated under reduced pressure. Ethyl acetate was added, washed with water and saturated saline, dried and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 1: 1).
0 → 1: 1) to give 2- [cyclohexyl (methyl) amino] ethyl [4- (1,3-dioxo-) as a pale yellow orange syrup.
1,3-Dihydro-2H-isoindol-2-yl) butyl] carbamic acid tert-butyl (1.78 g) was obtained. This was dissolved in ethanol (30 ml) and hydrazine monohydrate (0.92 ml)
Was added and stirred at 70 ° C. for 1.5 hours. After cooling, the insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. 5% aqueous sodium carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated under reduced pressure to give the title compound (1.23 g) as an orange syrup. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.90 (14H, m), 1.46 (9H, s),
2.29 (3H, s), 2.20-2.42 (1H, m), 2.46-2.63 (2H,
m), 2.71 (2H, t, J = 6.8Hz), 3.13-3.33 (4H, m).

Reference Example 18 N- (4,4-dimethoxybutyl) -2-naphthalenesulfonamide 2-naphthalenesulfonyl chloride (11.33 g) in THF (100
ml) solution, triethylamine (21 ml) and 4-mianobutyraldehyde dimethyl acetal (7.01 ml) were added at room temperature, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (14.94 g) as colorless crystals. MS m / z 292 (MH ⁺ -MeOH).

REFERENCE EXAMPLE 19 1- (2-Naphthylsulfonyl) -2-pyrrolidinol N- (4,4-dimethoxybutyl) -2-naphthalenesulfonamide (1.62 g) of Reference Example 18 in water (8 ml) and acetone ( 16ml)
Pyridinium p-toluenesulfonic acid (1.26
g) was added at room temperature, and the mixture was heated under reflux for 3 hours. After cooling, a 10% aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 1: 1) to give the title compound (1.21 g)
Was obtained as a colorless oil. MS m / z 260 (MH ⁺ -MeOH).

Reference Example 20 tert-butyl 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl (4-hydroxypentyl) carbamate In the same manner as in Reference Example 3, the cyclohexyl (2-
The title compound (2.13 g) was synthesized from tert-butyl (oxoethyl) carbamate (1.97 g) and 5-amino-1-pentanol (1.03 g). ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.90 (16H, m), 1.47 (18H, s),
3.05-3.35 (6H, m), 3.50-4.10 (3H, m).

Reference Example 21 tert-butyl 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl [4- (2-naphthylsulfanyl) butyl] carbamate 2-[(tert-butoxycarbonyl) of Reference Example 3 (Cyclohexyl) amino] ethyl (4-hydroxybutyl) carbamic acid te
rt-Butyl (0.21 g) and triethylamine (0.13 g) were dissolved in tetrahydrofuran (3 ml), methanesulfonyl chloride (0.14 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Reaction solution 5
After washing with aqueous sodium hydrogen carbonate and saturated brine, the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 2). The obtained oil and 2-naphthalene diol (0.068
g) in dimethylformamide (4 ml), and
A powder washed with 0% oily sodium hydride (0.032 g) n-hexane was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was added to 5% aqueous sodium bicarbonate (60 ml), extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to give the title compound (0.20 g). ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (14H, m), 1.43 (18H,
s), 2.95-4.05 (9H, m), 7.25-7.35 (3H, m), 7.65-7.8
5 (4H, m).

Reference Example 22 tert-butyl 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl [4- (2-naphthylsulfanyl) pentyl] carbamate In the same manner as in Reference Example 21, the procedure of Reference Example 20 was repeated. An oil (0.20 g) synthesized from tert-butyl 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl (4-hydroxypentyl) carbamate (0.22 g) and 2-naphthalene diol (0.078 g)
g) to give the title compound (0.21 g). ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.85 (16H, m), 1.45 (18H,
s), 3.02 (2H, t, J = 7.3Hz), 3.05-3.30 (6H, m), 3.
40-4.05 (1H, b), 7.25-7.55 (3H, m), 7.65-7.85 (4H,
m).

Reference Example 23 Cyclopentyl (2-hydroxyethyl) carbamic acid tert
-Butyl cyclopentanone (12.65 g) and 2-aminoethanol (9.19
A solution of g) in toluene (120 ml) was heated to reflux for 3 hours while azeotropically removing the generated water. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. Residue in methanol (100 ml)
Dissolved in sodium triacetoxyborohydride (63.
74 g) was added little by little at room temperature, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with an 8N aqueous sodium hydroxide solution and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To a solution of the obtained crude 2- (N-cyclopentylamino) ethanol in ethanol (200 ml) was added di-dicarbonate.
Tert-butyl (30.34 g) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a colorless oil (1
4.34 g). ¹ H-NMR (CDCl ₃ ) δ: 1.34-1.71 (17H, m), 3.22 (1H, b
r), 3.31 (2H, t, J = 5.6Hz), 3.72 (2H, t, J = 5.6H
z), 4.78 (1H, br).

Reference Example 24 To a solution of tert-butyl cyclopentyl (2-oxoethyl) carbamate in oxalyl chloride (2.0 ml) in dichloromethane (50 ml) was added dropwise a solution of dimethyl sulfoxide (3.4 mL) in dichloromethane (10 ml) at -78 ° C. did. To the resulting solution was added dropwise a solution of tert-butyl cyclopentyl (2-hydroxyethyl) carbamate of Reference Example 23 (4.59 g) in dichloromethane (10 ml) at -78 ° C, and the mixture was stirred at -78 ° C for 15 minutes. . Triethylamine (14.0 ml) was added dropwise to the mixture at -78 ° C, and the reaction solution was stirred for 15 minutes. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and water and ethyl acetate were added to the residue for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a colorless oil (4.79 g). ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.38 (2H, m), 1.45 (9H, s),
1.53-1.77 (4H, m), 1.77-1.99 (2H, m), 3.74 (2H,
m), 4.59 (1H, br), 9.53 (1H, t, J = 1.4Hz).

Reference Example 25 tert-Cycloheptyl (2-hydroxyethyl) carbamic acid
-Butyl In the same manner as in Reference Example 23, cycloheptanone (11.22 g)
To give the title compound (17.06 g). ¹ H-NMR (CDCl ₃ ) δ: 1.32-1.87 (21H, m), 2.63 (1H, b
r), 3.32 (2H, t, J = 5.6Hz), 3.72 (2H, t, J = 5.6H
z), 3.80 (1H, br).

Reference Example 26 tert-butyl cyclopentyl (2-oxoethyl) carbamate In the same manner as in Reference Example 24, the cycloheptyl (2
Tert-Butyl (-hydroxyethyl) carbamate (5.16 g)
To give the title compound (4.76 g). ¹ H-NMR (CDCl ₃ ) δ: 1.36-1.58 (13H, m), 1.58-1.80 (4
H, m), 1.97-2.38 (4H, m), 3.56-3.65 (2H, m), 4.78-
5.16 (1H, m), 9.47 (1H, t, J = 1.6Hz).

Reference Example 27 Methyl 3-trifluoromethyl-1,7b-diazacyclopent [cd] indene-4-carboxylate imidazo [1,2-a] pyridine-5-acetate (0.95 g) Trifluoroacetic anhydride (2.12 ml) was added dropwise to a dichloromethane solution (20 ml) of pyridine (1.21 ml) at 0 ° C. The mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was poured into ice water and extracted by adding chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ether was added to the residue and mixed, and the crystals were collected by filtration.
The crystals were washed with a small amount of ether and dried under reduced pressure to give the title compound as white crystals (1.13 g). ¹ H-NMR (CDCl ₃ ) δ: 4.09 (3H, s), 8.22 (1H, m), 8.28
(1H, d, J = 7.8 Hz), 8.59 (1H, d, J = 7.8 Hz), 8.8
7 (1H, s).

Reference Example 28 3-trifluoromethyl-1,7b-diazacyclopent [cd] indene-4-carboxylic acid 3-trifluoromethyl-1,7b-diazacyclopent [cd] of Reference Example 27 Indene-4-carboxylic acid methyl ester (2.68
g) was added to a mixed solution of ethanol (20 ml) and tetrahydrofuran (40 ml), 2N aqueous sodium hydroxide solution (22 ml) was further added, and the mixture was stirred at room temperature for 6 hours. After the reaction, 12N hydrochloric acid was added to the reaction solution at 0 ° C until the pH of the mixture became 4. The resulting precipitate was collected by filtration, washed with ethanol and ether, and dried under reduced pressure to give the title compound as a pale yellow powder (2.26
g). ¹ H-NMR (CDCl ₃ ) δ: 8.34 (1H, t, J = 8.0 Hz), 8.53 (1
H, d, J = 7.8 Hz), 8.65 (1H, d, J = 8.0 Hz), 9.12
(1H, s).

REFERENCE EXAMPLE 29 5-chloromethylimidazo [1] was added to a mixed solution of 4-chloro-3-trifluoromethyl-1,7b-diazacyclopent [cd] indenepyridine (36.06 ml) and dichloromethane (200 ml). , 2-a] pyridine hydrochloride (1
9.36 g) and further added at 0 ° C. trifluoroacetic anhydride (62.
98 ml) was added dropwise over 1 hour. After the addition, triethylamine (31.1 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. After the reaction, the reaction solution was poured into ice water, a 2N aqueous sodium hydroxide solution was added to neutralize the mixture, and chlorophorom was added thereto for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:
Purification with methanol = 10: 1) gave the title compound as a pale yellow solid (17.69 g). ¹ H-NMR (CDCl ₃ ) δ: 8.12 (1H, t, J = 7.8 Hz), 8.24 (1
H, d, J = 7.8 Hz), 8.30 (1H, d, J = 7.8 Hz), 8.70
(1H, s).

REFERENCE EXAMPLE 30 4-Chloro-1,7b-diazacyclopent [cd] indene-3-carboxylic acid 4-chloro-3-trifluoromethyl-1,7b-diazacyclopent [Reference Example 29] [cd] indene (5.00 g) was added to sulfuric acid (25 ml) and the mixture was heated at 130 ° C. under argon for 18 hours.
After the reaction, the reaction solution was poured into ice water, and a 2N aqueous sodium hydroxide solution was added to the resulting mixture under cooling to adjust the pH of the mixture to 4-5. The resulting precipitate was collected by filtration, washed with a small amount of purified water, acetone and ether, and dried under reduced pressure to give the title compound as an off-white solid (6.86 g). ¹ H-NMR (DMSO-d ₆ ) δ: 8.20 (1H, t, J = 8.0 Hz), 8.42
(1H, d, J = 8.0 Hz), 8.46 (1H, d, J = 8.0 Hz), 8.8
1 (1H, s).

Reference Example 31 3-pentafluoroethyl-1,7b-diazacyclopent [cd]
Methyl indene-4-carboxylate imidazo [1,2-a] pyridine-5-acetate (0.95 g), triethylamine (1.39 ml), pyridine (0.99 ml) in chloroform solution (25 ml), perfluoropropionic acid Anhydrous
(1.97 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was heated at reflux for 20 hours. After cooling, the reaction mixture was poured into ice water and neutralized with aqueous sodium hydroxide. The mixture was extracted with chloroform and dried, and the solvent was distilled off. The residue was washed with diethyl ether / ethyl acetate to give the title compound.
(0.87 g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 3.43 (3H, s), 7.23 (1H, d, J =
7.0 Hz), 7.76 (1H, d, J = 8.8 Hz), 7.88 (1H, dd, J
= 7.4, 8.6 Hz), 8.09 (1H, s).

Reference Example 32 3-Pentafluoroethyl-1,7b-diazacyclopent [cd]
Indene-4-carboxylic acid methyl ester of 3-pentafluoroethyl-1,7b-diazacyclopent [cd] indene-4-carboxylic acid of Reference Example 31 (3.13
To a suspension of g) in ethanol (15 ml), 2N aqueous sodium hydroxide (10 ml) was added at room temperature, and the mixture was stirred for 3 hours. Concentrated hydrochloric acid was added to the reaction mixture while cooling to adjust the pH to 4. The insolubles were collected by filtration, washed with acetone and diethyl ether, and dried to give the title compound as a white powder (1.95 g). ¹ H-NMR (DMSO-d ₆ ) δ: 8.38 (1H, t, J = 8.0 Hz), 8.56
(1H, d, J = 8.2 Hz), 8.67 (1H, d, J = 7.8 Hz), 9.1
1 (1H, s).

Reference Example 33 tert-butyl 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl (4-oxobutyl) carbamate A solution of sulfoxide (2.6 ml) in dichloromethane (10 ml) was added dropwise. The obtained solution was added at −78 ° C. to tert-butyl 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl (4-hydroxybutyl) carbamate (6.22 g) of Reference Example 3 in dichloromethane (10 m
The solution dissolved in l) was added dropwise and the mixture was stirred at -78 ° C for 15 minutes. Triethylamine (10.5 ml) was added to the mixture at -78 ° C.
Was added dropwise, and the reaction solution was stirred for 15 minutes. Filter the reaction solution,
The filtrate was concentrated under reduced pressure, and water and ethyl acetate were added to the residue for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
3: 1) to give the title compound as a colorless oil (6.07g)
As obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 0.92-1.38 (6H, m), 1.47 (18H,
m), 1.54-1.96 (6H, m), 2.45 (2H, t, J = 7.0Hz), 3.0
6-3.35 (6H, m), 3.52-4.03 (1H, m), 9.78 (1H, s).

The chemical structure of the compound obtained in Reference Example is shown below.

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Example 1 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3,5-bis (trifluoromethyl) benzamide dihydrochloride 4-aminobutyl {2 -[(tert-Butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamic acid tert-
Butyl (50mg) and triethylamine (15mg) in tetrahydrofuran solution (2ml) in 3,5-bis (trifluoromethyl)
After adding benzoyl chloride (39 mg) and stirring at room temperature for 1 hour, the reaction solution was filtered. After nitrogen was blown onto the filtrate to remove the solvent, silica gel column chromatography (ethyl acetate) was performed using Flashtube ™ 2008 manufactured by Biolinks. The purified product was dissolved in 4N hydrogen chloride / ethyl acetate (2 ml), stirred for 1 hour, and then blown with nitrogen to remove the solvent, thereby obtaining the title compound as a colorless solid (28 mg). MS m / z: 454 (MH +).

Example 2 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1-benzothiophene-2-carboxamide dihydrochloride benzothiophene-2-carbonyl chloride (27 mg), The title compound was synthesized in the same manner as in Example 1. MS m / z: 374 (MH +).

Example 3 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-furamide dihydrochloride furan-2-carbonyl chloride
(18 mg) and the title compound was synthesized in the same manner as in Example 1. MS m / z: 308 (MH +).

Example 4 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamide dihydrochloride The title compound was synthesized in the same manner as in Example 1 using 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride (31 mg). MS m / z: 399 (MH +).

Example 5 As in Example 1 except that N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-thiophenecarboxamide dihydrochloride thiophene-2-carbonyl chloride (21 mg) was used. The title compound was synthesized by the method described above. MS m / z: 324 (MH +).

Example 6 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1-phenyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxamide dihydrochloride 1- Phenyl-5- (trifluoromethyl) -1H-pyrazole-4-
The title compound was synthesized in the same manner as in Example 1 using carbonyl chloride (38 mg). MS m / z: 452 (MH +).

Example 7 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) [1,1′-biphenyl] -4-carboxamide dihydrochloride 4-phenylbenzoic acid (15 mg), for reference 4-aminobutyl of Example 5
{2-[(tert-Butoxycarbonyl) (cyclohexyl) amino] ethyl} solution of tert-butyl carbamate (32 mg) and 1-hydroxybenzotriazole (11 mg) in acetonitrile
(1 ml) in N, N'-dicyclohexylcarbodiimide (16
mg) and the mixture was stirred at room temperature for 2 hours, and then the reaction solution was filtered. Nitrogen was blown onto the filtrate to remove the solvent.
Silica gel column chromatography was performed using FlashTubeTM2008 manufactured by ks. The purified product was dissolved in 4N hydrogen chloride / ethyl acetate (2 ml), stirred for 1 hour, and then blown with nitrogen to remove the solvent, thereby obtaining the title compound as a colorless solid (10 mg). MS m / z: 394 (MH +).

Example 8 As in Example 7, using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-quinolinecarboxamide dihydrochloride quinoline-2-carboxylic acid (13 mg) The title compound was synthesized by the method described above. MS m / z: 369 (MH +).

Example 9 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-naphthamide dihydrochloride Naphthalene-2-carbonyl chloride (13 mg) was used in the same manner as in Example 1. The title compound was synthesized by the method. MS m / z: 368 (MH +).

Example 10 As in Example 1, except that N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-quinoxalinecarboxamide dihydrochloride quinoxaline-2-carbonyl chloride (31 mg) was used. The title compound was synthesized by the method described above. MS m / z: 370 (MH +).

Example 11 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4-phenoxybenzamide dihydrochloride Using 4-phenoxybenzoic acid (16 mg), the same procedure as in Example 7 was carried out. The title compound was synthesized by the method. MS m / z: 410 (MH +).

Example 12 4-Benzoyl-N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzamide dihydrochloride Using 4-benzoylbenzoic acid (17 mg) in the same manner as in Example 7 The title compound was synthesized by the method. MS m / z: 422 (MH +).

Example 13 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1H-indole-5-carboxamide diformate indole-5-carboxylic acid (110 mg); Tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate (200 mg) and 1
N, N'-Dicyclohexylcarbodiimide (142 mg) was added to a solution of 5-hydroxybenzotriazole (93 mg) in acetonitrile (5 ml), and the mixture was stirred at room temperature for 1 hour, and then the reaction solution was filtered. After the filtrate was concentrated under reduced pressure, the residue was concentrated in ethyl acetate.
Extracted with water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give a colorless syrup (213m
g) was obtained. This syrup (100 mg) was dissolved in formic acid (1 ml), stirred at room temperature for 18 hours, and concentrated under reduced pressure. The residue was lyophilized from water to give the title compound as a colorless amorphous solid (45 mg). MS m / z: 357 (MH +).

Example 14 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1H-benzimidazole-5-carboxamide dihydrochloride benzimidazole-5-carboxylic acid (63 mg), Reference Example 4 of 5
Tert-butyl-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate (113
mg) and 1-hydroxybenzotriazole (52 mg) in dimethylformamide solution (2 ml), N, N'-dicyclohexylcarbodiimide (69 mg) was added, the mixture was stirred at room temperature for 2 hours, and the reaction solution was filtered. After the filtrate was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (ethyl acetate)
Was purified. The purified product was dissolved in 4N hydrochloric acid / ethyl acetate (2 ml), stirred at room temperature for 30 minutes, and the solvent was removed under reduced pressure to give the title compound as a colorless solid (85 mg). MS m / z: 358 (MH +).

Example 15 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzamide dihydrochloride 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) of Reference Example 5 Amino] ethyl} carbamic acid tert-
Benzoyl chloride (38 mg) was added to a solution of butyl (100 mg) and triethylamine (30 mg) in tetrahydrofuran (4 ml), and the mixture was stirred at room temperature for 18 hours. ARGONAUT TECHN
OLOGIES Trisamine resin (80 mg) was added, the mixture was stirred at room temperature for 1 hour, and then filtered. After removing the solvent by blowing nitrogen to the filtrate, the residue was diluted with dichloromethane (1 ml) -1% citric acid.
(1 ml), and the organic layer was separated using a Whatman Filter Tube. After the solvent was removed by blowing nitrogen, the residue was dissolved in 4N hydrogen chloride / ethyl acetate (1 ml) and stirred at room temperature for 1 hour. The reaction solution was blown with nitrogen to remove the solvent, and the title compound was obtained as a colorless solid (70 mg). MS m / z: 318 (MH +).

Example 16 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) cyclohexanecarboxamide dihydrochloride cyclohexanecarbonyl chloride (40 mg), the title compound was obtained in the same manner as in Example 15. Synthesized. MS m / z: 324 (MH +).

Example 17 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzenesulfonamide dihydrochloride 4-aminobutyl {2-[(tert-butoxycarbonyl) ( Cyclohexyl) amino] ethyl} carbamic acid tert-
Butylsulfonyl chloride (23mg) in dichloromethane solution (2ml) of butyl (50mg) and triethylamine (18mg)
Was added and stirred at room temperature for 5 hours. ARGONAUT TECHNO
LOGIES Trisamine resin (about 40 mg) was added, and the mixture was stirred at room temperature for 1 hour. Then, 1% citric acid (2 ml) was added, and the mixture was stirred for 30 minutes. The organic layer was separated with a Whatman Filter Tube, the solvent was blown off with nitrogen, and the residue was dissolved in 4N hydrogen chloride / ethyl acetate (1 ml) and stirred at room temperature for 1 hour. The reaction solution was blown with nitrogen to remove the solvent, and the title compound was obtained as a colorless solid (38 mg). MS m / z: 354 (MH +).

Example 18 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4-methylbenzenesulfonamide dihydrochloride Example 17 was prepared using 4-methylbenzenesulfonyl chloride (24 mg). The title compound was synthesized in the same manner as described above. MS m / z: 368 (MH +).

Example 19 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4-fluorobenzenesulfonamide dihydrochloride Example 17 was prepared using 4-fluorobenzenesulfonyl chloride (25 mg). The title compound was synthesized in the same manner as described above. MS m / z: 372 (MH +).

Example 20 Using 4-chloro-N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzenesulfonamide dihydrochloride 4-chlorobenzenesulfonyl chloride (27 mg), the procedure of Example 17 was repeated. The title compound was synthesized in a similar manner. MS m / z: 388 (MH +).

Example 21 Example 17 was performed using 4-bromo-N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzenesulfonamide dihydrochloride 4-bromobenzenesulfonyl chloride (33 mg). The title compound was synthesized in the same manner as described above. MS m / z: 433 (MH +).

Example 22 Example 17 was repeated using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4-methoxybenzenesulfonamide dihydrochloride 4-methoxybenzenesulfonyl chloride (26 mg). The title compound was synthesized in the same manner as described above. MS m / z: 384 (MH +).

Example 23 N- (4-{[(4-{[2- (cyclohexylamino) ethyl] amino}
Butyl) amino] sulfonyl} phenyl) acetamide dihydrochloride 4-acetylaminobenzenesulfonyl chloride (30mg)
Was used to synthesize the title compound in the same manner as in Example 17. MS m / z: 411 (MH +).

Example 24 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4- (trifluoromethoxy) benzenesulfonamide dihydrochloride 4-trifluoromethoxybenzenesulfonyl chloride
(27 mg) and the title compound was synthesized in the same manner as in Example 17. MS m / z: 438 (MH +).

Example 25 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2,3,4,5,6-pentafluorobenzenesulfonamide dihydrochloride pentafluorobenzenesulfonyl chloride ( 34 mg) to give the title compound in the same manner as in Example 17. MS m / z: 444 (MH +).

Example 26 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) (phenyl) methanesulfonamide dihydrochloride Phenylmethanesulfonyl chloride (24 mg) was used in the same manner as in Example 17. The title compound was synthesized by the method. MS m / z: 368 (MH +).

Example 27 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1-benzofuran-4-sulfonamide dihydrochloride 1-benzofuran-4-sulfonyl chloride (28 mg) The title compound was synthesized in the same manner as in Example 17. MS m / z: 394 (MH +).

Example 28 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-thiophene sulfonamide dihydrochloride thiophen-2-sulfonyl chloride (23 mg), the procedure of Example 17 was repeated. The title compound was synthesized in a similar manner. MS m / z: 360 (MH +).

Example 29 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -8-quinoline sulfonamide dihydrochloride quinoline-8-sulfonyl chloride (38 mg), the procedure of Example 17 was repeated. The title compound was synthesized in a similar manner. MS m / z: 405 (MH +).

Example 30 3- (acetylamino) -N- (4-{[2- (cyclohexylamino)
[Ethyl] amino} butyl) benzamide dihydrochloride The title compound was synthesized in the same manner as in Example 7 using 3-acetylaminobenzoic acid (30 mg). MS m / z: 375 (MH +).

Example 31 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4-cinnolinecarboxamide dihydrochloride cinnoline-4-carboxylic acid (29 mg), the procedure of Example 7 was repeated. The title compound was synthesized in a similar manner. MS m / z: 370 (MH +).

Example 32 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -1,2,3,4-tetrahydro-2-naphthalenecarboxamide dihydrochloride 1,2,3,4 -Tetrahydronaphthalene-2-carboxylic acid (29mg)
Was used to synthesize the title compound in the same manner as in Example 7. MS m / z: 372 (MH +).

Example 33 As in Example 7, N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2- (2-naphthyl) acetamide dihydrochloride naphthyl acetic acid (31 mg) was used. The title compound was synthesized by the method described above. MS m / z: 382 (MH +).

Example 34 As in Example 15 except that N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-pyridinecarboxamide dihydrochloride pyridine-2-carbonyl chloride (29 mg) was used. The title compound was synthesized by the method described above. MS m / z: 319 (MH +).

Example 35 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) nicotinamide dihydrochloride nicotinoyl chloride (29 mg), the title compound was obtained in the same manner as in Example 15. Synthesized. MS m / z: 319 (MH +).

Example 36 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) isonicotinamide dihydrochloride isonicotinoyl chloride (29 mg), the title was obtained in the same manner as in Example 15. Compounds were synthesized. MS m / z: 319 (MH +).

Example 37 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-[(4-methylphenyl) sulfanyl] nicotinamide dihydrochloride 2-[(4-methylphenyl ) Sulfanyl] nicotinoyl chloride (44 mg) was used to synthesize the title compound in the same manner as in Example 15. MS m / z: 441 (MH +).

Example 38 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1-adamantanecarboxamide dihydrochloride adamantane-1-carbonyl chloride (33 mg),
The title compound was synthesized in the same manner as in Example 15. MS m / z: 376 (MH +).

Example 39 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -9,10-dioxo-9,10-dihydro-2-anthracenecarboxamide dihydrochloride 9,10-dioxo The title compound was synthesized in the same manner as in Example 15 using -9,10-dihydro-2-anthracenecarbonyl chloride (45 mg). MS m / z: 448 (MH +).

Example 40 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3,4,5-trimethoxybenzamide dihydrochloride 3,4,5-trimethoxybenzoyl chloride (38 mg ) Was synthesized in the same manner as in Example 15. MS m / z: 408 (MH +).

Example 41 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2,3,4,5,6-pentafluorobenzamide dihydrochloride pentafluorobenzoyl chloride (38 mg) was obtained. And the title compound was synthesized in the same manner as in Example 15. MS m / z: 408 (MH +).

Example 42 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4-methoxybenzamide dihydrochloride As in Example 15, using 4-methoxynbenzoyl chloride (28 mg). The title compound was synthesized by the method described above. MS m / z: 348 (MH +).

Example 43 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1-naphthamide dihydrochloride Naphthalene-1-carbonyl chloride (31 mg) was used in the same manner as in Example 15. The title compound was synthesized by the method. MS m / z: 368 (MH +).

Example 44 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -9-oxo-9H-fluorene-4-carboxamide dihydrochloride 9-oxo-9H-fluoren-4- Carbonyl chloride (40mg)
Was used to synthesize the title compound in the same manner as in Example 15. MS m / z: 420 (MH +).

Example 45 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4-fluorobenzamide dihydrochloride Example 4 was prepared using 4-fluorobenzoyl chloride (26 mg).
The title compound was synthesized in the same manner as in 15. MS m / z: 336 (MH +).

Example 46 Example 15 was carried out using 4-chloro-N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzamide dihydrochloride 4-chlorobenzoyl chloride (29 mg).
The title compound was synthesized in the same manner as described above. MS m / z: 352 (MH +).

Example 47 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1H-indole-2-carboxamide diformate indole-2-carboxylic acid (202 mg) Tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate (500 mg), 1
To a solution of -hydroxybenzotriazole (169 mg) in acetonitrile (5 ml) was added N, N'-dicyclohexylcarbodiimide (257 mg), the mixture was stirred at room temperature for 3 hours, and the reaction solution was filtered. After the filtrate was concentrated under reduced pressure, the residue was concentrated in ethyl acetate.
The mixture was extracted with water, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give a colorless syrup (482 mg). Dissolve this colorless syrup (140mg) in formic acid (5ml)
After stirring for 18 hours, the mixture was concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound (85 mg) as a colorless solid
I got MS m / z: 357 (MH +).

Example 48 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1H-indole-3-carboxamide diformate indole-3-carboxylic acid (83 mg); Tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate (150 mg), 1
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (99 mg) was added to a solution of 5-hydroxybenzotriazole (69 mg) in dimethylformamide (5 ml), and the mixture was stirred at room temperature for 18 hours. . The residue was extracted with ethyl acetate-water, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 1: 1). The purified product was dissolved in formic acid (5 ml), stirred at room temperature for 18 hours, and concentrated under reduced pressure. The residue was lyophilized from water to give the title compound (100m
g) was obtained. MS m / z: 357 (MH +).

Example 49 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1H-indole-4-carboxamide diformate Indole-4-carboxylic acid (83 mg) was used. The title compound was synthesized in the same manner as in 48. MS m / z: 357 (MH +).

Example 50 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1H-indole-6-carboxamide diformate Using indole-6-carboxylic acid (83 mg), The title compound was synthesized in the same manner as in 48. MS m / z: 357 (MH +).

Example 51 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-phenoxynicotinamide dihydrochloride 2-phenoxynicotinoyl chloride (38 mg), the procedure of Example 15 was repeated. The title compound was synthesized in a similar manner. MS m / z: 411 (MH +).

Example 52 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -5-methyl-3-isoxazolecarboxamide dihydrochloride 5-methyl-3-isoxazolecarbonyl chloride (24 m
g) was used to synthesize the title compound in the same manner as in Example 15. MS m / z: 323 (MH +).

Example 53 N-[(5-{[(4-{[2- (cyclohexylamino) ethyl] amino} butyl) amino] sulfonyl} -2-thienyl) methyl] benzamide dihydrochloride 5- (benzoyl) The title compound was synthesized in the same manner as in Example 17 using (aminomethyl) -thiophen-2-sulfonyl chloride (52 mg). MS m / z: 493 (MH +).

Example 54 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -5- (2-methyl-1,3-thiazol-4-yl) -2-thiophenesulfonamide The title compound was synthesized in the same manner as in Example 17 using hydrochloride 5- (2-methyl-1,3-thiazol-4-yl) -thiophen-2-sulfonyl chloride (46 mg). MS m / z: 457 (MH +).

Example 55 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -5- [5- (trifluoromethyl) -3-isoxazole]-
Example 1 using 2-thiophene sulfonamide dihydrochloride 5- [5- (trifluoromethyl) -3-isoxazole] -thiophen-2-sulfonyl chloride (52 mg)
The title compound was synthesized in the same manner as in 7. MS m / z: 495 (MH +).

Example 56 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -5- [1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl]- 2-thiophene sulfonamide dihydrochloride 5- [1-methyl-3- (trifluoromethyl) -1H-pyrazole-5
The title compound was synthesized in the same manner as in Example 17 using -yl] -thiophen-2-sulfonyl chloride (54 mg). MS m / z: 508 (MH +).

Example 57 Example 15 was performed using 3-chloro-N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzamide dihydrochloride 3-chlorobenzoyl chloride (29 mg).
The title compound was synthesized in the same manner as described above. MS m / z: 352 (MH +).

Example 58 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -5- [1-methyl-5- (trifluoromethyl) -1H-pyrazol-3-yl]- 2-thiophene sulfonamide dihydrochloride 5- [1-methyl-5- (trifluoromethyl) -1H-pyrazole-3
The title compound was synthesized in the same manner as in Example 17 using -yl] -thiophen-2-sulfonyl chloride (54 mg). MS m / z: 508 (MH +).

Example 59 4-Chloro-N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5- The title compound was synthesized in the same manner as in Example 15 using carboxamide dihydrochloride 1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbonyl chloride (40 mg). MS m / z: 421 (MH +).

Example 60 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3- (2,6-dichlorophenyl) -4-isoxazolecarboxamide dihydrochloride 3- (2,6 The title compound was synthesized in the same manner as in Example 15 using (-dichlorophenyl) -isoxazole-4-carbonyl chloride (48 mg). MS m / z: 454 (MH +).

Example 61 Example 15 was performed using 2-chloro-N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzamide dihydrochloride 2-chlorobenzoyl chloride (29 mg).
The title compound was synthesized in the same manner as described above. MS m / z: 352 (MH +).

Example 62 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-methoxybenzamide dihydrochloride Example 2 was prepared using 2-methoxybenzoyl chloride (28 mg).
The title compound was synthesized in the same manner as in 15. MS m / z: 348 (MH +).

Example 63 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -6-hydroxy-2-naphthamide dihydrochloride 6-hydroxynaphthalene-2-carboxylic acid (31 mg), reference An example
Tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate of 5
(50 mg) and 1-hydroxybenzotriazole (24 mg) in dichloromethane solution (2 ml) were added with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (35 mg) and added at room temperature.
Stirred for hours. Add ARGONAUT TECHNOLOGIES Tri
After adding samine resin (about 40mg) and stirring at room temperature for 1 hour,
1% citric acid (2 ml) was added and stirred for 30 minutes. Wha organic layer
Separation was performed with a Filter Tube manufactured by tman, and the mixture was stirred with a saturated aqueous sodium hydrogen carbonate solution for about 30 minutes, and then separated again with the Filter Tube. After removing the solvent by blowing nitrogen, the residue was washed with 4N hydrogen chloride / ethyl acetate.
(1 ml) and stirred at room temperature for 1 hour. The reaction solution was blown with nitrogen to remove the solvent, and the title compound was converted to a colorless solid (31
mg). MS m / z: 384 (MH +).

Example 64 Using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -6-methoxy-1-naphthamide dihydrochloride 6-methoxynaphthalene-1-carboxylic acid (33 mg) ,
The title compound was synthesized in the same manner as in Example 63. MS m / z: 398 (MH +).

Example 65 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4-fluoro-1-naphthamide dihydrochloride Using 4-fluoronaphthalene-1-carboxylic acid (31 mg). ,
The title compound was synthesized in the same manner as in Example 63. MS m / z: 386 (MH +).

Example 66 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -6-fluoro-1-benzothiophene-2-carboxamide dihydrochloride 6-fluorobenzothiazole-2-carboxylic acid The title compound was synthesized in the same manner as in Example 63 using acid (32 mg). MS m / z: 392 (MH +).

Example 67 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -5-methoxy-1-benzothiophene-2-carboxamide dihydrochloride 5-methoxybenzothiazole-2-carboxylic acid The title compound was synthesized in the same manner as in Example 63 using acid (34 mg). MS m / z: 404 (MH +).

Example 68 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -7-fluoro-1-benzothiophene-2-carboxamide dihydrochloride 7-fluorobenzothiazole-2-carboxylic acid The title compound was synthesized in the same manner as in Example 63 using acid (32 mg). MS m / z: 392 (MH +).

Example 69 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -5-methyl-1- (3-methylbenzyl) -1H-pyrazole-3-
The title compound was synthesized in the same manner as in Example 63 using carboxamide dihydrochloride 5-methyl-1- (3-methylbenzyl) -1H-pyrazole-3-carboxylic acid (38 mg). MS m / z: 426 (MH +).

Example 70 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -5-methoxy-1-phenyl-1H-pyrazole-3-carboxamide dihydrochloride 5-methoxy-1- Phenyl-1H-pyrazole-3-carboxylic acid
(36 mg) and the title compound was synthesized in the same manner as in Example 63. MS m / z: 414 (MH +).

Example 71 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3-methoxy-5-isoxazolecarboxamide dihydrochloride 3-methoxyisoxazole-5-carboxylic acid (24 mg ) Was synthesized in the same manner as in Example 63. MS m / z: 339 (MH +).

Example 72 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -4-fluoro-1-benzothiophene-2-carboxamide dihydrochloride 4-fluorobenzothiazole-2-carboxylic acid The title compound was synthesized in the same manner as in Example 63 using acid (32 mg). MS m / z: 392 (MH +).

Example 73 2- (1H-benzimidazol-2-ylsulfanyl) -N- (4-
{[2- (cyclohexylamino) ethyl] amino} butyl) acetamide trihydrochloride (1H-benzothiazol-2-ylsulfanyl) acetic acid (34m
g), tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate
(50 mg) and 1-hydroxybenzotriazole (24 mg) in dichloromethane (2 ml) were added with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (35 mg) and added at room temperature.
Stirred for hours. ARGONAUT TECHNOLOGIES 'Tri
Add samine resin (about 40 mg) and stir at room temperature for 1 hour.
% Citric acid (2 ml) was added and stirred for 30 minutes. What is the organic layer
Separation was performed using a Filter Tube manufactured by man, and the mixture was stirred with a saturated aqueous solution of sodium bicarbonate for about 30 minutes, and then separated again using the Filter Tube. After removing the solvent by blowing nitrogen, the residue was subjected to silica gel column chromatography (ethyl acetate) using a Flashtube manufactured by Biolinks. Purify the product with 4N hydrogen chloride / ethyl acetate
l) and stirred for 1 hour, then nitrogen was blown off to remove the solvent to give the title compound as a colorless solid (10 mg). MS m / z: 404 (MH +).

Example 74 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -2- (4-pyridinylsulfanyl) acetamide trihydrochloride 4-pyridinylsulfanylacetic acid (28 mg) Example using
The title compound was synthesized in the same manner as in 73. MS m / z: 365 (MH +).

Example 75 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2- {4-methoxy-1- [4- (trifluoromethyl) phenyl] -1H-pyrazolo- 3-yl} acetamide dihydrochloride 4-methoxy-1- [4- (trifluoromethyl) phenyl] -1H-
The title compound was synthesized in the same manner as in Example 63 using pyrazolo-3-ylacetic acid (50 mg). MS m / z: 496 (MH +).

Example 76 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -4-methyl-1,2,3-thiadiazole-5-carboxamide dihydrochloride 4-methyl-1, 2,3-thiadiazole-5-carboxylic acid (24mg)
Was used to synthesize the title compound in the same manner as in Example 63. MS m / z: 340 (MH +).

Example 77 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-phenyl-1,3-thiazole-4-carboxamide dihydrochloride 2-phenyl-1,3- The title compound was synthesized in the same manner as in Example 63 using thiazole-4-carboxylic acid (34 mg). MS m / z: 401 (MH +).

Example 78 2- (benzylsulfanyl) -N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1H-benzimidazole
-5-Carboxamide trihydrochloride The title compound was synthesized in the same manner as in Example 73 using 2-benzylsulfanylbenzimidazole-5-carboxylic acid (47 mg). MS m / z: 480 (MH +).

Example 79 Using 3- (aminomethyl) -N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzamide trihydrochloride 3-tert-butoxycarbonylaminobenzoic acid (41 mg) The title compound was synthesized in the same manner as in Example 63. MS m / z: 347 (MH +).

Example 80 2- (6-chloroimidazo [1,2-b] pyridazin-2-yl) -N- (4-
{[2- (cyclohexylamino) ethyl] amino} butyl) acetamide dihydrochloride 6-chloroimidazo [1,2-b] pyridazin-2-ylacetic acid (35m
g) was used to synthesize the title compound in the same manner as in Example 63. MS m / z: 407 (MH +).

Example 81 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2- (4-pyridinyl) -1,3-thiazole-4-carboxamide trihydrochloride 2- (4 -Pyridinyl) -1,3-thiazole-4-carboxylic acid (34m
g) was used to synthesize the title compound in the same manner as in Example 73. MS m / z: 402 (MH +).

Example 82 (E) -N- (4-{[2- (cyclohexylamino) ethyl] amino}
(Butyl) -3- [5- (4-methylphenyl) -2-thienyl] -2-propenamide dihydrochloride (E) -3- [5- (4-methylphenyl) -2-thienyl] -2- The title compound was synthesized in the same manner as in Example 63 using propenoic acid (40 mg). MS m / z: 440 (MH +).

Example 83 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) imidazo [1,2-a] pyridine-5-carboxamide dihydrochloride imidazo [1,2-a] pyridine The title compound was synthesized in the same manner as in Example 63 using -5-carboxylic acid (27 mg). MS m / z: 358 (MH +).

Example 84 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) imidazo [1,2-a] pyridine-2-carboxamide dihydrochloride imidazo [1,2-a] pyridine- The title compound was synthesized in the same manner as in Example 63 using 2-carboxylic acid (27 mg). MS m / z: 358 (MH +).

Example 85 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) imidazo [1,2-a] pyridine-6-carboxamide dihydrochloride imidazo [1,2-a] pyridine The title compound was synthesized in the same manner as in Example 63 using -6-carboxylic acid (27 mg). MS m / z: 358 (MH +).

Example 86 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -5-fluoro-1-benzothiophen-2-carboxamide dihydrochloride 5-fluorobenzothiophen-2-carboxylic acid The title compound was synthesized in the same manner as in Example 63 using acid (32 mg). MS m / z: 392 (MH +).

Example 87 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) imidazo [2,1-b] [1,3] thiazole-3-carboxamide dihydrochloride imidazo [2, 1-b] [1,3] thiazole-3-carboxylic acid (28mg)
Was used to synthesize the title compound in the same manner as in Example 63. MS m / z: 364 (MH +).

Example 88 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -1H-1,2,3-benzotriazole-5-carboxamide dihydrochloride 1,2,3-benzoic acid The title compound was synthesized in the same manner as in Example 73 using triazole-5-carboxylic acid (27 mg). MS m / z: 359 (MH +).

Example 89 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3- (1H-indol-3-yl) propanamide dihydrochloride 3- (indol-3-yl ) The title compound was synthesized in the same manner as in Example 63 using propanoic acid (31 mg). MS m / z: 385 (MH +).

Example 90 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3-phenoxybenzamide dihydrochloride The same as in Example 63 except that 3-phenoxybenzoic acid (35 mg) was used. The title compound was synthesized by the method. MS m / z: 410 (MH +).

Example 91 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3-methoxybenzamide dihydrochloride The same as in Example 63 except that 3-methoxybenzoic acid (25 mg) was used. The title compound was synthesized by the method. MS m / z: 348 (MH +).

Example 92 2- (2H-1,2,3-benzotriazol-2-yl) -N- (4-{[2-
The title compound was synthesized in the same manner as in Example 73, using (cyclohexylamino) ethyl] amino} butyl) acetamide trihydrochloride 1,2,3-benzotriazol-2-ylacetic acid (29 mg). MS m / z: 373 (MH +).

Example 93 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3- (1H-indazol-1-yl) propanamide dihydrochloride 3- (1H-indazole-1 The title compound was synthesized in the same manner as in Example 63 using (-yl) propanoic acid (31 mg). MS m / z: 386 (MH +).

Example 94 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole
-3-carboxamide dihydrochloride 5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-
The title compound was synthesized in the same manner as in Example 63 using carboxylic acid (34 mg). MS m / z: 400 (MH +).

Example 95 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3-methyl-1-benzofuran-2-carboxamide dihydrochloride 3-methyl-1-benzofuran-2- The title compound was synthesized in the same manner as in Example 63 using carboxylic acid (29 mg). MS m / z: 372 (MH +).

Example 96 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1- (3-fluorobenzyl) -5-methyl-1H-pyrazole-
The title compound was synthesized in the same manner as in Example 63, using 3-carboxamide dihydrochloride 1- (3-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxylic acid (38 mg). MS m / z: 430 (MH +).

Example 97 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3- (1H-tetrazol-1-yl) benzamide dihydrochloride 3- (1H-tetrazole-1- Yl) benzoic acid (31mg)
The title compound was synthesized in the same manner as in Example 73. MS m / z: 386 (MH +).

Example 98 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -4- (dimethylamino) -1-naphthamide trihydrochloride 4- (dimethylamino) naphthalene-1-carboxylic acid Acid (36mg)
Was used to synthesize the title compound in the same manner as in Example 73. MS m / z: 411 (MH +).

Example 99 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1-benzofuran-2-carboxamide dihydrochloride Example 27 was prepared using benzofuran-2-carboxylic acid (27 mg). 63
The title compound was synthesized in the same manner as described above. MS m / z: 358 (MH +).

Example 100 3- (Aminosulfonyl) -4-chloro-N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzamide dihydrochloride 3- (aminosulfonyl) -4-chloro The title compound was synthesized in the same manner as in Example 63 using benzoic acid (39 mg). MS m / z: 431 (MH +).

Example 101 Using 4- (aminosulfonyl) -N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) benzamide dihydrochloride 4-aminosulfonylbenzoic acid (33 mg) 63
The title compound was synthesized in the same manner as described above. MS m / z: 397 (MH +).

Example 102 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-phenoxybenzamide dihydrochloride The same as in Example 63 except that 2-phenoxybenzoic acid (35 mg) was used. The title compound was synthesized by the method. MS m / z: 410 (MH +).

Example 103 (E) -N- (4-{[2- (cyclohexylamino) ethyl] amino}
The title compound was synthesized in the same manner as in Example 63 using butyl) -3- (4-hydroxyphenyl) -2-propenamide dihydrochloride 4-hydroxycinnamic acid (27 mg). MS m / z: 360 (MH +).

Example 104 (E) -N- (4-{[2- (cyclohexylamino) ethyl] amino}
(Butyl) -3- (1H-imidazol-4-yl) -2-propenamide trihydrochloride (E) -3- (imidazol-4-yl) -2-propenoic acid (95 mg),
Reference Example 5 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamic acid tert-
Butyl (200mg) and 1-hydroxybenzotriazole (93m
g) in dimethylformamide solution (5 ml).
(3-Dimethylaminopropyl) carbodiimide hydrochloride (131
mg) and stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water, and the organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was stirred in 4N hydrogen chloride / ethyl acetate (5 ml) for 1 hour, and the precipitated solid was collected by filtration to give the title compound as a colorless solid (79 mg). As obtained. MS m / z: 334 (MH +).

Example 105 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3- (propionylamino) benzamide dihydrochloride 4-[(3-aminobenzoyl) amino of Reference Example 7 ] Butyl {2-
[(tert-butoxycarbonyl) (cyclohexyl) amino]
To a dichloromethane solution (2 ml) of tert-butyl ethyl} carbamate (50 mg) and triethylamine (19 mg) was added propanoyl chloride (13 ml), and the mixture was stirred at room temperature for 1 hour.
g) and stirred at room temperature for 1 hour, then 1% citric acid (2 ml)
Was added and stirred for 30 minutes. Filter the organic layer with Whatman Filter Tu
After stirring with saturated aqueous sodium bicarbonate for about 30 minutes,
Separated by lter Tube. After the solvent was removed by blowing nitrogen, the residue was dissolved in 4N hydrogen chloride / ethyl acetate (2 ml) and stirred for 1 hour. Then, the solvent was removed by blowing nitrogen to obtain the title compound as a colorless solid (25 mg). MS m / z: 389 (MH +).

Example 106 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -N-methyl-1H-indole-5-carboxamide diformate Reference example 9 4- (methylamino) Tert-butyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate (140 mg), indole-5-carboxylic acid (5
5 mg) and 1-hydroxybenzotriazole (63 mg) in acetonitrile (5 ml) were added with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (89 mg), and the mixture was stirred at room temperature for 24 hours. After the reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water, and the organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 1: 1), and the purified product was treated with formic acid (5
ml) for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was lyophilized from water to give the title compound as a pale yellow solid (80 mg)
As obtained. MS m / z: 371 (MH +).

Example 107 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -N-methyl-2-naphthamide dihydrochloride Reference Example 9 4- (methylamino) butyl {2- A dichloromethane solution (2 ml) of tert-butyl [(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate (70 mg), naphthalene-2-carbonyl chloride (47 mg) and triethylamine (33 mg) was stirred at room temperature for 1 hour. ARGONA in the reaction solution
Trisamine resin (about 100 mg) manufactured by UT TECHNOLOGIES was added, and the mixture was stirred at room temperature for 1 hour. Then, 1% citric acid (2 ml) was added and stirred for 30 minutes. The organic layer was separated with a Whatman Filter Tube, stirred with a saturated aqueous solution of sodium bicarbonate for about 30 minutes, and then filtered again.
Separated by e. After the solvent was removed by blowing nitrogen, the residue was dissolved in 4N hydrogen chloride / ethyl acetate (2 ml) and stirred for 1 hour. Then, the solvent was removed by blowing nitrogen to obtain the title compound as a colorless solid (38 mg). MS m / z: 382 (MH +).

Example 108 N ¹ , N ⁴ -Bis (4-{[2- (cyclohexylamino) ethyl] amino} butyl) terephthalamide tetrahydrochloride 4-ethoxycarbonylbenzoic acid (93 mg), Reference Example 5-4 Tert-butyl 2-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate (150 m
g), 1-hydroxybenzotriazole (69 mg) in acetonitrile solution (5 ml) was added with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (98 mg), and the mixture was added
Stirred for hours. After the reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water, and the organic layer was washed successively with a 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (10 ml) -1N sodium hydroxide (10 ml), stirred at room temperature for 2 hours, adjusted to pH = 3.0 with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dimethylformamide (5 ml), and tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate of Reference Example 5 (150 mg), 1-hydroxybenzotriazole ( 69 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (98 mg) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water, and the organic layer was washed successively with a 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 2), and the purified product was purified.
The mixture was stirred in 4N hydrochloric acid / ethyl acetate (5 ml) for 1 hour. The precipitate was collected by filtration to give the title compound as a colorless solid (57 mg). MS m / z: 557 (MH +).

Example 109 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -4-hydroxybenzamide dihydrochloride The same as in Example 63 except that 4-hydroxybenzoic acid (19 mg) was used. The title compound was synthesized by the method. MS m / z: 334 (MH +).

Example 110 Example 1 was repeated using N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3,4-dihydroxybenzamide dihydrochloride 3,4-dihydroxybenzoic acid (21 mg). The title compound was synthesized in the same manner as in 63. MS m / z: 350 (MH +).

Example 111 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2,4-dihydroxybenzamide dihydrochloride Example using 2,4-dihydroxybenzoic acid (21 mg) The title compound was synthesized in the same manner as in 63. MS m / z: 350 (MH +).

Example 112 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2,5-dihydroxybenzamide dihydrochloride Example 2 was prepared using 2,5-dihydroxybenzoic acid (21 mg). The title compound was synthesized in the same manner as in 63. MS m / z: 350 (MH +).

Example 113 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -3,4,5-trihydroxybenzamide dihydrochloride 3,4,5-trihydroxybenzoic acid (26 mg )
The title compound was synthesized in the same manner as in 63. MS m / z: 366 (MH +).

Example 114 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -3-hydroxybenzamide dihydrochloride Using 3-hydroxybenzoic acid (19 mg), the same procedures as in Example 63 were carried out. The title compound was synthesized by the method. MS m / z: 334 (MH +).

Example 115 (E) -N- (4-{[2- (cyclohexylamino) ethyl] amino}
(Butyl) -3- (1-methyl-1H-imidazol-4-yl) -2-propenamide trihydrochloride (E) -3- (1-methylimidazol-4-yl) -2-propenoic acid
Hydrochloride (65 mg), 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} tert-butylcarbamate of Reference Example 5 (150 mg), 1-hydroxybenzotriazole (70 mg) and ethyl Isopropylamine (4
4 mg) in dimethylformamide solution (5 ml) was added to 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride (99m
g) was added and the mixture was stirred at room temperature for 18 hours. After the reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water, and the organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and the purified product was
After stirring for 1 hour in hydrogen chloride / ethyl acetate (5 ml), the precipitated solid was collected by filtration to give the title compound as a colorless solid. MS m / z: 348 (MH +).

Example 116 3-Benzoyl-N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -N-methyl-2,3,4,5-tetrahydro-1H
-3-Benzazepine-7-sulfonamide dihydrochloride 2,2-diethoxyethylamine (4.00 g), cyclohexanone (2.94 g), acetic acid (1.72 ml) in tetrahydrofuran (70 m
l) In solution, add sodium triacetoxyborohydride (7.6
3 g) was added and the mixture was stirred at room temperature for 1 hour. 10% aqueous sodium carbonate (100 ml) and carbobenzoxy chloride (5.12 g) were added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. Extract with ethyl acetate,
The extract was washed with saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 4: 1) to obtain colorless oily benzyl cyclohexyl (2,2-diethoxyethyl) carbamate (10.4 g). Benzocyclohexyl (2,2-diethoxyethyl) carbamate (227 mg) in acetone (4 ml)
1N Hydrochloric acid (2 ml) was added to the solution, and the mixture was stirred at 60 ° C. for 30 minutes.
Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and concentrated. The obtained oil was N- (4-aminobutyl) -3-benzoyl-N-methyl-2,3,3 obtained in Reference Example 13.
It was added to a mixture of 4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride (271 mg), sodium acetate (49 mg), tetrahydrofuran (5 ml), and methanol (1 ml). After stirring for 30 minutes, sodium triacetoxyborohydride (230 mg) was added, and the mixture was most stirred at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 2 → 0: 1 →
Purification with ethyl acetate: ethanol = 95: 5) gave 2-({4-[[(3-benzoyl-2,3,4,5-tetrahydrol) as a pale yellow oil.
There was obtained benzyl (-1H-3-benzazepin-7-yl) sulfonyl] (methyl) amino] butyl} amino) ethyl (cyclohexyl) carbamate (242 mg). This pale yellow oil (220 m
g) in ethanol (5 ml) and 10% palladium on carbon
(40 mg) was added and the mixture was vigorously stirred for 2 hours under a hydrogen stream. After removing the catalyst, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography (hexane: ethyl acetate = 1: 2 → 0: 1 → ethyl acetate: ethanol = 90: 10). Purified. Ethanol and 4N hydrochloric acid / ethyl acetate were added to the obtained oil, and the mixture was concentrated under reduced pressure to obtain a colorless amorphous title compound (154 mg). MS m / z: 541 (MH ⁺ ).

Example 117 3-Benzoyl-N- (4-{[2- (cycloheptylamino) ethyl] amino} butyl) -N-methyl-2,3,4,5-tetrahydro-1H
-3-Benzazepine-7-sulfonamide dihydrochloride In the same manner as in Example 116, using cycloheptanone instead of cyclohexanone, the title compound was obtained as colorless crystals. MS m / z: 555 (MH ⁺ ).

Example 118 3-Benzoyl-N- [4-({2- [cycloheptyl (methyl) amino] ethyl} amino) butyl] -N-methyl-2,3,4,5-tetrahydro-1H- 3-Benzazepine-7-sulfonamide dihydrochloride N- (4-chlorobutyl) -N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3 obtained in Reference Example 12 A mixture of -benzazepine-7-sulfonamide (3.46 g), 10% aqueous sodium carbonate (20 ml), and methanol (100 ml) was stirred at room temperature for 3 hours. The methanol was distilled off under reduced pressure, and ethyl acetate (5
0 ml) and benzoyl chloride (1.16 ml) were added, and the mixture was stirred at room temperature for 1 hour. After liquid separation, the ethyl acetate layer was washed with saturated saline, dried and concentrated. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 0: 1)
And colorless syrup-like 3-benzoyl-N- (4-chlorobutyl) -N-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide (2.99 g) Obtained. This colorless syrup-like substance (217 mg), N ¹ -cycloheptyl-N ¹ -methyl-1,2-ethylenediamine obtained in Reference Example 15 (511 m
g), potassium carbonate (138 mg), potassium iodide (83 mg),
Acetonitrile (8 ml), N, N-dimethylformamide (2 m
The mixture of l) was stirred at 70 ° C. for 2 days. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline,
After drying, it was concentrated. The residue was subjected to basic silica gel column chromatography (hexane: ethyl acetate = 1: 2 → 0: 1).
→ ethyl acetate: methanol = 9: 1), basic alumina column chromatography (ethyl acetate: methanol =
1: 0 → 9: 1), and ethanol and 4N hydrochloric acid / ethyl acetate were added to the obtained oil, followed by concentration under reduced pressure to obtain an amorphous title compound (222 mg). MS m / z: 569 (MH ⁺ ).

Example 119 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H- 3-Benzazepine-7-sulfonamide dihydrochloride N- (4-chlorobutyl) -N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3 obtained in Reference Example 12 -Benzazepine-7-sulfonamide (598 mg), N obtained in Reference Example 14
¹ -cyclohexyl-1,2-ethylenediamine dihydrochloride (452
mg), potassium carbonate (967 mg), potassium iodide (232 m
g), a mixture of acetonitrile (10 ml) and N, N-dimethylformamide (10 ml) was stirred at 80 ° C. for one day. After the reaction solution was filtered and concentrated under reduced pressure, ethyl acetate was added, washed with water and saturated saline, dried and concentrated. The residue was subjected to basic alumina column chromatography (ethyl acetate: methanol =
1: 0 → 4: 1). The resulting oil (362 m
To a portion (130 mg) of g), ethanol (2 ml) and 4N hydrochloric acid / ethyl acetate (8 ml) were added, and the mixture was concentrated under reduced pressure to obtain an amorphous title compound (126 mg). MS m / z: 533 (MH ⁺ ).

Example 120 N- (4-{[2- (cycloheptylamino) ethyl] amino} butyl) -N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H -3-Benzazepine-7-sulfonamide dihydrochloride Using N ¹ -cycloheptyl-1,2-ethylenediamine dihydrochloride of Reference Example 16, the title compound was obtained as colorless crystals in the same manner as in Example 119. . MS m / z: 547 (MH ⁺ ).

Example 121 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -N-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide Trihydrochloride N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro obtained in Example 119 Aqueous ammonia (1 ml) was added to a solution of -1H-3-benzazepine-7-sulfonamide (213 mg) in methanol (5 ml). After stirring at room temperature for 7 hours, the reaction solution was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (ethyl acetate: methanol = 1: 0 →
3: 1), ethanol and 4N were added to the obtained oil.
After adding hydrochloric acid / ethyl acetate, the mixture was concentrated under reduced pressure to give the title compound (155 mg) as colorless crystals. MS m / z: 437 (MH ⁺ ).

Example 122 N- (4-{[2- (Cycloheptylamino) ethyl] amino} butyl) -N-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfone Amide trihydrochloride In the same manner as in Example 121, N- (4-{[2-
(Cycloheptylamino) ethyl] amino} butyl) -N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1
The title compound was obtained as colorless crystals using H-3-benzazepine-7-sulfonamide. MS m / z: 451 (MH ⁺ ).

Example 123 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide trihydrochloride Reference 4-aminobutyl- {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamic acid t obtained in Example 5
ert-butyl (930 mg), 3- (trifluoroacetyl) -2,3,
4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride (342 mg), sodium bicarbonate (168 mg), ethyl acetate (12 m
l), a mixture of water (10 ml) was stirred at room temperature for 1 hour. After liquid separation, the ethyl acetate layer was washed with saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 2: 3), and amorphous 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl [4-({[3 -(2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7
There was obtained tert-butyl [-yl] sulfonyl} amino) butyl] carbamate (889 mg). 2-[(tert-butoxycarbonyl)
(Cyclohexyl) amino] ethyl [4-({[3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfonyl} amino) Aqueous ammonia (2 ml) was added to a solution of tert-butyl [butyl] carbamate (622 mg) in methanol (10 ml), and the mixture was stirred at room temperature for 4 hours, and then concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane: ethyl acetate = 1: 3 → 0:
1 → ethyl acetate: methanol = 85: 15) and purified by 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl {4-[(2,3,4,5-tetrahydro-1H-3- Benzazepin-7-ylsulfonyl) amino] butyl} carbamic acid
Tert-butyl (405 mg) was obtained. This 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl {4-[(2,3,4,5
To a mixture of tert-butyl-tetrahydro-1H-3-benzazepin-7-ylsulfonyl) amino] butyl} carbamate (187 mg) with ethanol (1 ml) and 4N hydrochloric acid / ethyl acetate (4 ml) was added at room temperature. Stirred overnight. The precipitated crystals were collected by filtration and washed with a small amount of ethanol to give the title compound as colorless crystals (173 m
g) was obtained. MS m / z: 423 (MH ⁺ ).

Example 124 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -3- (trifluoroacetyl) -2,3,4,5-tetrahydro-
1H-3-benzazepine-7-sulfonamide dihydrochloride 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl [4-({[3- (2,2,2-tri (Fluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine
-7-yl] sulfonyl} amino) butyl] carbamic acid tert-
After adding 4N hydrochloric acid / ethyl acetate (5 ml) to butyl (267 mg), the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give a free product, which was then subjected to basic silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 4:
Purified in 1). Ethanol, 4N to the obtained oil
After adding hydrochloric acid / ethyl acetate, the mixture was concentrated under reduced pressure to give the title compound (98 mg) as colorless crystals. MS m / z: 519 (MH ⁺ ).

Example 125 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -N-methyl-2-naphthalenesulfonamide dihydrochloride 4-aminobutyl- {obtained in Reference Example 5 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamic acid t
ert-butyl (207 mg), 2-naphthalenesulfonyl chloride
(136 mg), baking soda (84 mg), ethyl acetate (5 ml), water (2 ml)
Was stirred at room temperature for 1 hour. After liquid separation, the ethyl acetate layer was washed with saturated saline, dried and concentrated. Residue is N, N-
Dissolve in dimethylformamide (5 ml) and add methyl iodide
(0.049 ml) and potassium carbonate (138 mg) were added, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1), and colorless syrup-like 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl {4- [methyl ( Tert-Butyl 2-naphthylsulfonyl) amino] butyl} carbamate (304 mg) was obtained.
[(tert-butoxycarbonyl) (cyclohexyl) amino]
Ethyl {4- [methyl (2-naphthylsulfonyl) amino] butyl} tert-butylcarbamate (230 mg) was added to ethanol (2 m
l), 4N hydrochloric acid / ethyl acetate (8 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the title compound (159 mg) as colorless crystals. MS m / z: 418 (MH ⁺ ).

Example 126 N- (3-{[2- (Cyclohexylamino) ethyl] amino} propyl) -N-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide Trihydrochloride N-methyl-3- (trifluoroacetyl) -2, obtained in Reference Example 11
3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide (1.15 g), 1-bromo-3-chloropropane (787 m
g), potassium carbonate (912 mg), acetonitrile (8 ml), N,
A mixture of N-dimethylformamide (2 ml) was stirred at 70 ° C. overnight. Ethyl acetate was added to the reaction solution, washed with water and saturated saline, dried and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 1:
Purified in 1), colorless syrup-like N- (3-chloropropyl) -N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7- Sulfonamide (1.2
0 g) was obtained. N- (3-chloropropyl) -N-methyl-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide (1.15 g), N ¹ -cyclohexyl -1,2-ethylenediamine (593 mg), potassium carbonate (77
0 mg), potassium iodide (462 mg), acetonitrile (14 m
l), a mixture of N, N-dimethylformamide (7 ml) was stirred at 70 ° C for 1 day. After the reaction solution was filtered and concentrated under reduced pressure, ethyl acetate was added, washed with water and saturated saline, dried and concentrated. The residue was dissolved in methanol (10 ml), and aqueous ammonia (2 ml) was added. After stirring at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure. The residue was dissolved in an ethanol solution (10 ml), and triethylamine (0.70 ml) and di-tert-butyl dicarbonate (2.23 ml) were added. After stirring at room temperature for one day, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 2). An ethanol solution (1 ml) and 4N hydrochloric acid / ethyl acetate (4 ml) were added thereto, followed by stirring at room temperature for one day. The reaction solution was concentrated under reduced pressure to give a free product, which was purified by basic silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 4: 1). After adding ethanol and 4N hydrochloric acid / ethyl acetate to the obtained oil, the mixture was concentrated under reduced pressure to give the title compound as colorless crystals (95 mg). MS m / z: 423 (MH ⁺ ).

Example 127 N- (5-{[2- (cyclohexylamino) ethyl] amino} pentyl) -N-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide Trihydrochloride The title compound as pale pink crystals was obtained in the same manner as in Example 126, except that 1-bromo-5-chloropentane was used instead of 1-bromo-3-chloropropane. MS m / z: 451 (MH ⁺ ).

Example 128 N- (4-{[2- (Cyclooctylamino) ethyl] amino} butyl) -2-naphthalenesulfonamide dihydrochloride 1,2-ethylenediamine (3.61 g) and cyclooctanone (3.7
9 g) were mixed and stirred at room temperature overnight. Part of this (0.74 g)
Was dissolved in methanol (15 ml), sodium borohydride (223 mg) was added under ice cooling, and the mixture was stirred at room temperature. continue
5.18 g was reduced in a similar manner. After the reaction solution was concentrated under reduced pressure, 6N sodium hydroxide was added, and the mixture was extracted with ether. The extract was dried and concentrated under reduced pressure to obtain colorless oily N ¹ -cyclooctyl-1,2-ethylenediamine (3.07 g). 1- (2-Naphthylsulfonyl) -2-pyrrolidinol (139 mg) obtained in Reference Example 19, N ¹ -cyclooctyl-1,2-ethylenediamine (102 mg), acetic acid (0.069 ml) in tetrahydrofuran (10
ml) solution was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (212 mg) was added, and the mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was subjected to basic silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 9: 1) and basic alumina column chromatography (ethyl acetate: methanol =
1: 0 → 2: 1). After adding ethanol and 4N hydrochloric acid / ethyl acetate to the obtained oil, the mixture was concentrated under reduced pressure to obtain the amorphous title compound (125 mg). MS m / z: 432 (MH ⁺ ).

Example 129 N- [4-({2- [Cyclohexyl (methyl) amino] ethyl} amino) butyl] -2-naphthalenesulfonamide dihydrochloride 4-aminobutyl {2- [cyclohexyl) of Reference Example 17 (Methyl)
Amino] ethyl} tert-butylcarbamate (328 mg), 2-
A mixture of naphthalenesulfonyl chloride (249 mg), 10% aqueous sodium carbonate (5 ml) and ethyl acetate (10 ml) was added at room temperature to give a mixture.
Stirred for hours. After liquid separation, the ethyl acetate layer was washed with saturated saline, dried and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 3 → 0: 1).
→ Ethyl acetate: methanol = 7: 3), and purified in pale yellow syrup form 2- [cyclohexyl (methyl) amino] ethyl {4-[(2-naphthylsulfonyl) amino] butyl} tert-butylcarbamate ( 505 mg). Add ethanol (2
ml) and 4N hydrochloric acid / ethyl acetate (10 ml).
Stirred for hours. After the reaction solution was concentrated under reduced pressure, it was crystallized from ethanol to give the title compound (365 mg) as colorless crystals. MS m / z: 418 (MH ⁺ ).

Example 130 N- {4-[[2- (Cyclohexylamino) ethyl] (methyl) amino] butyl} -2--2-naphthalenesulfonamide dihydrochloride benzyl 4-aminobutylcarbamate (517 mg) , Reference example
2, cyclohexyl (2-oxoethyl) carbamic acid tert-
A solution of butyl (483 mg) and triethylamine (0.28 ml) in methanol (10 ml) was stirred at room temperature for 1 hour, and then sodium borohydride (151 mg) was added under ice-cooling. After stirring at room temperature for 2 hours, formalin (0.30 ml) was added. After stirring at room temperature for 1 hour, sodium borohydride (151 mg) was added under ice cooling, and the mixture was stirred for one day. Sodium borohydride (1
51 mg) and the mixture was further stirred for 3 hours. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added to make it once weakly acidic, and then 1N sodium hydroxide was added to make it basic again. The mixture was extracted with ethyl acetate, washed with saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1: 0 → 1: 1) to give a colorless syrup.
There was obtained benzyl 4-[{2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} (methyl) amino] butylcarbamate (649 mg). This was dissolved in ethanol (10 ml), and 10% palladium on carbon (150 mg) was added.
Stir vigorously for hours. After removing the catalyst, the solvent was distilled off under reduced pressure to give 2-[(4-aminobutyl) (methyl) amino] ethyl
There was obtained tert-butyl (cyclohexyl) carbamate (431 mg). In the same manner as in Example 129, 2-[(4-aminobutyl)
(Methyl) amino] ethyl (cyclohexyl) carbamic acid t
The title compound was obtained as colorless crystals using ert-butyl. MS m / z: 418 (MH ⁺ ).

Example 131 N- {4-[{2- [Cyclohexyl (methyl) amino] ethyl} (methyl) amino] butyl} -2-naphthalenesulfonamide dihydrochloride N- [4 A solution of-({2- [cyclohexyl (methyl) amino] ethyl} amino) butyl] -2-naphthalenesulfonamide dihydrochloride (196 mg), formalin (0.06 ml), and triethylamine (0.112 ml) in methanol (10 ml) After stirring at room temperature for 1 hour, sodium borohydride (30 mg) was added. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure. Add 10% aqueous sodium carbonate and extract with ethyl acetate.
The extract was washed with saturated saline, dried and concentrated. The residue was treated with hydrochloric acid to give the hydrochloride, thereby obtaining the title compound (167 mg) as colorless crystals. MS m / z: 432 (MH ⁺ ).

Example 132 N- (4-{[3-Cyclohexyl (amino) propyl] amino} butyl) -2-naphthalenesulfonamide dihydrochloride 1- (2-naphthylsulfonyl) -2 obtained in Reference Example 19 -Pyrrolidinol (139mg) and N-cyclohexylpropylenediamine
(0.102 ml) in THF (2 ml) was added sodium triacetoxyborohydride (159 mg) at room temperature, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by alumina column chromatography (methanol: ethyl acetate = 1: 10), and 4N hydrochloric acid in ethyl acetate and ether were added to give the title compound (70 mg) as colorless crystals. MS m / z 418 (MH ⁺ ).

Example 133 N- (4-{[2-Cycloheptyl (amino) ethyl] amino} butyl) -2-naphthalenesulfonamide dihydrochloride In the same manner as in Example 132, N-cycloheptylethylenediamine was used. The title compound was synthesized. MS m / z 418 (MH ⁺ ).

Example 134 N- (4-{[2-Cyclopentyl (amino) ethyl] amino} butyl) -2-naphthalenesulfonamide dihydrochloride The title compound was obtained in the same manner as in Example 132 using N-cyclopentylethylenediamine. Was synthesized. MS m / z 390 (MH ⁺ ).

Example 135 2-Naphthoic acid 4-{[2- (cyclohexylamino) ethyl] amino} butyl dihydrochloride 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl obtained in Reference Example 3 4-Hydroxybutyl) tert-butyl carbamate (0.050 g) and triethylamine (0.024 g) were dissolved in dichloromethane (3 ml), and the mixture was dissolved in ice under cooling with ice.
Naphthoyl chloride (0.21 g) was added, and the mixture was stirred at room temperature for 17 hours. A mixture obtained by adding PS-trisamine (0.015 g) to the reaction solution and stirring for 1 hour was purified by silica gel column chromatography (n-hexane: ethyl acetate = 7: 1) to obtain an oil. Dissolve this in 0.5 ml of ethyl acetate and add 1 ml of 4N
A hydrochloric acid / ethyl acetate solution was added, and the mixture was left at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to obtain the title compound (0.045 g). MS m / z: 369 (MH +).

[0236] Example 136 N ¹ - cyclohexyl -N ² - [4- (2- naphthyloxy) butyl] -
1,2-ethanediamine dihydrochloride tert-butyl 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl (4-hydroxybutyl) carbamate (0.050 g) obtained in Reference Example 3, and 2-naphthol (0.052 g) and triphenylphosphine (0.042 g) were dissolved in 1 ml of dichloromethane. To this mixture was added 31 μl of diisopropyl azodicarboxylate and stirred at room temperature for 30 minutes. 3 ml of ethyl acetate was added to the reaction solution, which was washed with 2 ml of 5% aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 7: 1) to obtain an oil. To this was added 1 ml of a 4N hydrochloric acid / ethyl acetate solution, and the mixture was allowed to stand at room temperature overnight. The precipitated solid was collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to obtain the title compound (0.014 g). MS m / z: 341 (MH +).

[0237] Example 137 N ¹ - cyclohexyl -N ² - [4- (2- naphthylsulfanyl) butyl] -1,2-ethanediamine dihydrochloride obtained in Reference Example 21 2 - [(tert- butoxycarbonyl) (Cyclohexyl) amino] ethyl [4- (2-naphthylsulfanyl)
Butyl] tert-butylcarbamate (0.050 g) in ethyl acetate
(2 ml), 1 ml of 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was allowed to stand at room temperature overnight. The precipitated solid was collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to give the title compound (0.035
g) was obtained. MS m / z: 355 (MH +).

[0238] Example 138 N ¹ - cyclohexyl -N ² - in the 5- (2-naphthyloxy) pentyl] -1,2-ethanediamine dihydrochloride Example 136 In the same manner as was obtained in Reference Example 20 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl (4-
(Hydroxypentyl) tert-butyl carbamate (0.050 g)
The title compound (0.015 g) was synthesized from and 2-naphthol (0.050 g). MS m / z: 355 (MH +).

[0239] Example 139 N ¹ - cyclohexyl -N ² - [4- (2- naphthylmethoxy) butyl] -1,2-ethanediamine dihydrochloride Reference Example 3 obtained in 2 - [(tert- butoxycarbonyl) Tert-butyl (cyclohexyl) amino] ethyl (4-hydroxybutyl) carbamate (0.050 g) and 2- (bromomethyl) naphthalene
(0.053 g) was dissolved in N, N-dimethylformamide (2 ml). A powder obtained by washing 60% sodium hydride (0.01 g) with n-hexane was added to the mixture, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added 5 ml of 5% aqueous sodium hydrogencarbonate solution, and the mixture was extracted three times with 2 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain an oil. To this was added 1 ml of a 4N hydrochloric acid / ethyl acetate solution, and the mixture was allowed to stand at room temperature overnight. The precipitated solid was collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to obtain the title compound (0.018 g). MS m / z: 355 (MH +).

[0240] Example 140 N ¹ - cyclohexyl -N ² - with [4- (2- naphthylsulfanyl) pentyl] -1,2-ethanediamine dihydrochloride Example 137 with the same method, obtained in Reference Example 22 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl [4-
(2-Naphthylsulfanyl) pentyl] carbamic acid tert-
The title compound (0.020 g) was synthesized from butyl (0.051 g). MS m / z: 371 (MH +).

[0241] Example 141 N ¹ - cyclohexyl -N ² - [5- (2- naphthylsulfinyl) pentyl] -1,2-ethanediamine dihydrochloride obtained in Reference Example 22 2 - [(tert- butoxycarbonyl) (Cyclohexyl) amino] ethyl [4- (2-naphthylsulfanyl)
Tert-Butyl [pentyl] carbamate (0.081 g) was dissolved in dichloromethane (5 ml), and m-chloroperbenzoic acid (0.038 g) was added thereto under ice-cooling, followed by stirring for 1 hour. 20 ml for the reaction solution
Was added, and the mixture was treated with 5 ml of a 5% aqueous sodium thiosulfate solution, washed with 10 ml of a 5% aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2) to obtain an oil. This was dissolved in 1 ml of ethyl acetate, 1 ml of a 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was allowed to stand at room temperature overnight. The precipitated solid was collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to obtain the title compound (0.034 g). MS m / z: 387 (MH +).

[0242] Example 142 N ¹ - cyclohexyl -N ² - In [4- (2-naphthylsulfonyl) butyl] -1,2-ethanediamine dihydrochloride Example 141 In the same manner as was obtained in Reference Example 21 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl [4-
The title compound (0.034 g) was synthesized from tert-butyl (2-naphthylsulfanyl) butyl] carbamate (0.081 g) and m-chloroperbenzoic acid (0.077 g). MS m / z: 359 (MH +).

[0243] Example 143 N ¹ - cyclohexyl -N ² - in the 5- (2-naphthylsulfonyl) pentyl] -1,2-ethanediamine dihydrochloride Example 141 In the same manner as was obtained in Reference Example 22 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl [4-
(2-Naphthylsulfanyl) pentyl] carbamic acid tert-
From butyl (0.143 g) and m-chloroperbenzoic acid (0.139 g),
The title compound (0.078 g) was synthesized. MS m / z: 403 (MH +).

Example 144 Benzyl dihydrochloride 6-{[2- (cyclohexylamino) ethyl] amino} hexanoic acid Cyclohexyl obtained in Reference Example 2 in the same manner as in Reference Example 3.
Tert-butyl (2-oxoethyl) carbamate (0.48 g) and 6-
Benzyl aminohexanoate p-toluenesulfonate (0.
From 94 g), tert-butyl 2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl (5-benzyloxycarbonylpentyl) carbamate (1.02 g) was synthesized. From this compound (0.032 g), the title compound (0.022 g) was synthesized in the same manner as in Example 137. MS m / z: 347 (MH +).

Example 145 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1H-benzimidazole-4-carboxamide trihydrochloride Example 14 was repeated using benzimidazole-4-carboxylic acid.
The title compound was synthesized as described above. MS m / z: 358 (MH +).

Example 146 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -2-naphthalenesulfonamide dihydrochloride 4-aminobutyl {2-[(tert. -Butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamic acid
To a solution of ert-butyl (380 mg) and triethylamine (131 mg) in acetonitrile (10 ml) was added 2-naphthalenesulfonyl chloride (259 mg) under ice-cooling, and the mixture was stirred for 3 hours and then at room temperature for 3 days. After the reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained compound was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride / ethyl acetate (6 ml) was added, and the mixture was stirred at room temperature for 2 hours.
The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol.
The title compound was obtained as a colorless solid (95mg). MS m / z: 404 (MH +).

Example 147 N- (4-{[2- (cyclohexylamino) ethyl] amino} butyl) -1-naphthalenesulfonamide dihydrochloride 1-naphthalenesulfonyl chloride was prepared in the same manner as in Example 146. The title compound was synthesized. MS m / z: 404 (MH +).

Example 148 1- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -3-methyl-1,4,7b-triazacyclopenta [cd] indene-2 (1H)- One trihydrochloride 1,2-dihydro-1- (4-aminobutyl) -3-methyl-1,4,7b-triazacyclopento [cd] inden-2-one (4.78 g) and Reference Example 2 A solution of the obtained tert-butyl cyclohexyl (2-oxoethyl) carbamate (4.72 g) in methanol (50 ml) was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (8.29 g) was added little by little at room temperature. . Mix at room temperature
Stir for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with an 8N aqueous sodium hydroxide solution and chloroform.
The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (chloroform: methanol = 10: 1).
And purified by 1,2-dihydro-1- [4- [2- (N-cyclohexyl-
N-tert-butoxycarbonylamino) ethylamino] butyl] -3-methyl-1,4,7b-triazacyclopent [cd] inden-2-one was obtained as a pale yellow oil. 12N hydrochloric acid (6.7 ml) was added to an ethanol solution (40 ml) of this oil at room temperature, and the mixture was heated at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and ethanol and ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ether and dried under reduced pressure to give the title compound as white crystals (2.19 g). MS m / z: 370 (MH +).

Example 149 1- (4-{[2- (Cyclopentylamino) ethyl] amino} butyl) -3-methyl-1,4,7b-triazacyclopenta [cd] indene-2 (1H)- On trihydrochloride The title compound was synthesized as in Example 148 using tert-butyl cyclopentyl (2-oxoethyl) carbamate obtained in Reference Example 24. MS m / z: 356 (MH +).

Example 150 1- (4-{[2- (Cycloheptylamino) ethyl] amino} butyl) -3-methyl-1,4,7b-triazacyclopenta [cd] indene-2 (1H) The title compound was synthesized in the same manner as in Example 148, using tert-butyl cycloheptyl (2-oxoethyl) carbamate obtained in Reference Example 26. MS m / z: 384 (MH +).

Example 151 1- (4-{[2- (Cyclohexylamino) ethyl] amino} pentyl) -3-methyl-1,4,7b-triazacyclopenta [cd] indene-2 (1H)- On trihydrochloride 1,2-dihydro-1- (5-aminopentyl) -3-methyl-1,4,7b-
Triazacyclopent [cd] inden-2-one dihydrochloride (3.
1,8-diazabicyclo in a solution of 25 g) in methanol (50 ml)
[5.4.0] Unde-7-cene (2.94 ml) was added at room temperature and stirred,
Further cyclohexyl (2-oxoethyl) obtained in Reference Example 2
Tert-butyl carbamate (2.37 g) was added, and the mixture was stirred at room temperature for 30 minutes. To the resulting mixture was added sodium triacetoxyborohydride (4.16 g) little by little at room temperature, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with an 8N aqueous sodium hydroxide solution and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 1).
0: 1), and purified by 1,2-dihydro-1- [5- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethylamino]
Pentyl] -3-methyl-1,4,7b-triazacyclopent [cd]
Inden-2-one was obtained as a pale yellow oil. To a solution of this oil in ethanol (30 ml) was added 12 N hydrochloric acid (5.4 ml) at room temperature, and the mixture was heated at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and ethanol and ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ether and dried under reduced pressure to give the title compound as white crystals (2.18 g). MS m / z: 384 (MH +).

Example 152 1- (4-{[2- (Cyclohexylamino) ethyl] amino} propyl) -3-methyl-1,4,7b-triazacyclopenta [cd] indene-2 (1H)- On trihydrochloride 1,2-dihydro-1- (3-aminopropyl) -3-methyl-1,4,7b-
The title compound was synthesized in the same manner as in Example 148 using triazacyclopent [cd] inden-2-one (4.78 g) and tert-butyl cyclohexyl (2-oxoethyl) carbamate obtained in Reference Example 2. MS m / z: 356 (MH +).

Example 153 N ¹ -Cyclohexyl-N ^2- {4-[(3-methyl-1,4,7b-triazacyclopenta [cd] inden-2-yl) sulfanyl] butyl} -1,2 -Ethanediamine trihydrochloride 2- (4-aminobutyl) thio-3-methyl-1,4,7b-triazacyclopent [cd] indene (0.75 g), cyclohexyl (2-oxoethyl) obtained in Reference Example 2 ) Tert-Butyl carbamate
(0.54 g), 1,8-diazabicyclo [5.4.0] unde-7-cene (0.
67 ml) and a mixture of sodium chloride (10 g) and methanol (20 ml) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.95 g) was added little by little, and the mixture was stirred for 15 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) was added to the residue, and the mixture was extracted with chloroform (100 ml × 2). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 25: 1) to give 2- [4- [2- (N-tert-butoxycarbonyl). -N-cyclohexyl) aminoethyl] aminobutyl]
Thio-3-methyl-1,4,7b-triazacyclopent [cd] indene (0.35 g) was obtained as an oil. Concentrated hydrochloric acid (10 ml) was added to a solution of the oil in ethanol (20 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, and the residue was crystallized from ethanol-diethyl ether to give the title compound (0.33 g) as a colorless solid. MS m / z: 386 (MH +).

Example 154 4- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -3H-1,4,8b-triazaacenaphthylene-3,5 (4H) -dione trihydrochloride Salt 5-carbethoxy-3-trichloroacetylimidazo [1,2-
a] pyridine (1.68 g, 5.0 mmol), tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate obtained in Reference Example 5 (2.07 g,
A solution of 5.0 mmol) and triethylamine (1.4 ml) in acetonitrile (25 ml) was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and purified water and ethyl acetate were added to the residue for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 4,5-dihydro
-4- [4- [N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino] butyl] -1,4,8b-triazaacenaphthylene -3,5-dione (2.44 g) was obtained as a pale yellow amorphous substance. To a solution of this pale yellow amorphous substance (0.61 g) in ethanol (20 ml) was added 12N hydrochloric acid (0.9 ml) at room temperature, and the mixture was heated at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and ethanol and ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ether and dried under reduced pressure to give the title compound as white crystals (0.37 g). MS m / z: 384 (MH +).

Example 155 N ¹ -Cyclohexyl-N ^2- [4- (3,5-dihydro-4H-1,4,8b-triazaacenaphthylene-4-yl) butyl] -1,2-ethane Diamine tetrahydrochloride 5-chloromethylimidazo [1,2-a] pyridine hydrochloride (1.66
g) and tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate (3.48 g) obtained in Reference Example 5 and N, N-diisopropyl-N-ethylamine ( 4.0 ml) of acetonitrile (40 ml) solution was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, and chloroform and water were added to the residue for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 5-N- [4- [N-
[2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino] butyl
Aminomethylimidazo [1,2-a] pyridine (3.94 g) was obtained as a light brown amorphous substance. This light brown amorphous substance (2.72
g) and a 37% aqueous solution of formalin (3.75 ml) in acetic acid (10 ml) were heated at 100 ° C. for 1 hour. The solvent was distilled off, and the residue was extracted with an 8N aqueous sodium hydroxide solution, sodium chloride and chloroform. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 4,5-dihydro-4- [4- [N- [2- (N-cyclohexyl-N-te
[rt-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino] butyl] -3H-1,4,8b-triazaacenaphthylene (1.75 g) was obtained as a light brown amorphous substance. 12 N hydrochloric acid (2.6 ml) was added to a solution of this pale brown amorphous substance in ethanol (20 ml) at room temperature, and the mixture was heated at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and ethanol and ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ether and dried under reduced pressure to give the title compound as white crystals (0.79 g). MS m / z: 356 (MH +).

[0256] Example 156 N ¹ - [2- (cyclohexylamino) ethyl] -N ⁴ - (imidazo
[1,2-a] Pyridin-5-ylmethyl) -1,4-butanediaminetetrahydrochloride 5-N- [4- [N- [2- (N-cyclohexyl-) synthesized in Example 155
N-tert-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino] butyl] aminomethylimidazo
To a solution of [1,2-a] pyridine (1.14 g) in ethanol (20 ml) was added 12
Normal hydrochloric acid (1.73 ml) was added at room temperature, and the mixture was heated at 50 ° C for 1 hour. The solvent was distilled off under reduced pressure, and ethanol and ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ether and dried under reduced pressure to give the title compound as white crystals (0.
64 g). MS m / z: 344 (MH +).

Example 157 N ¹ -Cyclohexyl-N ^2- {5-[(3-methyl-1,4,7b-triazacyclopenta [cd] inden-2-yl) sulfanyl] pentyl} -1,2 -Ethanediamine trihydrochloride 1- (5-aminopentylthio) -3-methyl-1,4,7b-triazacyclopent [cd] indene dihydrochloride and cyclohexyl (2-oxoethyl) obtained in Reference Example 2 The title compound was synthesized as in Example 151 using tert-butyl carbamate. MS m / z: 400 (MH +).

[0258] Example 158 N ¹ - cyclohexyl -N ² - [4- (2- phenyl-3,5-dihydro -4
H-1,4,8b-Triazaacenaphthylene-4-yl) butyl] -1,2
-Ethanediamine tetrahydrochloride 5-hydroxymethyl-2-phenylimidazo [1,2-a] pyridine (2.24 g) was added to thionyl chloride (3.7 ml), and the resulting mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (20 ml), and the resulting solution was added with 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl)) obtained in Reference Example 5. Tert-butyl [amino] ethyl} carbamate (2.07 g) and N, N-diisopropyl-N-ethylamine (2.6 ml) were added, and the mixture was heated under reflux for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and purified water and chloroform were added to the residue for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-N- [4- [N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl] -Nt.
ert-butoxycarbonylamino] butyl] aminomethyl-2
-Phenylimidazo [1,2-a] pyridine (3.76 g) was obtained as a colorless amorphous substance. This colorless amorphous substance (2.48 g) and 37
100% aqueous solution of formalin (3.0 ml) in acetic acid (10 ml)
For 1 hour. The solvent was distilled off, and the residue was extracted with an 8N aqueous sodium hydroxide solution, sodium chloride and chloroform. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 4,5-
Dihydro-4- [4- [N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino] butyl] -2-phenyl-3H-1,4, 8b-Triazaacenaphthylene (1.80 g) was obtained as a light brown amorphous substance.
To a solution of this pale brown amorphous substance (1.80 g) in ethanol (20 ml) was added 12N hydrochloric acid (2.3 ml) at room temperature, and the mixture was heated at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and ethanol and ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ether and dried under reduced pressure to give the title compound as white crystals (1.19 g). MS m / z: 432 (MH +).

Example 159 N ^1- [2- (Cyclohexylamino) ethyl] -N ⁴ -[(2-methylimidazo [1,2-a] pyridin-5-yl) methyl] -1,4-butanediamine Tetrahydrochloride 5-hydroxymethyl-2-methylimidazo [1,2-a] pyridine
(1.62 g) was added to thionyl chloride (3.7 ml), and the resulting mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (20 ml), and the resulting solution was added with 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) obtained in Reference Example 5. To the mixture were added tert-butyl [amino] ethyl} carbamate (2.07 g) and N, N-diisopropyl-N-ethylamine (2.6 ml), and the mixture was heated under reflux for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and purified water and chloroform were added to the residue for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-N- [4- [N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl] -Nt.
ert-butoxycarbonylamino] butyl] aminomethyl-2
-Methylimidazo [1,2-a] pyridine was converted to a colorless amorphous substance (3.
67 g). To a solution of this colorless amorphous substance (1.67 g) in ethanol (20 ml) was added 12N hydrochloric acid (2.47 ml) at room temperature, and the mixture was heated at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and ethanol and ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ether, dried under reduced pressure,
The title compound was obtained as white crystals (1.10 g). MS m / z: 358 (MH +).

Example 160 N ^1- [2- (Cyclohexylamino) ethyl] -N ⁴ -[(2-phenylimidazo [1,2-a] pyridin-5-yl) methyl] -1,4-butanediamine Tetrahydrochloride 5-N- [4- [N- [2- (N-cyclohexyl-N-te
[rt-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino] butyl] aminomethyl-2-phenylimidazo [1,2-a] pyridine (1.86 g) in ethanol (20 ml)
12 N hydrochloric acid (2.47 ml) was added to the solution at room temperature, and the mixture was heated at 50 ° C for 1 hour. The solvent was distilled off under reduced pressure, and ethanol and ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ether and dried under reduced pressure to give the title compound as white crystals (1.19 g). MS m / z: 420 (MH +).

Example 161 N ^1- [2- (Cyclohexylamino) ethyl] -N ⁴ -{[2- (4-fluorophenyl) imidazo [1,2-a] pyridin-5-yl] methyl} -1 In the same manner as in Example 158, 2- (4-fluorophenyl) -5-
5-N- [4- [N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino synthesized from hydroxymethylimidazo [1,2-a] pyridine The title compound was obtained in the same manner as in Example 160 using [butyl] aminomethyl-2- (4-fluorophenyl) imidazo [1,2-a] pyridine. MS m / z: 438 (MH +).

Example 162 N ¹ -{[2- (4-Chlorophenyl) imidazo [1,2-a] pyridine-5
- yl] methyl} -N ⁴ - [2- (cyclohexylamino) ethyl] -
1,4-Butanediaminetetrahydrochloride 5 Synthesized from 2- (4-chlorophenyl) -5-hydroxymethylimidazo [1,2-a] pyridine in the same manner as in Example 158
-N- [4- [N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino] butyl] aminomethyl-2- (4-chlorophenyl) imidazo [ The title compound was obtained in the same manner as in Example 160 using 1,2-a] pyridine. MS m / z: 454 (MH +).

[0263] Example 163 N ¹ - cyclohexyl ^{-N 2 - {4- [2- (} 4- fluorophenyl) -3,
5-dihydro-4H-1,4,8b-triazaacenaphthylene-4-yl] butyl} -1,2-ethanediaminetetrahydrochloride 2- (4-fluorophenyl) -5-hydroxymethylimidazo
The title compound was obtained in the same manner as in Example 158 using [1,2-a] pyridine. MS m / z: 450 (MH +).

Example 164 N ^1- {4- [2- (4-chlorophenyl) -3,5-dihydro-4H-1,4,8b
-Triazaacenaphthylene-4-yl] butyl} -N ² -cyclohexyl-1,2-ethanediaminetetrahydrochloride 2- (4-chlorophenyl) -5-hydroxymethylimidazo [1,
The title compound was obtained in the same manner as in Example 158 using 2-a] pyridine. MS m / z: 466 (MH +).

[0265] Example 165 N ¹ - [2- (cyclohexylamino) ethyl] -N ⁴ - (imidazo
[1,2-a] pyridin-3-ylmethyl) -1,4-butanediaminetetrahydrochloride imidazo [1,2-a] pyridine-3-carboxaldehyde (0.7
To a solution of 3 g) in methanol (25 ml) was added tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate (2.07 g) obtained in Reference Example 5 and room temperature was added. For 30 minutes. To the resulting mixture was added sodium triacetoxyborohydride (2.12 g) in small portions at room temperature, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with an 8N aqueous sodium hydroxide solution and chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue
(Chloroform: methanol = 10: 1) and purified by 3-N- [4
-N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethylamino] -4-N-tert-butoxycarbonylaminobutyl] aminomethylimidazo [1,2-a] pyridine (2.5
9) was obtained as a colorless amorphous substance. To a solution of this colorless amorphous substance in ethanol (20 ml) was added 12N hydrochloric acid (3.91 ml) to add 50
Heated at ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with ether, and dried under reduced pressure to give the title compound as white crystals (1.82 g). MS m / z: 344 (MH +).

Example 166 N ^1- [2- (Cyclohexylamino) ethyl] -N ⁴ -[(2-phenylimidazo [1,2-a] pyridin-3-yl) methyl] -1,4-butanediamine Tetrahydrochloride 2-phenylimidazo [1,2-a] pyridine-3-methanol (1.1
2 g) was added to thionyl chloride (3.7 ml) and the resulting mixture was added to 1
Heated to reflux for an hour. After the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethanol (20 ml).
4-aminobutyl {2-[(tert-butoxycarbonyl) obtained in
(Cyclohexyl) amino] ethyl} tert-butylcarbamate (2.07 g) and N, N-diisopropyl-N-ethylamine (2.
6 ml) and heated under reflux for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and purified water and chloroform were added to the residue for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 1).
0: 1) to give 3-N- [4-N- [2- (N-cyclohexyl-N-
tert-butoxycarbonylamino) ethylamino] -4-N-te
rt-butoxycarbonylaminobutyl] aminomethyl-2-
Phenylimidazo [1,2-a] pyridine (2.42 g) was obtained as a colorless amorphous substance. The colorless amorphous substance ethanol (2
0N) solution was added with 12N hydrochloric acid (3.21 ml) and heated at 50 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration.
After washing with ether, drying under reduced pressure gave the title compound as white crystals (1.51 g). MS m / z: 420 (MH +).

Example 167 3-trifluoromethyl-1,7b-diazacyclopent [cd] indene-4- [N- [4-N- [2- (N-cyclohexylamino) ethylamino] aminobutyl] ] Carboxamide trihydrochloride The suspension of 3-trifluoromethyl-1,7b-diazacyclopent [cd] indene-4-carboxylic acid (1.27 g) obtained in Reference Example 28 in acetonitrile (20 ml) was diluted with 1- Hydroxybenzotriazole monohydrate (1.15 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.44 g) were added, and the mixture was stirred at room temperature for 1 hour. The obtained reaction solution was obtained in Reference Example 5.
4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} tert-butylcarbamate (3.1
0 g) and triethylamine (2.1 ml) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and purified water and chloroform were added to the residue for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue
(Chloroform: methanol = 10: 1) to give 3-trifluoromethyl-1,7b-diazacyclopent [cd] indene-4- [4-N- [2- (N-cyclohexyl-N- [tert-butoxycarbonylamino) ethyl-N-tert-butoxycarbonylamino] butyl] carboxamide (2.78 g) was obtained as a yellow amorphous substance. 12N hydrochloric acid (3.52 ml) was added to a solution of this yellow amorphous substance in ethanol (20 ml), and the mixture was heated at 50 ° C. for 1 hour.
The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with ether, and dried under reduced pressure to obtain the title compound as pale yellow crystals (1.88 g). MS m / z: 450 (MH +).

Example 168 4-Chloro-1,7b-diazacyclopent [cd] indene-3- [4-
N- [2- (N-cyclohexylamino) ethylamino] aminobutyl] carboxamide trihydrochloride 4-chloro-1,7b-diazacyclopent [cd] obtained in Reference Example 30
The title compound was synthesized in the same manner as in Example 167 using indene-3-carboxylic acid. MS m / z: 416 (MH +).

Example 169 N ^1- [2- (Cyclohexylamino) ethyl] -N ⁴ -{[2- (4-methylphenyl) imidazo [1,2-a] pyridin-5-yl] methyl}-
1,4-butanediamine tetrahydrochloride In the same manner as in Example 158, 5-hydroxymethyl-2- (4-
Synthesized from methylphenyl) imidazo [1,2-a] pyridine
5-N- [4- [N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino] butyl] aminomethyl-2- (4-methylphenyl) The title compound was obtained in the same manner as in Example 160 using imidazo [1,2-a] pyridine. MS m / z: 434 (MH +).

Example 170 N ¹ -{[2- (4-Bromophenyl) imidazo [1,2-a] pyridine-5
- yl] methyl} -N ⁴ - [2- (cyclohexylamino) ethyl] -
1,4-butanediamine tetrahydrochloride 5 Synthesized from 2- (4-bromophenyl) -5-hydroxymethylimidazo [1,2-a] pyridine in the same manner as in Example 158
-N- [4- [N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl] -N-tert-butoxycarbonylamino] butyl] aminomethyl-2- (4-bromophenyl) imidazo The title compound was obtained by treating [1,2-a] pyridine in the same manner as in Example 160. MS m / z: 500 (MH +).

[0271] Example 171 N ¹ - cyclohexyl ^{-N 2 - {4- [2- (} 4- methylphenyl) -3,5
Dihydro-4H-1,4,8b-triazaacenaphthylene-4-yl]
Butyl} -1,2-ethanediaminetetrahydrochloride 5-hydroxymethyl-2- (4-methylphenyl) imidazo [1,
The title compound was synthesized in the same manner as in Example 158 using 2-a] pyridine. MS m / z: 446 (MH +).

Example 172 N ^1- {4- [2- (4-bromophenyl) -3,5-dihydro-4H-1,4,8b
- triazaacenaphthylen acenaphthylene-4-yl] butyl} - N ² - cyclohexyl-1,2-ethanediamine tetrahydrochloride 5-hydroxymethyl-2- (4-bromophenyl) imidazo [1,
The title compound was obtained by treating in the same manner as in Example 158 using 2-a] pyridine. MS m / z: 512 (MH +).

Example 173 4- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-
3-one trihydrochloride 3-carbethoxy-5-chloromethylimidazo [1,2-a] pyridine / sulfate (1.68 g), 1,8-diazabicyclo [5.4.0] unde-7-cene (1.5 ml) And tert-butyl 4-aminobutyl {2-[(tert-butoxycarbonyl) (cyclohexyl) amino] ethyl} carbamate obtained in Reference Example 5 in a suspension of sodium iodide (0.75 g) in acetonitrile (25 ml) (2.28 g) and triethylamine (1.4 ml) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was distilled off under reduced pressure, and purified water and chloroform were added to the residue for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue
(Chloroform: methanol = 10: 1), and purified by 4,5-dihydro-4- [4-N- [2- (N-cyclohexyl-N-tert-butoxycarbonyl) amino] ethyl-N-tert-butoxy Carbonylamino] butyl] -3H-1,4,8b-triazaacenaphthylene-3-
On (2.15 g) was obtained as a colorless amorphous material. 12N hydrochloric acid (3.25 m) was added to a solution of this colorless amorphous substance in ethanol (20 ml).
l) was added and the mixture was heated at 50 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with ether, and dried under reduced pressure to give the title compound as white crystals (1.36 g). MS m / z: 370 (MH +).

Example 174 N- (4-{[2- (Cyclohexylamino) ethyl] amino} butyl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 5-thia- The title compound was synthesized as in Example 167 using 1,8b-diazaacenaphthylene-4-carboxylic acid. MS m / z: 414 (MH +).

Example 175 3-Pentafluoroethyl-1,7b-diazacyclopent [cd]
Indene-4-N- [4-N- [2- (N-cyclohexylamino) ethylamino] butyl]] carboxamide trihydrochloride 3-pentafluoroethyl-1,7b-diazacyclopent obtained in Reference Example 32 Example 1 using [cd] indene-4-carboxylic acid
The title compound was synthesized as in 67. MS m / z: 500 (MH +).

Example 176 7,8,9,10-Tetrahydro-9- [4-N- [2- (N-cyclohexylamino) ethylamino] butyl] -6-thia-2,9,10b-triaza Cyclopent [cd] indene tetrahydrochloride 5- (2-aminoethyl) thioimidazo [1,2-a] pyridine dihydrochloride (4.79 g) and 1,8-diazabicyclo [5.4.0] unde-7-cene ( (5.4 ml) in methanol (60 ml) solution obtained in Reference Example 33.
-[(tert-butoxycarbonyl) (cyclohexyl) amino]
Tert-butyl ethyl (4-oxobutyl) carbamate (6.19
g) was added and the mixture was stirred at room temperature for 30 minutes. To the resulting solution was added sodium triacetoxyborohydride (6.36 g) little by little at room temperature, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with an 8N aqueous sodium hydroxide solution and chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5- [2- [4-N
-[2- (N-Cyclohexyl-N-tert-butoxycarbonylamino) ethylamino] -4-N-tert-butoxycarbonylaminobutyl] aminoethyl] thioimidazo [1,2-a] pyridine
(6.29 g) was obtained as a colorless amorphous substance. To a solution of this colorless amorphous substance (2.95 g) in acetic acid (10 ml) was added a 37% aqueous formalin solution (3.8 ml), and the mixture was heated at 100 ° C for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was extracted with an 8N aqueous sodium hydroxide solution and chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (chloroform: methanol = 10: 1).
And purified by 7,8,9,10-tetrahydro-9- [4-N- [2- (N-cyclohexyl-N-tert-butoxycarbonylamino) ethyl-
N-tert-butoxycarbonylamino] butyl] -6-thia-2,
9,10b-Triazacyclopent [cd] indene (6.29 g) was obtained as a colorless amorphous substance. This colorless amorphous substance (2.48
12N hydrochloric acid (3.39 ml) was added to a solution of g) in ethanol (20 ml), and the mixture was heated at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with ether, and dried under reduced pressure.
The title compound was obtained as orange crystals (1.54 g). MS m / z: 402 (MH +).

Example 177 5- [2- [4-N- [2- (N-cyclohexylamino) ethylamino]
Butyl] aminoethyl] thioimidazo [1,2-a] pyridine tetrahydrochloride 5- [2- [4-N- [2- (N-cyclohexyl-N-te) obtained in Example 176
rt-butoxycarbonylamino) ethyl-N-tert-butoxycarbonylamino] butyl] aminoethyl] thioimidazo
To a solution of [1,2-a] pyridine (2.36 g) in ethanol (20 ml) was added 12
Normal hydrochloric acid (3.29 ml) was added, and the mixture was heated at 50 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with ether, and dried under reduced pressure to give the title compound as white crystals (1.84 g).
As obtained. MS m / z: 390 (MH +). The chemical structure of the compound obtained in the example is shown below.

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Experimental Example Confirmation of CXCR4 Expression in Jurkat E6-1 It has been reported that CXCR4 is expressed in Jurkat cells (J. Immunol. (1998) 160: 877-883). The following experiment was conducted to confirm that CXCR4 was expressed in the Jurkat E6-1 strain (ATCC) used for compound evaluation. Ju
rkat E6-1 (ATCC) strain in cell culture flask 150 cm
² 10% fetal bovine serum (G
RPMI medium containing IBCO BRL) (Nikken Institute of Biomedical Research)
The cells were inoculated into 60 ml and cultured until they reached 1 × 10 ⁶ cells / ml. The cultured cells were collected by centrifugation at 1200 rpm for 5 minutes, and assay buffer (composition: Dulbecco's Phos
phate-Buffered Saline (GIBCO BRL), 20mM HEPES, 0.5
After washing the cells with 20 ml of (% BSA, pH 7.0), the cells were suspended at 6 × 10 ⁶ cells / ml in assay buffer. Next, 50 μl / well of cells suspended in the above assay buffer was dispensed into a 96-well microplate (Sumitomo Bakelite), and 25 parts of the anti-CXCR4 antibody (12G5, Dainippon Pharmaceutical) adjusted to each concentration with the assay buffer was added.
μl / well was dispensed. 100 for non-specific binding determination
nM SDF-1alpha (R & D SYSTEMS) was added and determined. Next, 2 [ ¹²⁵ I] SDF-1alpha (Daiichi Pure Chemicals) adjusted to 200 pM with assay buffer was added.
5 μl / well was added, and the reaction was performed at room temperature for 60 minutes.
After the completion of the reaction, the cells were treated with 0.3% polyethyleneimine (Wako Pure Chemical Industries) using a cell harvester (Packard) 9
Suction-filtered into a 6-well GF / C filter plate (Packard) and further cooled Dulbecco's Phosphate-Buff
Washed 4 times with ered Saline (GIBCO BRL). The plate was dried at 45 ° C. for 2 hours and then
(Packard) was added to each well in an amount of 25 μl, and the radioactivity was measured with a top count (Packard).
It was confirmed that CXCR4 was expressed in E6-1. Evaluation of compounds based on CXCR4 antagonism Jurkat E6-1 (ATCC) strain was added to cell culture flask 150
The cells were inoculated into 60 ml of RPMI medium (Niken Institute of Biomedical Research) containing 10% fetal bovine serum (GIBCO BRL) in cm ² (Corning Coaster), and cultured to 1 × 10 ⁶ cells / ml. The cultured cells are collected by centrifugation at 1200 rpm for 5 minutes, washed with 20 ml of assay buffer, and then washed with assay buffer at 6 × 10 ⁶ cells / ml.
Suspended in water. Next, the cells suspended in the assay buffer in a 96-well microplate (Sumitomo Bakelite) were collected for 5 minutes.
Dispense 0 μl / well and add 1 μM in assay buffer
The test compound prepared above was dispensed at 25 μl / well and adjusted to 200 pM with assay buffer [ ¹²⁵ I] SD.
F-1alpha (a first chemical) was added at 25 μl / well and reacted at room temperature for 60 minutes. After completion of the reaction, suction filtration was performed using a cell harvester (Packard) on a 96-well GF / C filter plate (Packard) treated with 0.3% polyethyleneimine (Wako Pure Chemical Industries, Ltd.), and further cooled Dulbecco's Phosphate-Buffered Saline ( GIBCO B
RL) four times. After the plate was dried at 45 ° C. for 2 hours, 25 μl of Microscint 0 (Packard) was added to each well, and the radioactivity was measured with a top count (Packard) to measure the binding inhibition rate. 100n MSDF-1alpha (R & D SYSTEM) for non-specific binding
The radioactivity to which S) was added was measured and determined. [Table 1] Compound No. Binding inhibitory rate (%) 17 81 50 99 106 94 108 94 131 45 146 95 160 98 From the results in Table 1, the test compound was obtained at a concentration of 1 μM.
Moderate (~ 50%) binding of SDF-1alpha to CXCR4
It has been found that the inhibitory rate at the above rate, from this, the compounds of the present invention prevent or treat HIV infection based on CXCR4 inhibitory activity, prevent or treat AIDS or suppress AIDS disease progression, or It is expected to be useful as a drug such as an anticancer drug having an antimetastatic effect.

[0279]

The compound of the present invention has unexpectedly excellent chemokine receptor (CX) based on its unique chemical structure.
CR4, etc.), which have an antagonistic effect and prevent or treat HIV infection in human peripheral blood mononuclear cells, particularly AIDS.
It is useful as a medicament such as an AIDS disease progression inhibitor and an anticancer drug having an antimetastatic effect. Furthermore, it has excellent oral absorbability and the like, and has excellent properties as a medicine.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/215 A61K 31/215 4C037 31/24 31/24 4C050 31/34 31/34 4C055 31/381 31 / 381 4C056 31/40 31/40 4C063 31/404 31/404 4C065 31/415 31/415 4C072 31/4155 31/4155 4C084 31/4184 31/4184 4C086 31/4192 31/4192 4C204 31/42 31 / 42 4C206 31/422 31/422 4H006 31/425 31/425 31/427 31/427 31/429 31/429 31/437 31/437 31/44 31/44 31/4402 31/4402 31/4409 31 / 4409 31/4439 31/4439 31/455 31/455 31/47 31/47 31/498 31/498 31/542 31/542 31/55 31/55 31/7068 31/7068 45/00 45/00 A61P 31/18 A61P 31/18 43/00 111 43/00 111 C07C 217/14 C07C 217/14 229/12 229/12 233/62 233/62 233/78 233/7 8 235/50 235/50 235/70 235/70 311/13 311/13 311/16 311/16 311/18 311/18 311/29 311/29 311/46 311/46 317/28 317/28 323 / 25 323/25 C07D 209/08 C07D 209/08 209/42 209/42 213/70 213/70 213/78 213/78 213/81 213/81 213/82 213/82 215/48 215/48 223 / 16 223/16 Z 231/14 231/14 233/64 106 233/64 106 235/08 235/08 235/28 235/28 237/28 237/28 241/44 241/44 249/10 249/10 249/18 501 249/18 501 261/18 261/18 277/56 277/56 285/06 285/06 307/68 307/68 307/79 307/79 333/34 333/34 333/40 333/40 333/70 333/70 409/04 409/04 413/04 413/04 417/04 417/04 471/04 106 471/04 106A 106C 107 107Z 108 108Z 471/16 471/16 487/16 487/16 513 / 04 331 513/04 331 513/16 513/16 (72) Inventor Manabu Mochizuki 50-1 Yamada Minami, Suita City, Osaka Prefecture Takeda Pharmaceutical Co., Ltd. in the Dormitory (72) Inventor Tetsuji Kawamoto 26 No. 2 F term (reference) 4C023 HA02 4C031 MA01 4C033 AD09 AD16 AD17 AD20 4C034 DQ01 DQ10 4C 036 AD16 AD23 AD27 AD30 4C037 MA02 PA01 QA10 4C050 AA01 AA02 BB05 CC05 DD02 EE03 FF02 GG03 HH01 4C055 AA01 BA02 BA34 BA48 BB04 BB10 CA02 CA34 DA01 DA34 DB04 DB10 4C056 AA01 AB01 DD01 FC01 DD01 FC01 FA01 FB01 DD01 4C065 AA07 BB05 CC03 DD03 EE03 HH01 JJ01 KK01 KK06 LL04 PP02 4C072 AA02 BB03 CC03 CC16 EE16 EE19 FF05 GG01 GG09 4C084 AA19 DC32 MA02 NA05 NA14 ZB33 ZC55 4C086 AA03 BC02 BC02 BC05 BC03 BC NA14 ZB33 ZC55 4C204 AB00 BB01 CB03 DB01 EB01 FB01 GB18 4C206 AA01 AA03 AA04 GA08 JA13 KA01 MA02 MA04 NA05 NA14 ZB33 ZC55 4H006 AA01 AA02 AA03 AB20 AB28 AC52 AC53 AC62 BJ50 BP30 BU42 TA04

Claims (25)

[Claims] 1. A compound of the formula: [Wherein, R ¹ and R ² each represent a hydrogen atom or an alkyl group, A represents an optionally substituted cyclic group, X represents a bond, or an alkylene which may be bound to A via a hetero atom. A group or an alkenylene group, Y is (1) a sulfur atom, (2) an oxygen atom, (3) -C (= O) -N (R ¹⁵ )-(R ¹⁵ is a hydrogen atom or an optionally substituted alkyl Represents a group), (4)-
SO ₂ -N (R ¹⁶ )-(R ¹⁶ represents a hydrogen atom or an optionally substituted alkyl group), (5) -C (= O) -O-, (6) -SO-, (7 )
-SO ₂ - or ^{(8) -N (R 17)} , - (R 17 represents a hydrogen atom or an optionally substituted alkyl group) indicates, A-X-
The group represented by Y- may form an optionally substituted heterocyclic group, l is an integer from 2 to 6, m is an integer from 2 to 4, and n is an integer from 0 to 8. Indicates an integer. However, when Y is —N (R ¹⁷ ) —, A represents an optionally substituted aromatic heterocyclic group. Or a salt thereof. (2) R¹And R^TwoAre each independently a hydrogen atom
Or C_1-6A is an alkyl group wherein (1) (i) halogen is 1 to
5 optionally substituted C_1-6Alkoxy group, (ii) c
1 to 3 with a substituent selected from
C optionally substituted_6-14An aryloxy group, (ii
i) halogen atom, (iv) C_3-8Cycloalkyl group, (v) amido
Group, (vi) (a) carbamoyl, (b) C_1-6Alkylsulfo
Nil, (c) C_1-6Alkyl, (d) mono or di (C_1-6A
Alkyl) optionally substituted with one or two amino
C_1-6Alkyl, and substitution selected from (e) benzoyl
An amino group substituted by one or two groups, (vii) C_1-6A
Carbamo optionally substituted by 1 or 2 alkyl
Yl group, (viii) formyl group, (ix) C_2-6Alkanoyl
Group, (x) C_1-6Substitution selected from alkyl and halogen
Optionally substituted with 1 to 5 C_6-14Aryl group,
(xi) C_6-14Aryl-carbonyl group, (xii) C_7-13Ara
Alkyl-carbonyl group, (xiii) hydroxyl group, (xiv) C_2-5Al
Canoyloxy group, (xv) C_7-13Aralkyl-carbonyl
Oxy group, (xvi) nitro group, (xvii) C_1-6Alkyl as well
Or an optionally substituted sulfamoyl group, (x
viii) C_1-6C optionally substituted with 1 to 3 alkyl (s)
_6-14An arylthio group, (xix) -N = N-Ar (Ar is C
_6-14Represents an aryl group), (xx) cyano
Group, (xxi) amidino group, (xxii) carboxyl group, (xxiii)
C_1-4Alkoxycarbonyl group, (xxiv) C_1-6Alkyl
O group, (xxv) C_1-6Alkylsulfinyl group, (xxvi) C
_1-6Alkylsulfonyl group, (xxvii) C_6-14Arylchi
Oh, (xxviii) C_6-14Arylsulfinyl group, (xxix) C
_6-14An arylsulfonyl group, and (xxx) C_1-6Archi
Le, C_1-6Alkoxy, halogen, oxo, thioxo
And C_{1 -6}1 to 5 substituents selected from alkylthio
Or a 5- or 6-membered heterocyclic group optionally substituted with
6-membered heterocyclic ring or fused ring group with benzene ring:
C which may be substituted with 1 to 5 substituents_1-6
Alkyl group, (2) (i) 1 to 5 halogen-substituted,
Good C_1-6Alkoxy group, (ii) halogen and carba
Even if substituted with 1 to 3 substituents selected from moyl
Good C_6-14Aryloxy group, (iii) halogen atom, (i
v) C_3-8Cycloalkyl group, (v) amino group, (vi) (a)
Bamoyl, (b) C_1-6Alkylsulfonyl, (c) C_1-6Al
Kill, (d) mono or di (C_1-6Alkyl) amino with 1
Or two optionally substituted C_1-6Alkyl
And (e) 1 or 2 with a substituent selected from benzoyl
(Vii) C-substituted amino group_1-6Alkyl or 1
Is a carbamoyl group which may be substituted two times, (viii)
Lumil group, (ix) C_2-6Alkanoyl group, (x) C_1-6Archi
And 1 to 5 substituents selected from
C that may be_6-14Aryl group, (xi) C_6-14Aryl
-Carbonyl group, (xii) C_7-13Aralkyl-carbonyl
Group, (xiii) hydroxyl group, (xiv) C_2-5Alkanoyloxy group,
(xv) C_7-13Aralkyl-carbonyloxy group, (xvi)
Toro group, (xvii) C_1-61 or 2 substituted with alkyl
An optionally substituted sulfamoyl group, (xviii) C_1-6Archi
Optionally substituted with 1 to 3 carbon atoms_6-14Arylthio
Group, (xix) -N = N-Ar (Ar is C_6-14Aryl group
(Xx) cyano group, (xxi) amidino
Group, (xxii) carboxyl group, (xxiii) C_1-4Alkoxyka
Rubonyl group, (xxiv) C_1-6Alkylthio group, (xxv) C_1-6
Alkylsulfinyl group, (xxvi) C_1-6Alkylsulfo
Nyl group, (xxvii) C_6-14Arylthio, (xxviii) C_6-14
Arylsulfinyl group, (xxix) C_6-14Arylsulfo
Nil group, and (xxx) C_1-6Alkyl, C_1-6Alkoki
Si, halogen, oxo, thioxo and C_{1 -6}Alkyl
Even if substituted with 1 to 5 substituents selected from thio
A good 5- to 6-membered heterocyclic group or its 5- to 6-membered heterocyclic group or
Is a condensed ring group with a benzene ring: 1 to 5 positions selected from
C optionally substituted with a substituent_2-6Alkenyl group, (3)
(i) C optionally substituted with 1 to 5 halogens_1-6Al
Oxy group, (ii) selected from halogen and carbamoyl
Which may be substituted by 1 to 3 substituents_6-14Ally
Loxy group, (iii) halogen atom, (iv) C_3-8Cycloal
Kill group, (v) amino group, (vi) (a) carbamoyl, (b) C_1-6
Alkylsulfonyl, (c) C_1-6Alkyl, (d) mono-if
Kuhaji (C_1-61 or 2 substituted with alkyl) amino
C that may be_1-6Alkyl, and (e) benzoyl
Amino substituted with one or two substituents selected from
Group, (vii) C_1-6Substituted with one or two alkyl groups
Carbamoyl group, (viii) formyl group, (ix) C
_2-6Alkanoyl group, (x) C_1-6Alkyl and halogen
C may be substituted with 1 to 5 substituent (s) selected from
_6-14Aryl group, (xi) C_6-14An aryl-carbonyl group,
(xii) C_7-13Aralkyl-carbonyl group, (xiii) hydroxyl
Group, (xiv) C_2-5Alkanoyloxy group, (xv) C_7-13Ara
Alkyl-carbonyloxy group, (xvi) nitro group, (xvii)
C_1-61 or 2 may be substituted with alkyl
Sulfamoyl group, (xviii) C_1-6Place 1 to 3 with alkyl
C which may be replaced_6-14Arylthio group, (xix) -N
= N-Ar (Ar is C_6-14Represents an aryl group)
Group, (xx) cyano group, (xxi) amidino group, (xxii)
Boxyl group, (xxiii) C_1-4An alkoxycarbonyl group, (x
xiv) C_1-6Alkylthio group, (xxv) C_1-6Alkylsulf
Ynyl group, (xxvi) C_1-6Alkylsulfonyl group, (xxvii)
C_6-14Arylthio, (xxviii) C_6-14Aryl sulfy
Nyl group, (xxix) C_6-14An arylsulfonyl group, and (x
xx) C_1-6Alkyl, C_1-6Alkoxy, halogen, oki
So, thioxo and C_{1 -6}1 selected from alkylthio
5 to 6-membered heterocyclic ring optionally substituted with up to 5 substituents
Of a group or its 5- or 6-membered heterocyclic or benzene ring
Condensed group: substituted with 1 to 5 substituents selected from
May be C_2-6Alkynyl group, (4) (i) halogen with 1 to 5
C optionally substituted_1-6Alkoxy group, (ii) halo
1 to 3 substituents selected from gen and carbamoyl
Optionally substituted C_6-14Aryloxy group, (iii)
Halogen atom, (iv) 1 to 5 halogen atoms are substituted
Good C_1-6Alkyl group, (v) C_3-8Cycloalkyl group,
(vi) amino group, (vii) (a) carbamoyl, (b) C_1-6Archi
Rusulfonyl, (c) C_1-6Alkyl and (d) mono or
Is di (C_1-6Alkyl or amino substituted with 1 or 2
C that may be_1-61 with a substituent selected from alkyl
Or two substituted amino groups, (viii) C_1-6Archi
Carbamoyl optionally substituted by 1 or 2
Group, (ix) formyl group, (x) C_2-6Alkanoyl group, (xi) C
_6-14Aryl group, (xii) C_6-14Aryl-carbonyl
Group, (xiii) C_7-13Aralkyl-carbonyl group, (xiv) water
Acid group, (xv) C_2-5Alkanoyloxy group, (xvi) C_7-13A
Aralkyl-carbonyloxy group, (xvii) nitro group, (xvi
ii) C_1-6May be substituted with 1 or 2 alkyl groups
Sulfamoyl group, (xix) C_1-6Place 1 to 3 with alkyl
C which may be replaced_6-14Arylthio group, (xx) -N =
N-Ar (Ar is C_6-14Represents an aryl group)
Group, (xxi) cyano group, (xxii) amidino group, (xxiii)
Boxyl group, (xxiv) C_1-4Alkoxycarbonyl group, (xx
v) C_1-6Alkylthio group, (xxvi) C_1-6Alkylsulfi
Nyl group, (xxvii) C_1-6Alkylsulfonyl group, (xxviii)
C_6-14Arylthio, (xxix) C_6-14Arylsulfini
Group, (xxx) C_6-14Arylsulfonyl group, and (xxx
i) C_1-6Alkyl, C_1-6Alkoxy, halogen, oki
So, thioxo and C _1-61 selected from alkylthio
5 to 6-membered heterocyclic ring optionally substituted with up to 5 substituents
Of a group or its 5- or 6-membered heterocyclic or benzene ring
Condensed group: substituted with 1 to 5 substituents selected from
May be C_6-14Aryl group, (5) (i) 1 to 5 halogens
Optionally substituted C_1-6Alkoxy group, (ii) halogen
1-3 substituents selected from carbamoyl and carbamoyl
C which may be replaced_6-14Aryloxy group, (iii) c
A halogen atom, (iv) 1 to 5 halogen atoms
Good C_1-6Alkyl group, (v) C_3-8Cycloalkyl group, (v
i) amino group, (vii) (a) carbamoyl, (b) C_1-6Alkyl
Sulfonyl, (c) C_1-6Alkyl and (d) mono or
J (C_1-6Alkyl or amino substituted by 1 or 2
May be C_1-6One of the substituents selected from alkyl
Or two substituted amino groups, (viii) C_1-6Alkyl
May be substituted with one or two carbamoyls
Group, (ix) formyl group, (x) C_2-6Alkanoyl group, (xi) C
_6-14Aryl group, (xii) C_6-14Aryl-carbonyl
Group, (xiii) C_7-13Aralkyl-carbonyl group, (xiv) water
Acid group, (xv) C_2-5Alkanoyloxy group, (xvi) C_7-13A
Aralkyl-carbonyloxy group, (xvii) nitro group, (xvi
ii) C_1-6May be substituted with 1 or 2 alkyl groups
Sulfamoyl group, (xix) C_1-6Place 1 to 3 with alkyl
C which may be replaced_6-14Arylthio group, (xx) -N =
N-Ar (Ar is C_6-14Represents an aryl group)
Group, (xxi) cyano group, (xxii) amidino group, (xxiii)
Boxyl group, (xxiv) C_1-4Alkoxycarbonyl group, (xx
v) C_1-6Alkylthio group, (xxvi) C_1-6Alkylsulfi
Nyl group, (xxvii) C_1-6Alkylsulfonyl group, (xxviii)
C_6-14Arylthio, (xxix) C_6-14Arylsulfini
Group, (xxx) C_6-14Arylsulfonyl group, and (xxx
i) C_1-6Alkyl, C_1-6Alkoxy, halogen, oki
So, thioxo and C _1-61 selected from alkylthio
5 to 6-membered heterocyclic ring optionally substituted with up to 5 substituents
Of a group or its 5- or 6-membered heterocyclic or benzene ring
Meridyl group: each substituted with 1 to 5 substituents selected from
C that may be_3-7Cycloalkyl group or C_3-6
Cycloalkenyl group, (6) (i) 1 to 5 substituents with halogen
C that may be_1-6Alkyl, (ii) C_1-6Alkoki
(Iii) halogen, (iv) oxo, (v) thioxo and (v
i) C_1-6With 1 to 5 substituents selected from alkylthio
5- or 6-membered heterocyclic group which may be substituted or
6-membered heterocyclic ring or fused ring group with benzene ring, (7) (i)
Logen and C_6-141 to 5 positions selected from aryl
C optionally substituted with a substituent_1-6Alkyl group, (ii) C
_1-6C 1-5 optionally substituted with alkyl_6-14A
Reel group, (iii) formyl group, (iv) C_2-6Alkanoyl
Group, (v) C_6-14Aryl-carbonyl group, (vi) C_1-6Al
Killsulfonyl group, (vii) C_1-6Substitute 1-3 with alkyl
C that may be_6-14An arylsulfonyl group, and
(viii) C optionally substituted by 1 to 3 halogens_1-6
An alkoxy-carbonyl group, and (ix) C_1-6Alkyl
Or one or two of which may be substituted with formyl
Substituted with one or two substituents selected from a midino group
An optionally substituted amino group (where two substituents
Together with the atom, C_1-6Alkyl group, C_7-10Aral
Kill group and C_6-101 to 3 selected from aryl groups
3- to 8-membered cyclic amino group which may be substituted with a substituent
(8) (i) halogen and C_6-14Ants
Even when substituted with 1 to 5 substituents selected from
Good C_1-6Alkyl group, (ii) C_1-6Alkyl 1-5 places
C which may be replaced_6-14Aryl group, (iii) formyl
Group, (iv) C_2-6Alkanoyl group, (v) C_6-14Aryl-ka
Rubonyl group, (vi) C_1-6Alkylsulfonyl group, (vii) C
_1-6C optionally substituted with 1 to 3 alkyl (s)_6-14A
1 to 3 reelsulfonyl groups and (viii) halogen
Optionally substituted C_1-6Alkoxy-carbonyl group
Substituted with one or two substituents selected from
Amidino group, (9) (i) halogen and C_6-14Ally
May be substituted with 1 to 5 substituents selected from
C_1-6Alkyl group, (ii) C_1-6Substitute 1 to 5 with alkyl
C that may be_6-14Aryl group, (iii) formyl
Group, (iv) C_2-6Alkanoyl group, (v) C_6-14Aryl-ka
Rubonyl group, (vi) C_1-6Alkylsulfonyl group, (vii) C
_1-6C optionally substituted with 1 to 3 alkyl (s)_6-14A
1 to 3 reelsulfonyl groups and (viii) halogen
Optionally substituted C_1-6Alkoxy-carbonyl group
A hydroxyl group which may be substituted with a substituent selected from (1)
0) (i) halogen and C_6-141 selected from aryl
C optionally substituted with 5 substituents_1-6Alkyl
Group, (ii) C_1-61 to 5 alkyl groups may be substituted
C_6-14Aryl group, (iii) formyl group, (iv) C_2-6Al
Canoyl group, (v) C_6-14Aryl-carbonyl group, (vi)
C_1-6Alkylsulfonyl group, (vii) C_1-61 with alkyl
Up to 3 optionally substituted C_6-14Arylsulfonyl
Group, and (viii) even if substituted with 1 to 3 halogens
Good C_1-6Substitution selected from alkoxy-carbonyl group
A thiol group which may be substituted with a group, (11) (i)
A xyl group, (ii) C_1-6An alkoxy-carbonyl group, (iii)
 (a) hydroxyl group, (b) C_1-6Alkyl group, mono- or di-
C_1-6C substituted with 1 to 3 alkylamino_1-6Archi
Group, mono- or di-C_3-6Cycloalkylamino
Substituted with one to three C_1-6Alkyl group, formyl, C
_2-6One if selected from alkanoyl and benzoyl
Or an amino group optionally substituted with two substituents,
(c) halogen atom, (d) nitro, (e) cyano, (f) 1 to 5
C optionally substituted with halogen_1-6Alkyl group,
And (g) optionally substituted with 1 to 5 halogens
C_1-6Substituted with 1 to 3 substituents selected from alkoxy groups
C which may be replaced_6-10Aryloxy-carbonyl
And (iv) (a) hydroxyl, (b) C_1-6Alkyl group, mono
-Or di-C_1-61-3 substituted with alkylamino
C_1-6Alkyl group, mono- or di-C_3-6Cyclo
C substituted with 1 to 3 alkylamino_1-6Alkyl
Group, formyl, C_2-6Alkanoyl and benzoyl?
Even if it is substituted with one or two substituents selected from
Good amino group, (c) halogen atom, (d) nitro, (e) shea
No, (f) C optionally substituted with 1 to 5 halogens
_1-6Alkyl group, and (g) substituted with 1 to 5 halogens.
C that may be_1-61-3 selected from alkoxy groups
C which may be substituted with_7-10Aralquilo
Esterified selected from xy-carbonyl groups,
Carboxyl group, (12) (i) (a) hydroxyl group, (b) C_1-6A
Alkyl group, mono- or di-C_1-6With alkylamino
1-3 substituted C_1-6Alkyl groups, mono- or
Di-C_3-61-3 substituted by cycloalkylamino
C_1-6Alkyl group, formyl, C_2-6Alkanoyl and
Substituted with one or two substituents selected from benzoyl
Optionally substituted amino group, (c) halogen atom, (d) nitro
B, (e) cyano, and (f) substituted with 1 to 5 halogens
C that may be_1-61 to 1 selected from an alkoxy group
C optionally substituted with three substituents_1-6Alkyl
Group, (ii) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono-if
Kuha-C_1-6C substituted with 1 to 3 alkylamino
_1-6Alkyl group, mono- or di-C_3-6Cycloalkyl
C substituted with 1 to 3 amino acids_1-6Alkyl group, phor
Mill, C_2-6Selected from alkanoyl and benzoyl
Amino which may be substituted with one or two substituents
Group, (c) halogen atom, (d) nitro, (e) cyano, (f) 1
C optionally substituted with up to 5 halogens_1-6Archi
And (g) substituted with 1 to 5 halogens.
Good C_1-61-3 substitutions selected from alkoxy groups
C optionally substituted with a group_3-6A cycloalkyl group, (ii
i) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono- or di-
-C_1-6C substituted with 1 to 3 alkylamino_1-6Al
Kill group, mono- or di-C_3-6Cycloalkylamide
C substituted 1 to 3 times_1-6Alkyl group, formyl,
C_2-6Also one selected from alkanoyl and benzoyl
Or an amino group optionally substituted with two substituents,
(c) halogen atom, (d) nitro, (e) cyano, (f) 1 to 5
C optionally substituted with halogen_1-6Alkyl group,
And (g) optionally substituted with 1 to 5 halogens
C_1-6Substituted with 1 to 3 substituents selected from alkoxy groups
C which may be replaced_6-10Aryl group, (iv) (a) hydroxyl
Group, (b) C_1-6Alkyl group, mono- or di-C_1-6A
C substituted with 1 to 3 alkylamino_1-6Alkyl group,
Mono- or Di-C_3-61 to cycloalkylamino
Three substituted C_1-6Alkyl group, formyl, C_2-6Al
One or two selected from canoyl and benzoyl
An amino group optionally substituted with a substituent of
Atom, (d) nitro, (e) cyano, (f) 1 to 5 halogen
C optionally substituted with_1-6An alkyl group, and (g)
C optionally substituted with 1 to 5 halogens_1-6Al
Substituted with 1 to 3 substituents selected from a oxy group
May be C_7-10An aralkyl group, and (v) (a) a hydroxyl group,
(b) C_1-6Alkyl group, mono- or di-C_1-6Archi
C substituted with 1 to 3 amino acids_1-6Alkyl group, mono
-Or di-C_3-61 to 3 cycloalkylamino
Replaced C_1-6Alkyl group, formyl, C_2-6Alkano
One or two positions selected from yl and benzoyl
An amino group which may be substituted with a substituent, (c) a halogen atom
(D) nitro, (e) cyano, (f) 1 to 5 halogens
Optionally substituted C_1-6An alkyl group, and (g) 1
C optionally substituted with 5 halogens_1-6Alkoki
Even when substituted with 1 to 3 substituents selected from
A good 5- to 6-membered heterocyclic group or its 5- to 6-membered heterocyclic group or
Is one or two selected from a condensed ring group with a benzene ring
A carbamoyl group (two
Together with the adjacent nitrogen atom form C_1-6A
Alkyl group, C_7-10Aralkyl group and C_6-10Aryl group
May be substituted with 1 to 3 substituents selected from
(A 3- to 8-membered cyclic amino group may be formed), (13) (i)
(a) hydroxyl group, (b) C_1-6Alkyl group, mono- or di-
C_1-6C substituted with 1 to 3 alkylamino_1-6Archi
Group, mono- or di-C_3-6Cycloalkylamino
Substituted with one to three C_1-6Alkyl group, formyl, C
_2-6One if selected from alkanoyl and benzoyl
Or an amino group optionally substituted with two substituents,
(c) a halogen atom, (d) nitro, (e) cyano, and (f) 1
C optionally substituted with up to 5 halogens_1-6Arco
Substituted with 1 to 3 substituents selected from xy groups,
Good C_1-6Alkyl group, (ii) (a) hydroxyl group, (b) C_1-6A
Alkyl group, mono- or di-C_1-6With alkylamino
1-3 substituted C_1-6Alkyl groups, mono- or
Di-C_3-61-3 substituted by cycloalkylamino
C_1-6Alkyl group, formyl, C_2-6Alkanoyl and
Substituted with one or two substituents selected from benzoyl
Optionally substituted amino group, (c) halogen atom, (d) nitro
B) (e) cyano, (f) substituted with 1 to 5 halogens.
May be C_1-6An alkyl group, and (g) 1 to 5 halogen
C optionally substituted with_1-6Choose from alkoxy groups
C optionally substituted with 1 to 3 substituents_3-6Shi
Chloroalkyl group, (iii) (a) hydroxyl group, (b) C_1-6Alkyl
Group, mono- or di-C_1-61-3 with alkylamino
Replaced C_1-6Alkyl group, mono- or di-C
_3-6C substituted with 1 to 3 cycloalkylamino_1-6A
Alkyl group, formyl, C_2-6Alkanoyl and benzo
Substituted with one or two substituents selected from yl
Optionally amino group, (c) halogen atom, (d) nitro,
(e) cyano, (f) even when substituted with 1 to 5 halogens
Good C_1-6An alkyl group, and (g) 1 to 5 halogens
Optionally substituted C_1-6Selected from alkoxy groups
C optionally substituted with 1 to 3 substituents_6-10Ally
(Iv) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono-
Or Di-C_1-61-3 substituted with alkylamino
C_1-6Alkyl group, mono- or di-C_3-6Cycloal
C substituted with 1 to 3 alkylamino_1-6Alkyl group, e
Lumil, C_2-6Choose from alkanoyl and benzoyl
A which may be substituted with one or two substituents
Amino group, (c) halogen atom, (d) nitro, (e) cyano, (f)
C optionally substituted with 1 to 5 halogens_1-6Al
A alkyl group, and (g) substituted with 1 to 5 halogens.
May be C_1-61 to 3 positions selected from alkoxy groups
C optionally substituted with a substituent_7-10Aralkyl groups and
(V) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono- or
Is Di-C_1-6C substituted with 1 to 3 alkylamino_1-6
Alkyl group, mono- or di-C_3-6Cycloalkyl
C substituted with 1 to 3 amino groups_1-6Alkyl group, holmi
Le, C_2-6Selected from alkanoyl and benzoyl
Amino optionally substituted with one or two substituents
Group, (c) halogen atom, (d) nitro, (e) cyano, (f) 1
C optionally substituted with 5 halogens_1-6Alkyl
And (g) even if substituted with 1 to 5 halogens
Good C_1-61 to 3 substituents selected from alkoxy groups
Or a 5- or 6-membered heterocyclic group optionally substituted with
Selected from a 6-membered heterocyclic ring or a condensed ring group with a benzene ring
Which may be substituted with one or two substituents
Ocarbamoyl group (where two substituents are
Together, C_1-6Alkyl group, C_7-10Aralkyl group
And C_6-101 to 3 substituents selected from aryl groups
Forms a 3- to 8-membered cyclic amino group which may be substituted with
(14) halogen atom, (15) cyano group, (16)
Nitro group, (17) (i) (a) hydroxyl group, (b) C_1-6Alkyl group, mo
No- or di-C_1-6Substitute 1-3 with alkylamino
Done C_1-6Alkyl group, mono- or di-C_3-6Shiku
C substituted with 1-3 alkylamino_1-6Alkyl
Group, formyl, C_2-6Alkanoyl and benzoyl?
Even if it is substituted with one or two substituents selected from
Good amino group, (c) halogen atom, (d) nitro, (e) shea
And (f) even when substituted with 1 to 5 halogens
Good C_1-61 to 3 substituents selected from alkoxy groups
C optionally substituted with_1-6Alkyl group, (ii) (a) water
Acid group, (b) C_1-6Alkyl group, mono- or di-C_1-6
C substituted with 1 to 3 alkylamino_1-6Alkyl
Group, mono- or di-C_3-6With cycloalkylamino
1-3 substituted C_1-6Alkyl group, formyl, C_2-6
One selected from alkanoyl and benzoyl or
An amino group optionally substituted with two substituents, (c)
A halogen atom, (d) nitro, (e) cyano, (f) 1-5
C optionally substituted with a logen_1-6Alkyl group and
And (g) C optionally substituted with 1 to 5 halogens_1-6
Substituted with 1 to 3 substituents selected from an alkoxy group
May be C_3-6Cycloalkyl group, (iii) (a) hydroxyl
Group, (b) C_1-6Alkyl group, mono- or di-C_1-6A
C substituted with 1 to 3 alkylamino_1-6Alkyl group,
Mono- or Di-C_3-61 to cycloalkylamino
Three substituted C_1-6Alkyl group, formyl, C_2-6Al
One or two selected from canoyl and benzoyl
An amino group optionally substituted with a substituent of
Atom, (d) nitro, (e) cyano, (f) 1 to 5 halogen
C optionally substituted with_1-6An alkyl group, and (g)
C optionally substituted with 1 to 5 halogens_1-6Al
Substituted with 1 to 3 substituents selected from a oxy group
May be C_6-10Aryl group, (iv) (a) hydroxyl group, (b) C_1-6
Alkyl group, mono- or di-C_1-6Alkylamino
Substituted with one to three C_1-6Alkyl groups, mono- or
Is Di-C_3-61-3 substituted with cycloalkylamino
C_1-6Alkyl group, formyl, C_2-6Alkanoyl and
And one or two substituents selected from benzoyl
Optionally substituted amino group, (c) halogen atom, (d)
Toro, (e) cyano, (f) substituted with 1 to 5 halogens
May be C_1-6An alkyl group, and (g) 1 to 5 halo
C optionally substituted with gen_1-6Select from alkoxy groups
C which may be substituted with 1 to 3 substituents_7-10
Aralkyl group, and (v) (a) hydroxyl group, (b) C_1-6Archi
Group, mono- or di-C_1-61 to alkylamino
Three substituted C_1-6Alkyl group, mono- or di-
C_3-6C substituted with 1 to 3 cycloalkylamino_1-6
Alkyl group, formyl, C_2-6Alkanoyl and ben
Substituted with one or two substituents selected from zoyl
Optionally an amino group, (c) a halogen atom, (d) nitro,
(e) cyano, (f) even when substituted with 1 to 5 halogens
Good C_1-6An alkyl group, and (g) 1 to 5 halogens
Optionally substituted C_1-6Selected from alkoxy groups
5 to 6-membered heterocyclic group which may be substituted by 1 to 3 substituents
A cyclic group or a 5- or 6-membered heterocyclic or benzene ring
A sulfonyl group bonded to a sulfonyl group
Acyl group derived from fonic acid, (18) hydrogen atom, or (i) (a) water
Acid group, (b) C_1-6Alkyl group, mono- or di-C_1-6
C substituted with 1 to 3 alkylamino_1-6Alkyl
Group, mono- or di-C_3-6With cycloalkylamino
1-3 substituted C_1-6Alkyl group, formyl, C_2-6
One selected from alkanoyl and benzoyl or
An amino group optionally substituted with two substituents, (c)
A halogen atom, (d) nitro, (e) cyano, and (f) 1-5
C optionally substituted with two halogens_1-6Alkoxy
May be substituted with 1 to 3 substituents selected from
C_1-6Alkyl group, (ii) (a) hydroxyl group, (b) C_1-6Archi
Group, mono- or di-C_1-61 to alkylamino
Three substituted C_1-6Alkyl group, mono- or di-
C_3-6C substituted with 1 to 3 cycloalkylamino_1-6
Alkyl group, formyl, C_2-6Alkanoyl and ben
Substituted with one or two substituents selected from zoyl
Optionally an amino group, (c) a halogen atom, (d) nitro,
(e) cyano, (f) even when substituted with 1 to 5 halogens
Good C_1-6An alkyl group, and (g) 1 to 5 halogens
Optionally substituted C_1-6Selected from alkoxy groups
C optionally substituted with 1 to 3 substituents_3-6Cyclo
Alkyl group, (iii) (a) hydroxyl group, (b) C_1-6Alkyl group,
Mono- or Di-C_1-6Place 1 to 3 with alkylamino
Transformed C_1-6Alkyl group, mono- or di-C_3-6Shi
C substituted with 1 to 3 cycloalkylamino_1-6Archi
Group, formyl, C_2-6Alkanoyl and benzoyl
Substituted with one or two substituents selected from
Amino group, (c) halogen atom, (d) nitro, (e)
Ano, (f) optionally substituted with 1 to 5 halogens
C_1-6Substituted with an alkyl group and (g) 1 to 5 halogens
C that may be_1-61 to 1 selected from an alkoxy group
C optionally substituted with three substituents_6-10Aryl
Group, (iv) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono-if
Kuha-C_1-6C substituted with 1 to 3 alkylamino
_1-6Alkyl group, mono- or di-C_3-6Cycloalkyl
C substituted with 1 to 3 amino acids_1-6Alkyl group, phor
Mill, C_2-6Selected from alkanoyl and benzoyl
Amino which may be substituted with one or two substituents
Group, (c) halogen atom, (d) nitro, (e) cyano, (f) 1
C optionally substituted with up to 5 halogens_1-6Archi
And (g) substituted with 1 to 5 halogens.
Good C_1-61-3 substitutions selected from alkoxy groups
C optionally substituted with a group_7-10An aralkyl group, and
(v) (a) hydroxyl group, (b) C_1-6Alkyl groups, mono- or
Di-C_1-6C substituted with 1 to 3 alkylamino_1-6A
Alkyl group, mono- or di-C_3-6Cycloalkylua
C substituted with 1 to 3 amino acids_1-6Alkyl group, holmi
Le, C_2-6Selected from alkanoyl and benzoyl
Amino optionally substituted with one or two substituents
Group, (c) halogen atom, (d) nitro, (e) cyano, (f) 1
C optionally substituted with 5 halogens_1-6Alkyl
And (g) even if substituted with 1 to 5 halogens
Good C_1-61 to 3 substituents selected from alkoxy groups
Or a 5- or 6-membered heterocyclic group optionally substituted with
Selected from a 6-membered heterocyclic ring or a condensed ring group with a benzene ring
Derived from a carboxylic acid in which the group
Group, (19) oxo group, (20) thioxo group, and (21) sulfo group.
Each with 1 to 5 substituents selected from a famoyl group
Optionally substituted (1) C_6-14No aryl group, (2) 5
6-membered aromatic monocyclic heterocyclic group or 8-12-membered aromatic condensed
Heterocyclic group, (3) C_3-9Cycloalkyl group, 1-indani
Group, 2-indanyl group, C_3-6Also cycloalkenyl groups
Or C_4-6Cycloalkanedienyl group, or (4) 3-
X represents a cyclic group selected from an 8-membered non-aromatic heterocyclic group;
Bonded to A by hand or through an oxygen or sulfur atom
May be, C _1-6Alkylene group or C_2-6Alkenelle
Group, Y is (1) sulfur atom, (2) oxygen atom, (3) -C (= O) -N
(R¹⁵)-(R¹⁵Is substituted with 1 to 3 hydrogen atoms or halogens
C that may be_1-6Alkyl group), (4) -SO_Two-N
(R¹⁶)-(R¹⁶Is substituted with 1 to 3 hydrogen atoms or halogens
C that may be_1-6Alkyl group), (5) -C (= O)
-O-, (6) -SO-, (7) -SO_Two-Or (8) -N (R¹⁷)-(R¹⁷Is
1 to 3 hydrogen atoms or halogens may be substituted
C_1-6Represents an alkyl group), and represented by A-X-Y-.
May be carried by the cyclic group represented by A.
1 to 5 substituents may be substituted with the same substituents as
5 to 8 membered heterocyclic group or 5 to 8 membered heterocyclic ring and ben
A condensed heterocyclic ring obtained by condensing 1 to 3 rings selected from a zen ring
L may be an integer from 2 to 6, and m may be
An integer from 2 to 4 and n is an integer from 0 to 8
A compound according to claim 1. 3. The compound according to claim 1, wherein R ¹ and R ² are each a hydrogen atom or a methyl group. 4. X is a bond, CH ₂ , CH ₂ CH ₂ CH ₂ , S
_{2. The method according to} claim 1, wherein CH ₂ , SCH ₂ CH ₂ or CH = CH.
A compound as described. 5. The compound according to claim 1, wherein X is a bond or CH ₂ . 6. Y is -C (= O) -N (R ¹⁵ )-(R ¹⁵ is as defined in claim 1) or -SO ₂ -N (R ¹⁶ )-(R ¹⁶ is The compound according to claim 1, which has the same significance as described in item 1.). 7. The compound according to claim 1, wherein 1 is 3, 4 or 5. 8. The compound according to claim 1, wherein m is 2 or 3. 9. The compound according to claim 1, wherein n is an integer from 2 to 5. 10. The method according to claim 1, wherein 1 is 4, m is 2, and n is 3.
A compound as described. 11. R ¹ and R ² each represent a hydrogen atom or a C _1-6 alkyl group, and A represents A cyclic group having a bond in a ring selected from the group consisting of (1) (i) a halogen atom, (ii) an amino group, (iii) an amino group substituted by one or two benzoyl groups, and ( iv)
A substituent selected from C _1-6 alkyl and halogen;
A C _1-6 alkyl group _optionally substituted with 1 to 5 substituents selected from an optionally substituted C _6-14 aryl group, (2) (i) a halogen atom, and ( ii) optionally have been 1-5 substituted with a halogen substituted with 1 to 5 substituents, also selected from optionally C _1-6 alkyl group C _6-14
Aryl group, (3) 1-3 optionally substituted with 1 to 5 halogen-substituted C _1-6 alkyl,
A 6-membered heterocyclic group, (4) an amino group optionally substituted with one or two substituents selected from a C _1-6 alkyl group and a C _2-6 alkanoyl group, (5) (i) halogen Or an optionally substituted C _1-6 alkyl group or (ii) C
_6-14 hydroxyl group _optionally substituted with an aryl group, (6) (i)
C _{1-6 optionally} substituted with 1 to 3 C _6-14 aryl
An alkyl group, or (ii) a thiol group optionally substituted with 1 to 5 C _6-14 aryl groups optionally substituted with C _1-6 alkyl, (7) C _3-6 cycloalkylamino- C
_1-6 alkylamino -C _1-6 alkyl carbamoyl group which may be substituted with a group, (8) halogen atoms, (9) a halogen 1-3 optionally substituted by C _1-6 alkyl atoms -
Carbonyl group, (10) benzoyl group (11) oxo group, and
(12) A C _1-6 alkylene group or C ₂ which may be respectively substituted with 1 to 5 substituents selected from a sulfamoyl group, and X may be bonded to A via a bond or a sulfur atom. _-6 alkenylene group, Y is (1) a sulfur atom, (2) an oxygen atom, (3) -C (= O ) -N (R 15) - and (R ¹⁵ is a hydrogen atom or a C _{1 -6} alkyl group _{shown), (4) -SO 2 -N} (R 16) - (R 16 represents a hydrogen atom or a C _1-6 alkyl group), (5) -C (= O) -O -, (6) - S
O—, (7) —SO ₂ —, or (8) —N (R ¹⁷ ) — (R ¹⁷ represents a hydrogen atom or a C _1-6 alkyl group), and is represented by AXY—. Groups are (i) a C _1-6 alkyl group and (ii)
(a) 1 to 5 substituents selected from halogen and (b) C _1-6 alkyl group, which are substituted with 1 to 3 substituents selected from C _6-14 aryl group which may be substituted. It may be And may form a heterocyclic group selected from
The compound according to claim 1, wherein m is an integer from 2 to 4, and n is an integer from 0 to 8. [12] a prodrug of the compound according to [1] or a salt thereof; 13. A compound of the formula: [Wherein, R ¹ and R ² each represent a hydrogen atom or an alkyl group, A represents an optionally substituted cyclic group, X represents a bond, or an alkylene which may be bound to A via a hetero atom. A group or an alkenylene group, Y is (1) a sulfur atom, (2) an oxygen atom, (3) -C (= O) -N (R ¹⁵ )-(R ¹⁵ is a hydrogen atom or an optionally substituted alkyl Represents a group), (4)-
SO ₂ -N (R ¹⁶ )-(R ¹⁶ represents a hydrogen atom or an optionally substituted alkyl group), (5) -C (= O) -O-, (6) -SO-, (7 )
-SO ₂ - or ^{(8) -N (R 17)} , - (R 17 represents a hydrogen atom or an optionally substituted alkyl group) indicates, A-X-
The group represented by Y- may form an optionally substituted heterocyclic group, l is an integer from 2 to 6, m is an integer from 2 to 4, and n is an integer from 0 to 8. Or a salt thereof, or a prodrug thereof. 14. The composition according to claim 13, which is a chemokine receptor antagonist. 15. The composition according to claim 14, wherein the chemokine receptor is CXCR4. 16. The composition according to claim 13, which is an agent for preventing or treating HIV infection. (17) a prophylactic / therapeutic agent for AIDS;
3. The composition according to 3. (18) the composition according to the above (13), which is an AIDS disease progression inhibitor; 19. The composition according to claim 16, which is combined with one or more agents selected from a protease inhibitor, a reverse transcriptase inhibitor and a CCR5 antagonist. 20. The composition according to claim 19, wherein the reverse transcriptase inhibitor is one or more selected from zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, nevirapine, delavirdine and efavirenz. 21. The composition according to claim 19, wherein the protease inhibitor is one or more selected from saquinavir, ritonavir, indinavir and nelfinavir. 22. The composition according to claim 13, which is an anticancer agent having an antimetastatic effect. (23) The formula (1): [Wherein R ³ represents a carboxyl group, a sulfo group or a reactive derivative thereof, a leaving group or a formyl group, and the other symbols have the same meanings as in claim 1] or a salt thereof and a formula: Embedded image [Wherein, R ⁴ represents an amino group or a substituted amino group, a hydroxyl group or a thiol group, R ⁵ and R ⁶ each represent a hydrogen atom, an alkyl group or an amino group protecting group, and the other symbols are as defined in claim 1. Or a salt thereof, or (2) with the formula: AXR ⁴ (II ′) wherein each symbol is as defined above. A compound represented by the formula or a salt thereof and a compound represented by the formula: Wherein each symbol in the formula has the same meaning as described above, and a protecting group for an amino group is removed if necessary. [The symbols in the formula are as defined in claim 1] or a method for producing a salt thereof. 24. The formula (1): [Wherein R ⁷ is a protecting group for a hydrogen atom, an alkyl group or an amino group, and other symbols are as defined in claim 1] or a salt thereof and a compound represented by the formula: Wherein R ⁸ is a formyl group or a leaving group, R ⁹ is a protecting group for a hydrogen atom, an alkyl group or an amino group, and other symbols are as defined in claim 1. Or a salt thereof, or a compound represented by the formula (2): AXY- (CH ₂ ) ₁ -R ⁸ (IV ′) wherein each symbol is as defined above, or a salt thereof. And the formula: Wherein each symbol in the formula is as defined above, or a salt thereof, and the amino-protecting group is removed as required. [The symbols in the formula are as defined in claim 1] or a method for producing a salt thereof. 25. A compound represented by the formula: AX-NH ₂ (XIX) wherein the symbols are as defined in claim 1, or a salt thereof, and a compound represented by the formula: Wherein R ⁵ and R ⁶ are each a protecting group for a hydrogen atom, an alkyl group or an amino group, and the other symbols are as defined in claim 1. Optionally removing the protecting group of the amino group: [The symbols in the formula are as defined in claim 1] or a method for producing a salt thereof.