WO2006137465A1

WO2006137465A1 - Nitrogenated heterocyclic derivative

Info

Publication number: WO2006137465A1
Application number: PCT/JP2006/312466
Authority: WO
Inventors: Moriyasu Masui; Akira Matsumura
Original assignee: Shionogi & Co., Ltd.
Priority date: 2005-06-24
Filing date: 2006-06-22
Publication date: 2006-12-28
Also published as: JPWO2006137465A1

Abstract

It is found that a nitrogenated heterocyclic derivative represented by the formula (I) can bind specifically to an NR1/NR2B receptor and can be used as an analgestic agent. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or the like: (I) wherein A1 represents a nitrogenated aromatic monocyclic group or nitrogenated aromatic fused-ring group which has at least one hydroxyl and/or amino and which may be substituted by other group or a nitrogenated aromatic monocyclic ring or nitrogenated aromatic fused-ring group which has -NH- in the ring and in which other ring-constituting atom may be substituted; A2 represents an aromatic hydrocarbon cyclic group which may have a substituent or the like; R1 and R2 independently represent a hydrogen, hydroxyl or the like; m is 0 or 1; X represents a lower alkylene, -CO(CR3R4)n- or -A3-(CR3R4)n- which may have a substituent or the like; Y represents a single bond, a lower alkylene or the like; and R3 to R15 independently represent a hydrogen, a lower alkyl or the like.

Description

Specification

Nitrogen-containing heterocyclic derivatives

Technical field

[0001] The present invention shows a specific antagonistic action on a central nerve cell glutamate receptor, particularly NR1ZNR2B receptor, which is one of NMDA receptors, preferably motor function (eg, sensory abnormality), mental The present invention relates to a nitrogen-containing heterocyclic derivative which has few side effects on symptoms (eg, schizophrenia) and is useful as a medicine such as an analgesic.

Background art

Amino acids such as L-glutamic acid and L-aspartic acid are important for neuronal activity as neurotransmitters in the central nervous system. However, the extracellular accumulation of these excitatory amino acids is due to various neurological disorders such as Parkinson's disease, senile dementia, Huntington's chorea, epilepsy, as well as oxygen deficiency, ischemia, hypoglycemia It is thought to cause a loss of mental and motor function, such as that seen during conditions, head or spinal cord injury.

It is known that the activity of the excitatory amino acid on central nerve cells acts via a dalmatate receptor present on the nerve cell, and a glutamate receptor antagonist is a therapeutic agent for the above diseases and symptoms, For example, it is considered useful as an antiepileptic drug, an ischemic brain injury preventive drug, or an antiparkinsonian drug.

The NMDA receptor, one of the glutamate receptors mentioned above, is composed of two subunits, NR1 and NR2, and there are four additional (NR2A, 2B, 2C, 2D) subfamilies in the NR2 subunit. To do. The NR1ZNR2A receptor is exclusively involved in memory formation and learning acquisition, and the NR1ZNR2B receptor is said to be involved in neurodegenerative cell death and pain transmission during cerebral ischemia. Therefore, a drug having high affinity for the NR1ZNR2B receptor is likely to be an effective analgesic with few side effects.

In addition, compounds similar to the nitrogen-containing heterocyclic derivative of the present invention are described in Patent Documents 1 to 12, but the compounds according to the present invention are also described.

Patent Document 1: International Publication No. 2004Z11430 Pamphlet Patent Document 2: International Publication No. 2003Z084948 Pamphlet

Patent Document 3: JP-A-8-22569

Patent Document 4: Pamphlet of International Publication No.98Z18793

Patent Document 5: Pamphlet of International Publication No. 2003Z010159

Patent Document 6: International Publication No. 2004Z054579 Pamphlet

Patent Document 7: Japanese Patent Laid-Open No. 11 71350

Patent Document 8: Pamphlet of International Publication No. 99Z45925

Patent Document 9: Japanese Patent Laid-Open No. 3-206086

Patent Document 10: Pamphlet of International Publication No. 03Z035641

Patent Document 11: Pamphlet of International Publication No. 2005Z030720

Patent Document 12: International Publication No. 2002Z50070 Pamphlet

Disclosure of the invention

Problems to be solved by the invention

[0003] An NMDA receptor antagonist, particularly an analgesic for cancer pain or the like, which is highly active and more preferably exhibits a high affinity for subtypes, particularly the NR1ZNR2B receptor.

Means for solving the problem

[0004] The present invention provides:

Formula (I):

(Where

A ¹ is

Protected, hydroxy, and / or protected, having at least one amino and further substituted with other groups, nitrogen-containing aromatic monocyclic Group or nitrogen-containing aromatic fused cyclic group or The ring contains —NH—, and other ring-constituting atoms may be protected by hydroxy and protected, or may be substituted by substituents other than amino. A nitrogen aromatic monocyclic group or a nitrogen-containing aromatic fused cyclic group,

A ² is

It may be substituted, may be an aromatic hydrocarbon cyclic group or may be substituted, is an aromatic heterocyclic group,

R ¹ is hydrogen, hydroxy, acyloxy, lower alkoxy or lower alkyl,

R ² is hydrogen, hydroxy or lower alkyl,

R ¹ and R ² may be joined together to form a single bond

m is 0 or 1,

X is

It may have a substituent, may be a lower alkylene, may have a substituent, may be a lower alkylene, —CO (CR ³ R ⁴ ) n—, —CONR ⁵ (CR ³ R ⁴ ) n—, — NR ⁵ CO (CR ³ R ⁴ ) n—, -NR ⁵ CONR ⁶ (CR ³ R ⁴ ) n—, — C (= N—OR ⁷ ) (CR ³ R ⁴ ) n—, -(CR ⁸ R ⁹ ) rO (CR ³ R ⁴ ) n―, ― (CR ⁸ R ⁹ ) rS (CR ³ R ⁴ ) n―, ― (CR ⁸ R ⁹ ) rNR ⁶ (CR ³ R ⁴ ) n ―, ― (CR ⁸ R ⁹ ) rS 0 (CR ³ R ⁴ ) n―, ― (CRV) rSO (CR ³ R ⁴ ) n―, ― CR ⁹ = N― O (CR ³ R ⁴ ) n―, -

2

C (= 0) 0 (CR ³ R ⁴ ) n-, -A ^3- (CR ³ R ⁴ ) n— or — A ³ — CI ^^ CR ¹¹ (CR ³ R ⁴ ) n—

When m = 1, X may be a lower alkylene which may be substituted with hydroxy n and r are each independently an integer of 0 to 4, n + r is 4 or less,

A ³ is

[Chemical 2]

(In the formula, the broken line indicates the presence or absence of a bond, and R ^x is hydrogen or lower alkyl)

And

— X— (CO) m—, optionally substituted lower alkylene, optionally substituted lower alkylene, CO (CR ³ R ⁴ ) n—, — NR ⁶ CO (CR ³ R ⁴ ) n, — (where n is 1 or 2), 1 NR ⁶ COCO, 1 NR ⁶ (CR ³ R ⁴ ) nCO, 1 S (CR ³ R ⁴ ) n—, 1 SO (CR ³ R ⁴ ) n— or one A ³ — (CR ³ R ⁴ ) n—

A ¹ may be protected, hydroxy, and / or protected, may have at least one amino group, and may be further substituted with another group. Formulas or rings containing —NH— and other ring-constituting nuclear, optionally protected hydroxy and protected, or substituted with substituents other than amino It is an aromatic monocyclic group,

— X— (CO) m— is — S (CR ³ R ⁴ ) n— —Y—A ² is not substituted with unsubstituted benzyl

Y is

i) When m = 0, single bond, —CR

CH COR 'or NR ^{1 &} , together with R = CR ¹⁴

ii) when m = l, a single bond, lower alkylene, lower alkylene, lower alkylene,

O, 1 S, 1 NR —, 1 CR RO-CR RS-or-CR R NR-, together with R ^z = CR ¹⁴ — (CR ¹⁵ R ^lD ) p may be formed p is an integer from 0 to 5 Number,

R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , ¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently hydrogen or substituent Or a pharmaceutically acceptable salt thereof, which is lower alkyl, and may be different when there are a plurality of R ³ and R ⁴ , respectively. Or a solvate thereof.

(1,) Formula (I):

[Chemical 3]

(Where

A ¹ is

Protected, hydroxy, and / or protected, having at least one amino and further substituted with other groups, nitrogen-containing aromatic monocyclic Group or nitrogen-containing aromatic fused cyclic group or

The ring contains —NH—, and other ring-constituting atoms may be protected by hydroxy and protected, or may be substituted by substituents other than amino. A nitrogen aromatic monocyclic group or a nitrogen-containing aromatic fused cyclic group,

A ² is

R ¹ is hydrogen or hydroxy;

R ² is hydrogen, hydroxy or lower alkyl,

R ¹ and R ² may be joined together to form a single bond

m is 0 or 1,

X is

It may have a substituent, may be a lower alkylene, may have a substituent, may be a lower alkylene, —CO (CR ³ R ⁴ ) n—, —CONR ⁵ (CR ³ R ⁴ ) n—, — NR ⁵ CO (CR ³ R ⁴ ) n—,- NR ⁵ CONR ⁶ (CR ³ R ⁴ ) n—, — C (= N—OR ⁷ ) (CR ³ R ⁴ ) n—, — (CR ⁸ R ⁹ ) rO (CR ³ R ⁴ ) n—, — ( CR ⁸ R ⁹ ) rS (CR ³ R ⁴ ) n—, — (CR ⁸ R ⁹ ) rNR ⁶ (CR ³ R ⁴ ) n—, — (CR ⁸ R ⁹ ) rS 0 (CR ³ R ⁴ ) n— , — (CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) n—, — CR ⁹ = N— O (CR ³ R ⁴ ) n-,-

2

When m = l, X may be a lower alkylene which may be substituted with hydroxy n and r are each independently an integer of 0 to 4, n + r is 4 or less,

A ³ is

[Chemical 4]

And

― X— (CO) m— optionally substituted lower alkylene, optionally substituted lower alkylene, —CO (CR ³ R ⁴ ) n—, —NR ⁶ CO (CR ³ R ⁴ ) n, — (where n is 1 or 2), 1 NR ⁶ COCO—, 1 NR ⁶ (CR ³ R ⁴ ) nCO—, 1 S (CR ³ R ⁴ ) n— , One SO (CR ³ R ⁴ ) n— or one A ³ — (CR ³ R ⁴ ) n—

A ¹ may be protected, hydroxy, and / or protected, may have at least one amino group, and may be further substituted with another group. Formulas or rings containing —NH— and other ring-constituting nuclear, optionally protected hydroxy and protected, or substituted with substituents other than amino It is an aromatic monocyclic group, — X— (CO) m— is — S (CR ³ R ⁴ ) n— —Y— A ² is not substituted with unsubstituted benzyl

Y is

i) when m = 0, single bond, one CR ¹² R ¹³ —, one O, one S or one NR ¹⁵ — and together with R ² may form = CR ¹⁴

ii) when m = l, single bond, lower alkylene, lower alkylene, lower alkylene, O, 1 S—, 1 NR ¹⁵ , 1 CR ¹² R ¹³ 0—, 1 CR ¹² R ¹³ S or 1 CR ¹² R ¹³ NR ¹⁵ — and together with R ² = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p may be formed p is an integer from 0 to 5,

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,

R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ each independently have hydrogen or a substituent, and may be lower alkyl, and a plurality of R ³ and R ⁴ are present respectively. Each is different! /, But! /,)

Or a pharmaceutically acceptable salt thereof or a solvate thereof.

(1,) Formula (I):

[Chemical 5]

(Where

A ¹ is

In the ring—containing NH, and other ring-constituting atoms may be protected by hydroxy and protected, or may be substituted with substituents other than amino, or nitrogen-containing An aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,

A ² is

It may have a substituent, and may have an aromatic hydrocarbon cyclic group or a substituent. An aromatic heterocyclic group,

R ¹ is hydrogen or hydroxy;

R ² is hydrogen, hydroxy or lower alkyl,

R ¹ and R ² may be joined together to form a single bond

m is 0 or 1,

X is

May have a substituent, may be a lower alkylene, may have a substituent, may be a lower alkylene, —CO (CR ³ R ⁴ ) n—, —CONR ⁵ (CR ³ R ⁴ ) n—, — NR ⁵ CO (CR ³ R ⁴ ) n—, -NR ⁵ CONR ⁶ (CR ³ R ⁴ ) n—, — C (= N—OR ⁷ ) (CR ³ R ⁴ ) n—, -(CR ⁸ R ⁹ ) rO (CR ³ R ⁴ ) n―, ― (CR ⁸ R ⁹ ) rS (CR ³ R ⁴ ) n―, ― (CR ⁸ R ⁹ ) rNR ⁶ (CR ³ R ⁴ ) n ―, ― (CR ⁸ R ⁹ ) rS 0 (CR ³ R ⁴ ) n―, ― (CRV) rSO (CR ³ R ⁴ ) n―, ― CR ⁹ = N― O (CR ³ R ⁴ ) n―, -

10 11

C (= 0) 0 (CR ³ R ⁴ ) n Α ^ύ- (CR ³ R ⁴ ) n- ^or- Α ^ΰ — CR ^1U = CR "-, and when m = l, X is substituted with hydroxy N and r are each independently an integer of 0 to 4, n + r is 4 or less,

A ³ is

[Chemical 6]

(In the formula, a broken line indicates the presence or absence of a bond)

And

A ¹ may be protected, hydroxy and / or protected, may be less amino At least one nitrogen-containing aromatic monocyclic group which may be substituted with another group or —NH— in the ring, and other ring-constituting nuclear power, protected Good hydroxy and protected, substituted with substituents other than amino, may be aromatic monocyclic groups,

When —X— (CO) m— is — S (CR ³ R ⁴ ) n—, —Y—A ² is not substituted with unsubstituted benzyl.

Y is

i) when m = 0, single bond, CR ¹² R ¹³ , 1 O, 1 S or 1 NR ¹⁵ together with R ² = CR ¹⁴ may be formed

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,

Or a pharmaceutically acceptable salt thereof or a solvate thereof.

(2) pyridyl A ¹ is substituted with at least hydroxy, quinolyl substituted with at least hydroxy, downy substituted with at least hydroxy Nzuokisazoriru, downy substituted with at least hydroxy Nzuimidazoriru, at least protected, even in goodヽAmino A substituted pyridyl, an imidazolyl ring which may be substituted with a ring atom other than —NH, a ring atom other than NH may be substituted, or a ring atom other than pyrrolyl or NH may be substituted; Ring atoms other than virazolyl and NH may be substituted !, or benzopyrazolyl, benzimidazolyl, which may be substituted with a ring atom other than NH—, or other than NH Or a pharmaceutically acceptable compound thereof, which is an indolyl which may be substituted on a ring-constituting atom of (1), (1 ′) or (1 ′ ′) Acceptable salts or solvates thereof.

(3) Yahata [Chemical 7]

(Where Ms is methanesulfol)

Or a pharmaceutically acceptable salt or solvate thereof according to (1), (1 ′) or (1 ″).

(4) — X— is CO (CHR ³ ) n— CONH (CHR ³ ) n— NHCO (CHR ³ ) n— 0 (CHR ³ ) n SO (CHR ³ ) n SO (CHR ³ ) n CH = NO (CHR ³ )

2

n C (= 0) 0 (CHR ³ ) n A ³ — CHR ³ or A ³ — CH

twenty four

(1), (1 ′) or (1 ′ ′), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(4,) One X—Power -CO (CH) n -CONH (CH) n NHCO (CH) n

2 2 2

0 (CH) n—, —SO (CH) n—, —SO (CH) n—, —CH = NO (CH) n— or

2 2 2 2 2

— C (= 0) 0 (CH 3) n—, the compound according to (1), (1 ′) or (1 ″) above or

2

The pharmaceutically acceptable salt or solvate thereof.

(5) The compound according to (4) or (4 ′) above, wherein n is 2 or 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(6) The compound according to any one of (1) to (4 ′) above, wherein m is 0, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(7) A force wherein R ¹ is hydrogen and R ² is hydrogen or hydroxy R ¹ and R ² together form a single bond, described in any one of (1) to (4 ′) above Or a pharmaceutically acceptable salt thereof or a solvate thereof. (8) Force where Y is a single bond or —CH—, together with R ² to form = CH—,

2

The compound according to any one of (1) to (4 ′) or a pharmaceutically acceptable salt thereof or a solvate thereof.

(9) The above (1), wherein A ² is a phenyl optionally substituted with one or more groups selected from a nonogen, a sheared lower alkyl, a halogeno lower alkyl, a lower alkoxy and a halogeno lower alkoxy force To (4 ′), a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(10) The compound according to any one of (1) to (4 ′) and (9) above, wherein A ² is para-substituted phenyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(11) A pharmaceutical composition comprising the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof.

(12) The pharmaceutical composition according to the above (11), which has an NMDA receptor antagonistic action.

(13) The pharmaceutical composition according to the above (12), which has an NR1ZNR2B receptor antagonistic action.

(14) Painkillers or migraine, stroke, head trauma, Alzheimer's disease, Parkinson's disease

The pharmaceutical composition according to (13) above, which is a therapeutic agent for tinnitus, epilepsy, Huntington's disease, movement disorder or alcoholism.

(15) A method for alleviating pain or single-headed pain, comprising administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof, Treatment of stroke, head injury, Arno, Imah's disease, Parkinson's disease, tinnitus, epilepsy, Huntington's disease, movement disorders or alcoholism.

(16) Painkillers or migraine, stroke, head trauma, Alzheimer's disease, Parkinson's disease

, Tinnitus, epilepsy, Huntington's disease, dyskinesia or alcohol dependence, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Use of solvates.

(17) A pharmaceutical composition comprising the compound according to any one of (1) to (10) above, which is an analgesic, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(18) A disease caused by an NMDA receptor, characterized by administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof. How to prevent or treat a patient.

(19) Use of the compound according to any one of (1) to (10) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic agent for a disease caused by an NMDA receptor. .

(20) A method for alleviating pain, comprising administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof.

(21) Use of the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of an analgesic.

I will provide a.

The invention's effect

[0006] The compound of the present invention is useful as an analgesic (eg, cancer pain analgesic) having few side effects with force, and used for neurodegeneration treatment such as stroke and brain trauma.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, “protected or hydroxy” means, for example, lower alkyl (methyl, tert-butyl, etc.), aryl lower alkyl (trifluoromethyl, benzyl, etc.), tri-lower alkylsilyl, etc. (Trimethylsilyl, tert-butyldimethylsilyl, triethylsilyl, triisopropylpropylsilyl, etc.), lower alkyldiarylsilyl (tert-butyldiphenylsilyl, etc.), triaryl lower alkylsilyl (tribenzylsilyl, etc.), lower alkoxy lower alkyl (Methoxymethyl, 1 ethoxyethyl, 1-methyl-1-methoxyethyl, etc.), lower alkoxy lower alkoxy lower alkyl (methoxymethoxymethyl, etc.), lower alkylthio lower alkyl (methylthiomethyl etc.), tetrahydrobiral (tetrahydropyran —2- Le, 4—Met Citetrahydropyran-1-yl, etc.), tetrahydrothiopyranyl (tetrahydrothiopyran-1-2-yl, etc.), tetrahydrofuran (tetrahydrofuran-2-yl, etc.), tetrahydrothiofuran (tetrahydrothio) Furan 2-yl, etc.), aryl lower alkyl lower alkyl (benzyloxymethyl etc.), lower alkyl sulfone, aryl sulfone, lower alkyl aryl sulfone (p toluenesulfol etc.) and Protected with a protecting group selected from acyl and the like !, but may include hydroxy. Preferred protective groups are lower alkyl, aryl lower alkyl or lower alkylsulfonyl, etc. The

[0008] "Protected but optionally amino" means, for example, a lower alkoxy carbo yl (tert-butyloxy carbol etc.), a lower alkoxy carbo bol (buluoxy carbol, allyloxy) Carbon, etc.), halogeno lower alkoxy carbo yl (2-iodinated carbo carbonyl, 2, 2, 2-trichloro ethoxy carbo ol, etc.), aryl lower alkoxy carbonyl (benzyloxycarbonyl, p- Methoxybenzyloxycarbonyl, o-nitrobenzenoreoxycanoleboninole, p-nitrobenenoxoxynoleboninole, pheninore xycarbonyl, etc., tri-lower alkylsilyl (trimethylsilyl, triethylsilyl, tert-butyl) Dimethylsilyl), diazo, acyl (formyl, acetyl, bivaloyl, benzoyl, etc.), halogenoacyl ( Rifluoroacetyl, etc.), lower alkyl sulphone (methane sulphone, etc.), halogeno lower alkyl sulphone (trifluoroethane sulphone, etc.), aryl sulol, lower alkyl sulyl sulol (toluene) And amino groups which may be protected with a protecting group selected from sulfo, 4-tert butylbenzene sulfone, etc.), aryl lower alkyl (triphenylmethyl, etc.) and the like. Preferably, the protecting group is acyl or lower alkyl sulfol.

[0009] The "nitrogen-containing aromatic monocyclic group" is a 5- to 6-membered aromatic cyclic group having at least one N in the ring and optionally having O or S. Include. For example

[Chemical 8]

Etc. The “nitrogen-containing aromatic fused cyclic group” means that it has at least one N in the ring and further has O or S, and may be a 5- to 6-membered aromatic cyclic group, Includes a group in which one or two benzene rings or aromatic heterocycles are condensed. For example

[Chemical 9]

Etc. The bond is in the wrong ring!

“Protected !, may be hydroxy and Z or protected, may have at least one amino and may be further substituted with another group, nitrogen-containing aromatic The term “cyclic group or nitrogen-containing aromatic condensed cyclic group” means a hydroxy group in which the above “nitrogen-containing aromatic monocyclic group” or “nitrogen-containing aromatic condensed cyclic group” may be protected on the ring. And Z or at least one optionally protected amino group, and further substituted with one or more groups selected by the substituent group α force, including a cyclic group.

Here, the substituent group a is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, lower alkylamino-substituted carbon. Boxy, lower alkoxy carbo, nitro-containing nitro.

[0012] "At least hydroxy-substituted pyridyl", "at least hydroxy-substituted quinolyl", "at least hydroxy-substituted benzoxazolyl" and "at least hydroxy-substituted benzimidazolyl" respectively Including pyridyl, quinolyl, benzoxazolyl and benzimidazolyl, which has at least one hydroxy as a substituent and is further substituted with one or more groups selected from substituent group a To do. For example, 6-hydroxypyridine-3-yl, 2-hydroxypyridine-3-yl, 6-hydroxy-4-methylpyridine 3-yl, 4-acetyl-1-hydroxybenzoxazol 6-yl.

“At least one optionally protected amino-substituted pyridyl” refers to one or more groups having at least one amino group or protected amino group as a substituent, and further selected from substituent group a. Substituted with !, which includes pyridyl.

[0013] "In the ring-NH and other ring-constituting atoms may be protected by hydroxy and protected, or may be substituted by a substituent other than amino. The term “nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic condensed cyclic group” refers to the above-mentioned “nitrogen-containing aromatic monocyclic group” and “nitrogen-containing aromatic condensed cyclic group”. Including a group containing an NH group. For example

[Chemical 10]

Etc. The bond may be present in any ring, and any ring member other than NH may be substituted with one or more groups selected from the substituent group β force. Here, the substituent group β is halogen, lower alkyl, halogeno lower alkyl, acyl, carboxy, lower alkoxy carbo, cyan and -tro.

“Ring atoms other than 1st—may be substituted with imidazolyl”, “ring atoms other than 1st—may be substituted with pyrrolyl”, “rings other than 1st— Ring atoms other than “virazolyl” and “one--are substituted!”, And ring atoms other than “benzopyrazolyl” and “one--” are substituted. The ring atoms other than -ΝΗ- may be substituted with a ring atom other than -ΝΗ-! May be substituted with a ring atom other than -ΝΗ-, respectively. Includes imidazolyl, pyrrolyl, pyrazolyl, benzpyrazolyl, benzimidazolyl and indolyl optionally substituted with one or more selected groups.

The “aromatic hydrocarbon cyclic group” includes phenyl, naphthyl, phenanthryl and the like.

Examples of the substituent of the “aromatic hydrocarbon cyclic group which may have a substituent” include halogen, hydroxy, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, lower alkyl sulfo-loxy. , Halogeno lower alkyl sulfo-loxy, acyl, acyloxy, ami-substituted lower alkyl ami-sil acylamino, nitro, sialin-ruboxy, lower alkoxy carbo-yl, rubamoyl, lower alkyl rubamoyl, substituent group 1 The aryl group which may be substituted with the above groups, the substituent group y force is also selected. The aryl group which may be substituted with one or more groups, which is substituted with one or more groups selected from the substituent group γ. An aryloxy group which may be substituted with one or more groups selected from the substituent group γ, ! Substituted with one or more groups selected from the substituent group γ, even I, Arirusuruho - it is Ruokishi.

Here, the substituent group γ is halogen, hydroxy, lower alkyl, halogeno-lower alkyl, lower alkoxy, halogeno-lower alkoxy, acyl, acyloxy, amino-containing lower alkylamino, acylamino, carboxy, lower alkoxycarbonyl, silane-containing nitro. The

“Arylsulfol”, “Arylsulfoxy”, “Aryloxy”, “ArylChio”, “Arylamino”, “ArylLoweralkyl”, “Loweralkyldiarylsilyl”, “TriarylLoweralkylsilyl”, “Aryl” Lower alkoxy lower alkyl "," low The aryl moiety of the “secondary alkyl aryl sulfone” and “aryl aryl lower alkoxy carbo” is the same as the above “aromatic hydrocarbon cyclic group”. Preferred is phenyl.

[0015] An "aromatic heterocyclic group" is a heteroatom that also has a group force consisting of N 2 O and S 1

4-6 5 6-membered aromatic monocyclic groups (e.g., pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, triazolyl, triazyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, Thiazolyl, thiadiazolyl, furyl and chale, etc.) and aromatic fused cyclic groups (eg indolyl, isoindolyl, indolizyl, benzimidazolyl, benzpyrazolyl, indazolyl, cinnolinyl, phthalajur, benzoxazolyl, benz) Isoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzocenyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, Imidazothiazolyl, birazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, quinoxalinyl, purinyl, pteridinyl, naphthyridyl and virazinopyridazyl).

The substituent of the “aromatic heterocyclic group which may have a substituent” is the same as the substituent of the above “having a substituent! Or may be an aromatic hydrocarbon cyclic group”. It is.

[0016] "Halogen" includes F 2 Cl Br and the like.

The lower alkyl part and the halogen part of “halogeno lower alkyl”, “halogeno lower alkoxy”, “halogeno lower alkoxy group”, “halogenoacyl” and “halogeno lower alkyl sulfol” are the same as the above “halogen”. .

“Lower alkyl” includes linear or branched alkyl having 1 to LO, preferably 16 carbon atoms, more preferably 13 carbon atoms, and includes methyl, ethyl, and n-propyl. , Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-butyl, isoheptyl, n-octyl, isooctyl, n-nor and Examples include n-decyl and the like. Particularly preferred is methyl or ethyl.

The lower alkyl part of “lower alkyl which may have a substituent” is the same as the above “lower alkyl”. Examples of the substituent include halogen, hydroxy, lower alkoxy, Halogeno lower alkoxy, acyl, acyloxy, amide-containing lower alkyl amide-containing carboxy, lower alkoxy carbo, cyano-nitro, and the like. Preferred examples of the substituted lower alkyl include trihalogeno-lower alkyl.

“Halogeno lower alkyl”, “lower alkoxy lower alkyl”, “lower alkoxy lower alkoxy lower alkyl”, “lower alkylthio lower alkyl”, “aryl aryl lower alkyl lower alkyl”, “lower alkoxy”, “halogeno lower alkoxy”, “ "Lower Alkoxy Carbon", "Halogeno Lower Alkoxy Carbon", "Aryl Lower Alkoxy Carbon", "Lower Alkyl Force Rubamoyl", "Lower Alkyl Sulfonyl", "Lower Alkyl Carylol" , “Lower alkyl sulfo-oxy”, “halogeno lower alkyl sulfo”, “halogen lower alkyl sulfo-oxy”, “lower alkyl amino”, “aryl lower alkyl”, “tri-lower alkyl silyl”, “lower alkyl di” Reel reel, triary The lower alkyl part of “lower alkylsilyl” is the same as the above “lower alkyl”.

[0017] The "lower alcohol" is a straight chain having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, having one or more double bonds at any position. Includes branched alkenyl. Specifically, bur, aryl, probe, isoprobe, butur, isobutenyl, prennore, butagenyl, pentenyl, isopentenyl, pentageninore, hexeninore, isohexenore, hexageninore, hepteninore, otatenore, none Including dill and desalin.

The lower alkenyl portion of the “lower alkyloxyball” is the same as the above “lower alkell”.

“Lower alkylene” includes a divalent carbon chain having 1 to 6 carbon atoms, preferably alkylene having 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms.

The “lower alkenylene” includes a straight or branched divalent carbon chain having 2 to 6 carbon atoms having a double bond at an arbitrary position. Preferably, it has 2 to 4 carbon atoms, more preferably 2 or 3 carbon atoms. Specific examples include beylene, probelene, buterene, butadiene, methylpropylene, pentylene and hexylene, with beylene being preferred. Examples of the substituent of “having a substituent and may be a lower alkylene” include the same substituents as the above-mentioned “lower alkyl optionally having a substituent”, preferably halogen, It is hydroxy.

“Lower alkylene” is a straight or branched divalent carbon chain having 2 to 6 carbon atoms which has a triple bond at an arbitrary position and may further have a double bond. Include. Preferably, it has 2 to 4 carbon atoms, more preferably 2 or 3 carbon atoms. Specific examples include ethylene, propylene, petitylene, pentylene and hexylene.

Examples of the substituent of “may be substituted or lower alkylene” include the same substituents as the above-mentioned “lower alkyl optionally having substituent”, preferably halogen, hydroxy It is.

“Asil” includes aliphatic asil and Caroyl having 1 to 7 carbon atoms. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, bivaloyl, hexanoyl, attalyloyl, propioroyl, methacryloyl, crotonol and benzoyl.

The acyl moiety of “acyloxy”, “acylamino” and “halogenoacyl” is the same as the above “acyl”.

When "scale ¹ and R ² join together to form a single bond"

[Chemical 11]

It means that.

Y force "such together with R ² connexion

Is

[Chemical 12]

(Wherein each symbol is as defined above) It means that. Further, Y is - a "and the a connexion = CR ^M together (CR ¹⁵ R ¹⁶⁾ form a p-" is

[Chemical 13]

(Wherein each symbol is as defined above)

It means that.

The compound (I) of the present invention includes all possible isomers and racemates, not limited to specific isomers. For example, it contains a ketoeenol tautomer as follows.

[Chemical 14]

H

[0022] A general method for synthesizing the compound of the present invention is shown below, but is not limited to this synthesis method.

[0023] Method A: Synthesis of (la) from Compound (Π) (m = l)

In the presence of a condensing agent, the amine compound represented by the formula (Π) (hereinafter referred to as the compound ()) and the carboxylic acid compound represented by the formula (以下) (hereinafter referred to as the compound (ΠΙ)) are condensed. The amido compound represented by (la) (hereinafter referred to as compound (la)) can be synthesized.

[Chemical 15]

(Wherein A ¹ A ² , R \ R ² , X and Y are as defined above)

The compound (Π) is described in T. Kumagai et al. Bioorg. Med. Chem., 9, 1357 (2001), S. Imamura et al. Bio org. Med. Chem., 13, 397 (2005), S. Sakamuri et al. Bioorg. Med. Chem. Lett., 11, 495 (2001), Z.-L.Zhou et al. J. Org. Chem., 64, 3763 (1999), SMN Efange et al. J. Med. Chem., 33, 3133 (1990), the method described in Reference Examples 1 to 3, and a method analogous thereto. Compound (III) can be synthesized by the methods described in Reference Examples 4 and 5 and methods analogous thereto.

Compound (III) can be used at 0.5 to 2 molar equivalents relative to compound ().

Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.

Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N′-carbonyldiimidazole, etc., and for the compound represented by the formula (V), 0.5 to 2 molar equivalents can be used. 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole may be used as a condensation aid.

Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. It is possible to use 0.05 to 2 molar equivalents of compound (Π), respectively.

An example of a reaction temperature is 0 to 100 ° C.

An example of the reaction time is 0.5 to 72 hours.

The obtained compound (la) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method B: Synthesis of (lb) from Compound (Π) (m = 0)

In the presence of a base, the compound (Π) and the compound represented by formula (IV) (hereinafter referred to as compound (IV)) are condensed to form an amine compound represented by formula (lb) (hereinafter referred to as compound (lb)). Can be synthesized.

[Chemical 16] 2

(Wherein L ¹ is halogen or CI 4 alkyl sulfo-loxy; AA ² , R \ R ² , X and Y are as defined above)

The compound (IV) can be used at 0.5 to 3 molar equivalents relative to the compound (Π).

Examples of the reaction solvent include acetonitrile, acetone, Ν, ジメチル dimethylformamide, Ν, Ν-dimethylacetamide, dimethyl sulfoxide and the like.

Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound (Π). Potassium iodide and sodium iodide should be used at 0.05-1. 5 molar equivalents relative to the compound (Π).

Examples of the reaction temperature include 20 ° C to the reflux temperature of the solvent.

An example of the reaction time is 0.5 to 72 hours.

The resulting compound (lb) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method C: Synthesis of (Ic) from compound (Π) (m = 0)

Compound (II) and a compound represented by formula (V) (hereinafter referred to as compound (V)) are condensed in the presence of a reducing agent to synthesize an amine compound represented by formula (Ic) (hereinafter referred to as compound (Ic)). can do.

[Chemical 17]

(Wherein X ¹ is an optionally substituted lower alkylene, an optionally substituted lower alkylene, CO (CR ³ R ⁴ ) p-, — CONR ⁵ ( CR ³ R ⁴ ) q―, NR ⁵ CO (CR ³ R ⁴ ) p, one NR ⁵ CONR ⁶ (CR ³ R ⁴ ) q, one C (= N—OR ⁷ ) (CR ³ R ⁴ ) p, (CR ⁸ R ⁹ ) rO (CR ³ R ⁴ ) q—,-(CR ⁸ R ⁹ ) rS (CR ³ R ⁴ ) q-,-(CR ⁸ R ⁹ ) rNR ⁶ (CR ³ R ⁴ ) q -(CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) p-, — (CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) p-, — CR ⁹ = N— 0 (CR ³

2

R ⁴ ) p, one C (= O) O (CR ³ R ⁴ ) q one or one A ³ — (CR ³ R ⁴ ) p,

p is an integer from 0 to 3, q is an integer from 1 to 3; A \ A ² , R \ R ² , R ³ and Y are as defined above)

The compound (V) can be used at 0.5 to 2 molar equivalents relative to the compound (Π). Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran and the like.

Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanohydrohydroboron and the like, and 0.5 to 6 molar equivalents can be used with respect to the compound (Π).

Examples of the reaction temperature include 0 to 80 ° C.

If necessary, acetic acid or the like as an acid can be used in an amount of 0.5 to 2 molar equivalents relative to the compound (Π).

An example of the reaction time is 0.5 to 72 hours.

The obtained compound (Ic) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0026] Method D: Synthesis of (Id) from the compound (Π) (X = CONR ⁵ (CR ³ R ⁴ ) n, n = 2-4)

[Chemical 18]

(Wherein Z ¹ is a CI 3 alkyl carbo yl or tert butoxy carbo ol, t is an integer from 2 to 4;

R ⁴ , R ⁵ and Y are as defined above)

[0027] Synthesis of (VII) from Compound (Π)

In the presence of a base, the compound (Π) and the compound represented by the formula (VI) (hereinafter referred to as the compound (VI)) are condensed to form an amine compound represented by the formula (VII) (hereinafter referred to as the compound (VII)). Can be synthesized. Compound (VI) can be used at 0.5 to 3 molar equivalents relative to compound (). Examples of the reaction solvent include acetonitrile, acetone, Ν, ジメチル dimethylformamide, Ν, Ν-dimethylacetamide, dimethyl sulfoxide, and the like. Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound (Π). Potassium iodide and sodium iodide should be used at 0.05-1. 5 molar equivalents relative to the compound (Π).

An example of the reaction time is 0.5 to 72 hours.

The obtained compound (VII) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

[0028] Synthesis of (VIII) from Compound (VII)

Compound (VII) can be acid-treated to synthesize a compound represented by the formula (VIII) (hereinafter referred to as Compound (VIII)).

Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran, dioxane, and no solvent.

Examples of the acid include hydrochloric acid, trifluoroacetic acid and the like, and 2 to: LOO molar equivalent can be used with respect to compound (VII).

Examples of the reaction temperature include 0 to 80 ° C.

An example of the reaction time is 0.5 to 72 hours.

After distilling off the solvent, water was added, and 1 to 5 molar equivalents of sodium carbonate with respect to compound (VIII) were used at a reaction temperature of 0 to 80 ° C and a reaction time of 0.5 to 4 hours. It can be used as a free amine, but it can be used in the next step as a salt!

The obtained compound (VIII) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0029] Synthesis of (Id) from Compound (VIII)

In the presence of a condensing agent, compound (VIII) and a carboxylic acid compound represented by formula (IX) (hereinafter referred to as compound (IX)) are condensed to form an amide compound represented by formula (Id) (hereinafter referred to as compound (Id)). ) Can be synthesized.

Compound (IX) can be used at 0.5 to 2 molar equivalents relative to Compound (VIII). Reaction solvents include methylene chloride, tetrahydrofuran, N, N-dimethylformamide Etc.

Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N, carbodiimidazole and the like. 5 to 2 molar equivalents can be used. 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole may be used as a condensation aid.

Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. The compound (VIII) can be used in an amount of 0.05 to 2 mole equivalents, respectively.

An example of a reaction temperature is 0 to 100 ° C.

An example of the reaction time is 0.5 to 72 hours.

The resulting compound (Id) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0030] Method E: Synthesis of (Ie) from the compound (Π) (X = CONR ⁵ (CR ³ R ⁴ ) n, n = 2-4)

[Chemical 19]

(XII) (le)

(In the formula, AA ² , L \ R \ R ² , R ³ , R ⁴ , R ⁵ , Y, Z ¹ and q are as defined above)

[0031] Synthesis of (XI) from Compound (Π)

In the presence of a reducing agent, compound (II) and a compound represented by formula (X) (hereinafter referred to as compound (X)) are condensed to form an amine compound represented by formula (XI) (hereinafter referred to as compound (XI)). Can be synthesized. Compound (X) can be used at 0.5 to 2 molar equivalents relative to compound (Π). Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran and the like.

Examples of the reaction temperature include 0 to 80 ° C.

An example of the reaction time is 0.5 to 72 hours.

The resulting compound (XI) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0032] Synthesis of (ΧΠ) from Compound (XI)

Compound (XI) can be acid-treated to synthesize a compound represented by the formula (ΧΠ) (hereinafter referred to as compound ()).

Examples of the acid include hydrochloric acid, trifluoroacetic acid and the like, and 2 to LOO molar equivalents can be used with respect to compound (XI).

Examples of the reaction temperature include 0 to 80 ° C.

An example of the reaction time is 0.5 to 72 hours.

After distilling off the solvent, water was added, and 1 to 5 molar equivalents of sodium carbonate with respect to compound (XI) were used at a reaction temperature of 0 to 80 ° C and a reaction time of 0.5 to 4 hours. It can be used as a free amine, but it can be used in the next step as a salt!

The obtained compound (ΧΠ) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0033] Synthesis of (Ie) from Compound (ΧΠ)

Compound (XII) and compound (IX) can be condensed in the presence of a condensing agent to synthesize an amido compound represented by formula (Ie) (hereinafter referred to as compound (Ie)).

Compound (IX) can be used at 0.5 to 2 mole equivalent based on Compound (XII).

Reaction solvents include methylene chloride, tetrahydrofuran, N, N-dimethylformamide Etc.

Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N′-carbonyldiimidazole, etc., and for the compound represented by the formula (ΧΠ), 0.5 to 2 molar equivalents can be used. 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole may be used as a condensation aid.

Examples of the base include triethylamine, 4-dimethylaminopyridine, and the like. For the compound (XII) that can be used alone or in combination, 0.05 to 2 molar equivalents! /, Respectively. it can.

An example of a reaction temperature is 0 to 100 ° C.

An example of the reaction time is 0.5 to 72 hours.

The obtained compound (Ie) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0034] Method F: Synthesis of (If) from a compound (Π) (X = CONH (CR ³ R ⁴ ) n, n = 2-4)

[Chemical 20]

(Where

R ³ , R ⁴ , Y and t are as defined above)

[0035] Synthesis of (XIV) from Compound (Π)

In the presence of a base, a compound (Π) and a phthalimide compound (hereinafter referred to as compound (XIII)) represented by formula (ΧΙΠ) are condensed to form an amine compound (hereinafter referred to as compound (XIV)) represented by formula (XIV). ) Can be synthesized.

The compound (ΧΙΠ) can be used at 0.5 to 3 molar equivalents relative to the compound (Π). Examples of the reaction solvent include acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like.

An example of the reaction time is 0.5 to 72 hours.

The obtained compound (XIV) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

[0036] Synthesis of (XV) from Compound (XIV)

By treating compound (XIV) with hydrazine hydrate, an amine compound represented by formula (XV) (hereinafter, compound (XV)) can be synthesized.

Hydrazine hydrate can be used at 1.0 to 5 molar equivalents relative to compound (XV). Examples of the reaction solvent include methanol, ethanol, dichloromethane, N, N-dimethylformamide and the like.

An example of a reaction temperature is 0 to 100 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The obtained compound (XV) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0037] Synthesis of (If) from Compound (XV)

Compound (XV) and compound (IX) can be condensed in the presence of a condensing agent to synthesize an amido compound represented by formula (If) (hereinafter referred to as compound (If)).

0.5 to 2 molar equivalents of compound (IX) can be used relative to compound (XV). Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.

Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N'-carbodiimidazole, and the like. Two molar equivalents can be used. 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole may be used as a condensation aid.

Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. The compound (XV) can be used in an amount of 0.05 to 2 mole equivalents, respectively.

An example of a reaction temperature is 0 to 100 ° C.

An example of the reaction time is 0.5 to 72 hours.

The obtained compound (If) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method G: Synthesis of (Ig) from compound (Π) (X = CONH (CR ³ R ⁴ ) n, n = 2-4)

[Chemical 21]

(XVII I) (| g)

(Where

R ² , R ³ , R ⁴ , Y and q are as defined above)

Synthesis of (XVII) from compound (Π)

In the presence of a reducing agent, compound (II) and a compound represented by formula (XVI) (hereinafter referred to as compound (XVI)) are condensed to form an amine compound represented by formula (XVII) (hereinafter referred to as compound (XVII)). Can be synthesized.

The compound (XVI) can be used at 0.5 to 2 mole equivalent based on the compound (Π).

Examples of the reaction solvent include 1,2-dichloroethane, tetrahydrofuran and the like.

Examples of the reducing agent include sodium triacetoxyborohydride and cyanohydrohydroboron sodium. And 0.5 to 6 molar equivalents can be used with respect to the compound (Π).

Examples of the reaction temperature include 0 to 80 ° C.

An example of the reaction time is 0.5 to 72 hours.

The obtained compound (XVII) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0040] Synthesis of (XVIII) from Compound (XVII)

By treating compound (XVII) with hydrazine hydrate, an amine compound represented by formula (XVIII) (hereinafter referred to as compound (χνπι)) can be synthesized.

Hydrazine hydrate can be used in an amount of 1.0 to 5 molar equivalents relative to compound (XVII). Examples of the reaction solvent include methanol, ethanol, dichloromethane, N, N-dimethylformamide and the like.

An example of a reaction temperature is 0 to 100 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The obtained compound (XVIII) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0041] Synthesis of (Ig) from Compound (XVII)

Compound (XVIII) and compound (IX) can be condensed in the presence of a condensing agent to synthesize an amide compound represented by formula (Ig) (hereinafter referred to as compound (Ig)).

Compound (IX) can be used at 0.5 to 2 molar equivalents relative to Compound (XVIII). Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.

Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N′-carbodiimidazole, etc., and 0.5% relative to compound (XVIII). ˜2 molar equivalents can be used. 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole may be used as a condensation aid.

Examples of the base include triethylamine, 4-dimethylaminopyridine, and the like. Can be used as a mixture. The compound (XVIII) can be used in an amount of 0.05 to 2 mole equivalents, respectively.

An example of a reaction temperature is 0 to 100 ° C.

An example of the reaction time is 0.5 to 72 hours.

The resulting compound (Ig) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method H: Synthesis of (Ih) from compound (Π) (X = NR ⁵ CO (CR ³ R ⁴ ) n, n = 1 to 4)

[Chemical 22]

(ll) (XX)

Wherein Z ² is CI—4 alkyl, u is an integer from 1 to 4;

R ⁵ and ひ are as defined above)

Synthesis of (XX) from compound (Π)

In the presence of a base, compound (Π) and a compound represented by formula (XIX) (hereinafter referred to as compound (XIX)) are condensed to produce an ester compound represented by formula (XX) (hereinafter referred to as compound (XX)). Can be synthesized.

Compound (XIX) can be used at 0.5 to 3 molar equivalents relative to compound (Π).

Examples of the reaction solvent include acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like.

Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound (Π). Potassium iodide and sodium iodide should be used at 0.05-1. 5 molar equivalents relative to the compound (Π). Examples of the reaction temperature include 20 ° C to the reflux temperature of the solvent.

An example of the reaction time is 0.5 to 72 hours.

The obtained compound (XX) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0044] Synthesis of (XXI) from Compound (XX)

By hydrolyzing the compound (XX), a carboxylic acid represented by the formula (XXI) (hereinafter, compound (XXI)) can be synthesized.

1.0 to 5 molar equivalents of sodium hydroxide or potassium hydroxide can be used with respect to the compound represented by the formula (XX).

Examples of the reaction solvent include methanol, ethanol, water and the like.

Examples of the reaction temperature include 0 to 80 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The obtained compound (XXI) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

[0045] Synthesis of (Ih) from Compound (XXI)

In the presence of a condensing agent, compound (XXI) and an amine compound represented by formula (XXII) (hereinafter referred to as compound (XXII)) are condensed to form an amide compound represented by formula (Ih) (hereinafter referred to as compound (Ih)). ) Can be synthesized.

Compound (XXII) can be used at 0.5 to 2 molar equivalents relative to compound (XXI). Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.

Examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N′-carbonyldiimidazole, etc., and 0.5 to Two molar equivalents can be used. 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole may be used as a condensation aid.

Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. The compound (XXI) can be used in an amount of 0.05 to 2 mole equivalents, respectively. An example of a reaction temperature is 0 to 100 ° C.

An example of the reaction time is 0.5 to 72 hours.

The obtained compound (Ih) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

[0046] It should be noted that A ¹ is protected, hydroxy and / or protected! A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group or —NH 2 in the ring, which is substituted with another group. Substituted with a substituent other than protected hydroxy and protected amino !, may! /, Nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic group In the case of a fused cyclic group, the protecting group is removed under commonly used reaction conditions (for example, the method described in TW Green et al., Protective Groups in Organic Chemistry, Second Edition, John Wiley & Sons (1991)). Can be protected.

[0047] When the compound of the present invention contains an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, these are also included as the compound of the present invention, and are synthesized by a known synthesis method or separation method. Each can be obtained as a single item. For example, when an optical isomer exists in the compound of the present invention, an optical isomer resolved from the compound is also included in the compound of the present invention. The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving a final racemic mixture according to a conventional method.

[0048] As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like described in detail below are used.

1) Fractional recrystallization method

Racemates and optically active compounds (eg (+) mandelic acid, (1) mandelic acid, (+)-tartaric acid, (1) -tartaric acid, (+)-1-1-phenethylamine, (1) -1-phenethylamine, cinchonine, (1) -cinchon-zine, brucine, etc.) to form a salt, which is separated by fractional recrystallization and optionally freed through a neutralization step To obtain an optical isomer of

2) Chiral column method

Separation of racemates or their salts through an optical isomer separation column (chiral column) Law. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO- OVM (manufactured by Toso Corporation) or CHIRAL series manufactured by Daicel Corporation, water, various buffers (for example, phosphate buffer), Optical isomers are separated by developing an organic solvent (for example, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, jetylamine, etc.) as a single solution or a mixed solution. For example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).

3) Diastereomer method

The racemic mixture is converted into a diastereomer mixture by chemical reaction with an optically active reagent, and this is converted into a single substance through normal separation means (for example, fractional recrystallization, chromatography, etc.), and then a hydrolysis reaction, etc. A method of obtaining optical isomers by separating optically active reagent sites by chemical treatment. For example, when the compound of the present invention has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (for example, MTPA [a-methoxy-ex (trifluoromethyl) phenolacetic acid], ( 1) -menthoxyacetic acid or the like) can be subjected to a condensation reaction to obtain diastereomers of ester or amide, respectively. On the other hand, when the compound of the present invention has a carboxylic acid group, an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted to the optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis.

As the salt of the compound of the present invention, a pharmaceutically acceptable salt can be used. Examples of the basic carbonate include alkali metal salts such as sodium salt and potassium salt; alkaline earth such as calcium salt and magnesium salt. Metal salts; for example, ammonium salts; for example, trimethylamine salts, triethylamine salts; aliphatic amine salts such as dicyclohexylamine salts, ethanolamine salts, jetanolamine salts, triethanolamine salts, brocaine salts; —Aralkylamine salts such as dibenzylethylenediamine; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt and isoquinoline salt; for example, tetramethylammonium salt, tetraethylammonium salt, benzyl Trimethylammonium salt, benzyltri Ethylammo-um salt, benzyltributylammo-um salt, methyltrioctylammo

Examples include quaternary ammonium salts such as humic salts and tetraptyl ammonium humic salts; arginine salts; basic amino acid salts such as lysine salts.

Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; for example, oxalate, acetate, propionate, and lactate. , Maleate, fumarate, tartrate, malate, citrate, ascorbate, etc .; for example, methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, etc. Examples thereof include acidic amino acids such as aspartate and dartamate.

Compound (I) may be a solvate such as water, acetonitrile, ethyl acetate, methanol or ethanol. The solvation number of the solvate of the compound of the present invention can usually vary depending on the synthesis method, purification method, crystallization conditions, etc., but is, for example, in the range of 1 to 5 molecules per molecule.

Of the compounds (I) of the present invention, the following compounds are particularly preferred.

In formula (I):

Pyridyl 1) A ¹ is substituted with at least hydroxy, at least hydroxy substituted benz O hexa benzisoxazolyl, downy substituted with at least hydroxy Nzuimidazoriru, pyridyl substituted with Amino which may be at least protected, -NH Ring atoms other than imidazolyl and NH may be substituted, and pyrrolyl and -NH- may be substituted. Or a benzimidazolyl (hereinafter referred to as A ¹ is al) optionally substituted by a ring member atom other than NH—,

2) A ¹ is hydroxypyridyl, hydroxybenzoxazolyl, hydroxybenzimidazolyl, aminobilidyl, lower alkylsulfo-laminopyridyl, unsubstituted ^ midazolyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl or unsubstituted benzimidazolyl. A compound (hereinafter, A ¹ is a2),

3) A ¹ is hydroxypyridyl, hydroxybenzoxazolyl, hydroxybenzimidazolyl, unsubstituted midazolyl unsubstituted pyrazolyl or unsubstituted pyrrolyl (hereinafter A ¹ is a3 Compound),

4) a compound wherein A ¹ is hydroxypyridyl, unsubstituted imidazolyl or unsubstituted pyrrolyl (hereinafter, A ¹ is a4),

[0051] 5) X is lower alkylene, CO (CHR ³ ) n-CONH (CHR ³ ) n- NHCO (CHR ³ ) n 0 (CHR ³ ) n S (CHR ³ ) n SO (CHR ³ ) n SO (CH

2

R ³ ) n CH = NO (CH R ³ ) n C (= 0) 0 (CHR ³ ) n—or one A ³ —CHR ³

2

A compound in which each R ³ may be different (hereinafter, X is xl),

6) Is one. 0 (z11) 11 CONH (CHR ³ ) n—NHCO (CHR ³ ) n— or one A ³ —CHR ³ — (hereinafter, X is assumed to be x2),

7) is one. 0 (z11) 11 CONH (CHR ³ ) n—NHCO (CHR ³ ) n— or one A ³ —CHR ³ —, n is 1 to 3, and R ³ is hydrogen or methyl (each R ³ may be different) (hereinafter, X is assumed to be x3),

8) X is one CO (CHR ³ ) CONH (CHR ³ ) NHCO (CHR ³ ) —or one

3 2 2

A ³ -CHR ³ —, wherein R ³ is hydrogen or methyl (each R ³ is different! /, May! / ても) (hereinafter, X is assumed to be x4),

[0052] 9) R ¹ is hydrogen, R ² is hydrogen, hydroxy or lower alkyl, and R ¹ and may be joined together to form a single bond (hereinafter R ¹ and R Compound, assuming ² is rl)

10) a compound in which R ¹ is hydrogen and R ² is hydrogen or hydroxy (hereinafter R ¹ and R ² are assumed to be r2),

1DR ¹ and R ² are joined together to form a single bond (hereinafter R ¹ and R ² are assumed to be r3),

[0053] 12) m is 0 and Y is a single bond, CH 2 O— or NH, or R

2

^A compound that forms ═CH ² with ² (assuming m and Y are yl),

13) m is 0 and Y is a single bond or CH— (hereinafter m and Y are y2

2

Compound),

14) m is 1, Y is a single bond, -CH -CH CH ― CH = CH ― C≡C

2 2 2

OS NH—, —CH 2 O—, —CH 2 S or 1 CH NH , Together with R ² to form = CH— or = CHCH— (hereinafter m and Y are y3

2

Compound),

15) m is 1, Y is a single bond, CH—, —O—, —S or —NH, or R

2

² together with ² to form = CH ² (hereinafter, m and Y are y4),

16) m is 1 and Y is a single bond or CH— (hereinafter m and Y are y5

2

Compound),

17) A compound in which A ² is phenyl optionally substituted with one or more groups selected from halogen, halogenated lower alkyl and halogeno lower alkoxy (hereinafter A ² is a5),

18) A ² is substituted with one or more groups which are also selected from halogen, trifluoromethyl and trifluoromethoxy, and may be a phenol (hereinafter A ² is a6) )Compound,

19) A ² is a phenyl substituted with one or more groups in which para-position is also selected from halogen, trifluoromethyl and trifluoromethoxyca (hereinafter, A ² is a7),

20)

A compound in which the combination of m, Y and A ² is

(A \ X, R ¹ and R ² , m and Y, A ² ) = (al, xl, rl, yl, a5), (al, xl, rl, yl, a6), (al, xl, rl, yl, a7), (al, xl, rl, y2, a5), (al, xl, rl, y2, a6), al, xl, rl, y2, a7), (al, xl, rl, y3, a5 ), (al, xl, rl, y 3, a6), (al, xl, rl, y3, a7), (al, xl, rl, y4, a5), (al, xl, rl, y4, a6) , (al, xl, rl, y4, a7), (al, xl, rl, y5, a5), (al, xl, rl, y5, a6), (al, xl, rl, y5, a7), ( al, xl, r2, yl, a5), (al, xl, r2, yl, a6), (al, xl, r2, yl, a7) al, xl, r2, y2, a5), (al, xl , r2, y2, a6) al, xl, r2, y2, a7), (al, xl, r2, y3, a5), (al, xl, r2, y3, a 6), (al, xl, r2 , y3, a7), (al, xl, r2, y4, a5), (al, xl, r2, y4, a6), (al, xl, r2, y4, a7), (al, xl, r2, y5 , a5), (al, xl, r2, y5, a6), (al, xl, r2, y5, a7), (al, xl, r3, yl, a5), (al, xl, r3, yl, a6 ), (al, xl, r3, yl, a7), (al, xl, r3, y2, a5), (al, xl, r3, y2, a6), (al, xl, r3, y2, a7), (al, xl, r3, y3, a5), (al, xl, r3, y3, a6) al, xl, r3, y3, a7) al, xl, r3, y4, a5) al, xl, r3, y4, a6) al, xl, r3, y4, a7), (al, xl, r3, y5, a5) a

1, xl, r3, y5, a6), (al, xl, r3, y5, a7), al, x2, rl, yl, a5), (al, x2, rl, yl, a6), (al, x2 , rl, yl, a7), (al, x2, rl, y2, a5), (al, x2, rl, y2, a6) s al, x2, rl, y2, a7), (al, x2, rl, y3, a5), (al, x2, rl, y3, a6), (al, x2, rl, y3, a7), (al, x2, rl, y4, a5) s al, x2, rl, y4, a6 ) Al, x2, rl, y4, a7) Al, x2, rl, y5, a5), (al, x

2, rl, y5, a6), (al, x2, rl, y5, a7), (al, x2, r2, yl, a5), (al, x2, r2, yl, a6), (al, x2, r2, yl, a7), (al, x2, r2, y2, a5), (al, x2, r2, y2, a6), (al, x2, r2, y2, a7), (al, x2, r2, y3, a5), (al, x2, r2, y3, a6) s al, x2, r

y (y (y ((dimension 9 dimension ε dimension 9 ε dimension ggggA xBA xBBA xB χ χ ------- (y (y (y (y (9 (IKIKI9IIIIssJJXXAXA.x ----- ----- y ((() (() ΐ ΐε ΐ ΐΐ9εΐΐεΐΐΐΐs3χχ ^ χ ^ χχ ---------- y (y (y (y (y (y (9III ^ ggggJJJJJ BAxAxAxAXx ----- ----- //: / O 993ϊε900ί1 £ s9s-2900iAV) (() (((ΐ9 ΐε ΐΐ ε ΐ9ΐ ε ΐΐ ε ΐ33χχχχχ -------- y (y (y (y (Ig (y (Ig9ggg9 gggggJJJJJxAxAxAx Ax- --------- y (y (y (y (y (9III9IIIg¾gJJJJJxxxAxAxA ----------

y (y (y (y (y (9 £ 9 inch gjxx xA xB Λ X ----------- y (y (y (y (Ig (I9ggIIIJJJJJXBAxxxxA --------- -

y (y (y (y (y (g g9 ε s ε9 εsSAxχχχ "----

§S yyyyy ,,,,,,,,,,,,,,,,,, 3a7a4x4r34a5a4x4r34a6a4x4r34a7a4x4r35a5a4x4r3

yyyyy ,,,,,,,,,,,,,,,,, 32a5a4x4r32a6a4x4r32a7a4x4r33a5a4x4r33a6a4x4r3

yyyyy ,,,,,,,,,,,,,,,,,,, r25a6a4x4r25a7a4x4r3la5a4x4r3la6a4x4r3la7a4x4r

yyyyy ,,,,,,,,,,,,,,,,, 4r23a7a4x4r24a5a4x4r24a6a4x4r24a7a4x4r25a5a4x4

yyyyy ,,,,,,,,,,,,,,,,,, x4r22a5a4x4r22a6a4x4r22a7a4x4r23a5a4x4r23a6a4x

yyyyy ,,,,,,,,,,,,,,,,,,, x4rl5a6a4x4rl5a7a4x4r2la5a4x4r2la6a4x4r2la7a4

yyyyy ,,,, A ,,,,,,,,,,,,,,,,)) 4x4rl3a7a4x4rl4a5a4x4rl4a6a4x4rl4a7a4x4rl5a5a4

yyyyy ,,,,,,,,,,,,,,,,, a ^ x4rl2a5a4x4rl2a6a4x4rl2a7a4x4rl3a5a4x4rl3a6a

yyyyy ,,,,,,,,,,,,,,,, (a4x3r35a6a4x3r35a7a4x4rlla5a4x4rlla6a4x4rlla7

yyyyy ,,,,,,,,,,,,,,,,, a4x3r33a7a4x3r34a5a4x3r34a6a4x3r34a7a4x3r35a5

yyyyy ,,,,,,,,,,,,,,,,,, 7a4x3r32a5a4x3r32a6a4x3r32a7a4x3r33a5a4x3r33a6

yyyyy ,,,,,,,,,,,,,,,, a5a4x3r25a6a4x3r25a7a4x3r3la5a4x3r3la6a4x3r3la

yyyyy ,,,,,,,,,,,,,,,,,, a6a4x3r23a7a4x3r24a5a4x3r24a6a4x3r24a7a4x3r25

yyyyy ,,,,,,,,,,,,,,,, a7a4x3r22a5a4x3r22a6a4x3r22a7a4x3r23a5a4x3r23

yyyyyy ,,,,,,,,,,,,,,,,,, 5a5a4x3rl5a6a4x3rl5a7a4x3r2la5a4x3r2la6a4x3r2

yyyyy ,,,,,,,,,,,,,,,,,,,, 3a6a4x3rl3a7a4x3rl4a5a4x3rl4a6a4x3rl4a7a4x3rl yyyyy ,,,,,,,,,,,,,,,, la7a4x4x3a33 ^{^{CR 3 R 4) n -,}} - NR 5 CO (CR 3 R 4) n -, - 0 (CR 3 R 4) n -, - S (CR 3 R 4) n -, - NR 6 (CR 3 R ⁴ ) n-, — SO (CR ³ R ⁴ ) n—, —SO (CR ³ R ⁴ ) n— or — A ³ — CR ³ R ⁴ —

2

Yes,

n is an integer from 0 to 4,

R ¹ is hydrogen,

R ² is hydrogen, hydroxy or lower alkyl,

R ¹ and R ² may be joined together to form a single bond

R ³ , R ⁴ and R ⁶ are each independently hydrogen or lower alkyl,

Y is a single bond or - CR ¹² R ¹³ - a and, connexion = CR ¹⁴ such together with R ² - may be formed

A compound wherein R is hydrogen, halogen, lower alkoxy, halogeno lower alkyl, halogeno lower alkoxy or cyan;

Preferably

R ^A is hydroxy,

X is — CONR ⁵ (CR ³ R ⁴ ) n—, — NR ⁵ CO (CR ³ R ⁴ ) n — or — A ³ — CR ³ R ⁴ —, and n is an integer from 0 to 4,

A force in which R ¹ and R ² are both hydrogen together may form a single bond R ³ , R ⁴ and R ⁶ are each independently hydrogen or lower alkyl;

Y is a single bond or CH—

2

Q ¹ is 0, NH or CR ^B R ^e (wherein R ^B and R ^e are each independently hydrogen or a group selected by the substituent group a force),

Q ² is N or CH,

A compound wherein Q ³ is N or CH,

22) Formulas (In) to (Iq):

[Chemical 24]

Y is a single bond, lower alkylene, lower alkylene, lower alkylene, O or one CR ¹² R ¹³ 0—, and together with R ² = CR ¹⁴ — (CR 1 ⁵ R ¹⁶ ) Other symbols that may form P— are the same as those in 20) above,

[0057] 23) In formula (Ii)

R ^A is hydroxy or amino

X is lower alkylene, CO (CHR ³ ) n― CONR ⁵ (CHR ³ ) n― NR ⁵ CO (C HR ³ ) n or A ³ — CHR ³

n is 2 or 3,

R ¹ is hydrogen,

R ² is hydrogen, hydroxy or methyl;

R ¹ and R ² may be joined together to form a single bond

R ³ is hydrogen or lower alkyl (each R ³ is different! /, May! /),

R ⁵ is hydrogen or lower alkyl,

Y is a single bond or a single CH—, which may be combined with R ² to form = CH—

2

A compound wherein R is hydrogen, halogen or halogeno lower alkyl,

[0058] 24) In the formula (Ij),

R ^A is hydroxy or amino

Q ¹ is O or NH,

X is one CONR ⁵ (CHR ³ ) n NR ⁵ CO (CHR ³ ) — or one A ³ — CHR ³ —

2

R ¹ is hydrogen,

R ² is hydrogen or hydroxy;

R ¹ and R ² may be joined together to form a single bond R ³ is hydrogen or lower alkyl It ’s a quinole (each R ³ is different! /, But! /),

R ⁵ is hydrogen or lower alkyl,

Y is a single bond or CH—

2

A compound wherein R is hydrogen, halogen, lower alkoxy, halogeno lower alkyl or halogeno lower alkoxy;

[0059] 25) In the formula (Ik),

Q ² is N or CH,

X is — CO (CHR ³ ) —, — CONR ⁵ (CHR ³ ) —, — NR ⁵ CO (CH) — or — A ³

2 2 2 2

CHR ³ and

R ¹ is hydrogen,

R ² is hydrogen, hydroxy or lower alkyl,

R ¹ and R ² may be joined together to form a single bond

R ³ is hydrogen or lower alkyl (each R ³ may be different), R ⁵ is hydrogen or lower alkyl,

Y is a single bond or CH—

2

A compound wherein R is hydrogen, halogen or halogeno lower alkyl,

[0060] 26) In the formula (Im),

Q ³ is N or CH,

X is — CONR ⁵ (CHR ³ ) —, — NR ⁵ CO (CHR ³ ) — or — A ³ — CHR ³ ;

twenty two

R ¹ is hydrogen,

R ² is hydrogen or hydroxy;

R ¹ and R ² may be joined together to form a single bond

Y is a single bond or CR ¹² R ¹³

R is a compound which is hydrogen, halogen, halogeno lower alkyl or lower alkoxy, [0061] 27) In the formula (In):

R ^A is hydroxy or amino But

Substituted by hydroxy, may be lower alkylene, may have a substituent! /, May be lower alkylene, optionally substituted lower alkylene, CO (CHR ³ ) n — C

ONR ⁵ (CHR ³ ) n— — NR ⁵ CO (CHR ³ ) n— — 0 (CHR ³ ) n— — CH = N— 0 (C

HR ³ ) n C (= 0) 0 (CHR ³ ) n A ³ — (CHR ³ ) n—or one A ³ —CH = CH

(CHR ³ ) n—

n is 0 3

A ³ is phenylene,

R ¹ is hydrogen,

R ² is hydrogen or hydroxy;

R ¹ and R ² may be joined together to form a single bond

R ³ is hydrogen or lower alkyl (each R ³ is different! /, May! /),

R ⁵ is hydrogen or lower alkyl,

Y is a single bond, lower alkylene, lower alkylene, lower alkylene, O or —CR ¹² R ¹³ 0— and together with R ² = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p R is hydrogen, halogen, halogeno lower alkyl or cyan compounds,

28) In formula (Io)

R ^A is hydroxy or amino

Q ¹ is 0 NH or CH,

2

X is one CO (CHR ³ ) n CONR ⁵ (CHR ³ ) n NR ⁵ CO (CHR ³ ) n—or one

A ³ —CHR ³ —

n is 1 or 2,

R ¹ is hydrogen,

R ² is hydrogen or hydroxy;

R ¹ and R ² may be joined together to form a single bond

R ³ is hydrogen or lower alkyl (each R ³ is different! /, May! /),

R ⁵ is hydrogen or lower alkyl,

Y is a single bond or lower alkylene, A compound wherein R is hydrogen, halogen or halogeno lower alkyl,

[0063] 29) In the formula (Ip),

Q ² is N or CH,

X is one CO (CHR ³ ) n—, one CONR ⁵ (CHR ³ ) n—, one NR ⁵ CO (CHR ³ ) n—, or one A ³ —CHR ³ —,

n is 0-2,

R ¹ is hydrogen,

R ² is hydrogen, hydroxy or lower alkyl,

R ¹ and R ² may be joined together to form a single bond

R ³ is hydrogen or lower alkyl (each R ³ is different! /, May! /),

R ⁵ is hydrogen or lower alkyl,

Y is a single bond or lower alkylene,

A compound wherein R is hydrogen, halogen or halogeno lower alkyl,

[0064] 30) In the formula (Iq),

Q ³ is N or CH,

X is one CO (CHR ³ ) n-, one CONR ⁵ (CHR ³ ) n-, one NR ⁵ CO (CHR ³ ) n, one or one

A ³ —CHR ³ —

n is 1 or 2,

R ¹ is hydrogen,

R ² is hydrogen or hydroxy;

R ¹ and R ² may be joined together to form a single bond

R ³ is hydrogen or lower alkyl (each R ³ is different! /, May! /),

R ⁵ is hydrogen or lower alkyl,

Y is a single bond or lower alkylene,

A compound wherein R is hydrogen, halogen, halogeno lower alkyl or lower alkoxy.

[0065] A compound in which the following formula (Ir), (Is), (It) or (Iu) has the following combination of AX, Y and R is also a preferred embodiment of the present invention. It is.

[Chemical 25]

[0066] [Table 1]

[0067] [Table 2]

[¾006

^ [¾ [¾600

,,,,,,,,,,,, 8Y2R3A11X8Y2R4A11X8Y2R5A11X8Y2R6A11X9Y1R -------- I

,,,,,,,,,,, A11X8Y1R5A11X8Y1R6A11X8Y2R1A11X8Y2R2A11XI --------

,,,,,,,,,,,, R6A11X8Y1R1A11X8Y1R2A11X8Y1R3A11X8Y1R4I ------- I

,,,,,,,,,,,, 1X7Y2R2A11X7Y2R3A11X7Y2R4A11X7Y2R5A11X7Y2 -------- ,,,,,,,,,, 3A11X7Y1R4A11X7Y1R5A11X7Y1-R1-A1-

,,,,,,,,,,,, 6Y2R5A11X6Y2R6A11X7Y1R1A11X7Y1R2A11X7Y1R -------- I

,,,,,,,,,,, A11X6Y2R1A11X6Y2R2A11X6Y2R3A11X6Y2R4A11XI --------

,,,,,,,,,,,, R2A11X6Y1R3A11X6Y1R4A11X6Y1R5A11X6Y1R6I ------- I

,,,,,,,,,,,, 1X5Y2R4A11X5Y2R5A11X5Y2R6A11X6Y1-R1A11X6Y1 -------- ,,,,,,,,,, 5A11X5Y1R6A11X5Y2-R2A11X5Y5-R2

,,,,,,,,,,, 5Y1R1A11X5Y1R2A11X5Y1R3A11X5Y1R4A11X5Y1R -------- I

,,,,,,,,,,, A11X4Y2R3A11X4Y2R4A11X4Y2R5A11X4Y2R6A11XI -------- ,,,,,,,,,,,,,

,,,,,,,,,,,,

,,,,,,,,,,, 3Y1R3A11X3Y1R4A11X3Y1R5A11X3Y1R6A11X3Y2R -------- I

,,,,,,,,,,, A11X2Y2R5A11X2Y2R6A11X3Y1R1A11X3Y1R2A11XI --------

,,,,,,,,,,,, R6A11X2Y2R1A11X2Y2R2A11X2Y2R3A11X2Y2R4I ------- I

,,,,,,,,,,,, 1X2Y1R2A11X2Y1R3A11X2Y1R4A11X2Y1R5A11X2Y1 -------- ,,,,,,,,,, 3A11X1Y2R4A11X1Y2R5A11X1Y2-R1-A11X1Y2-R1-

,,,,,,,,,,, 1Y1R5A11X1Y1R6A11X1Y2R1A11X1Y2R2A11X1Y2R -------- I

,,,,,,,,,,, (0070A11X1Y1R1A11X1Y1R2A11X1Y1R3A11X1Y1R4A11X ---------

,,,,,,,,,, (A11X18Y1R1A11X18Y1R2A11X18Y1R3A11X18Y1R4A1 -------- ,,,,,,, Y2R3A11Y2R4A11Y2R5A11Y2R6 ---

,,,,,,,, 1Y1R5A11Y1R6A11Y2R1A11Y2R2A11 I ------- I

,,,,,,, (A11Y1R1A11Y1R2A11Y1R3A11Y1R4A1I ------- ,,,,,,,,, X16Y2R3A11X16Y2R4A11X16Y2R5A11X16Y2R6 ----- I

,,,,,,,,,,, 1X16Y1R5A11X16Y1R6A11X16Y2R1A11X16Y2R2A11 I ------- I

,,,,,,,,,, (A11X16Y1R1A11X16Y1R2A11X16Y1R3A11X16Y1R4A1I ------- ,,,,,,, Y2R3A11Y2R4A11Y2R5A11Y2R6 ---

,,,,,,,, 1Y1R5A11Y1R6A11Y2R1A11Y2R2A11 I ------- I

,,,,,,, (A11Y1R1A11Y1R2A11Y1R3A11Y1R4A1I ------- ,,,,,,,,, X14Y2R3A11X14Y2R4A11X14Y2R5A11X14Y2R6 ----- I

,,,,,,,,,,, 1X14Y1R5A11X14Y1R6A11X14Y2R1A11X14Y2R2A11 I ------- I

,,,,,,,,,, (A11X14Y1R1A11X14Y1R2A11X14Y1R3A11X14Y1R4A1I ------- ,,,,,,, Y2R3A11Y2R4A11Y2R5A11Y2R6 ---

,,,,,,,, 1Y1R5A11Y1R6A11Y2R1A11Y2R2A11 I ------- I

,,,,,,, (A11Y1R1A11Y1R2A11Y1R3A11Y1R4A1I ------- ,,,,,,,,, X12Y2R3A11X12Y2R4A11X12Y2R5A11X12Y2R6 ------

,,,,,,,,,,, 1X12Y1R5A11X12Y1R6A11X12Y2R1A11X12Y2R2A11 I ------- I

...

,,,,,,,,,,, 1X11Y1R5A11X11Y1R6A11X11Y2R1A11X11Y2R2A11 I ------- I

,,,,,,,,,, (A11X11Y1R1A11X11Y1R2A11X11Y1R3A11X11Y1R4A1I ------- ,,,,, 1X10Y2R5A11X10Y2R6--I

,,,,,,,,,, 11X10Y2R1A11X10Y2R2A11X10Y2R3A11X10Y2R4A1I ------- I

,,,,,,,,,,, (A11X10Y1R3A11X10Y1R4A11X10Y1R5A11X10Y1R6A --------

,,,,,,,,,,,) R4A11X9Y2R5A11X9Y2R6A11X10Y1R1A11X10Y1R2I ------- I

,,,,,,,,,,,, 1X9Y1R6A11X9Y2R1A11X9Y2R2A11X9Y2R3A11X9Y2 -------- ,,,,,,,,,, 1A11X9Y1R2A11X9Y1R3A11X9Y1-R5 ,,,,,,,,,,, (A12X10Y1R3A12X10Y1R4A12X10Y1R5A12X10Y1R6A --------

,,,,,,,,,,,) R4A12X9Y2R5A12X9Y2R6A12X10Y1R1A12X10Y1R2I ------- I

,,,,,,,,,,,,, 2X9Y1R6A12X9Y2R1A12X9Y2R2A12X9Y2R3A12X9Y2 -------- ,,,,,, ,,,, ((1A12X9Y1 R2A12X9Y1- R3A12X9- l

,,,,,,,,,,,, 8Y2R3A12X8Y2R4A12X8Y2R5A12X8Y2R6A12X9Y1R -------- I

,,,,,,,,,,, A12X8Y1R5A12X8Y1R6A12X8Y2R1A12X8Y2R2A12XI --------

,,,,,,,,,,,, R6A12X8Y1R1A12X8Y1R2A12X8Y1R3A12X8Y1R4I ------- I

,,,,,,,,,,,, 2X7Y2R2A12X7Y2R3A12X7Y2R4A12X7Y2R5A12X7Y2 -------- ,,,,,,,,,, 3A12X7Y1R4A12X7Y1R5A12X7Y1-R1-A1-

,,,,,,,,,,,, 6Y2R5A12X6Y2R6A12X7Y1R1A12X7Y1R2A12X7Y1R -------- I

,,,,,,,,,,, A12X6Y2R1A12X6Y2R2A12X6Y2R3A12X6Y2R4A12XI --------

,,,,,,,,,,,, R2A12X6Y1R3A12X6Y1R4A12X6Y1R5A12X6Y1R6I ------- I

,,,,,,,,,,, 2X5Y2R4A12X5Y2R5A12X5Y2R6A12X6Y11A12X6Y1 -------- ,,,,,,,,,, 5A12X5Y1R6A12X5Y2R1A12X5Y2R2A-X

,,,,,,,,,,,, 5Y1R1A12X5Y1R2A12X5Y1R3A12X5Y1R4A12X5Y1R -------- I

,,,,,,,,,,,, A12X4Y2R3A12X4Y2R4A12X4Y2R5A12X4Y2R6A12XI -------- ,,,,,,,,,,,,,

,,,,,,,,,,, 1A12X3Y2R2A12X3Y2R3A12X3Y2R4A12X3Y2R5A1 -------- I

,,,,,,,,,,,, 3Y1R3A12X3Y1R4A12X3Y1R5A12X3Y1R6A12X3Y2R -------- I

,,,,,,,,,,, A12X2Y2R5A12X2Y2R6A12X3Y1R1A12X3Y1R2A12XI --------

,,,,,,,,,,,, R6A12X2Y2R1A12X2Y2R2A12X2Y2R3A12X2Y2R4I ------- I

,,,,,,,,,,,,, 2X2Y1R2A12X2Y1R3A12X2Y1R4A12X2Y1R5A12X2Y1 -------- ,,,,,,,,,,, 3A12X1Y2R4A12X1Y2R5A12X1Y2-R1-A1-

,,,,,,,,,,, 1Y1R5A12X1Y1R6A12X1Y2R1A12X1Y2R2A12X1Y2R -------- I

,,,,,,,,,,, (0071A12X1Y1R1A12X1Y1R2A12X1Y1R3A12X1Y1R4A12X --------- ,,,,,,,,,,, X18Y2R3A11X18Y2R4A11X18Y2R5I11-Y, ,,,,,, 1X18Y1R5A11X18Y1R6A11X18Y2R1A11X18Y2R2A11 I ------- I ,,,,,,,,,,, 1Y1R5A13X1Y1R6A13X1Y2R1A13X1Y2R2A13X1Y2R -------- I

,,,,,,,,,,, (0072A13X1Y1R1A13X1Y1R2A13X1Y1R3A13X1Y1R4A13X --------- ,,,,,,,,, 3A12X18Y2R4A12X18Y2R5A12X18Y2R-I-

,,,,,,,,,,,, 1R5A12X18Y1R6A12X18Y2R1A12X18Y2R2A12X18Y2RI ------- ,,,,,,,,,,, 8Y1R1A12X18Y1R2A12X18Y1R, A12X12Y18, ,, Y2R3A12Y2R4A12Y2R5A12Y2R6A12X1 -------- ,,,,,,,, 2Y1R5A12Y1R6A12Y2R1A12Y2R2A12 I ------- I

,,,,,,, (A12Y1R1A12Y1R2A12Y1R3A12Y1R4A1I ------- ,,,,,,,,, X16Y2R3A12X16Y2R4A12X16Y2R5A12X16Y2R6 ----- I

,,,,,,,,,,, 2X16Y1R5A12X16Y1R6A12X16Y2R1A12X16Y2R2A12 I ------- I

,,,,,,,,,, (A12X16Y1R1A12X16Y1R2A12X16Y1R3A12X16Y1R4A1I ------- ,,,,,,, Y2R3A12Y2R4A12Y2R5A12Y2R6 ----- I

,,,,,,,,, 2Y1R5A12Y1R6A12Y2R1A12Y2R2A12 I ------- I

,,,,,,, (A12Y1R1A12Y1R2A12Y1R3A12Y1R4A1I ------- ,,,,,,,,, X14Y2R3A12X14Y2R4A12X14Y2R5A12X14Y2R6 ----- I

,,,,,,,,,,, 2X14Y1R5A12X14Y1R6A12X14Y2R1A12X14Y2R2A12 I ------- I

,,,,,,,,,, (A12X14Y1R1A12X14Y1R2A12X14Y1R3A12X14Y1R4A1I ------- ,,,,,,, Y2R3A12Y2R4A12Y2R5A12Y2R6 ------ I

,,,,,,,,, 2Y1R5A12Y1R6A12Y2R1A12Y2R2A12 I ------- I

,,,,,,, (A12Y1R1A12Y1R2A12Y1R3A12Y1R4A1I ------- ,,,,,,,,, X12Y2R3A12X12Y2R4A12X12Y2R5A12X12Y2R6 ----- I

,,,,,,,,,,, 2X12Y1R5A12X12Y1R6A12X12Y2R1A12X12Y2R2A12 I ------- I

,,,,,,,,,, (A12X12Y1R1A12X12Y1R2A12X12Y1R3A12X12Y1R4A1 -------- ,,,,,,,,,,, Y2R1A12X11Y2R2A12X11Y2R-A12X11Y11-, ,,,,,, 11Y1R3A12X11Y1R4A12X11Y1R5A12X11Y1R6A12X11 ------- ,,,,,,,,,,, 2X10Y2R5A12X10Y2R6A12X11Y1R1A12X11Y1R2A,-, 12X10Y2R1A12X10Y2R2A12X10Y2R3A12X10Y2R4A1I ------- I ''Πχ'ε-iv)'(-' S people 'πχ'ε- ιν)' (ε- 'S people'πχ'ε- iv) '-' S people 'πχ'ε- ιν)' (ΐ -'S input'πχ'ε- ιν) '(9- Η'Ϊ 入'πχ'ε- iv) '(s- Η'Ϊ 入'πχ'ε- ΐν) '(G Η'Ϊ 入' πχ 'ε- ιν)' (ε- Η'Ϊ 入 'π χ'ε- ιν)'-Η'Ϊ 入 'πχ'ε- ιν)' (ΐ- Η'Ϊ 入 'πχ'ε- ιν)' (9- 'S-in'οιχ'ε- iv) '(s-' S-in 'οιχ'ε-iv)'('Speople'οιχ'ε- ιν) '(ε-' S people 'οιχ'ε -iv) '-' S people 'οιχ'ε- ιν)' (ΐ- 'S people'οιχ'ε- ΐ ν) '(9— Η'Ϊ 入'οιχ'ε— iv) '(s— Η 'Ϊ 入'οιχ'ε— ΐν) '(t Η'Ϊ 入'οιχ'ε— ιν) '(ε— Η'Ϊ 入'οιχ'ε— ιν) '— Η'Ϊ 入'οιχ'ε— ιν) '(ΐ— Η'ΐ 入'οιχ'ε—IV)'(9—' S people '6χ'ε— iv)' (s— 'S people'6χ'ε— ιν) '(g Η's'6χ'ε—ιν)'(ε—' S people '6χ'ε— iv)' — 'S people'6χ'ε— ιν) '(ΐ—' S people '6χ'ε— ιν)' (9— Η'Ϊ 人 '6χ'ε — iv)' (s— Η'Ϊ 人 '6χ'ε— ιν)' (t Η'Ϊ 人 '6χ'ε— ιν)' (ε— Η'Ϊ People '6χ'ε— ιν)' — Η'Ϊ 人 '6χ'ε— ιν) '(ΐ — Η' Ϊ 人 '6χ'ε— ιν)' (9— 'S people'8χ'ε— iv) '(s—' S people '8χ'ε— ιν)' (g 'S '8χ'ε—ιν)' (ε— 'S' 8 χ'ε— iv) '—' S people '8χ'ε— ιν)' (ΐ— 'S people'8χ'ε— ιν) '(9—Η'Η 人 '8χ'ε—iv)'(s—Η'Ϊ 人 '8χ'ε—iv

) '(T Η'Ϊ 人' 8χ'ε— ιν) '(ε— Η'ΐ 人' 8Χ'ε— IV) '— Η'ΐ 人' 8Χ'ε— ΐν) '(ΐ— Η'ΐ ON '8Χ'ε—IV)' (9—Η's into 'ζχ'ε— iv)' (s— 'S people' ζχ'ε— iv) 'o—' S people 'ζχ'ε— ιν) '(ε—' S people 'ζχ'ε— ιν)' — 'S people' ζχ'ε — ιν) '(ΐ—' S people 'ζχ'ε— ιν)' (9— Η'Ϊ 人 'ζχ 'ε— iv)' (s— Η'Ϊ 人 'ζχ'ε— ΐν)' (t Η'Ϊ 人 'ζχ'ε— ιν)' (ε — Η'Ϊ 人 'ζχ'ε— ιν)' — Η'Ϊ 人 'ζχ'ε— ιν)' (ΐ— Η'Ϊ 人 'ζχ'ε— IV)' (9— 'S people' 9χ'ε— iv) '(s—' S entered '9 χ'ε— iv) '(g' S people '9χ'ε— ιν)' (ε— 'S people' 9χ'ε— iv) '—' S people '9χ'ε— ιν)' (ΐ— ' S people '9χ'ε—iv)' (9—Η'Ϊ 人 '9χ'ε—iv)' (s—Η'Ϊ 人 '9χ'ε—iv)' (t Η'Ϊ 人 '9χ'ε — Ιν) '(ε— Η'ΐ 入' 9Χ'ε— IV) '— Η' ΐ 入 '9Χ'ε— ιν)' (ΐ— Η'ΐ 入 '9Χ'ε— IV)' (9— 'S people' SX'S—IV) '(S—' S people 'SX'S—IV)' (G 'S people' sx's — ιν) '(ε—' S people 'SX'S—IV)' — — 'S people' sx's — Ιν) '(ΐ— 'S people' SX'S—IV) '(9— Η'ΐ 人' SX'S—IV) '(S — Η'ΐ 人' SX'S—IV) '(t Η'ΐ 人' SX'S— ΐν) '(ε— Η'ΐ 人 'SX'S— IV)' — Η'ΐ 人 'SX'S— ΐν)' (ΐ— Η'ΐ 入 'S χ'ε— ιν)' (9— 'S people ^ χ'ε— iv) '(s—' S people ^ χ'ε— ΐν) '(G' S people ^ χ'ε— ιν) '(ε—' S people ^ χ'ε— iv) '—' S people 'χ'ε — Ιν) '(ΐ—' S people 'χ'ε— ιν)' (9— Η'Ϊ 人 'χ'ε— iv)' (s— Η'Ϊ 入 'χ'ε— ΐν)' ( Η 'ΐ 入 ^ χ'ε— ιν)' (ε— Η'Ϊ 入 'χ'ε— ιν)' — Η'Ϊ 人 'χ'ε— ιν)' (ΐ— Η'Ϊ 人 'χ' ε— ιν) '(9—' S people 'εχ'ε — iv)' (s— 'S people' εχ'ε— ιν) '(G' S people 'εχ'ε— ιν)' (ε— ' S people 'εχ'ε— ιν)' — 'S people' εχ'ε— ιν) '(ΐ —' S people 'εχ'ε— ιν)' (9— Η'Ϊ 人 'εχ'ε— iv) '(s— Η'Ϊ 人' εχ'ε— ΐν) '(t Η'Ϊ 人' εχ'ε— ιν) '(ε— Η'Ϊ 入' ε χ'ε— ιν) '— Η'Ϊ People 'εχ'ε—ιν)' (ΐ— Η'Ϊ 人 'εχ'ε—ιν)' (9— 'S people' sx's— iv) '(s—' S people 'sx's— ιν

) '(G' S people 'SX'S—ΐν)' (ε— 'S people' SX'S—IV) '—' S people 'SX'S—ΐν)' (ΐ— 'S people' SX'S—IV) '(9— 'ΐ 入' sx's— iv) '(s— Η'Ϊ 入' sx's— iv) '(t Η'Ϊ 人' sx's— ιν) '(ε— Η'ΐ 人' SX'S— IV) '— Η' ΐ 人 'sx's-ιν)' (ΐ- Η'Ϊ 人 'sx's- iv)' (9- 'S-in' ιχ'ε- iv) '(s-' S-in 'ιχ'ε- iv)' ( -'S input' ιχ'ε- ιν) '(ε

99l7ZlC / 900Zdf / X3d S9l7.Cl/900Z OAV ,,,,,,,,,,,, A14X2Y2R5A14X2Y2R6A14X3Y1R1A14X3Y1R2A14XI -------- ,,,,,,,,,, 3A14X1Y2R4A14X1Y2R5A14X1Y2R1-A1-X2

,,,,,,,,,,, 1Y1R5A14X1Y1R6A14X1Y2R1A14X1Y2R2A14X1Y2R -------- I

,,,,,,,,,,, (0073A14X1Y1R1A14X1Y1R2A14X1Y1R3A14X1Y1R4A14X --------- ,,,,,,,,, 3A13X18Y2R4A13X18Y2R5A13X18Y2R-I-

,,,,,,,,,,,, 1R5A13X18Y1R6A13X18Y2R1A13X18Y2R2A13X18Y2RI ------- ,,,,,,,,,, 8Y1R1A13X18Y1R2A13X18Y1R, A3X13X18-, ,, Y2R3A13Y2R4A13Y2R5A13Y2R6A13X1 -------- ,,,,,,,, 3Y1R5A13Y1R6A13Y2R1A13Y2R2A13 I ------- I

,,,,,,,,,, (A13X17Y1R1A13X17Y1R2A13X17Y1R3A13X17Y1R4A1I ------- ,,,,,,,,, X16Y2R3A13X16Y2R4A13X16Y2R5A13X16Y-R6-

,,,,,,,,,,, 3X16Y1R5A13X16Y1R6A13X16Y2R1A13X16Y2R2A13 I ------- I

,,,,,,,,,, (A13X16Y1R1A13X16Y1R2A13X16Y1R3A13X16Y1R4A1I ------- ,,,,,,, Y2R3A13Y2R4A13Y2R5A13Y2R6 ----- I

,,,,,,,,,,, 3X15Y1R5A13X15Y1R6A13X15Y2R1A13X15Y2R2A13 I ------- I

,,,,,,,,,, (A13X15Y1R1A13X15Y1R2A13X15Y1R3A13X15Y1R4A1I ------- ,,,,,,,,, X14Y2R3A13X14Y2R4A13X14Y2R5A13X14Y-R6-

,,,,,,,,,,, 3X14Y1R5A13X14Y1R6A13X14Y2R1A13X14Y2R2A13 I ------- I

,,,,,,,,,, (A13X14Y1R1A13X14Y1R2A13X14Y1R3A13X14Y1R4A1I ------- ,,,,,,, Y2R3A13Y2R4A13Y2R5A13Y2R6 ----- I

,,,,,,,,,,, 3X13Y1R5A13X13Y1R6A13X13Y2R1A13X13Y2R2A13 I ------- I

,,,,,,,,,, (A13X13Y1R1A13X13Y1R2A13X13Y1R3A13X13Y1R4A1I ------- ,,,,,,,,, X12Y2R3A13X12Y2R4A13X12Y2R5A13X12Y-R6-

,,,,,,,,,,, 3X12Y1R5A13X12Y1R6A13X12Y2R1A13X12Y2R2A13 I ------- I

,,,,,,,,,, (A13X12Y1R1A13X12Y1R2A13X12Y1R3A13X12Y1R4A1 -------- ,,, ?? 5A13X11Y2R6III ,,,,,,,,,, X12Y2R3A14X12Y2R4A14X12Y2R5A14X12Y2R6 ------ I

,,,,,,,,,,, 4X12Y1R5A14X12Y1R6A14X12Y2R1A14X12Y2R2A14 I ------- I

,,,,,,,,,, (A14X12Y1R1A14X12Y1R2A14X12Y1R3A14X12Y1R4A1 --------

,,,,,,,,,,,,,,

,,,,,,,,, 4Y1R5A14Y1R6A14Y2R1A14Y2R2A14 I ------- I

,,,,,,, (A14Y1R1A14Y1R2A14Y1R3A14Y1R4A1 -------- ,,,,,,,,, X14Y2R3A14X14Y2R4A14X14Y2R5A14X14Y2R6IIII-II

,,,,,,,,,,, 4X14Y1R5A14X14Y1R6A14X14Y2R1A14X14Y2R2A14 I ------- I

,,,,,,,,,, (A14X14Y1R1A14X14Y1R2A14X14Y1R3A14X14Y1R4A1 -------- ,,,,,,, Y2R3A14Y2R4A14Y2R5A14Y2R6IIII-II

,,,,,,,, 4Y1R5A14Y1R6A14Y2R1A14Y2R2A14 I ------- I ,,,,,, (A14Y1R1A14Y1R2A14Y1R3A14Y1R4A1 ------- It varies depending on the age, body weight, symptom, administration method, etc., but it is usually about 1 mg to about 5000 mg for adults per day for oral administration and about 0.1 mg to about lOOOmg for parenteral administration. is there.

[0075] Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples. Melting points listed in the text are uncorrected values. In addition, ¹ H-NMR is obtained from heavy chloroform (CDC1) or heavy dimethyl sulfoxide (DMSO-d) solvent.

In 36, tetramethylsilane was measured as an internal standard. The δ value was expressed in ppm, and the binding constant 0) was expressed in Hz. In the data, s is single line, d is double line, t is triple line, q is quadruple line, quint is quintet line, m is multiple line, br is wide line, brs is wide single line, brt is wide Means a triple line.

Each abbreviation has the meaning shown below.

Boc: tert-butoxycanoreboninole

Et: Echil

THF: tetrahydrofuran

LDA: Lithium diisopropylamide

DIBAL: Diisobutylaluminum hydride

DMSO: Dimethyl sulfoxide

Bn: Benzinore

DMF: N, N-dimethylformamide

HOBt: 1-hydroxybenzotriazolene

DMAP: 4-Dimethylaminopyridine

EDC: 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

[0076] Reference Example 1 Synthesis of Compound 5

[Chemical 26]

a) Synthesis of Compound 2

Under a nitrogen atmosphere, ester 1 (5.15 g, 20.0 mmol) prepared by the method described in PJ Gilligan et al., J. Med. Chem., 37, 364 (1994) was dissolved in THF (80 ml) and dried ice-acetate. The solution was cooled to -78 ° C with a water bath. LDA (2.0 M heptane / THF / benzene solution, 11 ml, 22.0 mmol) was added dropwise, and the mixture was stirred at -70 ° C or lower for 1 hour. 4-Fluorobenzyl bromide (3.97 g, 21.0 mmol) in 20 ml THF was added dropwise, and the mixture was stirred at -70 ° C or lower for 1 hour and at room temperature for 16 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer is water, 10% aqueous citrate solution, water

The extract was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane acetate) to give Compound 2 (7.17 g, yield 98%) as a pale yellow oil.

1H-NMR (CDC1 I TMS) δ ppm: 1.19 (t, J = 7.3Hz, 3H), 1.35—1.45 (m, 2H), 1.44 (s,

Three

9H), 2.03-2.12 (m, 2H), 2.75-2.85 (m, 2H), 2.79 (s, 2H), 3.87—3.98 (m, 2H), 4.10 (q, J = 7.3Hz, 2H), 6.90 —7.04 (m, 4H).

b) Synthesis of compound 3

Under a nitrogen atmosphere, Compound 2 (3.14 g, 8.59 mmol) was dissolved in methylene chloride (100 ml) and cooled to −78 ° C. with a dry ice-acetone bath. -DIBAL (1.0 M toluene solution, 25.8 ml, 25.8 mmol) was added dropwise at -70 ° C or lower, and the mixture was stirred at -70 ° C or lower for 1 hour. After adding 10 ml of methanol, the reaction mixture was poured into a mixed solution of jetyl ether and saturated sodium potassium tartrate aqueous solution and stirred at room temperature for 16 hours. After extraction with jetyl ether, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane monoacetate) Compound 3 (1.66 g, yield 60%) was obtained as a white solid.

1H-NMR (CDC1 I TMS) δ ppm: 1.30 (t, J = 4.6Hz, 1H), 1.38—1.50 (m, 4H), 1.46 (s,

Three

9H), 2.70 (s, 2H), 3.33-3.42 (m, 4H), 3.45-3.58 (m, 2H), 6.97 (t, J = 8.6Hz, 2H), 7.14 (dd, J = 8.6, (5.3Hz, 2H).

c) Synthesis of compound 4

Compound 3 (0.22 g, 0.68 mmol) was dissolved in methylene chloride (8 ml), triethylamine (0.14 g, 1.36 mmol), sulfur trioxide pyridine complex (0.22 g, 1.36 mmol), DMSO (0.53 g, 6.8 mmol) Was stirred and stirred at room temperature for 48 hours. The solvent was distilled off under reduced pressure, and water was extracted from the residue with vigorous jetyl ether. The organic layer was washed with 1 mol / L hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 4 (0.09 g, yield 41%) as a colorless oil.

1H-NMR (CDC1 I TMS) δ ppm: 1.44 (s, 9H), 1.45—1.57 (m, 2H), 1.88—1.97 (m, 2H)

Three

, 2.76 (s, 2H), 2.78-2.93 (m, 2H), 3.83-3.94 (m, 2H), 6.92-7.04 (m, 4H), 9.56 (s, 1 H).

d) Synthesis of compound 5

Compound 4 (0.17 g, 0.53 mmol), ethylene glycol (5 ml) and hydrazine monohydrate (0.53 g, 10.6 mmol) were mixed and stirred at 160 ° C. for 4 hours. After allowing to cool to room temperature, sodium hydroxide (0.47 g, 11.7 mmol) was stirred at 180 ° C. for 2 hours. After allowing to cool to room temperature, water and 1 mol / L hydrochloric acid were added, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride / methanol). Compound 5 (0.05 g, yield 46%) was obtained as a pale yellow oil.

1H-NMR (CDC1 I TMS) δ ppm: 0.89 (s, 3H), 1.20—1.32 (m, 2H), 1.37—1.50 (m, 2H)

Three

, 1.63 (br, 1H), 2.54 (s, 2H), 2.74-2.94 (m, 4H), 6.95 (t, J = 8.6Hz, 2H), 7.04-7.10 (m, 2H).

Reference Example 2 Synthesis of Compound 9

[Chemical 27]

a) Synthesis of Compound 7

Under a nitrogen atmosphere, 4-chlorobenzoyltriphosphor-um chloride (12.70 g, 30.0 mmol) was suspended in THF (80 ml) and cooled in an ice bath. After 1.58M n-butyllithium monohexane solution (20.9 ml, 33.0 mmol) was added dropwise, a 20 ml THF solution of compound 6 (5.98 g, 30.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added, the mixture was extracted with jetyl ether, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane monoacetate) to obtain Compound 7 (7.56 g, yield 82%) as a pale yellow oil.

1H-NMR (CDC1 I TMS) δ ppm: 1.48 (s, 9H), 2.32 (t, J = 5.6Hz, 2H), 2.42 (t, J = 5.

Three

6Hz, 2H), 3.40 (t, J = 5.6Hz, 2H), 3.50 (t, J = 5.6Hz, 2H), 6.30 (s, 1H), 7.11 (d, J = 8.6Hz, 2H), 7.28 ( d, J = 8.6Hz, 2H).

b) Synthesis of compound 8

Compound 7 (7.56 g, 24.6 mmol) is dissolved in toluene (100 ml), black mouth (trifluorophosphine) rhodium (I) (0.52 g, 0.56 mmol) is added, and hydrogen gas at 4 atm. The mixture was stirred at ° C for 48 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane ethyl acetate) to obtain Compound 8 (7.02 g, yield 92%) as a pale yellow solid.

1H-NMR (CDC1 I TMS) δ ppm: 1.05- 1.17 (m, 2H), 1.45 (s, 9H), 1.55—1.65 (m, 3H)

Three

, 2.50 (d, J = 6.9Hz, 2H), 2.55-2.70 (m, 2H), 4.02—4.15 (m, 2H), 7.06 (d, J = 8.6Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H).

c) Synthesis of compound 9

To compound 8 (7.02 g, 22.7 mmol) was added 10% hydrochloric acid methanol (30 ml), and the mixture was stirred at room temperature for 1 hour and at 50 ° C for 0.5 hour. The solvent was distilled off under reduced pressure, and the residue was ethanol-jetyl ether. Recrystallization gave compound 9 (5.34 g, yield 96%) as white crystals.

1H-NMR (DMSO-d / TMS) δ ppm: 1.30— 1.50 (m, 2H), 1.66—1.86 (m, 3H), 2.52 (d,

6

J = 6.9Hz, 2H), 2.76 (dd, J = 10.2, 2.3Hz, 2H), 3.19 (d, J = 10.2Hz, 2H), 7.21 (d, J = 8.3Hz, 2H), 7.35 (d, J = 8.3Hz, 2H), 8.96 (brs, 2H).

Reference Example 3 Synthesis of Compound 13

[Chemical 28]

a) Synthesis of Compound 11

Compound 10 (4.07 g, 20.0 mmol) was dissolved in acetone (50 ml), benzyl chloride (2.53 g, 2 0.0 mmol) was stirred at room temperature for 18 hours, and then refluxed for 48 hours. After allowing to cool to room temperature, jetty ether was added and the precipitated solid was collected by filtration. After drying, compound 11 (4.73 g, yield 72%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d / TMS) δ ppm: 4.28 (s, 2H), 5.79 (s, 2H), 7.35-7.55 (m, 9H), 8

6

.02 (d, J = 6.6Hz, 2H), 9.10 (d, J = 6.6Hz, 2H).

b) Synthesis of Compound 12

Compound 11 (4.73 g, 14.3 mmol) was dissolved in ethanol (50 ml) and cooled in an ice bath. Sodium borohydride (2.17 g, 57.4 mmol) was added in small portions and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the residue was acidified with 2 mol / L hydrochloric acid, made alkaline with sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 12 (3.40 g, yield 80%) as a yellow oil.

1H-NMR (CDC1 I TMS) δ ppm: 1.98— 2.08 (m, 2H), 2.52 (t, J = 5.6Hz, 2H), 2.94—3.

Three

03 (m, 2H), 3.20-3.29 (m, 2H), 3.56 (s, 2H), 5.32—5.38 (m, 1H), 7.09 (d, J = 8.6Hz, Hma fH ^ T i ^0UI IO ^ra os) / — ^ eko Ki ^0UIUI s'si ^<s irs) ei

• (HI 's-iq)' (Ηΐ 'ZH9

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° ¾ っ;: # 圑 ^% 9z * ¾i 's · ε) 9ΐ

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9 (SLI oS a) H NH X 8 ¾i 'S ££' Z) £ l, Etsu ¹ Iche ^ d over / - ^, one

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¾ ^^ o) 6i 呦 ^^ Kq

• (Ηΐ 'ZH9 = f' Ρ) 9Γ8 '(Ηΐ' WZ '6 · 8 = f' ΡΡ) 06 · '(Ηΐ' s jq) WL '(HS' ω) 9VL-9Z'L '(Ηΐ' ΖΗ6 · 8 = f 'Ρ) 8Z "9 HZ' ^s ) TS '(HS'ZHS" = f ' ^b ) ΐ · 6 "2-29"2' (HS 'ZHS "= f ST ^ dd 9 (SL / ^ DOD) H NH _X

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"(HS 's-iq) 00 ΐ' (Ηΐ 'ZHS'S = f · 8' (Ηΐ 'ΖΗ9 = f' Ρ) Ζ6" Ζ '(Ηΐ' ΖΗ9 '9 · 6 = f' ΡΡ) S8 "Z ' (Ηΐ 9'6 = f 'Ρ) SS "9' (Η2 'ZHS"' S "S = f '^ Ρ)' (Η2 'ZHS" = f S2 "2' (HS 'ZHS" = f' ^ m) Qfy.mAA g (SL / oS a) H NH _X

UIUI o'zz

0Ζ) Μ

t9

99l7ZlC / 900Zdf / X3d S9l7.Cl/900Z OAV The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride-methanol) to obtain Compound 19 (0.33 g, yield 100%) as a white solid.

1H-NMR (CDC1 I TMS) δ ppm: 1.27 (t, J = 7.3Hz, 3H), 2.63-2.77 (m, 4H), 4.16 (q

Three

, J = 7.3Hz, 2H), 6.51 (d, J = 9.6Hz, 1H), 7.40 (dd, J = 9.6, 2.3Hz, 1H), 7.88 (s, 1H), 8.19 (d, J = 2.3Hz , 1H), 12.32 (br, 1H).

c) Synthesis of compound 20

Methanol (15 ml) and 1 mol / L aqueous sodium hydroxide solution (4.2 ml, 4.2 mmol) were added to compound 19 (0.33 g, 1.39 mmol), and the mixture was stirred at room temperature for 5 hours. After adding 1 mol / L hydrochloric acid (4.3 ml, 4.3 mmol), the solvent was concentrated under reduced pressure, cooled in an ice bath, and the precipitated solid was collected by filtration. The extract was washed with water and ethyl acetate and then dried to obtain Compound 16 (0.24 g, yield 89%) as a white solid. 1H-NMR (DMSO-d / TMS) δ ppm: 2.45-2.55 (m, 4H), 6.34 (d, J = 9.6Hz, 1H), 7.4

6

1 (dd, J = 9.6, 2.6Hz, 1H), 7.83 (d, J = 2.6Hz, 1H), 9.71 (s, 1H), 11.71 (brs, 1H). Example 1

Synthesis of compound (I 95)

[Chemical 31]

Amine 13 (100 mg, 0.41 mmol) obtained in Reference Example 3 was added to DMF (10 ml), carboxylic acid 16 (100 mg, 0.45 mmol), HOBt-hydrate (68 mg) obtained in Reference Example 4. , 0.45 mmol), triethylenoamine (99 mg, 0.98 mmol), DMAP (5 mg, 0.04 mmol), and EDC (86 mg, 0.45 mmol) were stirred and stirred at room temperature for 6 hours. DMF was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 10% aqueous citrate solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl hexane acetate to obtain the compound (1-95) (117 mg, yield 69%) as a white solid. mp 200 201 ° C

1H-NMR (DMSO-d I TMS) δ ppm: 0.84- 1.15 (m, 2H), 1.48—1.58 (m, 2H), 1.62—1.8

6

0 (m, 3H), 2.31 (t, J = 7.3Hz, 2H), 2.37-2.47 (m, 1H), 2.82—2.93 (m, 1H), 3.20 (q, J = 6.6Hz, 2H), 3.74 -3.84 (m, 1H), 4.28—4.38 (m, 1H), 6.33 (d, J = 9.6Hz, 1H), 7.19 (d, J = 8.2Hz, 2H), 7.33 (d, J = 8.2Hz, 2H), 7.84 (dd, J = 9.6, 2.6Hz, 1H), 7.96 (d, J = 2.6Hz, 1H), 8.19 (t, J = 6.6Hz, 1H), 11.92 (brs, 1H).

Example 2

Synthesis of Compound (I-101)

[Chemical 32]

Amine 13 obtained in Reference Example 3 (110 mg, 0.45 mmoW DMF (10 ml), Carboxylic acid 20 obtained in Reference Example 5 (103 mg, 0.49 mmol), HOBt—hydrate (75 mg, 0.49 mmol), triethylenoleamine (109 mg, 1.08 mmol), DMAP (5 mg, 0.04 mmol), EDC (94 mg, 0.49 mmol) and stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.The organic layer was washed with water, 10% aqueous citrate solution, water, saturated aqueous sodium bicarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was recrystallized from methanol-water to give compound (1-101) (82 mg, yield 46%) as a white solid.

mp 221 222 ° C

1H-NMR (DMSO-d I TMS) δ ppm: 0.85— 1.18 (m, 2H), 1.49—1.62 (m, 2H), 1.65—1.8

6

0 (m, 1H), 2.38-2.60 (m, 7H), 2.91 (t, J = 12.2Hz, 1H), 3.80—3.90 (m, 1H), 4.27-4. 37 (m, 1H), 6.34 ( d, J = 9.6Hz, 1H), 7.20 (d, J = 8.2Hz, 2H), 7.33 (d, J = 8.2Hz, 2H), 7.41 (dd, J = 9.6, 2.6Hz, 1H), 7.84 ( d, J = 2.6Hz, 1H), 9.68 (s, 1H), 11.27 (br, 1 H).

Example 3 Synthesis of compound (I 6)

[Chemical 33]

a) Synthesis of Compound 22

Compound 21 (3.14 g, 13.6 mmol) was dissolved in acetonitrile (100 ml), and N-Boc-2-chloroethylamine (2.70 g, 15.0 mmol), potassium carbonate (5.66 g, 41.0 mmol), potassium iodide ( 0.23 g, 1.4 mmol) was refluxed for 3 days. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane to give Compound 22 (1.79 g, 39% yield) as a pale yellow solid. Obtained.

1H-NMR (CDC1) δ ppm: 1.45 (s, 9H), 2.48—2.60 (m, 4H), 2.71 (t, J = 5.6Hz, 2H), 3

Three

.13-3.18 (m, 2H), 3.26-3.36 (m, 2H), 5.03 (br, IH), 6.06 (brs, IH), 7.29 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2Hz, 2H).

b) Synthesis of compound 23

Compound 22 (2.50 g, 7.42 mmol) was dissolved in methanol (10 ml), 10% hydrochloric acid methanol (20 ml) was added, and the mixture was stirred at 50 ° C. for 20 hr. The solvent was concentrated under reduced pressure, crystallized by adding ethyl acetate, and the crystals were collected by filtration to give compound 23 (2.29 g, yield 100%) as white crystals.

1H-NMR (DMSO-d / TMS) δ ppm: 2.78-2.89 (m, 2H), 3.38—3.47 (m, 6H), 3.72-4.0

6

4 (m, 2H), 6.24 (s, IH), 7.45 (d, J = 8.6Hz, 2H), 7.53 (d, J = 8.6Hz, 2H), 8.51 (br, 3H), 11.37 (br, IH ).

c) Synthesis of compound (I 6) . ¾ え；： # 圑 ^ · = ^ 、一 ¾ (% SS ¾ί 93) (6-1)

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(HI · 9- 8Γ9 '(Η2 ' ΖΗ9 · 9 = f 6ST '(Η2' ω) 8ΐ · ε - ΐ · ε '{ΗΖ' Ζ Η6 · = f 6

9 '(Η2' ΖΗ9 · 9 = f 8S ΗΖ 'ω) — SS: radd ρ (SL / oS a) H NH _X

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89

99l7ZlC / 900Zdf / X3d S9l7.Cl/900Z OAV ^{\ HZ 'ζ ΗΟ · ε'} 9'S = f 'PP) fS'L HZ' ζ ΗΟ · ε '9 "S = f' PP) \ L HZ 'Ζ Η9 · 8 = f' P) IZ'L HZ ' ^Ζ Η9 ・ 8 = f 'P) fVL HZ' ^Ζ Η9 · 9 = f 28 "S HZ 's) ZL'Z HZ Z-QL'Z HZ' ^Ζ Η9 · 9 = f WZ HZ 'ZHS'II' 9 'Ζ = f' ^ P

) SS "2 HZ 'ω) 0Z" T-8S "T HZ' ω) SS'I— ε · ΐ '(Ηΐ' s) en: uidd9 ( ^S DaD) H NH _x

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• (HI 'jq) 6 ΐ

'(Η2' ω) S9 "Z-8S" Z '(Ηΐ' s) IS'Z '(Η2' ^ HZ'S = f 'Ρ) S ^ "HZ' ^Z HS'8 = f 'P) WL

: (Ηΐ 'ω) 8Γ9- εΐ9' (Η2 'ΖΗ9 · 9 = f ε · ε' (HZ 'ω) ε― 9ΐ · ε' (Η2 'ZHS'S = (') Ζ

Z ΗΖ ' ^Ζ Η9 · 9 = f 29 "2 ΗΖ' ω) S: ω (9 (SL / Ρ- OSW.) 顺-Η _τ

OoSZT ZLl dm

69

99l7ZlC / 900Zdf / X3d S9l7.Cl/900Z OAV Compound 26 (3.25 g, 7.25 mmol) was dissolved in ethanol (35 ml), and hydrazine monohydrate (0.73 g, 14.5 mmol) was refluxed for 24 hours. After cooling, the precipitated crystals were removed by filtration, and the filtrate was concentrated under reduced pressure to give crude compound 27 (2.35 g, crude yield 100%) as a yellow oil. Compound 30 was used in the next step as a crude product.

c) Synthesis of compound (I 15)

Amine 27 (150 mg, 0.47 mmol) to DMF (10 ml), 6-hydroxynicotinic acid (72 mg, 0.52 mmol), HOBt—hydrate (86 mg, 0.56 mmol), Triethylamine (57 mg, 0.56 mmol) , DMAP (6 mg, 0.05 mmol) and EDC (107 mg, 0.56 mmol) were added and stirred at room temperature for 24 hours. DMF was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate was extracted from the residue with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by alumina column chromatography (ethyl acetate / methanol / methylene chloride / methanol). Hexane was added to crystallize, and the crystal was collected by filtration to give compound (1-15) (103 mg, yield 50%) as a pale yellow solid.

mp 98 101 ° C

1H-NMR (DMSO-d I TMS) δ ppm: 1.31- 1.36 (m, 2H), 1.44—1.52 (m, 2H), 2.24-2.3

6

2 (m, 2H), 2.39-2.50 (m, 2H), 2.51-2.53 (m, 2H), 2.68 (s, 2H), 3.23-3.31 (m, 2H), 4.19 (s, 1H), 6.33 ( d, J = 9.6Hz, 1H), 7.24 (d, J = 8.2Hz, 2H), 7.31 (d, J = 8.2Hz, 2H), 7.83 (d, J = 9.6Hz, 1H), 7.95 (s , 1H), 8.14 (brt, J = 5.9Hz, 1H), 11.95 (br, 1H). Example 6

Synthesis of compound (I 22)

[Chemical 36]

a) Synthesis of Compound 29

Under a nitrogen atmosphere, Compound 28 (7.92 g, 30.0 mmol) was dissolved in THF (100 ml) and cooled to −78 ° C. with a dry ice-acetone bath. 1.58M n-butyllithium monohexane solution (20.3 ml, 32.0 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 2 hours. A 50 ml THF solution of 4-chloro-N-methoxy-N-methylbutyric acid amide (3.31 g, 20.0 mmol) was added and stirred at -78 ° C for 1 hour. Water was added, the temperature was raised to room temperature, and the solvent was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate) to give Compound 29 (4.88 g, yield from 4-chloro-N-methoxy-N-methylbutyric acid amide 84%) as white crystals. Obtained.

1H-NMR (CDC1) δ ppm: 2.23 (m, 2H), 3.13 (t, J = 7.3Hz, 2H), 3.68 (t, J = 5.9Hz, 2

Three

H), 5.48 (s, 2H), 6.85 (d, J = 8.9Hz, 1H), 7.26-7.48 (m, 5H), 8.16 (dd, J = 8.9, 2.4 Hz, 1H), 8.83 (d, J = 2.4Hz, 1H).

b) Synthesis of compound 30

4- (4-Fluorobenzyl) piperidine (0.39 g, 2.0 mmol), compound 29 (0.70 g, 2.4 mmol) dissolved in acetonitrile (10 ml), potassium carbonate (0.41 g, 3.0 mmol), potassium iodide (33 mg, 0.2 mmol) was stirred at 60 ° C for 4 hours and at room temperature for 60 hours. The solvent was removed under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by alumina column chromatography (methylene chloride) to give a yield from compound 30 (0.42 g, 4- (4-fluorobenzyl) piperidine. 47%) was obtained as white crystals.

1H-NMR (CDC1 I TMS) 6 ppm: 1.18 (m, 2H), 1.36—1.58 (m, 3H), 1.80—2.01 (m, 4H

Three

), 2.35 (t, J = 6.9Hz, 2H), 2.46 (d, J = 5.7Hz, 2H), 2.83—2.94 (m, 4H), 5.46 (s, 2H), 6.83 (d, J = 8.9Hz , 1H), 6.93 (m, 2H), 7.04 (m, 2H), 7.29-7.48 (m, 5H), 8.15 (dd, J = 8.9, 2.4Hz, 1H), 8.80 (d, J = 2.4Hz, 1H).

c) Synthesis of compound (I 22)

Compound 30 (0.42 g, 0.94 mmol) was dissolved in asol (10 ml) and cooled in an ice bath. Add aluminum chloride (0.63 g, 4.7 mmol) and stir at room temperature for 16 hours, then at 60 ° C for 0.5 hour

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[0089] [Chemical 38]

[0090] [Chemical 39]

[0091] [Chemical 40] [ΐ ^] [2600]

9L

99tZU / 900Zdr / LDd S9 Z. i / 900i ΟΛΧ

42] [ε] 600]

99tZU / 900Zdr / 13d S9l7.Cl/900∑: OAV

44]

[0096] [Chemical 45] [9 ^ 600]

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49]

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[0104] [Table 8]

68

99 ^ iie / 9003df / X3d S9f ^ n / 900Z OAV //: / O 993ϊε900ί1 £ s9s-2900iAV 60ΐο3

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99tZU / 900Zdr / ∑Jd S9l7.Cl/900Z OAV [0107] [Table 11]

[0108] Test Example 1 Binding experiment to NMDA receptor (NR1ZNR2B receptor)

Receptor competition experiments with test compounds were conducted using Ifenprodil, an NR1ZNR2B subtype receptor-specific antagonist, as the ligand.

The animals were male, Sl _C : Wistar rats, and the brains after decapitation were removed and the cerebral cortex was fractionated. The cerebral cortex was homogenized with 20 times the amount of ice-cold 50 mM Tris'HCl buffer (pH 7.4) and centrifuged at 4 ° C. and 27,500 × g for 10 minutes. The resulting precipitate was suspended in the same buffer and then centrifuged again. This operation was repeated three times, and the resulting precipitate was suspended in a buffer and stored at −80 ° C. Immediately before the experiment, after thawing at room temperature, the mixture was centrifuged at 27 ° C. for 10 minutes at 4 ° C., and the resulting precipitate was suspended in a buffer solution. Furthermore, it was diluted 10-fold with a buffer solution, and this was used for experiments as a membrane preparation.

In the binding experiment, 10 1 different concentrations of the test compound, 10 1 labeling ligand [ ³ H] -Ifenprodil and 10 μ 1 GBR-12909 were added to 470 μ 1 of the above membrane preparation, and 120 ° C. at ice temperature. Incubated for a minute. The final concentration of [ ³ H] -Ifenprodil for the labeled ligand was 5 ηΜ, and the concentration of GBR-12909 was 3 最終. The total amount of binding is measured using DMS0, a solvent, and nonspecific 100 / z M Ifenprodil was used to measure the amount of binding. GBR-12909 was added to block [ ³ H] -Ifenpr odil binding to non-polyamine-sensitive sites. After incubation, the bound and free bodies were separated using Whatman GF / C filter paper (Whatman), and the filter paper was washed 4 times with 2.5 ml of ice-cold buffer. The filter paper was immersed in a liquid scintillation (Clearsol I, manufactured by Nacalai Tester) in a vial, and the radioactivity (dpm) was measured with a liquid scintillation counter. Based on the measured value, the binding inhibition rate (%) was determined by the following formula, and the dose (IC) that suppressed binding by 50% was calculated. Table 11 shows the IC values of the test substances.

50 50

The formula of GBR-12909 (vanoxerin) is shown below.

[Chemical 50]

Binding inhibition rate (%) = 100

A bone non-specific binding amount)]

[Table 12]

Compound! C50 (wM) 1-122 0.053

I 1 2 0.002 1-124 0.05

I 1 3 0.004 I― 134 0.013

I-4 0.008 1-1 35 0.053

I 1 6 0.001 I― 158 0.022

I-9 0.007 1-160 0.058

0.01.5 1-163 0.019

1 -24 0.005 1-1 69 0.013

I― 25 0.001 1― 170 0.014

1 -26 0.016 1-17 1 0.062

1 -28 0.005 1-175 0.023

`` ϊ ώ '' 0.012 I-177 0.026

1—3 1 0.006 I-178 0.029

1-32 0.005 1— 179 0.008

1-33 0.005 I 18 1 0.026

I ― 39 0.011 1-182 0.021

1 -40 0.006 1-184 0.053

1 -41 0.01 1— 186 0.066

1—42 0.018 ί-187 0.082

1 -46 0.011 I '188 0.022

1 -53 0.009 1-1 89 0.059

1 -75 0.016 1— 1 90 0.016

I — 10 1 0.001 1-1 91 0.065

1-106 0.016 1-1 95 0.041

I — 1 1 0 0.008 1-196 0.027

1-1 13 0.032 1— 197 0.038

From the above results, it was revealed that the compound of the present invention exhibits strong binding to the NR1ZNR2B subtype receptor.

Test Example 2 NMDA receptor expression and Ca ion inflow measurement

The complementary DNA (cDNA) of the mouse NMDA receptor subunit was transiently introduced into HEK293 cells, and one day after the introduction, changes in intracellular Ca content induced by glutamate Z-glycine were measured using a Ca ion-reactive fluorescent dye.

HEK293 cells were cultured and passaged using modified Dulbecco's Eagle medium (DMEM, low glucose).

20,000 HEK293 Z-wells are seeded in a 96-well plate, and the NR1 and NR2B subunits of the NMDA receptor incorporated into the pcDAN3.1 plasmid are transiently introduced into the cell to co-express the subunits. Was done. The amount of DNA introduced is NR1 0.025 g and NR2B subunit 0.075 g. After the introduction, the cell death was suppressed by using 50 μΜ of NMDA receptor antagonist MK-801.

A Krepes 'Ringer' Hepes buffer (KRH, Ca: 5 mM) was used for the preparation of test compounds and cell washing.

One day after introduction, the NMDA receptor antagonist MK-801 was washed away with KRH buffer, and the Ca ion-directed fluorescent dye Fluo-3 / -3 was taken up into the cells. Ca ion influx was induced by glutamate 20 μ ミ glycine 2 μΜΖ. Changes in the amount of fluorescence due to Ca ion inflow into the cells were measured using a fluorescence imaging system FDSS3000 at an excitation of 480 nm.

Normally, if the test compound shows NMDA receptor antagonism, the influx of Ca ions into the cell decreases, and the amount of fluorescence decreases.

The inhibition rate (%) of Ca ion influx was determined from the measured value of the test compound by the following formula, and the dose (IC) that inhibits inflow by 50% was calculated. Table 12 shows the IC values of the test substances.

50 50

Ca ion inflow inhibition rate (%) = 100 [(fluorescence amount in the presence of test compound-background fluorescence amount) I (total fluorescence amount background fluorescence amount)] X 100

[Table 13]

From the above results, it is clear that the compound of the present invention exhibits NMDA receptor antagonistic action. became.

Industrial applicability

The present invention shows specific antagonism to glutamate receptors of central nerve cells, particularly NR1ZNR2B receptor, which is one of NMDA receptors, such as motor function (sensory abnormalities), psychiatric symptoms (schizophrenia), etc. It is useful as an analgesic and Z or neuroprotective agent with few side effects.

Claims

Claim [1] Formula (I)

[Chemical 1]

(Where

A ¹ is

A ² is

R ¹ is hydrogen, hydroxy, acyloxy, lower alkoxy or lower alkyl,

R ² is hydrogen, hydroxy or lower alkyl,

R ¹ and R ² may be joined together to form a single bond

m is 0 or 1,

X is

It may have a substituent, may be a lower alkylene, may have a substituent, may be a lower alkylene, —CO (CR ³ R ⁴ ) n—, —CONR ⁵ (CR ³ R ⁴ ) n—, — NR ⁵ CO (CR ³ R ⁴ ) n—, -NR ⁵ CONR ⁶ (CR ³ R ⁴ ) n—, — C (= N—OR ⁷ ) (CR ³ R ⁴ ) n—, -(CR ⁸ R ⁹ ) rO (CR ³ R 4) n―, ― (CR ⁸ R ⁹ ) rS (CR ³ R ⁴ ) n―, ― (CR ⁸ R ⁹ ) rNR ⁶ (CR ³ R ⁴ ) n ― 、 ― (CR ⁸ R ⁹ ) rS

0 (CR ³ R ⁴ ) n- (CRV) rSO (CR ³ R ⁴ ) n- CR ⁹ = N-0 (CR ³ R ⁴ ) ri-

, 3 ^ 4 10 11, 3 ^ 4,

CC = 0) 0 (CR ³ R ⁴ ) n-A ^3- (C) n—or — Α ^ΰ — CR = CRi 丄 (C) n—

A ³ is

[Chemical 2]

And

— X— (CO) m—, optionally substituted lower alkylene, optionally substituted lower alkylene, — CO (CR ³ R ⁴ ) n—, —NR ⁶ CO (CR ³ R ⁴ ) n, — (where n is 1 or 2), 1 NR ⁶ COCO—, 1 NR ⁶ (CR ³ R ⁴ ) nCO—, 1 S (CR ³ R ⁴ ) n— , One SO (CR ³ R ⁴ ) n— or one A ³ — (CR ³ R ⁴ ) n—

— When X— (CO) m— is —S (CR ³ R ⁴ ) n—, —Y—A ² is not substituted with unsubstituted benzyl.

Y is

i) When m = 0, single bond, —CR ¹² R ¹³ —, — O—, — S—, — C (= N—OR ¹⁷ ) —, — C ( = 0) 1, -CH (OR ¹⁷ ) or NR ¹⁵ and together with R ² = CR ¹⁴

ii) when m = l, single bond, lower alkylene, lower alkylene, lower alkylene, O, 1 S-, 1 NR ¹⁵ , 1 CR ¹² R ¹³ 0—, 1 CR ¹² R ¹³ S or 1 CR ¹² R ¹³ NR ¹⁵ — and together with R ² = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p may be formed p is an integer from 0 to 5,

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,

R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ each independently have hydrogen or a substituent, and may be lower alkyl, and each of R ³ and R ⁴ may be plural. If there are pieces, they may be different.)

Or a pharmaceutically acceptable salt thereof or a solvate thereof.

[2] pyridyl A ¹ is substituted with at least hydroxy, quinolyl substituted with at least hydroxy, downy substituted with at least hydroxy Nzuokisazoriru, at least hydroxy substitution has been benzimidazolyl, at least protected, even if goodヽPyridyl substituted with amino, imidazolyl which may be substituted with ring atoms other than —NH, ring atoms other than NH may be substituted, or ring atoms other than pyrrolyl and NH may be substituted. But ring atoms other than virazolyl and NH are substituted! 2. The compound according to claim 1, wherein a ring member atom other than /, benzpyrazolyl, NH— may be substituted, or a ring member atom other than NH may be substituted or indolyl. The pharmaceutically acceptable salt or solvate thereof.

[3] A ¹ is

[Chemical 3]

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[4] — X— is CO (CHR ³ ) n CONH (CHR ³ ) n NHCO (CHR ³ ) n—or — 0 (CHR ³ ) n—, —SO (CHR ³ ) n—, —SO ( CHR ³ ) n−, — CH = NO (CHR ³

2

) n— C (= 0) 0 (CHR ³ ) n A ³ — CHR ³ or A ³ — CH—

twenty four

The compound according to claim 1 or a pharmaceutically acceptable salt thereof or a solvate thereof.

[5] The compound according to claim 4, wherein n is 2 or 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[6] The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 0.

[7] The compound according to any one of claims 1 to 4, wherein R ¹ is hydrogen, R ² is hydrogen or hydroxy, and R ¹ and R ² are combined to form a single bond. Pharmaceutically acceptable salts or solvates thereof.

[8] Y is a single bond or —CH— or, together with R ² , forms = CH—

2

5. The compound according to any one of 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvent thereof.

[9] The method according to any one of claims 1 to 4, wherein A ² is a halogen, a lower alkyl group containing a halogen, a lower alkyl group having a halogeno group, a lower alkoxy group and a halogeno-lower alkoxy group, which may be substituted with one or more selected groups. A compound according to any one of the above or a pharmaceutically acceptable salt or solvate thereof.

[10] The compound according to any one of claims 1 to 4 and 9, or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein A ² is a para-substituted file.

[11] A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

12. The pharmaceutical composition according to claim 11, which has an NMDA receptor antagonistic action.

[13] The pharmaceutical composition according to claim 12, having an NR1ZNR2B receptor antagonistic action.

[14] A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, which is an analgesic, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[15] Prevention of a disease caused by an NMDA receptor, comprising administering the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or Method of treatment.

[16] Use of the compound according to any one of claims 1 to: or a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic agent for a disease caused by an NMDA receptor.