WO2007063839A1

WO2007063839A1 - Cyclohexane derivative

Info

Publication number: WO2007063839A1
Application number: PCT/JP2006/323693
Authority: WO
Inventors: Moriyasu Masui; Hidenori Mikamiyama; Naoki Tsuno; Akira Matsumura; Hiroyuki Kai; Kousuke Anan
Original assignee: Shionogi & Co., Ltd.
Priority date: 2005-11-30
Filing date: 2006-11-28
Publication date: 2007-06-07
Also published as: JPWO2007063839A1; TW200730172A

Abstract

Disclosed is a cyclohexane derivative represented by the formula (I), which can bind specifically to an NR1/NR2B receptor and therefore can be used as an analgesic agent (a therapeutic agent for pain): (I) wherein A1 represents a (substituted) aromatic cyclic group having -NH- in the ring or the like; A2 represents a (substituted) phenyl or the like; R1, R2a, R2b and R2c independently represent a hydrogen, a hydroxy or the like; m represents 0 or 1; X represents -CONH(CR3R4)n-, -NHCO(CR3R4)n-, -A3-(CR3R4)n- or the like; R3 and R4 independently represent a hydrogen or a (substituted) lower alkyl; n is an integer of 0 to 4; A3 represents a phenylene or the like; and Y represents a single bond, a lower alkylene or the like.

Description

Cyclohexane derivative

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 cyclohexane derivative that has few side effects on symptoms (eg, schizophrenia) and is useful as a medicine for analgesics.

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 subfamily (NR2A, 2B, 2C, 2D) 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 cyclohexane derivative of the present invention are described in Patent Documents 1 to 7; however, the compounds according to the present invention are also described.

Patent Document 1: International Publication No. 2005Z080317 Pamphlet Patent Document 2: US Patent Application Publication 2002Z0032207 Specification

Patent Document 3: US Patent Application Publication US2002Z055519 Specification

Patent Document 4: International Publication No. 01Z32634 Pamphlet

Patent Document 5: International Publication No. 2005Z19221 Pamphlet

Patent Document 6: International Publication No. 01Z94321 Pamphlet

Patent Document 7: International Publication 2004Z054579 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 the following.

(1) Formula (I):

(Where

A ¹ may have a substituent, or may be a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group which may have a substituent,

The nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic condensed cyclic group has the following conditions:

0 optionally protected hydroxy, optionally protected amino and optionally substituted aminoxica also have at least one group selected

Or

ii) Containing NH in the ring

Satisfying at least one of A ² may have a substituent, may be an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group which may have a substituent,

R \ R ^2a , R ^2b and R ^2e are each independently hydrogen, hydroxy or lower alkyl, and R ¹ and R ^2a or R ^2b and R ^2e may be joined together to form a single bond R ^2a and R ^2b may be joined together to form one O or OCH 2-

2

m is 0 or 1,

X may have a substituent, may be lower alkylene, or may have a substituent, lower alkylene, CO (CR ³ R ⁴ ) n CONR ⁵ (CR ³ R ⁴ ) n CONR ⁵ (CR ³ R ⁴ ) q— NR ⁶ —, — 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 ) rSO (CR ³ R ⁴ ) n—, — (CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) n—, — CR ⁹ = N— 0 (CR ³ R ⁴ ) n—

2

, — C (= 0) 0 (CR ³ R ⁴ ) n—, — A ³ — (CR ³ R ⁴ ) n—, — A ³ — (CR ³ R ⁴ ) qNR ⁶ —, —A

³ -NR ⁶ (CR ³ R ⁴ ) n-or — A ³ — CR ¹⁰ = CR ¹¹ (CR ³ R ⁴ ) n—

n and r are each independently an integer of 0 to 4, q is an integer of 1 to 4,

A ³ may have a substituent, may be an aromatic hydrocarbon cyclic group, or may have a substituent! /, Or may have an aromatic heterocyclic group or a substituent. Is a good non-aromatic heterocyclic group,

Y is a single bond, lower alkylene, lower alkylene, lower alkylene, -O-, -S- NR ¹⁵ CR ¹² R ¹³ 0 CR ¹² R ¹³ S or one CR ¹² R ¹³ NR ¹⁵ , where When —X— (CO) m— is — CONR ⁵ CR ³ R ⁴ — Y is a single bond,

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ⁿ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently hydrogen or substituent Or a lower alkyl, and when there are a plurality of each of R ³ and R ⁴ , they are different from each other! /.

Also,

Y and R ^2a may form together = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p— (p is an integer from 0 to 5), when m is 0 and n is 1 or more, R ^2b may combine with the carbon atom to which R ^2b is bonded to R ³ on the adjacent CR ³ R ⁴ to form a single bond.)

Or a pharmaceutically acceptable salt thereof or a solvate thereof.

(1,) Formula (I): [Chemical 2]

(Where

A ¹ is protected, may be hydroxy, protected !, may be amino or substituted V, may have at least one aminooxy, and is further substituted with another group; Anyway! /, A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group, or

In the ring — containing NH and other ring atoms may be protected, protected, protected, amino and substituted, may be substituted other than aminooxy , May be !, a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,

A ² may have a substituent, may be an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group which may have a substituent,

R ^2a , R ^2b and R ^2e are each independently hydrogen, hydroxy or lower alkyl, and R ¹ and R ^2a or R ^2b and R ^2e may be joined together to form a single bond R ^2a And R ^2b together may form a single O or OCH-

2

m is 0 or 1,

2

n and r are each independently an integer of 0 to 4, q is an integer of 1 to 4,

A ³ may have a substituent, may be an aromatic hydrocarbon cyclic group, has a substituent! /, Or may! An aromatic heterocyclic group or a non-aromatic heterocyclic group which may have a substituent,

Y is a single bond, lower alkylene, lower alkylene, lower alkylene, —O—, — S— ゝ one NR ¹⁵ —, one CR ¹² R ¹³ 0—, one CR ¹² R ¹³ S— or one CR ¹² R ¹³ NR ¹⁵ — where —X— (CO) m— is — CONR ⁵ CR ³ R ⁴ — Y is a single bond,

Also,

Y and R ^2a may form together = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p— (p is an integer from 0 to 5) when m is 0 and n is 1 or more, R ^2b may combine with the carbon atom to which R ^2b is bonded to R ³ on the adjacent CR ³ R ⁴ to form a single bond.)

Or a pharmaceutically acceptable salt thereof or a solvate thereof.

(1,) Formula (I):

[Chemical 3]

(Where

-NH- in the ring and other ring atoms may be protected hydroxy, protected, may, amino and substituted! /, May !, other than aminooxy Substituted with any of the above substituents !, may !, a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,

A ² may have a substituent, may be an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group which may have a substituent, R \ R ^2a , R ^2b and R ^2e are each independently hydrogen, hydroxy or lower alkyl, and R ¹ and R ^2a or R ^2b and R ^2e may be joined together to form a single bond m is 0 or 1,

2

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

n and r are each independently an integer of 0 to 4, q is an integer of 1 to 4,

A ³ is

[Chemical 4]

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

And

Y is a single bond, lower alkylene, lower alkylene, lower alkylene, —O—, —S—NR ¹⁵ — CR ¹² R ¹³ 0 CR ¹² R ¹³ S— or one CR ¹² R ¹³ NR ¹⁵ —. However, when X— (CO) m— is —CONR ⁵ CR ³ R ⁴ —, Y is a single bond,

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. Or lower alkyl, and each of R ³ and R ⁴ is If there are several, they are different!

Also,

Y and R ^2a may form together = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p- (p is an integer from 0 to 5), when m is 0 and n is 1 or more, R ^2b may combine with the carbon atom to which R ^2b is bonded to R ³ on the adjacent CR ³ R ⁴ to form a single bond.)

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 Substituted pyridyl, imidazolyl optionally substituted with a ring atom other than —NH, substituted with a ring atom other than —NH, substituted with a ring atom other than pyrrolyl and NH In addition, ring atoms other than virazolyl and NH— may be substituted !, and benzopyrazolyl and benzimidazolyl or ring atoms other than NH— in which the ring atom may be substituted may be substituted. The compound according to the above (1) or a pharmaceutically acceptable salt thereof, which is an indolyl in which a ring member atom other than NH may be substituted. Their solvates.

(3) A ¹ ^

Or a pharmaceutically acceptable salt or solvate thereof according to (1) above.

(4) — X— is one CO (CHR ³ ) n—, one CONH (CHR ³ ) n—, one 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 —, A ³ — CHA ³ — (CR ³ R ⁴ )

twenty four

qNR ⁶ —, — A ³ — NR ⁶ (CR ³ R ⁴ ) n—, the compound according to the above (1), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(5) The compound according to (4) above, wherein n is 2 or 3, or a pharmaceutically acceptable salt or 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) The force according to any one of the above (1) to (4), wherein R ¹ is hydrogen and R ^2a is hydrogen or hydroxy, and R ¹ and R ^2a are combined to form a single bond. Compound or a pharmaceutically acceptable salt thereof or a solvate thereof.

(8) R ^2b and R ^2e are both hydrogen forces, R ^2b and R ^2e join together to form a single bond, or m is 0, n is 1 or more, and R ^2b is A compound of any one of (1) to (6) above, which forms a single bond with R ³ on adjacent CR ³ R ⁴ together with the carbon atom to which R ^2b is bonded, The pharmaceutically acceptable salt or solvate thereof.

(9) Force where Y is a single bond or one CH—, together with R ^2a to form = CH—,

2

The compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof or a solvate thereof.

(10) The above (1) to (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. The compound according to 9) or a pharmaceutically acceptable salt thereof or a solvate thereof.

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

(12) is a nitrogen-containing aromatic monocyclic group which may have a substituent, and the group may be protected! /, Hydroxy or protected! Hey! /, The compound according to any one of (1), (4) or (6) to (11), or a pharmaceutically acceptable salt thereof, which has at least one amino and n is 2 or more, or Solvates. (13) is a nitrogen-containing aromatic condensed cyclic group which may have a substituent, and the group may be protected, hydroxy, or protected, and may contain at least one amino Or a compound or a pharmaceutically acceptable salt thereof according to any one of (1) or (6) to (11) above, wherein X is —NR ⁵ CO (CR ³ R ⁴ ) n— Their solvates.

(14) A pharmaceutical composition comprising the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt thereof or a solvate thereof.

(15) The pharmaceutical composition according to the above (14), which has an NMDA receptor antagonistic action.

(16) The pharmaceutical composition according to the above (15), which has an NR1ZNR2B receptor antagonistic action.

(17) Analgesic or migraine, stroke, head injury, Alzheimer's disease, Parkinson's disease

The pharmaceutical composition according to (14) above, which is a therapeutic agent for tinnitus, epilepsy, Huntington's disease, movement disorder or alcoholism.

(18) A method for alleviating pain or migraine, stroke, head trauma, Alzheimer's disease, Parkinson's disease, tinnitus, epilepsy characterized by administering the compound according to any one of (1) to (13) above , Treatment for Huntington's disease, movement disorders or alcoholism.

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

Use of the compound according to any one of (1) to (13) above for the manufacture of a therapeutic agent for tinnitus, epilepsy, Huntington's disease, movement disorder or alcoholism.

The invention's effect

[0005] The compound of the present invention is also useful as an analgesic (eg, cancer pain analgesic) having few side effects with force and used for the treatment of neurodegeneration such as stroke and brain trauma.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, “protected and optionally 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 alkyl Kirthio lower alkyl (such as methylthiomethyl), tetrahydrobiral (tetrahydropyran)

—2-yl, 4-methoxytetrahydropyran-4-yl, etc.), tetrahydrothiopyranyl (tetrahydrothiopyran-2-yl, etc.), tetrahydrofuran (tetrahydrofuran-2-yl, etc.), Tetrahydrothiofurol (tetrahydrothiofuran 1-2yl, etc.), aryl lower alkyl lower alkyl (benzyloxymethyl, etc.), lower alkyl sulfole, aryl sulfone, lower alkyl aryl sulfole ( p protected with a protecting group selected from toluenesulfol, etc.) and acyl !, but may include hydroxy. Preferred protecting groups are lower alkyl, aryl lower alkyl, lower alkylsulfonyl and the like.

[0007] “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.

Examples of the substituent of “substituted and optionally aminooxy” include lower alkyl and acyl.

[0008] 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 6]

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 7]

Etc. The bond is in the wrong ring!

[ooio] satisfies the condition “0 protected !, may, hydroxy, protected !, may, amino, and optionally substituted aminoxica are also selected” “A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group which may have a substituent, a nitrogen-containing aromatic monocyclic group” or “an optionally protected hydroxy group” May be protected

V, amino or substituted, may have at least one aminooxy group, and may be further substituted with another group. A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group. `` Means that the above `` nitrogen-containing aromatic monocyclic group '' or `` nitrogen-containing aromatic condensed cyclic group '' is protected on the ring !, may! /, Hydroxy, protected! Moly! /, Amino and substituted !, optionally an aminoxica, also has at least one group selected and is further selected from the substituent group a. It may be substituted with one or more groups which include cyclic groups.

Here, the substituent group a is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, lower alkylamino-containing carboxy, lower alkoxycarbole, sia-containing nitro.

“Nitrogen-containing aromatic monocyclic group, which may be protected, hydroxy or protected, may have at least one amino and may be further substituted with other groups” and “Protected, may! /, Hydroxy or protected !, may! /, Have at least one amino and may be further substituted with other groups, nitrogen-containing aroma “Aromatic condensed cyclic group” means that the above “nitrogen-containing aromatic monocyclic group” or “nitrogen-containing aromatic condensed cyclic group” is protected on the ring! It has at least one hydroxy or optionally protected amino group, and is further substituted with one or more groups selected from the above substituent group a force, including a cyclic group To do.

[0011] "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.

[0012] It may have a nitrogen-containing aromatic monocyclic group or a substituent which may have a substituent satisfying the condition of "ii) containing -NH- in the ring".窒素 "Nitrogen-containing aromatic condensed cyclic group", "in the ring-containing NH, and other ring atoms may be protected hydroxy, protected, amino and substituted. The nitrogen-containing aromatic monocyclic group or the nitrogen-containing aromatic condensed cyclic group ”may be substituted with a substituent other than aminooxy! Monocyclic group "and" nitrogen-containing aromatic fused cyclic group " That is, it includes a group containing an NH group in the ring. For example

[Chemical 8]

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.

“A ring atom other than 1ΝΗ may be substituted, imidazolyl”, “A ring atom other than 1ΝΗ may be substituted, pyrrolyl”, “A ring atom other than 1ΝΗ may be placed. May be substituted with virazolyl "," other than one ring atom is substituted !, may be benzopyrazolyl "," other than one ring atom may be substituted. "N-midazolyl" and "-ring atoms other than -ΝΗ are substituted !, but indolyl" means that each ring atom other than -ΝΗ- is selected from the substituent group β. Includes imidazolyl, pyrrolyl, pyrazolyl, benzpyrazolyl, benzimidazolyl and indolyl optionally substituted with 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 alkyl. Lucoxy, lower alkyl sulfo-loxy, halogeno lower alkyl sulfo-loxy, isyl, acyloxy, ami-substituted lower alkyl ami-sil acylamino, nitro, sial-input ruboxy, lower alkoxy carbo-yl, force rubermoyl, lower alkyl force rubermoyl, substituent group Ύ It may be substituted with one or more selected groups ヽ Aromatic hydrocarbon cyclic group, substituent group γ force is also selected Arylthio, optionally substituted with one or more groups A group selected from the group of γ groups, such as aryloxy, which may be substituted with one or more groups, and a group of γ forces, which are also selected. A group of aryl substituents which may be substituted with one or more groups γ And arylsulfonyloxy which may be substituted with one or more selected groups.

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” The aryl moiety of “lower alkoxy lower alkyl”, “lower alkyl aryl sulfo”, and “aryl lower alkoxy carbo” is the same as the above “aromatic hydrocarbon cyclic group”. Preferred is phenyl. An “aromatic heterocyclic group” is a 5- to 6-membered aromatic monocyclic group containing 1 to 4 heteroatoms (eg, pyrrolyl, imidazolyl, pyrazolyl) that also has a group power consisting of Ν, Ο, and S. , Pyridyl, pyridazil, pyrimidyl, pyrajyl, triazolyl, triazyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and chael) and aromatic condensed cyclic groups ( For example, indolyl, isoindolyl, indolizol, benzimidazolyl, benzpyrazolyl, indazolyl, cinnolinyl, phthalajuryl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Benzofuryl, Isobenzov Ril, benzocenyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, birazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl Quinoxalinyl, purinyl, pteridinyl, naphthyridyl and virazinopyridazil).

“Non-aromatic heterocyclic group” means a 5- to 6-membered aromatic monocyclic group containing 1 to 4 heteroatoms (for example, thials, N, O and S). Oxylanyl, azetidiyl, pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolyl, pyrazolidyl, pyrazolinyl, tetrahydrofuryl, dihydrofuryl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, oxadi Azolinyl, oxathiolanyl, dioxolanyl, dioxolyl, tetrahydrochenyl, dihydrochenyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, tetrahydrobilanyl, thianyl, piperidinyl, dioxaninole, piperazinyl, monomorpholinol, morpholinol, morpholinol Thiomorpholine Encompasses dihydropyridyl, etc.).

In particular, the “aromatic heterocyclic group” and “non-aromatic heterocyclic group” in A ³ include the divalent groups of the above “aromatic heterocyclic group” and “non-aromatic heterocyclic group”. To do. Bonding hands are acceptable

.One

Specifically, the following groups may be mentioned, which may be present at any position capable of functioning.

Ha s

[Chemical 9]

.〇 ■ S

_ _ Ν.

N "

“Having a substituent, may be an aromatic heterocyclic group”, “having a substituent, may be a 5- to 6-membered aromatic monocyclic group” and “having a substituent. The substituents for “! /, May !, non-aromatic heterocyclic groups” are the same as the substituents for the above-mentioned “having substituents, may be aromatic hydrocarbon cyclic groups”. It is. “Halogen” includes F, Cl, Br and the like.

“Halogeno Lower Alkyl”, “Halogeno Lower Alkoxy”, “Halogeno Lower Alkoxy Power Lol”, “Halogenoacyl”, “Halogeno Lower Alkyl Sulfo”, “Halogeno Lower Alkyl Sulfo-Luoxy” Lower Alkyl and Halogen Part Is the same as the above “halogen”.

“Lower alkyl” includes linear or branched alkyl having 1 to LO, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, such as methyl, ethyl, n — Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n— Examples thereof include nol and n-decyl. 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, amino-containing lower alkylamino-containing amino carboxy, lower alkoxycarbol, cyanated nitro and the like. Preferred examples of 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”.

[0016] 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 an arbitrary position. Branched arche -Including le. Specifically, bur, aryl, probe, isoprobe, butur, isobutenyl, prennore, butagenyl, pentenyl, isopentenyl, pentageninore, hexeninore, isohexenore, hexageninore, hepteninole, otatenore, none Including dill and desalin.

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

The “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.

[0018] "Acyl" 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 “acyloxy”, “acylamino”, and “halogenoacyl” acyl moieties are It is the same.

rR ¹ and R ^2a or R ^2b and R together form a single bond.

It means that.

When "R ^2a and R ^2b are joined together to form O or OCH-"

2

[Chemical 11]

It means that.

Y and R ^2a is - as the case of "together such connexion = CR ¹⁴ the formation"

[Chemical 12]

(Wherein each symbol is as defined above)

It means that. In addition, the case where Y and R ^2a "form together = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p- (p is an integer from 0 to 5)"

[Chemical 13]

(Wherein each symbol is as defined above)

It means that. “When m is 0 and n is 1 or more, R ^2b forms a single bond with R ³ on the adjacent CR 4 with the carbon atom to which is bonded.”

[Chemical 14]

(Wherein, x ^a is an optionally substituted lower alkylene, an optionally substituted lower alkylene, —CO CONR ′ NR “CO NR” CONR.

C (= N— OR ⁷ ) — One (CRV) rO (CRV) rS (CR ° R ⁹ ) rSO

R ⁸ R ⁹ ) rSO CR ⁹ = N— OC (= 0) 0 AA ³ — NR ⁶ or

2

-A ³ -CR ¹⁰ = CR-and other symbols are 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 tautomers as follows.

[Chemical 15]

The general synthesis method of the compound of the present invention is shown below, but is not limited to this synthesis method.

[0021] Method A: Synthesis of (I a) from (Π)

In the presence of a base, a ketone represented by general formula (Π) and an organic phosphorus compound represented by general formula (ΠΙ) or (IV) are condensed to synthesize a compound represented by general formula (I—a). be able to.

[Chemical 16] A ¹ — X ¹ -CH ₂ P ⁺ P ₃ -Z-

(Wherein X ¹ is optionally substituted lower alkylene, optionally substituted V, lower alkylene, one (CR ⁸ R ⁹ ) rO (CR ³ R ⁴ ) s, one (CR ⁸ R ⁹ ) rS (CR ³ R ⁴ ) s, one (CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) s, one (CR ⁹ ) rSO (CR ³ R ⁴ ) s, one CR ⁹ = N— 0 (CR ³ R ⁴

2

) s, 1 A ³ — (CR ³ R ⁴ ) s, 1 A ³ — NR ⁶ (CR ³ R ⁴ ) s, or 1 A ³ scale ¹ . : ! ^ ¹ . R ³ R ⁴ ) s, R ¹⁷ is C alkyl, s is an integer of 0 to 3, Z is a chlorine atom or bromine source

1-4

A wavy line indicates a cis or trans form, and other symbols are as defined above)

The ketone represented by the general formula (Π) can be synthesized by the method described in Reference Examples 1 to 4 described later and a method analogous thereto. In addition, the carboxylic acid compound represented by the general formula (III) can be synthesized by the method described in New Experimental Chemistry Course 14, Maruzen Co., Ltd. (1977) and a method analogous thereto.

The organic phosphorus compound represented by the general formula (III) or (IV) can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (II).

Examples of the reaction solvent include tetrahydrofuran, jetyl ether, acetonitrile, N, N dimethylformamide, dimethyl sulfoxide, liquid ammonia and the like.

Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium Examples include oxamethyl disilazide, potassium hexamethyl disilazide, sodium amide and the like. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (Π).

An example of a reaction temperature is 70 to 100 ° C.

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

The resulting compound represented by the general formula (Ia) can be obtained by known means (for example, chromatography 1 and recrystallization).

[0022] Method B: Synthesis of (I b) from (I a)

By reducing the compound represented by the general formula (Ia) with hydrogen in the presence of a metal catalyst, the compound represented by the general formula (Ib) can be synthesized.

[Chemical 17]

(l-a) (l-b)

(In the formula, each symbol is as defined above.)

Examples of the reaction solvent include methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.

Examples of the metal catalyst include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, and chlorotris (triphenylphosphine) rhodium (I). In the compound represented by the general formula (Ia), On the other hand, 0.01 to 0.5 weight percent can be used.

The hydrogen pressure is 1 to 50 atm.

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 represented by the general formula (Ib) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

[0023] Method C: Synthesis of (I c) from (Π)

A compound represented by the general formula (Ic) can be synthesized by reacting a ketone represented by the general formula (II) with an organometallic compound represented by the general formula (V).

[Chemical 18]

(Wherein x ² is optionally substituted lower alkylene, optionally substituted V, lower alkylene, one (CR ⁸ R ⁹ ) rO (CR ³ R ⁴ ) n―,-(CR ⁸ R ⁹ ) rS (CR ³ R ⁴ ) n―,-(CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) n―, — (CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) n−, — CR ⁹ = N— 0 (CR ³

2

R ⁴ ) n A ³ — (CR ³ R ⁴ ) n A ³ — NR ⁶ (CR ³ R ⁴ ) n—or one A ³ — CR ¹⁰ = CR]

!! —

L ¹ is lithium, MgCl, MgBr or Mgl

Other symbols are as defined above)

The compound represented by the general formula (V) can be used in an amount of 1 to 3 mole equivalent to the ketone represented by the general formula (式).

Examples of the reaction solvent include jetyl ether and tetrahydrofuran.

The reaction temperature is -70 to 50 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (Ic) can be isolated and purified by the known means (eg, chromatography, recrystallization, etc.).

Method D: Synthesis of (I-d) from compound (VI)

[Chemical 19]

(Wherein X ³ is NR ⁵ , CONR ^5- (CR ³ R ⁴ ) qNR. One, R ¹⁸ is C alkyl,

1-4

Other symbols are as defined above)

The compounds represented by the general formulas (VI) and (VII) can be synthesized by the methods described in Reference Examples 5 to 6 described later and a method analogous thereto.

Synthesis of (VII) from (VI)

By hydrolyzing the compound represented by the general formula (VI), the carboxylic acid represented by the general formula (VII) can be synthesized.

Lithium hydroxide, sodium hydroxide or water for the compound represented by the general formula (VI) 1 to 5 molar equivalents of potassium oxide can be used.

Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.

Examples of the reaction temperature include 0 ° C to the reflux temperature of the solvent.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (VII) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (Id) from (VII)

In the presence of a condensing agent, a carboxylic acid represented by general formula (VII) and an amine compound represented by general formula (VIII) can be condensed to synthesize an amidy compound represented by general formula (Id). it can. The compound represented by the general formula (VIII) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (VII).

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

Examples of condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol, salt oxalyl and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (VII). 1-Hydroxybenzotriazole may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.

Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. 0.05 to 2 molar equivalents can be used for each compound represented by the general formula (VII).

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 represented by the general formula (Id) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method E: Synthesis of Compound (VII) Force (I e)

[Chemical 20]

(Wherein each symbol is as defined above)

Synthesis of (IX) from (VII)

In the presence of a reducing agent, the compound represented by the general formula (VII) can be reduced to synthesize the alcohol represented by the general formula (IX).

Examples of the reaction solvent include jetyl ether, tetrahydrofuran, toluene, ethanol and the like, and these can be used alone or in combination.

Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like, and 0.5 to 6 moles relative to the compound represented by the general formula (VI). An equivalent amount can be used.

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

The resulting compound represented by the general formula (IX) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (I e) from (IX)

In the presence of a condensing agent, an alcohol represented by general formula (IX) and a carboxylic acid represented by general formula (X) may be condensed to synthesize an ester compound represented by general formula (I-e). it can. The compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (IX).

Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethyl carpositimide hydrochloride, and the like. For the compound represented by the general formula (IX), 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. Can be used as a mixture. Each of them can be used at 0.05 to 2 mole equivalents relative to the compound represented by the general formula (IX).

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 represented by the general formula (I e) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Method F: Synthesis of (If) from Compound (IX)

[Chemical 21]

(Wherein each symbol is as defined above)

Synthesis of (IX) force (XI)

In the presence of a azo compound and a trivalent phosphorus compound, an alcohol represented by general formula (IX) and phthalimide can be condensed to synthesize a compound represented by general formula (XI).

Phthalimide can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (IX).

Examples of the reaction solvent include tetrahydrofuran, jetyl ether, and acetonitrile.

Examples of the azo compound include jetyl azodicarboxylate, diisopropyl azodicarboxylate and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (IX).

Examples of trivalent phosphorus compounds include triphenylphosphine and tributylphosphine. In addition, it can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (IX).

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

The resulting compound represented by the general formula (XI) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).

Synthesis of (ΧΠ) from (XI)

By treating the compound represented by the general formula (XI) with hydrazine hydrate, an amine compound represented by the general formula (XII) can be synthesized.

Hydrazine hydrate can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (XI).

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 resulting compound represented by the general formula (XII) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Synthesis of (I— f) from (XII)

In the presence of a condensing agent, an amin compound represented by the general formula (If) is synthesized by condensing the amine compound represented by the general formula (XII) and the carboxylic acid represented by the general formula (X). Can do.

The compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XII).

Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, thionyl chloride, chlorooxalyl, and the like. The base can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (ΧΠ). 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole may be used as a condensation aid. Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XII).

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 represented by the general formula (I f) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method G: Synthesis of (I-g) from y compound (XII)

A compound represented by the general formula (I-g) can be synthesized by reacting an amine represented by the general formula (XII) with an isocyanate represented by the general formula (ΧΙΠ) or a carbamate represented by (XI V). I'll do it.

[Chemical 22]

1— NCO (XIII)

(In the formula, R ¹⁹ is full, 4-tropol, and other symbols are as defined above)

The compound represented by the general formula (ΧΙΠ) or (XIV) can be used at 0.5 to 3 mole equivalents relative to the compound represented by the general formula (XII).

Examples of the reaction solvent include methylene chloride, 1,2-dichloroethane, toluene, acetonitrile, and tetrahydrofuran.

If necessary, an amine such as triethylamine or diisopropylethylamine can be used at 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XX).

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 represented by the general formula (Ig) can be obtained by known means (for example, chromatography 1 and recrystallization).

Method H: Synthesis of compound (VII) force (I—h)

[Chemical 23]

(In the formula, other symbols are as defined above.)

Synthesis of (XV) from (VII)

An amide compound represented by the general formula (XV) can be synthesized by condensing a carboxylic acid represented by the general formula (VII) and N, O dimethylhydroxylamine hydrochloride in the presence of a condensing agent.

N, O dimethylhydroxylamine hydrochloride can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (VII).

Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like, and these can be used alone or in combination.

Examples of condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol and salt oxalyl, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (VII). 1-Hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.

Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 3 molar equivalents relative to the compound represented by the general formula (VII).

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 represented by the general formula (XV) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.). Synthesis of (I h) from (XV)

The compound represented by the general formula (Ih) can be synthesized by reacting the amide compound represented by the general formula (XV) with the organometallic compound represented by the general formula (V).

Examples of the reaction solvent include jetyl ether and tetrahydrofuran.

The reaction temperature is -70 to 50 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (I h) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Method I: Synthesis of (I i) from Compound (Π)

[Chemical 24]

(Wherein X ⁴ is (CR ³ R ⁴ ) s; other symbols are as defined above)

Synthesis of (XVIII) from (Π)

A compound represented by the general formula (XVIII) can be synthesized by condensing a ketone represented by the general formula (示) and an organophosphorus compound represented by the general formula (XVI) or (XVII) in the presence of a base. .

The organic phosphorus compound represented by the general formula (XVI) or (XVII) can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (II).

Reaction solvents include tetrahydrofuran, jetyl ether, acetonitrile, N, N di- Examples include methylformamide, dimethyl sulfoxide, and liquid ammonia.

Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride

, Potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide and the like. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (Π).

An example of a reaction temperature is 70 to 100 ° C.

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

The resulting compound represented by the general formula (XVIII) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (XIX) from (XVIII)

A carboxylic acid represented by the general formula (XIX) can be synthesized by hydrolyzing the compound represented by the general formula (XVIII).

Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used at 1.0 to 5 molar equivalents with respect to the compound represented by the general formula (XVIII).

Examples of the reaction temperature include o ° c to the reflux temperature of the solvent.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (XIX) can be isolated and purified by the known means (eg, chromatography, recrystallization, etc.).

Synthesis of (I i) from (XIX)

In the presence of a condensing agent, a carboxylic acid represented by general formula (XIX) and an amine compound represented by general formula (XX) can be condensed to synthesize an amidy compound represented by general formula (I i). it can. The compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XIX).

Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like. Examples of condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples of the compound represented by the general formula (XIX) include 0.5 to 2 molar equivalents. 1-Hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents. Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XIX).

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 represented by the general formula (I i) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Method: Synthesis of compound (XVIII) force (I j)

[Chemical 25]

(XVIII) (XXI)

H

(Wherein each symbol is as defined above)

Synthesis of (XXI) from (XVIII)

A compound represented by the general formula (XXI) can be synthesized by reducing a compound represented by the general formula (XVIII) with hydrogen in the presence of a metal catalyst.

Examples of the reaction solvent include methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. Examples of the metal catalyst include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, chlorotris (trifluorophosphine) rhodium (I), and the like, and 0 for the compound represented by the general formula (XVIII) 01 to 0.5 weight percent can be used.

Examples of the hydrogen pressure include 1 to 50 atmospheres.

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

The resulting compound represented by the general formula (XXI) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Synthesis of (XXII) from (XXI)

By hydrolyzing the compound represented by the general formula (XXI), the carboxylic acid represented by the general formula (ΧΧΠ) can be synthesized.

Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used at 1.0 to 5 molar equivalents with respect to the compound represented by the general formula (XXI).

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (ΧΧΠ) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Synthesis of (I j) from (XXII)

In the presence of a condensing agent, the amide acid compound represented by the general formula (I j) can be synthesized by condensing the carboxylic acid represented by the general formula (XXII) and the amine compound represented by the general formula (XX). it can. The compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXII).

Condensation agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, black carbonic acid Ethyl, isoptil carbonate, salt and salt, oxalyl and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXII). 1-Hydroxybenzotriazole or the like may be used at 0.5 to 2 molar equivalents as a condensation aid. Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. 0.05 to 2 molar equivalents can be used for each compound represented by the general formula (一般).

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 represented by the general formula (Ij) can be isolated and purified by the known means (eg, chromatography, recrystallization, etc.).

Method K: Compound (XVIII-a), (XXI-a), (XIX-a) or (XXII-a) to (I-k)

[Chemical 26]

(In the formula, X ⁵ is (CR ⁴ ) t, t is an integer of 0 to 2, the dotted line indicates the presence or absence of a bond, and other symbols are as defined above)

Synthesis of (X) from (XVIII-a), (XXI-a), (XIX-a) or (XXII-a) or (XXII-a) In the presence of a reducing agent, general formula (XVIII-a), (XXI-a), (XIX — A) or (XXII— a) The alcohol represented by the general formula (ΧΧΠΙ) can be synthesized by reducing the compound obtained.

Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, etc., and are represented by the general formulas (XVIII—a), (X XI—a), (ΧΙΧ— a) or 0.5 to 6 molar equivalents of the compound represented by (XXII—a) can be used.

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

The resulting compound represented by the general formula (ΧΧΙΠ) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (I k) from (ΧΧΙΠ)

In the presence of a condensing agent, an alcohol represented by the general formula (I) and a carboxylic acid represented by the general formula (X) can be condensed to synthesize an ester compound represented by the general formula (I—k). The compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXIII).

Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethyl carpositimide hydrochloride, and the like. For the compound represented by the general formula (ΧΧΙΠ), 0.5 to Two molar equivalents can be used. 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole or the like 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 represented by the general formula (用いる) can be used at 0.05 to 2 mole equivalents.

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 represented by the general formula (I k) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Method L: Synthesis of (1-1) from y compound (XXIII)

[Chemical 27]

(XXV) (i-i)

(Wherein each symbol is as defined above)

Synthesis of (XXIV) from (XXIII)

A compound represented by the general formula (XXIV) can be synthesized by condensing an alcohol represented by the general formula (ΧΧΙΠ) and aphthalimide in the presence of a azo compound and a trivalent phosphorus compound. One to three molar equivalents of phthalimide can be used with respect to the compound represented by the general formula (ΧΧΙΠ).

Examples of the azo compound include jetyl azodicarboxylate, diisopropyl azodicarboxylate and the like, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (ΧΧΠΙ).

Examples of the trivalent phosphorus compound include triphenylphosphine and tributylphosphine, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (式). Examples of the reaction temperature include 0 ° C to the reflux temperature of the solvent.

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

The resulting compound represented by the general formula (XXIV) is obtained by known means (for example, chromatograph And recrystallization).

Synthesis of (XXV) from (XXIV)

By treating the compound represented by the general formula (XXIV) with hydrazine hydrate, an amine compound represented by the general formula (XXV) can be synthesized.

Hydrazine hydrate can be used in an amount of 1.0 to 5 molar equivalents relative to the compound represented by the general formula (XXIV).

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

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (XXV) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (I 1) from (XXV)

In the presence of a condensing agent, an amin compound represented by the general formula (1-1) is synthesized by condensing the amine compound represented by the general formula (XXV) and the force rubonic acid represented by the general formula (X). Can do. The compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXV).

Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, thionyl chloride, chlorooxalyl, and the like. The base can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXV). 1-Hydroxybenzotriazole may be used at 0.5 to 2 molar equivalents as a condensation aid.

Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. 0.05 to 2 molar equivalents can be used for each compound represented by the general formula (XXV).

The resulting compound represented by the general formula (I 1) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Method M: Synthesis of (I m) from compound (XXV)

The amine represented by the general formula (XXV) can be reacted with the isocyanate represented by the general formula (式) or the carbamate represented by (XIV) to synthesize the compound represented by the general formula (I-m). Monkey.

[Chemical 28]

A ¹ — NCO (XII I)

(XXV) (l-m

(Wherein each symbol is as defined above)

The compound represented by the general formula (ΧΙΠ) or (XIV) can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (XXV).

If necessary, an amine such as triethylamine or diisopropylethylamine can be used in an amount of 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XXV).

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 represented by the general formula (Im) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Method N: Synthesis of (I n) from compound (XIX) or (XXII)

[Chemical 29]

(XIX) or (XXII) (XXVI)

(l-n)

(Wherein each symbol is as defined above)

Synthesis of (XXVI) from (XIX) or (XXII)

In the presence of a condensing agent, a carboxylic acid represented by general formula (XIX) or (XXII) and N, O dimethylhydroxylamine hydrochloride are condensed to form an amidy compound represented by general formula (XXVI). can do.

N, O dimethylhydroxylamine hydrochloride or the like can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (XIX) or (ΧΧΠ).

Examples of condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol and salt oxalyl, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (XIX) or (XXII). 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole or the like may be used as a condensation aid.

Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. The base can be used at 0.05 to 3 molar equivalents relative to the compound represented by the general formula (XIX) or (ΧΧΠ).

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 represented by the general formula (XXVI) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (I n) from (XXVI)

A compound represented by the general formula (In) can be synthesized by reacting an amidy compound represented by the general formula (XXVI) with an organometallic compound represented by the general formula (XXVII).

The compound represented by the general formula (XXVII) can be used at 1 to 3 molar equivalents relative to the amido compound represented by the general formula (XXVI).

Examples of the reaction solvent include jetyl ether and tetrahydrofuran.

The reaction temperature is -70 to 50 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (In) can be isolated and purified by known means (for example, chromatography, recrystallization, etc.).

Method O: Synthesis of (I o) from y compound (I n)

An oxime compound represented by the general formula (I-o) can be synthesized by reacting a ketone represented by the general formula (In) with a compound represented by the general formula (XXVIII).

[Chemical 30]

(Wherein each symbol is as defined above)

The compound represented by the general formula (XXVIII) can be used at 0.5 to 3 molar equivalents relative to the ketone represented by the general formula (In). Hydrochloride or sulfate of the compound represented by the general formula (XXVIII) may be used.

Examples of the reaction solvent include methanol, ethanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.

Bases such as triethylamine and salts such as sodium acetate and potassium acetate have the general formula (I—n) 0.5 to 5 molar equivalents may be used with respect to the ketone represented by!

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 represented by the general formula (I o) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Method P: Synthesis of (I p) from compound (XVIII—a) or (XIX—a)

[Chemical 31]

(XlX-a)

(i-P)

(Wherein each symbol is as defined above)

Synthesis of (XXIX) from (XVIII-a) or (XIX—a)

In the presence of a reducing agent, the compound represented by the general formula (XVIII-a) or (XIX-a) is reacted with a borane compound and then reacted with a peroxide to combine the diol represented by the general formula (XXIX). Can be made.

Examples of the reaction solvent include jetyl ether and tetrahydrofuran.

Examples of borane compounds include borane-tetrahydrofuran complex and borane-dimethylsulfide complex, and 2 to 20 molar equivalents are used with respect to the compound represented by the general formula (XVIII-a) or (XIX-a). be able to.

An example of a reaction temperature is 0 to 50 ° C.

An example of the reaction time is 0.5 to 72 hours. After performing the above reaction with a borane compound, the reaction is performed by adding a peroxide to the reaction system.

Examples of the reaction solvent include jetyl ether, tetrahydrofuran, water and the like, and these can be used alone or in combination.

Examples of the peroxide include 5 to 35% hydrogen peroxide solution, and 3 to 30 molar equivalents of the compound represented by the general formula (XVIII-a) or (XIX-a) can be used. it can.

A salt of sodium acetate, potassium acetate, sodium hydrogen carbonate, sodium carbonate, potassium carbonate or the like may be used in an amount of 3 to 50 molar equivalents relative to the compound represented by the general formula (XVIII-a) or (XIX-a).

An example of a reaction temperature is 0 to 50 ° C.

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

The resulting compound represented by the general formula (XXIX) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (XXX) from (XXIX)

A carboxylic acid represented by the general formula (XXX) can be synthesized by oxidizing the diol represented by the general formula (XXIX).

Examples of the reaction solvent include acetone, N, N dimethylformamide and the like.

Examples of the oxidizing agent include Diyons reagent and chromium oxide. The oxidizing agent can be used in an amount of 2 to 10 molar equivalents relative to the compound represented by the general formula (XXIX).

An example of a reaction temperature is 0 to 50 ° C.

The reaction time includes 0.5 to 5 hours.

The resulting compound represented by the general formula (XXX) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Synthesis of (I p) from (XXX)

In the presence of a condensing agent, the carboxylic acid represented by the general formula (XXX) and the amine compound represented by the general formula (XX) are condensed to synthesize an amidy compound represented by the general formula (I—P). Can do. The compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXX). Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.

Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol and salt oxalyl, and the compound can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXX). 1-Hydroxybenzotriazole or the like may be used at 0.5 to 2 molar equivalents as a condensation aid. Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. 0.05 to 2 molar equivalents can be used for each compound represented by the general formula (XXX).

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 represented by the general formula (IP) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method Q: Synthesis of (I q) from compound (XXX)

[Chemical 32]

(XXXII) (l-q)

(Wherein each symbol is as defined above)

Synthesis of (XXXI) from (XXX)

A compound represented by the general formula (XXXI) can be synthesized by reacting a compound represented by the general formula (XXX) with diphenyl phosphate azide in the presence of a base. An example of the reaction solvent is tert butanol.

Diphenol phosphate azide can be used in an amount of 1 to 2 molar equivalents relative to the compound represented by the general formula (XXX).

Examples of the base include triethylamine and diisopropylethylamine, and the base can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (XX X).

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

The reaction time is 1 to 24 hours.

The resulting compound represented by the general formula (XXXI) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Synthesis of (XXXII) from (XXXI)

A compound represented by the general formula (XXXII) can be synthesized by reacting a compound represented by the general formula (XXXI) with an acid.

Examples of the reaction solvent include methanol, ethanol, and no solvent.

Examples of the acid include hydrochloric acid hydrogen, trifluoroacetic acid and the like, and 1 to 30 molar equivalents can be used with respect to the compound represented by the general formula (XXXI).

An example of a reaction temperature is 0 to 50 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (XXXII) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Synthesis of (I q) from (ΧΧΧΠ)

In the presence of a condensing agent, an amin compound represented by the general formula (I q) can be synthesized by condensing the amine compound represented by the general formula (XXXII) and the force rubonic acid represented by the general formula (X). it can. The compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXII).

Examples of condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, chloride Examples thereof include thionyl, salt oxalyl and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (用いる). 1-hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.

Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XXXII).

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 represented by the general formula (I q) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method R: Synthesis of (I r) from compound (IX)

[Chemical 33]

(Wherein each symbol is as defined above)

Synthesis of (ΧΧΧΙΠ) from (IX)

A compound represented by the general formula (IX) can be synthesized by reacting a compound represented by the general formula (IX) with an oxidizing agent.

Examples of the reaction solvent include ethyl acetate, methylene chloride, dimethyl sulfoxide and the like.

1-Hydroxy 1 1, 2 Benzodoxol 3 (1H) —On 1— 1, 1-dihydro-1, 1,1 triacetoxy 1,2-benzobenzoxol 3 (1H) ON, etc., 1 to 5 mole equivalents relative to the compound represented by the general formula (IX) Can be used.

An example of a reaction temperature is 0 to 50 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (ΧΧΧΙΠ) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (XXXV) from (XXXIII)

A compound represented by the general formula (XXXV) can be synthesized by condensing a compound represented by the general formula (XXXIII) and an organophosphorus compound represented by the general formula (XXXIV) in the presence of a base.

The organophosphorus compound represented by the general formula (XXXIV) can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (式).

, Potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide and the like. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (式).

An example of a reaction temperature is 70 to 100 ° C.

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

The resulting compound represented by the general formula (XXXV) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Synthesis of (XXXVI) from (XXXV)

The compound represented by the general formula (XXXVI) can be synthesized by reducing the compound represented by the general formula (XXXV).

Examples of the reaction solvent include methanol, ethanol, N, N dimethylformamide and the like. Can be used alone or in combination.

Examples of the reducing agent include sodium borohydride, and 1.0 to 6 molar equivalents can be used with respect to the compound represented by the general formula (XXXV). Metal salts such as cobalt chloride, nickel chloride, and hydrates thereof may be used in an amount of 0.1 to 6 molar equivalents relative to the compound represented by the general formula (XXXV).

An example of a reaction temperature is 0 to 50 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (XXXVI) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (XXXVII) from (XXXVI)

A carboxylic acid represented by the general formula (XXXVII) can be synthesized by hydrolyzing the compound represented by the general formula (XXXVI).

Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used at 1.0 to 5 molar equivalents with respect to the compound represented by the general formula (XXXVI).

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (XXXVII) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (I r) from (XXXVII)

In the presence of a condensing agent, the amide compound represented by the general formula (Ir) can be synthesized by condensing the carboxylic acid represented by the general formula (XXXVII) and the amine compound represented by the general formula (XX). The

The compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXVII).

Examples of the reaction solvent include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like. Examples of condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol and salt oxalyl, and the compound can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXVII). 1-Hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents. Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. The base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXVII).

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 represented by the general formula (I r) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method S: Synthesis of (I s) from compound (II)

[Chemical 34]

(Wherein each symbol is as defined above)

Synthesis of (XXXVIII) from (II)

In the presence of a reducing agent, the compound represented by the general formula (II) can be reduced to synthesize the alcohol represented by the general formula (XXXVIII).

Examples of the reaction solvent include jetyl ether, tetrahydrofuran, toluene, ethanol and the like. They can be used alone or in combination.

Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and the like. For the compound represented by the general formula (Π), 0.5 to 6 molar equivalents can be used.

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

The resulting compound represented by the general formula (XXXVIII) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Synthesis of (XXXIX) from (XXXVIII)

In the presence of a azo compound and a trivalent phosphorus compound, an alcohol represented by the general formula (XXXVIII) and phthalimide can be condensed to synthesize a compound represented by the general formula (XXIV). Phthalimide can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (XXXVIII).

Examples of the azo compound include jetyl azodicarboxylate, diisopropyl azodicarboxylate and the like, and can be used in an amount of ι to 3 molar equivalents relative to the compound represented by the general formula (xxxvm).

Examples of the trivalent phosphorus compound include triphenylphosphine, tributylphosphine and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (XXXVIII). c to the reflux temperature of the solvent.

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

The resulting compound represented by the general formula (XXXIX) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (XXXX) from (XXXIX)

By treating the compound represented by the general formula (XXXIX) with hydrazine hydrate, an amine compound represented by the general formula (XXXX) can be synthesized. Hydrazine hydrate can be used in an amount of 1.0 to 5 molar equivalents relative to the compound represented by the general formula (XXXIX).

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

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (XXXX) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (I s) from (XXXX)

In the presence of a condensing agent, an amin compound represented by the general formula (I s) can be synthesized by condensing the amine compound represented by the general formula (XXXX) and the force rubonic acid represented by the general formula (X). it can. The compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXX).

Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, thionyl chloride, chlorooxalyl, and the like. The base can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXXX). 1-hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.

Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXX).

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 represented by the general formula (I s) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).

Method T: Synthesis of (I t) from compound (XXXX) The compound represented by the general formula (It) can be synthesized by reacting the amine represented by the general formula (XXXX) with the isocyanate represented by the general formula (ΧΙΠ) or the carbamate represented by (XIV). .

[Chemical 35]

(Wherein each symbol is as defined above)

The compound represented by the general formula (XIII) or (XIV) can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (XXXX).

If necessary, an amine such as triethylamine or diisopropylethylamine can be used in an amount of 0.05 to 2 mole equivalents relative to the compound represented by the general formula (XXXX).

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 represented by the general formula (It) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Method U: Synthesis of (I u) from compound (Π)

[Chemical 36]

Hydrolysis

(Wherein each symbol is as defined above)

The compound represented by the general formula (XXXXI) can be synthesized by the method described in JP-A-62-258342 and a method analogous thereto.

Synthesis of (II) from (II)

In the presence of a base, the compound represented by the general formula (II) is condensed with the organic phosphorus compound represented by the general formula (XXXXI), and then treated with an acid to synthesize the compound represented by the general formula (XXXXII). Can do.

The organic phosphorus compound represented by the general formula (XXXXI) can be used in an amount of 1 to 5 molar equivalents relative to the compound represented by the general formula (II).

Examples of the reaction solvent include tetrahydrofuran, jetyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, liquid ammonia and the like.

An example of a reaction temperature is 70 to 100 ° C.

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

Examples of the acid used in the acid treatment include p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, and sulfuric acid, and 0.1 to 10 molar equivalents can be used with respect to the compound represented by (Π). wear.

Examples of the reaction solvent include methanol, ethanol, toluene, water and the like, and these can be used alone or in combination.

An example of a reaction temperature is 20 to 100 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (ΧΧΧΧΠ) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (ΧΧΧΧΙΠ) from (XXXXII)

By hydrolyzing the compound represented by the general formula (ΧΧΧΧΠ), the carboxylic acid represented by the general formula (ΧΧΧΧΠΙ) can be synthesized.

Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used at 1.0 to 5 molar equivalents with respect to the compound represented by the general formula (xxxxn).

Examples of the reaction time include 0.5 to 24 hours.

The obtained compound represented by the general formula (ΧΧΧΧΙΠ) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (I u) from (XXXXIII)

In the presence of a condensing agent, the carboxylic acid represented by the general formula (XXXXIII) and the amine compound represented by the general formula (XX) are condensed to synthesize the amide compound represented by the general formula (Iu). Is possible.

The compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXXIII).

Condensation agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, black carbonic acid Ethyl, isoptil carbonate, salt, salt, oxalyl, and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (ΧΧΧΧΠΙ). 1-Hydroxybenzotriazole or the like may be used in an amount of 0.5 to 2 molar equivalents as a condensation aid. Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like. be able to. Each of them can be used at 0.05 to 2 mole equivalents relative to the compound represented by the general formula (ΧΧΧΧΙΠ).

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 represented by the general formula (Iu) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Method V: Synthesis of (IV) from compound (XXXXIV)

[Chemical 37]

R ¹⁸ 〇 ₂ C— X ⁴ — CH ₂ P + Ph ₃ 'Z (XVI)

(Wherein each symbol is as defined above)

The compound represented by the general formula (XXXXIV) can be synthesized by the method described in Reference Example 4 described later and a method analogous thereto.

Synthesis of (XXXXV) from (XXXXIV)

In the presence of a base, a ketone represented by general formula (XXXXIV) and an organophosphorus compound represented by general formula (XVI) or (XVII) can be condensed to synthesize a compound represented by general formula (XVIII). Monkey.

A compound represented by the general formula (XXXXIV) is represented by the general formula (XVI) or (XVII). 1 to 5 molar equivalents of the organic phosphorus compound can be used.

Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium Examples include oxamethyl disilazide, potassium hexamethyl disilazide, sodium amide and the like. The base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (XXXXIV).

An example of a reaction temperature is 70 to 100 ° C.

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

The resulting compound represented by the general formula (XXXXV) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (XXXXVI) from (XXXXV)

By reducing the compound represented by the general formula (xxxxv) with hydrogen in the presence of a metal catalyst

A compound represented by the general formula (XXXXVI) can be synthesized.

Examples of the metal catalyst include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, chlorotris (trifluorophosphine) rhodium (I), etc., and 0% of the compound represented by the general formula (XXXXVI) 01 to 0.5 weight percent can be used.

The hydrogen pressure is 1 to 50 atm.

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

The resulting compound represented by the general formula (XXXXVI) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Synthesis of (χχχχνπ) from (XXXXVI)

A carboxylic acid represented by the general formula (χχχχνπ) can be synthesized by treating the compound represented by the general formula (XXXXVI) with thionyl chloride and then reacting with a base. The compound represented by the general formula (XXXXVI) can be used in an amount of 1 to 30 molar equivalents of thiol chloride.

Examples of the reaction solvent include tetrahydrofuran, jetyl ether, toluene and the like. Examples of the reaction temperature include o ° c to the reflux temperature of the solvent.

Examples of the reaction time include 0.5 to 24 hours.

Examples of the base used in the base treatment include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and they can be used at 0.1 to 10 molar equivalents relative to the compound represented by (XXXXVI).

An example of a reaction temperature is 20 to 100 ° C.

Examples of the reaction time include 0.5 to 24 hours.

The resulting compound represented by the general formula (XXXXVII) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Synthesis of (IV) from (XXXXVII)

In the presence of a condensing agent, the carboxylic acid represented by the general formula (XXXXVII) and the amine compound represented by the general formula (XX) are condensed to synthesize the amido compound represented by the general formula (Iv). can do.

The compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXXVII).

Examples of condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol and salt oxalyl, and the compound can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXXVII). 1-Hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents. Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. 0.052 molar equivalents can be used for each of the compounds represented by the general formula (XXXXVII).

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

The reaction time is 0.5 72 hours.

The resulting compound represented by the general formula (IV) can be isolated and purified by known means (for example, chromatography recrystallization and the like).

Method W: Synthesis of compound (XXXXVII—a) force (I w)

[Chemical 38]

(Wherein each symbol is as defined above)

Synthesis of (XXXXVIII) from (XXXXVII a)

In the presence of a reducing agent, the compound represented by the general formula (XXXXVII-a) can be reduced to synthesize the alcohol represented by the general formula (XX XXVIII).

Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, etc., and 0.5 6 for the compound represented by the general formula (XXXXVII-a) A molar equivalent can be used.

Examples of the reaction temperature include 0 ° C to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 72 hours.

The resulting compound represented by the general formula (xxxxvm) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Synthesis of (XXXXIX) from (XXXXVIII)

In the presence of a azo compound and a trivalent phosphorus compound, an alcohol represented by the general formula (XXXXVIII) and phthalimide can be condensed to synthesize a compound represented by the general formula (XXXXIX).

It is possible to use 1 to 3 molar equivalents of phthalimide with respect to the compound represented by the general formula (XXXXVIII).

Examples of azo compounds include jetyl azodicarboxylate, diisopropyl azodicarboxylate, and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (xxxxvm).

Examples of the trivalent phosphorus compound include triphenylphosphine and tributylphosphine, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (XXXXVIII).

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

The resulting compound represented by the general formula (XXXXIX) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Synthesis of (L) from (XXXXIX)

By treating the compound represented by the general formula (XXXXIX) with hydrazine hydrate, an amine compound represented by the general formula (L) can be synthesized.

Hydrazine hydrate can be used in an amount of 1.0 to 5 mole equivalent to the compound represented by the general formula (XXXXIX).

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 resulting compound represented by the general formula (L) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).

Synthesis of (I-w) from (L)

An amide compound represented by the general formula (Iw) can be synthesized by condensing the amine compound represented by the general formula (L) and the carboxylic acid represented by the general formula (X) in the presence of a condensing agent. . The compound represented by the general formula (X) can be used at 0.5 to 2 mole equivalents relative to the compound represented by the general formula (L).

Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, thionyl chloride, chlorooxalyl, and the like. The base can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (L). 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole or the like as a condensation aid may be used.

Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 mole equivalents relative to the compound represented by the general formula (L).

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 represented by the general formula (Iw) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

Method X: Synthesis of Compound (L) Force (I X)

A compound represented by the general formula (IX) can be synthesized by reacting an amine represented by the general formula (L) with an isocyanate represented by the general formula (ΧΙΠ) or a carbamate represented by (XIV).

[Chemical 39] A ¹ _NC〇 (XII I)

H ₂ N

(i-x)

(Wherein each symbol is as defined above)

The compound represented by the general formula (XIII) or (XIV) can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (L).

If necessary, an amine such as triethylamine or diisopropylethylamine can be used in an amount of 0.05 to 2 molar equivalents relative to the compound represented by the general formula (L).

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 represented by the general formula (IX) can be isolated and purified by known means (for example, chromatography, recrystallization, etc.).

Method Y: Synthesis of (I—z) from y compound (I—y)

A compound represented by the general formula (I z) can be synthesized by reacting a compound represented by the general formula (I y) with a base.

[Chemical 40]

(Wherein χ ⁶ is an optionally substituted lower alkylene, optionally having a substituent V, lower alkylene, one (CR ⁸ R ⁹ ) rO (CR ³ R ⁴ ) s, one (CR ⁸ R ⁹ ) rS (CR ³ R ⁴ ) s, one (CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) s, one (CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) s , One CR ⁹ = N— 0 (CR ³ R ⁴

2

) s, 1 A ³ — (CR ³ R ⁴ ) s, 1 A ³ — NR ⁶ (CR ³ R ⁴ ) s, or 1 A ³ scale ¹ . : ! ^ ¹ .

R ³ RV NR ° (CR ° R ⁴ ) s CO CH X CONHCH One X —, One N

2 2 2 R ⁵ CONHCH—X ⁵ , 1 CO—X ⁴ or 1 C (= N—OR ⁷ ) —X ⁴

2

(Other symbols are as defined above)

The compound represented by the general formula (I y) can be synthesized by the methods shown in Method A, Method I, Method K, Method L, Method M, Method N, and Method O.

Lithium diisopropylamide, lithium hexamethyldisilazide, n-butyllithium, potassium tert-butoxide, 1,8 diazabicyclo [5.4.0] undecar 7 against the compound represented by the general formula (I—y) A base such as N can be used at 0.1 to 10 molar equivalents.

Examples of the reaction solvent include tetrahydrofuran, jetyl ether, toluene and the like. Reaction temperature includes −70 to 100 ° C.

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

The resulting compound represented by the general formula (Iz) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).

R ^2a and R ^2b are combined to form one O or one OCH—.

2

The product can be synthesized by subjecting it to the following crosslinking reaction at an appropriate stage.

[Chemical 41]

(W is 0 or 1, X ⁷ is a force that is A ¹ — X— or a group derivable to A—X—, and other symbols are as defined above)

Synthesis of (LIII) from (LI)

A compound represented by the general formula (LIII) can be synthesized by condensing a ketone represented by the general formula (LI) and an organic phosphorus compound represented by the general formula (LII) in the presence of a base.

An organophosphorus compound represented by the general formula (LII) is added to the compound represented by the general formula (LI). Examples of the reaction solvent include tetrahydrofuran, jetyl ether, acetonitrile, N, N dimethylformamide, dimethyl sulfoxide, liquid ammonia and the like.

Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium Examples include oxamethyl disilazide, potassium hexamethyl disilazide, sodium amide and the like. The compound represented by the general formula (LI) can be used at 2.0 to 20 molar equivalents.

An example of a reaction temperature is 70 to 100 ° C.

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

The resulting compound represented by the general formula (LIII) can be isolated and purified by the known means (eg, chromatography, recrystallization, etc.).

[0046] It is noted that A ¹ may have a substituent, or may have a nitrogen-containing aromatic monocyclic group or a substituent! / A nitrogen-containing aromatic condensed cyclic group The nitrogen-containing aromatic monocyclic group or the nitrogen-containing aromatic condensed cyclic group has the following conditions:

0 protected, hydroxy, or protected, having at least one amino

Or

ii) Containing NH in the ring

In the reaction conditions normally used (for example, the method described in TW Green et al., Protective uroups in Organic Chemistry, Second Edition, John Wiley & Sons (1991)). Can be deprotected.

[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. 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 (for example, (+) mandelic acid, (1) mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-1-phenethylamine, (-)-1-phenethylamine, Cinchonine, (1) -cinco-zine, brucine, etc.) are formed and separated by fractional recrystallization. If desired, a free optical isomer is obtained through a neutralization step.

2) Chiral column method

A method in which a racemate or a salt thereof is separated on a column for chiral separation (chiral column). 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 Co., Ltd.) or CHIRAL series manufactured by Daicel, and 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.), followed by a hydrolysis reaction. A method of obtaining optical isomers by separating optically active reagent sites by chemical treatment such as 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, MTP ー [α-methoxy-ex (trifluoromethyl) furacetic acid], (1) -menthoxyacetic acid etc.) 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 diester or an ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is subjected to an acid hydrolysis or basic hydrolysis reaction to produce a photocatalyst of the original compound. Converted to an academic isomer.

[0049] As the salt of the compound of the present invention, a pharmaceutically acceptable salt can be used. Examples of basic carbonates include alkali metal salts such as sodium salt and potassium salt; for example calcium salt and magnesium salt. Alkaline earth metal salts, such as ammonium salts; trimethylamine salts, triethylamine salts; aliphatic amine salts such as dicyclohexylamine, ethanolamine salts, ethanolamine salts, triethanolamine salts, brocaine salts; N, N —Aralkylamine salts such as dibenzylethylenediamine; heterocyclic aromatic amines such as pyridine salt, picoline salt, quinoline salt, isoquinoline salt, etc .; eg tetramethyl ammonium salt, tetraethyl ammonium salt Salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzil Examples include quaternary ammonium salts such as tributyl ammonium salt, methyl trioctyl ammonium salt, and tetraptyl ammonium salt; arginine salts; basic amino acid salts such as lysine salts, and the like. .

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.

[0050] Among 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 Other ring member atoms may be substituted, or ring member atoms other than imidazolyl and NH may be substituted. Pyrrolyl, a pyrazolyl that may be substituted with a ring atom other than —NH—, or a compound that is substituted with a ring atom other than NH and is benzimidazolyl (hereinafter A1 is al) )

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 compound in which A ¹ is hydroxypyridyl, hydroxybenzoxazolyl, hydroxybenzimidazolyl, unsubstituted midazolyl unsubstituted pyrazolyl or unsubstituted pyrrolyl (hereinafter A 1 is a3),

4) A compound wherein A ¹ is hydroxypyridyl, hydroxybenzoxazolyl, unsubstituted imidazolyl or unsubstituted pyrrolyl (hereinafter, A1 is a4),

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 (CHR ³ ) n C (= 0) 0 (CHR ³ ) n A ³ — CHR ³ —, A ³ — (CHR ³ ) qNR ⁶ or A ³ — NR ⁶ (CHR ³ ) n (Each R ³ is different !, may be) a compound (hereinafter, X is xl),

6)-0 (1) 11-CONH (CHR ³ ) n-,-NHCO (CHR ³ ) n-,-A ³ -CHR ³ -,-A ³ -CHR ³ NR ⁶ or-A ^3- A compound of NR ⁶ (hereinafter, X is x2),

7) -00 (11) 11-CONH (CHR ³ ) n-,-NHCO (CHR ³ ) n-,-A ³ -CHR ³ -A ³ -CHR ³ NR ⁶ or one A ³ -NR ⁶ N is 13; A ³ is an aromatic heterocyclic group; and R ³ is hydrogen or methyl (each R ³ may be different) (hereinafter, X is x3 Suppose)

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

3 2 2

CHR ³ —, — A ³ — CHR ³ NR ⁶ or — A ³ — NR ⁶ , R ³ is hydrogen or methyl, A ³ is phenylene or a 56-membered aromatic monocyclic group (Each R ³ is different!), A compound (hereinafter, X is assumed to be x4), [0052] 9) R ¹ is hydrogen, R ^2a is hydrogen, hydroxy or lower alkyl, or R ¹ and R ² ^a may be combined to form a single bond (hereinafter referred to as RR) ^2a and R ^2b are rl),

10) 1 ^ is hydrogen and R ^2a is hydrogen or hydroxy (hereinafter, RR ^2a and R ^2b are r2),

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

[0053] 12) m is 0 and Y is a single bond, CH—, 1O, 1S— or NH, or R

2

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

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

2

Suppose)

14) m is 1, Y is a single bond, -CH 1, -CH 2 CH 1, CH = CH—, — C≡C

2 2 2

One, O, one S, one NH—, —CH 2 O, —CH 2 S or one CH NH

2 2 2

, Compounds with R ^2a to form = CH or = CHCH (hereinafter m and

2

Y is assumed to be y3),

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

2

A compound which forms = CH with ^2a (hereinafter m and Y are y4),

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

2

Suppose)

[0054] 17) A compound in which A ² is phenyl optionally substituted with one or more groups selected from halogen, halogenated halogeno lower alkyl, and halogeno lower alkoxy (hereinafter A ² is a 5 And)

18) A ² is halogen, triflate Ruo Russia methyl and triflusulfuron Ruo b methoxy mosquitoes be substituted with one or more groups selected, even I, Hue - Le, compound (hereinafter, the A ² is a a6 )

19) A ² is para halogen, triflate Ruo Russia methyl and triflusulfuron Ruo b methoxy mosquitoes also full alkenyl substituted with one or more groups selected compounds (hereinafter, A ² is assumed to be a7) ,

20) A ¹ may have a substituent, or may be a nitrogen-containing aromatic monocyclic group, which is protected! /, Hydroxy or protected! Hey! /, With at least one amino, X— εες ()) ¾ / $ ϊ ^ ρ3ν3003 3κ3κΗΗΝΚΗΗΝ. 'ββυ ιιιιΙιι, ,,

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y () ((() (I ε ΐεεΐ9εεΐεεΐεs3xχ ^ χ ^ χ ^ χ ---------- y () (((((ΐs ΐ9εΐεΐ ε ΐ9s333χ ^ χ ^ χχ ------- ---- y (y (y (y (y (9IIII9IIIggJJJJJ AxxxAxAxBA ----------- y (y (y (y (2 (9gggJJJxAxAxAx ----- y (y (y ( y (y (9 ΐ9 ΐggJXλ AB-- y (y (y (y (y (9 s9 sSs 卜 x-(y (3 (3 (y (3 (22g g gBAA---------(y (((y (9 S εε ε9εε ε εss --------) ((() ((ΐε9ΐΐεΐΐ9ΐΐ3χχ ^^ -------------

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y (y (y (y (y (Dimension 9 ^ ¾ ^ ££ 9 ££ ggJJJ X BBBAxBAxAxB ---- //: / O ε69Ώε900ί1 £ 6ε8ε90 / -00ίAVZ.

(y (ε dimension ε9 ε dimension ε dimension s ss s X X ---- y (y (y (y () [9II ^ I ^ I ^ 9II ^ II ^ 00ggJJJJXBBXAxAxAx --------- -

¾l ^ ¾χιαέ ヤ τ005 R ;; tlu>

[42

) T¾ () () 005823¾liIn ~

yyy ,,,,,,,,,, 4r35a5a4x4r35a6a4x4r35a7

yyyyy ,,,,,,,,,,,,,,,,,, x4r33a6a4x4r33a7a4x4r34a5a4x4r34a6a4x4r34a7a4x

yyyyy ,,,,,,,,,,,,,,,,,,, x4r3la7a4x4r32a5a4x4r32a6a4x4r32a7a4x4r33a5a4

yyyyy ,,,,,,,,,,,,,,,,,, 4x4r25a5a4x4r25a6a4x4r25a7a4x4r3la5a4x4r3la6a4

yyyyy ,,,,,,,,,,,,,,,, a4x4r23a6a4x4r23a7a4x4r24a5a4x4r24a6a4x4r24a7a

yyyyy ,,,,,,,,,,,,,,, (a4x4r2la7a4x4r22a5a4x4r22a6a4x4r22a7a4x4r23a5

yyyyyA ,,,,,,,,,,,,,,,,,,,)) a4x4rl5a5a4x4rl5a6a4x4rl5a7a4x4r2la5a4x4r2la6

yyyyy ,,,,,,,,,,,,,,,,,, 5a4x4rl3a6a4x4rl3a7a4x4rl4a5a4x4rl4a6a4x4rl4a7

yyyyy ,,,,,,,,,,,,,,,,, a6a4x4rlla7a4x4rl2a5a4x4rl2a6a4x4rl2a7a4x4rl3a

yyyyy ,,,,,,,,,,,,,,,,,,,, a7a4x3r35a5a4x3r35a6a4x3r35a7a4x4rlla5a4x4rll yyyyy ,,,,,,,,,,,,,,,, 3a5a4x4x3r3a3r4 A ³ may have a substituent, may be a phenol or a substituent, and may be a 5- to 6-membered aromatic monocyclic group,

Y is - CR ¹² R ¹³ - a and, connexion = CR ¹⁴ such together with R ^2a - Yogu be formed

R is a substituent of “aromatic hydrocarbon cyclic group having a substituent,”

R \ R ^2a , R ^2b , R ^2c , R ³ , R ⁴ , R ¹² , R ¹³ and R ¹⁴ are compounds as defined above (1), and [0060] R ^A is hydroxy, ami-substituted lower alkylamino or Is an asilamino,

Lower alkylene which X may have a substituent, CO (CR ³ R ⁴ ) n—, — CONR ⁵ (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—, —SO (CR ³ R ⁴ ) n—, 1 SO (CR ³ R ⁴ ) n—, 1 A ³ — CHR ^3- , 1 A ³ -CHR ³ NR ⁶ or

2

A ³ — NR ⁶

n is an integer from 0 to 4,

R ¹ is hydrogen,

R ^2a is hydrogen, hydroxy or lower alkyl,

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

R ^2b and R ^2e may both be hydrogen and 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, together such connexion = CR ¹⁴ and R ^2a -, may form a

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

[0061] Preferably

R ^A is hydroxy,

X is — CONR ⁵ (CR ³ R ⁴ ) n—, — NR ⁵ CO (CR ³ R ⁴ ) n—, — A ³ — CR ³ R ⁴ —, — A ³ — C HR ³ NR ⁶ , 1 A ³ — NR ⁶ or NR ⁵ CONR ⁶ ,

n is an integer from 0 to 4,

R ¹ and R ^2a may be hydrogen together, and they may be joined together to form a single bond R ^2b and R ^2e are both hydrogen together, and they are joined together to form a single bond ヽR ³ , R ⁴ and R ⁶ are each independently hydrogen or lower alkyl, Y is a single bond or CH—

2

[0062] 24) Formulas (Io) to (Ir):

[Chemical 43]

Y is a single bond, lower alkylene, lower alkylene, lower alkylene, Ο or — CR ¹² R ¹³ 0—, together with R ^2a = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) Other symbols that may form p— are the same as in 23) above,

[0063] 25) 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 A ³ — CHR ³ or NR ONR ⁶

n is an integer of 1 3

R ¹ is hydrogen,

R ² is hydrogen, hydroxy or methyl;

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

R ^2b is hydrogen or hydroxy, and R ^2e is hydrogen or 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

R is hydrogen, halogen, halogeno lower alkyl or halogeno lower alkoxy object,

[0064] 2 ⁶ ) In the formula (Ij),

R ^A is hydroxy or amino

Q ¹ is O or NH,

X is one NR ⁵ CO (CHR ³ ) A ³ — CHR ³ or one NR ⁵ CONR ⁶ ;

2

n is 2 or 3,

R ¹ is hydrogen,

R ² is hydrogen or hydroxy;

R ¹ and R ^2a 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, lower alkoxy, halogeno lower alkyl or halogeno lower alkoxy;

[0065] 27) In the formula (Ik),

Q ² is N or CH,

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

2 2 2 2

R ³ —or NR ⁵ CONR ⁶ and

R ¹ is hydrogen,

R ^2a is hydrogen, hydroxy or lower alkyl,

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

Y is a single bond or CH— R is hydrogen, halogen, halogeno lower alkyl or halogeno lower alkoxy,

[0066] 28) In the formula (Im),

Q ³ is N or CH,

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

twenty two

CONR ⁶ ,

R ¹ is hydrogen,

R ^2a is hydrogen or hydroxy;

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

R ^2b is hydrogen or hydroxy, R ^2e is hydrogen or may be joined together to form a single bond,

Y is a single bond or CR ¹² R ¹³

R is hydrogen, halogen, halogeno lower alkyl, lower alkoxy or halogeno lower alkoxy,

[0067] 29) In the formula (In),

Q ² is N or CH,

2 2 2 2

R ³ —or —NR ⁵ CONR ⁶ and

R ¹ is hydrogen,

R ^2a is hydrogen, hydroxy or lower alkyl,

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

[0068] 30) In formula (Io),

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 ^2a is hydrogen or hydroxy;

R ¹ and R ^2a 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 ^2a = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p May

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

[0069] 31) In formula (Ip)

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 ^2a is hydrogen or hydroxy;

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

R ^2b and R ^2e are both hydrogen and may be combined to form a single bond! / R ³ may be hydrogen or lower alkyl (each R ³ may be different! /, Moyo! /)),

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,

[0070] 32) In the formula (Iq),

Q ² is N or CH,

n is 0 2,

R ¹ is hydrogen,

R ^2a is hydrogen, hydroxy or lower alkyl,

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

R ^2b and R ^2e may be both hydrogen and 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 lower alkylene,

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

[0071] 33) In the formula (Ir),

Q ³ is N or CH,

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

n is 1 or 2,

R ¹ is hydrogen,

R ^2a is hydrogen or hydroxy; R ¹ and R ^2a may be joined together to form a single bond

R ^2b and R ^2e are both hydrogen, and together they can 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, or a pharmaceutically acceptable salt thereof or a solvate thereof.

In the following formula (Is), (It), (Iu) or (Iv)! /, A compound in which the combination of AA ² , X and Y (A \ A ² , X, Y) is as follows: The pharmaceutically acceptable salt or solvate thereof is also a preferred embodiment of the present invention.

[Chemical 44]

[table 1]

3]

V'l—IV) '(U'OIX'I—SV'I—IV)' person '6Χ'ΐ—SV'I—IV)' (I input 6 入 'ΐ—SV'I—IV)' person '8Χ'ΐ—' ΐ—IV) '(I input' 8Χ'ΐ—SV'I—IV) 'people' ΖΧ'ΐ—SV'I—IV) '(U'ZX'I—SV'I— IV) 'People' 9Χ'ΐ—SV'I — IV) '(I entered' 9Χ'ΐ—SV'I—IV) 'People' SX'I—SV'I—IV) '(U'SX'I — SV'I— IV) 'People ^ Χ'ΐ— SV'I— ΐ

ν) '(ΐ 人' χ'ΐ— sv'i— ΐν) 'people' εχ'ΐ— sv'i— ιν) '(ΐ 人' εχ'ΐ— sv'i— ΐν) i—sv'i—iv)

[9Z00]

C69CZC / 900Zdf / X3d 38 6C8C90 / .00Z OAV ,,,,,,,,, 23X16Y1A11A23X16Y2A11A23X17Y1A11A23X17Y2A11I ------ I

,,,,,,,,,, 3X14Y1A11A23X14Y2A11A23X15Y1A11A23X15Y2A11A ------- ,,,,,,,,, X12Y1A11A23X12Y2A11A23X13Y1A11A23X13Y2A11A ---

,,,,,,,,,, 0Y1A11A23X10Y2A11A23X11Y1A11A23X11Y2A11A23 ------- I

,,,,,,,,,, X8Y1A11A23X8Y2A11A23X9Y1A11A23X9Y2A11A23X1 -------- ,,,,,,,,,,, 3X6Y1A11A23X6Y2A11A23X7Y-A11A23X23-1-2

,,,,,,,,,, 23X4Y1A11A23X4Y2A11A23X5Y1A11A23X5Y2A11A2I ------- I

,,,,,,,,,,, A23X2Y1A11A23X2Y2A11A23X3Y1A11A23X3Y2A11A --------

,,,,,,,,,,, A22X24Y1A11A22X24Y2A11A23X1Y1A11A23X1Y2A11I ------ I

,,,,,,,,,, 22X22Y1A11A22X22Y2A11A22X23Y1A11A22X23Y2A11I ------ I

,,,,,,,,,, 2X20Y1A11A22X20Y2A11A22X21Y1A11A22X21Y2A11A ------- ,,,,,,,,, X18Y1A11A22X18Y2A11A22X19Y1A11A22X19Y2A11A ---

,,,,,,,,,,, 6Y1A11A22X16Y2A11A22X17Y1A11A22X17Y2A11A22 ------- I

,,,,,,,,, Y1A11A22X14Y2A11A22X15Y1A11A22X15Y2A11A22X1 -------- ,,,,,,,,,, A11A22X10Y2A11A22X11Y1A11A22X11Y2A, AA12X12Y, I-A, ,,

,,,,,,,,,,, 1A11A22X6Y2A11A22X7Y1A11A22X7Y2A11A22X8Y1 --------

,,,,,,,,,,,, Y1A11A22X4Y2A11A22X5Y1A11A22X5Y2A11A22X6Y -------- ,,,,,,,,,, X2Y1A11A22X2Y2A11A22X3Y1A11A22X3Y-A11-A22X3Y-A

,,,,,,,,,,, X24Y1A11A21X24Y2A11A22X1Y1A11A22X1Y2A11A22 ------- I

,,,,,,,,,,, 2Y1A11A21X22Y2A11A21X23Y1A11A21X23Y2A11A21 ------- I

,,,,,,,,, Y1A11A21X20Y2A11A21X21Y1A11A21X21Y2A11A21X2 -------- ,,,,,,,,,, A11A21X18Y2A11A21X19Y1A11A21X19Y2A, A, A21X20-,-,- ,,, A11A21X16Y2A11A21X17Y1A11A21X17Y2A11A21X18Y1I ------- ,,,,,,,,,, 1A21X14Y2A11A21X15Y1A11A21X15Y2A11A21X16Y1

,,,,,,,,,, A21X12Y2A11A21X13Y1A11A21X13Y2A11A21X14Y1A1I ------ ,,,,,,,,, 21X10Y2A11A21X11Y1A11A21X11Y2A11A21X12Y1A11- -ΐνΥ (ΙλΊΧ'9-ΖΥΐ-ΐνΥ (Ζλ 'ΖΧ' -ΖΥΐ-ΐνΥ (Ιλ 'ΖΧ' -ΖνΊ-ΐν) Ζλ'ζΖΧ '-Ζν' 1-ΐνΥ (Ιλ'ζΖΧ '-ΖΥΐ-ΐνΥ (Ζλ 'ΖΖΧ' -ΖΥΐ-ΐνΥ (Ιλ'ΖΖΧ '-ΖΥΐ-ΐνΥ (Ζλ'ΙΖΧ' -Ζ V'T-TV) '(TA'T2X'e-2V'T-TV)'(2AO2X'e-2V'T-TV)'(O2X'e-2V'T-TV)'(2A'6TX'e-2V'T-TV)'('6TX'e-2V'T-TV)'(2A'8TX'e-2V'T-TV)'(TA'8TX'e-2V'T-TV)'(2A'ZTX'S—SV'I—ΐν)' (ΐ 入 'ZIX'S—SV'I—IV)' ON '9IX'S—SV'I—IV)'(U'9IX'S—SV'I—IV)'ON' S IX'S—SV'I—IV) '(U'SIX'S—SV'I—IV)' ON 'WX'S — SV'I—IV) '(I input WX'S—SV'I—IV)' Input 'STX'e-2V'T-TV)'('STX'e-2V'T-TV)' (2A '2TX'e-2V'T-TV)'('2TX'e-2V'T-TV)'(2λ'πΧ'3-2ν'ΐ-ΐν)'(ΐλ'πΧ'3-2ν'ΐ-ΐν ) '(2λ'0ΐΧ'3-2ν'ΐ-ΐν)'(ΐλΌΐΧ'3-2ν'ΐ-ΐν)'In'6X'S—SV'I—IV)'(IIn'6X'S—SV'I—IV ) 'People'8X'S—SV'I—IV)'(U'8X'S—SV'I—IV)' (S input 'ZX'S—SV'I—IV)'(U'ZX'S—SV'I—IV)' People '9X'S—SV'I—IV)' (I people '9X'S—SV'I—IV)' Enter 'SX'S—SV'I—IV)' (I people 'SX'S — SV'I—IV) 'People'X'S—SV'I—IV)'(U'X'S—SV'I—IV)'Enter' ε X'S—SV'I—IV) '(I Plot'SX'S—SV'I—IV)' People 'SX'S—SV'I—IV)'(U'SX'S—SV'I—IV)'People' ΐΧ '-ζν'ι-ινΥ (ΐλΊχ' -ζνΊ-ιν) ζλ 'ζχ '-ζΥΐ-ινΥ (ΐλ' ζχ '-ζΥΐ-ινΥ (ζλ'ζζχ

'SV'I- ιν)' (ΐ 入 SV'I-IV) '入' ^ X 'SV'I-IV)' (U '^ X' SV'I-IV) 'Enter' ΐ ZX'f- ZYl-WYdA 'ΐ SX'-SV 'ΐ- ΐ V)' On 'OSX'f- SV' ΐ- ν ν) '(ΐ 入' OSX'f- SV 'ΐ- ΐ V)' On '6TX -2V'T-TV) '(' 6TX ^ -2V'T-TV) '(2A'8TX ^ -2V'T-TV)' ('8TX ^ -2V'T-TV)' (2A'ZTX ^ -2V'T-TV) '(' ZTX ^ -2V'T-TV) '(2A'9TX ^ -2V'T-TV)' (TA'9TX ^ -2V'T-TV

) ζλ 'ΐχ' -ζΥΐ-ιν) ΐλ 'ΐχ' -ζΥΐ-ιν) ζλ 'χ' -ζν'ι-ιν) ΐλ 'χ' -ζν'ι- ιν) ζλ'ζΐχ '-ζΥΐ-ινΥ ( ΐλ'ζΐχ '-ζΥΐ-ιν) ζλ'ζιχ' -ζν'ι-ινΥ (ΐλ'ζιχ '-ζν'

T-TV) '(2A'nX ^ -2V'T-TV)' (TA'nX ^ -2V'T-TV) '(2AOTX ^ -2V'T-TV)' (OTX ^ -2 ν'ΐ — IV) 'People' 6X'G SV'I- ΐν) '(ΐ 入' 6X'G SV'I—IV) 'People' 8X'G SV'I-IV) '(U'8X'G SV' ΐ—IV) 'person SV'I—IV)' (I input SV'I—IV) 'person' 9X'to SV'I—IV) '(U'9X'to SV'I—IV)' People 'SX'G SV'I-IV)' (U'SX'G SV'I-IV) 'People'Χ'G SV'I-IV)' (I people'Χ'G SV'I-IV

) 'Enter' εχ 'and sv'i—ιν)' (ΐ 入 'εχ' and sv'i—iv) 'People' sx 'and sv'i—iv)' (u'sx 'and sv'i— ιν) '(

Ζλ'ΙΧ '-ΖΥΐ-ΐν) Ιλ'ΙΧ' -ΖΥΐ-ΐνΥ (Ζλ 'ΖΧ'ζ-ΖΥΐ-ΐνΥ (Ιλ' ΖΧ'ζ-Ζν'1-ΐν) Ζλ'ζΖΧ'ζ-ΖνΊ-ΐνΥ ( Ιλ'ζΖΧ'ζ-ΖνΊ-ΐν) Ζλ'ΖΖΧ'ζ-ΖΥΐ-ΐνΥ (Ιλ'ΖΖΧ'ζ-ΖΥΐ-ΐν) '(2λ'ΐ2Χ'ε-2ν'ΐ-ΐν)' (ΐλ'ΐ2Χ ' ε-2ν'ΐ-ΐν) '(2λ'02Χ'ε-2ν'ΐ-ΐν)' (ΐλΌ2Χ'ε-2ν'ΐ-TV) '(2A'6TX'S-2V'T-TV)' ('6TX'S -2V'T-TV) '(2A'8TX'S-2V'T-TV)' ('8TX'S-2V'

C69CZC / 900Zdf / X3d 8 6C8C90 / .00Z OAV SV'S—IV) 'People'8Χ'ΐ—SV'S—IV)'(Ipeople'8Χ'ΐ—SV'S—IV)'People'ΖΧ'ΐ—SV'S—IV)'(Iinput'ΖΧ'ΐ—'S — IV) 'People'9Χ'ΐ—SV'S—IV)'(Ientered'9Χ'ΐ—SV'S—IV)'People'SX'I—SV'S—IV)'(U'SX'I—SV'S

— Iv) 'people' χ'ΐ— sv's— ιν) '(ΐ 入' χ'ΐ— sv's— iv) 'people' εχ'ΐ— sv's— ιν) '(ΐΑ'εχ'ΐ— sv's— ΐ

V) 'people' SX'I—SV'S—IV) '(I people' SX'I—SV'S—IV) 'enter' ΐΧ'ΐ—SV'S—ΐν) '(ΐΛ'ΐΧ'ΐ—SV'S—IV) [ ZOO]

Ζλ 'ΖΧΊ-ΖνΊ-ΐνΥ (Ιλ' ΖΧΊ-ΖΥΐ-ΐνΥ (Ζλ'ζΖΧΊ-ΖΥΐ-ΐνΥ (Ιλ'ζΖΧ

Ί-ΖνΊ-ΐνΥ (Ζλ'ΖΖΧΊ-ΖΥΐ-ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥΐ-ΐνΥ (ΖλΊΖΧΊ-ΖΥΐ-ΐνΥ (ΙλΊ

SX'Z-SV'I-IV) 'people' OSX'Z-SV'I-IV) '(U'OSX'Z-SV'I-IV)' people '6IX'Z-SV'I-IV) '(I input

'6TX'Z-2V'T-TV)' (2A'8TX'Z-2V'T-TV) '(' 8TX'Z-2V'T-TV) '(2A'ZTX'Z-2V'T- TV) '(

'ZTX'Z-2V'T-TV)' (2A'9TX'Z-2V'T-TV) '(' 9TX'Z-2V'T-TV) '(2A'eTX'Z-2V'T- TV

) '(' eTX'Z-2V'T-TV) '(2A ^ TX'Z-2V'T-TV)' (^ TX'Z-2V'T-TV) '(2A'STX'Z-2V 'T-TV)' ('STX'Z-2V'T-TV)' (2A'2TX'Z-2V'T-TV) '(' 2TX'Z-2V'T-TV) '(2A'nX 'Z-2V' ΐ—IV) '(U'nX'Z—SV'I—IV)' ON 'OIX'Z—SV'I—IV)' (U'OIX'Z—SV'I—IV) ' Man'

'ΐ—IV)' (I input 6X'Z—SV'I—IV) 'person' 8X'Z—SV'I—IV) '(U'8X'Z—SV'I—IV)' person ' ZX'Z—SV'I — IV) '(I input' ZX'Z—SV'I—IV) 'people' 9X'Z—SV'I—IV) '(U'9X'Z—SV'I— IV) 'People' SX'Z—SV'I—ΐ

ν) '(ΐ 人' sx'z— sv'i— ΐν) 'person' x'z—sv'i— ιν) '(ΐ 人' x'z—sv'i— ΐν) 'person' sx ' z—sv'i—iv)

'(ΐ 入 iv)' 人 'sx'z—sv'i—ιν)' (ΐ 入 'sx'z—sv'i—iv)' input 'IX'Z—SV'I ιν)' (ΐ input 'IX'Z—SV'I—IV)' Enter 'SV'I—IV)' (U'WX'9—SV'I—IV) 'Enter' SSX'9—SV'I—IV) '(

'S2X'9-2V'T-TV)' (2A'22X'9-2V'T-TV) '(' 22X'9-2V'T-TV) '(2A'T2X'9-2V'T- TV

) '(' T2X'9-2V'T-TV) '(2AO2X'9-2V'T-TV)' (O2X'9-2V'T-TV) '(2A'6TX'9-2V'T- TV) '(' 6TX'9-2V'T-TV) '(2A'8TX'9-2V'T-TV)' ('8TX'9-2V'T-TV)' (2A'ZTX'9- 2V 'T-TV)' (TA'ZTX'9-2V'T-TV) '(2A'9TX'9-2V'T-TV)' ('9TX'9-2V'T-TV)' (2A 'eTX'9-2

V'T-TV) '(TA'eTX'9-2V'T-TV)' (2A ^ TX'9-2V'T-TV) '(^ TX'9-2V'T-TV)' (2A 'STX'9

-2V'T-TV) '(' STX'9-2V'T-TV) '(2A'2TX'9-2V'T-TV)' (TA'2TX'9-2V'T-TV) '( 2A'nX

'9-2V'T-TV)' (TA'nX'9-2V'T-TV) '(2AOTX'9-2V'T-TV)' (OTX'9-2V'T-TV) '(2A '6

Χ'9—SV'I—ΐν) '(ΐ 人' 6Χ'9—SV'I—IV) 'people' 8Χ'9—SV'I—IV) '(U'8X'9—SV'I— IV) 'People' ΖΧ '9—SV'I—IV)' (I people 'ZX'9—SV'I—IV)' People '9Χ'9—SV'I—IV)' (U'9X'9 — SV'I— IV) 'People' SX'9—

SV'I—IV) '(U'SX'9—SV'I—IV)' person 'X'9—SV'I—IV)' (I input X'9—SV'I—IV) 'person 'εχ'9—

'ΐ—ιν)' (ΐ 入 'εχ'9—SV'I—IV)' People 'SX'9—SV'I—IV)' (U'SX'9—SV'I—IV) 'Enter' ΐΧ'9—SV'I

C69CZC / 900Zdf / X3d 98 6C8C90 / .00Z OAV ΖΥΖ-ΐνΥ (Ιλ'91Χ'ζ-ΖΥΖ-ΐνΥ (Ζλ '1Χ'ζ-ΖΥΖ-ΐνΥ (Ιλ'1Χ'ζ-ΖΥΖ-ΐνΥ(Ζλ'ηΧ'ζ-ζν'ζ-ινΥ(ΐλ'ηχ' ζ-ζνζ-ινΥ (ζλ'ζΐχ'ζ-ζΥζ-ινΥ (ΐλ'ζΐχ'ζ-ζΥζ-ινΥ (ζλ'ζι

Χ'ζ-Ζν'Ζ-ΐνΥ (Ιλ'ΖΙΧ'ζ-ΖΥΖ-ΐνΥ (Ζλ'ΠΧ'ζ-ΖΥΖ-ΐνΥ (Ιλ'ΠΧ'ζ-ΖΥΖ-ΐνΥ (Ζλ 'οιχ'ε- sv's- ιν) '(ΐ 入' οιχ'ε- sv's- ιν) 'People' 6χ'ε- sv's- iv) '(u'6x's- sv's- ιν)' Enter '

8X'S-2V'2-TV) '(' 8X'S-2V'2-TV) '(2A'ZX'S-2V'2-TV)' (TA'ZX'S-2V'2-TV) '(2A'9X' ζ -ΖΥΖ-ΐνΥ (Ιλ'9Χ'ζ-ΖΥΖ-ΐνΥ (Ζλ 'Χ'ζ-ΖΥΖ-ΐνΥ (Ιλ' Χ'ζ-ΖΥΖ-ΐνΥ (Ζλ 'Χ'ζ -ΖΥΖ-ΐνΥ (Ιλ' Χ'ζ -ΖΥΖ-ΐνΥ (Ζλ'ζΧ'ζ-ΖΥΖ-ΐνΥ (Ιλ'ζΧ'ζ-ΖΥΖ-ΐνΥ (Ζλ'ΖΧ'ζ-Ζ

Υζ-ινΥ (ΐλ'ζχ'ζ-ζΥζ-ινΥ (ζλ'ιχ'ζ-ζΥζ-ινΥ (ΐλΊχ'ζ-ζΥζ-ινΥ (ζλ 'ζχ'ζ-ζν

'Ζ-ΐνΥ (Ιλ' ΖΧ'Ζ-ΖΥΖ-ΐνΥ (Ζλ'ζΖΧ'Ζ-ΖΥΖ-ΐνΥ (Ιλ'ζΖΧ'Ζ-ΖΥΖ-ΐνΥ (Ζλ'ΖΖΧ'Ζ- ΖΥΖ-ΐνΥ (Ιλ'ΖΖΧ'Ζ -ΖΥΖ-ΐνΥ (ΖλΊΖΧ'Ζ-ΖΥΖ-ΐνΥ (ΙλΊΖΧ'Ζ-ΖΥΖ-ΐνΥ (Ζλ'ΟΖΧ 'Ζ-Ζν'Ζ-ΐνΥ (Ιλ'0ΖΧ'Ζ-ΖΥΖ-ΐνΥ (Ζλ'61Χ'Ζ-ΖΥΖ -ΐνΥ (Ιλ'61Χ'Ζ-ΖΥΖ-ΐνΥ (Ζλ'81 χ'ζ-ζν'ζ-ινΥ (ΐλ'8ΐχ'ζ-ζΥζ-ινΥ (ζλΊΐχ'ζ-ζΥζ-ινΥ (ΐλΊΐχ'ζ-ζΥζ- ινΥ (ζλ '

9TX'2-2V'2-TV) '(' 9TX'2-2V'2-TV) '(2A'eTX'2-2V'2-TV)' ('STX'2-2V'2-TV) '(2 into' wx's- sv's- ιν) '(ΐ 入' WX'S-SV'S-IV) 'with' SIX'S-SV'S-IV) '(U'SIX'S-SV'S-IV)' (2A'2TX'2-2V '2-TV)' ('2TX'2-2V'2-TV)' (2A'nX'2-2V'2-TV) '(' nX'2-2V'2-T ν) '(2λΌΐΧ' 2-2ν'2-ΐν) '(ΐλΌΐΧ'2-2ν'2-ΐν)' (2λ'6Χ'2-2ν'2-ΐν) '(ΐλ'6Χ'2-2ν'2-ΐ νΥ (Ζλ '8Χ'Ζ-ΖΥΖ-ΐνΥ (Ιλ'8Χ'Ζ-ΖΥΖ-ΐνΥ (ΖλΊΧ'Ζ-ΖΥΖ-ΐνΥ (ΙλΊΧ'Ζ-ΖΥΖ-ΐν)' (Ζλ'9Χ'Ζ-ΖΥΖ-ΐνΥ (Ιλ'9Χ 'Ζ-ΖΥΖ-ΐνΥ (Ζλ' Χ'Ζ-ΖΥΖ-ΐνΥ (Ιλ 'Χ'Ζ-Ζν'Ζ-ΐν) 入入 ^ X'S— SV'S— ιν)' (ΐ 人 'X'S— SV'S— IV)' People 'SX'S—SV'S—IV)' (U'SX'S—SV'S—IV) 'Enter' ζχ'ζ-ζν'ζ-ινΥ (ΐλ'ζχ'ζ-ζΥζ-ινΥ (ζλ'ιχ'ζ-ζΥζ-ινΥ (ΐλΊχ'ζ-ζΥζ-ινΥ (ζλ 'ζ

ΧΊ-Ζν'Ζ-ΐνΥ (Ιλ 'ΖΧ'1-ΖΥΖ-ΐνΥ (Ζλ'ζΖΧΊ-ΖΥΖ-ΐνΥ (Ιλ'ζΖΧΊ-ΖΥΖ-ΐνΥ (Ζλ' ΖΖΧΊ-ΖΥΖ-ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥΖ-ΐνΥ ( ΖλΊΖΧΊ-ΖΥΖ-ΐνΥ (ΙλΊΖΧΊ-Ζν'Ζ-ΐν) Ζ λ'0ΖΧΊ-ΖΥΖ-ΐνΥ (Ιλ'0ΖΧΊ-ΖΥΖ-ΐνΥ (Ζλ'61ΧΊ-ΖΥΖ-ΐνΥ (Ιλ'61ΧΊ-ΖΥΖ-ΐν) '(Ζλ '81 ΧΊ-ΖΥΖ-ΐνΥ (Ιλ'81ΧΊ-ΖΥΖ-ΐνΥ (ΖλΊΐΧΊ-Ζν'Ζ-ΐνΥ (ΙλΊΐΧΊ-Ζν'Ζ-1 νΥ (Ζλ'91ΧΊ-ΖΥΖ-ΐνΥ (Ιλ'91ΧΊ-ΖΥΖ-ΐνΥ (Ζλ ' 1ΧΊ-Ζν'Ζ-ΐν) Ιλ '1ΧΊ-Ζν'Ζ

-ινΥ (ζλ'ηχ'ι-ζνζ-ινΥ (ΐλ'ηχ'ι-ζΥζ-ινΥ (ζλ'ζΐχ'ι-ζΥζ-ινΥ (ΐλ'ζΐχ'ι-ζν

'Ζ-ΐνΥ (Ζλ'ΖΙΧΊ-ΖΥΖ-ΐνΥ (Ιλ'ΖΙΧΊ-ΖΥΖ-ΐνΥ (Ζλ'ΠΧΊ-ΖΥΖ-ΐνΥ (Ιλ'ΠΧ'1- SV'S—IV)' in 'ΟΐΧ'ΐ— SV'S— ΐν) '(ΐ 入' ΟΐΧ'ΐ— SV'S—IV) 'people' 6Χ'ΐ—SV'S—IV) '(U'6X'I—

C69CZC / 900Zdf / X3d 98 6C8C90 / .00Z OAV ,,,,,,,,,,, 5X22Y1A12A25X22Y2A12A25X23Y1A12A25X23Y2A12 I ------ I

,,,,,,,,,,, X20Y1A12A25X20Y2A12A25X21Y1A12A25X21Y2A12A2 ------- ,,,,,,,,, 18Y1A12A25X18Y2A12A25X19Y1A12A25X19Y2, A12A2,,

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

,,,,,,,,,, A12A25X8Y2A12A25X9Y1A12A25X9Y2A12A25X10Y1AI ------- ,,,,,,,,,, A12A25X6Y2A12A25X7Y1A12A25X7Y, 2-A12A25-8-, 1-A12A25X8- ,,, Y1A12A25X4Y2A12A25X5Y1A12A25X5Y2A12A25X6Y1 -------- ,,,,,,,,,,,, 2Y1A12A25X2Y2A12A25X3Y1A12A25X3Y2A12A25X3 ---- ,,,

,,,,,,,,,,, Y1A12A24X22Y2A12A24X23Y1A12A24X23Y2A12A24X -------- ,,,,,,,,, 1A12A24X20Y2A12A24X21Y1A12A24X21Y2A, A12A24X22-,-, ,,, (A12A24X18Y2A12A24X19Y1A12A24X19Y2A12A24X20Y -------- ,,,,,, 12A24Y2A12A24Y1A12A24Y2A12A24Y1I -------, ,,,,,,, 24 ,,,,,,, A24X12Y2A12A24Y1A12A24Y2A12A24X14Y1A1I ------ I

,,,,,,,,,,, 4X10Y2A12A24X11Y1A12A24X11Y2A12A24X12Y1A12 I ------ I

,,,,,,,,,,, 24X8Y2A12A24X9Y1A12A24X9Y2A12A24X10Y1A12A2I -------

,,,,,,,,,,, A24X6Y2A12A24X7Y1A12A24X7Y2A12A24X8Y1A12AI ------- ,,,,,,,,,, 2A24X4Y2A12A24X5Y1A12A24X5Y2A12A12X-Y-A-

,,,,,,,,,, A12A24X2Y2A12A24X3Y1A12A24X3Y2A12A24X4Y1A1I ------- ,,,,,,,,,,,,

,,,,,,,,,,, 12A23X22Y2A12A23X23Y1A12A23X23Y2A12A23X24Y1I ------- ,,,,,,,,,, 2A23X20Y2A12A23X21Y1A12A23X21Y2A, A, A, 23X22Y1, A, A23X22Y, , A23X18Y2A12A23X19Y1A12A23X19Y2A12A23X20Y1A1I ----- I ,,,,,,, 3Y2A12A23Y1A12A23Y2A12A23Y1A12 I ------ I 'ε-IV)' People '9ΐ'ΐ- SV'S-IV)' (I entered '9Χ'ΐ- SV'S-IV)' People 'SX'I- SV'S-IV)'(U'SX'I-sv's

— Iv) 'people' χ'ΐ— sv's— ιν) '(ΐ 入' χ'ΐ— sv's— iv) 'people' εχ'ΐ— sv's— iv) '(u'sx'i— sv's— ΐ

V) 'people' SX'I—SV'S—IV) '(I people' SX'I—SV'S—IV) 'enter' ΐΧ'ΐ—SV'S—ΐν) '(ΐΛ'ΐΧ'ΐ—SV'S—IV) [ 8Z00]

'(Ζλ' ΖΧΊ-ΖΥΖ-ΐνΥ (Ιλ 'ΖΧΊ-ΖΥΖ-ΐνΥ (Ζλ'ζΖ

ΧΊ-Ζν'Ζ-ΐνΥ (Ιλ'ζΖΧΊ-ΖΥΖ-ΐνΥ (Ζλ'ΖΖΧΊ-ΖΥΖ-ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥΖ-ΐνΥ (Ζλ 'ΙΖΧΊ-ΖΥΖ-ΐνΥ (ΙλΊΖΧΊ-ΖΥΖ-ΐνΥ (Ζλ'ΟΖΧΊ- ΖΥΖ-ΐνΥ (ΙλΌΖΧΊ-Ζν'Ζ-ΐνΥ (Ζ input '6IX'Z-SV'S-IV)' (I input '6IX'Z-SV'S-IV)' input '8IX'Z-SV'S-IV)' (U '8IX'Z-SV'S- IV)' (ΖλΊΐΧΊ-ΖΥΖ-ΐνΥ (ΙλΊΐΧΊ-ΖΥΖ-ΐνΥ (Ζλ'91ΧΊ-Ζν'Ζ-ΐνΥ (Ιλ'91ΧΊ-Ζν'Ζ-1

V) '(2A'eTX'Z-2V'2-TV)' ('eTX'Z-2V'2-TV)' (2A ^ TX'Z-2V'2-TV) '(^ TX'Z- 2V'2

-ΐνΥ (Ζλ'ζΙΧΊ-ΖΥΖ-ΐνΥ (Ιλ'ζΙΧΊ-ΖΥΖ-ΐνΥ (Ζλ'ΖΙΧΊ-ΖΥΖ-ΐνΥ (Ιλ'ΖΙΧΊ-Ζν

'Ζ-ΐνΥ (ΖλΊ ΐΧΊ-ΖΥΖ-ΐνΥ (ΙλΊ ΐΧΊ-ΖΥΖ-ΐνΥ (Ζλ'01ΧΊ-ΖΥΖ-ΐνΥ (ΙλΌΐΧΊ- SV'S—IV)' person '6X'Z—SV'S— ΐν)' (ΐ 人 '6X 'Z—SV'S—IV)' people '8X'Z—SV'S— ΐν)' (ΐ 入 '

'S—IV)' People 'ZX'Z—SV'S—IV)' (I input 'ZX'Z—SV'S—IV)' People '9X'Z—SV'S—IV)' (I Plot '9X'Z—SV'S — IV) 'People' SX'Z—SV'S—IV) '(I input' SX'Z—SV'S—IV) 'People' X'Z—SV'S—IV) '(U' X'Z—SV'S— ΐ

v) 'people ιν)' (ΐ 人 iv) 'people' sx'z—sv's—ιν) '(ΐ 人' sx'z—sv's—iv)

ΖλΊχΊ-ΖΥΖ-ΐνΥ (ΙλΊχΊ-ΖΥΖ-ΐνΥ (Ζλ 'ΖΧ'9-ΖΥΖ-ΐνΥ (Ιλ' ΖΧ'9-ΖΥΖ-ΐν)

'(2A'S2X'9-2V'2-TV)' ('S2X'9-2V'2-TV)' (2A'22X'9-2V'2-TV) '(' 22X'9-2V ' 2-T

νΥ (ΖλΊΖΧ'9-ΖΥΖ-ΐνΥ (ΙλΊΖΧ'9-ΖΥΖ-ΐνΥ (Ζλ'0ΖΧ'9-Ζν'Ζ-ΐν)) ΙλΌΖΧ'9-Ζν'Ζ

-TV) '(2A'6TX'9-2V'2-TV)' ('6TX'9-2V'2-TV)' (2A'8TX'9-2V'2-TV) '(' 8TX'9 -2V

'2-TV)' (2A'ZTX'9-2V'2-TV) '(TA'ZTX'9-2V'2-TV)' (2A'9TX'9-2V'2-TV) '(' 9TX'9- ΖΥΖ-ΐνΥ (Ζλ '1Χ'9-ΖΥΖ-ΐνΥ (Ιλ' 1Χ'9-ΖΥΖ-ΐνΥ (Ζλ'ηΧ'9-ΖΥΖ-ΐνΥ (Ιλ'ηΧ '9- SV'S-IV)') 'ειχ'9- sv's- ιν)' (ΐ 入 'ειχ'9- SV'S- IV)' Enter 'SIX'9- SV'S- IV)' (U'SI

X'9—SV'S—IV) 'Input' ΐ ΐΧ'9—SV'S—IV) '(I Input' ΐ ΐΧ'9—SV'S—IV) 'Input' ΟΐΧ'9—SV'S—IV) '(U' ΟΐΧ '9—SV'S—IV)' people '6X'9—SV'S—IV)' (I people '6X'9—SV'S—IV)' people '8X'9—SV'S—IV)' (U'8

X'9—SV'S—IV) 'person' ZX'9—SV'S—IV) '(I person' ZX'9—SV'S—IV) 'person' 9X'9—SV'S—IV) '(U'9X' 9 — SV'S—IV) 'People' SX'9—SV'S—IV) '(I People' SX'9—SV'S—IV) 'People' X'9—SV'S—IV) '(U' X'9—

SV'S—IV) 'person' SX'9—SV'S—IV) '(I person' SX'9—SV'S—IV) 'person' SX'9—SV'S—IV) '(I entered SX'9—

'Ζ-ΐνΥ (ΖλΊΧ'9-ΖΥΖ-ΐνΥ (Ιλ'ΙΧ'9-ΖΥΖ-ΐνΥ (Ζλ' ΖΧ '-ΖΥΖ-ΐνΥ (Ιλ' ΖΧ '-Ζν

C69CZC / 900Zdf / X3d 88 6C8C90 / .00Z OAV ε-2ν'ε-ΐν) '(ΐλ ^ ΐχ'ε-2ν'ε-ΐν)'(2λ'εΐχ'ε-2ν'ε-ΐν)'(ΐλ'εΐχ'ε-2ν'ε-ΐν)'(2λ'2ΐχ'ε-2ν'ε-ΐν)'(ΐλ'2ΐχ'ε-2ν'ε-ΐν)'(2λ'πχ'ε-2ν'ε-ΐν)'(ΐλ'πχ'ε-2ν'ε-ΐν)'(2λ'οιχ'ε-sv's- ιν) '(ΐ 入'οιχ'ε-sv's- ιν) 'person'6χ'ε-sv's- iv) '(u'6x's- sv's -ιν) 'Enter'8χ'ε-2ν'ε-ΐν)'(ΐλ'8χ'ε-2ν'ε-ΐν)'(2λ'ζχ'ε-2ν'ε-ΐν)'(ΐλ'ζχ'ε-2ν'ε-ΐν)'(2λ'9χ'ε-2ν'ε-ΐν)'(ΐλ'9χ'ε-2ν'ε-ΐν)'(2λ'3χ'ε-2ν'ε-ΐν)'(ΐλ'3χ'ε-2ν'ε-ΐν)' (2λ ^ χ'ε -2ν'ε-ΐν) '(ΐλ ^ χ'ε-2ν'ε-ΐν)'(2λ'εχ'ε-2ν'ε-ΐν)'(ΐλ'εχ'ε-2ν'ε-ΐν)'(2λ'2χ'ε-2ν'ε- ιν) '(ΐ 人'sx's-sv's- ΐν) 'person' ιχ 'ε- sv's- ιν)' (ΐ 人 'ιχ'ε- sv's- ΐν)' people 'wx's-

'S-TV)' (TA '^ X'2-2V'S-TV)' (2A'S2X'2-2V'S-TV) '(' S2X'2-2V'S-TV) '(2A'22X'2-2V'S -TV) '(TA'22X'2-2V'S-TV)' (2A'T2X'2-2V'S-TV) '(' T2X'2-2V'S-TV) '(2AO2X' 2-2V'S-TV) '( TAO2X'2-2V'S-TV) '(2A'6TX'2-2V'S-TV)' ('6TX'2-2V'S-TV)' (2A'8T X'2-2V'S-TV) '(TA'8TX' 2-2V'S-TV) '(2A'ZTX'2-2V'S-TV)' ('ZTX'2-2V'S-TV)' (2A '9TX'2-2V'S-TV)' ('9TX'2-2V'S- TV) '(2A'eTX'2-2V'S-TV)' ('eTX'2-2V'S-TV)' (2 input 'wx's-sv's-ιν)' (ΐ 入 'WX'S-SV'S-IV) SIX'S-SV'S-IV) '(U'SIX'S-SV'S-IV)' (2A'2TX'2-2V'S-TV) '(' 2TX'2-2V'S-TV) '(2A'nX'2-2V'S-TV ) '(' nX'2-2V'S-TV) '(2AOTX'2-2V'S-TV)' (OTX'2-2V'S-TV) '(2A'6X'2-2V'S-TV)' ('6X'2 -2V'S-TV) '(2A'8X'2-2V'S-TV)' (TA'8X'2-2V'S-TV) '(2A'ZX'2-2V'S-TV)' ('ZX'2-2V'S- TV) '(2A'9X'2-2V'S-TV)' ('9X'2-2V'S-TV)' (2A'eX'2-2V'S-TV) '(' eX'2-2V'S-TV) '( 2 entering ^ X'S— SV'S— ιν) '(ΐ 人' X'S— SV'S— IV) 'person' SX'S— SV'S— IV) '(U'SX'S— SV'S— IV)' entering '2X'2-2V'S-TV) '(TA'2X'2-2V'S-TV)' (2A'TX'2-2V'S-TV) '(' TX'2-2V'S-TV) '(2A' ^ χ'ΐ-2ν'ε-ΐν) '(ΐλ' ^ χ'ΐ-2ν'ε-ΐν) '(2λ'ε2χ'ΐ-2ν'ε-ΐν ) '(ΐλ'ε2χ'ΐ-2ν'ε-ΐν)' (2λ '

ΖΖΧΊ-ΖΥζ-ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥζ-ΐνΥ (ΖλΊΖΧΊ-ΖΥζ-ΐνΥ (ΙλΊΖΧΊ-Ζν'ζ-ΐν))

AO2X'T-2V'S-TV) '(TAO2X'T-2V'S-TV)' (2A'6TX'T-2V'S-TV) '(' 6TX'T-2V'S-TV) '(2A'8TX'T-2V'S -TV) '(' 8TX'T-2V'S-TV) '(2A'ZTX'T-2V'S-TV)' ('ZTX'T-2V'S-TV)' (2A'9TX'T-2V'S-TV) ' ('9TX'T-2V'S-TV)' (2A'ETX'T-2V'S-TV) '(' ETX'T-2V'S-TV) '(2A ^ TX'T-2V'S-TV)' (^ TX ' T-2V'S-TV) '(2A'STX'T-2V'S-TV)' ('STX'T-2V' ε-ΐν) '(2λ'2ΐχ'ΐ-2ν'ε-ΐν)' (ΐλ'2ΐχ 'ΐ-2ν'ε-ΐν)' (2λ'πχ'ΐ-2ν'ε-ΐν) '(ΐλ'πχ'ΐ-

SV'S—IV) 'Enter' ΟΐΧ'ΐ—SV'S—ΐν) '(ΐ 入' ΟΐΧ'ΐ—SV'S—IV) 'People' 6Χ'ΐ—SV'S—IV) '(U'6X'I—SV'S—IV ) 'People' 8Χ'ΐ—SV'S—IV) '(I people' 8Χ'ΐ—SV'S—IV) 'People' ΖΧ'ΐ—SV'S—IV) '(I input' ΖΧ'ΐ—

C69CZC / 900Zdf / X3d 68 6C8C90 / .00Z OAV 2V'S-TV) '(2A'T2X'e-2V'S-TV)'(TA'T2X'e-2V'S-TV)'(2AO2X'e-2V'S-TV)' (O2X 'e-2V'S-TV)' ( 2A'6TX'e-2V'S-TV) '(TA'6TX'e-2V'S-TV)'(2A'8TX'e-2V'S-TV)'(' 8T X'e-2V'S-TV) '(2A'ZTX'e-2V'S-TV)'(TA'ZTX'e-2V'S-TV)'(2A'9TX'e-2V'S-TV)'('9TX'e-2V'S-TV)'(2A'eTX'e-2V'S-TV)'('eTX'e-2V'S-TV)'(2A ^ TX'e-2V'S-TV)' (T input 'WX'S-SV'S-IV)' input 'SIX'S-sv's-ιν)' ( (Iritsu 'SIX'S-SV'S-IV)' Iri 'SIX'S-SV'S-IV)

'(ΐλ'2ΐχ'3-2ν'ε-ΐν)' (2λ'πχ'3-2ν'ε-ΐν) '(ΐλ'πχ'3-2ν'ε-ΐν)' (2λΌΐχ'3-2ν ' ε-ΐ

V) '(I person'OIX'S-SV'S-IV)'person'6X'S-SV'S-IV)'(Iperson'6X'S-SV'S-IV)'person'8X'S-SV'S-IV)'('8X'e-2V'S -TV) '(2A'ZX'e-2V'S-TV)'('ZX'e-2V'S-TV)'(2A'9X'S-2V'S-TV)'(ΐ入'9X'S-SV'S-IV)'people'SX'S-SV'S-IV)'(Ipeople'SX'S-SV'S-IV)'people'X'S-SV'S-IV)'(I input ^ X'e-2V'S-TV)'(2A'SX'e-2V'S-TV ) '(TA'SX'e-2V'S-TV)'(2A'2X'e-2V'S-TV)'(' 2 Χ '-Ζν'ζ-ΐνΥ (ΖλΊΧ' -ΖΥζ-ΐνΥ (Ιλ'ΙΧ '- ΖΥζ-ΐνΥ (Ζλ 'ΖΧ' -ΖΥζ-ΐνΥ (Ιλ 'Ζ Χ'-Ζν'ζ-ΐνΥ(Ζλ'ζΖΧ'-ΖΥζ-ΐνΥ(Ιλ'ζΖΧ' -ΖΥζ-ΐνΥ (Ζλ'ΖΖΧ '-ΖΥζ- ΐνΥ (Ιλ '

λ'0ΖΧ '-ΖΥζ-ΐνΥ (Ζλ'61Χ' -ΖΥζ-ΐνΥ (Ιλ'61Χ '-ΖΥζ-ΐνΥ (Ζλ'81Χ' -ΖΥζ-ΐν) '(' 8TX ^ -2V'S-TV) '(2A' ZTX ^ -2V'S-TV) '(' ZTX ^ -2V'S-TV) '(2A'9TX ^ -2V'S-T ν) ΐλ'9ΐχ' -ζΥζ-ιν) ζλ 'ΐχ' -ζΥζ-ιν) ΐλ 'ΐχ '-ζν'ζ-ιν) ζλ'ηχ' -ζν'ζ -ιν) ΐλ'ηχ '-ζΥζ-ιν) ζλ'ζΐχ' -ζΥζ-ινΥ (ΐλ'ζΐχ '-ζΥζ-ινΥ (ζλ'ζιχ' -ζν 'ε-ΐν)' (ΐλ'2ΐχ ^ -2ν'ε-ΐν) '(2λ'πχ ^ -2ν'ε-ΐν)' (ΐλ'πχ ^ -2ν'ε-ΐν) '(2λΌΐχ ^ -

SV'S—ΐν) '(ΐ 入' ΟΐΧ'to SV'S—IV) 'person' 6X'to SV'S—IV) '(U'6X'to SV'S—IV)' person '8X'—S ν'ε—IV) '(I input' 8X 'G SV'S—IV)' people G SV'S—IV) '(U'ZX'G SV'S—IV)' people '9X'G sv' S—IV) '(I I'9X'G SV'S—IV) 'people' SX'to SV'S—IV) '(U'SX'to SV'S—IV)' people 'χ'to sv's—ιν)' (ΐ 入 'χ'to sv's—iv)' people ' εχ 'and sv's— iv)' (u'sx 'and sv's— iv)' people 'sx' and sv's— iv) '(ΐ 入' sx 'and sv's- iv)' enter 'ΪΧ' and sv's- ιν) '(ΐ 入' ΪΧ 'sv's- iv)' (in 'χ'ε- sv's- iv)' (ΐλ '^ χ'ε-2ν'ε-ΐν)' (2λ'ε2χ'ε-2ν'ε- ΐν) '(ΐλ'ε2χ'ε-2ν'ε-ΐν)' (2λ'22χ'ε-2ν'ε-ΐ ν) '(ΐλ'22χ'ε-2ν'ε-ΐν)' (2λ'ΐ2χ 'ε-2ν'ε-ΐν)' (ΐλ'ΐ2χ'ε-2ν'ε-ΐν) '(2λΌ2χ'ε-2ν'ε -ΐν)' (ΐλΌ2χ'ε-2ν'ε-ΐν) '(2λ '6ΐχ'ε-2ν'ε-ΐν)' (ΐλ'6ΐχ'ε-2ν'ε-ΐν) '(2λ'8ΐχ'ε-2ν' ε-ΐν) '(ΐλ'8ΐχ'ε-2ν'ε -ΐν) '(2λ'ζΐχ'ε-2ν'ε-ΐν)' (ΐλ'ζΐχ'ε-2ν'ε-ΐν) '(2λ'9ΐχ'ε-2ν'ε-ΐν)' (ΐλ'9ΐχ 'ε-2ν'ε-ΐν)' (2 λ'3ΐχ'ε-2ν'ε-ΐν) '(ΐλ'3ΐχ'ε-2ν'ε-ΐν)' (2λ ^ ΐχ '

C69CZC / 900Zdf / X3d 06 6C8C90 / .00Z OAV — Iv) 'People'χ'ΐ—sv't ιν) '(ΐ 入'χ'ΐ—sv't iv) 'People'εχ'ΐ— sv ''ΐ

V) 'People' SX'I—SV'G IV) '(I people' SX'I—SV'G IV) 'Enter' ΐΧ'ΐ—SV'G ΐν) '(ΐΛ'ΐΧ'ΐ—SV' G IV) [6Z00]

'(Zk' Z 'L-ZW'Z- \ W)' {\ k 'Z L-ZW'Z- \ W)' {Zk'ZZ

ΧΊ-Ζν'ζ-ΐνΥ (Ιλ'ζΖΧΊ-ΖΥζ-ΐνΥ (Ζλ'ΖΖΧΊ-ΖΥζ-ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥζ-ΐνΥ (Ζλ 'ΙΖΧΊ-ΖΥζ-ΐνΥ (ΙλΊΖΧΊ-ΖΥζ-ΐνΥ (Ζλ'ΟΖΧΊ- ΖΥζ-ΐνΥ (ΙλΌΖΧΊ-Ζν'ζ-ΐνΥ (Ζ 入 '6ix'z-sv's- ιν)' (ΐ 入 '6ix'z-sv's-iv)' Enter '8ix'z-sv's-iv)' (u '8ix'z-sv's-iv)' (2A'ZTX'Z-2V'S-TV) '(' ZTX'Z-2V'S-TV) '(2A'9TX'Z-2V'S-TV)' ('9TX'Z -2V'S-T

V) '(2A'ETX'Z-2V'S-TV)' ('ETX'Z-2V'S-TV)' (2A ^ TX'Z-2V'S-TV) '(^ TX'Z-2V'S

-TV) '(2A'STX'Z-2V'S-TV)' ('STX'Z-2V'S-TV)' (2A'2TX'Z-2V'S-TV) '(' 2TX'Z-2V

'ε-ΐν)' (2λ'πχ'ζ-2ν'ε-ΐν) '(ΐλ'πχ'ζ-2ν'ε-ΐν)' (2λΌΐχ'ζ-2ν'ε-ΐν) '(ΐλΌΐχ'ζ -

SV'S—IV) 'people' 6X'Z—SV'S—ΐν) '(ΐ 人' 6X'Z—SV'S—IV) 'people' 8X'Z—SV'S—ΐν) '(ΐ 入')

'ε—IV)' person 'ZX'Z—SV'S—IV)' (I input 'ZX'Z—SV'S—IV)' person '9X'Z—SV'S—IV)' (I person '9X'Z—SV'S — IV) 'People' SX'Z—SV'S—IV) '(I input' SX'Z—SV'S—IV) 'People' X'Z—SV'S—IV) '(I People' X'Z—SV'S—ΐ ν) 'people' εχ'ζ—ζν'ε— ιν) '(ΐ 人' εχ'ζ—ζν'ε— ΐν) 'people' sx'z—sv's— ιν) '(ΐ 人' sx'z— sv's— iv)

'(2A'TX'Z-2V'S-TV)' (TA'TX'Z-2V'S-TV) '(2A' ^ X'9-2V'S-TV) '(' ^ X'9-2V'S-TV) ' (2A'S2X'9-2V'S-TV) '(' S2X'9-2V'S-TV) '(2A'22X'9-2V'S-TV)' ('22X'9-2V'S-T ν)' (2λ ' ΐ2Χ'9-2ν'ε-ΐν) '(ΐλ'ΐ2Χ'9-2ν'ε-ΐν)' (2λ'02Χ'9-2ν'ε-ΐν) '(ΐλΌ2Χ'9-2ν'ε

-TV) '(2A'6TX'9-2V'S-TV)' ('6TX'9-2V'S-TV)' (2A'8TX'9-2V'S-TV) '(' 8TX'9-2V

'S-TV)' (2A'ZTX'9-2V'S-TV) '(TA'ZTX'9-2V'S-TV)' (2A'9TX'9-2V'S-TV) '(' 9TX'9-2V'S- TV) '(2A'eTX'9-2V'S-TV)' (TA'eTX'9-2V'S-TV) '(2A ^ TX'9-2V'S-TV)' (^ TX '9- SV'S-IV)' Entry 'ειχ'9- sv's- ιν)' (ΐEntry 'ειχ'9- SV'S-IV)' Entry 'SIX'9- SV'S-IV)' (U'SI χ'9-2ν'ε-ΐν) ' (2λ'πχ'9-2ν'ε-ΐν) '(ΐλ'πχ'9-2ν'ε-ΐν)' (2λΌΐχ'9-2ν'ε-ΐν) '(ΐλ'

ΟΐΧ'9—SV'S—IV) 'people' 6X'9—SV'S—IV) '(I people 6X'9—SV'S—IV)' people '8X'9—SV'S—IV)' (U'8

'S-TV)' (2A'TX'9-2V'S-TV) '(' TX'9-2V'S-TV) '(2A' ^ X'e-2V'S-TV) '(' ^ X'e-2V

'ζ-ΐνΥ (Ζλ'ζΖΧ' -ΖΥζ-ΐνΥ (Ιλ'ζΖΧ '-ΖΥζ-ΐνΥ (Ζλ'ΖΖΧ' -ΖΥζ-ΐνΥ (Ιλ'ΖΖΧ '-

C69CZC / 900Zdf / X3d 1-6 6C8C90 / .00Z OAV Χ'ζ-Ζν '-ΐνΥ (Ιλ'ΖΙΧ'ζ-ΖΥ -ΐνΥ (Ζλ'ΠΧ'ζ-ΖΥ -ΐνΥ (Ιλ'ΠΧ'ζ-ΖΥ -ΐνΥ (Ζλ'οιχ'ε—sv'— ιν) '(ΐ 入'οιχ'ε—sv'— ΐν) 'People'6χ'ε—sv'— iv) '(u'6x's— sv'— ΐν)' Enter '8χ'ε— sv'(ΐΛ'8χ'ε—sv't iv) 'people'ζχ'ε—sv'to ιν) '(ΐ 人'ζχ'ε—sv'to iv) 'enter' 9x 'ε—sv'to ιν) '(ΐ 人'9χ'ε—sv't ΐν) 'people'sx's—sv'to iv) '(u'sx's—sv'to ΐν)' people ^ χ'ε — sv'—iv) '(i People 'χ'ε— sv' ΐν) 'People'εχ'ε— sv 'ιν)'(ΐΛ'εχ'ε— sv 'ト ν)' People 'sx's— s ν' iv) '(u 'sx's- sv' and ΐν) 'Enter'ιχ'ε-sv'to ιν) '(ΐΛ'ΐχ'ε- sv'to ΐν)' Enter 'wx's-

'-ΐνΥ (Ιλ' ΖΧ'Ζ-ΖΥ -ΐνΥ (Ζλ'ζΖΧ'Ζ-ΖΥ -ΐνΥ (Ιλ'ζΖΧ'Ζ-ΖΥ -ΐνΥ (Ζλ'ΖΖΧ'Ζ- ΖΥ -ΐνΥ (Ιλ'ΖΖΧ'Ζ- ΖΥ -ΐνΥ (ΖλΊΖΧ'Ζ-ΖΥ -ΐνΥ (ΙλΊΖΧ'Ζ-ΖΥ -ΐνΥ (Ζλ'ΟΖΧ 'Ζ-Ζν' -ΐνΥ (Ιλ'0ΖΧ'Ζ-ΖΥ -ΐνΥ (Ζλ'61Χ'Ζ-ΖΥ -ΐνΥ (Ιλ'61Χ'Ζ-ΖΥ -ΐνΥ (Ζλ'81 Χ'Ζ-Ζν '-ΐνΥ (Ιλ'81Χ'Ζ-ΖΥ -ΐνΥ (ΖλΊΐΧ'Ζ-ΖΥ -ΐνΥ (ΙλΊΐΧ'Ζ-ΖΥ -ΐνΥ (Ζλ '91 Χ'Ζ-ΖΥ -ΐνΥ (Ιλ'91Χ'Ζ-ΖΥ -ΐνΥ (Ζλ '1Χ'Ζ-ΖΥ -ΐνΥ (Ιλ' 1Χ'Ζ-Ζν '-ΐν) Ζ In' WX'S—SV'to ιν) '(ΐ 入' WX'S—SV'to IV) '(' SIX'S—SV'to IV) '(U'SIX'S—SV'to IV)'

'(ζλ'ζιχ'ζ-ζΥ -ινΥ (ΐλ'ζιχ'ζ-ζΥ -ινΥ (ζλ'πχ'ζ-ζν' -ινΥ (ΐλ'πχ'ζ-ζν '-ι

V) 'Enter' OIX'S—SV'd IV) '(U'OIX'S—SV'd IV)' People '6X'S—SV'd IV)' (U'6X'S—

V) 'person' 8X'S—SV'd IV) '(I person' 8X'S—SV'd IV) 'person' ZX'S—SV'd IV) '(U'ZX'S—SV'd IV)

'Enter' 9X'S—SV'G IV) '(I'9X'S—SV'G IV)' People 'SX'S—SV'G IV)' (U'SX'S—SV'G IV) 'Enter ^ X'S—SV' (IV) '(I' X'S-SV'V) 'Person' SX'S-SV'V) '(U'SX'S-SV'V)

SX'S-SV'G IV) '(I's SX'S-SV'G IV)' Enter 'IX'S-SV'G IV)' (U'IX'S-SV'G IV) 'Enter' w

ΧΊ-Ζν '-ΐνΥ (Ιλ' ΖΧΊ-ΖΥ -ΐνΥ (Ζλ'ζΖΧΊ-ΖΥ -ΐνΥ (Ιλ'ζΖΧΊ-ΖΥ -ΐνΥ (Ζλ '

ΖΖΧΊ-ΖΥ -ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥ -ΐνΥ (ΖλΊΖΧΊ-ΖΥ -ΐνΥ (ΙλΊΖΧΊ-Ζν '-ΐν) Ζ λ'0ΖΧΊ-ΖΥ -ΐνΥ (Ιλ'0ΖΧΊ-ΖΥ -ΐνΥ (Ζλ'61ΧΊ-ΖΥ- ΐνΥ (Ιλ'61ΧΊ-ΖΥ -ΐν)

'(2A'8TX'T-2V ^ -TV)' ('8TX'T-2V ^ -TV)' (2A'ZTX'T-2V ^ -TV) '(' ZTX'T-2V ^ -T νΥ (Ζλ'91Χ'1-ΖΥ -ΐνΥ (Ιλ'91Χ'1-ΖΥ -ΐνΥ (Ζλ '1Χ'1-Ζν' -ΐν) Ιλ '1Χ'1-Ζν'

-ιν) ζλ'ηχ'ι-ζν -ινΥ (ΐλ'ηχ'ι-ζΥ -ινΥ (ζλ'ζΐχ'ι-ζΥ -ινΥ (ΐλ'ζΐχ'ι-ζν

'-ΐνΥ (Ζλ'ΖΙΧΊ-ΖΥ -ΐνΥ (Ιλ'ΖΙΧΊ-ΖΥ -ΐνΥ (Ζλ'ΠΧΊ-ΖΥ -ΐνΥ (Ιλ'ΠΧ'1- SV'—IV)' Enter 'ΟΐΧ'ΐ— SV'— ΐν ) '(ΐ 入' ΟΐΧ'ΐ—SV'—IV) 'People' 6Χ'ΐ—SV'—IV) '(U'6X'I—SV'V)' People '8Χ'ΐ—SV' IV) '(U'8X'I—SV'G)' People 'ΖΧ'ΐ—SV'G IV)' (I input 'ΖΧ'ΐ—'G IV)' People '9Χ'ΐ—SV'G IV) '(I input' 9 Χ 'ΐ-SV' G IV) 'people' SX'I-SV 'G IV)' (U'SX'I-sv '

C69CZC / 900Zdf / X3d 36 6C8C90 / .00Z OAV -Ζν '-ΐνΥ (Ζλ'61Χ' -ΖΥ -ΐνΥ (Ιλ'61Χ '-ΖΥ -ΐνΥ (Ζλ'81Χ' -ΖΥ -ΐνΥ (Ιλ'81 X'e-2V ^ -TV) '(2A'ZTX 'e-2V ^ -TV)'(TA'ZTX'e-2V ^ -TV) '(2A'9TX'S-2V ^ -TV)'('91Χ' -ΖΥ -ΐν) Ζλ '1Χ' -ΖΥ -ΐνΥ (Ιλ '1Χ' -ΖΥ -ΐνΥ (Ζλ'ηΧ '-Ζν' -ΐν) 1 input 'WX'S— SV' — IV) 'input'SIX'S— SV '— ιν)' (ΐ input 'SIX'S— SV' — IV) 'Enter'SIX'S—SV'—IV)'(Ιλ'ΖΙΧ'-ΖΥ -ΐνΥ (Ζλ'ΠΧ' -ΖΥ -ΐνΥ (Ιλ'ΠΧ '-Ζν' -ΐν) Ζλ'01Χ '-Ζν'- 1 V) '(I input'OIX'S — SV 'G IV)' people '6X'S — SV' G IV) '(U'6X'S — SV' G IV) 'people'8X'S — SV 'G IV)' (Purchase '8X'S-SV' G IV) 'People'ZX'S-SV'GIV)' (I ''ZX'S-SV'GIV)' People '9X'S-SV' G IV) '(ΐ 入'9X'S-SV'G IV) 'people'SX'S—SV's IV) '(U'SX'S—SV's IV)' people 'X'S—SV's IV)' (I 'X'S—SV's IV)' people 'sx's— sv'to ιν) '(ΐ 人'SX'S—SV'to IV) 'people'SX'S—SV'to IV) '(U'S Χ' -Ζν '-ΐνΥ (Ζλ'ΙΧ' -ΖΥ -ΐνΥ (Ιλ'ΙΧ '-ΖΥ -ΐνΥ (Ζλ' ΖΧ '-ΖΥ -ΐνΥ (Ιλ' Ζ X ^ -2V ^ -TV) '(2A'S2X ^ -2V ^ -TV)'(TA'S2X ^ -2V ^ -TV) '(2A'22X ^ -2V ^ -TV)'('22X ^ -2V ^ -TV) '(2A'T2X ^ -2V ^ -TV)'('T2X ^ -2V ^ -TV)'(2A'02X ^ -2V ^ -TV) '(T AO2X ^ -2V ^- TV) '(2A'6TX ^ -2V ^ -TV)'(TA'6TX ^ -2V ^ -TV) '(2A'8TX ^ -2V ^ -TV) ΐλ'8ΐχ' -ζΥ -ιν) ζλ'ιιχ '-ζΥ -ινΥ (ΐλ'ιιχ' -ζν '-ιν) ζλ'9ΐχ' -ζν '-ι ν) ΐλ'9ΐχ' -ζΥ -ιν) ζλ 'ΐχ' -ζΥ -ιν) ΐλ 'ΐχ'- ζν '-ιν) ζλ'ηχ' -ζν '-ιν) ΐλ'ηχ' -ζν -ιν) ζλ'ζΐχ '-ζΥ -ιν) ΐλ'ζΐχ' -ζΥ -ινΥ (ζλ'ζιχ '-ζν

'-ΐν) Ιλ'ΖΙΧ' -ΖΥ -ΐνΥ (Ζλ'ΠΧ '-ΖΥ -ΐνΥ (Ιλ'ΠΧ' -ΖΥ -ΐνΥ (Ζλ'ΟΙΧ '-SV'-IV)' (I input 'ΟΐΧ' 'G IV)' Human '6X'G SV'G IV)' (U'6X'G SV'G IV) 'Human' 8X '—S ν'—ΐν)' (ΐ 入 '8X'G SV'G IV) 'Human SV' G IV) '(U'ZX'H SV'H IV)' Human '9X'H SV' ― IV) '(I input' 9X'H SV'G IV) 'Human' SX 'To SV' To IV) '(U'SX' To SV 'To IV)' People 'Χ'To SV' ιν) '(ΐ 入' χ'To sv'To IV) 'People' εχ 'To sv' Iv) '(u'sx'to sv'to IV)' people 'sx'to sv'to IV)' (ΐ 入 'sx'to sv'to IV)' enter 'ΪΧ'to sv'to ιν) '(ΐ 入' ΪΧ 'and sv' and IV) 'Input' χ'ε—sv 'and IV)

'(Ιλ' ΖΧ'ζ-ΖΥ -ΐνΥ (Ζλ'ζΖΧ'ζ-ΖΥ -ΐνΥ (Ιλ'ζΖΧ'ζ-Ζν '-ΐνΥ (Ζλ'ΖΖΧ'ζ-Ζν' -1 vydA'zzx'z-zYf -wyizA'izx'z-zYf-wydA'izx'z-zv'f-wyizA'ozx'z-zv'f -TV) '(O2X'S-2V ^ -TV)' (2A'6TX'S-2V ^ -TV ) '(' 6TX'S-2V ^ -TV) '(2A'8TX'S-2V ^ -TV)' (TA'8TX'S-2V ^ -TV) '(2A'ZTX'S-2V ^ -TV)' ('ZTX'S-2V ^ -TV) '(2A'9TX'S-

ΖΥ -ΐνΥ (Ιλ'91Χ'ζ-ΖΥ -ΐνΥ (Ζλ '1Χ'ζ-ΖΥ -ΐνΥ (Ιλ' 1Χ'ζ-ΖΥ -ΐνΥ (Ζλ'ηΧ 'ε- sv' ιν) '(ΐ 入' wx's -sv 'ιν)' Enter 'ειχ'ε- sv' ΐν) '(ΐΛ'ειχ'ε- sv' ιν) 'Enter' si

C69CZC / 900Zdf / X3d 86 6C8C90 / .00Z OAV V) 'people'SX'I—SV'S—IV)'(Ipeople'SX'I—SV'S—IV)'enter'ΐΧ'ΐ—SV'S—ΐν)'(ΐΛ'ΐΧ'ΐ—SV'S—IV) [ 0800]

'(zA'fzx'L-zYf-wydA'fzx'L-zYf-wyizA'zz

ΧΊ-Ζν '-ΐνΥ (Ιλ'ζΖΧΊ-ΖΥ -ΐνΥ (Ζλ'ΖΖΧΊ-ΖΥ -ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥ -ΐνΥ (Ζλ' izx'L-zYf-wydA'izx'L-zYf-wyizA'ozx 'L-zYf-wydA' ozx'L-zv'f-wyiz Entry '6IX'Z—SV'G IV)' (I Entry'6IX'Z—SV'G IV) 'Entry' 8IX'Z—SV ' (IV) '(U'8IX'Z—SV'G)' (2A'ZTX'Z-2V ^ -TV) '(' ZTX'Z-2V ^ -TV) '(2A'9TX'Z-2V ^ -TV) '(' 9TX'Z-2V ^ -T

V) '(2A'eTX'Z-2V ^ -TV)' ('eTX'Z-2V ^ -TV)' (2A ^ TX'Z-2V ^ -TV) '(^ TX'Z-2V ^

-wyizA'zix'L-zYf-wydA'zix'L-zYf-wyizA'zix'L-zYf-wydA'zix'L-zv

^ -TV) '(2A'nX'Z-2V ^ -TV)' (TA'nX'Z-2V ^ -TV) '(2AOTX'Z-2V ^ -TV)' (OTX'Z-SV ' IV) 'People' IV) '(U'6X'Z—SV'G IV)' People 'IV)' (I entered)

'G IV)' People 'ZX'Z-SV'G IV)' (I 'ZX'Z-SV'G IV)' People 'G IV)' (U'9X'Z-SV '— IV)' People 'SX'Z—SV'G IV)' (I 'SX'Z-SV'G IV)' People 'X'Z-SV'G IV)' (U 'X'Z-SV' ΐ ν) 'People ιν)' (People ΐν) 'People' sx'z—sv't iv) '(u'sx'z—sv'G)

Ζλ'ΙΧ'1-ΖΥ -ΐνΥ (Ιλ'ΙΧ'1-ΖΥ -ΐνΥ (Ζλ 'ΖΧ'9-ΖΥ -ΐνΥ (Ιλ' ΖΧ'9-ΖΥ -ΐν) '(Ζλ'ζΖΧ'9-ΖΥ- ΐνΥ (Ιλ'ζΖΧ'9-ΖΥ -ΐνΥ (Ζλ'ΖΖΧ'9-Ζν '-ΐν) Ιλ'ΖΖΧ'9-Ζν' -1 νΥ (ΖλΊΖΧ'9-ΖΥ -ΐνΥ (ΙλΊΖΧ'9-ΖΥ -ΐνΥ (Ζλ'0ΖΧ'9-Ζν '-ΐν) ΙλΌΖΧ'9-Ζν'

-TV) '(2A'6TX'9-2V ^ -TV)' ('6TX'9-2V ^ -TV)' (2A'8TX'9-2V ^ -TV) '(' 8TX'9-2V

^ -TV) '(2A'ZTX'9-2V ^ -TV)' (TA'ZTX'9-2V ^ -TV) '(2A'9TX'9-2V ^ -TV)' ('9TX'9- ΖΥ -ΐνΥ (Ζλ '1Χ'9-ΖΥ -ΐνΥ (Ιλ' 1Χ'9-ΖΥ -ΐνΥ (Ζλ'ηΧ'9-ΖΥ -ΐνΥ (Ιλ'ηΧ '9— SV' — IV) 'input' ειχ ' 9— sv '— ιν)' (ΐ 入 'ειχ'9—SV' — IV) 'Enter' SIX'9—SV '— IV)' (U'SI

X'9-2V ^ -TV) '(2A'nX'9-2V ^ -TV)' (TA'nX'9-2V ^ -TV) '(2A'0TX'9-2V ^ -TV)' ( 'ΟΐΧ'9—SV'—IV)' people '6X'9—SV'—IV)' (I people '6X'9—SV'—IV)' people '8X'9—SV'—IV)' ( U'8

X'9—SV'd IV) 'person' ZX'9—SV'd IV) '(I person' ZX'9—SV'd IV) 'person' 9X'9—SV'd IV) '(U '9X' 9—SV'd IV) 'people' SX'9—SV'd IV) '(I people' SX'9—SV'd IV) 'people' X'9—SV'd IV) '( U 'X'9—

SV'd IV) 'People' εχ'9—SV'd IV) '(U'SX'9—SV'd IV)' People 'SX'9—SV'd IV)' (I entered 'SX'9 —

'-ΐν) Ζλ'ΙΧ'9-ΖΥ -ΐνΥ (Ιλ'ΙΧ'9-ΖΥ -ΐνΥ (Ζλ' ΖΧ '-ΖΥ -ΐνΥ (Ιλ' ΖΧ '-Ζν

'-ΐνΥ (Ζλ'ζΖΧ' -ΖΥ -ΐνΥ (Ιλ'ζΖΧ '-ΖΥ -ΐνΥ (Ζλ'ΖΖΧ' -ΖΥ -ΐνΥ (Ιλ'ΖΖΧ '-ΖΥ -ΐνΥ (ΖλΊΖΧ' -ΖΥ -ΐνΥ (ΙλΊΖΧ '- ΖΥ -ΐνΥ (Ζλ'0ΖΧ '-ΖΥ -ΐνΥ (Ιλ'0ΖΧ'

C69CZC / 900Zdf / X3d 6 6C8C90 / .00Z OAV ,,,,,,,,,,, Y2A15A23X9Y1A15A23X9Y2A15A23X10Y1A15A23X10 -------- ,,,,,,,,,, X6Y2A15A23X7Y1A15A23X7Y2A15A, XXYY-A-X ,,,,, 3X4Y2A15A23X5Y1A15A23X5Y2A15A23X6Y1A15A23 ------- I

,,,,,,,,,, 23X2Y2A15A23X3Y1A15A23X3Y2A15A23X4Y1A15A2I ------- I

,,,,,,,,,, A22X24Y2A15A23X1Y1A15A23X1Y2A15A23X2Y1A15AI ------- ,,,,,,,,,, 2X22Y2A15A22X23Y1A15A22X23Y2A15A22X24Y-A-I-X

,,,,,,,,,,, X20Y2A15A22X21Y1A15A22X21Y2A15A22X22Y1A15A2 ------- ,,,,,,,,, 18Y2A15A22X19Y1A15A22X19Y2A15A22X20Y1-A15A22 ----

,,,,,,,,,,, Y2A15A22X17Y1A15A22X17Y2A15A22X18Y1A15A22X ------- I

,,,,,, 2A15A22Y1A15A22Y2A15A22Y1A15A22 -------- ,,,,, (A15A22X13Y1A15A22X13Y2A15A22X14Y1A15A22X14YI ---, 11,15,22 ------- ,,,,,,,,,,, 15A22X9Y1A15A22X9Y2A15A22X10Y1A15A22X10Y2AI ------- ,,,,,,,,,, (A15A22X7Y1A15A22X7Y2A15A22X8X1-A-A- ,,,,,,,,, 2A15A22X5Y1A15A22X5Y2A15A22X6Y1A15A22X6Y2 -------- ,,,,,,,,,, 24Y2A15A22X1Y1A15A22X1Y2A15A22X2Y1A15-22-2-

,,,,,,,,,,, Y2A15A21X23Y1A15A21X23Y2A15A21X24Y1A15A21X ------- I

,,,,,,,,, 2A15A21X21Y1A15A21X21Y2A15A21X22Y1A15A21X22 -------- ,,,,,,,,, (A15A21X19Y1A15A21X19Y2A15A21X20Y-I, 15A21X20Y, ,,, 15A21X17Y1A15A21X17Y2A15A21X18Y1A15A21X18Y2I ------- ,,,,,,,,,, 5A21X15Y1A15A21X15Y2A15A21X16Y1A15A21X16Y2A ------, 21,

,,,,,,,,,,, 1X11Y1A15A21X11Y2A15A21X12Y1A15A21X12Y2A15

,,,,,,,,,,, 1X9Y1A15A21X9Y2A15A21X10Y1A15A21X10Y2A15A2 I ------- ,,,,,,,,,, A21X7Y1A15A21X7Y2A15A21X8Y-A, 15A21X8-, ,,,, 5A21X5Y1A15A21X5Y2A15A21X6Y1A15A21X6Y2A15 ------- I ,,,,,,,,,, 15A21X3Y2A15A21X3Y2A15A21X4Y1A15A21X4Y2A1I ----- x'e-2V'e-TV) '(2A'ZTX'e-2v'e-TV)'(TA'ZTX'e-2v'e-TV)'(2A'9ix'e-2v'e- TV) '('

9IX'S-SV'S-IV) 'People' SIX'S-SV'S-IV) '(U'SIX'S-SV'S-IV)' People 'WX'S-SV'S-IV)' (I 'WX'S-SV'S-IV)' Enter 'SIX'S- SV'S-IV) '(I input' SIX'S-SV'S-IV) 'Input' SIX'S-SV'S-IV)

'(' 2TX'e-2v'e-TV) '(2A'nx'e-2v'e-TV)' ('nx'e-2v'e-TV)' (2AOix'e-2v'e-T

V) '(I person' OIX'S-SV'S-IV) 'person' 6X'S-SV'S-IV) '(I person 6X'S-SV'S-IV)' person '8X'S-SV'S-IV

) '(' 8x'e-2v'e-TV) '(2A'zx'e-2v'e-TV)' ('zx'e-2v'e-iv)' (2A'9x'e-2v 'e-TV)' (Purchase '9X'S-SV'S-IV)' People 'SX'S-SV'S-IV)' (I Puppet 'SX'S-SV'S-IV)

^ x'e-2V'e-TV) '(2A'sx'e-2v'e-TV)' (TA'sx'e-2v'e-TV) '(2A'2x'e-2v'e -iv) '(' 2

Χ '-Ζν' -ΐνΥ (ΖλΊΧ '-ΖΥ -ΐνΥ (Ιλ'ΙΧ' -ΖΥ -ΐνΥ (Ζλ 'ΖΥ' -ΖΥ -ΐνΥ (Ιλ 'Ζ Ζ' -Ζν '-ΐνΥ (Ζλ'ζΖΧ' -ΖΥ -ΐνΥ (Ιλ'ζΖΧ '-ΖΥ -ΐνΥ (Ζλ'ΖΖΧ' -ΖΥ -ΐνΥ (Ιλ 'ΖΖΧ' -ΖΥ -ΐνΥ (Ζλ'ΙΖΧ '-ΖΥ -ΐνΥ (ΙλΊΖΧ' -ΖΥ -ΐνΥ (Ζλ'0ΖΧ ' -Ζν '-ΐν) 1 λ'0ΖΧ' -ΖΥ -ΐνΥ (Ζλ'61Χ '-ΖΥ -ΐνΥ (Ιλ'61Χ' -ΖΥ -ΐνΥ (Ζλ'81Χ '-ΖΥ -ΐν)' ('8TX ^ -2V 'e-TV)' (2A'ZTX ^ -2V'e-TV) '(' ZTX ^ -2V'S-TV) '(2A'9TX ^ -2V'eT ν) Ιλ'91Χ' -ΖΥ -ΐν) Ζλ '1Χ' -ΖΥ -ΐν) Ιλ '1Χ' -Ζν '-ΐν) Ζλ'ηΧ' -Ζν '

-ιν) ΐλ'ηχ '-ζΥ -ιν) ζλ'ζΐχ' -ζΥ -ινΥ (ΐλ'ζΐχ '-ζΥ -ινΥ (ζλ'ζιχ' -ζν

'-ΐνΥ (Ιλ'ΖΙΧ' -ΖΥ -ΐνΥ (Ζλ'ΠΧ '-ΖΥ -ΐνΥ (Ιλ'ΠΧ' -ΖΥ -ΐνΥ (Ζλ'01Χ '-SV'S— ΐν)' (ΐ 入 'ΟΐΧ' IV) 'People' 6X'G SV'S-IV) '(U'6X'G SV'S-IV)' People '8X'-S V'S-IV)' (I '8'X SV'S-IV)' People SV'S — IV) '(U'ZX'v SV'S—IV)' People '9X'v SV'S—IV)' (I '9x'v SV'S—IV)' People 'SX'v SV'S-IV)' ( U'SX 'and SV'S—IV)' people 'χ'to sv's— ιν)' (ΐ 入 'χ'to sv's—iv)' people 'εχ' and sv's—iv) '(u'sx' iv) 'People' sx 'sv's— iv)' (ΐ 入 'sx' sv's- iv) 'Enter' ΪΧ 'and sv's- ιν)' (ΐ 入 'ΪΧ' 'ε- sv's- iv)

'(Ιλ' ΖΧ'ζ-ΖΥ -ΐνΥ (Ζλ'ζΖΧ'ζ-ΖΥ -ΐνΥ (Ιλ'ζΖΧ'ζ-Ζν '-ΐν) Ζλ'ΖΖΧ'ζ-Ζν' -1 ν) '(ΐ 人' ^ χ'ε- sv's- ΐν) 'person' χ'ε- sv's- ιν) '(ΐΛ' χ'ε- sv's- ΐν) 'person' osx's- sv's-iv) '(u'osx's- sv's- iv ) 'People' 6ΐχ'ε- sv's- ιν) '(ΐΛ'6ΐχ'ε- sv's- iv)' People 'six's-

'e-TV)' (TA'8TX'S-2V'e-TV) '(2A'ZTX'S-2V'e-TV)' ('ZTX'S-2V'e-TV)' (2A'9TX'S-SV'S-IV) '(I people' 9ΐΧ'ε- SV'S- IV) 'people' SIX'S- SV'S- IV) '(U'SIX'S- SV'S- IV)' people 'wx' ε- sv's- ιν) '(ΐ people' wx's- sv's- iv) 'People' ειχ'ε- sv's- ΐν) '(ΐΛ'ειχ'ε- sv's- iv)' Enter 'si χ'ε- sv's- ιν)' (ΐ 人 '^ χ'ε- sv's -iv) 'People' πχ'ε- sv's- ΐν) '(ΐΛ'πχ'ε- sv's- iv)' On '

C69CZC / 900Zdf / X3d 96 6C8C90 / .00Z OAV '(Ζλ' ΖΧΊ-ΖΥ -ΐνΥ (Ιλ 'ΖΧΊ-ΖΥ -ΐνΥ (Ζλ'ζΖ ΧΊ-Ζν' -ΐνΥ (Ιλ'ζΖΧΊ-ΖΥ -ΐνΥ (Ζλ'ΖΖΧΊ-ΖΥ -ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥ- ΐνΥ (Ζλ 'ΙΖΧΊ-ΖΥ -ΐνΥ (ΙλΊΖΧΊ-ΖΥ -ΐνΥ (Ζλ'0ΖΧΊ-ΖΥ -ΐνΥ (ΙλΌΖΧΊ-Ζν' -ΐνΥ (Ζ insert '6IX'Z-SV'S- ΐν)') (ΐ insert '6IX'Z -SV'S-IV) 'On'8IX'Z-SV'S-IV)'(U'8IX'Z-SV'S-IV)'(2A'ZTX'Z-2V'e-TV)'('ZTX'Z-2V'e-TV)'(2A'9TX'Z-2V'S-TV)'('9TX'Z-2V'eT v) '(2A'eTX'z-2v'e-TV)'('eTX'z-2v'e-TV)'(2A ^ TX'z-2v'e-iv)' (^ TX'z-2v'e

-TV) '(2A'STX'Z-2V'e-TV)' ('STX'Z-2V'e-TV)' (2A'2TX'Z-2V'S-TV) '(' 2TX'Z-2V '3-ΐν)' (2λ'πΧ'Ζ-2ν'3-ΐν) '(ΐλ'πΧ'Ζ-2ν'3-ΐν)' (2λ'0ΐΧ'Ζ-2ν'3-ΐν) '(ΐλΌΐΧ 'Ζ-

SV'S—IV) 'people' 6X'Z—SV'S—IV) '(I people' 6X'Z—SV'S—IV) 'people' 8X'Z—SV'S—IV) '(I entered)

'S—IV)' People 'ZX'Z—SV'S—ΐν)' (ΐ 人 'ZX'Z—SV'S—IV)' People '9X'Z—SV'S—ΐν)' (ΐ 人 '9X'Z—SV'S

— IV) 'People' SX'Z—SV'S—IV) '(I input' SX'Z—SV'S—IV) 'People' X'Z—SV'S—IV) '(I People' X'Z—SV'S—ΐ v) 'people ιν)' (ΐ 人 iv) 'people' sx'z—sv's—ιν) '(ΐ 人' sx'z—sv's—iv) ΖλΊχΊ-ΖΥ -ΐνΥ (ΙλΊχΊ-ΖΥ -ΐνΥ (Ζλ ' ΖΧ'9-ΖΥ -ΐνΥ (Ιλ 'ΖΧ'9-ΖΥ -ΐν)' (Ζλ'ζΖΧ'9-ΖΥ -ΐνΥ (Ιλ'ζΖΧ'9-ΖΥ -ΐνΥ (Ζλ'ΖΖΧ'9-Ζν '-ΐν) ) Ιλ'ΖΖΧ'9-Ζν '-1 V)' (2A'T2X'9-2V'e-TV) '(' T2X'9-2V'e-TV) '(2AO2X'9-2V'e- (TV) '(' 02X'9-2V'e-IV) 'Enter' 6ΐΧ'9-SV'S-IV) '(U'6IX'9-SV'S-IV)' Enter '8ΐΧ'9-SV'S-IV)' (U'8IX'9- 'e-TV)' (2A'ZTX'9-2V'e-TV) '(TA'ZTX'9-2V'e-TV)' (2A'9TX'9-2V'S- (TV) '(' 9TX'9-SV'S-IV) '' SIX'9-SV'S-IV) '(I'SIX'9-SV'S-IV)' 'WX'9-SV'S-IV)' ( U'WX '9- SV'S- IV)' Enter 'ειχ'9- SV'S- IV)' (I enter 'ειχ'9- SV'S- IV)' Enter 'SIX'9- SV'S-IV)' (U'SI X'9—SV'S—IV) 'Input' ΐ ΐΧ'9—SV'S—IV) '(I Input' ΐ ΐΧ'9—SV'S—IV) 'Input' ΟΐΧ'9—SV'S—IV) '(U' ΟΐΧ '9—SV'S—IV)' person '6X'9—SV'S—IV)' (I person '6X'9—S V'S—IV) 'person' 8X'9—SV'S—IV) '(U'8 X'9—SV'S—IV)' person 'ZX'9—SV'S—IV)' (I person 'ZX'9—SV'S— IV) 'People' 9X'9—SV'S—IV) '(U'9X'9—SV'S—IV)' People 'SX'9—SV'S—IV)' (I Plot 'SX'9—SV'S—IV)' People 'X'9—SV'S—IV)' (U'X'9—SV'S—IV) 'People' SX'9—SV'S—IV) '(I People' SX'9—SV'S—IV) 'People' SX '9—SV'S—IV)' (I input 'SX'9—

'e-TV)' (2A'TX'9-2V'e-TV) '(' TX'9-2V'e-TV) '(2A' ^ x'e-2v'e-iv) '(' ^ x'e-2v 'e-TV)' (2A's2x'e-2v'e-TV) '(TA's2x'e-2v'e-TV)' (2A'22x'e-2v'e -iv) '(' 22x'e-

2V'e-TV) '(2A'T2X'e-2V'e-TV)' (TA'T2X'e-2V'e-TV) '(2A'02X'e-2V'e-TV)' ( O2X'e-2v'e-TV) '(2A'6TX'e-2v'e-TV)' (TA'6TX'e-2v'e-TV) '(2A'8ix'e-2v'e- TV) '(' 8T

C69CZC / 900Zdf / X3d Z6 6C8C90 / .00Z OAV 8X'S—SV'9—ΐν) '(ΐΛ'8Χ'ε—SV'9—IV)' People 'ζχ'ε—SV'9—ιν)' (ΐ 人 'ζχ'ε—SV'9—IV) 'ON' 9X

'ε—SV'9—IV)' (I person '9X'S—SV'9—IV)' person 'SX'S—SV'9—IV)' (U'SX'S—SV'9—IV) 'person ^ χ' ε

— Sv'9— ιν) '(ΐ 人' χ'ε— sv'9— iv) 'person' εχ'ε— sv'9— ιν) '(ΐΛ'εχ'ε— sv'9— iv)' People 'sx's—s

V'9-IV) '(U'SX'S-SV'9-IV)' In 'ιχ'ε- SV'9- ΐν)' (ΐΛ'ΐΧ'ε-SV'9-IV) 'In' wx's- '9-ΐνΥ (Ιλ' ΖΧ'Ζ-ΖΥ9-ΐνΥ (Ζλ'ζΖΧ'Ζ-ΖΥ9-ΐνΥ (Ιλ'ζΖΧ'Ζ-ΖΥ9-ΐνΥ (Ζλ'ΖΖΧ'Ζ- ΖΥ9-ΐνΥ (Ιλ'ΖΖΧ'Ζ -ΖΥ9-ΐνΥ (ΖλΊΖΧ'Ζ-ΖΥ9-ΐνΥ (ΙλΊΖΧ'Ζ-ΖΥ9-ΐνΥ (Ζλ'0ΖΧ '

SV'9—IV) '(I input' OSX'S—SV'9—IV) 'input' 6IX'S—SV'9—IV) '(U'6IX'S—SV'9—IV)' input '8ΐ

X'2-2V'9-TV) '(TA'8TX'2-2V'9-TV)' (2A'ZTX'2-2V'9-TV) '(' ZTX'2-2V'9-TV ) '(2A' 9IX'S—SV'9—IV) '(U'9IX'S—SV'9—IV)' Enter 'SIX'S—SV'9—IV)' (U'SIX'S—SV'9—IV) 'Enter 'WX'S—SV'9—IV)' (I 'WX'S—SV'9—IV)' Enter 'SIX'S—SV'9—IV)' (U'SIX'S—SV'9—IV) '(2A'2TX '2-2V'9-TV)' ('2TX'2-2V'9-TV)' (2A'nX'2-2V'9-TV) '(' nX'2-2V'9-T

V) 'ON' OIX'S—SV'9—IV) '(U'0IX'S—SV'9—IV)' People '6X'S—SV'9—IV)' (U'6X'S—SV'9—ΐ

V) 'person' 8X'S—SV'9—IV) '(I person' 8X'S—SV'9—IV) 'person' ZX'S—SV'9—IV) '(U'ZX'S—SV'9—IV)' ON'9X'S—SV'9—IV) '(I ON'9X'S—SV'9—IV)' People 'SX'S—SV'9—IV)' (U'SX'S—SV'9—IV) 'Enter ^ X'S — SV'9—IV) '(I person' X'S—SV'9—IV) 'person' SX'S—SV'9—IV) '(U'SX'S—SV'9—IV)' enter 'SX'S-SV' 9-IV) '(I person' SX'S-SV'9-IV) 'Enter' IX'S-SV'9-IV) '(U'IX'S-SV'9-IV)' Enter 'W

Χ'ΐ—SV'9—IV) '(I input' Χ'ΐ—SV'9—IV) 'Input' SSX'I—SV'9—IV) '(U'SSX'I—SV'9— IV) 'On' ΖΖΧΊ-ΖΥ9-ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥ9-ΐνΥ (ΖλΊΖΧΊ-ΖΥ9-ΐνΥ (ΙλΊΖΧΊ-Ζν'9-ΐν) Ζ In 'OSX'I—SV'9—IV)' (I In 'OSX'I—SV'9—IV)' ON '6ΐΧ'ΐ—SV'9—IV)' (U'6IX'I—SV'9—IV) '(2A'8TX'T-2V'9- TV) '(' 8TX'T-2V'9-TV) '(2A'ZTX'T-2V'9-TV)' ('ZTX'T-2V'9-T

V) '(2A'9TX'T-2V'9-TV)' ('9TX'T-2V'9-TV)' (2A'eTX'T-2V'9-TV) '(' eTX'T- 2V'9

-IV) 'On' WX'I-SV'9-IV) '(U'WX'I-SV'9-IV)' On 'εΐΧ'ΐ- SV'9-ΐν)' (ΐΛ'εΐΧ'ΐ -'9-TV)' (2A'2TX'T-2V'9-TV) '(TA'2TX'T-2V'9-TV)' (2A'nX'T-2V'9-TV) '( 'nX'T- SV'9—IV)' Enter 'ΟΐΧ'ΐ—SV'9—IV)' (I enter 'ΟΐΧ'ΐ—SV'9—IV)' Person '6Χ'ΐ—SV'9— IV) '(U'6X'I—

SV'9—IV) 'People' 8Χ'ΐ—SV'9—IV) '(U'8X'I—SV'9—IV)' People 'ΖΧ'ΐ—SV'9—IV)' (I input 'ΖΧ'ΐ—

'9—IV)' People '9Χ'ΐ—SV'9—IV)' (I input '9Χ'ΐ—SV'9—IV)' People 'SX'I—SV'9—IV)' (U ' SX'I—

— Iv) 'People' χ'ΐ— sv'9— ιν) '(ΐ 入' χ'ΐ— sv'9— iv) 'People' εχ'ΐ— SV'9— ιν) '(ΐΑ'εχ' ΐ— SV'9— ΐ

V) 'People' SX'I—SV'9—IV) '(I People' SX'I—SV'9—IV) 'Enter' ΐΧ'ΐ—SV'9—ΐν) '(ΐΛ'ΐΧ'ΐ — SV'9— IV) [Ϊ800]

C69CZC / 900Zdf / X3d 86 6C8C90 / .00Z OAV 9IX'S—SV'9—IV) 'On'SIX'S—SV'9—IV)'(U'SIX'S—SV'9—IV)' On 'WX'S—SV'9—IV)' (I On 'WX'S—SV '9—IV)' Enter 'SIX'S—SV'9—IV)' (I enter 'SIX'S—SV'9—IV)' Enter 'SIX'S—SV'9—IV)'('2TX'e-2V'9 -TV) '(2A'nX'e-2V'9-TV)'('nX'e-2V'9-TV)'(2A'0TX'e-2V'9-TV)'(Iinput'OIX'S — SV'9—IV) 'People'6X'S—SV'9—IV)'(U'6X'S—SV'9—IV)' People '8X'S—SV'9—IV 9—IV) 'Person'ZX'S—SV'9—IV)'(Iinput'ZX'S—SV'9—IV)'Person'9X'S—SV'9—IV)' IV) 'People'SX'S—SV'9—IV)'(U'SX'S—SV'9—IV)' People 'X'S—SV'9—IV)' (I input X'S—SV'9—IV) ' People 'SX'S—SV'9—IV)' (I people 'SX'S—SV'9—IV)' People 'SX'S—SV'9—IV)'(U'SX'e-2V'9-TV)'(2A'TX'e-2V'9-TV)'(TA'TX'S-2V'9-TV)'(2A' ^ X ^ -2V'9-TV) '(' ^ Χ '-Ζν'9-ΐνΥ ( Ζλ'ζΖΧ '-ΖΥ9-ΐνΥ (Ιλ'ζΖΧ' -ΖΥ9-ΐνΥ (Ζλ'ΖΖΧ '-ΖΥ9-ΐνΥ (Ιλ' ΖΖΧ '-ΖΥ9-ΐνΥ (Ζλ'ΙΖΧ' -ΖΥ9-ΐνΥ (ΙλΊΖΧ '-ΖΥ9- ΐνΥ (Ζλ'0ΖΧ '-Ζν'9-ΐν) 1 'OSX'f—SV'9—IV)' Enter '6ΐΧ' — SV'9—IV) '(I enter' 6ΐΧ '— SV'9—IV)' Enter '8ΐΧ' — SV'9—IV) '('8TX ^ -2V'9-TV)'(2A'ZTX ^ -2V'9-TV) '(' ZTX ^ -2V'9-TV) '(2A'9TX ^ -2V'9-T ν) Ιλ'91Χ '-ΖΥ9-ΐν) Ζλ' 1Χ '-ΖΥ9-ΐν) Ιλ' 1Χ '-Ζν'9-ΐν) Ζλ'ηΧ'-Ζν'9 -ΐν) Ιλ'ηΧ '-ΖΥ9-ΐν) Ζλ 'ζΙΧ' -ΖΥ9-ΐνΥ (Ιλ'ζΙΧ '-ΖΥ9-ΐνΥ (Ζλ'ΖΙΧ' -Ζν '9-TV)'(TA'2TX ^ -2V'9-TV) '(2A'nX ^ -2V' 9-TV) '(' nX ^ -2V'9-TV) '(2AOTX ^-SV'9—ΐν)' (ΐ 入 'ΟΐΧ'to SV'9—IV)' people '6X'to SV'9 — IV) '(U'6X'V SV'9—IV)' People '8X' —S V'9—IV) '(I'8X'VSV'9—IV)'PeopleSV'9— IV) '(U'ZX'v SV'9—IV)' People '9X'v SV' 9—IV) '(I'9x'vSV'9—IV)'People'SX'vSV'9 — IV) '(U'SX'G SV'9—IV)' People 'Χ'G SV'9— ιν)' (ΐ 入 'χ'G sv'9—iv)' People 'εχ' G SV 9—IV) '(U'SX'G SV'9—IV)' People 'SX'G SV'9—IV)' (Buy 'SX'G SV'9—IV)''9—IV)' (I input 'ΐΧ' and SV'9—IV) 'input'χ'ε—SV'9—IV)'(' ^ X'S-2V'9-TV ) '(2A'S2X'S-2V'9-TV)'('S2X'S-2V'9-TV)'(2A'22X'S-2V'9-T ν) '(ΐ 入' ^ χ'ε- SV'9 -IV) 'On'χ'ε-SV'9-IV)'(U'X'S-SV'9-IV)' On 'OSX'S-TV)'(O2X'S-2V'9-TV)'(2A'6TX'S-2V'9-TV)'('6TX'S-2V'9-TV)'(2A'8TX'S-2V' 9-TV) '(TA'8TX'S-2V'9-TV)'(2A'ZTX'S-2V'9-TV)'('ZTX'S-2V'9-TV)'(2A'9TX'S-SV'9—IV)'(Iinput'9ΐΧ'ε—SV'9—IV)'input'SIX'S—SV' 9—IV) '(U'SIX'S—SV'9—IV)' Enter 'WX'ε—sv'9—ιν)'(Insertion'wx's—sv'9—iv)'9—ΐν)'(ΐΛ'ειχ'ε—sv'9—iv)'Enter' si χ'ε—sv'9—ιν) '(ΐ 入' ^ χ'ε—sv'9—iv) '''Πχ'ε—sv'9— ΐν) '(ΐΛ'πχ'ε— sv'9— iv)

ΟΐΧ'ε—SV'9—IV) '(I input' ΟΐΧ'ε—SV'9—IV) 'People' 6X'S—SV'9—IV) '(U'6X'S—SV'9—IV)' Input '

C69CZC / 900Zdf / X3d 66 6C8C90 / .00Z OAV ΧΊ-Ζν'9-ΐνΥ (Ιλ'ζΖΧΊ-ΖΥ9-ΐνΥ (Ζλ'ΖΖΧΊ-ΖΥ9-ΐνΥ (Ιλ'ΖΖΧΊ-ΖΥ9-ΐνΥ (Ζλ 'ΙΖΧΊ-ΖΥ9-ΐνΥ (ΙλΊΖΧΊ-ΖΥ9-ΐνΥ (Ζλ'0ΖΧΊ- ΖΥ9-ΐνΥ (ΙλΌΖΧΊ-Ζν'9-ΐνΥ (Ζ input '6IX'Z—SV'9—IV)' (I input '6IX'Z—SV'9—IV)' input '8IX'Z—SV'9 — IV) '(U'8IX'Z—SV'9—IV)'(2A'ZTX'Z-2V'9-TV)'('ZTX'Z-2V'9-TV)'(2A'9TX'Z-2V'9-TV)'('9TX'Z-2V'9-TV)'(2A'eTX'Z-2V'9-TV)'('eTX'Z-2V'9-TV)' ( 2A ^ TX'Z-2V'9-TV) '(^ TX'Z-2V'9-TV)'(2A'STX'Z-2V'9-TV)'('STX'Z-2V'9- TV) '(2A'2TX'Z-2V'9-TV)'('2TX'Z-2V' 9-TV) '(2A'nX'Z-2V'9-TV)'(TA'nX'Z-2V'9-TV)'(2AOTX'Z-2V'9-TV)'(OTX'Z-SV'9—IV)'people'6X'Z—SV'9—IV)'(U'6X'Z—SV'9—IV)'people'8X'Z—SV'9—9ν)'(ΐ入')

'9—IV)' People IV) '(I input IV)' People '9X'Z—SV'9—IV)' (U'9X'Z—SV'9 — IV) 'People' SX'Z—SV '9—IV)' (I input 'SX'Z—SV'9—IV)' person 'IV)' (U 'X'Z—SV'9—ΐV)' person 'SX'Z—SV'9 — IV) '(I people' SX'Z—SV'9—IV) 'people' IV) '(U'SX'Z—SV'9—IV)' (2A'TX'Z-2V'9-TV ) '(TA'TX'Z-2V'9-TV)' (2A '^ X'9-2V'9-TV)' ('^ X'9-2V'9-TV)' (2A'S2X ' 9-2V'9-TV) '(' S2X'9-2V'9-TV) '(2A'22X'9-2V'9-TV)' ('22X'9-2V'9-TV)' ( 2A'T2X'9-2V'9-TV) '(' T2X'9-2V'9-TV) '(2A'02X'9-2V'9-TV)' (O2X'9-2V'9 — IV ) 'In' 6ΐΧ'9—SV'9—IV) '(U'6IX'9—SV'9—IV)' In '8ΐΧ'9—SV'9—IV)' (U'8IX'9— ' 9-TV) '(2A'ZTX'9-2V'9-TV)' (TA'ZTX'9-2V'9-TV) '(2A'9TX'9-2V'9-TV)' ('9TX '9- SV'9—IV)' On 'SIX'9—SV'9—IV)' (I On'SIX'9—SV'9—IV) 'On' WX'9—SV'9—IV) '(U'WX' 9—SV'9—IV) 'Enter' εΐΧ'9—SV'9—IV) '(I enter' εΐΧ'9—SV'9—IV) 'Enter' SIX'9—SV '9—IV)' (U'SI X'9—SV'9—IV) 'Input' ΐ ΐΧ'9—SV'9—IV) '(I input' ΐ ΐΧ'9—SV'9—IV) 'Enter' ΟΐΧ'9—SV'9—IV) '(U' ΟΐΧ'9—SV'9— IV) 'person' 6X'9—SV'9—IV) '(I person' 6X'9—SV'9—IV) 'person' 8X'9—SV'9—IV) '(U'8 X' 9—SV'9—IV) 'person' ZX'9—SV'9—IV) '(I person' ZX'9—SV'9—IV) 'person' 9X'9—SV'9—IV) ' (U'9X '9—SV'9—IV)' person 'SX'9—SV'9—IV)' (I person 'SX'9—SV'9—IV)' person 'X'9—SV' 9—IV) '(U' X'9—SV'9—IV) 'person' SX'9—SV'9—IV) '(U'SX'9—SV'9—IV)' person 'SX' 9—SV'9—IV) '(I input' SX'9—'9-TV) '(2A'TX'9-2V'9-TV)' ('TX'9-2V'9-TV)' (2A '^ X'S-2V'9-TV)' ('^ X'e-2V' 9-IV) 'input' SSX'S-SV'9-IV) '(I input' SSX'S-SV'9-IV) 'On' ^ X'S-SV'9-IV) '(U' ^ X'S-SV'9—IV) 'On' X'S—SV'9—IV) '(I On' X'S—SV'9—IV) ' ON 'OSX'S-SV'9-IV)' (U'OSX'e-2V'9-TV) '(2A'6TX'e-2V'9-TV)' (TA'6TX'e-2V'9- TV) '(2A'8TX'S-2V'9-TV)' ('8T X'e-2V'9-TV)' (2A'ZTX'e-2V'9-TV) '(TA'ZTX'e- 2V'9-TV) '(2A'9TX'S-2V'9-TV)' ('

C69CZC / 900Zdf / X3d 001 6C8C90 / .00Z OAV 'ε—SV'Z—IV)' (I people '9χ'ε—sv'z—iv)' people 'sx's—sv'z—iv)'(u'sx's—sv'z—iv)'people ^ χ'ε — SV'Z—IV) '(I people'χ'ε—sv'z—iv)'people'εχ'ε—sv'z—iv)'(u'sx's—sv'z—iv)'People'sx's— s v'z-iv) '(u'sx's- sv'z-iv)' Enter 'ιχ'ε- SV'Z-IV)'(U'IX'S-sv'z-iv)''Wx's-'L-wydA'fzx'z-zYL-wyizA'zzx'z-zYL-wydA'zzx'z-zYL-wyizA'zzx'z-zYL-wydA'zzx'z-zYL-wyizA'izx'z-zYL-wydA'izx'z-zYL-wyizA'ozx'

(SV'Z-IV) '(I person' OSX'S-SV'Z-IV) 'person' 6IX'S-SV'Z-IV) '(U'6IX'S-SV'Z-IV)' input '81

X'2-2V'Z-TV) '(TA'8TX'2-2V'Z-TV)' (2A'ZTX'2-2V'Z-TV) '(' ZTX'2-2V'Z-TV ) '(2A' 9TX'2-2V'Z-TV) '(' 9TX'2-2V'Z-TV) '(2A'eTX'2-2V'Z-TV)' ('STX'2-2V 'Z-TV)' (2 input 'WX'S-SV'Z-IV)' (I input 'WX'S-SV'Z-IV)' input 'SIX'S-SV'Z-IV)' (U'SIX'S-SV ' Z-IV) '(ZA'ZlX'Z-ZYL-WydA'ZlX'Z-ZYL-WyiZA' l lX'Z-ZV'L-WydA 'l lX'Z-ZV'Ll

V) 'ON' OIX'S—SV'Z—IV) '(U'OIX'S—SV'Z—IV)' People '6X'S—SV'Z—IV)' (U'6X'S—SV'Z— ΐ

V) 'people' 8X'S—SV'Z—IV) '(I people 8X'S—SV'Z—IV)' people 'ZX'S—SV'Z—IV)' (I people 'ZX'S—SV'Z—IV) 'Enter' 9X'S—SV'Z—IV) '(I input' 9X'S—SV'Z—IV) 'Person' SX'S—SV'Z—IV) '(I Person' SX'S—SV'Z—IV) 'Enter ^ X'S—SV'Z—IV) '(I person' X'S—SV'Z—IV) 'person' SX'S—SV'Z—IV) '(U'SX'S—SV'Z—IV)' enter 'SX'S- (SV'Z-IV) '(I person' SX'S-SV'Z-IV) 'Enter' IX'S-SV'Z-IV) '(U'IX'S-SV'Z-IV)' Enter 'w

X'T-2V'Z-TV) '(TA' ^ X'T-2V'Z-TV) '(2A'S2X'T-2V'Z-TV)' ('S2X'T-2V'Z- TV) '(2A' 22X'T-2V'Z-TV) '(' 22X'T-2V'Z-TV) '(2A'T2X'T-2V'Z-TV)' ('T2X'T- 2V'Z-TV) '(2

AO2X'T-2V'Z-TV) '(TAO2X'T-2V'Z-TV)' (2A'6TX'T-2V'Z-TV) '(' 6TX'T-2V'Z-TV) ' (2A'8TX'T-2V'Z-TV) '(' 8TX'T-2V'Z-TV) '(2A'ZTX'T-2V'Z-TV)' ('ZTX'T-2V'ZT

V) '(2A'9TX'T-2V'Z-TV)' ('9TX'T-2V'Z-TV)' (2A'eTX'T-2V'Z-TV) '(' eTX'T- 2V'Z

-TV) '(2A ^ TX'T-2V'Z-TV)' (^ TX'T-2V'Z-TV) '(2A'STX'T-2V'Z-TV)' ('STX'T -2V

'Z-TV)' (2A'2TX'T-2V'Z-TV) '(TA'2TX'T-2V'Z-TV)' (2A'nX'T-2V'Z-TV) '(' nX'T-SV'Z-IV) '(SA'0IX'I-SV'Z-IV)' (IA'0IX'I-SV'Z-IV) '(SA'6X'I-SV'Z- IV) '(U'6X'I—

SV'Z—IV) 'people' 8Χ'ΐ—SV'Z—IV) '(I people' 8Χ'ΐ—SV'Z—IV) 'people' ΖΧ'ΐ—SV'Z—IV) '(I Enter 'ΖΧ'ΐ—

UV) 'People' 9ΐ'ΐ—SV'Z—IV) '(I' 9Χ'ΐ—SV'Z—IV) 'People' SX'I—SV'Z—IV) '(U'SX'I — SV '

— Iv) 'People' χ'ΐ—SV'Z—IV) '(I input' χ'ΐ—sv'z—iv) 'People' εχ'ΐ—SV'Z—IV) '(U'SX' I—

V) 'People' SX'I—SV'Z—IV) '(I People' SX'I—SV'Z—IV) 'Enter' '' ΐ—SV'Z—IV) '(U'IX'I — SV'Z—IV) [2800]

'(Ζλ' ΖΧΊ-ΖΥ9-ΐνΥ (Ιλ 'ΖΧΊ-ΖΥ9-ΐνΥ (Ζλ'ζΖ

C69CZC / 900Zdf / X3d Η (Η 6C8C90 / .00Z OAV On 'WX'S-SV'Z-IV)' On 'SIX'S-SV'Z-IV)' (I On 'SIX'S-SV'Z-IV)' On 'SIX'S-SV'Z-IV)'('2TX'e-2V'Z-TV)'(2A'nX'e-2V'Z-TV)'('nX'e-2V'Z-TV)'(2A'0TX'e-2V'ZT V) '( 'I'OIX'S—SV'Z—IV)'people'6X'S—SV'Z—IV)'(U'6X'S—SV'Z—IV)' people '8X'S—SV'Z—IV)' (ΐ 入 '8X'S—SV'Z—IV)'People'ZX'S—SV'Z—IV)'(Iinput'ZX'S—SV'Z—IV)'People'9X'S—SV'Z—IV)'(ΐ入'9X'S—SV'Z—IV)'people'SX'S—SV'Z—IV)'(U'SX'S—SV'Z—IV)' people 'X'S—SV'Z—IV)' (I entered 'X'S—SV'Z —IV) 'person'SX'S—SV'Z—IV)'(Iperson'SX'S—SV'Z—IV)'person'SX'S—SV'Z—IV)'(U'SX'e-2V'Z-TV ) '(2A'TX'e-2V'Z-TV)'(TA'TX'S-2V'Z-TV)'(2A' ^ X ^ -2V'Z-TV) '(' ^ x'f-zv 'L-wyizA'zzx'f-zYL-wydA'zzx'f-zYL-wyizA'zzx'f-zYL-wydA'zzx'f-zYL-wyizA'izx'f-zYL-wydA'izx'f-zYL-wyizA'ozx'f-zv'L-wyd

A'OZX'f-ZYL-WyiZA'eiX'f-ZYL-WydA'eiX'f-ZYL-WyiZA'SlX'f-ZYL-W) '(' 8TX ^ -2V'Z-TV) '(2A' ZTX ^ -2V'Z-TV) '(' ZTX ^ -2V'Z-TV) '(2A'9TX ^ -2V'ZT V)' ('9TX ^ -2V'Z-TV)' (2A'eTX ^ -2V'Z-TV) '(' STX ^ -2V'Z-TV) '(2A ^ TX ^ -2V'Z-TV)' (^ TX ^ -2V'Z-TV) '(2A'STX ^ -2V'Z-TV) '(' STX ^ -2V'Z-TV) '(2A'2TX ^ -2V' Z-TV) '(TA'2TX ^ -2V'Z-TV)' (2A ' nX ^ -2V'Z-TV) '(' nX ^ -2V'Z-TV) '(2AOTX ^-SV'Z—IV)' (IA'0IX '—SV'Z—IV)' (SA'6X '—SV'Z—IV)' (U'6X '—SV'Z—IV)' (SA'8X ^ —S V'Z—IV) '(IA'8X' —SV'Z—IV) '( SA'ZX '—SV'Z—IV)' (U'ZX '—SV'Z—IV)' (SA'9X '—SV' IV) '(I input 9X' and SV'Z—IV) ' People 'SX'G SV'Z-IV)' (U'SX'G SV'Z-IV) 'People' Χ'G SV'Z-ιν) '(ΐ 入' χ'G sv'z-iv) 'People' εχ 'and sv'z—iv)' (u'sx 'and sv'z—iv)' People 'sx' and sv'z—iv) '(Purchasing' sx 'and sv'z-iv ) 'Enter' ΪΧ 'to SV'Z-IV)' (I enter 'ΪΧ' to sv'z-iv) 'Enter' χ'ε- sv'z-iv) \ k '' Z-ZW 'L- \ W) Zk'ZZ 'Z-ZW' L- \ W) \ k'ZZ 'Z-ZW' L- \ W) Zk'ZZ 'Z-ZW' L- \ V) '(' 22X'S-2V ' Z-TV) '(2A'T2X'S-2V'Z-TV)' ('T2X'S-2V'Z-TV)' (2AO2X'S-2V'Z-TV) '(O2X'S-2V'Z-TV)' (2A '6TX'S-2V'Z-TV)' ( '6TX'S-2V'Z-TV)' (2A'8TX'S-2V 'Z-TV)' (TA'8TX'S-2V'Z-TV) '(2A'ZTX'S-2V'Z-TV)' ('ZTX'S- 2V'Z-TV) '(2A'9TX'S-2V'Z-TV)' (TA'9TX'S-2V'Z-TV) '(2A'eTX'S-2V'Z-TV)' ('eTX'S-2V'Z -TV) '(2A ^ TX' ε-2ν'ζ-ΐν) '(ΐλ ^ ΐχ'ε-2ν'ζ-ΐν)' (2λ'εΐχ'ε-2ν'ζ-ΐν) '(ΐλ'εΐχ 'ε-2ν'ζ-ΐν)' (2λ'2ΐ χ'ε-2ν'ζ-ΐν) '(ΐλ'2ΐχ'ε-2ν'ζ-ΐν)' (2λ'πχ'ε-2ν'ζ- ΐν) '(ΐλ'πχ'ε-2ν'ζ-ΐν)' (2λ 'οιχ'ε- SV'Z-IV)' (I input 'οιχ'ε- sv'z-iv)' person '6χ' ε-sv'z-iv) '(u'6x's-sv'z-iv)' Enter '8χ'ε—SV'Z—IV)' (I person '8χ'ε—sv'z—iv)' person 'ζχ'ε—SV'Z—IV)' (I people 'ζχ'ε—sv'z—iv)' Enter '9x

C69CZC / 900Zdf / X3d 301-6C8C90 / .00Z OAV IZX'L-ZYL-WydA'IZX'L-ZYL-WyiZA'OZX'L-ZYL-WydA'OZX'L-ZV'L-WyiZ In '6IX'Z-SV'Z-IV)'(IA'6IX'Z-SV'Z-IV)'(SA'8IX'Z-SV'Z-IV)'(U'8IX'Z-SV'Z-IV)'(2A'ZTX'Z-2V'Z-TV ) '('ZTX'Z-2V'Z-TV)'(2A'9TX'Z-2V'Z-TV)'('9TX'Z-2V'ZTV)'(2A'eTX'Z-2V' Z-TV) '('eTX'Z-2V'Z-TV)'(2A ^ TX'Z-2V'Z-TV)' (^ TX'Z-2V'Z-TV) '(2A'STX'Z-2V'Z-TV)'('STX'Z-2V'Z-TV)'(2A'2TX'Z-2V'Z-TV)'('2TX'Z-2V' Z-TV) '( 2A'nX'Z-2V'Z-TV) '(TA'nX'Z-2V'Z-TV)'(2AOTX'Z-2V'Z-TV)'(OTX'Z-SV'Z—IV)'(SA'6X'Z-SV'Z-IV)'(IA'6X'Z-SV'Z-IV)'(SA'8X'Z-SV'Z-IV)'(IA'8X'Z- SV 'Z-IV)'(SA'ZX'Z-SV'Z-IV)'(IA' LX 'L-SV' L-IV) '(SA'9X' L-SV 'L-IV)' ( IA'9X 'L—SV' L — IV) 'person'SX'Z—SV'Z—IV)'(Iperson'SX'Z—SV'Z—IV)'person ^ X'Z—SV'Z —IV) '(I people ^

ν) 'people' sx'z—sv'z—iv) '(i people' sx'z—sv'z—iv) 'people' SX'Z—SV'Z—IV) '(I people' sx ' z—sv'z—iv)

'(2A'TX'Z-2V'Z-TV)' (TA'TX'Z-2V'Z-TV) '(2A' ^ X'9-2V'Z-TV) '(' ^ X'9 -2V'Z-TV) '(2A'S2X'9-2V'Z-TV)' ('S2X'9-2V'Z-TV)' (2A'22X'9-2V'Z-TV) '( '22X'9-2V'ZT V)' (2A'T2X'9-2V'Z-TV) '(' T2X'9-2V'Z-TV) '(2A'02X'9-2V'Z-TV ) '(O2X'9-2V'Z -TV)' (2A'6TX'9-2V'Z-TV) '(' 6TX'9-2V'Z-TV) '(2A'8TX'9-2V' Z-TV) '(' 8TX'9-2V 'Z-TV)' (2A'ZTX'9-2V'Z-TV) '(TA'ZTX'9-2V'Z-TV)' (2A'9TX '9-2V'Z-TV)' ('9TX'9-2V'Z-TV)' (2A'eTX'9-2V'Z-TV) '(TA'eTX'9-2V'Z-TV) '(2A ^ TX'9-2V'Z-TV)' (^ TX '9-2V'Z-TV)' (2A'STX'9-2V'Z-TV) '(TA'STX'9-2V 'Z-TV)' (2A'2TX'9-2V'Z-TV) '(' 2T X'9-2V'Z-TV) '(2A'nX'9-2V'Z-TV)' (TA 'nX'9-2V'Z-TV)' (2A'0TX'9-2V'Z-TV) '(' ΟΐΧ'9—SV'Z—IV) 'people' 6Χ'9—SV'Z—IV ) '(I person' 6Χ'9—SV'Z—IV) 'person' 8Χ'9—SV'Z—IV) '(U'8 X'9—SV'Z—IV)' person 'ZX'9 — SV'Z—IV) '(I person' ZX'9—SV'Z—IV) 'person' 9X'9—SV'Z—IV) '(U'9X' 9—SV'Z—IV) ' (SA'SX'9-SV'Z-IV) '(IA'SX'9-SV'Z-IV)' (SA'X'9-SV'Z-IV) '(U' X'9- SV 'Z—IV)' person 'SX'9—SV'Z—IV)' (I person 'SX'9—SV'Z—IV)' person 'SX'9—SV'Z—IV)' (I input 'SX'9—'Z-TV)' (2A 'TX'9-2V'Z-TV)' ('TX'9-2V'Z-TV)' (2A '^ X'S-2V'Z-TV)' ('^ X'e-2V' Z-TV ) '(2A'S2X'e-2V'Z-TV)' (TA'S2X'e-2V'Z-TV) '(2A'22X'S-2V'Z-TV)' ('22X'e-2V' Z-TV) '(2A'T2X'e-2V'Z-TV)' (TA'T2X'e-2V'Z-TV) '(2A'02X'e-2V'Z-TV)' (O2X ' e-2V'Z-TV) '(2A'6TX'e-2V'Z-TV)' (TA'6TX'e-2V'Z-TV) '(2A'8TX'S-2V'Z-TV)' ( '8T X'e-2V'Z-TV)' (2A'ZTX'e-2V'Z-TV) '(TA'ZTX'e-2V'Z-TV)' (2A'9TX'S-2V'Z- TV) '('

9TX'e-2v'z-TV) '(2A'eTX'e-2v'z-TV)' ('eTX'e-2v'z-iv)' (2A ^ TX'e-2v'z-TV ) '(T

C69CZC / 900Zdf / X3d εοΐ6C8C90 / .00Z OAV , Y2), (A1-7, A2-7, X22, Y1), (A1-7, A2-7, X22, Y2), (A1-7, A2-7, X23, Y1), (A1-7 , A2-7, X23, Y2), (A1-7, A2-7, X24, Y1), (A1-7, A2-7, X24, Y2).

[0083] Compound (I) has a high affinity for NMDA receptors, particularly NR1ZNR2B receptors, and has high receptor selectivity, and therefore can be a pharmaceutical with reduced side effects. It also has advantages such as high stability, high oral absorption, good BA, low clearance, high brain migration, long half-life, and high non-protein binding rate.

Compound (I) is a prophylactic / therapeutic agent for drugs, especially NMDA receptors, especially various central diseases caused by NR1ZNR2B receptors (eg, stroke, cerebral infarction, brain trauma, chronic neurodegenerative diseases), or cancer. As an analgesic for pain, etc., it can be administered orally or parenterally to animals including humans. Examples of dosage forms include granules, tablets, capsules, injections and the like. In formulating, various additives such as excipients, disintegrants, binders, lubricants, stabilizers, colorants, and coating agents can be used as desired. The dosage varies depending on the subject's age, weight, symptoms and administration method, and is not particularly limited, but is usually about 1 mg to about 5000 mg per day for an adult and about 0 mg for parenteral administration. lmg to about lOOOmg.

[0084] Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. Melting points listed in the text are uncorrected values. In addition, ¹ H-NMR can be obtained from heavy chloroform (CDC1), heavy dimethyl sulfoxide (DMSO-d),

3 6

Tetramethylsilane was measured as an internal standard in pyridine (Pyridine-d) solvent. δ value is

Five

The binding constant (J) is expressed in ppm and in ppm. In the data, s means single line, d means double line, t means triple line, q means quadruple line, m means multiple line, br means wide line, brs means wide single line, brd means wide-multiple line .

Each abbreviation has the meaning shown below.

THF: tetrahydrofuran

DMF: N, N-dimethylformamide

HOBt: 1-hydroxybenzotriazolene

DMAP: 4-Dimethylaminopyridine

EDC: 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride LDA: Lithium diisopropylamide

IBX: 1-Hydroxy-1,2-Benzodoxol-3 (1H) -one 1-oxide

Ph: Fuel

Me: Mechinole

Et: Echil

Reference Example 1 Synthesis of Compound 4

[Chemical 45]

a) Synthesis of Compound 3

Compound 2 (12.4 g, 48.7 mmol) was dissolved in DMF (70 ml), compound 1 (7.6 g, 48.7 mmo 1) was added, and the mixture was cooled in an ice bath. Sodium hydride (60% oily, 2.34 g, 58.4 mmol) was added and stirred at room temperature for 35 minutes. Ice water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane monoacetate) to obtain Compound 3 (12.72 g, yield 99%).

1H-NMR (CDC1 I TMS) δ ppm: 1.68 (t, J = 6.2Hz, 2H), 1.79 (t, J = 6.2Hz, 2H), 2.

Three

42 (dt, J = 1.2, 6.5Hz, 2H), 2.48 (dt, J = 1.2, 6.5Hz, 2H), 3.98 (s, 4H), 6.24 (brs, 1 H), 7.12 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6Hz, 2H).

b) Synthesis of compound 4

Compound 3 (12.7 g, 48.0 mmol) was dissolved in THF (200 ml), and 2 mol / L hydrochloric acid (107 ml, 214.0 mmol) was stirred at 90 ° C. for 2 hours. The mixture was cooled in an ice bath, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with black mouth form. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 4 (7.72 g, yield 73%).

1H-NMR (CDC1 I TMS) δ ppm: 2.48 (t, J = 7.0Hz, 2H), 2.52 (t, J = 7.0Hz, 2H), 2.

Three

68 (dt, J = 1.2, 7.0Hz, 2H), 2.73 (dt, J = 1.2, 7.0Hz, 2H), 6.43 (brs, 1H), 7.16 (d, J = 8.4Hz, 2H), 7.31 (d, J = 8.6Hz, 2H).

Reference Example 2 Synthesis of Compound 5

[Chem 46]

Compound 4 (5.70 g, 25.8 mmol) was dissolved in toluene (250 ml), chlorotris (triphenylphosphine) rhodium (I) (716 mg, 0.77 mmol) was replaced with hydrogen gas in the vigorous system, The mixture was stirred for 22 hours at 5 atm and 70 ° C under hydrogen pressure. After cooling, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl hexane monoacetate) to obtain Compound 5 (5.93 g, yield 100%).

1H-NMR (CDC1 I TMS) δ ppm: 1.35— 1.52 (m, 2H), 1.90—2.06 (m, 3H), 2.22-2.42 (

Three

m, 4H), 2.58 (d, J = 6.7Hz, 2H), 7.09 (d, J = 8.2Hz, 2H), 7.27 (d, J = 8.2Hz, 2H). Reference Example 3 Synthesis of Compound 9

[Chemical 47]

9

a) Synthesis of Compound 7

Under a nitrogen atmosphere, Compound 6 (12.64 g, 28.0 mmol) was dissolved in THF (100 ml) and cooled in an ice bath. 1.6M n-butyllithium monohexane solution (19.0 ml, 30.3 mmol) was added dropwise and stirred at 0 ° C for 1 hour, and then Compound 1 (3.64 g, 23.3 mmol) was stirred at room temperature for 22 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 1 (hexane ethyl acetate) to obtain Compound 7 (5.31 g, yield 92%). H-NMR (CDC1 I TMS) δ ppm: 1.68 (t, J = 6.6Hz, 2H), 1.79 (t, J = 6.5Hz, 2H), 2.

Three

38-2.52 (m, 4H), 3.99 (s, 4H), 6.25 (s, 1H), 6.95—7.04 (m, 2H), 7.10-7.18 (m, 2H). B) Synthesis of Compound 8

Compound 7 (5.26 g, 21.2 mmol) was dissolved in methanol (90 ml), and 5% palladium carbon (526 mg) was prepared together with methanol (10 ml). The system was replaced with hydrogen gas and stirred at room temperature for 5 hours. The reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure to give compound 8 (5.41 g, yield 100%).

1H-NMR (DMSO-d / TMS) δ ppm: 1.08—1.25 (m, 2H), 1.30—1.42 (m, 2H), 1.42—1.6

6

9 (m, 5H), 2.57 (d, J = 7.2Hz, 2H), 3.82 (s, 4H), 7.07 (t, J = 6.6Hz, 2H), 7.18 (dd, J = 6.6Hz, 4.5 Hz, 2H).

c) Synthesis of compound 9

Compound 8 (5.41 g, 21.2 mmol) was dissolved in methanol (60 ml), and water (60 ml) and amberlite IR120 + (2.0 g) were refluxed for 15 hours. Amberlite IR120 + (2.0 g) was added, and the mixture was further refluxed for 48 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained by silica gel column chromatography (hexane acetate) was purified to give compound 9 (3.63 g, yield 8

3%).

1H-NMR (CDC1 I TMS) δ ppm: 1.35— 1.52 (m, 2H), 1.89—2.07 (m, 3H), 2.23-2.44 (

Three

m, 4H), 2.59 (d, J = 6.8Hz, 2H), 6.94—7.03 (m, 2H), 7.08-7.16 (m, 2H).

Reference Example 4 Synthesis of Compound 11

[Chemical 48]

a) Synthesis of Compound 10

Under a nitrogen atmosphere, 4-bromobenzotrifluoride (5.00 g, 22.2 mmol) was dissolved in THF (45 ml) and cooled to −78 ° C. with a dry ice acetone bath. 1.57M tert-butyllithium pentane solution (28.0 ml, 44.4 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 0.5 hr. Compound 1 A solution of (3.47 g, 22.2 mmol) in THF (20 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. Water was added, the temperature was raised to room temperature, saturated saline water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane monoacetate) to obtain Compound 10 (4.57 g, yield 68%).

1H-NMR (DMSO-d / TMS) δ ppm: 1.57 (d, J = 9.6Hz, 2H), 1.65 (d, J = 9.6Hz, 2H)

6

, 1.96 (d, J = 9.6Hz, 4H), 3.90 (s, 4H), 5.17 (s, 1H), 7.67 (s, 4H).

b) Synthesis of compound 11

Compound 10 (4.57 g, 15.1 mmol) is dissolved in acetone (105 ml), water (10 ml) and pyridinium P-toluenesulfonic acid (1.14 g, 4.5 mmol) are added and the mixture is stirred at 90 ° C for 4.5 hours. Stir. After allowing to cool to room temperature, the solvent was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue for neutralization. The precipitated solid was collected by filtration, washed with water and dried to give compound 11 (3.19 g, yield 82%).

1H-NMR (DMSO-d / TMS) δ ppm: 1.79— 1.84 (m, 2H), 2.13-2.22 (m, 2H), 2.24-2.3

6

5 (m, 2H), 2.79 (dt, J = 4.2, 10.0Hz, 2H), 5.61 (s, 1H), 7.67 (d, J = 6.3Hz, 2H), 7.7 8 (d, J = 6.3Hz, 2H).

Reference Example 5 Synthesis of Compound 14

[Chemical 49]

a) Synthesis of Compound 13

In a nitrogen atmosphere, 4 bromobenzotrifluoride (5.00 g, 22.2 mmol) was dissolved in jetyl ether (35 ml), and magnesium (0.59 g, 24.4 mmol), 1,2-dibromoethane (0.21 g, 1.1 mmol) was dissolved in the solution. It was prepared and stirred at 85 ° C for 45 minutes. After cooling in an ice bath, a solution of compound 12 (3.74 g, 22.2 mmol) in jetyl ether (30 ml) was added dropwise and stirred at room temperature for 1 hour. The mixture was ice-cooled again, water was added, the temperature was raised to room temperature, and saturated salt water was extracted with ketyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound 13. The obtained compound 13 was used crude in the next reaction. b) Synthesis of Compound 14

Crude compound 13 was dissolved in isopropanol (30 ml), and potassium hydroxide (2.94 g, 44.4 mmol) and water (30 ml) were stirred at 80 ° C. for 30 minutes. After cooling in an ice bath, the solvent was concentrated under reduced pressure, and the residue was adjusted to pH 4 by adding 5 mol / L hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate) to obtain Compound 14 (4.81 g, yield of Compound 12 at 75% yield).

1H-NMR (CDC1 I TMS) δ ppm: 1.50— 1.97 (m, 9H), 5.03 (m, IH), 7.62 and 7.65 (ea

Three

ch d, J = 7.2Hz, 2H), 7.68 and 7.71 (each d, J = 7.2Hz, 2H).

Reference Example 6 Synthesis of Compound 15

[Chemical 50]

Compound 14 (4.81 g, 16.7 mmol) was dissolved in trifluoroacetic acid (45 ml) and stirred at 75 ° C. for 30 minutes. Trifluoroacetic acid was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue to adjust the pH to 5. The precipitated solid was collected by filtration, washed with water, and dried to obtain Compound 15 (4.19 g, yield 93%).

1H-NMR (CDC1 I TMS) δ ppm: 1.67-1.77 (m, IH), 1.80—1.99 (m, 2H), 2.05—2.15 (

Three

m, IH), 2.30-2.60 (m, 3H), 6.32 (s, IH), 7.61 (d, J = 7.2Hz, 2H), 7.66 (d, J = 7.2Hz, 2H), 12.17 (br, IH ).

Example 1

Synthesis of compound (I 3)

[Chemical 51] Ζ '(Η98' ^ζ Ηε · = f 'Ρ) Οζ-Ζ' (cloth · ΐ 'WL = f' Ρ) VZ '(Η8' ω) OVZ-ZZ'l '(HS' ζ ΗΓΖ = f '; q.B3) 92 "ΐ pus Z'l HZ-G 8 · ο: υκ 9 (SL / ^ DOD) H NH _X

(^ 爵 ϊί

5 (^ ^ Κ ^ ^ ^ ΎΟ ^ (\ ^omm WO ' ^§ ω O ^) (I)

/ -E fH)

60 · ΐ ^<s 2S) 9T 呦 ^

\ HZ ' ^Z HS'8 = f

'Ρ) fZ'L HZ' ^Z HS'8 = f 'Ρ) 90 ·' (Ηΐ Ί 09 "3 ΗΖ ' ^ζ Ηΐ · Ζ = f gf £' (Ηΐ 'ω) 0 8 · ε- U'S' { ΗΖ 'ω) ^ Z-ZVZ' (Ηΐ 'ω) 62 "2-T2"2' (Ηΐ 'ω) ZI'S- 90' (Η 'ω) 6'1-f 9 · ΐ' (HS 'ΖΗΓ = f 92 "ΐ '(Η2' ω) 02" T-S0 "T ^ dd 9 (SL / oS a) H NH _X

98 ¾τ '§ εε

, The splendor s teaching, ¾ ¾ ma / ^ mu ^ 雜

¾ # 圑

Θ '§ sro)

( ^s 38)

¾ (louiui οε ^ 'Sui SOI) Ma ^ fi ^ 邈氺 I ^0UIUI 93 "ΐ' S ss'o) ^

(Lui S)

C69CZC / 900Zdf / X3d 0 6C8C90 / .00Z OAV .45 (d, J = 7.3Hz, 1.14H), 2.53 (d, J = 7.3 Hz, 0.86H), 4.10 and 4.13 (each q, J = 7.1 Hz, 2H), 7.05 and 7.06 (each d, J = 8.3Hz, 2H), 7.22 and 7.23 (each d, J = 8.3Hz, 2H).

c) Synthesis of compound 18

Under a nitrogen atmosphere, lithium aluminum hydride (53 mg, 1.40 mmol) was suspended in THF (2 ml) and cooled in an ice bath. A solution of compound 17 (0.33 g, 1.11 mmol) in THF (3 ml) was added dropwise, and the mixture was stirred at room temperature for 0.5 hour. The mixture was ice-cooled again, ethyl acetate 551, 10% aqueous sodium hydroxide solution 55 μ1, and water 165 μ1 were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was distilled off under reduced pressure to obtain Compound 18 (0.28 g, yield 100%).

1H-NMR (CDC1 I TMS) δ ppm: 0.82—1.40 (m, 2H), 1.22-1.78 (m, 10H), 2.45 (d, J

Three

= 7.2Hz, 1.17H), 2.53 (d, J = 7.2Hz, 0.83H), 3.67 and 3.68 (each t, J = 6.7Hz, 2H), 7.03- 7.08 (m, 2H), 7.22 and 7.23 (each d, J = 8.4 Hz, 2H).

d) Synthesis of compound 19

Compound 18 (0.28 g, 1.11 mmol) dissolved in THF (11 ml), phthalimide (0.21 g, 1.45 mmol), triphenylphosphine (0.38 g, 1.45 mmol), diisopropyl azodicarboxylate (0.29 g, 1.45 mmol) Was stirred and stirred at room temperature for 1 hour. Diisopropyl azodicarboxylate (0.05 g, 0.25 mmol) was added, and the mixture was further stirred at room temperature for 0.5 hour. The solvent was concentrated 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, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate) to give compound 19 (0.41 g, yield). 98%).

1H-NMR (CDC1 I TMS) δ ppm: 0.94—1.04 (m, 2H), 1.16—1.90 (m, 10H), 2.44 (d, J

Three

= 7.0Hz, 1.15H), 2.53 (d, J = 7.0Hz, 0.85H), 3.66—3.76 (m, 2H), 7.02-7.09 (m, 2H), 7.20-7.25 (m, 2H), 7.68- 7.74 (m, 2H), 7.82-7.87 (m, 2H).

e) Synthesis of Compound 20

Compound 19 (0.41 g, 1.08 mmol) was dissolved in ethanol (3.5 ml), and hydrazine monohydrate (0.14 g, 2.70 mmol) was refluxed for 1 hour. Black mouth form methanol (19: 1 mixture, 5 ml) was added and the solid was filtered off and washed with black mouth form methanol (9: 1 mixture, 20 ml). Filtrate, The washings were combined and concentrated under reduced pressure, and the resulting residue was purified by amino column chromatography (black form-methanol) to obtain Compound 20 (0.23 g, yield 85%).

1H-NMR (CDC1 I TMS) δ ppm: 0.79—1.02 (m, 2H), 1.16—1.75 (m, 10H), 2.49 (d, J

Three

= 7.0Hz, 1.14H), 2.53 (d, J = 7.6 Hz, 0.86H), 2.66-2.74 (m, 2H), 7.05 and 7.06 (ea ch d, J = 8.6Hz, 2H), 7.22 and 7.22 ( each d, J = 8.6Hz, 2H).

f) Synthesis of compound (I 3)

Compound 20 (230 mg, 0.91 mmol) to DMF (2 ml), 6 hydroxynicotinic acid (140 mg, 1.00 mmol), HOBt (148 mg, 1.10 mmol), triethinoreamine (111 mg, 1.10 mmol), DM AP (11 mg, 0.09 mmol) and EDC (199 mg, 1.09 mmol) were added, and the mixture was stirred at room temperature for 4 hours. 1 mol / L hydrochloric acid (12 ml, 12.0 mmol) was extracted with sodium ketyl acetate, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. Distilled under reduced pressure. The obtained residue was recrystallized twice from methanol to obtain the compound (1-3) (62 mg, yield 18%).

mp 228 ° C

1H-NMR (Pyridine-d I TMS) δ ppm: 0.72— 0.90 (m, 4H), 1.20—1.42 (m, 2H), 1.48—1

Five

.70 (m, 6H), 2.34 (d, J = 7.0Hz, 2H), 3.62 (dt, J = 6.4, 7.0Hz, 2H), 6.74 (d, J = 9.6 Hz, 1H), 7.08 (d, J = 8.2Hz, 2H), 7.35 (d, J = 8.2Hz, 2H), 8.31 (dd, J = 2.7,9.6Hz, 1 H), 8.59 (d, J = 2.6Hz, 1H), 8.65—8.72 (m, 1H), 13.51 (brs, 1H).

Example 2

Synthesis of compound (I 17)

[Chemical 52]

1-17 a) Synthesis of Compound 21

Sodium hydride (60% oily, 94 mg, 2.36 mmol) was suspended in THF (2 ml) and cooled in an ice bath. A solution of compound 5 (0.50 g, 2.25 mmol) in THF (3 ml) was stirred at 0 ° C for 30 minutes and at room temperature for 1 hour. The mixture was ice-cooled again, a solution of jetyl phosphono 2-methoxymethyl acetate (0.67 g, 2.36 mmol) in THF (3 ml) was added, and the mixture was stirred at 60 ° C for 3 hr. Water was added to the reaction mixture, 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 dissolved in ethanol (2.5 ml), and P-toluenesulfonic acid monohydrate (47 mg, 0.25 mmol) was refluxed for 1 hour. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane ethyl acetate) to give compound 21 (0.16 g, yield 23%). 1H-NMR (CDC1 I TMS) δ ppm: 1.01- 1.41 (m, 5H), 1.53—1.86 (m, 5H), 1.91—2.01 (

Three

m, 2H), 2.51 (d, J = 7.3Hz, 2H), 2.95—3.04 (m, 0.23H), 3.16—3.23 (m, 0.77H), 4.32 and 4.34 (each q, J = 7.1Hz, 2H ), 7.06 and 7.07 (each d, J = 8.1Hz, 2H), 7.24 and 7.25 (each d, J = 8.1 Hz, 2H).

b) Synthesis of compound 22

Compound 21 (0.16 g, 0.50 mmol) was dissolved in ethanol monohydrate (10: 1 mixture, 1 ml), and 85% potassium hydroxide (50 mg, 0.75 mmol) was stirred at room temperature for 2.5 hours. . Under ice-cooling, 2 mol / L hydrochloric acid (1 ml, 2.0 mmol) and the solvent were distilled off under reduced pressure. To the residue was added 2 mol / L hydrochloric acid (0.5 ml, 1.0 mmol), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 22 (0.14 g, yield 100%).

1H-NMR (DMSO-d / TMS) δ ppm: 0.94—1.08 (m, 2H), 1.09—1.24 (m, 2H), 1.39—1.5

6

3 (m, 1H), 1.69 (d, J = 12.6Hz, 2H), 1.88 (d, J = 12.6Hz, 2H), 2.47 (d, J = 6.8Hz, 2H), 2.82-2.93 (m, 1H), 7.17 (d, J = 8.3Hz, 2H), 7.32 (d, J = 8.3Hz, 2H).

c) Synthesis of compound (I 17)

Compound 22 (141 mg, 0.50 mmol) to DMF (1 ml), 6-aminobenzoxazolone (83 mg, 0.55 mmol), HOBt (81 mg, 0.60 mmol), triethinoreamine (61 mg, 0.60 mmol), DM AP (6.1 mg, 0.05 mmol) and EDC (109 mg, 0.60 mmol) were added and stirred at room temperature for 17 hours. 1 mol / L hydrochloric acid (15 ml, 15.0 mmol) was extracted with sodium ketyl acetate, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. Distilled under reduced pressure. The obtained residue was recrystallized from methanol to obtain Compound (1-17) (182 mg, yield 87%).

mp 218 ° C

1H-NMR (DMSO-d I TMS) δ ppm: 0.98— 1.12 (m, 2H), 1.14—1.28 (m, 2H), 1.49 (br,

6

1H), 1.71 (d, J = 12.1Hz, 2H), 1.90 (d, J = 12.1Hz, 2H), 2.48 (d, J = 6.8Hz, 2H), 3.24 (t, J = 11.7Hz, 1H), 7.08 (d, J = 8.3Hz, 1H), 7.18 (d, J = 8.3Hz, 2H), 7.32 (d, J = 8.3Hz, 2H), 7.57 (d, J = 8.3Hz, 1H) , 7.82 (s, 1H), 10.56 (s, 1H).

Example 3

Synthesis of Compound (I 36)

[Chemical 53]

1-36

a) Synthesis of Compound 23

Compound 9 (1.90 g, 9.21 mmol) obtained in Reference Example 3 was dissolved in THF (90 ml), and ethyl phosphonoacetate (2.58 g, 11.51 mmol) was stirred at 60 ° C. for 5 minutes. Lithium hydroxide (728 mg, 30.39 mmol) was refluxed for 2 hours, then ethylphosphonoacetate ethyl (0.51 g, 2.30 mmol) and molecular sieves 4A (2 g) were added, and the mixture was further refluxed for 5 hours. After allowing to cool to room temperature, the solvent was distilled off under reduced pressure, 2 mol / L hydrochloric acid and water were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane acetate To give compound 23 (1.50 g, yield 59%).

1H-NMR (CDC1 I TMS) δ ppm: 1.05—1.22 (m, 2H), 1.27 (t, J = 7.2Hz, 3H), 1.66—1.

Three

96 (m, 4H), 2.07-2.20 (m, IH), 2.22-2.32 (m, IH), 2.41-2.56 (m, 2H), 3.71-3.82 (m, IH), 4.13 (q, J = 7.1 Hz, 2H), 5.61 (s, IH), 6.91-7.01 (m, 2H), 7.04-7.12 (m, 2H) .b) Synthesis of Compound 24

Compound 23 (276 mg, 1.0 mmol) was dissolved in ethanol (2 ml), and 4 mol / L sodium hydroxide (1 mg, 4.0 mmol) was stirred at 50 ° C. for 3 hours. The solvent was distilled off under reduced pressure, 2 mol / L hydrochloric acid was added to the residue to make it acidic, and the precipitated crystals were collected by filtration. Compound 24 (214 mg, yield 86%) was obtained after drying.

1H-NMR (CDC1 I TMS) δ ppm: 1.05— 1.25 (m, 2H), 1.68—1.81 (m, IH), 1.81—1.98 (

Three

m, 3H), 2.09-2.22 (m, IH), 2.25—2.36 (m, IH), 2.42-2.57 (m, 2H), 3.68—3.81 (m, 1 H), 5.64 (s, IH), 6.92 -7.01 (m, 2H), 7.04-7.13 (m, 2H), 11.62 (brs, IH).

c) Synthesis of compound (I 36)

Compound 24 (99 mg, 0.40 mmol) was dissolved in THF (4 ml) and cooled on ice. Oxalyl chloride (76 mg, 0.60 mmol), DMF—drops were stirred at 0 ° C. for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in THF (3 ml), and a solution of 6-aminobenzoxazolone (60 mg, 0.40 mmol) in THF (2 ml) was stirred at room temperature for 1 hour. 2 mol / L hydrochloric acid was made acidic and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by amino column chromatography (methylene chloride-methanol), recrystallized from acetone-water, and the crystals were collected by filtration to give Compound (I 36) (49 mg, 32% yield). Obtained.

mp 224 226 ° C

1H-NMR (DMSO-d I TMS) δ ppm: 0.96- 1.18 (m, 2H), 1.64—1.82 (m, 3H), 1.89 (t,

6

J = 9.8Hz, IH), 2.03-2.29 (m, 2H), 3.20-3.41 (m, 2H), 3.83 (d, J = 10.2Hz, IH), 5. 78 (s, IH), 7.00 (d , J = 6.3Hz, IH), 7.09 (t, J = 6.6Hz, 2H), 7.20 (dd, J = 4.5, 6.6H z, 2H), 7.22 (d, J = 6.3Hz, IH), 7.74 ( s, IH), 9.90 (s, IH), 11.49 (brs, IH).

Example 4

Synthesis of compound (I 42) [Chemical 54]

I-36 I -42 The compound (I 36) (127 mg, 0.33 mmol) obtained in Example 3 was dissolved in THF (3 ml) and cooled to -78 ° C with a dry ice / acetone bath. A 2.0M LDA-THF / heptane / ethyl benzene solution (0.66 ml, 1.32 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 1 hour. The mixture was acidified with 2 mol / L hydrochloric acid, extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogen carbonate 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 (methylene chloride / methanol), recrystallized from acetone, and the crystals were collected by filtration to give compound (1-42) (21 mg, yield 17%).

mp 195 197 ° C

1H-NMR (DMSO-d I TMS) δ ppm: 1.11- 1.31 (m, IH), 1.60—1.80 (m, 3H), 1.88—2.1

6

1 (m, 3H), 2.52 (d, J = 6.0Hz, 2H), 2.93 (s, 2H), 5.49 (s, IH), 7.00 (d, J = 6.3Hz, 1 H), 7.08 (t, J = 6.3Hz, IH), 7.14-7.23 (m, 3H), 7.67 (s, IH), 9.92 (s, IH), 11.49 (br s, IH).

Example 5

Synthesis of compound (I 20)

[Chemical 55]

a) Synthesis of Compound 25

Compound 11 (3.19 g, 12.4 mmol) obtained in Reference Example 4 was dissolved in THF (60 ml), and then ethyl phosphonoacetate (3.68 g, 18.5 mmol) and molecular sieves 4A (7.4 g) were mixed for 5 minutes. Refluxed. Lithium hydroxide (10.36 g, 43.3 mmol) was refluxed for 2.5 hours, allowed to cool to room temperature, and the reaction mixture was filtered. The filtrate was acidified with dilute hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate, 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 25 (1.66 g, yield 41%).

1H-NMR (DMSO-d / TMS) δ ppm: 1.20 (t, J = 7.2Hz, 3H), 1.79—1.84 (m, 4H), 2.2

6

2 (d, J = 12.0Hz, IH), 2.38 (dt, J = 6.6, 12.0Hz, IH), 2.68 (dt, J = 4.8, 12.0Hz, IH), 3.67 (d, J = 12.0Hz, IH ), 4.08 (q, J = 7.2Hz, 2H), 5.37 (s, IH), 5.72 (s, IH), 7.66 (d, J = 8.4Hz, 2H), 7.68 (d, J = 8.4Hz, 2H ).

b) Synthesis of compound 26

Compound 25 (1.66 g, 5.05 mmol) was dissolved in methanol (10 ml), 10% palladium carbon (332 mg) was added, the system was replaced with hydrogen gas, and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered to remove insolubles, and the filtrate was distilled off under reduced pressure to obtain Compound 26 (1.60 g, yield 96%). 1H-NMR (DMSO-d / TMS) δ ppm: 1.18 and 1.20 (each t, J = 7.2Hz, 3H), 1.42—1.4

6

9 (m, 3H), 1.63 (d, J = 9.3Hz, 2H), 1.73—1.88 (m, 2H), 1.89—2.12 (m, 2H), 2.23 and 2.38 (each d, J = 5.1Hz, 2H), 4.06 and 4.08 (each d, J = 7.2Hz, 2H), 4.94 and 5.01 (each s, 1H), 7.66 (d, J = 8.4Hz, 2H), 7.72 (d, J = 8.4Hz, 2H).

c) Synthesis of compound 27

Compound 26 (1.60 g, 4.84 mmol) was dissolved in THF (50 ml), and thiol chloride (5.8 ml, 79.5 mmol) was added thereto, followed by stirring at 80 ° C. for 0.5 hour. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethanol (25 ml). A solution of potassium hydroxide (2.88 g, 51.3 mmol) in water (25 ml) was added and stirred at 80 ° C. for 0.5 hour. The mixture was allowed to cool to room temperature, neutralized with 6 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, trifluoroacetic acid (10 ml) was added to the obtained residue, and the mixture was stirred at 80 ° C. for 15 min. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue to make it alkaline, and the precipitated crystals were collected by filtration. After washing with water and drying, compound 27 (1.28 g, yield 93%) was obtained.

1H-NMR (DMSO-d / TMS) δ ppm: 1.22— 1.63 (m, 1H), 1.83—2.08 (m, 3H), 2.19 (d,

6

J = 5.1Hz, 2H), 2.32-2.53 (m, 3H), 6.28 (brs, 1H), 7.60 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4Hz, 2H).

d) Synthesis of compound 28

Under a nitrogen atmosphere, lithium aluminum hydride (114 mg, 3.00 mmol) was suspended in jetyl ether (15 ml) and cooled in an ice bath. A solution of Compound 27 (0.57 g, 2.00 mmol) in Jettier® (10 ml) was added dropwise and stirred at room temperature for 1 hour. The mixture was ice-cooled again, and 0.8 ml of water was added and stirred at 0 ° C for 0.5 hour. The reaction solution was filtered, and the residue obtained by evaporating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 28 (0.45 g, yield 84%).

1H-NMR (DMSO-d / TMS) δ ppm: 1.32— 1.38 (m, 1H), 1.40—1.55 (m, 2H), 1.65—1.9

6

3 (m, 3H), 2.34-2.45 (m, 3H), 3.53 (brd, J = 2.7Hz, 2H), 4.41 (s, 1H), 6.29 (s, 1H), 7.59 (d, J = 8.3Hz , 2H), 7.64 (d, J = 8.3Hz, 2H).

d) Synthesis of compound 29

Compound 28 (0.45 g, 1.67 mmol) was dissolved in THF (14 ml), phthalimide (0.30 g, 2.00 mmol), triphenylphosphine (0.53 g, 2.00 mmol), diisopropyl azodicarboxylate ( 9 m

• (HI 's-iq) WW' (Ηΐ 'ZHS' = f ') ZZ'S' (Ηΐ 'ZHS'I = f' Ρ) 66 "Z '(HI' z HZ'L 'S'l = f' PP) Z8 "Z HZ ' ^Z HS'8 = f' P) S9" Z '(H2'ZHS'8 = f 'P) WL' (Ηΐ '^ ΗΖ' Z = f 'Ρ) Γ9' (Ηΐ ' s-iq) ΐε · 9 '(Η2' ZHS '= f TST' (HS 'ω) OS'S- SS'S' (H2 q 6 · ΐ— SZ'I '(HS 2 "T- FT' (Ηΐ 'ω) IF T-2S "T ^ dd 9 (SL / OSW I) WN— Η _τ

OoOSS 6fZ dm

. (% ooi ¾ί ε9ΐ) (os -ι)

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'0U) 0S 呦 ^

^ O) (0S-I) i¾J ^ (J \ HZ ' ^Z HS'8 = f' Ρ) WL ΗΖ ' ^ζ Ηε8 = f' Ρ) WL '(HI' s-iq) οε · 9 '( Ηΐ 's) S9' (Ηΐ 's) ζνζ' (Ηΐ · εΐ = f ') ΖΖ'Ζ' {ΗΖ 'ω) ε 6 · ΐ— 08 · ΐ' (Ηΐ 'ω) · ΐ— 09 · ΐ '(Η' ω) 8 · ΐ— ΐε · ΐ: ω (ρ (SL / oS a) H NH _x

°-(% οοΐ * ¾ί '§ 8ε · ο) οε α ^ Μ Teaching, 翁: ^ Ma (Η 邈 ^ 氺雜 # ^ a ^ ¾ ^ m a ^ ¾W ^

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• (H 68'Z-08 "Z '(H2'ZHS'8 = f 'Ρ), 9 · HZ' ^Z HS'8 = f 'P) WL' (HI 's-iq) 0S'9' ( Η2 'ZHI'S = f';) 89T '(Ηΐ' ω) 8 '(Η2' s) ^ '(Η2' ω) ΐ 0 "2-28" T '(HS' ω) Z9 "T-SS" T '(Ηΐ' ω) · ΐ— ΐε · ΐ: ω (9 (SL / oS a) H NH _X

^ ^ ^-^^^ m -M ^ ^^ ^ m, ¾ ¾ ma rw 邈

Samurai

C69CZC / 900Zdf / X3d 6 6C8C90 / .00Z OAV f 'ρ) WL' (HI q) os'9 '(HI' s-iq) ιε · 9 '(ΗΖ' ω) οε · ε '(Ηε os — εε ΗΖ e

6 · ΐ— 08 · ΐ '(HS' ω) ZL'l-Wl '(Ηΐ' ω) sri-Te-i: uid g 丄 / oS a) H NH _x

0 _o \ fZ OfZ ^d ^ 會! ^ (% 00ΐ umbrella ¾ί 09ΐ) (33-

'Add ε

[s]

^ (ZZ— I) 呦 ^ [Z600]

• (HI 's-iq) ZO

• ΐΐ '(Ηΐ' ω) ΐΖ'Ζ '(Η2' ZHS'8 = ['Ρ) S9 "Z' (Η2 'ZHS'8 = Γ' Ρ) Ϊ9" Ζ '(Ηΐ' s) '(Η

I ( ^s ) Ζ 9 '(HI' s) 9 9 '(HI' s-iq) ΐε9 '(Η2') OSX '(HS' ω) 0S "2-SS" 2 '(Η2' ω ) S

6 · ΐ— 08 · ΐ '(HS' ω) · ΐ— 9 · ΐ '(Ηΐ' ω): uidd ρ (SL path Ρ— OSWa) ^ N— Η _τ

. ¾ (% 6 ¾ί Ο ^ ΐ) (IS

-D ^ ^^ n ^^ ^ m ^ m ^ r ^^ ⁰ ^ o '

OS)

[9S]

¾tf ^ O) (IS-I) i ^ [9600]

C69CZC / 900Zdf / X3d 031- 6 £ 8 £ 90 / .00Z OAV = 8.3Hz, 2H), 7.65 (d, J = 8.3Hz, 2H), 8.03 (br, 3H).

Example 8

Synthesis of compound (I 30)

[Chemical 58]

a) Synthesis of Compound 31

Under a nitrogen atmosphere, lithium aluminum hydride (0.74 g, 19.5 mmol) was suspended in jetyl ether (50 ml) and cooled in an ice bath. A solution of compound 15 (4.19 g, 15.5 mmol) obtained in Reference Example 6 in jetyl ether (100 ml) was added dropwise and stirred at room temperature for 1 hour. The mixture was ice-cooled again, 1 ml of water was added, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was filtered using Celite, and the residue obtained by evaporating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane acetate) to obtain Compound 31 (2.82 g, yield 71%). It was.

1H-NMR (DMSO-d / TMS) δ ppm: 1.28— 1.39 (m, IH), 1.65—1.75 (m, IH), 1.83—1.9

6

7 (m, 2H), 2.30 (d, J = 14.4Hz, IH), 2.42 (brs, 2H), 3.30 (m, 2H), 4.53 (t, J = 3.9Hz, IH), 6.32 (s, IH ), 7.62 (d, J = 8.3Hz, 2H), 7.65 (d, J = 8.3Hz, 2H).

b) Synthesis of compound 32

Compound 31 (2.44 g, 9.52 mmol) was dissolved in ethyl acetate (120 ml), and IBX (8.00 g, 28.6 mmol) was stirred at 85 ° C. for 3.5 hours. The mixture was cooled in an ice bath, and the precipitated solid was removed by filtration and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure to give crude compound 32 (2.43 g, crude yield). 6 "ΐ-ΖΖ · ΐ '(HS' ω) 29" T-8FT '(Ηΐ' ω) 6S "T-62" T ^ dd g (SL / oS a) H NH _X ο ^ ¾ (% 66 * ¾ί 's 99-T) es ^. Tsu ¾ 氺 m

(OS) 氺 Ι. ωυι VSZ '§ 8S'I) ma fi 邈氺、 tsu (\ ^M 0 ^) — (louiui Z9'^<s 8 · ΐ) ε 呦 ^

"(HS 'ZHS'8 = f' Ρ) S9" Z '(HS'ZHS'8 = f 'P) WL' (Ηΐ Ί 6 Z'9 HZ ' ^Z H' S = f 90 ·, '(HS 'ω) WZ ~ Z'Z HZ' ω) S6'I-ΐ '(HS' ω) S9'I- S

S'I '(HI ss'i— ιε · ΐ' (Ηε 'zwe = f evi-^^ 9 (SL / os a) H NH _X

¾ (% 96 ¾i '§ 8 · ΐ) ε

^ w ^ ^ m ^ ^ ^ m ^^ ^ n ^ m! ^ 翻 s'o

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"(HS 'ZHS'8 = f' Ρ) 99" Ζ ΗΖ 'Ζ Η ε · 8 = f' Ρ) Z9'L '(Ηΐ' ΖΗΟ ΐ 'Γ3 = f' ΡΡ) 96 · 9 '(Ηΐ 9 '(Ηΐ' ΖΗΟ ΐ = ΓΡ) ΐ

6's' {ΗΖ 'we = [zvf LVZ- ^ Z' (HI 'ω) srs-so ^' (HI oo-ε

6 · ΐ '(Ηΐ' ω) ε9 · ΐ— ¾ · ΐ '(HS' ZWS = f S2 "i: radd 9 (SL / oS a) H NH _X

C) T (Ye 4S—Be ^

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C69CZC / 900Zdf / X3d ZZY 6C8C90 / .00Z OAV "(Ηΐ 's) ΐΟ ΐ' (Ηΐ 's) Ml HZ' ^Z HS'8 = f 'Ρ) S9" Z HZ' ^ζ Ηε · 8 = f 'Ρ) Z9'L' (Ηΐ 'ZHS'9 = f 'Ρ) WL' (Ηΐ '^ Η ε · 9 = f' Ρ) 00 "Ζ '(Ηΐ' s) ΐε · 9 '(HS O ^ Z-OVZ' (HZ ' ^Z HS' = f ' ) 6S '(HZ' ω) 8 6 · ΐ— S8'I '(HS' ω) 2 "T-WT '(Ηΐ' ω) · ΐ— ^ · ΐ: ω (9 (SL / oS a) H NH _x

0 _o S82182 din

' ^§ ω SZ)

OS ^'§ ω SS) Baie, ίί, one S

[6S]

^) (χε-ι) ί¾? ^

6 m

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6 · ΐ— S8'I '(HS' ω) 89 · ΐ— ½ · ΐ '(Ηΐ' ω) WI— SS'I ^ dd 9 (SL / oS a) H NH _x

0 _o 9S2 SS2 din

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"(HS 'ZHS'8 = f' Ρ) S9" Z HZ ' ^Ζ Η ε · 8 = f' Ρ) WL '(Ηΐ' s) 62 "9 '(HS 8 —' ((2 'ZHS' = f OS '(Η2' ω) S

C69CZC / 900Zdf / X3d 831- 6C8C90 / .00Z OAV Thereafter, other compounds (I) are synthesized in the same manner. The structural formula and physical constant are shown below.

[Table 5] Compounds

Number Structural formula Saddle point or NMR

(D SO-d _e / TS) <5 pm: 1.30- 1.50 (m, 2H), 1.60-1.75 (m, 6H) 2.22-2.38 (m, 1H), 2.70 (s, 2H), 2.79 (t, J = 5.6Hz, 2H), 3.60 (dt, J = 5.6, 5.6Hz, 2H), 6.54 (d, J = 9.6Hz, 1H), 6.97 (m, 2H), 7.15 (m, 2H), 7.83 ( dd, J = 9.6, 2.4Hz, 1H), 8.07 (d, J = 2.4Hz, 1H).

(DMSO-d _e / TMS) <Sppm: 0.95- 1.05 (m, 1H), 1,20-1.38 (m, 2H), 1.40-1.62 (m, 1H), 1.72-1.92 (m, 4H), 2.22 -2.38 (m, 1H), 2.46 (d, J = 7.2Hz, 2H), 2.78 (t, J = 5.6Hz, 2H), 3.61 (dt, J = 5.6, 5.6Hz, 2H), 6.55 (d, J = 9.6Hz, 1H), 6.95 (m _t 2H), 7.06 (m, 2H), 7.80 (dd, J = 9.6, 2.4Hz, 1H), 8.05 (d, J = 2.4Hz, 1H).

228

255-256

260-261

223-226

194

[0103] [Table 8] [e [rain o]

C69CZC / 900Zdf / X3d 831- 6C8C90 / .00Z OAV

[0106] [Table 11]

[0107] [Table 12]

C69CZC / 900Zdf / X3d 6C8C90 / .00Z OAV [0109] [Table 14]

C69CZC / 900Zdf / X3d 981- 6C8C90 / .00Z OAV

C69CZC / 900Zdf / X3d 9ε ΐ 6C8C90 / .00Z OAV [0113] [Table 18]

[0116] [Table 21]

C69CZC / 900Zdf / X3d 6C8C90 / .00Z OAV [0119] [Table 24]

[0121] [Table 26]

[0122] 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, S1 Wistar rats, and the brains were decapitated 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.

Binding experiments consisted of adding 470 μl of the above membrane preparation with 10 μl of different concentrations of the test compound, 10 μl of the labeled ligand [ ³ H] -Ifenprodil and 10 μl of GBR-12909, And incubated for 120 minutes. The final concentration of labeled ligand [ ³ H] -Ifenprodil was 5 ηΜ, and the final concentration of GBR-12909 was 3 M. DMSO, a solvent, was used to measure the total amount of binding, and ifenprodil at 100 / z M was used to measure the amount of non-specific 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 27 shows the IC values of the test substances.

50 50

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

[0123] [Chemical 60]

Binding inhibition rate (%) = 100 [(binding in the presence of test compound) non-specific binding amount) / (total binding amount non-specific binding amount)] X 100

[Table 27]

The following compounds had an IC force of ^ M or less.

50

1-41, 1-47, 1-46, 1-48, 1-52, 1-59, I--66, 1-67, 1-71, 1-72, 1--7 3, 1-75, 1—77, 1—78, 1—80, 1—81, 1—82, 1—84, 1—85, 1—87, 1—90, I

— 91, 1-93, 1-94, 1-95, 1-96, 1-97, 1-98, 1-99, 1-103, 1-104, I-106, 1-107, 1-109 , 1-110, 1-111, 1-112, 1-113, 1-114, 1-118, I

— 119, 1—120, 1—121, 1—123, 1—124, 1—127, 1—128, 1—130, 1—132, 1—133, 1—134, 1—135, 1—136 , 1-137, 1-138, 1-139, 1-141, 1-144, 1-148, 1-149, 1-150, 1-152, 1-153, 1-154, 1-157, 1 —158, 1-15 9, I 160, etc.

From the above results, it was clarified that the compound of the present invention shows 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 1 day after the introduction, changes in glutamate Z-glycine-induced intracellular Ca content were measured using a Ca ion-reactive fluorescent dye.

HEK293 cells are cultured using modified Dulbecco's Eagle medium (DMEM, low glucose). Nourished and passed.

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 was 0.025 g NR1 subunit per well and 0.075 g NR2B subunit per hole. After the introduction, the cell death was suppressed by using 50 μΜ of NMDA receptor antagonist MK-801.

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

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

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

From the measured value of the test compound, the Ca ion influx inhibition rate (%) was determined by the following equation, and the dose (IC) that inhibited inflow by 50% was calculated. Table 28 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 28]

The following compounds showed IC below 0.1 μΜ _c 1—59, 1—66, 1—67, 1—73, 1—74, 1—75, 1—76, 1—77, 1—79, 1—80, 1—8 1, 1—84, 1 — 85, 1—90, 1—92, 1—96, 1—97, 1—98, 1—99, 1—103, 1—106, 1—107, 1—108, 1—109, 1—110 , 1-111, 1-112, 1-113, 1-114, I- 11 5, 1-116, 1-117, 1-118, 1-119, 1-120, 1-122, 1-123, 1-124, I- 1 25, 1-126, 1-127, 1-128, 1-129, 1-130, 1-131, 1-132, 1-134, I- 135, 1-136, 1 —137, 1—141, 1—144, 1—145, 1—146, 1—148, 1—150, I—152, I—153, etc.

From the above results, it was clarified that the compound of the present invention exhibits NMDA receptor antagonistic action.

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

Or

ii) Containing NH in the ring

Satisfying at least one of

R ^2a , R ^2b and R ^2e are each independently hydrogen, hydroxy or lower alkyl, R 1 and R ^2a or R ^2b and R ^2e may be joined together to form a single bond,

R ^2a and R ^2b may be joined together to form one O or OCH 2-

2

m is 0 or 1,

X may have a substituent, may be lower alkylene, or may have a substituent, lower alkylene, CO (CR ³ R ⁴ ) n CONR ⁵ (CR ³ R ⁴ ) n CONR ⁵ (CR ³ R ⁴ ) q— NR ⁶ —, — NR ⁵ CO (CR ³ R ⁴ ) n—, — NR ⁵ CONR ⁶ (CR ³ R ⁴ ) n—, — C (= N— OR ⁷ )

(CR R) n―, ― (CR¾ ^M ) rO (ClT) n (CR ⁸ R ⁹ ) rS (CR ³ R ⁴ ) n―,-(CR.R 9) rSO (CR ³ R ⁴ ) n- ( CR ⁸ R ⁹ ) rSO (CR ³ R ⁴ ) n CR ⁹ = N-0 (CR ³ R ⁴ ) n

C (= 0) 0 (CR ³ R ⁴ ) n- A ^3- (CR ³ R ⁴ ) n-A ³ — (CR ³ R ⁴ ) qNR ⁶ --A ³ -NR ⁶ (CR ³ R ⁴ ) n-or — A ³ — CR ¹⁰ = CR ¹¹ (CR ³ R ⁴ ) n, n and r are each independently an integer from 0 to 4, q is An integer from 1 to 4,

Y is a single bond, lower alkylene, lower alkylene, lower alkylene, O—, — S— ゝ one NR ¹⁵ , one CR ¹² R ¹³ 0—, one CR ¹² R ¹³ S or one CR ¹² R ¹³ NR ¹⁵ where X— (CO) m is —CONR ⁵ CR ³ R ⁴ Y is a single bond, R ³ , R ⁴ , R ⁵ ,

R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , ¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ may each independently have hydrogen or a substituent, and may be lower It is alkyl, and when there are two or more R ³ and R ⁴ , they are different from each other! /.

Also,

Y and R ^2a may form together = CR ¹⁴ — (CR ¹⁵ R ¹⁶ ) p— (p is an integer from 0 to 5) when m is 0 and n is 1 or more, R ^2b may combine with the carbon atom to which R ^2b is bonded to R ³ on the adjacent CR ³ R 4 to form a single bond.)

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 2]

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-0 (CHR ³ ) n— — SO (CHR ³ ) n— —SO ( CHR ³ ) n― ― CH = NO (CHR ³ ) n―

2

C (= 0) 0 (CHR ³ ) n— A ³ — CHR ³ — A ³ — CHA ³ — (CR ³ R ⁴ ) qN

twenty four

The compound according to claim 1, which is R ⁶ — or — A ³ — NR ⁶ (CR ⁴ ) q—, 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 14 to 14, wherein m is 0, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[7] The compound according to any one of claims 14 to ¹⁴ , wherein R ¹ is hydrogen, R ^2a is hydrogen or hydroxy, and R ¹ and R ^2a are combined to form a single bond. An acceptable salt or a solvate thereof.

[8] R ^2b is hydrogen or hydroxy and R ^2e is hydrogen, R ^2b and R ^2e are combined to form a single bond, or m is 0 and n is 1 or more There, and R ^2b are, and together form a connexion single bond and R ³ on CR ³ R ⁴ and the adjacent carbon atom to which R ^2b is attached, the compound according to any one of claims 1 to 6 or The pharmaceutically acceptable salt or solvate thereof.

[9] Y is a single bond or —CH— or together with R ^2a to form = CH— Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[10] A ² is halogen, Xia input lower alkyl, halogeno-lower alkyl, lower alkoxy and halogeno lower alkoxy force selected by one or more optionally substituted with a group off - a le, of claims 1 to 9 A compound according to any one of the above or a pharmaceutically acceptable salt or solvate thereof.

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

[12] A ¹ may have a substituent, or may be a nitrogen-containing aromatic monocyclic group, which may be protected! Or may be hydroxy or protected. The compound or a pharmaceutically acceptable salt thereof or a solvate thereof according to any one of claims 1, 4 and 6 to: wherein L has at least one amino and n is 2 or more.

[13] A ¹ is a nitrogen-containing aromatic condensed cyclic group which may have a substituent, and the group is protected

V, may, hydroxy or protected, have at least one amino and X is one N

The compound or a pharmaceutically acceptable salt thereof or a solvate thereof according to any one of claims 1 to 6, wherein the compound is R ⁵ CO (CR ³ R ⁴ ) n—.

[14] A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

15. The pharmaceutical composition according to claim 14, which has an NMDA receptor antagonistic action.

16. The pharmaceutical composition according to claim 15, which has an NR1ZNR2B receptor antagonistic action.

[17] Pain or migraine, stroke, head trauma, Alzheimer's disease, Parkinson's disease, tinnitus

15. The pharmaceutical composition according to claim 14, which is a therapeutic agent for epilepsy, Huntington's disease, movement disorder or alcoholism.

[18] A method for alleviating pain or migraine, stroke, head trauma, Alzheimer's disease, Parkinson's disease, tinnitus, characterized by administering a compound according to any one of claims 1-13

, Treatment of epilepsy, Huntington's disease, movement disorders or alcoholism.

[19] Manufacture of analgesics or treatments for migraine, stroke, head trauma, Alzheimer's disease, Parkinson's disease, tinnitus, epilepsy, Huntington's disease, movement disorders or alcoholism Use of a compound according to any of claims 1 to 13 for.