JP2001031652A - Six-membered heterocyclic compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new compound useful in medicinal and veterinary fields, because of having hypoglycemic action and low toxicity, and especially useful for preventing or treating diabetes and diabetic complications, such as diabetic ophthalmia, diabetic neutropathy, diabetic nephropathy, etc. SOLUTION: This compound is a six-membered heterocyclic compound of formula I A is expressed by formulae II, III or IV [(m), (n), (n1), (n2) are each 0, 1, 2 or 3; R1 is H, a halogen or the like; R2 is H, a halogen or the like; R3 and R3' are each a 1-7C alkyl; R4 is H, a 1-7C alkyl or the like; D is a covalent bond, CH2 or the like; X1, X2, X3, X4 and X5 are each N or the like, provided that at least one of the X1, X2, X3, X4 and X5 is N]} or its salt, for example, methyl (R)-3-[4-chloro-6-(2-phenoxyethoxy)pyimidin-2-yl]amino-4-tert- butoxycarbonylamino-butyrate. A compound of formula I is, for example, is obtained by reacting a compound expressed by such a formula that D-A in formula I is replaced by R16 (R16 is an eliminating group such as a halogen) with a compound expressed by the formula of H-D-A in the presence of a base in a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel 6-membered heterocycle having a hypoglycemic action, which is used in the field of medicine or veterinary medicine, particularly for the prevention and treatment of diabetes and diabetic complications. is there.

[0002]

2. Description of the Prior Art Various sulfonylurea agents and biguanides have been widely used as oral diabetic drugs for lowering blood sugar levels. However, these drugs can cause severe hypoglycemic coma and lactic acidosis, and their use requires great care. Insulin sensitizers developed in recent years also have a blood glucose lowering effect, are particularly useful for obese type II diabetes, and have attracted attention as drugs that are unlikely to cause hypoglycemic disorders unlike the previous oral diabetes drugs, It is known that patients with insufficient insulin secretion cannot obtain a sufficient effect. The drugs shown above do not necessarily lower fasting blood glucose. Recently, carnitine palmitoyltransferase (CPT) inhibitors not only have a hypoglycemic effect in various diabetes model animals and diabetic patients (Horm. Metab. Res., Vol. 25, 9-12, 1993, Japanese published patent publication No. 57-501233, Japanese Patent Application Laid-Open No. 6-73077, European Patent Application EP-0127098), it has been reported that it also reduces fasting blood glucose (Metabolism, vol. 40, 118).
5-1190, 1991), and has attracted attention as a drug having a fasting blood glucose lowering action, which is difficult to treat with conventional drugs. CPT
The inhibitor has a mechanism of lowering blood glucose by suppressing hepatic gluconeogenesis without relying on insulin secretion from the pancreas, and is therefore expected to be effective for patients with insulin secretion deficiency. In addition, it has been confirmed that insulin sensitivity is reduced in type II diabetes patients, that is, it has an effect of improving sugar utilization (Horm Metab.
s., vol. 24, 115-118, 1992).

[0003] The present CPT inhibitor has an effect of effectively lowering the blood glucose level, but has various complications associated with diabetes, such as diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neurosis and the like. Its efficacy in preventing onset and progress has not yet been fully proven. However, II
CPT inhibitors have also been reported to suppress renal immunopathological changes that occur in db / db mice, which are considered models of type 2 diabetes (Diabetes, vol. 31, 12-18, 198
2) In addition, since the progress of these various complications is suppressed by strict glycemic control, they are useful as preventive and therapeutic agents for these complications.

[0004] In addition, CPT inhibitors have been shown to have potent ketone body lowering effects in diabetic model animals and diabetic patients (Proc. Soc. Exp. Biol. Med.,
vol.178, 288-296, 1985, Metabolism, vol.40, 1185-
1190, 1991). It is also expected to prevent not only diabetes but also all pathologies caused by increased cytopathologically produced ketone bodies.

[0005]

Under such a background, the inventors of the present invention have conducted various synthetic studies of six-membered heterocycles which are not specifically described in the above-mentioned patent gazettes. A compound having an excellent blood glucose lowering action was found. The present invention
Provided are six-membered heterocycles that can be used for prevention and treatment of diabetes and diabetic complications.

That is, the present invention provides a compound of the formula [I]

Embedded image [Where A is

Embedded image｛M, n, n¹And n^TwoAre independently 0, 1, 2,
Or 3 for R¹Is hydrogen, halogen, nitro
Group, cyano group, formyl group, sulfonic acid group, sulfonic acid
Amide group, PO_TwoH_Two, PO_ThreeH_Two, 5-tetrazolyl group, C (O) OR⁶
(R⁶Is a hydrogen atom, or C_1-7Represents an alkyl group. ), C (O)
NR⁷R^{7 '}(R⁷And R^{7 '}Are each independently a hydrogen atom, or C
_1-7Represents an alkyl group. ), OR⁸(R⁸Is a hydrogen atom, C_1-7A
Represents a alkyl group or a phenyl group. ) Or NR⁹R^{9 '}(R⁹
And R^{9 '}Are each independently a hydrogen atom, C_1-7Alkyl
Represents a phenyl group or a phenyl group. ), And R^TwoIs a hydrogen atom,
Halogen atom, nitro group, cyano group, formyl group, guar
Nidyl group, amidino group, NR^TenR^Ten'(R^TenAnd R^Ten'Is it
Each independently a hydrogen atom, C_1-7Alkyl group, C_1-7Aliphatic
Sill, C_6-10Represents an aromatic acyl or a protecting group. ),or
Is N⁺R¹¹R^{11 '}R^{11 ''}(R¹¹, R^{11 '}And R^{11 ''}Are independent
Then C_1-7Represents an alkyl group. ), And R^ThreeAnd R ^{3 '}Haso
Each independently C_1-7Represents an alkyl group, R^FourIs a hydrogen atom,
C_1-7Alkyl group, C_1-7Aliphatic acyl, C_6-10Aromatic reed
Or a protecting group. Represents｝. D is a covalent bond, -C
H_Two-, -O-, -S-, -S (O)-, -S (O)_Two-, -NR¹²-, -C (O) -NR¹²
-, -NR¹²-C (O)-or -NR¹²-C (O) -NR^{12 '}-(R¹²And R
^{12 '}Are each independently a hydrogen atom, or C_1-7Alkyl group
Represents ). X¹, X^Two, X^Three, X^Four, And X^FiveIs
Each independently a nitrogen atom or CR^Five｛R^FiveIs hydrogen field
, A halogen atom, or -EG (E is -L¹-(CR¹³R^13')_k-
L^Two-(CR¹⁴R^14')_l-L^Three-(K represents 1 to 10. l is 0 to 10.
Represents R¹³, R^13', R¹⁴, And R^14'Are independent of each other
Hydrogen atom, halogen atom, hydroxyl group, C_1-7Al
Kill group or C_1-7Represents an alkoxy group. L¹, L^Two, And L^Three
Are each independently a covalent bond, -O-, -S-, -S (O)-, -S
(O)_Two-, -C (O)-, -C≡C-, -CR^Fifteen= CR^{15 '}-, -NR^Fifteen-, -NR
^Fifteen-C (O)-, -C (O) -NR^Fifteen-Or -NR^Fifteen-C (O) -NR^{15 '}-(R^Fifteen
And R^{15 '}Are each independently a hydrogen atom, C_1-7Alkyl
Group or C_6-14Represents an aromatic group. ). ).
G is a hydrogen atom, C_1-12Heterocyclic aromatic group (the heterocyclic aromatic group
The group is selected from oxygen, sulfur and nitrogen
Up to five heteroatoms as ring constituents
May be. ), C_1-6A heteroalicyclic group (the heteroalicyclic group
Is selected from oxygen, sulfur and nitrogen
Contains up to three heteroatoms as ring members
You may. ), C_3-10Cycloalkyl group, C_3-7Cycloa
Lucenyl group or C_6-14Aromatic group (C_1-12Heterocyclic aromatic
Group, C_1-6Heteroalicyclic group, C_3-10Cycloalkyl group, C_3-7
Cycloalkenyl group and C_6-145 or more aromatic groups
(Wherein the substituent is a hydrogen atom, C_1-7Alkyl group, C
_3-7Cycloalkyl group, C_3-7A cycloalkenyl group,
Alkyl, cycloalkyl and cycloalkenyl groups
May be substituted by a hydroxyl group. ), Hydroxyl, C
_1-7Alkoxy group, C_1-7Alkylthio group, halogen source
Child, trifluoromethyl group, nitro group, amino group, methyl
Amino group, dimethylamino group, acetamido group, meta
Sulfonylamide group, carboxyl group, C_1-3Alkoki
Cicarbonyl group, nitrile group, carbamoyl group, sulf
Amamoyl group, phenoxy group, benzyloxy group, tri-C
_1-7Alkylsilyloxy group, phenyl, naphthyl, phenyl
Ril, thienyl, imidazolyl, pyridyl, benzyl
(The phenyl, naphthyl, furyl, thienyl, imidazo
Ryl, pyridyl and benzyl are all C_1-7Archi
Group, C_3-7Cycloalkyl group, C_1-3Alkoxy group, C_1-3
Alkylthio group, hydroxyl group, halogen atom, nitro group or
Even when substituted with up to 5 dimethylamino groups
Good. ). ) May be included. ). )
Represents Represents｝. Where X¹To X^FiveAt least one of
Represents a nitrogen atom. 6-membered heterocyclic ring represented by
Are their salts and pharmaceutical compositions containing them as active ingredients
It is about an adult.

The definition of the substituent of the compound represented by the formula [I] will be described with reference to specific examples, and preferred examples of each substituent will be described. The scope of the present invention is not limited by these specific examples.

[0008] Each substituent represented by the formula [I] will be specifically described.

A is

Embedded image Represents

In A,

M, n, n ¹ and n ² are each independently 0,
Represents 1, 2, or 3, and preferably represents 0 or 1.

R ¹ is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a sulfonic acid group, a sulfonamide group, a PO ₂ H ₂ , a PO ₃ H ₂ , a 5-tetrazolyl group, a C (O) OR
⁶ (R ⁶ represents a hydrogen atom or a C _1-7 alkyl group), C
(O) NR ⁷ R ^{7 ′} (R ⁷ and R ^{7 ′} each independently represent a hydrogen atom or a C _1-7 alkyl group.), OR ⁸ (R ⁸ is a hydrogen atom, C _1-
7 represents an alkyl group or a phenyl group. ) Or NR ⁹ R ^{9 '}
(R ⁹ and R ^{9 ′} each independently represent a hydrogen atom, a C _1-7 alkyl group, or a phenyl group.). Preferably, a sulfonic acid group, PO ₃ H ₂ , 5-tetrazolyl group, C (O) O
R ⁶ (R ⁶ represents a hydrogen atom or a C _1-7 alkyl group); and more preferably C (O) OR ⁶ (R ⁶ represents a hydrogen atom or a C _1-7 alkyl group). ). Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom, a chlorine atom and a bromine atom. As a C _1-7 alkyl group,
Methyl, ethyl, n-propyl, i-propyl, n-butyl,
Examples include i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and n-heptyl.

R ² includes a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a guanidyl group,
Amidino group, NR ¹⁰ R ^{10 ′} (R ¹⁰ and R ^{10 ′} each independently represent a hydrogen atom, a C _1-7 alkyl group, a C _1-7 aliphatic acyl,
_6-10 represents an aromatic acyl or a protecting group. ) Or N ⁺ R ¹¹ R
^{11 ′} R ^{11 ″} (R ¹¹ , R ^{11 ′} and R ^{11 ″} are each independently C _1-7
Represents an alkyl group. ). Preferably, a guanidyl group, an amidino group, NR ¹⁰ R ^{10 ′} (R ¹⁰ and R ^{10 ′} each independently represent a hydrogen atom or a C _1-7 alkyl group), or N ⁺ R ¹¹ R ^{11 ′} R ^{11 ''} (R ¹¹ , R ^{11 ′} and R ^{11 ″} each independently represent a C _1-7 alkyl group);
More preferably, NR ¹⁰ R ^{10 ′} (R ¹⁰ and R ^{10 ′} each independently represent a hydrogen atom or a C _1-7 alkyl group), or
N ⁺ R ¹¹ R ^{11 ′} R ^{11 ″} (R ¹¹ , R ^{11 ′} and R ^{11 ″} each independently represent a C _1-7 alkyl group). _{Examples of the} C _1-7 alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and n-heptyl. No. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom, a chlorine atom and a bromine atom.

R ³ and R ^{3 ′} each independently represent C
_{And 1-7} alkyl groups. _{Examples of the} C _1-7 alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and n-heptyl. No.

R ⁴ represents a hydrogen atom, a C _1-7 alkyl group,
_Examples thereof include _1-7 aliphatic acyl, C _6-10 aromatic acyl, and a protecting group, and preferably, a hydrogen atom or a C _1-7 alkyl group. As the C _1-7 alkyl group, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-
Butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and the like. _{Examples of the} C _1-7 aliphatic acyl include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and pivaloyl. As C _6-10 aromatic acyl, benzoyl, 2
-Tolu oil, 3-tolu oil, 4-tolu oil, α-
Naphthoyl, β-naphthoyl, cinnamoyl and the like. As the protecting group, a C _1-4 alkoxymethyl group (for example, MOM: methoxymethyl, MEM: 2-methoxyethoxymethyl, ethoxymethyl, n-propoxymethyl, i-propoxymethyl, n-butoxymethyl, iBM: isobutyloxymethyl , BUM: t-butoxymethyl, POM: pivaloyloxymethyl, SEM: trimethylsilylethoxymethyl and the like, preferably C _1-2 alkoxymethyl group and the like, and aryloxymethyl group (for example, BO
M: benzyloxymethyl, PMBM: p-methoxybenzyloxymethyl and p-AOM: P-anisyloxymethyl and the like, preferably benzyloxymethyl and the like, a C _1-4 alkylaminomethyl group ( Dimethylaminomethyl), substituted acetamide methyl groups (eg Ac
m: acetamidomethyl and Tacm: trimethylacetamidomethyl and the like, a substituted thiomethyl group (for example, MT
M: methylthiomethyl, PTM: phenylthiomethyl, Bt
m: benzylthiomethyl and the like), carboxyl group, C _1-7 acyl group (for example, formyl, acetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, propionyl, Pv: pivaloyl And tigloyl and the like), an arylcarbonyl group (for example, benzoyl, benzoylformyl, benzoylpropionyl, phenylpropionyl and the like), a _C1-4 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i -Propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, BOC: t-butoxycarbonyl, AOC: t-amyloxycarbonyl, VOC: vinyloxycarbonyl, AOC: allyloxycarbonyl , Teoc: 2- (trimethylsilyl) ethoxycarbonyl, Troc: 2,2,2
-Trichloroethoxycarbonyl and the like, preferably BOC and the like), aryloxycarbonyl group (for example, Z: benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, MOZ: p-methoxybenzyloxycarbonyl and the like) , A C _1-4 alkylaminocarbonyl group (eg, methylcarbamoyl, Ec: ethylcarbamoyl, n-propylcarbamoyl, etc.), an arylaminocarbonyl group (eg, phenylcarbamoyl, etc.), a trialkylsilyl group (eg, TMS) : Trimethylsilyl, TES: triethylsilyl, TIPS: triisopropylsilyl, DEIPS: diethylisopropylsilyl, DMIPS: dimethylisopropylsilyl, DTBMS: di-t-butylmethylsilyl, IPDMS: isopropyldimethylsilyl, TBDMS: t- Tyldimethylsilyl, TDS: texyldimethylsilyl, etc., and preferably t-butyldimethylsilyl, etc., and a trialkylarylsilyl group (eg, DPMS: diphenylmethylsilyl, TBDPS: t-butyldiphenylsilyl, TBMPS: t-butyldimethoxyphenylsilyl, TPS: triphenylsilyl, etc., an alkylsulfonyl group (eg, Ms: methanesulfonyl, ethanesulfonyl, etc.) and an arylsulfonyl group (eg, benzenesulfonyl, Ts: p-) Toluenesulfonyl, p-chlorobenzenesulfonyl, MBS: p-methoxybenzenesulfonyl, m-nitrobenzenesulfonyl, iM
ds: 2,6-dimethoxy-4-methylbenzenesulfonyl, Mds: 2,6-dimethyl-4-methoxybenzenesulfonyl, Mtb: 2,4,6-trimethoxybenzenesulfonyl, Mte: 2,3,5,6 -Tetramethyl-4-
Methoxybenzenesulfonyl, Mtr: 2,3,6-trimethyl-4-methoxybenzenesulfonyl, Mts: 2,
4,6-trimethylbenzenesulfonyl, Pme: pentamethylbenzenesulfonyl, etc.) and the like, and preferably BOC, Z and the like.

D is a covalent bond, -CH_Two-, -O-, -S
-, -S (O)-, -S (O)_Two-, -NR¹²-, -C (O) -NR ¹²-, -NR¹²-C
(O)-or -NR¹²-C (O) -NR^{12 '}-(R¹²And R^{12 '}Each
Independently a hydrogen atom, or C_1-7Represents an alkyl group. )But
And preferably -O-, -NR¹²-Or -C (O) -NR¹²-
(R¹²Is a hydrogen atom, or C_1-7Represents an alkyl group. )
And more preferably -O- or -NH-
You. C_1-7Alkyl groups include methyl, ethyl, n-pro
Pill, i-propyl, n-butyl, i-butyl, s-butyl, t-
Butyl, n-pentyl, n-hexyl and n-heptyl, etc.
I can do it.

As X ¹ , X ² , X ³ , X ⁴ and X ⁵ ,
Each independently nitrogen atom or CR ⁵ and the like, as preferably X ^1, X ^3, and X ^5, independently nitrogen atom or CH. Examples X ² and X ^4,
CR ⁵ and the like independently. More preferably, X ⁴ is CR ⁵ (R ⁵ represents a hydrogen atom or a halogen atom). However, at least one of X ¹ to X ⁵ means a nitrogen atom.

R ⁵ is a hydrogen atom, a halogen atom, or
-EG. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom, a chlorine atom and a bromine atom.

E is -L ^1- (CR ¹³ R ^{13 '} ) _k -L ^2- (CR ¹⁴ R ^14' ) _l -L ^3-
Represents

K represents 1 to 10. l represents 0 to 10.

R ¹³ , R ^{13 ′} , R ¹⁴ and R ^{14 ′} each independently represent a hydrogen atom, a halogen atom, a hydroxyl group,
C _1-7 alkyl group, or C _1-7 alkoxy group,
Preferably, R ¹³ , R ^{13 ′} , R ¹⁴ , and R ^{14 ′} each independently include a hydrogen atom, a C _1-7 alkyl group, or a C _1-7 alkoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom, a chlorine atom and a bromine atom. As the C _1-7 alkyl group, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,
t-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The C _1-7 alkoxy group includes methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy, heptyloxy and the like.

L ¹ , L ² and L ³ each independently represent a covalent bond, -O-, -S-, -S (O)-, -S (O) _2- , -C (O) -, -C
^{≡C -, - CR 15 = CR} 15 '-, -NR 15 -, - NR 15 -C (O) -, - C (O) -NR
¹⁵ -, or ^{-NR 15 -C (O) -NR 15} '- (R 15 and R ^15' are each independently hydrogen atom, C _1-7 alkyl group, or a C _6-14 aromatic group. ) Is preferable, and L ¹ , L ² , and L ³ are preferably each independently a covalent bond, -O-, -C (O)-, -CR ^{15
= CR 15 '-, -NR 15} -, - NR 1 5 -C (O) -, or ^{-C (O) -NR 15 - (} R
¹⁵ and R ^{15 'each} independently represents a hydrogen atom, or a C _1-7 alkyl group. ). _{Examples of the} C _1-7 alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and n-heptyl. No. As the C _6-14 aromatic group, phenyl, α-naphthyl, β-naphthyl, 1-
Indenyl, 2-indenyl, 3-indenyl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl, 1-indenyl, 2-indanyl, 4-indanyl, 5-indanyl, 1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4-fluorenyl and 9-fluorenyl and the like. As a specific example of E

Embedded image Wherein, k represents 1 to 10, representing the R ¹⁵ and R ^{15 'each} independently represent a hydrogen atom, or a C _{1 -7} alkyl group. ], And preferably

Embedded image Wherein, k represents 1 to 10, representing the R ¹⁵ and R ^{15 'each} independently represent a hydrogen atom, or a C _{1 -7} alkyl group. ].

[0023] As G, a hydrogen atom, C _3-10 cycloalkyl groups, C _3-7 cycloalkenyl groups, C _{6- 14} aromatic groups, C
_4-12 heterocyclic aromatic group, or a C _4-12 heteroalicyclic group, preferably a hydrogen atom, a C _6-14 aromatic group, a C _4-12 heterocyclic aromatic group, or C _{4- And 12} heteroalicyclic groups.

In G, in addition to the hydrogen atom,

The C _3-10 cycloalkyl group includes cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl, 4-methylcyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, 1-adamantyl, 2-adamantyl and the like, and preferably,
As the C _6-10 cycloalkyl group, cyclohexyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1]
Examples include heptyl, bicyclo [2.2.2] octyl, 1-adamantyl and 2-adamantyl. In each case, a total of 5 or less substituents (the substituent is a hydrogen atom, C _1-7
Alkyl group, C _{3 -7} cycloalkyl, C _3-7 cycloalkenyl group, (the alkyl group, cycloalkyl group and cycloalkenyl group may be substituted by a hydroxyl group.), A hydroxyl group, C _1-7 alkoxy Group, C _1-7 alkylthio group, halogen atom, trifluoromethyl group, nitro group,
Amino group, methylamino group, dimethylamino group, acetamido group, methanesulfonylamide group, carboxyl group, C _1-3 alkoxycarbonyl group, nitrile group, carbamoyl group, sulfamoyl group, phenoxy group, benzyloxy group, tri-C _{1- 7} alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (the phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl are all C _1-7 alkyl groups, C _3-7 A cycloalkyl group, a C _1-3 alkoxy group, a C _1-3 alkylthio group, a hydroxyl group, a halogen atom, a nitro group or a dimethylamino group which may be substituted up to 5). ) May be included.

Examples of the C _3-7 cycloalkenyl group include cyclohexenyl (the cyclohexenyl includes 1-cyclohexenyl, 2-cyclohexenyl and 3-cyclohexenyl), cyclopentadienyl, 2-bicyclo [ 2.2.1] Heptenyl and 2,5-bicyclo [2.
2.1] Heptadienyl and the like. In each case, a total of 5 or less substituents (the substituents are a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkenyl group, (the alkyl group, the cycloalkyl group and The cycloalkenyl group may be substituted by a hydroxyl group.), A hydroxyl group, a C _1-7 alkoxy group, a C _1-7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group,
Methylamino group, dimethylamino group, acetamido group,
Methanesulfonylamide group, carboxyl group, C _1-3 alkoxycarbonyl group, nitrile group, carbamoyl group, sulfamoyl group, phenoxy group, benzyloxy group, tri-C _1-7 alkylsilyloxy group, phenyl, naphthyl,
Furyl, thienyl, imidazolyl, pyridyl or benzyl (the phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl are all C _1-7 alkyl groups, C _3-7 cycloalkyl groups, C _1-3 alkoxy groups , C
Up to 5 substituents may be substituted by _1-3 alkylthio groups, hydroxyl groups, halogen atoms, nitro groups or dimethylamino groups. ). ) May be included.

As C _6-14 aromatic groups, phenyl, naphthyl (α-naphthyl, β-naphthyl), indenyl (1-indenyl, 2-indenyl, 3-indenyl, 4-indenyl, 5-indenyl, 6-indenyl) , 7-indenyl), indanyl (1-indanyl, 2-indanyl, 4-indanyl, 5-indanyl), or fluorenyl (1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4-fluorenyl, 9-fluorenyl) and the like. And preferably C _6-14
As the aromatic group, phenyl, naphthyl (α-naphthyl,
β-naphthyl) or fluorenyl (1-fluorenyl,
2-fluorenyl, 3-fluorenyl, 4-fluorenyl, 9-
Fluorenyl) and the like. In each case, a total of 5 or less substituents (the substituents are a hydrogen atom, a C _1-7 alkyl group,
_{A 3-7} cycloalkyl group, a C _3-7 cycloalkenyl group, (the alkyl group, the cycloalkyl group and the cycloalkenyl group may be substituted by a hydroxyl group), a hydroxyl group, a C
_1-7 alkoxy group, C _1-7 alkylthio group, halogen atom, trifluoromethyl group, nitro group, amino group, methylamino group, dimethylamino group, acetamido group, methanesulfonylamide group, carboxyl group, C _1-3 Alkoxycarbonyl group, nitrile group, carbamoyl group, sulfamoyl group, phenoxy group, benzyloxy group, tri-C
_1-7 alkylsilyl group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (the phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl, both, C _1-7 alkyl groups, C _{3 -7} cycloalkyl group, C _1-3 alkoxy group, C _1-3
Up to five alkylthio groups, hydroxyl groups, halogen atoms, nitro groups or dimethylamino groups may be substituted. ). ) May be included.

The C _1-12 heterocyclic aromatic group has a maximum of 5 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
It means a 5- to 15-membered monocyclic or condensed-ring heterocyclic aromatic group which may be contained as a constituent of a ring up to a single ring. Specifically, furyl (2-furyl, 3-furyl), thienyl (2-thienyl, 3-thienyl), pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), oxazolyl (2-oxazolyl, 4- Oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), isothiazolyl (3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl) ), Frazanil (3-Frazanyl), Pyrazolyl (1-
Pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), oxopyrazolyl (3-oxopyrazol-1-yl, 3-oxopyrazol-2-yl, 3-oxopyrazol-3-yl, 3-oxopyrazol-4-yl, 4-oxopyrazol-3-yl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl), oxoimidazolyl (2-oxoimidazol-1-yl, 2-oxoimidazole-4-yl), triazolyl (1 , 2,3-Triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-1-yl, 1,2 , 4-Triazol-3-yl, 1,2,4-triazol-4-yl), triazolonyl (3-oxo-1,2,
4 (2H, 4H) -triazol-2-yl, 3-oxo-1,2,4 (2H, 4
H) -Triazol-4-yl, 3-oxo-1,2,4 (2H, 4H) -triazol-5-yl, 3-oxo-1,2,4 (1H, 2H) -triazol-1-yl , 3-oxo-1,2,4 (1H, 2H) -triazol-2-yl, 3-oxo-1,2,4 (1H, 2H) -triazol-5-yl),
Tetrazolyl (1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), pyranyl (2-pyranyl, 3-pyranyl, 4-
Pyranyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyridonyl (2-pyridone-1-yl, 2-pyridone-3-yl, 2-pyridone-4-yl, 2-pyridone-5- Il, 2
-Pyridone-6-yl, 4-pyridone-1-yl, 4-pyridone-2-
Yl, 4-pyridin-3-yl), pyridazinyl (3-pyridazinyl, 4-pyridazinyl), pyridazinonyl (3 (2H) -pyridazinone-2-yl, 3 (2H) -pyridazinone-4-yl, 3 (2
H) -Pyridazinone-5-yl, 3 (2H) -pyridazinone-6-yl, 4 (1H) -pyridazinone-1-yl, 4 (1H) -pyridazinone-
3-yl, 4 (1H) -pyridazinone-5-yl, 4 (1H) -pyridazinone-6-yl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrimidinonyl (2 (1
H) -Pyrimidinone-1-yl, 2 (1H) -pyrimidinone-4-yl, 2 (1H) -pyrimidinone-5-yl, 2 (1H) -pyrimidinone-
6-yl, 4 (3H) -pyrimidinone-2-yl, 4 (3H) -pyrimidinone-3-yl, 4 (3H) -pyrimidinone-5-yl, 4 (3H) -pyrimidinone-6-yl, 4 ( 1H) -Pyrimidinone-1-yl, 4 (1H)-
Pyrimidinone-2-yl, 4 (1H) -pyrimidinone-5-yl, 4
(1H) -pyrimidinone-6-yl), pyrazinyl (2-pyrazinyl, 2 (1H) -pyrazin-1-yl, 2 (1H) -pyrazin-3-yl,
2 (1H) -pyrazin-5-yl, 2 (1H) -pyrazin-6-yl), triazinyl (1,2,3-triazin-4-yl, 1,2,3-triazin-5-yl, 1 , 2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl), tetrazinyl (1,2,3,4-tetrazin-5-yl) Yl, 1,2,4,5-tetrazine-
3-yl), in-drill (1-in-drill, 2-in-drill,
3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl ), Quinolonyl (2-quinolon-1-yl, 2
-Quinolone-3-yl, 2-quinolone-4-yl, 2-quinolone-5-
Yl, 2-quinolone-6-yl, 2-quinolone-7-yl, 2-quinolone-8-yl, 4-quinolone-1-yl, 4-quinolone-2-yl, 4-quinolone-3-yl, 4-quinolone-5-yl, 4-quinolone-6-yl, 4-quinolone-7-yl, 4-quinolone-8-yl), benzofuryl (2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl) , 6-benzofuryl, 7-benzofuryl), benzothienyl (2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), isoquinolonyl (1-isoquinolone-2-yl, 1-isoquinolone-3-yl, 1-isoquinolone-4-yl , 1-isoquinolone-5-yl, 1-isoquinolone-6
-Yl, 1-isoquinolone-7-yl, 1-isoquinolone-8-yl, 3-isoquinolone-2-yl, 3-isoquinolone-4-yl,
3-isoquinolone-5-yl, 3-isoquinolone-6-yl, 3-isoquinolone-7-yl, 3-isoquinolone-8-yl), benzoxazolyl (2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl , 7-benzoxazolyl), benzothiazolyl (2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), benzopyrazolyl (1-benzopyrazolyl, 2-benzopyrazolyl, 3-benzopyrazolyl, 4-benzo) Pyrazolyl, 5-benzopyrazolyl, 6-benzopyrazolyl, 7-benzopyrazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), benzotriazolyl (1-benzotriazolyl, 4 -
Benzotriazolyl, 5-benzotriazolyl), benzopyranyl (2-benzopyranyl, 3-benzopyranyl, 4-benzopyranyl, 5-benzopyranyl, 6-benzopyranyl,
7-benzopyranyl, 8-benzopyranyl), indolizinyl (1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl), purinyl (2-purinyl, 6-purinyl, 7-purinyl, 8-purinyl), phthalazinyl (1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), oxophthalazinyl (1-oxophthalazin-2-yl, 1-oxophthalazin-4-yl, 1-oxophthalazin-
5-yl, 1-oxophthalazin-6-yl, 1-oxophthalazin-7-yl, 1-oxophthalazin-8-yl), naphthyridinyl (2-naphthyridinyl, 3-naphthyridinyl, 4-naphthyridinyl), quinoxalinyl (2-quinoxalinyl, Five-
Quinoxalinyl, 6-quinoxalinyl), quinazolinyl (2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl,
6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl),
Cinnolinyl (3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), benzodioxolyl (1,3-benzodioxol-4-yl, 1,3-benzodioxo- Le-5-yl),
Benzodioxanyl (1,4-benzodioxan-2-yl,
1,4-benzodioxan-5-yl, 1,4-benzodioxane-
6-yl), oxonaphthalenyl (1,4-oxonaphthalene)
2-yl, 1,4-oxonaphthalen-5-yl, 1,4-oxonaphthalen-6-yl), 2,3-dihydrobenzofuryl (2,3-
Dihydro-4-benzofuryl, 2,3-dihydro-5-benzofuryl, 2,3-dihydro-6-benzofuryl, 2,3-dihydro-7-
Benzofuryl), benzothiazinyl (1,4-benzothiazin-2-yl, 1,4-benzothiazin-3-yl, 1,4-benzothiazin-4-yl, 1,4-benzothiazin-5-yl, 1,4- Benzothiazin-6-yl, 1,4-benzothiazin-7-yl, 1,4-
Benzothiazin-8-yl), pteridinyl (2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), pyrazolo [1,5-a] pyrimidinyl (pyrazolo [1,5
-a] pyrimidin-2-yl, pyrazolo [1,5-a] pyrimidine
-3-yl, pyrazolo [1,5-a] pyrimidin-5-yl, pyrazolo [1,5-a] pyrimidin-6-yl, pyrazolo [1,5-a]
Pyrimidin-7-yl), pyrazolo [5,1-c] [1,2,4] triazinyl (pyrazolo [5,1-c] [1,2,4] triazine-3
-Yl, pyrazolo [5,1-c] [1,2,4] triazin-4-yl, pyrazolo [5,1-c] [1,2,4] triazin-7-yl,
Pyrazolo [5,1-c] [1,2,4] triazin-8-yl), thiazolo [3,2-b] triazolyl (thiazolo [3,2-b] triazol-2-yl, thiazolo [3, 2-b] triazole-5-
Yl, thiazolo [3,2-b] triazol-6-yl), benzopyrano [2,3-b] pyridyl (benzopyrano [2,3-b] pyridin-2-yl, benzopyrano [2,3-b] pyridine -3-yl, benzopyrano [2,3-b] pyridin-4-yl, benzopyrano [2,3-b] pyridin-5-yl, benzopyrano [2,3-
b] pyridin-6-yl, benzopyrano [2,3-b] pyridine-
7-yl, benzopyrano [2,3-b] pyridin-8-yl, benzopyrano [2,3-b] pyridin-9-yl), 5H-oxobenzopyrano [2,3-b] pyridyl (5H- 5-oxobenzopyrano [2,3-b] pyridin-2-yl, 5H-5-oxobenzopyrano [2,3-b] pyridin-3-yl, 5H-5-oxobenzopyrano [2 , 3-b] Pyridin-4-yl, 5H-5-oxobenzopyrano [2,3-b] pyridin-6-yl, 5H-5-oxobenzopyrano [2,3-b] pyridin-7 -Yl, 5H-5-oxobenzopyrano [2,3-b] pyridin-8-yl), xanthenyl (1-xanthenyl, 2-xanthenyl, 3-xanthenyl, 4-xanthenyl, 9-xanthenyl), phenoxati Inyl (1-phenoxathiinyl, 2-phenoxathiinyl, 3-phenoxathiinyl, 4-phenoxathiinyl), carbazolyl (1-
Carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, 9-carbazolyl), acridinyl (1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), phenazinyl (1-phenazinyl, 2- Phenazinyl, 3-phenazinyl, 4-phenazinyl), phenothiazinyl (1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl, 10-phenothiazinyl), phenoxazinyl (1-phenoxazinyl, 2-phenoxazinyl, 3-phenoxazinyl, 4-phenoxazinyl, 10-phenoxazinyl),
Or thianthrenyl (1-thianthrenyl, 2-thianthrenyl, 3-thianthrenyl, 4-thianthrenyl, 6-thanthrenyl, 7-thianthrenyl, 8-thianthrenyl, 9-thianthrenyl) and the like. Preferred C _1-12 heterocyclic aromatic groups include furyl (2-furyl, 3-furyl), thienyl (2-thienyl, 3-thienyl), pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), Oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), isothiazolyl (3-isothiazolyl) , 4-isothiazolyl, 5-isothiazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (3-pyridazinyl,
4-pyridazinyl), pyridazinonyl (3 (2H) -pyridazinone-2-yl, 3 (2H) -pyridazinone-4-yl, 3 (2H) -pyridazinone-5-yl, 3 (2H) -pyridazinone-6-yl ), Pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (2-pyrazinyl), indolyl (1-
Indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7 -Quinolyl, 8-quinolyl), benzoxazolyl (2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl), benzothiazolyl (2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7 -Benzothiazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,
4-benzimidazolyl, 5-benzimidazolyl), phthalazinyl (1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), quinoxalinyl (2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), benzodioxolyl (1,3-benzodioxo- -4-yl, 1,3-benzodioxol-5-yl), benzothiazinyl (1,4-benzothiazin-2-yl, 1,4-benzothiazin-3-yl, 1,4-benzothiazin-4-yl) Yl, 1,4-benzothiazin-5-yl, 1,4-benzothiazin-6-yl, 1,4-benzothiazin-7-yl, 1,
4-benzothiazin-8-yl), pyrazolo [1,5-a] pyrimidinyl (pyrazolo [1,5-a] pyrimidin-2-yl, pyrazolo [1,5-a] pyrimidin-3-yl, pyrazolo [1 , 5-a] pyrimidin-5-yl, pyrazolo [1,5-a] pyrimidin-6-yl, pyrazolo [1,5-a] pyrimidin-7-yl), pyrazolo [5,1-c] [1 , 2,4] triazinyl (pyrazolo [5,1-c]
[1,2,4] triazin-3-yl, pyrazolo [5,1-c] [1,
2,4] triazin-4-yl, pyrazolo [5,1-c] [1,2,4]
Triazin-7-yl, pyrazolo [5,1-c] [1,2,4] triazin-8-yl), thiazolo [3,2-b] triazolyl (thiazolo [3,2-b] triazole-2- Il, thiazolo [3,2-
b] triazol-5-yl, thiazolo [3,2-b] triazol-6-yl), and benzopyrano [2,3-b] pyridyl (benzopyrano [2,3-b] pyridin-2-yl, benzopyrano [ 2,3-b] pyridin-3-yl, benzopyrano [2,3-b]
Pyridin-4-yl, benzopyrano [2,3-b] pyridin-5-
Yl, benzopyrano [2,3-b] pyridin-6-yl, benzopyrano [2,3-b] pyridin-7-yl, benzopyrano [2,3-
b] pyridin-8-yl, benzopyrano [2,3-b] pyridine-
9-yl) and the like. In each case, a total of 5 or less substituents (the substituents are a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkenyl group, (the alkyl group, the cycloalkyl group cycloalkenyl groups may be substituted by a hydroxyl group.), a hydroxyl group, C _{1 -7} alkoxy, C _1-7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, methylamino group,
Dimethylamino group, acetamido group, methanesulfonylamide group, carboxyl group, _C1-3 alkoxycarbonyl group, nitrile group, carbamoyl group, sulfamoyl group,
Phenoxy group, benzyloxy group, tri-C _1-7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (the phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl are all C _1-7 alkyl group, C _3-7
Up to five cycloalkyl groups, C _1-3 alkoxy groups, C _1-3 alkylthio groups, hydroxyl groups, halogen atoms, nitro groups or dimethylamino groups may be substituted. ). ) May be included.

The C _1-6 heteroalicyclic group is a group consisting of a three-membered ring which may contain up to three heteroatoms selected from oxygen, sulfur and nitrogen as ring constituents. A membered monocyclic or fused bicyclic heterocyclic group is meant. Specifically, piperidyl (1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl), pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), imidazolidinyl (1-imidazolidinyl, 2-imidazolidinyl, 4 -
Imidazolidinyl), pyrazolidinyl (1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl), morpholinyl (2-morpholinyl, 3-morpholinyl, 4-morpholinyl), or tetrahydrofuryl (2-tetrahydrofuryl, 3-tetrahydrofuryl) and the like. Can be In each case, a total of 5 or less substituents (the substituent is a hydrogen atom, C _1-7
Alkyl group, C _3-7 cycloalkyl group, C _3-7 cycloalkenyl group, (the alkyl group, cycloalkyl group and cycloalkenyl group may be substituted by a hydroxyl group), hydroxyl group, C _1-7 alkoxy Group, C _1-7 alkylthio group, halogen atom, trifluoromethyl group, nitro group,
Amino group, methylamino group, dimethylamino group, acetamido group, methanesulfonylamide group, carboxyl group, C _1-3 alkoxycarbonyl group, nitrile group, carbamoyl group, sulfamoyl group, phenoxy group, benzyloxy group, tri-C _{1- 7} alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (the phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl are all C _1-7 alkyl groups, C _3-7 A cycloalkyl group, a C _1-3 alkoxy group, a C _1-3 alkylthio group, a hydroxyl group, a halogen atom, a nitro group or a dimethylamino group which may be substituted up to 5). ) May be included.

In R ^a , R ^b and R ^c ,

As the C _1-7 alkyl group, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-
Butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and the like. Preferably, methyl, ethyl and
n-propyl and the like. Any of them may be substituted with a hydroxyl group.

Examples of the C _3-7 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl and bicyclo [3.1.1] heptyl.
Preferably, cyclopropyl, cyclohexyl and the like are mentioned. Any of them may be substituted with a hydroxyl group.

Examples of the C _3-7 cycloalkenyl group include 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, cyclopentadienyl, 2-bicyclo [2.2.
1] heptenyl and 2,5-bicyclo [2.2.1] heptadienyl. Any of them may be substituted with a hydroxyl group.

The C _1-7 alkoxy group includes methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-
Butoxy, s-butoxy, t-butoxy, pentyloxy,
Hexyloxy and heptyloxy and the like.

As the C _1-7 alkylthio group, methylthio, ethylthio, n-propylthio, i-propylthio, n-
Butylthio, i-butylthio, s-butylthio, t-butylthio, pentylthio, hexylthio, heptylthio and the like.

The tri-C _1-7 alkylsilyloxy group includes trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, diethylisopropylsilyloxy, dimethylisopropylsilyloxy, di-t-butylmethylsilyloxy, isopropyldimethylsilyloxy , T-butyldimethylsilyloxy,
Texyl dimethylsilyloxy and the like, preferably t-butyldimethylsilyloxy and the like.

The naphthyl group includes an α-naphthyl group and a β-naphthyl group. As the furyl group, 2-
And a furyl group and a 3-furyl group. Examples of the thienyl group include a 2-thienyl group and a 3-thienyl group. Examples of the imidazolyl group include a 1-imidazolyl group,
Examples include an imidazolyl group and a 4-imidazolyl group. Examples of the pyridyl group include a 2-pyridyl group, a 3-pyridyl group and a 4-pyridyl group. Both are C _1-7
Substituted with up to 5 alkyl groups, C _3-7 cycloalkyl groups, C _1-3 alkoxy groups, C _1-3 alkylthio groups, hydroxyl groups, fluorine atoms, chlorine atoms, bromine atoms, nitro groups or dimethylamino groups You may.

The phenyl and benzyl groups, C _1-7 alkyl, C _3-7 cycloalkyl group, C _1-3 alkoxy, C _1-3
Up to five alkylthio groups, hydroxyl groups, fluorine atoms, chlorine atoms, bromine atoms, nitro groups or dimethylamino groups may be substituted.

Examples of the C _1-3 alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl and the like.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom, a chlorine atom and a bromine atom.

In this specification, n is normal, i is iso, s is secondary, t is tertiary, c is cyclo, Me is methyl, Et is ethyl, Pr is propyl, Bu is
Represents a butyl group, Pen represents a pentyl group, Hex represents a hexyl group, Ph represents a phenyl group, and Hal represents a halogen atom.

Among the compounds represented by the formula [I], preferred compounds include the following.

(1) When the C _3-10 cycloalkyl group represented by G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [2.2.
1] heptyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.2] or octyl, or adamantyl, the C _{3 -7} cycloalkenyl group, cyclohexenyl, cyclopentadienyl, 2-bicyclo [ 2.2.1] heptenyl or 2,5-bicyclo [2.2.1] heptadienyl, or the C _6-14 aromatic group is phenyl, naphthyl, indenyl, indanyl or fluorenyl, C _{1- 12} heterocyclic aromatic groups, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,
Isothiazolyl, furazanil, pyrazolyl, oxopyrazolyl, imidazolyl, oxoimidazolyl, triazolyl, triazolonyl, tetrazolyl, pyranyl, pyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrimidinyl, pyrimidinonyl, pyrazinyl, triazinyl, benzoyl, quinolyl, indolyl, quinolyl , Isoquinolyl, isoquinolonyl, benzoxazolyl, benzothiazolyl,
Benzopyrazolyl, benzimidazolyl, benzotriazolyl, benzopyranyl, indolizinyl, purinyl,
Phthalazinyl, oxophthalazinyl, naphthyridinyl,
Quinoxalinyl, quinazolinyl, cinnolinyl, benzodioxolyl, benzodioxanyl, oxonaphthalenyl, dihydrobenzofuryl, benzothiazinyl, pteridinyl, pyrazolo [1,5-a] pyrimidinyl, pyrazolo [5,1-c] [1 , 2,4] triazinyl, thiazolo [3,2-b]
Triazolyl, benzopyrano [2,3-b] pyridyl, 5H-benzopyrano [2,3-b] pyridonyl, xanthenyl, phenoxathiinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or thianthrenyl, or C _{1 -6} heteroalicyclic group, piperidyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl or tetrahydrofuryl, C _3-10 cycloalkyl, C _3-7 cycloalkenyl group, C _6-14 aromatic group described above , C _1-12 heterocyclic aromatic group or a C _1-6 heterocycloaliphatic groups, a total of 5 or fewer substituents (said substituent is a hydrogen atom, C _1-7 alkyl groups, C _{3 -7} cycloalkyl Group, C _3-7 cycloalkenyl group, (the alkyl group, cycloalkyl group and cycloalkenyl group may be substituted by a hydroxyl group), hydroxyl group, C _1-7 alkoxy Group, C _1-7 alkylthio group, halogen atom, trifluoromethyl group, nitro group, amino group, methylamino group, dimethylamino group, acetamido group, methanesulfonylamide group, carboxyl group, C _1-3 alkoxycarbonyl group, Nitrile group, carbamoyl group, sulfamoyl group, phenoxy group, benzyloxy group, tri-C _1-7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (the phenyl, naphthyl, furyl, thienyl, imidazolyl , Pyridyl and benzyl are each a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a C _1-3 alkoxy group, a C _1-3 alkylthio group, a hydroxyl group, a halogen atom, a nitro group or a dimethylamino group. Which may be substituted up to 5 times.). Six-membered ring heterocycles or a salt thereof I].

(2) G is a hydrogen atom, or

[0045]

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[0046]

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[Wherein, R ^a and R ^b each independently represent a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkenyl group, (the alkyl group, The cycloalkyl group and the cycloalkenyl group may be substituted by a hydroxyl group.), A hydroxyl group, a C _1-7 alkoxy group, a C _1-7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group Group, amino group, methylamino group, dimethylamino group, acetamido group, methanesulfonylamide group, carboxyl group, _C1-3 alkoxycarbonyl group, nitrile group, carbamoyl group, sulfamoyl group,
Phenoxy group, benzyloxy group, tri-C _1-7 alkylsilyloxy group, phenyl, α-naphthyl, β-naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (the phenyl, α-naphthyl, β-naphthyl, furyl, Thienyl, imidazolyl, pyridyl and benzyl are each a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a C _1-3 alkoxy group, a C _1-3 alkylthio group, a hydroxyl group,
Up to five substituents may be substituted by a fluorine atom, a chlorine atom, a bromine atom, a nitro group or a dimethylamino group. Wherein R ^c is a hydrogen atom, a C _1-7 alkyl group, C _3-7
Represents a cycloalkyl group or a hydroxymethyl group. ] Or a salt thereof represented by the above (1).

(3) G is a hydrogen atom, or

[0049]

Embedded image

[0050]

Embedded image

Wherein R ^a and R ^b are each independently a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkenyl group, (the alkyl group, The cycloalkyl group and the cycloalkenyl group may be substituted by a hydroxyl group.), A hydroxyl group, a C _1-7 alkoxy group, a C _1-7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group Group, amino group, methylamino group, dimethylamino group, acetamido group, methanesulfonylamide group, carboxyl group, _C1-3 alkoxycarbonyl group, nitrile group, carbamoyl group, sulfamoyl group,
Phenoxy group, benzyloxy group, tri-C _1-7 alkylsilyloxy group, phenyl, α-naphthyl, β-naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (the phenyl, α-naphthyl, β-naphthyl, furyl, Thienyl, imidazolyl, pyridyl and benzyl are each a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a C _1-3 alkoxy group, a C _1-3 alkylthio group, a hydroxyl group,
Up to five substituents may be substituted by a fluorine atom, a chlorine atom, a bromine atom, a nitro group or a dimethylamino group. Wherein R ^c is a hydrogen atom, a C _1-7 alkyl group, C _3-7
Represents a cycloalkyl group or a hydroxymethyl group. Or a salt thereof, represented by the above (2).

(4) R¹Is a sulfonic acid group, PO_ThreeH_Two, 5-te
Tolazolyl group, C (O) OR⁶(R⁶Is a hydrogen atom, or C_1-7Al
Represents a kill group. ), And R^TwoIs a guanidyl group, amidi
No group, NR ^TenR^Ten'(R^TenAnd R^Ten'Are each independently hydrogen
Atom or C_1-7Represents an alkyl group. ) Or N⁺R¹¹R^{11 '}R
^{11 ''}(R¹¹, R^{11 '}And R^{11 ''}Are each independently C_1-7Al
Represents a kill group. ), And R^FourIs a hydrogen atom, or C_1-7Al
Represents a kill group, and D represents -O-, -NR¹²-Or -C (O) -NR¹²-
(R¹²Is a hydrogen atom, or C_1-7Represents an alkyl group. )
Then R¹³, R^13', R¹⁴, And R^14'Are each independently hydrogen
Atom, C_1-7Alkyl group, or C_1-7Represents an alkoxy group,
L¹, L^Two, And L^ThreeAre each independently a covalent bond, -O-, -C
(O)-, -CR^Fifteen= CR^{15 '}-, -NR^Fifteen-, -NR^Fifteen-C (O)-or -C
(O) -NR^Fifteen-(R^FifteenAnd R^{15 '}Are each independently a hydrogen atom,
Or C_1-7Represents an alkyl group. ) Represents (3)
And 6-membered heterocycles or salts thereof.

(5) E is

Embedded image Wherein, k represents 1 to 10, representing the R ¹⁵ and R ^{15 'each} independently represent a hydrogen atom, or a C _{1 -7} alkyl group. ] Or a salt thereof, represented by the above (4).

(6) X ¹ , X ³ , and X ⁵ each independently represent a nitrogen atom or CH, and X ² and X ⁴ each independently represent CR ^5. Or a salt thereof.

(7) E is

Embedded image Wherein, k represents 1 to 10, representing the R ¹⁵ and R ^{15 'each} independently represent a hydrogen atom, or a C _{1 -7} alkyl group. Or a salt thereof, represented by the above (6).

(8) m, n, n ¹ and n ² each independently represent 0 or 1, and R ¹ is C (O) OR ⁶ (R ⁶ is a hydrogen atom,
Or a C _1-7 alkyl group. ) And R ² is NR ¹⁰ R ^{10 ′}
(R ¹⁰ and R ^{10 ′} are each independently a hydrogen atom, or C _1-7
Represents an alkyl group. ) Or N ⁺ R ¹¹ R ^{11 '} R ^11'' (R ¹¹ , R
^{11 ′} and R ^{11 ″} each independently represent a C _1-7 alkyl group. D represents -O- or -NH-, and X ⁴ represents C
R ⁵ (R ⁵ is a hydrogen atom or a. Represents a halogen atom,) six-membered ring heterocycles or a salt thereof represented by the above (7) representing the.

The compound represented by the formula [I] of the present invention can be used for the purpose of the present invention either in a free form or a pharmaceutically acceptable salt thereof.

[0058]

BEST MODE FOR CARRYING OUT THE INVENTION A six-membered heterocycle, which is a compound represented by the formula [I], is produced according to the following synthesis method.

The reaction solvent used in the production is preferably a solvent which is stable under the reaction conditions, is inert and does not hinder the reaction. Such solvents include water, alcohols (eg, methanol, ethanol, propanol, butanol, octanol, etc.), cellosolves (eg, methoxyethanol, ethoxyethanol, etc.), aprotic polar organic solvents (eg, dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), dimethylacetamide, tetramethylurea, sulfolane, N, N-dimethylimidazolidinone (DMI), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H ) -Pyrimidinone (DMP
U), hexamethylphosphoric triamide (HMPA), etc.), ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), aliphatic hydrocarbons (eg, pentane, n-hexane, c-hexane, octane, Decalin, petroleum ether, etc.), aromatic hydrocarbons (benzene, chlorobenzene, nitrobenzene, toluene, xylene, tetralin, etc.), halogenated hydrocarbons (eg, chloroform,
Dichloromethane, dichloroethane, etc., ketones (acetone, methyl ethyl ketone, methyl butyl ketone, etc.), lower aliphatic acid esters (eg, methyl acetate, ethyl acetate, methyl propionate, etc.), alkoxyalkanes (eg, dimethoxyethane, diethoxyethane, etc.) ) And acetonitrile. These solvents are appropriately selected according to the easiness of the reaction, and are used alone or as a mixture. In some cases, it is used as a non-aqueous solvent using an appropriate dehydrating agent or desiccant. The solvent described above is an example when carrying out the present invention, and the present invention is not limited to these conditions.

Manufacturing method 1

[0061]

Embedded image

Wherein A, D, X ¹ , X ² , X ³ , X ⁴ and X ⁵ have the same meaning as described above. R ¹⁶ represents a suitable leaving group at the time of nucleophilic substitution in the reaction, and examples thereof include halogens such as chloro, bromo, and iodo; And aromatic or aliphatic sulfonyloxy groups. ]

In the formula [I], D is O, S, or NR
^The compound represented by ¹² (R ¹² represents the same meaning as described above) is obtained by reacting a compound represented by the formula [II] with a compound represented by the formula [III] in the absence or presence of a catalyst. Can be obtained by:

This reaction is usually carried out in a suitable solvent in the presence of a base. Such solvents include water, alcohols, cellosolves, aprotic polar organic solvents (eg, dimethylformamide, dimethylacetamide,
Tetramethylurea, N, N-dimethylimidazolidinone (DMI), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-
Solvents such as pyrimidinone (DMPU), hexamethylphosphoric triamide (HMPA)), ethers, aromatic hydrocarbons, halogenated hydrocarbons, ketones, lower aliphatic acid esters, alkoxyalkanes and acetonitrile. No.

Examples of such bases include organic amines (eg, diisopropylethylamine, trimethylamine, triethylamine, N-methylmorpholine, pyridine and the like), metal alkoxides (eg, sodium methoxide, sodium ethoxide, lithium isopropoxide and the like). Potassium t-butoxide, etc.) and inorganic alkali metal salts (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride,
Sodium acetate, potassium acetate and the like) and alkali metal amides (eg, sodium amide and the like).
These are appropriately selected and used according to the easiness of the reaction.

Examples of the catalyst include palladiums such as tetrakis (triphenylphosphine) palladium (0), palladium (II) chloride, 1,3-bis (diphenylphosphino) propane / Pd ₂ (dba) ₃ complex, and dichloro [1 , 3-bis (diphenylphosphino) propane] nickel (II), nickels such as tetrakis (triphenylphosphite) nickel (0), rutheniums such as dichlorotris (triphenylphosphine) ruthenium, chlorotris (triphenylphosphine) ) Rhodiums such as rhodium can be used if necessary.

This reaction is carried out usually at a temperature in the range of -100 ° C to the boiling point of the solvent used in the reaction, preferably 20 ° C to 1 ° C.
Perform at 50 ° C. The reaction time is usually 0.5 to 30 hours.

Reaction examples of halopyridines with alkylamines are described in J. Org. Chem, 1953, 18, 1484, Tetrahedron Lett, 19
71,1875, Chem.Ber, 1969,102,1161, Recl.Trav.Chim.Pa
ys-Bas, 1969, 88, 1391, and as a reaction using a palladium catalyst, J. Org.Chem, 1996, 61, 7240, i
bid 1997,62,1568. Examples of the reaction of halopyridazine or halopyrazine with amines are described in Bull. Soc. Chim. Fr, 1
970, 1346, and J. Chem. Soc, 1960, 242. Examples of the reaction of halopyrimidine or halothriazine with alkylamines are described in J. Med.Chem, 1984, 27, 1621, J. Chem. Soc, 1946, 343,
ibid 1965, 2778, Chem. Ber, 1963, 96, 2977, J. Org.
1953, 18, 1484, ibid 1961, 26, 2786, J. Am. Chem. Soc, 195
4,73,2981. These reaction conditions are the same as those in Production method 1
In the formula [I], D can be applied to the synthesis of a compound represented by NR ¹¹ (R ¹¹ has the same meaning as described above).

Production method 2

[0070]

Embedded image

[Wherein A, D, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R
¹⁶ represents the same meaning as described above. ]

In the formula [I], D is O, S, or NR
^The compound represented by ¹² (R ¹² has the same meaning as described above) can be obtained by nucleophilic substitution of the compound represented by the formula [V] with the compound represented by the formula [IV]. it can.
This reaction can be carried out under the same conditions as in Production Method 1.

Production method 3

[0074]

Embedded image

Wherein A, X ¹ , X ² , X ³ , X ⁴ , X ⁵ and R ¹² have the same meaning as described above. R ¹⁷ is chlor, brom, or OC
(0) OR ¹⁸ (R ¹⁸ represents a C _1-7 alkyl group or a phenyl group). ]

[0076] formula [I] in, D is ^{-C (O) -NR 12 - (} . R 12 is of the same meaning as defined above), the compound represented by i.e. formula
The compound represented by [I-2] can be obtained by nucleophilic substitution of the compound represented by the formula [VI] with a compound represented by the formula [III-2].

This reaction is usually carried out in a suitable organic solvent, and if necessary, the reaction can be promoted by using a suitable base. Such solvents include aprotic polar organic solvents, ethers, aromatic hydrocarbons, halogenated hydrocarbons, alkoxyalkanes and solvents such as acetonitrile.

Examples of such bases include organic amines (eg, diisopropylethylamine, trimethylamine, triethylamine, N-methylpiperidine, N-methylmorpholine, pyridine, 2,6-lutidine, collidine, etc.), metal alkoxides (eg, Sodium methoxide, sodium ethoxide, lithium isopropoxide, potassium t-butoxide, etc.) and inorganic alkali metal salts (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, hydrogencarbonate) Potassium, sodium hydride, sodium acetate, potassium acetate, etc.), alkali metal amides (eg, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, 2,2,6,6-tetramethylpiperidide) And alkyl metals (eg, methyllithium, n-butyllithium, etc.) and the like, which are appropriately selected and used according to the likelihood of reaction.

The reaction is usually carried out in the range of -78 ° C to the boiling point of the solvent used in the reaction, and the reaction time is usually 0.5 to
30 hours.

Production method 4

[0081]

Embedded image

Wherein A, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ¹² , R
¹⁷ has the same meaning as described above. ]

In the formula [I], D is -NR ¹² -C (O)-(R ¹² has the same meaning as described above), that is, a compound represented by the formula:
The compound represented by [I-3] can be obtained by nucleophilic substitution of the compound represented by the formula [VII] with a compound represented by the formula [IV-2].

This reaction can be carried out under the same conditions as in Production Method 3.

Production method 5

[0086]

Embedded image

Wherein A, X ¹ , X ² , X ³ , X ⁴ , X ⁵ and R ¹² have the same meaning as described above. M is -NCO, or -N (R ¹² ) -C (O) -O
R ¹⁸ (.R ¹⁸ R ¹² is of the same meaning as above, represents. A C _1-7 alkyl group, or a phenyl group). ]

[0088] formula [I] in, D is ^{-NR 12 -C (O) -NR 12} - (R 12
Has the same meaning as described above. ), That is, a compound represented by the formula [I-4] is obtained by reacting a compound represented by the formula [VIII] with a compound represented by the formula [III-2]. Can be.

This reaction can be carried out under the same conditions as in Production Method 3.

Production method 6

[0091]

Embedded image

Wherein A, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ¹² ,
M represents the same meaning as described above. ]

[0093] formula [I] in, D is ^{-NR 12 -C (O) -NR 12} - (R 12
Has the same meaning as described above. ), That is, a compound represented by the formula [I-4] is obtained by reacting a compound represented by the formula [IV-2] with a compound represented by the formula [IX]. Can be.

This reaction can be carried out under the same conditions as in Production Method 3.

Next, a method for producing an intermediate for synthesizing the compound of the present invention will be described.

(Reaction formula 1)

[0097]

Embedded image

[Wherein, R ⁴ and R ⁶ have the same meanings as described above. ]

As shown in Reaction Scheme 1, the intermediate represented by the formula [XIII] can be obtained by solvolysis of β-lactams represented by the formula [XII] (for example, alcohol, water and the like). These β-lactams can be added to the piperidones represented by the formula [X] by a conventional olefinating agent (eg, Wittig reagent).
A suitable isocyanate (eg, ClSO ₂ NCO, etc.) is added to the compound represented by the formula [XI] obtained by reacting
And cyclized.

(Reaction formula 2)

[0101]

Embedded image

[Wherein, R^Four, R⁶Has the same meaning as described above.
R²⁰Is a hydrogen atom, C_1-7Aliphatic acyl, C _6-10Aromatic reed
Or a protecting group. ]

As shown in Reaction Scheme 2, the intermediate represented by the formula [XV] is different from the compound represented by the formula [XIV] by Arndt-E
It is synthesized by performing an istert reaction. That is, the formula [XI
V] with diazomethane on the carboxylic acid chloride or mixed acid anhydride of the compound represented by the formula [V], and in the presence of a suitable alcohol on the resulting diazoketone, a suitable catalyst (for example, a silver compound (eg Or the like, or light irradiation to give a 4-amino-4-piperidylacetic acid derivative. If necessary, deprotection is performed to obtain the compound of formula [XIII]
To obtain an intermediate represented by The compound represented by the formula [XIV] is described in, for example, US Pat. No. 3,313,819 and 3,330,8
No. 36 or J. Org. Chem., 1957, 22, 1061. Deprotection is performed as necessary to obtain an intermediate represented by the formula [XVI].

(Reaction formula 3)

[0105]

Embedded image

[Wherein R ⁴ , R ⁶ and R ⁸ have the same meaning as described above. D represents O, S, or NR ¹² (R ¹² has the same meaning as described above). Q is lithium, copper, magnesium bromide,
Represents zinc bromide, trialkyltin, or trialkylsilicon. ]

As shown in Reaction Scheme 3, the intermediate represented by the formula [XIII] is synthesized from the compound represented by the formula [X] by various reactions. Among them, for the compound of D = O,
Reaction of the corresponding piperidone derivative with an acetate represented by the formula [XVII] under suitable basic conditions, or enol ethers represented by the formula [XVIII] under suitable Lewis acidic conditions To give 4-hydroxy-4-piperidinyl acetic acid esters represented by the formula [XIII (D = O)]. It can also be obtained by reacting the corresponding piperidone derivative with an alkyne represented by [XIX], and then hydrolyzing the obtained compound represented by the formula [XX] under appropriate acidic conditions. . Furthermore, a compound represented by the formula [XI] obtained by allowing the compound represented by the formula [XXI] to act on the corresponding piperidone derivative [X (D = O)]
From the compound represented by the formula [XII], a compound represented by the formula [XIII (D = O)] can also be obtained using a suitable oxidizing agent.
Further, the compound represented by the formula [XIII (D = O)] was converted to a thiol represented by the formula [XIII-2] in which a hydroxyl group was converted to a mercapto group or an amino group by a known method. It can lead to amines represented by the formula [XIII-1]. On the other hand, the compound represented by the formula [XXII] is treated with an appropriate oxidizing agent and then subjected to an appropriate reduction treatment, whereby the compound represented by the formula [XIII-d] To give each of the compounds represented by the formula [XIII-e]. Also the formula [X (D = O)]
By reacting the compound represented by the formula [XXIII] with the piperidone represented by the same manner as in the synthesis of the compound represented by the formula [XXII], the compound represented by the formula [XIII-c] Obtainable. These can be led to the compounds represented by the formulas [XIII-d] and [XIII-e] by selecting an appropriate reducing agent. Furthermore, piperidones [X
(D = O)], the compound represented by the formula [XIII-b] can be obtained by acting a carboxylic acid derivative represented by the formula [XXIV]. This compound is converted to a thiol represented by the formula [XIII-2b] or an amine represented by the formula [XIII-1b] in the same manner as described above for the compound represented by the formula [XIII]. be able to. For those D = NR ^12, to the corresponding piperidone derivative [X (D = O)] synthesized in a known manner from the formula ^{[X (D = NR 12)} ] represented by imines, By the same reaction as that of D = O, the corresponding 4-
An aminopiperidine derivative can be obtained. Among them, the compound represented by the formula [XXII] is described in J. Org. Chem.,
It can be synthesized according to the method described in 1998, 63, 4554.
Further, if necessary, deprotection is carried out to obtain a compound of the formula [XIII], [XIII-b],
An intermediate represented by [XIII-d] and [XIII-e] is obtained.

(Reaction formula 4)

[0109]

Embedded image

[Wherein R ⁴ , R ⁶ and R ²⁰ have the same meaning as described above. ]

As shown in Reaction Scheme 4, the intermediate represented by the formula [XIII] can also be synthesized by Michael addition to various olefin derivatives. A piperonidone represented by the formula [X] is reacted with a malonate, malononitrile or cyanoacetic acid derivative by a known method to give a compound represented by the formula [XXV], [XXVI] or [XXVII], respectively. Combine. After that, ammonia is added to them, an azide is added, and then an appropriate reducing agent is applied, or an amine having an appropriate protecting group (for example, benzylamine) is added, followed by deprotection. Each of the formulas [XXVII
The compounds represented by [I], [XXIX] and [XXX] are obtained. The compound represented by the formula [XXVIII] is led to an intermediate represented by the formula [XV] by a known method (for example, hydrolysis of one ester and subsequent decarboxylation), if necessary. In this case, the intermediate represented by the formula [XIII] can be obtained by deprotection. After hydrolyzing the cyano group of the compound represented by the formula [XXIX], an intermediate represented by the formula [XIII] can be obtained in the same manner as in the case of the compound represented by the formula [XXVIII]. The compound represented by the formula [XXX] is obtained by hydrolyzing a cyanoacetic acid derivative represented by the formula [XXXI] obtained after decarboxylation as described above, thereby obtaining an intermediate represented by the formula [XV]. The body is further deprotected and the formula [XII
The intermediate represented by I] can be obtained. Also, the expression [XXX
The amide derivative represented by the formula [XXXII] and the formula [XXXII] can be obtained from the cyanoacetic acid derivative represented by the formula [I] by a known method.
The alkylaminos represented by I] can also be synthesized.

(Reaction formula 5)

[0113]

Embedded image

[Wherein R ⁴ , R ⁶ and R ²⁰ have the same meaning as described above. ]

As shown in Reaction Scheme 5, an αβ-unsaturated carboxylic acid represented by the formula [XXXIV] or an αβ-unsaturated nitrile represented by the formula [XXXV] can be synthesized by a known method. An intermediate represented by the formula [XIII] can be synthesized by introducing an amino group by Michael addition in the same manner as in Reaction Scheme 4.

[0116]

(Reaction formula 6)

Embedded image

[Wherein R ⁴ , R ⁶ and R ²⁰ have the same meaning as described above. ]

As shown in Reaction Scheme 6, the compounds are represented by Formulas [XVI] and [XIII] by a synthesis method via Overman rearrangement (see, for example, J. Am. Chem. Soc. 1974, 96, 597). Intermediate can be obtained. That is, a reaction between an alcohol represented by the formula [XXXVI] synthesized by a known method (eg, Wittig reaction) and an acetonitrile derivative (such as Cl ₃ CCN) is performed on the piperidone represented by the formula [X]. The precursor represented by the formula [XXXVII] obtained by the above is heated under reflux under a suitable condition (for example, in a high boiling point solvent such as xylene, or reacted in the presence of a metal reagent such as mercury trifluoroacetate). ) By rearrangement, the formula [XXXVII
I] to 4-vinylpiperidine-4-amides. Thereafter, the vinyl group is converted into a carboxylic acid derivative by an appropriate oxidation method (for example, ozone oxidation) and, if necessary, deprotected to obtain an intermediate represented by the formula [XVI]. The compound represented by the formula [XXXVIII] can be converted into an intermediate represented by the formula [XIII-d] after being converted into an alcohol by a known suitable reducing agent and then deprotected if necessary. Further, this intermediate is oxidized by a known suitable oxidation method and, if necessary, deprotected, whereby the intermediate represented by the formula [XIII] can be obtained.

(Reaction formula 7)

Embedded image

[Wherein, k, l, R ⁴ , R ¹³ , R ^{13 ′} , R ¹⁴ ,
R ^{14 ′} , R ¹⁶ and L ² represent the same meaning as described above. G represents a C _1-12 heterocyclic aromatic group, a C _1-6 heteroalicyclic group, a C _3-10 cycloalkyl group, a C _3-7 cycloalkenyl group or a C _6-14 aromatic group. L ¹ and L ³ are each independently -O-, -S-, or -NR
^15- (R ¹⁵ has the same meaning as described above.) ]

As shown in Reaction Scheme 7, the compound represented by the formula [XXXXI] is an alcohol represented by the formula [XXXIX] (L ¹ =
O), thiols (L ¹ = S) or amines (L ¹ = NR
¹⁵ (R ¹⁵ represents the same meaning as described above).
It is synthesized by a nucleophilic substitution reaction to the compound represented by [XXXX]. In the formula [XXXX], R ¹⁶ represents a suitable leaving group.
The obtained compound represented by the formula [XXXXI] can be deprotected if necessary and used as a substituent represented by R ⁵ . The phenols (L ¹ = O) and thiophenols (L ¹ = S) represented by the formula [XXXIX (G = phenyl group)] are described in Bull. Chem. Soc. Jpn., 1973, 46, respectively. 553 and S
ynthesis, 1975, 641, according to the formula [XX
By reacting the compound represented by the formula [XXII] with an appropriate basic condition, an alcohol represented by the formula [XXXXIII] can be obtained.

The compounds shown in Tables 1 to 9 and pharmacologically acceptable salts thereof are examples of the compounds of the present invention.

Table 1

[0125]

Embedded image

[0126]

[Table 001] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HHH--1 NNN NH Cl H MeO H--1 NNN NH Cl H n-PrO H--1 NNN NH Cl H nC ₆ H ₁₃ OH--1 NNN NH Cl H Me H--1 NNN NH Cl H MeNH H--1 NNN NH Cl H Cl H--1 NNN NH Cl HFH--1 NNN NH Cl H NO ₂ H--1 NNN NH Cl H CF ₃ H--1 NNN NH Cl HHHO-1 NNN NH Cl H MeO HO-1 NNN NH Cl H n -PrO HO-1 NNN NH Cl H nC ₆ H ₁₃ OHO-1 NNN NH Cl H Me HO-1 NNN NH Cl H MeNH HO-1 NNN NH Cl H Cl HO-1 NNN NH Cl HFHO-1 NNN NH Cl H NO ₂ HO-1 NNN NH Cl H CF ₃ HO-1 NNN NH Cl HHH-O 1 NNN NH Cl H MeO H-O 1 NNN NH Cl H n-PrO H-O 1 NNN NH Cl ────── ────────────────────────────

[0127]

[Table 002] a R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ OH-O 1 NNN NH Cl H Me H-O 1 NNN NH Cl H MeNH H-O 1 NNN NH Cl H Cl H-O 1 NNN NH Cl HFH-O 1 NNN NH Cl H NO ₂ H-O 1 NNN NH Cl H CF ₃ H-O 1 NNN NH Cl HHH NH-1 NNN NH Cl H MeO H NH-1 NNN NH Cl H n-PrO H NH-1 NNN NH Cl H nC ₆ H ₁₃ OH NH-1 NNN NH Cl H Me H NH -1 NNN NH Cl H MeNH H NH-1 NNN NH Cl H Cl H NH-1 NNN NH Cl HFH NH-1 NNN NH Cl H NO ₂ H NH-1 NNN NH Cl H CF ₃ H NH-1 NNN NH Cl HHH-NH 1 NNN NH Cl H MeO H-NH 1 NNN NH Cl H n-PrO H-NH 1 NNN NH Cl H nC ₆ H ₁₃ OH-NH 1 NNN NH Cl H Me H-NH 1 NNN NH Cl H MeNH H-NH 1 NNN NH Cl ──────────────────────────────────

[0128]

[Table 003] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl H-NH 1 NNN NH Cl HFH-NH 1 NNN NH Cl H NO ₂ H-NH 1 NNN NH Cl H CF ₃ H-NH 1 NNN NH Cl HHH--2 NNN NH Cl H MeO H--2 NNN NH Cl H n-PrO H-- 2 NNN NH Cl H nC ₆ H ₁₃ OH--2 NNN NH Cl H Me H--2 NNN NH Cl H MeNH H---2 NNN NH Cl H Cl H--2 NNN NH Cl HFH--2 NNN NH Cl H NO ₂ H--2 NNN NH Cl H CF ₃ H--2 NNN NH Cl HHHO-2 NNN NH Cl H MeO HO-2 NNN NH Cl H n-PrO HO-2 NNN NH Cl H nC ₆ H ₁₃ OHO -2 NNN NH Cl H Me HO-2 NNN NH Cl H Me NH HO-2 NNN NH Cl H Cl HO-2 NNN NH Cl HFHO-2 NNN NH Cl H NO ₂ HO-2 NNN NH Cl ────── ────────────────────────────

[0129]

[Table 004] a R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ HO-2 NNN NH Cl HHH-O 2 NNN NH Cl H MeO H-O 2 NNN NH Cl H n-PrO H-O 2 NNN NH Cl H nC ₆ H ₁₃ OH-O 2 NNN NH Cl H Me H-O 2 NNN NH Cl H MeNH H-O 2 NNN NH Cl H Cl H-O 2 NNN NH Cl HFH-O 2 NNN NH Cl H NO ₂ H-O 2 NNN NH Cl H CF ₃ H-O 2 NNN NH Cl HHHOO 2 NNN NH Cl H MeO HOO 2 NNN NH Cl H n- PrO HOO 2 NNN NH Cl H nC 6 H 13 OHOO 2 NNN NH Cl H Me HOO 2 NNN NH Cl H MeNH HOO 2 NNN NH Cl H Cl HOO 2 NNN NH Cl HFHOO 2 NNN NH Cl H NO ₂ HOO 2 NNN NH Cl H NH ₂ HOO 2 NNN NH Cl H OH HOO 2 NNN NH Cl H CHO HOO 2 NNN NH Cl ──────────────────── ──────────────

[0130]

００５ R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CH ₂ OH HOO 2 NNN NH Cl H COOH HOO 2 NNN NH Cl H CH ₃ C (O) HOO 2 NNN NH Cl NO ₂ NO ₂ HOO 2 NNN NH Cl NO ₂ H NO ₂ OO 2 NNN NH Cl H CF ₃ HOO 2 NNN NH Cl HHHOO 2 NNNO Cl H MeO HOO 2 NNNO Cl H n -PrO HOO 2 NNNO Cl H nC 6 H 13 OHOO 2 NNNO Cl H Me HOO 2 NNNO Cl H MeNH HOO 2 NNNO Cl H Cl HOO 2 NNNO Cl HFHOO 2 NNNO Cl H NO 2 HOO 2 _{NNNO Cl H CF 3 HOO 2 NNNO} Cl HHHOO 2 NNNOHH MeO HOO 2 NNNOHH n-PrO HOO 2 NNNOHH nC 6 H 13 OHOO 2 NNNOHH Me HOO 2 NNNOHH MeNH HOO 2 NNNOHH Cl HOO 2 NNNOH ───────── ─────────────────────────

[0131]

[Table 006] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HFHOO 2 NNNOHH NO ₂ HOO 2 NNNOHH CF _{3 HOO 2 NNNOHHHHOO 2 NNN NH HH} MeO HOO 2 NNN NH HH n-PrO HOO 2 NNN NH HH nC 6 H 13 OHOO 2 NNN NH HH Me HOO 2 NNN NH HH MeNH HOO 2 NNN NH HH Cl HOO 2 NNN NH HHFHOO 2 NNN NH HH NO ₂ HOO 2 NNN NH HH NH ₂ HOO 2 NNN NH HH OH HOO 2 NNN NH HH CHO HOO 2 NNN NH HH CH ₂ OH HOO 2 NNN NH HH COOH HOO 2 NNN NH HH CH ₃ C (O) HOO 2 NNN NH H NO ₂ NO ₂ HOO 2 NNN NH H NO ₂ H NO ₂ OO 2 NNN NH HH CF ₃ HOO 2 NNN NH HHHHHOO 2 NNN NH Me H MeO HOO 2 NNN NH Me ───────── ─────────────────────────

[0132]

[Table 007] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-PrO HOO 2 NNN NH Me _{H nC 6 H 13 OHOO 2 NNN} NH Me H Me HOO 2 NNN NH Me H MeNH HOO 2 NNN NH Me H Cl HOO 2 NNN NH Me HFHOO 2 NNN NH Me H NO 2 HOO 2 NNN NH Me H CF 3 HOO 2 NNN NH Me HHHOO 2 NNN NH MeO H MeO HOO 2 NNN NH MeO H n-PrO HOO 2 NNN NH MeO H nC 6 H 13 OHOO 2 NNN NH MeO H Me HOO 2 NNN NH MeO H MeNH HOO 2 NNN NH MeO H Cl HOO 2 NNN NH MeO HFHOO 2 NNN NH MeO H NO ₂ HOO 2 NNN NH MeO H CF ₃ HOO 2 NNN NH MeO HHH NH-2 NNN NH Cl H MeO H NH-2 NNN NH Cl H n-PrO H NH-2 NNN NH Cl H nC ₆ H ₁₃ OH NH-2 NNN NH Cl H Me H NH-2 NNN NH Cl ─────────────────────────── ───────

[0133]

[Table 008] a R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeNH H NH-2 NNN NH Cl H Cl H NH-2 NNN NH Cl HFH NH-2 NNN NH Cl H NO ₂ H NH-2 NNN NH Cl H CF ₃ H NH-2 NNN NH Cl HHH-NH 2 NNN NH Cl H MeO H-NH 2 NNN NH Cl H n-PrO H-NH 2 NNN NH Cl H nC ₆ H ₁₃ OH-NH 2 NNN NH Cl H Me H-NH 2 NNN NH Cl H MeNH H-NH 2 NNN NH Cl H Cl H-NH 2 NNN NH Cl HFH-NH 2 NNN NH Cl H NO ₂ H-NH 2 NNN NH Cl H CF ₃ H-NH 2 NNN NH Cl HHH NH NH 2 NNN NH Cl H MeO H NH NH 2 NNN NH Cl H n-PrO H NH NH 2 NNN NH Cl H nC 6 H 13 OH NH NH 2 NNN NH Cl H Me H NH NH 2 NNN NH Cl H MeNH H NH NH 2 NNN NH Cl H Cl H NH NH 2 NNN NH Cl HFH NH NH 2 NNN NH Cl ──────────────────────────────────

[0134]

[Table 009] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H NO ₂ H NH NH 2 NNN NH Cl H CF ₃ H NH NH 2 NNN NH Cl HHHOO 3 NNN NH Cl H MeO HOO 3 NNN NH Cl H n-PrO HOO 3 NNN NH Cl H nC ₆ H ₁₃ OHOO 3 NNN NH Cl H Me HOO 3 NNN NH Cl H MeNH HOO 3 NNN NH Cl H Cl HOO 3 NNN NH Cl HFHOO 3 NNN NH Cl H NO ₂ HOO 3 NNN NH Cl H NH ₂ HOO 3 NNN NH Cl H OH HOO 3 NNN NH Cl H CHO HOO 3 NNN NH Cl H CH ₂ OH HOO 3 NNN NH Cl H COOH HOO 3 NNN NH Cl H CH ₃ C (O) HOO 3 NNN NH Cl NO ₂ NO ₂ HOO 3 NNN NH Cl NO ₂ H NO ₂ OO 3 NNN NH Cl H CF ₃ HOO 3 NNN NH Cl HHHOO 3 NNNO Cl H MeO HOO 3 NNNO Cl H n-PrO HOO 3 NNNO Cl ───────────────────────────── ─────

[0135]

[Table 010] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ OHOO 3 NNNO Cl H Me HOO 3 NNNO Cl H MeNH HOO 3 NNNO Cl H Cl HOO 3 NNNO Cl HFHOO 3 NNNO Cl H NO ₂ HOO 3 NNNO Cl H CF ₃ HOO 3 NNNO Cl HHHOO 3 NNN NH HH MeO HOO 3 NNN NH HH n-PrO HOO 3 NNN NH HH nC ₆ H ₁₃ OHOO 3 NNN NH HH Me HOO 3 NNN NH HH MeNH HOO 3 NNN NH HH Cl HOO 3 NNN NH HHFHOO 3 NNN NH HH NO ₂ HOO 3 NNN NH HH NH ₂ HOO 3 NNN NH HH OH HOO 3 NNN NH HH CHO HOO 3 NNN NH HH CH ₂ OH HOO 3 NNN NH HH COOH HOO 3 NNN NH HH CH ₃ C (O) HOO 3 NNN NH H NO ₂ NO ₂ HOO 3 NNN NH H ──── ──────────────────────────────

[0136]

[Table 011] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── NO ₂ H NO ₂ OO 3 NNN NH HH CF ₃ HOO 3 NNN NH HHHHOO 3 NNN NH Me H MeO HOO 3 NNN NH Me H n-PrO HOO 3 NNN NH Me H nC ₆ H ₁₃ OHOO 3 NNN NH Me H Me HOO 3 NNN NH Me H MeNH HOO 3 NNN NH Me H Cl HOO 3 NNN NH Me HFHOO 3 NNN NH Me H NO ₂ HOO 3 NNN NH Me H CF ₃ HOO 3 NNN NH Me HHHOO 3 NNN NH MeO H MeO HOO 3 NNN NH MeO H n-PrO HOO 3 NNN NH _{MeO H nC 6 H 13 OHOO 3} NNN NH MeO H Me HOO 3 NNN NH MeO H MeNH HOO 3 NNN NH MeO H Cl HOO 3 NNN NH MeO HFHOO 3 NNN NH MeO H NO 2 HOO 3 NNN NH MeO H CF 3 HOO 3 NNN NH MeO HHH--1 N CH CH NH Cl ──────────────────────────────────

[0137]

[Table 012] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeO H--1 N CH CH NH Cl H n-PrO H--1 N CH CH NH Cl H nC ₆ H ₁₃ OH--1 N CH CH NH Cl H Me H--1 N CH CH NH Cl H MeNH H--1 N CH CH NH Cl H Cl H--1 N CH CH NH Cl HFH--1 N CH CH NH Cl H NO ₂ H--1 N CH CH NH Cl H CF ₃ H--1 N CH CH NH Cl HHHO-1 N CH CH NH Cl H MeO HO-1 N CH CH NH Cl H n-PrO HO-1 N CH CH NH Cl H nC ₆ H ₁₃ OHO-1 N CH CH NH Cl H Me HO-1 N CH CH NH Cl H MeNH HO-1 N CH CH NH Cl H Cl HO-1 N CH CH NH Cl HFHO-1 N CH CH NH Cl H NO ₂ HO-1 N CH CH NH Cl H CF ₃ HO-1 N CH CH NH Cl HHH- O 1 N CH CH NH Cl H MeO H-O 1 N CH CH NH Cl H n-PrO H-O 1 N CH CH NH Cl H nC ₆ H ₁₃ OH-O 1 N CH CH NH Cl ───── ───────── ───────────────────

[0138]

[Table 013] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me H-O 1 N CH CH NH Cl H MeNH H-O 1 N CH CH NH Cl H Cl H-O 1 N CH CH NH Cl HFH-O 1 N CH CH NH Cl H NO ₂ H-O 1 N CH CH NH Cl H CF ₃ H- O 1 N CH CH NH Cl HHH NH-1 N CH CH NH Cl H MeO H NH-1 N CH CH NH Cl H n-PrO H NH-1 N CH CH NH Cl H nC ₆ H ₁₃ OH NH-1 N CH CH NH Cl H Me H NH-1 N CH CH NH Cl H MeNH H NH-1 N CH CH NH Cl H Cl H NH-1 N CH CH NH Cl HFH NH-1 N CH CH NH Cl H NO ₂ H NH-1 N CH CH NH Cl H CF ₃ H NH-1 N CH CH NH Cl HHH-NH 1 N CH CH NH Cl H MeO H-NH 1 N CH CH NH Cl H n-PrO H-NH 1 N CH CH NH Cl H nC ₆ H ₁₃ OH-NH 1 N CH CH NH Cl H Me H-NH 1 N CH CH NH Cl H MeNH H-NH 1 N CH CH NH Cl H Cl H-NH 1 N CH CH NH Cl ──────── ─────────────────────────

[0139]

[Table 014] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HFH-NH 1 N CH CH NH Cl H NO ₂ H-NH 1 N CH CH NH Cl H CF ₃ H-NH 1 N CH CH NH Cl HHH--2 N CH CH NH Cl H MeO H--2 N CH CH NH Cl H n-PrO H- -2 N CH CH NH Cl H nC ₆ H ₁₃ OH--2 N CH CH NH Cl H Me H--2 N CH CH NH Cl H MeNH H--2 N CH CH NH Cl H Cl H--2 N CH CH NH Cl HFH--2 N CH CH NH Cl H NO ₂ H--2 N CH CH NH Cl H CF ₃ H--2 N CH CH NH Cl HHHO-2 N CH CH NH Cl H MeO HO-2 N CH CH NH Cl H n-PrO HO-2 N CH CH NH Cl H nC ₆ H ₁₃ OHO-2 N CH CH NH Cl H Me HO-2 N CH CH NH Cl H MeNH HO-2 N CH CH NH Cl H Cl HO-2 N CH CH NH Cl HFHO-2 N CH CH NH Cl H NO ₂ HO-2 N CH CH NH Cl H CF ₃ HO-2 N CH CH NH Cl ────────── ─────── ─────────────────

[0140]

[Table 015] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HHH-O 2 N CH CH NH Cl H MeO H-O 2 N CH CH NH Cl H n-PrO H-O 2 N CH CH NH Cl H nC ₆ H ₁₃ OH-O 2 N CH CH NH Cl H Me H-O 2 N CH CH NH Cl H MeNH H-O 2 N CH CH NH Cl H Cl H-O 2 N CH CH NH Cl HFH-O 2 N CH CH NH Cl H NO ₂ H-O 2 N CH CH NH Cl H CF ₃ H-O 2 N CH CH NH Cl HHHOO 2 N CH CH NH Cl H MeO HOO 2 N CH CH NH Cl H n-PrO HOO 2 N CH CH NH Cl H nC ₆ H ₁₃ OHOO 2 N CH CH NH Cl H Me HOO 2 N CH CH NH Cl H MeNH HOO 2 N CH CH NH Cl H Cl HOO 2 N CH CH NH Cl HFHOO 2 N CH CH NH Cl H NO ₂ HOO 2 N CH CH NH Cl H NH ₂ HOO 2 N CH CH NH Cl H OH HOO 2 N CH CH NH Cl H CHO HOO 2 N CH CH NH Cl H CH 2 OH HOO 2 N CH CH NH Cl ───────────────────── ────────────

[0141]

[Table 016] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H COOH HOO 2 N CH CH NH Cl H CH ₃ C (O) HOO 2 N CH CH NH Cl NO ₂ NO ₂ HOO 2 N CH CH NH Cl NO ₂ H NO ₂ OO 2 N CH CH NH Cl H CF ₃ HOO 2 N CH CH NH Cl HHHOO 2 N CH CH O Cl H MeO HOO 2 N CH CH Cl H n-PrO HOO 2 N CH CH O Cl H nC ₆ H ₁₃ OHOO 2 N CH CH O Cl H Me HOO 2 N CH CH O Cl H MeNH HOO 2 N CH CH O Cl H Cl HOO 2 N CH CH O Cl HFHOO 2 N CH CH O Cl H NO ₂ HOO 2 N CH CH O Cl H CF ₃ HOO 2 N CH CH O Cl HHHOO 2 N CH CH OHH MeO HOO 2 N CH CH OHH n-PrO HOO 2 N CH CH OHH nC ₆ H ₁₃ OHOO 2 N CH CH OHH Me HOO 2 N CH CH OHH MeNH HOO 2 N CH CH OHH Cl HOO 2 N CH CH OHHFHOO 2 N CH CH OH ── ────────────────────────────────

[0142]

[Table 017] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H NO ₂ HOO 2 N CH CH OHH CF ₃ HOO 2 N CH CH OHHHHOO 2 N CH CH NH HH MeO HOO 2 N CH CH NH HH n-PrO HOO 2 N CH CH NH HH nC ₆ H ₁₃ OHOO 2 N CH CH NH HH Me HOO 2 N CH CH NH HH MeNH HOO 2 N CH CH NH HH Cl HOO 2 N CH CH NH HHFHOO 2 N CH CH NH HH NO ₂ HOO 2 N CH CH NH HH NH ₂ HOO 2 N CH CH NH HH OH HOO 2 N CH CH NH HH CHO HOO 2 N CH CH NH HH CH ₂ OH HOO 2 N CH CH NH HH COOH HOO 2 N CH CH NH HH CH ₃ C (O) HOO 2 N CH CH NH H NO ₂ NO ₂ HOO 2 N CH CH NH H NO ₂ H NO ₂ OO 2 N CH CH NH HH CF ₃ HOO 2 N CH CH NH HHHHOO 2 N CH CH NH Me H MeO HOO 2 N CH CH NH Me H n-PrO HOO 2 N CH CH NH Me ──── ──────────────────────────────

[0143]

[Table 018] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ OHOO 2 N CH CH NH Me H Me HOO 2 N CH CH NH Me H MeNH HOO 2 N CH CH NH Me H Cl HOO 2 N CH CH NH Me HFHOO 2 N CH CH NH Me H NO ₂ HOO 2 N CH CH NH Me H CF ₃ HOO 2 N CH CH NH Me HHHOO 2 N CH CH NH MeO H MeO HOO 2 N CH CH NH MeO H n-PrO HOO 2 N CH CH NH MeO H nC ₆ H ₁₃ OHOO 2 N CH CH NH MeO H Me HOO 2 N CH CH NHMeO H MeNH HOO 2 N CH CH NH MeO H Cl HOO 2 N CH CH NH MeO HFHOO 2 N CH CH NH MeO H NO ₂ HOO 2 N CH CH NH MeO H CF ₃ HOO 2 N CH CH NH MeO HHH NH-2 N CH CH NH Cl H MeO H NH-2 N CH CH NH Cl H n-PrO H NH-2 N CH CH NH Cl H nC ₆ H ₁₃ OH NH-2 N CH CH NH Cl H Me H NH-2 N CH CH NH Cl H MeNH H NH-2 N CH CH NH Cl ───────────────── ────────────────

[0144]

[Table 019] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl H NH-2 N CH CH NH Cl HFH NH-2 N CH CH NH Cl H NO ₂ H NH-2 N CH CH NH Cl H CF ₃ H NH-2 N CH CH NH Cl HHH-NH 2 N CH CH NH Cl H MeO H-NH 2 N CH CH NH Cl H n-PrO H-NH 2 N CH CH NH Cl H nC ₆ H ₁₃ OH-NH 2 N CH CH NH Cl H Me H-NH 2 N CH CH NH Cl H MeNH H-NH 2 N CH CH NH Cl H Cl H-NH 2 N CH CH NH Cl HFH-NH 2 N CH CH NH Cl H NO ₂ H-NH 2 N CH CH NH Cl H CF ₃ H-NH 2 N CH CH NH Cl HHH NH NH 2 N CH CH NH Cl H MeO H NH NH 2 N CH CH NH Cl H n-PrO H NH NH 2 N CH CH NH Cl H nC ₆ H ₁₃ OH NH NH 2 N CH CH NH Cl H Me H NH NH 2 N CH CH NH Cl H MeNH H NH NH 2 N CH CH NH Cl H Cl H NH NH 2 N CH CH NH Cl HFH NH NH 2 N CH CH NH Cl H NO ₂ H NH NH 2 N CH CH NH Cl ─ ─── ─────────────────────────────

[0145]

[Table 020] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ H NH NH 2 N CH CH NH Cl HHHOO 3 N CH CH NH Cl H MeO HOO 3 N CH CH NH Cl H n-PrO HOO 3 N CH CH NH Cl H nC ₆ H ₁₃ OHOO 3 N CH CH NH Cl H Me HOO 3 N CH CH NH Cl H MeNH HOO 3 N CH CH NH Cl H Cl HOO 3 N CH CH NH Cl HFHOO 3 N CH CH NH Cl H NO ₂ HOO 3 N CH CH NH Cl H NH ₂ HOO 3 N CH CH NH Cl H OH HOO 3 N CH CH NH Cl H CHO HOO 3 N CH CH NH Cl H CH ₂ OH HOO 3 N CH CH NH Cl H COOH HOO 3 N CH CH NH Cl H CH ₃ C (O) HOO 3 N CH CH NH Cl NO ₂ NO ₂ HOO 3 N CH CH NH Cl NO ₂ H NO ₂ OO 3 N CH CH NH Cl H CF ₃ HOO 3 N CH CH NH Cl HHHOO 3 N CH CH O Cl H MeO HOO 3 N CH CH O Cl H n- PrO HOO 3 N CH CH O Cl H nC 6 H 13 OHOO 3 N CH CH O Cl ───────────────────── ────────────

[0146]

[Table 021] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me HOO 3 N CH CH O Cl H MeNH HOO 3 N CH CH O Cl H Cl HOO 3 N CH CH O Cl HFHOO 3 N CH CH O Cl H NO ₂ HOO 3 N CH CH O Cl H CF ₃ HOO 3 N CH CH O Cl HHHOO 3 N CH CH NH HH MeO HOO 3 N CH CH NH HH n-PrO HOO 3 N CH CH NH HH nC ₆ H ₁₃ OHOO 3 N CH CH NH HH Me HOO 3 N CH CH NH HH MeNH HOO 3 N CH CH NH HH Cl HOO 3 N CH CH NH HHFHOO 3 N CH CH NH HH NO ₂ HOO 3 N CH CH NH HH NH ₂ HOO 3 N CH CH NH HH OH HOO 3 N CH CH NH HH CHO HOO 3 N CH CH NH HH CH ₂ OH HOO 3 N CH CH NH HH COOH HOO 3 N CH CH NH HH CH ₃ C (O) HOO 3 N CH CH NH H NO ₂ NO ₂ HOO 3 N CH CH NH H NO ₂ H NO ₂ OO 3 N CH CH NH H ─ ─────────────────────────────────

[0147]

[Table 022] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ HOO 3 N CH CH NH HHHHOO 3 N CH CH NH Me H MeO HOO 3 N CH CH NH Me H n-PrO HOO 3 N CH CH NH Me H nC ₆ H ₁₃ OHOO 3 N CH CH NH Me H Me HOO 3 N CH CH NH Me H MeNH HOO 3 N CH CH NH Me H Cl HOO 3 N CH CH NH Me HFHOO 3 N CH CH NH Me H NO ₂ HOO 3 N CH CH NH Me H CF ₃ HOO 3 N CH CH NH Me HHHOO 3 N CH CH NH MeO H MeO HOO 3 N CH CH NH MeO H n-PrO HOO 3 N CH CH NH MeO H nC ₆ H ₁₃ OHOO 3 N CH CH NH MeO H Me HOO 3 N CH CH NH MeO H MeNH HOO 3 N CH CH NH MeO H Cl HOO 3 N CH CH NH MeO HFHOO 3 N CH CH NH MeO H NO ₂ HOO 3 N CH CH NH MeO H CF ₃ HOO 3 N CH CH NH MeO HHH--1 CH CH N NH Cl H MeO H-- 1 CH CH N NH Cl ────────────────────────── ───────

[0148]

[Table 023] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-PrO H--1 CH CH N NH Cl H nC ₆ H ₁₃ OH--1 CH CH N NH Cl H Me H--1 CH CH N NH Cl H MeNH H--1 CH CH N NH Cl H Cl H--1 CH CH N NH Cl HFH--1 CH CH N NH Cl H NO ₂ H--1 CH CH N NH Cl H CF ₃ H--1 CH CH N NH Cl HHHO-1 CH CH N NH Cl H MeO HO-1 CH CH N NH Cl H n-PrO HO-1 CH CH N NH Cl H nC ₆ H ₁₃ OHO-1 CH CH N NH Cl H Me HO-1 CH CH N NH Cl H MeNH HO-1 CH CH N NH Cl H Cl HO -1 CH CH N NH Cl HFHO-1 CH CH N NH Cl H NO ₂ HO-1 CH CH N NH Cl H CF ₃ HO-1 CH CH N NH Cl HHH-O 1 CH CH N NH Cl H MeO H- O 1 CH CH N NH Cl H n-PrO H-O 1 CH CH N NH Cl H nC ₆ H ₁₃ OH-O 1 CH CH N NH Cl H Me H-O 1 CH CH N NH Cl ───── ───────── ───────────────────

[0149]

[Table 024] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeNH H-O 1 CH CH N NH Cl H Cl H-O 1 CH CH N NH Cl HFH-O 1 CH CH N NH Cl H NO ₂ H-O 1 CH CH N NH Cl H CF ₃ H-O 1 CH CH N NH Cl HHH NH-1 CH CH N NH Cl H MeO H NH-1 CH CH N NH Cl H n-PrO H NH-1 CH CH N NH Cl H nC ₆ H ₁₃ OH NH-1 CH CH N NH Cl H Me H NH-1 CH CH N NH Cl H MeNH H NH-1 CH CH N NH Cl H Cl H NH-1 CH CH N NH Cl HFH NH-1 CH CH N NH Cl H NO ₂ H NH-1 CH CH N NH Cl H CF ₃ H NH-1 CH CH N NH Cl HHH-NH 1 CH CH N NH Cl H MeO H-NH 1 CH CH N NH Cl H n-PrO H-NH 1 CH CH N NH Cl H nC ₆ H ₁₃ OH-NH 1 CH CH N NH Cl H Me H-NH 1 CH CH N NH Cl H MeNH H-NH 1 CH CH N NH Cl H Cl H-NH 1 CH CH N NH Cl HFH-NH 1 CH CH N NH Cl ── ─────── ────────────────────────

[0150]

[Table 025] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H NO ₂ H-NH 1 CH CH N NH Cl H CF ₃ H-NH 1 CH CH N NH Cl HHH--2 CH CH N NH Cl H MeO H--2 CH CH N NH Cl H n-PrO H--2 CH CH N NH Cl H nC ₆ H ₁₃ OH--2 CH CH N NH Cl H Me H--2 CH CH N NH Cl H MeNH H--2 CH CH N NH Cl H Cl H--2 CH CH N NH Cl HFH--2 CH CH N NH Cl H NO ₂ H--2 CH CH N NH Cl H CF ₃ H--2 CH CH N NH Cl HHHO-2 CH CH N NH Cl H MeO HO-2 CH CH N NH Cl H n-PrO HO-2 CH CH N NH Cl H nC ₆ H ₁₃ OHO-2 CH CH N NH Cl H Me HO-2 CH CH N NH Cl H MeNH HO-2 CH CH N NH Cl H Cl HO-2 CH CH N NH Cl HFHO-2 CH CH N NH Cl H NO ₂ HO-2 CH CH N NH Cl H CF ₃ HO-2 CH CH N NH Cl HHH-O 2 CH CH N NH Cl ────────── ─────── ────────────────

[0151]

[Table 026] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeO H-O 2 CH CH N NH Cl H n-PrO H -O 2 CH CH N NH Cl H nC ₆ H ₁₃ OH -O 2 CH CH N NH Cl H Me H -O 2 CH CH N NH Cl H MeNH H-O 2 CH CH N NH Cl H Cl H-O 2 CH CH N NH Cl HFH-O 2 CH CH N NH Cl H NO ₂ H-O 2 CH CH N NH Cl H CF ₃ H-O 2 CH CH N NH Cl HHHOO 2 CH CH N NH Cl H MeO HOO 2 CH CH N NH Cl H n-PrO HOO 2 CH CH N NH Cl H nC ₆ H ₁₃ OHOO 2 CH CH N NH Cl H Me HOO 2 CH CH N NH Cl H MeNH HOO 2 CH CH N NH Cl H Cl HOO 2 CH CH N NH Cl HFHOO 2 CH CH N NH Cl H NO ₂ HOO 2 CH CH N NH Cl H NH ₂ HOO 2 CH CH N NH Cl H OH HOO 2 CH CH N NH Cl H CHO HOO 2 CH CH N NH Cl H CH 2 OH HOO 2 CH CH N NH Cl H COOH HOO 2 CH CH N NH Cl ──────────────────── ─────────────

[0152]

[Table 027] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CH ₃ C (O) HOO 2 CH CH N NH Cl NO ₂ NO ₂ HOO 2 CH CH N NH Cl NO ₂ H NO ₂ OO 2 CH CH N NH Cl H CF ₃ HOO 2 CH CH N NH Cl HHHOO 2 CH CH NO Cl H MeO HOO 2 CH CH NO Cl H n-PrO HOO 2 CH CH NO Cl H nC ₆ H ₁₃ OHOO 2 CH CH NO Cl H Me HOO 2 CH CH NO Cl H MeNH HOO 2 CH CH NO Cl H Cl HOO 2 CH CH NO Cl HFHOO 2 CH CH NO Cl H NO ₂ HOO 2 CH CH NO Cl H CF ₃ HOO 2 CH CH NO Cl HHHOO 2 CH CH NOHH MeO HOO 2 CH CH NOHH n-PrO HOO 2 CH CH NOHH nC ₆ H ₁₃ OHOO 2 CH CH NOHH Me HOO 2 CH CH NOHH MeNH HOO 2 CH CH NOHH Cl HOO 2 CH CH NOHHFHOO 2 CH CH NOHH NO ₂ HOO 2 CH CH NOH ────────────────────── ────────────

[0153]

[Table 028] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ HOO 2 CH CH NOHHHHOO 2 CH CH N NH HH MeO HOO 2 CH CH N NH HH n-PrO HOO 2 CH CH N NH HH nC ₆ H ₁₃ OHOO 2 CH CH N NH HH Me HOO 2 CH CH N NH HH MeNH HOO 2 CH CH N NH HH Cl HOO 2 CH CH N NH HHFHOO 2 CH CH N NH HH NO ₂ HOO 2 CH CH N NH HH NH ₂ HOO 2 CH CH N NH HH OH HOO 2 CH CH N NH HH CHO HOO 2 CH CH N NH HH CH ₂ OH HOO 2 CH CH N NH HH COOH HOO 2 CH CH N NH HH CH ₃ C (O) HOO 2 CH CH N NH H NO ₂ NO ₂ HOO 2 CH CH N NH H NO ₂ H NO ₂ OO 2 CH CH N NH HH CF ₃ HOO 2 CH CH N NH HHHHOO 2 CH CH N NH Me H MeO HOO 2 CH CH N NH Me H n-PrO HOO 2 CH CH N NH Me H nC ₆ H ₁₃ OHOO 2 CH CH N NH Me ─ ─────────────────────────────────

[0154]

[Table 029] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me HOO 2 CH CH N NH Me H MeNH HOO 2 CH CH N NH Me H Cl HOO 2 CH CH N NH Me HFHOO 2 CH CH N NH Me H NO ₂ HOO 2 CH CH N NH Me H CF ₃ HOO 2 CH CH N NH Me HHHOO 2 CH CH N NH MeO H MeO HOO 2 CH CH n NH MeO H n-PrO HOO 2 CH CH n NH MeO H nC 6 H 13 OHOO 2 CH CH n NH MeO H Me HOO 2 CH CH n NH MeO H MeNH HOO 2 CH CH n NH MeO H Cl HOO 2 CH CH N NH MeO HFHOO 2 CH CH N NH MeO H NO ₂ HOO 2 CH CH N NH MeO H CF ₃ HOO 2 CH CH N NH MeO HHH NH-2 CH CH N NH Cl H MeO H NH-2CH CH N NH Cl H n-PrO H NH-2 CH CH N NH Cl H nC ₆ H ₁₃ OH NH-2 CH CH N NH Cl H Me H NH-2 CH CH N NH Cl H MeNH H NH -2 CH CH N NH Cl H Cl H NH-2 CH CH N NH Cl ─────────────────── ──────────────

[0155]

[Table 030] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HFH NH-2 CH CH N NH Cl H NO ₂ H NH-2 CH CH N NH Cl H CF ₃ H NH-2 CH CH N NH Cl HHH-NH 2 CH CH N NH Cl H MeO H-NH 2 CH CH N NH Cl H n-PrO H- NH 2 CH CH N NH Cl H nC ₆ H ₁₃ OH-NH 2 CH CH N NH Cl H Me H-NH 2 CH CH N NH Cl H MeNH H-NH 2 CH CH N NH Cl H Cl H-NH 2 CH CH N NH Cl HFH-NH 2 CH CH N NH Cl H NO ₂ H-NH 2 CH CH N NH Cl H CF ₃ H-NH 2 CH CH N NH Cl HHH NH NH 2 CH CH N NH Cl H MeO H NH NH 2 CH CH N NH Cl H n-PrO H NH NH 2 CH CH N NH Cl H nC ₆ H ₁₃ OH NH NH 2 CH CH N NH Cl H Me H NH NH 2 CH CH N NH Cl H MeNH H NH NH 2 CH CH N NH Cl H Cl H NH NH 2 CH CH N NH Cl HFH NH NH 2 CH CH N NH Cl H NO ₂ H NH NH 2 CH CH N NH Cl H CF ₃ H NH NH 2 CH CH N NH Cl ─── ──────────────────────────────

[0156]

[Table 031] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HHHOO 3 CH CH N NH Cl H MeO HOO 3 CH CH N NH Cl H n-PrO HOO 3 CH CH N NH Cl H nC ₆ H ₁₃ OHOO 3 CH CH N NH Cl H Me HOO 3 CH CH N NH Cl H MeNH HOO 3 CH CH N NH Cl H Cl HOO 3 CH CH N NH Cl HFHOO 3 CH CH N NH Cl H NO ₂ HOO 3 CH CH N NH Cl H NH ₂ HOO 3 CH CH N NH Cl H OH HOO 3 CH CH N NH Cl H CHO HOO 3 CH CH N NH Cl H CH ₂ OH HOO 3 CH CH N NH Cl H COOH HOO 3 CH CH N NH Cl H CH ₃ C (O) HOO 3 CH CH N NH Cl NO ₂ NO ₂ HOO 3 CH CH N NH Cl NO ₂ H NO ₂ OO 3 CH CH N NH Cl H CF ₃ HOO 3 CH CH N NH Cl HHHOO 3 CH CH NO Cl H MeO HOO 3 CH CH NO Cl H n-PrO HOO 3 CH CH NO Cl H nC ₆ H ₁₃ OHOO 3 CH CH NO Cl H Me HOO 3 CH CH NO Cl ───────────────────────── ────────

[0157]

[Table 032] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeNH HOO 3 CH CH NO Cl H Cl HOO 3 CH CH NO Cl HFHOO 3 CH CH NO Cl H NO ₂ HOO 3 CH CH NO Cl H CF ₃ HOO 3 CH CH NO Cl HHHOO 3 CH CH N NH HH MeO HOO 3 CH CH N NH HH n-PrO HOO 3 CH CH N NH HH nC ₆ H ₁₃ OHOO 3 CH CH N NH HH Me HOO 3 CH CH N NH HH MeNH HOO 3 CH CH N NH HH Cl HOO 3 CH CH N NH HHFHOO 3 CH CH N NH HH NO ₂ HOO 3 CH CH N NH HH NH ₂ HOO 3 CH CH N NH HH OH HOO 3 CH CH N NH HH CHO HOO 3 CH CH N NH HH CH ₂ OH HOO 3 CH CH N NH HH COOH HOO 3 CH CH N NH HH CH ₃ C (O) HOO 3 CH CH N NH H NO ₂ NO ₂ HOO 3 CH CH N NH H NO ₂ H NO ₂ OO 3 CH CH N NH HH CF ₃ HOO 3 CH CH N NH H ────── ────────────────────────────

[0158]

[Table 033] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HHHOO 3 CH CH N NH Me H MeO HOO 3 CH CH N NH Me H n-PrO HOO 3 CH CH N NH Me H nC ₆ H ₁₃ OHOO 3 CH CH N NH Me H Me HOO 3 CH CH N NH Me H MeNH HOO 3 CH CH N NH Me H Cl HOO 3 CH CH N NH Me HFHOO 3 CH CH N NH Me H NO ₂ HOO 3 CH CH N NH Me H CF ₃ HOO 3 CH CH N NH Me HHHOO 3 CH CH N NH MeO H MeO HOO 3 CH CH N NH MeO H n-PrO HOO 3 CH CH N NH MeO H nC ₆ H ₁₃ OHOO 3 CH CH N NH MeO H Me HOO 3 CH CH N NH MeO H MeNH HOO 3 CH CH N NH MeO H Cl HOO 3 CH CH N NH MeO HFHOO 3 CH CH N NH MeO H NO ₂ HOO 3 CH CH N NH MeO H CF ₃ HOO 3 CH CH N NH MeO HHH--1 NN CH NH Cl H MeO H--1 NN CH NH Cl H n-PrO H --1 NN CH NH Cl ────────────────────────── ───────

[0159]

[Table 034] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ OH--1 NN CH NH Cl H Me H--1 NN CH NH Cl H MeNH H--1 NN CH NH Cl H Cl H--1 NN CH NH Cl HFH--1 NN CH NH Cl H NO ₂ H--1 NN CH NH Cl H CF ₃ H--1 NN CH NH Cl HHHO-1 NN CH NH Cl H MeO HO-1 NN CH NH Cl H n-PrO HO-1 NN CH NH Cl H nC ₆ H ₁₃ OHO-1 NN CH NH Cl H Me HO-1 NN CH NH Cl H MeNH HO-1 NN CH NH Cl H Cl HO-1 NN CH NH Cl Cl HFHO-1 NN CH NH Cl H NO ₂ HO-1 NN CH NH Cl H CF ₃ HO-1 NN CH NH Cl HHH-O 1 NN CH NH Cl H MeO H-O 1 NN CH NH Cl H n-PrO H-O 1 NN CH NH Cl H nC ₆ H ₁₃ OH-O 1 NN CH NH Cl H Me H-O 1 NN CH NH Cl H MeNH H-O 1 NN CH NH Cl ────────────────────────────── ───

[0160]

[Table 035] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl H-O 1 NN CH NH Cl HFH-O 1 NN CH NH Cl H NO ₂ H-O 1 NN CH NH Cl H CF ₃ H-O 1 NN CH NH Cl HHH NH-1 NN CH NH Cl H MeO H NH-1 NN CH NH Cl H n-PrO H NH - 1 NN CH NH Cl H nC 6 H 13 OH NH - 1 NN CH NH Cl H Me H NH - 1 NN CH NH Cl H MeNH H NH - 1 NN CH NH Cl H Cl H NH - 1 NN CH NH Cl HFH NH-1 NN CH NH Cl H NO ₂ H NH-1 NN CH NH Cl H CF ₃ H NH-1 NN CH NH Cl HHH-NH 1 NN CH NH Cl H MeO H-NH 1 NN CH NH Cl H n-PrO H-NH 1 NN CH NH Cl H nC ₆ H ₁₃ OH-NH 1 NN CH NH Cl H Me H-NH 1 NN CH NH Cl H MeNH H-NH 1 NN CH NH Cl H Cl H - NH 1 NN CH NH Cl HFH - NH 1 NN CH NH Cl H NO 2 H - NH 1 NN CH NH Cl ──────────────────────── ─────────

[0161]

[Table 036] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ H-NH 1 NN CH NH Cl HHH--2 NN CH NH Cl H MeO H--2 NN CH NH Cl H n-PrO H--2 NN CH NH Cl H nC ₆ H ₁₃ OH--2 NN CH NH Cl H Me H-- 2 NN CH NH Cl H MeNH H--2 NN CH NH Cl H Cl H--2 NN CH NH Cl HFH--2 NN CH NH Cl H NO ₂ H--2 NN CH NH Cl H CF ₃ H-- 2 NN CH NH Cl HHHO-2 NN CH NH Cl H MeO HO-2 NN CH NH Cl H n-PrO HO-2 NN CH NH Cl H nC ₆ H ₁₃ OHO-2 NN CH NH Cl H Me HO-2 NN CH NH Cl H MeNH HO-2 NN CH NH Cl H Cl HO-2 NN CH NH Cl HFHO-2 NN CH NH Cl H NO ₂ HO-2 NN CH NH Cl H CF ₃ HO-2 NN CH NH Cl HHH- O 2 NN CH NH Cl H MeO H-O 2 NN CH NH Cl ─────────────────────────────────

[0162]

[Table 037] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-PrO H-O 2 NN CH NH Cl H nC ₆ H ₁₃ OH-O 2 NN CH NH Cl H Me H-O 2 NN CH NH Cl H MeNH H-O 2 NN CH NH Cl H Cl H-O 2 NN CH NH Cl HFH-O 2 NN CH NH Cl H NO ₂ H-O 2 NN CH NH Cl H CF ₃ H-O 2 NN CH NH Cl HHHOO 2 NN CH NH Cl H MeO HOO 2 NN CH NH Cl H n-PrO HOO 2 NN CH NH Cl H nC ₆ H ₁₃ OHOO 2 NN CH NH Cl H Me HOO 2 NN CH NH Cl H MeNH HOO 2 NN CH NH Cl H Cl HOO 2 NN CH NH Cl HFHOO 2 NN CH NH Cl H NO ₂ HOO 2 NN CH NH Cl H NH ₂ HOO 2 NN CH NH Cl H OH HOO 2 NN CH NH Cl H CHO HOO 2 NN CH NH Cl H CH ₂ OH HOO 2 NN CH NH Cl H COOH HOO 2 NN CH NH Cl H CH ₃ C (O) HOO 2 NN CH NH Cl ──────────────────────────────────

[0163]

[Table 038] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── NO ₂ NO ₂ HOO 2 NN CH NH Cl NO ₂ H NO ₂ OO 2 NN CH NH Cl H CF ₃ HOO 2 NN CH NH Cl HHHOO 2 NN CH O Cl H MeO HOO 2 NN CH O Cl H n-PrO HOO 2 NN CH O Cl H nC ₆ H ₁₃ OHOO 2 NN CH O Cl H Me HOO 2 NN CH O Cl H MeNH HOO 2 NN CH O Cl H Cl HOO 2 NN CH O Cl HFHOO 2 NN CH O Cl H NO ₂ HOO 2 NN CH O Cl H CF ₃ HOO 2 NN CH O Cl HHHOO 2 NN CH OHH MeO HOO 2 NN CH OHH n-PrO HOO 2 NN CH OHH nC ₆ H ₁₃ OHOO 2 NN CH OHH Me HOO 2 NN CH OHH MeNH HOO 2 NN CH OHH Cl HOO 2 NN CH OHHFHOO 2 NN CH OHH NO ₂ HOO 2 NN CH OHH CF ₃ HOO 2 NN CH OH ──────────────────────────────── ──

[0164]

[Table 039] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HHHOO 2 NN CH NH HH MeO HOO 2 NN CH NH HH n-PrO HOO 2 NN CH NH HH nC 6 H 13 OHOO 2 NN CH NH HH Me HOO 2 NN CH NH HH MeNH HOO 2 NN CH NH HH Cl HOO 2 NN CH NH HHFHOO 2 NN CH NH HH NO ₂ HOO 2 NN CH NH HH NH ₂ HOO 2 NN CH NH HH OH HOO 2 NN CH NH HH CHO HOO 2 NN CH NH HH CH ₂ OH HOO 2 NN CH NH HH COOH HOO 2 NN CH NH HH CH ₃ C (O ) HOO 2 NN CH NH H NO ₂ NO ₂ HOO 2 NN CH NH H NO ₂ H NO ₂ OO 2 NN CH NH HH CF ₃ HOO 2 NN CH NH HHHHHOO 2 NN CH NH Me H MeO HOO 2 NN CH NH Me H n-PrO HOO 2 NN CH NH Me H nC ₆ H ₁₃ OHOO 2 NN CH NH Me H Me HOO 2 NN CH NH Me ────────────

[0165]

[Table 040] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeNH HOO 2 NN CH NH Me H Cl HOO 2 NN CH NH Me HFHOO 2 NN CH NH Me H NO ₂ HOO 2 NN CH NH Me H CF ₃ HOO 2 NN CH NH Me HHHOO 2 NN CH NH MeO H MeO HOO 2 NN CH NH MeO H n-PrO HOO _{2 NN CH NH MeO H nC 6} H 13 OHOO 2 NN CH NH MeO H Me HOO 2 NN CH NH MeO H MeNH HOO 2 NN CH NH MeO H Cl HOO 2 NN CH NH MeO HFHOO 2 NN CH NH MeO H NO 2 HOO 2 NN CH NHMeO H CF ₃ HOO 2 NN CH NH MeO HHH NH-2 NN CH NH Cl H MeO H NH-2 NN CH NH Cl H n-PrO H NH-2 NN CH NH Cl H nC ₆ H ₁₃ OH NH-2 NN CH NH Cl H Me H NH-2 NN CH NH Cl H MeNH H NH-2 NN CH NH Cl H Cl H NH-2 NN CH NH Cl HFH NH-2 NN CH NH Cl ───── ─────────────────────────────

[0166]

[Table 041] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H NO ₂ H NH-2 NN CH NH Cl H CF ₃ H NH-2 NN CH NH Cl HHH-NH 2 NN CH NH Cl H MeO H-NH 2 NN CH NH Cl H n-PrO H-NH 2 NN CH NH Cl H nC ₆ H ₁₃ OH- NH 2 NN CH NH Cl H Me H-NH 2 NN CH NH Cl H MeNH H-NH 2 NN CH NH Cl H Cl H-NH 2 NN CH NH Cl HFH-NH 2 NN CH NH Cl H NO ₂ H-NH 2 NN CH NH Cl H CF ₃ H-NH 2 NN CH NH Cl HHH NH NH 2 NN CH NH Cl H MeO H NH NH 2 NN CH NH Cl H n-PrO H NH NH 2 NN CH NH Cl H nC ₆ H ₁₃ OH NH NH 2 NN CH NH Cl H Me NH NH NH 2 NN CH NH Cl H MeNH H NH NH 2 NN CH NH Cl H Cl H NH NH 2 NN CH NH Cl HFH NH NH 2 NN CH NH Cl H NO ₂ H NH NH 2 NN CH NH Cl H CF ₃ H NH NH 2 NN CH NH Cl HHHOO 3 NN CH NH Cl ──────────────────── ──────────────

[0167]

[Table 042] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeO HOO 3 NN CH NH Cl H n-PrO HOO 3 NN CH NH Cl H nC ₆ H ₁₃ OHOO 3 NN CH NH Cl H Me HOO 3 NN CH NH Cl H MeNH HOO 3 NN CH NH Cl H Cl HOO 3 NN CH NH Cl HFHOO 3 NN CH NH Cl H NO ₂ HOO 3 NN CH NH Cl H NH ₂ HOO 3 NN CH NH Cl H OH HOO 3 NN CH NH Cl H CHO HOO 3 NN CH NH Cl H CH ₂ OH HOO 3 NN CH NH Cl H COOH HOO 3 NN CH NH Cl H CH ₃ C (O) HOO 3 NN CH NH Cl NO ₂ NO ₂ HOO 3 NN CH NH Cl NO ₂ H NO ₂ OO 3 NN CH NH Cl H CF ₃ HOO 3 NN CH NH Cl HHHOO 3 NN CH O Cl H MeO HOO 3 NN CH O Cl H n-PrO HOO 3 NN CH O Cl H nC ₆ H ₁₃ OHOO 3 NN CH O Cl H Me HOO 3 NN CH O Cl H MeNH HOO 3 NN CH O Cl ──── ──────────────────────────────

[0168]

[Table 043] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl HOO 3 NN CH O Cl HFHOO 3 NN CH O Cl H NO ₂ HOO 3 NN CH O Cl H CF ₃ HOO 3 NN CH O Cl HHHOO 3 NN CH NH HH MeO HOO 3 NN CH NH HH n-PrO HOO 3 NN CH NH HH nC ₆ H ₁₃ OHOO 3 NN CH NH HH Me HOO 3 NN CH NH HH MeNH HOO 3 NN CH NH HH Cl HOO 3 NN CH NH HHFHOO 3 NN CH NH HH NO ₂ HOO 3 NN CH NH HH NH ₂ HOO 3 NN CH NH HH OH HOO 3 NN CH NH HH CHO HOO 3 NN CH NH HH CH ₂ OH HOO 3 NN CH NH HH COOH HOO 3 NN CH NH HH CH ₃ C (O) HOO 3 NN CH NH H NO ₂ NO ₂ HOO 3 NN CH NH H NO ₂ H NO ₂ OO 3 NN CH NH HH CF ₃ HOO 3 NN CH NH HHHHOO 3 NN CH NH Me ─────────────────────────── ───────

[0169]

[Table 044] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeO HOO 3 NN CH NH Me H n-PrO HOO 3 NN CH NH Me H nC ₆ H ₁₃ OHOO 3 NN CH NH Me H Me HOO 3 NN CH NH Me H MeNH HOO 3 NN CH NH Me H Cl HOO 3 NN CH NH Me HFHOO 3 NN CH NH Me _{H NO 2 HOO 3 NN CH NH} Me H CF 3 HOO 3 NN CH NH Me HHHOO 3 NN CH NH MeO H MeO HOO 3 NN CH NH MeO H n-PrO HOO 3 NN CH NH MeO H nC 6 H 13 OHOO 3 NN CH NH MeO H Me HOO 3 NN CH NH MeO H MeNH HOO 3 NN CH NH MeO H Cl HOO 3 NN CH NH MeO HFHOO 3 NN CH NH MeO H NO ₂ HOO 3 NN CH NH MeO H CF ₃ HOO 3 NN CH NH MeO HHH--1 CH NN NH Cl H MeO H--1 CH NN NH Cl H n-PrO H--1 CH NN NH Cl H nC ₆ H ₁₃ OH--1 CH NN NH Cl ────── ────────────────────────────

[0170]

[Table 045] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me H--1 CH NN NH Cl H MeNH H--1 CH NN NH Cl H Cl H--1 CH NN NH Cl HFH--1 CH NN NH Cl H NO ₂ H--1 CH NN NH Cl H CF ₃ H--1 CH NN NH Cl HHHO-1 CH NN NH Cl H MeO HO-1 CH NN NH Cl H n-PrO HO-1 CH NN NH Cl H nC ₆ H ₁₃ OHO-1 CH NN NH Cl H Me HO-1 CH NN NH Cl H MeNH HO-1 CH NN NH Cl H Cl HO-1 CH NN NH Cl HFHO-1 CH NN NH Cl H NO ₂ HO-1 CH NN NH Cl H CF ₃ HO-1 CH NN NH Cl HHH-O 1 CH NN NH Cl H MeO H-O 1 CH NN NH Cl H n-PrO H-O 1 CH NN NH Cl H nC ₆ H ₁₃ OH-O 1 CH NN NH Cl H Me H-O 1 CH NN NH Cl H MeNH H -O 1 CH NN NH Cl H Cl H-O 1 CH NN NH Cl ───────────────────────────────── ─

[0171]

[Table 046] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HFH-O 1 CH NN NH Cl H NO ₂ H-O 1 CH NN NH Cl H CF ₃ H-O 1 CH NN NH Cl HHH NH-1 CH NN NH Cl H MeO H NH-1 CH NN NH Cl H n-PrO H NH-1 CH NN NH Cl H nC ₆ H ₁₃ OH NH-1 CH NN NH Cl H Me H NH-1 CH NN NH Cl H MeNH H NH-1 CH NN NH Cl H Cl H NH-1 CH NN NH Cl HFH NH-1 CH NN NH Cl H NO ₂ H NH-1 CH NN NH Cl H CF ₃ H NH-1 CH NN NH Cl HHH-NH 1 CH NN NH Cl H MeO H-NH 1 CH NN NH Cl H n-PrO H-NH 1 CH NN NH Cl H nC ₆ H ₁₃ OH-NH 1 CH NN NH Cl H Me H-NH 1 CH NN NH Cl H MeNH H-NH 1 CH NN NH Cl H Cl H-NH 1 CH NN NH Cl HFH-NH _{1 CH NN NH Cl H NO 2} H - NH 1 CH NN NH Cl H CF 3 H - NH 1 CH NN NH Cl ─────────────────────── ──────────

[0172]

[Table 047] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HHH--2 CH NN NH Cl H MeO H--2 CH NN NH Cl H n-PrO H--2 CH NN NH Cl H nC ₆ H ₁₃ OH--2 CH NN NH Cl H Me H--2 CH NN NH Cl H MeNH H--2 CH NN NH Cl H Cl H--2 CH NN NH Cl HFH--2 CH NN NH Cl H NO ₂ H--2 CH NN NH Cl H CF ₃ H--2 CH NN NH Cl HHHO-2 CH NN NH Cl H MeO HO-2 CH NN NH Cl H n-PrO HO-2 CH NN NH Cl H nC ₆ H ₁₃ OHO-2 CH NN NH Cl H Me HO-2 CH NN NH Cl H MeNH HO-2 CH NN NH Cl H Cl HO-2 CH NN NH Cl HFHO-2 CH NN NH Cl H NO ₂ HO-2 CH NN NH Cl H CF ₃ HO-2 CH NN NH Cl HHH-O 2 CH NN NH Cl H MeO H-O 2 CH NN NH Cl H n-PrO H-O 2 CH NN NH Cl ─────────────────────────────────

[0173]

[Table 048] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ OH-O 2 CH NN NH Cl H Me H-O 2 CH NN NH Cl H Me NH H-O 2 CH NN NH Cl H Cl H-O 2 CH NN NH Cl HFH-O 2 CH NN NH Cl H NO ₂ H-O 2 CH _{NN NH Cl H CF 3 H -} O 2 CH NN NH Cl HHHOO 2 CH NN NH Cl H MeO HOO 2 CH NN NH Cl H n-PrO HOO 2 CH NN NH Cl H nC 6 H 13 OHOO 2 CH NN NH Cl H Me HOO 2 CH NN NH Cl H MeNH HOO 2 CH NN NH Cl H Cl HOO 2 CH NN NH Cl HFHOO 2 CH NN NH Cl H NO ₂ HOO 2 CH NN NH Cl H NH ₂ HOO 2 CH NN NH Cl H OH HOO 2 CH NN NH Cl H CHO HOO 2 CH NN NH Cl H CH ₂ OH HOO 2 CH NN NH Cl H COOH HOO 2 CH NN NH Cl H CH ₃ C (O) HOO 2 CH NN NH Cl NO ₂ NO ₂ HOO 2 CH NN NH Cl ──────────────────────────────────

[0174]

[Table 049] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── NO ₂ H NO ₂ OO 2 CH NN NH Cl H CF ₃ HOO 2 CH NN NH Cl HHHOO 2 CH NNO Cl H MeO HOO 2 CH NNO Cl H n-PrO HOO 2 CH NNO Cl H nC ₆ H ₁₃ OHOO 2 CH NNO Cl H Me HOO 2 CH NNO Cl H MeNH HOO 2 CH NNO Cl H Cl HOO 2 CH NNO Cl HFHOO 2 CH NNO Cl H NO ₂ HOO 2 CH NNO Cl H CF ₃ HOO 2 CH NNO Cl HHHOO 2 CH NNOHH MeO HOO 2 CH NNOHH n-PrO HOO 2 CH NNOHH nC ₆ H ₁₃ OHOO 2 CH NNOHH Me HOO 2 CH NNOHH MeNH HOO 2 CH NNOHH Cl HOO 2 CH NNOHHFHOO 2 CH NNOHH NO ₂ HOO 2 CH NNOHH CF ₃ HOO 2 CH NNOHHHHOO 2 CH NN NHH ─────── ───────────────────────────

[0175]

[Table 050] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeO HOO 2 CH NN NH HH n -PrO HOO 2 CH NN NH HH nC 6 H 13 OHOO 2 CH NN NH HH Me HOO 2 CH NN NH HH MeNH HOO 2 CH NN NH HH Cl HOO 2 CH NN NH HHFHOO 2 CH NN NH HH NO 2 HOO 2 CH NN NH HH NH ₂ HOO 2 CH NN NH HH OH HOO 2 CH NN NH HH CHO HOO 2 CH NN NH HH CH ₂ OH HOO 2 CH NN NH HH COOH HOO 2 CH NN NH HH CH ₃ C (O) HOO 2 CH NN NH H NO ₂ NO ₂ HOO 2 CH NN NH H NO ₂ H NO ₂ OO 2 CH NN NH HH CF ₃ HOO 2 CH NN NH HHHHOO 2 CH NN NH Me H MeO HOO 2 CH NN NH Me H n-PrO HOO 2 CH NN NH Me H nC ₆ H ₁₃ OHOO 2 CH NN NH Me H Me HOO 2 CH NN NH Me H Me NH HOO 2 CH NN NH Me ───────────────

[0176]

[Table 051] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl HOO 2 CH NN NH Me HFHOO 2 CH NN NH Me H NO ₂ HOO 2 CH NN NH Me H CF ₃ HOO 2 CH NN NH Me HHHOO 2 CH NN NH MeO H MeO HOO 2 CH NN NH MeO H n-PrO HOO 2 CH NN NH MeO H nC ₆ H ₁₃ OHOO 2 CH NN NH MeO H Me HOO 2 CH NN NH MeO H MeNH HOO 2 CH NN NH MeO H Cl HOO 2 CH NN NH MeO HFHOO 2 CH NN NH MeO H NO ₂ HOO 2 CH NN NH MeO H CF ₃ HOO 2 CH NN NH MeO HHH NH-2 CH NN NH Cl H MeO H NH-2 CH NN NH Cl H n-PrO H NH-2 CH NN NH Cl H nC ₆ H ₁₃ OH NH-2 CH NN NH Cl H Me H NH-2 CH NN NH Cl H MeNH H NH-2 CH NN NH Cl H Cl H NH-2 CH NN NH Cl HFH NH-2 CH NN NH Cl H NO ₂ H NH-2 CH NN NH Cl ── ───────────────────────────────

[0177]

[Table 052] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ H NH-2 CH NN NH Cl HHH-NH 2 CH NN NH Cl H MeO H-NH 2 CH NN NH Cl H n-PrO H-NH 2 CH NN NH Cl H nC ₆ H ₁₃ OH-NH 2 CH NN NH Cl H Me H-NH 2 CH NN NH Cl H MeNH H-NH 2 CH NN NH Cl H Cl H-NH 2 CH NN NH Cl HFH-NH 2 CH NN NH Cl H NO ₂ H-NH 2 CH NN NH Cl H CF ₃ H-NH 2 CH NN NH Cl HHH NH NH 2 CH NN NH Cl H MeO H NH NH 2 CH NN NH Cl H n-PrO H NH NH 2 CH NN NH Cl H nC ₆ H ₁₃ OH NH NH 2 CH NN NH Cl H Me H NH NH 2 CH NN NH Cl H MeNH H NH NH 2 CH NN NH Cl H Cl H NH NH 2 CH NN NH Cl HFH NH NH 2 CH NN NH Cl H NO ₂ H NH NH 2 CH NN NH Cl H CF ₃ H NH NH 2 CH NN NH Cl HHHOO 3 CH NN NH Cl H MeO HOO 3 CH NN NH Cl ───────────────────── ────────────

[0178]

[Table 053] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-PrO HOO 3 CH NN NH Cl H nC ₆ H ₁₃ OHOO 3 CH NN NH Cl H Me HOO 3 CH NN NH Cl H MeNH HOO 3 CH NN NH Cl H Cl HOO 3 CH NN NH Cl HFHOO 3 CH NN NH Cl H NO ₂ HOO 3 CH NN NH Cl H NH ₂ HOO 3 CH NN NH Cl H OH HOO 3 CH NN NH Cl H CHO HOO 3 CH NN NH Cl H CH ₂ OH HOO 3 CH NN NH Cl H COOH HOO 3 CH NN NH Cl H CH ₃ C (O ) HOO 3 CH NN NH Cl NO ₂ NO ₂ HOO 3 CH NN NH Cl NO ₂ H NO ₂ OO 3 CH NN NH Cl H CF ₃ HOO 3 CH NN NH Cl HHHOO 3 CH NNO Cl H MeO HOO 3 CH NNO Cl H n-PrO HOO 3 CH NNO Cl H nC ₆ H ₁₃ OHOO 3 CH NNO Cl H Me HOO 3 CH NNO Cl H MeNH HOO 3 CH NNO Cl H Cl HOO 3 CH NNO Cl ─────────── ───────────────────────

[0179]

[Table 054] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HFHOO 3 CH NNO Cl H NO ₂ HOO 3 CH NNO Cl H CF ₃ HOO 3 CH NNO Cl HHHOO 3 CH NN NH HH MeO HOO 3 CH NN NH HH n-PrO HOO 3 CH NN NH HH nC ₆ H ₁₃ OHOO 3 CH NN NH HH Me HOO 3 CH NN NH HH MeNH HOO 3 CH NN NH HH Cl HOO 3 CH NN NH HHFHOO 3 CH NN NH HH NO ₂ HOO 3 CH NN NH HH NH ₂ HOO 3 CH NN NH HH OH HOO 3 CH NN NH HH CHO HOO 3 CH NN NH HH CH ₂ OH HOO 3 CH NN NH HH COOH HOO 3 CH NN NH HH CH ₃ C (O) HOO 3 CH NN NH H NO ₂ NO ₂ HOO 3 CH NN NH H NO ₂ H NO ₂ OO 3 CH NN NH HH CF ₃ HOO 3 CH NN NH HHHHOO 3 CH NN NH Me H MeO HOO 3 CH NN NH Me ────────────────────────────── ────

[0180]

[Table 055] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-PrO HOO 3 CH NN NH Me H nC ₆ H ₁₃ OHOO 3 CH NN NH Me H Me HOO 3 CH NN NH Me H MeNH HOO 3 CH NN NH Me H Cl HOO 3 CH NN NH Me HFHOO 3 CH NN NH Me H NO ₂ HOO 3 CH NN NH Me H CF ₃ HOO 3 CH NN NH Me HHHOO 3 CH NN NH MeO H MeO HOO 3 CH NN NH MeO H n-PrO HOO 3 CH NN NH MeO H nC ₆ H ₁₃ OHOO 3 CH NN NH MeO H Me HOO 3 CH NN NH MeO H MeNH HOO 3 CH NN NH MeO H Cl HOO 3 CH NN NH MeO HFHOO 3 CH NN NH MeO H NO ₂ HOO 3 CH NN NH MeO H CF ₃ HOO 3 CH NN NH MeO HHH--1 N CH N NH Cl H MeO H--1 N CH N NH Cl H n-PrO H--1 N CH N NH Cl H nC ₆ H ₁₃ OH--1 N CH N NH Cl H Me H--1 N CH N NH Cl ─────────────────────────────────

[0181]

[Table 056] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl H--1 N CH N NH Cl HFH--1 N CH N NH Cl H CF ₃ H--1 N CH N NH Cl HHHO-1 N CH N NH Cl H MeO HO-1 N CH N NH Cl H n-PrO HO-1 N CH N NH Cl H nC ₆ H ₁₃ OHO-1 N CH N NH Cl H Me HO-1 N CH N NH Cl H Me HO-1 N CH N NH Cl H Cl HO-1 N CH N NH Cl HFHO-1 N CH N NH Cl H NO ₂ HO-1 N CH N NH Cl H CF ₃ HO-1 N CH N NH Cl HHH-O 1 N CH N NH Cl H MeO H-O 1 N CH N NH Cl H EtO H- O 1 N CH N NH Cl H n-PrO H-O 1 N CH N NH Cl H i-PrO H-O 1 N CH N NH Cl H c-PrO H-O 1 N CH N NH Cl H n-BuO H-O 1 N CH N NH Cl H nC ₅ H ₁₁ OH-O 1 N CH N NH Cl H nC ₆ H ₁₃ OH-O 1 N CH N NH Cl H nC ₈ H ₁₇ OH-O 1 N CH N NH Cl ────────────────── ───────────────

[0182]

[Table 057] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₁₀ H ₂₁ OH-O 1 N CH N NH Cl H Me H-O 1 N CH N NH Cl H Et H-O 1 N CH N NH Cl H n-Pr H-O 1 N CH N NH Cl Hi-Pr H-O 1 N CH N NH Cl H c-Pr H-O 1 N CH N NH Cl H n-Bu H-O 1 N CH N NH Cl H nC ₅ H ₁₁ H-O 1 N CH N NH Cl H nC ₆ H ₁₃ H- O 1 N CH N NH Cl H nC ₈ H ₁₇ H-O 1 N CH N NH Cl H nC ₁₀ H ₂₁ H-O 1 N CH N NH Cl H MeNH H-O 1 N CH N NH Cl H EtNH H- O 1 N CH N NH Cl H n-PrNH H-O 1 N CH N NH Cl H i-PrNH H-O 1 N CH N NH Cl H c-PrNH H-O 1 N CH N NH Cl H n-BuNH H-O 1 N CH N NH Cl H nC ₅ H ₁₁ NH H-O 1 N CH N NH Cl H n C ₆ H ₁₃ NH H-O 1 N CH N NH Cl H nC ₈ H ₁₇ NH H-O 1 N CH N NH Cl H nC ₁₀ H ₂₁ NH H-O 1 N CH N NH Cl H Cl H-O 1 N CH N NH Cl HFH-O 1 N CH N NH Cl ──────────────────────────────────

[0183]

[Table 058] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Br H-O 1 N CH N NH Cl H NO ₂ H-O 1 N CH N NH Cl H NH ₂ H-O 1 N CH N NH Cl H OH H-O 1 N CH N NH Cl H CHO H-O 1 N CH N NH Cl H CH ₂ OH H-O 1 N CH N NH Cl H COOH H-O 1 N CH N NH Cl H CH ₃ C (O) H-O 1 N CH N NH Cl NO ₂ NO ₂ H-O 1 N CH N NH Cl NO ₂ H NO ₂ -O 1 N CH N NH Cl H CF ₃ H-O 1 N CH N NH Cl HHH NH-1 N CH N NH Cl H MeO H NH-1 N CH N NH Cl H n-PrO H NH-1 N CH N NH Cl H nC ₆ H ₁₃ OH NH-1 N CH N NH Cl H Me H NH-1 N CH N NH Cl H MeNH H NH-1 N CH N NH Cl H Cl H NH- 1 N CH N NH Cl HFH NH-1 N CH N NH Cl H NO ₂ H NH-1 N CH N NH Cl H CF ₃ H NH-1 N CH N NH Cl HHH-NH 1 N CH N NH Cl H MeO H-NH 1 N CH N NH Cl ───────────── ─────────────────────

[0184]

[Table 059] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H EtO H-NH 1 N CH N NH Cl H n-PrO H-NH 1 N CH N NH Cl H i-PrO H-NH 1 N CH N NH Cl H c-PrO H-NH 1 N CH N NH Cl H n-BuO H-NH 1 N CH N NH Cl H nC ₅ H ₁₁ OH-NH 1 N CH N NH Cl H nC ₆ H ₁₃ OH-NH 1 N CH N NH Cl H nC ₈ H ₁₇ OH-NH 1 N CH N NH Cl H nC ₁₀ H ₂₁ OH-NH 1 N CH N NH Cl H Me H-NH 1 N CH N NH Cl H Et H-NH 1 N CH N NH Cl H n-Pr H-NH 1 N CH N NH Cl H i-Pr H -NH 1 N CH N NH Cl H c-Pr H-NH 1 N CH N NH Cl H n-Bu H-NH 1 N CH N NH Cl H nC ₅ H ₁₁ H-NH 1 N CH N NH Cl H nC ₆ H ₁₃ H-NH 1 N CH N NH Cl H nC ₈ H ₁₇ H-NH 1 N CH N NH Cl H nC ₁₀ H ₂₁ H-NH 1 N CH N NH Cl H MeNH H-NH 1 N CH N NH Cl H EtNH H-NH 1 N CH N NH Cl H n-PrNH H-NH 1 N CH N NH Cl Hi i-PrN H H-NH 1 N CH N NH Cl ──────────────────────────────────

[0185]

[Table 060] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H c-PrNH H-NH 1 N CH N NH Cl H n-BuNH H-NH 1 N CH N NH Cl H nC ₅ H ₁₁ NH H-NH 1 N CH N NH Cl H nC ₆ H ₁₃ NH H-NH 1 N CH N NH Cl H nC ₈ H ₁₇ NH H-NH 1 N CH N NH Cl H nC ₁₀ H ₂₁ NH H-NH 1 N CH N NH Cl H Cl H-NH 1 N CH N NH Cl HFH-NH 1 N CH N NH Cl H Br H -NH 1 N CH N NH Cl H NO ₂ H-NH 1 N CH N NH Cl H NH ₂ H-NH 1 N CH N NH Cl H OH H-NH 1 N CH N NH Cl H CHO H-NH 1 N CH N NH Cl H CH ₂ OH H-NH 1 N CH N NH Cl H COOH H-NH 1 N CH N NH Cl H CH ₃ C (O) H-NH 1 N CH N NH Cl NO ₂ NO ₂ H- NH 1 N CH N NH Cl NO ₂ H NO ₂ -NH 1 N CH N NH Cl H CF ₃ H-NH 1 N CH N NH Cl HHH--2 N CH N NH Cl H MeO H--2 N CH N NH Cl H n-PrO H--2 N CH N NH Cl H nC ₆ H ₁₃ OH--2 N CH N NH Cl ──────────────────────────────────

[0186]

[Table 061] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me H--2 N CH N NH Cl H MeNH H--2 N CH N NH Cl H Cl H--2 N CH N NH Cl HFH--2 N CH N NH Cl H NO ₂ H--2 N CH N NH Cl H CF ₃ H- -2 N CH N NH Cl HHHO-2 N CH N NH Cl H MeO HO-2 N CH N NH Cl H n-PrO HO-2 N CH N NH Cl H nC ₆ H ₁₃ OHO-2 N CH N NH Cl H Me HO-2 N CH N NH Cl H MeNH HO-2 N CH N NH Cl H Cl HO-2 N CH N NH Cl HFHO-2 N CH N NH Cl H NO ₂ HO-2 N CH N NH Cl H CF ₃ HO-2 N CH N NH Cl HHH-O 2 N CH N NH Cl MeO HH-O 2 N CH N NH Cl H MeO H-O 2 N CH N NH Cl HH MeO-O 2 N CH N NH Cl EtO HH-O 2 N CH N NH Cl H EtO H-O 2 N CH N NH Cl HH EtO-O 2 N CH N NH Cl ─────────────────── ────────── ────

[0187]

[Table 062] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── n-PrO HH-O 2 N CH N NH Cl H n-PrO H-O 2 N CH N NH Cl HH n-PrO-O 2 N CH N NH Cl i-PrO HH-O 2 N CH N NH Cl Hi i-PrO H-O 2 N CH N NH Cl HH i-PrO-O 2 N CH N NH Cl c-PrO HH-O 2 N CH N NH Cl H c-PrO H-O 2 N CH N NH Cl HH c-PrO-O 2 N CH N NH Cl n-BuO HH-O 2 N CH N NH Cl H n-BuO H-O 2 N CH N NH Cl HH n-BuO-O 2 N CH N NH Cl nC ₅ H ₁₁ OHH-O 2 N CH N NH Cl H nC ₅ H ₁₁ OH-O 2 N CH N NH Cl HH nC ₅ H ₁₁ O-O 2 N CH N NH Cl nC ₆ H ₁₃ OHH-O 2 N CH N NH Cl H nC ₆ H ₁₃ OH- O 2 N CH N NH Cl HH nC ₆ H ₁₃ O-O 2 N CH N NH Cl nC ₈ H ₁₇ OHH-O 2 N CH N NH Cl H nC ₈ H ₁₇ OH-O 2 N CH N NH Cl HH nC ₈ H ₁₇ O-O 2 N CH N NH Cl nC ₁₀ H ₂₁ OHH-O 2 N CH N NH Cl H nC ₁₀ H ₂₁ OH -O 2 N CH N NH Cl ──────────────────────────────────

[0188]

[Table 063] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HH nC ₁₀ H ₂₁ O-O 2 N CH N NH Cl Me HH-O 2 N CH N NH Cl H Me H-O 2 N CH N NH Cl HH Me-O 2 N CH N NH Cl Et HH-O 2 N CH N NH Cl H Et H- O 2 N CH N NH Cl HH Et-O 2 N CH N NH Cl n-Pr HH-O 2 N CH N NH Cl H n-Pr H-O 2 N CH N NH Cl HH n-Pr-O 2 N CH N NH Cl i-Pr HH-O 2 N CH N NH Cl H i-Pr H-O 2 N CH N NH Cl HH i-Pr-O 2 N CH N NH Cl c-Pr HH-O 2 N CH N NH Cl H c-Pr H -O 2 N CH N NH Cl HH c-Pr -O 2 N CH N NH Cl n-Bu HH -O 2 N CH N NH Cl H n-Bu H -O 2 N CH N NH Cl HH n-Bu-O 2 N CH N NH Cl nC ₅ H ₁₁ HH-O 2 N CH N NH Cl H nC ₅ H ₁₁ H-O 2 N CH N NH Cl HH nC ₅ H ₁₁ -O 2 _{N CH N NH Cl nC 6 H} 13 HH - O 2 N CH N NH Cl ─────────────── ──────────────────

[0189]

[Table 064] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ H-O 2 N CH N NH Cl HH nC ₆ H ₁₃ -O 2 N CH N NH Cl nC ₈ H ₁₇ HH-O 2 N CH N NH Cl H nC ₈ H ₁₇ H-O 2 N CH N NH Cl HH nC ₈ H ₁₇ -O 2 N CH N NH Cl nC ₁₀ H ₂₁ HH-O 2 N CH N NH Cl H nC ₁₀ H ₂₁ H-O 2 N CH N NH Cl HH nC ₁₀ H ₂₁ -O 2 N CH N NH Cl MeNH HH -O 2 N CH N NH Cl H MeNH H-O 2 N CH N NH Cl EtNH HH-O 2 N CH N NH Cl H EtNH H-O 2 N CH N NH Cl n-PrNH HH-O 2 N CH N NH Cl H n-PrNH H-O 2 N CH N NH Cl i-PrNH HH-O 2 N CH N NH Cl H i-PrNH H-O 2 N CH N NH Cl c-PrNH HH-O 2 N CH N NH Cl H c-PrNH H - O 2 n CH n NH Cl n-BuNH HH - O 2 n CH n NH Cl H n-BuNH H - O 2 n CH n NH Cl nC 5 H 11 NH HH - O 2 n CH N NH Cl H nC ₅ H ₁₁ NH H-O 2 N CH N NH Cl nC ₆ H ₁₃ NH HH-O 2 N CH N NH Cl ──────────────────────────────────

[0190]

[Table 065] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ NH H-O 2 N CH N NH Cl nC ₈ H ₁₇ NH HH-O 2 N CH N NH Cl H nC ₈ H ₁₇ NH H-O 2 N CH N NH Cl nC ₁₀ H ₂₁ NH HH-O 2 N CH N NH Cl H nC ₁₀ H ₂₁ NH H-O 2 N CH N NH Cl Cl HH-O 2 N CH N NH Cl H Cl H-O 2 N CH N NH Cl HH Cl-O 2 N CH N NH Cl FHH-O 2 N CH N NH Cl HFH-O 2 N CH N NH Cl HHF-O 2 N CH N NH Cl Br HH-O 2 N CH N NH Cl H Br H-O 2 N CH N NH Cl HH Br-O 2 N CH N NH Cl NO ₂ HH-O 2 N CH N NH Cl H NO ₂ H-O 2 N CH N NH Cl HH NO ₂ -O 2 N CH N NH Cl NH ₂ HH-O 2 N CH N NH Cl H NH ₂ H-O 2 N CH N NH Cl HH NH ₂ -O 2 N CH N NH Cl OH HH-O 2 N CH N NH Cl H OH H-O 2 N CH N NH Cl HH OH-O 2 N CH N NH Cl ──────────────── ─────────────────

[0191]

[Table 066] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── CHO HH-O 2 N CH N NH Cl H CHO H-O 2 N CH N NH Cl HH CHO-O 2 N CH N NH Cl CH ₂ OH HH-O 2 N CH N NH Cl H CH ₂ OH H-O 2 N CH N NH Cl HH CH ₂ OH-O 2 N CH N NH Cl COOH HH-O 2 N CH N NH Cl H COOH H-O 2 N CH N NH Cl HH COOH-O 2 N CH N NH Cl CH ₃ C (O) HH-O 2 N CH N NH Cl H CH ₃ C (O) H-O 2 N CH N NH Cl HH CH ₃ C (O)-O 2 N CH N NH Cl NO ₂ NO ₂ H-O 2 N CH N NH Cl NO ₂ H NO ₂ -O 2 N CH N NH Cl CF ₃ HH -O 2 N CH N NH Cl H CF ₃ H -O 2 N CH N NH Cl HH CF ₃ -O 2 N CH N NH Cl HHH -O 2 N CH N NH HH MeO H-O 2 N CH N NH HH n-PrO H-O 2 N CH N NH HH nC ₆ H ₁₃ OH-O 2 N CH N NH HH Me H-O 2 N CH N NH HH MeNH H-O 2 N CH N NH H ───────────── ────────────────────

[0192]

[Table 067] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl H-O 2 N CH N NH HHFH-O 2 N CH N NH HH NO ₂ H-O 2 N CH N NH HH CF ₃ H-O 2 N CH N NH HHHH-O 2 N CH N NH Me H MeO H-O 2 N CH N NH Me H n-PrO H-O 2 N CH N NH Me H nC ₆ H ₁₃ OH-O 2 N CH N NH Me H Me H-O 2 N CH N NH Me H Me NH H-O 2 N CH N NH Me H Cl H-O 2 N CH N NH Me HFH-O 2 N CH N NH Me H NO ₂ H-O 2 N CH N NH Me H CF ₃ H-O 2 N CH N NH Me HHH-O 2 N CH N NH MeO H MeO H-O 2 N CH N NH MeO H n-PrO H-O 2 N CH N NH MeO H nC ₆ H ₁₃ OH-O 2 N CH N NH MeO H Me H-O 2 N CH N NH MeO H MeNH H-O 2 N CH N NH MeO H Cl H-O 2 N CH N NH MeO HFH-O 2 N CH N NH MeO H NO ₂ H-O 2 N CH N NH MeO ───── ───────────────── ───────────

[0193]

[Table 068] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ H-O 2 N CH N NH MeO HHH-O 2 N CH NO Cl H MeO H-O 2 N CH NO Cl H n-PrO H-O 2 N CH NO Cl H nC ₆ H ₁₃ OH-O 2 N CH NO Cl H Me H- O 2 N CH NO Cl H MeNH H-O 2 N CH NO Cl H Cl H-O 2 N CH NO Cl HFH-O 2 N CH NO Cl H NO ₂ H-O 2 N CH NO Cl H CF ₃ H- O 2 N CH NO Cl HHH-O 2 N CH NOHH MeO H-O 2 N CH NOHH n-PrO H-O 2 N CH NOHH nC ₆ H ₁₃ OH-O 2 N CH NOHH Me H-O 2 N CH NOHH MeNH H-O 2 N CH NOHH Cl H-O 2 N CH NOHHFH-O 2 N CH NOHH NO ₂ H-O 2 N CH NOHH CF ₃ H-O 2 N CH NOHHHHOO 2 N CH N NH Cl MeO HHOO 2 N CH N NH Cl ──────────────────────────────────

[0194]

[Table 069] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeO HOO 2 N CH N NH Cl HH MeO OO 2 N CH N NH Cl EtO HHOO 2 N CH N NH Cl H EtO HOO 2 N CH N NH Cl HH EtO OO 2 N CH N NH Cl n-PrO HHOO 2 N CH N NH Cl H n-PrO HOO 2 N CH N NH Cl HH n-PrO OO 2 N CH N NH Cl i-PrO HHOO 2 N CH N NH Cl H i-PrO HOO 2 N CH N NH Cl HH i-PrO OO 2 N CH N NH Cl c -PrO HHOO 2 N CH N NH Cl H c-PrO HOO 2 N CH N NH Cl HH c-PrO OO 2 N CH N NH Cl n-BuO HHOO 2 N CH N NH Cl H n-BuO HOO 2 N CH N NH Cl HH n-BuO OO 2 N CH N NH Cl nC ₅ H ₁₁ OHHOO 2 N CH N NH Cl H nC ₅ H ₁₁ OHOO 2 N CH N NH Cl HH nC ₅ H ₁₁ OOO 2 N CH N NH Cl nC ₆ H ₁₃ OHHOO 2 N CH N NH Cl H nC ₆ H ₁₃ OHOO 2 N CH N NH Cl HH nC ₆ H ₁₃ OOO 2 N CH N NH Cl ───────────────── ─ ───────────────

[0195]

[Table 070] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── nC ₈ H ₁₇ OHHOO 2 N CH N NH Cl H nC ₈ H ₁₇ OHOO 2 N CH N NH Cl HH nC ₈ H ₁₇ OOO 2 N CH N NH Cl nC ₁₀ H ₂₁ OHHOO 2 N CH N NH Cl H nC ₁₀ H ₂₁ OHOO 2 N CH N NH Cl HH nC ₁₀ H ₂₁ OOO 2 N CH N NH Cl Me HHOO 2 N CH N NH Cl H Me HOO 2 N CH N NH Cl HH Me OO 2 N CH N NH Cl Et HHOO 2 N CH N NH Cl H Et HOO 2 N CH N NH Cl HH Et OO 2 N CH N NH Cl n-Pr HHOO 2 N CH N NH Cl H n-Pr HOO 2 N CH N NH Cl HH n-Pr OO 2 N CH N NH Cl i-Pr HHOO 2 N CH N NH Cl H i-Pr HOO 2 N CH N NH Cl HH i-Pr OO 2 N CH N NH Cl c-Pr HHOO 2 N CH N NH Cl H c-Pr HOO 2 N CH N NH Cl HH c -Pr OO 2 N CH N NH Cl n-Bu HHOO 2 N CH N NH Cl H n-Bu HOO 2 N CH N NH Cl ──────────────────── ──── ─────────

[0196]

[Table 071] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HH n-Bu OO 2 N CH N NH Cl nC ₅ H ₁₁ HHOO 2 N CH N NH Cl H nC ₅ H ₁₁ HOO 2 N CH N NH Cl HH nC ₅ H ₁₁ OO 2 N CH N NH Cl nC ₆ H ₁₃ HHOO 2 N CH N NH Cl H nC ₆ H ₁₃ HOO 2 N CH N NH Cl HH nC ₆ H ₁₃ OO 2 N CH N NH Cl nC ₈ H ₁₇ HHOO 2 N CH N NH Cl H nC ₈ H ₁₇ HOO 2 N CH N NH Cl HH nC ₈ H ₁₇ OO 2 N CH N NH Cl nC ₁₀ H ₂₁ HHOO 2 N CH N NH Cl H nC ₁₀ H ₂₁ HOO 2 N CH N NH Cl HH nC ₁₀ H ₂₁ OO 2 N CH N NH Cl MeNH HHOO 2 N CH N NH Cl H MeNH HOO 2 N CH N NH Cl EtNH HHOO 2 N CH N NH Cl H EtNH HOO 2 N CH N NH Cl n-PrNH HHOO 2 N CH N NH Cl H n-PrNH HOO 2 N CH N NH Cl i-PrNH HHOO 2 N CH N NH Cl Hi-PrNH HOO 2 N CH N NH Cl c-PrNH HHOO 2 N CH N NH Cl H c-PrNH HOO 2 N CH N NH Cl ──────── ─────────────────────────

[0197]

[Table 072] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── n-BuNH HHOO 2 N CH N NH Cl H n-BuNH HOO 2 N CH N NH Cl nC ₅ H ₁₁ NH HHOO 2 N CH N NH Cl H nC ₅ H ₁₁ NH HOO 2 N CH N NH Cl nC ₆ H ₁₃ NH HHOO 2 N CH N NH Cl H nC ₆ H ₁₃ NH HOO 2 N CH N NH Cl nC ₈ H ₁₇ NH HHOO 2 N CH N NH Cl H nC ₈ H ₁₇ NH HOO 2 N CH N NH Cl nC ₁₀ H ₂₁ NH HHOO 2 N CH N NH Cl H nC ₁₀ H ₂₁ NH HOO 2 N CH N NH Cl Cl HHOO 2 N CH N NH Cl H Cl HOO 2 N CH N NH Cl HH Cl OO 2 N CH N NH Cl FHHOO 2 N CH N NH Cl HFHOO 2 N CH N NH Cl HHFOO 2 N CH N NH Cl Br HHOO 2 N CH N NH Cl H Br HOO 2 N CH N NH Cl HH Br OO 2 N CH N NH Cl NO ₂ HHOO 2 N CH N NH Cl H NO ₂ HOO 2 N _{CH N NH Cl HH NO 2 OO} 2 N CH N NH Cl NH 2 HHOO 2 N CH N NH Cl ─────────────────── ──────────────

[0198]

[Table 073] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H NH ₂ HOO 2 N CH N NH Cl HH NH ₂ OO 2 N CH N NH Cl OH HHOO 2 N CH N NH Cl H OH HOO 2 N CH N NH Cl HH OH OO 2 N CH N NH Cl CHO HHOO 2 N CH N NH Cl H CHO HOO 2 N CH N NH Cl HH CHO OO 2 N CH N NH Cl CH ₂ OH HHOO 2 N CH N NH Cl H CH ₂ OH HOO 2 N CH N NH Cl HH CH ₂ OH OO 2 N CH N NH Cl COOH HHOO 2 N CH N NH Cl H COOH HOO 2 N CH N NH Cl HH COOH OO 2 N CH N NH Cl CH ₃ C (O) HHOO 2 N CH N NH Cl H CH ₃ C (O) HOO 2 N CH N NH Cl HH CH ₃ C (O) OO 2 N CH N NH Cl NO ₂ NO ₂ HOO 2 N CH N NH Cl NO ₂ H NO ₂ OO 2 N CH N NH Cl CF ₃ HHOO 2 N CH N NH Cl H CF ₃ HOO 2 N _{CH N NH Cl HH CF 3 OO} 2 N CH N NH Cl HHHOO 2 N CCl N NH Cl ────────────────────────── ───────

[0199]

[Table 074] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeO HOO 2 N CCl N NH Cl H n-PrO HOO 2 N CCl N NH Cl H nC ₆ H ₁₃ OHOO 2 N CCl N NH Cl H Me HOO 2 N CCl N NH Cl H MeNH HOO 2 N CCl N NH Cl H Cl HOO 2 N CCl N NH Cl HFHOO 2 N CCl N NH Cl H NO ₂ HOO 2 N CCl N NH Cl H CF ₃ HOO 2 N CCl N NH Cl HHHOO 2 N CMe N NH Cl H MeO HOO 2 N CMe N NH Cl H n-PrO HOO 2 N CMe N NH Cl H nC ₆ H ₁₃ OHOO 2 N CMe N NH Cl H Me HOO 2 N CMe N NH Cl H MeNH HOO 2 N CMe N NH Cl H Cl HOO 2 N CMe N NH Cl HFHOO 2 N CMe N NH Cl H NO ₂ HOO 2 N CMe N NH Cl H CF ₃ HOO 2 N CMe N NH Cl HHHOO 2 N COMe N NH Cl H MeO HOO 2 N COMe N NH Cl H n-PrO HOO 2 N COMe N NH Cl H nC ₆ H ₁₃ OHOO 2 N COMe N NH Cl ───────────────────────── ─────────

[0200]

[Table 075] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me HOO 2 N COMe N NH Cl H MeNH HOO 2 N COMe N NH Cl H Cl HOO 2 N COMe N NH Cl HFHOO 2 N COMe N NH Cl H NO ₂ HOO 2 N COMe N NH Cl H CF ₃ HOO 2 N COMe N NH Cl HHHOO 2 N CH N NH H MeO HHOO 2 N CH N NH HH MeO HOO 2 N CH N NH HHH MeO OO 2 N CH N NH H EtO HHOO 2 N CH N NH HH EtO HOO 2 N CH N NH HHH EtO OO 2 N CH N NH H n-PrO HHOO 2 N CH N NH HH n-PrO HOO 2 N CH N NH HHH n-PrO OO 2 N CH N NH H i-PrO HHOO 2 N CH N NH HH i-PrO HOO 2 N CH N NH HHH i-PrO OO 2 N CH N NH H c-PrO HHOO 2 N CH N NH HH c-PrO HOO 2 N CH N NH HHH c-PrO OO 2 N CH N NH H n-BuO HHOO 2 N CH N NH H ──────────────────────────────────

[0201]

[Table 076] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-BuO HOO 2 N CH N NH HHH n-BuO OO 2 N CH N NH H nC ₅ H ₁₁ OHHOO 2 N CH N NH HH nC ₅ H ₁₁ OHOO 2 N CH N NH HHH nC ₅ H ₁₁ OOO 2 N CH N NH H nC ₆ H ₁₃ OHHOO 2 N CH N NH HH nC ₆ H ₁₃ OHOO 2 N CH N NH HHH nC ₆ H ₁₃ OOO 2 N CH N NH H nC ₈ H ₁₇ OHHOO 2 N CH N NH HH nC ₈ H ₁₇ OHOO 2 N CH N NH HHH nC ₈ H ₁₇ OOO 2 N CH N NH H nC ₁₀ H ₂₁ OHHOO 2 N CH N NH HH nC ₁₀ H ₂₁ OHOO 2 N CH N NH HHH nC ₁₀ H ₂₁ OOO 2 N CH N NH H Me HHOO 2 N CH N NH HH Me HOO 2 N CH N NH HHH Me OO 2 N CH N NH H Et HHOO 2 N CH N NH HH Et HOO 2 N CH N NH HHH Et OO 2 N CH N NH H n-Pr HHOO 2 N CH N NH HH n-Pr HOO 2 N CH N NH HHH n-Pr OO 2 N CH N NH H ──────────────────────── ──────────

[0202]

[Table 077] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── i-Pr HHOO 2 N CH N NH HH i-Pr HOO 2 N CH N NH HHH i-Pr OO 2 N CH N NH H c-Pr HHOO 2 N CH N NH HH c-Pr HOO 2 N CH N NH HHH c-Pr OO 2 N CH N NH H n-Bu HHOO 2 n CH n NH HH n-Bu HOO 2 n CH n NH HHH n-Bu OO 2 n CH n NH H nC 5 H 11 HHOO 2 n CH n NH HH nC 5 H 11 HOO 2 n CH _{N NH HHH nC 5 H 11 OO} 2 N CH N NH H nC 6 H 13 HHOO 2 N CH N NH HH nC 6 H 13 HOO 2 N CH N NH HHH nC 6 H 13 OO 2 N CH N NH H nC 8 H ₁₇ HHOO 2 N CH N NH HH nC ₈ H ₁₇ HOO 2 N CH N NH HHH nC ₈ H ₁₇ OO 2 N CH N NH H nC ₁₀ H ₂₁ HHOO 2 N CH N NH HH nC ₁₀ H ₂₁ HOO 2 N CH N NH HHH nC ₁₀ H ₂₁ OO 2 N CH N NH H MeNH HHOO 2 N CH N NH HH MeNH HOO 2 N CH N NH H ───────────────────── ──── ─────────

[0203]

[Table 078] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── EtNH HHOO 2 N CH N NH HH EtNH HOO 2 N CH N NH H n-PrNH HHOO 2 N CH N NH HH n-PrNH HOO 2 N CH N NH H i-PrNH HHOO 2 N CH N NH HH i-PrNH HOO 2 N CH N NH H c-PrNH HHOO 2 N CH N NH HH c-PrNH HOO 2 N CH N NH H n-BuNH HHOO 2 N CH N NH HH n-BuNH HOO 2 N CH N NH H nC ₅ H ₁₁ NH HHOO 2 N CH N NH HH nC ₅ H ₁₁ NH HOO 2 N CH N NH H nC ₆ H ₁₃ NH HHOO 2 N CH N NH HH nC ₆ H ₁₃ NH HOO 2 N CH N NH H nC ₈ H ₁₇ NH HHOO 2 N CH N NH HH nC ₈ H ₁₇ NH HOO 2 N CH N NH H nC ₁₀ H ₂₁ NH HHOO 2 N CH N NH HH nC ₁₀ H ₂₁ NH HOO 2 N CH N NH H Cl HHOO 2 N CH N NH HH Cl HOO 2 N CH N NH HHH Cl OO 2 N CH N NH HFHHOO 2 N CH N NH HHFHOO 2 N CH N NH H ──────────────────────── ──────────

[0204]

[Table 079] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HHFOO 2 N CH N NH H Br HHOO 2 N CH N NH HH Br HOO 2 N CH N NH HHH Br OO 2 N CH N NH H NO ₂ HHOO 2 N CH N NH HH NO ₂ HOO 2 N CH N NH HHH NO ₂ OO 2 N CH N NH H NH ₂ HHOO 2 N CH N NH HH NH ₂ HOO 2 N CH N NH HHH NH ₂ OO 2 N CH N NH H OH HHOO 2 N CH N NH HH OH HOO 2 N CH N NH HHH OH OO 2 N CH N NH H CHO HHOO 2 N CH N NH HH CHO HOO 2 N CH N NH HHH CHO OO 2 N CH N NH H CH ₂ OH HHOO 2 N CH N NH HH CH ₂ OH HOO 2 N CH N NH HHH CH ₂ OH OO 2 N CH N NH H COOH HHOO 2 N CH N NH HH COOH HOO 2 N CH N NH HHH COOH OO 2 N CH N NH H CH ₃ C (O) HHOO 2 N CH N NH H ───────── ─────────────────────────

[0205]

[Table 080] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CH ₃ C (O) HOO 2 N CH N NH HHH CH ₃ C (O) OO 2 N CH N NH H NO ₂ NO ₂ HOO 2 N CH N NH H NO ₂ H NO ₂ OO 2 N CH N NH H CF ₃ HHOO 2 N CH N NH HH _{CF 3 HOO 2 n CH n NH} HHH CF 3 OO 2 n CH n NH HHHHOO 2 n CCl n NH HH MeO HOO 2 n CCl n NH HH n-PrO HOO 2 n CCl n NH HH nC 6 H 13 OHOO 2 n CCl N NH HH Me HOO 2 N CCl N NH HH MeNH HOO 2 N CCl N NH HH Cl HOO 2 N CCl N NH HHFHOO 2 N CCl N NH HH NO ₂ HOO 2 N CCl N NH HH CF ₃ HOO 2 N CCl N NH HHHHOO 2 n CMe n NH HH MeO HOO 2 n CMe n NH HH n-PrO HOO 2 n CMe n NH HH nC 6 H 13 OHOO 2 n CMe n NH HH Me HOO 2 n CMe n NH HH MeNH HOO 2 n CMe n NH H ──────────────────────────────────

[0206]

[Table 081] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl HOO 2 N CMe N NH HHFHOO 2 N CMe N NH HH NO ₂ HOO 2 N CMe N NH HH CF ₃ HOO 2 N CMe N NH HHHHOO 2 N COMe N NH HH MeO HOO 2 N COMe N NH HH n-PrO HOO 2 N COMe N NH HH nC ₆ H ₁₃ OHOO 2 N COMe N NH HH Me HOO 2 N COMe N NH HH MeNH HOO 2 N COMe N NH HH Cl HOO 2 N COMe N NH HHFHOO 2 N COMe N NH HH NO ₂ HOO 2 N COMe N NH HH CF ₃ HOO 2 N COMe N NH HHHHOO 2 N CH N NH Me H MeO HOO 2 N CH N NH Me H EtO HOO 2 N CH N NH Me H n-PrO HOO 2 N CH N NH Me Hi i-PrO HOO 2 N CH N NH Me H c-PrO HOO 2 N CH N NH Me H n-BuO HOO 2 N CH N NH Me H nC ₅ H ₁₁ OHOO 2 N CH N NH Me H nC ₆ H ₁₃ OHOO 2 N CH N NH Me ─ ─────────────────────────────────

[0207]

[Table 082] a R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₈ H ₁₇ OHOO 2 N CH N NH Me H nC ₁₀ H ₂₁ OHOO 2 N CH N NH Me H Me HOO 2 N CH N NH Me H Et HOO 2 N CH N NH Me H n-Pr HOO 2 N CH N NH Me Hi-Pr HOO 2 N CH N NH Me H c-Pr HOO 2 N CH N NH Me H n-Bu HOO 2 N CH N NH Me H nC ₅ H ₁₁ HOO 2 N CH N NH Me H nC ₆ H ₁₃ HOO 2 N CH N NH Me H nC ₈ H ₁₇ HOO 2 N CH N NH Me H nC ₁₀ H ₂₁ HOO 2 N CH N NH Me H MeNH HOO 2 N CH N NH Me H EtNH HOO 2 N CH N NH Me H n-PrNH HOO 2 N CH n NH Me H i-PrNH HOO 2 n CH n NH Me H c-PrNH HOO 2 n CH n NH Me H n-BuNH HOO 2 n CH n NH Me H nC 5 H 11 NH HOO 2 n CH n NH Me H nC ₆ H ₁₃ NH HOO 2 N CH N NH Me H nC ₈ H ₁₇ NH HOO 2 N CH N NH Me H nC ₁₀ H ₂₁ NH HOO 2 N CH N NH Me H Cl HOO 2 N CH N NH Me ── ───── ──────────────────────────

[0208]

[Table 083] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HFHOO 2 N CH N NH Me H Br HOO 2 N CH N NH Me H NO ₂ HOO 2 N CH N NH Me H NH ₂ HOO 2 N CH N NH Me H OH HOO 2 N CH N NH Me H CHO HOO 2 N CH N NH Me H CH ₂ OH HOO 2 N CH N NH Me H COOH HOO 2 N CH N NH Me H CH ₃ C (O) HOO 2 N CH N NH Me NO ₂ NO ₂ HOO 2 N CH N NH Me NO ₂ H NO ₂ OO 2 N CH N NH Me H CF ₃ HOO 2 N CH N NH Me HHHOO 2 N CH N NH MeO H MeO HOO 2 N CH N NH MeO H EtO HOO 2 N CH N NH MeO H n-PrO HOO 2 N CH N NH MeO H i -PrO HOO 2 N CH N NH MeO H c-PrO HOO 2 N CH N NH MeO H n-BuO HOO 2 N CH N NH MeO H nC ₅ H ₁₁ OHOO 2 N CH N NH MeO H nC ₆ H ₁₃ OHOO 2 N CH N NH MeO H nC ₈ H ₁₇ OHOO 2 N CH N NH MeO H nC ₁₀ H ₂₁ OHOO 2 N CH N NH MeO ────────────────── ────────────────

[0209]

[Table 084] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me HOO 2 N CH N NH MeO H Et HOO 2 N CH N NH MeO H n-Pr HOO 2 N CH N NH MeO H i-Pr HOO 2 N CH N NH MeO H c-Pr HOO 2 N CH N NH MeO H n-Bu HOO 2 N CH _{N NH MeO H nC 5 H 11} HOO 2 N CH N NH MeO H nC 6 H 13 HOO 2 N CH N NH MeO H nC 8 H 17 HOO 2 N CH N NH MeO H nC 10 H 21 HOO 2 N CH N NH MeO H MeNH HOO 2 N CH N NH MeO H EtNH HOO 2 N CH N NH MeO H n-PrNH HOO 2 N CH N NH MeO Hi-PrNH HOO 2 N CH N NH MeO H c-PrNH HOO 2 N CH N NH MeO H n-BuNH HOO 2 N CH N NH MeO H nC ₅ H ₁₁ NH HOO 2 N CH N NH MeO H nC ₆ H ₁₃ NH HOO 2 N CH N NH MeO H nC ₈ H ₁₇ NH HOO 2 N CH N _{NH MeO H nC 10 H 21 NH} HOO 2 N CH N NH MeO H Cl HOO 2 N CH N NH MeO HFHOO 2 N CH N NH MeO H Br HOO 2 N CH N NH MeO ────── ───────────────────────────

[0210]

[Table 085] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H NO ₂ HOO 2 N CH N NH MeO H NH ₂ HOO 2 N CH N NH MeO H OH HOO 2 N CH N NH MeO H CHO HOO 2 N CH N NH MeO H CH ₂ OH HOO 2 N CH N NH MeO H COOH HOO 2 N CH N NH MeO H CH ₃ C (O) HOO 2 N CH N NH MeO NO ₂ NO ₂ HOO 2 N CH N NH MeO NO ₂ H NO ₂ OO 2 N CH N NH MeO H CF ₃ HOO 2 N CH N NH MeO HHHOO 2 N CH N NH n-PrO H MeO HOO 2 N CH N NH n-PrO H EtO HOO 2 N CH N NH n-PrO H n-PrO HOO 2 N CH N NH n-PrO H i-PrO HOO 2 N CH N NH n-PrO H c-PrO HOO 2 N CH N NH n-PrO H n-BuO HOO 2 N CH N NH n-PrO H nC ₅ H ₁₁ OHOO 2 N CH N NH n-PrO H nC ₆ H ₁₃ OHOO 2 N CH N NH n-PrO H nC ₈ H ₁₇ OHOO 2 N CH N NH n-PrO H nC ₁₀ H ₂₁ OHOO 2 N CH N NH n-PrO H Me HOO 2 N CH N NH n-PrO H Et HOO 2 N CH N NH n-PrO ──── ─────────────────────────────

[0211]

[Table 086] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-Pr HOO 2 N CH N NH n-PrO H i-Pr HOO 2 n CH n NH n-PrO H c-Pr HOO 2 n CH n NH n-PrO H n-Bu HOO 2 n CH n NH n-PrO H nC 5 H 11 HOO 2 n CH n NH n-PrO H nC 6 H 13 HOO 2 n CH n NH n-PrO H nC 8 H 17 HOO 2 n CH n NH n-PrO H nC 10 H 21 HOO 2 n CH n NH n-PrO H MeNH HOO 2 N CH N NH n-PrO H EtNH HOO 2 N CH N NH n-PrO H n-PrNH HOO 2 N CH N NH n-PrO H i-PrNH HOO 2 N CH N NH n-PrO H c- PrNH HOO 2 N CH N NH n-PrO H n-BuNH HOO 2 N CH N NH n-PrO H nC ₅ H ₁₁ NH HOO 2 N CH N NH n-PrO H nC ₆ H ₁₃ NH HOO 2 N CH N NH _{n-PrO H nC 8 H 17} NH HOO 2 n CH n NH n-PrO H nC 10 H 21 NH HOO 2 n CH n NH n-PrO H Cl HOO 2 n CH n NH n-PrO HFHOO 2 n CH n NH n-PrO H Br HOO 2 N CH N NH n-PrO H NO ₂ HOO 2 N CH N NH n-PrO H NH ₂ HOO 2 N CH N NH n-PrO ──────────────────────────────────

[0212]

[Table 087] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H OH HOO 2 N CH N NH n -PrO H CHO HOO 2 N CH N NH n-PrO H CH ₂ OH HOO 2 N CH N NH n-PrO H COOH HOO 2 N CH N NH n-PrO H CH ₃ C (O) HOO 2 N CH N NH n-PrO NO ₂ NO ₂ HOO 2 N CH N NH n-PrO NO ₂ H NO ₂ OO 2 N CH N NH n-PrO H CF ₃ HOO 2 N CH N NH n-PrO HHHOO 2 N CH NO Cl H MeO HOO 2 N CH NO Cl H n-PrO HOO 2 N CH NO Cl H nC ₆ H ₁₃ OHOO 2 N CH NO Cl H Me HOO 2 N CH NO Cl H MeNH HOO 2 N CH NO Cl H Cl HOO 2 N CH NO Cl HFHOO 2 N CH NO Cl H NO ₂ HOO 2 N CH NO Cl H NH ₂ HOO 2 N CH NO Cl H CF ₃ HOO 2 N CH NO Cl HHHOO 2 N CH NOHH MeO HOO 2 N CH NOHH n-PrO HOO 2 N CH NOHH nC ₆ H ₁₃ OHOO 2 N CH NOH ──────────────────────────────────

[0213]

[Table 088] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me HOO 2 N CH NOHH MeNH HOO 2 N CH NOHH Cl HOO 2 N CH NOHHFHOO 2 N CH NOHH NO ₂ HOO 2 N CH NOHH CF ₃ HOO 2 N CH NOHHHHOO 2 N CH NO Me H MeO HOO 2 N CH NO Me H n-PrO HOO 2 N CH NO Me H nC ₆ H ₁₃ OHOO 2 N CH NO Me H Me HOO 2 N CH NO Me H MeNH HOO 2 N CH NO Me H Cl HOO 2 N CH NO Me HFHOO 2 N CH NO Me H NO ₂ HOO 2 N CH NO Me H NH ₂ HOO 2 N CH NO Me H CF ₃ HOO 2 N CH NO Me HHHOO 2 N CH NO MeO H MeO HOO 2 N CH NO MeO H n-PrO HOO 2 N CH NO MeO H nC ₆ H ₁₃ OHOO 2 N CH NO MeO H Me HOO 2 N CH NO MeO H MeNH HOO 2 N CH NO MeO ────────────────────────────── ────

[0214]

[Table 089] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl HOO 2 N CH NO MeO HFHOO 2 N CH NO MeO H NO ₂ HOO 2 N CH NO MeO H CF ₃ HOO 2 N CH NO MeO HHH NH O 2 N CH N NH Cl H MeO H NH O 2 N CH N NH Cl H n-PrO H NH O 2 N CH N NH Cl H nC ₆ H ₁₃ OH NH O 2 N CH N NH Cl H Me H NH O 2 N CH N NH Cl H MeNH H NH O 2 N CH N NH Cl H Cl H NH O 2 N CH N NH Cl HFH NH O 2 N CH N NH Cl H NO ₂ H NH O 2 N CH N NH Cl H CF ₃ H NH O 2 N CH N NH Cl HHH NH O 2 N CH N NH HH MeO H NH O 2 N CH N NH HH n-PrO H NH O 2 N CH N NH HH nC ₆ H ₁₃ OH NH O 2 N CH N NH HH Me H NH O 2 N CH N NH HH MeNH H NH O 2 N CH N NH HH Cl H NH O 2 N CH N NH HHFH NH O 2 N CH N NH HH NO ₂ H NH O 2 N CH N NH H ───────────────────── ───── ───────

[0215]

[Table 090] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ H NH O 2 N CH N NH HHHH NMe O 2 N CH N NH Cl H MeO H NMe O 2 N CH N NH Cl H n-PrO H NMe O 2 N CH N NH Cl H nC ₆ H ₁₃ OH NMe O 2 N CH N NH Cl H Me H NMe O 2 N CH N NH Cl H MeNH H NMe O 2 N CH N NH Cl H Cl H NMe O 2 N CH N NH Cl HFH NMe O 2 N CH N NH Cl H NO ₂ H NMe O 2 N CH N NH Cl H CF ₃ H NMe O 2 N CH N NH Cl HHH NMe O 2 N CH N NH HH MeO H NMe O 2 N CH N NH HH n-PrO H NMe O 2 N CH N NH HH nC ₆ H ₁₃ OH NMe O 2 N CH N NH HH Me H NMe O 2 N CH N NH HH MeNH H NMe O 2 N CH N NH HH Cl H NMe O 2 N CH N NH HHFH NMe O 2 N CH N NH HH NO ₂ H NMe O 2 N CH N NH HH CF ₃ H NMe O 2 N CH N NH HHHHO NH 2 N CH N NH Cl H MeO HO NH 2 N CH N NH Cl ────────────── ── ─────────────────

[0216]

[Table 091] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-PrO HO NH 2 N CH N NH Cl H nC ₆ H ₁₃ OHO NH 2 N CH N NH Cl H Me HO NH 2 N CH N NH Cl H Me NH HO NH 2 N CH N NH Cl H Cl HO NH 2 N CH N NH Cl HFHO NH 2 N CH N NH Cl H NO ₂ HO NH 2 N CH N NH Cl H CF ₃ HO NH 2 N CH N NH Cl HHHO NH 2 N CH N NH HH MeO HO NH 2 N CH N NH HH n-PrO HO NH 2 N CH N NH HH nC ₆ H ₁₃ OHO NH 2 N CH N NH HH Me HO NH 2 N CH N NH HH MeNH HO NH 2 N CH N NH HH Cl HO NH 2 N CH N NH HHFHO NH 2 N CH N NH HH NO ₂ HO NH 2 N CH N NH HH CF ₃ HO NH 2 N CH N NH HHHH NH-2 N CH N NH Cl H MeO H NH-2 N CH N NH Cl H n-PrO H NH-2 N CH N NH Cl H nC ₆ H ₁₃ OH NH-2 N CH N NH Cl H Me H NH-2 N CH N NH Cl ─────────────────────── ─ ──────────

[0219]

[Table 092] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeNH H NH-2 N CH N NH Cl H Cl H NH-2 N CH N NH Cl HFH NH-2 N CH N NH Cl H CF ₃ H NH-2 N CH N NH Cl HHH-NH 2 N CH N NH Cl H MeO H-NH 2 N CH N NH Cl H EtO H-NH 2 N CH N NH Cl H n-PrO H-NH 2 N CH N NH Cl H i-PrO H-NH 2 N CH N NH Cl H c-PrO H-NH 2 N CH N NH Cl H n-BuO H-NH 2 N CH N NH Cl H nC ₅ H ₁₁ OH-NH 2 N CH N NH Cl H nC ₆ H ₁₃ OH-NH 2 N CH N NH Cl H nC ₈ H ₁₇ OH-NH 2 N CH N NH Cl H nC ₁₀ H ₂₁ OH-NH 2 N CH N NH Cl H Me H-NH 2 N CH N NH Cl H Et H-NH 2 N CH N NH Cl H n-Pr H -NH 2 N CH N NH Cl H i-Pr H-NH 2 N CH N NH Cl H c-Pr H-NH 2 N CH N NH Cl H n-Bu H-NH 2 N CH N NH Cl H nC _{5 H 11 H - NH 2 N CH} N NH Cl H nC 6 H 13 H - NH 2 N CH N NH Cl ─────────────────────────────────

[0218]

[Table 093] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₈ H ₁₇ H-NH 2 N CH N NH Cl H nC ₁₀ H ₂₁ H-NH 2 N CH N NH Cl H MeNH H-NH 2 N CH N NH Cl H n-PrNH H-NH 2 N CH N NH Cl H i-PrNH H-NH 2 N CH N NH Cl H c-PrNH H-NH 2 N CH N NH Cl H n-BuNH H-NH 2 N CH N NH Cl H nC ₅ H ₁₁ NH H-NH 2 N CH N NH Cl H nC ₆ H ₁₃ NH H-NH 2 N CH N NH Cl H nC ₈ H ₁₇ NH H-NH 2 N CH N NH Cl H nC ₁₀ H ₂₁ NH H-NH 2 N CH N NH Cl H Cl H-NH 2 N CH N NH Cl HFH-NH 2 N CH N NH Cl H Br H-NH 2 N CH N NH Cl H NO ₂ H-NH 2 N CH N NH Cl H NH ₂ H-NH 2 N CH N NH Cl H OH H -NH 2 N CH N NH Cl H CHO H-NH 2 N CH N NH Cl H CH ₂ OH H-NH 2 N CH N NH Cl H COOH H-NH 2 N CH N NH Cl H CH ₃ C (O) H-NH 2 N CH N NH Cl NO ₂ NO ₂ H-NH 2 N CH N NH Cl NO ₂ H NO ₂ -NH 2 N CH N NH Cl ──────────────────────────────────

[0219]

[Table 094] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ H-NH 2 N CH N NH Cl HHH NH NH 2 N CH N NH Cl H MeO H NH NH 2 N CH N NH Cl H n-PrO H NH NH 2 N CH N NH Cl H nC ₆ H ₁₃ OH NH NH 2 N CH N NH Cl H Me H NH NH 2 N CH N NH Cl H MeNH H NH NH 2 N CH N NH Cl H Cl H NH NH 2 N CH N NH Cl HFH NH NH 2 N CH N NH Cl H NO ₂ H NH NH 2 N CH N NH Cl H CF ₃ H NH NH 2 N CH N NH Cl HHH--3 N CH N NH Cl H MeO H---3 N CH N NH Cl H n-PrO H--3 N CH N NH Cl H nC ₆ H ₁₃ OH--3 N CH N NH Cl H Me H--3 N CH N NH Cl H MeNH H--3 N CH N NH Cl H Cl H--3 N CH N NH Cl HFH--3 N CH N NH Cl H NO ₂ H--3 N CH N NH Cl H CF ₃ H--3 N CH N NH Cl HHHO-3 N CH N NH Cl H MeO HO-3 N CH N NH Cl ─── ───────────── ─────────────────

[0220]

[Table 095] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-PrO HO-3 N CH N NH Cl H Me HO-3 N CH N NH Cl H Me NH HO-3 N CH N NH Cl H Cl HO-3 N CH N NH Cl HFHO-3 N CH N NH Cl H NO ₂ HO-3 N CH N NH Cl H CF ₃ HO-3 N CH N NH Cl HHH-O 3 N CH N NH Cl H MeO H-O 3 N CH N NH Cl H EtO H-O 3 N CH N NH Cl H n-PrO H- O 3 N CH N NH Cl H i-PrO H-O 3 N CH N NH Cl H c-PrO H-O 3 N CH N NH Cl H n-BuO H-O 3 N CH N NH Cl H nC ₅ H ₁₁ OH-O 3 N CH N NH Cl H nC ₆ H ₁₃ OH-O 3 N CH N NH Cl H nC ₈ H ₁₇ OH-O 3 N CH N NH Cl H nC ₁₀ H ₂₁ OH-O 3 N CH N NH Cl H Me H-O 3 N CH N NH Cl H Et H-O 3 N CH N NH Cl H n-Pr H-O 3 N CH N NH Cl Hi i-Pr H-O 3 N CH N NH Cl H c-Pr H-O 3 N CH N NH Cl ────────────── ───────────────────

[0221]

[Table 096] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-Bu H-O 3 N CH N NH Cl H nC ₅ H ₁₁ H-O 3 N CH N NH Cl H nC ₆ H ₁₃ H-O 3 N CH N NH Cl H nC ₈ H ₁₇ H-O 3 N CH N NH Cl H nC ₁₀ H ₂₁ H-O 3 N CH N NH Cl H MeNH H-O 3 N CH N NH Cl H EtNH H-O 3 N CH N NH Cl H n-PrNH H-O 3 N CH N NH Cl H i-PrNH H -O 3 N CH N NH Cl H c-PrNH H-O 3 N CH N NH Cl H n-BuNH H-O 3 N CH N NH Cl H nC ₅ H ₁₁ NH H-O 3 N CH N NH Cl H nC ₆ H ₁₃ NH H -O 3 N CH N NH Cl H nC ₈ H ₁₇ NH H -O 3 N CH N NH Cl H nC ₁₀ H ₂₁ NH H -O 3 N CH N NH Cl H Cl H -O 3 N CH N NH Cl HFH-O 3 N CH N NH Cl H Br H-O 3 N CH N NH Cl H NO ₂ H-O 3 N CH N NH Cl H NH ₂ H-O 3 N CH N NH Cl H OH H-O 3 N CH N NH Cl H CHO H-O 3 N CH N NH Cl H CH ₂ OH H-O 3 N CH N NH Cl ──────────────────────────────────

[0222]

[Table 097] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H COOH H-O 3 N CH N NH Cl H CH ₃ C (O) H-O 3 N CH N NH Cl NO ₂ NO ₂ H-O 3 N CH N NH Cl NO ₂ H NO ₂ -O 3 N CH N NH Cl H CF ₃ H-O 3 N CH N NH Cl HHHOO 3 N CH N NH Cl H MeO HOO 3 N CH N NH Cl H EtO HOO 3 N CH N NH Cl H n-PrO HOO 3 N CH N NH Cl Hi i-PrO HOO 3 N CH N NH Cl H c-PrO HOO 3 N CH N NH Cl H n-BuO HOO 3 N CH N NH Cl H nC ₅ H ₁₁ OHOO 3 N CH N NH Cl H nC ₆ H ₁₃ OHOO 3 N CH N NH Cl H nC ₈ H ₁₇ OHOO 3 N CH N NH Cl H nC ₁₀ H ₂₁ OHOO 3 N CH N NH Cl H Me HOO 3 N CH N NH Cl H Et HOO 3 N CH N NH Cl H n-Pr HOO 3 N CH N NH Cl H i-Pr HOO 3 N CH N NH Cl H c-Pr HOO 3 N CH N NH Cl H n-Bu HOO 3 N CH N NH Cl H nC ₅ H ₁₁ HOO 3 N CH N NH Cl ─── ───────────── ──────────────────

[0223]

[Table 098] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ HOO 3 N CH N NH Cl H nC ₈ H ₁₇ HOO 3 N CH N NH Cl H nC ₁₀ H ₂₁ HOO 3 N CH N NH Cl H MeNH HOO 3 N CH N NH Cl H EtNH HOO 3 N CH N NH Cl H n-PrNH HOO 3 N CH N NH Cl H i-PrNH HOO 3 N CH N NH Cl H c-PrNH HOO 3 N CH N NH Cl H n-BuNH HOO 3 N CH N NH Cl H nC ₅ H ₁₁ NH HOO 3 N CH N NH Cl H nC ₆ H ₁₃ NH HOO 3 N CH N NH Cl H nC ₈ H ₁₇ NH HOO 3 N CH N NH Cl H nC ₁₀ H ₂₁ NH HOO 3 N CH N NH Cl H Cl HOO 3 N CH N NH Cl HFHOO 3 N CH N NH Cl H Br HOO 3 N CH N NH Cl H NO ₂ HOO 3 N CH N NH Cl H NH ₂ HOO 3 N CH N NH Cl H OH HOO 3 N CH N NH Cl H CHO HOO 3 N CH N NH Cl H CH ₂ OH HOO 3 N CH N NH Cl H COOH HOO 3 N CH N NH Cl H CH ₃ C (O) HOO 3 N CH N NH Cl ──────────── ─ ─────────────────────

[0224]

[Table 099] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── NO ₂ NO ₂ HOO 3 N CH N NH Cl NO ₂ H NO ₂ OO 3 N CH N NH Cl H CF ₃ HOO 3 N CH N NH Cl HHHOO 3 N CCl N NH Cl H MeO HOO 3 N CCl N NH Cl H n-PrO HOO 3 N CCl N NH Cl H nC ₆ H ₁₃ OHOO 3 N CCl N NH Cl H Me HOO 3 N CCl N NH Cl H MeNH HOO 3 N CCl N NH Cl H Cl HOO 3 N CCl N NH Cl HFHOO 3 N CCl N NH Cl H NO ₂ HOO 3 N CCl N NH Cl H CF ₃ HOO 3 N CCl N NH Cl HHHOO 3 N CMe N NH Cl H MeO HOO 3 N CMe N NH Cl H n-PrO HOO 3 N CMe N NH Cl H nC ₆ H ₁₃ OHOO 3 N CMe N NH Cl H Me HOO 3 N CMe N NH Cl H MeNH HOO 3 N CMe N NH Cl H Cl HOO 3 N CMe N NH Cl HFHOO 3 N CMe N NH Cl H NO ₂ HOO 3 N CMe N NH Cl H CF ₃ HOO 3 N CMe N NH Cl ─────────────────────────── ───────

[0225]

[Table 100] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HHHOO 3 N COMe N NH Cl H MeO HOO 3 N COMe N NH Cl H n-PrO HOO 3 N COMe N NH Cl H nC ₆ H ₁₃ OHOO 3 N COMe N NH Cl H Me HOO 3 N COMe N NH Cl H MeNH HOO 3 N COMe N NH Cl H Cl HOO 3 N COMe N NH Cl HFHOO 3 N COMe N NH Cl H NO ₂ HOO 3 N COMe N NH Cl H CF ₃ HOO 3 N COMe N NH Cl HHHOO 3 N CH N NH HH MeO HOO 3 N CH N NH HH EtO HOO 3 N CH N NH HH n-PrO HOO 3 N CH N NH HH i-PrO HOO 3 N CH N NH HH c-PrO HOO 3 N CH N NH HH n-BuO HOO 3 N CH N NH HH nC ₅ H ₁₁ OHOO 3 N CH N NH HH nC ₆ H ₁₃ OHOO 3 N CH N NH HH nC ₈ H ₁₇ OHOO 3 N CH N NH HH nC ₁₀ H ₂₁ OHOO 3 N CH N NH HH Me HOO 3 N CH N NH HH Et HOO 3 N CH N NH H ───────────────────────────── ─────

[0226]

[Table 101] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-Pr HOO 3 N CH N NH HH i-Pr HOO 3 N CH N NH HH c-Pr HOO 3 N CH N NH HH n-Bu HOO 3 N CH N NH HH nC ₅ H ₁₁ HOO 3 N CH N NH HH nC ₆ H ₁₃ HOO 3 N CH N NH HH nC ₈ H ₁₇ HOO 3 N CH N NH HH nC ₁₀ H ₂₁ HOO 3 N CH N NH HH MeNH HOO 3 N CH N NH HH EtNH HOO 3 N CH N NH HH n-PrNH HOO 3 N CH N NH HH i-PrNH HOO 3 N CH N NH HH c-PrNH HOO 3 N CH N NH HH n-BuNH HOO 3 N CH N NH HH nC ₅ H ₁₁ NH HOO 3 N CH N NH HH nC ₆ H ₁₃ NH HOO 3 N CH N NH HH nC ₈ H ₁₇ NH HOO 3 N CH N NH HH nC ₁₀ H ₂₁ NH HOO 3 N CH N NH HH Cl HOO 3 N CH N NH HHFHOO 3 N CH N NH HH Br HOO 3 N CH N NH HH NO ₂ HOO 3 N CH N NH HH NH ₂ HOO 3 N CH N NH H ──────────────────────────── ──────

[0227]

[Table 102] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H OH HOO 3 N CH N NH HH CHO HOO 3 N CH N NH HH CH ₂ OH HOO 3 N CH N NH HH COOH HOO 3 N CH N NH HH CH ₃ C (O) HOO 3 N CH N NH H NO ₂ NO ₂ HOO 3 N CH N NH H NO ₂ H NO ₂ OO 3 N CH N NH HH CF ₃ HOO 3 N CH N NH HHHHHOO 3 N CCl N NH HH MeO HOO 3 N CCl N NH HH n-PrO HOO 3 N CCl N NH HH nC ₆ H ₁₃ OHOO 3 N CCl N NH HH Me HOO 3 N CCl N NH HH MeNH HOO 3 N CCl N NH HH Cl HOO 3 N CCl N NH HHFHOO 3 N CCl N NH HH NO ₂ HOO 3 N CCl N NH HH CF ₃ HOO 3 N CCl N NH HHHHOO 3 N CMe N NH HH MeO HOO 3 N CMe N NH HH n-PrO HOO 3 N CMe N NH HH nC ₆ H ₁₃ OHOO 3 N CMe N NH HH Me HOO 3 N CMe N NH H ─── ───────────────────────────────

[0228]

[Table 103] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeNH HOO 3 N CMe N NH HH Cl HOO 3 N CMe N NH HHFHOO 3 N CMe N NH HH NO ₂ HOO 3 N CMe N NH HH CF ₃ HOO 3 N CMe N NH HHHHOO 3 N COMe N NH HH MeO HOO 3 N COMe N NH HH n-PrO HOO 3 N COMe N NH HH nC ₆ H ₁₃ OHOO 3 N COMe N NH HH Me HOO 3 N COMe N NH HH MeNH HOO 3 N COMe N NH HH Cl HOO 3 N COMe N NH HHFHOO 3 N COMe N NH HH NO ₂ HOO 3 N COMe N NH HH CF ₃ HOO 3 N COMe N NH HHHHOO 3 N CH N NH Me H MeO HOO 3 N CH N NH Me H EtO HOO 3 N CH N NH Me H n-PrO HOO 3 N CH N NH Me H i-PrO HOO 3 N CH N NH Me H c-PrO HOO 3 N CH N NH Me H n-BuO HOO 3 N CH N NH Me H nC ₅ H ₁₁ OHOO 3 N CH N NH Me ───── ─────────────────────────────

[0229]

[Table 104] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ OHOO 3 N CH N NH Me H nC ₈ H ₁₇ OHOO 3 N CH N NH Me H nC ₁₀ H ₂₁ OHOO 3 N CH N NH Me H Me HOO 3 N CH N NH Me H Et HOO 3 N CH N NH Me H n-Pr HOO 3 N CH N NH Me H i-Pr HOO 3 N CH N NH Me H c-Pr HOO 3 N CH N NH Me H n-Bu HOO 3 N CH N NH Me H nC ₅ H ₁₁ HOO 3 N CH N NH Me H nC ₆ H ₁₃ HOO 3 N CH N NH Me H nC ₈ H ₁₇ HOO 3 N CH N NH Me H nC ₁₀ H ₂₁ HOO 3 N CH N NH Me H MeNH HOO 3 N CH N NH Me H EtNH HOO 3 N CH N NH Me H n-PrNH HOO 3 N CH N NH Me H i-PrNH HOO 3 N CH N NH Me H c-PrNH HOO 3 N CH N NH Me H n-BuNH HOO 3 N CH N NH Me H nC ₅ H ₁₁ NH HOO 3 N CH N NH Me H nC ₆ H ₁₃ NH HOO 3 N CH N NH Me H nC ₈ H ₁₇ NH HOO 3 N CH N NH Me H nC ₁₀ H ₂₁ NH HOO 3 N CH N NH Me ───── ─────────────────────────────

[0230]

[Table 105] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl HOO 3 N CH N NH Me HFHOO 3 N CH N NH Me H Br HOO 3 N CH N NH Me H NO ₂ HOO 3 N CH N NH Me H NH ₂ HOO 3 N CH N NH Me H OH HOO 3 N CH N NH Me H CHO HOO 3 N CH N NH Me H CH ₂ OH HOO 3 N CH N NH Me H COOH HOO 3 N CH N NH Me H CH ₃ C (O) HOO 3 N CH N NH Me NO ₂ NO ₂ HOO 3 N CH N NH Me NO ₂ H NO ₂ OO 3 N CH N NH Me H CF ₃ HOO 3 N CH N NH Me HHHOO 3 N CH N NH MeO H MeO HOO 3 N CH N NH MeO H EtO HOO 3 N CH N NH MeO H n-PrO HOO 3 N CH N NH MeO Hi i-PrO HOO 3 N CH N NH MeO H c-PrO HOO 3 N CH N NH MeO H n-BuO HOO 3 N CH N NH MeO H nC ₅ H ₁₁ OHOO 3 N CH N _{NH MeO H nC 6 H 13 OHOO} 3 N CH N NH MeO H nC 8 H 17 OHOO 3 N CH N NH MeO ───────────────────── ────────────

[0231]

[Table 106] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₁₀ H ₂₁ OHOO 3 N CH N NH MeO H Me HOO 3 N CH N NH MeO H Et HOO 3 N CH N NH MeO H n-Pr HOO 3 N CH N NH MeO H i-Pr HOO 3 N CH N NH MeO H c-Pr HOO 3 N CH n NH MeO H n-Bu HOO 3 n CH n NH MeO H nC 5 H 11 HOO 3 n CH n NH MeO H nC 6 H 13 HOO 3 n CH n NH MeO H nC 8 H 17 HOO 3 n CH n NH MeO H nC ₁₀ H ₂₁ HOO 3 N CH N NH MeO H MeNH HOO 3 N CH N NH MeO H EtNH HOO 3 N CH N NH MeO H n-PrNH HOO 3 N CH N NH MeO H i-PrNH HOO 3 N CH n NH MeO H c-PrNH HOO 3 n CH n NH MeO H n-BuNH HOO 3 n CH n NH MeO H nC 5 H 11 NH HOO 3 n CH n NH MeO H nC 6 H 13 NH HOO 3 n CH n NH _{MeO H nC 8 H 17 NH HOO} 3 N CH N NH MeO H nC 10 H 21 NH HOO 3 N CH N NH MeO H Cl HOO 3 N CH N NH MeO HFHOO 3 N CH N NH MeO ─── ──────────────────────────────

[0232]

[Table 107] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Br HOO 3 N CH N NH MeO H NO ₂ HOO 3 N CH N NH MeO H NH ₂ HOO 3 N CH N NH MeO H OH HOO 3 N CH N NH MeO H CHO HOO 3 N CH N NH MeO H CH ₂ OH HOO 3 N CH N NH MeO H COOH HOO 3 N CH N NH MeO H CH ₃ C (O) HOO 3 N CH N NH MeO NO ₂ NO ₂ HOO 3 N CH N NH MeO NO ₂ H NO ₂ OO 3 N CH N NH MeO H CF ₃ HOO 3 N CH N NH MeO HHHOO 3 N CH N NH n-PrO H MeO HOO 3 N CH N NH n-PrO H EtO HOO 3 N CH N NH n-PrO H n-PrO HOO 3 N CH N NH n-PrO H i-PrO HOO 3 N CH N NH n-PrO H c-PrO HOO 3 N CH N NH n-PrO H n-BuO HOO 3 N CH N NH n-PrO H nC ₅ H ₁₁ OHOO 3 N CH N NH n -PrO H nC ₆ H ₁₃ OHOO 3 N CH N NH n-PrO H nC ₈ H ₁₇ OHOO 3 N CH N NH n-PrO H nC ₁₀ H ₂₁ OHOO 3 N CH N NH n-PrO H Me HOO 3 N CH N NH n-PrO ───── ─────────────────────────────

[0233]

[Table 108] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Et HOO 3 N CH N NH n -PrO H n-Pr HOO 3 N CH N NH n-PrO Hi-Pr HOO 3 N CH N NH n-PrO H c-Pr HOO 3 N CH N NH n-PrO H n-Bu HOO 3 N CH N NH n-PrO H nC ₅ H ₁₁ HOO 3 N CH N NH n-PrO H nC ₆ H ₁₃ HOO 3 N CH N NH n-PrO H nC ₈ H ₁₇ HOO 3 N CH N NH n-PrO H nC ₁₀ H ₂₁ HOO 3 N CH N NH n-PrO H MeNH HOO 3 N CH N NH n-PrO H EtNH HOO 3 N CH N NH n-PrO H n-PrNH HOO 3 N CH N NH n-PrO H i-PrNH HOO 3 N CH N NH n-PrO H c-PrNH HOO 3 N CH N NH n-PrO H n-BuNH HOO 3 N CH N NH n-PrO H nC ₅ H ₁₁ NH HOO 3 N CH N NH n-PrO H nC ₆ H ₁₃ NH HOO 3 N CH N NH n-PrO H nC ₈ H ₁₇ NH HOO 3 N CH N NH n-PrO H nC ₁₀ H ₂₁ NH HOO 3 N CH N NH n-PrO H Cl HOO 3 N CH N NH n-PrO HFHOO 3 N CH N NH n-PrO H Br HOO 3 N CH N NH n-PrO HN O ₂ HOO 3 N CH N NH n-PrO ──────────────────────────────────

[0234]

[Table 109] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H NH ₂ HOO 3 N CH N NH n-PrO H OH HOO 3 N CH N NH n-PrO H CHO HOO 3 N CH N NH n-PrO H CH ₂ OH HOO 3 N CH N NH n-PrO H COOH HOO 3 N CH N NH n-PrO H CH ₃ C (O) HOO 3 N CH N NH n-PrO NO ₂ NO ₂ HOO 3 N CH N NH n-PrO NO ₂ H NO ₂ OO 3 N CH N NH n-PrO H CF ₃ HOO 3 N CH N NH n-PrO HHHOO 3 N CH NO Cl H MeO HOO 3 N CH NO Cl H n-PrO HOO 3 N CH NO Cl H nC ₆ H ₁₃ OHOO 3 N CH NO Cl H Me HOO 3 N CH NO Cl H MeNH HOO 3 N CH NO Cl H Cl HOO 3 N CH NO Cl HFHOO 3 N CH NO Cl HNO ₂ HOO 3 N CH NO Cl H NH ₂ HOO 3 N CH NO Cl H CF ₃ HOO 3 N CH NO Cl HHHOO 3 N CH NOHH MeO HOO 3 N CH NOHH n-PrO HOO 3 N CH NOH ──────────────────────────────────

[0235]

[Table 110] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ OHOO 3 N CH NOHH Me HOO 3 N CH NOHH MeNH HOO 3 N CH NOHH Cl HOO 3 N CH NOHHFHOO 3 N CH NOHH NO ₂ HOO 3 N CH NOHH CF ₃ HOO 3 N CH NOHHHHOO 3 N CH NO Me H MeO HOO 3 N CH NO Me H n-PrO HOO 3 N CH NO Me H nC ₆ H ₁₃ OHOO 3 N CH NO Me H Me HOO 3 N CH NO Me H MeNH HOO 3 N CH NO Me H Cl HOO 3 N CH NO Me HFHOO 3 N CH NO Me H NO ₂ HOO 3 N CH NO Me H NH ₂ HOO 3 N CH NO Me H CF ₃ HOO 3 N CH NO Me HHHOO 3 N CH NO MeO H MeO HOO 3 N CH NO MeO H n-PrO HOO 3 N CH NO MeO H nC ₆ H ₁₃ OHOO 3 N CH NO MeO H Me HOO 3 N CH NO MeO ───────────────────────────── ─────

[0236]

[Table 111] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeNH HOO 3 N CH NO MeO H Cl HOO 3 N CH NO MeO HFHOO 3 N CH NO MeO H NO ₂ HOO 3 N CH NO MeO H CF ₃ HOO 3 N CH NO MeO HHH NH O 3 N CH N NH Cl H MeO H NH O 3 N CH N NH Cl H n-PrO H NH O 3 N CH N NH Cl H nC ₆ H ₁₃ OH NH O 3 N CH N NH Cl H Me H NH O 3 N CH N NH Cl H MeNH H NH O 3 N CH N NH Cl H Cl H NH O 3 N CH N NH Cl HFH NH O 3 N CH N NH Cl H NO ₂ H NH O 3 N CH N NH Cl H CF ₃ H NH O 3 N CH N NH Cl HHH NH O 3 N CH N NH HH MeO H NH O 3 N CH N NH HH n-PrO H NH O 3 N CH N NH HH nC ₆ H ₁₃ OH NH O 3 N CH N NH HH Me H NH O 3 N CH N NH HH MeNH H NH O 3 N CH N NH HH Cl H NH O 3 N CH N NH HHFH NH O 3 N CH N NH H ──────────────────────── ─── ───────

[0237]

[Table 112] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H NO ₂ H NH O 3 N CH N NH HH CF ₃ H NH O 3 N CH N NH HHHH NMe O 3 N CH N NH Cl H MeO H NMe O 3 N CH N NH Cl H n-PrO H NMe O 3 N CH N NH Cl H nC ₆ H ₁₃ OH NMe O 3 N CH N NH Cl H Me H NMe O 3 N CH N NH Cl H MeNH H NMe O 3 N CH N NH Cl H Cl H NMe O 3 N CH N NH Cl HFH NMe O 3 N CH N NH Cl H NO ₂ H NMe O 3 N CH N NH Cl H CF ₃ H NMe O 3 N CH N NH Cl HHH NMe O 3 N CH N NH HH MeO H NMe O 3 N CH N NH HH n-PrO H NMe O 3 N CH N NH HH nC ₆ H ₁₃ OH NMe O 3 N CH N NH HH Me H NMe O 3 N CH N NH HH MeNH H NMe O 3 N CH N NH HH Cl H NMe O 3 N CH N NH HHFH NMe O 3 N CH N NH HH NO ₂ H NMe O 3 N CH N NH HH CF ₃ H NMe O 3 N CH N NH HHHHO NH 3 N CH N NH Cl ───────────── ─── ─────────────────

[0238]

[Table 113] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeO HO NH 3 N CH N NH Cl H n-PrO HO NH 3 N CH N NH Cl H nC ₆ H ₁₃ OHO NH 3 N CH N NH Cl H Me HO NH 3 N CH N NH Cl H Me NH HO NH 3 N CH N NH Cl H Cl HO NH 3 N CH N NH Cl HFHO NH 3 N CH N NH Cl H NO ₂ HO NH 3 N CH N NH Cl H CF ₃ HO NH 3 N CH N NH Cl HHHO NH 3 N CH N NH HH MeO HO NH 3 N CH N NH HH n-PrO HO NH 3 N CH N NH HH nC ₆ H ₁₃ OHO NH 3 N CH N NH HH Me HO NH 3 N CH N NH HH MeNH HO NH 3 N CH N NH HH Cl HO NH 3 N CH N NH HHFHO NH 3 N CH N NH HH NO ₂ HO NH 3 N CH N NH HH CF ₃ HO NH 3 N CH N NH HHHH NH-3 N CH N NH Cl H MeO H NH-3 N CH N NH Cl H n-PrO H NH-3 N CH N NH Cl H nC ₆ H ₁₃ OH NH-3 N CH N NH Cl ──────────────────────── ──────────

[0239]

[Table 114] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me H NH-3 N CH N NH Cl H MeNH H NH-3 N CH N NH Cl H Cl H NH-3 N CH N NH Cl HFH NH-3 N CH N NH Cl H NO ₂ H NH-3 N CH N NH Cl H CF ₃ H NH -3 N CH N NH Cl HHH-NH 3 N CH N NH Cl H MeO H-NH 3 N CH N NH Cl H EtO H-NH 3 N CH N NH Cl H n-PrO H-NH 3 N CH N NH Cl H i-PrO H-NH 3 N CH N NH Cl H c-PrO H-NH 3 N CH N NH Cl H n-BuO H-NH 3 N CH N NH Cl H nC ₅ H ₁₁ OH-NH 3 N CH N NH Cl H nC ₆ H ₁₃ OH-NH 3 N CH N NH Cl H nC ₈ H ₁₇ OH-NH 3 N CH N NH Cl H nC ₁₀ H ₂₁ OH-NH 3 N CH N NH Cl H Me H- NH 3 N CH N NH Cl H Et H-NH 3 N CH N NH Cl H n-Pr H-NH 3 N CH N NH Cl H i-Pr H-NH 3 N CH N NH Cl H c-Pr H- NH 3 N CH N NH Cl H n-Bu H-NH 3 N CH N NH Cl ──── ─────────────────────────────

[0240]

[Table 115] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₅ H ₁₁ H-NH 3 N CH N NH Cl H nC ₆ H ₁₃ H-NH 3 N CH N NH Cl H nC ₈ H ₁₇ H-NH 3 N CH N NH Cl H nC ₁₀ H ₂₁ H-NH 3 N CH N NH Cl H MeNH H -NH 3 N CH N NH Cl H EtNH H-NH 3 N CH N NH Cl H n-PrNH H-NH 3 N CH N NH Cl H i-PrNH H-NH 3 N CH N NH Cl H c-PrNH H -NH 3 N CH N NH Cl H n-BuNH H-NH 3 N CH N NH Cl H nC ₅ H ₁₁ NH H-NH 3 N CH N NH Cl H nC ₆ H ₁₃ NH H-NH 3 N CH N NH Cl H nC ₈ H ₁₇ NH H-NH 3 N CH N NH Cl H nC ₁₀ H ₂₁ NH H-NH 3 N CH N NH Cl H Cl H-NH 3 N CH N NH Cl HFH-NH 3 N CH N NH Cl H Br H-NH 3 N CH N NH Cl H NO ₂ H-NH 3 N CH N NH Cl H NH ₂ H-NH 3 N CH N NH Cl H OH H-NH 3 N CH N NH Cl H CHO H -NH 3 N CH N NH Cl H CH ₂ OH H-NH 3 N CH N NH Cl H COOH H-NH 3 N CH N NH Cl ──────────────────────────────────

[0241]

[Table 116] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CH ₃ C (O) H- NH 3 N CH N NH Cl NO ₂ NO ₂ H-NH 3 N CH N NH Cl NO ₂ H NO ₂ -NH 3 N CH N NH Cl H CF ₃ H-NH 3 N CH N NH Cl HHH NH NH 3 N CH N NH Cl H MeO H NH NH 3 N CH N NH Cl H n-PrO H NH NH 3 N CH N NH Cl H nC ₆ H ₁₃ OH NH NH 3 N CH N NH Cl H Me H NH NH 3 N CH N NH Cl H MeNH H NH NH 3 N CH N NH Cl H Cl H NH NH 3 N CH N NH Cl HFH NH NH 3 N CH N NH Cl H NO ₂ H NH NH 3 N CH N NH Cl H CF ₃ H NH NH 3 N CH N NH Cl HHH--4 N CH N NH Cl H MeO H--4 N CH N NH Cl H n-PrO H--4 N CH N NH Cl H nC ₆ H ₁₃ OH--4 N CH N NH Cl H Me H--4 N CH N NH Cl H MeNH H--4 N CH N NH Cl H Cl H---4 N CH N NH Cl HFH--4 N CH N NH Cl H NO ₂ H--4 N CH N NH Cl ───────── ─────────────────────────

[0242]

[Table 117] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ H--4 N CH N NH Cl HHHO-4 N CH N NH Cl H MeO HO-4 N CH N NH Cl H n-PrO HO-4 N CH N NH Cl H nC ₆ H ₁₃ OHO-4 N CH N NH Cl H Me HO- 4 N CH N NH Cl H MeNH HO-4 N CH N NH Cl H Cl HO-4 N CH N NH Cl HFHO-4 N CH N NH Cl H NO ₂ HO-4 N CH N NH Cl H CF ₃ HO- 4 N CH N NH Cl HHH-O 4 N CH N NH Cl H MeO H-O 4 N CH N NH Cl H n-PrO H-O 4 N CH N NH Cl H nC ₆ H ₁₃ OH-O 4 N CH N NH Cl H Me H-O 4 N CH N NH Cl H MeNH H-O 4 N CH N NH Cl H Cl H-O 4 N CH N NH Cl HFH-O 4 N CH N NH Cl H NO ₂ H- O 4 N CH N NH Cl H COOH H-O 4 N CH N NH Cl H CF ₃ H-O 4 N CH N NH Cl HHHOO 4 N CH N NH Cl ───────────── ───────────── ───────

[0243]

[Table 118] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H MeO HOO 4 N CH N NH Cl H n-PrO HOO 4 N CH N NH Cl H nC ₆ H ₁₃ OHOO 4 N CH N NH Cl H Me HOO 4 N CH N NH Cl H MeNH HOO 4 N CH N NH Cl H Cl HOO 4 N CH N NH Cl HFHOO 4 N CH N NH Cl H NO ₂ HOO 4 N CH N NH Cl H CF ₃ HOO 4 N CH N NH Cl HHH NH O 4 N CH N NH Cl H MeO H NH O 4 N CH N NH Cl H n- PrO H NH O 4 N CH N NH Cl H nC ₆ H ₁₃ OH NH O 4 N CH N NH Cl H Me H NH O 4 N CH N NH Cl H MeNH H NH O 4 N CH N NH Cl H Cl H NH O 4 N CH N NH Cl HFH NH O 4 N CH N NH Cl H NO ₂ H NH O 4 N CH N NH Cl H CF ₃ H NH O 4 N CH N NH Cl HHH NMe O 4 N CH N NH Cl H MeO H NMe O 4 N CH N NH Cl H n-PrO H NMe O 4 N CH N NH Cl H nC ₆ H ₁₃ OH NMe O 4 N CH N NH Cl ───────────── ───── ───────────────

[0244]

[Table 119] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Me H NMe O 4 N CH N NH Cl H MeNH H NMe O 4 N CH N NH Cl H Cl H NMe O 4 N CH N NH Cl HFH NMe O 4 N CH N NH Cl H NO ₂ H NMe O 4 N CH N NH Cl H CF ₃ H NMe O 4 N CH N NH Cl HHHO NH 4 N CH N NH Cl H MeO HO NH 4 N CH N NH Cl H n-PrO HO NH 4 N CH N NH Cl H nC ₆ H ₁₃ OHO NH 4 N CH N NH Cl H Me HO NH 4 N CH N NH Cl H MeNH HO NH 4 N CH N NH Cl H Cl HO NH 4 N CH N NH Cl HFHO NH 4 N CH N NH Cl H NO ₂ HO NH 4 N CH N NH Cl H CF ₃ HO NH 4 N CH N NH Cl HHH NH-4 N CH N NH Cl H MeO H NH-4 N CH N NH Cl H n-PrO H NH-4 N CH N NH Cl H nC ₆ H ₁₃ OH NH -4 N CH N NH Cl H MeNH H NH-4 N CH N NH Cl H Cl H NH-4 N CH N NH Cl H NO ₂ H NH-4 N CH N NH Cl ───────── ────── ───────────────────

[0245]

[Table 120] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H CF ₃ H NH-4 N CH N NH Cl HHH-NH 4 N CH N NH Cl H MeO H-NH 4 N CH N NH Cl H n-PrO H-NH 4 N CH N NH Cl H nC ₆ H ₁₃ OH-NH 4 N CH N NH Cl H Me H-NH 4 N CH N NH Cl H MeNH H-NH 4 N CH N NH Cl H Cl H-NH 4 N CH N NH Cl HFH-NH 4 N CH N NH Cl H NO ₂ H-NH 4 N CH N NH Cl H CF ₃ H-NH 4 N CH N NH Cl HHH NH NH 4 N CH N NH Cl H MeO H NH NH 4 N CH N NH Cl H n-PrO H NH NH 4 N CH N NH Cl H nC ₆ H ₁₃ OH NH NH 4 N CH N NH Cl H Me H NH NH 4 N CH N NH Cl H MeNH H NH NH 4 N CH N NH Cl H Cl H NH NH 4 N CH N NH Cl HFH NH NH 4 N CH N NH Cl H NO ₂ H NH NH 4 N CH N NH Cl H CF ₃ H NH NH 4 N CH N NH Cl HHH--5 N CH N NH Cl H MeO H--5 N CH N NH Cl ─ ─────────── ─────────────────────

[0246]

[Table 121] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H n-PrO H--5 N CH N NH Cl H nC ₆ H ₁₃ OH--5 N CH N NH Cl H Me H--5 N CH N NH Cl H MeNH H--5 N CH N NH Cl H Cl H--5 N CH N NH Cl HFH--5 N CH N NH Cl H NO ₂ H--5 N CH N NH Cl H CF ₃ H--5 N CH N NH Cl HHHO-5 N CH N NH Cl H MeO HO-5 N CH N NH Cl H n-PrO HO-5 N CH N NH Cl H nC ₆ H ₁₃ OHO-5 N CH N NH Cl H Me HO-5 N CH N NH Cl H MeNH HO-5 N CH N NH Cl H Cl HO -5 N CH N NH Cl HFHO-5 N CH N NH Cl H CF ₃ HO-5 N CH N NH Cl HHH-O 5 N CH N NH Cl H MeO H-O 5 N CH N NH Cl H n-PrO H-O 5 N CH N NH Cl H nC ₆ H ₁₃ OH-O 5 N CH N NH Cl H Me H-O 5 N CH N NH Cl H MeNH H-O 5 N CH N NH Cl ───── ───────────────── ────────────

[0247]

[Table 122] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl H-O 5 N CH N NH Cl HFH-O 5 N CH N NH Cl H NO ₂ H-O 5 N CH N NH Cl H CF ₃ H-O 5 N CH N NH Cl HHHOO 5 N CH N NH Cl H MeO HOO 5 N CH N NH Cl H n-PrO HOO 5 N CH N NH Cl H nC ₆ H ₁₃ OHOO 5 N CH N NH Cl H Me HOO 5 N CH N NH Cl H MeNH HOO 5 N CH N NH Cl H Cl HOO 5 N CH N NH Cl HFHOO 5 N CH N NH Cl H NO ₂ HOO 5 N CH N NH Cl H CF ₃ HOO 5 N CH N NH Cl HHH NH-5 N CH N NH Cl H MeO H NH-5 N CH N NH Cl H n -PrO H NH-5 N CH N NH Cl H n-BuO H NH-5 N CH N NH Cl H nC ₆ H ₁₃ OH NH-5 N CH N NH Cl H Me H NH-5 N CH N NH Cl H MeNH H NH-5 N CH N NH Cl H Cl H NH-5 N CH N NH Cl HFH NH-5 N CH N NH Cl ──────────────────── ────── ───────

[0248]

[Table 123] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H NO ₂ H NH-5 N CH N NH Cl H CF ₃ H NH-5 N CH N NH Cl HHH-NH 5 N CH N NH Cl H MeO H-NH 5 N CH N NH Cl H n-PrO H-NH 5 N CH N NH Cl H nC ₅ H ₁₁ OH-NH 5 N CH N NH Cl H nC ₆ H ₁₃ OH-NH 5 N CH N NH Cl H Me H-NH 5 N CH N NH Cl H MeNH H-NH 5 N CH N NH Cl H Cl H-NH 5 N CH N NH Cl HFH-NH 5 N CH N NH Cl H NO ₂ H-NH 5 N CH N NH Cl H CF ₃ H-NH 5 N CH N NH Cl HHH NH NH 5 N CH N NH Cl H MeO H NH NH 5 N CH N NH Cl H n-PrO H NH NH 5 N CH N NH Cl H nC ₆ H ₁₃ OH NH NH 5 N CH N NH Cl H Me H NH NH 5 N CH N NH Cl H MeNH H NH NH 5 N CH N NH Cl H Cl H NH NH 5 N CH N NH Cl HFH NH NH 5 N CH N NH Cl H NO ₂ H NH NH 5 N CH N NH Cl H CF ₃ H NH NH 5 N CH N NH Cl ─────── ──────────────────────────

[0249]

[Table 124] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── HHH--6 N CH N NH Cl H MeO H--6 N CH N NH Cl H n-PrO H--6 N CH N NH Cl H nC ₆ H ₁₃ OH--6 N CH N NH Cl H Me H--6 N CH N NH Cl H MeNH H--6 N CH N NH Cl H Cl H--6 N CH N NH Cl HFH--6 N CH N NH Cl H NO ₂ H--6 N CH N NH Cl H CF ₃ H--6 N CH N NH Cl HHHO-6 N CH N NH Cl H MeO HO-6 N CH N NH Cl H n-PrO HO-6 N CH N NH Cl H nC ₆ H ₁₃ OHO-6 N CH N NH Cl H Me HO -6 N CH N NH Cl H MeNH HO-6 N CH N NH Cl H Cl HO-6 N CH N NH Cl Cl HFHO-6 N CH N NH Cl H NO ₂ HO-6 N CH N NH Cl H CF ₃ HO -6 N CH N NH Cl HHH-O 6 N CH N NH Cl H MeO H-O 6 N CH N NH Cl H n-PrO H-O 6 N CH N NH Cl ────────── ─────────────── ────────

[0250]

[Table 125] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H nC ₆ H ₁₃ OH-O 6 N CH N NH Cl H Me H-O 6 N CH N NH Cl H MeNH H-O 6 N CH N NH Cl H Cl H-O 6 N CH N NH Cl HFH-O 6 N CH N NH Cl H NO ₂ H-O 6 N CH N NH Cl H CF ₃ H-O 6 N CH N NH Cl HHHOO 6 N CH N NH Cl H MeO HOO 6 N CH N NH Cl H n-PrO HOO 6 N CH N NH Cl H nC ₆ H ₁₃ OHOO 6 N CH N NH Cl H Me HOO 6 N CH N NH Cl H MeNH HOO 6 N CH N NH Cl H Cl HOO 6 N CH N NH Cl HFHOO 6 N CH N NH Cl H NO ₂ HOO 6 N CH N NH Cl H CF ₃ HOO 6 N CH N NH Cl HHH NH-6 N CH N NH Cl H MeO H NH-6 N CH N NH Cl H n-PrO H NH-6 N CH N NH Cl H nC ₆ H ₁₃ OH NH-6 N CH N NH Cl H Me H NH-6 N CH N NH Cl H MeNH H NH-6 N CH N NH Cl ───────────────── ─────── ──────────

[0251]

[Table 126] ────────────────────────────────── R ^a R ^b R ^c L ¹ L ³ k X ¹ X ³ X ⁵ DR ⁵ ────────────────────────────────── H Cl H NH-6 N CH N NH Cl HFH NH-6 N CH N NH Cl H NO ₂ H NH-6 N CH N NH Cl H CF ₃ H NH-6 N CH N NH Cl HHH-NH 6 N CH N NH Cl H MeO H-NH 6 N CH N NH Cl H n-PrO H-NH 6 N CH N NH Cl H nC ₆ H ₁₃ OH-NH 6 N CH N NH Cl H Me H-NH 6 N CH N NH Cl H MeNH H-NH 6 N CH N NH Cl H Cl H-NH 6 N CH N NH Cl HFH-NH 6 N CH N NH Cl H NO ₂ H-NH 6 N CH N NH Cl H CF ₃ H-NH 6 N CH N NH Cl HHH NH NH 6 N CH N NH Cl H MeO H NH NH 6 N CH N NH Cl H n-PrO H NH NH 6 N CH N NH Cl H nC ₆ H ₁₃ OH NH NH 6 N CH N NH Cl H Me H NH NH 6 N CH N NH Cl H MeNH H NH NH 6 N CH N NH Cl HFH NH NH 6 N CH N NH Cl H NO ₂ H NH NH 6 N CH N NH Cl H CF ₃ H NH NH 6 N CH N NH Cl ─────────── ──────────────────────

Table 2

[0253]

Embedded image

[0254]

[Table 127] ────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ ────────────── ────────CNCHOCHNCHCHSCHCHCOCHNCHCHSCHCHNCHCHCNNNMeCHCHCHCHCHCHCHCHCHOCHCHCHCHCHCHCH CH SCH C N N Me CH CH C N Me N CH CH C C CH N Me N CH C N Me CH CH CH C C CH CH N Me CH C C N Me CH N CH C N CH CH N CH CH N CH CH N CH CH CH CH NC CH CH NOC CH NOCH CHCNHOCH CHNCHNCHCH

Table 3

[0256]

Embedded image

[0257]

[Table 128] ────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ ──────────── ────────── C N CH CH CH CH CH C CH N CH CH CH CH C CH CH N N CH CH N CO CH CH CH CH CH N CH CH CO CO CH CH CN CH CH CH CH N CN N CH N CH CH C CH N CH NCH CH CNN NCH CH CH CH C CH NNNCH CH CHNNCH CH CH COCNCH CH CHNCH ────

Table 4

[0259]

Embedded image

[0260]

[Table 129] ────────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ W ⁹ ────────────────────────────────── CH CH CH CH C CH CH CH CH CH C C CMe NH C CH CH CH CH CH C C CMe NMe C CH CH CH CH C C CH NH C CH CH CH CH CH C C CH S C CH CH CH CH CH C N CH N C CH CH CH CH CH C C CH O C CH CH CH CH C C CH CH C CH CH CH CH CH N C N NH C CH CH CH CH CH C C N NMe C CH CH CH CH CH C N N N C CH CH CH CH CH C N CH N N C N CH N CH C C CH NN CH CH CH N NC C CH N N CH CH N N C C CMe SNC CCF ₃ N- * NC CMe SCN CMe N- NCCH SCNCH N-N} ─────────── *; covalent bond

Table 5

[0262]

Embedded image

[0263]

[Table 130] ───────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ W ⁹ ───────────────────────────────── CH ₂ C CMe C CH CH CH CH CH C CH ₂ CCH C CH CH CH CH CH C NMe C CH C CH CH CH CH CH C NH C CH C CH CH CH CH C C NMe C CMe C CH CH CH CH CH C NH C CMe C CH CH CH CH CH CNH C CH C CH CH CMe CH CH C NH C CH C CH CBr CH CH C NH C CH C CH CPh CH CH C NMe C CH C CH CMe CH CH C C NMe C CH C CH CBr CH CH C NMe C CH C CH CPh CH CH C CS C CMe C CH CCl CH C CSC CMe C CH CH CH CH C C S C CH C CH CH CH CH CH C S C CH C CH CPh CH CH C S C CMe C CH CPh CH CH CO C CH C CH CH CH CH COMe CO C CMe C CH CH CH CH CH OC C CH C CH CH CH CH CH COC CH C CH CPh CH CH CH C CMe C CH CPh CH CH C NH C N C CH CH CH CH CH C ────────────────────────

[0264]

[Table 131] ───────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ W ⁹ ───────────────────────────────── NMe C NC CH CH CH CH CH C NH C N C CH CMe CMe CH C NMe C NC C CH CMe CMe CH C NH C N C CH CPh CH CH C C NMe C N C CH CPh CH CH C C NMe C N C CH CH CH CCh CH C N C O C CH CH CH CH CNCOCCHCPhCHCHCHCNCOCCHCHCHCPhCHCNCCOCCHCMeCHCHCHCNCOCCHCHCHMEChCHCNCSCCHCHCHCHCHCHNCSCS CH CPh CH CH C N C S S C CH CH CPh CH C N CSC CH CMeCH CH CH C N C S C CH CH C C Me CH C CH C C CH C CH CH CH CH N NH C N C N CH N N CH C NMe C N C N CH N N CH C N C CH C C N CH CH CH NNC CH CNNCH CH CH NSC CMeNN CCF ₃ N- * CSC CMeNN CMeN-C ────────────────── ───────────────

[0265]

[Table 132] ───────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ W ⁹ {SCCHNNNNCHN-C} ────────────────────────────── *; covalent bond

Table 6

[0267]

Embedded image

[0268]

[Table 133] ───────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ W ⁹ ＣＨ CH ₂ CH CH C C CH CH CH CH C CH CH CH ₂ C C CH CH CH C C NMe CH CH C C CH CH CH CH C CH CH NMEC C CH CH CH C CH CH CH C C CH CH CH CH C CH CH S C C CH CH CH CH CO CH CH C C CH CH CH C CH CHOCCC CH CH CH C NH C N C C CH CH CH C NMeCN C C CH CH CH CH C N C NMe C C CH CH CH C N C O C C CH CH CH CH C O C NCCCHCHCHCHCNCSCCCCHCHCHCHCSCNCCCCHC H CH C CH CH CH C C CH CH CH CH N CH CH CH CH N C CH CH CH C NH CH N C C N CH N C CH CH NNN C CH CH N C CH CH N N C N C CH N N C ───────────────────────────────

Table 7

[0270]

Embedded image

[0271]

[Table 134] ────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ W ⁹ ＣＨ CH ₂ CH CH C CH C CH CH CH C CH CH CH CH ₂ C CH C CH CH C NMe CH CH C C C C CH CH C CH CH NMe C CH C CH CH C S CH CH C CH C CH CH C C CH CH S C CH C CH CH C C S CH ₂ CH ₂ C CH C CH CH C C CH ₂ CH ₂ SC CH C CH CH CO CH CH C CH CH C CH CH C CH CHOC C CH C CH CH CO CH ₂ CH ₂ C CH C CH CH C CH ₂ CH ₂ OC C CH C CH CH C NH C N C CH C C CH CH C NMe C N C CH C C CH CH C N C N M e C CH C CH CH C N OC C CH C CH CH C O C N C CH C CH CH CH C N C S C CH C CH CH C C S C N C CH C C CH CH C CH CH CH C C CH C CH CHNCHCHCHCHNCHCCHCHCHNHCHNCHNCNCNCHCHCHCHNNNCHCCHNCNC ─────────

[0272]

[Table 135] ────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ W ⁹ ＣＨ CH CMeNN CMeC CH CH NC CH CH NNCH CNN NC CH CMeNN CMe CNN CCH CPhNN CMeC CH NCCH CPhNN CMe CNN C ─────────────────────── ───────

Table 8

[0274]

Embedded image

[0275]

[Table 136] ────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ ────────────────────────────── C CH CH CH CH CH CH CH CH CH C CH CH CH CH CH CH CH CH NCH CH CH CH N CH CH CH C CH CH N N CH CH CH CH CH C CH CH CH CH CH CH N CH C CH CH CH CH CH N CH CH C CH N CH CH CH CH CH CH CH N CH CH CH CH CH CH CH C CH CH CH O CH ₂ CH ₂ OC CH CH CH CH O CH CHOC N N CH CH CH CH CH CH CH C CH CH CH CH N N CH C CH CH NNN CH CH CH C CH CH CH CH N CH CH N C CH CH CH CH CH N CH NC CH CH CH N H N CH C CH CH CH CH CH CH NNN C CH CH CH CH N N CH CH C N CH N N CH CH NNN CH CH S CH CH CH CH CH C CH CH CH CH S CH CH NH C CH CH CH CH CH CH CH NMe C CH CH CH CH NH CH CH S ──────────────────────────────

[0276]

[Table 137] ────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ ────────────────────────────── C CH CH CH NMeCH CH CH S N CO CH CH CH CH CH CH CH CH N CH CH CO CH CH CH CH CH CH CH CH NH NH CO CH CH C CH CH CH CH NMeCO CO CH CH C CH CH CH CH CH CH CH CO NH C CH CH CH CH CH CH CO NMe C CH CH CH NH CH CH CO C CH CH CHN CHM CH CO C CH CH CH CO CO CH CH NH NH C CH CH CH CH CO CH CH NMe C CH NH CO CH CH CH CH CH C CH NMe CO CH CH CH CH CH C CH CH CH CH CO NH CH CH C CH CH CH CH CO NMeCH CH CH C CH CH CH CH CH CH NH CO C CH CH CH CH CH CH NMe CO C CO NH CH CH CH CH CH CH C CO NMe CH CH CH CH CH CH NH CO CH CH CH CH CH CH N CH CH CH CH CH C C CH CH CH CH CH NH CO CH C CH CH CH CH CH NMe CO CH ──────────────────────────────

[0277]

[Table 138] ────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ ────────────────────────────── C CH CH CH CH CH CO NH CH C CH CH CH CH CH CO CO NMe CH CN NH CO CH CH CH CH C CN NMe CO CH CH CH CH CH C CH CH CH CH CH NNH CO C CH CH CH CH CH N NMe CO C CH CH CH CH CO NH N CH C CH CH CH CO NMe NCH CH ────────────────────────

Table 9

[0279]

Embedded image

[0280]

[Table 139] ────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ ＣＨ CH C CH CH CH CH CH CH CH CH CH C CH CH CH CH CH CH N CH C CH CH N CH CH CH NC CH CH CH CH CH CH CH CH CH C C CH N CH CH CH CH CH CH C CH CH CH CH CH NCH CH C CH CH CH CH N CH CH CH C NCH CH CH CH CH CH CH C CH CH O CH ₂ CH ₂ O CH C CH CH O CH CH O CH C CH CH CH CH N N CH CH C C CH N N CH CH CH N C CH CH CH CH CH CH N N C CH N CH CH CH CH CH C C CH CH N CH CHNNNCNNCHCHC CH CH CH C CH CH CH CH N CH N N CH C CH CH CH N CH NCH CH CH CN N CH CH CH CH CH CH C CH CH CH CH CH N N CH C CH CH CH N N CH CH N N C N CH N CH N CH N NCCHNCHNCHNNN

[0281]

[Table 140] ────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ Ｎ NCCHNNCHNCHCHSCCHCHNHCHCHCHCHCHSCCHCHNMe CH CH CH CH NH C CH S CH CH CH CH CH NMe C CH S CH CH CH CH CH CH C CH CH NH CH CH CH S CH C CH CH NMe CH CH CH CH CH CH CH CH CH NH NH CH C CH CHCH CH NMe S C CMe NH CH CH CH CH CH S C CMe NMe CH CH CH CH CH CH C CO NH CH CH CH CH CH CH C CO NMe CH CH CH CH CH CH CH CH CH NH CO CH CH CH CHN CHM H CH CH C CH CH CH CH CH CO NH CH C CH CH CH CH CH CO NMeNH C CH CO CH CH CH CH CH NMe C CH CO CH CH CH CH CH CO C CH NH NH CH CH CH CH CO C CH NMe CH CH CON CH CH CH CH CH CH CH CH CH C NH CO CH CH CH CH CH ──────────────────────────────

[0282]

[Table 141] ────────────────────────────── W ¹ W ² W ³ W ⁴ W ⁵ W ⁶ W ⁷ W ⁸ ────────────────────────────── CH C NMe CO CH CH CH CH CH CH CH C CH CH CO NH CH CH CH CH C CH CH CO NMe CH CH CH CH C CH CH CH CH CH NH CO CH C CH CH CH CH CH NMe CO CH N CO CH CH CH CH CH CH CH C CH CH CH CH CO NH CH CH C CH CH CH CO NMe CH CH CH CH CH CO CH CH C CH CH CH CH NMe CO CH CH CONNCH CH CH CH CH CH CH C CH CH CH N NH CO CH C CH CH CH N NMe CO CH C CH CH CH CO NHN CH CH C CH H CO NMe N CH ──────────────────────────────

The compound [I] of the present invention or a pharmacologically acceptable salt thereof, as shown by the test results described below,
Mammals, including humans, such as humans and mice, which have hypoglycemic activity and are therefore used as such or as a mixture with known pharmaceutically acceptable binders, excipients, lubricants, disintegrants, etc. It is useful as a preventive or therapeutic agent for diabetes in rats, rabbits, dogs, monkeys, cattle, horses, pigs and the like. The compound [I] of the present invention or a pharmacologically acceptable salt thereof includes various insulin preparations, sulfonylurea agents, insulin sensitizers, oral diabetes drugs such as α-glucosidase inhibitors and biguanides, aldose reductase inhibitors When used in combination with an agent or the like, the effect of treating diabetes can be obtained.

The active ingredient can be formulated into various types depending on the administration route. The compound [I] of the present invention or a pharmacologically acceptable salt thereof may be any of the pharmaceutically acceptable binders (hydroxypropylcellulose, syrup,
Gum arabic, gelatin, sorbit, tragacanth,
Polyvinylpyrrolidone, CMC-Ca, etc.), excipients (lactose, sugar, corn starch, calcium phosphate, sorbite, glycine, microcrystalline cellulose, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (Eg, potato starch) and the like, and can be in the form of powder, granules, tablets, capsules, or the like, and is preferably administered orally.

However, the present invention is not limited to this, and parenteral administration is also possible.

For example, suppositories using oleaginous bases such as cocoa butter, polyethylene glycol, lanolin and fatty acid triglyceride, or liquid paraffin, white petrolatum,
Transdermal preparations using higher alcohols, macrogol ointments, hydrophilic ointments, aqueous gel bases, etc., as well as polyethylene glycol, aqueous gel bases, distilled water, distilled water for injection, excipients (lactose, corn starch, etc.) ) Can be administered as an injection using one or two or more selected from the group consisting of: ophthalmic mucosa, nasal mucosa, and oral mucosa.

The dosage is in the range of about 0.05 to about 50 mg / kg of patient body weight daily, preferably in the range of about 0.10 to about 10 mg / kg body weight daily 1-3 times daily. However, the dosage increases or decreases depending on age, weight, symptoms, and the like.

[0288]

The synthesis examples, pharmacological test examples and preparation examples of the compounds of the present invention are described below. The present invention is not limited by these.

Reference Example 1 Synthesis of methyl (S) -2-benzyloxycarbonylamino-3-tert-butoxycarbonylaminopropionate (compound (1))

(S) -2-benzyloxycarbonylamino-3-tert-butoxycarbonylaminopropionic acid synthesized according to the method described in J. Med. Chem., 1987, 30, 1458-1463 (2.
An ether solution (50 ml) of 82 g, 8.34 mmol) was cooled to 0 ° C., and diazomethane was added until the solution turned yellow, and the solvent was distilled off. Compound (1) (2.94 g, 8.34 mmol) was obtained as a colorless oil. Was obtained quantitatively.

¹ H-NMR (CDCl ₃ , rt, 60 MHz) δ 7.03-7.37
(5H, m) 5.78 (1H, br s) 5.12 (2H, s) 4.83 (1H, br
s) 4,40 (1H, br s) 3.76 (3H, s) 3.55 (2H, s) 1.42
(9H, s) FAB-MS m / z (M + H) ⁺ 353

Reference Example 2 Synthesis of methyl (S) -2-amino-3-tert-butoxycarbonylaminopropionate (compound (2))

Compound (1) (2.94) synthesized in Reference Example 1
g, 8.34 mmol) in methanol solution (15 ml) with 10% Pd-C
(294 mg) and the mixture was stirred at room temperature for 17 hours. After filtration of the reaction solution, the solvent was distilled off to obtain a colorless oil. The residue was purified by column chromatography (CHCl 3: MeOH = 20: 1) to quantitatively obtain compound (2) (2.14 g) as a pale yellow oil.

¹ H-NMR (CDCl ₃ , rt, 60 MHz) δ 5.18 (1
H, br s) 5.30 (1H, br s) 4.78 (2H, br s) 5.25 (1H,
m) 4.02 (1H, br s) 3.48 (3H, s) 1.42 (9H, s) FAB-MS m / z (M + H) ⁺ 353

Reference Example 3 8-benzyl-2,4-dioxo-1,3,8-triazaspiro [4.5]
Synthesis of decane (compound (3))

As in US Pat. No. 3,330,836, 1-benzyl-4-
50% ethanol of piperidone (64.8 g, 0.342 mol)
Add ammonium carbonate (98.6 g, 1.03 mo) to the aqueous solution (1.5 l)
l) and sodium cyanide (16.8 g, 0.342 mol) were added, and the mixture was stirred at 68 ° C for 3.5 hours. After concentrating the solvent under reduced pressure, the mixture was cooled, and the resulting solid was collected by filtration, and 50% ethanol-water (200
ml), water (200 ml) and then diethyl ether (100 ml)
And washed. The obtained solid was dried under reduced pressure at 50 ° C. for 6.5 hours. As a result, compound (3) (79.3 g, 0.306 mol) was obtained as a colorless solid in a yield of 89%.

Mp 278.0-278.1 ° C. ¹ H-NMR ((CD ₃ ) ₂ SO, rt, 400 MHz) δ 10.62 (1H, s) 8.
43 (1H, s) 7.22-7.34 (5H, m) 3.48 (2H, s) 2.68 (2H,
m) 2.28 (2H, m) 1.82 (2H, m) 1.52 (2H, m) EI-MS m / z (M) ⁺ 259

Reference Example 4 Synthesis of 4-amino-1-benzylpiperidine-4-carboxylic acid (compound (4))

Compound (3) as in US Pat. No. 3,330,836
(58.8 g, 0.227 mol) was dissolved in a 1 M aqueous sodium hydroxide solution (1.2 l), and the mixture was refluxed for 33 hours. After cooling the reaction solution to room temperature, neutralize with 3M hydrochloric acid, and further add 25 ml of concentrated hydrochloric acid.
Was added to make the solution acidic, and then 50 ml of concentrated aqueous ammonia was added to make the solution alkaline. The obtained solid was collected by filtration and water 100
After washing with 100 ml of diethyl ether and then 60 ml under reduced pressure
As a result of drying at 9.5 hours, compound (4) (51.0 g, 0.218
mol) was obtained as a colorless solid in 96% yield.

Mp 246.2-246.6 ° C. ¹ H-NMR (CD ₃ CO ₂ D, rt, 400 MHz) δ 7.55 (2H, m) 7.46
(3H, m) 4.38 (2H, s) 3.8 (2H, m) 3.6 (2H, m) 2.45
(4H, m) FD-MS m / z (M + H) ⁺ 235

Reference Example 5 Synthesis of 1-benzyl-4- (tert-butoxycarbonyl) aminopiperidine-4-carboxylic acid (compound (5))

Compound (4) (50.0 g, 0.213 mol) of 67
Triethylamine (45.3 g, 0.448 mol) was added to a suspension of 1.5% tetrahydrofuran-water (1.5 l). Di-t-butyl dicarbonate (70.0 g, 0.321 mol) was added dropwise to the suspension, and 4
Stirred at 7 ° C. for 21.5 hours. Furthermore, di-t-butyl dicarbonate (20.
0 g, 0.092 mol) and stirred for 23 hours.
After adding t-butyl (10.0 g, 0.046 mol) and triethylamine (6.5 g, 0.064 mol), the mixture was stirred for 62 hours, and then cooled to room temperature. After the solvent was dried, 40 ml of methanol and 100 ml of diisopropyl ether were added to solidify, and the solid was collected by filtration and washed with 100 ml of diisopropyl ether. After drying at 50 ° C. under reduced pressure for 10 hours, compound (5) (59.1) was obtained.
g, 0.177 mol) as a colorless powder with a yield of 83%.

Mp 304.3-309.8 ° C. (decomp.) ¹ H-NMR ((CD ₃ ) ₂ SO, rt, 400 MHz) δ 7.24-7.32 (5H,
m) 7.01 (1H, br s) 3.48 (2H, br s) 2.53 (2H, m) 2.
23 (2H, m) 1.85-1.92 (4H, m) 1.37 (9H, s) FAB-MS m / z (M + H) ⁺ 335

Reference Example 6 Synthesis of 4- (tert-butoxycarbonyl) aminopiperidine-4-carboxylic acid (compound (6))

Compound (5) (20.0 g, 59.8 mmol) was added to 67
After dissolving in tetrahydrofuran-water (3 l) and triethylamine (6.0 g, 59.5 mmol), 10% palladium-carbon (4.6 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 46 hours. The catalyst was removed by filtration through Celite, washed with a mixed solution of 67% tetrahydrofuran-water (1.5 l) and triethylamine (10 ml), and then washed with a mixed solution of 50% methanol-water (1 l) and triethylamine (10 ml). And the solvent was evaporated to dryness. As a result, compound (6) (13.7 g, 56.1 mmol) was obtained.
Was obtained as a light gray solid in 94% yield.

Mp 262.8-263.7 ° C. ¹ H-NMR (CD ₃ CO ₂ D, rt, 400 MHz) δ 3.3-3.5 (4H, m)
2.3-2.5 (4H, m) 1.45 (9H, s) EI-MS m / z (M) ⁺ 244

Reference Example 7 1-benzyloxycarbonyl-4- (tert-butoxycarbonyl) aminopiperidine-4-carboxylic acid (compound (7))
Synthesis of

Compound (6) (15.0 g, 61.4 mmol) was added to 1
M solution of sodium hydroxide (62 ml), benzyl chloroformate (10.8 g, 63.0 mmol) in ethyl ether (80 ml) and 1 M sodium hydroxide solution (64
ml) was simultaneously added dropwise at −2 to 5 ° C. over 1 hour.
The mixture was stirred at 2 to 0 ° C for 3 hours and 45 minutes. After washing the reaction solution with ether, a 1M aqueous solution of citric acid (30 ml) was added to the aqueous layer under cooling to adjust the pH to about 4, extraction with ethyl acetate (200 ml × 2), and the organic layer dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off, and the resulting crude product was recrystallized (benzene-hexane). As a result, compound (7) (16.9 g, 44.7 mmol)
Was obtained as colorless crystals in a yield of 73%.

Mp 92.0-93.7 ° C. ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.29-7.38 (5H, m)
6.1 (1H, br s) 5.13 (2H, s) 3.94 (2H, m) 3.23 (2H, s)
m) 1.98-2.05 (4H, m) 1.41 (9H, s) EI-MS m / z (M) ⁺ 321

Reference Example 8 Methyl 1-benzyloxycarbonyl-4- (tert-butoxycarbonyl) amino-4-piperidylacetate (Compound (9))
Synthesis of

To a solution of compound (7) (4.97 g, 13.1 mmol) in tetrahydrofuran (10 ml) was added triethylamine (1.9 ml, 13.6 mmol), and methyl chloroformate (1.24 g, 13.1 mmol) was added at -17 to -11 ° C. ) In tetrahydrofuran (1 ml) was added dropwise. After the reaction solution was stirred for 45 minutes under cooling, the precipitated solid was separated by filtration, and tetrahydrofuran (4
ml). Diazomethane was introduced into the filtrate along with a nitrogen stream (precursor p-toluenesulfonyl-N-methyl-
After 4.3 equivalents as N-nitrosamide), the solvent was distilled off. The obtained crude product was purified by column chromatography (ethyl acetate-hexane = 2: 3) to obtain diazoketone (1.89 g, 4.70 mmol) in a yield of 36%. At this time, methyl 1-benzyloxycarbonyl-4- (tert-butoxycarbonyl) aminopiperidine-4-carboxylate (compound (8)) (2.24 g, 5.72 mmol) was also obtained with a yield of 44%.

Methyl 1-benzyloxycarbonyl-4- (tert-butoxycarbonyl) aminopiperidine-4-carboxylate (Compound (8))

Mp 122.9-123.1 ° C. ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.30-7.36 (5H, m)
5.13 (2H, s) 4.73 (1H, s) 3.87-3.91 (2H, m) 3.73
(3H, s) 3.22-3.27 (2H, m) 2.02-2.09 (2H, m) 1.93-
1.96 (2H, m) 1.43 (9H, s) FD-MS m / z (M + H) ⁺ 393

To a solution of diazoketone (3.70 g, 9.19 mmol) in methanol (50 ml) was added triethylamine (2.8 ml, 2
0 mmol) and silver benzoate (422 mg, 1.85 mmol) was added. After stirring at room temperature under light shielding overnight, silver benzoate (344 mg, 1.50 mmol) was added, and the mixture was stirred at room temperature overnight. After filtration through celite, the crude product obtained by evaporating the solvent was subjected to column chromatography (ethyl acetate-hexane =
2: 3) to give Compound (9) (2.78)
g, 6.84 mmol) as a colorless amorphous in 74% yield.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.30-7.
36 (5H, m) 5.12 (2H, s) 4.51 (1H, s) 3.88 (2H, m)
3.68 (3H, s) 3.15 (2H, m) 2.76 (2H, s) 2.20 (2H, m)
1.6 (2H, m) 1.43 (9H, s) FD-MS m / z (M + H) ⁺ 407

Reference Example 9 Synthesis of methyl 4-amino-1-benzyloxycarbonyl-4-piperidylacetate (Compound (10))

Compound (9) (859 mg, 2.11 mmol) was added to 4
The mixture was dissolved in M hydrochloric acid-dioxane (2 ml) and stirred at room temperature for 6 hours. After evaporating the solvent, the obtained crude product was dissolved in ethyl acetate (10 ml), washed with saturated aqueous sodium hydrogen carbonate, the organic layer was dried over sodium sulfate, and the drying agent was filtered off. ) (599 mg, 1.96 mmol) was obtained as yellow amorphous in 93% yield.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.29-7.
36 (5H, m) 5.12 (2H, s) 3.72 (3H, s) 3.7 (2H, m)
3.6 (2H, m) 2.77 (2H, s) 1.95 (2H, m) 1.8 (2H, m) FAB-MS m / z (M + H) ⁺ 307

Reference Example 10 Synthesis of methyl (1-benzyloxycarbonyl-4-phenoxycarbonylamino-4-piperidyl) acetate (Compound (11))

TH of compound (10) (76 mg, 0.2481 mmol)
F solution (2 ml) under ice-cooling, phenyl chloroformate (31 μl, 0.2
481 mmol) and Et ₃ N (35 μl, 0.2481 mmol) were added, and the mixture was stirred at the same temperature for 1 hour. After filtering the reaction solution, the solvent was distilled off to obtain Compound (11) as a crude product (104 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.40-7.15 (10
(H, m) 5.42 (1H, s) 5.13 (2H, s) 3.89 (2H, br s) 3.7
2 (3H, s) 3.19 (2H, t, 12.0 Hz) 2.79 (2H, s) 2.27 (2
H, s) 1.60 (2H, br s)

Reference Example 11 Synthesis of 1-benzyloxycarbonyl-4-piperidone (compound (12))

Ice-cooled 4-piperidone hydrochloride monohydrate
(154 g, 1.00 mol) in 50% tetrahydrofuran-water solution (1000 ml) in sodium carbonate (127 g, 1.20 mol),
A solution of benzyl chloroformate (143 ml, 1.00 mol) in tetrahydrofuran (500 ml) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (500 ml) was added to the residue, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (200 ml), and the collected organic layers were washed with saturated saline and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (30% ethyl acetate-hexane) to give compound (12) (230 g, 0.986 mol) as a pale yellow oily product 99% obtained.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.31-7.
39 (5H, m) 5.18 (2H, s) 3.80 (4H, m) 2.46 (4H, m) EI-MS m / z (M) ⁺ 233

Reference Example 12 Synthesis of 1-benzyloxycarbonyl-4-methylenepiperidine (compound (13))

Ice-cooled triphenylphosphonium bromide (110 g, 0.308 mol), diethyl ether (500 ml)
Potassium tert-butoxide (37.8 g, 0.
337 mol), and the mixture was stirred under ice-cooling for 1 hour.
2) (71.9 g, 0.308 mol) in diethyl ether (200
ml), and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was diluted with hexane (1400 ml), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a 25% diethyl ether-hexane solution (250 ml), silica gel (100 g) was added, the mixture was stirred at room temperature for 1 hour, and then filtered. Wash the silica gel with 25% diethyl ether-hexane solution,
The collected filtrate was concentrated under reduced pressure to give compound (13) (64.4 g,
0.278 mol) as a pale yellow oil in 90% yield.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.31-7.
37 (5H, m) 5.15 (2H, s) 4.76 (2H, s) 3.51 (4H, m)
2.20 (4H, brs) EI-MS m / z (M) ⁺ 231

Reference Example 13 Synthesis of 7-benzyloxycarbonyl-2-oxo-1,7-diazaspiro [3.5] nonane (compound (14))

Compound (13) (6.18 g, 26.7 mm) cooled on ice
ol) in a dichloromethane solution (40 ml) was added with a dichloromethane solution (20 ml) of chlorosulfonyl isocyanate (2.80 ml, 32.2 mmol), and the mixture was stirred at room temperature for 14 hours.
The reaction mixture was diluted with diethyl ether (120 ml), cooled on ice, and sodium thiosulfate pentahydrate (16.0 g, 64.5 mol)
Aqueous solution (120 ml) and 10% aqueous potassium hydroxide solution (30
ml) was added dropwise, and the mixture was stirred under ice cooling for 3 hours. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (30 ml × 2), and the collected organic layers were washed with brine and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was dissolved in hot ethyl acetate. Hexane was added, the solid formed after cooling was collected by filtration, and the obtained solid was dried under reduced pressure at 50 ° C for 5 hours. As a result, compound (14) (5.46 g, 19.9 mmol) was obtained as a pale yellow powder in a yield of 74. %.

Mp: 93.6-95.2 ° C ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.31-7.38 (5H, m)
6.26 (1H, s) 5.13 (2H, s) 3.73 (2H, dt) 3.33 (2H, s)
ddd) 2.74 (2H, m) 1.79 (4H, brs) EI-MS m / z (M) ⁺ 274

Reference Example 14 Synthesis of methyl 4-amino-1-benzyloxycarbonyl-4-piperidylacetate (Compound (10))

Compound (14) cooled on ice (44.7 g, 0.986 m)
ol) in methanol (200 ml) was added with concentrated sulfuric acid (15 ml), and the mixture was stirred at room temperature for 17.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (300 ml) was dissolved in the residue, and a saturated aqueous solution of sodium hydrogen carbonate (250 ml) was added. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (200 ml), and the collected organic layers were washed with saturated saline and dried over sodium sulfate. After filtration, the solvent is distilled off under reduced pressure to give compound (10).
(44.9 g, 0.146 mol) as pale yellow amorphous
90% obtained.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.30-7.
39 (5H, m) 5.12 (2H, s) 3.72 (2H, m) 3.69 (3H, s)
3.39 (2H, m) 2.41 (2H, s) 1.55 (4H, m) EI-MS m / z (M) ⁺ 306

Reference Example 15 2- (2,4-dinitrophenoxy) ethanol (compound (1
5)) Synthesis

2,4-Dinitrophenol (5.34 g, 29.0 mmol) as in Bull. Chem. Soc. Jpn., 1973, 46, 553.
And a mixture of 1,3-dioxolan-2-one (3.88 g, 44.0 mmol) in tetraethylammonium iodide (3.57 g, 1
3.9 mmol) and stirred at 140 ° C. for 2.5 hours. After completion of the reaction, chloroform was extracted from water, and the obtained crude product was recrystallized from ethanol to give compound (15).
(3.13 g, 13.7 mmol) was obtained as pale yellow crystals in a yield of 47%.

Mp: 100.0-102.0 ° C. ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 8.77 (1H, d) 8.52
(1H, dd) 7.57 (1H, d) 4.42 (2H, t) 3.98 (2H, t) FAB-MS m / z (M + H) ⁺ 229

Reference Example 16 Synthesis of 6-chloro-2-methylthio-4- (2-phenoxyethoxy) pyrimidine (compound (16))

Sodium hydride (60%) (507 mg, 12.7 mm
ol) in acetonitrile suspension (10 ml) was added dropwise a solution of 2-phenoxyethanol (1.58 g, 11.4 mmol) in acetonitrile (6 ml) under ice-cooling, and after stirring for 1 hour, 4,6-
Dichloro-2-methylthiopyrimidine (2.02 g, 10.4 mmo
l) acetonitrile solution (5 ml) was added dropwise on ice cooling,
After stirring for minutes, the mixture was heated to room temperature and stirred overnight. After stopping the reaction with a saturated aqueous solution of ammonium chloride, the crude product obtained by extraction with ethyl acetate was recrystallized from methanol-water to give Compound (16) (3.09 g, 10.4 g).
mmol) were obtained quantitatively as pale yellow crystals.

Mp: 80.0-86.0 ° C. ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.28-7.32 (2H, m)
6.98 (1H, m) 6.92 (2H, m) 6.48 (1H, s) 4.72-4.74
(2H, m) 4.29 (2H, t) 2.55 (3H, s) EI-MS m / z (M) ⁺ 296

Reference Example 17 Synthesis of 6-chloro-2-methylsulfonyl-4- (2-phenoxyethoxy) pyrimidine (compound (17))

Compound (16) synthesized in Reference Example 16 (1.
Sodium tungstate dihydrate (28 mg, 0.084 mmol) was added to an acetic acid solution (3 ml) of 50 g, 5.05 mmol), and aqueous hydrogen peroxide (35%) (1.23 g, 12.7 mmol) was added dropwise. The mixture was stirred at room temperature for 2.5 hours. Compound (17) (1.13 g, 3.44 mmo) was purified by column chromatography (ethyl acetate-hexane = 1: 2), and the crude product obtained by adding water to the reaction solution and extracting with ethyl acetate was purified.
l) was obtained as a colorless amorphous with a yield of 68%.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.28-7.
33 (2H, m) 6.99 (1H, s) 6.97-7.01 (1H, m) 6.91-6.9
4 (2H, m) 4.86-4.89 (2H, m) 4.32-4.35 (2H, m) 3.55
(3H, s) EI-MS m / z (M) ⁺ 328

Reference Example 18 Synthesis of 2-azido-4-chloro-6- (2-phenoxyethoxy) -pyrimidine (compound (18))

2,6-dichloro-4- (2-phenoxyethoxy)-
Pyrimidine (compound (22)) (138 mg, 0.4840 mmol) in DMF
Sodium azide (63 mg, 0.9680 mmol) was added to the solution (2 ml), and the mixture was stirred at 50 ° C for 3.5 hours. The reaction solution was diluted with ethyl acetate, washed with water, and the solvent was distilled off to obtain a residue (956 mg). This was purified by column chromatography (hexane: ethyl acetate = 4: 1) to give compound (18) (129.6 mg, 0.4443).
mmol) as a colorless oil in a yield of 92%.

Reference Example 19 Synthesis of 2-amino-4-chloro-6- (2-phenoxyethoxy) -pyrimidine (compound (19))

To a methanol solution (5 ml) of compound (18) (91 mg, 0.3120 mmol) was added 10% Pd-C, and the mixture was stirred at room temperature for 35 minutes. After the reaction solution was filtered, the solvent was distilled off to obtain a residue (956 mg). This was subjected to column chromatography (chloroform:
Purification was performed using methanol (5: 1) to give compound (19) (73.0 m
g, 0.4443 mmol) as a colorless oil in a yield of 88%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.28 (2H, m)
6.95 (3H, d, J = 8.4 Hz) 6.01 (2H, d, J = 8.0 Hz) 5.8
9 (1H, s) 4.40 (2H, m) 4.20 (2H, d, J = 3.6 Hz)

Reference Example 20 2,6-Dichloro-4- (2-phenylethylamino) pyrimidine (compound (20)) and 4,6-dichloro-2- (2-phenylethylamino) pyrimidine (compound (21) ) Synthesis

1.00 g of 2,4,6-trichloropyrimidine
(5.37 mmol) of DMF in 3 ml of 2-phenylethylamine 712.3 mg (5.89 mmol) of D
After dropping 2 ml of MF solution, 1 ml of triethylamine (7.
17 mmol) and stirred at room temperature for 3 hours. 5 ml of a saturated aqueous ammonium chloride solution and 3 m of water were added to the reaction solution.
After adding l, the mixture was extracted three times with 40 ml of ethyl acetate, and the organic layer was dried over sodium sulfate. After filtering off the drying agent, the crude product obtained by distilling off the solvent was purified by column chromatography (ethyl acetate-hexane = 1: 7) to give 963 mg (66%) of compound (20). As a colorless solid, 468 mg (32
%) As a colorless solid.

[0350] Compound ^{(20) 1 H-NMR (} CDCl 3, rt, 60 MHz) δ 2.89 (t, 2H, NHCH 2 C H 2
Ph), 3.66 (t, 2H, NHC H ₂ CH ₂ Ph), 5.4 (br, 1H, NH ), 6.
20 (s, 1H, 5-H of pyrimidine), 7.25 (s, 5H, arom H
of Ph) MS (FAB) m / z 268 (M) ⁺ mp 108-110 ° C Rf 0.32 (AcOEt-hexane = 1: 2)

[0351] Compound ^{(21) 1 H-NMR (} CDCl 3, rt, 60 MHz) δ 2.94 (t, 2H, NHCH 2 C H 2
Ph), 3.70 (t, 2H, NHC H ₂ CH ₂ Ph), 5.6 (br, 1H, NH ), 6.
62 (s, 1H, 5-H of pyrimidine), 7.29 (s, 5H, arom H
of Ph) MS (FAB) m / z 268 (M + H) ⁺ mp 126-128 ° C Rf 0.61 (AcOEt-hexane = 1: 2)

Reference Example 21 Synthesis of 2,6-dichloro-4- (2-phenoxyethoxy) pyrimidine (compound (22))

[0353] 7.72 g of 2-phenoxyethanol (5
5.9 mmol) in 200 ml of THF at room temperature.
2.38 g (59.5 mmol) of 0% sodium hydride
Was added and stirred for 30 minutes. Cool the reaction to -78 ° C,
10.54 g of 2,4,6-trichloropyrimidine (53.3 m
mol), and the temperature was gradually returned to room temperature over 3 hours.
100 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with 300 ml of ethyl acetate, and the organic layer was dried over magnesium sulfate. After removing the drying agent by filtration, the crude product obtained by evaporating the solvent was purified by recrystallization (ether-hexane) to give 5.89 g of compound (22) (3.
9%) as colorless crystals.

M.p .: 50.0-52.0 ° C

The following compounds were synthesized in the same manner as in Reference Example 21.

[0356]

Embedded image

[0357] Compound (23) mp 61-63 ℃ FAB- MS (m / z) (M + H) + 319

[0358] Compound (24) mp 39-41 ℃ FAB- MS (m / z) (M + H) + 319

[0359] Compound (25) mp 40-42 ℃ FAB- MS (m / z) (M + H) + 299

[0360] Compound (26) mp 48-51 ℃ FD- MS (m / z) (M) + 312

[0361] Compound (28) FAB-MS (m / z) (M + H) + 327

[0362] Compound (29) FAB-MS (m / z) (M + H) + 297

[0363] Compound (30) FAB-MS (m / z) (M + H) + 283

[0364] Compound (31) mp 101-103 ℃ FAB- MS (m / z) (M + H) + 269

[0365] Compound (32) FAB-MS (m / z) (M + H) + 255

[0366] Compound (33) FAB-MS (m / z) (M + H) + 241

Synthesis Example 1 (R) -3- (4-chloro-6- (2-phenoxyethoxy) pyrimidine
Synthesis of methyl-2-yl) amino-4-tert-butoxycarbonylamino-butyrate (compound (34))

Compound (22) (26) synthesized in Reference Example 21
9 mg, 0.943 mmol) in a DMI solution (9 ml) was added to J. Med. Chem.,
3-Amino-4- synthesized by the method described in 1987, 30, 1458-1463.
Methyl (tert-butoxycarbonylamino) butyrate (329 mg,
1.42 mmol) followed by diisopropylethylamine (493
μl, 2.83 mmol) and stirred at 60 ° C. for 17.5 hours. The reaction solution was diluted with EtOAc, washed with a saturated aqueous solution of ammonium chloride, dried and filtered with magnesium sulfate, and the solvent was distilled off to obtain a pale yellow oil. The residue was purified by column chromatography (Hexane: EtOAc = 4: 1) to give compound (34)
(389 mg, 0.808 mmol) as a colorless oil in 86% yield.

¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.27-7.
31 (2H, m) 6.92-6.99 (3H, m) 6.11 (1H, s) 5.88 (1
H, br s) 4.97 (1H, m) 4.64 (2H, m) 4.45 (1H, m) 4.2
6 (2H, m) 3.68 (3H, s) 3.40 (2H, m) 2.65 (2H, m)
1.42 (9H, s) FAB-MS m / z (M + H) ⁺ 481

Compound (3) was prepared in the same manner as in Synthesis Example 1.
(49) was synthesized from 5).

[0371]

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[0372]

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Compound (35) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 1.42 (s, 9H, tC ₄ H ₉ ), 2.87 (t, 2H, J = 7.1 Hz, N
HCH ₂ C H ₂ Ph), 3.55 (br, 2H, NHC H ₂ CH ₂ Ph), 3.62 (br, 2
H, C H ₂ NHBOC), 3.74 (s, 3H, CO ₂ C H ₃ ), 4.65 (br, 1H,
N H ), 5.0 (br, 1H, C H (CO ₂ Me) CH ₂ NHBOC), 5.1 (br, 1H,
N H ), 5.75 (s, 1H, 5-H of pyrimidine), 5.8 (br, 1
H, NH ), 7.19-7.21 (m, 3H, ortho and para H of Ph),
7.30-7.34 (m, 2H, meta H of Ph) MS (FAB) m / z 450 (M + H) ⁺

Compound (36) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.23-7.31 (2H, m)
6.91-6.99 (3H, m) 6.27 (1H, br s) 6.15 (1H, s) 5.04
(1H, br s) 4.61 (2H, m) 4.25 (2H, m) 3.76 (3H, s)
3.65 (1H, m) 1.42 (9H, s) FAB-MS m / z (M + H) ⁺ 467

Compound (37) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.19-7.34 (2H, m)
6.90-6.97 (2H, m) 6.10 (1H, s) 5.88 (1H, br s) 5.0
8 (1H, br s) 4.68 (2H, m) 4.45 (1H, m) 4.33 (1H, s)
3.67 (3H, s) 3.40 (2H, dd, J = 6.8, 12.6 Hz) 2.65
(2H, m) 1.41 (9H, s) FAB-MS m / z (M + H) ⁺ 515

Compound (38) ¹ H-NMR (CDCl ₃ , rt, 60 MHz) δ 7.25 (2H, d, J = 8.4 H)
z) 6.85 (2H, d, J = 8.4 Hz) 6.09 (1H, s) 6.03 (1H, s)
5.20 (1H, br s) 4.60 (3H, m) 4.24 (2H, m) 3.68 (3
H, s) 3.37 (2H, dd, J = 6.0, 12.0 Hz) 2.65 (2H, d, J
= 6.6 Hz) 1.38 (9H, s) FAB-MS m / z (M + H) ⁺ 515

Compound (39) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.25-7.31 (2H, m)
6.89-6.96 (3H, m) 6.04 (1H, s) 5.82 (1H, br s) 4.9
5 (1H, br s) 4.45 (3H, m) 4.09 (2H, m) 3.67 (3H, s)
3.38 (2H, m) 2.63 (2H, ddd, J = 5.8, 16.1, 22.0 Hz)
2.21 (2H, dd, J = 5.8, 11.6 Hz) 1.41 (9H, s) FAB-MS m / z (M + H) ⁺ 479

Compound (40) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.11 (2H, d, J = 8.6)
Hz) 6.83 (2H, d, J = 8.6 Hz) 6.01 (1H, s) 5.70 (1H, b
rs) 4.98 (1H, br s) 4.41 (1H, m) 4.26 (2H, m) 3.7
9 (3H, s) 3.68 (3H, s) 3.38 (2H, m) 2.68 (2H, dd, J
= 7.5, 15.0 Hz) 2.62 (2H, m) 2.00 (2H, m) 1.41 (9H,
s) FAB-MS m / z (M + H) ⁺ 509

Compound (42) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.09 (2H, d, J = 8.4 H)
z) 6.82 (2H, d, J = 8.4 Hz) 6.10 (1H, br s) 6.00 (1H,
s) 5.13 (1H, br s) 4.42 (1H, m) 4.25 (2H, br s) 3.
77 (3H, s) 3.66 (3H, s) 3.39 (2H, m) 2.64 (4H, m)
1.72 (4H, s) 1.41 (9H, s) FAB-MS m / z (M + H) ⁺ 522

Compound (43) ¹ H-NMR (CDCl ₃ , rt, 60 MHz) δ 7.22 (5H, s) 6.03 (1
(H, s) 5.18 (1H, br s) 4.29 (5H, m) 3.64 (3H, s) 3.
37 (2H, m) 2.70 (2H, m) 1.70 (4H, m) 1.37 (9H, s) FAB-MS m / z (M + H) ⁺ 493

Compound (44) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.19-7.31 (5H, m)
6.06 (1H, s) 5.74 (1H, m) 4.89 (1H, br s) 4.41 (1
(H, m) 4.27 (2H, m) 3.68 (3H, s) 3.37 (2H, m) 2.74
(2H, m) 2.62 (2H, m) 2.05 (2H, m) 1.41 (9H, s) FAB-MS m / z (M + H) ⁺ 479

Compound (45) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.21-7.33 (5H, m)
6.04 (1H, s) 5.76 (1H, br d, J = 7.9 Hz) 4.90 (1H, b
rs) 4.48 (2H, br s) 4.42 (1H, m) 3.66 (3H, s) 3.38
(2H, dd, J = 6.0, 12.0Hz) 2.66 (1H, dd, J = 5.7, 16.0
Hz) 2.60 (1H, dd, J = 6.2, 16.0 Hz) 1.41 (9H, s) FAB-MS m / z (M + H) ⁺ 465

Compound (46) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.31-7.39 (5H, m)
6.11 (1H, s) 5.78 (1H, br s) 5.33 (2H, s) 4.80 (1
H, br s) 4.44 (1H, dd, J = 5.9, 14.5 Hz) 3.69 (3H, s)
3.36 (2H, br s) 2.61 (2H, m) 1.42 (9H, s)

Compound (47) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.38-7.43 (2H, m)
7.28 (1H, m) 7.11 (1H, d, J = 7.7 Hz) 6.02 (1H, s)
5.88 (1H, br s) 4.42 (1H, br s) 3.66 (3H, s) 3.27
(2H, br s) 2.55 (2H, brs) 1.42 (9H, s)

Compound (48) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 1.43 (s, 9H, tC
₄ H ₉ ), 2.85 (t, 2H, J = 7.1 Hz, NHCH ₂ C H ₂ Ph), 3.6 (m,
2H + 2H, NHC H ₂ CH ₂ Ph and C H ₂ NHBOC), 3.75 (s, 3H, CO _{2
C H 3), 4.68 (br} , 1H, N H), 4.96 (br, 1H, C H (CO 2 Me) CH 2
NHBOC), 5.15 (br, 1H, NH ), 5.81 (s, 1H, 5-H ofpyri
midine), 5.87 (br, 1H, NH ), 7.20-7.23 (m, 3H, orth
o and para H of Ph), 7.28-7.32 (m, 2H, meta H of P
h) MS (FAB) m / z 450 (M + H) ⁺

Compound (49) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 1.43 (s, 9H, tC
₄ H ₉ ), 2.5-2.6 (m, 1H, C H H'CO ₂ H), 2.7-2.8 (m, 1H, C
H H ' CO ₂ H), 2.87 (t, 2H, J = 7.0 Hz, NHCH ₂ C H ₂ Ph), 3.3
6 (m, 2H, C H 2 NHBOC), 3.6 (m, 2H, NHC H 2 CH 2 Ph), 3.67
(s, 3H, CO ₂ C H ₃ ), 4.3-4.4 (br, 1H, C H (CH ₂ CO ₂ Me) -CH ₂
NHBOC), 4.9 (br, 1H, NH ), 5.0 (br, 1H, NH ), 5.7 (b
r, 1H, NH ), 5.73 (s, 1H, 5-H of pyrimidine), 7.20-
7.23 (m, 3H, ortho and para H of Ph), 7.30 (m, 2H,
meta H of Ph) MS (FAB) m / z 464 (M + H) ⁺

Synthesis Example 2 (R) -3- (4-chloro-6- (2-phenoxyethoxy) pyrimidine
Synthesis of -2-yl) amino-4-tert-butoxycarbonylamino-butyric acid (compound (50))

Compound (34) (199) synthesized in Synthesis Example 1
(Mg, 0.414 mmol) in methanol (8 ml) was added with a 1M aqueous solution of NaOH (4 ml) and stirred at room temperature for 16 hours. The reaction solution was acidified with a 10% aqueous citric acid solution, and then diluted with EtOAc. After the organic layer was dried and filtered with magnesium sulfate, the solvent was distilled off to obtain a colorless oil. The residue was purified by column chromatography (Hexane: EtOAc = 2: 1) to give compound (50) (16
4 mg, 0.350 mmol) as a colorless oil in a yield of 85%.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.26-7.
31 (2H, m) 6.92-6.99 (3H, m) 6.10 (1H, d, J = 5.7 H
z) 5.09 (1H, br s) 4.69 (2H, br s) 4.46 (2H, br s)
4.28 (2H, m) 3.51 (2H, m) 2.71 (1H, m) 1.42 (9H, s) FAB-MS m / z (M + H) ⁺ 467

Compound (5) was prepared in the same manner as in Synthesis Example 2.
(65) was synthesized from 1).

[0391]

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[0392]

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Compound (51) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 1.46 (s, 9H, tC
₄ H ₉ ), 2.88 (t, 2H, J = 6.8 Hz, NHCH ₂ C H ₂ Ph), 3.5-3.9
(br, 2H + 2H, NHC H ₂ CH ₂ Ph, C H ₂ NHBOC), 4.66 (br, 1H,
C H (CO ₂ Me) CH ₂ NHBOC), 5.43 (br, 1H, N H ), 5.73 (s, 1
H, 5-H of pyrimidine), 5-6 (br, 1Hx2, NH x2), 7.19
-7.33 (m, 5H, arom H of Ph), 8.3 (br, 1H, CO ₂ H) MS (FAB) m / z 436 (M + H) ⁺

Compound (52) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 9.55 (1H, brs) 7.5
6 (1H, br s) 7.23-7.27 (2H, m) 6.88-6.95 (3H, m)
6.11 (1H, s) 5.35 (1H, br s) 4.67 (2H, m) 4.23 (2
H, m) 3.65 (2H, s) 1.37 (9H, s) FAB-MS m / z (M + H) ⁺ 453

Compound (53) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.19-7.37 (2H, m)
6.90-6.97 (2H, m) 6.09 (1H, s) 5.17 (1H, br s) 4.7
4 (2H, br s) 4.46 (1H, br s) 4.34 (2H, s) 3.54 (1H,
m) 3.45 (1H, m) 2.70 (2H, d, J = 4.9 Hz) 1.42 (9H,
s) FAB-MS m / z (M + H) ⁺ 501

Compound (54) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 8.27 (1H, brs) 7.8
6 (1H, br s) 7.37-7.19 (2H, m) 6.99-6.90 (2H, m)
6.09 (1H, d, J = 6.2 Hz) 5.29 (1H, br s) 4.78 (1H, b
rs) 4.73 (1H, br s) 4.45 (1H, br s) 4.36 (1H, m)
4.30 (1H, m) 3.56 (1H, dd, J = 7.5, 12.4 Hz) 3.44 (2
H, m) 2.69 (1H, dd, J = 5.3, 16.3 Hz) 2.63 (1H, dd,
J = 4.4, 16.1 Hz) 1.40 (9H, s) FAB-MS m / z (M + H) ⁺ 467

Compound (55) ¹ H-NMR (CDCl ₃ , rt, 60 MHz) δ 7.72 (1H, brs) 7.27
(2H, d, J = 9.0 Hz) 6.85 (2H, d, J = 9.0 Hz) 6.11 (1
(H, s) 5.16 (1H, br s) 4.63 (2H, m) 4.26 (3H, m) 3.
48 (2H, m) 2.72 (2H, m) 1.39 (9H, s)

Compound (56) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.26-7.30 (3H, m)
7.21 (1H, br s) 6.89-6.96 (2H, m) 6.03 (1H, s) 5.1
2 (1H, br s) 4.51 (2H, br s) 4.42 (1H, br s) 4.09
(2H, m) 3.46 (2H, br s) 2.68 (2H, dd, J = 5.8, 11.6)
2.22 (2H, m) 1.40 (9H, s)

Compound (57) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.24 (1H, brs) 7.1
0 (2H, d, J = 8.6 Hz) 6.83 (2H, d, J = 8.6 Hz) 6.03 (1
(H, s) 5.16 (1H, m) 4.39 (1H, m) 4.31 (2H, br s) 3.
78 (3H, s) 3.47 (2H, m) 2.68 (2H, m) 2.00 (2H, m)
1.41 (9H, s) FAB-MS m / z (M + H) ⁺ 496

Compound (59) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 10.9 (1H, brs) 7.2
6 (1H, br s) 7.09 (2H, d, J = 8.6 Hz) 6.82 (2H, d, J =
8.6 Hz) 5.99 (1H, s) 5.24 (1H, br s) 5.13 (1H, br)
s) 4.42 (1H, m) 4.30 (2H, br s) 3.71 (3H, s) 3.47
(2H, m) 2.68 (2H, d, J = 4.8 Hz) 2.60 (2H, m) 1.72 (4
H, br s) 1.40 (9H, s) FAB-MS m / z (M + H) ⁺ 509

Compound (60) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 9.49 (1H, brs) 7.2
3 (5H, s) 6.01 (1H, s) 5.24 (1H, br s) 4.29 (5H, s)
m) 3.46 (2H, m) 2.61 (2H, m) 1.71 (4H, m) 1.40 (9
H, s)

Compound (61) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.29-7.20 (5H, m)
6.04 (1H, s) 5.09 (1H, s) 4.38 (1H, m) 4.32 (2H,
m) 3.49 (2H, m) 2.72 (4H, m) 2.05 (2H, m) 2.74 (2H, m
m) 1.41 (9H, s)

Compound (62) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.27 (5H, m) 6.00
(1H, s) 5.20 (1H, br s) 4.52 (1H, br s) 4.46 (2H, s
br s) 3.48 (1H, m) 3.30 (2H, dd, J = 6.8, 13.5 Hz)
2.68 (2H, s) 1.39 (9H, s)

Compound (63) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.30-7.38 (5H, m)
7.18 (1H, br s) 6.09 (1H, s) 5.35 (2H, br s) 5.04
(1H, br s) 4.45 (1H, br s) 3.46 (2H, m) 2.66 (2H,
d, J = 4.9 Hz) 1.41 (9H, s)

Compound (64) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 1.45 (s, 9H, tC
_{4 H 9), 2.88 (t} , 2H, J = 7.1 Hz, NHCH 2 C H 2 Ph), 3.52-3.
63 (br, 2H + 2H, NHC H ₂ CH ₂ Ph, C H ₂ NHBOC), 4.75 (br, 1
H, C H (CO ₂ H) CH ₂ NHBOC), 5.03 (br, 3H, NH x3), 5.92
(s, 1H, 5-H of pyrimidine), 7.18-7.22 (m, 1H, para
H of Ph), 7.26-7.32 (m, 4H, ortho and meta H of P
h) MS (FAB) m / z 436 (M + H) ⁺

Compound (65) ¹ H-NMR (CD ₃ OD + CDCl ₃ , rt, 400 MHz) δ 1.40 (s, 9H,
tC ₄ H ₉ ), 2.54 (br, 2H, C H ₂ CO ₂ H), 2.87 (t, 2H, J =
7.0 Hz, NHCH ₂ CH ₂ Ph), 3.2-3.3 (br, 2H, CH ₂ NHBOC), 3.
60 (m, 2H, NHC H ₂ CH ₂ Ph), 3.7 (br, 1H, NH ), 4.4 (br,
1H, C H (CH ₂ CO ₂ H) CH ₂ NHBOC), 5.5-5.6 (br, 1H, N H ), 5.
8 (s, 1H, 5-H of pyrimidine), 7.20-7.23 (m, 3H, or
tho and para H of Ph), 7.27-7.31 (m, 2H, meta H of
Ph) MS (FAB) m / z 450 (M + H) ⁺

Synthesis Example 3 (S) -2- (4-Chloro-6- (2-phenylethylamino) pyrimidin-2-yl) amino-3-amino-propionic acid trifluoroacetate (Compound (66)) Synthesis of

Compound (51) 35 mg (0.080 mm
ol) was dissolved in 1 ml of trifluoroacetic acid and stirred at room temperature for 7.5 hours. After evaporating the solvent, compound (66) was added with 4
Obtained as 8 mg (quantitative) of brown amorphous.

¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 2.87
(t, 2H, J = 7.3 Hz, NHCH ₂ C H ₂ Ph), 3.46-3.64 (br, 2H +
_{2H, NHC H 2 CH 2 Ph} , C H 2 NH 2), 4.76 (m, 1H, C H (CO 2 H) CH 2 N
H ₂ ), 6.01 (s, 1H, 5-H of pyrimidine), 7.17-7.30
(m, 5H, arom H of Ph) MS (FAB) m / z 336 (M + H) ⁺

Compound (6) was prepared in the same manner as in Synthesis Example 3.
(80) was synthesized from 7). Data are shown below for the isolated ones of these compounds, but those not showing the data are used for the next reaction without isolation.

[0411]

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[0412]

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Compound (79) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 2.87 (t, 2H, J = 7.3)
Hz, NHCH ₂ C H ₂ Ph), 3.3-3.4 (br, NH ₂ ), 3.51-3.66 (b
r, 2H + 2H, NHC H ₂ CH ₂ Ph, C H ₂ NH ₂ ), 4.85 (dd, 1H, ₃ J _HH
= 5.0, 8.5 Hz, C H (CO ₂ H) CH ₂ NH ₂ ), 6.12 (s, 1H, 5-H o
f pyrimidine), 7.16-7.20 (m, 1H, para H of Ph), 7.
24-7.29 (m, 4H, ortho and meta H of Ph) MS (FAB) m / z 336 (M + H) ⁺

Compound (80) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 2.78 (m, 2H, CH ₂ CO ₂
H), 2.94 (m, 2H, NHCH ₂ C H ₂ Ph), 3.29-3.35 (m, 2H, C H
₂ NHBOC, NH ), 3.62-3.67 (m, 2H, NHC H H'CH ₂ Ph), 3.83
(m, 2H, NHCH H ' CH ₂ Ph), 4.89 (m, 1H, C H (CH ₂ CO ₂ H) CH ₂ NH
BOC), 5.17 (s, 2H, NH ₂ ), 6.21 (s, 1H, 5-H of pyrim
idine), 7.19-7.29 (m, 5H + 1H, arom H of Ph, NH), 8.
33 (br, 1H, CO ₂ H ) MS (FAB) m / z 350 (M + H) ⁺

Synthesis Example 4 (R) -3- (4-Chloro-6- (2-phenoxyethoxy) pyrimidine
Synthesis of 2--2-yl) amino-4-trimethylammonium-butyric acid inner salt (compound (81))

Compound (50) (160) synthesized in Synthesis Example 2
mg, 0.343 mmol), and TFA (3 ml) was added thereto, followed by stirring at room temperature for 10 minutes. The solvent was distilled off from the reaction solution to obtain a residue (287 mg). A 10% NaOH aqueous solution (3 ml), Me ₂ SO ₄ (146 μl, 1.
54 mmol) and stirred at room temperature for 16 hours. Evaporate the solvent,
The residue was subjected to column chromatography (CHCl ₃ : MeOH: NH ₃ aq =
5: 1: 0.1) to give Compound (81) (72 mg, 0.176 mmo
l) as a colorless oil in 52% yield.

¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.25-7.
29 (2H, m) 6.93 (3H, dd, J = 7.3, 14.6 Hz) 6.18 (1H,
s) 4.72 (1H, br s) 4.60 (2H, br s) 4.28 (2H, br)
s) 3.69 (1H, br s) 3.60 (1H, d, J = 12.3 Hz) 3.21 (9
H, s) 2.54 (2H, d, J = 5.5 Hz) FD-MS m / z (M + H) ⁺ 409

Compound (92) was synthesized from compound (82) in the same manner as in Synthesis Example 4.

[0419]

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Compound (82) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.33-7.35 (1H, m)
7.24-7.28 (1H, m) 7.10 (1H, br s) 6.91-6.95 (1H, m)
6.12 (1H, s) 4.80 (2H, br s) 4.68 (1H, br s) 4.37
(2H, br s) 3.70 (2H, s) 3.25 (9H, s) 2.61 (2H, d, J
= 6.2 Hz) FD-MS m / z (M + H) ⁺ 443

Compound (83) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.25 (2H, d, J = 8.4)
Hz) 6.93 (2H, d, J = 8.4 Hz) 6.19 (1H, s) 4.63 (2H, b
rs) 4.28 (2H, br s) 3.79 (1H, br s) 3.65 (2H, m)
3.26 (9H, s) 2.64 (2H, d, J = 6.2 Hz) FAB-MS m / z (M + H) ⁺ 443

Compound (84) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.24-7.28 (2H, m)
6.89-6.93 (3H, m) 6.15 (1H, s) 4.49 (2H, br s) 4.1
0 (2H, br s) 3.82 (1H, br s) 3.71 (3H, s) 3.25 (9H,
s) 2.65 (2H, m) 2.20 (2H, m) FAB-MS m / z (M + H) ⁺ 421

Compound (85) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.09 (2H, br s) 6.8
4 (2H, d, J = 8.4 Hz) 6.12 (1H, s) 4.37 (1H, br s)
4.24 (1H, br s) 3.75 (3H, s) 3.66 (1H, br s) 3.65
(2H, m) 3.20 (9H, s) 2.67 (2H, br s) 2.50 (2H, J =
5.5 Hz) 2.00 (2H, br s) FAB-MS m / z (M + H) ⁺ 438

Compound (87) mp 101-106 ° C. ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.08 (2H, d, J = 8.5)
Hz) 6.81 (2H, d, J = 8.5 Hz) 6.12 (1H, s) 4.38 (1H, b
rs) 4.30 (2H, br s) 3.75 (3H, s) 3.61 (1H, br d,
J = 13.4 Hz) 3.24 (9H, s) 2.61 (4H, m) 1.79 (4H, br
s) FAB-MS m / z (M + H) ⁺ 451

Compound (88) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.13-7.27 (5H, s)
6.13 (1H, s) 4.31 (4H, br s) 3.81 (1H, br s) 3.69
(1H, s) 3.63 (1H, d, J = 13.5 Hz) 3.25 (9H, s) 2.64
(2H, m) 1.74 (4H, br s)

Compound (89) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.29-7.15 (5H, m)
6.14 (1H, s) 4.27 (2H, br s) 3.79 (1H, br s) 3.62
(2H, d, J = 13.6 Hz) 3.14 (9H, s) 2.74 (2H, br s) 2.
59 (2H, d, J = 5.6 Hz) 2.05 (2H, br s) FAB-MS m / z (M + H) ⁺ 407

Compound (90) mp 121-127 ° C. ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.19-7.28 (5H, m)
6.09 (1H, s) 4.63 (1H, br s) 4.49 (2H, br s) 3.79
(1H, br s) 3.62 (1H, d, J = 12.4 Hz) 3.35 (1H, s)
3.24 (9H, s) 3.03 (2H, br s) 2.63 (2H, d, J = 6.4 H
z) FAB-MS m / z (M + H) ⁺ 393

Compound (91) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.32 (5H, m) 6.21
(1H, s) 5.41 (2H, m) 3.58 (2H, m) 3.23 (3H, br s)
3.10 (6H, br s) 2.58 (2H, br s) FAB-MS m / z (M + H) ⁺ 379

Compound (92) ¹ H-NMR (CD ₃ OD, rt, 400 MHz) δ 7.13-7.48 (5H, m)
6.34 (1H, s) 4.52 (1H, br s) 3.59 (2H, m) 3.22 (3
H, br s) 2.69 (6H, br s) 2.50 (2H, m) FAB-MS m / z (M + H) ⁺ 365

Synthesis Example 5 (R) -3- (4-Chloro-6- (2-phenoxyethoxy) pyrimidine
Synthesis of methyl -2-yl) amino-4-amino-butyrate trifluoroacetate (Compound (93))

The compound (34) synthesized in Synthesis Example 1 (47 m
g, 0.0977 mmol) in a TFA solution (1 ml) was stirred at room temperature for 15 minutes. The solvent was distilled off from the reaction solution to give compound (93) (55 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 8.56 (1
(H, br s) 8.01 (2H, br s) 7.26-7.30 (2H, m) 6.89-6.
99 (3H, m) 6.23 (1H, s) 4.76 (1H, br s) 4.68 (1H,
br s) 4.28 (2H, s) 3.66 (3H, s) 3.43 (2H, br s) 2.
79 (2H, s) FAB-MS m / z (M + H) ⁺ 381

Compound (101) was synthesized from compound (94) in the same manner as in Synthesis Example 5.

[0434]

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Compound (94) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.76 (2H, brs) 7.2
6-7.31 (2H, m) 6.99 (1H, dd, J = 7.3, 14.6Hz) 6.88
(2H, d, J = 7.9 Hz) 6.41 (1H, s) 5.02 (1H, m) 4.70
(2H, m) 4.29 (2H, m) 3.79 (3H, s) 3.66 (1H, m) 3.5
3 (2H, s) FAB-MS m / z (M + H) ⁺ 367

Compound (95) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 8.41 (2H, s) 7.17-
7.34 (2H, m) 6.88-6.96 (2H, m) 6.03 (1H, s) 4.67
(2H, m) 4.31 (2H, s) 3.62 (3H, s) 3.46 (1H, m) 2.8
8 (1H, m) 2.79 (1H, m) FAB-MS m / z (M + H) ⁺ 415

Compound (96) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 8.15 (1H, m) 7.35 (1
H, dd, J = 1.3,7.8Hz) 7.28 (1H, dd, J = 7.8,15.6Hz) 6.9
5 (2H, dd, J = 7.1,14.2Hz) 6.57 (1H, m) 4.48 (2H, s) 4.
40 (1H, brs) 3.69 (3H, s) 3.37 (1H, s) 2.91 (1H, m)

Compound (97) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.22 (2H, d, J = 8.8
Hz) 6.84 (2H, d, J = 8.8 Hz) 6.02 (1H, s) 4.59 (3H,
m) 4.21 (2H, m) 3.62 (3H, s) 3.27 (2H, m) 2.76 (2
H, m)

Compound (98) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 9.04 (1H, br s) 7.7
2 (2H, br s) 7.09 (2H, d, J = 8.6 Hz) 6.84 (2H, d, J
= 8.6 Hz) 6.30 (1H, s) 4.78 (1H, br s) 4.45 (1H, br
s) 4.40 (1H, br s) 3.79 (3H, s) 3.48 (3H, s) 2.81
(2H, d, J = 3.3 Hz) 2.68 (2H, m) 2.06 (2H, m) FAB-MS m / z (M + H) ⁺ 409

Compound (100) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 8.36 (2H, brs) 7.9
1 (1H, br s) 7.10 (2H, d, J = 6.2 Hz) 6.82 (2H, d, J =
7.3 Hz) 6.02 (1H, s) 4.81 (2H, br s) 4.38 (2H, br)
s) 3.78 (3H, s) 3.63 (3H, s) 3.06 (1H, br s) 2.85
(1H, br s) 2.60 (2H, s) 1.73 (4H, s) FAB-MS m / z (M + H) ⁺ 422

Compound (101) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.17-7.30 (5H, s)
6.63 (1H, br s) 6.06 (1H, s) 4.61 (1H, br s) 4.46
(1H, br s) 4.24 (3H, m) 3.63 (3H, s) 3.15 (2H, br)
s) 2.66 (2H, m) 1.74 (4H, m)

Synthesis Example 6 Methyl (S) -2- (4-chloro-2- (2-phenylethylamino) pyrimidin-6-yl) amino-3-amino-propionate trifluoroacetate (compound (102) ) Synthesis

Compound (48) 46 mg (0.10 mmol
From l), Compound (102) was obtained as a brown solid (56 mg, quantitative) in the same manner as in Synthesis Example 5.

¹ H-NMR (CD ₃ OD + CDCl ₃ , rt, 400 MHz) δ
2.87 (t, 2H, J = 7.5 Hz, NHCH ₂ C H ₂ Ph), 3.45-3.55 (m,
2H, C H ₂ NHBOC), 3.59 (m, 2H, NHC H ₂ CH ₂ Ph), 3.74 (s, 3
H, CO ₂ C H ₃ ), 4.0 (br, 2H, NH x2), 4.86 (dd, 1H, J = 8.
2, 4.9 Hz, C H ( CO 2 Me) CH 2 NHBOC), 6.13 (s, 1H, 5-H of
pyrimidine), 7.22-7.23 (m, 3H, ortho and para H o
f Ph), 7.28-7.32 (m, 2H, meta H ofPh) MS (FAB) m / z 350 (M + H) ⁺

Synthesis Example 7 (R) -3- (4- (3- (4-methoxyphenyl) propoxy) pyrimidin-2-yl) amino-4-tert-butoxycarbonylamino
Synthesis of methyl-butyrate (compound (103))

To a methanol solution (5 ml) of compound (40) (106 mg, 0.208 mmol) was added 10% Pd-C (11 mg).
The mixture was stirred at room temperature under a hydrogen atmosphere for 52 hours. After the reaction solution was filtered, the solvent was distilled off, and the residue was subjected to thin layer chromatography (Hexa
ne: EtOAc = 1: 1) to give compound (103) (36 mg, 0.
0748 mmol) as a colorless oil in a yield of 36%.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.99 (1
H, d, J = 5.7 Hz) 7.12 (2H, d, J = 8.8 Hz) 6.84 (2H,
d, J = 8.8 Hz) 6.03 (1H, d, J = 5.7 Hz) 5.65 (1H, br s)
5.02 (1H, s) 4.42 (1H, m) 4.26 (2H, m) 3.79 (3H,
s) 3.67 (3H, s) 3.39 (2H, dd, J = 5.9, 11.8 Hz) 2.6
9 (2H, m) 2.60 (2H, dd, J = 6.4, 9.3 Hz) 2.01 (2H, m
m) 1.41 (9H, s) FAB-MS m / z (M + H) ⁺ 474

Compound (109) was synthesized from compound (108) in the same manner as in Synthesis Example 7.

[0449]

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Compound (108) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 8.03 (1H, d, J = 5.5)
Hz) 7.22-7.34 (2H, m) 7.90 (1H, d, J = 8.2 Hz) 6.90-
6.94 (1H, m) 6.15 (1H, d, J = 5.5 Hz) 4.97 (1H, m)
4.71 (2H, br s) 4.36 (2H, t, J = 4.2 Hz) 3.70 (1H,
m) 3.58 (1H, d, J = 13.5 Hz) 3.20 (9H, s) 2.52 (2H,
m) FAB-MS (m / z) (M + H) ⁺ 409

Compound (109) ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 8.07 (1H, brs) 7.4
1 (2H, br s) 7.26 (1H, s) 6.92 (2H, s) 6.25 (1H, b
rs) 4.57 (2H, br s) 4.13 (2H, br s) 3.87 (1H, br
s) 3.69 (2H, s) 3.26 (9H, s) 2.75 (2H, s) 2.25 (2
H, br s) FAB-MS (m / z) (M + H) ⁺ 389

Synthesis Example 8 Methyl 2- (4- (2,6-dichloropyrimidin-4-yl) amino-1-benzyloxycarbonyl-piperidin-4-yl) acetate (Compound (104)) and 2- (4 Synthesis of Methyl-(4,6-dichloropyrimidin-2-yl) amino-1-benzyloxycarbonyl-piperidin-4-yl) acetate (Compound (105))

2,4,6-Trichloropyrimidine (10.4 g, 5
Compound (10) (17.4) was added to a DMPU solution (25 ml) of 6.60 mmol).
g, 56.70 mmol) and diisopropylethylamine (19.
8 ml, 113.4 mmol) and stirred at 100 ° C. for 5 hours. The reaction solution was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous ammonium chloride, and saturated saline, and the solvent was distilled off.The residue (33.7 g)
I got This was subjected to column chromatography (hexane:
The resulting crude product was washed with hexane and ethyl acetate, and the compound (104) (9.25 g,
20.40 mmol) as a pale yellow powder in 36% yield. In addition, compound (105) which is an isomer (3.69 g, 8.142 mm
ol) was also obtained as a pale yellow powder in a yield of 14%.

Compound (104) mp 153-158 ° C. ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.21-7.34 (5H, m),
7.07 (1H, s), 6.62 (1H, s), 5.12 (2H, s), 3.90 (2H, b
rs), 3.58 (3H, s), 3.19 (2H, br s), 2.99 (2H, m), 2.49
(2H, br s), 1.69 (2H, m)

Compound (105) mp 105-109 ° C. ¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.20-7.35, (5H, m),
6.62 (1H, s), 5.69 (1H, s), 5.13 (2H, s), 3.91 (2H, b
rs), 3.60 (3H, s), 3.18 (2H, m), 2.97 (2H, s), 2.43 (2
H, d, J = 13.7 Hz), 1.70 (2H, m)

Synthesis Example 9 2- (4- (6-chloro-2- (2-phenoxyethoxy) pyrimidine-
Synthesis of 4-yl) amino-1-benzyloxycarbonyl-piperidin-4-yl) acetic acid (compound (106))

To a solution of NaH (22 mg, 0.5593 mmol) in acetonitrile (2 ml) was added 2-phenoxyethanol (71 mg, 0.5163 mmol).
(2 mmol) in acetonitrile and stirred at room temperature for 15 minutes, after which the compound (104) (195 mg, 0.4303 mmol) was added.
Acetonitrile solution (2 ml) was added and the mixture was stirred at the same temperature for 19 hours. The reaction solution was diluted with ethyl acetate, washed with water, and the solvent was distilled off.
A residue (177 mg) was obtained. This is column chromatography
(Hexane: ethyl acetate = 2: 1) to give the compound (10
6) Yield (41.4 mg, 0.07652 mmol) as a colorless oil
Obtained at 18%.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.23-7.
36 (7H, m) 6.89-7.00 (3H, m) 6.11 (1H, s) 5.50 (1
(H, s) 5.11 (2H, s) 4.57 (2H, m) 4.25 (2H, m) 3.83
(2H, br s) 3.14 (2H, t, J = 11.5 Hz) 3.03 (1H, br s)
2.91 (1H, br s) 2.47 (1H, br s) 2.38 (1H, br s) 1.
67 (2H, m) FAB-MS (m / z) (M + H) ⁺ 541

Synthesis Example 10 2- (4- (4-chloro-6- (2-phenoxyethoxy) pyrimidine-
Synthesis of methyl 2-yl) amino-1-benzyloxycarbonyl-piperidin-4-yl) acetate (Compound (107))

To a solution of NaH (18 mg, 0.4446 mmol) in acetonitrile (2 ml) was added 2-phenoxyethanol (57 mg, 0.4104 mmol).
mmol) in acetonitrile (2 ml) and stirred at room temperature for 15 minutes, after which compound (105) (155 mg, 0.3420 mmol)
Was added and the mixture was stirred at the same temperature for 16.5 hours. The reaction solution was diluted with ethyl acetate, washed with water and the solvent was distilled off to obtain a residue (219 mg). This was purified by thin-layer chromatography (hexane: ethyl acetate = 1: 1) to give the compound (10
7) Yield (41.4 mg, 0.07652 mmol) as a colorless oil
Obtained at 25%.

¹ H-NMR (CDCl ₃ , rt, 400 MHz) δ 7.26-7.
36 (7H, m) 6.90-6.99 (3H, m) 6.14 (1H, s) 5.20 (1
H, br s) 5.12 (2H, s) 4.59 (2H, m) 4.26 (2H, t, J =
4.8 Hz) 3.93 (2H, br s) 3.59 (3H, s) 3.19 (2H, m)
2.96 (2H, s) 2.43 (2H, t, J = 13.5 Hz) 1.69 (2H, t,
J = 10.8Hz) FAB-MS (m / z) (M + H) ⁺ 555

Synthesis Example 11 2- (4- (4-Chloro-6- (2-phenoxyethoxy) piperidin-2-yl) amino-1-benzyloxycarbonylpiperidin-4-yl) acetic acid (of compound (110)) Composition)

Ice-cooled sodium hydride (60% oil disp
ersion, 111 mg, 2.33 mmol) in acetonitrile
(30 ml) in phenoxyethanol (359 ml, 2.79 mmol)
Was added and stirred for 40 minutes. Compound (105) under ice cooling
(1.03 g, 2.33 mmol) was added to the reaction mixture, and the mixture was stirred for 10 hours while slowly warming to room temperature. After ice cooling,
To the reaction mixture were added a saturated aqueous ammonium chloride solution (20 ml) and water (10 ml), and the mixture was diluted with ethyl acetate (10 ml).
After separating the organic phase, the aqueous phase was extracted with ethyl acetate (10 ml), and the collected organic phases were washed with saturated saline and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (4 ml), 1 M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 14 hours. A 10% aqueous citric acid solution was added until the reaction solution became acidic, and the mixture was extracted with ethyl acetate (30 ml). The collected organic phases were washed with saturated sodium chloride and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained oil was purified by column chromatography (25% methanol-chloroform) to give compound (110) (802 mg, 1.48 mol)
Was obtained as a colorless powder in a yield of 63%.

Mp 157.1-157.8 ° C. ¹ H-NMR ((CD ₃ ) ₂ SO, rt, 400 MHz) δ 12.02 (1H, s) 7.
54 (1H, brs) 7.25-7.41 (5H, m) 6.91-6.97 (2H, m)
6.22 (1H, s) 5.06 (2H, s) 4.56-4.61 (2H, m) 4.26-4.
31 (2H, m) 3.72 (2H, brd, J = 14.4 Hz) 3.12 (2H, br
s) 2.83 (2H, s) 2.40 (2H, d, J = 14.4 Hz) 1.57-1.6
7 (2H, m) EI-MS m / z 539 (MH) ⁺

Synthesis Example 12 Synthesis of inner salt of 2- (4- (4- (2-phenoxyethoxy) piperidin-2-yl) amino-1,1-dimethylpiperidin-4-yl) acetic acid (compound (111)) )

Compound (110) (301 mg, 0.556 mmol)
10% palladium-carbon (3 ml) in methanol solution (20 ml)
2.1 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 14 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (20 ml), and 10% palladium-carbon (32.1 mg) was added.
Stirred for hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in aqueous sodium hydroxide solution (5 ml), and dimethyl sulfate (260 ml, 2.75 m
mol) was added. After stirring at room temperature for 3 hours, 1 M hydrochloric acid was added dropwise until the reaction solution became neutral. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography.
(Chloroform / methanol / aqueous ammonia solution = 3/1
/0.1) to give compound (111) (181 mg, 0.452 mmo
l) was obtained as a colorless powder in a yield of 81%.

Mp 232.0-233.1 ° C. ¹ H-NMR ((CD ₃ ) ₂ SO, rt, 400 MHz) δ 8.05 (1H, d, J =
5.6 Hz) 7.30 (2H, brt, J = 8.0 Hz) 6.92-7.00 (3H,
m) 6.09 (1H, d, J = 5.6 Hz) 4.51-4.55 (2H, m) 4.26-
4.30 (2H, m) 3.28-3.47 (6H, m) 3.21 (3H, s) 3.15 (3
(H, s) 2.94-3.16 (2H, m) 2.35 (2H, s) FAB-MS m / z 401 (M + H) ⁺

Test Example 1 CPT Inhibitory Activity 1 (Preparation of Mitochondria) A 6-week-old male ddY mouse was fasted overnight, and then 150 mg of streptozotocin (STZ; Sigma) dissolved in 3 mM citrate buffer (pH 4.5). / kg Intraperitoneal administration, use blood glucose of 300 mg / dl or more.
When rats are used, the normal blood glucose level of 6
Weekly male SD rats are used.

Liver mitochondria were obtained according to the method of McGarry et al.
Biol. Chem., Vol. 253, 4128-4136, 1978) was modified as follows. That is, mouse liver was homogenized in a 0.25 M sucrose solution (25 ml buffer / 10 g tissue) and centrifuged at 600 × g. The obtained supernatant fraction was centrifuged at 7,700 × g, and the obtained sediment was again resuspended in a 0.25 M sucrose solution and then centrifuged again at 7,700 × g. 0.15 M KCl, 5 mM Tris-H
It was resuspended in Cl (pH 7.2) to give a mitochondrial preparation. All operations were performed at 4 ° C. The mitochondrial preparation obtained above was used in experiments as a CPT enzyme source.

(Measurement of CPT activity) CPT activity was determined to be 5,5-L-dithiobi
s-L2-nitrobenzoil acid (DTNB) method (diabetes research strategy, 342-343) method modified as follows, namely free CoA and DTNB generated when CPT was acted on in the presence of palmitoyl-CoA and carnitine Was measured by the change in absorbance at 412 nm. The assay consists of a mitochondrial suspension and various concentrations of the test compound, 0.1 mM DTNB, 12.
5 mg / ml bovine serum albumin, 5 mM MgCl ₂ , 0.5 mM EDT
A, was performed in 50 mM Tris-HCl buffer (pH 7.4) containing 0.1 mM palmitoyl-CoA. The reaction was started at 25 ° C. by addition of the substrate L-carnitine (final concentration 1.6 mM), and the reaction rate was measured for 1 minute. A standard blank contains all of the above compounds except L-carnitine. The evaluation compound was dissolved in dimethyl sulfoxide (DMSO), and the final concentration of the DMSO in the reaction mixture did not exceed 1%. The test results are shown in Table 10.

Table 10

[0472]

[Table 142] ───────────────────────── Compound No. concentration (μM) Inhibition rate (%) ───────── {81 30 35.6 34 30 53.4 103 30 41.4 87 30 35.7} ───────────

Test Example 2 CPT Inhibitory Activity 2 (Method for Preparing Rat Liver Mitochondria) Rat liver mitochondria were prepared according to the method of McGarry et al. (J. Biol. Chem., Vol. 253,
4128-4136, 1978) by the following modified method. Rat liver was minced with scissors and homogenized in a 10-fold volume of a 0.25 M sucrose solution.
Centrifuged for 5 minutes. The resulting supernatant fraction was collected at 7,700 xg for 1
Centrifuge for 5 minutes.
After resuspending in M sucrose solution, it was centrifuged again at 7,700 xg for 15 minutes. The obtained precipitate is washed with 150 mM KCl, 5 mM Tris
The suspension was resuspended in -HCl (pH 7.2) to prepare a mitochondrial preparation. All operations were performed at 4 ° C.

(Measurement of CPT I activity) The CPT I activity was measured by the method of McGarry et al. (Biochem. J., vol. 214, 21-28, 1983) as follows, ie, in the presence of palmitoyl-CoA and carnitine. It was measured from the rate of formation of palmitoylcarnitine upon the action of CPTI. The reaction was performed in an 80 μl incubation buffer (131.2
5 mM Tris-HCl, 0.31 mM reduced glutathione, 5 mM A
TP, 5 mM MgCl ₂ , 18.75 mM KCl, 2.5 mM KCN, 0.005% r
otenone, 1.25% BSA (FFA free), 62.5 μM palmitoyl-Co
A, 250 μM L-carnitine), 1 μl of compound to be evaluated at various concentrations, and 10 μl of L- [methyl- ¹⁴ C] carnitine (0.2 μCi)
To 10 μl of the mitocontroller suspension (0.02-0.05 m
g protein / 10 μl). 30 ℃
After incubation for 10 minutes at, the reaction was terminated by adding 100 μl of 1.2 M HCl. To this was added 100 μl of phthalanol, shaken vigorously, and centrifuged. Of the obtained ethanol layer
50 μl was transferred to another tube previously containing 50 μl of water-saturated phenol, shaken vigorously again, and then centrifuged. 20 μl of the obtained phenol layer was collected and its radioactivity was measured with a liquid scintillation counter. The evaluation compound was dissolved in permethylsulfoxide (DMSO), and the final concentration of DMSO in the reaction mixture did not exceed 1%. The effect of the inhibitory activity was evaluated as the concentration (IC ₅₀ ) that inhibited the enzyme activity by 50%.

Test Example 3 Blood glucose lowering activity ddY mice (male, 5 weeks old) were obtained from SLC Japan. Preliminary rearing for at least one week under free-feeding and water-feeding conditions was used for the experiment. After an overnight fast, streptozotocin was administered intraperitoneally at 150 mg / kg. Blood sugar> 300 mg
Those with / dl were judged as diabetes and subjected to the experiment.

The diabetic model mice were fasted overnight, loaded with olive oil by oral gavage, and immediately after administration of the test compound. Blood was collected from the fundus before and 6 hours after administration of the test compound, and the blood glucose level was measured.

The test compound was suspended in 0.5% carboxymethylcellulose (CMC) physiological saline and orally administered by gavage.
The blood glucose level was determined by collecting 20 μl of blood from the fundus, diluting with 60 units of sodium heparin, centrifuging, and measuring glucose in the supernatant by glucose oxidase method. The blood glucose lowering activity was shown by a reduction rate with respect to the control group.

Formulation Example 1 Tablets Compound of the present invention 1.0 g Lactose 5.0 g Microcrystalline cellulose 8.0 g Corn starch 3.0 g Hydroxypropyl cellulose 1.0 g CMC-Ca 1.5 g Magnesium stearate 0.5 g Total amount 20 After mixing the above ingredients in a conventional manner, 100 sugar-coated tablets each containing 10 mg of the active ingredient are produced.

Formulation Example 2 Capsule Compound of the present invention 1.0 g Lactose 3.5 g Microcrystalline cellulose 10.0 g Magnesium stearate 0.5 g Total amount 15.0 g After mixing the above ingredients by a conventional method, the mixture was mixed into a No. 4 gelatin capsule. Fill to make 100 capsules containing 10 mg of active ingredient in one capsule.

Formulation Example 3 Soft Capsule Compound of the present invention 1.00 g PEG400 3.89 g Saturated fatty acid triglyceride 15.00 g Mentha oil 0.01 g Polysorbate 80 0.10 g Total amount 20.00 g No. 3 soft gelatin capsules are filled by the method to produce 100 capsules of soft capsules containing 10 mg of the active ingredient in one capsule.

Formulation Example 4 Ointment Compound of the present invention 1.0 g (10.0 g) Liquid paraffin 10.0 g (10.0 g) Cetanol 20.0 g (20.0 g) White petrolatum 68.4 g (59.4 g) Ethyl paraben 0.1 g (0.1 g) 1-menthol 0.5 g (0.5 g) Total amount 100.0 g The above components are mixed by a conventional method to prepare a 1% (10%) ointment.

Formulation Example 5 Suppository Compound of the present invention 1.0 g Witepsol H15 * 46.9 g Witepsol W35 * 52.0 g Polysorbate 80 0.1 g Total amount 100.0 g "* Trademark of triglyceride compound Name Witepsol = Witepsol 1 g of suppository 1 containing 10 mg of active ingredient, melt-mixed in a conventional manner, poured into a suppository container, solidified by cooling and
00 pieces are manufactured.

Formulation Example 6 Granules Compound of the present invention 1.0 g Lactose 6.0 g Microcrystalline cellulose 6.5 g Corn starch 5.0 g Hydroxypropyl cellulose 1.0 g Magnesium stearate 0.5 g Total amount 20.0 g Granulate according to the method and pack 200 mg into 100 packets to contain 10 mg of the active ingredient.

[0484]

The compound of the present invention has a glycemic effect, a CPT inhibitory activity, and low toxicity, so that it has diabetic ophthalmopathy, diabetic neuropathy, diabetic nephropathy, diabetic necrosis and the like. It is useful as a prophylactic or therapeutic drug for complications.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/495 603 A61K 31/495 603 31/50 601 31/50 601 31/505 601 31/505 601 31 / 53 31/53 C07D 213/64 C07D 213/64 213/74 213/74 239/42 239/42 Z 239/47 239/47 239/48 239/48 239/52 239/52 239/54 251/16 C 251/16 251/22 C 251/22 401/12 401/12 401/14 401/14 403/12 403/12 405/12 405/12 405/14 405/14 409/12 409/12 409/14 409/14 413/12 413/12 413/14 413/14 417/12 417/12 417/14 417/14 239/55 (72) Inventor Hiromitsu Matsumoto 722 Tsuboi-cho, Funabashi-shi, Chiba 1 Nissan Chemical Industrial Co., Ltd. (72) Inventor Koji Toyama 722-1, Tsuboi-cho, Funabashi-shi, Chiba Prefecture Nissan Chemical Industry Co., Ltd.Central Research Laboratory (72) Inventor Maki Kitahara Minami-Saitama-gun, Saitama 1470, Shiraoka, Okamachi, Nissan Chemical Industry Co., Ltd.Biological Science Research Laboratory (72) Inventor Takashi Yomoto, 1470, Shirooka, Shirookamachi, Minamisaitama-gun, Saitama Prefecture Nissan Chemical Industry Co., Ltd.Bioscience Research Institute F term (reference) 4C055 AA01 BA02 BA03 BA39 BA39 BA42 BA52 BB01 BB02 BB03 BB07 BB10 BB11 CA01 DA01 DA05 DA06 DA39 DA42 DB01 DB02 DB07 DB08 DB10 4C063 AA01 AA03 BB08 BB09 CC12 CC22 CC29 CC34 CC44 CC51 CC52 CC62 CC75 CC92 DD04 DD10 DD25 DD28 DD29 EE01 4C086 A03 BC31 BC BC69 BC82 GA02 GA04 GA07 GA08 GA09 GA10 MA01 MA04 NA14 ZA33 ZA81 ZC20 ZC35

Claims (12)

[Claims] 1. A compound of the formula [I][Wherein, A is｛M, n, n¹And n^TwoAre independently 0, 1, 2,
Or 3 for R¹Is hydrogen, halogen, nitro
Group, cyano group, formyl group, sulfonic acid group, sulfonic acid
Amide group, PO_TwoH_Two, PO_ThreeH_Two, 5-tetrazolyl group, C (O) OR⁶
(R⁶Is a hydrogen atom, or C_1-7Represents an alkyl group. ), C (O)
NR⁷R^{7 '}(R⁷And R^{7 '}Are each independently a hydrogen atom, or C
_1-7Represents an alkyl group. ), OR⁸(R⁸Is a hydrogen atom, C_1-7A
Represents a alkyl group or a phenyl group. ) Or NR⁹R^{9 '}(R⁹
And R^{9 '}Are each independently a hydrogen atom, C_1-7Alkyl
Represents a phenyl group or a phenyl group. ), And R^TwoIs a hydrogen atom,
Halogen atom, nitro group, cyano group, formyl group, guar
Nidyl group, amidino group, NR^TenR^Ten'(R^TenAnd R^Ten'Is it
Each independently a hydrogen atom, C_1-7Alkyl group, C_1-7Aliphatic
Sill, C_6-10Represents an aromatic acyl or a protecting group. ),or
Is N⁺R¹¹R^{11 '}R^{11 ''}(R¹¹, R^{11 '}And R^{11 ''}Are independent
Then C_1-7Represents an alkyl group. ), And R^ThreeAnd R ^{3 '}Haso
Each independently C_1-7Represents an alkyl group, R^FourIs a hydrogen atom,
C_1-7Alkyl group, C_1-7Aliphatic acyl, C_6-10Aromatic reed
Or a protecting group. Represents｝. D is a covalent bond, -C
H_Two-, -O-, -S-, -S (O)-, -S (O)_Two-, -NR¹²-, -C (O) -NR¹²
-, -NR¹²-C (O)-or -NR¹²-C (O) -NR^{12 '}-(R¹²And R
^{12 '}Are each independently a hydrogen atom, or C_1-7Alkyl group
Represents ). X¹, X^Two, X^Three, X^Four, And X^FiveIs
Each independently a nitrogen atom or CR^Five｛R^FiveIs hydrogen field
, A halogen atom, or -EG (E is -L¹-(CR¹³R^13')_k-
L^Two-(CR¹⁴R^14')_l-L^Three-(K represents 1 to 10. l is 0 to 10.
Represents R¹³, R^13', R¹⁴, And R^14'Are independent of each other
Hydrogen atom, halogen atom, hydroxyl group, C_1-7Al
Kill group or C_1-7Represents an alkoxy group. L¹, L^Two, And L^Three
Are each independently a covalent bond, -O-, -S-, -S (O)-, -S
(O)_Two-, -C (O)-, -C≡C-, -CR^Fifteen= CR^{15 '}-, -NR^Fifteen-, -NR
^Fifteen-C (O)-, -C (O) -NR^Fifteen-Or -NR^Fifteen-C (O) -NR^{15 '}-(R^Fifteen
And R^{15 '}Are each independently a hydrogen atom, C_1-7Alkyl
Group or C_6-14Represents an aromatic group. ). ).
G is a hydrogen atom, C_1-12Heterocyclic aromatic group (the heterocyclic aromatic group
The group is selected from oxygen, sulfur and nitrogen
Up to five heteroatoms as ring constituents
May be. ), C_1-6A heteroalicyclic group (the heteroalicyclic group
Is selected from oxygen, sulfur and nitrogen
Contains up to three heteroatoms as ring members
You may. ), C_3-10Cycloalkyl group, C_3-7Cycloa
Lucenyl group or C_6-14Aromatic group (C_1-12Heterocyclic aromatic
Group, C_1-6Heteroalicyclic group, C_3-10Cycloalkyl group, C_3-7
Cycloalkenyl group and C_6-145 or more aromatic groups
(Wherein the substituent is a hydrogen atom, C_1-7Alkyl group, C
_3-7Cycloalkyl group, C_3-7A cycloalkenyl group,
Alkyl, cycloalkyl and cycloalkenyl groups
May be substituted by a hydroxyl group. ), Hydroxyl, C
_1-7Alkoxy group, C_1-7Alkylthio group, halogen source
Child, trifluoromethyl group, nitro group, amino group, methyl
Amino group, dimethylamino group, acetamido group, meta
Sulfonylamide group, carboxyl group, C_1-3Alkoki
Cicarbonyl group, nitrile group, carbamoyl group, sulf
Amamoyl group, phenoxy group, benzyloxy group, tri-C
_1-7Alkylsilyloxy group, phenyl, naphthyl, phenyl
Ril, thienyl, imidazolyl, pyridyl, benzyl
(The phenyl, naphthyl, furyl, thienyl, imidazo
Ryl, pyridyl and benzyl are all C_1-7Archi
Group, C_3-7Cycloalkyl group, C_1-3Alkoxy group, C_1-3
Alkylthio group, hydroxyl group, halogen atom, nitro group or
Even when substituted with up to 5 dimethylamino groups
Good. ). ) May be included. ). )
Represents Represents｝. Where X¹To X^FiveAt least one of
Represents a nitrogen atom. 6-membered heterocyclic ring represented by
Is its salt. 2. The C _3-10 cycloalkyl group represented by G is cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl or adamantyl, or C
_{The 3-7} cycloalkenyl group is cyclohexenyl, cyclopentadienyl, 2-bicyclo [2.2.1] heptenyl or 2,5-bicyclo [2.2.1] heptadienyl, or a C _6-14 aromatic group; Group is phenyl, naphthyl, indenyl, indanyl or fluorenyl, C
_1-12 heterocyclic aromatic group is furyl, thienyl, pyrrolyl,
Oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, flazanil, pyrazolyl, oxopyrazolyl, imidazolyl, oxoimidazolyl, triazolyl, triazolonyl, tetrazolyl, pyranyl, pyridyl, pyridonyl, pyridazinyl, pyridazinyl, pyrimidinyl, pyrimidinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl Quinolonyl, benzofuryl, benzothienyl, isoquinolyl, isoquinolonyl, benzoxazolyl, benzothiazolyl,
Benzopyrazolyl, benzimidazolyl, benzotriazolyl, benzopyranyl, indolizinyl, purinyl,
Phthalazinyl, oxophthalazinyl, naphthyridinyl,
Quinoxalinyl, quinazolinyl, cinnolinyl, benzodioxolyl, benzodioxanyl, oxonaphthalenyl, dihydrobenzofuryl, benzothiazinyl, pteridinyl, pyrazolo [1,5-a] pyrimidinyl, pyrazolo [5,1-c] [1 , 2,4] triazinyl, thiazolo [3,2-b]
Triazolyl, benzopyrano [2,3-b] pyridyl, 5H-benzopyrano [2,3-b] pyridonyl, xanthenyl, phenoxathiinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or thianthrenyl, or C _{1 -6} heteroalicyclic group, piperidyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl or tetrahydrofuryl, C _3-10 cycloalkyl, C _3-7 cycloalkenyl group, C _6-14 aromatic group described above , A C _1-12 heterocyclic aromatic group or a C _1-6 heteroalicyclic group has a total of up to 5 substituents (the substituents are a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, C _3-7 cycloalkenyl group, (the alkyl group, cycloalkyl group and cycloalkenyl group may be substituted by a hydroxyl group.), a hydroxyl group, C _1-7 alkoxy , C _1-7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, methylamino group, dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, C _1-3 alkoxycarbonyl group, a nitrile Group, carbamoyl group, sulfamoyl group, phenoxy group, benzyloxy group, tri-C _1-7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (the phenyl, naphthyl, furyl, thienyl, imidazolyl, Pyridyl and benzyl are all up to C _1-7 alkyl, C _3-7 cycloalkyl, C _1-3 alkoxy, C _1-3 alkylthio, hydroxyl, halogen, nitro or dimethylamino. Which may have up to 5 substituents.). Item 6. The six-membered heterocyclic ring or the salt thereof according to Item 1. 3. G is a hydrogen atom, or Embedded image Wherein R ^a and R ^b are each independently a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkenyl group, (the alkyl group, the cycloalkyl group And the cycloalkenyl group may be substituted by a hydroxyl group.),
Hydroxyl group, C _1-7 alkoxy group, C _1-7 alkylthio group, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group,
Nitro group, amino group, methylamino group, dimethylamino group, acetamido group, methanesulfonylamide group, carboxyl group, _C1-3 alkoxycarbonyl group, nitrile group, carbamoyl group, sulfamoyl group, phenoxy group, benzyloxy group, tribenzyl group C _1-7 alkylsilyloxy group, phenyl, α-naphthyl, β-naphthyl, furyl,
Thienyl, imidazolyl, pyridyl or benzyl (the phenyl, α-naphthyl, β-naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl are all C _1-7 alkyl, C _3-7 cycloalkyl, C _{1 -3} alkoxy group, C _1-3 alkylthio group, hydroxyl group, fluorine atom,
Up to 5 substituents may be substituted with a chlorine atom, a bromine atom, a nitro group or a dimethylamino group. ) And R ^c
Represents a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, or a hydroxymethyl group. The 6-membered heterocyclic ring or a salt thereof according to claim 2, wherein 4. G is a hydrogen atom, or Embedded image Wherein R ^a and R ^b are each independently a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkenyl group, (the alkyl group, the cycloalkyl group And the cycloalkenyl group may be substituted by a hydroxyl group.),
Hydroxyl group, C _1-7 alkoxy group, C _1-7 alkylthio group, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group,
Nitro group, amino group, methylamino group, dimethylamino group, acetamido group, methanesulfonylamide group, carboxyl group, C _1-3 alkoxycarbonyl group, nitrile group, carbamoyl group, sulfamoyl group, phenoxy group, benzyloxy group, tribenzyl group C _1-7 alkylsilyloxy group, phenyl, α-naphthyl, β-naphthyl, furyl,
Thienyl, imidazolyl, pyridyl or benzyl (the phenyl, α-naphthyl, β-naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl are all C _1-7 alkyl groups, C _3-7 cycloalkyl groups, C _{1 -3} alkoxy group, C _1-3 alkylthio group, hydroxyl group, fluorine atom,
Up to 5 substituents may be substituted with a chlorine atom, a bromine atom, a nitro group or a dimethylamino group. ) And R ^c
Represents a hydrogen atom, a C _1-7 alkyl group, a C _3-7 cycloalkyl group, or a hydroxymethyl group. The 6-membered heterocyclic ring according to claim 3 or a salt thereof. 5. R ¹ represents a sulfonic acid group, PO ₃ H ₂ , 5-tetrazolyl group, C (O) OR ⁶ (R ⁶ represents a hydrogen atom or a C _1-7 alkyl group), R ² is a guanidyl group, an amidino group, NR ¹⁰ R ^{10 ′} (R ¹⁰ and R ^{10 ′} each independently represent a hydrogen atom or a C _1-7 alkyl group), or N ⁺ R ¹¹ R ^{11 ′} R
^{11 ″} (R ¹¹ , R ^{11 ′} and R ^{11 ″} each independently represent a C _1-7 alkyl group); R ⁴ represents a hydrogen atom or a C _1-7 alkyl group; ^{is, -O -, - NR 12 -} , or -C (O) -NR ¹² -
(R ¹² is. Represents a hydrogen atom, or a C _1-7 alkyl group) ^{represents, R 13, R 13 ',} R 14, and R ^14' are each independently hydrogen atom, C _{1 -7} alkyl group, Or represents a C _1-7 alkoxy group,
L ¹ , L ² , and L ³ are each independently a covalent bond, -O-, -C
^{(O) -, - CR 15} = CR 15 '-, -NR 15 -, - NR 15 -C (O) -, or -C
^{(O) -NR 15 - (R} 15 and R ^{15 'are} each independently a hydrogen atom,
Or a C _1-7 alkyl group. The 6-membered heterocyclic ring or a salt thereof according to claim 4, wherein 6. A method according to claim 1, wherein E is Wherein, k represents 1 to 10, representing the R ¹⁵ and R ^{15 'each} independently represent a hydrogen atom, or a C _{1 -7} alkyl group. The 6-membered heterocyclic ring or a salt thereof according to claim 5, wherein 7. The six member according to claim 6, wherein X ¹ , X ³ and X ⁵ each independently represent a nitrogen atom or CH, and X ² and X ⁴ each independently represent CR ^5. A ring heterocycle or a salt thereof. 8. The method according to claim 1, wherein E is Wherein, k represents 1 to 10, representing the R ¹⁵ and R ^{15 'each} independently represent a hydrogen atom, or a C _{1 -7} alkyl group. The 6-membered heterocyclic ring or a salt thereof according to claim 7, wherein 9. m, n, n¹And n^TwoAre each independently 0
Or 1 for R ¹Is C (O) OR⁶(R⁶Is a hydrogen atom,
Is C_1-7Represents an alkyl group. ), And R^TwoIs NR ^TenR
^Ten'(R^TenAnd R^Ten'Are each independently a hydrogen atom, or C
_1-7Represents an alkyl group. ) Or N⁺R¹¹R^{11 '}R^{11 ''}(R¹¹,
R^{11 '}And R^{11 ''}Are each independently C_1-7Table showing alkyl groups
You. D represents -O- or -NH-, and X^FourIs C
R^Five(R^FiveRepresents a hydrogen atom or a halogen atom. Represents)
A six-membered heterocyclic ring according to claim 8, or a salt thereof. 10. A hypoglycemic agent comprising the six-membered heterocyclic ring according to claim 1 or a salt thereof. 11. A carnitine palmitoyltransferase inhibitor comprising the six-membered heterocyclic ring according to claim 1 or a salt thereof. 12. A preventive or therapeutic agent for diabetes or diabetic complications, comprising the six-membered heterocyclic ring or the salt thereof according to claim 1.