JPH09124609A - Benzimidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the above derivative having substance P antagonism and antihistaminic activity and especially useful as a medicine for preventing and treating I type allergic diseases. SOLUTION: This benzimidazole derivative represented by formula I (A is a 1-2C alkylene; B is NR<3> , NR<3> CONR<4> , NR<3> NR<4> CONR<5> , etc., R<3> , R<4> and R<5> are independently H or a 1-4C alkyl; D is a 1-2C alkylene, a 2-3C alkyleneoxy, etc.; Ar<1> is phenyl, etc.; Ar<2> is benzyl, diphenylmethyl, etc.; R<1> and R<2> are each H), e.g. 1-(4-fluorobenzyl)-2-(2-methoxybenzylamino) methylbenzimidazole. The derivative of formula I is obtained by reacting a compound represented by formula II (R<7> is H or a 1-4C alkyl) in an amount of 0.8-1.5 times by mol (based on the compound of formula III) with a compound of formula III in a solvent such as benzene in the presence of a base such as potassium carbonate or trimethylamine at -78 deg.C to a boiling point of the reaction solvent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzimidazole derivative having an antiallergic action and a medicine containing them as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION In the treatment of type I allergic diseases represented by hay fever, urticaria, atopic dermatitis, allergic rhinitis, asthma and the like, antihistamines and steroids have hitherto been used. Agents have been widely used. However, their clinical utility remains a challenge. The above allergic diseases are
It is triggered by an immune reaction between the specific antigen and the IgE antibody, and changes to a chronic state through inflammation and tissue damage in the affected area. In this process, it has been suggested that various chemical mediators are intimately involved in the progress of their pathological conditions. Among them, histamine is considered to be mainly involved in the early stage of the pathological progression also from the aspect of its pharmacological action. It is speculated that this is why antihistamines pose a challenge to clinical efficacy. On the other hand, steroids, which are prescribed mainly in severe cases, are considered to exhibit high efficacy because they show a pharmacological action that multilaterally inhibits a series of immunoinflammatory reaction processes. However, steroids have serious side effects, and there are many restrictions on their use during oral administration and continuous administration. As described above, in the treatment of type I allergic diseases, there is a strong demand for the development of a drug having a new mechanism of action and showing high efficacy.

In recent years, substance P, which is a neuropeptide,
Has been reported to act as a mediator that exacerbates the symptoms of allergies and is deeply involved in inflammatory symptoms particularly in the chronic stage (TIPS, 81, 24 (1987); Am. J.
Respir. Crit. Care Med., 151, 613 (1995); J. Allerg
y Clin. immunol., 92, 95 (1993)). Therefore, it is considered that substance P antagonists can effectively treat allergic symptoms (especially chronic inflammation) in the chronic stage.

[0004] Substance P is one of the neurokinins, and is widely involved in immunity and inflammation as a regulator of macrophage and lymphocyte activation and production of cytokines (IL1, TNF, IL6), and has vascular permeability. It is known to cause inflammatory symptoms such as increase in blood pressure, plasma leakage, and secretory gland stimulation. It also functions as a nociceptive messenger from the periphery to the center, and regulates the dopamine and adrenaline transduction system in the brain.

Therefore, it is suggested that the substance P antagonists are effective not only as antiallergic agents but also as analgesics and psychotropic drugs.

Further, a drug having both an antihistamine action in addition to a substance P antagonistic action is considered to be effective in treating a wide range of allergic symptoms from the acute phase to the chronic phase, and therefore, it is clinically highly treated. This suggests the possibility of becoming a drug with expected effects.

[0007]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that the benzimidazole derivative of the present invention has a substance P antagonistic action. It was also found that many of the compounds of the present invention also have antihistamine activity.

Already, JP-A-59-199679, 58-79983,
European Patent Nos. 232937, 144101, U.S. Pat. No. 4,219,559 and the like describe benzimidazoles having antihistamine activity, but the compounds of the present invention are not included therein. Further, the above-mentioned document does not make any description about the substance P antagonistic activity.

Therefore, the compound of the present invention is a more excellent compound as an antiallergic drug and can be an active ingredient of a preventive or therapeutic drug for pollinosis, urticaria, atopic dermatitis, allergic rhinitis, asthma and the like. Not only other substance P-mediated diseases such as conjunctivitis and ocular diseases such as spring catarrh; inflammatory diseases such as rheumatoid arthritis; migraine, headache, toothache, pain associated with various diseases; ulcerative colitis, clone It was found that the present invention is also effective for digestive disorders such as illnesses; depression, psychiatric disorders such as dysthymia, etc., and completed the present invention.

That is, the present invention relates to a compound of the formula (I)

[0011]

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[Wherein A is C_1-2Alkylene group (the al
The xylene group is C_1-4Arbitrarily substituted with alkyl group or oxygen atom
, And B is NR^Three, NR^ThreeCONR^Four, NR^Three
NR^Four, NR^ThreeNR^FourCONR^Five, N (CH_TwoCH_Two)_TwoN, N (CH_TwoCH_Two)_TwoNCONR ^Three, N
R^ThreeCH_TwoCH_TwoNR^FourOr NR^ThreeCH_TwoCH_TwoCH_TwoNR^Four(R^Three, R^FourAnd R^FiveIs
Each independently a hydrogen atom or C_1-4Indicates an alkyl group)
, D is C_1-2Alkylene group or C_2-3Alkyleneo
Xy group (the alkylene group and alkyleneoxy group are
Deviation C_1-4Optionally substituted with an alkyl group or oxygen atom
May be present), Ar¹Is a phenyl group {the phenyl
The group is a halogen atom, a trifluoromethyl group, C_1-4Al
Kill group, C_1-4Alkoxy group, formyl group, hydroxyl group
Chill group or CH _TwoNHC (O)_nR⁶(N means 1 or 2. R⁶
Is C_1-4An alkyl group is shown)
Good} or naphthyl group, Ar^TwoIs a phenyl group,
Group or diphenylmethyl group (the phenyl group, benzyl group
Both the dil group and diphenylmethyl group are halogenated
Child, C_1-4Alkyl group or C_1-4Optionally substituted with an alkoxy group
R)¹And R^TwoAre independent
Then, hydrogen atom, halogen atom, C_1-4Alkyl group or C
_1-4It means an alkoxy group. ] Benzimi represented by
Dazole derivative and its salt, its production method and these
The present invention relates to a pharmaceutical composition containing as an active ingredient
You.

The substituents of the compound of the present invention will be described below.

In the present specification, n is normal, i is iso, s is secondary, t is tertiary, and M is
e means methyl, Bu means butyl, and Ph means phenyl.

Examples of C _1-2 alkylene groups include methylene and ethylene.

Examples of the C _2-3 alkyleneoxy group include ethyleneoxy and trimethyleneoxy.

The C _1-4 alkyl group may be linear, branched or cyclic and may be methyl, ethyl, n-propyl or i-
Examples include propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl and c-butyl.

The C _1-4 alkoxy group may be linear, branched or cyclic and is methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-butoxy, s. -Butoxy, t-butoxy and c-butoxy.

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

Hereinafter, A in the compound (I) of the present invention,
B, D, Ar ¹ , Ar ² , R ¹ and R ² will be specifically described.

Specific examples of A include CH ₂ , CHMe, and CH ₂ C.
H ₂ , CH ₂ CHMe, CO, CH ₂ CO, COCH ₂ and COCHMe and the like can be mentioned, and CH ₂ , CH ₂ CH ₂ and CO and the like can be mentioned preferably.

Specific examples of B include NH, NMe, NHCONH, N
MeCONH, NHCONMe, NMeCONMe, NHNH, NHNMe, NMeNH, NMe
NMe, NMeNHCONH, NMeNHCONMe, N (CH ₂ CH ₂ ) ₂ N, N (CH ₂ CH ₂ )
₂ NCONH, N (CH ₂ CH ₂ ) ₂ NCONMe, NMeCH ₂ CH ₂ NMe and NMeCH ₂ CH
₂ CH ₂ NMe and the like, preferably NH, NMe, NHCONH,
_{NHCONMe, NMeNHCONH, N (CH 2} CH 2) 2 N, N (CH 2 CH 2) 2 NCONH,
N (CH ₂ CH ₂ ) ₂ NCONMe, NMeCH ₂ CH ₂ NMe and NMeCH ₂ CH ₂ CH ₂ NMe
And the like.

As a specific example of D, CH_Two, CHMe, CH_TwoC
H_Two, CH_TwoCHMe, COCH_Two, COCHMe, COCH_TwoO, CH_TwoCH_TwoO and CH_Two
CH_TwoCH_TwoO and the like, preferably CH_Two, CHMe, CH_TwoC
H_Two, COCH _Two, COCHMe and COCH_TwoO can be mentioned
You.

Specific examples of Ar ¹ include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-
Iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3 -Dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,
3-dibromophenyl, 2,4-dibromophenyl, 2,5-dibromophenyl, 2,6-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 2,3-diiodophenyl, 2, 4-diiodophenyl, 2,5-diiodophenyl, 2,
6-diiodophenyl, 3,4-diiodophenyl, 3,5-diiodophenyl, 2,3-ditrifluoromethylphenyl, 2,
4-ditrifluoromethylphenyl, 2,5-ditrifluoromethylphenyl, 2,6-ditrifluoromethylphenyl,
3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4- Dimethylphenyl, 3,5-dimethylphenyl,
2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,
5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-
Dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 2-methoxy-5-hydroxymethylphenyl, 2-methoxy-4-hydroxymethylphenyl, 2-methoxy-5-formylphenyl, Examples thereof include 2-methoxy-4-formylphenyl, 2-methoxy-5-t-butoxycarbonylaminomethylphenyl, α-naphthyl and β-naphthyl, and preferably phenyl, 2-chlorophenyl, 2-methoxyphenyl, 3, 5-dimethylphenyl, 3,5-ditrifluoromethylphenyl, 3,5-dimethoxyphenyl, 2,5-dichlorophenyl, 2-chloro-5-trifluoromethylphenyl, 2-methoxy-5-hydroxymethylphenyl, 2- Methoxy-4-hydroxymethylphenyl, 2-methoxy-5-formylphenyl, 2-methoxy-4-formylphenyl, 2-methoxy-5-t-butoxycarbonylami Mention may be made of methyl phenyl, alpha-naphthyl and β- naphthyl.

Specific examples of Ar ² include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-
Iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, benzyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluoro Phenylmethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl, 2-bromophenylmethyl, 3-bromophenylmethyl, 4-bromophenylmethyl, 2-iodophenylmethyl, 3-iodophenylmethyl, 4- Iodophenylmethyl, 2-methylphenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 2-methoxyphenylmethyl, 3-methoxyphenylmethyl, 4-methoxyphenylmethyl, diphenylmethyl and the like, and preferably, Phenyl, 4-fluorophenyl, 4-chlorophenyl, benzyl , 4-fluorophenylmethyl, 4-chlorophenylmethyl, diphenylmethyl and the like.

Specific examples of R ¹ and R ² are a hydrogen atom, fluorine, chlorine, bromine, iodine, methyl, ethyl,
n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy,
n-butoxy, i-butoxy, s-butoxy, t-butoxy,
C-butoxy can be mentioned, and preferably a hydrogen atom can be mentioned.

Preferred compounds in the compound of the present invention represented by the general formula (1) include the following compounds.

(1) A is CH ₂ , CHMe, CH ₂ CH ₂ , CH ₂ CHMe,
CO, CH ₂ CO, COCH ₂ or COCHMe, and B is NH, NMe, NHC
ONH, NMeCONH, NHCONMe, NMeCONMe, NHNH, NHNMe, NMeN
H, NMeNMe, NMeNHCONH, NMeNHCONMe, N (CH ₂ CH ₂ ) ₂ N, N (C
H ₂ CH ₂ ) ₂ NCONH, N (CH ₂ CH ₂ ) ₂ NCONMe, NMeCH ₂ CH ₂ NMe or NM
eCH ₂ CH ₂ CH ₂ NMe and D is CH ₂ , CHMe, CH ₂ CH ₂ , CH ₂ CHM
e, COCH ₂ , COCHMe, COCH ₂ O, CH ₂ CH ₂ O or CH ₂ CH ₂ CH ₂ O, and Ar ¹ is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl. ,
3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethyl Phenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
2,3-difluorophenyl, 2,4-difluorophenyl, 2,
5-difluorophenyl, 2,6-difluorophenyl, 3,4-
Difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3- Dibromophenyl, 2,
4-dibromophenyl, 2,5-dibromophenyl, 2,6-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 2,3-diiodophenyl, 2,4-diiodophenyl, 2 , 5-diiodophenyl, 2,6-diiodophenyl, 3,
4-diiodophenyl, 3,5-diiodophenyl, 2,3-ditrifluoromethylphenyl, 2,4-ditrifluoromethylphenyl, 2,5-ditrifluoromethylphenyl, 2,6-ditrifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2,3-
Dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxy Phenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 2-methoxy-5-hydroxymethylphenyl , 2-methoxy-4-hydroxymethylphenyl, 2-
Methoxy-5-formylphenyl, 2-methoxy-4-formylphenyl, 2-methoxy-5-t-butoxycarbonylaminomethylphenyl, α-naphthyl or β-naphthyl,
Ar ² is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-
Bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- Methoxyphenyl, benzyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl, 2-bromophenylmethyl, 3-bromophenylmethyl, 4-bromophenylmethyl, 2-iodophenylmethyl, 3-iodophenylmethyl, 4-iodophenylmethyl, 2-methylphenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 2-methoxyphenylmethyl, 3- methoxyphenyl methyl, 4-methoxyphenyl methyl or diphenylmethyl, R ¹ Fine R ² are each a hydrogen atom, a halogen atom, and salts thereof represented by the formula (I) is a methyl group or a methoxy group.

(2) A is CH_Two, CH_TwoCH_TwoOr CO, B
Is NH, NMe, NHCONH, NHCONMe, NMeNHCONH, N (CH_TwoCH_Two)
_TwoN, N (CH_TwoCH_Two)_TwoNCONH, N (CH_TwoCH_Two)_TwoNCONMe, NMeCH_TwoCH_TwoNM
e or NMeCH_TwoCH _TwoCH_TwoNMe, D is CH_Two, CHMe, CH_TwoC
H_Two, COCH_Two, COCHMe or COCH_TwoO, Ar¹Is phenyl,
2-chlorophenyl, 2-methoxyphenyl, 3,5-dimethyl
Phenyl, 3,5-ditrifluoromethylphenyl, 3,5-di
Methoxyphenyl, 2,5-dichlorophenyl, 2-chloro-5
-Trifluoromethylphenyl, 2-methoxy-5-hydroxy
Cimethylphenyl, 2-methoxy-4-hydroxymethylphenyl
2-methyl-5-formylphenyl, 2-methoxy-
4-formylphenyl, 2-methoxy-5-t-butoxycarbo
Nylaminomethylphenyl, α-naphthyl or β-naphthyl
And Ar^TwoIs phenyl, 4-fluorophenyl, 4-
Lorophenyl, benzyl, 4-fluorophenylmethyl,
4-chlorophenylmethyl or diphenylmethyl,
R¹And R^TwoIs represented by formula (I) in which each is a hydrogen atom.
Compounds and their salts.

Hereinafter, representative compounds of the benzimidazole derivative represented by the general formula (I) which is the compound of the present invention are shown in Table I, but the present invention is not limited thereto.

In addition, Q1 to Q32 in Table I are groups represented by the following formula.

[0032]

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[0033]

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Table I

[0035]

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[0036]

[Table 1] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NH CH ₂ Ph Q30 H H CH ₂ NH CH ₂ Q1 Q30 H _{H CH 2 NH CH 2 Q2 Q30} H H CH 2 NH CH 2 Q3 Q30 H H CH 2 NH CH 2 Q4 Q30 H H CH 2 NH CH 2 Q5 Q30 H H CH 2 NH CH 2 Q6 Q30 H H CH 2 NH CH ₂ Q7 Q30 H H CH ₂ NH CH ₂ Q8 Q30 H H CH ₂ NH CH ₂ Q9 Q30 H H CH ₂ NH CH ₂ Q10 Q30 H H CH ₂ NH CH ₂ Q11 Q30 H H CH ₂ NH CH ₂ Q12 Q30 H H CH ₂ NH CH ₂ Q13 Q30 H H CH ₂ NH CH ₂ Q14 Q30 H H CH ₂ NMe CH ₂ Ph Ph Q30 H H CH ₂ NMe CH ₂ Q1 Q30 H H CH ₂ NMe CH ₂ Q2 Q30 H H CH ₂ NMe CH ₂ Q3 Q30 H H CH ₂ NMe CH ₂ HQQ 30 H ₂ NMe CH ₂ Q5 Q30 H H CH ₂ NMe CH ₂ Q6 Q30 H H CH ₂ NMe CH ₂ Q7 Q30 ────────────────────────── ───────

[0037]

[Table 2] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 NMe CH 2} Q8 Q30 H H CH 2 NMe CH 2 Q9 Q30 H H CH ₂ NMe CH ₂ Q10 Q30 H H CH ₂ NMe CH ₂ Q11 Q30 H H CH ₂ NMe CH ₂ Q12 Q30 H H CH ₂ NMe CH ₂ Q13 Q30 H H CH ₂ NMe CH ₂ Q14 Q30 H H CH ₂ NH ₂ CH ₂ Ph Q30 H H CH ₂ NH CH ₂ CH ₂ Q1 Q30 H H CH ₂ NH CH ₂ CH ₂ Q2 Q30 H H CH ₂ NH CH ₂ CH ₂ Q3 Q30 H H CH ₂ NH CH ₂ CH ₂ Q4 Q30 H _{H CH 2 NH CH 2 CH 2} Q5 Q30 H _{CH 2 NH CH 2 CH 2 Q6} Q30 H H CH 2 NH CH 2 CH 2 Q7 Q30 H H CH 2 NH CH 2 CH 2 Q8 Q30 H H CH 2 NH CH 2 CH 2 Q9 Q30 H H CH 2 NH CH 2 CH ₂ Q10 Q30 H H CH ₂ NH CH ₂ CH ₂ Q11 Q30 H H CH ₂ NH CH ₂ CH ₂ Q12 Q30 H H CH ₂ NH CH ₂ CH ₂ Q13 Q30 H H CH ₂ NH CH ₂ CH ₂ Q14 Q30 H H CH ₂ NMe CH ₂ CH ₂ Ph Q30 ──────────────────────────────────

[0038]

[Table 3] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NMe CH ₂ CH ₂ Q 1 Q 30 H H CH ₂ NMe CH ₂ CH ₂ Q2 Q30 H H CH ₂ NMe CH ₂ CH ₂ Q3 Q30 H H CH ₂ NMe CH ₂ CH ₂ Q4 Q30 H H CH ₂ NMe CH ₂ CH ₂ Q5 Q30 H H CH ₂ NMe CH ₂ CH ₂ Q6 Q30 H H CH ₂ NMe CH ₂ CH ₂ Q7 Q30 H H CH ₂ NMe CH ₂ CH ₂ Q8 Q30 H H CH ₂ NMe CH ₂ CH ₂ Q9 Q30 H H CH ₂ NMe CH ₂ CH ₂ Q10 Q30 H H CH ₂ NMe CH ₂ CH _{2 Q11 Q30 H H CH 2 NMe CH} 2 CH 2 Q12 _{30 H H CH 2 NMe CH 2} CH 2 Q13 Q30 H H CH 2 NMe CH 2 CH 2 Q14 Q30 H H CH 2 Q16 CH 2 Ph Q30 H H CH 2 Q16 CH 2 Q1 Q30 H H CH 2 Q16 CH 2 Q2 Q30 H H CH ₂ Q16 CH ₂ Q3 Q30 H H CH ₂ Q16 CH ₂ Q4 Q30 H H CH ₂ Q16 CH ₂ Q5 Q30 H H CH ₂ Q16 CH ₂ Q6 Q30 H H CH ₂ Q16 CH ₂ Q7 Q30 H H CH ₂ Q16 CH ₂ Q8 Q30 ──────────────────────────────────

[0039]

[Table 4] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 Q16 CH 2} Q9 Q30 H H CH 2 Q16 CH 2 Q10 Q30 H _{H CH 2 Q16 CH 2 Q11 Q30} H H CH 2 Q16 CH 2 Q12 Q30 H H CH 2 Q16 CH 2 Q13 Q30 H H CH 2 Q16 CH 2 Q14 Q30 H H CH 2 Q21 Q25 Ph Q30 H H CH 2 Q21 Q25 Q1 _{Q30 H H CH 2 Q21 Q25 Q2} Q30 H H CH 2 Q21 Q25 Q3 Q30 H H CH 2 Q21 Q25 Q4 Q30 H H CH 2 Q21 Q25 Q5 Q30 H H CH 2 Q21 Q25 Q6 Q30 H H CH 2 Q21 Q2 _{Q7 Q30 H H CH 2 Q21 Q25} Q8 Q30 H H CH 2 Q21 Q25 Q9 Q30 H H CH 2 Q21 Q25 Q10 Q30 H H CH 2 Q21 Q25 Q11 Q30 H H CH 2 Q21 Q25 Q12 Q30 H H CH 2 Q21 Q25 Q13 Q30 H H CH ₂ Q21 Q25 Q14 Q30 H H CH ₂ Q21 CH ₂ Ph Q30 H H CH ₂ Q21 CH ₂ Q1 Q30 ───────────────────────── ─────────

[0040]

[Table 5] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 Q21 CH 2} Q2 Q30 H H CH 2 Q21 CH 2 Q3 Q30 H H CH ₂ Q21 CH ₂ Q4 Q30 H H CH ₂ Q21 CH ₂ Q5 Q30 H H CH ₂ Q21 CH ₂ Q6 Q30 H H CH ₂ Q21 CH ₂ Q7 Q30 H H CH ₂ Q21 CH ₂ Q8 Q30 H H CH ₂ Q21 CH ₂ Q9 Q30 H H CH ₂ Q21 CH ₂ Q10 Q30 H H CH ₂ Q21 CH ₂ Q11 Q30 H H CH ₂ Q21 CH ₂ Q12 Q30 H H CH ₂ Q21 CH ₂ Q13 Q30 H H CH ₂ Q21 CH ₂ Q14 Q30 H H CH ₂ Q22 CH ₂ P _{Q30 H H CH 2 Q22 CH 2} Q1 Q30 H H CH 2 Q22 CH 2 Q2 Q30 H H CH 2 Q22 CH 2 Q3 Q30 H H CH 2 Q22 CH 2 Q4 Q30 H H CH 2 Q22 CH 2 Q5 Q30 H H CH 2 _{Q22 CH 2 Q6 Q30 H H CH} 2 Q22 CH 2 Q7 Q30 H H CH 2 Q22 CH 2 Q8 Q30 H H CH 2 Q22 CH 2 Q9 Q30 ────────────────── ───────────────

[0041]

[Table 6] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 Q22 CH 2} Q10 Q30 H H CH 2 Q22 CH 2 Q11 Q30 H H CH ₂ Q22 CH ₂ Q12 Q30 H H CH ₂ Q22 CH ₂ Q13 Q30 H H CH ₂ Q22 CH ₂ Q14 Q30 H H CH ₂ Q21 COCH ₂ Ph Q30 H H CH ₂ Q21 COCH ₂ Q1 Q30 H H CH ₂ Q21 COCH ₂ Q2 Q30 H H CH ₂ Q21 COCH ₂ Q3 Q30 H H CH ₂ Q21 COCH ₂ Q4 Q30 H H CH ₂ Q21 COCH ₂ Q5 Q30 H H CH ₂ Q21 COCH ₂ Q6 Q30 H H CH ₂ Q21 COCH ₂ Q7 Q 30 H H CH ₂ Q21 COCH ₂ Q8 Q30 H H CH ₂ Q21 COCH ₂ Q9 Q30 H H CH ₂ Q21 COCH ₂ Q10 Q30 H H CH ₂ Q21 COCH ₂ Q11 Q30 H H CH ₂ Q21 COCH ₂ Q12 Q30 H H CH ₂ Q21 COCH ₂ Q13 Q30 H H CH ₂ Q21 COCH ₂ Q14 Q30 H H CH ₂ Q21 Q26 Ph Q30 H H CH ₂ Q21 Q26 Q1 Q30 H H CH ₂ Q21 Q26 Q2 Q30 ───────────── ─────────────────────

[0042]

[Table 7] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ Q21 Q26 Q3 Q30 H H CH ₂ Q21 Q26 Q4 Q30 H H CH _{2 Q21 Q26 Q5 Q30 H H CH} 2 Q21 Q26 Q6 Q30 H H CH 2 Q21 Q26 Q7 Q30 H H CH 2 Q21 Q26 Q8 Q30 H H CH 2 Q21 Q26 Q9 Q30 H H CH 2 Q21 Q26 Q10 Q30 H H CH 2 Q21 _{Q26 Q11 Q30 H H CH 2 Q21} Q26 Q12 Q30 H H CH 2 Q21 Q26 Q13 Q30 H H CH 2 Q21 Q26 Q14 Q30 H H CH 2 Q21 CH 2 Ph Q29 H H CH 2 Q21 _{H 2 Q1 Q29 H H CH 2} Q21 CH 2 Q2 Q29 H H CH 2 Q21 CH 2 Q3 Q29 H H CH 2 Q21 CH 2 Q4 Q29 H H CH 2 Q21 CH 2 Q5 Q29 H H CH 2 Q21 CH 2 Q6 Q29 H H CH ₂ Q21 CH ₂ Q7 Q29 H H CH ₂ Q21 CH ₂ Q8 Q29 H H CH ₂ Q21 CH ₂ Q9 Q29 H H CH ₂ Q21 CH ₂ Q10 Q29 ──────────────── ──────────────────

[0043]

[Table 8] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 Q21 CH 2} Q11 Q29 H H CH 2 Q21 CH 2 Q12 Q29 H H CH ₂ Q21 CH ₂ Q13 Q29 H H CH ₂ Q21 CH ₂ Q14 Q29 H H CH ₂ Q22 CH ₂ Ph Q29 H H CH ₂ Q22 CH ₂ Q1 Q29 H H CH ₂ Q22 CH ₂ Q2 Q29 H H CH ₂ Q22 CH ₂ Q3 Q29 H H CH ₂ Q22 CH ₂ Q4 Q29 H H CH ₂ Q22 CH ₂ Q5 Q29 H H CH ₂ Q22 CH ₂ Q6 Q29 H H CH ₂ Q22 CH ₂ Q7 Q29 H H CH ₂ Q22 CH ₂ Q8 Q29 H H CH ₂ Q22 CH ₂ Q9 _{29 H H CH 2 Q22 CH 2} Q10 Q29 H H CH 2 Q22 CH 2 Q11 Q29 H H CH 2 Q22 CH 2 Q12 Q29 H H CH 2 Q22 CH 2 Q13 Q29 H H CH 2 Q22 CH 2 Q14 Q29 H H CH 2 _{NH CH 2 Ph Ph H H CH} 2 NH CH 2 Q1 Ph H H CH 2 NH CH 2 Q2 Ph H H CH 2 NH CH 2 Q3 Ph ────────────────── ───────────────

[0044]

[Table 9] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NH CH ₂ Q4 Ph H H H CH ₂ NH CH ₂ Q5 Ph H _{H CH 2 NH CH 2 Q6 Ph} H H CH 2 NH CH 2 Q7 Ph H H CH 2 NH CH 2 Q8 Ph H H CH 2 NH CH 2 Q9 Ph H H CH 2 NH CH 2 Q10 Ph H H CH 2 NH CH ₂ Q11 Ph H H CH ₂ NH CH ₂ Q12 Ph H H CH ₂ NH CH ₂ Q13 Ph H H CH ₂ NH CH ₂ Q14 Ph H H CH ₂ NMe CH ₂ Ph Ph H H CH ₂ NMe CH ₂ Q1 Ph H H _{CH 2 NMe CH 2 Q2 Ph H} H CH 2 NMe CH 2 Q3 Ph H H C _{2 NMe CH 2 Q4 Ph H H} CH 2 NMe CH 2 Q5 Ph H H CH 2 NMe CH 2 Q6 Ph H H CH 2 NMe CH 2 Q7 Ph H H CH 2 NMe CH 2 Q8 Ph H H CH 2 NMe CH 2 Q9 Ph H H CH ₂ NMe CH ₂ Q10 Ph H H CH ₂ NMe CH ₂ Q11 Ph ──────────────────────────────── ──

[0045]

[Table 10] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NMe CH ₂ Q12 Ph H H H CH ₂ NMe CH ₂ Q13 Ph H H CH ₂ NMe CH ₂ Q14 Ph H H CH ₂ NH CH ₂ CH ₂ Ph Ph H H CH ₂ NH CH ₂ CH ₂ Q 1 Ph H H CH ₂ NH CH ₂ CH ₂ Q 2 Ph H H CH ₂ NH CH ₂ CH ₂ Q3 Ph H H CH ₂ NH CH ₂ CH ₂ Q4 Ph H H CH ₂ NH CH ₂ CH ₂ Q5 Ph H H CH ₂ NH CH ₂ CH ₂ Q6 Ph H H CH ₂ NH CH ₂ CH ₂ Q7 Ph H H CH ₂ NH CH ₂ CH ₂ Q8 Ph H H CH ₂ NH CH ₂ CH ₂ Q9 Ph H H CH ₂ NH _{CH 2 CH 2 Q10 Ph H H} CH 2 NH CH 2 CH 2 Q11 Ph H H CH 2 NH CH 2 CH 2 Q12 Ph H H CH 2 NH CH 2 CH 2 Q13 Ph H H CH 2 NH CH 2 CH 2 Q14 Ph _{H H CH 2 NMe CH 2 CH} 2 Ph Ph H H CH 2 NMe CH 2 CH 2 Q1 Ph H H CH 2 NMe CH 2 CH 2 Q2 Ph H H CH 2 NMe CH 2 CH 2 Q3 Ph H H CH 2 NMe CH ₂ CH ₂ Q4 Ph ─────────────────────────────────

[0046]

[Table 11] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ───────────────────────────────────── H H CH ₂ NMe CH ₂ CH ₂ Q 5 Ph H H CH ₂ NMe CH ₂ CH _{2 Q6 Ph H H CH 2 NMe} CH 2 CH 2 Q7 Ph H H CH 2 NMe CH 2 CH 2 Q8 Ph H H CH 2 NMe CH 2 CH 2 Q9 Ph H H CH 2 NMe CH 2 CH 2 Q10 Ph H H CH ₂ NMe CH ₂ CH ₂ Q11 Ph H H CH ₂ NMe CH ₂ CH ₂ Q12 Ph H H CH ₂ NMe CH ₂ CH ₂ Q13 Ph H H CH ₂ NMe CH ₂ CH ₂ Q14 Ph H H CH ₂ Q21 CH ₂ Ph Ph _{H H CH 2 Q21 CH 2 Q1} Ph H H CH 2 Q21 CH 2 _{2 Ph H H CH 2 Q21 CH} 2 Q3 Ph H H CH 2 Q21 CH 2 Q4 Ph H H CH 2 Q21 CH 2 Q5 Ph H H CH 2 Q21 CH 2 Q6 Ph H H CH 2 Q21 CH 2 Q7 Ph H H CH _{2 Q21 CH 2 Q8 Ph H H} CH 2 Q21 CH 2 Q9 Ph H H CH 2 Q21 CH 2 Q10 Ph H H CH 2 Q21 CH 2 Q11 Ph H H CH 2 Q21 CH 2 Q12 Ph ──────── ─────────────────────────

[0047]

[Table 12] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 Q21 CH 2} Q13 Ph H H CH 2 Q21 CH 2 Q14 Ph H _{H CH 2 Q22 CH 2 Ph Ph} H H CH 2 Q22 CH 2 Q1 Ph H H CH 2 Q22 CH 2 Q2 Ph H H CH 2 Q22 CH 2 Q3 Ph H H CH 2 Q22 CH 2 Q4 Ph H H CH 2 Q22 CH ₂ Q5 Ph H H CH ₂ Q22 CH ₂ Q6 Ph H H CH ₂ Q22 CH ₂ Q7 Ph H H H CH ₂ Q22 CH ₂ Q8 Ph H H CH ₂ Q22 CH ₂ Q9 Ph H H CH ₂ Q22 CH ₂ Q10 Ph H H CH ₂ Q22 CH ₂ Q11 Ph H H CH ₂ Q22 C _{H 2 Q12 Ph H H CH 2} Q22 CH 2 Q13 Ph H H CH 2 Q22 CH 2 Q14 Ph H H CH 2 Q21 COCH 2 Ph Ph H H CH 2 Q21 COCH 2 Q1 Ph H H CH 2 Q21 COCH 2 Q2 Ph H H CH ₂ Q21 COCH ₂ Q3 Ph H H CH ₂ Q21 COCH ₂ Q4 Ph H H CH ₂ Q21 COCH ₂ Q5 Ph ───────────────────────── ─────────

[0048]

[Table 13] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ Q21 COCH ₂ Q6 Ph H H H CH ₂ Q21 COCH ₂ Q7 Ph H H CH ₂ Q21 COCH ₂ Q8 Ph H H CH ₂ Q21 COCH ₂ Q9 Ph H H CH ₂ Q21 COCH ₂ Q10 Ph H H CH ₂ Q21 COCH ₂ Q11 Ph H H CH ₂ Q21 COCH ₂ Q12 Ph H H CO ₂ Q21 ₂ Q13 Ph H H CH ₂ Q21 COCH ₂ Q14 Ph H H CH ₂ Q23 CH ₂ Ph Ph Ph H H CH ₂ Q23 CH ₂ Q1 Ph H H CH ₂ Q23 CH ₂ Q2 Ph Ph H H CH ₂ Q23 CH ₂ Q3 Ph H H CH ₂ Q2 3 CH ₂ Q4 Ph H H CH ₂ Q23 CH ₂ Q5 Ph H H CH ₂ Q23 CH ₂ Q6 Ph H H CH ₂ Q23 CH ₂ Q7 Ph Ph H H CH ₂ Q23 CH ₂ Q8 Ph H H CH ₂ Q23 CH ₂ Q9 Ph H H CH ₂ Q23 CH ₂ Q10 Ph H H CH ₂ Q23 CH ₂ Q11 Ph H H CH ₂ Q23 CH ₂ Q12 Ph H H CH ₂ Q23 CH ₂ Q13 Ph ─────────────── ────────────────────

[0049]

[Table 14] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ Q23 CH ₂ Q14 Ph H H CH ₂ CH ₂ NH CH ₂ Ph _{Q30 H H CH 2 CH 2 NH} CH 2 Q1 Q30 H H CH 2 CH 2 NH CH 2 Q2 Q30 H H CH 2 CH 2 NH CH 2 Q3 Q30 H H CH 2 CH 2 NH CH 2 Q4 Q30 H H CH 2 CH ₂ NH CH ₂ Q5 Q30 H H CH ₂ CH ₂ NH CH ₂ Q6 Q30 H H CH ₂ CH ₂ NH CH ₂ Q7 Q30 H H CH ₂ CH ₂ NH CH ₂ Q8 Q30 H H CH ₂ CH ₂ NH CH ₂ Q9 Q30 _{H H CH 2 CH 2 NH CH} 2 Q10 Q30 H H CH 2 CH 2 NH C _{2 Q11 Q30 H H CH 2 CH} 2 NH CH 2 Q12 Q30 H H CH 2 CH 2 NH CH 2 Q13 Q30 H H CH 2 CH 2 NH CH 2 Q14 Q30 H H CH 2 CH 2 NMe CH 2 Ph Q30 H H CH ₂ CH ₂ NMe CH ₂ Q1 Q30 H H CH ₂ CH ₂ NMe CH ₂ Q2 Q30 H H CH ₂ CH ₂ NMe CH ₂ Q3 Q30 H H CH ₂ CH ₂ NMe CH ₂ Q4 Q30 H H CH ₂ CH ₂ NMe CH _{2 Q5 Q30 H H CH 2 CH 2} NMe CH 2 Q6 Q30 ─────────────────────────────────

[0050]

[Table 15] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ NMe CH ₂ Q7 Q30 H H CH ₂ CH ₂ NMe CH ₂ Q8 Q30 H H CH ₂ CH ₂ NMe CH ₂ Q9 Q30 H H CH ₂ CH ₂ NMe CH ₂ Q10 Q30 H H CH ₂ CH ₂ NMe CH ₂ Q11 Q30 H H CH ₂ CH ₂ NMe CH ₂ Q12 Q30 H H CH _{2 CH 2 NMe CH 2 Q13 Q30} H H CH 2 CH 2 NMe CH 2 Q14 Q30 H H CH 2 CH 2 Q17 CH 2 Ph Q30 H H CH 2 CH 2 Q17 CH 2 Q1 Q30 H H CH 2 CH 2 Q17 CH 2 Q2 Q30 H H CH ₂ CH ₂ Q17 CH ₂ Q3 Q30 H H CH ₂ CH ₂ Q17 CH ₂ Q4 Q30 H H CH ₂ CH ₂ Q17 CH ₂ Q5 Q30 H H CH ₂ CH ₂ Q17 CH ₂ Q6 Q30 H H CH ₂ CH ₂ Q17 CH ₂ Q7 Q30 H H CH _{2 CH 2 Q17 CH 2 Q8 Q30 H} H CH 2 CH 2 Q17 CH 2 Q9 Q30 H H CH 2 CH 2 Q17 CH 2 Q10 Q30 H H CH 2 CH 2 Q17 CH 2 Q11 Q30 H H CH 2 CH 2 Q17 CH 2 Q12 Q30 H H CH ₂ CH ₂ Q17 CH ₂ Q13 Q30 H H CH ₂ CH ₂ Q17 CH ₂ Q14 Q30 ──────────────────────────── ──────

[0051]

[Table 16] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ Q18 CH ₂ Ph Q30 H H CH ₂ CH ₂ Q18 CH ₂ Q1 Q30 H H CH ₂ CH ₂ Q18 CH ₂ Q2 Q30 H H CH ₂ CH ₂ Q18 CH ₂ Q3 Q30 H H CH ₂ CH ₂ Q18 CH ₂ Q4 Q30 H H CH ₂ CH ₂ Q18 CH ₂ Q5 Q30 H H CH ₂ CH ₂ Q18 CH ₂ Q6 Q30 H H CH ₂ CH ₂ Q18 CH ₂ Q7 Q30 H H CH ₂ CH ₂ Q18 CH ₂ Q8 Q30 H H CH ₂ CH ₂ Q18 CH ₂ Q9 Q30 H H CH ₂ CH ₂ Q18 CH _{2 Q10 Q30 H H CH 2 CH 2} Q18 CH 2 Q11 _{30 H H CH 2 CH 2 Q18} CH 2 Q12 Q30 H H CH 2 CH 2 Q18 CH 2 Q13 Q30 H H CH 2 CH 2 Q18 CH 2 Q14 Q30 H H CH 2 NH CH 2 Ph Q29 H H CH 2 NH CH 2 Q1 Q29 H H CH ₂ NH CH ₂ Q2 Q29 H H CH ₂ NH CH ₂ Q3 Q29 H H CH ₂ NH CH ₂ Q4 Q29 H H CH ₂ NH CH ₂ Q5 Q29 H H CH ₂ NH CH ₂ Q6 Q29 H H CH ₂ NH CH ₂ Q7 Q29 ──────────────────────────────────

[0052]

[Table 17] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NH CH ₂ Q8 Q29 H H CH ₂ NH CH ₂ Q9 Q29 H _{H CH 2 NH CH 2 Q10 Q29} H H CH 2 NH CH 2 Q11 Q29 H H CH 2 NH CH 2 Q12 Q29 H H CH 2 NH CH 2 Q13 Q29 H H CH 2 NH CH 2 Q14 Q29 H H CH 2 NMe CH ₂ Ph Q29 H H CH ₂ NMe CH ₂ Q1 Q29 H H CH ₂ NMe CH ₂ Q2 Q29 H H CH ₂ NMe CH ₂ Q3 Q29 H H CH ₂ NMe CH ₂ Q4 Q29 H H CH ₂ NMe CH ₂ H5 Q29 H5 Q5 H29 CH ₂ NMe CH ₂ Q6 Q29 H _{CH 2 NMe CH 2 Q7 Q29 H} H CH 2 NMe CH 2 Q8 Q29 H H CH 2 NMe CH 2 Q9 Q29 H H CH 2 NMe CH 2 Q10 Q29 H H CH 2 NMe CH 2 Q11 Q29 H H CH 2 NMe CH 2 Q12 Q29 H H CH ₂ NMe CH ₂ Q13 Q29 H H CH ₂ NMe CH ₂ Q14 Q29 H H CH ₂ NH CH ₂ Ph Ph Q31 ───────────────────── ─────────────

[0053]

[Table 18] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ───────────────────────────────────── H H CH ₂ NH CH ₂ Q1 Q31 H H CH ₂ NH CH ₂ Q2 Q31 H _{H CH 2 NH CH 2 Q3 Q31} H H CH 2 NH CH 2 Q4 Q31 H H CH 2 NH CH 2 Q5 Q31 H H CH 2 NH CH 2 Q6 Q31 H H CH 2 NH CH 2 Q7 Q31 H H CH 2 NH CH ₂ Q8 Q31 H H CH ₂ NH CH ₂ Q9 Q31 H H CH ₂ NH CH ₂ Q10 Q31 H H CH ₂ NH CH ₂ Q11 Q31 H H CH ₂ NH CH ₂ Q12 Q31 H H CH ₂ NH CH ₂ Q13 Q31 H H CH ₂ NH CH ₂ Q14 Q31 H H CH ₂ NMe CH ₂ Ph Q31 H H CH ₂ NMe CH ₂ Q1 Q31 H H CH ₂ NMe CH ₂ Q2 Q31 H H CH ₂ NMe CH ₂ Q3 Q31 H H CH ₂ NMe CH ₂ Q4 Q31 H H CH ₂ NMeQ ₃ H 5 Q5 H5 H CH ₂ NMe CH ₂ Q6 Q31 H H CH ₂ NMe CH ₂ Q7 Q31 H H CH ₂ NMe CH ₂ Q8 Q31 ───────────────────────── ─────────

[0054]

[Table 19] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 NMe CH 2} Q9 Q31 H H CH 2 NMe CH 2 Q10 Q31 H H CH ₂ NMe CH ₂ Q11 Q31 H H CH ₂ NMe CH ₂ Q12 Q31 H H CH ₂ NMe CH ₂ Q13 Q31 H H CH ₂ NMe CH ₂ Q14 Q31 H H CO NH CH ₂ Ph Ph Q30 H H CO NH Q ₂ CH ₂ Q30 H H CO NH CH ₂ Q2 Q30 H H CO NH CH ₂ Q3 Q30 H H CO NH CH ₂ Q4 Q30 H H CO CO NH CH ₂ Q5 Q30 H H CO NH CH ₂ Q6 Q30 H H CO CO NH CH ₂ Q7 Q30 H H CO NH C H ₂ Q8 Q30 H H CO NH CH ₂ Q9 Q30 H H CO NH CH ₂ Q10 Q30 H H CO NH CH ₂ Q11 Q30 H H CO NH CH ₂ Q12 Q30 H H CO NH CH ₂ Q13 Q30 H H CO NH NH ₂ Q14 Q30 H H CO NMe CH ₂ Ph Q30 H H CO NMe CH ₂ Q1 Q30 ──────────────────────────────── ─

[0055]

[Table 20] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CO NMe CH ₂ Q2 Q30 H H CO NMe CH ₂ Q3 Q30 H H CO NMe CH ₂ Q4 Q30 H H CO NMe CH ₂ Q5 Q30 H H CO NMe CH ₂ Q6 Q30 H H CO NMe CH ₂ Q7 Q30 H H CO NMe CH ₂ Q8 Q30 H H CO NMe CH ₂ HQ CO 9 HQ _{2 Q10 Q30 H H CO NMe CH} 2 Q11 Q30 H H CO NMe CH 2 Q12 Q30 H H CO NMe CH 2 Q13 Q30 H H CO NMe CH 2 Q14 Q30 H H CO Q21 CH 2 Ph Q30 H H C _{Q21 CH 2 Q1 Q30 H H CO} Q21 CH 2 Q2 Q30 H H CO Q21 CH 2 Q3 Q30 H H CO Q21 CH 2 Q4 Q30 H H CO Q21 CH 2 Q5 Q30 H H CO Q21 CH 2 Q6 Q30 H H CO Q21 CH _{2 Q7 Q30 H H CO Q21 CH} 2 Q8 Q30 H H CO Q21 CH 2 Q9 Q30 ─────────────────────────────── ──

[0056]

[Table 21] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CO Q21 CH 2 Q10} Q30 H H CO Q21 CH 2 Q11 Q30 H H CO _{Q21 CH 2 Q12 Q30 H H CO} Q21 CH 2 Q13 Q30 H H CO Q21 CH 2 Q14 Q30 H H CH 2 NH CHMe Ph Q30 H H CH 2 NH CHMe Q1 Q30 H H CH 2 NH CHMe Q2 Q30 H H CH 2 NH CHMe Q3 Q30 H H CH ₂ NH CHMe Q4 Q30 H H CH ₂ NH CHMe Q5 Q30 H H CH ₂ NH CHMe Q6 Q30 H H CH ₂ NH CHMe Q7 Q30 H H CH ₂ NH CHMe Q 8 Q30 H H CH ₂ NH CHMe Q9 Q30 H H CH ₂ NH CHMe Q10 Q30 H H CH ₂ NH CHMe Q11 Q30 H H CH ₂ NH CHMe Q12 Q30 H H CH ₂ NH CHMe Me Q13 Q30 HQ CHH NH ₂ CHCH H H CH ₂ NMe CHMe Ph Q30 H H CH ₂ NMe CHMe Q1 Q30 H H CH ₂ NMe CHMe Q2 Q30 ─────────────────────────── ───────

[0057]

[Table 22] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NMe CHMe Q3 Q30 H H CH ₂ NMe CHMe Q4 Q30 H H CH ₂ NMe CHMe Q5 Q30 H H CH ₂ NMe CHMe Q6 Q30 H H CH ₂ NMe CHMe Q7 Q30 H H CH ₂ NMe CHMe Q8 Q30 H H CH ₂ NMe CHMe Q9 Q30 HQ CHN HMe CH ₂ HMe CH ₂ HMe CH ₂ NMe CHMe Q11 Q30 H H CH ₂ NMe CHMe Q12 Q30 H H CH ₂ NMe CHMe Q13 Q30 QH H CH ₂ NMe CHMe Q14 Q30 H H CH ₂ Q21 CHMe P _{h Q30 H H CH 2 Q21 CHMe} Q1 Q30 H H CH 2 Q21 CHMe Q2 Q30 H H CH 2 Q21 CHMe Q3 Q30 H H CH 2 Q21 CHMe Q4 Q30 H H CH 2 Q21 CHMe Q5 Q30 H H CH 2 Q21 CHMe Q6 Q30 H H CH ₂ Q21 CHMe Q7 Q30 H H CH ₂ Q21 CHMe Q8 Q30 H H CH ₂ Q21 CHMe Q9 Q30 H H CH ₂ Q21 CHMe Q10 Q30 ──────────────────── ───────────────

[0058]

[Table 23] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 Q21 CHMe Q11} Q30 H H CH 2 Q21 CHMe Q12 Q30 H H CH _{2 Q21 CHMe Q13 Q30 H H CH} 2 Q21 CHMe Q14 Q30 H H CH 2 Q17 CHMe Ph Q30 H H CH 2 Q17 CHMe Q1 Q30 H H CH 2 Q17 CHMe Q2 Q30 H H CH 2 Q17 CHMe Q3 Q30 H H CH 2 Q17 CHMe Q4 Q30 H H CH ₂ Q17 CHMe Q5 Q30 H H CH ₂ Q17 CHMe Q6 Q30 H H CH ₂ Q17 CHMe Q7 Q30 H H CH ₂ Q17 CHMe Q8 _{Q30 H H CH 2 Q17 CHMe Q9} Q30 H H CH 2 Q17 CHMe Q10 Q30 H H CH 2 Q17 CHMe Q11 Q30 H H CH 2 Q17 CHMe Q12 Q30 H H CH 2 Q17 CHMe Q13 Q30 H H CH 2 Q17 CHMe Q14 Q30 H H CH ₂ Q18 CHMe Ph Ph Q30 H H CH ₂ Q18 CHMe Q1 Q30 H H CH ₂ Q18 CHMe Q2 Q30 H H CH ₂ Q18 CHMe Q3 Q30 ──────────────────── ──────────────

[0059]

[Table 24] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 Q18 CHMe Q4} Q30 H H CH 2 Q18 CHMe Q5 Q30 H H CH _{2 Q18 CHMe Q6 Q30 H H CH} 2 Q18 CHMe Q7 Q30 H H CH 2 Q18 CHMe Q8 Q30 H H CH 2 Q18 CHMe Q9 Q30 H H CH 2 Q18 CHMe Q10 Q30 H H CH 2 Q18 CHMe Q11 Q30 H H CH 2 Q18 CHMe Q12 Q30 H H CH ₂ Q18 CHMe Q13 Q30 H H CH ₂ Q18 CHMe Q14 Q30 H H CH ₂ Q22 CHMe Ph Q30 H H CH ₂ Q22 CHMe Q _{1 Q30 H H CH 2 Q22 CHMe} Q2 Q30 H H CH 2 Q22 CHMe Q3 Q30 H H CH 2 Q22 CHMe Q4 Q30 H H CH 2 Q22 CHMe Q5 Q30 H H CH 2 Q22 CHMe Q6 Q30 H H CH 2 Q22 CHMe Q7 Q30 H H CH ₂ Q22 CHMe Q8 Q30 H H CH ₂ Q22 CHMe Q9 Q30 H H CH ₂ Q22 CHMe Q10 Q30 H H CH ₂ Q22 CHMe Q11 Q30 ─────────────────── ───────────────

[0060]

[Table 25] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ Q22 CHMe Q12 Q30 H H CH ₂ Q22 CHMe Q13 Q30 H H CH _{2 Q22 CHMe Q14 Q30 H H CH} 2 Q23 CHMe Ph Q30 H H CH 2 Q23 CHMe Q1 Q30 H H CH 2 Q23 CHMe Q2 Q30 H H CH 2 Q23 CHMe Q3 Q30 H H CH 2 Q23 CHMe Q4 Q30 H H CH 2 Q23 _{CHMe Q5 Q30 H H CH 2 Q23} CHMe Q6 Q30 H H CH 2 Q23 CHMe Q7 Q30 H H CH 2 Q23 CHMe Q8 Q30 H H CH 2 Q23 CHMe Q9 _{30 H H CH 2 Q23 CHMe Q10} Q30 H H CH 2 Q23 CHMe Q11 Q30 H H CH 2 Q23 CHMe Q12 Q30 H H CH 2 Q23 CHMe Q13 Q30 H H CH 2 Q23 CHMe Q14 Q30 H H CH 2 NH Q28 Ph Q30 H H CH ₂ NH Q28 Q1 Q30 H H CH ₂ NH Q28 Q2 Q30 H H CH ₂ NH Q28 Q3 Q30 H H CH ₂ NH Q28 Q4 Q30 ─────────────────── ──────────────

[0061]

[Table 26] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NH Q28 Q5 Q30 H H CH ₂ NH Q28 Q6 Q30 H H CH _{2 NH Q28 Q7 Q30 H H CH} 2 NH Q28 Q8 Q30 H H CH 2 NH Q28 Q9 Q30 H H CH 2 NH Q28 Q10 Q30 H H CH 2 NH Q28 Q11 Q30 H H CH 2 NH Q28 Q12 Q30 H H CH 2 NH _{Q28 Q13 Q30 H H CH 2 NH} Q28 Q14 Q30 H H CH 2 NMe Q28 Ph Q30 H H CH 2 NMe Q28 Q1 Q30 H H CH 2 NMe Q28 Q2 Q30 H H CH 2 NMe Q28 Q3 Q30 _{H CH 2 NMe Q28 Q4 Q30 H} H CH 2 NMe Q28 Q5 Q30 H H CH 2 NMe Q28 Q6 Q30 H H CH 2 NMe Q28 Q7 Q30 H H CH 2 NMe Q28 Q8 Q30 H H CH 2 NMe Q28 Q9 Q30 H H CH ₂ NMe Q28 Q10 Q30 H H CH ₂ NMe Q28 Q11 Q30 H H CH ₂ NMe Q28 Q12 Q30 ───────────────────────────── ────

[0062]

[Table 27] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ───────────────────────────────────── H H CH ₂ NMe Q28 Q13 Q30 H H CH ₂ NMe Q28 Q14 Q30 H H CH _{2 Q17 CH 2 Ph Q30 H H} CH 2 Q17 CH 2 Q1 Q30 H H CH 2 Q17 CH 2 Q2 Q30 H H CH 2 Q17 CH 2 Q3 Q30 H H CH 2 Q17 CH 2 Q4 Q30 H H CH 2 Q17 CH 2 Q5 Q30 H H CH ₂ Q17 CH ₂ Q6 Q30 H H CH ₂ Q17 CH ₂ Q7 Q30 H H CH ₂ Q17 CH ₂ Q8 Q30 H H CH ₂ Q17 CH ₂ Q9 Q30 H H CH ₂ Q17 CH ₂ Q10 Q30 H H CH ₂ Q17 CH ₂ Q1 1 Q30 H H CH ₂ Q17 CH ₂ Q12 Q30 H H CH ₂ Q17 CH ₂ Q13 Q30 H H CH ₂ Q17 CH ₂ Q14 Q30 H H CH ₂ Q18 CH ₂ Ph Q30 H H CH ₂ Q18 CH ₂ Q1 Q30 H H CH _{2 Q18 CH 2 Q2 Q30 H H} CH 2 Q18 CH 2 Q3 Q30 H H CH 2 Q18 CH 2 Q4 Q30 H H CH 2 Q18 CH 2 Q5 Q30 ───────────────── ────────────────

[0063]

[Table 28] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 Q18 CH 2} Q6 Q30 H H CH 2 Q18 CH 2 Q7 Q30 H H CH ₂ Q18 CH ₂ Q8 Q30 H H CH ₂ Q18 CH ₂ Q9 Q30 H H CH ₂ Q18 CH ₂ Q10 Q30 H H CH ₂ Q18 CH ₂ Q11 Q30 H H CH ₂ Q18 CH ₂ Q12 Q30 H H CH ₂ Q18 CH ₂ Q13 Q30 H H CH ₂ Q18 CH ₂ Q14 Q30 H H CH ₂ Q23 CH ₂ Ph Q30 H H CH ₂ Q23 CH ₂ Q1 Q30 H H CH ₂ Q23 CH ₂ Q2 Q30 H H CH ₂ Q23 CH ₂ Q3 Q30 H H CH ₂ Q23 CH _{2 4 Q30 H H CH 2 Q23 CH} 2 Q5 Q30 H H CH 2 Q23 CH 2 Q6 Q30 H H CH 2 Q23 CH 2 Q7 Q30 H H CH 2 Q23 CH 2 Q8 Q30 H H CH 2 Q23 CH 2 Q9 Q30 H H CH _{2 Q23 CH 2 Q10 Q30 H H} CH 2 Q23 CH 2 Q11 Q30 H H CH 2 Q23 CH 2 Q12 Q30 H H CH 2 Q23 CH 2 Q13 Q30 ───────────────── ────────────────

[0064]

[Table 29] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ Q23 CH ₂ Q14 Q30 H H CH ₂ Q21 Q27 Ph Ph Q30 H H _{CH 2 Q21 Q27 Q1 Q30 H H} CH 2 Q21 Q27 Q2 Q30 H H CH 2 Q21 Q27 Q3 Q30 H H CH 2 Q21 Q27 Q4 Q30 H H CH 2 Q21 Q27 Q5 Q30 H H CH 2 Q21 Q27 Q6 Q30 H H CH 2 _{Q21 Q27 Q7 Q30 H H CH 2} Q21 Q27 Q8 Q30 H H CH 2 Q21 Q27 Q9 Q30 H H CH 2 Q21 Q27 Q10 Q30 H H CH 2 Q21 Q27 Q11 Q30 H H CH 2 Q21 Q _{7 Q12 Q30 H H CH 2 Q21} Q27 Q13 Q30 H H CH 2 Q21 Q27 Q14 Q30 H H CH 2 Q17 CH 2 Ph Ph H H CH 2 Q17 CH 2 Q1 Ph H H CH 2 Q17 CH 2 Q2 Ph H H CH 2 Q17 CH ₂ Q3 Ph H H CH ₂ Q17 CH ₂ Q4 Ph H H CH ₂ Q17 CH ₂ Q5 Ph H H H CH ₂ Q17 CH ₂ Q6 Ph Ph ────────────────── ───────────────

[0065]

[Table 30] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ───────────────────────────────────── H H CH ₂ Q17 CH ₂ Q7 Ph H H CH ₂ Q17 CH ₂ Q8 Ph H H CH ₂ Q17 CH ₂ Q9 Ph H H CH ₂ Q17 CH ₂ Q10 Ph H H CH ₂ Q17 CH ₂ Q11 Ph H H CH ₂ Q17 CH ₂ Q12 PhH H CH ₂ Q17 CH ₂ Q13 Ph H H CH ₂ Q17 CH ₂ Q14 Ph H H CH ₂ Q18 CH ₂ Ph Ph H H CH ₂ Q18 CH ₂ Q1 Ph H H CH ₂ Q18 CH ₂ Q2 Ph H H CH ₂ Q18 CH ₂ Q3 Ph H H CH ₂ Q18 CH ₂ Q4 Ph H H CH ₂ Q18 CH ₂ Q5 Ph H H CH ₂ Q18 CH ₂ Q6 Ph H H CH ₂ Q18 CH ₂ Q7 Ph H H H CH ₂ Q18 CH ₂ Q8 Ph H H CH ₂ Q18 CH ₂ Q9 Ph H H CH ₂ Q18 CH ₂ Q10 Ph H H CH ₂ Q18 CH ₂ Q11 Ph H H CH ₂ Q18 CH ₂ Q12 Ph H H CH ₂ Q18 CH ₂ Q13 Ph H H CH ₂ Q18 CH ₂ Q14 Ph ──────────────────────── ─────────

[0066]

[Table 31] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NH CHMe Me Ph Ph H H CH ₂ NH CHMe Q1 Ph H H CH _{2 NH CHMe Q2 Ph H H CH} 2 NH CHMe Q3 Ph H H CH 2 NH CHMe Q4 Ph H H CH 2 NH CHMe Q5 Ph H H CH 2 NH CHMe Q6 Ph H H CH 2 NH CHMe Q7 Ph H H CH 2 NH _{CHMe Q8 Ph H H CH 2 NH} CHMe Q9 Ph H H CH 2 NH CHMe Q10 Ph H H CH 2 NH CHMe Q11 Ph H H CH 2 NH CHMe Q12 Ph H H CH 2 NH CHMe Q13 Ph H H CH 2 _{NH CHMe Q14 Ph H H CH 2} NMe CHMe Ph Ph H H CH 2 NMe CHMe Q1 Ph H H CH 2 NMe CHMe Q2 Ph H H CH 2 NMe CHMe Q3 Ph H H CH 2 NMe CHMe Q4 Ph H H CH 2 NMe CHMe Q5 Ph H H CH ₂ NMe CHMe Q6 Ph H H CH ₂ NMe CHMe Q7 Ph ────────────────────────────────── ─

[0067]

[Table 32] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NMe CHMe Q8 Ph H H CH ₂ NMe CHMe Q9 Ph H H CH _{2 NMe CHMe Q10 Ph H H CH} 2 NMe CHMe Q11 Ph H H CH 2 NMe CHMe Q12 Ph H H CH 2 NMe CHMe Q13 Ph H H CH 2 NMe CHMe Q14 Ph H H CH 2 NH Q28 Ph Ph H H CH 2 NH _{Q28 Q1 Ph H H CH 2 NH} Q28 Q2 Ph H H CH 2 NH Q28 Q3 Ph H H CH 2 NH Q28 Q4 Ph H H CH 2 NH Q28 Q5 Ph H H CH 2 NH Q28 Q6 Ph H H C _{2 NH Q28 Q7 Ph H H CH} 2 NH Q28 Q8 Ph H H CH 2 NH Q28 Q9 Ph H H CH 2 NH Q28 Q10 Ph H H CH 2 NH Q28 Q11 Ph H H CH 2 NH Q28 Q12 Ph H H CH 2 NH Q28 Q13 Ph H H CH ₂ NH Q28 Q14 Ph H H CH ₂ NMe Q28 Ph Ph Ph ──────────────────────────────── ──

[0068]

[Table 33] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ NMe Q28 Q1 Ph H H CH ₂ NMe Q28 Q2 Ph H H H CH _{2 NMe Q28 Q3 Ph H H CH} 2 NMe Q28 Q4 Ph H H CH 2 NMe Q28 Q5 Ph H H CH 2 NMe Q28 Q6 Ph H H CH 2 NMe Q28 Q7 Ph H H CH 2 NMe Q28 Q8 Ph H H CH 2 NMe _{Q28 Q9 Ph H H CH 2 NMe} Q28 Q10 Ph H H CH 2 NMe Q28 Q11 Ph H H CH 2 NMe Q28 Q12 Ph H H CH 2 NMe Q28 Q13 Ph H H CH 2 NMe Q28 Q14 Ph H H C _{2 Q21 CHMe Ph Ph H H CH} 2 Q21 CHMe Q1 Ph H H CH 2 Q21 CHMe Q2 Ph H H CH 2 Q21 CHMe Q3 Ph H H CH 2 Q21 CHMe Q4 Ph H H CH 2 Q21 CHMe Q5 Ph H H CH 2 Q21 CHMe Q6 Ph H H CH ₂ Q21 CHMe Q7 Ph H H CH ₂ Q21 CHMe Q8 Ph ─────────────────────────────── ──

[0069]

[Table 34] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 Q21 CHMe Q9} Ph H H CH 2 Q21 CHMe Q10 Ph H H CH _{2 Q21 CHMe Q11 Ph H H CH} 2 Q21 CHMe Q12 Ph H H CH 2 Q21 CHMe Q13 Ph H H CH 2 Q21 CHMe Q14 Ph H H CH 2 Q21 Q24 Ph Ph H H CH 2 Q21 Q24 Q1 Ph H H CH 2 Q21 _{Q24 Q2 Ph H H CH 2 Q21} Q24 Q3 Ph H H CH 2 Q21 Q24 Q4 Ph H H CH 2 Q21 Q24 Q5 Ph H H CH 2 Q21 Q24 Q6 Ph H H CH 2 Q21 Q24 Q7 _{h H H CH 2 Q21 Q24 Q8} Ph H H CH 2 Q21 Q24 Q9 Ph H H CH 2 Q21 Q24 Q10 Ph H H CH 2 Q21 Q24 Q11 Ph H H CH 2 Q21 Q24 Q12 Ph H H CH 2 Q21 Q24 Q13 Ph H H CH ₂ Q21 Q24 Q14 Ph H H CH ₂ CH ₂ Q21 CHMe Ph Q30 H H CH ₂ CH ₂ Q21 Q21 CHMe Q1 Q30 ─────────────────────── ──────────

[0070]

[Table 35] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 CH 2 Q21} CHMe Q2 Q30 H H CH 2 CH 2 Q21 CHMe Q3 Q30 H H CH ₂ CH ₂ Q21 CHMe Q4 Q30 H H CH ₂ CH ₂ Q21 CHMe Q5 Q30 H H CH ₂ CH ₂ Q21 CHMe Q6 Q30 H H CH ₂ CH ₂ Q21 CHMe Q7 Q30 H H Q2 CH2 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH _{2 Q30 H H CH 2 CH 2 Q21} CHMe Q9 Q30 H H CH 2 CH 2 Q21 CHMe Q10 Q30 H H CH 2 CH 2 Q21 CHMe Q11 Q30 H H CH 2 CH 2 Q21 CHMe Q12 Q30 H H CH ₂ CH ₂ Q21 CHMe Q13 Q30 QH H CH ₂ CH ₂ Q21 CHMe Q14 Q30 H H CH ₂ CH ₂ CH2 Q21 CH ₂ Ph Q30 H H CH ₂ CH ₂ Q21 CH ₂ Q1 Q30 H H CH ₂ CH ₂ Q21 CH ₂ Q2 Q30 H H CH ₂ CH ₂ Q 21 CH ₂ Q 3 Q 30 H H CH ₂ CH ₂ Q 21 CH ₂ Q ₄ Q 30 H H CH ₂ CH ₂ Q 21 CH ₂ Q 5 Q 30 H H CH ₂ CH ₂ Q 21 CH ₂ Q 6 Q 30 H H CH ₂ CH _{2 Q21 CH 2 Q7 Q30 H H} CH 2 CH 2 Q21 CH 2 Q8 Q30 H H CH 2 CH 2 Q21 CH 2 Q9 Q30 ────────────────────── ───────────

[0071]

[Table 36] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 CH 2 Q21} CH 2 Q10 Q30 H H CH 2 CH 2 Q21 CH ₂ Q11 Q30 H H CH ₂ CH ₂ Q21 CH ₂ Q12 Q30 H H CH ₂ CH ₂ Q21 CH ₂ Q13 Q30 H H CH ₂ CH ₂ Q21 CH ₂ Q14 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Ph Ph Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q1 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q2 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q3 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q4 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q5 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q6 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q7 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q8 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q9 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q10 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q11 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q12 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q13 Q30 H H CH ₂ CH ₂ Q22 CH ₂ Q14 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Ph Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q1 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q2 Q30 ──────────────────────────── ──────

[0072]

[Table 37] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CH 2 CH 2 Q23} CH 2 Q3 Q30 H H CH 2 CH 2 Q23 CH ₂ Q4 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q5 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q6 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q7 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q8 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q9 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q10 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q11 Q30 H H CH ₂ CH ₂ Q23 CH ₂ Q12 Q30 H H CH ₂ CH ₂ Q23 CH _{2 Q13 Q30 H H CH 2 CH 2} Q23 CH 2 Q 14 Q30 H H CH ₂ CH ₂ NH CHMe Ph Q30 H H CH ₂ CH ₂ NH CHMe Q1 Q30 H H CH ₂ CH ₂ NH CHMe Q2 Q30 H H CH ₂ CH ₂ NH CHMe Q3 Q30 H H CH ₂ CH ₂ CH ₂ NH _{Q4 Q30 H H CH 2 CH 2} NH CHMe Q5 Q30 H H CH 2 CH 2 NH CHMe Q6 Q30 H H CH 2 CH 2 NH CHMe Q7 Q30 H H CH 2 CH 2 NH CHMe Q8 Q30 H H CH 2 CH 2 NH CHMe Q9 Q30 H H CH ₂ CH ₂ NH CHMe Q10 Q30 ──────────────────────────────────

[0073]

[Table 38] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ NH CHMe Q11 Q30 H H CH ₂ CH ₂ NH CHMe Q12 Q30 H H CH ₂ CH ₂ NH CHMe Q13 Q30 H H CH ₂ CH ₂ NH CHMe Q14 Q30 H H CH ₂ CH ₂ NMe CHMe Ph Ph Q30 H H CH ₂ CH ₂ NMe CHMe CH1 Q30 H H CHe CH ₂ CH ₂ CH ₂ CH ₂ CH 2M Q30 H H CH ₂ CH ₂ NMe CHMe Q3 Q30 H H CH ₂ CH ₂ NMe CHMe Q4 Q30 H H CH ₂ CH ₂ NMe CHMe Q5 Q30 H H CH ₂ CH ₂ NMe CHMe Q6 Q30 H H CH _{2 CH 2 NMe CHMe Q7 Q30 H H} CH 2 CH 2 NMe CHMe Q8 Q30 H H CH 2 CH 2 NMe CHMe Q9 Q30 H H CH 2 CH 2 NMe CHMe Q10 Q30 H H CH 2 CH 2 NMe CHMe Q11 Q30 H H CH 2 CH ₂ NMe CHMe Q12 Q30 H H CH ₂ CH ₂ NMe CHMe Q13 Q30 H H CH ₂ CH ₂ NMe CHMe Q14 Q30 H H CH ₂ CH ₂ NH CH ₂ CH ₂ Ph ₂ Q ₂ H ₂ CH ₂ CH ₂ NH ₂ CH ₂ Q1 Q30 H H CH ₂ CH ₂ NH CH ₂ CH ₂ Q2 Q30 H H CH ₂ CH ₂ NH CH ₂ CH ₂ Q3 Q30 ────────────────────── ───────────

[0074]

[Table 39] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ NH CH ₂ CH ₂ Q ₄ Q 30 H H CH ₂ CH ₂ NH CH ₂ CH ₂ Q 5 Q 30 H H CH ₂ CH ₂ NH CH ₂ CH ₂ Q 6 Q 30 H H CH ₂ CH ₂ NH CH ₂ CH ₂ Q 7 Q 30 H H CH ₂ CH ₂ NH CH ₂ CH ₂ Q 8 Q 30 H H CH _{2 CH 2 NH CH 2 CH 2 Q9} Q30 H H CH 2 CH 2 NH CH 2 CH 2 Q10 Q30 H H CH 2 CH 2 NH CH 2 CH 2 Q11 Q30 H H CH 2 CH 2 NH CH 2 CH 2 Q12 Q30 H H _{CH 2 CH 2 NH CH 2 CH} 2 Q13 Q30 H H CH 2 CH 2 NH CH 2 CH 2 Q14 Q30 H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Ph Q 30 H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Q 1 Q 30 H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Q ₂ Q 30 H H CH ₂ CH ₂ NMe CH _{2 CH 2 Q3 Q30 H H CH 2} CH 2 NMe CH 2 CH 2 Q4 Q30 H H CH 2 CH 2 NMe CH 2 CH 2 Q5 Q30 H H CH 2 CH 2 NMe CH 2 CH 2 Q6 Q30 H H CH 2 CH 2 NMe CH ₂ CH ₂ Q7 Q30 H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Q8 Q30 H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Q9 Q30 H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Q10 Q30 H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Q11 Q30 ──────────────────────────────────

[0075]

[Table 40] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Q 12 Q 30 H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Q13 Q30 H H CH ₂ CH ₂ NMe CH ₂ CH ₂ Q14 Q30 H H CH ₂ CH ₂ NH COCH ₂ Ph Q30 H H CH ₂ CH ₂ NH COCH ₂ Q1 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q2 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q3 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q4 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q5 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q6 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q7 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q8 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q9 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q10 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q11 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q12 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q13 Q30 H H CH ₂ CH ₂ NH COCH ₂ Q14 Q30 H H CH ₂ CH ₂ NMe COCH ₂ Ph Q30 H H CH ₂ CH ₂ NMe COCH ₂ Q1 Q30 H H CH ₂ CH ₂ NMe COCH ₂ Q2 Q30 H H CH ₂ CH ₂ NMe COCH ₂ Q3 Q30 H H CH ₂ CH ₂ NMe COCH ₂ Q4 Q30 ─────────────────── ───────────────

[0076]

[Table 41] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ NMe COCH ₂ Q5 Q30 H H CH ₂ CH ₂ NMe COCH ₂ Q6 Q30 H H CH ₂ CH ₂ NMe COCH ₂ Q7 Q30 H H CH ₂ CH ₂ NMe COCH ₂ Q8 Q30 H H CH ₂ CH ₂ NMe COCH ₂ Q9 Q30 H H CH ₂ CH ₂ NMe COCH ₂ Q10 CH30 H _{2 CH 2 NMe COCH 2 Q11 Q30} H H CH 2 CH 2 NMe COCH 2 Q12 Q30 H H CH 2 CH 2 NMe COCH 2 Q13 Q30 H H CH 2 CH 2 NMe COCH 2 Q14 Q30 H H CH 2 CH 2 NH Q24 P _{Q30 H H CH 2 CH 2 NH} Q24 Q1 Q30 H H CH 2 CH 2 NH Q24 Q2 Q30 H H CH 2 CH 2 NH Q24 Q3 Q30 H H CH 2 CH 2 NH Q24 Q4 Q30 H H CH 2 CH 2 NH Q24 Q5 _{Q30 H H CH 2 CH 2 NH} Q24 Q6 Q30 H H CH 2 CH 2 NH Q24 Q7 Q30 H H CH 2 CH 2 NH Q24 Q8 Q30 H H CH 2 CH 2 NH Q24 Q9 Q30 H H CH 2 CH 2 NH Q24 Q10 Q30 H H CH ₂ CH ₂ NH Q24 Q11 Q30 H H CH ₂ CH ₂ NH Q24 Q12 Q30 ────────────────────────────── ────

[0077]

[Table 42] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ NH Q24 Q13 Q30 H H CH ₂ CH ₂ NH Q24 Q14 _{Q30 H H CH 2 CH 2 NMe} Q24 Ph Q30 H H CH 2 CH 2 NMe Q24 Q1 Q30 H H CH 2 CH 2 NMe Q24 Q2 Q30 H H CH 2 CH 2 NMe Q24 Q3 Q30 H H CH 2 CH 2 NMe Q24 Q4 _{Q30 H H CH 2 CH 2 NMe} Q24 Q5 Q30 H H CH 2 CH 2 NMe Q24 Q6 Q30 H H CH 2 CH 2 NMe Q24 Q7 Q30 H H CH 2 CH 2 NMe Q24 Q8 Q30 H H CH 2 CH 2 NMe Q24 Q 9 Q30 H H CH ₂ CH ₂ NMe Q24 Q10 Q30 H H CH ₂ CH ₂ NMe Q24 Q11 Q30 H H CH ₂ CH ₂ NMe Q24 Q12 Q30 H H CH ₂ CH ₂ NMe Q24 Q13 Q30 H H N CH ₂ CH ₂ CH ₂ CH ₂ Q Q14 Q30 H H CH ₂ CH ₂ NH CH ₂ Ph Ph H H CH ₂ CH ₂ NH CH ₂ Q 1 Ph H H CH ₂ CH ₂ NH CH ₂ Q 2 Ph H H CH ₂ CH ₂ NH CH ₂ Q 3 Ph H H CH ₂ CH ₂ NH CH ₂ Q4 Ph H H CH ₂ CH ₂ NH CH ₂ Q5 Ph ───────────────────────────────── ─

[0078]

[Table 43] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ NH CH ₂ Q 6 Ph H H CH ₂ CH ₂ NH CH ₂ Q7 Ph H H CH ₂ CH ₂ NH CH ₂ Q8 Ph H H CH ₂ CH ₂ NH CH ₂ Q9 Ph H H CH ₂ CH ₂ NH CH ₂ Q10 Ph H H CH ₂ CH ₂ NH CH ₂ Q11 Ph H H CH ₂ CH ₂ NH CH ₂ Q12 Ph H H CH ₂ CH ₂ NH CH ₂ Q13 Ph H H CH ₂ CH ₂ NH CH ₂ Q14 Ph H H CH ₂ CH ₂ NMe CH ₂ Ph Ph H H CH ₂ CH ₂ NMe CH _{2 Q1 Ph H H CH 2 CH 2} NMe CH 2 Q2 Ph H H CH 2 CH 2 NMe CH 2 _{3 Ph H H CH 2 CH 2} NMe CH 2 Q4 Ph H H CH 2 CH 2 NMe CH 2 Q5 Ph H H CH 2 CH 2 NMe CH 2 Q6 Ph H H CH 2 CH 2 NMe CH 2 Q7 Ph H H CH 2 CH ₂ NMe CH ₂ Q8 Ph H H CH ₂ CH ₂ NMe CH ₂ Q9 Ph H H CH ₂ CH ₂ NMe CH ₂ Q10 Ph H H CH ₂ CH ₂ NMe CH ₂ Q11 Ph H H CH ₂ CH ₂ NMe CH ₂ Q12 Ph H H CH ₂ CH ₂ NMe CH ₂ Q13 Ph ─────────────────────────────────

[0079]

[Table 44] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ NMe CH ₂ Q14 Ph H H CH ₂ CH ₂ Q17 CH ₂ Ph Ph H H CH ₂ CH ₂ Q17 CH ₂ Q1 Ph H H CH ₂ CH ₂ Q17 CH ₂ Q2 Ph H H CH ₂ CH ₂ Q17 CH ₂ Q3 Ph H H CH ₂ CH ₂ Q17 CH ₂ Q4 Ph H H CH ₂ CH ₂ Q17 CH ₂ Q5 Ph H H CH ₂ CH ₂ Q17 CH ₂ Q6 Ph H H CH ₂ CH ₂ Q17 CH ₂ Q7 Ph H H CH ₂ CH ₂ Q17 CH ₂ Q8 Ph H H CH ₂ CH ₂ Q17 CH _{2 Q9 Ph H H CH 2 CH 2} Q17 CH 2 Q10 Ph H H CH 2 CH 2 _{17 CH 2 Q11 Ph H H CH} 2 CH 2 Q17 CH 2 Q12 Ph H H CH 2 CH 2 Q17 CH 2 Q13 Ph H H CH 2 CH 2 Q17 CH 2 Q14 Ph H H CH 2 CH 2 Q18 CH 2 Ph Ph H _{H CH 2 CH 2 Q18 CH 2} Q1 Ph H H CH 2 CH 2 Q18 CH 2 Q2 Ph H H CH 2 CH 2 Q18 CH 2 Q3 Ph H H CH 2 CH 2 Q18 CH 2 Q4 Ph H H CH 2 CH 2 Q18 CH ₂ Q5 Ph H H CH ₂ CH ₂ Q18 CH ₂ Q6 Ph ──────────────────────────────────

[0080]

[Table 45] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ Q18 CH ₂ Q7 Ph H H CH ₂ CH ₂ Q18 CH ₂ Q8 Ph H H CH ₂ CH ₂ Q18 CH ₂ Q9 Ph H H CH ₂ CH ₂ Q18 CH ₂ Q10 Ph H H CH ₂ CH ₂ Q18 CH ₂ Q11 Ph H H CH ₂ CH ₂ Q18 CH ₂ Q12 Ph H H CH ₂ CH ₂ Q18 CH ₂ Q13 Ph H H CH ₂ CH ₂ Q18 CH ₂ Q14 Ph H H CH ₂ CH ₂ Q21 CH ₂ Ph Ph H H CH ₂ CH ₂ Q21 CH ₂ Q1 Ph H H CH ₂ CH ₂ Q21 CH _{2 Q2 Ph H H CH 2 CH 2} Q21 CH 2 Q3 Ph H H CH 2 _{H 2 Q21 CH 2 Q4 Ph H} H CH 2 CH 2 Q21 CH 2 Q5 Ph H H CH 2 CH 2 Q21 CH 2 Q6 Ph H H CH 2 CH 2 Q21 CH 2 Q7 Ph H H CH 2 CH 2 Q21 CH 2 Q8 _{Ph H H CH 2 CH 2 Q21} CH 2 Q9 Ph H H CH 2 CH 2 Q21 CH 2 Q10 Ph H H CH 2 CH 2 Q21 CH 2 Q11 Ph H H CH 2 CH 2 Q21 CH 2 Q12 Ph H H CH 2 CH _{2 Q21 CH 2 Q13 Ph H H} CH 2 CH 2 Q21 CH 2 Q14 Ph ─────────────────────────────────

[0081]

[Table 46] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ Q22 CH ₂ Ph Ph H H H CH ₂ CH ₂ Q22 CH ₂ Q1 Ph H H CH ₂ CH ₂ Q22 CH ₂ Q2 Ph H H CH ₂ CH ₂ Q22 CH ₂ Q3 Ph H H CH ₂ CH ₂ Q22 CH ₂ Q4 Ph H H CH ₂ CH ₂ Q22 CH ₂ Q5 Ph H H CH ₂ CH ₂ Q22 CH ₂ Q6 Ph H H CH ₂ CH ₂ Q22 CH ₂ Q7 Ph H H CH ₂ CH ₂ Q22 CH ₂ Q8 Ph H H CH ₂ CH ₂ Q22 CH ₂ Q9 Ph H H CH ₂ CH ₂ Q22 CH _{2 Q10 Ph H H CH 2 CH 2} Q22 CH 2 Q11 Ph H H CH 2 CH 2 _{22 CH 2 Q12 Ph H H CH} 2 CH 2 Q22 CH 2 Q13 Ph H H CH 2 CH 2 Q22 CH 2 Q14 Ph H H CH 2 CH 2 Q23 CH 2 Ph Ph H H CH 2 CH 2 Q23 CH 2 Q1 Ph H _{H CH 2 CH 2 Q23 CH 2} Q2 Ph H H CH 2 CH 2 Q23 CH 2 Q3 Ph H H CH 2 CH 2 Q23 CH 2 Q4 Ph H H CH 2 CH 2 Q23 CH 2 Q5 Ph H H CH 2 CH 2 Q23 CH ₂ Q6 Ph H H CH ₂ CH ₂ Q23 CH ₂ Q7 Ph ──────────────────────────────────

[0082]

[Table 47] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CH ₂ Q23 CH ₂ Q8 Ph H H CH ₂ CH ₂ Q23 CH ₂ Q9 Ph H H CH ₂ CH ₂ Q23 CH ₂ Q10 Ph H H CH ₂ CH ₂ Q23 CH ₂ Q11 Ph H H CH ₂ CH ₂ Q23 CH ₂ Q12 Ph H H CH ₂ CH ₂ Q23 CH ₂ Q13 Ph H H CH ₂ CH ₂ Q23 CH ₂ Q14 Ph H H CO NH CH ₂ Ph Ph Ph H H CO NH CH ₂ Q1 Ph H H H CO NH CH ₂ Q2 Ph H H CO NH CH ₂ Q3 Ph H H CO NH CH ₂ Q4 Ph H H CO NH CH ₂ Q5 Ph H H CO CO NH CH ₂ Q6 Ph H H CO NH CH ₂ Q7 Ph H H CO NH CH ₂ Q8 Ph H H CO CO NH CH ₂ Q9 Ph H H H CO NH CH ₂ Q10 Ph H H CO CO NH CH ₂ Q11 Ph H H CO NH CH ₂ Q12 Ph H H CO NH CH ₂ Q13 Ph H H CO NH CH ₂ Q14 Ph H H CO NMe CH ₂ Ph Ph ───────────────────────────── ─────

[0083]

[Table 48] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ───────────────────────────────────── H H CO NMe CH ₂ Q1 Ph H H CO NMe CH ₂ Q2 Ph H H CO NMe CH ₂ Q3 Ph H H CO NMe CH ₂ Q4 Ph H H CO NMe CH ₂ Q5 Ph H H CO NMe CH ₂ Q6 Ph H H CO NMe CH ₂ Q7 Ph H H CO NMe CH ₂ H8COH _{2 Q9 Ph H H CO NMe CH} 2 Q10 Ph H H CO NMe CH 2 Q11 Ph H H CO NMe CH 2 Q12 Ph H H CO NMe CH 2 Q13 Ph H H CO NMe CH 2 Q14 Ph H H CO Q21 CH 2 Ph Ph H H _{CO Q21 CH 2 Q1 Ph H H} CO Q21 CH 2 Q2 Ph H H CO Q21 CH 2 Q3 Ph H H CO Q21 CH 2 Q4 Ph H H CO Q21 CH 2 Q5 Ph H H CO Q21 CH 2 Q6 Ph H H CO Q21 CH ₂ Q7 Ph H H CO Q21 CH ₂ Q8 Ph ──────────────────────────────────

[0084]

[Table 49] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── H H CO Q21 CH 2 Q9} Ph H H CO Q21 CH 2 Q10 Ph H H CO Q21 CH ₂ Q11 Ph H H CO CO21 CH ₂ Q12 Ph H H CO Q21 CH ₂ Q13 Ph H H CO Q21 CH ₂ Q14 Ph H H CH ₂ CO NMe CH ₂ Ph Ph Q30 H H CH ₂ CO NMeQ 30 H 1 Q ₂ H _{H CH 2 CO NMe CH 2 Q2} Q30 H H CH 2 CO NMe CH 2 Q3 Q30 H H CH 2 CO NMe CH 2 Q4 Q30 H H CH 2 CO NMe CH 2 Q5 Q30 H H CH 2 CO NMe CH 2 Q6 Q30 H H CH _{2 O NMe CH 2 Q7 Q30 H H} CH 2 CO NMe CH 2 Q8 Q30 H H CH 2 CO NMe CH 2 Q9 Q30 H H CH 2 CO NMe CH 2 Q10 Q30 H H CH 2 CO NMe CH 2 Q11 Q30 H H CH 2 CO NMe CH ₂ Q12 Q30 H H CH ₂ CO NMe CH ₂ Q13 Q30 H H CH ₂ CO NMe CH ₂ Q14 Q30 H H CH ₂ CO Q21 CH ₂ Ph Q30 H H CH ₂ CO Q21 CH ₂ Q1 Q30 ── ─────────────────────────────

[0085]

[Table 50] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CO Q21 CH ₂ Q2 Q30 H H CH ₂ CO Q21 CH ₂ Q3 _{Q30 H H CH 2 CO Q21 CH} 2 Q4 Q30 H H CH 2 CO Q21 CH 2 Q5 Q30 H H CH 2 CO Q21 CH 2 Q6 Q30 H H CH 2 CO Q21 CH 2 Q7 Q30 H H CH 2 CO Q21 CH 2 Q8 Q30 H H CH ₂ CO Q21 CH ₂ Q9 Q30 H H CH ₂ CO Q21 CH ₂ Q10 Q30 H H CH ₂ CO Q21 CH ₂ Q11 Q30 H H CH ₂ CO Q21 CH ₂ Q12 Q30 H H CH ₂ CO Q21 CH ₂ Q13 Q30 H H _{H 2 CO Q21 CH 2 Q14 Q30} H H CH 2 CO NH CH 2 Ph Q30 H H CH 2 CO NH CH 2 Q1 Q30 H H CH 2 CO NH CH 2 Q2 Q30 H H CH 2 CO NH CH 2 Q3 Q30 H H _{CH 2 CO NH CH 2 Q4 Q30} H H CH 2 CO NH CH 2 Q5 Q30 H H CH 2 CO NH CH 2 Q6 Q30 H H CH 2 CO NH CH 2 Q7 Q30 H H CH 2 CO NH CH 2 Q8 Q30 H H CH ₂ CO NH CH ₂ Q9 Q30 ──────────────────────────────────

[0086]

[Table 51] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CH ₂ CO NH CH ₂ Q10 Q30 H H CH ₂ CO NH CH ₂ Q11 Q30 H H CH ₂ CO NH CH ₂ Q12 Q30 H H CH ₂ CO NH CH ₂ Q13 Q30 H H CH ₂ CO NH CH ₂ Q14 Q30 H H CO Q21 CHMe Ph Ph30 H H CO Q21 CHMe Q1 Q30 HCH COe Q2 Q30 H H CO Q21 CHMe Q3 Q30 H H CO Q21 CHMe Q4 Q30 H H CO CO21 CHMe Q5 Q30 H H CO Q21 CHMe Q6 Q30 H H CO Q21 CHMe Q7 Q30 HCO Q21 CHMe Q8 Q30 H H CO Q21 CHMe Q9 Q30 H H CO Q21 CHMe Q10 Q30 H H CO Q21 CHMe Q11 Q30 H H CO Q21 CHMe Q21 HQ COH21 Q30 HQ COH21 Q30 HQ H13 CHQ CO NH CHMe Ph Q30 H H CO NH CHMe Q1 Q30 H H CO NH CHMe Me Q2 Q30 ─────────────────────────────── ──

[0087]

[Table 52] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── H H CO NH CHMe Q3 Q30 H H CO CO NH CHMe Q4 Q30 H H CO NH CHMe Q5 Q30 H H CO NH CHMe Q6 Q30 H H CO NH CHMe Q7 Q30 H H CO CO NH CHMe Q8 Q30 H H CO NH CHMe Q9 Q30 H H CO NH CHQ COH 11 HQ COH 11 HQ COH 11 Q30 H H CO NH CHMe Q13 Q30 H H CO NH CHMe Q14 Q30 H H CO Q22 CH 2 Ph Q30 H H CO Q22 CH 2 Q1 Q30 _{H CO Q22 CH 2 Q2 Q30 H} H CO Q22 CH 2 Q3 Q30 H H CO Q22 CH 2 Q4 Q30 H H CO Q22 CH 2 Q5 Q30 H H CO Q22 CH 2 Q6 Q30 H H CO Q22 CH 2 Q7 Q30 H H CO _{Q22 CH 2 Q8 Q30 H H CO} Q22 CH 2 Q9 Q30 H H CO Q22 CH 2 Q10 Q30 ───────────────────────────── ────

[0088]

[Table 53] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── _{─────────────────────────────── H H CO Q22 CH 2 Q11} Q30 H H CO Q22 CH 2 Q12 Q30 H H CO _{Q22 CH 2 Q13 Q30 H H CO} Q22 CH 2 Q14 Q30 H H CO Q23 CH 2 Ph Q30 H H CO Q23 CH 2 Q1 Q30 H H CO Q23 CH 2 Q2 Q30 H H CO Q23 CH 2 Q3 Q30 H H CO Q23 CH _{2 Q4 Q30 H H CO Q23 CH} 2 Q5 Q30 H H CO Q23 CH 2 Q6 Q30 H H CO Q23 CH 2 Q7 Q30 H H CO Q23 CH 2 Q8 Q30 H H CO Q23 CH 2 Q9 Q30 H H CO _{23 CH 2 Q10 Q30 H H CO} Q23 CH 2 Q11 Q30 H H CO Q23 CH 2 Q12 Q30 H H CO Q23 CH 2 Q13 Q30 H H CO Q23 CH 2 Q14 Q30 H H CO NMe CHMe Ph Q30 H H CO NMe CHMe Q1 Q30 H H CO NMe CHMe Q2 Q30 H H CO NMe CHMe Q3 Q30 ──────────────────────────────────

[0089]

[Table 54] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── H H CO NMe CHMe Q4 Q30 H H CO NMe CHMe Q5 Q30 H H CO NMe CHMe Q6 Q30 H H CO NMe CHMe Q7 Q30 H H CO NMe CHMe Q8 Q30 H H CO NMe CHMe Q9 Q30 H H CO NMe CHMe Q10 Q30 HH CO CO NMe CHMe HQ COHMe Q11 H30 HQ CO HMe COQ Me HQ HQ CO Q30 H H CO NMe CHMe Q14 Q30 5-Me H CH ₂ NH CHMe Q1 Q30 5-Me H CH ₂ NH CHMe Q2 Q30 5-Me H C H ₂ NH CHMe Q6 Q30 5-Me H CH ₂ NMe CHMe Q1 Q30 5-Me H CH ₂ NMe CHMe Q2 Q30 5-Me H CH ₂ NMe CHMe Q6 Q30 5-Me H CH ₂ Q21 CHMe Q1 Q30 5-Me H CH ₂ Q21 CHMe Q2 Q30 5-Me H CH ₂ Q21 CHMe Q6 Q30 5-Me H CH ₂ NH CH ₂ Q1 Q30 5-Me H CH ₂ NH CH ₂ Q2 Q30 5-Me H CH ₂ NH CH ₂ Q6 Q30 ─ ────────────────────────────────

[0090]

[Table 55] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── 5-Me H CH ₂ NMe CH ₂ Q1 Q30 5-Me H CH ₂ NMe CH ₂ Q2 Q30 5-Me H CH ₂ NMe CH ₂ Q6 Q30 5-Me H CH ₂ Q21 CH ₂ Q1 Q30 5-Me H CH ₂ Q21 CH ₂ Q2 Q30 5-Me H CH ₂ Q21 CH ₂ Q6 Q30 5-Me H CH ₂ NH CHMe Q1 Ph 5-Me H CH ₂ NH CHMe Q2 Ph 5-Me H CH ₂ NH CHMe Q6 Ph 5-Me H CH ₂ NMe CHMe Q1 Ph 5-Me H CH ₂ NMe CHMe Q2 Ph 5-Me _{H CH 2 NMe CHMe Q6 Ph 5} -Me H CH 2 Q21 CHMe Q1 Ph 5-Me H CH 2 Q21 CHMe _{2 Ph 5-Me H CH 2} Q21 CHMe Q6 Ph 5-Me H CH 2 NH CH 2 Q1 Ph 5-Me H CH 2 NH CH 2 Q2 Ph 5-Me H CH 2 NH CH 2 Q6 Ph 5-Me H CH ₂ NMe CH ₂ Q1 Ph 5-Me H CH ₂ NMe CH ₂ Q2 Ph 5-Me H CH ₂ NMe CH ₂ Q6 Ph 5-Me H CH ₂ Q21 CH ₂ Q1 Ph 5-Me H CH ₂ Q21 CH ₂ Q2 Ph ──────────────────────────────────

[0091]

[Table 56] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── _{─────────────────────────────── 5-Me H CH 2 Q21} CH 2 Q6 Ph 5-Me H CH 2 Q15 CH ₂ Q6 Q30 5-Me H CH ₂ Q19 CH ₂ Q6 Q30 5-Me H CH ₂ Q20 CH ₂ Q6 Q30 5-Me H CH ₂ Q21 CH ₂ Q6 Q32 6-Cl H CH ₂ NH CHMe Q1 Q30 6-Cl H CH ₂ NH CHMe Q2 Q30 6-Cl H CH ₂ NH CHMe Q6 Q30 6-Cl H CH ₂ NMe CHMe Q1 Q30 6-Cl H CH ₂ NMe CHMe Q2 Q30 6-Cl H CH ₂ NMe CHMe 6 Cl 30 Q6 H6 Q6 H6 _{CH 2 Q21 CHMe Q1 Q30 6-} Cl H CH 2 Q21 CHMe Q2 Q30 6-Cl H CH 2 21 CHMe Q6 Q30 6-Cl H CH 2 NH CH 2 Q1 Q30 6-Cl H CH 2 NH CH 2 Q2 Q30 6-Cl H CH 2 NH CH 2 Q6 Q30 6-Cl H CH 2 NMe CH 2 Q1 Q30 6- Cl H CH ₂ NMe CH ₂ Q2 Q30 6-Cl H CH ₂ NMe CH ₂ Q6 Q30 6-Cl H CH ₂ Q21 CH ₂ Q1 Q30 6-Cl H CH ₂ Q21 CH ₂ Q2 Q30 6-Cl H CH ₂ Q21 CH ₂ Q6 Q30 ──────────────────────────────────

[0092]

[Table 57] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── 6-Cl H CH ₂ NH CHMe Q1 Ph 6-Cl H CH ₂ NH CHMe Q2 _{Ph 6-Cl H CH 2 NH} CHMe Q6 Ph 6-Cl H CH 2 NMe CHMe Q1 Ph 6-Cl H CH 2 NMe CHMe Q2 Ph 6-Cl H CH 2 NMe CHMe Q6 Ph 6-Cl H CH 2 Q21 CHMe Q1 Ph 6-Cl H CH ₂ Q21 CHMe Q2 Ph 6-Cl H CH ₂ Q21 CHMe Q6 Ph 6-Cl H CH ₂ NH CH ₂ Q1 Ph 6-Cl H CH ₂ NH CH ₂ Q2 Ph 6-Cl H CH ₂ NH _{CH 2 Q6 Ph 6-Cl H} CH 2 NMe CH 2 Q1 Ph 6-Cl H CH 2 NMe CH 2 Q2 Ph 6-Cl H _{H 2 NMe CH 2 Q6 Ph 6} -Cl H CH 2 Q21 CH 2 Q1 Ph 6-Cl H CH 2 Q21 CH 2 Q2 Ph 6-Cl H CH 2 Q21 CH 2 Q6 Ph 6-Cl H CH 2 Q15 CH 2 Q6 Q30 6-Cl H CH ₂ Q19 CH ₂ Q6 Q30 6-Cl H CH ₂ Q20 CH ₂ Q6 Q30 6-Cl H CH ₂ Q21 CH ₂ Q6 Q32 5-Br H CH ₂ NH CHMe Q1 Q30 ─────── ────────────────────────────

[0093]

[Table 58] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── 5-Br H CH ₂ NH CHMe Q2 Q30 5-Br H CH ₂ NH CHMe Q6 Q30 5-Br H CH ₂ NMe CHMe Q1 Q30 5-Br H CH ₂ NMe CHMe Q2 Q30 5-Br H CH ₂ NMe CHMe Q6 Q30 5-Br H CH ₂ Q21 CHMe Q1 Q30 5-Br H CH ₂ Q21 Q2 CHMe Q30 5-Br H CH ₂ Q21 CHMe Q6 Q30 5-Br H CH ₂ NH CH ₂ Q1 Q30 5-Br H CH ₂ NH CH ₂ Q2 Q30 5-Br H CH ₂ NH CH ₂ Q6 Q30 5-Br H CH _{2 NMe CH 2 Q1 Q30 5-Br} H CH 2 NMe CH 2 Q2 Q30 5-Br H CH 2 N _{e CH 2 Q6 Q30 5-Br} H CH 2 Q21 CH 2 Q1 Q30 5-Br H CH 2 Q21 CH 2 Q2 Q30 5-Br H CH 2 Q21 CH 2 Q6 Q30 5-Br H CH 2 NH CHMe Q1 Ph 5- Br H CH ₂ NH CHMe Q2 Ph 5-Br H CH ₂ NH CHMe Q6 Ph 5-Br H CH ₂ NMe CHMe Q1 Ph 5-Br H CH ₂ NMe CHMe Q2 Ph 5-Br H CH ₂ NMe CHMe Q6 Ph- ───────────────────────────────

[0094]

[Table 59] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── 5-Br H CH ₂ Q21 CHMe Q1 Ph 5-Br H CH ₂ Q21 CHMe Q2 _{Ph 5-Br H CH 2 Q21} CHMe Q6 Ph 5-Br H CH 2 NH CH 2 Q1 Ph 5-Br H CH 2 NH CH 2 Q2 Ph 5-Br H CH 2 NH CH 2 Q6 Ph 5-Br H CH 2 _{NMe CH 2 Q1 Ph 5-Br} H CH 2 NMe CH 2 Q2 Ph 5-Br H CH 2 NMe CH 2 Q6 Ph 5-Br H CH 2 Q21 CH 2 Q1 Ph 5-Br H CH 2 Q21 CH 2 Q2 Ph 5 _{-Br H CH 2 Q21 CH 2 Q6} Ph 5-Br H CH 2 Q15 CH 2 Q6 Q30 5-Br H CH 2 Q19 CH 2 Q6 Q30 5-Br H CH 2 _{20 CH 2 Q6 Q30 5-Br} H CH 2 Q21 CH 2 Q6 Q32 5-F H CH 2 NH CHMe Q1 Q30 5-F H CH 2 NH CHMe Q2 Q30 5-F H CH 2 NH CHMe Q6 Q30 5-F H CH ₂ NMe CHMe Q1 Q30 5-F H CH ₂ NMe CHMe Q2 Q30 5-F H CH ₂ NMe CHMe Q6 Q30 5-F H CH ₂ Q21 CHMe Q1 Q30 ──────────────── ────────────────────

[0095]

[Table 60] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── 5-F H CH ₂ Q21 CHMe Q2 Q30 5-F H CH ₂ Q21 CHMe Q6 Q30 5-F H CH ₂ NH CH ₂ Q1 Q30 5-F H CH ₂ NH CH ₂ Q2 Q30 5-F H CH ₂ NH CH ₂ Q6 Q30 5-F H CH ₂ NMe CH ₂ Q1 Q30 5-F H CH ₂ NMe CH ₂ Q2 Q30 5-F H CH ₂ NMe CH ₂ Q6 Q30 5-F H CH ₂ Q21 CH ₂ Q1 Q30 5-F H CH ₂ Q21 CH ₂ Q2 Q30 5-F H CH ₂ Q21 CH ₂ Q6 Q30 5-F H CH ₂ NH CHMe Q1 Ph 5-F H CH ₂ NH CHMe Q2 Ph 5-F H CH ₂ NH CHMe Q6 Ph 5-F H CH ₂ NMe CHMe Q1 Ph 5-F H CH ₂ NMe CHMe Q2 Ph 5-F H CH ₂ NMe CHMe Q6 Ph 5-F H CH ₂ Q21 CHMe Q1 Ph 5-F H CH ₂ Q21 CHMe Q2 Ph 5-F CH ₂ Q21 CHMe Q6 Ph 5-F H CH ₂ NH CH ₂ Q1 Ph 5-F H CH ₂ NH CH ₂ Q2 Ph 5-F H CH ₂ NH CH ₂ Q6 Ph ──────────── ──────────────────────

[0096]

[Table 61] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── 5-F H CH ₂ NMe CH ₂ Q1 Ph 5-F H CH ₂ NMe CH ₂ Q2 Ph 5-F H CH ₂ NMe CH ₂ Q6 Ph 5-F H CH ₂ Q21 CH ₂ Q1 Ph 5-F H CH ₂ Q21 CH ₂ Q2 Ph 5-F H CH ₂ Q21 CH ₂ Q6 Ph 5-F H CH ₂ Q15 CH ₂ Q6 Q30 5-F H CH ₂ Q19 CH ₂ Q6 Q30 5-F H CH ₂ Q20 CH ₂ Q6 Q30 5-F H CH ₂ Q21 CH ₂ Q6 Q32 6-OMe H CH ₂ NH CHMe Q1 Q30 6-OMe H CH ₂ NH CHMe Q2 Q30 6-OMe H CH ₂ NH CHMe Q6 Q30 6-OMe H CH ₂ NMe CHMe Q1 Q30 6-O _{Me H CH 2 NMe CHMe Q2 Q30} 6-OMe H CH 2 NMe CHMe Q6 Q30 6-OMe H CH 2 Q21 CHMe Q1 Q30 6-OMe H CH 2 Q21 CHMe Q2 Q30 6-OMe H CH 2 Q21 CHMe Q6 Q30 6- OMe H CH ₂ NH CH ₂ Q1 Q30 6-OMe H CH ₂ NH CH ₂ Q2 Q30 6-OMe H CH ₂ NH CH ₂ Q6 Q30 6-OMe H CH ₂ NMe CH ₂ Q2 Q30 ───────── ─────────────────────────

[0097]

[Table 62] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── 6-OMe H CH ₂ NMe CH ₂ Q6 Q30 6-OMe H CH ₂ Q21 CH ₂ Q1 Q30 6-OMe H CH ₂ Q21 CH ₂ Q2 Q30 6-OMe H CH ₂ Q21 CH ₂ Q6 Q30 6-OMe H CH ₂ NH CHMe Q1 Ph 6-OMe H CH ₂ NH CHMe Q2 Ph 6-OMe H CH ₂ NH CHMe Q6 Ph 6-OMe H CH ₂ NMe CHMe Q1 Ph 6-OMe H CH ₂ NMe CHMe Q2 Ph 6-OMe H CH ₂ NMe CHMe Q6 Ph 6-OMe H CH ₂ Q21 HCH 6 Meh _{2 Q21 CHMe Q2 Ph 6-OMe} H CH 2 Q21 CHMe Q6 Ph 6-OMe H CH 2 NH _{H 2 Q1 Ph 6-OMe H} CH 2 NH CH 2 Q2 Ph 6-OMe H CH 2 NH CH 2 Q6 Ph 6-OMe H CH 2 NMe CH 2 Q1 Ph 6-OMe H CH 2 NMe CH 2 Q2 Ph 6- OMe H CH ₂ NMe CH ₂ Q6 Ph 6-OMe H CH ₂ Q21 CH ₂ Q1 Ph 6-OMe H CH ₂ Q21 CH ₂ Q2 Ph 6-OMe H CH ₂ Q21 CH ₂ Q6 Ph 6-OMe H CH ₂ Q15 CH ₂ Q6 Q30 ──────────────────────────────────

[0098]

[Table 63] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── 6-OMe H CH ₂ Q19 CH ₂ Q6 Q30 6-OMe H CH ₂ Q20 CH ₂ Q6 Q30 6-OMe H CH ₂ Q21 CH ₂ Q6 Q32 6-OMe 5-OMe CH ₂ NH CHMe Q1 Q30 6-OMe 5-OMe CH ₂ NH CHMe Q2 Q30 6-OMe 5-OMe CH ₂ NH CHMe Q6 Q30 6-OMe 5-OMe CH ₂ NMe CHMe Q1 Q30 6-OMe 5-OMe CH ₂ NMe CHMe Q2 Q30 6-OMe 5-OMe CH ₂ NMe CHMe Q6 Q30 6-OMe 5-OMe CH ₂ Q21 CHMe Q1 Q30 6-OMe OMe 5-OMe CH ₂ Q21 CHMe Q2 Q30 6-OMe 5-OMe CH ₂ Q21 CHMe Q6 Q30 6-OMe 5-OMe CH ₂ NH CH ₂ Q1 Q30 6-OMe 5-OMe CH ₂ NH CH ₂ Q2 Q30 6-OMe 5-OMe CH ₂ NH CH ₂ Q6 Q30 6-OMe 5-OMe CH ₂ NMe CH ₂ Q2 Q30 6-OMe 5-OMe CH ₂ NMe CH ₂ Q6 Q30 6-OMe 5-OMe CH ₂ Q21 CH ₂ Q1 Q30 6-OMe 5-OMe CH ₂ Q21 CH ₂ Q2 Q30 6-OMe 5-OMe CH ₂ Q21 CH ₂ Q6 Q30 6-OMe 5-OMe CH ₂ NH CHMe Q1 Ph 6-OMe 5-OMe CH ₂ NH CHMe Q2 Ph 6-OMe 5-OMe CH ₂ NH CHMe Q6 Ph ────────────────────── ─────────────

[0099]

[Table 64] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── 6-OMe 5-OMe CH ₂ NMe CHMe Q1 Ph 6-OMe 5-OMe CH _{2 NMe CHMe Q2 Ph 6-OMe} 5-OMe CH 2 NMe CHMe Q6 Ph 6-OMe 5-OMe CH 2 Q21 CHMe Q1 Ph 6-OMe 5-OMe CH 2 Q21 CHMe Q2 Ph 6-OMe 5-OMe CH 2 Q21 CHMe Q6 Ph 6-OMe 5-OMe CH ₂ NH CH ₂ Q1 Ph 6-OMe 5-OMe CH ₂ NH CH ₂ Q2 Ph 6-OMe 5-OMe CH ₂ NH CH ₂ Q6 Ph 6-OMe 5-OMe CH ₂ NMe CH ₂ Q1 Ph 6-OMe 5-OMe CH ₂ NMe CH ₂ Q2 Ph 6-OMe 5-OMe CH ₂ NMe CH ₂ Q6 Ph 6-OMe 5-OMe CH ₂ Q21 CH ₂ Q1 Ph 6-OMe 5-OMe CH ₂ Q _{1 CH 2 Q2 Ph 6-OMe} 5-OMe CH 2 Q21 CH 2 Q6 Ph 6-OMe 5-OMe CH 2 Q15 CH 2 Q6 Q30 6-OMe 5-OMe CH 2 Q19 CH 2 Q6 Q30 6-OMe 5-OMe CH ₂ Q20 CH ₂ Q6 Q30 6-OMe 5-OMe CH ₂ Q21 CH ₂ Q6 Q32 5-Me 6-Me CH ₂ NH CHMe Q1 Q30 5-Me 6-Me CH ₂ NH CHMe Q2 Q30 5-Me 6-Me CH ₂ NH CHMe Q6 Q30 5-Me 6-Me CH ₂ NMe CHMe Q1 Q30 ────────────────────────────────── ─

[0100]

[Table 65] ───────────────────────────────── R ¹ R ² A B D D Ar ¹ Ar ² ── ─────────────────────────────── 5-Me 6-Me CH ₂ NMe CHMe Q2 Q30 5-Me 6-Me CH ₂ NMe CHMe Q6 Q30 5-Me 6-Me CH ₂ Q21 CHMe Q1 Q30 5-Me 6-Me CH ₂ Q21 CHMe Q2 Q30 5-Me 6-Me CH ₂ Q21 CHMe Q6 Q30 5-Me 6-Me CH ₂ NH CH ₂ Q1 Q30 5-Me 6-Me CH ₂ NH CH ₂ Q2 Q30 5-Me 6-Me CH ₂ NH CH ₂ Q6 Q30 5-Me 6-Me CH ₂ NMe CH ₂ Q1 Q30 5-Me 6-Me CH ₂ NMe CH ₂ Q2 Q30 5-Me 6-Me CH ₂ NMe CH ₂ Q6 Q30 5-Me 6-Me CH ₂ Q21 CH ₂ Q1 Q30 5-Me 6-Me CH ₂ Q21 CH ₂ Q2 Q30 5-Me 6- Me CH _{2 Q21 CH 2 Q6 Q30 5-} Me 6-Me CH 2 NH CHMe Q1 Ph 5-Me 6-Me CH 2 NH CHMe Q2 Ph 5-Me 6-Me CH 2 NH CHMe Q6 Ph 5-Me 6-Me CH 2 NMe CHMe Q1 Ph 5-Me 6-Me CH ₂ NMe CHMe Q2 Ph 5-Me 6-Me CH ₂ NMe CHMe Q6 Ph 5-Me 6-Me CH ₂ Q21 CHMe Q1 Ph 5-Me 6-Me CH ₂ Q21 CHMe Q2 Ph 5-Me 6-Me CH ₂ Q21 CHMe Q6 Ph ──────────────────────────────────

[0101]

[Table 66] ───────────────────────────────── R ¹ R ² AB D Ar ¹ Ar ² ── ─────────────────────────────── 5-Me 6-Me CH ₂ NH CH ₂ Q1 Ph 5-Me 6-Me CH ₂ NH CH ₂ Q 2 Ph 5-Me 6-Me CH ₂ NH CH ₂ Q 6 Ph 5-Me 6-Me CH ₂ NMe CH ₂ Q 1 Ph 5-Me 6-Me CH ₂ NMe CH ₂ Q 2 Ph 5-Me 6 -Me CH ₂ NMe CH ₂ Q6 Ph 5-Me 6-Me CH ₂ Q21 CH ₂ Q1 Ph 5-Me 6-Me CH ₂ Q21 CH ₂ Q2 Ph 5-Me 6-Me CH ₂ Q21 CH ₂ Q6 Ph 5- Me 6-Me CH ₂ Q15 CH ₂ Q6 Q30 5-Me 6-Me CH ₂ Q19 CH ₂ Q6 Q30 5-Me 6-Me CH ₂ Q20 CH ₂ Q6 Q30 5-Me 6-Me CH ₂ Q21 CH ₂ Q6 Q32 ───────────────────── ────────────

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

Examples of such acid addition salts include, for example, mineral acid salts (hydrochloride, hydrobromide, sulfate, hydrogensulfate, nitrate, phosphate, hydrogenphosphate, dihydrogenphosphate, etc.). ),
Organic acid salts (formate, acetate, propionate, succinate, malonate, oxalate, maleate, fumarate, malate, citrate, tartrate, lactate, glutamic acid) Salts, aspartates, picrates, carbonates, etc.) and sulfonates (methanesulfonate, benzenesulfonate, toluenesulfonate, etc.).

[0104]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a method for producing the compound of the present invention will be described.

In the benzimidazole derivative represented by the general formula (I) which is the compound of the present invention, A is CHR ⁷ (R ⁷ represents a hydrogen atom or a C _1-4 alkyl group). The compounds represented by (Ia), (Iaa) and (Iab) can be produced by the methods represented by the following reaction formulas (1) to (5).

Reaction formula (1)

[0107]

[Chemical 6]

(Wherein B, D, Ar ¹ , Ar ² , R ¹ , R ² and R ⁷
Is the same as above. X means a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, and a leaving group such as a methanesulfonyloxy group, a paratoluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. )

In reaction formula (1), a compound represented by the general formula (IIa) is reacted with a compound represented by the general formula (IIIa), and in the compound (I) of the present invention, A is CHR ⁷ A method for producing a compound represented by the general formula (Ia).

This reaction can usually be carried out in the presence or absence of an inorganic base or an organic base.

Examples of the inorganic base include metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate, metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, hydrogenation. Sodium, metal hydrides such as potassium hydride and n-butyllithium, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyl Examples include inorganic bases such as metal amides such as disilazide and 2,2,6,6-tetramethylpiperidide.

Examples of the organic base include organic bases such as trimethylamine, triethylamine, pyridine and diisopropylethylamine.

As the reaction solvent, any solvent which does not participate in the reaction may be used, such as benzene, toluene, hexane and other hydrocarbon solvents, tetrahydrofuran, diethyl ether, ether solvents such as 1,4-dioxane, formamide, N 2 and the like. , N-dimethylacetamide, N, N-dimethylformamide, amide solvents such as N-methylpyrrolidone, alcohol solvents such as methanol, ethanol and propanol,
Examples thereof include halogen-based solvents such as chloroform, methylene chloride and ethylene dichloride, solvents such as acetonitrile and dimethyl sulfoxide, water and the like, or mixed solvents thereof.

The reaction temperature may be in the range of -78 ° C to the boiling point of the solvent used in the reaction.

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (IIa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IIIa). .

Reaction formula (2)

[0117]

Embedded image

(In the formula, B, D, Ar ¹ , Ar ² , X, R ¹ , R ² and R ⁷ are the same as above.)

The reaction formula (2) is the reaction of the compound represented by the general formula (IVa) with the compound represented by the general formula (Va),
In the compound (I) of the present invention, a compound represented by the general formula (I) in which A is CHR ⁷
It is a method for producing the compound represented by a). This reaction can be carried out under the same conditions as in reaction formula (1). The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (Va) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IVa).

Reaction formula (3)

[0121]

Embedded image

(In the formula, B, D, Ar ¹ , Ar ² , R ¹ , R ² and R ⁷
Is the same as above. )

The reaction formula (3) is obtained by reductively condensing the compound represented by the general formula (VIa) with the compound represented by the general formula (IIIa). A method for producing a compound represented by the general formula (Ia), which is CHR ⁷ .

In this reaction, a reducing agent such as sodium borohydride or sodium cyanoborohydride is used. In some cases, the addition of a Lewis acid such as aluminum chloride or trifluoroborane ether complex may give better results.

As a reaction solvent, tetrahydrofuran,
Ether-based solvents such as diethyl ether and 1,4-dioxane, amide-based solvents such as formamide, N, N-dimethylacetamide, N, N-dimethylformamide and N-methylpyrrolidone, alcohol-based solvents such as methanol, ethanol and propanol , Water and the like, or a mixed solvent thereof.

The reaction temperature may be in the range of -78 ° C to the boiling point of the solvent used in the reaction.

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (VIa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IIIa). .

Reaction formula (4)

[0129]

Embedded image

(Wherein D, Ar ¹ , Ar ² , R ¹ , R ² and R ⁷ are the same as above. R ⁸ represents a hydrogen atom or a C _1-4 alkyl group, and B ¹ represents NR ³ , NR ³ CONR ⁴ , NR ³ NR ⁴ , NR ³ NR ⁴ CONR ⁵ , N (CH
₂ CH ₂ ) ₂ N, N (CH ₂ CH ₂ ) ₂ NCONR ³ , NR ³ CH ₂ CH ₂ NR ⁴ , NR ³ CH ₂ CH ₂
It means CH ₂ NR ⁴ (R ³ , R ⁴ and R ⁵ are the same as above). )

The reaction formula (4) is represented by the general formula (VIIa).
And a compound of general formula (VIIIa) or general formula (IXa)
Of the compound (I) of the present invention
CHR ⁷And has a urea structure in B (Ia
It is a method for producing the compound represented by a). ((IXa)
R when using⁸Becomes a hydrogen atom. )

This reaction is carried out in a solvent or in the absence of a solvent (VI
It can be achieved by heating or cooling Ia) and (VIIIa) or (VIIa) and (IXa), but it can also be carried out under the same conditions as in reaction formula (1).

The molar ratio of the raw materials can be arbitrarily set, but it is preferable to use the compound represented by the general formula (VIIIa) or (IXa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (VIIa). Is enough.

Reaction formula (5)

[0135]

Embedded image

(In the formula, B, Ar ¹ , Ar ² , R ¹ , R ² and R ⁷ are the same as above. R ⁹ represents a hydrogen atom or a C _1-4 alkyl group, and D ¹ represents Single bond, methylene group (the methylene group is C _1-4
Optionally substituted with an alkyl group of) or C _1-2
An alkyleneoxy group of (wherein the alkyleneoxy group is C _1-4
Optionally substituted with an alkyl group of). )

The reaction formula (5) is obtained by reductively condensing the compound represented by the general formula (IVa) with the compound represented by the general formula (Xa). CHR ⁷ ,
The general formula (Ia
A method for producing a compound represented by b).

This reaction can be carried out under the same conditions as in the reaction formula (3).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (Xa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IVa). .

Among the benzimidazole derivatives represented by the general formula (I) which are the compounds of the present invention, A is CH ₂ CHR ⁷ (R
⁷ has the same meaning as above. ) Is a general formula (Ib), (I
The compounds represented by ba) and (Ibb) can be produced by the methods represented by the following reaction formulas (6) to (10).

Reaction formula (6)

[0142]

Embedded image

(In the formula, B, D, Ar ¹ , Ar ² , X, R ¹ , R ² and R ⁷ are the same as above.)

The reaction formula (6) is the reaction of the compound represented by the general formula (IIb) with the compound represented by the general formula (IIIa), wherein A is CH ₂ CHR in the compound (I) of the present invention. A method for producing a compound represented by the general formula (Ib) ⁷

This reaction can be carried out under the same conditions as in the reaction formula (1).

The molar ratio of the raw materials can be arbitrarily set, but it is sufficient to use the compound represented by the general formula (IIb) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IIIa). .

Reaction formula (7)

[0148]

Embedded image

(In the formula, B, D, Ar ¹ , Ar ² , X, R ¹ , R ² and R ⁷ are the same as above.)

The reaction formula (7) is obtained by reacting the compound represented by the general formula (IVb) with the compound represented by the general formula (Va),
A method for producing a compound represented by the general formula (Ib) in which A is CH ₂ CHR ⁷ among the compounds (I) of the present invention.

This reaction can be carried out under the same conditions as in the reaction formula (1).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (Va) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IVb). .

Reaction formula (8)

[0154]

Embedded image

(In the formula, B, D, Ar ¹ , Ar ² , R ¹ , R ² and R ⁷
Is the same as above. )

The reaction formula (8) is such that the compound represented by the general formula (VIb) and the compound represented by the general formula (IIIa) are reductively condensed, and in the compound (I) of the present invention, A is A method for producing a compound represented by the general formula (Ib), which is CH ₂ CHR ⁷ .

This reaction can be carried out under the same conditions as in the reaction formula (3).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (VIb) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IIIa). .

Reaction formula (9)

[0160]

Embedded image

(In the formula, B ¹ , D, Ar ¹ , Ar ² , R ¹ , R ² , R ⁸ and R ⁷ are the same as above.)

The reaction formula (9) is obtained by reacting the compound represented by the general formula (VIIb) with the compound represented by the general formula (VIIIa) or (IXa) to obtain the compound (I) of the present invention. , A
It is a method for producing a compound represented by the general formula (Iba), which is CH ₂ CHR ⁷ and has a urea structure in B. ((I
R ⁸ when Xa) is used is a hydrogen atom. )

This reaction is carried out in a solvent or in the absence of a solvent (VI
It can be achieved by heating or cooling Ib) and (VIIIa) or (VIIb) and (IXa), but it can also be carried out under the same conditions as in reaction formula (1).

The molar ratio of the raw materials can be arbitrarily set, but it is preferable to use the compound represented by the general formula (VIIIa) or (IXa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (VIIb). Is enough.

Reaction formula (10)

[0166]

Embedded image

(In the formula, B, D ¹ , Ar ¹ , Ar ² , R ¹ , R ² and R ⁹
And R ⁷ are the same as above. )

The reaction formula (10) is a reductive condensation of the compound represented by the general formula (IVb) with the compound represented by the general formula (Xa). It is CH ₂ CHR ^7, which is a method for producing a compound represented by the general formula (Ibb) in which D and B are not linked by an amide bond.

This reaction can be carried out under the same conditions as in the reaction formula (3).

The molar ratio of the raw materials can be arbitrarily set, but it is sufficient to use the compound represented by the general formula (Xa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IVb). .

Among the benzimidazole derivatives represented by the general formula (I) which are the compounds of the present invention, the compounds represented by the general formulas (Ic), (Ica) and (Icb) in which A is CO are:
It can be produced by the method represented by the following reaction formulas (11) to (15).

Reaction formula (11)

[0173]

Embedded image

(In the formula, B, D, Ar ¹ , Ar ² , R ¹ and R ² are the same as above. X ¹ is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a C _1-4 alkoxy group, Phenoxy group, benzyloxy group, C _1-4 alkylthio group, phenylthio group, and
It means a benzylthio group or the like. )

The reaction formula (11) is a reaction of the compound represented by the general formula (IIc) with the compound represented by the general formula (IIIa), and in the compound (I) of the present invention, A is CO. It is a method for producing a compound represented by the general formula (Ic).

This reaction can be carried out under the same conditions as in the reaction formula (1).

The molar ratio of the raw materials can be arbitrarily set, but it is sufficient to use the compound represented by the general formula (IIc) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IIIa). .

Reaction formula (12)

[0179]

Embedded image

(Wherein B, D, Ar ¹ , Ar ² , X, R ¹ and R ²
Is the same as above. )

The reaction formula (12) is the reaction of the compound represented by the general formula (IVc) with the compound represented by the general formula (Va),
In the compound (I) of the present invention, a compound represented by the general formula (Ic) in which A is CO
Is a method for producing a compound represented by.

This reaction can be carried out under the same conditions as in reaction formula (1).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (Va) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IVc). .

Reaction formula (13)

[0185]

Embedded image

(Wherein B, D, Ar ¹ , Ar ² , X, R ¹ and R ²
Is the same as above. )

The reaction formula (13) is the reaction of the compound represented by the general formula (VIc) with the compound represented by the general formula (Vc),
In the compound (I) of the present invention, a compound represented by the general formula (Ic) in which A is CO
Is a method for producing a compound represented by.

This reaction can be carried out under the same conditions as in reaction formula (1).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (Vc) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (VIc). .

Reaction formula (14)

[0191]

Embedded image

(Wherein B ¹ , D, Ar ¹ , Ar ² , R ¹ , R ² and R ⁸
Is the same as above. )

The reaction formula (14) is obtained by reacting the compound represented by the general formula (VIIc) with the compound represented by the general formula (VIIIa) or (IXa) , A
The general formula (Ic
It is a method for producing the compound represented by a). ((IXa)
When using, R ⁸ is a hydrogen atom. )

This reaction is carried out in a solvent or in the absence of a solvent (VI
This can be achieved by heating or cooling Ic) and (VIIIa) or (VIIc) and (IXa), but it can also be carried out under the same conditions as in reaction formula (1).

The molar ratio of the raw materials can be set arbitrarily, but it is possible to use the compound represented by the general formula (VIIIa) or (IXa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (VIIc). Is enough.

Reaction formula (15)

[0197]

Embedded image

(In the formula, B, D ¹ , Ar ¹ , Ar ² , R ¹ , R ² and R
⁹ is the same as above. )

The reaction formula (15) is obtained by reductively condensing the compound represented by the general formula (IVc) with the compound represented by the general formula (Xa). CO and D
And B are not linked by an amide bond, general formula (Icb)
Is a method for producing a compound represented by.

This reaction can be carried out under the same conditions as in the reaction formula (3).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (Xa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IVc). .

Among the benzimidazole derivatives represented by the general formula (I) which are the compounds of the present invention, the compounds represented by the general formulas (Id), (Ida) and (Idb) in which A is CH ₂ CO Can be produced by the methods represented by the following reaction formulas (16) to (20).

Reaction formula (16)

[0204]

Embedded image

(Wherein B, D, Ar ¹ , Ar ² , X ¹ , R ¹ and R ²
Is the same as above. )

In reaction formula (16), the compound represented by the general formula (IId) is reacted with the compound represented by the general formula (IIIa), and in the compound (I) of the present invention, A is CH ₂ CO _2. Is a method for producing a compound represented by the general formula (Id).

This reaction can be carried out under the same conditions as in the reaction formula (11).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (IId) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IIIa). .

Reaction formula (17)

[0210]

Embedded image

(In the formula, B, D, Ar ¹ , Ar ² , X, R ¹ and R ²
Is the same as above. In the reaction formula (17), the compound represented by the general formula (IVd) is reacted with the compound represented by the general formula (Va), and in the compound (I) of the present invention, A is CH ₂ CO _2. It is a method for producing a compound represented by the general formula (Id).

This reaction can be carried out under the same conditions as in reaction formula (1).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (Va) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IVd). .

Reaction formula (18)

[0215]

Embedded image

(In the formula, B, D, Ar ¹ , Ar ² , X, R ¹ and R ²
Is the same as above. )

The reaction formula (18) is the reaction of the compound represented by the general formula (VId) with the compound represented by the general formula (Vc),
Among the present compounds (I), Formula A is CH ₂ CO (I
This is a method for producing the compound represented by d).

This reaction can be carried out under the same conditions as in the reaction formula (1).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (Vc) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (VId). .

Reaction formula (19)

[0221]

Embedded image

(In the formula, B ¹ , D, Ar ¹ , Ar ² , R ¹ , R ² and R ⁸
Is the same as above. )

The reaction formula (19) is obtained by reacting the compound represented by the general formula (VIId) with the compound represented by the general formula (VIIIa) or the general formula (IXa). , A
It is CH ₂ CO and has a urea structure in B.
This is a method for producing a compound represented by da). ((IX
When using a), R ⁸ is a hydrogen atom. )

This reaction is carried out in a solvent or without a solvent (VI
This can be achieved by heating or cooling Id) and (VIIIa) or (VIId) and (IXa), but it can also be carried out under the same conditions as in reaction formula (1).

The molar ratio of the raw materials can be arbitrarily set, but it is preferable to use the compound represented by the general formula (VIIIa) or (IXa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (VIId). Is enough.

Reaction formula (20)

[0227]

Embedded image

(Wherein B, D ¹ , Ar ¹ , Ar ² , R ¹ , R ² and R
⁹ is the same as above. )

The reaction formula (20) is a reductive condensation of the compound represented by the general formula (IVd) with the compound represented by the general formula (Xa). This is a method of producing a compound represented by the general formula (Idb), which is CH ₂ CO and D and B are not linked by an amide bond.

This reaction can be carried out under the same conditions as in reaction formula (3).

The molar ratio of the raw materials can be set arbitrarily, but it is sufficient to use the compound represented by the general formula (Xa) in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula (IVd). .

Next, the method for producing the starting material for the compound of the present invention will be described.

Among the starting materials for the compound of the present invention, the compounds represented by the general formulas (IIa), (IVa) and (VIa) in which A is CHR ⁷ are produced by the method represented by the reaction formula (21). be able to. The method for producing the compound represented by the general formula (VIIa) is included in the method for producing the compound represented by the general formula (IVa).

Reaction formula (21)

[0235]

Embedded image

(In the formula, B, Ar ² , R ¹ , R ² , R ⁷ and X are the same as defined above. R ¹⁰ is a methyl group, a trifluoromethyl group,
It means a phenyl group or a 4-methylphenyl group, and W is
It means a protecting group for an amino group such as a formyl group, an acetyl group, a benzyloxycarbonyl group and a t-butoxycarbonyl group. )

(IIa) is converted to (IIaa) by halogenating (IIab) or reacting R ¹⁰ SO ₂ Cl, and then condensing with (Vc), or (IIab) and (Vc) are combined. It can be produced by condensing (IIac) and then halogenating or reacting with R ¹⁰ SO ₂ Cl.

For (IVa), (XIaa) is allowed to act on (IIa), (XIab) is allowed to act on (IIa) and (IVac) is deprotected, or (XIaa) is changed to (XIaa). ) Is reacted with (IVaa) and then condensed with (Vc), or (IVaa)
After introducing a protecting group into the NH group and making it (IVab), it is condensed with (Vc) to make (IVac) and then deprotected, or (XIab) is allowed to act on (IIaa) to give (IVab) And then condensed with (Vc) to (IVac) and then deprotected or (IVab) deprotected to (IVaa) and then condensed with (Vc) to produce. You can

(VIa) oxidizes (IIac) or (IIa)
It can be produced by oxidizing b) and then condensing it with (Vc).

Among the starting materials for the compounds of the present invention, A is CH ₂ CHR ⁷
The compounds represented by the general formulas (IIb), (IVb) and (VIb) can be produced by the method represented by the reaction formula (22). The method for producing the compound represented by the general formula (VIIb) is included in the method for producing the compound represented by the general formula (IVb).

Reaction formula (22)

[0242]

Embedded image

(In the formula, B, Ar ² , R ¹ , R ² , R ⁷ , R ¹⁰ , X and W are the same as above.)

(IIb) is converted to (IIba) by halogenating (IIbb) or reacting with R ¹⁰ SO ₂ Cl and then condensing with (Vc), or (IIbb) and (Vc) are combined. It can be produced by condensing (IIbc) and then halogenating or reacting with R ¹⁰ SO ₂ Cl.

(IVb) is treated with (XIaa) on (IIb) or (XIab) on (IIb) and then (IVbc), followed by deprotection or (XIba) on (XIaa). ) Acts on (IVba) and then condenses with (Vc) or
After introducing a protecting group into the NH group and making it (IVbb), it is condensed with (Vc) to make (IVbc) and then deprotected, or (XIab) is allowed to act on (IIba) to give (IVbb) Then, it is condensed with (Vc) to form (IVbc) and then deprotected, or (IVbb) is deprotected to form (IVba) and then condensed with (Vc) to produce it. You can

(VIb) oxidizes (IIbc) or (IIb)
It can be produced by oxidizing b) and then condensing it with (Vc). Among the raw materials of the compound of the present invention, A is
The compounds represented by the general formulas (IIc), (IVc) and (VIc), which are CO, can be produced by the method represented by the reaction formula (23). The method for producing the compound represented by the general formula (VIIc) is included in the method for producing the compound represented by the general formula (IVc).

Reaction formula (23)

[0248]

Embedded image

(Wherein B, D, Ar ¹ , Ar ² , R ¹ , R ² , X,
X ¹ and W are the same as above. )

(IIc) is obtained by oxidizing the hydroxyl group of (IIcb) to give a carboxylic acid, or by converting it to (IIca) by simultaneous or stepwise esterification or thioesterification, and then condensing it with (Vc). Or by condensing (IIcb) and (Vc) to (IIcc) and then oxidizing the hydroxyl group to a carboxylic acid, or by esterifying or thioesterifying simultaneously with the oxidation or stepwise. it can.

For (IVc), either (XIaa) is allowed to act on (IIc), (XIab) is allowed to act on (IIc), and (IVcc) is deprotected, or (IIca) is changed to (XIaa). ) Acts as (IVca) and then condenses with (Vc) or
After introducing a protecting group into the NH group to form (IVcb) and then condensing with (Vc) to form (IVcc), deprotection is performed or (IIca) is reacted with (XIab) to give (IVcb) And then condensed with (Vc) to (IVcc) and then deprotected or (IVcb) deprotected to (IVca) and then condensed with (Vc) to produce. You can

(VIc) can be produced by reacting (IIca) with (IIIa) or (IIca) with (XIaa) (IVca) and then condensing with (Va). it can. In the structure of (IIca), a compound in which X ¹ is a halogen atom generally has the structure of (IIcd).
(IIcd) may be used instead of

Among the starting materials for the compound of the present invention, the compounds represented by the general formulas (IId), (IVd) and (VId) in which A is CH ₂ CO are produced by the method represented by the reaction formula (24). can do. The method for producing the compound represented by the general formula (VIId) is included in the method for producing the compound represented by the general formula (IVd).

Reaction formula (24)

[0255]

Embedded image

(In the formula, B, D, Ar ¹ , Ar ² , R ¹ , R ² , X,
X ¹ and W are the same as above. )

(IId) is obtained by oxidizing the hydroxyl group of (IIdb) to give a carboxylic acid, or (IIda) by simultaneous or stepwise esterification or thioesterification at the same time as the oxidation, followed by condensation with (Vc). Or by condensing (IIdb) and (Vc) into (IIdc) and then oxidizing the hydroxyl group to a carboxylic acid, or by esterifying or thioesterifying simultaneously with oxidation or stepwise. it can.

(IVd) is either (XIaa) acting on (IId) or (XIab) is acting on (IId) to be (IVdc), followed by deprotection or (IIda) (XIaa). ) To (IVda) and then condense with (Vc) or
After introducing a protecting group into the NH group to make it (IVdb) and then condensing it with (Vc) to make it (IVdc), either deprotect it or let (XIab) act on (IIda) to give (IVdb) And then condensed with (Vc) to (IVdc) and then deprotected or (IVdb) deprotected to (IVda) and then condensed with (Vc) to produce. You can

(VId) can be produced by reacting (IIa) with (IIIa) or (IIda) with (XIaa) (IVda) and then condensing with (Va). it can. As a method for producing the benzimidazole skeleton, the method shown in reaction formula (25) can be used.

Reaction formula (25)

[0261]

Embedded image

(In the formula, Ar^Two, R¹And R^TwoIs the same as above. E
CHR⁷X, CHR⁷BH, COR⁷, CHR⁷B-D-Ar ¹, CHR⁷OH, CHR⁷
BW, CH_TwoCHR⁷X, CH_TwoCHR⁷BH, CH_TwoCOR⁷, CH_TwoCHR⁷B-D-Ar¹,
CH_TwoCHR⁷OH, CH_TwoCHR⁷BW, COX¹, COBH, COB-D-Ar¹, CH_TwoO
H, COBW, CH_TwoCOX¹, CH_TwoCOBH, CH_TwoCOB-D-Ar¹, CH_TwoCH_TwoOH
Or CH_TwoCOBW (B, D, Ar¹, R¹, R^Two, R⁷, X, X¹And W
Means the same as above), Ar^ThreeIs a phenyl group (the
The nyl group is a halogen atom, C_{1- Four}Alkyl group or C_1-4Al
R, which may be optionally substituted with a coxy group), R
¹¹Is C_1-4It means an alkyl group or a phenyl group, and G is CO
OH, COCl, COBr, CONH_Two, CSNH_Two, CHO, CN, COOR¹²(R¹²
Is C_1-4Alkyl group, C_1-4Acyl group, phenyl group or
Benzyl group), C (= NH) OR¹³, CH (OR¹³)_Two(R¹³
Is C_1-4Of alkyl group, phenyl group or benzyl group of
Taste) or CONHNHR¹²(R¹²Means the same as above)
You. )

The diaminobenzene derivative of (XIIa) was converted to (XI
The benzimidazole derivative of (XIIIa) can be produced by condensation with IIc), and the diaminobenzene derivative of (XIIb) can be produced by condensation with (XIIIc). Manufacturing conditions include: J. Org. Chem., 28, 1931 (1963);
J. Chem. Soc., 2238 (1953); J. Am. Chem. Soc., 77,
5652 (1955); J. Chem. Soc., 673 (1956); J. Am.
Chem. Soc., 73, 5907 (1951); J. Am. Chem. Soc.,
70, 2415 (1948); J. Chem. Soc., 625, (1943); K
him. Geterotsikl. Soedin., 5, 684 (1982); J. Or
g. Chem., 56 (6), 2260 (1991); Synth. Commnnn., 16
(1), 35 (1986); Khim. Geterotsikl. Soedin., 71
(1980); J. Chem. Soc. C., 20 (1967); Chim. Ther.,
2, 95 (1967); J. Org. Chem., 27, 2163 (1962);
Chem. Pharm. Bull., 12, 773 (1964); J. Chem. So
c., 2296 (1959); J. Am. Chem. Soc., 79, 4391 (19
57); The method described in J. Chem. Soc., 1401 (1949) and the like can be used.

By the above-mentioned production method, directly from (XIIa), (VIaa), (IIab), (IIaa), (IVaa), (IVab),
(VIba), (IIbb), (IIba), (IVba), (IVbb),
(VIc), (VId), (IIcb), (IIca), (IVcb),
(IVca), (IIdb), (IIda), (IVdb) and (IVda) can also be produced. Directly from (XIIb) (Ia),
(Ib), (Ic), (Id), (IIa), (IIb), (II
c), (IId), (IIac), (IIbc), (IIcc), (IId
c), (IVa), (IVb), (IVc), (IVd), (IVa
c), (IVbc), (IVcc), (IVdc), (VIa), (VI
b) can also be manufactured.

As the method for producing (XIIa) and (XIIb), the method shown in reaction formula (26) can be used.

Reaction formula (26)

[0267]

Embedded image

(In the formula, X, Ar ² , R ¹ and R ² are the same as above.)

Ammonia is allowed to act on (XIVa) (XIVb)
Then, (XIIa) can be produced by reduction. In addition, Ar ₂ NH ₂ is applied to (XIVa), and (XIVc)
Then, (XIIb) can be produced by reduction.

As described above, the inventor of the present invention has the general formula (I):
The compound of the present invention represented by is a more excellent compound as a strong anti-allergic drug, and can only be an active ingredient of a preventive or therapeutic drug for pollinosis, urticaria, atopic dermatitis, allergic rhinitis, asthma and the like. No other substance P-mediated diseases such as conjunctivitis, ocular diseases such as spring catarrh; inflammatory diseases such as rheumatoid arthritis; migraine, headache, toothache, pain associated with various diseases; ulcerative colitis, Crohn's disease, etc. It was found that it is also effective for mental disorders such as depression and dysthymia. Accordingly, the present invention provides pharmaceutical compositions containing an effective amount of a compound of the present invention for these treatments.

The administration form of the compound of the present invention includes parenteral administration by injection (subcutaneous, intravenous, intramuscular, intraperitoneal injection), ointment, suppository, aerosol, etc. or tablets, capsules, granules, Oral administration in the form of pills, syrups, solutions, emulsions, suspensions and the like can be mentioned. The above-mentioned pharmaceutical or veterinary composition containing the compound of the present invention comprises about 0.01-99.5% of the compound of the present invention based on the weight of the total composition.
It preferably contains about 0.1 to 30%.

Other pharmaceutically or veterinary active compounds can be included in addition to the compounds of the present invention or compositions containing the compounds of the present invention. Also, these compositions may contain a plurality of compounds of the present invention. The clinical dose of the compound of the present invention varies depending on the age, body weight, susceptibility of the patient, degree of symptoms, etc., but usually the effective dose is 0.003 to 1.5 g, preferably 0.01 to 0.6 g per day for an adult. .
However, if necessary, an amount outside the above range can be used.

The compounds of the present invention are formulated for administration by conventional pharmaceutical means.

That is, tablets, capsules, granules and pills for oral administration are excipients such as sucrose, lactose, glucose, starch, mannitol; binders such as hydroxypropylcellulose, syrup, gum arabic and gelatin. , Sorbit, tragacanth, methylcellulose, polyvinylpyrrolidone; disintegrants such as starch, carboxymethylcellulose or calcium salts thereof, microcrystalline cellulose, polyethylene glycol; lubricants such as talc,
Prepared using magnesium or calcium stearate, silica; lubricants such as sodium laurate, glycerol and the like.

Injectables, solutions, emulsions, suspensions, syrups and aerosols include active ingredient solvents such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; surface active agents. Agents such as sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ethers of hydrogenated castor oil, lecithin; suspending agents, such as carboxymethyl sodium salt, cellulose derivatives such as methylcellulose, tragacanth, Natural gums such as gum arabic; prepared by using preservatives such as esters of paraoxybenzoic acid, benzalkonium chloride, sorbate and the like.

For the ointment which is a transdermal preparation, for example, white petrolatum, liquid paraffin, higher alcohol, macrogol ointment, hydrophilic ointment, aqueous gel base and the like are used.

Suppositories are prepared using, for example, cocoa butter, polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil, polysorbate and the like.

[0278]

【Example】

Examples (Synthesis Examples, Formulation Examples, Test Examples) Hereinafter, the present invention will be described in detail with reference to Examples (synthesis examples, formulation examples, test examples), but the present invention is not limited to these Examples. Not a thing. In addition, "mp", "NM
The symbols "R" and "MS" represent "melting point", "nuclear magnetic resonance spectrum", and "mass spectrum", respectively.

Reference Example 1 1- (4-Fluorobenzyl) -2-chloromethylbenzimidazole 15 g (132 mmol) of orthophenylene ediamine and 15 g (198 mmol) of glyoxylic acid were dissolved in 150 ml of 4N hydrochloric acid and heated under reflux for 3 hours. After cooling, pH 10 using 35% ammonia water
And the resulting crystals were filtered. The crystals were washed with water and ether and then vacuum dried at 60 ° C. to obtain 20.7 g of 2-hydroxymethylbenzimidazole as white crystals.

2 g (3.5 mmol) of this crystal and 2.15 g (3.9 mmol) of parafluorobenzyl chloride were dissolved in 20 ml of dimethylformamide, and further 2.8 g (5.3 mmo of anhydrous potassium carbonate).
l) was added, and the mixture was stirred at 60 ° C for 24 hours. The potassium carbonate was filtered, the solvent was evaporated under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystals were filtered and washed with ether, and 1-parafluorobenzyl-2-
2.37 g of hydroxymethylbenzimidazole was obtained as white crystals.

500 mg (2 mmol) of this crystal was dissolved in 5 ml of chloroform dried with molecular sieves, 2 ml of chloroform and 350 mg (3 mmol) of thionyl chloride were added under ice-cooling, and under ice-cooling.
The mixture was stirred for 1.5 hours and room temperature for 2 hours. The solvent is distilled off under reduced pressure,
After adding 2 ml of methanol, 200 mg of sodium hydrogen carbonate and 100 mg of anhydrous sodium sulfate and stirring, the precipitate was filtered off.
The solvent was distilled off under reduced pressure to obtain 700 mg of the title compound as white crystals.

Reference Example 2 1-Benzyl-2-aminomethylbenzimidazole 1.2 g (5.5 mmol) of 2-aminomethylbenzimidazole was dissolved in a mixed solution of 10 ml of dioxane and 5 ml of 1M aqueous potassium hydroxide solution, and dicarbonic acid di-t. -Butyl 1.31 g (6.1 mmol)
Was added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized with diethyl ether,
1.05 g of 2-t-butoxycarbonylaminomethylbenzimidazole was obtained as white crystals. This crystal 800 mg (3.2
mmol) and benzyl chloride 410 mg (3.5 mmol) in 10 ml of dimethylformamide, and anhydrous potassium carbonate 580 mg (4.
2 mmol) was added, and the mixture was stirred at 60 ° C. for 24 hours. After the precipitate was filtered off, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ether was added to the precipitated crystals and the crystals were filtered to obtain 1.37 g of 1-benzyl-2-t-butoxycarbonylaminomethylbenzimidazole as white crystals.

700 mg (2.1 mmol) of this crystal was added to chloroform 10
Dissolve in ml and add 3.4 g (30 mmol) of trifluoroacetic acid to 60
The mixture was stirred at 0 ° C for 1 hour. Chloroform 30 ml, 1N hydrochloric acid 30 ml
After adding 5 to make the mixture acidic, the aqueous layer is taken and a 5N aqueous sodium hydroxide solution is added until the pH reaches 9, and the mixture is adjusted to 3 with chloroform.
Extracted times. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (470 mg) as a colorless oil.

Reference Example 3 1- (4-Fluorobenzyl) -2- (1-methylhydrazino) methylbenzimidazole 1- (4-Fluorobenzyl) -2-chloromethylbenzimidazole 500 mg (1.8 mmol) in methanol 6 ml 220 mg (4.7 mmol) of methylhydrazine was added and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified twice by silica gel thin layer chromatography (eluent; chloroform / methanol = 25/1) to obtain 420 mg of the title compound as a colorless oil.

Reference Example 4 1-Benzyl-2- (1-piperazinyl) methylbenzimidazole 24.6 g (148 mmol) of 2-chloromethylbenzimidazole was dissolved in 200 ml of dimethylformamide and 26.5 g of potassium carbonate was added.
(192 mmol) and 20.2 g (178 mmol) of N-formylpiperazine were added, and the mixture was stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether to give 2-
22.5 g of (4-formyl-1-piperazinyl) methylbenzimidazole was obtained as white crystals.

5 g (20 mmol) of this crystal was dissolved in 50 ml of dimethylformamide, 3.7 g (26 mmol) of potassium carbonate and 2.8 g (22 mmol) of benzyl chloride were added, and the mixture was stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether to give 1-benzyl-2- (4-formyl-1-
3.9 g of piperazinyl) methylbenzimidazole was obtained as white crystals.

3.5 g (10.5 mmol) of this crystal was added to 30 ml of methanol.
And stir at room temperature, 1.7 g of sodium hydroxide (42 mmo
l) and a solution consisting of 5 ml of water were added dropwise and the mixture was heated under reflux for 2 hours.
The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was dried under vacuum to give 3.4 g of the title compound.
Was obtained as a colorless oil.

Similarly, 1- (4-fluorobenzyl) -2- (1-piperazinyl) methylbenzimidazole and 1- (4-chlorobenzyl) -2- (1-piperazinyl) methylbenzimidazole were synthesized.

Reference Example 5 1-Phenyl-2-chloromethylbenzimidazole N-phenyl 1,2-phenylenediamine 5 g (27.1 mmo)
l) dissolved in 25 ml of dichloromethane and 8.6 g of pyridine (108 mmo
l) is added, and chloroacetyl chloride 4.3g is added at 5 ° C to 10 ° C.
(38 mmol) was added dropwise and the mixture was stirred for 3 hours. Water was added and the mixture was extracted with dichloromethane. The extract was washed with a dilute aqueous hydrochloric acid solution and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Benzene 150 ml, paratoluene sulfonic acid 500
mg was added and the mixture was heated under reflux for 3 hours under azeotropic dehydration. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate / benzene = 1/5) to obtain 4.7 g of the title compound as brown crystals.

Reference Example 6 1-Phenyl-2- (1-piperazinyl) methylbenzimidazole 1-Phenyl-2-chloromethylbenzimidazole 2.
5 g (10.3 mmol) was dissolved in 25 ml of dimethylformamide, and 2.1 g (15.5 mmol) of potassium carbonate and N-formylpiperazine 1.
4 g (12.4 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After washing with an aqueous solution of potassium hydrogen carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform / methanol = 19/1), and 1
2.6 g of -phenyl-2- (4-formyl-1-piperazinyl) methylbenzimidazole was obtained as a colorless oil.

2.6 g (8.1 mmol) 1-phenyl-2- (4-formyl-1-piperazinyl) methylbenzimidazole
Is dissolved in 20 ml of methanol, 5 ml of water, sodium hydroxide
An aqueous solution consisting of 1.3 g (32.4 mmol) was gradually added. 60 ° C
After heating for 2 hours, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diethyl ether to give the title compound (2.5 g) as pale brown crystals.

Reference Example 7 1- (4-Fluorobenzyl) -2- (2-aminoethyl)
Benzimidazole orthophenylenediamine 32.4 g (0.3 mol) and β-alanine 26.7 g (0.3 mol) were added to 15% hydrochloric acid 300 ml, and the mixture was heated under reflux for 17 hours. After cooling, 50 g of sodium hydroxide was added little by little under ice cooling, and sodium hydroxide was further added until the pH reached 11. The aqueous layer was removed, the remaining oily substance was dissolved in 300 ml of tetrahydrofuran, and 40 g of di-t-butyl dicarbonate under ice cooling.
Was added little by little, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 200 ml of water was added, and the mixture was extracted with 300 ml of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diethyl ether to obtain 2- (2-t-butoxycarbonylaminoethyl) benzimidazole (36 g) as light brown crystals. (mp 189.0-190.0 ° C) 5.0 g (19.16 mmol) of this crystal, 3.2 g (22.15 mmol) of parafluorobenzyl chloride, 6.0 g (43.48 mmol) of potassium carbonate were added to 30 ml of dimethylformamide, and 3 hours, 40 ° C to 50 ° C.
With stirring. After cooling, 50 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diethyl ether-hexane to give 1- (4-fluorobenzyl) -2- (2-t-butoxycarbonylaminoethyl).
6.36 g of benzimidazole was obtained as white crystals. (M.
p. 119.0-120.0 ° C) 1.5 g (4.07 mmol) of this crystal and 8 g of trifluoroacetic acid were added to 5 ml of chloroform, and the mixture was stirred at 60 ° C for 3 hours. Aqueous potassium carbonate solution was added to make it basic, and the mixture was extracted with 50 ml of chloroform. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (1.08 g) as a colorless oil.

Reference Example 8 Anhydrous-2-benzimidazolecarboxylic acid 2-hydroxymethylbenzimidazole 6 g (40 mmol),
60 ml of water was added to 600 mg (5.66 mmol) of sodium carbonate and dissolved by heating. 9.6 g (60 mmol) of potassium permanganate was gradually added, and the mixture was stirred with heating under reflux for 1 hour. The reaction solution was filtered through Celite, and the filtered product was thoroughly washed with stirring in an aqueous potassium carbonate solution with heating. The filtrate was adjusted to pH 7 with dilute hydrochloric acid, the precipitated crystals were collected by filtration, washed with water, and vacuum dried at 40 ° C. for 2 hours to give benzimidazole-2-carboxylic acid 4.
4 g was obtained as white crystals.

To 2 g (12.3 mmol) of this crystal was added 12 ml of thionyl chloride.
Was added and heated at room temperature for 1 hour and at 90 ° C. for 4 hours. After cooling, the precipitate was filtered, washed with ether and water, suspended in warm water-acetone, and washed with heat. The crystals were collected by filtration and vacuum dried at 80 ° C. for 2 hours to give 1.1 g of the title compound as yellow crystals.

Synthesis Example 1 1- (4-Fluorobenzyl) -2- (2-methoxybenzylamino) methylbenzimidazole 1- (4-Fluorobenzyl) -2-chloromethylbenzimidazole (550 mg, 2 mmol) was added to ethanol (7 ml). After dissolution, 260 mg (2.6 mmol) of triethylamine and 380 mg (2.8 mmol) of 2-methoxybenzylamine were added, and the mixture was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After washing with aqueous potassium carbonate solution,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (eluent; chloroform / methanol = 39/1) to give the title compound (700 mg) as a colorless oil.

MS (m / z): 374 (M ⁺ ), 109 (100%)

Synthesis Example 2 1- (4-Fluorobenzyl) -2- (N-2-chlorobenzyl-N-methylamino) methylbenzimidazole 1- (4-fluorobenzyl) -2- (2-chlorobenzylamino) ) Methylbenzimidazole 260mg (0.68mmo
l) was dissolved in 3 ml of anhydrous tetrahydrofuran, 35 mg (0.88 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 20 minutes. Methyl iodide 150 mg (1 mmol), anhydrous tetrahydrofuran 2 ml
The resulting solution was added dropwise and stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (eluent;
Purified by chloroform / methanol = 39/1),
140 mg of the title compound was obtained as a colorless oil.

MS (m / z): 239 (M ⁺ -154), 109 (100%)

Synthesis Example 3 1-Benzyl-2- (1- (2-chlorophenyl) ethylamino) methylbenzimidazole 1-Benzyl-2-aminomethylbenzimidazole 17
0 mg (0.72 mmol) was dissolved in 2 ml of methanol dried by molecular sieves, 10% hydrochloric acid-methanol 1.2 ml,
230 mg (1.5 mmol) of 2-chloroacetophenone, 300 mg of molecular sieves, 103 mg of sodium cyanoborohydride
(1.6 mmol) was added and the mixture was stirred for 3 days at room temperature. After removing the precipitate by filtration, the solvent was evaporated under reduced pressure, water was added to the obtained residue,
Extracted with chloroform. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (eluent: chloroform / methanol = 39/1) to give the title compound (250 mg) as a colorless oil.

Hydrochloride MS (m / z): 375 (M ⁺ -HCl), 222 (100%)

Synthesis Example 4 N- (1-benzylbenzimidazol-2-yl) methyl-N '-(2-chlorobenzyl) urea 1-benzyl-2-aminomethylbenzimidazole 15
A mixture of 0 mg (0.63 mmol) and 170 mg (0.65 mmol) of phenyl N- (2-chlorobenzyl) carbamate was dissolved in 0.3 ml of tetrahydrofuran and heated at 120 ° C. for 2 hours while stirring. After cooling, the solidified mixture was crystallized from diethyl ether. After filtration, vacuum drying (50 ° C., 2 hours) gave 220 mg of the title compound as white crystals.

Mp: 174.0-175.0 ° C MS (m / z): 404 (M ⁺ ), 91 (100%)

Synthesis Example 5 1- (1- (4-Fluorobenzyl) benzimidazol-2-yl) methyl-1-methyl-4- (2chlorobenzyl) semicarbazide 1- (4-fluorobenzyl) -2- ( 1-Methylhydrazino) methylbenzimidazole 200 mg (0.7 mmol), phenyl N- (2-chlorobenzyl) carbamate 180 m
Dissolve g (0.7 mmol) in 1 ml of tetrahydrofuran, 120
Stirred at C for 3 hours. Water was added to the residue and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (eluent; chloroform / methanol = 19/1) to give the title compound.
32 mg was obtained as white crystals.

Mp: 122.0-124.0 ° C MS (m / z): 436 (M ⁺ -15), 109 (100%)

Synthesis Example 6 1- (4-Fluorobenzyl) -2- (4- (2-chlorobenzyl) -1-piperazinyl) methylbenzimidazole 1- (4-fluorobenzyl) -2- (1-piperazinyl) Methylbenzimidazole 300 mg (0.93 mmol) was dissolved in dimethylformamide 5 ml, and potassium carbonate 190 mg (1.4
mmol) and 180 mg (1.1 mmol) of 2-chlorobenzyl chloride were added, and the mixture was stirred at 60 ° C for 24 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (eluent; chloroform / methanol = 25/1) to give 300 mg of the title compound.
Was obtained as a colorless oil.

MS (m / z): 448 (M ⁺ ), 109 (100%)

Synthesis Example 7 1- (4-Fluorobenzyl) -2- (4- (2-chlorobenzylaminocarbonyl) -1-piperazinyl) methylbenzimidazole 1- (4-fluorobenzyl) -2- (1- Piperazinyl) methylbenzimidazole 250 mg (0.77 mmol), 2-
Phenyl N- (2-chlorobenzyl) carbamate 20
A mixture of 0 mg (0.76 mmol) was dissolved in 0.8 ml of tetrahydrofuran and heated at 120 ° C. for 3 hours while stirring. After cooling,
The solidified mixture was crystallized from diethyl ether. After filtration and vacuum drying (50 ° C., 2 hours), 310 mg of the title compound was obtained as white crystals.

Mp: 189.0-190.0 ° C MS (m / z): 492 (M ⁺ ), 109 (100%)

Synthesis Example 8 1- (4-Fluorobenzyl) -2- (4- (1-oxo-2- (2-chlorophenyl) ethyl) -1-piperazinyl) methylbenzimidazole 1- (4-fluorobenzyl) 2- (1-Piperazinyl) methylbenzimidazole 300 mg (0.9 mmol) was dissolved in tetrahydrofuran 4 ml and triethylamine 140 mg (1.4
mmol), orthochlorophenylacetic acid chloride 230 mg (1.2
mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diethyl ether to give the title compound (300 mg) as brown crystals.

Mp: 165.0-166.0 ° C MS (m / z): 476 (M ⁺ ), 109 (100%)

Synthesis Example 9 1-Phenyl-2- (4- (2-chlorobenzylmethylaminocarbonyl) -1-piperazinyl) methylbenzimidazole 1-phenyl-2- (4- (2-chlorobenzylaminocarbonyl)- 1-Piperazinyl) methylbenzimidazole 100 mg (0.22 mmol) was dissolved in dimethylformamide 2 ml, sodium hydride 20 mg (0.44 mmol) was added, and the mixture was stirred at room temperature
Stirred for 0 minutes. Methyl iodide (50 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Aqueous ammonium chloride solution was added, the solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (eluent; chloroform / methanol = 19/1) to obtain 90 mg of the title compound as a colorless oil.

MS (m / z): 473 (M ⁺ ), 207 (100%)

Synthesis Example 10 1-benzyl-2- (4- (1- (2-chlorophenyl) ethyl) -1-piperazinylmethyl) benzimidazole 1-benzyl-2- (1-piperazinyl) methylbenzimidazole 3000 mg (0.98 mmol) was dissolved in 2 ml of methanol dried by molecular sieves, 10% hydrochloric acid-methanol 1.2 ml, 2-chloroacetophenone 320 mg (2.1 mm
ol), 300 mg of molecular sieves and 150 mg (2.4 mmol) of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 3 days.
After removing the precipitate by filtration, the solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After washing with an aqueous solution of potassium carbonate, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (eluent; chloroform / methanol = 1).
Purification by 9/1) gave 140 mg of the title compound as a colorless oil.

Hydrochloride mp 144.0-146.0 ° C MS (m / z) 44
3 (M ⁺ ), 91 (100%)

Synthesis Example 11 1- (4-Fluorobenzyl) -2- (4- (2-
(2,5-Dichlorophenyloxy) -1-oxoethyl) -1-piperazinyl) methylbenzimidazole 1- (4-fluorobenzyl) -2- (1-piperazinyl) methylbenzimidazole 620 mg (1.9 mmol) was dissolved in tetrahydrofuran 8 ml. , 2-chloroacetyl chloride 260 mg (2.3 mmol) at -30 ° C, tetrahydrofuran 2 m
The solution consisting of l was added dropwise. It returned to room temperature and stirred for 6 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue,
Extracted with chloroform. After washing with an aqueous solution of potassium carbonate and saturated saline, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 1- (4-fluorobenzyl).
820 mg of 2- (4-chloroacetyl-1-piperazinyl) methylbenzimidazole was obtained as a colorless oil.

380 mg (9.5 mmol) of this compound, 4 ml of dimethylformamide, 170 mg (12.4 mmol) of potassium carbonate, 2,5-
Dichlorophenol 170mg (10.5mmol) mixture at 60 ℃
It was stirred for 24 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (eluent: chloroform / methanol = 19/1) to give 270 mg of the title compound.
Was obtained as brown crystals.

Mp: 168.0-169.0 ° C MS (m / z): 526 (M ⁺ ), 109 (100%)

Synthesis Example 12 1- (4-fluorobenzyl) -2- (4- (2- (2
-Methoxy-5-hydroxymethylphenyloxy)-
1-oxoethyl) -1-piperazinyl) methylbenzimidazole 1- (4-fluorobenzyl) -2- (4- (2- (2
-Methoxy-5-formylphenyloxy) -1-oxoethyl) -1-piperazinyl) methylbenzimidazole 600 mg (1.2 mmol) was dissolved in ethanol 10 ml, sodium borohydride 90 mg (2.4 mmol) was added, and the mixture was stirred at room temperature for 6 hours. . Water was added, the solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The extract was washed with aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (eluent; ethyl acetate / methanol = 19/1) to give the title compound (310 mg) as a colorless oil.

MS (m / z): 518 (M ⁺ ), 240 (100%)

Synthesis Example 13 1- (4-Fluorobenzyl) -2- (4- (2-
(2,5-Dichlorophenyloxy) ethyl) -1-piperazinyl) methylbenzimidazole 1- (4-fluorobenzyl) -2- (4- (2-
(2,5-Dichlorophenyloxy) -1-oxoethyl) -1-piperazinyl) methylbenzimidazole 15
0 mg (0.28 mmol) was dissolved in 4 ml of tetrahydrofuran, 14 mg (1.3 equivalents) of lithium aluminum hydride was added, and the mixture was heated under reflux for 2 hours. After cooling, Celite, methanol and water were added, and the mixture was stirred at room temperature for 1 hr. The precipitate was filtered off, the solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (eluent; chloroform / methanol = 19/1) to give the title compound.
30 mg was obtained as a colorless oil.

Hydrochloride mp: 147.0-149.0 ° C MS (m / z): 23
9 (M ⁺ -346-2HCl), 109 (100%)

Synthesis Example 14 1- (4-Fluorobenzyl) -2- (2- (2-chlorobenzylamino) ethyl) benzimidazole dimethylformamide 4 ml, sodium hydride 110 mg (2.5
2 mmol 50% oil) in 1- (4-fluorobenzyl) -2
800 mg (2.17 mmol) of-(2-t-butoxycarbonylaminoethyl) benzimidazole was added, and the mixture was stirred at room temperature for 30 minutes. 420 mg (2.61 mmol) of 2-chlorobenzyl chloride was added, and the mixture was reacted at room temperature for 2 hours. 20 ml of water was added, and the mixture was extracted with 30 ml of ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; ethyl acetate / hexane = 2/1).
Rf = 0.6), 1- (4-fluorobenzyl) -2
940 mg of-(2- (N-2-chlorobenzyl-Nt-butoxycarbonylamino) ethyl) benzimidazole was obtained as a pale yellow oil.

850 mg (1.72 mmole) of this compound was dissolved in 2 ml of chloroform, 2 ml of trifluoroacetic acid was added, and the mixture was stirred overnight at room temperature. The mixture was made basic with an aqueous potassium carbonate solution and extracted with 30 ml of chloroform. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound as a pale-yellow solid. mp: 50.0-52.0 ℃ MS (m / z): 393 (M +), 109 (100%)

Synthesis Example 15 N- (2- (1- (4-Fluorobenzyl) benzimidazol-2-yl) ethyl) -N ′-(2-chlorobenzyl) urea 1- (4-fluorobenzyl) -2 -(2-aminoethyl)
Benzimidazole (300 mg, 1.12 mmol) and phenyl N-
350 mg (1.34 mmol) of (2-chlorobenzyl) carbamate was added, and the mixture was stirred at 120 ° C for 2 hours. After cooling, chloroform-
By crystallizing from diethyl ether, 410 mg of the title compound was obtained as white crystals.

Mp: 152.0-154.0 ° C MS (m / z): 436 (M ⁺ ), 109 (100%)

Synthesis Example 16 1-Benzyl-2- (4- (3,5-ditrifluoromethylbenzyl) -1-piperazinyl) carbonylbenzimidazole anhydrous-2-benzimidazolecarboxylic acid 150 mg (0.52 mm)
ol) was dissolved in 2 ml of dimethylformamide, and N-3,5-
410 mg of ditrifluoromethylbenzylpiperazine (1.3 mmo
l) was added and heated at 120 ° C. for 4 hours. After cooling, dimethylformamide was distilled off under reduced pressure, and crystallized from diethyl ether-petroleum ether to obtain 2- (4- (3,5-ditrifluoromethylbenzyl) -1-piperazinyl) carbonylbenzimidazole 400 mg as white crystals. .

A mixture of 200 mg (0.44 mmol) of the crystals, 3 ml of dimethylformamide, 79 mg (0.57 mmol) of potassium carbonate and 61 mg (0.48 mmol) of benzyl chloride was stirred at 60 ° C. for 5 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform / methanol = 39/1) and crystallized from diethyl ether to give the title compound (240 mg) as brown crystals.

Hydrochloride mp: 155.0-157.0 ° C MS (m / z): 54
6 (M ⁺ -HCl), 227 (100%)

Synthetic Example 17 1- (4-Fluorobenzyl) -2- (2-chlorobenzylamino) carbonylbenzimidazole anhydrous-2-benzimidazolecarboxylic acid 200 mg (0.7 mmo
l) was dissolved in 3 ml of dimethylformamide, 300 mg (2.1 mmol) of 2-chlorobenzylamine was added, and the mixture was heated at 130 ° C. for 4 hours. After cooling, dimethylformamide was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from diisoproether to obtain 330 mg of 2- (2-chlorobenzylamino) carbonylbenzimidazole as white crystals.

A mixture of 200 mg (0.7 mmol) of this crystal, 3 ml of dimethylformamide, 126 mg (0.91 mmol) of potassium carbonate and 111 mg (0.77 mmol) of parafluorobenzyl chloride was added to 60 parts.
Stirred at C for 5 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform / methanol = 39/1) and crystallized from diethyl ether to give the title compound (290 mg) as white crystals.

Mp: 126.0-129.0 ° C MS (m / z): 393 (M ⁺ ), 109 (100%)

Synthesis Example 18 1- (4-Fluorobenzyl) -2- (2-chlorobenzylamino) methylbenzimidazole By the same procedure as in Synthesis Example 1, the title compound was obtained as white crystals. mp 49.0-51.0 ℃ MS (m / z): 380 (M ⁺⁺ 1), 109 (100%)

Synthesis Example 19 1- (4-Fluorobenzyl) -2- (α-naphthylmethylamino) methylbenzimidazole By the same procedure as in Synthesis Example 1, the title compound was obtained as a colorless oil. MS (m / z): 395 (M ⁺ ), 109 (100%)

Synthesis Example 20 1- (4-Fluorobenzyl) -2- (3,5-dimethoxybenzylamino) methylbenzimidazole By the same procedure as in Synthesis Example 1, the title compound was obtained as a colorless oil. MS (m / z): 406 (M ⁺⁺ 1), 241 (100%)

Synthesis Example 21 1-Phenyl-2- (2-chlorobenzylamino) methylbenzimidazole By the same procedure as in Synthesis Example 1, the title compound was obtained as a colorless oil. MS (m / z): 207 (M ⁺ -140), 125 (100%)

Synthesis Example 22 1-Phenyl-2- (3.5-ditrifluoromethylbenzylamino) methylbenzimidazole By the same procedure as in Synthesis Example 1, the title compound was obtained as light brown crystals. mp: 93.0-94.0 ℃ MS (m / z): 449 (M ⁺ ), 207 (100%)

Synthesis Example 23 1- (4-Fluorobenzyl) -2- (2- (2-chlorophenyl) ethylamino) methylbenzimidazole By the same procedure as in Synthesis Example 1, the title compound was obtained as a colorless oil. It was MS (m / z): 393 (M ⁺ ), 109 (100%)

Synthesis Example 24 1-Phenyl-2- (2- (2-chlorophenyl) ethylamino) methylbenzimidazole By the same procedure as in Synthesis Example 1, the title compound was obtained as a colorless oil. MS (m / z): 361 (M ⁺ -125), 207 (100%)

Synthesis Example 25 1- (4-Fluorobenzyl) -2- (N-2-methoxybenzyl-N-methylamino) methylbenzimidazole The title compound was obtained as a colorless oil by the same procedure as in Synthesis Example 2. Got as. MS (m / z): 239 (M ⁺ -150), 109 (100%)

Synthesis Example 26 1- (4-Fluorobenzyl) -2- (N-α-naphthylmethyl-N-methylamino) methylbenzimidazole The title compound was obtained as a colorless oil by the same procedure as in Synthesis Example 2. Got as. MS (m / z): 410 (M ⁺⁺ 1), 170 (100%)

Synthesis Example 27 1- (4-Fluorobenzyl) -2- (N-3,5-dimethoxybenzyl-N-methylamino) methylbenzimidazole The title compound was obtained by the same procedure as in Synthesis Example 2. Obtained as a brown oil.

¹ H-NMR (CDCl ₃ ) δ: 2.27 (s, 3H), 3.47 (s, 2
H), 3.64 (s, 3H), 3.70 (s, 2H), 5.38 (s, 2H), 6.19-6.
44 (m, 3H), 6.80-7.30 (m, 7H), 7.54-7.84 (m, 1H)

Synthesis Example 28 1-Phenyl-2- (N-2-chlorobenzyl-N-methylamino) methylbenzimidazole By the same procedure as in Synthesis Example 2, the title compound was obtained as a pale brown oil.

MS (m / z): 207 (M ⁺ -154), 125 (100%)

Synthesis Example 29 1-Phenyl-2- (N-3,5-ditrifluoromethylbenzyl-N-methylamino) methylbenzimidazole By the same procedure as in Synthesis Example 2, the title compound was obtained as white crystals. It was mp: 89.0-91.0 ℃ MS (m / z): 463 (M ⁺ ), 207 (100%)

Synthesis Example 30 1- (4-Fluorobenzyl) -2- (N-2- (2-
Chlorophenyl) ethyl-N-methylamino) methylbenzimidazole By the same procedure as in Synthesis Example 2, the title compound was obtained as a pale brown oil.

MS (m / z): 282 (M ⁺ -125), 109 (100%)

Synthesis Example 31 1-Phenyl-2- (N-2- (2-chlorophenyl)
Ethyl-N-methylamino) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 2.

MS (m / z): 250 (M ⁺ -125), 207 (100%)

Synthesis Example 32 N- (1-benzylbenzimidazol-2-yl) methyl-N ′-(3,5-ditrifluoromethylbenzyl)
Urea By the same procedure as in Synthesis Example 4, the title compound was obtained as white crystals. mp: 189.0-190.0 ℃ MS (m / z): 506 (M ⁺ ), 91 (100%)

Synthetic Example 33 1- (4-Fluorobenzyl) -2- (4- (4-fluorobenzyl) -1-piperazinyl) methylbenzimidazole The title compound was pale brown by the same procedure as in Synthetic Example 6. Obtained as an oil.

MS (m / z): 432 (M ⁺ ), 109 (100%)

Synthesis Example 34 1-Benzyl-2- (4- (2-chlorobenzyl) -1
-Piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 6.

Hydrochloride mp 117.0-119.0 ° C MS (m / z): 43
0 (M ⁺ -HCl), 193 (100%)

Synthesis Example 35 1- (4-Fluorobenzyl) -2- (4- (3,5-ditrifluoromethylbenzyl) -1-piperazinyl) methylbenzimidazole By the same procedure as in Synthesis Example 6, the title was obtained. The compound was obtained as a light brown oil.

Hydrochloride mp: 158.0-160.0 ° C MS (m / z): 55
1 (M ⁺ -2HCl), 239 (100%)

Synthesis Example 36 1-Benzyl-2- (4- (3,5-ditrifluoromethylbenzyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 6. I got it as a thing.

Hydrochloride mp: 149.0-151.0 ° C MS (m / z): 53
2 (M ⁺ -2HCl), 91 (100%)

Synthesis Example 37 1- (4-Chlorobenzyl) -2- (4- (3,5-ditrifluoromethylbenzyl) -1-piperazinyl) methylbenzimidazole By the same procedure as in Synthesis Example 6, the title was obtained. The compound was obtained as a light brown oil.

Hydrochloride mp: 189.0-191.0 ° C MS (m / z): 56
7 (M ⁺ -2HCl), 125 (100%)

Synthesis Example 38 1-Phenyl-2- (4- (2-chlorobenzyl) -1
-Piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 6.

MS (m / z) 416 (M ⁺ ), 207 (100%)

Synthesis Example 39 1-Phenyl-2- (4- (4-fluorobenzyl)-
1-Piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 6.

MS (m / z) 400 (M +), 207 (100%)

Synthesis Example 40 1- (4-Fluorobenzyl) -2- (4- (2-methoxybenzylaminocarbonyl) -1-piperazinyl)
Methylbenzimidazole The title compound was obtained as white crystals by performing the same operations as in Synthesis Example 7. mp: 177.0-178.0 ℃ MS (m / z): 487 (M ⁺ ), 109 (100%)

Synthesis Example 41 1-Benzyl-2- (4- (2-chlorobenzylaminocarbonyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oily substance by the same procedure as in Synthesis Example 7. Obtained.

Hydrochloride mp: 146.0-148.0 ° C MS (m / z): 47
3 (M ⁺ -HCl), 91 (100%)

Synthesis Example 42 1-Phenyl-2- (4- (2-methoxybenzylaminocarbonyl) -1-piperazinyl) methylbenzimidazole By the same procedure as in Synthesis Example 7, the title compound was obtained as white crystals. . mp: 182.0-184.0 ℃ MS (m / z): 455 (M ⁺ ), 208 (100%)

Synthesis Example 43 1-Phenyl-2- (4- (2-chlorobenzylaminocarbonyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as white crystals by the same procedure as in Synthesis Example 7. . mp: 197.0-199.0 ℃ MS (m / z): 459 (M ⁺ ), 208 (100%)

Synthesis Example 44 1-Phenyl-2- (4- (1-oxo-2- (2-chlorophenyl) ethyl) -1-piperazinyl) methylbenzimidazole The title compound was prepared in the same manner as in Synthesis Example 8. Was obtained as a light brown oil.

MS (m / z) 444 (M ⁺ ), 207 (100%)

Synthesis Example 45 1-Phenyl-2- (4- (2-methoxybenzylmethylaminocarbonyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by the same procedure as in Synthesis Example 9. Got as.

MS (m / z) 470 (M ⁺ +1), 236 (100%)

Synthesis Example 46 1- (4-Fluorobenzyl) -2- (4- (2- (2
-Chloro-5-trifluoromethylphenyloxy)-
1-Oxoethyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as white crystals by performing the same operations as in Synthesis Example 11.

Mp: 137.0-138.0 ° C MS (m / z): 560 (M ⁺ ), 109 (100%)

Synthesis Example 47 1- (4-Fluorobenzyl) -2- (4- (2- (2
-Methoxy-5-formylphenyloxy) -1-oxoethyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 11.

¹ H-NMR (CDCl ₃ ) δ: 2.31-2.71 (m, 4H), 3.20
-3.64 (m, 4H), 3.74 (s, 2H), 3.87 (s, 3H), 4.72 (s, 2
H), 6.46 (s, 2H), 6.81-7.88 (m, 11H), 9.71 (s, 1H)

Synthesis Example 48 1- (4-fluorobenzyl) -2- (4- (2- (2
-Methoxy-4-formylphenyloxy) -1-oxoethyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 11.

MS (m / z): 516 (M ⁺ ), 109 (100%)

Synthesis Example 49 1- (4-fluorobenzyl) -2- (4- (2- (2
-Methoxy-5-t-butoxycarbonylaminomethylphenyloxy) -1-oxoethyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 11.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 9H), 2.27-2.67
(m, 4H), 3.24-3.60 (m, 4H), 3.60-3.85 (m, 5H), 4.13
(d, 2H J = 6.0Hz), 4.58 (s, 2H), 4.97-5.47 (m, 1H), 5.
45 (s, 2H), 6.67-7.90 (m, 11H)

Synthesis Example 50 1- (4-Fluorobenzyl) -2- (4- (2- (2
-Methoxy-4-hydroxymethylphenyloxy)-
1-Oxoethyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 12.

¹ H-NMR (CDCl ₃ ) δ: 2.09-2.62 (m, 4H), 3.11
-3.81 (m, 10H), 4.54 (s, 4H), 5.40 (s, 4H), 6.50-7.30
(m, 10H), 7.45-7.77 (m, 1H)

Synthesis Example 51 1- (4-fluorobenzyl) -2- (4- (2- (2
-Chloro-5-trifluoromethylphenyloxy) ethyl) -1-piperazinyl) methylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 13.

Hydrochloride mp: 132.0-133.0 ° C MS (m / z): 54
6 (M ⁺ -2HCl), 109 (100%)

Synthesis Example 52 1- (4-Fluorobenzyl) -2- (2- (4-fluorobenzylamino) ethyl) benzimidazole The title compound was obtained as white crystals by performing the same operation as in Synthesis Example 14. . mp: 87.0-88.4 ℃ MS (m / z): 377 (M ⁺ ), 109 (100%)

Synthesis Example 53 N- (2- (1- (4-Fluorobenzyl) benzimidazol-2-yl) ethyl) -N ′-(2-methoxybenzyl) urea Perform the same operation as in Synthesis Example 15. Gave the title compound as white crystals. mp: 134.0-140.0 ℃ MS (m / z): 432 (M ⁺ ), 109 (100%)

Synthesis Example 54 1- (4-Fluorobenzyl) -2- (4-benzyl-)
1-Piperazinyl) carbonylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 16.

Hydrochloride mp: 227.0-229.0 ° C MS (m / z): 42
8 (M ⁺ -HCl), 109 (100%)

Synthesis Example 55 1-Benzyl-2- (4- (2-chlorobenzyl) -1
-Piperazinyl) carbonylbenzimidazole The title compound was obtained as a pale brown oil by performing the same operation as in Synthesis Example 16.

Hydrochloride mp: 166.0-168.0 ° C MS (m / z): 44
4 (M ⁺ -HCl), 91 (100%)

Synthesis Example 56 1-Benzyl-2- (3,5-ditrifluoromethylbenzylamino) carbonylbenzimidazole By the same procedure as in Synthesis Example 17, the title compound was obtained as white crystals. mp: 108.0-110.0 ℃ MS (m / z): 477 (M ⁺ ), 91 (100%)

[Formulation Example]

Formulation Example 1 Tablet formulation Compound of the present invention 10 g Lactose 260 g Microcrystalline cellulose 600 g Corn starch 350 g Hydroxypropyl cellulose 100 g CMC-Ca 150 g Magnesium stearate 30 g Total amount 1,500 g The above ingredients were mixed by a conventional method and then in 1 tablet 10,000 sugar-coated tablets containing 1 mg of the active ingredient were prepared.

Formulation Example 2 Capsule Compound of the present invention 10 g Lactose 440 g Microcrystalline cellulose 1,000 g Magnesium stearate 50 g Total amount 1,500 g The above ingredients were mixed by a conventional method and filled into a gelatin capsule, and 1 mg per capsule was obtained. Capsules containing 10,000 active ingredients were prepared.

Formulation Example 3 Soft Capsule Compound of the present invention 10 g PEG400 479 g Saturated fatty acid triglyceride 1,500 g Mint oil 1 g Polysorbate 80 10 g Total amount 2,000 g After mixing the above ingredients, a No. 3 soft gelatin capsule was prepared by a conventional method. 10,000 soft capsules were prepared, filled and containing 1 mg of active ingredient per capsule.

Formulation Example 4 Ointment Compound of the present invention 1.0 g Liquid paraffin 10.0 g Cetanol 20.0 g White petrolatum 68.4 g Ethylparaben 0.1 g l-Menthol 0.5 g Total amount 100.0 g The above components were prepared by a conventional method. Mix to make 1% ointment.

Formulation Example 5 Suppository Compound of the present invention 1 g Wittepsol H15 ^* 478 g Wittepsol W35 ^* 520 g Polysorbate 80 1 g Total amount 1,000 g “ ^* Trade name of triglyceride compound Witepsol = Witepsol” The ingredients were melt mixed in a conventional manner and poured into a suppository container to be cooled and solidified to prepare 1,000 1 g suppositories containing 1 mg of the active ingredient.

Formulation Example 6 Injectable compound Compound of the present invention 1 mg Distilled water for injection 5 ml Used and dissolved.

[Test Example] Inhibitory activity against substance P and histamine contraction using an ileal specimen of guinea pig

Drug The test drug is used by dissolving and diluting it in 100% dimethyl sulfoxide. Substance P (SP, Peninsula) and histamine (His, Wako Pure Chemical Industries) are dissolved and diluted in distilled water. Final concentration of dimethyl sulfoxide in the bath is 0.25 v / v%
The following is assumed.

Method 300-400 g of guinea pigs were exsanguinated to death, the ileum was excised, the contents and mesentery were removed, and strips having a length of 15-20 mm were prepared. Specimens containing modified-Tyrode's solution (glucose 5.5 mM) aerated with 30%, 95% O ₂ + 5% CO ₂ 20
Suspended in a ml organ bath, a load of 0.5 g was applied, and the contraction of muscle was measured isotonicity. After allowing the sample to rest for 15 minutes, the test drug was added and incubated for 5 minutes to contract with substance P 0.01 μM. The drug effect was expressed as a percentage of the contraction height after drug treatment with respect to the control contraction height. The IC ₅₀ (50% inhibitory concentration) of a drug causes contraction
It was calculated from the percent inhibition at two drug concentrations sandwiching the 50% inhibition concentration. Inhibition of histamine contraction was performed by the same test with histamine 0.1 μM instead of substance P.

The compound number of the test drug corresponds to the number of the synthetic example.

[0404]

[Table 67] ───────────────────────────── Test compound IC ₅₀ (μM) Substance P Histamine ──────── ────────────────────── 1 9.5 2.4 2 5.1 0.93 3 (hydrochloride) 1.6 3.1 4 2. 2 0.46 5 1.4 0.85 6 1.6 0.058 7 3.9 0.20 8 4.2 0.68 9 2.9 4.2 10 (hydrochloride) 3.5 0.091 11 5.4 14 (hydrochloride) 3.8 0.22 15 2.9 0.010 16 (hydrochloride) 2.1 0.51 18 2.9 2.5 19 5.7 3.2 20 20 6. 2 9.3 21 6.4 5.6 22 0.45 1.1 23 3.7 3.7 0.23 24 5.2 1.2 25 1.8 1.8 3.8 ──────────── ───────────── ─────

[0405]

[Table 68] ───────────────────────────── Test compound IC ₅₀ (μM) Substance P Histamine ──────── ────────────────────── 28 1.0 4.5 4.5 29 0.84 30 5.6 0.074 31 7.4 32 32 1.2 0. 45 34 (hydrochloride) 2.9 0.02 38 1.5 1.5 39 39 4.0 0.91 40 6.9 0.20 41 (hydrochloride) 5.6 0.38 42 4.1 6.1. 0 43 0.85 2.6 44 3.3 6.3 45 1.6 7.6 46 1.5 0.18 47 6.5 1.9 48 9.5 0.34 49 1.4 0.28 52 (hydrochloride) 3.8 0.22 53 3.2 0.021 54 (hydrochloride) 3.6 0.34 55 (hydrochloride) 1.6 1.4 ─────────── ─ ─────────────────

[0406]

INDUSTRIAL APPLICABILITY The compound of the present invention exhibits a substance P antagonistic action and is useful as an antiallergic agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 31/495 AAH A61K 31/495 AAH AAK AAK AAN AAN (72) Inventor Takehisa Iwama Saitama Prefecture Minami Saitama County 1470 Shiraoka, Shiraoka-machi, Institute of Biological Sciences, Nissan Chemical Industry Co., Ltd. (72) Inventor Akiko Yamamoto 1470, Shiraoka, Shiraoka-cho, Minamisaitama-gun, Saitama 1470, Institute of Biological Sciences, Nissan Chemical Industries, Ltd.

Claims (4)

[Claims] 1. A compound of the formula (I)[Where A is C_1-2An alkylene group (the alkylene group is
C_1-4Optionally substituted by an alkyl group or an oxygen atom
Good), B is NR^Three, NR^ThreeCONR^Four, NR^ThreeNR^Four, NR^ThreeNR^FourCONR^Five, N (CH_TwoC
H_Two)_TwoN, N (CH_TwoCH_Two)_TwoNCONR ^Three, NR^ThreeCH_TwoCH_TwoNR^FourOr NR^ThreeCH_TwoCH_Two
CH_TwoNR^Four(R^Three, R^FourAnd R^FiveAre each independently a hydrogen atom
Or C_1-4Represents an alkyl group), D is C_1-2Alkylene group or C_2-3Alkyleneoxy group
(The alkylene group and alkyleneoxy group are both
C_1-4Optionally substituted by an alkyl group or an oxygen atom
Good), Ar¹Is a phenyl group (the phenyl group is a halogen atom,
Trifluoromethyl group, C_1-4Alkyl group, C_1-4Alkoki
Si group, formyl group, hydroxymethyl group or CH _TwoNHC (O)_n
R⁶(N means 1 or 2. R⁶Is C_1-4An alkyl group
Are optionally substituted with)} or a naphthyl group
Indicates Ar^TwoIs a phenyl group, a benzyl group or diphenylmethyl
Group (the phenyl group, benzyl group and diphenylmethyl group
Is a halogen atom, C_1-4Alkyl group or C_1-4A
Optionally substituted with a lucoxy group), R¹And R^TwoAre each independently a hydrogen atom or a halogen atom.
Child, C_1-4Alkyl group or C_1-4Means an alkoxy group
You. ] The benzimidazole derivative represented by
salt. 2. A is CH_Two, CHMe, CH_TwoCH_Two, CH_TwoCHMe, CO,
CH_TwoCO, COCH_TwoOr COCHMe and B is NH, NMe, NHCON
H, NMeCONH, NHCONMe, NMeCONMe, NHNH, NHNMe, NMeN
H, NMeNMe, NMeNHCONH, NMeNHCONMe, N (CH_TwoCH_Two)_TwoN, N (C
H_TwoCH_Two)_TwoNCONH, N (CH_TwoCH_Two)_TwoNCONMe, NMeCH_TwoCH_TwoNMe or NM
eCH_TwoCH_TwoCH_TwoNMe, D is CH_Two, CHMe, CH _TwoCH_Two, CH_TwoCHM
e, COCH_Two, COCHMe, COCH_TwoO, CH_TwoCH_TwoO or CH_TwoCH_TwoCH_TwoAt O
Yes, Ar¹Is phenyl, 2-fluorophenyl, 3-fluor
Rophenyl, 4-fluorophenyl, 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl
Le, 3-bromophenyl, 4-bromophenyl, 2-iodof
Phenyl, 3-iodophenyl, 4-iodophenyl, 2-tri
Fluoromethylphenyl, 3-trifluoromethylpheny
, 4-trifluoromethylphenyl, 2-methylpheny
, 3-methylphenyl, 4-methylphenyl, 2-methoxy
Phenyl, 3-methoxyphenyl, 4-methoxyphenyl,
2,3-difluorophenyl, 2,4-difluorophenyl, 2,
5-difluorophenyl, 2,6-difluorophenyl, 3,4-
Difluorophenyl, 3,5-difluorophenyl, 2,3-di
Chlorophenyl, 2,4-dichlorophenyl, 2,5-dichloro
Phenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl
, 3,5-dichlorophenyl, 2,3-dibromophenyl, 2,
4-dibromophenyl, 2,5-dibromophenyl, 2,6-dibu
Lomophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl
Phenyl, 2,3-diiodophenyl, 2,4-diiodopheny
2,5-diiodophenyl, 2,6-diiodophenyl, 3,
4-diiodophenyl, 3,5-diiodophenyl, 2,3-dito
Lifluoromethylphenyl, 2,4-ditrifluoromethyl
Phenyl, 2,5-ditrifluoromethylphenyl, 2,6-di
Trifluoromethylphenyl, 3,4-ditrifluoromethyi
Ruphenyl, 3,5-ditrifluoromethylphenyl, 2,3-
Dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethyl
Ruphenyl, 2,6-dimethylphenyl, 3,4-dimethylphen
Nyl, 3,5-dimethylphenyl, 2,3-dimethoxyphenyl
2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl
2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl
, 3,5-dimethoxyphenyl, 2-chloro-5-trifluoro
Romethylphenyl, 2-methoxy-5-hydroxymethylphenyl
2-methyl-4-hydroxymethylphenyl, 2-
Methoxy-5-formylphenyl, 2-methoxy-4-formyl
Phenyl, 2-methoxy-5-t-butoxycarbonylamino
Methylphenyl, α-naphthyl or β-naphthyl,
Ar^TwoIs phenyl, 2-fluorophenyl, 3-fluorophen
Nyl, 4-fluorophenyl, 2-chlorophenyl, 3-chloro
Rophenyl, 4-chlorophenyl, 2-bromophenyl, 3-
Bromophenyl, 4-bromophenyl, 2-iodopheny
3-iodophenyl, 4-iodophenyl, 2-methylphenyl
Phenyl, 3-methylphenyl, 4-methylphenyl, 2-meth
Xyphenyl, 3-methoxyphenyl, 4-methoxyphenyl
Ru, benzyl, 2-fluorophenylmethyl, 3-fluoro
Phenylmethyl, 4-fluorophenylmethyl, 2-chloro
Phenylmethyl, 3-chlorophenylmethyl, 4-chlorophenyl
Phenylmethyl, 2-bromophenylmethyl, 3-bromophen
Nylmethyl, 4-bromophenylmethyl, 2-iodopheny
Lumethyl, 3-iodophenylmethyl, 4-iodophenyl
Methyl, 2-methylphenylmethyl, 3-methylphenylmethyl
Chill, 4-methylphenylmethyl, 2-methoxyphenylmeth
Chill, 3-methoxyphenylmethyl, 4-methoxyphenyl
Methyl or diphenylmethyl, R¹And R^TwoEach
Hydrogen atom, halogen atom, methyl group or methoxy group
A compound or a salt thereof according to claim 1. 3. A is CH_Two, CH_TwoCH_TwoOr CO and B is N
H, NMe, NHCONH, NHCONMe, NMeNHCONH, N (CH_TwoCH_Two)_TwoN, N
(CH_TwoCH_Two)_TwoNCONH, N (CH_TwoCH_Two)_TwoNCONMe, NMeCH_TwoCH _TwoNMe or
NMeCH_TwoCH_TwoCH_TwoNMe, D is CH_Two, CHMe, CH_TwoCH_Two, COCH
_Two, COCHMe or COCH_TwoO, Ar¹Is phenyl, 2-chloro
Phenyl, 2-methoxyphenyl, 3,5-dimethylphenyl
Le, 3,5-ditrifluoromethylphenyl, 3,5-dimethoxy
Cyphenyl, 2,5-dichlorophenyl, 2-chloro-5-tri
Fluoromethylphenyl, 2-methoxy-5-hydroxyme
Tylphenyl, 2-methoxy-4-hydroxymethylpheny
2-methoxy-5-formylphenyl, 2-methoxy-4-pho
Rumilphenyl, 2-methoxy-5-t-butoxycarbonyl
Aminomethylphenyl, α-naphthyl or β-naphthyl
Yes, Ar^TwoIs phenyl, 4-fluorophenyl, 4-chloro
Phenyl, benzyl, 4-fluorophenylmethyl, 4-chloro
Rolophenylmethyl or diphenylmethyl, R¹Passing
And R^TwoWherein each is a hydrogen atom, and
And its salt. 4. A therapeutic agent for allergic diseases, which comprises the compound according to claim 1.