Substituted AZA- and diazacycloheptane and -cyclooctane

Abstract

Aza- and diazacyclohexane and -cyclooctane compounds of the following formula:Ar1—A—B—Ar2  (I)where Ar1, A, B and Ar2 have the meanings stated in the description have a high affinity for the dopamine D3 receptor and can therefore be used to treat disorders which respond to dopamine D3 ligands.

Description

The invention relates to substituted aza- and diazacycloheptane and -cyclooctane compounds and to the use of such compounds. Said compounds have valuable therapeutic properties and can be used in particular for treating disorders which respond to dopamine D 3 ligands.

Compounds of the type under discussion here and having physiological activity have in some cases been disclosed. Thus, DE 21 39 082 and DE 22 58 561 describe pyrimidine derivatives and pyrimidone derivatives with basic substituents as drugs for lowering blood pressure. These pyrimidine and pyrimidone derivatives have the formulae:

where in (A) X is, inter alia, a sulfur atom, A is a C 1 -C 6 -alkylene group, and R 1 , R 2 , R 3 and Z are various substituents. In (B), X and Y are an oxygen or sulfur atom, A is a C 2 -C 6 -alkylene group, W is a vinylene group and R and Z are various substituents.

EP-A-361271 describes pyridyl and pyrimidyl derivatives of the formula:

where R 1 is halogen or hydrogen, and R 2 is halogen; X is oxygen, sulfur or methylene; R 3 and R 4 , which are identical or different, are hydrogen or lower alkyl; n is 2 or 3; A is a 2-pyrimidyl group or a 2- or 3-pyridyl group, it being possible for these groups to be substituted.

These compounds can be used to treat mental disturbances.

EP-A-454498 describes compounds of the formula

where A is, inter alia, —(CH 2 )m— or —B—(CH 2 )k—, where B is O, S, an unsubstituted or substituted amino group, —CONH— or —COO—, R 1 and R 2 can, inter alia, together form an alkylene chain, R 3 and R 4 are a hydrogen atom or a lower alkyl group, and X 1 , X 2 and X 3 are various substituents. These compounds can be used to treat cardiac arrhythmias.

EP-A-452107 and EP-A-369627 describe structurally similar compounds which can likewise be used for treating cardiac arrhythmias.

In addition, BE-A-628 766 describes compounds of the formula

where X is a halogen atom or a lower alkyl radical, T is piperazine, methylpiperazine, homopiperazine or methylhomopiperazine; Z is alkylene or alkenylene; A is O or S; and Y is a naphthyl, halonaphthyl or an unsubstituted or mono- to trisubstituted phenyl radical. These compounds can be used to treat schistosomiasis.

Neurones obtain their information inter alia via G-protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of these is dopamine. Confirmed information on the presence of dopamine and its physiological function as neurotransmitter is available. Cells responding to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other diseases are treated with drugs which interact with dopamine receptors. Up to 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, mainly the D 1 and D 2 receptors.

More recently, a third subtype has been found, namely the D 3 receptor, which appears to mediate some of the effects of antipsychotics (J. C. Schwartz et al., The Dopamine D 3 Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H.Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144). D 3 receptors are mainly expressed in the limbic system. It is therefore assumed that a selective D 3 antagonist is likely to have the antipsychotic properties of the D 2 antagonists but not their 10 neurological side effects (P. Sokoloff et al., Localization and Function of the D 3 Dopamine Receptor, Arzneim. Forsch./Drug Res . 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D 3 ) as a Target for Neuroleptics, Nature , 347, 146 (1990)).

P. J. Murray et al., Bioorganic & Medicinal Chemistry Letters, Vol. 5, No. 3, 219-222 (1995), have described arylpiperazines of the formula

where R 1 and R 2 are H or CH 3 O, and X is Br, 4-acetylphenyl, 4-methylsulfonylphenyl or 4-aminophenyl, with higher affinity and selectivity for the dopamine D 3 receptor.

We have now found, surprisingly, that certain aza- and diazacycloheptane and -cyclooctane compounds have a high affinity for the dopamine D 3 receptor and a low affinity for the D 2 receptor. They are thus selective D 3 ligands.

The present invention therefore relates to the compounds of the general formula I:

Ar 1 —A—B—Ar 2   (I)

where

Ar 1 is

 or a 5- or 6-membered heteroaromatic ring with 1, 2 or 3 heteroatoms which are selected, independently of one another, from O, N and S, where Ar 1 may have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR 1 , alkyl which is unsubstituted or substituted by OH, OC 1 -C 8 -alkyl or halogen, or C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, halogen, CN, CO 2 R 1 , NO 2 , NR 1 R 2 , SR 1 , CF 3 , CHF 2 , phenyl which is unsubstituted or substituted by C 1 -C 6 -alkyl, OC 1 -C 6 -alkyl, acyl, phenyl, amino, nitro, cyano or halogen, or phenoxy which is unsubstituted or substituted by C 1 -C 6 -alkyl, OC 1 -C 6 -alkyl or halogen, or C 1 -C 6 -alkanoyl or benzoyl;

R 1 is H, alkyl which is unsubstituted or substituted by OH, OC 1 -C 6 -alkyl, phenyl or halogen;

R 2 has the meanings stated for R 1 or is COR 1 or CO 2 R 1 ;

A is a C 3 -C 15 -alkylene group when Ar 1 is C 6 H 5 CONH, or, when Ar 1 is a 5- or 6-membered heteroaromatic ring, is a C 4 -C 15 -alkylene group or a C 3 -C 15 -alkylene group which comprises at least one group Z which is selected from O, S, NR 1 , a double and a triple bond, where R 1 is as defined above,

B is a 7- or 8-membered saturated ring with one or two nitrogen heteroatoms, the nitrogen heteroatoms being located in the 1,4 or 1,5 position and the ring being bonded in position 1 to the radical A and in position 4 or 5 to the radical Ar 2 , and it additionally being possible for the ring to have a double bond in position 3 or 4 in the monoaza ring and in position 6 in the 1,4-diaza ring;

Ar 2 is phenyl, pyridyl, pyrimidinyl or triazinyl, it being possible for Ar 2 to have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR 1 , alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, alkoxyalkyl, haloalkyl, halogen, CN, CO 2 R 1 , NO 2 , SO 2 R 1 , NR 1 R 2 , SO 2 NR 1 R 2 , SR 1 , a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic aromatic or non-aromatic ring with 1 to 3 heteroatoms which are selected from O, S and N, the carbocyclic or heterocyclic ring being unsubstituted or substituted by C 1 -C 8 -alkyl, phenyl, phenoxy, halogen, OC 1 -C 8 -alkyl, OH, NO 2 or CF 3 , where R 1 and R 2 have the abovementioned meanings, and Ar 2 may 40 also be fused to a carbocyclic ring of the type defined above, and where Ar 2 cannot be a pyrimidinyl radical substituted by 2 hydroxyl groups,

and the salts thereof with physiologically tolerated acids.

The compounds according to the invention are selective dopamine D 3 receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D 2 receptor, have fewer side effects than classical neuroleptics, which are D 2 receptor antagonists. The compounds can therefore be used to treat disorders which respond to dopamine D 3 receptor antagonists or agonists, eg. for treating disorders of the central nervous system, in particular schizophrenia, depression, neuroses and psychoses.

For the purpose of the present invention, the following terms have the meanings indicated thereafter:

alkyl (also in radicals such as alkoxy, alkylamino etc.) is a straight-chain or branched alkyl group with 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group may have one or more substituents which are selected, independently of one another, from OH and OC 1 -C 8 -alkyl.

Examples of an alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, etc.

Cycloalkyl is in particular C 3 -C 6 -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkylene is a straight-chain or branched radical with, preferably, 4 to 15 carbon atoms, particularly preferably 4 to 10 carbon atoms, or with 3 to 15, in particular 3 to 10, carbon atoms when the alkylene group comprises one of said groups.

The alkylene groups may comprise at least one of the groups Z indicated above in the definition of A. This may, just like the said double or triple bond, be located anywhere in the alkylene chain or in position 1 or 2 of group A (seen from the Ar 1 radical). A is particularly preferably compounds according to formula I where A is —Z—C 3 -C 6 -alkylene, in particular —Z—CH 2 CH 2 CH 2 —, —Z—CH 2 CH 2 CH 2 CH 2 —, —Z—CH 2 CH═CHCH 2 , —Z—CH 2 C(CH 3 )═CHCH 2 —, —Z—CH 2 C (═CH 2 )CH 2 —, —Z—CH 2 CH(CH 3 )CH 2 — or a linear —Z—C 7 -C 10 -alkylene radical. In this case, A is particularly preferably —Z—C 3 -C 6 -alkylene when Ar 1 is an unsubstituted or substituted pyrimidine or triazole residue, and a linear —Z—C 7 -C 10 -alkylene radical when Ar 1 is an unsubstituted or substituted thiadiazole residue. In this case, Z can also be CH 2 and is preferably CH 2 , O and, in particular, S.

Halogen is F, Cl, Br or I.

Haloalkyl may comprise one or more, in particular 1, 2 or 3, halogen atoms which can be located on one or more carbon atoms, preferably in the α or ω position. CF 3 , CHF 2 , CF 2 Cl or CH 2 F is particularly preferred.

Acyl is preferably HCO or C 1 -C 6 -alkyl-CO, in particular acetyl. If Ar 1 is substituted, the substituent can also be located on the nitrogen heteroatom.

Ar 1 is preferably compounds of the formula I where Ar 1 is

where

R 3 to R 6 are H or one of the abovementioned substituents of the Ar 1 radical,

R 7 has the meanings indicated above for R 2 , and

X is N or CH. When the benzamide residue is substituted, the substituents are preferably in the m or p position.

Ar 1 is particularly preferably compounds of the formula I where

Ar 1 is

 where R 3 to R 5 , R 7 and X have the abovementioned meanings, and in particular compounds of the formula I where Ar 1 is

 where R 3 to R 5 , R 7 and X have the abovementioned meanings.

The radicals R 3 to R 6 are preferably H, C 1 -C 6 -alkyl, OR 1 , NR 1 R 2 , SR 1 , phenyl which is substituted or unsubstituted with C 1 -C 6 alkyl, acyl or halogen, and halogen, where R 1 and R 2 have the abovementioned meanings.

The radical B is preferably

The radical Ar 2 may have one, two, three or four substituents, preferably one or two substituents, which are located in particular in the m position and/or p position. They are preferably selected, independently of one another, from C 1 -C 6 -alkyl, haloalkyl, NO 2 , halogen, in particular chlorine, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, cyclopentyl and cyclohexyl. If one of the substituents is C 1 -C 8 -alkyl, a branched group is preferred, in particular isopropyl or t-butyl.

Ar 2 is preferably unsubstituted or substituted phenyl, 2-, 3- or 4-pyridinyl or 2-, 4(6)- or 5-pyrimidinyl.

If one of the substituents on the radical Ar 2 is a 5- or 6-membered heterocyclic ring, it is, for example, a pyrrolidine, piperidine, morpholine, piperazine, pyridine, 1,4-dihydropyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole or thiadiazole residue, with a pyrrole, imidazole, pyrrazole or thienyl radical being preferred.

If one of the substituents on the radical Ar 2 is a carbocyclic radical, it is, in particular, a phenyl, cyclopentyl or cyclohexyl radical.

If Ar 2 is fused to a carbocyclic radical, it is, in particular, a naphthalene, di- or tetrahydronaphthalene residue.

The invention also comprises the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung, Volume 10, pages 224 et seq., Birkhäuser Verlag, Basel and Stuttgart, 1966.

The compounds of the formula I may have one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The particular tautomeric forms are also included in the invention.

The process for preparing the compounds (I) comprises

a) reacting a compound of the general formula II

Ar 1 —Z—A—Y 1   (II)

 where Y 1 is a conventional leaving group such as Hal, alkanesulfonyloxy, arylsulfonyloxy etc., and Z has the abovementioned meanings, with a compound of the general formula (III)

H—B—Ar 2   (III)

 or

b) reacting a compound of the general formula (IV)

Ar 1 —A 1 —Z 1 H  (IV)

 where Z 1 is O, NR 1 or S and A 1 is C 1 -C 15 -alkylene or a bond, with a compound of the general formula V

Y 1 —A 2 —B—Ar 2   (V)

where Y 1 has the abovementioned meaning, and A 2 is C 2 -C 15 -alkylene, where A 1 and A 2 together have 3 to 15 carbon atoms; or

c) reacting a compound of the general formula (VI)

Ar 1 —Y 1   (VI)

 where Y 1 has the abovementioned meaning, with a compound of the general formula VII

H—Z 1 —A—B—Ar 2   (VII)

 where Z 1 has the abovementioned meanings; or

d) converting a compound of the formula (VIII)

NC—A—B—Ar 2   (VIII)

 into a compound of the type of (IX)

 and reacting the latter with a dicarbonyl compound in a conventional way; or

e) to prepare a compound of the formula I where Ar 1 is a benzamide residue:

reacting a compound of the general formula (X)

 where Y 2 is OH, OC 1 -C 4 —alkyl, Cl or together with CO an activated ester group, with a compound of the formula (XI)

Z 2 —A 2 —B—Ar 2   (XI)

 where A 2 has the abovementioned meanings, and Z 2 is OH or NH 2 .

The compounds of the formula III are starting compounds for preparing compounds of the formulae V, VII and VIII and are prepared by

a) reacting a compound of the general formula (XII)

HB 1   (XII)

 where B 1 is

 with a compound of the general formula (XIII)

Y 1 —Ar 2   (XIII)

 where Y 1 is one of the abovementioned leaving groups and Ar 2 has the abovementioned meaning, in a conventional way; or

b) reacting a compound of the general formula (XIV)

H—B 2

 where B 2 is

 with n=1 or 2, with a compound of the general formula (XV)

Y 2 —Ar 2

 where Y 2 is Br, Cl or I, and Ar 2 has the above meanings, by known processes as described, for example, by S. C. Buchwald et al., Angew. Chem. 1995, 107, 1456 or J. F. Hartweg et al., Tetrahedron Lett 1995, 36, 3604 and J. K. Stille et al., Angew. Chem. 1986, 98, 504 or Pereyre M. et al., in Organic Synthesis, Butterworth 1987; or

c) reacting a compound of the general formula (XVI)

 where n=1 or 2, with a compound M—Ar 2 where M is a metal such as Li or MgY 2 . MAr 2 can be obtained from compounds of the formula XV by methods known from the literature.

Compounds of the type of Ar 1 and Ar 2 are either known or can be prepared by known processes as described, for example, in A. R. Katritzky, C W. Rees (ed.) “Comprehensive Heterocyclic Chemistry”, Pergamon Press, or “The Chemistry of Heterocyclic Compounds”, J. Wiley & Sons Inc. NY and the literature cited therein.

Compounds of type B are either known or can be prepared by processes similar to known ones, for example

1,4- and 1,5-diazacycloalkanes: L. Börjeson et al. Acta Chem. Scand. 1991, 45, 621 Majahrzah et al Acta Pol. Pharm., 1975, 32, 145

1,4-diazacyclooct-6-enes: W. Schroth et al. Z. Chem. 1969, 9, 143

1-azacyclooctanones: N. J. Leonard et al. J. Org. Chem. 1964, 34, 1066

1-azacyclo-heptanones: A. Yokoo et al. Bull Chem. Soc. Jpn. 1956, 29, 631

The novel compounds and the starting materials and intermediates can also be prepared by methods similar to those described in the patent publications mentioned at the outset.

The reactions described above generally take place in a solvent at temperatures between room temperature and the boiling point of the solvent used. Solvents which can be used are, for example, ethyl acetate, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, a ketone such as acetone or methyl ethyl ketone, or an alcohol such as ethanol or butanol.

An acid-binding agent is present if required. Suitable acid-binding agents are inorganic bases such as sodium or potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride or organometallic compounds such as butyllithium or alkylmagnesium compounds, or organic bases such as triethylamine or pyridine. The latter can also act as solvent.

The reactions take place where appropriate with use of a catalyst such as transition metals or complexes thereof, eg. Pd(PPh 3 ) 4 , Pd(OAc) 2 or Pd(P(oTol) 3 ) 4 , or of a phase-transfer catalyst, eg. tetrabutylammonium chloride or tetrapropylammonium bromide.

The crude product is isolated in a conventional way, for example by filtration, removal of the solvent by distillation, or extraction from the reaction mixture etc. The resulting compounds can be purified in a conventional way, for example by recrystallization from a solvent, chromatography or conversion into an acid addition compound.

The acid addition salts are prepared in a conventional way by mixing the free base with the appropriate acid, where appropriate in solution in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol, an ether such as methyl t-butyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate.

To treat the abovementioned disorders, the compounds according to the invention are administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is about 10 to 1000 mg per patient and day on oral administration and about 1 to 500 mg per patient and day on parenteral administration.

The invention also relates to pharmaceutical compositions which comprise the compounds according to the invention. These compositions are in the form of the conventional solid or liquid pharmaceutical presentations, for example as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions or sprays. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The presentations obtained in this way normally contain from 1 to 99% by weight of active substance.

The following examples serve to illustrate the invention without limiting it.

EXAMPLE 1

1-[2-t-Butyl-6-trifluoromethyl-pyrimidin-4-yl]-4-[3-[4-hydroxypyrimidin-2-ylmercapto)-propyl]-hexahydro-(1H)-1,4-diazepine fumarate

Preparation of the starting materials:

a) 2-t-Butyl-4-hydroxy-6-trifluoromethylpyrimidine.

The above pyridimine was synthesized in a conventional way by condensing 2,2-dimethylpropionamidine with ethyl trifluoroacetoacetate and sodium ethoxide in ethanol, see

Heterocyclic Compounds, Vol. 52, The Pyrimidines, page 189 et seq., D. J. Brown et al. (Eds.) John Wiley and Sons, 1994.

Melting point 187-188° C.

The 4-hydroxypyrimidines of the formula

were obtained in a similar way.

R                                M.p. [° C.]
t-C                                                                        4                                                                    H                                                                        9 169
n-C                                                                        3                                                                    H                                                                        7 120
CF                                                                        2                                                                    Cl 135-136

b) 2-t-Butyl-4-chloro-6-trifluoromethylpyrimidine

The hydroxypyrimidine from stage a) was converted with phosphorus oxychloride or thionyl chloride in a conventional way into the chlorine compound, see Heterocyclic Compounds, Vol. 52, The pyrimidines, page 329 et seq., John Wiley and Sons, 1994. The compound is in the form of a yellowish oil.

The 4-chloropyrimidines of the formula

were obtained in a similar way:

R                                M.p. [° C.]
t-C                                                                        4                                                                    H                                                                        9 oil
n-C                                                                        3                                                                    H                                                                        7 oil
CF                                                                        2                                                                    Cl oil

c) 1-[2-t-Butyl-6-trifluoromethylpyrimidin-4-yl]hexahydro-(1H)-, 1,4-diazepine 18 g (0.18 mol) of homopiperazine were dissolved in 25 ml of ethanol and, while refluxing, a solution of 7.2 g (0.03 mol) of the chloride obtained in b), dissolved in 10 ml of ethanol, was added dropwise over the course of 1 h. After reacting for a further 30 min, the cooled mixture was worked up by adding 200 ml of water and extracting several times with a total of 200 ml of methylene chloride. The organic phase was then washed with water, dried with anhydrous sodium sulfate and concentrated. The required compound was obtained as a yellowish oil which was further processed unpurified. Yield: 98% of theory.

The following compounds were obtained in a corresponding way: 1-aryl-1,4-diazepine of the formula:

Ar                                                                        2 M.p. [° C.]
                                 Oil
                                 Oil
                                 Oil
                                 74-75

d) 1-[2-t-Butyl-6-trifluoromethylpyrimidin-4-yl]-4-(3-chloropropyl)hexahydro-(1H)-1,4-diazepine 5 g (0.0165 mol) of the compound obtained above under c) were refluxed together with 2.5 g (0.025 mol) of triethylamine and 3.15 g (0.02 mol) of 1-bromo-3-chloropropane in 50 ml of tetrahydrofuran for 10 h. The solvent was then removed by distillation, and the residue was washed with water and extracted with methylene chloride. The residue obtained after drying and concentrating was then purified by flash chromatography (silica gel).

Yield: 4.8 g (77% of theory) of yellow oil

The compounds listed below were obtained in a similar manner:

1-aryl-4-haloalkyl-1,4-diazepines of the formula

Hal	alk	Ar 2	M.p. [° C.]
Cl			Oil
″		″	Oil
″	—(CH 2 ) 3 —		Oil
″	″		Oil
″	″		Oil
″			Oil
″	—(CH 2 ) 3 —		Oil
″	″		Oil

Preparation of the final product

5 g 0.013 mol) of the product obtained in d) were dissolved in 25 ml of dimethylformamide and added dropwise to a stirred solution at 100° C. of 2.03 g (0.016 mol) of 2-thiouracil, 0.38 g (0.016 mol) of lithium hydroxide and 1 g of sodium iodide in 50 ml of dimethylformamide over the course of 1 h. After reaction for 3 hours, the solvent was removed by distillation under reduced pressure, and the residue was mixed with 150 ml of water and extracted twice with ethyl acetate. The residue obtained after washing with water, drying with sodium sulfate and concentrating was purified by chromatography. (Flash chromatography, silica gel, mobile phase methylene chloride with 2.5-5% methanol)

Yield: 4 g of pale oil NMR:CDCl 3 . δ 1.3(s,9H); 1.85-2.25(m,4H); 2.6(m,4H); 2.8(m,2H); 3.2(t,2H); 3.5(m,2H); 4.0(m,2H); 6.2(d,1H); 6.5(s,1H); 7.8(d;1H)

The substance was obtained as fumarate by adding an ethanolic solution of fumaric acid.

C 21 H 29 F 3 N 6 OS. C 4 H 4 O 4 MW 586.6 Melting point: 188-189° C.

The compounds listed in the following Table 1 were obtained in a similar way using various haloalkyl-1,4-diazepines (eg. 1d) and various mercapto-substituted heterocycles such as thiouracil, 5-amino-2-mercaptotriazoles and 5-amino-2-mercaptothiadiazole:

TABLE 1
Ex. No.	Ar 1	alk	Ar 2	M.p. [° C.]
2		—(CH 2 ) 3 —		155-162 Oxalate
3	″	″		83-85 Oxalate
4	″	″		177-182 Fumarate
5	″	″		72-74
6	″			116-119
7	″			174-180 Oxalate
8	″	″		60-70 Oxalate
9		—(CH 2 ) 3 )—		166-167 Fumarate
10	″	″		55-60
11	″	″		110-115 Oxalate
12	″	″		136-140 Hydro- chloride
13	″	″		95-98
14		″		142-144
15				125-128
16	″			113-119 Oxalat
17	″	″		230-232 Hydro- chloride
18		—(CH 2 ) 3 —		Oil
19	″	″		109-110
20	″	″		60-67
21	″		″	180-190 Hydro- chloride
22	″		″	119-122
23	″			92-97 Oxalate

EXAMPLE 24

1-(4-Bromobenzamido)-4-[4-(2,6-bis-t-butyl-4-pyrimidinyl)hexahydro-(1H)-1,4-diazepin-1-yl]butane

Preparation of the starting materials

a) Hexahydro-1-[2-t-butyl-6-trifluoromethyl-4-pyrimidinyl]-4-(4-phthalimidobutyl)-(1H)-1,4-diazepine

10 g (0.033 mol) of the diazepine prepared in Example 1c) were refluxed with 9.8 g (0.035 mol) of N-(4-bromobutyl)phthalimide and 9.1 g (0.066 mol) of potassium carbonate in 120 ml of acetonitrile for 8 h. The mixture was filtered and the filtrate was concentrated. The residue was processed further unpurified.

Yield: 16.2 g (98% of theory) A sample was recrystallized from ethanol. Melting point 97-99° C.

The following were obtained in a similar way:

alk	Ar 2	M.p. [° C.]
—(CH 2 ) 3 —		89-92
	″	130-132
—(CH 2 ) 3 —		119-121
—(CH 2 ) 4 —	″	207-209
—(CH 2 ) 4 —		190-192

b) Hexahydro-1H-1-[2-t-butyl-6-trifluoromethyl-4-pyrimidinyl]-4-(4-aminobutyl)-1,4-diazepine

15 g (0.03 mol) of the product described above under a) were refluxed with 6 g of hydrazine hydrate in 200 ml of ethanol for 2 h, and then the precipitate was filtered off with suction and the filtrate was evaporated. The residue was taken up in ethyl acetate, filtered again, washed with water, dried and again evaporated.

9.2 g (83% of theory) were obtained as an oil.

The following were obtained in a similar way:

alk	Ar 2	M.p. [° C.]
—(CH 2 ) 4 —		Oil
—(CH 2 ) 3 —	″	Oil
—(CH 2 ) 4 —		Oil
—(CH 2 ) 3 —		Di-Hydro- chloride: 241-245

Preparation of the final products:

3 g (0.0083 mol) of the product obtained above under b) were dissolved with 0.9 g (0.009 mol) of triethylamine in 60 ml of tetrahydrofuran, and a solution of 2 g (0.009 mol) of 4-bromobenzoyl chloride in 10 ml of tetrahydrofuran was added dropwise at room temperature over the course of 10 min. After 1 h, the solvent was removed by distillation under reduced pressure, and the residue was mixed with water and extracted twice with methylene chloride. The dried and concentrated solvent phase was purified by flash chromatography (silica gel, mobile phase methylene chloride with 3% methanol).

Yield: 4.2 g (93% of theory) Melting point 125-127° C. (from diisopropyl ether/isopropanol) C 28 H 42 BrN 5 O (544.6)

The compounds listed in Table 2 below were obtained using various amino derivatives (similar to 24b) and known benzoyl chlorides.

TABLE 2
Ex.				M.p.
No.	R	n	Ar 2	[° C.]
25	Br	3	″	169- 171
26	″	4		74-76 Oxalate
27	t-Butyl	4		165- 167 Oxalate
28		4	″	104- 107 Oxalate
29	Br	4		92-94 Oxalate
30	I	4	″	110- 115 Oxalate

EXAMPLE 31

4-[4-{4-Benzyloxy-2-pyrimidinylamino}butyl]-1-[2-t-butyl-6-trifluoromethyl-4-pyrimidinyl]hexahydro-1H-1,4-diazepine oxalate

2.7 g (0.007 mol) of the amino compound prepared in Example 24b) were introduced with 0.3 g of sodium hydride (0.009 mol) into 20 ml of dimethylformamide. After reaction for 1 h, 1.6 g (0.006 mol) of 4-benzyloxy-2-methylsulfonylpyrimidine (prepared by oxidizing 4-benzyloxy-2-methylmercaptopyrimidine), dissolved in 10 ml of dimethylformamide, were added, and the mixture was stirred at room temperature for 72 h. Subsequently, water was added, the mixture was extracted with ethyl acetate, and the solution was dried and concentrated. The residue was purified by column chromatography (silica gel, methylene chloride with 4% methanol)

Pure yield: 1.0 g (30% of theory) Oxalate: Melting point 145-150° C. C 29 H 38 F 3 N 7 O.C 2 H 2 O 4 (647.7)

EXAMPLE 32

1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-[4-{4-hydroxy-2-pyrimidinylamino}butyl]hexahydro-(1H)-1,4-diazepine

0.7 g (0.001 mol) of the compound described in the previous example was hydrogenated in methanol with palladium on carbon catalyst (10% Pd) under normal conditions.

Yield: 0.6 g (100% of theory) Melting point 111-115° C. C 22 H 32 F 3 N 7 O.C 2 H 4 O 4 (557.5)

EXAMPLE 33

1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-[4-(4-hydroxy-2-pyrimidinyl)butyl]hexahydro-1H-1,4-diazepine

a) 1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-(4-cyanobutyl)hexahydro-1,4-diazepine

9.1 g (0.03 mol) of the diazepine from Example 1c) were dissolved with 3.5 g (0.03 mol) of 5-chlorovaleronitrile and 9.1 g of triethylamine (0.09 mol) in 100 ml of dimethylformamide and heated at 100° C. for 24 h. The solvent was then removed by distillation under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and this phase was dried with sodium sulfate and concentrated. The residue was processed further unpurified.

Yield: 9.1 g as brown oil

b) 1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-(4-amidinobutyl)hexahydro-1,4-diazepine hydrochloride

9.1 g (0.024 mol) of the nitrile described above were dissolved in 2 ml of ethanol and 50 ml of methylene chloride (both anhydrous) and, while cooling to 0-10° C., dry hydrogen chloride gas was passed in to saturation. After stirring overnight, the precipitate was filtered off with suction and the filtrate was concentrated.

Yield: 7.6 g (58% of theory)

Preparation of the final product

4.4 g (0.01 mol) of the amidine described above were stirred with the sodium compound of ethyl formylacetate (preparation J. Org. Chem. 35 (1970), 2515 et seq.) (2.8 g (0.02 mol)) in 50 ml of water and 20 ml of tetrahydrofuran overnight. The reaction mixture was then extracted several times with ethyl acetate, and the organic phase was dried and concentrated. The residue was purified by column chromatography (silica gel, eluent methylene chloride with 4% methanol)

Yield: 1.9 g (42%) of oil NMR: (CDCl 3 ) δ: 1.3(s,9H); 1.8-2.0(m,4H); 2.0(m,2H); 2.4-2.6(m/br,6H); 2.5(t,2H); 3.5(m,1H); 4.0(m,2H); 6.2(d,1H); 6.5(s,1H); 7.8(d,1H) C 22 H 31 F 3 N 6 O (425.5) Oxalate: C 22 H 31 F 3 N 6 O.C 2 H 2 O 4 (542.5) Melting point 173-177° C. (decomposition)

EXAMPLE 34

1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-[3-{4-benzyloxy-pyrimidinyloxy}propyl]hexahydro-(1H)-1,4-diazepine

a) Starting material

8.9 g (64.5 mmol) of 3-bromo-1-propanol were taken up in 50 ml of abs. THF, and 6.52 g (64.5 mmol) of triethylamine, a catalytic amount of sodium iodide and 16.2 g (53.7 mmol) of the azepine prepared in Example 1c) were successively added, and the mixture was refluxed for 16 h. For workup, the precipitate salts were filtered off and the mother liquor was concentrated under reduced pressure. The resulting oil was taken up in dichloromethane, and the organic phase was washed with water, dried over sodium sulfate and then purified by column chromatography (SiO2, mobile phase CH 2 Cl 2 :MeOH=98:2) to result in a colorless oil.

Yield: 10.11 g (53%)

b) Final product

0.26 g (8.52 mmol) of sodium hydride (80%) was added in portions to 2.45 g of the product described above, dissolved in 25 ml of abs. DMF, at room temperature under a protective gas atmosphere, and the mixture was stirred for 30 min. Then 1.5 g (5.68 mmol) of 2-methanesulfonyl-4-benzyloxypyrimidine (prepared by methods similar to the literature: W. E. Barnett, R. F. Koebel Tetrahedron Lett. 1971, 20, 2867) dissolved in 15 ml of abs. DMF, were added dropwise. After 7 h, the mixture was worked up by pouring into water and extracting with tert-butyl methyl ether. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by column chromatography (SiO 2 , mobile phase CH 2 Cl 2 :MeOH=98:2) to afford the substance as an oil.

Yield: 1.6 g (2.9 mmol, 52%)

To form the hydrochloride, the oil was dissolved in ethyl acetate/Et 2 O, ethereal hydrochloric acid was added under protective gas, and the resulting salt was filtered off with suction.

Melting point: 110-112° C. C 28 H 36 ClF 3 N 6 O 2 (581.1)

EXAMPLE 35

1-[2-t-Butyl-6-trifluoromethyl-2-pyrimidinyl]-4-[3-(4-hydroxy-2-pyrimidinyloxy)propyl]hexahydro-(1H)-1,4-diazepine

1.4 g (2.6 mmol) of the substance from Example 34, dissolved in 40 ml of ethyl acetate, were mixed at room temperature with 0.2 g of Pd/C (10% Pd) and hydrogenated with hydrogen at 40-50° C. under atmospheric pressure. After the reaction was complete, the catalyst was filtered off with suction and, after washing with ethyl acetate, the filtrated was concentrated under reduced pressure.

Yield: 1.2 g (100%)

To form the hydrochloride, the oil was dissolved in ethyl acetate/Et 2 O, ethereal hydrochloric acid was added under protective gas, and the resulting salt was filtered off with suction.

Melting point: 78-80° C. C 21 H 30 ClF 3 N 6 O 2 (491)

The compounds mentioned in the following Tables 3 to 17 are obtained in a similar way.

TABLE 3

Example

No.

R1

R2

R3

R6

R7

R8

R9

R10

W

X—Y—Z

A

B

36

H

H

OH

H

tBut

H

Me

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 3 —

37

H

H

OH

H

tBut

H

Ph

H

CH 2 —CH 2

CH═C—CH 2

S

—(CH 2 ) 3 —

38

Me

H

OH

H

tBut

H

1-Pyrrolyl

H

CH 2

CH═C—CH 2

S

—(CH 2 ) 3 —

39

H

H

NH 2

H

iProp

H

2-Napht

H

CH 2 —CH 2

CH 2 —CH═C

S

—(CH 2 ) 3 —

40

H

Me

OH

H

Et

H

tBut

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 3 —

41

H

H

OH

H

CHF 2

H

H

H

CH 2

CH 2 —CH═C

S

—(CH 2 ) 3 —

42

H

H

NH 2

OMe

CF 3

H

H

H

CH 2

CH═C—CH 2

S

—(CH 2 ) 3 —

43

H

H

OH

H

CF 3

H

tBut

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 3 —

44

H

H

NHMe

H

iProp

H

H

H

CH 2

CH 2 —N—CH 2

O

—(CH 2 ) 4 —

45

Me

H

OH

H

H

CN

tBut

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 3 —

46

H

H

OH

H

H

F

tBut

H

CH 2 —CH 2

CH 2 —CH═C

S

—(CH 2 ) 3 —

47

H

Me

NH 2

H

H

Cl

iProp

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 3 —

48

H

H

NHMe

H

tBut

H

H

OMe

CH 2

CH 2 —CH═C

S

—(CH 2 ) 3 —

49

H

H

OH

H

iProp

H

H

OMe

CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 4 —

50

H

H

OH

H

CHF 2

H

tBut

H

CH 2 —CH 2

CH═C—CH 2

S

—(CH 2 ) 3 —

51

H

H

OH

OMe

tBut

H

CF 3

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 3 —

52

Me

H

OH

H

CF 3

H

tBut

H

CH 2

CH 2 —N—CH 2

O

—(CH 2 ) 5 —

53

H

H

NH 2

H

nProp

CN

tBut

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 3 —

54

H

Me

OH

H

CF 3

CN

iProp

H

CH 2

CH═C—CH 2

S

—(CH 2 ) 3 —

55

H

H

OH

H

Ph

C≡CH

tBut

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 3 —

56

H

H

NH 2

H

tBut

CN

H

H

CH 2

CH 2 —CH═C

S

—(CH 2 ) 3 —

57

H

H

NHMe

H

tBut

CN

CF 3

OMe

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 5 —

58

H

H

OH

OMe

nProp

F

tBut

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 4 —

59

H

H

OH

H

Ph

CN

tBut

Me

CH 2

CH 2 —CH═C

S

—(CH 2 ) 3 —

60

H

H

OH

OMe

tBut

F

H

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—(CH 2 ) 3 —

61

H

H

OH

H

tBut

H

Me

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —C(═CH 2 )—CH 2 —

62

H

H

OH

H

tBut

H

Ph

H

CH 2

CH 2 —CH═C

S

—CH 2 —C(═CH 2 )—CH 2 —

63

Me

H

OH

H

tBut

H

1-Pyrrolyl

H

CH 2 —CH 2

CH═C—CH 2

S

—CH 2 —C(═CH 2 )—CH 2 —

64

H

H

NH 2

H

iProp

H

2-Napht

H

CH 2 —CH 2

CH 2 —CH═C

S

—CH 2 —C(CH 3 )═CH—CH 2 —

65

H

Me

OH

H

Et

H

tBut

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —CH(CH 3 )—CH 2 —

66

H

H

OH

H

CHF 2

H

H

H

CH 2 —CH 2

CH═C—CH 2

S

—CH 2 —C(═CH 2 )—CH 2 —

67

H

H

NH 2

OMe

CF 3

H

H

H

CH 2

CH 2 —CH═C

S

—CH 2 —CH(CH 3 )—CH 2 —

68

H

H

OH

H

CF 3

H

tBut

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —C(═CH 2 )—CH 2 —

69

H

H

NHMe

H

iProp

H

H

H

CH 2

CH 2 —N—CH 2

O

—CH 2 —C(═CH 2 )—CH 2 —

70

Me

H

OH

H

H

CN

tBut

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —CH═CH—CH 2 —

71

H

H

OH

H

H

F

tBut

H

CH 2 —CH 2

CH 2 —CH═C

S

—CH 2 —C(CH 3 )═CH—CH 2 —

72

H

Me

NH 2

H

H

Cl

iProp

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —C(═CH 2 )—CH 2 —

73

H

H

NHMe

H

tBut

H

H

OMe

CH 2

CH 2 —CH═C

S

—CH 2 —CH(CH 3 )—CH 2 —

74

H

H

OH

H

iProp

H

H

OMe

CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —CH(CH 3 )—CH 2 —

75

H

H

OH

H

CHF 2

H

tBut

H

CH 2 —CH 2

CH 2 —CH═C

S

—CH 2 —C(═CH 2 )—CH 2 —

76

H

H

OH

OMe

tBut

H

CF 3

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —CH═CH—CH 2 —

77

Me

H

OH

OMe

CF 3

H

tBut

H

CH 2

CH 2 —N—CH 2

O

—CH 2 —C(═CH 2 )—CH 2 —

78

H

H

NH 2

H

nProp

CN

tBut

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —C(CH 3 )═CH—CH 2 —

79

H

Me

OH

H

CF 3

CN

iProp

H

CH 2

CH 2 —CH═C

S

—CH 2 —CH(CH 3 )—CH 2 —

80

H

H

OH

H

Ph

C≡CH

tBut

H

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —CH(CH 3 )—CH 2 —

81

H

H

NH 2

H

tBut

CN

H

H

CH 2

CH 2 —CH═C

S

—CH 2 —C(CH 3 )═CH—CH 2 —

82

H

H

NHMe

H

tBut

CN

CF 3

OMe

CH 2 —CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —CH—CH—CH 2 —

83

H

H

OH

H

nProp

F

tBut

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —CH(CH 3 )—CH 2 —

84

H

H

OH

H

Ph

CN

tBut

Me

CH 2 —CH 2

CH 2 —CH═C

S

—CH 2 —C(CH 3 )═CH—CH 2 —

85

H

H

OH

H

tBut

F

H

H

CH 2

CH 2 —N—CH 2

—CH 2 —

—CH 2 —C(═CH 2 )—CH 2 —

TABLE 4
Example
No.	R1	R2	R3	R7	R9	R10	W	X—Y—Z	A	B
86	H	H	OH	tBut	Ph	H	CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
87	H	H	OH	tBut	2-Napht	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
88	Me	H	OH	tBut	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
89	H	H	NH 2	tBut	cHex	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(CH 3 )═CH—CH 2 —
90	H	H	OH	tBut	nHex	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
91	H	H	OH	tBut	H	OMe	CH 2	CH 2 —N—CH 2	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
92	H	Me	OH	iProp	F	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—CH 2 —CH═CH—CH 2 —
93	H	H	NH 2	CH 3	1-Pyrrolyl	H	CH 2	CH 2 —C═CH	NH	—(CH 2 ) 3 —
94	H	H	OH	OMe	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	O	—CH 2 —CH(CH 3 )—CH 2 —
95	H	H	OH	tBut	H	CH 3	CH 2 —CH 2	CH═C—CH 2	S	—CH 2 —CH(CH 3 )—CH 2 —
96	H	H	OH	tBut	tBut	OMe	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
97	Me	H	OH	tBut	iProp	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
98	H	H	NH 2	Ph	tBut	Cl	CH 2	CH 2 —C═CH	—CH 2 —	—CH 2 —C(CH 3 )═CH—CH 2 —
99	H	H	OH	2-Napht	tBut	Me	CH 2 —CH 2	CH═C—CH 2	S	—(CH 2 ) 3 —
100	H	H	OH	tBut	CF 3	Me	CH 2	CH 2 —N—CH 2	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —

TABLE 5
Example
No.	R1	R2	R3	R7	R8	R9	R10	W	X—Y—Z	A	B
101	H	H	OH	tBut	H	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
102	H	H	OH	tBut	CN	H	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
103	Me	H	OH	tBut	H	Cl	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
104	H	H	OH	H	CN	tBu	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
105	H	H	NH 2	CF 3	H	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
106	H	H	OH	nProp	H	iProp	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
107	H	Me	OH	H	H	iProp	OMe	CH 2 —CH 2	CH 2 —CH═C	S	—(CH 2 ) 3 —
108	H	H	OH	tBut	H	tBut	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
109	H	H	OH	tBut	CN	H	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
110	H	H	NH 2	tBut	H	Cl	H	CH 2	CH 2 —N—CH 2	O	—(CH 2 ) 3 —
111	Me	H	OH	H	CN	tBu	H	CH 2	CH═C—CH 2	S	—CH 2 —C(CH 3 )═CH—CH 2 —
112	H	H	OH	CF 3	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
113	H	H	OH	nProp	H	iProp	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
114	H	H	NHMe	H	H	iProp	OMe	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
115	H	H	OH	nProp	CN	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
116	H	H	OH	CF 3	CN	iProp	H	CH 2 —CH 2	CH 2 —CH═C	S	—(CH 2 ) 3 —
117	Me	H	OH	Ph	C≡CH	tBut	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —CH(CH 3 )—CH 2 —
118	H	H	OH	tBut	CN	tBut	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
119	H	H	NH 2	tBut	H	nProp	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
120	H	H	OH	Ph	H	tBut	OMe	CH 2	CH 2 —CH═C	—CH 2 —	—(CH 2 ) 5 —
121	H	Me	OH	CF 3	H	tBut	F	CH 2 —CH 2	CH═C—CH 2	S	—CH 2 —CH(CH 3 )—CH 2 —
122	H	H	OH	tBut	F	H	Me	CH 2	CH 2 —N—CH 2	NH	—CH 2 —CH═CH—CH 2 —
123	H	H	OH	nProp	CN	tBut	Me	CH 2 —CH 2	CH 2 —CH═C	S	—CH 2 —C(═CH 2 )—CH 2 —
124	H	H	NH 2	nProp	C≡CH	tBut	H	CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(CH 3 )═CH—CH 2 —
125	H	H	OH	tBut	CN	H	Me	CH 2	CH 2 —N—CH 2	S	—(CH 2 )4—

TABLE 6
Example
No.	R1	R2	R3	R6	R8	R9	R10	W	X—Y—Z	A	B
126	H	H	OH	OMe	H	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
127	H	H	OH	OMe	H	CF 3	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
128	Me	H	OH	OMe	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
129	H	H	OH	H	CN	tBut	H	CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(CH 3 )═CH—CH 2 —
130	H	H	NH 2	H	F	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
131	H	H	OH	Me	Cl	iProp	H	CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
132	H	Me	OH	H	H	iProp	H	CH 2 —CH 2	CH═C—CH 2	S	—(CH 2 ) 3 —
133	H	H	OH	H	H	tBut	OMe	CH 2 —CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
134	H	H	OH	CN	H	CF 3	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
135	H	H	NH 2	H	CN	H	OMe	CH 2	CH 2 —N—CH 2	O	—CH 2 —CH(CH 3 )—CH 2 —
136	Me	H	OH	H	H	tBu	F	CH 2	CH 2 —CH═C	S	—CH 2 —C(CH 3 )═CH—CH 2 —
137	H	H	OH	H	CN	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
138	H	H	OH	Me	H	iProp	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
139	H	H	NHMe	OMe	H	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—CH 2 —CH(CH 3 )—CH 2 —
140	H	H	OH	OMe	CN	tBut	H	CH 2	CH═C—CH 2	S	—(CH 2 ) 3 —
141	H	H	OH	OMe	Me	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
142	Me	H	OH	H	CN	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	NH	—CH 2 —CH═CH—CH 2 —
143	H	H	OH	Me	H	tBut	H	CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
144	H	H	NH 2	H	Cl	CF 3	Me	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
145	H	H	OH	OMe	CN	tBut	Me	CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
146	H	Me	OH	Me	Me	iProp	Me	CH 2	CH 2 —CH═C	S	—(CH 2 )3—

TABLE 7
Example
No.	R1	R2	R3	R6	R7	R9	R10	W	X—Y—Z	A	B
147	H	H	OH	H	tBut	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
148	H	H	OH	H	tBut	Ph	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
149	Me	H	OH	H	tBut	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
150	H	H	OH	H	nPropyl	tBut	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —C(CH 3 )═CH—CH 2 —
151	H	H	NH 2	H	CF 3	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
152	H	H	OH	H	2-Napht	tBut	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
153	H	Me	OH	OMe	tBut	H	H	CH 2 —CH 2	CH 2 —CH═C	S	—(CH 2 ) 3 —
154	H	H	OH	OMe	iProp	H	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
155	H	H	OH	OMe	H	CF 3	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
156	H	H	NH 2	H	tBut	H	H	CH 2	CH 2 —N—CH 2	O	—CH 2 —CH(CH 3 )—CH 2 —
157	Me	H	OH	H	iProp	H	Me	CH 2	CH═C—CH 2	S	—CH 2 —C(CH 3 )—CH—CH 2 —
158	H	H	OH	CN	tBut	H	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
159	H	H	OH	H	H	CF 3	Me	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
160	H	H	NHMe	H	nProp	tBut	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —CH(CH 3 )—CH 2 —
161	H	H	OH	OMe	tBut	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
162	H	H	OH	OMe	CF 3	tBut	H	CH 2 —CH 2	CH═C—CH 2	NH	—(CH 2 ) 3 —
163	Me	H	OH	Me	tBut	nProp	H	CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —CH═CH—CH 2 —
164	H	H	OH	Me	tBut	H	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
165	H	H	NH 2	H	tBut	tBut	H	CH 2	CH═C—CH 2	—CH 2 —	—(CH 2 ) 3 —
166	H	H	OH	Me	CF 3	tBut	H	CH 2	CH 2 —CH═C	S	—CH 2 —CH(CH 3 )—CH 2 —

TABLE 8
Exam-
ple
No.	Q	R2	R5	R6	R7	R8	R9	W	X—Y—Z	A	B
167	NCH 3	NH 2	H	tBut	H	Me	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
168	S	NH 2	H	tBut	H	Ph	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
169	NCH 3	NH 2	H	tBut	H	1-Pyrrolyl	H	CH 2 —CH 2	CH 2 —N—CH 2	NH	—(CH 2 ) 3 —
170	NCH 3	NH 2	H	iProp	H	2-Napht	H	CH 2	CH 2 —CH═C	—CH 2 —	—(CH 2 ) 3 —
171	S	NH 2	H	Et	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
172	S	NH 2	H	CHF 2	H	H	H	CH 2	CH═C—CH 2	—CH 2 —	—(CH 2 ) 8 —
173	NCH 3	NH 2	H	CHF 2	H	tBut	H	CH 2	CH 2 —CH═C	S	—(CH 2 ) 10 —
174	NCH 3	NH 2	H	CF 3	H	tBut	H	CH 2	CH 2 —N—CH 2	NH	—(CH 2 ) 3 —
175	NCH 3	NH 2	H	iProp	F	H	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
176	NCH 3	NH 2	H	H	CN	tBut	H	CH 2	CH 2 —CH═C	O	—(CH 2 ) 3 —
177	S	NH 2	H	H	F	tBut	H	CH 2 —CH 2	CH═C—CH 2	S	—(CH 2 ) 3 —
178	NCH 3	NH 2	H	H	Cl	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
179	NCH 3	NH 2	H	tBut	H	H	OMe	CH 2	CH═C—CH 2	S	—(CH 2 ) 3 —
180	S	NH 2	H	nProp	CN	tBut	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —	—(CH 2 ) 3 —
181	NCH 3	NH 2	H	CF 3	CN	iProp	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
182	NCH 3	NH 2	H	Ph	C≡CH	tBut	H	CH 2	CH═C—CH 2	—CH 2 —	—(CH 2 ) 3 —
183	NCH 3	NH 2	OMe	tBut	CN	H	H	CH 2	CH 2 —CH═C	S	—(CH 2 ) 3 —
184	S	NH 2	H	tBut	CN	CF 3	OMe	CH 2 —CH 2	CH 2 —N—CH 2	NH	—(CH 2 ) 3 —
185	NCH 3	NH 2	H	Ph	CN	tBut	Me	CH 2 —CH 2	CH 2 —N—CH 2	O	—(CH 2 ) 3 —
186	NCH 3	NH 2	Me	tBut	F	H	H	CH 2 —CH 2	CH 2 —CH═C	S	—(CH 2 ) 3 —
187	S	NH 2	H	iProp	H	H	OMe	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
188	N(iProp)	NH 2	H	tBut	H	Me	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
189	N(iProp)	NH 2	H	tBut	H	Ph	H	CH 2 —CH 2	CH 2 —N—CH 2	NH	—(CH 2 ) 4 —
190	S	NH 2	H	tBut	H	1-Pyrrolyl	H	CH 2	CH═C—CH 2	S	—(CH 2 ) 8 —
191	N(iProp)	NH 2	H	iProp	H	2-Napht	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
192	S	NH 2	H	Et	H	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 10 —
193	N(iProp)	NH 2	H	CF 3	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 4 —
194	N(iProp)	NH 2	H	H	CN	tBut	H	CH 2 —CH 2	CH═C—CH 2	NH	—(CH 2 ) 3 —
195	N(iProp)	NH 2	H	H	F	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
196	N(iProp)	NH 2	H	H	Cl	iProp	H	CH 2	CH═C—CH 2	—CH 2 —	—(CH 2 ) 3 —
197	S	NH 2	H	tBut	H	H	OMe	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 8 —
198	N(iProp)	NH 2	H	nProp	CN	tBut	H	CH 2	CH 2 —CH═C	—CH 2 —	—(CH 2 ) 3 —
199	S	NH 2	H	CF 3	CN	iProp	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
200	N(iProp)	NH 2	H	Ph	C≡CH	tBut	H	CH 2 —CH 2	CH═C—CH 2	—CH 2—	—(CH 2 ) 3 —
201	N(iProp)	NH 2	H	tBut	CN	CF 3	OMe	CH 2	CH 2 —N—CH 2	NH	—(CH 2 ) 3 —
202	N(iProp)	NH 2	H	Ph	CN	tBut	Me	CH 2 —CH 2	CH 2 —N—CH 2	O	—(CH 2 ) 3 —
203	S	NH 2	H	iProp	H	H	OMe	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 8 —
204	N(iProp)	NHMe	H	tBut	H	Me	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
205	N(iProp)	NHMe	H	tBut	H	Ph	H	CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
206	S	NHMe	H	tBut	H	1-Pyrrolyl	H	CH 2 —CH 2	CH═C—CH 2	S	—CH 2 —CH═CH—CH 2 —
207	N(iProp)	NHMe	H	iProp	H	2-Napht	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —CH(CH 3 )—CH 2 —
208	N(iProp)	NHMe	H	Et	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—CH 2 —C(CH 3 )═CH—CH 2 —
209	N(iProp)	OH	H	tBut	H	Cl	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
210	N(iProp)	OH	H	CF 3	H	Cl	H	CH 2	CH═C—CH 2	NH	—CH 2 —CH(CH 3 )—CH 2 —
211	N(iProp)	OH	H	CF 3	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
212	S	OH	H	iProp	CN	F	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 ——
213	N(iProp)	OMe	H	H	CN	tBut	H	CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
214	N(iProp)	OMe	H	H	F	tBut	H	CH 2	CH 2 —CH═C	S	—CH 2 —C(CH 3 )═CH—CH 2 —
215	S	OMe	H	H	Cl	iProp	H	CH 2	CH═C—CH 2	O	—CH 2 —CH(CH 3 )—CH 2 —
216	N(iProp)	OMe	H	tBut	H	H	OMe	CH 2 —CH 2	CH═C—CH 2	NH	—CH 2 —C(CH 3 )═CH—CH 2 —
217	N(iProp)	NHMe	H	nProp	CN	tBut	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —CH(CH 3 )—CH 2 —
218	S	NHMe	H	CF 3	CN	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—CH 2 —CH(CH 3 )—CH 2 —
219	N(iProp)	OH	H	Ph	C≡CH	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—CH 2 —C(CH 3 )═CH—CH 2 —
220	N(iProp)	OH	OMe	tBut	CN	H	H	CH 2	CH 2 —CH═C	NH	—CH 2 —CH(CH 3 )—CH 2 —
221	N(iProp)	OH	H	tBut	CN	CF 3	OMe	CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
222	S	OH	H	nProp	F	tBut	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
223	S	OMe	H	Ph	CN	tBut	Me	CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
224	N(iProp)	OMe	OMe	tBut	F	H	H	CH 2	CH═C—CH 2	S	—CH 2 —CH(CH 3 )—CH 2 —
225	N(iProp)	OMe	H	iProp	H	H	OMe	CH 2	CH 2 —CH═C	S	—CH 2 —C(CH 3 )═CH—CH 2 —

TABLE 9
Example
No.	Q	R2	R6	R8	R9	W	X—Y—Z	A	B
226	NCH 3	NH 2	tBut	Ph	H	CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
227	NCH 3	NH 2	tBut	2-Napht	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
228	NCH 3	NH 2	tBut	1-Pyrrolyl	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
229	NCH 3	NHMe	tBut	cHex	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —	—(CH 2 ) 3 —
230	NCH 3	NH 2	tBut	nHex	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 5 —
231	S	NH 2	tBut	Ph	H	CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 8 —
232	S	NHMe	iProp	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —CH(CH 3 )—CH 2 —
233	S	NH 2	CH 3	CH 3	H	CH 2 —CH 2	CH 2 —CH═C	NH	—(CH 2 ) 3 —
234	NCH 3	NH 2	H	CHF 2	H	CH 2	CH 2 —N—CH 2	O	—CH 2 —C(═CH 2 )—CH 2 —
235	S	NH 2	tBut	tBut	H	CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 10 —
236	S	NHMe	tBut	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—CH 2 —C(CH 3 )═CH—CH 2 —
237	NCH 3	NH 2	tBut	tBut	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
238	NCH 3	NH 2	2-Napht	tBut	Me	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
239	S	NH 2	tBut	CF 3	H	CH 2 —CH 2	CH 2 —CH═C	S	—(CH 2 ) 8 —
240	NCH 3	NH 2	tBut	H	CH 3	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
241	N(iProp)	NH 2	tBut	Ph	H	CH 2 —CH 2	CH═C—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
242	N(iProp)	NH 2	tBut	2-Napht	H	CH 2	CH 2 —CH═C	NH	—(CH 2 ) 3 —
243	N(iProp)	NH 2	tBut	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	O	—CH 2 —CH(CH 3 )—CH 2 —
244	N(iProp)	NH 2	tBut	cHex	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
245	S	NH 2	tBut	tBut	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
246	S	OH	tBut	F	H	CH 2 —CH 2	CH═C—CH 2	S	—(CH 2 ) 10 —
247	N(nProp)	OMe	iProp	tBut	H	CH 2	CH 2 —N—CH 2	—CH 2 —	—CH 2 —CH═CH—CH 2 —
248	N(nProp)	OMe	CH 3	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
249	N(nProp)	NCH 2 Ph	H	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—CH 2 —C(CH 3 )═CH—CH 2 —
250	N(iProp)	OH	tBut	tBut	H	CH 2	CH═C—CH 2	—CH 2 —	—(CH 2 ) 4 —
251	N(iProp)	OH	tBut	iProp	F	CH 2 —CH 2	CH 2 —N—CH 2	S	—CH 2 —CH═CH—CH 2 —
252	N(iProp)	OMe	Ph	tBut	Cl	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 5 —
253	N(nProp)	OMe	2-Napht	tBut	Me	CH 2	CH═C—CH 2	—CH 2 —	—(CH 2 ) 3 —
254	N(nProp)	NCH 2 Ph	tBut	CF 3	OMe	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
255	N(nProp)	NHMe	tBut	H	CH 3	CH 2	CH═C—CH 2	S	—CH 2 —CH(CH 3 )—CH 2 —

TABLE 10
Example
No.	O	R2	R6	R7	R8	R9	W	X—Y—Z	A	B
256	NCH 3	NH 2	tBut	H	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
257	S	OH	tBut	CN	H	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 8 —
258	N(iProp)	NHMe	tBut	H	Cl	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
259	NCH 3	NH 2	H	CN	tBu	H	CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
260	NCH 3	NHMe	CF 3	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
261	N(cProp)	NH 2	nProp	H	iProp	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
262	S	NHMe	H	H	iProp	H	CH 2	CH 2 —CH═C	S	—(CH 2 ) 10 —
263	NCH 3	NH 2	tBut	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
264	N(iProp)	NH 2	tBut	CN	H	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
265	NOH	NHMe	tBut	H	H	OMe	CH 2	CH 2 —CH═C	O	—(CH 2 ) 3 —
266	NCH 3	OH	H	CN	tBu	H	CH 2	CH═C—CH 2	S	—CH 2 —CH(CH 3 )—CH 2 —
267	NEt	NH 2	CF 3	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
268	S	NH 2	nProp	H	iProp	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
269	NCH 3	NH 2	nProp	CN	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
270	NCH 3	OH	CF 3	CN	iProp	H	CH 2 —CH 2	CH═C—CH 2	S	—(CH 2 ) 3 —
271	N(iProp	NHMe	Ph	C≡CH	tBut	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
272	S	NH 2	tBut	CN	tBut	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
273	NCH 3	NHMe	tBut	H	nProp	OMe	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
274	N(cProp)	NH 2	Ph	H	tBut	H	CH 2	CH═C—CH 2	—CH 2 —	—(CH 2 ) 4 —
275	S	NHMe	CF 3	H	tBut	H	CH 2 —CH 2	CH 2 —CH═C	S	—(CH 2 ) 3 —
276	NCH 3	NH 2	tBut	F	H	Me	CH 2	CH 2 —N—CH 2	NH	—CH 2 —CH═CH—CH 2 —
277	S	NH 2	nProp	CN	tBut	Me	CH 2 —CH 2	CH═C—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
278	NCH 3	OH	nProp	C≡CH	tBut	OMe	CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(CH 3 )═CH—CH 2 —
279	N(iProp)	OMe	tBut	CN	H	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
280	NCH 3	OMe	H	H	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —

TABLE 11
Example
No.	Q	R2	R5	R7	R8	R9	W	X—Y—Z	A	B
281	NCH 3	NH 2	H	CN	tBut	H	CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
282	NCH 3	NHMe	H	F	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
283	N(cProp)	NH 2	Me	Cl	iProp	H	CH 2	CH 2 —CH═C	—CH 2 —	—(CH 2 ) 3 —
284	S	NHMe	H	H	iProp	H	CH 2 —CH 2	CH═C—CH 2	S	—(CH 2 ) 10 —
285	NCH 3	NH 2	H	H	tBut	OMe	CH 2 —CH 2	CH 2 —N—CH 2	NH	—CH 2 —CH(CH 3 )—CH 2 —
286	N(iProp)	NH 2	CN	H	CF 3	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
287	S	NHMe	H	CN	tBut	H	CH 2	CH 2 —N—CH 2	O	—(CH 2 ) 8 —
288	S	OH	H	H	tBu	H	CH 2 —CH 2	CH═C—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
289	NEt	NH 2	H	CN	CHF 2	H	CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
290	NCH 3	NH 2	Me	H	iProp	H	CH 2	CH 2 —CH═C	S	—(CH 2 ) 3 —
291	N(iProp)	NH 2	F	CN	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
292	S	NH 2	OMe	Me	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 10 —
293	NCH 3	NHMe	H	CN	tBut	F	CH 2 —CH 2	CH 2 —N—CH 2	NH	—CH 2 —CH(CH 3 )—CH 2 —
294	NCH 3	NH 2	H	C≡CH	tBut	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —C(CH 3 )═CH—CH 2 —
295	N(iProp)	NH 2	H	Cl	CF 3	Me	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 5 —
296	NEt	NHMe	H	CN	tBut	Me	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —C(═CH 2 )—CH 2 —
297	S	OH	H	C≡CH	iProp	Me	CH 2	CH 2 —CH═C	S	—(CH 2 ) 8 —
298	NCH 3	OH	Cl	H	iProp	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —

TABLE 12
Example
No.	Q	R2	R5	R6	R8	R9	W	X—Y—Z	A	B
299	NCH 3	NH 2	H	tBut	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
300	S	OH	H	tBut	Ph	H	CH 2	CH 2 —N—CH 2	S	—CH 2 —C(═CH 2 )—CH 2 —
301	N(iProp)	NHMe	H	tBut	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —CH═CH—CH 2 —
302	NCH 3	NH 2	H	nPropyl	tBut	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
303	NCH 3	NHMe	H	CF 3	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
304	N(cProp)	NH 2	H	2-Napht	tBut	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —	—(CH 2 ) 3 —
305	S	NHMe	H	tBut	H	H	CH 2 —CH 2	CH 2 —CH═C	S	—(CH 2 ) 8 —
306	NCH 3	NH 2	H	iProp	CHF 2	H	CH 2	CH 2 —N—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
307	N(iProp)	NH 2	OMe	H	CF 3	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 4 —
308	NOH	NHMe	H	tBut	H	F	CH 2 —CH 2	CH 2 —CH═C	O	—(CH 2 ) 3 —
309	NCH 3	OH	H	iProp	H	Me	CH 2	CH═C—CH 2	S	—CH 2 —C(CH 3 )═CH—CH 2 —
310	NEt	NH 2	CN	tBut	H	H	CH 2	CH 2 —N—CH 2	—CH 2 —	—(CH 2 ) 3 —
311	NCH 3	NH 2	H	H	CF 3	Me	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —
312	S	NHMe	H	1-Pyrrolyl	H	H	CH 2 —CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 10 —
313	NCH 3	OH	H	CF 3	tBut	H	CH 2	CH═C—CH 2	NH	—CH 2 —C(═CH 2 )—CH 2 —
314	NEt	NH 2	Me	tBut	nProp	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
315	NCH 3	NH 2	Me	tBut	H	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 5 —
316	S	NH 2	H	tBut	tBut	H	CH 2	CH═C—CH 2	—CH 2 —	—CH 2 —CH(CH 3 )—CH 2 —
317	N(iProp)	NH 2	Me	CF 3	tBut	H	CH 2 —CH 2	CH 2 —CH═C	S	—(CH 2 ) 4 —
318	NCH 3	OH	H	nProp	tBut	H	CH 2	CH 2 —N—CH 2	S	—(CH 2 ) 3 —

TABLE 13
Exam-
ple
No.	R1	R2	R3	R6	R7	R8	R9	R10	W	X—Y—Z	O
319	H	Br	H	H	tBut	H	Me	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
320	H	I	H	H	tBut	H	Ph	H	CH 2 —CH 2	CH═C—CH 2	—(CH 2 ) 4 —
321	H	Ph	H	H	tBut	H	1-Pyrrolyl	H	CH 2	CH═C—CH 2	—(CH 2 ) 4 —
322	H	p(iProp)-Ph	H	H	iProp	H	2-Napht	H	CH 2 —CH 2	CH 2 —CH═C	—(CH 2 ) 4 —
323	H	pAcetyl-Ph	H	H	Et	H	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 3 —
324	H	pBr—Ph	H	H	CHF 2	H	H	H	CH 2	CH 2 —CH═C	—(CH 2 ) 4 —
325	H	pI—Ph	H	OMe	CF 3	H	H	H	CH 2	CH═C—CH 2	—(CH 2 ) 4 —
326	H	iProp	H	H	CF 3	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
327	H	tBut	H	H	iProp	H	H	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
328	H	CN	H	H	H	CN	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 3 —
329	H	COOEt	H	H	H	F	tBut	H	CH 2 —CH 2	CH 2 —CH═C	—(CH 2 ) 4 —
330	H	OPh	H	H	H	Cl	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
331	Me	Br	H	H	tBut	H	H	OMe	CH 2	CH 2 —CH═C	—(CH 2 ) 4 —
332	CN	I	H	H	iProp	H	H	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
333	Me	Ph	H	H	CHF 2	H	tBut	H	CH 2 —CH 2	CH═C—CH 2	—(CH 2 ) 3 —
334	F	p(iProp)-Ph	H	OMe	tBut	H	CF 3	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
335	Me	pAcetyl-Ph	H	H	CF 3	H	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 5 —
336	H	pBr—Ph	Me	H	nProp	CN	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
337	H	pI—Ph	F	H	CF 3	CN	iProp	H	CH 2	CH═C—CH 2	—(CH 2 ) 4 —
338	H	iProp	Me	H	Ph	C≡CH	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
339	H	tBut	CN	H	tBut	CN	H	H	CH 2	CH 2 —CH═C	—(CH 2 ) 4 —
340	H	CN	Me	H	tBut	CN	CF 3	OMe	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 5 —
341	H	COOEt	Me	H	nProp	F	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
342	H	OPh	F	H	Ph	CN	tBut	Me	CH 2	CH 2 —CH═C	—(CH 2 ) 3 —
343	Cl	F	H	H	tBut	F	H	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
344	H	Br	H	H	tBut	H	Me	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
345	H	I	H	H	tBut	H	Ph	H	CH 2	CH 2 —CH═C	—CH 2 —C(═CH 2 )—CH 2 —
346	H	Ph	H	H	tBut	H	1-Pyrrolyl	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
347	H	NEt 2	H	H	iProp	H	2-Napht	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —C(CH 3 )═CH—CH 2 —
348	H	pAcetyl-Ph	H	H	Et	H	tBut	H	CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
349	H	pBr—Ph	H	H	CHF 2	H	H	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
350	H	pI—Ph	H	F	CF 3	H	H	H	CH 2	CH 2 —CH═C	—CH 2 —CH(CH 3 )—CH 2 —
351	H	iProp	H	H	CF 3	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
352	H	tBut	H	H	iProp	H	H	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
353	H	CN	H	H	H	CN	tBut	H	CH 2	CH 2 —N—CH 2	—CH 2 —CH═CH—CH 2 —
354	H	COOEt	H	H	H	F	tBut	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —C(CH 3 )═CH—CH 2 —
355	H	OPh	H	H	H	Cl	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
356	Me	Br	H	H	tBut	H	H	OMe	CH 2	CH 2 —CH═C	—CH 2 —CH(CH 3 )—CH 2 —
357	Me	I	H	H	iProp	H	H	OMe	CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
358	Cl	Ph	H	H	CHF 2	H	tBut	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —C(═CH 2 —CH 2 —
359	CN	p(iProp)-Ph	H	OMe	tBut	H	CF 3	H	CH 2	CH 2 —N—CH 2	—CH 2 —CH═CH—CH 2 —
360	F	pAcetyl-Ph	H	OMe	CF 3	H	tBut	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
361	Me	pBr—Ph	H	H	nProp	CN	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —C(CH 3 )═CH—CH 2 —
362	H	pI—Ph	CN	H	CF 3	CN	iProp	H	CH 2	CH 2 —CH═C	—CH 2 —CH(CH 3 )—CH 2 —
363	H	iProp	Cl	H	Ph	C≡CH	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
364	H	tBut	F	H	tBut	CN	H	H	CH 2	CH 2 —CH═C	—CH 2 —C(CH 3 )═CH—CH 2 —
365	H	CN	Cl	H	tBut	CN	CF 3	OMe	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —CH═CH—CH 2 —
366	H	COOEt	CN	H	nProp	F	tBut	H	CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
367	H	OPh	Cl	H	Ph	CN	tBut	Me	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —C(CH 3 )═CH—CH 2 —
368	H	F	Me	H	tBut	F	H	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —

TABLE 14
Example No.	R1	R2	R3	R7	R9	R10	W	X—Y—Z	B
369	H	Br	H	tBut	Ph	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
370	H	I	H	tBut	2-Napht	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
371	H	Ph	H	tBut	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
372	H	p(iProp)-Ph	H	tBut	cHex	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —C(CH 3 )═CH—CH 2 —
373	H	pAcetyl-Ph	H	tBut	nHex	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
374	H	pBr-Ph	H	tBut	H	OMe	CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
375	H	pI-Ph	H	iProp	F	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —CH═CH—CH 2 —
376	H	iProp	H	CH 3	1-Pyrrolyl	H	CH 2	CH 2 —C═CH	—(CH 2 ) 4 —
377	H	iBul	H	OMe	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
378	H	CN	H	tBut	H	CH 3	CH 2 —CH 2	CH—C—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
379	H	COOEt	H	tBut	tBut	OMe	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
380	H	OPh	H	tBut	iProp	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
381	Me	Br	H	Ph	tBut	Cl	CH 2	CH 2 —C═CH	—CH 2 —C(CH 3 )═CH—CH 2 —
382	CN	I	H	2-Napht	tBut	Me	CH 2 —CH 2	CH═C—CH 2	—(CH 2 ) 4 —
383	Me	Ph	H	tBut	CF 3	Me	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —

TABLE 15
Example No.	R1	R2	R3	R7	R8	R9	R10	W	X—Y—Z	B
384	H	Br	H	tBut	H	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 )4—
385	H	I	H	tBut	CN	H	H	CH 2	CH 2 —N—CH 2	—(CH 2 )4—
386	H	Ph	H	tBut	H	Cl	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
387	H	p(iProp)-Ph	H	H	CN	tBu	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —CH(CH 3 )—CH 2 —
388	H	pAcetyl-Ph	H	CF 3	H	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 )4—
389	H	pBr-Ph	H	nProp	H	iProp	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
390	H	pI-Ph	H	H	H	iProp	OMe	CH 2 —CH 2	CH 2 —CH═C	—(CH 2 )4—
391	H	iProp	H	tBut	H	tBut	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
392	H	tBut	H	tBut	CN	H	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
393	H	CN	H	tBut	H	Cl	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 3 —
394	H	COOEt	H	H	CN	tBu	H	CH 2	CH═C—CH 2	—CH 2 —C(CH 3 )═CH—CH 2 —
395	H	OPh	H	CF 3	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
396	Me	Br	H	nProp	H	iProp	H	CH 2	CH 2 —N—CH 2	—(CH 2 )4—
397	CN	I	H	H	H	iProp	OMe	CH 2	CH 2 —N—CH 2	—(CH 2 )4—
398	Me	Ph	H	nProp	CN	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
399	F	p(iProp)-Ph	H	CF 3	CN	iProp	H	CH 2 —CH 2	CH 2 —CH═C	—(CH 2 ) 4 —
400	Me	pAcetyl-Ph	H	Ph	C═CH	tBut	H	CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
401	H	pBr-Ph	Me	tBut	CN	tBut	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
402	H	pI-Ph	F	tBut	H	nProp	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 3 —
403	H	iProp	Me	Ph	H	tBut	OMe	CH 2	CH 2 —CH═C	—(CH 2 ) 5 —
404	H	tBut	CN	CF 3	H	tBut	F	CH 2 —CH 2	CH═C—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
405	H	CN	Me	tBut	F	H	Me	CH 2	CH 2 —N—CH 2	—CH 2 —CH═CH—CH 2 —
406	H	COOEt	Me	nProp	CN	tBut	Me	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —C(═CH 2 )—CH 2 —
407	H	pAcetyl-Ph	F	nProp	C═CH	tBut	H	CH 2	CH═C—CH 2	—CH 2 —C(CH 3 )═CH—CH 2 —
408	Cl	F	H	tBut	CN	H	Me	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —

TABLE 16
Example No.	R1	R2	R3	R6	R8	R9	R10	W	X—Y—Z	B
409	H	Br	H	OMe	H	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
410	H	I	H	OMe	H	CF 3	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
411	H	Ph	H	OMe	H	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
412	H	p(iProp)-Ph	H	H	CN	tBut	H	CH 2	CH═C—CH 2	—CH 2 —C(CH 3 )═CH—CH 2 —
413	H	pAcetyl-Ph	H	H	F	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
414	H	pBr-Ph	H	Me	Cl	iProp	H	CH 2	CH 2 —CH═C	—CH 2 —C(═CH 2 )—CH 2 —
415	H	pI-Ph	H	H	H	iProp	H	CH 2 —CH 2	CH═C—CH 2	—(CH 2 ) 4 —
416	H	iProp	H	H	H	tBut	OMe	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
417	H	tBut	H	CN	H	CF 3	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
418	H	CN	H	H	CN	H	OMe	CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
419	H	COOEt	H	H	H	tBu	F	CH 2	CH 2 —CH═C	—CH 2 —C(CH 3 )═CH—CH 2 —
420	H	OPh	H	H	CN	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 3 —
421	Me	Br	H	Me	H	iProp	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
422	CN	I	H	OMe	H	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
423	Me	Ph	H	OMe	CN	tBut	H	CH 2	CH═C—CH 2	—(CH 2 ) 4 —
424	F	p(iProp)-Ph	H	OMe	Me	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
425	Me	pAcetyl-Ph	H	H	CN	tBut	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —CH═CH—CH 2 —
426	H	pBr-Ph	Me	Me	H	tBut	H	CH 2	CH 2 —CH═C	—CH 2 —C(═CH 2 )—CH 2 —
427	H	pI-Ph	F	H	Cl	CF 3	Me	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
428	H	iProp	Me	OMe	CN	tBut	Me	CH 2	CH═C—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
429	H	tBut	CN	Me	Me	iProp	Me	CH 2	CH 2 —CH═C	—(CH 2 ) 4 —

TABLE 17
Example No.	R1	R2	R3	R6	R7	R9	R10	W	X—Y—Z	B
430	H	Br	H	H	tBut	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
431	H	I	H	H	tBut	Ph	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
432	H	Ph	H	H	tBut	1-Pyrrolyl	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
433	H	p(iProp)-Ph	H	H	nPropyl	tBut	H	CH 2 —CH 2	CH 2 —CH═C	—CH 2 —C(CH 3 )═CH—CH 2 —
434	H	pAcetyl-Ph	H	H	CF 3	tBut	H	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
435	H	pBr-Ph	H	H	2-Napht	tBut	H	CH 2 —CH 2	CH═C—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
436	H	pI-Ph	H	OMe	tBut	H	H	CH 2 —CH 2	CH 2 —CH═C	—(CH 2 ) 4 —
437	H	iProp	H	OMe	iProp	H	H	CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
438	H	tBut	H	OMe	H	CF 3	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
439	H	CN	H	H	tBut	H	H	CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
440	H	COOEt	H	H	iProp	H	Me	CH 2	CH═C—CH 2	—CH 2 —C(CH 3 )═CH—CH 2 —
441	H	OPh	H	CN	tBut	H	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 3 —
442	Me	Br	H	H	H	CF 3	Me	CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
443	CN	I	H	H	nProp	tBut	H	CH 2	CH 2 —N—CH 2	—CH 2 —CH(CH 3 )—CH 2 —
444	Me	Ph	H	OMe	tBut	iProp	H	CH 2 —CH 2	CH 2 —N—CH 2	—(CH 2 ) 4 —
445	F	p(iProp)-Ph	H	OMe	CF 3	tBut	H	CH 2 —CH 2	CH═C—CH 2	—(CH 2 ) 4 —
446	Me	pAcetyl-Ph	H	Me	tBut	nProp	H	CH 2	CH 2 —CH═C	—CH 2 —CH═CH—CH 2 —
447	H	pBr-Ph	Me	Me	tBut	H	H	CH 2 —CH 2	CH 2 —N—CH 2	—CH 2 —C(═CH 2 )—CH 2 —
448	H	pI-Ph	F	H	tBut	tBut	H	CH 2	CH═C—CH 2	—(CH 2 ) 3 —
449	H	iProp	Me	Me	CF 3	tBut	H	CH 2	CH 2 —CH═C	—CH 2 —CH(CH 3 )—CH 2 —

Examples of Pharmaceutical Presentations

A) Tablets

Tablets of the following composition were compressed in a tabletting machine in a conventional way:

40 mg   of substance of Example 1
120 mg  of corn starch
13.5 mg of gelatin
45 mg   of lactose
2.25 mg of Aerosil ® (chemically pure silica in
        submicroscopically fine distribution)
6.75 mg of potato starch (as 6% paste)

B) Coated tablets

20 mg of substance from Example 4
60 mg of core composition
70 mg of sugar-coating composition

The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer. The sugar-coating composition consists of 5 parts of sucrose, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The coated tablets produced in this way are subsequently provided with an enteric coating.

Biological Investigations—Receptor-binding Studies

1) D 3 binding assay

Cloned CCL 1,3 mouse fibroblasts which express the human D 3 receptor and which are obtainable from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were employed for the binding studies.

Cell preparation

The D 3 expressing cells were grown in RPMI-1640 with 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U/ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. After neutralization with medium, the cells were collected by centrifugation at 300 g. For cell lysis, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 107 cells/ml of lysis buffer at 4° C. for 30 min. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen.

Binding assays

For the D 3 receptor binding assay, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 2 mM MgCl 2 , 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA) at a concentration of about 10 6 cells/250 μl of assay mixture and incubated with 0.1 nM 125 I-sulphide in the presence and absence of test substance at 30° C. The non-specific binding was determined with 10 −6 M spiperone.

After 60 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) separated the free and the bound radioligand, and the filters were washed with ice-cold tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K i values were determined by non-linear regression analysis using the LIGAND program.

2) D 2 binding assay

Cell culture

HEK-293 cells with stably expressed human dopamine D2A receptors were cultivated in RPMI 1640 with Glutamax I™ and 25 mM HEPES with 10% fetal calf serum albumin. All the media contained 100 units of penicillin per ml and 100 μg/ml streptomycin. The cells were maintained at 37° C. in a moist atmosphere with 5% CO 2 .

The cells were prepared for binding studies by trypsinization (0.05% trypsin solution) at room temperature for 3-5 minutes. The cells were then centrifuged at 250 g for 10 minutes and treated with lysis buffer (5 mM tris-HCl, 10% glycerol, pH 7.4) at 4° C. for 30 minutes. After centrifugation at 250 g for 10 minutes, the residue was stored at-20° C. until used.

Receptor binding assays

1) Dopamine D 2 receptor “low affinity state” with 125 I-spiperone (81 TBq/mmol, Du Pont de Nemours, Dreieich)

The mixtures (1 ml) consisted of 1×10 5 cells in incubation buffer (50 mM tris, 120 mM NaCl, 5 mM KCl, 2 mM MgCl 2 and 2 mM CaCl 2 , pH 7.4 with HCl) and 0.1 nM 125 I-spiperone (total binding) or with the addition of 1 μM haloperidol (nonspecific binding) or test substance.

After incubation at 25° C. for 60 minutes, the mixtures were filtered through GF/B glass fiber filters (Whatman, England) in a skatron cell collector (Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Evaluation took place as under a).

The K i values were determined by nonlinear regression analysis using the ligand program or by conversion of the IC 50 values using the formula of Cheng and Prusoff.

In these assays, the compounds according to the invention show very good affinities on the D 3 receptor and high selectivities for the D 3 receptor.

The compounds listed below were obtained in a similar way:

Ex.
No.	Ar 1	A	Ar 2	M.p. [° C.]
450				80-90 (Oxalate)
451				110-113
452				106-108
453				129-131
454		—S—(CH 2 ) 3 —		227-131 (Hydro- chloride)
455		—S—(CH 2 ) 3 —		165-166 (Hydro- chloride)
456		—(CH 2 ) 5 —		115-118 (Oxalate)
457		—(CH 2 ) 4 —		94-97 (Hydro- chloride)
458		—(CH 2 ) 4 —		123-126 (Fumarate)
459				130-133 (Fumarate)
460				118-125 (Fumarate)
461				130-132 (Oxalate)
462		—(CH 2 ) 6 —		144-150 (Fumarate)
463		—(CH 2 ) 4 —		148-154 (Oxalate)
464				171-176 (Fumarate)
465		—(CH 2 ) 4 —		122-124 (Fumarate)
466		—(CH 2 ) 4 —		108-112 (Oxalate)
467		—(CH 2 ) 4 —		140-142 (Oxalate)
468		—(CH 2 ) 4 —		149-152 (Fumarate)
469		—(CH 2 ) 4 —		147-149 (Hydro- chloride)
470		—(CH 2 ) 4 —		235-236 (Fumarate)
471				92-98
472				87-90
473		—(CH 2 ) 4 —		112-115 (Fumarate)
474		—(CH 2 ) 6 —		101-105 (Oxalate)
475		—(CH 2 ) 4 —		127-129 (Oxalate)
476		—S—(CH 2 ) 3 —
477		—S—(CH 2 ) 3 —
478		—S—(CH 2 ) 3 —		126-128 (Fumarate)
479		—S—(CH 2 ) 3 —		150-156 (Fumarate)
480		—S—(CH 2 ) 3 —		158-165 (Fumarate)
481		—S—(CH 2 ) 3 —
482		—S—(CH 2 ) 3 —		184-188 (Oxalate)
483		—S—(CH 2 ) 3 —		185-187 (Oxalate)
484
485				127
486				128
487		—S—(CH 2 ) 3 —		123
488		—S—(CH 2 ) 3 —		120
489		—S—(CH 2 ) 3 —		187-191 (Oxalate)
490		—S—(CH 2 ) 3 —		187-191 (Oxalate)
491		—S—(CH 2 ) 3 —
492		—S—(CH 2 ) 3 —
493		—S—(CH 2 ) 3 —
494		—S—(CH 2 ) 3 —		93-94 (Oxalate)
495		—S—(CH 2 ) 3 —
496		—S—(CH 2 ) 3 —		168-170 (Fumarate)
497		—S—(CH 2 ) 3 —
498		—S—(CH 2 ) 3 —
499
500		—S—(CH 2 ) 3 —
501		—S—(CH 2 ) 3 —
502
503
504
505		—S—(CH 2 ) 3 —
506		—S—(CH 2 ) 3 —
507
508
509
510
511		—S—(CH 2 ) 3 —
512		—S—(CH 2 ) 3 —
513
514
515		—S—(CH 2 ) 3 —
516		—S—(CH 2 ) 3 —		81-85
517
518
519
520				75-80
521				110-112 (Hydro- chloride)
522		—S—(CH 2 ) 3 —		78-80
523				95-97 (Hydro- chloride)
524				142-145
525				80-81
526				Oxalate
527		—S—(CH 2 ) 8 —		Hydrochloride
528		—S—(CH 2 ) 3 —		Oxalate
529		—S—(CH 2 ) 3 —		DiHydro- chloride
530				Oxalate
531
532
533
534				95-96
535		—S—(CH 2 ) 3 —		92
536		—S—(CH 2 ) 3 —		90
537				97
538		—S—(CH 2 ) 3 —		98-100
539
540
541		—S—(CH 2 ) 3 —		66-72
542		—S—(CH 2 ) 3 —
543		—S—(CH 2 ) 3 —
544		—S—(CH 2 ) 3 —
545		—S—(CH 2 ) 3 —
546		—S—(CH 2 ) 3 —
547		—S—(CH 2 ) 3 —
548		—S—(CH 2 ) 3 —
549		—S—(CH 2 ) 3 —
550		—S—(CH 2 ) 3 —
551		—S—(CH 2 ) 3 —
552
553
554
555
556
557
558				100-103
559		—S—(CH 2 ) 3 —
560		—S—(CH 2 ) 3 —		109-112
561		—S—(CH 2 ) 3 —
562		—S—(CH 2 ) 3 —
563		—S—(CH 2 ) 3 —
564		—S—(CH 2 ) 3 —
565				84-85
566
567
568		—S—(CH 2 ) 3 —
569		—S—(CH 2 ) 3 —
570		—S—(CH 2 ) 3 —
571		—S—(CH 2 ) 3 —
572		—S—(CH 2 ) 3 —
573		—S—(CH 2 ) 3 —		185-190
574				145-148
575				120-122
576				70-80 (Oxalate)
577				155-160 (Hydro- chloride)
578		—S—(CH 2 ) 3 —		97-98 (Hydro- chloride)
579				141-143 (Fumarate)
580				105-108 (Hydro- chloride)
581				139-143 (Hydro- chloride)
582				89-95
583		—S—(CH 2 ) 3 —		160-165 (Oxalate)
584		—(CH 2 ) 4 —		62-64
585		—(CH 2 ) 4 —		148-149
586		—(CH 2 ) 4 —		38-41
587		—CH═CH—(CH 2 ) 2 —		Oil
588		—S—(CH 2 ) 3 —		90 (Decom- position) (Hydro- chloride)
589		—S—(CH 2 ) 3 —		90-93 (Fumarate)
590		—S—(CH 2 ) 3 —		75-78 (Fumarate)
591				Oil
592		—S—(CH 2 ) 3 —		130-133 (Hydro- chlorid)
593		—S—(CH 2 ) 3 —		Oil
594				126-130 (Hydro- chloride)
595		—S—(CH 2 ) 3 —		90-95 (Decom- position) (Hydro- chloride)
596				Oil
597		—S—(CH 2 ) 3 —		Oil
598		—S—(CH 2 ) 3 —		106 (Hydro- chloride)
599		—S—(CH 2 ) 3 —		148 (Hydro- chloride)
600		—S—(CH 2 ) 3 —		137-139 (Hydro- chloride)
601				109-115 (Hydro- chloride)
602		—S—(CH 2 ) 3 —		90 (Decom- position) (Hydro- chloride)
603				132 (Decom- position) (Hydro- chloride)
604				103-105 (Hydro- chloride)
605		—S—(CH 2 ) 3 —		142-144
606		—S—(CH 2 ) 3 —		Oil
607		—S—(CH 2 ) 3 —		Oil
608		—S—(CH 2 ) 3 —		120-123 (Hydro- chloride)
609		—S—(CH 2 ) 3 —		187-189 (Fumarate)
610				95-98 (Fumarate)
611				68-72 (Fumarate)
612		—S—(CH 2 ) 3 —		240 (Hydro- chloride)
613				190 (Hydro- chloride)
614		—S—(CH 2 ) 3 —		243 (Hydro- chloride)
615		—S—(CH 2 ) 3 —		101-104
616		—S—(CH 2 ) 3 —		Oil
617				90-94 (Decom- position) (Hydro- chloride)
618				152 (Hydro- chloride)
619		—S—(CH 2 ) 3 —		Oil
620		—S—(CH 2 ) 3 —		Oil
621				152 (Hydro- chloride)
622		—S—(CH 2 ) 3 —		110 (Hydro- chloride)
623		—S—(CH 2 ) 3 —		126-131 (Hydro- chloride)
624		—S—(CH 2 ) 3 —		91 (Hydro- chloride)
625		—S—(CH 2 ) 3 —		116-120 (Hydro- chloride)
626				103 (Hydro- chloride)
627		—S—(CH 2 ) 3 —		150 (Hydro- chloride)
628				140 (Hydro- chloride)
629		—S—(CH 2 ) 3 —		130 (Hydro- chloride)
630		—S—(CH 2 ) 3 —		98-104 (Hydro- chloride)
631				65-68 (Hydro- chloride)
632		—S—(CH 2 ) 3 —		131-136 (Hydro- chloride)
633				105 (Hydro- chloride)
634				132 (Hydro- chloride)
635				92 (Hydro- chloride)
636				95 (Hydro- chloride)
637				102 (Hydro- chloride)
638		—S—(CH 2 ) 3 —		214-216 (Hydro- chloride)
639		—S—(CH 2 ) 3 —		160-162 (Hydro- chloride)
640		—S—(CH 2 ) 3 —		73-75 (Fumarate)
641				178
642		—S—(CH 2 ) 3 —		155
643		—S—(CH 2 ) 3 —		125-128 (Hydro- chloride)
644		—S—(CH 2 ) 3 —		102 (Hydro- chloride)
645		—S—(CH 2 ) 3 —		88 (Hydro- chloride)
646		—S—(CH 2 ) 3 —		132 (Hydro- chloride)
647				190 (Hydro- chloride)
648		—S—(CH 2 ) 3 —		134-138 (Hydro- chloride)
649		—S—(CH 2 ) 3 —		170-174 (Hydro- chloride)
650		—S—(CH 2 ) 3 —		115 (Hydro- chloride)
651		—S—(CH 2 ) 3 —		117 (Hydro- chloride)
652				151-155
653				158-161 (Hydro- chloride)
654		—S—(CH 2 ) 3 —		184-185 (Hydro- chloride)
655				194-195 (Hydro- chloride)
656				114 (Hydro- chloride)
Ph = Phenyl

The compounds listed above which are not characterized by a melting point, have the following NMR spectra (d6-DMSO)

Ex. no.
476		1,8-2,1 (m,4H); 2,6-2,7 (m,4H); 2,8 (t,2H); 3,2
		(t,2H); 3,5-3,7 (b,2H); 3,7-3,9 (b,2H); 4,5
		(d,2H); 5,1 (t,1H); 5,2 (s,1H); 6,1 (d,1H); 6,2
		(m,2H); 7,3 (m,5H); 7,7 (m,2H); 7,8 (d,1H)
477		1,8-1,9 (m,4H); 2,5-2,6 (m,4H); 2,7 (t,2H); 3,0
		(t,2H); 3,3 (s,3H); 3,5-3,8 (b,4H); 4,2 (s,2H);
		4,5 (d,2H); 5,1 (t,1H); 5,2 (s,1H); 6,2 (m,2H);
		7,3-7,4 (m,5H); 7,7 (m,2H)
481	Oxalate	2,1 (b,4H); 3,2-3,4 (m,8H); 3,6 (s,3H); 3,7
		(b,2H); 6,6-6,8 (m,3H); 7,2 (t,1H); 7,6 (m,3H);
		7,7 (m,2H)
484	Oxalate	2,0 (b,2H); 2,8-3,0 (b,4H); 3,4-3,5 (m,4H); 3,6-
		3,7 (b,2H); 3,9 (s,2H); 5,3 (d,2H); 6,1 (d,1H);
		6,5-6,8 (m,3H); 7,21 (t,1H); 7,9 (d,1H);
491	Oxalate	2,0-2,3 (b,4H); 3,0-3,4 (b,8H); 3,6 (s,3H); 3,9
		(b,2H); 4,1 (b,2H); 7,1-7,3 (b,1H); 7,5 (m,3H);
		7,6 (m,2H); 8,6 (s,1H);
492		1,7-1,9 (m,4H); 2,6 (b,2H); 2,8 (b,2H); 3,1
		(t,2H); 3,6-3,9 (b,4H); 6,1 (d,1H); 7,0 (d,1H);
		7,8 (d,1H); 8,5 (s,1H)
493	Oxalate	1,9-2,1 (b,4H); 2,7 (s,3H); 2,8 (t,2H); 3,0-3,3
		(b, 6H); 3,3 (s,3H); 3,4 (t,2H); 3,7 (b,2H); 6,3
		(b, 1H); 6,4-6,5 (m,3H); 7,0(m,1H)
495	Fumarate	1,6-1,8 (b,4H); 2,6 (m,2H); 2,7 (t,2H); 3,2
		(s,3H); 3,3-3,5 (m,4H); 5,9 (s,2H); 6,2-6,5
		(m,3H); 7,0 (m,1H);
497	Fumarate	1,6-1,8 (m,2H); 1,8-2,0 (b,2H); 2,5-2,7 (b,4H);
		2,8-2,9 (m,4H); 3,2 (s,3H); 3,7-3,9 (m,4H); 5,9
		(b,2H); 6,5 (s,2H); 7,4 (d,1H);
498	Fumarate	1,3 (s,9H); 1,8-2,1 (b,4H); 2,7-3,0 (b,6H); 3,3
		(s,3H); 3,5-3,8 (b,6H); 6,1 (b,2H); 6,6 (s,2H);
		6,7 (s,1H);
499	Hydro-	1,3 (s,9H); 1,9 (b,2H); 2,2 (s,2H); 2,5 (b,2H);
	chloride	2,7 (b,2H); 3,1 (s,2H); 3,4 (s,3H); 3,7 (s,2H);
		3,8 (s,3H); 3,9 (s,3H); 5,0 (d,2H); 6,5 (s,1H);
		6,9 (d,1H); 7,5 (d,1H); 7,7 (s,1H); 11,3 (b,1H);
500	Fumarate	1,3 (s,9H); 1,7-1,9 (b,4H); 2,5-2,7 (b,4H); 2,8-
		2,9 (b,2H); 3,1 (t,2H); 3,6-3,7 (b,2H); 3,8-4,0
		(b,2H); 6,1 (d,1H); 6,6 (s,2H); 6,9 (d,1H); 7,8
		(d, 1H)
501		1,3 (s,9H); 1,8-2,0 (m,4H); 2,6 (m,4H); 2,8
		(b,2H); 3,1 (t,2H); 3,4 (s,3H); 3,5 (b,2H); 3,9-
		4,1 (b,2H); 4,4 (b,2H); 6,5 (s,1H)
502	Fumarate	1,3 (s,9H); 1,8-1,9 (b,2H); 2,5-2,6 (b,2H); 2,7
		(b,2H); 3,1 (s,2H); 3,6-3,7 (b,2H); 3,7-4,0
		(m, 4H); 5,1 (s,1H); 5,2 (s,1H); 6,1 (d,1H); 6,6
		(s,2H); 6,9 (d,1H); 7,8 (d,1H)
503	Fumarate	1,3 (s,9H); 1,8-1,9 (b,2H); 2,5-2,6 (b,2H); 2,7-
		2,8 (b,2H); 3,2 (s,2H); 3,6 (s,3H); 3,6-3,7
		(b,2H); 3,7 (s,2H); 3,8-4,0 (b,2H); 5,0 (s,1H);
		5,1 (s,1H); 6,6 (s,2H); 6,9 (d,1H); 7,6 (m,3H);
		7,7 (m,2H)
504	Fumarate	1,3 (s,9H); 1,8-1,9 (b,2H); 2,5 (b,2H); 2,6-2,7
		(b,2H); 3,1 (s,2H); 3,3 (s,3H); 3,4 (s,2H); 3,5-
		3,7 (b,2H); 3,8-4,0 (b,2H); 4,9 (d,2H); 6,0
		(s,2H); 6,6 (s,2H); 6,9 (d,1H)
505	Fumarate	1,3 (s,9H); 1,7-1,9 (b,4H); 2,5-2,7 (b,4H); 2,8
		(t,2H); 3,1 (t,2H); 3,4-4,0 (b,4H); 6,1 (d,1H);
		6,5 (d,1H); 6,6 (s,2H); 7,8 (d,1H); 8,2 (d,1H)
506		1,4 (s,9H); 1,8 (m,2H); 2,1-2,2 (b,2H); 2,6
		(m,4H); 2,7 (t,2H); 3,0 (t,2H); 3,4 (s,3H); 3,5-
		4,0 (b,4H); 4,6 (b,2H); 6,2 (d,1H); 8,2 (d,1H)
507		0,9 (t,3H); 1,3 (s,9H); 1,4 (m,2H); 1,7 (m,2H);
		2,1 (b,2H); 2,6 (t,2H); 2,7 (t,2H); 2,8 (t,2H);
		3,3 (s,2H); 3,6-3,7 (b,2H); 3,8 (s,2H); 3,9-4,0
		(b,2H); 5,1 (s,1H); 5,2 (s,1H); 6,1 (s,1H); 6,2
		(d,1H); 7,8 (d,1H)
508		0,9 (t,3H); 1,3 (s,9H); 1,4 (m,2H); 1,7 (m,2H);
		1,9 (m,2H); 2,6 (m,4H); 2,7 (t,2H); 3,1(d,3H)
		3,2 (s,2H); 3,3 (s,3H); 3,6 (m,1H); 3,7 (s,2H);
		3,6-3,8 (b,4H); 5,0 (d,2H); 6,0 (s,1H)
509	Dihydro-	0,9 (t,3H); 1,3 (m,2H); 1,4 (s,9H); 1,7 (m,2H);
	chloride	2,4-2,5 (b,2H); 2,9 (t,2H); 3,2-3,4 (b,4H); 3,5
		(s,3H); 3,7-3,8 (b,2H); 3,9 (s,2H); 3,9-4,2
		(b,2H); 4,1 (s,2H); 5,4 (s,2H); 6,9 (s,1H); 8,5
		(s,2H); 11,7 (b,1H); 14,0 (b,1H)
510		1,3 (s,9H); 2,0-2,1 (b,2H); 2,7 (t,2H); 2,8
		(t,2H); 3,3 (s,2H); 3,5-3,8 (b,2H); 3,8 (s,2H);
		3,8-4,1 (b,2H); 5,1 (s,1H); 5,2 (s,1H); 6,2
		(m,2H); 7,8 (d,1H); 8,2 (d,1H)
511		1,3 (s,18H); 1,6-1,9 (b,4H); 2,4 (b,2H); 2,7
		(b,2H); 2,8 (t,2H); 3,2 (s,3H); 3,7 (m,4H); 5,8
		(s,1H) ;
512		1,3 (s,18H); 1,7-1,8 (m,4H); 2,5 (b,2H); 2,7
		(b,2H); 3,0 (t,2H); 3,7-3,8 (m,4H); 6,0 (d,1H);
		7,8 (d,1H);
513		1,6-2,1 (m,17H); 2,7 (s,2H); 3,1 (s,2H); 3,3-3,6
		(b,6H); 3,4 (s,3H); 3,8-3,9 (b,2H); 4,8 (b,2H)
		6,0 (b,2H); 6,8 (s,1H);
514		1,6-2,0 (m,17H); 2,5 (s,2H); 2,6 (s,2H); 3,0
		(s,2H); 3,5-3,9 (b,6H); 5,0 (d,2H); 6,0 (d,1H);
		6,8 (d,1H); 7,8 (d,1H);
515		1,7-2,0 (m,19H); 2,5 (b,2H); 2,7 (s,2H); 3,0
		(t,2H); 3,5-3,8 (b,4H); 6,0 (d,1H); 6,8 (d,1H)
		7,8 (d,1H);
517	Dihydro-	1,4 (s,9H); 2,4-2,5 (b,2H); 3,3-3,6 (b,4H); 3,5
	chloride	(s,3H); 3,7-3,8 (b,2H); 3,8-3,9 (b,2H); 3,9-4,2
		(b,4H); 5,4 (s,2H); 7,1 (d,1H); 8,3 (d,1H); 8,5
		(s,2H); 11,7 (b,1H); 14,5 (b,1H)
518		1,3 (s,9H); 1,8-2,0 (b,2H); 2,6 (t,2H); 2,7
		(t,2H); 3,0 (d,3H); 3,2 (s,2H); 3,3 (s,3H); 3,6
		(s,2H); 3,6-3,9 (b,5H); 5,0 (d,2H); 6,2 (s,1H);
		6,3 (m,2H); 7,8 (m,2H)
519		1,4 (s,9H); 1,9 (m,2H); 2,6 (t,2H); 2,7 (t,2H);
		3,0 (d,3H); 3,2 (s,2H); 3,3 (s,3H); 3,7 (s,2H);
		3,6-3,9 (b,5H); 5,0 (d,2H); 6,1 (s,1H); 6,3
		(m,2H); 7,6 (m,2H)
527	Hydro-	1,2-1,5 (b,10H); 1,5-1,8 (b,4H); 3,1 (m,4H); 3,5
	chloride	(m,4H); 3,8-4,0 (b,4H); 6,8 (t,1H); 6,9 (b,3H);
		7,1 (t,1H); 10,5 (b,1H);
526	Oxalate	1,3 (s,9H); 1,9-2,1 (b,2H); 2,7-3,0 (b,4H); 3,4
		(b,2H); 3,6 (s,3H); 3,6-3,8 (b,2H); 3,8 (s,2H);
		3,9-4,1 (b,2H); 5,2 (d,2H); 6,2 (m,2H); 6,4
		(s,1H); 7,6 (m,3H); 7,7 (m,4H)
528	Oxalate	0,9 (t,3H); 1,3 (s,9H); 1,4 (m,2H); 1,6 (m,2H);
		1,9-2,2 (b,4H); 2,5 (m,2H); 3,0-3,2 (b,4H); 3,2-
		3,4 (b,4H); 3,5-3,7 (b,2H); 3,9-4,1 (b,2H); 6,1
		(d,1H); 6,4 (s,1H); 7,8 (d,1H)
529	Dihydro-	0,9 (t,3H); 1,3 (m,2H); 1,4 (s,9H); 1,7 (m,2H);
	chloride	2,2 (b,3H); 3,0 (t,2H); 3,2 (b,SH); 3,5 (s,3H);
		3,5-4,2 (b,7H); 4,5-4,7 (b,1H); 7,0 (d,1H); 8,6
		(s,2H); 11,7 (b,1H); 14,2 (b,1H)
530	Oxalate	1,3 (s,9H); 1,9-2,1 (b,2H); 2,7-3,0 (b,4H); 2,3-
		2,4 (b,2H); 2,6-4,1 (b,4H); 3,9 (s,2H); 5,2
		(s,1H); 5,3 (s,1H); 6,1 (d,1H); 6,2 (m,2H); 6,4
		(s,1H); 7,7 (m,2H); 7,8 (d,1H)
531		1,3 (s,9H); 1,9 (mn,2H); 2,6 (t,2H); 2,7 (t,2H);
		3,2 (s,2H); 3,3 (s,3H); 3,7 (s,2H); 3,6-3,9
		(b,4H); 4,3 (s,2H); 5,0 (d,2H); 6,2 (s,1H); 6,3
		(m,2H); 7,8 (m,2H)
533		1,3 (s,9H); 2,1 (m,2H); 2,7 (m,2H); 2,9 (m,2H);
		3,3 (s,2H); 3,6-3,8 (b,2H); 3,8 (s,2H); 3,9-4,1
		(b,2H); 5,1 (s,1H); 5,2 (s,1H); 6,1 (s,1H); 6,2
		(d,1H); 6,3 (m,2H); 7,5 (m,2H); 7,8 (d,1H)
532		1,3 (s,9H); 1,9 (m,2H); 2,6 (t,2H); 2,7 (t,2H);
		3,2 (s,2H); 3,3 (s,3H); 3,7 (s,2H); 3,6-3,6
		(b,4H); 4,3 (s,2H); 5,0 (s,2H); 6,1 (s,1H); 6,3
		(m,2H); 7,6 (m,2H)
539	Hydro-	2,2-2,3 (b,2H); 3,0-3,2 (b,2H); 3,5-4,0 (b,8H),
	chloride	4,2 (s,2H); 5,5 (d,2H); 6,2 (d,1H); 6,9-7,0
		(m,3H); 7,0 (t,1H); 7,4 (m,1H); 7,9 (d,1H); 10,9
		(b,1H)
540	Hydro-	2,4 (b,2H); 3,2 (b,4H); 3,4 (s,3H); 3,5 (m,2H)
	chloride	3,7 (b,4H); 4,0 (s,2H); 5,3 (d,2H); 6,8-7,1
		(m,4H); 7,2-7,4 (m,3H) ;
542		1,3 (s,9H); 1,9 (m,2H); 1,9-2,1 (b,2H); 2,6
		(m,4H); 2,8 (b,2H); 3,2 (t,2H); 3,5-3,7 (b,2H);
		3,9-4,2 (b,2H); 6,2 (d,1H); 6,5 (s,1H); 6,8
		(d,1H)
543		1,3 (s,9H); 1,9 (m,2H); 1,9-2,0 (b,2H); 2,6-2,7
		(b,4H); 2,8 (b,2H); 3,1 (t,2H); 3,2 (s,3H); 3,5-
		3,6 (b,2H); 3,9-4,1 (b,2H); 6,5 (s,1H); 10,8
		(b,1H)
544		1,3 (s,9H); 1,8-2,0 (b,4H); 2,6 (m,4H); 2,7-2,8
		(b,2H); 3,0 (m,5H); 3,3 (s,3H); 3,5-3,6 (b,2H);
		3,9-4,1 (b,3H); 6,5 (s,1H)
545	Hydro-	1,3 (s,9H); 2,1-2,2 (b,3H); 2,5-2,6 (b,1H); 3,1-
	chloride	3,3 (b,6H); 3,4 (s,3H); 3,4-3,8 (b,4H); 4,0-4,1
		(b,1H); 4,6-4,7 (b,1H); 7,0 (s,1H); 8,6 (s,2H);
		11,3 (b,1H)
546		1,3 (s,9H); 1,9 (m,2H); 2,1 (m,2H); 2,7 (m,4H);
		2,9 (m,2H); 3,2 (t,2H); 3,8-3,9 (b,2H); 3,9-4,0
		(b,2H); 6,2 (d,2H); 6,3 (m,2H); 7,8 (m,3H)
547		1,3 (s,9H); 1,9 (m,4H); 2,6 (m,4H); 2,8 (t,2H);
		3,1 (t,2H); 3,2 (s,3H); 3,6-4,0 (b,4H); 6,2
		(s,1H); 6,3 (m,2H); 7,8 (m,2H); 9,2 (s,1H)
548		1,3 (s,9H); 1,9 (m,4H); 2,6 (t,4H); 2,8 (t,2H);
		3,1 (t,2H); 3,3 (s,3H); 3,5-3,9 (b,4H); 4,1
		(s,2H); 6,2 (s,1H); 6,3 (m,2H); 7,8 (m,2H)
549		1,4 (s,9H); 1,9 (m,2H); 2,0-2,1 (b,2H); 2,7
		(m,4H); 2,9 (m,2H); 3,2 (t,2H); 3,6-3,8 (b,2H);
		3,8-4,1 (b,2H); 6,1 (s,1H); 6,2 (d,1H); 6,3
		(m,2H); 7,6 (m,2H), 7,8 (d,1H)
550		1,4 (s,9H); 1,9 (m,4H); 2,6 (m,4H); 2,8 (b,2H);
		3,1 (t,2H); 3,2 (s,3H); 3,6-4,0 (b,4H); 6,1
		(s,1H); 6,3 (m,2H); 7,5 (m,2H); 10,0 (b,1H)
551		1,4 (s,9H); 1,9 (m,4H); 2,6 (m,4H); 2,8 (b,2H);
		3,1 (t,2H); 3,4 (s,3H); 3,5-4,0 (b,4H); 4,3
		(s,2H); 6,1 (s,1H); 6,3 (m,2H); 7,5 (m,2H)
552		1,3 (s,9H); 2,1 (m,2H); 2,8 (m,2H); 2,9 (m,2H);
		3,3 (s,2H); 3,8 (s,2H); 3,9 (t,2H); 4,1 (b,2H);
		5,1 (s,1H); 5,2 (s,1H); 6,2 (d,1H); 6,5 (d,1H);
		7,8 (d,1H); 8,2 (d,1H)
553	Hydro-	1,3 (s,9H); 2,2-2,3 (b,1H); 2,5-2,7 (b,1H); 3,1
	chloride	(s,3H); 3,0-3,2 (b,2H); 3,5-3,7 (b,3H); 3,8-4,1
		(m,6H); 4,4-4,5 (b,1H); 5,4 (d,2H); 6,8 (d,1H);
		8,3 (d,1H); 11,2 (b,1H); 11,9 (s,1H)
554		1,3 (s,9H); 1,9 (m,2H); 2,6 (t,2H); 2,7 (t,2H);
		3,2 (s,2H); 3,4 (s,3H); 3,7 (s,2H); 3,8 (m,4H);
		4,4 (s,2H); 5,0 (s,2H); 6,5 (d,1H); 8,2 (d,1H)
555		1,3 (s,18H); 2,1 (m,2H); 2,8 (t,2H); 3,0 (t,2H);
		3,3 (s,2H); 3,8 (s,2H); 3,9 (t,2H); 4,1 (t,2H);
		5,1 (s,1H); 5,2 (s,1H); 6,2 (d,1H); 6,5 (s,1H)
		7,8 (d,1H)
556		1,3 (s,18H); 1,9 (m,2H); 2,6 (t,2H); 2,7 (t,2H);
		3,2 (s,2H); 3,4 (s,3H); 3,6 (s,2H); 3,9 (m,4H);
		4,2 (s,2H); 5,0 (s,2H); 6,5 (s,1H)
557	Hydro-	1,3 (d,6H); 2,2 (b,1H); 2,6 (b,1H); 3,0 (b,4H);
	chloride	3,4 (s,3H); 3,5-3,7 (b,4H); 3,8 (s,2H); 4,1
		(s,2H); 5,4 (s,2H); 6,8 (t,1H); 6,9 (s,1H); 8,5
		(b,2H); 11,6 (b,1H);
559	Hydro-	1,2 (d,6H); 2,1 (b,4H); 3,0-3,2 (b,8H); 3,5-4,2
	chloride	(b,4H); 6,1 (d,1H); 6,8 (t,1H); 6,9 (b,1H); 7,8
		(d,1H); 11,3 (b,1H);
561		1,3 (s,18H); 1,9 (m,2H); 2,0 (m,2H); 2,7 (t,2H);
		2,8 (t,2H); 3,0 (t,2H); 3,2 (t,2H); 3,9 (t,2H);
		4,0 (t,2H); 6,1 (d,1H); 6,5 (s,1H); 7,8 (d,1H)
562		1,3 (s,18H); 1,9 (m,4H); 2,6 (m,4H); 2,8 (t,2H);
		3,0 (t,2H); 3,4 (s,3H); 3,8 (t,2H); 3,9 (t,2H);
		4,3 (s,2H); 6,5 (s,1H)
564	Oxalate	1,3 (s,9H); 2,0 (b,2H); 2,2 (b,2H); 3,1-3,4
		(b,8H); 3,3 (b,2H); 3,8 (s,3H); 4,0 (b,2H); 6,1
		(d,2H); 6,9 (s,1H); 7,0 (d,1H); 7,8 (d,1H); 8,1
		(d,1H);
563	Oxalate	1,3 (s,9H); 1,9 (b,2H); 2,2 (b,2H); 2,9 (t,2H);
		3,1 (t,2H); 3,3 (b,4H); 3,4 (s,3H); 3,7 (b,2H);
		3,8 (s,3H); 4,0 (b,2H); 5,3 (b,2H); 6,8 (s,1H);
		6,9 (d,1H); 8,0 (d,1H);
566		1,4 (s,9H); 1,9 (b,2H); 2,5 (b,2H); 2,8 (b,2H);
		3,2 (s,2H); 3,3 (s,3H); 3,6 (s,2H); 3,6-3,8
		(b,4H); 3,8 (s,3H); 4,8 (b,2H); 5,0 (s,2H); 6,5
		(s,1H); 7,0 (d,1H); 8,0 (d,1H);
567	Oxalate	2,0 (b,2H); 2,8 (b,2H); 3,0 (b,2H); 3,3 (s,3H);
		3,4 (s,2H); 3,6 (b,4H); 3,8 (b,2H); 5,1 (s,2H);
		5,5 (b,2H); 7,0 (m,2H); 7,7 (t,1H);
568	Oxalate	2,0 (b,2H); 2,2 (b,2H); 3,0 (t,2H); 3,1 (m,2H);
		3,2 (b,4H); 3,4 (s,3H); 3,6 (m,2H); 3,9 (b,2H);
		6,7 (b,2H); 7,0 (t,2H); 7,7 (t,1H);
569	Oxalate	2,0-2,2 (b,4H); 3,0-3,4 (m,8H); 3,5 (m,2H); 3,9
		(b,2H); 6,1 (d,1H); 6,5 (b,2H); 7,0 (t,2H); 7,7
		(t,1H); 7,8 (d,1H);
570	Hydro-	1,3 (s,9H); 2,0-2,2 (b,3H); 2,3-2,4 (b,1H); 3,2
	chloride	(m, 6H); 3,4-4,0 (b,5H); 4,3-4,5 (b,1H); 6,2
		(d,1H); 6,8 (d,1H); 7,9 (d,1H); 8,3 (d,1H); 10,8
		(b,1H)
571	Hydro-	1,3 (s,9H); 2,0-2,2 (b,3H); 2,3-2,4 (b,1H); 3,1
	chloride	(s,3H); 3,0-3,2 (m,6H); 3,4-4,0 (b,5H); 4,3-4,5
		(b,1H); 6,8 (d,1H); 8,3 (d,1H); 10,9 (b,1H);
		11,9 (s,1H)
572		1,3 (s,9H); 1,9-2,0 (m,4H); 2,6 (m,4H); 2,8
		(t,2H); 3,0 (t,2H); 3,4 (s,3H); 3,8 (t,2H); 3,9
		(b,2H); 4,6 (b,2H); 6,5 (d,1H); 8,2 (d,1H)

Claims

1. A compound of the formula IAr1—A—B—Ar2  (I) whereAr1 is  or a 5-membered heteroaromatic ring with 1, 2 or 3 heteroatoms which are selected, independently of one another, from O, N and S, where Ar1 may have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR1, alkyl which is unsubstituted or substituted by OH, OC1-C8-alkyl or halogen, or C2-C6-alkenyl, C2-C6-alkynyl, cycloalkyl, halogen, CN, CO2R1, NO2, NR1R2, SR1, CF3, CHF2, phenyl which is unsubstituted or substituted by C1-C6-alkyl, OC1-C6-alkyl, HCO, C1-C8-alkyl-CO, phenyl, amino, nitro, cyano or halogen, or phenoxy which is unsubstituted or substituted by C1-C6-alkyl, OC1-C6-alkyl, or halogen, or C1-C6-alkanoyl or benzoyl; R1 is H, alkyl which is unsubstituted or substituted by OH, OC1-C6-alkyl, phenyl or halogen; R2 has the meanings stated for R1 or is COR1 or CO2R1; A is a C3-C15-alkylene group when Ar1 is C6H5 CONH, or, when Ar1 is a 5- or 6-membered heteroaromatic ring, is a C4-C15-alkylene group or a C3-C15-alkylene group which comprises at least one group Z which is selected from O, S, NR1, a double and a triple bond, where R1 is as defined above, B is a 7- or 8-membered saturated ring with one or two nitrogen heteroatoms, the nitrogen heteroatoms being located in the 1,4 or 1,5 position and the ring being bonded in position 1 to the radical A and in position 4 or 5 to the radical Ar2, and it additionally being possible for the ring to have a double bond in position 3 or 4; Ar2 is phenyl, pyridyl, pyrimidinyl or triazinyl, it being possible for Ar2 to have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR1, alkyl, C2-C6-alkenyl, C2-C6-alkynyl, alkoxyalkyl, haloalkyl, halogen, CN, CO2R1, NO2, SO2R1, NR121, SO2NR12, SR1, a 5- or 6-membered carbocyclic, aromatic or, non-aromatic ring and a 5- or 6-membered heterocyclic aromatic or non-aromatic ring with 1 to 3 heteroatoms which are selected from O, S and N, the carbocyclic or heterocyclic ring being unsubstituted or substituted by C1-C6-alkyl, phenyl, halogen, OC1-C6-alkyl, OH, NO2 or CF3, and Ar2 may also be fused to a carbocyclic ring of the type defined above, and where Ar2 cannot be a pyrimidinyl radical substituted by 2 hydroxyl groups, and the salts thereof with physiologically tolerated acids.

2. A compound as claimed in claim 1 of the formula I where Ar1 is whereR3 to R6 are, independently of one another, H or the substituents mentioned in claim 1 for the radical Ar1, R7 has the meanings stated for R2 in claim 1 or is cycloalkyl, and X is N or CH.

3. A compound as claimed in claim 1 of the formula I where Ar1 is R3 to R5 are independently of one another, H, OR1, alkyl which is unsubstituted or substituted by OH, OC1-C8-alkyl or halogen, or C2-C6-alkenyl, C2-C6-alkynyl, cycloalkyl, halogen, CN, CO2R1, NO2, NR1R2, SR1, CF3, CHF2, phenyl which is unsubstituted or substituted by C1-C6-alkyl, OC1-C6-alkyl, HCO, C1-C8-alkyl-CO, phenyl, amino, nitro, cyano or halogen, or phenoxy which is unsubstituted or substituted by C1-C6-alkyl, OC1-C6-alkyl, or halogen, or C1-C6-alkanoyl or benzoyl; R7 is H, alkyl which is unsubstituted or substituted by OH, OC1-C6-alkyl, phenyl or halogen, COR1, CO2R1 or cycloalkyl; and X is N or CH.

4. A compound as claimed in claim 1 of the formula I where Ar1 is whereR3 to R5 are, independently of one another, H, OR1, alkyl which is unsubstituted or substituted by OH, OC1-C8-alkyl or halogen, or C2-C6-alkenyl, C2-C6-alkynyl, cycloalkyl, halogen, CN, CO2R1, NO2, NR1R2, SR1, CF3, CHF2, phenyl which is unsubstituted or substituted by C1-C6-alkyl, OC1-C6-alkyl, HCO, C1-C8-alkyl-CO, phenyl, amino, nitro, cyano or halogen, or phenoxy which is unsubstituted or substituted by C1-C6-alkyl, OC1-C6-alkyl, or halogen, or C1-C6-alkanoyl or benzoyl; R7 is H, alkyl which is unsubstituted or substituted by OH, OC1-C6-alkyl, phenyl or halogen, COR1, CO2R1 or cycloalkyl.

5. A compound as claimed in claim 4 of the formula I where R3, R4 and R5 are, independently of one another, H, OR1, alkyl, NR1R2, halogen, phenoxy, CN, phenyl which is unsubstituted or substituted by C1-C6-alkyl, acyl or halogen, or COOR1;R1 and R2 are, independently of one another, H, alkyl or benzyl; R7 is H, alkyl which is unsubstituted or substituted by OH, OC1-C8-alkyl, phenyl, halogen, or COO2R; and X is N or CH.

6. A compound as claimed in claim 5, where R3 to R6 are selected, independently of one another, from H, C1-C6-alkyl, OR1, NR1R2, phenyl which is unsubstituted or substituted by C1-C6-alkyl, HCO, C1-C6-alkyl-CO, or halogen, where R1 and R2 have the abovementioned meanings, R7 is H or alkyl, and X is N.

7. A compound as claimed in claim 6, where Ar1 is: where R3 is NR1R2, where R1 and R2 are, independently of one another H, alkyl or benzyl and R7 is H or alkyl.

8. A compound as claimed in claim 6, where Ar1 is thiadiazole which is unsubstituted or substituted by NR1R2, where R1 and R2 are, independently of one another H, alkyl or benzyl.

9. A compound as claimed in claim 6, where Ar1 is where R3 and R5 are independently of each other H or halogen, alkyl or phenyl.

10. A compound as claimed in claim 1 of the formula I, where A is —Z—C3-C6-alkylene, in particular —Z—CH2CH2CH2—, —Z—CH2CH2CH2CH2—, —Z—CH2CH═CHCH2—, —Z—CH2C(CH3)═CHCH2—, —Z—CH2C(═CH2)CH2—, —Z—CH2CH(CH3)CH2—or a linear —Z—C7-C10-alkylene radical, where Z is bonded to Ar1 and is CH2, O or S.

11. A compound as claimed in claim 1 of the formula I, where B is

12. A compound as claimed in claim 1 of the formula I, where Ar2 is phenyl, pyridinyl or pyrimidinyl, which may have one or two substituents which are selected, independently of one another, from C1-C6-alkyl, C2-C6-alkynyl, halogen, CN, haloalkyl, Oalkyl, NO2, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, cyclopentyl and cyclohexyl.

13. A compound as claimed in claim 12 of the formula I, where the substituent(s) are selected, independently of one another, from C1-C6-alkyl, NO2 and haloalkyl, in particular CF3, CHF2 and CF2Cl.

14. A pharmaceutical composition comprising at least one compound as claimed in claim 1, with physiologically acceptable vehicles and/or ancillary substances.

15. A method for treating schizophrenia, depression, neuroses or psychoses which comprises administering to a host a compound of claim 1.