# Patent

## Title
Heteroaryl fused aminoalkyl imidazole derivatives: selective modulators of GABAa receptors

## Abstract

Disclosed are compounds of the formula:




or the pharmaceutically acceptable non-toxic salts thereof wherein the A, B, C, D, X, R1, R2, R3, R4, R5, and R6, are variables defined herein, which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors, and are therefore useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, depression, overdose with benzodiazepine drugs, and enhancement of memory and alertness.

## Background
This application claims the benefit of U.S. Provisional Application No. 60/127,526, filed Apr. 2, 1999.


FIELD OF THE INVENTION
This invention relates to heteroaryl fused aminoalkylimidazole derivatives which when appropriately substituted selectively bind to GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down Syndrome, depression, sleep, seizure and cognitive disorders both in human as well as domestic pets and livestock.
The compounds of this invention are also useful as probes for the localization of cell surface receptors.
BACKGROUND
The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, γ-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization.
A number of cDNAs for GABAA receptor subunits have been characterized. To date at least 6α, 3β, 3γ, 1ε, 1δ and 2ρ subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2α, 2β, and 1γ subunits (Pritchett & Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are α1β2γ2, α2β3γ2, α3β3γ2, and α5β3γ2 (Mohler et. al. Neuroch. Res. 1995; 20(5): 631-636).
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site, the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABAA receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABAA receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABAA selective ligands may also act to potentiate the effects of certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when when used in combination with GABAA selective ligands than when used alone.
SUMMARY OF THE INVENTION
This invention relates to heteroaryl fused aminoalkyl-derivatives. Preferred compounds of the invention that bind with high affinity to the benzodiazepine site of the GABAA receptor, including human GABAA receptors. Preferred compounds of the invention also bind with high selectivity to the benzodiazepine site of the GABAA receptor.
The invention provides novel compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.
The invention further comprises methods of treating patients suffering from certain CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABAA receptors in tissue sections. Such probes are useful for in vitro studies, such as binding assays and autoradiography of tissue sections and for in vivo techniques such as PET and SPECT scans.
Packaged pharmaceutical compositions including instructions for use of the composition are also included.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
The invention furthermore provides methods of using compounds of this invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors, particularly GABAA receptors, in tissue sections. Such probes are useful for in vitro studies, such as binding assays and autoradiography of tissue sections and for in vivo techniques such as PET and SPECT scans.
Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:




or the pharmaceutically acceptable non-toxic salts thereof wherein:

    W represents






where Z is O, or S;

    R1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
    R2 represents hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5, 6, 7 member ring; or O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5, 6, 7 member heterocyclic ring;
    R3 represents C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6)alkylamino, additionally the alkyl portion can form a 5, 6, 7 member ring; or O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5, 6, 7 member heterocyclic ring, additional substitution on the benzyl ring can be directly bound or O(CH2)n (where n=1, 2, 3, 4) linked SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8, as well-as tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;
    R4, R5 and R6 are the same or different and represent hydrogen, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6)alkylamino, additionally the alkyl portion can form a 5, 6, 7 member ring, C1-C6 alkylthiol, or halogen, or O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, additionally R8 and R9 can be a 5, 6, 7 member heterocyclic ring, additionally R4 and R5 can form a 1,3-dioxolene ring;
    X represents a bond, CH2, or CHCH;
    A, B, C, D are the same or different and represent CH or N with the proviso that not more than two of A, B, C, or D represent N.


Preferred compounds of the invention are highly selective agonists, antagonists or inverse agonists for GABAA brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors, the benzodiazepine receptor. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, depression, sleep and seizure disorders, cognitive disorders overdose with benzodiazepine drugs, and enhancement of alertness, both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.
Thus, the invention also provides methods and compositions for treating and diagnosing anxiety, Down Syndrome, depression, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs.
In another aspect, the invention encompasses compounds that are intermediates in the synthesis of the compounds of Formula I.


DETAILED DESCRIPTION OF THE INVENTION
The compounds encompassed by the instant invention are represented by the general formula I:




or pharmaceutically acceptable non-toxic salts thereof wherein:

    W represents






where

    Z is O, or S;
    R1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
    R2 represents hydroxyl;
    
        C1-C6 alkyl or C1-C6 alkoxy, each of which are optionally substituted with amino, mono or di(C1-C6)alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
        O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl; or
        NR8R9 forms a 5-, 6-, or 7-membered heterocyclic ring;
    
    
    R3 represents
    
        C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or
        benzyl optionally mono-, di-, or trisubstituted independently with
        
            halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, or hydroxy;
            C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
            O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
            NR8R9 forms a 5-, 6-, 7-membered heterocyclic ring;
            SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8 where R8 is defined as above;
            O(CH2)n-G where n=1, 2, 3, 4 and G is SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, or CONHSO2R8, where R8 is as defined above; or
            tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl;
        
        
    
    
    R4, R5 and R6 are the same or different and represent hydrogen; or
    
        C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6)alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion, C1-C6 alkylthiol, or halogen;
        O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
        NR9R9 forms a 5-, 6-, or 7-membered heterocyclic ring; or
        R4 and R5 can form a 1,3-dioxolene ring;
    
    
    X represents a bond, CH2, or CHCH; and
    A, B, C, and D are the same or different and represent CH or N with the proviso that not more than two of A, B, C, or D represent N.


In formula I, R2 may also represent
hydrogen or
a group of the formula




    
    
        where
        Rn and Rk independently represent C1-C6 alkyl, C2-C6 alkenyl, C1-C6 cycloalkyl(C1-C6)alkyl, benzoyl where the phenyl portion is optionally substituted with halgoen, C1-C6 alkyl, or C1-C6 alkoxy;
        a group of the formula IV-a
    
    






    
    
        
        
            where p, s, and t independently represent 1 or 2;
            J is CH, N, O, S, or a carbon atom substituted with C1-C6 alkyl; or
        
        
        NRkRn represents
    
    






    
    
        where s, t, and J are as defined above.
    
    


Preferred compounds of the invention are represented by Formula II.




    R1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
    R2 represents hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5, 6, 7 member ring; or O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5, 6, 7 member heterocyclic ring;
    R3 represents C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6)alkylamino, additionally the alkyl portion can form a 5, 6, 7 member ring; or O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5, 6, 7 member heterocyclic ring, additional substitution on the benzyl ring can be directly bound or O(CH2)n (where n=1, 2, 3, 4) linked SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8, as well as tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;
    R4, R5 and R6 are the same or different and represent hydrogen, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6)alkylamino, additionally the alkyl portion can form a 5, 6, 7 member ring, C1-C6 alkylthiol, or halogen, or O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, additionally R8 and R9 can be a 5, 6, 7 member heterocyclic ring, additionally R4 and R5 can form a 1,3-dioxolene ring;
    X represents a bond, CH2, CHCH;
    A, B, C, D are the same or different and represent CH or N with the proviso that not more than two of A, B, C, or D represent N.


Other preferred compounds of the invention are represented by Formula III.




where Z is O, or S;

    R1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
    R2 represents hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6) alkylamino, additionally the alkyl portion can form a 5, 6, 7 member ring; or O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5, 6, 7 member heterocyclic ring;
    R3 represents C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6)alkylamino, additionally the alkyl portion can form a 5, 6, 7, member ring; or O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl, additionally R8 and R9 can be a 5, 6, 7 member heterocyclic ring, additional substitution on the benzyl ring can be directly bound or O(CH2)n (where n=1, 2, 3, 4) linked SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8, as well as tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;
    R4, R5 and R6 are the same or different and represent hydrogen, C1-C6 alkyl or C1-C6 alkoxy, either of which could be substituted with amino or mono or di(C1-C6)alkylamino, additionally the alkyl portion can form a 5, 6, 7 member ring, C1-C6 alkylthiol, or halogen, or O(CH2)nCO2R9 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, additionally R8 and R9 can be a 5, 6, 7 member heterocyclic ring, additionally R4 and R5 can form a 1,3-dioxolene ring;
    X represents a bond, CH2, CHCH;
    A, B, C, D are the same or different and represent CH or N with the proviso that not more than two of A, B, C, or D represent N.


More preferred compounds of Formula I are represented by Formula IV




where

    R4, R5, and R6 are as defined above for Formula I;
    R1 and R3 are independently C1-C6 alkyl;
    and Ra and Rb are independently


hydrogen or
a group of the formula




    
    
        where
        Rn and Rk independently represent C1-C6 alkyl, C2-C6 alkenyl, C1-C6 cycloalkyl(C1-C6)alkyl, benzoyl where the phenyl portion is optionally substituted with halgoen, C1-C6 alkyl, or C1-C6 alkoxy;
        a group of the formula IV-a
    
    






    
    
        
        
            where p, s, and t independently represent 1 or 2;
            J is CH, N, O, or a carbon atom substituted with C1-C6 alkyl; or
        
        
        NRkRn represents
    
    






    
    
        where s, t, and J are as defined above.
    
    


Preferred compounds of Formula IV include those where R1 is propyl and R3 is C3-C5 alkyl, preferably isobutyl. More preferred compounds of IV are those where Rb is hydrogen and Ra is —NHRn where Rn is defined as above or —NRkRn where both Rn and Rk are allyl or C1-C6 alkyl.
Preferred —NRkRn groups include diallylamino, dimethylamino, diethylamino, and N-ethyl-N-cyclopropylmethylamino.
Preferred NHRn groups include those where Rn is allyl, C1-C6 alkyl, or a group of IV-a. Preferred IV-a groups include pyrrolidinyl, morpholinyl and piperidinyl.
Particularly preferred compounds of IV are those where R1 is propyl, R3 is isobutyl, Rb is hydrogen, and Ra is
In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds described in the Examples and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH2)n—COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
By “alkyl” or “lower alkyl” in the present invention is meant C1-C6 alkyl, i.e., straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. Preferred C1-C6 alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl or cyclopropylmethyl.
By “alkoxy” or “lower alkoxy” in the present invention is meant C1-C6 alkoxy, i.e., straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
By (hetero) cyclic ring is meant a ring that is either aliphatic or aromatic and optionally contains at least one hetero atom. Hetero atoms include nitrogen, sulfur, and oxygen. Examples of such (hetero) cyclic rings are cyclohexyl, cyclopenyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, etc.
By heteroaryl (aromatic heterocycle) in the present invention is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four hetero atoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, imidazolyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.
Specific examples of heteroaryl groups are the following:




wherein

L is nitrogen or —CR11;
T is —NR19, oxygen, or sulfur;

    
    
        R11 and R11f are the same or different and are selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, (C1-C6)alkoxy, amino, or mono- or di(C1-C6)alkylamino;
        R2, R2f, and R13 are the same or different and are selected from hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, amino, mono- or di(C1-C6)alkylamino, hydroxy, or trifluoromethyl; and
        R19 is hydrogen, lower alkyl having 1-6 carbon atoms.
    
    


The invention encompasses all possible tautomers and rotamers represented by Formula I.
By the term “halogen” in the present invention is meant fluorine, bromine, chlorine, and iodine.
Aryl and heteroaryl fused aminoalkyl-imidazoles of Formula I and their salts are suitable for the diagnosis and treatment of anxiety, Down Syndrome, sleep and seizure disorders, overdoses of benzodiazepine-type drugs, depression and cognitive disorders and for the enhancement of alertness, both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle. These interactions result in the pharmacological activites of these compounds.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety or depression a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously. Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).
The present invention also pertains to packaged pharmaceutical compositions for treating disorders responsive to GABAA receptor modulation, e.g., treatment of cognitive deficits, anxiety or depression by GABAA receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABAA receptor ligand is to be used for treating a disorder responsive to GABAA receptor modulation in the patient.
The present invention also pertains to methods for altering the signal-tranducing activity of GABAA receptors, said method comprising exposing cells expressing such receptor to an effective amount of a compound of the invention.
A method of inhibiting the binding of a benzodiazepine compound to the benzodiazepine site of the GABAA receptor, comprising contacting a compound of Formula I with cells expressing such a receptor in the presence of a the benzodiazepine compound, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine compound binding to cells expressing a cloned human GABAA receptor in vitro is provided by a separate aspect of the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer's dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.
Combination administration can be carried out in an analogous fashion to that disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; and Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(S-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalzine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
The disclosures of all articles and references mentioned in in this application, including patents, are incorporated herein by reference.
The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Compounds of the invention can be prepared using the reactions depicted in Schemes I to VI.




















Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples.
The following examples illustrate the general procedures for the preparation of compounds of the invention using the reactions outlined above in Schemes I-VI. These examples are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.
Analysis is performed on a Hewlett Packard 6890 GC, equipped with a dual cool on-column inlets and flame ionization detectors or mass spec detectors. All gas flows are regulated via electronic pneumatic control. The analytical column used is a Supelco PTE-5 QTM, 15 m×0.53 mm ID×0.50 μm film. GC instrument control and data collection are handled using a Perkin Elmer TurboChrom Client/Server data system. GC conditions: On-column injector 163 C for 2.5 min., ramp at 40 C/min to 323 C. Oven program 100 C for 1 minute, ramp at 40 C/min to 320 C. Detector temperature is set at 325 C. GC conditions: for compounds 7-12 initial temperature 200 C, ramp to 300 C at 20 C/min on a 12 m, DB-5 column.
EXAMPLE 1
General Procedure for the Preparation of Chloromethylbenzimidazoles as Outlined in Scheme I
1. Imidate Hydrochloride
A solution of 150 mL (2.37 mole) of chloroacetonitrile, 139 mL (2.37 mole) of ethanol in 1,200 mL of dry benzene is cooled to 0° C. in an ice/ethanol bath. Dry HCl gas is bubbled through the vigorously stirred solution for approximately 30 min. while the internal temperature is maintained below 10° C. The solution is allowed to stand at rt. overnight. The resulting solid is filtered and washed with 2 L of dry ether and allowed to air dry to afford 328 g (88%) of imidate hydrochloride.
2. 1-n-Propyl-2-(chloromethyl)-5-fluorobenzimidazole:




A solution of 11.25 g (0.07 mole) of 2-n-Propyl-5-fluorophenelyenediamine in 200 mL of anhydrous CHCl3 is treated with 11.06 g (0.07 mole) of imidate at room temperature. The heterogeneous reaction mixture is allowed to stir for 45 min. at which time no starting material is detectable by TLC. 100 mL of saturated NaHCO3 is added and extracted 3×50 mL of CH2Cl2. The extracts are dried over anhydrous MgSO4, the solvent removed in vacuo, and the residue chromatgraphed (SiO2) with 50% ethyl acetate/hexane to afford 15 g (95%) of 1-n-Propyl-2-(chloromethyl)-5-fluorobenzimidazole.
EXAMPLE 2
General Procedure for the Preparation of Benzimidazoles as Shown in Scheme II
N-[benzoyl]-N-methyl-1-n-propyl-2-(methanamine)-5-fluorobenzimidazole




A solution of 8 mmole of 1-n-Propyl-2-(chloromethyl)-5-fluorobenzimidazole (alternatively named 2-(chloromethyl)-5-fluoro-1-propylbenzimidazole) in 20 mL of dry Acetonitrile is treated with 10 mL of 40% aqueous methylamine for 16 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 1.68 g 95% of 1-n-Propyl-2-(methanamine)-5-fluorobenzimidazole. Benzoylchloride 1.5 eq is treated with of 1-n-Propyl-2-(methanamine)-5-fluorobenzimidazole 1.0 eq in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried with Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 95% of N-[benzoyl]-N-methyl-1-n-propyl-2-(methanamine)-5-fluorobenzimidazole [alternatively named N-((5-fluorobenzimidazol-2-yl)methyl)-N-methylbenzamide] (Compound A1).
EXAMPLE 3
General Procedure for the Preparation of Benzimidazoles as Shown in Scheme 3
(2,5-difluorophenyl)-N-{[5-(morpholin-4-ylmethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide




A solution of 20 g (0.095 mole) of [3-nitro-4-(propylamino)phenyl]methan-1-ol and 19.2 g (0.28 mole) of imidazole in 200 mL of anhydrous DMF is treated with 19 g (0.13 mole) of t-butyldimethylsilyl chloride at room temperature for 30 min. The resulting mixture is diluted with 400 mL of ethyl acetate and washed 3×200 mL of water and 1×200 mL of brine. The resulting orgainc layer is dried over anhydrous Na2SO4 and the solvent removed in vacuo. The resulting oil is column chromatographed 5% ethyl acetate/hexanes to afford 11 g (35%) of {2-nitro-4-[(1,1,2,2-tetramethy-1-silapropoxy)methyl]phenyl}propylamine.
A solution of 11 g (0.033 mole) of {2-nitro-4-[(1,1,2,2-tetramethy-1-silapropoxy)methyl]phenyl}propylamine in 100 mL of ethanol and 1 g 10% Pd/C is treated with 50 psi of H2 at room temperature for 2 hr. The resulting mixture is filtered through celite, washed with 200 mL of ethanol and the solvent removed in vacuo. The crude material is treated with 9.7 g (0.06 mole) of imidate hydrochloride in 250 mL of chloroform at room temperature for 1 hr. The reaction mixture is partitioned between 200 mL sat NaHCO3 and 200 mL of chloroform. The organic layer is dried over anhydrous anhydrous Na2SO4 and the solvent removed in vacuo. The resulting oil is column chromatographed 50% ethyl acetate/hexanes to afford 6 g (52% for 2 steps) of 1-{([2-(chloromethyl)-1-propylbenzimidazol-5-yl]methoxy}-1,1,2,2-tetramethyl-1-silapropane.
A solution of 2.0 g (5.6 mmole) of 1-{[2-(chloromethyl)-1-propylbenzimidazol-5-yl]methoxy}-1,1,2,2-tetramethyl-1-silapropane in 20 mL of anhydrous acetonitrile is treated with 10 mL of propylamine for 16 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 2.1 g (99%) of propyl({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)amine.
2,5-difluorobenzoylchloride 1.5 eq is treated with 1.0 eq 1.25 g (3.3 mmole) of propyl({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)amine in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried over anhydrous Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 74% of (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamide.
A solution 1.25 g (2.4 mmole) of (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamide in 20 mL of THF is treated at room temperature with 3 mL of 1M tetrabutylammonium fluoride for 1 hr. The reaction solution is diluted with 20 mL of sat NaHCO3 and extracted with 3×100 mL of dichloromethane. The organic extracts are dried over anhydrous Na2SO4 and the solvent removed in vacuo to afford 0.96 g (99%) of (2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.
(2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide 0.96 g (2.3 mmole) is treated with 30 mL of thionyl chloride for 15 min a room temperature. The resulting mixture is concentrated in vacuo and partitioned between 100 mL sat NaHCO3 and 100 mL of ethyl acetate. The ethyl acetate layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting oil is chroamtoagraphed 50% ethyl acetate/hexanes to afford 0.9 g (93%) of (2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl)-N-propylcarboxamide.
A solution of 0.2 mL of 0.2M (2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl)-N-propylcarboxamide in 1-methyl-2-pyrrolidinone is treated at room temperature for 16 hr with 0.3 mL of 0.2M solution of morpholine in toluene. The resulting mixture is diluted with 2 mL of ethyl acetate and washed 2×2 mL of water 1×2 mL brine. The ethyl acetate layer is dried over anhydrous Na2SO4 and concentrated in vacuo to afford 70% of (2,5-difluorophenyl)-N-{[5-(morpholin-4-ylmethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.
EXAMPLE 4
The following compounds are prepared essentially according to the procedure described in Examples 1-5, and as shown in Schemes 1-6:




(a) (2,5-difluorodifluorophenyl)-N-methyl-N-((1-propylbenzimidazol-2-yl)methyl)carboxamide (Compound A5); GC retention time=5.26 minutes.





(b) N-((3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl)methyl) (3-fluorophenyl)-N-propylcarboxamide (Compound A6); GC retention time=5.07 minutes.





(c) N-[(3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl)methyl](2,5-difluorophenyl)-N-propylcarboxamide (Compound A7); GC retention time=4.80 minutes.





(d) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](2,5-difluorophenyl)-N-propylcarboxamide (Compound A8); GC retention time=MS (CI) M+453 amu.





(e) N-({5-(diethylamino)methyl]-1-butylbenzimidazol-2-yl}methyl) (3-fluorophenyl)-N-propylcarboxamide (Compound A9); GC retention time=5.96 minutes.





(f) N-((3-n-butyl-imidazolo[5,4-b]pyridin-2-yl)methyl](3-iodophenyl)-N-propylcarboxamide (Compound A10); GC retention time=6.12 minutes.

(g) N-[(7-chloro-1-propylbenzimidazol-2-yl)methyl](3-fluorophenyl)-N-methylcarboxamide M+361 amu

(h) N-[(7-chloro-1-propylbenzimidazol-2-yl)methyl](3-fluorophenyl)-N-propylcarboxamide M+389 amu

(i) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]{3-[(methylamino)methyl]phenyl)-N-propylcarboxamide M+414 amu

(j) (3-fluorophenyl)-N-[(4-fluoro-1-propylbenzimidazol-2-yl)methyl]-N-propylcarboxamide M+372 amu

(k) (2,5-difluorophenyl)-N-([1-(cyclopropylmethyl)benzimidazol-2-yl]methyl}-N-propylcarboxamide M+384 amu

(l) N-([5-(N,N-diethylcarbamoyl)-1-propylbenzimidazol-2-yl]methyl}(3-fluorophenyl)-N-propylcarboxamide M+454 amu

(m) (2,5-difluorophenyl)-N-[(4-fluoro-1-propylbenzimidazol-2-yl)methyl]-N-propylcarboxamide M+391 amu

(n) N-{[6-chloro-1-(cyclopropylmethyl)benzimidazol-2-yl]methyl}(3-fluorophenyl)-N-propylcarboxamide M+401 amu

(o) (2,5-difluorophenyl)-N-({5-[(ethylamino)methyl]-1-propylbenzimidazol-2-yl}methyl)-N-propylcarboxamide M+430 amu

(p) (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(propylamino)methyl]benzimidazol-2-yl}methyl)carboxamide M+444 amu

(q) (2,5-difluorophenyl)-N-({5-[(methylamino)methyl]-1-propylbenzimidazol-2-yl}methyl)-N-propylcarboxamide M+416 amu

(r) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](4-[2-(ethylamino)ethoxy]phenyl)-N-(3-methylbutyl)carboxamide M+486 amu

(s) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(3-methylbutyl){4-[2-(propylamino)ethoxy]phenyl}carboxamide M+500 amu

(t) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](2-methyl(1,3-thiazol-4-yl))-N-(2-methylpropyl)carboxamide M+406 amu

(u) (5-bromo(2-thienyl))-N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(2-methylpropyl)carboxamide M+470 amu

(v) [3-(2-bromoethoxy)phenyl]-N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(2-methylpropyl)carboxamide M+508 amu

(w) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(2-methylpropyl)(3-[2-(propylamino)ethoxy]phenyl}carboxamide M+486 amu

(x) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](3-{2-[(2-methoxyethyl)amino]ethoxy}phenyl)-N-(2-methylpropyl)carboxamide M+502 amu

(y) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](3-{2-[(2-ethoxyethyl)amino]propoxy}phenyl)-N-(2-methylpropyl)carboxamide M+530 amu

(z) N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](3-(2-{[2-(methylethoxy)ethyl]amino}propoxy)phenyl]-N-(2-methylpropyl)carboxamide M+544 amu

EXAMPLES 5-41
The compounds of Examples 5-41 are prepared essentially according to the procedure described in Examples 1-3, and as shown in Schemes 1-6. These compounds are represented by the formulae presented in each of the examples with the definitions of the substituents found within the table. It is noted for the reader that the R2 and R3 groups used in these formulae are not the same R2 and R3 groups used in Formula I.
Structures for the compounds of Examples 5-42 are shown in Appendices 1 and 2 hereto.
EXAMPLE 5




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R2
R3

















1
Methyl
3-Fluorophenyl


2
Allyl
3-Fluorophenyl


3
Propyl
3-Fluorophenyl


4
Allyl
3-Fluorophenyl


5
Propyl
3-Fluorophenyl


6
Propyl
3,4-Difluorophenyl


7
Allyl
2,5-Difluorophenyl


8
Propyl
2,5-Difluorophenyl


9
Propyl
1,3-Benzodioxol-5-yl


10
Allyl
3-Chloro-4-fluorophenyl


11
Propyl
3-Chloro-4-fluorophenyl


12
Methyl
5-Chloro-2-methoxyphenyl


13
3-Methylbutyl
3-{2-[(3-




Methoxypropyl)amino]ethoxy}




phenyl


14
3-Methylbutyl
3-{2-[(3-




Ethoxypropyl)amino]ethoxy}




phenyl


15
3-Methylbutyl
3-{2-[(3-




Ethoxypropyl)amino]ethoxy}




phenyl


16
3-Methylbutyl
3-[2-(Benzylamino)




ethoxy]phenyl


17
3-Methylbutyl
3-[2-(Benzylamino)




ethoxy]phenyl


18
2-Methylpropyl
3-{2-[(3-i-




Propoxypropyl)amino]ethoxy}




phenyl


19
3-Methylbutyl
3-{2-[(3-i-




Propoxypropyl)amino]ethoxy}




phenyl


20
Benzyl
3-Chloro-2-thienyl


21
4-Fluorobenzyl
3-Chloro-2-thienyl


22
Benzyl
3-Chloro-4-methylphenyl


23
2-Fluorobenzyl
3-Chloro-4-methylphenyl


24
4-Fluorobenzyl
3-Chloro-4-methylphenyl


25
4-Fluorobenzyl
2-Fluoro-6-trifluoromethylphenyl


26
4-Fluorobenzyl
3,5-Dibromophenyl


27
Pentyl
3-Bromophenyl


28
3-Methylbutyl
3-Bromophenyl


29
2-Methylpropyl
4-Bromophenyl


30
3-Methylbutyl
4-Bromophenyl


31
Butyl
2-Bromophenyl


32
Pentyl
2-Bromophenyl


33
3-Methylbutyl
2-Bromophenyl


34
3-Methylbutyl
3-Methoxyphenyl


35
3-Methylbutyl
2-Methoxyphenyl


36
3-Methylbutyl
3-Chlorophenyl


37
3-Methylbutyl
2-Chlorophenyl


38
3-Methylbutyl
2-Chlorophenyl


39
Ethyl
5-Chloro-2-methoxyphenyl


40
Allyl
5-Chloro-2-methoxyphenyl


41
Propyl
5-Chloro-2-methoxyphenyl


42
Methyl
2,5-Dichlorophenyl


43
Allyl
2,5-Dichlorophenyl


44
Propyl
2,5-Dichlorophenyl


45
Propyl
5-Methyl-2-thienyl


46
Propyl
Phenyl


47
Propyl
3-Methylphenyl


48
Propyl
3-Fluoro-4-methylphenyl


49
Allyl
5-Fluoro-2-methylphenyl


50
Propyl
5-Fluoro-2-methylphenyl


51
Benzyl
2,3,5,6-Tetrafluorophenyl


52
4-Fluorobenzyl
2,3,5,6-Tetrafluorophenyl


53
Benzyl
2,4,6-Trifluorophenyl


54
Benzyl
2,3,6-Trifluorophenyl


55
4-Fluorobenzyl
2,3,6-Trifluorophenyl


56
4-Fluorobenzyl
2-Chloro-6-fluorophenyl


57
Benzyl
2-Fluoro-6-trifluoromethylphenyl


58
2-Methylpropyl
3-(2-{[(4-Methylphenyl)




methyl]amino}




ethoxy)phenyl


59
3-Methylbutyl
3-{2-[(2-Cyclohex-1-enylethyl)




amino]ethoxy}




phenyl


60
2-Methylpropyl
3-(2-{[(2-Methylphenyl)




methyl]amino}




ethoxy)phenyl


61
2-Methylpropyl
3-(2-{[(3-Methylphenyl)




methyl]amino}




ethoxy)phenyl


62
2-Methylpropyl
3-(2-{[(2-Methoxyphenyl)




methyl]amino}




ethoxy)phenyl


63
2-Fluorobenzyl
3-Iodo-4-methylphenyl


64
4-Fluorobenzyl
3-Iodo-4-methylphenyl


65
4-Fluorobenzyl
2-Thienyl


66
Benzyl
2-Thienyl


67
4-Fluorobenzyl
2-Thienyl


68
Benzyl
3-Methyl-2-thienyl


69
4-Fluorobenzyl
3-Methyl-2-thienyl


70
Benzyl
5-Methyl-2-thienyl


71
2-Fluorobenzyl
5-Methyl-2-thienyl


72
4-Fluorobenzyl
5-Methyl-2-thienyl


73
4-Fluorobenzyl
4,5-Dimethyl-2-furyl


74
2-Methylpropyl
3,4-Dichlorophenyl


75
Pentyl
3,4-Dichlorophenyl


76
3-Methylbutyl
3,4-Dichlorophenyl


77
3-Methylbutyl
3,5-Dichlorophenyl


78
3-Methylbutyl
2,3-Dichlorophenyl


79
Butyl
2,5-Dichlorophenyl


80
2-Methylpropyl
2,5-Dichlorophenyl


81
Pentyl
2,5-Dichlorophenyl


82
3-Methylbutyl
2,5-Dichlorophenyl


83
Butyl
2,4-Dichlorophenyl


84
2-Methylpropyl
2,4-Dichlorophenyl


85
3-Methylbutyl
2,4-Dichlorophenyl


86
Allyl
3-Chlorophenyl


87
Propyl
3-Chlorophenyl


88
Propyl
2,3,6-Trifluorophenyl


89
Methyl
5-Chloro-2-methoxyphenyl


90
Ethyl
5-Chloro-2-methoxyphenyl


91
Allyl
5-Chloro-2-methoxyphenyl


92
Methyl
2,5-Dichlorophenyl


93
Methyl
3-Bromophenyl


94
Ethyl
3-Bromophenyl


95
Propyl
3-Bromophenyl


96
Methyl
3-Bromo-4-fluorophenyl


97
Methyl
3-Iodophenyl


98
3-Methylbutyl
3-(2-{[(2-Methoxyphenyl)




methyl]amino}




ethoxy)phenyl


99
2-Methylpropyl
3-(2-{[(3-Methoxyphenyl)




methyl]amino}




ethoxy)phenyl


100
2-Methylpropyl
3-(2-{[(4-Methoxyphenyl)




methyl]amino}




ethoxy)phenyl


101
2-Methylpropyl
3-(2-{[(2-Chlorophenyl)




methyl]amino}




ethoxy)phenyl


102
Benzyl
2,5-Dimethoxyphenyl


103
2-Fluorobenzyl
2,5-Dimethoxyphenyl


104
4-Fluorobenzyl
2,5-Dimethoxyphenyl


105
Butyl
4-Pentylphenyl


106
2-Methylpropyl
4-Pentylphenyl


107
3-Methylbutyl
4-Pentylphenyl


108
Butyl
3-Bromophenyl


109
2-Methylpropyl
3-Bromophenyl


110
Pentyl
3-Bromophenyl


111
3-Methylbutyl
3-Bromophenyl


112
2-Methylpropyl
4-Bromophenyl


113
3-Methylbutyl
4-Bromophenyl


114
Butyl
2-Bromophenyl


115
Pentyl
2-Bromophenyl


116
3-Methylbutyl
2-Bromophenyl


117
Ethyl
3-Iodophenyl


118
Allyl
3-Iodophenyl


119
Propyl
3-Chloro-4-methylphenyl


120
Propyl
5-Bromo-2-thienyl


121
Ethyl
Phenyl


122
Allyl
Phenyl


123
Propyl
Phenyl


124
Allyl
3-Methylphenyl


125
Propyl
3-Methylphenyl


126
Propyl
4-Methylphenyl


127
Methyl
3-Fluorophenyl


128
Propyl
3-Fluorophenyl


129
Butyl
3-Chloro-4-methoxyphenyl


130
2-Methylpropyl
3-Chloro-4-methoxyphenyl


131
3-Methylbutyl
3-Chloro-4-methoxyphenyl


132
Butyl
5-Chloro-2-methoxyphenyl


133
2-Methylpropyl
5-Chloro-2-methoxyphenyl


134
Pentyl
5-Chloro-2-methoxyphenyl


135
3-Methylbutyl
5-Chloro-2-methoxyphenyl


136
Butyl
3-Trifluoromethylphenyl


137
Pentyl
3-Trifluoromethylphenyl


138
3-Methylbutyl
3-Trifluoromethylphenyl


139
3-Methylbutyl
2-Trifluoromethylphenyl


140
Butyl
3,4-Dichlorophenyl


141
Propyl
4-Fluorophenyl


142
Methyl
2-Fluorophenyl


143
Allyl
2-Fluorophenyl


144
Propyl
2-Fluorophenyl


145
Propyl
3-Fluoro-4-methylphenyl


146
Methyl
5-Fluoro-2-methylphenyl


147
Propyl
5-Fluoro-2-methylphenyl


148
Methyl
3-Chlorophenyl


149
Allyl
3-Chlorophenyl


150
Propyl
3-Chlorophenyl


151
3-Methylbutyl
4-Hexylphenyl


152
3-Methylbutyl
2-Fluoro-3-




trifluoromethylphenyl


153
Butyl
2,5-Dichlorophenyl


154
2-Methylpropyl
2,5-Dichlorophenyl


155
Pentyl
2,5-Dichlorophenyl


156
3-Methylbutyl
2,5-Dichlorophenyl


157
Butyl
2,4-Dichlorophenyl


158
2-Methylpropyl
2,4-Dichlorophenyl


159
3-Methylbutyl
2,4-Dichlorophenyl


160
Butyl
4-Pentylphenyl


161
2-Methylpropyl
4-Pentylphenyl


162
3-Methylbutyl
4-Pentylphenyl


163
Butyl
3-Bromophenyl


164
2-Methylpropyl
3-Bromophenyl


165
2-Methylpropyl
3-Bromo-4-methylphenyl


166
3-Methylbutyl
3-Bromo-4-methylphenyl


167
Butyl
3-Bromo-4-fluorophenyl


168
2-Methylpropyl
3-Bromo-4-fluorophenyl


169
3-Methylbutyl
3-Bromo-4-fluorophenyl


170
Butyl
3-Iodophenyl


171
2-Methylpropyl
3-Iodophenyl


172
Pentyl
3-Iodophenyl


173
3-Methylbutyl
3-Iodophenyl


174
2-Methylpropyl
4-Iodophenyl


175
3-Methylbutyl
3-Iodo-4-methylphenyl


176
Butyl
2-Thienyl


177
Pentyl
2-Thienyl


178
3-Methylbutyl
2-Thienyl


179
Butyl
3-Thienyl


180
Pentyl
3-Thienyl


181
3-Methylbutyl
3-Thienyl


182
3-Methylbutyl
Benzyl


183
Butyl
3-Methyl-2-thienyl


184
Pentyl
3-Methyl-2-thienyl


185
3-Methylbutyl
3-Methyl-2-thienyl


186
Pentyl
3-Methyl-5-thienyl


187
3-Methylbutyl
3-Methyl-5-thienyl


188
3-Methylbutyl
3-Methylphenyl


189
2-Methylpropyl
5-Chloro-2-methoxyphenyl


190
Pentyl
5-Chloro-2-methoxyphenyl


191
3-Methylbutyl
5-Chloro-2-methoxyphenyl


192
Butyl
3-Trifluoromethylphenyl


193
Pentyl
3-Trifluoromethylphenyl


194
3-Methylbutyl
3-Trifluoromethylphenyl


195
3-Methylbutyl
2-Trifluoromethylphenyl


196
Butyl
3,4-Dichlorophenyl


197
2-Methylpropyl
3,4-Dichlorophenyl


198
3-Methylbutyl
3,4-Dichlorophenyl


199
3-Methylbutyl
3,5-Dichlorophenyl


200
3-Methylbutyl
2,3-Dichlorophenyl


201
Butyl
Phenyl


202
Pentyl
Phenyl


203
3-Methylbutyl
Phenyl


204
Pentyl
3-Methylphenyl


205
3-Methylbutyl
3-Methylphenyl


206
2-Methylpropyl
4-Methylphenyl


207
3-Methylbutyl
4-Methylphenyl


208
Pentyl
2-Methylphenyl


209
3-Methylbutyl
2-Methylphenyl


210
Butyl
3-Fluorophenyl


211
2-Methylpropyl
3-Fluorophenyl


212
Pentyl
3-Fluorophenyl


213
3-Methylbutyl
3-Fluorophenyl


214
Pentyl
4-Fluorophenyl


215
3-Methylbutyl
4-Fluorophenyl


216
Pentyl
2-Fluorophenyl


217
3-Methylbutyl
2-Fluorophenyl


218
2-Methylpropyl
3,4-Dimethylphenyl


219
3-Methylbutyl
3,4-Dimethylphenyl


220
Pentyl
2,5-Dimethylphenyl


221
3-Methylbutyl
2,5-Dimethylphenyl


222
2-Methylpropyl
2,4-Dimethylphenyl


223
3-Methylbutyl
2,4-Dimethylphenyl


224
2-Methylpropyl
3-Methoxyphenyl


225
Pentyl
3-Methoxyphenyl


226
3-Methylbutyl
3-Methoxyphenyl


227
2-Methylpropyl
4-Methoxyphenyl


228
3-Methylbutyl
4-Methoxyphenyl


229
Pentyl
2-Methoxyphenyl


230
3-Methylbutyl
2-Methoxyphenyl


231
2-Methylpropyl
3-Fluoro-4-methylphenyl


232
Pentyl
3-Fluoro-4-methylphenyl


233
3-Methylbutyl
3-Fluoro-4-methylphenyl


234
3-Methylbutyl
3-Fluoro-2-methylphenyl


235
2-Methylpropyl
5-Fluoro-2-methylphenyl


236
Pentyl
5-Fluoro-2-methylphenyl


237
2-Methylpropyl
3-Chloro-4-fluorophenyl


238
Pentyl
3-Chloro-4-fluorophenyl


239
3-Methylbutyl
3-Chloro-4-fluorophenyl


240
3-Methylbutyl
3,4,5-Trifluorophenyl


241
3-Methylbutyl
4-Butylphenyl


242
Pentyl
4-i-propylphenyl


243
3-Methylbutyl
4-i-propylphenyl


244
Butyl
4-Ethylthiophenyl


245
2-Methylpropyl
4-Ethylthiophenyl


246
3-Methylbutyl
4-Ethylthiophenyl


247
3-Methylbutyl
3-Chloro-4-methoxyphenyl


248
Butyl
5-Chloro-2-methoxyphenyl


249
3-Methylbutyl
5-Fluoro-2-methylphenyl


250
2-Methylpropyl
2-Fluoro-3-methylphenyl


251
Pentyl
2-Fluoro-3-methylphenyl


252
3-Methylbutyl
2-Fluoro-3-methylphenyl


253
2-Methylpropyl
3-Chlorophenyl


254
Pentyl
3-Chlorophenyl


255
3-Methylbutyl
3-Chlorophenyl


256
2-Methylpropyl
4-Chlorophenyl


257
3-Methylbutyl
4-Chlorophenyl


258
3-Methylbutyl
2-Chlorophenyl


259
3-Methylbutyl
3,4-Difluorophenyl


260
3-Methylbutyl
1,2-Difluorophenyl


261
Pentyl
2,5-Difluorophenyl


262
3-Methylbutyl
2,5-Difluorophenyl


263
Pentyl
2,4-Difluorophenyl


264
3-Methylbutyl
2,4-Difluorophenyl


265
3-Methylbutyl
4-Propylphenyl


266
Pentyl
1,3-Benzodioxol-5-yl


267
3-Methylbutyl
1,3-Benzodioxol-5-yl


268
3-Methylbutyl
4-Methylthiophenyl


269
3-Methylbutyl
3-Fluoro-4-methoxyphenyl


270
2-Methylpropyl
4-Chloro-3-methylphenyl


271
3-Methylbutyl
4-Chloro-3-methylphenyl


272
Butyl
3-Chloro-4-fluorophenyl









EXAMPLE 6




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R2
R3







273
2-Methylpropyl
2,4,6-Trifluorophenyl


274
3-Methylbutyl
2,4,6-Trifluorophenyl


275
2-Methylpropyl
2,3,6-Trifluorophenyl


276
Pentyl
2,3,6-Trifluorophenyl


277
3-Methylbutyl
2,3,6-Trifluorophenyl


278
Pentyl
2-Chloro-6-fluorophenyl


279
3-Methylbutyl
2-Chloro-6-fluorophenyl


280
Pentyl
2-Fluoro-6-




trifluoromethylphenyl


281
3-Methylbutyl
2-Fluoro-6-




trifluoromethylphenyl


282
Pentyl
3-Bromo-4-fluorophenyl


283
2-Methylpropyl
4-Hexylphenyl


284
Butyl
4-Pentoxyphenyl


285
2-Methylpropyl
4-Pentoxyphenyl


286
Butyl
2-Fluoro-3-




trifluoromethylphenyl


287
2-Methylpropyl
2-Fluoro-3-




trifluoromethylphenyl


288
3-Methylbutyl
3-Bromo-4-fluorophenyl


289
2-Methylpropyl
4-heptylphenyl


290
Butyl
3-Iodophenyl


291
2-Methylpropyl
3-Iodophenyl


292
Pentyl
3-Iodophenyl


293
3-Methylbutyl
3-Iodophenyl


294
Butyl
4-Iodophenyl


295
2-Methylpropyl
4-Iodophenyl


296
2-Methylpropyl
4-Pentylphenyl


297
3-Methylbutyl
2-Fluoro-3-




trifluoromethylphenyl


298
Butyl
3-Bromo-4-methylphenyl


299
2-Methylpropyl
3-Bromo-4-methylphenyl


300
Pentyl
3-Bromo-4-methylphenyl


301
3-Methylbutyl
3-Bromo-4-methylphenyl


302
Butyl
3-Bromo-4-fluorophenyl


303
2-Methylpropyl
3-Bromo-4-fluorophenyl


304
3-Methylbutyl
3,4-Dichlorophenyl


305
Butyl
2,3-Dichlorophenyl


306
2-Methylpropyl
2,3-Dichlorophenyl


307
3-Methylbutyl
2,3-Dichlorophenyl


308
Butyl
2,5-Dichlorophenyl


309
Butyl
3-Bromophenyl


310
2-Methylpropyl
3-Bromophenyl


311
Pentyl
3-Bromophenyl


312
3-Methylbutyl
3-Bromophenyl


313
Butyl
4-Bromophenyl


314
2-Methylpropyl
4-Bromophenyl


315
3-Methylbutyl
4-Bromophenyl


316
Butyl
2-Bromophenyl


317
Pentyl
2-Bromophenyl


318
3-Methylbutyl
2-Bromophenyl


319
Pentyl
4-Hexylphenyl


320
2-Methylpropyl
4-Chloro-2-methoxyphenyl


321
2-Methylpropyl
2,5-Dichlorophenyl


322
Pentyl
2,5-Dichlorophenyl


323
3-Methylbutyl
2,5-Dichlorophenyl


324
Butyl
2,4-Dichlorophenyl


325
2-Methylpropyl
2,4-Dichlorophenyl


326
Pentyl
2,4-Dichlorophenyl


327
3-Methylbutyl
2,4-Dichlorophenyl


328
2-Methylpropyl
2,5-Dimethoxyphenyl


329
Pentyl
2,5-Dimethoxyphenyl


330
3-Methylbutyl
2,5-Dimethoxyphenyl


331
2-Methylpropyl
2,4-Dimethoxyphenyl


332
3-Methylbutyl
2,4-Dimethoxyphenyl


333
Pentyl
4-Chloro-2-methoxyphenyl


334
3-Methylbutyl
4-Chloro-2-methoxyphenyl


335
Butyl
3-Trifluoromethylphenyl


336
2-Methylpropyl
3-Trifluoromethylphenyl


337
Pentyl
3-Trifluoromethylphenyl


338
3-Methylbutyl
3-Trifluoromethylphenyl


339
2-Methylpropyl
4-Trifluoromethylphenyl


340
Butyl
2-Trifluoromethylphenyl


341
3-Methylbutyl
2-Trifluoromethylphenyl


342
Butyl
3,4-Dichlorophenyl


343
2-Methylpropyl
3,4-Dichlorophenyl


344
Butyl
4-Methylthiophenyl


345
Butyl
3-Chloro-4-methoxyphenyl


346
2-Methylpropyl
3-Chloro-4-methoxyphenyl


347
3-Methylbutyl
3-Chloro-4-methoxyphenyl


348
Butyl
5-Chloro-2-methoxyphenyl


349
2-Methylpropyl
5-Chloro-2-methoxyphenyl


350
Pentyl
5-Chloro-2-methoxyphenyl


351
3-Methylbutyl
5-Chloro-2-methoxyphenyl


352
Butyl
2,5-Difluorophenyl


353
2-Methylpropyl
2,5-Difluorophenyl


354
Pentyl
2,5-Difluorophenyl


355
3-Methylbutyl
2,5-Difluorophenyl


356
Butyl
2,4-Difluorophenyl


357
2-Methylpropyl
4-Methylthiophenyl


358
Butyl
3-Fluoro-4-methoxyphenyl


359
2-Methylpropyl
3-Fluoro-4-methoxyphenyl


360
3-Methylbutyl
3-Fluoro-4-methoxyphenyl


361
2-Methylpropyl
4-Chloro-3-methylphenyl


362
Butyl
3-Chloro-4-fluorophenyl


363
2-Methylpropyl
3-Chloro-4-fluorophenyl


364
Pentyl
3-Chloro-4-fluorophenyl


365
3-Methylbutyl
3-Chloro-4-fluorophenyl


366
2-Methylpropyl
4-Ethylthiophenyl


367
Butyl
2,5-Dimethoxyphenyl


368
Butyl
2-Chlorophenyl


369
2-Methylpropyl
2,4-Difluorophenyl


370
Pentyl
2,4-Difluorophenyl


371
3-Methylbutyl
2,4-Difluorophenyl


372
Butyl
1,3-Benzodioxol-5-yl


373
2-Methylpropyl
1,3-Benzodioxol-5-yl


374
Pentyl
1,3-Benzodioxol-5-yl


375
3-Methylbutyl
1,3-Benzodioxol-5-yl


376
3-Methylbutyl
3-Fluoro-2-methylphenyl


377
Butyl
5-Fluoro-2-methylphenyl


378
2-Methylpropyl
5-Fluoro-2-methylphenyl


379
Pentyl
5-Fluoro-2-methylphenyl


380
3-Methylbutyl
5-Fluoro-2-methylphenyl


381
2-Methylpropyl
2-Chlorophenyl


382
Pentyl
2-Chlorophenyl


383
3-Methylbutyl
2-Chlorophenyl


384
Butyl
3,4-Difluorophenyl


385
2-Methylpropyl
3,4-Difluorophenyl


386
Pentyl
3,4-Difluorophenyl


387
3-Methylbutyl
3,4-Difluorophenyl


388
Butyl
2,3-Difluorophenyl


389
2-Methylpropyl
2,3-Difluorophenyl


390
Pentyl
2,3-Difluorophenyl


391
3-Methylbutyl
2,3-Difluorophenyl


392
2-Methylpropyl
4-Methoxyphenyl


393
Butyl
3-Chlorophenyl


394
2-Methylpropyl
3-Chlorophenyl


395
Pentyl
3-Chlorophenyl


396
3-Methylbutyl
3-Chlorophenyl


397
Butyl
4-Chlorophenyl


398
2-Methylpropyl
4-Chlorophenyl


399
3-Methylbutyl
4-Chlorophenyl


400
Butyl
2,5-Dimethylphenyl


401
2-Methylpropyl
2,5-Dimethylphenyl


402
Pentyl
2,5-Dimethylphenyl


403
3-Methylbutyl
2,5-Dimethylphenyl


404
Butyl
2,4-Dimethylphenyl


405
3-Methylbutyl
4-Methoxyphenyl


406
Butyl
2-Methoxyphenyl


407
2-Methylpropyl
2-Methoxyphenyl


408
Pentyl
2-Methoxyphenyl


409
3-Methylbutyl
2-Methoxyphenyl


410
Butyl
3-Fluoro-4-methylphenyl


411
2-Methylpropyl
3-Fluoro-4-methylphenyl


412
Pentyl
3-Fluoro-4-methylphenyl


413
3-Methylbutyl
3-Fluoro-4-methylphenyl


414
Butyl
3-Fluoro-2-methylphenyl


415
2-Methylpropyl
3-Fluoro-2-methylphenyl


416
Butyl
4-Fluorophenyl


417
2-Methylpropyl
2,4-Dimethylphenyl


418
3-Methylbutyl
2,4-Dimethylphenyl


419
Butyl
3-Methoxyphenyl


420
2-Methylpropyl
3-Methoxyphenyl


421
Pentyl
3-Methoxyphenyl


422
3-Methylbutyl
3-Methoxyphenyl


423
Butyl
4-Methoxyphenyl


424
3-Methylbutyl
3-Methylphenyl


425
Butyl
4-Methylphenyl


426
2-Methylpropyl
4-Methylphenyl


427
Pentyl
4-Methylphenyl


428
3-Methylbutyl
4-Methylphenyl


429
2-Methylpropyl
4-Fluorophenyl


430
Pentyl
4-Fluorophenyl


431
3-Methylbutyl
4-Fluorophenyl


432
Butyl
2-Fluorophenyl


433
2-Methylpropyl
2-Fluorophenyl


434
Pentyl
2-Fluorophenyl


435
3-Methylbutyl
2-Fluorophenyl


436
2-Methylpropyl
4-Ethylphenyl


437
Butyl
3,4-Dimethylphenyl


438
2-Methylpropyl
3,4-Dimethylphenyl


439
3-Methylbutyl
3,4-Dimethylphenyl


440
Butyl
2-Methylphenyl


441
Pentyl
2-Methylphenyl


442
3-Methylbutyl
2-Methylphenyl


443
Butyl
3-Fluorophenyl


444
2-Methylpropyl
3-Fluorophenyl


445
Pentyl
3-Fluorophenyl


446
3-Methylbutyl
3-Fluorophenyl


447
Butyl
Phenyl


448
2-Methylpropyl
Phenyl


449
Pentyl
Phenyl


450
3-Methylbutyl
Phenyl


451
Butyl
3-Methylphenyl


452
2-Methylpropyl
3-Methylphenyl


453
Pentyl
3-Methylphenyl









EXAMPLE 7




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R2
R3







454
Allyl
2,5-Dichlorophenyl


455
Propyl
2,5-Dichlorophenyl


456
Propyl
2,4-Dichlorophenyl


457
Propyl
4-Pentylphenyl


458
Allyl
3-Bromophenyl


459
Propyl
3-Bromophenyl


460
Propyl
4-Bromophenyl


461
Propyl
2-Chlorophenyl


462
Methyl
Phenyl


463
Propyl
Phenyl


464
Methyl
3-Methylphenyl


465
Propyl
3-Methylphenyl


466
Propyl
2-Chlorophenyl


467
Propyl
3,4-Difluorophenyl


468
Methyl
2,3-Difluorophenyl


469
Propyl
2,3-Difluorophenyl


470
Methyl
2,5-Difluorophenyl


471
Allyl
2,5-Difluorophenyl


472
Propyl
2,5-Difluorophenyl


473
Propyl
2,4-Difluorophenyl


474
Allyl
1,3-Benzodioxol-5-yl


475
Propyl
1,3-Benzodioxol-5-yl


476
Propyl
4-Methylthiophenyl


477
Propyl
4-Chloro-3-methylphenyl


478
Propyl
4-Methylphenyl


479
Propyl
3-Fluorophenyl


480
Propyl
4-Fluorophenyl


481
Methyl
2-Fluorophenyl


482
Allyl
2-Fluorophenyl


483
Propyl
2-Fluorophenyl


484
Propyl
3,4-Dimethylphenyl


485
Propyl
3-Fluoro-4-methylphenyl


486
Propyl
2-Fluoro-3-methylphenyl


487
Allyl
3-Chlorophenyl


488
Propyl
3-Chlorophenyl


489
Propyl
4-Chlorophenyl


490
2-Methylpropyl
3-Chloro-2-thienyl


491
Pentyl
3-Chloro-2-thienyl


492
3-Methylbutyl
3-Chloro-2-thienyl


493
Butyl
3-Ethoxy-2-thienyl


494
Pentyl
3-Ethoxy-2-thienyl


495
3-Methylbutyl
2-Methoxybenzyl


496
3-Methylbutyl
2-(2-Fluorophenyl)




ethenyl


497
2-Methylpropyl
2-(2-Chlorophenyl)




ethenyl


498
3-Methylbutyl
2-(2-Chlorophenyl)




ethenyl


499
Pentyl
2-Fluoro-6-




trifluoromethylphenyl


500
3-Methylbutyl
3-Ethoxy-2-thienyl


501
Butyl
5-Methylthio-2-thienyl


502
2-Methylpropyl
5-Methylthio-2-thienyl


503
3-Methylbutyl
5-Methylthio-2-thienyl


504
3-Methylbutyl
4-Fluorophenyl


505
3-Methylbutyl
2-Fluorophenyl


506
3-Methylbutyl
3-Methoxyphenyl


507
3-Methylbutyl
2,3,5,6-Tetrafluoro phenyl


508
2-Methylpropyl
2,4,6-Trifluorophenyl


509
3-Methylbutyl
2,4,6-Trifluorophenyl


510
Butyl
2,3,6-Trifluorophenyl


511
2-Methylpropyl
2,3,6-Trifluorophenyl


512
3-Methylbutyl
2-Fluoro-6-




trifluoromethylphenyl


513
2-Methylpropyl
2,4,6-Trichlorophenyl


514
Pentyl
2,5-Dimethyl-3-furyl


515
3-Methylbutyl
4,5-Dimethyl-2-furyl


516
Butyl
3,4-Dimethyl-2-furyl


517
2-Methylpropyl
3,4-Dimethyl-2-furyl


518
Pentyl
3,4-Dimethyl-2-furyl


519
3-Methylbutyl
3,4-Dimethyl-2-furyl


520
Butyl
4-Methoxy-3-thienyl


521
3-Methylbutyl
4-Methoxy-3-thienyl


522
Butyl
3-Chloro-2-thienyl


523
Allyl
3-Bromo-4-fluorophenyl


524
Propyl
3-Bromo-4-fluorophenyl


525
Methyl
3-Iodophenyl


526
Ethyl
3-Iodophenyl


527
Allyl
3-Iodophenyl


528
Propyl
3-Iodophenyl


529
Propyl
3-Methyl-2-thienyl


530
Propyl
3-Fluorobenzyl


531
Pentyl
2,3,6-Trifluorophenyl


532
3-Methylbutyl
2,3,6-Trifluorophenyl


533
Butyl
2-Chloro-6-fluorophenyl


534
2-Methylpropyl
2-Chloro-6-fluorophenyl


535
Pentyl
2-Chloro-6-fluorophenyl


536
3-Methylbutyl
2-Chloro-6-fluorophenyl


537
Butyl
2-Fluoro-6-




trifluoromethylphenyl


538
3-Methylbutyl
3-Chlorobenzyl


539
2-Methylpropyl
4-Chlorobenzyl


540
3-Methylbutyl
2-Chlorobenzyl


541
Butyl
2,3,5,6-Tetrafluoro phenyl


542
2-Methylpropyl
2,3,5,6-Tetrafluoro phenyl


543
Pentyl
2,3,5,6-Tetrafluoro phenyl


544
Allyl
3-Chloro-4-fluorophenyl


545
Propyl
3-Chloro-4-fluorophenyl


546
Propyl
4-Butylphenyl


547
Propyl
3-Chloro-4-methoxyphenyl


548
Allyl
5-Chloro-2-methoxyphenyl


549
Propyl
5-Chloro-2-methoxyphenyl


550
Propyl
3,4-Dichlorophenyl


551
Propyl
4-Hexylphenyl


552
Methyl
3-Bromo-4-methylphenyl


553
Allyl
3-Bromo-4-methylphenyl


554
Propyl
3-Bromo-4-methylphenyl


555
Methyl
3-Bromo-4-fluorophenyl


556
Butyl
2-Methoxybenzyl









EXAMPLE 8




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R2
R3







557
Propyl
3-Chlorophenyl


558
Propyl
Phenyl


559
Allyl
2-Fluorophenyl


560
Propyl
2-Fluorophenyl


561
Propyl
3-Fluoro-4-




methylphenyl


562
Methyl
2,5-Dichlorophenyl


563
Propyl
2,5-Dichlorophenyl


564
Propyl
4-Pentylphenyl


565
Propyl
3-Bromophenyl


566
Propyl
3-Methyl-2-thienyl









Compound No. 567: (5-Chloro-2-methoxyphenyl)-N-({3-[(2-chlorophenyl)methyl]imidazolo[5,4-b]pyridin-2-yl}methyl-N-pentylcarboxamide.

EXAMPLE 9




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R2
R3

















568
Methyl
Phenyl


569
Methyl
3-Chlorophenyl


570
Butyl
2,5-Dimethylphenyl


571
Butyl
5-Fluoro-2-methylphenyl


572
Butyl
2,3-Dimethylphenyl


573
Propyl
3-Fluorophenyl


574
Butyl
3-Methylphenyl


575
Butyl
4-Fluorophenyl


576
Butyl
3-Methoxyphenyl


577
Butyl
2,5-Difluorophenyl


578
Methyl
2-Fluorophenyl


579
Butyl
4-Methylphenyl


580
Butyl
2-Fluorophenyl


581
Butyl
4-Methoxyphenyl


582
Butyl
3-Chlorophenyl


583
Methyl
2,5-Dimethylphenyl


584
Butyl
2-Methylphenyl


585
Butyl
4-Ethylphenyl


586
Butyl
2-Methoxyphenyl


587
Butyl
3-Chlorophenyl


588
Propyl
3-Fluoro-4-methylphenyl


589
Butyl
3-Fluorophenyl


590
Butyl
3,4-Dimethylphenyl


591
Butyl
3-Fluoro-4-methylphenyl


592
Butyl
3,4-Difluorophenyl


593
Propyl
2,4-Dimethoxyphenyl


594
Methyl
2,5-Dichlorophenyl


595
Butyl
5-Chloro-2-methoxyphenyl


596
Butyl
3-Methyl-2-thienyl


597
Butyl
3-Methylphenyl


598
Pentyl
3-Fluorophenyl


599
Pentyl
2,5-Dimethylphenyl


600
Propyl
2,5-Dichlorophenyl


601
Butyl
3-Methyl-2-thienyl


602
Pentyl
3-Methylphenyl


603
Butyl
2-Fluorophenyl


604
Pentyl
3-Methoxyphenyl


605
Methyl
3-Bromophenyl


606
Butyl
3-Iodophenyl


607
Butyl
4-Fluorophenyl


608
2-Methylpropyl
4-Methylphenyl


609
2-Methylpropyl
2-Fluorophenyl


610
2-Methylpropyl
4-Methoxyphenyl


611
Propyl
3-Bromophenyl


612
Allyl
4-Octylphenyl


613
Butyl
Phenyl


614
Pentyl
2-Methylphenyl


615
Pentyl
2-Fluorophenyl


616
Butyl
2-Methoxyphenyl


617
Butyl
3-Chloro-4-methoxyphenyl


618
Propyl
4-Octylphenyl


619
Pentyl
Phenyl


620
Butyl
3-Fluorophenyl


621
2-Methylpropyl
3,4-Dimethylphenyl


622
Pentyl
2-Methoxyphenyl


623
Butyl
3-Fluoro-4-methylphenyl


624
Butyl
2-Fluoro-3-methylphenyl


625
2-Methylpropyl
4-Chlorophenyl


626
2-Methylpropyl
2,3-Difluorophenyl


627
2-Methylpropyl
1,3-Benzodioxol-5-yl


628
2-Methylpropyl
3-Chloro-4-methoxyphenyl


629
2-Methylpropyl
3-Fluoro-4-methylphenyl


630
Pentyl
2-Fluoro-3-methylphenyl


631
Pentyl
2-Chlorophenyl


632
Pentyl
2,3-Difluorophenyl


633
Butyl
4-Methylthiophenyl


634
2-Methylpropyl
3-Chloro-4-methoxyphenyl


635
Butyl
5-Fluoro-2-methylphenyl


636
Butyl
3-Chlorophenyl


637
Butyl
3,4-Difluorophenyl


638
Butyl
2,5-Difluorophenyl


639
Butyl
3-Chloro-4-fluorophenyl


640
Butyl
5-Chloro-2-methoxyphenyl


641
2-Methylpropyl
5-Fluoro-2-methylphenyl


642
2-Methylpropyl
3-Chlorophenyl


643
2-Methylpropyl
3,4-Difluorophenyl


644
Pentyl
2,5-Difluorophenyl


645
2-Methylpropyl
4-Ethylthiophenyl


646
2-Methylpropyl
5-Chloro-2-methoxyphenyl


647
Pentyl
5-Fluoro-2-methylphenyl


648
Pentyl
3-Chlorophenyl


649
Butyl
2,3-Difluorophenyl


650
2-Methylpropyl
2,4-Difluorophenyl


651
Butyl
3-Chloro-4-methoxyphenyl


652
Pentyl
5-Chloro-2-methoxyphenyl


653
3-Methylbutyl
5-Chloro-2-methoxyphenyl


654
3-Methylbutyl
2,5-Dichlorophenyl


655
2-Methylpropyl
4-Bromophenyl


656
Butyl
2-Thienyl


657
3-Methylbutyl
3-Thienyl


658
2-Methylpropyl
3-Methyl-2-thienyl


659
3-Methylbutyl
3-Trifluoromethylphenyl


660
Butyl
3-Bromophenyl


661
3-Methylbutyl
2-Bromophenyl


662
Pentyl
2-Thienyl


663
Butyl
5-Methyl-2-thienyl


664
3-Methylbutyl
3-Methyl-2-thienyl


665
2-Methylpropyl
3,4-Dichlorophenyl


666
2-Methylpropyl
3-Bromophenyl


667
3-Methylbutyl
3-Bromo-4-fluorophenyl


668
3-Methylbutyl
2-Thienyl


669
Pentyl
5-Methyl-2-thienyl


670
Butyl
3-Fluorophenyl


671
Butyl
2,5-Dichlorophenyl


672
Pentyl
3-Bromophenyl


673
Pentyl
3-Iodophenyl


674
Butyl
3-Thienyl


675
3-Methylbutyl
5-Methyl-2-thienyl


676
3-Methylbutyl
3-Fluorophenyl


677
Pentyl
2,5-Dichlorophenyl


678
3-Methylbutyl
3-Bromophenyl


679
3-Methylbutyl
3-Iodophenyl


680
Pentyl
3-Thienyl


681
Butyl
3-Methyl-2-thienyl


682
2-Methylpropyl
2-Chlorophenyl


815
2-Methylpropyl
3,5-Difluorophenyl


816
3-Methylbutyl
3,5-Difluorophenyl


817
Butyl
3,5-Difluorophenyl


2238
Benzyl
3-Fluorophenyl


2242
Benzyl
2-Fluorophenyl


2253
Benzyl
2-Methoxyphenyl


2257
Benzyl
5-Fluoro-2-methylphenyl


2260
Benzyl
3-Chlorophenyl


2268
Benzyl
2,3-Difluorophenyl


2271
Benzyl
2,5-Difluorophenyl









EXAMPLE 10




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R2
R3

















683
Allyl
3-Fluorophenyl


684
Allyl
3,4-Difluorophenyl


685
Propyl
1,3-Benzodioxol-5-yl


686
Allyl
5-Chloro-2-methoxyphenyl


687
Propyl
3-Methyl-2-Thienyl


688
Propyl
3-Fluoro-4-methylphenyl


689
Propyl
3-Fluorophenyl


690
Propyl
3,4-Difluorophenyl


691
Allyl
3-Chloro-4-fluorophenyl


692
Propyl
5-Chloro-2-methoxyphenyl


693
Allyl
Phenyl


694
Allyl
5-Fluoro-2-methylphenyl


695
Propyl
4-Fluorophenyl


696
Allyl
2,5-Difluorophenyl


697
Propyl
3-Chloro-4-fluorophenyl


698
Methyl
2,5-Dichlorophenyl


699
Propyl
Phenyl


700
Propyl
5-Fluoro-2-methylphenyl


701
Allyl
2-Fluorophenyl


702
Propyl
2,5-Difluorophenyl


703
Methyl
5-Chloro-2-methoxyphenyl


704
Allyl
2,5-Dichlorophenyl


705
Allyl
3-Methylphenyl


706
Allyl
3-Chlorophenyl


707
Propyl
2-Fluorophenyl


708
Allyl
1,3-Benzodioxol-5-yl


709
Ethyl
5-Chloro-2-methoxyphenyl


710
Propyl
2,5-Dichlorophenyl


711
Propyl
3-Methylphenyl


712
Propyl
3-Chlorophenyl


713
Propyl
4-Methylthiophenyl


714
Propyl
3-Iodo-4-methylphenyl


887
Propyl
2,3,6-Trifluorophenyl


2306
3-Methylbutyl
2,3,6-Trifluorophenyl


2347
3-Methylbutyl
3-(2-1,2,3,4-Teterahydro




isoquinolinyl




methyl)




phenyl


2348
3-Methylbutyl
3-(Diethylamino




methyl)phenyl


2349
3-Methylbutyl
3-(Hexylmethyl




amino




methyl)phenyl


2351
3-Methylbutyl
3-(Dibutylamino




methyl)phenyl


2364
3-Methylbutyl
3-[(1-methylethyl)




methylamino




methyl]phenyl


2365
3-Methylbutyl
3-(Cyclohexyl




ethylamino




methyl)phenyl


2367
3-Methylbutyl
3-[bis(2-Methoxyethyl)




aminomethyl]




phenyl


2369
3-Methylbutyl
3-[(3,3,5-Trimethylaza




perhydroepinyl)methyl]phenyl









EXAMPLE 11




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R2
R3

















715
Methyl
3-Fluorophenyl


716
Methyl
5-Fluoro 2-methylphenyl


717
Methyl
3-Chlorophenyl


718
Methyl
5-Chloro-2-methoxyphenyl


839
2-Methylpropyl
2,3,6-Trifluorophenyl


840
Pentyl
2,3,6-Trifluorophenyl


841
3-Methylbutyl
2,3,6-Trifluorophenyl


938
Butyl
Phenyl


939
2-Methylpropyl
Phenyl


940
Pentyl
Phenyl


941
3-Methylbutyl
Phenyl


942
Butyl
3-Methylphenyl


943
2-Methylpropyl
3-Methylphenyl


944
3-Methylbutyl
3-Methylphenyl


945
2-Methylpropyl
4-Methylphenyl


946
Butyl
3-Fluorophenyl


947
Pentyl
3-Fluorophenyl


948
3-Methylbutyl
3-Fluorophenyl


949
3-Methylbutyl
4-Fluorophenyl


950
Butyl
2-Fluorophenyl


951
2-Methylpropyl
2-Fluorophenyl


952
Pentyl
2-Fluorophenyl


953
3-Methylbutyl
2-Fluorophenyl


954
2-Methylpropyl
3,4-Dimethylphenyl


1002
Butyl
2-Chlorophenyl


1003
Pentyl
2-Chlorophenyl


1004
3-Methylbutyl
2-Chlorophenyl


1005
Butyl
3,4-Difluorophenyl


1006
2-Methylpropyl
3,4-Difluorophenyl


1007
Pentyl
3,4-Difluorophenyl


1008
3-Methylbutyl
3,4-Difluorophenyl


1009
Butyl
2,3-Difluorophenyl


1010
2-Methylpropyl
2,3-Difluorophenyl


1011
Pentyl
2,3-Difluorophenyl


1012
3-Methylbutyl
2,3-Difluorophenyl


1013
Butyl
2,5-Difluorophenyl


1014
2-Methylpropyl
2,5-Difluorophenyl


1015
Pentyl
2,5-Difluorophenyl


1016
3-Methylbutyl
2,5-Difluorophenyl


1017
Butyl
2,4-Difluorophenyl


1018
2-Methylpropyl
2,4-Difluorophenyl


1019
3-Methylbutyl
2,4-Difluorophenyl


1020
2-Methylpropyl
3-Ethoxyphenyl


1021
Butyl
1,3-Benzodioxol-5-yl


1022
2-Methylpropyl
1,3-Benzodioxol-5-yl


1023
3-Methylbutyl
1,3-Benzodioxol-5-yl


1024
2-Methylpropyl
4-Methylthiophenyl


1025
3-Methylbutyl
4-Methylthiophenyl


1026
2-Methylpropyl
3-Fluoro-4-methoxyphenyl


1027
3-Methylbutyl
3-Fluoro-4-methoxyphenyl


1028
2-Methylpropyl
4-Chloro-3-methylphenyl


1029
Butyl
3-Chloro-4-fluorophenyl


1030
2-Methylpropyl
3-Chloro-4-fluorophenyl


1031
Pentyl
3-Chloro-4-fluorophenyl


1032
3-Methylbutyl
3-Chloro-4-fluorophenyl


1033
2-Methylpropyl
3,4,5-Trifluorophenyl


1034
3-Methylbutyl
3,4,5-Trifluorophenyl


1035
2-Methylpropyl
4-Butylphenyl


1036
2-Methylpropyl
4-Ethylthiophenyl


1109
Cyclopropyl
Phenyl



methyl


1110
Cyclopropyl
3-Methylphenyl



Methyl


1111
Cyclopropyl
4-Methylphenyl



Methyl


1112
Cyclopropyl
3-Fluorophenyl



Methyl


1113
Cyclopropyl
2-Fluorophenyl



Methyl


1114
Cyclopropyl
3-Methoxyphenyl



Methyl


1115
Cyclopropyl
3-Fluoro-4-methylphenyl



Methyl


1116
Cyclopropyl
5-Fluoro-2-methylphenyl



methyl


1130
Cyclopropyl
5-Chloro-2-methoxyphenyl



Methyl


1131
Cyclopropyl
2,5-Dichlorophenyl



Methyl


1132
Cyclopropyl
3-Bromophenyl



Methyl


1133
3-Methylbutyl
5-Chloro-2-methoxyphenyl


1134
Butyl
2,5-Dichlorophenyl


1135
2-Methylpropyl
2,5-Dichlorophenyl


1136
Pentyl
2,5-Dichlorophenyl


1137
3-Methylbutyl
2,5-Dichlorophenyl


1138
2-Methylpropyl
2,4-Dichlorophenyl


1139
2-Methylpropyl
4-Pentylphenyl


1140
Butyl
3-Bromophenyl


1141
2-Methylpropyl
3-Bromophenyl


1142
Pentyl
3-Bromophenyl


1143
3-Methylbutyl
3-Bromophenyl


1144
2-Methylpropyl
4-Bromophenyl


1256
Cyclopropyl
3,4-Difluorophenyl



Methyl


1257
Cyclopropyl
2,4-Difluorophenyl



Methyl


1258
Propyl
1,3-Benzodioxol-5-yl


1259
Cyclopropyl
1,3-Benzodioxol-5-yl



Methyl


1260
Cyclopropyl
3-Chloro-4-fluorophenyl



Methyl


1261
3-Methylbutyl
3-Iodo-4-methylphenyl


1262
3-Methylbutyl
2-Thienyl


1263
3-Methylbutyl
3-Thienyl


1264
2-Methylpropyl
5-Methyl-2-thienyl


1265
Pentyl
5-Methyl-2-thienyl


1266
3-Methylbutyl
5-Methyl-2-thienyl


1267
3-Methylbutyl
3-Fluorobenzyl


1448
Methyl
2,5-Difluorophenyl


1449
Methyl
2,5-Dichlorophenyl


2005
3-Methylbutyl
5-Bromo-2-thienyl


2239
Benzyl
3-Fluorophenyl


2243
Benzyl
2-Fluorophenyl


2245
Benzyl
3,4-Dimethylphenyl


2251
Benzyl
3-Methoxyphenyl


2254
Benzyl
2-Methoxyphenyl


2258
Benzyl
5-Fluoro-2-methylphenyl


2261
Benzyl
3-Chlorophenyl


2266
Benzyl
3,4-Difluorophenyl


2269
Benzyl
2,3-Difluorophenyl


2272
Benzyl
2,5-Difluorophenyl


2281
Benzyl
5-Chloro-2-methoxyphenyl


2289
Benzyl
2,5-Dichlorophenyl


2292
Benzyl
3-Bromophenyl


2295
Benzyl
2-Bromophenyl


2298
Benzyl
3-Iodophenyl


2302
Benzyl
2,5-Dimethylpyrrol-3-yl


2305
Benzyl
3-Methylbutyl


2320
3-Methylbutyl
3-(Methylamino




methyl)phenyl


2321
3-Methylbutyl
3-(Ethylamino




methyl)phenyl


2322
3-Methylbutyl
3-(Cyclobutyl




amino




methyl)phenyl


2323
3-Methylbutyl
3-[(1-Methylpropyl)




amino




methyl]phenyl


2324
3-Methylbutyl
3-(Cyclopentyl




amino




methyl)phenyl


2350
3-Methylbutyl
3-(Dibutylamino




methyl)phenyl


2366
3-Methylbutyl
3-[bis(2-Methoxyethyl)




aminomethyl]




phenyl


2368
3-Methylbutyl
3-[(3,3,5-Trimethylaza




perhydroepinyl)methyl]phenyl


2391
Methyl
2,5-Difluorophenyl









EXAMPLE 12




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R2
R3

















719
Propyl
3-Fluorophenyl


720
Propyl
1,3-Benzodioxol-5-yl


721
Propyl
5-Fluoro-2-methylphenyl


722
Allyl
2-Fluorophenyl


723
Propyl
3-Chloro-4-fluorophenyl


724
Propyl
3-Chlorophenyl


725
Propyl
2-Fluorophenyl


726
Allyl
5-Chloro-2-methoxyphenyl


727
Allyl
3-Chlorophenyl


728
Methyl
3-Fluorophenyl


729
Methyl
2,5-Difluorophenyl


730
Propyl
Phenyl


731
Propyl
3-Chlorophenyl


732
Allyl
3-Fluorophenyl


733
Propyl
2,5-Difluorophenyl


734
Propyl
3-Fluoro-4-methylphenyl


735
Propyl
4-Methylthio phenyl


736
3-Methylbutyl
3-Fluorophenyl


737
2-Methylpropyl
2-Fluorophenyl


738
Butyl
3,4-Difluorophenyl


739
2-Methylpropyl
2,5-Difluorophenyl


740
3-Methylbutyl
1,3-Benzodioxol-5-yl


741
Butyl
4-Fluorophenyl


742
Pentyl
2-Fluorophenyl


743
2-Methylpropyl
3,4-Difluorophenyl


744
Pentyl
2,5-Difluorophenyl


745
Butyl
3-Chloro-4-fluorophenyl


746
Butyl
3-Fluorophenyl


747
2-Methylpropyl
4-Fluorophenyl


748
3-Methylbutyl
2-Fluorophenyl


749
Pentyl
3,4-Difluorophenyl


750
3-Methylbutyl
2,5-Difluorophenyl


751
2-Methylpropyl
3-Chloro-4-fluorophenyl


752
2-Methylpropyl
3-Fluorophenyl


753
3-Methylbutyl
4-Fluorophenyl


754
2-Methylpropyl
2,5-Dimethylphenyl


755
3-Methylbutyl
3,4-Difluorophenyl


756
Butyl
1,3-Benzodioxol-5-yl


757
Pentyl
3-Chloro-4-fluorophenyl


758
Pentyl
3-Fluorophenyl


759
Butyl
2-Fluorophenyl


760
3-Methylbutyl
2,5-Dimethylphenyl


761
Butyl
2,5-Difluorophenyl


762
2-Methylpropyl
1,3-Benzodioxol-5-yl


763
3-Methylbutyl
3-Chloro-4-fluorophenyl


764
Butyl
5-Chloro-2-methoxyphenyl


765
2-Methylpropyl
2,5-Dichlorophenyl


766
Pentyl
5-Methyl-2-thienyl


767
3-Methylbutyl
Phenyl


768
2-Methylpropyl
2-Methylphenyl


769
3-Methylbutyl
5-Fluoro-2-methylphenyl


770
2-Methylpropyl
5-Chloro-2-methoxyphenyl


771
Pentyl
2,5-Dichlorophenyl


772
3-Methylbutyl
5-Methyl-2-thienyl


773
Butyl
3-Methylphenyl


774
3-Methylbutyl
2-Methylphenyl


775
Butyl
3-Chlorophenyl


776
Pentyl
5-Chloro-2-methoxyphenyl


777
3-Methylbutyl
2,5-Dichlorophenyl


778
Butyl
Phenyl


779
2-Methylpropyl
3-Methylphenyl


780
2-Methylpropyl
3-Fluoro-4-methylphenyl


781
2-Methylpropyl
3-Chlorophenyl


782
3-Methylbutyl
5-Chloro-2-methoxyphenyl


783
Butyl
5-Methyl-2-thienyl


784
2-Methylpropyl
Phenyl


785
Pentyl
3-Methylphenyl


786
3-Methylbutyl
3-Fluoro-4-methylphenyl


787
Pentyl
3-Chlorophenyl


788
Butyl
2,5-Dichlorophenyl


789
2-Methylpropyl
5-Methyl-2-thienyl


790
Pentyl
Phenyl


791
3-Methylbutyl
3-Methylphenyl


792
Pentyl
5-Fluoro-2-methylphenyl


793
3-Methylbutyl
3-Chlorophenyl


794
2-Methylpropyl
4-Methylthiophenyl


795
2-Methylpropyl
3-Fluoro-4-methoxyphenyl


796
3-Methylbutyl
3-Fluoro-4-methoxyphenyl


797
2-Methylpropyl
2,4,6-Trifluorophenyl


798
Butyl
2,3,6-Trifluorophenyl


799
2-Methylpropyl
2,3,6-Trifluorophenyl


885
Methyl
2,3,6-Trifluorophenyl


886
Propyl
2,3,6-Trifluorophenyl


933
Propyl
Phenyl


934
Propyl
3-Fluorophenyl


935
Propyl
4-Fluorophenyl


936
Allyl
2-Fluorophenyl


937
Propyl
2-Fluorophenyl


1037
Butyl
3-Chlorophenyl


1038
2-Methylpropyl
3-Chlorophenyl


1039
Pentyl
3-Chlorophenyl


1040
3-Methylbutyl
3-Chlorophenyl


1041
Butyl
3,4-Difluorophenyl


1042
2-Methylpropyl
3,4-Difluorophenyl


1043
Pentyl
3,4-Difluorophenyl


1044
3-Methylbutyl
3,4-Difluorophenyl


1045
Butyl
2,3-Difluorophenyl


1046
2-Methylpropyl
2,3-Difluorophenyl


1047
Pentyl
2,3-Difluorophenyl


1048
3-Methylbutyl
2,3-Difluorophenyl


1049
Butyl
2,5-Difluorophenyl


1050
2-Methylpropyl
2,5-Difluorophenyl


1051
Pentyl
2,5-Difluorophenyl


1052
3-Methylbutyl
2,5-Difluorophenyl


1053
Butyl
2,4-Difluorophenyl


1054
2-Methylpropyl
2,4-Difluorophenyl


1055
Pentyl
2,4-Difluorophenyl


1056
3-Methylbutyl
2,4-Difluorophenyl


1057
2-Methylpropyl
4-Propylphenyl


1058
2-Methylpropyl
4-Ethoxyphenyl


1059
Butyl
1,3-Benzodioxol-5-yl


1060
2-Methylpropyl
1,3-Benzodioxol-5-yl


1061
Pentyl
1,3-Benzodioxol-5-yl


1062
3-Methylbutyl
1,3-Benzodioxol-5-yl


1063
Butyl
4-Methylothiophenyl


1064
2-Methylpropyl
4-Methylothiophenyl


1065
Butyl
3-Fluoro-4-methoxyphenyl


1066
2-Methylpropyl
3-Fluoro-4-methoxyphenyl


1067
3-Methylbutyl
3-Fluoro-4-methoxyphenyl


1068
2-Methylpropyl
4-Chloro-3-methylphenyl


1069
3-Methylbutyl
4-Chloro-3-methylphenyl


1070
Butyl
3-Chloro-4-fluorophenyl


1071
2-Methylpropyl
3-Chloro-4-fluorophenyl


1072
Pentyl
3-Chloro-4-fluorophenyl


1073
3-Methylbutyl
3-Chloro-4-fluorophenyl


1074
2-Methylpropyl
3,4,5-Trifluorophenyl


1075
3-Methylbutyl
3,4,5-Trifluorophenyl


1076
2-Methylpropyl
4-Ethylthiophenyl


1077
3-Methylbutyl
2,3,6-Trifluorophenyl


1078
Allyl
5-Chloro-2-methoxyphenyl


1079
Propyl
5-Chloro-2-methoxyphenyl


1080
Propyl
3-Trifluoromethylphenyl


1081
Allyl
2,5-Dichlorophenyl


1082
Propyl
2,5-Dichlorophenyl


1083
Methyl
3-Bromophenyl


1084
Allyl
3-Bromophenyl


1085
Propyl
3-Bromo-4-fluorophenyl


1086
Methyl
3-Iodophenyl


1087
Allyl
3-Iodophenyl


1088
Propyl
3-Iodophenyl


1089
2-Methoxyethyl
2,5-Difluorophenyl


1090
2-Methoxyethyl
2,5-Dichlorophenyl


1091
2-Methoxyethyl
3-Bromophenyl


1145
2-Methylpropyl
3-Chloro-4-methoxyphenyl


1146
3-Methylbutyl
3-Chloro-4-methoxyphenyl


1147
2-Methylpropyl
5-Chloro-2-methoxyphenyl


1148
Pentyl
5-Chloro-2-methoxyphenyl


1149
3-Methylbutyl
5-Chloro-2-methoxyphenyl


1150
Pentyl
3-Trifluoromethylphenyl


1151
3-Methylbutyl
3-Trifluoromethylphenyl


1152
Butyl
2-Trifluoromethylphenyl


1153
3-Methylbutyl
2-Trifluoromethylphenyl


1154
Butyl
3,4-Dichlorophenyl


1155
2-Methylpropyl
3,4-Dichlorophenyl


1156
3-Methylbutyl
3,4-Dichlorophenyl


1157
2-Methylpropyl
2,5-Dichlorophenyl


1158
Pentyl
2,5-Dichlorophenyl


1159
3-Methylbutyl
2,5-Dichlorophenyl


1160
2-Methylpropyl
2,4-Dichlorophenyl


1161
2-Methylpropyl
3-Bromophenyl


1162
Pentyl
3-Bromophenyl


1163
3-Methylbutyl
3-Bromophenyl


1164
2-Methylpropyl
4-Bromophenyl


1165
2-Methylpropyl
2-Bromophenyl


1166
Pentyl
2-Bromophenyl


1167
3-Methylbutyl
2-Bromophenyl


1194
2-Methylpropyl
3-Phenoxyphenyl


1195
2-Methylpropyl
4-Phenoxyphenyl


1196
Butyl
3-Bromo-4-methylphenyl


1197
2-Methylpropyl
3-Bromo-4-methylphenyl


1198
Butyl
3-Bromo-4-fluorophenyl


1199
2-Methylpropyl
3-Bromo-4-fluorophenyl


1200
Pentyl
3-Bromo-4-fluorophenyl


1201
3-Methylbutyl
3-Bromo-4-fluorophenyl


1202
Butyl
3-Iodophenyl


1203
Pentyl
3-Iodophenyl


1204
3-Methylbutyl
3-Iodophenyl


1205
2-Methylpropyl
4-Iodophenyl


1206
Methyl
3-Iodophenyl


1239
Cyclopentyl
4-Methylphenyl


1240
Cyclopentyl
3-Fluoro-4-methylphenyl


1241
Cyclopropyl
5-Chloro-2-methoxyphenyl



Methyl


1242
Cyclopropyl
3-Trifluoromethylphenyl



Methyl


1243
Cyclopropyl
2,5-Dichlorophenyl



Methyl


1244
Cyclopropyl
3-Bromophenyl



Methyl


1245
Cyclopentyl
3-Methoxybenzyl


1246
Cyclopentyl
2-(2-Chlorophenyl)




ethenyl


1247
Cyclopropyl
3-Bromo-4-methylphenyl



Methyl


1248
Cyclopropyl
3-Bromo-4-fluorophenyl



Methyl


1249
Cyclopropyl
3-Iodophenyl



Methyl


1253
Cyclopentyl
3-Chloro-4-methoxyphenyl


1254
Cyclopropyl
5-Chloro-2-methoxyphenyl



Methyl


1255
Cyclopentyl
2,4-Dichlorophenyl


1268
Cyclopentyl
3-Fluorobenzyl


1269
Cyclopentyl
2-(2-




Trifluoromethylphenyl) ethenyl


1270
Cyclopentyl
2-(2-Bromophenyl)




ethenyl


1271
Cyclopropyl
2,3,6-Trifluorophenyl



Methyl


1274
Cyclopentyl
3-Chloro-4-methylphenyl


1275
Cyclopropyl
2,4,5-Trifluorophenyl



Methyl


1425
Propyl
3-Fluoro-4-methylphenyl


1426
Propyl
3-Chlorophenyl


1427
Allyl
3-Bromo-4-fluorophenyl


1428
Propyl
3-Bromo-4-fluorophenyl


1429
Allyl
3-Iodophenyl


1430
Propyl
3-Iodophenyl


1431
Propyl
3-Iodo-4-methylphenyl


1433
Propyl
3,4-Difluorophenyl


1434
Propyl
2,3-Difluorophenyl


1435
Propyl
2,4-Difluorophenyl


1436
Propyl
1,3-Benzodioxol-5-yl


1437
Propyl
3-Chloro-4-fluorophenyl


1438
Propyl
5-Chloro-2-methoxyphenyl


1439
Methyl
2,5-Dichlorophenyl


1440
Allyl
2,5-Dichlorophenyl


1441
Propyl
2,5-Dichlorophenyl


1442
Propyl
2,4-Dichlorophenyl


1443
Methyl
3-Bromophenyl


1444
Allyl
3-Bromophenyl


1445
Propyl
3-Bromophenyl


1446
Propyl
5-Methyl-2-thienyl


1447
Propyl
2,6-Difluorophenyl


1977
3-Methylbutyl
4,5-Dimethyl-2-furyl


1978
3-Methylbutyl
3-Chloro-4-methylphenyl


1980
3-Methylbutyl
2,4,5-Trifluorophenyl


1982
3-Methylbutyl
2,6-Difluorophenyl


1983
3-Methylbutyl
2-Bromo-5-methoxyphenyl


1984
3-Methylbutyl
3,5-Difluorophenyl


2006
3-Methylbutyl
5-Bromo-2-thienyl


2008
3-Methylbutyl
3-Bromo-2-thienyl









EXAMPLE 13




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3

















800
Propyl
Phenyl


801
Methyl
3-Chlorophenyl


802
Allyl
3-Chlorophenyl


803
Propyl
3-Chlorophenyl


804
Propyl
5-Chloro-2-methoxyphenyl


805
Propyl
3-Trifluoromethylphenyl


806
Propyl
2,5-Dichlorophenyl


807
Propyl
3-Bromophenyl


808
Propyl
3-Bromo-4-fluorophenyl


809
Methyl
3-Iodophenyl


810
Allyl
3-Iodophenyl


811
Propyl
3-Iodophenyl


888
Allyl
5-Chloro-2-methoxyphenyl


931
Propyl
3-Fluorophenyl


932
Propyl
2-Fluorophenyl


1092
Propyl
3-Fluorophenyl


1093
Propyl
2-Fluorophenyl


1094
Allyl
2,5-Difluorophenyl


1095
Propyl
2,5-Difluorophenyl


1096
Propyl
1,3-Benzodioxol-5-yl


1097
Methyl
5-Chloro-2-methoxyphenyl


1098
Allyl
5-Chloro-2-methoxyphenyl


1099
Methyl
2,5-Dichlorophenyl


1168
Methyl
5-Chloro-2-methoxyphenyl


1169
Allyl
5-Chloro-2-methoxyphenyl


1170
Propyl
5-Chloro-2-methoxyphenyl


1171
Propyl
3,4-Dichlorophenyl


1172
Allyl
2,5-Dichlorophenyl


1173
Propyl
2,5-Dichlorophenyl


1174
Propyl
2,4-Dichlorophenyl


1175
Methyl
3-Bromophenyl


1176
Allyl
3-Bromophenyl


1177
Propyl
3-Bromophenyl


1178
Cyclopropyl
5-Chloro-2-methoxyphenyl



methyl


1179
Cyclopropyl
2,5-Dichlorophenyl



methyl


1180
Propyl
3-Bromophenyl


1181
Cyclopropyl
3-Bromophenyl



methyl


1182
Pentyl
3-Bromo-4-fluorophenyl


1183
3-Methylbutyl
3-Bromo-4-fluorophenyl


1184
Pentyl
3-Iodophenyl


1185
Cyclopropyl
3-Bromo-4-fluorophenyl



Methyl


1186
Cyclopropyl
3-Iodophenyl



Methyl


1756
Butyl
2-Thienyl


1757
2-Methylpropyl
2-Thienyl


1758
Pentyl
2-Thienyl


1759
3-Methylbutyl
2-Thienyl


1760
Butyl
3-Thienyl


1761
2-Methylpropyl
3-Thienyl


1762
Pentyl
3-Thienyl


1763
3-Methylbutyl
3-Thienyl


1764
3-Methylbutyl
Benzyl


1765
Butyl
5-Methyl-2-thienyl


1766
2-Methylpropyl
5-Methyl-2-thienyl


1767
Pentyl
5-Methyl-2-thienyl


1768
3-Methylbutyl
5-Methyl-2-thienyl


1769
3-Methylbutyl
3-Fluorobenzyl


1770
3-Methylbutyl
4-Fluorobenzyl


1771
3-Methylbutyl
3-Methoxybenzyl


1787
3-Methylbutyl
2,3,6-Trifluorophenyl


1788
2-Methylpropyl
2,3,6-Trifluorophenyl


1789
3-Methylbutyl
2,3,6-Trifluorophenyl


1790
3-Methylbutyl
2-Chloro-6-fluorophenyl


1791
Butyl
Phenyl


1792
2-Methylpropyl
Phenyl


1793
Pentyl
Phenyl


1794
3-Methylbutyl
Phenyl


1795
Butyl
3-Methylphenyl


1796
2-Methylpropyl
3-Methylphenyl


1797
Pentyl
3-Methylphenyl


1798
3-Methylbutyl
3-Methylphenyl


1799
Butyl
4-Methylphenyl


1800
2-Methylpropyl
4-Methylphenyl


1801
Butyl
3-Fluorophenyl


1802
2-Methylpropyl
3-Fluorophenyl


1803
Pentyl
3-Fluorophenyl


1804
3-Methylbutyl
3-Fluorophenyl


1805
Butyl
4-Fluorophenyl


1806
3-Methylbutyl
4-Fluorophenyl


1807
Butyl
2-Fluorophenyl


1808
2-Methylpropyl
2-Fluorophenyl


1809
Pentyl
2-Fluorophenyl


1810
3-Methylbutyl
2-Fluorophenyl


1811
2-Methylpropyl
4-Ethylphenyl


1812
2-Methylpropyl
3,4-Dimethylphenyl


1813
3-Methylbutyl
3-Methoxyphenyl


1814
2-Methylpropyl
3-Fluoro-4-methylphenyl


1815
3-Methylbutyl
3-Fluoro-4-methylphenyl


1816
2-Methylpropyl
5-Fluoro-2-methylphenyl


1817
Pentyl
5-Fluoro-2-methylphenyl


1818
3-Methylbutyl
5-Fluoro-2-methylphenyl


1857
Butyl
2,5-Dichlorophenyl


1858
2-Methylpropyl
2,5-Dichlorophenyl


1859
Pentyl
2,5-Dichlorophenyl


1860
3-Methylbutyl
2,5-Dichlorophenyl


1861
2-Methylpropyl
4-Pentylphenyl


1862
Butyl
3-Bromophenyl


1863
2-Methylpropyl
3-Bromophenyl


1864
Pentyl
3-Bromophenyl


1865
3-Methylbutyl
3-Bromophenyl


1866
2-Methylpropyl
4-Bromophenyl


1922
Butyl
3,4-Dimethylphenyl


1923
2-Methylpropyl
3-Iodo-4-methylphenyl


1924
3-Methylbutyl
3-Iodo-4-methylphenyl


1986
Butyl
4,5-Dimethyl-2-furyl


1987
2-Methylpropyl
4,5-Dimethyl-2-furyl


1988
3-Methylbutyl
4,5-Dimethyl-2-furyl


1989
3-Methylbutyl
4-Methoxy-3-thienyl


1990
Butyl
3-Chloro-2-thienyl


1991
2-Methylpropyl
3-Chloro-2-thienyl


1992
Pentyl
3-Chloro-2-thienyl


1993
3-Methylbutyl
3-Chloro-2-thienyl


1994
2-Methylpropyl
3-Chloro-4-methylphenyl


1995
3-Methylbutyl
3-Chloro-4-methylphenyl


1996
3-Methylbutyl
2,4,5-Trifluorophenyl


1997
Pentyl
2,6-Difluorophenyl


1998
3-Methylbutyl
2,6-Difluorophenyl


1999
Pentyl
2-Bromo-5-methoxyphenyl


2000
3-Methylbutyl
2-Bromo-5-methoxyphenyl


2001
3-Methylbutyl
3,5-Difluorophenyl


2002
2-Methylpropyl
5-Bromo-2-thienyl


2003
3-Methylbutyl
5-Bromo-2-thienyl


2009
Butyl
5-Ethyl-2-thienyl


2010
2-Methylpropyl
5-Ethyl-2-thienyl


2011
3-Methylbutyl
5-Ethyl-2-thienyl


2012
2-Methylpropyl
5-Propyl-2-thienyl


2013
2-Methylpropyl
5-Butyl-2-thienyl


2014
2-Methylpropyl
5-Pentyl-2-thienyl


2015
2-Methylpropyl
5-Hexyl-2-thienyl









EXAMPLE 14




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3

















889
Methyl
2,5-Difluorophenyl


890
Methyl
2,5-Dichlorophenyl


891
Propyl
3-Bromophenyl


892
Methyl
3-Iodophenyl


893
Allyl
3-Iodophenyl


894
Propyl
3-Iodophenyl


1126
Propyl
2,5-Dichlorophenyl


1127
Methyl
3-Bromophenyl


1128
Allyl
3-Bromophenyl


1432
Propyl
3-Bromo-4-fluorophenyl


1517
2-Methylpropyl
3-Fluorophenyl


1518
2-Methylpropyl
3,4-Dimethylphenyl


1519
2-Methylpropyl
3-Methoxyphenyl


1520
2-Methylpropyl
3-Fluoro-4-methylphenyl


1521
Cyclopentyl
3-Fluoro-4-methylphenyl


1522
2-Methylpropyl
5-Fluoro-2-methylphenyl


1523
2-Methylpropyl
2-Fluoro-3-methylphenyl


1524
2-Methylpropyl
3-Chlorophenyl


1525
2-Methylpropyl
4-Chlorophenyl


1567
2-Methylpropyl
1,3-Benzodioxol-5-yl


1568
Cyclopentyl
4-Methoxyphenyl


1569
Cyclopentyl
4-Butylphenyl


1570
3-Methylbutyl
3-Chloro-4-methoxyphenyl


1571
Cyclopentyl
3-Chloro-4-methoxyphenyl


1572
2-Methylpropyl
3,4-Dichlorophenyl


1573
3-Methylbutyl
2,5-Dichlorophenyl


1574
Cyclopentyl
2,4-Dichlorophenyl


1575
Cyclopentyl
4-Pentylphenyl


1576
3-Methylbutyl
3-Bromophenyl


1619
2-Methylpropyl
4-Hexylphenyl


1620
Cyclopentyl
4-Hexylphenyl


1621
2-Methylpropyl
3-Bromo-4-methylphenyl


1622
2-Methylpropyl
3-Bromo-4-fluorophenyl


1623
3-Methylbutyl
3-Bromo-4-fluorophenyl


1624
2-Methylpropyl
3-Iodophenyl


1625
3-Methylbutyl
3-Iodophenyl


1653
2-Methylpropyl
3-Iodo-4-methylphenyl


1654
3-Methylbutyl
2-Thienyl


1655
3-Methylbutyl
Benzyl


1656
2-Methylpropyl
5-Methyl-2-thienyl


1657
3-Methylbutyl
5-Methyl-2-thienyl


1658
3-Methylbutyl
3-Fluorobenzyl


1659
Cyclopentyl
3-Fluorobenzyl


1678
Cyclopentyl
2-Chlorobenzyl


1682
2-Methylpropyl
2-(2-Chlorophenyl)




ethenyl


1683
Cyclopentyl
2-(2-Chlorophenyl)




ethenyl


1701
2-Methylpropyl
2,3,6-Trifluorophenyl


1702
2-Methylpropyl
4,5-Dimethyl-2-furyl









EXAMPLE 15




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







895
Propyl
5-Bromo-2-thienyl


993
Propyl
1,3-Benzodioxol-5-yl









EXAMPLE 16




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3

















896
Propyl
3-Bromo-4-fluorophenyl


897
Allyl
3-Iodophenyl


898
Propyl
3-Iodophenyl


899
Propyl
3-Iodo-4-methylphenyl


900
Methyl
2-Thienyl


901
Methyl
5-Methyl-2-thienyl


923
Propyl
3-Methylphenyl


1117
Propyl
5-Chloro-2-methoxyphenyl


1118
Propyl
2,5-Dichlorophenyl


1119
Propyl
3-Bromophenyl


1979
3-Methylbutyl
3-Chloro-4-methylphenyl


1981
3-Methylbutyl
2,4,5-Trifluorophenyl


1985
3-Methylbutyl
3,5-Difluorophenyl


2007
3-Methylbutyl
5-Bromo-2-thienyl


2386
2-(2-
2,5-Dichlorophenyl



Fluorophenyl)



ethyl


2387
2-(2-
3-Bromophenyl



Fluorophenyl)



ethyl


2388
2-(2-
3-Iodophenyl



Fluorophenyl)



ethyl









EXAMPLE 17




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3

















902
Allyl
3-Bromo-4-methylphenyl


903
Propyl
3-Bromo-4-methylphenyl


904
Allyl
3-Bromo-4-fluorophenyl


905
Propyl
3-Bromo-4-fluorophenyl


906
Methyl
3-Iodophenyl


907
Allyl
3-Iodophenyl


908
Propyl
3-Iodophenyl


909
Propyl
3-Iodo-4-methylphenyl


910
Methyl
2-Thienyl


911
Methyl
3-Thienyl


912
Methyl
3-Methyl-2-thienyl


913
Propyl
5-Methyl-2-thienyl


914
Propyl
Phenyl


915
Methyl
3-Methylphenyl


916
Propyl
3-Fluorophenyl


917
Propyl
2-Fluorophenyl


918
Methyl
5-Fluoro-2-methylphenyl


919
Allyl
5-Fluoro-2-methylphenyl


920
Methyl
3-Chlorophenyl


921
Propyl
3-Chlorophenyl


976
Propyl
2-Chlorophenyl


977
Allyl
3,4-Difluorophenyl


978
Propyl
3,4-Difluorophenyl


979
Methyl
2,3-Difluorophenyl


980
Allyl
2,3-Difluorophenyl


981
Propyl
2,3-Difluorophenyl


982
Methyl
2,5-Difluorophenyl


983
Allyl
2,5-Difluorophenyl


984
Propyl
2,5-Difluorophenyl


985
Propyl
2,4-Difluorophenyl


986
Propyl
1,3-Benzodioxol-5-yl


987
Allyl
3-Chloro-4-fluorophenyl


988
Propyl
3-Chloro-4-fluorophenyl


1120
Allyl
5-Chloro-2-methoxyphenyl


1121
Propyl
5-Chloro-2-methoxyphenyl


1122
Allyl
2,5-Dichlorophenyl


1123
Propyl
2,5-Dichlorophenyl


1124
Allyl
3-Bromophenyl


1125
Propyl
3-Bromophenyl


1516
Methyl
5-Ethoxy-2-thienyl


1706
2-Methylpropyl
2,4,6-Trifluorophenyl


1707
2-Methylpropyl
2,3,6-Trifluorophenyl


1708
3-Methylbutyl
2,3,6-Trifluorophenyl


1709
2-Methylpropyl
4,5-Dimethyl-2-furyl


1710
3-Methylbutyl
4,5-Dimethyl-2-furyl


1711
2-Methylpropyl
3-Chloro-2-thienyl


1712
3-Methylbutyl
3-Chloro-2-thienyl


1713
2-Methylpropyl
5-Methylthio-2-thienyl


1719
2-Methylpropyl
3-Chlorophenyl


1720
3-Methylbutyl
2,4,5-Trifluorophenyl


1725
2-Methylpropyl
2,6-Difluorophenyl


1727
3-Methylbutyl
Phenyl


1728
2-Methylpropyl
3-Methylphenyl


1729
3-Methylbutyl
3-Methylphenyl


1730
2-Methylpropyl
4-Methylphenyl


1731
3-Methylbutyl
4-Methylphenyl


1732
2-Methylpropyl
2-Methylphenyl


1733
3-Methylbutyl
2-Methylphenyl


1734
2-Methylpropyl
3-Fluorophenyl


1735
3-Methylbutyl
3-Fluorophenyl


1736
2-Methylpropyl
3-Fluorophenyl


1737
3-Methylbutyl
4-Fluorophenyl


1738
2-Methylpropyl
2-Fluorophenyl


1739
3-Methylbutyl
2-Fluorophenyl


1740
2-Methylpropyl
4-Ethylphenyl)


1741
2-Methylpropyl
3,4-Dimethylphenyl


1742
2-Methylpropyl
3-Fluoro-4-methylphenyl


1743
Cyclopentyl
3-Fluoro-4-methylphenyl


1744
2-Methylpropyl
4-Chlorophenyl


1745
Cyclopentyl
4-Methoxyphenyl


1746
3-Methylbutyl
3-Chloro-4-fluorophenyl


1747
3-Methylbutyl
2-Thienyl









EXAMPLE 18




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







812
Methyl
2,5-Difluorophenyl


813
Propyl
2,5-Dichlorophenyl


814
Propyl
3-Iodophenyl









EXAMPLE 19




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3

















818
Propyl
3-Fluorophenyl


819
Propyl
2-Fluorophenyl


820
Propyl
3,4-Difluorophenyl


821
Methyl
2,5-Difluorophenyl


822
Allyl
2,5-Difluorophenyl


823
Propyl
2,5-Difluorophenyl


824
Propyl
1,3-Benzodioxol-5-yl


825
Propyl
3-Chloro-4-fluorophenyl


826
Methyl
5-Chloro-2-methoxyphenyl


827
Ethyl
5-Chloro-2-methoxyphenyl


828
Allyl
5-Chloro-2-methoxyphenyl


829
Propyl
5-Chloro-2-methoxyphenyl


830
Methyl
2,5-Dichlorophenyl


831
Allyl
2,5-Dichlorophenyl


832
Propyl
2,5-Dichlorophenyl


833
Propyl
Phenyl


834
Propyl
3-Fluoro-4-methylphenyl


835
Propyl
5-Fluoro-2-methylphenyl


836
Methyl
3-Chlorophenyl


837
Allyl
3-Chlorophenyl


838
Propyl
3-Chlorophenyl


842
Methyl
5-Chloro-2-methoxyphenyl


843
Ethyl
5-Chloro-2-methoxyphenyl


844
Allyl
5-Chloro-2-methoxyphenyl


845
Propyl
5-Chloro-2-methoxyphenyl


846
Methyl
3-Trifluorophenyl


847
Propyl
3-Trifluorophenyl


848
Methyl
2,5-Dichlorophenyl


849
Allyl
2,5-Dichlorophenyl


850
Propyl
2,5-Dichlorophenyl


851
Methyl
3-Bromophenyl


852
Allyl
3-Bromophenyl


853
Propyl
3-Bromophenyl


854
Propyl
3-Bromo-4-fluorophenyl


855
Methyl
3-Iodophenyl


856
Allyl
3-Iodophenyl


857
Propyl
3-Iodophenyl


859
Allyl
2-Fluorophenyl


860
Propyl
2-Fluorophenyl


861
Propyl
2-Chlorophenyl


862
Propyl
3,4-Difluorophenyl


863
Propyl
2,3-Difluorophenyl


864
Methyl
2,5-Difluorophenyl


865
Propyl
4-Methylthio




phenyl


866
Propyl
3-Fluoro-4-methoxphenyl


867
Propyl
4-Chloro-3-methylphenyl


868
Methyl
3-Chloro-4-fluorophenyl


869
Allyl
3-Chloro-4-fluorophenyl


870
Propyl
3-Chloro-4-fluorophenyl


871
Propyl
3,4,5-Trifluorophenyl


872
Propyl
4-Butylphenyl


873
Propyl
4-Methylthio




phenyl


1772
Butyl
2-Thienyl


1773
2-Methylpropyl
2-Thienyl


1774
Pentyl
2-Thienyl


1775
3-Methylbutyl
2-Thienyl


1776
Butyl
3-Thienyl


1777
2-Methylpropyl
3-Thienyl


1778
Pentyl
3-Thienyl


1779
3-Methylbutyl
3-Thienyl


1780
3-Methylbutyl
Benzyl


1781
Butyl
5-Methyl-2-thienyl


1782
2-Methylpropyl
5-Methyl-2-thienyl


1783
Pentyl
5-Methyl-2-thienyl


1784
3-Methylbutyl
5-Methyl-2-thienyl


1785
3-Methylbutyl
3-Fluorobenzyl


1786
3-Methylbutyl
3-Methoxybenzyl


1819
Butyl
Phenyl


1820
2-Methylpropyl
Phenyl


1821
Pentyl
Phenyl


1822
3-Methylbutyl
Phenyl


1823
Butyl
3-Methylphenyl


1824
2-Methylpropyl
3-Methylphenyl


1825
Pentyl
3-Methylphenyl


1826
3-Methylbutyl
3-Methylphenyl


1827
Butyl
4-Methylphenyl


1828
2-Methylpropyl
4-Methylphenyl


1829
3-Methylbutyl
4-Methylphenyl


1830
Butyl
3-Fluorophenyl


1831
2-Methylpropyl
3-Fluorophenyl


1832
Pentyl
3-Fluorophenyl


1833
3-Methylbutyl
3-Fluorophenyl


1834
Butyl
4-Fluorophenyl


1835
2-Methylpropyl
4-Fluorophenyl


1836
Pentyl
4-Fluorophenyl


1837
3-Methylbutyl
4-Fluorophenyl


1838
Butyl
2-Fluorophenyl


1839
2-Methylpropyl
2-Fluorophenyl


1840
Pentyl
2-Fluorophenyl


1841
3-Methylbutyl
2-Fluorophenyl


1842
2-Methylpropyl
4-Ethylphenyl


1843
2-Methylpropyl
3,4-Dimethylphenyl


1844
3-Methylbutyl
2,5-Dimethylphenyl


1845
2-Methylpropyl
2,4-Dimethylphenyl


1846
2-Methylpropyl
3-Methoxyphenyl


1847
3-Methylbutyl
3-Methoxyphenyl


1848
3-Methylbutyl
2-Methoxyphenyl


1849
2-Methylpropyl
3-Fluoro-4-methylphenyl


1850
3-Methylbutyl
3-Fluoro-4-methylphenyl


1851
Butyl
5-Fluoro-2-methylphenyl


1852
2-Methylpropyl
5-Fluoro-2-methylphenyl


1853
Pentyl
5-Fluoro-2-methylphenyl


1854
3-Methylbutyl
5-Fluoro-2-methylphenyl


1855
2-Methylpropyl
4-Chlorophenyl


1856
3-Methylbutyl
4-Chlorophenyl


1867
2-Methylpropyl
2,5-Dichlorophenyl


1868
Pentyl
2,5-Dichlorophenyl


1869
3-Methylbutyl
2,5-Dichlorophenyl


1870
2-Methylpropyl
4-Pentylphenyl


1871
2-Methylpropyl
3-Bromophenyl


1872
Pentyl
3-Bromophenyl


1873
3-Methylbutyl
3-Bromophenyl


1925
2-Methylpropyl
3-Iodo-4-methylphenyl


1926
3-Methylbutyl
3-Iodo-4-methylphenyl


1928
Butyl
2-Chlorophenyl


1929
2-Methylpropyl
2-Chlorophenyl


1930
Pentyl
2-Chlorophenyl


1931
Butyl
3,4-Difluorophenyl


1932
2-Methylpropyl
3,4-Difluorophenyl


1933
Pentyl
3,4-Difluorophenyl


1934
3-Methylbutyl
3,4-Difluorophenyl


1935
Butyl
2,3-Difluorophenyl


1936
2-Methylpropyl
2,3-Difluorophenyl


1937
Pentyl
2,3-Difluorophenyl


1938
3-Methylbutyl
2,3-Difluorophenyl


1939
Butyl
2,5-Difluorophenyl


1940
2-Methylpropyl
2,5-Difluorophenyl


1941
Pentyl
2,5-Difluorophenyl


1942
3-Methylbutyl
2,5-Difluorophenyl


1943
Butyl
2,4-Difluorophenyl


1944
2-Methylpropyl
2,4-Difluorophenyl


1945
Pentyl
2,4-Difluorophenyl


1946
3-Methylbutyl
2,4-Difluorophenyl


1947
2-Methylpropyl
4-Propylphenyl


1948
2-Methylpropyl
4-i-Propylphenyl


1949
Butyl
1,3-Benzodioxol-5-yl


1950
2-Methylpropyl
1,3-Benzodioxol-5-yl


1951
Pentyl
1,3-Benzodioxol-5-yl


1952
3-Methylbutyl
1,3-Benzodioxol-5-yl


1953
Butyl
3-Bromo-4-methylphenyl


1954
2-Methylpropyl
3-Bromo-4-methylphenyl


1955
Pentyl
3-Bromo-4-Methylphenyl


1956
3-Methylbutyl
3-Bromo-4-methylphenyl


1957
2-Methylpropyl
4-Heptylphenyl


1958
Butyl
3-Iodophenyl


1959
2-Methylpropyl
3-Iodophenyl


1960
Pentyl
3-Iodophenyl


1961
3-Methylbutyl
3-Iodophenyl


1962
2-Methylpropyl
4-Iodophenyl


2016
Butyl
5-Ethyl-2-thienyl


2017
2-Methylpropyl
5-Ethyl-2-thienyl


2018
3-Methylbutyl
5-Ethyl-2-thienyl


2019
2-Methylpropyl
5-Propyl-2-thienyl









EXAMPLE 20




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3

















874
Methyl
3-Fluorophenyl


875
Allyl
3-Fluorophenyl


876
Propyl
3-Fluorophenyl


877
Propyl
4-Fluorophenyl


878
Methyl
3-Chloro-4-methylphenyl


879
Allyl
3-Chloro-4-methylphenyl


880
Propyl
3-Chloro-4-methylphenyl


881
Allyl
5-Bromo-2-thienyl


882
Propyl
5-Bromo-2-thienyl


883
Propyl
3-Fluoro-4-methylphenyl


884
Propyl
5-Fluoro-2-methylphenyl


922
Propyl
3-Methoxyphenyl


1450
Propyl
3-Bromo-4-methylphenyl


1451
Allyl
3-Bromo-4-fluorophenyl


1452
Propyl
3-Bromo-4-fluorophenyl


1453
Allyl
3-Iodophenyl


1454
Propyl
3-Iodophenyl


1455
Allyl
5-Chloro-2-methoxyphenyl


1456
Propyl
5-Chloro-2-methoxyphenyl


1457
Propyl
3,4-Dichlorophenyl


1458
Ethyl
2,5-Dichlorophenyl


1459
Allyl
2,5-Dichlorophenyl


1460
Propyl
2,5-Dichlorophenyl


1461
Propyl
2,4-Dichlorophenyl


1462
Ethyl
3-Bromophenyl


1463
Allyl
3-Bromophenyl


1464
Propyl
3-Bromophenyl


1465
Propyl
5-Methyl-2-thienyl


1466
Propyl
4-Chloro-3-methylphenyl


1467
Propyl
3-Chloro-4-fluorophenyl


1526
2-Methylpropyl
Phenyl


1527
3-Methylbutyl
Phenyl


1528
2-Methylpropyl
3-Methylphenyl


1529
3-Methylbutyl
3-Methylphenyl


1530
2-Methylpropyl
4-Methylphenyl


1531
Cyclopentyl
4-Methylphenyl


1532
2-Methylpropyl
2-Methylphenyl


1533
3-Methylbutyl
2-Methylphenyl


1534
2-Methylpropyl
3-Fluorophenyl


1535
3-Methylbutyl
3-Fluorophenyl


1536
2-Methylpropyl
4-Fluorophenyl


1537
3-Methylbutyl
4-Fluorophenyl


1538
2-Methylpropyl
2-Fluorophenyl


1539
Cyclopentyl
2-Fluorophenyl


1540
2-Methylpropyl
4-Ethylphenyl


1541
2-Methylpropyl
3,4-Dimethylphenyl


1542
2-Methylpropyl
2,3-Dimethylphenyl


1543
2-Methylpropyl
2,5-Dimethylphenyl


1544
3-Methylbutyl
2,5-Dimethylphenyl


1545
2-Methylpropyl
2,4-Dimethylphenyl


1546
3-Methylbutyl
2,4-Dimethylphenyl


1547
Cyclopentyl
2,4-Dimethylphenyl


1548
2-Methylpropyl
3-Methoxyphenyl


1549
3-Methylbutyl
3-Methoxyphenyl


1550
2-Methylpropyl
4-Methoxyphenyl


1551
3-Methylbutyl
4-Methoxyphenyl


1552
Cyclopentyl
4-Methoxyphenyl


1553
2-Methylpropyl
2-Methoxyphenyl


1554
3-Methylbutyl
2-Methoxyphenyl


1555
2-Methylpropyl
3-Fluoro-4-methylphenyl


1556
Cyclopentyl
3-Fluoro-4-methylphenyl


1557
2-Methylpropyl
3-Fluoro-2-methylphenyl


1558
3-Methylbutyl
3-Fluoro-2-methylphenyl


1559
2-Methylpropyl
5-Fluoro-2-methylphenyl


1560
3-Methylbutyl
5-Fluoro-2-methylphenyl


1561
2-Methylpropyl
2-Fluoro-3-methylphenyl


1562
2-Methylpropyl
3-Chlorophenyl


1563
3-Methylbutyl
3-Chlorophenyl


1564
Cyclopentyl
3-Chlorophenyl


1565
2-Methylpropyl
4-Chlorophenyl


1566
Cyclopentyl
4-Chlorophenyl


1577
3-Methylbutyl
2-Chlorophenyl


1578
Cyclopentyl
2-Chlorophenyl


1579
2-Methylpropyl
3,4-Difluorophenyl


1580
3-Methylbutyl
3,4-Difluorophenyl


1581
2-Methylpropyl
2,3-Difluorophenyl


1582
3-Methylbutyl
2,3-Difluorophenyl


1583
Cyclopentyl
2,3-Difluorophenyl


1584
2-Methylpropyl
2,5-Difluorophenyl


1585
3-Methylbutyl
2,5-Difluorophenyl


1586
2-Methylpropyl
2,4-Difluorophenyl


1587
3-Methylbutyl
2,4-Difluorophenyl


1588
Cyclopentyl
2,4-Difluorophenyl


1589
2-Methylpropyl
1,3-Benzodioxol-5-yl


1590
3-Methylbutyl
1,3-Benzodioxol-5-yl


1591
Cyclopentyl
1,3-Benzodioxol-5-yl


1592
2-Methylpropyl
4-Methylthiophenyl


1593
Cyclopentyl
4-Methylthiophenyl


1594
Cyclopentyl
3-Fluoro-4-methoxy


1595
Cyclopentyl
4-Butylphenyl


1596
Cyclopentyl
4-Ethylthiophenyl


1597
2-Methylpropyl
3-Chloro-4-methoxyphenyl


1598
3-Methylbutyl
3-Chloro-4-methoxyphenyl


1599
Cyclopentyl
3-Chloro-4-methoxyphenyl


1600
2-Methylpropyl
2-Trifluoromethylphenyl


1601
3-Methylbutyl
2-Trifluoromethylphenyl


1602
2-Methylpropyl
3,4-Dichlorophenyl


1603
3-Methylbutyl
3,4-Dichlorophenyl


1604
2-Methylpropyl
2,3-Dichlorophenyl


1605
2-Methylpropyl
2,5-Dichlorophenyl


1606
3-Methylbutyl
2,5-Dichlorophenyl


1607
2-Methylpropyl
2,4-Dichlorophenyl


1608
Cyclopentyl
2,4-Dichlorophenyl


1609
2-Methylpropyl
3-Bromophenyl


1610
3-Methylbutyl
3-Bromophenyl


1611
Cyclopentyl
3-Bromophenyl


1612
2-Methylpropyl
4-Bromophenyl


1613
Cyclopentyl
4-Bromophenyl


1614
2-Methylpropyl
2-Bromophenyl


1615
3-Methylbutyl
2-Bromophenyl


1626
2-Methylpropyl
3-Bromo-4-methylphenyl


1627
3-Methylbutyl
3-Bromo-4-methylphenyl


1628
Cyclopentyl
3-Bromo-4-methylphenyl


1629
2-Methylpropyl
3-Bromo-4-fluorophenyl


1630
3-Methylbutyl
3-Bromo-4-fluorophenyl


1631
2-Methylpropyl
3-Iodophenyl


1632
3-Methylbutyl
3-Iodophenyl


1633
2-Methylpropyl
4-Iodophenyl


1660
2-Methylpropyl
3-Iodo-4-methylphenyl


1661
2-Methylpropyl
4-Iodobenzyl


1662
2-Methylpropyl
2-Thienyl


1663
3-Methylbutyl
2-Thienyl


1664
2-Methylpropyl
Benzyl


1665
3-Methylbutyl
Benzyl


1666
Cyclopentyl
Benzyl


1667
2-Methylpropyl
5-Methyl-2-thienyl


1668
3-Methylbutyl
5-Methyl-2-thienyl


1669
Cyclopentyl
5-Methyl-2-thienyl


1670
Cyclopentyl
3-Methylbenzyl


1671
2-Methylpropyl
3-Fluorobenzyl


1672
3-Methylbutyl
3-Fluorobenzyl


1673
Cyclopentyl
3-Fluorobenzyl


1679
3-Methylbutyl
2-Methoxybenzyl


1680
Cyclopentyl
1-(4-Fluorophenyl)




ethyl


1681
Cyclopentyl
2-Chlorobenzyl


1684
Cyclopentyl
2-(2-Chlorophenyl)




ethenyl


1703
2-Methylpropyl
2,4,6-Trifluorophenyl


1704
2-Methylpropyl
2,3,6-Trifluorophenyl


1705
2-Methylpropyl
2-Chloro-6-fluorophenyl


1714
2-Methylpropyl
3-Chloro-4-methylphenyl









EXAMPLE 21




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3

















923
Propyl
Phenyl


924
Propyl
3-Methylphenyl


925
Propyl
4-Methylphenyl


926
Propyl
3-Fluorophenyl


927
Methyl
2-Fluorophenyl


928
Allyl
2-Fluorophenyl


929
Propyl
2-Fluorophenyl


1000
Methyl
2,3-Difluorophenyl


1001
Methyl
2,5-Difluorophenyl


1129
Ethyl
5-Chloro-2-methoxyphenyl


2307
3-Methylbutyl
2,3,6-Trifluorophenyl









EXAMPLE 22




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3

















955
Methyl
Phenyl


956
Propyl
Phenyl


957
Methyl
3-Methylphenyl


958
Propyl
3-Methylphenyl


959
Methyl
3-Fluorophenyl


960
Propyl
3-Fluorophenyl


961
Methyl
2-Fluorophenyl


962
Allyl
2-Fluorophenyl


963
Propyl
2-Fluorophenyl


964
Methyl
5-Fluoro-2-methylphenyl


965
Methyl
3-Chlorophenyl


966
Propyl
3-Chlorophenyl


989
Propyl
3-Chloro-4-fluorophenyl


994
Methyl
2-Thienyl


995
Propyl
2-Thienyl


996
Methyl
3-Thienyl


997
Methyl
3-Methyl-2-thienyl


998
Methyl
5-Methyl-2-thienyl


999
Propyl
5-Methyl-2-thienyl


1100
Propyl
5-Chloro-2-methoxyphenyl


1101
Methyl
3-Bromophenyl


1102
Propyl
3-Bromophenyl









EXAMPLE 23




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3

















967
Propyl
Phenyl


968
Propyl
3-Methylphenyl


969
Propyl
4-Methylphenyl


970
Propyl
3-Fluorophenyl


971
Propyl
2-Fluorophenyl


972
Propyl
5-Fluoro-2-methylphenyl


973
Ethyl
3-Chlorophenyl


974
Allyl
3-Chlorophenyl


975
Propyl
3-Chlorophenyl


990
Propyl
1,3-Benzodioxol-5-yl


991
Allyl
3-Chloro-4-fluorophenyl


992
Propyl
3-Chloro-4-fluorophenyl


1103
Propyl
5-Chloro-2-methoxyphenyl


1104
Propyl
3-Trifluoromethylphenyl


1105
Propyl
3,4-Dichlorophenyl


1106
Allyl
2,5-Dichlorophenyl


1107
Allyl
3-Bromophenyl


1108
Propyl
3-Bromophenyl


1187
Propyl
3-Bromo-4-methylphenyl


1188
Methyl
3-Bromo-4-fluorophenyl


1189
Allyl
3-Bromo-4-fluorophenyl


1190
Propyl
3-Bromo-4-fluorophenyl


1191
Methyl
3-Iodophenyl


1192
Allyl
3-Iodophenyl


1193
Propyl
3-Iodophenyl


1207
Propyl
3-Bromo-4-fluorophenyl


1208
Methyl
3-Bromo-4-fluorophenyl


1209
Allyl
3-Bromo-4-fluorophenyl


1210
Propyl
3-Bromo-4-fluorophenyl


1211
Methyl
3-Iodophenyl


1212
Ethyl
3-Iodophenyl


1213
Allyl
3-Iodophenyl


1214
Propyl
3-Iodophenyl


1215
Propyl
3-Iodo-4-methylphenyl


1216
Methyl
2-Thienyl


1217
Propyl
2-Thienyl


1218
Allyl
5-Methyl-2-thienyl


1219
Propyl
5-Methyl-2-thienyl









EXAMPLE 24




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







1220
2-Methylpropyl
Phenyl


1221
2-Methylpropyl
3-Methylphenyl


1222
2-Methylpropyl
4-Methylphenyl


1223
2-Methylpropyl
2-Fluorophenyl


1224
2-Methylpropyl
4-Ethylphenyl


1225
2-Methylpropyl
3,4-Dimethylphenyl


1227
2-Methylpropyl
2,5-Difluorophenyl


1228
2-Methylpropyl
2,4-Difluorophenyl


1229
2-Methylpropyl
1,3-Benzodioxol-5-yl


1230
2-Methylpropyl
4-Bromophenyl


1251
2-Methylpropyl
3-Bromo-4-methylphenyl


1272
2-Methylpropyl
3-Chloro-4-methylphenyl


1273
2-Methylpropyl
2,4,5-Trifluorophenyl









EXAMPLE 25




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







1226
Propyl
2-Fluorophenyl


1231
Allyl
5-Chloro-2-methoxyphenyl


1232
Propyl
5-Chloro-2-methoxyphenyl


1233
Methyl
2,5-Dichlorophenyl


1234
Allyl
2,5-Dichlorophenyl


1235
Propyl
2,5-Dichlorophenyl


1236
Methyl
3-Bromophenyl


1237
Allyl
3-Bromophenyl


1238
Propyl
3-Bromophenyl


1252
Propyl
3-Iodophenyl


1748
2-Methylpropyl
2,3,6-Trifluorophenyl


1749
3-Methylbutyl
2,3,6-Trifluorophenyl


1750
2-Methylpropyl
3-Chloro-4-phenyl


1751
3-Methylbutyl
3-Chloro-4-phenyl


1752
2-Methylpropyl
2,4,5-Trifluorophenyl


1753
3-Methylbutyl
2,4,5-Trifluorophenyl


1754
2-Methylpropyl
2,6-Difluorophenyl


1755
3-Methylbutyl
2,6-Difluorophenyl


1881
Butyl
Phenyl


1882
2-Methylpropyl
Phenyl


1883
Pentyl
Phenyl


1884
3-Methylbutyl
Phenyl


1885
Butyl
3-Methylphenyl


1886
2-Methylpropyl
3-Methylphenyl


1887
Pentyl
3-Methylphenyl


1888
3-Methylbutyl
3-Methylphenyl


1889
2-Methylpropyl
4-Methylphenyl


1890
3-Methylbutyl
4-Methylphenyl


1891
Butyl
3-Fluorophenyl


1892
2-Methylpropyl
3-Fluorophenyl


1893
Pentyl
3-Fluorophenyl


1894
3-Methylbutyl
3-Fluorophenyl


1895
2-Methylpropyl
4-Fluorophenyl


1896
3-Methylbutyl
4-Fluorophenyl


1897
Butyl
2-Fluorophenyl


1898
2-Methylpropyl
2-Fluorophenyl


1899
Pentyl
2-Fluorophenyl


1900
3-Methylbutyl
2-Fluorophenyl


1901
2-Methylpropyl
3,4-Dimethylphenyl


1902
Butyl
2-Chlorophenyl


1903
2-Methylpropyl
2-Chlorophenyl


1904
Pentyl
2-Chlorophenyl


1905
3-Methylbutyl
2-Chlorophenyl


1906
Butyl
3,4-Difluorophenyl


1907
2-Methylpropyl
3,4-Difluorophenyl


1908
Pentyl
3,4-Difluorophenyl


1909
3-Methylbutyl
3,4-Difluorophenyl


1910
Butyl
2,3-Difluorophenyl


1911
2-Methylpropyl
2,3-Difluorophenyl


1912
Pentyl
2,3-Difluorophenyl


1913
3-Methylbutyl
2,3-Difluorophenyl


1914
Butyl
2,5-Difluorophenyl


1915
2-Methylpropyl
2,5-Difluorophenyl


1916
Pentyl
2,5-Difluorophenyl


1917
3-Methylbutyl
2,5-Difluorophenyl


1918
2-Methylpropyl
2,4-Difluorophenyl


1919
3-Methylbutyl
2,4-Difluorophenyl


1920
2-Methylpropyl
1,3-Benzodioxol-5-yl


1921
3-Methylbutyl
1,3-Benzodioxol-5-yl


1927
3-Methylbutyl
3-Iodo-4-methylphenyl


1963
2-Methylpropyl
2-(2-Chlorophenyl)




ethenyl


1964
Butyl
2-Thienyl


1965
Pentyl
2-Thienyl


1966
3-Methylbutyl
2-Thienyl


1967
Pentyl
3-Thienyl


1968
3-Methylbutyl
3-Thienyl


1969
3-Methylbutyl
Benzyl


1970
Butyl
5-Methyl-2-thienyl


1971
2-Methylpropyl
5-Methyl-2-thienyl


1972
Pentyl
5-Methyl-2-thienyl


1973
3-Methylbutyl
5-Methyl-2-thienyl


1974
3-Methylbutyl
3-Fluorobenzyl


1975
3-Methylbutyl
3-Methoxybenzyl









EXAMPLE 26




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







1250
Propyl
3-Iodophenyl


1616
2-Methylpropyl
3-Chloro-4-fluorophenyl


1617
2-Methylpropyl
3-Bromophenyl


1618
3-Methylbutyl
3-Bromophenyl


1634
2-Methylpropyl
3-Bromo-4-methylphenyl


1635
2-Methylpropyl
3-Bromo-4-fluorophenyl


1636
3-Methylbutyl
3-Bromo-4-fluorophenyl


1637
2-Methylpropyl
3-Iodophenyl


1638
3-Methylbutyl
3-Bromo-4-fluorophenyl


1639
2-Methylpropyl
Phenyl


1640
3-Methylbutyl
Phenyl


1641
2-Methylpropyl
3-Methylphenyl


1642
3-Methylbutyl
3-Methylphenyl


1643
2-Methylpropyl
4-Methylphenyl


1644
2-Methylpropyl
3-Fluorophenyl


1645
3-Methylbutyl
3-Fluorophenyl


1646
2-Methylpropyl
4-Fluorophenyl


1647
2-Methylpropyl
2-Fluorophenyl


1648
3-Methylbutyl
2-Fluorophenyl


1649
2-Methylpropyl
3,4-Dimethylphenyl


1650
2-Methylpropyl
3-Fluoro-4-methylphenyl


1651
2-Methylpropyl
3-Chlorophenyl


1652
3-Methylbutyl
3-Chlorophenyl


1674
2-Methylpropyl
3-Iodo-4-methylphenyl


1675
2-Methylpropyl
5-Methyl-2-thienyl


1676
3-Methylbutyl
5-Methyl-2-thienyl


1677
3-Methylbutyl
3-Fluorobenzyl


1715
2-Methylpropyl
3-Chloro-4-methylphenyl


1716
2-Methylpropyl
2,4,5-Trifluorophenyl


1874
Butyl
3,4-Dimethylphenyl


1875
2-Methylpropyl
3,4-Dimethylphenyl


1876
3-Methylbutyl
3,4-Dimethylphenyl


1877
3-Methylbutyl
2,3-Dimethylphenyl


1878
2-Methylpropyl
2,5-Dimethylphenyl


1879
3-Methylbutyl
2,5-Dimethylphenyl


1880
2-Methylpropyl
1,3-Benzodioxol-5-yl


1976
3-Methylbutyl
3-Methoxybenzyl


2262
Benzyl
3-Chlorophenyl


2282
Benzyl
5-Chloro-2-methoxyphenyl


2293
Benzyl
3-Bromophenyl


2299
Benzyl
3-Iodophenyl









EXAMPLE 27




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







1276
2-Methylpropyl
Phenyl


1277
Pentyl
Phenyl


1278
3-Methylbutyl
Phenyl


1279
3-Methylbutyl
3-Methylphenyl


1280
2-Methylpropyl
4-Methylphenyl


1281
2-Methylpropyl
3-Fluorophenyl


1282
3-Methylbutyl
3-Fluorophenyl


1283
2-Methylpropyl
4-Fluorophenyl


1284
Butyl
2-Fluorophenyl


1285
2-Methylpropyl
2-Fluorophenyl


1286
Pentyl
2-Fluorophenyl


1287
3-Methylbutyl
2-Fluorophenyl


1288
2-Methylpropyl
3-Methoxyphenyl


1289
3-Methylbutyl
3-Methoxyphenyl


1290
3-Methylbutyl
4-Methoxyphenyl


1291
2-Methylpropyl
3-Fluoro-4-methylphenyl


1292
3-Methylbutyl
2-Fluoro-3-methylphenyl


1293
Butyl
3-Chlorophenyl


1294
2-Methylpropyl
3-Chlorophenyl


1295
Pentyl
3-Chlorophenyl


1296
3-Methylbutyl
3-Chlorophenyl


1297
2-Methylpropyl
3,4-Difluorophenyl


1298
2-Methylpropyl
2,3-Difluorophenyl


1299
3-Methylbutyl
2,3-Difluorophenyl


1300
3-Methylbutyl
2,5-Difluorophenyl


1301
2-Methylpropyl
1,3-Benzodioxol-5-yl


1302
2-Methylpropyl
1,3-Benzodioxol-5-yl


1386
3-Methylbutyl
5-Chloro-2-methoxyphenyl


1387
3-Methylbutyl
3-Bromophenyl


1388
2-Methylpropyl
4-Bromophenyl


1389
2-Methylpropyl
5-Methyl-2-thienyl


1390
3-Methylbutyl
5-Methyl-2-thienyl


1685
3-Methylbutyl
2,3,6-Trifluorophenyl









EXAMPLE 28




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







1303
Butyl
Phenyl


1304
2-Methylpropyl
Phenyl


1305
Pentyl
Phenyl


1306
3-Methylbutyl
Phenyl


1307
Butyl
3-Methylphenyl


1308
2-Methylpropyl
3-Methylphenyl


1309
Pentyl
3-Methylphenyl


1310
3-Methylbutyl
3-Methylphenyl


1311
Butyl
4-Methylphenyl


1312
2-Methylpropyl
4-Methylphenyl


1313
3-Methylbutyl
4-Methylphenyl


1314
3-Methylbutyl
2-Methylphenyl


1315
Butyl
3-Fluorophenyl


1316
2-Methylpropyl
3-Fluorophenyl


1317
Pentyl
3-Fluorophenyl


1318
3-Methylbutyl
3-Fluorophenyl


1319
2-Methylpropyl
4-Fluorophenyl


1320
3-Methylbutyl
4-Fluorophenyl


1321
Butyl
2-Fluorophenyl


1322
2-Methylpropyl
2-Fluorophenyl


1323
Pentyl
2-Fluorophenyl


1324
3-Methylbutyl
2-Fluorophenyl


1325
2-Methylpropyl
4-Ethylphenyl


1326
Butyl
3,4-Dimethylphenyl


1327
2-Methylpropyl
3,4-Dimethylphenyl


1328
3-Methylbutyl
3,4-Dimethylphenyl


1329
2-Methylpropyl
2,4-Dimethylphenyl


1330
Butyl
3-Methoxyphenyl


1331
2-Methylpropyl
3-Methoxyphenyl


1332
Pentyl
3-Methoxyphenyl


1333
3-Methylbutyl
3-Methoxyphenyl


1334
Butyl
4-Methoxyphenyl


1335
2-Methylpropyl
4-Methoxyphenyl


1336
3-Methylbutyl
4-Methoxyphenyl


1337
Pentyl
2-Methoxyphenyl


1338
3-Methylbutyl
2-Methoxyphenyl


1339
Butyl
3-Fluoro-4-methylphenyl


1340
Pentyl
3-Fluoro-4-methylphenyl


1341
3-Methylbutyl
3-Fluoro-4-methylphenyl


1342
3-Methylbutyl
3-Fluoro-2-methylphenyl


1343
Butyl
2-Fluoro-3-methylphenyl


1344
2-Methylpropyl
2-Fluoro-3-methylphenyl


1345
Pentyl
2-Fluoro-3-methylphenyl


1346
3-Methylbutyl
2-Fluoro-3-methylphenyl


1347
Butyl
3-Chlorophenyl


1348
2-Methylpropyl
3-Chlorophenyl


1349
Pentyl
3-Chlorophenyl


1350
3-Methylbutyl
3-Chlorophenyl


1351
2-Methylpropyl
4-Chlorophenyl


1352
Pentyl
4-Chlorophenyl


1353
3-Methylbutyl
4-Chlorophenyl


1354
Butyl
2-Chlorophenyl


1355
2-Methylpropyl
2-Chlorophenyl


1356
Pentyl
2-Chlorophenyl


1357
3-Methylbutyl
2-Chlorophenyl


1358
Butyl
3,4-Difluorophenyl


1359
2-Methylpropyl
3,4-Difluorophenyl


1360
Pentyl
3,4-Difluorophenyl


1361
3-Methylbutyl
3,4-Difluorophenyl


1362
Butyl
2,3-Difluorophenyl


1363
2-Methylpropyl
2,3-Difluorophenyl


1364
Pentyl
2,3-Difluorophenyl


1365
3-Methylbutyl
2,3-Difluorophenyl


1366
Butyl
2,5-Difluorophenyl


1367
2-Methylpropyl
2,5-Difluorophenyl


1368
Pentyl
2,5-Difluorophenyl


1369
3-Methylbutyl
2,5-Difluorophenyl


1370
Butyl
2,4-Difluorophenyl


1371
2-Methylpropyl
2,4-Difluorophenyl


1372
Pentyl
2,4-Difluorophenyl


1373
3-Methylbutyl
2,4-Difluorophenyl


1374
2-Methylpropyl
3-Ethoxyphenyl


1375
3-Methylbutyl
3-Ethoxyphenyl


1376
Butyl
1,3-Benzodioxol-5-yl


1377
2-Methylpropyl
1,3-Benzodioxol-5-yl


1378
Pentyl
1,3-Benzodioxol-5-yl


1379
3-Methylbutyl
1,3-Benzodioxol-5-yl


1380
Butyl
4-Methylthio




phenyl


1381
2-Methylpropyl
4-Methylthio




phenyl


1382
3-Methylbutyl
3-Fluoro-4-methoxyphenyl


1383
Butyl
3-Chloro-4-fluorophenyl


1384
2-Methylpropyl
3-Chloro-4-fluorophenyl


1385
3-Methylbutyl
3-Chloro-4-fluorophenyl


1391
3-Methylbutyl
3-Chloro-4-methoxyphenyl


1392
Pentyl
5-Chloro-2-methoxyphenyl


1393
3-Methylbutyl
5-Chloro-2-methoxyphenyl


1394
2-Methylpropyl
3,4-Dichlorophenyl


1395
3-Methylbutyl
3,4-Dichlorophenyl


1396
Butyl
2,5-Dichlorophenyl


1397
2-Methylpropyl
2,5-Dichlorophenyl


1398
Pentyl
2,5-Dichlorophenyl


1399
3-Methylbutyl
2,5-Dichlorophenyl


1400
2-Methylpropyl
2,4-Dichlorophenyl


1401
3-Methylbutyl
2,4-Dichlorophenyl


1402
Butyl
3-Bromophenyl


1403
2-Methylpropyl
3-Bromophenyl


1404
Pentyl
3-Bromophenyl


1405
3-Methylbutyl
3-Bromophenyl


1406
2-Methylpropyl
4-Bromophenyl


1407
3-Methylbutyl
4-Bromophenyl


1408
3-Methylbutyl
2-Bromophenyl


1409
3-Methylbutyl
3-Bromo-4-methylphenyl


1410
Butyl
3-Bromo-4-fluorophenyl


1411
2-Methylpropyl
3-Bromo-4-fluorophenyl


1412
Pentyl
3-Bromo-4-fluorophenyl


1413
3-Methylbutyl
3-Bromo-4-fluorophenyl


1414
Butyl
3-Iodophenyl


1415
2-Methylpropyl
3-Iodophenyl


1416
Pentyl
3-Iodophenyl


1417
3-Methylbutyl
3-Iodophenyl


1418
Butyl
5-Methyl-2-thienyl


1419
2-Methylpropyl
5-Methyl-2-thienyl


1420
Pentyl
5-Methyl-2-thienyl


1421
3-Methylbutyl
5-Methyl-2-thienyl


1422
3-Methylbutyl
3-Fluorobenzyl


1423
3-Methylbutyl
3-Methoxybenzyl


1424
3-Methylbutyl
2-Methoxybenzyl


1686
2-Methylpropyl
2,4,6-Trifluorophenyl


1687
Butyl
2,3,6-Trifluorophenyl


1688
2-Methylpropyl
2,3,6-Trifluorophenyl


1689
Pentyl
2,3,6-Trifluorophenyl


1690
3-Methylbutyl
2,3,6-Trifluorophenyl


1691
3-Methylbutyl
2,5-Dimethyl-3-furyl


1692
Butyl
4,5-Dimethyl-2-furyl


1693
2-Methylpropyl
4,5-Dimethyl-2-furyl


1694
Pentyl
4,5-Dimethyl-2-furyl


1695
3-Methylbutyl
4,5-Dimethyl-2-furyl


1696
2-Methylpropyl
2-(3-Thienyl)ethenyl


1697
Pentyl
3-Chloro-2-thienyl


1698
3-Methylbutyl
3-Chloro-2-thienyl


1699
2-Methylpropyl
5-Methylthio-2-thienyl


1700
3-Methylbutyl
5-Methylthio-2-thienyl


1721
Butyl
3-Chloro-4-methylphenyl


1722
2-Methylpropyl
3-Chloro-4-methylphenyl


1723
3-Methylbutyl
3-Chloro-4-methylphenyl


1724
2-Methylpropyl
2,4,5-Trichlorophenyl









EXAMPLE 29




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







1468
Methyl
Phenyl


1469
Allyl
Phenyl


1470
Propyl
Phenyl


1471
Methyl
3-Methylphenyl


1472
Allyl
3-Methylphenyl


1473
Propyl
3-Methylphenyl


1474
Propyl
4-Methylphenyl


1475
Methyl
3-Fluorophenyl


1476
Allyl
3-Fluorophenyl


1477
Propyl
3-Fluorophenyl


1478
Propyl
4-Fluorophenyl


1479
Methyl
2-Fluorophenyl


1480
Allyl
2-Fluorophenyl


1481
Propyl
2-Fluorophenyl


1482
Propyl
3,4-Dimethylphenyl


1483
Propyl
3-Methoxyphenyl


1484
Propyl
3-Fluoro-4-methylphenyl


1485
Allyl
3-Chlorophenyl


1486
Propyl
3-Chlorophenyl


1487
Propyl
2-Chlorophenyl


1488
Propyl
3,4-Difluorophenyl


1489
Methyl
2,3-Difluorophenyl


1490
Propyl
2,3-Difluorophenyl


1491
Methyl
2,5-Difluorophenyl


1492
Allyl
2,5-Difluorophenyl


1493
Propyl
2,5-Difluorophenyl


1494
Propyl
2,4-Difluorophenyl


1495
Propyl
1,3-Benzodioxol-5-yl


1496
Propyl
3-Chloro-4-fluorophenyl


1497
Methyl
5-Chloro-2-methoxyphenyl


1498
Methyl
3-Trifluoromethylphenyl


1499
Propyl
3-Trifluoromethylphenyl


1500
Methyl
2,5-Dichlorophenyl


1501
Propyl
2,5-Dichlorophenyl


1502
Methyl
3-Bromophenyl


1503
Allyl
3-Bromophenyl


1504
Propyl
3-Bromophenyl


1505
Propyl
3-Bromo-4-methylphenyl


1506
Methyl
3-Bromo-4-fluorophenyl


1507
Allyl
3-Bromo-4-fluorophenyl


1508
Propyl
3-Bromo-4-fluorophenyl


1509
Methyl
3-Iodophenyl


1510
Ethyl
3-Iodophenyl


1511
Allyl
3-Iodophenyl


1512
Propyl
3-Iodophenyl


1513
Propyl
5-Methyl-2-thienyl


1514
Propyl
3-Fluorobenzyl


1515
Methyl
5-Ethoxy-2-thienyl









EXAMPLE 30




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R2
R3







1717
Propyl
3-Chloro-4-methylphenyl


1718
Propyl
2,4,5-Trifluorophenyl


2237
Benzyl
Phenyl


2240
Benzyl
3-Fluorophenyl


2241
Benzyl
4-Fluorophenyl


2244
Benzyl
2-Fluorophenyl


2246
Benzyl
3,4-Dimethylphenyl


2247
Benzyl
3,5-Dimethylphenyl


2248
Benzyl
2,3-Dimethylphenyl


2249
Benzyl
2,5-Dimethylphenyl


2250
Benzyl
2,4-Dimethylphenyl


2252
Benzyl
3-Methoxyphenyl


2255
Benzyl
2-Methoxyphenyl


2256
Benzyl
3-Fluoro-4-methylphenyl


2259
Benzyl
5-Fluoro-2-methylphenyl


2263
Benzyl
3-Chlorophenyl


2264
Benzyl
4-Chlorophenyl


2265
Benzyl
2-Chlorophenyl


2267
Benzyl
3,4-Difluorophenyl


2270
Benzyl
2,3-Difluorophenyl


2273
Benzyl
2,5-Difluorophenyl


2274
Benzyl
2,4-Difluorophenyl


2275
Benzyl
3-Ethoxyphenyl


2276
Benzyl
1,3-Benzodioxol-5-yl


2277
Benzyl
4-Chloro-3-methylphenyl


2278
Benzyl
3-Chloro-4-fluorophenyl


2279
Benzyl
3,4,5-Trifluorophenyl


2280
Benzyl
2,5-Dimethoxyphenyl


2283
Benzyl
5-Chloro-2-methoxyphenyl


2284
Benzyl
4-Chloro-2-methoxyphenyl


2285
Benzyl
3-Trifluoromethylphenyl


2286
Benzyl
2-Trifluoromethylphenyl


2287
Benzyl
3,4-Dichlorophenyl


2288
Benzyl
2,3-Dichlorophenyl


2290
Benzyl
2,5-Dichlorophenyl


2291
Benzyl
2,4-Dichlorophenyl


2294
Benzyl
3-Bromophenyl


2296
Benzyl
2-Bromophenyl


2297
Benzyl
3-Bromo-4-fluorophenyl


2300
Benzyl
3-Iodophenyl


2301
Benzyl
2-Methoxyphenyl


2303
Benzyl
2,5-Dimethylpyrrol-3-yl


2308
Benzyl
2,3,6-Trifluorphenyl


2309
3-Methylbutyl
2-Chloro-6-fluorophenyl


2325
3-Methylbutyl
3-(Methylamino




methyl)phenyl


2326
3-Methylbutyl
3-(Ethylamino




methyl)phenyl


2327
3-Methylbutyl
3-(allylamino




methyl)phenyl


2328
3-Methylbutyl
3-(propylamino




methyl)phenyl


2329
3-Methylbutyl
3-[(Cyclopropyl




methyl)amino




methyl]phenyl


2330
3-Methylbutyl
3-(butylamino




methyl)phenyl


2331
3-Methylbutyl
3-[(2-Methylpropyl)




amino




methyl]phenyl


2332
3-Methylbutyl
3-(Pentylamino




methyl)phenyl


2333
3-Methylbutyl
3-[(3-Methylbutyl)




amino




methyl]phenyl


2334
3-Methylbutyl
3-[(2-Methylbutyl)




amino




methyl]phenyl


2335
3-Methylbutyl
3-(Hexylamino




methyl)phenyl


2336
3-Methylbutyl
3-(Cyclopropyl




amino




methyl)phenyl


2337
3-Methylbutyl
3-[(1-Methylethyl)




aminomethyl]




phenyl


2338
3-Methylbutyl
3-(Cyclobutyl




amino




methyl)phenyl


2339
3-Methylbutyl
3-[(1-Methylpropyl)




aminomethyl]




phenyl


2340
3-Methylbutyl
3-[(1,1-Dimethylethyl)




aminomethyl]




phenyl


2341
3-Methylbutyl
3-(Cyclopentyl




amino




methyl)phenyl


2342
3-Methylbutyl
3-[(1-Methylbutyl)




aminomethyl]




phenyl


2343
3-Methylbutyl
3-[(1,2-Dimethylpropyl)




aminomethyl]




phenyl


2344
3-Methylbutyl
3-[(1-Ethylpropyl)




aminomethyl]




phenyl


2345
3-Methylbutyl
3-[(1,1-Dimethylpropyl)




aminomethyl]




phenyl


2346
3-Methylbutyl
3-(Cyclohexyl




amino




methyl)phenyl


2352
3-Methylbutyl
3-(Piperidyl




methyl)phenyl


2353
3-Methylbutyl
3-(Morpholin-4-yl




methyl)phenyl


2354
3-Methylbutyl
3-(Azaperhydroepinylmethyl)




phenyl


2355
3-Methylbutyl
3-(Azaperhydroocinylmethyl)




phenyl


2356
3-Methylbutyl
3-(2-1,2,3,4-Teterahydro




isoquinolinyl




methyl)




phenyl


2357
3-Methylbutyl
3-(Methylpropyl




aminomethyl)




phenyl


2358
3-Methylbutyl
3-(i-propylethyl




aminomethyl)




phenyl


2359
3-Methylbutyl
3-(Diethyl




aminomethyl)




phenyl


2360
3-Methylbutyl
3-(Butylethyl




aminomethyl)




phenyl


2361
3-Methylbutyl
3-[(Cyclopropyl




methyl)propyl




aminomethyl]




phenyl


2362
3-Methylbutyl
3-(Hexylmethyl




aminomethyl)




phenyl


2363
3-Methylbutyl
3-(Dibutyl




aminomethyl)




phenyl


2370
3-Methylbutyl
3-[(1-methylethyl)




methyl




aminomethyl]




phenyl


2371
3-Methylbutyl
3-[(2-Methyl




piperidyl)




methyl]phenyl


2372
3-Methylbutyl
3-[Ethyl(2-Methylprop-2-enyl)amino




methyl]phenyl


2373
3-Methylbutyl
3-[(2-Ethyl




piperidyl)




methyl]phenyl


2374
3-Methylbutyl
3-(Cyclohexyl




ethyl




aminomethyl)




phenyl


2375
3-Methylbutyl
3-[bis(2-Methoxyethyl)




aminomethyl]




phenyl


2376
3-Methylbutyl
3-[(3,3,5-Trimethylazaperhydroepinyl)




methyl]phenyl


2377
3-Methylbutyl
3-[(8-Aza-1,4-dioxaspiro[4.5]dec-8-




yl)methyl]




phenyl


2378
3-Methylbutyl
3-(Dipentylamino




methyl)phenyl


2379
3-Methylbutyl
3-(Dihexylamino




methyl)phenyl









EXAMPLE 31




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







2004
2-Methylpropyl
2-(4-Chlorophenyl) ethenyl









EXAMPLE 32




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







2020
Methyl
3-Thienyl


2021
i-Propyl
3-Methyl-2-thienyl


2022
Methyl
4-Methylbenzyl


2023
Methyl
2-Methylbenzyl


2024
Methyl
3-Fluorobenzyl









EXAMPLE 33




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound




No.
R4
R3







2025
3-Pyrrolinyl
2,5-Difluorophenyl


2026
3-Pyrrolinyl
3-Fluorophenyl


2027
Pyrrolidinyl
2,5-Difluorophenyl


2028
Pyrrolidinyl
3-Fluorophenyl


2029
1,2,5,6-Tetrahydro
2,5-Difluorophenyl



pyridyl


2030
1,2,5,6-Tetrahydro
3-Fluorophenyl



pyridyl


2031
Piperidyl
2,5-Difluorophenyl


2032
Piperidyl
3-Fluorophenyl


2039
Morpholinyl
2,5-Difluorophenyl


2040
Morpholinyl
3-Fluorophenyl


2043
4-Methyl
2,5-Difluorophenyl



piperidyl


2044
4-Methyl
3-Fluorophenyl



piperidyl


2046
Azaperhydro
2,5-Difluorophenyl



epinyl


2047
Azaperhydro
3-Fluorophenyl



Epinyl


2049
1,4-Thiazaper
2,5-Difluorophenyl



hydroin-4-yl


2050
1,4-Thiazaper
3-Fluorophenyl



hydroin-4-yl


2053
3,3-dimethyl
2,5-Difluorophenyl



piperidyl


2054
3,3-dimethyl
3-Fluorophenyl



piperidyl


2057
Azaperhydro
2,5-Difluorophenyl



ocinyl


2058
Azaperhydro
3-Fluorophenyl



Ocinyl


2061
2-(1,2,3,4-Tetrahydroiso
2,5-Difluorophenyl



quinolyl)


2062
2-(1,2,3,4-Tetrahydroiso
3-Fluorophenyl



quinolyl)


2065
Methylprop-2-enylamino
2,5-Difluorophenyl


2066
Methylprop-2-enylamino
3-Fluorophenyl


2068
Diethylamino
2,5-Difluorophenyl


2069
Diethylamino
3-Fluorophenyl


2072
Methylpropyl
2,5-Difluorophenyl



amino


2073
Methylpropyl
3-Fluorophenyl



Amino


2076
Butylmethyl
2,5-Difluorophenyl



amino


2077
Butylmethyl
3-Fluorophenyl



Amino


2080
i-Propylethyl
2,5-Difluorophenyl



amino


2081
i-Propylethyl
3-Fluorophenyl



amino


2084
Diallylamino
2,5-Difluorophenyl


2085
Diallylamino
3-Fluorophenyl


2088
Dipropylamino
2,5-Difluorophenyl


2089
Dipropylamino
3-Fluorophenyl


2092
Butylethyl
2,5-Difluorophenyl



Amino


2093
Butylethyl
3-Fluorophenyl



Amino


2096
(Cyclo
2,5-Difluorophenyl



propylmethyl)



propylamino


2097
(Cyclo
3-Fluorophenyl



propylmethyl)



propylamino


2100
Hexylmethyl
2,5-Difluorophenyl



amino


2101
Hexylmethyl
3-Fluorophenyl



Amino


2104
Dibutylamino
2,5-Difluorophenyl


2105
Dibutylamino
3-Fluorophenyl


2107
Methylamino
2,5-Difluorophenyl


2108
Methylamino
3-Fluorophenyl


2110
Ethylamino
2,5-Difluorophenyl


2111
Ethylamino
3-Fluorophenyl


2114
Allylamino
2,5-Difluorophenyl


2115
Allylamino
3-Fluorophenyl


2118
Propylamino
2,5-Difluorophenyl


2119
Propylamino
3-Fluorophenyl


2122
(Cyclopropyl
2,5-Difluorophenyl



methyl)amino


2123
(Cyclopropyl
3-Fluorophenyl



methyl)amino


2126
Butyl
2,5-Difluorophenyl


2127
Butyl
3-Fluorophenyl


2130
(2-Methylpropyl)
2,5-Difluorophenyl



amino


2131
(2-Methylpropyl)
3-Fluorophenyl



amino


2134
Pentylamino
2,5-Difluorophenyl


2135
Pentylamino
3-Fluorophenyl


2138
(3-Methylbutyl)
2,5-Difluorophenyl



amino


2139
(3-Methylbutyl)
3-Fluorophenyl



amino


2141
(2-Methylbutyl)
2,5-Difluorophenyl



amino


2142
(2-Methylbutyl)
3-Fluorophenyl



amino


2145
Hexylamino
2,5-Difluorophenyl


2146
Hexylamino
3-Fluorophenyl


2148
[2-(Dimethyl
2,5-Difluorophenyl



amino)ethyl]



amino


2149
[2-(Dimethyl
3-Fluorophenyl



amino)ethyl]



amino


2150
[3-(Dimethyl
2,5-Difluorophenyl



amino)propyl]



amino


2151
[3-(Dimethyl
3-Fluorophenyl



amino)propyl]



amino


2153
(2-Pyrrolidinyl
2,5-Difluorophenyl



ethyl)amino


2154
(2-Pyrrolidinyl
3-Fluorophenyl



ethyl)amino


2157
[2-(Diethyl
2,5-Difluorophenyl



amino)ethyl]



amino


2158
[2-(Diethyl
3-Fluorophenyl



amino)ethyl]



amino


2161
(2-Piperidyl
2,5-Difluorophenyl



ethyl)amino


2162
(2-Piperidyl
3-Fluorophenyl



ethyl)amino


2164
[2-(1-Methyl
2,5-Difluorophenyl



pyrrolidin-2-yl)ethyl]amino


2165
[2-(1-Methyl
3-Fluorophenyl



pyrrolidin-2-yl)ethyl]amino


2168
[2-(Diethyl
2,5-Difluorophenyl



amino)propyl]



amino


2169
[2-(Diethyl
3-Fluorophenyl



amino)propyl]



amino


2172
(2-Morpholin-4-yl
2,5-Difluorophenyl



ethyl)amino


2173
(2-Morpholin-4-yl
3-Fluorophenyl



ethyl)amino


2176
(3-Morpholin-4-yl
2,5-Difluorophenyl



propyl)amino


2177
(3-Morpholin-4-yl
3-Fluorophenyl



propyl)amino


2180
[3-(2-Methyl
2,5-Difluorophenyl



piperidyl)



propyl]amino


2181
[3-(2-Methyl
3-Fluorophenyl



piperidyl)



propyl]amino


2184
[3-(2-Oxo
2,5-Difluorophenyl



pyrrolidinyl)



propyl]amino


2185
[3-(2-Oxo
3-Fluorophenyl



pyrrolidinyl)



propyl]amino









EXAMPLE 34




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R4
R3







2033
Pyrrolidinyl
2,5-Difluorophenyl


2034
Pyrrolidinyl
3-Fluorophenyl


2035
1,2,5,6-Tetrahydro
2,5-Difluorophenyl



pyridyl


2036
1,2,5,6-Tetrahydro
3-Fluorophenyl



pyridyl


2037
Piperidyl
2,5-Difluorophenyl


2038
Morpholinyl
3-Fluorophenyl


2041
4-Methyl
2,5-Difluorophenyl



piperidyl


2042
4-Methyl
3-Fluorophenyl



piperidyl


2045
Azaperhydro
3-Fluorophenyl



Epinyl


2048
1,4-Thiazaper
3-Fluorophenyl



hydroin-4-yl


2051
3,3-dimethyl
2,5-Difluorophenyl



piperidyl


2052
3,3-dimethyl
3-Fluorophenyl



piperidyl


2055
Azaperhydro
2,5-Difluorophenyl



ocinyl


2056
Azaperhydro
3-Fluorophenyl



Ocinyl


2059
2-(1,2,3,4-
2,5-Difluorophenyl



Tetrahydroiso



quinolyl)


2060
2-(1,2,3,4-
3-Fluorophenyl



Tetrahydroiso



quinolyl)


2063
Methylprop-2-
2,5-Difluorophenyl



enylamino


2064
Methylprop-2-
3-Fluorophenyl



enylamino


2067
Diethylamino
3-Fluorophenyl


2070
Methylpropyl
2,5-Difluorophenyl



amino


2071
Methylpropyl
3-Fluorophenyl



Amino


2074
Butylmethyl
2,5-Difluorophenyl



amino


2075
Butylmethyl
3-Fluorophenyl



Amino


2078
i-Propylethyl
2,5-Difluorophenyl



amino


2079
i-Propylethyl
3-Fluorophenyl



amino


2082
Diallylamino
2,5-Difluorophenyl


2083
Diallylamino
3-Fluorophenyl


2086
Dipropylamino
2,5-Difluorophenyl


2087
Dipropylamino
3-Fluorophenyl


2090
Butylethyl
2,5-Difluorophenyl



Amino


2091
Butylethyl
3-Fluorophenyl



Amino


2094
(Cyclo
2,5-Difluorophenyl



propylmethyl)



propylamino


2095
(Cyclo
3-Fluorophenyl



propylmethyl)



propylamino


2098
Hexylmethyl
2,5-Difluorophenyl



Amino


2099
Hexylmethyl
3-Fluorophenyl



Amino


2102
Dibutylamino
2,5-Difluorophenyl


2103
Dibutylamino
3-Fluorophenyl


2106
Methylamino
3-Fluorophenyl


2109
Ethylamino
3-Fluorophenyl


2112
Allylamino
2,5-Difluorophenyl


2113
Allylamino
3-Fluorophenyl


2116
Propylamino
2,5-Difluorophenyl


2117
Propylamino
3-Fluorophenyl


2120
(Cyclopropyl
2,5-Difluorophenyl



methyl)amino


2121
(Cyclopropyl
3-Fluorophenyl



methyl)amino


2124
Butyl
2,5-Difluorophenyl


2125
Butyl
3-Fluorophenyl


2128
(2-Methylpropyl)
2,5-Difluorophenyl



amino


2129
(2-Methylpropyl)
3-Fluorophenyl



amino


2132
Pentylamino
2,5-Difluorophenyl


2133
Pentylamino
3-Fluorophenyl


2136
(3-Methylbutyl)
2,5-Difluorophenyl



amino


2137
(3-Methylbutyl)
3-Fluorophenyl



amino


2140
(2-Methylbutyl)
3-Fluorophenyl



amino


2143
Hexylamino
2,5-Difluorophenyl


2144
Hexylamino
3-Fluorophenyl


2152
(2-Pyrrolidinyl
3-Fluorophenyl



ethyl)amino


2155
[2-(Diethyl
2,5-Difluorophenyl



amino)ethyl]



amino


2156
[2-(Diethyl
3-Fluorophenyl



amino)ethyl]



amino


2159
(2-Piperidyl
2,5-Difluorophenyl



ethyl)amino


2160
(2-Piperidyl
3-Fluorophenyl



ethyl)amino


2163
[2-(1-Methyl
3-Fluorophenyl



pyrrolidin-2-



yl)ethyl]amino


2166
[2-(Diethyl
2,5-Difluorophenyl



amino)propyl]



amino


2167
[2-(Diethyl
3-Fluorophenyl



amino)propyl]



amino


2170
(2-Morpholin-4-yl
2,5-Difluorophenyl



ethyl)amino


2171
(2-Morpholin-4-yl
3-Fluorophenyl



ethyl)amino


2174
(3-Morpholin-4-yl
2,5-Difluorophenyl



propyl)amino


2175
(3-Morpholin-4-yl
3-Fluorophenyl



propyl)amino


2178
[3-(2-Methyl
2,5-Difluorophenyl



piperidyl)



propyl]amino


2179
[3-(2-Methyl
3-Fluorophenyl



piperidyl)



propyl]amino


2182
[3-(2-Oxo
2,5-Difluorophenyl



pyrrolidinyl)



propyl]amino


2183
[3-(2-Oxo
3-Fluorophenyl



pyrrolidinyl)



propyl]amino









EXAMPLE 35




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







2147
3-Methylbutyl
3-Chlorophenyl


2219
3-Methylbutyl
3-Trifluoromethylphenyl


2220
Butyl
3-Bromophenyl


2221
2-Methylpropyl
3-Bromophenyl


2222
3-Methylbutyl
3-Bromophenyl









EXAMPLE 36




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







2186
Butyl
2,5-Dimethoxyphenyl


2187
2-Methylpropyl
2,5-Dimethoxyphenyl


2188
3-Methylbutyl
2,5-Dimethoxyphenyl


2189
Butyl
3-Chloro-4-methoxyphenyl


2190
2-Methylpropyl
3-Chloro-4-methoxyphenyl


2191
3-Methylbutyl
3-Chloro-4-methoxyphenyl


2192
Butyl
5-Chloro-2-methoxyphenyl


2193
2-Methylpropyl
5-Chloro-2-methoxyphenyl


2194
3-Methylbutyl
5-Chloro-2-methoxyphenyl


2195
2-Methylpropyl
4-Chloro-2-methoxyphenyl


2196
Butyl
3-Trifluoromethylphenyl


2197
2-Methylpropyl
3-Trifluoromethylphenyl


2198
3-Methylbutyl
3-Trifluoromethylphenyl


2199
Butyl
2-Trifluoromethylphenyl


2200
3-Methylbutyl
2-Trifluoromethylphenyl


2201
Butyl
3,4-Dichlorophenyl


2202
2-Methylpropyl
3,4-Dichlorophenyl


2203
3-Methylbutyl
3,4-Dichlorophenyl


2204
Butyl
2,5-Dichlorophenyl


2205
2-Methylpropyl
2,5-Dichlorophenyl


2206
Pentyl
2,5-Dichlorophenyl


2207
3-Methylbutyl
2,5-Dichlorophenyl


2208
Butyl
2,4-Dichlorophenyl


2209
2-Methylpropyl
2,4-Dichlorophenyl


2210
3-Methylbutyl
2,4-Dichlorophenyl


2211
Butyl
3-Bromophenyl


2212
2-Methylpropyl
3-Bromophenyl


2213
Pentyl
3-Bromophenyl


2214
3-Methylbutyl
3-Bromophenyl


2215
2-Methylpropyl
4-Bromophenyl


2216
Butyl
2-Bromophenyl


2217
2-Methylpropyl
2-Bromophenyl


2218
3-Methylbutyl
2-Bromophenyl


2223
2-Methylpropyl
3-Phenoxyphenyl


2224
2-Methylpropyl
4-Phenoxyphenyl


2225
2-Methylpropyl
3-Bromo-4-methylphenyl


2226
Pentyl
3-Bromo-4-methylphenyl


2227
3-Methylbutyl
3-Bromo-4-methylphenyl


2228
Butyl
3-Bromo-4-methylphenyl


2229
2-Methylpropyl
3-Bromo-4-methylphenyl


2230
Pentyl
3-Bromo-4-methylphenyl


2231
3-Methylbutyl
3-Bromo-4-methylphenyl


2232
Butyl
3-Iodophenyl


2233
2-Methylpropyl
3-Iodophenyl


2234
Pentyl
3-Iodophenyl


2235
3-Methylbutyl
3-Iodophenyl


2236
2-Methylpropyl
4-Iodophenyl


2310
2-Methylpropyl
2,3,5,6-Tetrafluoro




phenyl


2311
2-Methylpropyl
2,4,6-Trifluorophenyl


2312
Butyl
2,3,6-Trifluorophenyl


2313
2-Methylpropyl
2,3,6-Trifluorophenyl


2314
Pentyl
2,3,6-Trifluorophenyl


2315
3-Methylbutyl
2,3,6-Trifluorophenyl


2316
Butyl
3-Chloro-6-fluorophenyl


2317
Pentyl
3-Chloro-6-fluorophenyl


2318
3-Methylbutyl
3-Chloro-6-fluorophenyl


2319
Butyl
2-Fluoro-6-




trifluoromethylphenyl









EXAMPLE 37




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







2304
2-Methylpropyl
5-Methyl-2-thienyl









EXAMPLE 38




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







2380
2-Methylpropyl
2,4-Difluorophenyl


2381
2-Methylpropyl
2H-Benzo[d]1,3-dioxolane


2382
2-Methylpropyl
3-Chloro-4-methylphenyl









EXAMPLE 39




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







2390
2-Methylpropyl
5-Methyl-2-thienyl









EXAMPLE 40




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







2383
2-Methylpropyl
3-Chloro-4-methylphenyl


2384
2-Methylpropyl
2,4-Difluorophenyl


2385
2-Methylpropyl
2H-Benzo[d]1,3-dioxolane









EXAMPLE 41




For each compound, the definitions of R2 and R3 are specified in the following table.













Compound No.
R2
R3







2389
Pentyl
3-Fluoro-4-methylphenyl









EXAMPLE 42
Assay for GABAA Receptor Binding
The following assay is a standard assay for GABAA receptor binding.
The high affinity and high selectivity of compounds of this invention for the benzodiazepine site of the GABAA receptor is confirmed using the binding assay described in Thomas and Tallman (J. Bio. Chem. 1981; 156:9838-9842, and J. Neurosci. 1983; 3:433-440).
Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4° C.) at 20,000×g for 20 minutes. The supernatant is decanted, the pellet rehomogenized in the same volume of buffer, and centrifuged again at 20,000×g. The supernatant of this centrifugation step is decanted and the pellet stored at −20° C. overnight. The pellet is then thawed and resuspended in 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000×g and the supernatant decanted. This wash step is repeated once. The pellet is finally resuspended in 50 volumes of Buffer A.
Incubations containi 100 l of tissue homogenate, 100 l of radioligand, (0.5 nM 3H-Ro15-1788 [3H-Flumazenil], specific activity 80 Ci/mmol), and test compound or control (see below), and are brought to a total volume of 500 l with Buffer A. Incubations are carried for 30 min at 4° C. and then rapidly filtered through Whatman GFB filters to separate free and bound ligand. Filters are washed twice with fresh Buffer A and counted in a liquid scintillation counter. Nonspecific binding (control) is determined by displacement of 3H Ro15-1788 with 10 M Diazepam (Research Biochemicals International, Natick, Mass.). Data were collected in triplicate, averaged, and percent inhibition of total specific binding (Total Specific Binding=Total−Nonspecific) was calculated for each compound.
A competition binding curve is obtained with up to 11 points spanning the compound concentration range from 10−12M to 10−5M obtained per curve by the method described above for determining percent inhibition. Ki values are calculated according the Cheng-Prussof equation. When tested in this assay compounds of the invention exihibit Ki values of less than 1 uM, preferred compounds of the invention have Ki values of less than 500 nM and more compounds of the invention have Ki values of less than 100 nM.
EXAMPLE 43
Assay for GABAA Receptor Functional Activity
Electrophysiology
The following assay is used to determine if a compound of the invention act as an agonist, an antagonist, or an inverse agonist at the benzodiazepine site of the GABAA receptor.
Assays are carried out as described in White and Gurley (NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995) with modifications. Electrophysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potential of −70 mV. Xenopus Laevis oocytes are enzymatically isolated and injected with non-polyadenylated cRNA mixed in a ratio of 4:1:4 for, and subunits, respectively. Of the nine combinations of, and subunits described in the White et al. publications, preferred combinations are 1 2 2, 2 3 2, 3 3 2, and 5 3 2. Preferably all of the subunit cRNAs in each combination are human clones or all are rat clones. The sequence of each of these cloned subunits is available from GENBANK, e.g., human 1, GENBANK accession no. X14766, human 2, GENBANK accession no. A28100; human 3, GENBANK accession no. A28102; human 5, GENBANK accession no. A28104; human 2, GENBANK accession no. M82919; human 3, GENBANK accession no. Z20136; human 2, GENBANK accession no. X15376; rat 1, GENBANK accession no. L08490, rat 2, GENBANK accession no. L08491; rat 3, GENBANK accession no. L08492; rat 5, GENBANK accession no. L08494; rat 2, GENBANK accession no. X15467; rat 3, GENBANK accession no. X15468; and rat 2, GENBANK accession no. L08497. For each subunit combination, sufficient message for each constituent subunit is injected to provide current amplitudes of >10 nA when 1 μM GABA is applied.
Compounds are evaluated against a GABA concentration that evokes <10% of the maximal evokable GABA current (e.g. 1 M-9 M). Each oocyte is exposed to increasing concentrations of compound in order to evaluate a concentration/effect relationship. Compound efficacy is calculated as a percent-change in current amplitude: 100*((Ic/I)−1), where Ic is the GABA evoked current amplitude observed in the presence of test compound and I is the GABA evoked current amplitude observed in the absence of the test compound.
Specificity of a compound for the benzodiazepine site is determined following completion of a concentration/effect curve. After washing the oocyte sufficiently to remove previously applied compound, the oocyte is exposed to GABA+1 μM R015-1788, followed by exposure to GABA+1 μM RO15-1788+test compound. Percent change due to addition of compound is calculated as described above. Any percent change observed in the presence of RO15-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 μM R015-1788. These net values are used for the calculation of average efficacy and EC50 values by standard methods. To evaluate average efficacy and EC50 values, the concentration/effect data are averaged across cells and fit to the logistic equation.
EXAMPLE 44
Preparation of Radiolabeled Probe Compounds of the Invention
The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably 14C), hydrogen (preferably 3H), sulfur (preferably 35S), or iodine (preferably 125I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.
Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
EXAMPLE 45
Use of Compounds of the Invention as Probes for GABAA Receptors in Cultured Cells and Tissue Samples
Receptor autoradiography (receptor mapping) of NK-3 or GABAA receptors in cultured cells or tissue samples is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example.
The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

## Claims

1. A method for localizing GABAA receptors in a tissue sample comprising:
a) contacting the sample in vitro with a detectably-labeled compound under conditions that permit binding of the compound to GABAA receptors, wherein said compound has the formula:





or pharmaceutically acceptable salts thereof wherein:
W represents





where Z is O, or S;

R1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
R2 represents hydroxyl;
C1-C6 alkyl or C1-C6 alkoxy, each of which are optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl; or
NR8R9 forms a 5-, 6-, or 7-membered heterocyclic ring;

or R2 represents
hydrogen or
a group of the formula







where
Rn and Rk independently represent C1-C6 alkyl, C2-C6 alkenyl, C1-C6 cycloalkyl (C1-C6)alkyl, benzoyl where the phenyl portion is optionally substituted with halogen, C1-C6 alkyl, or C1-C6 alkoxy;

a group of the formula IV-a







where p, s, and t independently represent 1 or 2;
J is CH, N, O, or a carbon atom substituted with C1-C6 alkyl; or
NRkRn represents








where s, t, and J are as defined above;


R3 represents
C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or
benzyl optionally mono-, di-, or trisubstituted independently with
halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, or hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
NR8R9 forms a 5-, 6-, 7-membered heterocyclic ring;
SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8 where R8 is defined as above;
O(CH2)n—G where n=1,2,3,4 and G is SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, or CONHSO2R8, where R8 is as defined above; or
tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl;


R4, R5 and R6 are the same or different and represent hydrogen; or
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion, C1-C6 alkylthiol, or halogen;
O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
NR8R9 forms a 5-, 6-, or 7-membered heterocyclic ring; or
R4 and R5 can form a 1,3-dioxolene ring;

X represents a bond, CH2, or CH═CH; and
A, B, C, and D are the same or different and represent CH or N with the proviso that at least one, but not more than two of A, B, C, or D represent N;
b) washing the sample to remove unbound compound; and
c) detecting the bound compound.

2. A method for altering the signal-transducing activity of GABAA receptors, the method comprising exposing cells expressing GABAA receptors in vitro to a compound at a concentration sufficient to inhibit RO15-1788 binding to cells expressing a cloned human GABAA receptor in vitro, wherein said compound has the formula:




or pharmaceutically acceptable salts thereof wherein:
W represents





where Z is O, or S;

R1 represents phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
R2 represents hydroxyl;
C1-C6 alkyl or C1-C6 alkoxy, each of which are optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl; or
NR8R9 forms a 5-, 6-, or 7-membered heterocyclic ring;

or R2 represents
hydrogen or
a group of the formula







where
Rn and Rk independently represent C1-C6 alkyl, C2-C6 alkenyl, C1-C6 cycloalkyl (C1-C6) alkyl, benzoyl where the phenyl portion is optionally substituted with halogen, C1-C6 alkyl, or C1-C6 alkoxy;

a group of the formula IV-a







where p, s, and t independently represent 1 or 2;
J is CH, N, O, or a carbon atom substituted with C1-C6 alkyl; or
NRkRn represents








where s, t, and J are as defined above;


R3 represents
C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl; or
benzyl optionally mono-, di-, or trisubstituted independently with
halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, or hydroxy;
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
NR8R9 forms a 5-, 6-, 7-membered heterocyclic ring;
SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8 where R8 is defined as above;
O(CH2)n—G where n=1,2,3,4 and G is SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, or CONHSO2R8, where R8 is as defined above; or
tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl;


R4, R5 and R6 are the same or different and represent hydrogen; or
C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino, mono or di(C1-C6) alkylamino, a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion, C1-C6 alkylthiol, or halogen;
O(CH2)nCO2R8 where n=1, 2, 3, 4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
NR8R9 forms a 5-, 6-, or 7-membered heterocyclic ring; or
R4 and R5 can form a 1,3-dioxolene ring;

X represents a bond, CH2, or CH═CH; and
A, B, C, and D are the same or different and represent CH or N with the proviso that at least one, but not more than two of A, B, C, or D represent N.

3. A process for the preparation of a compound of formula:




or a pharmaceutically acceptable salt thereof, wherein
R1 is phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, cyclopropylmethyl, or thienylmethyl;
R2 is hydrogen or halogen;
R3 is C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl, or benzyl, wherein the benzyl group is optionally substituted with 1, 2, or 3 substituents that are independently halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, —O(CH2)n—CO2R8, or —NR8R9;
X is a bond, CH2, or CH═CH; and
W is




wherein
R4, R5, and R6 are independently hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, —O(CH2)n—CO2R8, or —NR8R9, wherein the C1-C6 alkyl and the C1-C6 alkoxy are optionally substituted with NR8R9;
R8 and R9 are independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or phenyl, wherein the phenyl is optionally substituted with halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, or C1-C6 alkoxy; and
n is 1, 2, 3, or 4;
comprising
(1) treating a compound of formula





with a compound of formula H2N—R3, to provide a compound of formula





(2) treating the product of (1) with a compound of formula Cl—C(O)—X—W, to provide a compound of formula

4. A method of preparing a compound of formula




or a pharmaceutically acceptable salt thereof, wherein
R1 is phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, cyclpropylmethyl, or thienylmethyl;
R3 is C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl, or benzyl, wherein the benzyl group is optionally substituted with 1, 2, or 3 substituents that are independently halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, —O(CH2)n—CO2R8, or —NR8R9;
X is a bond, CH2, or CH═CH; and
W is




wherein
R4, R5, and R6 are independently hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, —O(CH2)n—CO2R8, or NR8R9, wherein the C1-C6 alkyl and the C1-C6 alkoxy are optionally substituted with NR8R9;
R8 and R9 are independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or phenyl, wherein the phenyl is optionally substituted with halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, or C1-C6 alkoxy;
comprising
(1) treating 2-chloro-3-nitropyridine with a compound of formula H2N—R1, to provide a compound of formula




(2) treating the product of (1) with hydrogen gas and Pd/C, or TiCl3 and an acid, or SnCl2 and an acid, to provide a compound of formula




(3) treating the product of (2) with RO—C(═NH)—CH2Cl, wherein R is C1-C6 alkyl, to provide a compound of formula




(4) treating the product of (3) with a compound of formula H2N—R3, to provide a compound of formula




(5) treating the product of (4) with a compound of formula Cl—C(O)—X—W, to provide a compound of formula

5. A method of preparing a compound of formula




or a pharmaceutically acceptable salt thereof, wherein
R1 is phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, cyclpropylmethyl, or thienylmethyl;
R3 is C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl, or benzyl, wherein the benzyl group is optionally substituted with 1, 2, or 3 substituents that are independently halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, —O(CH2)n—CO2R8, or —NR8R9;
X is a bond, CH2, or CH═CH; and
W is




wherein
R4, R5, and R6 are independently hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, —O(CH2)n—CO2R8, or —NR8R9, wherein the C1-C6 alkyl and the C1-C6 alkoxy are optionally substituted with NR8R9;
R8 and R9 are independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or phenyl, wherein the phenyl is optionally substituted with halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, or C1-C6 alkoxy; and
n is 1, 2, 3, or 4;
comprising
(1) treating 4-chloro-3-nitropyridine with a compound of formula H2N—R1, to provide a compound of formula




(2) treating the product of (1) with hydrogen gas and Pd/C, or TiCl3 and an acid, or SnCl2 and an acid, to provide a compound of formula




(3) treating the product of (2) with RO—C(═NH)—CH2Cl, wherein R is C1-C6 alkyl, to provide a compound of formula




(4) treating the product of (3) with a compound of formula H2N—R3, to provide a compound of formula




(5) treating the product of (4) with a compound of formula Cl—C(O)—X—W, to provide a compound of formula

6. A method of preparing a compound of formula




or a pharmaceutically acceptable salt thereof, wherein
RA and RB are independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with —NR8R9 or a heterocycyle wherein the heterocycle is morpholinyl, pyrrolidinyl, or piperidinyl, wherein the heterocycle is optionally substituted with C1-C6 alkyl or oxo; or
RA and RB together form a heterocycle, wherein the heterocycle is morpholine, pyrrolidine, piperidine, tetrahydropyridine, tetrahydroisoquinolinyl, wherein the heterocycle is optionally substituted with C1-C6 alkyl
R1 is phenyl, C1-C6 alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, cyclpropylmethyl, or thienylmethyl;
R3 is C1-C6 alkyl, allyl, cyclopropylmethyl, cyclopentyl, or benzyl, wherein the benzyl group is optionally substituted with 1, 2, or 3 substituents that are independently halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, —O(CH2)n—CO2R8, or —NR8R9;
X is a bond, CH2, or CH═CH; and
W is




wherein
R4, R5, and R6 are independently hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, —O(CH2)n—CO2R8, or —NR8R9, wherein the C1-C6 alkyl and the C1-C6 alkoxy are optionally substituted with NR8R9;
R8 and R9 are independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or phenyl, wherein the phenyl is optionally substituted with halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, or C1-C6 alkoxy; and
n is 1, 2, 3, or 4;
comprising
(1) treating a compound of formula





with tert-butyldimethylsilyl chloride and a base to provide a compound of formula





(2) treating the product of (1) with hydrogen gas and Pd/C, or TiCl3 and an acid, or SnCl2 and an acid, to provide a compound of formula




(3) treating the product of (2) with RO—C(═NH)—CH2Cl, wherein R is C1-C6 alkyl, to provide a compound of formula




(4) treating the product of (3) with a compound of formula H2N—R3, to provide a compound of formula




(5) treating the product of (4) with a compound of formula Cl—C(O)—X—W, to provide a compound of formula




(6) treating the product of (5) with tetrabutyl ammonium fluoride to provide a compound of formula




(7) treating the product of (6) with thionyl chloride to provide a compound of formula




(8) treating the product of (7) with HNRARB to provide a compound of formula