KR20070022718A - Substituted enaminones, their derivatives and uses thereof - Google Patents

Abstract

The present invention relates to substituted enaminones of the formula I and derivatives thereof, and the compounds modulating the effect of γ-aminobutyric acid (GABA) on the GABA _A receptor complex in a therapeutically relevant manner, and following the regulation of the GABA _A receptor complex It is about the discovery that it can be used to improve CNS disorders:

[Formula I]

Description

Substituted enaminens, derivatives thereof and uses thereof {SUBSTITUTED ENAMINONES, THEIR DERIVATIVES AND USES THEREOF}

This application is incorporated by reference in U.S. Patent application on May 6, 2004, which is incorporated herein by reference. Claims the benefit of provisional application 60 / 569,465.

The present invention is in the field of medical chemistry. Specifically, the present invention relates to substituted Cenaminone and derivatives thereof, and CNS, in which these compounds modulate the effect of γ-aminobutyric acid (GABA) on the GABA _A receptor complex in a therapeutically relevant manner and subject to the regulation of the GABA _A receptor complex. It is related to the discovery that it can be used to ameliorate the disorder.

GABA is the most abundant inhibitory neurotransmitter in the mammalian brain. GABA controls brain excitability by exerting a function on inhibition of neuronal membranes by altering the permeability of neuronal membranes to specific ions. Binding of GABA to GABA _A -type (GABA _A ) receptors increases the permeability of neuronal membranes to chloride ions (Cl ⁻ ). In most neurons, the Cl ⁻ ion concentration is relatively greater outside than inside the membrane. Thus, the selective permeability to Cl ⁻ initiated by GABA binding pushes Cl ⁻ into the cell. Most rapid inhibitory synaptic transmission is the result of GABA binding to the GABA _A receptor. GABA _A receptors are expressed everywhere in the CNS, given almost all neuron staining to confirm their presence. The GABA _A receptor is a hetero-pentameric protein structure of the nicotinic acetylcholine receptor superfamily. The original GABA _A receptor is formed from 19 or more related subunits. The subunits are classified into the α, β, δ, ε, π and ρ families. The most common combination of GABA _A receptors is the stoichiometric combination of 2 × α, 2 × β and 1 × γ subunits, allowing the remaining subunits to substitute for the γ subunits during specific developmental expression or at very specific brain region sites. . The adult brain predominantly expresses the α ₁ β ₂ γ ₂ subunit combination (60%) with α ₂ β ₃ γ ₂ and α ₃ β _n γ ₂ subunits comprising the majority of the remaining receptors (35%). The relative effects of GABA are influenced by GABA _A receptor subunits expressed in specific brain regions or neural circuits.

The neurophysiological effects of GABA result from alterations in the conformation that occurs when GABA binds to the GABA _A receptor. GABA _A receptors and associated ion channel complexes (GRCs) recognize many compounds that allostericly enhance the ability of GABA to bind to GABA _A receptors. Allosteric modulators have distinct sites on the GRC. This site is isolated from the site that recognizes GABA and is unique. The most widely studied characteristic classification of allosteric modulators of GRC is to interact with benzodiazepines (BZ) -sites.

Alternative sites for GRC regulation are described. For example, neurostimulatory steroids are non-hormonal steroids that bind and functionally regulate GRC. The current role of neurostimulatory steroids in GABA _A receptor pharmacology is supported by overwhelming evidence. Electrophysiology and biochemistry techniques have confirmed the ability to allosterically regulate GRC through the unique site of action of neurostimulatory steroids. Experimentally, neurostimulatory steroids appear similar in pharmacological profile to benzodiazepines but are not identical. Neurostimulatory steroids have anti-anxiety, antiepileptic and soothing sleep properties.

It is documented in detail that the GRC is responsible for coordinating anxiety, paroxysmal activity and sedation. Thus, drugs that act with or promote the effects of GABA (eg, therapeutically useful barbiturates and benzodiazepines (BZs), such as Valium), may be associated with specific regulatory sites on the GRC receptor complex. Interactions result in their therapeutically useful effects.

Related technology

Sayyed, I. A. et al. (Synthetic Comm. 2000, 30 (14), 2533) disclose the synthesis of the following compounds as synthetic intermediates:

Palamo Colt, A. Spanish Patent 2049640 (1994) discloses the following compounds as synthetic intermediates:

Summary of the invention

The present invention is directed to the disclosure that certain substituted enaminens represented by Formula I serve as enhancers of GABA-promoting Cl ⁻ flow mediated through the GABA _A receptor complex (GRC).

The present invention is directed to treating disorders that respond to enhanced GABA action on GABA receptors in mammals by administering an effective amount of a compound of Formula (I) described herein.

Thus, compounds of the present invention, which are GABA _A receptor ligands, are beneficial in the treatment and / or prevention of various disorders of the central nervous system (CNS). In one aspect, the compounds are useful for the treatment and / or prevention of CNS disorders including neuronal hyperexcitement. Such disorders include, but are not limited to, anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animals and other phobias including social fears, obsessive compulsive disorder, posttraumatic stress disorder and acute Stress disorders including stress disorders, and generalized anxiety disorders or substance-induced anxiety disorders, neurosis, cramps, migraine and depressive disorders or bipolar disorders such as simple episodes or recurrent major depressive disorders, mood disorders, bipolar I and Bipolar II manic disorder and circulatory disorder.

Another aspect of the invention relates to the use of a compound of formula (I) as an enhancer of GABA-promoting Cl ⁻ flow mediated through the GABA _A receptor complex. In addition, one aspect of the present invention is to treat disorders reactive to GABA-promoting Cl ⁻ flow enhancing mediated through GRC, which contain an effective amount of a compound of formula I mixed with one or more pharmaceutically acceptable carriers or diluents. To provide a pharmaceutical composition useful for.

Compounds useful in the present invention have not been reported to date. Accordingly, the present invention also relates to a novel substituted enaminone having the structure of formula (I). Without being bound by the theory presented herein, a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be selected from [ ³ H] -flunitrazepam, barbiturate, loreclezole, [ ³ H] -mumol, or 3α, 20α. It is believed that it acts by binding to a site other than the site to which pregnandiol binds, thereby changing the chloride conductivity through the GABA _A receptor complex therapeutically.

The present invention also relates to their use as radioligands for compounds labeled with ³ H, ³⁵ S, ³⁶ Cl, ¹⁴ C and ¹²⁵ I radioisotopes of formula I and their binding sites on GRC.

Additional embodiments and advantages of the invention will be set forth in part in part in the description which follows, or in part will be obvious from the description, or may be learned by practice of the invention. Embodiments and advantages of the invention will be realized and attained in particular using the elements and combinations set forth in the appended claims.

As claimed, it should be understood that the foregoing general description and the following description are exemplary and explanatory only and do not limit the invention.

[Brief Description of Drawings]

1: Ethyl 2-chloro-α-[[(4-ethynylphenyl) amino] methylene] -β-oxo-benzenepropionate, α for 0.2 nM [ ³ H] flunitrazepam binding in rat brain cortex Dose of-[[(4-ethynylphenyl) -amino] methylene] -2-chloro-β-oxo-N-propyl benzenepropanamide, 5α-pregnan-3α-ol-20-one and clonazepam reaction.

2: 30 nM ethyl 2-chloro-α-[[(4-ethynylphenyl) amino] methylene] -β-oxo-benzenepropionate for 2 nM [ ³⁵ S] TBPS binding in the rat brain cortex Administration of 5α-Pregnan-3α, 20α-diol in the absence and presence of 100 nM α-[[(4-ethynylphenyl) amino] methylene] -2-chloro-β-oxo-N-propyl-benzenepropanamide Volume reaction

Figure 3: Ethyl 2-chloro-α-[[(4-ethynylphenyl) amino] methylene] -β-oxo-benzenepropionate, α- for 5 nM [ ³ H] heavy molar binding in rat brain cortex Dose response of [[(4-ethynylphenyl) amino] methylene] -2-chloro-β-oxo-N-propyl-benzenepropanamide, and y-aminobutyric acid.

Figure 4: 300 nM ethyl 2 chloro-α-[[(4-ethynylphenyl) amino] methylene] -β-oxo-benzenepropionate for 0.2 nM [ ³ H] flunitrazepam binding in rat brain cortex Response to administration of lorecresol in the absence and presence of a.

Figure 5: 300 nM ethyl 2 chloro-α-[[(4-ethynylphenyl) amino] methylene] -β-oxo-benzenepropionate for 0.2 nM [ ³ H] flunitrazepam binding in rat brain cortex Dose response of pentobarbital in the presence and absence of.

Detailed description of the invention

In one embodiment there is provided a substituted enaminone or a pharmaceutically acceptable salt, prodrug or solvate thereof represented by Formula I:

[In the meal,

R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted;

R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl;

R ₃ is fluoro, chloro, bromo, iodo, C _{1 - 10} alkoxy, nitro, halo-C _{1 - 10} alkyl, C _{1 perhalo-the} group consisting of _{10-alkyl-10-alkyl} and unsubstituted or substituted C ₁ Is selected from;

Each R ₄ is halogen, nitro, C _{1 -} consisting of ₁₀ alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and _{heterocycloalkyl-10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C ₁ Independently selected from the group, each being unsubstituted or substituted, or forming an unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring, wherein R ₃ and adjacent R ₄ are fused together;

R ₅ is C _{1 - 10} alkyl, C _{1 - 10} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each unsubstituted or Substituted;

R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5 or 6 membered ring;

m is 0, 1, 2, 3 or 4; Provided that when R ₅ is -OEt, R ₄ is not halogen and the compounds of formula I are compounds ethyl α-[(benzyl) aminomethylene] -2-chloro-β-oxobenzenepropionate and 1- (2 , 4-dichloro-5-fluorophenyl) -2-[[but not (2,4-difluorophenyl) amino] methylene] -1,3-pentanedione].

In another embodiment, there is provided a substituted enaminone or a pharmaceutically acceptable salt, prodrug or solvate thereof represented by Formula Ia:

[In the meal,

R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted;

R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl;

R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Is unsubstituted or substituted;

Each R ₄ is halogen, nitro, C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{1 -1O} alkoxy, aralkyl consisting of alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl Independently selected from the group, each being unsubstituted or substituted, or forming an unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring in which R ₃ and adjacent R ₄ are fused together;

R ₅ is C _{1 - 10} alkyl, CH ₃ O-, C _{3 -1O} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each Is unsubstituted or substituted;

R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom Together with an unsubstituted or substituted 4,5 or 6 membered ring;

m is 0, 1, 2, 3 or 4]. In certain variations of the compound of Formula (la), the compound is a compound in which R ₅ is not CH ₃ CH ₂ 0-.

In one aspect, there is provided a compound of Formula (Ib) or a pharmaceutically acceptable salt, prodrug or solvate thereof:

[In the meal,

R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted;

R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl;

R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Is unsubstituted or substituted;

Each R ₄ is hydrogen, halo, nitro, halo-C _{1 - 10} alkyl, C _{1 -1O} alkyl, perhaloalkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C ₂ alkenyl _-1O , C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, a group from the group consisting of already Independently selected, each being unsubstituted or substituted, or forming an unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring wherein R ₃ and adjacent R ₄ are fused together;

R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} from ₁₀ alkyl, and each is either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5, 6 membered ring;

R ₁₈ is an optionally substituted C _{1 -} is selected from the group consisting of _10-alkyl, arylalkyl and heterocycloalkyl;

m is 0, 1, 2, 3 or 4;

In yet another aspect, the compounds of formula (I), as R ₅ is a C _{1 -1O} case of alkylamino, INC -NHR ₁ is -COR ₅ group and the same side (syn) stereochemistry as indicated in formula Ib is a nomin to same:

Formula Ib

In another aspect of formula Ib, -NHC _{1 - 20} alkyl group is -NHC _{2 -} is selected from the group consisting of _10-alkyl. In still another aspect, C _{2 - 10} alkyl group is an iso-a-propyl, propyl, sec- butyl, tert- butyl, 2-methyl-1-butyl and 3-methyl-1-butyl.

In another aspect, there is provided a compound of Formula (Ic) or a pharmaceutically acceptable salt, prodrug or solvate thereof:

[In the meal,

R ₂ is selected from the group consisting of hydrogen, methyl and ethyl;

R ₃ is hydrogen, halo, halo-C _{1 -1O} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Is unsubstituted or substituted;

Each R ₄ is hydrogen, halo, nitro, halo-C _{1 -1O} alkyl, C _{1 -1O} alkyl, perhaloalkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, , C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, a group from the group consisting of already Independently selected, each being unsubstituted or substituted, or R ₃ and adjacent R ₄ taken together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;

_{R 6, R 7, R 8} , R 9 and R ₁₀ is hydrogen, halo, C _{1 - 10} alkyl, C _{2 - 10} alkynyl, C _{1 -1O} alkoxy, aralkyl, cycloalkyl, aryl C _{1 - 10} alkyl, and heteroaryl C ₁ each independently selected from the group consisting of alkyl or _-1O; Or R ₆ and R ₇ , or R ₇ and R ₈ , or R ₈ and R ₉ , or R ₉ and R ₁₀ together with the carbon atoms to which they are attached are unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated To form a ring, aryl or heteroaryl;

R ₁₈ is C _{1 - 10} alkyl and is selected from aryl and heterocycloalkyl group consisting of alkyl, each of which is unsubstituted or substituted; m is 0, 1, 2, 3 or 4].

In another aspect, there is provided a compound of Formula II or a pharmaceutically acceptable salt, prodrug or solvate thereof:

[In the meal,

R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted;

R ₂ is hydrogen and unsubstituted or substituted C _{1 -} it is selected from the group consisting of _10-alkyl;

R ₅ is C _{1 - 10} alkyl, C _{1 - 10} alkoxy, -NH _2, C _{1 -1O} alkyl are selected from amino, di (C _1-1O) the group consisting of alkylamino and aryl, each or which is unsubstituted or Substituted;

R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, and C _{1 -1O} alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ Together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5 or 6 membered ring;

R ₁₉ and R ₂₀ is halo, cyano, nitro, halo (C _1-10) alkyl, perhalo (C _1-5) alkyl, aryl, heteroaryl, cycloalkyl, C _{1 - 10} alkyl, aryl (C _{1 -10} ) alkyl, cycloalkyl (C _1-10 ) alkyl, hydroxy (C _1-10 ) alkyl, amino (C _1-10 ) alkyl, alkoxy (C _1-10 ) alkyl, amino, hydroxyl, thio, C _1-10 alkoxy, and C _{1 - 10} alkyl thiol are each independently selected from the group consisting of;

v and w are each independently 0, 1, 2 or 3;

In yet another embodiment, there is provided a compound of Formula III, or a pharmaceutically acceptable salt, prodrug or solvate thereof:

[In the meal,

R ₂ is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;

R ₃ is fluoro, chloro, bromo, iodo, C _{1 - 10} alkoxy, nitro, halo-C _{1 - 10} alkyl, C _{1 perhalo-the} group consisting of _{10-alkyl-10-alkyl} and unsubstituted or substituted C ₁ Is selected from;

Each R ₄ is halogen, nitro, C _{1 -} is independently selected from the ₁₀ alkynyl, C _{1 -1O} alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl group consisting of _alkyl-10 alkyl, C ₂ Each is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;

R ₅ is C _{1 - 10} alkyl, C _{1 - 10} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each or which is unsubstituted or Substituted;

_{R 6, R 7, R 8} , R 9 and R ₁₀ is hydrogen, halo, C _{1 - 10} alkyl, C _{2 - 10} alkynyl, C _{1 - 10} alkoxy, aralkyl, cycloalkyl, aryl C _{1 - 10} alkyl, and heteroaryl C _{1 -,} each independently selected from the group consisting of alkyl, or _10; Or R ₆ and R ₇ , or R ₇ and R ₈ , or R ₈ and R ₉ , or R ₉ and R ₁₀ together with the carbon atoms to which they are attached are unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated To form a ring, aryl or heteroaryl; m is 0, 1, 2, 3 or 4].

In another aspect, there is provided a compound of Formula (IV), or a pharmaceutically acceptable salt, prodrug or solvate thereof:

[In the meal,

R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl;

R ₃ is fluoro, chloro, bromo, iodo, C _{1 -1O} alkoxy, nitro, halo-C _{1 - 10} alkyl, C _{1 perhalo-the} group consisting of _{10-alkyl-10-alkyl} and unsubstituted or substituted C ₁ Is selected from;

Each R ₄ is halogen, nitro, C _{1 -} is independently selected from _10, alkyl, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl group consisting of alkyl, _{- 10} alkyl, C _{2 - 10} alkynyl, C ₁ Each is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;

R ₅ is C _{1 - 10} alkyl, C _{1 - 10} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each or which is unsubstituted or Substituted;

_{R 6, R 7, R 8} , R 9 and R ₁₀ is hydrogen, halo, C _{1 - 10} alkyl, C _{2 - 10} alkynyl, C _{1 - 10} alkoxy, aralkyl, cycloalkyl, aryl C _{1 - 10} alkyl, and heteroaryl C _{1 -,} each independently selected from the group consisting of alkyl, or _10; Or R ₆ and R ₇ , or R ₇ and R ₈ , or R ₈ and R ₉ , or R ₉ and R ₁₀ together with the carbon atoms to which they are attached are unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated To form a ring, aryl or heteroaryl;

R ₁₁ is hydrogen or unsubstituted or substituted C _{1 - 10} alkyl, and; m is 0, 1, 2, 3 or 4; n is O, 1, 2, 3, 4 or 5;

In another embodiment, there is provided a compound of Formula IVa, or a pharmaceutically acceptable salt, prodrug or solvate thereof:

[In the meal,

R ₂ is selected from the group consisting of hydrogen, methyl and ethyl;

R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 1O} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Is unsubstituted or substituted;

Each R ₄ is halogen, nitro, C _{1 -} is independently selected from _10, alkyl, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl group consisting of _alkyl-10 alkyl, C _{2 - 10} alkynyl, C ₁ Each is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;

R ₅ is C _{1 - 10} alkyl, C _{1 - 10} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each or which is unsubstituted or Substituted;

_{R 6, R 7, R 8} , R 9 and R ₁₀ is hydrogen, halo, C _{1 - 10} alkyl, C _{2 - 10} alkynyl, C _{1 - 10} alkoxy, aralkyl, cycloalkyl, aryl C _{1 - 10} alkyl, and heteroaryl C _{1 -,} each independently selected from the group consisting of alkyl, or _10; Or R ₆ and R ₇ , or R ₇ and R ₈ , or R ₈ and R ₉ , or R ₉ and R ₁₀ are unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated rings together with the carbon atoms to which they are attached; , Aryl or heteroaryl;

R ₁₁ is hydrogen, or unsubstituted or substituted C _{1 - 10} alkyl, and;

R ₁₈ is C _{1 -} is selected from the group consisting of _10-alkyl, arylalkyl and heterocycloalkyl, each unsubstituted or substituted; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4 or 5;

In another aspect, there is provided a compound comprising Formula V or a pharmaceutically acceptable salt, prodrug or solvate thereof:

[In the meal,

R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Is unsubstituted or substituted;

Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 -2 0} alkyl, C _{2 -1O} alkenyl, independently from ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group _- C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C ₁ Each is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;

R ₅ is selected from the group consisting of alkyl, alkoxy, amino, alkylamino, dialkylamino and aryl, each of which is unsubstituted or substituted;

Each R ₁₉ is halogen, C _{1 - 10} alkyl, C _{2 -1O} alkynyl, C _{1 -1O} alkoxy, aralkyl, and are independently selected from the group consisting of cycloalkyl, each unsubstituted or substituted; m is 0, 1, 2, 3 or 4; u is 0, 1 or 2].

In another aspect, there is provided a compound of Formula Va, or a pharmaceutically acceptable salt, prodrug or solvate thereof:

[In the meal,

R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl;

R ₃ hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 -1O} alkenyl, C _{2 - 10} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Unsubstituted or substituted;

Each R ₄ is hydrogen, halo, halo-C _{1 -1O} alkyl, C _{1 -1O} alkyl, perhaloalkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _2-10 independently from the alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group Each of which is substituted or unsubstituted or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;

R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, and C _{1 -1O} alkyl, each unsubstituted or optionally substituted, or R ₁₆ and R ₁₇ together with the nitrogen atom to which they are attached To form an unsubstituted or substituted 4, 5 or 6 membered ring;

R ₁₈ is C _{1 - 10} alkyl, and aryl alkyl, and heterocycloalkyl group consisting of alkyl, each unsubstituted or substituted;

m is 0, 1, 2, 3 or 4].

In another aspect, there is provided a compound or pharmaceutically acceptable salt, prodrug or solvate of Formula (VI):

[In the meal,

R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₇ N—, each being unsubstituted or substituted;

R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl;

R ₃ is hydrogen, halo, halo _{1 - 10} alkyl, C _{1 -1O} alkyl, perhaloalkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 -1O} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each Beach Ring or substituted;

Each R ₄ is halogen, nitro, C _{1 - 10} is independently selected from the alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl group consisting of _alkyl-10 alkyl, C _{2 -1O} alkynyl, C ₁ Or, each unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;

R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, each unsubstituted or optionally substituted, or R ₁₆ and R ₁₇ together with the nitrogen atom to which they are attached To form an unsubstituted or substituted 4, 5 or 6 membered ring;

Each R ₂₀ is halo, cyano, nitro, halo (C _1-1O) alkyl, perhalo (C _1-5) alkyl, aryl, heteroaryl, C _{1 - 10} alkyl, aryl (C _1-10) alkyl , alkoxy (C _1-10) alkyl, amino, hydroxyl, thio, and C _{1 -1O} independently selected from the group consisting of alkoxy and m and p are each independently 0, 1, 2, 3 or 4].

In one variation of the above compounds, R ₈ is C _{1 -} is selected from the group consisting of _10-alkoxy-10 alkyl, halogen, and C _1; R ₆ , R ₇ , R ₉ and R ₁₀ are hydrogen. In another variation of the compound, R ₃ is selected from the group consisting of methyl, trifluoromethyl and chloro; m is zero.

In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier selected from the group consisting of excipients and auxiliaries:

[Formula I]

[In the meal,

R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N-, each being unsubstituted or substituted;

R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl;

R ₃ is fluoro, chloro, bromo, iodo, C _{1 -1O} alkoxy, nitro, halo-C _{1 -1O} alkyl, perhalo C _{1 -1O} alkyl, and the group consisting of unsubstituted or substituted C ₁ alkyl _-1O Is selected from;

Each R ₄ is halogen, nitro, C _{1 - 10} alkynyl, C _{1 -1O} alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and _{heterocycloalkyl-10} alkyl, C _{2 - 10} alkenyl, C ₂ Independently selected from the group consisting of: each unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;

R ₅ is an optionally substituted C _{1 - 10} selected from alkoxy, -NH _2, C _{1 -1O} alkylamino, di (C _1-1O) the group consisting of alkylamino and _{aryl-10-alkyl,} C _1;

R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, each unsubstituted or optionally substituted, or R ₁₆ and R ₁₇ together with the nitrogen atom to which they are attached To form an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4; Provided that when R ₅ is -OEt R ₄ is not halogen and the compound of formula I is a compound ethyl α-[(benzyl) aminomethylene] -2-chloro-β-oxobenzenepropionate and 1- (2, 4-dichloro-5-fluorophenyl) -2-[[(2,4-difluorophenyl) amino] methylene] -1,3-pentanedione is not].

Also provided herein are such compounds, wherein the compound is present as a single stereoisomer and as a mixture of stereoisomers and pharmaceutically acceptable salts thereof. In addition, pharmaceutical compositions of such compounds are formulated for oral administration, parenteral, intravenous, transdermal, sublingual, intramuscular, rectal, intranasal, intraocular or subcutaneous administration.

In another aspect, there is provided a pharmaceutical composition comprising each of the above compounds and a pharmaceutically acceptable carrier selected from the group consisting of excipients and adjuvants.

In another aspect, a method of treating CNS disorders according to the regulation of a GABA _A receptor complex, wherein the method comprises administering to a patient in need thereof such a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof Methods are provided that include administering:

[Formula I]

Wherein each variable is as defined above.

In one variation of the method, the CNS disorder is an anxiety disorder. In another variation, the CNS disorder is cramps. In another variation, the CNS disorder is insomnia. Also in another variant, the CNS disorder is a major depressive disorder or bipolar disorder. Also in another variation, the CNS disorder is chronic or acute pain. In another variation, the CNS disorder is neurosis. In certain variations the CNS disorder is withdrawal induced convulsions from drug misuse. In another particular variation, the CNS disorder is phobia. In another variation of the method, the CNS disorder is panic disorder.

In one variation of the method, the CNS disorder is a generalized anxiety disorder. In another variation, the CNS disorder is obsessive compulsive disorder. In another variation, the CNS disorders are post-traumatic and acute stress disorders. In another variation, the CNS disorder is migraine. In certain variations of the method CNS disorders include bipolar mania disorders; Or cognitive deficit disorder. In certain variations of the method the CNS disorder is selected from the group consisting of anxiety and stress related disorders, depression and other affective disorders, epilepsy and other seizure disorders, insomnia and related sleep disorders, acute and chronic pain and cough.

In another aspect, there is provided a method of treating disorders related to learning and memory, comprising administering a compound of formula (I) to a patient in need thereof. In one variation of the method, the learning and memory related disorders are selected from the group consisting of mild cognitive impairment, age related cognitive decline, elderly dementia, Alzheimer's disease, and sleep disorders including reduced wakefulness. In another variation, the sleep disorder comprising a reduced waking state is selected from the group consisting of narcolepsy and idiopathic hypersleep. In another variation, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from [ ³ H] -flunitrazepam, barbiturate, lorlezole, [ ³ H] -musmol, or 3α, 20α-pregnane Methods are provided for altering chloride conductivity via the GABA _A receptor complex in a therapeutically useful manner by acting by binding to a site other than the site to which the diol is bound. In another aspect, provided are methods of treating CNS disorders following modulation of the GABA _A receptor complex, comprising administering a compound of Formula (I) to a patient in need thereof.

α7 Nicotinic  Acetylcholine Receptor Modulators:

The present invention also relates to the discovery that certain substituted enaminens represented by formulas (I) to (VI) serve as novel regulators of the α7 nicotinic acetylcholine receptors (nAChRs). The present invention relates to the treatment of disorders that are responsive to enhancing acetylcholine action on a7 nAChRs in mammals by administering an effective amount of a compound of Formulas I-VI described herein. Thus, compounds of the invention that are ligands for α7 nAChRs are useful in the treatment and / or prevention of disorders of various central nervous systems. Such disorders include neuropathic disease, elderly dementia and schizophrenia. Another aspect of the invention relates to the use of compounds of formulas (I) to (VI) as enhancers of acetylcholine-promoting monovalent and divalent cation flow mediated through α7 nAChR. In addition, one aspect of the present invention relates to the acetylcholine-promoted monovalent and divalent cation flow mediated through nAChR containing an effective amount of a compound of Formulas I-VI mixed with one or more pharmaceutically acceptable carriers or diluents. It is to provide a pharmaceutical composition useful for treating disorders responsive to an adjuvant.

In one aspect, a method of treating CNS disorders following modulation of the nAChR complex, the method comprising administering to a patient in need thereof such a compound of Formula I or a pharmaceutically acceptable salt, prodrug or solvate thereof This is provided:

[Formula I]

[In the meal,

R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted;

R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl;

R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} it is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Unsubstituted or substituted;

Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 - 10} alkoxy, aryloxy, heteroaryloxy, a car Viterbo group, a sulfonyl group, a sulfinyl group, the group consisting of already a group from Independently selected, each unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;

R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1;

R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5 or 6 membered ring;

m is 0, 1, 2, 3 or 4].

In another aspect, a method of treating a neuropathic disorder is provided comprising administering an effective amount of a compound of Formulas I-VI to a patient in need thereof. In another aspect there is provided a method of treating elderly dementia comprising administering an effective amount of a compound of Formulas I-VI to a patient in need thereof. In another aspect, a method of treating schizophrenia is provided comprising administering an effective amount of a compound of Formulas I-VI to a patient in need thereof. In yet another aspect, there is provided a method comprising administering an effective amount of a compound of Formulas I-VI to a patient in need of such treatment as a method of treating a cognitive deficit disorder. In another aspect, learning and memory, such as mild cognitive impairment, age-related cognitive decline, elderly dementia, Alzheimer's disease, due to inhibition of monovalent and divalent cation conductivity through sites mediating the action of compounds of Formulas I-VI above Related methods of treating disorders are provided.

Compounds of Formulas I-VI include:

Ethyl 2-chloro-β-oxo-α-[[[4- (1,2,3,4-tetrahydronaphthyl-1-amino) phenyl] amino] methylene] benzenepropionate;

Ethyl 2-chloro-5-nitro-β-oxo-α-[[[4- (1,2,3,4-tetrahydronaphthyl-1- amino) phenyl] amino] methylene] benzenepropionate;

Ethyl 2-chloro-α-[(cyclohexylamino) methylene] -β-oxobenzenepropionate;

Ethyl 2-chloro-α-[(4-iodophenyl) aminomethylene] -β-oxo-benzenepropionate;

Ethyl α-[(4-bromophenyl) aminomethylene] -2-chloro-β-oxo-benzenepropionate;

Ethyl 2-chloro-α-[(4-methoxyphenyl) aminomethylene] -β-oxo-benzene-propionate;

Ethyl 2-chloro-α-[(3-chloro-4-fluorophenyl) aminomethylene] -β-oxo-benzene-propionate;

Ethyl 2-chloro-α-[(4-fluorophenyl) aminomethylene] -β-oxo-benzenepropionate;

Ethyl α-[(4-iodophenyl) aminomethylene] -β-oxo-1-naphthalenepropionate;

Ethyl α-[(4-fluorophenyl) aminomethylene] -β-oxo-1-naphthalenepropionate;

Ethyl α-[(benzyl) aminomethylene] -β-oxo-1-naphthalenepropionate;

Ethyl β-oxo-α-[(2-phenylethyl) aminomethylene] -1-naphthalenepropionate;

Ethyl β-oxo-α-[(3-phenylpropyl) aminomethylene] -1-naphthalenepropionate;

Ethyl β-oxo-α-[(4-phenylbutyl) aminomethylene] -1-naphthalenepropionate;

Ethyl 2-chloro-α-[(3-phenylpropyl) aminomethylene] -β-oxo-benzenepropionate;

Ethyl 2-chloro-α-[(3,3-diphenylpropyl) aminomethylene] -β-oxo-benzenepropionate;

Ethyl 2-chloro-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate;

Ethyl 2-bromo-α-[(4-fluorophenyl) aminomethylene] -β-oxo-benzenepropionate;

Ethyl α-[(4-fluorophenyl) aminomethylene] -2-nitro-β-oxo-benzenepropionate;

Ethyl α-[(4-fluorophenyl) aminomethylene] -2-methyl-β-oxo-benzenepropionate;

Ethyl 2-methyl-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate;

Ethyl 2-nitro-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate;

Ethyl 2-ethoxy-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate;

Methyl 2-chloro-α-[(4-iodophenyl) aminomethylene] -β-oxo-benzenepropionate;

Ethyl α-[(4-iodophenyl) aminomethylene] -β-oxo-2-trifluoromethyl-benzenepropionate;

Ethyl α-[(4-iodophenyl) aminomethylene] -2-methyl-β-oxo-benzenepropionate;

Ethyl α-[(4-methoxyphenyl) aminomethylene] -β-oxo-2-trifluoromethyl-benzenepropionate;

Ethyl 2-bromo-α-[(4-iodophenyl) aminomethylene] -β-oxo-benzenepropionate;

Ethyl 2-chloro-α-[(4-methylphenyl) aminomethylene] -β-oxo-benzenepropionate;

Ethyl α-[(4-butylphenyl) aminomethylene] -2-chloro-β-oxo-benzenepropionate;

Ethyl 2-chloro-α-[(4-isopropylphenyl) aminomethylene] -β-oxo-benzene-propionate;

Ethyl 2-bromo-α-[(4-iodophenyl) aminomethylene] -β-oxo-benzenepropionate;

2-chloro-α-[[(4-cyanophenyl) amino] methylene] -N-ethyl-β-oxo-benzenepropanamide;

2-chloro-N-ethyl-α-[[(4-iodophenyl) amino] methylene] -β-oxo-benzenepropanamide;

2-chloro-α-[[(4-iodophenyl) amino] methylene] -β-oxo-N- (2-propynyl) benzenepropaneamide;

2-chloro-α-[[(4-ethynylphenyl) amino] methylene] -β-oxo-N-propyl-benzenepropanamide;

α-[[(4-ethynylphenyl) amino] methylene] -2-methyl-β-oxo-N-propyl-benzenepropanamide;

α-[[(4-cyanophenyl) amino] methylene] -2-methyl-β-oxo-N-propyl-benzenepropanamide;

α-[[(4-ethynylphenyl) amino] methylene] -2-methyl-β-oxo-N- (2-propynyl) -benzenepropanamide;

2-chloro-α-[[(4-cyanophenyl) amino] methylene] -β-oxo-N-propyl-benzenepropanamide;

Ethyl α-[(4-iodophenyl) aminomethylene] -2-methyl-β-oxo-benzenepropionate;

2-chloro-N-ethyl-α-[(isoxazolyl-3-amino) methylene] -β-oxo-benzenepropanamide;

α-[(4-ethynylphenyl) aminomethylene] -β-oxo-N-propyl-1-naphthalenepropanamide;

2-chloro-α-[(isoxazolyl-3-amino) methylene] -β-oxo-N-propyl-benzenepropanamide;

2-Chloro-N-ethyl-β-oxo-α-[(1,2,4-triazolyl-4-amino) methylene] benzene-propanamide;

Ethyl α-[(4-ethynylphenyl) aminomethylene] -2-fluoro-β-oxobenzenepropionate;

α-[(4-ethynylphenyl) aminomethylene] -β-oxo-N-propyl-1-naphthalenepropanamide; And

2-Chloro-N-ethyl-β-oxo-α-[(pyrazinyl) amino] -benzenepropanamide.

For medical use, the salts of the compounds of Formulas I-VI will be pharmaceutically acceptable salts. However, other salts may also be useful in the preparation of the compounds according to the invention or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds of the invention include, for example, solutions of the compounds of the invention, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid or phosphoric acid. Acid addition salts that can be formed by mixing with a solution of a pharmaceutically acceptable acid such as Moreover, when the compounds of the present invention have an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts; Alkaline earth metal salts such as calcium or magnesium salts; And salts formed with suitable organic ligands, such as quaternary ammonium salts. Standard methods for preparing pharmaceutically acceptable salts and formulations thereof are well known in the art and are described, for example, in "Remington: The Science and Practice of Pharmacy", A. Gennaro, ed, 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA].

The present invention includes prodrugs of the compounds of Formulas I-VI within the scope of the present invention. Generally the prodrug will be a functional derivative of a compound of formulas I-VI that can be readily converted in vivo to the desired compound of formulas I-VI. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

If a compound of the invention has one or more asymmetric centers, it may therefore exist as enantiomers. If the compounds according to the invention have two or more asymmetric centers, they may additionally exist as diastereoisomers. It is to be understood that all of the above isomers and mixtures thereof in any ratio are included within the scope of the present invention.

By "disease" is meant any unhealthy condition of an animal, or any unhealthy condition of an animal that can be caused by medical therapy in the animal by treatment. Examples of diseases by treatment include treatments that can result in, for example, one or more side effects.

"Halogen" or "halo" means fluorine, bromine, chlorine and iodine. Useful halogens include fluorine, bromine chlorine and iodine.

"Alkyl" means a straight or branched, saturated or unsaturated aliphatic radical having the indicated number of carbon atoms. Alkyl groups may include heteroatoms such as oxygen, nitrogen or sulfur inserted into or in the chain of the alkyl group. Useful alkyl group in a straight chain and branched C _{1 - 20} alkyl group are included. In one aspect, the alkyl groups of the invention include C _{5 - 20} alkyl group are included. Typical C _{5 - 20} alkyl group, the n- phenyl, n- hexyl, n- heptyl, n- octyl, n- nonyl, n- decyl, n- undecyl, n- dodecyl, n- tree sedil, n- tetradecyl , n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl and eicosanyl groups. Alkyl groups can also be represented by other groups such as “arylalkyl” groups such as benzyl groups. See below.

“Aryl” groups can be monocyclic, bicyclic or polycyclic ring systems, each ring being aromatic or, when fused or linked to one or more rings, forms a polycyclic ring system. Aryl rings can also be fused with non-aromatic rings. Aryl rings may also contain heteroatoms to form heteroaryl rings. Useful aryl groups are C _{6 - 10} aryl _a-14 aryl, especially C _6. Typical C 6-14 aryl groups include phenyl, naphthyl, anthracyl, indenyl and biphenyl groups.

"Arylalkyl" or "aralkyl" groups are any C ₆ mentioned above _- include ₂₀ alkyl _- C ₁ mentioned in any of the above substituted by an aryl _10. Similarly, substituted C _{1 -1O} alkyl is also C _{1 - 10} alkyl group may represent a case of the substituted aryl, arylalkyl or an aralkyl group (or heteroarylalkyl, etc.). Useful arylalkyl groups include benzyl, phenethyl and phenylpropyl. In the case of a compounding group such as an arylalkyl or aralkyl group, the group is bonded in the latter or last group. For example, "aryl C _{1 - 10} alkyl" groups such as benzyl group is, for example, aryl C _{1 -} is coupled at the coupling portion, as shown here - ₁₀ alkyl- or benzyl.

It includes any of a group _{of 20 -} Useful cycloalkylalkyl group is a C ₁ mentioned above that any substitution of the previously mentioned cycloalkyl groups. Cycloalkyl groups can also contain one or more heteroatoms in the cyclic group. Examples of useful cycloalkylalkyl groups include cyclohexylmethyl and cyclopropylmethyl groups.

Useful halomethyl group, the fluoromethyl, difluoro methyl, trifluoromethyl, methyl and ethyl groups containing 1,1-difluoro, one or more fluorine, chlorine, bromine or iodine atom-substituted C _{1 - 20} alkyl groups include the do. Perhaloalkyl groups include, for example, trifluoromethyl and pentafluoroethyl groups.

Useful hydroxyalkyl groups include a group comprising hydroxymethyl, 1-and 2-hydroxyethyl and 1-hydroxy-propyl, a C ₁ is substituted by a _{hydroxy-alkyl} group include _20.

Useful alkoxy groups include C ₁ according to the above _- include oxygen substituted by one of the ₂₀ group. Examples of the alkoxy group include methoxy, ethoxy, propoxy, butoxy and the like.

Useful alkylthio groups include, for example thiomethyl, thio, butyl-decyl-include sulfur substituted by one of the _{20 group-thio-hexadecyl,} and the C ₁ described comprising a.

An "amino" group is -NH ₂ . Alkylamino and dialkylamino groups include, for example, -NHR ₁₂ and -NR ₁₂ R ₁₃ Wherein each of R ₁₂ and R ₁₃ is independently a substituted or unsubstituted C _1-20 alkyl group. Examples of such groups include -NHMe, -NHEt, -NHcyclohexyl, -NHCH ₂ phenyl, -N (Me) ₂ , and the like. Useful dialkylamino alkyl group is C ₁ mentioned in any of the above _- and that contains ₁₀ alkyl group, respectively unsubstituted or substituted. Substituted amino groups may also include, for example, -NHMe, -NHEt, -NHcyclohexyl, -N (Me) _2, etc., and -NHCOMe, -NHCOEt, -NHCONHMe, and the like.

“Imino” may bind to other ligands such as —NR _a R _b or —OR _a groups to form, eg, —C (═N) NR _a R _b or —C (═N) OR _a , respectively; C (= N)-group.

And a group _{10 -} Useful alkylthio group of C ₁ referred to in any of the substituted group -SH.

"Carbonyl" is -C (O)-which can bind to other ligands such as -NR _a R _b or -OR _a groups to form -C (O) NR _a R _b or -C (0) 0R _a , respectively. Means a flag. Examples of additional carbonyl groups include carboxyl groups, aldehydes, acid halides or ketones. The carboxy or carboxyl group is -COOH.

"Heterocyclic" means a saturated or partially unsaturated 3-7 membered monocyclic or 7-10 membered bicyclic ring system, which is independently selected from the group consisting of carbon atoms and O, N and S Consisting of 1 to 4 heteroatoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, the nitrogen may be optionally quaternized, and any of the above defined heterocyclic rings are fused to the benzene ring Bicyclic rings are included, meaning that the heterocyclic ring can be substituted on carbon or nitrogen when the resulting compound is stable. Examples include, but are not limited to, pyrrolidine, piperidine, piperazine, morpholine, quinoline, 1,2,3,4-tetrahydroquinoline, and the like.

"Heteroaryl" is a fully unsaturated 5 and 6 membered monocyclic, or 9 and 10 membered bicyclic ring system consisting of carbon and 1 to 4 heteroatoms independently selected from the group consisting of O, N and S Wherein the nitrogen and sulfur hetero atoms can be optionally oxidized, the nitrogen can be optionally quaternized, and any bicyclic wherein any heterocyclic ring as defined above is fused to the benzene ring Also included are wherein the heterocyclic ring may be substituted on carbon or nitrogen when the resulting compound is stable. Examples include, but are not limited to, thiophene, benzothiophene, imidazole, pyridine, pyrimidine, quinoline, naphthyridine, purine, and the like. Heteroaryl groups can be unsubstituted or substituted.

By "substituted or unsubstituted" is meant that the group may consist solely of hydrogen substituents (unsubstituted) or may further comprise one or more non-hydrogen substituents (substituted), unless otherwise specified. For example, the tert-butyl group may be an example of a propyl group substituted with a methyl group. Examples of substituents include, but are not limited to, (C _{1 -10)} alkyl, (C _{2 -10)} alkylene, amide, amino, aryl, carbamoyl, carbonyl, cycloalkyl, ester, halo, heteroaryl, oxo , Hydroxy or nitro groups are included, each of which may also be substituted or unsubstituted, upon acceptance of the valence. Optional substituents on R ₁ to R ₂₀ include any one or more of the aforementioned halo, cyano, nitro, halo (C _1-20 ) alkyl, perhalo (C _1-20 ) alkyl, aryl, cycloalkyl, C _{1 - 20} alkyl, aryl (C _1-20) alkyl, cycloalkyl (C _1-20) alkyl, hydroxy (C _1-20) alkyl, amino (C _1-20) alkyl, alkoxy (C _1-20) alkyl ₂₀ include alkyl thiol group _-, amino, hydroxy, thiol, alkoxy and C _1. In one aspect, preferred is optionally substituted halo, (C _{1 -6)} alkyl, halo (C _1-6) alkyl, amino (C _1-6) alkyl, C _{1 - 210} include alkoxy and amino.

"Isomer" means any compound that has the same molecular formula but differs in the order or nature of the bonding or arrangement of atoms in space. Examples of such isomers include, for example, the E and Z isomers, enantiomers and diastereomers of a double bond. Compounds of the invention that show a bond with a "squiggly line" are intended to include both isomers and / or single isomers of a double bond, as shown below.

"Prodrug" means a compound that can be metabolized metabolically in vivo to a compound of the invention. For example, a prodrug of a compound of the invention may or may not have biological activity as an agonist. Examples of prodrugs are known in the art. Examples of prodrugs are described in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series; And Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. Prodrugs can also be considered analogs or derivatives of the compounds of the present invention.

The preparation of the compounds of the present invention can be carried out using standard methods known in the art of organic synthesis. Reaction conversion using a compound with a functional group can be carried out on a compound with a functional group that can be protected. By "protected" compound or derivative is meant a derivative of a compound in which one or more reaction sites or sites or functional groups are blocked by a protecting group. Protected derivatives are essentially or useful in the preparation of the compounds of the present invention, which protected derivatives may be biologically active. An example of a comprehensive text listing suitable protectors is given in [T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999].

Synthesis of compounds of Formulas II and III is in Scheme 1. Compound 2 with R ₅ = 0Et is commercially available from Acros. Compound 2 with R ₅ = 0Me is described in Navarro-Vazquez et al. J. Org. Chem. 2002, 67 (10), 3220] can be prepared from dimethylamine and methyl propiorate. Corresponding amides are described in Nuvole, A. et al. J. Chem. Soc. Perkin Trans. 1, 1989, 1007-1011 and Dabrowski, J. et al. Tetrahedron, 1976, 32, 1025-1029.

Scheme 1

Intermediate 3 can also be prepared as shown in Scheme 2.

Scheme 2

When R ₅ = alkyl, compound 5 is described in Collins, JL et al. US 6,498,174 or in Atkins, RJ, et al. Organic Process Research & Development 1997, 1, 185-197 or Popic, etc. Synthesis 1991, 195-198. R ₅ = for alkoxy Compound 5 is described in Oikawa, Y. et al. J. Org Chem. 1978, 43 (10), 2087-2088. For R ₅ = NMe ₂ Compound 3 is prepared from 2 (R ₅ = NMe 2 ) using the method of Grohe, K. of US Pat. No. 4,699,992. Compound 5 , wherein R ₅ = amino or alkoxy, starts from Meldrum acid ( 6 ) as shown in Scheme 3, and synthesizes acyl Meldrum acid ( 7 ): Yamamoto, Y. et al. Chem. Pharm. Bull. 1987, 35, 1860-70; Reaction of Amine with Acyl Meldrum Acids: Andrews, IP et al. Tetrahedron Lett. 1995, 36 (42), 7743-46; Pak, CS et al. Synthesis 1992, 1213-1214; Moya, P. et al. J. Org. Chem. 1998, 63, 8530-35.

Scheme 3

Amide 12, Scheme 4, may also be prepared from the corresponding tert-butyl ester 10 prepared as in Scheme 3 (R ₁₄ OH = tert-butanol). The reaction of the tert-butyl ester with trifluoroacetic acid in the presence of thioanisole provides the acid (11). Standard methods for amide bond formation are then used (isobutyl chloroformate and triethylamine; carbonyl diimidazole, dicyclohexylcarbodiimide and the like).

Scheme 4

In vitro binding assay 1

[ ³⁵ S] TBPS binding assay. The cerebral cortex (160-200 g weight) of male Sprague-Dawley rats was choked and immediately detached and dissected on ice. P ₂ homogenate was prepared for binding assays as previously described (Gee, Mol. Pharmacol. 30: 218-225, 1986). Tissues were homogenized in 0.32 M sucrose (JT Baker Chemical Co., Pllillipsburg, NJ, USA) using Teflon-coated pestle and then centrifuged at 1,000 X g for 10 minutes. Supernatants were collected and centrifuged at 9,000 × g for 20 minutes. The resulting P ₂ pellets were resuspended in ice cold 50 mM sodium potassium phosphate (JT Baker) buffer (pH 7.4) containing 200 mM NaCl (JT Baker) and immediately used for binding assays. 100 μl of tissue in the presence or absence of 5 μM GABA (Sigma Chem. Co., St. Louis, Mo.) at [ ³⁵ S] TBPS (86 Ci / mmol; New England Nuclear, Boston, Mass., USA) at 2 nM concentration Incubated with homogeneous suspension (10%, w / v) and 5 μl aliquots of test drug (Sigma Chem. Co.) dissolved in dimethyl sulfoxide (≦ 10 μl solvent of solvent used in all assays). . At the concentrations used (≦ 1%), dimethyl sulfoxide did not affect certain [ ³⁵ S] TBPS binding. 50 mM sodium potassium phosphate buffer (pH 7.4) containing 200 mM NaCl brought the final volume of all assays to 1 mL. Nonspecific binding is defined as binding in the presence of 2 μM TBPS (NEN, Boston, Mass.) And accounts for ˜30% of total binding. The assay was terminated after 90 minutes of steady state incubation at 25 ° C. by rapid filtration through a glass fiber filter (no. 32; Schleicher & Schuell, Keene, NH). Filter binding radioactivity was quantified by liquid flash spectrophotometry. Data was evaluated by nonlinear regression (GraphPad, Inc., San Diego, Calif.) To obtain IC ₅₀ values (concentrations at which half maximal inhibition of radioligand occurs).

Electrophysiological Test 1

Pregnant Sprague-Dawley rats bearing fetuses with a 17 to 19 day gestation period were sacrificed by cervical dislocation. The fetus was removed under aseptic conditions, and the brain was excised rapidly at ambient temperature (18-22 ° C.) and placed in Hank's balanced salt solution (HBSS, Gibco). The hippocampus was excised and cut into fragments (˜2 mm ³ ) and transferred to an enzyme solution (mM) containing (mM) and incubated for 1 hour at 37 ° C., 5% CO ₂ , 100% relative humidity: NaCl 116, KCl 5.4, NaHCO ₃ 26, NaH ₂ PO ₄ 1, CaCl ₂ 1.5, MgSO ₄ 1, EDTA 0.5, Glucose 25, Cysteine 1, and Papain 20 U / ml (Sigma). Tissue fragments were washed in HBSS containing 1 mg / ml bovine serum albumin (BSA) and 1 mg / ml ovomucoid (both Sigmna). Tissue was further transferred to 3-4 ml of this solution and slowly triturated into a single cell suspension using a fire-polished Pasteur pipette. Single cell suspensions were layered onto 5 mL HBSS containing 10 mg / ml BSA and 10 mg / ml ovomucoid and centrifuged at 100 × g for 10 minutes. Discard the supernatant and resuspend cells in 3-4 ml of glutamine free mineral essential medium (MEM, Gibco) to heat inactivate fetal calf serum (5% v / v Gibco), heat-inactivated horse serum (5 % v / v Gibco), streptomycin and penicillin (50 μg / ml and 5000 iu / ml, respectively), glutamine and glucose (final concentrations 2 mM and 20 mM [Gibco and BDH], respectively). About 1-2 x 10 ⁵ cells were plated with each 35 mm (Falcon “Primaria”) tissue culture dish containing MEM containing ˜1 ml of serum. The plates were maintained at 37 ° C., 5% CO ₂ , and 100% relative humidity until used for electrophysiological studies. Cytosine arabinoside (10 μM, Sigma) inhibited background proliferation of non-neuronal elements for 48 hours 7 days after first isolation.

미세조작기에 단단히 고정시켜 연구 하 세포에 근접(<1mm)하게 위치시켰다. 조 용액(Bath solution)을, 구부리기 쉬운 튜브에 의해 유리수조 빨펌프에 연결된 19 G 바늘을 통해 디쉬로부터 회수했다. 기록 전극을 하기로 이루어진 내부 용액(mM)으로 채웠다 : CsCl 또는 KCl 140, MgCl₂ 2, CaCl₂ 0.1, EGTA 1.1 (자유 Ca^{2 +} ~ 10^-8 M), HEPES NaOH 10, 및 ATP-Mg^{2 +} 2. 기록 전극을 Narishige PB7 두 단계 전극 풀러(puller) 상 유리 헤마토크리트 튜브(glasss hematocrit tube: Kimble sodalime tubes 73811) 로부터 제작했다. 전극을 "Sylgard" (Dow Corning)으로 100 ㎛ 의 팁 내에서 코팅하고 사용하기 바로 직전에 파이어 폴리싱하였다. 화합물을 체세포의 전압고정된 뉴런에, Picospritzer II 장치(General Valve Corporation)를 이용해 변형된 기록 피펫의 팁으로부터 가압 배출(1.4 Kpa, 10 ~ 18 msec, 0.1 ~ 0.033 Hz)함으로써 국소적으로 적용시켰다. 화합물 함유 피펫을 0.1 mm 의 세포 내에서 Leitz 미세조작기를 이용해 위치시켰다. 현미경 및 미세조작기를, Faraday 상자 내부에 위치된 진동-없는 단리 공기 테이블 (vibration-free isolation air table: Wentworth)상에 모두 단단히 고정시켰다. 화합물로 야기된 전 세포 전류를 저장 오실로스코프(Tektronix 2212)상에서 모니터링하고, 디지털 펄스 부호 변조 (주파 감도 14 kHz, Sony PCM 701)후에 기록하고 Multitrace(Electromed) 펜 차트 기록기 (주파 감도 0.5 kHz) 상에서 디스플레이했다. 본 발명의 화합물 이외의 모든 약물을 과융해(superfusion)시스템을 이용해 세포에 적용시켰다. 화합물로 야기된 전체 세포 전류를 그의 정점에서 측정했다. 약물 존재하 응답성을 약물 부재하(대조군)의 응답성의 산술 평균 ± SEM 으로 나타냈다. Compounds of the invention that produce membrane currents were recorded from hippocampal neurons using whole cell batches of patch-clamp techniques. The neurons were fixed at -60 mV using a List electronics L / M EPC-7 converter head stage and amplifier. Cells were perfusing with external (crude) recording solution (mM) containing: NaCl 140, KCl 2.8, MgCl ₂ 2, CaCl ₂ 1 and HEPES-NaOH 10 (pH 7.2). Tetrodotoxin (TTX, 0.3 μM) was included in the recording solution to inhibit synaptic activity. The external solution was delivered (-2 ml / min) through a non-sterile tube connected to a plastic cannula with a tip diameter of 1 mm with a Watson-Marlow flow pump. Priority Input Cannula

Tightly secured to the micromanipulator and placed close to the cells under study (<1 mm). The bath solution was withdrawn from the dish via a 19 G needle connected to a glass bath pump by a flexible tube. The recording electrode was filled with an internal solution (mM) consisting of: CsCl or KCl 140, MgCl ₂ 2, CaCl ₂ 0.1, EGTA 1.1 (free Ca ^{2 + ˜10-8} M), HEPES NaOH 10, and ATP-Mg ^{2 +} 2. The recording electrode was constructed from glass hematocrit tube (Kimble sodalime tubes 73811) on a Narishige PB7 two-stage electrode puller. The electrode was coated in a tip of 100 μm with “Sylgard” (Dow Corning) and fire polished just before use. Compounds were applied topically to voltage-fixed neurons of somatic cells by pressurized evacuation (1.4 Kpa, 10-18 msec, 0.1-0.033 Hz) from the tip of the modified recording pipette using the Picospritzer II apparatus (General Valve Corporation). Compound containing pipettes were placed using Leitz micromanipulators within 0.1 mm of cells. Microscopes and micromanipulators were all securely mounted on a vibration-free isolation air table (Wentworth) located inside a Faraday box. The whole cell current caused by the compound is monitored on a storage oscilloscope (Tektronix 2212), recorded after digital pulse sign modulation (frequency sensitivity 14 kHz, Sony PCM 701) and displayed on a Multitrace (Electromed) pen chart recorder (frequency sensitivity 0.5 kHz). did. All drugs other than the compounds of the present invention were applied to the cells using a superfusion system. The total cell current caused by the compound was measured at its peak. Responsiveness in the presence of drug is expressed as an arithmetic mean ± SEM of response in the absence of drug (control).

Electrophysiology Test 2

HEK cells transfected with GABA _A subunit contain L-glutamine but are free of sodium pyruvate (Irvine Scientific # 9031, Irvine CA) and 10% fetal bovine serum (Irivine Scientific # 3000), 10 U / ml Dulbecco supplemented with an antibiotic cocktail consisting of mycin B (Calbiochem # 400051), and 100 μg / ml streptomycin sulfate, 0.25 μg / ml amphotericin B, 100 units / ml penicillin G (Gibco 15240-096, Gaithersburg MD) Modified Eagle's Medium was used at 37 ° C. and 5% CO ₂ . When the saturation reaches ~ 90%, the cells are phosphated by one lift using trypsin / EDTA solution (0.5 mg / ml trypsin, 0.2 mg / ml EDTA, Irvine Scientific # 9342) in PBS. Washed twice with buffered saline (PBS) pH 7.4 and passaged.

GABA _A subunit transfected HEK cells were grown to ˜70% saturation on slides. Cells were transferred to a bath that was continuously overfused with extracellular saline. The extracellular medium contained 145 mM NaCl, 3 mM KCl, 1.5 mM CaCl ₂ , 1 mM MgCl ₂ , 5.5 mM d-glucose and 10 mM HEPES and was pH 7.4 at 320-330 mosM osmolality. Recordings were made at room temperature using whole cell patch clamp technology. The patch pipette solution contains 147 mM N-methyl-D-glucamine hydrochloride, 5 mM CsCl, 5 mM K ₂ ATP, 5 mM HEPES, 1 mM MgCl ₂ , 0.1 mM CaCl ₂ , and 1.1 mM EGTA, 315 It was pH 7.2 at the osmolality of mosM. Pipette control resistance was typically 3-5 Mohms. The cells were voltage fixed at -60 mV and the chloride equilibrium potential was about 0 mV. The drug was dissolved in extracellular medium and rapidly applied to the cells by local overfusion. The solution was changed to approximately 20 ms with a motor-driven multichannel switching system.

In vivo  Pharmacology

Antiepileptic Assay : Mature male non-Swiss albino (NSA) mice (25-30 g) were utilized in the study. Time to anticonvulsant effect peaks were measured for seizure induced with picrotoxin (Sigma). Mice were injected at various time points up to 50 minutes after drug injection (30 mg / kg ip) with picrotoxin (3.15 mg / kg sc) and the time at which the maximum protection time was observed was defined as the peak effect time. Six animals were used per dose of test drug. Mice were treated with various doses of vehicle (DMSO 5 μl / g body weight) or drug dissolved in DMSO, with CD ₉₇ dose of metrazole (85 mg / kg), (+)-bicouculin (2.7 mg / kg), Or peak effect time prior to administration of picrotoxin (3.15 mg / kg), or vehicle (5 μl / g body weight of 0.9% saline). Mice were observed for 45-60 minutes immediately after infusion. The number of animals causing tonic spasms / clonic spasms was recorded.

Vogel  Vogel conflict

Mature male rats were randomly divided into 6 groups per group. The animals were not watered overnight (16 hours). When I was thirsty, I had to eat food at will. Thirty minutes after the test drug, control drug (diazepam), or vehicle control injection (i.p.), the rats were placed in a square plexiglass box containing a stainless steel bottom connected to one side of a drinkometer circuit. On the other side of the breathalyzer, a water bottle is connected so that the beverage tube extends into the plexiglass box. When the subject drinks from the bottle, the meter is closed and the electron shock is recorded on the tube after 7 licks. The number of licks was recorded during the 10 minute session.

Contrast change

Male NSA mice (25-30 g) were used. The device, which consists of an open top box, was divided into partitions with holes at the bottom level, in narrow and wide areas. Narrow partitions were painted black and wide partitions were painted white. The white partition was illuminated with a bright light and the black partition was illuminated with red light. After a period of time in the bright partition, the number change between the partitions was recorded during the three-minute test session. Vehicle or test compound was administered 30 minutes before testing. Diazepam was administered at 2 mg / kg (i.p.).

Example  One

Ethyl 2- Chloro -α-[(dimethylamino) methylene) -β-oxo- Benzene Propanoate

A mixture of ethyl 3,3-dimethylaminoacrylate (4.68 g, 32.7 mmol) and N, N-diisopropylethylamine (12 mL, 8.9 g, 69 mmol) was stirred at room temperature and 2 in 30 mL of toluene A solution of -chlorobenzoyl chloride (5.72 g, 32.7 mmol) was added over 5 minutes. The yellow solution formed was placed in an oil bath at 85-90 ° C. After 3 h the mixture formed was filtered and the solid was washed with toluene (4 × 25 mL). Pooled toluene washes were extracted with water (3 × 50 mL) and brine (1 × 30 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The dark filtrate was concentrated and the oily residue triturated with hexane (100 mL). The solid formed was isolated by filtration and washed with hexane (25 mL). The crude product was dissolved in a minimum volume of EtOAc and added to 16.5 cm of flash silica gel in a 5 cm diameter column. Elution with 100% EtOAc gave a solidified oil after trituration with hexanes. The melting point of the solid having a weight of 5.68 g (62%) was 70 to 71.5 ° C.

The following compounds were prepared using the method described above:

Ethyl 4-chloro-α-[(dimethylamino) methylene] -β-oxo-benzenepropanoate;

Ethyl 2-chloro-α-[(dimethylamino) methylene] -4-fluoro-3-methyl-β-oxo-benzenepropanoate, melting point 104.5-106.5 ° C .;

Ethyl α-[(dimethylamino) methylene] -β-oxo-1-naphthalenepropanoate, oil after flash chromatography with 4: 1 hexanes / EtOAc;

Ethyl 2-chloro-α-[(dimethylamino) methylene] -5-nitro-β-oxo-benzenepropanoate (03DJH60B);

Ethyl α-[(dimethylamino) methylene] -2-methyl-β-oxo-benzenepropanoate, oil after flash chromatography;

Ethyl 2-bromo-α-[(dimethylamino) methylene] -β-oxo-benzenepropanoate;

Ethyl α-[(dimethylamino) methylene] -β-oxo-2-trifluoromethyl benzenepropanoate; And

Ethyl α-[(dimethylamino) methylene] -2-nitro-β-oxo-benzenepropanoate.

Example  2

methyl  2- Chloro -α-[(dimethylamino) methylene] -β-oxo- Benzene Propanoate

A mixture of methyl 2-chlorobenzoylacetate (Acros; 266 mg, 1.25 mmol) and N, N-dimethylformamide dimethylacetal (161 mg, 1.35 mmol) was stirred for 2 weeks at room temperature under N ₂ . The reaction was then concentrated in vacuo and the residue was taken up on a silica gel and chromatographed. Elution with 3: 1 EtOAc / hexanes gave 193 mg of the title compound as a yellow solid.

Example  3

1,1-dimethylethyl 2- Chloro -α-[[(4- Iodophenyl ) Amino] methylene] -β-oxo- Benzene Propanoate

1,1-dimethylethyl 2 -chlorobenzoyl acetate . 0.6 mL (465 mg, 6.27 mmol) of a solution of 5- (2-chlorobenzoyl) -2,2-dimethyl-1,3-dioxane-4,6-dione (539 mg, 1.91 mmol) in 17 mL of toluene. It treated with 2-methyl-2-propanol of and heated at 80-85 degreeC. After 4.5 hours, the reaction was concentrated under cooling and vacuum. The crude product was absorbed onto 2 g of flash silica and added to 22.5 cm of flash silica in a 2 cm diameter column. Elution with 9: 1 hexanes / EtOAc gave 416 mg (86%) of β-ketoester as an oil.

1,1-dimethylethyl 2 -chloro- α-[(dimethylamino) methylene] -β-oxo- benzenepropanoate . 1,1-dimethylethyl 2-chlorobenzoyl acetate (87 mg, 0.342 mmol) and N, N-dimethylformamide dimethyl acetal (50 μl, 45 mg, 0.375 mmol) were stirred in 1 mL of toluene. After 6 days, the reaction was concentrated in vacuo and the residue was subjected to flash chromatography. Elution with 1: 1 hexanes / EtOAc gave 61 mg (58%) of the title compound as a solidified oil upon standing (melting point 97-99 ° C.).

1,1-dimethylethyl 2 -chloro- α-[[(4- iodophenyl ) amino] methylene] -β-oxo- benzene propanoate. A solution of 1,1-dimethylethyl 2-chloro-α-[(dimethylamino) methylene] -β-oxo-benzenepropanoate (25.5 mg, 0.082 mmol) in 1 mL of toluene was added in 1 portion as a solid. 4 was treated with iodoaniline (17.9 mg, 0.082 mmol). After stirring overnight, the reaction was concentrated in vacuo and the residue absorbed onto silica gel and added to 19.5 cm of flash silica in a 2 cm diameter column. Elution with 5: 1 hexanes / EtOAc gave the title compound as a solid.

Example  4

2- Chloro -α-[[(4- Cyanophenyl ) Amino] methylene] -β-oxo-N-propyl- Benzene Propane amides

5- (2 -Chlorobenzoyl ) -2,2-dimethyl-1,3-dioxane-4,6- dione . A solution of 4- (dimethylamino) pyridine (33.96 g; 278 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (20.0 g, 139 mmol) in 50 mL of CH ₂ Cl ₂ . Was cooled to −10 ° C. in an ice-salt bath. A solution of 2-chlorobenzoyl chloride (29.2 g, 167 mmol) in 20 mL of CH ₂ Cl ₂ was added dropwise over 1 hour via an addition funnel. After cooling stirring for 1 hour, the reaction was warmed to room temperature and stirred for an additional 3 hours. The resulting yellow-orange solution was then extracted with 10% aqueous HCl solution (200 mL) and 200 mL of brine. After drying with MgSO ₄ , the mixture was filtered and the solvent removed in vacuo. The resulting orange oil was triturated with hexane (3 x 50 mL) to give the title compound (20 g) as a yellow solid.

2 -Chloro- β-oxo-N- propylbenzenepropanamide . Neat profile in which a suspension of 5- (2-chlorobenzoyl) 2,2-dimethyl-1,3-dioxane-4,6-dione (2.06 g, 7.30 mmol) in 100 mL of toluene was added dropwise via syringe. Treated with amine (550 μl, 395 mg, 6.70 mmol). The reaction was then heated at 80-90 ° C. for 4 h. The reaction was concentrated to dryness at room temperature once. The residue was taken up on flash silica gel and added to 19 cm of flash silica gel in a 5 cm diameter column. Elution with 4: 1 hexanes / EtOAc gave 851 mg (53%) of the title compound as a yellow oil.

2 -Chloro- α-[(dimethylamino) methylene] -β-oxo-N- propylbenzenepropanamide . Pure N, N-dimethylformamide dimethylacetal (450 μl) of 789 mg (3.29 mmol) of 2-chloro-β-oxo-N-propyl-benzenepropanamide solution in 5 mL of CH ₂ Cl ₂ was added dropwise via syringe. , 402 mg, 3.38 mmol). The reaction was stirred overnight and then concentrated in vacuo. Flash chromatography eluting with 2% MeOH / CH ₂ Cl ₂ (11 cm in a 5 cm column) gave 756 mg (79%) of the title compound as a yellow foam. Trituration with hexane gave a yellow solid (melting point 76-78 ° C).

2 -Chloro- β-oxo-N-propyl-α-[[[(4 -trifluoromethyl ) phenyl ] amino] methylene] -benzenpropanamide . 4- (trifluoromethyl) aniline (27 μl, 34.6 mg, 0.215 mmol in 2-chloro-α-[(dimethylamino) methylene] -β-oxo-N-propylbenzenepropanamide (63.5 mg, 0.215 mmol) ) And toluene (3 mL) were added. The mixture was heated to reflux for 3 hours. Once at room temperature the reaction was concentrated in vacuo. The residue was taken up on flash silica gel and added to 20 cm of flash silica gel in a 2 cm diameter column. Elution with 6: 1 hexanes / EtOAc gave 57 mg of the desired product as a solid (melting point 96-97.5 ° C.).

The following compounds were prepared using the method described above:

Sulfur-orange solid after trituration with 5- (2-chloro-4-fluoro-3-methylbenzoyl) -2,2-dimethyl-1,3-dioxane-4,6-dione, hexane;

2-chloro-β-oxo-N-propylbenzenepropanamide, light yellow oil after chromatography with 4: 1 hexanes / EtOAc;

2-chloro-N-ethyl-β-oxobenzenepropanamide, light yellow oil after chromatography with 4: 1 hexanes / EtOAc;

4-Chloro-β-oxo-N-propylbenzenepropanamide, light yellow solid after chromatography with 1.5: 1 hexanes / EtOAc;

2-fluoro-β-oxo-N-propylbenzenepropanamide, light brown oil after chromatography with 1.5: 1 hexanes / EtOAc;

2-chloro-α-[(dimethylamino) methylene] -N-ethyl-β-oxo-N-benzenepropanamide, light yellow solid after chromatography with 2.5% MeOH / CH ₂ Cl ₂ , melting point 97.5-100 ° C .;

Red orange semisolid after trituration with 2,2-dimethyl-5- (2-methylbenzoyl) -1,3-dioxane-4,6-dione, hexane;

2-methyl-β-oxo-N-propyl-benzenepropanamide, light yellow oil after chromatography with 2: 1 hexanes / EtOAc;

2-methyl-β-oxo-N- (2-propynyl) -benzenepropanamide, light yellow oil after chromatography with 2: 1 hexanes / EtOAc;

light yellow oil after chromatography with α-[(dimethylamino) methylene] -2-methyl-β-oxo-N-propyl-benzenepropanamide, 2.5% MeOH / CH ₂ Cl ₂ ;

Light yellow oil after chromatography with α-[(dimethylamino) methylene] -2-methyl-β-oxo-N- (2-propynyl) -benzenepropanamide, 2.5% MeOH / CH ₂ Cl ₂ .

2-chloro-α-[[(4-iodophenyl) amino] methylene] -β-oxo-N-propyl-benzenepropanamide;

2-chloro-N-ethyl-α-[[(4-iodophenyl) amino] methylene] -β-oxo-benzenepropanamide;

= 7.3 Hz);

α-[[(4-ethynylphenyl) amino] methylene] -2-methyl-β-oxo-N-propyl-benzenepropanamide, after chromatography with 7: 1 hexanes / EtOAc (Rf 0.36), melting point 160- 161.5 ° C. ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.90 (d, 1H, J = 12.6 Hz), 9.73 (br s, 1H), 7.77 (d, 1H, J = 12.5 Hz), 7.40 (d, 2H, J = 8.7 Hz), 7.36 (dt, 1H, = 7.5, 1.4 Hz), 7.29-7.25 (m, 2H), 7.21 (d, 1H, J = 6.3 Hz), 6.79 (d, 2H, J = 8.7 Hz) , 3.40 (q, 2H, J = 6.5 Hz), 3.07 (s, 1H), 2.32 (s, 3H), 1.69 (doublet, 2H, J = 7.3 Hz), 1.04 (t, 3H, J = 7.4 Hz ). Analytical Calcd C ₂₂ H ₂₂ N ₂ O ₂ : C, 76.28; H, 6. 40; N, 8.09. Found: C, 76.09; H.6.45; 7.91 .;

α-[[(4-ethynylphenyl) amino] methylene] -2-methyl-β-oxo-N- (2-propynyl) -benzenepropanamide;

α-[[(4-cyanophenyl) amino] methylene] -2-methyl-β-oxo-N-propyl-benzenepropanamide;

α-[[(1-azabicyclo [[3.3.0] octyl) -1-amino] methylene] -2-chloro-β-oxo-N-propyl-benzenepropanamide, 5: 1 hexanes / EtOAc (Rf 0.34 After chromatography with), melting point 111.5-113 ° C .;

2-chloro-α-[[(4-ethynylphenyl) amino] methylene] -β-oxo-N-propyl-benzenepropanamide;

2-chloro-α-[[(4-fluorophenyl) amino] methylene] -β-oxo-N-propyl-benzenepropanamide, melting point 95-96 ° C .;

2-chloro-α-[[(4-iodophenyl) amino] methylene] -β-oxo-N- (2-propynyl) -benzenepropanamide;

2-chloro-N-ethyl-β-oxo-α-[(pyrazinyl) amino] -benzenepropanamide, chromatographed with 2% MeOH / CH ₂ Cl ₂ (R _f 0.6), white solid, melting point 134.5- 137 ° C .;

2-chloro-α-[(isoxazolyl-3-amino) methylene] -β-oxo-N-propyl-benzenepropanamide, after chromatography with 1% MeOH / CH ₂ Cl ₂ , white solid, melting point 116.5 to 118.5 ° C .;

2-chloro-N-ethyl-β-oxo-α-[(1,2,4-triazolyl-4-amino) methylene] -benzenepropanamide, white solid precipitated from toluene and washed twice with toluene, melting point 189.5 to 190 ° C .;

2-Chloro-N-ethyl-α-[(isoxazolyl-3-amino) methylene] -β-oxo-benzenepropanamide, chromatographed with 2% MeOH / CH ₂ Cl ₂ (R _f 0.7), white Solid, melting point 139-140 ° C .; And

2-Chloro-α-[(4-ethynylphenyl) aminomethylene] -β-oxo-N-propyl-1-naphthalenepropanamide, chromatographed with 8: 1 hexanes / EtOAc (R _f 0.25), grayish White solid, melting point 155-156 캜.

Example  5

Ethyl 2- Chloro -α-[[(3- Chloro -4- Fluorophenyl ) Amino] methylene] -β-oxo- Benzene Propionate

A solution of ethyl 2-chloro-α-[(dimethylamino) methylene] -β-oxo-benzenepropanoate (50 mg, 0.177 mmol) in 1 mL of EtOH was purified with pure 3-chloro-4-fluoroaniline (25.8 mg, 0.177 mmol). After stirring at room temperature until completion by TLC, the reaction was concentrated in vacuo. The residue was subjected to flash chromatography (1: 1 EtOAc / hexanes) to give 42.6 mg (63%) of the product as a white solid (melting point 96-102 ° C.). ¹ H NMR (400 MHz, alkene isomer in CDCl ₃ 9: 1 ratio, major isomer NMR shown) δ 12.66 (d, 1H, J = 12.8 Hz), 8.50 (d, 1H, J = 13.2 Hz), 7.37-7.16 (m, 7H), 4.01 (q, 2H, J = 7.1 Hz), 0.93 (t, 2H, = 7.1 Hz).

Example  6

Ethyl 2- Chloro -β-oxo-α-[[(4- Phenylbutyl ) Amino] methylene]- Benzene Propionate

A solution of 4-phenylbutylamine (24.5 mg, 0.164 mmol) in 1 mL of EtOH was dissolved in solid ethyl 2-chloro-α-[(dimethylamino) methylene] -β-oxo-benzenepropanoate (46.5 mg, 0.165 mmol). ). After stirring at room temperature for 5 minutes, the reaction was concentrated in vacuo and the residue was chromatographed (10 cm silica gel in a 2 cm diameter column; eluted with 100% CH ₂ Cl ₂ ) of 60.4 mg (96%). The title compound was obtained as a white solid (melting point 90-92 ° C.). Compounds by ¹ H NMR are double bond isomers of a 4.5: 1 mixture. ¹ H NMR (CDCl ₃ , 400 MHz) major isomers δ 11.06 (br m, 1H), 8.11 (d, 1H, J = 14.0 Hz), 7.34-7.17 (m, 9H), 3.94 (q, 2H, J = 7.1 Hz), 3.43 (m, 2H), 2.68 (m, 2H), 1.73 (m, 4H), 0.88 (t, 3H, J = 7.1 Hz). ¹ H NMR (CDCl ₃ , 400 MHz) minor isomers (only peaks shifted from the major isomers are given) δ 9.52 (br m, 1H), 8.17 (d, 1H, J = 9.4 Hz), 3.89 (q , 2H, J = 7.1 Hz), 0.77 (t, 3H, J = 7.1 Hz).

Example  7

Ethyl 2- Chloro -β-oxo-α-[[[4- (1,2,3,4- Tetrahydronaphthyl -1-amino) Fe Nil] amino] methylene]- Benzene Propionate

4- (1,2,3,4- tetrahydronaphthyl- 1-amino) nitrobenzene. Pure 1,2,3,4-tetrahydro-1-aminonaphthalene (3.0 mL, 3.08 g) added dropwise through 10 mL of DMSO solution of 4-fluoro-1-nitrobenzene (2.82 g, 20.0 mmol). , 20.9 mmol). The resulting orange solution was stirred at room temperature. After 6 days, the reaction was added to cold water / EtOAc. The aqueous layer was washed with EtOAc (3 x 50 mL) and the pooled organic layer was washed with 100 mL of 0.7 M HCl aqueous solution, water and brine. After drying (Na ₂ SO ₄ ), the mixture was filtered and the solvent removed in vacuo. The residue was triturated with 100 mL of hexanes to give 2.35 g of the desired product as a light yellow solid.

4- (1,2,3,4- tetrahydronaphthyl- 1-amino) aniline. A suspension of 115 mL of glacial HOAc nitro compound (1.06 g, 3.93 mmol) was treated with the added solid Zn metal (1.32 g, 20.2 mmol). After 25 minutes, an additional 1.14 g of Zn was added. After 30 minutes, the mixture was filtered. The solid was washed with HOAc (2 x 25 mL). HOAc was then removed in vacuo and the residue was partitioned between EtOAc and half a saturated aqueous NaHCO ₃ solution (50 mL each). The organic layer was separated, washed with 25 mL of NaHCO _{3 half} saturated aqueous solution and brine, dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. Aniline (891 mg, 95%) was isolated as an air sensitive solid.

Ethyl 2 -chloro- β-oxo-α-[[[4- (1,2,3,4- tetrahydronaphthyl- 1-amino) phenyl ] amino] methylene] -benzenepropionate . 4- (1,2,3,4-tetrahydronaphthyl-1-amino) aniline (869 mg, 3.65 mmol) and ethyl 2-chloro-α-[(dimethylamino) methylene]-in EtOH (10 mL) A solution of β-oxo-benzenepropanoate (1.027 g, 3.65 mmol) was added as one split solid. After stirring for 4 days at room temperature, the formed solid precipitate was isolated by filtration and washed with EtOH (3 × 10 mL). The resulting yellow green solid was absorbed onto flash silica gel and subjected to column chromatography. Elution with 6: 1 hexanes / EtOAc gave a yellow oil. Trituration with hexane gave 623 mg (36%) of a yellow solid (melting point 118-121 ° C). ¹ H NMR (400 MHz, alkene isomer of CDCl ₃ 4.6: 1 ratio, given major isomer) δ 12.87 (d, 1H, J = 13.7 Hz), 8.54 (d, 1H, J = 13.7 Hz), 7.38-7.17 ( m, 8H), 7.14 (d, 2H, J = 8.8 Hz), 6.69 (d, 2H, J = 8.7 Hz), 4.63 (m, 1H), 4.04-3.94 (m, 4H), 2.90-2.74 (m , 2H), 2.01-1.80 (m, 4H), 0.92 (t, 3H, J = 7.1 Hz).

The following compounds were prepared as described in the following examples:

Ethyl 2-chloro-α-[[(4-ethynylphenyl) amino] methylene] -β-oxo-benzenepropionate, melting point 128.5-133 ° C;

Ethyl 2-bromo-α-[[(4-fluorophenyl) amino] methylene] -β-oxo-benzenepropionate, melting point 83.5-84.5 ° C .;

Ethyl α-[(benzyl) aminomethylene] -β-oxo-1-naphthalenepropionate, melting point 142-143.5 ° C .;

Ethyl β-oxo-α-[(2-phenylethyl) aminomethylene] -1-naphthalenepropionate, melting point 131-133 degreeC;

Ethyl β-oxo-α-[(3-phenylpropyl) aminomethylene] -1-naphthalenepropionate, melting point 86-88 ° C .;

Ethyl α-[(octyl) aminomethylene] -β-oxo-1-naphthalenepropionate, melting point 88-89 ° C .;

Ethyl α-[(octyl) aminomethylene] -β-oxo-1-naphthalenepropionate, melting point 72-73 ° C .;

Ethyl 2-methyl-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate, melting point 87-88 ° C .;

Ethyl 2-nitro-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate, melting point 120-121.5 ° C .;

Ethyl α-[[(4-fluorophenyl) amino] methylene] -2-nitro-β-oxo-benzenepropionate, melting point 109-110 ° C .;

Ethyl α-[[(4-iodophenyl) amino] methylene] -β-oxo-2-trifluoromethyl-benzene-propionate, melting point 110-111 ° C .;

Ethyl α-[[(4-methoxyphenyl) amino] methylene] -β-oxo-2-trifluoromethyl-benzene-propionate, melting point 80-83 ° C .;

Ethyl 2-chloro-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate, melting point 91 to 92 ° C;

Ethyl 2-bromo-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate, melting point 96-97 캜,

Ethyl β-oxo-α-[(4-phenylbutyl) aminomethylene] -2-trifluoromethyl-benzenepropionate, melting point 104-106 ° C .;

Ethyl 2-chloro-α-[[(2-naphthyl) amino] methylene] -β-oxo-benzenepropionate, melting point 121-122 ° C .;

Ethyl 2-chloro-α-[[[((3,4-methylenedioxy) phenyl] amino] methylene] -β-oxo-benzenepropionate, melting point 99-101 ° C .;

Ethyl 2-chloro-α-[[(4-iodophenyl) amino] methylene] -β-oxo-benzenepropionate (05DJH133A; RMG 20062). Prepared by a 23: 1 mixture of double bond isomers (melting point 152-153 ° C.). ¹ H NMR (CDCl ₃ , 400 MHz) major isomersδ 12.65 (d, 1H, J = 13.1 Hz), 8.58 (d, 1H, J = 13.4 Hz), 7.73 (d, 2H, J = 8.5 Hz), 7.37 7.24 (m, 4H), 7.04 (d, 2H, J = 8.6 Hz), 4.01 (q, 2H, J = 7.1 Hz), 0.93 (d, 3H, J = 7.1 Hz);

Methyl 2-chloro-α-[[(4-iodophenyl) amino] methylene] -β-oxo-benzenepropionate, melting point 159.5-160.5 ° C .;

Ethyl 2-chloro-β-oxo-α-[[[(2-phenoxy) ethyl] amino] methylene] -benzenepropionate, melting point 134.5-135.5 ° C .;

Ethyl 2-chloro-α-[[(1-methyl-3-phenylpropyl) amino] methylene] -β-oxo-benzenepropionate, melting point 82.5-85 ° C .;

Ethyl 2-chloro-β-oxo-α-[[[(2-phenylamino) ethyl] amino] methylene] -benzenepropionate (05DJH151 C);

Ethyl 2-chloro-α-[[(4-hydroxyphenyl) amino] methylene] -β-oxo-benzenepropionate, melting point 197.5 to 198.5 ° C .;

Ethyl 2-chloro-α-[[(4-chlorophenyl) amino] methylene] -β-oxo-benzenepropionate, melting point 121.5-122.5 ° C .;

Ethyl 2-chloro-α-[[(3-chlorophenyl) amino] methylene] -β-oxo-benzenepropionate (05D1H11OA);

Ethyl 2-chloro-α-[[(2-chlorophenyl) amino] methylene] -β-oxo-benzenepropionate (05DJH11OA);

Ethyl 2-chloro-α-[[(4-methylphenyl) amino] methylene] -β-oxo-benzenepropionate, melting point: 106 to 108 ° C;

Ethyl 2-chloro-α-[[(4-methoxyphenyl) amino] methylene] -β-oxo-benzenepropionate, melting point 96-97 ° C .;

Ethyl 2-chloro-α-[[(4-isopropylphenyl) amino] methylene] -β-oxo-benzenepropionate, melting point 83 ° C. to 85 ° C .;

Ethyl α-[[(4-butylphenyl) amino] methylene] -2-chloro-β-oxo-benzenepropionate (05DJH108D);

Ethyl 2-chloro-β-oxo-α-[[(4-trifluoromethylphenyl) amino] methylene] benzenepropionate, melting point 127-131 ° C .;

Ethyl 2-chloro-α-[[(4-ethylphenyl) amino] methylene] -β-oxo-benzenepropionate, melting point 80-84 ° C .;

Ethyl 2-chloro-α-[[[(4-methylthio) phenyl] amino] methylene] -β-oxo-benzenepropionate, melting point 127-128 ° C .;

Ethyl 2-chloro-α-[[[4- (methylsulfinyl) phenyl] amino] methylene] -β-oxo-benzenepropionate and ethyl 2-chloro-α-[[[4- (methylsulfonyl) Phenyl] amino] -methylene] -β-oxo-benzenepropionate.

Reaction of the corresponding sulfoxide and sulfone by reaction of ethyl 2-chloro-α-[[[(4-methylthio) phenyl] amino] methylene] -β-oxo-benzenepropionate with 1.5 equivalents of 3-chloroperoxybanzoic acid Was obtained, which was separated by chromatography (2% MeOH / CH ₂ Cl ₂ );

Ethyl 2-chloro-α-[[(4-propylphenyl) amino] methylene] -β-oxo-benzenepropionate;

Ethyl 2-chloro-β-oxo-α-[[(4-trifluoromethoxyphenyl) amino] methylene] benzenepropionate, melting point 98.5-103.5 ° C .; And

Ethyl α-[[(4-butylphenyl) amino] methylene] -2-nitro-β-oxo-benzenepropionate.

Example  8

2- Chloro -α-[[(4- Iodophenyl ) Amino] methylene] -β- Oxobenzenepropanoic acid

A solution of 1,1-dimethylethyl 2-chloro-α-[[(4-iodophenyl) amino] methylene] -β-oxo-benzenepropanoate (17.9 mg, 0.037 mmol) in CH ₂ Cl ₂ was removed. Treated with thioanisole (17.5 μl, 18.5 mg, 0.15 mmol) and trifluoroacetic acid (35 μl, 52 mg, 0.454 mmol) at ° C. The reaction was stirred at rt for 45 min and concentrated in vacuo. The residue was purified by flash chromatography (2.5% MeOH / CH ₂ Cl ₂ ) to give 13 mg of acid as a white solid (melting point 202.5-205 ° C.). MS 450 (M + Na ⁺ ) 100, 428 (M ⁺ ) 27.

Example  9

2- Chloro -N, N-dimethyl-α-[[(4- Iodophenyl ) Amino] methylene] -β- Oxobenzenepropanamide

To a suspension of 2-chloro-α-[[(4-iodophenyl) amino] methylene] -β-oxo benzenepropanoic acid (43 mg, 0.10 mmol) in 1 mL of CH ₂ C1 ₂ , N, N′- Dicyclohexylcarbodiimide (21 mg, 0.10 mmol) was added. The mixture was cooled in an ice bath and 50 μl (0.10 mmol) of dimethylamine 2M solution in THF was added. The reaction mixture was stirred at rt for 16 h. The formed DCU was filtered off. The filtrate was washed with water and evaporated to dryness. The title compound (22 mg, 50%) was isolated by column chromatography (5% MeOH in CH ₂ Cl ₂ ); MS 410 (M-45), 455 (M + 1), 477 (M + Na ⁺ ).

The following compounds were prepared as described in the following examples:

2-Chloro-N-[(2-dimethylamino) ethyl)]-α-[[(4-iodophenyl) amino] methylene] -β-oxobenzenepropanamide, melting point 145-147 degreeC, MS: 497 ( 100); 520 (22).

Example  10

1,3- Diphenyl -2-[(4- Iodophenyl ) Amino) methylene] -1,3- Propanedione

2-[(dimethylamino) methylene] -1,3-diphenyl-1,3-propanedione: pure N, N-dimethylformamide in a solution of dibenzoylmethane (1.072 g, 4.78 mmol) in 6 mL of toluene Dimethylacetal (0.7 mL, 630 mg, 5.25 mmol) was added dropwise via syringe. The resulting solution was stirred at room temperature for 1 hour and then heated to reflux for 16 hours. At room temperature the reaction was concentrated in vacuo once. The residue was dissolved in a minimum amount of CH ₂ C1 ₂ and added in 13 cm of flash silica gel in a 5 cm diameter column. Elution with 1 L of 1%, 500 mL of 2% and 300 mL of 3% MeOH / CH ₂ Cl ₂ gave 975 mg of the desired product as semisolid. Trituration with 50 mL of hexane gave 772 mg of the title compound as a light yellow solid (melting point 123-124 ° C.) (lit mp 120 ° C., Schenone, P. et al. J. Het. Chem. 1982, 19 (6J, 1355). -61).

1,3 -diphenyl- 2-[[(4- iodophenyl ) amino] methylene] -1,3- propanedione : 1,3-diphenyl-2-[(dimethylamino) methylene in 5.5 mL of MeOH ] -1,3-propanedione (317 mg, 1.13 mmol) solution was treated with solid 4-iodoaniline (245 mg, 1.12 mmol). The resulting solution was stirred overnight at room temperature. The resulting precipitate was isolated by filtration and washed with MeOH. The title compound was isolated as a light yellow solid.

Additional compounds were prepared as follows:

α-[[(4-chlorophenyl) amino] methylene] -N-isopropyl-β-oxobenzenepropanamide;

4-chloro-α-[[(4-ethoxyphenyl) amino] methylene] -N-propyl-β-oxobenzene-propanamide;

α-[[(4-chlorophenyl) amino] methylene] -N-isopropyl-β-oxobenzenepropanamide; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.83 (d, 1H, J = 12.4 Hz), 9.50 (d, 1H, J = 6.5 Hz), 7.93 (d, 1H, J = 12.4 Hz), 7.53-7.44 (m, 5H), 7.25 (d, 2H, J = 8.7 Hz), 6.85 (d, 2H, J = 8.7 Hz), 4.19 (middle term, 1H, J = 6.7 Hz), 1.28 (d, 6H, J = 6.4 Hz).

2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N-isopropyl-β-oxobenzene-propanamide; TOF MS ES + m / z 399, 401 (M + Na ⁺ );

2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N-ethyl-β-oxobenzenepropaneamide; TOF MS ES + m / z 285, 287 (M + Na ⁺ );

2-chloro-α-[[(4-ethoxyphenyl) amino] methylene] -N-ethyl-β-oxobenzene-propanamide; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.89 (d, 1H, J = 12.5 Hz), 9.59 (s, 1H), 7.60 (d, 1H, J = 12.7 Hz), 7.46-7.29 (m, 4H) , 6.82 (m, 4H), 3.96 (q, 2H, J = 7.0 Hz), 3.45 (br m, 2H), 1.38 (t, 3H, J = 6. 9 Hz), 1.28 (t, 3H, J = 7.2 Hz);

2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N-propyl-β-oxobenzene-propanamide; TOF MS ES + m / z 399, 401 (M + Na ⁺ );

2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N- (1-methylpropyl) -β-oxobenzene-propanamide; (07TBCJ71) ¹ H NMR (400 MHz, CDCl ₃ ) δ13.00 (d, 1H, J = 12.2 Hz), 9.46 (d, 1H, J = 7.6 Hz), 7.64 (d, 1H, J = 12.4 Hz) , 7.48-7.24 (m, 6H), 6.83 (d, 2H, J = 8.8 Hz), 4.04 (m, 1H), 1.63 (m, 2H), 1.27 (d, 3H, J = 6.6 Hz), 1.00 ( t, 3H, J = 7.6 Hz). TOF MS ES + m / z 413, 415 (M + Na ⁺ );

2-chloro-N-ethyl-α-[[(α-methyl-4-fluorobenzyl) amino] methylene] -β-oxobenzene propanamide;

2-chloro-N-ethyl-α-[[(α-methylbenzyl) amino] methylene] -β-oxobenzene-propanamide;

2-chloro-N-propyl-α-[(2-methyl-1-phenylhydrazino) methylene] -β-oxobenzene-propanamide;

2-chloro-α-[[(4-iodophenyl) amino] methylene] -N-methyl-β-oxobenzene-propanamide; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.94 (d, 1H, J = 12.4 Hz), 9.48 (br s, 1H), 7.65 (d, 1H, J = 12.4 Hz), 7.60 (d, 2H, J = 8.7 Hz), 6.65 (d, 2H, J = 8.7 Hz), 2.97 (d, 3H, J = 4.6 Hz);

2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N-methyl-β-oxobenzene-propanamide; TOF MS ES + m / z 371, 373 (M + Na ⁺ );

2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N- (α-methylbenzyl) -β-oxobenzene propanamide;

α-[[(4-chlorophenyl) amino] methylene] -N-isopropyl-β-oxobenzenepropanamide; ¹ H NMR (400 MHz, CDCl ₃ ) δ12.83 (d, 1H, J = 12.4 Hz), 9.50 (d, 1H, J = 6.5 Hz), 7.93 (d, 1H, J = 12.4 Hz), 7.53- 7.44 (m, 5H), 7.25 (d, 2H, J = 8.7 Hz), 6.85 (d, 2H, J = 8.7 Hz), 4.19 (octane, 1H, J = 6.7 Hz), 1.28 (d, 6H, J = 6.4 Hz).

4-chloro-α-[[(4-ethoxyphenyl) amino] methylene] -N-propyl-β-oxobenzene-propanamide;

Inhibition of [ ³⁵ S] TBPS Binding by Enaminon compound [ ³⁵ S] TBPS IC ₅₀ (μM) I _max (%) Ethyl 2-chloro-α-[[(4-ethynylphenyl) -amino] methylene] -β-oxobenzenepropionate 0.01 95 Ethyl 2-chloro-α-[[(4-iodophenyl) -amino] menylene] -β-oxobenzenepropionate 0.02 86 α-[[(4-ethynylphenyl) amino] methylene] -2-methyl-β-oxo-N-propyl-benzenepropanamide 0.02 95 Ethyl 2-chloro-α-[[(4-cyanophenyl) -amino] methylene] -β-oxobenzenepropionate 0.06 100 2-Methyl-α-[[(4-methylphenyl) amino] methylene-β-oxo-N-propyl-benzenepropanamide 0.10 100 Ethyl α-[(4-fluorophenyl) amino] methylene] -β-oxo-1-naphthalenepropionate 0.20 81 Ethyl 2-chloro-α-[[(2-chlorophenyl) -amino] methylene] -β-oxobenzenepropionate 0.42 100

Claims (37)

A compound comprising Formula I: or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is selected from hydrogen, and unsubstituted or substituted C _{1 -10} the group consisting of alkyl; R ₃ is fluoro, chloro, bromo, iodo, C _{1 - 10} alkoxy, nitro, halo-C _{1 - 10} alkyl, C _{1 perhalo-the} group consisting of _{10-alkyl-10-alkyl} and unsubstituted or substituted C ₁ Is selected from; Each R ₄ is halogen, nitro, C _{1 -} consisting of ₁₀ alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and _{heterocycloalkyl-10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C ₁ Independently selected from the group, each being unsubstituted or substituted, or forming an unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring wherein R ₃ and adjacent R ₄ are fused together; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 - 10} alkyl, and each is either unsubstituted or substituted, or R ₁₆ and R ₁₇ Together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4,5 or 6 membered ring; m is 0, 1, 2, 3 or 4; Provided that when R ₅ is -OEt, R ₄ is not halogen and the compounds of formula I are compounds ethyl α-[(benzyl) aminomethylene] -2-chloro-β-oxobenzenepropionate and 1- (2 , 4-dichloro-5-fluorophenyl) -2-[[but not (2,4-difluorophenyl) amino] methylene] -1,3-pentanedione]. A compound comprising Formula Ia, or a pharmaceutically acceptable salt, prodrug or solvate thereof: Formula Ia

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is fluoro, chloro, bromo, iodo, C _{1 - 10} alkoxy, nitro, halo-C _{1 - 10} alkyl, C _{1 perhalo-the} group consisting of _{10-alkyl-10-alkyl} and unsubstituted or substituted C ₁ Is selected from; Each R ₄ is halogen, nitro, C _{1 -} consisting of ₁₀ alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and _{heterocycloalkyl-10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C ₁ Independently selected from the group, each being unsubstituted or substituted, or forming an unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring in which R ₃ and adjacent R ₄ are fused together; R ₅ is C _{1 - 10} alkyl, CH ₃ O-, C _{3 -1O} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each Is unsubstituted or substituted; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4,5 or 6 membered ring; m is 0, 1, 2, 3 or 4; A compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or solvate thereof: Formula Ib

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Is unsubstituted or substituted; Each R ₄ is hydrogen, halo, nitro, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C ₂ alkenyl _-1O , C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, a group from the group consisting of already Independently selected and each is unsubstituted or substituted, or forms an unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring wherein R ₃ and adjacent R ₄ are fused together; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} from ₁₀ alkyl, and each is either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5, 6 membered ring; R ₁₈ is an optionally substituted C _{1 -} is selected from the group consisting of _10-alkyl, arylalkyl and heterocycloalkyl; m is 0, 1, 2, 3 or 4; 4. A compound according to claim 3, or a pharmaceutically acceptable salt, prodrug or solvate thereof, comprising: Formula Ic

[In the meal, R ₂ is selected from the group consisting of hydrogen, methyl and ethyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Is unsubstituted or substituted; Each R ₄ is hydrogen, halo, nitro, halo-C _{1 -1O} alkyl, C _{1 -1O} alkyl, perhaloalkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, , C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, a group from the group consisting of already Independently selected, each being unsubstituted or substituted, or R ₃ and adjacent R ₄ taken together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; _{R 6, R 7, R 8} , R 9 and R ₁₀ is hydrogen, halo, C _{1 - 10} alkyl, C _{2 - 10} alkynyl, C _{1 -1O} alkoxy, aralkyl, cycloalkyl, aryl C _{1 - 10} alkyl, and heteroaryl C ₁ each independently selected from the group consisting of alkyl or _-1O; Or R ₆ and R ₇ , or R ₇ and R ₈ , or R ₈ and R ₉ , or R ₉ and R ₁₀ together with the carbon atoms to which they are attached are unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated To form a ring, aryl or heteroaryl; R ₁₈ is C _{1 - 10} alkyl and is selected from aryl and heterocycloalkyl group consisting of alkyl, each of which is unsubstituted or substituted; m is 0, 1, 2, 3 or 4]. A compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula II]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₅ is C _{1 - 10} alkyl, C _{1 - 10} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each or which is unsubstituted or Substituted; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C ₁ and _-1O alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is a nitrogen atom they are attached and Together form an unsubstituted or substituted 4, 5 or 6 membered ring; R ₁₉ and R ₂₀ is halo, cyano, nitro, halo (C _1-10) alkyl, perhalo (C _1-5) alkyl, aryl, heteroaryl, cycloalkyl, C _{1 - 10} alkyl, aryl (C _{1 -10} ) alkyl, cycloalkyl (C _1-10 ) alkyl, hydroxy (C _1-10 ) alkyl, amino (C _1-10 ) alkyl, alkoxy (C _1-10 ) alkyl, amino, hydroxyl, thio, C _1-10 alkoxy, and C _{1 - 10} alkyl thiol are each independently selected from the group consisting of; v and w are each independently 0, 1, 2 or 3; A compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula III]

[In the meal, R ₂ is selected from the group consisting of hydrogen, and unsubstituted or substituted C _{1 -1O} alkyl; R ₃ is fluoro, chloro, bromo, iodo, C _{1 - 10} alkoxy, nitro, halo-C _{1 - 10} alkyl, C _{1 perhalo-the} group consisting of _{10-alkyl-10-alkyl} and unsubstituted or substituted C ₁ Is selected from; Each R ₄ is halogen, nitro, C _{1 -} is independently selected from _10, alkyl, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl group consisting of _alkyl-10 alkyl, C _{2 - 10} alkynyl, C ₁ Each is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is C _{1 - 10} alkyl, C _{1 - 10} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each or which is unsubstituted or Substituted; _{R 6, R 7, R 8} , R 9 and R ₁₀ is hydrogen, halo, C _{1 - 10} alkyl, C _{2 - 10} alkynyl, C _{1 - 10} alkoxy, aralkyl, cycloalkyl, aryl C _{1 - 10} alkyl, and heteroaryl C _{1 -,} each independently selected from the group consisting of alkyl, or _10; Or R ₆ and R ₇ , or R ₇ and R ₈ , or R ₈ and R ₉ , or R ₉ and R ₁₀ together with the carbon atoms to which they are attached are unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated To form a ring, aryl or heteroaryl; m is 0, 1, 2, 3 or 4]. The compound of claim 1, wherein the compound comprises Formula IV, or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula IV]

[In the meal, R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is fluoro, chloro, bromo, iodo, C _{1 -1O} alkoxy, nitro, halo-C _{1 - 10} alkyl, C _{1 perhalo-the} group consisting of _{10-alkyl-10-alkyl} and unsubstituted or substituted C ₁ Is selected from; Each R ₄ is halogen, nitro, C _{1 -} is independently selected from _10, alkyl, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl group consisting of alkyl, _{- 10} alkyl, C _{2 - 10} alkynyl, C ₁ Each is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is C _{1 - 10} alkyl, C _{1 - 10} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each or which is unsubstituted or Substituted; _{R 6, R 7, R 8} , R 9 and R ₁₀ is hydrogen, halo, C _{1 - 10} alkyl, C _{2 - 10} alkynyl, C _{1 - 10} alkoxy, aralkyl, cycloalkyl, aryl C _{1 - 10} alkyl, and heteroaryl C _{1 -,} each independently selected from the group consisting of alkyl, or _10; Or R ₆ and R ₇ , or R ₇ and R ₈ , or R ₈ and R ₉ , or R ₉ and R ₁₀ together with the carbon atoms to which they are attached are unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated To form a ring, aryl or heteroaryl; R ₁₁ is hydrogen or unsubstituted or substituted C _{1 - 10} alkyl, and; m is 0, 1, 2, 3 or 4; n is O, 1, 2, 3, 4 or 5; 8. A compound according to claim 7, or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula IVa]

[In the meal, R ₂ is selected from the group consisting of hydrogen, methyl and ethyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 1O} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Is unsubstituted or substituted; Each R ₄ is halogen, nitro, C _{1 -} is independently selected from _10, alkyl, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl group consisting of _alkyl-10 alkyl, C _{2 - 10} alkynyl, C ₁ Each is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is C _{1 - 10} alkyl, C _{1 - 10} alkoxy, -NH _2, C _{1 - 10} alkylamino, di (C _1-10) is selected from the group consisting of alkylamino and aryl, each or which is unsubstituted or Substituted; _{R 6, R 7, R 8} , R 9 and R ₁₀ is hydrogen, halo, C _{1 - 10} alkyl, C _{2 - 10} alkynyl, C _{1 - 10} alkoxy, aralkyl, cycloalkyl, aryl C _{1 - 10} alkyl, and heteroaryl C _{1 -,} each independently selected from the group consisting of alkyl, or _10; Or R ₆ and R ₇ , or R ₇ and R ₈ , or R ₈ and R ₉ , or R ₉ and R ₁₀ Together with the carbon atoms to which they are attached form an unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated ring, aryl or heteroaryl; R ₁₁ is hydrogen, or unsubstituted or substituted C _{1 - 10} alkyl, and; R ₁₈ is C _{1 -} is selected from the group consisting of _10-alkyl, arylalkyl and heterocycloalkyl, each unsubstituted or substituted; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4 or 5; A compound according to claim 1 or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula V]

[In the meal, R ₃ Is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo C _{1 -1O} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl carbonyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, each of which Beach Ring or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 -2 0} alkyl, C _{2 -1O} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 - 10} alkoxy, aryloxy, heteroaryloxy, a car Viterbo group, a sulfonyl group, a sulfinyl group, the group consisting of already a group Independently selected from each other, which is unsubstituted or substituted, or R ₃ and adjacent R ₄ taken together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is selected from the group consisting of alkyl, alkoxy, amino, alkylamino, dialkylamino and aryl, each of which is unsubstituted or substituted; Each R ₁₉ is halogen, C _{1 - 10} alkyl, C _{2 -1O} alkynyl, C _{1 -1O} alkoxy, aralkyl, and are independently selected from the group consisting of cycloalkyl, each unsubstituted or substituted; m is 0, 1, 2, 3 or 4; u is 0, 1 or 2]. A compound according to claim 1 or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula Va]

[In the meal, R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 -1O} alkenyl, C _{2 - 10} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Unsubstituted or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 -1O} alkyl, C _{1 -1O} alkyl, perhaloalkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _2-10 independently from the alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group Each is unsubstituted or substituted, or R ₃ and adjacent R ₄ Together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, and C _{1 -1O} alkyl, each unsubstituted or optionally substituted, or R ₁₆ and R ₁₇ together with the nitrogen atom to which they are attached To form an unsubstituted or substituted 4, 5 or 6 membered ring; R ₁₈ is C _{1 -} is selected from the group consisting of _10-alkyl, aryl-alkyl, and heterocycloalkyl, each unsubstituted or substituted; m is 0, 1, 2, 3 or 4]. A compound according to claim 1 or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula VI]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, C _{1 -1O} alkyl, perhaloalkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 1O} alkynyl is selected from cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -1O} alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, already the group consisting of a group, each of Is unsubstituted or substituted; Each R ₄ is halogen, nitro, C _{1 -} is independently selected from the ₁₀ alkyl, C _{2 -1O} alkynyl, C _{1 -1O} alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl group consisting of alkyl Each of which is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5 or 6 membered ring; Each R ₂₀ is halo, cyano, nitro, halo (C _1-1O) alkyl, perhalo (C _1-5) alkyl, aryl, heteroaryl, C _{1 - 10} alkyl, aryl (C _1-10) alkyl , alkoxy (C _1-10) alkyl, amino, hydroxyl, are independently selected from the group consisting of thio, and C _{1 -1O} alkoxy; m and p are each independently 0, 1, 2, 3 or 4; The compound of claim 6, wherein R ₈ A C _{1 - 10} alkyl, halogen and C _{1 - 10} selected from the group consisting of alkoxy, R _6, R _7, R ₉ and R ₁₀ are hydrogen. 13. The compound of claim 12, wherein R ₃ is selected from the group consisting of methyl, trifluoromethyl and chloro, and m is 0. A compound according to claim 1 which is Ethyl 2-chloro-β-oxo-α-[[[4- (1,2,3,4-tetrahydronaphthyl-1-amino) phenyl] amino] methylene] benzenepropionate; Ethyl 2-chloro-5-nitro-β-oxo-α-[[[4- (1,2,3,4-tetrahydronaphthyl-1- amino) phenyl] amino] methylene] benzenepropionate; Ethyl 2-chloro-α-[(cyclohexylamino) methylene] -β-oxobenzenepropionate; Ethyl 2-chloro-α-[(4-iodophenyl) aminomethylene] -β-oxo-benzenepropionate; Ethyl α-[(4-bromophenyl) aminomethylene] -2-chloro-β-oxo-benzenepropionate; Ethyl 2-chloro-α-[(4-methoxyphenyl) aminomethylene] -β-oxo-benzene-propionate; Ethyl 2-chloro-α-[(3-chloro-4-fluorophenyl) aminomethylene] -β-oxo-benzene-propionate; Ethyl 2-chloro-α-[(4-fluorophenyl) aminomethylene] -β-oxo-benzenepropionate; Ethyl α-[(4-iodophenyl) aminomethylene] -β-oxo-1-naphthalenepropionate; Ethyl α-[(4-fluorophenyl) aminomethylene] -β-oxo-1-naphthalenepropionate; Ethyl α-[(benzyl) aminomethylene] -β-oxo-1-naphthalenepropionate; Ethyl β-oxo-α-[(2-phenylethyl) aminomethylene] -1-naphthalenepropionate; Ethyl β-oxo-α-[(3-phenylpropyl) aminomethylene] -1-naphthalenepropionate; Ethyl β-oxo-α-[(4-phenylbutyl) aminomethylene] -1-naphthalenepropionate; Ethyl 2-chloro-α-[(3-phenylpropyl) aminomethylene] -β-oxo-benzenepropionate; Ethyl 2-chloro-α-[(3,3-diphenylpropyl) aminomethylene] -β-oxo-benzenepropionate; Ethyl 2-chloro-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate; Ethyl 2-bromo-α-[(4-fluorophenyl) aminomethylene] -β-oxo-benzenepropionate; Ethyl α-[(4-fluorophenyl) aminomethylene] -2-nitro-β-oxo-benzenepropionate; Ethyl α-[(4-fluorophenyl) aminomethylene] -2-methyl-β-oxo-benzenepropionate; Ethyl 2-methyl-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate; Ethyl 2-nitro-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate; Ethyl 2-ethoxy-β-oxo-α-[(4-phenylbutyl) aminomethylene] -benzenepropionate; Methyl 2-chloro-α-[(4-iodophenyl) aminomethylene] -β-oxo-benzenepropionate; Ethyl α-[(4-iodophenyl) aminomethylene] -β-oxo-2-trifluoromethyl-benzenepropionate; Ethyl α-[(4-iodophenyl) aminomethylene] -2-methyl-β-oxo-benzenepropionate; Ethyl α-[(4-methoxyphenyl) aminomethylene] -β-oxo-2-trifluoromethyl-benzenepropionate; Ethyl 2-bromo-α-[(4-iodophenyl) aminomethylene] -β-oxo-benzenepropionate; Ethyl 2-chloro-α-[(4-methylphenyl) aminomethylene] -β-oxo-benzenepropionate; Ethyl α-[(4-butylphenyl) aminomethylene] -2-chloro-β-oxo-benzenepropionate; Ethyl 2-chloro-α-[(4-isopropylphenyl) aminomethylene] -β-oxo-benzene-propionate; Ethyl 2-bromo-α-[(4-iodophenyl) aminomethylene] -β-oxo-benzenepropionate; 2-chloro-α-[[(4-cyanophenyl) amino] methylene] -N-ethyl-β-oxo-benzenepropaneamide; 2-chloro-N-ethyl-α-[[(4-iodophenyl) amino] methylene] -β-oxo-benzenepropanamide; 2-chloro-α-[[(4-iodophenyl) amino] methylene] -β-oxo-N- (2-propynyl) benzenepropanamide; 2-chloro-α-[[(4-ethynylphenyl) amino] methylene] -β-oxo-N-propyl-benzenepropanamide; α-[[(4-ethynylphenyl) amino] methylene] -2-methyl-β-oxo-N-propyl-benzenepropanamide; α-[[(4-cyanophenyl) amino] methylene] -2-methyl-β-oxo-N-propyl-benzenepropanamide; α-[[(4-ethynylphenyl) amino] methylene] -2-methyl-β-oxo-N- (2-propynyl) -benzenepropanamide; 2-chloro-α-[[(4-cyanophenyl) amino] methylene] -β-oxo-N-propyl-benzenepropanamide; Ethyl α-[(4-iodophenyl) aminomethylene] -2-methyl-β-oxo-benzenepropionate; 2-chloro-N-ethyl-α-[(isoxazolyl-3-amino) methylene] -β-oxo-benzenepropanamide; α-[(4-ethynylphenyl) aminomethylene] -β-oxo-N-propyl-1-naphthalenepropanamide; 2-chloro-α-[(isoxazolyl-3-amino) methylene] -β-oxo-N-propyl-benzenepropanamide; 2-Chloro-N-ethyl-β-oxo-α-[(1,2,4-triazolyl-4-amino) methylene] benzene-propanamide; Ethyl α-[(4-ethynylphenyl) aminomethylene] -2-fluoro-β-oxobenzenepropionate; α-[(4-ethynylphenyl) aminomethylene] -β-oxo-N-propyl-1-naphthalenepropanamide; 2-Chloro-N-ethyl-β-oxo-α-[(pyrazinyl) amino] -benzenepropanamide; α-[[(4-chlorophenyl) amino] methylene] -N-isopropyl-β-oxobenzenepropanamide; 2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N-isopropyl-β-oxobenzene-propanamide; 2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N-ethyl-β-oxobenzenepropanamide; 2-chloro-α-[[(4-ethoxyphenyl) amino] methylene] -N-ethyl-β-oxobenzene-propanamide; 2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N-propyl-β-oxobenzene-propanamide; 2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N- (1-methylpropyl) -β-oxobenzene-propanamide; 2-chloro-N-ethyl-α-[[(α-methyl-4-fluorobenzyl) amino] methylene] -β-oxobenzene-propanamide; 2-chloro-N-ethyl-α-[[(α-methylbenzyl) amino] methylene] -β-oxobenzene-propanamide; 2-Chloro-N-propyl-α-[(2-methyl-1-phenylhydrazino) methylene] -β-oxobenzene-propanamide; 2-chloro-α-[[(4-iodophenyl) amino] methylene] -N-methyl-β-oxobenzene-propanamide; 2-chloro-α-[[(4-chlorophenyl) amino] methylene] -N-methyl-β-oxobenzene-propanamide; And 2-Chloro-α-[[(4-chlorophenyl) amino] methylene] -N- (α-methylbenzyl) -β-oxobenzene-propanamide. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier selected from the group consisting of excipients and auxiliaries: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen and unsubstituted or substituted C _{1 -} it is selected from the group consisting of _10-alkyl; R ₃ is fluoro, chloro, bromo, iodo, C _{1 -1O} alkoxy, nitro, halo-C _{1 -1O} alkyl, perhalo C _{1 -1O} alkyl, and the group consisting of unsubstituted or substituted C ₁ alkyl _-1O Is selected from; Each R ₄ is halogen, nitro, C _{1 - 10} alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and _{heterocycloalkyl-10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C ₁ Independently selected from the group consisting of: each unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, each unsubstituted or optionally substituted, or R ₁₆ and R ₁₇ together with the nitrogen atom to which they are attached To form an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4; Provided that when R ₅ is -OEt R ₄ is not halogen and the compound of formula I is a compound ethyl α-[(benzyl) aminomethylene] -2-chloro-β-oxobenzenepropionate and 1- (2, 4-dichloro-5-fluorophenyl) -2-[[(2,4-difluorophenyl) amino] methylene] -1,3-pentanedione is not]. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable carrier selected from the group consisting of excipients and adjuvants. _A method of treating CNS disorders following modulation of the GABA _A receptor complex, the method comprising administering to a patient in need thereof such a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} it is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Unsubstituted or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 - 10} alkoxy, aryloxy, heteroaryloxy, a car Viterbo group, a sulfonyl group, a sulfinyl group, already the group consisting of a group Independently selected from each other, which is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4]. The method of claim 17, wherein the CNS disorder is selected from the group consisting of anxiety disorders, insomnia, major depressive disorders, and bipolar disorders. 18. The method of claim 17, wherein the CNS disorder is withdrawal induced convulsions from convulsions or substance misuse. 18. The method of claim 17, wherein the CNS disorder is chronic or acute pain. 18. The method of claim 17, wherein the CNS disorder is selected from the group consisting of neurosis, phobia, panic disorder, general anxiety disorder, obsessive compulsive disorder and bipolar mania disorder. 18. The method of claim 17, wherein the CNS disorder is post traumatic and acute stress disorder. The method of claim 17, wherein the CNS disorder is migraine. 18. The method of claim 17, wherein the CNS disorder is cognitive deficit disorder. The method of claim 17, wherein the CNS disorder is selected from the group consisting of anxiety and stress related disorders, depression and other affective disorders, epilepsy and other seizure disorders, insomnia and related sleep disorders, acute and chronic pain and cough. A method of treating learning and memory related disorders, the method comprising administering to a patient in need thereof a compound of formula I, or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} it is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Unsubstituted or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 - 10} alkoxy, aryloxy, heteroaryloxy, a car Viterbo group, a sulfonyl group, a sulfinyl group, already the group consisting of a group Independently selected from each other, which is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4]. 27. The method of claim 26, wherein the learning and memory related disorders are selected from the group consisting of mild cognitive impairment, age related cognitive decline, elderly dementia, Alzheimer's disease, sleep disorders, including reduced waking conditions. 27. The method of claim 25, wherein the sleep disorder comprising a reduced waking state is selected from the group consisting of narcolepsy and idiopathic hypersleep. 18. The compound according to claim 17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from [ ³ H] -flunitrazepam, barbiturate, lorlezole, [ ³ H] -musmol or 3α, 20α-pre _A method of altering chloride conductivity through a GABA _A receptor complex in a therapeutically useful manner by acting by binding to a site other than a site that binds Gnandiol. _A method of treating CNS disorders following modulation of the GABA _A receptor complex, the method comprising administering the compound of claim 1 to a patient in need thereof. _A method of treating CNS disorders following modulation of the GABA _A receptor complex, the method comprising administering the compound of claim 2 to a patient in need thereof. A method of treating CNS disorders following modulation of the nAChR complex, the method comprising administering a compound of Formula I or a pharmaceutically acceptable salt, prodrug or solvate thereof to a patient in need thereof: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} it is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Unsubstituted or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C independently from ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group _{- 2 - 10} alkynyl, cycloalkyl, heterocyclic claw alkyl, aryl, aralkyl, heteroaryl, C ₁ Each of which is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4]. A method of treating neurodegenerative disorders comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, to a patient in need thereof: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} it is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Unsubstituted or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 - 10} alkoxy, aryloxy, heteroaryloxy, a car Viterbo group, a sulfonyl group, a sulfinyl group, the group consisting of already a group from Independently selected, each unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4]. A method of treating elderly dementia comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} it is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Unsubstituted or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 -} independently from ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group _{- 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C ₁ Are each unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4]. A method of treating schizophrenia comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, to a patient in need thereof: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 - 10} being selected from the group consisting of alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} it is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Unsubstituted or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 -} independently from ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group _{- 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C ₁ Are each unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom Together with an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4]. A method of treating cognitive deficit disorders, the method comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, to a patient in need thereof: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} it is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Is unsubstituted or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 -} independently from ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group _{- 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C ₁ Each is unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, respectively, are either unsubstituted or substituted, or R ₁₆ and R ₁₇ is they are attached are a nitrogen atom and Together form an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4]. Mild cognitive impairment, age-related cognitive decline due to inhibiting monovalent and divalent cation conductivity through a site that modulates the action of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof, Treatment of learning and memory-related disorders such as dementia and Alzheimer's disease in the elderly: [Formula I]

[In the meal, R ₁ is selected from the group consisting of aryl, heteroaryl, aralkyl and R ₁₆ R ₁₇ N—, each being unsubstituted or substituted; R ₂ is hydrogen, and unsubstituted or substituted C _{1 -} is selected from the group consisting of _10-alkyl; R ₃ is hydrogen, halo, halo C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C _{1 -} it is selected from the ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group, respectively, Is unsubstituted or substituted; Each R ₄ is hydrogen, halo, halo-C _{1 - 10} alkyl, perhalo a C _{1 - 10} alkyl, amino, cyano, nitro, hydroxy, thio, C _{1 - 20} alkyl, C _{2 - 10} alkenyl, C _{2 -} independently from ₁₀ alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, a sulfinyl group, the group consisting of already a group _{- 10} alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C ₁ Are each unsubstituted or substituted, or R ₃ and adjacent R ₄ together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring; R ₅ is an optionally substituted C _{1 -} is selected from the ₁₀ alkylamino, di (C _1-10) the group consisting of alkylamino and aryl ₁₀ alkyl, C _{1 - - 10} alkoxy, -NH _2, C _1; R ₁₆ and R ₁₇ are each independently a C _{3 - 12} cycloalkyl, aryl, heteroaryl, C _{1 -} is a _10-alkyl, each of which is unsubstituted or optionally substituted, or R ₁₆ and R ₁₇ together with the nitrogen atom to which they are attached To form an unsubstituted or substituted 4, 5 or 6 membered ring; m is 0, 1, 2, 3 or 4].

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