KR20100033981A - Benzamide mglur5 positive allosteric modulators and methods of making and using same - Google Patents

Abstract

In one aspect, the invention provides compounds useful as positive allosteric modulators of metabolic glutamate receptor subtype 5 (mGluR5), including benzamide derivatives and cyclic benzamide derivatives; Synthetic preparation methods of these compounds; Pharmaceutical compositions comprising such compounds; And methods of treating neurological and mental disorders associated with glutamate dysfunction using such compounds and compositions. This Summary is provided as a research tool for searching in the field and is not intended to limit the invention.

Benzamide Derivatives, Cyclic Benzamide Derivatives

Description

BENZAMIDE MGLUR5 POSITIVE ALLOSTERIC MODULATORS AND METHODS OF MAKING AND USING SAME}

Cross Reference to Related Application

 This application claims the priority of US Patent Application No. 60 / 941,686, filed June 3, 2007 and US Patent Application No. 60 / 985,041, filed November 2, 2007, which applications are herein incorporated by reference. It is attached to the literature.

Acknowledgment

The present invention was made with government support under Grants NIH / NIMH R01 MH062646 and F32 NS049865 awarded by the National Institutes of Health. The United States government has certain rights in this invention.

background

L-glutamic acid, the most commonly occurring neurotransmitter in the central nervous system, plays a role in many physiological processes. Glutamate-dependent stimulus receptors are divided into two main groups. The first major group forms ligand-controlled ion channels. The second major group is metabolic glutamate receptors (mGluRs), which belong to the group of G-protein-coupled receptors. Metabolic glutamate receptors, including mGluR5, have been involved in a wide range of biological functions, meaning that mGluR5 receptors play a potential role in various diseases in mammals. Ligands of metabolic glutamate receptors can be used for the treatment or prevention of acute and / or chronic neurological and / or mental disorders, such as glutamate dysfunction, such as psychiatric disorders, schizophrenia, cognitive decline following aging, and the like.

 Selective positive allosteric modulators do not directly activate receptors themselves, but the binding of these compounds increases the affinity of the glutamate-site agonist at the extracellular N-terminal binding site. Positive allosteric modulating action (enhancing) is therefore an advantageous mechanism for enhancing proper physiological receptor activation.

Unfortunately, there is a lack of selective positive allosteric modulators for the mGluR5 receptor. Moreover, conventional mGluR5 receptor modulators typically lack sufficient water solubility and exhibit poor oral bioavailability. Therefore, there is still a need for methods and compositions that overcome these shortcomings and effectively provide selective positive allosteric modulators for the mGluR5 receptor.

summary

In accordance with the object of the invention as embodied and broadly described herein, the invention provides, in one aspect, compounds useful as positive allosteric modulators (ie, enhancers) of metabolic glutamate receptor subtype 5 (mGluR5), such compounds of Methods of preparation, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat neurological and psychiatric disorders associated with glutamate dysfunction.

A method of treating a disorder in a mammal is disclosed, which method comprises treating one or more compounds having a structure represented by the following formula or a pharmaceutically acceptable salt or N-oxide thereof in the treatment of a disorder in a mammal. Administering to the mammal in an effective dosage and dosage form:

Where each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; R ¹ and R ² are independently selected from hydrogen or an optionally substituted organic radical comprising 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Is selected from organic radicals comprising 1 to 5 carbon atoms, selected from amino-carbonyl, and alkylamine-carbonyl; R ⁸ is optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally Substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl And hydrogen and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted heteroaryl.

Also disclosed is a method for enhancing metabolic glutamate receptor activity in a mammal, which method comprises one or more compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof, Administering to the mammal at a dosage and a dosage effective to enhance metabolic glutamate receptor activity in the mammal:

Where each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radicals containing 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Is selected from organic radicals comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl.

Also disclosed is a method for partial agonism of metabolic glutamate receptor activity in a mammal, wherein the method comprises one or more compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N- Administering the oxide to the mammal at a dosage and a dosage effective to demonstrate partial action of metabolic glutamate receptor activity in the mammal:

Where each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or are independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optional Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3- C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, Organic radicals containing 1 to 5 carbon atoms selected from amino-carbonyl, and alkylamine-carbonyl.

Also disclosed is a method of enhancing cognition in a mammal, wherein the method comprises one or more compounds having a structure represented by the following general formulae or a pharmaceutically acceptable salt or N-oxide thereof: Administering to the mammal at a dosage and a dose effective for:

Where each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing from 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an organic radical containing 4 to 14 carbon atoms and optionally substituted; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons together, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted egg Coxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carbox Imide, amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl group.

Also disclosed are methods of treating a disorder in a mammal, wherein the method comprises one or more compounds having the following structure, or a pharmaceutically acceptable salt or N-oxide thereof, in a dosage and dosage effective for treating the disorder in a mammal. Administering to the mammal;

Wherein n is 0, 1, 2, 3 or 4; Y ¹ and Y ² are independently selected from C and N; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b , if present, together comprise = O or = S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to An organic radical containing six carbon atoms; R ^3a and R ^3b together comprise = O or = S, or each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; R ⁴ comprises hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or 1, 2 or 3 substituents independently present as organic radicals containing 1 to 12 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms.

Also disclosed are compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ and R ² are independently an optionally substituted organic radical comprising 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² and Z ³ are independently selected from N and CR ⁴ , and two or less of Z ¹ , Z ² , and Z ³ are nitrogen; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents independently selected from amine-carbonyl, wherein the compound is a moiety of the compound Enhancement of the mGluR5 response to glutamate compared to the response to glutamate in the presence is shown as an increase in response to non-maximal concentrations of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound.

Also disclosed are compounds having structures represented by the following general formulae, or their pharmaceutically acceptable salts or N-oxides:

Wherein R ¹ and R ² are independently hydrogen or an optionally substituted organic radical comprising 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; R ⁴ is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted Cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optional Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, And up to 5 substituents selected from alkylamine-carbonyl; R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3- C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl , Optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, a Dorsal sulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase in.

Also disclosed are compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ and R ² are independently an optionally substituted organic radical comprising 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents independently selected from amine-carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase in.

Also disclosed are compounds having a structure represented by the following general formula: or pharmaceutically acceptable salts or N-oxides thereof:

Wherein R ¹ and R ² are independently hydrogen or an optionally substituted organic radical comprising 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents selected from amine-carbonyl; R ⁸ is selected from hydrogen and lower alkyl; The compound, compared to the response to glutamate in the absence of the compound, enhances the mGluR5 response to glutamate in response to non-maximal concentrations of glutamate in human fetal kidney cells infected with rat mGluR5 in the presence of the compound. Shown as an increase.

Also disclosed are compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; and R ¹ and R ² are independently hydrogen or 1 to An optionally substituted organic radical containing 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or are hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cyclo Alkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally Substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-car Carbonyl, and alkyl amines are selected from organic radicals containing selected, one to five carbon atoms in a carbonyl; R ⁸ is hydrogen, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl Optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally Selected from substituted aryl, and optionally substituted heteroaryl, an organic radical comprising 1 to 6 carbon atoms; The compound, compared to the response to glutamate in the absence of the compound, enhances the mGluR5 response to glutamate in response to non-maximal concentrations of glutamate in human fetal kidney cells infected with rat mGluR5 in the presence of the compound. Shown as an increase.

Also disclosed are compounds, or pharmaceutically acceptable salts or N-oxides thereof, which enhance the mGluR5 response to glutamate, as compared to the response to glutamate in the absence of the compound. As an increase in response to non-maximal concentrations of glutamate in human fetal kidney cells infected with rat mGluR5 in the presence of the compound:

Isoindolin-1-one derivatives having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl;

Isoindolin-1,3-dione derivatives having the structure:

Wherein R ¹ is hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, and , R ¹ does not comprise silicon; R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, and when R ¹ is methyl, R ⁵ is An organic radical containing 4 to 14 carbon atoms;

3,4-Dihydroisoquinolin-1 (2H) -one derivative having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms;

Isoquinoline-1,3 (2H, 4H) -dione derivatives having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms and R ⁵ does not comprise a triphenylamine residue or a benzimidamide residue;

Or cyclic compounds having the structure:

Wherein n is 2, 3 or 4; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; R ⁵ is an organic radical containing 4 to 14 carbon atoms and Y ¹ is selected from N and CR ⁴ ; Y ² is selected from N and CH; Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Is selected from an organic radical comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl; R ⁸ is hydrogen, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl Optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally And an organic radical comprising 1 to 6 carbon atoms selected from substituted aryl, and optionally substituted heteroaryl.

Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds disclosed above and a pharmaceutically acceptable carrier.

Also disclosed are methods of making the compounds disclosed above.

Also disclosed are products of the methods disclosed above.

A method of preparing a medicament for enhancing metabolic glutamate receptor activity in a mammal, comprising combining the one or more compounds disclosed above or a pharmaceutically acceptable salt or N-oxide thereof with a pharmaceutically acceptable carrier. Also disclosed.

Also disclosed is the use of the compounds disclosed above or their pharmaceutically acceptable salts or N-oxides to enhance the mGluR5 response in mammals.

Aspects of the invention may be described and claimed in a specific class of law, such as a system of law, but this is for convenience only and one of ordinary skill in the art would appreciate that each aspect of the invention may be described in any legal group. I will understand. Unless otherwise stated, any method or aspect described herein should not be construed as requiring the steps to be performed in a particular order. Accordingly, unless the method claims specifically state the steps in the claims or the detailed description as limiting the steps to a particular order, the order in which the steps are performed is not to be stated. This may be any nondescriptive description of the invention, including logical problems relating to the arrangement or operational flow of steps, clear meanings inferred from grammatical or punctuation, or the number or type of aspects described herein. The same applies to expressions.

Brief description of the drawings

The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate several aspects of the invention and, together with the description, explain the principles of the invention.

1 shows a schematic of the NMDA receptor.

2 shows a schematic illustrating that activation of mGluR5 enhances NMDA receptor function.

Figure 3 illustrates the allosteric regulatory action of mGluR5.

4 shows CDPPB as a potent and selective mGluR5 enhancer with adequate efficacy for antipsychotic activity in rodent behavior models.

5 shows the categorization of compounds as agonists, enhancers, and antagonists.

6 shows a schematic illustration of the optimization of candidates.

FIG. 7 shows the binding to MPEP sites with different affinity tabulations of [3H] methoxyPEPy.

8 shows in vivo efficacy against (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (compound VU13).

9 shows in vivo efficacy against (4-hydroxy-4-propylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (Compound VU60).

10 shows in vivo efficacy against (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (compound VU14 / C104B2).

11 shows cognitive improvement in the Cognitive Memory (NOR) paradigm for new objects by ADX47273.

12 shows the effect of VU000067 on amphetamine-induced hyperlocomotion (Sprague-Dawley male rats-200-225 grams; N = 4 / treatment group; VU000067 pretreatment 30 min i.p.).

FIG. 13 shows the effect of VU000098 on amphetamine-induced hypermobility (Sprague-Dawley male rats-200-225 grams; N = 4 / treatment group; VU000098 pretreatment 30 min i.p.).

FIG. 14 shows the effect of VU000069 on amphetamine-induced hypermobility (Sprague-Dawley male rats-200-225 grams; N = 4 / treatment group; VU000069 pretreatment 30 min i.p.).

15 shows the chemical structure of mGluR5 PAM with in vivo activity in a preclinical antipsychotic model.

FIG. 16 shows the restoration of amphetamine-induced hyperwalking by CDPPB and ADX47273.

FIG. 17 shows restoration of amphetamine-induced hyperwalking by VU00013 and VU000067.

18 shows the restoration of amphetamine-induced prepulse inhibition (PPI) by CDPPB.

19 shows the restoration of amphetamine-induced prepulse inhibition (PPI) by ADX47273.

FIG. 20 shows the increase in the strength of synaptic connections after stimulation to synapses in the absence and presence of two structurally distinct mGluR5 PAM, VU29 (top panel) and ADX47273 (bottom panel).

Additional advantages of the invention will be set forth in part in the description which follows, and in part will be apparent from the description or may be learned by the embodiments of the invention. Advantages of the present invention will be realized and attained by means of the elements and combinations of these elements particularly pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit the invention as claimed.

details

The invention may be more readily understood by reference to the following detailed description of the invention and examples contained herein.

Before disclosing and describing the compounds, compositions, products, systems, devices, and / or methods of the invention, they are not limited to specific synthetic methods unless otherwise specified, or to specific reactants unless otherwise specified. It is to be understood that this may not, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although exemplary methods and materials are described herein, methods and materials similar or equivalent to the methods and materials described herein may be used in the examples or experiments of the present invention.

All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in conjunction with the methods and / or materials mentioned in the publications cited. Publications discussed herein are provided only for disclosing these publications prior to the filing date of the present application. There is no description in the present specification which may be construed as preventing the present invention from making the publication of these publications precede the prior invention. In addition, the publication date provided herein may be different from the actual publication date, and may need to be checked individually.

A. Definition

As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plurals unless the context clearly dictates otherwise. Thus, for example, referring to “one functional group”, “one alkyl” or “one residue” includes two or more mixtures of such functional groups, alkyls, or residues.

Ranges may be expressed herein as from “about” one particular figure and / or to “about” another particular figure. When such a range is expressed, another aspect includes from one particular value and / or up to another specific value. Similarly, when numbers are expressed as approximations using the preceding term “about,” it will be understood that certain numbers form another aspect. It will also be understood that the terminal values in each of the ranges are important in relation to one other terminal value and independently of the other terminal value. In addition, there are a number of numerical values in the present specification, it is to be understood that each numerical value is also disclosed herein as "about" in addition to the numerical value itself. For example, if the number "10" is disclosed, then "about 10" is also disclosed. It should also be understood that each unit existing between two specific units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

As used herein and in the claims, the term residue of a species refers to a portion of the product or subsequent formulation or subsequent chemical product produced by the species in a particular reaction scheme, wherein the portion is In practice it is irrelevant whether or not it is obtained from a chemical species in a particular reaction scheme. Therefore, ethylene glycol residues in polyester mean one or more —OCH ₂ CH ₂ O—units present in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, the sebacic acid residue in a polyester refers to one or more -CO (CH ₂ ) ₈ CO- present in the polyester, whether or not it has been obtained by reacting sebacic acid or an ester thereof to obtain a polyester. Means part.

As used herein, the term "optional" or "optionally" means that an event or context described subsequently may or may not occur, and the description may or may not occur when the event or context occurs. It means to include.

As used herein, the term “mGluR5 receptor positive allosteric modulator” refers to the expression of the mGluR5 receptor in the presence or absence of an endogenous ligand (eg, glutamate) in an animal, particularly in a mammal, eg, a human. Refers to an externally administered compound or agent that directly or indirectly increases activity. The term “mGluR5 receptor positive allosteric modulator” refers to “mGluR5 receptor allosteric enhancer” or “mGluR5 receptor allosteric”. Agonist ”and“ mGluR5 receptor allosteric enhancers ”and“ mGluR5 receptor allosteric agonists ”include compounds with mixed activity.

As used herein, the term “mGluR5 receptor allosteric potentiator” refers to an endogenous ligand (when the enhancer binds to an orthosteric site of the mGluR5 receptor in an animal, in particular a mammal, eg, a human). Eg, an externally administered compound or agent that directly or indirectly increases the response produced by glutamate). The mGluR5 receptor allosteric enhancer binds to a site other than the orthosteric site (allosteric site), positively increasing the receptor's response to the agonist. Because this does not lead to desensitization of the receptor, the activity of the compound as an mGluR5 receptor allosteric enhancer offers advantages over using pure mGluR5 receptor allosteric agonists. Such advantages may include, for example, increased safety margin, higher tolerability, reduced likelihood of abuse, and reduced toxicity.

The term “mGluR5 receptor allosteric agonist” as used herein directly increases the activity of the mGluR5 receptor in the absence of endogenous ligands (eg, glutamate) in animals, particularly mammals, such as humans. Means any compound or agent administered externally. mGluR5 receptor allosteric agonists directly affect the orthosteric glutamate site of the mGluR5 receptor and directly affect the orthosteric site of the mGluR5 receptor. Since this agonist does not require the presence of endogenous ligands, the activity of the compound as an mGluR5 receptor allosteric agonist outweighs using pure mGluR5 receptor allosteric enhancers, such as the expression of faster action. (onset of action)

"Treatment" means medically managing a patient with the intention of treating, alleviating, stabilizing, or preventing a disease, morbidity, or disorder. This term encompasses active treatment, ie, treatment specifically directed at ameliorating a disease, morbidity, or disorder, and also aims at eliminating the cause of the cause, ie, causing the associated disease, morbidity, or disorder. Treatment also includes. The term also refers to conventional treatment, ie treatment intended to alleviate symptoms rather than to treat a disease, morbidity, or disorder; Prophylactic treatment, ie, treatment directed to reducing, partially or completely inhibiting the development of the associated disease, pathological abnormality, or disorder; And supportive therapies, ie, therapies used to supplement other specific therapies aimed at improving related diseases, pathological abnormalities, or disorders.

"Preventing" or "preventing" means, inter alia, to prevent, prevent, prevent, proactively, suspend or delay anything else by proactive action. Where the terms reduce, inhibit or prevent are used, unless otherwise stated, the use of the other two terms should also be understood to be expressly disclosed.

As used herein, “diagnosed as needing to enhance metabolic glutamate receptor activity” refers to those having symptoms that can be treated or diagnosed by a person skilled in the art, for example, a physician, by enhancing the metabolic glutamate receptor activity. Means to be found. As used herein, “diagnosed as requiring partial agonism of metabolic glutamate receptor activity” refers to a person skilled in the art, for example, a physician, who can be treated or diagnosed by partial action of metabolic glutamate receptor activity. It means that you have been found to have symptoms. As used herein, “diagnosed as requiring the treatment of one or more neurological and / or psychiatric disorders associated with glutamate dysfunction” refers to one or more nerves associated with glutamate dysfunction and / or examined by a person of ordinary skill in the art, for example, a physician. Or it has been found to have a mental disorder.

As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical formulation to a subject. Such methods are known to those skilled in the art and are oral, transdermal, inhaled, nasal, topical, vaginal, ocular, medial, intracranial, rectal, and injectable, such as intravenous. Parenteral administration, including but not limited to intramuscular administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, the agent may be administered therapeutically; That is, to treat a disease or condition present. In still other various aspects, the agent may be administered prophylactically; That is, it can be administered for the prevention of disease or abnormality.

As used herein, “therapeutically effective amount” means an amount sufficient to achieve a desired therapeutic result or to affect unwanted symptoms, but generally insufficient to cause side effects. Specific therapeutically effective dosage levels for a particular patient may include the disorder and the severity of the disorder being treated in combination with or in combination with the specific compound employed; The specific composition employed; The age, body weight, general health, sex and diet of the patient; Dosing time; Route of administration; The rate of release of the specific compound employed; Duration of treatment; It will depend on various factors including the drug used and other similar factors known in the pharmaceutical art. For example, it is within the skill of one of ordinary skill in the art to start with a dose of a compound lower than the dose required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If necessary, the effective daily dose may be divided into several doses for administration. As a result, the single dose composition may contain a single dose or divided doses to prepare a daily dose. Such dosage may be adjusted by the physician in the presence of any contraindications. Dosages may vary and may be administered once or more daily for one or several days. Guidance on appropriate dosages for a given pharmaceutical family can be found in the literature. In another various aspect, the formulation may be a “prophylactically effective amount”; That is, it may be administered in an amount effective for preventing a disease or condition.

As used herein, “pharmaceutically acceptable carrier” means a sterile powder for reconstitution with sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as with injectable sterile solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or media include water, ethanol, polyols (eg glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (eg olive oil) And injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Inhibition of the action of microorganisms can be ensured by containing various antibacterial and antibacterial agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Injectable pharmaceutical forms can be continuously absorbed by including agents that delay absorption, such as aluminum monostearate and gelatin. Injectable drug depot forms are prepared by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters) and poly (anhydrides). Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Injectable drug storage formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. Such injectable formulations may be sterilized, for example, by sterile water or other injection of the sterilant by filtration through a bacteria-retaining filter or in the form of a sterile solid composition that can be dissolved or dispersed. It can be sterilized by incorporation into a sterile medium as soon as possible before use. Suitable inert carriers can include sugars such as lactose. Preferably, at least 95% by weight of the active ingredient particles have an effective particle size in the range of 0.01 to 10 micrometers.

The term "substituted" as used herein is considered to include all acceptable organic compound substituents. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, for example, those described below. Acceptable substituents with respect to suitable organic compounds may be one or more and the same or different. For this disclosure, heteroatoms such as nitrogen may have substituents and / or hydrogen substituents of acceptable organic compounds described herein and that satisfy the valence of the heteroatoms. This disclosure is not intended to limit the substituents of acceptable organic compounds in any way. In addition, the term “substituted” or “substituted with” refers to compounds in which such substitutions are made depending on the substituted atoms and the allowed valences of the substituents and are stable as a result of substitution, such as spontaneous modification, such as rearrangement, cyclization, Implying conditions for producing a compound that does not undergo modification by removal or the like.

In defining various terms, “A ¹ ,” “A ² ,” “A ³ ,” and “A ⁴ ” are used herein as generic symbols to denote various specific substituents. These symbols are not limited to the substituents disclosed herein and may be any substituent, and when these symbols are defined as specific substituents in one example, they may also be defined as some other substituent in another example.

The term “alkyl” as used herein refers to branched or unbranched saturated hydrocarbon groups of 1 to 24 carbon atoms, such as methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, s -butyl, t -butyl, n -pentyl, isopentyl, s -pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. Alkyl groups may also be substituted or unsubstituted. Alkyl groups may be substituted with one or more functional groups, including optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halides, hydroxy, nitro, silyl, sulfo-oxo, or thiols, as described herein, It is not limited to this. A "lower alkyl" group is an alkyl group containing 1 to 6 (eg 1 to 4) carbon atoms.

Throughout the specification “alkyl” is generally used to refer to both unsubstituted and substituted alkyl groups; However, substituted alkyl groups may also be specifically referred to herein by identifying specific substituents for the alkyl group. For example, the term “halogenated alkyl” specifically refers to an alkyl group substituted with one or more halides, such as fluorine, chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "alkylamino" refers to an alkyl group substituted with one or more amino groups and the like as described below. When "alkyl" is used in one example and a specific term such as "alkylalcohol" is used in another example, it does not mean that the term "alkyl" does not refer to specific terms such as "alkylalcohol" or the like.

It is also used for other functional groups described herein. That is, terms such as “cycloalkyl” refer to both unsubstituted and substituted cycloalkyl moieties, although substituted moieties may be specifically identified herein; For example, certain substituted cycloalkyls may also be referred to, for example, as “alkylcycloalkyls”. Similarly, substituted alkoxy may be specifically referred to as, for example , “halogenated alkoxy”, and specific substituted alkenyl may be, for example , “alkenyl alcohol” and the like. In addition, examples using general terms such as “cycloalkyl” and specific terms such as “alkylcycloalkyl” are not intended to mean that the specific terms do not include special terms.

As used herein, the term “cycloalkyl” is a non-aromatic carbon-based ring composed of three or more carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above and is included within the meaning of the term “cycloalkyl” wherein one or more carbon atoms in the ring are heteroatoms such as nitrogen, oxygen, sulfur, or phosphorus (But not limited to). The cycloalkyl group and heterocycloalkyl group may be substituted or unsubstituted. Cycloalkyl groups and heterocycloalkyl groups include one or more functional groups as described herein, including optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiols. Can be substituted.

As used herein, the term "polyalkylene group" is a functional group having two or more CH ₂ groups linked together. Polyalkylene group is formulas - (CH _{2) a} - it said to be able to indicate, where "a" is an integer from 2 to 500.

As used herein, the terms "alkoxy" and "alkoxyl" refer to an alkyl or cycloalkyl group bonded via an ether bond; That is, an "alkoxy" group can be defined as -OA ¹ where A ¹ is alkyl or cycloalkyl as defined above. "Alkoxy" also includes polymers of alkoxy groups as described above; That is, alkoxy can be a polyether, such as -OA ¹ -OA ² or -OA ^1- (OA ² ) _a -OA ³ , where "a" is an integer from 1 to 200 and A ¹ , A ² , And A ³ is an alkyl and / or cycloalkyl group.

As used herein, the term “alkenyl” is a hydrocarbon group of 2 to 24 carbon atoms with a structure having one or more carbon-carbon double bonds. Asymmetric structures such as (A ¹ A ² ) C═C (A ³ A ⁴ ) are intended to include both E and Z isomers. This can be inferred from the structure in which the asymmetric alkene is present or can be explicitly represented by the binding symbol C = C. Alkenyl groups, as described herein, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehydes, amino, carboxylic acids, esters, ethers, It may be substituted with one or more functional groups, including but not limited to halides, hydroxy, ketones, azides, nitro, silyl, sulfo-oxo, or thiols.

As used herein, “cycloalkenyl” is a non-aromatic carbon ring composed of three or more carbon atoms and having one or more carbon-carbon double bonds, ie , C═C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above and is included in the meaning of the term “cycloalkenyl” wherein at least one carbon atom of the ring is a heteroatom such as nitrogen, Substituted with oxygen, sulfur, or phosphorus. Cycloalkenyl groups and heterocycloalkenyl groups may be substituted or unsubstituted. Cycloalkenyl groups and heterocycloalkenyl groups, as described herein, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, It may be substituted with one or more functional groups, including but not limited to carboxylic acids, esters, ethers, halides, hydroxy, ketones, azides, nitros, silyls, sulfo-oxos, or thiols.

As used herein, the term “alkynyl” is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula having at least one carbon-carbon triple bond. Alkynyl groups, as described herein, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, It may or may not be substituted with one or more functional groups, including but not limited to halides, hydroxy, ketones, azide, nitro, silyl, sulfo-oxo, or thiols.

As used herein, the term “cycloalkynyl” is a non-aromatic carbon-based ring consisting of seven or more carbon atoms with one or more carbon-carbon triple bonds. Examples of cycloalkynyl groups include, but are not limited to, cycloheptinyl, cyclooctynyl, cyclononinyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above and is included in the meaning of the term “cycloalkynyl” wherein at least one carbon atom in the ring is a heteroatom such as nitrogen, oxygen , Sulfur, or phosphorus, but is not limited thereto. The cycloalkynyl group and heterocycloalkynyl group may be substituted or unsubstituted. Cycloalkynyl and heterocycloalkynyl groups, as described herein, are optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, One or more functional groups can be substituted, including, but not limited to, carboxylic acids, esters, ethers, halides, hydroxy, ketones, azides, nitros, silyls, sulfo-oxos, or thiols.

As used herein, the term “aryl” is a functional group containing a carbon-based aromatic functional group, including but not limited to benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. Heteroaryl ”, wherein heteroaryl is defined as a functional group containing an aromatic functional group incorporating one or more heteroatoms in the ring of the aromatic functional group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Similarly, the term “non-heteroaryl”, also included in the term “aryl”, defines functional groups containing aromatic functional groups that do not contain heteroatoms. Aryl groups may be substituted or unsubstituted. Aryl groups are optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehydes, amino, carboxylic acids, esters, ethers, halides, as described herein. And one or more functional groups, including but not limited to, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol. The term “biaryl” is a special type of aryl group and is included in the definition of “aryl”. Biaryl refers to two aryl groups bonded together through a bonded ring structure as in naphthalene, or two aryl groups attached through one or more carbon-carbon bonds as in biphenyl.

As used herein, the term "aldehyde" is represented by the general formula -C (O) H. Throughout this specification "C (O)" is a shorthand notation for a carbonyl group, ie C = O.

The term "amine" or "amino" as used herein is represented by the general formula NA ¹ A ² A ³ , wherein A ¹ , A ² , and A ³ are independently hydrogen or optional as described herein. It may be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group substituted with.

The term "carboxylic acid" as used herein is represented by the general formula -C (O) OH.

The term “ester” as used herein is represented by the general formula —OC (O) A ¹ or —C (O) OA ¹ , wherein A ¹ is optionally substituted alkyl, cyclo, as described herein. Alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groups. The term "polyester" as used herein refers to the general formula-(A ¹ O (O) CA ² -C (O) O) _a -or-(A ¹ O (O) CA ² -OC (O)) _a - makin represented by wherein a ¹ and a ² are, independently, an optionally substituted alkyl, as described herein, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, alkynyl, aryl, or heteroaryl group It may be a group, "a" is an integer of 1 to 500. “Polyester” is a term used to describe a functional group produced by a reaction between a compound having at least two hydroxyl groups and a compound having at least two carboxylic acid groups.

The term "ether" as used herein is represented by the general formula A ¹ OA ² , wherein A ¹ and A ² are independently substituted, optionally substituted alkyl, cycloalkyl, alkenyl, as described herein, Cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groups. As used herein, the term “polyether” is represented by the general formula — (A ¹ OA ² O) _a −, wherein A ¹ and A ² are independently an optionally substituted alkyl, as described herein. , Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group, where "a" is an integer from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

The term "halide" as used herein refers to halogen, ie fluorine, chlorine, bromine, and iodine.

As used herein, “hydroxyl” is represented by the general formula —OH.

As used herein, the term “ketone” is represented by the general formula A ¹ C (O) A ² , wherein A ¹ and A ² are independently an optionally substituted alkyl, cycloalkyl, as described herein. , Alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groups.

As used herein, the term “azide” is represented by the general formula —N ₃ .

The term "nitro" as used herein is represented by the general formula -NO ₂ .

As used herein, the term "nitrile" is represented by the general formula -CN.

The term "silyl" as used herein is represented by the general formula -SiA ¹ A ² A ³ , wherein A ¹ , A ² , and A ³ are independently hydrogen or optionally substituted, as described herein. Alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groups.

As used herein, the term “sulfo-oxo” may refer to the general formula —S (O) A ¹ , —S (O) ₂ A ¹ , —OS (O) ₂ A ¹ , or —OS (O) ₂ OA ¹ Wherein A ¹ may be hydrogen or an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group, as described herein. Throughout this specification, "S (O)" is a shorthand notation for S = O. The term "sulfonyl" as used herein is used to mean a sulfo-oxo group represented by the general formula -S (O) ₂ A ¹ , wherein A ¹ is optionally hydrogen or as described herein. It may be a substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group. As used herein, the term “sulfone” is represented by the general formula A ¹ S (O) ₂ A ² , wherein A ¹ and A ² are independently an optionally substituted alkyl, cyclo, as described herein. Alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groups. The term “sulfoxide” as used herein is represented by the general formula A ¹ S (O) A ² , wherein A ¹ and A ² are independently substituted, optionally substituted alkyl, cyclo, as described herein. Alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groups.

The term "thiol" as used herein is represented by the general formula -SH.

The term “organic moiety” defines a carbon containing moiety, ie, a moiety comprising one or more carbon atoms, and includes, but is not limited to, carbon-containing functional groups, moieties, or radicals as defined above. The organic moiety may contain various heteroatoms or be bound to another molecule through heteroatoms including oxygen, nitrogen, sulfur, phosphorus and the like. Examples of organic moieties include, but are not limited to, alkyl or substituted alkyl, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, and the like. The organic moiety preferably comprises 1 to 18 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms do. In another aspect, the organic moiety is 2 to 18 carbon atoms, 2 to 15 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms It may include.

The closest synonym of the term “residue” is the term “radical”, which is used in the specification and claims, and refers to a fragment, group or substructure of a molecule described herein, regardless of how the molecule is produced. For example, a 2,4-thiazolidinedione radical in a particular compound has the following structure regardless of whether thiazolidinedione is used to prepare that particular compound:

In some embodiments, radicals (eg, alkyl) may be further modified (ie, substituted alkyl) by binding one or more “substituent radicals” to the radicals. Unless stated to the contrary elsewhere in this specification, the number of atoms in a given radical is not critical to the invention.

The term "organic radical" as defined and used herein contains one or more carbon atoms. Organic radicals may be, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms It can have In another aspect, the organic radical is 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms It can have Organic radicals often bind hydrogen to at least some carbon atoms of the organic radical. One example of an organic radical that contains no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, the organic radicals may contain 1-10 inorganic heteroatoms, including halogen, oxygen, sulfur, nitrogen, phosphorus, etc., attached to or within the organic radicals. Examples of organic radicals include alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted Alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted Aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, including but not limited to, wherein the terms are defined elsewhere in this specification. Some non-limiting examples of organic radicals including heteroatoms include, but are not limited to, alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals, and the like.

As defined and used herein, an "inorganic radical" does not contain any carbon atoms and includes only atoms other than carbon. Inorganic radicals include combinations of atoms, selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine and iodine, which atoms are individually present or chemically stable Can be combined together in combination. The inorganic radical has 10 or less, or preferably 1 to 6, or 1 to 4 inorganic atoms listed as bonded together above. Examples of inorganic radicals may include, but are not limited to, amino, hydroxy, halogen, nitro, thiols, sulfates, phosphates and commonly known inorganic radicals. Inorganic radicals do not have a metal element of the periodic table (eg, alkali metal, alkaline earth metal, transition metal, lanthanide metal, or actinium metal) bound therein, but these metal ions are sometimes anionic inorganic radicals, such as sulfate, It can act as a pharmaceutically acceptable cation for phosphate or similar anionic inorganic radicals. Inorganic radicals do not include metalloid elements, such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or inert gas elements, unless specifically noted otherwise in this section.

The compounds described herein may contain one or more double bonds, which may result in cis / trans (E / Z) isomers and other conformational isomers. Unless stated to the contrary, the present invention includes all such possible isomers as described above and mixtures of these isomers.

Unless stated to the contrary, general formulas having chemical bonds shown only in solid lines, not as wedges or dotted lines, each of the possible isomers, such as the respective enantiomers and diastereomers and mixtures of isomers, such as racemic mixtures or Consider a scalemic mixture. The compounds described herein may contain one or more asymmetric centers and thus can generate diastereomers and optical isomers. Unless stated to the contrary, the present invention relates to all such possible diastereomers and racemic mixtures thereof, substantially purely separated enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof. It includes. Stereoisomers and mixtures of specific stereoisomers isolated are also included. During the course of synthetic procedures known to those skilled in the art used to prepare these compounds, or in using racemization or epimerization procedures, the products of these procedures may be mixtures of stereoisomers.

The following abbreviations are used herein. DMF: Dimethyl formamide. EtOAc: ethyl acetate. THF: tetrahydrofuran. DIPEA or DIEA: diisopropylethylamine. HOBt: 1-hydroxybenzotriazole. EDC: 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride. DMSO: Dimethylsulfoxide. DMAP: 4-dimethylaminopyridine. RT: room temperature. H: Time. Min: Min. DCM: dichloromethane. MeCN: acetonitrile. MeOH: Methanol. iPrOH: 2-propanol. n-BuOH: 1-butanol.

The components used to prepare the compositions of the present invention and the compositions themselves used in the methods disclosed herein are disclosed. These and other materials are also disclosed herein and specific reference to each of the various individual and collective combinations and alterations of these compounds, when combinations, subsets, interactions, groups, etc., of these materials are disclosed. Although not expressly disclosed, it is to be understood that each of these is specifically considered and described herein. For example, where specific compounds are disclosed and discussed and the numerous modifications that may be made to numerous molecules, including those compounds, are discussed, each and all combinations and alterations of the compound and possible modifications unless specifically stated to the contrary. This is specifically considered. Therefore, if molecular groups A, B, and C, and molecular groups D, E, and F are disclosed, and examples of combination molecules, AD are disclosed, each is considered to be individually disclosed, even if each is not individually mentioned, Combinations of meaning considered collectively, AE, AF, BD, BE, BF, CD, CE, and CF are considered to be disclosed. Similarly, subsets or combinations thereof are also disclosed. Thus, for example, subgroups of A-E, B-F, and C-E will be considered to be disclosed. This concept applies to, but is not limited to, all aspects of the present application, including steps in methods of making and using the compositions of the present invention. Therefore, it is to be understood that where there are various additional steps that can be performed, each of these additional steps can be performed in conjunction with a specific embodiment of the methods of the present invention or in combination with these embodiments.

It is understood that the compositions disclosed herein have certain functions. It is understood that the specific structural requirements necessary to carry out the disclosed functions are disclosed herein, and that there are various structures associated with the disclosed structures and capable of performing the same functions and that these structures will typically achieve the same results. shall.

B. mGluR5 of New Allosteric  Development of Enhancers

Penciclidine (PCP) and other NMDA receptor antagonists cause schizophrenia-like psychiatric conditions in humans. In schizophrenic patients, PCP and ketamine exacerbate / promote positive and negative symptoms that were already present in stable patients. Treatment with NMDA receptor co-agonists can improve positive and negative symptoms. An overview of the NMDA receptor is shown in FIG. 1. Activation of mGluR5 enhances NMDA receptor function. See FIG. 2. Orthosteric ligands are not subtype selective and can cause unwanted side effects. Allosteric modulators targeting the transmembrane site (see FIG. 3) provide an alternative: TMD is significantly less conserved.

4-cyano-N- (1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) is a potent and selective mGluR5 with moderate efficacy in rodent behavioral models for antipsychotic activity. It's an enhancer. See FIG. 4. However, this compound lacks satisfactory water solubility and is poor in oral bioavailability. Approximately 160,000 compounds were screened as potent mGluR5 modulators. After identification, the compounds were classified as agonists, enhancers and antagonists. See FIG. 5.

Based on the identified structure, an amide library could be prepared as shown below.

Typically, small, nonpolar morpholino side chains provided the highest efficacy. Also, typically, increasing ring size and steric bulk decreased activity. Polar side chains were tolerated but typically reduced in activity. In addition, the side chains could be further modified as shown below.

The relevant data is summarized in the table below. In general, methyl substitution provided better results.

Substitution of hydroxypiperidine with azitidine was tolerated and usually small R-groups were preferred.

Typically, the incorporation of mono-fluoro substituents increased the potency and efficacy.

Leading compounds were then identified; All identified compounds gave nearly maximum response and 3-fluoro substitutions and morpholino amides gave satisfactory results.

Linkers were studied as shown in the following scheme:

Subsequent substitution of [3 H] methoxyPEPy was studied. These compounds were found to bind to the MPEP site while changing the affinity. See FIG. 7. These compounds have also been tested for activity on other receptors ( eg mGluR1, mGluR4, mGluR7, M3). Early tests demonstrated selectivity for mGluR5. These compounds were also tested for stability in rat liver microsomes. Typically, these compounds continue to retain 90% of their parent after 45 minutes.

The compounds were then evaluated for activity against amphetamine-induced hyperlocomotion. See FIGS. 8, 9, and 10.

C. Compounds

In one aspect, the present invention relates to compounds useful as positive allosteric modulators (potentiators) of metabolic glutamate receptor subtype 5 (mGluR5). More specifically, the present invention relates to compounds which allosterically modulate mGluR5 receptor activity, which does not act as an orthosteric agonist itself but affects the selectivity of the mGluR5 receptor for agonists. The compounds of the present invention are useful for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction and for other diseases involving metabolic glutamate receptors, as described in detail herein.

One. Benzamide  derivative

In one aspect, the invention relates to compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ and R ² are independently an optionally substituted organic radical comprising 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing from 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cyclo Alkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally Substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and Up to 5 substituents independently selected from alkylamine-carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase in.

In another aspect, R ¹ and R ² are alkyl having 1 to 6 carbons. In another aspect, N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons together. In another aspect, Z ¹ , Z ² , and Z ³ are all carbon. In another aspect, R ⁴ comprises up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. In another aspect, both Y ¹ and Y ² are carbon.

In still another aspect, the compound has a structure represented by the following general formula:

In another aspect, R ¹ and R ² are independently alkyl having 1 to 6 carbons or N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons; ; R comprises 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl; R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.

In one aspect, the present invention relates to compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ and R ² are independently hydrogen or an optionally substituted organic radical comprising 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or from 1 to 12 carbon atom organic radicals; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents independently selected from amine-carbonyl; R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or are independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3- C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl Optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, Shown sulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase in.

In another aspect, R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons. In another aspect, N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons. In another aspect, Z ¹ , Z ² , and Z ³ are all carbon. In another aspect, R ⁴ comprises up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. In another aspect, both Y ¹ and Y ² are carbon. In another aspect, both R ^7a and R ^7b are hydrogen.

In still another aspect, the compound has a structure represented by the following general formula:

In another aspect, R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons, or N, R ¹ , and R ² together form an optionally substituted heterocyclic ring having 2 to 7 carbons. Includes; R comprises 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl; R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.

In one aspect, the present invention relates to compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ and R ² are independently an optionally substituted organic radical comprising 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents independently selected from amine-carbonyl; Wherein the compound, in comparison to the response to glutamate in the absence of the compound, enhances the mGluR5 response to glutamate in response to non-maximal concentrations of glutamate in human fetal kidney cells infected with rat mGluR5 in the presence of the compound. Represented as an increase of.

In another aspect, R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons. In another aspect, N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons. In another aspect, Z ¹ , Z ² , and Z ³ are all carbon. In another aspect, R ⁴ comprises up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. In another aspect, both Y ¹ and Y ² are carbon.

In still another aspect, the compound has a structure represented by the following general formula:

In another aspect, R ¹ and R ² are independently alkyl having 1 to 6 carbons or N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons; R comprises 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl; R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.

In one aspect, the present invention relates to compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ and R ² are independently hydrogen or an optionally substituted organic radical comprising 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents independently selected from amine-carbonyl; R ⁸ is selected from hydrogen and lower alkyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase of.

In another aspect, R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons. In another aspect, N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons. In another aspect, Z ¹ , Z ² , and Z ³ are all carbon. In another aspect, R ⁴ comprises up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. In another aspect, both Y ¹ and Y ² are carbon. In another aspect, R ⁸ is hydrogen.

In still another aspect, the compound has a structure represented by the following general formula:

In another aspect, R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons, or N, R ¹ , and R ² together form an optionally substituted heterocyclic ring having 2 to 7 carbons. Including; R comprises 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl; R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.

In another aspect, the invention provides N-cyclopentyl-4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; Morpholino (4- (phenylethynyl) phenyl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; N-cyclohexyl-4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; 4- (phenylethynyl) -N-propylbenzamide; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; N- (3,3-dimethylbutyl) -4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl yl) phenyl) (morpholino) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; N-isopentyl-4- (phenylethynyl) benzamide; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (3-methoxypropyl) -4- (phenylethynyl) benzamide; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N-butyl-4- (phenylethynyl) benzamide; (R) -4- (phenylethynyl) -N- (2-phenylpropyl) benzamide; (4-((3,4-difluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-hydroxy-4-methylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4- (pentan-2-ylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (cyclohexylmethyl) -4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; N- (2-cyclohexenylethyl) -4- (phenylethynyl) benzamide; N- (4-methylcyclohexyl) -4- (phenylethynyl) benzamide; (4- (cyclohexylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; N- (3-hydroxypropyl) -4- (phenylethynyl) benzamide; (2,6-dimethylmorpholino) (4- (phenylethynyl) phenyl) methanone; (4- (phenylethynyl) phenyl) (4- (4- (pyridin-4-yl) piperazin-1-yl) piperidin-1-yl) methanone; (3-hydroxy-3-methylazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (S)-(4- (1-cyclohexylethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (4-methylpiperazin-1-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (2-chlorophenethyl) -4- (phenylethynyl) benzamide; N- (2-morpholinoethyl) -4- (phenylethynyl) benzamide; N- (2,3-dihydro-1H-inden-1-yl) -4- (phenylethynyl) benzamide; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; N- (2,3-dihydro-1H-inden-2-yl) -4- (phenylethynyl) benzamide; (4-((4-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-methylpiperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (4-chlorophenethyl) -4- (phenylethynyl) benzamide; (4-((2-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; N- (3-chlorophenethyl) -4- (phenylethynyl) benzamide; (4- (cyclobutylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (4-bromophenethyl) -4- (phenylethynyl) benzamide; (3-hydroxyazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (2-morpholinoethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; N- (3,3-dimethylbutyl) -4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) benzamide; (4- (4-chloro-2- (trifluoromethyl) phenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxy-3-propylazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (Octahydroisoquinolin-2 (1H) -yl) (4- (phenylethynyl) phenyl) methanone; (4-((4-fluoro-3-methylphenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((3,5-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (S) -N-((1-ethylpyrrolidin-2-yl) methyl) -4- (phenylethynyl) benzamide; (4-hydroxy-4- (thiophen-2-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (azetidin-1-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; 4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) -N- (3-methoxypropyl) benzamide; 4-phenyl-1- (4- (phenylethynyl) benzoyl) piperidine-4-carbonitrile; N- (3,3-dimethylbutyl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzamide; (4-isopropylpiperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (2-methoxyethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (3-morpholinopropyl) -4- (phenylethynyl) benzamide; (4- (4-fluorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; 1- (4-phenyl-1- (4- (phenylethynyl) benzoyl) piperidin-4-yl) ethanone; 1- (1- (4- (phenylethynyl) benzoyl) piperidin-4-yl) -1H-benzo [d] imidazol-2 (3H) -one; (4-hydroxy-4-propylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxy-3- (thiophen-2-yl) azetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (3-fluorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; 4- (phenylethynyl) -N- (2- (piperidin-1-yl) ethyl) benzamide; (4-hydroxy-4-isopropylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (cyclohexylethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (E)-(4-hydroxypiperidin-1-yl) (4-styrylphenyl) methanone; 4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) -N-propylbenzamide; (4-((2,4-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4- (phenylethynyl) phenyl) (4-phenylpiperazin-1-yl) methanone; (4- (2-methoxyphenyl) piperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxypiperidin-1-yl) (4-((3- (trifluoromethyl) phenyl) ethynyl) phenyl) methanone; 4- (3-phenyl-1,2,4-oxadiazol-5-yl) -N-propylbenzamide; (4-hydroxypyridin-1-yl) (4- (pyridin-2-ylethynyl) phenyl) methanone; (4- (4-bromophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxy-4- (4-methoxyphenyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (cyclopropylmethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (phenylethynyl) phenyl) (4- (pyridin-2-yl) piperazin-1-yl) methanone; N- (2- (dimethylamino) ethyl) -4- (phenylethynyl) benzamide; N- (4-fluorophenyl) -4- (2-methylpiperidine-1-carbonyl) benzamide; N- (2- (1-methylpyrrolidin-2-yl) ethyl) -4- (phenylethynyl) benzamide; (4-hydroxy-4-phenylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (phenylethynyl) phenyl) (4- (pyridin-4-yl) piperazin-1-yl) methanone; 5-chloro-1- (4- (phenylethynyl) benzoyl) -3- (piperidin-4-yl) -1H-benzo [d] imidazol-2 (3H) -one; (4- (phenylethynyl) phenyl) (4- (pyrrolidin-1-yl) piperidin-1-yl) methanone; 2- (4- (4- (phenylethynyl) benzoyl) piperazin-1-yl) benzonitrile; (4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) phenyl) (4- (pyridin-4-yl) piperazin-1-yl) methanone; (4- (phenylethynyl) phenyl) (piperazin-1-yl) methanone; (4- (2-fluorophenyl) piperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; And (4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone or a pharmaceutically acceptable salt thereof do.

In another aspect, the compound comprises (2,6-dimethylmorpholino) (4- (phenylethynyl) phenyl) methanone; (3-hydroxy-3- (thiophen-2-yl) azetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxy-3-methylazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxy-3-propylazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxyazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((2,4-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((3,5-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((4-fluoro-3-methylphenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4- (2-fluorophenyl) piperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (2-methoxyethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (2-methoxyphenyl) piperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (2-morpholinoethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (3-fluorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (4-bromophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (4-chloro-2- (trifluoromethyl) phenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (4-fluorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (4-methylpiperazin-1-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (azetidin-1-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (cyclobutylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (cyclohexylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (cyclopropylmethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (pentan-2-ylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (phenylethynyl) phenyl) (4- (4- (pyridin-4-yl) piperazin-1-yl) piperidin-1-yl) methanone; (4- (phenylethynyl) phenyl) (4- (pyridin-2-yl) piperazin-1-yl) methanone; (4- (phenylethynyl) phenyl) (4- (pyridin-4-yl) piperazin-1-yl) methanone; (4- (phenylethynyl) phenyl) (4- (pyrrolidin-1-yl) piperidin-1-yl) methanone; (4- (phenylethynyl) phenyl) (4-phenylpiperazin-1-yl) methanone; (4- (phenylethynyl) phenyl) (piperazin-1-yl) methanone; (4-hydroxy-4- (4-methoxyphenyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxy-4- (thiophen-2-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxy-4-isopropylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxy-4-methylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxy-4-phenylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxy-4-propylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxypiperidin-1-yl) (4-((3- (trifluoromethyl) phenyl) ethynyl) phenyl) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-isopropylpiperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-methylpiperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; (Octahydroisoquinolin-2 (1H) -yl) (4- (phenylethynyl) phenyl) methanone; (R) -4- (phenylethynyl) -N- (2-phenylpropyl) benzamide; (S)-(4- (1-cyclohexylethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (S) -N-((1-ethylpyrrolidin-2-yl) methyl) -4- (phenylethynyl) benzamide; 1- (1- (4- (phenylethynyl) benzoyl) piperidin-4-yl) -1H-benzo [d] imidazol-2 (3H) -one; 1- (4-phenyl-1- (4- (phenylethynyl) benzoyl) piperidin-4-yl) ethanone; 2- (4- (4- (phenylethynyl) benzoyl) piperazin-1-yl) benzonitrile; 4- (phenylethynyl) -N- (2- (piperidin-1-yl) ethyl) benzamide; 4- (phenylethynyl) -N-propylbenzamide; 4-phenyl-1- (4- (phenylethynyl) benzoyl) piperidine-4-carbonitrile; 5-chloro-1- (4- (phenylethynyl) benzoyl) -3- (piperidin-4-yl) -1H-benzo [d] imidazol-2 (3H) -one; Morpholino (4- (phenylethynyl) phenyl) methanone; N- (2- (1-methylpyrrolidin-2-yl) ethyl) -4- (phenylethynyl) benzamide; N- (2- (dimethylamino) ethyl) -4- (phenylethynyl) benzamide; N- (2,3-dihydro-1H-inden-1-yl) -4- (phenylethynyl) benzamide; N- (2,3-dihydro-1H-inden-2-yl) -4- (phenylethynyl) benzamide; N- (2-chlorophenethyl) -4- (phenylethynyl) benzamide; N- (2-cyclohexenylethyl) -4- (phenylethynyl) benzamide; N- (2-morpholinoethyl) -4- (phenylethynyl) benzamide; N- (3,3-dimethylbutyl) -4- (phenylethynyl) benzamide; N- (3-chlorophenethyl) -4- (phenylethynyl) benzamide; N- (3-hydroxypropyl) -4- (phenylethynyl) benzamide; N- (3-methoxypropyl) -4- (phenylethynyl) benzamide; N- (3-morpholinopropyl) -4- (phenylethynyl) benzamide; N- (4-bromophenethyl) -4- (phenylethynyl) benzamide; N- (4-chlorophenethyl) -4- (phenylethynyl) benzamide; N- (4-methylcyclohexyl) -4- (phenylethynyl) benzamide; N- (cyclohexylmethyl) -4- (phenylethynyl) benzamide; N-butyl-4- (phenylethynyl) benzamide; N-cyclohexyl-4- (phenylethynyl) benzamide; N-cyclopentyl-4- (phenylethynyl) benzamide; And N-isopentyl-4- (phenylethynyl) benzamide.

In another aspect, the compound is N-cyclopentyl-4- (phenylethynyl) benzamide; N-cyclohexyl-4- (phenylethynyl) benzamide; 4- (phenylethynyl) -N-propylbenzamide; N- (3,3-dimethylbutyl) -4- (phenylethynyl) benzamide; N-isopentyl-4- (phenylethynyl) benzamide; N- (3-methoxypropyl) -4- (phenylethynyl) benzamide; N-butyl-4- (phenylethynyl) benzamide; (R) -4- (phenylethynyl) -N- (2-phenylpropyl) benzamide; N- (cyclohexylmethyl) -4- (phenylethynyl) benzamide; N- (2-cyclohexenylethyl) -4- (phenylethynyl) benzamide; N- (4-methylcyclohexyl) -4- (phenylethynyl) benzamide; N- (3-hydroxypropyl) -4- (phenylethynyl) benzamide; N- (2-chlorophenethyl) -4- (phenylethynyl) benzamide; N- (2-morpholinoethyl) -4- (phenylethynyl) benzamide; N- (2,3-dihydro-1H-inden-1-yl) -4- (phenylethynyl) benzamide; N- (2,3-dihydro-1H-inden-2-yl) -4- (phenylethynyl) benzamide; N- (4-chlorophenethyl) -4- (phenylethynyl) benzamide; N- (3-chlorophenethyl) -4- (phenylethynyl) benzamide; N- (4-bromophenethyl) -4- (phenylethynyl) benzamide; (S) -N-((1-ethylpyrrolidin-2-yl) methyl) -4- (phenylethynyl) benzamide; N- (3-morpholinopropyl) -4- (phenylethynyl) benzamide; 4- (phenylethynyl) -N- (2- (piperidin-1-yl) ethyl) benzamide; N- (2- (dimethylamino) ethyl) -4- (phenylethynyl) benzamide; And N- (2- (1-methylpyrrolidin-2-yl) ethyl) -4- (phenylethynyl) benzamide.

In another aspect, the compound comprises (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; Morpholino (4- (phenylethynyl) phenyl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-hydroxy-4-methylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4- (pentan-2-ylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4- (cyclohexylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (2,6-dimethylmorpholino) (4- (phenylethynyl) phenyl) methanone; (4- (phenylethynyl) phenyl) (4- (4- (pyridin-4-yl) piperazin-1-yl) piperidin-1-yl) methanone; (3-hydroxy-3-methylazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (S)-(4- (1-cyclohexylethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (4-methylpiperazin-1-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-methylpiperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4- (cyclobutylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxyazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (2-morpholinoethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4- (4-chloro-2- (trifluoromethyl) phenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxy-3-propylazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (Octahydroisoquinolin-2 (1H) -yl) (4- (phenylethynyl) phenyl) methanone; (4-((4-fluoro-3-methylphenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-((3,5-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-hydroxy-4- (thiophen-2-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (azetidin-1-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; 4-phenyl-1- (4- (phenylethynyl) benzoyl) piperidine-4-carbonitrile; (4-isopropylpiperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (2-methoxyethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (4-fluorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; 1- (4-phenyl-1- (4- (phenylethynyl) benzoyl) piperidin-4-yl) ethanone; 1- (1- (4- (phenylethynyl) benzoyl) piperidin-4-yl) -1H-benzo [d] imidazol-2 (3H) -one; (4-hydroxy-4-propylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxy-3- (thiophen-2-yl) azetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (3-fluorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxy-4-isopropylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((2,4-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4- (phenylethynyl) phenyl) (4-phenylpiperazin-1-yl) methanone; (4- (2-methoxyphenyl) piperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxypiperidin-1-yl) (4-((3- (trifluoromethyl) phenyl) ethynyl) phenyl) methanone; (4- (4-bromophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-hydroxy-4- (4-methoxyphenyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (cyclopropylmethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (phenylethynyl) phenyl) (4- (pyridin-2-yl) piperazin-1-yl) methanone; (4-hydroxy-4-phenylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (phenylethynyl) phenyl) (4- (pyridin-4-yl) piperazin-1-yl) methanone; 5-chloro-1- (4- (phenylethynyl) benzoyl) -3- (piperidin-4-yl) -1H-benzo [d] imidazol-2 (3H) -one; (4- (phenylethynyl) phenyl) (4- (pyrrolidin-1-yl) piperidin-1-yl) methanone; 2- (4- (4- (phenylethynyl) benzoyl) piperazin-1-yl) benzonitrile; (4- (phenylethynyl) phenyl) (piperazin-1-yl) methanone; (4- (2-fluorophenyl) piperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; And (4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone.

In another aspect, the compound comprises 4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) -N- (3-methoxypropyl) benzamide; N- (3,3-dimethylbutyl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzamide; 4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) -N-propylbenzamide; 4- (3-phenyl-1,2,4-oxadiazol-5-yl) -N-propylbenzamide; (4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) phenyl) (4- (pyridin-4-yl) piperazin-1-yl) methanone; N- (3,3-dimethylbutyl) -4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) benzamide; (E)-(4-hydroxypiperidin-1-yl) (4-styrylphenyl) methanone; (4-hydroxypiperidin-1-yl) (4- (pyridin-2-ylethynyl) phenyl) methanone; (4- (cyclohexylethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; And N- (4-fluorophenyl) -4- (2-methylpiperidine-1-carbonyl) benzamide.

In another aspect, the compound comprises 4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) -N- (3-methoxypropyl) benzamide; N- (3,3-dimethylbutyl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzamide; 4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) -N-propylbenzamide; 4- (3-phenyl-1,2,4-oxadiazol-5-yl) -N-propylbenzamide; (4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) phenyl) (4- (pyridin-4-yl) piperazin-1-yl) methanone; And N- (3,3-dimethylbutyl) -4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) benzamide.

In yet another aspect, the compound is (E)-(4-hydroxypiperidin-1-yl) (4-styrylphenyl) methanone. In yet another aspect, the compound is (4-hydroxypiperidin-1-yl) (4- (pyridin-2-ylethynyl) phenyl) methanone. In yet another aspect, the compound is (4- (cyclohexylethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone. In yet another aspect, the compound is N- (4-fluorophenyl) -4- (2-methylpiperidine-1-carbonyl) benzamide.

In another aspect, the compound is N-cyclopentyl-4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; Morpholino (4- (phenylethynyl) phenyl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; N-cyclohexyl-4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; 4- (phenylethynyl) -N-propylbenzamide; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; N- (3,3-dimethylbutyl) -4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; N-isopentyl-4- (phenylethynyl) benzamide; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (3-methoxypropyl) -4- (phenylethynyl) benzamide; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N-butyl-4- (phenylethynyl) benzamide; (R) -4- (phenylethynyl) -N- (2-phenylpropyl) benzamide; (4-((3,4-difluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-hydroxy-4-methylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4- (pentan-2-ylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (cyclohexylmethyl) -4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; N- (2-cyclohexenylethyl) -4- (phenylethynyl) benzamide; N- (4-methylcyclohexyl) -4- (phenylethynyl) benzamide; (4- (cyclohexylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; N- (3-hydroxypropyl) -4- (phenylethynyl) benzamide; (2,6-dimethylmorpholino) (4- (phenylethynyl) phenyl) methanone; (4- (phenylethynyl) phenyl) (4- (4- (pyridin-4-yl) piperazin-1-yl) piperidin-1-yl) methanone; (3-hydroxy-3-methylazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (S)-(4- (1-cyclohexylethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (4-methylpiperazin-1-yl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (2-chlorophenethyl) -4- (phenylethynyl) benzamide; N- (2-morpholinoethyl) -4- (phenylethynyl) benzamide; N- (2,3-dihydro-1H-inden-1-yl) -4- (phenylethynyl) benzamide; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; N- (2,3-dihydro-1H-inden-2-yl) -4- (phenylethynyl) benzamide; (4-((4-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-methylpiperazin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (4-chlorophenethyl) -4- (phenylethynyl) benzamide; (4-((2-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; N- (3-chlorophenethyl) -4- (phenylethynyl) benzamide; (4- (cyclobutylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (4-bromophenethyl) -4- (phenylethynyl) benzamide; (3-hydroxyazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (2-morpholinoethylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; N- (3,3-dimethylbutyl) -4- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) benzamide; (4- (4-chloro-2- (trifluoromethyl) phenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (3-hydroxy-3-propylazetidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (Octahydroisoquinolin-2 (1H) -yl) (4- (phenylethynyl) phenyl) methanone; And (4-((4-fluoro-3-methylphenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone.

In another aspect, the compound is N-cyclopentyl-4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; Morpholino (4- (phenylethynyl) phenyl) methanone; (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; N-cyclohexyl-4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; 4- (phenylethynyl) -N-propylbenzamide; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; N- (3,3-dimethylbutyl) -4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; N-isopentyl-4- (phenylethynyl) benzamide; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (3-methoxypropyl) -4- (phenylethynyl) benzamide; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N-butyl-4- (phenylethynyl) benzamide; (R) -4- (phenylethynyl) -N- (2-phenylpropyl) benzamide; (4-((3,4-difluorophenyl) ethynyl) phenyl) (morpholino) methanone; (4-((2-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4-hydroxy-4-methylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((4-fluorophenyl) ethynyl) phenyl) (4-hydroxy-4-methylpiperidin-1-yl) methanone; (4- (pentan-2-ylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; N- (cyclohexylmethyl) -4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; N- (2-cyclohexenylethyl) -4- (phenylethynyl) benzamide; N- (4-methylcyclohexyl) -4- (phenylethynyl) benzamide; (4- (cyclohexylamino) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone; (4-((3,4-difluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone; N- (3-hydroxypropyl) -4- (phenylethynyl) benzamide; And (2,6-dimethylmorpholino) (4- (phenylethynyl) phenyl) methanone.

In another aspect, the compound is N-cyclopentyl-4- (phenylethynyl) benzamide; (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone; Morpholino (4- (phenylethynyl) phenyl) methanone; And (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone.

In still another aspect, the compound is a phenylethynylbenzamide derivative, cycloalkylethynylbenzamide derivative, styrylbenzamide derivative, 4- (3-phenyl-1,2,4-oxadiazol-5-yl) Benzamide derivatives, 4- (pyridinylethynyl) benzamide derivatives, or N ¹ -phenylterephthalamide derivatives.

a. Phenylethynylbenzamide  derivative

In one aspect, the invention relates to phenylethynylbenzamide derivatives. In one aspect, the compound is a compound or a pharmaceutically acceptable salt thereof comprising the structure:

Wherein R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to An optionally substituted heterocyclic ring having 7 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 5 substituents independently selected from amine-carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase of.

In one aspect, the compound is the EC ₅₀ of about 1.0 × 10 ^{- 6} below shows the mineralization. For example, the compound may exhibit potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁷ . As another example, the compound may exhibit potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In another aspect, R ¹ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, R ² is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, one or more R ³ Substituents may be optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocyclo Alkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have 2 to 7 carbons.

In another aspect, the one or more R ₄ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, and has 2 to 7 carbons.

In one aspect, each R ¹ , R ² , R ³ , and / or R ₄ comprises optionally substituted alkyl or optionally substituted cycloalkyl. In one aspect, optionally substituted alkyl of R ¹ , R ² , R ³ , and / or R ₄ is a C1 to C6 substituent; That is, it includes a substituent having 1 to 6 carbons. For example, in one aspect, optionally substituted alkyl may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, or hexyl. In another aspect, all of R ³ are hydrogen.

In another aspect, at least one R ⁴ is halogen selected from F and Cl. In another aspect, R ⁴ comprises 4 hydrogen and 1 or 2 substituents selected from hydrogen, F, and Cl.

In one aspect, the compound may have a structure represented by the following general formula:

In one aspect, at least one R ⁴ is optionally substituted alkyl selected from methyl and trifluoromethyl. In another aspect, the compound may have a structure represented by the following general formula:

In another aspect, R ⁴ comprises 5 hydrogen and 1 optionally substituted alkyl. In another aspect, all of R ⁴ are hydrogen.

In another aspect, the compound has a structure represented by the following general formula:

In another aspect, R ¹ and R ² are independently hydrogen, (1-ethylpyrrolidin-2-yl) methyl; 2- (1-methylpyrrolidin-2-yl) ethyl; 2- (dimethylamino) ethyl; 2- (piperidin-1-yl) ethyl; 2,3-dihydro-1H-inden-1-yl; 2-chlorophenethyl; 2-morpholinoethyl; 2-phenylpropyl; 3,3-dimethylbutyl; 3-chlorophenethyl; 3-hydroxypropyl; 3-methoxypropyl; 3-morpholinopropyl; 4-bromophenethyl; 4-chlorophenethyl; Butyl; Cyclohexenylethyl; Cyclohexylcyclohexylmethylcyclopentyl; Isopentyl; Methylcyclohexyl; And in the profile. In still another aspect, the compound has a structure represented by the following general formula:

In yet another aspect, N, R ¹ , and R ² together comprise a cyclic alkyl moiety optionally substituted. In another aspect, the optionally substituted cyclic alkyl moiety is (E) -4-hydroxypiperidin-1-yl; (S)-(4- (1-cyclohexylethylamino) piperidin-1-yl; 1- (piperidin-4-yl) -1H-benzo [d] imidazol-2 (3H) -one 1- (piperidin-4-yl) ethanone; 2- (piperazin-1-yl) benzonitrile; 2,6-dimethylmorpholino; 2-morpholinoethyl; 3-hydroxy-3 -(Thiophen-2-yl) azetidin-1-yl; 3-hydroxy-3-methylazetidin-1-yl; 3-hydroxy-3-propylazetidin-1-yl; 3-hydroxy Azetidin-1-yl; 3-hydroxypiperidin-1-yl; 4- (2-fluorophenyl) piperazin-1-yl; 4- (2-methoxyethylamino) piperidin-1 -Yl; 4- (2-methoxyphenyl) piperazin-1-yl; 4- (2-morpholinoethylamino) piperidin-1-yl; 4- (3-fluorophenyl) -4- Hydroxypiperidin-1-yl; 4- (4- (pyridin-4-yl) piperazin-1-yl) piperidin-1-yl; 4- (4-bromophenyl) -4-hydroxy Roxypiperidin-1-yl; 4- (4-chloro-2- (trifluoromethyl) phenyl) -4-hydroxypiperidin-1-yl; 4- (4-chlorophenyl) -4- Hydroxypiperidin-1-yl; 4- (4- Fluorophenyl) -4-hydroxypiperidin-1-yl; 4- (4-methylpiperazin-1-yl) piperidin-1-yl; 4- (azetidin-1-yl) piperi Din-1-yl; 4- (cyclobutylamino) piperidin-1-yl; 4- (cyclopropylmethylamino) piperidin-1-yl; 4- (hydroxymethyl) piperidin-1- Yl; 4- (pyridin-2-yl) piperazin-1-yl; 4- (pyrrolidin-1-yl) piperidin-1-yl; 4-hydroxy-4- (4-methoxyphenyl ) Piperidin-1-yl; 4-hydroxy-4- (thiophen-2-yl) piperidin-1-yl; 4-hydroxy-4-isopropylpiperidin-1-yl; 4 -Hydroxy-4-methylpiperidin-1-yl; 4-hydroxypiperidin-1-yl; 4-isopropylpiperazin-1-yl; 4-methylpiperazin-1-yl; 4- Phenyl-1-piperidin-4-carbonitrile; 6-chloro-1- (piperidin-4-yl) -1H-benzo [d] imidazol-2 (3H) -one; morpholino; octa Hydroisoquinolin-2 (1H) -yl and piperazin-1-yl.

In another aspect, the compound has a structure represented by the following general formula:

It is to be understood that the compounds can be provided by the disclosed preparation methods, can be used in the disclosed compositions, and can be used in the disclosed methods of use.

b. Cycloalkylethynylbenzamide  derivative

In one aspect, the invention relates to cycloalkylethynylbenzamide derivatives. In one aspect, the compound is a compound or a pharmaceutically acceptable salt thereof comprising the structure:

Wherein R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to An optionally substituted heterocyclic ring having 7 carbons;

R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl;

Z comprises 0 to 2 carbons;

R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 9 to 13 substituents independently selected from amine-carbonyl; And

Wherein the compound enhances the mGluR5 response to glutamate relative to the response to glutamate in the absence of the compound against non-maximal concentrations of glutamate in human fetal kidney cells infected with rat mGluR5 in the presence of the compound. Shown as an increase in response.

In one aspect, the compound exhibits potentiation of less than about 1.0 × 10 ⁻⁶ . For example, the compound is from about 1.0 × 10 ^- can exhibit a less than ⁷ mineralization. As another example, the compound may exhibit potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In another aspect, R ¹ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have 2 to 7 carbons.

In another aspect, R ² is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In another aspect, the one or more R ³ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, and has 2 to 7 carbons.

In another aspect, the one or more R ₄ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, and has 2 to 7 carbons.

In one aspect, optionally substituted alkyl of R ¹ , R ² , R ³ , and / or R ₄ includes optionally substituted alkyl or optionally substituted cycloalkyl. In another aspect, all of R ³ are hydrogen.

In another aspect, N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons. In another aspect, N, R ¹ , and R ² together comprise 4-hydroxypiperidin-1-yl.

In another aspect, Z is 1 and R ⁴ comprises 11 substituents.

In another aspect, at least one R ⁴ is halogen selected from F and Cl. In another aspect, all of R ⁴ are hydrogen.

In one aspect, the compound has a structure represented by the following general formula:

It is to be understood that the compounds can be provided by the disclosed methods of preparation, can be used in the disclosed compositions, and can be used in the disclosed methods of use.

c. Styrylbenzamide  derivative

In one aspect, the invention relates to styrylbenzamide derivatives. In one aspect, the compound is a compound or a pharmaceutically acceptable salt thereof comprising the structure:

Wherein R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to An optionally substituted heterocyclic ring having 7 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally Substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and 5 substituents independently selected from alkylamine-carbonyl; The compound, compared to the response to glutamate in the absence of the compound, enhances the mGluR5 response to glutamate in response to non-maximal concentrations of glutamate in human fetal kidney cells infected with rat mGluR5 in the presence of the compound. Shown as an increase.

In one aspect, the compound is from about 1.0 × 10 ^{- 6} below shows the mineralization. For example, the compound is the EC ₅₀ of about 1.0 × 10 ^- can exhibit a less than ⁷ mineralization. As another example, the compound may exhibit potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In another aspect, R ¹ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, R ² is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, the one or more R ³ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have 2 to 7 carbons.

In another aspect, the one or more R ₄ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have 2 to 7 carbons.

In another aspect, N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons. In another aspect, N, R ¹ , and R ² together comprise 4-hydroxypiperidin-1-yl.

In another aspect, optionally substituted alkyl of R ¹ , R ² , R ³ , and / or R ₄ includes optionally substituted alkyl or optionally substituted cycloalkyl. In another aspect, all of R ³ are hydrogen.

In another aspect, at least one R ⁴ is halogen selected from F and Cl. In another aspect, all of R ⁴ are hydrogen. In another aspect, the compound has a structure represented by the following general formula:

It is to be understood that the compounds can be provided by the disclosed preparation methods, can be used in the disclosed compositions, and can be used in the disclosed methods of use.

d. 4- (3- Phenyl -1,2,4- Oxadiazole -5 days) Benzamide  derivative

In one aspect, the invention relates to 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzamide derivatives. In one aspect, the compound is a compound comprising the following structure or a pharmaceutically acceptable salt thereof:

Wherein R ¹ and R ² are hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl , Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to An optionally substituted heterocyclic ring having 7 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 5 substituents independently selected from amine-carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase of.

In one aspect, the compound shows a potentiation of less than about 1.0 × 10 ⁻⁶ . For example, the compound may be EC ₅₀ It can show a strengthening effect of less than about 1.0 × 10 ⁻⁷ . As another example, the compound is EC ₅₀ It can show a strengthening effect of less than about 1.0 × 10 ⁻⁸ .

In another aspect, R ¹ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In another aspect, R ² is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have 2 to 7 carbons.

In another aspect, the one or more R ³ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, the one or more R ₄ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons. In another aspect, N, R ¹ , and R ² together comprise 4- (pyridin-4-yl) piperazin-1-yl.

In another aspect, optionally substituted alkyl of R ¹ , R ² , R ³ , and / or R ₄ includes optionally substituted alkyl or optionally substituted cycloalkyl. In another aspect, R ¹ and R ² are independently H; 3-methoxypropyl; 3,3-dimethylbutyl; And N-propyl.

In another aspect, the compound has a structure represented by the following general formula:

In another aspect, the compound has a structure represented by the following general formula:

In another aspect, all of R ³ are hydrogen. In another aspect, at least one R ⁴ is halogen selected from F and Cl. In another aspect, four R ⁴ is hydrogen and one R ⁴ is F.

It is to be understood that the compound can be provided by the disclosed preparation methods, can be used in the disclosed compositions, and can be used in the disclosed methods of use.

e. 4-( Pyridinylethynyl ) Benzamide  derivative

In one aspect, the invention relates to 4- (pyridinylethynyl) benzamide derivatives. In one aspect, the compound is a compound comprising a structure selected from or a pharmaceutically acceptable salt thereof:

Where R ¹ and R ² Is independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² Comprises an optionally substituted heterocyclic ring having 2 to 7 carbons together; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase of.

In one aspect, the compound shows a potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁶ . For example, the compound may show potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁷ . As another example, the compound may show potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In another aspect, R ¹ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, R ² is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, the one or more R ³ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, the one or more R ₄ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, optionally substituted alkyl of R ¹ , R ² , R ³ , and / or R ₄ includes optionally substituted alkyl or optionally substituted cycloalkyl.

In another aspect, N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons. In another aspect, N, R ¹ , and R ² together comprise 2-methylpiperidinyl.

In another aspect, the compound has a structure represented by the following general formula:

In another aspect, N, R ¹ , and R ² Together include a cyclic alkyl moiety optionally substituted. In another aspect, the optionally substituted cyclic alkyl moiety is 2-methylpiperidinyl. In another aspect, all of R ³ are hydrogen. In another aspect, at least one R ⁴ is halogen selected from F and Cl. In another aspect, all of R ⁴ are hydrogen. In another aspect, the compound has a structure represented by the following general formula:

It is to be understood that the compound can be provided by the disclosed preparation methods, can be used in the disclosed compositions, and can be used in the disclosed methods of use.

f. N ^One - Phenylterephthalamide  derivative

In one aspect, the invention relates to a N ¹ -phenylterephthalamide derivative. In one aspect, the compound is a compound comprising the following structure or a pharmaceutically acceptable salt thereof:

Where R ¹ and R ² Is independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² Comprises an optionally substituted heterocyclic ring having 2 to 7 carbons together; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 5 substituents independently selected from amine-carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase of.

In one aspect, the compound shows a potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁶ . For example, the compound may show potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁷ . As another example, the compound may show potentiation with an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In another aspect, R ¹ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have 2 to 7 carbons.

In another aspect, R ² is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have 2 to 7 carbons.

In another aspect, the one or more R ³ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has 2 to 7 carbons.

In another aspect, the one or more R ₄ substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have 2 to 7 carbons.

In another aspect, N, R ¹ , and R ² Includes optionally substituted heterocyclic rings having from 2 to 7 carbons. In another aspect, N, R ¹ , and R ² together comprise 2-methylpiperidinyl.

In another aspect, optionally substituted alkyl of R ¹ , R ² , R ³ , and / or R ₄ includes optionally substituted alkyl or optionally substituted cycloalkyl. In another aspect, R ³ All are hydrogen.

In another aspect, at least one R ⁴ Is a halogen selected from F and Cl. In another aspect, 4 R ⁴ is hydrogen and 1 R ⁴ Is F. In another aspect, the compound has a structure represented by the following general formula:

It is to be understood that the compound is provided by the disclosed preparation methods, can be used in the disclosed compositions, and can be used in the disclosed methods of use.

2. annular Benzamide  derivative

In one aspect, the present invention relates to compounds useful as positive allosteric modulators (potentiators) of metabolic glutamate receptor subtype 5 (mGluR5). More specifically, the present invention relates to compounds which allosterically modulate mGluR5 receptor activity so that they do not function as orthosteric agonists and affect the sensitivity of mGluR5 receptors to agonists. The compounds of the invention are useful for the treatment of neurological and mental disorders associated with glutamate dysfunction and other diseases involving metabolic glutamate receptors, as described in more detail herein.

In general, the compounds disclosed above enhance the mGluR5 response to glutamate compared to the response to glutamate in the absence of the compound for non-maximal concentrations of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Shown as an increase in response. In various aspects, the compounds are isoindolin-1-one derivatives, isoindolin-1,3-dione derivatives, 3,4-dihydroisoquinolin-1 (2H) -one derivatives, isoquinolin-1, 3 (2H, 4H) -dione derivatives, other related cyclic compounds, or pharmaceutically acceptable salts or N-oxides thereof.

In one aspect, the present invention relates to compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; R ¹ and R ² Is independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ Is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl , Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxami , Amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl; R ⁸ is hydrogen, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkyne One, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optional And an organic radical comprising 1 to 6 carbon atoms selected from aryl substituted with, and optionally substituted heteroaryl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Represented as an increase of.

For example, the disclosed compounds can have a structure represented by the following general formula:

Wherein R ¹ is hydrogen or alkyl having 1 to 6 carbons; R ^3a and R ^3b are independently hydrogen, halogen, or lower alkyl; R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.

For example, the disclosed compounds can have a structure represented by the following general formula:

Wherein R ¹ is hydrogen or alkyl having 1 to 6 carbons; R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.

For example, the disclosed compounds can have a structure represented by the following general formula:

Wherein R ¹ is hydrogen or alkyl having 1 to 6 carbons; R ^2a , R ^2b , R ^3a , and R ^3b Is independently hydrogen, halogen, or lower alkyl; R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.

For example, the disclosed compounds can have a structure represented by the following general formula:

Wherein R ¹ is hydrogen or alkyl having 1 to 6 carbons; R ^3a and R ^3b are independently hydrogen, halogen, or lower alkyl; R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.

For example, the disclosed compounds can have a structure represented by the following general formula:

Wherein R ¹ is hydrogen or alkyl having 1 to 6 carbons; R ^2a , R ^2b , R ^3a , and R ^3b are independently hydrogen, halogen, or lower alkyl; R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.

In various aspects, Y ¹ may be selected from N and CR ⁴ . In still other various aspects, Y ² may be selected from N and CH. In still other various embodiments, each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms. In still other various embodiments, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical having 1 to 12 carbon atoms. In still other various aspects, R ^3a and R ^3b, if present, may comprise cycloalkyl having 2-12 carbon atoms together, but R ^3a and R ^3b do not form bridges with adjacent aromatic rings.

In still other various embodiments, L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:

In still other various embodiments, R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or are independently hydrogen, halogen, hydroxyl, cyano, nitro , Thiol, amino, and, optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkyne 1, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl , Optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycar Carbonyl, carboxamide, amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl group.

In still other various embodiments, R ⁸ is hydrogen and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroal Kenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl Or an organic radical comprising 1 to 6 carbon atoms selected from C6 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

It should be understood that each derivative may optionally be further substituted. It should also be considered that one or more derivatives may optionally be omitted from the present invention. It is also to be understood that each substituent may be optionally further substituted. It is also to be considered that one or more substituents may be optionally omitted from the present invention.

a. Isoindolin -1-one derivative

In one aspect, the present invention relates to isoindolin-1-one derivatives or pharmaceutically acceptable salts thereof or N-oxides thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

b. Isoindolin -1,3- Dion  derivative

In one aspect, the invention relates to an isoindolin-1,3-dione derivative or a pharmaceutically acceptable salt thereof or an N-oxide thereof having the structure:

Wherein R ¹ is hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, and , R ¹ does not contain silicon; R ⁵ is an organic radical containing 4 to 14 carbon atoms, when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, and when R ¹ is methyl, R ⁵ is Organic radicals containing 4 to 14 carbon atoms.

c. 3,4- Dihydroisoquinoline -1 (2H) -one derivative

In one aspect, the invention relates to 3,4-dihydroisoquinolin-1 (2H) -one derivatives or pharmaceutically acceptable salts thereof or N-oxides thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms.

d. Isoquinoline-1,3 (2H, 4H)- Dion  derivative

In one aspect, the invention relates to an isoquinoline-1,3 (2H, 4H) -dione derivative or a pharmaceutically acceptable salt thereof or an N-oxide thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms and R ⁵ does not comprise a triphenylamine residue or a benzimidamide residue.

e. Cyclic  Compounds

In one aspect, the invention relates to cyclic compounds having the structure: or pharmaceutically acceptable salts or N-oxides thereof:

Wherein n is 2, 3 or 4; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; R ⁵ is an organic radical containing 4 to 14 carbon atoms.

f. Structural composition

In one aspect, C ¹ -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl optionally substituted C 1 -C 6 heteroalkyl or C 2 -C 6 heteroalkenyl or C 2 -C 6 heteroalkyne 1, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocyclo is an organic radical comprising from 1 to 12 carbon atoms selected from heterocycle, - alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and substituted with - (CH _{2) m-aryl} or - (CH _{2) m} m is 1, 2, 3 or 4; R ^2a and R ^2b , if present, together comprise ═O or ═S, or each of R ^2a and R ^2b is independently an optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 Alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkinyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl Optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally Substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Line from amine-carbonyl An organic radical containing 1 to 6 carbon atoms taken; R ^3a and R ^3b together comprise ═O or = S, or each R ^3a and R ^3b is independently an optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, optionally Substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, Optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl 1 to 6 selected from An organic radical containing two carbon atoms; R ⁴ , if present, is optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl or C 2 -C 6 heteroalkenyl or C 2 -C 6 hetero Alkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 hetero Cycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally Organic radicals comprising 1 to 12 carbon atoms independently selected from substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl .; R ⁵ is optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted There is provided a compound which is an organic radical comprising 4 to 14 carbon atoms selected from heteroaryl.

In another aspect, the compound has a structure comprising the following general formula:

In another aspect, the compound has a structure comprising the following general formula:

In another aspect, the compound has a structure comprising the following general formula:

In another aspect, the compound has a structure comprising the following general formula:

In another aspect, the compound has a structure comprising the following general formula:

In yet another aspect, n is 0 or 1.

In another aspect, the compound has a structure having the general formula:

In one aspect, C ¹ -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl optionally substituted C 1 -C 6 heteroalkyl or C 2 -C 6 heteroalkenyl or C 2 -C 6 heteroalkyne 1, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocyclo Alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; R ¹ is hydroxy, oxo, halo, C1-C6 alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, C1-C4 Alkyl-CF ₃ , C1-C4 alkyl-CHF ₂ , C1-C4 alkyl-CH ₂ F, C1-C6 alkoxyl, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, C1-C4 alkoxyl-CF ₃ , C1-C4 Alkoxyl-CHF ₂ , C1-C4 alkoxyl-CH ₂ F, -hydroxy-C1-C4 alkyl, -S (O) ₂ -R ⁹ , -C (O) -C1-C6 alkoxyl, -C ( O) -NR ⁹ R ¹⁰ , -C (O) -OC (CH ₃ ) ₃ , C3-C6 Mono with a substituent selected from cycloalkyl, -NR ⁹ R ¹⁰ , -NH-C (O) -R ⁹ , -NH-C (O) -NR ⁹ R ¹⁰ , and -NH-S (O) ₂ -R ⁹ Or di-substituted; R ⁹ is hydrogen, -CF ₃ , C1-C4 alkyl, C3-C6 Cycloalkyl, aryl, and heterocycle; And R ¹⁰ is selected from hydrogen and C1-C4 alkyl.

In another aspect, R ¹ is a heterocycle selected from optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, and optionally substituted heteroaryl.

In another aspect, R ¹ is hydroxy, oxo, halo, C1-C6 alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, C1-C4 alkyl-CF ₃ , C1-C4 alkyl-CHF ₂ , C1 -C4 alkyl-CH ₂ F, C1-C6 alkoxyl, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, C1-C4 alkoxyl-CF ₃ , C1-C4 alkoxyl-CHF ₂ , C1-C4 alkoxyl -CH ₂ F, -hydroxy-C1-C4 Alkyl, -S (O) ₂ -R ⁹ , -C (O) -C1-C6 Alkoxyl, -C (O) -NR ⁹ R ¹⁰ , -C (O) -OC (CH ₃ ) ₃ , C3-C6 cycloalkyl, -NR ⁹ R ¹⁰ , -NH-C (O) -R ⁹ , Mono- or di-substituted with a substituent selected from -NH-C (O) -NR ⁹ R ¹⁰ , and -NH-S (O) ₂ -R ⁹ ; R ⁹ is hydrogen, -CF ₃ , C1-C4 Alkyl, C3-C6 cycloalkyl, aryl, and heterocycle; R ¹⁰ is provided with a compound selected from hydrogen and C1-C4 alkyl.

In another aspect, R ¹ is pyridine; Pyrimidine; Furan; Thiophene; Pyrrole; Isoxazole; Isothiazole; Pyrazole; Oxazole; Thiazole; Imidazole; Oxazole; 1,2,3-oxadiazole; 1,2,5-oxadiazole; 1,3,4-oxadiazole; Thiadiazole; 1,2,3-thiadiazole; 1,2,5-thiadiazole; 1,3,4-thiadiazole; Triazoles; 1,2,3-triazole; 1,3,4-triazole; Tetrazole; 1,2,3,4-tetrazole; 1,2,4,5-tetrazole; Pyridazine; Pyrazine; Triazine; 1,2,4-triazine; 1,3,5-triazine; Tetrazine; 1,2,4,5-tetrazin; Pyrrolidine; Piperidine; Piperazine; Morpholine; Azetidine; Tetrahydroparan; Tetrahydrofuran; And residues of dioxane.

In another aspect, R ¹ is hydroxy, oxo, halo, C1-C6 alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, C1-C4 alkyl-CF ₃ , C1-C4 alkyl-CHF ₂ , C1 -C4 alkyl-CH ₂ F, C1-C6 Alkoxyl, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, C1-C4 Alkoxyl-CF ₃ , C1-C4 alkoxyl-CHF ₂ , C1-C4 Alkoxyl-CH ₂ F, -hydroxy-C1-C4 Alkyl, -S (O) ₂ -R ⁹ , -C (O) -C1-C6 Alkoxyl, -C (O) -NR ⁹ R ¹⁰ , -C (O) -OC (CH ₃ ) ₃ , C3-C6 cycloalkyl, -NR ⁹ R ¹⁰ , -NH-C (O) -R ⁹ , Mono- or di-substituted with a substituent selected from -NH-C (O) -NR ⁹ R ¹⁰ , and -NH-S (O) ₂ -R ⁹ ; R ⁹ is hydrogen, -CF ₃ , C1-C4 Alkyl, C3-C6 Cycloalkyl, aryl, and heterocycle; R ¹⁰ is provided with a compound selected from hydrogen and C1-C4 alkyl.

In another aspect, R ¹ is 2- (4-hydroxypiperidin-1-yl) -2-oxoethyl, 2- (4-hydroxypiperidin-1-yl) ethyl, 2- (azene Thidin-1-yl), 2-acetamide, 2-morpholino-2-oxoethyl, 2-morpholinoethyl, benzyl, benzyl 2-acetate, cyclobutylmethyl, cyclopropylmethyl, ethyl 2-propano Ate, hydrogen, methyl, N- (2- (dimethylamino) ethyl acetamide, N-2-methoxyethyl acetamide, N-cyclopropyl-2-acetamide, and N-cyclopropylmethyl acetamide .

In another aspect, R ⁵ is selected from:

Wherein Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , and Z ⁶ are independently selected from C and N; R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-10 selected from nyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl burnt Independently selected from 1, 2, 3 in an organic radical containing the atom, 4, 5, 6, or is provided with, a compound comprising seven substituents.

In another aspect, R ⁶ is selected from chloro, dimethylamino, fluoro, methoxy, methyl, and trifluoromethyl.

In another aspect, R ⁵ is selected from:

R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl Or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl , Optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl There is provided a compound comprising 1, 2, 3, 4 or 5 substituents independently selected from organic radicals comprising an atom.

In another aspect, R ⁵ is selected from:

In another aspect, R ⁵ comprises a structure having the following general formula:

R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-8 selected from nil, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl carbon There is provided a compound comprising one or two substituents independently selected from organic radicals comprising an atom.

In certain aspects, the compounds may be alkyne derivatives, alkene derivatives, 1,2,4-oxadiazole derivatives, or amide derivatives. That is, in certain aspects, L can be an alkyne residue, and an alkene residue, 1,2,4-oxadiazole residue, or an amide residue. It is understood that alkyne, alkenes, 1,2,4-oxadiazoles, and amide residues may be further substituted. It is also contemplated that one or more alkynes, alkenes, 1,2,4-oxadiazoles, or amide residues may optionally be omitted from the present invention.

g. Alkin  derivative

In one aspect, the compound has a structure having the general formula:

In another aspect, R ⁵ is selected from:

R ⁶ Is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2 -C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3- C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optional Alkylsulfonyl substituted with 1 to 10 carbon atoms selected from optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl There is provided a compound comprising 1, 2, 3, 4 or 5 substituents independently selected from organic radicals comprising a molecule.

In another aspect, there is provided a compound as a structure having the following general formula:

Where n is 0 or 1; R ¹ is hydrogen or, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl , Optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkyne yl, optionally substituted aryl, optionally substituted heteroaryl, and - (CH _{2) m} - aryl or - (CH _{2) m} - is an organic radical comprising from 1 to 12 carbon atoms selected from the hetero ring, m Is 1, 2, 3 or 4; R ^2a and R ^2b , if present, together comprise ═O or ═S, or each of R ^2a and R ^2b is independently hydrogen and optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl Or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkinyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6- C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted egg Coxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-car Carbonyl, and alkylamine-carbo Selected from organic radicals containing from 1 to 6 carbon atoms selected from and; R ^3a and R ^3b Together comprise = O or = S, or each R ^3a and R ^3b are independently hydrogen and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3- C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optional In alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl 1 to 6 selected Of it is selected from organic radicals containing carbon atoms; R ⁴ is hydrogen and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl , Optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkyne One, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted Independently selected from organic radicals comprising 1 to 12 carbon atoms selected from amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl 1, includes two, or three substituents; Z ¹ , Z ² , and Z ³ are independently selected from C and N; R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-10 selected from nyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl carbon One or two substituents independently selected from organic radicals comprising an atom.

In another aspect, the compound comprises a structure having the general formula:

In another aspect, the compound is selected from:

In another aspect, the compound is selected from:

In another aspect, the compound is selected from:

In another aspect, the compound comprises a structure having the general formula:

Wherein R ¹ is hydrogen and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkyne 1, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocyclo alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and - (CH _{2) m} - aryl or - (CH _{2) m} - selected from organic radicals which contain from 1 to 12 carbon atoms selected from the hetero ring M is 1, 2, 3 or 4; n is 0 or 1; when n is 0, R ^3a and R ^3b are hydrogen or together comprise ═O; when n is 1, R ^2a and R ^2b are hydrogen or together comprise ^═O and R ^3a and R ^3b are hydrogen; Z is selected from C and N; R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-10 selected from nyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl carbon One or two substituents independently selected from organic radicals comprising an atom.

In another aspect, the compound comprises a structure having the general formula:

In another aspect, R ¹ is 2- (4-hydroxypiperidin-1-yl) -2-oxoethyl, 2- (4-hydroxypiperidin-1-yl) ethyl, 2- (azene Thidin-1-yl), 2-acetamide, 2-morpholino-2-oxoethyl, 2-morpholinoethyl, benzyl, benzyl 2-acetate, cyclobutylmethyl, cyclopropylmethyl, ethyl 2-propano Selected from ate, hydrogen, methyl, N- (2- (dimethylamino) ethyl acetamide, N-2-methoxyethyl acetamide, N-cyclopropyl-2-acetamide, and N-cyclopropylmethyl acetamide R ⁶ comprises one or two substituents selected from chloro, dimethylamino, fluoro, methoxy, methyl, and trifluoromethyl; and Z is C is provided.

In another aspect, the compound is selected from:

Or pharmaceutically acceptable salts or N-oxides thereof.

In another aspect, the compound is selected from:

2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide,

2- (2- (4-hydroxypiperidin-1-yl) -2-oxoethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (2- (4-hydroxypiperidin-1-yl) ethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (2- (azetidin-1-yl) ethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (2-morpholino-2-oxoethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (2-morpholinoethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (cyclobutylmethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (cyclopropylmethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2-benzyl-6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2-methyl-5- (phenylethynyl) isoindolin-1,3-dione,

2-methyl-6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

5-((2,3-difluorophenyl) ethynyl) isoindolin-1-one,

5-((3,4-difluorophenyl) ethynyl) isoindolin-1-one,

5- (phenylethynyl) isoindolin-1-one,

5- (phenylethynyl) isoindolin-1,3-dione,

6-((2,4-difluorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((2-chlorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((2-fluorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((3- (trifluoromethyl) phenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((3,5-difluorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((3-chlorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((3-methoxyphenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4- (dimethylamino) phenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4-chlorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4-fluoro-3-methylphenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4-fluorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4-methoxyphenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6- (m-tolylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6- (o-tolylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6- (pyridin-4-ylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

Benzyl 2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetate,

Ethyl 2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) propanoate,

N- (2- (dimethylamino) ethyl) -2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide,

N- (2-methoxyethyl) -2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide,

N- (cyclopropylmethyl) -2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide, and

N-cyclopropyl-2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide,

Or pharmaceutically acceptable salts or N-oxides thereof.

In another aspect, the compound is selected from:

2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide,

2- (2- (4-hydroxypiperidin-1-yl) -2-oxoethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (2- (4-hydroxypiperidin-1-yl) ethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (2- (azetidin-1-yl) ethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (2-morpholino-2-oxoethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (2-morpholinoethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (cyclobutylmethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (cyclopropylmethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2-benzyl-6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2-methyl-6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((2,4-difluorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((2-chlorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((2-fluorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((3- (trifluoromethyl) phenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((3,5-difluorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((3-chlorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((3-methoxyphenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4- (dimethylamino) phenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4-chlorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4-fluoro-3-methylphenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4-fluorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4-methoxyphenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6- (m-tolylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6- (o-tolylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

Benzyl 2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetate,

Ethyl 2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) propanoate,

N- (2- (dimethylamino) ethyl) -2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide,

N- (2-methoxyethyl) -2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide,

N- (cyclopropylmethyl) -2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide, and

N-cyclopropyl-2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide.

In another aspect, the compound is selected from:

6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2- (1-oxo-6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide,

2- (cyclopropylmethyl) -6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

2-methyl-6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,

6-((4-fluorophenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one, and

6-((4-fluoro-3-methylphenyl) ethynyl) -3,4-dihydroisoquinolin-1 (2H) -one.

In another aspect, the compound is selected from:

5- (phenylethynyl) isoindolin-1,3-dione and

2-methyl-5- (phenylethynyl) isoindolin-1,3-dione.

In another aspect, the compound is selected from:

5- (phenylethynyl) isoindolin-1-one,

5-((2,3-difluorophenyl) ethynyl) isoindolin-1-one, and

5-((3,4-difluorophenyl) ethynyl) isoindolin-1-one.

In another aspect, the compound is present as 6- (pyridin-4-ylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one.

h. Alkene  derivative

In one aspect, the compound has a structure having the general formula:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and Optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted Aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thio Not shown, Dorsal sulfonyl amino, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl group.

In another aspect, R ⁵ is selected from:

R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-10 selected from nyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl carbon There is provided a compound comprising 1, 2, 3, 4 or 5 substituents independently selected from organic radicals comprising an atom.

In another aspect, the compound comprises a structure having the general formula:

Wherein R ^7a and R ^7b are independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally Optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl Optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbon Bonil It is selected from an organic radical containing a selected one to five carbon atoms.

In another aspect, the compound is selected from:

Wherein R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 Heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocyclo Alkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl 1 to 10 selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl A is independently, including the selected 1, 2, 3, 4 or 5 substituents in an organic radical containing a carbon atom.

i. 1,2,4- Oxadiazole  derivative

In one aspect, the compound has a structure having the general formula:

In another aspect, R ⁵ is selected from:

R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-10 selected from nyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl carbon There is provided a compound comprising 1, 2, 3, 4 or 5 substituents independently selected from organic radicals comprising an atom.

j. Amide derivatives

In one aspect, the compound has a structure having the general formula:

Wherein R ⁸ is hydrogen and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkyne 1, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocyclo And an organic radical comprising 1 to 6 carbon atoms selected from alkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, R ⁵ is selected from:

R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-10 selected from nyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl carbon There is provided a compound comprising 1, 2, 3, 4 or 5 substituents independently selected from organic radicals comprising an atom.

k. mGluR5  Intensification of reaction

In one aspect, the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with rat mGluR5 in the presence of the compound. As an increase in. About less than 1.0 × 10 ^-6 of the EC _50, for example, about 5.0 × 10 ^-7 or less, about 1.0 × 10 ^-7 or less, about 5.0 × 10 ^-8 or less, or about 1.0 × 10 ^-8 less than the EC ₅₀ Has

D. Metabolic Glutamate  Receptor activity

The utility of the compounds according to the invention as potentiators of metabolic glutamate receptor activity, in particular mGluR5 activity, can be demonstrated by methodologies known in the art. Human fetal kidney (HEK) cells infected with rat mGluR5 are plated in clean bottom assay plates for analysis in a Functional Drug Screening System (FDSS). The cells Ca ^{2 +} - was treated with sensitive fluorescent dyes (e.g., Fluo-4), wash the plate, and placed in a FDSS apparatus. After generating a fluorescent baseline for 12 seconds, the compound of the present invention was added to the cells and the response in the cells was measured. After 5 minutes, an mGluR5 agonist ( eg , glutamate, 3,5-dihydroxyphenylglycine, or quisqualic acid) was added to the cells and the response of the cells was measured. Enhancement of the agonist reaction of mGluR5 by a compound of the present invention, when compared to the reaction with an agonist in the absence of the compound, results in the reaction of a non-maximal concentration of agonist (here glutamate) in the presence of the compound. An increase was observed.

The analysis described above was performed in two ways. In the first manner, a range of concentrations of the compound of the invention were added to the cells, followed by one fixed concentration of agonist. If the compound acts as an adjuvant, EC ₅₀ values for strengthening by the compound and maximum extent of strengthening at this concentration of agonist were determined by non-linear curve conjugation. In a second manner, several fixed concentrations of the compound of the present invention were added to various wells on the plate, followed by a range of concentrations of agonist for each concentration of the compound of the present invention; EC ₅₀ values for agonists at each concentration of compound were determined by non-linear curve conjugation. Increasing the concentration of the compound of the present invention can increase the EC ₅₀ Decreasing the value (left shift of agonist concentration-response curve) is indicative of the degree of mGluR5 enrichment in a compound of the invention at a given concentration. Increasing the concentration of the compound of the present invention can increase the EC ₅₀ Increasing the value (shift to the right of the agonist concentration-response curve) is indicative of the degree of mGluR5 antagonism at a given concentration of the compound of the invention. The second mode also indicates whether the compounds of the present invention also affect the maximum response of mGluR5 to the agonist.

In particular, the disclosed compounds had an active standing in Sikkim enhance the mGluR5 receptor in the aforementioned analysis, EC ₅₀ for generally reinforced with the Less than about 10 M. In another aspect, certain compounds were active in enhancing the mGluR5 receptor, with an EC ₅₀ for enrichment of less than about 500 nM. Preferred compounds additionally resulted in three times greater left shift of agonist EC ₅₀ . These compounds did not cause mGluR5 to react in the absence of agonist and did not induce a significant increase in the maximum response of mGluR5 to the agonist. These compounds are positive allosteric modulators (enhancers) of human and murine mGluR5 and were selective for mGluR5 compared to the other seven subtypes of the metabolic glutamate receptor.

In certain aspects, the compounds also showed in vivo efficacy in numerous preclinical rat behavioral models in which known, clinically useful antipsychotics similarly tested positive. For example, the compounds of the present invention restore amphetamine-induced hyperlocomotion at doses ranging from 1 to 100 mg / kg ip in Sprague-Dawley male rats. EC ₅₀ for enhancing the mGluR5 receptor, for the disclosed compounds, are listed in Table 1 below:

Preferred compounds of the invention have also shown in vivo efficacy in numerous preclinical rat behavioral models in which known, clinically useful antipsychotics are similarly positive. For example, the compounds of the present invention restored amphetamine-induced hyperlocomotion at doses of 1-100 mg / kg i.p in Sprague-Dawley male rats. Data on three exemplary compounds are as follows:

FIG. 8 shows efficacy in restoring amphetamine-induced hyperlocomotion to (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (Compound VU13 Ex vivo: 13.6 nm; 50% Glu max).

FIG. 9 shows efficacy in restoring amphetamine-induced hyperlocomotion to (4-hydroxy-4-propylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone. (Compound VU60 / C109B2; ex vivo: 1250 nm; 90% Glu max).

10 shows efficacy in restoring amphetamine-induced hyperlocomotion for (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (Compound VU14 / C104B2; Ex vivo: 29.6 nm; 41% Glu Max).

ND = not measured

Schizophrenic patients show decreased sensorymotor gating, such as measurement of surprise prepulse suppression (PPI), and PPI in preclinical models in rats is commonly used to predict antipsychotic efficacy. In fact, PPI can be measured in humans and rats using the same stimulus parameters that produce similar responses (Braff, DL; Geyer, MA; Swerdlow, NR 'Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies Psychopharmacology 2001, 156 ( 2-3), 234-258;. Braff, DL;.. Geyer, MA 'sensorimotor gating and schizophrenia Human and animal model studies Archives of general psychiatry 1990 , 47 (2), 181-8; Braff, DL; Geyer, MA; Swerdlow, NR 'Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology 2001 , 156 (2-3), 234-258; Weiss, IC; Feldon, J. 'Environmental animal models for sensor motor gating deficiencies in schizophrenia: a review. Psychopharmacology 2001 , 156 (2-3), 305-326; Thomsen, M .; Woertwein, G .; Fink-Jensen, A .; Woldbye, DPD; Wess, J .; Caine, SB 'Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice. Psychopharmacology 2007 , 192 (1), 97-110.). In addition, all clinically relevant antipsychotic agents (both atypical and atypical) show efficacy in preclinical models of PPI and amphetamine-induced hyperlocomotion, these preclinical models of novel antipsychotic agents. It is used to guide the development (Geyer, MA 'Behavioral studies of hallucinogenic drugs in animal:. implications for schizophrenia research Pharmacopsychiatry 1998 , 31 (Suppl. 2), 73-79; Geyer, MA; McIlwain, KL; Paylor, R. 'Mouse genetic models for prepulse inhibition: an early review. Molecular Psychiatry 2002 , 7 (10), 1039-1053; Powell, SB; Risbrough, VB; Geyer, MA 'Potential use of animal models to examine antipsychotic prophylaxis for schizophrenia. Clinical Neuroscience Research 2003 , 3 (4-5), 289-296.).

Positive allosteric modulators (PAMs) of mGluR5 obtained from five distinct structural series ( FIG. 15 ) showed antipsychotic-like effects that enable us to predict antipsychotic efficacy in humans in a rat behavioral model ( Lindsley, CW; Wisnoski, DD; Leister, WH; O'Brien, JA; Lemiare, W .; Williams, Jr., DL; Burno, M .; Sur, C .; Kinney, GG; Pettibone, DJ; Miller, PR; Smith, S .; Duggan, ME; Hartman, GD; Conn, PJ; Huff, JR 'Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N- (1,3-Diphenyl-1H- pyrazol-5-yl) benzamides that potentiate receptor fuction in vivo ' J. Med . Chem . 2004 , 47 , 5825; Kinney, GG; O' Brien, Lemaire, W .; Burno, M. Bickel, DJ; Clements, MK ; Wisnoski, DD; Lindsley, CW; Tiller, PR; Smith, S .; Jacobson, MA; Sur, C .; Duggan, ME; Pettibone, DJ; Williams, Jr., DW 'A novel selective allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5) has an antipsycho ... tic profile in rat behavioral models' J. Pharmacol Exp Therapeut 2005, 313 (1), 199; Epping-Jordan MP, Nayak, S., Derouet, F., Dominguez, H., Bessis AS, Le Poul E ., Ludwig BL Mutel V.,, Poli SM and Rocher JP in vivo Characterization of mGluR5 Positive Allosteric Modulators as Novel Treatments for Schizophrenia and Cognitive Dysfunction Neuropharmacology 2005 , 49 , 243).

CDPPB (Lindsley, CW; Wisnoski, DD; Leister, WH; O'Brien, JA; Lemiare, W .; Williams, Jr., DL; Burno, M .; Sur, C .; Kinney, GG; Pettibone, DJ; iller, PR; Smith, S .; Duggan, ME .; Hartman, GD; Conn, PJ; Huff, JR 'Discovery of positive allosteric modulators for the the metabotropic glutamate receptor subtype 5 from a series of N- (1,3- Diphenyl-1H-pyrazol-5-yl) benzamides that potentiate receptor function in in vivo ' J. Med . Chem. 2004 , 47 , 5825; Kinney, GG; O 'Brien, Lemaire, W .; Burno, M. Bickel, DJ; Clements, MK; Wisnoski, DD; Lindsley, CW; Tiller, PR; Smith, S .; Jacobson, MA; Sur, C .; Duggan, ME; Pettibone, DJ; Williams, Jr., DW 'A novel selective allosteric modulator of metabotropic glutamate receptor subtype 5 (mGluR5) has an antipsychotic profile in rat behavioral models' J. Pharmacol . Exp . Therapeut . 2005 , 313 (1), 199) were the first centrally active mGlur5 PAMs that restored amphetamine-induced hypermobility in rats, and recent data using structurally distinct ADX47273 gave similar results ( FIG. 16 ) . ). Recently, similar data have been reported using DFB. Two new mGluR5 PAMS ( FIG. 17 ; VU000013 and VU000067) likewise provided similar results, indicating that positive allosteric regulation of mGluR5 provides antipsychotic-like efficacy in this preclinical model.

In addition, both CDPPB and ADX47273 showed the same efficacy as PPI, preclinical models directly related to clinical efficacy, and behavior in schizophrenic patients. As shown in FIG. 18, CDPPB restores PPI in a dose-dependent manner at four different total pulse intensities above the background. ADX47273 gives similar results ( FIG. 19 ).

E. Methods of Making the Compounds

In one aspect, the invention relates to methods of making compounds useful as positive allosteric modulators (enhancers) of metabolic glutamate receptor subtype 5 (mGluR5), which compounds include neurological and mental disorders associated with glutamate dysfunction and It may be useful for the treatment of other diseases involving metabolic glutamate receptors.

The compounds of the present invention can be prepared using the reactions shown in the following schemes and other standard procedures known in the literature, illustrated in the experimental section, or apparent to those skilled in the art. Substituent numbering as seen in the schemes does not necessarily correspond to the numbering used in the claims, and often, for clarity, one substituent is attached to the compound when multiple substituents are allowed under the definitions disclosed herein. It is shown to be.

In one aspect, the invention provides phenylethynylbenzamide derivatives, cycloalkylethynylbenzamide derivatives, styrylbenzamide derivatives, 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benz Amide derivatives, 4- (pyridinylethynyl) benzamide derivatives, and methods for preparing N ¹ -phenylterephthalamide derivatives.

One. Phenylethynylbenzamide  derivative

In one aspect, the invention relates to a process for preparing phenylethynylbenzamide derivatives, the method comprising coupling an aryl halide and an arylacetylene, wherein one of the aryl acetylenes or aryl halides has a carboxyl functional group; And forming an amide derivative of the carboxyl functional group by reaction with an amine. Typically, this method involves a coupling reaction ( eg , a transition metal catalyst cross coupling reaction) and a reaction to form an amide moiety. This reaction can be represented by the following scheme:

In another aspect, the method can be represented by the following scheme, which illustrates a synthesis method useful for preparing large amounts of the disclosed compounds:

In one aspect, the coupling step is performed prior to the forming step. In another aspect, the method further comprises converting the carboxyl functional group to carboxylic acid. In one aspect, the carboxyl functional group is an ester moiety. In one aspect, the aryl halide has a carboxyl functional group. The halide may be Br or I. It is understood that pseudohalides can be substituted with respect to halides.

In one aspect, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In another aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the coupling step is palladium-catalyst cross-coupling.

In one aspect, the forming step is performed using PS-carbodiimide and 1-hydroxybenzotriazole.

In one aspect, the aryl halide has a structure represented by the following general formula:

Wherein R is optionally substituted alkyl; R ³ comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In another aspect, arylacetylene has a structure represented by the following general formula:

Wherein R ⁴ comprises five substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

It is understood that the method can be used to provide the disclosed compounds.

2. Cycloalkylethynylbenzamide  derivative

In one aspect, the invention relates to a process for preparing a cycloalkylethynylbenzamide derivative, the method comprising coupling a cycloalkylacetylene with an aryl halide, wherein the aryl halide has a carboxyl functional group; And forming an amide derivative of the carboxyl functional group by reaction with an amine. Typically, this method involves a coupling reaction ( eg , a transition metal catalyst cross coupling reaction) and a reaction to form an amide moiety. This method can be represented by the following scheme:

In one aspect, the coupling step is performed before the forming step.

In one aspect, the method further comprises converting the carboxyl functional group to carboxylic acid. In another aspect, the carboxyl functional group is an ester moiety.

In one aspect, the halide is Br, I, or similar halide.

In one aspect, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In another aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the coupling step is palladium-catalyst cross-coupling.

In one aspect, the forming step is performed using PS-carbodiimide and 1-hydroxybenzotriazole.

In one aspect, the aryl halide has a structure represented by the following general formula:

Wherein R is optionally substituted alkyl; And R ³ comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one aspect, cycloalkylacetylene has a structure represented by the following general formula:

Wherein Z comprises 0 to 2 carbons; And R ⁴ Comprises 9 to 13 substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

It is understood that the method can be used to provide the disclosed compounds.

3. Styrylbenzamide  derivative

In one aspect, the invention relates to a method of making a styrylbenzamide derivative, the method comprising coupling a styryl boronic acid or styryl boronic ester with an aryl halide, wherein the styryl boronic acid or One of the styryl boronic esters or aryl halides has a carboxyl functional group; And forming an amide derivative of the carboxyl functional group by reaction with an amine. Typically, this method involves a coupling reaction ( eg , a transition metal catalyst cross coupling reaction) and a reaction to form an amide moiety. This method can be represented by the following scheme:

In another aspect, the method can be represented by the following scheme, which illustrates a synthesis method useful for preparing large amounts of the disclosed compounds:

In one aspect, the coupling step is performed before the forming step.

In one aspect, the method further comprises converting the carboxyl functional group to carboxylic acid. In one aspect, the carboxyl functional group is an ester moiety. In another aspect, the aryl halide has a carboxyl functional group.

In one aspect, the halide is Br, I, or pseudolide.

In one aspect, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In another aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the coupling step is palladium-catalyst cross-coupling.

In one aspect, the forming step is performed using PS-carbodiimide and 1-hydroxybenzotriazole.

In one aspect, the aryl halide has a structure represented by the following general formula:

Wherein R is optionally substituted alkyl; And R ³ comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one aspect, the styryl boronic acid or styryl boronic ester has the structure represented by the following general formula:

Wherein R is H or optionally substituted alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

It is understood that the method can be used to provide the disclosed compounds.

4. 4- (3- Phenyl -1,2,4- Oxadiazole -5 days) Benzamide  derivative

In one aspect, the invention relates to a process for the preparation of 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzamide derivatives, which method comprises N'-hydroxybenzimidamides. Condensing with an aryl carboxylic acid, wherein one of N'-hydroxybenzimidamide or aryl carboxylic acid has an ester functionality; And forming an amide derivative of the ester functional group by reaction with an amine. Typically, this method involves condensation reactions ( eg , the formation of oxadiazoles) and reactions that form amide moieties. This method can be represented by the following scheme:

In one aspect, the condensation step is performed before the forming step.

In one aspect, the method further comprises converting the ester functional group to carboxylic acid. In another aspect, the aryl carboxylic acid has an ester functionality.

In one aspect, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In another aspect, the amine is an optionally substituted cyclic amine.

In one aspect, one or both of the condensation step and the formation step are performed using 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride and 1-hydroxybenzotriazole.

In one aspect, the aryl carboxylic acid has a structure represented by the following general formula:

Wherein R is optionally substituted alkyl; And R ³ comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one aspect, N'-hydroxybenzimidamide has a structure represented by the following general formula:

Wherein R ⁴ comprises five substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

It is understood that the method can be used to provide the disclosed compounds.

5. 4- ( Pyridinylethynyl ) Benzamide  derivative

In one aspect, the invention relates to a process for preparing a 4- (pyridinylethynyl) benzamide derivative, which method comprises coupling arylacetylene with an aryl halide, wherein one of arylacetylene or aryl halide is Possess a cyclic functional group; And forming an amide derivative of the carboxyl functional group by reaction with an amine. Typically, this method involves a coupling reaction ( eg , a transition metal catalyst cross coupling reaction) and a reaction to form an amide moiety. This method can be represented by the following scheme:

In one aspect, the coupling step is performed before the forming step.

In one aspect, the method further comprises converting the carboxyl functional group to carboxylic acid. In one aspect, the carboxyl functional group is an ester moiety.

In another aspect, the aryl halide has a carboxyl functional group.

In one aspect, the halide is Br, I, or similar halide.

In one aspect, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In another aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the coupling step is palladium-catalyst cross-coupling.

In one aspect, the forming step is performed using PS-carbodiimide and 1-hydroxybenzotriazole.

In one aspect, the aryl halide has a structure represented by the following general formula:

Wherein R is optionally substituted alkyl; And R ³ comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one aspect, arylacetylene has a structure represented by the following general formula:

Wherein R ⁴ comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

It is understood that the method can be used to provide the disclosed compounds.

6. N ^One - Phenylterephthalamide  derivative

In one aspect, the invention relates to a method of preparing an N ¹ -phenylterephthalamide derivative, the method comprising reacting an aniline compound with a benzoic acid compound, wherein the benzoic acid compound has a carboxyl functional group; And forming an amide derivative of the carboxyl functional group by reaction with an amine. Typically, this method involves two separate reactions to form an amide moiety. This method can be represented by the following scheme:

In one aspect, the reaction step is performed before the formation step.

In one aspect, the method further comprises converting the carboxyl functional group to carboxylic acid. In another aspect, the carboxyl functional group is an ester moiety.

In one aspect, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In another aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the reaction step is carried out using 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride and 1-hydroxybenzotriazole.

In one aspect, the forming step is performed using 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride and 1-hydroxybenzotriazole.

In one aspect, the benzoic acid compound has a structure represented by the following general formula:

Wherein R is optionally substituted alkyl; And R ³ comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one aspect, the aniline compound has a structure represented by the following general formula:

Wherein R is H or optionally substituted alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

7. Annular Benzamide

In another aspect, the methods disclosed above may be useful in providing compounds having a cyclic benzamide structure, which may be useful as a positive allosteric modulator (enhancer) of metabolic glutamate receptor subtype 5 (mGluR5).

The reactions used to produce the compounds of the invention are prepared using the reactions shown in Schemes I and II, and other standard procedures known in the art or known to those skilled in the art. The following examples are provided so that the present invention may be more fully understood, which are for illustrative purposes only and should not be construed as limiting.

Scheme I

As illustrated in Scheme I, suitably substituted 6-bromo-3,4-dihydro-2H-isoquinoline ( I-1 ) is microwave Sonogashira / Castro-Stephens coupling reaction using appropriately functionalized acetylene and catalytic copper iodide (I) and catalytic palladium (0) under irradiation to yield the corresponding product ( I- 2 ) In this case, suitably substituted 6-bromo-3,4-dihydro-2H-isoquinoline ( I-1 ) is It was commercially available or could be readily prepared according to the methods of the literature. The following examples are provided to better understand the present invention. These examples are illustrative only and should not be construed as limiting the invention in any way.

Reaction Scheme II

As shown in Scheme II , suitably 6-substituted-3,4-dihydro-2H-isoquinoline ( II- 1 ) with S _N 2 with an appropriately functionalized electrophile (R3-X) Through the reaction, the corresponding product ( II- 2 ) is obtained. In this case, an appropriately substituted 6-substituted-3,4-dihydro-2H-isoquinoline ( II- 1 ) Prepared according to Scheme I and the electrophiles were commercially available or could be readily prepared according to the methods of the literature. The following examples are provided to better understand the present invention. These examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

Reaction Scheme III

As shown in Scheme III , an appropriately substituted 5-bromoisobenzofuran-1 (3H) -one ( III- 1 ) is treated with ammonium hydroxide in methanol to give 4-bromo-2- ( Calculate hydroxylmethyl) benzamide ( III- 2 ), Subsequently the Mitsunobu reaction under standard conditions yields 5-bromoisoindolin-1-one ( III- 3 ). Intermediate ( III- 3 ) is microwave Sonogashira / Castro-Stephens coupling reaction using appropriately functionalized acetylene ( III- 4 ) and catalytic copper iodide (I) and catalytic palladium (0) under irradiation, corresponding To yield the product ( III- 5 ). In this case, the appropriately substituted 5-bromoisobenzofuran-1 (3H) -one ( III- 1 ) It was commercially available or could be readily prepared according to the methods of the literature. The following examples are provided to better understand the present invention. These examples are illustrative only and should not be construed as limiting the invention in any way.

Reaction Scheme IV

As shown in Scheme IV , suitably substituted 5- (phenylethynyl) isobenzofuran-1,3-dione ( IV- 1 ) is treated with urea dissolved in DMF under microwave irradiation, Calculate 5- (phenethylyl) isoindolin-1,3-dione ( IV- 2 ). Intermediate (IV -2) is alkylated with an appropriately functionalized alkyl halide (Cl, Br, I), alkyl-5-2- (phen-ethynyl), 1, 3-dione isoindoline (IV - 3 ) In this case, suitably substituted 5- (phenylethynyl) isobenzofuran-1,3-dione ( IV- 1 ) is commercially available or could be readily prepared according to the methods of the literature.

In one aspect, the invention relates to a method for preparing a compound comprising the following steps: providing a first reactant or a pharmaceutically acceptable salt or N-oxide thereof having the structure represented by the following formula step:

Wherein n is 0, 1, 2, 3 or 4; Y ¹ and Y ² are independently selected from C and N; R ¹ is hydrogen and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkyne 1, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocyclo alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and - (CH _{2) m} - aryl or - (CH _{2) m} - selected from organic radicals which contain from 1 to 12 carbon atoms selected from the hetero ring M is 1, 2, 3 or 4; R ^2a and R ^2b , if present, together comprise = O or = S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optional Optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3- C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, optionally substituted Heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, Alkoxycarbonyl, carbon Selected from organic radicals comprising 1 to 6 carbon atoms selected from voxamide, amino-carbonyl, and alkylamine-carbonyl; R ^3a and R ^3b together comprise = O or = S, or each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1- C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3 -C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optional Substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carbox Amide, Army No-carbonyl, and an organic radical comprising 1 to 6 carbon atoms selected from alkylamine-carbonyl; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-12 selected from nil, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl burnt Independently selected include, one, two, or three substituents on the organic radical containing an atom; X ¹ Silver halides, pseudohalides, carboxylic acids, carboxylic acid derivatives, terminal acetylene moieties, activated vinyl moieties, N'-hydroxybenzimidamides, or primary or secondary amines;

Providing a second reactant having a structure represented by the following general formula:

Wherein R ⁵ is optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted Organic radical containing 4 to 14 carbon atoms selected from heteroaryl; X ² comprises a halide, pseudohalide, carboxylic acid, carboxylic acid derivative, terminal acetylene moiety, activated vinyl moiety, N′-hydroxybenzimidamide, or primary or secondary amine;

Coupling the first reactant with the second reactant to form a linking moiety L to provide a compound having a structure represented by the following general formula:

Wherein L is optionally substituted C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 An organic divalent radical comprising 1 to 7 carbon atoms selected from heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amido; When X ¹ is a halide or pseudohalide, X ² is a terminal acetylene moiety or an activated vinyl moiety; When X ¹ is a carboxylic acid or carboxylic acid derivative, X ² is N′-hydroxybenzimidamide, or a primary or secondary amine; When X ² is a halide or pseudohalide, X ¹ is a terminal acetylene moiety, or an activated vinyl moiety; When X ² is a carboxylic acid or carboxylic acid derivative, X ¹ is N′-hydroxybenzimidamide, or a primary or secondary amine; And

Optionally, alkylating the lactam or imide moiety when R ¹ is hydrogen.

In another aspect, L is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted egg Coxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxami , Amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl; R ⁸ is hydrogen, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkyne One, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6 heterocycloalkynyl, And an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, when R ¹ is H, the compound may be alkylated with an electrophilic alkyl functional group such as an alkyl halide or pseudohalide.

In another aspect, the reactive vinyl moiety comprises a monosubstituted vinyl moiety, vinyl boronic acid, vinyl boronic ester, or vinyltrialkylstannan.

In another aspect, the coupling reaction step comprises a Sonogashira / Castro-Stephens coupling reaction; X ¹ comprises a halide or pseudohalide; X ² comprises a terminal acetylene moiety; The compound has a structure represented by the following general formula:

In another aspect, the coupling reaction step comprises a Sonogashira / Castro-Stephens coupling reaction; X ¹ comprises a terminal acetylene moiety; X ² comprises a halide or pseudohalide; The compound has a structure represented by the following general formula:

In another aspect, the coupling reaction step includes a Suzuki coupling reaction and X ¹ comprises a vinyl boronic acid or vinyl boronic ester; X ² comprises a halide or pseudohalide; The compound has a structure represented by the following general formula:

In another aspect, the coupling reaction step includes a Suzuki coupling reaction and X ¹ comprises a halide or pseudohalide; X ² comprises vinyl boronic acid or vinyl boronic ester; The compound has a structure represented by the following general formula:

In another aspect, the coupling reaction step comprises a Still coupling reaction; X ¹ comprises vinyltrialkylstannan; X ² comprises a halide or pseudohalide; The compound has a structure represented by the following general formula:

In another aspect, the coupling reaction step comprises a Still coupling reaction; X ¹ comprises a halide or pseudohalide; X ² comprises vinyltrialkylstannan; The compound has a structure represented by the following general formula:

In another aspect, the coupling step comprises a Heck reaction and X ¹ comprises a monosubstituted vinyl moiety; X ² comprises a halide or pseudohalide; The compound has a structure represented by the following general formula:

In another aspect, the coupling step comprises a Heck reaction and X ¹ comprises a halide or pseudohalide; X ² comprises a monosubstituted vinyl moiety; The compound has a structure represented by the following general formula:

In another aspect, the coupling reaction step includes a condensation reaction; X ¹ comprises a carboxylic acid or a carboxylic acid derivative; X ² comprises N'-hydroxybenzimidamide; The compound has a structure represented by the following general formula:

In another aspect, the coupling reaction step includes a condensation reaction; X ¹ comprises N′-hydroxybenzimidamide; X ² comprises a carboxylic acid or a carboxylic acid derivative; The compound has a structure represented by the following general formula:

In another aspect, the coupling reaction step comprises an amide formation reaction; X ¹ comprises a carboxylic acid or a carboxylic acid derivative; X ² comprises a primary or secondary amine; The compound has a structure represented by the following general formula:

Wherein R ⁸ is hydrogen and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 hetero Alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, And an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, the coupling step comprises an amide formation reaction; X ¹ comprises a primary or secondary amine; X ² comprises a carboxylic acid or a carboxylic acid derivative; The compound has a structure represented by the following general formula:

Wherein R ⁸ is hydrogen and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 hetero Alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, And an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, providing the first reactant comprises the following steps:

Anhydrides having structures represented by the following general formulas are treated with ammonia or primary amines:

Where n is 0 or 1;

Providing a compound having a structure represented by the following general formula:

Optionally alkylating the imide moiety when R 1 is hydrogen.

In another aspect, providing the first reactant comprises the following steps:

Treating lactones having the structure represented by the following general formula with ammonia or primary amines:

Wherein n is 0, 1, 2, 3 or 4;

Providing an intermediate having a structure represented by the following general formula:

Cyclizing the intermediate to provide a compound having a structure represented by the following general formula:

And

Optionally, alkylating the lactam moiety when R ¹ is hydrogen.

In another aspect, the cyclization step comprises subjecting the intermediate to Mitsunobu reaction conditions; Or converting a hydroxyl functional group to a pseudohalide.

In another aspect, the first reactant has a structure comprising the following general formula:

In another aspect, the first reactant has a structure comprising the following general formula:

In another aspect, the first reactant has a structure comprising the following general formula:

In another aspect, the first reactant has a structure comprising the following general formula:

In another aspect, the first reactant has a structure comprising the following general formula:

In another aspect, the second reactant has a structure represented by the following general formula:

Wherein Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , and Z ⁶ are independently selected from C and N; R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hete Roalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocyclo Alkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl 1 to 10 selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Shots Be independently selected include, 1, 2, 3, 4, 5, 6, or 7 substituents on the organic radicals containing atoms. In another aspect, R ⁶ is selected from chloro, dimethylamino, fluoro, methoxy, methyl, and trifluoromethyl.

In another aspect, the second reactant has a structure represented by the following general formula:

Wherein R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 Heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cyclo alkynyl, optionally substituted C3-C8 heterocyclo Alkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl 1 to 10 selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl A is independently, including the selected 1, 2, 3, 4 or 5 substituents in an organic radical containing a carbon atom.

In another aspect, the second reactant has a structure represented by the following general formula:

In another aspect, the second reactant has a structure represented by the following general formula:

Wherein R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 Heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocyclo Alkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl 1 to 10 selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl dog One or two substituents independently selected from organic radicals containing a carbon atom of.

In another aspect, the alkylation step is carried out by reaction with a base and an alkyl halide or alkyl pseudohalide. In another aspect, the base is sodium hydride.

In another aspect, the alkyl portion of the alkyl halide or alkyl pseudohalide is optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2 -C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3- C8 heterocyclo-alkenyl or C6-C8 heterocycloalkyl alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or - (CH _{2) m} - aryl or - (CH _{2) m} - 1 to selected from the heterocyclic Organic radicals comprising 12 carbon atoms, where m is 1, 2, 3 or 4.

In another aspect, the alkylation step is performed before the coupling reaction step.

In one aspect, the invention relates to a process for the preparation of a compound comprising the following steps:

Providing a reactant comprising an anhydride having a structure represented by the following formula or a pharmaceutically acceptable salt or N-oxide thereof:

Where n is 0 or 1; Y ¹ and Y ² are independently selected from C and N; R ^2a and R ^2b , if present, together comprise = O or = S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optional Optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3- C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, optionally substituted Heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amido sulfonyl, Alkoxycarbonyl, carbon Selected from organic radicals comprising 1 to 6 carbon atoms selected from voxamide, amino-carbonyl, and alkylamine-carbonyl; R ^3a and R ^3b together comprise = O or = S, or each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1- C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3 -C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optional Substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carbox Amide, Army No-carbonyl, and an organic radical comprising 1 to 6 carbon atoms selected from alkylamine-carbonyl; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl 1-12 selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Shots It comprise one, two or three substituents independently selected from organic radicals containing atoms; R ⁵ is optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted An organic radical containing 4 to 14 carbon atoms selected from heteroaryl; X ¹ comprises a halide or pseudohalide or —LR ⁵ , where L is an organic divalent radical containing 1 to 7 carbon atoms and R ⁵ is an organic radical containing 4 to 14 carbon atoms ;

Treating the reactant with ammonia or primary amine to provide a compound having the structure represented by

및

And

Optionally, alkylating the imide moiety when R ¹ is hydrogen.

In another aspect, R ¹ is 2- (4-hydroxypiperidin-1-yl) -2-oxoethyl, 2- (4-hydroxypiperidin-1-yl) ethyl, 2- (azene Thidin-1-yl), 2-acetamide, 2-morpholino-2-oxoethyl, 2-morpholinoethyl, benzyl, benzyl 2-acetate, cyclobutylmethyl, cyclopropylmethyl, ethyl 2-propano Ate, hydrogen, methyl, N- (2- (dimethylamino) ethyl acetamide, N-2-methoxyethyl acetamide, N-cyclopropyl-2-acetamide, and N-cyclopropylmethyl acetamide .

In another aspect, R ⁵ is selected from:

Wherein Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , and Z ⁶ are independently selected from C and N; R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-10 selected from nil, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Shots Be independently selected include, 1, 2, 3, 4, 5, 6, or 7 substituents on the organic radicals containing atoms. In another aspect, R ⁶ is selected from chloro, dimethylamino, fluoro, methoxy, methyl, and trifluoromethyl.

In another aspect, R ⁵ is selected from:

Wherein R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 Heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocyclo Alkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl 1 to 10 selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl dog 1, 2, 3, 4 or 5 substituents independently selected from organic radicals containing a carbon atom of.

In another aspect, R ⁵ is selected from:

In another aspect, R ⁵ comprises a structure having the following general formula:

Wherein R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 Heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocyclo Alkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl 1 to 10 selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl dog One or two substituents independently selected from organic radicals containing a carbon atom of.

In another aspect, L is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or are independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, And optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally Substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thio Selected from organic radicals comprising 1 to 5 carbon atoms selected from amido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl; R ⁸ is hydrogen, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkyne 1, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocyclo And an organic radical comprising 1 to 6 carbon atoms selected from alkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, the alkylation step is carried out by reaction with a base and an alkyl halide or alkyl pseudohalide. In another aspect, the base is sodium hydride.

In another aspect, the alkyl portion of the alkyl halide or alkyl pseudohalide is optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2 -C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3- C8 heterocyclo-alkenyl or C6-C8 heterocycloalkyl alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and - (CH _{2) m} - aryl or - (CH _{2) m} - 1 to selected from the heterocyclic Organic radicals comprising 12 carbon atoms, where m is 1, 2, 3 or 4.

In another aspect, the alkylation step is performed before the coupling reaction step.

In one aspect, the invention relates to a process for preparing a compound, comprising the following steps:

Providing a reactant comprising a lactone or a pharmaceutically acceptable salt or N-oxide thereof having a structure represented by the following formula:

Wherein n is 0, 1, 2, 3 or 4; Y ¹ and Y ² are independently selected from C and N; R ^2a and R ^2b When present, together comprise = O or = S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1- C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3 -C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optional Substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carbox amides Is selected from an organic radical comprising 1 to 6 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl; R ^3a and R ^3b together comprise = O or = S, or each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1- C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3 -C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optional Substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carbox Amide, Army No-carbonyl, and an organic radical comprising 1 to 6 carbon atoms selected from alkylamine-carbonyl; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 hetero Alkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl Or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulphi 1-12 selected from nil, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl carbon One, two or three substituents independently selected from organic radicals containing atoms; R ⁵ is optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted An organic radical containing 4 to 14 carbon atoms selected from heteroaryl; X ¹ comprises a halide or pseudohalide or —LR ⁵ , where L is an organic divalent radical containing 1 to 7 carbon atoms and R ⁵ is an organic radical containing 4 to 14 carbon atoms ;

Treating the reactant with ammonia or primary amine to provide an intermediate having the structure represented by the general formula:

Cyclizing the intermediate to provide a compound having a structure represented by the following general formula:

및

And

Optionally, alkylating the lactam moiety when R ¹ is hydrogen.

In another aspect, the cyclization step comprises subjecting the intermediate to Mitsunobu reaction conditions; Or converting a hydroxyl functional group to a pseudohalide.

In another aspect, L is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted egg Coxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxami , Amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl; R ⁸ is hydrogen, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkyne One, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optional And an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, the alkylation step is carried out by reaction with a base and an alkyl halide or alkyl pseudohalide. In another aspect, the base is sodium hydride.

In another aspect, the alkyl portion of the alkyl halide or alkyl pseudohalide is optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2 -C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3- C8 heterocyclo-alkenyl or C6-C8 heterocycloalkyl alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and - (CH _{2) m} - aryl or - (CH _{2) m} - 1 to selected from the heterocyclic Organic radicals comprising 12 carbon atoms, where m is 1, 2, 3 or 4. In another aspect, the alkylation step is performed before the coupling reaction step.

In another aspect, the method provides the disclosed compounds, eg, the compounds listed in Table 3. The compounds in Table 3 were synthesized as shown in Schemes I and II, except that they were substituted with appropriately substituted acetylene and electrophiles as described in Schemes 1 and 2. Essential starting materials are commercially available, described in the literature, or readily synthesized by those skilled in the art of organic synthesis.

Therefore, it is understood that the disclosed methods can be used to provide the disclosed compounds.

F. Pharmaceutical Composition

In one aspect, the present invention relates to a pharmaceutical composition comprising the disclosed compounds. For example, the composition may comprise one or more phenylethynylbenzamide derivatives, cycloalkylethynylbenzamide derivatives, styrylbenzamide derivatives, 4- (3-phenyl-1,2,4-oxadiazol-5-yl ) Benzamide derivatives, 4- (pyridinylethynyl) benzamide derivatives, and / or N ¹ -phenylterephthalamide derivatives. In another aspect, the composition comprises isoindolin-1-one derivatives, isoindolin-1,3-dione derivatives, 3,4-dihydroisoquinolin-1 (2H) -one derivatives, isoquinoline-1, 3 (2H, 4H) -dione derivatives, and / or cyclic compounds.

In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more disclosed compounds and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more products produced by the disclosed methods and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more phenylethynylbenzamide derivatives and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more cycloalkylethynylbenzamide derivatives and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more styrylbenzamide derivatives and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one 4- (3-phenyl-1,2,4-oxadiazol-5 yl) benzamide derivative and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more 4- (pyridinylethynyl) benzamide derivatives and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more N ¹ -phenylterephthalamide derivatives and a pharmaceutically acceptable carrier.

In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more isoindolin-1-one derivatives and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more isoindolin-1,3-dione derivatives and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more 3,4-dihydroisoquinolin-1 (2H) -one derivative and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of one or more isoquinoline-1,3 (2H, 4H) -dione derivatives and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of a cyclic compound and a pharmaceutically acceptable carrier.

In certain aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds as active ingredients (including their pharmaceutically acceptable salt (s)), pharmaceutically acceptable carriers, and, optionally, other therapeutic ingredients or Contains supplements. In any given case the most appropriate route will depend on the nature and severity of the condition in which the particular host and active ingredient are administered, but the compositions of the present invention include oral, rectal, topical and parenteral (subcutaneous, intramuscular, and intravenous) ) Compositions suitable for administration. Pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy.

As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, the corresponding salts thereof can be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from these inorganic bases include aluminum, ammonium, calcium, copper (copper and cuprous), trivalent iron, divalent iron, lithium, magnesium, manganese (manganese and manganese), potassium, sodium, zinc, etc. Contains salts. Particularly preferred salts are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic and substituted amines such as natural and synthetic substituted amines. Included. Other pharmaceutically acceptable organic non-toxic bases capable of forming salts include ion exchange resins such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, di Ethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

As used herein, the term “pharmaceutically acceptable non-toxic acid” includes inorganic acids, organic acids, and salts prepared therefrom, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, Ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isetionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, slime acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid , Succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid are preferred.

Indeed, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be well mixed with the pharmaceutical carrier and combined as the active ingredient according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, such as oral or parenteral (including intravenous). Therefore, the pharmaceutical compositions of the present invention may be presented as individual units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of active ingredient. The compositions may also be provided as powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions or water-in-oil emulsions. In addition to the usual dosage forms described above, the compounds of the invention, and / or their pharmaceutically acceptable salt (s), may also be administered by controlled release means and / or delivery devices. The composition can be prepared by any pharmaceutical method. In general, these methods include the step of combining the active ingredient with the carrier which constitutes one or more necessary ingredients. Generally, the composition is prepared by uniformly and well mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both. The product can then be conveniently shaped to the desired presentation.

Therefore, the pharmaceutical compositions of the present invention may include pharmaceutically acceptable carriers and compounds or pharmaceutically acceptable salts of the compounds of the present invention. Compounds of the present invention, or pharmaceutically acceptable salts thereof, may also be included in pharmaceutical compositions in combination with other one or more therapeutically active compounds.

The pharmaceutical carrier used may be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Carbon dioxide and nitrogen of the gas carrier.

In preparing a composition for oral dosage form, any convenient pharmaceutical medium may be used. For example, water, glycols, oils, alcohols, flavors, preservatives, colorants and the like can be used to form oral liquid formulations such as suspensions, elixirs and solutions; Carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used to form oral solid formulations such as powders, capsules and tablets. For ease of administration, tablets and capsules are the preferred oral dosage units using solid pharmaceutical carriers. Alternatively, tablets may be coated by standard aqueous or nonaqueous techniques.

Tablets containing a composition of the present invention may be prepared by pressing or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by pressurizing, in a suitable device, the active ingredient of a free-flowing type, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets can be made by molding in a suitable device a mixture of the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions of the invention suitable for parenteral administration can be prepared as solutions or suspensions of water of the active compounds. Suitable surfactants can include, for example, hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Preservatives may also be included to inhibit harmful growth of microorganisms.

Pharmaceutical compositions of the invention suitable for use for injection include sterile aqueous solutions or aqueous dispersions. Furthermore, the composition may be in the form of sterile powder for instant preparation of the sterile injectable solution or dispersion. In all cases, the final injection form must be sterile and must be an effective fluid for easy injection. Pharmaceutical compositions must be stable under the conditions of manufacture and storage; It should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, polyols ( eg , glycerol, propylene glycol and liquid polyethylene glycols), vegetable oils, and appropriate mixtures thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as, for example, aerosols, creams, ointments, lotions, dusting powders, toothpaste solutions, gargles and the like. The composition may also be in a form suitable for use in a transdermal device. These formulations can be prepared via conventional processing methods, using the compounds of the present invention, or their pharmaceutically acceptable salts. As an example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 5% to about 10% by weight of said compound to produce a cream or ointment having the desired viscosity.

Pharmaceutical compositions of the invention may be in a form suitable for rectal administration wherein the carrier is a solid. The mixture preferably forms a single dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently molded by mixing the composition with a softened or melted carrier and then molding or quenching in a mold.

In addition to the carrier components described above, the pharmaceutical formulations described above may, where appropriate, contain one or more additional carrier components such as diluents, buffer solutions, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants), and the like. It may include. Moreover, other adjuvants may be included to render the formulation isotonic with the blood of the intended receptor. Compositions containing a compound of the invention and / or pharmaceutically acceptable salts thereof may be prepared in powder or liquid concentrate form.

The potentiated amount of mGluR agonist administered in combination with an effective amount of a compound of Formula I may vary from about 0.1 milligrams (mg / kg / day) to about 100 mg / kg / day per kilogram of body weight per day It is expected that there will be less than the amount necessary to provide the same effect when administered without using an effective amount of the disclosed compounds. One skilled in the art can determine the desired amount of mGluR agonist to be co-administered.

The invention also relates directly to a method for the manufacture of a medicament that enhances glutamate receptor activity ( eg , treatment of one or more neurological and / or psychiatric disorders associated with glutamate dysfunction) in a mammal (eg, a human). Combining the compound of the invention with a pharmaceutically acceptable carrier or diluent.

Therefore, in one aspect, the invention relates to a pharmaceutical composition comprising the disclosed compounds. That is, a pharmaceutical composition can be provided comprising a therapeutically effective amount of one or more disclosed compounds or one or more products produced by the disclosed methods and a pharmaceutically acceptable carrier.

The disclosed pharmaceutical compositions may further comprise other therapeutically active compounds conventionally used for the treatment of the above mentioned pathological conditions. For example, the disclosed compounds and compositions can be administered with one or more antipsychotic agents. In one aspect, the antipsychotic agent may be any compound that has been shown to be useful or thought to be useful, at least for treating benign symptoms of schizophrenia.

Antipsychotic agents useful at least in treating benign symptoms of schizophrenia include orthopedic antipsychotic agents, atypical antipsychotic agents, and others that may or may not be classified as orphan or atypical antipsychotic agents. Other antipsychotic agents are included. In certain embodiments, the antipsychotic agent is stereotyped. In certain embodiments, the antipsychotic agent is a dopamine D2 receptor antagonist, which may be a selective dopamine D2 receptor antagonist or a partially dopamine D2 receptor antagonist. Orthopedic antipsychotic agents are generally recognized as selective dopamine D2 receptor antagonists.

Antipsychotic agents useful for the treatment of positive symptoms of schizophrenia include acetophenazine, alseroxylon, amitriptyline, aripiprazole, astemisol, benzquinamide, caffeazine, chlormezanone, chlorpromazine, and chlorpro Thixen, Clozapine, Desipramine, Droperidol, Alloperidol, Flufenazine, Flufenticol, Glycine, Oxapine, Mesodazine, Molinedon, Olanzapine, Ondansetron, Perfenazine, Pimozide, Prochlorferra Gin, procclidine, promazine, propiomazine, quetiapine, remoxiprie, reserpin, risperidone, sertindol, sulfide, terpenadine, thiethylperzaine, thiolidazine, thiotitice , Trifluoroperazine, triflupromazine, trimetaprazine, and ziprasidone. Examples of orthopedic antipsychotic agents useful for treating benign symptoms of schizophrenia include acetophenazine, chlorpromazine, chlorproticsen, dropperidol, flufenazine, haloperidol, roxapine, mesoridazine, and methotrimezazine , Molindon, perfenazine, pimozide, lacloprid, remoxiprie, thiolidazine, thioticsen, and trifluoroperazine. Examples of atypical antipsychotic agents useful for treating benign symptoms of schizophrenia include aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindol, and ziprasidone.

Other antipsychotic agents useful for the treatment of benign symptoms of schizophrenia include amisulprid, valaperidone, blonanserine, butaperazine, caffeazine, eflavaneserine, iloperidone, lamictal and onsane Onsanetant, paliperidone, pherespyrone, piperazetazine, lacloprid, remoxipri, sarizotan, sonepiprazole, sulfide, ziprasidone, and zopepin; Serotonin and dopamine (5HT / D2) agonists such as acenapine and bifefranox; Neurokinin 3 antagonists such as Talnetant and Osanetant; Ampakain, such as CX-516, galantamine, memantine, modafinil, ocaperidone, and tolcapone; And alpha-amino acids such as D-serine, D-alanine, D-cycloserine, and N-methylglycine. Therefore, antipsychotic agents include orthopedic antipsychotic agents, atypical antipsychotic agents, and other compounds useful for treating schizophrenia in a patient, in particular for treating benign symptoms of schizophrenia.

Therefore, in one aspect, the invention also relates to methods of coadministering a mammal with at least one disclosed compound and one or more other therapeutically active compounds commonly used in the treatment of the above mentioned pathological conditions. For example, the disclosed methods may involve administering a therapeutically effective amount of one or more disclosed compounds with one or more antipsychotic agents.

In another aspect, the invention also relates to a kit comprising at least one disclosed compound and at least one other therapeutically active compound commonly used in the treatment of the above mentioned pathological conditions. For example, the disclosed kits may comprise a therapeutically effective amount of one or more disclosed compounds and one or more antipsychotic agents. These kits may be packaged with, or formulated with, and / or administered together with antipsychotic agents. For example, drug manufacturers, drug resellers, physicians, or pharmacists can provide the disclosed kits for administration to a patient.

In therapeutic conditions that require enhanced metabolic glutamate receptor activity, an appropriate dosage level will generally be from about 0.01 to 500 mg / kg body weight of the patient per day and may be administered in one or multiple doses. Preferably, the dosage level is about 0.1 to about 250 mg / kg per day; More preferably 0.5 to 100 mg / kg per day. Suitable dosage levels can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the composition preferably comprises 1.0 to 1000 milligrams of the active ingredient, in particular 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, to control the dosage of the patient to be treated symptomatically. It is provided in the form of tablets containing 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of the active ingredient. Such compounds may be administered in prescriptions one to four times a day, preferably one or two times a day. Such dosage regimens may be adjusted to provide the optimum therapeutic response.

However, it is understood that the specific dosage level for any particular patient will depend on various factors. These factors include the age, weight, general health, sex, and diet of the patient. Other factors include time and route of administration, rate of release, drug combinations, and the type and severity of the particular disease being treated.

It is understood that the disclosed compositions can be used in the disclosed methods of use.

G. Methods of Using Compounds and Compositions

The amino acid L-glutamate (hereinafter referred to simply as glutamate) is the major excitatory neurotransmitter in the central nervous system (CNS) of mammals. Within the CNS, glutamate plays an important role in synaptic plasticity (eg, organ reinforcement (foundation of learning and memory)), motor control and sensory perception. It is now well understood that various neurological and psychiatric disorders, including but not limited to schizophrenia, general psychiatric disorders and cognitive deficits, are associated with dysfunction in the glutamate system. Therefore, regulation of glutamateic systems is an important therapeutic goal. Glutamate acts through two separate receptors: ionic and metabolic glutamate receptors. The first kind, the ionic glutamate receptor, is a multi-subunit ligand-gate ion channel that mediates excitatory post-synaptic currents. Three subtypes of ionic glutamate receptors have been identified, and although glutamate functions as an agonist for all three receptor subtypes, it has been found that selective ligands activate each subtype. Ionic glutamate receptors are named after their respective selective ligands: kineite receptors, AMPA receptors and NMDA receptors.

Metabolic glutamate receptors, the second type of glutamate receptors called (mGluRs), are G-protein coupled receptors (GPCRs), which are based on their location (pre-synaptic or post-synaptic) neurotransmitter release or intensity of synaptic transmission Adjust mGluRs are a group of C GPCRs characterized by a large (~ 560 amino acid) “paris hell” agonist binding region in the amino-terminal region of the receptor. This unique agonist binding region is a group of C GPCRs, with extracellular loops in which the agonist binding regions are located within the seven-strand transmembrane (7TM) region or connect seven strands to this region. Distinguish from the group of A and B GPCRs located in it. To date, eight distinct mGluRs have been identified, cloned and sequenced. Based on structural similarity, primary coupling to intracellular signaling pathways and pharmacology, mGluRs were assigned to three groups: group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3) and group III (mGluR4). , mGluR6, mGluR7 and mGluR8). Group I mGluRs are linked via Gαq / 11 to increase inositol phosphate and increase metabolism and product of intracellular calcium. Group I mGluRs are predominantly located at the synapse-back and have a modulating effect on ion channel activity and neuronal excitability. Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8) mGluRs are primarily located before synapses that regulate the release of neurotransmitters such as glutamate. Group II and Group III mGluRs bind to G? I and related effectors such as adenylate cyclase.

Post-synaptic mGluRs are known to functionally interact with post-synaptic ionic glutamate receptors, such as the NMDA receptor. For example, activation of mGluR5 by selective agonists has been shown to increase postsynaptic NMDA currents (Mannaioni et al. J. Neurosci. 21: 5925-5934 (2001)). Therefore, regulation of mGluRs is one approach to modulating glutamate delivery. Numerous reports have reported that mGluR5 is anxiety (Spooren et al. J. Pharmacol. Exp. Therapeut. 295: 1267-1275 (2000), Tatarczynska et Br. J. Pharmaol. 132: 1423-1430 (2001)), schizophrenia (reviewed in Chavez Noriega et al. Curr.Drug Targets: CNS & Neurological Disorders 1: 261-281 (2002), Kinney, GG et al. J. Pharmacol.Exp. Therapeut. 313: 199-206 (2005)), cocaine addiction (Chiamulera et al. Nature Neurosci 4: 873-874 (2001), Parkinson's disease (Awad et al. J. Neurosci. 20: 7871-7879 (2000), Ossowska et al. Neuropharmacol. 41: 413-420 (2001) and pain (Salt and Binns Neurosci. 100: 375-380 (2001) and many other disease states.

The compounds disclosed may be used alone or in combination with one or more other drugs in treating, preventing, controlling, mitigating or reducing the risk of the aforementioned diseases, disorders, and conditions for which the compounds of Formula I or other drugs are useful. It can be used in combination, where combining drugs together is more stable or more effective than drugs alone. The other drug (s) may be administered by the route and amount conventionally employed, and thus simultaneously or sequentially with the disclosed compounds. When the disclosed compounds are used simultaneously with one or more other drugs, pharmaceutical compositions in unit dosage form containing these drugs and the disclosed compounds are preferred. However, combination therapy may also be administered on an overlapping schedule. It is also expected that combining the disclosed compounds with one or more active ingredients will be more potent than as a single agent.

In one aspect, the subject compounds include anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, muscarinic agonists, muscarinic enhancers HMG-CoA reductase inhibitors, NSAIDs and anti-amyloid antibodies May be administered together.

In another aspect, the subject compounds are combined with sedatives, hypnotics, anti-anxiety agents, antipsychotics, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GlyT1 inhibitors, etc. It may be administered, but is not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomelin, lithium, phenobarbitol, and salts thereof and combinations thereof.

In another aspect, the subject compound is a levodopa (with or without a selective extra brain decarboxylase inhibitor), an anticholinergic agent, such as biferdene, a COMT inhibitor, such as entacapone, A2a adenosine antagonist, choline agonist, It can be used in combination with NMDA receptor antagonists and dopamine agonists.

The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds referred to herein, which are commonly used in the treatment of the above mentioned pathological conditions.

In some aspects, mGluR of the disclosed methods is type I mGluR. In some aspects, mGluR of the disclosed methods is mGluR5.

1. Treatment Methods

The compounds disclosed herein are useful for treating, preventing, mitigating, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction. Therefore, one or more disclosed compounds; One or more disclosed pharmaceutical compositions; And / or administering one or more disclosed products to the subject in a dosage and dosage effective for the treatment of the disorder in the subject.

Also one or more disclosed compounds; One or more disclosed pharmaceutical compositions; And / or administering one or more disclosed products to the subject in a dosage and dosage effective for the treatment of the disorder in the subject. 1. A method for treating one or more neurological and / or mental disorders associated with glutamate dysfunction in a subject. Is also provided.

Examples of disorders associated with glutamate dysfunction include: acute and chronic neurological and mental disorders, such as brain defects associated with cardiac lateral circulation and transplantation, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia , Heart failure, hypoglycemia neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's chorea, atrophic lateral sclerosis, eye damage, retinopathy, cognitive impairment, idiopathic and drug-induced Parkinson's disease, tremor, epilepsy, Muscle spasms and disorders related to spasms, including cramps, migraine headaches (including migraine headaches), incontinence, substance tolerance, addiction behavior, substances (including opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.) Addictive behaviors, including addiction, and other addictive substances (such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.) Withdrawal, obesity, mental disorders, schizophrenia, anxiety (including general anxiety disorders, panic disorders, and obsessive compulsive disorder), mood disorders (including depression, mania, manic depression), trigeminal neuralgia, hearing loss, tinnitus, eyes Macular degeneration, vomiting, cerebral edema, pain (including acute and chronic pain conditions, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), delayed dyskinesia, sleep disorders (including narcolepsy), excessive attention deficit Behavioral disorders, and behavioral disorders.

Anxiety disorders that can be treated or prevented by the compositions disclosed herein include generalized anxiety disorders, panic disorders, and obsessive compulsive disorders. Toxic behaviors include: addiction to substances (including opiates, nicotine, tobacco products, alcohols, benzodiazepines, cocaine, sedatives, hypnotics, etc.); Withdrawal and substance resistance from substances such as hypnotics and the like.

Therefore, in some aspects of the disclosed methods, the disorder is dementia, delirium, memory loss disorder, cognitive dysfunction with aging, schizophrenia, schizophrenia including schizophrenia, schizophrenic disorder, schizoaffective disorder, delusional disorder, Short-term psychotic disorders, substance-related disorders, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorders, narcolepsy, anxiety, affective disorders, panic attacks, unipolar depression, Manic depression and psychotic depression.

A method of treating or preventing schizophrenia is therefore provided, comprising the following steps: one or more disclosed compounds; One or more disclosed pharmaceutical compositions; And / or administering one or more disclosed products to the subject in a dosage and dosage effective for treating the disorder in the subject. Currently, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.) provides diagnostic tools that include schizophrenia and related disorders.

Also one or more disclosed compounds; One or more disclosed pharmaceutical compositions; And / or administering one or more disclosed products to the subject in a dosage and dosage effective for treating the disorder in the subject. Currently, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.) provides diagnostic tools including anxiety and related disorders. These disorders include: panic disorder with or without agoraphobia, agoraphobia without panic disorder, specific phobias, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, general anxiety disorder, general medical conditions Anxiety Disorders, Substance-Induced Anxiety Disorders, and other anxiety disorders not specifically mentioned.

a. Metabolic Glutamate  Enhancing Receptor Activity

In one aspect, the present invention provides a method of administering one or more compounds having a structure represented by the general formula or a pharmaceutically acceptable salt or N-oxide thereof in a mammal at a dosage and dosage effective for enhancing metabolic glutamate receptor activity in a mammal. A method of enhancing metabolic glutamate receptor activity in a mammal, comprising administering to the animal:

Wherein each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing from 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; And L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide And an organic radical comprising 1 to 5 carbon atoms selected from amino-carbonyl, and alkylamine-carbonyl.

And administering to the mammal at least one compound having the following structure, or a pharmaceutically acceptable salt or N-oxide thereof, in dosages and dosages effective for enhancing metabolic glutamate receptor activity in the mammal. Methods of enhancing metabolic glutamate receptor activity in animals are also provided:

Wherein n is 0, 1, 2, 3 or 4; Y ¹ and Y ² are independently selected from C and N; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b , if present, together comprise = O or = S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 An organic radical containing from 6 to 6 carbon atoms; R ^3a and R ^3b together comprise = O or = S, or each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; R ⁴ comprises hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or 1, 2 or 3 substituents independently present as organic radicals containing 1 to 12 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

In one aspect, the mammal is a human. In another aspect, the mammal has been diagnosed with the need to enhance metabolic glutamate receptor activity prior to the administering step.

b. Metabolic Glutamate  Partial operation of receptor activity

In one aspect, the present invention relates to one or more compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof, useful for demonstrating the partial operation of metabolic glutamate receptor activity in a mammal and A method for partial operation of metabolic glutamate receptor activity in a mammal, comprising administering to the mammal at a dose:

Wherein each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing from 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or are independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optional Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3- C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, Organic radicals containing 1 to 5 carbon atoms selected from amino-carbonyl, and alkylamine-carbonyl.

And administering to the mammal one or more compounds having the following structure, or a pharmaceutically acceptable salt or N-oxide thereof, in dosages and dosages effective for indicating partial action of metabolic glutamate receptor activity in the mammal. Methods for partial operation of metabolic glutamate receptor activity in mammals are also provided:

Wherein n is 0, 1, 2, 3 or 4; Y ¹ and Y ² are independently selected from C and N; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b , if present, together comprise = O or = S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 Organic radicals containing from 6 to 6 carbon atoms; R ^3a and R ^3b together comprise = O or = S, or each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; R ⁴ comprises hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or 1, 2 or 3 substituents independently present as organic radicals containing 1 to 12 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

In one aspect, Y ¹ is selected from N and CR ⁴ . In another aspect, Y ² is selected from N and CH.

In another aspect, each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms.

In another aspect, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms.

In another aspect, L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxami , Amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl; And R ⁸ is hydrogen and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 hetero Alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, And an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, the compound comprises an isoindolin-1-one derivative having the structure: or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

In another aspect, the compound comprises an isoindolin-1,3-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is selected from hydrogen or optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, R ¹ does not contain silicon; And R ⁵ is an organic radical containing 4 to 14 carbon atoms, and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, and when R ¹ is methyl, R is ⁵ is an organic radical containing 4 to 14 carbon atoms.

In another aspect, the compound comprises a 3,4-dihydroisoquinolin-1 (2H) -one derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

In another aspect, the compound comprises an isoquinoline-1,3 (2H, 4H) -dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms and R ⁵ does not comprise a triphenylamine residue or a benzimidamide residue.

In another aspect, the compound comprises cyclic compounds having the structure: or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein n is 2, 3 or 4; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

In one aspect, the mammal is a human. In another aspect, the mammal has been diagnosed as requiring partial action of metabolic glutamate receptor activity prior to the administering step.

c. In mammals  Treatment of Disorders

In one aspect, the invention provides one or more compounds having a structure represented by the following formula or a pharmaceutically acceptable salt or N-oxide thereof to a mammal in a dosage and effective amount effective for treating a disorder in the mammal: A method of treating a disorder in a mammal, comprising administering:

Wherein each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing from 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Is selected from an organic radical comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl; And R ⁸ is hydrogen and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 hetero Alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, And an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, the method further comprises identifying a mammal in need of treatment of the disorder. In another aspect, the mammal has a need to treat the disorder prior to administration. In another aspect, the mammal has been diagnosed with the need to treat the disorder prior to administration.

In one aspect, the disorder is one or more neurological and / or mental disorders associated with glutamate dysfunction in a mammal. For example, the disorder may include dementia, delirium, amnesia, cognitive decline with aging, schizophrenia, schizophrenia including schizophrenia, schizophrenic disorder, schizoaffective disorder, delusional disorder, short-term psychotic disorder, Substance-related disorders, dyskinesia, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorders, narcolepsy, anxiety, affective disorders, panic attacks, unipolar depression, mood swings, and mental Abnormal depression may be one or more of the following.

Further, in a mammal, comprising administering to the mammal one or more compounds having the following structure, or a pharmaceutically acceptable salt or N-oxide thereof, in a dosage and dosage effective for treating the disorder in the mammal. Methods of treating the disorder are also provided:

Wherein n is 0, 1, 2, 3 or 4; Y ¹ and Y ² are independently selected from C and N; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b , if present, together comprise = O or = S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 Organic radicals containing from 6 to 6 carbon atoms; R ^3a and R ^3b together comprise = O or = S, or each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; R ⁴ comprises hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or 1, 2 or 3 substituents independently present as organic radicals containing 1 to 12 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

In another aspect, Y ¹ is selected from N and CR ⁴ .

In another aspect, Y ² is selected from N and CH.

In another aspect, each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms.

In another aspect, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms.

In another aspect, L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:

In another aspect, R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, Amino, and optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optional C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally Substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carbon It is selected from organic radicals comprising 1 to 5 carbon atoms selected from voxamide, amino-carbonyl, and alkylamine-carbonyl.

In another aspect, R ⁸ is hydrogen and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 hetero Cycloalkinyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, the compound comprises an isoindolin-1-one derivative having the structure: or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms, and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

In another aspect, the compound comprises an isoindolin-1,3-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, and , R ¹ does not contain silicon; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms, and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, and when R ¹ is methyl, R is ⁵ is an organic radical containing 4 to 14 carbon atoms.

In another aspect, the compound comprises a 3,4-dihydroisoquinolin-1 (2H) -one derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

In another aspect, the compound comprises an isoquinoline-1,3 (2H, 4H) -dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms and R ⁵ does not comprise a triphenylamine residue or a benzimidamide residue.

In another aspect, the compound comprises cyclic compounds or their pharmaceutically acceptable salts or N-oxides:

Wherein n is 2, 3 or 4; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

In another aspect, the disorder is a neurological and / or mental disorder associated with glutamate dysfunction. In another aspect, the disorder is dementia, delirium, amnesia, cognitive decline with age, schizophrenia, schizophrenia including schizophrenia, schizophrenic disorder, schizoaffective disorder, delusional disorder, short-term psychotic disorder , Substance-related disorders, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorders, lethargic seizures, anxiety, affective disorders, panic attacks, unipolar depression, mood swings, and It is selected from psychotic depression.

In one aspect, the mammal is a human. In another aspect, the mammal has been diagnosed with the need to treat the disorder prior to the administering step.

d. Cognitive improvement

Schizophrenic symptoms can be classified as positive, negative, or cognitive. Positive schizophrenic symptoms include delusions and hallucinations, which can be measured using, for example, the Positive and Negative Syndrome Scale (PANSS) (see Kay et al., 1987, Schizophrenia Bulletin 13, 261-276). Negative schizophrenic symptoms include affect blunting, asthenia, inability to express, and social withdrawal, which can be measured using, for example, a negative symptom measurement scale (SANS) (Andreasen, 1983, Scales for the Assessment of Negative Symptoms, Iowa City, Iowa. Cognitive schizophrenic symptoms include the use of positive and negative syndrome scale-cognitive subscales (PANSS-cognitive scale) (Lindenmayer et al., J Nerv Ment Dis 1994, 182, 631-638), and the ability to perform cognitive tasks. By evaluating, for example, the Wisconsin Card Sorting Test (see, eg, Green et al., Am J Psychiatry 1992, 149, 162-67; and Koren et al., Schizophr Bull 2006, 32 (2), 310-26). Obstacles in obtaining, organizing and using intellectual knowledge that can be measured by use and evaluation.

In one aspect, the invention administers to a mammal one or more compounds having a structure represented by the following formula or a pharmaceutically acceptable salt or N-oxide thereof, in a dosage and dosage effective for improving cognition in the mammal: A method for improving cognition in a mammal, comprising the steps of:

Wherein each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing from 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl , Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxami , Amino-are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl-carbonyl, and alkyl amines. In another aspect, cognitive improvement is a significant statistical increase in cognitive memory for new things. In another aspect, cognitive improvement is a significant statistical increase in synaptic plasticity. In another aspect, cognitive improvement is a significant statistical increase in the performance of the Wisconsin Card Sorting Test.

MGluR5 fortification was also associated with cognitive improvement (Kinney, GG; O 'Brien, Lemaire, W .; Burno, M. Bickel, DJ; Clements, MK; Wisnoski, DD; Lindsley, CW; Tiller, PR; Smith, S Jacobson, MA; Sur, C .; Duggan, ME; Pettibone, DJ; Williams, Jr., DW 'A novel selective allosteric modulator of metabotropic glutamate receptor subtype 5 (mGluR5) has an antipsychotic profile in rat behavioral models' J .... Pharmacol Exp Therapeut 2005 , 313 (1), 199; Lindsley, CW; Wisnoski, DD; Leister, WH ;; O'Brien, JA; Lemiare, W .; Williams, Jr., DL; Burno, M ;; Sur, C .; Kinney, GG; Pettibone, DJ; iller, PR; Smith, S .; Duggan, ME.; Hartman, GD; Conn, PJ; Huff, JR 'Discovery of positive allosteric modulator for the metabotropic glutamate receptor subtype 5 from a series of N- (1,3-Diphenyl-1H-pyrazol-5-yl) benzamides that potentiate receptor function in in vivo ' J. Med . Chem. 2004 , 47 , 5825; Epping-Jordan MP, Nayak, S., Derouet, F., Dominguez, H., Bessis AS, Le Poul E., Ludwig BL Mutel V.,, Poli SM and Rocher JP In Vivo Characterization of mGluR5 Positive Allosteric Modulators as Novel Treatments for Schizophrenia and Cognitive Dysfunction Neuropharmacology 2005 , 49 , 243.). This theory has been confirmed in long-term, constantly changing cellular models of synaptic transmission that are thought to be the basis for plural forms of learning and memory. This model, called Hippocampal Organ Strengthening (LTP), is involved in measuring strength in synaptic connections between neurons in the brain, which is important for learning to occur. 20 shows that the strength of synaptic connections increases after stimulation of synapses in the absence and presence of two structurally distinct mGluR5 PAMs, VU29 (top panel) and ADX47273 (bottom panel). Both PAMs cause a firm increase in synaptic connectivity to the extent that it is expected to improve learning and memory. This could provide an approach for improving cognition in disorders related to impaired cognitive function, including schizophrenia, Alzheimer's disease, Parkinson's disease, and brain disorders of multiple others. Representative mGluR5 PAM, which improves hippocampal LTP, is also active in preclinical cognitive models of cognitive memory (NOR) for new objects, where mGluR5 PAM, ADX47273, shows a robust and significant improvement in NOR, and known cognitive improvement H3 Equivalent to antagonist thioferide ( FIG. 11 ).

2. Manufacturing of Pharmaceuticals

And metabolic in mammals for the treatment of disorders in mammals, the method comprising the step of combining one or more compounds having the following structure or a pharmaceutically acceptable salt or N-oxide thereof with a pharmaceutically acceptable carrier Methods for the manufacture of a medicament for partial operation of glutamate receptor activity, for enhancing metabolic glutamate receptor activity in a mammal, and / or for improving cognition in a mammal are provided:

Wherein each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing from 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Is selected from an organic radical comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl; And R ⁸ is hydrogen and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 hetero Alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, And an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl.

In addition, a pharmaceutical agent for enhancing metabolic glutamate receptor activity in a mammal, comprising combining one or more compounds having the following structure or a pharmaceutically acceptable salt or N-oxide thereof with a pharmaceutically acceptable carrier. Manufacturing methods are also provided:

Wherein n is 0, 1, 2, 3 or 4; Y ¹ and Y ² are independently selected from C and N; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b , if present, together comprise = O or = S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 An organic radical containing from 6 to 6 carbon atoms; R ^3a and R ^3b together comprise = O or = S, or each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; R ⁴ comprises hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or 1, 2 or 3 substituents independently present as organic radicals containing 1 to 12 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms. In another aspect, Y ¹ is selected from N and CR ⁴ . In another aspect, Y ² is selected from N and CH. In another aspect, each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms. In one aspect, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms.

In another aspect, L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:

In another aspect, R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, Amino, and optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optional C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally Substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carbon It is selected from organic radicals comprising 1 to 5 carbon atoms selected from voxamide, amino-carbonyl, and alkylamine-carbonyl.

In another aspect, R ⁸ is hydrogen and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 hetero Cycloalkinyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, the compound comprises an isoindolin-1-one derivative having the structure: or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

In another aspect, the compound comprises an isoindolin-1,3-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, and , R ¹ does not contain silicon; And R ⁵ is an organic radical containing 4 to 14 carbon atoms, and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, and when R ¹ is methyl, R is ⁵ is an organic radical containing 4 to 14 carbon atoms.

In another aspect, the compound comprises a 3,4-dihydroisoquinolin-1 (2H) -one derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

In another aspect, the compound comprises an isoquinoline-1,3 (2H, 4H) -dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms and R ⁵ does not comprise a triphenylamine residue or a benzimidamide residue.

In another aspect, the compound comprises cyclic compounds having a structure or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein n is 2, 3 or 4; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

3. Use of Compound

Also provided is the use of the disclosed compounds. For example, the use of compounds having the following structure or pharmaceutically acceptable salts or N-oxides thereof is provided:

Wherein each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl , Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxami , Amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl; And R ⁸ is hydrogen and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 hetero Alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, And an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl.

As another example, the use of compounds having the following structure or a pharmaceutically acceptable salt or N-oxide thereof to enhance the mGluR5 response in a mammal is provided:

Wherein n is 0, 1, 2, 3 or 4; Y ¹ and Y ² are independently selected from C and N; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b , When present, together comprise ═O or ═S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or, 1 to 6 carbon atoms It is an organic radical containing; R ^3a and R ^3b together comprise = O or = S, or each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; R ⁴ comprises hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or 1, 2 or 3 substituents independently present as organic radicals containing 1 to 12 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms. In another aspect, Y ¹ is selected from N and CR ⁴ . In another aspect, Y ² is selected from N and CH. In another aspect, each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms. In another aspect, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms.

In another aspect, L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:

In another aspect, R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, Amino, and optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optional C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally Substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carbon 'S amide, amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl group.

In another aspect, R ⁸ is hydrogen and, optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 hetero Cycloalkinyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another aspect, the compound comprises an isoindolin-1-one derivative having the structure: or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

In another aspect, the compound comprises an isoindolin-1,3-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, and , R ¹ does not contain silicon; And R ⁵ is an organic radical containing 4 to 14 carbon atoms, and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl and when R ¹ is methyl, R ⁵ Is an organic radical containing 4 to 14 carbon atoms.

In another aspect, the compound comprises a 3,4-dihydroisoquinolin-1 (2H) -one derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms.

In another aspect, the compound comprises an isoquinoline-1,3 (2H, 4H) -dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms and R ⁵ does not comprise a triphenylamine residue or a benzimidamide residue.

In another aspect, the compound comprises cyclic compounds having the structure: or a pharmaceutically acceptable salt or N-oxide thereof:

Wherein n is 2, 3 or 4; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; Wherein R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbons Organic radicals containing atoms; And R ⁵ is an organic radical comprising 4 to 14 carbon atoms.

In one aspect, the use is characterized in that the mammal is a human.

In one aspect, the use relates to the treatment of a disorder in a mammal.

In one aspect, the use is characterized in that the disorder is a neurological and / or mental disorder associated with glutamate dysfunction.

In one aspect, the use relates to potentiation for partial action of metabolic glutamate receptor activity in a mammal.

4. Subject

Subjects of the methods disclosed herein can be vertebrates, such as mammals, fish, birds, reptiles, or amphibians. Thus, subjects of the methods disclosed herein can be humans, primates, but not humans, horses, pigs, rabbits, dogs, sheep, goats, cattle, cats, guinea pigs, or rodents. The term does not indicate a particular age or gender. Therefore, it is intended to include female or male, grown and newborn subjects, as well as fetuses. Patient refers to a subject suffering from a disease or disorder. The term “patient” includes human and animal subjects.

In some aspects of the disclosed methods, the subject has been diagnosed with the need to treat one or more neurological and / or mental disorders associated with glutamate dysfunction prior to the administering step. In some aspects of the disclosed methods, the subject has been diagnosed with the need to enhance metabolic glutamate receptor activity prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed as requiring partial operation of metabolic glutamate receptor activity prior to the administering step.

H. Experiment

The following examples are provided to provide a complete disclosure and description of how the compounds, compositions, products, devices, and / or methods claimed herein are prepared and evaluated, are considered to be purely representative of the invention, and the inventors It is not intended to limit the scope of what they regard as inventions. Efforts have been made to ensure accuracy with respect to numbers ( eg amounts, temperature, etc.) but some error and standard deviation should be considered. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Centigrade or ambient temperature, and pressure is at or near atmospheric.

Several methods for preparing the compounds of the present invention are described in the following examples. Starting materials and necessary intermediates are in some cases commercially available or can be prepared according to the procedures described in the literature or as described herein. All ¹ H NMR spectra were obtained on instruments at field strengths from 300 to 500 MHz.

Ethyl 4- ( Phenylethynyl ) Benzoate

Phenylacetylene (2.25 g, 22.1 mmol), Pd (Ph ₃ P) ₄ (502 mg, 0.45 mmol), CuI in a solution of ethyl 4-iodobenzoate (5.0 g, 18.2 mmol) dissolved in DMF (8 mL) (172 mg, 0.91 mmol) and diethylamine (2 mL) were added. The reaction vessel was sealed and heated at 60 ° C. for 1 h in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc: hexanes (2: 1, 150 mL) and rinsed with water (2 × 100 mL) and brine (100 mL). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using 0-10% EtOAc / hexanes to afford ethyl 4- (phenylethynyl) benzoate (7.89 g, 86%) as a pale yellow solid. ; ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.05 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.56 (dd, J = 8.0, 2.0 Hz, 2H), 7.41-7.37 (m, 3H), 4.41 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H); LC (275 nM) 5.79 min (>98%); MS (ESI) m / z = 250.9.

2. 4- ( Phenylethynyl Benzoic acid

A solution of LiOH (5.24 g, 124 mmol) dissolved in MeOH (15 mL) and water (15 mL) in a solution of ethyl 4- (phenylethynyl) benzoate (7.81 g, 31.2 mmol) dissolved in THF (80 mL). Was added. The reaction was stirred at rt for 4 h. The reaction was acidified with 1 N HCl (50 mL) to separate 4- (phenylethynyl) benzoic acid as a white solid (5.78 g, 83%); ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 8.0 Hz, 2H), 7.75-7.68 (m, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.62-7.56 (m , 2H), 7.52-7.47 (m, 1 H), 7.43-7.36 (m, 3H); LC (275 nM) 5.12 min (>98%); MS (ESI) m / z = 222.9.

3. (4- Hydroxypiperidine -1-yl) (4- Phenylethynyl ) Phenyl ) Methanone

4- (phenylethynyl) benzoic acid dissolved in DMF (25 mL) (1.40 g, 6.30 mmol) and DIPEA (2.70 g, 20.8 mmol) in a solution of EDC (1.41 g, 7.56 mmol), HOBt (850 mg, 6.30 mmol) and 4-hydroxypiperidine hydrochloride (1.29 g, 9.46 mmol) was added. The reaction was stirred at rt for 18 h. The reaction was diluted with water (100 mL) to separate (4-hydroxypiperidin-1-yl) (4-phenylethynyl) phenyl) methanone as a white solid by vacuum filtration (1.84 g, 98% ); ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.58 (d, J = 8.0 Hz, 2H), 7.56-7.52 (m, 2H), 7.44-7.34 (m, 5H), 4.21-4.08 (m, 1H) , 4.03-3.96 (m, 1H), 3.81-3.48 (m, 1H), 3.47-3.16 (m, 2H), 2.08-1.79 (m, 2H), 1.71-1.42 (m, 2H); LC (275 nM) 5.01 min (>98%); MS (ESI) m / z = 305.9.

4. 4-((3- Fluorophenyl ) Ethinyl Benzoic acid

In a solution of ethyl 4-iodobenzoate (10.0 g, 36.2 mmol) dissolved in DMF (30 mL), 3-fluorophenylacetylene (5.22 g, 43.4 mmol), Pd (Ph ₃ P) ₄ (1.04 g, 0.91 mmol), CuI (346 mg, 1.82 mmol) and diethylamine (6 mL) were added. The reaction vessel was sealed and heated in a microwave reactor at 60 ° C. for 1 h. The reaction was cooled to rt, diluted with EtOAc: hexane (2: 1, 250 mL) and rinsed with water (2 × 200 mL) and brine (200 mL). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was dissolved in THF (130 mL), a solution of LiOH (3.04 g, 72.4 mmol) dissolved in water (28 mL) and MeOH (28 mL) were added. The reaction was stirred at rt for 4 h. The reaction was acidified with 1 N HCl (100 mL) to separate 4-((3-fluorophenyl) ethynyl) benzoic acid as a light tan solid (6.89 g, 79%); ¹ H-nmr (400 MHz, d ₆ -DMSO ) δ 7.97 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.55-7.42 (m, 3H), 7.21 (td, J = 8.0, 2.0 Hz, 1H); LC (290 nM) 5.27 min (>98%); MS (ESI) m / z = 240.7.

5. (4-((3- Fluorophenyl ) Ethinyl ) Phenyl ) ( Morpholino ) Methanone

EDC (1.86 g, 10.0 mmol), HOBt in a solution of 4-((3-fluorophenyl) ethynyl) benzoic acid (2.0 g, 8.33 mmol) and DIPEA (2.38 g, 18.3 mmol) dissolved in DMF (35 mL) (1.35 g, 10.0 mmol) and morpholine (1.07 g, 12.5 mmol) were added. The reaction was stirred at rt for 18 h. The reaction was diluted with water (200 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were rinsed with water (2 × 100 mL) and brine (100 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel) using 0-90% EtOAc / hexanes to give (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone (2.35 g, 89%) was calculated as a light tan solid; ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.38-7.31 (m, 2H), 7.28-7.21 (m , 1H), 7.13-7.05 (m, 1H), 4.00-3.31 (bd s, 8H); LC (290 nM) 5.08 min (>98%); MS (ESI) m / z = 310.

6. (4 ((3- Fluorophenyl ) Ethinyl ) Phenyl) (4- Hydroxylpiperidine -1 day- Methanone

(4-((3-fluorophenyl) ethynyl) phenyl) (4-((3-fluorophenyl) ) Ethynyl) phenyl) (4-hydroxypiperidin-1-yl-methanone (2.61 g, 97%); ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.38-7.31 (m, 2H), 7.28-7.21 (m, 1H), 7.11-7.03 (m, 1H), 4.21-4.08 (m, 1H) , 4.03-3.96 (m, 1H), 3.81-3.48 (m, 1H), 3.47-3.15 (m, 2H), 2.05-1.78 (m, 2H), 1.71-1.42 (m, 2H); LC (290 nM ) 4.86 min (>98%); LC (290 nM) 4.93 min (>98%); MS (ESI) m / z = 324.

7. (4-((3- Fluorophenyl ) Ethinyl ) Phenyl )(4- Hydroxymethyl ) Piperidin-1-yl) methanone

Light cream solid, amide (4-((3-fluorophenyl) ethynyl) phenyl, prepared in the same manner as (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone ) (4-hydroxy methyl) piperidin-1-yl) methanone (2.32 g, 78%); ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.56 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.38-7.30 (m, 2H), 7.28-7.21 (m , 1H), 7.09-7.02 (m, 1H), 3.89-3.71 (m, 1H), 3.61-3.52 (m, 2H), 3.12-2.71 (m, 2H), 1.96-1.69 (m, 3H), 1.41 -1.12 (m, 3 H); LC (290 nM) 4.98 min (>98%); MS (ESI) m / z = 338.

8. 4-((3,4- Difluorophenyl ) Ethinyl Benzoic acid

In a solution of ethyl 4-iodobenzoate (5.0 g, 18.1 mmol) dissolved in DMF (15 mL), 3,4-difluorophenylacetylene (2.99 g, 21.7 mmol), Pd (Ph ₃ P) ₄ ( 520 mg, 0.45 mmol), CuI (173 mg, 0.90 mmol) and diethylamine (3 mL) were added. The reaction vessel was sealed and heated in a microwave reactor at 60 ° C. for 1 h. The reaction was cooled to rt, diluted with EtOAc: hexanes (2: 1, 150 mL) and rinsed with water (2 × 100 mL) and brine (100 mL). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was dissolved in THF (60 mL) and LiOH (1.52 g, 36.2 mmol) and MeOH (14 mL) dissolved in water (14 mL). The reaction was stirred at rt for 4 h. The reaction was acidified with 1 N HCl (60 mL) to separate 4-((3,4-difluoro phenyl) ethynyl) benzoic acid as a white solid (2.45 g, 57%); ¹ H-nmr (400 MHz, d ₆ -DMSO ) δ 7.96 (d, J = 8.5 Hz, 2H), 7.73 (td, J = 8.5, 2.0 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.55-7.43 (m, 2H); LC (290 nM) 5.08 min (>98%); MS (ESI) m / z = 258.7.

9. (4-((3,4- Difluorophenyl ) Ethinyl ) Phenyl ) ( Morpholino ) Methanone

In a solution of acid (7) (2.40 g, 9.30 mmol) and DIPEA (3.34 g, 18.6 mmol) dissolved in DMF (35 mL), EDC (2.07 g, 11.2 mmol), HOBt (1.25 g, 9.3 mmol) and Mor Pauline (1.04 g, 12.1 mmol) was added. The reaction was stirred at rt for 18 h. The reaction was diluted with water (100 mL) and vacuum filtered to separate (4-((3,4-difluorophenyl) ethynyl) phenyl) (morpholino) methanone as a white solid (2.91 g, 96 %); ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.56 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.31- 7.25 (m, 1 H), 7.15 (dd, J = 18.0, 8.0 Hz, 1 H), 4.00-3.31 (bd s, 8H); LC (290 nM) 5.10 min (>98%); MS (ESI) m / z = 327.9.

10. methyl  4- (3- Phenyl -1,2,4- Oxadiazole -5 days) Benzoate

In a suspension of mono-methyl terephthalate (1.50 g, 8.33 mmol) in acetonitrile (16 mL), EDC (4.65 g, 25.0 mmol), HOBt (1.12 g, 8.33 mmol), DIPEA (3.24g, 25.0 mmol) and N -hydroxybenzimidamide (1.36 g, 10.0 mmol) was added. The reaction was heated in microwave at 100 ° C. for 30 minutes. The reaction was then cooled to rt, diluted with water (60 mL) and the crude white precipitate was separated by vacuum filtration. Dissolve in CH ₂ Cl ₂ and pass through a silica plug to yield methyl 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzoate as a grayish white solid (640 mg, 23 %). ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.33 (d, J = 8 Hz, 2H), 8.24 (d, J = 8 Hz, 2H), 8.21-8.11 (m, 2H), 7.59-7.51 (m , 3H), 4.00 (s, 3H); MS (ESI) m / z 280.9

11. 4- (3- Phenyl -1,2,4- Oxadiazole -5-yl) benzoic acid

H ₂ O in a solution of methyl 4- (3- (4-fluorophenyl) 1,2,4-oxadiazol-5-yl) benzoate (600 mg, 2.14 mmol) dissolved in THF (12 mL). A solution of LiOH (351 mg, 8.57 mmol) dissolved in (3 mL) and MeOH (3 mL) were added. The reaction was stirred at rt for 2 h. The reaction was quenched by addition of 1N HCl (30 mL) and extracted with EtOAc (2 × 30 mL). The organic extract was dried over MgSO ₄ and concentrated in vacuo to yield 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzoic acid (550 mg, 87%) as a white solid. ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.37 (d, J = 8 Hz, 2H), 8.30 (d, J = 8 Hz, 2H), 8.26-8.19 (m, 2H), 7.62-7.52 (m , 3H); MS (ESI) m / z 266.8

12.  N -(3,3- Dimethylbutyl ) -4- (3- Phenyl -1,2,4- Oxadiazole -5 days- Benzamide

EDC (167 mg, 0.90 mmol), HOBt in a solution of 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzoic acid (200 mg, 0.75 mmol) dissolved in DMF (2 mL) (122 mg, 0.90 mmol), DIPEA (200 mg, 1.50 mmol) and 3,3-dimethylbutylamine (113 mg, 1.12 mmol) were added. The reaction was stirred at rt for 18 h. The reaction was diluted with water (10 mL) and the white precipitate separated by vacuum filtration to give N- (3,3-dimethylbutyl) -4- (3-phenyl-1,2,4-oxadiazol-5-yl -Benzamide (248 mg, 95%) was calculated. ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.31 (d, J = 8 Hz, 2H), 8.23-8.17 (m, 2H), 7.95 (d, J = 8 Hz, 2H), 7.59-7.52 (m , 3H), 6.12 (s, 1H), 3.57-3.51 (m, 2H) 1.62-1.58 (m, 2H), 1.02 (s, 9H); MS (ESI) m / z 349.9.

13. (E) -ethyl 4- Styryl benzoate

To a solution of ethyl 4-iodobenzoate (1.0 g, 3.6 mmol) dissolved in DMF (4 mL) was added commercial (E) -styrylboronic acid (538 mg, 3.6 mmol) and catalyst Pd (tBuP) ₂ . Added. The reaction vessel was sealed and heated in a microwave reactor at 160 ° C. for 10 minutes. The reaction was cooled to rt, diluted with EtOAc: hexanes (2: 1, 20 mL) and rinsed with water (2 x 20 mL) and brine (20 mL). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using 0-10% EtOAc / hexanes to give (E) -ethyl 4-styrylbenzoate (771 mg, 85%) as a pale yellow solid. ; ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.05 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.56 (dd, J = 8.0, 2.0 Hz, 2H), 7.41-7.37 (m, 3H), 6.95 (d, 1H), 6.89 (d, 1H), 4.41 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H); LCMS (214 nM) 3.58 min (>98%); MS (ESI) m / z = 253.1.

14. (E) -ethyl 4- Styryl benzoic acid

A solution of LiOH (360 mg, 10 mmol) and MeOH dissolved in water (25 mL) in a solution of ester (E) -ethyl 4-styrylbenzoate (600 mg, 2.3 mmol) dissolved in THF (5 mL) (2 mL) was added. The reaction was stirred at rt for 4 h. The reaction was acidified with 1 N HCl (10 mL) to separate (E) -ethyl 4-styrylbenzoic acid (440 mg, 83%) as a white solid; ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 8.0 Hz, 2H), 7.75-7.68 (m, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.62-7.56 (m , 2H), 7.52-7.47 (m, 1H), 7.43-7.36 (m, 3H), 6.97 (d, 1H), 6.88 (d, 1H) ,; LCMS (214 nM) 3.22 min (>98%); MS (ESI) m / z = 225.1.

15. (4- Hydroxypiperidine -1-yl) (4- Styrylphenyl ) Methanone

In a solution of (E) -ethyl 4-styrylbenzoic acid (300 mg, 1.3 mmol) and DIPEA (270 uL, 2.1 mmol) dissolved in DMF (5 mL), EDC (280 mg, 1.5 mmol), HOBt (270 mg) , 2.0 mmol) and 4-hydroxypiperidine hydrochloride (258 mg, 1.8 mmol) were added. The reaction was stirred at rt for 18 h. The reaction was diluted with water (10 mL) and vacuum filtered to separate (4-hydroxypiperidin-1-yl) (4-styrylphenyl) methanone as a white solid (390 mg, 98%); ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.58 (d, J = 8.0 Hz, 2H), 7.56-7.52 (m, 2H), 7.44-7.34 (m, 5H), 6.95 (d, 1H), 6.89 (d, 1H), 4.21-4.08 (m, 1H), 4.03-3.96 (m, 1H), 3.81-3.48 (m, 1H), 3.47-3.16 (m, 2H), 2.08-1.79 (m, 2H) , 1.71-1.42 (m, 2H); LCMS (214 nM) 3.32 min (>98%); MS (ESI) m / z = 308.1.

16. methyl  4- (4- Fluorophenylcarbamoyl ) Benzoate

To a suspension of mono-methyl terephthalate (2.0 g, 11.1 mmol) in DMF (10 mL) EDC (2.48 g, 13.3 mmol), HOBt (1.80 g, 13.3 mmol), and 4-fluoroaniline (1.48 g, 13.3 mmol) was added. The reaction was stirred at rt for 72 h. The reaction was diluted with water (80 mL) and vacuum filtered to separate methyl 4- (4-fluorophenylcarbamoyl) benzoate (3.00 g, 98%) as a white precipitate. ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.18 (d, J = 8 Hz, 2H), 7.95 (d, J = 8 Hz, 2H), 7.82 (br s, 1H), 7.66-7.59 (m, 2H), 7.15-7.07 (m, 2H), 3.99 (s, 3H); MS (ESI) m / z 273.9.

17. 4- (4- Fluorophenylcarbamoyl Benzoic acid

LiOH (1.79 g, 43.6 mmol) dissolved in H ₂ O (8 mL) in a solution of methyl 4- (4-fluorophenylcarbamoyl) benzoate (2.98 g, 10.9 mmol) dissolved in THF (35 mL). ) And MeOH (8 mL) were added. The reaction was stirred at rt for 2 h. The reaction was quenched upon addition of 1N HCl (50 mL) and extracted with EtOAc (2 × 60 mL). The organic extract was dried over MgSO ₄ and concentrated in vacuo to yield 4- (4-fluorophenylcarbamoyl) benzoic acid (2.43 g, 86%) as a white solid. ¹ H-nmr (400 MHz, d ₆ -DMSO) δ 10.49 (s, 1H), 8.11-8.02 (m, 4H), 7.87-7.77 (m, 2H), 7.25-7.16 (m, 2H); MS (ESI) m / z 259.9.

18.  N -(4- Fluorophenyl ) -4- (2- Methylpiperidine -1-carbonyl) Benzamide

PS-carbodiimide (125 mg, 0.25 mmol), HOBt (26 mg, 0.19) in a solution of 4- (4-fluorophenylcarbamoyl) benzoic acid (50 mg, 0.19 mmol) dissolved in DMF (1 mL) mmol), DIPEA (52 mg, 0.40 mmol) and 2-methylpiperidine (25 mg, 0.25 mmol) were added. The reaction was stirred at rt for 18 h. MP-carbonate was added to the reaction and stirred for a further 8 h. The reaction was filtered and concentrated in vacuo, diluted with water (10 mL) and vacuum filtered to separate the white precipitate, N- (4-fluorophenyl) -4- (2-methylpiperidine-1-carbonyl Benzamide (248 mg, 95%) was calculated. ¹ H-nmr (400 MHz, d ₆ -DMSO) δ 10.37 (br s, 1H), 8.00 (d, J = 7 Hz, 2H), 7.83-7.72 (m, 2H), 7.49 (d, J = 7 Hz, 2H), 7.21 (t, J = 8 Hz, 2H), 3.52-3.01 (m, 3H), 1.75-1.29 (m, 6H), 1.21 (m, 3H); MS (ESI) m / z 341.4.

19. 6- ( Penethynyl ) -3,4- Dihydroisoquinoline -1- (2 H ) -On (I-2)

Phenylacetylene (266 mg, 2.61 mmol) in a solution of 6-bromo-3,4-dihydro-2H-isoquinoline, ( I-1) (600 mg, 2.65 mmol) dissolved in DMF (3 mL), Pd (PPh ₃ ) ₄ (127 mg, 0.11 mmol), Cu (I) I (42 mg, 0.22 mmol) and diethylamine (2.02 g, 27.7 mmol) were added. The reaction vessel was sealed and heated at 60 ° C. for 1 h using a microwave reactor. The reaction was diluted with EtOAc / hexanes (1: 1, 40 mL), rinsed with water (× 2, 30 mL) and brine (30 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was triturated with CH ₂ Cl ₂ / hexanes (1: 3, 50 mL) to give 6- (phenethynyl) -3,4-dihydroisoquinolin-1- ( 2H ) -one, ( I -2) was calculated as a tan solid (309 mg. 47%). ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.02 (bd s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.59-7.54 (m, 2H), 7.53-7.49 (m, 2H), 7.47-7.43 (m, 3H), 3.42 (t, J = 6.5 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H); MS (ESI) m / z 248.0.

20. 6- ( Phenylethynyl ) -2-propyl-3,4- Dihydroisoquinoline -1- (2H) -one ( II -2)

NaH (9) in a solution of 6- (phenethylyl) -3,4-dihydroisoquinolin-1 ( 2H ) -one ( II-1 ) (50 mg, 0.20 mmol) dissolved in DMF (0.5 mL). mg, 0.22 mmol) was added and stirred for 1 h. 1-iodopropane (110 mg, 0.64 mmol) was added and stirred for 18 h. PS-Ph ₃ P (200 mg) was added and stirred for 4 h. The insoluble matter was removed by filtration and the filtrate was concentrated in vacuo to give 6- (phenylethynyl) -2-propyl-3,4-dihydroisoquinolin-1- (2H) -one ( II -2 ). Calculated as a yellowish waxy solid (44 mg, 76%). ¹ H-nmr (400 MHz, d ₆ -DMSO) δ 8.08 (d, J = 8 Hz, 1H), 7.59-7.52 (m, 2H), 7.51 (d, J = 8 Hz, 1H), 7.41-7.35 (m, 4H), 3.57 (q, J = 7 Hz, 4H), 3.00 (t, J = 6.5 Hz, 2H), 1.69 (sextet, J = 7 Hz, 2H), 0.99 (t, J = 7 Hz , 3H); MS (ESI) m / z 303.9.

21. 4- Bromo -2-( Hydroxymethyl ) Benzamide  ( III -2)

To a suspension of 5-bromoisobenzofuran-1 (3H) -one ( III- 1) (6.57 g, 30.1 mmol) in MeOH (140 mL) was added NH ₄ OH (60 mL). The reaction vessel was sealed and stirred for 36 h. The reaction was concentrated in vacuo to yield 4-bromo-2- (hydroxymethyl) benzamide (7.10 g, 99%) as a white solid; ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.68 (s, 2H), 7.61 (s, 1H), 7.59-7.50 (m , 2H), 6.34 (br s, 1 H), 5.72 (br s, 1 H), 4.64 (s, 2 H); LC (254 nM) 1.12 min (>98%); MS (ESI) m / z = 231.8.

22. 5- Bromoisoindolin -1-one ( III -3)

To a solution of 4-bromo-2- (hydroxymethyl) benzamide ( III- 2) (3.50 g, 15.2 mmol) dissolved in THF (100 mL), Ph ₃ P (4.78 g, 18.3 mmol) and DIAD ( 3.38 g, 16.7 mmol) was added. The reaction was stirred at rt for 20 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel) using 0-25% EtOAc dissolved in hexanes to afford 5-bromoisoindolin-1-one ( III- 3) . Calculated as a white solid (786 mg, 24%); ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.67 (s, 2H), 5.31 (s, 2H); LC (254 nM) 4.88 min (>98%); MS (ESI) m / z = 212.8, 214.8.

23. 5-((3- Fluorophenyl ) Ethinyl ) Isoindolin -1-one ( III -5)

3-fluorophenylacetylene ( III- 4) (67 mg, 0.56 mmol) in a solution of 5-bromoisoindolin-1-one ( III- 3) (100 mg, 0.47 mmol) dissolved in DMF (2 mL) ), Pd (Ph ₃ P) ₄ (27 mg, 0.02 mmol), CuI (9 mg, 0.04 mmol) and diethylamine (200 μL) were added. The reaction vessel was sealed and heated in a microwave reactor at 60 ° C. for 1 h. The reaction was cooled to rt, diluted with EtOAc: hexanes (2: 1, 8 mL) and rinsed with water (2 x 5 mL) and brine (5 mL). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by mass directed preparative HPLC (5-((3-fluorophenyl) ethynyl) isoindolin-1-one ( III -5) (42 mg, 35%) Was yielded as a light brown solid; ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.92 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.40-7.31 (m, 2H ), 7.28-7.22 (m, 1 H), 7.14-7.07 (m, 1 H), 5.36 (s, 2H); LC (214 nM) 3.38 min (>98%); MS (ESI) m / z = 253.1.

24. 5- ( Penethynyl ) Isoindolin -1,3- Dion  ( IV -2)

10 mL microwave vial in urea (121 mg, 2.02 mmol), 5- (phenylethynyl) isobenzofuran-1,3-dione ( IV- 1) (100 mg, 0.403 mmol), and anhydrous DMF (3 ml) was added. The reaction vessel was sealed and heated to 200 ° C. for 15 min. The reaction was diluted with EtOAc (20 ml), rinsed with water (20 ml) and then brine (20 ml). The organic extract was dried over The MgSO ₄ and filtered through a silica plug to yield 5- (phenethylyl) isoindolin-1,3-dione ( IV- 2) as a tan solid (82 mg, 83%). . ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.89-7.84 (m, 2H), 7.65 (br s, 1H), 7.58-7.56 (m, 2H), 7.41-7.39 ( m, 3H); MS (ESI) m / z 248.0.

25. 2-ethyl-5- ( Penethynyl ) Isoindolin -1,3- Dion  ( IV -3)

In a 10 mL microwave vial K ₂ CO ₃ (276 mg, 2.02 mmol), 5- (phenethylyl) isoindolin-1,3-dione ( IV- 2) (100 mg, 0.403 mmol), ethyl bromide (45 mg, 0.4 mmol) and anhydrous DMF (3 ml) were added. The reaction vessel was sealed and heated to 150 ° C. for 15 min. The reaction was diluted with EtOAc (20 ml) and rinsed with water (20 ml) and then with brine (20 ml). The organic extract was dried over MgSO ₄ and filtered through a plug of silica to afford 2-ethyl-5- (phenethylyl) isoindolin-1,3-dione ( IV- 3) as a white solid (100 mg, 91%). Calculated as ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.89-7.84 (m, 2H), 7.65 (br s, 1H), 7.58-7.56 (m, 2H), 7.41-7.39 ( m, 3H) 3.61 (q, J = 7 Hz, 2H), 1.22 (t, J = 7Hz, 3H); MS (ESI) m / z 276.3.

26. In vitro  Research

Human fetal kidney (HEK) cells infected with mouse mGluR5 were placed in clean bottomed, poly-D-lysine-coated assay plates in glutamate-glutamine-free culture medium and incubated overnight at 37 ° C. at 5% CO ₂ . The following day, cells were dropped 2 μM of calcium indicating dye, Fluor-4 AM, at 37 ° C. for 1 h. The dye was removed and transferred to an assay buffer of pH 7.4 containing 1 × Hanks salt equilibrium solution (Invitrogen, Carlsbad, Calif.), 20 mM HEPES, and 2.5 mM probebeneside. Cell plates were then placed into functional drug search system 6000 (FDSS 6000, Hamamatsu, Japan). After generating a fluorescent baseline for 12 seconds, the compounds of the present invention were added to the cells and the response in the cells was measured. After 5 minutes, an mGluR5 agonist ( eg , glutamate, 3,5-dihydroxyphenylglycine, or quisqualic acid) was added to the cells and the response of the cells was measured during 1 minute incubation with the agonist. Typically, EC _{20 of} glutamate The effect of the test compounds of the present invention on the concentration was measured. All test compounds were dissolved and diluted in 100% DMSO and subsequently diluted in assay buffer solution for 2.5x stock solution of 0.25% DMSO; Stock compounds were then added to the assay buffer solution for a final DMSO concentration of 0.1%. Calcium fluorescence measurements were recorded as a fold over background fluorescence; Raw data was then normalized to the maximum response to the agonist. Enhancement of the agonist reaction of mGluR5 by the compounds of the invention is compared to the response to the agonist in the absence of the compound as an increase in the response to a non-maximal concentration of the agonist (here glutamate) in the presence of the compound. Observed.

27. Behavior assessment

Average locomotor activity is the average distance traveled in a standard 16 x 16 photocell test chamber (Med Associates, St. Albans, VT), measured 43.2 cm (L) x 43.2 cm (W) x 30.5 cm (H). (cm). Animals may become accustomed to the individual active chambers for at least 60 min prior to drug administration. After administration of the appropriate drug or medium, the activity can be recorded at 3 hr time intervals. The data can be expressed as mean (± SEM) travel distances recorded at intervals of 10 min over the test period. Data can be assessed by repeated measurements of ANOVA followed by post-hoc testing using Tukey's HSD test if appropriate. The deviation can be considered significant when p ≦ 0.05.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those of ordinary skill in the art in view of the detailed description and examples of the invention disclosed herein. The detailed description and examples of the present invention should be considered as illustrative only, and the true scope and spirit of the present invention is indicated by the following claims.

Claims (90)

One or more compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof, are effective and dosages for treating neurological and / or mental disorders associated with glutamate dysfunction in a mammal. A method of treating neurological and / or mental disorders associated with glutamate dysfunction in a mammal, comprising administering to the mammal as follows:

here Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms, L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Is selected from an organic radical comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl; And Wherein R ⁸ is hydrogen and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 hetero Alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, An organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl. Administering to the mammal at least one compound having a structure represented by the following formula or a pharmaceutically acceptable salt or N-oxide thereof in a dosage and dosage effective for enhancing metabolic glutamate receptor activity in the mammal; A method of enhancing metabolic glutamate receptor activity in a mammal, comprising:

here Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms; And L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Selected from organic radicals comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl. The administration of one or more compounds having a structure represented by the following formula or a pharmaceutically acceptable salt or N-oxide thereof to the mammal at a dosage and a dosage effective to induce partial action of metabolic glutamate receptor activity in the mammal. A method of partially operating metabolic glutamate receptor activity in a mammal, comprising the steps of: here Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms, L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Selected from organic radicals comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl. Administering to the mammal at least one compound having a structure represented by the following formula, or a pharmaceutically acceptable salt or N-oxide thereof, in dosages and dosages effective for improving cognition in the mammal: How to improve cognition in mammals:

here Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms, L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Selected from organic radicals comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl. 5. The method of claim 4, wherein the cognitive improvement is a significant statistical increase in cognitive memory for the new thing. 5. The method of claim 4, wherein the cognitive improvement is a significant statistical increase in Wisconsin card sorting scores. The method of any one of claims 1 to 4, wherein the mammal is a human. The method of claim 1, wherein the mammal has a need to treat the disorder prior to administration. The method of claim 1, wherein the mammal has been diagnosed as having a need to treat the disorder prior to administration. The method of claim 1, wherein the disorder is dementia, delirium, amnesia, cognitive decline due to aging, schizophrenia, schizophrenia, schizophrenia, schizoaffective disorder, delusional disorder, short-term psychotic disorder , Substance-related disorders, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorders, lethargic seizures, anxiety, affective disorders, panic attacks, unipolar depression, mood swings, and A method of treating neurological and / or mental disorders associated with glutamate dysfunction in a mammal, characterized in that it is selected from psychotic depression. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

Wherein R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to To form an optionally substituted heterocyclic ring having 7 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 5 substituents independently selected from amine-carbonyl. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

Wherein R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 Optionally substituted heterocyclic rings having from 7 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; Z comprises 0 to 2 carbons; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and, 9 to 13 substituents independently selected from alkylamine-carbonyl. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

Wherein R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to An optionally substituted heterocyclic ring having 7 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and, 5 substituents independently selected from alkylamine-carbonyl. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

Wherein R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to Optionally substituted heterocyclic rings having 7 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and, 5 substituents independently selected from alkylamine-carbonyl. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

Wherein R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to An optionally substituted heterocyclic ring having 7 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 5 substituents independently selected from amine-carbonyl. The compound of claim 11, wherein R ¹ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons, How to feature. The compound of claim 11, wherein R ² is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl. Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons Characterized by the above. The process of claim 11, wherein at least one R ³ Substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocyclo And is selected from alkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, and having from 2 to 7 carbons. The process of claim 11, wherein at least one R ₄ Substituents are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocyclo And is selected from alkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, and has 2 to 7 carbons. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

Wherein R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl; Y ¹ is selected from N and CR ⁴ ; Y ² is selected from N and CH; Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

here R ¹ is hydrogen or optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, R ¹ does not contain silicon; And R ⁵ is an organic radical containing 4 to 14 carbon atoms, and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, and when R ¹ is methyl, R ⁵ is An organic radical containing 4 to 14 carbon atoms; Y ¹ is selected from N and CR ⁴ ; And Y ² is selected from N and CH. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

here Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms; Y ¹ is selected from N and CR ⁴ ; And Y ² is selected from N and CH. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

here Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; Y ¹ is selected from N and CR ⁴ ; Y ² is selected from N and CH; And R ⁵ is an organic radical containing 4 to 14 carbon atoms and R ⁵ does not comprise a triphenylamine residue or a benzimidamide residue. The method according to any one of claims 1 to 4, wherein the compound has a structure represented by the following general formula:

here n is 2, 3 or 4; R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; And Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; Y ¹ is selected from N and CR ⁴ ; Y ² is selected from N and CH; And R ⁵ is an organic radical containing 4 to 14 carbon atoms. The method according to any one of claims 20 to 24, R ¹ is optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally Substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optional Is an organic radical comprising 1 to 12 carbon atoms selected from aryl, optionally substituted heteroaryl, and-(CH ₂ ) _m -aryl or-(CH ₂ ) _m -heterocycle, m being 1, 2, 3 or 4; R ^2a and R ^2b , if present, together comprise ═O or ═S, or each R ^2a and R ^2b is, independently, optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 Alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkinyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl Optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally Substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Line from amine-carbonyl An organic radical containing 1 to 6 carbon atoms taken; R ^3a and R ^3b together comprise ═O or = S, or each R ^3a and R ^3b is independently an optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, optionally Substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, Optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl 1 to 6 selected from Of an organic radical containing a carbon atom; R ⁴ , If present, is optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl , Optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkyne One, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted An organic radical comprising 1 to 12 carbon atoms independently selected from amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl; And R ⁵ is optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted And an organic radical comprising 4 to 14 carbon atoms selected from heteroaryl. Administering to the mammal at least one compound having the following structure, or a pharmaceutically acceptable salt or N-oxide thereof, in a dosage and dosage effective for treating the disorder in the mammal; How to treat:

here n is 0, 1, 2, 3 or 4; Y ¹ and Y ² are independently selected from C and N; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b , When present, together comprise ═O or ═S, or each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or, 1 to 6 carbon atoms It is an organic radical containing; R ^3a and R ^3b together comprise = O or = S, or each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; R ⁴ comprises hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or 1, 2 or 3 substituents independently present as organic radicals containing 1 to 12 carbon atoms;       L is an organic divalent radical containing 1 to 7 carbon atoms; And R ⁵ is an organic radical containing 4 to 14 carbon atoms. The method of claim 26, wherein the compound comprises or a pharmaceutically acceptable salt or N-oxide thereof: a. Isoindolin-1-one derivatives having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl; b. Isoindolin-1,3-dione derivatives having the structure:

Wherein R ¹ is hydrogen or optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, R ¹ does not contain silicon; And R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl and when R ¹ is methyl, R ⁵ is An organic radical containing 4 to 14 carbon atoms; c. 3,4-Dihydroisoquinolin-1 (2H) -one derivative having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; And R ⁵ is an organic radical containing 4 to 14 carbon atoms; d. Isoquinoline-1,3 (2H, 4H) -dione derivatives having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical containing 4 to 14 carbon atoms and R ⁵ does not comprise a triphenylamine residue or a benzimidamide residue; or e. Cyclic compounds having the structure:

Wherein n is 2, 3 or 4; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; And R ⁵ is an organic radical containing 4 to 14 carbon atoms, Y ¹ is selected from N and CR ⁴ ; Y ² is selected from N and CH; Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted egg Coxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxami , Amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl; And R ⁸ is hydrogen, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkyne One, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optional And an organic radical comprising 1 to 6 carbon atoms selected from aryl substituted with, and optionally substituted heteroaryl. 28. The method of claim 26 or 27, wherein the mammal is a human. 28. The method of claim 26 or 27, wherein the mammal has been diagnosed with the need to treat the disorder prior to administration. 28. The method of claim 26 or 27, wherein the disorder is one or more neurological and / or mental disorders associated with glutamate dysfunction in a mammal. 28. The method of claim 26 or 27, wherein the disorder is dementia, delirium, amnesia, cognitive decline following aging, schizophrenia, schizophrenia, schizophrenia, schizoaffective disorder, delusional disorder , Short term psychotic disorder, substance-related disorder, mobility disorder, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorder, brain edema, sleep disorder, narcolepsy, anxiety, affective disorder, panic attack, unipolarity And depression, mood swings, and psychotic depression. Compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

here R ¹ and R ² are independently an optionally substituted organic radical containing 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents independently selected from amine-carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Shown as an increase in 33. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 32, wherein R ¹ and R ² are independently alkyl having 1 to 6 carbons. 33. The compound or pharmaceutically acceptable salt thereof of claim 32, wherein N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having from 2 to 7 carbons; N-oxides. 33. The compounds or pharmaceutically acceptable salts or N-oxides of claim 32, wherein Z ¹ , Z ² , and Z ³ are all carbon. 33. The compounds or pharmaceutically acceptable salts or N-oxides of claim 32, wherein R ⁴ comprises up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. 33. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 32, wherein both Y ¹ and Y ² are carbon. 33. A compound or a pharmaceutically acceptable salt or N-oxide thereof according to claim 32, having a structure represented by the following general formula:

The compound of claim 38, wherein R ¹ and R ² are independently alkyl having 1 to 6 carbons, or N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons. To; R comprises 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl; or a pharmaceutically acceptable salt or N-oxide thereof. 33. A compound or a pharmaceutically acceptable salt or N-oxide thereof according to claim 32, having a structure represented by the following general formula: Wherein R ¹ and R ² are independently optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl , Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to 7 Optionally substituted heterocyclic rings having carbon; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 5 substituents independently selected from amine-carbonyl. 33. A compound or a pharmaceutically acceptable salt or N-oxide thereof according to claim 32, having a structure represented by the following general formula:

Wherein R ¹ and R ² are independently optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl , Optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to 7 Optionally substituted heterocyclic rings having carbon; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 4 substituents independently selected from amine-carbonyl. Compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

here R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents independently selected from amine-carbonyl; And R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or are independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally Optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3- C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl Optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, Shown sulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl amines are selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Shown as an increase in 43. The compounds or pharmaceutically acceptable salts or N-oxides of claim 42, wherein R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons. 43. The compound or pharmaceutically acceptable salt thereof of claim 42, wherein N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having from 2 to 7 carbons; N-oxides. 43. The compounds or pharmaceutically acceptable salts or N-oxides of claim 42, wherein Z ¹ , Z ² , and Z ³ are all carbon. 43. The compounds or pharmaceutically acceptable salts or N-oxides of claim 42, wherein R ⁴ comprises up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. 43. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 42, wherein both Y ¹ and Y ² are carbon. 43. The compounds or pharmaceutically acceptable salts or N-oxides of claim 42, wherein both R ^7a and R ^7b are hydrogen. The compound or a pharmaceutically acceptable salt or N-oxide thereof, according to claim 42, wherein the compound has a structure represented by the following general formula:

The optionally substituted hetero of claim 49, wherein R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons, or N, R ¹ , and R ² together have 2 to 7 carbons. Cyclic rings; R comprises 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl; or a pharmaceutically acceptable salt or N-oxide thereof. The compound or a pharmaceutically acceptable salt or N-oxide thereof, according to claim 42, wherein the compound has a structure represented by the following general formula:

here R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkyne One, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to 7 An optionally substituted heterocyclic ring having 3 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 5 substituents independently selected from amine-carbonyl. Compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

here R ¹ and R ² are independently an optionally substituted organic radical containing 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents independently selected from amine-carbonyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Shown as an increase in The compound or pharmaceutically acceptable salt or N-oxide thereof according to claim 52, wherein R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons. 53. The compound or pharmaceutically acceptable salt thereof of claim 52, wherein N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having from 2 to 7 carbons; N-oxides. The compound of claim 52, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Z ¹ , Z ² , and Z ³ are all carbon. The compound or pharmaceutically acceptable salt or N-oxide of claim 52, wherein R ⁴ comprises up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. 53. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 52, wherein both Y ¹ and Y ² are carbon. The compound or a pharmaceutically acceptable salt or N-oxide thereof, according to claim 52, wherein the compound has a structure represented by the following general formula:

59. The compound of claim 58, wherein R ¹ and R ² are independently alkyl having 1 to 6 carbons, or N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having 2 to 7 carbons. and; R comprises 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl; or a pharmaceutically acceptable salt or N-oxide thereof. The compound or a pharmaceutically acceptable salt or N-oxide thereof, according to claim 52, wherein the compound has a structure represented by the following general formula:

Wherein R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cyclo Alkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to An optionally substituted heterocyclic ring having 7 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 5 substituents independently selected from amine-carbonyl. Compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

here R ¹ and R ² are independently hydrogen or an optionally substituted organic radical comprising 1 to 12 carbon atoms; Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; Z ¹ , Z ² , and Z ³ are independently selected from N and CR ^{4 and} at least two of Z ¹ , Z ² , and Z ³ are nitrogen; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Up to 5 substituents independently selected from amine-carbonyl; And R ⁸ is selected from hydrogen and lower alkyl; Wherein the compound enhances the mGluR5 response to glutamate in response to glutamate in the absence of the compound, in response to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Shown as an increase in 62. The compounds or pharmaceutically acceptable salts or N-oxides of claim 61, wherein R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein N, R ¹ , and R ² together comprise an optionally substituted heterocyclic ring having from 2 to 7 carbons; N-oxides. 62. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 61, wherein Z ¹ , Z ² , and Z ³ are all carbon. 62. The compounds or pharmaceutically acceptable salts or N-oxides of claim 61, wherein R ⁴ comprises up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. 62. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 61, wherein both Y ¹ and Y ² are carbon. 62. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 61, wherein R ⁸ is hydrogen. 62. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 61, wherein the compound has a structure represented by the following general formula:

The compound of claim 68, wherein R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons, or N, R ¹ , and R ² together are optionally substituted hetero having 2 to 7 carbons. Cyclic rings; R comprises 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl; or a pharmaceutically acceptable salt or N-oxide thereof. 62. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 61, wherein the compound has a structure represented by the following general formula:

here R ¹ and R ² are independently hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkyne One, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together are 2 to 7 Optionally substituted heterocyclic ring having 6 carbons; R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Four substituents independently selected from amine-carbonyl; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl Or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl 5 substituents independently selected from amine-carbonyl. Compounds having a structure represented by the following general formula or a pharmaceutically acceptable salt or N-oxide thereof:

here Each ----- is an optional covalent bond; Y ¹ and Y ² are independently selected from N and CR; Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or organic radical containing 1 to 12 carbon atoms; R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms; R ⁰ is an optionally substituted organic radical containing 4 to 14 carbon atoms, L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Is selected from an organic radical comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl; And R ⁸ is hydrogen, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkyne One, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optional And an organic radical comprising 1 to 6 carbon atoms selected from aryl substituted with, and optionally substituted heteroaryl; Wherein the compound enhances the mGluR5 response to glutamate compared to the response to glutamate in the absence of the compound, to a non-maximal concentration of glutamate in human fetal kidney cells infected with murine mGluR5 in the presence of the compound. Shown as an increase in 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound has a structure represented by the following general formula:

here R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl; Y ¹ is selected from N and CR ⁴ ; Y ² is selected from N and CH; Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; And R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound has a structure represented by the following general formula:

here R ¹ is hydrogen or alkyl having 1 to 6 carbons; R ^3a and R ^3b are independently hydrogen, halogen, or lower alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound has a structure represented by the following general formula:

Wherein R ¹ is hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, and , R ¹ does not contain silicon; And R ⁵ is an organic radical containing 4 to 14 carbon atoms, and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl and when R ¹ is methyl, R ⁵ is An organic radical containing 4 to 14 carbon atoms; Y ¹ is selected from N and CR ⁴ ; And Y ² is selected from N and CH. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound has a structure represented by the following general formula:

here R ¹ is hydrogen or alkyl having 1 to 6 carbons; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound has a structure represented by the following general formula:

here Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; R ⁵ is an organic radical containing 4 to 14 carbon atoms; Y ¹ is selected from N and CR ⁴ ; And Y ² is selected from N and CH. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound has a structure represented by the following general formula:

here R ¹ is hydrogen or alkyl having 1 to 6 carbons; R ^2a , R ^2b , R ^3a , and R ^3b are independently hydrogen, halogen, or lower alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound has a structure represented by the following general formula:

here Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; Y ¹ is selected from N and CR ⁴ ; Y ² is selected from N and CH; And R ⁵ is an organic radical containing 4 to 14 carbon atoms and R ⁵ does not comprise a triphenylamine residue or a benzimidamide residue. 72. The compound or pharmaceutically acceptable salt or N-acid compound thereof according to claim 71, wherein the compound has a structure represented by the following general formula:

here R ¹ is hydrogen or alkyl having 1 to 6 carbons; R ^3a and R ^3b are independently hydrogen, halogen, or lower alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound has a structure represented by the following general formula:

here n is 2, 3 or 4; R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; And Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; Y ¹ is selected from N and CR ⁴ ; Y ² is selected from N and CH; And R ⁵ is an organic radical containing 4 to 14 carbon atoms. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound has a structure represented by the following general formula:

here R ¹ is hydrogen or alkyl having 1 to 6 carbons; R ^2a , R ^2b , R ^3a , and R ^3b are independently hydrogen, halogen, or lower alkyl; And R ⁴ comprises five substituents independently selected from hydrogen, halogen, and lower alkyl. 82. The method of any of claims 71-81, R ¹ is optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally Substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optional Is an organic radical comprising 1 to 12 carbon atoms selected from aryl, optionally substituted heteroaryl, and-(CH ₂ ) _m -aryl or-(CH ₂ ) _m -heterocycle, wherein m is 1, 2, 3 or 4; R ^2a and R ^2b , if present, together comprise ═O or ═S, or each R ^2a and R ^2b is, independently, optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 Alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkinyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl Optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally Substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Line from amine-carbonyl An organic radical containing 1 to 6 carbon atoms taken; R ^3a and R ^3b together comprise ═O or = S, or each R ^3a and R ^3b is independently an optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, optionally Substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, Optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl 1 to 6 selected from And the carbon atom to an organic radical containing; R ⁴ , If present, is optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl , Optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkyne One, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted An organic radical comprising 1 to 12 carbon atoms independently selected from amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl; And R ⁵ is optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted Characterized in that it is an organic radical containing 4 to 14 carbon atoms selected from heteroaryl, Compounds or their pharmaceutically acceptable salts or N-oxides. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound comprises a structure having the general formula:

72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound comprises a structure having the general formula:

here, R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or are independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, optionally Optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3- C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl Optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, Shown sulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl amines selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl group. 72. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 71, wherein the compound comprises a structure having the general formula:

Wherein R ^7a and R ^7b are independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, optionally Optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl Optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbon Bonil Selected from organic radicals containing from 1 to 5 carbon atoms. Enhancing the mGluR5 response to glutamate in the presence of the compound, as compared to the response to glutamate in the absence of the compound, as a compound or a pharmaceutically acceptable salt or N-oxide thereof, comprising Compounds or their pharmaceutically acceptable salts or N-oxides, which show as an increase in response to non-maximal concentrations of glutamate in human fetal kidney cells infected with: a. Isoindolin-1-one derivatives having the structure:

Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And Wherein R ⁵ is an organic radical containing 4 to 14 carbon atoms and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl; b. Isoindolin-1,3-dione derivatives having the structure:

here, R ¹ is hydrogen or is selected from optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, R ¹ does not contain silicon; And R ⁵ is an organic radical containing 4 to 14 carbon atoms, and when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl and when R ¹ is methyl, R ⁵ is An organic radical containing 4 to 14 carbon atoms; c. 3,4-Dihydroisoquinolin-1 (2H) -one derivative having the structure:

here, R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; Each of R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; And R ⁵ is an organic radical containing 4 to 14 carbon atoms; d. Isoquinoline-1,3 (2H, 4H) -dione derivatives having the structure:

here, R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; And R ⁵ is an organic radical containing 4 to 14 carbon atoms and R ⁵ does not comprise a triphenyl amine residue or a benzimidamide residue; or e. Cyclic compounds having the structure:

here, n is 2, 3 or 4; R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms; R ^2a and R ^2b together comprise = O or = S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 to 6 carbon atoms It is an organic radical containing; And R ⁵ is an organic radical containing 4 to 14 carbon atoms, Y ¹ is selected from N and CR ⁴ ; Y ² is selected from N and CH; Each of R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms; L is an organic divalent radical containing 1 to 7 carbon atoms and is selected from:

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3 -C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl Optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide Is selected from an organic radical comprising 1 to 5 carbon atoms selected from amino, carbonyl, and alkylamine-carbonyl; And Wherein R ⁸ is hydrogen and optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 hetero Alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, An organic radical comprising 1 to 6 carbon atoms selected from optionally substituted aryl, and optionally substituted heteroaryl. 87. The method of claim 86, R ¹ is optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally Substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optional Is an organic radical comprising 1 to 12 carbon atoms selected from aryl substituted with, optionally substituted heteroaryl, and-(CH ₂ ) _m -aryl or-(CH ₂ ) _m -heterocycle, wherein m is 1 , 2, 3 or 4; R ^2a and R ^2b , if present, together comprise ═O or ═S, or each R ^2a and R ^2b is, independently, optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 Alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkinyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl Optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally Substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Line from amine-carbonyl An organic radical containing 1 to 6 carbon atoms taken; R ^3a and R ^3b together comprise ═O or = S, or each R ^3a and R ^3b is independently an optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, optionally Substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, Optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl 1 to 6 selected from And the carbon atom to an organic radical containing; R ⁴ , if present, is optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl or C 2 -C 6 heteroalkenyl or C 2 -C 6 Heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 Heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optional Organic radicals comprising 1 to 12 carbon atoms independently selected from amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl substituted by High; And R ⁵ is optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted Characterized in that it is an organic radical containing 4 to 14 carbon atoms selected from heteroaryl, Compounds or their pharmaceutically acceptable salts or N-oxides. 87. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 86, wherein the compound comprises a structure having the general formula

87. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 86, wherein the compound comprises a structure having the general formula

Wherein R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2 to 5 carbons, or independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and, Optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3 -C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted Aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thio Not shown, Dorsal sulfonyl amino, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl amines selected from organic radicals which contain from 1 to 5 carbon atoms selected from a carbonyl group. 87. The compound or pharmaceutically acceptable salt or N-oxide thereof, according to claim 86, wherein the compound comprises a structure having the general formula

Wherein R ^7a and R ^7b are independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, optionally Optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl Optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbon Bonil Chosen from organic radicals containing a selected one to five carbon atoms.

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