JP2010529135A - Positive allosteric modulators of benzamide mGluR5 and methods of making and using the same - Google Patents

Abstract

In one aspect, the present invention provides compounds comprising benzamide derivatives and cyclic benzamide derivatives that are useful as positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGluR5), and synthetic methods for making the compounds And a pharmaceutical composition comprising the compound, and a method for treating neurological and psychiatric disorders associated with glutamate dysfunction using the compound and the composition. This summary is intended as a means of reviewing the summary for searching in a particular field and is not intended to limit the invention.

Description

(Cross-reference of related applications)
This application claims the benefit of US Application No. 60 / 941,686, filed June 3, 2007, and US Application No. 60 / 985,041, filed November 2, 2007. And are hereby incorporated by reference in their entirety.

(Approve)
This invention was made with US government support under grant numbers NIH / NIMH R01 MH062646 and F32 NS049865 awarded by the National Institutes of Health. The US government has certain rights in the invention.

L-glutamate, the most common neurotransmitter in the central nervous system, is involved in a number of physiological processes. Glutamate-dependent stimulatory receptors are divided into two main groups. The first major group forms ligand-controlled ion channels. The second major group is the metabotropic glutamate receptor (mGluR), which belongs to the family of G protein coupled receptors. Metabotropic glutamate receptors, including mGluR5, are involved in a wide range of biological functions, indicating a possible role for the mGluR5 receptor in various disease processes in mammals. Metabotropic glutamate receptor ligands should be used to treat or prevent acute and / or chronic nerves and / or psychiatric disorders associated with glutamate dysfunction such as psychosis, schizophrenia, cognitive decline with age Can do.

Selective positive allosteric modulators are compounds that do not directly activate the receptor by themselves, but the binding of these compounds increases the affinity of glutamate site agonists at their extracellular N-terminal binding site Let Thus, positive allosteric modulation (enhancement) is an attractive mechanism for enhancing the activation of appropriate physiological receptors.

Unfortunately, there are few selective positive allosteric modulators for the mGluR5 receptor. Furthermore, conventional mGluR5 receptor modulators generally lack sufficient aqueous solubility and exhibit poor oral bioavailability. Thus, there is a need for methods and compositions that overcome these deficiencies and that effectively provide selective positive allosteric modulators for the mGluR5 receptor.

In accordance with the purpose of the present invention, as embodied and broadly described herein, in one aspect, the present invention provides a positive allosteric modulator of metabotropic glutamate receptor subtype 5 (mGluR5) ( That is, the present invention relates to a compound useful as an enhancer), a method for producing the same, a pharmaceutical composition containing the same, and a method for treating neurological and psychiatric disorders associated with glutamate dysfunction using the compound.

Disclosed is a method for the treatment of a disease in a mammal, the method comprising the formula

により表される構造を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における疾患を治療するのに有効な投与量および用量で、投与するステップを含む。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Administering at least one compound having a structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof in a dosage and dose effective to treat a disease in a mammal.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成する、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1 to 5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms, 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 Properly it is chosen from organic radicals containing C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, 1-6 carbon atoms selected optionally substituted aryl, and optionally substituted heteroaryl.

Also disclosed is a method for enhancing metabotropic glutamate receptor activity in a mammal, the method comprising:

により表される構造を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における代謝型グルタミン酸受容体活性を増強するのに有効な用量および量で、投与するステップを含む。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

At least one compound having a structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof in a dosage and amount effective to enhance metabotropic glutamate receptor activity in a mammal Includes steps.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成する、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1 to 5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms.

Also disclosed is a method for a receptor partial activation effect of metabotropic glutamate receptor activity in a mammal, the method comprising:

により表される構造を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における代謝型グルタミン酸受容体活性の受容体部分活性化作用を示すのに有効な投与量および用量で、投与するステップを含む。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Administration of at least one compound having a structure represented by the formula: or a pharmaceutically acceptable salt or N-oxide thereof, effective to exhibit a receptor partial activation action of metabotropic glutamate receptor activity in a mammal Administering in an amount and dose.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成する、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1 to 5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms.

Also disclosed is a method for enhancing cognition in a mammal, the method comprising:

により表される構造を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における認知を増進するのに有効な投与量および用量で、投与するステップを含む。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Administering at least one compound having the structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof in a dosage and dose effective to enhance cognition in a mammal.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成する、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個炭素原子を含む有機ラジカルから独立して選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1 to 5 carbons selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl It is independently selected from organic radicals containing atoms.

Also disclosed is a method for treating a disease in a mammal, the method comprising:

を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における疾患を治療するのに有効な投与量および用量で、投与するステップを含む。
ここで式中、ｎは、０、１、２、３、または４であり、Ｙ^１およびＹ^２は、ＣおよびＮから独立して選択され、Ｒ^１は、水素、または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルとして独立して存在する１個、２個、または３個の置換基を含み、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

Administering at least one compound having the formula: or a pharmaceutically acceptable salt or N-oxide thereof in a dosage and dose effective to treat a disease in a mammal.
Where n is 0, 1, 2, 3, or 4, Y ¹ and Y ² are independently selected from C and N, and R ¹ is hydrogen or 1-12 An organic radical containing a carbon atom, and R ^2a and R ^2b, if present, together form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, Nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b independently hydrogen, halogen, hydroxyl, cyano, an organic radical comprising a nitro, thiol, amino, or 1 to 6 carbon atoms, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or, Including one, two, or three substituents present independently as an organic radical containing ˜12 carbon atoms, L is an organic divalent radical containing 1-7 carbon atoms, R ⁵ is an organic radical containing 4 to 14 carbon atoms.

Also the formula

により表される構造を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物を開示し、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、Ｒ^１およびＲ^２は独立して、１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｚ^１、Ｚ^２、およびＺ^３は、ＮおよびＣ−Ｒ^４から独立して選択され、但し、Ｚ^１、Ｚ^２、およびＺ^３のうち最大２つまでが、窒素であり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される最大５個の置換基を含む。

Or a pharmaceutically acceptable salt or N-oxide thereof, wherein the compound is present in the presence of the compound as compared to the reaction to glutamic acid in the absence of the compound. Below, the enhancement of mGluR5 response to glutamate is shown as increased response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5.
Where R ¹ and R ² are independently an optionally substituted organic radical containing 1 to 12 carbon atoms, each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, wherein each R is independently from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Contains up to 5 substituents independently selected from amine-carbonyl.

Also the formula

により表される構造を有する化合物であって、またはその医薬的に許容される塩もしくはＮ酸化物を開示し、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｚ^１、Ｚ^２、およびＺ^３は、ＮおよびＣ−Ｒ^４から独立して選択され、但し、Ｚ^１、Ｚ^２、およびＺ^３のうち最大２つまでが、窒素であり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される最大５個の置換基を含み、Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択される。

Or a pharmaceutically acceptable salt or N-oxide thereof, wherein the compound has a structure as compared to the reaction to glutamic acid in the absence of the compound, In the presence of compounds, in rat embryonic kidney cells transfected with rat mGluR5, enhanced mGluR5 response to glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
Wherein R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms, each ----- is any covalent bond , Y ¹ and Y ² are independently selected from N and C—R, where each R is independent of hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 heteroalkyl Quinyl, 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamines - contain up to 5 substituents independently selected from carbonyl, R ^7a and R ^7b together form a carbocyclic or heterocyclic ring optionally substituted with 2-5 carbons 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 alkyl 1-5 carbon atoms selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. It is independently selected from the organic radicals it contains.

Also, the formula

により表される構造を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物を開示し、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、Ｒ^１およびＲ^２は独立して、１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｚ^１、Ｚ^２、およびＺ^３は、ＮおよびＣ−Ｒ^４から独立して選択され、但し、Ｚ^１、Ｚ^２、およびＺ^３の最大２つまでが、窒素であり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される最大５個の置換基を含む。

Or a pharmaceutically acceptable salt or N-oxide thereof, wherein the compound is present in the presence of the compound as compared to the reaction to glutamic acid in the absence of the compound. Below, the enhancement of mGluR5 response to glutamate is shown as increased response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5.
Where R ¹ and R ² are independently an optionally substituted organic radical containing 1 to 12 carbon atoms, each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C-R, each R is hydrogen, halogen, hydroxyl, cyano, nitro, independently thiol or an organic radical containing 1 to 12 carbon atoms, Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine- Contains up to 5 substituents independently selected from carbonyl.

Also the formula

により表される構造を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物を開示し、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｚ^１、Ｚ^２、およびＺ^３は、ＮおよびＣ−Ｒ^４から独立して選択され、但し、Ｚ^１、Ｚ^２、およびＺ^３のうち最大２つまでが、窒素であり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される最大５個の置換基を含み、Ｒ^８は、水素および低級アルキルから選択される。

Or a pharmaceutically acceptable salt or N-oxide thereof, wherein the compound is present in the presence of the compound as compared to the reaction to glutamic acid in the absence of the compound. Below, the enhancement of mGluR5 response to glutamate is shown as increased response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5.
Wherein R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms, each ----- is any covalent bond , Y ¹ and Y ² are independently selected from N and C—R, where each R is independent of hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 heteroalkyl Quinyl, 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, And up to 5 substituents independently selected from alkylamine-carbonyl, R ⁸ is selected from hydrogen and lower alkyl.

Also, the formula

により表される構造を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物も開示し、該化合物は、該化合物の不在下で、グルタミンへの反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は独立して、ＮおよびＣ−Ｒから選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Or a pharmaceutically acceptable salt or N-oxide thereof, wherein the compound is present in the absence of the compound as compared to the reaction to glutamine. Below, the enhancement of mGluR5 response to glutamate is shown as increased response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成する、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1 to 5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms, 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 Properly it is chosen from organic radicals containing C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, 1-6 carbon atoms selected optionally substituted aryl, and optionally substituted heteroaryl.

Glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound as compared to response to glutamate in the absence of the compound Also disclosed are compounds that exhibit enhanced mGluR5 response to, including:
Construction

を有するイソインドリン−１−オン誘導体であって、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルである。
構造

An isoindoline-1-one derivative having:
In the formula, 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, provided that R ¹ is hydrogen. , R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.
Construction

を有するイソインドリン−１，３−ジオン誘導体であって、
式中、Ｒ^１は、水素である、または任意に置換されたＣ１−Ｃ１２アルキル、任意に置換されたＣ１−Ｃ１２ヘテロアルキル、任意に置換されたＣ３−Ｃ１２シクロアルキル、または任意に置換されたＣ３−Ｃ１２ヘテロシクロアルキルから選択され、但し、Ｒ^１は、シリコンを含まず、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルであり、但し、Ｒ^１がメチルである場合、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。構造

An isoindoline-1,3-dione derivative having:
Wherein R ¹ is hydrogen or an optionally substituted C1-C12 alkyl, an optionally substituted C1-C12 heteroalkyl, an optionally substituted C3-C12 cycloalkyl, or an optionally substituted Selected from C 3 -C 12 heterocycloalkyl, wherein R ¹ is silicon free and R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that when R ¹ is hydrogen, ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that when R ¹ is methyl, R ⁵ is an organic radical containing 4 to 14 carbon atoms. Construction

を有する３，４−ジヒドロイソキノリン−１（２Ｈ）−オン誘導体であって、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、各Ｒ^２ａおよびＲ^２ｂは、それぞれ独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。
構造

A 3,4-dihydroisoquinolin-1 (2H) -one derivative having:
Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing from 1 to 6 carbon atoms, R ⁵ is an organic radical containing 4 to 14 carbon atoms.
Construction

を有するイソキノリン−１，３（２Ｈ，４Ｈ）−ジオン誘導体であって、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^５は、トリフェニルアミン残基またはベンズイミダアミド残基を含まない。
または、構造

An isoquinoline-1,3 (2H, 4H) -dione derivative having:
In which 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, provided that R ⁵ is triphenylamine Does not contain residues or benzimidamide residues.
Or structure

を有する二環式化合物であって、
式中、ｎは、２、３、または４であり、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、もしくは１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである、二環式化合物、またはこれらの医薬的に許容される塩もしくはＮ酸化物を含む、化合物であって、Ｙ^１は、ＮおよびＣ−Ｒ^４から選択され、Ｙ^２は、ＮおよびＣ−Ｈから選択され、各Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子含む有機ラジカルであり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

A bicyclic compound having:
In the formula, n is 2, 3, or 4, R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and R ^2a and R ^2b together form ═O or ═S. Or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, and R ⁵ is 4 to 14 A bicyclic compound which is an organic radical containing one carbon atom, or a compound comprising a pharmaceutically acceptable salt or N oxide thereof, wherein Y ¹ is selected from N and C—R ⁴ Y ² is selected from N and C—H and each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic containing 1 to 6 carbon atoms radical There, R ⁴ is hydrogen, halogen, hydroxyl, cyano, an organic radical comprising a nitro, thiol, or 1 to 12 carbon atoms, L is an organic divalent radical containing from 1 to 7 carbon atoms Yes,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成する、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子含む有機ラジカルから選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1 to 5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms, 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 Properly is selected from C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, and 1-6 carbon atoms include organic radical selected from optionally substituted heteroaryl.

Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound and a pharmaceutically acceptable carrier.

Also disclosed are methods for preparing the disclosed compounds.

The product of the disclosed method is also disclosed.

Also disclosed is a method of producing a medicament for enhancing metabotropic glutamate receptor activity in a mammal, the method comprising at least one disclosed compound, or a pharmaceutically acceptable salt or N-oxide thereof, Mixing with a pharmaceutically acceptable carrier.

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

Aspects of the invention may be described and claimed in certain legal classifications, such as system legal classifications, but this is for convenience only and those skilled in the art will recognize that each aspect of the invention can be It will be appreciated that can be described and claimed. Unless otherwise specifically stated, any method or aspect described herein is not intended to be construed as requiring that the steps be performed in a specific order. Thus, unless the method claims specifically state in the claims or description that the steps are limited to a particular order, the order is not intended to be inferred in any way. This may be of any possibility for interpretation, including an explicit meaning arising from the sequence of steps or workflows, grammatical construction or punctuation, or the number or type of aspects described herein. It also applies to some extraordinary standards.

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects, and are accompanied by explanations, serve to explain the principles of the invention.
Schematic of NMDA receptor. Schematic illustrating that activation of mGluR5 enhances NMDA receptor function. The figure explaining the allosteric adjustment of mGluR5. FIG. 3 shows CDPPB as a potent and selective mGluR5 potentiator with mild efficacy in a rodent behavior model for antipsychotic activity. The figure which shows the classification | category of the compound as an agonist, an enhancer, and an antagonist. The schematic diagram explaining optimization of a candidate. [3H] methoxy PEPy substitution table and diagram showing binding to MPEP sites with various affinities. The figure which shows the in vivo effectiveness of (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (compound VU13). The figure which shows the in-vivo effectiveness of (4-hydroxy-4-propyl piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (compound VU60). The figure which shows the in vivo effectiveness of (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (compound VU14 / C104B2). The figure which shows the improvement of recognition in the novel object recognition (NOR) paradigm by ADX47273. The figure which shows the effect of VU000067 with respect to amphetamine-induced excessive exercise (male Sprague-Dawley rat-200 to 225 grams, N = 4 / treatment group, VU000067 was intraperitoneally treated for 30 minutes). The figure which shows the effect of VU000098 with respect to the amphetamine-induced hypermotion (male Sprague-Dawley rat -200-225 grams, N = 4 / treatment group, VU000098 was pretreated intraperitoneally for 30 minutes). The figure which shows the effect of VU000069 with respect to amphetamine-induced hypermotion (male Sprague-Dawley rat-200-225 grams, N = 4 / treatment group, VU000069 intraperitoneally for 30 minutes, pretreatment). The figure which shows the chemical structure of mGluR5 PAM which has the in vivo activity in the antipsychotic model before a clinic. The figure which shows the improvement of the amphetamine-induced excessive exercise by CDPPB. The figure which shows the improvement of the amphetamine induced excessive exercise by ADX47273. The figure which shows the improvement of the amphetamine-induced excessive exercise | movement by VU00013 and VU000067. The figure which shows the improvement of the amphetamine induced prepulse suppression (PPI) by CDPPB. The figure which shows the improvement of the amphetamine induced prepulse suppression (PPI) by ADX47273. The figure which shows the improvement of the amphetamine induced prepulse suppression (PPI) by ADX47273. FIG. 4 shows an increase in the strength of synaptic binding after stimulation of synapses in the presence and absence of two structurally different mGluR5 PAMs, VU29 (upper panel), and ADX47273 (lower panel).

Additional advantages of the invention will be set forth in the description that follows, and in part will be apparent from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

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

Prior to disclosing and describing the present compounds, compositions, articles, systems, devices, and / or methods, unless otherwise specified, not limited to specific synthetic methods or specific reagents, unless otherwise specified, Thus, it should be understood that it can of course be different. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the example methods and materials are now described.

All publications mentioned in this specification are herein incorporated by reference to disclose and explain the methods and / or materials associated with those cited in the publication. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing in this specification should be construed as an admission that the invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may differ from the actual publication dates and may need to be independently confirmed.

A. Definitions As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural meanings unless the context clearly indicates otherwise. Thus, for example, the meaning of “a functional group” or “an alkyl” or “a residue” means two or more such functional groups, alkyls, residues, etc. A mixture of

Ranges can be expressed herein as from “about” one particular value and / or to “about” another particular value. When such a range is expressed, another aspect includes up to one specific value and / or another specific value. Similarly, where values are expressed as approximations, it will be understood that the particular value forms another aspect by the use of the preceding “about”. It will be further understood that the endpoints of each range are significant in relation to and not related to the other endpoint. It should also be understood that there are many values disclosed herein, and that each value is also disclosed herein as a specific value of “about” in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It should also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13, and 14 are also disclosed.

As used herein and in the last claims, a residue of a chemical species refers to a chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually derived from the chemical species. Refers to the portion that is the product resulting from Thus, the residue of ethylene glycol in the polyester refers to one or more —OCH ₂ CH ₂ O— units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, the residue of sebacic acid in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or its ester to obtain a polyester, is one or more —CO (CH ₂ ) Refers to the ₈ CO- moiety.

As used herein, the term “optional” or “optionally” means that a subsequent event or situation described may or may not occur, the explanation being , Is meant to include instances where the event or situation occurs and instances where it does not occur.

As used herein, the term “positive allosteric modulator of mGluR5 receptor” refers to the presence or absence of an endogenous ligand (such as glutamate) in an animal, particularly a mammal, eg, a human, Refers to any ex vivo administered compound or agent that directly or indirectly increases the activity of the mGluR5 receptor. The term “mGluR5 receptor positive allosteric modulator” refers to compounds that are “mGluR5 receptor allosteric enhancers” or “mGluR5 receptor allosteric agonists”, as well as “mGluR5 receptor allosteric enhancers” and “mGluR5 receptor allosteric enhancers”. A compound having both activities as an “agonist” is included.

As used herein, the term “mGluR5 receptor allosteric potentiator” refers to an endogenous ligand when binding to the orthosteric site of the mGluR5 receptor in animals, particularly mammals, eg, humans. It refers to any exogenously administered compound or drug that directly or indirectly increases the reaction produced by (such as glutamic acid). The mGluR5 receptor allosteric enhancer binds to a site other than the orthosteric site (allosteric site) and positively increases the response of the receptor to the agonist. Since it does not induce receptor desensitization, the activity of the compound as an mGluR5 receptor allosteric enhancer offers advantages over the use of purely mGluR5 receptor allosteric agonists. Such benefits can include, for example, increased safety margins, higher tolerance, reduced potential for abuse, and reduced toxicity.

As used herein, the term “mGluR5 receptor allosteric agonist” refers directly to the activity of the mGluR5 receptor in the absence of endogenous ligands (such as glutamate) in animals, particularly mammals, eg, humans. Refers to any exogenously administered compound or drug that increases. The mGluR5 receptor allosteric agonist binds to the orthosteric glutamate site of the mGluR5 receptor and directly affects the orthosteric site of the mGluR5 receptor. As it does not require the presence of an endogenous ligand, the activity of the compound as a receptor allosteric agonist offers advantages over the use of purely mGluR5 receptor allosteric enhancers, such as rapid onset of action. .

“Treatment” refers to the medical management of a patient for the purpose of curing, ameliorating, stabilizing, or preventing a disease, condition, or disease. The term includes aggressive treatments, i.e., treatments specifically directed to the amelioration of the disease, condition, or disease, and causal treatments, i.e., treatments directed to eliminating the cause of the related disease, condition, or disease. Including. In addition, the term minimizes the development of palliative treatment, i.e., treatment, prophylactic treatment, i.e., related disease, condition, or disease designed to alleviate symptoms rather than cure the disease, condition, or disease. To supplement treatment directed to limiting or partially or completely inhibiting, as well as ancillary treatments, ie other specific treatments directed to the improvement of the relevant disease, condition or disease Including the treatment used,

“Prevent” or “preventing” means making something impossible, avoiding, preventing, stopping, stopping, or interfering, especially with proactive measures It means to do. It should be understood that when alleviating, inhibiting or preventing, as used herein, the use of the other two words is also expressly disclosed unless otherwise indicated.

As used herein, “diagnosed that enhancement of metabotropic glutamate receptor activity is necessary” means that an expert, for example, a doctor who has undergone a physical examination, enhances metabotropic glutamate receptor activity. It is meant to be recognized as a medical condition that can be diagnosed or treated. As used herein, “diagnosed that the receptor partial activation action of metabotropic glutamate receptor activity is necessary” means that an expert, for example, a doctor who has undergone physical examination, receives metabotropic glutamate receptor It means that it is recognized as a pathological condition that can be diagnosed or treated by a receptor partial activation effect of somatic activity. As used herein, “diagnosed as requiring treatment of one or more neurological and / or psychiatric disorders associated with glutamate dysfunction” is subject to physical examination by an expert, eg, a physician. Means that it is found to have one or more neurological and / or psychiatric disorders associated with glutamate dysfunction.

The terms “administering” and “administration” as used herein refer to any method of providing a formulation to a subject. Such methods are known to those skilled in the art, and are oral administration, transdermal administration, administration by inhalation, intranasal administration, topical administration, intravaginal administration, intraocular administration, intraocular administration, intracerebral administration, rectal administration. And parenteral administration including but not limited to injection, such as intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various embodiments, the formulation can be administered therapeutically, that is, administered to treat an existing disease or condition. In further various embodiments, the formulation can be administered prophylactically, that is, administered to prevent a disease or condition.

As used herein, a “therapeutically effective amount” is sufficient to obtain the desired therapeutic result or to have an effect in an undesirable condition, but is generally insufficient to cause side effects. Refers to the quantity. The specific therapeutically effective dose level for any particular patient is the disease being treated and the severity of the disease; the particular compound used; the patient's age, weight, general health, sex, and dietary habits; Route of administration; excretion rate of the particular compound used; various factors including drugs used in combination with or simultaneously with the particular compound used, as well as known factors in the medical arts, etc. For example, one of skill in the art knows to start compound doses at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. is there. If desired, the effective daily dose can be divided into multiple doses for administration. Thus, a single dose composition can contain such amounts, or submultiples thereof, which constitute a daily dose. The dosage can be adjusted by the individual physician in any contraindicated event. The dosage may vary and may be administered in one or more doses administered per day for a day or days. Guidance can be found in the instructions for appropriate dosages for a given class of pharmaceutical products. In further various embodiments, the formulation can be administered in a “prophylactically effective amount”, that is, an amount effective to prevent a disease or condition.

As used herein, “pharmaceutically acceptable carrier” refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as for reconstitution into injections or dispersions just prior to use. Refers to a sterile powder. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), And injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size during dispersion and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. It is also desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of injectable pharmaceutical dosage forms can be brought about by the inclusion of agents such as aluminum monostearate and gelatin that delay absorption. Injectable depot forms are made by forming microencapsule 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 utilized, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. Injectable formulations are, for example, in the form of sterile solid compositions that can be dissolved or dispersed in a sterile water or by filtration through a bacteria-retaining filter, or other sterile injectable medium that can be injected just before use. And can be sterilized by encapsulating a sterilant. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the active ingredient particles have an effective particle size of 0.01 to 10 micrometers.

As used herein, the term “substituted” is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic substituents of organic compounds, or branched and unbranched substituents, carbocyclic and heterocyclic substituents, and aromatic and non-aromatic substituents. Including. Exemplary substituents include those described below, for example. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or allowed substituents on the organic compounds described herein that meet the valence of the heteroatom. This disclosure is not intended to be limited in any way by the permissible substituents of organic compounds. Also, “substitution” or “substituted with” refers to substitution of such stable compounds according to the substituted atom and the allowed valence of the substituent, For example, implicit conditions are included that result in compounds that do not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like.

In defining various terms, “A ¹ ”, “A ² ”, “A ³ ”, and “A ⁴ ” are used herein as general symbols to represent various specific substituents. Is done. These symbols are not limited to those disclosed herein, and may be any substituent, and in one example, when defined to be a certain substituent, in another example, some other Can be defined as a substituent.

The term “alkyl” as used herein is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, A branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms such as hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. An alkyl group can also be substituted or unsubstituted. Alkyl groups can include optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. Without limitation, it can be substituted with one or more groups. A “lower alkyl” group is an alkyl group containing 1 to 6 (eg, 1 to 4) carbon atoms.

Throughout this specification, “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups, although substituted alkyl groups are also referred to by specifying a particular substituent in an alkyl group. Specified in the description. For example, the term “halogenated alkyl” specifically refers to an alkyl group that is substituted with one or more halides, eg, fluorine, chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “alkylamino” specifically refers to an alkyl group that is substituted with one or more amino groups, as described below. When “alkyl” is used in one example and a specific term such as “alkyl alcohol” is used elsewhere, the term “alkyl” does not include a specific term such as “alkyl alcohol” and the like. It does not mean to imply.

This manner of reference is also used for other groups described herein. That is, terms such as “cycloalkyl” refer to both unsubstituted and substituted cycloalkyl moieties, which can further be specifically identified herein, for example, a particular substituted cycloalkyl is For example, it can be referred to as “alkylcycloalkyl”. Similarly, substituted alkoxy can be specifically referred to as, for example, “halogenated alkoxy”, and a particular substituted alkenyl can be, for example, “alkenyl alcohol”. Furthermore, the use of general terms such as “cycloalkyl” and specific terms such as “alkylcycloalkyl” does not imply that the general term does not include the specific terms. .

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least 3 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 at least one carbon atom of the ring is nitrogen. Is replaced by a heteroatom such as, but not limited to, oxygen, sulfur, or phosphorus. Cycloalkyl groups and heterocycloalkyl groups can be substituted or unsubstituted. Cycloalkyl groups and heterocycloalkyl groups can be optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. One or more groups may be substituted, including but not limited to.

As used herein, a “polyalkylene group” is a group having two or more CH ₂ groups bonded to each other. A polyalkylene group may be represented by the formula — (CH ₂ ) _a — when “a” is an integer from 2 to 500.

As used herein, the terms “alkoxy” and “alkoxyl” refer to an alkyl or cycloalkyl group attached through an ether linkage. That is, an “alkoxy” group may be defined as —OA1, where A1 is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of the alkoxy groups described above. That is, alkoxy is —OA ¹ —OA ² or —OA ¹ — (OA, wherein “a” is an integer from 1 to 200, and A ¹ , A ² , and A ³ are alkyl and / or cycloalkyl groups. ²⁾ it may be a polyether such as _a -OA ^3.

The term “alkenyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a formula containing at least one carbon-carbon double bond. 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 estimated in the equations herein, where an asymmetric alkene exists or can be clearly indicated by the combined symbol C = C. An alkenyl group is an optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, as described herein. One or more groups may be substituted, including but not limited to halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol.

As used herein, the term “cycloalkenyl” is a non-aromatic carbon-based ring composed of at least 3 carbon atoms and has at least one carbon-carbon double bond, ie, C═C. contains. 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 within the meaning of the term “cycloalkenyl” wherein at least one carbon atom of the ring is nitrogen. Is replaced by a heteroatom such as, but not limited to, oxygen, sulfur, or phosphorus. Cycloalkenyl groups and heterocycloalkenyl groups can be substituted or unsubstituted. Cycloalkenyl groups and heterocycloalkenyl groups are optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic, as described herein. It can be substituted with one or more groups including, but not limited to, acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a formula containing at least one carbon-carbon triple bond. An alkynyl group is an optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, as described herein. It can be unsubstituted or substituted with one or more groups including, but not limited to, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least 7 carbon atoms and contains at least one carbon-carbon triple bond. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononinyl and the like. The term “heterocycloalkynyl” is a type of cycloalkynyl group as defined above, and is included within the meaning of the term “cycloalkynyl”, wherein at least one carbon atom of the ring is nitrogen. Is replaced by a heteroatom not limited to oxygen, sulfur, phosphorus, or the like. Cycloalkynyl groups and heterocycloalkynyl groups can be substituted or unsubstituted. Cycloalkynyl groups and heterocycloalkynyl groups are optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic, as described herein. It can be substituted with one or more groups including, but not limited to, acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol.

The term “aryl” as used herein is a group containing any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” also includes “heteroaryl,” which is defined as a group that contains an aromatic group having at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to nitrogen, oxygen, sulfur, and phosphorus. Similarly, the term “non-heteroaryl,” which is also included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom. Aryl groups can be substituted or unsubstituted. An aryl group is an optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, as described herein. One or more groups may be substituted, including but not limited to halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl”. Biaryl refers to two aryl groups that are joined together via a fused ring structure, such as naphthalene, or attached via one or more carbon-carbon bonds, such as biphenyl.

The term “aldehyde” as used herein is represented by the formula —C (O) H. Throughout this specification “C (O)” is a short hand notation for a carbonyl group, ie, C═O.

The term “amine” or “amino” as used herein is represented by the formula NA ¹ A ² A ³ , wherein A ¹ , A ² , and A ³ are independently hydrogen or as used herein. It can be an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group.

The term “carboxylic acid” as used herein is represented by the formula —C (O) OH.

The term “ester” as used herein is represented by the formula —OC (O) A ¹ or —C (O) OA ^{1 wherein} A ¹ is an optionally substituted, as described herein. It may be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group. The term “polyester” as used herein refers to the formula — (A ¹ O (O) C—A ² —C (O) O) _a — or — (A ¹ O (O) C—A ² — OC (O)) _a- and A1 and A2 are independently substituted, as described herein, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or It may be a heteroaryl group, and “a” is an integer of 1 to 500. “Polyester” is a term used to describe a group produced by a reaction between a compound having at least two carboxylic acid groups and a compound having at least two hydroxyl groups.

The term “ether” as used herein is represented by the formula A ¹ OA ² , wherein A ¹ and A ² are independently optionally substituted alkyl, cycloalkyl, as described herein, It can be an alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group. The term “polyether” as used herein is represented by the formula — (A ¹ O—A ² O) _a —, wherein A ¹ and A ² are independently any of those described herein. Can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group substituted with “a” being an integer from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

As used herein, the term “halide” refers to halogens (fluorine, chlorine, bromine, and iodine).

The term “hydroxyl” as used herein is represented by the formula —OH.

The term “ketone” as used herein is represented by the formula A ¹ C (O) A ² , and A ¹ and A ² are independently optionally substituted as described herein. It can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group.

The term “azido” as used herein is represented by the formula —N ₃ .

The term “nitro” as used herein is represented by the formula —NO ₂ .

The term “nitrile” as used herein is represented by the formula —CN.

The term “silyl” as used herein is represented by the formula —SiA ¹ A ² A ³ , where A ¹ , A ² , and A ³ are independently hydrogen or as described herein. Can be an optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group.

As used herein, the term “sulfo-oxo” refers to the formula —S (O) A ¹ , —S (O) ₂ A ¹ , —OS (O) ₂ A ¹ , or —OS (O) _2. Represented by OA ¹ , A ¹ can 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 an abbreviation for S═O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S (O) ₂ A ¹ , where A ¹ is hydrogen or any of the It can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group substituted with. The term “sulfone” as used herein is represented by the formula A ¹ S (O) ₂ A ² , and A ¹ and A ² are independently substituted as described herein. It may be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group. The term “sulfoxide” as used herein is represented by the formula A ¹ S (O) A ² , wherein A ¹ and A 2 are independently optionally substituted alkyl, as described herein, It can be a cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group.

The term “thiol” as used herein is represented by the formula —SH.

The term “organic residue” defines a carbon-containing residue, ie, a residue containing at least one carbon atom, and a carbon-containing group, residue, or radical as defined herein above. However, it is not limited to these. Organic residues contain various heteroatoms or can be bonded to another molecule through heteroatoms including oxygen, nitrogen, sulfur, phosphorus and the like. Examples of organic residues include, but are not limited to, alkyl or substituted alkyl, alkoxy or substituted alkoxy, mono- or disubstituted amino, amide groups, and the like. The organic residue is preferably 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 It can contain up to 4 carbon atoms. In further embodiments, the organic residue has 2 to 18 carbon atoms, 2 to 15 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms. Can be included.

A very close synonym for the term “residue” is the term “radical” and, as used herein and in the end claims, is used herein regardless of how the molecule is prepared. Refers to a fragment, group, or substructure of the molecule described in. For example, in certain compounds, the 2,4-thiazolidinedione radical has the structure regardless of whether the thiazolidinedione radical is used to prepare the compound.

を有する。一部の実施形態において、該ラジカル（例えば、アルキル）は、１つ以上の「置換基ラジカル」をそこに結合させることによりさらに修飾（すなわち、置換アルキル）され得る。所与のラジカルにおいて原子数は、本明細書の他の部分にそうでない旨が示されない限り、本発明に重要な意味を持たない。

Have In some embodiments, the radical (eg, alkyl) can be further modified (ie, substituted alkyl) by attaching one or more “substituent radicals” thereto. The number of atoms in a given radical is not critical to the invention unless otherwise indicated elsewhere herein.

The term “organic radical” as defined and used herein contains one or more carbon atoms. For example, the organic radical is 1 to 26 carbon atoms, 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. May have 1 carbon atom. In further embodiments, the organic radical has 2 to 26 carbon atoms, 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 It can have ˜4 carbon atoms. Organic radicals often have hydrogen bonded to at least some of the carbon atoms of the organic radical. An example of an organic radical that does not contain an inorganic atom is a 5,6,7,8-tetrahydro-2-naphthyl radical. In some embodiments, the organic radical can include 1 to 10 inorganic heteroatoms, including, or bonded to, halogen, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino, disubstituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, Alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocycle, or substituted heterocycle radicals include, but are not limited to, Terminology is defined elsewhere in this specification. Some non-limiting examples of organic radicals containing heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals, and the like.

The term “inorganic radical” as defined and used herein does not include carbon atoms, ie, includes only non-carbon atoms. Inorganic radicals include hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and bonded combinations of atoms selected from halogens such as fluorine, chlorine, bromine, and iodine, and their chemically stable In such combinations, they may be present individually or combined together. Inorganic radicals have 10 or less, or preferably 1 to 6 or 1 to 4 inorganic atoms, as described above, bonded together. Examples of inorganic radicals include, but are not limited to, amino, hydroxy, halogen, nitro, thiol, sulfate, phosphate, and similar generally known inorganic radicals. Organic-free radicals do not bind metal elements (such as alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals) in the periodic table therein. However, such metal ions sometimes serve as pharmaceutically acceptable cations for anionic inorganic radicals, such as sulfate and phosphate anionic inorganic radicals. Inorganic radicals do not include metalloid elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or noble gas elements, unless otherwise indicated elsewhere herein.

The compounds described herein contain one or more double bonds and thus can potentially generate cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated otherwise, the invention includes all such possible isomers, as well as mixtures of such isomers.

Unless otherwise specified, formulas having chemical bonds shown only by solid lines, rather than wedges or dashed lines, are each possible isomers, such as the respective optical isomers and diastereomers, and Consider mixtures of isomers such as racemic or non-racemic mixtures. The compounds described herein contain one or more asymmetric centers and can therefore potentially generate diastereomers and any isomers. Unless stated otherwise, the invention covers all such possible diastereomers, as well as their racemic mixtures, their substantially purely resolved optical isomers, all possible Including the geometric isomers as well as their pharmaceutically acceptable salts. Also included are mixtures of stereoisomers as well as isolated specific stereoisomers. During the course of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the product of such procedures is a mixture of stereoisomers. It can be.

The following abbreviations are used herein. DMF: dimethylformamide EtOAc: ethyl acetate THF: tetrahydrofuran DIPEA or DIEA: diisopropylethylamine HOBt: 1-hydroxybenzotriazole EDC: 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride DMSO: dimethyl sulfoxide DMAP: 4- Dimethylaminopyridine RT: room temperature H: hour Min: minute DCM: dichloromethane MeCN: acetonitrile MeOH: methanol iPrOH: 2-propanol n-BuOH: 1-butanol

Disclosed are the ingredients to be used to prepare the compositions of the present invention, as well as the compositions themselves to be used within the scope of the methods disclosed herein. Although disclosed herein for these and other materials, when combinations, subsets, interactions, groups, etc., of these materials are disclosed, various individual and collective combinations of each, as well as these compounds It should be understood that specific references to the permutations of may not be explicitly disclosed, but each is disclosed as specifically discussed and described herein. For example, if a particular compound is disclosed and discussed, and some recombination is discussed that may form several molecules containing that compound, the potential compound and recombinant Each and every combination and permutation is specifically considered. Thus, if the classes of molecules A, B, and C, and the classes of molecules D, E, and F are disclosed and examples of combined molecules, AD, are disclosed, Are discussed individually and generally, ie, combinations AE, AF, BD, BE, BF, CD, CE, and CF are disclosed. Means to be considered. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of AE, BF, and CE is considered disclosed. This concept applies to all aspects herein, including but not limited to steps in methods of making and using the compositions of the invention. Thus, if there are various additional steps that can be performed, it should be understood that each of these additional steps may be performed in conjunction with any specific embodiment or combination of method embodiments of the present invention.

It should be understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural conditions for performing the disclosed functions, and there are various structures that can perform the same function with respect to the disclosed structures, and these structures generally have the same results. I hope you will achieve that.

B. Development of novel allosteric potentiators of mGluR5 Fencyclidine (PCP) and other NMDA receptor antagonists induce a psychotic condition in humans that resembles schizophrenia. In schizophrenic patients, PCP and ketamine exacerbate / cause existing positive and negative symptoms in stable patients. Treatment with NMDA receptor co-agonists can ameliorate positive and negative symptoms. A schematic diagram of the NMDA receptor is shown in FIG. Activation of mGluR5 enhances NMDA receptor function. See FIG. Orthosteric ligands lack subtype selectivity and can cause unwanted side effects. Allosteric modulators that target the transmembrane domain (see Figure 3) are an alternative. That is, TMD is preserved significantly low.

4-Cyano-N- (1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) is potent and selective with mild efficacy in rodent behavior models for antipsychotic activity MGluR5 potentiator. See FIG. However, this compound lacks sufficient aqueous solubility and exhibits poor oral bioavailability. Approximately 160,000 compounds were screened as potential mGluR5 modulators. After validation, the compounds were classified as agonists, potentiators, and antagonists. See FIG.

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

In general, small non-polar morpholino side chains provided the greatest potency. Also, generally, activity decreased with increasing ring size and volume. Polar side chains were tolerated but generally reduced activity. In addition, the side chain could be further modified as shown below.

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

Replacement of hydroxypiperidine with azidine is tolerated and generally a small R group is preferred.

In general, the incorporation of monofluoro substituents increased potency and effectiveness.

The lead compound was identified. All identified compounds yielded nearly maximum reaction, with 3-fluoro substitution and morpholino amide yielding satisfactory results.

The linker was investigated as shown in the diagram below.

Substitution of [3H] methoxy PEPy was then investigated. The compounds were found to bind to MPEP sites with different affinities. See FIG. The compounds were also tested for activity at other receptors (eg, mGluR1, mGluR4, mGluR7, M3). Initial tests show selectivity for mGluR5. The compounds were also tested for stability in rat liver microsomes. In general, the compound maintains 90% of the parent over the course of 45 minutes.

The compounds were then evaluated for activity against amphetamine-induced hypermotor. See FIG. 8, FIG. 9, and FIG.

C. Compounds In one aspect, the invention relates to compounds useful as positive allosteric modulators (enhancers) of metabotropic glutamate receptor subtype 5 (mGluR5). More specifically, the present invention per se modulates mGluR5 receptor activity that affects the sensitivity of the mGluR5 receptor to agonists without serving as an orthosteric agonist. Relates to compounds. The compounds of the present invention are useful for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction, and other diseases involving metabotropic glutamate receptors, as further described herein.

1. Benzamide Derivatives In one aspect, the present invention provides compounds of the formula

により表される構造を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物に関し、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、Ｒ^１およびＲ^２は独立して、１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｚ^１、Ｚ^２、およびＺ^３は、ＮおよびＣ−Ｒ^４から独立して選択され、但し、Ｚ^１、Ｚ^２、およびＺ^３のうちの最大２つまでが窒素であり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される最大５個の置換基を含む。

Or a pharmaceutically acceptable salt or N-oxide thereof in the presence of the compound as compared to the reaction to glutamic acid in the absence of the compound. Figure 3 shows the enhancement of mGluR5 response to glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5.
Where R ¹ and R ² are independently an optionally substituted organic radical containing 1 to 12 carbon atoms, each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, wherein each R is independently from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Contains up to 5 substituents independently selected from amine-carbonyl.

In a further aspect, R ¹ and R ² are independently alkyl having 1-6 carbons. In a further aspect, N, R ¹ , and R ² together form an optionally substituted heterocycle having 2-7 carbons. In a further aspect, Z ¹ , Z ² , and Z ³ are all carbon. In further embodiments, R ⁴ contains up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. In a further aspect, both Y ¹ and Y ² are carbon.

In yet a further aspect, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In further embodiments, R ¹ and R ² are independently alkyl having 1-6 carbons, or N, R ¹ , and R ² are both optionally substituted having 2-7 carbons. Wherein R contains 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl, and R ⁴ is independent of hydrogen, halogen, and lower alkyl. Containing 5 substituents.

In one aspect, the invention provides a compound of formula

を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物に関し、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｚ^１、Ｚ^２、およびＺ^３は、ＮおよびＣ−Ｒ^４から独立して選択され、但し、Ｚ^１、Ｚ^２、およびＺ^３のうちの最大２つまでが窒素であり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される最大５個の置換基を含み、Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成する、または水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択される。

Or a pharmaceutically acceptable salt or N-oxide thereof, wherein the compound is transduced in rat mGluR5 in the presence of the compound as compared to a response to glutamic acid in the absence of the compound. Shows enhanced mGluR5 response to glutamate as increased response to non-maximal concentrations of glutamate in transfected human embryonic kidney cells.
Where R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms, each ----- is any covalent bond , Y ¹ and Y ² are independently selected from N and C—R, wherein each R is independent of hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 heteroalkyl Quinyl, 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamines - contain up to 5 substituents independently selected from carbonyl, R ^7a and R ^7b together form a carbocyclic or heterocyclic ring optionally substituted with 2-5 carbons 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 hetero Cycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl Contains 1 to 5 carbon atoms selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Selected independently from organic radicals.

In a further embodiment, R ¹ and R ² are independently hydrogen or alkyl having 1-6 carbons. In a further aspect, N, R ¹ , and R ² together form an optionally substituted heterocycle having 2-7 carbons. In a further aspect, Z ¹ , Z ² , and Z ³ are all carbon. In further embodiments, R ⁴ contains up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. In a further aspect, both Y ¹ and Y ² are carbon. In a further aspect, both R ^7a and R ^7b are hydrogen.

In yet a further aspect, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In further embodiments, R ¹ and R ² are independently hydrogen or alkyl having 1-6 carbons, or N, R ¹ , and R ² are both optionally having 2-7 carbons. Wherein R includes 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl, and R ⁴ is selected from hydrogen, halogen, and lower alkyl. Contains 5 independently selected substituents.

In one aspect, the invention provides a compound of formula

により表される構造を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物に関し、該化合物は、該化合物の不在下でのグルタミンへの反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、Ｒ^１およびＲ^２は独立して、１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｚ^１、Ｚ^２、およびＺ^３は、ＮおよびＣ−Ｒ^４から独立して選択され、但し、Ｚ^１、Ｚ^２、およびＺ^３のうちの最大２つまでが窒素であり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される最大５個の置換基を含む。

Or a pharmaceutically acceptable salt or N oxide thereof in the presence of the compound as compared to the reaction to glutamine in the absence of the compound. Figure 5 shows the enhancement of mGluR5 response to glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5.
Where R ¹ and R ² are independently an optionally substituted organic radical containing 1 to 12 carbon atoms, each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, wherein each R is independently from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkyl Contains up to 5 substituents independently selected from amine-carbonyl.

In a further embodiment, R ¹ and R ² are independently hydrogen or alkyl having 1-6 carbons. In a further aspect, N, R ¹ , and R ² together form an optionally substituted heterocycle having 2-7 carbons. In a further aspect, Z ¹ , Z ² , and Z ³ are all carbon. In further embodiments, R ⁴ contains up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. In a further aspect, both Y ¹ and Y ² are carbon.

In yet a further aspect, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In further embodiments, R ¹ and R ² are independently alkyl having 1-6 carbons, or N, R ¹ , and R ² are both optionally substituted having 2-7 carbons. Wherein R contains 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl, and R ⁴ is independent of hydrogen, halogen, and lower alkyl. Containing 5 substituents.

In one aspect, the invention provides a compound of formula

により表される構造を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物に関し、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｚ^１、Ｚ^２、およびＺ^３は、ＮおよびＣ−Ｒ^４から独立して選択され、但し、Ｚ^１、Ｚ^２、およびＺ^３のうちの最大２つまでが窒素であり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される最大５個の置換基を含み、Ｒ^８は、水素および低級アルキルから選択される。

Or a pharmaceutically acceptable salt or N-oxide thereof in the presence of the compound as compared to the reaction to glutamic acid in the absence of the compound. Figure 3 shows the enhancement of mGluR5 response to glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5.
Where R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms, each ----- is any covalent bond , Y ¹ and Y ² are independently selected from N and C—R, wherein each R is independent of hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 heteroalkyl Quinyl, 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, And up to 5 substituents independently selected from alkylamine-carbonyl, R ⁸ is selected from hydrogen and lower alkyl.

In a further embodiment, R ¹ and R ² are independently hydrogen or alkyl having 1-6 carbons. In a further aspect, N, R ¹ , and R ² together form an optionally substituted heterocycle having 2-7 carbons. In a further aspect, Z ¹ , Z ² , and Z ³ are all carbon. In further embodiments, R ⁴ contains up to 5 substituents independently selected from hydrogen, halogen, and lower alkyl. In a further aspect, both Y ¹ and Y ² are carbon. In a further aspect, R ⁸ is hydrogen.

In yet a further aspect, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In further embodiments, R ¹ and R ² are independently hydrogen or alkyl having 1-6 carbons, or N, R ¹ , and R ² are both optionally having 2-7 carbons. Forming a substituted heterocycle, wherein R contains 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl; and R ⁴ is independent of hydrogen, halogen, and lower alkyl Containing 5 substituents.

In a further aspect, the present invention relates to 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- (phenylethyl) Nyl) -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- (hydroxy Methyl) piperidin-1-yl) methanone, N-isopentyl-4- (phenylethynyl) benzami , (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-y ) 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- Tyrazetidin-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- ( -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-y ) (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-isopropylpiperazine-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) Enyl) 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- (thiophene) 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- Sopropylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone, (4- (cyclohexylethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone, (E)-(4-hydroxypiperidine- 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-methoxy Phenyl) piperazin-1-yl) (4- (phenylethynyl) phenyl) methanone, (4-hydroxypiperidine- 1-yl) (4-((3- (trifluoromethyl) phenyl) ethynyl) phenyl) methanone, 4- (3-phenyl-1,2,4-oxadiazol-5-yl) -N-propylbenzamide , (4-hydroxypiperidin-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) pipe Gin-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- (piperidine- 4-yl) -1H-benzo [d] imidazol-2 (3H) -one, (4- (phenylethynyl) phenyl) (4- (pyrrolidi) -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- ( It relates to a compound selected from phenylethynyl) phenyl) methanone or a pharmaceutically acceptable salt thereof.

In a further embodiment, the compound is (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-hydroxypiperi N-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-hydroxyazetidine-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-fluoro Enyl) 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-methoxy Ethylamino) 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- (phen Nylethynyl) 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- (phenyl Ethynyl) phenyl) methanone, (4- (pentan-2-ylamino) piperidine-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) Peridin-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) piperidine-1 -Yl) (4- (phenylethynyl) phenyl) methanone, (S) -N-((1-ethyl Loridin-2-yl) methyl) -4- (phenylethynyl) benzamide, 1- (1- (4- (phenylethynyl) benzoyl) piperidin-4-yl) -1H-benzo [d] imidazole-2 (3H) -One, 1- (4-phenyl-1- (4- (phenylethynyl) benzoyl) piperidin-4-yl) ethanone, 2- (4- (4- (phenylethynyl) benzoyl) piperazin-1-yl) benzo Nitrile, 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- (piperidine 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- (phenyl) Ethynyl) 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) ben Zamide, 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, is selected N- cyclohexyl-4- (phenylethynyl) benzamide, N- cyclopentyl-4- (phenylethynyl) benzamide, and N- isopentyl-4- (phenylethynyl) benzamide.

In a further 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- (phenyl) Ethynyl) 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) Selected from ethyl) -4- (phenylethynyl) benzamide.

In a further embodiment, 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-(( , 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-hydroxyazetidine- 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-cyclohex (Ruethylamino) 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) Tanone, (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-hydroxyazetidine-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, (octahydroisoquinoline-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- (phenyl Ethynyl) 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- (phenyl Ethynyl) phenyl) methanone, 1- (4-phenyl-1- (4- (phenylethynyl) benzoyl) piperidin-4-yl) ethanone, 1- (1- (4- (phenylethynyl) benzoyl) piperidine-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) Nyl) -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) piperidine-1- Yl) (4- (phenylethynyl) phenyl) methanone, (4- (phenylethynyl) phenyl) (4- (pyridin-2-yl) piperazin-1-yl) methanone, (4-hydroxy-4-phenylpiperidine- 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] imidazole-2 3H) -one, (4- (phenylethynyl) phenyl) (4- (pyrrolidin-1-yl) piperidin-1-yl) methanone, 2- (4- (4- (phenylethynyl) benzoyl) piperazine-1- Yl) benzonitrile, (4- (phenylethynyl) phenyl) (piperazin-1-yl) methanone, (4- (2-fluorophenyl) piperazin-1-yl) (4- (phenylethynyl) phenyl) methanone, and Selected from (4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone.

In a further 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-oxadiazole -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 Selected from -1-carbonyl) benzamide.

In a further 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-oxadiazole -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-Fluorofe Le) -1,2,4-oxadiazol-5-yl) is selected from benzamide.

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

In a further aspect, the compound comprises 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- (phenyl) Tinyl) -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- (hydroxy Methyl) piperidin-1-yl) methanone, N-isopentyl-4- (phenylethynyl) benza (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) methano (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-hydroxypiperidine-1- ) Methanone, N- (2-cyclohexenylethyl) -4- (phenylethynyl) benzamide, N- (4-methylcyclohexyl) -4- (phenylethynyl) benzamide, (4- (cyclohexylamino) piperidine-1- Yl) (4- (phenylethynyl) phenyl) methanone, (4-((3,4-difluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone, N- (3-hydroxy Propyl) -4- (phenylethynyl) benzamide, (2,6-dimethylmorpholino) (4- (phenylethynyl) phenyl) methanone, (4- (phenylethynyl) phenyl) (4- (4- (pyridine-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-indene-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-fluoro Phenyl) 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) piperidine-1- Yl) (4- (phenylethynyl) phenyl) methanone, (4-((3,4-difluorophenyl) ethynyl) phenyl) (3-hydroxyazetidin-1-yl) methanone, N- (3,3-dimethyl) Butyl) -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-propylazetidine-1- ) (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 a further aspect, the compound comprises 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- (phenyl) Tinyl) -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- (hydroxy Methyl) piperidin-1-yl) methanone, N-isopentyl-4- (phenylethynyl) benza (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) methano (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-hydroxypiperidine-1- ) Methanone, N- (2-cyclohexenylethyl) -4- (phenylethynyl) benzamide, N- (4-methylcyclohexyl) -4- (phenylethynyl) benzamide, (4- (cyclohexylamino) piperidine-1- Yl) (4- (phenylethynyl) phenyl) methanone, (4-((3,4-difluorophenyl) ethynyl) phenyl) (4- (hydroxymethyl) piperidin-1-yl) methanone, N- (3-hydroxy Propyl) -4- (phenylethynyl) benzamide and (2,6-dimethylmorpholino) (4- (phenylethynyl) phenyl) methanone.

In a further aspect, the compound comprises N-cyclopentyl-4- (phenylethynyl) benzamide, (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxypiperidin-1-yl) methanone, morpholino (4- Selected from (phenylethynyl) phenyl) methanone and (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone.

In still further embodiments, the compound comprises a phenylethynylbenzamide derivative, a cycloalkylethynylbenzamide derivative, a styrylbenzamide derivative, a 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzamide derivative, 4- It may be a (pyridinylethynyl) benzamide derivative or an N ¹ -phenylterephthalamide derivative.

a. Phenylethynylbenzamide derivatives In one aspect, the invention relates to phenylethynylbenzamide derivatives. In one embodiment, the compound has the structure

を含む化合物またはその医薬的に許容される塩であって、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸の増強を示す。
ここで式中、Ｒ^１およびＲ^２は、水素、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、ならびに任意に置換されたヘテロアリールから独立して選択されるか、またはＮ、Ｒ^１、およびＲ^２は共に、２〜７個の炭素を有する任意に置換された複素環を成し、Ｒ^３は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される４個の置換基を含み、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される５個の置換基を含む。

Or a pharmaceutically acceptable salt thereof, wherein the compound was transfected with rat mGluR5 in the presence of the compound as compared to a response to glutamic acid in the absence of the compound In human embryonic kidney cells, the enhancement of glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 7 carbons, and R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or Alkynyl, optional 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, thioamide, amidosulfonyl , alkoxycarbonyl, carboxamido, amino - carbonyl, and alkyl amine - includes four substituents independently selected from carbonyl, R ⁴ is hydrogen, halogen, Droxyl, 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, as well as optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbohydrate Alkenyl, and alkyl amine - containing 5 substituents selected independently from carbonyl.

In one aspect, the compound exhibits an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁶ . For example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁷ . As a further example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In a further embodiment, R ¹ is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, R ² is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, one or more of the substituents for R ³ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In a further embodiment, one or more of the substituents for R ⁴ are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In one aspect, each of R ¹ , R ² , R ³ , and / or R ⁴ includes optionally substituted alkyl or optionally substituted cycloalkyl. In one embodiment, the optionally substituted alkyl of R ¹ , R ² , R ³ , and / or R ⁴ includes a C1 to C6 substituent, ie, a substituent having 1 to 6 carbons. For example, in one embodiment, the optionally substituted alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, or hexyl. In a further aspect, all of R ³ are hydrogen.

In a further aspect, at least one of R ⁴ is a halogen selected from F and Cl. In a further embodiment, R ⁴ includes 4 hydrogens and 1 or 2 substituents selected from hydrogen, F, and Cl.

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

In one embodiment, at least one of R ⁴ is an optionally substituted alkyl selected from methyl and trifluoromethyl. In a further embodiment, the compound has the formula

により表される構造を有し得る。

It may have a structure represented by

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

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

In a further embodiment, R ¹ and R ² are 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 -Independently selected from hydroxypropyl, 3-methoxypropyl, 3-morpholinopropyl, 4-bromophenethyl, 4-chlorophenethyl, butyl, cyclohexenylethyl, cyclohexylcyclohexylmethylcyclopentyl, isopentyl, methylcyclohexyl, and propyl. In yet a further aspect, the compound has a structure represented by the following formula:

In still further embodiments, N, R ¹ , and R ² together form a cyclic, optionally substituted alkyl residue. In a further embodiment, the cyclic optionally substituted alkyl residue 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-propylazeti Gin-1-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypiperidin-1-yl, 4- (2-fluorophenyl) piperazine-1- 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 Piperidin-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- (azeti) N-1-yl) piperidin-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-piperidine-4-carboni Tolyl, 6-chloro-1- (piperidin-4-yl) -1H-benzo [d] imidazol-2 (3H) -one, morpholino, octahydroisoquinolin-2 (1H) -yl, and piperazin-1-yl Selected from.

In a further embodiment, the compound has a structure represented by the formula:

It should be understood that the compounds can be provided by the disclosed methods of making, utilized in the disclosed compositions, and used in the disclosed methods of use.

b. Cycloalkylethynylbenzamide derivatives In one aspect, the invention relates to cycloalkylethynylbenzamide derivatives. In one embodiment, the compound has the structure

を含む化合物またはその医薬的に許容される塩であって、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸の増強を示す。
ここで式中、Ｒ^１およびＲ^２は、水素、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキレン、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから独立して選択されるか、またはＮ、Ｒ^１、およびＲ^２は共に、２〜７個の炭素を有する任意に置換された複素環を成し、
Ｒ^３は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキレン、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される４個の置換基を含み、
Ｚは、０〜２個の炭素を含み、
Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキレン、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される９〜１３個の置換基を含む。

Or a pharmaceutically acceptable salt thereof, wherein the compound was transfected with rat mGluR5 in the presence of the compound as compared to a response to glutamic acid in the absence of the compound In human embryonic kidney cells, the enhancement of glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
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 Independently selected from cycloalkylene, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl or cycloalkylene, 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl;
Z contains 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 cyclo Alkenyl or cycloalkylene, 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 9 to 13 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl.

In one aspect, the compound exhibits an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁶ . For example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁷ . As a further example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In a further embodiment, R ¹ is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, R ² is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, one or more of the substituents for R ³ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In a further embodiment, one or more of the substituents for R ⁴ are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

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

In a further aspect, N, R ¹ , and R ² together form an optionally substituted heterocycle having 2-7 carbons. In a further aspect, N, R ¹ , and R ² together form 4-hydroxypiperidin-1-yl.

In a further aspect, Z is 1 and R ⁴ contains 11 substituents.

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

In one embodiment, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

It should be understood that the compounds can be provided by the disclosed methods of making, utilized in the disclosed compositions, and used in the disclosed methods of use.

c. Styrylbenzamide derivatives In one aspect, the invention relates to styrylbenzamide derivatives. In one embodiment, the compound has the structure

を含む、化合物またはその医薬的に許容される塩であって、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸の増強を示す。
ここで式中、Ｒ^１およびＲ^２は、水素、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、ならびに任意に置換されたヘテロアリールから独立して選択されるか、またはＮ、Ｒ^１、およびＲ^２は共に、２〜７個の炭素を有する任意に置換された複素環を成し、Ｒ^３は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される４個の置換基を含み、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される５個の置換基を含む。

Or a pharmaceutically acceptable salt thereof, wherein the compound is transfected with rat mGluR5 in the presence of the compound as compared to a response to glutamic acid in the absence of the compound. In human embryonic kidney cells, the enhancement of glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 7 carbons, and R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or Alkynyl, optional 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, thioamide, amidosulfonyl , alkoxycarbonyl, carboxamido, amino - carbonyl, and alkyl amine - includes four substituents independently selected from carbonyl, R ⁴ is hydrogen, halogen, Droxyl, 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, as well as optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbohydrate Alkenyl, and alkyl amine - containing 5 substituents selected independently from carbonyl.

In one aspect, the compound exhibits an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁶ . For example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁷ . As a further example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In a further embodiment, R ¹ is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, R ² is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, one or more of the substituents for R ³ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In a further embodiment, one or more of the substituents for R ⁴ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl. Or selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further aspect, N, R ¹ , and R ² together form an optionally substituted heterocycle having 2-7 carbons. In a further aspect, N, R ¹ , and R 2 together form 4-hydroxypiperidin-1-yl.

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

In a further aspect, at least one of R ⁴ is a halogen selected from F and Cl. In a further aspect, all of R ⁴ are hydrogen. In a further embodiment, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

It should be understood that the compounds can be provided by the disclosed methods of making, utilized in the disclosed compositions, and used in the disclosed methods of use.

d. 4- (3-Phenyl-1,2,4-oxadiazol-5-yl) benzamide derivative In one embodiment, the present invention provides 4- (3-phenyl-1,2,4-oxadiazole-5- I) Benzamide derivatives. In one embodiment, the compound has the structure

を含む、化合物またはその医薬的に許容される塩であって、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸の増強を示す。
ここで式中、Ｒ^１およびＲ^２は、水素、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、ならびに任意に置換されたヘテロアリールから独立して選択されるか、またはＮ、Ｒ^１、およびＲ^２は共に、２〜７個の炭素を有する任意に置換された複素環を成し、Ｒ^３は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される４個の置換基を含み、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される５個の置換基を含む。

Or a pharmaceutically acceptable salt thereof, wherein the compound is transfected with rat mGluR5 in the presence of the compound as compared to a response to glutamic acid in the absence of the compound. In human embryonic kidney cells, the enhancement of glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 7 carbons, and R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or Alkynyl, optional 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, thioamide, amidosulfonyl , alkoxycarbonyl, carboxamido, amino - carbonyl, and alkyl amine - includes four substituents independently selected from carbonyl, R ⁴ is hydrogen, halogen, Droxyl, 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, as well as optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbohydrate Alkenyl, and alkyl amine - containing 5 substituents selected independently from carbonyl.

In one aspect, the compound exhibits an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁶ . For example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁷ . As a further example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In a further embodiment, R ¹ is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, R ² is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, one or more of the substituents for R ³ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In a further embodiment, one or more of the substituents for R ⁴ are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In a further aspect, N, R ¹ , and R ² together form an optionally substituted heterocycle having 2-7 carbons. In a further aspect, N, R ¹ , and R ² together form 4-hydroxypiperidin-1-yl.

In further embodiments, the optionally substituted alkyl of R ¹ , R ² , R ³ , and / or R ⁴ includes optionally substituted alkyl or optionally substituted cycloalkyl. In a further aspect, R ¹ and R 2 ^are independently selected from H, 3-methoxypropyl, 3,3-dimethylbutyl, and N-propyl.

In a further embodiment, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further embodiment, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

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

It should be understood that the compounds can be provided by the disclosed methods of making, utilized in the disclosed compositions, and used in the disclosed methods of use.

e. 4- (Pyridinylethynyl) benzamide Derivatives In one aspect, the present invention relates to 4- (pyridinylethynyl) benzamide derivatives. In one embodiment, the compound is

から選択される構造を含む化合物またはその医薬的に許容される塩であって、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸の増強を示す。
ここで式中、Ｒ^１およびＲ^２は、水素、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、ならびに任意に置換されたヘテロアリールから独立して選択されるか、またはＮ、Ｒ^１、およびＲ^２は共に、２〜７個の炭素を有する任意に置換された複素環を成し、Ｒ^３は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される４個の置換基を含み、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される４個の置換基を含む。

A compound comprising a structure selected from: Shows enhanced glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 7 carbons, and R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or Alkynyl, optional 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, thioamide, amidosulfonyl , alkoxycarbonyl, carboxamido, amino - carbonyl, and alkyl amine - includes four substituents independently selected from carbonyl, R ⁴ is hydrogen, halogen, Droxyl, 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, as well as optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbohydrate Alkenyl, and alkyl amine - containing 4 substituents selected independently from carbonyl.

In one aspect, the compound exhibits an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁶ . For example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁷ . As a further example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In a further embodiment, R ¹ is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, R ² is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, one or more of the substituents for R ³ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In a further embodiment, one or more of the substituents for R ⁴ are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In further embodiments, the optionally substituted alkyl of R ¹ , R ² , R ³ , and / or R ⁴ includes optionally substituted alkyl or optionally substituted cycloalkyl.

In a further aspect, N, R ¹ , and R ² together form an optionally substituted heterocycle having 2-7 carbons. In a further aspect, N, R ¹ , and R ² together form 2-methylpiperidinyl.

In a further embodiment, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, N, R ¹ , and R ² together form a cyclic, optionally substituted alkyl residue. In a further aspect, the cyclic optionally substituted alkyl residue is 2-methylpiperidinyl. In a further aspect, all of R ³ are hydrogen. In a further aspect, at least one of R ⁴ is a halogen selected from F and Cl. In a further aspect, all of R ⁴ are hydrogen. In a further embodiment, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

It should be understood that the compounds can be provided by the disclosed methods of making, utilized in the disclosed compositions, and used in the disclosed methods of use.

f. N ¹ -phenyl terephthalamide derivative In one aspect, the invention relates to a N ¹ -phenyl terephthalamide derivative. In one embodiment, the compound has the structure

を含む化合物またはその医薬的に許容される塩であって、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸の増強を示す。
ここで式中、Ｒ^１およびＲ^２は、水素、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、ならびに任意に置換されたヘテロアリールから独立して選択されるか、またはＮ、Ｒ^１、およびＲ^２は共に、２〜７個の炭素を有する任意に置換された複素環を成し、Ｒ^３は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される４個の置換基を含み、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、任意に置換されたアルキルもしくはアルケニルもしくはアルキニル、任意に置換されたヘテロアルキルもしくはヘテロアルケニルもしくはヘテロアルキニル、任意に置換されたシクロアルキルもしくはシクロアルケニルもしくはシクロアルキニル、任意に置換されたヘテロシクロアルキルもしくはヘテロシクロアルケニルもしくはヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから独立して選択される５個の置換基を含む。

Or a pharmaceutically acceptable salt thereof, wherein the compound was transfected with rat mGluR5 in the presence of the compound as compared to a response to glutamic acid in the absence of the compound In human embryonic kidney cells, the enhancement of glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 7 carbons, and R ³ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or Alkynyl, optional 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, thioamide, amidosulfonyl , alkoxycarbonyl, carboxamido, amino - carbonyl, and alkyl amine - includes four substituents independently selected from carbonyl, R ⁴ is hydrogen, halogen, Droxyl, 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, as well as optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbohydrate Alkenyl, and alkyl amine - containing 5 substituents selected independently from carbonyl.

In one aspect, the compound exhibits an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁶ . For example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁷ . As a further example, the compound can exhibit an enhancement that has an EC ₅₀ of less than about 1.0 × 10 ⁻⁸ .

In a further embodiment, R ¹ is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, R ² is an optionally substituted alkyl or alkenyl or alkynyl, an optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, an optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons.

In a further embodiment, one or more of the substituents for R ³ is optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In a further embodiment, one or more of the substituents for R ⁴ are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or Selected from cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons .

In a further aspect, N, R ¹ , and R ² together form an optionally substituted heterocycle having 2-7 carbons. In a further aspect, N, R ¹ , and R ² together form 2-methylpiperidinyl.

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

In a further aspect, at least one of R ⁴ is a halogen selected from F and Cl. In a further aspect, ^four of R ⁴ are hydrogen and one of R ⁴ is F. In a further embodiment, the compound has the formula

により表される構造を有する。

It has the structure represented by these.

It should be understood that the compounds can be provided by the disclosed methods of making, utilized in the disclosed compositions, and used in the disclosed methods of use.

2. Cyclic benzamide derivatives In one aspect, the present invention relates to compounds useful as positive allosteric modulators (enhancers) of metabotropic glutamate receptor subtype 5 (mGluR5). More specifically, the present invention per se modulates mGluR5 receptor activity that affects the sensitivity of the mGluR5 receptor to agonists without serving as an orthosteric agonist. Relates to compounds. The compounds of the invention are useful for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction, as well as other diseases involving metabotropic glutamate receptors, as further described herein.

In general, the disclosed compounds have non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound as compared to response to glutamate in the absence of the compound. The increase in mGluR5 response to glutamic acid is shown as an increase in response to. In various embodiments, the compound comprises an isoindoline-1-one derivative, an isoindoline-1,3-dione derivative, a 3,4-dihydroisoquinolin-1 (2H) -one derivative, an isoquinoline-1,3 (2H, 4H) -dione derivatives, other related bicyclic compounds, or pharmaceutically acceptable salts or N-oxides thereof.

In one aspect, the invention provides a compound of formula

により表される構造を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物に関し、該化合物は、該化合物の不在下でのグルタミン酸への反応と比較して、該化合物の存在下で、ラットｍＧｌｕＲ５でトランスフェクトされたヒト胚腎臓細胞内で、非最大濃度のグルタミン酸への反応の増加として、グルタミン酸へのｍＧｌｕＲ５反応の増強を示す。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は独立して、ＮおよびＣ−Ｒから選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Or a pharmaceutically acceptable salt or N-oxide thereof in the presence of the compound as compared to the reaction to glutamic acid in the absence of the compound. Figure 3 shows the enhancement of mGluR5 response to glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2-5 carbons, or 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 with thioalkyl, optional 1-5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms, 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, are selected from organic radicals containing from 1 to 6 carbon atoms selected optionally substituted aryl, and optionally substituted heteroaryl.

For example, the disclosed compounds are

For example, the disclosed compounds have the formula

により表される構造を有し得、
式中、Ｒ^１は、水素または１〜６個の炭素を有するアルキルであり、Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、または低級アルキルであり、Ｒ^４は、水素、ハロゲン、および低級アルキルから独立して選択される５個の置換基を含む。

Having the structure represented by
Wherein 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 is hydrogen, halogen, and Contains 5 substituents independently selected from lower alkyl.

For example, the disclosed compounds have the formula

により表される構造を有し得、
式中、Ｒ^１は、水素または１〜６個の炭素を有するアルキルであり、Ｒ^４は、水素、ハロゲン、および低級アルキルから独立して選択される５個の置換基を含む。

Having the structure represented by
Wherein R ¹ is hydrogen or alkyl having 1 to 6 carbons, and R ⁴ includes 5 substituents independently selected from hydrogen, halogen, and lower alkyl.

For example, the disclosed compounds have the formula

により表される構造を有し得、
式中、Ｒ^１は、水素または１〜６個の炭素を有するアルキルであり、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^３ａ、およびＲ^３ｂは独立して、水素、ハロゲン、または低級アルキルであり、Ｒ^４は、水素、ハロゲン、および低級アルキルから独立して選択される５個の置換基を含む。

Having the structure represented by
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, and R ⁴ Contains 5 substituents independently selected from hydrogen, halogen, and lower alkyl.

For example, the disclosed compounds have the formula

により表される構造を有し得、
式中、Ｒ^１は、水素または１〜６個の炭素を有するアルキルであり、Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、または低級アルキルであり、Ｒ^４は、水素、ハロゲン、および低級アルキルから独立して選択される５個の置換基を含む。

Having the structure represented by
Wherein 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 is hydrogen, halogen, and Contains 5 substituents independently selected from lower alkyl.

For example, the disclosed compounds have the formula

により表される構造を有し得、
式中、Ｒ^１は、水素または１〜６個の炭素を有するアルキルであり、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^３ａ、およびＲ^３ｂは独立して、水素、ハロゲン、または低級アルキルであり、Ｒ^４は、水素、ハロゲン、および低級アルキルから独立して選択される５個の置換基を含む。

Having the structure represented by
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, and R ⁴ Contains 5 substituents independently selected from hydrogen, halogen, and lower alkyl.

In various embodiments, Y ¹ can be selected from N and C—R ⁴ . In various further embodiments, Y ² can be selected from N and C—H. In various further embodiments, each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms. In various further embodiments, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. In various further embodiments, R ^3a and R ^3b (if present) together form a cycloalkyl having 2-12 carbon atoms, while R ^3a and R ^3b form a bridge with an adjacent aromatic ring. do not do.

In various further embodiments, L is an organic divalent radical containing 1 to 7 carbon atoms;

から選択される。

Selected from.

In various further embodiments, R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or hydrogen, halogen, hydroxyl, cyano, nitro, thiol, Amino, as well as 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 placed Selected from substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. Independently selected from organic radicals containing 1 to 5 carbon atoms.

In various further 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 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 Selected from organic radicals containing 1 to 6 carbon atoms selected from: optionally substituted aryl, and optionally substituted heteroaryl.

It should be understood that each derivative can optionally be further substituted. It is also contemplated that any one or more derivatives may optionally be excluded from the present invention. It should also be understood that each substituent may optionally be further substituted. It is also contemplated that any one or more substituents may optionally be excluded from the present invention.

a. Isoindoline-1-one derivatives In one aspect, the invention provides a structure

を有するイソインドリン−１−オン誘導体、またはその医薬的に許容される塩もしくはＮ酸化物に関する。
ここで式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルである。

It relates to an isoindoline-1-one derivative having the formula: or a pharmaceutically acceptable salt or N oxide thereof.
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, provided that R ¹ is hydrogen. In certain instances, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

b. Isoindoline-1,3-dione derivative In one aspect, the invention provides a structure

を有するイソインドリン−１，３−ジオン誘導体、またはその医薬的に許容される塩もしくはＮ酸化物に関する。
ここで式中、Ｒ^１は、水素であるか、または任意に置換されたＣ１−Ｃ１２アルキル、任意に置換されたＣ１−Ｃ１２ヘテロアルキル、任意に置換されたＣ３−Ｃ１２シクロアルキル、または任意に置換されたＣ３−Ｃ１２ヘテロシクロアルキルから選択され、但し、Ｒ^１は、シリコンを含まず、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルであり、但し、Ｒ^１がメチルである場合、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

The present invention relates to an isoindoline-1,3-dione derivative having the formula:
Wherein R ¹ is hydrogen or optionally substituted C1-C12 alkyl, optionally substituted C1-C12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally Selected from substituted C3-C12 heterocycloalkyl, wherein R ¹ is silicon free and R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that R ¹ is hydrogen. In the case, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that when R ¹ is methyl, R ⁵ is an organic radical containing 4 to 14 carbon atoms.

c. 3,4-Dihydroisoquinolin-1 (2H) -one derivatives In one aspect, the invention provides a structure

を有する３，４−ジヒドロイソキノリン−１（２Ｈ）−オン誘導体、またはその医薬的に許容される塩もしくはＮ酸化物に関する。
ここで式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

It relates to 3,4-dihydroisoquinolin-1 (2H) -one derivatives having the formula:
Where R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, Or it is an organic radical containing 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 derivative In one embodiment, the present invention provides a structure

を有するイソキノリン−１，３（２Ｈ，４Ｈ）−ジオン誘導体、またはその医薬的に許容される塩もしくはＮ酸化物に関する。
ここで式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^５は、トリフェニルアミン残基またはベンズイミダアミド残基を含まない。

The present invention relates to an isoquinoline-1,3 (2H, 4H) -dione derivative having the following formula:
Here in the formula, ^{R 1} is an organic radical containing hydrogen or from 1 to 12 carbon atoms, ^{R 5} is an organic radical containing 4 to 14 carbon atoms, provided that, ^{R 5} is tri Does not contain phenylamine or benzimidazole residues.

e. Bicyclic Compound In one embodiment, the present invention provides a structure

を有する二環式化合物、またはその医薬的に許容される塩もしくはＮ酸化物に関する。
ここで式中、ｎは、２、３、または４であり、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、もしくは１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

Or a pharmaceutically acceptable salt or N-oxide thereof.
Where n is 2, 3, or 4, R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and R ^2a and R ^2b are both ═O or ═S. Or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, and R ⁵ is 4 Organic radicals containing -14 carbon atoms.

f. Structural Composition In one aspect, a compound is provided, wherein R ¹ is an optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, an 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, heteroaryl optionally substituted, and - _{(CH 2) m} - aryl or - _{(CH 2) m} - 1 which is selected from heterocyclic Organic la containing ~ 12 carbon atoms Is dical, m is 1, 2, 3, or 4, and when R ^2a and R ^2b are present, both form ═O or ═S, or each R ^2a and R ^2b independently 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, optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine An organic radical comprising 1 to 6 carbon atoms selected from carbonyl, wherein R ^3a and R ^3b together represent ═O or ═S, or each R ^3a and R ^3b is independently 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide , amino - carbonyl, and alkyl amines - an organic radical containing from 1 to 6 carbon atoms selected from carbonyl, if R ⁴ is present, R ⁴ is, C1-C6 alkyl or C, optionally substituted -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, thioamide, amidosulfonyl, alkoxycarbonyl An organic radical containing 1 to 12 carbon atoms independently selected from ru, carboxamide, amino-carbonyl, and alkylamine-carbonyl, wherein R ⁵ is an optionally substituted C 3 -C 8 cycloalkyl or C 3 4-14 carbon atoms selected from -C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl An organic radical containing

In a further embodiment, the compound has the formula

を含む構造を有する。

It has the structure containing.

In a further embodiment, the compound has the formula

を含む構造を有する。

It has the structure containing.

In a further embodiment, the compound has the formula

を含む構造を有する。

It has the structure containing.

In a further embodiment, the compound has the formula

を含む構造を有する。

It has the structure containing.

In a further embodiment, the compound has the formula

を含む構造を有する。
なおさらなる態様において、ｎは、０または１である。

It has the structure containing.
In a still further aspect, n is 0 or 1.

In a further embodiment, the compound has a structure comprising the following formula:

In one embodiment, a compound is provided, wherein R ¹ is an optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, an 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 selected from C 6 -C 8 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R ¹ is hydroxy, oxo, halo, C 1 -C 6 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)} -O-C (CH 3) 3, C3-C6 ^{cycloalkyl, -NR 9 R 10, -NH-} C (O) -R 9, -NH-C (O) - Mono- or disubstituted with a substituent selected from NR ⁹ R ¹⁰ , and —NH—S (O) ₂ —R ⁹ , wherein R ⁹ is hydrogen, —CF ₃ , C1-C4 alkyl, C3-C6 cyclo Alkyl, ant Le, and is selected from ^{heterocycle, R 10} is selected from hydrogen and C1-C4 alkyl.

In a further embodiment, 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 a further aspect, there is provided a compound, wherein, ^{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) -O-C (CH} 3) 3, C3-C6 ^{cycloalkyl, -NR 9 R 10, -NH-} C (O) -R 9, -NH-C (O) -NR 9 R 10 and, NH-S _(O) mono- or disubstituted with substituents selected from 2 -R ^{9, R 9} is _hydrogen, -CF 3, C1-C4 alkyl, C3-C6 cycloalkyl, aryl, and heterocyclic R ¹⁰ is selected from hydrogen and C1-C4 alkyl.

In a further embodiment, 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, triazole, 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-tetrazine, pyrrolidine, piperidine, piperazi , Morpholine, azetidine, tetrahydropyran, tetrahydrofuran, and dioxane residues.

In a further aspect, there is provided a compound, wherein, ^{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) —O—C (CH ₃ ) ₃ , C 3 -C 6 cycloalkyl, —NR ⁹ R ¹⁰ , —NH—C (O) —R ⁹ , —NH—C (O) —NR ⁹ R ¹⁰ , Yo -NH-S _(O) mono- or disubstituted with substituents selected from 2 -R ^{9, R 9} is _hydrogen, -CF 3, C1-C4 alkyl, C3-C6 cycloalkyl, aryl, and heterocyclic Selected from the ring, R ¹⁰ is selected from hydrogen and C1-C4 alkyl.

In a further embodiment, R ¹ is 2- (4-hydroxypiperidin-1-yl) -2-oxoethyl, 2- (4-hydroxypiperidin-1-yl) ethyl, 2- (azetidin-1-yl), 2 -Acetamide, 2-morpholino-2-oxoethyl, 2-morpholinoethyl, benzyl, benzyl 2-acetate, cyclobutylmethyl, cyclopropylmethyl, ethyl 2-propanoate, hydrogen, methyl, N- (2- (dimethylamino) ethyl Selected from acetamide, N-2-methoxyethylacetamide, N-cyclopropyl-2-acetamide, and N-cyclopropylmethylacetamide.

In a further aspect, there is provided a compound, wherein, R ⁵ is

から選択され、
Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５、およびＺ^６は、ＣおよびＮから独立して選択され、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、５個、６個、または７個の置換基を含む。

Selected from
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 any 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, optional Substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, 1, 2, 3, 4, 5, 6, or 7 substitutions independently selected from organic radicals containing 1 to 10 carbon atoms selected from alkylamine-carbonyl Contains groups.

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

In a further aspect, there is provided a compound, wherein, R ⁵ is

から選択され、
式中、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜８個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、または５個の置換基を含む。

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, C1-C6 optionally substituted 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 alkyl 1 to 8 carbon atoms selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. It contains 1, 2, 3, 4, or 5 substituents independently selected from the organic radicals it contains.

In a further aspect, R ⁵ is

から選択される。

Selected from.

In a further aspect, a compound is provided wherein R ⁵ is of the formula

を有する構造を含み、
Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜８個の炭素原子を含む有機ラジカルから独立して選択される１個または２個の置換基を含む。

Including a structure having
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 alkylsulfur Containing 1 to 8 carbon atoms selected from finyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Contains one or two substituents independently selected from organic radicals.

In certain embodiments, the compound can be an alkyne derivative, alkene derivative, 1,2,4-oxadiazole derivative, or amide derivative. That is, in certain embodiments, L can be an alkyne residue, and an alkene residue, a 1,2,4-oxadiazole residue, or an amide residue. It should be understood that alkyne, alkene, 1,2,4-oxadiazole, and amide residues can be further substituted. It is also contemplated that any one or more alkyne, alkene, 1,2,4-oxadiazole, or amide residues can be optionally excluded from the present invention.

g. Alkyne Derivatives In one embodiment, the compound has the formula

を有する構造を有する。

It has the structure which has.

In a further aspect, there is provided a compound, wherein, R ⁵ is

から選択され、
Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、または５個の置換基を含む。

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 alkylsulfur Containing 1 to 10 carbon atoms selected from finyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Contains 1, 2, 3, 4, or 5 substituents independently selected from organic radicals.

In a further embodiment, the compound has the formula

を有する構造として提供し、
式中、ｎは、０または１であり、Ｒ^１は、水素、または任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、および−（ＣＨ_２）_ｍ−アリールもしくは−（ＣＨ_２）_ｍ−複素環から選択される１〜１２個の炭素原子を含む有機ラジカルであり、ｍは、１、２、３、または４であり、Ｒ^２ａおよびＲ^２ｂは存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜６個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜６個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^４は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１２個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、または３個の置換基を含み、Ｚ^１、Ｚ^２、およびＺ^３は、ＣおよびＮから独立して選択され、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個または２個の置換基を含む。

Provided as a structure having
In which n is 0 or 1 and 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 1 selected from heterocycloalkenyl or C 6 -C 8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and — (CH ₂ ) _m -aryl or — (CH ₂ ) _m -heterocycle Organic radicals containing ~ 12 carbon atoms There, m is 1, 2, 3 or 4, ^when the ^{R 2a} and ^{R 2b} present, together, = O or = or form a S or each ^{R 2a} and ^{R 2b,} is hydrogen, 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, optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine- Independently selected from organic radicals containing 1 to 6 carbon atoms selected from carbonyl, R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b 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 heterocycloalkynyl, optionally substituted aryl, optionally substituted Heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl , carboxamido, amino - carbonyl, and alkyl amines - are independently selected from organic radicals containing from 1 to 6 carbon atoms selected from carbonyl, R ⁴ is substituted hydrogen, and optionally C -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, thioamide, amidosulfur 1, 2, or 3 substituents independently selected from organic radicals containing 1 to 12 carbon atoms selected from onyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Z ¹ , Z ² , and Z ³ are independently selected from C and N, and R ⁶ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C ^1- 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 Selected from substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl 1 or 2 substituents independently selected from organic radicals containing 1 to 10 carbon atoms.

In a further embodiment, the compound has the formula

を有する構造を含む。

Including a structure having

In a further aspect, the compound is selected from:

In a further embodiment, the compound is

から選択される。

Selected from.

In a further embodiment, the compound is

In a further embodiment, the compound has the formula

を有する構造を含み、
ここで式中、Ｒ^１は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、および−（ＣＨ_２）_ｍ−アリールもしくは−（ＣＨ_２）_ｍ−複素環から選択される１〜１２個の炭素原子を含む有機ラジカルから選択され、ｍは、１、２、３、または４であり、ｎは、０または１であり、ｎが０である場合、Ｒ^３ａおよびＲ^３ｂは、水素であるか、または共に＝Ｏを成し、ｎが１である場合、Ｒ^２ａおよびＲ^２ｂは、水素であるか、または共に＝Ｏを成し、Ｒ^３ａおよびＲ^３ｂは、水素であり、Ｚは、ＣおよびＮから選択され、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個または２個の置換基を含む。

Including a structure having
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 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 1-12 carbon atoms selected from heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and — (CH ₂ ) _m -aryl or — (CH ₂ ) _m -heterocycle Selected from organic radicals containing m 1, 2, 3 or a 4,, n is 0 or 1, when n is ^{0, R 3a} and ^{R 3b} is hydrogen or forms together = O, n is When R 1, R ^2a and R ^2b are hydrogen or together form ═O, R ^3a and R ^3b are hydrogen, Z is selected from C and N, and 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 hetero Alkenyl 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 Selected from substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl 1 or 2 substituents independently selected from organic radicals containing 1 to 10 carbon atoms.

In a further embodiment, the compound has the formula

を有する構造を含む。

Including a structure having

In a further aspect, a compound is provided, wherein R ¹ is 2- (4-hydroxypiperidin-1-yl) -2-oxoethyl, 2- (4-hydroxypiperidin-1-yl) ethyl, 2- ( Azetidin-1-yl), 2-acetamide, 2-morpholino-2-oxoethyl, 2-morpholinoethyl, benzyl, benzyl 2-acetate, cyclobutylmethyl, cyclopropylmethyl, ethyl 2-propanoate, hydrogen, methyl, N- (Selected from 2- (dimethylamino) ethylacetamide, N-2-methoxyethylacetamide, N-cyclopropyl-2-acetamide, and N-cyclopropylmethylacetamide, R ⁶ is chloro, dimethylamino, fluoro, methoxy One selected from methyl, methyl, and trifluoromethyl Other contains two substituents, Z is C.

In a further embodiment, the compound is

から選択されるか、またはその医薬的に許容される塩もしくはＮ酸化物である。

Or a pharmaceutically acceptable salt or N-oxide thereof.

In a further embodiment, the compound is
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) isoindoline-1,3-dione,
2-methyl-6- (phenylethynyl) -3,4-dihydroisoquinolin-1 (2H) -one,
5-((2,3-difluorophenyl) ethynyl) isoindoline-1-one,
5-((3,4-difluorophenyl) ethynyl) isoindoline-1-one,
5- (phenylethynyl) isoindoline-1-one,
5- (phenylethynyl) isoindoline-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 a pharmaceutically acceptable salt or N-oxide thereof.

In a further embodiment, the compound is
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 Selected from -6- (phenylethynyl) -3,4-dihydroisoquinolin-2 (1H) -yl) acetamide.

In a further embodiment, the compound is
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-dihydroisoquinoline- 1 (2H) -ON.

In a further embodiment, the compound is
Selected from 5- (phenylethynyl) isoindoline-1,3-dione and 2-methyl-5- (phenylethynyl) isoindoline-1,3-dione.

In a further embodiment, the compound is
5- (phenylethynyl) isoindoline-1-one,
It is selected from 5-((2,3-difluorophenyl) ethynyl) isoindoline-1-one and 5-((3,4-difluorophenyl) ethynyl) isoindoline-1-one.

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

h. Alkene Derivatives In one embodiment, the compound has the formula

を有する構造を有し、
式中、Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される、１〜５個の炭素原子を含む有機ラジカルから独立して選択される。

Having a structure with
In which R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 replaced Teloaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, Independently selected from organic radicals containing 1 to 5 carbon atoms, selected from amino-carbonyl and alkylamine-carbonyl.

In a further aspect, there is provided a compound, wherein, R ⁵ is

から選択され、
Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、または５個の置換基を含む。

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 alkylsulfur Containing 1 to 10 carbon atoms selected from finyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Contains 1, 2, 3, 4, or 5 substituents independently selected from organic radicals.

In a further embodiment, the compound has the formula

を有する構造を含み、
式中、Ｒ^７ａおよびＲ^７ｂは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択される。

Including a structure having
Wherein R ^7a and R ^7b are 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 hetero Cycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally 1 to 5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms.

In a further embodiment, the compound is

から選択され、
式中、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、または５個の置換基を含む。

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, C1-C6 optionally substituted 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 alkyl 1 to 10 carbon atoms selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. It contains 1, 2, 3, 4, or 5 substituents independently selected from the organic radicals it contains.

i. 1,2,4-oxadiazole derivatives In one embodiment, the compound has the formula

を有する構造を有する。

It has the structure which has.

In a further aspect, there is provided a compound, wherein, R ⁵ is

から選択され、
Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、または５個の置換基を含む。

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 alkylsulfur Containing 1 to 10 carbon atoms selected from finyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Contains 1, 2, 3, 4, or 5 substituents independently selected from organic radicals.

j. Amide derivatives In one embodiment, the compound has the formula

を有する構造を有し、
式中、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Having a structure with
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 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 heterocyclo Selected from organic radicals containing 1 to 6 carbon atoms selected from alkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, there is provided a compound, wherein, R ⁵ is

から選択され、
Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、または５個の置換基を含む。

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 alkylsulfur Containing 1 to 10 carbon atoms selected from finyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Contains 1, 2, 3, 4, or 5 substituents independently selected from organic radicals.

k. Enhancement of mGluR5 response In one embodiment, the compound is non-expressed in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound as compared to response to glutamate in the absence of the compound. An increase in response to glutamic acid at the maximum concentration shows an enhancement of the mGluR5 response to glutamic acid, with an EC _{50 of} less than about 1.0 × 10 ⁻⁶ , for example, less than about 5.0 × 10 ⁻⁷ , about 1.0 × having less than ^{10 -7,} less than about 5.0 × ^{10 -8,} or less than about 1.0 × ^{10 -8.}

D. Metabotropic glutamate receptor activity The utility of the compounds according to the invention as metabotropic glutamate receptor activity, in particular mGluR5 activity potentiators, can be demonstrated by methodologies known in the art. Human embryonic kidney (HEK) cells transfected with rat mGluR5 were seeded into clear bottom assay plates for assay in the Functional Drug Screening System (FDSS). Cells were loaded with Ca ²⁺ sensitive fluorescent dye (eg, Fluo-4), plates were washed and placed in the FDSS apparatus. After building a fluorescence baseline in 12 seconds, the compounds of the present invention were added to the cells and the reaction in the cells was measured. After 5 minutes, an mGluR5 agonist (eg, glutamic acid, 3,5-dihydroxyphenylglycine, or quiscaric acid) was added to the cells and the cellular response was measured. Enhancement of the agonist response of mGluR5 by the compounds of the present invention was observed as an increased response to an agonist (here glutamate) in the presence of the compound compared to the response to the agonist in the absence of the compound.

The above assay was performed in two modes. In the first mode, a series of concentrations of the compound were added to the cells, followed by a single fixed concentration of agonist. When the compound served as an enhancer, at this concentration of agonist, the EC ₅₀ value for enhancement and the maximum degree of enhancement by the compound was determined by non-linear curve fitting. In the second mode, several fixed concentrations of the compound are added to various wells on the plate, and then a series of concentrations of agonist are added to each concentration of the compound, at each concentration of the compound. EC ₅₀ values for agonists were determined by non-linear curve fitting. A decrease in agonist EC ₅₀ value with increasing concentration of the compound (shift to the left of the agonist concentration response curve) is an indicator of mGluR5 enhancement at a given concentration of the compound. An increase in the agonist EC ₅₀ value with increasing concentration of the compound (shift to the right of the agonist concentration response curve) is an indicator of mGluR5 enhancement at a given concentration of the compound. The second mode also shows whether the present compounds also affect the maximum response of mGluR5 to agonists.

Specifically, the disclosed compounds were active in potentiating mGluR5 receptors in the aforementioned assays, generally with an EC ₅₀ for enhancement of less than about 10 μM. In further embodiments, certain compounds were active in potentiating the mGluR5 receptor with an EC50 for enhancement of less than about 500 nM. Preferred compounds further resulted in a left shift of the agonist EC ₅₀ that is more than 3-fold. These compounds did not elicit mGluR5 response in the absence of agonist and did not cause a significant increase in mGluR5 maximal response to agonist. These compounds are positive allosteric modulators (enhancers) of human and rat mGluR5 and were selective for mGluR5 compared to the other seven subtypes of metabotropic glutamate receptors.

In certain embodiments, the compounds have also shown in vivo efficacy in a number of preclinical rat behavioral models in which well-known, clinically useful antipsychotic agents show similar positive responses. For example, the compounds of the present invention improved amphetamine-induced hypermotor in male Sprague-Dawley rats when administered intraperitoneally at a dose of 1-100 mg / kg. For disclosed compounds, EC ₅₀ for potentiation of mGluR5 receptor is listed in Table 1 below.

Preferred compounds of the invention have also shown in vivo efficacy in a number of preclinical rat behavioral models in which well-known, clinically useful antipsychotic agents show similar positive responses. For example, the compounds of the present invention improved amphetamine-induced hypermotor in male Sprague-Dawley rats when administered intraperitoneally at a dose of 1-100 mg / kg. Data for three example compounds are shown.

FIG. 8 shows the efficacy of (4-hydroxypiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (compound VU13, extracorporeal: 13.6 nm, 50% of maximum Glu) to improve amphetamine-induced hyperactivity. Indicates.

FIG. 9 shows amphetamine-induced hypermotility of (4-hydroxy-4-propylpiperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (compound VU60 / C109B2, in vitro: 1250 nm, 90% of maximum Glu). The effectiveness to improve is shown.

FIG. 10 shows amphetamine-induced hyperactivity of (4- (hydroxymethyl) piperidin-1-yl) (4- (phenylethynyl) phenyl) methanone (compound VU14 / C104B2, in vitro: 29.6 nm, 41% of maximum Glu). Effectiveness to improve

Schizophrenic patients show a decrease in sensorimotor gating measurements such as prepulse inhibition (PPI) consisting of surprises and pre-clinical models of PPI in rats to predict the effectiveness of antipsychotic drugs Is used on a daily basis. Indeed, PPI can be measured in humans and rats using the same stimulation parameters that produce a similar response (Braff, DL; Geyer, MA; Swedish, N.R. ' 'Psychopharmacology 2001, 156, 2-3 (2-3), ff. schizophrenia.Human and animal model studies.'Archi es of general psychiatry 1990, 47 (2), 181-8, Braff, DL, Geyer, MA, Swedish, N. R. 'Human studies of prejudation of spills of sculptures: and pharmacologic studies. 'Psychopharmacology 2001, 156 (2-3), 234-258, Weiss, I. C .; Feldon, J.' Environmental animal models in sensors. Psychopharmacology 2001, 156 (2-3), 305-326, Thomsen, M .; Wortwein, G .; Fink-Jensen, A .; Waldbye, D.P.D .; Wess, J .; .'Decreased prepulse inhibition and increased sensitivity to Muscarinic, but not dopametric drags in M5 muscarinic acetylcholine receptor. 'Psychopharmacology 2007, 192 (1), 97-110). In addition, all clinically relevant antipsychotic agents (both typical and atypical) have been shown to be effective in preclinical models of PPI and amphetamine-induced hyperactivity and lead to the development of new antipsychotic agents. These preclinical models are utilized (Geyer, MA, “Behavioral studies of hallucinogenic drugs in animal: implications for schizophrenia research. Gemmapyr. McIlwain, KL; Paylor, R. 'Mouse genetic models for preperation inhibition: an ea ly review. 'Molecular Psychiatry 2002, 7 (10), 1039-1053, Powell, S.B .; Risbrough, V.B .; Geyer, M.A.' 'Clinical Neuroscience Research 2003, 3 (4-5), 289-296).

A positive allosteric modulator (PAM) of mGluR5 from five different structural series (FIG. 15) has shown antipsychotic-like effects in a rat behavior model that predicts the efficacy of antipsychotics in humans (Lindsley, C. et al. W .; Wisnoski, DD; Leister, WH; O'Brien, JA; Lemaire, W .; Williams, Jr., DL; Kinney, GG; Pettibone, D.J .; Miller, PR; Smith, S.; Duggan, M.E .; Hartman, G.D .; Conn, P.J .; JR'Discovery of positive allomodulators for the m tabotropic glutamate receptor subtype 5 from a series of N- (1,3-Diphenyl-1H-pyrazol-5-yl) benzamides that potentiate. O'Brien, Lemaire, W .; Burno, M.'Bickel, DJ; Elements, M.K .; Wisnoski, DD; Lindsley, C.W.; Tiller, PR Smith, S .; Jacobson, M.A .; Sur, C .; Duggan, M.E .; Pettibone, D.J .; Jr., D.W.'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, Epping- Jordan MP, Nayak, S., Derouet, F., Dominguez, H., Besissis AS, Le Paul E., Ludwig B. L. Mutel V. , Poli S. M.M. and Rocher J. et al. P. See In Vivo Charactorization of mGluR5 Positive Allosteric Modulators as Novel Treatments for Schizophrenia and Cognitive Dysfunction3, 49.

CDPPB (Lindsley, C.W .; Wisnoski, DD; Leister, WH; O'Brien, JA; Lemaire, W .; Williams, Jr., DL; Burno, M.) Surrey, C .; Kinney, G. G .; Pettibone, D. J.; ller, PR; Smith, S.; Duggan, M.E .; Hartman, G.D .; Conn, P. Huff, JR, 'Discovery of positive allomodulatory modulators for the metatropic glutamate receptor-receptor subtype 5-N1 -D ) Benzamides that potentiate receptor function in vivo 'J. Med. Chem. 2004, 47, 5825, Kinney, GG; O'Brien, Lemaire, W.; Burno, M.'BickelC. Wisnoski, DD; Lindsley, CW; Tiller, PR; Smith, S.; Jacobson, MA; Sur, C.; Duggan, M.E. Petribone, DJ; Williams, Jr., D. W. 'A novel selective allomodulator of metabotropic glutamate receptor sub type 5 (mGluR5) has an antipsychotic profile in rat behavioral models' J. Pharmacol. Exp. Therapeut. 2005, 313 (1), 199) induced an amphetamine-induced excess of amphetamine in rats. The latest data with mGlur5 PAM and structurally different ADX47273 has obtained similar results (FIG. 16). Recently, similar data has been reported in the DFB. Two new mGluR5 PAMSs (FIG. 17, VU000001 and VU000067) also obtained similar results, indicating that positive allosteric modulators of mGluR5 provide antipsychotic-like efficacy in this preclinical model.

Both CDPPB and ADX47273 have also demonstrated efficacy in PPI, preclinical models with direct implications for clinical efficacy, and identical behavior in schizophrenic patients. As shown in FIG. 18, CDPPB improves PPI in a dose-dependent manner with four different prepulse intensities above background. ADX47273 gives similar results (FIG. 19).

E. In one aspect, the present invention relates to a method for making a compound useful as a positive allosteric modulator (enhancer) of metabotropic glutamate receptor subtype 5 (mGluR5), which is associated with glutamate dysfunction It may be useful for the treatment of neurological and psychiatric disorders and other diseases involving metabotropic glutamate receptors.

The compounds of the invention react as shown in the following schemes, as well as other standard procedures known in the literature or apparent to those skilled in the art, exemplified in the experimental section herein. Can be prepared by utilizing. The numbering of substituents shown in the schemes does not necessarily correlate with that used in the claims, and often, for clarity, multiple substituents are defined under the definitions disclosed herein. Where allowed, a single substituent is shown attached to the compound.

In one embodiment, the present invention provides a phenylethynylbenzamide derivative, a cycloalkylethynylbenzamide derivative, a styrylbenzamide derivative, a 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzamide derivative, 4- ( The present invention relates to a method for producing a pyridinylethynyl) benzamide derivative and an N ¹ -phenylterephthalamide derivative.

1. Phenylethynylbenzamide derivative In one aspect, the present invention relates to a method for preparing a phenylethynylbenzamide derivative, the method comprising coupling an aryl halide and an arylacetylene, wherein one of arylacetylene or aryl halide. Comprises carrying a carboxyl functional group and forming an amide derivative of the carboxyl functional group by reaction with an amine. In general, the method involves a coupling reaction (eg, a transition metal catalyzed cross-coupling reaction) and a reaction that forms an amide moiety. Such a method may be represented in the schematic diagram below.

In a further aspect, the method can be represented in the following schematic, which illustrates a synthetic method that is useful for the preparation of large quantities of the disclosed compounds.

In one aspect, the coupling step is performed before the forming step. In a further aspect, the method further comprises converting the carboxyl functionality to a carboxylic acid. In one embodiment, the carboxyl functional group is an ester moiety. In one embodiment, the aryl halide carries a carboxyl functionality. The halide can be Br or I. It should be understood that pseudohalides can be substituted for halides.

In one embodiment, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the coupling step is a palladium catalyzed cross coupling.

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

In one embodiment, the aryl halide has the formula

により表される構造を有し、
式中、Ｒは、任意に置換されたアルキルであり、Ｒ^３は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される４個の置換基を含む。

Having a structure represented by
Wherein R is an optionally substituted alkyl and R ³ includes four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In a further embodiment, the aryl acetylene is of the formula

により表される構造を有し、
式中、Ｒ^４は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される５個の置換基を含む。

Having a structure represented by
Wherein R ⁴ includes 5 substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

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

2. Cycloalkylethynylbenzamide derivatives In one aspect, the present invention relates to a method for preparing a cycloalkylethynylbenzamide derivative, comprising coupling an aryl halide and a cycloalkylacetylene, wherein the aryl halide has a carboxyl functionality. Supporting, and forming an amide derivative of the carboxyl functional group by reaction with an amine. In general, the method involves a coupling reaction (eg, a transition metal catalyzed cross-coupling reaction) and a reaction that forms an amide moiety. Such a method may be represented in the schematic diagram below.

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

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

In one embodiment, the halide is Br, I, or pseudohalide.

In one embodiment, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the coupling step is a palladium catalyzed cross coupling.

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

In one embodiment, the aryl halide has the formula

により表される構造を有し、
式中、Ｒは、任意に置換されたアルキルであり、Ｒ^３は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される４個の置換基を含む。

Having a structure represented by
Wherein R is an optionally substituted alkyl and R ³ includes four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one embodiment, the cycloalkylacetylene has the formula

により表される構造を有し、
式中、Ｚは、０〜２個の炭素を含み、Ｒ^４は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される９〜１３個の置換基を含む。

Having a structure represented by
Wherein Z contains 0 to 2 carbons and R ⁴ contains 9 to 13 substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

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

3. In one aspect, the present invention relates to a method for preparing a styryl benzamide derivative, comprising coupling an aryl halide and a styryl boronic acid or styryl boronic ester, wherein the styryl boronic acid or styryl boronic acid One of the ester or aryl halide comprises carrying a carboxyl functional group and reacting with an amine to form an amide derivative of the carboxyl functional group. In general, the method involves a coupling reaction (eg, a transition metal catalyzed cross-coupling reaction) and a reaction that forms an amide moiety. Such a method may be represented in the schematic diagram below.

In a further aspect, the method can be represented in the following schematic, which illustrates a synthetic method that is useful for the preparation of large quantities 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 functionality to a carboxylic acid. In one embodiment, the carboxyl functional group is an ester moiety. In a further embodiment, the aryl halide carries a carboxyl functionality.

In one embodiment, the halide is Br, I, or pseudohalide.

In one embodiment, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the coupling step is a palladium catalyzed cross coupling.

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

In one embodiment, the aryl halide has the formula

により表される構造を有し、
式中、Ｒは、任意に置換されたアルキルであり、Ｒ^３は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される４個の置換基を含む。

Having a structure represented by
Wherein R is an optionally substituted alkyl and R ³ includes four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one embodiment, the styrylboronic acid or styrylboronic acid ester has the formula

により表される構造を有し、
式中、Ｒは、Ｈまたは任意に置換されたアルキルであり、Ｒ^４は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される５個の置換基を含む。

Having a structure represented by
Wherein R is H or optionally substituted alkyl, and R ⁴ includes 5 substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

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

4). 4- (3-Phenyl-1,2,4-oxadiazol-5-yl) benzamide derivative In one embodiment, the present invention provides 4- (3-phenyl-1,2,4-oxadiazole-5- I) Concerning a method for preparing a benzamide derivative, the step of condensing an aryl carboxylic acid and N'-hydroxybenzimide amide, wherein one of the N'-hydroxybenzimide amide or aryl carboxylic acid is an ester Carrying a functional group and forming an amide derivative of the ester functional group by reaction with an amine. In general, the method involves a condensation reaction (eg, formation of an oxadiazole) and a reaction that forms an amide moiety. Such a method may be represented in the schematic diagram below.

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

In one aspect, the method further comprises converting the ester functionality to a carboxylic acid. In a further aspect, the aryl carboxylic acid yields an ester functionality.

In one embodiment, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.

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

In one embodiment, the aryl carboxylic acid has the formula

により表される構造を有し、
式中、Ｒは、任意に置換されたアルキルであり、Ｒ^３は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される４個の置換基を含む。

Having a structure represented by
Wherein R is an optionally substituted alkyl and R ³ includes four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one embodiment, the N'-hydroxybenzimidoamide has the formula

により表される構造を有し、
式中、Ｒ^４は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される５個の置換基を含む。

Having a structure represented by
Wherein R ⁴ includes 5 substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

It should be 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 method for preparing a 4- (pyridinylethynyl) benzamide derivative, comprising coupling an aryl halide and an arylacetylene. One of arylacetylene or aryl halide comprises carrying a carboxyl functional group and reacting with an amine to form an amide derivative of the carboxyl functional group. In general, the method involves a coupling reaction (eg, a transition metal catalyzed cross-coupling reaction) and a reaction that forms an amide moiety. Such a method may be represented in the schematic diagram below.

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

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

In a further embodiment, the aryl halide carries a carboxyl functionality.

In one embodiment, the halide is Br, I, or pseudohalide.

In one embodiment, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the coupling step is a palladium catalyzed cross coupling.

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

In one embodiment, the aryl halide has the formula

により表される構造を有し、
式中、Ｒは、任意に置換されたアルキルであり、Ｒ^３は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される４個の置換基を含む。

Having a structure represented by
Wherein R is an optionally substituted alkyl and R ³ includes four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one embodiment, the arylacetylene has the formula

により表される構造を有し、
式中、Ｒ^４は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される４個の置換基を含む。

Having a structure represented by
Wherein R ⁴ includes ⁴ substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

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

6). N ¹ -phenyl terephthalamide derivative In one aspect, the present invention relates to a method for preparing an N ¹ -phenyl terephthalamide derivative, comprising reacting a benzoic acid compound with an aniline compound, wherein the benzoic acid compound is a carboxyl Carrying a functional group and forming an amide derivative of the carboxyl functional group by reaction with an amine. In general, the method involves two separate reactions that form an amide moiety. Such a method may be represented in the schematic diagram below.

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

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

In one embodiment, the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.

In one aspect, the reaction step is performed 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 embodiment, the benzoic acid compound has the formula

により表される構造を有し、
式中、Ｒは、任意に置換されたアルキルであり、Ｒ^３は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される４個の置換基を含む。

Having a structure represented by
Wherein R is an optionally substituted alkyl and R ³ includes four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

In one embodiment, the aniline compound has the formula

により表される構造を有し、
式中、Ｒは、Ｈまたは任意に置換されたアルキルであり、Ｒ^４は、水素、ハロゲン、および任意に置換されたアルキルから独立して選択される５個の置換基を含む。

Having a structure represented by
Wherein R is H or optionally substituted alkyl, and R ⁴ includes 5 substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.

7). Cyclic benzamide In a further aspect, the disclosed method may be useful for providing a compound having a bicyclic benzamide structure, wherein the compound is a positive allosteric modulation of metabotropic glutamate receptor subtype 5 (mGluR5) It may be useful as a factor (enhancer).

The reactants used to generate the compounds of the invention are prepared by using the reactions shown in Reaction Schemes I and II, as well as other standard procedures known in the literature or in the art. The following examples are provided so that the invention may be more fully understood, are exemplary only, and are not to be construed as limiting.
Reaction Scheme I

As illustrated in Reaction Scheme I, a suitably substituted 6-bromo-3,4-dihydro-2H-isoquinoline I-1 can undergo catalytic copper (I) iodide and catalytic palladium ( 0), and suitably functionalized acetylenes, are subjected to a Sonogashira / Castro-Stephens coupling reaction to give the corresponding product I-2. In this example, suitably substituted 6-bromo-3,4-dihydro-2H-isoquinoline I-1 was commercially available or could be readily prepared according to literature methods. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting in any way.
Reaction Scheme II

As illustrated in Reaction Scheme II, a suitably substituted 6-substituted-3,4-dihydro-2H-isoquinoline II-1 can be prepared using a suitably functionalized electrophile (R3-X). Exposure to the S _N 2 reaction yields the corresponding product II-2. In this example, a suitably substituted 6-substituted-3,4-dihydro-2H-isoquinoline II-1 was prepared according to Reaction Scheme I and the electrophile was either commercially available or literature Could easily be prepared according to the method of The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting in any way.
Reaction Scheme III

As illustrated in Reaction Scheme III, a suitably substituted 5-bromoisobenzofuran-1 (3H) -one III-1 is treated with ammonium hydroxide in methanol to give 4-bromo-2- (hydroxyl). Methyl) benzamide III-2 is obtained and subsequent Mitsunobu reaction under standard conditions yields 5-bromoisoindoline-1-one III-3. Intermediate III-3 was subjected to a Sonogashira / Castro-Stephens coupling reaction using catalytic copper (I) iodide and catalytic palladium (0) and a suitably functionalized acetylene III-4 under microwave irradiation. It is exposed to give the corresponding product III-5. In this example, suitably substituted 5-bromoisobenzofuran-1 (3H) -one III-1 was either commercially available or could be readily prepared according to literature methods. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting in any way.
Reaction Scheme IV

As illustrated in Reaction Scheme IV, a suitably substituted 5- (phenylethynyl) isobenzofuran-1,3-dione IV-1 is treated with urea in DMF under microwave irradiation to give 5- (Phenethynyl) isoindoline-1,3-dione IV-2 is obtained. Intermediate IV-2 is alkylated with a suitably functionalized alkyl halide (Cl, Br, I) to give 2-alkyl-5- (phenethynyl) isoindoline-1,3-dione IV-3. In this example, suitably substituted 5- (phenylethynyl) isobenzofuran-1,3-dione IV-1 was either commercially available or could be readily prepared according to literature methods.

In one aspect, the invention relates to a method for preparing a compound comprising the following steps.
formula

により表される構造を有する第１の反応物質、またはその医薬的に許容される塩もしくはＮ酸化物を提供するステップであって、
式中、ｎは、０、１、２、３、または４であり、Ｙ^１およびＹ^２は、ＣおよびＮから独立して選択され、Ｒ^１は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、および−（ＣＨ_２）_ｍ−アリールもしくは−（ＣＨ_２）_ｍ−複素環から選択される１〜１２個の炭素原子を含む有機ラジカルから選択され、ｍは、１、２、３、または４であり、Ｒ^２ａおよびＲ^２ｂは存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜６個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜６個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１２個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、または３個の置換基を含み、Ｘ^１は、ハロゲン化物、疑似ハライド、カルボン酸、カルボン酸誘導体、末端アセチレン部分、活性ビニル部分、Ｎ’−ヒドロキシベンズイミドアミド、または第１級もしくは第２級アミンを含み、
式

Providing a first reactant having a structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof,
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 C ^1- 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, and - _{(CH 2) m} - aryl or - (CH ) _M - is selected from organic radicals containing 1 to 12 carbon atoms selected from heterocycle, m is 1, 2, 3 or 4, ^when the ^{R 2a} and ^{R 2b} present, together, Each R ^2a and R ^2b 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-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycle Alkenyl or C6 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkyl Independently selected from sulfonyl and organic radicals containing 1 to 6 carbon atoms selected from optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl , R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b 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-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cyclo Alkynyl, optionally substituted C3-C8 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxa Independently selected from organic radicals containing 1 to 6 carbon atoms selected from amide, amino-carbonyl, and alkylamine-carbonyl, wherein 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 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, thioamide, 1, 2, or 3 substitutions independently selected from organic radicals containing 1 to 12 carbon atoms selected from amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl X ¹ comprises a halide, pseudohalide, carboxylic acid, carboxylic acid derivative, terminal acetylene moiety, active vinyl moiety, N′-hydroxybenzimidoamide, or primary or secondary amine;
formula

により表される構造を有する第２の反応物を提供するステップであって、
式中、Ｒ^５は、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される４〜１４個の炭素原子を含む有機ラジカルであり、Ｘ^２は、ハロゲン化物、疑似ハライド、カルボン酸、カルボン酸誘導体、末端アセチレン部分、活性ビニル部分、Ｎ’−ヒドロキシベンズイミドアミド、または第１級もしくは第２級アミンを含み、
および、
第１の反応物を第２の反応物とカップリングさせ、それにより、結合部分Ｌを形成し、式

Providing a second reactant having a structure represented by:
Wherein R ⁵ is an optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, an optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, an optionally substituted aryl, And an organic radical containing 4 to 14 carbon atoms selected from optionally substituted heteroaryl, wherein X ² is a halide, pseudohalide, carboxylic acid, carboxylic acid derivative, terminal acetylene moiety, active vinyl moiety N′-hydroxybenzimidoamide, or a primary or secondary amine,
and,
Coupling the first reactant with the second reactant, thereby forming the binding moiety L;

により表される構造を有する化合物を得るステップであって、
式中、Ｌは、任意に置換されたＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、および任意に置換されたアミドから選択される１〜７個の炭素原子を含む有機２価ラジカルであり、Ｘ^１がハロゲン化物または疑似ハライドである場合、Ｘ^２は、末端アセチレン部分、または活性ビニル部分であり、Ｘ^１がカルボン酸またはカルボン酸誘導体である場合、Ｘ^２は、Ｎ’−ヒドロキシベンズイミドアミド、または第１級もしくは第２級アミンであり、Ｘ^２がハロゲン化物または疑似ハライドである場合、Ｘ^１は、末端アセチレン部分、または活性ビニル部分であり、Ｘ^２がカルボン酸またはカルボン酸誘導体である場合、Ｘ^１は、Ｎ’−ヒドロキシベンズイミドアミド、または第１級もしくは第２級アミンであり、任意に、Ｒ^１が水素である場合、ラクタムまたはイミド部分をアルキル化する。

Obtaining a compound having a structure represented by
Where L is an optionally substituted C2-C6 alkenyl or C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl, an optionally substituted C3-C6 heterocycloalkyl or An organic divalent radical containing 1 to 7 carbon atoms selected from C3-C6 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amide; ^{When 1} is a halide or pseudohalide, X ² is a terminal acetylene moiety or an active vinyl moiety, and when X ¹ is a carboxylic acid or carboxylic acid derivative, X ² is N′-hydroxybenzimidoamide , or a primary or secondary amine, X ² is a halide or pseudo halide Some cases, X ¹ is terminal acetylene moiety or active vinyl moiety, when X ² is a carboxylic acid or carboxylic acid derivative, X ¹ is, N'- hydroxybenzimidamide or a primary or secondary, If it is a secondary amine and optionally R ¹ is hydrogen, the lactam or imide moiety is alkylated.

In a further aspect, L is

から選択され、
式中、Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択された１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
In which R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1-5 selected from optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing one carbon atom, 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 heterocyclo Alkyl or C3-C8 heterocycloalkenyl or C6 heterocycloalkynyl, are selected from organic radicals containing from 1 to 6 carbon atoms selected optionally substituted aryl, and optionally substituted heteroaryl.

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

In further embodiments, the reactive vinyl moiety comprises a mono-substituted vinyl moiety, vinyl boronic acid, vinyl boronate ester, or vinyl trialkylstannane.

In a further aspect, the coupling step comprises a Sonogashira / Castro-Stephens coupling reaction, wherein X ¹ comprises a halide or pseudohalide, X ² comprises a terminal acetylene moiety, and the compound comprises: formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises a Sonogashira / Castro-Stephens coupling reaction, wherein X ¹ comprises a terminal acetylene moiety, X ² comprises a halide or pseudohalide, and the compound comprises: formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises a Suzuki coupling reaction, wherein X ¹ comprises a vinyl boronic acid or vinyl boronic ester, X ² comprises a halide or pseudohalide, and the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises a Suzuki coupling reaction, wherein X ¹ comprises a halide or pseudohalide, X ² comprises a vinyl boronic acid or vinyl boronate ester, and the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises a Stille coupling reaction, wherein X ¹ comprises a vinyltrialkylstannane, X ² comprises a halide or pseudohalide, and the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises a Stille coupling reaction, wherein X ¹ comprises a halide or pseudohalide, X ² comprises a vinyltrialkylstannane, and the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises a Heck reaction, wherein X ¹ comprises a monosubstituted vinyl moiety, X ² comprises a halide or pseudohalide, and the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises a Heck reaction, wherein X ¹ comprises a halide or pseudohalide, X ² comprises a monosubstituted vinyl moiety, and the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises a condensation reaction, wherein X ¹ comprises a carboxylic acid or carboxylic acid derivative, X ² comprises N′-hydroxybenzimidoamide, wherein the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises a condensation reaction, wherein X ¹ comprises N′-hydroxybenzimidoamide, X ² comprises a carboxylic acid or carboxylic acid derivative, and the compound has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the coupling step comprises an amide-forming reaction, wherein X ¹ comprises a carboxylic acid or carboxylic acid derivative, X ² comprises a primary or secondary amine, and the compound is ,formula

により表される構造を有し、
式中、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Having a structure represented by
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 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 organic radicals containing from 1 to 6 carbon atoms selected from substituted aryl and optionally substituted heteroaryl.

In a further aspect, the coupling step comprises an amide-forming reaction, wherein X ¹ comprises a primary or secondary amine, X ² comprises a carboxylic acid or carboxylic acid derivative, and the compound is ,formula

により表される構造を有し、
式中、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Having a structure represented by
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 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 organic radicals containing from 1 to 6 carbon atoms selected from substituted aryl and optionally substituted heteroaryl.

In a further aspect, providing the first reactant comprises
formula

により表される構造を有する無水物（式中、ｎは、０または１である）を、アンモニアまたは第１級アミンで処理して、式

An anhydride having the structure represented by the formula (wherein n is 0 or 1) is treated with ammonia or a primary amine to give the formula

により表される構造を有する化合物を得るステップと、
任意に、Ｒ^１が水素である場合、イミド部分をアルキル化するステップと、を含む。

Obtaining a compound having the structure represented by:
Optionally, when R ¹ is hydrogen, alkylating the imide moiety.

In a further aspect, providing the first reactant comprises
formula

により表される構造を有するラクトン（式中、ｎは、０、１、２、３、または４である）を、アンモニアまたは第１級アミンで処理して、式

A lactone having a structure represented by the formula (wherein n is 0, 1, 2, 3, or 4) is treated with ammonia or a primary amine to give the formula

により表される構造を有する中間体を得るステップと、
該中間体を環化して、式

Obtaining an intermediate having a structure represented by:
The intermediate is cyclized to form the formula

により表される構造を有する化合物を得るステップと、
任意に、Ｒ^１が水素である場合、ラクタム部分をアルキル化するステップと、を含む。

Obtaining a compound having the structure represented by:
Optionally, when R ¹ is hydrogen, alkylating the lactam moiety.

In a further aspect, the cyclizing step comprises subjecting the intermediate to Mitsunobu reaction conditions or converting the hydroxyl functionality to a pseudohalide.

In a further aspect, the first reactant has the formula

を含む構造を有する。

It has the structure containing.

In a further aspect, the first reactant has the formula

を含む構造を有する。

It has the structure containing.

In a further aspect, the first reactant has the formula

を含む構造を有する。

It has the structure containing.

In a further aspect, the first reactant has the formula

を含む構造を有する。

It has the structure containing.

In a further aspect, the first reactant has the formula

を含む構造を有する。

It has the structure containing.

In a further embodiment, the second reactant, formula

により表される構造を有し、
式中、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５、およびＺ^６は、ＣおよびＮから独立して選択され、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、５個、６個、または７個の置換基を含む。さらなる態様において、Ｒ^６は、クロロ、ジメチルアミノ、フルオロ、メトキシ、メチル、およびトリフルオロメチルから選択される。

Having a structure represented by
Wherein Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , and Z ⁶ are independently selected from C and N, and 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino- 1, 2, 3, 4, 5, 6, or 7 independently selected from carbonyl and an organic radical containing 1 to 10 carbon atoms selected from alkylamine-carbonyl Including substituents. In a further aspect, R ⁶ is selected from chloro, dimethylamino, fluoro, methoxy, methyl, and trifluoromethyl.

In a further aspect, the second reactant has the formula

により表される構造を有し、
式中、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、または５個の置換基を含む。

Having a structure represented by
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, C1-C6 optionally substituted 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 alkyl 1 to 10 carbon atoms selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. It contains 1, 2, 3, 4, or 5 substituents independently selected from the organic radicals it contains.

In a further aspect, the second reactant has the formula

により表される構造を有する。

It has the structure represented by these.

In a further aspect, the second reactant has the formula

により表される構造を有し、
式中、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個または２個の置換基を含む。

Having a structure represented by
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, C1-C6 optionally substituted 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 alkyl 1 to 10 carbon atoms selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. Contains one or two substituents independently selected from the organic radicals it contains.

In a further embodiment, the alkylating step is performed by reaction with a base and an alkyl halide or alkyl pseudohalide. In a further embodiment, the base is sodium hydroxide.

In a further aspect, the alkyl moiety 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 heterocycloalkenyl Or 1-12 selected from C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, or-(CH2) m-aryl or-(CH2) m-heterocycle It includes an organic radical containing carbon atoms, wherein, m is 1, 2, 3, or 4.

In a further embodiment, the alkylation step is performed before the coupling step.

In one aspect, the invention relates to a method for preparing a compound comprising the following steps.
formula

により表される構造を有する無水物、またはその医薬的に許容される塩もしくはＮ酸化物、を含む反応体を提供するステップであって、
式中、ｎは、０または１であり、Ｙ^１およびＹ^２は、ＣおよびＮから独立して選択され、Ｒ^２ａおよびＲ^２ｂは存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜６個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜６個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１２個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、または３個の置換基を含み、Ｒ^５は、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される４〜１４個の炭素原子を含む有機ラジカルを含み、Ｘ^１は、ハロゲン化物または疑似ハライドまたは−Ｌ−Ｒ^５を含み、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。
および、
反応物を、アンモニアまたは第１級アミンで処理して、式

Providing a reactant comprising an anhydride having the structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof,
Wherein n is 0 or 1, Y ¹ and Y ² are independently selected from C and N, and R ^2a and R ^2b, if present, together form ═O or ═S, Or each R ^2a and R ^2b 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-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycl Alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally Independently selected from organic radicals containing 1 to 6 carbon atoms selected from substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl, R ^3a and R ^{3 3b} together form ═O or ═S, or each R ^3a and R ^3b is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C1-C6 alkyl or C2-C6 Alkenyl or C2-C6 Lucynyl, 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, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally Substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and Rukiruamin - C1 are independently selected from organic radicals containing from 1 to 6 carbon atoms selected from carbonyl, R ⁴ is hydrogen, substituted with halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally -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 hetero Reel, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, Comprising one, two or three substituents independently selected from organic radicals containing 1 to 12 carbon atoms selected from amino-carbonyl and alkylamine-carbonyl, 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 hetero 4 to 14 selected from aryl Includes an organic radical containing carbon atoms, ^{X 1} is comprises a halide or pseudo halide or ^{-L-R 5,} L is an organic divalent radical containing from 1 to 7 carbon atoms, ^{R 5} is Organic radicals containing 4 to 14 carbon atoms.
and,
The reaction is treated with ammonia or a primary amine to give the formula

により表される構造を有する化合物を得るステップであって、
任意に、Ｒ^１が水素である場合、イミド部分をアルキル化するステップ。

Obtaining a compound having a structure represented by
Optionally, when R ¹ is hydrogen, alkylating the imide moiety.

In a further embodiment, R ¹ is 2- (4-hydroxypiperidin-1-yl) -2-oxoethyl, 2- (4-hydroxypiperidin-1-yl) ethyl, 2- (azetidin-1-yl), 2 -Acetamide, 2-morpholino-2-oxoethyl, 2-morpholinoethyl, benzyl, benzyl 2-acetate, cyclobutylmethyl, cyclopropylmethyl, ethyl 2-propanoate, hydrogen, methyl, N- (2- (dimethylamino) ethyl Selected from acetamide, N-2-methoxyethylacetamide, N-cyclopropyl-2-acetamide, and N-cyclopropylmethylacetamide.

In a further aspect, R ⁵ is

から選択され、
式中、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５、およびＺ^６は、ＣおよびＮから独立して選択され、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、５個、６個、または７個の置換基を含む。さらなる態様において、Ｒ^６は、クロロ、ジメチルアミノ、フルオロ、メトキシ、メチル、およびトリフルオロメチルから選択される。

Selected from
Wherein Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , and Z ⁶ are independently selected from C and N, and 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino- 1, 2, 3, 4, 5, 6, or 7 independently selected from carbonyl and an organic radical containing 1 to 10 carbon atoms selected from alkylamine-carbonyl Including substituents. In a further aspect, R ⁶ is selected from chloro, dimethylamino, fluoro, methoxy, methyl, and trifluoromethyl.

In a further aspect, R ⁵ is

から選択され、
式中、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、３個、４個、または５個の置換基を含む。

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, C1-C6 optionally substituted 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 alkyl 1 to 10 carbon atoms selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. It contains 1, 2, 3, 4, or 5 substituents independently selected from the organic radicals it contains.

In a further aspect, R ⁵ is

から選択される。

Selected from.

In a further aspect, R ⁵ is of the formula

を有する構造を含み、
式中、Ｒ^６は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１０個の炭素原子を含む有機ラジカルから独立して選択される１個または２個の置換基を含む。

Including a structure having
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, C1-C6 optionally substituted 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 alkyl 1 to 10 carbon atoms selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. Contains one or two substituents independently selected from the organic radicals it contains.

In a further aspect, L is

から選択され、
式中、Ｒ^７ａおよびＲ^７ｂは共に、任意に置換された炭素環もしくは２〜５個の炭素を有する複素環を形成するか、または水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択され１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
^Where R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 Replaced by Teloaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, Independently selected from organic radicals containing 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-C8 cycloalkyl or C3-C8 cycloalkyl From Nyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl Selected from organic radicals selected from 1 to 6 carbon atoms.

In a further embodiment, the alkylating step is performed by reaction with a base and an alkyl halide or alkyl pseudohalide. In a further embodiment, the base is sodium hydroxide.

In a further embodiment, the alkyl moiety of the alkyl halide or alkyl pseudohaloid 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 1-12 selected from C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, or-(CH2) m-aryl or-(CH2) m-heterocycle It includes an organic radical containing carbon atoms, wherein, m is 1, 2, 3, or 4.

In a further embodiment, the alkylation step is performed before the coupling step.

In one aspect, the invention relates to a method for preparing a compound comprising the following steps.
formula

により表される構造を有するラクトン、またはその医薬的に許容される塩もしくはＮ酸化物を含む反応物を提供するステップであって、
式中、ｎは、０、１、２、３、または４であり、Ｙ^１およびＹ^２は、ＣおよびＮから独立して選択され、Ｒ^２ａおよびＲ^２ｂは存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜６個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜６個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニルもしくはＣ６−Ｃ８シクロアルキニル、任意に置換されたＣ３−Ｃ８ヘテロシクロアルキルもしくはＣ３−Ｃ８ヘテロシクロアルケニルもしくはＣ６−Ｃ８ヘテロシクロアルキニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜１２個の炭素原子を含む有機ラジカルから独立して選択される１個、２個、または３個の置換基を含み、Ｒ^５は、任意に置換されたＣ３−Ｃ８シクロアルキルもしくはＣ３−Ｃ８シクロアルケニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される４〜１４個の炭素原子を含む有機ラジカルであり、Ｘ^１は、ハロゲン化物または疑似ハライドまたは−Ｌ−Ｒ^５を含み、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、
反応物を、アンモニアまたは第１級アミンで処理して、式

Providing a reactant comprising a lactone having a structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof,
Where n is 0, 1, 2, 3, or 4, Y ¹ and Y ² are independently selected from C and N, and when R ^2a and R ^2b are present, both are ═O Or = S or each R ^2a and R ^2b 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-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or 6 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, And independently selected from organic radicals containing 1 to 6 carbon atoms selected from optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl, R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and optionally substituted C1-C6 alkyl or C2-C6 alkenyl Is 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, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carboxyl Alkenyl, and alkyl amines - are independently selected from organic radicals containing from 1 to 6 carbon atoms selected from 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 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cyclo Alkyl 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, thioamide, amidosulfonyl, alkoxycarbonyl 1, 2, or 3 substituents independently selected from organic radicals containing 1 to 12 carbon atoms selected from: carboxamide, amino-carbonyl, and alkylamine-carbonyl, R ⁵ is an optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, an optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, an optionally substituted aryl, and an optionally substituted Selected from heteroaryl That is an organic radical containing 4 to 14 carbon atoms, ^{X 1} is comprises a halide or pseudo halide or ^{-L-R 5,} L is an organic divalent radical containing from 1 to 7 carbon atoms R ⁵ is an organic radical containing 4 to 14 carbon atoms,
The reaction is treated with ammonia or a primary amine to give the formula

により表される構造を有する中間体を得るステップと、
該中間体を環化して、式

Obtaining an intermediate having a structure represented by:
The intermediate is cyclized to form the formula

により表される構造を有する中間体を得るステップと、
任意に、Ｒ^１が水素である場合、ラクタム部分をアルキル化するステップ。

Obtaining an intermediate having a structure represented by:
Optionally, when R ¹ is hydrogen, alkylating the lactam moiety.

In further embodiments, the cyclization step comprises subjecting the intermediate to Mitsunobu reaction conditions or converting the hydroxyl functionality to a pseudohalide.

In a further aspect, L is

から選択され、
式中、Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択された１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
In which R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1-5 selected from optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing one carbon atom, 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 heterocyclo Alkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, are selected from organic radicals containing from 1 to 6 carbon atoms selected optionally substituted aryl, and optionally substituted heteroaryl.

In a further embodiment, the alkylating step is performed by reaction with a base and an alkyl halide or alkyl pseudohalide. In a further embodiment, the base is sodium hydroxide.

In a further aspect, the alkyl moiety 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 heterocycloalkenyl Or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and-(CH2) m-aryl or-(CH2) m-heterocycle (m is 1, 2, 3, Also It includes an organic radical containing 1 to 12 carbon atoms selected from 4 a is). In a further embodiment, the alkylation step is performed before the coupling step.

In a further aspect, the method provides a disclosed compound, eg, a compound described in Table 3. The compounds in Table 3 were synthesized as shown in Reaction Schemes I and II, but substituted with appropriately substituted acetylenes and electrophiles as described in Schemes 1 and 2. Necessary starting materials were either commercially available, described in the literature, or readily synthesized by one skilled in the art of organic synthesis.

Thus, it should be understood that the disclosed methods can be used to provide the disclosed compounds.

F. Pharmaceutical Compositions In one aspect, the invention relates to pharmaceutical compositions comprising the disclosed compounds. For example, the composition comprises 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 N1-phenylterephthalamide derivatives may be included. In a further aspect, the composition comprises isoindoline-1-one derivatives, isoindoline-1,3-dione derivatives, 3,4-dihydroisoquinolin-1 (2H) -one derivatives, isoquinoline-1,3 (2H, 4H ) -Dione derivatives and / or one or more of bicyclic compounds.

In a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one disclosed compound and a pharmaceutically acceptable carrier. In a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one product of the disclosed method and a pharmaceutically acceptable carrier. In a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one phenylethynylbenzamide derivative and a pharmaceutically acceptable carrier. In a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one cycloalkylethynylbenzamide derivative and a pharmaceutically acceptable carrier. In a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one styrylbenzamide derivative and a pharmaceutically acceptable carrier. In a further embodiment, 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 a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one 4- (pyridinylethynyl) benzamide derivative and a pharmaceutically acceptable carrier. In a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one N ¹ -phenylterephthalamide derivative and a pharmaceutically acceptable carrier.

In a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one isoindoline-1-one derivative and a pharmaceutically acceptable carrier. In a further embodiment, the pharmaceutical composition comprises a therapeutically effective amount of at least one isoindoline-1,3-dione derivative and a pharmaceutically acceptable carrier. In a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one 3,4-dihydroisoquinolin-1 (2H) -one derivative and a pharmaceutically acceptable carrier. In a further embodiment, the pharmaceutical composition comprises a therapeutically effective amount of at least one isoquinoline-1,3 (2H, 4H) -dione derivative and a pharmaceutically acceptable carrier. In a further aspect, the pharmaceutical composition comprises a therapeutically effective amount of at least one bicyclic compound and a pharmaceutically acceptable carrier.

In certain embodiments, a disclosed pharmaceutical composition comprises a compound disclosed as an active ingredient (including pharmaceutically acceptable salts thereof), a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. Including. The compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, but the optimal route in any given case is It will depend on the particular host and the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical composition is appropriately shown in a unit dosage form, and can be prepared by any method known in the pharmaceutical field.

As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be suitably prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases or organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (cupric and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganese and manganous) , Salts of potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, as well as cyclic and substituted amines such as naturally occurring and synthetic substituted amines. It is done. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include, for example, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethyl. Aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, Examples thereof include ion exchange resins such as triethylamine, trimethylamine, tripropylamine, and tromethamine.

As used herein, the term “pharmaceutically acceptable non-toxic acid” refers to 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, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothene Examples include acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Preference is given to citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

Indeed, the compounds of the present invention, or pharmaceutically acceptable salts of the present invention, can be mixed with a pharmaceutical carrier as the active ingredient in an essential mixture according to conventional pharmaceutical conjugation techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral (including intravenous). Accordingly, the pharmaceutical compositions of the invention may be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the composition may be shown as a powder, granule, solution, suspension in aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition to the general dosage forms presented above, the compounds of the present invention, and / or pharmaceutically acceptable salts thereof, can also be administered by controlled release means and / or delivery devices. The composition may be prepared by any method of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be suitably finished to the desired form.

Accordingly, the pharmaceutical composition of the present invention can comprise a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt of the compound. The compounds of the invention or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically effective compounds.

The pharmaceutical carrier used can 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. Examples of gas carriers include carbon dioxide and nitrogen.

Any suitable pharmaceutical medium may be utilized in preparing the composition for oral dosage forms. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid formulations such as suspensions, elixirs, and solutions while starch Oral solid preparations such as powders, capsules, and tablets can be formed using sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Tablets and capsules are preferred oral dosage units because of their ease of administration, and solid pharmaceutical carriers are used for these. Optionally, tablets can be coated by standard aqueous or non-aqueous techniques.

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets optionally compress the active ingredient in a free-flowing form, such as a powder or granules, mixed with a binder, lubricant, inert diluent, surfactant, or dispersant with a suitable machine. Can be prepared. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the invention for suitable parenteral administration can be prepared as solutions or suspensions of the active compounds in water. Suitable surfactants can include, for example, hydroxypropylcellulose and the like. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures in oils thereof. In addition, preservatives can be included to prevent harmful growth of microorganisms.

Suitable pharmaceutical compositions of the invention for injection include sterile aqueous solutions or dispersions. Furthermore, the composition may be in the form of a sterile powder for the immediate preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid so that it can be injected easily. The pharmaceutical composition must be stable under the conditions of manufacture and storage and should therefore preferably be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical composition of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting agent and the like. Furthermore, the composition can be in a form suitable for use in a transdermal device. These formulations can be prepared using the compounds of the present invention or pharmaceutically acceptable salts thereof by conventional processing methods. As an example, a cream or ointment is prepared by mixing from about 5% to about 10% by weight of the compound with a hydrophilic material and water to produce a cream or ointment having the desired softness.

The pharmaceutical composition of the invention may also be in a form suitable for rectal administration wherein the carrier is a solid. The mixture preferably forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppository can be appropriately formed by first mixing the softened or melted carrier and the present composition, then cooling in a mold and molding.

In addition to the carrier materials described above, the pharmaceutical formulations described above may contain diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (antioxidants) as necessary. One or more additional carrier components such as an agent). In addition, other adjuvants can be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing the compounds of the invention and / or pharmaceutically acceptable salts thereof can also be prepared in the form of a powder or liquid concentrate.

The enhancing amount of mGluR agonist to be administered in combination with an effective amount of a compound of formula I varies from about 0.1 milligrams per kg body weight per day (mg / kg / day) to about 100 mg / kg / day. Is expected to be less than that required to achieve the same effect when administered without an effective amount of the disclosed compound. The preferred amount of mGluR agonist administered in combination can be determined by one skilled in the art.

The present invention further provides a method for producing a medicament for enhancing glutamate receptor activity (eg, treatment of one or more neurological and / or psychiatric disorders associated with glutamate dysfunction) in a mammal (eg, human). The subject method includes mixing a compound of the present invention with a pharmaceutically acceptable carrier or diluent.

Accordingly, in one aspect, the invention relates to pharmaceutical compositions comprising the disclosed compounds. That is, a pharmaceutical composition is provided and can comprise a therapeutically effective amount of at least one disclosed compound or at least one product comprising a disclosed method and a pharmaceutically acceptable carrier.

The disclosed pharmaceutical composition can further comprise other therapeutically effective compounds, which are usually applied in the treatment of the above mentioned pathological conditions. For example, the disclosed compounds and compositions can be used in combination with one or more antipsychotic agents. In one aspect, the antipsychotic agent can be any compound that has been shown or thought to be useful in treating at least one positive symptom of schizophrenia.

Antipsychotics useful for treating at least one positive symptom of schizophrenia may or may not be classified as typical antipsychotics, atypical antipsychotics, and typical or atypical antipsychotics Other antipsychotic agents are mentioned. In certain embodiments, the antipsychotic agent is a typical antipsychotic agent. In certain embodiments, the antipsychotic agent is a dopamine D2 receptor antagonist, which can be a selective dopamine D2 receptor antagonist or a partial dopamine D2 receptor antagonist. Typical antipsychotics are generally recognized as selective dopamine D2 receptor antagonists.

Antipsychotics useful for treating positive symptoms of schizophrenia include acetophenazine, arteroxylone, amitriptyline, aripiprazole, astemizole, benzquinamide, calphenazine, chlormezanone, chlorpromazine, chlorprothixene, clozapine, desipramine , Droperidol, haloperidol, fluphenazine, flupentixol, glycine, oxapine, mesoridazine, morindon, olanzapine, ondansetron, perphenazine, pimozide, prochlorperazine, procyclidine, promazine, propiomazine, quetiapine, remoxiprid, reserpine, risperidone , Sertindole, sulpiride, terfenadine, thiethylperazine, thioridazine, thiothixene, trifloperazine, Furupuromajin, trimeprazine, and ziprasidone include, but are not limited to. Examples of typical antipsychotics useful for treating positive symptoms of schizophrenia include acetophenazine, chlorpromazine, chlorprothixene, droperidol, fluphenazine, haloperidol, loxapine, mesoridazine, methotrimeprazine, molindone, Perphenazine, pimozide, lacloprid, remoxiprid, thioridazine, thiothixene, and trifloperazine. Examples of atypical antipsychotics useful for treating positive symptoms of schizophrenia include aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone.

Other antipsychotic agents useful for treating the positive symptoms of schizophrenia include amisulpride, valeraperdone, blonanserin, butaperazine, carfenadine, epravanserin, iloperidone, ramictal, onsanetant , Paliperidone, perospirone, piperacetazine, lacloprid, remoxiprid, sarizotan, sonepiperazole, sulpiride, ziprasidone, and zotepine; serotonin and dopamine (5HT / D2) agonists such as asenapine and bifeprunox; Kinin 3 antagonist; CX-516, galantamine, memantine, modafi Le, ocaperidone, and Anne Parkin as tolcapone; and D- serine, D- alanine, D- cycloserine, and N- alpha such as methyl glycine - amino acids. Thus, antipsychotics include typical antipsychotics, atypical antipsychotics, and other useful for treating schizophrenia in patients, especially useful for treating positive symptoms of schizophrenia. Compounds.

Accordingly, in one aspect, the invention also relates to a method of co-administering to a mammal at least one disclosed compound and one or more other therapeutically effective compounds, which are commonly used in the treatment of the above-mentioned pathological conditions. Applied. For example, the disclosed methods can relate to the co-administration of a therapeutically effective amount of one or more disclosed compounds with one or more antipsychotic agents.

In a further aspect, the present invention also relates to a kit comprising at least one disclosed compound and one or more other therapeutic compounds, which are usually applied to the treatment of the above mentioned pathological conditions. For example, the disclosed kit can include a therapeutically effective amount of one or more disclosed compounds and one or more antipsychotic agents. The kit can be packaged, formulated, and / or delivered with an antipsychotic agent. For example, a pharmacist, drug reseller, physician, or pharmacist can provide a disclosed kit for delivery to a patient.

In treatment conditions that require enhanced metabotropic glutamate receptor activity, suitable dosage levels are generally about 0.01-500 mg / kg patient body weight per day, administered in single or multiple doses can do. Preferably, the dose level may be about 0.1 to about 250 mg / kg per day, more preferably 0.5 to 100 mg / kg per day. A suitable dose level may 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 dose may be 0.05-0.5, 0.5-5.0, or 5.0-50 mg / kg per day. For oral administration, the composition comprises 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10, of active ingredient for symptomatic adaptation of the dose of the patient to be treated. It is preferably provided in the form of a tablet containing 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response.

However, it should be understood that the specific dosage level for any particular patient will depend on various factors. Such factors include the patient's age, weight, general health, sex, and eating habits. Other factors include the time and route of administration, excretion rates, drug combinations, and the type and severity of the particular disease being treated.

It should be understood that the disclosed compositions can be utilized in the disclosed methods of use.

G. Methods of Use of Compounds and Compositions The amino acid L-glutamic acid (simply referred to herein as glutamic acid) is a major excitatory neurotransmitter in the mammalian central nervous system (CNS). Within the CNS, glutamate plays an important role in synaptic plasticity (eg, long-term potentiation (learning and memory basis)), motor control, and perception. It is now well understood that a variety of neurological and psychiatric disorders, including but not limited to schizophrenia, generalized psychosis, and cognitive impairment, are associated with dysfunction of the glutamate system. Therefore, modulation of the glutamate system is an important therapeutic goal. Glutamate acts through two different receptors, the ion channel and metabotropic glutamate receptors. The first class, the ion channel glutamate receptor, is a multi-subunit ligand-gated ion channel that mediates excitatory postsynaptic currents. Three subtypes of ion channel glutamate receptors have been identified, and glutamate serves as an agonist for all three receptor subtypes, but is a selective ligand that activates each subtype Has been identified. The ion channel glutamate receptors are named after their selective ligands: kainite receptor, AMPA receptor, and NMDA receptor.

A second class of glutamate receptors, called metabotropic glutamate receptors (mGluR), regulates the strength of neurotransmitter release or synaptic transmission based on their location (pre-synaptic or post-synaptic). Protein coupled receptor (GPCR). mGluR is a C-family GPCR and is characterized by a large (about 560 amino acids) “flyus fly trap” agonist binding domain in the amino-terminal domain of the receptor. This unique agonist binding domain distinguishes C family GPCRs from A and B family GPCRs, which are in the 7-strand transmembrane (7TM) region or in the extracellular loop that connects the strand to this region. To position. To date, eight different mGluRs have been identified, cloned, and sequenced. Based on structural similarity, first coupling to intracellular signaling pathways, and pharmacology, mGluR is divided into three groups: group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), And Group III (mGluR4, mGluR6, mGluR7, and mGluR8). Group I mGluRs are bound through Gαq / 11 and increase inositol phosphate metabolism and consequently increase intracellular calcium. Group I mGluRs are first located post-synaptic and have regulatory effects on ion channel activity and neuronal excitability. Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7, and mGluR8) mGluRs are primarily located presynapically where they regulate the release of neurotransmitters such as glutamate. Group II and Group III mGluR are bound to G □ i and its related effectors such as adenylate cyclase.

Post-synaptic mGluR is known to functionally interact with post-synaptic ion channel glutamate receptors such as the NMDA receptor. For example, activation of mGluR5 by selective agonists has been shown to increase post-synaptic NMDA currents (Mannaioni et. Al. J. Neurosci. 21: 5925-5934 (2001)). Thus, modulation of mGluR is an approach for modulating glutamate permeability. Numerous reports have shown that mGluR5 is associated with anxiety (Spooren et.al.J.Pharmacol.Exp.Therapeut.295: 1267-1275 (2000), Tatarczynska et al.Br.J. Pharmaol. 132: 1423-1430 ( 2001)), schizophrenia (reviewed in Chavez-Noriga et al. Curr. Drug Targets: CNS & Neurological Disorders 1: 261-281 (2002), Kinney, G. G. et al. 313: 199-206 (2005)), cocaine poisoning (Chiamulera et al. Nature Neurosci). 4: 873-874 (2001), Parkinson's disease (Awad et al. J. Neurosci. 20: 7871-7879 (2000), Ososska et al. Neuropharmacol. 41: 413-420 (2001), and pain (Salt and Binns). Neurosci.100: 375-380 (2001) has been shown to be involved in several medical conditions.

The disclosed compounds can be used as a single agent or in combination with one or more other drugs in the treatment, prevention, control, amelioration, or risk reduction of the aforementioned diseases, disorders, and conditions. In contrast, compounds of formula I or other drugs are practical, and both drug combinations are safer and more effective than drugs alone. Other drugs may be administered with the disclosed compounds, commonly used and thus simultaneously or by sequential routes and amounts. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and the disclosed compounds is more effective than a single agent.

In one embodiment, the subject compound can be used in combination with an anti-Alzheimer agent, β-secretase inhibitor, γ-secretase inhibitor, muscarinic agonist, muscarinic enhancer HMG-CoA reductase inhibitor, NSAID, anti-amyloid antibody.

In another embodiment, the subject compound is sedative, hypnotic, anxiolytic, anti-anxiety, such as, but not limited to, risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbital, and salts thereof and combinations thereof. It can be administered in combination with psychotic agents, selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAOI), 5-HT2 antagonists, GlyT1 inhibitors and the like.

In another embodiment, the subject compound is levodopa (with or without a selective extracerebral decarboxylase inhibitor), an anticholinergic agent such as biperiden, a COMT inhibitor such as entacapone, an A2a adenosine antagonist, a cholinergic agonist, NMDA receptor Can be administered in combination with body antagonists and dopamine agonists.

The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically effective compounds as noted herein that are usually applied in the treatment of the above mentioned pathological conditions.

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

1. Methods of Treatment The compounds disclosed herein are useful for the treatment, prevention, amelioration, control or risk reduction of various neurological and psychiatric disorders associated with glutamate dysfunction. Accordingly, the subject is administered at least one disclosed compound, at least one disclosed pharmaceutical composition, and / or at least one disclosed product in a dosage effective to treat a disease in the subject and Provided is a method of treating or preventing a disease in a subject comprising administering at a dose.

The subject can also be administered at least one disclosed compound, at least one disclosed pharmaceutical composition, and / or at least one disclosed product in a dosage effective to treat a disease in the subject and Also provided is a method for the treatment of one or more neurological and / or psychiatric disorders associated with glutamate dysfunction in a subject comprising administering at a dose.

Examples of diseases associated with glutamate dysfunction include acute and chronic neurological and psychiatric disorders such as brain injury after cardiac bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia , Cardiac arrest, hypoglycemic nerve injury, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive disease, idiopathic and drug-induced Sexual Parkinson's disease, tremors, epilepsy, convulsions, muscle spasms and disorders associated with muscle cramps, including migraine (including migraine headaches), urinary incontinence, drug resistance, drug addiction (opiates, nicotine, tobacco products, alcohol Addiction, including benzodiazepines, cocaine, sedatives, hypnotics, such addictive drugs (opiates, nicotine, tobacco products) Withdrawal from alcohol, including benzodiazepines, cocaine, sedatives, hypnotics, obesity, psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder), mood disorders (Including depression, mania, bipolar emotional disorder), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eyes, vomiting, brain edema, pain (acute and chronic pain pathologies, severe pain, refractory pain, nerves Intrinsic pain and post-traumatic pain), late-onset dyskinesia, sleep disorders (including narcolepsy), attention deficit / hyperactivity disorder, and behavioral disorders.

Anxiety disorders that can be treated or prevented by the compositions disclosed herein include generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. Addictions include drug addiction (including opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics), and such addictive drugs (opiates, nicotine, tobacco Products, alcohol, benzodiazepines, drugs such as cocaine, sedatives, hypnotics) and drug resistance.

Thus, in some embodiments of the disclosed methods, the disease is dementia, frenzy, amnestic disorder, cognitive decline with age, schizophrenia, psychosis including schizophrenia, schizophrenia-like disorder, Schizophrenia emotional disorder, delusional disorder, short-term psychotic disorder, drug-related disorder, movement disorder, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorder, brain edema, sleep disorder, narcolepsy Anxiety, anxiety, emotional disorder, panic attack, unipolar depression, bipolar emotional disorder, psychotic depression.

Accordingly, the subject is administered at least one disclosed compound, at least one disclosed pharmaceutical composition, and / or at least one disclosed product in a dosage effective to treat a disease in the subject and A method is provided for treating or preventing schizophrenia comprising the step of administering at a dose. For now, the fourth edition of the Guide to Classification and Diagnosis of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, DC) provides diagnostic tools including schizophrenia and related disorders. .

The subject can also be administered at least one disclosed compound, at least one disclosed pharmaceutical composition, and / or at least one disclosed product in a dosage effective to treat a disease in the subject and Also provided is a method for treating or preventing anxiety, comprising administering at a dose. For now, the fourth edition of the Guide to Classification and Diagnosis of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, DC) provides diagnostic tools including anxiety and related disorders . These include panic disorder with or without agoraphobia, agoraphobia with no history of panic disorder, specific phobia, interpersonal phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety Includes disorders, anxiety disorders due to general medical conditions, drug-induced anxiety disorders, and other anxiety disorders.

a. Enhancement of metabotropic glutamate receptor activity In one aspect, the invention relates to a method of enhancing metabotropic glutamate receptor activity in a mammal, said method comprising:

により表される構造を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における代謝型グルタミン酸受容体活性を増強するのに有効な投与量および用量で、投与するステップを含む。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は、ＮおよびＣ−Ｒから独立して選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Administering at least one compound having a structure represented by the formula: Including the steps of:
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、および任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個炭素原子を含む有機ラジカルから独立して選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2-5 carbons, or 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 1 to 5 carbons selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl It is independently selected from organic radicals containing atoms.

Also provided is a method for enhancing metabotropic glutamate receptor activity in a mammal, the method comprising:

を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における代謝型グルタミン酸受容体活性を増強するのに有効な投与量および用量で、投与するステップを含む。
ここで式中、ｎは、０、１、２、３、または４であり、Ｙ^１およびＹ^２は、ＣおよびＮから独立して選択され、Ｒ^１は、水素、または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂが存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルとして独立して存在する１個、２個、または３個の置換基を含み、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

Administering at least one compound having the formula:
Where n is 0, 1, 2, 3, or 4, Y ¹ and Y ² are independently selected from C and N, and R ¹ is hydrogen or 1-12 An organic radical containing carbon atoms and when R ^2a and R ^2b are present, both form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, Nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b independently hydrogen, halogen, hydroxyl, cyano, an organic radical comprising a nitro, thiol, amino, or 1 to 6 carbon atoms, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or, Including one, two, or three substituents present independently as an organic radical containing ˜12 carbon atoms, L is an organic divalent radical containing 1-7 carbon atoms, R ⁵ is an organic radical containing 4 to 14 carbon atoms.

In one embodiment, the mammal is a human. In a further aspect, the mammal has been diagnosed with a need for enhanced metabotropic glutamate receptor activity prior to the administering step.

b. Receptor partial activation action of metabotropic glutamate receptor activity In one aspect, the present invention relates to a method of receptor partial activation action of metabotropic glutamate receptor activity in a mammal, the method comprising: formula

により表される構造を有する少なくとも１つの化合物であっておよび またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における代謝型グルタミン酸受容体活性の受容体部分活性化作用を示すのに有効な投与量および用量で、投与するステップを含む。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は独立して、ＮおよびＣ−Ｒから選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

At least one compound having the structure represented by: and / or a pharmaceutically acceptable salt or N-oxide thereof for demonstrating a receptor partial activation effect of metabotropic glutamate receptor activity in a mammal Administering at an effective dosage and dose.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、および任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個の炭素原子を含む有機ラジカルから独立して選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2-5 carbons, or 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 1 to 5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms.

Also provided is a method for a receptor partial activation action of metabotropic glutamate receptor activity in a mammal, the method comprising:

を有する少なくとも１つの化合物であって、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における代謝型グルタミン酸受容体活性の受容体部分活性化作用を示すのに有効な投与量および用量で、投与するステップを含む。
式中、ｎは、０、１、２、３、または４であり、Ｙ^１およびＹ^２は、ＣおよびＮから独立して選択され、Ｒ^１は、水素、または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは、存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルとして独立して存在する１個、２個、または３個の置換基を含み、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

Or a pharmaceutically acceptable salt or N-oxide thereof having a dosage effective to exhibit a receptor partial activating action of metabotropic glutamate receptor activity in a mammal, and Administering at a dose.
Where n is 0, 1, 2, 3, or 4, Y ¹ and Y ² are independently selected from C and N, and R ¹ is hydrogen or 1 to 12 carbon atoms R ^2a and R ^2b , if present, together form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro , Thiol, amino, or an organic radical containing 1 to 6 carbon atoms, R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b is independently hydrogen halogen, hydroxyl, cyano, a nitro, an organic radical containing thiol, amino, or 1-6 carbon atoms, ^{R 4} represents hydrogen, halogen, hydroxy, cyano, nitro, thiol or 1, 1 exist independently as an organic radical containing 2 carbon atoms, including two or three substituents, L is an organic divalent radical containing from 1 to 7 carbon atoms, R ⁵ is an organic radical containing 4 to 14 carbon atoms.

In one embodiment, Y ¹ is selected from N and C—R ⁴ . In a further aspect, Y ² is selected from N and C—H.

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

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

In a further aspect, L is an organic divalent radical containing 1 to 7 carbon atoms,

から選択され、
式中、Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択された１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
In which R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1-5 selected from optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing one carbon atom, 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 heterocyclo Alkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, are selected from organic radicals containing from 1 to 6 carbon atoms selected optionally substituted aryl, and optionally substituted heteroaryl.

In a further embodiment, the compound has the structure

を有するイソインドリン−１−オン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルである。

An isoindoline-1-one derivative having the pharmaceutically acceptable salt or N-oxide thereof,
In the formula, 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, provided that R ¹ is hydrogen. , R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

In a further embodiment, the compound has the structure

を有するイソインドリン−１，３−ジオン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素であるか、または任意に置換されたＣ１−Ｃ１２アルキル、任意に置換されたＣ１−Ｃ１２ヘテロアルキル、任意に置換されたＣ３−Ｃ１２シクロアルキル、または任意に置換されたＣ３−Ｃ１２ヘテロシクロアルキルから選択され、但し、Ｒ^１は、シリコンを含まず、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルであり、但し、Ｒ^１がメチルである場合、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

An isoindoline-1,3-dione derivative having the pharmaceutically acceptable salt or N oxide thereof,
Wherein R ¹ is hydrogen or an optionally substituted C1-C12 alkyl, an optionally substituted C1-C12 heteroalkyl, an optionally substituted C3-C12 cycloalkyl, or an optionally substituted Selected from C3-C12 heterocycloalkyl, wherein R ¹ is silicon free and R ⁵ is an organic radical containing 4-14 carbon atoms, provided that R ¹ is hydrogen; R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that when R ¹ is methyl, R ⁵ is an organic radical containing 4 to 14 carbon atoms.

In a further embodiment, the compound has the structure

を有する３，４−ジヒドロイソキノリン−１（２Ｈ）−オン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

A 3,4-dihydroisoquinolin-1 (2H) -one derivative having the pharmaceutically acceptable salt or N-oxide thereof,
Where R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 It is an organic radical containing ˜6 carbon atoms and R ⁵ is an organic radical containing 4-14 carbon atoms.

In a further embodiment, the compound has the structure

を有するイソキノリン−１，３（２Ｈ，４Ｈ）−ジオン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^５は、トリフェニルアミン残基またはベンズイミダアミド残基を含まない。

An isoquinoline-1,3 (2H, 4H) -dione derivative having the pharmaceutically acceptable salt or N oxide thereof,
In which 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, provided that R ⁵ is triphenylamine Does not contain residues or benzimidamide residues.

In a further embodiment, the compound has the structure

を有する二環式化合物またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、ｎは、２、３、または４であり、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、もしくは１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

Or a pharmaceutically acceptable salt or N-oxide thereof,
Where n is 2, 3, or 4, R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and R ^2a and R ^2b together form ═O or ═S. Or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, and R ⁵ is 4 to 14 An organic radical containing carbon atoms.

In one embodiment, the mammal is a human. In a further embodiment, the mammal has been diagnosed with a receptor partial activation effect of metabotropic glutamate receptor activity prior to the administering step.

c. Treatment of Diseases in Mammals In one aspect, the invention relates to a method of treating a disease in a mammal, said method comprising the steps of:

により表される構造を有する少なくとも１つの化合物、化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における疾患を治療するのに有効な投与量および用量で、投与するステップを含む。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は独立して、ＮおよびＣ−Ｒから選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Administering at least one compound having the structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof in a dosage and dose effective to treat a disease in a mammal. Including.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択された１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2-5 carbons, or 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 with thioalkyl, optional 1-5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms, 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, are selected from organic radicals containing from 1 to 6 carbon atoms selected optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, the method includes identifying a mammal in need of treatment for the disease. In a further embodiment, the mammal is in need of treatment for the disease prior to administration. In a further embodiment, the mammal has been diagnosed with a need for treatment of the disease prior to administration.

In one aspect, the disease is one or more neurological and / or psychiatric disorders associated with glutamate dysfunction in a mammal. For example, the disease can be dementia, frenzy, amnestic disorder, cognitive decline due to aging, schizophrenia, psychosis including schizophrenia, schizophrenia-like disorder, schizophrenic emotional disorder, paranoid disorder, Psychotic disorder, substance-related disorder, movement disorder, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorder, brain edema, sleep disorder, narcolepsy, anxiety, emotional disorder, panic attack, There may be one or more of unipolar depression, bipolar affective disorder, and psychotic depression.

Also provided is a method of treating a disease in a mammal, the method comprising:

を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における疾患を治療するのに有効な投与量および用量で、投与するステップを含む。
ここで式中、ｎは、０、１、２、３、または４であり、Ｙ^１およびＹ^２は、ＣおよびＮから独立して選択され、Ｒ^１は、水素、または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは、存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルとして独立して存在する１個、２個、または３個の置換基を含み、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

Administering at least one compound having the formula: or a pharmaceutically acceptable salt or N-oxide thereof in a dosage and dose effective to treat a disease in a mammal.
Where n is 0, 1, 2, 3, or 4, Y ¹ and Y ² are independently selected from C and N, and R ¹ is hydrogen or 1-12 An organic radical containing a carbon atom, R ^2a and R ^2b , if present, together form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b independently , hydrogen, halogen, hydroxyl, cyano, an organic radical comprising a nitro, thiol, amino, or 1 to 6 carbon atoms, ^{R 4} is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, also 1, 2 or 3 substituents present independently as an organic radical 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.

In a further aspect, Y ¹ is selected from N and C—R4.

In a further aspect, Y ² is selected from N and C—H.

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

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

In a further aspect, L is an organic divalent radical containing 1 to 7 carbon atoms,

から選択される。

Selected from.

In a further embodiment, R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, As well as 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 1 selected from thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing ˜5 carbon atoms.

In a further embodiment, 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, optional Selected from organic radicals containing 1 to 6 carbon atoms selected from aryl substituted on and optionally substituted heteroaryl.

In a further embodiment, the compound has the structure

を有するイソインドリン−１−オン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルである。

An isoindoline-1-one derivative having the pharmaceutically acceptable salt or N-oxide thereof,
In the formula, 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, provided that R ¹ is hydrogen. , R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

In a further embodiment, the compound has the structure

を有するイソインドリン−１，３−ジオン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素であるか、または任意に置換されたＣ１−Ｃ１２アルキル、任意に置換されたＣ１−Ｃ１２ヘテロアルキル、任意に置換されたＣ３−Ｃ１２シクロアルキル、または任意に置換されたＣ３−Ｃ１２ヘテロシクロアルキルから選択され、但し、Ｒ^１は、シリコンを含まず、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルであり、但し、Ｒ^１がメチルである場合、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

An isoindoline-1,3-dione derivative having the pharmaceutically acceptable salt or N oxide thereof,
Wherein R ¹ is hydrogen or an optionally substituted C1-C12 alkyl, an optionally substituted C1-C12 heteroalkyl, an optionally substituted C3-C12 cycloalkyl, or an optionally substituted Selected from C3-C12 heterocycloalkyl, wherein R ¹ is silicon free and R ⁵ is an organic radical containing 4-14 carbon atoms, provided that R ¹ is hydrogen; R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that when R ¹ is methyl, R ⁵ is an organic radical containing 4 to 14 carbon atoms.

In a further embodiment, the compound has the structure

を有する３，４−ジヒドロイソキノリン−１（２Ｈ）−オン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

A 3,4-dihydroisoquinolin-1 (2H) -one derivative having the pharmaceutically acceptable salt or N-oxide thereof,
Where R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 It is an organic radical containing ˜6 carbon atoms and R ⁵ is an organic radical containing 4-14 carbon atoms.

In a further embodiment, the compound has the structure

を有するイソキノリン−１，３（２Ｈ，４Ｈ）−ジオン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^５は、トリフェニルアミン残基またはベンズイミダアミド残基を含まない。

An isoquinoline-1,3 (2H, 4H) -dione derivative having the pharmaceutically acceptable salt or N oxide thereof,
In which 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, provided that R ⁵ is triphenylamine Does not contain residues or benzimidamide residues.

In a further embodiment, the compound has the structure

を有する二環式化合物またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、ｎは、２、３、または４であり、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、もしくは１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

Or a pharmaceutically acceptable salt or N-oxide thereof,
Where n is 2, 3, or 4, R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and R ^2a and R ^2b together form ═O or ═S. Or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, and R ⁵ is 4 to 14 An organic radical containing carbon atoms.

In a further embodiment, the disease is a neurological and / or psychiatric disorder associated with glutamate dysfunction. In a further embodiment, the disease is dementia, frenzy, amnestic disorder, cognitive decline due to aging, schizophrenia, psychosis including schizophrenia, schizophrenia-like disorder, schizophrenic emotional disorder, paranoid disorder , Short-term psychotic disorder, substance-related disorder, movement disorder, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorder, brain edema, sleep disorder, narcolepsy, anxiety, emotional disorder, panic Selected from seizures, unipolar depression, bipolar affective disorder, and psychotic depression.

In one embodiment, the mammal is a human. In a further embodiment, the mammal has been diagnosed with a need for treatment of the disease prior to the administering step.

d. Cognitive enhancement Symptoms of schizophrenia can be classified as positive, negative, or cognitive. Positive symptoms of schizophrenia include delusions and hallucinations, which can be measured using, for example, the positive and negative symptom rating scale (PANSS) (Kay et al., 1987, Schizophrenia Bulletin 13,261). -276). Negative symptoms of schizophrenia include emotional dullness, anergy, aphasia, and withdrawal, which can be measured using, for example, the Negative Symptom Rating Scale (SANS) (Andreasen, 1983, Scales for the Assessment). of Negative Symptoms, Iowa City, Iowa). Cognitive symptoms of schizophrenia include impairments in acquiring, organizing, and using intellectual knowledge, which is the cognitive function subscale (PANSS cognitive function subscale) in the positive and negative symptom rating scale (Lindenmayer et al. al., J Nerv Ment Dis 1994, 182, 631-638) or, for example, Wisconsin Card Sorting test (eg, Green et al., Am J Psychiatry 1992, 149, 162-67, And Koren et al., Schizophr Bull 2006, 32 (2), 310-26).

In one aspect, the present invention relates to a method for enhancing cognition in a mammal, comprising:

により表される構造を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、哺乳動物における認知を増進するのに有効な投与量および用量で、投与するステップを含む。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は独立して、ＮおよびＣ−Ｒから選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Administering at least one compound having the structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof in a dosage and dose effective to enhance cognition in a mammal.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、および任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、ならびに任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択される１〜５個炭素原子を含む有機ラジカルから独立して選択される。さらなる態様において、該認知増進は、新規物体認識（Ｎｏｖｅｌ Ｏｂｊｅｃｔ Ｒｅｃｏｇｎｉｔｉｏｎ）における、統計的に有意な増加である。さらなる態様において、該認知増進は、シナプス可塑性における、統計的に有意な増加である。さらなる態様において、該認知増進は、ウィスコンシンカード分類（Ｗｉｓｃｏｎｓｉｎ Ｃａｒｄ Ｓｏｒｔｉｎｇ）テストの実施における、統計的に有意な増加である。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2-5 carbons, or 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 1 to 5 carbons selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl It is independently selected from organic radicals containing atoms. In a further aspect, the cognitive enhancement is a statistically significant increase in novel object recognition. In a further embodiment, the cognitive enhancement is a statistically significant increase in synaptic plasticity. In a further aspect, the cognitive enhancement is a statistically significant increase in the performance of a Wisconsin Card Sorting test.

mGluR5 enhancement has also been implicated in cognitive improvement (Kinney, GG; O'Brien, Lemayre, W .; Burno, M. 'Bickel, DJ; Clements, M.K. Lindsley, C .; Tiller, PR; Smith, S .; Jacobson, MA; Surgan, C .; Duggan, M .; Pettibone, D .; Williams, Jr., D.W.'A novel selective allotropic modulator of metabotropic glutamate receptor type 5 (mGluR5) has an antitip. Evidential models' J. Pharmacol. Exp. Therapeut. 2005, 313 (1), 199, Lindsley, C.W .; Wisnoski, DD; Leister, WH ;; O'Brien, JA. Williams, Jr., DL; Burno, M .; Sur, C.; Kinney, GG; Petibone, D.J.; ller, PR; Smith, S. Duggan, M.E .; Hartman, G.D.; Conn, PJ; Huff, JR 'Discovery of positive allomodulators for the metamorphic glutamate subtype 5 from a series of N- (1,3-Diphenyl-1H-pyrazol-5-yl) benzamides that potentiate receptor in vivo ', J. Med. , Nayak, S., Derouet, F., Dominguez, H., Besissis AS, Le Poul E., Ludwig BL Mutel V., Poli SM and Rocher J. P. See In Vivo Charactorization of mGluR5 Positive Allosteric Modulators as Novel Treatments for Schizophrenia and Cognitive Dysfunction3, 49. This theory has been demonstrated in a cellular model of long-term changes in synaptic transmission that may be the basis for many forms of learning and memory. This model, referred to as hippocampal long-term potentiation (LTP), involves the measurement of the strength of synaptic connections between neurons in the brain that are important for generating learning. FIG. 20 shows the strength of synaptic binding after stimulation of synapses in the presence and absence of two structurally different mGluR5 PAMs, VU29 (upper panel) and ADX47273 (lower panel). Increase. Both PAMs elicited a robust increase in synaptic connections in a manner expected to enhance learning and memory. This may provide an approach to improving cognition in diseases involving cognitive dysfunction, including schizophrenia, Alzheimer's disease, Parkinson's disease, and many other human brain diseases. A representative mGluR5 PAM that enhances hippocampal LTP is also active in the preclinical cognitive model of Novel Object Recognition (NOR), and the mGluR5 PAM, ADX47273, has a robust and significant improvement in NOR. And was comparable to the known thioperamide, an H3 antagonist that enhances cognition (FIG. 11).

2. Manufacturing of a medicament Also a method of manufacturing a medicament for the treatment of a disease in a mammal, a method for the partial activation of metabotropic glutamate receptor activity in a mammal, a method for enhancing cognition in a mammal, and A method for enhancing metabotropic glutamate receptor activity in a mammal, comprising:

を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、医薬的に許容される担体と混合するステップを含む。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は独立して、ＮおよびＣ−Ｒから選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Mixing at least one compound having the formula: or a pharmaceutically acceptable salt or N-oxide thereof with a pharmaceutically acceptable carrier.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成する、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択された１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1-5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms, 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 Properly it is chosen from organic radicals containing C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, 1-6 carbon atoms selected optionally substituted aryl, and optionally substituted heteroaryl.

Also provided is a method for producing a drug for enhancing metabotropic glutamate receptor activity in a mammal, the method comprising a structure

を有する少なくとも１つの化合物、またはその医薬的に許容される塩もしくはＮ酸化物を、医薬的に許容される担体と混合するステップを含む。
ここで式中、ｎは、０、１、２、３、または４であり、Ｙ^１およびＹ^２は、ＣおよびＮから独立して選択され、Ｒ^１は、水素、または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは、存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルとして独立して存在する１個、２個、または３個の置換基を含み、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。さらなる態様において、Ｙ^１は、ＮおよびＣ−Ｒ^４から選択される。さらなる態様において、Ｙ^２は、ＮおよびＣ−Ｈから選択される。さらなる態様において、各Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルである。一態様において、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルである。

Mixing at least one compound having the formula: or a pharmaceutically acceptable salt or N-oxide thereof with a pharmaceutically acceptable carrier.
Where n is 0, 1, 2, 3, or 4, Y ¹ and Y ² are independently selected from C and N, and R ¹ is hydrogen or 1-12 An organic radical containing a carbon atom, R ^2a and R ^2b , if present, together form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b independently , hydrogen, halogen, hydroxyl, cyano, an organic radical comprising a nitro, thiol, amino, or 1 to 6 carbon atoms, ^{R 4} is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, also 1, 2 or 3 substituents present independently as an organic radical 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. In a further aspect, Y ¹ is selected from N and C—R ⁴ . In a further aspect, Y ² is selected from N and C—H. In further embodiments, each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms. In one aspect, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms.

In a further aspect, L is an organic divalent radical containing 1 to 7 carbon atoms,

から選択される。

Selected from.

In a further embodiment, R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, As well as 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 1 selected from thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing ˜5 carbon atoms.

In a further embodiment, 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, optional Selected from organic radicals containing 1 to 6 carbon atoms selected from aryl substituted on and optionally substituted heteroaryl.

In a further embodiment, the compound has the structure

を有するイソインドリン−１−オン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルである。

An isoindoline-1-one derivative having the pharmaceutically acceptable salt or N-oxide thereof,
In the formula, 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, provided that R ¹ is hydrogen. , R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

In a further embodiment, the compound has the structure

を有するイソインドリン−１，３−ジオン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素であるか、または任意に置換されたＣ１−Ｃ１２アルキル、任意に置換されたＣ１−Ｃ１２ヘテロアルキル、任意に置換されたＣ３−Ｃ１２シクロアルキル、または任意に置換されたＣ３−Ｃ１２ヘテロシクロアルキルから選択され、但し、Ｒ^１は、シリコンを含まず、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルであり、但し、Ｒ^１がメチルである場合Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

An isoindoline-1,3-dione derivative having the pharmaceutically acceptable salt or N oxide thereof,
Wherein R ¹ is hydrogen or an optionally substituted C1-C12 alkyl, an optionally substituted C1-C12 heteroalkyl, an optionally substituted C3-C12 cycloalkyl, or an optionally substituted Selected from C3-C12 heterocycloalkyl, wherein R ¹ is silicon free and R ⁵ is an organic radical containing 4-14 carbon atoms, provided that R ¹ is hydrogen; R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that when R ¹ is methyl, R ⁵ is an organic radical containing 4 to 14 carbon atoms.

In a further embodiment, the compound has the structure

を有する３，４−ジヒドロイソキノリン−１（２Ｈ）−オン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

A 3,4-dihydroisoquinolin-1 (2H) -one derivative having the pharmaceutically acceptable salt or N-oxide thereof,
Where R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 It is an organic radical containing ˜6 carbon atoms and R ⁵ is an organic radical containing 4-14 carbon atoms.

In a further embodiment, the compound has the structure

を有するイソキノリン−１，３（２Ｈ，４Ｈ）−ジオン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^５は、トリフェニルアミン残基またはベンズイミダアミド残基を含まない。

An isoquinoline-1,3 (2H, 4H) -dione derivative having the pharmaceutically acceptable salt or N oxide thereof,
In which 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, provided that R ⁵ is triphenylamine Does not contain residues or benzimidamide residues.

In a further embodiment, the compound has the structure

を有する二環式化合物またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、ｎは、２、３、または４であり、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、もしくは１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

Or a pharmaceutically acceptable salt or N-oxide thereof,
Where n is 2, 3, or 4, R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and R ^2a and R ^2b together form ═O or ═S. Or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, and R ⁵ is 4 to 14 An organic radical containing carbon atoms.

3. Use of Compounds Also provided is the use of disclosed compounds. For example, the structure

を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物の使用を提供する。
ここで式中、各−−−−−は、任意の共有結合であり、Ｙ^１およびＹ^２は独立して、ＮおよびＣ−Ｒから選択され、各Ｒは、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^１およびＲ^２は独立して、水素または１〜１２個の炭素原子を含む任意に置換された有機ラジカルであり、Ｒ^０は、４〜１４個の炭素原子を含む任意に置換された有機ラジカルであり、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、

Or a pharmaceutically acceptable salt or N-oxide thereof.
Where each ----- is any covalent bond, Y ¹ and Y ² are independently selected from N and C—R, each R is hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, or an organic radical containing 1-12 carbon atoms, R ¹ and R ² are independently hydrogen or optionally substituted containing 1-12 carbon atoms An organic radical, 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,

から選択され、
式中、Ｒ^７ａおよびＲ^７ｂは共に、２〜５個の炭素を有する任意に置換された炭素環または複素環を形成するか、または、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、ならびに任意に置換されたＣ１−Ｃ５アルキルもしくはＣ２−Ｃ５アルケニルもしくはＣ２−Ｃ５アルキニル、任意に置換されたＣ１−Ｃ５ヘテロアルキルもしくはＣ２−Ｃ５ヘテロアルケニルもしくはＣ２−Ｃ５ヘテロアルキニル、任意に置換されたＣ３−Ｃ５シクロアルキルもしくはＣ３−Ｃ５シクロアルケニル、任意に置換されたＣ３−Ｃ５ヘテロシクロアルキルもしくはＣ３−Ｃ５ヘテロシクロアルケニル、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたアルコキシル、任意に置換されたチオアルキル、任意に置換されたアルキルスルフィニル、任意に置換されたアルキルスルホニル、および任意に置換されたアミノ、チオアミド、アミドスルフォニル、アルコキシカルボニル、カルボキサミド、アミノ−カルボニル、およびアルキルアミン−カルボニルから選択された１〜５個の炭素原子を含む有機ラジカルから独立して選択され、Ｒ^８は、水素、ならびに任意に置換されたＣ１−Ｃ６アルキルもしくはＣ２−Ｃ６アルケニルもしくはＣ２−Ｃ６アルキニル、任意に置換されたＣ１−Ｃ６ヘテロアルキルもしくはＣ２−Ｃ６ヘテロアルケニルもしくはＣ２−Ｃ６ヘテロアルキニル、任意に置換されたＣ３−Ｃ６シクロアルキルもしくはＣ３−Ｃ６シクロアルケニルもしくはＣ６シクロアルキニル、任意に置換されたＣ３−Ｃ６ヘテロシクロアルキルもしくはＣ３−Ｃ６ヘテロシクロアルケニルもしくはＣ６ヘテロシクロアルキニル、任意に置換されたアリール、および任意に置換されたヘテロアリールから選択される１〜６個の炭素原子を含む有機ラジカルから選択される。

Selected from
In which R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 1-5 selected from optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing one carbon atom, 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 heterocyclo Alkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, are selected from organic radicals containing from 1 to 6 carbon atoms selected optionally substituted aryl, and optionally substituted heteroaryl.

As a further example, structure

を有する化合物、またはその医薬的に許容される塩もしくはＮ酸化物の使用を提供し、哺乳動物におけるｍＧｌｕＲ５反応を増強する。
ここで式中、ｎは、０、１、２、３、または４であり、Ｙ^１およびＹ^２は、ＣおよびＮから独立して選択され、Ｒ^１は、水素、または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは、存在する場合、共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^３ａおよびＲ^３ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルとして独立して存在する１個、２個、または３個の置換基を含み、Ｌは、１〜７個の炭素原子を含む有機２価ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。さらなる態様において、Ｙ^１は、ＮおよびＣ−Ｒ^４から選択される。さらなる態様において、Ｙ^２は、ＮおよびＣ−Ｈから選択される。さらなる態様において、各Ｒ^３ａおよびＲ^３ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルである。さらなる態様において、Ｒ^４は、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、または１〜１２個の炭素原子を含む有機ラジカルである。

Or a pharmaceutically acceptable salt or N-oxide thereof, and enhances the mGluR5 response in mammals.
Where n is 0, 1, 2, 3, or 4, Y ¹ and Y ² are independently selected from C and N, and R ¹ is hydrogen or 1-12 An organic radical containing a carbon atom, R ^2a and R ^2b , if present, together form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano , Nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b independently , hydrogen, halogen, hydroxyl, cyano, an organic radical comprising a nitro, thiol, amino, or 1 to 6 carbon atoms, ^{R 4} is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, also 1, 2 or 3 substituents present independently as an organic radical 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. In a further aspect, Y ¹ is selected from N and C—R ⁴ . In a further aspect, Y ² is selected from N and C—H. In further embodiments, each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms. In a further aspect, R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms.

In a further aspect, L is an organic divalent radical containing 1 to 7 carbon atoms,

から選択される。

Selected from.

In a further embodiment, R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, As well as 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 1 selected from thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing ˜5 carbon atoms.

In a further embodiment, 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, optional Selected from organic radicals containing 1 to 6 carbon atoms selected from aryl substituted on and optionally substituted heteroaryl.

In a further embodiment, the compound has the structure

を有するイソインドリン−１−オン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルである。

An isoindoline-1-one derivative having the pharmaceutically acceptable salt or N-oxide thereof,
In the formula, 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, provided that R ¹ is hydrogen. , R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.

In a further embodiment, the compound has the structure

を有するイソインドリン−１，３−ジオン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素であるか、または任意に置換されたＣ１−Ｃ１２アルキル、任意に置換されたＣ１−Ｃ１２ヘテロアルキル、任意に置換されたＣ３−Ｃ１２シクロアルキル、または任意に置換されたＣ３−Ｃ１２ヘテロシクロアルキルから選択され、但し、Ｒ^１は、シリコンを含まず、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^１が水素である場合、Ｒ^５は、任意に置換されたフェニルまたは任意に置換されたピリジニルであり、但し、Ｒ^１がメチルである場合、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

An isoindoline-1,3-dione derivative having the pharmaceutically acceptable salt or N oxide thereof,
Wherein R ¹ is hydrogen or an optionally substituted C1-C12 alkyl, an optionally substituted C1-C12 heteroalkyl, an optionally substituted C3-C12 cycloalkyl, or an optionally substituted Selected from C3-C12 heterocycloalkyl, wherein R ¹ is silicon free and R ⁵ is an organic radical containing 4-14 carbon atoms, provided that R ¹ is hydrogen; R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that when R ¹ is methyl, R ⁵ is an organic radical containing 4 to 14 carbon atoms.

In a further embodiment, the compound has the structure

を有する３，４−ジヒドロイソキノリン−１（２Ｈ）−オン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、または１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

A 3,4-dihydroisoquinolin-1 (2H) -one derivative having the pharmaceutically acceptable salt or N-oxide thereof,
Where R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 It is an organic radical containing ˜6 carbon atoms and R ⁵ is an organic radical containing 4-14 carbon atoms.

In a further embodiment, the compound has the structure

を有するイソキノリン−１，３（２Ｈ，４Ｈ）−ジオン誘導体またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルであり、但し、Ｒ^５は、トリフェニルアミン残基またはベンズイミダアミド残基を含まない。

An isoquinoline-1,3 (2H, 4H) -dione derivative having the pharmaceutically acceptable salt or N oxide thereof,
In which 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, provided that R ⁵ is triphenylamine Does not contain residues or benzimidamide residues.

In a further embodiment, the compound has the structure

を有する二環式化合物またはその医薬的に許容される塩もしくはＮ酸化物を含み、
式中、ｎは、２、３、または４であり、Ｒ^１は、水素または１〜１２個の炭素原子を含む有機ラジカルであり、Ｒ^２ａおよびＲ^２ｂは共に、＝Ｏもしくは＝Ｓを成すか、または各Ｒ^２ａおよびＲ^２ｂは独立して、水素、ハロゲン、ヒドロキシル、シアノ、ニトロ、チオール、アミノ、もしくは１〜６個の炭素原子を含む有機ラジカルであり、Ｒ^５は、４〜１４個の炭素原子を含む有機ラジカルである。

Or a pharmaceutically acceptable salt or N-oxide thereof,
Where n is 2, 3, or 4, R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms, and R ^2a and R ^2b together form ═O or ═S. Or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms, and R ⁵ is 4 to 14 An organic radical containing 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 disease in a mammal.

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

In one aspect, the use relates to enhancement of metabotropic glutamate receptor activity to a receptor partial activation effect in a mammal.

4). Subjects Subjects of the methods disclosed herein can be vertebrates such as mammals, fish, birds, reptiles, or amphibians. Thus, the subject of the methods disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, it is intended to cover mature and neonatal subjects, as well as fetal subjects, whether male or female. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more neurological and / or psychiatric disorders associated with glutamate dysfunction prior to the administering step. In some embodiments of the disclosed methods, the subject has been diagnosed with a need for enhanced metabotropic glutamate receptor activity prior to the administering step. In some embodiments of the disclosed methods, the subject has been diagnosed with a receptor partial activation effect of metabotropic glutamate receptor activity prior to the administering step.

H. Experimental The following examples provide those skilled in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods claimed herein are made and evaluated. And are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (eg, amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, percentages are by weight, temperatures are in degrees Celsius, or are ambient temperatures, and pressure is at or near atmospheric pressure.

Several methods for preparing the compounds of this invention are illustrated in the following examples. Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared by literature procedures or as described herein. All ¹ H NMR spectra were obtained by instrument use with a field strength of 300-500 MHz.

1. Ethyl 4- (phenylethynyl) benzoate

To a solution of ethyl 4-iodobenzoate (5.0 g, 18.2 mmol) in DMF (8 mL) was added phenylacetylene (2.25 g, 22.1 mmol), Pd (Ph ₃ P) ₄ (502 mg, 0.45 mmol). , CuI (172 mg, 0.91 mmol), and diethylamine (2 mL) were added. The reaction vessel was sealed and heated in a microwave reactor at 60 ° C. for 1 hour. The reaction was cooled to room temperature, diluted with EtOAc: hexane (2: 1, 150 mL) and washed 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 give 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

To a solution of ethyl 4- (phenylethynyl) benzoate (7.81 g, 31.2 mmol) in THF (80 mL) was added a solution of LiOH (5.24 g, 124 mmol) in MeOH (15 mL) and water (15 mL). . The reaction was stirred at room temperature for 4 hours. The reaction was acidified with 1N HCl (50 mL) and 4- (phenylethynyl) benzoic acid (5.78 g, 83%) was isolated 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); LC (275 nM) 5.12 min (>98%); MS (ESI) m / z = 222.9.

3. (4-Hydroxypiperidin-1-yl) (4-phenylethynyl) phenyl) methanone

To a solution of 4- (phenylethynyl) benzoic acid (1.40 g, 6.30 mmol) and DIPEA (2.70 g, 20.8 mmol) in DMF (25 mL) was added EDC (1.41 g, 7.56 mmol), HOBt. (850 mg, 6.30 mmol), and 4-hydroxypiperidine hydrochloride (1.29 g, 9.46 mmol) were added. The reaction was stirred at room temperature for 18 hours. The reaction was diluted with water (100 mL) and (4-hydroxypiperidin-1-yl) (4-phenylethynyl) phenyl) methanone (1.84 g, 98%) was isolated as a white solid by vacuum filtration. . 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, 1H) 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) ethynyl) benzoic acid

To a solution of ethyl 4-iodobenzoate (10.0 g, 36.2 mmol) in DMF (30 mL) was added 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). The reaction vessel was sealed and heated at 60 ° C. for 1 hour in a microwave reactor. The reaction was cooled to room temperature, diluted with EtOAc: hexane (2: 1, 250 mL) and washed 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) and a solution of LiOH (3.04 g, 72.4 mmol) in MeOH (28 mL) and water (28 mL) was added. The reaction was stirred at room temperature for 4 hours. The reaction was acidified with 1N HCl (100 mL) and 4-((3-fluorophenyl) ethynyl) benzoic acid (6.89 g, 79%) was isolated as a light brown solid. ¹ H-nmr (400 MHz, d ₆ -DMSO) δ 7.97 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 8.5 Hz, 1 H), 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) ethynyl) phenyl) (morpholino) methanone

To a solution of 4-((3-fluorophenyl) ethynyl) benzoic acid (2.0 g, 8.33 mmol) and DIPEA (2.38 g, 18.3 mmol) in DMF (35 mL) was added EDC (1.86 g, 10 0.0 mmol), HOBt (1.35 g, 10.0 mmol), and morpholine (1.07 g, 12.5 mmol) were added. The reaction was stirred at room temperature for 18 hours. The reaction was diluted with water (200 mL) and extracted with EtOAc (2 × 150 mL). The combined organic extracts were washed 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 and (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone (2. 35 g, 89%). 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 (bds, 8H); LC (290 nM) 5.08 min (>98%); MS (ESI) m / z = 310.

6). (4 ((3-Fluorophenyl) ethynyl) phenyl) (4-hydroxylpiperidin-1-yl-methanone

In the same manner as (4 ((3-fluorophenyl) ethynyl) phenyl) (4-hydroxylpiperidin-1-yl-methanone, (4 ((3-fluorophenyl) ethynyl) phenyl) (4-hydroxylpiperidine-1 -Ile-methanone (2.61 g, 97%) was prepared as a light cream 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), 7.11-7.03 (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, 1H) 2H), 2.05-1.78 (m, 2H), 1.71-1. 2 (m, 2H); LC (290nM) 4.86 minutes (>98%); LC (290nM) 4.93 minutes (>98%); MS (ESI) m / z = 324.

7). (4-((3-Fluorophenyl) ethynyl) phenyl) (4-hydroxymethyl) piperidin-1-yl) methanone

In the same manner as (4-((3-fluorophenyl) ethynyl) phenyl) (morpholino) methanone, amide (4-((3-fluorophenyl) ethynyl) phenyl) (4-hydroxymethyl) piperidin-1-yl ) Methanone (2.32 g, 78%) was prepared as a light cream solid. 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, 3H); LC (290 nM). 98 min (>98%); MS (ESI) m / z = 338.

8.4-((3,4-Difluorophenyl) ethynyl) benzoic acid

To a solution of ethyl 4-iodobenzoate (5.0 g, 18.1 mmol) in DMF (15 mL) was added 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). The reaction vessel was sealed and heated at 60 ° C. for 1 hour in a microwave reactor. The reaction was cooled to room temperature, diluted with EtOAc: hexane (2: 1, 150 mL) and washed 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 a solution of LiOH (1.52 g, 36.2 mmol) in MeOH (14 mL) and water (14 mL) was added. The reaction was stirred at room temperature for 4 hours. The reaction was acidified with 1N HCl (60 mL) and 4-((3,4-difluorophenyl) ethynyl) benzoic acid (2.45 g, 57%) was isolated as a white solid. ¹ H-nmr (400 MHz, d ₆ -DMSO) δ 7.96 (d, J = 8.5 Hz, 2 H), 7.73 (td, J = 8.5, 2.0 Hz, 1 H), 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) ethynyl) phenyl) (morpholino) methanone

To a solution of acid 7 (2.40 g, 9.30 mmol) and DIPEA (3.34 g, 18.6 mmol) in DMF (35 mL) was added EDC (2.07 g, 11.2 mmol), HOBt (1.25 g, 9 .3 mmol), and morpholine (1.04 g, 12.1 mmol) were added. The reaction was stirred at room temperature for 18 hours. Dilute the reaction with water (100 mL) and isolate (4-((3,4-difluorophenyl) ethynyl) phenyl) (morpholino) methanone (2.91 g, 96%) as a white solid by vacuum filtration. did. ^{1 H-nmr (400MHz, CDCl} 3) δ7.56 (d, J = 8.5Hz, 2H), 7.41 (d, J = 8.5Hz, 2H), 7.35 (t, J = 8. 0 Hz, 1H), 7.31-7.25 (m, 1H), 7.15 (dd, J = 18.0, 8.0 Hz, 1H), 4.00-3.31 (bds, 8H) LC (290 nM) 5.10 min (>98%); MS (ESI) m / z = 327.9.

10. Methyl 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzoate

To a suspension of mono-methyl terephthalate (1.50 g, 8.33 mmol) in acetonitrile (16 mL) was added EDC (4.65 g, 25.0 mmol), HOBt (1.12 g, 8.33 mmol), DIPEA (3 .24 g, 25.0 mmol), and N-hydroxybenzimidoamide (1.36 g, 10.0 mmol) were added. The reaction was heated in the microwave at 100 ° C. for 30 minutes. The reaction was then cooled to room temperature, diluted with water (60 mL), and the crude white precipitate was isolated by vacuum filtration. Dissolved in CH ₂ Cl ₂ , passed through a silica plug, and methyl 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzoate (640 mg, 23%) as an off-white solid. Got. 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-oxadiazol-5-yl) benzoic acid

To a solution of methyl 4- (3- (4-fluorophenyl) 1,2,4-oxadiazol-5-yl) benzoate (600 mg, 2.14 mmol) in THF (12 mL) was added MeOH (3 mL) and H. A solution of LiOH (351 mg, 8.57 mmol) in ₂ O (3 mL) was added. The reaction was stirred at room temperature for 2 hours. The reaction was quenched when 1N HCl (30 mL) was added and extracted with EtOAc (2 × 30 mL). The organic extract was dried over MgSO ₄ and concentrated in vacuo to give 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzoic acid (550 mg, 87%) as a white solid. Got. 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-oxadiazol-5-yl-benzamide

To a solution of 4- (3-phenyl-1,2,4-oxadiazol-5-yl) benzoic acid (200 mg, 0.75 mmol) in DMF (2 mL) was added EDC (167 mg, 0.90 mmol), HOBt. (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 room temperature for 18 hours. The reaction was diluted with water (10 mL), the white precipitate was isolated by vacuum filtration, and N- (3,3-dimethylbutyl) -4- (3-phenyl-1,2,4-oxadiazole-5 -Yl-benzamide (248 mg, 95%) was obtained 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-styrylbenzoate

To a solution of ethyl 4-iodobenzoate (1.0 g, 3.6 mmol) in DMF (4 mL) was added commercially available (E) -styrylboronic acid (538 mg, 3.6 mmol) and catalyst Pd (tBuP) ₂ . . The reaction vessel was sealed and heated in a microwave reactor at 160 ° C. for 10 minutes. The reaction was cooled to room temperature, diluted with EtOAc: hexane (2: 1, 20 mL) and washed with water (2 × 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-styrylbenzoic acid

To a solution of ester (E) -ethyl 4-styrylbenzoate (600 mg, 2.3 mmol) in THF (5 mL) was added a solution of LiOH (360 mg, 10 mmol) in MeOH (2 mL) and water (25 mL). The reaction was stirred at room temperature for 4 hours. The reaction was acidified with 1N HCl (10 mL) and (E) -ethyl 4-styrylbenzoic acid (440 mg, 83%) was isolated 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, 1 H); LCMS (214 nM) 3.22 min (>98%); MS (ESI) m / z = 225.1.

15. (4-Hydroxypiperidin-1-yl) (4-styrylphenyl) methanone

To a solution of (E) -ethyl 4-styrylbenzoic acid (300 mg, 1.3 mmol) and DIPEA (270 uL, 2.1 mmol) in DMF (5 mL) was added EDC (280 mg, 1.5 mmol), HOBt (270 mg, 2 0.0 mmol), and 4-hydroxypiperidine hydrochloride (258 mg, 1.8 mmol) were added. The reaction was stirred at room temperature for 18 hours. The reaction was diluted with water (10 mL) and (4-hydroxypiperidin-1-yl) (4-styrylphenyl) methanone (390 mg, 98%) was isolated as a white solid by vacuum filtration. 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) was added 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 room temperature for 72 hours. The reaction was diluted with water (80 mL) and methyl 4- (4-fluorophenylcarbamoyl) benzoate (3.00 g, 98%) was isolated as a white precipitate by vacuum filtration. 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

To a solution of methyl 4- (4-fluorophenylcarbamoyl) benzoate (2.98 g, 10.9 mmol) in THF (35 mL) was added LiOH (1.79 g, 43 in MeOH (8 mL) and H ₂ O (8 mL). .6 mmol) solution was added. The reaction was stirred at room temperature for 2 hours. The reaction was quenched when 1N HCl (50 mL) was added and extracted with EtOAc (2 × 60 mL). The organic extract was dried over MgSO ₄ and concentrated in vacuo to give 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

To a solution of 4- (4-fluorophenylcarbamoyl) benzoic acid (50 mg, 0.19 mmol) in DMF (1 mL) was added PS-carbodiimide (125 mg. 0.25 mmol), HOBt (26 mg, 0.19 mmol), DIPEA ( 52 mg, 0.40 mmol), and 2-methylpiperidine (25 mg, 0.25 mmol) were added. The reaction was stirred at room temperature for 18 hours. MP-carbonate was added to the reaction and stirred for an additional 8 hours. The reaction was filtered, concentrated in vacuo, diluted with water (10 mL), the white precipitate was isolated by vacuum filtration and N- (4-fluorophenyl) -4- (2-methylpiperidine-1-carbonyl ) Benzamide (248 mg, 95%) was obtained. ¹ H-nmr (400 MHz, d ₆ -DMSO) δ 10.37 (br s, 1 H), 8.00 (d, J = 7 Hz, 2 H), 7.83-7.72 (m, 2 H), 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- (phenethynyl) -3,4-dihydroisoquinolin-1- (2H) -one (I-2)

To a solution of 6-bromo-3,4-dihydro-2H-isoquinoline, I-1 (600 mg, 2.65 mmol) in DMF (3 mL), phenylacetylene (266 mg, 2.61 mmol), 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 in a microwave reactor at 60 ° C. for 1 hour. The reaction was diluted with EtOAc / hexane (1: 1, 40 mL), washed 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 / hexane (1: 3, 50 mL) and as a brown solid, 6- (phenethynyl) -3,4-dihydroisoquinolin-1- (2H) -one, I-2 (309 mg 47%). ¹ H-nmr (400 MHz, CDCl ₃ ) δ 8.02 (bds, 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-dihydroisoquinolin-1- (2H) -one (II-2)

To a solution of 6- (phenethynyl) -3,4-dihydroisoquinolin-1 (2H) -one (II-1) (50 mg, 0.20 mmol) in DMF (0.5 mL) was added NaH (9 mg, 0.22 mmol). ) Was added and stirred for 1 hour. 1-Iodopropane (110 mg, 0.64 mmol) was added and stirred for 18 hours. PS-Ph ₃ P (200 mg) was added and stirred for 4 hours. Insoluble material was removed by filtration and the filtrate was concentrated in vacuo to give 6- (phenylethynyl) -2-propyl-3,4-dihydroisoquinolin-1- (2H) -one as a waxy yellow solid ( II-2) (44 mg, 76%) was obtained. ¹ H-nmr (400 MHz, d ₆ -DMSO) δ 8.08 (d, J = 8 Hz, 1 H), 7.59-7.52 (m, 2 H), 7.51 (d, J = 8 Hz, 1 H) , 7.41-7.35 (m, 4H), 3.57 (q, J = 7 Hz, 4H), 3.00 (t, J = 6.5 Hz, 2H), 1.69 (6-wire, 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)

MeOH (140 mL) solution of 5-bromo-isobenzofuran -1 (3H) - on III-1 (6.57g, 30.1mmol) to a suspension _of, was added NH 4 OH to (60 mL). The reaction vessel was sealed and stirred for 36 hours. The reaction was concentrated in vacuo to give 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, 1 H), 7.70 (s, 1 H), 7.68 (s, 2 H), 7.61 (s, 1 H ), 7.59-7.50 (m, 2H), 6.34 (br s, 1H), 5.72 (br s, 1H), 4.64 (s, 2H); LC (254 nM) 1. 12 min (>98%); MS (ESI) m / z = 231.8.

22.5-Bromoisoindoline-1-one (III-3)

To a solution of 4-bromo-2- (hydroxymethyl) benzamide III-2 (3.50 g, 15.2 mmol) in THF (100 mL) was added Ph ₃ P (4.78 g, 18.3 mmol) and DIAD (3. 38 g, 16.7 mmol) was added. The reaction was stirred at room temperature for 20 hours. The reaction mixture was concentrated under vacuum and purified by column chromatography (silica gel) using 0-25% EtOAc in hexanes as a white solid, 5-bromoisoindoline-1-one III-3 (786 mg, 24%). ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.0 Hz, 1 H), 7.70 (s, 1 H), 7.67 (s, 2 H), 5.31 (s, 2 H ); LC (254 nM) 4.88 min (>98%); MS (ESI) m / z = 212.8, 214.8.

23.5-((3-Fluorophenyl) ethynyl) isoindoline-1-one (III-5)

To a solution of 5-bromoisoindoline-1-one III-3 (100 mg, 0.47 mmol) in DMF (2 mL) was added 3-fluorophenylacetylene III-4 (67 mg, 0.56 mmol), 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 hour. The reaction was cooled to room temperature, diluted with EtOAc: hexane (2: 1, 8 mL) and washed with water (2 × 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 to yield 5-((3-fluorophenyl) ethynyl) isoindoline-1-one III-5 (42 mg, 35%) 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, 1H), 7.14-7.07 (m, 1H), 5.36 (s, 2H); LC (214 nM) ) 3.38 min (>98%); MS (ESI) m / z = 253.1.

24.5- (phenethynyl) isoindoline-1,3-dione (IV-2)

２００℃

200 ° C

To a 10 mL microwave vial was added urea (121 mg, 2.02 mmol), 5- (phenylethynyl) isobenzofuran-1,3-dione IV-1 (100 mg, 0.403 mmol), and anhydrous DMF (3 ml). . The reaction vessel was sealed and heated at 200 ° C. for 15 minutes. The reaction was diluted with EtOAc (20 ml) and washed sequentially with water (20 ml) and brine (20 ml). The organic extract was dried over MgSO ₄ and filtered through a silica plug to give 5- (phenethynyl) isoindoline-1,3-dione IV-2 (82 mg, 83%) as a brown solid. ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.9 (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- (phenethynyl) isoindoline-1,3-dione (IV-3)

To a 10 mL microwave vial was added K ₂ CO ₃ (276 mg, 2.02 mmol), 5- (phenethynyl) isoindoline-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 at 150 ° C. for 15 minutes. The reaction was diluted with EtOAc (20 ml) and washed sequentially with water (20 ml) and brine (20 ml). The organic extract was dried over MgSO ₄ and filtered through a silica plug to give 2-ethyl-5- (phenethynyl) isoindoline-1,3-dione IV-3 (100 mg, 91%) as a white solid. . %). ¹ H-nmr (400 MHz, CDCl ₃ ) δ 7.9 (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 = 7 Hz, 3H); MS (ESI) m / z 276 .3.

26. In vitro research

Rat embryonic kidney (HEK) cells transfected with mGluR5 were seeded in clear-bottom poly-D-lysine coated assay plates in glutamate-glutamate-free medium growth and in 5% CO ₂ . Incubate overnight at 37 ° C. The next day, cells were loaded with fluo-4 AM, a 2 μM calcium indicator dye, for 1 hour at 37 ° C. The dye was removed and replaced with assay buffer containing 1 × Hanks solution (Invitrogen, Carlsbad, Calif.), 20 mM HEPES, and 2.5 mM probenecid, pH 7.4. Thereafter, the cell plate was loaded onto a Functional Drug Screening System 6000 (FDSS 6000, Hamamatsu, Japan). After building a fluorescent baseline for 12 seconds, the compounds of the invention were added to the cells and the reaction in the cells was measured. After 5 minutes, mGluR5 agonist (eg, glutamate, 3,5-dihydroxyphenylglycine or quiscaric acid) was added to the cells and the cellular response was measured during a 1 minute incubation with the agonist. Typically, the effect of the test compounds of the present invention on the EC ₂₀ concentration of glutamate was measured. All test compounds are dissolved and diluted in 100% DMSO, then serially diluted in assay buffer for 2.5 × stock solution in 0.25% DMSO, and the stock compound is then diluted to 0. Added to assay for 1% DMSO final concentration. Calcium fluorescence measurements were recorded as a fold over reference fluorescence, after which the raw data was normalized to the maximum response to agonist. Enhancement of the agonist response of mGluR5 by the compounds of the present invention is observed as an increased response to the agonist (here glutamate) in the presence of the compound compared to the response to the agonist in the absence of the compound. It was.

27. Behavior evaluation

Spontaneous motion is evaluated as the average distance traveled (cm) in a test chamber measuring 43.2 cm (L) × 43.2 cm (W) × 30.5 cm (H) in a standard 16 × 16 photocell. (Med Associates, St. Albans, VT). Animals can be acclimated to individual activity chambers for at least 60 minutes prior to drug administration. Following administration of the appropriate drug or vehicle, activity can be recorded for 3 hours. Data can be presented as the mean of travel distance (± standard error) recorded at 10 minute intervals over the test period. Data were analyzed using repeated measures analysis of variance (ANOVA) and then post-hoc tested using Tukey's HSD test, where appropriate. A difference can be considered significant if 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 skilled in the art from consideration of the specification and practice of the invention disclosed herein. The specification and examples are to be regarded as illustrative only, and the true scope and spirit of the invention is intended to be indicated by the following claims.

Claims (90)

A method for the treatment of a neurological and / or psychiatric disorder associated with glutamate dysfunction in a mammal comprising the steps of:

At least one compound having a structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof for treating the neurological and / or psychiatric disorders associated with glutamate dysfunction in the mammal Administering at a suitable dose and dose.
Where each ----- is any covalent bond,
Y ¹ and Y ² are independently selected from N and C—R;
Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an 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,

Selected from
R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2-5 carbons, or 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 with thioalkyl, optional 1 to independently selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Selected from organic radicals containing 5 carbon atoms,
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 substituted Selected from organic radicals containing 1 to 6 carbon atoms selected from aryl and optionally substituted heteroaryl. A method for enhancing metabotropic glutamate receptor activity in a mammal comprising the steps of:

At least one compound having the structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof at a dosage and dose effective to enhance metabotropic glutamate receptor activity in said mammal, Administering the method.
Where each ----- is any covalent bond,
Y ¹ and Y ² are independently selected from N and C—R;
Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an 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,

Selected from
R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2-5 carbons, or 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 with thioalkyl, optional 1 to independently selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Selected from organic radicals containing 5 carbon atoms. A method for a receptor partial activation action of metabotropic glutamate receptor activity in a mammal, wherein the mammal has the formula

At least one compound having a structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof, effective to exhibit a receptor partial activation effect of metabotropic glutamate receptor activity in said mammal Administering at a dosage and dose.
Where each ----- is any covalent bond,
Y ¹ and Y ² are independently selected from N and C—R;
Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an 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,

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 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 thioal 1 selected from alkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Selected from organic radicals containing ˜5 carbon atoms. A method for enhancing cognition in a mammal comprising the steps of:

Administering at least one compound having the structure represented by: or a pharmaceutically acceptable salt or N-oxide thereof in a dosage and dose effective to enhance cognition in said mammal. ,Method.
Where each ----- is any covalent bond,
Y ¹ and Y ² are independently selected from N and C—R;
Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an 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,

Selected from
R ^7a and R ^7b together form a carbocyclic or heterocyclic ring optionally substituted with 2-5 carbons, or, independently, hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, As well as 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 Selected from: optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. Selected from organic radicals containing 5 carbon atoms. The method of claim 4, wherein the cognitive enhancement is a statistically significant increase in novel object recognition. 5. The method of claim 4, wherein the cognitive enhancement is a statistically significant increase in the performance of a Wisconsin Card Sorting test. The method according to claim 1, wherein the mammal is a human. 2. The method of claim 1, wherein the mammal is in need of treatment for the disease prior to administration. 2. The method of claim 1, wherein the mammal has been diagnosed with a need for treatment of the disease prior to administration. The diseases include dementia, frenzy, amnesia, cognitive decline due to aging, schizophrenia, psychosis including schizophrenia, schizophrenia-like disorder, schizophrenic emotional disorder, paranoid disorder, short-term psychotic Disorder, substance-related disorder, movement disorder, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorder, brain edema, sleep disorder, narcolepsy, anxiety, emotional disorder, panic attack, unipolar 2. The method of claim 1, wherein the method is selected from depression, bipolar affective disorder, and psychotic depression. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl;
Z contains 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 9 to 13 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
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 Independently selected from cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , And R ² together form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. 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 heterocyclo 16. Any one of claims 11 to 15, selected from alkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons. Compound. 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 heterocyclo 16. Any one of claims 11 to 15, selected from alkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons. Compound. One or more substituents of R ³ are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, 16. Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl optionally substituted, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons. The compound in any one of these. One or more substituents of R ⁴ are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, 16. Selected from heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl optionally substituted, optionally substituted aryl, and optionally substituted heteroaryl, having 2 to 7 carbons. A compound according to any of the above. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
Wherein R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl. And
Y ¹ is selected from N and C—R ⁴
Y ² is selected from N and C—H;
Each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
Wherein R ¹ is hydrogen or an optionally substituted C1-C12 alkyl, an optionally substituted C1-C12 heteroalkyl, an optionally substituted C3-C12 cycloalkyl, or optionally Selected from substituted C3-C12 heterocycloalkyl, wherein R ¹ does not include silicon;
R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that When R ¹ is methyl, R ⁵ is an organic radical containing 4 to 14 carbon atoms,
Y ¹ is selected from N and C—R ⁴
Y ² is selected from N and C—H. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
Wherein each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
Each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
R ⁵ is an organic radical containing 4 to 14 carbon atoms,
Y ¹ is selected from N and C—R ⁴
Y ² is selected from N and C—H. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
Where each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
Y ¹ is selected from N and C—R ⁴
Y ² is selected from N and C—H;
R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that R ⁵ does not contain a triphenylamine residue or a benzimidoamide residue. The compound has the formula

The method in any one of Claims 1-4 which has the structure represented by these.
Where n is 2, 3, or 4;
R ^2a and R ^2b together form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1-6 carbons An organic radical containing atoms,
Each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
Y ¹ is selected from N and C—R ⁴
Y ² is selected from N and C—H;
R ⁵ is an organic radical containing 4 to 14 carbon atoms. 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, optionally substituted An organic radical containing 1 to 12 carbon atoms selected from aryl, optionally substituted heteroaryl, and — (CH ₂ ) _m -aryl or — (CH ₂ ) _m -heterocycle, , 1, 2, 3, or 4;
R ^2a and R ^2b , if present, together form ═O or ═S, or each R ^2a and R ^2b 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, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted Thioalkyl, optionally 1-6 independently selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl An organic radical containing carbon atoms,
R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b 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, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted Alkyl 1-6 carbons independently selected from sulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl An organic radical containing atoms,
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 heterocycloalkynyl, Optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally An organic radical containing 1 to 12 carbon atoms independently selected from amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl substituted with
R ⁵ is, C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted, C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl optionally substituted, optionally substituted aryl, and optionally 25. A method according to any one of claims 20 to 24, which is an organic radical comprising 4 to 14 carbon atoms selected from substituted heteroaryl. A method for the treatment of a disease in a mammal, comprising:

Having at least one compound, or a pharmaceutically acceptable salt or N-oxide thereof,
Administering at a dosage and dose effective to treat the disease in said mammal.
Where 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 form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1 An organic radical containing ~ 6 carbon atoms,
R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1-6 carbons An organic radical containing atoms,
R ⁴ includes one, two, or three substituents present independently as 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,
R ⁵ is an organic radical containing 4 to 14 carbon atoms. 27. The method of claim 26, wherein the compound comprises:
A. Construction

An isoindoline-1-one derivative having:
In the formula, ^{R 1} is an organic radical containing hydrogen or from 1 to 12 carbon atoms,
R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that when R ¹ is hydrogen, R ⁵ is an optionally substituted phenyl or an optionally substituted pyridinyl. -1-one derivatives,
b. Construction

An isoindoline-1,3-dione derivative having:
Wherein R ¹ is hydrogen or an optionally substituted C1-C12 alkyl, an optionally substituted C1-C12 heteroalkyl, an optionally substituted C3-C12 cycloalkyl, or an optionally substituted Selected from C3-C12 heterocycloalkyl, wherein R ¹ does not include silicon;
R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that When R ¹ is methyl, R ⁵ is an isoindoline-1,3-dione derivative, which is an organic radical containing 4 to 14 carbon atoms,
c. Construction

A 3,4-dihydroisoquinolin-1 (2H) -one derivative having:
In which R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms;
Each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
R ⁵ is an organic radical containing 4 to 14 carbon atoms, a 3,4-dihydroisoquinolin-1 (2H) -one derivative,
d. Construction

An isoquinoline-1,3 (2H, 4H) -dione derivative having:
In which 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, provided that, ^{R 5} does not include triphenylamine residue or benzimidamide amide residue, isoquinoline -1,3 (2H, 4H) - A dione derivative, or e. Construction

A bicyclic compound having:
Where 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 form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1-6 carbons An organic radical containing atoms,
R ⁵ is an organic radical containing 4 to 14 carbon atoms.
Or a compound comprising a pharmaceutically acceptable salt or N-oxide thereof,
Wherein Y ¹ is selected from N and C—R ⁴ ,
Y ² is selected from N and C—H;
Each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 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,

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 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 thioal 1 selected from alkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Selected from organic radicals containing ˜5 carbon atoms,
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 substituted Selected from organic radicals containing 1 to 6 carbon atoms selected from aryl 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 a need for treatment of the disease prior to administration. 28. The method of claim 26 or 27, wherein the disease is one or more neurological and / or psychiatric diseases associated with glutamate dysfunction in a mammal. The diseases include dementia, frenzy, amnesia, cognitive decline due to aging, schizophrenia, psychosis including schizophrenia, schizophrenia-like disorder, schizophrenic emotional disorder, paranoid disorder, short-term psychotic Disorder, substance-related disorder, movement disorder, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorder, brain edema, sleep disorder, narcolepsy, anxiety, emotional disorder, panic attack, unipolar 28. A method according to claim 26 or 27, wherein the method is selected from depression, bipolar affective disorder, and psychotic depression. formula

Or a pharmaceutically acceptable salt or N-oxide thereof, wherein the compound is present in the presence of the compound compared to the reaction to glutamic acid in the absence of the compound. Below, the enhancement of the mGluR5 response to glutamate is shown as increased response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5.
Where R ¹ and R ² are independently an optionally substituted organic radical containing 1 to 12 carbon atoms,
Each ----- is any covalent bond,
Y ¹ and Y ² are independently selected from N and C—R;
Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms;
Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains up to 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. R ¹ and ^{R 2} are independently alkyl having 1 to 6 carbons, the compound according to claim 32. N, R ^1, and R ² together form a heterocyclic ring optionally substituted with 2-7 carbons, the compound according to claim 32. All of Z ^{1, Z 2,} and ^{Z 3} are carbon, A compound according to claim 32. R ⁴ is hydrogen, halogen, and up to five substituents independently selected from lower alkyl, A compound according to claim 32. Both Y ¹ and ^{Y 2} is a carbon compound according to claim 32. formula

33. The compound of claim 32, having a structure represented by: R ¹ and R ² are independently alkyl having 1 to 6 carbons, or N, R ¹ , and R ² are both optionally substituted heterocycles having 2 to 7 carbons. Wherein R includes 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl, and R ⁴ is independently selected from hydrogen, halogen, and lower alkyl. 40. The compound of claim 38, comprising 1 substituent. formula

33. The compound of claim 32, having a structure represented by:
Wherein R ¹ and R ² are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl Independently substituted, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. formula

33. The compound of claim 32, having a structure represented by:
Wherein R ¹ and R ² are optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl Independently substituted, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or N, R ¹ , and R ² together form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. formula

Or a pharmaceutically acceptable salt or N-oxide thereof, wherein the compound is present in the presence of the compound as compared to a reaction to glutamic acid in the absence of the compound. Thus, in human embryonic kidney cells transfected with rat mGluR5, the enhancement of mGluR5 response to glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
Wherein R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms,
Each ----- is any covalent bond,
Y ¹ and Y ² are independently selected from N and C—R;
Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms;
Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Containing up to 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl,
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 carbons, or 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 cyclo Alkyl 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 Hetero Reel, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, Selected from organic radicals containing 1 to 5 carbon atoms, independently selected from amino-carbonyl and alkylamine-carbonyl. R ¹ and R ² are independently hydrogen or alkyl of 1 to 6 carbons, the compound according to claim 42. N, R ^1, and R ² together form a heterocyclic ring optionally substituted with 2-7 carbons, the compound according to claim 42. All of Z ^{1, Z 2,} and ^{Z 3} are carbon, A compound according to claim 42. R ⁴ is hydrogen, halogen, and up to five substituents independently selected from lower alkyl, A compound according to claim 42. Both Y ¹ and ^{Y 2} is a carbon compound according to claim 42. 43. The compound of claim 42, wherein both R ^7a and R ^7b are hydrogen. formula

43. The compound of claim 42, having a structure represented by: R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons, or N, R ¹ , and R ² are both optionally substituted having 2 to 7 carbons Forming a heterocycle, wherein R contains 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl, and R ⁴ is independently selected from hydrogen, halogen, and lower alkyl 50. The compound of claim 49, comprising 5 substituents as defined above. formula

43. The compound of claim 42, having a structure represented by:
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 Selected from 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 form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. formula

Or a pharmaceutically acceptable salt or N-oxide thereof having a structure represented by the formula: wherein the compound is compared to the reaction to glutamic acid in the absence of the compound. In the presence, in rat embryonic kidney cells transfected with rat mGluR5, the enhancement of mGluR5 response to glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
Where R ¹ and R ² are independently an optionally substituted organic radical containing 1 to 12 carbon atoms,
Each ----- is any covalent bond,
Y ¹ and Y ² are independently selected from N and C—R;
Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms;
Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains up to 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. R ¹ and R ² are independently hydrogen or alkyl of 1 to 6 carbons, the compound according to claim 52. N, R ^1, and R ² together form a heterocyclic ring optionally substituted with 2-7 carbons, the compound according to claim 52. All of Z ^{1, Z 2,} and ^{Z 3} are carbon, A compound according to claim 52. R ⁴ is hydrogen, halogen, and up to five substituents independently selected from lower alkyl, A compound according to claim 52. Both Y ¹ and ^{Y 2} is a carbon compound according to claim 52. formula

53. The compound of claim 52, having a structure represented by: R ¹ and R ² are independently alkyl having 1 to 6 carbons, or N, R ¹ , and R ² are both optionally substituted heterocycles having 2 to 7 carbons. And R contains 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl, and R ⁴ is independently selected from hydrogen, halogen, and lower alkyl 59. The compound of claim 58, comprising 5 substituents. formula

53. The compound of claim 52, having a structure represented by:
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 Selected from 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 form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. formula

Or a pharmaceutically acceptable salt or N-oxide thereof having a structure represented by the formula: wherein the compound is compared to the reaction to glutamic acid in the absence of the compound. In the presence, in rat embryonic kidney cells transfected with rat mGluR5, the enhancement of mGluR5 response to glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
Wherein R ¹ and R ² are independently hydrogen or an optionally substituted organic radical containing 1 to 12 carbon atoms,
Each ----- is any covalent bond,
Y ¹ and Y ² are independently selected from N and C—R;
Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms;
Z ¹ , Z ² , and Z ³ are independently selected from N and C—R ⁴ , provided that up to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Containing up to 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl,
R ⁸ is selected from hydrogen and lower alkyl. R ¹ and R ² are independently hydrogen or alkyl of 1 to 6 carbons, the compound according to claim 61. N, R ^1, and R ² together form a heterocyclic ring optionally substituted with 2-7 carbons, the compound according to claim 61. All of Z ^{1, Z 2,} and ^{Z 3} are carbon, A compound according to claim 61. R ⁴ is hydrogen, halogen, and up to five substituents independently selected from lower alkyl, A compound according to claim 61. Both Y ¹ and ^{Y 2} is a carbon compound of claim 61. R ⁸ is hydrogen A compound according to claim 61. formula

62. The compound of claim 61, having a structure represented by: R ¹ and R ² are independently hydrogen or alkyl having 1 to 6 carbons, or N, R ¹ , and R ² are both optionally substituted having 2 to 7 carbons Forming a heterocycle, wherein R contains 3 or 4 substituents independently selected from hydrogen, halogen, and lower alkyl, and R ⁴ is independently selected from hydrogen, halogen, and lower alkyl 69. The compound of claim 68, comprising 5 substituents as defined above. formula

62. The compound of claim 61, having a structure represented by:
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 Selected from 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 form an optionally substituted heterocycle having 2 to 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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Comprising four substituents independently selected from boxamide, amino-carbonyl, and alkylamine-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 cyclo Alkenyl 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, thioamide, amidosulfonyl, alkoxycarbonyl, Contains 5 substituents independently selected from boxamide, amino-carbonyl, and alkylamine-carbonyl. formula

Or a pharmaceutically acceptable salt or N-oxide thereof having the structure represented by: wherein the compound is compared to a reaction to glutamic acid in the absence of the compound, In the presence, in rat embryonic kidney cells transfected with rat mGluR5, enhancement of mGluR5 response to glutamate is shown as an increase in response to non-maximal concentrations of glutamate.
Where each ----- is any covalent bond,
Y ¹ and Y ² are independently selected from N and C—R;
Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an 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,

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 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 thioal 1 selected from alkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Selected from organic radicals containing ˜5 carbon atoms,
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 substituted Selected from organic radicals containing 1 to 6 carbon atoms selected from aryl and optionally substituted heteroaryl. formula

72. The compound of claim 71, having a structure represented by:
Wherein R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl. And
Y ¹ is selected from N and C—R ⁴
Y ² is selected from N and C—H;
Each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
R ⁴ is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical containing 1 to 12 carbon atoms. formula

72. The compound of claim 71, having a structure represented by:
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 includes 5 substituents independently selected from hydrogen, halogen, and lower alkyl. formula

72. The compound of claim 71, having a structure represented by:
Wherein R ¹ is hydrogen or an optionally substituted C1-C12 alkyl, an optionally substituted C1-C12 heteroalkyl, an optionally substituted C3-C12 cycloalkyl, or an optionally substituted Selected from C3-C12 heterocycloalkyl, wherein R ¹ does not include silicon;
R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that When R ¹ is methyl, R ⁵ is an organic radical containing 4 to 14 carbon atoms,
Y ¹ is selected from N and C—R ⁴ ;
Y ² is selected from N and C—H. formula

72. The compound of claim 71, having a structure represented by:
Wherein R ¹ is hydrogen or alkyl having 1 to 6 carbons,
R ⁴ includes 5 substituents independently selected from hydrogen, halogen, and lower alkyl. formula

72. The compound of claim 71, having a structure represented by:
Wherein each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
Each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
R ⁵ is an organic radical containing 4 to 14 carbon atoms,
Y ¹ is selected from N and C—R ⁴ ;
Y ² is selected from N and C—H. formula

72. The compound of claim 71, having a structure represented by:
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 includes 5 substituents independently selected from hydrogen, halogen, and lower alkyl. formula

72. The compound of claim 71, having a structure represented by:
Where each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
Y ¹ is selected from N and C—R ⁴
Y ² is selected from N and C—H;
R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that R ⁵ does not contain a triphenylamine residue or a benzimidoamide residue. formula

72. The compound of claim 71, having a structure represented by:
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 includes 5 substituents independently selected from hydrogen, halogen, and lower alkyl. formula

72. The compound of claim 71, having a structure represented by:
Where n is 2, 3, or 4;
R ^2a and R ^2b together form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1-6 carbons An organic radical containing atoms,
Each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
Y ¹ is selected from N and C—R ⁴ ;
Y ² is selected from N and C—H;
R ⁵ is an organic radical containing 4 to 14 carbon atoms. formula

72. The compound of claim 71, having a structure represented by:
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 includes 5 substituents independently selected from hydrogen, halogen, and lower alkyl. 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, optionally substituted An organic radical containing 1 to 12 carbon atoms selected from aryl, optionally substituted heteroaryl, and — (CH ₂ ) _m -aryl or — (CH ₂ ) _m -heterocycle, , 1, 2, 3, or 4;
R ^2a and R ^2b , if present, together form ═O or ═S, or each R ^2a and R ^2b is independently an 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, 1-6 selected from optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl An organic radical containing carbon atoms of
R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b is independently an optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optional 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 replaced 1 to 6 carbon atoms selected from alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. Containing organic radicals,
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 heterocycloalkynyl, Optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally An organic radical containing 1 to 12 carbon atoms independently selected from amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl substituted with
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 82. A compound according to any one of claims 71 to 81, which is an organic radical comprising 4 to 14 carbon atoms selected from substituted heteroaryl. formula

72. The compound of claim 71, comprising a structure having formula

72. The compound of claim 71, comprising a structure having
Where R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2-5 carbons, or hydrogen, halogen, hydroxyl, cyano, nitro, thiol, Amino, as well as 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, thioamide, amidosulfonyl, alkoxycarbonyl Selected from organic radicals containing 1 to 5 carbon atoms, independently selected from: carboxamide, amino-carbonyl, and alkylamine-carbonyl. formula

72. The compound of claim 71, comprising a structure having
Wherein R ^7a and R ^7b are 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 hetero Cycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally 1 to 5 selected from substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing carbon atoms. A compound showing enhanced mGluR5 response to glutamic acid in human embryonic kidney cells transfected with rat mGluR5 in the presence of said compound as compared to response to glutamic acid in the absence of said compound A compound that exhibits it as an increase in response to non-maximal concentrations of glutamic acid, including:
a. Construction

An isoindoline-1-one derivative having:
In which 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, provided that when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl.
b. Construction

An isoindoline-1,3-dione derivative having:
Wherein R ¹ is hydrogen or an optionally substituted C1-C12 alkyl, an optionally substituted C1-C12 heteroalkyl, an optionally substituted C3-C12 cycloalkyl, or optionally Selected from substituted C3-C12 heterocycloalkyl, wherein R ¹ does not include silicon;
R ⁵ is an organic radical containing 4 to 14 carbon atoms, provided that when R ¹ is hydrogen, R ⁵ is optionally substituted phenyl or optionally substituted pyridinyl, provided that When R ¹ is methyl, R ⁵ is an organic radical containing 4 to 14 carbon atoms.
c. Construction

3,4-Dihydroisoquinolin-1 (2H) -one derivative having
Wherein R ¹ is hydrogen or an organic radical containing 1 to 12 carbon atoms,
Each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 1 to 6 carbon atoms;
R ⁵ is an organic radical containing 4 to 14 carbon atoms.
d. Construction

An isoquinoline-1,3 (2H, 4H) -dione derivative having:
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, provided that R ⁵ does not contain a triphenylamine residue or a benzimidoamide residue.
Or
e. Construction

A bicyclic compound having:
Where 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 form ═O or ═S, or each R ^2a and R ^2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or 1-6 carbons An organic radical containing atoms,
R ⁵ is an organic radical containing 4 to 14 carbon atoms.
Or a pharmaceutically acceptable salt or N oxide thereof.
Wherein Y ¹ is selected from N and C—R ⁴
Y ² is selected from N and C—H;
Each R ^3a and R ^3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical containing 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,

Selected from
R ^7a and R ^7b together form an optionally substituted carbocycle or heterocycle having 2-5 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 thioal 1 selected from alkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Selected from organic radicals containing ˜5 carbon atoms,
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 substituted Selected from organic radicals containing 1 to 6 carbon atoms selected from aryl and optionally substituted heteroaryl. 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, optionally substituted An organic radical containing 1 to 12 carbon atoms selected from aryl, optionally substituted heteroaryl, and — (CH ₂ ) _m -aryl or — (CH ₂ ) _m -heterocycle, 1, 2, 3, or 4;
R ^2a and R ^2b , if present, together form ═O or ═S, or each R ^2a and R ^2b is independently an 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, 1-6 selected from optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl An organic radical containing carbon atoms of
R ^3a and R ^3b together form ═O or ═S, or each R ^3a and R ^3b is independently an optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optional 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 replaced 1 to 6 carbon atoms selected from alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl. Containing organic radicals,
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 heterocycloalkynyl, Optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally An organic radical containing 1 to 12 carbon atoms independently selected from amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl substituted with
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 90. The compound of claim 86, wherein the compound is an organic radical comprising 4 to 14 carbon atoms selected from substituted heteroaryl. formula

90. The compound of claim 86 comprising a structure having formula

90. The compound of claim 86, comprising a structure having
Where R ^7a and R ^7b together form an optionally substituted carbocyclic or heterocyclic ring having 2-5 carbons, or hydrogen, halogen, hydroxyl, cyano, nitro, thiol, Amino, as well as 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, thioamide, amidosulfonyl, alkoxycarbonyl Selected from organic radicals containing 1 to 5 carbon atoms, independently selected from: carboxamide, amino-carbonyl, and alkylamine-carbonyl. formula

90. The compound of claim 86, comprising a structure having
Where R ^7a and R ^7b are 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, 1-5 selected from optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamide, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl Independently selected from organic radicals containing one carbon atom.

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