JP2009522287A - Fatty acid amide hydrolase inhibitor - Google Patents

Abstract

Pharmacological inhibition of fatty acid amide hydrolase (FAAH) activity results in increased levels of fatty acid amides. Disclosed are alkyl carbamates that are inhibitors of FAAH activity. The compounds disclosed herein inhibit FAAH activity. Described herein are esters of alkylcarbamic acid compounds, methods of preparing compositions containing them, and methods of using them.

Description

  Compounds for inhibiting the activity of fatty acid amide hydrolase (FAAH), methods for producing such compounds, pharmaceutical compositions and medicaments containing such compounds and methods of using such compounds and compositions Is described here.

  Fatty acid amide hydrolase (FAAH) is an enzyme that hydrolyzes the fatty acid amide (FAA) family of endogenous signaling lipids. Common types of FAAs include N-acylethanolamines (NAF) and fatty acid primary amides (FAPA). Examples of NAE include anandamide (AEA), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA). Pharmacological inhibition of FAAH activity results in increased levels of these fatty acid amides.

SUMMARY OF THE INVENTION Compounds, compositions and methods are provided for inhibiting the activity of fatty acid amide hydrolase (FAAH). The compounds provided herein are inhibitors of fatty acid amide hydrolase (FAAH). As well as methods for preparing compounds that inhibit the activity of fatty acid amide hydrolase, compositions containing such compounds, methods of using such compounds are provided.

  The compounds provided herein have the formula (I)

［上記式において、
ＤはＯまたはＮＲ^１１であり；ＡまたはＢの一方は（ＣＨ_２）_ｍＣ（Ｏ）−アルキル、（ＣＨ_２）_ｍＣ（Ｏ）−Ｎ（Ｒ^２）_２でありおよび他方はＨ，アルキルまたはヘテロアルキルであり、ｍは０、１、２、または３であり；またはＡおよびＢは、一諸になって場合により置換されたオキソ−置換複素環を形成し；またはＡおよびＢは、一諸になって少なくとも１個のＮ、ＮＲ^２、ＳまたはＯ基を含む、場合により置換されたヘテロ芳香族基を形成し；またはＡおよびＢは、一諸になって場合により置換された非芳香族もしくは芳香族の炭素環基を形成し；またはＡおよびＢはＨ、場合により置換されたアルキル、場合により置換されたヘテロアルキル、場合により置換された複素環基、場合により置換されたアリール基、場合により置換されたヘテロアリール基、場合により置換されたケトアルキルおよび場合により置換されたケトヘテロアルキルからそれぞれ独立して選択され；Ｒ^１は、Ｃ_３−Ｃ_９シクロアルキル、Ｃ_１−Ｃ_４アルキル（Ｃ_３−Ｃ_９シクロアルキル）、Ｃ_１−Ｃ_４アルキル（アリール）およびＣ_１−Ｃ_４アルキル（ヘテロアリール）から選択される場合により置換された基であり、Ｒ^１のシクロアルキル環のいずれの炭素も、場合によりＹおよびＺで置換されることができ、各Ｙおよび各Ｚはハロゲン、メチル、またはトリフルオロメチルから独立して選択され、またはＹおよびＺは一緒になって３−、４−、もしくは５員の炭素環基またはオキソ（＝Ｏ）を形成することができ；各Ｒ^２はＨまたは場合により置換されたアルキルから独立して選択され；Ｒ^１１はＨまたは場合により置換されたアルキルである。］の構造を有するものおよび医薬的に許容される塩、医薬的に許容されるＮ−オキシド、医薬的に活性な代謝物、医薬的に許容されるプロドラッグまたは医薬的に許容される溶媒和物を含む。

[In the above formula,
D is O or NR ¹¹ ; one of A or B is (CH ₂ ) _m C (O) -alkyl, (CH ₂ ) _m C (O) —N (R ² ) ₂ and the other is H, Alkyl or heteroalkyl, m is 0, 1, 2, or 3; or A and B together form an optionally substituted oxo-substituted heterocycle; or A and B are Forming an optionally substituted heteroaromatic group, which together comprises at least one N, NR ² , S or O group; or A and B are optionally substituted Forming a non-aromatic or aromatic carbocyclic group; or A and B are H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted Aryl group, in case Ri substituted heteroaryl group, each independently selected from keto heteroalkyl, optionally substituted, which has been ketoalkyl and optionally substituted; R ¹ is, C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl ( C ₃ -C _{9 cycloalkyl),} substituted groups optionally selected from C 1 -C ₄ alkyl (aryl) and _C 1 -C ₄ alkyl (heteroaryl), any cycloalkyl ring of ^{R 1} Can also be optionally substituted with Y and Z, each Y and each Z being independently selected from halogen, methyl, or trifluoromethyl, or Y and Z taken together are 3-, 4- or 5-membered carbocyclic groups or oxo (═O) can be formed; each R ² can be independently selected from H or optionally substituted alkyl. R ¹¹ is H or optionally substituted alkyl. And pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates Including things.

For any and all embodiments, substituents can be selected from a subset of the listed options. For example, in certain embodiments, one of A or B _{is, (CH 2) n C (} O) - _{alkyl, (CH 2) n C (} O) -N (R 2) _2, the other is H, alkyl Or it is heteroalkyl. In certain embodiments, A and B _{^{together, -C (O) - (CR}} q R q) n -, - C (O) -NR 2 - (CR q R q) n -, - NR _{^{2 -C (O) - (CR}} q R q) n -, - C (O) -NR 2 -NR 2 - (CR q R q) n -, - C (O) -NR 2 -N = (CR ^{q) -, - O-C} (O) -O-, O-C (O) -NR 2 -, - NR 2 -C (O) -NR 2 -, - O-C (O) -O- ( ^{_{CR q R q) n -,}} - O-C (O) - (CR q R q) n -O -, - n-C (O) - (CR q R q) n -N -, - O-C _{^{(O) - (CR q R}} q) n -N -, - n-C (O) - (CR q R q) n -O -, - O-C (O) -NR 2 - (CR q R q ^{_{) n -, - NR 2 -C}} (O) -O- (CR q R q) n ^{-, - NR 2 -C (O} ) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -O- (CR q R q) n -, - ( ^{_{CR q R q) n -C (}} O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -NR 2 -NR 2 -, - (CR q R ^{_{q) n -C (O) -}} (CR q R q) n -, - C (O) -O- (CR q R q) n -O -, - C (O) -O- (CR q R q ^{_{) n -NR 2 -, - C}} (O) -NR 2 - (CR q R q) n -NR 2, -C (O) -NR 2 - (CR q R q) n -O -, - C ( ^{O) -NR 2 -CR q = CR} q -, C (O) -CR q = CR q -NR 2 -, - C (O) -CR q = CR q -O -, - C (O) -CR ^q = when selected from ^CR q -S- More substituted oxo - substituted heterocycle to form; each n is to 1, 2 or 3 independently; and each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, keto Independently selected from heteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle or substituted heterocycle; or any of the two groups of R ^q can form a carbocycle or heterocycle.

In certain embodiments, A and B taken together comprise an optionally substituted non-aromatic comprising a C (O) — (CH ₂ ) _n — moiety, where n is 1, 2, 3, or 4. A group ring group is formed. In another embodiment, A and B are taken together to form an optionally substituted heteroaromatic group comprising at least one N, NR ² , S or O group. In certain embodiments, R ¹ is C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl ( Optionally substituted groups, wherein any carbon of the cycloalkyl ring of R ¹ can optionally be substituted with Y and Z, wherein each Y and each Z is halogen, Independently selected from methyl or trifluoromethyl, or Y and Z can be taken together to form a 3, 4 or 5 membered carbocyclic group or oxo (= O). In certain embodiments, R ² is H or optionally substituted alkyl. In other embodiments, D is O. In another embodiment, a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate. It is.

In certain embodiments, R ² is H. In another embodiment, R ¹¹ is H. In certain embodiments, one of A or B is C (O) -alkyl and the other is H. In a further embodiment, the alkyl group is a methyl group.

In other embodiments, as non-limiting examples, 3-carbamoylphenylcyclohexylcarbamate; 3-carbamoylphenylcyclohexylmethylcarbamate; 3-acetylphenylcyclohexylcarbamate; 3-acetylphenylcyclohexylmethylcarbamate; 3-acetylphenylisopropylcarbamate; Selected from 3-acetylphenylisobutylcarbamate; and 3-acetylphenylphenethylcarbamate. In certain embodiments, A and B taken together comprise an optionally substituted non-containing C (O) — (CH ₂ ) _n — moiety, where n is 1, 2, 3, or 4. An aromatic ring group is formed. In another embodiment, n is 2. In certain embodiments, R ² is H.

  In certain embodiments, as a non-limiting example, 2,3-dihydro-1-oxo-1H-inden-6-ylcyclohexyl carbamate; 2,3-dihydro-1-oxo-1H-inden-6-ylcyclohexyl Selected from 2,3-dihydro-1-oxo-1-H-inden-5-ylcyclohexylcarbamate; and 2,3-dihydro-1-oxo-1H-inden-5-ylcyclohexylmethylcarbamate; .

In a further embodiment, A and B are taken together to form an optionally substituted heteroaromatic group comprising at least one N, NR ² , S or O group. In certain embodiments, the heteroaromatic ring further comprises a — (CH ₂ ) _n — moiety, where n is 1, 2 or 3. In another embodiment, A and B are taken together to form an optionally substituted heteroaromatic group containing 1 N in the ring.

  In certain embodiments, as non-limiting examples, quinolin-7-ylcyclohexylcarbamate; quinolin-7-ylcyclohexylmethylcarbamate; quinolin-7-ylcycloheptylcarbamate; quinolin-7-yl (furan-2-yl) Quinolin-7-ylcyclohexylmethylcarbamate; quinolin-6-ylcyclohexylcarbamate; quinolin-6-ylcyclohexylmethylcarbamate; quinolin-6-yl (furan-2-yl) methylcarbamate; isoquinolin-7-yl Selected from cyclohexyl carbamate; isoquinolin-7-ylcyclohexylmethyl carbamate; isoquinolin-7-ylcycloheptyl carbamate; and their pharmaceutically acceptable N-oxides. That.

  In certain embodiments, the optionally substituted heteroaromatic group comprises 2 heteroatoms selected from N, S and O.

  In certain embodiments, as non-limiting examples, 2-methylbenzo [d] thiazol-5-ylcyclohexylcarbamate; 2-methylbenzo [d] thiazol-5-ylcyclohexylmethylcarbamate; 2-methylbenzo [d] oxazole- 2-methylbenzo [d] oxazol-5-ylcyclohexylmethylcarbamate; 2-methylbenzo [d] oxazol-6-ylcyclohexylcarbamate; 2-methylbenzo [d] oxazol-6-ylcyclohexylmethylcarbamate; Selected from the group of 2-methylbenzo [d] thiazol-6-ylcyclohexylmethyl carbamate and 2-methylbenzo [d] thiazol-6-ylcyclohexylmethyl carbamate.

In another embodiment, D is NR ¹¹ . In certain embodiments, as non-limiting examples, 1- (3-acetylphenyl) -3-cyclohexylurea, 1- (3-acetylphenyl) -3- (cyclohexylmethyl) urea, 1- (3-acetylphenyl) ) -3-isobutylurea, 1- (3-acetylphenyl) -3-isopropylurea, and 1- (3-acetylphenyl) -3-phenethylurea. In certain embodiments, non-limiting examples include 1-cyclohexyl-3- (2,3-dihydro-1-oxo-1H-inden-6-yl) urea, 1- (cyclohexylmethyl) -3- ( 2,3-dihydro-1-oxo-1H-inden-6-yl) urea, 1-cyclohexyl-3- (2,3-dihydro-1-oxo-1H-inden-5-yl) urea, and 1- Selected from the group of (cyclohexylmethyl) -3- (2,3-dihydro-1-oxo-1H-inden-5-yl) urea.

  In another embodiment, as non-limiting examples, 1-cyclohexyl-3- (quinolin-7-yl) urea, 1- (cyclohexylmethyl) -3- (quinolin-7-yl) urea, 1-cycloheptyl -3- (quinolin-7-yl) urea, 1-((furan-2-yl) methyl) -3- (quinolin-7-yl) urea, 1-cyclohexyl-1-methyl-3- (quinoline-7) -Yl) urea, 1-cyclohexyl-3- (quinolin-6-yl) urea, 1- (cyclohexylmethyl) -3- (quinolin-6-yl) urea, 1-((furan-2-yl) methyl) -3- (quinolin-6-yl) urea, 1-cyclohexyl-3- (isoquinolin-7-yl) urea, 1- (cyclohexylmethyl) -3- (isoquinolin-7-yl) urea, Beauty 1- cycloheptyl-3- selected from the group of (isoquinolin-7-yl) urea.

  In another embodiment, as non-limiting examples, 1- (cyclohexylmethyl) -3- (2-methylbenzo [d] thiazol-5-yl) urea, 1-cyclohexyl-3- (2-methylbenzo [d] Thiazol-5-yl) urea, 1-cyclohexyl-3- (2-methylbenzo [d] oxazol-5-yl) urea, and 1- (cyclohexylmethyl) -3- (2-methylbenzo [d] oxazole-5- Il) Selected from the group of urea.

  In another embodiment, as a non-limiting example, it is selected from any of the compounds shown in Figures 1, 2, 3, 4, 5, 6, 7 and 8.

  In some embodiments, the compound of formula (II)

［上記式において、
ＤはＯまたはＮＲ^１１であり；各ＸはＣＨまたはＮであり；
Ｒ^１は、

[In the above formula,
D is O or NR ¹¹ ; each X is CH or N;
R ¹ is

（上記式において、
Ｍは結合、場合により置換されたＣ_１−Ｃ_８アルキレン、場合により置換された４個の原子のヘテロアルキレン、場合により置換されたＣ_２−Ｃ_８アルケニレン、場合により置換されたＣ_３−Ｃ_８シクロアルキルまたは場合により置換されたＣ_２−Ｃ_８アルキニレンであり；
ＪはＣＨまたはＮであり、ＫはＣＨまたはＮであり、但し、ＫがＣＨのときは、ＪはＣＨではあり得ず；
各Ｒ^３は、Ｃ_１−Ｃ_６アルキル−（アリール）、Ｃ_１−Ｃ_６アルキル−（ヘテロアリール）、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６アルキルアミン、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、−Ｃ（Ｏ）−Ｒ^１２、アリール、ヘテロアリール、ヘテロシクロアルキル、フェニル、ピリジル、ピリダジニル、ピペラジニル、ピペリジニル、モルホリニル、フラニル、チオフェニル、チオフェニル、ジベンゾフラニル、ジベンゾチエニル、インドリル、フルオレニル、カルボゾリル、ピリミジニル、ピラジニル、トリアジニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、ナフチル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、シンノリル、イミダゾピリミジニル、チエノピリミジニル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、ピロロピリジル、フロピリジル、ジヒドロフロピリジル、チエノピリジル、ジヒドロチエノピリジル、イミダゾピリジル、ピラゾロピリジル、オキサオロピリジル、イソオキサオロピリジルまたはチアゾロピリジルから選択される場合により置換された基からなる群から独立して選択され；
各Ｒ’は独立して、Ｈ、アルキルまたは置換アルキルであり；
各Ｒ^５は独立して、Ｈ、Ｃ_１−Ｃ_３アルキルまたはハロゲンであり；
Ｒ^６はＣ_１−Ｃ_３アルキルまたはＣ_３−Ｃ_７シクロアルキルであり；
Ｒ^２およびＲ^１１はＨまたは場合により置換されたアルキルであり；
Ｒ^１２は、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_７シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、ベンジルオキシ、フラニル、フェニル、ベンジルまたはピリジルからなる群から選択される。）からなる群から選択され；
または、Ｒ^１およびＲ^２は一緒になって、

(In the above formula,
M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;
J is CH or N, K is CH or N, provided that when K is CH, J cannot be CH;
Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C _{6 alkenyl,} C 3 -C _{8 cycloalkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl , Morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, na Til, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoisoxazolyl, azoisoxazolyl Benzoisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl Independently selected from the group consisting of groups;
Each R ′ is independently H, alkyl or substituted alkyl;
Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;
R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;
R ² and R ¹¹ are H or optionally substituted alkyl;
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl. ) Selected from the group consisting of:
Or R ¹ and R ² together,

(N is 1, 2, 3, or 4; m is 1, 2, 3, or 4);
A and B together form an optionally substituted non-aromatic ring group containing a C (O) — (CH ₂ ) _q — moiety, where q is 1, 2, 3, or 4. And
Or A and B together form an optionally substituted oxo-substituted heterocycle;
Or A and B together form an optionally substituted aromatic or non-aromatic ring group containing at least one N, NR ² , S, or O group;
Or one of A or B is and the other a -L-G is selected from C ₁ -C ₆ alkyl substituted by H and optionally;
Or A and B together form an optionally substituted aromatic carbocyclic group;
Or A and B are H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally Each independently selected from a substituted ketoalkyl, an optionally substituted amide and an optionally substituted ketoheteroalkyl;
L is a bond, or _C 1 -C _{6 alkylene,} C 1 -C _{6 heteroalkylene,} C 1 -C _{6 ^{Ketoarukiren, -C (O) NR 9 -}} (CH 2) j -, - NR 9 -C (O _{) - (CH 2) j -} , - OC (O) O- (CH 2) j -, - NHC (O) O- (CH 2) j -, - O (O) CNH- (CH 2) j - _{, -C (O) O- (CH} 2) j -, - OC (O) - (CH 2) j -, - NR 9 C (O) N (R 9) - (CH 2) j -, - S _{(O) - (CH 2)} j -, - S (O) 2 - (CH 2) j -, - C (= NR 10) N (R 9) - (CH 2) j - and ^-NR 9 C ( = An optionally substituted group selected from NR ¹⁰ ) N (R ⁹ ) — (CH ₂ ) _j —;
G is tetrazolyl, —NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHR ^S , —S (═O) ₂ NH-phenyl, —OH, —SH, —OC (O) NHR ⁸ , —NHC (O) OR ⁸ , —C (O) NHC (O) R ⁸ , —C (O) NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHC (O) R ⁸ , —S (═O) ₂ NHC (O) NHR ^S , —NHC (O) R ⁸ , —NHC (O) N (R ⁹ ) ₂ , —C (═NR ¹⁰ ) N (R ⁹ ) ₂ , —NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , _{^{-C (O) NR 9 C (}} = NR 10) N (R 9) 2, -C (O) NR 9 C (= CHR 10) N (R 9) 2, -CO 2 H, - ^{_{OP (= O) OH) x}} OH, -OP (= O) OR 8 OH, -OP (= O) R 8 OH, -NR 9 P (= O) OR 8 OH, -NR 9 P (= O) in _{-NR 9 S (O) y OH} ; R 8 OH, -P (= O) OR 8 OH ;-P (= O) R 8 OH, -S (O) y OH; -OS (O) y OH Yes;
Each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ⁹ is independently H, substituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkyl;
Each R ¹⁰ is independently selected from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN, and —NO ₂ ;
j is 0, 1, 2, 3 or 4; x is 1, 2 or 3; y is 0, 1 or 2;
Each substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano, benzyloxy-C (O) R ′, —C (O)-(alkyl or substituted alkyl). ),-(Alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl),-(alkyl or Substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -NR'C (O) R'-, -SR ', -S- (alkyl or substituted alkyl),- S (O) _k R ′ (k is 1 or 2), —S (O) _k (alkyl or substituted alkyl), —C (S) — (alkyl or substituted alkyl), —CSN (R ′ ) ₂ , —CSN (R ′) — (alkyl or substituted alkyl), —N (R ′) CO— (alkyl or substituted alkyl), —N (R ′) C (O) OR ′, — (alkyl or substituted) Alkyl) -O-N = C (R ') ₂ ,-(alkyl or substituted alkyl) -C (O) NR'-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- (Alkyl or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N (R ' ) ₂ , —N (R ′) C (S) N (R ′) ₂ , —N (R ′) S (O) _k N (R ′) ₂ , -C (R ') = NR'-C (R') = NN (R ') ₂ and -C (R') ₂ -N (R ')-N (R') ₂ independent of Selected. ]
And pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates.

In certain embodiments, R ¹ is

からなる群から選択される。

Selected from the group consisting of

In certain embodiments, M is a bond, optionally C ₁ -C ₄ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₄ alkenylene, or optionally substituted C. it is a ₂ -C ₄ alkynylene.

  In another embodiment, J is CH or N; K is CH or N; provided that when K is CH, J cannot be CH.

In another embodiment, R ³ is optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, —C (O) —R ¹² , phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, Morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthylhydroquinolyl Ril, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyrimimi Nyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, Selected from the group consisting of oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl, these groups being C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano, or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted alkyl), — (alkyl or substituted alkyl) —C (O) R ′, —C (O) N (R ′) ₂ , —C (O ) N (R ′)-(alkyl or substituted alkyl) , - (alkyl or substituted alkyl) -C (O) N (R ') 2, -OC (O) N (R') 2, -OC (O) N (R ') - ( alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) - NR'C (O) R ' , - SR', - S- ( alkyl or substituted _{alkyl), - S (O) k} R '(k is 1, or 2),. - S (O) _k (alkyl or substituted alkyl), —C (S) — (alkyl or substituted alkyl), —CSN (R ′) ₂ , —CSN (R ′) — (alkyl or substituted alkyl), —N ( R ′) CO— (alkyl or substituted alkyl), —N (R ′) C (O) OR ′, — (alkyl or Conversion alkyl) -O-N = C (R ') 2, - ( alkyl or substituted alkyl) -C (O) NR' - (alkyl or substituted alkyl), - (alkyl or substituted alkyl) -S _{(O) k} -(Alkyl or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N (R ') ₂ , -N (R') C (S) N (R ') ₂ , -N (R') S (O) _k N (R ') ₂ , -C (R') = NR'-C (R ′) = N—N (R ′) ₂ and —C (R ′) ₂ —N (R ′) — N (R ′) ₂ optionally substituted with one or more groups from ₂ . In another embodiment, each R ′ is independently H, alkyl, or substituted alkyl. In certain embodiments, each R ⁵ is independently H, C1-C3 alkyl, or halogen. In another embodiment, R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl. In certain embodiments, R ² and R ¹¹ are H or optionally substituted alkyl. In another embodiment, R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl. In some embodiments, n is 1, 2, 3 or 4. In another embodiment, m is 1, 2, 3 or 4. In another embodiment, A and B are taken together and comprise a C (O) — (CH ₂ ) _q — moiety, where q is 1, 2, 3, or 4; An aromatic ring group is formed. In another embodiment, A and B are taken together to form an optionally substituted aromatic or non-aromatic ring group comprising at least one N, NR ² , S or O group. In certain embodiments, one of A or B is —LG, and the other is selected from H and optionally substituted C ₁ -C ₆ alkyl. In another embodiment, A and B are taken together to form an optionally substituted aromatic carbocyclic group. In certain embodiments, A and B are H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted hetero Each is independently selected from an aryl group, an optionally substituted ketoalkyl, and an optionally substituted ketoheteroalkyl. In certain embodiments, L is a bond, or C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₁ -C ₆ ketoalkylene, —C (O) NR ⁹ — (CH ₂ ) _j —, —NR. _{^{9 -C (O) - (CH}} 2) j -, - OC (O) O- (CH 2) j -, - NHC (O) O- (CH 2) j -, - O (O) CNH- ( _{CH 2) j -, - C} (O) O- (CH 2) j -, - OC (O) - (CH 2) j -, - NR 9 C (O) N (R 9) - (CH 2) _{j -, - S (O)} - (CH 2) j -, - S (O) 2 - (CH 2) j -, - C (= NR 10) N (R 9) - (CH 2) j - and An optionally substituted group selected from —NR ⁹ C (═NR ¹⁰ ) N (R ⁹ ) — (CH ₂ ) _j —. In another embodiment, G is tetrazolyl, —NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHR ⁸ , —S (═O) ₂ NH-phenyl, —OH, —SH, —OC. (O) NHR ⁸ , —NHC (O) OR ⁸ , —C (O) NHC (O) R ⁸ , —C (O) NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHC (O _{^{) R 8, -S (= O}} ) 2 NHC (O) NHR 8, -NHC (O) R 8, -NHC (O) N (R 9) 2, -C (= NR 10) N (R 9) ₂ , -NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N _{^{(R 9) 2, -C (}} O) NR 9 C (= NR 10) N (R 9) 2, -C (O) NR 9 C (= CHR 10) N (R 9 _{2, -CO 2 H, - (} OP (= O) OH) x OH, -OP (= O) OR 8 OH, -OP (= O) R 8 OH, -NR 9 P (= O) OR 8 OH ^{, -NR 9 P (= O)} R 8 OH, -P (= O) OR 8 OH ;-P (= O) R 8 OH, -S (O) y OH; -OS (O) y OH; - NR ⁹ S (O) _y OH. In certain embodiments, each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, each R ⁹ is independently H, substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, each R ¹⁰ is independently from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN and —NO _2. Selected. In another embodiment, j is 0, 1, 2, 3 or 4. In further embodiments, x is 1, 2 or 3. In yet another embodiment, y is 0, 1 or 2. In further embodiments, with a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate. is there.

In certain embodiments, A and B _{^{together, -C (O) - (CR}} q R q) n -, - C (O) -NR 2 - (CR q R q) n -, - NR _{^{2 -C (O) - (CR}} q R q) n -, - C (O) -NR 2 -NR 2 - (CR q R q) n -, - C (O) -NR 2 -N = (CR ^{q) -, - OC (O} ) -O-, OC (O) -NR 2, -NR 2 -C (O) -NR 2, -O-C (O) -O- (CR q R q ^{_{) n -, - O-C}} (O) - (CR q R q) n -O -, - n-C (O) - (CR q R q) n -N -, - O-C (O) - ^{_{(CR q R q) n -N}} -, - n-C (O) - (CR q R q) n -O -, - O-C (O) -NR 2 - (CR q R q) n -, ^{-NR 2 -C (O) -O- (} CR q R q) n -, - ^{NR 2 -C (O) -NR 2} - (CR q R q) n -, - (CR q R q) n -C (O) -O- (CR q R q) n -, - (CR q R ^{_{q) n -C (O) -NR}} 2 - (CR q R q) n -, - (CR q R q) n -C (O) -NR 2 -NR 2 -, - (CR q R q) n _{^{-C (O) - (CR q}} R q) n -, - C (O) -O- (CR q R q) n -O -, - C (O) -O- (CR q R q) n - ^{NR 2 -, - C (O} ) -NR 2 - (CR q R q) n -NR 2, -C (O) -NR 2 - (CR q R q) n -O -, - C (O) - ^{NR 2 -CR q = CR q -} , C (O) -CR q = CR q -NR 2 -, - C (O) -CR q = CR q -O -, - C (O) -CR q = CR If it is selected from ^q -S- Substituted oxo - the (each n to form a substituted heterocyclic be independently 1, 2 or 3; and wherein each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted Independently selected from ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle or substituted heterocycle).

  In certain embodiments, the compound of formula (III)

［上記式において、
ＤはＯまたはＮＲ^１１であり；各ＸはＣＨまたはＮであり；
Ｒ^１は、

[In the above formula,
D is O or NR ¹¹ ; each X is CH or N;
R ¹ is

（上記式において、
Ｍは、結合、場合により置換されたＣ_１−Ｃ_８アルキレン、場合により置換された４個の原子のヘテロアルキレン、場合により置換されたＣ_２−Ｃ_８アルケニレン、場合により置換されたＣ_３−Ｃ_８シクロアルキルまたは場合により置換されたＣ_２−Ｃ_８アルキニレンであり；
ＪはＣＨまたはＮであり、ＫはＣＨまたはＮであり、但し、ＫがＣＨのときは、ＪはＣＨではあり得ず；
各Ｒ^３は、Ｃ_１−Ｃ_６アルキル−（アリール）、Ｃ_１−Ｃ_６アルキル−（ヘテロアリール）、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６アルキルアミン、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、
Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、−Ｃ（Ｏ）−Ｒ^１２、アリール、ヘテロアリール、ヘテロシクロアルキル、フェニル、ピリジル、ピリダジニル、ピペラジニル、ピペリジニル、モルホリニル、フラニル、チオフェニル、チオフェンイル、ジベンゾフラニル、ジベンゾチエニル、インドリル、フルオレニル、カルボゾリル、ピリミジニル、ピラジニル、トリアジニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、ナフチル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、シンノリル、イミダゾピリミジニル、チエノピリミジニル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、ピロロピリジル、フロピリジル、ジヒドロフロピリジル、チエノピリジル、ジヒドロチエノピリジル、イミダゾピリジル、ピラゾロピリジル、オキサオロピリジル、イソオキサオロピリジルまたはチアゾロピリジルから選択される場合により置換された基からなる群から独立して選択され；
各Ｒ’は独立してＨ、アルキルまたは置換アルキルであり；
各Ｒ^５は独立してＨ、Ｃ_１−Ｃ_３アルキルまたはハロゲンであり；
Ｒ^６はＣ_１−Ｃ_３アルキルまたはＣ_３−Ｃ_７シクロアルキルであり；
Ｒ^２およびＲ^１１はＨまたは場合により置換されたアルキルであり；
Ｒ^１２は、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_７シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、ベンジルオキシ、フラニル、フェニル、ベンジルまたはピリジルからなる群から選択される。）からなる群から選択され；
または、Ｒ^１およびＲ^２は、一緒になって、

(In the above formula,
M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C _3- C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;
J is CH or N, K is CH or N, provided that when K is CH, J cannot be CH;
Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl,
C ₃ -C _{8 cycloalkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, Thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, isoquinolyl Quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyr Dinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, Independently selected from the group consisting of optionally substituted groups selected from oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl;
Each R ′ is independently H, alkyl or substituted alkyl;
Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;
R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;
R ² and R ¹¹ are H or optionally substituted alkyl;
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl. ) Selected from the group consisting of:
Or R ¹ and R ² are taken together

(N is 1, 2, 3 or 4; m is 1, 2, 3 or 4);
Each substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano, benzyloxy-C (O) R ′, —C (O)-(alkyl or substituted alkyl). ),-(Alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl),-(alkyl or Substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ′ (k is 1 or 2), —S (O) _k (alkyl or substituted alkyl), —C (S) — (alkyl or substituted alkyl), —CSN (R ′) ₂ , -CSN (R ')-(alkyl or substituted alkyl), -N (R') CO- (alkyl or substituted alkyl), -N (R ') C (O) OR',-(alkyl or substituted alkyl) ) -O-N = C (R ') ₂ ,-(alkyl or substituted alkyl) -C (O) NR'-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- ( Alkyl or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N (R ') _{2, -N (R ') C} (S) N (R') 2, -N (R ') S (O) k N (R') , -C (R ') = NR' -C (R') = N-N (R ') 2 , and _{-C (R') 2 -N (} R ') - N (R') 2 independently from Selected. ]
And pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates.

  In another embodiment, the structure

［上記式において、Ｒ^１は、

[In the above formula, R ¹ is

（式中、Ｍは結合、場合により置換されたＣ_１−Ｃ_８アルキレン、場合により置換された４個の原子のヘテロアルキレン、場合により置換されたＣ_２−Ｃ_８アルケニレン、場合により置換されたＣ_３−Ｃ_８シクロアルキルまたは場合により置換されたＣ_２−Ｃ_８アルキニレンであり；
ＪはＣＨまたはＮであり；ＫはＣＨまたはＮであり；但し、ＫがＣＨのときは、ＪはＣＨではあり得ず；
各Ｒ^３は、Ｃ_１−Ｃ_６アルキル−（アリール）、Ｃ_１−Ｃ_６アルキル−（ヘテロアリール）、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６アルキルアミン、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、
Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、−Ｃ（Ｏ）−Ｒ^１２、アリール、ヘテロアリール、ヘテロシクロアルキル、フェニル、ピリジル、ピリダジニル、ピペラジニル、ピペリジニル、モルホリニル、フラニル、チオフェニル、チオフェンイル、ジベンゾフラニル、ジベンゾチエニル、インドリル、フルオレニル、カルボゾリル、ピリミジニル、ピラジニル、トリアジニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、ナフチル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、シンノリル、イミダゾピリミジニル、チエノピリミジニル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、ピロロピリジル、フロピリジル、ジヒドロフロピリジル、チエノピリジル、ジヒドロチエノピリジル、イミダゾピリジル、ピラゾロピリジル、オキサオロピリジル、イソオキサオロピリジルまたはチアゾロピリジルから選択される場合により置換された基からなる群から独立して選択され；
各Ｒ’はＨ、アルキルまたは置換アルキルであり；
各Ｒ^５はＨ、Ｃ_１−Ｃ_３アルキルまたはハロゲンであり；
Ｒ^６はＣ_１−Ｃ_３アルキルまたはＣ_３−Ｃ_７シクロアルキルであり；
Ｒ^２およびＲ^１１はＨまたは場合により置換されたアルキルであり；
Ｒ^１２は、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_７シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、ベンジルオキシ、フラニル、フェニル、ベンジル、またはピリジルからなる群から選択される。）からなる群から選択され；
または、Ｒ^１およびＲ^２は一緒になって、

Wherein M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted. C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;
J is CH or N; K is CH or N; provided that when K is CH, J cannot be CH;
Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl,
C ₃ -C _{8 cycloalkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, Thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, isoquinolyl Quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyr Dinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, Independently selected from the group consisting of optionally substituted groups selected from oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl;
Each R ′ is H, alkyl or substituted alkyl;
Each R ⁵ is H, C ₁ -C ₃ alkyl or halogen;
R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;
R ² and R ¹¹ are H or optionally substituted alkyl;
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl, or pyridyl. ) Selected from the group consisting of:
Or R ¹ and R ² together,

(N is 1, 2, 3 or 4; m is 1, 2, 3 or 4);
Each substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano, or benzyloxy-C (O) R ′, —C (O)-(alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-( Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) ) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl) , -S (O) _k R '(k is 1 or 2), -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN ( R ′) ₂ , —CSN (R ′) — (alkyl or substituted alkyl), —N (R ′) CO— (alkyl or substituted alkyl), —N (R ′) C (O) OR ′, — (alkyl Or substituted alkyl) -O-N = C (R ') ₂ ,-(alkyl or substituted alkyl) -C (O) NR'-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- (alkyl or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N ( _{R ') 2, -N (R} ') C (S) N (R ') 2, -N (R') S (O) k N ( _{') 2, -C (R'} ) = NR'-C (R ') = N-N (R') 2 , and _{-C (R ') 2 -N (} R') - N (R ') ₂ Independently selected. ]
And a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate .

The compounds provided herein include any of the carbamates and ureas described above, wherein at least one of the groups covalently bonded to the “N” portion of the carbamate, or one of the two “N” portions of the urea is , (CH ₂ ) _z (C ₃ -C ₈ cycloalkyl) group, (CH ₂ ) _z (C ₃ -C ₈ heterocycloalkyl) group or (CH ₂ ) _z (C ₇ -C ₁₂ polycycloalkyl) group (Z is 0 or 1, and at least one of the carbon atoms in the cycloalkyl ring or optionally one of the carbon atoms in the polycycloalkyl ring is mono- or di-substituted, and each substituent is methyl, halogen, are independently selected from the group consisting of trifluoromethyl, or C ₃ -C ₆ cycloalkyl, or one in the cycloalkyl ring Are substituted with an oxo group, or one carbon atom in the cycloalkyl ring is disubstituted to form a 3-, 4-, or 5-membered carbocyclic group, or , Two adjacent atoms in the cycloalkyl ring are each substituted with a group forming a 3-membered, 4-membered, 5-membered or 6-membered carbocyclic group, or covalently bonded to the “N” portion of the carbamate Or at least one of the two “N” moieties of the urea is optionally substituted (CH ₂ ) _z (bridged carbocyclic group) (z is 0 or 1). And any of the substituents is a methyl group, a halogen group or a trifluoromethyl group.

  The compounds provided herein include any of the carbamates and ureas described above, wherein at least one of the groups covalently bonded to the “N” portion of the carbamate or one of the two “N” portions of the urea. Is

ネオペンチル、ネオヘキシル、メチレンシクロプロピル、メチレンシクロブチル、およびメチレンシクロペンチルからなる群から選択され；各Ｐは独立してハロゲン、メチル、トリフルオロメチルであり；または各Ｐは、一緒になって３員、４員または５員の炭素環基を形成することができ；各Ｑは独立してＨ、ハロゲン、メチル、トリフルオロメチル、であり、または各Ｑは、一緒になって３員、４員または５員の炭素環基を形成し；およびＴは、Ｏ、Ｎ−（Ｃ_１−Ｃ_６アルキル）またはＳＯ_２である。

Selected from the group consisting of neopentyl, neohexyl, methylenecyclopropyl, methylenecyclobutyl, and methylenecyclopentyl; each P is independently halogen, methyl, trifluoromethyl; or each P is taken together as a 3-membered, 4 or 5 membered carbocyclic groups can be formed; each Q is independently H, halogen, methyl, trifluoromethyl, or each Q taken together is a 3 member, 4 member or Forms a 5-membered carbocyclic group; and T is O, N- (C ₁ -C ₆ alkyl) or SO ₂ .

  The compounds provided herein include compounds having the structure of formula (I) and pharmaceutically acceptable salts, N-oxides, solvates, SLs, acids and prodrugs thereof. In certain embodiments, isomers and chemically protected forms of compounds having the structure represented by formula (I) are also provided.

In another embodiment, R ¹ is

ネオペンチル、ネオヘキシル、メチレンシクロプロピル、メチレンシクロブチル、およびメチレンシクロペンチルからなる群から選択され；各Ｐは独立してハロゲン、メチル、トリフルオロメチルであり；または各Ｐは、一緒になって３員、４員または５員の炭素環基を形成することができ；各Ｑは独立してＨ、ハロゲン、メチル、トリフルオロメチルであり、または各Ｑは、一緒になって３員、４員または５員の炭素環基を形成することができ；Ｔは、Ｏ、Ｎ−（Ｃ_１−Ｃ_６アルキル）またはＳＯ_２である、式（Ｉ）を有する化合物である。

Selected from the group consisting of neopentyl, neohexyl, methylenecyclopropyl, methylenecyclobutyl, and methylenecyclopentyl; each P is independently halogen, methyl, trifluoromethyl; or each P is taken together as a 3-membered, 4 or 5 membered carbocyclic groups can be formed; each Q is independently H, halogen, methyl, trifluoromethyl, or each Q taken together is a 3 member, 4 member or 5 member. A compound having the formula (I), which can form a membered carbocyclic group; T is O, N— (C ₁ -C ₆ alkyl) or SO ₂ .

In another embodiment, R ₁ is a (CH ₂ ) _z (C ₃ -C ₈ cycloalkyl) group (z is 0 or 1 and at least one carbon atom in the cycloalkyl ring is mono Substituted or disubstituted and each substituent is independently selected from the group consisting of methyl, halogen, trifluoromethyl or C ₃ -C ₆ cycloalkyl; or one of the cycloalkyl rings The carbon atom is substituted with an oxo group; or one carbon atom in the cycloalkyl ring is disubstituted to form a 3-, 4- or 5-membered carbocyclic group; or a cycloalkyl Two adjacent atoms in the ring are each substituted with a group forming a 3-, 4-, 5- or 6-membered carbocyclic group. In another embodiment, R ¹ is optionally substituted (CH ₂ ) _z (bridged carbocyclic group) (z is 0 or 1) (all substituents are methyl, halogen or tri A fluoromethyl group).

In certain embodiments, the FAAH inhibitor is a compound of formula (1) disclosed in US Provisional Patent Application No. 60 / 755,035, filed December 29, 2005, which is hereby incorporated by reference. , Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), Formula (9), Formula (10), Formula (11) , Formula (12), Formula (13), Formula (14), Formula (15), Formula (16), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21) , Formula (22), Formula (23), Formula (24), Formula (25), Formula (26), Formula (27), Formula (28) or Formula (29), and a medicament Pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates It is. However, R ¹ group has the following structure

［Ｍは、結合、場合によりＣ_１−Ｃ_４アルキレン、場合により置換された４個の原子のヘテロアルキレン、場合により置換されたＣ_２−Ｃ_４アルケニレン（または場合により置換されたＣ_２−Ｃ_４アルキニレンであり；ＪはＣＨまたはＮであり；ＫはＣＨまたはＮであり（但し、ＫがＣＨのときは、ＪはＣＨではあり得ない。）；Ｒ^３は、場合により置換されたＣ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ヘテロアルキル、−Ｃ（Ｏ）−Ｒ^１２、フェニル、ピリジル、ピリダジニル、ピペラジニル、ピペリジニル、モルホリニル、フラニル、チオフェニル、チオフェンイル、ジベンゾフラニル、ジベンゾチエニル、インドリル、フルオレニル、カルボゾリル、ピリミジニル、ピラジニル、トリアジニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、ナフチル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、シンノリル、イミダゾピリミジニル、チエノピリミジニル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、ピロロピリジル、フロピリジル、ジヒドロフロピリジル、チエノピリジル、ジヒドロチエノピリジル、イミダゾピリジル、ピラゾロピリジル、オキサオロピリジル、イソオキサオロピリジルまたはチアゾロピリジルからなる群から選択され、これらの基は、Ｃ_１−Ｃ_３アルキル、Ｃ_１−Ｃ_３アルコキシ、ベンジル、ハロゲン、ニトロ、シアノ、ベンジルオキシ−Ｃ（Ｏ）Ｒ’、−Ｃ（Ｏ）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−Ｃ（Ｏ）Ｒ’、−Ｃ（Ｏ）Ｎ（Ｒ’）_２、−Ｃ（Ｏ）Ｎ（Ｒ’）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−Ｃ（Ｏ）Ｎ（Ｒ’）_２、−ＯＣ（Ｏ）Ｎ（Ｒ’）_２、−ＯＣ（Ｏ）Ｎ（Ｒ’）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−ＯＣ（Ｏ）Ｎ（Ｒ’）_２、−Ｎ（Ｒ’）Ｃ（Ｏ）Ｒ’、−ＮＲ’Ｃ（Ｏ）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−ＮＲ’Ｃ（Ｏ）Ｒ’、−ＳＲ’、−Ｓ−（アルキルまたは置換アルキル）、−Ｓ（Ｏ）_ｋＲ’（ｋは１、または２）、−Ｓ（Ｏ）_ｋ（アルキルまたは置換アルキル）、−Ｃ（Ｓ）−（アルキルまたは置換アルキル）、−ＣＳＮ（Ｒ’）_２、−ＣＳＮ（Ｒ’）−（アルキルまたは置換アルキル）、−Ｎ（Ｒ’）ＣＯ−（アルキルまたは置換アルキル）、−Ｎ（Ｒ’）Ｃ（Ｏ）ＯＲ’、−（アルキルまたは置換アルキル）−Ｏ−Ｎ＝Ｃ（Ｒ’）_２、−（アルキルまたは置換アルキル）−Ｃ（Ｏ）ＮＲ’−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−Ｓ（Ｏ）_ｋ−（アルキルまたは置換アルキル）−ＳＲ’、−（アルキルまたは置換アルキル）−Ｓ−ＳＲ’、−Ｓ（Ｏ）_ｋＮ（Ｒ’）_２、−Ｎ（Ｒ’）Ｃ（Ｏ）Ｎ（Ｒ’）_２、−Ｎ（Ｒ’）Ｃ（Ｓ）Ｎ（Ｒ’）_２、−Ｎ（Ｒ’）Ｓ（Ｏ）_ｋＮ（Ｒ’）_２、−Ｃ（Ｒ’）＝ＮＲ’−Ｃ（Ｒ’）＝Ｎ−Ｎ（Ｒ’）_２、および−Ｃ（Ｒ’）_２−Ｎ（Ｒ’）−Ｎ（Ｒ’）_２からの１個もしくはそれ以上の基で場合により置換されており；各Ｒ’は独立してＨ、アルキル、または置換アルキルであり；各Ｒ^５は独立してＨ、Ｃ_１−Ｃ_３アルキルまたはハロゲンであり；Ｒ^６はＣ_１−Ｃ_３アルキルまたはＣ_３−Ｃ_７シクロアルキルであり；Ｒ^１２はＣ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_７シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、ベンジルオキシ、フラニル、フェニル、ベンジルまたはピリジルからなる群から選択され；ｎは１、２，３または４であり；ｍは１、２、３または４である。］を有し；
または、Ｒ^１およびＲ^２は一緒になって、

[M is a bond, optionally C ₁ -C ₄ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₄ alkenylene (or optionally substituted C ₂ -C _{4 is} alkynylene; J is CH or N; K is CH or N (provided that when K is CH, J cannot be CH); R ³ is optionally substituted C ₁ -C _{6 alkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophen-yl, dibenzofuranyl, dibenzothienyl, indolyl Fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, Azolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazolpyrimidinyl, thienopyrimidinyl, thienopyrimidinyl Benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, oxaolopyridyl, isoxaolopyridyl or Selected from the group consisting of thiazolopyridyl, these groups are ₁ -C _{3 alkyl,} C 1 -C ₃ alkoxy, benzyl, halogen, nitro, cyano, benzyloxy -C (O) R ', - C (O) - ( alkyl or substituted alkyl), - (alkyl or substituted alkyl ) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -C (O ) N (R ′) ₂ , —OC (O) N (R ′) ₂ , —OC (O) N (R ′) — (alkyl or substituted alkyl), — (alkyl or substituted alkyl) —OC (O) N (R ′) ₂ , —N (R ′) C (O) R ′, —NR′C (O) — (alkyl or substituted alkyl), — (alkyl or substituted alkyl) —NR′C (O) R ', -SR', - S- (alkyl or substituted _{alkyl), - S (O) k} R '(k is 1 Or _{2), - S (O)} k ( alkyl or substituted alkyl), - C (S) - ( alkyl or substituted _{alkyl), - CSN (R ')} 2, -CSN (R') - ( alkyl or substituted alkyl ), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -O-N = C (R') ₂ ,- (Alkyl or substituted alkyl) -C (O) NR '-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- (alkyl or substituted alkyl) -SR',-(alkyl or substituted Alkyl) -S-SR ', -S (O) _kN (R') ₂ , -N (R ') C (O) N (R') ₂ , -N (R ') C (S) N ( R ′) ₂ , —N (R ′) S (O) _k N (R ′) ₂ , —C (R ′) = NR′—C (R ′ ) = N—N (R ′) ₂ , and optionally substituted with one or more groups from —C (R ′) ₂ —N (R ′) — N (R ′) ₂ ; R ′ is independently H, alkyl, or substituted alkyl; each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen; R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ ^{cycloalkyl; R 12} is selected _C 1 -C _{6 alkyl,} C 3 -C _{7 cycloalkyl,} C 1 -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, the group consisting of benzyl or pyridyl; n Is 1, 2, 3 or 4; m is 1, 2, 3 or 4. ];
Or R ¹ and R ² together,

（ｎは１、２，３または４であり；ｍは１、２，３または４である。）を形成する。

(N is 1, 2, 3 or 4; m is 1, 2, 3 or 4).

  Combinations of any of the groups set forth above with respect to various variables are contemplated herein. The substituents and substitution patterns of the compounds provided herein can be selected by those skilled in the art and, like the compounds described herein, are chemically stable and synthesized by techniques known in the art. It is understood that compounds that can be provided can be provided.

  In another embodiment, a compound of any compound of formula (I), (II), (III) or (IIIa) (including any of the named compounds or any of the illustrated compounds), pharmaceuticals. Pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates and pharmaceutically acceptable A pharmaceutical composition comprising a diluent, excipient or binder.

  In certain embodiments, a compound of any compound of formula (I), (II), (III) or (IIIa) (including any of the named compounds or any of the illustrated compounds), pharmaceuticals. A therapeutically effective amount of a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate. A method of inhibiting fatty acid amide hydrolase comprising administering to a patient or a method of treating a disease, disorder or condition that would benefit from inhibition of fatty acid amide hydrolase activity in a patient.

  In another embodiment, a compound of any compound of formula (I), (II), (III) or (IIIa) (including any of the named compounds or any of the illustrated compounds), pharmaceuticals. A therapeutically effective amount of a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate A method of inhibiting fatty acid amide hydrolase, or a method of treating a disease, disorder, or symptom by administering to a patient, the disease, disorder or symptom being acute or chronic pain, eating disorder, heart disease, metabolic Disease, disorder or symptom, renal ischemia, cancer, immune system disorder, allergic disease, metabolic disease, disorder or symptom, renal ischemia, cancer, immune system disorder, allergic disease, parasitic, viral or Fungal infections, inflammatory diseases, osteoporosis, eye diseases, pulmonary diseases, selected from gastrointestinal diseases and urinary incontinence.

  In certain embodiments, formula (I), (II) for inhibiting the activity of fatty acid amide hydrolase activity or treating a disease, disorder or condition that would benefit from inhibition of fatty acid amide hydrolase activity. ), (III) or (IIIa) (including any of the named compounds or any of the illustrated compounds). In other embodiments, a compound of any of formulas (I), (II), (III), or (IIIa) for the formulation of a medicament to inhibit fatty acid amide hydrolase (named any Or any of the illustrated compounds). In another embodiment, the packaging material, a compound of any formula (I), (II), (III) or (IIIa) (nomenclature) that is effective in inhibiting fatty acid amide hydrolase activity in the packaging material And any of the compounds shown)), and the compound or composition, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically A product comprising an active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvate, indicating that the fatty acid amide hydrolase (FAAH) activity is used for inhibition.

  In a further aspect, the structure

（上記式において、Ｒ^１およびＲ^２は、式（Ｉ）または（ＩＩ）のいずれかにおける指定を有し、Ｙ^１はＯまたはＳであり、およびＨＯ−ＴＡは、治療剤および治療剤のヒドロキシル基誘導体である。）を有する治療薬放出剤である。式（ＸＸ）の化合物は、酸アミド加水分解酵素（例えばＦＡＡＨなど）と相互作用してＨＯ−ＴＡを放出することができる。したがって、例示だけではあるが、式（ＸＸ）の化合物は、患者に投与されるとＦＡＡＨと相互作用してＨＯ−ＴＡを放出する。次に、このＨＯ−ＴＡは、患者にさらなる治療的恩恵をもたらすことができる。

(Wherein R ¹ and R ² have the designations in either formula (I) or (II), Y ¹ is O or S, and HO-TA is the therapeutic agent and therapeutic agent A therapeutic agent release agent having a hydroxyl group derivative). The compound of formula (XX) can interact with an acid amide hydrolase (eg, FAAH) to release HO-TA. Thus, by way of example only, a compound of formula (XX) interacts with FAAH and releases HO-TA when administered to a patient. This HO-TA can then provide additional therapeutic benefits to the patient.

  To give just an example, HO-TA is

であり得、これは抗高血圧剤である。

This is an antihypertensive agent.

  In another example, HO-TA is

であり得、これはセロトニンであり、うつ病を治療するために使用されてきた補充剤である。

This is serotonin, a supplement that has been used to treat depression.

  In another example, HO-TA is

であり得、これはフェニレフリンであり、充血除去剤である。

Which is phenylephrine and a decongestant.

  In another example, HO-TA is

であり得、これはチロシンであり、アミノ酸および栄養補助食品である。

This is tyrosine, an amino acid and a dietary supplement.

  As a further example, HO-TA is a NSAID containing hydroxy selected from salicylic acid, salicylamide, salsalate, diflunisal, gentisic acid, piroxicam and meloxicam; acetylsalicylic acid, salicylic acid, salicylamide, salsalate, diflunisal, gentisic acid, indomethacin , Sulindac, tolmetine, diclofenac, etodolac, nabumetone, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, suprofen, carprofen, naproxen, ketorolac, oxaprozin, mefenamic acid, sodium meclofenamic acid, piroxicam, meloxicam, ducoxib 697 Rofecoxib, valdecoxib, nimesulide, ns-398, parecoxib and Metabolites of NSAID selected from etoricoxib; or acetaminophen.

  In another example, the HO-TA is a dietary supplement such as tyrosol, oleocanthal, p-coumaric acid, resveratrol or 7-hydroxycoumarin.

  In another example, HO-TA is an agent (or hydroxy analog of a drug) such as cisapride and metoclopramide for treating gastrointestinal disorders; an anti-obesity agent (or hydroxy analog of an anti-obesity agent) such as mazindol A compound (or a hydroxy analog of the compound) such as a β-blocker for controlling blood pressure; or a drug (or a hydroxy analog of the drug) such as a compound of the glitazone family for the treatment of type II diabetes.

  For example, some HO-TAs (hereinafter “released therapeutic agents”) may have known anti-inflammatory or analgesic effects. Some released therapeutic agents can have a therapeutic effect on metabolic disorders. Administration of the compound of formula (XX) can have an additive or synergistic effect. Furthermore, the activity of the released therapeutic agent may counteract or modulate the potentially unwanted effects of FAAH inhibitors. In one example, the cholesterol-lowering effect of a statin (or statin-like) release therapeutic can reduce or prevent the transient cholesterol-boosting effect of a FAAH inhibitor under certain conditions or in certain individuals. Further advantages of compounds of formula (XX) include better delivery of the released drug to plasma or target tissue and include biochemical components or supplements of pharmaceuticals, diagnostics and food (nutrients, dietary supplements, Including nutritional supplements, etc.).

  In a further aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising at least one or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolism of any compound herein. A therapeutically effective amount of a product, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate. In certain embodiments, the compositions provided herein further comprise a pharmaceutically acceptable diluent, excipient and / or binder.

  Provided herein is a pharmaceutical composition formulated for administration by an appropriate route or means, the pharmaceutical composition comprising an effective concentration of one or more of the compounds provided herein or a pharmaceutically effective derivative thereof. (This delivers an amount effective to treat, prevent or ameliorate one or more symptoms of a disease, disorder or condition that is modulated or otherwise affected by, or implicated by, FAAH activity. Contain). This effective amount and effective concentration is effective to ameliorate any of the signs of any of the diseases, disorders or symptoms disclosed herein.

  In certain embodiments, provided herein is a pharmaceutical composition comprising i) a physiologically acceptable carrier, diluent and / or excipient, and ii) one or more compounds provided herein. The

  In one aspect, provided herein is a method of treating a patient by administering a compound provided herein. In certain embodiments, at least one of the compounds herein for treating a disease, disorder, or condition that would benefit from inhibiting fatty acid amide hydrolase activity or inhibiting fatty acid amide hydrolase activity in a patient, in certain embodiments. Or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate A method is provided that comprises administering an effective amount to a patient.

  In certain embodiments, the compounds and compositions provided herein are effective for treating, preventing or ameliorating one or more signs of a disease, disorder or condition, and such diseases, disorders or symptoms are , Acute or chronic pain, eating disorders, heart diseases, metabolic diseases, disorders or symptoms, renal ischemia, cancer, immune system disorders, allergic diseases, parasitic, viral or bacterial infections, inflammatory diseases Selected from osteoporosis, ocular symptoms, pulmonary symptoms, gastrointestinal diseases, and urinary incontinence.

  In other embodiments, the compounds provided herein are pain, nociceptive pain, neuropathic pain, inflammatory pain, non-inflammatory pain, painful hemorrhagic cystitis, herpes virus-related pain, diabetes-related Pain, peripheral neuropathic pain, central pain, blocking pain, chronic nociceptive pain, nociceptor stimulation, phantom limb pain and transient acute pain, Parkinson's disease, muscle spasticity, epilepsy, obesity, Hyperlipidemia, insulin resistance syndrome, fatty liver disease, obesity, atherosclerosis, arteriosclerosis, metabolic disorders, feeding and fasting, appetite change, hypertension, septic shock, cardiogenic shock, intestinal Inflammation and exercise, irritable bowel syndrome, colitis, diarrhea, ileitis, ischemia, cerebral ischemia, liver ischemia, myocardial infarction, arthritis, rheumatoid arthritis, spondylitis, shoulder tendonitis or bursitis, gouty arthritis , Aloymy one or more signs of a disease, disorder or condition selected from lgia rheumatism, thyroiditis, hepatitis, inflammatory bowel disease, asthma, multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis and heart disease It is effective for treating, preventing or ameliorating.

  Certain compounds provided herein are irreversible inhibitors of fatty acid amide hydrolase (FAAH). Other compounds described herein are reversible inhibitors of FAAH. The compounds provided herein increase the level of endogenous fatty acid amides. The compounds provided herein increase the level of endogenous fatty acid amides selected from AEA, OEA and PEA.

  Fatty acid amide hydrolase (FAAH) is present in the body. In some cases, it is desirable to limit FAAH inhibitors to peripheral tissues to minimize or eliminate any psychotropic effects. In certain embodiments, the compounds provided herein preferentially inhibit FAAH activity in peripheral tissues and fluids and minimize potentially unwanted central nervous system side effects.

  In certain embodiments, a compound provided herein is administered to a human.

  In certain embodiments, the compounds provided herein are administered orally.

  In certain embodiments, the compounds provided herein are used to inhibit fatty acid amide hydrolase (FAAH) activity. In certain embodiments, the compounds provided herein are used to inhibit the activity of fatty acid amide hydrolase activity or to treat a disease or condition that would benefit from inhibition of fatty acid amide hydrolase activity. .

  In other embodiments, the compounds provided herein are used for the formulation of a medicament for inhibiting fatty acid amide hydrolase (FAAH).

  In certain embodiments, the compounds and compositions provided herein include acute or chronic pain, dizziness, vomiting, nausea, eating disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, Epilepsy, sleep disorder, heart disease, renal ischemia, cancer, immune system disorder, allergic disease, parasitic, viral or bacterial infection, inflammatory disease, osteoporosis, ocular symptoms, lung symptoms, gastrointestinal diseases and urine Effective to treat, prevent, or ameliorate one or more signs of a disease, disorder or condition selected from incontinence.

  In certain embodiments, the compounds and compositions provided herein are pain, nociceptive pain, neuropathic pain, inflammatory pain, non-inflammatory pain, painful hemorrhagic cystitis, herpes virus-related pain, Diabetes-related pain, peripheral neuropathic pain, central pain, blocking pain, chronic nociceptive pain, nociceptor stimulation, phantom limb pain and transient acute pain, depression, anxiety, generality Anxiety disorder (GAD), obsessive-compulsive disorder, stress, stress urinary incontinence, attention deficit hyperactivity disorder, schizophrenia, psychosis, Parkinson's disease, muscle spasticity, epilepsy, obesity, hyperlipidemia, insulin resistance syndrome, Fatty liver disease, obesity, atherosclerosis, arteriosclerosis, metabolic disorders, feeding and fasting, appetite change, memory, aging, hypertension, septic shock, cardiogenic shock, intestinal inflammation and exercise, Hypersensitivity Syndrome, colitis, diarrhea, ileitis, ischemia, cerebral ischemia, liver ischemia, myocardial infarction, brain excitotoxicity, seizure, thermal convulsions, neurotoxicity, neuropathy, sleep, sleep induction, sleep duration, insomnia, Arthritis, rheumatoid arthritis, spondylitis, shoulder tendonitis or bursitis, gouty arthritis, aloymyalgia rheumatism, thyroiditis, hepatitis, inflammatory bowel disease, asthma, multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergy Effective to treat, prevent or ameliorate one or more signs of a disease, disorder or condition selected from rhinitis and heart disease.

  In certain other embodiments, the compounds and compositions provided herein are effective for treating, preventing or ameliorating one or more symptoms of pain and / or inflammation.

  In one aspect, provided herein is a method of inhibiting fatty acid amide hydrolase activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound or composition provided herein. . In certain embodiments, the mammal is a human. In other embodiments, the compound or composition is administered orally.

  In another aspect, the compounds provided herein are used for the preparation of a medicament for the inhibition of fatty acid amide hydrolase (FAAH).

  Packaging materials, compounds or compositions or pharmaceutically acceptable derivatives provided herein that are effective in inhibiting fatty acid amide hydrolase (FAAH) activity in the packaging materials, and compounds or compositions thereof Or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate thereof. A product is provided that contains a label indicating that it is used to inhibit degrading enzyme (FAAH) activity.

  Combinations of any of the above groups for various variables are contemplated herein.

  Other objects, features and advantages of the methods and compositions described herein will become apparent from the following detailed description. However, since various changes and modifications within the spirit and scope of this disclosure will be apparent to those skilled in the art from this detailed description, the detailed description and specific examples, while indicating specific embodiments, It should be understood that it is given only for that purpose. All references cited herein, including patents, patent applications and publications, are hereby incorporated by reference in their entirety.

(Incorporation by reference)
All publications and patent applications mentioned in this specification are as comparable as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Incorporated herein by reference.

(Brief description of the drawings)
A better understanding of the features and advantages of the methods and compositions of the present application may be obtained using the detailed description (our method principles, compositions, devices and apparatus) describing exemplary embodiments. ) And the attached drawings.

  FIGS. 1-8 illustrate non-limiting examples of the types of compounds of formula (I) described herein. Such compounds can be used or incorporated in any method, composition, technique and strategy for making, purifying, characterizing and using the compounds of formula (I) described herein. Can do.

(Detailed description of the invention)
The novel features are set forth with particularity in the appended claims. For a better understanding of the features and advantages of the present disclosure, refer to the following detailed description, in which the principles described herein are used, which describe exemplary embodiments. Can be obtained.

  Disclosed herein are compounds that inhibit the activity of fatty acid amide hydrolase (FAAH) activity, compositions comprising the compounds, and methods of use thereof. The compounds disclosed herein are inhibitors of fatty acid amide hydrolase (FAAH) and are useful in the treatment of diseases, disorders or conditions that benefit from the inhibition of fatty acid amide hydrolase, and include endogenous fatty acid amides Increase in.

Endocannabinoid system The endocannabinoid signaling system consists of three elements (Lambert et al. J. Med. Chem. 2005, vol. 48, no. 16, 5059-5087). The first is represented by G protein-coupled receptors that bind to endogenous and exogenous cannabinoid ligands. Two such receptors, the CB ₁ receptor (found almost everywhere in the body, but most abundant in the central nervous system (CNS) (Freund et al. Physiol. Rev. 2003; 83: 1017- . 1066)) and CB ₂ receptors (but is mainly expressed in the immune and hematopoietic cells, also present at low levels in the brain (Munro et al.Nature, 1993; 365 : 61-65; Van Sickle et al. Science 2005; 310: 329-332; Hanus et al., Proc. Nat. Acad. Sci, USA, 1999; 96: 14228-14233))).

  The second element is the endocannabinoid, a naturally occurring lipid molecule that binds to and activates cannabinoid receptors (Devane et al. Science 1992; 258: 1946-1949; Mechoulam et al. Biochem. Pharmacol. 1995; 50: 83-90; Sugria et al. Biochem. Biophys. Res. Commun. 1995; 215: 89-97), which is generated by the demand for neurons and other cells (Di Marzo et al. Nature 1994; 372: 686-691; Giuffrida et al. Nat.Neuroci.1999; 2: 358-363; Stella et al. ; 388: 773-778) is, are rapidly removed (Beltramo et al.FEBS Lett.1997; 403: 263-267; Stella et al.Nature 2001; 388: 773-778).

  The third element is represented by proteins involved in the formation and removal of various endocannabinoid ligands (Piomelli, D. Nat Rev. Neurosci. 2003; 4: 873-884).

  Cannabinoid receptors can be activated not only by endocannabinoids, but also by synthetic ligands.

  Anandamide (arachidonoylethanolamide) was the first endocannabinoid substance discovered (Devane et al. Science 1992; 258: 1946-1949; Piomelli, D. Nat Rev. Neurosci. 2003; 4: 873-884). ). Current evidence indicates that this lipid-derived mediator is released upon demand of stimulated neurons (Di Marzo et al. Nature, 1994; 372: 686-691; Giuffrida et al. Nat. Neurosci. 1999, 2: 358-363); potently activates cannabinoid receptors (Devane et al. Science 1992; 258: 1946-1949) and rapidly by a two-step process consisting of carrier-mediated internalization followed by intracellular hydrolysis (metabolism) (Beltramo et al. Science 1997; 277: 1094-1997; Di Marzo et al. Nature 1994; 372: 686-691; Hillard et al. J. Lipid. es.1997; 38: 2383-2398).

A endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) is intended to produce a majority of effects by binding to both CB ₁ receptors are released under tension, the basal nociceptive threshold (Meng et al., Nature 1998; Sep 24; 395 (6700): 381-3). In particular, anandamide acts as a CB ₁ agonist and exhibits pharmacological activity in mice as well as other synthetic cannabinoids.

Fatty acid amide hydrolase (FAAH)
Fatty acid amide hydrolase (FAAH) is an enzyme that hydrolyzes the fatty acid amide (FAA) family of endogenous signaling lipids. Common types of fatty acid amides include N-acylethanolamines (NAE) and fatty acid primary amides (FAPA). Examples of NAE include anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Examples of FAPA include 9-Z-octadecenamide or oleamide. (McKinney MK, Cravatt BF. 2005. Annu Rev Biochem 74: 411-32)]. FAAH can act as a hydrolase not only for fatty acid ethanolamides and primary amides, but also for esters such as 2-arachidonylglycerol (2-AG) (Mechoulam et al. Biochem. Pharmacol. 1995; 50: 83-90; Stella et al. Nature, 1997; 388: 773-778; Suguria et al. Biochem. Biophys. Res. Commun. 1995; 215: 89-97).

  FAAH is expressed abundantly throughout the CNS (Frund et al. Physiol. Rev. 2003; 83: 1017-1066) and similarly, for example, in the pancreas, brain, kidney, skeletal muscle, placenta and liver (Giang, D. K. et al.Molecular Characteristic of Human and Mouse Fatty Acid Acid Hydroides.Proc.Natl.Acad.Sci.U.S.A. 1997, 94, 2238-2242; 101, no. 29, 10821-10826).

Anandamide or arachidonylethanolamide is a NAE that acts as an endogenous ligand for the cannabinoid type 1 (CB ₁ ) receptor (Devane WA, et al. 1992. Science 25 8: 1946-49). Anandamide is rapidly removed by a two-step process consisting of carrier-mediated transport followed by intracellular hydrolysis by FAAH. Hydrolysis of anandamide by FAAH results in the formation of arachidonic acid and ethanolamine. The current hypothesis of the catalytic mechanism for the hydrolysis of anandamide by FAAH involves the nucleophilic attack of the amino acid residue serine 241 of FAAH on the amide site of anandamide, which results in the formation of arachidonic acid and ethanolamine (Deutsch et al. The fatter acid acid amide (FAAH) Prostaglandins, Leukotrienes and Essential Fatty Acids (2002) 66 (2 & 3), 201-210; Alexander et al. Chem.

  Mutant mice deficient in the gene encoding FAAH show a significant decrease in hydrolytic activity on anandamide and other fatty acid amides, showing signs of increased anandamide activity at cannabinoid receptors, such as reduced pain sensation This results in an observable physiological phenomenon (Cravatt BF, et al. 2001. Proc Nat Acad Sci USA 98: 9371-9376). This suggests that therapeutic agents that alter the activity of the FAAH enzyme can enhance the action of anandamide and other fatty acid amides in the body. Such agents avoid multiple, often undesired effects caused by indiscriminate activation of cannabinoid receptors by administration of Δ9-THC (the active ingredient in marijuana) and other directly acting cannabinoids. Can also.

Many endogenous fatty acid amides other than anandamide not bind CB ₁ receptors. Some things these lipids have been shown to produce specific cellular effects and behavioral effects, represent a large family of endogenous signaling lipids that act in vivo to a different receptor systems and CB ₁ There are things to do. These are palmitoylethanolamide (PEA) (Calignano A, et al. 1998. Nature 394: 277-8 1; Jaggar SI, et al. 1998. Pain 76: 189-99; Franklin A, Parmentier-Batteur et al. 2003. J Neurosci 23: 7767-75), stearoyl ethanolamide (SEA) (Terrazino et al. 2004 FASEB J: 18: 1580-82; Maccarrone M, et al. 2002. Biochem J 366: 137-44), and Oil ethanolamide (OEA) (deFonseca FR, et al. 2001. Nature 414: 209-12; Fu J, et al. 200 3. Nature 425: 90-93; Fu J, et al., 2005. Neuropharmacology 48 (8): 1 147-53). Both OEA and PEA have been shown to activate peroxisome proliferator activated receptor α (PPAR-α) (Fu J, et al. 2003. Nature 425: 90-93; Guzman M, et al., 2004, J Biol Chem 279 (27): 27849-54; Lo Verme J, et al. 2005. Cell MoI Life Sci 62 (6): 708-16, Lo Verme J, et al. 2005. Life Sci. 77 (14): 1685-98; Lo Verme J, et al. 2005. Mol Pharmacol 67 (1): 15-9). Through these actions, OEA and PEA can control several biological pathways, including but not limited to feeding, metabolism, pain and inflammation. Thus, agents that alter FAAH enzyme activity can control the levels of various fatty acid amides in vivo and then have therapeutic effects through various targets.

  Without being bound by theory, certain fatty acid amides, such as OEA, act through peroxisome proliferator-activated receptor alpha (PPAR-alpha) and control a variety of physiological processes including, for example, feeding and lipolysis To do. Consistent with this, human adipose tissue has been shown to bind and metabolize endocannabinoids such as anandamide and 2-arachidonylglycerol. Spoto et al. , August 22, 2006, Biochimie (pre-published paper); and Matias et al. (2006), J. et al. Clin. Endocrin. & Met. , 91 (8): 3171-3180. Thus, inhibition of FAAH activity in vivo leads to a decrease in body fat, body weight, caloric intake and liver triglyceride levels. However, unlike other antihyperlipidemic agents that act through PPAR-α, such as fibrates, FAAH inhibitors are rashes, fatigue, headaches, erectile dysfunction, and, more rarely, anemia, leukopenia, blood vessels Does not cause side effects such as edema and hepatitis. For example, Muscari et al. (2002), Cardiology, 97: 115-121. A further therapeutic property of FAAH inhibitors is that, due to their ability to increase the levels of anandamide, they effectively ameliorate symptoms often associated with metabolic disorders (EMD) such as depression and anxiety and obesity. Simon et al. (2006), Archives of Gen. Psychiatry, 63 (7): 824-830. In certain embodiments, the FAAH inhibitor compound is restricted to the periphery and cannot inherently affect neurological disorders such as depression and anxiety. Finally, cannabinoid receptor agonism has also been shown to reduce the progression of atherosclerosis in animal models. Stephens et al. (2005), Nature, 434: 782-786; and Stephens et al. (2006), Curr. Opin. Lipid. 17: 519-526. Thus, increasing the level of endogenous cannabinoid fatty acid amides (eg, anandamide) is expected to effectively treat or reduce the risk of developing atherosclerosis.

  Many fatty acid amides are produced on demand and are rapidly degraded by FAAH. As a result, hydrolysis by FAAH appears to be one of the essential steps in the control of fatty acid amide levels in the central nervous system as well as in peripheral tissues and fluids. The wide distribution of FAAH (both endocannabinoid and non-endocannabinoid mechanisms) combined with the broadly listed biological actions of fatty acid amides indicates that inhibition of FAAH is altered in many tissues and fluids. Suggesting that it may be useful in treating many different medical conditions. FAAH inhibitors increase the level of endogenous fatty acid amides. FAAH inhibitors block the degradation of endocannabinoids and increase the tissue levels of these endogenous substances. FAAH inhibitors can be used in this regard for the prevention and treatment of pathologies involving endogenous cannabinoids and / or any other substrate metabolized by the FAAH enzyme.

  Inhibition of FAAH is expected to lead to increased levels of anandamide and other fatty acid amides. This increase in fatty acid amides may lead to an increase in nociceptive threshold. Thus, in one embodiment, FAAH inhibitors are useful for treating pain. Such inhibitors can also be treated with modulators of fatty acid amides or cannabinoid receptors, for example in the treatment of other diseases such as anxiety, eating disorders, metabolic disorders, heart disease and inflammation. May be useful.

  Various fatty acid ethanolamides have important and diverse physiological functions. As a result, inhibitor molecules that selectively inhibit FAAH enzyme activity allow for the corresponding selective preparation of intracellular and extracellular concentrations of FAAH substrate. Biologically compatible FAAH inhibitors can be effective pharmaceutical compounds when formulated as therapeutics for any clinical indication for which an FAAH enzyme inhibitor is desired. In certain embodiments, FAAH activity in peripheral tissues can be preferentially inhibited. In certain embodiments, FAAH inhibitors that substantially cross the blood brain barrier can be used to preferentially inhibit FAAH activity in peripheral tissues. In certain embodiments, FAAH inhibitors that preferentially inhibit FAAH activity in peripheral tissues can minimize the effects of FAAH inhibition in the central nervous system. In certain embodiments, it is preferred to inhibit FAAH activity in peripheral tissues and to minimize the effects of FAAH inhibition in the central nervous system.

  Diseases, disorders, signs and / or symptoms that benefit from inhibition of FAAH enzyme activity include, for example, Alzheimer's disease, schizophrenia, depression, alcoholism, addiction, suicide, Parkinson's disease, Huntington's chorea, stroke, vomiting Miscarriage, early embryo transfer, endotoxin shock, cirrhosis, atherosclerosis, cancer, traumatic head injury, glaucoma and bone cement transplant syndrome.

  Other diseases, disorders, signs and / or symptoms that benefit from inhibition of FAAH activity are, for example, multiple sclerosis, retinitis, amyotrophic lateral sclerosis, immunodeficiency virus-induced encephalitis, attention deficit hyperactivity Disorder, pain, nociceptive pain, neuropathic pain, inflammatory pain, non-inflammatory pain, painful hemorrhagic cystitis pain, obesity, hyperlipidemia, metabolic disorders, feeding and fasting, appetite change, Stress, memory, aging, hypertension, septic shock, cardiogenic shock, intestinal inflammation and exercise, irritable bowel syndrome, colitis, diarrhea, ileitis, ischemia, cerebral ischemia, liver ischemia, myocardial infarction, Includes brain excitotoxicity, seizures, febrile convulsions, neurotoxicity, neuropathy, sleep, sleep induction, sleep persistence, insomnia and inflammatory diseases.

  Neurological and mental illnesses that benefit from inhibition of FAAH activity include, for example, pain, depression, anxiety, generalized anxiety disorder (GAD), obsessive compulsive disorder, stress, stress urinary incontinence, attention deficit hyperactivity Includes sexual disorders, schizophrenia, psychosis, Parkinson's disease, muscle spasticity, epilepsy, dyskinesia, seizure disorder, jet lag and insomnia.

  FAAH inhibitors are also used in various metabolic signs, diseases, disorders and / or symptoms such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis and arteriosclerosis. However, it is not limited to these.

  FAAH inhibitors are characterized by non-inflammatory pain, inflammatory pain, peripheral neuropathic pain, central pain, blocking pain, chronic nociceptive pain, nociceptor stimulation, phantom limb pain and transplant acute pain, etc. Useful for, but not limited to, treating a variety of pain signs, diseases, disorders and / or symptoms.

  Inhibition of FAAH activity can also be used to treat various conditions related to inflammation. These symptoms include arthritis (such as rheumatoid arthritis, shoulder tendonitis or bursitis, gouty arthritis, and aloymyalgia rheumatism), organ-specific inflammatory diseases (such as thyroiditis, hepatitis, inflammatory bowel disease), asthma. , Other autoimmune diseases such as multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis and heart disease.

  In some cases, FAAH inhibitors are useful for preventing neurodegeneration or for neuroprotection.

  Furthermore, when FAAH activity is reduced or absent, anandamide acts as a substrate for COX-2 as one of the substrates, and COX-2 has been shown to convert anandamide to prostamides (Weber et al. J. Lipid. Res. 2004; 45: 757). The concentration of certain prostamides can be increased in the presence of FAAH inhibitors. Certain prostamides are associated with reduced intraocular pressure and high intraocular pressure. Thus, in one embodiment, FAAH inhibitors may be useful for treating glaucoma.

  In certain embodiments, FAAH inhibitors can be used to treat or reduce the risk of EMD, which is obesity, anorexia, overweight, cellulite, type I and type II diabetes, hyperglycemia, lipids Abnormalities, steatohepatitis, hepatic steatosis, nonalcoholic steatohepatitis, syndrome X, insulin resistance, diabetic dyslipidemia, anorexia, bulimia, anorexia nervosa, hyperlipidemia, high triglycerides Including, but not limited to, thrombosis, atherosclerosis, arteriosclerosis, inflammatory disorders or symptoms, Alzheimer's disease, Crohn's disease, vascular inflammation, inflammatory bowel disorder, rheumatoid arthritis, asthma, thrombosis or cachexia It is not limited.

  In other embodiments, the FAAH inhibitor is used to treat or reduce the risk of diabetes in both primary and secondary non-essential diabetes, such as insulin resistance syndrome and type I or type II diabetes. can do. By administering a composition containing a therapeutically effective amount of an in vivo FAAH inhibitor, the severity of the symptoms of diabetes or atherosclerosis, hypertension, hyperlipidemia, hepatic steatosis, nephropathy, neurosis Reduce the risk of developing diabetic symptoms such as retinopathy, foot ulceration or cataracts.

  In another embodiment, FAAH inhibitors can be used to treat food abuse behaviors, particularly behaviors that tend to cause overweight (eg, bulimia, appetite for sugar or fat and non-insulin dependent diabetes). .

  In certain embodiments, FAAH inhibitors can be used to treat subjects suffering from EMD and can be used to treat subjects suffering from depression or anxiety. Preferably, the subject is diagnosed as suffering from depression or mental illness prior to administration of the FAAH inhibitor composition. Accordingly, a dose of a FAAH inhibitor that is therapeutically effective for both EMD and depression or anxiety is administered to the subject. Methods for treating anxiety and depression with FAAH inhibitors are described, for example, in US Patent Application Nos. 10 / 681,858 and 60 / 755,035.

  Preferably, the subject to be treated is a human. However, this method can also be used to treat mammals other than humans. For example, animal models of EMD such as those described in US Pat. No. 6,946,491 are particularly useful.

Signs, diagnostic tests and prognostic tests for each of the aforementioned symptoms are known in the art. For example, “Harrison's Principles of Internal Medicine ^(C) ”, 16th ed. , 2004, The McGraw-Hill Companies, Inc. , And “Diagnostic and Statistical Manual of Mental Disorders ^(C) ”, 4th ed. 1994, American Psychiatric Association.

  The FAAH inhibitor composition can also be used to reduce the weight of an individual desired to lose weight for cosmetic purposes, not necessarily from medical considerations.

  The FAAH inhibitor composition can be administered in combination with a drug (eg, statins, niacin, a fibric acid derivative, or a bile acid-binding resin) for lowering circulatory cholesterol levels. The FAAH inhibitor composition can also be used in combination with a weight loss drug such as orlistat or an appetite inhibitor such as diethylpropion, mazindol, orlistat, phendimetrazine, phentermine or sibutramine.

  The methods described herein can also provide exercise therapy to a subject or can provide a calorie restricted diet (eg, a triglyceride restricted diet).

  Esters of alkyl carbamic acid and alkyl thiocarbamic acid have been shown to have promise as selective FAAH inhibitors (Kathuria et al., Nat. Med. 2003, 9: 76-81). For example, cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester (also known as 5′-carbamoylbiphenyl-3-yl-cyclohexylcarbamate, UCM597, URB597, and KDS-4103 (URB-597)). Has been shown to be a strong selective inhibitor of FAAH activity. Alkylcarbamic acid aryl esters such as cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester have been shown to be strong selective inhibitors of FAAH activity, which are selected serine hydrolases. Alternatively, it does not interact significantly with cannabinoid receptors (Mor et al. J. Med. Chem. 2004, 47: 4998-5008; Piomelli et al. International Patent Publication No. WO 2004/033422; incorporated by reference).

  Alkylcarbamic acid aryl esters inhibit FAAH activity, possibly by irreversible interaction with FAAH by nucleophilic attack of FAAH's active serine residue (serine 241) on the carbamate moiety of alkylcarbamic acid aryl ester compounds (Kathuria et al. al. Nature Medicine, vol.9, no.1, 76-81, 2003; Deutsch et al. Prostaglandins, Leuktrienes and Essential Fatty Acids (2002) 66 (2 & 3), Biol. 12, 1179-1187; 2005.). Metabolism of the alkyl carbamate aryl ester inhibitor by the FAAH enzyme results in hydrolysis of the carbamate compound, releasing the aryloxy moiety of the alkyl carbamate aryl ester inhibitor.

  Provided herein are compounds that are alkyl carbamates, compositions containing them, and methods of use thereof. The compounds provided herein have a structure selected from: and their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically Or a pharmaceutically acceptable solvate.

［式中、ＤはＯまたはＮＲ^１１であり；各ＸはＣＨまたはＮであり；ＡまたはＢの一方は（ＣＨ_２）_ｎＣ（Ｏ）−アルキル、（ＣＨ_２）_ｎＣ（Ｏ）−Ｎ（Ｒ^２）_２であり、および他方はＨ，アルキルまたはヘテロアルキルであり、ｎは０、１、２、３または４であり；各Ｒ^２はＨまたは場合により置換されたアルキルであり；またはＡおよびＢは一緒になって、Ｃ（Ｏ）−（ＣＨ_２）_ｎ−部分（ｎは１、２、３または４である。）を含む、場合により置換された非芳香族環基を形成し；またはＡおよびＢは、一諸になって少なくとも１つのＮ、ＮＲ^２、ＳまたはＯ基を含む、場合により置換されたヘテロ芳香族基を形成し；またはＡおよびＢは、一諸になって場合により置換されたオキソ−置換複素環を形成し；Ｒ^１は、Ｃ_３−Ｃ_９シクロアルキル、Ｃ_１−Ｃ_４アルキル（Ｃ_３−Ｃ_９シクロアルキル）、Ｃ_１−Ｃ_４アルキル（アリール）およびＣ_１−Ｃ_４アルキル（ヘテロアリール）から選択される、場合により置換された基であり、Ｒ^１のシクロアルキル環のいずれの炭素も、場合によりＹおよびＺで置換されることができ、各Ｙおよび各Ｚは、ハロゲン、メチルまたはトリフルオロメチルからそれぞれ独立して選択され、またはＹおよびＺは一緒になって３員、４員、または５員の炭素環基、またはオキソ（＝Ｏ）を形成することができ；Ｒ^２およびＲ^１１はＨまたは場合により置換されたアルキルである。］

[Wherein D is O or NR ¹¹ ; each X is CH or N; one of A or B is (CH ₂ ) _n C (O) -alkyl, (CH ₂ ) _n C (O) — N (R ² ) ₂ and the other is H, alkyl or heteroalkyl, n is 0, 1, 2, 3 or 4; each R ² is H or optionally substituted alkyl; Or A and B taken together form an optionally substituted non-aromatic ring group containing a C (O) — (CH ₂ ) _n — moiety, where n is 1, 2, 3, or 4. Or A and B together form an optionally substituted heteroaromatic group containing at least one N, NR ² , S or O group; or A and B To form an optionally substituted oxo-substituted heterocycle; R ¹ is C ₃ Optionally substituted, selected from —C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl (heteroaryl) Any carbon of the cycloalkyl ring of R ¹ can be optionally substituted with Y and Z, each Y and each Z being independently from halogen, methyl or trifluoromethyl. Selected, or Y and Z can be taken together to form a 3-, 4-, or 5-membered carbocyclic group, or oxo (═O); R ² and R ¹¹ are H or optionally substituted Alkyl. ]

In a further embodiment, A and B _{^{together, -C (O) - (CR}} q R q) n -, - C (O) -NR 2 - (CR q R q) n -, - NR _{^{2 -C (O) - (CR}} q R q) n -, - C (O) -NR 2 -NR 2 - (CR q R q) n -, - C (O) -NR 2 -N = (CR ^{q) -, - OC (O} ) -O-, OC (O) -NR 2 -, - NR 2 -C (O) -NR 2 -, - OC (O) -O- (CR q R q ^{_{) n -, - O-C}} (O) - (CR q R q) n -O -, - n-C (O) - (CR q R q) n -N -, - O-C (O) - ^{_{(CR q R q) n -N}} -, - n-C (O) - (CR q R q) n -O -, - O-C (O) -NR 2 - (CR q R q) n -, —NR ² —C (O) —O— (CR ^q R ^q ) _n ^{-, - NR 2 -C (O} ) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -O- (CR q R q) n -, - ( ^{_{CR q R q) n -C (}} O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -NR 2 -NR 2 -, - (CR q R ^{_{q) n -C (O) -}} (CR q R q) n -, - C (O) -O- (CR q R q) n -O -, - C (O) -O- (CR q R q ^{_{) n -NR 2 -, - C}} (O) -NR 2 - (CR q R q) n -NR 2, -C (O) -NR 2 - (CR q R q) n -O -, - C ( ^{O) -NR 2 -CR q = CR} q -, C (O) -CR q = CR q -NR 2 -, - C (O) -CR q = CR q -O -, - C (O) -CR ^q = field is selected from ^CR q -S- Oxo substituted by - substituted heterocyclic to form; be each n is independently 1, 2 or 3; and each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, Forms an optionally substituted oxo-substituted heterocycle independently selected from ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle or substituted heterocycle.

  Further compounds provided herein are:

［上記式において、
ＤはＯまたはＮＲ^１１であり；
Ｒ^１は、

[In the above formula,
D is O or NR ¹¹ ;
R ¹ is

（上記式において、
Ｍは結合、場合により置換されたＣ_１−Ｃ_８アルキレン、場合により置換された４個の原子のヘテロアルキレン、場合により置換されたＣ_２−Ｃ_８アルケニレン、場合により置換されたＣ_３−Ｃ_８シクロアルキルまたは場合により置換されたＣ_２−Ｃ_８アルキニレンであり；
ＪはＣＨまたはＮであり；ＫはＣＨまたはＮであり；但し、ＫがＣＨのときは、ＪはＣＨではあり得ず；
各Ｒ^３は、Ｃ_１−Ｃ_６アルキル−（アリール）、Ｃ_１−Ｃ_６アルキル−（ヘテロアリール）、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６アルキルアミン、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、−Ｃ（Ｏ）−Ｒ^１２、アリール、ヘテロアリール、ヘテロシクロアルキル、フェニル、ピリジル、ピリダジニル、ピペラジニル、ピペリジニル、モルホリニル、フラニル、チオフェニル、チオフェンイル、ジベンゾフラニル、ジベンゾチエニル、インドリル、フルオレニル、カルボゾリル、ピリミジニル、ピラジニル、トリアジニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、ナフチル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、シンノリル、イミダゾピリミジニル、チエノピリミジニル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、ピロロピリジル、フロピリジル、ジヒドロフロピリジル、チエノピリジル、ジヒドロチエノピリジル、イミダゾピリジル、ピラゾロピリジル、オキサオロピリジル、イソオキサオロピリジルまたはチアゾロピリジルから選択される場合により置換された基からなる群から独立して選択され；
各Ｒ’は独立してＨ、アルキルまたは置換アルキルであり；
各Ｒ^５は独立して、Ｈ、Ｃ_１−Ｃ_３アルキルまたはハロゲンであり；
Ｒ^６はＣ_１−Ｃ_３アルキルまたはＣ_３−Ｃ_７シクロアルキルであり；
Ｒ^２およびＲ^１１はＨまたは場合により置換されたアルキルであり；
Ｒ^１２は、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_７シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、ベンジルオキシ、フラニル、フェニル、ベンジル、またはピリジルからなる群から選択される。）からなる群から選択され；
または、Ｒ^１およびＲ^２は、一緒になって、

(In the above formula,
M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;
J is CH or N; K is CH or N; provided that when K is CH, J cannot be CH;
Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C _{6 alkenyl,} C 3 -C _{8 cycloalkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl , Morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, Futyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoisoxazolyl, azoisoxazolyl Benzoisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl Independently selected from the group consisting of groups;
Each R ′ is independently H, alkyl or substituted alkyl;
Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;
R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;
R ² and R ¹¹ are H or optionally substituted alkyl;
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl, or pyridyl. ) Selected from the group consisting of:
Or R ¹ and R ² are taken together

(N is 1, 2, 3 or 4; m is 1, 2, 3 or 4);
Any of the _{substituents,} C 1 -C _{3 alkyl,} C 1 -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy -C, (O) R ', - C (O) - ( alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-( Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) ) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl) , —S (O) _k R ′ (k is 1 or 2), —S (O) _k (alkyl or substituted alkyl), —C (S) — (alkyl or substituted alkyl), —CSN (R ′) ₂ , -CSN (R ')-(alkyl or substituted alkyl), -N (R') CO- (alkyl or substituted alkyl), -N (R ') C (O) OR',-(alkyl or substituted alkyl) ) -O-N = C (R ') ₂ ,-(alkyl or substituted alkyl) -C (O) NR'-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- ( Alkyl or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N (R ') _{2, -N (R ') C} (S) N (R') 2, -N (R ') S (O) k N (R') 2 -C (R ') = NR'- C (R') = N-N (R ') 2 , and _{-C (R') 2 -N (} R ') - N (R') independently selected from ₂ Is done. ]
And a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable Solvate.

  In certain embodiments, the compound of formula (IIIa) has the structure

を有する。

Have

  Further compounds described here are:

［上記式において、
ＤはＯまたはＮＲ^１１であり；
Ｒ^１は、

[In the above formula,
D is O or NR ¹¹ ;
R ¹ is

（上記式において、Ｍは結合、場合により置換されたＣ_１−Ｃ_８アルキレン、場合により置換された４個の原子のヘテロアルキレン、場合により置換されたＣ_２−Ｃ_８アルケニレン、場合により置換されたＣ_３−Ｃ_８シクロアルキルまたは場合により置換されたＣ_２−Ｃ_８アルキニレンであり；
ＪはＣＨまたはＮであり；ＫはＣＨまたはＮであり；但し、ＫがＣＨのときは、ＪはＣＨではあり得ず；
各Ｒ^３は、Ｃ_１−Ｃ_６アルキル−（アリール）、Ｃ_１−Ｃ_６アルキル−（ヘテロアリール）、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６アルキルアミン、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、
Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、−Ｃ（Ｏ）−Ｒ^１２、アリール、ヘテロアリール、ヘテロシクロアルキル、フェニル、ピリジル、ピリダジニル、ピペラジニル、ピペリジニル、モルホリニル、フラニル、チオフェニル、チオフェンイル、ジベンゾフラニル、ジベンゾチエニル、インドリル、フルオレニル、カルボゾリル、ピリミジニル、ピラジニル、トリアジニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、ナフチル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、シンノリル、イミダゾピリミジニル、チエノピリミジニル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、ピロロピリジル、フロピリジル、ジヒドロフロピリジル、チエノピリジル、ジヒドロチエノピリジル、イミダゾピリジル、ピラゾロピリジル、オキサオロピリジル、イソオキサオロピリジルまたはチアゾロピリジルから選択される場合により置換された基からなる群から独立して選択され；
各Ｒ’は独立してＨ、アルキルまたは置換アルキルであり；
各Ｒ^５は独立してＨ、Ｃ_１−Ｃ_３アルキルまたはハロゲンであり；
Ｒ^６はＣ_１−Ｃ_３アルキルまたはＣ_３−Ｃ_７シクロアルキルであり；
Ｒ^２およびＲ^１１はＨまたは場合により置換されたアルキルであり；
Ｒ^１２は、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_７シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、ベンジルオキシ、フラニル、フェニル、ベンジル、またはピリジルからなる群から選択される。）からなる群から選択され；
またはＲ^１およびＲ^２は一緒になって、

Wherein M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted. C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;
J is CH or N; K is CH or N; provided that when K is CH, J cannot be CH;
Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl,
C ₃ -C _{8 cycloalkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, Thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, isoquinolyl Quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyr Dinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, Independently selected from the group consisting of optionally substituted groups selected from oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl;
Each R ′ is independently H, alkyl or substituted alkyl;
Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;
R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;
R ² and R ¹¹ are H or optionally substituted alkyl;
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl, or pyridyl. ) Selected from the group consisting of:
Or R ¹ and R ² together

（ｎは１、２、３または４であり；ｍは１、２、３または４である。）を形成し；
ＡおよびＢは一緒になって、Ｃ（Ｏ）−（ＣＨ_２）_ｑ−部分（ｑは１、２、３または４である。）を含む場合により置換された非芳香族環基を形成し；
またはＡおよびＢは一緒になって、場合により置換されたオキソ−置換複素環を形成し；
またはＡおよびＢは一緒になって、少なくとも１個のＮ、ＮＲ^２、ＳまたはＯ基を含有する、場合により置換された芳香族環もしくは非芳香族環基を形成し；
またはＡまたはＢの一方は−Ｌ−Ｇでありおよび他方はＨおよび場合により置換されたＣ_１−Ｃ_６アルキルから選択され；
またはＡおよびＢは一緒になって、場合により置換された芳香族炭素環基を形成し；
またはＡおよびＢは、Ｈ、場合により置換されたアルキル、場合により置換されたヘテロアルキル、場合により置換された複素環基、場合により置換されたアリール基、場合により置換されたヘテロアリール基、場合により置換されたケトアルキル、場合により置換されたアミドおよび場合により置換されたケトヘテロアルキルからそれぞれ独立して選択され；
Ｌは結合、またはＣ_１−Ｃ_６アルキレン、Ｃ_１−Ｃ_６ヘテロアルキレン、Ｃ_１−Ｃ_６ケトアルキレン、−Ｃ（Ｏ）ＮＲ^９−（ＣＨ_２）_ｊ−、−ＮＲ^９−Ｃ（Ｏ）−（ＣＨ_２）_ｊ−、−ＯＣ（Ｏ）Ｏ−（ＣＨ_２）_ｊ−、−ＮＨＣ（Ｏ）Ｏ−（ＣＨ_２）_ｊ−、−Ｏ（Ｏ）ＣＮＨ−（ＣＨ_２）_ｊ−、−Ｃ（Ｏ）Ｏ−（ＣＨ_２）_ｊ−、−ＯＣ（Ｏ）−（ＣＨ_２）_ｊ−、−ＮＲ^９Ｃ（Ｏ）Ｎ（Ｒ^９）−（ＣＨ_２）_ｊ−、−Ｓ（Ｏ）−（ＣＨ_２）_ｊ−、−Ｓ（Ｏ）_２−（ＣＨ_２）_ｊ、−Ｃ（＝ＮＲ^１０）Ｎ（Ｒ^９）−（ＣＨ_２）_ｊ−、および−ＮＲ^９Ｃ（＝ＮＲ^１０）Ｎ（Ｒ^９）−（ＣＨ_２）_ｊ−から選択される場合により置換された基であり；
Ｇは、テトラゾリル、−ＮＨＳ（＝Ｏ）_２Ｒ^８、−Ｓ（＝Ｏ）_２ＮＨＲ^８、−Ｓ（＝Ｏ）_２ＮＨ−フェニル、−ＯＨ、−ＳＨ、−ＯＣ（Ｏ）ＮＨＲ^８、−ＮＨＣ（Ｏ）ＯＲ^８、−Ｃ（Ｏ）ＮＨＣ（Ｏ）Ｒ^８、−Ｃ（Ｏ）ＮＨＳ（＝Ｏ）_２Ｒ^８、−Ｓ（＝Ｏ）_２ＮＨＣ（Ｏ）Ｒ^８、−Ｓ（＝Ｏ）_２ＮＨＣ（Ｏ）ＮＨＲ^８、−ＮＨＣ（Ｏ）Ｒ^８、−ＮＨＣ（Ｏ）Ｎ（Ｒ^９）_２、−Ｃ（＝ＮＲ^１０）Ｎ（Ｒ^９）_２、−ＮＲ^９Ｃ（＝ＮＲ^ｌ０）Ｎ（Ｒ^９）_２、−ＮＲ^９Ｃ（＝ＮＲ^１０）ＮＨＣ（＝ＮＲ^１０）Ｎ（Ｒ^９）_２、−ＮＲ^９Ｃ（＝ＣＨＲ^１０）Ｎ（Ｒ^９）_２、−Ｃ（Ｏ）ＮＲ^９Ｃ（＝ＮＲ^１０）Ｎ（Ｒ^９）_２、−Ｃ（Ｏ）ＮＲ^９Ｃ（＝ＣＨＲ^１０）Ｎ（Ｒ^９）_２、−ＣＯ_２Ｈ、−（ＯＰ（＝Ｏ）ＯＨ）_ｘＯＨ、−ＯＰ（＝Ｏ）ＯＲ^８ＯＨ、−ＯＰ（＝Ｏ）Ｒ^８ＯＨ、−ＮＲ^９Ｐ（＝Ｏ）ＯＲ^８ＯＨ、−ＮＲ^９Ｐ（＝Ｏ）Ｒ^８ＯＨ、−Ｐ（＝Ｏ）ＯＲ^８ＯＨ；−Ｐ（＝Ｏ）Ｒ^８ＯＨ、−Ｓ（Ｏ）_ｙＯＨ；−ＯＳ（Ｏ）_ｙＯＨ；−ＮＲ^９Ｓ（Ｏ）_ｙＯＨであり；
各Ｒ^８は、独立して置換または非置換のＣ_１−Ｃ_６アルキルであり；
各Ｒ^９は、独立してＨ、置換Ｃ_１−Ｃ_６アルキルまたは非置換Ｃ_１−Ｃ_６アルキルであり；
各Ｒ^１０はＨ、−Ｓ（＝Ｏ）_２Ｒ^８、−Ｓ（＝Ｏ）_２ＮＨ_２、−Ｃ（Ｏ）Ｒ^８、−ＣＮおよび−ＮＯ_２から独立して選択され；
ｊは０、１、２、３または４であり；ｘは１、２または３であり；ｙは０、１または２であり；
各置換基のいずれも、Ｃ_１−Ｃ_３アルキル、Ｃ_１−Ｃ_３アルコキシ、ベンジル、ハロゲン、ニトロ、シアノ、またはベンジルオキシ−Ｃ（Ｏ）Ｒ’、−Ｃ（Ｏ）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−Ｃ（Ｏ）Ｒ’、−Ｃ（Ｏ）Ｎ（Ｒ’）_２、−Ｃ（Ｏ）Ｎ（Ｒ’）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−Ｃ（Ｏ）Ｎ（Ｒ’）_２、−ＯＣ（Ｏ）Ｎ（Ｒ’）_２、−ＯＣ（Ｏ）Ｎ（Ｒ’）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−ＯＣ（Ｏ）Ｎ（Ｒ’）_２、−Ｎ（Ｒ’）Ｃ（Ｏ）Ｒ’、−ＮＲ’Ｃ（Ｏ）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−ＮＲ’Ｃ（Ｏ）Ｒ’、−ＳＲ’、−Ｓ−（アルキルまたは置換アルキル）、−Ｓ（Ｏ）_ｋＲ’（ｋは１、または２）、−Ｓ（Ｏ）_ｋ（アルキルまたは置換アルキル）、−Ｃ（Ｓ）−（アルキルまたは置換アルキル）、−ＣＳＮ（Ｒ’）_２、−ＣＳＮ（Ｒ’）−（アルキルまたは置換アルキル）、−Ｎ（Ｒ’）ＣＯ−（アルキルまたは置換アルキル）、−Ｎ（Ｒ’）Ｃ（Ｏ）ＯＲ’、−（アルキルまたは置換アルキル）−Ｏ−Ｎ＝Ｃ（Ｒ’）_２、−（アルキルまたは置換アルキル）−Ｃ（Ｏ）ＮＲ’−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−Ｓ（Ｏ）_ｋ−（アルキルまたは置換アルキル）−ＳＲ’、−（アルキルまたは置換アルキル）−Ｓ−ＳＲ’、−Ｓ（Ｏ）_ｋＮ（Ｒ’）_２、−Ｎ（Ｒ’）Ｃ（Ｏ）Ｎ（Ｒ’）_２、−Ｎ（Ｒ’）Ｃ（Ｓ）Ｎ（Ｒ’）_２、−Ｎ（Ｒ’）Ｓ（Ｏ）_ｋＮ（Ｒ’）_２、−Ｃ（Ｒ’）＝ＮＲ’−Ｃ（Ｒ’）＝Ｎ−Ｎ（Ｒ’）_２、および−Ｃ（Ｒ’）_２−Ｎ（Ｒ’）−Ｎ（Ｒ’）_２から独立して選択される。］
であり、および医薬的に許容される塩、医薬的に許容されるＮ−オキシド、医薬的に活性な代謝物、医薬的に許容されるプロドラッグまたは医薬的に許容される溶媒和物である。

(N is 1, 2, 3 or 4; m is 1, 2, 3 or 4);
A and B together form an optionally substituted non-aromatic ring group containing a C (O) — (CH ₂ ) _q — moiety, where q is 1, 2, 3, or 4. ;
Or A and B together form an optionally substituted oxo-substituted heterocycle;
Or A and B together form an optionally substituted aromatic or non-aromatic ring group containing at least one N, NR ² , S or O group;
Or one of A or B is and the other a -L-G is selected from C ₁ -C ₆ alkyl substituted by H and optionally;
Or A and B together form an optionally substituted aromatic carbocyclic group;
Or A and B are H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, Each independently selected from a ketoalkyl substituted by, an optionally substituted amide and an optionally substituted ketoheteroalkyl;
L is a bond, or _C 1 -C _{6 alkylene,} C 1 -C _{6 heteroalkylene,} C 1 -C _{6 ^{Ketoarukiren, -C (O) NR 9 -}} (CH 2) j -, - NR 9 -C (O _{) - (CH 2) j -} , - OC (O) O- (CH 2) j -, - NHC (O) O- (CH 2) j -, - O (O) CNH- (CH 2) j - _{, -C (O) O- (CH} 2) j -, - OC (O) - (CH 2) j -, - NR 9 C (O) N (R 9) - (CH 2) j -, - S _{(O) - (CH 2)} j -, - S (O) 2 - (CH 2) j, -C (= NR 10) N (R 9) - (CH 2) j -, and ^-NR 9 C ( = An optionally substituted group selected from NR ¹⁰ ) N (R ⁹ ) — (CH ₂ ) _j —;
G is tetrazolyl, —NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHR ⁸ , —S (═O) ₂ NH-phenyl, —OH, —SH, —OC (O) NHR ⁸ , —NHC (O) OR ⁸ , —C (O) NHC (O) R ⁸ , —C (O) NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHC (O) R ⁸ , —S (═O) ₂ NHC (O) NHR ⁸ , —NHC (O) R ⁸ , —NHC (O) N (R ⁹ ) ₂ , —C (═NR ¹⁰ ) N (R ⁹ ) ₂ , —NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , _{^{-C (O) NR 9 C (}} = NR 10) N (R 9) 2, -C (O) NR 9 C (= CHR 10) N (R 9) 2, -CO 2 H, - ^{_{OP (= O) OH) x}} OH, -OP (= O) OR 8 OH, -OP (= O) R 8 OH, -NR 9 P (= O) OR 8 OH, -NR 9 P (= O) in _{-NR 9 S (O) y OH} ; R 8 OH, -P (= O) OR 8 OH ;-P (= O) R 8 OH, -S (O) y OH; -OS (O) y OH Yes;
Each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ⁹ is independently H, substituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkyl;
Each R ¹⁰ is independently selected from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN and —NO ₂ ;
j is 0, 1, 2, 3 or 4; x is 1, 2 or 3; y is 0, 1 or 2;
Any of the _{substituents,} C 1 -C _{3 alkyl,} C 1 -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy -C, (O) R ', - C (O) - ( alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-( Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) ) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl) , —S (O) _k R ′ (k is 1 or 2), —S (O) _k (alkyl or substituted alkyl), —C (S) — (alkyl or substituted alkyl), —CSN (R ′) ₂ , -CSN (R ')-(alkyl or substituted alkyl), -N (R') CO- (alkyl or substituted alkyl), -N (R ') C (O) OR',-(alkyl or substituted alkyl) ) -O-N = C (R ') ₂ ,-(alkyl or substituted alkyl) -C (O) NR'-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- ( Alkyl or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N (R ') _{2, -N (R ') C} (S) N (R') 2, -N (R ') S (O) k N (R') 2 -C (R ') = NR'- C (R') = N-N (R ') 2, and _{-C (R') 2 -N (} R ') - N (R') 2 independently from Selected. ]
And are pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates. .

In a further embodiment, A and B _{^{together, -C (O) - (CR}} q R q) n -, - C (O) -NR 2 - (CR q R q) n -, - NR _{^{2 -C (O) - (CR}} q R q) n -, - C (O) -NR 2 -NR 2 - (CR q R q) n -, - C (O) -NR 2 -N = (CR ^{q) -, - O-C} (O) -O-, O-C (O) -NR 2 -, - NR 2 -C (O) -NR 2 -, - O-C (O) -O- ( ^{_{CR q R q) n -,}} - O-C (O) - (CR q R q) n -O -, - n-C (O) - (CR q R q) n -N -, - O-C _{^{(O) - (CR q R}} q) n -N -, - n-C (O) - (CR q R q) n -O -, - O-C (O) -NR 2 - (CR q R q ^{_{) n -, - NR 2 -C}} (O) -O- (CR q R q ^{_{n -, - NR 2 -C (}} O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -O- (CR q R q) n -, - ^{_{(CR q R q) n -C}} (O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -NR 2 -NR 2 -, - (CR q ^{_{R q) n -C (O)}} - (CR q R q) n -, - C (O) -O- (CR q R q) n -O -, - C (O) -O- (CR q R ^{_{q) n -NR 2 -, -}} C (O) -NR 2 - (CR q R q) n -NR 2, -C (O) -NR 2 - (CR q R q) n -O -, - C ^{(O) -NR 2 -CR q =} CR q -, C (O) -CR q = CR q -NR 2 -, - C (O) -CR q = CR q -O -, - C (O) - It is selected from ^{CR q} = CR ^q -S- , Oxo optionally substituted - form a substituted heterocycle (each n is 1, 2 or 3 independently; and each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl , Ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle or substituted heterocycle.

Additional compounds described herein may be represented by the formula (1), formula disclosed in US Provisional Patent Application No. 60 / 755,035, filed December 29, 2005, which is hereby incorporated by reference. (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), Formula (9), Formula (10), Formula (11), Formula (12), Formula (13), Formula (14), Formula (15), Formula (16), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21), Formula (22), Formula (23), Formula (24), Formula (25), Formula (26), Formula (27), Formula (28), or Formula (29). However, R ¹ group is

［上記式において、Ｍは結合、場合により置換されたＣ_１−Ｃ_８アルキレン、場合により置換された４個の原子のヘテロアルキレン、場合により置換されたＣ_２−Ｃ_８アルケニレン、場合により置換されたＣ_３−Ｃ_８シクロアルキルまたは場合により置換されたＣ_２−Ｃ_８アルキニレンであり；
ＪはＣＨまたはＮであり；ＫはＣＨまたはＮであり；但し、ＫがＣＨのときは、ＪはＣＨではあり得ず；
各Ｒ^３は、Ｃ_１−Ｃ_６アルキル−（アリール）、Ｃ_１−Ｃ_６アルキル−（ヘテロアリール）、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６アルキルアミン、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、
Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、−Ｃ（Ｏ）−Ｒ^１２、アリール、ヘテロアリール、ヘテロシクロアルキル、フェニル、ピリジル、ピリダジニル、ピペラジニル、ピペリジニル、モルホリニル、フラニル、チオフェニル、チオフェンイル、ジベンゾフラニル、ジベンゾチエニル、インドリル、フルオレニル、カルボゾリル、ピリミジニル、ピラジニル、トリアジニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、ナフチル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、シンノリル、イミダゾピリミジニル、チエノピリミジニル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、ピロロピリジル、フロピリジル、ジヒドロフロピリジル、チエノピリジル、ジヒドロチエノピリジル、イミダゾピリジル、ピラゾロピリジル、オキサオロピリジル、イソオキサオロピリジルまたはチアゾロピリジルからなる群から独立して選択され；
各Ｒ’は独立してＨ、アルキル、または置換アルキルであり；
各Ｒ^５は独立してＨ、Ｃ_１−Ｃ_３アルキルまたはハロゲンであり；
Ｒ^６はＣ_１−Ｃ_３アルキルまたはＣ_３−Ｃ_７シクロアルキルであり；
Ｒ^１２は、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_７シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、ベンジルオキシ、フラニル、フェニル、ベンジル、またはピリジルからなる群から選択される。）からなる群から選択され；
または、Ｒ^１およびＲ^２は一緒になって、

[Wherein M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted. C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;
J is CH or N; K is CH or N; provided that when K is CH, J cannot be CH;
Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl,
C ₃ -C _{8 cycloalkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, Thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, isoquinolyl Quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyr Dinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, Independently selected from the group consisting of oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl;
Each R ′ is independently H, alkyl, or substituted alkyl;
Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;
R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl, or pyridyl. ) Selected from the group consisting of:
Or R ¹ and R ² together,

（ｎは１、２、３、または４であり；ｍは１、２、３、または４である。）を形成し；
各置換基のいずれも、Ｃ_１−Ｃ_３アルキル、Ｃ_１−Ｃ_３アルコキシ、ベンジル、ハロゲン、ニトロ、シアノ、またはベンジルオキシ−Ｃ（Ｏ）Ｒ’、−Ｃ（Ｏ）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−Ｃ（Ｏ）Ｒ’、−Ｃ（Ｏ）Ｎ（Ｒ’）_２、−Ｃ（Ｏ）Ｎ（Ｒ’）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−Ｃ（Ｏ）Ｎ（Ｒ’）_２、−ＯＣ（Ｏ）Ｎ（Ｒ’）_２、−ＯＣ（Ｏ）Ｎ（Ｒ’）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−ＯＣ（Ｏ）Ｎ（Ｒ’）_２、−Ｎ（Ｒ’）Ｃ（Ｏ）Ｒ’、−ＮＲ’Ｃ（Ｏ）−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−ＮＲ’Ｃ（Ｏ）Ｒ’、−ＳＲ’、−Ｓ−（アルキルまたは置換アルキル）、−Ｓ（Ｏ）_ｋＲ’（ｋは１、または２）、−Ｓ（Ｏ）_ｋ（アルキルまたは置換アルキル）、−Ｃ（Ｓ）−（アルキルまたは置換アルキル）、−ＣＳＮ（Ｒ’）_２、−ＣＳＮ（Ｒ’）−（アルキルまたは置換アルキル）、−Ｎ（Ｒ’）ＣＯ−（アルキルまたは置換アルキル）、−Ｎ（Ｒ’）Ｃ（Ｏ）ＯＲ’、−（アルキルまたは置換アルキル）−Ｏ−Ｎ＝Ｃ（Ｒ’）_２、−（アルキルまたは置換アルキル）−Ｃ（Ｏ）ＮＲ’−（アルキルまたは置換アルキル）、−（アルキルまたは置換アルキル）−Ｓ（Ｏ）_ｋ−（アルキルまたは置換アルキル）−ＳＲ’、−（アルキルまたは置換アルキル）−Ｓ−ＳＲ’、−Ｓ（Ｏ）_ｋＮ（Ｒ’）_２、−Ｎ（Ｒ’）Ｃ（Ｏ）Ｎ（Ｒ’）_２、−Ｎ（Ｒ’）Ｃ（Ｓ）Ｎ（Ｒ’）_２、−Ｎ（Ｒ’）Ｓ（Ｏ）_ｋＮ（Ｒ’）_２、−Ｃ（Ｒ’）＝ＮＲ’−Ｃ（Ｒ’）＝Ｎ−Ｎ（Ｒ’）_２および−Ｃ（Ｒ’）_２−Ｎ（Ｒ’）−Ｎ（Ｒ’）_２から独立して選択される。］からなる群から選択される構造を有する。

(N is 1, 2, 3, or 4; m is 1, 2, 3, or 4);
Any of the _{substituents,} C 1 -C _{3 alkyl,} C 1 -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy -C, (O) R ', - C (O) - ( alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-( Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) ) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl) , —S (O) _k R ′ (k is 1 or 2), —S (O) _k (alkyl or substituted alkyl), —C (S) — (alkyl or substituted alkyl), —CSN (R ′) ₂ , -CSN (R ')-(alkyl or substituted alkyl), -N (R') CO- (alkyl or substituted alkyl), -N (R ') C (O) OR',-(alkyl or substituted alkyl) ) -O-N = C (R ') ₂ ,-(alkyl or substituted alkyl) -C (O) NR'-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- ( Alkyl or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N (R ') _{2, -N (R ') C} (S) N (R') 2, -N (R ') S (O) k N (R') 2 -C (R ') = NR'- C (R') = N-N (R ') 2 , and _{-C (R') 2 -N (} R ') - N (R') independently selected from ₂ Is done. A structure selected from the group consisting of

Some chemical terms Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications referred to throughout this disclosure are hereby incorporated by reference in their entirety unless otherwise specified. Where there are multiple definitions for a term here, the term in this paragraph prevails. When referring to URLs or other such identifiers or addresses, it is understood that such identifiers can change and specific information on the Internet changes, but equivalent information can be found by Internet search. . References to these prove the effectiveness and public dissemination of such information.

  It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. As used in the specification and claims, the singular forms “a”, “an”, and “the” refer to the plural form unless the context clearly dictates otherwise. It should be noted that the instruction object is included. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” is non-limiting, as are other forms such as “include”, “includes”, and “included”. is there.

  The paragraph headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All references cited in this application, including patents, patent applications, articles, books, manuals and articles, or parts of references, are hereby expressly incorporated herein in their entirety for any purpose by reference. It is.

Definitions of standard chemical terms are given by Carey and Sundberg, “ADVANCED ORGANIC CHEMISTRY 4 ^TH ED.” Vols. It can be found in reference materials such as A (2000) and B (2001), Plenum Press, and New York. Unless otherwise noted, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used within the art. Unless otherwise defined, nomenclature and laboratory procedures and techniques used in connection with analytical chemistry, synthetic organic chemistry, and medicinal chemistry and medicinal chemistry described herein are well known in the art. is there. Standard techniques can be used for chemical synthesis, chemical analysis, formulation, formulation and delivery and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis and tissue culture and transformation (eg, electroporation, lipofection). Reaction and purification techniques can be performed, for example, using a manufacturer's specification kit or as commonly performed in the art or as described herein. The techniques and procedures described above may be performed generally in conventional ways well known in the art and as described in various general and more specific references cited and discussed throughout. it can.

  An “alkoxy” group refers to a (alkyl) O— group, where alkyl is as defined herein.

  An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a “saturated alkyl” group, which means that it does not contain any alkene or alkyne moiety. The alkyl moiety may also be an “unsaturated alkyl” moiety, meaning that it contains at least one alkene or alkyne moiety. An “alkene” moiety refers to a group having at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group having at least one carbon-carbon triple bond. The alkyl moiety can be saturated or unsaturated and branched, linear or cyclic. Depending on the structure, an alkyl group can be a monoradical or a diradical (ie, an alkylene group).

As used herein, C ₁ -C _x includes C ₁ -C ₂ , C ₁ -C ₃ ,... C ₁ -C _x .

An “alkyl” moiety is 1 to 10 carbon atoms (wherever this appears, a numerical range such as “1 to 10” refers to each integer in a given range, eg, “1 to 10 “Carbon atom of” means that an alkyl group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., and no more than 10 carbon atoms, and this definition has a specified numerical range. It also covers the presence of the term “alkyl” when not present). The alkyl group of the compounds described herein can be designated as “C ₁ -C ₄ alkyl” or similar indications. By way of example only, “C ₁ -C ₄ alkyl” has 1 to 4 carbon atoms in the alkyl chain, ie the alkyl chain is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, Selected from sec-butyl and t-butyl. _Thus, C 1 -C ₄ alkyl _includes C 1 -C ₂ alkyl and _C 1 -C ₃ alkyl. Alkyl groups can be substituted or unsubstituted. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Will never be done.

  As used herein, the term “acyclic alkyl” refers to an alkyl that is not cyclic (ie, a straight or branched chain containing at least one carbon atom). Acyclic alkyl can be fully saturated or can contain acyclic alkenes and / or alkynes. Acyclic alkyl can be optionally substituted.

The term “alkylamine” refers to the group —N (alkyl) _x H _y (x and y are selected from among x = 1, y = 1 and x = 2, y = 0). When x is 2, the alkyl groups together with the N atom to which they are attached can optionally form a ring system.

The term “alkenyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with an atom of —C (R) ═C (R) —R, where R refers to the remainder of the alkenyl group and R may be the same or different. Non-limiting examples of alkenyl groups _{include -CH = CH 2, -C (CH} 3) = CH 2, -CH = CHCH 3 and _{-C (CH 3) = CHCH 3} . The alkenyl moiety can be branched, straight chain, or cyclic (also known in this case as a “cycloalkenyl” group). Depending on the structure, an alkenyl group can be a monoradical or a diradical (ie, an alkenylene group). Alkenyl groups can be optionally substituted.

The term “alkynyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atom —C≡C—R, where R refers to the remaining portion of the alkynyl group and may be the same or different. Non-limiting examples of alkynyl groups include —C≡CH, —C≡CCH ₃ , and —C≡CCH ₂ CH ₃ . The “R” portion of the alkynyl moiety can be branched, straight chain, or cyclic. Depending on the structure, an alkynyl group can be a monoradical or a diradical (ie, an alkynylene group). Alkynyl groups can be optionally substituted.

An “amide” is a chemical moiety having the formula —C (O) NHR or —NHC (O) R, where R is alkyl, cycloalkyl, aryl, heteroaryl (attached by a ring carbon). And a heteroalicyclic group (bonded by ring carbons). An “amide” moiety may form a bond between an amino acid or peptide molecule and a compound described herein, thereby forming a prodrug. Any amine or carboxyl side chain on the compounds described herein can be amidated. The procedures and specific groups to make such amides are known to those skilled in the art, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed. , John Wiley & Sons, New York, NY, 1999, etc., which is easily incorporated herein by reference in its entirety.

  The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n + 2π electrons, where n is an integer. Aromatic rings can be formed by 5, 6, 7, 8, 9, or 10 or more atoms. Aromatics can be optionally substituted. The term “aromatic” includes both carbocyclic aryl (eg, phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic ring”) groups (eg, pyridine). The term includes monocyclic or fused-ring polycyclic groups (ie, rings that share adjacent pairs of carbon atoms).

  As used herein, the term “aryl” refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be formed by 5, 6, 7, 8, 9, or 10 or more carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (ie, an arylene group).

  An “aryloxy” group refers to an (aryl) O— group, where aryl is as defined herein.

  The term “bond” or “single bond” refers to a chemical bond between two parts when the atoms connected by the bond or when the atoms connected by the bond are considered part of a larger substructure.

  The term “carbocycle” refers to a compound containing one or more covalently closed ring structures in which all of the atoms forming the ring skeleton are carbon atoms. The term thus thus distinguishes carbocycles from heterocycles in which the ring backbone contains at least one atom different from carbon.

  The term “cycloalkyl” refers to a monocyclic or polycyclic group containing only carbon and hydrogen, and may be saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms. Specific examples of the cycloalkyl group are as follows:

などを含む。構造によっては、シクロアルキル基は、モノラジカルまたはジラジカル（例えばシクロアルキレン基）となり得る。

Etc. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (eg, a cycloalkylene group).

  As used herein, the term “carbocycle” refers to a ring and each of the atoms forming the ring is a carbon atom. A carbocycle can be formed by 3, 4, 5, 6, 7, 8, 9, or 10 or more atoms. The carbocycle can be optionally substituted.

The term “ester” refers to a chemical moiety of the formula —COOR, where R is alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Selected from.) Any hydroxy or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those skilled in the art, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed. , John Wiley & Sons, New York, NY, 1999, etc., which is hereby incorporated by reference in its entirety.

  The term “halo” or interchangeably “halogen” or “halide” means fluorine, chlorine, bromine or iodine.

  The terms “haloalkyl”, “haloalkenyl”, “haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures, in which at least one hydrogen has been replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as each other. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as each other. The terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, where halo is fluorine. In certain embodiments, the haloalkyl is optionally substituted.

  As used herein, the terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl groups where one or more backbone chain atoms are carbon. Other atoms such as oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof.

  The term “heteroatom” refers to an atom other than carbon or hydrogen. Heteroatoms are usually independently selected from oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms can all be the same as each other, or some or all of the two or more heteroatoms can each be different from the other atoms. it can.

  As used herein, the term “ring” refers to any covalently closed ring structure. Rings can be, for example, carbocycles (eg aryl and cycloalkyl), heterocycles (eg heteroaryl and non-aromatic heterocycles), aromatic (eg aryl and heteroaryl) and non-aromatic (eg cycloalkyl and non-aromatic). Heterocycle). Rings can be optionally substituted. The ring can form part of a ring system.

  As used herein, the term “ring system” refers to two or more rings fused with two or more rings. The term “fused” refers to a structure in which two or more rings share one or more bonds.

  The term “heteroaryl” or interchangeably “heteroaromatic” refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the ring's backbone atoms is a nitrogen atom. The polycyclic heteroaryl group may or may not be fused. Specific examples of heteroaryl groups include the following moieties:

などを含む。構造によっては、ヘテロアリール基はモノラジカルまたはジラジカル（即ち、ヘテロアリーレン基）となり得る。

Etc. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (ie, a heteroarylene group).

  As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl”, or “heteroalicyclic” refers to a non-aromatic ring in which one or more of the atoms forming the ring is a heteroatom. Point to. A “non-aromatic heterocycle” or “heterocycloalkyl” group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur. These groups may be fused with aryl or heteroaryl. A heterocycloalkyl ring can be formed with 3, 4, 5, 6, 7, 8, 9, or 10 or more atoms. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, the non-aromatic heterocycle contains one or more carbonyl or thiocarbonyl groups such as, for example, oxo-containing groups and thio-containing groups. Examples of heterocycloalkyl include lactam, lactone, cyclic imide, cyclic thioimide, cyclic carbamate, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4- Dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbitur Acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyra Phosphorus, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1 , 3-oxathiolane and the like, but are not limited thereto. Specific examples of heterocycloalkyl groups, also called non-aromatic heterocycles, include:

などが挙げられる。用語「ヘテロ脂環族」は、また、炭水化物の全ての環状形態を含み、非限定的に単糖類、２糖類およびオリゴ糖類を含む。

Etc. The term “heteroalicyclic” also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides.

The term “heterocycle” refers to heteroaromatic and heteroalicyclic groups containing from 1 to 4 heteroatoms each selected from O, S and N, each heterocyclic group having 4 to 10 It has atoms in this ring system provided that the ring of the group does not contain two adjacent O or S atoms. Here, whenever the number of carbon atoms in a heterocycle is indicated (eg a C ₁ -C ₆ heterocycle), at least one other atom (heteroatom) must be present in the ring. Don't be. An indication such as “C ₁ -C ₆ heterocycle” refers only to the number of carbon atoms in the ring and not to the total number of atoms in the ring. It is understood that a heterocycle can have additional heteroatoms in the ring. Names such as “4- to 6-membered heterocycle” refer to the total number of atoms contained within the ring (ie, a 4-, 5- or 6-membered ring is at least one atom is a carbon atom). Wherein at least one atom is a heteroatom and the remaining 2 to 4 atoms are either carbon atoms or heteroatoms). In heterocycles having two or more heteroatoms, these two or more heteroatoms can be the same or different from each other. Heterocycles can be optionally substituted. The bond to the heterocycle may be at a heteroatom or via a carbon atom. Non-aromatic heterocyclic groups include groups having only 4 atoms in the ring system, but aromatic heterocyclic groups must have at least 5 atoms in the ring system. Heterocyclic groups include benzofused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl , Thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl include 3H- indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolinyl, indolyl, benzoimidazolyl, benzofuranyl, cinnolinyl, , Indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and flopyridinyl. The aforementioned groups may be C-linked or N-linked at possible positions as derived from the groups listed above. For example, the group derived from pyrrole includes pyrrol-1-yl (N-bond) or pyrrol-3-yl (C-bond). Furthermore, the groups derived from imidazole include imidazol-1-yl, imidazol-3-yl (both N-linked), imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C -Bond). Heterocyclic groups include benzofused ring systems and ring systems substituted with one or two oxo (= O) moieties, such as pyrrolidin-2-one. Depending on the structure, the heterocyclic group can be a monoradical or a diradical (ie, a heterocyclene group).

  The term “membered ring” can also include any cyclic structure. The term “membered” means an indication of the number of skeletal atoms that make up the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan and thiophene are 5-membered rings.

  An “isocyanato” group refers to a —NCO group.

  An “isothiocyanato” group refers to a —NCS group.

  The term “ketoalkyl” group refers to an alkyl group substituted with an oxo group.

  The term “heteroketoalkyl” group refers to a heteroalkyl group in which one of the carbon atoms is replaced with an oxo group.

  The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized as chemicals embedded or attached to molecules.

  The term “polycycloalkyl” refers to an alkyl group containing a bicyclic or tricyclic hydrocarbon ring structure, including a bridged cycloalkyl ring, a spirocycloalkyl ring or a fused cycloalkyl ring. Examples include norbornyl group, adamantyl group, bicyclo [x. y. z] an alkyl group (each of x, y and z is independently 1, 2, 3 or 4) or a tricyclic alkyl group.

  A “sulfinyl” group refers to —S (═O) —R.

A “sulfonyl” group refers to —S (═O) ₂ —R.

  A “thioalkoxy” group refers to an —S-alkyl group.

  As used herein, the term “O-carboxy” refers to a group of formula RC (═O) O—.

  As used herein, the term “C-carboxy” refers to a group of formula —C (═O) OR.

As used herein, the term “acetyl” refers to a group of formula —C (═O) CH ₃ .

As used herein, the term “trihalomethanesulfonyl” refers to a group of formula X ₃ CS (═O) ₂ —, where X is a halogen.

  As used herein, the term “cyano” refers to a group of formula —CN.

As used herein, the term “S-sulfonamido” refers to a group of formula —S (═O) ₂ NR ₂ —.

As used herein, the term “N-sulfonamido” refers to a group of formula RS (═O) ₂ NH—.

As used herein, the term “O-carbamyl” refers to a group of formula —OC (═O) NR ₂ —.

  As used herein, the term “N-carbamyl” refers to a group of formula ROC (═O) NH—.

As used herein, the term “Othiocarbamyl” refers to a group of formula —OC (═S) NR ₂ —.

  As used herein, the term “N thiocarbamyl” refers to a group of formula ROC (═S) NH—.

As used herein, the term “C-amido” refers to a group of formula —C (═O) NR ₂ .

  As used herein, the term “N-amido” refers to a group of formula RC (═O) NH—.

  As used herein, the substituent “R” that appears alone without a number designation is alkyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon) and non-aromatic heterocycle (ring carbon A substituent selected from:

The term “optionally substituted” or “substituted” means that the group referred to is alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, Alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, cyano, halo, carbonyl, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, perhaloalkyl, perfluoroalkyl, silyl and amino (mono- and di-substituted amino groups) As well as one or more additional groups each independently selected from these protected derivatives. Illustratively, the optional substituent is L ₅ R ₅ (each L ₅ is a bond, —O—, —C (═O) —, —S—, —S (═O) —, —S (═O ) ₂ —, —NH—, —NHC (O) —, —C (O) NH—, S (═O) ₂ NH—, —NHS (═O) ₂ , —OC (O) NH—, —NHC Independently selected from (O) O—, — (substituted or unsubstituted C ₁ -C ₆ alkyl), or — (substituted or unsubstituted C ₂ -C ₆ alkenyl); and each R ₅ is H, (Independently selected from substituted or unsubstituted lower alkyl), (substituted or unsubstituted lower cycloalkyl), heteroaryl or heteroalkyl. Protecting groups that form protected derivatives of the above substituents are known to those skilled in the art and can be found in reference materials such as Greene and Wuts described above.

  The compounds shown herein can have one or more stereocenters, and each center can exist in the R or S configuration. The compounds shown here include not only all diastereomeric, enantiomeric and epimeric forms, but also suitable mixtures thereof. Stereoisomers can be obtained, if desired, by methods known in the art such as, for example, separation of stereoisomers by chiral chromatography columns.

  The methods and formulations described herein provide similar types of activity, as well as N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein. Including the use of active metabolites of these compounds. In some cases, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. Furthermore, the compounds described herein can exist not only in non-solvate form, but also in the form of solvates with water, pharmaceutically acceptable solvents such as ethanol. . Solvate forms of the compounds shown herein are also considered to be disclosed herein.

  Throughout the specification, groups and their substituents can be selected by one skilled in the art to provide stable moieties and compounds.

Compounds Certain compounds that inhibit the activity of fatty acid amide hydrolase (FAAH) play a health role. In certain embodiments, FAAH inhibitor compounds are useful for treating any of a variety of diseases, disorders, or symptoms. In certain embodiments, the compounds provided herein are selective FAAH inhibitor compounds.

  FAAH inhibitor compositions are described in US patent application Ser. Nos. 10 / 681,858, 60 / 755,035; US Pat. Nos. 6,462,054, 6,949,574 and 6,891,043; International Patent Application Publication Nos. WO04020430, WO04067498, WO04099176, WO05033066, WO02087569, WO03065989, WO9749667, WO9926584, WO04036352 and WO06044617; Cravatt et al. Current Opinion in Chemical Biology, 2003, 7: 469-475; Kathuria et al. Nature Medicine, vol. 9, no. 1, pp 76-81, 2003; Tarzia et al. J. et al. Med. Chem. 2003, 46, 2352-2360; and Drysdale et al. Current Medicinal Chemistry, 2003, 10, 2719-2732.

  Also described herein are pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions comprising at least one such compound or a pharmaceutically acceptable salt, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such a compound are provided.

  In certain embodiments, the compounds provided herein are ionizable and do not substantially cross the blood brain barrier. In certain embodiments, provided herein are carbamate FAAH inhibitors that are capable of ionization at physiological pH and are therefore less likely to cross the blood brain barrier. In certain embodiments, the compounds provided herein have a site that is ionizable at physiological pH. In other embodiments, the compounds provided herein have a moiety that ionizes at physiological pH. In other embodiments, the compounds provided herein have a charge at physiological pH. In some other embodiments, the compounds provided herein are protonated at physiological pH. In other embodiments, the compounds provided herein are deprotonated at physiological pH. Such FAAH inhibitors are particularly useful when it is desired to minimize and / or avoid psychotropic effects caused by FAAH inhibition in the central nervous system.

  In certain embodiments, a compound provided herein is

［上記式において、
ＤはＯまたはＮＲ^１１であり；
ＡまたはＢの一方は、（ＣＨ_２）_ｎＣ（Ｏ）−アルキル、（ＣＨ_２）_ｎＣ（Ｏ）−Ｎ（Ｒ^２）_２であり、および他方はＨ，アルキル、またはヘテロアルキルであり、ｎは０、１、２、３、または４であり；
またはＡおよびＢは一緒になって、Ｃ（Ｏ）−（ＣＨ_２）_ｎ−部分を含む場合により置換された非芳香族環基を形成し、ｎは１、２、３または４であり；
またはＡおよびＢは、一諸になって少なくとも１つのＮ、ＮＲ^２、ＳまたはＯ基を含む、場合により置換されたヘテロ芳香族基を形成し；
またはＡおよびＢは、一諸になって場合により置換された非芳香族もしくは芳香族の炭素環基を形成し；
またはＡおよびＢは、一諸になって場合により置換されたオキソ−置換複素環を形成し；
またはＡおよびＢはＨ、場合により置換されたアルキル、場合により置換されたヘテロアルキル、場合により置換された複素環基、場合により置換されたアリール基、場合により置換されたヘテロアリール基、場合により置換されたケトアルキルおよび場合により置換されたケトヘテロアルキルからそれぞれ独立して選択され；
Ｒ^１は、Ｃ_３−Ｃ_９シクロアルキル、Ｃ_１−Ｃ_４アルキル（Ｃ_３−Ｃ_９シクロアルキル）、Ｃ_１−Ｃ_４アルキル（アリール）およびＣ_１−Ｃ_４アルキル（ヘテロアリール）から選択される場合により置換された基であり；
Ｒ^１のシクロアルキル環のいずれの炭素も、場合によりＹおよびＺで置換されることができ、各Ｙおよび各Ｚはハロゲン、メチルまたはトリフルオロメチルから独立して選択され、またはＹおよびＺは一緒になって３員、４員または５員の炭素環基またはオキソ（＝Ｏ）を形成することができ；
各Ｒ^２およびＲ^１１はＨまたは場合により置換されたアルキルから独立している。］
から選択される構造を有する、およびこれらの医薬的に許容される塩、医薬的に許容されるＮ−オキシド、医薬的に活性な代謝物、医薬的に許容されるプロドラッグまたは医薬的に許容される溶媒和物である。

[In the above formula,
D is O or NR ¹¹ ;
One of A or B _{is, (CH 2) n C (} O) - _{alkyl, (CH 2) n C (} O) -N (R 2) _2, and the other is an H, alkyl or heteroalkyl, , N is 0, 1, 2, 3, or 4;
Or A and B together form an optionally substituted non-aromatic ring group containing a C (O) — (CH ₂ ) _n — moiety, where n is 1, 2, 3 or 4;
Or A and B together form an optionally substituted heteroaromatic group comprising at least one N, NR ² , S or O group;
Or A and B together form an optionally substituted non-aromatic or aromatic carbocyclic group;
Or A and B together form an optionally substituted oxo-substituted heterocycle;
Or A and B are H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally Each independently selected from substituted ketoalkyl and optionally substituted ketoheteroalkyl;
R ¹ is selected from C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl (heteroaryl) Optionally substituted group;
Any carbon of the cycloalkyl ring of R ¹ can be optionally substituted with Y and Z, wherein each Y and each Z is independently selected from halogen, methyl or trifluoromethyl, or Y and Z are Taken together can form a 3-, 4- or 5-membered carbocyclic group or oxo (= O);
Each R ² and R ¹¹ is independent of H or optionally substituted alkyl. ]
And a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable thereof. Solvate.

In a further embodiment, A and B _{^{together, -C (O) - (CR}} q R q) n -, - C (O) -NR 2 - (CR q R q) n -, - NR _{^{2 -C (O) - (CR}} q R q) n -, - C (O) -NR 2 -NR 2 - (CR q R q) n -, - C (O) -NR 2 -N = (CR ^{q) -, - O-C} (O) -O-, O-C (O) -NR 2 -, - NR 2 -C (O) -NR 2 -, - O-C (O) -O- ( ^{_{CR q R q) n -,}} - O-C (O) - (CR q R q) n -O -, - n-C (O) - (CR q R q) n -N -, - O-C _{^{(O) - (CR q R}} q) n -N -, - n-C (O) - (CR q R q) n -O -, - O-C (O) -NR 2 - (CR q R q ^{_{) n -, - NR 2 -C}} (O) -O- (CR q R q ^{_{n -, - NR 2 -C (}} O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -O- (CR q R q) n -, - ^{_{(CR q R q) n -C}} (O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -NR 2 -NR 2 -, - (CR q ^{_{R q) n -C (O)}} - (CR q R q) n -, - C (O) -O- (CR q R q) n -O -, - C (O) -O- (CR q R ^{_{q) n -NR 2 -, -}} C (O) -NR 2 - (CR q R q) n -NR 2, -C (O) -NR 2 - (CR q R q) n -O -, - C ^{(O) -NR 2 -CR q =} CR q -, C (O) -CR q = CR q -NR 2 -, - C (O) -CR q = CR q -O -, - C (O) - It is selected from ^{CR q} = CR ^q -S- , Optionally oxo substituted - to form a substituted heterocyclic ring; be each n is independently 1, 2 or 3; and each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, Independently selected from substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle or substituted heterocycle.

  In certain embodiments, the compounds provided herein have the formula (II)

［式中、
ＤはＯまたはＮＲ^１１であり；
Ｒ^１は、

[Where:
D is O or NR ¹¹ ;
R ¹ is

（式中、Ｍは結合、場合により置換されたＣ_１−Ｃ_８アルキレン、場合により置換された４個の原子のヘテロアルキレン、場合により置換されたＣ_２−Ｃ_８アルケニレン、場合により置換されたＣ_３−Ｃ_８シクロアルキルまたは場合により置換されたＣ_２−Ｃ_８アルキニレンであり；
ＪはＣＨまたはＮであり；ＫはＣＨまたはＮであり；但し、ＫがＣＨのときは、ＪはＣＨではあり得ず；
各Ｒ^３は、Ｃ_１−Ｃ_６アルキル−（アリール）、Ｃ_１−Ｃ_６アルキル−（ヘテロアリール）、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６アルキルアミン、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、
Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、−Ｃ（Ｏ）−Ｒ^１２、アリール、ヘテロアリール、ヘテロシクロアルキル、フェニル、ピリジル、ピリダジニル、ピペラジニル、ピペリジニル、モルホリニル、フラニル、チオフェニル、チオフェンイル、ジベンゾフラニル、ジベンゾチエニル、インドリル、フルオレニル、カルボゾリル、ピリミジニル、ピラジニル、トリアジニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、ナフチル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、シンノリル、イミダゾピリミジニル、チエノピリミジニル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、ピロロピリジル、フロピリジル、ジヒドロフロピリジル、チエノピリジル、ジヒドロチエノピリジル、イミダゾピリジル、ピラゾロピリジル、オキサオロピリジル、イソオキサオロピリジルまたはチアゾロピリジルから選択される場合により置換された基から成る群から独立して選択され；
各Ｒ’は独立してＨ、アルキル、または置換アルキルであり；
各Ｒ^５は独立してＨ、Ｃ_１−Ｃ_３アルキルまたはハロゲンであり；
Ｒ^６はＣ_１−Ｃ_３アルキルまたはＣ_３−Ｃ_７シクロアルキルであり；
Ｒ^２およびＲ^１１はＨまたは場合により置換されたアルキルであり；
Ｒ^１２は、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_７シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、ベンジルオキシ、フラニル、フェニル、ベンジル、またはピリジルからなる群から選択される。）からなる群から選択され；
または、Ｒ^１およびＲ^２は一緒になって、

Wherein M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted. C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;
J is CH or N; K is CH or N; provided that when K is CH, J cannot be CH;
Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl,
C ₃ -C _{8 cycloalkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, Thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, isoquinolyl Quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyr Dinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, Independently selected from the group consisting of optionally substituted groups selected from oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl;
Each R ′ is independently H, alkyl, or substituted alkyl;
Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;
R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;
R ² and R ¹¹ are H or optionally substituted alkyl;
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl, or pyridyl. ) Selected from the group consisting of:
Or R ¹ and R ² together,

(N is 1, 2, 3 or 4; m is 1, 2, 3 or 4);
A and B together form an optionally substituted non-aromatic ring group containing a C (O) — (CH ₂ ) _q — moiety, where q is 1, 2, 3, or 4;
Or A and B together form an optionally substituted oxo-substituted heterocycle;
Or A and B together form an optionally substituted aromatic or non-aromatic ring group containing at least one N, NR ² , S or O group;
Or one of A or B is -L-G, and the other is selected from C ₁ -C ₆ alkyl substituted by H and optionally;
Or A and B together form an optionally substituted aromatic carbocyclic group;
Or A and B are H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally Independently selected from substituted ketoalkyl, optionally substituted amide and optionally substituted ketoheteroalkyl;
L is a bond, or _C 1 -C _{6 alkylene,} C 1 -C _{6 heteroalkylene,} C 1 -C _{6 ^{Ketoarukiren, -C (O) NR 9 -}} (CH 2) j -, - NR 9 -C (O _{) - (CH 2) j -} , - OC (O) O- (CH 2) j -, - NHC (O) O- (CH 2) j -, - O (O) CNH- (CH 2) j - _{, -C (O) O- (CH} 2) j -, - OC (O) - (CH 2) j -, - NR 9 C (O) N (R 9) - (CH 2) j -, - S _{(O) - (CH 2)} j -, - S (O) 2 - (CH 2) j, -C (= NR 10) N (R 9) - (CH 2) j - and ^-NR 9 C (= ^{NR 10) N (R 9)} - (CH 2) j - if selected by a substituted radicals from;
G is tetrazolyl, —NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHR ⁸ , —S (═O) ₂ NH-phenyl, —OH, —SH, —OC (O) NHR ⁸ , —NHC (O) OR ⁸ , —C (O) NHC (O) R ⁸ , —C (O) NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHC (O) R ⁸ , —S (═O) ₂ NHC (O) NHR ⁸ , —NHC (O) R ⁸ , —NHC (O) N (R ⁹ ) ₂ , —C (═NR ¹⁰ ) N (R ⁹ ) ₂ , —NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , _{^{-C (O) NR 9 C (}} = NR 10) N (R 9) 2, -C (O) NR 9 C (= CHR 10) N (R 9) 2, -CO 2 H, - ^{_{OP (= O) OH) x}} OH, -OP (= O) OR 8 OH, -OP (= O) R 8 OH, -NR 9 P (= O) OR 8 OH, -NR 9 P (= O) in _{-NR 9 S (O) y OH} ; R 8 OH, -P (= O) OR 8 OH ;-P (= O) R 8 OH, -S (O) y OH; -OS (O) y OH Yes;
Each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ⁹ is independently H, substituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkyl;
Each R ¹⁰ is independently selected from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN and —NO ₂ ;
j is 0, 1, 2, 3 or 4; x is 1, 2 or 3; y is 0, 1 or 2;
Any of the _{substituents,} C 1 -C _{3 alkyl,} C 1 -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy -C, (O) R ', - C (O) - ( alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-( Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) ) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl) , —S (O) _k R ′ (k is 1 or 2), —S (O) _k (alkyl or substituted alkyl), —C (S) — (alkyl or substituted alkyl), —CSN (R ′) ₂ , -CSN (R ')-(alkyl or substituted alkyl), -N (R') CO- (alkyl or substituted alkyl), -N (R ') C (O) OR',-(alkyl or substituted alkyl) ) -O-N = C (R ') ₂ ,-(alkyl or substituted alkyl) -C (O) NR'-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- ( Alkyl or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N (R ') _{2, -N (R ') C} (S) N (R') 2, -N (R ') S (O) k N (R') 2 -C (R ') = NR'- C (R') = N-N (R ') 2 , and _{-C (R') 2 -N (} R ') - N (R') independently selected from ₂ Is done. And a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvent It is a Japanese product.

In a further embodiment, A and B _{^{together, -C (O) - (CR}} q R q) n -, - C (O) -NR 2 - (CR q R q) n -, - NR _{^{2 -C (O) - (CR}} q R q) n -, - C (O) -NR 2 -NR 2 - (CR q R q) n -, - C (O) -NR 2 -N = (CR ^{q) -, - O-C} (O) -O-, O-C (O) -NR 2 -, - NR 2 -C (O) -NR 2 -, - O-C (O) -O- ( ^{_{CR q R q) n -,}} - O-C (O) - (CR q R q) n -O -, - n-C (O) - (CR q R q) n -N -, - O-C _{^{(O) - (CR q R}} q) n -N -, - n-C (O) - (CR q R q) n -O -, - O-C (O) -NR 2 - (CR q R q ^{_{) n -, - NR 2 -C}} (O) -O- (CR q R q ^{_{n -, - NR 2 -C (}} O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -O- (CR q R q) n -, - ^{_{(CR q R q) n -C}} (O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -NR 2 -NR 2 -, - (CR q ^{_{R q) n -C (O)}} - (CR q R q) n -, - C (O) -O- (CR q R q) n -O -, - C (O) -O- (CR q R ^{_{q) n -NR 2 -, -}} C (O) -NR 2 - (CR q R q) n -NR 2, -C (O) -NR 2 - (CR q R q) n -O -, - C ^{(O) -NR 2 -CR q =} CR q -, C (O) -CR q = CR q -NR 2 -, - C (O) -CR q = CR q -O -, - C (O) - It is selected from ^{CR q} = CR ^q -S- , Optionally oxo substituted - to form a substituted heterocyclic ring; be each n is independently 1, 2 or 3; and each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, Independently selected from substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle or substituted heterocycle.

  In certain embodiments, the compound provided herein has formula (IIa):

の構造を有する。

It has the following structure.

  In other embodiments, the compound provided herein has formula (IIb):

の構造を有する。

It has the following structure.

    In certain embodiments, the compound provided herein has formula (IIc):

の構造を有する。

It has the following structure.

  In another embodiment, the compound provided herein has formula (IId):

の構造を有する。

It has the following structure.

  In still some other embodiments, the compounds provided herein have the formula (IIe):

を有する。

Have

  In certain embodiments, A and B are both H. However, there is at least one X, which is N. In embodiments where X is present, at least one X is N.

  In certain embodiments, formula (I)

［上記式において、ＤはＯまたはＮＲ^１１であり；ＡまたはＢの一方は（ＣＨ_２）_ｍＣ（Ｏ）−アルキル、（ＣＨ_２）_ｍＣ（Ｏ）−Ｎ（Ｒ^２）_２であり、および他方はＨ，アルキル、またはヘテロアルキルであり、式中、ｍは０、１、２または３であり；またはＡおよびＢは、一諸になって場合により置換されたオキソ−置換複素環を形成し；またはＡおよびＢは、一諸になって場合により置換された少なくとも１つのＮ、ＮＲ^２、ＳまたはＯ基を含むヘテロ芳香族基を形成し；またはＡおよびＢは、一諸になって場合により置換された非芳香族もしくは芳香族の炭素環基を形成し；またはＡおよびＢはＨ、場合により置換されたアルキル、場合により置換されたヘテロアルキル、場合により置換された複素環基、場合により置換されたアリール基、場合により置換されたヘテロアリール基、場合により置換されたケトアルキルおよび場合により置換されたケトヘテロアルキルからそれぞれ独立して選択され；Ｒ^１は、Ｃ_３−Ｃ_９シクロアルキル、Ｃ_１−Ｃ_４アルキル（Ｃ_３−Ｃ_９シクロアルキル）、Ｃ_１−Ｃ_４アルキル（アリール）およびＣ_１−Ｃ_４アルキル（ヘテロアリール）から選択される、場合により置換された基であり、Ｒ^１のシクロアルキル環のいずれの炭素も、場合によりＹおよびＺで置換されることができ、各Ｙおよび各Ｚはハロゲン、メチルまたはトリフルオロメチルから独立して選択され、またはＹおよびＺは一緒になって３員、４員もしくは５員の炭素環基またはオキソ（＝Ｏ）を形成することができ；各Ｒ^２はＨまたは場合により置換されたアルキルから独立して選択され；Ｒ^１１はＨまたは場合により置換されたアルキルである。］の構造のおよび医薬的に許容される塩、医薬的に許容されるＮ−オキシド、医薬的に活性な代謝物、医薬的に許容されるプロドラッグまたは医薬的に許容される溶媒和物である化合物がここに提供される。

[In the above formula, D is O or NR ¹¹ ; one of A or B is (CH ₂ ) _m C (O) -alkyl, (CH ₂ ) _m C (O) —N (R ² ) ₂ And the other is H, alkyl, or heteroalkyl, wherein m is 0, 1, 2, or 3; or A and B are optionally substituted oxo-substituted heterocycles Or A and B together form a heteroaromatic group comprising at least one optionally substituted N, NR ² , S or O group; or A and B are To form an optionally substituted non-aromatic or aromatic carbocyclic group; or A and B are H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted hetero Cyclic group, optionally substituted Aryl group, optionally substituted heteroaryl group, optionally each independently selected from keto heteroalkyl, optionally substituted, which has been ketoalkyl and substituted; R ¹ is, C ₃ -C ₉ cycloalkyl alkyl, C ₁ -C ₄ alkyl _(C 3 -C _{9 cycloalkyl),} is selected from C 1 -C ₄ alkyl (aryl) and _C 1 -C ₄ alkyl (heteroaryl), a optionally substituted radical, R any carbon of ¹ cycloalkyl rings, can optionally be substituted with Y and Z, each Y and each Z is independently selected from halogen, methyl or trifluoromethyl, or Y and Z together To form a 3-membered, 4-membered or 5-membered carbocyclic group or oxo (═O); each R ² is H or optionally substituted Independently selected from substituted alkyl; R ¹¹ is H or optionally substituted alkyl; And a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate Certain compounds are provided herein.

For any and all embodiments, substituents may be selected from a subset of the listed options. For example, in certain embodiments, one of A or B is C (O) -alkyl and the other is H or alkyl or heteroalkyl. In certain embodiments, A and B are taken together to form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _n — moiety, where n is 1, 2, 3 Or 4. In other embodiments, A and B are taken together to form an optionally substituted heteroaromatic ring group comprising at least one N, NR ² , S or O group. In certain embodiments, R ¹ is C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl ( Heteroaryl) is an optionally substituted group, and any carbon of the cycloalkyl ring of R ¹ can be optionally substituted with Y and Z, wherein each Y and each Z is halogen, methyl Or independently selected from trifluoromethyl, or Y and Z can be taken together to form a 3-, 4- or 5-membered carbocyclic group or oxo (= O). In certain embodiments, R ² is H or optionally substituted alkyl. In certain embodiments, R ¹¹ is H. In other embodiments, pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates. It is.

In a further embodiment, A and B _{^{together, -C (O) - (CR}} q R q) n -, - C (O) -NR 2 - (CR q R q) n -, - NR _{^{2 -C (O) - (CR}} q R q) n -, - C (O) -NR 2 -NR 2 - (CR q R q) n -, - C (O) -NR 2 -N = (CR ^{q) -, - O-C} (O) -O-, O-C (O) -NR 2 -, - NR 2 -C (O) -NR 2 -, - O-C (O) -O- ( ^{_{CR q R q) n -,}} - O-C (O) - (CR q R q) n -O -, - n-C (O) - (CR q R q) n -N -, - O-C _{^{(O) - (CR q R}} q) n -N -, - n-C (O) - (CR q R q) n -O -, - O-C (O) -NR 2 - (CR q R q ^{_{) n -, - NR 2 -C}} (O) -O- (CR q R q ^{_{n -, - NR 2 -C (}} O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -O- (CR q R q) n -, - ^{_{(CR q R q) n -C}} (O) -NR 2 - (CR q R q) n -, - (CR q R q) n -C (O) -NR 2 -NR 2 -, - (CR q ^{_{R q) n -C (O)}} - (CR q R q) n -, - C (O) -O- (CR q R q) n -O -, - C (O) -O- (CR q R ^{_{q) n -NR 2 -, -}} C (O) -NR 2 - (CR q R q) n -NR 2, -C (O) -NR 2 - (CR q R q) n -O -, - C ^{(O) -NR 2 -CR q =} CR q -, C (O) -CR q = CR q -NR 2 -, - C (O) -CR q = CR q -O -, - C (O) - It is selected from ^{CR q} = CR ^q -S- Optionally oxo substituted - to form a substituted heterocyclic ring; be each n is independently 1, 2 or 3; and each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl , Ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle or substituted heterocycle.

In certain embodiments, R ² is H. In certain embodiments, one of A or B is C (O) —CH ₃ and the other is CH ₃ .

In other embodiments, as non-limiting examples, 3-carbamoylphenylcyclohexylcarbamate; 3-carbamoylphenylcyclohexylmethylcarbamate; 3-acetylphenylcyclohexylcarbamate; 3-acetylphenylcyclohexylmethylcarbamate; 3-acetylphenylisopropylcarbamate; Selected from 3-acetylphenylisobutylcarbamate; and 3-acetylphenylphenethylcarbamate. In certain embodiments, A and B are taken together to form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _n — moiety, where n is 1, 2, 3 or 4. In another embodiment, n is 2. In certain embodiments, R ² is H. In other embodiments, A or B is C (O) —CH ₂ CH ₃ .

  In certain embodiments, as a non-limiting example, 2,3-dihydro-1-oxo-1H-inden-6-ylcyclohexyl carbamate; 2,3-dihydro-1-oxo-1H-inden-6-ylcyclohexyl Selected from 2,3-dihydro-1-oxo-1H-inden-5-ylcyclohexyl carbamate; and 2,3-dihydro-1-oxo-1-H-inden-5-ylcyclohexylmethyl carbamate; .

In a further embodiment, A and B are taken together to form an optionally substituted heteroaromatic ring group comprising at least one N, NR ² , S or O group. In certain embodiments, further comprising a — (CH) _n — moiety, wherein n is 1, 2 or 3. In another embodiment, an optionally substituted heteroaromatic group containing 1 N in the ring.

  In certain embodiments, as non-limiting examples, quinolin-7-ylcyclohexylcarbamate; quinolin-7-ylcyclohexylmethylcarbamate; quinolin-7-ylcycloheptylcarbamate; quinolin-7-yl (furan-2-yl) Quinolin-7-ylcyclohexylmethylcarbamate; quinolin-6-ylcyclohexylcarbamate; quinolin-6-ylcyclohexylmethylcarbamate; quinolin-6-yl (furan-2-yl) methylcarbamate; isoquinolin-7-yl Cyclohexyl carbamate; isoquinolin-7-ylcyclohexylmethyl carbamate; isoquinolin-7-ylcycloheptyl carbamate; and their pharmaceutically acceptable N-oxides .

  In certain embodiments, the optionally substituted heteroaromatic group comprises 2 heteroatoms selected from N, S and O.

  In certain embodiments, non-limiting examples include 2-methylbenzo [d] thiazol-5-ylcyclohexylcarbamate; 2-methylbenzo [d] thiazol-5-ylcyclohexylmethylcarbamate; 2-methylbenzo [d] oxazole- Selected from the group of 5-ylcyclohexylcarbamate; and 2-methylbenzo [d] oxazol-5-ylcyclohexylmethylcarbamate.

  Further compounds provided herein are:

［上記式において、ＤはＯまたはＮＲ^１１であり；
Ｒ^１は、

[In the above formula, D is O or NR ¹¹ ;
R ¹ is

（上記式において、Ｍは結合、場合により置換されたＣ_１−Ｃ_８アルキレン、場合により置換された４個の原子のヘテロアルキレン、場合により置換されたＣ_２−Ｃ_８アルケニレン、場合により置換されたＣ_３−Ｃ_８シクロアルキルまたは場合により置換されたＣ_２−Ｃ_８アルキニレンであり；
ＪはＣＨまたはＮであり；ＫはＣＨまたはＮであり；但し、ＫがＣＨのときは、ＪはＣＨではあり得ず；
各Ｒ^３は、Ｃ_１−Ｃ_６アルキル−（アリール）、Ｃ_１−Ｃ_６アルキル−（ヘテロアリール）、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６アルキルアミン、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、
Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、−Ｃ（Ｏ）−Ｒ^１２、アリール、ヘテロアリール、ヘテロシクロアルキル、フェニル、ピリジル、ピリダジニル、ピペラジニル、ピペリジニル、モルホリニル、フラニル、チオフェニル、チオフェンイル、ジベンゾフラニル、ジベンゾチエニル、インドリル、フルオレニル、カルボゾリル、ピリミジニル、ピラジニル、トリアジニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、ナフチル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、シンノリル、イミダゾピリミジニル、チエノピリミジニル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、ピロロピリジル、フロピリジル、ジヒドロフロピリジル、チエノピリジル、ジヒドロチエノピリジル、イミダゾピリジル、ピラゾロピリジル、オキサオロピリジル、イソオキサオロピリジルまたはチアゾロピリジルから選択される場合により置換された基からなる群から独立して選択され；
各Ｒ’は独立してＨ、アルキル、または置換アルキルであり；
各Ｒ^５は独立してＨ、Ｃ_１−Ｃ_３アルキルまたはハロゲンであり；
Ｒ^６はＣ_１−Ｃ_３アルキルまたはＣ_３−Ｃ_７シクロアルキルであり；
Ｒ^２およびＲ^１１はＨまたは場合により置換されたアルキルであり；
Ｒ^１２は、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_７シクロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、ベンジルオキシ、フラニル、フェニル、ベンジル、またはピリジルからなる群から選択される。）からなる群から選択され；
または、Ｒ^１およびＲ^２は一緒になって、

Wherein M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted. C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;
J is CH or N; K is CH or N; provided that when K is CH, J cannot be CH;
Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl,
C ₃ -C _{8 cycloalkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, Thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, isoquinolyl Quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyr Dinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, Independently selected from the group consisting of optionally substituted groups selected from oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl;
Each R ′ is independently H, alkyl, or substituted alkyl;
Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;
R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;
R ² and R ¹¹ are H or optionally substituted alkyl;
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl, or pyridyl. ) Selected from the group consisting of:
Or R ¹ and R ² together,

(N is 1, 2, 3 or 4; m is 1, 2, 3 or 4);
Each of the substituents may be C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano, benzyloxy-C (O) R ′, —C (O)-(alkyl or substituted alkyl ),-(Alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl),-(alkyl or Substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ′ (k is 1 or 2), —S (O) _k (alkyl or substituted alkyl), —C (S) — (alkyl or substituted alkyl), —CSN (R ′) ₂ , — CSN (R ′)-(alkyl or substituted alkyl), —N (R ′) CO— (alkyl or substituted alkyl), —N (R ′) C (O) OR ′, — (alkyl or substituted alkyl) —O -N = C (R ') ₂ ,-(alkyl or substituted alkyl) -C (O) NR'-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- (alkyl or substituted Alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N (R ') ₂ ,- N (R ') C (S ) N (R') 2, -N (R ') S (O) k N (R') 2, -C R ') = NR'-C ( R') = N-N (R ') 2 , and _{-C (R') 2 -N (} R ') - N (R') 2 independently from selected. And a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable Solvate.

  In certain embodiments, the compound of Formula (IIIa) has the structure:

を有する。

Have

Compound Preparation Compounds provided herein that inhibit FAAH activity can be prepared using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. Can be synthesized. As a further guide, the following synthesis methods can be used.

  The reaction may be used in a linear order to provide the compounds described herein, or a fragment is synthesized and this fragment is subsequently treated by methods described herein and / or methods known in the art. May be used to bind.

Use of Protecting Groups The term “protecting group” refers to a chemical moiety that blocks some or all reactive moieties and prevents such groups from participating in chemical reactions until the protecting group is removed. Each protecting group is preferably removable by different means. Protecting groups that are cleaved under completely different reaction conditions meet different removal requirements. Protecting groups are removed by acid, base and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and in the presence of amino groups protected by hydrogenolysis and removable Cbz groups or base labile Fmoc groups. Used to protect the reactive part of carboxy and hydroxyl groups. The carboxyl or hydroxyl reactive moieties are amine-blocked with acid-labile groups such as t-butyl carbamate or with both acid and base stable but hydrolytically removable carbamates. Can be blocked by base labile groups such as, but not limited to, methyl, ethyl and acetyl.

  Carboxylic acid and hydroxyl reactive moieties can also be blocked with hydrolytically removable protecting groups such as benzyl groups, whereas amine groups capable of hydrogen bonding to acids are bases such as Fmoc. It can be blocked with unstable groups. Carboxylic acid reactive moieties can be protected by conversion to the simple ester derivatives exemplified herein, or can be blocked by oxidatively removable protecting groups such as 2,4-dimethoxybenzyl. On the other hand, the coexisting amino group can be blocked by silyl carbamates which are unstable to fluoride. In one embodiment, a compound that contains both a carboxylic acid reactive moiety and a hydroxyl reactive moiety has one of the blocked reactive moieties while the other reactive moiety is not blocked.

Allyl protecting groups are useful in the presence of acid-protecting groups and base-protecting groups. This is because the former is stable and can then be removed by a metal or pi acid catalyst. For example, allyl protected carboxylic acids can be deprotected by Pd ⁰ catalyzed reaction in the presence of acid labile t-butyl carbamate or base labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, this functional group is blocked and cannot react. Once released from the resin, the functional group is available for reaction.

  Typically, the blocking / protecting group is

から選択することができる。

You can choose from.

  Other protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed. , John Wiley & Sons, New York, NY, 1999, which is hereby incorporated by reference in its entirety.

Methods for Preparing Alkyl Carbamate Esters In certain embodiments, provided herein are methods and methods of making the FAAH inhibitor compounds provided herein. In certain embodiments, the compounds provided herein can be synthesized using the following synthetic scheme. The compounds can be synthesized using methodologies similar to those described below by the use of appropriate alternative starting materials.

  Compounds that inhibit the activity of fatty acid amide hydrolase (FAAH) and processes for their preparation are described herein. Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds. A medicament comprising at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such a compound A composition is provided.

The alkyl carbamates disclosed herein are prepared by the general process shown in Scheme 1. Ar—OH (2) represents a hydroxy-containing compound selected from substituted phenols and heteroaryls containing a hydroxyl moiety. R ¹ and R ² are as defined herein.

  Scheme 1. Synthesis of alkyl carbamates

Treatment of Ar-OH (2) with an isocyanate or isothiocyanate (3) in the presence of a base (such as triethylamine) in an organic solvent (such as ethanol or acetonitrile) to form an alkyl carbamate of structure 1 (Eg, US Pat. No. 5,112,859; WO 2004/033422; US Patent Application 2006/0014830; J. Med. Chem. 2004, 47 (21); 4998-5008; Tarzia et al. J). Med.Chem.46: 2352-2360 (2003); Kathuria et al. Nature Medicine 9 (1): 76 (2003)). Isocyanates or isothiocyanates are commercially available. Methods for preparing isocyanates or isothiocyanates (3) are well known in the art. For example, isocyanates (3, Q═O) can be obtained from the corresponding carboxylic acid (ie R ¹ —COOH) or acid derivative (eg R ¹ —C (O) Cl) to an azide source (eg sodium azide or diphenylphosphoryl azide). ) And then prepared by the Curtius transition (see, for example, Synth. Commun. 1993, 23, 335; Heterocycles 1993, 36, 1305).

Alternatively, the alkylcarbamic acid esters (1) may be prepared from the structure (4) (G = 4) in the presence of a base (such as triethylamine) in order to obtain the desired compound (1). -Nitrophenoxy, chlorine or imidazol-1-yl) by treatment with alkylcarbamic acid derivatives. Compounds of structure (4) are described, for example, in Greene, T .; W. and Wuts, P.A. G. M “Protective Groups in Organic Synthesis”, 3rd Edition, p. 549, New York: Wiley, 1999, and other procedures well known in the art. Briefly, treatment of alkylamines (eg, R ¹ —NH ₂ ) with phosgene or a phosgene equivalent (eg, trichloromethyl chloroformate or carbonyldiimidazole) produces compounds of structure (4).

  Alkyl (thio) carbamic acid esters can also be synthesized by the method outlined in Scheme 2.

  Scheme 2. Synthesis of alkyl (thio) carbamate.

Alkyl (thio) carbamic acid esters can be prepared by a two-step procedure. Thiophosgene, phosgene or an equivalent thereof is first treated with Ar—OH (2) in the presence of a base in a suitable organic solvent and then with an alkylamine such as R ¹ R ² NH. The order of the reactions can be reversed. That is, thiophosgene, phosgene or equivalents thereof can be treated with alkylamine and then with Ar-OH (2). Thiophosgene and phosgene equivalents include, but are not limited to, 1,1′-thiocarbonyldiimidazole, 1,1′-carbonyldiimidazole, and trichloromethyl chloroformate.

  The required hydroxyl-containing compound, Ar—OH (2), can be purchased from commercial sources or prepared using procedures known in the art or as outlined herein.

  Using the reaction conditions described herein, the alkyl carbamates disclosed herein are obtained in good yield and purity. Compounds prepared by the methods disclosed herein are purified by conventional means known in the art, such as filtration, recrystallization, chromatography, distillation and combinations thereof.

  Combinations of any of the groups set forth above with respect to various variables are contemplated herein.

Pharmaceutical compositions / formulations Pharmaceutical compositions employ one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. And can be formulated by conventional methods. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers and excipients can be used as appropriate and understood in the art. For an overview of the pharmaceutical compositions described herein, see, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E. , Remington's Pharmaceutical Sciences, Mack Publishing Co. , Easton, Pennsylvania 1975; A. and Lachman, L .; Eds. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N .; Y. 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which is incorporated herein by reference in its entirety.

  Provided herein are pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable diluent, excipient or carrier. Furthermore, the compounds described herein can be administered as a pharmaceutical composition in which the compounds described herein are mixed with other active ingredients, as in combination therapy. In certain embodiments, the pharmaceutical composition includes, for example, other medical or pharmaceutical agents such as preservatives, stabilizers, wetting or emulsifying agents, solubility enhancers, salts and / or buffers for osmotic pressure adjustment, Carriers, adjuvants and the like may be included. Furthermore, the pharmaceutical composition can also contain other therapeutically valuable substances.

  In certain embodiments, the composition also includes acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid, sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate And bases such as trishydroxymethylaminomethane, and one or more pH adjusting or buffering agents such as citrate / glucose, buffering agents such as sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in amounts necessary to maintain the pH of the composition within acceptable limits.

  In other embodiments, the composition can also include an amount of one or more salts necessary to bring the osmotic pressure of the composition within an acceptable range. Such salts include the anions of sodium, potassium or ammonium cations and chlorides, citrates, ascorbates, borates, phosphates, bicarbonates, sulfates, thiosulfates or bisulfites. Including those having ions. Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

  As used herein, the term “pharmaceutical combination” means a product resulting from the mixing or formulation of a plurality of active ingredients, including fixed and non-fixed combinations of active ingredients. The term “fixed combination” means that both the active ingredient, eg, a compound described herein and a combination agent, are administered to a patient simultaneously in the form of a single item or a single dosage. The term “non-fixed combination” means that the active ingredients, such as the compounds described herein and the concomitant drug, are administered to a patient as separate substances simultaneously, in parallel or in sequence without specific time interval restrictions. means. Such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, eg the administration of 3 or more active ingredients.

  The pharmaceutical composition used herein is a combination of the compounds described herein with other chemicals such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. Refers to a mixture. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in the form of a pharmaceutical composition to a mammal having the disease, disorder or condition to be treated. Is done. Preferably the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used alone or in combination with multiple therapeutic agents as a mixture component.

  The pharmaceutical formulations described herein can be administered to a subject by a number of administration routes, including oral, parenteral (eg, intravenous, subcutaneous, intramuscular), nasal, buccal, topical, rectal. Or including, but not limited to, transdermal routes of administration. The pharmaceutical formulations described here are aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, immediate dissolution formulations, tablets, Examples include, but are not limited to, capsules, pills, timed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations and mixed formulations of fast release and controlled release.

  The pharmaceutical compositions comprising the compounds described herein are by way of example only and are conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, encapsulating or compressing processes. Can be produced in a conventional manner.

  The pharmaceutical composition comprises at least one of the compounds described herein as the active ingredient in the form of the free acid or free base, or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxide crystalline forms (also known as polymorphs) of these compounds having similar activity types as well as active metabolites. In some situations, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. Furthermore, the compounds described herein can exist in the form of solvates as well as non-solvated forms with pharmaceutically acceptable solvents such as water and ethanol. The solvate forms of the compounds presented herein are also considered to be disclosed herein.

Certain pharmaceutical terms The term “treat”, “treating” or “treatment” as used herein refers to prophylactically and / or therapeutically, an extra sign that reduces, reduces or ameliorates a disease or condition. Diseases that prevent, ameliorate or prevent the underlying metabolic causes of symptoms, inhibit a disease or condition (eg, stop the progression of the disease or condition), relieve the disease or condition, or cause a reduction in the disease or condition Or alleviating symptoms caused by symptoms or stopping signs of a disease or condition.

  With respect to a formulation, composition or ingredient, the term “acceptable” as used herein means having no lasting deleterious effect on the general health of the subject being treated.

  As used herein, the term “selective inhibitor compound” refers to a compound that selectively inhibits a specific function / activity of one or more target proteins.

As used herein, the term “selectively inhibit” refers to a specific function / target protein of the target protein, such as, for example, the fatty acid amide hydrolyzing activity of a fatty acid amide hydrolase that has a potency that is stronger than the activity of the non-target protein. Refers to the ability of a selective inhibitor compound to inhibit activity. In certain embodiments, selectively inhibiting is selective inhibition having an IC ₅₀ that is at least 10, 50, 100, 250, 500, 1000, or more lower than for non-target protein activity. It refers to inhibiting target protein activity with an agent.

  As used herein, amelioration of a sign of a particular disease, injury or symptom by administration of a particular compound or pharmaceutical composition can be permanent or temporary due to or associated with administration of the compound or composition. Refers to all reductions in severity, delayed onset, delayed progression, or shortened duration, whether mental, persistent or transient.

  As used herein, the term “target activity” refers to a biological activity that can be modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes and remission of one or more symptoms associated with a disease or condition.

As used herein, IC ₅₀ refers to the amount, concentration or dose of a particular test compound, such as a FAAH inhibitor, that achieves 50% inhibition of maximal response in an assay that measures that response.

As used herein, EC ₅₀ is the dose, concentration or amount of a particular test compound that causes a dose-dependent response at 50% of the maximum indication of that particular response introduced, induced or enhanced by that particular test compound. Point to.

  The term “carrier” as used herein refers to a relatively non-toxic compound or agent that facilitates the uptake of a compound into cells or tissues.

  The term “co-administration” and the like, as used herein, includes the administration of a selected therapeutic agent to a single patient, where the agents are administered by the same or different routes of administration or at the same or different times. It is meant to include the law.

  The term “effective amount”, or “therapeutically effective amount”, as used herein, is sufficient to alleviate to some extent one or more signs of a disease or condition being treated of an administered drug or compound. Refers to the quantity. The outcome of treatment may be a reduction and / or alleviation of signs, signs or causes of illness or any other desired change in the biological system. For example, an “effective amount” for therapeutic purposes is a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms without undue side effects. Is the amount. An appropriate “effective amount” in the case of any individual can be determined using techniques, such as a dose escalation study. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a compound disclosed herein is an amount effective to achieve the desired pharmacological effect or therapeutic improvement without undue side effects. “Effective amount” or “therapeutically effective amount” refers to the metabolism, age, weight, general health condition of the subject, symptoms being treated, severity of symptoms being treated, and variability in the judgment of the prescribing physician. Can vary from subject to subject.

  The term “enhance” or “enhancing” as used herein means increasing or prolonging in the potency or duration of a desired effect. Thus, with respect to enhancing the effect of a therapeutic agent, the term “enhancing” refers to the effect of increasing or prolonging the effect of other therapeutic agents in the system in potency or duration. As used herein, “enhancing effective amount” refers to an amount adequate to enhance the effect of another therapeutic agent in the desired system.

  The terms “kit” and “product” are used synonymously.

  A “metabolite” of a compound disclosed herein is a derivative of this compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized” as used herein refers to the synthesis of processes (including but not limited to hydrolysis reactions and enzymatic catalysis reactions such as, for example, oxidation reactions), whereby specific substances are identified. Converted by the organism. In this way, enzymes can cause specific structural changes in compounds. For example, cytochrome P450 catalyzes various oxidative and reductive reactions, while uridine diphosphate glucuronosyltransferase is an aromatic, aliphatic alcohol, activated glucuronic acid molecule, Catalyze the transfer to carboxylic acids, amines and free sulfhydryl groups. Detailed information on metabolism can be obtained from The Pharmaceutical Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein are identified by administering the compound to a host and analyzing a tissue sample from the host or incubating the compound with hepatocytes in vivo and analyzing the resulting compound Can do. Both methods are well known in the art. In certain embodiments, the metabolite of the compound is formed by an oxidative process and corresponds to the corresponding hydroxyl-containing compound. In certain embodiments, the compound is metabolized and metabolized to a pharmacologically active metabolite.

  “Prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, under certain circumstances, they are easier to administer than the parent drug. These are bioavailable by oral administration, for example, but not the parent drug. Prodrugs may have improved solubility in pharmaceutical compositions over the parent drug. One non-limiting example of a prodrug is the compound described herein, which can be administered as an ester (“prodrug”) to facilitate passage through the cell membrane. Although water solubility is detrimental to migration, once the prodrug is then metabolically hydrolyzed to the carboxylic acid, or active body, solubility becomes beneficial within the cell. A further example of a prodrug may be a short peptide (polyamino acid) attached to an acidic group where the peptide is metabolized to expose the active site. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to convert the compound to the biologically pharmaceutically or therapeutically more active form. In certain embodiments, prodrugs are enzymatically metabolized by one or more steps or processes to convert the compound to a biologically pharmaceutically or therapeutically more active form. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound is regenerated by in vivo administration. Prodrugs are designed to alter metabolic stability or drug transport properties, mask side effects or toxicity, improve drug taste, or alter other characteristics or properties of the drug be able to. With knowledge of in vivo pharmacodynamic processes and drug metabolism, one of ordinary skill in the art can design prodrugs of a compound once it is known to be pharmaceutically active (eg, Nogrady (1985) Medicinal Chemistry). A Biochemical Approach, Oxford University Press, New York, pages 388-392;

  As used herein, “pharmaceutically acceptable” refers to a substance such as a carrier or diluent that does not abolish the biological activity or properties of the compound and is relatively nontoxic. That is, the substance does not cause unwanted biological effects and can be administered to an individual without interacting in a deleterious manner with any of the components of the composition in which it is contained. .

  The term “pharmaceutically acceptable salt” refers to the formulation of a compound that does not cause significant irritation to the administered in vivo and does not abrogate the biological activity and properties of the compound. Pharmaceutically acceptable salts are compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. It can be obtained by reacting. Also, pharmaceutically acceptable salts can be prepared by reacting the compounds described herein with a base to produce ammonium, alkali metal (eg, sodium or potassium) salts, alkaline earth metal (eg, calcium or magnesium). Salt), salts with organic bases (eg dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine), and amino acids (eg arginine, lysine). Or can be obtained by methods known in the art.

  “Antifoaming agents” reduce foam formation during processing, resulting in solidification of the aqueous dispersion, generation of foam in the finished film, or generally detrimental processing. Typical antifoaming agents include silicon emulsions or sorbitan oleates.

  “Antioxidants” include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, optionally, the antioxidant enhances chemical stability.

  In certain embodiments, the compositions provided herein also include one or more preservatives that inhibit microbial activity. Suitable preservatives include mercury containing materials such as melfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

  The formulations described herein can benefit from antioxidants, metal chelators, thiol-containing compounds, and other common stabilizers. Examples of such stabilizers include (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0 1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) about 0 0.003% to about 0.02% w / v polysorbate 80, (g) about 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran Including, but not limited to, sulfuric acid, (k) cyclodextrin, (1) pentosan polysulfate and other heparinoids (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

  “Binders” provide adhesive properties, such as alginic acid and its salts; carboxymethylcellulose, methylcellulose (eg Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (eg Klucel®) ), Ethylcellulose (eg, Ethocel®), and cellulose derivatives such as microcrystalline cellulose (eg, Avicel®); microcrystalline dextrose; amylose; aluminum magnesium silicate; polysaccharide acid; bentonite; Polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth gum, dextrin, sucrose (eg Dipac ), Glucose, dextrose, molasses, mannitol, sorbitol, xylitol (eg Xylitab®) and lactose; gum arabic, gum tragacanth, gati gum, isapol husks mucus, polyvinylpyrrolidone ( For example, natural or synthetic such as Polyvidone (registered trademark) CL, Kollidon (registered trademark) CL, Polyplasmone (registered trademark) XL-10), larch arabogalactan, Veegum (registered trademark), polyethylene glycol, waxes, sodium alginate, etc. Contains rubber.

“Bioavailability” refers to the weight percent of a compound disclosed and dosed delivered to the systemic circulation of the animal or human being tested. The total drug exposure (AUC _(0-∞) ) when administered intravenously is usually defined as 100% availability (F%). “Oral bioavailability” refers to the extent to which a compound disclosed herein is absorbed into the systemic circulation when a pharmaceutical composition is taken orally compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of a compound provided herein in the plasma component of a subject's blood. It is understood that the plasma concentrations of the compounds provided herein can vary significantly from subject to subject due to changes in the metabolism and / or possible interactions of other therapeutic agents. According to one embodiment disclosed herein, blood plasma concentrations of the compounds disclosed herein vary from subject to subject. Similarly, the maximum plasma concentration (C _max ) or the time to reach maximum plasma concentration (T _max ) or the area under the plasma concentration-time curve (AUC _(0−∞) ) may vary from subject to subject. Because of this variability, the amount necessary to constitute a “therapeutically effective amount” of a compound provided herein can vary from subject to subject.

  The “carrier material” includes any excipient commonly used in pharmacy and should be selected based on compatibility with the compounds disclosed herein and the release profile characteristics of the desired dosage form. It is. Typical carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricating oils, wetting agents, diluents and the like. “Pharmaceutically compatible carrier materials” include gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, Including sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars, sodium stearoyl lactate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, etc. It is not limited to these. See, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E .; , Remington's Pharmaceutical Sciences, Mack Publishing Co. , Easton, Pennsylvania 1975; A. and Lachman, L .; Eds. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N .; Y. And 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).

  “Dispersants” and / or “viscosity modifiers” include materials that control drug diffusion and homogeneity by liquid media or granulation or mixing methods. In certain embodiments, these agents also promote the effectiveness of the coating matrix or erosion matrix. Typical diffusion promoters / dispersants are, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; known as Plasdone®) in the market. And carbohydrate-based dispersants such as hydroxypropylcellulose (eg HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (eg HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxy Ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS) Amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4- (1,1,3,3-tetramethylbutyl) of ethylene oxide and formaldehyde ) -Phenolic polymers (also known as tyloxapol), poloxamers (eg Pluronics F68®, F88®, and F108®), which block ethylene oxide and propylene oxide And poloxamines (eg Tetronic 908®, also known as Poloxamine 908®), due to the sequential addition of propylene oxide and ethylene oxide to ethylenediamine. (BASF Corporation, Parsippany, NJ.), Polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S -630), polyethylene glycol (eg, polyethylene glycol can have a molecular weight from about 300 to about 6000, or from about 3350 to about 4000, or from about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, polysorbate-80 Sodium alginate, gums such as gum tragacanth and gum arabic, guar gum, xanthan including xanthan gum, sugars, cellulose Compounds such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginate, Including chitosans and combinations thereof. Plasticizers such as cellulose or triethyl cellulose can also be used as a dispersant. Particularly useful dispersants in liposome and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from egg, natural phosphatidylglycerol from egg, cholesterol and isopropyl myristate.

  Also, combinations of one or more diffusion promoters and one or more erosion promoters can be used in the composition of the present invention.

  The term “diluent” refers to a compound used to dilute a compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffers (which can provide pH control or maintenance) are used in the art as diluents and include, but are not limited to, phosphate buffered saline. In certain embodiments, the diluent increases the bulk of the composition to promote compression, or produces sufficient bulk for uniform mixing of capsule fills. Such compounds include, for example, microcrystalline cellulose such as lactose, starch, mannitol, sorbitol, dextrose, Avicel®; dibasic calcium phosphate; calcium hydrogen phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous Lactose, spray-dried lactose; pregelatinized starch, compressed sugar such as Di-Pac® (Amstar); mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluent, powdered sugar; monobasic sulfuric acid Calcium monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrate; hydrolyzed grain solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride Inositol, bentonite and the like; arm.

  The term “disintegrates” includes both degradation and dispersion of the dosage form upon contact with gastrointestinal fluid. A “disintegrant or dispersant” promotes the degradation or disintegration of a substance. Examples of disintegrants are starches, eg natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolates such as Promogel® or Explotab® For example, cellulose such as wood products, methyl crystalline cellulose, such as Avicel (registered trademark), Avicel (registered trademark) PH101, Avicel (registered trademark) PH102, Avicel (registered trademark) PH105, Elcema (registered trademark) P100, Emococel (Registered trademark), Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or Bridged cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starch such as sodium glycolate starch, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone Alginate such as alginic acid or salt of alginic acid such as sodium alginate, clay such as Veegum® HV (aluminum magnesium silicate), gum such as agar, guar, carob, caraya, pectin, or tragacanth gum, starch sodium glycolate , Bentonite, natural sponge, surfactant, cation exchange resin and other resins, citrus pulp, sodium lauryl sulfate, laur in combination with starch Including Le sodium sulfate.

  “Drug absorption” or “absorption” typically refers to a drug that travels from the site of administration of the drug through the barrier into the blood vessel or site of action, for example, from the gastrointestinal tract to the portal vein or lymphatic system. .

  An “enteric coating” is a substance that remains substantially intact in the stomach but dissolves in the small intestine or colon and releases the drug. In general, enteric coatings are prevented from release in the low pH environment in the stomach, but ionize at higher pH, typically 6 to 7, and thus dissolve well in the small intestine or colon and become active agents. A polymeric material which releases the

  “Erosion promoter” includes materials that control the erosion of certain substances in gastrointestinal fluids. Erosion promoters are generally known to those skilled in the art. Typical erosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides and amino acids.

  `` Fillers '' include lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, Including sorbitol, sodium chloride, polyethylene glycol and other compounds.

  Useful “flavoring agents” and / or “sweetening agents” for the formulations described herein include, for example, acacia syrup, acesulfame K, alitum, anise, apples, aspartame, bananas, bavalores, berries, blackcurrants, butterballs, Calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry cream, cool citrus, cyclamate, thyramate, dextrose, eucalyptus Tree, eugenol, fructose, fruit punch, ginger, glycyl retinate, licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, glycyrrhizic acid monoa Monium (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, Raspberry, Root Beer, Rum, Saccharin, Safrol, Sorbitol, Spearmint, Spearmint Cream, Strawberry, Strawberry Cream, Stevia, Sucralose, Sucrose, Saccharin Sodium, Saccharin, Aspartame, Acesulfame Potassium, Mannitol, Tallinn, Silitol, Sucralose, Sorbitol, Swiss Cream , Tagatose, tangerine, thaumatin, mixed fruit sugar (tutti frui) tti), vanilla, walnut, watermelon, wild cherry, pearl oyster, xylitol or combinations of these flavorings, such as anise-menthol, cherry-anis, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon Includes lime, lemon-mint, menthol-eucalyptus tree, orange-cream, vanilla-mint and mixtures thereof.

  “Lubricants” and “glue aids” are compounds that prevent, reduce, or inhibit material adhesion or friction. Typical lubricating oils include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, hydrocarbons such as mineral oil, hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®), higher fatty acids And their alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerin, talc, waxes, (Stearowet®), boric acid, sodium benzoate, acetic acid Methoxypolyethylene glycol such as sodium, sodium chloride, leucine, polyethylene glycol (eg PEG-4000) or Carbowax ™, sodium oleate, sodium benzoate Glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid ™, Cab-O-Sil ™, starch such as corn starch, silicone oil, surfactants, and the like.

  “Measurable serum concentration” or “Measurable plasma concentration” refers to the concentration of blood serum or blood plasma, 1 ml of blood serum absorbed into the blood stream after administration, mg of therapeutic agent per dl or l, Measured as μg or ng. As used herein, measurable plasma concentrations are generally measured as ng / ml or μg / ml.

  “Pharmacodynamics” refers to the factors that determine the biological response observed with respect to drug concentration at the site of action.

  “Pharmacokinetics” refers to the factors that determine the achievement and maintenance of an appropriate concentration of a drug at the site of action.

  A “plasticizer” is a compound used to make a microcapsule encapsulating material or film coating soft and not brittle. Suitable plasticizers include, for example, polyethylene glycols such as PEG300, PEG400, PEG600, PEG1450, PEG3350 and PEG800, stearic acid, propylene glycol, oleic acid, triethylcellulose and triacetin. In certain embodiments, the plasticizer can also function as a dispersant or wetting agent.

  “Solubilizers” include triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, doxate sodium, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, Including hydroxypropylmethylcellulose, hydroxypropylcyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol and dimethylisosorbide.

  “Stabilizer” includes any antioxidant, buffer, acid, preservative, and other compounds.

  “Steady state”, as used herein, is that the amount of drug administered is equal to the amount of drug removed and leveled out or constant plasma drug exposure within one dosing interval.

  “Suspending agents” include polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol (eg, polyethylene glycol Can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400.), sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose acetate stearate, polysorbate-80, hydroxy Ethyl cellulose, sodium alginate, gums such as tragacanth gum, and gum arabic, guar gum, Xanthan, saccharides and cellulose compounds containing suntan gum such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaur Contains compounds such as rate and povidone.

  “Surfactants” include sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaxomer, bile salt, glyceryl monostearate And copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF). Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers such as octoxynol 10, octoxynol 40 including. In certain embodiments, surfactants may be included to enhance physical stability or for other purposes.

  “Viscosity enhancers” include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginate, acacia, chitosan and combinations thereof including.

  “Wetting agents” include oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, Contains sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salt and the like.

Dosage Forms The compositions described herein can be oral, parenteral (eg, intravenous, subcutaneous, or intramuscular), buccal, nasal, rectal, or transdermal routes of administration. Can be formulated for administration to a subject by any conventional means. As used herein, the term “subject” is used to mean an animal, preferably a mammal, including a human or non-human. The terms “patient” and “subject” may be used interchangeably.

  In addition, the pharmaceutical compositions described herein include the compounds provided herein, but can be formulated into any suitable dosage form and are aqueous oral for oral intake by the patient to be treated. Dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, etc., solid oral dosage forms, aerosols, controlled release formulations, fast melting formulations, effervescent formulations, lyophilized formulations, tablets, powders , Pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations and mixed formulations of immediate release and controlled release types.

  Oral pharmaceutical preparations are prepared by mixing one or more solid excipients with one or more of the compounds described herein, optionally milling the resulting mixture, and adding appropriate adjuvants as necessary. Can be obtained by adding and then processing the mixture of granules to obtain tablets or dragee cores. Suitable excipients are, for example, fillers such as sugars including lactose, sucrose, mannitol or sorbitol; for example corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose Cellulose preparations such as sodium carboxymethylcellulose; polyvinyl pyrrolidone (PVP or povidone) or others such as calcium phosphate. If desired, disintegrating agents may be added, such as cross-linked croscarmellose sodium, polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

  Dragee cores are provided in a properly coated state. For this purpose, concentrated sugar solutions can be used, which are optionally acacia gum, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable Various organic solvents or mixtures of solvents. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

  Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate and optionally a stabilizer. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

  In certain embodiments, the solid dosage forms disclosed herein are tablets (including suspension tablets, fast dissolving tablets, bite disintegrating tablets, quick disintegrating tablets, effervescent tablets or caplets), pills, powders ( Including sterile packaged powders, dispersible powders or effervescent powders, capsules (both soft or hard capsules, eg capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkles” Capsules "), solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulsatile release formulations, multiparticulate formulations, pellets, granules or aerosols. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet and includes, but is not limited to, a fast dissolving tablet. Furthermore, the pharmaceutical formulations of the invention may be administered as a single capsule or in multiple capsule dosage forms. In certain embodiments, the pharmaceutical formulation is administered in two or three or four capsules or tablets.

  In certain embodiments, solid dosage forms such as tablets, effervescent tablets and capsules are prepared by mixing particles of a compound provided herein with one or more pharmaceutical excipients to form a bulk mixed composition. Is done. When these bulk blend compositions are homogeneous, the composition is such that the particles of the compound provided herein are easily divided into equally effective single dosage forms such as tablets, pills and capsules. It means that it is uniformly distributed throughout the whole thing. Individual unit doses may also include a coating that degrades upon oral ingestion or upon contact with a diluent. These preparations can be produced by conventional pharmacological techniques.

  Conventional pharmacological techniques are, for example, one or a combination of methods: (1) dry mixing, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) wet granulation Or (6) including melting. See, for example, Lachman et al. , The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluid bed spray drying or coating (eg, Wurster coating), tangential coating, top spray method, tablet formation, extrusion method, etc. Is included.

  The solid dosage forms of the medicament provided herein include a compound provided herein and one or more pharmaceutically acceptable compatible carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents. , Disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, moisturizer, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative Or one or more additives such as combinations thereof may be included. In yet another aspect, using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), film coating is provided for the formulation of compounds provided herein. The In another embodiment, some or all of the particles of the compound provided herein are coated. In one embodiment, some or all of the particles of a compound provided herein are microencapsulated. In yet another embodiment, the particles of the compound provided herein are not microencapsulated or coated.

  Suitable carriers used in solid dosage forms are acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, Examples include, but are not limited to, dipotassium phosphate, sodium stearoyl lactate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

  Suitable fillers used in the solid dosage forms described herein are lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, α Including, but not limited to, modified starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like.

  In order to release the compounds provided herein from the solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, particularly when the dosage form is compressed with a binder. The disintegrant assists in rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants used in the solid dosage forms provided herein include natural starches such as corn starch and potato starch, pregelatinized starches such as National 1551 or Amijel®, or Promogel® or Explotab ( Sodium starch glycolate such as (registered trademark), cellulose such as wood products, methyl crystalline cellulose, such as Avicel (registered trademark), Avicel (registered trademark) PH101, Avicel (registered trademark) PH102, Avicel (registered trademark) PH105, Elcema (R) P100, Emococel (R), Vivacel (R), Ming Tia (R), and Solka-Floc (R), methylcellulose, croscarme Or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starch such as sodium glycolate starch, crospovidone, crosslinked polyvinylpyrrolidone Cross-linked polymers such as alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (aluminum magnesium silicate), gums such as agar, guar, carob, karaya, pectin, or tragacanth gum, Combined with sodium glycolate starch, bentonite, natural sponge, surfactant, cation exchange resin, citrus pulp, sodium lauryl sulfate, starch Including sodium lauryl sulfate combined, without limitation.

  The binder imparts tackiness to the solid oral dosage form formulation. For capsule formulations filled with powder, the binder helps form a filling that fills soft shell capsules or hard shell capsules, and for tablet formulations, the binder ensures that the tablet remains completely after compression and is compressed Helps ensure uniformity of the mixture before or before the filling step. Suitable materials used as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (eg, Methocel®), hydroxypropylmethylcellulose (eg, Hypermellose USP Pharmacoat-603, hydroxypropyl methylcellulose acetate) Stearate (Aquaate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (eg Klucel®), ethylcellulose (eg Ethocel®), and microcrystalline cellulose (eg Avicel®) ), Microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinyl Loridone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (eg, Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (eg, Xylitab®) )), Sugars such as lactose, acacia, tragacanth, gati gum, isapol Husks mucus, starch, polyvinylpyrrolidone (eg Povidone® CL, Kollidon® CL, Polyplasmone®) XL-10, and Povidone® K-12)), larch arabogalactan, Veegum®, polyethylene glycol, waxes Including natural or synthetic gums such as sodium alginate, and the like.

  In general, binder levels of 20 to 70% are used in powder-filled gelatin capsule formulations. The level of binder used in the tablet formulation varies, either directly compression, wet granulation, roller compression, or the use of other excipients such as fillers that can act as moderate binders themselves. . Persons of ordinary skill in the art can determine the level of binder for formulation, but binder use levels of up to 70% are common in tablet formulation.

  Suitable lubricating oils or glidants used in the solid dosage forms described herein include stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali metals such as aluminum, calcium, magnesium, zinc, and Alkaline earth metal salts, stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene Glycols such as Carbowax ™, PEG4000, PEG5000, PEG6000, propylene glycol, sodium oleate, glyceryl behenate, palmitostearin Glycerin, glycerin acid, including lauryl magnesium or sodium sulfate, and the like.

  Suitable diluents used in the solid dosage forms described herein include sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrins), polyols (mannitol, xylitol). And sorbitol)), cyclodextrins and the like.

The term “water-insoluble diluent” refers to calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, and microcellulose (eg, having a density of about 0.45 g / cm ³⁾ commonly used in pharmaceutical formulations. For example, it represents compounds such as Avicel, powdered cellulose), and talc.

  Suitable wetting agents used in the solid dosage forms described herein are, for example, oleic acid, glycerin monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate. Acid, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (eg, Polyquat 10 (registered trademark)), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

  Suitable surfactants used in the solid dosage forms described herein are, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, monostearic acid Copolymers of glycerin, ethylene oxide and propylene oxide, such as Pluronic® (BASF).

  Suitable suspending agents used in the solid dosage forms described herein are polyvinyl pyrrolidone, such as polyvinyl pyrrolidone K12, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, or polyvinyl pyrrolidone K30, polyethylene glycol (eg, polyethylene glycol is Having a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), vinylpyrrolidone / vinyl acetate copolymer (S-630), sodium carboxymethylcellulose, methylcellulose, hydroxy- Propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth and gum arabic, guar gum, xanthan Xanthan, saccharides, cellulose compounds such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaur Including, but not limited to, rate, povidone and the like.

  Suitable antioxidants used in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate and tocopherol.

  It should be appreciated that considerable overlap exists between the additives used in the solid dosage forms described herein. Accordingly, the above listed additives are merely illustrative and not limiting on the types of additives that can be included in the solid dosage forms of the present invention. The amount of such additives can be readily determined by those skilled in the art according to the particular characteristics desired.

  In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Specifically, the plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% weight (w / w) of the coating composition. Plasticizers include diethyl phthalate, citrate ester, polyethylene glycol, glycerin, acetylated glycerin, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate or castor oil Including, but not limited to.

  A compressed tablet is a solid dosage form produced by compressing the bulk powder blend of the above formulation. In various embodiments, compressed tablets designed to dissolve in the mouth include one or more flavoring agents. In other embodiments, the compressed tablet includes a film surrounding the final compressed tablet. In certain embodiments, the film coating provides delayed release from the formulation of the compounds described herein. In other embodiments, the film coating aids patient compliance (eg, Opadry® coating or sugar coating). Film coatings including Opadry® typically range from about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablets include, but are not limited to, one or more excipients.

  Capsules can be prepared, for example, by placing a bulk powder mixture of the above-mentioned compound formulation inside the capsule. In certain embodiments, the formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the formulation is placed in a standard gelatin capsule or in a non-gelatin capsule, such as a capsule containing HPMC. In other embodiments, the formulation is placed in a sprinkle capsule where the entire capsule is swallowed or the capsule is opened or the contents are sprinkled on the food prior to a meal. In certain embodiments, the therapeutic dose is divided into multiple (eg, 2, 3 or 4) capsules. In certain embodiments, the entire dose of the formulation is delivered in capsule form.

  In various embodiments, particles of the compound disclosed herein and one or more excipients are dry mixed and compressed into a mass such as a tablet. The tablet has a pharmaceutical composition that substantially disintegrates within about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes or less than about 60 minutes after oral administration. It is hard enough to provide a product, thereby releasing the formulation into the gastrointestinal fluid.

  In another aspect, the dosage form can comprise a microencapsulated formulation. In certain embodiments, one or more other compatible materials are present in the microencapsulation material. Typical materials include, but are not limited to, pH modifiers, erosion promoters, antifoaming agents, antioxidants, flavoring and binding agents, suspending agents, disintegrating agents, fillers, surfactants, solubilizing aids. Carrier materials such as agents, stabilizers, lubricants, wetting agents and diluents.

  The materials used for the microencapsulation described herein include materials that are compatible with the compounds described herein, which are disclosed herein from other incompatible excipients. The compound is sufficiently separated. Materials that are compatible with the compounds disclosed herein will delay the in vivo release of the compounds described herein.

  Exemplary microencapsulation materials useful for delaying release of formulations containing the compounds disclosed herein are hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nissan HPC, low substituted hydroxypropyl cellulose Ethers (L-HPC), hydroxypropyl methylcellulose ethers (HPMC), such as Sepfifilm-LC, Pharmacoat®, Metrose SR, Memocel®-E, Opadry YS, PrimeFlo, Benecel MP824, and Bencel MP824 Methylcellulose polymers, such as Methocel®-A, hydroxypropyl methylcellulose acetate stearate Aqo at (HF-LS, HF-LG, HF-MS) and Metrose (R), ethylcellulose (EC) and mixtures thereof such as E461, Ethocel (R), Aqualon (R) -EC, Surelease (R) Trademark), polyvinyl alcohol (PVA), such as Opadry AMB, hydroxyethylcelluloses, such as Natrosol®, carboxymethylcellulose and carboxymethylcellulose (CMC) salts, such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol copolymers For example, Kollicoat IR®, monoglyceride (Myverol), triglyceride (KLX), polyethylene glycol, modified Dietary starch, acrylic polymers and mixtures of acrylic polymers and cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® L100-55 Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® (Trademark) NE30D, and Eudragit (registered trademark) NE 40D, sepifilms such as cellulose acetate phthalate, a mixture of HPMC and stearic acid, Cyclodextrin, and mixtures of these materials, without limitation.

  In still other embodiments, plasticizers such as polyethylene glycol (eg, PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, PEG 800), stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulated material useful for delaying the release of the pharmaceutical composition is from the United States Pharmacopeia (USP) or National Pharmaceutical Collection (NF). In still other embodiments, the microencapsulation material is Klucel. In yet other embodiments, the microencapsulation material is methocel.

  The microencapsulated compounds disclosed herein can be formulated by methods known to those skilled in the art. Such known methods are, for example, spray drying processes, rotating disk-solvent processes, hot melt processes, spray cooling methods, fluidized beds, electrostatic deposition, extrusion centrifugation, rotary suspension separation, liquid-gas or solids. -Gas interfacial polymerization reaction, pressure extrusion method, spray solvent extraction bath or the like. In addition to these, several chemical techniques such as complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization reactions in liquid media, in situ polymerization reactions, submerged drying methods, and liquid media Desolvation in, etc. can be used. In addition, other methods such as roller compaction, extrusion / granulation, coacervation, or nanoparticle coating may also be used.

  In one embodiment, the particles of the compound disclosed herein are encapsulated before being formulated into one of the above forms. In yet another embodiment, some or all of the particles are coated by standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000) before further formulation.

  In other embodiments, solid dosage forms of the compounds disclosed herein are plasticized (coated) with one or more layers. Illustratively, plasticizers are generally high boiling solids or liquids. Suitable plasticizers can be added from about 0.01% to about 50% (w / w) of the coating composition by weight. Plasticizers include, but are not limited to, diethyl phthalate, citrate ester, polyethylene glycol, glycerin, acetylated glyceride, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate And castor oil.

  In other embodiments, powders containing formulations of the compounds disclosed herein can be formulated to include one or more pharmaceutical excipients and flavoring agents. Such powders can be prepared, for example, by mixing the formulation and any excipients to form a bulk powder composition. In additional embodiments, it also includes a suspending agent and / or wetting agent. This bulk mixture is divided into single dose packages or multiple dose packages.

  In yet other embodiments, foamed powder is also prepared according to the present disclosure. Foamed salts have been used to disperse medicines in water for oral administration. The effervescent salt is a granule or coarse powder containing the medicament, usually in the form of a dry mixture consisting of sodium bicarbonate, citric acid and / or tartaric acid. When the salts of the present invention are added to water, the acid and base react to release carbon dioxide, resulting in “foaming”. Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. Any acid-base combination that releases carbon dioxide can be used in place of the sodium bicarbonate and citric acid combination as long as the ingredients are suitable for pharmaceutical use and exhibit a pH of about 6.0 or higher. .

  In other embodiments, the formulations described herein are solid dispersions containing the compounds disclosed herein. Methods for producing such solid dispersions are known in the art and include, but are not limited to, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5 , 700,485, 5,723,269, and US Patent Application Publication 2004/0013734, each of which is specifically incorporated by reference. In still other embodiments, the formulations described herein are solid solutions. The solid solution dissolves the drug by heating the active agent and the mixture, and the resulting composition is then cooled to provide a solid mixture that is further formulated or added directly to the capsule or The substance is incorporated with other excipients, such as compressed into tablets. Methods for producing such solid solutions are known in the art and include, but are not limited to, for example, US Pat. Nos. 4,151,273, 5,281,420 and 6,083,518, Each of which is specifically incorporated by reference.

  Pharmaceutical solid oral dosage forms comprising the formulations described herein include the compounds disclosed herein and are further formulated to provide controlled release of the compounds disclosed herein. Controlled release refers to the release of a compound disclosed herein from a dosage form in which the compound is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, extended release, pulsatile release and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of a drug to a subject according to a predetermined profile for an extended period of time. Such a release rate can provide a therapeutically effective level of the drug for an extended period of time, thereby minimizing side effects and longer periods of time compared to conventional immediate release dosage forms. Can provide a pharmacological response. Such a longer period of response provides a number of inherent advantages not achieved with the corresponding short acting immediate release formulations.

  In certain embodiments, the solid dosage forms described herein can be formulated as enteric coated sustained release oral dosage forms. That is, it can be formulated as an oral dosage form of a pharmaceutical composition as described herein that utilizes an enteric coating to affect release in the small intestine of the gastrointestinal tract. Enteric coated dosage forms are compressed or molded or extruded containing granules, powders, beads or particles of the active ingredient and / or other composition ingredients (which are themselves coated or uncoated). Tablets / molded articles (coated or uncoated). The enteric coated dosage form may be a capsule (coated or uncoated), a solid carrier pellet, bead or granule of the composition, which is itself coated or coated. It may be.)

  As used herein, the term “sustained release” refers to an approximately generally predictable location in the intestinal tract distal to the location that would have been achieved if there was no change in sustained release. Refers to delivery that can achieve release. In certain embodiments, the method for delaying release is a coating. Either coating should be used at a sufficient thickness so that the total coating does not dissolve in the gastrointestinal fluid at a pH below about 5, but dissolves at a pH above 5. Any anionic polymer that exhibits a pH-dependent solubility profile can be used as an enteric coating in the practice of the invention and is expected to achieve lower delivery of the gastrointestinal tract. In certain embodiments, the polymer used in the present invention is an anionic carboxylic acid polymer. In other embodiments, the polymers and compatible mixtures thereof, and some of these properties include, but are not limited to:

  Shellac (which is also referred to as purified rack and is a refined product obtained from insect resinous secretions). This coating dissolves in a medium of pH> 7.

  Acrylic acid polymer. The performance of acrylic acid polymers (mainly their solubility in biological fluids) can vary depending on the degree and type of substituents. Examples of suitable acrylic acid polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series of E, L, S, RL, RS and NE (Rohm Pharma) are available as liquids, aqueous dispersions or dry powders dissolved in organic solvents. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract, but are permeable and are used primarily to target the colon. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach and dissolve in the intestine.

  Cellulose derivative. Examples of suitable cellulose derivatives are: ethyl cellulose; a reaction mixture of cellulose and a partial acetate ester of phthalic anhydride. This performance can vary depending on the degree and type of substituents. Cellulose acetate phthalate (CAP) dissolves at pH> 6. Aquatic (FMC) is an aqueous system and is a spray-dried CAP pseudolatex with <1 μm particles. Other ingredients in Aquateric may include pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include the following: Trimellitic acid cellulose acetate (Eastman), methylcellulose (Pharmacacoat, Methocel); hydroxypropylmethylcellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS), hydroxypropylmethylcellulose acetate succinate (eg AQOAT) (Shin Etsu)) . This performance can vary depending on the degree and type of substituents. For example, HPMCP such as HP-50, HP-55, HP-55S, and HP-55F grade is suitable. This performance can vary depending on the degree and type of substituents. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate are AS-LG (LF) (which dissolves at pH 5), AS-MG (MF) (which dissolves at pH 5.5), and AS. -Including but not limited to HG (HF), which dissolves at higher pH. These polymers are provided as granules or as finely divided powders of aqueous dispersions.

  Polyvinyl phthalate acetate (PVAP). PVAP dissolves at pH> 5, which is not very permeable to water vapor and gastric fluid.

  In certain embodiments, the coating may contain and usually contain plasticizers and possibly other coating excipients such as colorants, talc and / or magnesium stearate well known in the art. is doing. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated Contains monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers typically contain 10 to 25% (by weight) of a plasticizer, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques such as spray coating or pan coating are used to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of local delivery in the intestine is reached.

  Coloring agents, detackifying agents, surfactants, antifoaming agents, lubricating oils (eg carnauba wax or PEG) are added to the coating agent in addition to the plasticizer to dissolve or disperse the coating agent, covering performance And the coated product can be improved.

  In other embodiments, the formulations described herein comprise a compound disclosed herein and are delivered using a pulsatile release dosage form. The pulsatile release dosage form can provide one or more immediate release pulses at a predetermined time after a controlled delay time or at a particular site. Pulsatile release dosage forms comprising the formulations described herein, including the compounds disclosed herein, can be administered using a variety of pulsatile release formulations known in the art. For example, such formulations are described in US Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329, each of which is incorporated by reference. However, it is not limited to these. Other pulsatile release dosage forms suitable for use with the present formulations include, for example, US Pat. Nos. 4,871,549, 5,260,068, 5,260,069, 5,508, Including, but not limited to, 040, 5,567,441 and 5,837,284, all of which are specifically incorporated by reference. In one embodiment, the controlled release dosage form is a pulsatile release solid oral formulation comprising at least two groups of particles (ie, multiparticulates), each containing a formulation described herein. The first group of particles provides a substantially immediate dose of the compounds disclosed herein upon food intake by a mammal. The first group of particles can be uncoated or include a coating and / or sealant. The second group of particles comprises coated particles, which are from about 2% to about 75%, preferably from about 2.5% to about 70% of the total dose of the compounds disclosed herein by weight in the formulation. %, And more preferably from about 40% to about 70% with one or more binders. The coating includes an amount sufficient to provide a delay of about 2 hours to about 7 hours after ingestion of the pharmaceutically acceptable ingredient prior to the release of the second dose. Suitable coatings are one or more different degradable coatings, by way of example only, but for example pH sensitive (enteric) coatings such as acrylic resins (eg Eudragit® EPO, Eudragit® L30D-55). Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, and Eudragit® NE30D, Eudragit® NE 40D®) alone or a cellulose derivative (eg ethyl cell Those mixed with over scan), or has a thickness that may vary, including non-enteric coating to provide a formulation with different release comprising a compound disclosed herein.

Many other types of controlled release systems are known to those skilled in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include polymer-based systems such as polylactic acid and polyglycolic acid, polyanhydrides and polycaprolactone; porous matrices, sterols such as cholesterol, cholesterol esters and fatty acids, or mono, di, And non-polymeric systems that are lipids containing triglycerides such as triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; bioerodible forms; including compressed tablets using conventional binders . Liberman et al. , Pharmaceutical Dosage Forms, 2 Ed. , Vol. 1, pp. 209-214 (1990); Singh et al. ^{, Encyclopedia of Pharmaceutical Technology, 2 nd} Ed. , Pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527 No. 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983, each of which is referred to Is incorporated more specifically.

  In certain embodiments, a pharmaceutical formulation is provided comprising particles of a compound disclosed herein and at least one dispersing or suspending agent for oral administration to a subject. These formulations may be powders and / or granules for suspension, and when combined with water, a substantially constant suspension is obtained.

Liquid dosage forms for oral administration can be aqueous suspensions selected from the group comprising pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels and syrups, It is not limited to these. Singh et al. ^{, Encyclopedia of Pharmaceutical Technology, 2 nd} Ed. , Pp. 754-757 (2002). In addition to the particles of the compound disclosed herein, the liquid dosage form comprises (a) a disintegrant, (b) a dispersant, (c) a wetting agent, (d) at least one preservative, (e) a viscosity enhancing agent. , (F) at least one sweetener and (g) at least one flavoring agent. In certain embodiments, the aqueous dispersion can further comprise a crystallization inhibitor.

  The aqueous suspensions and dispersions described herein can remain in a homogeneous state for at least 4 hours as defined in The USP Pharmaceuticals' Pharmacopeia (2005 edition, chapter 905). Homogeneity should be measured by a consistent sampling method for measuring homogeneity of the entire composition. In one embodiment, the aqueous suspension can be resuspended in a homogeneous suspension by physical agitation lasting less than 1 minute. In another embodiment, the aqueous suspension can be resuspended in a homogeneous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended in a homogeneous suspension by physical agitation that lasts less than 30 seconds. In yet another embodiment, agitation to maintain a homogeneous aqueous dispersion is not necessary.

  Examples of disintegrants used in aqueous suspensions and dispersions include starches, eg natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or Promogel® or Sodium starch glycolate such as Explotab®; cellulose such as wood products, methyl crystalline cellulose such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® ) PH105, Elcema (R) P100, Emcocel (R), Vivacel (R), Ming Tia (R), and Solka-Floc (R), Methyl Cellulo , Croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starch such as sodium glycolate starch; crospovidone, etc. Cross-linked polymers of; cross-linked polyvinyl pyrrolidone; alginates such as alginic acid or alginic acid salts such as sodium alginate; clays such as Veegum® HV (aluminum magnesium silicate); agar, guar, carob, caraya, pectin, or tragacanth Gum starch; sodium starch glycolate; bentonite; natural sponge; surfactant; cation exchange resin and other resins; citrus pulp; sodium lauryl sulfate Including sodium lauryl sulfate in combination starch, and the like.

  In certain embodiments, suitable dispersants for the aqueous suspensions and dispersions described herein are known in the art, eg, hydrophilic polymers, electrolytes, Tween® 60 or 80. , PEG, polyvinyl pyrrolidone (PVP; known as Plasdone®), and carbohydrate-based dispersants such as hydroxypropyl cellulose and hydroxypropyl cellulose ethers (eg HPC, HPC-SL, and HPC-L) ), Hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ether (eg HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxy Cylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymer (Plasdone ( Registered trademark), eg S630), 4- (1,1,3,3-tetramethylbutyl) -phenol polymer of ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (eg Pluronics F68®) , F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (eg, Te ronic 908®, also known as Poloxamine 908®, is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine.) (BASF Corporation, Parsippany , NJ.)) And the like. In other embodiments, the dispersing agent is selected from the group that does not include one of the following agents. Hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropylcellulose ethers (eg, HPC, HPC-SL, and HPC-L); hydroxypropylmethylcellulose and Hydroxypropyl methylcellulose ether (eg, HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); sodium carboxymethylcellulose; methylcellulose; hydroxyethylcellulose; hydroxypropylmethylcellulose phthalate; hydroxypropyl Methyl-cellulose acetate stearate Amorphous cellulose; magnesium magnesium silicate; triethanolamine; polyvinyl alcohol (PVA); 4- (1,1,3,3-tetramethylbutyl) -phenol polymer of ethylene oxide and formaldehyde; poloxamers (eg Pluronics) F68 (R), F88 (R) and F108 (R), which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (e.g. Tetronic 908 (R) Also known as Poloxamine 908®).

  Suitable wetting agents for the aqueous suspensions and dispersions described herein are known in the art and include, for example, cetyl alcohol, glyceryl monostearate, polyoxyethylene sorbitan fatty acid esters (eg, Tween 20®). ) And Tween 80® (commercially available Tween®) such as ICI Specialty Chemicals) and polyethylene glycols (eg Carbowax 3350® and 1450® and Carbopol 934®) Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan mono Reeto, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate acid, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, including such phosphite choline, and the like.

  Suitable preservatives for the aqueous suspensions and dispersions described herein are, for example, potassium sorbate, parabens (eg methylparaben and propylparaben), benzoic acid and its salts, parahydroxybenzoates such as butylparaben Other esters of acids, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. The preservative, as used herein, is formulated into the dosage form at a concentration sufficient to inhibit microbial growth.

  Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein are methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Plasdone®, S-630, carbomer, polyvinyl Including but not limited to alcohol, alginate, acacia, chitosan and combinations thereof. The concentration of the viscosity enhancing agent depends on the drug selected and the desired viscosity.

  Suitable sweeteners for the aqueous suspensions and dispersions described herein are, for example, acacia syrup, acesulfame K, alitam, anise, apples, aspartame, banana, bavaroa, berry, black currant, butterball, Calcium acid, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, silamate, dextrose, eucalyptus tree, Eugenol, fructose, fruit punch, ginger, glycyl retinate, licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (Magna (weet (registered trademark)), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet (registered trademark) Powder, raspberry, Root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, tallin, sucralose, sorbitol, swiss cream, tagatose, tangerine , Thaumatin, mixed fruit with sugar, vanilla, walnut, watermelon, wild cherry, himekoji, Silitol, or combinations of these flavors, such as anise-menthol, cherry-anis, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus tree, orange- Includes cream, vanilla mint and mixtures thereof. In one embodiment, the aqueous liquid dispersion can include sweetening or flavoring agents at a concentration of about 0.001% to about 1.0% volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion can include a sweetening or flavoring agent at a concentration of about 0.005% to about 0.5% volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion can include sweetening or flavoring agents at a concentration of about 0.01% to about 1.0% volume of the aqueous dispersion.

  In addition to the additives listed above, the liquid formulation can also include inert diluents, solubilizers and emulsifiers commonly used in the art such as water or other solvents. Typical emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol ester Oils such as taurocholic acid, phosphotidylcholine, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan or these substances It is a mixture.

  In certain embodiments, the pharmaceutical formulation described herein is a self-emulsifying drug delivery system (SEDDS). An emulsion is a dispersion of one phase that is immiscible with another phase, usually in the form of droplets. In general, emulsions are made by vigorous mechanical dispersion. SEDDS spontaneously forms an emulsion when added to excess water without any external mechanical dispersion or agitation, as opposed to an emulsion or microemulsion. The advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. In addition, water or an aqueous phase can be added just prior to administration, which ensures the stability of unstable or hydrophobic active ingredients. Accordingly, SEDDS provides an effective delivery system for oral or parenteral delivery of hydrophobic active ingredients. SEDDS can provide improved bioavailability of hydrophobic active ingredients. Methods for producing self-emulsifying dosage forms are known in the art, eg, US Pat. Nos. 5,858,401, 6,667,048 and 6,960,563, each of which is incorporated by reference Specifically incorporated)), but is not limited thereto.

  The given additives are often classified differently by different technicians in this field or are commonly used for any of several different functions, so the aqueous suspensions described herein are used. It should be appreciated that there is an overlap between the above listed additives used in suspensions and dispersions. Accordingly, it should be understood that the additives listed above are merely exemplary of the types of additives that can be included in the formulations described herein and are not limiting. The amount of such additives can be readily determined by those skilled in the art according to the specific properties desired.

Nasal formulations Nasal formulations are known in the art, eg, US Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each of which is specifically incorporated by reference. Is incorporated in.). Formulations containing the compounds provided herein are prepared by these methods or other techniques well known in the art, and are prepared using benzyl alcohol or other suitable preservatives, fluorocarbons and / or other solubilizing agents known in the art. Prepared as a solution in physiological saline using an agent or a dispersing agent. (See: Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995)). Preferably, these compositions and formulations are prepared using suitable non-toxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the art of producing nasal dosage forms, some of which are found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, a standard reference book in the field. be able to. The selection of an appropriate carrier is highly dependent on the exact nature of the desired nasal dosage form (eg, solution, suspension, ointment, or gel). Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Small amounts of other ingredients such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling or buffering and stabilizing agents and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions.

  For administration by inhalation, the compounds disclosed herein can be in the form of an aerosol, mist or powder. The pharmaceutical composition described herein is an aerosol spray or nebula in a pressurized pack using a suitable propellant (eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Conveniently delivered in the form of an Iser. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. By way of example only, capsules and cartridges such as gelatin used in inhalers or ventilators contain a powder mixture of the compounds described herein and a suitable powdery base such as lactose or starch. Formulated.

Buccal Formulations A buccal formulation comprising a compound disclosed herein can be administered using a variety of formulations known to those skilled in the art. For example, such formulations are described in US Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of which is incorporated by reference Specifically incorporated)), but is not limited thereto. Further, the buccal dosage forms described herein can further comprise a bioerodible (hydrolyzable) polymeric carrier that serves to adhere to the buccal mucosa. Buccal dosage forms are made to erode gradually over a period of time to provide delivery of the compounds disclosed herein substantially throughout. Buccal drug delivery is, as will be appreciated by those skilled in the art, disadvantages encountered with oral drug administration, such as slow absorption, degradation of the active agent by liquid present in the gastrointestinal tract and / or inactivation of the first pass in the liver. To avoid. With respect to bioerodible (hydrolyzable) polymeric carriers, as long as the desired drug release profile is not compromised, and any other optional carrier may be present in the compounds and buccal dosage form units disclosed herein. It will be appreciated that virtually any of these carriers can be used as long as they are compatible with the other ingredients. In general, polymeric carriers include hydrophilic (water soluble and water swellable) polymers that adhere to the moist surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and copolymers, such as “carbomer” (Carbopol®, which is one such polymer obtained from BF Goodrich. )). Other ingredients such as, but not limited to, disintegrants, diluents, binders, lubricants, flavoring agents, colorants, preservatives may also be incorporated into the buccal dosage forms described herein. For buccal or sublingual administration, the composition can take the form of tablets, lozenges or gels formulated in conventional manner.

Transdermal Formulations The transdermal formulations described herein can be administered using various devices described in the art. For example, such devices are disclosed in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814, 097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084 No. 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of which is incorporated herein by reference The whole is specifically incorporated . Containing) but not limited thereto.

  The transdermal dosage forms described herein may be formulated with certain pharmaceutically acceptable excipients conventional in the art. In one embodiment, a transdermal formulation described herein comprises at least three components: (1) a formulation of a compound disclosed herein; (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations can include additional ingredients such as gelling agents, creams and ointment bases. In certain embodiments, the transdermal formulation can further include a woven or non-woven backing material to enhance absorption and prevent the transdermal formulation from peeling off the skin. In other embodiments, the transdermal formulations described herein can remain saturated or supersaturated to promote diffusion into the skin.

  Formulations suitable for transdermal administration of the compounds disclosed herein can use transdermal delivery devices and transdermal delivery patches, and are lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives. It can be. Such patches can constitute continuous delivery, pulsatile delivery, or on-demand delivery of pharmaceutical agents. Still further, transdermal delivery of the compounds described herein can be accomplished by techniques such as iontophoretic patches. In addition, transdermal patches can provide controlled delivery of the compounds disclosed herein. The absorption rate can be slowed by the use of a rate controlling membrane or by trapping the compound in a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. Absorption enhancers or carriers can include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, a transdermal device is in the form of a bandage that delivers a compound to the host's skin at a controlled rate over a prolonged period, a reservoir containing the support, compound and optionally a carrier, or a predetermined rate. It is in the form of a bandage that includes a barrier that controls the rate at which it is applied, and means for securing the device to the skin.

Injectable Formulations Suitable for intramuscular, subcutaneous, or intravenous injection containing the compounds disclosed herein are physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile Sterile powders for reconstitution of injectable solutions or dispersions can be included. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol, cremophor), suitable mixtures thereof, vegetable oils (olive oil And injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Formulations suitable for subcutaneous injection can also contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride. Prolonged absorption of injectable formulations can be brought about by the use of agents that delay absorption such as aluminum monostearate and gelatin.

  For intravenous injection, the compounds described herein can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, suitable formulations can include aqueous or non-aqueous solutions, preferably physiologically compatible buffers or excipients. Such excipients are generally known in the art.

  Parenteral injections can include bolus injection and continuous infusion. Injectable preparations may be present in unit dosage form, for example in ampoules or multi-use containers with the addition of preservatives. The pharmaceutical composition described herein is a suspending, stabilizing and / or dispersing agent in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in an oily or aqueous vehicle. And the like. Formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or liposomes, such as sesame oil, or synthetic fatty acid esters (eg, ethyl oleate, triglycerides, etc.). Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle (eg, sterile, pyrogen-free water) prior to use.

Other Formulations In certain embodiments, delivery systems for pharmaceutical compounds such as liposomes and emulsions may be used. In certain embodiments, the compositions provided herein include, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, A mucoadhesive polymer selected from sodium alginate and dextran can be included.

  In certain embodiments, the compounds described herein can be administered topically, such as various topical administrations such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. It can be formulated into a possible composition. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

  In certain embodiments, the compounds described herein may be formulated into a composition for direct sunlight such as an enema, rectal gel, rectal foam, rectal aerosol, suppository, jelly suppository or long-lasting enema. These can contain not only conventional suppository bases such as cocoa butter or other glycerides, but also synthetic polymers such as polyvinylpyrrolidone, PEG as well. In the suppository form of the composition, a low melting wax, such as (but not limited to) a mixture of fatty acid glycerides, is first melted, optionally combined with cocoa butter.

Method of Dosing and Treatment Planning The compounds described herein are agents for the inhibition of fatty acid amide hydrolase or for the treatment of diseases or conditions that benefit at least in part from the inhibition of fatty acid amide hydrolase Can be used for the preparation of Also, a method of treating any disease or condition described herein in a subject in need of such treatment comprises at least one compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically Administering to a subject a pharmaceutical composition containing a therapeutically effective amount of an acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate Including that.

  Compositions containing the compounds described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to cure the disease or condition or at least partially block the signs of the disease or condition. The effective amount for this use depends on the severity and duration of the disease or condition, previous treatment, patient health, weight and response to the drug, and the judgment of the treating physician. It is well within the skill in the art to determine such therapeutically effective amounts by routine experimentation (including but not limited to dose escalation clinical trials).

  In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk for a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose”. In this use, the exact amount also depends on the patient's health, weight, etc. It is well within the skill of the art to determine such prophylactically effective amounts by routine experimentation (eg, dose escalation clinical trials). When used in a patient, the effective amount for this use depends on the severity and duration of the disease, disorder or condition, prior treatment, the patient's health and response to the drug, and the judgment of the treating physician.

  If the patient's condition does not improve, the compound may continue to be administered at the physician's discretion, i.e. it may be administered for an extended period of time, including throughout the patient's lifetime, thereby causing the patient's disease or condition. Remission, or otherwise control or suppress symptoms of

  When the patient's condition improves, the administration of the compound can be continued at the discretion of the physician, optionally the dose of the drug can be temporarily reduced, or temporarily for a period of time (ie a “drug holiday”) Can be interrupted. The length of the drug holiday can vary from 2 days to 1 year, and to name only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 Day 20, 20, 28, 35, 50, 70, 100, 120, 150, 180, 200, 250, 280, 300, 320, 350, or 365 days Including. The dose reduction during the drug holiday may range from 10% to 100%, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% , 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

  Once the patient's symptoms have improved, a maintenance dose is administered if necessary. Subsequently, the dose or frequency of administration or both are reduced as a function of symptoms to a level at which the improved disease, disorder or condition is retained. However, patients can require long-term intermittent treatment due to any recurrence of symptoms.

  The amount of a given drug corresponding to such an amount will vary depending on factors such as the particular compound, the disease or condition and its severity, the identity of the subject or host in need of treatment (eg, body weight), etc. Nevertheless, routinely in a manner known in the art according to the particular circumstances surrounding the case, including the particular drug being administered, the route of administration, the condition being treated, the subject or host being treated, etc. Can be determined. In general, however, doses used for the treatment of human adults are typically in the range of 0.02 to 5000 mg per day, preferably in the range of 1 to 1500 mg per day. The desired dose can be a single dose or as divided doses, simultaneously (or over a short period of time) or as a sub-dose at appropriate intervals, eg 2, 3, 4 or more times per day Can be provided conveniently.

  The pharmaceutical compositions described herein can be in a single dosage form suitable for single administration of precise doses. In unit dosage form, the formulation is divided into single doses containing appropriate quantities of one or more compounds. A single dose may be in the form of a package containing a discrete amount of the formulation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-resealable containers. Alternatively, multiple dose resealable containers can be used, in which case the composition typically includes a preservative. By way of example only, parenteral injection formulations are provided in a single dosage form including (but not limited to) ampoules or in multi-dose containers with preservatives added.

  A suitable daily dose of the compounds described herein is about 0.01 to 2.5 mg / kg body weight. The indicated daily dose in larger mammals, including humans, is not limited but ranges from about 0.5 mg to about 100 mg, but is not limited to up to 4 divided doses per day Or in a sustained release form. Suitable unit dosage forms for oral administration contain from about 1 to 50 mg of active ingredient. The above ranges are only suggestive as the number of variables for each treatment regime is large, and considerable deviations from the recommended values are not uncommon. Such dosage is not limited to a number of variables (the activity of the compound used, the disease or condition being treated, the mode of administration, the individual subject's requirements, the severity of the disease or condition being treated and the judgment of the practitioner). ).

The toxicity and therapeutic efficacy of such treatment regimes is that LD ₅₀ (a lethal dose for 50% of the population) and ED ₅₀ (for 50% of the population) in cell cultures or experimental animals. Including, but not limited to, determination of a therapeutically effective dose) and can be determined by standard pharmaceutical practice. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD ₅₀ and ED ₅₀ . Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED ₅₀ with minimal toxicity. The dose may vary within this range depending on the dosage form used and the route of administration utilized.

Combination Therapy The compositions and methods described herein can also be used in combination with other well known therapeutic agents selected for their particular usefulness against the condition being treated. In general, the other agents in the embodiments where the compositions and combination therapies described herein are used need not be administered in the same pharmaceutical composition, but due to different physical and chemical properties, different routes May have to be administered. Determination of the method of administration and, if possible, the appropriateness of administration with the same pharmaceutical composition is within the knowledge of a well-trained clinician. Initial administration can be according to established protocols known in the art, and then based on the observed results, a skilled clinician can modify the dose, method of administration, and number of administrations .

  In some cases, it may be appropriate to co-administer at least one compound described herein with another therapeutic agent. By way of example only, if one of the side effects experienced by the patient is nausea when taking one of the compounds of the present invention, it may be appropriate to administer the antiemetic in combination with the initial therapeutic agent. . Or, by way of example only, one therapeutic efficacy of the compounds described herein may be used in combination with another therapeutic agent to the patient, although the adjuvant itself may have minimal therapeutic benefit. Can enhance the overall therapeutic benefit of). Or, by way of example only, the benefit experienced by a patient can be increased by administration of one of the compounds described herein with another therapeutic agent that also has a therapeutic benefit, including a treatment plan. . In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient can be merely additive of the two therapeutic agents, or the patient can be a synergistic benefit Can experience.

  The particular choice of compound used will depend on the diagnosis of the attending physician and the determination of the patient's symptoms and the appropriate treatment protocol. The compounds may be simultaneously (eg, simultaneously, substantially simultaneously, or within the same treatment protocol) or sequentially depending on the nature of the disease, disorder or condition, the condition of the patient and the actual choice of compound used. Can be administered. Determination of the order of administration and the number of repeated administrations of each therapeutic agent in the treatment protocol is well within the knowledge of a skilled physician after assessment of the disease being treated and the symptoms of the patient.

  It is known to those skilled in the art that when a drug is used in combination therapy, the therapeutically effective amount can vary. Methods for experimentally determining therapeutically effective amounts of drugs and other drugs used in combination treatment regimens are described in the literature. The use of medications such as metronome, ie providing more frequent and lower doses to minimize toxic side effects has been extensively described in the literature. Combination treatment further includes periodic treatments that start and stop at various times to help the patient's clinical management.

  For the combination therapies described herein, the dose of the compound administered in combination will of course vary depending on the type of drug administered in combination, the particular drug used, the disease or condition being treated. Further, when administered in combination with one or more biologically active agents, the compounds provided herein may be administered either simultaneously with the biologically active agent or sequentially. . When administered sequentially, the attending physician will decide on the appropriate sequence of administering the protein in combination with the biologically active agent.

  In any case, the multiple therapeutic agents (one of which is a compound disclosed herein) can be administered in any order or even simultaneously. In the case of simultaneous administration, the multiple therapeutic agents may be provided in a single unified form or in multiple forms (only as an illustration, but as a single pill or two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given in multiple doses. If not co-administration, the timing between multiple doses can vary from more than 0 weeks to less than 4 weeks. Furthermore, the combination methods, compositions and formulations are not limited to the use of only two agents; the use of multiple therapeutic combinations is also envisaged.

  It will be appreciated that the treatment regimen for treating, preventing or ameliorating the symptoms sought to be removed can be modified according to various factors. These factors include the subject's age, weight, sex, diet and medical condition as well as the disorder the subject is suffering from. Thus, the treatment plan actually used varies widely and can thus deviate from the treatment plan described herein.

  The medicaments making up the combination therapy disclosed herein may be a combined dosage form or may be separate dosage forms intended for substantially simultaneous administration. A pharmaceutical agent that constructs a combination therapy can also be a continuous administration, with the compound being administered by a regime that requires two-step administration. A two-stage regimen may require continuous administration of the active agent or spaced apart administration of the active agent. The time period between multiple dosing phases can range from minutes to hours depending on the characteristics of each drug such as drug efficacy, solubility, bioavailability, plasma concentration half-life and kinetic profile. Circadian variation of the target molecule concentration can also determine the optimal dosing interval.

  Furthermore, the compounds described herein can also be used in conjunction with procedures that can provide an additive or synergistic benefit to the patient. By way of example only, patients are expected to find therapeutic and / or prophylactic benefits to the methods described herein, with the pharmaceutical compositions and / or other therapeutic agents of the compounds disclosed herein. The combination is combined with genetic testing to determine whether the individual is a carrier of a mutated gene known to be associated with a disease or condition.

  The compounds and combination therapies described herein can be administered before, during, or after the occurrence of the disease or condition, and the timing of administering the composition comprising the compounds can vary. Thus, for example, a compound can be used as a prophylactic and can be administered continuously to a subject with a tendency to develop symptoms or symptom disease to prevent the occurrence of the disease or condition. The compounds and compositions can be administered to a subject during onset of symptoms or as soon as possible after onset. Administration of the compound is within the first 48 hours of onset of symptoms, preferably within the first 48 hours of onset of symptoms, more preferably within the first 6 hours of onset of symptoms and most preferably onset of onset of symptoms. Can start in 3 hours. Initial administration may be practical via any route of intravenous injection, bolus injection, infusion of 5 minutes to about 5 hours, pills, capsules, transdermal patches, buccal delivery, etc. or combinations thereof. The compound is administered as soon as possible after the onset of a disease or symptom is detected or suspected, and is administered for a period of time necessary for the treatment of the disease, for example from about 1 month to about 3 months Is preferred. The duration of treatment varies for each subject, and the duration can be determined using known criteria. For example, the compound or formulation containing the compound can be administered for at least 2 weeks. Preferably from about 1 month to about 5 years and more preferably from about 1 month to about 3 years.

Kits / Products Kits and products are also described herein for use in the therapeutic applications described herein. Such a kit may include a carrier, package or container partitioned to receive one or more containers, such as vials, tubes, etc., each of which is a separate element used in the methods described herein. Including one of them. Suitable containers include, for example, bottles, vials, syringes and test tubes. The container can be formed from a variety of materials such as glass or plastic.

  The products provided herein include packaging materials. Packaging materials used for pharmaceutical packaging are well known to those skilled in the art. See, for example, US Pat. No. 5,323,907, US Pat. No. 5,052,558 and US Pat. No. 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles and selected formulations and the intended form of administration and treatment Any packaging material may be mentioned. A wide range of formulations of the compounds and compositions provided herein are any disease, injury or symptom that benefits from inhibition of fatty acid amide hydrolase (FAAH), or a mediator or contributor of FAAH sign or cause. A variety of treatments for any disease, injury or condition are contemplated.

  For example, a container can contain one or more compounds described herein, optionally in a composition or in combination with another agent disclosed herein. The container optionally has a sterile access port (eg, the container can be an intravenous solution bag or vial with a stopper that can be penetrated by a hypodermic needle). Such kits comprise a compound, optionally with instructions or labels or instructions for use in the methods described herein.

  A kit will usually include one or more additional containers, each of which may contain one or more different materials (eg, reagents (such as reagents) that are desirable from a commercial and user standpoint for the use of the compounds described herein. Optionally in concentrated form) and / or equipment). Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes, contents, and / or carriers, packages, containers, vials and / or tube labels listing instructions for use and Examples include, but are not limited to, package inserts with usage precautions. A set of instructions is also usually included.

  The label can be on or with the container. If letters, numbers or other letters forming the label are attached, molded or etched on the container itself, the label can be present on the container and present in the container or carrier holding the container, for example as a package insert If so, the label can accompany the container. A label can be used to indicate that the contents should be used for a particular therapeutic application. The label can also indicate instructions for use of the contents, for example, in the methods described herein.

  In certain embodiments, the pharmaceutical composition can be provided in a pack or in a dispensing device that can contain one or more unit dosage forms containing a compound provided herein. The pack can include a metal or plastic foil, such as a blister pack. The pack or dosing device can be combined with the dosing instructions. The pack or dosing device may also be accompanied by a notice accompanying the container in a manner prescribed by a government agency that regulates the manufacture, use or sale of the pharmaceutical product. This notice reflects the regulatory approval of the drug form for human or veterinary administration. Such notification can be, for example, labeling for prescription drugs by the US Food and Drug Administration or by an approved product package. A composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is also prepared, placed in a suitable container, and labeled for treatment of the indication be able to.

Treatment and / or Use of FAAH Inhibitor Compounds The enzyme FAAH includes, but is not limited to, N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine, N-oleoylethanolamine, oleamide, and 2-arachidonoylglycerol. .) Catalyzes the hydrolysis of endogenous amide and ester derivatives of various fatty acids. These derivatives interact with cannabinoid and vanilloid receptors, in particular, and exert various pharmacological activities. The compounds provided herein block this degradation pathway and increase the tissue content of these endogenous substances. They can be used in this regard in the prevention and treatment of pathologies involving endogenous cannabinoids and / or any other substrate metabolized by the enzyme FAAH.

  In certain embodiments, the compounds provided herein can be used to treat and / or prevent nausea, dizziness, vomiting and nausea, especially after chemotherapy.

  In certain embodiments, the compounds provided herein can be administered to alleviate a subject's pain. This treatment may be prophylactic or therapeutic. This treatment may be administered to a human subject. This treatment may or may not be administered in combination therapy with another analgesic or anti-inflammatory agent.

  In certain embodiments, the compounds provided herein may comprise other forms of chronic pain such as pain associated with cough symptoms, cancer-related pain, preoperative pain, joint pain and postoperative pain, lumbosacral pain, musculoskeletal It can be used in the treatment of all kinds of pain such as cramps, headaches, migraines, muscle pains, back and neck pains, toothaches. In certain embodiments, the compounds provided herein are useful for the treatment of neuropathic pain. Neuropathic pain syndrome can develop following neuropathy, and the resulting pain can last for months or years and can persist even after the initial injury has been repaired. Nerve cell damage can occur in certain areas of the peripheral nerve, dorsal root of the spinal cord, spinal cord or brain. Neuropathic pain syndrome has traditionally been classified by the disease or event that promoted them. Neuropathic pain syndrome includes the following: Diabetic neuropathy; sciatica; nonspecific low back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; neuralgia such as postherpetic neuralgia and trigeminal neuralgia; and physical trauma, amputation, cancer, Pain resulting from toxins or chronic inflammatory symptoms. The signs of neuropathic pain are heterogeneous and are often described as spontaneous shooting pain and electric shock, or ongoing burning pain. In addition, pain associated with usually painless sensations, such as “numbness and tingling sensation” (sensory abnormalities and sensory deficits), increased contact sensitivity (hypersensitivity), harmless stimuli (dynamic hyperalgesia, static hyperalgesia) Pain, hypersensitivity after noxious stimuli (thermal hyperalgesia), increased hypersensitivity to noxious stimuli (thermal hyperalgesia, cold hyperalgesia, mechanical hyperalgesia), persistent hyperalgesia after stimulus removal (abnormal analgesia) Hypersensitivity) or lack or deficiency in selective sensory pathways (hyperalgesia).

  In certain embodiments, the compounds provided herein are painful, particularly acute or chronic neurogenic pain, migraine, neuropathic pain including forms associated with herpesviruses and diabetes, acute associated with inflammatory diseases Or chronic pain: useful for the treatment and / or prevention of arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome and peripheral acute / sharp pain, or chronic pain .

In certain embodiments, the compounds and compositions provided herein can be used to treat non-inflammatory pain and / or inflammatory pain. The compound is administered as a therapeutic agent, including but not limited to, a therapeutic agent for non-inflammatory pain;
Peripheral neuropathic pain (pain caused by lesions or dysfunction of the peripheral nervous system, such as painful neuropathy that persists for a long time after the tissue disorder has healed);
Central pain (this is pain caused by a lesion or dysfunction of the central nervous system, eg thalamic lesions with severe pain in an unaffected part of the body;
Afferent block pain (this is pain due to loss of sensory transmission to the central nervous system, eg, pain due to damage when the dorsal root of the spinal cord is pulled away from the spinal cord);
Chronic nociceptive pain (eg, certain types of cancer pain);
Nociceptive stimuli of nociceptors (eg, pain felt in response to tissue damage or imminent tissue damage);
Phantom limb pain (pain felt in parts of the body that no longer exist);
Pain felt by psychiatric patients (pain without any physical cause);
Running pain (pain repeatedly changes position in the body).

  The compounds provided herein can be used to treat both non-inflammatory and inflammatory pain.

  In another embodiment, a composition provided herein is compatible with a compound provided herein and at least one art-recognized compound provided herein, preferably an oral dosage form. Contains effective analgesics or anti-inflammatory substances. Examples of analgesics and anti-inflammatory compounds recognized in the art include, but are not limited to: Aspirin, carbaspirin, choline salicylate, diflunisal, magnesium salicylate, salicylamide, salicylic acid, salsalate, sodium thiosalicylate, acetaminophen, phenacetin, aminopyrine, mefenamic acid, methotrimiprazine, oxyphenbutazone, phenylbutazone, indomethacin, Ibuprofen, sulindac, piroxicam, meclofenamate, zomepirac, codeine, morphine, meperidine, pethinin, alphaprozin, fentanyl, levorphanol, methadone, phenazosin, butorphanol, etoveptodin, nalbuphine, pentazocine, propoxyphene, phenoprofen, Naproxen, Tormeton, etc. In preferred embodiments, the compounds provided herein are administered in combination with such art-recognized analgesics and / or anti-inflammatory compounds to produce a synergistic anti-inflammatory and / or analgesic effect. Bring.

  In another embodiment, the compounds and compositions provided herein may be used to reduce neuropathic pain.

  As used herein, the term “neuropathic pain” means pain resulting from damage to a nerve. Neuropathic pain is distinguished from nociceptive pain, which is pain due to acute tissue damage involving small subcutaneous or small nerves in muscle or connective tissue. Pain usually associated with nociceptive mechanisms is limited during periods of tissue repair and is generally alleviated by available analgesics or opioids (Myers, Regional Anthesia 20: 173-184 (1995), which is by reference) Incorporated here.)

  Neuropathic pain is typically persistent or chronic, or progresses for days or months following the initial acute tissue injury. Neuropathic pain, like persistent spontaneous pain, can include allodynia that responds with pain to stimuli that are not normally painful. Neuropathic pain can be characterized by hyperalgesia, which usually has an exaggerated response to painful stimuli such as trivial pin bruises. The compounds provided herein can be used to relieve neuropathic pain regardless of the cause of pain. In certain embodiments, the compounds and compositions provided herein are derived from peripheral neuropathy such as neuroma; nerve compression; nerve compression; nerve extension or incomplete nerve amputation; mononeuritis or polyneuritis Can be used to relieve neuropathic pain.

  Neuromas can readily develop after traumatic injury to the nerve, especially when the entire nerve is severely broken or severed. In neuromas, neurite outgrowth, which usually regenerates peripheral nerves, is abnormal or has been misdirected by physical disorders such as scar tissue. Thus, regenerative nerve fibers are entangled in the environment, where mechanical and physical factors promote abnormal electrophysiological activity and pain (Myers, supra, 1995). Amputated neuromas can, for example, cause phantom limb pain, or trigger use of a limb prosthesis. As disclosed herein, such neuropathic pain can be alleviated by administration of a FAAH inhibitor, such as, for example, a compound provided herein.

  Nerve compression also results in neuropathic pain. Nerve compression can be abrupt, mild secondary to tumor growth or scar formation proximal to the main nerve bundle, as is the case with traumatic nerve compression. Compression neuropathy can result from changes in blood flow to the nerve, which can result in severe ischemia and inevitably nerve injury (Myers, supra, 1995).

  In other embodiments, compounds and compositions provided herein include dorsal root ganglion compression; myelitis; spinal cord contusion, tumor or unilateral amputation; brainstem, thalamus or cortical tumor; brainstem, thalamus or cortex It can be used to relieve neuropathic pain due to disorders such as trauma.

  In certain embodiments, administration of a compound provided herein can alleviate neuropathic pain resulting from mononeuritis or polyneuritis. As used herein, neuropathy is a dysfunction or pathological change in the peripheral nervous system and is clinically characterized by abnormalities in sensory or motor neurons. The term “mononeuritis” indicates that a single peripheral nerve is affected, while the term “polyneuritis” indicates that several peripheral nerves are affected. The etiology of neuropathy may be known or unknown (eg, Myers, supra, 1995; Galer, Neurology 45 (suppl 9): S17-S25 (1995); Stevens and Lowe, Pathology, Times Mirrorland Interims, Lancer International Interim). (1995)). Known etiologies are the most common metabolic abnormalities that cause neuropathy, such as complications of disease or addiction symptoms, such as diabetes. In certain embodiments, the compounds provided herein alleviate neuropathic pain of mononeuritis resulting from, for example, diabetes, radiation therapy, ischemia or vasculitis. In other embodiments, the compounds provided herein result from, for example, post-polio syndrome, diabetes, alcohol, amyloid, toxin, HIV, hypothyroidism, uremia, vitamin deficiency, chemotherapy, ddC or Fabry disease Alleviates the neuropathic pain of polyneuritis. In certain other embodiments, the compounds provided herein can also alleviate neuropathic pain of unknown etiology.

  In certain embodiments, the compounds provided herein can be used to treat inflammatory diseases such as, for example, autoimmune diseases.

  The term “inflammatory disease” includes pain (pain from the generation of harmful substances and nerve stimulation), heat (amount of heat from vasodilation), red (vasodilation and redness from increased blood flow), swelling (fluids of fluid A disease or symptom characterized by one or more signs of excessive inflow or restricted spill) and loss of function (partial or complete, temporary or permanent dysfunction). Inflammation takes various forms and includes, but is not limited to, one or more of the following: acute, adhesive, atrophic, catarrhal, chronic, cirrhosis, diffusive, disseminated, exudative, fibrotic , Fibrosis, local, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obstructive, substantial, plastic, productive, proliferative, pseudomembranous, purulent, Sclerosis, serum plasticity, serology, unity, specificity, subacute, purulent, toxic, traumatic, and / or ulcerative inflammation. Inflammatory diseases are further vascular (polyarteritis, temporal arteritis); joints (arthritis: crystal arthritis, osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, reiter arthritis) gastrointestinal tract (clone Disease, ulcerative colitis); skin (dermatitis); or inflammation that affects numerous organs and tissues (systemic lupus erythematosus) [Harrison's Principles of Internal Medicine, 16th Edition, Kasper DL, et al, Editors; McGraw-Hill, publishers].

  Immune disorders such as autoimmune diseases can be treated with the compounds provided herein or compositions comprising the compounds provided herein, including: arthritis (rheumatoid arthritis, spondyloarthropathy, gouty) Arthritis, osteoarthritis (ie osteoarthritis), systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, anaplastic spondylitis, Behcet's disease, hemorrhagic autoimmune anemia, multiple sclerosis, amyotrophic lateral sclerosis , Cereal, acute shoulder pain, psoriasis, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, dermatitis disorders (ie psoriasis, eczema, burns, dermatitis) ), Enuresis, eosinophilia, gastrointestinal disorders (inflammatory bowel disease, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal bleeding, Crohn's disease, gastritis, diarrhea, irritable bowel syndrome and ulcerative colon And disorders ameliorated by gastrointestinal motility drugs (ie, intestinal obstruction, eg, postoperative intestinal obstruction and intestinal obstruction in the course of sepsis; gastroesophageal reflux disease (GORD, or synonymous GERD)); Gastroparesis such as eosinophilic esophagitis, diabetic gastric paresis; food hypersensitivity and food allergy, and other functional bowel disorders such as non-ulcer dyspepsia (NUD) and non-cardiac chest pain (NCCP) )).

  A composition comprising a compound provided herein can also be used, for example, to treat inflammation associated with: vascular disease, migraine, tension headache, nodular periarteritis, thyroiditis , Aplastic anemia, Hodgkin's disease, cyerodoma, rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, multiple sclerosis And ischemia (eg, myocardial ischemia). These compounds may be used in the treatment of neuroinflammation associated with brain disorders (eg Parkinson's disease and Alzheimer's disease) and chronic inflammation associated with cranial radiation injury. These compounds may be used to treat acute inflammatory conditions (such as those resulting from an infection) and chronic inflammatory conditions (such as those resulting from asthma, arthritis and inflammatory bowel disease). . These compounds may further be used to treat inflammation associated with trauma and non-inflammatory myalgia. These compounds can also be administered before surgery or before taking anticoagulants. The compounds provided herein reduce the risk of thrombotic cardiovascular events, defined as platelet aggregation, thrombosis, and any type of sudden event known to be triggered by subsequent clinical ischemic events. Can be reduced. Such thrombotic cardiovascular events include thrombotic or thromboembolic stroke, myocardial ischemia, myocardial infarction, angina pectoris, transient ischemic stroke (TIA; transient cataract), reversible false Includes hematologic neuropathy and thrombotic events in any similar vascular bed (visceral, renal, aortic, peripheral, etc.).

  The compounds provided herein include flu or other viral infections colds, sprains and contusions, myositis, neuralgia, synovitis, sports injury and post-surgical and post-dental wounds, blood coagulation disorders, kidneys Diseases (eg, renal dysfunction), ophthalmic diseases (including glaucoma, retinitis, retinopathy, pleurisy, wet macular degeneration and acute damage to ocular tissues), liver diseases (ie, chronic viral hepatitis B) , Chronic viral hepatitis C, alcoholic liver disease, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis, and inflammatory liver disease including liver transplant rejection) and lung inflammatory diseases (Eg, including asthma, allergic rhinitis, respiratory distress syndrome chronic bronchitis and emphysema).

  The compounds provided herein can be used to inhibit hormone-induced uterine contractions and prostanoid-induced smooth muscle contractions. The compounds provided herein can be used to treat preterm birth, menstrual pain, irregular menstruation and dysmenorrhea.

  In certain embodiments, the compounds provided herein can inhibit malignant transformation of cells and metastatic tumor growth. These compounds may be involved in reducing the number of adenomatous colorectal polyps. Thus, the compounds provided herein may be useful in reducing the risk of certain types of cancer (eg, solid cancers such as colon cancer or colorectal cancer). In certain embodiments, the compounds provided herein are HER-2 / of the lung, kidney, pancreas, prostate, gallbladder and bile ducts, including bladder cancer, cervix, skin, esophagus, head and neck, and non-small cell lung cancer Treatment of cancers associated with overexpression of the neu oncogene and cancers such as, but not limited to, endometrial cancer, gastric cancer, glioma, hepatocellular carcinoma, colon adenoma, mammary tumor, ovarian cancer and salivary cancer. Or it can be used for prophylaxis and the compounds provided herein can be used to treat colon cancer and prostate cancer. These compounds are also used in patients with oral precancerous lesions, cervical intraepithelial neoplasia, chronic hepatitis, biliary hyperplasia, atypical adenomatous hyperplasia of the lung, prostatic intraepithelial neoplasia, bladder dysplasia, skin sunlight It can be used in cases at risk for cancer including keratosis, colorectal adenoma, gastric mucosal metaplasia and Barrett's esophagus.

  In certain embodiments, the compounds provided herein are benign skin tumors, papillomas and brain tumors, prostate tumors, brain tumors, glioblastomas, myeloblastomas, myeloblastomas, neuroblastomas, embryonic origin tumors Astrocytoma, astroblastoma, ependymoma, oligodendroglioma, choroid plexus papilloma, neuroepithelioma, pineal tumor, ventricular ependymoma, malignant meningioma, sarcoma, malignant black It can be used to treat tumors such as, but not limited to, Schwann cell carcinoma. In certain embodiments, the compounds provided herein can also be useful in the treatment and / or prevention of cyclooxygenase-mediated hyperplasia that can occur in diabetic retinopathy and tumor angiogenesis. In certain embodiments, the compounds provided herein can be used to inhibit angiogenesis as occurs in wet macular degeneration.

  For example, FAAH inhibitors, such as the compounds provided herein, can be associated with dementia, particularly degenerative dementia (senile dementia, Alzheimer's disease (and its precursors), Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt. -Including Jacob disease) and vascular dementia (including multiple infarct dementia) and intracranial space-occupying lesions, trauma, infection and related symptoms (including HIV infection), metabolism, toxins, anoxia It is useful for treating cognitive impairment such as dementia and dementia associated with vitamin deficiency and cognitive dysfunction related to aging, especially age-related memory impairment.

  For example, FAAH inhibitors, such as the compounds provided herein, can prevent nerve damage by inhibiting the generation of neuronal free radicals (and thus oxidative stress), and therefore stroke, epilepsy, and epilepsy Useful to treat convulsions (including major seizures, minor seizures, myoclonic epilepsy and partial seizures). FAAH inhibitors such as the compounds provided herein are useful for controlling or inhibiting convulsions (including those that are chemically induced).

  In certain embodiments, FAAH inhibitor compounds, such as, for example, the compounds provided herein include, for example, Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, cerebral ischemia and lesions associated with cranial and medullary trauma. Can be used for acute and chronic neurodegenerative diseases.

  In certain embodiments, FAAH inhibitory compounds, such as, for example, compounds provided herein, and compositions comprising them, can be useful in treating depression and depressive diseases or conditions. The compounds and compositions are useful for treating, for example, major depressive disorder (unipolar depression), dysthymic disorder (chronic mild depression), and bipolar disorder (manic depression) obtain. This depression can be clinical depression or subclinical depression.

  For example, FAAH inhibitory compounds, such as the compounds provided herein, and compositions comprising the compounds can be useful for treating anxiety and anxiety disorders or symptoms. These compounds and compositions include, for example, anxiety, clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder, specific phobias, social phobia, obsessive compulsive disorder, acute stress disorder and traumatic stress disorder And for treating anxiety-related adaptation disorders, anxiety disorders due to common medical conditions, substance-induced anxiety disorders, and other categories of anxiety disorders not otherwise specified. This treatment may be prophylactic or therapeutic. These compounds can be used to treat anxiety and anxiety disorders or symptoms of anxiety only and / or other diseases or conditions such as, for example, pain, obesity, depression, or other disorders Useful to treat at the same time.

  In certain embodiments, compounds that inhibit FAAH activity, such as, for example, the compounds provided herein, and compositions comprising the compounds are useful in the treatment of epilepsy and convulsive diseases or seizures. The compounds and compositions of the invention may be administered alone to reduce the severity or frequency of convulsions or seizures.

  In certain embodiments, the FAAH inhibitor induces sleep (US Pat. Nos. 6,096,784; 6,096,784; 6,271,015; WO98 / 24396). In one embodiment, the compounds provided herein can be administered to a mammal and the subsequent time spent in sleep (eg, closed eyes, pause in exercise) (eg, onset of sleep, sustained sleep) Can be increased.

  In certain embodiments, FAAH inhibitor compounds may be useful for treating schizophrenia and dopamine related diseases. In certain embodiments, the compounds and compositions provided herein are useful for the treatment of schizophrenia, paranoia, paranoid idealization, emotional flattening or other related diseases, or other disorders of dopamine transmission obtain.

  In certain embodiments, a compound provided herein and a composition comprising the compound provided herein are administered to induce or promote sleep in a mammal. This treatment may be prophylactic or therapeutic and can be administered to healthy human patients solely for the purpose of reducing the severity or frequency or time of insomnia. In other embodiments, the compounds and compositions provided herein can be used to treat sleep disorders such as, but not limited to, insomnia and apnea sleep.

  In certain embodiments, a compound that inhibits FAAH activity, such as, for example, a compound provided herein, and a composition comprising the compound may be used to reduce appetite or be used to reduce body fat. It may be used to treat or prevent obesity or overweight in mammals and may be used to prevent or treat diseases associated with these health conditions. In one embodiment, administration of a FAAH inhibitor, such as, for example, a compound provided herein, may reduce appetite, body fat or overweight or treat or prevent obesity or overweight in a mammal or food intake Can be used to reduce or treat appetite disorders.

  In one embodiment, the compounds and compositions provided herein are for reducing appetite, body fat or weight or obesity in a human patient, including changes in weight composition such as% fat or changes in lean body mass. Or it can be used to treat or prevent overweight or to reduce food intake or to treat persistent appetite disorders.

  In further embodiments, the FAAH inhibitor, eg, a compound provided herein, is administered in combination therapy with oleoylethanolamide (OEA) or other fatty acid alkanolamide compound, homologue or congener, which The body or like pair a) reduces appetite, reduces food consumption, reduces body fat or weight, and b) undergoes hydrolysis by FAAH.

  In certain embodiments, an FAAH inhibitor, such as a compound provided herein, is an amount sufficient to reduce body fat, weight, or prevent body fat or weight gain, or reduce appetite. Is administered to the subject. In another embodiment, a composition provided herein comprises a FAAH inhibitor such as a compound provided herein and oleoyl ethanolamide, or a fatty acid amide compound, analogs or analogs thereof.

  In certain embodiments, the FAAH inhibitor, such as a compound provided herein, is insulin resistant, diabetes, steatohepatitis, hyperlipidemia, fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis And can be used to treat various metabolic disorders such as arteriosclerosis. Methods for measuring the effects of compounds provided herein on such disorders are disclosed in US Pat. No. 6,946,491, which is hereby incorporated by reference.

  In one embodiment, a compound provided herein and a pharmaceutical composition comprising a compound provided herein comprise insulin resistance syndrome and diabetes (primary essential diabetes such as type I diabetes or type II diabetes, and secondary non- It can be used to treat a symptom selected from both essential diabetes). Administration of a compound or composition provided herein reduces symptoms of diabetes or atherosclerosis, hypertension, hyperlipidemia, fatty liver disease, kidney damage, neuropathy, retinopathy, leg ulceration Or it can reduce the chances of developing signs of diabetes such as cataracts, each sign being related to diabetes.

  In one embodiment, the compounds provided herein and pharmaceutical compositions comprising the compounds provided herein can be used to treat hyperlipidemia. Administration of the pharmaceutical compounds and compositions provided herein can reduce serum triglycerides and free fatty acids in hyperlipidemic subjects. In one embodiment, the compounds and compositions provided herein can be used to treat fatty liver disease. In another embodiment, the compounds and pharmaceutical compositions provided herein can be used to treat atherosclerosis or arteriosclerosis.

  In other embodiments, the compounds and compositions provided herein provide for eating behavior problems / eating disorders (ie, eating disorders, particularly anorexia and cachexia of various properties, cancer and other wasting conditions) Can be used to treat and / or prevent weight loss associated with

  In certain embodiments, FAAH inhibitors, such as the compounds provided herein, can be administered to treat or prevent glaucoma or to reduce intraocular pressure. In certain embodiments, these compounds can be administered systemically. In other embodiments, these FAAH inhibitors are applied directly to the ocular surface (eg, by eye drops). Ophthalmic carrier formulations for such ophthalmic applications are described in Remington's Pharmaceutical Sciences, Gennaro A Red. 20th edition, 2000: Williams & Wilkins Pa. , Taught during the USA.

  In certain embodiments, the compounds provided herein and compositions comprising the compounds can be administered to treat or prevent glaucoma or to reduce intraocular pressure. In certain embodiments, the compound can be administered systemically. In other embodiments, the compound is applied directly to the ocular surface (eg, via eye drops).

  Other diseases, disorders and / or symptoms that can be treated and / or prevented by the compounds provided herein include the following: lung disease (ie airway disease, bronchospasm, cough, asthma, chronic Bronchitis, chronic obstruction of the respiratory tract, emphysema); urinary incontinence, cystitis, urinary incontinence, bladder cystitis, movement disorder, psychomotor disorder, hypertension; heart disease, especially hypertension, arrhythmia, arteriosclerosis, heart attack, heart failure Blood, renal ischemia, neuropathology, mental tremor, movement disorder, dystonia, spasticity, obsessive-compulsive behavior, Tourette syndrome, emotional disorder, psychosis.

  Any combination of the disorders, diseases and / or symptoms listed here can be treated with the compounds provided herein.

EXAMPLES Those skilled in the art can appreciate various aspects and advantages of the present disclosure by further examining the following detailed, non-limiting examples.

Example 1
Preparation of FAAH inhibitor Synthesis of 3-acetylphenyl cyclohexyl carbamate: solution of 3-hydroxyacetophenone (1 mmol, 136 mg), triethylamine (1.1 mmols, 0.19 mL) and cyclohexyl isocyanate (1.1 mmols, 0.14 mL)) Was stirred for 3 hours at room temperature. Thereafter, the precipitated solid was filtered and dried under reduced pressure to obtain a white solid as a product.

(Example 2)
Methods for Screening Compounds for FAAH Inhibitory Activity In general, FAAH inhibitors used in the methods described herein are identified as FAAH inhibitors in vitro. A preferred in vitro assay is a reaction product (eg fatty acid amide or ethanolamine) due to increased levels of unchanged FAAH substrate (eg anandamide, OEA) or FAAH mediated hydrolysis of a substrate such as AEA or OEA Detects a decrease in the release of. The substrate can be labeled to facilitate detection of the released reaction product. High throughput assays for the detection or quantification of the presence or absence of specific reaction products are well known to those skilled in the art. In addition, high-throughput screening systems are commercially available (Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments, Inc. Fullerton, CA; Precision Systems. etc.). These systems are typically fully automated procedures, including pipetting of all samples and reagents, liquid dispersion, timed incubation and final reading of the microplate with a detector suitable for the assay. . The automated system allows the identification of many in vitro FAAH inhibitors without undue effort.

  Candidate FAAH inhibitors in vivo can be identified by their ability to increase systemic levels of one or more FAAs. Suitable FAAs include fatty acid ethanolamides having a fatty acid moiety containing 14 to 28 carbons, 0 to 6 double bonds, such as, for example, OEA, PEA, AEA, and stearoylethanolamide (SEA). Other suitable FAAs include primary fatty acid amides having a fatty acid moiety containing 14 to 28 carbons and 0 to 6 double bonds, such as oleamide. Biological samples that can be analyzed for FAA levels include, but are not limited to, plasma, serum, blood, cerebrospinal fluid, saliva or urine.

  FAA levels in a biological sample are assayed, for example, by liquid chromatography tandem mass spectrometry (LC-MS / MS). Increased assay reproducibility is achieved by adding a known amount of isotope-labeled FAA to the biological sample, which is used as an internal standard for the FAA to be assayed. The level of FAA can also be determined using spectrophotometric techniques (eg, fluorometry). Alternatively, FAA levels can be measured using biological assays. In certain embodiments, the level of FAA is measured using a combination of the aforementioned techniques. Any of the above-described assays for FAA levels can be partially or fully automated for high throughput. Similar to the details of this method and other FAA assays, methods for analyzing changes in FAA levels are also known in the art. For example, Quistad et al. (2002), Toxicology and Applied Pharmacology 179: 57-63; Quistad et al. (2001), Toxicology and Applied Pharmacology 173, 48-55; Boger et al. (2000), Proc. Natl. Acad. Sci. U. S. A. 97, 5044-49; Cravatt et al. Proc. Natl. Acad. Sci. U. S. A. 98, 9371-9376 (2001); Ramarao et al. (2005) Anal. Biochem. 343: 143-51. See also US Patent No. 6,096,784, US Patent Publication No. 2004/0127518, US Patent Application No. 10 / 681,858, International Patent Publication Nos. WO98 / 24396 and WO04 / 033422.

  The carbamate compounds shown in FIGS. 1-8 were tested for in vitro inhibition of FAAH compared to the reference compound KDS-4103 and found to have some inhibitory activity.

(Example 3)
Screening of compounds for FAAH activity inhibition-FAAH LC-MS / MS screening assay:
In one embodiment, inhibition of FAAH activity is measured using LC-MS / MS. The following are formulated in a 5-mL glass tube: Anandamide (5 μL of 200 ug / mL), 960 μL of 50 mM ammonium phosphate buffer (pH 7.4) containing 0.125% BSA (w / v). DMSO with or without FAAH inhibitor (1 μg / mL) (control) and 10 μL of DMSO and 25 μL of human liver microsomes (31.3 μg). Prior to incubation, an aliquot of 100 μL is transferred to a 96 well plate containing 0.25 mL of acetonitrile and D ₄ (deuterated) anandamide (0.2 μM). Each 5-mL tube is stoppered and placed in a shaking water bath maintained at 37 ° C. for 60 minutes. After 60 minutes of incubation, a second aliquot of 100 μL is transferred to a 96-well plate as before. The 96-well plate is then capped, vortex mixed, and placed on an HPLC for liquid chromatography / tandem mass spectrometry (LC / MS / MS) analysis. HPLC is performed on a Waters 2790 Alliance system (Milford, Mass.). Separation uses a gradient mobile phase (75: 25: 0.1, v / v / v) of acetonitrile: water: formic acid on a Phenomenex Polar RP column (2 mm × 150 mm, 4 μ; Torrance, Calif.) Performed at a flow rate of 3 mL / min- ¹ and a column temperature of 45 ° C. The HPLC system was coupled with a Micromass Quattro Ultimate tandem MS (Beverly, MA). Samples are analyzed with a cone voltage set at 40 V and a capillary of 3.2 kV using an electrospray probe in positive ionization mode. The source temperature and desolvation temperature settings are 130 ° C. and 500 ° C., respectively. The CID chamber voltage is set to -20 eV. Multiple reaction monitoring is used to detect the [M + H] anandamide as (m / z 348> 62) and [M + H] (m / z 352> 66) D 4 as anandamide (internal standard). Area ratio response (anandamide area response / D ₄ anandamide area response) was measured in each sample. The% anandamide hydrolysis of each sample is determined by the following equation: [(T = 0 response)] − (T = 60 response) / T = 0 response] ^* 100. The% hydrolysis normalized to the control is determined by dividing the% hydrolysis of the test sample by the% hydrolysis of the control sample.

For the determination of IC ₅₀ values for candidate FAAH inhibitor compounds, the above method is used at the prepared FAAH inhibitor concentration. For the IC ₅₀ assay, FAAH inhibitors are added in a concentration range of about 3 μM to 0.03 nM. The final calculation of IC ₅₀ is the first conversion of the concentration by “X = log (X)” and then the data is GraphPad for Windows® (GraphPad Software, San Diego California USA, www.graphpad.com). Determined by analysis on sigmoidal dose-response curves (no constraints) using Prism version 4.00.

(Example 4)
Compound Screening for FAAH Activity Inhibition—FAAH Fluorescence Screening Assay Black 96-well plate (Nunc, Cat. No. 267342), arachidonyl 7-amino, 4-methylcoumarinamide (AAMCA, 3 μM)) 180 μL, FAAH inhibitor ( Add to 20 μL of 0.05 μg / mL) in DMSO and 50 μL of human liver microsomes (0.25 mg / mL). The diluent for AAMCA and human liver microsomes is fatty acid free BSA (1.4 mg / mL) in HEPES / EDTA (50 mM / 1 mM) at pH 7.4. Plates are read on a fluorescence plate reader (SpectraMax GeminiXS, Molecular Devices) with an excitation wavelength of 355 nm and an emission wavelength of 460 nm when T = 0 and incubated at 37 ° C. for 30 minutes. After 30 minutes incubation, the plate was read for final time and% hydrolysis (normalized to control) was measured. The calculation for% hydrolysis is [(T = 0) − (T = 30) / T = 0] ^* 100. The% hydrolysis normalized to the control is determined by dividing the% hydrolysis of the test sample by the% hydrolysis of the control sample (DMSO).

(Example 5)
Screening of compounds for inhibition of FAAH activity-screening for in vivo FAAH inhibition in rats Potential FAAH inhibitors may be given to rats either orally (po), intraperitoneally (ip), or intravenously ( iv) Formulated for delivery. The formulated compound is administered and the animals are sacrificed at a predetermined time after taking. At sacrifice, blood samples were collected into EDTA plasma tubes and the entire brain snap snap frozen in liquid nitrogen. EDTA plasma was separated from blood samples after centrifugation. Brain and plasma samples are stored at −80 ° C. prior to analysis. All samples (brain and plasma) were analyzed by LC-MS / MS by test compound (FAAH inhibitor), test compound metabolite concentration, and endogenous fatty acid ethanolamide levels (anandamide, oleoyl ethanolamide, and palmitoyl). Including ethanolamide). The levels of these compounds are compared from time to time to determine the pharmacokinetic properties of the test compounds and the partial pharmacological effects that inhibit FAAH activity (including changes in fatty acid ethanolamide levels). Is done.

  In one embodiment, additional tissue and body fluid samples can be taken when the animals are sacrificed. In one embodiment, FAAH activity can also be measured in body fluids and tissue samples according to the disclosed methods or methods known in the art. In one embodiment, the metabolite of the test compound can be measured in body fluids and tissue samples.

(Example 6)
Pharmacokinetic measurements The pharmacokinetic properties of the compounds provided herein were evaluated in rats after oral administration as a solution. To test the oral bioavailability of the compounds provided herein, the solution for the test compound is a 10 mg / mL solution in 80% cremephor and 20% ethanol (w / w). Or as a 10 mg / mL solution of 90% PEG-400 and 10% Tween 80 (w / w). Test compound solutions were orally gavaged to rats at a dose of 10 mg / kg.

Animal Models Any of a variety of animal models can be used to test the compounds disclosed herein for their effects on reducing inflammation and treating pain. Useful compounds can show efficacy in reducing inflammation or pain in one or more animal models.

  Animal model for evaluation of anti-inflammatory activity

(Example 7)
Carrageenan-induced footpad edema model This model has been published, for example, by Winter et al. (1962 Proc Soc Exp Biol Med 111: 544). Briefly, rats are fasted for 17-19 hours with free access to water and then treated orally with up to three doses of test compound, indomethacin or celecoxib, or control vehicle (1% methylcellulose in deionized water). . One hour after the final treatment, 0.05 ml of 2% carrageenan solution is injected into the left hind limb to induce limb edema. Using a plethysmometer, the left hind limb volume of each rat is measured before oral treatment, at the time of carrageenan injection, 1.5 hours, 3 hours, and 4.5 hours after carrageenan injection. The edema volume of each rat at each time point is expressed as a change from the volume at the time of oral treatment, and the anti-inflammatory effect of the treatment group is 1.5, 3, and 4.5 hours after carrageenan injection. Expressed as a percentage of inhibition compared to the vehicle-only group. The significance of the difference between different edema groups is assessed by one-way analysis of variance (ANOVA) followed by Dunnett's non-paired t test. In this model, hyperalgesic response and PGE ₂ production can also be measured (Zhang et al. 1997 J Pharmacol and Exp Therap 283: 1069).

(Example 8)
Complete Freund's Adjuvant (CFA) -Induced Arthritis Model In this model, microbacterium fully ground in the sub-plantar region of the right hind limb on day 1 for a group of 8 Lewis male rats weighing 160 ± 10 g Arthritis is induced by injecting killed Mycobacterium tuberculosis (0.3 mg in 0.1 mL light mineral oil; complete Freund's adjuvant, CFA). The hindlimb volume was measured by water replacement on days 0, 1 and 5 (with right hindlimb CFA) and on days 0, 14 and 18 (left hindlimb, no CFA), and day 0 And on day 18, rats are weighed. Test compounds dissolved or suspended in 2% Tween 80 solution are prepared fresh daily and given orally twice a day for 5 consecutive days (1st to 5th day), 1 hour before the start of CFA infusion. To administer. For vehicle control rats injected with CFA, the increase in limb volume on day 5 (inflamed acute phase) compared to day 1 is generally 0.7 to 0.9 mL; and compared to day 14 The 18 day increase (late inflammation phase) is generally 0.2 to 0.4 mL. Therefore, anti-inflammatory activity in this model can be shown by values calculated in the acute and late phases. Also, animals are weighed on days 0 and 18; vehicle control animals infused with CFA generally gain 40 to 60 g of body weight during this period. The decrease in limb volume by 30% or more compared to the vehicle treated controls may be due to significant anti-inflammatory activity. The mean ± SEM for each treatment group was determined and Dunnett's test was applied to compare the vehicle group and the treatment group. The difference is considered significant at P <0.05. Multiple arthritis of the forelimbs, tail, nose and ears can be scored visually and entered on the first and last day, but the plus (+) sign means dilatation response and the minus (-) sign is normal is there. Radiographs of the hind limbs can also be performed to determine additional radiological indicators of joint inflammation symptoms. Hyperalgesia can also be measured in this model, allowing the analgesic effect of a test compound to be determined (Bertorelli et al. 1999 Brit. J. Pharmacol 128 1252).

Example 9
Air Sac Model This model is reported by Masferrer et al. (1994 Proc Natl Acad Sci USA 91: 3228). Briefly, 20 mL of sterile air is injected into the interscapular region of the back of Lewis male rats (175-200 g, Harlan Sprague-Dawley) to create an air cavity. An additional 10 mL of air is injected into this cavity every 3 days to keep the space open. Seven days after the first air infusion, 2 mL of a 1% carrageenan solution dissolved in sterile saline is injected directly into the sac to create an inflammatory response. For treated and untreated animals, the volume of exudate is measured and the number of white blood cells present in the exudate is measured by the Wright-Giemsa staining method. In addition, PGE ₂ and 6-keto-PGF _1α in cyst exudates from treated and untreated animals are measured by a special ELISA method (Cayman Chemicals, Ann Arbor, Mich).

  Animal model for evaluating analgesic activity

(Example 10)
Carrageenan-induced thermal hyperalgesia This model has been published by Hargreaves et al. (1988 Pain 32:77). Briefly, inflammation is induced by subplantar injection of 2% carrageenan suspension (01 mL) into the right hind limb. After 3 hours, the nociceptive threshold is assessed using thermal nociceptive stimuli (plantar test). The beam light (44% of maximum intensity) is focused directly under the hind limb and the thermal nociceptive threshold is determined by the limb flick response latency (blocking time: 30 seconds). Pain threshold is measured in the ipsilateral (inflammatory) and contralateral (control) hind limbs 1 hour after oral treatment with the test compound or control. The results can be expressed as a percentage of the nociceptive threshold expressed in seconds (sec) for each hind limb and the deviation of the nociceptive threshold from the vehicle group average for each rat (mean ± SEM). The Student's t-test was used to compare the nociceptive thresholds between the inflamed and control limbs of the vehicle treatment group and a statistically significant difference is considered P <0.05. Statistical significance between treatment and vehicle groups is determined by one-way analysis of variance using SigmaStat Software (P <0.05) followed by Dunnett's test using residual variance.

Example 11
Phenylbenzoquinone-induced writhing model This model has been published by Siegmund et al. (1957 Proc Soc Exp Bio Med 95: 729). Briefly, mice are infused 0.02% phenylbenzoquinone (PBQ) solution by intraperitoneal route 1 hour after oral administration of test compound, morphine or vehicle (12.5 mL / kg). Record the number of stretch reflexes and writhing from the 5th to the 10th minute after the PBQ injection, and between the 35th and 40th minutes, and from the 60th to the You may count between 65 minutes. Results are expressed as a percentage of nociceptive threshold deviation calculated from the number of stretch reflexes and agony behavior (mean ± SEM) and the mean of the vehicle treatment group. Statistical significance for any difference between treatment and control groups is determined by Dunnett's test with residual variance after one-way analysis of variance (P <0.05) using SigmaStat Software.

Example 12
Kaolin-induced arthritis model This model has been published by Hertz et al. (1980 Arzneim Forsch 30: 1549). Briefly, 0.1 mL of kaolin suspension is injected into the right hind knee joint of rats to induce arthritis. The test compound is administered subcutaneously after 15 minutes and again after 2 hours. The reference compound may be administered orally or subcutaneously. Assess gait every hour from 1.5 to 5.5 hours after treatment and score as follows: normal gait (0), mild disability (1), intermittent lifting of the foot (2) With the legs raised high (3). The results are expressed as the mean gait score calculated from the individual values at each time point (mean ± SEM), and the mean score calculated from the vehicle treatment group mean at 4.5 and 5.5 hours after treatment. Expressed as a percentage of deviation. Statistical significance for the difference between treatment and vehicle treatment groups is determined by Dunnett's test using residual variance after one-way analysis of variance (P <0.05) at each time point.

(Example 13)
Peripheral Mononeuropathy Model This model has been published by Bennett et al. (1988 Pain 33:87) and can be used to evaluate the antihyperalgesic effect of a test compound administered orally in a peripheral mononeuropathy model. The effect of the test substance can be compared to an untreated control or reference substance, such as morphine. Peripheral mononeuropathy is induced by anesthetizing male Sprague Dawley rats (pentobarbital; 45 mg / kg by intraperitoneal route) and loosely ligating the sciatic nerve. After 14 days, the nociceptive threshold is assessed using mechanical nociceptive stimulation (analgesic measurement limb compression test; Ugo Basile, Italy). Test and reference compounds and vehicle are administered orally (10 mL / kg in 1% methylcellulose). The pressure applied to the hind limbs of the animal is increased until a nociceptive response (speech or paw withdrawal) is reached. Pain threshold (grams of contact pressure) is measured on the ipsilateral (disorder) and contralateral (no disability) hind limbs 60 minutes after treatment. Results are expressed as a percentage of nociceptive threshold (mean ± SEM) of contact pressure (grams) for impaired and non-impaired limbs (vehicle treated group) and nociceptive threshold calculated from the average of vehicle treated groups expressed. Comparison of nociceptive thresholds between unaffected and impaired limbs in the vehicle treatment group is performed using Student's t-test. Statistical significance for the difference between the treatment group and the vehicle group is the one-way placement using SigmaStat Software (SigmaStat® v. 2.0.3 (SPSS Science Software, Erkrath GmbH) for the impaired hindlimb After analysis of variance (P <0.05), determine by Dunnett's test using residual variance.

(Example 14)
Chung Rat Model of Peripheral Neuropathy In one embodiment, the effectiveness of the compounds provided in the invention in alleviating neuropathic pain has been demonstrated using the well-recognized Chung rat model of peripheral neuropathy. The In the Chuang rat model, partial ligation of the left spinal nerve L-5 and L-6 spinal nerve results in persistent hypersensitivity to light pressure on the affected left leg. Hypersensitivity is similar to the pain experienced by humans with neuropathic symptoms of burning pain (Kim and Chung, Pain 50: 355-363 (1992), which is hereby incorporated by reference).

(Example 15)
Diabetic Neuropathy Limb Compression Test Details of the entire protocol are found in the article by Rakieten et al. (1963 Cancer Chemer Rep 29:91). Briefly, diabetes is induced by injecting streptozotocin intraperitoneally into rats. After 3 weeks, the nociceptive threshold is measured using a limb compression test to assess hyperalgesia. Test compounds or controls are administered intraperitoneally 30 minutes before pain measurement.

(Example 16)
Acetic acid lysing test Briefly, test compounds are administered orally 1 hour prior to the injection of acetic acid (0.5%, 10 ml / kg) into the peritoneal cavity of rats. If the decrease in the number of licings per animal group observed between 5 and 11 minutes after acetic acid administration is more than 50% (≧ 50) compared to the vehicle-treated control group, this suggests that analgesic activity may be present is doing. This assay is described in Inoue, K .; (1991 Arzneim. Forsch./Drug Res. 41: 235).

(Example 17)
Formalin test Details of all protocols can be found in the paper by Hunskaar et al. (1985 Neurosci. Meth. 14:69). Briefly, 30 minutes after intraperitoneal administration of test compound or control, the right hind limb of the rat is injected with 20 μL of 5% formalin solution via the subplantar route. Record the time to lick the hind legs early and late after formalin injection.

(Example 18)
Tail Flick Test Details of all protocols can be found in D'Amour and Smith paper (1941 J Pharmacol. ExpTher. 72:74). Briefly, 30 minutes after intraperitoneal administration of a test compound or control, the light beam is focused on the rat's tail. Record the latency of the nociceptive response characterized by tail withdrawal. The blocking time is set to 15 seconds.

Example 19
Tail immersion test In this test, the rat's tail is immersed in a 50-60 ° C water bath. The latency of the nociceptive response characterized by tail withdrawal is measured (Haurich et al. 1990 J Pharmacol Exp The 255: 511 and Lichtman et al. 2004 Pain 109: 319).

(Example 20)
Hot Plate Test Details of the entire protocol can be found in Eddy et al. (1950 J. Pharmacol. Exp. Ther. 98: 121). Briefly, mice are placed on a metal hot plate maintained at 52 ° C. 30 minutes after intraperitoneal administration of the test compound or control. Record the latency of the nociceptive response characterized by reflexes licking the forefoot or jumping off the hot plate. The blocking time is set to 30 seconds.

Assessment assays for anxiolytic effects Compounds provided herein that inhibit FAAH activity and thus modulate fatty acid amide levels may also have anxiolytic effects. Examples of animal models for evaluating the anxiolytic effect include the following.

(Example 21)
Elevated Cross Maze The Elevated Cross Maze consists of four cruciform shapes that effectively form a central platform, as described in van Gaalen and Steckler's paper (2000 Behavioral Brain Research 115: 95). Consists of a maze arm. The maze can be made of plexiglas and is usually elevated. Two of the maze arms have no walls (open) and two have walls (enclosed). The two open arms are well lit and the two surrounding arms are dark (Crawley 2000 What's Wron With My Mouse ?: Behavioral Phenotyping of Transgenic and Knockout Mice. Wiley-Lisor, New York). This test presupposes an instinctive conflict between the propensity of animals to explore new environments and the property of disgusting brightly lit open areas (Pellow et al. 1985 J. Neuroscience Methods. 14: 149).

  Details of the entire protocol can be found in the paper by Fedorova et al. (2001 J. Pharm. Exp. Ther. 299: 332). Briefly, 15 minutes after intraperitoneal administration of the test compound or control, the animals are individually placed on the central platform with their face facing one of the open arms opposite the observer. Record the number of times the animal enters the open and siege arms and the time spent in different sections of the maze (central platform, open and siege arms) (as described in the Gaalen et al. Paper (supra)). As described by Simonin et al. (1998 EMBO J. 17: 886), entry into the arm is recorded when all of the animal's limbs have moved into the arm. The behavior is recorded by an observer and / or video camera during a 5 minute test period. The amount of time spent by the animal in the open arm or the number of times of entry into the open arm compared to the siege arm is an indicator of anxiolytic effects.

(Example 22)
Elevated Zero Maze The Elevated Zero Maze is a variant of the elevated plus maze. Elevated zero maze is the same size 2
Consists of an annular Plexiglas device (ie, an annular runway with a diameter of 46 cm and a width of 5.5 cm) having two open areas and two wall enclosure areas. The circular track is elevated from the base to 1 meter. This apparatus is described in the papers of Simonin et al. (Supra) and Crawley (supra).

  Details of the entire protocol are found in the article by Kathuria et al. (2003 Nature Medicine 9:76). Briefly, 30 minutes after the test compound or control is administered intraperitoneally, the animal is placed in one of the open areas before the enclosed area. When all limbs have entered, record the time in the new area. The behavior is recorded by an observer and / or video camera during a 5 minute test period. More time spent by animals in open areas or more frequent entry into open areas compared to areas surrounded by walls is an indicator of anxiolytic effects.

(Example 23)
Isolation-induced ultrasound release test In another animal model, the isolation-induced ultrasound release test, the compounds provided herein are tested for their anxiolytic effects. The isolation-induced ultrasound emission test measures the number of stress-induced vocalizations produced by young rats detached from these nests (Insel, TR et al., Pharmacol. Biochem. Behav., 24, 1263). 1267 (1986); Miczek, KA et al., Psychopharmacology, 121, 38-56 (1995); Winslow, JT et al., Biol. Psychiatry, 15, 745-757 (1991); S. 6,323,156).

Assessment assays for antinociceptive mechanisms Compounds can be tested to determine whether these compounds affect pathways associated with nociception. The results of such assays can be used to investigate the mechanism by which test compounds mediate this antinociceptive effect.

(Example 24)
Elevated 3α, 5α-THP 3α-Hydroxy-5α-Pregan-20-one (3α, 5α-THP or allopregnanolone) is a pregnane steroid that acts as an agonist of inhibitory GABA _A receptor subtypes It is known to have both anxiolytic and analgesic effects in various animal systems, and there is evidence to support a similar role in humans. Thus, compounds that increase 3α, 5α-THP may have an antinociceptive effect. 3α, 5α-THP levels in the brain of animals treated with test compounds can be measured as described in VanDoren et al. (1982 JNeuroscience 20: 200). Briefly, after euthanasia, steroids are extracted from individual cortical hemispheres dissected in ice-cold saline. The cortex is frozen at −80 ° C. until use. Samples are digested by sonication in 0.3 N NaOH and extracted three times with 3 mL aliquots of 10% (v / v) ethyl acetate in heptane. Combine aliquots and dilute with 4 mL heptane. The extract is applied to a solid phase silica column (Burdick & Jacson, Muskegon, Mich.), Washed with pentane, 25% (v / v) acetone in heptane is added, and a steroid having a polarity similar to 3α, 5α-THP is added to the column. Elute from. The eluent was then dried under N ₂ and the steroids were treated with 20% (v / v) isopropanol RIA buffer (0.1 M NaH ₂ PO ₄ , 0.9 M NaCl, 0.1% w / v BSA, pH 7. Redissolve in 0). 50 μL of the redissolved extract is used for measurement of extraction efficiency by liquid scintillation spectroscopy, and the remaining sample is used for measurement of 3α, 5α-THP by radioimmunoassay. Reconstituted sample extract (75 μL) and 3α, 5α-THP standard (6.25% v / v ethanol, 31% v / v isopropyl alcohol / RIA buffer, 5 to 40,000 pg) in 725 μL RIA buffer, 100 [mu] L [< ³ > H] ³ [alpha], 5 [alpha] -THP (20,000 dpm), and 100 [mu] L anti- ³ [alpha], 5 [alpha] -THP antibody are assayed in duplicate. Total binding is measured in the absence of unlabeled 3α, 5α-THP, and nonspecific binding is measured in the absence of antibody. The antibody binding reaction can be allowed to equilibrate at room temperature for 120 minutes and is terminated by cooling the mixture to 4 ° C. Bound 3α, 5α-THP was unbound by incubating with 300 μL cold dextran-coated activated carbon (DCC; 0.04% dextran, 0.4% activated carbon powder in _double distilled H ₂ O) for 20 minutes. Separate from 3α, 5α-THP. Centrifuge at 2000 xg for 10 minutes to remove DCC. The bound radioactivity in the supernatant is measured by liquid scintillation spectroscopy. The sample value is compared with the standard curve of 3α, 5α-THP performed at the same time, and the extraction efficiency is corrected.

(Example 25)
Assessment of antidepressant effect In one embodiment, the compounds provided herein are assessed for antidepressant effect in animal models. Chronic mild stress-induced anxiety model is the observation that chronic mild stress causes a gradual decrease in susceptibility to a consumption of sucrose, such as sucrose consumption, and this reduction has used antidepressants Based on the observation that chronic treatment can be stopped in a dose-dependent manner. This method was previously described by Willner, Paul, Psychopharmacology, 1997, 134, 319-329.

  Another test for antidepressant activity is the forced swimming test (Nature 266, 730-732, 1977). In this test, the compound is administered to the animals 30 or 60 minutes prior to the test, preferably from the intraperitoneal route or by the oral route. The animal is placed in a crystal dish filled with water and the time that the animal remains stationary is recorded. This immobility time is then compared to that of a control group treated with distilled water. Imipramine (25 mg / kg) can be used as a positive control. Antidepressant compounds reduce the immobility time of mice so immersed.

  Another test for antidepressant activity is the tail suspension test on mice (Psychophorology, 85, 367-370, 1985). In this test, it is preferred that the animals be treated with a compound provided herein by the intraperitoneal route or by the oral route 30 minutes to 6 hours prior to the study. The animal is then hung at the tail and the immobility time is automatically recorded by the computer system. This immobility time is then compared to that of a control group treated with vehicle. Imipramine (25 mg / kg) can be used as a positive control. Antidepressant compounds reduce mouse immobility time.

  The antidepressant effect of the compounds provided herein can be tested with the DRL-72 TEST. This test is performed according to the protocol of Andrews et al. According to the protocol of Drug Effects Research 32, 5 8-66 (1994), which is conducted according to the protocol of Drug Effects Research, Drug Development Research. The effects of the compounds provided herein can also be tested in serotonin and bipolar disorders as described in US Pat. Nos. 6,403,573 and 5,952,315, etc. The patent is incorporated by reference.

(Example 26)
Assessment of Anticonvulsant Effect In another embodiment, compounds provided herein are tested in animal models for anticonvulsant activity as described in US Pat. Nos. 6,309,406 and 6,326,156. Is done.

(Example 27)
Effect of compounds on appetite behavior In one embodiment, a compound provided herein is administered to a rat to measure the effect on appetite behavior. The effect of the administered compound is assessed by examining the intake of sucrose solutions by rats. This method is described in W.W. C. Lynch et al., Physiol. Behav. 1993, 54, 877-880. Male Sprague-Dawley rats weighing about 190 g to about 210 g are placed in the normal light cycle (7 am to 7 pm) and have free access to water and food. For 6 days, between 11 am and 3 pm, the food and water bottles are removed and the rats are given a 5% sucrose beverage solution. Rats drinking less than 3 g of sucrose solution are excluded. On day 7, the test is performed according to the following procedure. 9 am: withdrawal of food, 10 am: administration of either compound or vehicle provided herein to test animals; 11 am = T0: introduction of a bottle containing a metered sucrose solution; T0 + 1 hour, T0 + 2 hours, T0 + 3 hours, T0 + 4 hours; weigh bottles and measure sucrose consumption. Subsequently, the sucrose solution intake of the experimental group (the group to which the compound provided herein is administered) and the control group are compared. The animal can be, for example, obese or normal guinea pig, rat, mouse, or rabbit. Suitable rats include, for example, Zucker rats. Suitable mice include, for example, normal mice, ALS / LtJ, C3.5W-H-2b / SnJ (NON / LtJ x NZO / HlJ) Fl, NZO / HlJ, ALR / LtJ, NON / LtJ, KK. cg-AALR / LtJ, NON / LtJ, KK. CgAy / J, B6. HRS (BKS) -Cpefat / +, B6.129P2-GcktmlEfr, B6. V-Lepob, BKS. Cg-m + 1 + Leprdb and dietary obesity C57BL / 6J.

  In another test, the effect of the compounds of the invention on the consumption of alcohol solutions is demonstrated in mice. For example, male C57BL6 mice are quarantined with two bottles filled with water on the day of arrival at the animal facility under the reverse cycle (10 am to 10 pm night). After one week, one of the water bottles is replaced with a bottle filled with 10% alcohol solution for 6 hours of testing. Every day, 30 minutes before the bottle of alcohol is introduced, the mice are treated with the compounds of the invention. The amount of alcohol and water consumed is measured after 6 hours. This test is repeated for 4 days. The results of the experimental group and the control group or vehicle group are compared.

(Example 28)
Decrease in body weight, body fat, and hepatic steatosis The inhibitory effect of FAAH activity on body weight, body fat, triglyceride level, and cholesterol level is shown in transgenic (E3L) mice of APOE ^* 3-Leiden, an animal model of hyperlipidemia Measured in E3L mice express a mutated variant of human apoE (apoE ^* 3-Leiden) that has apoE weakened binding to the LDL receptor. Thus, E3L mice show a reduced clearance rate of lipoproteins containing apoB and high serum lipid levels. van Vlijmen et al. (1994), J. MoI. Clin Invest. 93: 1403-1410. With high fat and high cholesterol feeding, these mice develop various stages of atherosclerotic lesions that depend on plasma total cholesterol levels and are similar to those seen in humans. Groot et al. (1996), Arterioscler. Thromb. Vasc Biol. 16: 926-933; Verschuren et al. (2005), Arterioscler. Thromb. Vasc. Biol. , 25: 161-167; and Lutgens et al. (1999), Circulation; 99 (2): 276-283. Thus, E3L mice are a suitable model for examining the efficacy of anti-atherosclerotic agents.

  E3L mice are bred on a high cholesterol (1% w / w) diet (HC diet) for 4 weeks. After this, the animals were matched based on their plasma cholesterol levels and divided into 5 groups, each maintained on an HC diet. Every day for the remainder of the study (4 weeks), the “control” group receives a diet without additives and the “fenofibrate” group contains fenofibrate (0.04% w / w). Ingested diet, "Oral Vehicle" group ingested oral suspension of vehicle, "Oral OEA" group ingested oral suspension of OEA at a dose of 500 mg / kg, and "Oral Carbamate" The group takes an oral suspension of a compound provided herein at a dose of 10 mg / kg.

  Blood samples are taken on the 0th, 14th and 28th days of the treatment period. At the end of the treatment period, the animals are sacrificed and various tissues and organs are analyzed.

(Example 29)
Cannabinoid receptor binding compound can exert an antinociceptive effects by binding to one or both of the cannabinoid receptors CB ₁ and CB _2. CB ₁ is expressed in the brain (Matsuda et al. 1990 Nature 346: 561) and CB ₂ is expressed in the spleen by macrophages (Munro et al. 1993 Nature 365: 61). Both of these receptors have been implicated in mediating analgesic effects through agonist binding (see, eg, Clayton et al. 2002 Pain 96: 253). Thus, test compounds can be assayed to determine whether these compounds bind to one or both of the human cannabinoid receptors. Assaying binding to CB ₁ has been described by Matsuda et al. (Supra). This assay utilizes recombinant cells expressing CB _1. Binding to CB ₂ uses a recombinant cell expressing a CB _2, it can be determined in a similar manner. Briefly, to determine the ability of a test compound to bind to CB ₁ , a labeled CB ₁ ligand, eg, [ ³ H] WIN 55212-, against membranes isolated from HEK-293 cells expressing recombinant CB ₁ The binding of 2 (2 nM for CB _{1 and} 0.8 nM for CB ₂ ) is measured in the presence and absence of compound. Non-specific binding is determined separately in the presence of several fold excess of unlabeled WIN552122-2 (5 μM for CB _{1 and} 10 μM for CB ₂ ). A specific ligand that binds to the receptor is defined as the difference between total binding and non-specific binding measured in the presence of excess unlabeled WIN552212-2. IC ₅₀ values and Hill coefficients (n _H ) are determined by non-linear regression analysis of competition curves using Hill equation curve fitting. Inhibition from the Cheng Prusoff equation (K _i = IC ₅₀ / (1+ (L / K _D )), where L = concentration of radioligand in the assay, K _D = radioligand affinity to receptor. A constant (Ki) is calculated.

  (Example 30)

  Pharmaceutical composition

(Example 30a)
Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of the compound provided herein is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is formulated into a dosage unit form suitable for injection administration.

(Example 30b)
Oral Composition To prepare a pharmaceutical composition for oral delivery, 100 mg of the compound described herein is mixed with 750 mg of starch. The mixture is formulated into an oral dosage unit such as a hard gelatin capsule suitable for oral administration.

(Example 30c)
Sublingual (hard lozenge) composition To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, 100 mg of the compound described herein, 420 mg of powdered sugar mixture, 1.6 ml of light corn syrup, 2 distilled water Mix with 4 mL and 0.42 mL of mint extract. The mixture is gently mixed and poured into a mold to form a lozenge suitable for buccal administration.

(Example 30d)
Inhalation Composition To prepare a pharmaceutical composition for inhalation delivery, 20 mg of the compound described herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is formulated into an inhalation delivery unit such as a nebulizer suitable for inhalation delivery.

(Example 30e)
Rectal Gel Composition To prepare a pharmaceutical composition for rectal delivery, 100 mg of the compound described herein is mixed with 2.5 g of methylcellulose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purified water. The resulting gel mixture is then formulated into a rectal delivery unit such as a syringe suitable for rectal administration.

(Example 30f)
Topical gel composition To prepare a pharmaceutical topical gel composition, 100 mg of the compound described herein, 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and purified alcohol (US Pharmacopeia) Mix with 100 mL. The resulting gel mixture is then formulated into a container such as a tube suitable for topical administration.

(Example 30g)
Ophthalmic Solution Composition To prepare a pharmaceutical ophthalmic solution composition, 100 mg of the compound described herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. . The resulting isotonic solution is then formulated into an ophthalmic delivery unit such as an eye drop container suitable for ocular administration.

  The examples and embodiments described herein are for illustrative purposes only, and modifications or alterations suggested to those skilled in the art are within the spirit and scope of this application and the claims appended hereto. Should be included. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

FIGS. 1-8 illustrate non-limiting examples of the types of compounds of formula (I) described herein. FIG. 2 illustrates a non-limiting example of the type of compound of formula (I) described herein. FIG. 3 illustrates a non-limiting example of the type of compound of formula (I) described herein. FIG. 4 illustrates a non-limiting example of the type of compound of formula (I) described herein. FIG. 5 illustrates non-limiting examples of the types of compounds of formula (I) described herein. FIG. 6 illustrates a non-limiting example of the type of compound of formula (I) described herein. FIG. 7 illustrates non-limiting examples of the types of compounds of formula (I) described herein. FIG. 8 illustrates a non-limiting example of the type of compound of formula (I) described herein.

Claims (24)

Formula (I)

[In the above formula,
D is O or NR ¹¹ ;
One of A or B is (CH ₂ ) _m C (O) -alkyl, (CH ₂ ) _m C (O) —N (R ² ) ₂ and the other is H, alkyl or heteroalkyl, m Is 0, 1, 2, or 3;
Or A and B together form an optionally substituted oxo-substituted heterocycle;
Or A and B together form an optionally substituted heteroaromatic group containing at least one N, NR ² , S or O group;
Or A and B together form an optionally substituted non-aromatic or aromatic carbocyclic group; or A and B are H, optionally substituted alkyl, optionally substituted hetero Independently selected from alkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl, and optionally substituted ketoheteroalkyl Is;
R ¹ is selected from C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl (heteroaryl) Optionally substituted groups, any carbon of the cycloalkyl ring of R ¹ can be optionally substituted with Y and Z, each Y and each Z being from halogen, methyl or trifluoromethyl. Independently selected or Y and Z can be taken together to form a 3, 4 or 5 membered carbocyclic group or oxo (= O);
Each R ² is independently selected from H or optionally substituted alkyl;
R ¹¹ is H or optionally substituted alkyl. And pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates. A and B are taken together to form —C (O) — (CR ^q R ^q ) _n —, —C (O) —NR ² — (CR ^q R ^q ) _n —, —NR ² —C (O _{^{) - (CR q R q)}} n -, - C (O) -NR 2 -NR 2 - (CR q R q) n -, - C (O) -NR 2 -N = (CR q) -, - O—C (O) —O—, O—C (O) —NR ² —, —NR ² —C (O) —NR ² —, —O—C (O) —O— (CR ^q R ^q ) _{^{n -, - O-C (}} O) - (CR q R q) n -O -, - n-C (O) - (CR q R q) n -N -, - O-C (O) - ( _{^{CR q R q) n -N -}} , - n-C (O) - (CR q R q) n -O -, - O-C (O) -NR 2 - (CR q R q) n -, - ^{NR 2 -C (O) -O- (} CR q R q) n -, - NR 2 -C (O _{^{-NR 2 - (CR q R q}} ) n -, - (CR q R q) n -C (O) -O- (CR q R q) n -, - (CR q R q) n -C (O _{^{) -NR 2 - (CR q R}} q) n -, - (CR q R q) n -C (O) -NR 2 -NR 2 -, - (CR q R q) n -CO- (CR q R _{^{q) n -, - C (}} O) -O- (CR q R q) n -O -, - C (O) -O- (CR q R q) n -NR 2 -, - C (O) - _{^{NR 2 - (CR q R q}} ) n -NR 2, -C (O) -NR 2 - (CR q R q) n -O -, - C (O) -NR 2 -CR q = CR q -, ^{C (O) -CR q = CR} q -NR 2 -, - C (O) -CR q = CR q -O -, - optionally ^{the C} (O) is selected from -CR ^{q =} CR ^q -S- Substituted oxo- Forming a換複ring; each n is 1, 2 or 3 independently; and each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, keto heteroalkyl, substituted Ketohetero 2. A compound according to claim 1 independently selected from alkyl, heteroalkyl, substituted heteroalkyl, heterocycle or substituted heterocycle. The compound of claim 1, wherein R ² is H and D is O. One of A or B is C (O) -alkyl and the other is H, or one of A or B is C (O) —N (R ² ) ₂ and the other is H The compound of claim 1, wherein A and B together form an optionally substituted non-aromatic ring group containing a C (O) — (CH ₂ ) _n — moiety, where n is 1, 2, 3, or 4. The compound according to claim 1. n is and R ² is H 2, and D is O, and A compound according to claim 5. A and B together comprise at least one N, NR 2, ^S or O groups optionally form a substituted heteroaromatic ring group, a compound of claim 1. 8. The compound of claim 7, further comprising a-(CH) _n- moiety, where n is 1, 2 or 3.   8. A compound according to claim 7, wherein the optionally substituted heteroaromatic ring group contains 1 N in the ring. R ² is H and D is O, and A compound according to claim 7.   8. A compound according to claim 7, wherein the optionally substituted heteroaromatic ring group contains two heteroatoms selected from N, S and O.   12. A compound according to claim 11 wherein the optionally substituted heteroaromatic ring group is selected from an optionally substituted benzoxazole group or an optionally substituted benzothiazole group.   The compound of claim 1, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvent. A pharmaceutical composition comprising a sum and a pharmaceutically acceptable diluent, excipient or binder.   The compound of claim 1, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvent. A method of inhibiting fatty acid amide hydrolase, or treating a disease, disorder or condition that would benefit from inhibition of fatty acid amide hydrolase activity in a patient, comprising administering to a patient a therapeutically effective amount of a Japanese product Method.   The disease, disorder or condition is acute or chronic pain, eating disorder, heart disease, metabolic disease, disorder or symptom, renal ischemia, cancer, immune system disorder, allergic disease, metabolic disease, disorder or symptom Selected from, renal ischemia, cancer, immune system disorder, allergic disease, parasitic, viral or bacterial infection, inflammatory disease, osteoporosis, ocular symptoms, pulmonary symptoms, gastrointestinal diseases and urinary incontinence Item 15. The method according to Item 14.   The packaging material, the compound according to claim 1, which is effective for inhibiting fatty acid amide hydrolase (FAAH) activity in the packaging material, and the compound or composition or a pharmaceutically acceptable salt or pharmaceutical thereof Pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates are used to inhibit fatty acid amide hydrolase (FAAH) activity. A product that includes a label that indicates Formula (II)

[In the above formula,
D is O or NR ¹¹ ; each X is CH or N;
R ¹ is

(In the above formula,
M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4 atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;
J is CH or N; K is CH or N; provided that when K is CH, J cannot be CH;
Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl,
C ₃ -C _{8 cycloalkyl,} C 1 -C ₆ heteroalkyl, -C (O) ^{-R 12,} aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycloalkyl, heterocycloalkoxy, phenyl, pyridyl, pyridazinyl , Piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiadiazolyl , Quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl Naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropridyl, thienopyridyl, dihydrothipyridyl Independently selected from the group consisting of optionally substituted groups selected from: imidazopyridyl, pyrazolopyridyl, oxaolopyridyl, isoxaolopyridyl or thiazolopyridyl;
Each R ′ is independently H, alkyl or substituted alkyl;
Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;
R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;
R ² and R ¹¹ are H or optionally substituted alkyl;
R ¹² is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, aryloxy, aryl, heteroaryl, heterocycloalkyl, benzyloxy, furanyl , Phenyl, benzyl or pyridyl. ) Selected from the group consisting of:
Or R ¹ and R ² together,

(N is 1, 2, 3 or 4; m is 1, 2, 3 or 4);
A and B together form an optionally substituted non-aromatic ring containing a C (O) — (CH ₂ ) _q — moiety, where q is 1, 2, 3, or 4. ;
Or A and B together form an optionally substituted aromatic or non-aromatic ring group containing at least one N, NR ² , S or O group;
Or one of A or B is and the other a -L-G is selected from C ₁ -C ₆ alkyl substituted by H and optionally;
Or A and B together form an optionally substituted aromatic carbocyclic group;
Or A and B together form an optionally substituted oxo-substituted heterocycle;
Or A and B are H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally Each independently selected from a substituted ketoalkyl, an optionally substituted amide and an optionally substituted ketoheteroalkyl;
L is a bond, or _C 1 -C _{6 alkylene,} C 1 -C _{6 heteroalkylene,} C 1 -C _{6 ^{Ketoarukiren, -C (O) NR 9 -}} (CH 2) j -, - NR 9 -C (O _{) - (CH 2) j -} , - OC (O) O- (CH 2) j -, - NHC (O) O- (CH 2) j -, - O (O) CNH- (CH 2) j - _{, -C (O) O- (CH} 2) j -, - OC (O) - (CH 2) j -, - NR 9 C (O) N (R 9) - (CH 2) j -, - S _{(O) - (CH 2)} j -, - S (O) 2 - (CH 2) j -, - C (= NR 10) N (R 9) - (CH 2) j - and ^-NR 9 C ( = An optionally substituted group selected from NR ¹⁰ ) N (R ⁹ ) — (CH ₂ ) _j —;
G is tetrazolyl, —NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHR ⁸ , —S (═O) ₂ NH-phenyl, —OH, —SH, —OC (O) NHR ⁸ , —NHC (O) OR ⁸ , —C (O) NHC (O) R ⁸ , —C (O) NHS (═O) ₂ R ⁸ , —S (═O) ₂ NHC (O) R ⁸ , —S (═O) ₂ NHC (O) NHR ⁸ , —NHC (O) R ⁸ , —NHC (O) N (R ⁹ ) ₂ , —C (═NR ¹⁰ ) N (R ⁹ ) ₂ , —NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , _{^{-C (O) NR 9 C (}} = NR 10) N (R 9) 2, -C (O) NR 9 C (= CHR 10) N (R 9) 2, -CO 2 H, - ( ^{_{OP (= O) OH) x}} OH, -OP (= O) OR 8 OH, -OP (= O) R 8 OH, -NR 9 P (= O) OR 8 OH, -NR 9 P (= O) in _{-NR 9 S (O) y OH} ; R 8 OH, -P (= O) OR 8 OH ;-P (= O) R 8 OH, -S (O) y OH; -OS (O) y OH Yes;
Each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl;
Each R ⁹ is independently H, substituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkyl;
Each R ¹⁰ is independently selected from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN and —NO ₂ ;
j is 0, 1, 2, 3 or 4; x is 1, 2 or 3; y is 0, 1 or 2;
Each substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano, benzyloxy-C (O) R ′, —C (O)-(alkyl or substituted alkyl). ),-(Alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') _2- , -OC (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) ) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl),- S (O) _k R ′ (k is 1 or 2), —S (O) _k (alkyl or substituted alkyl), —C (S) — (alkyl or substituted alkyl), —CSN (R ′ ) ₂ , —CSN (R ′) — (alkyl or substituted alkyl), —N (R ′) CO— (alkyl or substituted alkyl), —N (R ′) C (O) OR ′, — (alkyl or substituted) Alkyl) -O-N = C (R ') ₂ ,-(alkyl or substituted alkyl) -C (O) NR'-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- (Alkyl or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _kN (R ') ₂ , -N (R') C (O) N (R ' ) ₂ , —N (R ′) C (S) N (R ′) ₂ , —N (R ′) S (O) _k N (R ′) ₂ , -C (R ') = NR'-C (R') = NN (R ') ₂ and -C (R') ₂ -N (R ')-N (R') ₂ independent of Selected. ]
And pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates. Formula (III)

[In the above formula,
p is 0, 1 or 2; q is 0, 1 or 2;
R ¹³ and R ¹⁴ are H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, —C (O) R ^A , hydroxy- (C ₁ -C ₆ alkyl), amino- (C ₁ -C ₆ alkyl), —CH ₂ —NR ^A R ^B , -O- (C ₁ -C ₄ ), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, amino, -C (O) NR ^A R ^B , -ONR ^A R ^B ,- Each independently selected from O—C (O) NR ^A R ^B , —SO ₂ N R ^A R ^B ;
R ^A and R ^B are each independently selected from hydrogen, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl. ]
18. The compound of claim 17 having a structure and a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically An acceptable solvate. The following structure

19. A compound according to claim 18 having: R ² is H, A compound according to claim 19.   18. A compound according to claim 17, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvent. A pharmaceutical composition comprising a sum and a pharmaceutically acceptable diluent, excipient or binder.   18. A compound according to claim 17, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvent. A method of inhibiting fatty acid amide hydrolase, or treating a disease, disorder or condition that would benefit from inhibition of fatty acid amide hydrolase activity in a patient, comprising administering to a patient a therapeutically effective amount of a Japanese product Method.   If the disease, disorder or condition is acute or chronic pain, eating disorder, heart disease, metabolic disease, disorder or symptom, renal ischemia, cancer, immune system disorder, allergic disease, metabolic disease, disorder or symptom, Claims selected from renal ischemia, cancer, immune system disorders, allergic diseases, parasitic, viral or bacterial infections, inflammatory diseases, osteoporosis, ocular symptoms, pulmonary symptoms, gastrointestinal diseases and urinary incontinence 30. The method according to 30.   18. The packaging material, the compound according to claim 17 effective for inhibiting the activity of fatty acid amide hydrolase (FAAH) in the packaging material, and the compound or composition or pharmaceutically acceptable salt, pharmaceutical Pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates used to inhibit the activity of fatty acid amide hydrolase (FAAH) Product containing a label indicating that

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