Heteroaryl-substituted urea modulators of fatty acid amide hydrolaseCertain heteroaryl-substituted piperidinyl and piperazinyl urea compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, insulin resistance, diabetes, osteoporosis, and movement disorders (e.g., multiple sclerosis).The officinal salt of formula (i) chemical compound or described chemical compound, pharmaceutically acceptable prodrug or pharmaceutical active metabolite:wherein:ar 1it is benzo [d] isoxazole-3-base, the 6-fluorobenzene is [d] isoxazole-3-base also, 3-phenyl-[1,2,4] thiadiazoles-5-base, 1h-tetrazolium-5-base, benzo [1,2,5] thiadiazoles-4-base, benzo [1,2,5] oxadiazole-4-base, thiophene-2-base, thiene-3-yl-, 6-chloro-pyridazine-3-base, pyrazine-2-base isoxazole-3-base, 1h-benzotriazole-5-base, [1,5] naphthyridines-2-base, quinoline-2-base, benzothiazole-6-base, quinoline-5-base, the 1h-pyrazole-3-yl, 5-methylpyrazine-2-base, 3-chloropyrazine-2-base, pyridazine-3-base, 6-methoxyl group pyridazine-3-base, 5-methyl-isoxazole-3-base, 1,5-dimethyl-1h-pyrazole-3-yl, 4-bromo-1-methyl isophthalic acid h-pyrazole-3-yl, 2-ethyl-2h-pyrazole-3-yl, 5-methyl isophthalic acid h-pyrazole-3-yl or 5-phenyl-1h-pyrazole-3-yl; z is-n-or＞ch; andar 2be: (i) not by r apart replaces or by one or two r athe phenyl that part replaces; each r wherein apart is-c independently 1-4alkyl ,-c ≡ c-r d,-oc 1-4alkyl, halogen ,-cf 3,-ocf 3,-och 2cf 3,-scf 3,-s (o) 0-2c 1-4alkyl ,-so 2cf 3,-oso 2c 1-4alkyl ,-(ch 2) 0-1co 2c 1-4alkyl ,-co 2h ,-coc 1-4alkyl ,-n (r b) r c,-so 2nr br c,-nr bso 2r c,-c (o) nr br c,-no 2or-(ch 2) 0-1cn; perhaps two adjacent r apart lumps together formation-o (ch 2) 1-2o-or-ocf 2o-; r wherein band r cbe independently of one another-h or-c 1-4alkyl; and r dbe h, c 3-6cycloalkyl or-ch 2nr er fr wherein eand r fbe h or c independently of one another 1-4alkyl; (ii) in the 3-position or 4-position quilt-l-ar 3replace, not by r areplace or by r athe phenyl that replaces, wherein: l is the connection base that is selected from by the group of the basis set one-tenth of following connection :-(ch 2) 1-3-,-ch=ch-,-o-,-och 2-,-ch 2o-,-nh-,＞nc 1-4alkyl ,-s-,-c ≡ c-,-c (=o)-and covalent bond; and ar 3be: (a) phenyl;(b) naphthyl; or(c) bicyclic heteroaryl or bicyclic heteroaryl; or(iii) 9 yuan or 10 yuan of condensed-bicyclic heteroaryls;wherein work as ar 1during for 6-chloro-pyridazine-3-base, isoxazole-3-base or 1h-pyrazole-3-yl, ar then 2not benzo [1,3] dioxole-5-base or 2,2-two fluoro-benzo [1,3] dioxole-5-bases.
지방산 아미드 하이드롤라아제의 헤테로아릴-치환된 우레아 조절제FAAH 저해제로서 유용한 소정의 헤테로아릴-치환된 피페리디닐 및 피페라지닐 우레아 화합물이 개시된다. 그러한 화합물은 지방산 아미드 하이드롤라아제(fatty acid amide hydrolase, FAAH) 활성에 의해 매개되는 질환 상태, 장애 및 질병, 예를 들어 불안, 통증, 염증, 수면 장애, 섭식 장애, 인슐린 저항성, 당뇨병, 골다공증 및 운동 장애(예를 들어, 다발성 경화증)의 치료를 위한 약학 조성물 및 방법에 사용될 수 있다.하기 화학식 I의 화합물, 또는 그의 약학적으로 허용가능한 염, 약학적으로 허용가능한 전구약 또는 약학적으로 활성인 대사 산물: [화학식 I] [이미지] 상기 식에서, Ar1은 벤조[d]아이속사졸-3-일, 6-플루오로벤조[d]아이속사졸-3-일, 3-페닐-[1,2,4]티아다이아졸-5-일, 1H-테트라졸-5-일, 벤조[1,2,5]티아다이아졸-4-일, 벤조[1,2,5]옥사다이아졸-4-일, 티오펜-2-일, 티오펜-3-일, 6-클로로-피리다진-3-일, 피라진-2-일, 아이속사졸-3-일, 1H-벤조트라이아졸-5-일, [1,5]나프티리딘-2-일, 퀴놀린-2-일, 벤조티아졸-6-일, 퀴놀린-5-일, 1H-피라졸-3-일, 5-메틸피라진-2-일, 3-클로로피라진-2-일, 피리다진-3-일, 6-메톡시피리다진-3-일, 5-메틸아이속사졸-3-일, 1,5-다이메틸-1H-피라졸-3-일, 4-브로모-1-메틸-1H-피라졸-3-일, 2-에틸-2H-피라졸-3-일, 5-메틸-1H-피라졸-3-일 또는 5-페닐-1H-피라졸-3-일 기이고; Z는 -N- 또는 >CH이고; Ar2는 (i) 비치환되거나 1개 또는 2개의 Ra 부분(moiety)으로 치환된 페닐 (여기서, 각각의 Ra 부분은 독립적으로 -C1-4알킬, -C≡≡Rd, -OC1-4알킬, 할로, -CF3, -OCF3, -OCH2CF3, -SCF3, -S(O)0-2C1-4알킬, -SO2CF3, -OSO2C1-4알킬, -(CH2)0-1CO2C1-4알킬, -CO2H, -COC1-4알킬, -N(Rb)Rc, -SO2NRbRc, -NRbSO2Rc, -C(O)NRbRc, -NO2 또는 -(CH2)0-1CN이거나; 2개의 인접한 Ra 부분은 함께 -O(CH2)1-2O- 또는 -OCF2O-를 형성하고; 여기서, Rb 및 Rc는 각각 독립적으로 -H 또는 -C1-4알킬이고; Rd는 H, C3-6사이클로알킬 또는 -CH2NReRf이고; Re 및 Rf는 각각 독립적으로 H 또는 C1-4알킬임); (ii) 비치환되거나 Ra로 치환된, 3- 또는 4-위치가 -L-Ar3으로 치환된 페닐 (여기서, L은 -(CH2)1-3-, -CH=CH-, -O-, -OCH2-, -CH2O-, -NH-, >NC1-4알킬, -S-, -C≡C-, -C(=O)- 및 공유 결합으로 이루어진 군으로부터 선택된 링커이고; Ar3은 (a) 페닐; (b) 나프틸; 또는 (c) 단환식 또는 이환식 헤테로아릴 기임); 또는 (iii) 9- 또는 10-원의 융합된 이환식 헤테로아릴 기이고; Ar1이 6-클로로-피리다진-3-일, 아이속사졸-3-일 또는 1H-피라졸-3-일이면, Ar2는 벤조[1,3]다이옥솔-5-일 또는 2,2-다이플루오로-벤조[1,3]다이옥솔-5-일이 아니다.