BACE-2 inhibitors for the treatment of metabolic disordersThe present invention relates to the use of BACE-2 inhibitors and pharmaceutical compositions comprising BACE-2 inhibitors for treating metabolic disorders related to decreased beta cell mass and/or function.In individuality, regulate the method for bace-2 activity, wherein the method comprises formula (i) compound to individual administering therapeutic effective dose:or its officinal salt, wherein:x is o or s;r 1hydrogen; cyano group; halogen; (c 1-8) alkyl; halogen-(c 1-8) alkyl; (c 1-8) alkoxyl; halogen-(c 1-8) alkoxyl; (c 1-8) alkylthio group; halogen-(c 1-8) alkylthio group; (c 1-8) alkoxyl-(c 1-8) alkyl; (c 1-8) alkoxyl-(c 1-8) alkoxyl; (c 1-8) alkoxyl-(c 1-8) alkylthio group; (c 1-8) alkylthio group-(c 1-8) alkyl; (c 1-8) alkylthio group-(c 1-8) alkoxyl; (c 1-8) alkylthio group-(c 1-8) alkylthio group; (c 2-8) alkenyl; or (c 2-8) alkynyl; r 2it is group g 1, described group g 1aryl, heteroaryl or non-aromatic heterocycle, this group g 1optionally by 1,2,3 or 4, independently selected from following substituent group, replaced: cyano group, nitro, amino, amino carbonyl, amino-(c 1-8) alkyl, (c 1-4) alkyl-amino-(c 1-8) alkyl, two (c 1-4) alkyl-amino-(c 1-8) alkyl, halogen, (c 1-8) alkyl, halogen-(c 1-8) alkyl, hydroxyl, oxo, (c 1-8) alkoxyl, halogen-(c 1-8) alkoxyl, (c 1-8) alkylthio group, halogen-(c 1-8) alkylthio group, (c 1-8) alkoxyl-(c 1-8) alkyl, (c 1-8) alkoxyl-(c 1-8) alkoxyl, (c 1-8) alkoxyl-(c 1-8) alkylthio group, (c 1-8) alkylthio group-(c 1-8) alkyl, (c 1-8) alkylthio group-(c 1-8) alkoxyl, (c 1-8) alkylthio group-(c 1-8) alkylthio group, (c 2-8) alkenyl, (c 2-8) alkynyl, (c 2-8) alkenyloxy, (c 2-8) alkynyloxy group and group g 2, described group g 2(c 3-8) cycloalkyl, aryl, heteroaryl or non-aromatic heterocycle, this group g 2optionally by 1,2,3 or 4, independently selected from following substituent group, replaced: cyano group, amino carbonyl, halogen, (c 1-8) alkyl, halogen-(c 1-8) alkyl, hydroxyl, (c 1-8) alkoxyl, halogen-(c 1-8) alkoxyl, (c 1-8) alkylthio group, halogen-(c 1-8) alkylthio group, (c 1-8) alkoxyl-(c 1-8) alkyl, (c 1-8) alkoxyl-(c 1-8) alkoxyl, (c 1-8) alkoxyl-(c 1-8) alkylthio group, (c 1-8) alkylthio group-(c 1-8) alkyl, (c 1-8) alkylthio group-(c 1-8) alkoxyl, (c 1-8) alkylthio group-(c 1-8) alkylthio group, (c 2-8) alkenyl and (c 2-8) alkynyl; r 3hydrogen; cyano group; halogen; (c 1-8) alkyl; halogen-(c 1-8) alkyl; (c 1-8) alkoxyl; halogen-(c 1-8) alkoxyl; (c 1-8) alkylthio group; halogen-(c 1-8) alkylthio group; (c 1-8) alkoxyl-(c 1-8) alkyl; (c 1-8) alkoxyl-(c 1-8) alkoxyl; (c 1-8) alkoxyl-(c 1-8) alkylthio group; (c 1-8) alkylthio group-(c 1-8) alkyl; (c 1-8) alkylthio group-(c 1-8) alkoxyl; (c 1-8) alkylthio group-(c 1-8) alkylthio group; (c 2-8) alkenyl; or (c 2-8) alkynyl; r 4hydrogen; cyano group; halogen; (c 1-8) alkyl; halogen-(c 1-8) alkyl; (c 1-8) alkoxyl; halogen-(c 1-8) alkoxyl; (c 1-8) alkylthio group; halogen-(c 1-8) alkylthio group; (c 1-8) alkoxyl-(c 1-8) alkyl; (c 1-8) alkoxyl-(c 1-8) alkoxyl; (c 1-8) alkoxyl-(c 1-8) alkylthio group; (c 1-8) alkylthio group-(c 1-8) alkyl; (c 1-8) alkylthio group-(c 1-8) alkoxyl; (c 1-8) alkylthio group-(c 1-8) alkylthio group; (c 2-8) alkenyl; or (c 2-8) alkynyl; and r 5hydrogen; cyano group; halogen; (c 1-8) alkyl; halogen-(c 1-8) alkyl; (c 1-8) alkoxyl; halogen-(c 1-8) alkoxyl; (c 1-8) alkylthio group; halogen-(c 1-8) alkylthio group; (c 1-8) alkoxyl-(c 1-8) alkyl; (c 1-8) alkoxyl-(c 1-8) alkoxyl; (c 1-8) alkoxyl-(c 1-8) alkylthio group; (c 1-8) alkylthio group-(c 1-8) alkyl; (c 1-8) alkylthio group-(c 1-8) alkoxyl; (c 1-8) alkylthio group-(c 1-8) alkylthio group; (c 2-8) alkenyl; or (c 2-8) alkynyl; orr 4and r 5-c (h)=c (h)-c (h)=c (h)-or (c together 1-8) alkylidene, wherein (c 1-8) 1 or 2-ch of alkylidene 2-ring members is optionally independently selected from following heterocycle member and replaces :-n (h)-,-n[(c 1-8) alkyl]-,-o-,-s-,-s (=o)-or-s (=o) 2-; r 6hydrogen; (c 1-8) alkyl; halogen-(c 1-8) alkyl; hydroxyl-(c 1-8) alkyl; (c 1-8) alkoxyl-(c 1-8) alkyl; sulfydryl-(c 1-8) alkyl; (c 1-8) alkylthio group-(c 1-8) alkyl; amino-(c 1-8) alkyl; n-(c 1-8) alkyl amino-(c 1-8) alkyl; there are two identical or different (c 1-8) alkyl is at n, n-bis--[(c 1-8) alkyl] n in amino, n-bis--[(c 1-8) alkyl] amino-(c 1-8) alkyl; (c 2-8) alkenyl; or (c 2-8) alkynyl; e 1be-c (r 7) (r 8)-; or-c (r 7) (r 8)-c (r 9) (r 10)-; e 2be-c (r 11) (r 12)-; or-c (r 11) (r 12)-c (r 13) (r 14)-; r 7and r 8be selected from independently of one another hydrogen, cyano group, halogen, (c 1-8) alkyl, halogen-(c 1-8) alkyl, (c 1-8) alkoxyl-(c 1-8) alkyl and (c 1-8) alkylthio group-(c 1-8) alkyl; orr 7and r 8be together oxo or-ch 2-ch 2-; r 9and r 10be selected from independently of one another hydrogen, cyano group, halogen, (c 1-8) alkyl, halogen-(c 1-8) alkyl, (c 1-8) alkoxyl-(c 1-8) alkyl and (c 1-8) alkylthio group-(c 1-8) alkyl; orr 9and r 10be together oxo or-ch 2-ch 2-; r 11and r 12be selected from independently of one another hydrogen, cyano group, halogen, (c 1-8) alkyl, halogen-(c 1-8) alkyl, (c 1-8) alkoxyl-(c 1-8) alkyl and (c 1-8) alkylthio group-(c 1-8) alkyl; orr 11and r 12be together oxo or-ch 2-ch 2-; and r 13and r 14be sel...
대사 장애의 치료를 위한 ＢＡＣＥ-2 억제제본 발명은 감소된 β 세포 집단 및/또는 기능과 관련된 대사 장애를 치료하기 위한 BACE-2 억제제 및 상기 BACE-2 억제제를 포함하는 제약 조성물의 용도에 관한 것이다.치료 유효량의 하기 화학식 I의 화합물 또는 그의 제약상 허용되는 염을 대상체에게 투여하는 것을 포함하는, 상기 대상체에서 BACE-2 활성을 조절하는 방법:<화학식 I>[이미지]상기 식에서,X는 O 또는 S이고;R1은 수소; 시아노; 할로겐; (C1-8)알킬; 할로겐-(C1-8)알킬; (C1-8)알콕시; 할로겐-(C1-8)알콕시; (C1-8)알킬티오; 할로겐-(C1-8)알킬티오; (C1-8)알콕시-(C1-8)알킬; (C1-8)알콕시-(C1-8)알콕시; (C1-8)알콕시-(C1-8)알킬티오; (C1-8)알킬티오-(C1-8)알킬; (C1-8)알킬티오-(C1-8)알콕시; (C1-8)알킬티오-(C1-8)알킬티오; (C2-8)알케닐; 또는 (C2-8)알키닐이고;R2는 아릴, 헤테로아릴 또는 비-방향족 헤테로시클릴 기 G1이며, 상기 기 G1은 시아노, 니트로, 아미노, 아미노카르보닐, 아미노-(C1-8)알킬, (C1-4)알킬-아미노-(C1-8)알킬, 디(C1-4)알킬-아미노-(C1-8)알킬, 할로겐, (C1-8)알킬, 할로겐-(C1-8)알킬, 히드록시, 옥소, (C1-8)알콕시, 할로겐-(C1-8)알콕시, (C1-8)알킬티오, 할로겐-(C1-8)알킬티오, (C1-8)알콕시-(C1-8)알킬, (C1-8)알콕시-(C1-8)알콕시, (C1-8)알콕시-(C1-8)알킬티오, (C1-8)알킬티오-(C1-8)알킬, (C1-8)알킬티오-(C1-8)알콕시, (C1-8)알킬티오-(C1-8)알킬티오, (C2-8)알케닐, (C2-8)알키닐, (C2-8)알케녹시, (C2-8)알키녹시, 및 (C3-8)시클로알킬, 아릴, 헤테로아릴 또는 비-방향족 헤테로시클릴 기 G2로 이루어진 군으로부터 독립적으로 선택된 1, 2, 3 또는 4개의 치환체에 의해 임의로 치환되고, 상기 기 G2는 시아노, 아미노카르보닐, 할로겐, (C1-8)알킬, 할로겐-(C1-8)알킬, 히드록시, (C1-8)알콕시, 할로겐-(C1-8)알콕시, (C1-8)알킬티오, 할로겐-(C1-8)알킬티오, (C1-8)알콕시-(C1-8)알킬, (C1-8)알콕시-(C1-8)알콕시, (C1-8)알콕시-(C1-8)알킬티오, (C1-8)알킬티오-(C1-8)알킬, (C1-8)알킬티오-(C1-8)알콕시, (C1-8)알킬티오-(C1-8)알킬티오, (C2-8)알케닐 및 (C2-8)알키닐로 이루어진 군으로부터 독립적으로 선택된 1, 2, 3 또는 4개의 치환체에 의해 임의로 치환되고;R3은 수소; 시아노; 할로겐; (C1-8)알킬; 할로겐-(C1-8)알킬; (C1-8)알콕시; 할로겐-(C1-8)알콕시; (C1-8)알킬티오; 할로겐-(C1-8)알킬티오; (C1-8)알콕시-(C1-8)알킬; (C1-8)알콕시-(C1-8)알콕시; (C1-8)알콕시-(C1-8)알킬티오; (C1-8)알킬티오-(C1-8)알킬; (C1-8)알킬티오-(C1-8)알콕시; (C1-8)알킬티오-(C1-8)알킬티오; (C2-8)알케닐; 또는 (C2-8)알키닐이고;R4는 수소; 시아노; 할로겐; (C1-8)알킬; 할로겐-(C1-8)알킬; (C1-8)알콕시; 할로겐-(C1-8)알콕시; (C1-8)알킬티오; 할로겐-(C1-8)알킬티오; (C1-8)알콕시-(C1-8)알킬; (C1-8)알콕시-(C1-8)알콕시; (C1-8)알콕시-(C1-8)알킬티오; (C1-8)알킬티오-(C1-8)알킬; (C1-8)알킬티오-(C1-8)알콕시; (C1-8)알킬티오-(C1-8)알킬티오; (C2-8)알케닐; 또는 (C2-8)알키닐이고;R5는 수소; 시아노; 할로겐; (C1-8)알킬; 할로겐-(C1-8)알킬; (C1-8)알콕시; 할로겐-(C1-8)알콕시; (C1-8)알킬티오; 할로겐-(C1-8)알킬티오; (C1-8)알콕시-(C1-8)알킬; (C1-8)알콕시-(C1-8)알콕시; (C1-8)알콕시-(C1-8)알킬티오; (C1-8)알킬티오-(C1-8)알킬; (C1-8)알킬티오-(C1-8)알콕시; (C1-8)알킬티오-(C1-8)알킬티오; (C2-8)알케닐; 또는 (C2-8)알키닐이거나; 또는R4 및 R5는 함께, -C(H)=C(H)-C(H)=C(H)- 또는 (C1-8)알킬렌 기이며, 상기 (C1-8)알킬렌 기에서 1 또는 2개의 -CH2- 고리원은 -N(H)-, -N[(C1-8)알킬]-, -O-, -S-, -S(=O)- 또는 -S(=O)2-로 이루어진 군으로부터 독립적으로 선택된 헤테로 고리원으로 임의로 대체되고;R6은 수소; (C1-8)알킬; 할로겐-(C1-8)알킬; 히드록시-(C1-8)알킬; (C1-8)알콕시-(C1-8)알킬; 머캅토-(C1-8)알킬; (C1-8)알킬티오-(C1-8)알킬; 아미노-(C1-8)알킬; N-(C1-8)알킬아미노-(C1-8)알킬; N,N-디-[(C1-8)알킬]아미노 잔기에 2개의 동일하거나 상이한 (C1-8)알킬 잔기를 포함하는 N,N-디-[(C1-8)알킬]아미노-(C1-8)알킬; (C2-8)알케닐; 또는 (C2-8)알키닐이고;E1은 -C(R7)(R8)-; 또는 -C(R7)(R8)-C(R9)(R10)-이고;E2는 -C(R11)(R12)-; 또는 -C(R11)(R12)-C(R13)(R14)-이고;R7 및 R8 각각은 수소, 시아노, 할로겐, (C1-8)알킬, 할로겐-(C1-8)알킬, (C1-8)알콕시-(C1-8)알킬 및 (C1-8)알킬티오-(C1-8)알킬로 이루어진 군으로부터 독립적으로 선택되거나; 또는R7 및 R8은 함께, 옥소 또는 -CH2-CH2-이고;R9 및 R10 각각은 수소, 시아노, 할로겐, (C1-8)알킬, 할로겐-(C1-8)알킬, (C1-8)알콕시-(C1-8)알킬 및 (C1-8)알킬티오-(C1-8)알킬로 이루어진 군으로부터 독립적으로 선택되거나; 또는R9 및 R10은 함께, 옥소 또는 -CH2-CH2-이고;R11 및 R12 각각은 수소, 시아노, 할로겐, (C1-8)알킬, 할로겐-(C1-8)알킬, (C1-8)알콕시-(C1-8)알킬 및 (C1-8)알킬티오-(C1-8)알킬로 이루어진 군으로부터 독립적으로 선택되거나; 또는R11 및 R12는 함께, 옥소 또는 -CH2-CH2-이고;R13 및 R14 각각은 수소, 시아노, 할로겐, (C1-8)알킬, 할로겐-(C1-8)알킬, (C1-8)알콕시-(C1-8)알킬 및 (C1-8)알킬티오-(C1-8)알킬로 이루어진 군으로부터 독립적으로 선택되거나; 또는R13 및 R14는 함께, 옥소 또는 -CH2-CH2-이다.