NOVEL HETEROARYL SUBSTITUTED BENZOXAZOLESThe present invention relates to novel heteroaryl substituted benzoxazole derivatives and therapeutic uses for such compounds, having the structural formula (Ia) below:  and to their pharmaceutically acceptable salt, compositions and methods of use. Furthermore, the invention relates to novel heteroaryl substituted benzoxazole derivatives that are suitable for imaging amyloid deposits in living patients, their compositions, methods of use and processes to make such compounds. More specifically, the present invention relates to a method of imaging amyloid deposits in brain in vivo to allow antemortem diagnosis of Alzheimer's disease as well as measureing clinical efficacy of Alzheimer's disease therapeutic agents.A compound according to formula Ia(Ia) whereinRl is selected from hydrogen, halo, C1-6 alkyl, C1-6 fluoroalkyl, C1-3 alkyleneOC1-3 alkyl, C1-3 alkyleneOC1-3 fluorolkyl, C1-3 alkyleneNH2, C1-3 alkyleneNHC1-3 alkyl, C1-3 alkyleneN(C1-3 alkyl)2, C1-3 alkyleneNHC1-3 fluoroalkyl, C1-3 alkyleneN(C1-3 fluoroalkyl)2, C1-3 alkyleneN(C1-3 alkyl)Ci_3 fluoroalkyl, hydroxy, C1-6 alkoxy, C1-6 fluoroalkoxy, amino, NHC1-3 alkyl, NHC1-3 fluoroalkyl, N(C1-3 alkyl)2, N(C1-3 fluoroalkyl)2, N(C1-3 alkyl)C1-3 fluoroalkyl, NH(CO)C1-3 alkyl, NH(CO)C1-3 fluoroalkyl, NH(CO)C1-3 alkoxy, NH(CO)C1-3 fluoroalkoxy, NHSO2Ci-3 alkyl, NHSO2C1-3 fluoroalkyl, (CO)C1-3 alkyl, (CO)C1-3 fluoroalkyl, (CO)C1-3 alkoxy, (CO)C1-3 fluoroalkoxy, (CO)NH2, (CO)NHC1-3 alkyl, (CO)NHC1-3 fluoroalkyl, (CO)N(C1-3 alkyl)2, (CO)N(C1-3 fluoroalkyl)2, (CO)N(C1-3 alkyl)C1-3 fluoroalkyl, (CO)N(C4-6 alkylene), (CO)N(C4-6 fluoroalkylene), nitro and cyano;R2 is selected from hydrogen, fluoro, bromo, iodo, C1-6 alkyl, Ci-6 fluoroalkyl, Ci-3 alkyleneOC1-3 alkyl, C1-3 alkyleneOCi-3 fluorolkyl, Ci-3 alkyleneNH2, Ci-3 alkyleneNHC1-3 alkyl, C1-3 alkyleneN(C1-3 alkyl)2, C1-3 alkyleneNHCi-3 fluoroalkyl, C1-3 alkyleneN(Ci-3 fluoroalkyl)2, Ci-3 alkyleneN(Ci-3 alkyl)C1-3 fluoroalkyl, hydroxy, C1-6 alkoxy, C1-6 fluoroalkoxy, amino, NHC1-3 alkyl, NHC1-3 fluoroalkyl, N(C1-3 alkyl)2, N(C1- -;3 fluoroalkyl)2, N(Ci-3 alkyl)C1-3 fluoroalkyl, NH(CO)C1-3 alkyl, NH(CO)C1-3 fluoroalkyl, NH(CO)C1-3 alkoxy, NH(CO)Ci-3 fluoroalkoxy, NHSO2C1-3 alkyl, NHSO2C1-3 fluoroalkyl, (CO)C1-3 alkyl, (CO)C1-3 fluoroalkyl, (CO)C1-3 alkoxy, (CO)C1-3 fluoroalkoxy, (CO)NH2, (CO)NHC1-3 alkyl, (CO)NHC1-3 fluoroalkyl, (CO)N(C1-3 alkyl)2, (CO)N(C1-3 fluoroalkyl)2, (CO)N(C1-3 alkyl)C1-3 fluoroalkyl, (CO)N(C4-6 alkylene), (CO)N(C4-6 fluoroalkylene) and cyano;Q is a nitrogen-containing aromatic heterocycle selected from Ql to Q5;wherein Ql is a 6-membered aromatic heterocycle containing one or two N atoms, wherein X1, X2, X3 and X4 are independently selected from N or C; and wherein one or two OfX1, X2, X3 and X4 is N and the remaining is C, and wherein when the atom X1 is C, said C is optionally substituted with R4; and wherein when the atom X2 is C, said C is optionally substituted with R5;R3 is selected from fluoro, bromo, iodo, C1-4 alkyl, C1-4 fluoroalkyl, C1-3 alkyleneOC1-3 alkyl, C1-3 alkyleneOC1-3 fluoroalkyl, C1-3 alkyleneNH2, C1-3 alkyleneNHC1-3 alkyl, C1-3 alkyleneN(C1-3 alkyl)2, C1-3 alkyleneNHC1-3 fluoroalkyl, C1-3 alkyleneN(C1-3 fluoroalkyl)2, C1-3 alkyleneN(C1-3 alkyl)C1-3 fluoroalkyl, hydroxy, C1-4 alkoxy, C1-4 fluoroalkoxy, amino, NHC1-3 alkyl, NHC1-3 fluoroalkyl, N(C1-3 alkyl)2, N(C1-3 fluoroalkyl)2, N(C1-3 alkyl)C1-3 fluoroalkyl, NH(C0-3 alkylene)G2, N(C0-1 alkyl)N(C0.! alkyl)2, N(C0-I alkyl)OC0-1 alkyl, NC1-3 alkyl(CO)C1-3 alkyl, NH(CO)C1-3 alkyl, NH(CO)C1-3 fluoroalkyl, NH(C0)G2, (CO)C1-3 alkyl, (CO)C1-3 fluorolkyl, (CO)C1-3 alkoxy, (CO)C1-3 fluoroalkoxy, (CO)NH2, (CO)NHC1-3 alkyl, (CO)NHC1-3 fluoroalkyl, (CO)N(C1-3 alkyl)2, (CO)N(C1-3 fluoroalkyl)2, (CO)N(C1-3 alkyl)C1-3 fluoroalkyl, (CO)N(C4-6 alkylene), (CO)N(C4-6 fluoroalkylene), (CO)G2, (CO)NH2G2, SC1-3 alkyl, SC1-3 fluoroalkyl, SO2NH2, SO2NHC1-3 alkyl, SO2NHC1-3 fluoroalkyl, SO2N(C1-3 alkyl)2, SO2N(CL3 fluoroalkyl)2, SO2N(C1-3 alkyl)C1-3 fluoroalkyl, cyano and Gl5 wherein Gl is;G1 X5 is selected from O, NH, NC1-3 alkyl and NC1-3 fluoroalkyl;G2 is phenyl or a 5- or 6-membered aromatic heterocycle and optionally substituted with a substituent from fluoro, bromo, iodo, methyl and methoxy;R4 is selected from from fluoro, bromo, iodo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, amino, NHC1-3 alkyl and NHC1-3 fluoroalkyl;R5 is selected from from fluoro, bromo, iodo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, amino, NHC1-3 alkyl and NHC1-3 fluoroalkyl;R6 is selected from hydrogen, C1-4 alkyl, C1-4 fluoroalkyl and (CO)C 1-4alkoxy;R7 is selected from hydrogen, fluoro, bromo, iodo, C1-4 alkoxy and C1-4 fluoroalkoxy;and one or more of the atoms of formula Ia is optionally a detectable isotope;as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, with the following provisos: when Rl and R2 both are H, and X2 and X4 both are N, R3 is not NH(C0-1 alkylene)G2, Gl, chloro, hydroxy, SCH3, NHC0-1 alkyl, N(C1-2 alkyl)2, NHNH2 or NHOH; When Rl and R2 both are H, and either of X2 and X4 is N while the other is C, R3 is not chloro, hydroxy or methyl; when R3 is amino and X2 and X4 both are N, Rl or R2 is not methyl, ethyl, chloro or bromo; the compound is not2-(5-aminopyridin-2-yl)- 1 ,3-benzoxazol-6-amine;5-(6-methyl-l,3-benzoxazol-2-yl)pyrimidin-2-amine;5-(6-methoxy- 1 ,3-benzoxazol-2-yl)-iV-phenylpyrimidin-2-amine;2-(5-methylpyridin-2-yl)-l ,3-benzoxazole; or5-niethyl-2-(6-methylpyridin-3-yl)-l,3-benzoxazole.
신규 헤테로아릴 치환된 벤즈옥사졸본 발명은 하기 화학식 Ia의 신규 헤테로아릴 치환된 벤즈옥사졸 유도체 및 상기 화합물의 치료 용도, 및 이의 제약상 허용되는 염, 조성물 및 사용 방법에 관한 것이다. <화학식 Ia>  또한, 본 발명은 살아있는 환자에서 아밀로이드 침착물의 이미지화에 적합한 신규 헤테로아릴 치환된 벤즈옥사졸 유도체, 이들의 조성물, 사용 방법 및 이러한 화합물의 제조 방법에 관한 것이다. 보다 구체적으로, 본 발명은 뇌에서 생체내 아밀로이드 침착물을 이미지화하여 알쯔하이머병을 죽기 전에 진단할 뿐만 아니라 알쯔하이머병 치료제의 임상 효율을 측정하는 방법에 관한 것이다.유리 염기로서의 하기 화학식 Ia에 따른 화합물 또는 이의 제약상 허용되는 염, 용매화물 또는 염의 용매화물. <화학식 Ia>  상기 식에서, R1은 수소, 할로, C1-6알킬, C1-6플루오로알킬, C1-3알킬렌OC1-3알킬, C1-3알킬렌OC1-3플루오로알킬, C1-3알킬렌NH2, C1-3알킬렌NHC1-3알킬, C1-3알킬렌N(C1-3알킬)2, C1-3알킬렌NHC1-3플루오로알킬, C1-3알킬렌N(C1-3플루오로알킬)2, C1-3알킬렌N(C1-3알킬)C1-3플루오로알킬, 히드록시, C1-6알콕시, C1-6플루오로알콕시, 아미노, NHC1-3알킬, NHC1-3플루오로알킬, N(C1-3알킬)2, N(C1-3플루오로알킬)2, N(C1-3알킬)C1-3플루오로알킬, NH(CO)C1-3알킬, NH(CO)C1-3플루오로알킬, NH(CO)C1-3알콕시, NH(CO)C1-3플루오로알콕시, NHSO2C1-3알킬, NHSO2C1-3플루오로알킬, (CO)C1-3알킬, (CO)C1-3플루오로알킬, (CO)C1-3알콕시, (CO)C1-3플루오로알콕시, (CO)NH2, (CO)NHC1-3알킬, (CO)NHC1-3플루오로알킬, (CO)N(C1-3알킬)2, (CO)N(C1-3플루오로알킬)2, (CO)N(C1-3알킬)C1-3플루오로알킬, (CO)N(C4-6알킬렌), (CO)N(C4-6플루오로알킬렌), 니트로 및 시아노로부터 선택되고; R2는 수소, 플루오로, 브로모, 요오도, C1-6알킬, C1-6플루오로알킬, C1-3알킬렌OC1-3알킬, C1-3알킬렌OC1-3플루오로알킬, C1-3알킬렌NH2, C1-3알킬렌NHC1-3알킬, C1-3알킬렌N(C1-3알킬)2, C1-3알킬렌NHC1-3플루오로알킬, C1-3알킬렌N(C1-3플루오로알킬)2, C1-3알킬렌N(C1-3알킬)C1-3플루오로알킬, 히드록시, C1-6알콕시, C1-6플루오로알콕시, 아미노, NHC1-3알킬, NHC1-3플루오로알킬, N(C1-3알킬)2, N(C1-3플루오로알킬)2, N(C1-3알킬)C1-3플루오로알킬, NH(CO)C1-3알킬, NH(CO)C1-3플루오로알킬, NH(CO)C1-3알콕시, NH(CO)C1-3플루오로알콕시, NHSO2C1-3알킬, NHSO2C1-3플루오로알킬, (CO)C1-3알킬, (CO)C1-3플루오로알킬, (CO)C1-3알콕시, (CO)C1-3플루오로알콕시, (CO)NH2, (CO)NHC1-3알킬, (CO)NHC1-3플루오로알킬, (CO)N(C1-3알킬)2, (CO)N(C1-3플루오로알킬)2, (CO)N(C1-3알킬)C1-3플루오로알킬, (CO)N(C4-6알킬렌), (CO)N(C4-6플루오로알킬렌) 및 시아노로부터 선택되고; Q는 Q1 내지 Q5로부터 선택된 질소-함유 방향족 헤테로고리이고 , 이 때 Q1은 1 또는 2개의 N 원자를 함유하는 6-원 방향족 헤테로고리이고, 여기서 X1, X2, X3 및 X4는 N 또는 C로부터 독립적으로 선택되고; X1, X2, X3 및 X4 중 1 또는 2개는 N이고, 나머지는 C이고, 원자 X1이 C인 경우, 상기 C는 R4로 임의로 치환되고; 원자 X2가 C인 경우, 상기 C는 R5로 임의로 치환되고; R3은 플루오로, 브로모, 요오도, C1-4알킬, C1-4플루오로알킬, C1-3알킬렌OC1-3알킬, C1-3알킬렌OC1-3플루오로알킬, C1-3알킬렌NH2, C1-3알킬렌NHC1-3알킬, C1-3알킬렌N(C1-3알킬)2, C1-3알킬렌NHC1-3플루오로알킬, C1-3알킬렌N(C1-3플루오로알킬)2, C1-3알킬렌N(C1-3알킬)C1-3플루오로알킬, 히드록시, C1-4알콕시, C1-4플루오로알콕시, 아미노, NHC1-3알킬, NHC1-3플루오로알킬, N(C1-3알킬)2, N(C1-3플루오로알킬)2, N(C1-3알킬)C1-3플루오로알킬, NH(C0-3알킬렌)G2, N(C0-1알킬)N(C0-1알킬)2, N(C0-1알킬)OC0-1알킬, NC1-3알킬(CO)C1-3알킬, NH(CO)C1-3알킬, NH(CO)C1-3플루오로알킬, NH(CO)G2, (CO)C1-3알킬, (CO)C1-3플루오로알킬, (CO)C1-3알콕시, (CO)C1-3플루오로알콕시, (CO)NH2, (CO)NHC1-3알킬, (CO)NHC1-3플루오로알킬, (CO)N(C1-3알킬)2, (CO)N(C1-3플루오로알킬)2, (CO)N(C1-3알킬)C1-3플루오로알킬, (CO)N(C4-6알킬렌), (CO)N(C4-6플루오로알킬렌), (CO)G2, (CO)NH2G2, SC1-3알킬, SC1-3플루오로알킬, SO2NH2, SO2NHC1-3알킬, SO2NHC1-3플루오로알킬, SO2N(C1-3알킬)2, SO2N(C1-3플루오로알킬)2, SO2N(C1-3알킬)C1-3플루오로알킬, 시아노 및 G1로부터 선택되고, 여기서 G1은 이고; X5는 O, NH, NC1-3알킬 및 NC1-3플루오로알킬로부터 선택되고; G2는 플루오로, 브로모, 요오도, 메틸 및 메톡시로부터 선택된 치환기로 임의로 치환된, 페닐 또는 5-원 또는 6-원 방향족 헤테로고리이고; R4는 플루오로, 브로모, 요오도, C1-4알킬, C1-4플루오로알킬, C1-4알콕시, C1-4플루오로알콕시, 아미노, NHC1-3알킬 및 NHC1-3플루오로알킬로부터 선택되고; R5는 플루오로, 브로모, 요오도, C1-4알킬, C1-4플루오로알킬, C1-4알콕시, C1-4플루오로알콕시, 아미노, NHC1-3알킬 및 NHC1-3플루오로알킬로부터 선택되고; R6은 수소, C1-4알킬, C1-4플루오로알킬 및 (CO)C1-4알콕시로부터 선택되고; R7은 수소, 플루오로, 브로모, 요오도, C1-4알콕시 및 C1-4플루오로알콕시로부터 선택되고; 화학식 Ia의 원자들 중 하나 이상은 임의로는 검출가능한 동위원소이고; 단, R1 및 R2가 모두 H이고, X2 및 X4가 모두 N인 경우, R3은 NH(C0-1알킬렌)G2, G1, 클로로, 히드록시, SCH3, NHC0-1알킬, N(C1-2알킬)2, NHNH2 또는 NHOH가 아니고; R1 및 R2가 모두 H이고, X2 및 X4 중 하나가 N이고 다른 하나가 C인 경우, R3은 클로로, 히드록시 또는 메틸이 아니고; R3이 아미노이고, X2 및 X4가 모두 N인 경우, R1 또는 R2는 메틸, 에틸, 클로로 또는 브로모가 아니고; 상기 화합물은 2-(5-아미노피리딘-2-일)-1,3-벤즈옥사졸-6-아민; 5-(6-메틸-1,3-벤즈옥사졸-2-일)피리미딘-2-아민; 5-(6-메톡시-1,3-벤즈옥사졸-2-일)-N-페닐피리미딘-2-아민; 2-(5-메틸피리딘-2-일)-1,3-벤즈옥사졸; 또는 5-메틸-2-(6-메틸피리딘-3-일)-1,3-벤즈옥사졸이 아니다.