2 -arylaminoquinazolines for treating proliferative diseasesThe invention provides novel compounds that are inhibitors of PDKI. Also provided are pharmaceutical compositions including the compounds, and methods of treating proliferative diseases, such as cancers, with the compounds or composition.Formula (ia) compound or pharmaceutically acceptable salt thereof:wherein:r 1abe selected from h and halogen; r 3abe selected from c 2-6heterocyclylalkyl oxygen base and c 1-6heteroaryl-c 1-4-alkoxyl group; wherein said c 2-6heterocyclylalkyl oxygen base and c 1-6heteroaryl-c 1-4-alkoxyl group is all randomly by r wgroup replaces; r 4abe selected from h, thiazole ring, pyrazoles ring, triazole ring, tetrazole ring, pyridine ring, c 3-6cycloalkyl, cyano group, halogen, c 2-6alkynyl, c 1-6heteroaryl-c 1-4-alkyl, c 1-6heteroaryl-c 1-4-alkynyl ,-c (=o) r awith-c (=o) nr br cwherein said thiazole ring, pyrazoles ring, triazole ring, tetrazole ring, pyridine ring, c 1-6heteroaryl-c 1-4-alkyl and c 1-6heteroaryl-c 1-4-alkynyl is all randomly by 1 or 2 independent r that selects x' group replaces; ar 1abe selected from randomly on a position by a r y' or in contraposition by a r y' phenyl that replaces of group; each r wall be independently selected from halogen, c 1-6alkyl, amino, c 1-6alkylamino, two-c 1-4-alkylamino, c 1-6alkoxy carbonyl and c 1-6alkyl-carbamoyl; wherein said c 1-6alkyl and c 1-6alkylamino all randomly is selected from following group and is replaced: hydroxyl, c 1-6alkoxyl group, amino, c 1-6alkylamino and two-c 1-4-alkylamino; each r x' all be independently selected from halogen, hydroxyl, c 1-6alkyl, c 1-6alkoxy carbonyl and formamyl; wherein said c 1-6alkyl and c 1-6alkoxy carbonyl all randomly is selected from following group and is replaced: hydroxyl, amino, c 1-4alkylamino and amino-sulfonyl; r y' be selected from halogen, c 1-6alkoxyl group, c 1-6alkyl, formamyl, amino-sulfonyl and c 1-6alkyl sulfonyl-amino; wherein said c 1-6alkyl and c 1-6alkoxyl group all randomly is independently selected from following group by 1 or 2 and replaces: hydroxyl, amino, c 1-4alkylamino and amino-sulfonyl; r y' be selected from c 1-6haloalkyl; r abe selected from h, c 1-6alkoxyl group and c 2-6heterocyclylalkyl; r bbe selected from h and c 1-6alkyl; and r cbe selected from c 1-6alkyl, c 3-6cycloalkyl, c 1-6heteroaryl, c 2-6heterocyclylalkyl, c 2-6heterocyclylalkyl-c 1-4-alkyl and c 1-6heteroaryl-c 1-4-alkyl; wherein said c 1-6alkyl randomly is selected from hydroxyl and c 1-4the group of alkoxyl group replaces; condition is:(a) work as r 3awhen being piperidin-4-yl oxygen base or n-methyl piperidine-4-base oxygen base, r then 4be not selected from thiazol-2-yl, thiazole-4-base, thiazole-5-base, 5-methylthiazol-2-base, 5-(hydroxymethyl) thiazol-2-yl, 5-(hydroxymethyl) thiazole-4-base, pyridine-2-base, pyridin-4-yl, pyridin-3-yl, 4-picoline-3-base, 5-chloropyridine-4-base, 3-picoline-2-base and 1-methylpyrazole-5-base; (b) work as r 4abe ethynyl and ar 1awhen being the 3-fluorophenyl, r then 3it is different not to be selected from pyridin-3-yl methoxyl group, 6-chloropyridine-3-ylmethoxy, pyridine-2-ylmethoxy, pyridin-4-yl methoxyl group, 1-(pyridin-4-yl) oxyethyl group, 6-methoxypyridine-2-ylmethoxy, thiazole-5-ylmethoxy, pyrazine-2-ylmethoxy, 5-methyl azoles-3-base, azetidine-3-base oxygen base, n-methyl azetidine-3-base oxygen base, n-sec.-propyl azetidine-3-base oxygen base, tetramethyleneimine-3-base oxygen base, n-methyl and tetramethyleneimine-3-base oxygen base; (c) work as r 4awhen being ethynyl, ar then 1abe not selected from 3-(2-hydroxyl third-2-yl) phenyl, 3-(1-hydroxyethyl) phenyl, 3-amino-sulfonyl phenyl, phenyl, 3-(methyl sulphonyl amino) phenyl, 3-(n, n-dimethylaminomethyl) phenyl, 3-amino-sulfonyl phenyl and 3-formamyl phenyl; (d) work as r 4awhen being thiazol-2-yl, ar then 1abe not selected from 3-(methylamino alkylsulfonyl) phenyl, 3-chloro-phenyl-, 3-formamyl phenyl, 3-fluorophenyl, 2-(hydroxyl third-2-yl) phenyl, 1-hydroxyethyl, 3-amino-sulfonyl phenyl and phenyl; (e) work as r 4abe thiazol-2-yl and ar 1awhen being the 3-fluorophenyl, r then 3it is different not to be selected from pyridin-3-yl methoxyl group, 6-chloropyridine-3-ylmethoxy, 2-chloropyridine-4-ylmethoxy, 5-methyl azoles-3-base, azetidine-3-base oxygen base, n-methyl azetidine-3-base oxygen base, n-sec.-propyl azetidine-3-base oxygen base, tetramethyleneimine-3-base oxygen base, n-methyl, tetramethyleneimine-3-base oxygen base, piperidin-4-yl oxygen base and n-methyl piperidine-4-base oxygen base; (f) work as r 4awhen being bromine, ar then 1abe not selected from phenyl, 3-fluorophenyl, 2-(hydroxyl third-2-yl) phenyl, 1-hydroxyethyl and 3-amino-sulfonyl phenyl; (g) work as r 4awhen being cyano group, r then 3abe not selected from pyridin-4-yl methoxyl group, pyridine-2-ylmethoxy and 6-methoxypyridine-2-ylmethoxy; (h) work as r 4awhen being cyclopropyl, r then 3abe not selected from azetidine-3-base oxygen base; and (i) work as r 4awhen being hydrogen, ar then 1ait is 3-(amino-sulfonyl) phenyl.
증식성 질환을 치료하기 위한 2-아릴아미노퀴나졸린본 발명은 PDK1 억제제인 신규한 화합물을 제공한다. 또한 본 발명은 상기 화합물을 포함하는 제약 조성물, 및 상기 화합물 또는 조성물로 증식성 질환, 예컨대 암을 치료하는 방법을 제공한다.화학식 Ia의 화합물 또는 그의 제약상 허용되는 염:<화학식 Ia>[이미지]상기 식에서, R1a는 H 및 할로겐으로부터 선택되고;R3a는 C2-6 헤테로시클로알킬옥시 및 C1-6 헤테로아릴-C1-4-알콕시로부터 선택되고; 여기서 상기 C2-6 헤테로시클로알킬옥시 및 C1-6 헤테로아릴-C1-4-알콕시는 각각 Rw 기에 의해 임의로 치환되고;R4a는 H, 티아졸 고리, 피라졸 고리, 트리아졸 고리, 테트라졸 고리, 피리딘 고리, C3-6 시클로알킬, 시아노, 할로겐, C2-6 알키닐, C1-6 헤테로아릴-C1-4-알킬, C1-6 헤테로아릴-C1-4-알키닐, -C(=O)Ra, 및 -C(=O)NRbRc로부터 선택되고; 여기서 상기 티아졸 고리, 피라졸 고리, 트리아졸 고리, 테트라졸 고리, 피리딘 고리, C1-6 헤테로아릴-C1-4-알킬 및 C1-6 헤테로아릴-C1-4-알키닐은 각각 1 또는 2개의 독립적으로 선택된 Rx" 기에 의해 임의로 치환되고;Ar1a는 메타 위치에서 1개의 Ry'에 의해, 또는 다르게는 파라 위치에서 1개의 Ry" 기에 의해 임의로 치환된 페닐로부터 선택되고;각각의 Rw는 독립적으로 할로겐, C1-6 알킬, 아미노, C1-6 알킬아미노, 디-C1-4-알킬아미노, C1-6 알콕시카르보닐, 및 C1-6 알킬카르바밀로부터 선택되고; 여기서 상기 C1-6 알킬 및 C1-6 알킬아미노는 각각 히드록실, C1-6 알콕시, 아미노, C1-6 알킬아미노, 및 디-C1-4-알킬아미노로부터 선택된 기에 의해 임의로 치환되고;각각의 Rx"은 독립적으로 할로겐, 히드록실, C1-6 알킬, C1-6 알콕시카르보닐, 및 카르바밀로부터 선택되고; 여기서 상기 C1-6 알킬 및 C1-6 알콕시카르보닐은 각각 히드록실, 아미노, C1-4 알킬아미노, 및 아미노술포닐로부터 선택된 기에 의해 임의로 치환되고;Ry'은 할로겐, C1-6 알콕시, C1-6 알킬, 카르바밀, 아미노술포닐, 및 C1-6 알킬술포닐아미노로부터 선택되고; 여기서 상기 C1-6 알킬 및 C1-6 알콕시는 각각 히드록실, 아미노, C1-4 알킬아미노, 및 아미노술포닐로부터 독립적으로 선택된 1 또는 2개의 기에 의해 치환되고;Ry"은 C1-6 할로알킬로부터 선택되고;Ra는 H, C1-6 알콕시 및 C2-6 헤테로시클로알킬로부터 선택되고;Rb는 H 및 C1-6 알킬로부터 선택되고; Rc는 C1-6 알킬, C3-6 시클로알킬, C1-6 헤테로아릴, C2-6 헤테로시클로알킬, C2-6 헤테로시클로알킬-C1-4-알킬, 및 C1-6 헤테로아릴-C1-4-알킬로부터 선택되고; 여기서 상기 C1-6 알킬은 히드록실 및 C1-4 알콕시로부터 선택된 기에 의해 임의로 치환되고;단:(a) R3a가 피페리딘-4-일옥시 또는 N-메틸피페리딘-4-일옥시인 경우, R4는 티아졸-2-일, 티아졸-4-일, 티아졸-5-일, 5-메틸티아졸-2-일, 5-(히드록시메틸)티아졸-2-일, 5-(히드록시메틸)티아졸-4-일, 피리딘-2-일, 피리딘-4-일, 피리딘-3-일, 4-메틸피리딘-3-일, 5-클로로피리딘-4-일, 3-메틸피리딘-2-일, 및 1-메틸피라졸-5-일로부터 선택되지 않고;(b) R4a가 에티닐이고 Ar1a가 3-플루오로페닐인 경우, R3은 피리딘-3-일메톡시, 6-클로로피리딘-3-일메톡시, 피리딘-2-일메톡시, 피리딘-4-일메톡시, 1-(피리딘-4-일)에톡시, 6-메톡시피리딘-2-일메톡시, 티아졸-5-일메톡시, 피라진-2-일메톡시, 5-메틸이소옥사졸-3-일, 아제티딘-3-일옥시, N-메틸아제티딘-3-일옥시, N-이소프로필아제티딘-3-일옥시, 피롤리딘-3-일옥시, N-메틸, 및 피롤리딘-3-일옥시로부터 선택되지 않으며;(c) R4a가 에티닐인 경우, Ar1a는 3-(2-히드록시프로판-2-일)페닐, 3-(1-히드록시에틸)페닐, 3-아미노술포닐페닐, 페닐, 3-(메틸술포닐아미노)페닐, 3-(N,N-디메틸아미노메틸)페닐, 3-아미노술포닐페닐, 및 3-카르바밀페닐로부터 선택되지 않고;(d) R4a가 티아졸-2-일인 경우, Ar1a는 3-(메틸아미노술포닐)페닐, 3-클로로페닐, 3-카르바밀페닐, 3-플루오로페닐, 2-(히드록시프로판-2-일)페닐, 1-히드록시에틸, 3-아미노술포닐페닐, 및 페닐로부터 선택되지 않으며;(e) R4a가 티아졸-2-일이고 Ar1a가 3-플루오로페닐인 경우, R3은 피리딘-3-일메톡시, 6-클로로피리딘-3-일메톡시, 2-클로로피리딘-4-일메톡시, 5-메틸이소옥사졸-3-일, 아제티딘-3-일옥시, N-메틸아제티딘-3-일옥시, N-이소프로필아제티딘-3-일옥시, 피롤리딘-3-일옥시, N-메틸, 피롤리딘-3-일옥시, 피페리딘-4-일옥시, 및 N-메틸피페리딘-4-일옥시로부터 선택되지 않고; (f) R4a가 브로모인 경우, Ar1a는 페닐, 3-플루오로페닐, 2-(히드록시프로판-2-일)페닐, 1-히드록시에틸, 및 3-아미노술포닐페닐로부터 선택되지 않으며; (g) R4a가 시아노인 경우, R3a는 피리딘-4-일메톡시, 피리딘-2-일메톡시, 및 6-메톡시피리딘-2-일메톡시로부터 선택되지 않고; (h) R4a가 시클로프로필인 경우, R3a는 아제티딘-3-일옥시로부터 선택되지 않으며; (i) R4a가 수소인 경우, Ar1a는 3-(아미노술포닐)페닐이다.