TETRA-SUBSTITUTED HETEROARYL COMPOUNDS AND THEIR USE AS MDM2 AND/OR MDM4 MODULATORSThe invention relates to tetra-substituted heteroarylic compounds of the formula (I) wherein X1, X3 and X4 are independently C or N, Y is C-H, N-H or N, wherein the total number of nitrogen atoms represented by X1, X3, X4 and Y is 1 or 2; rings A and B are independently selected from phenyl or pyridyl; R1, R4, R', R", n and m are as defined herein. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of MDM2 and/or MDM4, or variants thereof.A compound of the formula (I), or a tautomer and/or a N-oxide and/or apharmaceutically acceptable salt thereof,whereinX1, X3 and X4 are independently C or N,Y is C-H1 N-H or N,wherein the total number of nitrogen atoms represented by X1, X3, X4 and Y is 1 or2;rings A and B are independently selected from phenyl or pyridyl, wherein the Chlorine substituents are independently in the 3 or 4 position;R1 is selected from the group consisting ofcyano- cyano-methyl- carboxyl-Ci-Cy-alkoxy-carbonyl- amino-carbonyl-N-d-Cr-alkyl-amino-carbonyl-N, ISNdJ-C1 -Cy-alkyl-amino-carbonyl-N-hydroxyl-amino-carbonyl-N-hydroxyl-N-Ci-Cy-alkyl-amino-carbonyl- N-d-Cr-alkoxy-amino-carbonyl- N-CrCy-alkoxy-N-CrCy-alkyl-amino-carbonyl-CrCT-alkyl-carbonyl-amino- CrC2-alkyl- heterocyclyl-C1-C7-alkyl-carbonyl- formyl- hy d TOXy-C1 -C2-a Iky I- heterocyclyl-carbonyl-S-CrCT-alkyl-sulfonimidoyl-S-CrCT-alkyl-N-Ci-CT-alkyl-sulfonimidoyl- S-CrCT-alkyl-N-Ci-Cy-aikyl-sulfonimidoyl-(VCγ-alkyl-sulfonyl- amino-S-CrCy-alkyl-sulfoximino-N-CrC7-alkyl-amino- N.N-di-CTCT-alkyl-amino-CrCy-alkoxy-carbonyl-amino-N-(C1 -C7-alkoxy-carbonyl)-N-CrC7-alkyl-amino-C1-C7^IKyI-Ca rbonyl-amino-N-fCt-Cr-alkyl-carbonylJ-N-C^C^alkyl-amino- amino-sulfonyl-N-C1-C7^ Ikyl-amino-sulfonyl-N.N-di-C^C^alkyl-amino-sulfonyl- hydrazinocarbonyl-N-C^C^alkyl-hydrazino-carbonyl- N.N-di-CrC^alkyl-hydrazino-carbonyl-N-CrCy-alkyl-hydrazino-carbonyl-N.N-di^^-alkyl-hydrazino-carbonyl-N.N-di-CrC^alkyl-N'-C-i-CT.-alkyl-hydrazino-carbonyl-C1-C7-alkyl-carbonyl-hydrazino-carbonyl- C1-C7-alkyl-carbonyl-N-C1-C7-alkyl-N'-CrC7-alkyl-hydrazino-carbonyl- phosphonyl-CrC7-alkyl-phosphonyl- di-CTC^alkyl-phosphonyl-, wherein C^C^alkyl or C1-C7^IkOXy groups are unsubstituted or substituted by 1-4 substituents selected from:amino- N-CrC7-alkyl-amino-N,N-di-CrC7-alkyl-amino-N-aryl-amino-N-aryl-N-d-d-alkyl-amino- heterocyclyl- heterocyclyl-carbonyl-C3-C10-cycloalkyl- hydroxy- cyano- halogen- halo-d-Cy-alkyl- d-d-alkoxy-Ci-Cy-alkyl-carbonyl-amino-N-td-Cy-alkyl-carbonyO-N-CrCr-alkyl-amino- d-Cz-alkyl-carbonyl- formyl- amino-carbony!-N-Ci-Cr-alkyl-amino-carbonyl-N.N-di-CrCT-alkyl-amino-carbonyl- amino-carbonyl-amino-N-d-Cr-alkyl-amino-carbonyl-amino-N^-di-CrCy-alkyl-amino-carbonyl-amino- amino-carbonyl-N'-(Ci-C7-alkyl)-amino-N-d-Cr-alkyl-amino-carbonyl-N'-tCrCT-alkyO-amino- N,N-di-Crd-alkyl-amino-carbonyl-N'-{CrC7-alkyl)-amino- carboxyl- d-C7-alkoxy-carbonyl- aryl- and wherein and d-C7-alkoxy groups as part of these substituents can be further substituted as described above for d-C7-alkyl and d-C7-alkoxy;and wherein heterocyclic groups are unsubstituted or substituted by 1-4 substituents selected from:amino-N-d-C7-alkyl-amino- N,N-di-CrC7-alkyl-amino- heterocyclyl- C3-C10-cycloalkyl- cyano- halogen- halo-d-Cy-alkyl- CrC7-alkoxy- d -Cy-alkoxy-d -C7-alky[- protected hydroxy-d-C7-alkyl-CrC7-alkyl-carbonyl-amino-N-(CrC7-alkyl-carbonyl)-N-CrC7-alkyl-amino- N.N-di-d-d-alkyl-amino^-d-alkyl-amino- d-d-alkoxy-d-C7-alkyl-amino- aryl-CrC7-alkyl-amino-Ci -C7-al kyl-carbonyl- formyl- amino-carbonyl-N-d-C^-alkyl-amino-carbonyl-N.N-di-CrCy-alkyl-amino-carbonyl- carboxyl-C1 -C7-alkoxy-carbonyl- CrC7-alkyl- oxo (O=)thiono (S=)wherein Ci-C7-alkyl and as part of these substituents can be further substituted as described above for d-C7-alkyl and CrC7-alkoxy.R4 is selected from the group consisting ofsubstituted C-i-alkyl-C2-C7-alkyl- aryl- heteroaryl- heterocyclyl-C3-C10-cycloalkyl- aryl-d-C7-alkyl- heteroaryl-Crd-alkyl- heterocyclyl-d -d-al kyl- Ca-C^-cycioalkyl-CrCT-alkyl- wherein substituents R4 are unsubstituted or substituted by 1-3 substituents selected fromhydroxy-Ci-C7-alkoxy- d-Cy-alkoxy-carbonyl- halogen- nitro-C1 -C7-alkyl-carbonyl- formyl-Ci-Cy-alkyl- amino-N-CrCr-alkyl-amino-N.N-di-CrC^alkyl-amino- C^CT-alkyl-carbonyl-amino-N-(C1-C7-alkyl-carbonyl)-N-C1-C7-alkyl-amino- hydrazino-carbonyl-CTCz-alkyl-amino-N-C1-C7-alkyl-hydrazino-carbonyl-C1-C7-alkyl-amino-N.N-di-CrC^alkyl-hydrazino-carbonyl-CrC^alkyl-amino- N-CrC7-alkyl-hydrazino-carbonyl-Ci-C7-alkyl-amino-N,N-di-C1-C7-alkyl-hydrazino-carbonyl-C1-C7-alkyl-amino-N.N-di-Ct-C^alkyl-N'-CrC^alkyl-hydrazino-carbonyl-Ci-C^alkyl-amino-CTCralkyl-carbonyl-hydrazino-carbonyl-CrC^alkyl-amino-Ci-CTr-alkyl-carbonyl-N-CrCralkyl-N'-Ci-CT-alkyl-hydrazino-carbonyl-Ci-C^alkyl- amino- hydrazinocarbonyl-Cr -alkyl-N-tCrC^alkylJ-amino-N-CrC7-alkyl-hydrazino-carbonyl-C1-C7-alkyl-N-(C1-C7-alkyl)-amino-N,N-di-C1-C7-alkyl-hydrazino-carbonyl-CrC7-alkyl-N-(C1-C7-alkyl)-annino-N-C1-C7-alkyl-hydrazino-carbonyl-Ci-C7-alkyl-N-(C1-C7-alkyl)-amino- N,N-di-CrC7-alkyl-hydrazino-carbonyl-C1-C7-alkyl-N-{C1-C7-alkyl)-amino-N,N-di-C1-C7-alkyl-N'-C1-C7-alkyl-hydrazino-carbonyl-C1-C7-alkyl-N-(C1-C7-alkyl)- amino-Ci-C7-alkyl-carbonyl-hydrazino-carbonyl-C1-C7-alkyl~N-(C1-C7-alkyl)-amino-CrCralkyl-carbonyl-N-C^CT-alkyl-N'-CrC^alkyl-hydrazino-carbonyl-Ci-CT-alkyl- N-(CrC7-alkyl)-amino- tert-butyl-diphenyl-silanyloxy- heterocyclyl- protected hydroxy- wherein CrC7-alkyl or C1-C^aIkOXy groups as part of substituents...
테트라-치환된 헤테로아릴 화합물 및 ＭＤＭ2 및/또는 ＭＤＭ4 조절제로서의 그의 용도본 발명은 하기 화학식 I의 테트라-치환된 헤테로아릴 화합물에 관한 것이다. <화학식 I> 상기 식에서, X1, X3 및 X4는 독립적으로 C 또는 N이고, Y는 C-H, N-H 또는 N 이며, 여기서, X1, X3, X4 및 Y에 의해 나타내어진 질소 원자의 전체 수는 1 또는 2이고; 고리 A 및 B는 독립적으로 페닐 또는 피리딜로부터 선택되고; R1, R4, R', R", n 및 m은 본원에 정의된 바와 같다. 이러한 화합물은 MDM2 및/또는 MDM4 또는 그의 변이체의 활성에 의해 매개되는 장애 또는 질환의 치료에 적합하다.하기 화학식 I의 화합물, 또는 그의 호변이성질체 및/또는 N-옥시드 및/또는 제약상 허용되는 염.<화학식 I>상기 식에서,X1, X3 및 X4는 독립적으로 C 또는 N이고,Y는 C-H, N-H 또는 N이고,여기서, X1, X3, X4 및 Y에 의해 나타내어진 질소 원자의 전체 수는 1 또는 2이고;고리 A 및 B는 독립적으로 페닐 또는 피리딜로부터 선택되고, 여기서 염소 치환기는 독립적으로 3 또는 4 위치에 존재하고;R1은시아노-시아노-메틸-카르복시-C1-C2-알킬-카르복실-C1-C7-알콕시-카르보닐-아미노-카르보닐-N-C1-C7-알킬-아미노-카르보닐-N,N-디-C1-C7-알킬-아미노-카르보닐-N-히드록실-아미노-카르보닐-N-히드록실-N-C1-C7-알킬-아미노-카르보닐-N-C1-C7-알콕시-아미노-카르보닐-N-C1-C7-알콕시-N-C1-C7-알킬-아미노-카르보닐-C1-C7-알킬-카르보닐-아미노-C1-C2-알킬-헤테로시클릴-C1-C7-알킬-카르보닐-포르밀-히드록시-C1-C2-알킬-헤테로시클릴-카르보닐-S-C1-C7-알킬-술폰이미도일-S-C1-C7-알킬-N-C1-C7-알킬-술폰이미도일-S-C1-C7-알킬-N-C1-C7-알킬-술폰이미도일-C1-C7-알킬-술포닐-아미노-S-C1-C7-알킬-술폭스이미노-N-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-아미노-C1-C7-알콕시-카르보닐-아미노-N-(C1-C7-알콕시-카르보닐)-N-C1-C7-알킬-아미노-C1-C7-알킬-카르보닐-아미노-N-(C1-C7-알킬-카르보닐)-N-C1-C7-알킬-아미노-아미노-술포닐-N-C1-C7-알킬-아미노-술포닐-N,N-디-C1-C7-알킬-아미노-술포닐-히드라지노카르보닐-N-C1-C7-알킬-히드라지노-카르보닐-N,N-디-C1-C7-알킬-히드라지노-카르보닐-N-C1-C7-알킬-히드라지노-카르보닐-N,N-디-C1-C7-알킬-히드라지노-카르보닐-N,N-디-C1-C7-알킬-N'-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-카르보닐-히드라지노-카르보닐-C1-C7-알킬-카르보닐-N-C1-C7-알킬-N'-C1-C7-알킬-히드라지노-카르보닐-포스포닐-C1-C7-알킬-포스포닐-디-C1-C7-알킬-포스포닐-로 이루어진 군으로부터 선택되고,여기서, C1-C7-알킬 또는 C1-C7-알콕시 기는 비치환되거나 또는아미노-N-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-아미노-N-아릴-아미노-N-아릴-N-C1-C7-알킬-아미노-헤테로시클릴-헤테로시클릴-카르보닐-C3-C10-시클로알킬-히드록시-시아노-할로겐-할로-C1-C7-알킬-C1-C7-알콕시-C1-C7-알킬-카르보닐-아미노-N-(C1-C7-알킬-카르보닐)-N-C1-C7-알킬-아미노-C1-C7-알킬-카르보닐-포르밀-아미노-카르보닐-N-C1-C7-알킬-아미노-카르보닐-N,N-디-C1-C7-알킬-아미노-카르보닐-아미노-카르보닐-아미노-N-C1-C7-알킬-아미노-카르보닐-아미노-N,N-디-C1-C7-알킬-아미노-카르보닐-아미노-아미노-카르보닐-N'-(C1-C7-알킬)-아미노-N-C1-C7-알킬-아미노-카르보닐-N'-(C1-C7-알킬)-아미노-N,N-디-C1-C7-알킬-아미노-카르보닐-N'-(C1-C7-알킬)-아미노-카르복실-C1-C7-알콕시-카르보닐-아릴-로부터 선택된 1 내지 4개의 치환기에 의해 치환되고,여기서, 이들 치환기의 일부로서 C1-C7-알킬 및 C1-C7-알콕시 기는 C1-C7-알킬 및 C1-C7-알콕시에 대해 상기 기재된 바와 같이 추가로 치환될 수 있고;여기서, 헤테로시클릭 기는 비치환되거나 또는아미노-N-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-아미노-헤테로시클릴-C3-C10-시클로알킬-시아노-할로겐-할로-C1-C7-알킬-C1-C7-알콕시-C1-C7-알콕시-C1-C7-알킬-보호된 히드록시-C1-C7-알킬-C1-C7-알킬-카르보닐-아미노-N-(C1-C7-알킬-카르보닐)-N-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-아미노-C1-C7-알킬-아미노-C1-C7-알콕시-C1-C7-알킬-아미노-아릴-C1-C7-알킬-아미노-C1-C7-알킬-카르보닐-포르밀-아미노-카르보닐-N-C1-C7-알킬-아미노-카르보닐-N,N-디-C1-C7-알킬-아미노-카르보닐-카르복실-C1-C7-알콕시-카르보닐-C1-C7-알킬-옥소 (O=)티오노 (S=)로부터 선택된 1 내지 4개의 치환기에 의해 치환되고,여기서, 이들 치환기의 일부로서 C1-C7-알킬 및 C1-C7-알콕시는 C1-C7-알킬 및 C1-C7-알콕시에 대해 상기 기재된 바와 같이 추가로 치환될 수 있고;R4는치환된 C1-알킬-C2-C7-알킬-아릴-헤테로아릴-헤테로시클릴-C3-C10-시클로알킬-아릴-C1-C7-알킬-헤테로아릴-C1-C7-알킬-헤테로시클릴-C1-C7-알킬-C3-C10-시클로알킬-C1-C7-알킬-로 이루어진 군으로부터 선택되고,여기서, 치환기 R4는 비치환되거나 또는히드록시-C1-C7-알콕시-C1-C7-알콕시-카르보닐-할로겐-할로-C1-C7-알킬-니트로-C1-C7-알킬-카르보닐-포르밀-C1-C7-알킬-아미노-N-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-아미노-C1-C7-알킬-카르보닐-아미노-N-(C1-C7-알킬-카르보닐)-N-C1-C7-알킬-아미노-히드라지노-카르보닐-C1-C7-알킬-아미노-N-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-아미노-N-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-N'-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-아미노-C1-C7-알킬-카르보닐-히드라지노-카르보닐-C1-C7-알킬-아미노-C1-C7-알킬-카르보닐-N-C1-C7-알킬-N'-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-아미노-히드라지노카르보닐-C1-C7-알킬-N-(C1-C7-알킬)-아미노-N-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-N-(C1-C7-알킬)-아미노-N,N-디-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-N-(C1-C7-알킬)-아미노-N-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-N-(C1-C7-알킬)-아미노-N,N-디-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-N-(C1-C7-알킬)-아미노-N,N-디-C1-C7-알킬-N'-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-N-(C1-C7-알킬)-아미노-C1-C7-알킬-카르보닐-히드라지노-카르보닐-C1-C7-알킬-N-(C1-C7-알킬)-아미노-C1-C7-알킬-카르보닐-N-C1-C7-알킬-N'-C1-C7-알킬-히드라지노-카르보닐-C1-C7-알킬-N-(C1-C7-알킬)-아미노-tert-부틸-디페닐-실라닐옥시-헤테로시클릴-보호된 히드록시-로부터 선택된 1 내지 3개의 치환기에 의해 치환되고,여기서, 상기 정의된 바와 같은 R4에 대한 치환기의 일부로서 C1-C7-알킬 또는 C1-C7-알콕시 기는 비치환되거나 또는아미노-N-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-아미노-N-아릴-아미노-N-아릴-N-C1-C7-알킬-아미노-헤테로시클릴-헤테로시클릴-카르보닐-C3-C10-시클로알킬-히드록시-시아노-할로겐-할로-C1-C7-알킬-C1-C7-알콕시-C1-C7-알킬-카르보닐-아미노-N-(C1-C7-알킬-카르보닐)-N-C1-C7-알킬-아미노-C1-C7-알킬-카르보닐-포르밀-아미노-카르보닐-N-C1-C7-알킬-아미노-카르보닐-N,N-디-C1-C7-알킬-아미노-카르보닐-아미노-카르보닐-아미노-N-C1-C7-알킬-아미노-카르보닐-아미노-N,N-디-C1-C7-알킬-아미노-카르보닐-아미노-아미노-카르보닐-N'-(C1-C7-알킬)-아미노-N-C1-C7-알킬-아미노-카르보닐-N'-(C1-C7-알킬)-아미노-N,N-디-C1-C7-알킬-아미노-카르보닐-N'-(C1-C7-알킬)-아미노-카르복실-C1-C7-알콕시-카르보닐-아릴-로부터 독립적으로 선택된 1 내지 4개의 기에 의해 치환되고,여기서, 이들 치환기의 일부로서 C1-C7-알킬 및 C1-C7-알콕시 기는 C1-C7-알킬 및 C1-C7-알콕시에 대해 상기 기재된 바와 같이 추가로 치환될 수 있고;여기서, 상기 정의된 바와 같은 R4에 대한 치환기의 일부로서 헤테로시클릴은 비치환되거나 또는아미노-N-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-아미노-헤테로시클릴-C3-C10-시클로알킬-시아노-할로겐-할로-C1-C7-알킬-C1-C7-알콕시-C1-C7-알콕시-C1-C7-알킬-보호된 히드록시-C1-C7-알킬-C1-C7-알킬-카르보닐-아미노-N-(C1-C7-알킬-카르보닐)-N-C1-C7-알킬-아미노-N,N-디-C1-C7-알킬-아미노-C1-C7-알킬-아미노-C1-C7-알콕시-C1-C7-알킬-아미노-아릴-C1-C7-알킬-아미노-C1-C7-알킬-카르보닐-포르밀-아미노-카르보닐-N-C1-C7-알킬-아미노-카르보닐-N,N-디-C1-C7-알킬-아미노-카르보닐-카르복실-C1-C7-알콕시-카르보닐-C1-C7-알킬-옥소 (O=)티오노 (S=)로부터 독립적으로 선택된 1 내지 4개의 기에 의해 치환되고,여기서, 이들 치환기의 일부로서 C1-C7-알킬 및 C1-C7-알콕시 기는 C1-C7-알킬 및 C1-C7-알콕시에 대해 상기 기재된 바와 같이 추가로 치환될 수 있고;R' 및 R"는히드록시-C1-C7-알콕시-할로겐-할로-C1-C7-알킬-시아노-C1-C7-알킬-카르보닐-포르밀-C1-C7-알킬-아미노-카르보닐-N-C1-C7-알킬-아미노-카르보닐-N,N-디-C1-C7-알킬-아미노-카르보닐-헤테로시클릴-N-(히드록시-C1-C7-알킬)-아미노-카르보닐-C1-C7-알킬-N-(C1-C7-알콕시-C1-C7-알킬)-아미노-카르보닐-C1-C7-알킬-N-(히드록시-C1-C7-알킬)-N-C1-C7-알킬-아미노-카르보닐-C1-C7-알킬-N-(C1-C7-알콕시-C1-C7-알킬)-N-C1-C7-알킬-아미노-카르보닐-C1-C7-알킬-C1-C7-알콕시-카르보닐-C1-C7-알킬-카르보닐-아미노-카르복실-로 이루어진 군으로부터 독립적으로 선택되고,여기서, A 및 B, 또는 A 또는 B가 피리딜인 경우에, R' 및 R"는 또한 독립적으로 =O로부터 선택되어 기 (이는 상기 기재된 바와 같은 R' 및 R"로 추가로 치환될 수 있다.