阅读说明：本技术 同时抑制lsd1和hdac靶点的化合物及其应用 (Compound for simultaneously inhibiting LSD1 and HDAC target and application thereof ) 是由 全军民 李勤凯 曾鑫 许正双 岳宏 张婷瑶 付佳苗 黄新仪 于 2018-01-04 设计创作，主要内容包括：一种化合物,所述化合物的结构通式如式I所示：X-AB-Y(式I)；上述式I中,X选自-CO<Sub>2</Sub>H、-CONHZ、-CH＝CH-CO<Sub>2</Sub>H、-CH＝CH-CONHZ中的任意一种,其中,Z选自被取代的或未被取代的C<Sub>1</Sub>-C<Sub>12</Sub>烷基、被取代的或未被取代的芳基、羟基中的任意一种；Y＝-NR<Sub>1</Sub>R<Sub>2</Sub>,其中,NR<Sub>1</Sub>R<Sub>2</Sub>为被取代的或未被取代的3元至9元的含氮杂环烃基；A、B分别独立选自取代的或未被取代的亚苯基、取代的或未被取代的氮杂亚苯基。该化合物或其相应的药用的盐的形式,可同时抑制LSD1和HDAC靶蛋白,从而抑制多种肿瘤细胞的增殖,具有很好的抗肿瘤作用。(A compound having a general structural formula as shown in formula I: X-AB-Y (formula I); in the formula I, X is selected from-CO 2 H、‑CONHZ、‑CH＝CH‑CO 2 H. -CH ═ CH-CONHZ, wherein Z is selected from substituted or unsubstituted C 1 ‑C 12 Any one of alkyl, substituted or unsubstituted aryl, and hydroxyl; y is-NR 1 R 2 Wherein NR is 1 R 2 Is a substituted or unsubstituted 3-to 9-membered nitrogen-containing heterocyclic hydrocarbon group; A. each B is independently selected from substituted or unsubstituted phenylene, substituted or unsubstituted azaphenylene. The compound or the corresponding medicinal salt form thereof can inhibit LSD1 and HDAC target protein simultaneously, thereby inhibiting the proliferation of various tumor cells and having good anti-tumor effect.)

A compound having a general structural formula as shown in formula I:

X-AB-Y

formula I

In the above-mentioned formula I, the compound of formula I,

x is selected from-CO₂H、-CONHZ、-CH＝CH-CO₂H. -CH ═ CH-CONHZ, wherein Z is selected from substituted or unsubstituted C₁-C₁₂Any one of alkyl, substituted or unsubstituted aryl, and hydroxyl;

Y＝-NR₁R₂wherein NR is₁R₂Is a substituted or unsubstituted 3-to 9-membered nitrogen-containing heterocyclic hydrocarbon group;

A. each B is independently selected from substituted or unsubstituted phenylene, substituted or unsubstituted azaphenylene.

The compound of claim 1, wherein, in formula I, A, B are each independently selected from the group consisting of:

any one of the above;

wherein R is₃、R₄、R₅、R₆Each independently selected from substituted or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Heteroalkyl, substituted or unsubstituted C₃-C₁₂Cycloalkyl, substituted or unsubstituted C₃-C₁₂Heterocycloalkyl, substituted or unsubstituted C₂-C₁₂Alkenyl, substituted or unsubstituted C₂-C₁₂Heteroalkenyl, substituted or unsubstituted C₃-C₁₂Cycloalkenyl, substituted or unsubstituted C₃-C₁₂Heterocycloalkenyl, substituted or unsubstituted C₂-C₁₂Alkynyl, substituted orUnsubstituted C₂-C₁₂Heteroalkynyl, substituted or unsubstituted C₃-C₁₂Cycloalkynyl, substituted or unsubstituted C₃-C₁₂Heterocycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryl (C)₁-C₁₂) Alkyl, heteroaryl (C)₁-C₁₂) Alkyl radical, C₂-C₁₂Alkenyl (C)₁-C₁₂) Alkyl radical, C₂-C₁₂Alkynyl (C)₁-C₁₂) Any one of alkyl, hydroxyl, amino, nitro, sulfo, halogen and hydrogen atoms.

A compound of claim 2, wherein in formula I, R is₃、R₄、R₅、 R₆Each independently selected from substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Heteroalkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted C₃-C₆Heterocycloalkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Heteroalkenyl, substituted or unsubstituted C₃-C₆Cycloalkenyl, substituted or unsubstituted C₃-C₆Heterocycloalkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₂-C₆Heteroalkynyl, substituted or unsubstituted C₃-C₆Cycloalkynyl, substituted or unsubstituted C₃-C₆Heterocycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryl (C)₁-C₆) Alkyl, heteroaryl (C)₁-C₆) Alkyl radical, C₂-C₆Alkenyl (C)₁-C₆) Alkyl radical, C₂-C₆Alkynyl (C)₁-C₆) Any one of alkyl groups.

The compound of claim 2, wherein in formula I, -AB-has a structure selected from the group consisting of:

any one of the above; wherein D is halogen.

The compound of claim 1, wherein in formula I, Z is substituted or unsubstituted C₁-C₄Alkyl or hydroxy.

The compound of claim 1, wherein in formula I, Z has the structureOr a hydroxyl group; wherein R is₇Optionally substituted or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Heteroalkyl, substituted or unsubstituted C₃-C₁₂Cycloalkyl, substituted or unsubstituted C₃-C₁₂Heterocycloalkyl, substituted or unsubstituted C₂-C₁₂Alkenyl, substituted or unsubstituted C₂-C₁₂Heteroalkenyl, substituted or unsubstituted C₃-C₁₂Cycloalkenyl, substituted or unsubstituted C₃-C₁₂Heterocycloalkenyl, substituted or unsubstituted C₂-C₁₂Alkynyl, substituted or unsubstituted C₂-C₁₂Heteroalkynyl, substituted or unsubstituted C₃-C₁₂Cycloalkynyl, substituted or unsubstituted C₃-C₁₂Heterocycloalkynyl, substituted or unsubstituted arylSubstituted or unsubstituted heteroaryl, aryl (C)₁-C₁₂) Alkyl, heteroaryl (C)₁-C₁₂) Alkyl radical, C₂-C₁₂Alkenyl (C)₁-C₁₂) Alkyl radical, C₂-C₁₂Alkynyl (C)₁-C₁₂) Any one of alkyl, hydroxyl, amino, nitro, sulfo, halogen and hydrogen atoms.

The compound of claim 1, wherein Y is a substituted or unsubstituted 5-or 6-membered nitrogen-containing azacyclo hydrocarbyl group in formula I.

The compound of claim 7, wherein Y is selected from the group consisting of:

any one of them.

The compound of claim 1, wherein said compound is selected from the group consisting of

Any one of them.

A pharmaceutically acceptable salt of a compound as claimed in any one of claims 1 to 9.

A pharmaceutical composition comprising a compound of any one of claims 1-9 and a pharmaceutically acceptable carrier.

The pharmaceutical composition of claim 11, wherein the pharmaceutical composition further comprises an anti-cancer drug.

The pharmaceutical composition of claim 12, wherein the anti-cancer drug is a LSD1 inhibitor and/or an HDAC inhibitor.

Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of a tumor or cancer associated with LSD1 and/or HDAC.

The use of claim 14, wherein the tumor or cancer is selected from the group consisting of: brain cancer, glioblastoma, leukemia, ban-zos syndrome, colepton's disease, cerebellar dysplastic ganglioneuroma, breast cancer, inflammatory breast cancer, wilms ' tumor, ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, kidney cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumors of bone and thyroid.