CN112876420B - Thiobenzoyl derivative and application thereof - Google Patents

Thiobenzoyl derivative and application thereof Download PDF

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CN112876420B
CN112876420B CN201911201699.7A CN201911201699A CN112876420B CN 112876420 B CN112876420 B CN 112876420B CN 201911201699 A CN201911201699 A CN 201911201699A CN 112876420 B CN112876420 B CN 112876420B
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CN112876420A (en
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冉兆晋
柴宝山
王云华
毕弋
王婉秋
焦佳媛
吴依蒙
赵宪成
石凯强
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Shenyang Research Institute of Chemical Industry Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the field of chemistry, and particularly relates to a thiobenzoyl derivative and application of the derivative in treating cancer, inflammation or immune system diseases. The structure of the thiobenzoyl derivative is shown in a general formula I; the definition of each substituent group in the formula is shown in the specification. The compounds of the invention are useful for the treatment of cancer diseases.

Description

Thiobenzoyl derivative and application thereof
Technical Field
The invention belongs to the field of chemistry, and particularly relates to a thiobenzoyl derivative and application of the derivative in treating cancer, inflammation or immune system diseases.
Background
Patent WO2018019252 discloses a general formula of pyrimidine compounds shown in the following general formula and a specific compound 11, which have an effect of treating cancer.
Figure BDA0002296044860000011
However, compounds having a structure similar to that of the present invention have not been reported.
Disclosure of Invention
The invention aims to provide a thiobenzoyl derivative and application of the derivative in treating cancer.
In order to achieve the purpose, the invention adopts the technical scheme that:
a thiobenzoyl derivative is a compound shown in a general formula I and pharmaceutically acceptable salts thereof:
Figure BDA0002296044860000012
wherein
X is selected from O or NH;
R 1 selected from H, hydroxy, amino, C 1 -C 12 Alkyl, halo C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy, halo C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 12 Alkylthio, halogeno C 1 -C 12 Alkylthio radical, C 2 -C 12 Alkenyl radical, C 2 -C 12 Alkynyl, C 2 -C 12 Alkenyloxy, halogeno C 2 -C 12 Alkenyloxy radical, C 2 -C 12 Alkynyloxy, halo C 2 -C 12 Alkynyloxy, C 1 -C 12 Alkylsulfonyl, halo C 1 -C 12 Alkylsulfonyl radical, C 1 -C 12 Alkylcarbonyl, halo C 1 -C 12 Alkylcarbonyl group, C 1 -C 12 Alkoxycarbonyl, halo C 1 -C 12 Alkoxycarbonyl group, C 1 -C 12 Alkoxy radical C 1 -C 12 Alkyl, halo C 1 -C 12 Alkoxy radical C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylthio group C 1 -C 12 Alkyl, halo C 1 -C 12 Alkylthio group C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxycarbonyl radical C 1 -C 12 Alkyl, halo C 1 -C 12 Alkoxycarbonyl radical C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylthio carbonyl group C 1 -C 12 Alkyl, halo C 1 -C 12 Alkylthio carbonyl group C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylcarbonyloxy, halo C 1 -C 12 Alkylcarbonyloxy, C 1 -C 12 Alkoxycarbonyloxy, halo C 1 -C 12 Alkoxycarbonyloxy, C 1 -C 12 Alkylsulfonyloxy, halo C 1 -C 12 Alkylsulfonyloxy, C 1 -C 12 Alkoxy radical C 1 -C 12 Alkoxy or halo C 1 -C 12 Alkoxy radical C 1 -C 12 An alkoxy group;
R 2 selected from 1-4H, halogen, hydroxyl, amino, nitro, cyano, C 1 -C 12 Alkyl, halo C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy, halo C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 12 Alkylthio, halogeno C 1 -C 12 Alkylthio radical, C 2 -C 12 Alkenyl radical, C 2 -C 12 Alkynyl, C 2 -C 12 Alkenyloxy, halogeno C 2 -C 12 Alkenyloxy radical, C 2 -C 12 Alkynyloxy, halo C 2 -C 12 Alkynyloxy, C 1 -C 12 Alkylsulfonyl, halo C 1 -C 12 Alkylsulfonyl radical, C 1 -C 12 Alkylcarbonyl, halo C 1 -C 12 Alkyl carbonyl, C 1 -C 12 Alkoxycarbonyl, halo C 1 -C 12 Alkoxycarbonyl group, C 1 -C 12 Alkoxy radical C 1 -C 12 Alkyl, halo C 1 -C 12 Alkoxy radical C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylthio group C 1 -C 12 Alkyl, halo C 1 -C 12 Alkylthio group C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxycarbonyl radical C 1 -C 12 Alkyl, halo C 1 -C 12 Alkoxycarbonyl radical C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylthio carbonyl group C 1 -C 12 Alkyl, halo C 1 -C 12 Alkylthio carbonyl group C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylcarbonyloxy, halo C 1 -C 12 Alkylcarbonyloxy, C 1 -C 12 Alkoxycarbonyloxy, halo C 1 -C 12 Alkoxycarbonyloxy, C 1 -C 12 Alkylsulfonyloxy, halo C 1 -C 12 Alkylsulfonyloxy, C 1 -C 12 Alkoxy radical C 1 -C 12 Alkoxy or halo C 1 -C 12 Alkoxy radical C 1 -C 12 An alkoxy group;
R 3 and R 4 Can be the same or different and is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1 -C 12 Alkyl, halo C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy, halo C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 12 Alkylthio, halo C 1 -C 12 Alkylthio radical, C 2 -C 12 Alkenyl radical, C 2 -C 12 Alkynyl, C 2 -C 12 Alkenyloxy, halogeno C 2 -C 12 Alkenyloxy radical, C 2 -C 12 Alkynyloxy, halo C 2 -C 12 Alkynyloxy, C 1 -C 12 Alkylsulfonyl, halo C 1 -C 12 Alkylsulfonyl radical, C 1 -C 12 Alkylcarbonyl, halo C 1 -C 12 Alkyl carbonyl, C 1 -C 12 Alkoxycarbonyl, halo C 1 -C 12 Alkoxycarbonyl group, C 1 -C 12 Alkoxy radical C 1 -C 12 Alkyl, halo C 1 -C 12 Alkoxy radical C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylthio group C 1 -C 12 Alkyl, halo C 1 -C 12 Alkylthio group C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxycarbonyl radical C 1 -C 12 Alkyl, halo C 1 -C 12 Alkoxycarbonyl radical C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylthio carbonyl group C 1 -C 12 Alkyl, halo C 1 -C 12 Alkylthio carbonyl group C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylcarbonyloxy, halo C 1 -C 12 Alkylcarbonyloxy, C 1 -C 12 Alkoxycarbonyloxy, halo C 1 -C 12 Alkoxycarbonyloxy, C 1 -C 12 Alkylsulfonyloxy, halo C 1 -C 12 Alkylsulfonyloxy, C 1 -C 12 Alkoxy radical C 1 -C 12 Alkoxy or halo C 1 -C 12 Alkoxy radical C 1 -C 12 An alkoxy group;
or, R 3 And R 4 Or can be combined with connected pyrimidine rings to form C, N, O or S-containing five-membered, six-membered, seven-membered or eight-membered heteroaromatic rings or heterocyclic alkanes;
R 5 selected from unsubstituted or substituted by 1-5R 8 Substituted C, N, O or S-containing five-membered, six-membered aromatic, heteroaromatic, benzoheteroaromatic or benzoheterocycloalkane;
R 6 、R 7 the same or different are respectively selected from hydrogen, hydroxyl, amino and C 1 -C 12 Alkyl, halo C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy, halo C 1 -C 12 Alkoxy radical, C 1 -C 12 Alkylamino, halogeno C 1 -C 12 An alkylamino group;
or, R 6 、R 7 Or can be connected with N to form ternary, quaternary, quinary, hexahydric, heptatomic or octatomic heterocyclic alkane containing C, N, O or S;
R 8 selected from H, halogenElement, hydroxy, amino, nitro, cyano, C 1 -C 12 Alkyl, halo C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy, halo C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 12 Alkylthio, halogeno C 1 -C 12 Alkylthio radical, C 2 -C 12 Alkenyl radical, C 2 -C 12 Alkynyl, C 2 -C 12 Alkenyloxy, halogeno C 2 -C 12 Alkenyloxy radical, C 2 -C 12 Alkynyloxy, halo C 2 -C 12 Alkynyloxy, C 1 -C 12 Alkylsulfonyl, halo C 1 -C 12 Alkylsulfonyl radical, C 1 -C 12 Alkylcarbonyl, halo C 1 -C 12 Alkylcarbonyl group, C 1 -C 12 Alkoxycarbonyl, halo C 1 -C 12 Alkoxycarbonyl group, C 1 -C 12 Alkoxy radical C 1 -C 12 Alkyl, halo C 1 -C 12 Alkoxy radical C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylthio group C 1 -C 12 Alkyl, halo C 1 -C 12 Alkylthio group C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxycarbonyl radical C 1 -C 12 Alkyl, halo C 1 -C 12 Alkoxycarbonyl radical C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylthio carbonyl group C 1 -C 12 Alkyl, halo C 1 -C 12 Alkylthio carbonyl group C 1 -C 12 Alkyl radical, C 1 -C 12 Alkylcarbonyloxy, halo C 1 -C 12 Alkylcarbonyloxy, C 1 -C 12 Alkoxycarbonyloxy, halo C 1 -C 12 Alkoxycarbonyloxy, C 1 -C 12 Alkylsulfonyloxy, halo C 1 -C 12 Alkylsulfonyloxy, C 1 -C 12 Alkoxy radical C 1 -C 12 Alkoxy or halo C 1 -C 12 Alkoxy radical C 1 -C 12 An alkoxy group.
Preferably, in the compound of formula I:
in the formula (I), the compound is shown in the specification,
x is selected from O or NH;
R 1 selected from H, hydroxy, amino, C 1 -C 6 Alkyl, halo C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 6 Alkylthio, halogeno C 1 -C 6 Alkylthio radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 2 -C 6 Alkenyloxy, halogeno C 2 -C 6 Alkenyloxy radical, C 2 -C 6 Alkynyloxy, halo C 2 -C 6 Alkynyloxy, C 1 -C 6 Alkylsulfonyl, halo C 1 -C 6 Alkylsulfonyl radical, C 1 -C 6 Alkylcarbonyl, halo C 1 -C 6 Alkylcarbonyl group, C 1 -C 6 Alkoxycarbonyl, halo C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Alkoxy radical C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxy radical C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylthio C 1 -C 6 Alkyl, halo C 1 -C 6 Alkylthio C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxycarbonyl radical C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxycarbonyl radical C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylthio carbonyl group C 1 -C 6 Alkyl, halo C 1 -C 6 Alkylthio carbonyl group C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylcarbonyloxy, halo C 1 -C 6 Alkylcarbonyloxy, C 1 -C 6 Alkoxycarbonyloxy, halo C 1 -C 6 Alkoxycarbonyloxy, C 1 -C 6 Alkylsulfonyloxy, halo C 1 -C 6 Alkylsulfonyloxy, C 1 -C 6 Alkoxy radical C 1 -C 6 Alkoxy or halo C 1 -C 6 Alkoxy radical C 1 -C 6 An alkoxy group;
R 2 selected from 1-4H, hydroxyl, amino and C 1 -C 6 Alkyl, halo C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 6 Alkylthio, halo C 1 -C 6 Alkylthio radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 2 -C 6 Alkenyloxy, halogeno C 2 -C 6 Alkenyloxy radical, C 2 -C 6 Alkynyloxy, halo C 2 -C 6 Alkynyloxy, C 1 -C 6 Alkylsulfonyl, halo C 1 -C 6 Alkylsulfonyl radical, C 1 -C 6 Alkylcarbonyl, halo C 1 -C 6 Alkylcarbonyl group, C 1 -C 6 Alkoxycarbonyl, halo C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Alkoxy radical C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxy radical C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylthio group C 1 -C 6 Alkyl, halo C 1 -C 6 Alkylthio C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxycarbonyl radical C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxycarbonyl radical C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylthio carbonyl group C 1 -C 6 Alkyl, halo C 1 -C 6 Alkylthio carbonyl group C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylcarbonyloxy, halo C 1 -C 6 Alkylcarbonyloxy, C 1 -C 6 Alkoxycarbonyloxy, halo C 1 -C 6 Alkoxycarbonyloxy, C 1 -C 6 Alkylsulfonyloxy, halo C 1 -C 6 Alkylsulfonyloxy, C 1 -C 6 Alkoxy radical C 1 -C 6 Alkoxy or halo C 1 -C 6 Alkoxy radical C 1 -C 6 An alkoxy group;
R 3 and R 4 Can be the same or different and are respectively selected from H, halogen, hydroxyl, amino, nitro, cyano and C 1 -C 6 Alkyl, halo C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 6 Alkylthio, halo C 1 -C 6 Alkylthio radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 2 -C 6 Alkenyloxy, halogeno C 2 -C 6 Alkenyloxy radical, C 2 -C 6 Alkynyloxy, halo C 2 -C 6 Alkynyloxy, C 1 -C 6 Alkylsulfonyl, halo C 1 -C 6 Alkylsulfonyl radical, C 1 -C 6 Alkylcarbonyl, halo C 1 -C 6 Alkylcarbonyl group, C 1 -C 6 Alkoxycarbonyl, halo C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Alkoxy radical C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxy radical C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylthio group C 1 -C 6 Alkyl, halo C 1 -C 6 Alkylthio C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxycarbonyl radical C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxycarbonyl radical C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylthio carbonyl group C 1 -C 6 Alkyl, halo C 1 -C 6 Alkylthio carbonyl group C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylcarbonyloxy, halo C 1 -C 6 Alkylcarbonyloxy, C 1 -C 6 Alkoxycarbonyloxy, halo C 1 -C 6 Alkoxycarbonyloxy, C 1 -C 6 Alkylsulfonyloxy, halo C 1 -C 6 Alkylsulfonyloxy, C 1 -C 6 Alkoxy radical C 1 -C 6 Alkoxy or halo C 1 -C 6 Alkoxy radical C 1 -C 6 An alkoxy group;
or, R 3 And R 4 Or can be combined with connected pyrimidine rings to form C, N, O or S-containing five-membered, six-membered, seven-membered or eight-membered heteroaromatic rings or heterocyclic alkanes;
R 5 selected from unsubstituted or substituted by 1-5R 8 A substituted C, N, O or S-containing five-membered, six-membered aromatic, heteroaromatic, benzoheteroaromatic or benzoheterocycloalkane;
R 6 、R 7 same or different and are respectively selected from hydrogen, hydroxyl, amino and C 1 -C 6 Alkyl, halo C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylamino, halogeno C 1 -C 6 An alkylamino group;
or, R 6 、R 7 Or N connected with the N can form ternary, quaternary, quinary, hexabasic, heptabasic or octabasic heterocyclic alkane containing C, N, O or S;
R 8 selected from H, halogen, hydroxy, amino, nitro, cyano, C 1 -C 6 Alkyl, halo C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 6 Alkylthio, halogeno C 1 -C 6 Alkylthio radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 2 -C 6 Alkenyloxy, halogeno C 2 -C 6 Alkenyloxy radical, C 2 -C 6 Alkynyloxy, halo C 2 -C 6 Alkynyloxy, C 1 -C 6 Alkylsulfonyl, halo C 1 -C 6 Alkylsulfonyl radical, C 1 -C 6 Alkylcarbonyl, halo C 1 -C 6 Alkyl carbonyl, C 1 -C 6 Alkoxycarbonyl, halo C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Alkoxy radical C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxy radical C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylthio C 1 -C 6 Alkyl, halo C 1 -C 6 Alkylthio C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxycarbonyl radical C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxycarbonyl radical C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylthio carbonyl group C 1 -C 6 Alkyl, halo C 1 -C 6 Alkylthio carbonyl group C 1 -C 6 Alkyl radical, C 1 -C 6 Alkylcarbonyloxy, halo C 1 -C 6 Alkylcarbonyloxy, C 1 -C 6 Alkoxycarbonyloxy, halo C 1 -C 6 Alkoxycarbonyloxy, C 1 -C 6 Alkylsulfonyloxy, halo C 1 -C 6 Alkylsulfonyloxy, C 1 -C 6 Alkoxy radical C 1 -C 6 Alkoxy or halo C 1 -C 6 Alkoxy radical C 1 -C 6 An alkoxy group;
or a salt of a compound of formula I.
Further preferably, in the compound represented by the formula I:
in the formula
X is selected from O or NH;
R 1 selected from H, hydroxy, amino, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 3 -C 4 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 3 Alkylthio, halo C 1 -C 3 Alkylthio radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 2 -C 4 Alkenyloxy, halogeno C 2 -C 4 Alkenyloxy radical, C 2 -C 4 Alkynyloxy, halo C 2 -C 4 Alkynyloxy, C 1 -C 3 Alkylsulfonyl, halo C 1 -C 3 Alkylsulfonyl radical, C 1 -C 3 Alkylcarbonyl, halo C 1 -C 3 Alkyl carbonyl, C 1 -C 3 Alkoxycarbonyl, halo C 1 -C 3 Alkoxycarbonyl group, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio group C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylcarbonyloxy, halo C 1 -C 3 Alkylcarbonyloxy, C 1 -C 3 Alkoxycarbonyloxy, halo C 1 -C 3 Alkoxycarbonyloxy, C 1 -C 3 Alkylsulfonyloxy, halo C 1 -C 3 Alkylsulfonyloxy, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkoxy or halo C 1 -C 3 Alkoxy radical C 1 -C 3 An alkoxy group;
R 2 selected from 1-4H, halogen, hydroxy, amino, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 3 -C 4 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 3 Alkylthio, halo C 1 -C 3 Alkylthio radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 2 -C 4 Alkenyloxy, halogeno C 2 -C 4 Alkenyloxy radical, C 2 -C 4 Alkynyloxy, halo C 2 -C 4 Alkynyloxy, C 1 -C 3 Alkylsulfonyl, halo C 1 -C 3 Alkylsulfonyl radical, C 1 -C 3 Alkylcarbonyl, halo C 1 -C 3 Alkylcarbonyl group, C 1 -C 3 Alkoxycarbonyl, halogeno C 1 -C 3 Alkoxycarbonyl group, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio group C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylcarbonyloxy, halo C 1 -C 3 Alkylcarbonyloxy, C 1 -C 3 Alkoxycarbonyloxy, halo C 1 -C 3 Alkoxycarbonyloxy, C 1 -C 3 Alkylsulfonyloxy, halo C 1 -C 3 Alkylsulfonyloxy, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkoxy or halo C 1 -C 3 Alkoxy radical C 1 -C 3 An alkoxy group;
R 3 and R 4 Identical or different from H, halogen, hydroxyl, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 3 -C 4 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 3 Alkylthio, halo C 1 -C 3 Alkylthio radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 2 -C 4 Alkenyloxy, halogeno C 2 -C 4 Alkenyloxy radical, C 2 -C 4 Alkynyloxy, halo C 2 -C 4 Alkynyloxy, C 1 -C 3 Alkylsulfonyl, halo C 1 -C 3 Alkylsulfonyl radical, C 1 -C 3 Alkylcarbonyl, halo C 1 -C 3 Alkylcarbonyl group, C 1 -C 3 Alkoxycarbonyl, halogeno C 1 -C 3 Alkoxycarbonyl group, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio group C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylcarbonyloxy, halo C 1 -C 3 Alkylcarbonyloxy, C 1 -C 3 Alkoxycarbonyloxy, halo C 1 -C 3 Alkoxycarbonyloxy, C 1 -C 3 Alkylsulfonyloxy, halo C 1 -C 3 Alkylsulfonyloxy, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkoxy or halo C 1 -C 3 Alkoxy radical C 1 -C 3 An alkoxy group;
or, R 3 And R 4 Or can be combined with connected pyrimidine rings to form C, N, O or S-containing five-membered, six-membered, seven-membered or eight-membered heteroaromatic rings or heterocyclic alkanes;
R 5 selected from unsubstituted or substituted by 1-5R 8 Substituted C, N, O or S-containing five-membered, six-membered aromatic, heteroaromatic, benzoheteroaromatic or benzoheterocycloalkane;
R 6 、R 7 the same or different are respectively selected from hydrogen, hydroxyl and amino、C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy or halo C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylamino, halogeno C 1 -C 3 An alkylamino group;
or, R 6 、R 7 Or can be connected with N to form ternary, quaternary, quinary, hexahydric, heptatomic or octatomic heterocyclic alkane containing C, N, O or S;
R 8 selected from H, halogen, hydroxy, amino, nitro, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 3 -C 3 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 3 Alkylthio, halo C 1 -C 3 Alkylthio radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 2 -C 4 Alkenyloxy, halogeno C 2 -C 4 Alkenyloxy radical, C 2 -C 4 Alkynyloxy, halo C 2 -C 4 Alkynyloxy, C 1 -C 3 Alkylsulfonyl, halo C 1 -C 3 Alkylsulfonyl radical, C 1 -C 3 Alkylcarbonyl, halo C 1 -C 3 Alkylcarbonyl group, C 1 -C 3 Alkoxycarbonyl, halo C 1 -C 3 Alkoxycarbonyl group, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio group C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio group C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylcarbonyloxy, halo C 1 -C 3 Alkylcarbonyloxy, C 1 -C 3 Alkoxycarbonyloxy, halo C 1 -C 3 Alkoxycarbonyloxy, C 1 -C 3 Alkylsulfonyloxy, halo C 1 -C 3 Alkylsulfonyloxy, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkoxy or halo C 1 -C 3 Alkoxy radical C 1 -C 3 An alkoxy group;
or a salt of a compound of formula I.
Still more preferably, in the compound represented by formula I:
in the formula (I), the compound is shown in the specification,
x is selected from O or NH;
R 1 selected from hydroxy, amino, C 1 -C 3 Alkoxy, NR 6 R 7 ；
R 2 Selected from H, halogen, C 1 -C 3 Alkyl radical, C 1 -C 3 An alkoxy group;
R 3 and R 4 Same or different and are respectively selected from H, halogen, hydroxyl, amino, cyano and C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 3 -C 4 Cycloalkyl, NR 6 R 7 ；
Or, R 3 And R 4 Or can be combined with connected pyrimidine rings to form five-membered or six-membered heteroaromatic rings or heterocyclic alkanes containing C, N, O or S;
R 5 selected from unsubstituted or substituted by 1-5R 8 Substituted C, N, O or S-containing five-membered, six-membered aromatic, heteroaromatic, benzoheteroaromatic or benzoheterocycloalkane;
R 6 、R 7 the same or different are respectively selected from hydrogen, hydroxyl, amino and C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 1 -C 3 An alkylamino group;
or, R 6 、R 7 N linked thereto may also be C-, N-, O-or S-containingA ternary, quaternary, pentanary or hexanary heterocyclic alkane;
R 8 selected from H, halogen, hydroxy, amino, nitro, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 3 -C 3 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 3 Alkylthio, halogeno C 1 -C 3 Alkylthio radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 2 -C 4 Alkenyloxy, halogeno C 2 -C 4 Alkenyloxy radical, C 2 -C 4 Alkynyloxy, halo C 2 -C 4 Alkynyloxy, C 1 -C 3 Alkylsulfonyl, halo C 1 -C 3 Alkylsulfonyl radical, C 1 -C 3 Alkylcarbonyl, halo C 1 -C 3 Alkyl carbonyl, C 1 -C 3 Alkoxycarbonyl, halo C 1 -C 3 Alkoxycarbonyl group, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio group C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl, halo C 1 -C 3 Alkoxycarbonyl radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl, halo C 1 -C 3 Alkylthio carbonyl group C 1 -C 3 Alkyl radical, C 1 -C 3 Alkylcarbonyloxy, halo C 1 -C 3 Alkylcarbonyloxy, C 1 -C 3 Alkoxycarbonyloxy, halo C 1 -C 3 Alkoxycarbonyloxy, C 1 -C 3 Alkylsulfonyloxy, halo C 1 -C 3 Alkylsulfonyloxy, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkoxy or haloC 1 -C 3 Alkoxy radical C 1 -C 3 An alkoxy group;
or a salt of a compound of formula I.
Still further preferred are compounds of formula I wherein:
in the formula
X is selected from O or NH;
R 1 selected from hydroxy, amino, methoxy, ethoxy or NR 6 R 7 ；
R 2 Selected from H, chloro, bromo, methyl or methoxy;
R 3 and R 4 Identical or different from H, halogen, methyl, trifluoromethyl, NR 6 R 7 ；
Or, R 3 And R 4 Or can be combined with connected pyrimidine rings to form five-membered or six-membered heteroaromatic rings or heterocyclic alkanes containing C, N, O or S;
R 5 selected from unsubstituted or substituted by 1-5R 8 Substituted phenyl, pyridyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl;
R 6 、R 7 the same or different is selected from hydrogen, hydroxyl, amino, methyl, ethyl and methoxy;
or, R 6 、R 7 Or N connected with the N can form ternary, quaternary, pentabasic or hexabasic heterocyclic alkane containing C, N, O or S;
R 8 selected from H, halogen, hydroxy, amino, nitro, cyano, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 3 -C 3 Cycloalkyl, NR 6 R 7 、C(＝O)NR 6 R 7 、C 1 -C 3 Alkylthio radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, C 1 -C 3 Alkylsulfonyl radical, C 1 -C 3 Alkylcarbonyl group, C 1 -C 3 Alkoxycarbonyl group, C 1 -C 3 Alkoxy radical C 1 -C 3 Alkyl radical, C 1 -C 3 Alkyl radicalCarbonyloxy radical, C 1 -C 3 Alkoxycarbonyloxy, C 1 -C 3 Alkoxy radical C 1 -C 3 An alkoxy group;
or a salt of a compound of formula I.
Still further preferably, in said compound of formula I:
in the formula
X is selected from O or NH;
R 1 selected from methoxy or NR 6 R 7 ；
R 2 Selected from H, chloro or methyl;
R 3 and R 4 Identical or different are selected from H, halogen, methyl or trifluoromethyl;
R 5 selected from unsubstituted or substituted by 1-5R 8 Substituted phenyl or pyridyl;
R 6 、R 7 the same or different are respectively selected from hydrogen, methyl and ethyl;
or, R 6 、R 7 N connected with the N can also form substituted piperidyl, substituted morpholinyl or substituted piperazinyl;
R 8 selected from H, halogen, hydroxy, amino, nitro, cyano, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, NR 6 R 7 ；
Or a salt of a compound of formula I.
Most preferably, in the compound of formula I:
in the formula
X is selected from NH;
R 1 selected from methoxy, methylamino, dimethylamino;
R 2 is selected from H;
R 3 selected from chlorine;
R 4 is selected from H;
R 5 selected from unsubstituted or substituted by 1-5R 8 Substituted phenyl, pyridyl;
R 8 selected from H, fluorine, chlorine, bromine, nitro, cyano, methyl, methoxyPiperidine, morpholine, piperazine, methylpiperazine;
or a salt of a compound of formula I.
The thiobenzoyl derivative shown in the formula I and corresponding acid form salt, which can be hydrochloride, sulfate, hydrobromide, mesylate, citrate, oxalate, succinate, maleate, citrate, acetate, lactate, phosphate, hydroiodide, nitrate, tartrate, p-toluenesulfonate and the like.
In the definitions given above for compounds of the general formula I, the terms used are generally defined as follows:
halogen: refers to fluorine, chlorine, bromine or iodine.
Alkyl groups: straight-chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.
Cycloalkyl: a substituted or unsubstituted heteroatom-containing cyclic alkyl group, such as cyclopropyl, cyclopentyl or cyclohexyl. Substituents such as methyl, halogen, and the like.
Heterocycloalkyl group: substituted or unsubstituted cyclic alkyl groups containing 1 or more heteroatoms N, O, S, e.g. tetrahydrofuranyl, cyclopentylpiperidinyl. Substituents such as methyl, halogen, and the like.
Halogenated alkyl groups: straight-chain or branched alkyl groups in which the hydrogen atoms may be partially or completely substituted with halogen atoms, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and the like.
Alkoxy group: straight or branched chain alkyl groups attached to the structure via oxygen atom linkages.
Haloalkoxy groups: straight-chain or branched alkoxy groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms. For example, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, trifluoroethoxy and the like.
An alkoxyalkyl group: the alkoxy group is attached to the structure via an alkyl group. Such as-CH 2 OCH 3 ，-CH 2 OCH 2 CH 3 。
HaloalkoxyAlkyl radical: the hydrogen atoms on the alkyl group of the alkoxyalkyl group may be partially or fully substituted by halogen atoms. Such as-CH 2 OCH 2 CH 2 Cl。
Alkylthio groups: straight or branched chain alkyl groups attached to the structure via a sulfur atom.
Halogenated alkylthio groups: straight-chain or branched alkylthio groups in which the hydrogen atoms may be partially or wholly replaced by halogen atoms. For example, chloromethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio and the like.
Alkenyl: straight-chain or branched alkenes, for example ethenyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl and hexenyl isomers. Alkenyl also includes polyenes such as 1, 2-allenyl and 2, 4-hexadienyl.
Alkynyl: straight-chain or branched alkynes, for example ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. Alkynyl also includes groups consisting of multiple triple bonds, such as2, 5-hexadiynyl.
Alkenyloxy: linear or branched alkenes attached to a structure via an oxygen atom bond.
Haloalkenyloxy: straight-chain or branched alkenyloxy groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms.
Alkynyloxy: straight or branched alkynes, linked to the structure via oxygen atom bonds.
Halogenated alkynyloxy: straight-chain or branched alkynyloxy, in which the hydrogen atoms may be partially or completely replaced by halogen atoms.
An alkylcarbonyl group: the linear or branched alkyl group is linked to the structure via a carbonyl group (-CO-), such as acetyl.
Halogenated alkylcarbonyl group: straight-chain or branched alkylcarbonyl whose alkyl hydrogen atoms may be partially or fully substituted with halogen atoms, such as trifluoroacetyl.
An alkoxycarbonyl group: the alkoxy group is attached to the structure via a carbonyl group. Such as-COOCH 3 ，-COOCH 2 CH 3 。
Halogenated alkoxyCarbonyl: the hydrogen atoms of the alkyl group of the alkoxycarbonyl group may be partially or wholly replaced by halogen atoms, e.g. -COOCH 2 CF 3 ，-COOCH 2 CH 2 Cl, and the like.
An alkylsulfonyl group: straight or branched chain alkyl via sulfonyl (-SO) 2 -) is attached to a structure, such as a methylsulfonyl group.
Haloalkylsulfonyl group: straight-chain or branched alkylsulfonyl wherein the hydrogen atoms of the alkyl group may be partially or wholly substituted by halogen atoms.
Alkylsulfonyloxy group: alkyl-SO 2 -O-。
Haloalkylsulfonyloxy: the hydrogen atoms of the alkyl group of the alkylsulfonyloxy group may be partially or wholly substituted by halogen atoms, e.g. CF 3 -SO 2 -O。
Alkoxycarbonylalkyl groups: alkoxycarbonyl-alkyl-, e.g. CH 3 OCOCH 2 -。
Haloalkoxycarbonylalkyl: the hydrogen atoms of the alkyl group of the alkoxycarbonylalkyl group may be partially or completely substituted by halogen atoms, e.g. CF 3 CH 2 OCOCH 2 -。
Alkylcarbonyloxy group: such as CH 3 COO-, etc.
Haloalkylcarbonyloxy: the hydrogen atoms of the alkylcarbonyloxy group may be partially or fully substituted by halogen atoms, e.g. CF 3 COO-, etc.
Alkoxycarbonyloxy: alkoxycarbonyl-oxy-, e.g. CH 3 OCOO-。
Haloalkoxycarbonyl group: the hydrogen atoms of the alkyl group of the alkoxycarbonyloxy group may be partially or fully substituted by halogen atoms, e.g. CF 3 OCOO-。
Alkylthio-carbonylalkyl: alkylthiocarbonyl-alkyl-, e.g. CH 3 SCOCH 2 -。
Haloalkylthiocarbonylalkyl: the hydrogen atoms of the alkyl group of the alkylthiocarbonylalkyl group may be partially or wholly replaced by halogen atoms, e.g. CF 3 CH 2 SCOCH 2 -。
Alkoxyalkoxy group: such as CH 3 OCH 2 O-, etc.
Haloalkoxyalkyl: the hydrogen atoms of the alkoxy groups being partially or wholly replaced by halogen atoms, e.g. CF 3 OCH 2 O-。
Alkylthioalkyl: alkyl-S-alkyl-, e.g. CH 3 SCH 2 -。
Haloalkylthioalkyl: the hydrogen atoms of the alkyl group of an alkylthioalkyl group may be partially or fully substituted by halogen atoms, e.g. ClCH 2 CH 2 SCH 2 -、CF 3 CH 2 SCH 2 -and the like.
Aryl groups and the aryl moiety in arylalkyl, aryloxy, arylalkoxy, arylamino, and the like include phenyl, naphthyl, and the like.
Heteroaryl is a five or six membered ring containing 1 or more heteroatoms N, O, S. Such as furyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, and the like.
Heteroaryl as well as the heteroaryl moiety in heteroarylalkyl, heteroaryloxy, heteroarylalkoxy and the like refer to five or six membered rings containing 1 or more heteroatoms N, O, S. Such as furyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, benzoxazolyl, indolyl, and the like.
The use of said thiobenzoyl derivatives for the treatment of cancer diseases.
The thiobenzoyl derivative is used as an active component in the preparation of medicines for treating cancer diseases.
The weight percentage of the active component is 0.1-99%.
The cancer is preferably (but not limited to) colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer or gastric cancer.
The compound shown in the formula I and the salt thereof can be used as an active ingredient of a cancer treatment drug, can be used independently, and can also be used together with other cancer treatment drugs. The combination therapy of the present invention includes the use of at least one compound of the present invention and its salts and active derivatives in combination with one or more other cancer therapeutic agents to increase the overall efficacy. The dosage and administration time of the combination should be determined according to the most reasonable therapeutic effect obtained under different conditions.
Some substituents of the compounds of formula I of the present invention are shown in tables 1-5, and some of the compounds of formula I of the present invention are illustrated by specific compounds listed in Table 6, but are not intended to limit the present invention.
Figure BDA0002296044860000111
R 1 The substituents are shown in Table 1 below, but do not limit the present invention.
Table 1:
Figure BDA0002296044860000112
R 2 the substituents are shown in Table 2 below, but do not limit the present invention.
Table 2:
Figure BDA0002296044860000113
Figure BDA0002296044860000121
R 3 R 4 the substituents may be the same or different, or may be linked to form a ring, as shown in Table 3 below, but are not intended to limit the present invention.
Table 3:
Figure BDA0002296044860000122
R 5 selected from unsubstituted or substitutedBy 1-5R 8 A substituted C, N, O or S-containing five-membered, six-membered aromatic, heteroaromatic, benzoheteroaromatic or benzoheterocycloalkane;
the aromatic ring, heteroaromatic ring, benzoheteroaromatic ring or benzoheterocycloalkane is shown in the following table 4, but does not limit the present invention.
TABLE 4
Figure BDA0002296044860000123
Figure BDA0002296044860000131
R 8 The substituents are shown in Table 5 below, but do not limit the present invention.
TABLE 5
Figure BDA0002296044860000132
Figure BDA0002296044860000141
Figure BDA0002296044860000151
The compounds are illustrated by the specific compounds listed in table 6, but do not limit the invention.
Figure BDA0002296044860000152
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is Cl, R 4 When is H, R 5 As shown in Table 6 below, numbered 6-1- - -6-311:
TABLE 6
Figure BDA0002296044860000153
Figure BDA0002296044860000161
Figure BDA0002296044860000171
Figure BDA0002296044860000181
Figure BDA0002296044860000191
Figure BDA0002296044860000201
Figure BDA0002296044860000211
Figure BDA0002296044860000221
The compounds are illustrated by the specific compounds listed below, but do not limit the invention.
Figure BDA0002296044860000231
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is Cl, R 4 When is H, R 5 As shown in Table 6, numbered from 7-1 to 7-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is Cl, R 4 When is H, R 5 As shown in Table 6, numbered 8-1- - -8-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is CF 3 ，R 4 When is H, R 5 As shown in Table 6, numbered 9-1- - -9-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is CF 3 ，R 4 When is H, R 5 As shown in Table 6, numbered from 10-1 to 10-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is CF 3 ，R 4 When is H, R 5 As shown in Table 6, numbered 11-1- -11-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is F, R 4 When is H, R 5 As shown in Table 6, numbered 12-1- -12-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is F, R 4 When is H, R 5 As shown in Table 6, numbered 13-1- -13-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is F, R 4 When is H, R 5 As shown in Table 6, numbered 14-1- -14-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is CH 3 ，R 4 When is H, R 5 As shown in Table 6, numbered 15-1 to 15-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is CH 3 ，R 4 When is H, R 5 As shown in Table 6, numbered 16-1 to 16-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is CH 3 ，R 4 When is H, R 5 As shown in Table 6, numbered 17-1- -17-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is H, R 4 When is H, R 5 As shown in Table 6, numbered 18-1- -18-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 When is H, R 5 As shown in Table 6, numbered 19-1 to 19-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 When is H, R 5 As shown in Table 6, numbered 20-1- -20-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is Cl, R 4 When Cl is present, R 5 As shown in Table 6, numbered 21-1 to 21-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is Cl, R 4 When it is Cl, R 5 As shown in Table 6, numbered 22-1-22-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is Cl, R 4 When Cl is present, R 5 As shown in Table 6, numbered 23-1 to 23-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is F, R 4 When is F, R 5 As shown in Table 6, numbered 24-1-24-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is F, R 4 When is F, R 5 As shown in Table 6, numbered 25-1- -25-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is F, R 4 When is F, R 5 As shown in Table 6, numbered 26-1-26-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is CH 3 ，R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 27-1- -27-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is CH 3 ，R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 28-1-28-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is CH 3 ，R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 29-1- -29-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is H, R 4 When Cl is present, R 5 As shown in Table 6, numbered as 30-1-30-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 When Cl is present, R 5 As shown in Table 6, numbered 31-1 to 31-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 When Cl is present, R 5 See Table 6, numbered 32-1- -32-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is H, R 4 Is CF 3 When R is 5 As shown in Table 6, numbered 33-1- -33-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 Is CF 3 When R is 5 As shown in Table 6, numbered 34-1- -34-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 Is CF 3 When R is 5 See Table 6, numbered 35- -35-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is H, R 4 When is F, R 5 As shown in Table 6, numbered 36-1- -36-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 When is F, R 5 See Table 6, numbered 37-1- -37-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 When is F, R 5 As shown in Table 6, numbered 38-1- -38-311.
R 1 Is N (CH) 3 ) 2 ，X＝NH，R 2 Is H, R 3 Is H, R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 39-1- -39-311.
R 1 Is NHCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 40-1- -40-311.
R 1 Is OCH 3 ，X＝NH，R 2 Is H, R 3 Is H, R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 41-1- -41-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is Cl, R 4 When is H, R 5 As shown in Table 6, numbered 42-1- -42-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is Cl, R 4 When is H, R 5 As shown in Table 6, numbered 43-1- -43-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is Cl, R 4 When is H, R 5 As shown in Table 6, numbered 44-1-44-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is CF 3 ，R 4 When is H, R 5 See Table 6, numbered 45-1 to 45-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is CF 3 ，R 4 When is H, R 5 As shown in Table 6, numbered 46-1- -46-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is CF 3 ，R 4 When is H, R 5 As shown in Table 6, numbered as 47-1 to 47-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is F, R 4 When is H, R 5 As shown in Table 6, numbered as 48-1 to 48-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is F, R 4 When is H, R 5 See Table 6, numbered 49-1 to 49-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is F, R 4 When is H, R 5 As shown in Table 6, numbered 50-1- -50-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is CH 3 ，R 4 When is H, R 5 As shown in Table 6, numbered 51-1- -51-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is CH 3 ，R 4 When is H, R 5 As shown in Table 6, numbered 52-1 to 52-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is CH 3 ，R 4 When is H, R 5 As shown in Table 6, numbered 53-1 to 53-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is H, R 4 When is H, R 5 As shown in Table 6, numbered 54-1- -54-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 When is H, R 5 See Table 6, numbered 55-1-55-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 When is H, R 5 See Table 6, numbered 56-1- -56-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is Cl, R 4 When Cl is present, R 5 As shown in Table 6, numbered 57-1-57-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is Cl, R 4 When Cl is present, R 5 See Table 6, numbered 58-1- -58-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is Cl, R 4 When it is Cl, R 5 As shown in Table 6, numbered 59-1-59-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is F, R 4 When is F, R 5 As shown in Table 6, numbered 60-1 to 60-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is F, R 4 When is F, R 5 As shown in Table 6, numbered as 61-1-61-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is F, R 4 When is F, R 5 See Table 6, numbered 62-1- -62-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is CH 3 ，R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 63-1- -63-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is CH 3 ，R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 64-1- -64-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is CH 3 ，R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 65-1 to 65-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is H, R 4 When Cl is present, R 5 See Table 6, numbered 66-1- -66-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 When Cl is present, R 5 See Table 6, numbered 67-1- -67-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 When Cl is present, R 5 As shown in Table 6, numbered 68-1- -68-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is H, R 4 Is CF 3 When R is 5 See Table 6, numbered 69-1- -69-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 Is CF 3 When R is 5 As shown in Table 6, numbered from 70-1 to 70-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 Is CF 3 When R is 5 As shown in Table 6, numbered as 71-1 to 71-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is H, R 4 When is F, R 5 See Table 6, numbered 72-1- -72-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 When is F, R 5 As shown in Table 6, numbered 73-1 to 73-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 When is F, R 5 As shown in Table 6, numbered 74-1 to 74-311.
R 1 Is N (CH) 3 ) 2 ，X＝O，R 2 Is H, R 3 Is H, R 4 Is CH 3 When R is 5 As shown in Table 6, numbered 75-1 to 75-311.
R 1 Is NHCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 Is CH 3 When R is 5 See Table 6, numbered 76-1- -76-311.
R 1 Is OCH 3 ，X＝O，R 2 Is H, R 3 Is H, R 4 Is CH 3 When R is 5 See Table 6, numbered 77-1 to 77-311.
The derivatives of the general formula I of the invention can be prepared according to the following route:
Figure BDA0002296044860000261
in the above scheme, intermediate 1 is prepared according to reference J.Heterocyclic chem.,43,1281 (2006), intermediate 3 is generated by reaction of commercially available intermediate 2 and intermediate 1 under alkaline conditions, intermediate 3 is reacted with R 5 -NH 2 And (3) reacting the amine compound to generate the compound shown in the general formula I.
In the above reaction scheme, the step one reaction is carried out in a suitable solvent, which may be selected from, for example, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, toluene, xylene, benzene, N-dimethylformamide, dimethylsulfoxide, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, or tert-butanol.
In the first step reaction scheme, the reaction is carried out in the presence of a suitable base, which may be selected from sodium tert-butoxide, potassium tert-butoxide, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide or sodium ethoxide.
In the above step one reaction scheme, the reaction temperature may be between room temperature and the boiling point temperature of the solvent, and is usually 20 to 150 ℃.
In the scheme 1 reaction formula above, the reaction time is 1 hour to 12 hours, usually 1 to 6 hours.
In the above step two reaction scheme, the reaction is carried out in a suitable solvent, which may be selected from, for example, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, toluene, xylene, benzene, N-dimethylformamide, dimethylsulfoxide, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, and the like.
In the above reaction formula of step two, the reaction can be carried out in the presence of a suitable base, which can be selected from sodium tert-butoxide, potassium tert-butoxide, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide or sodium ethoxide.
In the above step two reaction scheme, the reaction can also be carried out in the presence of a suitable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid.
In the above step two reaction scheme, the reaction temperature may be between room temperature and the boiling point temperature of the solvent, and is usually 20 to 120 ℃.
In the above step two reaction formula, the reaction time is 1 hour to 80 hours, usually 12 to 72 hours.
The invention has the advantages that:
the compound of the general formula I has a novel structure, has excellent cancer cell activity inhibition, is superior to a control compound in partial cancer cell tests, and is expected to play a role in the field of cancer treatment.
Detailed Description
The following description of the embodiments is provided to assist in a comprehensive understanding of the invention as defined by the claims and their equivalents, and not as a limitation of the invention.
Example 1: synthesis of Compounds 6-121
Figure BDA0002296044860000281
In a 100mL flask, 3.3g of 2-aminothiobenzoylmethylamine (J.heterocyclic chem.,43,1281 (2006)), 3.3g of 2,4,5 trichloropyrimidine, 2.2g of sodium carbonate and DMF50mL are added, stirred and heated at 80 ℃ for 4 hours, after TLC detection reaction is finished, 150mL of water and 50mL of ethyl acetate multiplied by 3 are added for extraction, organic phases are combined, anhydrous sodium sulfate is dried, and column chromatography (eluent is ethyl acetate and petroleum ether (boiling range is 60-90 ℃) with the volume ratio of 1 is carried out, so that 0.53g of compound 6-121,2- ((2, 5-dichloropyrimidin-4-yl) amino) -N-methylthiobenzamide and yellow solid are obtained through purification.
Example 2: synthesis of Compounds 7-120
Figure BDA0002296044860000282
In a 100mL flask were added 0.53g of 2- ((2, 5-dichloropyrimidin-4-yl) amino) -N-methylthiobenzamide, 0.3g of 4-morpholinoaniline, 0.3g of p-toluenesulfonic acid monohydrate, and 30mL of N-butanol, and the mixture was stirred and heated at 100 ℃ for 4 hours, and after the completion of TLC detection reaction, 150mL of water was added, 50mL of ethyl acetate × 3 was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (eluent was ethyl acetate and petroleum ether (boiling range 60-90 ℃ C.), volume ratio was 2) to obtain 0.11g of compound 7-120, gray solid.
The characterization data of some compounds prepared according to the above preparation method are as follows:
compounds 7-120:
1 H NMR(600MHz,DMSO- d6 )δ10.61(d,J＝4.0Hz,1H),9.62(s,1H),9.16(s,1H),8.22(d,J＝7.4Hz,1H),8.13(s,1H),7.48-7.44(m,3H),7.30(d,J＝7.5Hz,1H),7.19(t,J＝7.5Hz,1H),6.83(d,J＝8.6Hz,2H),3.74(t,J＝4.8Hz,4H),3.12(d,J＝4.4Hz,3H),3.02(t,J＝4.8Hz,4H).
meanwhile, other compounds represented by the general formula I of the present invention can be obtained by substituting the corresponding raw materials according to the contents described in the above synthetic examples.
In addition, the compound obtained above is reacted with an acid in a conventional manner to obtain the corresponding salt.
Application example
Example 3: the following assay for in vitro inhibition of cancer cells (MTT assay)
The human cancer tumor cell line used: human ovarian adenocarcinoma cell SK-OV-3, human cervical carcinoma cell Hela, human non-small cell lung cancer cell A549 and human metaplastic large cell KARPAS299.
The inhibition rate of 5 concentrations of test samples on the growth of each human cancer cell is determined by a conventional MTT method by adopting an in vitro cell culture technology.
The cells were removed from the incubator, washed twice with PBS solution, digested with 0.25% trypsin solution, added with medium to stop digestion, centrifuged, pipetted to form a cell suspension, and counted under an inverted microscope. Preparing cell into cell suspension with concentration of 5x104/mL, adding 100 μ L of cell into 96-well plate per well, placing in 5% carbon dioxide, and culturing at 37 deg.C in humidified airAnd (2) culturing overnight, adding the drug to be detected diluted into different concentration gradients, allowing the drug to act for 48 hours, adding MTT, reacting for 4 hours, reducing MTT tetrazolium (tetrazole) components by living cells to generate formazan, adding DMSO to dissolve the formazan, and finally measuring the absorbance value of 490nm and 630nm on a 96-well plate reader. IC was calculated using GraphPad Prism6 software using non-linear regression 50 The value is obtained.
Cell inhibition = (1-absorbance for experimental group/absorbance for control group) × 100%
Some of the test results are as follows:
cytotoxic Activity of the Compounds of Table 7 against human cancer cells
Figure BDA0002296044860000291
From the above data, it can be seen that the series of compounds have excellent cancer cell inhibitory activity, which is comparable to that of the control compound 11 (WO 2018019252) on Hela, a549 and Kappas299 cells, while exhibiting excellent activity on SK-OV-3 cells in which the compound 11 is not active.
It can be used for treating cancer-related diseases alone or in combination with other related antiviral agents, chemotherapeutic agents, immunosuppressive agents, radiation, anti-tumor vaccines, antiviral vaccines, cytokine therapy and/or tyrosine kinase inhibitors and other targeted cancer treatment drugs.
In addition, other compounds shown in the general formula I and salts thereof obtained by the preparation process have corresponding cancer cell inhibitory activity, and can be used for treating diseases related to cancers alone or in combination with other related antiviral agents, chemotherapeutic agents, immunosuppressants, radiation, antitumor vaccines, antiviral vaccines, cytokine therapy and/or tyrosine kinase inhibitors and other targeted cancer treatment drugs.

Claims (4)

1. A thiobenzoyl derivative characterized by: the thiobenzoyl derivative is a compound shown in a general formula I and pharmaceutically acceptable salts thereof:
Figure FDA0003856252080000011
x is selected from NH;
R 1 selected from methylamino, dimethylamino;
R 2 is selected from H;
R 3 selected from chlorine;
R 4 is selected from H;
R 5 is selected from 4-morpholinylphenyl;
or a salt of a compound of formula I.
2. Use of the thiobenzoyl derivative of claim 1 for the manufacture of a medicament for the treatment of cancer diseases.
3. Use according to claim 2, characterized in that the thiobenzoyl derivative of claim 1 is used as an active ingredient in the manufacture of a medicament for the treatment of cancer diseases.
4. The use according to claim 3, wherein the active ingredient is present in an amount of 0.1 to 99% by weight.
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WO2004074244A2 (en) * 2003-02-20 2004-09-02 Smithkline Beecham Corporation Pyrimidine compounds
CN1703405A (en) * 2001-11-01 2005-11-30 詹森药业有限公司 Aminobenzamide derivatives as glycogen synthase kinase 3 beta inhibitors
CN105377835A (en) * 2013-07-11 2016-03-02 贝达药业股份有限公司 Protein tyrosine kinase modulators and methods of use
WO2018019252A1 (en) * 2016-07-26 2018-02-01 Jacobio Pharmaceuticals Co., Ltd. Novel fused pyridine derivatives useful as fak/aurora kinase inhibitors

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Publication number Priority date Publication date Assignee Title
CN1703405A (en) * 2001-11-01 2005-11-30 詹森药业有限公司 Aminobenzamide derivatives as glycogen synthase kinase 3 beta inhibitors
WO2004074244A2 (en) * 2003-02-20 2004-09-02 Smithkline Beecham Corporation Pyrimidine compounds
CN105377835A (en) * 2013-07-11 2016-03-02 贝达药业股份有限公司 Protein tyrosine kinase modulators and methods of use
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