Search

CN-122010851-A - Phenyl ether-linked cyclohexylpyrimidine amine CDK12/13 inhibitor and preparation and application thereof

CN122010851ACN 122010851 ACN122010851 ACN 122010851ACN-122010851-A

Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a phenyl ether connected cyclohexylpyrimidine amine CDK12/13 inhibitor shown in a formula I or an isomer and pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition containing the same. The ether cyclohexylamine linking group of the compound of the formula I increases the affinity with CDK12/13 protein, improves the selectivity to CDK12/13 kinase, reduces the synthesis difficulty, greatly improves the drug property,

Inventors

  • ZHOU WEIYING
  • LI HONGYI
  • GAN ZONGJIE
  • YANG XUE
  • ZHOU YU
  • LIU MINGPU
  • CHEN BO
  • WU YUANLI

Assignees

  • 重庆医科大学

Dates

Publication Date
20260512
Application Date
20260127

Claims (9)

  1. 1. A phenyl ether linked cyclohexylpyrimidine amine compound represented by formula I or a pharmaceutically acceptable salt thereof, Wherein: R 1 is selected from hydrogen, methyl, methoxy, fluoro or chloro; r 2 is selected from chlorine, bromine or trifluoromethyl; R 3 is selected from hydrogen, methyl, methoxy; R 4 is selected from C 1-6 alkyl or C 3-6 cycloalkyl; r 5 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  2. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
  3. 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is bromo.
  4. 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
  5. 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from methyl, ethyl, propyl or cyclopropyl, preferably R 4 is methyl.
  6. 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from methyl, ethyl, propyl or cyclopropyl, preferably R 5 is methyl.
  7. 7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
  8. 8. A pharmaceutical composition comprising a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  9. 9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, in the manufacture of a medicament for the treatment of a CDK 12/13-related disorder.

Description

Phenyl ether-linked cyclohexylpyrimidine amine CDK12/13 inhibitor and preparation and application thereof Technical Field The invention belongs to the field of medicinal chemistry, and in particular relates to a phenyl ether-linked cyclohexylpyrimidine amine CDK12/13 inhibitor or an isomer and pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compounds and application of the compounds or the composition in preparing medicines for treating CDK12/13 mediated diseases. Background Cyclin-dependent kinases (CDKs) are a highly conserved class of serine/threonine protein kinases that play an important role in life processes such as cell cycle, transcriptional regulation and maintenance of cell homeostasis. In many tumors, CDK signaling pathways are abnormally activated and drive directly the unlimited proliferation and survival of tumor cells, and multiple CDK subtypes, including CDK7, 9, 12, 13, have been identified as important oncogenic drivers, with development of small molecule inhibitors targeting CDKs. The ATP binding pocket of CDK family members is highly conserved in three-dimensional structure, a structural feature that results in early development of pan-CDK inhibitors (e.g., flavopiridol, roscovitine, etc.) that show broad-spectrum antitumor activity in preclinical studies, but lower selectivity makes these compounds universally show stronger toxic responses in clinical trials, severely limiting their potential for clinical use. In recent years, the role of transcription related CDKs (such as CDK 12/13) in the development of tumorigenesis has been increasingly focused and has become one of the important directions for the study of antitumor drugs. In many tumor types (e.g., ovarian cancer, prostate cancer, etc.), abnormal expression, loss of function, or mutation of CDK12/13 is closely related to the development and progression of tumorigenesis. Related studies have shown that impaired CDK12 function can lead to down-regulation of gene expression associated with various DNA damage repair pathways, thereby eliciting increased genomic instability and promoting sensitivity of tumor cells to DNA damage. Because of the functional overlap between CDK12 and CDK13, dual-target inhibition strategies are believed to have potential advantages in regulating tumor cell transcriptional homeostasis. Therefore, CDK12 and CDK13 have been considered as anti-tumor therapeutic targets of great research value, and the development of small molecule inhibitors targeting CDK12/13 has great significance for anti-tumor drug development. CDK12/13 specific inhibitors (such as THZ531, SR-4835, etc.) show remarkable inhibition effect on transcription-dependent tumors in preclinical models, and can kill tumor cells by inducing intron retention and transcription collapse, however, existing CDK12/13 inhibitors have problems of off-target effect, poor in vivo pharmacokinetics, narrow therapeutic window, etc., and no CDK12/13 selective inhibitors are marketed in batches. Therefore, the development of novel CDK12/13 inhibitors is expected to provide a brand new scheme for clinical accurate treatment of tumor patients. Disclosure of Invention It is an object of the present invention to provide a phenyl ether linked cyclohexylpyrimidine amine CDK12/13 inhibitor, a pharmaceutically acceptable salt, of the general formula I. The ether cyclohexylamine linking group of the compound shown in the general formula I increases affinity with CDK12/13 protein, improves selectivity to CDK12/13 kinase, and simultaneously remarkably improves water solubility, reduces synthesis difficulty and greatly improves drug property. It is a further object of the present invention to provide a process for the preparation of the compounds of formula I of the present invention or a pharmaceutically acceptable salt thereof. It is a further object of the present invention to provide compositions comprising a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, as well as compositions comprising a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof and another drug or drugs. It is a further object of the present invention to provide the use of a compound of formula I of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of CDK12/13 related disorders. In order to achieve the above object, the present invention provides the following technical solutions: in a first aspect, the invention provides a CDK12/13 inhibitor represented by formula I: Wherein: r 1 is selected from hydrogen, methyl, methoxy, fluoro or chloro; R 2 is selected from chlorine, bromine, trifluoromethyl; R 3 is selected from hydrogen, methyl, methoxy; R 4 is selected from alkyl or cycloalkyl; R 5 is selected from alkyl or cycloalky