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KR-20260067130-A - PYRIDINYL PYRAZOLE DERIVATIVE COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT

KR20260067130AKR 20260067130 AKR20260067130 AKR 20260067130AKR-20260067130-A

Abstract

The present invention provides a novel pyridinyl pyrazole derivative compound having excellent inhibitory activity against MELK. More specifically, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a novel pyridinyl pyrazole derivative compound as an active ingredient.

Inventors

  • 정희정
  • 김광록

Assignees

  • 한국화학연구원

Dates

Publication Date
20260512
Application Date
20241105

Claims (8)

  1. Pyridinyl pyrazole derivative compounds represented by the following chemical formula 1 or pharmaceutically acceptable salts thereof: [Chemical Formula 1] In the above chemical formula 1, A is absent or selected from the group consisting of C 1-2 alkylenyl and C 6-12 arylenyl; R1 is selected from the group consisting of hydrogen, OH, C1-6 alkyloxy, C1-6 alkylcarbonyl, C3-10 cycloalkylcarbonyl, C6-12 aryl, C6-12 arylsulfonyl, C2-10 heterocycloalkyl containing one or two heteroatoms selected from the group consisting of N, O, and S, and C1-12 heteroaryl containing one to four heteroatoms selected from the group consisting of N, O, and S; L is absent, or -C(O)- or -S(O) 2 - and; R2 is hydrogen, a straight-chain or branched C1-6 alkyl, a straight-chain or branched C2-6 alkenyl, C6-12 arylC1-6 alkyl, C3-10 cycloalkyl, C6-12 aryl, a C2-10 heterocycloalkyl containing one or two heteroatoms selected from N, O, and S, and a C1-12 heteroaryl containing one to four heteroatoms selected from N, O , and S; B is O or S and; n is an integer of 1 or 2; Here, the C1-6 alkyl, C3-10 cycloalkyl, C6-12 aryl, C2-10 heterocycloalkyl, and C1-12 heteroaryl are each independently one or more identical or different substituents selected from the group consisting of H, halogen, cyano, straight-chain or branched C1-6 alkyl, straight-chain or branched C2-6 alkenyl, C3-10 cycloalkyl, haloC1-5 alkyl, haloC6-12 aryl, hydroxy, nitro, amino, mono or diC1-6 alkylamino, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C6-12 aryloxy, C6-12 arylsulfonyl , and C1-6 alkylsulfonyl They can be substituted, and the substituents can be connected to each other to form a 5 or 6-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring.
  2. In paragraph 1, A is absent or selected from the group consisting of C 1-2 alkylenyl and C 6-12 arylenyl; R1 is selected from the group consisting of C2-10 heterocycloalkyl containing one or two heteroatoms selected from the group consisting of hydrogen, C6-12 aryl, N, O, and S, and C1-12 heteroaryl containing one to four heteroatoms selected from the group consisting of N, O, and S; L is absent, or -C(O)- or -S(O) 2 - and; R2 is hydrogen, C6-12 aryl C1-6 alkyl, C3-10 cycloalkyl, C6-12 aryl, C2-10 heterocycloalkyl containing one or two heteroatoms selected from N, O, and S, and C1-12 heteroaryl containing one to four heteroatoms selected from N, O , and S; B is O, Pyridinyl pyrazole derivative compounds or pharmaceutically acceptable salts thereof.
  3. A pyridinyl pyrazole derivative compound or a pharmaceutically acceptable salt thereof, wherein A is a C 6-12 arylenyl and said C 6-12 arylenyl is phenylene.
  4. In claim 1 or 2, R1 is a pyridinyl pyrazole derivative compound selected from the group consisting of C2-10 heterocycloalkyl containing one or two heteroatoms selected from the group consisting of N, O and S, and C1-12 heteroaryl containing one to four heteroatoms selected from the group consisting of N, O and S, or a pharmaceutically acceptable salt thereof.
  5. In claim 1 or 2, R2 is a pyridinyl pyrazole derivative compound selected from the group consisting of hydrogen, C6-12 aryl C1-6 alkyl, C6-12 aryl, C2-10 heterocycloalkyl containing one or two heteroatoms selected from N, O and S, and C1-12 heteroaryl containing one to four heteroatoms selected from N, O and S, or a pharmaceutically acceptable salt thereof.
  6. In paragraph 1, A pyridinyl pyrazole derivative compound or a pharmaceutically acceptable salt thereof, characterized in that the pyridinyl pyrazole derivative compound represented by the above chemical formula 1 is selected from the group consisting of the following compounds: 4-(4-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1 H- pyrazole-1-yl)phenyl)morpholine hydrochloride; 3-(piperidine-4-ylmethoxy)-4-(1-(pyridine-2-yl)-1 H- pyrazole-4-yl)pyridine hydrochloride; 1-(6-(4-(3-(piperidin-4-ylmethoxy)pyridin-4-yl)-1 H- pyrazole-1-yl)pyridin-3-yl)ethane-1-one hydrochloride; 3-(piperidine-4-ylmethoxy)-4-(1-(thiophene-2-yl)-1 H- pyrazole-4-yl)pyridine hydrochloride; 3-(4-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1 H- pyrazole-1-yl)phenyl)isoxazole hydrochloride; 3-(piperidine-4-ylmethoxy)-4-(1-(3,4,5-trifluorophenyl)-1 H- pyrazole-4-yl)pyridine hydrochloride; 2-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1 H- pyrazole-1-yl)benzo[d]thiazole-6-ol hydrochloride; 3-(piperidine-4-ylmethoxy)-4-(1-(4-(thiophene-2-yl)phenyl)-1 H -pyrazole-4-yl)pyridine hydrochloride; 4-(1-([1,1'-biphenyl]-4-yl)-1 H -pyrazole-4-yl)-3-(piperidine-4-ylmethoxy)pyridine hydrochloride; 4-(1-(4-(phenylsulfonyl)phenyl)-1 H -pyrazole-4-yl)-3-(piperidine-4-ylmethoxy)pyridine hydrochloride; 4'-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1 H -pyrazole-1-yl)-[1,1'-biphenyl]-4-ol hydrochloride; 2-fluoro-6-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1H-pyrazole-1-yl)pyridine hydrochloride; 2-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1H-pyrazol-1-yl)pyrazine hydrochloride; 2-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1H-pyrazole-1-yl)benzo[d]thiazole hydrochloride; Fluoro-2-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1H-pyrazole-1-yl)benzo[d]thiazole hydrochloride; 4-(methylthio)-6-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1H-pyrazole-1-yl)pyrimidine hydrochloride; 2-(6-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1H-pyrazol-1-yl)pyridine-3-yl)acetonitrile hydrochloride; 6-Bromo-2-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1H-pyrazole-1-yl)benzo[d]thiazole hydrochloride; 6-Bromo-2-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1H-pyrazol-1-yl)quinazolin hydrochloride; 5-chloro-2-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1H-pyrazole-1-yl)pyridine hydrochloride; 2-(4-(3-(piperidine-4-ylmethoxy)pyridine-4-yl)-1 H -pyrazol-1-yl)pyrimidine hydrochloride; 4-(4-(4-(3-((1-(thiophene-2-ylsulfonyl)piperidine-4-yl)methoxy)pyridine-4-yl)-1H-pyrazol-1-yl)phenyl)morpholin; 4-(4-(4-(3-((1-(cyclopropylsulfonyl)piperidine-4-yl)methoxy)pyridine-4-yl)-1H-pyrazole-1-yl)phenyl)morpholin; 4-(4-(4-(3-((1-(phenylsulfonyl)piperidine-4-yl)methoxy)pyridine-4-yl)-1H-pyrazol-1-yl)phenyl)morpholin; 4-(4-(4-(3-((1-((3-fluorobenzyl)sulfonyl)piperidine-4-yl)methoxy)pyridine-4-yl)-1H-pyrazole-1-yl)phenyl)morpholin; and (4-(((4-(1-(6-fluoropyridine-2-yl)-1H-pyrazole-4-yl)pyridine-3-yl)oxy)methyl)piperidine-1-yl)(morpho)methanone.
  7. A pharmaceutical composition for preventing or treating cancer comprising a pyridinyl pyrazole derivative compound according to claim 1 as an active ingredient.
  8. A pharmaceutical composition for preventing or treating cancer, wherein the cancer is glioblastoma, hepatoblastoma, basal cell carcinoma, colorectal cancer, blood cancer, neuroblastoma, kidney cancer, breast cancer, lung cancer, bladder cancer, lymphoma, glioblastoma multiforme, cervical cancer, or sarcoma.

Description

Pyridinyl pyrazol derivative compounds or pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the same as active ingredient The present invention provides a novel pyridinyl pyrazole derivative compound having excellent inhibitory activity against MELK. More specifically, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a novel pyridinyl pyrazole derivative compound as an active ingredient. Maternal Embryonic Leucine zipper Kinase (MELK) was previously identified as a novel member of the snfl/AMPK serine-threonine kinase family involved in the development of mammalian embryos (Heyer BS et al. and Dev Dyn. 1999 Aug, 2 15(4):344-51). This gene is known to play an important role in stem cell regeneration, cell cycle progression, and mRNA precursor splicing. MELK has been known to be overexpressed in some cancer cells, such as lung cancer cells, bladder cancer cells, lymphoma cells, and cervical cancer cells. Northern blot analysis of various human tissues and cancer cell lines demonstrated that MELK is overexpressed at significantly high levels in most breast cancer and breast cancer cell lines, but is not expressed in major normal organs (heart, liver, lungs, and kidneys) (WO2006/016525). Specifically, as can be seen in Figure 1, the inventors confirmed that the amount of MELK protein increases in glioblastoma as the MELK protein is overexpressed, and consequently, migration and invasion increase. This indicates that as MELK expression increases, the growth of cancer cells also increases, and the migration and invasion of cancer cells also increase, which can serve as evidence that MELK contributes to the malignancy of tumors. In addition, by overexpressing DDK-MELK in glioblastoma, the inventors confirmed by immunoprecipitation that MELK binds to nucleostemin (which exists in the nuclei of stem cells and cancer cells and induces G1 cell-cycle arrest), and also confirmed using a pan-phospho antibody that the phosphorylation of nucleostemin is increased by MELK. Consequently, from the above research results, it was predicted that an increase in MELK would lead to a decrease in nucleostamine, which would in turn increase the growth of cancer cells and increase the metastasis of cancer cells. Therefore, it was concluded that by deriving an effective substance that inhibits MELK/nucleostamine phosphorylation, the growth of glioblastoma could be suppressed and apoptosis induced. As a result of designing and researching small molecule compounds that bind to these proteins, the present invention was completed. Figure 1 is a graph showing the results of cell migration and infiltration according to increased MELK expression using the Tet-on system. The definitions listed below are definitions of various terms used to describe the present invention. Unless otherwise limited, these definitions apply throughout this specification, individually or as part of terms including them. The term “halogen” or “halogen” as used in this specification means fluorine, chlorine, bromine or iodine or any one of these unless otherwise noted. The term "alkylenyl" as used herein refers to the divalent form of an alkyl group, used either as itself or as part of another group. In one embodiment, " C1-2 alkylenyl" is a C1-2 alkyl divalent hydrocarbon radical and represents methylenyl with the formula -CH2- and ethylenyl with the formula -CH2 - CH2- . The term "arylenyl" as used in this specification refers to the divalent form of an aryl group, used either as itself or as part of another group. In one embodiment, " C6-12 arylenyl" is a divalent hydrocarbon radical of a C6-12 aryl group, such as phenylenyl with the chemical formula -C6H4- , but is not limited to these. Unless otherwise noted, the term "alkyl" as used in this specification refers to a saturated, straight-chain or branched hydrocarbon radical represented by CnH 2n+1 , specifically a saturated, straight-chain or branched hydrocarbon radical containing between 1 and 6, between 1 and 8, between 1 and 10, or between 1 and 20 carbon atoms, respectively. Additionally, "C 1-6 alkyl" refers to a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms, and specific examples of these radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl radicals. Unless otherwise noted, the term “alkenyl” as used herein refers to a monovalent group derived from an unsaturated, straight-chain or branched hydrocarbon moiety having at least one carbon-carbon double bond, specifically an unsaturated, straight-chain or branched monovalent group comprising between 2 and 6, between 2 and 8, between 2 and 10, or between 2 and 20 carbon atoms, respectively. Examples of these include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, heptenyl, and octenyl radicals. The term “cycloalkyl” as used herein refers to a monovalent