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EP-4741391-A1 - NMT INHIBITOR, AND PREPARATION METHOD THEREFOR AND USE THEREOF

EP4741391A1EP 4741391 A1EP4741391 A1EP 4741391A1EP-4741391-A1

Abstract

Provided in the present invention are an NMT inhibitor, and a preparation method therefor and the use thereof. Specifically, the present invention relates to a compound as represented by formula (1) and a preparation method therefor, and a pharmaceutical composition containing the compound as represented by formula (1) and/or a pharmaceutically acceptable salt thereof, and a preparation method therefor and the use thereof as an NMT inhibitor in the preparation of an anti-tumor drug.

Inventors

  • FAN, HOUXING
  • Jiang, Qiangqiang
  • WANG, TIANCAI

Assignees

  • Nanjing Synnocare Pharmaceutical Technology Co., Ltd.
  • Tianjin Synnocare Biomedical Technology Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240627

Claims (13)

  1. A compound having the structure shown in Formula (1), or an isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof: wherein: n is 0, 1, 2 or 3; X 1 and X 2 are each independently selected from the group consisting of: CH, CR 1 or N; W is selected from the group consisting of: a bond, O, S or NH; Y is selected from the group consisting of: a bond, -(CH 2 ) m -, -(CH 2 ) m O- or -(CH 2 ) m O-(CH 2 ) m , wherein m is 1, 2 or 3; L is -(CH 2 ) m -; each R 1 is independently selected from the group consisting of: D, hydroxyl, halogen, CN, NO 2 , NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 saturated or partially unsaturated carbocyclic group, 3-8-membered saturated or partially unsaturated heterocyclyl, C 6-10 aryl or 5-12 membered heteroaryl; R 2 is -NR 6 R 7 , wherein R 6 and R 7 are each independently selected from the group consisting of: H, D, C 1-6 alkyl or C 1-6 haloalkyl; or, R 6 and R 7 are taken together with the attached nitrogen atom to form a 3-8-membered saturated or partially unsaturated heterocyclyl, or a 5-12 membered heteroaryl; R 3 is selected from the group consisting of: H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 saturated or partially unsaturated carbocyclic group, 3-8-membered saturated or partially unsaturated heterocyclyl, C 6-10 aryl or 5-12 membered heteroaryl; R 4 is selected from the group consisting of: C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 saturated or partially unsaturated carbocyclic group, 3-8-membered saturated or partially unsaturated heterocyclyl, C 6-10 aryl or 5-12 membered heteroaryl; R 5 is selected from the group consisting of: hydroxyl, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or -C(O)NR 8 R 9 ; wherein R 8 and R 9 are each independently selected from the group consisting of: H, D, C 1-6 alkyl or C 1-6 haloalkyl; or, R 8 and R 9 are taken together with the attached nitrogen atom to form a 3-8-membered saturated or partially unsaturated heterocyclyl, or a 5-12 membered heteroaryl; wherein, the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, carbocyclic group, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of: D, hydroxyl, halogen, CN, NO 2 , NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy.
  2. The compound according to claim 1, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R 1 is independently selected from the group consisting of: F, Cl, Br, CN, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or haloalkoxy.
  3. The compound according to claim 1, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2 is -NR 6 R 7 , wherein R 6 and R 7 are each independently selected from the group consisting of: H, D, C 1-3 alkyl or C 1-3 haloalkyl.
  4. The compound according to claim 1, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 3 is selected from the group consisting of: H, D, C 1-3 alkyl or C 1-3 haloalkyl.
  5. The compound according to claim 1, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 4 is selected from the group consisting of: C 1-3 alkyl or C 1-3 haloalkyl.
  6. The compound according to claim 1, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 5 is selected from the group consisting of: CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl or -C(O)NR 8 R 9 ; wherein R 8 and R 9 are each independently selected from the group consisting of: H, D, C 1-3 alkyl or C 1-3 haloalkyl.
  7. The compound according to claim 1, an isomer thereof, a crystal form, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from the group consisting of:
  8. A pharmaceutical composition for treating, regulating, and/or preventing a disease associated with NMT, characterized in that the pharmaceutical composition comprises: (1) the compound as an active ingredient according to any one of claims 1-7, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and optionally (2) a pharmaceutically acceptable excipient or carrier.
  9. Use of the compound according to any one of claims 1-7, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition according to claim 8, for preparing a pharmaceutical composition for treating, regulating and/or preventing a disease mediated by NMT.
  10. A method for treating, regulating, and/or preventing a disease mediated by NMT, characterized by comprising the steps of: administering to an individual in need with a compound according to any one of claims 1-7, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate, or a pharmaceutical composition according to claim 8.
  11. The use according to claim 9 or the method according to claim 10, wherein the related disease mediated by NMT includes infectious disease or hyperproliferative disease.
  12. The use or method according to claim 11, wherein the infectious disease includes protozoan infection and viral infection; preferably, the protozoan infection includes malaria and leishmaniasis; preferably, the viral infection includes human rhinovirus infection and HIV infection.
  13. The use or method according to claim 11, wherein the hyperproliferative disease is selected from the following group: lymphoma, leukemia, brain tumor, gastric tumor, liver cancer, lung cancer, intestinal cancer, pancreatic cancer, breast cancer, cervical cancer, ovarian cancer, endometrial cancer and prostate cancer.

Description

FIELD OF THE INVENTION The invention belongs to the field of medicinal chemistry, and more specifically, relates to a kind of NMT inhibitors as shown in Formula (1), and preparation methods therefor, as well as the use of these compounds for preparing pharmaceutial compositions for treating, regulating, and/or preventing diseases mediated by NMT. BACKGROUND NMT (N-myristoyltransferase) is an enzyme that catalyzes the myristoylation of over 100 proteins in human cells and affects downstream related signaling pathways. In humans, protein myristoylation is mediated by two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2. Myristoylation is a co- and post-translational modification reaction in eukaryotes, where, through the action of NMT1 and NMT2, a myristoyl group is transferred to the N-terminal glycine of substrate proteins [Cell Death and Disease, 2018, 9 (12): 1143]. It acts like a "switch", triggering various reversible protein-membrane and protein-protein interactions. NMT1 is highly expressed in various tumor tissues. In liver cancer, NMT1 is associated with poor prognosis; patients with high NMT1 expression have shorter survival times compared to those with low expression. The expression of NMT1 holds significant clinical importance. Detection in primary breast cancer tissues and adjacent tissues from 20 breast cancer patients showed that NMT1 expression was significantly higher in breast cancer tissues compared to adjacent tissues, particularly markedly elevated in triple-negative breast cancer tissues [Cell Death and Disease, 2018, 9 (12): 1143]. Elevated NMT1 is associated with tumor development and shorter patient survival. In colorectal cancer patients, NMT1 expression increased in peripheral blood and bone marrow and can serve as a diagnostic marker for colorectal cancer [J Transl Med. 2007, 5: 58]. High NMT1 expression is associated with poor prognosis in ovarian cancer and with the progression of liver cancer, brain cancer, etc. [Annals of medicine, 2023, 55 (1): 1422-1430]. NMT1 catalyzes the formation of myristoylated proteins from its substrate proteins, activating downstream signaling pathways such as NF-κB, C-Myc, and ERK, thereby promoting tumor cell proliferation, migration, and metastasis. Inhibiting NMT1 can induce cell cycle arrest and suppress cell proliferation and malignant growth [Annals of medicine, 2023, 55 (1): 1422-1430]. NMT1 is highly expressed in various tumors and is associated with tumor stage, prognosis, and survival, making it a potential target for precision cancer therapy. NMT inhibitors can significantly inhibit hematological tumor cells, including B lymphocyte activity, inhibit myristoylation in lymphoma cells, and suppress B-cell receptor signaling, leading to cell death and inhibiting tumor growth in mouse tumor models [Nature communications, 2020, 11 (1): 5348]. Although some small molecule NMT inhibitors have been disclosed, there remains a need to develop novel compounds with better activity and pharmacokinetic properties. The NMT inhibitor compounds of the present invention, having the structure represented by general formula (1), demonstrate excellent activity and profiles, potentially providing new options for precision cancer therapy. SUMMARY OF THE INVENTION The objective of the present invention is to provide a novel NMT inhibitor with potent activity, as well as preparation therefor and uses thereof. In the first aspect of the present invention, it provides a compound as shown in Formula (1), or an isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof: wherein: n is 0, 1, 2 or 3;X1 and X2 are each independently selected from the group consisting of: CH, CR1 or N;W is selected from the group consisting of: a bond, O, S or NH;Y is selected from the group consisting of: a bond, -(CH2)m-, -(CH2)mO- or -(CH2)mO-(CH2)m, wherein m is 1, 2 or 3;L is -(CH2)m-;each R1 is independently selected from the group consisting of: D, hydroxyl, halogen, CN, NO2, NH2, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 saturated or partially unsaturated carbocyclic group, 3-8-membered saturated or partially unsaturated heterocyclyl, C6-10 aryl or 5-12 membered heteroaryl;R2 is -NR6R7, wherein R6 and R7 are each independently selected from the group consisting of: H, D, C1-6 alkyl or C1-6 haloalkyl;or, R6 and R7 are taken together with the attached nitrogen atom to form a 3-8-membered saturated or partially unsaturated heterocyclyl, or a 5-12 membered heteroaryl;R3 is selected from the group consisting of: H, D, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 saturated or partially unsaturated carbocyclic group, 3-8-membered saturated or partially unsaturated heterocyclyl, C6-10 aryl or 5-12 membered heteroaryl;R4 is selected from the group consisting of: C1-4 alkyl, C1-4 haloalkyl, C3-6 saturated or partially unsaturated carbocyclic group, 3-8-membered saturated or partially un