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EP-4740942-A1 - AROMATIC AMIDE DERIVATIVE AND USE THEREOF

EP4740942A1EP 4740942 A1EP4740942 A1EP 4740942A1EP-4740942-A1

Abstract

An aromatic amide derivative, a preparation method therefor, and use of the compound in preventing and/or treating a disease, especially in tumor treatment. The aromatic amide derivative is a MEK/RAF inhibitor having advantages such as relatively good activity and safety, and shows good application prospects in preventing and/or treating a tumor related to a MAPK pathway.

Inventors

  • DU, FENGTIAN
  • YANG, XIANGYU
  • GUO, Na
  • LUO, Shuai
  • TIAN, Jingyu
  • QIAN, Qingqing

Assignees

  • HUAJIAN FUTURE (CHENGDU) TECHNOLOGY CO., LTD.

Dates

Publication Date
20260513
Application Date
20240628

Claims (16)

  1. A compound represented by formula (I), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein, W is selected from a bond, oxygen, or sulfur; V is selected from nitrogen or CR 4e ; L is selected from -NR 1 C(O)-, -C(O)NR 1 -, C 3-6 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; R 1 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl; each of R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b and R 6c is independently selected from hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered cyclic structure; R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkoxy, alkenyl, alkynyl ,and cycloalkyl are optionally substituted with one or more substituents selected from deuterium, halogen, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl; each of R 8a , R 8b , R 8c , R 8d and R 8e is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; m is 0, 1, 2, or 3; n is 1, 2, 3, or 4; and p is 0, 1, 2, or 3.
  2. A compound represented by formula (II), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein, W is selected from a bond, oxygen, or sulfur; V is selected from nitrogen or CR 4e ; R 1 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl; each of R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b and R 6c is independently selected from hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered cyclic structure; R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more substituents selected from deuterium, halogen, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl; each of R 8a , R 8b , R 8c , R 8d and R 8e is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl; n is 1, 2, 3, or 4;and p is 0, 1, 2, or 3.
  3. A compound as follows, or a stereoisomer, a tautomeror a pharmaceutically acceptable salt thereof,
  4. A compound represented by formula (III), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein, W is selected from a bond, oxygen, or sulfur; V is selected from nitrogen or CR 4e ; ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl; each of R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b and R 6c is independently selected from hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered cyclic structure; R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from deuterium, halogen, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl; each of R 8a , R 8b , R 8c , R 8d and R 8e is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl; m is 0, 1, 2, or 3; n is 1, 2, 3, or 4; p is 0, 1, 2, or 3.
  5. A compound as follows, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
  6. A compound represented by formula (IV), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein, U is selected from nitrogen or CR 5d ; V is selected from nitrogen or CR 4e ; each of R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 5a , R 5b , R 5c , R 5d , R 6a , R 6b and R 6c is independently selected from hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered cyclic structure; R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from deuterium, halogen, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl; each of R 8a , R 8b , R 8c , R 8d and R 8e is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; and n is 1, 2, 3, or 4.
  7. A compound represented by formula (IV-1), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein, U is selected from nitrogen or CH; V is selected from nitrogen or CR 4e ; each of R 4a , R 4b , R 4c , R 4d and R 4e is independently selected from hydrogen, deuterium, halogen, aldehyde group, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; each of R 5c , R 6b and R 6c is independently selected from hydrogen, halogen or C 1-6 alkyl; R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl or C 3-6 cycloalkyl; each of R 8a , R 8b , R 8c , R 8d and R 8e is independently selected from hydrogen, deuterium or C 1-6 alkyl; and n is 1, 2, or 3.
  8. A compound as follows, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
  9. A compound as follows, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
  10. A compound as follows, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
  11. A compound represented by formula (V), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein, U is selected from nitrogen or CH; V is selected from nitrogen or CR 4e ; each of R 4a , R 4b , R 4c , R 4d , R 4e , R 8c , R 6b and R 6c is independently selected from hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered cyclic structure; R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more substituents selected from deuterium, halogen, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl; each of R 8a , R 8b , R 8c , R 8d and R 8e is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; and n is 1, 2, 3, or 4.
  12. A compound as follows, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
  13. A pharmaceutical composition, comprising a therapeutically effective amount of the compound, or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, and a pharmaceutically acceptable carrier.
  14. Use of the compound, or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for preventing and/or treating a tumor.
  15. Use of the compound, or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for preventing and/or treating a disease mediated by RAF and/or MEK, wherein the disease is preferably a tumor.
  16. The use according to claim 14 or 15, wherein the tumor comprises kidney cancer, liver cancer, breast cancer, pancreatic cancer, prostate cancer, melanoma, leukemia, malignant lymphoma, ovarian cancer, head and neck cancer, lung cancer, colorectal cancer, bladder cancer and uterine cancer.

Description

TECHNICAL FIELD The present invention belongs to the field of medicinal chemistry, and relates to an aromatic amide derivative, a preparation method therefor, and use of the compound in preventing and/or treating a disease, especially in tumor treatment. BACKGROUND ART Aromatic amide structure is widely found in drug molecules, which is an important pharmacophore, may interact with a drug target protein, and can improve drug performance and the like. For example, all the following marketed drugs or molecular structures in the clinical stage contain an aromatic amide structure. RAS-RAF-MEK-ERK cascade reaction is an important signal pathway, which is one of the most actively studied pathways. Abnormal activation of this signal pathway will affect the proliferation, differentiation, apoptosis and metastasis of normal cells. In addition to lung cancer, the abnormal activation of this pathway has a larger proportion and a greater influence in high mortality cancer types, such as pancreatic cancer (> 90%) and colorectal cancer (> 50%). RAF is a serine/threonine protein kinase, which is usually activated by a RAS protein kinase. MEK is a bispecific kinase, which may phosphorylate a serine/threonine residue and a tyrosine residue. The activated MEK activates a downstream ERK, so as to make the kinase enter cell nuclei to regulate various transcription factors and induce the expression of some genes, thereby causing cell proliferation. The blockage of only a single target of this pathway is often insufficient to achieve an ideal anti-tumor effect, and a single-target drug has defects such as easy mutation and drug resistance, and great toxic and side effects. At present, the Raf and MEK inhibitors are used in combination to block two key targets of this pathway, so as to overcome drug resistance caused by the reactivation of this pathway, thereby delaying the emergence of drug resistance. It is an effective anti-tumor strategy to develop a RAF and MEK dual-target inhibitor. At present, among the RAF/MEK inhibitors under research, VS-6766 (related literatures such as WO2007091736) has made rapid clinical progress, which has shown efficacy in the treatment of various tumors activated by a MAPK pathway, and related adverse reactions have also been reported in clinical experiments; and another type of compound also shows activity in a lung cancer model (related literatures such as WO2021149776). The development of the RAF and MEK dual-target inhibitor is to improve the inhibitory activity and effectiveness of the compound on one hand, and needs to pay attention to the safety on the other hand. It is of great significance to develop a new RAF and MEK dual-target inhibitor with better efficacy and higher safety. SUMMARY The present invention discloses an aromatic amide MEK/RAF inhibitor, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, which has advantages such as good activity and safety, and shows good application prospects in preventing and/or treating a tumor related to a MAPK pathway. The present invention provides a compound represented by formula (A), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein, M is selected from oxygen or sulfur;X is selected from a bond, oxygen, sulfur, -C(O)-, -NR1C(O)-, -C(O)NR1-, -NR1S(O)-, -S(O)NR1-, -NR1SO2-, -SO2NR1-, -NR1-, or -CR1R2-;each of ring A and ring B is independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;L is selected from a bond, oxygen, sulfur, -C(O)-, -NR1C(O)-, -C(O)NR1-, -NR1S(O)-, -S(O)NR1-, -NR1SO2-, -SO2NR1-, -NR1-, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;R10 is selected from hydrogen, deuterium, halogen, aldehyde group, cyano, hydroxyl, -ORa, -SRa, -NRaRb, -C(O)Ra, -S(O)Ra, -S(O)2Ra, -(CR2aR2b)pSO2NRaRb, -(CR2aR28)pNRaSO2NRdRc, -(CR2aR2b)pNRaSO2Rb, -(CR2aR2b)pC(O)NRaRb, -(CR2aR2b)pNRaC(O)NRbRc, -(CR2aR2b)pNRaC(O)Rb, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;each of R9a and R9b is independently selected from hydrogen, deuterium, halogen, aldehyde group, cyano, hydroxyl, -ORa, -SRa, -NRaRb, -C(O)Ra, -S(O)Ra, -S(O)2Ra, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl,