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CN-122010925-A - Thia-heterocyclic compound, preparation method and application thereof

CN122010925ACN 122010925 ACN122010925 ACN 122010925ACN-122010925-A

Abstract

The invention discloses a thia-heterocyclic compound, a preparation method and application thereof, wherein the structure of the compound is shown as a formula (I), the compound has high-efficiency inhibition effect on KRAS protein subtypes such as KRAS G12D, KRAS G12C, KRAS G12V, KRAS WT, KRAS G12R, KRAS G12A and the like, and the compound can be used for preparing medicines for treating and/or preventing diseases related to multi-subtype KRAS mutation, including pancreatic cancer, lung cancer, colorectal cancer and the like, and has wide clinical application prospect.

Inventors

  • ZHANG XIAOJIN
  • LI YUHANG
  • YANG LE
  • Bing Tiande
  • WU YUE

Assignees

  • 中国药科大学

Dates

Publication Date
20260512
Application Date
20241111

Claims (11)

  1. 1. A compound having the structure of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, characterized in that, In the structure of formula (I): R 1a 、R 1b 、R 2a 、R 2b 、R 3a 、R 3b is selected from hydrogen, deuterium, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halogen, -NH 2 、-NH(C 1 -C 4 alkyl), -N (C 1 -C 4 alkyl) 2 、C 3 -C 5 cycloalkyl or 3-5 membered heterocyclyl containing 1-2N, O, S; Or R 1a 、R 1b 、R 2a 、R 2b 、R 3a 、R 3b together with the carbon atom to which it is attached in the form of (1) or (2) form a cyclopropane or cyclobutane ring: (1) One of R 1a 、R 1b and one of R 2a 、R 2b ; (2) One of R 2a 、R 2b and one of R 3a 、R 3b ; X is N or CR a ; R 1 、R a is selected from hydrogen, halogen, -OH, -NH 2 , cyano or C 1 -C 4 alkyl; Ring a is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, oxadiazole, isoxazole, thiazole, thiadiazole, isothiazole or triazole; Z, V, Y is selected from N or C; R 2 is selected from-O (C 1 -C 6 alkyl) substituted with hydrogen, one or more identical or different C 1 -C 6 alkyl groups, C 1 -C 6 alkoxy groups or 3-10 membered heterocyclic groups containing 1-2N, O, S substituted with 5-6 membered heterocyclic groups containing 1-2N, O, S or with hydrogen, 3-10 membered heterocyclic groups containing 1-2N, O, S, wherein C 1 -C 6 alkyl groups are substituted with hydrogen or 3-8 membered heterocyclic groups containing 1-2N, O, S, 3-10 membered heterocyclic groups are substituted with hydrogen, one or more identical or different R 5 ; R 5 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen or 3-10 membered heterocyclic groups containing 1-2N, O, S; w is N, O or C; R 3 、R 4 is selected from hydrogen, -NH 2 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl containing 1-2N, O, S, C 6 -C 10 aryl, 5-10 membered heteroaryl containing 1-4N, O, S or absent, wherein C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl containing 1-2N, O, S, C 6 -C 10 aryl or 5-10 membered heteroaryl containing 1-4N, O, S are substituted with hydrogen, one or more of the same or different R 6 or R 7 ; Or R 3 、R 4 together with the W to which it is attached is cyclized to form a C 3 -C 10 cycloalkane substituted with one or more R 6 or C 3 -C 10 heterocycloalkyl containing 1-2N, O, S; R 6 is selected from hydrogen, C 1 -C 6 alkyl, -OR 7 、-N(R 7 ) 2 , halogen, -CN, -NH 2 、-C(＝O)R 7 、-C(＝O)OR 7 、-C(＝O)N(R 7 ) 2 , OR-NHC (=o) OR 7 , OR (=o); R 7 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl containing 1-2N, O, S, C 6 -C 10 aryl or 5-10 membered heteroaryl containing 1-4N, O, S, wherein C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl containing 1-2N, O, S, C 6 -C 10 aryl or 5-10 membered heteroaryl containing 1-4N, O, S are substituted by one or more identical or different R 8 、R 9 ; R 8 is selected from hydrogen, -OR 9 、-N(R 9 ) 2 , OR-C (O) N (R 9 ) 2 ; R 9 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclic group containing 1-2N, O, S groups or 5-10 membered heteroaryl group containing 1-4N, O, S groups, wherein C 1 -C 6 alkyl is substituted with hydrogen, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or 3-10 membered heterocyclic group containing 1-2N, O, S groups substituted with hydrogen, C 1 -C 6 alkyl.
  2. 2. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (Ia): Wherein, ring A, X, W, Z, V, Y, R 1 、R 2 、R 3 、R 4 is defined as set forth in claim 1.
  3. 3. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (Ib): Wherein, ring A, X, W, Z, V, Y, R 1 、R 2 、R 3 、R 4 is defined as set forth in claim 1.
  4. 4. A compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein in the structure, ring a is selected from:
  5. 5. A compound according to claim 1, or a stereoisomer, pharmaceutically acceptable/salt thereof, wherein in the structure: R 3 、R 4 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl containing 1-2N, O, S, C 6 -C 10 aryl, or 5-10 membered heteroaryl containing 1-4N, O, S, R 3 、R 4 being substituted with hydrogen, one or more R 6 、R 7 , which may be the same or different; Or R 3 、R 4 together with the W to which it is attached is cyclized to form a C 3 -C 10 cycloalkane substituted with one or more R 6 or C 3 -C 10 heterocycloalkyl containing 1-2N, O, S; W, R 6 、R 7 is defined in claim 1.
  6. 6. A compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:
  7. 7. a compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein in the structure, Selected from the following groups substituted with hydrogen, one or more of the same or different R 6 、R 7 : R 6 、R 7 is as defined in claim 1.
  8. 8. A compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the following:
  9. 9. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a salt of the compound with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.
  10. 10. A process for the preparation of a compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, selected from any one of the following: method one when ring A is In the process, the compound I is obtained by substitution, coupling, aminolysis, condensation and cyclization of the compound I-1; Method II when ring A is In the process, the compound I is obtained by substitution, coupling, reduction, condensation and cyclization of the compound I-1; Method III when ring A is In the process, the compound I is obtained by substitution, coupling, aminolysis, condensation and cyclization of the compound I-1; Wherein ,X、W、Z、V、Y、R 1a 、R 1b 、R 2a 、R 2b 、R 3a 、R 3b 、R 1 、R 2 、R 3 、R 4 is as defined in claim 1; and salifying the corresponding acid with the compound I prepared by the method to obtain the pharmaceutically acceptable salt.
  11. 11. Use of a compound according to claim 1 or a stereoisomer, pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.

Description

Thia-heterocyclic compound, preparation method and application thereof Technical Field The invention relates to a thia-heterocyclic compound and a preparation method and application thereof, in particular to a thia-heterocyclic compound which can be prepared into a medicament for treating and/or preventing cancers and a preparation method and application thereof. Background KRAS (Kirsten rat sarcoma virus oncogene homolog) is a G protein, which acts as an intracellular "on/off" switch, combining extracellular mitogenic signaling with intracellular pro-proliferative responses. Mitogen stimulation induces GTP binding to KRAS, causing conformational changes that allow KRAS to interact with downstream effector proteins, resulting in cell proliferation. Typically pro-proliferative signaling is regulated by the action of Gtpase Activating Proteins (GAPs) to restore KRAS to its GDP-bound non-proliferative state. However, mutations in KRAS impair the regulatory cycle of KRAS between these GDP and GTP binding states, leading to accumulation of GTP binding activity states and deregulated cell proliferation. For example, a genetic alteration of codon 12 of KRAS replaces the naturally occurring glycine residue at this position with a different amino acid, such as, inter alia, aspartic acid (G12D mutation or KRAS G12D), cysteine (G12C mutation or KRAS G12C), valine (G12V mutation or KRAS G12V). Similarly, mutations within codons 13, 61 and 146 of KRAS are commonly found in KRAS genes. Mutations in KRAS protein are important factors in inducing tumors, and different KRAS mutant proteins are overexpressed in different tumors, such as pancreatic cancer, non-small cell lung cancer, colorectal cancer, etc., and moreover, overactivated endothelial cell KRAS G12V can also induce cerebral arteriovenous malformations. The existing KRAS protein inhibitors mainly aim at mutant proteins of KRAS G12C, KRAS G12D and other subtypes, such as AMG510, MRTX849, JDQ443 and the like, and the inhibitors mainly aim at KRAS proteins of specific subtypes, so that broad-spectrum inhibition is difficult to realize. Disclosure of Invention The invention aims at providing a thia heterocyclic compound with anti-tumor activity, a preparation method of the compound, and a pharmaceutical application of the compound. The technical proposal is that the compound with the structure of the formula (I) or the stereoisomer and the pharmaceutically acceptable salt thereof, In the structure of formula (I): R 1a、R1b、R2a、R2b、R3a、R3b is selected from hydrogen, deuterium, C 1-C4 alkyl, C 1-C4 haloalkyl, C 1-C4 alkoxy, C 1-C4 haloalkoxy, halogen, -NH 2、-NH(C1-C4 alkyl), -N (C 1-C4 alkyl) 2、C3-C5 cycloalkyl or 3-5 membered heterocyclyl containing 1-2N, O, S; Or R 1a、R1b、R2a、R2b、R3a、R3b together with the carbon atom to which it is attached in the form of (1) or (2) form a cyclopropane or cyclobutane ring: (1) One of R 1a、R1b and one of R 2a、R2b; (2) One of R 2a、R2b and one of R 3a、R3b; X is N or CR a; R 1、Ra is selected from hydrogen, halogen, -OH, -NH 2, cyano or C 1-C4 alkyl; Ring a is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, oxadiazole, isoxazole, thiazole, thiadiazole, isothiazole or triazole; Z, V, Y is selected from N or C; R 2 is selected from-O (C 1-C6 alkyl) substituted with hydrogen, one or more identical or different C 1-C6 alkyl groups, C 1-C6 alkoxy groups or 3-10 membered heterocyclic groups containing 1-2N, O, S substituted with 5-6 membered heterocyclic groups containing 1-2N, O, S or with hydrogen, 3-10 membered heterocyclic groups containing 1-2N, O, S, wherein C 1-C6 alkyl groups are substituted with hydrogen or 3-8 membered heterocyclic groups containing 1-2N, O, S, 3-10 membered heterocyclic groups are substituted with hydrogen, one or more identical or different R 5; R 5 is selected from C 1-C6 alkyl, C 1-C6 alkoxy, halogen or 3-10 membered heterocyclic groups containing 1-2N, O, S; w is N, O or C; R 3、R4 is selected from hydrogen, -NH 2、C1-C6 alkyl, C 1-C6 haloalkyl, C 3-C10 cycloalkyl, 3-10 membered heterocyclyl containing 1-2N, O, S, C 6-C10 aryl, 5-10 membered heteroaryl containing 1-4N, O, S or absent, wherein C 1-C6 alkyl, C 1-C6 haloalkyl, C 3-C10 cycloalkyl, 3-10 membered heterocyclyl containing 1-2N, O, S, C 6-C10 aryl or 5-10 membered heteroaryl containing 1-4N, O, S are substituted with hydrogen, one or more of the same or different R 6 or R 7; Or R 3、R4 together with the W to which it is attached is cyclized to form a C 3-C10 cycloalkane substituted with one or more R 6 or C 3-C10 heterocycloalkyl containing 1-2N, O, S; R 6 is selected from hydrogen, C 1-C6 alkyl, -OR 7、-N(R7)2, halogen 、-CN、-NH2、-C(＝O)R7、-C(＝O)OR7、-C(＝O)N(R7)2、-NHC(＝O)OR7 OR (=o); R 7 is selected from hydrogen, C 1-C6 alkyl, C 3-C10 cycloalkyl, 3-10 membered heterocyclyl containing 1-2N, O, S, C 6-C10 aryl or 5-10 membered heteroaryl containing 1-4N, O, S, wherein C 1-C6 alkyl, C 3-C10 cycloalkyl, 3-10 membered heterocyclyl containing 1-