Macrocyclic derivative inhibitors, methods of making and use thereof

Abstract

The present invention relates to inhibitors of macrocyclic derivatives, methods of making and using the same. In particular, the present invention relates to compounds of the general formula, methods of making the same, and pharmaceutical compositions containing the same, and their use in the treatment of cancer and other related diseases.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a macrocyclic derivative inhibitor, its preparation method, and its application. Background Technology

[0002] Rat sarcoma (RAS) proteins are encoded by the proto-oncogenes HRAS, NRAS, and KRAS, and consist of four proteins: HRAS, NRAS, KRAS4A, and KRAS4B. These proteins are GTP (guanosine triphosphate) binding proteins. RAS is located on the inner surface of the cell membrane, upstream of which is the receptor tyrosine kinase (RTK). Activation of RAS regulates downstream signaling pathways such as PI3K and RAF, thereby controlling cell growth, survival, migration, and differentiation.

[0003] RAS exists in two main states in the body: an inactive state bound to GDP (guanosine diphosphate) and an activated state bound to GTP. Its activity is regulated by two proteins: guanine nucleotide exchange factor (GEF) promotes the release of GDP from the RAS protein, enabling GTP binding and activation of RAS; GTPase activating protein (GAP) activates the GTPase activity of the RAS protein, hydrolyzing the GTP bound to RAS protein into GDP, thus inactivating RAS. Under normal circumstances, the RAS protein is in an inactive state. Mutations alter its conformation, leading to a persistently activated RAS state, and downstream signaling pathways are also continuously activated, resulting in the development of various cancers.

[0004] RAS was the first oncogene to be identified and also the most frequently mutated oncogene, accounting for an average of 25% of human cancers. The most common oncogene mutation in the RAS family is KRAS (85%), while NRAS (12%) and HRAS (3%) are less common. KRAS mutations are prevalent in a range of cancers, including pancreatic cancer (95%), colorectal cancer (52%), and lung cancer (31%). The most common type of KRAS mutation is point mutation, which occurs mostly in the G12, G13, and Q61 regions (aa59-76) of the p-loop (aa 10-17), with G12 mutations being the most common (83%).

[0005] The development of KRAS inhibitors is difficult due to two main factors. First, the RAS protein has a smooth structure, making it difficult for small molecules to bind to the protein surface. Second, the RAS GTPase has an affinity for GTP at the picomolar (pM) level, and the endogenous GTP level is high, making it difficult for small molecule drugs to block the binding of the two.

[0006] Currently, drugs that specifically target KRAS G12C, AMG-510 and MRTX-849, have been approved for marketing. However, there are currently no specific targeted drugs for KRAS G12D and KRAS G12V, indicating a significant clinical need. In addition, pan-KRAS inhibitors can target multiple KRAS pathogenic mutations simultaneously, making them suitable for more patients and potentially having a wider range of indications, thus possessing a broad market prospect. Summary of the Invention

[0007] The object of this invention is to provide a compound of general formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (I) has the following structure:

[0008] in: X1 is selected from N or CR4; X2 is selected from N or CR5; L is selected from -O-, -CR 1-3 R 1-4 -, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 The arylene and 5-14 heteroarylene groups are optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. a Replaced; L1 is selected from key, -O-, -S-, -NR N -, -C(O)-, -S(O)- or -SO2-; preferably -O-; L2 is selected from bonds, C1-C6 alkylene groups, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C1-C6 alkylene-C 3-8 Cycloalkylene or C1-C6 alkylene-3-8 membered heterocyclic alkylene, wherein the C1-C6 alkylene, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are optionally replaced by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Alternatively, two substituents on the same carbon atom in a C1-C6 alkylene group can be linked to form a C1-C6 alkylene group. 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups may optionally be further replaced by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; The ring C is selected from a macrocyclic system, wherein the macrocyclic system optionally further includes one or more N, O, S, and P heteroatoms; R1, R 1-1 R 1-2 R 1-3 and R 1-4 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12-membered heterocyclic group, -(CH2) n1 -C 6-14 Aryl, -(CH2) n1-5-14 heteroaryl groups, -(CH2) n1 -OR 1a -(CH2) n1 -NR 1a R 1b -(CH2) n1 -C(O)R 1a -(CH2) n1 -C(O)NR 1a R 1b -(CH2) n1 -NR 1a C(O)R 1b -(CH2) n1 -S(O) m1 R 1a -(CH2) n1 -NR aa S(O) m1 R 1b Or -(CH2) n1 -S(O) m1 NR 1a R 1b The above-mentioned groups, the hydrogen in the groups, and -(CH2) n1 - Any CH2 group may optionally be further reacted with hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions from aryl, 5-10 heteroaryl, =CH2, =CHF and =CF2; Or, R 1-1 With R 1-2 The links form 3-12-membered heterocyclic groups or 5-14-membered heteroaryl groups, wherein the 3-12-membered heterocyclic group or 5-14-membered heteroaryl group is optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. a Replaced; R2 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R3 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R4 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Alternatively, R2 and R4 can be linked to form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups, wherein the above groups may optionally be further replaced by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R5 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R6 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl groups, wherein the above groups are optionally further surrounded by one or more R groups. d replace; R a Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n2 -OR 2a -(CH2) n2 -C(O)R 2a -(CH2) n2 -C(O)OR 2a -(CH2) n2 -NR 2a R 2b -(CH2) n2 -P(O)R 2a R 2b -(CH2) n2 -NR 2c C(O)R 2a -(CH2) n2 -C(O)NR 2a R 2b -(CH2) n2 -S(O)2R 2a -(CH2) n2 -S(O)2NR 2a R 2b -(CH2) n2 -NR 2c S(O)2R 2a -(CH2) n2 -S(O)R 2a (=NR 2c-(CH2) n2 -N=S(O)R 2a R 2b =CR 2a R 2b =NR 2a =N-OR 2a or =CR 2a -CR 2c R 2d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n2 - Any CH2 in the mixture can optionally be further reacted with one or more R aa replace; R b Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n3 -OR 3a -(CH2) n3 -C(O)R 3a -(CH2) n3 -C(O)OR 3a -(CH2) n3 -NR 3a R 3b -(CH2) n3 -P(O)R 3a R 3b -(CH2) n3 -NR 3c C(O)R 3a -(CH2) n3 -C(O)NR 3a R 3b -(CH2) n3 -S(O)2R 3a -(CH2) n3 -S(O)2NR 3a R 3b -(CH2) n3 -NR 3cS(O)2R 3a -(CH2) n3 -S(O)R 3a (=NR 3c -(CH2) n3 -N=S(O)R 3a R 3b =CR 3a R 3b =NR 3a =N-OR 3a or =CR 3a -CR 3c R 3d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n3 - Any CH2 in the mixture can optionally be further reacted with one or more R bb replace; R c Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n4 -OR 4a -(CH2) n4 -C(O)R 4a -(CH2) n4 -C(O)OR 4a -(CH2) n4 -NR 4a R 4b -(CH2) n4 -P(O)R 4a R 4b -(CH2) n4 -NR 4c C(O)R 4a -(CH2) n4 -C(O)NR 4a R 4b -(CH2) n4 -S(O)2R 4a -(CH2)n4 -S(O)2NR 4a R 4b -(CH2) n4 -NR 4c S(O)2R 4a -(CH2) n4 -S(O)R 4a (=NR 4c -(CH2) n4 -N=S(O)R 4a R 4b =CR 4a R 4b =NR 4a =N-OR 4a or =CR 4a -CR 4c R 4d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n4 - Any CH2 in the mixture can optionally be further reacted with one or more R cc replace; R d Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n5 -OR 5a -(CH2) n5 -C(O)R 5a -(CH2) n5 -C(O)OR 5a -(CH2) n5 -OC(O)R 5a -(CH2) n5 -NR 5a R 5b -(CH2) n5 -P(O)R 5a R 5b -(CH2) n5 -NR 5c C(O)R5a -(CH2) n5 -C(O)NR 5a R 5b -(CH2) n5 -OC(O)NR 5a R 5b -(CH2) n5 -S(O)2R 5a -(CH2) n5 -S(O)2NR 5a R 5b -(CH2) n5 -NR 5c S(O)2R 5a -(CH2) n5 -S(O)R 5a (=NR 5c -(CH2) n5 -N=S(O)R 5a R 5b =CR 5a R 5b =NR 5a =N-OR 5a or =CR 5a -CR 5c R 5d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n5 - Any CH2 in the mixture can optionally be further reacted with one or more R dd replace; R N Selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 1a ~R 1d R 2a ~R 2d R 3a ~R 3d R 4a ~R 4d and R 5a ~R 5d Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n6 -OR ee -(CH2) n6 -C(O)R ee -(CH2) n6 -C(O)OR ee -(CH2) n6 -OC(O)R ee -(CH2) n6 -NR ee R ff -(CH2) n6 -P(O)R ee R ff-(CH2) n6 -NR ff C(O)R ee -(CH2) n6 -C(O)NR ee R ff -(CH2) n6 -S(O)2R ee -(CH2) n6 -S(O)2NR ee R ff -(CH2) n6 -NR ff S(O)2R ee -(CH2) n6 -S(O)R ee (=NR ff -(CH2) n6 -N=S(O)R ee R ff The above-mentioned groups, the hydrogen in the groups, and -(CH2) n6 - Any CH2 group may optionally be further reacted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Or, R 1a ~R 1d R 2a ~R 2d R 3a ~R 3d R 4a ~R 4d and R 5a ~R 5d Any two links in the chain form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; R aa R bb R cc R dd R ee and R ff Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Or, R ee and R ff The links in the middle form a ring system, which is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; m1 is selected from 0, 1, or 2; n1 is selected from 0, 1, 2, 3, 4, 5, or 6; n2 is selected from 0, 1, 2, 3, 4, 5, or 6; n3 is selected from 0, 1, 2, 3, 4, 5, or 6; n4 is selected from 0, 1, 2, 3, 4, 5, or 6; n5 is selected from 0, 1, 2, 3, 4, 5, or 6; n6 is selected from 0, 1, 2, 3, 4, 5, or 6; b is selected from 0, 1, 2, 3, 4, 5, or 6; and c is selected from 0, 1, 2, 3, 4, 5, or 6.

[0009] In certain embodiments of the invention, the compound represented by general formula (IA) or a pharmaceutically acceptable salt thereof, further as represented by general formula (II-A) or (II-B):

[0010] Ring A is selected from 3-12 membered heterocyclic groups or 5-14 membered heterocyclic groups; L3 is selected from the bond, -(CH2). n8 O-, -(CH2) n8 S-, -(CH2) n8 NR 6a -、-(CH2) n8C(O)-、-(CH2) n8 OC(O)-、-(CH2) n8 C(O)O-、-(CH2) n8 OC(O)O-、-(CH2) n8 C(O)NR 6a -、-(CH2) n8 NR 6a C(O)-、-(CH2) n8 OC(O)NR 6a -、-(CH2) n8 NR 6a C(O)O-、-(CH2) n8 S(O)2NR 6a -、-(CH2) n8 NR 6a S(O)2-, C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 alkylene, wherein the C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene and 5-10 heteroarylene groups may be optionally replaced by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; L4 is selected from the bond, -(CH2). n8 O-, -(CH2) n8 S-, -(CH2) n8 NR 6a -、-(CH2) n8 C(O)-、-(CH2) n8 OC(O)-、-(CH2) n8 C(O)O-、-(CH2) n8 OC(O)O-、-(CH2) n8 C(O)NR6a -、-(CH2) n8 NR 6a C(O)-、-(CH2) n8 OC(O)NR 6a -、-(CH2) n8 NR 6a C(O)O-、-(CH2) n8 S(O)2NR 6a -、-(CH2) n8 NR 6a S(O)2-, C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 alkylene, wherein the C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene and 5-10 heteroarylene groups may be optionally replaced by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; L5 is selected from the bond, -(CH2). n8 O-, -(CH2) n8 S-, -(CH2) n8 NR 6a -、-(CH2) n8 C(O)-、-(CH2) n8 OC(O)-、-(CH2) n8 C(O)O-、-(CH2) n8 OC(O)O-、-(CH2) n8 C(O)NR 6a -、-(CH2) n8 NR 6a C(O)-、-(CH2) n8 OC(O)NR 6a -、-(CH2) n8NR 6a C(O)O-、-(CH2) n8 S(O)2NR 6a -、-(CH2) n8 NR 6a S(O)2-, C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 alkylene, wherein the C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene and 5-10 heteroarylene groups may be optionally replaced by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 6a R 6b and R 6c Each is independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; a is selected from 0, 1, 2, 3, 4, 5 or 6; n7 is selected from 0, 1, 2, 3 or 4; n8 is selected from 0, 1, 2, 3 or 4.

[0011] In some embodiments of the present invention, L2 is selected from... or ; R g-1 and R g-2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R g-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R g-4 R g-5 R g-6 and R g-7 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; q is selected from 0, 1, 2, 3 or 4.

[0012] In some embodiments of the present invention, R6 is selected from 5-7 member monocyclic heterocyclic groups, 6-14 member spirocyclic heterocyclic groups, 6-14 member fused heterocyclic groups, or 6-14 member bridged heterocyclic groups, and optionally may be further composed of 1, 2, 3, 4, 5, or 6 R6 groups. d Replacement; preferably from 5-7 nucleotide monocyclic heterocyclic groups, 7-10 nucleotide spirocyclic heterocyclic groups, 7-10 nucleotide fused heterocyclic groups, or 7-10 nucleotide bridged heterocyclic groups, optionally further replaced by 1, 2, 3, 4, 5, or 6 R groups. d Replacement; preferably from 5-7 member monocyclic heterocyclic groups, 7-10 member fused heterocyclic groups, or 7-10 member bridged heterocyclic groups, optionally further replaced by 1, 2, 3, 4, 5, or 6 R groups. d replace; Preferably, R6 is selected from , , , , , , , , , , , , , , , , , , , or Optionally, it can be further divided into 1, 2, 3, 4, 5 or 6 Rs. d replace.

[0013] In some embodiments of the present invention, -L2-R6 is selected from... , , , , , , , , , , , , or ; Ring F is selected from C 3-6Cycloalkyl or 3-6 membered heterocyclic groups; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Ring G is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Ring H is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Ring I is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R d-1 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n5 -OR 5a -(CH2) n5 -C(O)R 5a -(CH2) n5 -C(O)OR 5a -(CH2) n5 -OC(O)R 5a -(CH2) n5 -NR 5a R 5b -(CH2) n5 -P(O)R 5a R 5b -(CH2) n5 -NR 5c C(O)R 5a -(CH2) n5 -C(O)NR 5a R 5b -(CH2) n5 -OC(O)NR 5a R 5b -(CH2) n5 -S(O)2R 5a -(CH2) n5-S(O)2NR 5a R 5b -(CH2) n5 -NR 5c S(O)2R 5a -(CH2) n5 -S(O)R 5a (=NR 5c -(CH2) n5 -N=S(O)R 5a R 5b =CR 5a R 5b =NR 5a =N-OR 5a or =CR 5a -CR 5c R 5d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n5 - Any CH2 in the mixture can optionally be further reacted with one or more R dd replace; R d-2 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n5 -OR 5a -(CH2) n5 -C(O)R 5a -(CH2) n5 -C(O)OR 5a -(CH2) n5 -OC(O)R 5a -(CH2) n5 -NR 5a R 5b -(CH2) n5 -P(O)R 5a R 5b -(CH2) n5 -NR 5c C(O)R 5a-(CH2) n5 -C(O)NR 5a R 5b -(CH2) n5 -OC(O)NR 5a R 5b -(CH2) n5 -S(O)2R 5a -(CH2) n5 -S(O)2NR 5a R 5b -(CH2) n5 -NR 5c S(O)2R 5a -(CH2) n5 -S(O)R 5a (=NR 5c -(CH2) n5 -N=S(O)R 5a R 5b =CR 5a R 5b =NR 5a =N-OR 5a or =CR 5a -CR 5c R 5d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n5 - Any CH2 in the mixture can optionally be further reacted with one or more R dd replace; r-1 is selected from 0, 1, 2 or 3; r-2 is selected from 0, 1, 2 or 3; r is selected from 0, 1, 2, 3, 4, 5 or 6.

[0014] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is further represented as shown in general formula (III-A) or (III-B):

[0015] Ring E is selected from 5-7 member monocyclic heterocyclic groups, 6-14 member spirocyclic heterocyclic groups, 6-14 member fused heterocyclic groups, or 6-14 member bridged heterocyclic groups.

[0016] In some embodiments of the present invention, ring A is selected from 6-membered heterocyclic groups, 7-membered heterocyclic groups, 8-membered heterocyclic groups, 5-14-membered fused heterocyclic groups, or 5-14-membered spiroheterocyclic groups; Preferably, ring A is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0017] In some embodiments of the present invention Selected from , , or ; M1 is selected from N or CH; M2 is selected from N or CH.

[0018] In some embodiments of the present invention, X1 is selected from N, CH, CCH3, CCH2CH3, C-Cl, CF, C-CF3 or C-CHF2; preferably N, CH, CCH3, CCH2CH3, C-Cl or CF.

[0019] In some embodiments of the present invention, R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3Hydroxyalkyl or C 1-3 Alkylamino; preferably, R2 is selected from hydrogen, deuterium, fluorine, chlorine or bromine; more preferably, R2 is selected from fluorine.

[0020] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the above-described compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0021] In some embodiments of the invention, the above-mentioned compound or its pharmaceutically acceptable salt constitutes 0.1% to 95% by weight in the composition, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, even more preferably 15-40%, even more preferably 20-30%, and even more preferably 20-25% (based on the total weight of the pharmaceutical composition).

[0022] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations, injections, suspensions, powders, granules, or lozenges, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0023] In some embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0024] The present invention further relates to the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, in the preparation of KRAS inhibitor medicaments; preferably in the use of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRASG13D inhibitor medicaments.

[0025] The present invention further relates to the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating diseases or conditions such as Noonan syndrome, panther syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer; preferably in the preparation of medicaments for treating non-small cell lung cancer, pancreatic cancer, colon cancer, esophageal cancer, and head and neck tumors.

[0026] The present invention further relates to methods for preparing the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of diseases or conditions such as Noonan syndrome, panther syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer; preferably, methods for preparing the treatment of non-small cell lung cancer, pancreatic cancer, colon cancer, esophageal cancer, and head and neck tumors.

[0027] The present invention also relates to a method for treating, preventing, and / or treating pre-prepared treatments for diseases or conditions such as Noonan syndrome, panther syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer, comprising administering to a patient a therapeutically effective dose of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; preferably in the preparation of a method for treating non-small cell lung cancer, pancreatic cancer, colon cancer, esophageal cancer, and head and neck tumors.

[0028] In some embodiments of the present invention, the above-mentioned disease or condition is a disease or condition mediated by a KRAS mutation; the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutations.

[0029] In some embodiments of the invention, the above-mentioned compounds or their pharmaceutically acceptable salts may be administered by any convenient method, such as oral, parenteral, oral, sublingual, nasal, rectal, intrathecal, or transdermal administration, and accordingly modified pharmaceutical compositions.

[0030] Detailed description of the invention

[0031] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art, and in particular, the terms used in the specification and claims have the following meanings.

[0032] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted with one or more substituents. In certain embodiments, alkyl refers to a group having a carbon density of 1 to 20 (C). 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 A straight-chain saturated hydrocarbon group with 3 to 20 carbon atoms, or a group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched saturated hydrocarbon group with 1 carbon atom. The straight-chain C group used here... 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl groups". For example, C 1-6Alkyl groups refer to linear saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In one embodiment, the C 1-6 The alkyl group contains 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, 6). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0033] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is defined as described above. Non-limiting examples of "alkylene" include methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0034] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group, and the alkenyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkenyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched unsaturated hydrocarbon group with 16 carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of alkenyl groups include: , , , , or Those skilled in the art will understand that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

[0035] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group. The alkynyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkynyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched unsaturated hydrocarbon group with 12 carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6Alkyne refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 The alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of the alkynyl group include: , , or In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

[0036] The term "cycloalkyl" refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring comprises 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring comprises 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 It has 10 carbon atoms; it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenedyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or an optionally fused cycloalkyl group with a heterocyclic group, aryl group, or heteroaryl group, as described elsewhere herein, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0037] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group that shares a single carbon atom (called a spiro atom) between its monocyclic rings. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group comprises 5 to 20 carbon atoms. 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with one embodiment being monospirocycloalkyl and bispirocycloalkyl. In one embodiment, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include: .

[0038] The term "fused-cycle alkyl" refers to a fully carbon polycyclic group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. In a particular embodiment, the fused-cycle alkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl groups. In one embodiment, the fused-ring alkyl group is an optionally substituted fused-ring alkyl group described elsewhere herein or an fused-ring alkyl group optionally fused with a heterocyclic group, aryl group, or heteroaryl group. Non-limiting examples of fused-ring alkyl groups include: , , , , , or .

[0039] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the bridged cycloalkyl group comprises 5 to 20 (C...) 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl group is an optionally substituted bridged alkyl group described elsewhere herein. Non-limiting examples of bridged alkyl groups include: .

[0040] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, the ring carbon atom may optionally be substituted with oxygen, excluding the -OO- or -OS- ring moiety, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic group comprises 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, wherein 1 to 4 are heteroatoms; in one embodiment, the heterocyclic group comprises 3 to 8, 5 to 10, or 6 to 11 ring atoms; in one embodiment, the heterocyclic group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrrole, azahexacyclic butyl, oxacyclobutyl, oxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0041] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of spiro atoms shared between the rings; monospirocyclic and bispirocyclic groups are preferred; in one embodiment, the spiroheterocyclic group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group; in one embodiment, the spiroheterocyclic group is an optionally substituted spiroheterocyclic group described elsewhere herein; non-limiting examples of spiroheterocyclic groups include: , , , , , , , , , , , , or .

[0042] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include: , , , , , , , , , , , , , , , , , , , , , or .

[0043] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In certain embodiments, the bridged heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include: , , , , , , , or .

[0044] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In certain embodiments, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocyclic groups. In one embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6-membered cycloalkyl, or benzo3-6-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomilecycloyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indene, tetrahydronaphthyl (naphthyl), , , , , , , , , , , , , and .

[0045] The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group, wherein the arylene group may be optionally substituted or unsubstituted, as defined above for aryl groups.

[0046] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In certain embodiments, a heteroaryl comprises 5 to 20, 5 to 14, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, a heteroaryl comprises 5 or 6 ring atoms; in certain embodiments, a heteroaryl may further refer to a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated carbocyclic rings, or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic group; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indazinyl, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridyl, acridineyl, benzoindolyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, xanthonyl, , , , , , , , , and .

[0047] The term "heteroaryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group may be optionally substituted or unsubstituted, as defined above.

[0048] The term "heteroalkyl" refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal positions), including positions where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0049] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0050] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0051] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said haloalkyl groups include: trifluoromethyl, -CH2CF3, or .

[0052] The term “haloalkoxy” refers to an alkoxy group that has been substituted with one or more halogens, where the definition of an alkoxy group is as described above.

[0053] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0054] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkathio group is an optionally substituted alkathio group described elsewhere herein.

[0055] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein the definition of alkylthio is as described above.

[0056] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as previously stated. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described elsewhere herein.

[0057] The term "aminocarbonyl" refers to NH2-C(O)-.

[0058] The term "alkylaminocarbonyl" refers to an aminocarbonyl group (NH2-C(O)-) in which one or both hydrogen atoms are replaced by an alkyl group, as defined above.

[0059] The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, as defined above.

[0060] The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All designations are interchangeable in the specification.

[0061] The term "hydroxyl group" refers to the -OH group.

[0062] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0063] The term "oxo" or "side oxygen" refers to =O.

[0064] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in the compound may be enriched with deuterium and / or tritium. Such isotope-enriched analogs may be prepared from suitable isotopically labeled starting materials available from commercial sources or by known literature procedures, wherein the hydrogen or hydrogen atom described in this patent comprises its isotopes (H) and / or mixtures thereof. 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof.

[0065] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0066] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0067] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0068] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0069] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0070] Unless otherwise stated, the indefinite articles “a” and “an” and the definite article “the” in this specification and claims include both plural and singular forms.

[0071] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0072] "Medicinal salts" refers to salts of the compounds of this invention that are safe and effective when used in mammals and have the appropriate biological activity.

[0073] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers of the present invention, as well as enantiomers / non-corresponding isomers / stereoisomers enriched in this invention.

[0074] "Stereoisopure" refers to a composition containing one stereoisomer of a compound but substantially lacking another stereoisomer of that compound. For example, a stereoisopure composition of a compound having one chiral center will substantially lack the opposing enantiomer of that compound. A stereoisopure composition of a compound having two chiral centers will substantially lack other diastereomers of that compound. A typical stereoisomeric pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

[0075] "Stereoisomeric enrichment" refers to a composition containing a stereoisomer of a compound at a mass content greater than about 55%, about 60%, about 70%, or about 80%.

[0076] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having a single chiral center.

[0077] "Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemic compound and about 5% or less of the subpreferred enantiomer or diastereomer.

[0078] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule.

[0079] The compounds of this invention include all of their "stereoisomers", "stereoisomeric purity", "stereoisomeric enrichment", "enantiomeric purity", "optical activity", "enantiomeric activity" and "optical isomers". Detailed Implementation

[0080] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0081] Example

[0082] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shift ( ) with 10 -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0083] MS measurements were performed using a Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0084] The HPLC determination was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C). 18 150×4.6mm chromatographic column) and Waters 2695-2996 high-performance liquid chromatograph (Gimini C) 18 (150×4.6mm chromatographic column).

[0085] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0086] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.15 mm to 0.2 mm, and the size used for thin-layer chromatography separation and purification of products is 0.4 mm to 0.5 mm.

[0087] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0088] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0089] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0090] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0091] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0092] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0093] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0094] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0095] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0096] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20 ℃ to 30 ℃.

[0097] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0098] The eluent systems for column chromatography and the developing solvent systems for thin-layer chromatography used to purify the compounds include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran system. The volume ratio of the solvents is adjusted according to the polarity of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0099] INT-A

[0100] 5-(3-(tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indazole

[0101] Step 1: At room temperature, palladium acetate (77 mg, 0.3 mmol) and allyl alcohol (0.7 mL, 10.0 mmol) were added to a solution of compound A-1 (3.0 g, 6.8 mmol), sodium bicarbonate (1.4 g, 17.0 mmol), and tetrabutylammonium chloride (2.0 g, 6.8 mmol) in dimethyl sulfoxide (50 mL). The mixture was stirred at 50°C for 16 hours under nitrogen protection to obtain a black solution. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indoleazol-5-yl)propionaldehyde A-2 (2.1 g, yield 84.0%). MS m / z (ESI): 371 [M+H].

[0102] Step 2: At room temperature, sodium borohydride (214 mg, 5.7 mmol) was added fractionally to a 15 mL ethanol solution of compound A-2 (2.1 g, 5.7 mmol). The mixture was stirred at 25°C for 1 hour under nitrogen protection. The reaction solution was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indoleazol-5-yl)prop-1-ol A-3 (2 g, 95.0% yield). The crude product was directly used in the next step. MS m / z (ESI): 373 [M+H].

[0103] Step 3: At room temperature, imidazole (548 mg, 8.1 mmol) and tert-butyldimethylchlorosilane (971 mg, 6.4 mmol) were added sequentially to a solution of compound A-3 (2.0 g, 5.4 mmol) in dichloromethane (50 mL). Under nitrogen protection, the mixture was stirred at 25°C for 3 hours to obtain a white suspension. The reaction solution was poured into a saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, washed sequentially with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 4-bromo-5-(3-(tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole A-4 (2.3 g, yield 88.1%). MS m / z (ESI): 487 [M+H].

[0104] Step 4: At room temperature, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (315 mg, 0.4 mmol) was added to a solution of compound A-4 (2.3 g, 4.3 mmol), potassium acetate (845 mg, 8.6 mmol), and pinacol diborate (1.3 g, 5.2 mmol) in dioxane (30 mL). Under nitrogen protection, the mixture was slowly heated to 110°C and stirred for 16 hours to obtain a yellow suspension. The reaction solution was filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain INT-A (1.9 g, yield 82.5%). MS m / z (ESI): 535 [M+H].

[0105] Example 1

[0106] (1 6 S)-3 6 -Chloride-2 2 -((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2 8 -Fluorine-3 1 H-7,9-dioxa-1(4,6)-oxazolidine-2(4,7)-pyrido[4,3-d]pyrimidine-3(4,5)-indazolecyclonaphthyl-8-one

[0107] Step 1: Under ice bath conditions, potassium tert-butoxide (2.2 g, 20.1 mmol) and trifluoroethanol (3.1 g, 30.2 mmol) were added to a tetrahydrofuran (20 mL) solution of compound 1-1 (2.5 g, 9.9 mmol). The mixture was stirred under nitrogen protection for 1 hour under ice bath conditions. The reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography to give 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine 1-2 (2.5 g, yield 80.6%). MS m / z (ESI): 317 [M+H].

[0108] Step 2: At room temperature, (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.7 g, 8.7 mmol) and [other ingredients] were added to 1,4-dioxane (30 mL) of compounds 1-2 (2.5 g, 7.9 mmol) and [other ingredients]. N, N -Diisopropylethylamine (2.1 g, 15.8 mmol) was reacted with the solution under nitrogen protection at 90°C for 10 hours. The reaction solution was cooled and concentrated directly under reduced pressure. The crude product was purified by silica gel column chromatography to (S)-7-chloro-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine 1-3 (2.4 g, yield 64.5%). MS m / z (ESI): 469 [M+H].

[0109] Step 3: At room temperature, react compounds 1-3 (1.0 g, 2.1 mmol) with... N, N Add (S)-1,4-oxazacycloheptan-6-ol (249 mg, 2.1 mmol) to a 20 mL solution of dimethylformamide and N, N -Diisopropylethylamine (0.5 mL), reacted at room temperature for 2 hours. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography to (6S)-4-(7-chloro-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazolidine-6-ol 1-4 (900 mg, yield 88.4%). MS m / z (ESI): 486 [M+H].

[0110] Step 4: At room temperature, potassium phosphate (1.5 g, 7.4 mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (131 mg, 0.2 mmol) were added to a tetrahydrofuran (15 mL) and water (5 mL) solution of compounds 1-4 (900 mg, 1.9 mmol) and intermediate A (1.5 g, 2.8 mmol). Under nitrogen protection, the mixture was slowly heated to 80 °C and reacted for 3 hours. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography to obtain (S)-4-(7-(5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazolidine-6-ol 1-5 (900 mg, yield 56.7%). MS m / z (ESI): 858 [M+H].

[0111] Step 5: At room temperature, carbonyl diimidazole (341 mg, 2.1 mmol) was added to a tetrahydrofuran (20 mL) solution of compounds 1-5 (900 mg, 1.1 mmol), and the mixture was stirred at 50°C for 6 hours. The reaction solution was concentrated to give the crude product (6S)-4-(7-(5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazol-6-yl 1H-imidazol-1-carboxylate 1-6 (1.2 g). MS m / z (ESI): 952 [M+H].

[0112] Step 6: At room temperature, add a tetrabutylammonium fluoride (1M, 5 mL) tetrahydrofuran solution to a tetrahydrofuran solution of compounds 1-6 (1.2 g, 1.3 mmol), under nitrogen protection, and stir at 45°C for 6 hours. Directly concentrate the reaction solution, and purify the crude product by silica gel column chromatography to obtain (1... 6 S)-3 6 -Chloride-2 2 -((2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2 8 -Fluorine-3 1 -(tetrahydro-2H-pyran-2-yl)-3 1H-7,9-dioxa-1(4,6)-oxazolidine-2(4,7)-pyrido[4,3-d]pyrimidine-3(4,5)-indazolecyclonaphthyl-8-one 1-7 (300 mg, two-step yield 37.1%). MS m / z(ESI): 770 [M+H].

[0113] Step 7: At room temperature, trifluoroacetic acid (1 mL) was added to a dichloromethane (4 mL) solution of compounds 1-7 (100 mg, 0.1 mmol), and the mixture was stirred for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain Example 1 (30 mg, yield 33.7%). MS m / z (ESI): 686 [M+H].

[0114] The following examples were prepared according to the synthesis method of Example 1:

[0115] Biological testing evaluation

[0116] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0117] I. Determination of the inhibitory activity of the compounds of this invention on the proliferation of KRAS G12D mutant tumor cell lines

[0118] 1. Experimental objective: To determine the inhibitory activity of the compounds in the examples on the proliferation of five KRAS G12D mutant cell lines: SNU-1, HPAF-II, Panc0403, AsPC-1, and GP2D.

[0119] 2. Experimental apparatus: 2.1 Instruments: Microplate reader (BioTek Synergy H1); pipettes (Eppendorf & Rainin).

[0120] 2.2 Reagents: HPAF-II, PANC0403, AsPC-1, and GP2D were purchased from Nanjing Kebai Biotechnology Co., Ltd.; SNU-1 was purchased from the Cell Bank of the Chinese Academy of Sciences; Cell Titer-Glo was purchased from Promega (Catalog No. G7573); RPMI 1640 was purchased from Gibco (Catalog No. 22400089); DMEM was purchased from Gibco (Catalog No. 11995065); FBS was purchased from Gibco (Catalog No. 10091148); PBS was purchased from Gibco (Catalog No. 10010023); trypsin was purchased from Gibco (Catalog No. 25200056); and cell culture plates were purchased from Corning (Catalog No. 3610).

[0121] 3. Experimental Methods: When SNU-1, HPAF-II, Panc0403, AsPC-1, or GP2D cells reached a suitable confluence, collect the cells and adjust them to a suitable cell density using complete culture medium. Spread the cell suspension into 96-well plates, 90 μL per well, and incubate overnight at 37°C with 5% CO2. Prepare compound solutions of different concentrations using DMSO and culture medium, and set up a solvent control. Add 10 μL of the compound solution to each well of the 96-well plate and incubate at 37°C with 5% CO2 for approximately 72 hours. Then add CellTiter-Glo solution, shake to mix thoroughly, and incubate in the dark for 10 minutes. Read the values ​​using a BioTek Synergy H1 microplate reader.

[0122] 4. Experimental Data Processing Methods: The inhibition rate was calculated using the emission signal value. The concentration and inhibition rate were then fitted using Graphpad Prism software to obtain the EC50. 50 value.

[0123] 5. Experimental Results: Based on the above methods, the compounds in the embodiments of this invention showed ECMO inhibitory activity against the proliferation of SNU-1, HPAF-II, Panc0403, AsPC-1, and GP2D cells. 50 value.

[0124] In some embodiments, the compounds of the present invention exhibit ECMO inhibitory activity against the proliferation of SNU-1, HPAF-II, Panc0403, AsPC-1, and GP2D cells. 50 Less than about 100 nM, preferably less than about 50 nM, more preferably less than about 5 nM, more preferably less than about 1 nM, and most preferably less than 0.1 nM among the compounds listed in this invention.

[0125] 6. Experimental conclusions: The compounds in the embodiments of the present invention have significant inhibitory effects on the proliferation of SNU-1, HPAF-II, Panc0403, AsPC-1 and GP2D cells.

[0126] II. Determination of the inhibitory activity of the compounds of this invention on the proliferation of KRAS-mutated and expanded tumor cell lines

[0127] 1. Experimental objective: To determine the inhibitory activity of the compounds in the examples on the proliferation of KRAS mutant and amplified cell lines SW620 and MKN1.

[0128] 2. Experimental apparatus: 2.1 Instruments: Nano-level dispensing system (I-DOT); microplate reader (BioTek Synergy H1); pipettes (Eppendorf & Rainin).

[0129] 2.2 Reagents: MKN1 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.; SW620 cells were purchased from ATCC; CellTiter-Glo was purchased from Promega (catalog number G7573); RPMI 1640 was purchased from Gibco (catalog number 22400089); DMEM was purchased from Gibco (catalog number 11995065); FBS was purchased from Gibco (catalog number 10091148); PBS was purchased from Gibco (catalog number 10010023); trypsin was purchased from Gibco (catalog number 25200056); and cell culture plates were purchased from Corning (catalog number 3610).

[0130] 3. Experimental Methods: When SW620 and MKN1 cells reached a suitable confluence, cells were collected and adjusted to an appropriate cell density using complete culture medium. The cell suspension was then seeded into 96-well plates (100 μL per well) and incubated overnight at 37°C with 5% CO2. Compound solutions of different concentrations were prepared using DMSO, and then the compound solutions were added to the 96-well plates using an I-DOT nanoliter separatory system (8 nL-600 nL per well). The plates were incubated at 37°C with 5% CO2 for 3-6 days. Afterward, 50 μL of CellTiter-Glo solution was added, the mixture was shaken to mix thoroughly, and the plates were incubated in the dark for 10 minutes. The readings were then taken using a BioTek Synergy H1 microplate reader.

[0131] 4. Experimental Data Processing Methods: The inhibition rate was calculated using the emission signal value. The concentration and inhibition rate were then fitted using Graphpad Prism software to obtain the IC50. 50 value.

[0132] 5. Experimental Results: Based on the above methods, the IC50 of the compounds in the embodiments of this invention against the proliferation inhibitory activity of SW620 and MKN1 cells was found to be [value missing]. 50 value.

[0133] In some embodiments, the IC50 of the compounds of the present invention for inhibiting the proliferation of SW620 cells is [not specified]. 50 Less than about 100 nM, preferably less than about 50 nM, more preferably less than about 10 nM, more preferably less than about 5 nM, and most preferably less than 1 nM among the compounds listed in this invention.

[0134] In some embodiments, the IC50 of the compounds of the present invention for inhibiting the proliferation of MKN1 cells is [not specified]. 50 Less than about 100 nM, preferably less than about 50 nM, more preferably less than about 10 nM, more preferably less than about 5 nM, and most preferably less than 1 nM among the compounds listed in this invention.

[0135] 6. Experimental conclusion: The compounds in the embodiments of the present invention have significant inhibitory effects on the proliferation of SW620 and MKN1 cells.

Claims

1. A compound of general formula (IA) or (IB) or a pharmaceutically acceptable salt thereof: in: X1 is selected from N or CR4; X2 is selected from N or CR5; L is selected from -O-, -CR 1-3 R 1-4 -, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 The arylene and 5-14 heteroarylene groups are optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. a Replaced; L1 is selected from key, -O-, -S-, -NR N -, -C(O)-, -S(O)- or -SO2-; L2 is selected from bonds, C1-C6 alkylene groups, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C1-C6 alkylene-C 3-8 Cycloalkylene or C1-C6 alkylene-3-8 membered heterocyclic alkylene, wherein the C1-C6 alkylene, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are optionally replaced by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Alternatively, two substituents on the same carbon atom in a C1-C6 alkylene group can be linked to form a C1-C6 alkylene group. 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups may optionally be further replaced by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; The ring C is selected from a macrocyclic system, wherein the macrocyclic system optionally further includes one or more N, O, S, and P heteroatoms; R1, R 1-1 R 1-2 R 1-3 and R 1-4 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12-membered heterocyclic group, -(CH2) n1 -C 6-14 Aryl, -(CH2) n1 -5-14 heteroaryl groups, -(CH2) n1 -OR 1a -(CH2) n1 -NR 1a R 1b -(CH2) n1 -C(O)R 1a -(CH2) n1 -C(O)NR 1a R 1b -(CH2) n1 -NR 1a C(O)R 1b -(CH2) n1 -S(O) m1 R 1a -(CH2) n1 -NR aa S(O) m1 R 1b Or -(CH2) n1 -S(O) m1 NR 1a R 1b The above-mentioned groups, the hydrogen in the groups, and -(CH2) n1 - Any CH2 group may optionally be further reacted with hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions from aryl, 5-10 heteroaryl, =CH2, =CHF and =CF2; Or, R 1-1 With R 1-2 The links form 3-12-membered heterocyclic groups or 5-14-membered heteroaryl groups, wherein the 3-12-membered heterocyclic group or 5-14-membered heteroaryl group is optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. a Replaced; R2 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R3 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R4 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Alternatively, R2 and R4 can be linked to form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups, wherein the above groups may optionally be further replaced by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R5 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R6 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl groups, wherein the above groups are optionally further surrounded by one or more R groups. d replace; R a Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n2 -OR 2a -(CH2) n2 -C(O)R 2a -(CH2) n2 -C(O)OR 2a -(CH2) n2 -NR 2a R 2b -(CH2) n2 -P(O)R 2a R 2b -(CH2) n2 -NR 2c C(O)R 2a -(CH2) n2 -C(O)NR 2a R 2b -(CH2) n2 -S(O)2R 2a -(CH2) n2 -S(O)2NR 2a R 2b -(CH2) n2 -NR 2c S(O)2R 2a -(CH2) n2 -S(O)R 2a (=NR 2c -(CH2) n2 -N=S(O)R 2a R 2b =CR 2a R 2b =NR 2a =N-OR 2a or =CR 2a -CR 2c R 2d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n2 - Any CH2 in the mixture can optionally be further reacted with one or more R aa replace; R b Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n3 -OR 3a -(CH2) n3 -C(O)R 3a -(CH2) n3 -C(O)OR 3a -(CH2) n3 -NR 3a R 3b -(CH2) n3 -P(O)R 3a R 3b -(CH2) n3 -NR 3c C(O)R 3a -(CH2) n3 -C(O)NR 3a R 3b -(CH2) n3 -S(O)2R 3a -(CH2) n3 -S(O)2NR 3a R 3b -(CH2) n3 -NR 3c S(O)2R 3a -(CH2) n3 -S(O)R 3a (=NR 3c -(CH2) n3 -N=S(O)R 3a R 3b =CR 3a R 3b =NR 3a =N-OR 3a or =CR 3a -CR 3c R 3d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n3 - Any CH2 in the mixture can optionally be further reacted with one or more R bb replace; R c Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n4 -OR 4a -(CH2) n4 -C(O)R 4a -(CH2) n4 -C(O)OR 4a -(CH2) n4 -NR 4a R 4b -(CH2) n4 -P(O)R 4a R 4b -(CH2) n4 -NR 4c C(O)R 4a -(CH2) n4 -C(O)NR 4a R 4b -(CH2) n4 -S(O)2R 4a -(CH2) n4 -S(O)2NR 4a R 4b -(CH2) n4 -NR 4c S(O)2R 4a -(CH2) n4 -S(O)R 4a (=NR 4c -(CH2) n4 -N=S(O)R 4a R 4b =CR 4a R 4b =NR 4a =N-OR 4a or =CR 4a -CR 4c R 4d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n4 - Any CH2 in the mixture can optionally be further reacted with one or more R cc replace; R d Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n5 -OR 5a -(CH2) n5 -C(O)R 5a -(CH2) n5 -C(O)OR 5a -(CH2) n5 -OC(O)R 5a -(CH2) n5 -NR 5a R 5b -(CH2) n5 -P(O)R 5a R 5b -(CH2) n5 -NR 5c C(O)R 5a -(CH2) n5 -C(O)NR 5a R 5b -(CH2) n5 -OC(O)NR 5a R 5b -(CH2) n5 -S(O)2R 5a -(CH2) n5 -S(O)2NR 5a R 5b -(CH2) n5 -NR 5c S(O)2R 5a -(CH2) n5 -S(O)R 5a (=NR 5c -(CH2) n5 -N=S(O)R 5a R 5b =CR 5a R 5b =NR 5a =N-OR 5a or =CR 5a -CR 5c R 5d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n5 - Any CH2 in the mixture can optionally be further reacted with one or more R dd replace; R N Selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 1a ~R 1d R 2a ~R 2d R 3a ~R 3d R 4a ~R 4d and R 5a ~R 5d Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n6 -OR ee -(CH2) n6 -C(O)R ee -(CH2) n6 -C(O)OR ee -(CH2) n6 -OC(O)R ee -(CH2) n6 -NR ee R ff -(CH2) n6 -P(O)R ee R ff -(CH2) n6 -NR ff C(O)R ee -(CH2) n6 -C(O)NR ee R ff -(CH2) n6 -S(O)2R ee -(CH2) n6 -S(O)2NR ee R ff -(CH2) n6 -NR ff S(O)2R ee -(CH2) n6 -S(O)R ee (=NR ff -(CH2) n6 -N=S(O)R ee R ff The above-mentioned groups, the hydrogen in the groups, and -(CH2) n6 - Any CH2 group may optionally be further reacted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Or, R 1a ~R 1d R 2a ~R 2d R 3a ~R 3d R 4a ~R 4d and R 5a ~R 5d Any two links in the chain form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; R aa R bb R cc R dd R ee and R ff Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Or, R ee and R ff The links in the middle form a ring system, which is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; m1 is selected from 0, 1, or 2; n1 is selected from 0, 1, 2, 3, 4, 5, or 6; n2 is selected from 0, 1, 2, 3, 4, 5, or 6; n3 is selected from 0, 1, 2, 3, 4, 5, or 6; n4 is selected from 0, 1, 2, 3, 4, 5, or 6; n5 is selected from 0, 1, 2, 3, 4, 5, or 6; n6 is selected from 0, 1, 2, 3, 4, 5, or 6; b is selected from 0, 1, 2, 3, 4, 5, or 6; and c is selected from 0, 1, 2, 3, 4, 5, or 6.

2. The compound of general formula (IA) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Further, as shown in general formula (II-A) or (II-B): Ring A is selected from 3-12 membered heterocyclic groups or 5-14 membered heterocyclic groups; L3 is selected from the bond, -(CH2). n8 O-, -(CH2) n8 S-, -(CH2) n8 NR 6a -、-(CH2) n8 C(O)-、-(CH2) n8 OC(O)-、-(CH2) n8 C(O)O-、-(CH2) n8 OC(O)O-、-(CH2) n8 C(O)NR 6a -、-(CH2) n8 NR 6a C(O)-、-(CH2) n8 OC(O)NR 6a -、-(CH2) n8 NR 6a C(O)O-、-(CH2) n8 S(O)2NR 6a -、-(CH2) n8 NR 6a S(O)2-, C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 alkylene, wherein the C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene and 5-10 heteroarylene groups may be optionally replaced by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; L4 is selected from the bond, -(CH2). n8 O-, -(CH2) n8 S-, -(CH2) n8 NR 6a -、-(CH2) n8 C(O)-、-(CH2) n8 OC(O)-、-(CH2) n8 C(O)O-、-(CH2) n8 OC(O)O-、-(CH2) n8 C(O)NR 6a -、-(CH2) n8 NR 6a C(O)-、-(CH2) n8 OC(O)NR 6a -、-(CH2) n8 NR 6a C(O)O-、-(CH2) n8 S(O)2NR 6a -、-(CH2) n8 NR 6a S(O)2-, C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 alkylene, wherein the C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene and 5-10 heteroarylene groups may be optionally replaced by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; L5 is selected from the bond, -(CH2). n8 O-, -(CH2) n8 S-, -(CH2) n8 NR 6a -、-(CH2) n8 C(O)-、-(CH2) n8 OC(O)-、-(CH2) n8 C(O)O-、-(CH2) n8 OC(O)O-、-(CH2) n8 C(O)NR 6a -、-(CH2) n8 NR 6a C(O)-、-(CH2) n8 OC(O)NR 6a -、-(CH2) n8 NR 6a C(O)O-、-(CH2) n8 S(O)2NR 6a -、-(CH2) n8 NR 6a S(O)2-, C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 alkylene, wherein the C1-C6 alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene and 5-10 heteroarylene groups may be optionally replaced by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 6a R 6b and R 6c Each is independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; a is selected from 0, 1, 2, 3, 4, 5 or 6; n7 is selected from 0, 1, 2, 3 or 4; n8 is selected from 0, 1, 2, 3 or 4.

3. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that, L2 is selected from or ; R g-1 and R g-2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R g-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R g-4 R g-5 R g-6 and R g-7 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; q is selected from 0, 1, 2, 3, or 4; Alternatively, R6 is selected from 5-7 member monocyclic heterocyclic groups, 6-14 member spirocyclic heterocyclic groups, 6-14 member fused heterocyclic groups, or 6-14 member bridged heterocyclic groups, and can optionally be further divided by 1, 2, 3, 4, 5, or 6 R6 groups. d Replacement; preferably from 5-7 nucleotide monocyclic heterocyclic groups, 7-10 nucleotide spirocyclic heterocyclic groups, 7-10 nucleotide fused heterocyclic groups, or 7-10 nucleotide bridged heterocyclic groups, optionally further replaced by 1, 2, 3, 4, 5, or 6 R groups. d Replacement; preferably from 5-7 member monocyclic heterocyclic groups, 7-10 member fused heterocyclic groups, or 7-10 member bridged heterocyclic groups, optionally further replaced by 1, 2, 3, 4, 5, or 6 R groups. d replace; Preferably, R6 is selected from , , , , , , , , , , , , , , , , , , , or Optionally, it can be further divided into 1, 2, 3, 4, 5 or 6 Rs. d replace; R d As defined in the claims.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that, -L2-R6 is selected from , , , , , , , , , , , , or ; Ring F is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Ring G is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Ring H is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Ring I is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R d-1 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n5 -OR 5a -(CH2) n5 -C(O)R 5a -(CH2) n5 -C(O)OR 5a -(CH2) n5 -OC(O)R 5a -(CH2) n5 -NR 5a R 5b -(CH2) n5 -P(O)R 5a R 5b -(CH2) n5 -NR 5c C(O)R 5a -(CH2) n5 -C(O)NR 5a R 5b -(CH2) n5 -OC(O)NR 5a R 5b -(CH2) n5 -S(O)2R 5a -(CH2) n5 -S(O)2NR 5a R 5b -(CH2) n5 -NR 5c S(O)2R 5a -(CH2) n5 -S(O)R 5a (=NR 5c -(CH2) n5 -N=S(O)R 5a R 5b =CR 5a R 5b =NR 5a =N-OR 5a or =CR 5a -CR 5c R 5d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n5 - Any CH2 in the mixture can optionally be further reacted with one or more R dd replace; R d-2 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -(CH2) n5 -OR 5a -(CH2) n5 -C(O)R 5a -(CH2) n5 -C(O)OR 5a -(CH2) n5 -OC(O)R 5a -(CH2) n5 -NR 5a R 5b -(CH2) n5 -P(O)R 5a R 5b -(CH2) n5 -NR 5c C(O)R 5a -(CH2) n5 -C(O)NR 5a R 5b -(CH2) n5 -OC(O)NR 5a R 5b -(CH2) n5 -S(O)2R 5a -(CH2) n5 -S(O)2NR 5a R 5b -(CH2) n5 -NR 5c S(O)2R 5a -(CH2) n5 -S(O)R 5a (=NR 5c -(CH2) n5 -N=S(O)R 5a R 5b =CR 5a R 5b =NR 5a =N-OR 5a or =CR 5a -CR 5c R 5d The above-mentioned groups, the hydrogen in the groups, and -(CH2) n5 - Any CH2 in the mixture can optionally be further reacted with one or more R dd replace; r-1 is selected from 0, 1, 2, or 3; r-2 is selected from 0, 1, 2, or 3; r is selected from 0, 1, 2, 3, 4, 5 or 6; R g-1 R g-2 R g-3 R g-4 R g-5 R g-6 R g-7 and q as defined in claim 3; R d R dd and R 5a ~R 5d As defined in claim 1.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that, Further, as shown in general formula (III-A) or (III-B): Ring E is selected from 5-7 member monocyclic heterocyclic groups, 6-14 member spirocyclic heterocyclic groups, 6-14 member fused heterocyclic groups, or 6-14 member bridged heterocyclic groups; R d As defined in claim 1; r as defined in claim 4.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that, Ring A is selected from 6-membered heterocyclic groups, 7-membered heterocyclic groups, 8-membered heterocyclic groups, 5-14-membered fused heterocyclic groups, or 5-14-membered spiroheterocyclic groups; Preferably, ring A is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; or, Selected from , , or ; M1 is selected from N or CH; M2 is selected from N or CH; Alternatively, X1 is selected from N, CH, CCH3, CCH2CH3, C-Cl, CF, C-CF3 or C-CHF2; preferably N, CH, CCH3, CCH2CH3, C-Cl or CF; Alternatively, R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl or C 1-3 Alkylamino; Preferably, R2 is selected from hydrogen, deuterium, fluorine, chlorine, or bromine; More preferably, R2 is selected from fluorine.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that, Selected from the following compounds: or .

8. A pharmaceutical composition comprising a therapeutically effective dose of any of the compounds shown in claims 1 to 7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

9. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 8, in the preparation of a KRAS inhibitor medicament; preferably in the preparation of a KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G13D inhibitor medicament.

10. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for treating diseases or conditions such as Noonan syndrome, panther syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer; preferably, in the preparation of a medicament for treating non-small cell lung cancer, pancreatic cancer, colon cancer, esophageal cancer, and head and neck tumors.

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