CN115724844A - Heterocyclic compound with antitumor activity and application thereof - Google Patents
Heterocyclic compound with antitumor activity and application thereof Download PDFInfo
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- CN115724844A CN115724844A CN202211473008.0A CN202211473008A CN115724844A CN 115724844 A CN115724844 A CN 115724844A CN 202211473008 A CN202211473008 A CN 202211473008A CN 115724844 A CN115724844 A CN 115724844A
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- Prior art keywords
- alkyl
- radical
- halogen
- cycloalkyl
- amino
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- 230000000259 anti-tumor effect Effects 0.000 title description 2
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a compound, or tautomer, optical isomer, hydrate, solvate, isotopic derivative, prodrug or pharmaceutically acceptable salt thereof. The compound designed by the invention has a novel structure, and provides a new direction for the development of SOS-1 inhibitor drugs. The research on the in vitro enzyme activity inhibition activity shows that the compounds have stronger inhibition effect on SOS-1 and can be used as prospect compounds for treating SOS-1 inhibitor mediated diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has the advantages of simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a compound serving as an SOS1 inhibitor, and a preparation method and application of the compound.
Background
The currently known RAS family shares three genes: KRAS (Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma RAS virus oncogene homolog), and HRAS (Harvey murine sarcoma virus oncogene). RAS family proteins are a class of small molecule gtpases and are the first oncogenes identified in human tumors. RAS family proteins have weak intrinsic gtpase activity and slow nucleotide exchange rates. Binding of Gtpase Activating Proteins (GAPs), such as NF1, increases gtpase activity of RAS family proteins.
Mutations in the RAS enzyme are closely associated with tumorigenesis, and RAS mutation types vary among different types of tumors. In human tumors, KRAS mutations (e.g. amino acids G12, G13, Q61, a 146) are most common, accounting for approximately 85%, NRAS (e.g. amino acids G12, G13, Q61, a 146) and HRAS (e.g. amino acids G12, G13, Q61) accounting for 12% and 3%, respectively. Alterations (e.g., mutations, overexpression, gene amplification) of RAS family proteins have also been described as resistance mechanisms against cancer drugs such as: EGFR antibodies cetuximab (cetuximab) and panitumumab (panitumumab)) and the EGFR tyrosine kinase inhibitor oxitinib (osimertinib). For oncogenic RAS mutants, GAP activity is impaired or greatly reduced, leading to permanent activation, which is the basis for oncogenic RAS signaling. Direct inhibition of RAS has proven to be extremely challenging and difficult to administer due to the picomolar affinity of GTP for its binding site, the lack of other well-defined pockets, and the fact that RAS interacts with GEF, GAP, and effectors via extended and flat protein-protein interaction surfaces. Therefore, inhibition of RAS activation by targeting the upstream guanine nucleotide exchange factor protein, SOS, may be of new interest.
There are two human isoforms of SOS, SOS1 and SOS2, but most studies have focused on SOS1. Human SOS1 comprises 1333 amino acids (15 kDa) and consists of an N-terminal domain, a Dbl Homology (DH) domain, a Pleckstrin Homology (PH) domain, including a Ras exchanger motif (Rem) domain and a Cdc25 domain, and a C-terminal region. Wherein pH, rem and Cdc25 are SOS cat Components of the core catalytic domain.
In the past decades, RAS family protein-SOS 1 protein interactions have gained increasing acceptance. In addition, more recently, research has been conducted to combine rational design and screening platforms to identify small molecule inhibitors to SOS1, i.e., compounds that bind to SOS1 and inhibit protein-protein interactions with RAS family proteins. SOS1 inhibitors of the bis-heterocyclic class are described, for example CN111372932A/CN 113200981A.
Although some small molecules of SOS1 inhibitors have been disclosed, no SOS1 inhibitors have yet been developed and marketed, and thus the development of new compounds with potential for marketing, with better potency and pharmacokinetic results, is still an urgent need. The invention designs a series of compounds with a new structure shown in a general formula, finds that the compounds with the structure show excellent effects and actions, and has positive significance for the development of the SOS1 inhibitor.
Disclosure of Invention
The invention aims to provide a compound with a brand-new structure as an SOS1 inhibitor, a preparation method of the compound and application of the compound in treating SOS1 mediated diseases.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R 1 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted with 0-3R which may be the same or different a Substitution;
R a each occurrence is independently selected from halogen, amino, cyano, hydroxy, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl) (C) 1-6 Alkyl), -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OC (O) -C 1-6 Alkyl, -NHCO-C 1-6 Alkyl, -CONH-C 1-6 Alkyl, -CON (C) 1-6 Alkyl) (C 1-6 Alkyl), -S (O) 2 -C 1-6 Alkyl, -NHS (O) 2 -C 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 4-10 Cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl) (C 1-6 Alkyl), -CO-C 1-6 Alkyl and substituted benzeneCOO-C 1-6 Alkyl, -OC (O) -C 1-6 Alkyl, -NHCO-C 1-6 Alkyl, -CONH-C 1-6 Alkyl, -CON (C) 1-6 Alkyl) (C) 1-6 Alkyl), -S (O) 2 -C 1-6 Alkyl, -NHS (O) 2 -C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 4-10 Cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl are each optionally substituted with one or more of the following substituents: halogen, amino, cyano, hydroxy, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NH (C) 1-6 Alkyl), -N (C) 1-6 Alkyl radical) 2 ；
R 2 Selected from hydrogen, halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -C 1-6 alkyl-NH (C) 1-6 Alkyl), -C 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -C 1-6 alkyl-NH (C) 1-6 Alkyl), -C 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted by one or more C 1-6 Alkyl, hydroxy, mercapto or halogen substitution;
R 3 selected from halogen, hydroxy, mercapto, cyano, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 0-6 alkyl-NH 2 、C 0-6 Alkyl radical-NH-C 1-6 Alkyl radical, C 0-6 alkyl-N (C) 1-6 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-6 Alkyl, -OC 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl, wherein said C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 0-6 alkyl-NH 2 、C 0-6 alkyl-NH-C 1-6 Alkyl radical, C 0-6 alkyl-N (C) 1-6 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-6 Alkyl, -OC 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl is each optionally substituted with one or more hydroxy, mercapto, amino, cyano, halogen, C 1-6 Alkyl substitution;
ring A is selected from C 4-12 Cycloalkyl of, C 4-12 Cycloalkenyl group of (1), C 6-12 Aryl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl;
R 4 each independently selected from hydrogen, cyano, halogen, amino, hydroxyl, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 0-6 alkyl-NH-C 1-6 Alkyl, -C 0-6 alkyl-N (C) 1-6 Alkyl) (C 1-6 Alkyl group), C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl; wherein, the C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy, -C 0-6 alkyl-NH-C 1-6 Alkyl, -C 0-6 alkyl-N (C) 1-6 Alkyl) (C) 1-6 Alkyl group), C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl are each optionally substituted with one or more of the following substituents: halogen, hydroxy, mercapto, amino, -SO 2 -C 1-4 Alkyl, oxo, C 1-6 Alkoxy radical, C 3-6 A cycloalkyloxy group; w =0,1,2,3,4.
Unless otherwise specified, the heteroatoms in the heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, with the number of heteroatoms being 1,2,3 or 4.
Preferably, the present invention provides a compound having a structure represented by formula (II), or a prodrug, tautomer, optical isomer, geometric isomer, solvate or pharmaceutically acceptable salt thereof:
the definition of each substituent in the formula (II) is described as the formula (I).
In a preferred embodiment of the invention, R 1 Is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 member heterocyclyl, said R 1 Are each optionally substituted by one or more of the same or different R a And (4) substitution.
Further preferably, R 1 Is selected from C 3-6 Monocyclic alkyl radical, said R 1 Are each optionally substituted by one or more of the same or different R a And (4) substitution.
Further preferably, R 1 Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, R 1 Are each optionally substituted by one or more identical or different R a And (4) substitution.
Even more preferably, R 1 Selected from cyclopropyl, said R 1 Are each optionally substituted by one or more identical or different R a And (4) substitution.
In a preferred embodiment of the invention, R a Independently at each occurrence is selected from halogen, amino, cyano, hydroxy, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 The alkoxy groups are each optionally substituted with one or more of the following substituents: halogen, amino, cyano, hydroxyl, oxo, nitro.
Further preferably, R a Each occurrence is independently selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl radical, said C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Each alkynyl group is optionally substituted with one or more of the following substituents: halogen, hydroxyl.
Further preferably, R a Each occurrence is independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl.
Even more preferably, R a Each occurrence is independently selected from trifluoromethyl, difluoromethyl, monofluoromethyl.
In a preferred embodiment of the invention, R 1 Selected from difluoromethyl-substituted cyclopropyl.
In a preferred embodiment of the invention, R 2 Selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 An alkynyl group; said C is 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 The alkynyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy, C 1-6 An alkyl group.
Further preferably, R 2 Selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, wherein said C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl is optionally substituted by one or more C 1-6 Alkyl, hydroxy or halogen;
further preferably, R 2 Selected from hydrogen, halogen, amino, C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, said C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Each alkyl is optionally substituted with one or two hydroxy or halo;
further preferably, R 2 Selected from hydrogen, methyl, ethyl, isopropyl, amino, F, cl, br, methoxy, ethoxy, formyl, acetyl.
Even more preferably, R 2 Selected from hydrogen, methyl, amino, F, cl, br, methoxy, acetyl.
In a preferred embodiment of the invention, R 3 Selected from halogen, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-4 Alkyl, -OC 1-6 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 3-6 Cycloalkyl, -O-3-10 membered heterocyclyl, wherein said C is 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-4 Alkyl, -OC 1-6 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 3-6 Cycloalkyl, -O-3-10 membered heterocyclylAre each optionally substituted by one or more halogens, C 1-6 Alkyl substitution.
Further preferably, R 3 Selected from halogen, amino, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-NH 2 、-OC 1-4 alkyl-NH-C 1-4 Alkyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 Alkyl radical-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-6 membered heterocyclyl, wherein said C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-NH 2 、-OC 1-4 alkyl-NH-C 1-4 Alkyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-6 membered heterocyclyl are each optionally substituted by one or more halogen, C 1-4 Alkyl substitution.
Further preferably, R 3 Selected from halogen, amino, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 Alkyl-3-6 membered heterocyclic group, said C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 The alkyl-3-6 membered heterocyclyl is each optionally substituted with one or two methyl groups.
Further excellenceOptionally, R 3 Selected from F, cl, br, amino, -OCH 3 、-SCH 3 Cyclopropyl, -CH 2 N(CH 3 ) 2 、-OCH 2 CH 2 N(CH 3 ) 2 、
In a preferred embodiment of the invention, ring A is selected from C 6-12 Aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl.
Further preferably, ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl.
Further preferably, ring a is selected from phenyl, pyridyl.
Further preferably, ring a is selected from phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
In a preferred embodiment of the invention, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl; wherein, the C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl are each optionally substituted with one or more of the following substituents: halogen, hydroxy, amino, -SO 2 -C 1-4 Alkyl, oxo; w =0,1,2,3.
Further preferably, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 A hydroxyalkyl group; wherein, the C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 The hydroxyalkyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy, amino; w =1,2,3.
Further preferably, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, methyl, ethyl, n-propyl, isopropyl; wherein, the nailThe radicals ethyl, n-propyl and isopropyl are each optionally substituted by one or more of the following substituents: halogen, hydroxy; w =1,2,3.
Further preferably, R 4 Each independently selected from hydrogen, halogen, amino, methyl, ethyl, isopropyl; wherein the methyl, ethyl, isopropyl groups are all optionally substituted with one or more of the following substituents: halogen, hydroxy; w =1,2,3.
Further preferably, R 4 Each independently selected from hydrogen, F, cl, br, I, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF 2 CH 2 OH、-C(CH 3 ) 2 OH、-CF 2 CH 3 ；w＝1,2,3。
Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
the invention also provides a pharmaceutical composition, which comprises the compound shown in the invention, or a tautomer, a stereoisomer, an optical isomer, a solvate, a prodrug or a pharmaceutically acceptable salt thereof.
The invention also provides a medicinal composition which comprises the compound shown in the invention, or tautomer, stereoisomer, optical isomer, solvate, prodrug or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials.
The invention also aims to provide the application of the compound shown in the invention, or the tautomer, the stereoisomer, the optical isomer, the solvate, the prodrug or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating diseases caused by SOS1 mediation and/or RAS mutation.
Preferably, the disease is cancer or tumor, and related diseases thereof. More preferably, the disease is lung cancer; still more preferably, the disease is non-small cell lung cancer. Still further, the disease is KRAS G12C mutant non-small cell lung cancer.
The invention also aims to provide application of the compound shown in the invention, or a tautomer, a stereoisomer, an optical isomer, a solvate, a prodrug or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating cancer or tumor diseases.
Preferably, the cancer or neoplastic disease is lung cancer; more preferably, the cancer or neoplastic disease is non-small cell lung cancer.
It is also an object of the present invention to provide a method for preventing and/or treating a disease mediated by SOS1 and/or mutated RAS comprising administering to a patient a therapeutically effective amount of a compound of the present invention, or a tautomer, stereoisomer, optical isomer, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.
In some embodiments, the disease is cancer or tumor, and diseases associated therewith. Further, the disease is lung cancer. Further, the disease is non-small cell lung cancer. Still further, the disease is KRAS G12C mutant non-small cell lung cancer.
The invention also aims to provide application of the compound shown in the invention, or a tautomer, a stereoisomer, an optical isomer, a solvate, a prodrug or a pharmaceutically acceptable salt thereof in vitro non-diagnostic and non-therapeutic inhibition of the activity of guanine nucleotide exchange factors (GEFs), wherein the guanine nucleotide exchange factors are selected from SOS1.
Definition of
The terms "optional," "any," "optionally," or "optionally" refer to a subsequently described event or circumstance which may, but need not, occur, and include instances where said event or circumstance occurs and instances where it does not.
The term "oxo" means that two hydrogen atoms at the same substitution position are replaced with the same oxygen atom to form a double bond.
Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 carbon atoms, preferably 1-10 carbon atoms (i.e., C) 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C) 1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e., C) 1-6 Alkyl) such as "C 1-6 By alkyl is meant that the group is alkyl and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1,2,3,4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.
Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C) 2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C) 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl), 2-5 carbon atoms (i.e., C) 2-5 Alkenyl), 2-4 carbon atoms (i.e., C) 2-4 Alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C) 2 Alkenyl) such as "C 2-6 By alkenyl "is meant that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl, and the like.
Unless otherwise specified, the term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. Alkynyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C) 2-10 Alkynyl) and further preferably contains 2 to 8 carbon atoms (C) 2-8 Alkynyl) and more preferably contains 2 to 6 carbon atoms (i.e., C) 2-6 Alkynyl), 2-5 carbon atoms (i.e., C) 2-5 Alkynyl), 2-4 carbon atoms (i.e., C) 2-4 Alkynyl), 2-3 carbon atoms (i.e., C) 2-3 Alkynyl), 2 carbon atoms (i.e., C) 2 Alkynyl) such as "C 2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having the specified number of carbon atoms, preferably comprising 3 to 12 carbon atoms (i.e., C) 3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C) 3-10 Cycloalkyl group), further preferably 3 to 6 carbon atoms (C) 3-6 Cycloalkyl), 4 to 6 carbon atoms (C) 4-6 Cycloalkyl), 5 to 6 carbon atoms (C) 5-6 Cycloalkyl groups). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
Unless otherwise specified, "cycloalkenyl" means consisting of the sub-groups monocyclic, bicyclic and spiro-hydrocarbon rings, however, the system is unsaturated, i.e. there is at least oneA C-C double bond but no aromatic system. Preferably containing 3 to 12 carbon atoms (i.e. C) 3-12 Cycloalkenyl) and more preferably 3 to 10 carbon atoms (C) 3-10 Cycloalkenyl group), further preferably 3 to 6 carbon atoms (C) 3-6 Cycloalkenyl) of 4 to 6 carbon atoms (C) 4-6 Cycloalkenyl group), 5 to 6 carbon atoms (C) 5-6 Cycloalkenyl groups).
Unless otherwise specified, the term "alkoxy" refers to an-O-alkyl group, as defined above, i.e. containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2,3,4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like. The term "alkylthio" is identical to the term "alkoxy", except that-O-alkyl is replaced by-S-alkyl.
The term "halogen" or "halo" means, unless otherwise specified, F, cl, br, I. The term "haloalkyl" means an alkyl group as defined above wherein one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl 3 、CF 3 、CHCl 2 、CH 2 Cl、CH 2 Br、CH 2 I、CH 2 CF 3 、CF 2 CF 3 And so on.
Unless otherwise specified, the term "heterocyclyl" means a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, of non-aromatic structure, containing from 3 to 20 ring atoms, wherein 1,2,3, or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably 3 to 14 ring atoms, further preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1-4, more preferably 1-3 (i.e. 1,2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
Unless otherwise specified, "heterocycloalkyl" means a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, the ring atoms being as defined above, i.e. containing from 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), the number of heteroatoms being from 1 to 4 (1, 2,3 or 4), preferably from 1 to 3 (1, 2 or 3), wherein the heteroatoms are each independently selected from N, O or S. Preferably 3 to 14 ring atoms ("3-14 membered heterocycloalkyl"), more preferably 3 to 10 ring atoms ("3-10 membered heterocycloalkyl"), even more preferably 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), even more preferably 4 to 7 ring atoms ("4-7 membered heterocycloalkyl"), even more preferably 5 to 10 ring atoms ("5-10 membered heterocycloalkyl"), even more preferably 5 to 6 ring atoms ("5-6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted (a "substituted heterocycloalkyl") with one or more substituents. Some exemplary "heterocycloalkyl" groups have been given above for the "heterocyclyl" or "heterocyclic" moiety, and also include, but are not limited to, aziridinyl, oxetanyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxiranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiacyclohexyl, oxazolidinyl, dioxanyl, dithiacyclohexyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinidinyl, and the like.
Unless otherwise specified, the term "aryl" denotes monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing from 6 to 16 carbon atoms, or from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms, or from 6 to 10 carbon atoms, preferably from 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, or the like.
Unless otherwise specified, the term "heteroaryl" denotes an aromatic monocyclic or polycyclic ring system containing a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2,3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms is preferably 1,2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, phthalizinyl, pyrrolo [ 4232 zft 4232-b ] pyridyl, imidazo [ 4234 zft 4234-a ] pyridyl, pyrazolo [ 5364 zft 5364-865a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [ 3525-b ] pyridazinyl, [ 3735 zxft 32385256-b ] pyridazinyl, triazolo [ 35523727-56 a ] triazolo [ 523883 ] pyrimidinyl, and the like.
Unless otherwise specified, the terms "pharmaceutically acceptable salt," "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refer to a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit/risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base or free acid with a suitable reagent. For example, the free base function may be reacted with a suitable acid.
Unless otherwise specified, the term "solvate" or "solvate" means a physical association of a compound of the invention with a solvent molecule (whether organic or inorganic). The physical association includes hydrogen bonding. Solvates may comprise stoichiometric or non-stoichiometric amounts of solvent molecules. In certain instances, the solvate will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular and/or disordered arrangement. Solvates encompass solution phases and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
The compounds of the invention include, unless otherwise specified, "isotopic derivatives" thereof, meaning that the compounds of the invention can exist in an isotopically labelled or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number which is the largest number found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes commonly used as isotopic labels are: an isotope of hydrogen, 2 h and 3 h; carbon isotope: 13 c and 14 c; chlorine isotope: 35 cl and 37 cl; fluorine isotope: 18 f; iodine isotope: 123 i and 125 i; nitrogen isotope: 13 n and 15 n; oxygen isotope: 15 O, 17 o and 18 isotopes of O and sulfur 35 And S. These isotopically labeled compounds can be used to study the distribution of pharmaceutically acceptable molecules in tissues. In particular 3 H and 13 c, because they are easy to label and convenient to detect, the application is more extensive. Certain heavy isotopes, such as heavy hydrogen (c: (b)) 2 H, i.e., deuterium), can enhance metabolic stability and extend half-life to provide therapeutic benefits with reduced dosage. Isotopically labeled compounds are generally synthesized by known synthetic techniques as are non-isotopically labeled compounds, starting with already labeled starting materials. In the present invention, "isotopic derivatives" (e.g., deuterons) are included within the scope of the compounds of the present invention.
Unless otherwise specified, the term "optical isomers" refers to substances that have identical molecular structures and similar physicochemical properties, but differ in optical activity.
Unless otherwise specified, the term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
Unless otherwise specified, the term "tautomer" refers to structural isomers that have different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): for example, the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
The term "prodrug", unless otherwise specified, refers to a drug that is converted in vivo to the parent drug. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they can be bioavailable by oral administration, whereas the parent cannot. The prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. An example, but not limiting of, of a prodrug would be any compound of formula I that is administered as an ester ("prodrug") to facilitate delivery across a cell membrane, where water solubility is detrimental to mobility, but once intracellular water solubility is beneficial, it is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to show an active moiety.
Unless otherwise specified, the terms "optionally substituted", "optionally substituted with … …", "optionally substituted with … …" mean that the hydrogen at the substitutable site of the group is unsubstituted or substituted with one or more substituents preferably selected from the group consisting of: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaromatic ring group, wherein C is 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaromatic ring radicals optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said oxo refers to a group in which two H at the same substitution position are replaced with the same O to form a double bond, and said "= NH" refers to a group in which two H at the same substitution position are replaced with the same-NH-to form a double bond.
The invention has the beneficial effects that:
the invention designs a compound with novel structure, and provides a new direction for the development of SOS1 inhibitor drugs. In-vitro enzymology inhibition test researches show that the compounds have stronger inhibition effect on SOS1 and can be used as prospect compounds for treating SOS 1-mediated diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has the advantages of simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials are shown herein for illustrative purposes only.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass spectrometry (LC-MS) or/and liquid chromatography (HPLC). NMR was measured using Bruker AVANCE III 600MHz, LC-MS using LCMS WATERS ACQUITY UPLC H-Class PLUS or/and SQD2; the instruments used for HPLC were WATERS e 2695-2998 or/and Agilent 1100.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
Preparation example 1: synthesis of intermediate A
(1) Synthesis of intermediate A-2:
1- (3-Nitro-5-trifluoromethyl-phenyl) -ethanone (10.00g, 43.0 mmol) was dissolved in ethanol (200 mL), followed by addition of iron powder (7.22g, 129.0 mmol), concentrated hydrochloric acid (50 mL) and reaction of the system at 80 ℃ for 2h. LCMS monitored no residue of starting material, temperature reduced filtration, solvent evaporated from filtrate under reduced pressure, and column chromatography of residue purified (dichloromethane: methanol =50, 1-20) to give a-2 (8.12g, 40.0mmol, 92%). ESI-MS (m/z): 204.12[ M ] +H] + 。
(2) Synthesis of intermediate A-3:
a-2 (27.02g, 133.0mmol) was dissolved in tetrahydrofuran (50 mL), followed by addition of (R) - (+) -2-methyl-2-propanesulfinamide (24.24g, 200.0mmol) and Ti (OEt) 4 (91.02g, 399mmol), the system is reacted at 80 ℃ for 2h, and LCMS monitors that no raw material remains. The reaction solution was quenched with ice water, and the precipitate was separatedDissolved in ethyl acetate and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, and the residue was column-chromatographically separated and purified (dichloromethane: methanol = 50. ESI-MS (m/z): 307.12[ deg. ] M + H] + 。
(3) Synthesis of intermediate A-4:
a-3 (34.65g, 113.1mmol) was dissolved in tetrahydrofuran (50 mL) and sodium borohydride (6.42g, 169.7 mmol) was added at-78 ℃. The reaction was allowed to slowly warm to room temperature and LCMS monitored that no starting material remained. The reaction solution was quenched with ice water, extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was column-chromatographically separated and purified (dichloromethane: methanol = 50. ESI-MS (m/z): 309.10[ M ] +H] + 。
(4) Synthesis of intermediate a:
a-4 (28.43g, 92.2mmol) was dissolved in dioxane hydrochloride solution (50 mL) and reacted at room temperature for 2h, LCMS monitored no residue, solvent was distilled off under reduced pressure to give intermediate A as hydrochloride salt which was directly used in the next reaction. ESI-MS (m/z): 205.22[ 2 ] M + H] + 。
The following intermediates can be obtained by reference to the synthetic method of intermediate a or by reference to the related synthetic method in CN110167928 a. If desired, the crude product is purified by chromatography.
Example 1: synthesis of Compound 1
Synthesis of intermediate 1-1
Cyclopropaneamidine hydrochloride (10.04g, 83.3 mmol) was dissolved in methanol (100 mL), dimethyl malonate (13.21g, 100.0 mmol) and sodium methoxide (11.24g, 208.0 mmol) were added, the system was heated to 60 ℃ and stirred for reaction for 1.5 hours, the system was cooled to room temperature, water (100 mL) was added, the system pH was adjusted to 4-5 with concentrated hydrochloric acid, and a white solid was precipitated. Suction filtration and drying of the solid gave 1-1 (11.01g, 87%). ESI-MS (m/z): 153.02[ 2 ] M + H] + 。
Synthesis of intermediate 1-2
Phosphorus oxychloride (55.43g, 361.5 mmol) was added dropwise to N, N-dimethylformamide (10.57g, 144.6 mmol) at 0 ℃ and stirring was continued at this temperature for 1 hour. Intermediate 1-1 (11.01g, 72.3mmol) was then added portionwise at 0 ℃. The reaction solution was allowed to spontaneously warm to room temperature and stirred for 1 hour. The reaction solution was heated to 120 ℃ and reacted for 3 hours. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate (40 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a brown oil, and the residue was column chromatographically separated and purified (petroleum ether: ethyl acetate =100: 1-40) to give 1-2 (4.02g, 26%). ESI-MS (m/z): 217.18[ M ] +H] + 。
Synthesis of intermediates 1 to 3
A mixture of intermediate 1-2 (4.02g, 18.5 mmol), p-toluenesulfonic acid (327.2mg, 1.90mmol), ethylene glycol (1.72g, 27.8 mmol) and toluene (50 mL) was heated to reflux for 3 hours and LCMS monitored for no residue. After the reaction mixture was concentrated, water (100 mL) was added to the residue, and extraction was performed with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50. ESI-MS (m/z): 261.28[ M ] +H] + 。
Synthesis of intermediates 1 to 4
A mixture of intermediates 1-3 (3.81g, 14.6 mmol), dimethyl 2-fluoromalonate (2.63g, 17.5 mmol), cesium carbonate (9.51g, 29.2mol) and dimethyl sulfoxide (50 mL) was reacted at room temperature for 5 hours and LCMS monitored for no residue of starting material. Water (100 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfateAnd (5) drying. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether: ethyl acetate =20: 1-5:1) to give 1-4 (4.49g, 82%). ESI-MS (m/z): 375.28[ M ] +H] + 。
Synthesis of intermediates 1 to 5
A mixture of intermediates 1 to 4 (4.49g, 12.0 mmol), lithium chloride (2.54g, 60.0 mmol) and dimethyl sulfoxide (50 mL) was heated to 110 ℃ and reacted for 2 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate =20: 1-3:1) to afford intermediates 1-5 (1.10g, 29%). ESI-MS (m/z): 317.12[ M ] +H] + 。
Synthesis of intermediates 1 to 6
A mixture of intermediate 1-5 (1.10g, 3.47mmol), intermediate D (776mg, 4.10mmol), N-diisopropylethylamine (879mg, 6.80mmol) and dimethyl sulfoxide (30 mL) was warmed to 110 ℃ for reaction for 3 hours, and LCMS monitored that no residue was left. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate =20: 1-2:1) to give 1-6 (798mg, 49%). ESI-MS (m/z): 470.28[ M ] +H] + 。
Synthesis of intermediates 1 to 8
Intermediates 1-6 (798mg, 1.70mmol) were dissolved in DMSO (10 mL) and CAN (5 mL). 20% aqueous sodium hydroxide (272mg, 6.80mmol) was added, the mixture was stirred for 30 minutes, and no residue was detected by LCMS to give intermediate 1-7, to the system were added triethylamine (344mg, 3.40mmol), 1-difluoromethylcyclopropane-1-amine hydrochloride (318mg, 2.21mmol), and HATU (856 mg, 2.25mmol), the mixture was stirred for 20 minutes, and no residue was detected by LCMS. Water (30 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1-1:2) to give 1-8 (204mg, 22%). ESI-MS (m/z): 545.12[ M ] +H] + 。
Synthesis of Compound 1
Intermediates 1-8 (204mg, 0.37mmol) were dissolved in 2-propanol (10 mL). 2 drops of concentrated HCl were added and the mixture was stirred at 50 ℃ for 1 hour and LCMS monitored that no starting material remained. The reaction mixture was basified with aqueous ammonia, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol =40, 1-15, 2% aqueous ammonia was added) to give compound 1 (100mg, 56%). ESI-MS (m/z): 483.12[ M ] +H] + 。
1 HNMR(600MHz,DMSO-d 6 )δ9.06-8.98(m,2H),7.57(dd,J＝7.2Hz,J＝7.2Hz,1H),7.53(dd,J＝6.6Hz,J＝6.6Hz,1H),7.32(d,J＝7.2Hz,1H),7.24(t,J＝54Hz,1H),6.34(t,J＝56Hz,1H),5.56-5.52(m,1H),1.84-1.79(m,1H),1.58(d,J＝7.2Hz,3H),1.53-1.43(m,4H),1.08-1.04(m,1H),0.89-0.86(m,1H),0.75-0.71(m,1H),0.47-0.43(m,1H).
Example 2: synthesis of Compound 2
Synthesis of intermediate 2-1
A mixture of intermediates 1-3 (3.81g, 14.6 mmol), dimethyl methylmalonate (2.56g, 17.5 mmol), cesium carbonate (9.51g, 29.2mol) and dimethyl sulfoxide (50 mL) was reacted at room temperature for 5 hours and LCMS monitored for no residue of starting material. The reaction mixture was added with water (100 mL), extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate =20: 1-5:1) to give intermediate 2-1 (4.50 g, yield 83%). ESI-MS (m/z): 371.88[ M ] +H] + 。
Synthesis of intermediate 2-2
A mixture of intermediate 2-1 (4.50g, 12.1mmol), lithium chloride (2.56g, 60.5mmol) and dimethyl sulfoxide (50 mL) was heated to 110 ℃ and reacted for 2 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, extraction was performed with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate =20: 1-3:1) to afford intermediate 2-2 (1.50 g, yield 40%)。ESI-MS(m/z)：313.72[M+H] + 。
Synthesis of intermediates 2-3
A mixture of compound 2-2 (1.50g, 4.80mmol), intermediate D (1.09g, 5.76mmol), N-diisopropylethylamine (1.24g, 9.60mmol) and dimethyl sulfoxide (30 mL) was warmed to 110 deg.C for 3 hours and LCMS monitored for the absence of residual material. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate =20: 1-2:1) to give intermediate 2-3 (1.70 g, yield 70%). ESI-MS (m/z): 466.28[ 2 ] M + H] + 。
Synthesis of intermediates 2 to 5
Intermediate 2-3 (1.70g, 3.65mmol) was dissolved in DMSO (10 mL) and CAN (5 mL). 20% aqueous sodium hydroxide (532mg, 13.3mmol) was added, the mixture stirred for 30 minutes and LCMS monitored for no residue of starting material to give intermediate 2-4. Triethylamine (737mg, 7.30mmol), 1-difluoromethylcyclopropane-1-amine hydrochloride (632mg, 4.40mmol) and HATU (1.67g, 4.40mmol) were added and the mixture stirred for 20 minutes and LCMS monitored that no starting material remained. Water (30 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1-1:2) gave intermediate 2-5 (593 mg, yield 30%). ESI-MS (m/z): 541.12[ M ] +H] + 。
Synthesis of Compound 2
Intermediate 2-5 (593mg, 1.10mmol) was dissolved in 2-propanol (10 mL), 2 drops of concentrated HCl were added, the mixture was stirred at 50 ℃ for 1 hour, and the starting material was monitored by LCMS for no residue. The reaction mixture was basified with aqueous ammonia, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol =40, 1-15, 2% aqueous ammonia was added) to obtain compound 2 (295 mg, yield 56%). ESI-MS (m/z): 479.21[ M ] +H] + 。
Examples 3 to 12
Examples 3-12 Compounds 3-12 can be prepared by reference to the preparation of example 1
Example 13: synthesis of Compound 13
A mixture of 2- (methylthio) -4,6-dichloro-5-pyrimidinecarbaldehyde (11.0g, 49.5mmol), p-toluenesulfonic acid (852mg, 4.95mmol), ethylene glycol (4.59g, 74.0mmol), and toluene (100 mL) was heated under reflux for 3 hours, and LCMS monitored that no starting material remained. After the reaction mixture was concentrated, water (100 mL) was added to the residue, and extraction was performed with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate =50: 1-20). ESI-MS (m/z): 267.10[ M ] +H] + 。
Synthesis of intermediate 13-2
A mixture of intermediate 13-1 (8.00g, 30.0mmol), dimethyl malonate (4.76g, 36.0mmol), cesium carbonate (19.5g, 60.0mmol), and dimethyl sulfoxide (100 mL) was reacted at room temperature for 2 hours, and LCMS monitored that no residue was left. The reaction mixture was added with water (100 mL), extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography separation and purification (petroleum ether: ethyl acetate =20: 1-5:1) to give intermediate 13-2 (9.00 g, yield 83%). ESI-MS (m/z): 363.08[ 2 ] M + H] + 。
Synthesis of intermediate 13-3
Intermediate 13-2 (9.00g, 24.8mmol), lithium chloride (5.26g, 124) were added.0 mmol) and dimethyl sulfoxide (100 mL) were heated to 110 ℃ for 2 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude was purified by silica gel column chromatography (petroleum ether: ethyl acetate =20: 1-3:1) to afford intermediate 13-3 (2.01 g, yield 26%). ESI-MS (m/z): 305.28[ M ] +H] + 。
Synthesis of intermediate 13-4
A mixture of intermediate 13-3 (2.00g, 6.56mmol), intermediate D (1.49g, 7.87mmol), N-diisopropylethylamine (1.70g, 13.1 mmol) and dimethyl sulfoxide (80 mL) was warmed to 110 deg.C for 3 hours and LCMS monitored for the absence of residual material. Water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography separation and purification (petroleum ether: ethyl acetate =20: 1-2:1) to give intermediate 13-4 (1.9 g, yield 63%). ESI-MS (m/z): 458.28[ M ] +H] + 。
Synthesis of intermediate 13-6
Intermediate 13-4 (1.903g, 4.16mmol) was dissolved in DMSO (10 mL) and CAN (5 mL). 20% aqueous sodium hydroxide (664mg, 16.6 mmol) was added, the mixture stirred for 30 minutes and LCMS monitored for no residue of starting material to give intermediate 13-5. Triethylamine (840mg, 8.32mmol), 1-difluoromethylcyclopropane-1-amine hydrochloride (717mg, 4.99mmol) and HATU (2.37g, 6.24mmol) were added, the mixture was stirred for 20 minutes, and LCMS was used to monitor that no residue was left. Water (30 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1-1:2) to give intermediate 13-6 (600 mg, yield 27%). ESI-MS (m/z): 533.12[ 2 ] M + H] + 。
Synthesis of Compound 13
13-6 (600mg, 1.13mmol) was dissolved in 2-propanol (10 mL). 2 drops of concentrated HCl were added and the mixture was stirred at 50 ℃ for 1 hour and LCMS monitored that no starting material remained. The reaction mixture was basified with aqueous ammonia, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol =40:1, 2% ammonia water added) to give compound 13 (319 mg, yield 60%) ESI-MS (m/z): 471.13[ 2 ] M + H] + 。
Examples 14 to 28
Examples 14-28 Compounds 14-28 can be prepared by the method of preparation of reference example 1
Comparative example 1
The compound I-82 (page 138 of the specification) in the prior art patent CN111372932A (published Japanese 2020.07.03) has the following structure:
(hereinafter referred to as control Compound 1).
Comparative example 2
Compound 21 (pages 31-33 of the specification) in prior art patent CN113200981a (published 2021.08.03) has the following structure:
(hereinafter referred to as control Compound 2).
Biological activity assay experiment:
1.K-Ras G12D binding assay with hSOS1
This assay can be used to examine the efficacy of compounds to inhibit protein-protein interactions between SOS1 and KRAS G12D. Determination of the binding of Compounds to K-Ras by homogeneous time-resolved fluorescence (HTRF) detection of Tag1-hSOS1 bound by anti-Tag1-Tb3+ (donor) to Tag2-KRASG12D (acceptor) bound by anti-Tag2-XL665 G12D Inhibition with hSOS1。
Reagent:
KRAS-G12D/SOS1 BINDING ASSAY KITS，Cisbio，Cat No.63ADK000CB21PEH；
GTP，Sigma，Cat No.V900868；
the test steps are as follows:
dissolving a compound to be tested in DMSO (dimethylsulfoxide) to prepare a 10mM stock solution; after 1000-fold dilution with DMSO solution, 3-fold gradient dilutions were performed sequentially, with 11 concentration gradients, starting at 10. Mu.M. 0.1. Mu.L of compound was transferred to 384-well plates by means of Echo acoustics system; adding 5 mu L of Tag2-KRASG12D & GTP mixed solution into each hole, and centrifuging at 1000rpm for 1min; add 5. Mu.L of Tag1-hSOS1 into each well, centrifuge at 1000rpm for 1min; incubating at 25 deg.C for 15min; adding 10 mu L of anti-Tag1-Tb3+ and anti-Tag2-XL665 mixed solution into each well, centrifuging at 1000rpm for 1min, and incubating for 2h at 4 ℃; the fluorescence signals at 615nm (Cryptote) and 665nm (XL 665) were read with an Envision 2104.
And (3) data analysis:
fitting Compound IC Using Graphpad Prism 8 nonlinear regression equation 50 A value;
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))；
X:Log of cpd concentration；
Y:665/615ratio；
compounds of the examples tested according to the above method, inhibit the activity IC of SOS-1 50 Less than 50nM.
Representative compounds of the examples were tested according to the above method and found to inhibit SOS-1 activity. Compound activity data are shown in the table below.
Note that A represents IC 50 Greater than or equal to 5nm and less than 10nm, B represents IC 50 Greater than or equal to 10nm and less than 20nm.
2.3D cell proliferation inhibition assay
Cell proliferation inhibition assay for detecting compounds inhibiting SOS1 mediation at the level of 3D cells in vitroProliferation and growth of tumor cell lines, using
3D detection method.
Reagents and materials:
NCI-H358: KRAS G12C mutant non-small cell lung cancer (NSCLC);
RPMI 1640medium，Gibco，A10491-01；
FBS，Gibco，10099141C；
the testing steps are as follows:
cell culture
Day 1, passage of NCI-H358 to T75 cell culture flasks;
day 3, remove medium, wash once with DPBS, use 2mL TrypLE at room temperature or 37 ℃ TM Express Enzyme digests cells until the cells shed; adding 5mL of fresh culture medium, and centrifuging at 1000rpm for 5min; the supernatant was discarded, 5mL of fresh medium was added to resuspend the cells, and 40. Mu.L/Well after cell counting was seeded in 3D cell plates (Echo modified 384-Well Polypropylene Microplate 2.0, clear, flat Bottom)
3D cell proliferation inhibition
Day 1, dissolving the test compound in DMSO to prepare a 10mM stock solution; diluting 1000 times by using a DMSO solution, and sequentially carrying out 3-time gradient dilution on the diluted solutions, wherein the initial concentration is 10 mu M; adding 200nL of compound to the plate;
day 8, 40. Mu.L/well 3D CTG reagent was added and signal values were measured by Envision.
And (3) data analysis:
fitting Compound IC Using Graphpad Prism 8 nonlinear regression equation 50 A value;
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))；
X:Log of cpd concentration；
Y:Percent inhibition(％inh)
the compounds in the examples tested according to the above method, NCI-H358 cell proliferation inhibitory activity data are shown in the following table.
Note that A represents IC 50 Greater than or equal to 50nm and less than 100nm, B represents IC 50 Greater than or equal to 100nm and less than 200nm.
3. In vivo pharmacokinetic study in mice
This experiment investigated the pharmacokinetic behavior of a single dose, single intravenous injection or gavage administration of the compound of example 1, control compound 1 and control compound 2 in ICR mice.
Test animals:
ICR mice were 6, male, divided into 2 groups of 3 mice each, purchased from beijing weitongli limited.
Drug solvent:
intravenous vehicle: 5% DMSO +95% HP- β -CD (0.1 g/ml);
gastric perfusion solvent: 5% DMSO +10% CrEL +85% water.
The sampling method comprises the following steps:
the intravenous injection group is used for 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after the administration is finished, the intragastric administration group is used for 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after the administration is finished, 100 mu L of blood is respectively taken from orbital veins of mice and placed in a heparin sodium anticoagulation tube, 8000rmp within 2h of the collected venous blood of the mice is centrifuged for 10 minutes to separate blood plasma, the blood plasma is transferred and placed in a 1.5mL centrifuge tube and transferred to a refrigerator at minus 80 ℃ for storage, and the test tube is used for LC-MS/MS analysis.
The results of the pharmacokinetic parameters of mice in vivo under intravenous injection dosage of 2mg/Kg and oral gavage dosage of 10mg/Kg of the embodiment of the invention are shown in the following table:
and (4) conclusion: the compounds of the invention exhibit better pharmacokinetic properties in mouse PK studies.
Claims (13)
1. A compound of formula (I), or a tautomer, stereoisomer, optical isomer, solvate, prodrug, or a pharmaceutically acceptable salt thereof, having the structure:
wherein the content of the first and second substances,
R 1 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkenyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted with 0-3R which may be the same or different a Substitution;
R a each occurrence is independently selected from the group consisting of halogen, amino, cyano, hydroxy, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl) (C 1-6 Alkyl), -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OC (O) -C 1-6 Alkyl, -NHCO-C 1-6 Alkyl, -CONH-C 1-6 Alkyl, -CON (C) 1-6 Alkyl) (C 1-6 Alkyl), -S (O) 2 -C 1-6 Alkyl, -NHS (O) 2 -C 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 4-10 Cycloalkenyl radicals4-10 membered heterocyclic group, C 6-10 Aryl, 5-to 10-membered heteroaryl, said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl) (C 1-6 Alkyl), -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OC (O) -C 1-6 Alkyl, -NHCO-C 1-6 Alkyl, -CONH-C 1-6 Alkyl, -CON (C) 1-6 Alkyl) (C 1-6 Alkyl), -S (O) 2 -C 1-6 Alkyl, -NHS (O) 2 -C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 4-10 Cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl are each optionally substituted with one or more of the following substituents: halogen, amino, cyano, hydroxy, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NH (C) 1-6 Alkyl), -N (C) 1-6 Alkyl radical) 2 ；
R 2 Selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano, amino, nitro and C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -C 1-6 alkyl-NH (C) 1-6 Alkyl), -C 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -C 1-6 alkyl-NH (C) 1-6 Alkyl), -C 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted by one or more C 1-6 Alkyl, hydroxy, mercapto or halogen substitution;
R 3 selected from halogen, hydroxy, mercapto, cyano, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 0-6 alkyl-NH 2 、C 0-6 alkyl-NH-C 1-6 Alkyl radical, C 0-6 alkyl-N (C) 1-6 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-6 Alkyl, -OC 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl, wherein said C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 0-6 alkyl-NH 2 、C 0-6 alkyl-NH-C 1-6 Alkyl radical, C 0-6 alkyl-N (C) 1-6 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-6 Alkyl, -OC 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl is each optionally substituted with one or more hydroxy, mercapto, amino, cyano, halogen, C 1-6 Alkyl substitution;
ring A is selected from C 4-12 Cycloalkyl of, C 4-12 Cycloalkenyl group of (A), C 6-12 Aryl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl;
R 4 each independently selected from hydrogen, cyano, halogen, amino, hydroxyl, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 0-6 alkyl-NH-C 1-6 Alkyl, -C 0-6 alkyl-N (C) 1-6 Alkyl) (C 1-6 Alkyl), C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl radicals, 3-a 6-membered heterocyclyl group; wherein, the C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy, -C 0-6 alkyl-NH-C 1-6 Alkyl, -C 0-6 alkyl-N (C) 1-6 Alkyl) (C 1-6 Alkyl group), C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl are each optionally substituted with one or more of the following substituents: halogen, hydroxy, mercapto, amino, -SO 2 -C 1-4 Alkyl, oxo, C 1-6 Alkoxy radical, C 3-6 A cycloalkyloxy group; w =0,1,2,3,4;
unless otherwise indicated, the heteroatoms in the heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, the number of heteroatoms being 1,2,3 or 4.
2. The compound of claim 1, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or pharmaceutically acceptable salt thereof, having the structure according to formula (II):
the definition of each substituent in the formula (II) is described as the formula (I).
3. The compound of claim 1 or 2, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is 1 Is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 member heterocyclyl, said R 1 Are each optionally substituted by one or more of the same or different R a Substitution;
further preferably, R 1 Is selected from C 3-6 Monocyclic alkyl radical, said R 1 Are each optionally substituted by one or more of the same or different R a Substitution;
further preferably, R 1 Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein R is 1 Are each optionally substituted by one or more identical or different R a Substitution;
even more preferably, R 1 Selected from cyclopropyl, said R 1 Are each optionally substituted by one or more identical or different R a Substitution;
most preferably, R 1 Selected from difluoromethyl-substituted cyclopropyl.
4. The compound of any one of claims 1-3, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is a Independently at each occurrence is selected from halogen, amino, cyano, hydroxy, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 The alkoxy groups are each optionally substituted with one or more of the following substituents: halogen, amino, cyano, hydroxy, oxo, nitro;
further preferably, R a Each occurrence is independently selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, said C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 The alkynyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy;
further preferably, R a Each occurrence is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl;
even more preferably, R a Each occurrence is independently selected from trifluoromethyl, difluoromethyl, monofluoromethyl.
5. The compound according to any one of claims 1 to 4, or a tautomer, stereoisomer, or photo-isomer thereofA chemical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is 2 Selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 An alkynyl group; said C is 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 The alkynyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy, C 1-6 An alkyl group;
further preferably, R 2 Selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, wherein said C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl is optionally substituted by one or more C 1-6 Alkyl, hydroxy or halogen substitution;
further preferably, R 2 Selected from hydrogen, halogen, amino, C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, said C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Each alkyl is optionally substituted with one or two hydroxy or halo;
further preferably, R 2 Selected from hydrogen, methyl, ethyl, isopropyl, amino, F, cl, br, methoxy, ethoxy, formyl, acetyl;
even more preferably, R 2 Selected from hydrogen, methyl, amino, F, cl, br, methoxy, acetyl.
6. The compound of any one of claims 1-5, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is 3 Selected from halogen, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-4 Alkyl, -OC 1-6 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, - -O- -C 0-6 Alkyl-3-10 membered heterocyclyl, wherein said C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-4 Alkyl, -OC 1-6 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl are each optionally substituted by one or more halogen, C 1-6 Alkyl substitution;
further preferably, R 3 Selected from halogen, amino, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-NH 2 、-OC 1-4 alkyl-NH-C 1-4 Alkyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-6 membered heterocyclyl, wherein said C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-NH 2 、-OC 1-4 alkyl-NH-C 1-4 Alkyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-6 membered heterocyclyl are each optionally substituted by one or more halogen, C 1-4 Alkyl substitution;
further preferably, R 3 Selected from halogen, amino, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 Alkyl-3-6 membered heterocyclic group, said C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 Each alkyl-3-6 membered heterocyclyl is optionally substituted with one or two methyl groups;
further preferably, R 3 Selected from F, cl, br, amino, -OCH 3 、-SCH 3 Cyclopropyl, -CH 2 N(CH 3 ) 2 、-OCH 2 CH 2 N(CH 3 ) 2 、
7. The compound of any one of claims 1-6, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein ring a is selected from C 6-12 Aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl;
further preferably, ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl;
further preferably, ring a is selected from phenyl, pyridyl;
even more preferably, ring A is selected from phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
8. The compound of any one of claims 1-7, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl; wherein, the C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl are each optionally substituted with one or more of the following substituents: halogen, hydroxy, amino, -SO 2 -C 1-4 Alkyl, oxo; w =0,1,2,3;
further preferably, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 A hydroxyalkyl group; wherein, the C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 The hydroxyalkyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy, amino; w =1,2,3;
further preferably, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, methyl, ethyl, n-propyl, isopropyl; wherein the methyl, ethyl, n-propyl, isopropyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy; w =1,2,3;
further preferably, R 4 Each independently selected from hydrogen, halogen, amino, methyl, ethyl, isopropyl; wherein the methyl, ethyl and isopropyl groups are all optionally substituted by one or more of the following substituents: halogen, hydroxy; w =1,2,3;
further preferably, R 4 Are respectively independentIs selected from hydrogen, F, cl, br, I, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF 2 CH 2 OH、-C(CH 3 ) 2 OH、-CF 2 CH 3 ；w＝1,2,3。
9. A compound, or a tautomer, optical isomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, characterized by: the compound has the following structure:
10. a compound, or a tautomer, optical isomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, characterized by: the compound has the following structure:
11. a pharmaceutical composition characterized by: comprising a compound of any one of claims 1-10, or a tautomer, optical isomer, solvate, prodrug, or a pharmaceutically acceptable salt thereof.
12. Use of a compound according to any one of claims 1 to 10, or a tautomer, an optical isomer, a solvate, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a medicament for the prophylaxis and/or treatment of a disease caused by SOS 1-mediated and/or RAS mutations; preferably, the disease is cancer or tumor, and related diseases thereof; more preferably, the disease is lung cancer; further preferably, the disease is non-small cell lung cancer; still further, the disease is KRAS G12C mutant non-small cell lung cancer.
13. Use of a compound according to any one of claims 1 to 10, or a tautomer, optical isomer, solvate, prodrug or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a medicament for the prophylaxis and/or treatment of cancer or a tumor disease; preferably, the cancer or neoplastic disease is lung cancer; more preferably, the cancer or neoplastic disease is non-small cell lung cancer.
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