CN116574104A - Biaryl benzylamine compound, preparation method and application - Google Patents

Biaryl benzylamine compound, preparation method and application Download PDF

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CN116574104A
CN116574104A CN202211068858.2A CN202211068858A CN116574104A CN 116574104 A CN116574104 A CN 116574104A CN 202211068858 A CN202211068858 A CN 202211068858A CN 116574104 A CN116574104 A CN 116574104A
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alkyl
membered
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heterocycloalkyl
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万惠新
王亚周
马金贵
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Rudong Ringene Pharmaceuticals Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses biaryl benzylamine compounds, a preparation method and application thereof, in particular to biaryl benzylamine compounds shown in a general formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs thereof, a preparation method thereof and application thereof in pharmacy, wherein the definition of each group is described in the specification.

Description

Biaryl benzylamine compound, preparation method and application
Technical Field
The invention belongs to the field of pharmaceutical chemistry, in particular to biaryl benzylamine compounds which have better SOS1 inhibition activity and can be used for preparing therapeutic and preventive medicines for treating diseases related to Ras activity or expression or mutation.
Background
Ras proteins are key mediators in normal cell growth and malignant transformation processes, including cell proliferation, survival and invasion, tumor angiogenesis and metastasis, and the like (Downward, nature Rev. Cancer,3,11-22 (2003)). In most human tumors, ras proteins are abnormally activated by mutations in the Ras gene itself or in the upstream or downstream Ras pathway components, or other changes in Ras signaling. Such mutations reduce the ability of RAS family gtpases to hydrolyze GTP, allowing the molecular switch to remain in an active GTP-bound form at all times, which drives unexamined oncogenic downstream signaling. One strategy to reduce the level of active RAS is directed to guanine nucleotide exchange factors (GEFs) that allow the RAS to cycle from an inactive GDP-bound state to an active GTP-bound form. By preventing the formation of KRAS-SOS1 complex, SOS1 inhibitors block the reloading of KRAS with GTP, resulting in antiproliferative activity. Inhibition of SOS1 may represent a viable approach to targeting RAS-driven tumors.
Ras-driven Cancer remains the most clinically refractory class of diseases at present, and new therapeutic and prophylactic strategies are urgently needed for this Cancer (Stephen et al, cancer Cell,25,272-281 (2014)). The discovery of Ras-selective targeting drugs by the global academy and industry has been continued for many years, but has not been approved for marketing to date (Spiegel, et al, nature chem.biol.,10,613-622 (2014)). In the last two years, targeting drugs against Ras drive have entered the clinical trial phase successively and showed better primary efficacy with encouraging results.
Therefore, the urgent need for Ras-driven tumors is that more therapeutic drugs with unique mechanisms, high efficiency and low toxicity enter the clinic, and the discovery and search of Ras-targeted drugs with high efficiency, low toxicity and novel structure is still a great hotspot field in the industry.
Disclosure of Invention
One of the technical problems to be solved by the invention is to provide a novel SOS1 inhibitor for preparing tumor therapeutic drugs.
The scheme for solving the technical problems is as follows:
biaryl benzylamine compounds having the general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsionally isomer, solvate, polymorph or prodrug thereof,
Wherein: m is M 1 And M 2 Each independently selected from N or CH;
cy is selected from 4-10 membered aromatic or saturated or partially unsaturated carbocyclic or heterocyclic ring;
l is selected from bond, -C 1 -C 3 Alkyl-, C 3 -C 12 Cycloalkyl, -OC 1 -C 10 Alkyl-, -NHC 1 -C 10 Alkyl-, -N (C) 1 -C 10 Alkyl) (C) 1 -C 10 Alkyl) -, -S-, -SO 2 -、-SC 1 -C 10 Alkyl-, -SOC 1 -C 10 Alkyl-, -SO 2 C 1 -C 10 Alkyl-, -O-, -CO-, -COO-, -CO C 1 -C 10 Alkyl-, -CONH C 1 -C 10 Alkyl-, -SO 2 NH C 1 -C 10 Alkyl-, -CO N (C) 1 -C 10 Alkyl) (C) 1 -C 10 Alkyl) -, SO 2 N(C 1 -C 10 Alkyl) (C) 1 -C 10 Alkyl) -SONH C 1 -C 10 Alkyl-, -SON C 1 -C 10 Alkyl-;
R 1 independently selected from hydrogen, halogen, C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C10 alkynyl, C 3 -C 14 Cycloalkyl, C 4 -C 14 Cycloalkenyl, 3-14 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, -OC 1 -C 10 Alkyl, -NHC 1 -C 10 Alkyl, -N (C) 1 -C 10 Alkyl) (C) 1 -C 10 Alkyl), -SC 1 -C 10 Alkyl, -SOC 1 -C 10 Alkyl, -SO 2 C 1 -C 10 An alkyl group, a carbocyclic ring, or a spiro/bridged/fused ring containing a heteroatom, wherein R is 1 The groups may be optionally substituted with 1 to 3 Rn; or the two Rn may form a 3-12 membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or heteroatom; said Rn is selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoroxy, alkylsilyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, haloalkyl, haloalkoxy, C 1 -C 6 Monoalkylamino, C 1 -C 6 Dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 6 alkyl-S-, C 1 -C 6 alkyl-SO-, C 1 -C 6 alkyl-SO 2- Etc.;
R 2a and R is 2b Are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl; and R is 2a And R is 2b Or R2a and the substituent Rm on Ar can form a 3-6 membered saturated or partially unsaturated or unsaturated ring system through a carbon chain or a heteroatom;
R 3 is H, deuterium, halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C6 alkylamino, 3-8 membered cycloalkyl or heterocycloalkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, 5-10 membered aromatic ring or aromatic heterocyclic group;
ar and R 4 An aryl or heteroaryl group, independently selected from 5-12 membered mono-or bicyclic, which may be substituted with one or more groups R selected from the group m The substitution is as follows: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoxy, alkylsilyl, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkoxyalkyl group,C 1 -C 10 Haloalkyl, C 1 -C 10 Haloalkoxy, C1-C 10 Haloalkoxyalkyl, C 1 -C 10 Monoalkylamino, C 1 -C 10 Dialkylamino, C 1 -C 10 Monoalkylaminoalkyl, C 1 -C 10 Dialkylaminoalkyl, C 1 -C 10 Alkenyl, C 1 -C 10 Alkynyl, 3-12 membered cycloalkyl or heterocycloalkyl, C 1 -C 10 alkyl-S-, C 1 -C 10 alkyl-SO-, C 1 -C 10 alkyl-SO 2 -, substituted or unsubstituted 5-to 12-membered aryl or heteroaryl, etc., or both R' s m A 3-to 12-membered saturated or partially unsaturated, or aromatic ring system may be formed by a carbon chain or a heteroatom; the C1-C 10 Haloalkoxyalkyl, C 1 -C 10 Alkoxyalkyl, C1-C 10 Haloalkoxyalkyl, C 1 -C 10 Monoalkylaminoalkyl, C 1 -C 10 The alkyl group in the dialkylaminoalkyl, 3-12 membered cycloalkyl or heterocycloalkyl alkyl group is preferably C1-C3 alkyl;
one or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, 3-6 membered cycloalkyl or heterocycloalkyl; wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising a spiro, bridged, fused, or other saturated or partially unsaturated ring system.
In some preferred embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, has the following characteristics: m is M 1 And M 2 Each independently selected from N or CH; cy is preferably self-contained
L is preferably a self bond, -C 1 -C 3 Alkyl-, -CO-, -COO-, -CONHC 1 -C 3 Alkyl-, -SO 2 -、-O-、-CO C 1 -C 3 Alkyl-;
R 1 preferably selected from C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl, C 3 -C 14 Cycloalkyl, C 4 -C 14 Cycloalkenyl, 3-14 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, spiro/bridged/fused ring containing 0-4 heteroatoms, and which are preferably substituted with one or more substituents selected from the group consisting of: deuterium, halogen, cyano, hydroxy, -C 1 -C 6 Alkyl, -COO C 1 -C 6 Alkyl, -CONH C 1 -C 6 Alkyl, -CON (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), -C 1 -C 6 Alkyl O C 1 -C 6 Alkyl, =o, -C 1 -C 3 Haloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, -OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OH, -OC 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkyl OH;
R 2a and R is 2b Preferably selected from hydrogen, halogen, C 1 -C 6 Alkyl, or R 2a And R is 2b Forming a 3-to 6-membered cycloalkyl or heterocycloalkyl group;
R 3 preferably selected from hydrogen, -C 1 -C 3 Alkyl, -C 1 -C 3 Alkoxy, cyclopropyl, halogen, cyano, -C 1 -C 3 Haloalkyl, -C 1 -C 3 Haloalkoxy;
ar and R 4 Each independently selected from a substituted or unsubstituted 6 membered aromatic ring or a 5-6 membered aromatic heterocyclic ring;
in other preferred embodiments, the compounds of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,
R 1 preferably selected from the following groups:
wherein one or more R c Are each independently selected from hydrogen, deuterium, halogen, -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, cyano, hydroxy, amino, -SC 1 -C 6 Alkyl, -SOC 1 -C 6 Alkyl, -SO 2 C 1 -C 6 Alkyl, -COC 1 -C 6 Alkyl, -COOC 1 -C 6 Alkyl, -CONHC 1 -C 6 Alkyl, -CON (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkoxy, -C 1 -C 6 Deuterated alkyl, -C 1 -C 6 Deuteroalkoxy, -O-3-6 membered cycloalkyl or heterocycloalkyl, -C 1 -C 6 Alkyl OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl NHCs 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OH, -C 1 -C 6 Alkyl N (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), and any two R c The carbon chain or heteroatom can lead to 3-10 membered saturated or partially unsaturated carbocycle or heterocycle; r is R d Independently selected from-C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl SC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl SOCs 1 -C 6 Alkyl, -C 1 -C 6 Alkyl SO 2 C 1 -C 6 Alkyl, -COC 1 -C 6 Alkyl group,-COOC 1 -C 6 Alkyl, -CONHC 1 -C 6 Alkyl, -CON (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkoxy, -C 1 -C 6 Deuterated alkyl, -C 1 -C 6 Deuterated alkoxy-C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl O-3-6 membered cycloalkyl or heterocycloalkyl, -C 1 -C 6 Alkyl NHCs 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OH, -C 1 -C 6 Alkyl N (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), and the like;
in other preferred embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, has the following characteristics:
wherein R is 1 、L、M 1 、M 2 、R 2a 、R 2b 、R 3 、R 4 And Ar and the like are as defined above.
In other preferred embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, has the following characteristics:
wherein R is 1 、L、Cy、M 1 、M 2 、R 2a 、R 2b 、R 3 、R 4 The definition of (2) is as indicated above.
In other preferred embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, has the following characteristics:
Wherein R is 1 、L、M 1 、M 2 、R 3 、R 4 And Ar and the like are as defined above.
In other preferred embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, has the following characteristics:
wherein R is 1 、R 3 、R 4 And Ar and the like are as defined above.
A process for preparing a compound of formula I, comprising steps a, b:
a) The compound of the general formula (A) and biaryl benzylamine compound of the general formula (B) are subjected to substitution reaction under the catalysis of alkali to generate an intermediate (C) compound;
b) The intermediate (C) is subjected to condensation reaction or coupling reaction with the compound of the general formula (D) under the catalysis of alkali or alkali and transition metal to generate the general formula (I).
X is halogen; the other groups are as defined above;
preferably, the steps are carried out in respective solvents, and the solvents are selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
Preferably, the inorganic base is selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic base is selected from the group consisting of: pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or combinations thereof.
Preferably, the transition metal catalyst is selected from the group consisting of: tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Tetrakis (triphenylphosphine) palladium (Pd (PPh) 3 ) 4 ) Palladium acetate, palladium chloride, dichloro-bis (triphenylphosphine) palladium, trifluoropalladium acetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (triphenylphosphine) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-benzylphosphine, or a combination thereof.
Preferably, the acid is selected from the group consisting of: hydrochloric acid, hydrofluoric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid or combinations thereof.
The invention provides a class of preferred compounds of formula (I) including, but not limited to, the following structures:
but excluding the following compounds 1-7:
it is another object of the present invention to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for achieving the purpose is as follows:
a pharmaceutical composition for treating tumors, which consists of biaryl benzylamine compounds shown in the general formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs thereof and pharmaceutically acceptable carriers. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
It is a further object of the present invention to provide the use of the above compounds. The technical scheme for achieving the purpose is as follows:
the biaryl benzylamine compound shown in the general formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof is used for preparing medicaments for treating diseases related to Ras mutation, activity or expression quantity, in particular to medicaments for treating tumors. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
The invention relates to a compound with the structural characteristics of a general formula (I), which can inhibit various tumor cells, especially can efficiently kill tumors related to abnormal Ras protein signal paths, and is a therapeutic drug with a brand-new action mechanism.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. The limited space is not described in any more detail herein.
Detailed Description
The inventor has prepared biaryl benzylamine compounds with novel structure shown in formula I through long-term and intensive research, and found that the biaryl benzylamine compounds have better SOS1 protein inhibition activity, and the compounds have specific inhibition effect on SOS1 protein at very low concentration (which can be lower than 20 nM), and have quite excellent cell proliferation inhibition activity related to Ras pathway, so that the biaryl benzylamine compounds can be used for treating related diseases caused by RAS mutation or activity or expression quantity abnormality, such as tumors. Based on the above findings, the inventors have completed the present invention.
Terminology
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 the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In the present application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY TH ED." vols. A (2000) and B (2001), plenum Press, new York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present application. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -。
The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxy (-OH); "carbonyl" refers to a-C (=o) -group; "nitro" means-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the "cyano" refers to-CN; "amino" means-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., mono-, di-, alkylamido, aralkylamino, heteroaralkylamino; "carboxy" refers to-COOH.
In the present application, as part of a group or other groups (e.g., as used in halogen-substituted alkyl groups and the like), the term "alkyl" means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and linked to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like.
In the present application, the term "alkenyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In the present application, the term "alkynyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being linked to the rest of the molecule by single bonds, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.
In the present application, as part of a group or other group, the term "cycloalkyl" means a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [ 2.1.1 ] octadienyl, adamantylene, and the like.
In the present application, as part of a group or other group, the term "heterocyclyl" means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless specifically indicated otherwise in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present application, heterocyclyl groups are preferably stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In the present application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present application, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.
In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
In the present application, the term "heteroaryl" as part of a group or other group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] and the like.
In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.
In the present application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.
"stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present application is intended to cover various stereoisomers and mixtures thereof.
When an olefinic double bond is contained in the compounds of the present application, the compounds of the present application are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the application are also intended to be included within the scope of the application.
The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, gerald gabiz and Martin g.schmid (eds.), chiral Separations, methods and Protocols, methods in Molecular Biology, vol.243,2004; m.stalcup, chiral Separations, annu.rev.animal.chem.3:341-63, 2010; fumigs et al (EDs.), VOGEL' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY.sup.TH ED, longman Scientific and Technical Ltd., essex,1991,809-816; heller, acc.chem.Res.1990,23,128.
In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.
By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
"polymorphs" refer to the different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.
In general, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases may also retain only adventitious water or a mixture of water plus a portion of the adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The application also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound that can be converted into the biologically active compound of the present application under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the application. Prodrugs may not be active when administered to an individual in need thereof, but are converted in vivo to the active compounds of the present application. Prodrugs are typically rapidly converted in vivo to the parent compounds of the present application, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific methods of prodrug preparation can be found in saunnier, m.g., et al, biorg. Med. Chem. Lett.1994,4,1985-1990; greenwald, r.b., et al, j.med.chem.2000,43,475.
In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.
The "tumor", "cell proliferation abnormality related disease", and the like of the present application include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, lung squamous carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
The terms "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively
(iv) Alleviating symptoms caused by the disease or condition.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Application techniques useful in the compounds and methods described herein are well known to those skilled in the art, for example, at Goodman and Gilman, the Pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, pharmaceutical Sciences (current edition), mack Publishing co., easton, pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients.
It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto-protecting groups include-C (O) -R "(wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, t.w. and p.g.m. wuts, protective Groups in Organic Synthesis, (1999), 4th Ed. The protecting group may also be a polymeric resin.
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples, in which specific conditions are not noted, are generally in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Example general preparation method one
The first step: 2, 4-dichloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carbonate intermediate (1 eq.) and amino intermediate B (1 eq.) are dissolved in a suitable solvent and an inorganic base (3 eq.) is added at low temperature. The reaction was slowly warmed to room temperature and stirred overnight. LC-MS monitors the reaction completely, water is added into the reaction solution, the water phase is extracted three times by ethyl acetate, the extract is dried by anhydrous sodium sulfate, the concentration is reduced, the remainder is separated and purified to obtain the target product, and the structure is confirmed by nuclear magnetism and mass spectrum.
And a second step of: the above intermediate C (1 eq.) was dissolved in an appropriate solvent and acid (2 eq.) was added at room temperature. The reaction was stirred at room temperature for several hours. After the LC-MS detection reaction is completed, the reaction solution is decompressed and concentrated to obtain a target product, and a nuclear magnetism and mass spectrum structure is adopted to confirm.
And a third step of: the intermediate of general formula (D) and compound E (or a halo thereof) (1.2 eq.) of the above first step product are dissolved in an appropriate solvent, followed by the addition of an organic base (2 eq). The reaction was stirred at room temperature overnight. TLC monitoring reaction is complete, decompression concentration is carried out, the residue is prepared and separated and purified by silica gel column chromatography or HPLC to obtain the target compound, and nuclear magnetism and mass spectrum are adopted to confirm the structure.
Intermediate preparation
Intermediate 1: (R) -1- (4- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-8-yl) phenyl) ethyl-1-amine hydrochloride
Step one: under the protection of nitrogen, 1' -bis-diphenylphosphine ferrocene palladium dichloride Pd (dppf) Cl 2 (272 mg,0.37 mmol) was added to 8-bromo-2-methyl-1, 2,3, 4-tetrahydroisoquinoline (800 mg,3.72 mmol),dual-frequency sodium alcohol borate (1.9 g,7.44 mmol) in 1, 4-dioxane (10 mL). The reaction mixture was heated to 100℃and reacted at this temperature for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL), and the reaction solution was washed with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether/purified ethyl acetate 10:1) to give intermediate compound (250 mg) as brown oil. LCMS (ESI) m/z 274.1[ M+H ]] + 。
Step two: tetrakis (triphenylphosphine) palladium (106 mg,0.092 mmol) was added to a mixed solution of the above intermediate compound (250 mg,0.92 mmol), R- (1- (4-bromophenyl) ethylamine-t-butyl carbonate (275 mg,0.92 mmol), potassium carbonate (274 mg,2 mmol) 1, 4-dioxane (10 mL) and water (2 mL) under nitrogen atmosphere, the reaction mixture was reacted at 100℃for 2 hours, LCMS was examined for completion of the reaction, ethyl acetate (50 mL) diluted the reaction solution, sodium chloride solution (30 mL) washed the organic phase was separated, the separated organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (ethyl acetate: methanol=20:1) to give a white solid intermediate compound (135 mg), LCMS (ESI) m/z:367.2 M+H) ] + 。1H NMR(400MHz,DMSO-d6)δ7.35(d,J＝8.0Hz,3H),7.26–7.17(m,3H),7.11(d,J＝6.9Hz,1H),6.97(d,J＝7.3Hz,1H),4.68(m,1H),3.95(s,1H),3.31(s,2H),2.89(s,2H),2.60(d,J＝5.9Hz,2H),2.24(s,2H),1.35(d,J＝6.0Hz,3H),1.07(s,9H).
Step three: a methanolic hydrochloric acid solution (4M, 1mL,4 mmol) was added to methanol (15 mL) of the above intermediate compound (500 mg,1.36 mmol). The reaction mixture was reacted at 20℃for 2 hours. LC-MS detection reaction is basically completed, and after decompression concentration and solvent removal, a pale yellow solid crude intermediate compound (300 mg) is obtained. LCMS (ESI) m/z 266.4[ M+H ]] + 。
Intermediate 2 (R) -1- (5- (2- (pyrrol-1-ylmethyl) phenyl) thiophen-2-yl) ethyl-1-amine hydrochloride
Step one: under the protection of nitrogen, tetraethyl titanate is prepared(30.1 g,132 mmol) was added to 1- (5-bromothiophen-2-yl) ethyl-1-one (14.9 g,72.61 mmol), (R) - (+) tert-butylsulfinamide (8.0 g,66 mmol) in tetrahydrofuran (100 mL) and the reaction mixture was heated to 70℃and reacted at this temperature for 16 hours. After the reaction solution was cooled to room temperature, 100mL of brine was added thereto, and stirring was continued for 10 minutes. The reaction mixture was filtered through celite, and the filtrate was extracted 2 times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=4:1) to give the intermediate compound (15 g, crude) as a brown solid. LCMS (ESI) m/z 307.9[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.64(d,J＝4.1Hz,1H),7.35(d,J＝4.1Hz,1H),2.64(s,3H),1.18(s,9H)。
Step two: diisobutylaluminum hydride (DIBAL-H) (61 mL,61 mmol) was slowly added dropwise to tetrahydrofuran (200 mL) of the above intermediate compound (9.3 g,30.17 mmol) under nitrogen protection, cooled at-78deg.C, the reaction mixture was slowly warmed to room temperature and reacted at this temperature for 16 hours, and LC-MS detected no starting material, most of which was converted into the desired product. Methanol (50 mL) was added for quenching, the solvent was removed by concentration under reduced pressure, and the crude product was slurried with methanol (200 mL) and filtered through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4:1) to give a brown oily liquid compound (15 g, crude). LCMS (ESI) m/z 309.9[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d6)δ7.06(d,J＝3.8Hz,1H),6.89(dd,J＝3.8,0.9Hz,1H),5.90(d,J＝7.1Hz,1H),4.57(m,1H),1.47(d,J＝6.8Hz,3H),1.12(s,9H)。
Step three: tetratriphenylphosphine palladium (1.12 g,0.965 mmol) was added to the above intermediate compound (3 g,9.65 mmol), 2-formylphenylboronic acid (1.88 g,12.55 mmol), potassium carbonate (2.67 g,19.3 mmol), and water (12 mL) in 1, 4-dioxane (60 mL) under nitrogen. The reaction mixture was heated to 100℃and reacted at this temperature for 16 hours. The reaction was diluted with ethyl acetate (200 mL) and then washed with water (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by HPLC preparation to give intermediate compound (2.6 g) as brown oil. LCMS (ESI) m/z 336.0[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ10.21(d,J＝0.6Hz,1H),8.00(dd,J＝7.8,1.1Hz,1H),7.61(m,1H),7.55-7.46(m,2H),7.08(d,J＝3.0Hz,1H),6.92(d,J＝3.6Hz,1H),4.90-4.82(m,1H),3.58(d,J＝3.6Hz,1H),1.66(d,J＝6.6Hz,3H),1.26(s,9H).
Step four: 1 drop of glacial acetic acid was added to the above intermediate compound (2.6 g,7.75 mmol) and tetrahydropyrrole (662 mg,9.3 mmol) in methanol (30 mL) at room temperature, and the reaction mixture was reacted at 20℃for 2 hours. Sodium cyanoborohydride (1.46 g,23.25 mmol) was then added to the reaction solution and the reaction was continued for 12 hours, with LCMS detecting the product as a dominant one. The crude product obtained by concentrating under reduced pressure to remove the solvent was purified by silica gel column chromatography (eluent: dichloromethane/methanol=9:1) to give the compound as a pale yellow solid intermediate compound (2.1 g). LCMS (ESI) m/z 391.1[ M+H ]] + 。
Step five: to methanol (15 mL) of the above intermediate compound (2.1 g,5.38 mmol) was added 3N hydrogen chloride/methanol solution HCl (g)/MeOH (15 mL,45 mmol). The reaction mixture was reacted at 20℃for 2 hours. LC-MS detection reaction was complete. After the solvent was removed by concentrating the reaction solution under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=9:1) to obtain the objective compound (1.2 g) as a pale yellow solid. LCMS (ESI) m/z 287.1[ M+H ] ] + 。 1 H NMR(400MHz,CD 3 OD)δ7.79-7.75(m,1H),7.60-7.50(m,3H),7.32(d,J＝3.6Hz,1H),7.13(d,J＝3.6Hz,1H),4.83(m,1H),4.58(s,2H),3.54-3.44(m,2H),3.02(d,J＝8.1Hz,2H),2.06-1.94(m,4H),1.77(d,J＝6.9Hz,3H)。
Reference to the preparation and isolation methods for the preparation of (R) -1- (4- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-8-yl) phenyl) ethyl-1-amine hydrochloride and (R) -1- (5- (2- (pyrrol-1-ylmethyl) phenyl) thiophen-2-yl) ethyl-1-amine hydrochloride, the following intermediates 3-9 were synthesized:
example 1: (R) - (2-chloro-4- ((1- (4- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-8-yl) phenyl) ethyl) amino-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) (4-methoxytetrahydro-2H-pyran-4-yl) methanone
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Step one: 2, 4-dichloro-5, 7-dihydro-6H-pyrrolo [3,4-d]Pyrimidine-6-carbonate (50.0 mg,0.19 mmol) and (R) -1- (4- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-8-yl) phenyl) ethyl-1-amine hydrochloride (142.0 mg,0.9 mmol) were dissolved in N, N-dimethylformamide DMF (10 mL), and after addition of N, N-diisopropylethylamine DIEA (73.2 mg,0.57 mmol), the reaction was stirred at room temperature overnight. LC-MS detected completion of the reaction, and water (20 mL) and ethyl acetate (30 mL) were added to the reaction solution. The separated aqueous phase was extracted twice with ethyl acetate (40 mL), the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio 5:1) to give intermediate product as a white solid (15 mg). MS [ M+H ]] + :m/z 520.4。
Step two: the intermediate product (15.0 mg,0.03 mmol) was dissolved in dichloromethane DCM (10.0 mL) and trifluoroacetic acid TFA (2.0 mL) was added at room temperature and the reaction stirred overnight. After concentration under reduced pressure, an oily liquid intermediate product (15 mg) was obtained. MS [ M+H ] ] + :m/z 420.3。
Step three: the above intermediate compound (15.0 mg,0.04 mmol) and 4-methoxytetrahydro-2H-pyran-4-carboxylic acid (13.0 mg,0.08 mmol) were dissolved in DMF (10.0 mL), DIEA (15.3 g,0.12 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate HATU (45.2 mg,0.12 mmol) were added and reacted overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by HPLC to give the compound of example 1 (8.2 mg) as a white solid.
LC-MS[M+H] + :m/z 562.1。 1 H NMR(400MHz,MeOD-d 4 ):δ7.53-7.50(m,2H),7.40-7.37(m,1H),7.29-7.27(m,3H),7.19-7.17(m,1H),5.69-5.67(m,1H),4.94-4.92(m,1H),4.74-4.70(m,3H),4.33-4.31(m,2H),3.77-3.71(m,6H),3.32-3.30(m,2H),3.13(s,3H),2.95(s,3H),1.96-2.09(m,4H),1.37(d,J＝6.8Hz,3H)。
Referring to the method of example 1, the synthetic method of substituting (R) -1- (4- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-8-yl) phenyl) ethyl-1-amine hydrochloride with different benzylamine as raw material and substituting (4-methoxytetrahydro-2H-pyran-4-carboxylic acid with different acid as raw material gave examples 2-18:
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test example 1 inhibition Activity test of enzyme
KRAS using CisBio G12C SOS1 kit for testing compound inhibition SOS1 and KRAS by using Binding assay method G12C Efficacy of protein-protein interactions between them, as a result of IC 50 The value represents.
The testing method comprises the following steps: (1) Test compounds were tested at 1000nM, 100% DMSO solution diluted to 200-fold final concentration in 384well plates 3-fold diluted compound, 10 concentrations. 50nL of compound at 200-fold final concentration was transferred to the 384well plate of interest using a dispenser Echo 550. 50nL of 100% DMSO is added to each of the negative control well and the positive control well; (2) Preparing Tag1SOS1 solution with 4 times of final concentration by using a reagent buffer; (3) 2.5. Mu.L of a 4-fold final concentration of Tag1SOS1 solution was added to 384-well plates; (4) Tag2KRAS was formulated at 4-fold final concentration with Diluentbuffer G12C A solution; (5) Tag2KRAS was added at a final concentration of 4-fold of 2.5. Mu.L to each of the compound well and positive control well G12C A solution; 2.5. Mu.L of diutentbuffer was added to the negative control well; (6) Centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating for 15 minutes at room temperature; (7) 1-fold final concentration of Anti Tag1Tb3+ solution and 1-fold final concentration of Anti Tag were formulated with Detection buffer2XL665 solution, after mixing the two solutions, adding 5. Mu.L of the mixed solution to each well; (8) Centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating for 120 minutes at room temperature; (9) reading Em665/620 with an Envision microplate reader; (10) Data analysis, calculation formulaWherein Min signal negative control Kong Junzhi Max signal positive control Kong Junzhi. The log value of concentration is taken as an X-axis of the fit-up dose-response curve, the percentage inhibition rate is taken as a Y-axis, and log (inhibitor) vs. response Variable slope fit-up dose-response curve of analysis software GraphPad Prism 5 is adopted, so that the IC of each compound on enzyme activity is obtained 50 Values. The fitting formula is: y=bottom+ (Top Bottom)/(1+10 ((log ic) 50 X)*HillSlope))。
Results: some of the inventive example Compounds are directed to KRAS G12C SOS1 enzyme showed high inhibitory activity, most of compound IC 50 Less than 10nM, as in example 1,2,13,14, etc. (IC) 50 The range of values is expressed as follows: a is that<20nM,20nM≤B<100nM,C≥100nM)
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1. Biaryl benzylamine compounds of formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof,
wherein: m is M 1 And M 2 Each independently selected from N or CH;
cy is independently selected from 4-10 membered aromatic or saturated or partially unsaturated carbocyclic or heterocyclic rings;
l is selected from bond, -C 1 -C 3 Alkyl-, C 3 -C 12 Cycloalkyl, -OC 1 -C 10 Alkyl-, -NHC 1 -C 10 Alkyl-, -N (C) 1 -C 10 Alkyl) (C) 1 -C 10 Alkyl) -, -S-, -SO 2 -、-SC 1 -C 10 Alkyl-, -SOC 1 -C 10 Alkyl-, -SO 2 C 1 -C 10 Alkyl-, -O-, -CO-, -COO-, -CO C 1 -C 10 Alkyl-, -CONH C 1 -C 10 Alkyl-, -SO 2 NH C 1 -C 10 Alkyl-, -CO N (C) 1 -C 10 Alkyl) (C) 1 -C 10 Alkyl) -, SO 2 N(C 1 -C 10 Alkyl) (C) 1 -C 10 Alkyl) -SONH C 1 -C 10 Alkyl-, -SONC 1 -C 10 Alkyl-;
R 1 independently selected from hydrogen, halogen, C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C10 alkynyl, C 3 -C 14 Cycloalkyl, C 4 -C 14 Cycloalkenyl, 3-14 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, -OC 1 -C 10 Alkyl, -NHC 1 -C 10 Alkyl, -N (C) 1 -C 10 Alkyl) (C) 1 -C 10 Alkyl), -SC 1 -C 10 Alkyl, -SOC 1 -C 10 Alkyl, -SO 2 C 1 -C 10 An alkyl group, a carbocyclic ring, or a spiro/bridged/fused ring containing a heteroatom, wherein R is 1 The groups may be optionally substituted with 1 to 3 Rn; or the two Rn may form a 3-12 membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or heteroatom; the saidRn of (2) is selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoroxy, alkylsilyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, haloalkyl, haloalkoxy, C 1 -C 6 Monoalkylamino, C 1 -C 6 Dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 6 alkyl-S-, C 1 -C 6 alkyl-SO-, C 1 -C 6 alkyl-SO 2- Etc.;
R 2a and R is 2b Are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl; and R is 2a And R is 2b Or R2a and the substituent Rm on Ar can form a 3-6 membered saturated or partially unsaturated or unsaturated ring system through a carbon chain or a heteroatom;
R 3 is H, deuterium, halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylamino, 3-8 membered cycloalkyl or heterocycloalkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, 5-10 membered aromatic ring or aromatic heterocyclic group;
ar and R 4 An aryl or heteroaryl group, independently selected from 5-12 membered mono-or bicyclic, which may be substituted with one or more groups R selected from the group m The substitution is as follows: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoxy, alkylsilyl, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkoxyalkyl, C 1 -C 10 Haloalkyl, C 1 -C 10 Haloalkoxy, C1-C 10 Haloalkoxyalkyl, C 1 -C 10 Monoalkylamino, C 1 -C 10 Dialkylamino, C 1 -C 10 Monoalkylaminoalkyl, C 1 -C 10 Dialkylaminoalkyl, C 1 -C 10 Alkenyl, C 1 -C 10 Alkynyl, 3-12 membered cycloalkyl or heterocycloalkyl, C 1 -C 10 alkyl-S-, C 1 -C 10 alkyl-SO-, C 1 -C 10 alkyl-SO 2 -, substituted or unsubstituted 5-to 12-membered aryl or heteroaryl, etc., or both R' s m A 3-to 12-membered saturated or partially unsaturated, or aromatic ring system may be formed by a carbon chain or a heteroatom; the C1-C 10 Haloalkoxyalkyl, C 1 -C 10 Alkoxyalkyl, C1-C 10 Haloalkoxyalkyl, C 1 -C 10 Monoalkylaminoalkyl, C 1 -C 10 The alkyl group in the dialkylaminoalkyl, 3-12 membered cycloalkyl or heterocycloalkyl alkyl group is preferably C1-C3 alkyl;
one or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, 3-6 membered cycloalkyl or heterocycloalkyl; wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising a spiro, bridged, fused, or other saturated or partially unsaturated ring system.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, having the following characteristics:
M 1 and M 2 Each independently selected from N or CH;
cy is preferably self-contained
L is preferably a self bond, -C 1 -C 3 Alkyl-, -CO-, -COO-, -CONHC 1 -C 3 Alkyl-, -SO 2 -、-O-、-CO C 1 -C 3 Alkyl-;
R 1 preferably selected from C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl, C 3 -C 14 Cycloalkyl, C 4 -C 14 Cycloalkenyl, 3-14 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, spiro/bridged/fused ring containing 0-4 heteroatoms, and which are preferably substituted with one or more substituents selected from the group consisting of: deuterium, halogen, cyano, hydroxy, -C 1 -C 6 Alkyl, -COO C 1 -C 6 Alkyl, -CONH C 1 -C 6 Alkyl, -CON (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), -C 1 -C 6 Alkyl O C 1 -C 6 Alkyl, =o, -C 1 -C 3 Haloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, -OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OH, -OC 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkyl OH;
R 2a and R is 2b Preferably selected from hydrogen, halogen, C 1 -C 6 Alkyl, or R 2a And R is 2b Forming a 3-to 6-membered cycloalkyl or heterocycloalkyl group;
R 3 preferably selected from hydrogen, -C 1 -C 3 Alkyl, -C 1 -C 3 Alkoxy, cyclopropyl, halogen, cyano, -C 1 -C 3 Haloalkyl, -C 1 -C 3 Haloalkoxy groups;
ar and R 4 Each independently selected from a substituted or unsubstituted 6 membered aromatic ring or a 5-6 membered aromatic heterocyclic ring.
3. The compound of any one of claims 1, 2, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsionally isomer, solvate, polymorph or prodrug thereof, R 1 Preferably selected from the following groups:
wherein one or more R c Are each independently selected from hydrogen, deuterium, halogen, -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, cyano, hydroxy, amino, -SC 1 -C 6 Alkyl, -SOC 1 -C 6 Alkyl, -SO 2 C 1 -C 6 Alkyl, -COC 1 -C 6 Alkyl, -COOC 1 -C 6 Alkyl, -CONHC 1 -C 6 Alkyl, -CON (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkoxy, -C 1 -C 6 Deuterated alkyl, -C 1 -C 6 Deuteroalkoxy, -O-3-6 membered cycloalkyl or heterocycloalkyl, -C 1 -C 6 Alkyl OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl NHCs 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OH, -C 1 -C 6 Alkyl N (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), and any two Rc may be 3-10 membered saturated or partially unsaturated carbocycle or heterocycle through a carbon chain or heteroatom; r is R d Independently selected from-C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl SC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl SOCs 1 -C 6 Alkyl, -C 1 -C 6 Alkyl SO 2 C 1 -C 6 Alkyl, -COC 1 -C 6 Alkyl, -COOC 1 -C 6 Alkyl, -CONHC 1 -C 6 Alkyl group,-CON(C 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkoxy, -C 1 -C 6 Deuterated alkyl, -C 1 -C 6 Deuterated alkoxy-C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl O-3-6 membered cycloalkyl or heterocycloalkyl, -C 1 -C 6 Alkyl NHCs 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OH, -C 1 -C 6 Alkyl N (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), and the like.
4. The compound of any one of claims 1,2, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, having the following characteristics:
wherein R is 1 、L、M 1 、M 2 、R 2a 、R 2b 、R 3 、R 4 Ar and the like are defined in claims 1 and 2.
5. The compound of any one of claims 1,2, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, having the following characteristics:
wherein R is 1 、L、Cy、M 1 、M 2 、R 2a 、R 2b 、R 3 、R 4 Is defined as in claims 1, 2.
6. The compound of any one of claims 1,2, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, having the following characteristics:
and/or +.>Wherein R is 1 、L、M 1 、M 2 、R 3 、R 4 Ar and the like are defined in claims 1 and 2.
7. The compound of any one of claims 1,2, 3, 4, 5, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, having the following characteristics:
wherein R is 1 、R 3 、R 4 Ar and the like are defined in claims 1,2, 3, 4 and 5.
8. The compound of any one of claim 1,2, 3, 4, 5, 6, 7, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, wherein the compound has the structure,
But excluding the following compounds 1-7:
9. use of a compound of formula I according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, tormer, solvate, polymorph or prodrug thereof, for the preparation of a medicament for the treatment of a disease associated with Ras protein activity or expression or mutation, in particular a therapeutic medicament for tumors. The tumor is independently selected from lung cancer, pancreatic cancer, liver cancer, colorectal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, melanoma, thyroid cancer, nasopharyngeal carcinoma, etc.
10. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, wherein said pharmaceutical composition comprises:
(i) An effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof; and
(ii) A pharmaceutically acceptable carrier.
CN202211068858.2A 2021-09-07 2022-09-02 Biaryl benzylamine compound, preparation method and application Pending CN116574104A (en)

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