CN117820305A - Heterocyclic substituted quinazoline and preparation method and application thereof - Google Patents

Heterocyclic substituted quinazoline and preparation method and application thereof Download PDF

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CN117820305A
CN117820305A CN202211186008.2A CN202211186008A CN117820305A CN 117820305 A CN117820305 A CN 117820305A CN 202211186008 A CN202211186008 A CN 202211186008A CN 117820305 A CN117820305 A CN 117820305A
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substituted
alkyl
group
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吕彬华
崔大为
庞旭东
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Priority to PCT/CN2023/122243 priority patent/WO2024067744A1/en
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Abstract

The invention relates to heterocyclic substituted quinazoline and a preparation method and application thereof. Specifically, the compound disclosed by the invention has a structure shown in a formula (I), and has a good selective regulation effect on SOS1 hydrolysis.

Description

Heterocyclic substituted quinazoline and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a heterocyclic substituted quinazoline and a preparation method and application thereof.
Background
Lung cancer is one of the leading causes of mortality in human cancers. Lung cancer can be classified according to cell type into Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for 85% of all lung cancer patients. The global NSCLC market in 2016 was counted to be about $209 billion, with the U.S. market accounting for half, followed by japan, germany, and china. From the current trend, the non-small cell lung cancer market remains on the rise, and the 2023 global market is expected to reach $ 540 billion.
At present, the main therapeutic drugs of NSCLC are chemotherapy drugs, molecular targeting drugs, tumor immunotherapy and the like. The chemotherapeutic drugs mainly comprise gemcitabine, taxol, platinum drugs and the like, but the drugs generally have poor selectivity and high toxicity, so that relatively strong toxic and side effects are caused. In recent years, molecular targeted drugs gradually become research hotspots due to the obvious advantages of high selectivity, relatively small toxic and side effects, capability of realizing accurate treatment and the like. Existing NSCLC molecular targeted drugs include EGFR inhibitors (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pyrotinib, rociletinib, osimertinib, etc.), ALK inhibitors (e.g., ceritinib, alectinib, brigatinib, lorlatinib, oxcartinib, etc.), and VEGFR inhibitors (Sorafenib, regorafenib, cabozantinib, sunitinib, dorafinib, etc.).
KRAS mutations occur in 20-40% of lung adenocarcinomas, with this prevalence being higher in the western (vs asia) population (26% vs 11%) and higher in smokers (vs non-smokers) (30% vs 10%). The most common mutations occur in codons 12 and 13, including G12C, G V and G12D. Up to now, no drugs against KRAS mutations have been approved for the market.
In cells, KRAS protein transitions between inactive and active states, is in an inactive state when KRAS binds Guanosine Diphosphate (GDP), is in an active state when it binds Guanosine Triphosphate (GTP), and can activate downstream signaling pathways. The switching of KRAS between inactive and active states is regulated by two classes of factors. One class is the guanine nucleotide exchange factor (GEF), which catalyzes the binding of KRAS to GTP, thereby promoting activation of KRAS, including SOS1 proteins. Another class is the GTPase Activating Proteins (GAPs) which promote hydrolysis of KRAS-bound GTP to GDP, thereby inhibiting KRAS activity.
Three major RAS-specific GEFs have been identified so far, with SOS proteins primarily found to be involved in tumors. SOS proteins are widely expressed in vivo, containing two subtypes SOS1 and SOS2. Published data indicate that SOS1 plays a key role in mutant KRAS activation and oncogenic signaling. The reduction of SOS1 levels resulted in a reduction of proliferation and survival of tumor cells harboring KRAS mutations, whereas KRAS wild-type cell lines were unaffected. The effect of SOS1 deletion cannot be rescued by introducing a SOS1 mutated at the catalytic site, which suggests an important role for SOS1 GEF activity in KRAS mutant cancer cells.
Since KRAS-bound GTP, both mutant and wild-type, is dependent on SOS1, selective inhibition of SOS1, whether mutated or not, prevents the interaction of SOS1 with KRAS and ultimately inhibits KRAS activation.
Proteolysis is critical and tightly regulated in the normal vital activity of the cell, the process of which is accomplished primarily through the involvement of the ubiquitin enzyme system. The proteins to be cleaved are labeled by the E1, E2 and E3 ubiquitin ligase systems, and are recognized and hydrolyzed by proteases. The proteolytic regulator molecule is one kind of bifunctional active compound, and has one end combined closely with target protein and the other end combined with E3 ubiquitin ligase and connected via various connecting chains. The bi-functional molecule can simultaneously recognize target protein and E3 ubiquitin ligase in vivo, and the target protein is ubiquitinated after the target protein and the E3 ubiquitin ligase are drawn together, and then hydrolyzed through ubiquitin-proteasome pathway. After target proteolysis, the bifunctional molecule can be released to participate in the proteolysis process of the next period, thereby having a catalytic effect, and therefore, a high-efficiency therapeutic effect can be realized clinically through a small drug administration dose.
Since SOS1 target proteins are pathologically associated with a variety of diseases, there is a need for new SOS1 inhibitors for clinical treatment. The high-selectivity high-activity heterocyclic substituted quinazoline can be used for effectively treating diseases such as cancers caused by KRAS mutation and reducing the potential of off-target effect, so that the high-selectivity high-activity heterocyclic substituted quinazoline has more urgent clinical requirements.
Disclosure of Invention
The invention aims to provide a novel heterocyclic substituted quinazoline, a preparation method and application thereof.
In a first aspect of the invention, there is provided a compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof:
wherein:
a is selected from the group consisting of substituted or unsubstituted: c (C) 6 -C 14 Aryl, or 5-14 membered heteroaryl; wherein said substitution means independently substituted with one or more R;
x is selected from the group consisting of substituted or unsubstituted: c (C) 1 -C 18 Alkyl, C 3 -C 20 Cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 Aryl, 5-14 membered heteroaryl, OX 1 、NHX 1 Or NX 1 X 2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said substitution means independently substituted with one or more R;
X 1 、X 2 independently selected from the group consisting of substituted or unsubstituted: c (C) 1 -C 18 Alkyl, C 3 -C 20 Cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 Aryl, or 5-14 membered heteroaryl; wherein said substitution means independently substituted with one or more R;
Y 1 、Y 2 Each independently selected from CH or N, and Y 1 、Y 2 CH is not simultaneously present;
n 1 、n 2 each independently selected from 1, 2 or 3;
L 1 、L 2 each independently selected from the group consisting of substituted or unsubstituted: bond, O, C =o, NH, N (C 1 -C 3 Alkyl group, C 2 -C 18 Alkenyl, C 2 -C 18 Alkynyl, C 1 -C 18 Alkylene, C 3 -C 20 Cycloalkylene, 4-20 membered heterocyclylene, C 3 -C 20 cycloalkylene-C 1 -C 18 Alkylene, or 4-20 membered heterocyclylene-C 1 -C 18 An alkylene group; wherein said substitution means independently substituted with one or more R;
z is selected from the group consisting of substituted or unsubstituted: bond, C 2 -C 18 Alkynyl, C 3 -C 20 Cycloalkyl, 4-20 membered heterocyclyl, C 3 -C 20 cycloalkylene-C 1 -C 18 Alkylene, or 4-20 membered heterocyclylene-C 1 -C 18 An alkylene group; wherein the substitution refers to substitution with one or more R;
P 1 、P 2 、P 3 each independently selected from CH, CF, or N;
P 4 、P 5 each independently selected from CH 2 Or c=o;
each R, which may be the same or different, is independently selected from: H. deuterium, vinyl, ethynyl, C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl alcohol, (C) 3 -C 6 Cycloalkyl) C 1 -C 6 Alkyl, (4-6 membered heterocyclic) C 1 -C 6 Alkyl, (C) 1 -C 6 Alkoxy) C 1 -C 6 Alkyl, (C) 3 -C 6 Cycloalkyloxy) C 1 -C 6 Alkyl, (4-6 membered heterocyclyloxy) C 1 -C 6 Alkyl, (C) 1 -C 6 Alkyl) vinyl, deuteration (C) 1 -C 6 Alkyl) vinyl, halo (C) 1 -C 6 Alkyl) vinyl, (C 1 -C 6 Alkyl) ethynyl, deuteration (C) 1 -C 6 Alkyl) ethynyl, halo (C) 1 -C 6 Alkyl) ethynyl, (C 3 -C 6 Cycloalkyl) ethynyl, (4-6 membered heterocyclyl) ethynyl, C 1 -C 6 Alkoxy, deuterated C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyloxy, 4-6 membered heterocyclyloxy, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclyl, and,C 6 -C 10 Aryl, 5-to 10-membered heteroaryl, halogen, nitro, hydroxy, oxo (=o), cyano, ester, amino, amide, sulfone or urea.
In another preferred embodiment, a is a substituted or unsubstituted phenyl; wherein, the substitution means that the substitution is independently performed by one or more R.
In another preferred embodiment, a is selected from:
in another preferred embodiment, X 1 Selected from: substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 Oxaalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 4 -C 6 Monooxacycloalkyl; wherein, the substitution means that the substitution is independently performed by one or more R.
In another preferred embodiment, X 1 Selected from:
in another preferred embodiment, Y 1 Selected from: n, Y 2 Selected from: n.
In another preferred embodiment, Y 1 Selected from: n, Y 2 Selected from: CH.
In another preferred embodiment, Y 1 Selected from: CH, Y 2 Selected from: n.
More preferably, Y 1 Selected from: n, Y 2 Selected from: n or CH.
In another preferred embodiment, n 1 Is 2, n 2 2.
In another preferred embodiment, n 1 Is 1, n 2 1.
In a further preferred embodiment of the present invention,selected from the group consisting of substituted or unsubstituted:
wherein, the substitution means that the substitution is independently performed by one or more R.
In another preferred embodiment, Z is selected from substituted or unsubstituted C 4 -C 6 Heterocycloalkylene, or substituted or unsubstituted C 2 -C 6 Alkynyl; wherein, the substitution means that the substitution is independently performed by one or more R.
In another preferred embodiment, Z is selected from substituted or unsubstituted C 4 -C 6 Heterocycloalkylene; wherein, the substitution means that the substitution is independently performed by one or more R.
In another preferred embodiment, Z is selected from the group consisting of substituted or unsubstituted:
wherein, the substitution means that the substitution is independently performed by one or more R.
In another preferred embodiment, -L 1 -L 2 -a group selected from the group consisting of substituted or unsubstituted: bond, C 1 -C 6 Alkyl group,
Wherein, the substitution means that the substitution is independently performed by one or more R.
In another preferred embodiment, the compound has the structure of formula (II):
wherein: A. x, Y 1 、Y 2 、L 1 、L、Z、P 1 、P 2 、P 3 、P 5 、n 1 、n 2 The method of claim 1.
In another preferred embodiment, the compound has the structure of formula (III):
wherein: A. x, Y 1 、Y 2 、L 1 、L、Z、P 1 、P 2 、P 5 、n 1 、n 2 The method of claim 1.
In another preferred embodiment, the compound has the structure of formula (IV):
wherein: A. x, Y 1 、Y 2 、L 1 、L、Z、P 2 、P 5 、n 1 、n 2 The method of claim 1.
In another preferred embodiment, the compound has the structure of formula (V):
wherein: A. x, Y 2 、L 1 、L、Z、P 2 、P 5 、n 1 、n 2 The method of claim 1.
In another preferred embodiment, the compound is selected from the group consisting of:
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in another preferred embodiment, A, X, Y of the compound of formula (I) 1 、Y 2 、L 1 、L、Z、P 1 、P 2 、P 3 、P 4 、P 5 、n 1 、n 2 Independently a group corresponding to the above compound.
In a second aspect of the invention there is provided a process for the preparation of a heterocyclic substituted quinazoline of the structure of the general formula (I), stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, selected from the following synthetic routes:
the compounds of the formula (V-I) and the formula (V-II) are subjected to substitution reaction, reductive amination reaction, coupling reaction, amide condensation reaction and the like to obtain a compound of the formula (I);
wherein:
A、X、Y 1 、Y 2 、L 1 、L、Z、P 1 、P 2 、P 3 、P 4 、P 5 、n 1 、n 2 the method of claim 1.
LG 1 Or LG (light emitting diode) 2 Identical or different, are leaving groups, each preferably selected from: hydrogen, OH, =o, halogen, OTs, OMs, OTf, B (OH) 2 Etc.
In a third aspect of the present invention there is provided a pharmaceutical composition comprising I) one or more compounds of the structure of formula (I) according to the first aspect of the present invention, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and ii) a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises one or more therapeutic agents selected from the group consisting of: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pimelizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226,STW204,HX008,HLX10,BAT 1306,AK105,LZM 009, or a biosimilar of the above), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or a biosimilar of the above), CD20 antibodies (e.g., rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,131I-tositumomab, ibrituximab, 90Y-ibrimimob, 90 In-irimamab, hutumamtuitum, 47, etc.), antibodies (e.g., CD4, etc.), CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM 01), ALK inhibitors (e.g., ceritinib, alectinib, brigatinib, lorlatinib, okatinib), PI3K inhibitors (e.g., idelalisib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, buparlisib, etc.), BTK inhibitors (e.g., ibrutinib, tirabrutinib, acalabrutinib, zanubrutinib, vecabrutinib, etc.), EGFR inhibitors (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, sapitinib, naquotinib, pyrotinib, rociletinib, osimertinib, etc.), VEGFR inhibitors (e.g., sorafenib, pazopanib, regorafenib, sitravatinib, ningetinib, cabozantinib, sunitinib, dorafinib, etc.), HDAC inhibitors (e.g., givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, tacedinaline, etc.), CDK inhibitors (e.g., palbociclib, ribociclib, abemaciclib, milciclib, trilaciclib, lerociclib, etc.), MEK inhibitors (e.g., selumetinib (AZD 6244), trametinib (GSK 1120212), PD0325901, U0126, pimasertib (AS-703026), PD 1843352 (CI-1040, etc.), mTOR inhibitors (e.g., vistuertib, etc.), MER inhibitors (e.g., vistusertib, etc.), MEK inhibitors (e.g., selumetinib, etc), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof.
In a fourth aspect, the present invention provides a compound according to the first aspect, a stereoisomer, a tautomer, a crystal, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition according to the third aspect of the present invention, for use in the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of a disease associated with SOS1 activity or expression level.
In another preferred embodiment, the disease is cancer.
In another preferred embodiment, the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.
In a fifth aspect of the present invention, there is provided a method for preventing and/or treating a disease associated with SOS1 activity or expression level, comprising the steps of: administering to a subject in need thereof an effective amount of a compound of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, as described in the first aspect of the invention, or administering a pharmaceutical composition according to the third aspect of the invention.
In another preferred embodiment, the subject is a mammal, such as a human, rat or mouse.
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. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 shows the measurement of SOS1 and beta-actin levels in H358 cells after 6 hours of treatment at different concentrations of compound example 26.
Detailed Description
The present inventors have conducted long and intensive studies and have unexpectedly found a novel class of proteolytic modulators against SOS 1. On this basis, the inventors completed the present invention.
Terminology
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
As used herein, the term "alkyl" refers to a straight or branched chain alkyl group containing several carbon atoms, such as "C 1 -C 18 Alkyl "means a straight-chain or branched alkyl group having 1 to 18 carbon atoms, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms, alkyl groups preferably being, for example, C 1 -C 2 、C 1 -C 3 、C 1 -C 4 、C 1 -C 5 、C 1 -C 6 、C 1 -C 7 、C 1 -C 8 、C 1 -C 9 、C 1 -C 10 、C 2 -C 3 、C 2 -C 4 、C 2 -C 5 、C 2 -C 6 、C 3 -C 4 、C 3 -C 5 、C 3 -C 6 、C 3 -C 7 、C 3 -C 8 、C 4 -C 5 、C 4 -C 6 Or C 5-6 . Typical "alkyl" groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, and,Pentyl, isopentyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. In the present invention, alkyl groups also include substituted alkyl groups. "substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1 to 4 substituents, and may be substituted at any position.
The term "alkylene" by itself or as part of another substituent refers to a group formed by the removal of one more hydrogen atom from an "alkyl" group, which may contain 1 to 18 carbon atoms, including, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms. For example, methylene, ethylene, propylene, isopropylene (e.g) Butylene (e.g.)>) Pentylene (e.g.)>) Hexyl ene (e.g.)>) Heptyl (e.g.)>) Etc.
As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl groups may include any number ofThe number of carbon atoms, wherein "C2-C18 alkenyl" refers to a straight or branched hydrocarbon having 2 to 18 carbon atoms and at least one double bond, e.g. C 2 、C 2- C 3 、C 2- C 4 、C 2- C 5 、C 2- C 6 、C 2- C 7 、C 2- C 8 、C 2- C 9 、C 2- C 10 、C 3 、C 3- C 4 、C 3- C 5 、C 3- C 6 、C 4 、C 4- C 5 、C 4- C 6 、C 5 、C 5- C 6 And C 6 . Alkenyl groups may have any suitable number of double bonds including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (vinyl group)), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1, 3-hexadienyl, 1, 4-hexadienyl, 1, 5-hexadienyl, 2, 4-hexadienyl, or 1,3, 5-hexatrienyl. As with the alkyl groups described above, alkenyl groups may be substituted or unsubstituted.
As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl groups may include any number of carbon atoms, "C2-C18 alkynyl" refers to straight or branched chain hydrocarbons having 2 to 18 carbon atoms and at least one triple bond, e.g., C 2 、C 2- C 3 、C 2- C 4 、C 2- C 5 、C 2- C 6 、C 2- C 7 、C 2- C 8 、C 2- C 9 、C 2- C 10 、C 3 、C 3- C 4 、C 3- C 5 、C 3- C 6 、C 4 、C 4- C 5 、C 4- C 6 、C 5 、C 5- C 6 And C 6 . Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, and isobutynylA group, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1, 3-pentadiynyl, 1, 4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1, 3-hexadiynyl, 1, 4-hexadiynyl, 1, 5-hexadiynyl, 2, 4-hexadiynyl, or 1,3, 5-hexadiynyl.
As used herein, the term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group having several carbon atoms, wherein "C 3 -C 20 Cycloalkyl "means a fully saturated cyclic hydrocarbon group having 3 to 20 carbon atoms, preferably C 3 -C 4 、C 3 -C 5 、C 3 -C 6 、C 3 -C 7 、C 3 -C 8 、C 3 -C 9 、C 3 -C 10 . "substitution C 3 -C 20 Cycloalkyl "means that one or more positions in the cycloalkyl group, especially 1-4 substituents, may be substituted at any position, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. In the present invention, "cycloalkyl" is intended to include "substituted cycloalkyl".
The term "cycloalkylene" by itself or as part of another substituent refers to a group formed by the removal of two hydrogen atoms from a cycloalkyl group as described above, such as:
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etc.
The term "alkylene cycloalkylene" refers to a radical formed by the removal of two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl radical as described above, wherein "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" have the same meaning, preferably C1-C6 alkylene C3-C12 cycloalkylene, including but not limited to:
etc.
As used herein, the term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group having several (3 or more) ring atoms and having 1-4 heteroatoms, wherein "4-20 membered heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group having 4-20 ring atoms and having 1-4 heteroatoms (including but not limited to, e.g., 4-7 membered monocyclic, 6-11 membered bicyclic, or 8-12 membered tricyclic ring systems). Wherein the nitrogen or sulfur atom may be oxidized and the nitrogen atom may be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of a ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.
The term "heterocyclylene" refers to a group formed by the removal of two hydrogen atoms from the heterocyclic group, such as including, but not limited to:
etc.
The term "heterocycloalkylalkylene" refers to a radical formed by the removal of two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, wherein "4-20 membered heterocycloalkylene C1-C18 alkylene" or "C1-C18 alkylene 4-20 membered heterocycloalkylene" have the same meaning, preferably 4-12 membered heterocycloalkylene C1-6 alkylene, including but not limited to:
etc.
The term "aryl" refers to aromatic cyclic hydrocarbon groups having 1 to 5 rings, especially to monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. The aromatic ring of the aryl group may be linked by a single bond (e.g., biphenyl), or condensed (e.g., naphthalene, anthracene, etc.), where the aromatic ring contains two or more aromatic rings (bicyclic, etc.). "substituted aryl" means that one or more positions in the aryl group are substituted, especially 1 to 3 substituents, and can be substituted at any position.
The term "arylene" refers to a group formed by the removal of two hydrogen atoms from an aryl group as described above.
The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 2 or 3) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur, and the heterocyclyl may include 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms. Heteroaryl is preferably a 5-to 10-membered ring, more preferably 5-or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. "heteroaryl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.
The term "heteroarylene" refers to a group formed by the removal of two hydrogen atoms from the heteroaryl group described above.
The term "C1-C18 alkoxy" refers to a straight or branched chain or cyclic alkyl oxy group having 1 to 18 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preferably C1-C8 alkoxy, more preferably C1-C6 alkoxy or C1-C4 alkoxy.
The term "C1-C18 alkyleneoxy" refers to a group obtained by removing one hydrogen atom from "C1-C18 alkyleneoxy".
The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.
The term "halo" refers to substitution with halogen.
The term "deuterated" refers to a compound which is deuterated 2 H) And (3) substitution.
The term "hydroxy" refers to a group with the structure OH.
The term "nitro" refers to a compound having the structure NO 2 Is a group of (2).
The term "cyano" refers to a group bearing the structure CN.
The term "ester group" refers to a group having the structure-COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
The term "amine group" refers to a group having the structure-NRR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.
The term "amide" refers to a group with the structure-CONRR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.
The term "sulfonamide" refers to a compound having the structure-SO 2 The group NRR 'wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.
The term "ureido" refers to a group bearing the structure-NRCONR 'R ", wherein R, R' and R" may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.
The term "alkylaminoalkyl" refers to a group with the structure-RNHR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different.
The term "dialkylaminoalkyl" refers to a group with the structure-RNHR 'R ", wherein R, R' and R" may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.
The term "heterocyclylalkyl" refers to a group bearing the structure-RR', wherein R may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; r' represents a heterocycle or a substituted heterocycle.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Preferably, unless otherwise specified, a substitution may be substituted with one or more substituents selected from the group consisting of: for example (but not limited to): halogen, hydroxy, cyano, carboxyl (-COOH), C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl, 4-12 membered heterocyclyl, aryl, heteroaryl, C 1 -C 8 Aldehyde group, C 2 -C 10 Acyl, C 2 -C 10 Ester group, amine group, C 1 -C 6 Alkoxy, C 1 -C 10 Sulfonyl and C 1 -C 6 Ureido, and the like.
Unless otherwise indicated, it is assumed that any heteroatom in an underfilling state has sufficient hydrogen atoms to complement its valence.
When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, e.g., alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.
As used herein, the term "plurality" refers to two or more, such as 2, 3, 4, 5 or 6.
Active ingredient
As used herein, "compounds of the invention" refers to compounds of formula I, and also includes stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs of the compounds of formula I:
wherein: A. x, Y 1 、Y 2 、L 1 、L、Z、P 1 、P 2 、P 3 、P 4 、P 5 、n 1 、n 2 As described above.
Salts which may be formed with the compounds of the present invention are also within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to salts formed with inorganic or organic acids and bases in the acid or base form. Furthermore, when the compound of the present invention contains a basic moiety, it includes, but is not limited to, pyridine or imidazole, and an acidic moiety, including, but not limited to, carboxylic acids, the possible formation of zwitterions ("inner salts") are included within the term "salts". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during the preparation process. The compounds of the invention may form salts, for example, by reacting compound I with an amount of, for example, an equivalent of, an acid or base, salting out in a medium, or lyophilizing in aqueous solution.
The compounds of the present invention contain basic fragments, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that may be salified include acetates (e.g., with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartate, benzoate, benzenesulfonates, bisulfate, borate, butyrate, citrate, camphorates, camphorsulfonates, cyclopentane propionates, diglycolates, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodite, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluene sulfonate such as p-toluenesulfonate, dodecanoate, and the like
Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, that may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, sea-bamine (salts with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and dipentyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.
Prodrugs and solvates of the compounds of the invention are also within the scope of coverage. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to produce a compound, salt, or solvate of the invention when used in the treatment of a related disorder. The compounds of the present invention include solvates, such as hydrates.
The compounds, salts or solvates of the present invention, may exist in tautomeric forms (e.g., amides and imine ethers). All of these tautomers are part of the present invention.
Stereoisomers of all compounds (e.g., those having asymmetric carbon atoms which may be present as a result of various substitutions), including enantiomeric and diastereoisomeric forms thereof, are contemplated as falling within the scope of the present invention. The individual stereoisomers of the compounds of the invention may not be present simultaneously with the other isomers (e.g., having particular activity as one pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures with all or a portion of the other stereoisomers. The chiral center of the present invention has two configurations, S or R, defined by the International Association of theory and application chemistry (IUPAC) 1974. The racemic forms can be resolved by physical methods, such as fractional crystallization, or by separation of crystals by derivatization into diastereomers, or by chiral column chromatography. Individual optical isomers may be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.
The compounds of the present invention are prepared, isolated and purified in sequence to give the compounds in an amount of 90% by weight or more, for example 95% or more and 99% or more ("very pure" compounds), as listed in the text description. Such "very pure" compounds of the invention are also included herein as part of the invention.
All configurational isomers of the compounds of the present invention are within the scope of coverage, whether in mixtures, pure or very pure form. The definition of compounds in the present invention includes both the cis (Z) and the trans (E) olefin isomers, as well as the cis and trans isomers of carbocycles and heterocycles.
Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
Specific functional groups and chemical term definitions are described in detail below. For the purposes of the present invention, chemical elements are described in conjunction with Periodic Table of the Elements, CAS version, handbook of Chemistry and Physics,75 th Ed. a defined inSo that. The definition of specific functional groups is also described herein. Furthermore, the basic principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, which is incorporated by reference in its entirety.
Certain compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures thereof. In addition, an asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers and mixtures thereof are encompassed by the present invention.
According to the invention, the mixture of isomers may contain various isomer ratios. For example, in a mixture of only two isomers, there may be a combination of: all ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomers are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are within the scope of the present invention, as would be readily understood by one of ordinary skill in the art.
The present invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as original compounds. In practice it will often occur that one or more atoms are replaced by an atom of a different atomic weight or mass number than it is. Examples of isotopes that can be listed as compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, respectively, such as 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, e.g 3 H and 14 radioactivity of CIsotopes are also useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. tritium 3 H and carbon-14, i.e 14 C, their preparation and detection are relatively easy. Is the first choice in isotopes. In addition, heavier isotopic substitutions such as deuterium, i.e 2 H may be preferred in some cases because of its good metabolic stability, which may be advantageous in certain therapies, such as increasing half-life or decreasing dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by using readily available isotopically-labeled reagents in place of non-isotopically-labeled reagents using the protocols disclosed in the examples.
If one is to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary, separating the resulting diastereomeric mixture and removing the chiral auxiliary to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith using an appropriate optically active acid or base, and then the resulting mixture can be separated by conventional means such as fractional crystallization or chromatography to give the pure enantiomer.
As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to extend their inclusion. In general, the term "substituted", whether appearing before or after the term "optional", includes the general formula of substituents in the formulations of the invention, means that the specified structural substituent is used in place of the hydrogen radical. When multiple of a particular structure are substituted at a position with multiple particular substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible organic compound substitutions. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any of the permissible organic compounds described hereinabove to supplement the valence state thereof. Furthermore, the present invention is not intended to be limited in any way to allow substitution of organic compounds. The present invention contemplates that the combination of substituents and variable groups is useful in the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds. The term "stable" as used herein refers to a compound that is stable for a period of time sufficient to maintain structural integrity of the compound, preferably for a period of time sufficient to be effective, as used herein for the purposes described above.
Metabolites of the compounds and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof, are also encompassed by the claims of the present application.
Preparation method
The process for preparing the compound of the formula (I) according to the present invention is described in more detail below, but these specific processes do not limit the present invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Typically, the compounds of the present invention are prepared by the following process wherein the starting materials and reagents used, unless otherwise specified, are commercially available.
The compounds of the formula (V-I) and the formula (V-II) are subjected to substitution reaction, reductive amination reaction, coupling reaction, amide condensation reaction and the like to obtain a compound of the formula (I);
wherein:
A、X、Y 1 、Y 2 、L 1 、L、Z、P 1 、P 2 、P 3 、P 4 、P 5 、n 1 、n 2 the method of claim 1.
LG 1 Or LG (light emitting diode) 2 Identical or different, are leaving groups, each preferably selected from: hydrogen, OH, =o, halogen, OTs, OMs, OTf, B (OH) 2 Etc.
Pharmaceutical compositions, uses and methods of administration
The pharmaceutical composition of the invention comprises the active ingredients and pharmaceutically acceptable carriers.
The compound of the present invention can reduce SOS1 activity, expression level, promote SOS1 protein degradation and/or reduce SOS1 level, and thus can be used for preventing and/or treating SOS1 activity or expression level-related diseases. The pharmaceutical composition provided by the invention can be used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
In another preferred embodiment, the cancer is a cancer caused by KRAS mutation.
In another preferred embodiment, the cancer includes (but is not limited to): lung cancer (small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
The compounds of formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug may remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, it may be preferable to use a pharmaceutical composition containing one or more known drugs together with the compound of formula I. Drug combinations also include administration of the compound of formula I with one or more other known drugs over overlapping time periods. When a compound of formula I is administered in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of the compound of formula I alone.
Drugs or active ingredients that may be used in combination with the compounds of formula (I) include, but are not limited to: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or a bio-analog of the above drugs, etc.), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-a167, F520, GR1405, MSB2311 or a biosimilar of the above, etc.), CD20 antibodies (e.g., rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibrituxomab, 90In-ibritumomab, ibritumomabtiuxetan, etc.), CD47 antibodies (e.g., hu5F9-G4, CC-90002, TTI-621, TTI-622, ose-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM 01), ALK inhibitors (e.g., ceritinib, alectinib, brigatinib, lorlatinib, oxcrinib), PI3K inhibitors (e.g., idelalisib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, buparlisib, etc.), BTK inhibitors (e.g., ibrutinib, tirabrutinib, acalabrutinib, zanubrutinib, vecabrutinib, etc.), EGFR inhibitors (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, sapitinib, naquotinib, pyrotinib, rociletinib, osimertinib, etc.), VEGFR inhibitors (e.g., sorafenib, pazopanib, regorafenib, sitravatinib, ningetinib, cabozantinib, sunitinib, donafinib, etc.), HDAC inhibitors (e.g., givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, tacedinaline, etc.), CDK inhibitors (e.g., palbociclib, ribociclib, abemaciclib, milciclib, trilaciclib, lerociclib, etc.), MEK inhibitors (e.g., selemetinib (AZD 6244), tramtinib (PD 1120212), PD 0325101, U0126, pimapib (AS-3026), pin 70352, etc., CI (cf. Etc.), etc., CI (e., mTOR inhibitors (e.g., vistuertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof.
Dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, external liniment, controlled release or sustained release preparation, or nanometer preparation.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-1000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: a pharmaceutically acceptable carrier is admixed with a compound of formula (I) or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof according to the invention, thereby forming a pharmaceutical composition.
The invention also provides a treatment method, which comprises the following steps: administering to a subject in need thereof a compound of formula (I) as described herein, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described herein, for selectively inhibiting SOS1.
Compared with the prior art, the invention has the following main advantages:
(1) The compound can selectively promote SOS1 protein hydrolysis, so that SOS1 activity or diseases related to expression quantity (especially high selectivity to tumor cells) can be prevented and/or treated, the activity is high, and the safety is good;
(2) The compounds of the present invention may exert an effect of inhibiting cell proliferation in a catalytic amount. The effect of degrading target proteins can be circularly exerted in cells, so that the dosage is reduced, the administration period is prolonged, and the safe and effective anti-tumor effect is achieved;
(3) The compounds have better in-vivo and in-vitro pharmacodynamics, pharmacokinetics and/or lower toxic and side effects.
The invention will be further illustrated with reference to specific examples. It is to 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 procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
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. 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 methods and materials described herein are presented for illustrative purposes only.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus, and the measuring solvent comprises deuterated dimethyl sulfoxide (DMSO), deuterated acetone (CD) 3 COCD 3 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), etc., the internal standard being Tetramethylsilane (TMS), the chemical shifts being measured in parts per million (ppm).
Liquid chromatography (LC-MS) was performed using a Waters SQD2 mass spectrometer. HPLC was determined using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100x3.0mm column).
The thin layer chromatography silica gel plate is Qingdao GF254 silica gel plate, TLC is 0.15-0.20mm, and the preparation thin layer chromatography is 0.4-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to literature reported in the art.
Except for the special descriptions, all reactions of the invention are carried out by continuous magnetic stirring under the protection of dry inert gas (such as nitrogen or argon), and the reaction temperature is in degrees centigrade.
Examples
Preparation of intermediate 1-1 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazine-4-carbaldehyde
The first step: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindole-1, 3-dione
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindole-1, 3-dione (2.00 g,7.24mmol,1.00 eq) in NMP (10 mL) was added DIEA (2.81 g,21.7mmol,3.78mL,3.00 eq) and 4-piperidinemethanol (1.67 g,14.5mmol,2.00 eq). The mixture was reacted at 100℃for 3 hours, followed by addition of EtOAc (200 mL) and saturated brine (200 mL). The organic phase was separated, washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the desired product (2.30 g,5.57mmol,77.0% yield).
LC-MS：m/z 372(M+H) + 。
And a second step of: preparation of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazine-4-carbaldehyde
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindole-1, 3-dione (2.40 g,6.45mmol,1.00 eq) in DCM (1.00 mL) was added Dess-Martin (5.48 g,12.5mmol,2.00 eq) at room temperature. The reaction was reacted at 25℃for 2h, then diluted with water (200 mL) and extracted with DCM/MeOH (V: V=5:1, 100 mL. Times.3). The combined organic phases were washed with saturated brine (100 ml x 2), dried over anhydrous magnesium sulfate and filtered. (1.00 g,2.48mmol,38.4% yield).
LC-MS：m/z 370(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ11.09(s,1H),9.62(s,1H),7.67(d,J＝8.5Hz,1H),7.35(d,J＝2.0Hz,1H),7.26(dd,J＝2.3,8.6Hz,1H),5.07(dd,J＝5.3,12.9Hz,1H),3.94(br d,J＝13.4Hz,2H),3.24-3.11(m,2H),2.95-2.82(m,1H),2.71-2.59(m,2H),2.59-2.53(m,1H),2.07-1.98(m,1H),1.97-1.86(m,2H),1.65-1.48(m,2H).
The following compounds were synthesized in the same manner as in intermediate 1-1:
intermediate 1-2 1- (2, 6-Dioxypiperidin-3-yl) -1, 3-Dioxisoindol-5-yl) azetidine-3-carbaldehyde
LC-MS：m/z 342(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ11.07(s,1H),9.85(d,J＝1.6Hz,1H),7.65(dd,J＝8.3,18.6Hz,1H),6.89-6.75(m,1H),6.74-6.59(m,1H),5.11-5.01(m,1H),4.22-4.15(m,2H),4.01(t,J＝8.4Hz,1H),3.83(dd,J＝5.7,8.3Hz,1H),3.30(s,1H),2.96-2.76(m,2H),2.59(d,J＝16.6Hz,2H).
Preparation of intermediate 1-3 1- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindol-5-yl) piperazine-4-carbaldehyde
LC-MS：m/z 388(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H)9.65(s,1H)7.72(d,J＝11.38Hz,1H)7.47(d,J＝7.38Hz,1H)5.11(dd,J＝12.76,5.38Hz,1H)3.49-3.60(m,2H)3.03(br t,J＝10.38Hz,2H)2.80-2.96(m,1H)2.57(br s,2H)1.88-2.10(m,4H)1.57-1.73(m,2H)。
Preparation of intermediate 2-1 1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) piperidine-4-carbaldehyde
The first step: preparation of methyl 2-bromo-4- (4- (dimethoxymethyl) piperidin-1-yl) benzoate
To a solution of methyl 2-bromo-4-fluorobenzoate (2.80 g,12.0mmol,1.00 eq) in DMSO (50.0 mL) was added 4- (dimethoxymethyl) piperidine (2.49 g,15.6mmol,1.30 eq) and DIEA (3.11 g,24.0mmol,4.19mL,2.00 eq). The mixture was reacted at 120 ℃ for 20h then diluted with ice water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the desired product (4.20 g,11.3mmol,93.9% yield). It was used in the next reaction without further purification.
LC-MS：m/z 372(M+H) + 。
And a second step of: preparation of methyl 4- (4- (dimethoxymethyl) piperidin-1-yl) -2-formylbenzoate
Na was added to a solution of methyl 2-bromo-4- (4- (dimethoxymethyl) piperidin-1-yl) benzoate (3.03 g,8.14mmol,1.00 eq) and 2-isonitrile-2-methyl-propane (1.35 g,16.9mmol,1.84mL,2.00 eq) in DMF (60.0 mL) under nitrogen 2 CO 3 (862mg, 8.14mmol,1.00 eq), tricyclohexylphosphorus (228 mg, 803 umol,263uL,0.100 eq), triethylsilane (2.84 g,24.4mmol,3.90mL,3.00 eq) and palladium acetate (182 mg, 803 umol,0.100 eq). The resulting mixture was reacted at 65 ℃ for 16h under nitrogen protection, then diluted with ice water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (1.60 g,4.98mmol,61.2% yield).
LC-MS：m/z 322(M+H) + 。
And a third step of: preparation of 3- (5- (4- (dimethoxymethyl) piperidin-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione
Acona (816 mg,9.96mmol,2.00 eq) was added to a solution of 3-aminopiperidine-2, 6-dione hydrochloride (901 mg,5.48mmol,1.10 eq) in MeOH (20.0 mL). The mixture was reacted at 25℃for 10min, followed by addition of methyl 4- (4- (dimethoxymethyl) piperidin-1-yl) -2-formylbenzoate (1.60 g,4.98mmol,1.00 eq) and AcOH (18M, 2.77mL,10.0 eq). The resulting mixture was reacted at 25℃for 20min, followed by addition of NaBH 3 CN (625 mg,9.96mmol,2.00 eq). The resulting mixture was reacted at 35℃for 16h, then poured into ice water (10 mL) andthe pH 8 was adjusted with saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc (10 ml x 3). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (900 mg,2.24mmol,45.0% yield).
LC-MS：m/z 402(M+H) + 。
Fourth step: preparation of 1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) piperidine-4-carbaldehyde
To a solution of 3- (5- (4- (dimethoxymethyl) piperidin-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione (900 mg,2.24mmol,1.00 eq) in DCM (6 mL) was added TFA (7.67 g,67.2mmol,4.98mL,30.0 eq). The reaction solution was reacted at 25℃for 1 hour and then concentrated under reduced pressure. EtOAc (5 mL) and MBTE (10 mL) were added to the residue, which was then filtered and the filtrate concentrated under reduced pressure to give the desired product (79mg, 2.11mmol,94.2% yield).
LC-MS：m/z 356(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.95(s,1H)9.63(s,1H)7.52(d,J＝8.44Hz,1H)7.00-7.15(m,2H)5.05(dd,J＝13.20,5.01Hz,1H)4.17-4.39(m,2H)3.79(br d,J＝13.08Hz,3H)2.79-3.09(m,3H)2.54-2.66(m,2H)2.29-2.41(m,1H)1.87-1.96(m,2H)1.75-1.84(m,1H)1.49-1.67(m,1H)
The following compounds were synthesized in the same manner as in intermediate 2-1:
preparation of intermediate 2-2 3- (1-oxo-5- (4-oxopiperidin-1-yl) isoindol-2-yl) piperidine-2, 6-dione
LC-MS：m/z 342(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.95(s,1H),7.57-7.54(m,1H),7.17-7.15(m,1H),7.14-7.10(m,1H),5.08-5.02(m,1H),4.37-4.18(m,2H),3.75(t,J＝6.0Hz,4H),2.95-2.85(m,1H),2.63-2.55(m,1H),2.44(t,J＝5.9Hz,4H),2.41-2.31(m,1H),2.00-1.92(m,1H)
Preparation of intermediate 3-1 1- (3- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) prop-2-yn-1-yl) piperidine-4-carbaldehyde
The first step: preparation of 4- (dimethoxymethyl) -1- (prop-2-yn-1-yl) piperidine
Under nitrogen protection, 4- (dimethoxymethyl) piperidine (4 g,25.12mmol,1 eq), 3-bromoprop-1-yne (4.48 g,37.68mmol,3.25mL,1.5 eq) and Cs 2 CO 3 (20.46 g,62.80mmol,2.5 eq) CHCl 3 (40 mL) and H 2 A mixed solution of O (40 mL) was reacted at 20℃for 8hr, followed by addition of DCM (40 mL) and H 2 O (80 mL) was layered. The organic phase was washed with saturated aqueous sodium chloride (40 ml x 2) and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the desired product (4 g,16.22mmol,64.57% yield). The reaction mixture was used in the next reaction without purification.
LC-MS：m/z 198(M+H) + 。
And a second step of: preparation of 3- (5- (3- (4- (dimethoxymethyl) piperidin-1-yl) prop-1-yn-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione
4- (Dimethoxymethyl) -1- (prop-2-yn-1-yl) piperidine (2 g,10.14mmol,1 eq), 3- (5-bromo-1-oxindol-2-yl) piperidine-2, 6-dione (3.28 g,10.14mmol,1 eq), cuI (193.08 mg,1.01mmol,0.1 eq), TEA (3.08 g,30.41mmol,4.23mL,3 eq) and PdCl under nitrogen 2 (PPh 3 ) 2 A mixture of (711.60 mg,1.01mmol,0.1 eq) in DMF (40 mL) was reacted at 60℃for 16hr. The resulting mixture was purified in DCM/MeOH (V: V=10:1, 50 mL) and H 2 O (100 mL) was split. The organic phase was washed with saturated aqueous sodium chloride (50 ml x 2) and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (2.8 g,5.73mmol,56.56% yield).
LC-MS：m/z 440(M+H) + 。
And a third step of: preparation of 1- (3- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) prop-2-yn-1-yl) piperidine-4-carbaldehyde
To a solution of 3- (5- (3- (4- (dimethoxymethyl) piperidin-1-yl) prop-1-yn-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione (1.8 g,4.10mmol,1 eq) in DCM (10 mL) was added TFA (14.01 g,122.87mmol,9.10mL,30 eq). The reaction solution was reacted at 20℃for 16hr and then concentrated under reduced pressure. The residue was chromatographed on a column of silica gel to give the desired product (170 mg,427.77 mol,10.44% yield).
LC-MS：m/z 394(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.99(s,1H),9.61(s,1H),8.15(s,1H),7.76-7.64(m,2H),7.56(d,J＝7.7Hz,1H),5.11(dd,J＝5.0,13.2Hz,1H),4.51-4.42(m,1H),4.37-4.31(m,1H),3.57(s,2H),2.98-2.86(m,2H),2.86-2.77(m,2H),2.61(d,J＝17.2Hz,1H),2.40(dd,J＝4.3,13.3Hz,1H),2.36-2.30(m,2H),2.06-1.98(m,1H),1.94-1.83(m,2H),1.62-1.46(m,2H).
The following compounds were synthesized in the same manner as in intermediate 3-1:
intermediate 3-2
LC-MS：m/z 380(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ11.02(s,1H),7.75-7.66(m,2H),7.57(d,J＝8.1Hz,1H),5.12(dd,J＝5.1,13.2Hz,1H),4.49-4.40(m,1H),4.38-4.29(m,1H),3.72(s,2H),2.97-2.89(m,1H),2.86(t,J＝5.9Hz,4H),2.61(d,J＝16.3Hz,1H),2.41(t,J＝6.1Hz,4H),2.39-2.33(m,1H),2.06-1.97(m,1H).
Preparation of intermediate 4-1 (3- ((R) -1- ((2-methyl-7- (piperazin-1-yl) -6- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) carbamic acid benzyl ester
The first step: preparation of (S) -4-bromo-2-nitro-5- ((tetrahydrofuran-3-yl) oxy) benzamide
To a round bottom flask was added the compound (S) -tetrahydrofuran-3-ol (10 g,115 mmol), and N, N-dimethylformamide (200 mL) in sequence, dissolved with stirring, sodium hydrogen (9.2 g,229 mmol) was added in portions and 4-bromo-5-fluoro-2-nitrobenzamide (20 g,76 mmol) was added slowly with stirring. After the addition was completed, the reaction was stirred at room temperature for 2 hours. Water was added thereto, concentrated, extracted with ethyl acetate, and the organic phase was concentrated to give the objective compound (25 g). The reaction mixture was used in the next reaction without purification.
LC-MS:m/z 331(M+H) + 。
And a second step of: preparation of (S) -2-amino-4-bromo-5- ((tetrahydrofuran-3-yl) oxy) benzamide
To a round bottom flask was added the compound (S) -4-bromo-2-nitro-5- ((tetrahydrofuran-3-yl) oxy) benzamide (25 g,75.8 mmol), iron powder (42 g,758 mmol), ammonium chloride (41 g,458 mmol), ethanol (250 mL) and water (50 mL) in sequence. After the addition, the mixture was heated under reflux and stirred for 2 hours. Filtration, concentration, addition of water to the resultant, extraction with ethyl acetate, drying of the organic phase over anhydrous magnesium sulfate, filtration and concentration gave the objective compound (17 g). The reaction mixture was used in the next reaction without purification.
LC-MS:m/z 301(M+H) + 。
And a third step of: preparation of (S) -7-bromo-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-ol
To a round bottom flask was added the compound (S) -2-amino-4-bromo-5- ((tetrahydrofuran-3-yl) oxy) benzamide (17 g,56 mmol), triethyl orthoformate (68 g,560 mmol) and ethanol (200 mL) in sequence. After the addition, the mixture was heated to 100℃and reacted with stirring for 16 hours. Cooling, filtering, washing the filter cake with ethanol, and drying to obtain the target compound (9 g). The reaction mixture was used in the next reaction without purification.
LC-MS:m/z 325(M+H) + 。
Fourth step: preparation of N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-bromo-2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) quinazolin-4-amine
To a round bottom flask was added the compound (S) -7-bromo-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) quinazolin-4-ol (4 g,0.012 mmol), (R) - (3- (1-aminoethyl) -5- (trifluoromethyl) phenyl) carbamic acid benzyl ester (5 g,14.7 mmol), a catter condensing agent (10.9 g,24.6 mmol), 1, 8-diazabicyclo [5.4.0] undec-7-ene (5.6 g,36.9 mmol) and N, N-dimethylformamide (50 mL) in sequence. After the addition, the mixture was heated to 100℃and stirred for 3 hours. The target compound (6 g) was isolated by medium pressure column chromatography.
LC-MS:m/z 645(M+H) + 。
Fifth step: preparation of tert-butyl 4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofu-ran-3-yl) oxy) quinazolin-7-yl) piperazine-1-carboxylate
To a round bottom flask was added the compound N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-bromo-2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) quinazolin-4-amine (2 g,3.1 mmol), tert-butyl piperazine-1-carboxylate (1.7 g,9.3 mmol), palladium acetate (70 mg,0.31 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (386 mg,0.62 mmol), cesium carbonate (3 g,9.3 mmol) and dioxane (50 mL) in sequence. After the completion of the addition, the reaction was heated to 100℃and stirred for 16 hours, then concentrated under reduced pressure, and the residue was separated by passing through a medium-pressure column chromatography to give the objective compound (600 mg).
LC-MS:m/z 617(M+H) + 。
Sixth step: preparation of tert-butyl 4- (4- (((R) -1- (3- (((benzyloxy) carbonyl) amino) -5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-7-yl) piperazine-1-carboxylate
To a round bottom flask was added the compound tert-butyl 4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuranyl-3-yloxy) quinazolin-7-yl) piperazine-1-carboxylate (600 mg,0.97 mmol), sodium carbonate (310 mg,2.92 mmol), tetrahydrofuran (5 mL) and water (1 mL) in sequence, and after the addition benzyl chloroformate (248 mg,1.46 mmol) was added dropwise with stirring. After the completion of the addition, the reaction was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the residue was separated by passing through a medium-pressure column chromatography to give the objective compound (700 mg).
LC-MS:m/z 751(M+H) + 。
Seventh step: preparation of benzyl (3- ((R) -1- ((2-methyl-7- (piperazin-1-yl) -6- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) carbamate
To a round bottom flask was added the compound tert-butyl 4- (4- (((R) -1- (3- (((benzyloxy) carbonyl) amino) -5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-7-yl) piperazine-1-carboxylate (700 mg,0.93 mmol) and dioxane hydrochloride (2 mL). After the completion of the addition, the reaction was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the residue was separated by passing through a medium-pressure column chromatography to give the objective compound (800 mg).
LC-MS:m/z 651(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ14.55(s,1H),10.32–10.11(m,2H),9.24(s,2H),8.19(s,1H),7.86(s,1H),7.79(s,1H),7.56(s,1H),7.46–7.33(m,5H),7.32–7.02(m,2H),5.86–5.72(m,1H),5.45–5.36(m,1H),5.17(s,2H),4.07–3.97(m,1H),3.92–3.82(m,3H),3.46–3.42(m,4H),3.30–3.28(m,2H),2.58(s,3H),2.46–2.35(m,1H),2.17–1.93(m,2H),1.72(d,J＝7.1Hz,3H).
The following compounds were synthesized in the same manner as in intermediate 4-1:
preparation of benzyl 4-2 (R) - (3- (1- ((6- (2-methoxyethoxy) -2-methyl-7- (piperazin-1-yl) quinazolin-4-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) carbamate as intermediate
LC-MS:m/z 639(M+H) + 。
Preparation according to intermediate 4-3, 1-difluoro-1- (2-fluoro-3- ((R) -1- ((2-methyl-7- (piperazin-1-yl) -6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) phenyl) -2-methylpropan-2-ol
LC-MS:m/z 560(M+H) + 。1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.72(t,J＝7.0Hz,1H),7.34–7.18(m,3H),7.07(s,1H),5.93–5.77(m,1H),5.46–5.36(m,1H),5.33(s,1H),4.02(dd,J＝10.3,4.3Hz,1H),3.96–3.77(m,3H),3.66–3.53(m,1H),3.40–3.34(m,4H),3.28–3.19(m,4H),2.45–2.29(m,4H),2.14–2.02(m,1H),1.64(d,J＝7.0Hz,3H),1.23(s,3H),1.20(s,3H).
Preparation according to intermediate 4-4 (R) -1, 1-difluoro-1- (2-fluoro-3- (1- ((6- (2-methoxyethoxy) -2-methyl-7- (piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) -2-methylpropan-2-ol
LC-MS:m/z 548(M+H) + 。
Example 1 5 preparation of 4- ((4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuranyl-3-yloxy) quinazolin-7-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione
The first step: preparation of benzyl (3- ((1R) -1- ((7- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) carbamate
To a round bottom flask was added, in sequence, benzyl (3- ((R) -1- ((2-methyl-7- (piperazin-1-yl) -6- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) carbamate (40 mg,0.06 mmol), 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidine-4-carbaldehyde (23 mg,0.06 mmol), sodium triacetoxyborohydride (26 mg,0.12 mmol) and dichloromethane (1 mL). After the addition was completed, the reaction was stirred at room temperature for 2 hours. The target compound (40 mg) was isolated by medium pressure column chromatography.
LC-MS:m/z 1004(M+H) + 。
And a second step of: preparation of 5- (4- ((4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-7-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione
Benzyl (40 mg,0.04 mmol) of the compound (3- ((1R) -1- ((7- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) carbamate and trifluoroacetic acid (1 mL) were added sequentially to a round bottom flask. After the addition, the reaction was stirred under reflux for 1 hour, and then concentrated under reduced pressure. The residue was separated by preparative liquid phase to give the title compound (8 mg).
LC-MS:m/z 870(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ11.08(s,1H),8.07(s,1H),7.67(d,J＝8.9Hz,2H),7.33(d,J＝2.6Hz,1H),7.25(dd,J＝8.9,2.4Hz,1H),6.96(s,1H),6.88(s,1H),6.85(s,1H),6.71(s,1H),5.66–5.50(m,3H),5.27–5.23(m,1H),5.08(dd,J＝12.8,5.5Hz,1H),4.11–4.03(m,2H),3.98(dd,J＝10.2,4.3Hz,1H),3.95–3.81(m,3H),3.21–3.09(m,3H),3.05–2.95(m,2H),2.95–2.84(m,1H),2.65–2.53(m,4H),2.37(s,3H),2.35–2.18(m,3H),2.13–1.96(m,3H),1.95–1.79(m,3H),1.57(d,J＝7.0Hz,3H),1.35–1.12(m,4H).
The following compounds were synthesized in the same manner as in example 1:
example 2 5- (4- ((4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuranyl-3-yloxy) quinazolin-7-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindole-1, 3-dione)
LC-MS:m/z 888(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ11.11(s,1H),7.93(d,J＝8.1Hz,1H),7.71(d,J＝11.4Hz,1H),7.66(s,1H),7.45(d,J＝7.4Hz,1H),6.95(s,1H),6.89(s,1H),6.86(s,1H),6.71(s,1H),5.66–5.48(m,3H),5.26–5.22(m,1H),5.11(dd,J＝12.8,5.5Hz,1H),3.98(dd,J＝10.2,4.3Hz,1H),3.95–3.81(m,3H),3.67–3.59(m,2H),3.20–3.06(m,4H),2.98–2.83(m,3H),2.66–2.52(m,5H),2.35(s,3H),2.34–2.21(m,3H),2.12–2.00(m,2H),1.92–1.73(m,3H),1.56(d,J＝6.9Hz,3H),1.37–1.20(m,2H).
Example 3 3- (5- (4- ((4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) quinazolin-7-yl) piperazin-1-yl) methyl) piperidin-1-yl) -1-oxoindol-2-yl) piperidine-2, 6-dione
LC-MS:m/z 856(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.94(s,1H),8.02(s,1H),7.67(s,1H),7.51(d,J＝8.5Hz,1H),7.06(d,J＝7.9Hz,2H),6.95(s,1H),6.88(s,1H),6.85(s,1H),6.71(s,1H),5.65–5.46(m,3H),5.27–5.22(m,1H),5.05(dd,J＝13.2,5.1Hz,1H),4.27(dd,J＝49.2,17.1Hz,2H),3.98(dd,J＝10.0,4.2Hz,1H),3.95–3.79(m,5H),3.22–3.05(m,4H),2.97–2.78(m,3H),2.65–2.52(m,4H),2.45–2.19(m,7H),2.12–2.03(m,1H),2.02–1.92(m,1H),1.89–1.75(m,3H),1.57(d,J＝7.0Hz,3H),1.33–1.14(m,3H).
Example 4 5- (3- ((4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofuranyl-3-yloxy) quinazolin-7-yl) methyl) piperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione)
LC-MS:m/z 842(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ11.08(s,1H),7.94(d,J＝8.2Hz,1H),7.65(d,J＝8.5Hz,2H),6.95(s,1H),6.88(s,1H),6.85(s,1H),6.80(d,J＝2.1Hz,1H),6.71(s,1H),6.67(dd,J＝8.4,2.1Hz,1H),5.65–5.48(m,3H),5.26–5.22(m,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.17(t,J＝8.2Hz,2H),3.98(dd,J＝10.1,4.3Hz,1H),3.96–3.81(m,3H),3.73(dd,J＝8.4,5.3Hz,2H),3.20–3.00(m,5H),2.95–2.83(m,1H),2.68(d,J＝7.3Hz,2H),2.65–2.52(m,6H),2.35(s,3H),2.33–2.26(m,1H),2.13–1.96(m,2H),1.56(d,J＝7.1Hz,3H).
Example 5 3- (5- (4- (4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) quinazolin-7-yl) piperazin-1-yl) piperidin-1-yl) -1-oxyisoindol-2-yl) piperidine-2, 6-dione
LC-MS:m/z 842(M+H) + 。
Example 6 3- (5- (3- (4- (4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) quinazolin-7-yl) piperazin-1-yl) piperidin-1-yn-1-yl) -1-oxoisoindol-2-yl) piperidin-2, 6-dione)
LC-MS:m/z 880(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ7.92(d,J＝8.1Hz,1H),7.76–7.69(m,1H),7.65(s,1H),7.57(d,J＝7.8Hz,1H),6.94(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),6.66(s,1H),5.62–5.51(m,3H),5.34(t,J＝4.8Hz,1H),5.24(s,1H),5.12(d,J＝8.2Hz,1H),4.52–4.30(m,2H),4.01–3.95(m,1H),3.95–3.80(m,2H),3.59–3.54(m,2H),3.46–3.22(m,7H),3.15–3.08(m,2H),2.98–2.90(m,2H),2.72–2.63(m,2H),2.48–2.31(m,4H),2.31–2.18(m,2H),2.07–1.95(m,3H),1.90–1.81(m,1H),1.56(d,J＝7.2Hz,1H),1.53–1.41(m,2H),1.34–1.22(m,3H).
Example 7 3- (5- (3- (4- ((4- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) quinazolin-7-yl) piperazin-1-yl) methyl) piperidin-1-yn-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione
LC-MS:m/z 894(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ11.01(s,1H),7.93(d,J＝8.2Hz,1H),7.75–7.69(m,2H),7.65(s,1H),7.57(d,J＝8.2Hz,1H),6.94(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.64–5.50(m,3H),5.27–5.20(m,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.49–4.33(m,2H),3.98(dd,J＝10.1,4.4Hz,1H),3.89–3.82(m,2H),3.59–3.54(m,2H),3.17–3.07(m,4H),2.97–2.82(m,4H),2.70–2.57(m,4H),2.47–2.38(m,2H),2.34(s,3H),2.28–2.19(m,4H),2.11–1.97(m,4H),1.80–1.71(m,2H),1.56(d,J＝7.1Hz,3H),1.21–1.09(m,2H).
Examples biological test evaluation
The following biological test examples further illustrate the invention, but these examples are not meant to limit the scope of the invention.
Inhibition of H358 cell proliferation by Compounds
Experimental procedure
1. Cell culture
(a) Resuscitates cells in T75 cell culture flasks:
TABLE 2 culture of H358 cells
Numbering device Cell lines Culture Medium (Medium) Passage # T75
1 NCI-H358 RPMI 1640+10％FBS+1％PS 2～3x10 6
(b) When the cell fusion degree reaches 80-90%, the cells are passaged.
2. Cell proliferation assay
Experimental procedure
And adding the diluted compound to be tested into a 384-well cell culture plate by utilizing a nanoliter pipetting system, and arranging multiple wells. Adding the positive control group into an equal volume of culture medium; the negative control group was added with an equal volume of DMSO and centrifuged at 1000rpm for 1min at room temperature.
Cells were inoculated into a) 384 plates, negative control groups were added with equal volumes of cells, positive control groups were added with equal volumes of medium only. Centrifugation at 1000rpm at room temperature for 1min, final compound DMSO concentration of 0.5%, and incubation in a 5% CO2 incubator at 37℃for 7 days.
Add 20. Mu.L/well CellTiter-Glo3D to b) 384-well cell culture plates, shake for 20min at 320rpm in the dark and incubate for 2hrs at room temperature in the dark.
And (5) reading the luminescence value by using an Envision multifunctional enzyme-labeled instrument.
The reference compound BI-3406 has the structure:
3. data analysis
The Inhibition Rate (IR) of the test compound was calculated using the following formula: IR (%) = (1- (RLU compound-RLU placebo)/(RLU vehicle control-RLU placebo)) × 100%. The inhibition rates of compounds at different concentrations were calculated in Excel, and then the inhibition graphs were used with GraphPad Prism software and relevant parameters were calculated, including minimum inhibition rate, maximum inhibition rate and IC 50 . The experimental results are shown in table 3.
TABLE 3 proliferation inhibitory Activity of Compounds H358 according to examples of the present invention
IC 50 (nM)
BI-3406 25.07
Example 1 3.09
Example 2 30.94
Example 3 1.82
Example 4 12.80
Example 5 9.81
Example 6 20.29
Regulation experiments of SOS1 proteolysis by Compounds
Experimental procedure
(1) Inoculating tumor cells (e.g., H358,5X 105-1X 06) and culturing in petri dishes (2D, P100 mm dish) for 2-4 days to 70-80% saturation;
(2) After replacing 10ml of fresh culture solution, the incubator was continued to be incubated overnight, and then the SOSi of the pro tac candidate of the present invention and the control pair were added at the same concentration, with gentle shaking, and mixed.
(3) The cells were incubated for 1-24 hours and time curves (1, 2,4,6,8, 24, 48) or dose curves (0.0001,0.001,0.01,0.1,1, 10 uM) at the same concentration (0.1 or 1 uM) or at 6, 24 or 48 hours were made.
(4) At the end of the designed time or concentration, the culture broth is discarded, the dish is transferred to ice, washed 3 times with 50 ml ice-cold PBS, the remaining fluid is sucked as dry as possible, and ice-cold lysate (containing a degenerent such as triton, NP40, etc.) and a proteolytic enzyme inhibitor are added.
(5) Cells were scraped off on ice with a cell scraper and then transferred to a 1.5 ml centrifuge tube, centrifuged at 4 degrees high speed for 20 minutes, the supernatant was removed and transferred to a new tube. After measuring the protein content, the protein supernatant is mixed with 4X sizing solution, heated (100 ℃ C., 5-10 minutes), cooled, added with 10X antioxidant to form a final sizing sample, and stored at-20 ℃.
(6) The sample is made into Western-blot, and electrophoresis is carried out by SDS-PAGE gel, the sample can be loaded with 10-50 microgram of total protein, and after electrotransformation of nitrocellulose membrane, the bands and the respective antibodies are cut off for incubation. Then, after the incubation is performed by using the mark 2, self-luminescence color development is performed, and a photo is taken.
(7) Finally, the IC of the compound is calculated by using GraphPad Prism software 50 Values, and drawing a fitting curve.
Experimental results show that the compound of the invention, example 1 (figure 1), has the effect of targeted degradation of SOS1 protein.
Pharmacokinetic test evaluation
Male SD rats weighing around 220g, were fed a solution of the compound of the invention [5%EtOH,15%solutol in D5W as vehicle ] with IP or PO after overnight fast. The concentrations of the compounds of the invention in plasma were determined by LC/MS after 0.5,1.0,2.0,4.0,6.0,8.0, 12 and 24 blood sampling, respectively, of the compounds of the invention.
Experimental results show that the compound has good pharmacokinetic properties when being administered through IP or PO.
All documents mentioned in this application are incorporated by reference 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 claims appended hereto.

Claims (10)

1. A compound of formula (I), stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof:
Wherein:
a is selected from the group consisting of substituted or unsubstituted: c (C) 6 -C 14 Aryl, or 5-14 membered heteroaryl; wherein said substitution means independently substituted with one or more R;
x is selected from the group consisting of substituted or unsubstituted: c (C) 1 -C 18 Alkyl, C 3 -C 20 Cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 Aryl, 5-14 membered heteroaryl, OX 1 、NHX 1 Or NX 1 X 2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said substitution means independently substituted with one or more R;
X 1 、X 2 independently selected from the group consisting of substituted or unsubstituted: c (C) 1 -C 18 Alkyl, C 3 -C 20 Cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 Aryl, or 5-14 membered heteroaryl; wherein said substitution means independently substituted with one or more R;
Y 1 、Y 2 each independently selected from CH or N, and Y 1 、Y 2 CH is not simultaneously present;
n 1 、n 2 each independently selected from 1, 2 or 3;
L 1 、L 2 each independently selected from the group consisting of substituted or unsubstituted: bond, O, C =o, NH, N (C 1 -C 3 Alkyl group, C 2 -C 18 Alkenyl, C 2 -C 18 Alkynyl, C 1 -C 18 Alkylene, C 3 -C 20 Cycloalkylene, 4-20 membered heterocyclylene, C 3 -C 20 cycloalkylene-C 1 -C 18 Alkylene, or 4-20 membered heterocyclylene-C 1 -C 18 An alkylene group; wherein said substitution means independently substituted with one or more R;
z is selected from the group consisting of substituted or unsubstituted: bond, C 2 -C 18 Alkynyl, C 3 -C 20 Cycloalkyl, 4-20 membered heterocyclyl, C 3 -C 20 cycloalkylene-C 1 -C 18 Alkylene, or 4-20 membered heterocyclylene-C 1 -C 18 An alkylene group; wherein the substitution refers to substitution with one or more R;
P 1 、P 2 、P 3 each independently selected from CH, CF, or N;
P 4 、P 5 each independently selected from CH 2 Or c=o;
each R, which may be the same or different, is independently selected from: H. deuterium, vinyl, ethynyl, C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl alcohol, (C) 3 -C 6 Cycloalkyl) C 1 -C 6 Alkyl, (4-6 membered heterocyclic) C 1 -C 6 Alkyl, (C) 1 -C 6 Alkoxy) C 1 -C 6 Alkyl, (C) 3 -C 6 Cycloalkyloxy) C 1 -C 6 Alkyl, (4-6 membered heterocyclyloxy) C 1 -C 6 Alkyl, (C) 1 -C 6 Alkyl) vinyl, deuteration (C) 1 -C 6 Alkyl) vinyl, halo (C) 1 -C 6 Alkyl) vinyl, (C 1 -C 6 Alkyl) ethynyl, deuteration (C) 1 -C 6 Alkyl) ethynyl, halo (C) 1 -C 6 Alkyl) ethynyl, (C 3 -C 6 Cycloalkyl) ethynyl, (4-6 membered heterocyclyl) ethynyl, C 1 -C 6 Alkoxy, deuterated C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyloxy, 4-6 membered heterocyclyloxy, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 Aryl, 5-to 10-membered heteroaryl, halogen, nitro, hydroxy, oxo (=o), cyano, ester, amino, amide, sulfone or urea.
2. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to claim 1, wherein a is substituted or unsubstituted phenyl; wherein, the substitution means that the substitution is independently performed by one or more R.
3. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to claim 1, wherein a is selected from the group consisting of:
4. the compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to claim 1, wherein X 1 Selected from: substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted C 1 -C 8 Oxaalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 4 -C 6 Monooxacycloalkyl; wherein, the substitution means that the substitution is independently performed by one or more R.
5. The compound of claim 1, a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof,selected from the group consisting of substituted and unsubstitutedThe group:
wherein, the substitution means that the substitution is independently performed by one or more R.
6. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to claim 1, wherein Z is selected from the group consisting of substituted and unsubstituted C 4 -C 6 Heterocycloalkylene, or substituted or unsubstituted C 2 -C 6 Alkynyl; wherein, the substitution means that the substitution is independently performed by one or more R.
7. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to claim 1, wherein-L 1 -L 2 -a group selected from the group consisting of substituted or unsubstituted: bond, C 1 -C 6 Alkyl group,
Wherein, the substitution means that the substitution is independently performed by one or more R.
8. The compound of claim 1, a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein the compound has a structure according to formula (II):
wherein: A. x, Y 1 、Y 2 、L 1 、L、Z、P 1 、P 2 、P 3 、P 5 、n 1 、n 2 The method of claim 1.
9. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of:
/>
10. use of a compound according to claim 1, a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, for the preparation of a pharmaceutical composition for the prevention and/or treatment of a disease associated with SOS1 activity or expression level.
CN202211186008.2A 2022-09-27 2022-09-27 Heterocyclic substituted quinazoline and preparation method and application thereof Pending CN117820305A (en)

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