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CN114380805A - Substituted benzo or pyrido pyrimidine amine inhibitor and preparation method and application thereof - Google Patents

Substituted benzo or pyrido pyrimidine amine inhibitor and preparation method and application thereof Download PDF

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CN114380805A
CN114380805A CN202011128302.9A CN202011128302A CN114380805A CN 114380805 A CN114380805 A CN 114380805A CN 202011128302 A CN202011128302 A CN 202011128302A CN 114380805 A CN114380805 A CN 114380805A
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compound
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吕彬华
崔大为
张青
柴传柯
梁辉
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Shanghai Zelgen Pharmatech Co Ltd
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Priority to CN202011128302.9A priority Critical patent/CN114380805A/en
Priority to KR1020237017306A priority patent/KR20230093300A/en
Priority to CN202180070062.8A priority patent/CN116323590A/en
Priority to PCT/CN2021/125084 priority patent/WO2022083657A1/en
Priority to AU2021367089A priority patent/AU2021367089B2/en
Priority to US18/032,930 priority patent/US20240336606A1/en
Priority to CA3196287A priority patent/CA3196287A1/en
Priority to JP2023524477A priority patent/JP2023546248A/en
Priority to EP21882072.8A priority patent/EP4234548A4/en
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Abstract

The invention relates to a substituted benzo or pyrido pyrimidine amine inhibitor and a preparation method and application thereof. The compound has a structure shown in a formula (I), and also discloses a preparation method of the compound and application of the compound as an SOS1 inhibitor, and the compound has a good selective inhibition effect on SOS1, better pharmacodynamics and pharmacokinetic properties and lower toxic and side effects.

Description

Substituted benzo or pyrido pyrimidine amine inhibitor and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a substituted benzo or pyrido pyrimidine amine inhibitor, and a preparation method and application thereof.
Background
Lung cancer is one of the leading causes of death in human cancers. Lung cancer can be divided into Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, with NSCLC accounting for 85% of all lung cancer patients. The global NSCLC market was statistically estimated to be $ 209 billion in 2016, with the U.S. market taking up half, followed by Japan, Germany, and China. From the current trend, the market for non-small cell lung cancer is continuing to grow, and the global market is expected to reach $ 540 billion in 2023 (Nature, 2018; 553(7689):446- > 454).
At present, the main therapeutic drugs for NSCLC include chemotherapeutic drugs, molecular targeted drugs, tumor immunotherapy and the like. The chemotherapy drugs mainly comprise gemcitabine, paclitaxel, 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 have become research hotspots due to the obvious advantages of high selectivity, relatively small toxic and side effects, 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, aletinib, Brigatinib, loretinib, ocatinib, etc.), and VEGFR inhibitors (Sorafenib, regrafenib, Cabozantinib, Sunitinib, doranib, etc.) (Current Medicinal Chemistry,2019,26, 1-39).
KRAS mutations occur in 20-40% of lung adenocarcinomas, with a higher prevalence in western (vs asia) populations (26% vs 11%) and in smokers (vs non-smokers) (30% vs 10%). The most common mutations occur in codons 12 and 13, the most common mutations include G12C, G12V, and G12D. To date, no drug against KRAS mutations has been approved for marketing in the market.
Within the cell, the KRAS protein transitions between an inactive and an active state, when KRAS is bound to Guanosine Diphosphate (GDP), it is in the inactive state, when it is bound to Guanosine Triphosphate (GTP), it is in the active state, and downstream signaling pathways can be activated. The transition of KRAS between inactive and active states is regulated by two types of factors. One class is guanine nucleotide exchange factor (GEF), which catalyzes the binding of KRAS to GTP, thereby promoting KRAS activation, including the SOS1 protein. Another class is the Gtpase Activating Proteins (GAPs), which promote the hydrolysis of KRAS-bound GTP to GDP, thereby inhibiting KRAS activity.
To date, three major RAS-specific GEFs have been identified, with SOS proteins being primarily found in tumors. SOS proteins are widely expressed in vivo and contain two isoforms SOS1 and SOS 2. Published data indicate that SOS1 plays a key role in mutant KRAS activation and oncogenic signaling. A decrease in the level of SOS1 resulted in a decrease in the proliferation and survival of tumor cells carrying the KRAS mutation, whereas KRAS wild-type cell lines were not affected. The effect of the loss of SOS1 could not be rescued by introducing a SOS1 mutated at the catalytic site, suggesting an important role for SOS1 GEF activity in KRAS mutant cancer cells (see WO2019122129a 1).
Since KRAS binding to GTP, whether mutated or wild-type, is dependent on SOS1, selective inhibition of SOS1, whether mutated or not, prevents interaction of SOS1 with KRAS and ultimately inhibits KRAS activation.
Since the SOS1 target protein is pathologically associated with a variety of diseases, there is also a need for novel SOS1 inhibitors for clinical therapy. The SOS1 inhibitor with high selectivity and high activity can be used for more effectively treating diseases such as cancers caused by KRAS mutation and reducing the potential of off-target effect, so that the clinical demand is more urgent.
Disclosure of Invention
The invention aims to provide a novel compound with selective inhibition effect on SOS1 and/or better pharmacodynamic property and application thereof.
In a first aspect of the present invention, there is provided a substituted benzo or pyrido pyrimidinamine compound having a structure of general formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:
Figure BDA0002734277190000021
in the formula:
x is selected from: CR6Or N, wherein R6Selected from: hydrogen, deuterium, halogen, cyano, C1-C6Alkyl radical, C3-C6Cycloalkyl or 4-6 membered heterocyclyl;
y is selected from the group consisting of: o, NH, or NR7Wherein R is7Selected from: c1-C6Alkyl radical, C3-C6Cycloalkyl or 4-6 membered heterocyclyl;
z is selected from the group consisting of substituted or unsubstituted groups: c1-C18Alkylene, deuterated C1-C18Alkylene, or halogeno C1-C18An alkylene group;
w is selected from the group consisting of substituted or unsubstituted: c3-C20Cycloalkylene, 4-20 membered heterocyclyleneRadical, OR11、NR11 R12、SO2、NR12SO2CO or NR12CO；R11Independently selected from the group consisting of substituted or unsubstituted: c3-C20Cycloalkylene, 4-20 membered heterocyclylene, C3-C20Cycloalkylene radical C1-C18Alkylene, or 4-20 membered heterocyclylene C1-C18An alkylene group; r12Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C6Alkyl or C3-C6A cycloalkyl group;
R1、R2independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, - (CH)2)mR8、-(CH2)mO(CH2)pR8、-(CH2)mSR8、-(CH2)mCOR8、-(CH2)mC(O)OR8、-(CH2)mS(O)qR8、-(CH2)mNR5R8、-(CH2)mC(O)NR8R9、-(CH2)mNR8C(O)R9、-(CH2)mNR8C(O)NR9R10、-(CH2)mS(O)qNR8R9、-(CH2)mNR8S(O)qR9、-(CH2)mNR8S(O)qNR9R10In which CH2H in (a) may be optionally substituted; r8、R9、R10Independently selected from the group consisting of substituted or unsubstituted: hydrogen, C1-C18Alkyl radical, C3-C20Cycloalkyl or 4-20 membered heterocyclyl;
R3selected from the group consisting of substituted or unsubstituted: c3-C18Cycloalkyl, 4-20 membered heterocyclyl, C6-C14Aryl, 5-14 membered heteroaryl;
R4、R5independently selected from the group consisting ofOr unsubstituted groups of the following group: c1-C6Alkyl radical, C3-C6Cycloalkyl, or 4-6 membered heterocyclyl;
wherein the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl, halo C1-C18Alkyl hydroxy, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy radical, C6-C14Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;
m, n are each independently 0, 1, 2, 3, 4 or 5;
p is 0, 1, 2, 3, 4 or 5;
q is 1 or 2.
In another preferred embodiment, the substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof has the structure of formula (II):
Figure BDA0002734277190000031
in the formula, R1、R2、R3、R4X, Y, Z, W, n are as defined above.
In another preferred embodiment, the substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof has the structure of formula (III):
Figure BDA0002734277190000032
in the formula: r1、R2、R3X, Y, Z, W, n are as defined above.
In another preferred embodiment, the substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof has the structure of formula (IV):
Figure BDA0002734277190000041
in the formula:
R1、R2、R3、R6x, Y, Z, W, n are as defined above.
In another preferred embodiment, the substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof has the structure of formula (V):
Figure BDA0002734277190000042
in the formula (I), the compound is shown in the specification,
R1、R2、R3、R6y, Z, W, n are as defined above.
In another preferred embodiment, the substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof has the structure of formula VI:
Figure BDA0002734277190000043
in the formula (I), the compound is shown in the specification,
R13and R14Each independently selected from: H. c1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl halogens, oxo groups, nitro groups, hydroxyl groups, cyano groups, ester groups, amine groups, amide groups, sulfonamide groups, or urea groups;
ring C is selected from the group consisting of substituted or unsubstituted: c3-C12Cycloalkylene, 4-12 membered heterocyclylene;
the substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl, halo C1-C18Alkyl hydroxy, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy radical, C6-C14Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.
t is 1, 2, 3, 4, 5 or 6;
R1、R2、R3、R6and n is as defined above.
In another preferred embodiment, the substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof has the structure of formula VII:
Figure BDA0002734277190000051
in the formula (I), the compound is shown in the specification,
R16and R17Each independently selected from: H. c1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl halogens, oxo groups, nitro groups, hydroxyl groups, cyano groups, ester groups, amine groups, amide groups, sulfonamide groups, or urea groups;
R18selected from: OR (OR)11、NR11R12、NR12SO2R2、COR2Or NR12COR2；R11Independently selected from the group consisting of substituted or unsubstituted: c3-C12Cycloalkyl, 4-12 membered heterocyclyl, C3-C12Cycloalkylene radical C1-C6Alkylene, or 4-12 membered heterocyclylene C1-C6An alkylene group; r12Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C6Alkyl or C3-C6A cycloalkyl group;
t is 1, 2, 3, 4, 5 or 6;
R1、R2、R3and R6Is as defined above.
In another preferred embodiment, R1、R2、R3、R4、R5X, Y, Z, W and n are specific groups corresponding to each specific compound in the examples.
In another preferred embodiment, the substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, is selected from the group consisting of:
Figure BDA0002734277190000061
Figure BDA0002734277190000071
Figure BDA0002734277190000081
Figure BDA0002734277190000091
Figure BDA0002734277190000101
Figure BDA0002734277190000111
Figure BDA0002734277190000121
Figure BDA0002734277190000131
Figure BDA0002734277190000141
Figure BDA0002734277190000151
Figure BDA0002734277190000161
Figure BDA0002734277190000171
Figure BDA0002734277190000181
Figure BDA0002734277190000191
Figure BDA0002734277190000201
Figure BDA0002734277190000211
Figure BDA0002734277190000221
Figure BDA0002734277190000231
Figure BDA0002734277190000241
Figure BDA0002734277190000251
Figure BDA0002734277190000261
Figure BDA0002734277190000271
Figure BDA0002734277190000281
Figure BDA0002734277190000291
in another preferred embodiment, the compound is preferably the compound prepared in the examples.
In a second aspect of the present invention, there is provided a method for preparing a substituted benzo-or pyrido-pyrimidinamine compound having a structure of formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, comprising the steps of:
Figure BDA0002734277190000301
(i) reacting a compound of formula V-1 with a compound of formula V-2 in the presence of a first base to provide a compound of formula V-3;
(ii) reacting a compound of formula V-3 with sulfonyl chloride (V-4) in the presence of a second base and a catalyst (e.g., DMAP) to produce a compound of formula V-5;
(iii) reacting the compound of formula V-5 with an amine (formula V-6) in the presence of a third base to provide a compound of formula (I);
in the formula (I), the compound is shown in the specification,
r' is selected from: halogen, OTs or OMs;
R1、R2、R3、R4、R5x, Y, Z, W and n are as defined above.
In another preferred embodiment, the first base is potassium carbonate or cesium carbonate, etc.
In another preferred embodiment, the second base is TEA or DIPEA, etc.
In another preferred embodiment, the third base is TEA or DIPEA, etc.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising I) one or more compounds having a structure according to general formula (I) of the first aspect, stereoisomers, tautomers, crystal 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, pidilizumab, cemipimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g., rituximab, obizumab, ofatumumab, tositumomab, MSB 131, tositumomab, TSB 90, TSH-55, TSB-35, TSB-102, TSB-35, TSB-52, TSB-35, TSC-35, TSB-35, TSC-35, TSB-55, TSB-D-35, TSB-D2, TSB-D, Alectonib, Brigatinib, Lorlatinib, oxcarinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipaliib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acalabastib, Zanbutrutinib, Vecabutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlottinib, Lapatinib, Dacomitib, Icotinib, Canertinib, Sapinotinib, Naquratinib, Pyrotinib, Rocilitiniib, Osimetiniib, etc.), inhibitors (e.g., Sorafenib, Parraertinib, Lorlatinib 6284, Lipocinib, etc.), inhibitors (e.g., Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib inhibitors (e, Lipocinib inhibitors, etc.), inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, etc.), etc. (e, VEGF-III inhibitors, etc.), and so AS inhibitors, VEGF-12, VEGF-inhibitors (e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, such AS inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, VEGF-12, Lipocinib inhibitors, e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, Lipocinib inhibitors, Lip.
In a fourth aspect of the present invention, there is provided a substituted benzo or pyrido pyrimidinamine compound having a structure of general formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, as described in the first aspect, or a use of a pharmaceutical composition as described in the third aspect, for preparing a pharmaceutical composition for preventing and/or treating a disease associated with an activity or an expression amount of SOS 1.
In another preferred embodiment, the disease is cancer.
In another preferred embodiment, the cancer is selected from: 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 non-diagnostic, non-therapeutic inhibition of SOS1, comprising the steps of: administering to a patient 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, according to the first aspect, or a pharmaceutical composition according to the third aspect.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
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Detailed Description
The present inventors have conducted extensive and intensive studies for a long time and have unexpectedly found a novel class of compounds which selectively inhibit SOS1 and/or exhibit improved pharmacodynamic properties. On this basis, the inventors have completed the present invention.
Term(s) for
In the present invention, unless otherwise specified, the terms used have the ordinary meanings well known to those skilled in the art.
The term "alkyl" refers to straight or branched chain or cyclic alkyl groups containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-butyl,
Figure BDA0002734277190000321
Pentyl, isopentyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like.
The term "C1-C18 alkyl" refers to straight or branched chain or cyclic alkyl groups, includingFrom 1 to 18 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl
Figure BDA0002734277190000322
N-butyl, t-butyl, isobutyl (e.g. butyl, isobutyl)
Figure BDA0002734277190000323
) N-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. "substituted alkyl" means an alkyl group which is substituted at one or more positions, especially 1 to 4 substituents, and may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcAnd N atomTaken together, may form a heterocyclic ring; reMay independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.
The term "alkylene" refers to a group formed by removing a hydrogen atom from an "alkyl" group, such as methylene, ethylene, propylene, isopropylene (e.g.
Figure BDA0002734277190000324
) Butylene (e.g. butyl oxide)
Figure BDA0002734277190000325
) Pentylene (e.g. ethylene)
Figure BDA0002734277190000326
) Hexamethylene (e.g. hexamethylene)
Figure BDA0002734277190000327
) Heptylene (e.g. ethylene)
Figure BDA0002734277190000328
) And the like.
The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group comprising 1 to 4 rings containing 3 to 8 carbon atoms in each ring. "substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1 to 4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalo substituents, the latter such as trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocyclic (excluding heteroaromatic rings), bridged cycloalkyl, bridged alkenyl, bridged heterocyclic (excluding heteroaromatic rings), fused cycloalkyl, fused alkenyl, fused heterocyclyl or fused aromatic ring groups, which may be optionally substituted. Any two or more atoms on the ring may be further ring-connected with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
The term "cycloalkylene" refers to a group formed by a cycloalkyl group minus two hydrogen atoms, such as:
Figure BDA0002734277190000331
Figure BDA0002734277190000332
Figure BDA0002734277190000333
and the like.
The term "cycloalkylene" refers to a cycloalkylalkyl or alkylcycloalkyl group as defined above, wherein "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning, preferably C1-C6 alkylene C3-C12 cycloalkylene, excluding, but not limited to:
Figure BDA0002734277190000334
Figure BDA0002734277190000335
Figure BDA0002734277190000341
and the like.
The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, e.g., a 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic ring system) in which at least one heteroatom is present in the ring having at least one carbon atom. Each heteroatom-containing heterocyclic ring may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may also be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the 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-piperidyl, tetrahydropyranyl, morphinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or are further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate groups, wherein any two or more atoms on the ring may be further ring-connected to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
The term "heterocyclylene" refers to a group formed by removing two hydrogen atoms from the above-mentioned heterocyclic group, and includes, but is not limited to:
Figure BDA0002734277190000342
Figure BDA0002734277190000343
and the like.
The term "heterocycloalkylene alkylene" refers to a cycloalkylalkyl or alkylcycloalkyl group formed by removal of two hydrogen atoms, wherein "4-20 membered heterocycloalkylene C1-C18 alkylene" or "C1-C18 alkylene 4-20 membered heterocycloalkylene" has the same meaning, preferably 4-12 membered heterocycloalkylene C1-6 alkylene, including but not limited to:
Figure BDA0002734277190000344
Figure BDA0002734277190000351
and the like.
The term "aryl" refers to aromatic cyclic hydrocarbon groups having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where the aromatic ring contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked by a single bond (e.g., biphenyl), or fused (e.g., naphthalene, anthracene, etc.). "substitutionAryl "means that one or more positions in the aryl group are substituted, especially 1 to 3 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclyl or fused ring aromatic ring groups, which cycloalkyl, cycloalkenyl, heterocyclyl and heterocyclylaryl groups may be optionally substituted.
The term "heteroaryl" refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. The heteroaryl group is preferably a 5-to 10-membered ring, more preferably a 5-or 6-membered ring, for example, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl and the like. "heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.
The term "C1-C18 alkoxy" refers to a straight or branched chain or cyclic alkoxy group having 1 to 18 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. Preferably a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group.
The term "C1-C18 alkyleneoxy" means a group resulting from the removal of one hydrogen atom from a "C1-C18 alkoxy group".
The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.
The term "halo" means substituted with halogen.
The term "deuterated" refers to a substitution by deuterium.
The term "hydroxy" refers to a group with the structure OH.
The term "nitro" refers to a group with the structure NO2A group of (1).
The term "cyano" refers to a group with the structure CN.
The term "ester group" refers to a group with the structure-COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic.
The term "amine" refers to a group having the structure-NRR ', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' may be the same or different in the dialkylamine fragment.
The term "amido" refers to a group with the structure-CONRR ', where 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 sulfonamide group having the structure-SO2NRR 'wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic as hereinbefore defined. R and R' may be the same or different in the dialkylamine fragment.
The term "ureido" refers to a group having the structure — NRCONR 'R ", where R, R' and R" may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.
The term "alkylaminoalkyl" refers to a group having 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 having the structure-RNHR 'R ", where R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, a heterocycle or a 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 having 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 specified group are replaced with a specified substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, a certain substituted group may have one substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 ureido, and the like.
Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has sufficient hydrogen to replenish its valence state.
When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.
Active ingredient
As used herein, "compounds of the invention" refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of formula I.
The compounds of formula I have the following structure:
Figure BDA0002734277190000371
in the formula, R1、R2、R3、R4、R5X, Y, Z, W, n are as defined above.
Preferably, the compound of formula I has the structure shown in formula (II):
Figure BDA0002734277190000372
in the formula, R1、R2、R3、R4X, Y, Z, W, n are as defined above.
Preferably, the compound of formula I has the structure of formula (III):
Figure BDA0002734277190000373
in the formula: r1、R2、R3X, Y, Z, W, n are as defined above.
Preferably, the compound of formula I has the structure of formula (IV):
Figure BDA0002734277190000381
in the formula:
R1、R2、R3、R6x, Y, Z, W, n are as defined above.
Preferably, the compound of formula I has the structure of formula (V):
Figure BDA0002734277190000382
in the formula (I), the compound is shown in the specification,
R1、R2、R3、R6y, Z, W, n are as defined above.
Preferably, the compound of formula I has the structure shown in formula VI:
Figure BDA0002734277190000383
in the formula, R1、R2、R3、R6、R13、R14T and n are as defined above.
Preferably, the compound of formula I has the structure shown in formula VII:
Figure BDA0002734277190000384
in the formula (I), the compound is shown in the specification,
R1、R3、R6、R16、R17、R18and t is as defined above.
Preferably, in each of the above formulae, R1、R2Independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, - (CH)2)mR8、-(CH2)mO(CH2)pR8、-(CH2)mSR8、-(CH2)mCOR8、-(CH2)mC(O)OR8、-(CH2)mS(O)qR8、-(CH2)mNR5R8、-(CH2)mC(O)NR8R9、-(CH2)mNR8C(O)R9、-(CH2)mNR8C(O)NR9R10、-(CH2)mS(O)qNR8R9、-(CH2)mNR8S(O)qR9、-(CH2)mNR8S(O)qNR9R10In which CH2H in (a) may be optionally substituted; r8、R9And R10Independently selected from the group consisting of substituted or unsubstituted: hydrogen, C1-C6Alkyl radical, C3-C12Cycloalkyl or 4-12 membered heterocyclyl;
R3selected from the group consisting of substituted or unsubstituted: c3-C12Cycloalkyl, 4-12 membered heterocyclyl, C6-C10Aryl, 5-10 membered heteroaryl;
R4、R5independently selected from the group consisting of substituted or unsubstituted: c1-C6Alkyl radical, C3-C6Cycloalkyl, or 4-6 membered heterocyclyl;
wherein the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkyl hydroxy, C3-C12Cycloalkyl radical, C1-C6Alkoxy, deuterated C1-C6Alkoxy, halo C1-C6Alkoxy radical, C6-C14Aryl, 5-14 membered heteroaryl, 4-12 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.
The salts which the compounds of the invention may form are also within the scope of the invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in either an acidic or basic form. Furthermore, when a compound of the present invention contains a basic moiety, including but not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts") that may form are included within the scope of the term "salt(s)". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps during manufacture. The compounds of the invention may form salts, for example, by reacting compound I with an amount of acid or base, e.g. an equivalent amount, and salting out in a medium, or lyophilizing in an aqueous solution.
The compounds of the invention may contain basic moieties, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids which may form salts include acetates (e.g. with acetic acid or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglycolates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g. 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g. 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g. 3-phenylpropionates), phosphates, propionates, citrates, and the like, Picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates, e.g., p-toluenesulfonate, dodecanoate, and the like
Acidic moieties that certain compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases. Typical salts with bases 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, hydrabamine (salt 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. The basic nitrogen-containing groups may 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 diamyl 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 contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to yield a compound, salt, or solvate of the present invention when used in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.
The compounds, salts or solvates of the invention may exist in tautomeric forms (e.g. amides and imino ethers). All of these tautomers are part of the present invention.
All stereoisomers of the compounds (e.g., those asymmetric carbon atoms that may exist due to various substitutions), including enantiomeric and diastereomeric forms thereof, are contemplated within the invention. The individual stereoisomers of the compounds of the invention may not be present in combination with the other isomers (e.g. as a pure or substantially pure optical isomer having a particular activity), or may be present as a mixture, e.g. as a racemate, or as a mixture with all or a portion of the other stereoisomers. The chiral center of the invention has two S or R configurations, and is defined by the International Union of theory and applied chemistry (IUPAC) proposed in 1974. The racemic forms can be resolved by physical methods such as fractional crystallization, or by separation of the crystals by derivatization into diastereomers, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.
The compounds of the present invention, obtained by preparing, isolating and purifying the compound in sequence, have a weight content of 90% or more, for example, 95% or more, 99% or more ("very pure" compounds), as set forth in the text. Such "very pure" compounds of the invention are also part of the invention herein.
All configurational isomers of the compounds of the invention are within the scope of the invention, whether in mixture, pure or very pure form. The definition of compounds in the present invention encompasses both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.
Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
Specific functional groups and definitions of chemical terms are detailed below. For purposes of the present invention, the chemical Elements are compatible with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,75thD. as defined in. The definition of a particular functional group is also described herein. In addition, the basic principles of Organic Chemistry, as well as specific functional groups and reactivities are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, which is incorporated by reference in its entirety.
Certain compounds of the present 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) isomer, (L) isomer, racemic mixtures and other mixtures thereof. Further the asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers, as well as mixtures thereof, are encompassed by the present invention.
According to the present invention, the mixture of isomers may contain a variety of isomer ratios. For example, in a mixture of only two isomers, the following combinations are possible: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, all ratios of isomers are within the scope of the invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention, as would be readily understood by one of ordinary skill in the art.
The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as the original compound. In practice, however, it will often occur that one or more atoms are replaced by an atom having a different atomic weight or mass number. Examples of isotopes that can be listed as compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and36and (4) 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-labelled compounds of the invention, e.g.3H and14among these, the radioactive isotope of C is useful in tissue distribution experiments of drugs and substrates. Tritium, i.e.3H and carbon-14, i.e.14C, their preparation and detection are relatively easy. Is the first choice among isotopes. In addition, heavier isotopes such as deuterium, i.e.2H, due to its good metabolic stability, may be advantageous in certain therapies, such as increased half-life in vivo or reduced dose, and therefore, may be preferred in certain circumstances. Isotopically labeled compounds can be prepared by conventional methods by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent using the protocols disclosed in the examples.
If it is desired 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 agents, separation of the resulting diastereomeric mixture and removal of the chiral auxiliary agent 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 with an appropriate optically active acid or base, and the isolated enantiomers can be obtained in pure form by conventional means such as fractional crystallization or chromatography.
As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to extend their inclusion range. In general, the term "substituted", whether occurring before or after the term "optional", in the formula of the present invention including substituents, means that the hydrogen radical is replaced with a substituent of the indicated structure. When a plurality of the specified structures are substituted at a position with a plurality of the specified substituents, each position of the substituents may be the same or different. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permissible organic compound described hereinabove to supplement its valence state. Furthermore, the present invention is not intended to be limited in any way as to the permissible substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is excellent in the treatment of diseases, such as infectious diseases or proliferative diseases, in the form of stable compounds. The term "stable" as used herein refers to compounds that are stable enough to maintain the structural integrity of the compound when tested for a sufficient period of time, and preferably are effective for a sufficient period of time, and are used herein for the purposes described above.
Metabolites of the compounds and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.
Preparation method
The following describes more specifically the processes for the preparation of the compounds of formula (I) according to the invention, but these particular processes do not constitute any limitation of the invention. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
Typically, the process for the preparation of the compounds of the present invention is as follows, wherein the starting materials and reagents used are commercially available without specific reference.
Figure BDA0002734277190000421
(i) Reacting a compound of formula V-1 with a compound of formula V-2 (wherein R' is a leaving group, such as halogen, OTs, OMs, or the like) in the presence of a first base (such as potassium carbonate, cesium carbonate, or the like) to produce a compound of formula V-3;
(ii) protecting the compound of formula V-3 with sulfonyl chloride (V-4) in the presence of a second base (e.g., TEA, DIPEA, or the like) and a catalyst (e.g., DMAP) to produce a compound of formula V-5;
(iii) reacting a compound of formula V-5 with an amine (formula V-6) in a third base (e.g., TEA, DIPEA, or the like) to form a compound of formula (I);
in the formula (I), the compound is shown in the specification,
R1、R2、R3、R4、R5x, Y, Z, W and n are as defined in claim 1.
Pharmaceutical compositions and methods of administration
The pharmaceutical composition of the invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immunological disease, and metabolic disease.
The compounds of general 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 be maintained 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 both one or more known drugs and the compound of formula I. The pharmaceutical combination also includes administration of the compound of formula I in an overlapping time period with one or more other known drugs. When a compound of formula I is administered in a pharmaceutical combination with one or more other drugs, the dose of the compound of formula I or the known drug may be lower than the dose at which they are administered 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 biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g., rituximab, obiumumab, ofutatumab, NI, tositumomab, 131-tositumomab, MSB-90, TSK-55, TSM-55, TSB-55, TSM-35, TSK-55, TSI-55, TSM-35, TSK-35, TSI-55, TSI-10, TSI-II, TSI-II-III-I inhibitors (e), such as HIV-I inhibitors, TSI-I-II-III-I-F2, TSI-II-F-II-III-II, such as HIV-II, TSI inhibitors, such as HIV-II, TSI inhibitors, such as HIV-II, TSI inhibitors, TSI-II, TSI inhibitors, TSI, such as shown In, TSI inhibitors, TSI-II, TSI inhibitors, TSI, such as shown In, TSI inhibitors, TSI, such as shown In, TSI, TSC 2, TSI-II, TSC-II, TSI, TSC 2, TSI-II, TSI, TSC-II, TSI-II, TSI, TS, Alectonib, Brigatinib, Lorlatinib, oxcarinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipaliib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acalabastib, Zanbutrutinib, Vecabutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlottinib, Lapatinib, Dacomitib, Icotinib, Canertinib, Sapinotinib, Naquratinib, Pyrotinib, Rocilitiniib, Osimetiniib, etc.), inhibitors (e.g., Sorafenib, Parraertinib, Lorlatinib 6284, Lipocinib, etc.), inhibitors (e.g., Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib inhibitors (e, Lipocinib inhibitors, etc.), inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, etc.), etc. (e, VEGF-III inhibitors, etc.), and so AS inhibitors, VEGF-12, VEGF-inhibitors (e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, such AS inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, VEGF-12, Lipocinib inhibitors, e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, Lipocinib inhibitors, Lip.
Dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, topical liniment, controlled release type or delayed release type or nanometer preparation.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically 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 composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-1000mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human useAnd must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing 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 sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0002734277190000431
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, 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 mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, 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 using 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 delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed 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 such materials and the like.
In addition to these inert diluents, the compositions can also contain 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, 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 vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention 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 treatment methods of the present invention can be administered alone or in combination with other therapeutic means or agents.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 50 to 1000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing a pharmaceutically acceptable carrier with the compound of the general formula (I) or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof to form the pharmaceutical composition.
The present invention also provides a method of treatment comprising the steps of: administering a compound of formula (I), or a crystalline form, a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, or a pharmaceutical composition as described herein, to a subject in need of such treatment, for selectively inhibiting SOS 1.
Compared with the prior art, the invention has the following main advantages:
(1) the compound has good selective inhibition effect on SOS 1;
(2) the compound has better in vivo and in vitro pharmacodynamics and pharmacokinetic performance and lower toxic and side effects.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.
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 embodiments and materials described herein are intended to be exemplary only.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) and liquid mass chromatography (LC-MS).
NMR was detected using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the assay solvent contained deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated acetone (CD)3COCD3) Deuterated chloroform (CDCl)3) And deuterated methanol (CD)3OD), and internal standards are Tetramethylsilane (TMS), chemical shifts are measured in parts per million (ppm).
Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. HPLC measurements were performed using an Agilent1100 high pressure chromatograph (Microsorb 5micron C18100 x 3.0.0 mm column).
Thin layer chromatography silica gel plate is blue island GF254 silica gel plate, TLC is 0.15-0.20mm, and preparative thin layer chromatography is 0.4-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be used or synthesized according to literature reports in the art.
All reactions of the present invention are carried out under continuous magnetic stirring under the protection of a dry inert gas (e.g., nitrogen or argon) except for the specific indications, and the reaction temperatures are all in degrees centigrade.
Examples
Example 11 preparation of 1, 1-difluoro-1- (2-fluoro-3- ((R) -1- ((7-methoxy-2-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) amino) ethyl) phenyl) -2-methylpropan-2-ol
Figure BDA0002734277190000461
The first step is as follows: preparation of (S) -2- (chloromethyl) -1-methylpyrroline
N-methyl-L-prolinol (500.0mg,4.34mmol) was dissolved in toluene (5mL), and thionyl chloride (2.0mL) was added. The resulting reaction solution was stirred at 100 ℃ for 2.0h, and then concentrated under reduced pressure. The crude product obtained was directly put into the next step without further purification.
The second step is that: preparation of (S) -7-methoxy-2-methyl-6- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one
6-hydroxy-7-methoxy-2-methyl-quinazolin-4 (3H) -one (120mg,0.58mmol) was added to N, N-dimethylformamide (10mL), followed by the addition of (S) -2- (chloromethyl) -1-methylpyrrolidine (77.8mg,0.58mmol) obtained in the previous step and potassium carbonate (402.2mg,2.91 mmol). The resulting reaction solution was stirred at 100 ℃ for 3.0h and then cooled to room temperature. The mixture was prepared by preparing a liquid phase to obtain the objective product (39mg, yield: 22%).
LC-MS：m/z 304(M+H)+。
Thirdly, preparing (S) -7-methoxy-2-methyl-6- ((1-methylpyrrolin-2-yl) methoxy) quinazoline-4-yl 2,4, 6-triisopropylbenzene sulfonate
(S) -7-methoxy-2-methyl-6- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one (38.0mg,0.13mmol) was added to dichloromethane (4mL), followed by 2,4, 6-triisopropylsulfonyl chloride (45.5mg,0.15mmol), triethylamine (25.4mg,0.25mmol), and 4-dimethylaminopyridine (1.5mg,0.013 mmol). The resulting reaction solution was stirred at room temperature overnight, then poured into water, and extracted with dichloromethane (10 mL). The organic phase was dried and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (PE: EA ═ 5:1) to obtain the objective product (14.0mg, yield: 20%).
LC-MS：m/z 570(M+H)+。
The fourth step preparation of 1, 1-difluoro-1- (2-fluoro-3- ((R) -1- ((7-methoxy-2-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) amino) ethyl) phenyl) -2-methylpropan-2-ol
(S) -7-methoxy-2-methyl-6- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl 2,4, 6-triisopropylbenzenesulfonate (31.0mg,0.054mmol) was added to dimethyl sulfoxide (2mL), followed by (R) -1- (3- (1-aminoethyl) -2-fluorophenyl) -1, 1-difluoro-2-methylpropan-2-ol (20.2mg,0.082mmol) and triethylamine (0.4 mL). The resulting reaction solution was reacted at 120 ℃ for 2.0 hours under microwave, then cooled to room temperature and quenched with water, followed by extraction with ethyl acetate (10 mL). The organic phase was dried and concentrated under reduced pressure, and the obtained residue was separated by using a preparative liquid phase to obtain the objective compound (4mg, yield: 13.9%).
LC-MS：m/z 533(M+H)+。1H NMR(400MHz,DMSO)δ8.07(m,1H),7.81(m,1H),7.57(d,J＝6.3Hz,1H),7.30(t,J＝7.1Hz,1H),7.25–7.17(m,1H),7.02(d,J＝3.0Hz,1H),5.79(m,1H),5.34(m,1H),4.10–3.97(m,1H),3.87(m,3H),2.43(m,2H),2.34–2.17(m,5H),2.13–1.94(m,2H),1.82–1.66(m,2H),1.58(m,3H),1.24(m,9H).
The following compounds were synthesized according to the procedure of example 1, starting from different starting materials:
EXAMPLE 2 preparation of N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-amine
Figure BDA0002734277190000471
LC-MS：m/z 490(M+H)+。
EXAMPLE 3 preparation of N- ((R) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -7-methoxy-2-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-amine
Figure BDA0002734277190000472
LC-MS：m/z 471(M+H)+。
EXAMPLE 4 preparation of N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-amine
Figure BDA0002734277190000473
LC-MS：m/z 460(M+H)+。
Example 5 preparation of N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2, 7-dimethyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy)) quinazolin-4-amine
Figure BDA0002734277190000481
LC-MS：m/z 474(M+H)+。
Example 6 preparation of (S) -5- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -1-methylpyrrolidin-2-one
Figure BDA0002734277190000482
LC-MS：m/z 504(M+H)+。1H NMR(400MHz,DMSO)δ14.28(brs,1H),9.71(d,J＝7.6Hz,1H),8.04(s,1H),7.17(m,3H),6.88(d,J＝4.3Hz,2H),6.76(s,1H),5.81–5.61(m,1H),4.33(m,1H),4.15(m,1H),3.97(m,4H),2.80(s,3H),2.59(s,3H),2.45(m,1H),2.27–2.13(m,2H),1.91(m,1H),1.64(d,J＝7.0Hz,3H).
EXAMPLE 7 preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (2-cyclopropoxy) -7-methoxy-2-methyl-quinazolin-4-amine
Figure BDA0002734277190000483
LC-MS：m/z 477(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.93(d,1H),7.71(s,1H),7.03(s,1H),6.86(d,1H),6.69(s,1H),5.57-5.53(m,3H),4.22-4.18(m,2H),3.91-3.84(m,5H),3.44-3.39(m,1H),2.35(s,3H),1.55-1.53(d,3H),0.54-0.44(m,4H).
EXAMPLE 8 preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (2- (cyclopropyl (methyl) amino) ethoxy) -7-methoxy-2-methylquinolin-4-amine
Figure BDA0002734277190000491
LC-MS：m/z 490(M+H)+。1H NMR(400MHz,DMSO)δ7.94(d,J＝8.0Hz,1H),7.69(s,1H),7.02(s,1H),6.87(d,J＝11.5Hz,2H),6.70(s,1H),5.64–5.44(m,3H),4.23–4.07(m,2H),3.86(s,3H),2.96(t,J＝5.9Hz,2H),2.39(s,3H),2.35(s,3H),1.87–1.74(m,1H),1.52(d,J＝8.0Hz,3H),0.51–0.40(m,2H),0.37–0.24(m,2H).
Example 9 preparation of (R) -1- (3- (1- ((6- (2- ((cyclobutylmethyl) (methyl) amino) ethoxy) -7-methoxy-2-methylquinolin-4-yl) amino) ethyl) -2-fluorophenyl) -1, 1-difluoro-2-methylpropan-2-ol
Figure BDA0002734277190000492
LC-MS：m/z 561(M+H)+。1H NMR(400MHz,DMSO)δ8.03(d,J＝7.4Hz,1H),7.74(s,1H),7.58(t,J＝6.7Hz,1H),7.30(t,J＝6.7Hz,1H),7.20(t,J＝7.7Hz,1H),7.02(s,1H),5.80(p,J＝7.0Hz,1H),5.31(s,1H),4.16(m,2H),3.86(s,3H),2.78(t,J＝6.0Hz,2H),2.27(d,J＝10.1Hz,6H),2.08–1.95(m,2H),1.93–1.73(m,3H),1.66(m,2H),1.58(d,J＝7.0Hz,3H),1.22(m,8H).
EXAMPLE 10 preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (2- ((cyclobutylmethyl) (methyl) amino) ethoxy) -7-methoxy-2-methylquinolin-4-amine
Figure BDA0002734277190000493
LC-MS：m/z 518(M+H)+。1H NMR(400MHz,DMSO)δ7.93(d,J＝8.0Hz,1H),7.69(s,1H),7.02(s,1H),6.87(d,J＝11.0Hz,2H),6.69(s,1H),5.63–5.46(m,3H),4.13(m,2H),3.86(s,3H),2.76(t,J＝6.0Hz,2H),2.47(m,2H),2.34(s,3H),2.25(s,3H),2.00(m,2H),1.90–1.71(m,3H),1.70–1.59(m,2H),1.55(d,J＝7.0Hz,3H).
EXAMPLE 11 preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -7-methoxy-2-methyl quinazolin-4-amine
Figure BDA0002734277190000501
LC-MS：m/z 504(M+H)+。1H NMR(400MHz,DMSO)δ7.95(d,J＝8.0Hz,1H),7.64(d,J＝9.6Hz,1H),7.02(s,1H),6.86(d,J＝10.4Hz,2H),6.69(s,1H),5.62–5.46(m,3H),3.96(m,2H),3.88(s,3H),2.39–2.10(m,11H),1.54(d,J＝7.1Hz,3H),0.67(s,2H),0.48(s,2H).
Example 12(R) -1- (3- (1- ((6- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -7-methoxy-2-methylquinolin-4-yl) amino) ethyl) -2-fluorophenyl) -1, 1-difluoro-2-methylpropan-2-ol
Figure BDA0002734277190000502
LC-MS：m/z 507(M+H)+。1H NMR(400MHz,DMSO)δ8.04(d,J＝7.4Hz,1H),7.67(s,1H),7.58(t,J＝6.6Hz,1H),7.30(t,J＝6.6Hz,1H),7.21(m,1H),7.01(s,1H),5.79(m,1H),5.31(s,1H),3.98(m,2H),3.89(s,3H),2.26(m,8H),1.58(d,J＝7.0Hz,3H),1.32–1.12(m,9H),0.68(m,2H),0.48(m,2H).
EXAMPLE 13 preparation of (R) -N- (2- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) oxy) ethyl) -N-methylmethanesulfonamide
Figure BDA0002734277190000503
LC-MS：m/z 528(M+H)+。1H NMR(400MHz,DMSO)δ7.99(d,J＝7.7Hz,1H),7.74(s,1H),7.05(s,1H),6.86(d,J＝10.6Hz,2H),6.69(s,1H),5.61–5.43(m,3H),4.20(t,J＝19.3Hz,2H),3.87(s,3H),3.59(t,J＝5.5Hz,2H),2.99(s,3H),2.92(s,3H),2.34(s,3H),1.52(t,J＝17.4Hz,3H).
Example 141 preparation of- ((S) -2- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) oxy) methyl) pyrrol-1-yl) ethan-1-one
Figure BDA0002734277190000511
LC-MS：m/z 518(M+H)+。1H NMR(400MHz,DMSO)δ7.92(d,J＝7.4Hz,1H),7.79(s,1H),7.02(s,1H),6.87(d,J＝14.3Hz,2H),6.69(s,1H),5.53(m,3H),4.32(m,2H),4.05(m,3H),3.88(s,3H),2.34(m,3H),2.17(m,2H),1.99(m,5H),1.54(d,J＝7.0Hz,3H).
EXAMPLE 15 preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ((1- (morpholinomethyl) cyclopropyl) methoxy) quinazolin-4-amine
Figure BDA0002734277190000512
LC-MS：m/z 546(M+H)+。1H NMR(400MHz,DMSO)δ7.92(d,J＝7.9Hz,1H),7.64(s,1H),7.01(s,1H),6.87(m,2H),6.70(s,1H),5.66–5.44(m,3H),4.28–3.93(m,2H),3.87(s,3H),3.60–3.48(m,4H),2.66–2.56(m,1H),2.50(s,3H),2.35(m,4H),2.07–1.95(m,1H),1.56(t,J＝8.6Hz,3H),0.63(m,2H),0.50(m,2H).
Example 16(S) -2- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) oxy) methyl) pyrroline-1-carboxylic acid tert-butyl ester
Figure BDA0002734277190000513
LC-MS：m/z 579(M+H)+。1H NMR(400MHz,DMSO)δ8.10(m,1H),7.77(m,2H),7.63(t,J＝7.1Hz,1H),7.34(t,J＝7.8Hz,1H),7.03(s,1H),5.75(m,1H),4.07(m,3H),3.87(s,3H),2.30(s,3H),1.91(m,4H),1.62(d,J＝7.1Hz,3H),1.40(m,11H).
Example 17N- ((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (((S) -pyrrolin-2-yl) methoxy) quinazolin-4-amine
Figure BDA0002734277190000521
LC-MS：m/z 479(M+H)+。1H NMR(400MHz,DMSO)δ8.14(t,J＝8.6Hz,1H),7.84–7.70(m,2H),7.62(t,J＝6.9Hz,1H),7.35(t,J＝7.8Hz,1H),7.03(s,1H),5.85–5.67(m,1H),4.23–3.92(m,2H),3.87(s,3H),3.56(m,1H),2.91(m,2H),2.30(s,3H),2.12–1.67(m,4H),1.62(d,J＝7.1Hz,3H).
EXAMPLE 18 preparation of N- ((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-amine
Figure BDA0002734277190000522
LC-MS：m/z 493(M+H)+。1H NMR(400MHz,DMSO)δ14.61(brs,1H),10.00(s,1H),8.21(d,J＝19.4Hz,1H),7.92(t,J＝7.2Hz,1H),7.72(t,J＝7.0Hz,1H),7.43(t,J＝7.8Hz,1H),7.28(s,1H),5.93(m,1H),4.66(d,J＝9.6Hz,1H),4.54–4.37(m,1H),4.23(m,1H),3.98(s,3H),3.71(m,2H),3.03(s,3H),2.54(s,3H),2.37(m,1H),2.25–1.90(m,3H),1.73(t,J＝10.3Hz,3H).
EXAMPLE 19 preparation of (R) -1- (3- (1- ((6- (2- (((3, 3-difluorocyclobutyl) methyl) (methyl) amino) ethoxy) -7-methoxy-2-methylquinolin-4-yl) amino) ethyl) -2-fluorophenyl) -1, 1-difluoro-2-methylpropan-2-ol
Figure BDA0002734277190000523
LC-MS：m/z 597(M+H)+。1H NMR(400MHz,DMSO)δ8.04(d,J＝7.4Hz,1H),7.74(s,1H),7.58(t,J＝6.7Hz,1H),7.31(m,1H),7.20(t,J＝7.7Hz,1H),7.02(s,1H),5.79(m,1H),5.34(s,1H),4.36(t,J＝5.1Hz,2H),3.83(s,3H),2.83(t,J＝5.7Hz,2H),2.75(d,J＝10.4Hz,2H),2.68–2.56(m,4H),2.39–2.15(m,7H),1.58(d,J＝7.0Hz,3H),1.20(m,6H).
EXAMPLE 20 preparation of N- ((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (((S) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) quinazolin-4-amine
Figure BDA0002734277190000531
LC-MS：m/z 557(M+H)+。1H NMR(400MHz,DMSO)δ8.15(d,J＝6.9Hz,1H),7.79(t,J＝7.1Hz,1H),7.74(s,1H),7.63(t,J＝7.0Hz,1H),7.35(t,J＝7.8Hz,1H),7.04(s,1H),5.75(p,J＝6.9Hz,1H),4.15(d,J＝10.8Hz,2H),4.08–3.95(m,1H),3.87(s,3H),3.32–3.24(m,2H),3.02(s,3H),2.28(s,3H),1.99(m,4H),1.62(d,J＝7.0Hz,3H).
EXAMPLE 21 preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (2- (((1-fluorocyclopropyl) methyl) (methyl) amino) ethoxy) -7-methoxy-2-methyl-quinazolin-4-amine
Figure BDA0002734277190000532
LC-MS：m/z 522(M+H)+。1H NMR(400MHz,DMSO)δ8.21–7.98(brs,1H),7.75(s,1H),7.04(s,1H),6.88(m,2H),6.71(s,1H),5.64–5.49(m,3H),4.21(m,2H),3.88(s,3H),2.91(m,4H),2.46(s,3H),2.36(s,3H),1.57(d,J＝7.0Hz,3H),0.99(m 2H),0.70(m,2H).
EXAMPLE 22 preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6- (2- (((3, 3-difluorocyclobutyl) methyl) (methyl) amino) ethoxy) -7-methoxy-2-methylquinazolin-4-amine
Figure BDA0002734277190000533
LC-MS：m/z 554(M+H)+。1H NMR(400MHz,DMSO)δ7.94(d,J＝7.9Hz,1H),7.70(s,1H),7.02(s,1H),6.86(m,2H),6.69(s,1H),5.62–5.48(m,3H),4.14(m,2H),3.86(s,3H),2.80(m,2H),2.75(m,1H),2.69–2.59(m,3H),2.58–2.54(m,2H),2.35(s,3H),2.27(s,3H),2.20(m,1H),1.55(d,J＝7.0Hz,3H).
Example 23 evaluation of biological tests
The following biological test examples further illustrate the present invention, but these examples are not meant to limit the scope of the present invention.
Compound pair KRASG12CInhibition assay for binding to SOS 1.
Experimental procedure
(1) Gradient dilution of test compound: 10mM stock solution (dissolved in 100% DMSO) was added to 384 well assay plates to a final DMSO content of 0.25%.
(2) 5ul of Tag1-SOS1 solution was added to the test plate and 5ul of dilution buffer was added to the control.
(4) 5ul of Tag2-KRAS was added to the test plateG12CAnd (3) solution.
(4) 10ul of Anti-Tag1-Tb3+ and Anti-Tag2-XL665 test solution were added to the test plate. Centrifuged at 1000rpm for 1 min and incubated at room temperature for 2 hr.
(5) Reading board
(6) Finally, IC of the compound was calculated using GraphPad Prism software50And (5) obtaining values, and drawing a fitting curve.
KRAS pairs of Compounds exemplified in the present inventionG12CThe inhibitory activity of the enzyme in combination with SOS1 is shown in Table 1.
Table 1 inhibitory Activity of the Compounds of the examples of the present invention
Figure BDA0002734277190000541
Figure BDA0002734277190000551
As can be seen from table 1:
example Compounds of the invention for KRASG12CAnd SOS1 junctionThe compound shows good inhibitory activity. In particular, examples 1, 7, 8, 9, 10, 11, 12, 15, etc. have very excellent inhibitory activity.
Pharmacokinetic testing evaluation
Male SD rats weighing about 220g were fasted overnight and then gavaged with 10mg/kg of a solution of the compound of the present invention [ CMC/TW80 as vehicle ]. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, 24, 36 and 48 hours after administration of the compound of the present invention, and the concentration of the compound of the present invention in plasma was determined by LC/MS/MS, respectively.
The detection result shows that the compound of the invention has good pharmacokinetic property.
Evaluation of antitumor Effect
100uL of 5x106The MIA PaCa-2 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. Mice were monitored daily for health and measurements were started when tumors grew to reach. The formula for calculating the tumor volume is 0.5xLxW2Wherein L, W represents tumor length and width, respectively. Tumor growth to 150mm3Mice were randomly grouped. Mice were gavaged daily with the corresponding dose (15, 50mg/Kg) of CMC-Na suspension of the compound while monitoring their general state. Tumors were measured 3 times per week and body weights were measured twice per week.
The detection result shows that the compound has good anti-tumor effect.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. Substituted benzo or pyrido pyrimidinamine compounds having the structure of formula (I), stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof:
Figure FDA0002734277180000011
in the formula:
x is selected from: CR6Or N, wherein R6Selected from: hydrogen, deuterium, halogen, cyano, C1-C6Alkyl radical, C3-C6Cycloalkyl or 4-6 membered heterocyclyl;
y is selected from the group consisting of: o, NH, or NR7Wherein R is7Selected from: c1-C6Alkyl radical, C3-C6Cycloalkyl or 4-6 membered heterocyclyl;
z is selected from the group consisting of substituted or unsubstituted groups: c1-C18Alkylene, deuterated C1-C18Alkylene, or halogeno C1-C18An alkylene group;
w is selected from the group consisting of substituted or unsubstituted: c3-C20Cycloalkylene, 4-20 membered heterocyclylene, OR11、NR11R12、SO2、NR12SO2CO or NR12CO；R11Independently selected from the group consisting of substituted or unsubstituted: c3-C20Cycloalkylene, 4-20 membered heterocyclylene, C3-C20Cycloalkylene radical C1-C18Alkylene, or 4-20 membered heterocyclylene C1-C18An alkylene group; r12Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C6Alkyl or C3-C6A cycloalkyl group;
R1、R2independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, - (CH)2)mR8、-(CH2)mO(CH2)pR8、-(CH2)mSR8、-(CH2)mCOR8、-(CH2)mC(O)OR8、-(CH2)mS(O)qR8、-(CH2)mNR5R8、-(CH2)mC(O)NR8R9、-(CH2)mNR8C(O)R9、-(CH2)mNR8C(O)NR9R10、-(CH2)mS(O)qNR8R9、-(CH2)mNR8S(O)qR9、-(CH2)mNR8S(O)qNR9R10In which CH2H in (a) may be optionally substituted; r8、R9、R10Independently selected from the group consisting of substituted or unsubstituted: hydrogen, C1-C18Alkyl radical, C3-C20Cycloalkyl or 4-20 membered heterocyclyl;
R3selected from the group consisting of substituted or unsubstituted: c3-C18Cycloalkyl, 4-20 membered heterocyclyl, C6-C14Aryl, 5-14 membered heteroaryl;
R4、R5independently selected from the group consisting of substituted or unsubstituted: c1-C6Alkyl radical, C3-C6Cycloalkyl, or 4-6 membered heterocyclyl;
wherein the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl, halo C1-C18Alkyl hydroxy, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy radical, C6-C14Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;
m, n are each independently 0, 1, 2, 3, 4 or 5;
p is 0, 1, 2, 3, 4 or 5;
q is 1 or 2.
2. The substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof according to claim 1, wherein the substituted benzo or pyrido pyrimidinamine compound has the structure of formula (III):
Figure FDA0002734277180000021
in the formula: r1、R2、R3X, Y, Z, W, n are as defined in claim 1.
3. The substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof according to claim 1, wherein the substituted benzo or pyrido pyrimidinamine compound has the structure of formula (IV):
Figure FDA0002734277180000022
in the formula:
R1、R2、R3、R6x, Y, Z, W, n are as defined in claim 1.
4. The substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, wherein the substituted benzo or pyrido pyrimidinamine compound has the structure of formula VI:
Figure FDA0002734277180000023
in the formula (I), the compound is shown in the specification,
R13and R14Each independently selected from: H. c1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl halogens, oxo groups, nitro groups, hydroxyl groups, cyano groups, ester groups, amine groups, amide groups, sulfonamide groups, or urea groups;
ring C is selected from the group consisting of substituted or unsubstituted: c3-C12Cycloalkylene, 4-12 membered heterocyclylene;
the substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C18Alkyl, deuterated C1-C18Alkyl, halo C1-C18Alkyl, halo C1-C18Alkyl hydroxy, C3-C20Cycloalkyl radical, C1-C18Alkoxy, deuterated C1-C18Alkoxy, halo C1-C18Alkoxy radical, C6-C14Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;
t is 1, 2, 3, 4, 5 or 6;
R1、R2、R3、R6and n is as defined in claim 1.
5. The substituted benzo or pyrido pyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, wherein the substituted benzo or pyrido pyrimidinamine compound has the structure of formula VII:
Figure FDA0002734277180000031
in the formula (I), the compound is shown in the specification,
R16and R17Each independently selected from: H. c1-C6Alkyl, deuterated C1-C6Alkyl, halo C1-C6Alkyl halogens, oxo groups, nitro groups, hydroxyl groups, cyano groups, ester groups, amine groups, amide groups, sulfonamide groups, or urea groups;
R18selected from: OR (OR)11、NR11R12、NR12SO2R2、COR2Or NR12COR2；R11Independently selected from the group consisting of substituted or unsubstituted: c3-C12Cycloalkyl, 4-12 membered heterocyclyl, C3-C12Cycloalkylene radical C1-C6Alkylene, or 4-12 membered heterocyclylene C1-C6An alkylene group; r12Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C1-C6Alkyl or C3-C6A cycloalkyl group;
t is 1, 2, 3, 4, 5 or 6;
R1、R2、R3and R6Is as defined in claim 1.
6. The substituted benzo or pyridopyrimidinamine compound having the structure of formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0002734277180000041
Figure FDA0002734277180000051
Figure FDA0002734277180000061
Figure FDA0002734277180000071
Figure FDA0002734277180000081
Figure FDA0002734277180000091
Figure FDA0002734277180000101
Figure FDA0002734277180000111
Figure FDA0002734277180000121
Figure FDA0002734277180000131
Figure FDA0002734277180000141
Figure FDA0002734277180000151
Figure FDA0002734277180000161
Figure FDA0002734277180000171
Figure FDA0002734277180000181
Figure FDA0002734277180000191
Figure FDA0002734277180000201
Figure FDA0002734277180000211
Figure FDA0002734277180000221
Figure FDA0002734277180000231
Figure FDA0002734277180000241
Figure FDA0002734277180000251
Figure FDA0002734277180000261
Figure FDA0002734277180000271
7. a process for the preparation of substituted benzo-or pyridopyrimidinamine compounds of general formula (I), their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, comprising the steps of:
Figure FDA0002734277180000281
(i) reacting a compound of formula V-1 with a compound of formula V-2 in the presence of a first base to provide a compound of formula V-3;
(ii) reacting a compound of formula V-3 with sulfonyl chloride (V-4) in the presence of a second base and a catalyst (e.g., DMAP) to produce a compound of formula V-5;
(iii) reacting the compound of formula V-5 with an amine (formula V-6) in the presence of a third base to provide a compound of formula (I);
in the formula (I), the compound is shown in the specification,
r' is selected from: halogen, OTs or OMs;
R1、R2、R3、R4、R5x, Y, Z, W and n are as defined in claim 1.
8. A pharmaceutical composition comprising I) one or more compounds of general formula (I) according to any one of claims 1 to 6, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof; and ii) a pharmaceutically acceptable carrier.
9. Use of the substituted benzo-or pyridopyrimidinamine compound having a structure according to any of claims 1 to 6, or a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or the pharmaceutical composition according to claim 8, for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of a disease associated with the activity or expression level of SOS 1.
10. A method is provided for non-diagnostic, non-therapeutic inhibition of SOS1, comprising the steps of: administering to a patient 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, according to any one of claims 1 to 6, or administering a pharmaceutical composition according to claim 8.
CN202011128302.9A 2020-10-20 2020-10-20 Substituted benzo or pyrido pyrimidine amine inhibitor and preparation method and application thereof Pending CN114380805A (en)

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