CN115215884A - Benzopyrimidine tricyclic derivative and preparation method and application thereof - Google Patents

Benzopyrimidine tricyclic derivative and preparation method and application thereof Download PDF

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CN115215884A
CN115215884A CN202110418431.XA CN202110418431A CN115215884A CN 115215884 A CN115215884 A CN 115215884A CN 202110418431 A CN202110418431 A CN 202110418431A CN 115215884 A CN115215884 A CN 115215884A
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alkyl
hydrogen
radical
halogen
hydroxy
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吕贺军
叶文武
高连超
冯昊
任利锋
纪海霞
葛建华
刘军锋
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Shanghai Kunheng Medical Technology Co ltd
KPC Pharmaceuticals Inc
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Shanghai Kunheng Medical Technology Co ltd
KPC Pharmaceuticals Inc
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Priority to PCT/CN2022/087301 priority patent/WO2022222875A1/en
Priority to TW111114719A priority patent/TWI807787B/en
Publication of CN115215884A publication Critical patent/CN115215884A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a benzopyrimidine tricyclic compound shown in a formula (I), an application of the benzopyrimidine tricyclic compound as an SOS1 inhibitor, a pharmaceutical composition containing the benzopyrimidine tricyclic compound and an application of the benzopyrimidine tricyclic compound as a medicament/medical application, in particular an application of the benzopyrimidine tricyclic compound as a medicament for treating and/or preventing oncological diseases.

Description

Benzopyrimidine tricyclic derivative and preparation method and application thereof
Technical Field
The invention relates to a benzopyrimidine tricyclic derivative shown in a formula (I) and application thereof as an SOS1 inhibitor, in particular to application of the benzopyrimidine tricyclic derivative in treating and/or preventing oncology diseases.
Background
Since the late 20 th century 80 s, mutations in the Ras family (which contains the members KRas, NRas and HRas) have been found to be associated with cancer, with an incidence of up to 20-30% in human cancer. Ras proteins belong to GTP-binding proteins and are molecular switches with two switch regions in the protein conformation: switch-I (aa 30-38) and switch-II (aa 59-76), in the active state KRas will bind GTP, initiating downstream cell growth signaling pathways, such as the Ras-Raf-MEK-ERK and Ras-PI3K-PDK1-AKT pathway; ras is turned off after GTP becomes GDP. Normally, ras is inactivated immediately after activation; however, after Ras gene mutation (such as KRas (G12C)), ras protein continuously maintains the activated state, is no longer dependent on the stimulation of superior signals, and is in a state of continuously combining with GTP, so that a downstream signal path is abnormally active, and cells are continuously proliferated. However, because of the unique molecular structure of Ras and the high similarity of the various Ras subtypes, D-domain, the development of Ras-selective inhibitors has been difficult, and Ras has been considered as an unforeseeable target for over 50 years since Ras was discovered to date.
The guanine nucleotide exchange factor (GEF) protein of Ras is a guanine nucleotide exchange factor (GEF) of Ras, SOS1 is one of two SOS family proteins (SOS 1 and SOS 2) and is a guanine nucleotide exchange factor of Ras, and the combination of SOS1 and Ras-GDP catalyzes the exchange of GDP and GTP in Ras molecules and plays an important role in activating Ras and transmitting cell growth and differentiation signals. In tumors with Ras overactivation, ras pathway can be blocked by inhibiting SOS1, thereby achieving the therapeutic effect of inhibiting tumor cell proliferation.
To date, SOS1-Ras interactions have gained increasing public acceptance, and small molecule inhibitors of SOS1 have binding, catalytic effects that bind to SOS1 and inhibit its binding to Ras proteins (Evelyn et al, chem. Biol.2014,21 (12): 1618-28; WO 2016/077793), and although compounds have been identified that have a slightly inhibitory effect on SOS1, the effects on guanine nucleotide exchange and modulation of cellular signaling (e.g., ERK phosphorylation) are still weak. In WO2018/115380 and WO2018/172250, a parent nucleus is disclosed as a quinazoline structure SOS inhibitor, and the compound remarkably improves the mutual inhibitory effect on SOS1 and Ras family proteins, particularly KRas, and therefore remarkably reduces ERK phosphorylation in KRas mutant cancer cell lines. Recently, a new benzylamino substituted pyridopyrimidinone and derivatives as SOS1 inhibitors have been disclosed in WO2019122129A1, with a certain effect as well.
Compounds that target SOS1 inhibitors can mediate diseases that include mutations in the Ras family protein pathway (e.g., KRas, NRas, HRas), receptor tyrosine kinases (e.g., EGFR, erbB2, erbB3, erbB4, PDGFR-a/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, trkA, trkB, trkC, RET, c-MET, VEGFR1/2/3, AXL), and GAP (e.g., NF 1). In addition, in Ras family protein mutations associated with other diseases (such as neurofibromatosis, noonan Syndrome (NS), cardio-facial skin syndrome (CFC) and type 1 hereditary gingival fibromatosis also has potential application value.
The invention provides a novel benzopyrimidine tricyclic derivative which shows exciting inhibition effect on SOS1 inhibitor, and partial compounds show unexpected pharmacokinetic property.
Disclosure of Invention
In view of the above, the present invention provides a benzopyrimidine tricyclic derivative useful for inhibiting the interaction of SOS1 catalytic site with Ras family protein, which is involved in cell proliferation. Thus, the compounds of the present invention are useful in, but not limited to, the treatment of diseases of excessive or abnormal cell proliferation.
In order to achieve the above objects, the present invention provides a benzopyrimidine tricyclic compound represented by formula (i) or a stereoisomer or a pharmaceutically acceptable salt thereof:
Figure BDA0003026842380000031
wherein
R 1 Selected from hydrogen, C 1-4 Alkyl radical, wherein said C 1-4 Alkyl is optionally substituted with one or more of the same or different halogen or hydroxy;
ring A is selected from: c 6-10 Aryl, 5-to 10-membered heteroaryl;
p represents 1,2 or 3;
each R 2 Independently selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, substituted or unsubstituted C 5 -C 7 Aryl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-N(C 1-4 Alkyl radical) 2 Cyano, nitro, -SO 2 -C 1-4 An alkyl group; wherein C is substituted or unsubstituted 5 -C 7 The aryl substituents are preferably: c 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, C 1-4 Aminoalkyl, (C) 1-4 Alkyl radical) 2 N-C 1-4 Alkyl radical, C 1-4 alkyl-NH-C 1-4 An alkyl group;
R 3 selected from hydrogen, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, oxo, -C (O) ORa, -C (O) NRaRa, wherein C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl are optionally substituted by one or more of the same or different halogen, hydroxy, -NH 2 Substituted, ra are each independently selected from hydrogen, C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 3-to 10-membered heteroaryl;
o represents 1 or 2;
R 4 selected from 3-10 membered saturated heterocyclic groups, whereinSaid 3-10 membered saturated heterocyclyl is optionally substituted with one or more same or different Rb;
rb is independently selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl, 5-to 10-membered heteroaryl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -S (O) 2 Rc、 -S(O) 2 NRcRc, halogen, cyano, hydroxy, and oxo; wherein Rb is said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl are all optionally substituted by one or more of the same or different halogen, cyano, hydroxy, -NH 2 And oxo-substitution, wherein oxo is not on a double bond;
rc is each independently selected from hydrogen, C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 0 -C 1 alkylene-C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl;
n represents 0, 1 or 2;
x is selected from O, S, NRd, CRdRd, rd is independently selected from hydrogen and C 1-3 An alkyl group;
R 5 selected from hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl radical) 2 And halogen;
R 6 selected from hydrogen, halogen;
wherein each two R are 3 May be linked to form a 3-6 membered ring.
In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R is 1 Is methyl.
In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring a is selected from: c 6-10 Aryl, preferably phenyl;
p represents 1,2 or 3;
each R 2 Independently selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, preferably hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 Wherein said halo is C 1-4 Alkyl is more preferably C substituted by 1,2 or 3 fluorine 1-4 Alkyl, exemplified by but not limited to-CF 3 、CHF 2 。
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring a is substituted with p R 2 The substituents together have the following substructure:
Figure BDA0003026842380000051
rg is selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-SO 2 -C 1-4 Alkyl, cyano; wherein C is 1-4 The haloalkyl group is preferably an alkyl group substituted with 1,2 or 3 fluorine atoms, and is more preferably-CF 3 、 -CHF 2 ；
Re is selected from: hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl, halogen, nitro and cyano, wherein the halogen is fluorine, chlorine, bromine and iodine, and fluorine is preferred.
In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring A is substituted with p substituents R 2 Together have the substructure:
Figure BDA0003026842380000052
rg is selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Alkyl halides, halogens, -NH 2 In which C is 1-4 The haloalkyl group is preferably an alkyl group substituted with 1,2 or 3 fluorine atoms, and is more preferably-CF 3 、-CHF 2 ；
Re is selected from hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl, halogen and nitro, wherein the halogen is fluorine, chlorine, bromine and iodine, and fluorine is preferred.
In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring A is substituted with p substituents R 2 Together have the substructure:
Figure BDA0003026842380000061
in another aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring a is selected from: 5-to 10-membered heteroaryl;
p represents 1,2 or 3;
each R 2 Independently selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, substituted or unsubstituted C 5 -C 7 Aryl, preferably hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 Substituted or unsubstituted C 5 -C 7 Aryl, wherein said halo is C 1-4 Alkyl is more preferably C substituted by 1,2 or 3 fluorine 1-4 Alkyl, such as but not limited to-CF 3 、CHF 2 Substituted or unsubstituted C 5 -C 7 The aryl substituents are preferably: c 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、 C 1-4 Alkoxy, nitro, cyano, C 1-4 Aminoalkyl radical, (C) 1-4 Alkyl radical) 2 N-C 1-4 Alkyl radical, C 1-4 alkyl-NH-C 1-4 An alkyl group.
In another aspect, the invention relates to a compound of formula (I) wherein ring a is selected from: a 5-to 7-membered heteroaryl monocyclic ring, more particularly selected from: pyridine ring, thiophene ring, thiazole ring.
In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring a is substituted with p substituents R 2 Together have the substructure:
Figure BDA0003026842380000071
in another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, methyl, oxo.
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the other two R are 3 Can be joined to form a 3-6 membered ring in a fused ring form with the attached rings, such as bridged, spiro forms well known to those skilled in the art, as shown by way of example below:
Figure BDA0003026842380000072
in another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R 4 Selected from 3-10 membered saturated heterocyclyl, wherein said 3-10 membered saturated heterocyclyl is optionally substituted with one or more same or different Rb;
rb is independently selected from C 1-6 Alkyl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -S (O) 2 Rc, wherein Rb is C 1-6 Alkyl is optionally substituted by one or more of the same or different halogen, cyano, hydroxy, -NH 2 And oxo;
rc is independently selected from hydrogen and C 1-6 Alkyl radical, C 3 -C 6 Cycloalkyl of, C 0 -C 1 alkylene-C 6-10 And (4) an aryl group.
In another aspectThe present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R is 4 Selected from tetrahydrofuranyl and pyrrolidinyl, wherein both the tetrahydrofuranyl and pyrrolidinyl are optionally substituted with one or more same or different Rb;
rb is independently selected from C 1-6 Alkyl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -S (O) 2 Rc、 -S(O) 2 NRcRc, oxo, wherein Rb is C 1-6 Alkyl is optionally substituted by one or more of the same or different halogen, cyano, hydroxy, -NH 2 And oxo;
rc is each independently selected from hydrogen, C 1-6 Alkyl radical, C 3 -C 6 Cycloalkyl of, C 0 -C 1 alkylene-C 6-10 And (4) an aryl group.
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R 4 Selected from tetrahydrofuranyl and pyrrolidinyl, wherein both the tetrahydrofuranyl and pyrrolidinyl are optionally substituted with one or more Rb, the preferred tetrahydrofuranyl and pyrrolidinyl meta positions are attached to the parent nucleus:
Figure BDA0003026842380000081
in another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R 4 Is pyrrolidinyl optionally substituted on nitrogen with Rb, independently selected from C 1-6 Alkyl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, rc are independently selected from hydrogen and C 1-6 Alkyl radical, C 3 -C 6 Cycloalkyl of, C 0 -C 1 alkylene-C 6-10 And (3) an aryl group.
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R 4 Is tetrahydrofuranyl optionally substituted by one or more identical or different Rb, independently selected from C 1-6 Alkyl, oxo.
In another aspect, the invention relates toAnd a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R 4 Selected from the group consisting of:
Figure BDA0003026842380000082
in another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein X is selected from O, CH 2 。
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, R 5 Selected from hydrogen, R 6 Selected from hydrogen.
In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, preferably of formula (IIa) and/or (IIb):
Figure BDA0003026842380000091
wherein
R 1 Selected from hydrogen, C 1-4 Alkyl radical, wherein said C 1-4 Alkyl is optionally substituted with one or more of the same or different halogen or hydroxy;
rg is selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-SO 2 -C 1-4 Alkyl, cyano, wherein C 1-4 The haloalkyl group is preferably an alkyl group substituted with 1,2 or 3 fluorine atoms, and is more preferably-CF 3 、 -CHF 2 ；
Re is selected from hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl, halogen, nitro and cyano, wherein the halogen is fluorine, chlorine, bromine and iodine, and fluorine is preferred.
Ring B is a 5-to 10-membered heteroaryl;
each R 2 Independently selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, substituted or unsubstituted C 5 -C 7 Aryl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-N(C 1-4 Alkyl radical) 2 Cyano, nitro, -SO 2 -C 1-4 An alkyl group; substituted or unsubstituted C 5 -C 7 The aryl substituents are preferably: c 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, C 1-4 Aminoalkyl radical, (C) 1-4 Alkyl radical) 2 N-C 1-4 Alkyl radical, C 1-4 alkyl-NH-C 1-4 An alkyl group;
p represents 1,2 or 3;
R 3 selected from hydrogen, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, oxo, -C (O) ORa, -C (O) NRaRa, wherein C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl are optionally substituted by one or more of the same or different halogen, hydroxy, -NH 2 Ra is independently selected from hydrogen and C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 3-to 10-membered heteroaryl;
o represents 1 or 2;
y is selected from O and NRh, rh is independently selected from hydrogen and C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl, 5-to 10-membered heteroaryl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -S (O) 2 Rc、-S(O) 2 NRcR C, wherein Rh is C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl are all optionally substituted by oneOr a plurality of identical or different halogen, cyano, hydroxy, and oxo substitutions, the oxo group not being at the double bond;
rc is independently selected from hydrogen and C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 0 -C 1 alkylene-C 6-10 Aryl radical, C 3-10 Heterocyclyl and C 5-10 A heteroaryl group;
n represents 0, 1 or 2;
m represents 1 or 2;
x is selected from O, S, NRd, CRdRd, rd is independently selected from hydrogen and C 1-3 An alkyl group;
R 5 selected from hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl radical) 2 And a halogen;
R 6 selected from hydrogen and halogen.
In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, more preferably a compound of formula (IIa) and/or (IIb) or a stereoisomer, pharmaceutically acceptable salt thereof:
Figure BDA0003026842380000111
wherein
R 1 Is methyl;
rg is selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 In which C is 1-4 The haloalkyl group is preferably an alkyl group substituted by 1,2 or 3 fluorine atoms, and more preferably-CF 3 、-CHF 2 ；
Re is selected from hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl and halogen, nitro;
ring B is pyridyl or thienyl;
each R 2 Independently selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, substituted or unsubstituted C 5 -C 7 Aryl, hydroxy, halogen, -NH 2 、-N(C 1-4 Alkyl radical) 2 A cyano group; substituted or unsubstituted C 5 -C 7 The aryl substituents are preferably: c 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy radical, C 1-4 Aminoalkyl radical, (C) 1-4 Alkyl radical) 2 N-C 1-4 Alkyl radical, C 1-4 alkyl-NH-C 1-4 An alkyl group;
p represents 1 or 2;
R 3 selected from hydrogen, C 1-4 Alkyl, oxo, -C (O) ORa, -C (O) NRaRa, wherein C 1-4 Alkyl is optionally substituted by one or more of the same or different halogen, hydroxy, amino, ra are each independently selected from hydrogen, C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl;
o represents 1;
y is selected from O and NRh, and Rh is independently selected from hydrogen and C 1-6 Alkyl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc;
rc is independently selected from hydrogen and C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 3-6 Cycloalkyl radical, C 0 -C 1 alkylene-C 6-10 An aryl group;
n represents 0 or 1;
m represents 1;
x is selected from O, CRdRd, rd is independently selected from hydrogen and C 1-3 An alkyl group;
R 5 and R 6 Independently selected from hydrogen and halogen.
In another aspect, the invention provides a specific compound, or a stereoisomer, pharmaceutically acceptable salt thereof,
Figure BDA0003026842380000121
Figure BDA0003026842380000131
in another aspect, the invention further provides the following specific compounds or stereoisomers, pharmaceutically acceptable salts thereof,
Figure BDA0003026842380000141
Figure BDA0003026842380000151
all the above mentioned structural aspects are preferred embodiments of the respective aspects. Structural aspects associated with the different molecular moieties of the compounds (I) of the present invention can be combined with each other as desired to obtain preferred compounds. Each combination represents and defines an individual embodiment or a general subset of the compounds (I) of the invention, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of the compounds of formula (I), including all embodiments thereof.
The present invention further relates to pharmaceutically acceptable salts of compounds of formula (I), including all embodiments thereof, including pharmaceutically acceptable salts of compounds of formula (I), including all embodiments thereof, with inorganic or organic acids or bases. Pharmaceutically acceptable salts include, but are not limited to: salts with inorganic acids such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and the like; and salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-isethionate, benzoate, salicylate, stearate, and alkanoates such as acetate, HOOC- (CH 2) n-COOH (where n is 0-4), and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to: sodium, potassium, calcium, aluminum, lithium, and ammonium.
In addition, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid or base group by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. When they have a plurality of asymmetric stereocenters, stereocombinations thereof and mixtures thereof are included within the scope of the present invention, and alternative forms of the stereogenic compounds may be obtained by techniques conventional to those skilled in the art, such as the introduction of chiral starting materials, chiral resolution, and the like.
For example: invention R 4 Selected from tetrahydrofuryl and pyrrolidinyl, and has stereoisomers, R or S configuration,
Figure BDA0003026842380000171
another example is: invention R 3 When substituted, the stereoisomerism also exists, the R or S configuration of the stereoisomeric fragment is shown as follows,
Figure BDA0003026842380000172
in another aspect, the compounds as described herein may be formulated into pharmaceutical compositions with human-acceptable carriers and administered to a mammalian host (such as a human patient) in a variety of forms suitable for the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical, transdermal, intrathecal, ocular, intranasal, intraperitoneal, or subcutaneous routes.
The compounds described herein may be administered systemically, e.g., orally or intravenously in combination with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be blended directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
In another aspect, the present invention relates to compounds of formula (I) (including all embodiments thereof) useful for the preparation, treatment or prevention of diseases and/or disorders associated with SOS1 or modulated by SOS 1; particularly diseases and/or disorders in which inhibition of the interaction of SOS1 with a Ras family protein and/or RAC1 is of therapeutic benefit.
Still further, the use of compounds of formula (I) as described above for the preparation, treatment and/or prevention of diseases and/or disorders associated with SOS1 or modulated by SOS1, including but not limited to the treatment and/or prevention of cancer. More preferably from the group consisting of: pancreatic cancer, lung cancer, colorectal cancer, cholangioepithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.
The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
The various starting materials, intermediates and compounds described herein can be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Characterization of these compounds can be performed using conventional methods, such as by melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses.
Some examples of compounds of the present invention can be realized by the following reaction scheme:
reaction scheme 1
Figure BDA0003026842380000181
Wherein the substituents are as defined above in the present invention.
Reaction scheme 2
Figure BDA0003026842380000191
Wherein the substituents are as defined above in the present invention.
Reaction scheme 3
Figure BDA0003026842380000201
Reaction scheme 4
Figure BDA0003026842380000211
Wherein the substituents are as defined above in the present invention, and wherein Y is N, the desired technical scheme of the present application can be further achieved by alkylation, acylation and the like by techniques well known to those skilled in the art.
While certain embodiments have been illustrated and described, it will be appreciated that changes and modifications may be made therein in accordance with ordinary skill in the art without departing from the technology as defined in the following claims in their broader aspects.
Compared with the prior art, the invention provides a benzo pyrimidine tricyclic derivative with a structure shown in a formula I or a stereoisomer and pharmaceutically acceptable salt thereof. The result of an activity experiment shows that the benzopyrimidine tricyclic derivative provided by the invention has higher activity and selectivity, and can be used for treating diseases related to thyroid hormone receptors.
Noun explanation
"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically non-feasible and/or inherently unstable.
"alkyl" includes straight and branched chains having the indicated number of carbon atoms (typically 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms). E.g. C 1-6 Alkyl groups include straight and branched chain alkyl groups of 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl, and the like. Alkylene is another subset of alkyl and refers to the same residue as alkyl, but with two points of attachment. The alkylene group typically has 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as 2 to 6 carbon atoms. When naming alkyl residues having a particular carbon number, all geometric isomers having that carbon number are intended to be included, e.g., "butyl" is intended to include n-butyl, sec-butyl, isobutyl, and tert-butyl; "propyl" includes n-propylPropyl and isopropyl. "lower alkyl" means an alkyl group having 1 to 4 carbons.
"alkenyl" means having the indicated number of carbon atoms (typically 1 to 8 carbon atoms, e.g., 2 to 4 carbon atoms) and at least 1 and preferably 1 to 2 vinyl groups (>C＝C<) A linear or branched hydrocarbon group of an unsaturated site. Examples of such groups are, for example, vinyl, allyl and but-3-en-1-yl. Included within the term are cis and trans isomers or mixtures of these isomers. "lower alkenyl" means an alkenyl group having 1-4 carbons which may pass through C 2-4 Alkenyl groups are used.
Haloalkyl (haloalkenyl, haloalkynyl) radicals are all derived from alkyl (alkenyl, alkynyl) radicals as previously defined by replacing one or more hydrogen atoms of the hydrocarbon chain with halogen atoms which may be the same or different, independently of one another. If the haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitution can be carried out in each case independently of one another on all of the carbon atoms bearing the hydrogen in monosubstituted or polysubstituted form. An example of a haloalkyl (haloalkenyl, haloalkynyl) is-CF 3 、-CHF 2 、-CH 2 F、-CF 2 CF 3 -CHFCF 3 、- CH 2 CF 3 、-CF 2 CH 3 、-CHFCH 3 、-CF 2 CF 2 CF 3 、-CF 2 CH 2 CH 3 、-CF＝CF 2 、-CCl ＝CH 2 、-CBr＝CH 2 、-C≡CCF 3 、-CHFCH 2 CH 3 、-CHFCH 2 CF 3 And the like.
"cycloalkyl" means a non-aromatic, partially saturated, or fully saturated, carbocyclic ring having the specified number of carbon ring atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms). Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl, as well as bridged and caged ring groups (e.g., bicyclo [2.2.2 [ ]]Octane). Lower cycloalkanes are in general C 3-6 The monocyclic ring, lower cycloalkyl in general, may be preferably a fully saturated carbocyclic ring, unless otherwise specified.
"hydroxyalkyl (hydroxycycloalkyl)" includes the substitution of one or more hydroxyl groups for the above-described straight and branched chain alkyl (cycloalkyl) groups having the indicated number of carbon atoms (typically 1 to 20 carbon atoms, e.g., 1 to 8 carbon atoms, such as 1 to 6 carbon atoms), as combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
"halo-hydroxyalkyl" includes the substitution of one or more hydroxyl groups and halogens for the above-described straight and branched chain alkyl groups having the indicated number of carbon atoms (typically 1 to 20 carbon atoms, e.g., 1 to 8 carbon atoms, such as 1 to 6 carbon atoms), as combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
"aryl" means an aromatic carbocyclic ring having the specified number of carbon atoms in the ring (e.g., 6 to 12 or 6 to 10 carbon atoms). The aryl group can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of the polycyclic aryl are aromatic (e.g., naphthyl). In other instances, the polycyclic aryl can include a non-aromatic ring fused to an aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) provided that the polycyclic aryl is bonded to the parent structure through an atom in the aromatic ring. Thus, a1, 2,3, 4-tetrahydronaphthalen-5-yl (in which the moiety is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, whereas a1, 2,3, 4-tetrahydronaphthalen-1-yl (in which the moiety is bonded to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, 1,2,3, 4-tetrahydroquinolin-8-yl (where the moiety is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, and 1,2,3, 4-tetrahydroquinolin-1-yl (where the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not include or overlap with "heteroaryl" as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl). In some cases, the aryl ring may be further substituted, without specific mention, with functional groups well known in the art, without affecting the aromatic ringDefinition of the number of carbon atoms. In some cases, aryl is phenyl or naphthyl. In some cases, aryl is phenyl. Other examples of aryl groups comprising an aromatic carbocyclic ring fused to a non-aromatic ring are described below. C as described herein 0 -C 1 alkylene-C 6-10 Aryl, typically when C 0 alkylene-C 6-10 When aryl is said to correspond to aryl, C 1 alkylene-C 6-10 By aryl is generally meant an aryl group which is adjacent to a methylene group, such as benzyl.
"carboxyl (carboxyl)" or "carboxyl (carboxyl)" means-COOH or a salt thereof.
"heteroaryl" means an aromatic ring (e.g., a 5-12 or 5-10 membered heteroaryl) containing the indicated number of ring atoms, which ring atoms are composed of one or more heteroatoms (e.g., 1,2,3, or 4 heteroatoms) selected from N, O, and S, and the remaining ring atoms are carbon. A 5-membered heteroaryl is a heteroaryl having 5 ring atoms. A 6-membered heteroaryl is a heteroaryl having 6 ring atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 1. Unless otherwise indicated, heteroaryl groups may be bonded to the parent structure through a carbon or nitrogen atom, as valency permits. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl. When a nitrogen is present in a heteroaryl ring, the nitrogen may be present in the oxidation state (i.e., N + -O-), as the nature of the adjacent atoms and groups permits. Further, when sulfur is present in a heteroaryl ring, the sulfur may be in the oxidation state (i.e., S + -O-or SO) as the nature of the adjacent atoms and groups permits 2 ) Are present. Heteroaryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2, 3-triazole, 1,2, 4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,3, 4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, 1,3, 4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2, 4-triazine, 1,3, 5-triazine), and tetrazine.
In other instances, the polycyclic heteroaryl can include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, so long as the polycyclic heteroaryl is bonded to the parent structure through an atom in the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo [ d ] thiazol-2-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while a 4,5,6,7-tetrahydrobenzo [ d ] thiazol-5-yl (wherein the moiety is bonded to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryls consisting of a heteroaryl ring fused to a non-aromatic ring are described below.
"heterocycloalkyl" means a non-aromatic, partially or fully saturated ring (e.g., 3-10 or 3-7 membered heterocycloalkyl), sometimes referred to herein as heterocyclyl, having the indicated number of ring atoms, which ring atoms are composed of one or more heteroatoms (e.g., 1,2,3, or 4 heteroatoms) selected from N, O, and S, and the remaining ring atoms are carbon. A 5-membered heterocycloalkyl group is a heterocycloalkyl group having 5 ring atoms. A 6-membered heterocycloalkyl group is a heterocycloalkyl group having 6 ring atoms. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl include oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. When nitrogen is present in the heterocycloalkyl ring, the nitrogen may be present in the oxidation state (i.e., N + -O-) as the nature of the adjacent atoms and groups permits. Examples include piperidinyl-N-oxide and morpholinyl-N-oxide. Further, when sulfur is present in the heterocycloalkyl ring, the sulfur may be in the oxidized state (i.e., S + -O-or-SO) as the nature of the adjacent atoms and groups permits 2 -) are present. Examples include thiomorpholine S-oxide and thiomorpholine S, S-dioxide. In addition, one ring of the polycyclic heterocycloalkyl group can be aromatic (e.g.,aryl or heteroaryl) as long as the polycyclic heterocycloalkyl is bonded to the parent structure through a non-aromatic carbon or nitrogen atom. For example, 1,2,3, 4-tetrahydroquinolin-1-yl (where the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while 1,2,3, 4-tetrahydroquinolin-8-yl (where the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group. Lower heterocycloalkanes are typically C 3-6 The monocyclic, lower heterocycloalkyl group may be preferably a fully saturated carbocyclic ring in general, unless otherwise specified.
"alkoxy" refers to an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, and the like. Alkoxy is also intended to include cycloalkyl groups as defined above also attached through an oxygen bridge. Alkoxy groups typically have 1-6 carbon atoms connected by an oxygen bridge. "lower alkoxy" means an alkoxy group having 1 to 4 carbons.
The term "halo" includes fluoro, chloro, bromo and iodo.
The term "substituted" as used herein means that any one or more hydrogens on the designated atom or group is replaced with a selection from the designated group, provided that the designated atom's normal valence is not exceeded. When the substituent is oxo (i.e., = O), then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply that the compound is sufficiently robust to survive isolation from the reaction mixture and subsequent formulation into an agent of at least practical utility. Unless otherwise indicated, substituents are named into the core structure. For example, it will be understood that when (cycloalkyl) alkyl is listed as a possible substituent, the point of attachment of that substituent to the core structure is in the alkyl moiety.
List of partial abbreviations
Abbreviations section Means for
HNO 3 Nitric acid
DMSO Dimethyl sulfoxide
NaBH(OAc) 3 Sodium triacetoxyborohydride
Xantphos 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene
DMF N, N-dimethylformamide
Dioxane 1, 4-dioxane
DIPEA Diisopropylethylamine
NBS N-bromosuccinimide
CBZ Benzyloxycarbonyl group
Detailed Description
The apparatus and method for separating and purifying the preparative liquid phase used in the present invention are as follows:
the instrument comprises the following steps: liquid-phase SIL-10AP prepared from Shimadzu
1. Acid chromatography column: welch Ultimate XB-C18, 21.2 x 250mm,10um
Mobile phase: a:0.05% aqueous TFA B: acetonitrile (ACN)
2. An alkaline chromatographic column: welch Xtimate C18, 21.2X 250mm,10um
Mobile phase: a:10mmol/L aqueous solution B: acetonitrile (ACN)
Column temperature: at room temperature
Flow rate: 25ml/min
Detection wavelength: 214/254nm
The present invention is described in further detail below with reference to the examples.
Example 1
N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-4-amine 1
Figure BDA0003026842380000271
First step of
2-bromo-4-fluoro-5-nitrobenzoic acid 1b
The compound 2-bromo-4-fluoro-benzoic acid 1a (10.00g, 45.66mmol) was dissolved in concentrated sulfuric acid (40 mL), the reaction solution was cooled to 0 ℃ in an ice water bath, fuming nitric acid (4 mL) was slowly added dropwise, and the reaction solution reacted at 0 to 5 ℃ for 1 hour, with a large amount of white solid precipitated. The reaction was slowly poured into ice water (300 mL), stirred for 30 min, filtered, the filter cake washed with water (300 mL), and the solid dried to give 2-bromo-4-fluoro-5-nitrobenzoic acid 1b (10.50 g, white solid) in 80% yield. MS m/z (ESI): 261.9[ 2 ] M-1] - 。 1 H NMR(400MHz,DMSO-d 6 )δ14.00(s,1H),8.50(d,J＝8.0Hz,1H),8.17(d,J ＝10.6Hz,1H)。
Second step of
2-bromo-4-hydroxy-5-nitrobenzoic acid 1d
The compound 2-bromo-4-fluoro-5-nitrobenzoic acid 1b (10.50g, 30.33mmol) and acetohydroxamic acid 1c (6.83g, 90.99mmol) were dissolved in dimethyl sulfoxide (150 mL), potassium carbonate (20.96g, 151.65mmol) was added to the solution, the reaction was heated to 80 ℃ for 2 hours, poured into ice water (600 mL), the PH was adjusted to 4-5 with concentrated hydrochloric acid, solid precipitated, stirring was continued for 30 minutes, filtration was performed, the filter cake was washed with water (100 mL), and drying was performed on a rotary evaporator to give 2-bromo-4-hydroxy-5-nitrobenzoic acid 1d (6.90 g, pale yellow solid) with yield: 87 percent. MS m/z (ESI): 259.9[ 2 ], [ M-1 ]] - 。
The third step
2-bromo-4-hydroxy-5-nitrobenzoic acid methyl ester 1e
Dissolving 2-bromo-4-hydroxy-5-nitrobenzoic acid 1d (6.90g, 26.33mmol) in methanol (150 mL), slowly adding thionyl chloride (8 mL) dropwise, after completion of the dropwise addition, heating the reaction solution to 80 ℃ for 4 hours, cooling to room temperature, removing the solvent by rotary evaporation, and purifying the obtained residue by silica gel column chromatography (petroleum ether: ethyl acetate =2: 1) to obtain 2-bromo-4-hydroxy-5-nitrobenzoic acid methyl ester 1e (6.40 g, golden solid), yield: 88 percent. MS m/z (ESI): 273.9[ 2 ] M-1] - 。
The fourth step
2-bromo-4-hydroxy-5-aminobenzoic acid methyl ester 1f
Dissolving the compound 2-bromo-4-hydroxy-5-nitrobenzoic acid methyl ester 1e (2.00g, 7.25mmol) in 50mL tetrahydrofuran, adding 5% rhodium carbon catalyst (0.20 g) in nitrogen atmosphere, reacting the reaction solution for 17 hours in hydrogen atmosphere, filtering, and spin-drying the filtrate to obtain 2-bromo-4-hydroxy-5-aminobenzoic acid methyl ester 1f (1.78 g, brown solid), yield: 97 percent. MS m/z (ESI): 244.0[ m-1 ]] - 。
The fifth step
2-bromo-4-hydroxy-5- ((tetrahydrofuran-3-yl) amino) benzoic acid methyl ester 1h
Dissolving compound 2-bromo-4-hydroxy-5-methyl aminobenzoate 1f (1.78g, 7.01mmol) in 50mL of 1, 2-dichloroethane, adding 1g (1.21g, 14.02mmol) of tetrahydrofuran-3-one, adding acetic acid (0.84g, 14.02mmol), adding triacetoxyborohydride under ice-water bathSodium chloride (2.96g, 14.02 mmol), the reaction was stirred for an additional 2 hours, quenched into 100mL of ice water, adjusted to PH around 8 with sodium bicarbonate, extracted with dichloromethane (100 mL), the organic layer was spun dry and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1) to give methyl 2-bromo-4-hydroxy-5- ((tetrahydrofuran-3-yl) amino) benzoate 1h (1.20 g, tan solid), yield: and 47 percent. 314.0[ 2 ] M-1] - 。
The sixth step
7-bromo-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 1j
Methyl 2-bromo-4-hydroxy-5- ((tetrahydrofuran-3-yl) amino) benzoate 1h (1.20g, 3.30 mmol), 1, 2-dibromoethane 1i (3.10g, 16.50mmol), and potassium carbonate (1.82g, 13.20mmol) were dissolved in 30mL of N, N-dimethylformamide and reacted at 80 ℃ for 16 hours. After diluting with 80mL of water, extraction with ethyl acetate (50 mL), the organic layer was washed with water (50 mL × 2), and saturated brine (50 mL), the organic layer was dried by spinning, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1) to obtain 7-bromo-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 1j (0.81 g, light yellow oil), yield: 65 percent. MS m/z (ESI): 342.0 [ M +1]] + 。
Step seven
7- ((tert-Butoxycarbonyl) amino) -4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 1l
Reacting 7-bromo-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 1j (1.06g, 2.81mmol), carbamic acid tert-butyl ester 1k (0.99g, 8.43mmol), cesium carbonate (2.75 g, 8.43mmol), palladium acetate (0.03g, 0.14mmol) and 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (0.08g, 0.14mmol) were dissolved in 30mL of 1, 4-dioxane, the reaction was heated to 110 ℃ under nitrogen protection for 4 hours, the reaction was filtered, the solvent was removed by rotary evaporator, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1) to give 7- ((tert-butoxycarbonyl) amino) -4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]1l of oxazine-6-carboxylic acid methyl ester (0.91 g, tan oil) to giveRate: 71 percent. MS m/z (ESI): 379.1[ 2 ] M +1] + 。
Eighth step
2-methyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1,4] oxazino [3,2-g ] quinazolin-4-one 1m
Taking 7- ((tert-butyloxycarbonyl) amino) -4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Dissolving 1l (0.85g, 2.25mmol) of oxazine-6-carboxylic acid methyl ester in 20mL of dioxane (4M) hydrochloride solution, adding acetonitrile (3 mL), heating the reaction solution to 50 ℃ for 2 hours, removing the solvent by rotary drying under reduced pressure, adding acetonitrile (20 mL), stirring thoroughly, adding sodium carbonate (1.19g, 11.25mmol), heating the reaction solution to 90 ℃ for 3 hours, cooling to room temperature after the reaction is finished, diluting with 20mL of water, adjusting pH =7-8 with 1M diluted hydrochloric acid, concentrating to remove acetonitrile, precipitating a tan solid, filtering, and drying the filter cake under reduced pressure to obtain 2-methyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1, 4-methyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1,4]Oxazino [3,2-g]Quinazolin-4-one 1m (0.34 g, white solid), yield: and 53 percent. MS m/z (ESI): 288.1[ 2 ] M +1] + 。
The ninth step
4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazoline 1n
Taking 2-methyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1,4]Oxazino [3,2-g]Quinazolin-4-one 1m (0.40g, 1.39mmol) was dissolved in 15mL of toluene, N-diisopropylethylamine (1.08g, 8.34mmol) and phosphorus oxychloride (0.64g, 4.17mmol) were added, the reaction solution was heated to 80 ℃ for 2 hours, the solvent was removed by rotary drying under reduced pressure, silica gel was added for sample stirring, and purification by silica gel column chromatography (petroleum ether: ethyl acetate =2]Oxazino [3,2-g]Quinazoline 1n (0.32 g, tan solid), yield: 77 percent. MS m/z (ESI): 306.1[ 2 ] M +1] + 。
The tenth step
N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-4-amine 1
Taking 4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazoline 1N (30mg, 0.10mmol) and (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline 1o (61 mg,0.30 mmol) were dissolved in 3mL of ethanol, N-diisopropylethylamine (129mg, 1.00 mmol) was added, the reaction mixture was heated to 130 ℃ using a microwave to react for 2 hours, the reaction mixture was subjected to rotary drying under reduced pressure to remove the solvent, and the crude product was purified by a preparative chromatography column (separation purification method one) to give N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1, 4%]Oxazines [3,2-g]Quinazolin-4-amine 1 (8 mg, tan solid), yield: 16 percent. MS m/z (ESI): 474.1 [ M +1]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ14.00(s,1H),9.57(dd,J＝7.6Hz,3.2 Hz,1H),7.74(s,1H),6.99(s,1H),6.86-6.88(m,2H),6.76(s,1H),5.75(m,1H), 4.76-4.80(m,1H),4.35-4.43(m,2H),3.70-3.99(m,5H),3.31-3.45(m,1H),2.54(s, 3H),2.31-2.38(m,1H),1.90-1.99(m,1H),1.64(d,J＝6.8Hz,3H)。
Example 2
2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 2
Figure BDA0003026842380000311
First step of
2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 2
Taking 4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazoline 1N (70mg, 0.23mmol) and (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine 2a (61mg, 0.30mmol) were dissolved in 3mL of ethanol, N-diisopropylethylamine (149 mg, 1.15mmol) was added, the reaction solution was heated to 140 ℃ using microwave for reaction for 4 hours, the solvent was removed from the reaction solution by rotary drying under reduced pressure, and the crude product was purified by preparative chromatography (separation purification method one) to give 2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4 [ -ethyl ] methyl-1]Oxazino [3,2-g]Quinazolin-4-amine 2 (55 mg, yellow solid), yield: 51 percent. MS m/z (ESI): 473.6[M+1] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.22(s,1H),8.05(d,J＝6.8Hz, 1H),7.76(d,J＝7.6Hz,1H),7.51-7.53(m,2H),7.34(t,J＝7.6Hz,1H),6.79(s, 1H),5.71-5.75(m,1H),4.84-4.88(m,1H),4.25-4.33(m,2H),3.96-3.99(m,1H), 3.83-3.89(m,2H),3.72-3.78(m,1H),3.25-3.37(m,2H),2.63(s,3H),2.33-2.36(m, 1H),2.24(d,J＝1.6Hz,3H),1.90-1.96(m,1H),1.56(d,J＝7.2Hz,3H)。
example 3
N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 3
Figure BDA0003026842380000321
Figure BDA0003026842380000331
First step of
N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 3
Taking 4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazoline 1N (30mg, 0.10mmol) and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 3a (47mg, 0.25mmol) were dissolved in 3mL of ethanol, N-diisopropylethylamine (65 mg, 0.50mmol) was added, the reaction mixture was heated to 140 ℃ using a microwave and reacted for 4 hours, the reaction mixture was spin-dried under reduced pressure to remove the solvent, and the crude product was purified by preparative chromatography (separation purification method one) to give N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]]Oxazino [3,2-g]Quinazolin-4-amine 3 (9 mg, yellow solid), yield: 20 percent. MS m/z (ESI): 459.1[ 2 ] M +1] + 。 1 H NMR(400MHz,DMSO-d 6 )δ14.03(s,1H),9.68(d,J＝7.2Hz, 1H),7.77(s,1H),7.73(t,J＝7.6Hz,1H),7.56(t,J＝6.8Hz,1H),7.35(d,J＝7.6 Hz,1H),7.24(t,J＝54.4Hz,1H),6.97(s,1H),5.92-5.96(m,1H),4.80-4.81(m, 1H),4.38-4.39(m,2H),3.95-4.00(m,1H),3.82-3.92(m,2H),3.74(dd,J＝15.2Hz, 8.4Hz,1H),3.33-3.38(m,2H),2.49(s,3H),2.33-2.38(m,1H),1.91-1.99(m,1H), 1.70(d,J＝6.8Hz,3H)。
Example 4
N- ((R) -1- (3- (trifluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 4
Figure BDA0003026842380000332
Figure BDA0003026842380000341
First step of
N- ((R) -1- (3- (trifluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 4
Taking 4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazoline 1N (30mg, 0.10mmol) and (R) -1- (3- (trifluoromethyl) -2-fluorophenyl) ethane-1-amine 4a (41mg, 0.20mmol) were dissolved in 3mL of ethanol, N-diisopropylethylamine (65 mg,0.50 mmol) was added, the reaction mixture was heated to 140 ℃ using microwaves and reacted for 4 hours, the reaction mixture was spin-dried under reduced pressure to remove the solvent, and the crude product was purified by preparative chromatography (separation purification method one) to give N- ((R) -1- (3- (trifluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]]Oxazino [3,2-g]Quinazolin-4-amine 4 (6 mg, yellow solid), yield: 13 percent. MS m/z (ESI): 477.1 [ M +1]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ14.04(s,1H),9.72(d,J＝6.8Hz,1H), 7.87(t,J＝6.8Hz,1H),7.77(s,1H),7.71(t,J＝7.2Hz,1H),7.43(t,J＝7.6Hz, 1H),6.97(s,1H),,5.89-5.93(m,1H),4.80-4.81(m,1H),4.38-4.39(m,2H), 3.95-4.01(m,1H),3.82-3.93(m,2H),3.74(dd,J＝15.6Hz,J＝8.4Hz,1H), 3.33-3.38(m,2H),2.48(d,J＝1.2Hz,3H),2.33-2.40(m,1H),1.91-1.97(m,1H), 1.72(d,J＝6.8Hz,3H)。
Example 5
4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1,4] oxazino [3,2-g ] quinazolin-7 (8H) -one 5
Figure BDA0003026842380000351
First step of
7-bromo-3-oxo-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 5b
Methyl 2-bromo-4-hydroxy-5- ((tetrahydrofuran-3-yl) amino) benzoate (1 h (300mg, 0.95mmol) and triethylamine (961mg, 9.50mmol) were dissolved in 15mL of dichloromethane, chloroacetyl chloride 5a (322mg, 2.85mmol) was added dropwise, and the reaction mixture was reacted at 25 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2)][1,4]Oxazine-6-carboxylic acid methyl ester 5b (220 mg, colorless oil), yield: 62 percent. MS m/z (ESI): 356.0[ M ] +1] + 。 1 H NMR(400MHz, DMSO-d 6 )δ7.88(s,1H),7.41(s,1H),5.41-5.45(m,1H),4.72(s,2H),4.14-4.20 (m,1H),3.87-3.92(m,2H),3.84(s,3H),3.70(q,J＝8.0Hz,1H)2.09-2.21(m, 2H)。
Second step of
2-methyl-6- (tetrahydrofuran-3-yl) -3, 6-dihydro-4H- [1,4] oxazino [3,2-g ] quinazoline-4, 7 (8H) -dione 5d
Reacting 7-bromo-3-oxo-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 5b (200mg, 0.56mmol), acetamidine hydrochloride 5c (159mg, 1.68mmol), palladium acetate (25 mg,0.11 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65mg, 0.11mmol) and cesium carbonate (912mg, 2.80mmol) were dissolved in 10mL of 1, 4-dioxane, the reaction mixture was heated to 110 ℃ under nitrogen protection for 4 hours, the reaction mixture was diluted with 10mL of water, the PH was adjusted to 4-5 with 1M HCl, extraction was performed with ethyl acetate (30 mL × 2), the organic layer was washed with saturated saline (20 mL), the solvent was removed by rotary evaporator of the organic layer, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol =202-methyl-6- (tetrahydrofuran-3-yl) -3, 6-dihydro-4H- [1,4]Oxazino [3,2-g]Quinazoline-4, 7 (8H) -dione 5d (85 mg, light yellow solid), yield: 49 percent. MS m/z (ESI): 302.1[ 2 ] M +1] + 。
The third step
4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1,4] oxazino [3,2-g ] quinazolin-7 (8H) -one 5e 2-methyl-6- (tetrahydrofuran-3-yl) -3, 6-dihydro-4H- [1,4] oxazino [3,2-g ] quinazoline-4, 7 (8H) -dione 5d (80mg, 0.26mmol) was dissolved in 10mL of toluene, N-diisopropylethylamine (336mg, 2.60mmol) and phosphorus oxychloride (199mg, 1.30mmol) were added, the reaction was heated to 80 ℃ for 2 hours, the solvent was removed under reduced pressure, silica gel was added for stirring, and the mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3) to give 4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1,4] oxazino [3,2-g ] quinazolin-7 (8H) -one 5e as a yellow solid: and 78 percent. MS m/z (ESI): 320.0[ M +1] +.
The fourth step
4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1,4] oxazino [3,2-g ] quinazolin-7 (8H) -one 5
Taking 4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1,4]Oxazino [3,2-g]Quinazoline-7 (8H) -one 5e (30mg, 0.10 mmol) and (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline 1o (61 mg,0.30 mmol) were dissolved in 3mL ethanol, N-diisopropylethylamine (58mg, 0.45mmol) was added, the reaction mixture was heated to 140 ℃ using microwave for 2 hours, the solvent was removed by rotary drying under reduced pressure, and the crude product was purified by preparative chromatography (separation purification method one) to give 4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1, 4)]Oxazino [3,2-g]Quinazolin-7 (8H) -one 5 (6 mg, white solid), yield: 14 percent. MS m/z (ESI): 488.2[ M +1]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.90(s,1H),8.27(d,J＝2.4Hz,1H), 7.26(s,1H),6.88(d,J＝5.6Hz,2H),6.77(s,1H),5.76-5.79(m,1H),4.78-4.89(m, 3H),4.14-4.22(m,1H),4.09-4.12(m,1H),3.93-3.96(m,1H),3.84-3.89(m,1H), 2.60(s,3H),2.25-2.33(m,1H),1.97-2.03(m,1H),1.66(d,J＝6.8Hz,3H)。
Example 6
4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1,4] oxazino [3,2-g ] quinazolin-7 (8H) -one 6
Figure BDA0003026842380000371
First step of
4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1,4] oxazino [3,2-g ] quinazolin-7 (8H) -one 6
Taking 4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1,4]Oxazino [3,2-g]Quinazolin-7 (8H) -one 5e (20mg, 0.06mmol) and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine 3a (34mg, 0.18mmol) were dissolved in 3mL of 1, 4-dioxane, N-diisopropylethylamine (78mg, 0.60mmol) was added, the reaction mixture was heated to 140 ℃ with a microwave and reacted for 4 hours, the reaction mixture was spin-dried under reduced pressure to remove the solvent, and the crude product was purified by preparative chromatography (separation and purification method II) to give 4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-6- (tetrahydrofuran-3-yl) -6H- [1, 4-dioxane]Oxazino [3,2-g]Quinazolin-7 (8H) -one 6 (8 mg, white solid), yield: 28 percent. MS m/z (ESI): 473.1[ M ] +1] + 。 1 HNMR(400MHz,DMSO-d 6 )δ8.34(d,J＝5.5Hz,1H), 8.11(s,1H),7.65-7.69(m,1H),7.51(t,J＝7.2Hz,1H),7.30(t,J＝8.0Hz,1H), 7.25(t,J＝54.4Hz,1H),7.14(s,1H),5.79-5.84(m,1H),4.96-5.00(m,1H), 4.63-4.73(m,2H),4.26(dd,J＝14.8Hz,8.0Hz,1H),4.11-4.14(m,1H),3.87-3.99 (m,2H),2.33-2.44(m,2H),2.31(d,J＝1.2Hz,3H),1.64(d,J＝7.2Hz,3H)。
Example 7
N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2, 8-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 7
Figure BDA0003026842380000381
Figure BDA0003026842380000391
First step of
4-fluoro-2-nitro-5- ((tetrahydrofuran-3-yl) amino) benzoic acid methyl ester 7c
Methyl 4, 5-difluoro-2-nitrobenzoate 7a (2.0g, 9.21mmol), 3-aminotetrahydrofuran 7b (1.60g, 18.42mmol) and sodium carbonate (2.93g, 27.63mmol) were dissolved in 20mLN, N-dimethylformamide and heated to 50 ℃ for reaction for 2 hours. The reaction was cooled to room temperature, diluted with 100mL of water, extracted with ethyl acetate (100 mL), the organic layer was washed with water (100 mL × 2), washed with saturated brine (100 mL), left to stand for layering, and the organic layer was rotary evaporated under reduced pressure to give a crude product which was purified with a preparative chromatography column (petroleum ether: ethyl acetate = 3) to give methyl 4-fluoro-2-nitro-5- ((tetrahydrofuran-3-yl) amino) benzoate 7c (2.20 g, yellow solid) in yield: 84 percent. MS m/z (ESI): 285.1 [ M +1]] + 。
Second step of
Methyl 4-fluoro-5- ((2-methylallyl) (tetrahydrofuran-3-yl) amino) -2-nitrobenzoate 7e methyl 4-fluoro-2-nitro-5- ((tetrahydrofuran-3-yl) amino) benzoate 7c (1.00 g,3.52 mmol), 3-bromo-2-methylpropene 7d (1.43g, 10.56mmol), and cesium carbonate (2.29g, 7.04 mmol) were dissolved in 15mLN, N-dimethylformamide and the reaction solution was reacted at 25 ℃ for 17 hours. 80mL of water was added, the pH was adjusted to about 7 with 1M hydrochloric acid, ethyl acetate (50 mL. Times.2) was extracted, the organic layer was washed with water (50 mL. Times.2), and a saturated saline solution (50 mL) was washed, and the mixture was allowed to stand for separation, and the organic layer was dried under reduced pressure, and the obtained crude product was purified by a preparative chromatography column (petroleum ether: ethyl acetate = 3) to give methyl 4-fluoro-5- ((2-methylallyl) (tetrahydrofuran-3-yl) amino) -2-nitrobenzoate 7e (1.20 g, yellow oil), yield: 98 percent. MS m/z (ESI): 339.1[ M ] +1] + 。 1 H NMR(400MHz, CDCl 3 )δ7.56(d,J＝14.0Hz,1H),6.85(d,J＝8.4Hz,1H),4.93(d,J＝1.2Hz, 1H),4.79(s,1H),4.61-4.63(m,1H),4.03-4.08(m,1H),3.86-3.93(m,6H), 3.78-3.83(m,1H),3.66-3.72(m,1H),2.30-2.36(m,1H),1.99-2.05(m,1H),1.71(s, 3H)。
The third step
4-fluoro-2-nitro-5- ((2-oxopropanyl) (tetrahydrofuran-3-yl) amino) phenylmethyl ester 7f
Methyl 4-fluoro-5- ((2-methylallyl) (tetrahydrofuran-3-yl) amino) -2-nitrobenzoate 7e (1.20g, 3.48mmol) was dissolved in 20mL of tetrahydrofuran and 20mL of water, potassium osmate dihydrate (0.06g, 0.17mmol), N-methylmorpholine oxide (0.80g, 6.96mmol) and sodium periodate (2.98g, 13.92mmol) were added under an ice-water bath, and the reaction was slowly warmed to room temperature and reacted at 25 ℃ for 17 hours. Extraction with ethyl acetate (50 mL), washing of the organic layer with water (50 mL × 2), washing with saturated brine (50 mL), standing for separation, and spin-drying of the organic layer under reduced pressure gave methyl 4-fluoro-2-nitro-5- ((2-oxopropyl) (tetrahydrofuran-3-yl) amino) benzoate 7f (1.15 g, tan oil), yield: 87 percent. MS m/z (ESI): 341.1[ 2 ] M +1] + 。
The fourth step
4-fluoro-5- ((2-hydroxypropyl) (tetrahydrofuran-3-yl) amino) -2-nitrobenzoic acid methyl ester 7g
Methyl 4-fluoro-2-nitro-5- ((2-oxopropyl) (tetrahydrofuran-3-yl) amino) benzoate 7f (1.15g, 3.01) was dissolved in 20mL of methanol, and sodium borohydride (0.11g, 3.01 mmol) was added thereto in an ice-water bath, followed by reaction of the reaction mixture at 0 ℃ for 1 hour. Diluting with 100mL of water, extracting with ethyl acetate (100 mL), washing the organic layer with saturated brine (100 mL), standing for separation, and spin-drying the organic layer under reduced pressure to give a crude product, which was purified by preparative chromatography (petroleum ether: ethyl acetate = 2) to give 7g (0.90 g, golden yellow oil) of methyl 4-fluoro-5- ((2-hydroxypropyl) (tetrahydrofuran-3-yl) amino) -2-nitrobenzoate, yield: 87 percent. MS m/z (ESI): 343.1[ M ] +1] + 。
The fifth step
2-methyl-7-nitro-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 7H
7g (0.50 g, 1.46mmol) of 4-fluoro-5- ((2-hydroxypropyl) (tetrahydrofuran-3-yl) amino) -2-nitrobenzoic acid methyl ester was dissolved in 10mL N, N-dimethylformamide, and sodium hydrogen (0.18 g, 7.30 mmol) was added in an ice-water bath to react the reaction mixture at 20 ℃ for 1 hour. Slowly pouring into 100mL of ice water to quench the reaction, adjusting pH to 6-7 with 1M hydrochloric acid, extracting with ethyl acetate (100 mL), and collecting the organic layerAfter washing with brine (100 mL), the mixture was allowed to stand for separation, and the crude product obtained by spin-drying the organic layer under reduced pressure was dissolved in 10mL LN, N-dimethylformamide, and methyl iodide (0.50g, 3.52mmol) and potassium carbonate (0.50g, 3.62 mmol) were added to stir the reaction mixture at 20 ℃ for 2 hours. After diluting with 100mL of ice water and adjusting the PH to 6 to 7 with 1M hydrochloric acid, ethyl acetate (100 mL) was extracted, the organic layer was washed with water (100 mL × 2), with saturated brine (100 mL), and the mixture was allowed to stand for separation, and the crude product obtained from the organic layer was dried by spin-drying under reduced pressure and purified by preparative chromatography (petroleum ether: ethyl acetate = 3) to give 2-methyl-7-nitro-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 7h (0.36 g, tan oil), yield: and 72 percent. MS m/z (ESI): 323.1[ M ] +1] + 。 1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝ 7.6Hz,1H),6.79(d,J＝5.6Hz,1H),4.49-4.55(m,1H),3.95-4.23(m,3H),3.89(s, 3H),3.74-3.82(m,2H),3.46-3.52(m,1H),2.98-3.17(m,1H),2.34-2.39(m,1H), 1.92-1.97(m,1H),1.40(dd,J＝6.4Hz,4.8Hz,3H)。
The sixth step
7-amino-2-methyl-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 7i
Taking 2-methyl-7-nitro-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 7h (0.36g, 1.12mmol) was dissolved in 10mL of methanol, 10% palladium on carbon (0.023g, 0.11mmol) was added under nitrogen protection, the reaction system was replaced with hydrogen gas 3 times, and the reaction was carried out at 20 ℃ for 17 hours under hydrogen atmosphere. Filtering the reaction solution, and performing rotary drying on the filtrate under reduced pressure to obtain 7-amino-2-methyl-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b)][1,4]Oxazine-6-carboxylic acid methyl ester 7i (0.32 g, tan solid). Yield: 94 percent. MS m/z (ESI): 293.1[ 2 ] M +1] + 。
Seventh step
2, 8-dimethyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1,4] oxazino [3,2-g ] quinazolin-4-one 7j
Taking 7-amino-2-methyl-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Dissolving oxazine-6-carboxylic acid methyl ester 7i (0.32g, 1.09mmol) in 15mL dioxane (4M) hydrochloride solution, adding acetonitrile (3 mL), heating the reaction solution to 50 deg.C, reacting for 2 hr, and removing by rotary drying under reduced pressureRemoving the solvent, adding acetonitrile (20 mL), stirring thoroughly, adding sodium carbonate (562mg, 5.30mmol), heating the reaction solution to 90 ℃ for 3 hours, after the reaction is completed, cooling to room temperature, adding 20mL of water for dilution, adjusting the pH to =7-8 with 1M diluted hydrochloric acid, concentrating to remove acetonitrile, extracting with ethyl acetate (50 mL × 2), standing for layering, spin-drying the organic layer under reduced pressure, and purifying the obtained crude product with a preparative chromatography column (dichloromethane: methanol = 100) to obtain 2, 8-dimethyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1,4]Oxazino [3,2-g]Quinazolin-4-one 7j (0.21 g, light yellow solid), yield: and 64 percent. MS m/z (ESI): 302.1[ 2 ] M +1] + 。
Eighth step
4-chloro-2, 8-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazoline 7k is 2, 8-dimethyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1, 4%]Oxazino [3,2-g]Quinazolin-4-one 7j (200mg, 0.64mmol) was dissolved in 10mL of toluene, N-diisopropylethylamine (827mg, 6.40mmol) and phosphorus oxychloride (294mg, 1.92mmol) were added, the reaction solution was heated to 80 ℃ for 2 hours, the solvent was removed by rotary drying under reduced pressure, silica gel was added for stirring, and purification by silica gel column chromatography (petroleum ether: ethyl acetate = 3)]Oxazino [3,2-g]Quinazoline 7k (120 mg, yellow solid), yield: 57 percent. MS m/z (ESI): 320.1[ 2 ] M +1] + 。 1 H NMR(400MHz,CDCl 3 )δ7.28(d,J＝6.8Hz, 1H),7.17(d,J＝4.8Hz,1H),4.55-4.66(m,1H),4.35-4.46(m,1H),4.05-4.14(m, 2H),3.81-3.91(m,2H),3.45-3.54(m,1H),2.97-3.19(m,1H),2.77(s,3H), 2.40-2.50(m,1H),1.97-2.10(m,1H),1.44-1.47(dd,J＝6.4Hz,J＝4.8Hz,3H)。
The ninth step
N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2, 8-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 7
Taking 4-chloro-2, 8-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazoline 7k (35mg, 0.11mmol) and (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline 1o (56 mg,0.28 mmol) were dissolved in 1 mLN-methylpyrrolidinone and N, N-diisopropylethylamine (14)2mg,1.10 mmol), heating the reaction solution to 140 ℃ by microwave for reaction for 3 hours, purifying the reaction solution by a preparative chromatography column (first separation and purification method) to obtain N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2, 8-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazolin-4-amine 7 (37 mg, tan solid), yield: and 69 percent. MS m/z (ESI): 488.1[ 2 ], [ M ] +1] + 。 1 H NMR(400MHz,DMSO-d 6 )δ13.88(s,1H),9.53(t,J＝7.6Hz,1H),7.72(d,J ＝2.8Hz,1H),6.95-6.96(m,1H),6.84-6.88(m,2H),6.75(s,1H),5.75(t,J＝7.2 Hz,1H),4.77(m,1H),4.41-4.45(m,1H),3.70-3.98(m,4H),3.49-3.55(m,1H), 2.93-3.08(m,1H),2.54(s,3H),2.30-2.43(m,1H),1.98-2.04(m,1H),1.64(d,J＝ 6.8Hz,3H),1.37(dd,J＝6.4Hz,1.6Hz,3H)。
Example 8
2, 8-dimethyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 8
Figure BDA0003026842380000431
Figure BDA0003026842380000441
First step of
2, 8-dimethyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 8
Taking 4-chloro-2, 8-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazoline 7k (35mg, 0.11mmol) and ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethan-1-amine 2a (67mg, 0.33mmol) were dissolved in 1mL of N-methylpyrrolidone, N-diisopropylethylamine (142mg, 1.10mmol) were added, the reaction mixture was heated to 140 ℃ using a microwave and reacted for 4 hours, and the reaction mixture was purified by preparative chromatography (separation purification method one) to give 2, 8-dimethyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1, 4-methyl-3- (trifluoromethyl) phenyl) ethyl ] -6, 1-1, 4]Oxazino[3,2-g]Quinazolin-4-amine 8 (29 mg, white solid), yield: 53 percent. MS m/z (ESI): 487.2[ M ] +1] + 。 1 H NMR(400MHz,DMSO-d 6 )δ14.04(s,1H),9.78(m,1H), 7.78-7.80(m,2H),7.60(d,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,1H),6.96(d,J＝2.8 Hz,1H),5.85-5.88(m,1H),4.83(s,1H),4.39-4.47(m,1H),3.69-4.02(m,4H), 3.50-3.55(m,1H),2.94-3.08(m,1H),2.60(s,3H),2.48(s,3H),2.32–2.42(m, 1H),1.83-2.03(m,1H),1.65(d,J＝7.2Hz,3H),1.37(dd,J＝6.0,2.8Hz,3H)。
Example 9
N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2, 7-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-4-amine 9
Figure BDA0003026842380000442
Figure BDA0003026842380000451
First step of
2-bromo-4- (2-oxopropoxy) -5- ((tetrahydrofuran-3-yl) amino) benzoic acid methyl ester 9b
Methyl 2-bromo-4-hydroxy-5- ((tetrahydrofuran-3-yl) amino) benzoate 1h (1.30g, 4.01mmol) and triethylamine (961mg, 9.50mmol) were dissolved in 30mL of acetonitrile, bromoacetone 9a (1.10 g, 8.02 mmol) was added, and the reaction mixture was reacted at 25 ℃ for 17 hours. The reaction was directly spin-dried under reduced pressure and the resulting crude product was purified by preparative chromatography (petroleum ether: ethyl acetate = 3) to give methyl 2-bromo-4- (2-oxopropoxy) -5- ((tetrahydrofuran-3-yl) amino) benzoate 9b (1.20 g, colorless oil) in: and 76 percent. MS m/z (ESI): 372.0[ M ] +1] + 。
Second step of
7-bromo-3-methyl-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 9c
Methyl 2-bromo-4- (2-oxopropoxy) -5- ((tetrahydrofuran-3-yl) amino) benzoate 9b (1.20 g, 3.05mmol) was dissolved in 20mL of methanol, and vinegar was addedThe reaction mixture was reacted with an acid (0.37g, 6.10 mmol) and sodium cyanoborohydride (0.38g, 6.10 mmol) at 25 ℃ for 4 hours. The reaction was quenched by the addition of 10mL of a saturated solution of sodium hydrogencarbonate, extracted with ethyl acetate (100 mL), the organic layer was washed with saturated brine (100 mL), allowed to stand for separation, and the organic layer was dried under reduced pressure, and the resulting crude product was purified by preparative chromatography (petroleum ether: ethyl acetate = 3) to give 7-bromo-3-methyl-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 9c (0.91 g, colorless oil), yield: 81 percent. MS m/z (ESI): 356.0[ M ] +1] + 。 1 HNMR(400MHz,CDCl 3 )δ7.27(d,J＝15.6Hz,1H),7.09 (d,J＝3.6Hz,1H),4.28-4.31(m,1H),3.96-4.14(m,4H),3.89(s,3H),3.78-3.87 (m,2H),3.68-3.73(m,1H),2.19-2.37(m,1H),2.02-2.11(m,1H),1.17(t,J＝7.6, 3H)。
The third step
7- ((tert-Butoxycarbonyl) amino) 3-methyl-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 9d
Reacting 7-bromo-3-methyl-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Methyl oxazine-6-carboxylate 9c (0.91g, 2.47mmol), tert-butyl carbamate 1k (0.87g, 7.41mmol), cesium carbonate (2.01g, 6.18mmol), palladium acetate (0.06g, 0.25mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.14g, 0.25mmol) were dissolved in 20mL of 1, 4-dioxane, the reaction liquid was heated to 110 ℃ under nitrogen protection for 4 hours, the reaction liquid was filtered, the solvent was removed by rotary evaporator, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1) to give 7- ((tert-butoxycarbonyl) amino) 3-methyl-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 9d (0.72 g, tan oil), yield: 72 percent. MS m/z (ESI): 354.0 2[ M-56 ] +1] + 。
The fourth step
2, 7-dimethyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1,4] oxazino [3,2-g ] quinazolin-4-one 9e
Taking 7- ((tert-butyloxycarbonyl) amino) 3-methyl-4- (tetrahydrofuran-3-yl) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 9d (0.72g, 1.77mmol) was dissolved in 20mL dioxane (4M) hydrochloride solution, andadding acetonitrile (5 mL), heating the reaction solution to 50 ℃ for 2 hours, removing the solvent by rotary drying under reduced pressure, adding acetonitrile (20 mL), stirring fully, adding sodium carbonate (0.94g, 8.85mmol), heating the reaction solution to 90 ℃ for 3 hours, cooling to room temperature after the reaction is finished, adding 20mL of water for dilution, adjusting the pH to 7-8 with 1M diluted hydrochloric acid, concentrating to remove the acetonitrile, extracting with ethyl acetate (50 mL × 2), washing the organic layer with saturated saline (50 mL), standing for layering, rotary drying the organic layer under reduced pressure, and purifying the obtained crude product by a preparative chromatographic column (dichloromethane: methanol = 100) to obtain 2, 7-dimethyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1,4]Oxazino [3,2-g]Quinazolin-4-one 9e (0.37 g, white solid), yield: and 69 percent. MS m/z (ESI): 302.1[ 2 ] M +1] + 。
The fifth step
4-chloro-2, 7-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazoline 9f
Taking 2, 7-dimethyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydrofuran-4H- [1,4]Oxazino [3,2-g]Quinazolin-4-one 9e (0.20g, 0.66mmol) was dissolved in 10mL of toluene, N-diisopropylethylamine (0.85g, 6.60mmol) and phosphorus oxychloride (0.30g, 1.98mmol) were added, the reaction solution was heated to 80 ℃ for 2 hours, the solvent was removed by spin-drying under reduced pressure, silica gel was added for sample stirring, and purification by silica gel column chromatography (petroleum ether: ethyl acetate =3]Oxazino [3,2-g]Quinazoline 9f (0.03 g, yellow solid), yield: 14 percent. MS m/z (ESI): 320.1[ deg. ] M +1] + 。
The sixth step
N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2, 7-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-4-amine 9
Taking 4-chloro-2, 7-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazoline 9f (30mg, 0.10mmol) and (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline 1o (55 mg, 0.27 mmol) were dissolved in 1 mLN-methylpyrrolidone, N-diisopropylethylamine (116 mg, 0.90 mmol) was added, the reaction mixture was heated to 140 ℃ using a microwave and reacted for 4 hours, and the reaction mixture was purified by preparative chromatography (separation purification method one)) To give N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2, 7-dimethyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazolin-4-amine 9 (16.5 mg, light yellow solid), yield: 37 percent. MS m/z (ESI): 488.2[ 2 ] M +1] + 。 1 H NMR(400MHz,DMSO-d 6 )δ13.88(s,1H),9.53(t,J＝4.4Hz,1H),7.59-7.64 (m,1H),7.03(m,1H),6.84-6.88(m,2H),6.76(s,1H),5.76(t,J＝7.2Hz,1H), 4.56-4.61(m,1H),4.31-4.34(m,1H),3.74-4.12(m,6H),2.54(s,3H),2.30-2.43(m, 1H),1.95-2.04(m,1H),1.64(d,J＝7.2Hz,3H),1.13(t,J＝5.6Hz,3H)。
Example 10
N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H-pyrrolo [2,3-g ] quinazolin-4-amine 10
Figure BDA0003026842380000481
First step of
Indoline 6-carboxylic acid methyl ester 10b
Methyl 1H-indole-6-carboxylate 10a (5.0 g,28.0 mmol) and acetic acid (50 mL) were added to the reactor and dissolved with stirring. Controlling the temperature by using an ice water bath, adding sodium cyanoborohydride (5.3 g, 84.0 mmol) in batches at the internal temperature of 10-20 ℃, and obviously discharging gas. After the addition is finished, the temperature is naturally raised, and the stirring is continued for 1 to 2 hours at the temperature of between 20 and 25 ℃. The reaction was concentrated to dryness under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with saturated aqueous sodium bicarbonate (50 mL), and the organic phases were dried and concentrated to dryness under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3) to give indoline 6-carboxylic acid methyl ester 10b (3.9 g, off-white solid) in yield: 76.1 percent. MS m/z (ESI): 178.1[ 2 ] M +1] + 。
Second step of
1- (tetrahydrofuran-3-yl) indoline-6-carboxylic acid methyl ester 10c
Indoline 6-carboxylic acid methyl ester 10b (3.9g, 19.5mmol), tetrahydrofuran-3-one 1g (3.4 g, 39.0 mmol), methanol (40 mL) and acetic acid (1 mL) were added to the reactor in this order, and the mixture was stirred to dissolveAnd (5) solving. Controlling the temperature by using an ice water bath, adding sodium triacetoxyborohydride (12.5g, 58.5mmol) in batches at the internal temperature of 10-20 ℃, and obviously discharging gas. After the addition is finished, the temperature is naturally raised, and the stirring is continued for 16 to 18 hours at the temperature of between 20 and 25 ℃. The reaction was concentrated to dryness under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with water (50 mL), and the organic phases were dried and concentrated to dryness under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2) to give methyl 1- (tetrahydrofuran-3-yl) indoline-6-carboxylate 10c (3.9 g, oil) in yield: 50 percent. MS m/z (ESI): 248.1[ 2 ] M +1] + 。
The third step
5-bromo-1- (tetrahydrofuran-3-yl) indoline-6-carboxylic acid methyl ester 10d
Methyl 5-bromo-1- (tetrahydrofuran-3-yl) indoline-6-carboxylate 10c (2.5g, 9.9 mmol) and N, N-dimethylformamide (25 mL) were added to the reactor and the solution was stirred. The temperature was controlled by an ice-water bath, and N-bromosuccinimide (2.0 g,10.9 mmol) was added in portions at an internal temperature of 5 to 10 ℃. After the addition is finished, the temperature is naturally raised, and the stirring is continued for 1 to 2 hours at the temperature of between 20 and 25 ℃. Water (100 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with saturated aqueous sodium sulfite (50 mL), the organic phases were dried and concentrated to dryness under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3) to give methyl 5-bromo-1- (tetrahydrofuran-3-yl) indoline-6-carboxylate 10d (2.6 g, oil), yield: 76 percent. MS m/z (ESI): 326.0[ 2 ] M +1] + 。
The fourth step
2-methyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydro-4H-pyrrolo [2,3-g ] quinazolin-4-one 10e
Methyl 5-bromo-1- (tetrahydrofuran-3-yl) indoline-6-carboxylate 10d (1.00g, 3.04mmol), acetamidine hydrochloride 5c (0.47g, 4.56mmol), cuprous iodide (0.06g, 0.30mmol), L-proline (0.07g, 0.61mmol), cesium carbonate (0.99g, 3.04mmol) and N, N-dimethylformamide (10 mL) were added to the reactor under nitrogen. The temperature of the reaction is raised to the internal temperature of 110 to 120 ℃, and the temperature is kept and the stirring is carried out for 30 to 32 hours. Water (40 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL. Times.3),the combined organic phases were washed with water (20 mL), dried and concentrated to dryness under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100) to give 2-methyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydro-4H-pyrrolo [2,3-g]Quinazolin-4-one 10e (0.28 g, brown solid), yield: 34 percent. MS m/z (ESI): 272.1[ 2 ] M +1] + 。
The fifth step
4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H-pyrrolo [2,3-g ] quinazoline 10f
2-methyl-6- (tetrahydrofuran-3-yl) -3,6,7, 8-tetrahydro-4H-pyrrolo [2,3-g]Quinazolin-4-one 10e (150mg, 0.49mmol), phosphorus oxychloride (225mg, 1.47mmol), N-diisopropylethylamine (316mg, 2.45mmol) and toluene (2 mL) were charged to the reactor under nitrogen. The temperature of the reaction is raised to 70 to 80 ℃ of the internal temperature, and the temperature is kept and the stirring is carried out for 2 to 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1) to give 4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H-pyrrolo [2,3-g]Quinazoline 10f (70 mg, yellow solid), yield: 44 percent. MS m/z (ESI): 290.1 2[ 2 ] M +1] + 。
The sixth step
N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H-pyrrolo [2,3-g ] quinazolin-4-amine 10
4-chloro-2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H-pyrrolo [2,3-g]Quinazoline 10f (20mg, 0.07mmol), (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline, 1o (21 mg, 0.11mmol), N-diisopropylethylamine (18mg, 0.14mmol), and absolute ethanol (2 mL) were added to the microwave tube. The reaction mixture was allowed to react for 5h at 130 ℃ under microwave conditions. The reaction solution is sent to the preparation separation (separation and purification method I), and N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (tetrahydrofuran-3-yl) -7, 8-dihydro-6H-pyrrolo [2, 3-g) is obtained after freeze-drying]Quinazolin-4-amine 10 (11 mg, off-white solid), yield: 34 percent. MS m/z (ESI): 458.2[ M ] +1] + 。 1 H NMR(400MHz,DMSO-d 6 )δ14.22(s,1H),9.46(d,J＝6.8Hz,1H),7.42(d,J＝5.2Hz,2H),6.89(s,1H),6.86(s,1H),6.75(s,1H),5.65–5.73(m,1H),4.45-4.47 (m,1H),3.71–3.96(m,4H),3.55–3.67(m,2H),3.18(t,J＝7.6Hz,2H),2.55(s, 3H),2.15–2.33(m,1H),1.94–2.03(m,1H),1.63(d,J＝7.2Hz,3H)。
Example 11
1- (3- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidin-1-yl) ethyl-1-one 11
Figure BDA0003026842380000511
First step of
Benzyl 3- ((4-bromo-2-hydroxy-5- (methoxycarbonyl) phenyl) amino) pyrrolidine-1-carboxylate 11b
The compound methyl 2-bromo-4-hydroxy-5-aminobenzoate 1f (1.8g, 7.35mmol) was dissolved in 50mL of 1, 2-dichloroethane, phenyl N-benzyloxycarbonyl-3-pyrrolidone 11a (3.22g, 14.69mmol) was added, acetic acid (0.88g, 14.69mmol) was added, sodium triacetoxyborohydride (3.11 g,14.69 mmol) was added under ice-water bath, the reaction solution was stirred for 2 hours, poured into 100mL of ice-water to quench, PH was adjusted to about 8 with sodium bicarbonate, dichloromethane was extracted (100 mL), the organic layer was spin-dried, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1) to give benzyl 3- ((4-bromo-2-hydroxy-5- (methoxycarbonyl) phenyl) amino) pyrrolidine-1-carboxylate 11b (3.0 g, brown solid) yield: 91 percent. MS m/z (ESI): 449.0[ M ] +1] + 。
Second step of
4- (1- ((benzyloxy) carbonyl) pyrrolidin-3-yl) -7-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 11c
Benzyl 3- ((4-bromo-2-hydroxy-5- (methoxycarbonyl) phenyl) amino) pyrrolidine-1-carboxylate 11b (3.0 g, 6.70 mmol), 1, 2-dibromoethane 1i (6.23g, 33.48mmol) and potassium carbonate (3.70g, 26.80 mmol) were dissolved in 60mL of N, N-dimethylformamide and heated to 80 ℃ for 16 hours. Diluting with 160mL of water, extracting with ethyl acetate (100 mL), washing the organic layer with water (100 mL. Times.2), washing with saturated brine (100 mL), and spin-drying the organic layer to obtain a residuePurification by silica gel column chromatography (petroleum ether: ethyl acetate = 1) afforded 4- (1- ((benzyloxy) carbonyl) pyrrolidin-3-yl) -7-bromo-3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 11c (2.3 g, light yellow oil), yield: 73 percent. MS m/z (ESI): 475.1[ 2 ] M +1] + 。
The third step
4- (1- ((benzyloxy) carbonyl) pyrrolidin-3-yl) -7- ((tert-butoxycarbonyl) amino) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid methyl ester 11d
Reacting 4- (1- ((benzyloxy) carbonyl) pyrrolidin-3-yl) -7-bromo-3, 4-dihydro-2H-benzo [ b][1,4]Methyl oxazine-6-carboxylate 11c (2.3g, 4.85mmol), tert-butyl carbamate 1k (1.70g, 14.56mmol), cesium carbonate (4.73g, 14.56mmol), palladium acetate (0.06g, 0.24mmol) and 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (0.14g, 0.24mmol) were dissolved in 40mL 1, 4-dioxane, the reaction was heated to 110 ℃ under nitrogen for 4 hours, the reaction was filtered, the solvent was removed by rotary evaporator, the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1) to give 4- (1- ((benzyloxy) pyrrolidin-3-yl) -7- ((tert-butoxycarbonyl) amino) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-6-carboxylic acid methyl ester 11d (1.2 g, tan oil), yield: 48 percent. MS m/z (ESI): 512.1[ 2 ] M +1] + 。
The fourth step
Benzyl 3- (2-methyl-4-one-3, 4,7, 8-tetrahydrofuran-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidine-1-carboxylate 11e
Taking 4- (1- ((benzyloxy) carbonyl) pyrrolidine-3-yl) -7- ((tert-butoxycarbonyl) amino) -3, 4-dihydro-2H-benzo [ b)][1,4]Dissolving oxazine-6-carboxylic acid methyl ester 11d (1.2 g, 2.35mmol) in 20mL dioxane (4M) hydrochloride solution, adding acetonitrile (3 mL), heating the reaction solution to 50 ℃ for 2 hours, removing the solvent by rotary drying under reduced pressure, adding acetonitrile (20 mL), stirring thoroughly, adding sodium carbonate (1.19g, 11.75 mmol), heating the reaction solution to 90 ℃ for 3 hours, cooling to room temperature after the reaction is finished, diluting with 20mL water, adjusting pH =7-8 with 1M dilute hydrochloric acid, concentrating to remove acetonitrile, precipitating a tan solid, filtering, and drying the filter cake under reduced pressure to obtain 3- (2-methyl-4-ketone-3, 4,7, 8-tetrahydrofuran-6H- [ 1-methyl-4-one-3, 4,7, 8-tetrahydrofuran-6H- [1,4]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidine-1-carboxylic acid benzyl ester 11e (0.63 g, white solid), yield: and 64 percent. MS m/z (ESI): 421.1[ 2 ] M +1] + 。
The fifth step
Benzyl 3- (4-chloro-2-methyl-7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidine-1-carboxylate 11f
Taking phenyl 3- (2-methyl-4-ketone-3, 4,7, 8-tetrahydrofuran-6H- [1,4]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidine-1-carboxylic acid methyl ester 11e (0.63g, 1.50mmol) was dissolved in 15mL of toluene, N-diisopropylethylamine (1.16g, 9.0 mmol) and phosphorus oxychloride (0.68g, 4.5 mmol) were added, the reaction solution was heated to 80 ℃ for 2 hours, the solvent was removed by spin-drying under reduced pressure, silica gel was added for sample stirring, and purification by silica gel column chromatography (petroleum ether: ethyl acetate =2: 1) To obtain 3- (4-chloro-2-methyl-7, 8-dihydro-6H- [1, 4)]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidine-1-carboxylic acid benzyl ester 11f (0.38 g, tan solid), yield: 58 percent. MS m/z (ESI): 439.0[ M ] +1] + 。
The sixth step
Benzyl 3- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidine-1-carboxylate 11g
Taking 3- (4-chloro-2-methyl-7, 8-dihydro-6H- [1, 4)]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidine-1-carboxylic acid benzyl ester 11f (100mg, 0.23mmol) and (R) -3- (1-aminoethyl) -5- (trifluoromethyl) aniline 1o (93mg, 0.46mmol) were dissolved in 3mL of 1, 4-dioxane, N-diisopropylethylamine (148mg, 1.15mmol) was added, the reaction solution was heated to 140 ℃ with a microwave and reacted for 2 hours, the reaction solution was spin-dried under reduced pressure to remove the solvent, and the crude product was purified by preparative chromatography to give 3- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1, 4-)]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidine-1-carboxylic acid benzyl ester 11g (96 mg, tan solid), yield: 70 percent. MS m/z (ESI): 607.0 [ M +1]] + 。 1 H NMR(400MHz,Methanol–d 4 )δ7.64(d,J＝5.2Hz,1H),7,27-7.43 (m,5H),6.92-6.99(m,3H),6.85(s,1H),5.70-5.82(m,1H),5.09-5.18(m,2H), 4.70-4.78(m,1H),4.31-4.43(m,2H),3.59-3.86(m,2H),3.37-3.58(m,4H),2.57(s, 3H),2.20-2.29(m,2H),1.69(d,J＝7.2Hz,3H)。
Seventh step
N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyrrolidin-3-yl) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-4-amine 1lh
Reacting 3- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1, 4)]Oxazines [3,2-g]11g (96mg, 0.16 mmol) of benzyl quinazolin-6-yl) pyrrolidine-1-carboxylate was dissolved in 30mL of methanol, followed by addition of palladium on carbon (19mg, 10%), three times replacement of the reaction system with hydrogen gas, reaction of the reaction mixture under hydrogen atmosphere at room temperature for 2 hours, filtration of the reaction mixture, and removal of the solvent by rotary evaporation to give N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyrrolidin-3-yl) -7, 8-dihydro-6H- [1, 4%]Oxazines [3,2-g]Quinazolin-4-amine 1lh (64 mg, tan oil), yield: 85 percent. MS m/z (ESI): 473.1[ M ] +1] + ， 1 H NMR(400MHz,Methanol–d 4 ) δ7.71(s,1H),6.95-7.06(m,3H),6.86(s,1H),5.73-5.82(m,1H),4.93-5.07(m,1H), 4.39-4.51(m,2H),3.63-3.74(m,1H),3.52-3.62(m,1H),3.34-3.51(m,4H),2.58(d, J＝2.0Hz,3H),2.15-2.53(m,2H),1.71(d,J＝7.2Hz,3H)。
The eighth step
1- (3- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidin-1-yl) ethyl-1-one 11
Taking N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (pyrrolidine-3-yl) -7, 8-dihydro-6H- [1,4]Oxazines [3,2-g]1lh (64mg, 0.14mmol) of quinazolin-4-amine and 11i (44mg, 0.28mmol) of N-succinimidyl acetate were dissolved in 3mL of methylene chloride, the reaction mixture was reacted at room temperature for 2 hours, the solvent was removed by spin-drying the reaction mixture under reduced pressure, and the crude product was purified by preparative chromatography (first isolation and purification method) to give 1- (3- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1, 4)]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidin-1-yl) ethyl-1-one 11 (8 mg, white solid), yield: 18 percent. MS m/z (ESI): 515.0 2[ M ] +1] + 。 1 H NMR(400MHz, Methanol-d 4 )δ7.60-7.76(m,1H),6.96(m,3H),6.85(s,1H),5.76-5.79(m,1H), 4.73-4.85(m,1H),4.41(d,J＝4.4Hz,2H),3.54-3.94(m,3H),3.41-3.54(m,3H), 2.58(t,J＝2.0Hz,3H),2.33(q,J＝7.0Hz,1H),2.18-2.27(m,1H),2.09(m,3H), 1.70(dd,J＝7.2Hz,2.0Hz,3H)。
The ninth step
1- ((S) -3- (4- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-6-yl) pyrrolidin-1-yl) ethan-1-one 11-1 and 1- ((R) -3- (4- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4] oxazino [3,2-g ] quinazolin-6-yl) pyrrolidin-1-yl) ethan-1-one 11-2
The compound 1- (3- (4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1, 4)]Oxazines [3,2-g]Purification of quinazolin-6-yl) pyrrolidin-1-yl) ethyl-1-one 11 (30 mg, white solid) by preparative chromatography (separation and purification method two) gave 1- ((S) -3- (4- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazolin-6-yl) pyrrolidin-1-yl) ethan-1-one 11-1 (4 mg, white solid). MS m/z (ESI): 515.0[ M ] +1] + 。 1 H NMR(400MHz,Methanol–d 4 ) δ 7.45 (d, J =8.0Hz, 1H), 6.90-7.00 (m, 3H), 6.79 (s, 1H), 5.59-5.68 (m, 1H), 4.73-4.87 (m, 1H), 4.28-4.37 (m, 2H), 3.59-3.94 (m, 3H), 3.34-3.58 (m, 3H), 2.41 (s, 3H), 2.26-2.35 (m, 1H), 2.18-2.27 (m, 1H), 2.09 (s, 3H), 1.63 (d, J =6.8hz, 3h). And 1- ((R) -3- (4- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7, 8-dihydro-6H- [1,4]Oxazino [3,2-g]Quinazolin-6-yl) pyrrolidin-1-yl) ethan-1-one 11-2 (4 mg, white solid). MS m/z (ESI): 515.0[ M ] +1] + ， 1 H NMR(400MHz,Methanol–d 4 )δ7.46 (d,J＝8.0Hz,1H),6.90–6.99(m,3H),6.79(s,1H),5.58–5.69(m,1H),4.74–4.86 (m,1H),4.29–4.37(m,2H),3.62–3.93(m,3H),3.35–3.58(m,3H),2.41(s,3H), 2.27–2.32(m,1H),2.16–2.27(m,1H),2.09(s,3H),1.63(d,J＝6.8Hz,3H)。
Example 12
1- (3- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidin-1-yl) ethyl-1-one 12
Figure BDA0003026842380000561
First step of
Benzyl 3- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidine-1-carboxylate 12a
Taking 3- (4-chloro-2-methyl-7, 8-dihydro-6H- [1, 4)]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidine-1-carboxylic acid benzyl ester 11f (100mg, 0.23mmol) and (R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl-1-amine 2a (93mg, 0.46mmol) were dissolved in 3mL 1, 4-dioxane, N-diisopropylethylamine (148mg, 1.15mmol) was added, the reaction was heated to 140 ℃ using microwaves for 2 hours, the reaction was spin-dried under reduced pressure to remove the solvent, and the crude product was purified by preparative chromatography to give 3- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7, 8-dihydro-6H- [1,4]]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidine-1-carboxylic acid benzyl ester 12a (119 mg, tan solid), yield: 86 percent. MS m/z (ESI): 606.1 [ M +1]] + 。
Second step of
2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (pyrrolidin-3-yl) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-4-amine 12b
Reacting 3- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7, 8-dihydro-6H- [1,4]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidine-1-carboxylic acid benzyl ester 12a (119mg, 0.20 mmol) was dissolved in 3mL of methanol, palladium on carbon (24mg, 10%) was added, the reaction system was replaced three times with hydrogen, the reaction mixture was reacted at room temperature for 2 hours under a hydrogen atmosphere, the reaction mixture was filtered, and the solvent was removed by rotary evaporation to give 2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (pyrrolidin-3-yl) -7, 8-dihydro-6H- [1, 4-yl ] pyrrole]Oxazines [3,2-g]Quinazolin-4-amine 12b (84 mg, tan oil), yield: 91 percent. MS m/z (ESI): 472.1[ M ] +1] + 。
The third step
1- (3- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidin-1-yl) ethyl-1-one 12
Taking 2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (pyrrolidine-3-yl) -7, 8-dihydro-6H- [1,4]Oxazines [3,2-g]Quinazoline-4-amine 12b (40mg, 0.08mmol) and acetyl chloride 12c (8 mg, 0.10mmol) were dissolved in 2mL of tetrahydrofuran, N-diisopropylethylamine (21mg, 0.16 mmol) was added, the reaction mixture was reacted at room temperature for 1 hour, the reaction mixture was subjected to rotary drying under reduced pressure to remove the solvent, and the crude product was purified by preparative chromatography to give 1- (3- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7, 8-dihydro-6H- [1,4]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidin-1-yl) ethyl-1-one 12 (10 mg, white solid), yield: 23 percent. MS m/z (ESI): 514.0[ m ] +1] + 。 1 H NMR(400MHz, Methanol-d 4 )δ7.69(d,J＝8.0Hz,1H),7.58-7.65(m,1H),7.55(d,J＝8.0Hz,1H), 7.32(t,J＝7.6Hz,1H),6.93(d,J＝2.0Hz,1H),5.89-5.92(m,1H),4.72-4.88(m, 1H),4.37(s,2H),3.56-3.96(m,2H),3.38-3.54(m,4H),2.63(s,3H),2.45(m,3H), 2.19-2.38(m,2H),2.11(s,3H),1.67(d,J＝6.8Hz,3H)。
Example 13
1- (3- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidin-1-yl) propyl-1-one 13
Figure BDA0003026842380000581
First step of
1- (3- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7, 8-dihydro-6H- [1,4] oxazine [3,2-g ] quinazolin-6-yl) pyrrolidin-1-yl) propyl-1-one 13
Taking 2-methyl-N- ((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) -6- (pyrrolidine-3-yl) -7, 8-dihydro-6H- [1,4]Oxazines [3,2-g]Quinazolin-4-amine 12b (40mg, 0.08mmol) and propionyl chloride 13a (9 mg,0.10 mmol) were dissolved in 2mL tetrahydrofuran, N-diisopropylethylamine (21mg, 0.16 mmol) was added, the reaction mixture was reacted at room temperature for 1 hour,the reaction solution is decompressed and dried to remove the solvent, and the crude product is purified by a preparative chromatographic column to obtain the 1- (3- (2-methyl-4- (((R) -1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -7, 8-dihydro-6H- [1,4]Oxazines [3,2-g]Quinazolin-6-yl) pyrrolidin-1-yl) ethyl-1-one 13 (12 mg, white solid), yield: 26 percent. MS m/z (ESI): 528.1[ 2 ] M +1] + 。 1 H NMR(400MHz, Methanol-d 4 )δ7.65-7.79(m,2H),7.58(d,J＝7.8Hz,1H),7.34(t,J＝8.0Hz,1H), 6.94(d,J＝2.8Hz,1H),5.95-5.97(m,1H),4.70-4.88(m,1H),4.40(s,2H),3.84 (m,2H),3.52-3.70(m,2H),3.42–3.52(m,2H),2.62(s,3H),2.53(t,J＝2.0Hz, 3H),2.32-2.37(m,3H),2.15–2.30(m,1H),1.63–1.77(m,3H),1.10–1.20(m, 3H)。
Example 14
Compounds 14 to 23 were prepared by analogous methods to example 1, wherein the starting materials for each compound were prepared by analogous methods known to those skilled in the art or by commercially available methods, and analogous synthetic methods for intermediates are readily available to those skilled in the art by reference to the existing methods.
Figure BDA0003026842380000591
Figure BDA0003026842380000601
Figure BDA0003026842380000611
Figure BDA0003026842380000621
Compounds 24, 25 were prepared by analogous methods to example 11, wherein the starting materials for each compound were prepared by analogous methods known to those skilled in the art or by commercially available methods, and analogous synthetic methods for intermediates readily available to those skilled in the art by reference to the existing methods.
Figure BDA0003026842380000622
Figure BDA0003026842380000631
Example 15
1. In vitro KRas (G12C) SOS1 homogeneous time-resolved fluorescence binding assay
Since binding of SOS1 inhibitors to Ras is not subtype selective, the Ras family protein selected in this experiment is the mutation at position 12 of KRas exon 2, i.e., KRas (G12C), which accounts for approximately 85% -90% of the total mutation pattern of KRas, and is found in approximately 13-30% of lung cancer, 3-5% of colorectal cancer, and 2% of other solid tumors.
The assay measures protein-protein interactions by homogeneous time-resolved fluorescence techniques. All protein interactions occurred in 150mM sodium chloride (SIGMA, S5886), 50mM HEPES (invitrogen, 15630080), 0.05% bovine serum albumin (SIGMA, B2064). To a 384 reaction plate (Corning, CLS 4514), 0.1. Mu.l of the compound was added, and after centrifugation, 5. Mu.l of a mixture of GST-KRas (G12C) protein at a final concentration of 15nM and GTP at a final concentration of 10. Mu.M was added. Then, 5. Mu.l of a His-SOS1 protein solution having a final concentration of 2.5nM was added thereto, and the reaction was carried out at room temperature for 15 minutes. Add 10. Mu.l of premixed 100 XAb Anti-6HIS Tb cryptate Gold (cisbio, 61HI2 TLA) and 25 XMAb Anti GST-XL665 (cisbio, 61 GSTXL) test solution and react for 60 minutes at room temperature. The reaction signals were detected by a multifunctional microplate reader and the data were analyzed using GraphPad Prism data analysis software.
The experimental results are as follows:
TABLE 1 inhibitory Activity of the compounds of the present disclosure on KRas (G12C) SOS1 binding.
Compound numbering IC50(nM)
1 18.72
2 77.86
3 42.48
4 35.84
5 35.52
6 58.63
7 21.45
8 62.63
9 12.12
10 17.27
11 4.785
11g 38.29
11h 6.585
11-1 3.888
11-2 6.457
12 13.22
13 6.854
14 17.64
15 23.68
16 479
19 229.2
23 147.3
24-1 4.671
24-2 10.19
25 33.28
Experiment for 3D proliferation of H358 cells
The diluted test compounds were added to 384-well cell culture plates (Corning, LS3830-50 EA) using a nanoliter pipetting system (LABCYTE, P-0200), plated into cells, and the plates were placed at 37 ℃ and 5% CO 2 A constant temperature incubator. After incubation of the compounds with the cells for 7 days, add
Figure BDA0003026842380000651
And (3) reading a luminescence value by using an Envision multifunctional microplate reader (an optical signal is in direct proportion to the ATP amount in the system, the ATP content directly represents the number of living cells in the system), and finally obtaining the IC50 (median inhibitory concentration) of the compound by using XLFIT software and a nonlinear fitting formula.
Inhibition (%) =100 × (negative control mean-compound reading)/(negative control mean-positive control mean);
negative control DMSO-treated cells;
positive control, medium only, no cells;
table 2 inhibition of H358 cell proliferation by compounds of the disclosure.
Figure BDA0003026842380000652
Figure BDA0003026842380000661
The pharmacokinetic determination of some specific compounds of the invention is carried out using experimental conditions which are conventional in the art.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims (20)

1. A benzopyrimidine tricyclic compound shown in formula (I) or a stereoisomer and pharmaceutically acceptable salt thereof:
Figure FDA0003026842370000011
wherein
R 1 Selected from hydrogen, C 1-4 Alkyl radical, wherein said C 1-4 Alkyl is optionally substituted with one or more of the same or different halogen or hydroxy;
ring A is selected from: c 6-10 Aryl, 5-to 10-membered heteroaryl;
p represents 1,2 or 3;
each R 2 Independently selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, substituted or unsubstituted C 5 -C 7 Aryl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-N(C 1-4 Alkyl radical) 2 Cyano, nitro, -SO 2 -C 1-4 Alkyl, wherein C is substituted or unsubstituted 5 -C 7 The aryl substituents are selected from: c 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, C 1-4 Aminoalkyl radical, (C) 1-4 Alkyl radical) 2 N-C 1-4 Alkyl radical, C 1-4 alkyl-NH-C 1-4 An alkyl group;
R 3 selected from hydrogen, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, oxo, -C (O) ORa, -C (O) NRaRa, wherein C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl are optionally substituted by one or more of the same or different halogen, hydroxy, -NH 2 Substituted, ra is independently selected fromFrom hydrogen, C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 3-to 10-membered heteroaryl;
o represents 1 or 2;
R 4 selected from 3-10 membered saturated heterocyclyl, wherein said 3-10 membered heterocyclyl is optionally substituted with one or more same or different Rb;
rb is independently selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl, 5-to 10-membered heteroaryl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -S (O) 2 Rc、-S(O) 2 NRcRc, halogen, cyano, hydroxy, and oxo; wherein Rb is said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl are all optionally substituted by one or more of the same or different halogen, cyano, hydroxy, -NH 2 And oxo-substituted, oxo not on a double bond;
rc is independently selected from hydrogen and C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 0 -C 1 alkylene-C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl;
n represents 0, 1 or 2;
x is selected from O, S, NRd, CRdRd, rd is independently selected from hydrogen and C 1-3 An alkyl group;
R 5 selected from hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl radical) 2 And halogen;
R 6 selected from hydrogen, halogen;
wherein each two R are 3 May be linked to form a 3-6 membered ring.
2. The compound of claim 1, wherein saidR 1 Is methyl.
3. A compound according to claim 1, which is a pharmaceutically acceptable salt thereof,
wherein ring a is selected from: c 6-10 An aryl group;
p represents 1,2 or 3;
each R 2 Independently selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, preferably hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 。
4. The compound of claim 1, wherein ring a is substituted with p R 2 The substituents together have the following substructure:
Figure FDA0003026842370000031
rg is selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-SO 2 -C 1-4 Alkyl, cyano;
re is selected from: hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl, halogen, nitro and cyano, wherein the halogen is fluorine, chlorine, bromine or iodine.
5. The compound of claim 4, wherein ring A is substituted with p substituents R 2 Together have the substructure:
Figure FDA0003026842370000032
rg is selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl groupHalogen, -NH 2 In which C is 1-4 The haloalkyl group is preferably an alkyl group substituted with 1,2 or 3 fluorine atoms, and is more preferably-CF 3 、-CHF 2 ；
Re is selected from hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl, halogen and nitro, wherein the halogen is fluorine, chlorine, bromine and iodine.
6. The compound of claim 4, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein ring a is substituted with p substituents R 2 Together have the following substructure:
Figure FDA0003026842370000033
Figure FDA0003026842370000041
7. the compound of claim 1, wherein R 3 Selected from hydrogen, methyl, oxo.
8. The compound of claim 1, wherein R 4 Wherein the 3-10 membered saturated heterocyclyl is optionally substituted with one or more same or different Rb;
rb is independently selected from C 1-6 Alkyl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -S (O) 2 Rc, oxo, wherein Rb is C 1-6 Alkyl is optionally substituted by one or more of the same or different halogen, cyano, hydroxy, -NH 2 And oxo;
rc is independently selected from hydrogen and C 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 0 -C 1 alkylene-C 6-10 And (4) an aryl group.
9. According to claim 8The compound of (1), wherein R 4 Selected from tetrahydrofuranyl and pyrrolidinyl, wherein both the tetrahydrofuranyl and pyrrolidinyl are optionally substituted with one or more same or different Rb;
rb is independently selected from C 1-6 Alkyl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -S (O) 2 Rc、-S(O) 2 NRcRc, oxo, wherein Rb is C 1-6 Alkyl is optionally substituted by one or more of the same or different halogen, cyano, hydroxy, -NH 2 And oxo;
rc is independently selected from hydrogen and C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 0 -C 1 alkylene-C 6-10 And (4) an aryl group.
10. The compound of claim 9, wherein R 4 Is pyrrolidinyl optionally substituted on nitrogen with Rb, independently selected from C 1-6 Alkyl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, rc are independently selected from hydrogen and C 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 0 -C 1 alkylene-C 6-10 And (3) an aryl group.
11. The compound of claim 9, wherein R 4 Is tetrahydrofuranyl optionally substituted by one or more identical or different Rb, independently selected from C 1-6 Alkyl, oxo.
12. The compound of claim 9, wherein R 4 Selected from the group consisting of:
Figure FDA0003026842370000051
13. the compound of claim 1, wherein X is selected from O, CH 2 。
14. The compound of claim 1, wherein R 5 Selected from hydrogen, R 6 Selected from hydrogen.
15. The compound of claim 1, having a structure according to formula (IIa) and/or formula (IIb):
Figure FDA0003026842370000052
wherein
R 1 Selected from hydrogen, C 1-4 Alkyl radical, wherein said C 1-4 Alkyl is optionally substituted with one or more of the same or different halogen or hydroxy;
rg is selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-SO 2 -C 1-4 Alkyl, cyano;
re is selected from hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl, halogen, nitro and cyano, wherein the halogen is fluorine, chlorine, bromine and iodine;
ring B is a 5-to 10-membered heteroaryl;
each R 2 Independently selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, substituted or unsubstituted C 5 -C 7 Aryl, hydroxy-C 3-6 Cycloalkyl, hydroxy, halogen, -NH 2 、-N(C 1-4 Alkyl radical) 2 Cyano, nitro, -SO 2 -C 1-4 An alkyl group; substituted or unsubstituted C 5 -C 7 The aryl substituents are preferably: c 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy, nitro, cyano, C 1-4 Aminoalkyl, (C) 1-4 Alkyl radical) 2 N-C 1-4 Alkyl radical, C 1-4 alkyl-NH-C 1-4 An alkyl group;
p represents 1,2 or 3;
R 3 selected from hydrogen, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, oxo, -C (O) ORa, -C (O) NRaRa, wherein C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl is optionally substituted by one or more of the same or different halogen, hydroxy, -NH 2 Ra are each independently selected from hydrogen, C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 3-to 10-membered heteroaryl;
o represents 1 or 2;
y is selected from O and NRh, rh is independently selected from hydrogen and C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl, 5-to 10-membered heteroaryl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -S (O) 2 Rc、-S(O) 2 NRcRc, wherein Rh is C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl, and 5-to 10-membered heteroaryl are all optionally substituted with one or more of the same or different halogen, cyano, hydroxy, and oxo, the oxo is not on the double bond;
rc is each independently selected from hydrogen, C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 0 -C 1 alkylene-C 6-10 Aryl radical, C 3-10 Heterocyclyl and C 5-10 A heteroaryl group;
n represents 0, 1 or 2;
m represents 1 or 2;
x is selected from O, S, NRd, CRdRd, rd is independently selected from hydrogen and C 1-3 An alkyl group;
R 5 selected from hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl radical) 2 And halogenA peptide;
R 6 selected from hydrogen and halogen.
16. The compound of claim 15, having a structure according to formula (IIa) and/or (IIb):
Figure FDA0003026842370000071
wherein
R 1 Is methyl;
rg is selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 In which C is 1-4 The haloalkyl group is preferably an alkyl group substituted by 1,2 or 3 fluorine atoms, and more preferably-CF 3 、-CHF 2 ；
Re is selected from hydrogen, halogen and-NH 2 ；
Rf is selected from: hydrogen, C 1-4 Alkyl and halogen, nitro;
ring B is pyridyl or thienyl;
each R 2 Independently selected from: hydrogen, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, substituted or unsubstituted C 5 -C 7 Aryl, hydroxy, halogen, -NH 2 、-N(C 1-4 Alkyl radical) 2 A cyano group; substituted or unsubstituted C 5 -C 7 The aryl substituents are preferably: c 1-4 Alkyl radical, C 1-4 Haloalkyl, halogen, -NH 2 、C 1-4 Alkoxy radical, C 1-4 Aminoalkyl radical, (C) 1-4 Alkyl radical) 2 N-C 1-4 Alkyl radical, C 1-4 alkyl-NH-C 1-4 An alkyl group;
p represents 1 or 2;
R 3 selected from hydrogen, C 1-4 Alkyl, oxo, -C (O) ORa, -C (O) NRaRa, wherein C 1-4 Alkyl is optionally substituted by one or more of the same or different halogen, hydroxy, amino, ra each independentlySelected from hydrogen and C 1-6 Alkyl radical, C 1-3 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-to 10-membered heterocyclyl and 5-to 10-membered heteroaryl;
o represents 1;
y is selected from O, NRh, rh is independently selected from C 1-6 Alkyl, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, rc are independently selected from hydrogen and C 1-6 An alkyl group;
rc is each independently selected from hydrogen, C 1-6 Alkyl radical, C 1-3 Haloalkyl, C3-C 6 Cycloalkyl radical, C 0 -C 1 alkylene-C 6-10 An aryl group;
n represents 0 or 1;
m represents 1;
x is selected from O, CRdRd, rd is independently selected from hydrogen and C 1-3 An alkyl group;
R 5 and R 6 Independently selected from hydrogen, halogen.
17. The compound of claim 1, having the specific structure:
Figure FDA0003026842370000081
Figure FDA0003026842370000091
Figure FDA0003026842370000101
Figure FDA0003026842370000111
18. compounds according to claims 1-17 for the preparation of, for the treatment or prevention of diseases related to SOS1 or modulated by SOS 1.
19. The disease of claim 18, which is a disease for which inhibition of the interaction of SOS1 with Ras family protein and/or RAC1 is of therapeutic benefit.
20. The disease of claim 19, wherein treating and/or preventing cancer comprises: pancreatic cancer, lung cancer, colorectal cancer, cholangioepithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.
CN202110418431.XA 2021-04-19 2021-04-19 Benzopyrimidine tricyclic derivative and preparation method and application thereof Pending CN115215884A (en)

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Publication number Priority date Publication date Assignee Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023165438A1 (en) * 2022-03-03 2023-09-07 浙江海正药业股份有限公司 Tricyclic derivative, preparation method therefor, and use thereof

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