Benzopyrimidine tricyclic derivatives, processes for their preparation and uses thereof

Abstract

Disclosed is a benzopyrimidine tricyclic compound shown in formula (I), use of the compound as a SOS1 inhibitor, a pharmaceutical composition containing the compound, and use of the compound as a medicament / medical application, especially as a medicament for treating and / or preventing an oncological disease.

Description

Technical Field

[0001] This invention relates to a benzopyrimidine tricyclic derivative of formula (I) and its use as an SOS1 inhibitor, particularly to its use as a benzopyrimidine tricyclic derivative for the treatment and / or prevention of oncological diseases. Background Technology

[0002] Since the late 1980s, mutations in the Ras family (including KRas, NRas, and HRas) have been found to be associated with cancer, with an incidence rate as high as 20%–30% in human cancers. Ras proteins are GTP-binding proteins, acting as molecular switches. Their protein conformation contains two switch regions: switch-I (aa 30-38) and switch-II (aa 59-76). In their active state, KRas binds to GTP, initiating downstream cell growth signaling pathways such as the Ras-Raf-MEK-ERK and Ras-PI3K-PDK1-AKT pathways. Once GTP is converted to GDP, Ras is deactivated. Normally, Ras activation is followed by immediate inactivation; however, after Ras gene mutations (such as KRas(G12C)), the Ras protein remains in an activated state, no longer dependent on upstream signal stimulation, and remains continuously bound to GTP, leading to abnormally active downstream signaling pathways and thus continuous cell proliferation. However, due to the unique molecular structure of Ras and the high similarity of the D-domains among the various Ras subtypes, it is difficult to develop Ras selective inhibitors. For the 50 years since Ras was discovered, it has been considered an undrugable target.

[0003] The guanine nucleotide exchange factor (SOS) protein is the guanine nucleotide exchange factor (GEF) of Ras. SOS1, one of the two SOS family proteins (SOS1 and SOS2), is also a Ras guanine nucleotide exchange factor. SOS1 binds to Ras-GDP and catalyzes the exchange of GDP and GTP in the Ras molecule, playing a crucial role in Ras activation and the transmission of cell growth and differentiation signals. In tumors with excessive Ras activation, inhibiting SOS1 can block the Ras pathway, thereby achieving a therapeutic effect of inhibiting tumor cell proliferation.

[0004] The SOS1-Ras interaction has gained increasing public acceptance. Small molecule inhibitors of SOS1 bind to SOS1 and inhibit its binding and catalytic activity with Ras proteins (Evelyn et al., Chem. Biol. 2014, 21(12):1618-28; WO2016 / 077793). Although compounds with mild inhibitory effects on SOS1 have been identified, their effects on guanine nucleotide exchange and cell signal transduction regulation (e.g., ERK phosphorylation) remain weak. A class of SOS inhibitors with a quinazoline core structure is disclosed in WO2018 / 115380 and WO2018 / 172250. These compounds significantly enhance the inhibitory effect of SOS1 on Ras family proteins, especially KRas, and thus significantly reduce ERK phosphorylation in KRas-mutant cancer cell lines. Recently, a novel benzylamino-substituted pyridopyrimidine ketone and its derivatives were disclosed in WO2019122129A1 as SOS1 inhibitors, which also achieved certain results.

[0005] SOS1 inhibitor compounds can mediate diseases involving mutations in Ras family protein pathways (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., NF1). Furthermore, they have potential applications in other diseases associated with Ras family protein mutations (e.g., neurofibromatosis, Noonan syndrome (NS), cardiofacial skin syndrome (CFC), and hereditary gingival fibromatosis type 1).

[0006] This invention provides a novel benzopyrimidine tricyclic derivative that exhibits exciting inhibitory effects on SOS1 inhibitors, with some compounds even showing unexpected pharmacokinetic properties. Summary of the Invention

[0007] In view of this, the present invention provides a benzopyrimidine tricyclic derivative that can be used to inhibit the interaction between the SOS1 catalytic site and Ras family proteins, an interaction involved in cell proliferation. Therefore, the compounds of the present invention can be used, but are not limited to, treating diseases of excessive or abnormal cell proliferation.

[0008] To achieve the above objectives, the present invention provides a pharmaceutically acceptable salt having a benzopyrimidine tricyclic compound or a stereoisomer thereof as shown in formula (I):

[0009]

[0010] in

[0011] R1 is selected from hydrogen, C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be substituted with one or more identical or different halogens or hydroxyl groups;

[0012] Ring A is selected from: C 6-10 Aryl, 5-10% heteroaryl;

[0013] p represents 1, 2, or 3;

[0014] Each R2 is independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, substituted or unsubstituted C5-C7 aryl groups, hydroxyl-C 3-6 Cycloalkyl, hydroxyl, halogen, -NH2, -N(C) 1-4 Alkyl group, cyano group, nitro group, -SO2-C 1-4 Alkyl; wherein the substituted or unsubstituted C5-C7 aryl substituent is preferably: C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, -NH2, C 1-4 Alkoxy, nitro, cyano, C 1-4 aminoalkyl, (C 1-4 (alkyl)2N-C 1-4 Alkyl, C 1-4 Alkyl-NH-C 1-4 alkyl;

[0015] R3 is selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, oxo, -C(O)ORa, -C(O)NRaRa, where C 1-4 Alkyl, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocyclic group are optionally substituted with one or more identical or different halogens, hydroxyl groups, or -NH2 groups, and Ra is independently selected from hydrogen and C. 1-6 Alkyl, C 1-3 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic and 3-10 heteroaryl;

[0016] o represents 1 or 2;

[0017] R4 is selected from 3-10 saturated heterocyclic groups, wherein the 3-10 saturated heterocyclic groups are optionally replaced by one or more identical or different Rb groups;

[0018] Rb is independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, halogen, cyano, hydroxyl, and oxo; wherein Rb is the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic and 5-10 heteroaryl groups are optionally substituted by one or more of the same or different halogens, cyano, hydroxyl, -NH2 and oxo groups, wherein the oxo group is not on the double bond;

[0019] Rc are each independently selected from hydrogen, C 1-6 Alkyl, C 1-3 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C0-C1 alkylene-C 6-10 Aryl, 3-10 heterocyclic and 5-10 heteroaryl;

[0020] n represents 0, 1, or 2;

[0021] X is selected from O, S, NRd, CRdRd, and Rd is selected independently from hydrogen and C. 1-3 alkyl;

[0022] R5 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl groups and halogens;

[0023] R6 is selected from hydrogen and halogens;

[0024] Two R3s can be connected to form a 3-6 element ring.

[0025] In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is a methyl group.

[0026] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: C 6-10 Aryl, preferably phenyl;

[0027] p represents 1, 2, or 3;

[0028] Each R2 is independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, -NH2, C 1-4 Alkoxy, nitro, cyano, with preference for hydrogen and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, -NH2, wherein the halogenated C 1-4 The alkyl group is more preferably substituted with 1, 2 or 3 fluorine atoms. 1-4 Alkyl groups, for example but not limited to -CF3, CHF2.

[0029] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, together with p R2 substituents, has the following substructure:

[0030]

[0031] Rg is selected from: hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl-C 3-6 Cycloalkyl, hydroxyl, halogen, -NH2, -SO2-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, more preferably -CF3 or -CHF2;

[0032] Re is selected from: hydrogen, halogens, and -NH2;

[0033] Rf is selected from: hydrogen, C 1-4 Alkyl groups and halogens, nitro groups, cyano groups, wherein the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0034] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, together with p substituents R2, has a substructure:

[0035]

[0036] Rg is selected from: hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkanes, halogens, -NH2, where C 1-4 The haloalkyl group is preferably an alkyl group substituted with 1, 2, or 3 fluorine atoms, more preferably -CF3 or -CHF2;

[0037] Re is selected from: hydrogen, halogens and -NH2;

[0038] Rf is selected from: hydrogen, C 1-4 Alkyl groups and halogens, nitro groups, wherein the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0039] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, together with p substituents R2, has a substructure:

[0040]

[0041] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: 5-membered to 10-membered heteroaryl groups;

[0042] p represents 1, 2, or 3;

[0043] Each R2 is independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, -NH2, C 1-4 Alkoxy, nitro, cyano, substituted or unsubstituted C5-C7 aryl, preferably hydrogen or C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, -NH2, substituted or unsubstituted C5-C7 aryl, wherein the haloC 1-4 The alkyl group is more preferably substituted with 1, 2 or 3 fluorine atoms. 1-4 Alkyl groups, such as but not limited to -CF3 and CHF2, with substituted or unsubstituted C5-C7 aryl substituents preferred: C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, -NH2, C 1-4 Alkoxy, nitro, cyano, C 1-4 aminoalkyl, (C 1-4 (alkyl)2N-C 1-4 Alkyl, C 1-4 Alkyl-NH-C 1-4 alkyl.

[0044] In another aspect, the present invention relates to a formula (I) wherein ring A is selected from: 5-membered to 7-membered heteroaryl monocyclic rings, and more specifically from: pyridine rings, thiophene rings, and thiazole rings.

[0045] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, together with p substituents R2, has a substructure:

[0046]

[0047] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydrogen, methyl, or oxo.

[0048] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the other two R3s can be connected to form a 3-6 membered ring, which forms a fused ring configuration with the connected ring, such as bridged rings or spiro rings well known to those skilled in the art, as exemplified below:

[0049]

[0050] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from 3-10 saturated heterocyclic groups, wherein the 3-10 saturated heterocyclic groups are optionally substituted by one or more identical or different Rb.

[0051] Rb is independently selected from C 1-6 Alkyl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -C(O)NRcRc, -S(O)2Rc, wherein Rb is the C 1-6 Alkyl groups are optionally converted to one or more of the same or different halogens, cyano groups, hydroxyl groups, -NH2 groups, and oxo groups;

[0052] Rc are each independently selected from hydrogen, C 1-6 Alkyl, C3-C6 cycloalkyl, C0-C1 alkylene-C 6-10 Aryl.

[0053] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from tetrahydrofuranyl and pyrrolidinyl, wherein the tetrahydrofuranyl and pyrrolidinyl are optionally substituted by one or more of the same or different Rb;

[0054] Rb is independently selected from C 1-6Alkyl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, oxo, wherein Rb is the C 1-6 Alkyl groups are optionally converted to one or more of the same or different halogens, cyano groups, hydroxyl groups, -NH2 groups, and oxo groups;

[0055] Rc are each independently selected from hydrogen, C 1-6 Alkyl, C3-C6 cycloalkyl, C0-C1 alkylene-C 6-10 Aryl.

[0056] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from tetrahydrofuranyl and pyrrolidinyl, wherein the tetrahydrofuranyl and pyrrolidinyl are optionally substituted by one or more identical or different Rb, and preferably the tetrahydrofuranyl and pyrrolidinyl are meta-linked to the parent nucleus:

[0057] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is a pyrrolidinyl group optionally substituted with Rb at nitrogen, and Rb is independently selected from C 1-6 Alkyl groups, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, where Rc is independently selected from hydrogen and C. 1-6 Alkyl, C3-C6 cycloalkyl, C0-C1 alkylene-C 6-10 Aryl.

[0058] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is optionally a tetrahydrofuran group substituted with one or more of the same or different Rb, wherein Rb is independently selected from C 1-6 Alkyl, oxo.

[0059] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from:

[0060]

[0061] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from O or CH2.

[0062] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, wherein R5 is selected from hydrogen and R6 is selected from hydrogen.

[0063] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, preferably of formula (IIa) and / or (IIb):

[0064]

[0065] in

[0066] R1 is selected from hydrogen, C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be substituted with one or more identical or different halogens or hydroxyl groups;

[0067] Rg is selected from: hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl-C 3-6 Cycloalkyl, hydroxyl, halogen, -NH2, -SO2-C 1-4 Alkyl, cyano, where C 1-4 The haloalkyl group is preferably an alkyl group substituted with 1, 2, or 3 fluorine atoms, more preferably -CF3 or -CHF2;

[0068] Re is selected from: hydrogen, halogens and -NH2;

[0069] Rf is selected from: hydrogen, C 1-4 Alkyl groups and halogens, nitro groups, cyano groups, wherein the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0070] Ring B is a 5-10 member heteroaryl group;

[0071] Each R2 is independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 2-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, substituted or unsubstituted C5-C7 aryl groups, hydroxyl-C 3-6 Cycloalkyl, hydroxyl, halogen, -NH2, -N(C) 1-4 Alkyl group, cyano group, nitro group, -SO2-C 1-4 Alkyl; preferably substituted or unsubstituted C5-C7 aryl substituents: C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, -NH2, C 1-4 Alkoxy, nitro, cyano, C 1-4 aminoalkyl, (C1-4 (alkyl)2N-C 1-4 Alkyl, C 1-4 Alkyl-NH-C 1-4 alkyl;

[0072] p represents 1, 2, or 3;

[0073] R3 is selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, oxo, -C(O)ORa, -C(O)NRaRa, where C 1-4 Alkyl, C 3-6 The cycloalkyl group, 3-6-membered heterocyclic group, is optionally surrounded by one or more identical or different halogens, hydroxyl groups, and -NH2 groups, with Ra each independently selected from hydrogen and C. 1-6 Alkyl, C 1-3 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic and 3-10 heteroaryl;

[0074] o represents 1 or 2;

[0075] Y is selected from O and NRh, and Rh is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic, 5-10 heteroaryl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -S(O)2Rc, -S(O)2NRcRc, wherein Rh is the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic and 5-10 heteroaryl groups are optionally substituted by one or more of the same or different halogens, cyano, hydroxyl and oxo groups, with the oxo group not on the double bond.

[0076] Rc are each independently selected from hydrogen, C 1-6 Alkyl, C 1-3 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C0-C1 alkylene-C 6-10 Aryl, C 3-10 Heterocyclic groups and C 5-10 Mixed aromatics;

[0077] n represents 0, 1, or 2;

[0078] m represents 1 or 2;

[0079] X is selected from O, S, NRd, CRdRd, and Rd is selected independently from hydrogen and C. 1-3 alkyl;

[0080] R5 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl groups and halogens;

[0081] R6 is selected from hydrogen and halogens.

[0082] In another aspect, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, more preferably a compound of formula (IIa) and / or (IIb) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof:

[0083]

[0084] in

[0085] R1 is a methyl group;

[0086] Rg is selected from: hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, -NH2, where C 1-4 The haloalkyl group is preferably an alkyl group substituted with 1, 2, or 3 fluorine atoms, more preferably -CF3 or -CHF2;

[0087] Re is selected from: hydrogen, halogens and -NH2;

[0088] Rf is selected from: hydrogen, C 1-4 Alkyl groups, halogens, and nitro groups;

[0089] Ring B is pyridinyl or thiophene;

[0090] Each R2 is independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, substituted or unsubstituted C5-C7 aryl groups, hydroxyl groups, halogens, -NH2, -N(C 1-4 alkyl)2, cyano; substituted or unsubstituted C5-C7 aryl substituents are preferred: C 1-4 Alkyl, C 1-4Halogenated alkyl groups, halogens, -NH2, C 1-4 Alkoxy, C 1-4 aminoalkyl, (C 1-4 (alkyl)2N-C 1-4 Alkyl, C 1-4 Alkyl-NH-C 1-4 alkyl;

[0091] p represents 1 or 2;

[0092] R3 is selected from hydrogen, C 1-4 Alkyl, oxo, -C(O)ORa, -C(O)NRaRa, where C 1-4 The alkyl group is optionally substituted with one or more identical or different halogens, hydroxyl groups, or amino groups, and Ra is independently selected from hydrogen, C, and N. 1-6 Alkyl, C 1-3 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic and 5-10 heteroaryl;

[0093] o represents 1;

[0094] Y is selected from O and NRh, and Rh is independently selected from hydrogen and C. 1-6 Alkyl groups, -C(O)Rc, -C(O)ORc, -C(O)NRcRc;

[0095] Rc are each independently selected from hydrogen, C 1-6 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, C0-C1 alkylene-C 6-10 Aryl;

[0096] n represents 0 or 1;

[0097] m represents 1;

[0098] X is selected from O, CRdRd, and Rd is selected independently from hydrogen and C. 1-3 alkyl;

[0099] R5 and R6 are independently selected from hydrogen and halogens.

[0100] In another aspect, the present invention provides specific compounds or their stereoisomers, and pharmaceutically acceptable salts thereof.

[0101]

[0102]

[0103] In another aspect, the present invention further provides the following specific compounds or their stereoisomers, and pharmaceutically acceptable salts,

[0104]

[0105]

[0106] All structural aspects mentioned above are preferred embodiments of their respective aspects. Structural aspects associated with different molecular moieties of the compound (I) of the present invention may be combined with each other as needed to obtain preferred compounds. Each combination represents and defines an individual embodiment or a general subset of the compound (I) of the present invention. Combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds or useful synthetic intermediates.

[0107] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of compounds of formula (I) (including all embodiments thereof).

[0108] This invention further relates to pharmaceutically acceptable salts of compounds of formula (I) (including all embodiments thereof), comprising compounds of formula (I) (including all embodiments thereof) with pharmaceutically acceptable salts of inorganic or organic acids or bases. Pharmaceutically acceptable salts include, but are not limited to: salts with inorganic acids, such as hydrochlorides, phosphates, diphosphates, hydrobroms, sulfates, sulfinates, nitrates, and similar salts; and salts with organic acids, such as malates, maleates, fumarates, tartrates, succinates, citrates, acetates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, and alkylates such as acetates, HOOC-(CH2)n-COOH (where n is 0-4), and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to: sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0109] Furthermore, the pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0110] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. When they have multiple asymmetric stereocenters, their stereocombinations and mixtures thereof are included within the scope of this invention. Selected stereo compounds can be obtained using techniques conventional to those skilled in the art, such as the introduction of chiral starting materials, chiral resolution, etc.

[0111] For example, in this invention, R4 is selected from tetrahydrofuranyl and pyrrolidinyl stereoisomers, and the stereoisomer fragments have R or S configurations as shown below.

[0112]

[0113] For example, when R3 is substituted in this invention, stereoisomers also exist. The stereoisomer fragments have R or S configurations as shown below.

[0114]

[0115] On the other hand, compounds as described herein can be formulated into pharmaceutical compositions with human-available carriers and administered to mammalian hosts (such as human patients) in a variety of forms suitable for a chosen route of administration, such as oral or parenteral, intravenous, intramuscular, local, transdermal, intrathecal, ocular, intranasal, intraperitoneal, or subcutaneous routes.

[0116] The compounds described herein can be administered systemically, for example, orally or intravenously in combination with pharmaceutically acceptable carriers (such as inert diluents or assimilated, edible carriers). They can be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly mixed with the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, sublingual tablets, lozenges, capsules, elixirs, suspensions, syrups, rice paper capsules, etc.

[0117] In another aspect, the present invention relates to compound (I) (including all embodiments thereof), which can be used to prepare, treat or prevent diseases and / or conditions associated with or regulated by SOS1; in particular diseases and / or conditions for which inhibition of the interaction between SOS1 and Ras family proteins and / or RAC1 has therapeutic benefits.

[0118] Furthermore, the above-mentioned use of compounds of formula (I) is for the preparation, treatment, and / or prevention of diseases and / or conditions related to or regulated by SOS1, including but not limited to the treatment and / or prevention of cancer. More preferably, it is free from the group consisting of: pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial carcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, 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.

[0119] The starting materials used in the following reactions are usually known compounds, or can be prepared by known operations or obvious modifications thereof.

[0120] Where appropriate, the various starting materials, intermediates, and compounds described herein can be separated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as melting point analysis, mass spectrometry, nuclear magnetic resonance, and a variety of other spectroscopic analyses.

[0121] Some embodiments of the compounds of this invention can be achieved by the following reaction process:

[0122] Reaction process 1

[0123]

[0124] The substituents are as defined above in this invention.

[0125] Reaction process 2

[0126]

[0127] The substituents are as defined above in this invention.

[0128] Reaction process 3

[0129]

[0130] Reaction process 4

[0131]

[0132] Wherein the substituents are as defined above in this invention, and when Y is N, alkylation, acylation and other reactions can be further performed using techniques well known to those skilled in the art to achieve the technical solution expressed in this application.

[0133] Although certain embodiments have been illustrated and described by way of example, it should be understood that variations and modifications may be made therein in accordance with common art without departing from the art as defined in its broader sense in the following claims.

[0134] Compared with existing technologies, this invention provides a benzopyrimidine tricyclic derivative having the structure shown in Formula I or its stereoisomers, or a pharmaceutically acceptable salt. Activity assays show that the benzopyrimidine tricyclic derivative provided by this invention exhibits high activity and selectivity, and can be used to treat diseases related to thyroid hormone receptors.

[0135] Glossary

[0136] "Optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes examples in which the event or condition occurs, as well as examples in which the event or condition does not occur. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined herein. Those skilled in the art will understand that for any group containing one or more substituents, such a group is not intended to introduce any sterically unrealizable, synthetically infeasible, and / or inherently unstable substitution or substituent form.

[0137] "Alkyl" includes straight and branched chains having a specified number of carbon atoms (typically 1-20 carbon atoms, e.g., 1-8 carbon atoms, such as 1-6 carbon atoms). For example, C 1-6 Alkyl groups include straight-chain and branched alkyl groups with 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-hexyl, 3-methylpentyl, etc. Alkylenes are another subset of alkyl groups, referring to the same residues as alkyl groups but with two bonding sites. Alkylenes typically have 2 to 20 carbon atoms, for example, 2 to 8 carbon atoms, such as 2 to 6 carbon atoms. When naming alkyl residues with a specific number of carbon atoms, all geometric isomers with that number of carbon atoms are intended to be included; for example, "butyl" is intended to include n-butyl, sec-butyl, isobutyl, and tert-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to alkyl groups having 1 to 4 carbon atoms.

[0138] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (typically 1-8 carbon atoms, e.g., 2-4 carbon atoms) and at least 1-2 vinyl (>C=C<) unsaturated sites. Examples of such groups are, for example, vinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers. "Lower alkenyl" refers to an alkenyl group having 1-4 carbon atoms, which can be depleted by C1... 2-4It is represented by an alkenyl group.

[0139] Haloalkyl groups (haloalkenyl groups, haloynyl groups) are derived from previously defined alkyl groups (alkenyl groups, ynyl groups) by independently substituting one or more hydrogen atoms in the hydrocarbon chain with the same or different halogen atoms. If a haloalkyl group (haloalkenyl group, haloynyl group) is to be further substituted, the substitution can be carried out independently on all hydrogen-carrying carbon atoms in each case, either as a single substitution or multiple substitution. Examples of haloalkyl groups (haloalkenyl groups, haloynyl groups) are -CF3, -CHF2, -CH2F, -CF2CF3-CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -C≡CCF3, -CHFCH2CH3, -CHFCH2CF3, etc.

[0140] “Cycloalkyl” refers to a non-aromatic, partially or fully saturated carbon ring having a specified number of carbon ring atoms (e.g., 3-10, 3-8, or 3-6 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 cage-like cyclic groups (e.g., bicyclic [2.2.2]octane). Lower cycloalkanes generally refer to C14-C ... 3-6 In the absence of specific instructions, lower cycloalkyl groups are generally preferred to be fully saturated carbon rings.

[0141] "Hydroxyalkyl (hydroxycycloalkyl)" includes straight-chain and branched alkyl (cycloalkyl) compounds in which one or more hydroxyl groups replace the aforementioned number of carbon atoms (typically 1-20 carbon atoms, e.g. 1-8 carbon atoms, such as 1-6 carbon atoms). Combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds or useful synthetic intermediates.

[0142] "Halogenated-hydroxyalkyl" refers to straight-chain and branched alkyl groups with one or more hydroxyl groups and halogens replacing the aforementioned number of carbon atoms (typically 1-20 carbon atoms, e.g. 1-8 carbon atoms, such as 1-6 carbon atoms). Combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds or useful synthetic intermediates.

[0143] "Aryl" refers to an aromatic carbon ring having a specified number of carbon atoms (e.g., 6-12 or 6-10 carbon atoms). Aryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl group may include a non-aromatic ring fused to an aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocyclic alkyl, heterocyclic alkenyl), provided that the polycyclic aryl group is bonded to the parent structure via atoms in the aromatic ring. Thus, 1,2,3,4-tetrahydronaphth-5-yl (wherein the portion is bonded to the parent structure via aromatic carbon atoms) is considered an aryl group, while 1,2,3,4-tetrahydronaphth-1-yl (wherein the portion is bonded to the parent structure via non-aromatic carbon atoms) is not considered an aryl group. Similarly, 1,2,3,4-tetrahydroquinoline-8-yl (where the portion is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinoline-1-yl (where the portion 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 connection point (e.g., quinoline-5-yl and quinoline-2-yl are both heteroaryl groups). In some cases, unless otherwise specified, the aryl ring may be further substituted with functional groups well known in the art without affecting the definition of the number of carbon atoms on the aromatic ring. In some cases, the aryl group is phenyl or naphthyl. In some cases, the aryl group is phenyl. Other examples of aryl groups comprising an aromatic carbon ring fused with a non-aromatic ring are described below. The C0-C1 alkylene-C 6-10 Aryl groups generally refer to those formed when C0 is an alkylene group and C1 is a alkylene group. 6-10 The aryl group refers to the corresponding aryl group, C1 alkylene-C 6-10 When aryl is used, it generally means that there is a methylene group next to the aryl group, such as benzyl.

[0144] "Carboxy" or "carboxyl" means -COOH or its salt.

[0145] "Heteroaryl" refers to an aromatic ring containing a specified number of ring atoms (e.g., 5-12 or 5-10 membered heteroaryls), wherein the ring atoms consist of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), 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 does not exceed 2. In some embodiments, the total number of S and O atoms in the heteroaryl does not exceed 1. Unless otherwise stated, the heteroaryl can be bonded to the parent structure by carbon or nitrogen atoms, provided the valence allows. For example, "pyridinyl" includes 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl, and "pyrroloyl" includes 1-pyrroloyl, 2-pyrroloyl, and 3-pyrroloyl. When nitrogen is present in a heteroaryl ring, it can exist in an oxidized state (i.e., N+-O-), provided that the properties of adjacent atoms and groups allow. Similarly, when sulfur is present in a heteroaryl ring, it can exist in an oxidized state (i.e., S+-O- or SO2), provided that the properties of adjacent atoms and groups allow. Heteroaryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0146] In some cases, heteroaryl groups are monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazolium, 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.

[0147] In other cases, polycyclic heteroaryl groups may include non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocyclic alkyl, heterocyclic alkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is bonded to the parent structure via atoms in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (wherein the portion is bonded to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the portion is bonded to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups composed of heteroaryl rings fused to non-aromatic rings are described below.

[0148] "Heterocyclic alkyl" refers to a non-aromatic, partially or fully saturated ring (e.g., 3-10 or 3-7 membered heterocyclic alkyl) having a specified number of ring atoms. It is sometimes also referred to herein as a heterocyclic group, a consistent designation, where the ring atoms consist of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. A 5-membered heterocyclic alkyl is a heterocyclic alkyl having 5 ring atoms. A 6-membered heterocyclic alkyl is a heterocyclic alkyl having 6 ring atoms. Heterocyclic alkyl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocyclic alkyl include oxopropyl, aziridinepropyl, aziridinebutyl, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. When nitrogen is present in the heterocyclic alkyl ring, it may be in an oxidized state (i.e., N+-O-) where the nature of adjacent atoms and groups allows. Examples include piperidinyl N-oxide and morpholinyl N-oxide. Furthermore, when sulfur is present in a heterocyclic alkyl ring, it can exist in an oxidized state (i.e., S+-O- or -SO2-), provided the nature of adjacent atoms and groups allows. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Additionally, one ring of a polycyclic heterocyclic alkyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocyclic alkyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2,3,4-tetrahydroquinoline-1-yl (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocyclic alkyl group, while 1,2,3,4-tetrahydroquinoline-8-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocyclic alkyl group. Lower heterocyclic alkanes generally refer to C164-C ... 3-6 In the absence of specific instructions, lower heterocyclic alkyl groups are generally preferred to be fully saturated carbon rings.

[0149] "Alkoxy" refers to an alkyl group with a specified number of carbon atoms connected by oxygen bridges, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentylooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy also includes cycloalkyl groups as defined above, which are also connected by oxygen bridges. Alkoxy groups typically have 1-6 carbon atoms connected by oxygen bridges. "Lower alkoxy" refers to an alkoxy group having 1-4 carbon atoms.

[0150] The term "halogenated" includes fluorinated, chlorinated, brominated, and iodinated.

[0151] As used herein, the term "substitution" means that any one or more hydrogen atoms on a specified atom or group are selectively replaced by a specified group, provided that the substitution does not exceed the normal valence of the specified atom. When the substituent is oxo (i.e., =O), then two hydrogen atoms on the stated atom are substituted. Combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds or useful synthetic intermediates. Stable compounds or stable structures are intended to imply that the compound is robust enough to withstand separation from the reaction mixture and subsequent formulation as a reagent with at least practical utility. Unless otherwise indicated, substituents are named to the core structure. For example, it should be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of connection between the substituent and the core structure is in the alkyl moiety.

[0152] Partial list of abbreviations

[0153] Abbreviation Meaning <![CDATA[HNO3]]> Nitric acid DMSO Dimethyl sulfoxide <![CDATA[NaBH(OAc)3]]> Sodium triacetoxyborohydride Xantphos 4,5-Bisdiphenylphosphine-9,9-Dimethyloxanthracene DMF N,N-Dimethylformamide Dioxane 1,4-Dioxane DIPEA Diisopropylethylamine NBS N-bromosuccinimide CBZ benzyloxycarbonyl Detailed Implementation

[0154] The instruments and methods used in this invention for separation and purification in the preparative liquid phase are as follows:

[0155] Instrument: Shimadzu Preparative Liquid Chromatography (SIL-10AP)

[0156] I. Acid chromatography column: Welch Ultimate XB-C18, 21.2*250mm, 10um

[0157] Mobile phase: A: 0.05% TFA aqueous solution; B: acetonitrile

[0158] II. Alkali chromatography column: Welch Xtimate C18, 21.2*250mm, 10µm

[0159] Mobile phase: A: 10 mmol / L aqueous solution; B: acetonitrile

[0160] Column temperature: room temperature

[0161] Flow rate: 25 ml / min

[0162] Detection wavelength: 214 / 254nm

[0163] The present invention will now be described in further detail with reference to the embodiments in the specification.

[0164] Example 1

[0165] 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

[0166]

[0167] first step

[0168] 2-Bromo-4-fluoro-5-nitrobenzoic acid 1b

[0169] 10.00 g (45.66 mmol) of compound 2-bromo-4-fluoro-benzoic acid 1a was dissolved in concentrated sulfuric acid (40 mL). The reaction solution was cooled to 0°C in an ice-water bath, and fuming nitric acid (4 mL) was slowly added dropwise. The reaction solution was reacted at 0–5°C for 1 hour, resulting in the precipitation of a large amount of white solid. The reaction solution was slowly poured into ice water (300 mL), stirred for 30 minutes, filtered, and the filter cake was washed with water (300 mL). The solid was dried to give 10.50 g (white solid) of 2-bromo-4-fluoro-5-nitrobenzoic acid 1b, yield 80%. MS m / z (ESI): 261.9 [M⁻¹] - . 1 H NMR (400MHz, DMSO-d6) δ14.00 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 10.6 Hz, 1H).

[0170] Step 2

[0171] 2-Bromo-4-hydroxy-5-nitrobenzoic acid 1d

[0172] Compounds 2-bromo-4-fluoro-5-nitrobenzoic acid 1b (10.50 g, 30.33 mmol) and acetyloxyoxime acid 1c (6.83 g, 90.99 mmol) were dissolved in dimethyl sulfoxide (150 mL). Potassium carbonate (20.96 g, 151.65 mmol) was added to the solution. The reaction mixture was heated to 80°C and reacted for 2 hours. The solution was then poured into ice water (600 mL), and the pH was adjusted to 4–5 with concentrated hydrochloric acid. A solid precipitated out. The mixture was stirred for another 30 minutes, filtered, and the filter cake was washed with water (100 mL) and dried using a rotary evaporator to give 2-bromo-4-hydroxy-5-nitrobenzoic acid 1d (6.90 g, pale yellow solid), yield: 87%. MS m / z (ESI): 259.9 [M⁻¹] - .

[0173] Step 3

[0174] methyl 2-bromo-4-hydroxy-5-nitrobenzoate 1e

[0175] 1d of 2-bromo-4-hydroxy-5-nitrobenzoic acid (6.90 g, 26.33 mmol) was dissolved in 150 mL of methanol, and thionyl chloride (8 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was heated to 80°C and reacted for 4 hours. The mixture was then cooled to room temperature, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give methyl 2-bromo-4-hydroxy-5-nitrobenzoate 1e (6.40 g, golden yellow solid), yield: 88%. MS m / z (ESI): 273.9 [M⁻¹] - .

[0176] Step 4

[0177] methyl 2-bromo-4-hydroxy-5-aminobenzoate 1f

[0178] 2.00 g (7.25 mmol) of methyl 2-bromo-4-hydroxy-5-nitrobenzoate 1e was dissolved in 50 mL of tetrahydrofuran. A 5% rhodium-carbon catalyst (0.20 g) was added under a nitrogen atmosphere. The reaction mixture was reacted under a hydrogen atmosphere for 17 hours. The mixture was filtered, and the filtrate was evaporated to dryness to give methyl 2-bromo-4-hydroxy-5-aminobenzoate 1f (1.78 g, brown solid), yield: 97%. MS m / z (ESI): 244.0 [M⁻¹] - .

[0179] Step 5

[0180] 2-Bromo-4-hydroxy-5-((tetrahydrofuran-3-yl)amino)methyl benzoate 1h

[0181] 1.78 g (7.01 mmol) of methyl 2-bromo-4-hydroxy-5-aminobenzoate was dissolved in 50 mL of 1,2-dichloroethane. 1 g (1.21 g, 14.02 mmol) of tetrahydrofuran-3-one was added, followed by acetic acid (0.84 g, 14.02 mmol). Sodium triacetoxyborohydride (2.96 g, 14.02 mmol) was added under ice-water bath conditions. The reaction mixture was stirred for 2 hours, then quenched in 100 mL of ice water. The pH was adjusted to approximately 8 with sodium bicarbonate. The mixture was extracted with 100 mL of dichloromethane. The organic layer was evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give 1 h (1.20 g, brownish-yellow solid), yield: 47%. 314.0 [M-1] - .

[0182] Step 6

[0183] 7-Bromo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 1j

[0184] Methyl 2-bromo-4-hydroxy-5-((tetrahydrofuran-3-yl)amino)benzoate 1h (1.20 g, 3.30 mmol), 1,2-dibromoethane 1i (3.10 g, 16.50 mmol), and potassium carbonate (1.82 g, 13.20 mmol) were dissolved in 30 mL of N,N-dimethylformamide and reacted at 80 °C for 16 h. The mixture was diluted with 80 mL of water, extracted with ethyl acetate (50 mL), and the organic layer was washed with water (50 mL × 2) and saturated brine (50 mL). The organic layer was evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give methyl 7-bromo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid 1j (0.81 g, pale yellow oil), yield: 65%. MS m / z (ESI): 342.0 [M+1] + .

[0185] Step 7

[0186] 7-((tert-Butoxycarbonyl)amino)-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 1l

[0187] Methyl 7-bromo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate 1j (1.06 g, 2.81 mmol), tert-butyl carbamate 1k (0.99 g, 8.43 mmol), cesium carbonate (2.75 g, 8.43 mmol), palladium acetate (0.03 g, 0.14 mmol), and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (0.08 g, 0.14 mmol) were dissolved in 30 mL In 1,4-dioxane, the reaction solution was heated to 110°C for 4 hours under nitrogen protection. The reaction solution was filtered, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give 1 liter (0.91 g, brownish-yellow oil) of methyl 7-((tert-butoxycarbonyl)amino)-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid, yield: 71%. MS m / z (ESI): 379.1 [M+1] + .

[0188] Step 8

[0189] 2-Methyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazinro[3,2-g]quinazolin-4-one 1m

[0190] Dissolve 1 L (0.85 g, 2.25 mmol) of methyl 7-((tert-butoxycarbonyl)amino)-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate in 20 mL of dioxane hydrochloride (4 M). Acetonitrile (3 mL) was added to the solution, and the reaction mixture was heated to 50°C and reacted for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and acetonitrile (20 mL) was added. After thorough stirring, sodium carbonate (1.19 g, 11.25 mmol) was added, and the reaction mixture was heated to 90°C and reacted for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with 20 mL of water, and adjusted to pH 7-8 with 1 M dilute hydrochloric acid. The acetonitrile was removed by concentration, resulting in the precipitation of a brownish-yellow solid. The solid was filtered, and the filter cake was dried under reduced pressure to give 1 mL (0.34 g, white solid) of 2-methyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazinro[3,2-g]quinazolin-4-one, yield: 53%. MS m / z (ESI): 288.1 [M+1] + .

[0191] Step 9

[0192] 4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolino1n

[0193] 2-Methyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazin[3,2-g]quinazolin-4-one 1m (0.40 g, 1.39 mmol) was dissolved in 15 mL of toluene. N,N-diisopropylethylamine (1.08 g, 8.34 mmol) and phosphorus oxychloride (0.64 g, 4.17 mmol) were added. The reaction mixture was heated to 80°C and reacted for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The sample was stirred with silica gel and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give 4-chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin 1n (0.32 g, brownish-yellow solid), yield: 77%. MS m / z (ESI): 306.1 [M+1] + .

[0194] Step 10

[0195] 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

[0196] 4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin 1n (30 mg, 0.10 mmol) and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline 1o (61 mg, 0.30 mmol) were dissolved in 3 mL of ethanol. N,N-diisopropylethylamine (129 mg, 1.00 mmol) was added. The reaction mixture was microwaved to 130°C for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography (Separation and Purification Method 1) to obtain 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 (8 mg, brownish-yellow solid), yield: 16%. MS m / z (ESI): 474.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) 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).

[0197] Example 2

[0198] 2-Methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinco[3,2-g]quinazolin-4-amine

[0199]

[0200] first step

[0201] 2-Methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinco[3,2-g]quinazolin-4-amine

[0202] Dissolve 4-chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinro[3,2-g]quinazoline 1n (70 mg, 0.23 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine 2a (61 mg, 0.30 mmol) in 3 mL of ethanol. Add N,N-diisopropylethylamine (149 mg, 1.15 mmol). Heat the reaction solution to 140°C using a microwave for 4 hours. Remove the solvent by rotary evaporation under reduced pressure. Purify the crude product using preparative chromatography (Separation and Purification Method 1) to obtain 2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4] Oxazizo[3,2-g]quinazolin-4-amine 2 (55 mg, yellow solid), yield: 51%. MS m / z (ESI): 473.6 [M+1] + . 1 H NMR (400MHz, DMSO-d6) 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).

[0203] Example 3

[0204] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine

[0205]

[0206]

[0207] first step

[0208] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine

[0209] 4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin 1n (30 mg, 0.10 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine 3a (47 mg, 0.25 mmol) were dissolved in 3 mL of ethanol. N,N-diisopropylethylamine (65 mg, 0.50 mmol) was added. The reaction mixture was microwaved to 140°C for 4 hours. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography (Separation and Purification Method 1) to obtain N-((R)-1-(3- (difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinro[3,2-g]quinazolin-4-amine 3 (9 mg, yellow solid), yield: 20%. MS m / z (ESI): 459.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) 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,1 H),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).

[0210] Example 4

[0211] N-((R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine

[0212]

[0213]

[0214] first step

[0215] N-((R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine

[0216] Dissolve 4-chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinro[3,2-g]quinazolin 1n (30 mg, 0.10 mmol) and (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine 4a (41 mg, 0.20 mmol) in 3 mL of ethanol, and add N,N-diisopropylethylamine (65 mg, The reaction solution was heated to 140°C in a microwave oven for 4 hours (0.50 mmol). The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography (Separation and Purification Method 1) to give N-((R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinro[3,2-g]quinazolin-4-amine 4 (6 mg, yellow solid), yield: 13%. MS m / z (ESI): 477.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) 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).

[0217] Example 5

[0218] 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazin[3,2-g]quinazolin-7(8H)-one 5

[0219]

[0220] first step

[0221] 7-Bromo-3-oxo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 5b

[0222] 2-Bromo-4-hydroxy-5-((tetrahydrofuran-3-yl)amino)benzoate methyl 1h (300 mg, 0.95 mmol) and triethylamine (961 mg, 9.50 mmol) were dissolved in 15 mL of dichloromethane, and chloroacetyl chloride 5a (322 mg, 2.85 mmol) was added dropwise. The reaction mixture was reacted at 25 °C for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give 7-bromo-3-oxo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 5b (220 mg, colorless oil), yield: 62%. MS m / z (ESI): 356.0 [M+1] + . 1 H NMR(400MHz, DMSO-d6)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).

[0223] Step 2

[0224] 2-Methyl-6-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-[1,4]oxazinco[3,2-g]quinazolin-4,7(8H)-dione 5d

[0225] Methyl 7-bromo-3-oxo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate 5b (200 mg, 0.56 mmol), acetamidine hydrochloride 5c (159 mg, 1.68 mmol), palladium acetate (25 mg, 0.11 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (65 mg, 0.11 mmol), and cesium carbonate (912 mg, 2.80 mmol) were dissolved in 10 mL. In 1,4-dioxane, the reaction solution was heated to 110°C for 4 hours under nitrogen protection. The reaction solution was diluted with 10 mL of water, and the pH was adjusted to 4-5 with 1 M HCl. Extraction was performed with ethyl acetate (30 mL × 2). The organic layer was washed with saturated brine (20 mL), and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 5 d (85 mg, pale yellow solid) of 2-methyl-6-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-[1,4]oxazinro[3,2-g]quinazolin-4,7(8H)-dione, yield: 49%. MS m / z (ESI): 302.1 [M+1] + .

[0226] Step 3

[0227] 4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazinro[3,2-g]quinazolin-7(8H)-one 5e 2-methyl-6-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-[1,4]oxazinro[3,2-g]quinazolin-4,7(8H)-dione 5d (80 mg, 0.26 mmol) was dissolved in 10 mL of toluene. N,N-diisopropylethylamine (336 mg, 2.60 mmol) and phosphorus oxychloride (199 mg, 1.30 mmol) were added. The reaction mixture was heated to 80°C and reacted for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. Silica gel was added and the mixture was stirred. The solution was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain 4-chloro-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4] Oxazin[3,2-g]quinazolin-7(8H)-one 5e (65 mg, yellow solid), yield: 78%. MS m / z (ESI): 320.0 [M+1]+.

[0228] Step 4

[0229] 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazin[3,2-g]quinazolin-7(8H)-one 5

[0230] Take 5e (30 mg, 0.10 mmol) of 4-chloro-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazinofo[3,2-g]quinazolin-7(8H)-one and 1o (61 mg, 0.10 mmol) of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline. 0.30 mmol) was dissolved in 3 mL of ethanol, and N,N-diisopropylethylamine (58 mg, 0.45 mmol) was added. The reaction solution was heated to 140°C in a microwave oven for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography (Separation and purification method 1) to give 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazinro[3,2-g]quinazolin-7(8H)-one 5 (6 mg, white solid), yield: 14%. MS m / z (ESI): 488.2 [M+1] + . 1 HNMR(400MHz,DMSO-d6)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,1 H), 2.60 (s, 3H), 2.25-2.33 (m, 1H), 1.97-2.03 (m, 1H), 1.66 (d, J = 6.8Hz, 3H).

[0231] Example 6

[0232] 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazin[3,2-g]quinazolin-7(8H)-one

[0233]

[0234] first step

[0235] 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazin[3,2-g]quinazolin-7(8H)-one

[0236] 4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazinro[3,2-g]quinazolin-7(8H)-one 5e (20 mg, 0.06 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine 3a (34 mg, 0.18 mmol) were dissolved in 3 mL of 1,4-dioxane. N,N-diisopropylethylamine (78 mg, 0.60 mmol) was added. The reaction mixture was heated to 140°C in a microwave oven for 4 hours. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography (Separation and purification method two) to obtain 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4] Oxazo[3,2-g]quinazolin-7(8H)-one 6 (8 mg, white solid), yield: 28%. MS m / z (ESI): 473.1 [M+1] + . 1 HNMR(400MHz,DMSO-d6)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).

[0237] Example 7

[0238] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine

[0239]

[0240]

[0241] first step

[0242] 4-Fluoro-2-nitro-5-((tetrahydrofuran-3-yl)amino)methyl benzoate 7c

[0243] Methyl 4,5-difluoro-2-nitrobenzoate 7a (2.0 g, 9.21 mmol), 3-aminotetrahydrofuran 7b (1.60 g, 18.42 mmol), and sodium carbonate (2.93 g, 27.63 mmol) were dissolved in 20 mL of N,N-dimethylformamide and reacted at 50 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with 100 mL of water, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL × 2) and saturated brine (100 mL). After standing and separation, the organic layer was evaporated to dryness under reduced pressure using a rotary evaporator. The crude product was purified by preparative chromatography (petroleum ether:ethyl acetate = 3:2) to give methyl 4-fluoro-2-nitro-5-((tetrahydrofuran-3-yl)amino)benzoate 7c (2.20 g, yellow solid), yield: 84%. MS m / z (ESI): 285.1 [M+1] + .

[0244] Step 2

[0245] 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 (1.43 g, 10.56 mmol), and cesium carbonate (2.29 g, 7.04 mmol) were dissolved in 15 mL of N,N-dimethylformamide, and the reaction solution was reacted at 25 °C for 17 hours. Add 80 mL of water, adjust the pH to approximately 7 with 1 M hydrochloric acid, extract with ethyl acetate (50 mL × 2), wash the organic layer with water (50 mL × 2), wash with saturated brine (50 mL), allow to stand for separation, evaporate the organic layer to dryness under reduced pressure, and purify the crude product using preparative chromatography (petroleum ether: ethyl acetate = 3:1) to give methyl 4-fluoro-5-((2-methylallyl)(tetrahydrofuran-3-yl)amino)-2-nitrobenzoate 7e (1.20 g, yellow oil), yield: 98%. MS m / z (ESI): 339.1 [M+1] + . 1 H NMR (400MHz, CDCl3) 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).

[0246] Step 3

[0247] 4-Fluoro-2-nitro-5-((2-oxopropyl)(tetrahydrofuran-3-yl)amino)methylbenzyl ester 7f

[0248] 4-Fluoro-5-((2-methylallyl)(tetrahydrofuran-3-yl)amino)-2-nitrobenzoate 7e (1.20 g, 3.48 mmol) was dissolved in 20 mL of tetrahydrofuran and 20 mL of water. Potassium osmium tetroxide dihydrate (0.06 g, 0.17 mmol), N-methylmorpholine oxide (0.80 g, 6.96 mmol), and sodium periodate (2.98 g, 13.92 mmol) were added under ice-water bath. The reaction solution was slowly heated to room temperature and reacted at 25 °C for 17 hours. Extracted with ethyl acetate (50 mL), the organic layer was washed with water (50 mL × 2) and saturated brine (50 mL). After standing and separating, the organic layer was evaporated to dryness under reduced pressure to give methyl 4-fluoro-2-nitro-5-((2-oxopropyl)(tetrahydrofuran-3-yl)amino)benzoate 7f (1.15 g, brownish-yellow oil), yield: 87%. MS m / z (ESI): 341.1 [M+1] + .

[0249] Step 4

[0250] 7g of methyl 4-fluoro-5-((2-hydroxypropyl)(tetrahydrofuran-3-yl)amino)-2-nitrobenzoate

[0251] 7g (1.15g, 3.01 mmol) of methyl 4-fluoro-2-nitro-5-((2-oxopropyl)(tetrahydrofuran-3-yl)amino)benzoate was dissolved in 20mL of methanol. Sodium borohydride (0.11g, 3.01 mmol) was added under ice-water bath conditions, and the reaction mixture was reacted at 0°C for 1 hour. The solution was diluted with 100mL of water, extracted with 100mL of ethyl acetate, and the organic layer was washed with 100mL of saturated brine. After standing and separation, the organic layer was evaporated under reduced pressure to obtain crude product, which was purified by preparative chromatography (petroleum ether:ethyl acetate = 2:1) to give 7g (0.90g, golden yellow oil) of methyl 4-fluoro-5-((2-hydroxypropyl)(tetrahydrofuran-3-yl)amino)-2-nitrobenzoate, yield: 87%. MS m / z (ESI): 343.1 [M+1] + .

[0252] Step 5

[0253] 2-Methyl-7-nitro-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 7h

[0254] 7 g (0.50 g, 1.46 mmol) of methyl 4-fluoro-5-((2-hydroxypropyl)(tetrahydrofuran-3-yl)amino)-2-nitrobenzoate was dissolved in 10 mL of N,N-dimethylformamide. Sodium hydroxide (0.18 g, 7.30 mmol) was added under ice-water bath conditions, and the reaction mixture was reacted at 20 °C for 1 hour. The reaction was quenched by slowly pouring the solution into 100 mL of ice water. The pH was adjusted to 6-7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL), and the organic layer was washed with saturated brine (100 mL). After standing and separation, the organic layer was evaporated under reduced pressure to obtain the crude product, which was then dissolved in 10 mL of N,N-dimethylformamide. Iodomethane (0.50 g, 3.52 mmol) and potassium carbonate (0.50 g, 3.62 mmol) were added, and the reaction mixture was stirred at 20 °C for 2 hours. Dilute with 100 mL of ice water, then adjust the pH to 6-7 with 1 M hydrochloric acid. Extract with 100 mL of ethyl acetate. Wash the organic layer with 100 mL of water (×2) and saturated brine (100 mL). Allow to stand for separation. Dry the organic layer under reduced pressure. Purify the crude product using preparative chromatography (petroleum ether: ethyl acetate = 3:2) to give methyl 2-methyl-7-nitro-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid ester 7h (0.36 g, brownish-yellow oil), yield: 72%. MS m / z (ESI): 323.1 [M+1] + . 1 H NMR (400MHz, CDCl3) 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).

[0255] Step 6

[0256] 7-Amino-2-methyl-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 7i

[0257] 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, 1.12 mmol) was dissolved in 10 mL of methanol. Under nitrogen protection, 10% palladium on carbon (0.023 g, 0.11 mmol) was added. The reaction system was then purged three times with hydrogen, and the reaction was carried out at 20 °C for 17 h under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was evaporated to dryness under reduced pressure to give 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, brownish-yellow solid). Yield: 94%. MS m / z (ESI): 293.1 [M+1] + .

[0258] Step 7

[0259] 2,8-Dimethyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazinro[3,2-g]quinazolin-4-one 7j

[0260] 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, 1.09 mmol) was dissolved in 15 mL of dioxane hydrochloride (4 M), and acetonitrile (3 mL) was added. The reaction solution was heated to 50 °C and reacted for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and acetonitrile (20 mL) was added. After thorough stirring, sodium carbonate (562 mg, 5.30 mmol) was added, and the reaction solution was heated to 90 °C and reacted for 3 hours. After the reaction was completed, the solution was cooled to room temperature, diluted with 20 mL of water, and adjusted to pH 7-8 with 1 M dilute hydrochloric acid. The solution was concentrated to remove acetonitrile, extracted with ethyl acetate (50 mL × 2), allowed to stand for separation, and the organic layer was rotary evaporated under reduced pressure. The crude product was purified by preparative chromatography (dichloromethane:methanol = 100:3). 2,8-Dimethyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazinro[3,2-g]quinazolin-4-one 7j (0.21 g, pale yellow solid) was obtained in 64% yield. MS m / z (ESI): 302.1 [M+1] + .

[0261] Step 8

[0262] 4-Chloro-2,8-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinro[3,2-g]quinazoline 7k 2,8-dimethyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazinro[3,2-g]quinazoline-4-one 7j (200 mg, 0.64 mmol) was dissolved in 10 mL of toluene. N,N-diisopropylethylamine (827 mg, 6.40 mmol) and phosphorus oxychloride (294 mg, 1.92 mmol) were added. The reaction mixture was heated to 80°C and reacted for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The sample was stirred with silica gel and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain 4-chloro-2,8-dimethyl-6-(tetrahydrofuran-3-yl). -7,8-dihydro-6H-[1,4]oxazinro[3,2-g]quinazoline 7k (120 mg, yellow solid), yield: 57%. MS m / z (ESI): 320.1 [M+1] + . 1 H NMR (400MHz, CDCl3) 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).

[0263] Step 9

[0264] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine

[0265] 4-Chloro-2,8-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazoline 7k (35 mg, 0.11 mmol) and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline 1o (56 mg, 0.28 mmol) were dissolved in 1 mL of N-methylpyrrolidone. N,N-diisopropylethylamine (142 mg, 1.10 mmol) was added. The reaction solution was heated to 140°C in a microwave oven for 3 hours. The reaction solution was purified by preparative chromatography (Separation and purification method 1) to obtain N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl) Ethyl)-2,8-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinro[3,2-g]quinazolin-4-amine 7 (37 mg, brownish-yellow solid), yield: 69%. MS m / z (ESI): 488.1 [M+1] + . 1 HNMR(400MHz,DMSO-d6)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).

[0266] Example 8

[0267] 2,8-Dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinco[3,2-g]quinazolin-4-amine

[0268]

[0269]

[0270] first step

[0271] 2,8-Dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinco[3,2-g]quinazolin-4-amine

[0272] 4-Chloro-2,8-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinro[3,2-g]quinazoline 7k (35 mg, 0.11 mmol) and ((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine 2a (67 mg, 0.33 mmol) were dissolved in 1 mL of N-methylpyrrolidone. N,N-diisopropylethylamine (142 mg, 1.10 mmol) was added. The reaction mixture was microwaved to 140°C for 4 hours. The reaction mixture was purified using preparative chromatography (Separation and Purification Method 1) to obtain 2,8-dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4] Oxazo[3,2-g]quinazolin-4-amine 8 (29 mg, white solid), yield: 53%. MS m / z (ESI): 487.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) 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).

[0273] Example 9

[0274] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine 9

[0275]

[0276]

[0277] first step

[0278] 2-Bromo-4-(2-Oxypropoxy)-5-((Tetrahydrofuran-3-yl)amino)methyl benzoate 9b

[0279] Methyl 2-bromo-4-hydroxy-5-((tetrahydrofuran-3-yl)amino)benzoate 1h (1.30 g, 4.01 mmol) and triethylamine (961 mg, 9.50 mmol) were dissolved in 30 mL of acetonitrile. Bromoacetone 9a (1.10 g, 8.02 mmol) was added, and the reaction mixture was reacted at 25 °C for 17 h. The reaction mixture was directly evaporated to dryness under reduced pressure. The crude product was purified by preparative chromatography (petroleum ether: ethyl acetate = 3:2) to give methyl 2-bromo-4-(2-oxopropoxy)-5-((tetrahydrofuran-3-yl)amino)benzoate 9b (1.20 g, colorless oil), yield: 76%. MS m / z (ESI): 372.0 [M+1] + .

[0280] Step 2

[0281] 7-Bromo-3-methyl-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 9c

[0282] Methyl 2-bromo-4-(2-oxopropoxy)-5-((tetrahydrofuran-3-yl)amino)benzoate 9b (1.20 g, 3.05 mmol) was dissolved in 20 mL of methanol, and acetic acid (0.37 g, 6.10 mmol) and sodium cyanoborohydride (0.38 g, 6.10 mmol) were added. The reaction solution was reacted at 25 °C for 4 hours. The reaction was quenched by adding 10 mL of saturated sodium bicarbonate solution, and the mixture was 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 evaporated to dryness under reduced pressure. The crude product was purified by preparative chromatography (petroleum ether: ethyl acetate = 3:2) to give methyl 7-bromo-3-methyl-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid 9c (0.91 g, colorless oil), yield: 81%. MS m / z (ESI): 356.0 [M+1] + . 1HNMR(400MHz, CDCl3)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).

[0283] Step 3

[0284] 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

[0285] 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, 2.47 mmol), tert-butyl carbamate 1k (0.87 g, 7.41 mmol), cesium carbonate (2.01 g, 6.18 mmol), palladium acetate (0.06 g, 0.25 mmol), and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (0.14 g, 0.25 mmol) were dissolved in 20 mL In 1,4-dioxane, the reaction solution was heated to 110°C for 4 hours under nitrogen protection. The reaction solution was filtered, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give methyl 7-((tert-butoxycarbonyl)amino)3-methyl-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid 9d (0.72 g, brownish-yellow oil), yield: 72%. MS m / z (ESI): 354.0 [M-56+1] + .

[0286] Step 4

[0287] 2,7-Dimethyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazinro[3,2-g]quinazolin-4-one 9e

[0288] 9d (0.72 g, 1.77 mmol) of 7-((tert-butoxycarbonyl)amino)3-methyl-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester was dissolved in 20 mL of dioxane hydrochloride (4 M). Acetonitrile (5 mL) was added, and the reaction mixture was heated to 50°C and reacted for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and acetonitrile (20 mL) was added. After thorough stirring, sodium carbonate (0.94 g, 8.85 mmol) was added, and the reaction mixture was heated to 90°C and reacted for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with 20 mL of water, and adjusted to pH 7-8 with 1 M dilute hydrochloric acid. The mixture was concentrated to remove acetonitrile, and extracted with ethyl acetate (50 mL × 2). The organic layer was washed with saturated brine (50 mL), allowed to stand for separation, and the organic layer was evaporated to dryness under reduced pressure. The crude product was purified by preparative chromatography (dichloromethane:methanol = 100:3) to give 2,7-dimethyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazinro[3,2-g]quinazolin-4-one 9e (0.37 g, white solid), yield: 69%. MS m / z (ESI): 302.1 [M+1] + .

[0289] Step 5

[0290] 4-Chloro-2,7-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin 9f

[0291] 2,7-Dimethyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazin[3,2-g]quinazolin-4-one 9e (0.20 g, 0.66 mmol) was dissolved in 10 mL of toluene. N,N-diisopropylethylamine (0.85 g, 6.60 mmol) and phosphorus oxychloride (0.30 g, 1.98 mmol) were added. The reaction mixture was heated to 80°C and reacted for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The mixture was stirred with silica gel and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to give 4-chloro-2,7-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin 9f (0.03 g, yellow solid), yield: 14%. MS m / z (ESI): 320.1 [M+1] + .

[0292] Step 6

[0293] 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

[0294] 4-Chloro-2,7-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazoline 9f (30 mg, 0.10 mmol) and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline 1o (55 mg, 0.27 mmol) were dissolved in 1 mL of N-methylpyrrolidone. N,N-diisopropylethylamine (116 mg, 0.90 mmol) was added. The reaction solution was heated to 140°C in a microwave oven for 4 hours. The reaction solution was purified by preparative chromatography (Separation and purification method 1) to obtain N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl) Ethyl)-2,7-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazinro[3,2-g]quinazolin-4-amine 9 (16.5 mg, pale yellow solid), yield: 37%. MS m / z (ESI): 488.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) 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).

[0295] Example 10

[0296] 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

[0297]

[0298] first step

[0299] Indoline 6-carboxylic acid methyl ester 10b

[0300] Methyl 1H-indole-6-carboxylic acid 10a (5.0 g, 28.0 mmol) and acetic acid (50 mL) were added to a reactor and stirred until dissolved. Sodium cyanoborohydride (5.3 g, 84.0 mmol) was added in portions at an internal temperature of 10–20 °C under ice-water bath control, with significant venting. After the addition was complete, the temperature was naturally raised and stirred for 1–2 h at 20–25 °C. The reaction solution was concentrated to dryness under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium bicarbonate aqueous solution (50 mL), dried, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give methyl indoline-6-carboxylic acid 10b (3.9 g, off-white solid), yield: 76.1%. MS m / z (ESI): 178.1 [M+1] + .

[0301] Step 2

[0302] 1-(tetrahydrofuran-3-yl)indoline-6-carboxylic acid methyl ester 10c

[0303] Methyl indoline 6-carboxylic acid ester 10b (3.9 g, 19.5 mmol), tetrahydrofuran-3-one 1 g (3.4 g, 39.0 mmol), methanol (40 mL), and acetic acid (1 mL) were added sequentially to the reactor and stirred to dissolve. Using an ice-water bath for temperature control, sodium triacetoxyborohydride (12.5 g, 58.5 mmol) was added in portions at an internal temperature of 10–20 °C, with noticeable gas release. After the addition was complete, the temperature was naturally raised and stirred for 16–18 h at 20–25 °C. The reaction solution was concentrated to dryness under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (50 mL), dried, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give 10c (3.9 g, oil) of methyl 1-(tetrahydrofuran-3-yl)indoline-6-carboxylic acid, yield: 50%. MS m / z (ESI): 248.1 [M+1] + .

[0304] Step 3

[0305] 5-Bromo-1-(tetrahydrofuran-3-yl)indoline-6-carboxylic acid methyl ester 10d

[0306] Methyl 5-bromo-1-(tetrahydrofuran-3-yl)indoline-6-carboxylic acid ester 10c (2.5 g, 9.9 mmol) and N,N-dimethylformamide (25 mL) were added to a reactor and stirred until dissolved. N-bromosuccinimide (2.0 g, 10.9 mmol) was added in portions at an internal temperature of 5–10 °C under ice-water bath control. After the addition was complete, the temperature was naturally raised and stirred at 20–25 °C for 1–2 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium sulfite aqueous solution (50 mL), dried, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give methyl 5-bromo-1-(tetrahydrofuran-3-yl)indoline-6-carboxylic acid ester 10d (2.6 g, oil), yield: 76%. MS m / z (ESI): 326.0 [M+1] + .

[0307] Step 4

[0308] 2-Methyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydro-4H-pyrrolo[2,3-g]quinazolin-4-one 10e

[0309] Methyl 5-bromo-1-(tetrahydrofuran-3-yl)indoline-6-carboxylic acid ester 10d (1.00 g, 3.04 mmol), acetamidine hydrochloride 5c (0.47 g, 4.56 mmol), cuprous iodide (0.06 g, 0.30 mmol), L-proline (0.07 g, 0.61 mmol), cesium carbonate (0.99 g, 3.04 mmol), and N,N-dimethylformamide (10 mL) were added to the reactor under nitrogen protection. The reaction was heated to an internal temperature of 110–120 °C and stirred for 30–32 h. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (20 mL), dried, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:3) 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%. MS m / z (ESI): 272.1 [M+1] + .

[0310] Step 5

[0311] 4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazoline 10f

[0312] 2-Methyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydro-4H-pyrrolo[2,3-g]quinazoline-4-one 10e (150 mg, 0.49 mmol), phosphorus oxychloride (225 mg, 1.47 mmol), N,N-diisopropylethylamine (316 mg, 2.45 mmol), and toluene (2 mL) were added to a reactor under nitrogen protection. The reaction was heated to an internal temperature of 70–80 °C and stirred for 2–3 h. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) 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%. MS m / z (ESI): 290.1 ​​[M+1] + .

[0313] Step 6

[0314] 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

[0315] 4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazoline 10f (20 mg, 0.07 mmol), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline 1o (21 mg, 0.11 mmol), N,N-diisopropylethylamine (18 mg, 0.14 mmol), and anhydrous ethanol (2 mL) were added to a microwave tube. The reaction mixture was reacted at 130 °C under microwave conditions for 5 h. The reaction solution was sent for preparative separation (separation and purification method one), and after lyophilization, 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 (11 mg, off-white solid) was obtained, yield: 34%. MS m / z (ESI): 458.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ14.22(s,1H),9.46(d,J=6.8Hz,1H),7.42(d,J=5.2H z,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).

[0316] Example 11

[0317] 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)pyrrolidine-1-yl)ethyl-1-one 11

[0318]

[0319] first step

[0320] 3-((4-bromo-2-hydroxy-5-(methoxycarbonyl)phenyl)amino)pyrrolidine-1-carboxylic acid benzyl ester 11b

[0321] 1.8 g (7.35 mmol) of methyl 2-bromo-4-hydroxy-5-aminobenzoate 1f was dissolved in 50 mL of 1,2-dichloroethane. Then, 3.22 g (14.69 mmol) of phenyl N-benzyloxycarbonyl-3-pyrrolidone 11a was added, followed by acetic acid (0.88 g, 14.69 mmol). Sodium triacetoxyborohydride (3.11 g) was then added under ice-water bath conditions. The reaction mixture was stirred for 2 hours, then quenched in 100 mL of ice water. The pH was adjusted to approximately 8 with sodium bicarbonate. Extraction was performed with 100 mL of dichloromethane. The organic layer was evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give 3-((4-bromo-2-hydroxy-5-(methoxycarbonyl)phenyl)amino)pyrrolidine-1-carboxylic acid benzyl ester 11b (3.0 g, brownish-yellow solid), yield: 91%. MS m / z (ESI): 449.0 [M+1] + .

[0322] Step 2

[0323] 4-(1-((benzyloxy)carbonyl)pyrrolidine-3-yl)-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 11c

[0324] 3-((4-bromo-2-hydroxy-5-(methoxycarbonyl)phenyl)amino)pyrrolidine-1-carboxylic acid benzyl ester 11b (3.0 g, 6.70 mmol), 1,2-dibromoethane 1i (6.23 g, 33.48 mmol) and potassium carbonate (3.70 g, 26.80 mmol) were dissolved in 60 mL of N,N-dimethylformamide and heated to 80 °C for 16 hours. Dilute with 160 mL of water, extract with ethyl acetate (100 mL), wash the organic layer with water (100 mL × 2), wash with saturated brine (100 mL), evaporate to dryness, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give methyl 4-(1-((benzyloxy)carbonyl)pyrrolidine-3-yl)-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid ester 11c (2.3 g, pale yellow oil), yield: 73%. MS m / z (ESI): 475.1 [M+1] + .

[0325] Step 3

[0326] 4-(1-((benzyloxy)carbonyl)pyrrolidine-3-yl)-7-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 11d

[0327] Methyl 4-(1-((benzyloxy)carbonyl)pyrrolidine-3-yl)-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid ester 11c (2.3 g, 4.85 mmol), tert-butyl carbamate 1k (1.70 g, 14.56 mmol), cesium carbonate (4.73 g, 14.56 mmol), palladium acetate (0.06 g, 0.24 mmol), and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (0.14 g, 0.24 mmol) were dissolved in 40 mL of water. In 1,4-dioxane, the reaction solution was heated to 110°C for 4 hours under nitrogen protection. The reaction solution was filtered, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give methyl 4-(1-((benzyloxy)carbonyl)pyrrolidine-3-yl)-7-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid ester 11d (1.2 g, brownish-yellow oil), yield: 48%. MS m / z (ESI): 512.1 [M+1] + .

[0328] Step 4

[0329] 3-(2-methyl-4-one-3,4,7,8-tetrahydrofuran-6H-[1,4]oxazine[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylic acid benzyl ester 11e

[0330] 11d (1.2 g, 2.35 mmol) of methyl 4-(1-((benzyloxy)carbonyl)pyrrolidine-3-yl)-7-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid was dissolved in 20 mL of dioxane hydrochloride (4 M). Acetonitrile (3 mL) was added, and the reaction mixture was heated to 50°C and reacted for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and acetonitrile (20 mL) was added. After thorough stirring, sodium carbonate (1.19 g, 11.75 mmol) was added. The reaction solution was heated to 90°C and reacted for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with 20 mL of water, and adjusted to pH 7-8 with 1 M dilute hydrochloric acid. The mixture was concentrated to remove acetonitrile, and a brown solid precipitated. The solid was filtered, and the filter cake was dried under reduced pressure to give 11e of 3-(2-methyl-4-one-3,4,7,8-tetrahydrofuran-6H-[1,4]oxazine[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylic acid benzyl ester (0.63 g, white solid), yield: 64%. MS m / z (ESI): 421.1 [M+1] + .

[0331] Step 5

[0332] 3-(4-chloro-2-methyl-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylic acid benzyl ester 11f

[0333] 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 (0.63 g, 1.50 mmol) was dissolved in 15 mL of toluene. N,N-diisopropylethylamine (1.16 g, 9.0 mmol) and phosphorus oxychloride (0.68 g, 4.5 mmol) were added. The reaction mixture was heated to 80°C and reacted for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The sample was stirred with silica gel and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give benzyl 3-(4-chloro-2-methyl-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 11f (0.38 g, brownish-yellow solid), yield: 58%. MS m / z (ESI): 439.0 [M+1] + .

[0334] Step 6

[0335] 11g of 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-carboxylic acid benzyl ester

[0336] Dissolve 11f (100 mg, 0.23 mmol) of 3-(4-chloro-2-methyl-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline 1o (93 mg, 0.46 mmol) in 3 mL of water. N,N-diisopropylethylamine (148 mg, 1.15 mmol) was added to 1,4-dioxane. The reaction solution was microwave-heated to 140°C for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography to obtain 11 g (96 mg, brownish-yellow solid) of 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-carboxylic acid benzyl ester, yield: 70%. MS m / z (ESI): 607.0 [M+1] + . 1 H NMR(400MHz, Methanol–d4)δ7.64(d,J=5.2Hz,1H),7,27-7.43(m,5H),6.92-6.99(m,3H),6.85(s,1H),5.70-5.8 2(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).

[0337] Step 7

[0338] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(pyrrolidine-3-yl)-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-4-amine 1lh

[0339] 11 g (96 mg, 0.16 mmol) of 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-carboxylic acid benzyl ester was dissolved in 30 mL of methanol, and then palladium on carbon (19 mg, 10%) was added. The reaction system was purged with hydrogen three times, and the reaction solution was reacted at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered, and the solvent was removed by rotary evaporation to obtain 1 l h (64 mg, brownish-yellow oil) of N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(pyrrolidine-3-yl)-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-4-amine, yield: 85%. MS m / z (ESI): 473.1 [M+1] + , 1 H NMR (400MHz, Methanol–d4) 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).

[0340] Step 8

[0341] 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)pyrrolidine-1-yl)ethyl-1-one 11

[0342] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(pyrrolidine-3-yl)-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-4-amine 11h (64 mg, 0.14 mmol) and N-succinimide acetate 11i (44 mg, 0.28 mmol) were dissolved in 3 mL of dichloromethane. The reaction solution was reacted at room temperature for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography (Separation and purification method 1) to obtain 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)pyrrolidone-1-yl)ethyl-1-one 11 (8 mg, white solid), yield: 18%. MS m / z (ESI): 515.0 [M+1] + . 1 H NMR(400MHz, Methanol-d4)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).

[0343] Step 9

[0344] 1-((S)-3-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidine-1-yl)ethyl-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]oxazin[3,2-g]quinazolin-6-yl)pyrrolidine-1-yl)ethyl-1-one 11-2

[0345] Compound 1-(3-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidine-1-yl)ethyl-1-one 11 (30 mg, white solid) was purified by preparative chromatography (Separation and purification method II) to obtain 1-((S)-3-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidine-1-yl)ethyl-1-one 11-1 (4 mg, white solid). MS m / z (ESI): 515.0 [M+1] + . 1 H NMR (400MHz, Methanol–d4) δ7.45 (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]oxazinro[3,2-g]quinazolin-6-yl)pyrrolidine-1-yl)ethyl-1-one 11-2 (4 mg, white solid). MS m / z (ESI): 515.0 [M+1] + , 1 H NMR(400MHz, Methanol–d4)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).

[0346] Example 12

[0347] 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)pyrrolidine-1-yl)ethyl-1-one 12

[0348]

[0349] first step

[0350] 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-carboxylic acid benzyl ester 12a

[0351] Dissolve 11f (100 mg, 0.23 mmol) of 3-(4-chloro-2-methyl-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylic acid benzyl ester 11f and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl-1-amine 2a (93 mg, 0.46 mmol) in 3 mL of water. N,N-diisopropylethylamine (148 mg, 1.15 mmol) was added to 1,4-dioxane. The reaction solution was microwave-heated to 140°C for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography to give 12a of 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-carboxylic acid (119 mg, brownish-yellow solid), yield: 86%. MS m / z (ESI): 606.1 [M+1] + .

[0352] Step 2

[0353] 2-Methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(pyrrolidone-3-yl)-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-4-amine 12b

[0354] 12a of 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-carboxylic acid (119 mg, 0.20 mmol) was dissolved in 3 mL of methanol, and then palladium on carbon (24 mg, 10%) was added. The reaction system was purged with hydrogen three times, and the reaction solution was reacted at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered, and the solvent was removed by rotary evaporation to obtain 12b of 2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(pyrrolidine-3-yl)-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-4-amine (84 mg, brownish-yellow oil), yield: 91%. MS m / z (ESI): 472.1 [M+1] + .

[0355] Step 3

[0356] 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)pyrrolidine-1-yl)ethyl-1-one 12

[0357] Dissolve 2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(pyrrolidone-3-yl)-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-4-amine 12b (40 mg, 0.08 mmol) and acetyl chloride 12c (8 mg, 0.10 mmol) in 2 mL of tetrahydrofuran, and add N,N-diisopropylethylamine (21 mg, 0.16 mmol). The reaction solution was reacted at room temperature for 1 hour. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography to give 12 (10 mg, white solid) 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)pyrrolidine-1-yl)ethyl-1-one, yield: 23%. MS m / z (ESI): 514.0 [M+1] + . 1H NMR(400MHz, Methanol-d4)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).

[0358] Example 13

[0359] 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)pyrrolidine-1-yl)propyl-1-one 13

[0360]

[0361] first step

[0362] 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)pyrrolidine-1-yl)propyl-1-one 13

[0363] Dissolve 2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(pyrrolidone-3-yl)-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-4-amine 12b (40 mg, 0.08 mmol) and propionyl chloride 13a (9 mg, 0.10 mmol) in 2 mL of tetrahydrofuran, and add N,N-diisopropylethylamine (21 mg, 0.16 mmol). The reaction solution was reacted at room temperature for 1 hour. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by preparative chromatography to give 13 (12 mg, white solid) 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)pyrrolidine-1-yl)ethyl-1-one, yield: 26%. MS m / z (ESI): 528.1 [M+1] + . 1H NMR(400MHz, Methanol-d4)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).

[0364] Example 14

[0365] Compounds 14 to 23 were prepared in a similar manner to that of Example 1, wherein the starting materials for each compound could be prepared by means of existing methods known to those skilled in the art or by commercially available materials, and similar synthetic methods for intermediates could be readily obtained by those skilled in the art by means of existing methods.

[0366]

[0367]

[0368]

[0369]

[0370] Compounds 24 and 25 were prepared in a similar manner to that in Example 11. The starting materials for each compound could be prepared using existing methods known to those skilled in the art or by means of commercially available materials. Similar synthetic methods for intermediates could be readily obtained by those skilled in the art using existing methods.

[0371]

[0372]

[0373] Example 15

[0374] 1. In vitro KRas(G12C):SOS1 homogeneous time-resolved fluorescence binding assay

[0375] Since SOS1 inhibitors do not select specific subtypes for binding to Ras, the Ras family protein selected in this experiment is the mutation at position 12 of exon 2 of KRas, namely KRas(G12C). KRas(G12C) accounts for approximately 85%-90% of all KRas mutation types and is found in approximately 13-30% of lung cancers, 3-5% of colorectal cancers, and 2% of other solid tumors.

[0376] Protein-protein interactions were determined using homogeneous time-resolved fluorescence spectrometry. All protein interactions occurred in 150 mM sodium chloride (SIGMA, S5886), 50 mM HEPES (Invitrogen, 15630080), and 0.05% bovine serum albumin (SIGMA, B2064). In a 384 reaction plate (Corning, CLS4514), 0.1 μL of the compound was added, centrifuged, and then 5 μL of a mixture of GST-KRas (G12C) protein (final concentration 15 nM) and GTP (final concentration 10 μM) was added. Finally, 5 μL of His-SOS1 protein solution (final concentration 2.5 nM) was added, and the mixture was incubated at room temperature for 15 minutes. Add 10 μL of premixed 100X Ab Anti-6HIS Tb cryptate Gold (cisbio, 61HI2TLA) and 25X MAb Anti GST-XL665 (cisbio, 61GSTXLA) detection solution, and react at room temperature for 60 minutes. Detect the reaction signal using a multi-well microplate reader, and analyze the data using GraphPad Prism data analysis software.

[0377] Experimental results:

[0378] Table 1. Inhibitory activity of the disclosed compounds against KRas(G12C):SOS1 binding.

[0379] 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

[0380] 2. 3D proliferation experiment of H358 cells

[0381] The diluted test compound was added to a 384-well cell culture plate (Corning, LS3830-50EA) using a nanoliter pipetting system (LABCYTE, P-0200). After seeding the cells, the plate was placed in a 37°C, 5% CO2 incubator. After co-incubating the compound with the cells for 7 days, the solution was added... The 3D reagent (Promega, 9683) was used, and the luminescence value was read using an Envision multi-functional microplate reader (the light signal is directly proportional to the amount of ATP in the system, and the ATP content directly represents the number of live cells in the system). Finally, the IC50 (half-maximum inhibitory concentration) of the compound was obtained by using a non-linear fitting formula with XLFIT software.

[0382] Inhibition rate (%) = 100 × (average value of negative control - compound reading) / (average value of negative control - average value of positive control);

[0383] Negative control: Cells treated with DMSO;

[0384] Positive control: only culture medium, no cells;

[0385] Table 2 shows the inhibitory effect of the disclosed compounds on the proliferation of H358 cells.

[0386]

[0387]

[0388] Some of the specific pharmacokinetic determination methods of the present invention are carried out under conventional experimental conditions in the art.

[0389] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A benzopyrimidine tricyclic compound having the shape of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Equation (I) in, R1 is selected from methyl; Ring A is selected from phenyl; p represents 1, 2, or 3; Each R2 is independently selected from: hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl-C 3-6 Cycloalkyl, hydroxyl, halogen, -NH2, -SO2-C 1-4 Alkyl, cyano, or nitro groups; R3 is selected from hydrogen, methyl, or oxo; o represents 1 or 2; R4 is a pyrrolidine-3-yl group, wherein the nitrogen atom of the pyrrolidine-3-yl group is substituted with Rb, where Rb is -C(O)Rc and Rc is a C1-C6 alkyl group. n represents 0 or 1; X is selected from O; R5 is selected from hydrogen; R6 is selected from hydrogen.

2. The compound according to claim 1, or its stereoisomers or pharmaceutically acceptable salts, wherein ring A, together with p R2 substituents, has the following substructure: 、 、 Rg is selected from: hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, hydroxy-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl-C 3-6 Cycloalkyl, hydroxyl, halogen, -NH2, -SO2-C 1-4 Alkyl, cyano; Re is selected from: hydrogen, halogens, and -NH2; Rf is selected from: hydrogen, C 1-4 Alkyl groups and halogens, nitro groups, cyano groups, wherein the halogens are fluorine, chlorine, bromine, and iodine.

3. The compound of claim 2 or its stereoisomers, or pharmaceutically acceptable salts thereof, wherein ring A, together with p substituents R2, has a substructure: Rg is selected from: hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, -NH2; Re is selected from: hydrogen, halogens, and -NH2; Rf is selected from: hydrogen, C 1-4 Alkyl groups and halogens, nitro groups, wherein the halogens are fluorine, chlorine, bromine, or iodine.

4. The compound or its stereoisomer, or a pharmaceutically acceptable salt, according to claim 2 or 3, C 1-4 Haloalkyl is an alkyl group that is substituted with 1, 2, or 3 fluorine atoms.

5. The compound or its stereoisomer, or a pharmaceutically acceptable salt according to claim 4, C 1-4 The alkyl halide is -CF3 or -CHF2.

6. The compound of claim 2 or its stereoisomers, or pharmaceutically acceptable salts thereof, wherein ring A, together with p substituents R2, has the following substructure: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 7. A compound having the following specific structure: 、 、 、 、 、 、 、 、 、 、 、 、 。 8. The use of any one of the compounds of claims 1-6, or their stereoisomers, pharmaceutically acceptable salts, or the compound of claim 7, in the preparation of medicaments for treating or preventing diseases associated with or regulated by SOS1.

9. The application according to claim 8, wherein the disease regulated by SOS1 is a disease for which inhibition of the interaction between SOS1 and Ras family proteins and / or RAC1 has therapeutic benefit.

10. The application according to claim 9, wherein the disease is cancer, and the cancer is pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial carcinoma, multiple myeloma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia, urothelial carcinoma, 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.

11. The application according to claim 9, wherein the disease is cancer, and the cancer is endometrial cancer or bladder cancer.

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