TWI807787B - Benzopyrimidine tricyclic derivative and preparation method and application thereof - Google Patents

Abstract

The invention discloses a benzopyrimidine tricyclic compound represented by formula (I), its use as an SOS1 inhibitor, a pharmaceutical composition comprising such a compound and its use as a medicament/medical application, especially its use as a medicament for the treatment and/or prevention of oncological diseases.

Description

Benzopyrimidine tricyclic derivative and its preparation method and application

The present invention relates to a benzopyrimidine tricyclic derivative of formula (I), its use as an SOS1 inhibitor, in particular to its use as a benzopyrimidine tricyclic derivative for treating and/or preventing tumor diseases.

Since the late 1980s, it has been found that mutations in the Ras family (KRas, NRas and HRas, which includes members thereof) are associated with cancer, and the incidence rate in human cancers is as high as 20% to 30%. Ras protein belongs to GTP-binding protein and is a molecular switch. There are two switch regions in its protein conformation: switch-I (aa 30-38) and switch-II (aa 59-76). In the active state, KRas will bind to GTP and start downstream cell growth signaling pathways, such as Ras-Raf-MEK-ERK and Ras-PI3K-PDK1-AKT pathways; after GTP changes to GDP, Ras is turned off. Under normal circumstances, after Ras is activated, it will be inactivated immediately; but after the Ras gene is mutated (such as KRas(G12C)), the Ras protein continues to maintain an activated state, no longer depends on the stimulation of superior signals, and is in a state of continuous binding to GTP, resulting in abnormally active downstream signaling pathways, resulting in continuous cell proliferation. However, due to the unique molecular structure of Ras and the high similarity of the D-domain of each subtype of Ras, it is difficult to develop a selective inhibitor of Ras. Since the discovery of Ras 50 years ago, Ras has been considered as an undruggable target.

The guanine nucleotide exchange factor (Son of sevenless homolog, SOS) protein is the guanine nucleotide exchange factor (GEF) of Ras. As one of the two SOS family proteins (SOS1 and SOS2), SOS1 is the guanine nucleotide exchange factor of Ras. SOS1 binds to Ras-GDP, catalyzes the exchange of GDP and GTP in the Ras molecule, and plays an important role in the activation of Ras and the transmission of cell growth and differentiation signals. In tumors with excessive Ras activation, the Ras pathway can be blocked by inhibiting SOS1, so as to achieve the therapeutic effect of inhibiting tumor cell proliferation.

So far, the SOS1-Ras interaction has been more and more recognized by the public. Small molecule inhibitors of SOS1 can bind SOS1 and inhibit its binding and catalytic effects with Ras protein (Evelyn et al., Chem. Biol. 2014, 21(12): 1618-28; WO2016/077793). Phosphorylation) effect is still weak. In WO2018/115380 and WO2018/172250, a class of SOS inhibitors with a quinazoline structure is disclosed, which significantly improves the mutual inhibitory effect on SOS1 and Ras family proteins, especially KRas, and thus significantly reduces ERK phosphorylation in KRas mutant cancer cell lines. Recently, WO2019122129A1 disclosed a novel benzylamino-substituted pyridopyrimidinone and its derivatives as SOS1 inhibitors, which also achieved certain effects.

Compounds targeting SOS1 inhibitors can mediate pathways involving proteins in the Ras family (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 G Diseases with mutations such as AP (eg NF1). In addition, it also has potential application value in other diseases related to Ras family protein mutations (such as neurofibromatosis, Noonan syndrome (Noonan syndrome, NS), cardiofaciocutaneous syndrome (Cardiofaciocutaneous, CFC) and type 1 hereditary gingival fibromatosis.

The present invention provides a novel benzopyrimidine tricyclic derivative that exhibits exciting inhibitory effects on SOS1 inhibitors, and some compounds even exhibit unexpected pharmacokinetic properties.

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

To achieve the above object, the present invention provides a benzopyrimidine tricyclic compound represented by formula (I) or its stereoisomer, pharmaceutically acceptable salt:

where R₁selected from hydrogen, C_1-4Alkyl, wherein the C_1-4Alkyl is optionally substituted by one or more identical or different halogens or hydroxyl; ring A is selected from: C_6-10Aryl, 5-10 membered heteroaryl; p represents 1, 2 or 3; each R₂independently selected from: hydrogen, C_1-4Alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_1-4Haloalkyl, Hydroxy-C_1-4Alkyl, Hydroxy-C_2-4Haloalkyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, substituted or unsubstituted C₅-C₇Aryl, Hydroxy-C_3-6Cycloalkyl, Hydroxy, Halogen, -NH₂, -N(C_1-4alkyl)₂, cyano, nitro, -SO₂-C_1-4Alkyl; wherein substituted or unsubstituted C₅-C₇The aryl substituent is preferably: C_1-4Alkyl, C_1-4Haloalkyl, halogen, -NH₂、C_1-4Alkoxy, nitro, cyano, C_1-4Aminoalkyl, (C_1-4alkyl)₂N-C_1-4Alkyl, C_1-4Alkyl-NH-C_1-4Alkyl; R₃selected from hydrogen, C_1-4Alkyl, C_3-6Cycloalkyl, 3-6-membered heterocyclyl, oxo, -C(O)ORa, -C(O)NRaRa, where C_1-4Alkyl, C_3-6Cycloalkyl, 3-6-membered heterocyclyl optionally replaced by one or more of the same or different halogen, hydroxyl, -NH₂Substitution, Ra each independently selected from hydrogen, C_1-6Alkyl, C_1-3Haloalkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Cycloalkyl, C_6-10Aryl, 3-10-membered heterocyclic group and 3-10-membered heteroaryl; o represents 1 or 2; R₄selected from 3-10 membered saturated heterocyclic groups, wherein the 3-10 membered saturated heterocyclic groups are optionally substituted by one or more identical or different Rb; Rb is independently selected from C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Cycloalkyl, C_6-10Aryl, 3-10-membered heterocyclic group, 5-10-membered heteroaryl group, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -S(O)₂Rc, -S(O)₂NRcRc, halogen, cyano, hydroxyl, and oxo; wherein Rb is C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Cycloalkyl, C_6-10Aryl, 3-10-membered heterocyclyl and 5-10-membered heteroaryl are all optionally By one or more same or different halogen, cyano, hydroxyl, -NH₂and oxo substitution, wherein oxo is not on the double bond; Rc is each independently selected from hydrogen, C_1-6Alkyl, C_1-3Haloalkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Cycloalkyl, C₀-C₁Alkylene-C₆-₁₀Aryl, 3-10-membered heterocyclyl and 5-10-membered heteroaryl; n represents 0, 1 or 2; X is selected from O, S, NRd, CRdRd, Rd is independently selected from hydrogen, C_1-3Alkyl; R₅selected from hydrogen, C_1-4Alkyl, C_1-4Alkoxy, -NH₂, -NH(C_1-4Alkyl), -N(C_1-4alkyl)₂and halogen; R₆selected from hydrogen, halogen; wherein two R₃Can be linked to form 3-6 membered rings.

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R ₁ is methyl.

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein ring A is selected from: C_6-10Aryl, preferably phenyl; p represents 1, 2 or 3; each R₂independently selected from: hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, halogen, -NH₂、C_1-4Alkoxy, nitro, cyano, preferably hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, halogen, -NH₂, wherein the halogenated C_1-4Alkyl is more preferably substituted by 1, 2 or 3 fluorine C_1-4Alkyl, for example but not limited to -CF₃、CHF₂.

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, wherein Ring A together with p _R substituents has the following substructure:

Rg is selected from: hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, Hydroxy-C_1-4Alkyl, Hydroxy-C_1-4Haloalkyl, C_3-6Cycloalkyl, 3-6-membered heterocyclyl, hydroxy-C_3-6Cycloalkyl, Hydroxy, Halogen, -NH₂、-SO₂-C_1-4Alkyl, cyano; where C_1-4Haloalkyl is preferably an alkyl group substituted by 1, 2 or 3 fluorines, more preferably -CF₃、-CHF₂; Re is selected from: hydrogen, halogen and -NH₂; Rf is selected from: hydrogen, C_1-4Alkyl and halogen, nitro, cyano, wherein halogen is fluorine, chlorine, bromine, iodine, preferably fluorine.

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, wherein ring A together with p substituents _R has the substructure:

Rg is selected from: hydrogen, C _1-4 alkyl, C _1-4 haloalkane, halogen, -NH ₂ , wherein C _1-4 haloalkyl is preferably alkyl substituted by 1, 2, 3 fluorines, more preferably -CF ₃ , -CHF ₂ ; Re is selected from: hydrogen, halogen and -NH ₂ ; Rf is selected from: hydrogen, C _1-4 alkyl, halogen, nitro, wherein halogen is fluorine, chlorine, bromine, iodine, preferably fluorine.

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, wherein ring A together with p substituents _R has the substructure:

In some embodiments, the present invention relates to a compound of formula (I) or its stereoisomer, pharmaceutically acceptable salt, wherein ring A is selected from: 5-10 membered heteroaryl; p represents 1, 2 or 3; each R2 is independently selected from: hydrogen, C1-4 alkyl, C1-4 haloalkyl, halogen, -NH2, C1-4 alkoxy, nitro, cyano, substituted or unsubstituted C₅-C₇Aryl, preferably hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, halogen, -NH_2,substituted or unsubstituted C₅-C₇Aryl, wherein the halo C_1-4Alkyl is more preferably substituted by 1, 2 or 3 fluorine C_1-4Alkyl, for example but not limited to -CF₃、CHF₂, substituted or unsubstituted C₅-C₇The aryl substituent is preferably: C_1-4Alkyl, C_1-4Haloalkyl, halogen, -NH₂、C_1-4Alkoxy, nitro, cyano, C_1-4Aminoalkyl, (C_1-4alkyl)₂N-C_1-4Alkyl, C_1-4Alkyl-NH-C_1-4alkyl.

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

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, wherein ring A together with p substituents _R has the substructure:

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R ₃ is selected from hydrogen, methyl, oxo.

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein the other two _R3 can be connected to form a 3-6-membered ring and a connected ring to form a ring form, such as bridged ring and spiro ring forms well known to those skilled in the art, as shown in the following examples:

In some embodiments, the present invention relates to a compound of formula (I) or its stereoisomer, pharmaceutically acceptable salt, wherein R₄selected from 3-10 membered saturated heterocyclic groups, wherein the 3-10 membered saturated heterocyclic groups are optionally substituted by one or more identical or different Rb; Rb is independently selected from C_1-6Alkyl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -C(O)NRcRc, -S(O)₂Rc, where Rb is the C_1-6Alkyl is optionally replaced by one or more of the same or different halogen, cyano, hydroxyl, -NH₂And oxo; Rc each independently selected from hydrogen, C_1-6Alkyl, C₃-C₆Cycloalkyl, C₀-C₁Alkylene-C₆-₁₀Aryl.

In some embodiments, the present invention relates to a compound of formula (I) or its stereoisomer, pharmaceutically acceptable salt, wherein R₄selected from tetrahydrofuryl and pyrrolidinyl, wherein the tetrahydrofuryl and pyrrolidinyl are optionally substituted by one or more of the same or different Rb; 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 said C_1-6Alkyl is optionally replaced by one or more of the same or different halogen, cyano, hydroxyl, -NH₂and oxo; Rc is each independently selected from hydrogen, C_1-6Alkyl, C₃-C₆Cycloalkyl, C₀-C₁Alkylene-C₆-₁₀Aryl.

In some embodiments, the present invention relates to a compound of formula (I) or its stereoisomer, pharmaceutically acceptable salt, wherein _R is selected from tetrahydrofuranyl and pyrrolidinyl, wherein the tetrahydrofuranyl and pyrrolidinyl are optionally substituted by one or more identical or different Rb, preferably tetrahydrofuranyl and pyrrolidinyl meta-position is connected to the mother nucleus:

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, wherein R ₄ is pyrrolidinyl optionally substituted on nitrogen by Rb, Rb is independently selected from C _1-6 alkyl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, Rc is each independently selected from hydrogen, C _1-6 alkyl, C ₃ -C ₆ cycloalkyl, C ₀ -C ₁ alkylene- C ₆ - ₁₀ aryl.

In some embodiments, the present invention relates to a compound of formula (I) or its stereoisomer, pharmaceutically acceptable salt, wherein R₄is pyrrolidinyl optionally substituted on the nitrogen by Rb, Rb independently selected from C_1-6Alkyl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, Rc are each independently selected from hydrogen, C_1-6Alkyl, C₃-C₆Cycloalkyl, C₀-C₁Alkylene-C₆-₁₀Aryl; wherein the C in Rc_1-6Alkyl, C₃-C₆Cycloalkyl, C₀-C₁Alkylene-C₆-₁₀Aryl is optionally substituted with one or more of the same or different halogen, amino or hydroxy.

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein R is pyrrolidinyl optionally substituted by Rb on nitrogen, Rb is _{independently} selected from _C1-6 alkyl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, and Rc is each independently selected from 5-10-membered heteroaryl; wherein the 5-10-membered heteroaryl in Rc is optionally selected from one or Multiple identical or different halogen, amino or hydroxyl substitutions.

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein _R is tetrahydrofuryl optionally substituted by one or more identical or different Rb, and Rb is independently selected from _C1-6 alkyl, oxo.

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein _R is selected from:

In some embodiments, the present invention relates to a compound of formula (I) or its stereoisomer, pharmaceutically acceptable salt, X is selected from O, CH ₂ .

In some embodiments, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, R ₅ is selected from hydrogen, R ₆ is selected from hydrogen.

In some embodiments, the present invention relates to a compound of formula (I) or its stereoisomer, pharmaceutically acceptable salt, preferably formula (IIa) and/or (IIb):

where R₁selected from hydrogen, C_1-4Alkyl, wherein the C_1-4Alkyl is optionally substituted by one or more identical or different halogens or hydroxyl; Rg is selected from: hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, Hydroxy-C_1-4Alkyl, Hydroxy-C_1-4Haloalkyl, C_3-6Cycloalkyl, 3-6-membered heterocyclyl, hydroxy-C_3-6Cycloalkyl, Hydroxy, Halogen, -NH₂、-SO₂-C_1-4Alkyl, cyano, where C_1-4Haloalkyl is preferably an alkyl group substituted by 1, 2 or 3 fluorines, more preferably -CF₃、-CHF₂; Re is selected from: hydrogen, halogen and -NH₂; Rf is selected from: hydrogen, C_1-4Alkyl and halogen, nitro, cyano, wherein halogen is fluorine, chlorine, bromine, iodine, Fluorine is preferred.

Ring B is a 5-10-membered heteroaryl group; each R₂independently selected from: hydrogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Haloalkyl, Hydroxy-C_1-4Alkyl, Hydroxy-C_2-4Haloalkyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, substituted or unsubstituted C₅-C₇Aryl, Hydroxy-C_3-6Cycloalkyl, Hydroxy, Halogen, -NH₂, -N(C_1-4alkyl)₂, cyano, nitro, -SO₂-C_1-4Alkyl; substituted or unsubstituted C₅-C₇The aryl substituent is preferably: C_1-4Alkyl, C_1-4Haloalkyl, halogen, -NH₂、C_1-4Alkoxy, nitro, cyano, C_1-4Aminoalkyl, (C_1-4alkyl)₂N-C_1-4Alkyl, C_1-4Alkyl-NH-C_1-4Alkyl; p means 1, 2 or 3; R₃selected from hydrogen, C_1-4Alkyl, C_3-6Cycloalkyl, 3-6-membered heterocyclyl, oxo, -C(O)ORa, -C(O)NRaRa, where C_1-4Alkyl, C_3-6Cycloalkyl, 3-6-membered heterocyclyl optionally replaced by one or more of the same or different halogen, hydroxyl, -NH₂, Ra each independently selected from hydrogen, C_1-6Alkyl, C_1-3Haloalkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Cycloalkyl, C_6-10Aryl, 3-10-membered heterocyclic group and 3-10-membered heteroaryl group; o represents 1 or 2; Y is selected from O, NRh, Rh is independently selected from hydrogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Cycloalkyl, C_6-10Aryl, 3-10-membered heterocyclic group, 5-10-membered heteroaryl group, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -S(O)₂Rc, -S(O)₂NRcRc, where Rh is the C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Cycloalkyl, C_6-10Aryl, 3-10-membered heterocyclyl and 5-10-membered heteroaryl are optionally substituted by one or more of the same or different halogens, cyano, hydroxyl, and oxo, and oxo is not on the double bond; Rc is independently selected from hydrogen, C_1-6Alkyl, C_1-3Haloalkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Cycloalkyl, C₀-C₁Alkylene-C₆-₁₀Aryl, C_3-10Heterocyclyl and C_5-10Heteroaryl; n represents 0, 1 or 2; m represents 1 or 2; X is selected from O, S, NRd, CRdRd, Rd is independently selected from hydrogen, C_1-3Alkyl; R₅selected from hydrogen, C_1-4Alkyl, C_1-4Alkoxy, -NH₂, -NH(C_1-4Alkyl), -N(C_1-4alkyl)₂and halogens; R₆selected from hydrogen, halogen.

In some embodiments, the present invention relates to a compound of formula (I) or its stereoisomer, pharmaceutically acceptable salt, more preferably a compound of formula (IIa) and/or (IIb) or its stereoisomer, pharmaceutically acceptable salt:

where R₁Be methyl; Rg is selected from: hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, halogen, -NH₂, where C_1-4Haloalkyl is preferably an alkyl group substituted by 1, 2 or 3 fluorines, more preferably -CF₃、-CHF₂; Re is selected from: hydrogen, halogen and -NH₂; Rf is selected from: hydrogen, C_1-4Alkyl and halogen, nitro; ring B is pyridyl, thienyl; each R₂independently selected from: hydrogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Haloalkyl, Hydroxy-C_1-4Alkyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, substituted or unsubstituted C₅-C₇Aryl, hydroxyl, halogen, -NH₂, -N(C_1-4alkyl)₂, cyano; substituted or unsubstituted C₅-C₇The aryl substituent is preferably: C_1-4Alkyl, C_1-4Haloalkyl, halogen, -NH₂、C_1-4Alkoxy, C_1-4Aminoalkyl, (C_1-4alkyl)₂N-C_1-4Alkyl, C_1-4Alkyl-NH-C_1-4Alkyl; p means 1 or 2; R₃selected from hydrogen, C_1-4Alkyl, oxo, -C(O)ORa, -C(O)NRaRa, where C_1-4Alkyl is optionally substituted by one or more identical or different halogens, hydroxyl, amino, and R is independently selected from hydrogen, C_1-6Alkyl, C_1-3Haloalkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-10Cycloalkyl, C_6-10Aryl, 3-10-membered heterocyclic group and 5-10-membered heteroaryl group; o represents 1; Y is selected from O, NRh, Rh is independently selected from hydrogen, C_1-6Alkyl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc; Rc is each independently selected from hydrogen, C_1-6Alkyl, C_1-3Haloalkyl, C_3-6Cycloalkyl, C₀-C₁Alkylene-C₆-₁₀Aryl; n represents 0 or 1; m represents 1; X is selected from O, CRdRd, Rd is independently selected from hydrogen, C_1-3Alkyl; R₅and R₆are independently selected from hydrogen, halogen.

In some embodiments, the present invention provides the following specific compounds or stereoisomers and pharmaceutically acceptable salts thereof,

In some embodiments, the present invention further provides the following specific compounds or stereoisomers and pharmaceutically acceptable salts thereof,

In some embodiments, the present invention further provides the following specific compounds or stereoisomers and pharmaceutically acceptable salts thereof,

All above mentioned structural aspects are respectively preferred embodiments of the respective aspects. Structural aspects related to the different molecular moieties of the compounds (I) of the present invention may be combined with each other as necessary to obtain preferred compounds. Each combination represents and defines an individual embodiment or a general subset of Compound (I) of the present invention, combinations of substituents and/or variables are permissible so long as such combinations result in stable compounds or useful synthetic intermediates.

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

The present invention further relates to pharmaceutically acceptable salts of compounds of formula (I) (including all embodiments thereof) including pharmaceutically acceptable salts of compounds of formula (I) (including all embodiments thereof) with inorganic or organic acids or bases. Pharmaceutically acceptable salts include, but are not limited to: salts with inorganic acids, such as salts and salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate and alkanoates such as acetate, HOOC-(CH2)n-COOH (where n is 0-4) and the like salt. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

In addition, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

The compounds of the invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. When they have multiple asymmetric stereocenters, their stereocombination forms and their mixtures are included within the scope of the present invention. The selected forms of stereo compounds can be obtained by conventional technical means of those skilled in the art, such as the introduction of chiral raw materials, chiral resolution and other means.

For example: in the present invention, _R4 is selected from tetrahydrofuryl and pyrrolidinyl, and there are stereoisomers, and the stereoisomer fragments have R or S configurations as shown below,

Another example: stereoisomerism also exists when _R3 is substituted in the present invention, and stereoisomer fragments have R or S configurations as shown below,

In another aspect, the compounds as described herein can be formulated into pharmaceutical compositions with a human acceptable carrier and administered to a mammalian host (such as a human patient) in a variety of forms suitable for the chosen route of administration, i.e., orally or parenterally, intravenously, intramuscularly, topically, transdermally, intrathecally, ocularly, intranasally, intraperitoneally or subcutaneously.

The compounds described herein can be administered systemically, for example, orally or intravenously in combination with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules, can be compressed into tablets, or can be admixed directly with the food of the patient's diet. For oral therapeutic administration, the active compounds can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.

In another aspect, the present invention relates to compounds of formula (I) (including all embodiments thereof), which are useful for the preparation, treatment or prevention of diseases and/or conditions associated with or regulated by SOS1; especially diseases and/or conditions in which the inhibition of the interaction of SOS1 with Ras family proteins and/or RAC1 has a therapeutic benefit.

Further, the above-mentioned use of the compound of formula (I) to prepare, treat and/or prevent diseases and/or conditions related to or regulated by SOS1, including but not limited to treating and/or preventing cancer. More preferred is the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

The starting materials for the following reactions are generally known compounds or may be prepared by known procedures or obvious modifications thereof.

The various starting materials, intermediates and compounds described herein can be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrometry, nuclear magnetic resonance and various other spectroscopic analyses. Some embodiments of the compound of the present invention can be realized by the following reaction scheme:

Wherein the substituents are as defined above in the present invention.

其中取代基如本發明以上內容定義。 Reaction flow 2

Wherein the substituents are as defined above in the present invention.

Reaction scheme 3

Reaction scheme 4

Wherein the substituents are as defined above in the present invention, wherein when Y is N, reactions such as alkylation and acylation can be further carried out by techniques well known to those skilled in the art, so as to realize the technical scheme to be expressed in the present invention.

While certain embodiments have been illustrated and described, it should be understood that changes and modifications may be made therein according to ordinary skill in the art without departing from the technology as defined in its broader aspects in the following claims.

Compared with the prior art, the present invention provides a benzopyrimidine tricyclic derivative, which has the structure shown in formula I or its stereoisomer and pharmaceutically acceptable salt. The results of activity experiments show that the benzopyrimidine tricyclic derivatives provided by the present invention have high activity and selectivity, and can be used to treat diseases related to SOS1 inhibitors.

Glossary

"Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined herein. Those skilled in the art will appreciate that for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically unavailable, synthetically infeasible, and/or inherently unstable.

"Alkyl" includes straight and branched chains having the indicated number of carbon atoms, typically 1-20 carbon atoms, eg 1-8 carbon atoms, such as 1-6 carbon atoms. For example, C _1-6 alkyl includes straight chain and branched chain alkyl groups of 1 to ₆ carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like. Alkylene is another subset of alkyl and refers to the same residues as alkyl but with two points of attachment. Alkylene groups generally have 2-20 carbon atoms, eg 2-8 carbon atoms, such as 2-6 carbon atoms. When naming an alkyl residue with a particular number of carbons, all geometric isomers with that number of carbons are intended to be included, for example, "butyl" is meant to include n-butyl, sec-butyl, isobutyl and tert-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" means an alkyl group having 1 to 4 carbons.

"Alkenyl" means a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (usually 1-8 carbon atoms, such as 2-4 carbon atoms) and at least 1 and preferably 1-2 vinyl (>C=C<) sites of unsaturation. Examples of such groups are, for example, vinyl, allyl and but-3-en-1-yl. Included within this term are the cis and trans isomers or mixtures of such isomers. "Lower alkenyl" means alkenyl having 1 to 4 carbons, which can be represented by C _{2 -4} alkenyl.

Haloalkyl (haloalkenyl, haloalkynyl) are each derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of each other by halogen atoms which may be the same or different. If haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions can take place independently of one another on all carbon atoms carrying hydrogen, in the form of mono- or polysubstitutions in each case. Examples of haloalkyl (haloalkenyl, haloalkynyl ₎ are _-CF3 , -CHF2 _{, -CH2F} , _-CF2CF3 -CHFCF3, _-CH2CF3 , _-CF2CH3 , _{-CHFCH3 , -CF2CF2CF3 , -CF2CH2CH3} , -CF= _{CF2 ,} -CCl=CH _2. -CBr= _{CH 2 ,} -C≡CCF _{3 , -CHFCH 2 CH 3 ,} -CHFCH ₂ CF ₃ , _etc.

"Cycloalkyl" means a non-aromatic partially saturated, or fully saturated carbocyclic ring having the indicated number of carbon ring atoms (eg, 3-10, or 3-8, or 3-6 ring carbon atoms). Cycloalkyl groups can be monocyclic or polycyclic (eg, bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl, as well as bridged and caged ring groups (eg, bicyclo[2.2.2]octane). Lower cycloalkane generally refers to C _3-6 monocyclic rings. Unless otherwise specified, lower cycloalkyl groups can generally be fully saturated carbocyclic rings.

"Hydroxyalkyl (hydroxycyclocycloalkyl)" includes one or more hydroxyl groups in place of the aforementioned straight and branched chain alkyl (cycloalkyl) having the indicated number of carbon atoms (usually 1-20 carbon atoms, for example 1-8 carbon atoms, such as 1-6 carbon atoms), and combinations of substituents and/or variables are permissible so long as such combinations result in stable compounds or useful synthetic intermediates.

"Halo-hydroxyalkyl" includes one or more hydroxy and halogen in place of the aforementioned straight and branched chain alkyl groups having the indicated number of carbon atoms (usually 1-20 carbon atoms, for example 1-8 carbon atoms, such as 1-6 carbon atoms), combinations of substituents and/or variables are permissible so long as such combinations result in stable compounds or useful synthetic intermediates.

"Aryl" means an aromatic carbocyclic ring having the indicated number of carbon atoms (eg, 6-12 or 6-10 carbon atoms) in the ring. Aryl groups can be monocyclic or polycyclic (eg, bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl are aromatic (eg, naphthyl). In other cases, a polycyclic aryl group can include a non-aromatic ring fused to an aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl), so long as the polycyclic aryl is bonded to the parent structure via an atom in the aromatic ring. Thus, 1,2,3,4-tetrahydronaphthalen-5-yl (where the moiety is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, whereas 1,2,3,4-tetrahydronaphthalen-1-yl (where the moiety is bonded to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, 1,2,3,4-tetrahydroquinolin-8-yl (where the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, whereas 1,2,3,4-tetrahydroquinolin-1-yl (where the moiety is bound 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 point of attachment (eg, quinolin-5-yl and quinolin-2-yl are heteroaryl). In some cases, unless otherwise specified, the aryl ring can be further substituted by a functional group well known in the art, which does not affect the definition of the number of carbon atoms on the aromatic ring. In some instances, aryl is phenyl or naphthyl. In certain instances, aryl is phenyl. Other examples of aryl groups comprising an aromatic carbocycle fused to a non-aromatic ring are described below. The C ₀ -C ₁ alkylene-C _{6 -10} aryl group mentioned herein generally refers to the corresponding aryl group when the C ₀ alkylene-C _{6 -10} aryl group, and the C ₁ alkylene- _{C 6 -10} aryl group generally refers to the aryl group adjacent to a methylene group, such as benzyl.

"Carboxy" or "carboxyl" means -COOH or a salt thereof.

"Heteroaryl" means an aromatic ring (e.g., 5-12 or 5-10 membered heteroaryl) containing the indicated number of ring atoms consisting of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. A 5-membered heteroaryl is a heteroaryl group having 5 ring atoms. A 6-membered heteroaryl is a heteroaryl group having 6 ring atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed one. Unless otherwise stated, a heteroaryl group can be bonded to the parent structure through a carbon or nitrogen atom, as valence permits. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl and 4-pyridyl, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl. When nitrogen is present in a heteroaryl ring, the nitrogen may exist in an oxidized state (ie, N+-O-) as the nature of the adjacent atoms and group permits. Furthermore, when sulfur is present in a heteroaryl ring, the sulfur may be present in an oxidized state (ie, S+-O- or _SO2 ) as the nature of the adjacent atoms and groups permits. Heteroaryl groups can be monocyclic or polycyclic (eg, bicyclic, tricyclic).

In some instances, heteroaryls are monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole Azole, thiadiazole (for example, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (for example, 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

In other cases, a polycyclic heteroaryl can include a non-aromatic ring fused to a heteroaryl ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) so long as the polycyclic heteroaryl is bonded to the parent structure via an atom in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (where the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (where the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl. Examples of polycyclic heteroaryl groups consisting of heteroaryl rings fused to non-aromatic rings are described below.

"Heterocycloalkyl" means a non-aromatic partially saturated or fully saturated ring (e.g., 3-10 or 3-7 membered heterocycloalkyl), sometimes also referred to herein as a heterocyclyl group, with the specified number of ring atoms consisting of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, and the remaining ring atoms being carbon. A 5-membered heterocycloalkyl is a heterocycloalkyl having 5 ring atoms. A 6-membered heterocycloalkyl is a heterocycloalkyl having 6 ring atoms. A heterocycloalkyl group can be monocyclic or polycyclic (eg, bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. When nitrogen is present in a heterocycloalkyl ring, the nitrogen may exist in an oxidized state (ie, N+-O-) as the nature of the adjacent atoms and group permits. Examples include piperidinyl N-oxide and morpholinyl-N-oxide. Furthermore, when sulfur is present in a heterocycloalkyl ring, the sulfur may exist in an oxidized state (ie, S+-O- or _-SO2- ) as the nature of the adjacent atoms and groups permits. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. In addition, one ring of a polycyclic heterocycloalkyl can be aromatic (eg, aryl or heteroaryl) so long as the polycyclic heterocycloalkyl is bonded to the parent structure through a non-aromatic carbon or nitrogen atom. For example, 1,2,3,4-tetrahydroquinolin-1-yl (where the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl, while 1,2,3,4-tetrahydroquinolin-8-yl (where the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl. Lower heterocycloalkane generally refers to C _3-6 monocyclic rings. Unless otherwise specified, lower heterocycloalkyl is generally preferably a fully saturated carbocycle.

"Alkoxy" means an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc. Alkoxy is also intended to include cycloalkyl groups as defined above also attached via an oxygen bridge. Alkoxy typically has 1-6 carbon atoms attached through an oxygen bridge. "Lower alkoxy" means alkoxy having 1 to 4 carbons.

The term "halo" includes fluoro, chloro, bromo and iodo.

As used herein, the term "substituted" means that any one or more hydrogens on a designated atom or group are replaced by a selection from the designated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo (ie, =0), then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is intended to imply that the compound is robust enough to survive isolation from a reaction mixture and subsequent formulation as at least a practically useful reagent. Substituents are named to the core structure unless otherwise indicated. For example, it is understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of that substituent to the core structure is in the alkyl moiety.

partial list of abbreviations

Experiment The used preparation liquid phase of the present invention carries out the instrument and method of separation and purification as follows: Instrument: Shimadzu preparation liquid phase SIL-10AP

1. Acid method Chromatographic column: Welch Ultimate XB-C18, 21.2*250mm, 10um

Mobile phase: A: 0.05% TFA in water B: Acetonitrile

2. Alkaline method Chromatographic column: Welch Xtimate C18, 21.2*250mm, 10um

Mobile phase: A: 10mmol/L aqueous solution B: Acetonitrile

Column temperature: room temperature

Flow rate: 25ml/min

Detection wavelength: 214/254nm

The present invention will be further described in detail below in conjunction with the embodiments of the specification.

Example 1

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

first step 2-Bromo-4-fluoro-5-nitrobenzoic acid 1b

Compound 2-bromo-4-fluoro-benzoic acid 1a (10.00g, 45.66mmol) was dissolved in concentrated sulfuric acid (40mL), the reaction solution was cooled to 0°C in an ice-water bath, and fuming nitric acid (4mL) was slowly added dropwise. The reaction solution was reacted at 0-5°C for 1 hour, and a large amount of white solids precipitated out. The reaction solution was slowly poured into ice water (300mL), stirred for 30 minutes, filtered, the filter cake was washed with water (300mL), and the solid was dried to give 2-bromo-4-fluoro-5-nitrobenzoic acid 1b (10.50g, white solid), yield, 80%. MS m/z (ESI): 261.9 [M-1] ^- . ¹ H NMR (400MHz, DMSO- d ₆ ) δ 14.00 (s, 1H), 8.50 (d, J =8.0Hz, 1H), 8.17 (d, J =10.6Hz, 1H).

second step 2-Bromo-4-hydroxy-5-nitrobenzoic acid 1d

將化合物2-溴-4-氟-5-硝基苯甲酸1b (10.50g，30.33mmol)和乙醯氧肟酸1c (6.83g,90.99mmol)溶解於二甲基亞碸(150mL)中，向該溶液在加入碳酸鉀(20.96g,151.65mmol)，反應液加熱至80度反應2小時，倒入冰水(600mL)中，用濃鹽酸調節PH至4~5，有固體析出，繼續攪拌30分鐘，過濾，濾餅用水洗滌(100mL)，旋轉蒸發儀乾燥，得到2-溴-4-羥基-5-硝基苯甲酸1d (6.90g，淡黃色固體)，產率：87%。 MS m/z (ESI): 259.9 [M-1] ^- .

third step Methyl 2-bromo-4-hydroxy-5-nitrobenzoate 1e

Take 2-bromo-4-hydroxy-5-nitrobenzoic acid 1d (6.90g, 26.33mmol) and dissolve it in methanol (150mL), slowly add phosphine chloride (8mL) dropwise, after the dropwise completion, the reaction solution is heated to 80°C for 4 hours, cooled to room temperature, spin-dried by a rotary evaporator to remove the solvent, and the obtained residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 2-bromo-4-hydroxy-5-nitro Methyl benzoate 1 e (6.40 g, golden yellow solid), yield: 88%. MS m/z (ESI): 273.9 [M-1] ^- .

the fourth step Methyl 2-bromo-4-hydroxy-5-aminobenzoate 1f

The compound 2-bromo-4-hydroxy-5-nitrobenzoic acid methyl ester 1 e (2.00 g, 7.25 mmol) was dissolved in 50 mL of tetrahydrofuran, and 5% rhodium carbon catalyst (0.20 g) was added under a nitrogen atmosphere. The reaction solution was reacted under a hydrogen atmosphere for 17 hours, filtered, and the filtrate was spin-dried to obtain 2-bromo-4-hydroxy-5-aminobenzoic acid methyl ester 1f (1.78 g, brown solid), yield: 97%. MS m/z (ESI): 244.0 [M-1] ^- .

the fifth step Methyl 2-bromo-4-hydroxy-5-((tetrahydrofuran-3-yl)amino)benzoate 1h

取化合物2-溴-4-羥基-5-氨基苯甲酸甲酯1f (1.78g,7.01mmol)溶解於50mL 1,2-二氯乙烷中，加入四氫呋喃-3-酮1g (1.21g,14.02mmol)，再加入乙酸(0.84g,14.02mmol)，冰水浴下加入三乙醯氧基硼氫化鈉(2.96g,14.02mmol)，反應液繼續攪拌2小時，倒入100mL冰水中淬滅，用碳酸氫鈉調節PH值至8左右，用二氯甲烷萃取(100mL)，有機層旋乾，得到的殘留物用矽膠柱層析法純化(石油醚：乙酸乙酯=1：1)得到2-溴-4-羥基-5-((四氫呋喃-3-基)氨基)苯甲酸甲酯1h (1.20g，棕黃色固體)，產率：47%。 314.0[M-1] ^- .

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

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

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

將7-溴-4-(四氫呋喃-3-基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯1j (1.06g，2.81mmol)，氨基甲酸叔丁酯1k (0.99g，8.43mmol)，碳酸銫(2.75g，8.43mmol)，醋酸鈀(0.03g,0.14mmol)和4,5-雙二苯基膦-9,9-二甲基氧雜蒽(0.08g,0.14mmol)溶解於30mL 1,4-二氧六環中，反應液在氮氣保護下加熱至110度反應4小時，反應液過濾，旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(石油醚：乙酸乙酯=1：1)得到7-((叔丁氧羰基)氨基)-4-(四氫呋喃-3-基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯1l (0.91g，棕黃色油狀物)，產率：71%。 MS m/z (ESI): 379.1 [M+1] ⁺ .

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

取7-((叔丁氧羰基)氨基)-4-(四氫呋喃-3-基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯1l (0.85g，2.25mmol)溶解於20mL鹽酸二氧六環(4M)溶液中，加入乙腈(3mL)，反應液加熱至50度反應2小時，減壓旋乾除去溶劑，加入乙腈(20mL)，攪拌充分後加入碳酸鈉(1.19g,11.25mmol)，反應液加熱至90度反應3小時，反應完畢後，冷卻至室溫，加入20mL水稀釋，用1M稀鹽酸調到pH=7-8，濃縮除去乙腈，有棕褐色固體析出，過濾，濾餅減壓乾燥得到2-甲基-6-(四氫呋喃-3-基)-3,6,7,8-四氫呋喃-4H-[1,4]惡嗪並[3,2-g]喹唑啉-4-酮1m (0.34g，白色固體)，產率：53%。 MS m/z (ESI): 288.1 [M+1] ⁺ .

Ninth step 4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazoline 1n

取2-甲基-6-(四氫呋喃-3-基)-3,6,7,8-四氫呋喃-4H-[1,4]惡嗪並[3,2-g]喹唑啉-4-酮1m (0.40g，1.39mmol)溶解於15mL甲苯中，加入N,N-二異丙基乙胺(1.08g,8.34mmol)和三氯氧磷(0.64g,4.17mmol)，反應液加熱至80度反應2小時，減壓旋乾除去溶劑，加入矽膠拌樣，用矽膠柱層析法純化(石油醚：乙酸乙酯=2：1)得到4-氯-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉1n (0.32g，棕黃色固體)，產率：77%。 MS m/z (ESI): 306.1 [M+1] ⁺ .

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

取4-氯-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉1n (30mg，0.10mmol)和(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺1o (61mg，0.30mmol)溶解於3mL乙醇中，加入N,N-二異丙基乙胺(129mg,1.00mmol)，反應液使用微波加熱至130度反應2小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法一)得到N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺1 (8mg，棕黃色固體)，產率：16%。 MS m/z (ESI): 474.1 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 14.00(s,1H),9.57(dd, J =7.6Hz,3.2Hz,1H),7.74(s,1H),6.99(s,1H),6.86-6.88(m,2H),6.76(s,1H),5.75(m,1H),4.76-4.80(m,1H),4.35-4.43(m,2H),3.70-3.99(m,5H),3.31-3.45(m,1H),2.54(s,3H),2.31-2.38(m,1H),1.90-1.99(m,1H),1.64(d, J =6.8Hz,3H)。

Example 2

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

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

取4-氯-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉1n (70mg，0.23mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺2a (61mg，0.30mmol)溶解於3mL乙醇中，加入N,N-二異丙基乙胺(149mg,1.15mmol)，反應液使用微波加熱至140度反應4小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法一)得到2-甲基-N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉-4-胺2 (55mg，黃色固體)，產率：51%。 MS m/z (ESI): 473.6 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 8.22(s,1H),8.05(d, J =6.8Hz,1H),7.76(d, J =7.6Hz,1H),7.51-7.53(m,2H),7.34(t, J =7.6Hz,1H),6.79(s,1H),5.71-5.75(m,1H),4.84-4.88(m,1H),4.25-4.33(m,2H),3.96-3.99(m,1H),3.83-3.89(m,2H),3.72-3.78(m,1H),3.25-3.37(m,2H),2.63(s,3H),2.33-2.36(m,1H),2.24(d, J =1.6Hz,3H),1.90-1.96(m,1H),1.56(d, J =7.2Hz,3H)。

Example 3

N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin- 4 -amine3

first step N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin- 4 -amine3

取4-氯-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉1n (30mg，0.10mmol)和(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺3a (47mg，0.25mmol)溶解於3mL乙醇中，加入N,N-二異丙基乙胺(65mg,0.50mmol)，反應液使用微波加熱至140度反應4小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法一)得到N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉-4-胺3 (9mg，黃色固體)，產率：20%。 MS m/z (ESI): 459.1 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 14.03(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 =7.6Hz,1H),7.24(t, J =54.4Hz,1H),6.97(s,1H),5.92-5.96(m,1H),4.80-4.81(m,1H),4.38-4.39(m,2H),3.95-4.00(m,1H),3.82-3.92(m,2H),3.74(dd, J =15.2Hz,8.4Hz,1H),3.33-3.38(m,2H),2.49(s,3H),2.33-2.38(m,1H),1.91-1.99(m,1H),1.70(d, J =6.8Hz,3H)。

Example 4

N-((R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin- 4- amine4

first step N-((R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin- 4- amine4

取4-氯-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉1n (30mg，0.10mmol)和(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺4a (41mg，0.20mmol)溶解於3mL乙醇中，加入N,N-二異丙基乙胺(65mg,0.50mmol)，反應液使用微波加熱至140度反應4小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法一)得到N-((R)-1-(3-(三氟甲基)-2-氟苯基)乙基)-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉-4-胺4 (6mg，黃色固體)，產率：13%。 MS m/z (ESI): 477.1 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 14.04(s,1H),9.72(d, J =6.8Hz,1H),7.87(t, J =6.8Hz,1H),7.77(s,1H),7.71(t, J =7.2Hz,1H),7.43(t, J =7.6Hz,1H),6.97(s,1H),,5.89-5.93(m,1H),4.80-4.81(m,1H),4.38-4.39(m,2H),3.95-4.01(m,1H),3.82-3.93(m,2H),3.74(dd, J =15.6Hz, J =8.4Hz,1H),3.33-3.38(m,2H),2.48(d, J =1.2Hz,3H),2.33-2.40(m,1H),1.91-1.97(m,1H),1.72(d, J =6.8Hz,3H)。

Example 5

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

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

Methyl 2-bromo-4-hydroxy-5-((tetrahydrofuran-3-yl)amino)benzoate 1h (300mg, 0.95mmol) and triethylamine (961mg, 9.50mmol) were dissolved in 15mL of dichloromethane, chloroacetyl chloride 5a (322mg, 2.85mmol) was added dropwise, and the reaction solution was reacted at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 7-bromo-3-oxo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 5b (220mg, colorless oil), yield: 62%. MS m/z (ESI): 356.0 [M+1] ⁺ . ¹ H NMR (400MHz,DMSO- d ₆ )δ 7.88(s,1H),7.41(s,1H),5.41-5.45(m,1H),4.72(s,2H),4.14-4.20(m,1H),3.87-3.92(m,2H),3.84(s,3H),3.70(q, J = 8.0Hz, 1H) 2.09-2.21 (m, 2H).

second step 2-Methyl-6-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-[1,4]oxazino[3,2-g]quinazoline-4,7(8H)-dione 5d

將7-溴-3-氧-4-(四氫呋喃-3-基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯5b (200mg，0.56mmol)，鹽酸乙脒5c (159mg,1.68mmol)，醋酸鈀(25mg，0.11mmol),4,5-雙二苯基膦-9,9-二甲基氧雜蒽(65mg,0.11mmol)和碳酸銫(912mg,2.80mmol)溶解於10mL 1,4-二氧六環中，反應液在氮氣保護下加熱至110度反應4小時，反應液加10mL水稀釋，用1M HCl調節PH值至4-5，用乙酸乙酯(30mL×2)萃取，有機層用飽和食鹽水(20mL)洗滌，有機層旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(二氯甲烷：甲醇=20：1)得到2-甲基-6-(四氫呋喃-3-基)-3,6-二氫-4H-[1,4]惡嗪並[3,2-g]喹唑啉-4,7(8H)-二酮5d (85mg，淡黃色固體)，產率：49%。 MS m/z (ESI): 302.1 [M+1] ⁺ .

third step 4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one 5e

取2-甲基-6-(四氫呋喃-3-基)-3,6-二氫-4H-[1,4]惡嗪並[3,2-g]喹唑啉-4,7(8H)-二酮5d (80mg，0.26mmol)溶解於10mL甲苯中，加入N,N-二異丙基乙胺(336mg,2.60mmol)和三氯氧磷(199mg,1.30mmol)，反應液加熱至80度反應2小時，減壓旋乾除去溶劑，加入矽膠拌樣，用矽膠柱層析法純化(石油醚：乙酸乙酯=3：2)得到4-氯-2-甲基-6-(四氫呋喃-3-基)-6H-[1,4]惡嗪並[3,2-g]喹唑啉-7(8H)-酮5e (65mg，黃色固體)，產率：78%。 MS m/z (ESI): 320.0 [M+1]+.

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

取4-氯-2-甲基-6-(四氫呋喃-3-基)-6H-[1,4]惡嗪並[3,2-g]喹唑啉-7(8H)-酮5e (30mg，0.10mmol)和(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺1o (61mg，0.30mmol)溶解於3mL乙醇中，加入N,N-二異丙基乙胺(58mg,0.45mmol)，反應液使用微波加熱至140度反應2小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法一)得到4-(((R)-1-(3-氨基-5-(三氟甲基) 苯基)乙基)氨基)-2-甲基-6-(四氫呋喃-3-基)-6H-[1,4]惡嗪並[3,2-g]喹唑啉-7(8H)-酮5 (6mg，白色固體)，產率：14%。 MS m/z (ESI): 488.2 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 9.90(s,1H),8.27(d,J=2.4Hz,1H),7.26(s,1H),6.88(d,J=5.6Hz,2H),6.77(s,1H),5.76-5.79(m,1H),4.78-4.89(m,3H),4.14-4.22(m,1H),4.09-4.12(m,1H),3.93-3.96(m,1H),3.84-3.89(m,1H),2.60(s,3H),2.25-2.33(m,1H),1.97-2.03(m,1H),1.66(d,J=6.8Hz,3H)。

Example 6

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

first step 4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(tetrahydrofuran-3-yl)-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one 6

取4-氯-2-甲基-6-(四氫呋喃-3-基)-6H-[1,4]惡嗪並[3,2-g]喹唑啉-7(8H)-酮5e (20mg，0.06mmol)和(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺3a (34mg，0.18mmol)溶解於3mL 1,4-二氧六環中，加入N,N-二異丙基乙胺(78mg,0.60mmol)，反應液使用微波加熱至140度反應4小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法二)得到4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-(四氫呋喃-3-基)-6H- [1,4]惡嗪並[3,2-g]喹唑啉-7(8H)-酮6 (8mg，白色固體)，產率：28%。 MS m/z (ESI): 473.1 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 8.34(d, J =5.5Hz,1H),8.11(s,1H),7.65-7.69(m,1H),7.51(t, J =7.2Hz,1H),7.30(t, J =8.0Hz,1H),7.25(t, J =54.4Hz,1H),7.14(s,1H),5.79-5.84(m,1H),4.96-5.00(m,1H),4.63-4.73(m,2H),4.26(dd, J =14.8Hz,8.0Hz,1H),4.11-4.14(m,1H),3.87-3.99(m,2H),2.33-2.44(m,2H),2.31(d, J =1.2Hz,3H),1.64(d, J =7.2Hz,3H)。

Example 7

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

first step Methyl 4-fluoro-2-nitro-5-((tetrahydrofuran-3-yl)amino)benzoate 7c

Methyl 4,5-difluoro-2-nitrobenzoate 7a (2.0g, 9.21mmol), 3-aminotetrahydrofuran 7b (1.60g, 18.42mmol) and sodium carbonate (2.93g, 27.63mmol) were dissolved in 20mL N,N-dimethylformamide, heated to 50°C for 2 hours. The reaction solution was cooled to room temperature, diluted with 100 mL of water, extracted with ethyl acetate (100 mL), the organic layer was washed with water (100 mL×2), washed with saturated brine (100 mL), left to stand for layers, and the organic layer was spin-dried under reduced pressure on a rotary evaporator. 20 g, yellow solid), yield: 84%. MS m/z (ESI): 285.1 [M+1] ⁺ .

second step Methyl 4-fluoro-5-((2-methylallyl)(tetrahydrofuran-3-yl)amino)-2-nitrobenzoate 7e

Methyl 4-fluoro-2-nitro-5-((tetrahydrofuran-3-yl)amino)benzoate 7c (1.00g, 3.52mmol), 3-bromo-2-methylpropene 7d (1.43g, 10.56mmol), and cesium carbonate (2.29g, 7.04mmol) were dissolved in 15mL N,N-dimethylformamide, and the reaction solution was reacted at 25°C for 17 hours. Add 80mL of water, adjust the pH value to about 7 with 1M hydrochloric acid, extract with ethyl acetate (50mL×2), wash the organic layer with water (50mL×2), wash with saturated brine (50mL), let stand for separation, and spin dry the organic layer under reduced pressure. Methyl ester 7e (1.20 g, yellow oil), yield: 98%. MS m/z (ESI): 339.1 [M+1] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ 7.56(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)。

third step 4-Fluoro-2-nitro-5-((2-oxopropanyl)(tetrahydrofuran-3-yl)amino)benzyl methyl ester 7f

Methyl 4-fluoro-5-((2-methylallyl)(tetrahydrofuran-3-yl)amino)-2-nitrobenzoate 7e (1.20g, 3.48mmol) was dissolved in 20mL tetrahydrofuran and 20mL water, and potassium osmate dihydrate (0.06g, 0.17mmol), N-methylmorpholine oxide (0.80g, 6.96mmol) and sodium periodate ( 2.98g, 13.92mmol), the reaction solution was slowly raised to room temperature, and reacted at 25°C for 17 hours. Ethyl acetate (50mL) was extracted, the organic layer was washed with water (50mL×2), saturated brine (50mL), left to stand and separated, and the organic layer was spin-dried under reduced pressure to obtain methyl 4-fluoro-2-nitro-5-((2-oxopropanyl)(tetrahydrofuran-3-yl)amino)benzoate 7f (1.15g, brown oil), yield: 87%. MS m/z (ESI): 341.1 [M+1] ⁺ .

the fourth step 4-fluoro-5-((2-hydroxypropyl)(tetrahydrofuran-3-yl)amino)-2-nitrobenzoic acid methyl ester 7g

Methyl 4-fluoro-2-nitro-5-((2-oxopropanyl)(tetrahydrofuran-3-yl)amino)benzoate 7f (1.15g, 3.0l) was dissolved in 20mL of methanol, sodium borohydride (0.11g, 3.01mmol) was added under an ice-water bath, and the reaction solution was reacted at 0°C for 1 hour. Add 100mL of water to dilute, extract with ethyl acetate (100mL), wash the organic layer with saturated brine (100mL), stand to separate and separate, the organic layer is spin-dried under reduced pressure, and the crude product obtained is purified by preparative chromatographic column (petroleum ether:ethyl acetate=2:1) to obtain 7g of methyl 4-fluoro-5-((2-hydroxypropyl)(tetrahydrofuran-3-yl)amino)-2-nitrobenzoate (0.90g, golden yellow oil), yield: 87%. MS m/z (ESI): 343.1 [M+1] ⁺ .

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

7g (0.50g, 1.46mmol) of methyl 4-fluoro-5-((2-hydroxypropyl)(tetrahydrofuran-3-yl)amino) -2 -nitrobenzoate was dissolved in 10mL of N,N-dimethylformamide, sodium hydrogen (0.18g, 7.30mmol) was added under an ice-water bath, and the reaction solution was reacted at 20°C for 1 hour. Slowly poured into 100mL ice water to quench the reaction, adjusted the pH value to 6-7 with 1M hydrochloric acid, extracted with ethyl acetate (100mL), washed the organic layer with saturated brine (100mL), stood to separate layers, and spin-dried the organic layer under reduced pressure. Stir at 20°C for 2 hours. Add 100mL of ice water to dilute, then adjust the pH value to 6-7 with 1M hydrochloric acid, extract with ethyl acetate (100mL), wash the organic layer with water (100mL×2), wash with saturated brine (100mL), stand and separate the layers, and the organic layer is spin-dried under reduced pressure to obtain the crude product. Methyl H-benzo[b][1,4]oxazine-6-carboxylate 7h (0.36 g, brown-yellow oil), yield: 72%. MS m/z (ESI): 323.1 [M+1]. ¹ H NMR(400MHz,CDCl ₃ )δ 7.50(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)。

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

Dissolve 2-methyl-7-nitro-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate methyl ester 7h (0.36g, 1.12mmol) in 10mL of methanol, add 10% palladium carbon (0.023g, 0.11mmol) under nitrogen protection, and replace the reaction system with hydrogen for 3 times. React for 17 hours. The reaction liquid was filtered, and the filtrate was spin-dried under reduced pressure to obtain 7-amino-2-methyl-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 7i (0.32g, brown solid). Yield: 94%. MS m/z (ESI): 293.1 [M+1] ⁺ .

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

取7-氨基-2-甲基-4-(四氫呋喃-3-基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯7i (0.32g，1.09mmol)溶解於15mL鹽酸二氧六環(4M)溶液中，加入乙腈(3mL)，反應液加熱至50度反應2小時，減壓旋乾除去溶劑，加入乙腈(20mL)，攪拌充分後加入碳酸鈉(562mg,5.30mmol)，反應液加熱至90度反應3小時，反應完畢後，冷卻至室溫，加入20mL水稀釋，用1M稀鹽酸調到pH=7-8，濃縮除去乙腈，乙酸乙酯(50mL×2)萃取，靜置分層，有機層減壓旋乾，得到的粗品用製備色譜柱純化(二氯甲烷：甲醇=100：3)得到2,8-二甲基-6-(四氫呋喃-3-基)-3,6,7,8-四氫呋喃-4H-[1,4]惡嗪並[3,2-g]喹唑啉-4-酮7j (0.21g，淡黃色固體)，產率：64%。 MS m/z (ESI): 302.1 [M+1] ⁺ .

eighth step 4-Chloro-2,8-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazoline 7k

取2,8-二甲基-6-(四氫呋喃-3-基)-3,6,7,8-四氫呋喃-4H-[1,4]惡嗪並[3,2-g]喹唑啉-4-酮7j (200mg,0.64mmol)溶解於10mL甲苯中，加入N,N-二異丙基乙胺(827mg,6.40mmol)和三氯氧磷(294mg,1.92mmol)，反應液加熱至80度反應2小時，減壓旋乾除去溶劑，加入矽膠拌樣，用矽膠柱層析法純化(石油醚：乙酸乙酯=3：2)得到4-氯-2,8-二甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉7k (120mg，黃色固體)，產率：57%。 MS m/z (ESI): 320.1 [M+1] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ 7.28(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)。

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

取4-氯-2,8-二甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉7k (35mg，0.11mmol)和(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺1o (56mg，0.28mmol)溶解於1mL N-甲基吡咯烷酮中，加入N,N-二異丙基乙胺(142mg,1.10mmol)，反應液使用微波加熱至140度反應3小時，反應液用製備色譜柱純化(分離純化方法一)得到N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,8-二甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉-4-胺7 (37mg，棕黃色固體)，產率：69%。 MS m/z (ESI): 488.1 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 13.88(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=7.2Hz,1H),4.77(m,1H),4.41-4.45(m,1H),3.70-3.98(m,4H),3.49-3.55(m,1H),2.93-3.08(m,1H),2.54(s,3H),2.30-2.43(m,1H),1.98-2.04(m,1H),1.64(d, J =6.8Hz,3H),1.37(dd, J =6.4Hz,1.6Hz,3H)。

Example 8

2,8-Dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4- amine8

first step 2,8-Dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4- amine8

Take 4-chloro-2,8-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazoline7k(35mg, 0.11mmol) and ((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine2a(67mg, 0.33mmol) was dissolved in 1mL of N-methylpyrrolidone, N,N-diisopropylethylamine (142mg, 1.10mmol) was added, and the reaction solution was heated to 140°C for 4 hours using a microwave. base)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4-amine8(29 mg, white solid), yield: 53%. MS m/z(ESI): 487.2[M+1]⁺.¹H NMR (400MHz, DMSO-d ₆ )δ 14.04(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=2.8Hz,1H),5.85-5.88(m,1H),4.83(s,1H),4.39-4.47(m,1H),3.69-4.02(m,4H),3.50-3.55(m,1H),2.94-3.08(m,1H),2.60(s,3H),2.48(s,3H) ,2.32-2.42(m,1H),1.83-2.03(m,1H),1.65(d,J=7.2Hz,3H),1.37(dd,J=6.0,2.8Hz,3H).

Example 9

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

first step Methyl 2-bromo-4-(2-oxopropoxy)-5-((tetrahydrofuran-3-yl)amino)benzoate 9b

Methyl 2-bromo-4-hydroxy-5-((tetrahydrofuran-3-yl)amino)benzoate 1h (1.30g, 4.01mmol) and triethylamine (961mg, 9.50mmol) were dissolved in 30mL of acetonitrile, bromoacetone 9a (1.10g, 8.02mmol) was added, and the reaction solution was reacted at 25°C for 17 hours. The reaction solution was directly spin-dried under reduced pressure, and the obtained crude product was purified by preparative chromatographic column (petroleum ether:ethyl acetate=3:2) to obtain 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] ⁺ .

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

Dissolve methyl 2-bromo-4-(2-oxopropoxy)-5-((tetrahydrofuran-3-yl)amino)benzoate 9b (1.20g, 3.05mmol) in 20mL of methanol, add acetic acid (0.37g, 6.10mmol) and sodium cyanoborohydride (0.38g, 6.10mmol), and react the reaction solution at 25°C for 4 hours. Add 10 mL of saturated sodium bicarbonate solution to quench the reaction, extract with ethyl acetate (100 mL), wash the organic layer with saturated brine (100 mL), let stand to separate layers, and spin the organic layer to dry under reduced pressure. The obtained crude product is purified by preparative chromatographic column (petroleum ether: ethyl acetate = 3:2) to obtain 7-bromo-3-methyl-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl Ester 9c (0.91 g, colorless oil), yield: 81%. MS m/z (ESI): 356.0 [M+1] ⁺ . ¹ H NMR (400MHz, CDCl ₃ )δ 7.27(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).

third step 7-((tert-butoxycarbonyl)amino)3-methyl-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 9d

將7-溴-3-甲基-4-(四氫呋喃-3-基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯9c (0.91g，2.47mmol)，氨基甲酸叔丁酯1k (0.87g，7.41mmol)，碳酸銫(2.01g，6.18mmol)，醋酸鈀(0.06g,0.25mmol)和4,5-雙二苯基膦-9,9-二甲基氧雜蒽(0.14g,0.25mmol)溶解於20mL 1,4-二氧六環中，反應液在氮氣保護下加熱至110度反應4小時，反應液過濾，旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(石油醚：乙酸乙酯=1：1)得到7-((叔丁氧羰基)氨基)3-甲基-4-(四氫呋喃-3-基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯9d (0.72g，棕黃色油狀物)，產率：72%。 MS m/z (ESI): 354.0 [M-56+1] ⁺ .

the fourth step 2,7-Dimethyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydrofuran-4H-[1,4]oxazino[3,2-g]quinazolin-4-one 9e

取7-((叔丁氧羰基)氨基)3-甲基-4-(四氫呋喃-3-基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯9d (0.72g,1.77mmol)溶解於20mL鹽酸二氧六環(4M)溶液中，加入乙腈(5mL)，反應液加熱至50度反應2小時，減壓旋乾除去溶劑，加入乙腈(20mL)，攪拌充分後加入碳酸鈉(0.94g,8.85mmol)，反應液加熱至90度反應3小時，反應完畢後，冷卻至室溫，加入20mL水稀釋，用1M稀鹽酸調到pH=7-8，濃縮除去乙腈，，乙酸乙酯(50mL×2)萃取，有機層用飽和食鹽水(50mL)洗滌，靜置分層，有機層減壓旋乾，得到的粗品用製備色譜柱純化(二氯甲烷：甲醇=100：3)得到2,7-二甲基-6-(四氫呋喃-3-基)-3,6,7,8-四氫呋喃-4H-[1,4]惡嗪並[3,2-g]喹唑啉-4-酮9e (0.37g，白色固體)，產率：69%。 MS m/z (ESI): 302.1 [M+1] ⁺ .

the fifth step 4-Chloro-2,7-dimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazoline 9f

取2,7-二甲基-6-(四氫呋喃-3-基)-3,6,7,8-四氫呋喃-4H-[1,4]惡嗪並[3,2-g]喹唑啉-4-酮9e (0.20g，0.66mmol)溶解於10mL甲苯中，加入N,N-二異丙基乙胺(0.85g,6.60mmol)和三氯氧磷(0.30g,1.98mmol)，反應液加熱至80度反應2小時，減壓旋乾除去溶劑，加入矽膠拌樣，用矽膠柱層析法純化(石油醚：乙酸乙酯=3：2)得到4-氯-2,7-二甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉9f (0.03g，黃色固體)，產率：14%。 MS m/z (ESI): 320.1 [M+1] ⁺ .

step six 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

取4-氯-2,7-二甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉9f (30mg，0.10mmol)和(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺1o (55mg，0.27mmol)溶解於1mL N-甲基吡咯烷酮中，加入N,N-二異丙基乙胺(116mg,0.90mmol)，反應液使用微波加熱至140度反應4小時，反應液用製備色譜柱純化(分離純化方法一)得到N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7-二甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉-4- 胺9 (16.5mg，淡黃色固體)，產率：37%。 MS m/z (ESI): 488.2 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 13.88(s,1H),9.53(t, J =4.4Hz,1H),7.59-7.64(m,1H),7.03(m,1H),6.84-6.88(m,2H),6.76(s,1H),5.76(t, J =7.2Hz,1H),4.56-4.61(m,1H),4.31-4.34(m,1H),3.74-4.12(m,6H),2.54(s,3H),2.30-2.43(m,1H),1.95-2.04(m,1H),1.64(d, J =7.2Hz,3H),1.13(t, J =5.6Hz,3H)。

Example 10

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 10

first step Methyl indoline 6-carboxylate 10b

Add 1H-indole-6-carboxylic acid methyl ester 10a (5.0 g, 28.0 mmol) and acetic acid (50 mL) into the reactor, stir to dissolve. Use an ice-water bath to control the temperature, and add sodium cyanoborohydride (5.3 g, 84.0 mmol) in batches at an internal temperature of 10-20 °C, and the outgassing is obvious. After the addition, the temperature was raised naturally, and stirring was continued at 20~25°C for 1~2h. 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 phase was washed with saturated aqueous sodium bicarbonate solution (50 mL), dried and concentrated to dryness under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain methyl indoline 6-carboxylate 10b (3.9 g, off-white solid), yield: 76.1%. MS m/z (ESI): 178.1 [M+1] ⁺ .

second step 1-(tetrahydrofuran-3-yl)indoline-6-carboxylic acid methyl ester 10c

Methyl indoline 6-carboxylate 10b (3.9g, 19.5mmol), tetrahydrofuran-3- one 1g (3.4g, 39.0mmol), methanol (40mL) and acetic acid (1mL) were sequentially added to the reactor and stirred to dissolve. Use an ice-water bath to control the temperature, and add sodium triacetyloxyborohydride (12.5 g, 58.5 mmol) in batches at an internal temperature of 10-20 °C, and the outgassing is obvious. After the addition, the temperature was raised naturally, and stirring was continued at 20~25°C for 16~18h. 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 obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain methyl 1-(tetrahydrofuran-3-yl)indoline-6-carboxylate 10c (3.9 g, oil), yield: 50%. MS m/z (ESI): 248.1 [M+1] ⁺ .

third step 5-Bromo-1-(tetrahydrofuran-3-yl)indoline-6-carboxylic acid methyl ester 10d

Add methyl 5-bromo-1-(tetrahydrofuran-3-yl)indoline-6-carboxylate 10c (2.5g, 9.9mmol) and N,N-dimethylformamide (25mL) into the reactor and stir to dissolve. Use an ice-water bath to control the temperature, and add N-bromosuccinimide (2.0 g, 10.9 mmol) in batches at an internal temperature of 5-10°C. After the addition, the temperature was raised naturally, and stirring was continued at 20~25°C for 1~2h. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×3), the combined organic phases were washed with saturated aqueous sodium sulfite (50 mL), dried and concentrated to dryness under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain methyl 5-bromo-1-(tetrahydrofuran-3-yl)indoline-6-carboxylate 10d (2.6 g, oily substance), yield: 76%. MS m/z (ESI): 326.0 [M+1] ⁺ .

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

Methyl 5-bromo-1-(tetrahydrofuran-3-yl)indoline-6-carboxylate 10d (1.00 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) was added to the reactor under nitrogen protection. The reaction was heated up to an internal temperature of 110~120°C, and kept stirring for 30~32h. Water (40 mL) was added to the reaction solution, 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 obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:3) to obtain 2-methyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydro-4H-pyrrolo[2,3-g]quinazolin-4-one 10e (0.28g, brown solid), yield: 34%. MS m/z (ESI): 272.1 [M+1] ⁺ .

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

2-Methyl-6-(tetrahydrofuran-3-yl)-3,6,7,8-tetrahydro-4H-pyrrolo[2,3-g]quinazolin-4- one 10e (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 the reactor, nitrogen gas protection. The reaction was heated up to an internal temperature of 70~80°C, and kept stirring for 2~3h. The reaction solution was concentrated to dryness under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 4-chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazoline 10f (70mg, yellow solid), yield: 44%. MS m/z (ESI): 290.1 [M+1] ⁺ .

step six N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 10

4-Chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazoline 10f (20mg, 0.07mmol), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline 1o (21mg, 0.11mmol), N,N-diisopropylethylamine (18mg, 0.14mmol) and absolute ethanol (2 mL) into a microwave tube. The reaction mixture was reacted under microwave conditions at 130° C. for 5 h. The reaction solution was sent to preparation for separation (separation and purification method 1), 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] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 14.22(s,1H),9.46(d, J =6.8Hz,1H),7.42(d, J =5.2Hz,2H),6.89(s,1H),6.86(s,1H),6.75(s,1H),5.65-5.73(m,1H),4.45-4.47(m,1H),3.71-3.96(m,4H),3.55-3.67(m,2H),3.18(t, J =7.6Hz,2H),2.55(s,3H),2.15 -2.33(m,1H),1.94-2.03(m,1H),1.63(d, J =7.2Hz,3H)。

Example 11

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

first step Benzyl 3-((4-bromo-2-hydroxy-5-(methoxycarbonyl)phenyl)amino)pyrrolidine-1-carboxylate 11b

取化合物2-溴-4-羥基-5-氨基苯甲酸甲酯1f (1.8g,7.35mmol)溶解於50mL 1,2-二氯乙烷中，加入苯基N-苄氧羰基-3-吡咯烷酮11a (3.22g,14.69mmol)，再加入乙酸(0.88g,14.69mmol)，冰水浴下加入三乙醯氧基硼氫化鈉(3.11g,14.69mmol)，反應液繼續攪拌2小時，倒入100mL冰水中淬滅，用碳酸氫鈉調節PH值至8左右，用二氯甲烷萃取(100mL)，有機層旋乾，得到的殘留物用矽膠柱層析法純化(石油醚：乙酸乙酯=1：1)得到3-((4-溴-2-羥基-5-(甲氧羰基)苯基)氨基)吡咯烷-1-羧酸苄酯11b (3.0g，棕黃色固體)，產率：91%。 MS m/z (ESI): 449.0 [M+1] ⁺ .

second step 4-(1-((Benzyloxy)carbonyl)pyrrolidin-3-yl)-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 11c

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

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

將4-(1-((苄氧基)羰基)吡咯烷-3-基)-7-溴-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯11c (2.3g，4.85mmol)，氨基甲酸叔丁酯1k(1.70g，14.56mmol)，碳酸銫(4.73g，14.56mmol)，醋酸鈀(0.06g,0.24mmol)和4,5-雙二苯基膦-9,9-二甲基氧雜蒽(0.14g,0.24mmol)溶解於40mL 1,4-二氧六環中，反應液在氮氣保護下加熱至110度反應4小時，反應液過濾，旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(石油醚：乙酸乙酯=1：1)得到4-(1-((苄氧基)羰基)吡咯烷-3-基)-7-((叔-丁氧基羰基)氨基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯11d (1.2g，棕黃色油狀物)，產率：48%。 MS m/z (ESI): 512.1 [M+1] ⁺ .

the fourth step Benzyl 3-(2-methyl-4-keto-3,4,7,8-tetrahydrofuran-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 11e

取4-(1-((苄氧基)羰基)吡咯烷-3-基)-7-((叔-丁氧基羰基)氨基)-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-羧酸甲酯11d (1.2g，2.35mmol)溶解於20mL鹽酸二氧六環(4M)溶液中，加入乙腈(3mL)，反應液加熱至50度反應2小時，減壓旋乾除去溶劑，加入乙腈(20mL)，攪拌充分後加入碳酸鈉(1.19g,11.75mmol)，反應液加熱至90度反應3小時，反應完畢後，冷卻至室溫，加入20mL水稀釋，用1M稀鹽酸調到pH=7-8，濃縮除去乙腈，有棕褐色固體析出，過濾，濾餅減壓乾燥得到3-(2-甲基-4-酮-3,4,7,8-四氫呋喃-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-羧酸苄酯11e (0.63g，白色固體)，產率：64%。 MS m/z (ESI): 421.1 [M+1] ⁺ .

the fifth step Benzyl 3-(4-chloro-2-methyl-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 11f

取苯基3-(2-甲基-4-酮-3,4,7,8-四氫呋喃-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-羧酸甲酯11e (0.63g，1.50mmol)溶解於15mL甲苯中，加入N,N-二異丙基乙胺(1.16g,9.0mmol)和三氯氧磷(0.68g,4.5mmol)，反應液加熱至80度反應2小時，減壓旋乾除去溶劑，加入矽膠拌樣，用矽膠柱層析法純化(石油醚：乙酸乙酯=2：1)得到3-(4-氯-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-羧酸苄酯11f (0.38g，棕黃色固體)，產率：58%。 MS m/z (ESI): 439.0 [M+1] ⁺ .

step six Benzyl 3-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 11g

取3-(4-氯-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-羧酸苄酯11f (100mg，0.23mmol)和(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺1o (93mg，0.46mmol)溶解於3mL 1,4-二氧六環中，加入N,N-二異丙基乙胺(148mg,1.15mmol)，反應液使用微波加熱至140度反應2小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化得到3-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-羧酸苄酯11g (96mg，棕黃色固體)，產率：70%。 MS m/z (ESI): 607.0 [M+1] ⁺ . ¹ H NMR(400MHz,Methanol- d ₄ )δ 7.64(d, J =5.2Hz,1H),7,27-7.43(m,5H),6.92-6.99(m,3H),6.85(s,1H),5.70-5.82(m,1H),5.09-5.18(m,2H),4.70-4.78(m,1H),4.31-4.43(m,2H),3.59-3.86(m,2H),3.37-3.58(m,4H),2.57(s,3H),2.20-2.29(m,2H),1.69(d, J =7.2Hz,3H)。

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

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-carboxylate11g(96mg, 0.16mmol), dissolved in 30mL of methanol, then palladium carbon (19mg, 10%) was added, the reaction system was replaced with hydrogen three times, the reaction solution was reacted at room temperature under a hydrogen atmosphere for 2 hours, the reaction solution was filtered, and the rotary evaporator was spin-dried to remove the solvent to obtain N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(pyrrolidine-3-yl)-7,8-dihydro-6H- [1,4]oxazin[3,2-g]quinazolin-4-amine1lh(64 mg, brown oil), yield: 85%. MS m/z(ESI): 473.1[M+1]⁺,¹H NMR (400MHz, Methanol-d ₄)δ 7.71(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).

eighth step 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)pyrrolidin-1-yl)ethyl-1-one 11

取N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-6-(吡咯烷-3-yl)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺1lh (64mg，0.14mmol)和乙酸-N-琥珀醯亞胺酯1 1i (44mg，0.28mmol)溶解於3mL二氯甲烷中，反應液在室溫下反應2小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法一)得到1-(3-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-基)乙基-1-酮11 (8mg，白色固體)，產率：18%。 MS m/z (ESI): 515.0 [M+1] ⁺ . ¹ H NMR(400MHz,Methanol- d ₄ )δ 7.60-7.76(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)。

Ninth step 1-((S)-3-(4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)pyrrolidin-1-yl)ethan-1-one 11-1 and 1-((R)-3-(4-((R)-1-(3-amino-5-( Trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)pyrrolidin-1-yl)ethan-1-one 11-2

將化合物1-(3-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-基)乙基-1-酮11 (30mg，白色固體)經過製備色譜柱純化(分離純化方法二)得到1-((S)-3-(4-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪並[3,2-g]喹唑啉-6-基)吡咯烷-1-基)乙-1-酮11-1 (4mg，白色固體)。 MS m/z (ESI): 515.0 [M+1] ⁺ . ¹ H NMR(400MHz,Methanol- d ₄ )δ 7.45(d, J =8.0Hz,1H),6.90-7.00(m,3H),6.79(s,1H),5.59-5.68(m,1H),4.73-4.87(m,1H),4.28-4.37(m,2H),3.59-3.94(m,3H),3.34-3.58(m,3H),2.41(s,3H),2.26-2.35(m,1H),2.18-2.27(m,1H),2.09(s,3H),1.63(d, J =6.8Hz,3H)。 and 1-((R)-3-(4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)pyrrolidin-1-yl)ethan-1-one 11-2 (4 mg, white solid). MS m/z(ESI)：515.0[M+1] ⁺ ， ¹ H NMR(400MHz,Methanol- d ₄ )δ 7.46(d, J =8.0Hz, 1H),6.90-6.99(m,3H),6.79(s,1H),5.58-5.69(m,1H),4.74-4.86(m,1H),4.29-4.37(m,2H),3.62-3.93(m,3H),3.35-3.58(m,3H),2.41(s,3H),2.27-2.32(m,1H),2.16-2.27(m,1H),2.09(s,3H),1.63(d, J =6.8Hz,3H)。

Example 12

1-(3-(2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidin-1-yl)ethyl-1-one 12

first step Benzyl 3-(2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 12a

取3-(4-氯-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-羧酸苄酯11f (100mg，0.23mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙基-1-胺2a (93mg，0.46mmol)溶解於3mL 1,4-二氧六環中，加入N,N-二異丙基乙胺(148mg,1.15mmol)，反應液使用微波加熱至140度反應2小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化得到3-(2-甲基-4-(((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-羧酸苄酯12a (119mg，棕黃色固體)，產率：86%。 MS m/z (ESI): 606.1 [M+1] ⁺ .

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

將3-(2-甲基-4-(((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-羧酸苄酯12a (119mg，0.20mmol)，溶解於3mL甲醇中，然後加入鈀碳(24mg，10%)，反應體系用氫氣置換三次，反應液在氫氣氛圍下室溫反應2小時，反應液過濾，旋轉蒸發儀旋乾除去溶劑，得到2-甲基-N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)-6-(吡咯烷-3-基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺12b (84mg，棕黃色油狀物)，產率：91%。 MS m/z (ESI): 472.1 [M+1] ⁺ .

third step 1-(3-(2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidin-1-yl)ethyl-1-one 12

取2-甲基-N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)-6-(吡咯烷-3-基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺12b (40mg，0.08mmol)和乙醯氯12c (8mg，0.10mmol)溶解於2mL四氫呋喃中，加入N,N-二異丙基乙胺(21mg,0.16mmol)，反應液在室溫下反應1小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化得到1-(3-(2-甲基-4-(((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-基)乙基-1-酮12 (10mg,白色固體)，產率：23%。 MS m/z (ESI): 514.0 [M+1] ⁺ . ¹ H NMR (400MHz,Methanol- d ₄ )δ 7.69(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 J =6 .8Hz, 3H).

Example 13

1-(3-(2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidin-1-yl)propyl-1-one 13

first step 1-(3-(2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)pyrrolidin-1-yl)propyl-1-one 13

取2-甲基-N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)-6-(吡咯烷-3-基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺12b (40mg，0.08mmol)和丙醯氯13a (9mg，0.10mmol)溶解於2mL四氫呋喃中，加入N,N-二異丙基乙胺(21mg,0.16mmol)，反應液在室溫下反應1小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化得到1-(3-(2-甲基-4-(((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)吡咯烷-1-基)乙基-1-酮13 (12mg，白色固體)，產率：26%。 MS m/z (ESI): 528.1 [M+1] ⁺ . ¹ H NMR(400MHz,Methanol- d ₄ )δ 7.65-7.79(m,2H),7.58(d, J =7.8Hz,1H),7.34(t, J =8.0Hz,1H),6.94(d, J =2.8Hz,1H),5.95-5.97(m,1H),4.70-4.88(m,1H),4.40(s,2H),3.84(m,2H),3.52-3.70(m,2H),3.42-3.52(m,2H),2.62(s,3H),2.53(t, J =2.0Hz,3H),2.32-2.37(m,3H),2.15-2.30(m,1H),1.63-1.77(m,3H),1.10-1.20(m,3H)。

Example 14

Compounds 14 to 23 were prepared by referring to the similar methods of Example 1 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and the similar synthesis methods of intermediates are easily obtained by referring to existing methods by those skilled in the art.

Example 15

Compounds 24 and 25 were prepared by referring to the similar methods of Example 11 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and similar synthesis methods of intermediates are easily obtained by referring to existing methods by those skilled in the art.

Example 16

2-Methyl-N-((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine 26

first step

N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine 26b

Dissolve 4-chloro-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazoline 1n (80mg, 0.26mmol) and (R)-1-(4-bromothiophen-2-yl)ethylamine 26a (110mg, 0.52mmol) in 5mL of ethanol, add N,N-diisopropylethylamine (40mg , 0.65mmol) and then heated to 150°C with microwave and kept stirring for 6 hours. The reaction solution was prepared and purified by high performance liquid chromatography (separation and purification method 1) to obtain the target product N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine 26b (80.0 mg, yellow solid), yield: 51%. MS m/z (ESI): 475.0 [M+1] ⁺ .

second step 2-Methyl-N-((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine 26

在氮氣保護下，把N-((R)-1-(4-溴噻吩-2-基)乙基)-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺26b (50.0mg,0.08mmol)和(2-((甲氨基)甲基)苯基)硼酸26c (30mg,0.16mmol)溶於5mL 1,4-二氧六環和0.5mL水中，依次加入二氯[1,1-雙(二叔丁基膦基)二茂鐵]鈀(II)(10mg,0.01mmol)和碳酸鉀(40mg，0.32mmol)，氮氣保護下反應升溫至110度反應10小時。 The reaction solution was prepared and purified by high performance liquid chromatography (separation and purification method 1) to obtain the target product 2-methyl-N-((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine 26 (5.0 mg, yellow solid), yield: 10% . MS m/z (ESI): 516.2 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 14.21(s,1H),9.81(s,1H),9.04(s,2H),7.70(s,1H),7.51(s,1H),7.43-7.49(m,2H),7.38(s,1H),7.25-7.28(m,1H),7.04(s,1H),6.09-6.17(m,1H),4.69-4.77(m,1H),4.35-4.44(m,2H),4.16(s,2H),3.92-3.98(m,1H),3.84-3.89(m,1H),3.75-3.82(m,1H),3.70(dd, J =15.6,8.4Hz,2H),2.61(s,3H),2.54(s,3H),2.26-2.33(m,1H),1.87-1.96(m,1H),1.81(d, J =6.8Hz,3H).

Example 17

Compounds 28 , 33, 39, and 41 were prepared by referring to the method of Example 16 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and similar synthetic methods of intermediates can be easily obtained by referring to existing methods by those skilled in the art.

Example 18

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4- amine50

first step Methyl 2-bromo-4-hydroxy-5-((tetrahydrofuran-3-yl)amino)benzoate 50b

將化合物2-溴-4-羥基-5-[(氧雜環戊烷-3-基)氨基]苯甲酸甲酯1h (1.2g,3.8mmol)，N,N-二異丙基乙胺(0.74g,5.7mmol)溶解於無水的20mL二氯甲烷中，在氮氣保護下反應液降至0度緩慢滴加2-溴-2-甲基丙醯溴50a (0.96g,4.18mmol)反應1小時，反應液加50mL水稀釋，用二氯甲烷(30mL×2)萃取，有機層合併用飽和食鹽水(50mL)洗滌，有機層旋轉蒸發儀旋乾除去溶劑，得到粗品2-溴-4-羥基-5-((四氫呋喃-3-基)氨基)苯甲酸甲酯50b (2g，紅棕色油狀物)，直接用於下一步。 Yield: 90%. MS m/z (ESI): 465.9 [M+1] ⁺ .

second step 7-Bromo-2,2-dimethyl-3-oxo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 50c

The crude compound 2-bromo-4-hydroxy-5-((tetrahydrofuran-3-yl)amino)methyl benzoate 50b (1.6g, 3.44mmol) was dissolved in 35mL of acetonitrile, anhydrous sodium carbonate (1.2g, 11.32mmol) was added and heated to 80°C for 6 hours, and the reaction solution was cooled to room temperature. The filtrate was filtered through Celite and spin-dried, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:2) to obtain 7-bromo-2,2-dimethyl-3-oxo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate methyl ester 50c (1.2 g, light brown solid), yield: 79%. MS m/z (ESI): 386.1 [M+1] ⁺ .

third step 2,8,8-Trimethyl-6-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-[1,4]oxazino[3,2-G]quinazoline-4,7(8H)-dione 50d

The compound 7-bromo-2,2-dimethyl-3-oxo-4-(tetrahydrofuran-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester 50c (550mg, 1.43mmol) was dissolved in anhydrous 1,4-dioxane (1mL) and acetamidine hydrochloride 5c (405mg, 4.29mmol), palladium acetate (84mg , 0.37mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (83mg, 0.14mmol) and cesium carbonate (2.33g, 7.15mmol).反應液在氮氣保護下加熱至110度反應7小時，反應液加50mL水稀釋，用乙酸乙酯(30mL×2)萃取，水相用1M HCl調節PH值至6-7，再用乙酸乙酯(30mL×2)萃取，有機層合併用飽和食鹽水(50mL)洗滌，有機層旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(二氯甲烷：甲醇=15：1)得到2,8,8-三甲基-6-(四氫呋喃-3-基)-3,6-二氫-4H-[1,4]惡嗪並[3,2-G]喹唑啉-4,7(8H)-二酮50d (120mg，淡黃色固體)，產率：20%。 MS m/z (ESI): 330.1 [M+1] ⁺ .

the fourth step N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 50e

Compound 2,8,8-trimethyl-6-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-[1,4]oxazino[3,2-G]quinazoline-4,7(8H)-dione 50d (50mg, 0.15mmol), Carter condensing agent (99.5mg, 0.22mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (34mg, 0.22mmol) was dissolved in 3mL N,N-dimethylacetamide and stirred at room temperature for 10 minutes.化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺1o (46mg，0.22mmol)加入到上述反應液中，加熱至80度反應3小時，反應液加20mL水稀釋，用乙酸乙酯(20mL×2)萃取，有機層合併用飽和食鹽水(20mL)洗滌，有機層旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(二氯甲烷：甲醇=10：1)得到N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(四氫呋喃-3-基)-7,8-二氫-6H-吡咯並[2,3-g]喹唑啉-4-胺50e (27 mg，淡黃色固體)，產率：35%。 MS m/z (ESI): 516.2 [M+1] ⁺ .

the fifth step 4-((3-amino-5-(trifluoromethyl)benzyl)amino)-2,8,8-trimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazine-[3,2-g]quinazolin-7-ol 50f

The compound N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 50e (30mg, 0.06mmol) was dissolved in anhydrous tetrahydrofuran (3mL), and 1.5M DIBAL-H (0.5mL, 0.75 mmol), the reaction was slowly warmed to room temperature and stirred for 1 hour. Quenched by pouring into 10 mL of ice water, extracted with ethyl acetate (10 mL*2), and the organic layer was spin-dried to obtain the crude product 4-((3-amino-5-(trifluoromethyl)benzyl)amino)-2,8,8-trimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazine-[3,2-g]quinazolin-7-ol 50f (30 mg, yellow-green oil). Rate: 96%. MS m/z (ESI): 518.2 [M+1] ⁺ .

step six N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4- amine50

The crude compound 4-((3-amino-5-(trifluoromethyl)benzyl)amino)-2,8,8-trimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazine-[3,2-g]quinazolin-7-ol 50f (30 mg, 0.06 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), and 47% boron trifluoride diethyl ether ( 0.5mL), triethylsilane (0.5mL), reacted for 1 hour. It was quenched by adding 10 mL of water, extracted with ethyl acetate (10 mL*2), and the organic layer was spin-dried to obtain a crude product. The crude product was purified by preparative chromatographic column (separation and purification method 1) to obtain N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(tetrahydrofuran-3-yl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4-amine 50 (4.2 mg, light yellow solid), yield: 14%. MS m/z (ESI): 502.2 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 7.90(t, J =7.6Hz,1H),7.51(s,1H),6.85-6.89(m,2H),6.78(s,1H),6.70(s,1H),5.59-5.63(m,1H),5.55(s,2H),4.87-4.92(m,1H),3.93-3.99(m,1H),3.70-3.88(m,3H),3.01-3.13(m,2H),2.31-2.38(m,4H),1.86-1.91(m,1H),1.56(d, J =6.8Hz,3H),1.31-1.33(m,6H).

Example 19

Compounds 51, 52, and 53 were prepared by referring to the similar methods of Example 18 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and similar synthetic methods of intermediates are easily obtained by referring to existing methods by those skilled in the art.

Example 20

1-(3-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-6-yl)pyrrolidin-1-yl)ethyl-1- one54

first step tert-butyl 2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-pyrrolo[2,3-g]quinazoline-6-carboxylate 54b

將化合物1-(叔丁基)6-甲基5-溴二氫吲哚-1,6-二羧酸54a (1g,2.81mmol)，鹽酸乙脒5c (800mg,8.43mmol)，醋酸鈀(58mg，0.26mmol),4,5-雙二苯基膦-9,9-二甲基氧雜蒽(300mg,0.52mmol)和碳酸銫(4.58g,14.05mmol)溶解於30mL 1,4-二氧六環中，反應液在氮氣保護下加熱至110度反應4小時，反應液加50mL水稀釋，用乙酸乙酯(30mL×2)萃取，水相用1M HCl調節PH值至6-7，再用乙酸乙酯(30mL×2)萃取，有機層合併用飽和食鹽水(50mL)洗滌，有機層旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(二氯甲烷：甲醇=10：1)得到2-甲基-4-氧代-3,4,7,8-四氫-6H-吡咯並[2,3-g]喹唑啉-6-羧酸叔丁酯54b (140mg，淡黃色固體)，產率：16.5%。 MS m/z (ESI): 302.1 [M+1] ⁺ .

second step Tert-butyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazoline-6-carboxylate 54c

The compound 2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-pyrrolo[2,3-g]quinazoline-6-carboxylate tert-butyl ester 54b (100mg, 0.33mmol), Carter condensing agent (219mg, 0.49mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (100mg, 0.66mmol) was dissolved in 5mL N,N-dimethylacetamide, stirred at room temperature for 10 minutes.化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺3a (94mg，0.49mmol)加入到上述反應液中，加熱至80度反應2小時，反應液加20mL水稀釋，用乙酸乙酯(20mL×2)萃取，有機層合併用飽和食鹽水(20mL)洗滌，有機層旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(二氯甲烷：甲醇=10：1)得到叔丁基(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-吡咯並[2,3-g]喹唑啉-6-羧酸鹽54c (96mg，淡黃色固體)，產率：61.5%。 MS m/z (ESI): 473.5 [M+1] ⁺ .

third step (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 54d

The compound tert-butyl(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazoline-6-carboxylate 54c (70mg, 0.15mmol) was dissolved in dichloromethane (1mL) and 4M hydrochloric acid methanol solution (3mL) was added to the reaction solution at 25°C for 5 hours. The reaction solution was concentrated at 25°C to obtain the crude product (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 54d , which was directly used in the next reaction without purification.

the fourth step Benzyl 3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 54e

Compound (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 54d (80mg, 0.21mmol) was dissolved in 9mL 1,2-dichloroethane and 1mL methanol, and phenyl N-benzyloxycarbonyl-3-pyrrolidone 11a (92mg, 0.42 mmol) reaction solution was reacted at 25° C. for 0.5 hour. Sodium cyanoborohydride (26mg, 0.42mmol) was added to the reaction solution and stirring was continued for 18 hours. Quenched by pouring into 10 mL of ice water, extracted with dichloromethane (10 mL), the organic layer was spin-dried, and the obtained residue was purified with a large plate (dichloromethane:methanol=10:1) to obtain benzyl 3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-6-yl)pyrrolidin-1 -Carboxylate 54e (50 mg, yellow oil), yield: 34%. MS m/z (ESI): 576.2 [M+1] ⁺ .

the fifth step N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(pyrrolidin-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 54f

The compound benzyl 3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 54e (43 mg, 0.07 mmol) was dissolved in 10 mL of dichloromethane and 1 mL of methanol, and 10% Pd/C (20 mg) was added, Stir at 25°C for 18 hours under hydrogen atmosphere. Celite was filtered to remove Pd/C, and the filtrate was concentrated and spin-dried to obtain the crude product of N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(pyrrolidin-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 54f (20 mg, yellow solid), yield: 42.7%. MS m/z (ESI): 442.2 [M+1] ⁺ .

step six 1-(3-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-6-yl)pyrrolidin-1-yl)ethan-1-one 54

將化合物N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(吡咯烷-3-基)-7,8-二氫-6H-吡咯並[2,3-g]喹唑啉-4-胺54f (22mg,0.05mmol)溶解於5mL二氯甲烷加入N,N-二異丙基乙胺(13mg,0.1mmol)冰浴反應降溫到0度，加入乙醯氯12c (7.85mg,0.1mmol)反應液在25度下反應1小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法一)得到1-(3-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-吡咯並[2,3-g]喹唑啉-6-基)吡咯烷-1-基)乙-1-酮54 (1.02mg，類白色固體)，產率：3.8%。 MS m/z (ESI): 484.2 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 7.78-7.85(m,1H),7.62-7.70(m,1H),7.48(t, J =7.2Hz,1H),7.10-7.37(m,4H),5.75-5.81(m,1H),4.31-4.49(m,1H),3.68-3.85(m,1H),3.44-3.60(m,5H),3.03-3.09(m,2H),2.24-2.28(m,4H),1.98-2.04(m,4H),1.60(d, J =6.8Hz,3H).

Example 21

Compounds 55 and 56 were prepared by referring to the similar method of Example 20 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and similar synthetic methods of intermediates are easily obtained by referring to existing methods by those skilled in the art.

Example 22

1-(3-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-[1,4]oxazino[3,2-G]quinazolin-6-yl)pyrrolidin-1-yl)propan-1- one57

first step 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-6-(pyrrolidin-3-yl)-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one 57b

The compound benzyl 3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8trimethyl-7-oxo-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 57a (600 mg, 0.95 mmol) was dissolved in dichloromethane (15 mL) and methanol ( 1 mL), 10% palladium carbon (100 mg) was added to replace the reaction system with hydrogen, and the reaction was carried out at room temperature in this system for 18 hours. After the reaction was completed, diatomaceous earth was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:methanol=10:1) to obtain 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-6-(pyrrolidin-3-yl)-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one 57b (330mg, white solid), yield: 69. 5%. MS m/z (ESI): 500.0 [M+1] ⁺ .

second step 4-{[(1R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl]amino}-2,8,8-trimethyl-6-(pyrrolidin-3-yl)-6H,7H,8H-[1,4]oxazino[3,2-G]quinazolin-7-ol 57c

Compound 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-6-(pyrrolidin-3-yl)-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one 57b (200mg, 0.4mmol) was dissolved in anhydrous THF (15mL), and 1.5M D IBAL-H (3 mL, 4.5 mmol), the reaction was slowly warmed to room temperature and stirred for 3 hours. Quenched by pouring into 10 mL of ice water, extracted with ethyl acetate (20 mL*2), and the organic layer was spin-dried to obtain the crude product 4-{[(1R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl]amino}-2,8,8-trimethyl-6-(pyrrolidin-3-yl)-6H,7H,8H-[1,4]oxazino[3,2-G]quinazolin-7-ol 57c (200mg , yellow-green oil), yield: 99%. MS m/z (ESI): 502.0 [M+1] ⁺ .

third step 1-(3-(4-{[(1R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl]amino}-7-hydroxy-2,8,8-trimethyl-6H,7H,8H-[1,4]oxazino[3,2-G]quinazolin-6-yl)pyrrolidin-1-yl)propan-1-one 57e

The crude compound 4-{[(1R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl]amino}-2,8,8-trimethyl-6-(pyrrolidin-3-yl)-6H,7H,8H-[1,4]oxazino[3,2-G]quinazolin-7-ol 57c (200mg, 0.36mmol) was dissolved in anhydrous dichloromethane (10mL), added N,N -Diisopropylethylamine (150mg, 1.2mmol), 2,5-dioxopyrrolidin-1-ylpropionate 57d (140mg, 0.8mmol), and the reaction was stirred at room temperature for 18 hours. Quenched by pouring into 10 mL of ice water, extracted with dichloromethane (10 mL*2), and spin-dried the organic layer to obtain the crude product 1-(3-(4-{[(1R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl]amino}-7-hydroxy-2,8,8-trimethyl-6H,7H,8H-[1,4]oxazino[3,2-G]quinazolin-6-yl)pyrrolidin-1-yl)propane -1-Kone 57e (200 mg, yellow-green oil), yield: 90%. MS m/z (ESI): 558.0 [M+1] ⁺ .

the fourth step 1-(3-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-[1,4]oxazino[3,2-G]quinazolin-6-yl)pyrrolidin-1-yl)propan-1- one57

The crude compound 1-(3-(4-{[(1R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl]amino}-7-hydroxy-2,8,8-trimethyl-6H,7H,8H-[1,4]oxazino[3,2-G]quinazolin-6-yl)pyrrolidin-1-yl)propan-1-one 57e (200 mg, 0.4 mmol) was dissolved in anhydrous dichloromethane Alkane (15mL), trifluoroacetic acid (82mg, 0.72mmol) and triethoxysilane (118mg, 0.72mmol) were added, and the reaction was stirred at room temperature for 1 hour. Poured into 10 mL of ice water to quench, extracted with dichloromethane (10 mL*2), and the organic layer was spin-dried to obtain the crude product. The reaction crude product was purified by preparative chromatographic column (separation and purification method 1) to obtain 1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-[1,4]oxazino[3,2-G]quinazolin-6-yl)pyrrolidin-1-yl)propan-1- one 57 (110mg, light yellow solid), yield : 56.4%. MS m/z (ESI): 542.3 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 9.58(m,1H),7.74-7.77(m,2H),7.55-7.59(m,1H),7.10-7.38(m,2H),6.93(d, J =2.4Hz,1H),5.92-5.98(m,1H),4.75-4.89(m,1H),3.56-3.88(m,4H),3.18-3.27(m,2H),2.48(s,3H),2.27-2.34(m,4H),1.71(d, J =7.2Hz,1H),1.32-1.34(m,6H),0.98-1.03(m,3H).

Example 23

Compounds 58 and 59 were prepared by referring to the similar methods of Example 22 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and similar synthesis methods of intermediates are easily obtained by referring to existing methods by those skilled in the art.

Example 24

1-(3-(4-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidin-1-yl)ethanone 60

first step 3,3-Dimethyl-2-oxindole-6-carboxylic acid methyl ester 60b

Methyl 2-oxindole-6-carboxylate 60a (10.0g, 52.31mmol) and methyl iodide (7.42g, 52.31mmol) were dissolved in 300mL of N,N-dimethylformamide solution and the temperature was lowered to zero, and 60% sodium hydrogen (4.18g, 104.62mmol) was added in batches and reacted at zero for 1 hour. Water (500 mL) was added to the reaction solution, extracted with ethyl acetate (300 mL×2), the organic layer was spin-dried, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain methyl 3,3-dimethyl-2-oxindole-6-carboxylate 60b (10.00 g, white solid), yield: 87%. MS m/z (ESI): 220.1 [M+1] ⁺ .

second step Methyl 3,3-dimethylindole-6-carboxylate 60c

3,3-Dimethyl-2-oxindole-6-carboxylic acid methyl ester 60b (10.00g, 45.61mmol) was dissolved in 200mL of tetrahydrofuran and cooled to minus 10°C, sodium borohydride (5.18g, 136.83mmol) was added and boron trifluoride ether solution (22.66g, 159.63mmol) was added dropwise, and the temperature was gradually raised to room temperature and stirred for 4 hours. Then the reaction solution was cooled to zero and the pH value was adjusted to acidic with 1M hydrochloric acid, stirred at room temperature for 3 hours, extracted with ethyl acetate (200mL×2), the organic layer was spin-dried, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain the target product 3,3-dimethylindole-6-carboxylic acid methyl ester 60c (8.00g, white solid), yield: 71%. MS m/z (ESI): 206.2 [M+1] ⁺ .

third step Methyl 5-bromo-3,3-dimethylindole-6-carboxylate 60d

Dissolve methyl 3,3-dimethylindole-6-carboxylate 60c (3.00g, 12.15mmol) in 80mL of acetonitrile, cool down to minus 30 degrees, then add N-bromosuccinimide (2.21g, 12.39mmol), and react at this temperature for 0.5 hours. Water (30 mL) was added to the reaction solution, ethyl acetate (50 mL×2) was extracted, the organic layer was spin-dried, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product 5-bromo-3,3-dimethylindole-6-carboxylic acid methyl ester 60d (2.3 g, brown solid), yield: 66%. MS m/z (ESI): 285.9 [M+1] ⁺ .

the fourth step 1-(1-((Benzyloxy)carbonyl)pyrrolidin-3-yl)-5-bromo-3,3-dimethylindole-6-carboxylic acid methyl ester 60e

Methyl 5-bromo-3,3-dimethylindole-6-carboxylate 60d (2.10 g, 7.39 mmol) and benzyl 3-oxopyrrolidine-1-carboxylate 11a (3.24 g, 14.78 mmol) were dissolved in 30 mL of methanol, sodium cyanoborohydride (1.83 g, 29.56 mmol) and a drop of acetic acid were added and stirred at room temperature for 12 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×2), the organic layer was spin-dried, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product 1-(1-((benzyloxy)carbonyl)pyrrolidin-3-yl)-5-bromo-3,3-dimethylindole-6-carboxylic acid methyl ester 60e (3.1 g, yellow oil), yield: 85%. MS m/z (ESI): 487.0 [M+1] ⁺ .

the fifth step 1-(1-(Benzyloxy)carbonyl)pyrrolidin-3-yl)-5-(tert-butoxycarbonyl)amino)-3,3-dimethylindole-6-carboxylic acid methyl ester 60f

1-(1-((Benzyloxy)carbonyl)pyrrolidin-3-yl)-5-bromo-3,3-dimethylindole-6-carboxylic acid methyl ester 60e (2.5g, 5.13mmol) and tert-butyl carbamate (3.00g, 25.65mmol) were dissolved in 30mL of 1,4-dioxane, and then 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.3 9g, 0.67mmol), palladium acetate (0.12g, 0.51mmol) and cesium carbonate (1.67g, 5.13mmol), replaced with nitrogen and heated to 120°C for 10 hours. The reaction solution was filtered and concentrated, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) to obtain the target product 1-(1-(benzyloxy)carbonyl)pyrrolidin-3-yl)-5-(tert-butoxycarbonyl)amino)-3,3-dimethylindole-6-carboxylic acid methyl ester 60f (2.14g, yellow oil), yield: 80%. MS m/z (ESI): 523.2 [M+1] ⁺ .

step six 5-Acetylaminoimidazole-1-(1-((benzyloxy)carbonyl)pyrrolidin-3-yl)-3,3-dimethylindole-6-carboxylic acid methyl ester 60g

1-(1-(Benzyloxy)carbonyl)pyrrolidin-3-yl)-5-(tert-butoxycarbonyl)amino)-3,3-dimethylindole-6-carboxylic acid methyl ester 60f (1.70g, 3.25mmol) was dissolved in 20mL of acetonitrile, and then 4mL of 3M dioxane hydrochloride solution was added and stirred at 50°C for 2 hours. The reaction solution was concentrated and spin-dried to obtain 60 g of the crude target product 5-acetylaminoimidazole-1-(1-((benzyloxy)carbonyl)pyrrolidin-3-yl) -3,3 -dimethylindole-6-carboxylate methyl ester and benzyl 3-(2,8,8-trimethyl-4-oxo-7,8-dihydro-3H-pyrrole[2,3-g]quinazolin-6(4H)-yl)pyrrolidine-1-carboxylate The mixture was used directly in the next step.

step seven Benzyl 3-(2,8,8-trimethyl-4-oxo-7,8-dihydro-3H-pyrrolo[2,3-g]quinazolin-6(4H)-yl)pyrrolidine-1-carboxylate 60h

Dissolve 5-acetylaminoimidazole-1-(1-((benzyloxy)carbonyl)pyrrolidin-3-yl)-3,3-dimethylindole-6-carboxylate methyl ester 60i and benzyl 3-(2,8,8-trimethyl-4-oxo-7,8-dihydro-3H-pyrrole[2,3-g]quinazolin-6(4H)-yl)pyrrolidin-1-carboxylate mixture in 20 mL of acetonitrile, and then Sodium carbonate (1.72 g, 16.25 mmol) was added and stirring was continued at 50 °C for 3 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=15:1) to obtain the target product benzyl 3-(2,8,8-trimethyl-4-oxo-7,8-dihydro-3H-pyrrole[2,3-g]quinazolin-6(4H)-yl)pyrrolidine-1-carboxylate 60h (1.30 g, yellow solid), yield: 92%. MS m/z (ESI): 433.1 [M+1] ⁺ .

eighth step Benzyl 3-(4-chloro-2,8,8-trimethyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 60i

Benzyl 3-(2,8,8-trimethyl-4-oxo-7,8-dihydro-3H-pyrrole[2,3-g]quinazolin-6(4H)-yl)pyrrolidine-1-carboxylate 60h (1.30g, 3.00mmol) and N,N-diisopropylethylamine (3.88g, 30.00mmol) were dissolved in 20mL of toluene, and phosphorus oxychloride (4.6g , 30.00mmol) and heated to 110 degrees and continued stirring for 10 hours. Concentrate the reaction solution, add 15 mL of ice water and extract with ethyl acetate (20 mL×2), combine the organic phases, and purify the obtained residue by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product benzyl 3-(4-chloro-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 60i (1.09g, yellow oil), yield: 81%. MS m/z (ESI): 451.1 [M+1] ⁺ .

Ninth step Benzyl 3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 60j

Benzyl 3-(4-chloro-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 60i (0.50g, 1.07mmol) and N,N-diisopropylethylamine (0.55g, 4.28mmol) were dissolved in 10mL of ethanol, and (R)-1-(3-(difluoromethyl)-2 -Fluorophenyl)ethylamine 3a (0.40g, 2.14mmol) was then microwaved to 140°C and kept stirring for 12 hours. The reaction solution was concentrated to remove the solvent, and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain the target product benzyl 3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 60j (0.54 g, yellow oil), yield: 81%. MS m/z (ESI): 604.1 [M+1] ⁺ .

tenth step N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,8,8-trimethyl-6-(pyrrolidin-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4- amine60k

Benzyl 3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidine-1-carboxylate 60j (0.50 g, 0.83 mmol) was dissolved in 15 mL of dichloromethane and 1 mL of methanol, and 10% palladium on carbon (0. 10 g) was stirred at room temperature under hydrogen atmosphere for 12 hours. The reaction solution was filtered and concentrated to remove the solvent to obtain the target product N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,8,8-trimethyl-6-(pyrrolidin-3-yl)-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolin-4-amine 60k (0.38g, yellow solid), yield: 97%. MS m/z (ESI): 470.2 [M+1] ⁺ .

Eleventh step 1-(3-(4-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidin-1-yl)ethanone 60

N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,8,8-trimethyl-6-(pyrrolidin-3-yl)-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-4-amine 60k (0.02g, 0.04mmol) was dissolved in 5 mL of dichloromethane, and 2,5-dioxypyrrolidine-1-acetic acid 11i was added ( 0.01 g, 0.08 mmol) and N,N-dimethyldiisopropylethylamine (0.01 g, 0.08 mmol) were stirred at room temperature for 2 hours. The reaction solution was concentrated to remove the solvent, and the obtained crude product was prepared and purified by high performance liquid chromatography (separation and purification method 1) to obtain the target product 1-(3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidin-1-yl)ethanone 60 (6.0mg, yellow solid), producing Rate: 27%. MS m/z (ESI): 512.1 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 14.11(s,1H),9.50-9.57(m,1H),7.69-7.76(m,1H),7.57(t, J =7.2Hz,1H),7.42-7.48(m,1H),7.30-7.38(m,2H),7.10-7.25(m,1H),5.88-5.98(m,1H),4.42-4.52(m,1H),4.31-4.41(m,1H),3.80-3.88(m,1H),3.61-3.78(m,2H),3.47-3.59(m,2H),2.51(s,3H),2.15-2.32(m,2H),1.98(s,3H),1.69(s,3H),1.28-1.38(m,6H).

Example 25

(R)-2-Methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4- amine61

first step Methyl 5-(((benzyloxy)carbonyl)amino)-2-bromo-4-hydroxybenzoate 61a

取化合物2-溴-4-羥基-5-氨基苯甲酸甲酯1f (2.8g,11.43mmol)溶解於30mL二氯甲烷中，加入氯甲酸苄酯(2.33g,13.71mmol)，再加入碳酸鈉(2.42g,22.86mmol)，反應液繼續攪拌2小時，倒入100mL水中淬滅，用2N鹽酸調節PH值至8左右，用二氯甲烷萃取(100mL)，有機層旋乾，得到的殘留物用矽膠柱層析法純化(石油醚：乙酸乙酯=1：1)得到甲基5-(((苄氧基)羰基)氨基)-2-溴-4-羥基苯甲酸酯61a (3.7g，棕黃色固體)，產率：85%。 MS m/z (ESI): 380.1 [M+1] ⁺ .

second step 4-Phenyl 6-methyl 7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4,6-dicarboxylate 61b

Methyl 5-(((benzyloxy)carbonyl)amino)-2-bromo-4-hydroxybenzoate 61a (3.7g, 9.76mmol), 1,2-dibromoethane 1i (3.63g, 19.53mmol) and potassium carbonate (4.04g, 29.28mmol) were dissolved in 60mL N,N-dimethylformamide, heated to 80°C for 16 hours. Diluted with 160 mL of water, extracted with ethyl acetate (100 mL), washed the organic layer with water (100 mL×2), washed with saturated brine (100 mL), and spin-dried the organic layer. The residue obtained was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 4-phenyl 6-methyl 7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4,6-dicarboxylate 61b (2 .8 g, pale yellow oil), yield: 71%. MS m/z (ESI): 406.1 [M+1] ⁺ .

third step 4-Benzyl 6-methyl 7-((tert-butoxycarbonyl)amino)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4,6-dicarboxylate 61c

將4-苯基6-甲基7-溴-2,3-二氫-4H-苯並[b][1,4]惡嗪-4,6-二甲酸酯61b (2.8g，6.91mmol)，氨基甲酸叔丁酯1k(0.97g，8.30mmol)，碳酸銫(4.49g，13.82mmol)，醋酸鈀(0.15g,0.69mmol)和4,5-雙二苯基膦-9,9-二甲基氧雜蒽(0.40g,0.69mmol)溶解於40mL 1,4-二氧六環中，反應液在氮氣保護下加熱至110度反應4小時，反應液過濾，旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(石油醚：乙酸乙酯=3：1)得到4-苄基6-甲基7-((叔丁氧羰基)氨基)-2,3-二氫-4H-苯並[b][1,4]惡嗪-4,6-二甲酸酯61c (1.37g，棕黃色油狀物)，產率：45%。 MS m/z (ESI): 443.1 [M+1] ⁺ .

the fourth step Benzyl 2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-[1,4]oxazine[3,2-g]quinazoline-6-carboxylate 61d

取4-苄基6-甲基7-((叔丁氧羰基)氨基)-2,3-二氫-4H-苯並[b][1,4]惡嗪-4,6-二甲酸酯61c (1.37g，3.10mmol)溶解於20mL鹽酸二氧六環(4M)溶液中，加入乙腈(5mL)，反應液加熱至50度反應2小時，減壓旋乾除去溶劑，加入乙腈(20mL)，攪拌充分後加入碳酸鈉(0.66g,6.20mmol)，反應液加熱至90度反應3小時，反應完畢後，冷卻至室溫，加入20mL水稀釋，用1M稀鹽酸調到pH=7-8，濃縮除去乙腈，有棕褐色固體析出，過濾，濾餅減壓乾燥得到苄基2-甲基-4-氧代-3,4,7,8-四氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-羧酸酯61d (0.71g，白色固體)，產率：64%。 MS m/z (ESI): 352.1 [M+1] ⁺ .

the fifth step Benzyl 4-chloro-2-methyl-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazoline-6-carboxylate 61e

取苄基2-甲基-4-氧代-3,4,7,8-四氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-羧酸酯61d (0.71g，2.02mmol)溶解於15mL甲苯中，加入N,N-二異丙基乙胺(1.56g,12.12mmol)和三氯氧磷(0.93g,6.06mmol)，反應液加熱至80度反應2小時，減壓旋乾除去溶劑，加入矽膠拌樣，用矽膠柱層析法純化(石油醚：乙酸乙酯=2：1)得到4-氯-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-羧酸苄酯61e (0.57g，棕黃色固體)，產率：76%。 MS m/z (ESI): 370.0 [M+1] ⁺ .

step six Benzyl (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazoline-6-carboxylate 61f

取4-氯-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-羧酸苄酯61e (200mg，0.23mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺2a (93mg，0.46mmol)溶解於3mL 1,4-二氧六環中，加入N,N-二異丙基乙胺(148mg,1.15mmol)，反應液使用微波加熱至140度反應2小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法二)得到苄基(R)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-羧酸酯61f (165mg，棕黃色固體)，產率：57%。 MS m/z (ESI): 537.2 [M+1] ⁺ .

step seven (R)-2-Methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine 61g

將苄基(R)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-羧酸酯61f (165mg，0.16mmol)，溶解於10mL甲醇中，然後加入鈀碳(17mg，10%)，反應體系用氫氣置換三次，反應液在氫氣氛圍下室溫反應2小時，反應液過濾，旋轉蒸發儀旋乾除去溶劑，得到(R)-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺61g (109mg，棕黃色油狀物)，產率：88%。 MS m/z (ESI): 403.1 [M+1] ⁺ .

eighth step (R)-2-Methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4- amine61

取(R)-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺61g (64mg，0.16mmol)，四氫-4H-吡喃-4-酮61h (32mg，0.32mmol)和三乙基矽烷(37mg，0.32mmol)溶解於3mL四氫呋喃中，反應體系用氮氣置換三次，然後在冰浴下加入四氯化鈦(61mg，0.32mmol)，反應液在冰浴下反應1小時，倒入10mL水中淬滅，用飽和碳酸氫鈉溶液調節pH值至8左右，用二氯甲烷萃取(30mL)，有機層旋乾，粗品用製備色譜柱純化(分離純化方法二)得到(R)-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-6-(四氫-2H-吡喃-4-基)-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺61 (6mg，白色固體)，產率：8%。 MS m/z (ESI): 487.0 [M+1] ⁺ . ¹ H NMR(400MHz,Methanol- d ₄ )δ 7.69(d, J =8.0Hz,1H),7.51(d, J =7.6Hz,1H),7.44(s,1H),7.25-7.31(m,1H),6.90(s,1H),5.78-5.86(m,1H),4.27-4.30(m,3H),4.08-4.11(m,2H),3.61-3.76(m,2H),3.36-3.39(m,2H),2.64(s,3H),2.33(s,3H),1.83-1.94(m,2H),1.75-1.78(m,2H),1.63(d, J =7.2Hz,3H)。

Example 26

Compound 62 was prepared by referring to the similar method of Example 25 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and the similar synthesis methods of intermediates are easily obtained by referring to existing methods by those skilled in the art.

Example 27

(R)-1-(4-(4-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)piperidin-1-yl)ethan-1-one 63

first step Benzyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazoline-6-carboxylate 63a

取4-氯-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-羧酸苄酯61f (350mg，0.95mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺3a (359mg，1.9mmol)溶解於5mL 1,4-二氧六環中，加入N,N-二異丙基乙胺(368mg,2.85mmol)，反應液使用微波加熱至140度反應2小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化(分離純化方法二)得到苄基(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-羧酸酯63a (327mg，棕黃色固體)，產率：66%。 MS m/z (ESI): 523.2 [M+1] ⁺ .

second step (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-4-amine 63b

將苄基(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8- 二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-羧酸酯63a (327mg，0.63mmol)，溶解於5mL甲醇中，然後加入鈀碳(33mg，10%)，反應體系用氫氣置換三次，反應液在氫氣氛圍下室溫反應2小時，反應液過濾，旋轉蒸發儀旋乾除去溶劑，得到(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺63b (207mg，棕黃色油狀物)，產率：85%。 MS m/z (ESI): 389.1 [M+1] ⁺ .

third step (R)-1-(4-(4-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)piperidin-1-yl)ethan-1-one 63

取(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺63b (55mg，0.14mmol)，1-乙醯呱啶-4-酮62a (40mg，0.28mmol)，對甲苯磺酸(5mg，0.03mmol)溶解於3mL甲苯中，反應液在110度下反應2小時，反應液減壓旋乾除去溶劑，粗品用四氫呋喃溶解，反應體系用氮氣置換三次，然後在冰浴下加入三氯矽氫(38mg，0.28mmol)，反應液在冰浴下反應1小時，倒入10mL水中淬滅，用飽和碳酸氫鈉溶液調節PH值至8左右，用二氯甲烷萃取(30mL)，有機層旋乾，粗品用製備色譜柱純化(分離純化方法二)得到(R)-1-(4-(4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)呱啶-1-基)乙烷-1-酮63 (7mg，白色固體)，產率：10%。 MS m/z (ESI): 514.0 [M+1] ⁺ . ¹ H NMR(400MHz,Methanol- d ₄ )δ 7.66(d, J =6.4Hz,2H),7.51-7.55(m,1H),7.27-7.31(m,1H),6.85-7.17(m,2H),5.96-6.02(m,1H),4.73-4.85(m,2H),4.34-4.37(m,2H),4.09-4.31(m,2H),3.40-3.43(m,2H),2.80(t, J =12.8Hz,1H),2.53(s,3H),2.16(s,3H),1.82-1.92(m,2H),1.77(d, J =7.2Hz,3H),1.65-1.75(m,2H)。

Example 28

(R)-3-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazinyl[3,2-g]quinazolin-6-yl)-N,N-dimethylbenzamide 64

first step (R)-3-(4-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazine[3,2-g]quinazolin-6-yl)benzoic acid methyl ester 64b

將(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-4-胺61h (50mg，0.13mmol),3-溴苯甲酸甲酯64a (42mg，0.20mmol)，碳酸銫(85mg，0.26mmol)，醋酸鈀(4mg,0.02mmol)和4,5-雙二苯基膦-9,9-二甲基氧雜蒽(12mg,0.02mmol)溶解於6mL 1,4-二氧六環中，反應液在氮氣保護下加熱至110度反應3小時，反應液過濾，旋轉蒸發儀旋乾除去溶劑，得到的殘留物用矽膠柱層析法純化(石油醚：乙酸乙酯=1：1)得到(R)-3-(4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)苯甲酸甲酯64b (28mg，棕黃色油狀物)，產率：42%。 MS m/z (ESI): 523.1 [M+1] ⁺ .

second step (R)-3-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazin[3,2-g]quinazolin-6-yl)benzoic acid 64c

將(R)-3-(4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)苯甲酸甲酯64b (28mg，0.20mmol)，溶解於1.5mL四氫呋喃和0.5mL水中，然後加入氫氧化鋰(19mg，0.80mmol)，反應液在室溫下反應2小時，反應完畢後，旋轉蒸發儀旋乾除去溶劑，用1M稀鹽酸調到pH=6-7，用二氯甲烷萃取(30mL)，有機層乾燥減壓旋乾得到(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)苯甲酸64c (23mg，棕黃色油狀物)，產率：85%。 MS m/z (ESI): 509.1 [M+1] ⁺ .

third step (R)-3-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-7,8-dihydro-6H-[1,4]oxazinyl[3,2-g]quinazolin-6-yl)-N,N-dimethylbenzamide 64

取(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪[3,2-g]喹唑啉-6-基)苯甲酸64c (23mg，0.05mmol)和二甲胺鹽酸鹽64d (41mg，0.5mmol)溶解於2mL N,N-二甲基甲醯胺中，加入2-(7-氮雜苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(29mg,0.08mmol)和N,N-二異丙基乙胺(77mg,0.60mmol)，反應液在室溫下反應2小時，反應液減壓旋乾除去溶劑，粗品用製備色譜柱純化得到(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7,8-二氫-6H-[1,4]惡嗪基[3,2-g]喹唑啉-6-基)-N,N-二甲基苯甲醯胺64 (3mg，白色固體)，產率：12%。 MS m/z (ESI): 536.0 [M+1] ⁺ . ¹ H NMR(400MHz,Methanol- d ₄ )δ 7.89(s,1H),7.53-7.67(m,2H),7.44-7.54(m,3H),7.21-7.34(m,2H),6.82-7.15(m,2H),5.94-5.99(m,1H),4.51(t, J =4.0Hz,2H),3.88(t, J =4.0Hz,2H),3.12(s,3H),3.03(s,3H),2.54(s,3H),1.64(d, J =7.2Hz,3H)。

Example 29

Compounds 65 to 72 were prepared by referring to the similar methods of Example 11 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and similar synthesis methods of intermediates are easily obtained by referring to existing methods by those skilled in the art.

Example 30

(3-(4-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidin-1-yl)(phenyl)methanone 73

first step (3-(4-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidin-1-yl)(phenyl)methanone 73

In In 5 mL of dichloromethane, cool down to zero and add benzoyl chloride 73a (0.01 g, 0.09 mmol) and stir at room temperature for 1 hour. The reaction solution was concentrated to remove the solvent, and the obtained crude product was prepared and purified by high performance liquid chromatography (separation and purification method 1) to obtain the target product (3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrole[2,3-g]quinazolin-6-yl)pyrrolidin-1-yl)(phenyl)methanone 73 (6.0mg, yellow solid), Yield: 17%. MS m/z (ESI): 574.1 [M+1] ⁺ . ¹ H NMR(400MHz,DMSO- d ₆ )δ 7.67-7.92(m,1H),7.40-7.62(m,6H),7.06-7.38(m,4H),5.67-5.85(m,1H),4.35-4.55(m,1H),3.68-3.81(m,1H),3.66-3.46(m,3H),3.19-3.29(m,2H),2.50(s,3H),2.20-2.29(m,2H),1.68-1.50(m,3H),1.39-1.18(m,6H).

Example 31

Compounds 74 to 78 were prepared by referring to the similar methods of Example 30 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and similar synthetic methods of intermediates are easily obtained by referring to existing methods by those skilled in the art.

Example 32

Compound 79 was prepared by referring to the similar method of Example 24 , wherein the starting materials of each compound can be prepared by referring to existing methods well known to those skilled in the art or by commercially available methods, and the similar synthesis methods of intermediates are easily obtained by referring to existing methods by those skilled in the art.

Example 33

1. In vitro KRas(G12C):SOS1 homogeneous time-resolved fluorescence binding experiment

Since the binding of SOS1 inhibitors to Ras does not select subtypes, the Ras family protein selected in this experiment is KRas (G12C), the 12th mutation of KRas exon 2. KRas (G12C) accounts for about 85%-90% of the total mutation types of KRas, and is found in about 13-30% of lung cancer, 3-5% of colorectal cancer and 2% of other solid tumors.

The assay measures protein-protein interactions by homogeneous time-resolved fluorescence techniques. All protein interactions occurred in 150 mM sodium chloride (SIGMA, S5886), 50 mM HEPES (invitrogen, 15630080), 0.05% bovine serum albumin (SIGMA, B2064). In a 384 reaction plate (Corning, CLS4514), 0.1 μl of the compound was added, and after centrifugation, 5 μl of GST-KRas (G12C) protein at a final concentration of 15 nM and a mixture of GTP at a final concentration of 10 μM were added. Add 5 microliters of His-SOS1 protein solution with a final concentration of 2.5 nM, and react at room temperature for 15 minutes. Add 10 microliters 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. The reaction signal was detected by a multifunctional microplate reader, and the data was analyzed using GraphPad Prism data analysis software.

Experimental results:

Table 1 Inhibitory activity of compounds of the disclosure on KRas(G12C):SOS1 binding.

2. 3D proliferation assay of H358 cells

The diluted compound to be tested was added to a 384-well cell culture plate (Corning, LS3830-50EA) using a nanoliter pipetting system (LABCYTE, P-0200). After spreading the cells, the culture plate was placed in a 37°C, 5% CO ₂ constant temperature incubator. After the compound was incubated with the cells for 7 days, CellTiter-Glo® 3D reagent (Promega, 9683) was added, and the luminescence value was read with an Envision multifunctional 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 viable cells in the system). Finally, the IC50 (half maximal inhibitory concentration) of the compound was obtained by using the XLFIT software with a nonlinear fitting formula.

Inhibition rate (%)=100×(negative control average value-compound reading value)/(negative control average value-positive control average value); negative control: cells treated with DMSO; positive control: only medium, no cells;

3. 3D proliferation assay of MIA PaCa-2 cells

BI-3406, a SOS1::KRAS inhibitor, was used as a positive compound. The diluted compound to be tested was added to a 384-well cell culture plate (Corning, LS3830-50A) using a nanoliter pipetting system (LABCYTE, P-0200). After spreading MIA PaCa-2 cells, the culture plate was placed in a 37°C, 5% CO2 constant temperature incubator. After the compound was incubated with the cells for 7 days, CellTiter-Glo® 3D reagent (Promega, 9683) was added, and the luminescence value was read with an Envision multifunctional 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 living cells in the system). Finally, use the XLFIT software to obtain the IC50 (half inhibitory concentration) of the compound with the nonlinear fitting formula.

Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))

X: log value of compound concentration

Y: inhibition rate (%)

Inhibition rate (%)=100×(negative control average value-compound reading value)/(negative control average value-positive control average value)

Negative control: DMSO

Positive control: Medium only

4. 3D proliferation assay of PC-9 cells

BI-3406, a SOS1::KRAS inhibitor, was used as a positive compound. The diluted compound to be tested was added to a 384-well cell culture plate (Corning, LS3830-50A) using a nanoliter pipetting system (LABCYTE, P-0200). After spreading PC-9 cells, the culture plate was placed in a 37°C, 5% CO2 constant temperature incubator. After the compound was incubated with the cells for 7 days, CellTiter-Glo® 3D reagent (Promega, 9683) was added, and the luminescence value was read with an Envision multifunctional 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 living cells in the system). Finally, use the XLFIT software to obtain the IC50 (half inhibitory concentration) of the compound with the nonlinear fitting formula.

Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))

X: log value of compound concentration

Y: inhibition rate (%)

Inhibition rate (%)=100×(negative control average value-compound reading value)/(negative control average value-positive control average value)

Negative control: DMSO

Positive control: Medium only

Some specific compound pharmacokinetics determination methods of the present invention adopt the conventional methods in this field The experimental conditions were implemented.

Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and equivalent technologies thereof, the present invention also intends to include these modifications and variations.

Claims (25)

A benzopyrimidine tricyclic compound represented by formula (I) or its stereoisomer, pharmaceutically acceptable salt:

其中R ₁選自氫、C _1-4烷基，其中所述C _1-4烷基任選地被一個或者多個相同或者不同的鹵素或者羥基取代；環A選自：C _6-10芳基、5元-10元雜芳基；p表示1、2或3；每一個R ₂獨立地選自：氫、C _1-4烷基、C _1-4烷氧基、C _2-4烯基、C _2-4炔基、C _1-4鹵代烷基、羥基-C _1-4烷基、羥基-C _2-4鹵代烷基、C _3-6環烷基、3元-6元雜環基、取代或者未取代的C ₅ -C ₇芳基、羥基-C _3-6環烷基、羥基、鹵素、-NH ₂ 、-N(C _1-4烷基) ₂ 、氰基、硝基、-SO ₂ -C _1-4烷基，其中取代或者未取代的C ₅ -C ₇芳基取代基為：C _1-4烷基、C _1-4鹵代烷基、鹵素、-NH ₂ 、C _1-4烷氧基、硝基、氰基、C _1-4氨基烷基、(C _1-4烷基) ₂ NC _1-4烷基，C _1-4烷基-NH-C _1-4烷基；R ₃選自氫、C _1-4烷基、C _3-6環烷基、3元-6元雜環基、氧代、-C(O)ORa、-C(O)NRaRa，其中C _1-4烷基、C _3-6環烷基、3元-6元雜環基任選地被一個或者多個相同或者不同的鹵素、羥基、-NH ₂取代，Ra各自獨立地選自氫、C _1-6烷基、C _1-3鹵代烷基、C _2-6烯基、C _2-6炔基、C _3-10環烷基、C _6-10芳基、3元-10元雜環基和3元-10元雜芳基；o表示1或2；R ₄選自3-10元飽和的雜環基，其中所述3-10元雜環基任選地被一個或多個相同或不同的Rb取代； Rb獨立地選自C _1-6烷基、C _2-6烯基、C _2-6炔基、C _3-10環烷基、C _6-10芳基、3元-10元雜環基、5元-10元雜芳基、-C(O)Rc、-C(O)ORc、-C(O)NRcRc、-S(O) ₂ Rc、-S(O) ₂ NRcRc、鹵素、氰基、羥基、和氧代；其中Rb所述C _1-6烷基、C _2-6烯基、C _2-6炔基、C _3-10環烷基、C _6-10芳基、3元-10元雜環基和5元-10元雜芳基均任選地被一個或多個相同或不同的鹵素、氰基、羥基、-NH ₂和氧代取代，氧代不在雙鍵上；Rc各自獨立地選自氫、C _1-6烷基、C _1-3鹵代烷基、C _2-6烯基、C _2-6炔基、C _3-10環烷基、C ₀ -C ₁亞烷基-C ₆ - ₁₀芳基、3元-10元雜環基和5元-10元雜芳基；n表示0、1或2；X選自O、S、NRd、CRdRd，Rd獨立的選自氫、C _1-3烷基；R ₅選自氫、C _1-4烷基、C _1-4烷氧基、-NH ₂ 、-NH(C _1-4烷基)、-N(C _1-4烷基) ₂和鹵素；R ₆選自氫、鹵素。 The compound or its stereoisomer, pharmaceutically acceptable salt as described in Claim 1, wherein said R ₁ is methyl. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, wherein ring A is selected from: C _6-10 aryl; p represents 1, 2 or 3; each R ₂ is independently selected from: hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, halogen, -NH ₂ , C _1-4 alkoxy, nitro, cyano. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, wherein each R ₂ is independently selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, halogen, -NH ₂ . The compound or its stereoisomer, pharmaceutically acceptable salt as described in claim item 1, wherein ring A and p _R substituents have the following substructure together:

Rg is selected from: hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, hydroxy-C _1-4 alkyl, hydroxy-C _1-4 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, hydroxy-C _3-6 cycloalkyl, hydroxyl, halogen, -NH ₂ , -SO ₂ -C _1-4 alkyl, cyano; Re is selected from: hydrogen, halogen and -NH ₂ ; Rf is selected from: hydrogen, C _1-4 Alkyl and halogen, nitro, cyano, wherein halogen is fluorine, chlorine, bromine, iodine. The compound or its stereoisomer, pharmaceutically acceptable salt as described in claim item 5, wherein ring A and p substituents _R together have substructure:

Rg is selected from: hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, halogen, -NH ₂ ; Re is selected from: hydrogen, halogen and -NH ₂ ; Rf is selected from: hydrogen, C _1-4 alkyl, halogen, nitro, wherein halogen is fluorine, chlorine, bromine, iodine. The compound as described in Claim 1 or its stereoisomer, pharmaceutically acceptable salt, wherein the C _1-4 haloalkyl group in the definition of Rg is an alkyl group substituted by 1, 2 or 3 fluorines. The compound or its stereoisomer, pharmaceutically acceptable salt as described in Claim 1, wherein the C _1-4 haloalkyl in the definition of Rg is -CF ₃ , -CHF ₂ . The compound as described in Claim 5 or its stereoisomer, pharmaceutically acceptable salt, wherein ring A and p substituents _R together have the following substructure:

The compound as described in Claim 1 or its stereoisomer, pharmaceutically acceptable salt, wherein R ₃ is selected from hydrogen, methyl, oxo. The compound as described in Claim 1 or its stereoisomer, pharmaceutically acceptable salt, wherein R₄The 3-10 membered saturated heterocyclic group in is optionally substituted by one or more identical or different Rb; Rb is independently selected from C_1-6Alkyl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -C(O)NRcRc, -S(O)₂Rc, oxo, wherein Rb said C_1-6Alkyl is optionally replaced by one or more identical or different halogen, cyano, hydroxyl, -NH₂And oxo; Rc each independently selected from hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl, C₀-C₁Alkylene-C₆-₁₀Aryl. The compound or its stereoisomer, pharmaceutically acceptable salt as described in claim item 11, wherein R₄Selected from tetrahydrofuryl and pyrrolidinyl, wherein the tetrahydrofuryl and pyrrolidinyl are any Optionally substituted by one or more of the same or different Rb; 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 said C_1-6Alkyl is optionally replaced by one or more identical or different halogen, cyano, hydroxyl, -NH₂And oxo; Rc each independently selected from hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl, C₀-C₁Alkylene-C₆-₁₀Aryl. The compound according to claim 12 or its stereoisomer, pharmaceutically acceptable salt, wherein R is pyrrolidinyl optionally substituted by Rb on nitrogen, Rb is _{independently} selected from C _1-6 alkyl, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, and Rc is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C ₀ -C ₁ alkylene-C _{6 -10} aryl. The compound according to claim 12 or its stereoisomer, pharmaceutically acceptable salt, wherein R ₄ is tetrahydrofuryl optionally substituted by one or more identical or different Rb, and Rb is independently selected from C _1-6 alkyl, oxo. The compound or its stereoisomer, pharmaceutically acceptable salt as described in claim item 12, wherein R ₄ is selected from:

The compound or its stereoisomer, pharmaceutically acceptable salt as described in Claim 1, wherein X is selected from O and CH ₂ . The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, wherein R ₅ is selected from hydrogen, and R ₆ is selected from hydrogen. The compound as described in Claim 1 or its stereoisomer, pharmaceutically acceptable salt has a structure as shown in formula (IIa) and/or formula (IIb):

其中R ₁選自氫、C _1-4烷基，其中所述C _1-4烷基任選地被一個或者多個相同或者不同的鹵素或者羥基取代；Rg選自：氫、C _1-4烷基、C _1-4鹵代烷基、羥基-C _1-4烷基、羥基-C _1-4鹵代烷基、C _3-6環烷基、3元-6元雜環基、羥基-C _3-6環烷基、羥基、鹵素、-NH ₂ 、-SO ₂ -C _1-4烷基、氰基；Re選自：氫、鹵素及-NH ₂ ；Rf選自：氫、C _1-4烷基及鹵素、硝基、氰基，其中鹵素為氟、氯、溴、碘；環B為5元-10元雜芳基；每一個R ₂獨立地選自：氫、C _1-4烷基、C _1-4烷氧基、C _1-4鹵代烷基、羥基-C _1-4烷基、羥基-C _2-4鹵代烷基、C _3-6環烷基、3元-6元雜環基、取代或者未取代的C ₅ -C ₇芳基、羥基-C _3-6環烷基、羥基、鹵素、-NH ₂ 、-N(C _1-4烷基) ₂ 、氰基、硝基、-SO ₂ -C _1-4烷基；取代或者未取代的C ₅ -C ₇芳基取代基為：C _1-4烷基、C _1-4鹵代烷基、鹵素、-NH ₂ 、C _1-4烷氧基、硝基、氰基、C _1-4氨基烷基、(C _1-4烷基) ₂ NC _1-4烷基，C _1-4烷基-NH-C _1-4烷基；p表示1、2或3；R ₃選自氫、C _1-4烷基、C _3-6環烷基、3元-6元雜環基、氧代、-C(O)ORa、-C(O)NRaRa，其中C _1-4烷基、C _3-6環烷基、3元-6元雜環基任選地被一個或者多個相同或者不同的鹵素、羥基、-NH ₂ ，Ra各自獨立地選自氫、C _1-6烷基、C _1-3鹵代烷基、C _2-6烯基、C _2-6炔基、C _3-10環烷基、C _6-10芳基、3元-10元雜環基和3元-10元雜芳基；o表示1或者2； Y選自O、NRh，Rh獨立地選自氫、C _1-6烷基、C _2-6烯基、C _2-6炔基、C _3-10環烷基、C _6-10芳基、3元-10元雜環基、5元-10元雜芳基、-C(O)Rc、-C(O)ORc、-C(O)NRcRc、-S(O) ₂ Rc、-S(O) ₂ NRcRc，其中Rh所述C _1-6烷基、C _2-6烯基、C _2-6炔基、C _3-10環烷基、C _6-10芳基、3元-10元雜環基和5元-10元雜芳基均任選地被一個或多個相同或不同的鹵素、氰基、羥基、和氧代取代，氧代不在雙鍵上；Rc各自獨立地選自氫、C _1-6烷基、C _1-3鹵代烷基、C _2-6烯基、C _2-6炔基、C _3-10環烷基、C ₀ -C ₁亞烷基-C ₆ - ₁₀芳基、C _3-10雜環基和C _5-10雜芳基；n表示0、1或者2；m表示1或者2；X選自O、S、NRd、CRdRd，Rd獨立的選自氫、C _1-3烷基；R ₅選自氫、C _1-4烷基、C _1-4烷氧基、-NH ₂ 、-NH(C _1-4烷基)、-N(C _1-4烷基) ₂和鹵素；R ₆選自氫、鹵素。 The compound or its stereoisomer, pharmaceutically acceptable salt as described in Claim 18 has a structure as shown in formula (IIa) and/or (IIb):

其中R ₁為甲基；Rg選自：氫、C _1-4烷基、C _1-4鹵代烷基、鹵素、-NH ₂ ；Re選自：氫、鹵素及-NH ₂ ；Rf選自：氫、C _1-4烷基及鹵素、硝基；環B為吡啶基、噻吩基； 每一個R ₂獨立地選自：氫、C _1-4烷基、C _1-4烷氧基、C _1-4鹵代烷基、羥基-C _1-4烷基、C _3-6環烷基、3元-6元雜環基、取代或者未取代的C ₅ -C ₇芳基、羥基、鹵素、-NH ₂ 、-N(C _1-4烷基) ₂ 、氰基；取代或者未取代的C ₅ -C ₇芳基取代基為：C _1-4烷基、C _1-4鹵代烷基、鹵素、-NH ₂ 、C _1-4烷氧基、C _1-4氨基烷基、(C _1-4烷基) ₂ NC _1-4烷基，C _1-4烷基-NH-C _1-4烷基；p表示1或2；R ₃選自氫、C _1-4烷基、氧代、-C(O)ORa、-C(O)NRaRa，其中C _1-4烷基任選地被一個或者多個相同或者不同的鹵素、羥基、氨基取代，Ra各自獨立地選自氫、C _1-6烷基、C _1-3鹵代烷基、C _2-6烯基、C _2-6炔基、C _3-10環烷基、C _6-10芳基、3元-10元雜環基和5元-10元雜芳基；o表示1；Y選自O、NRh，Rh獨立地選自C _1-6烷基、-C(O)Rc、-C(O)ORc、-C(O)NRcRc，Rc各自獨立地選自氫、C _1-6烷基；Rc各自獨立地選自氫、C _1-6烷基、C _1-3鹵代烷基、C _3- C ₆環烷基、C ₀ -C ₁亞烷基-C ₆ - ₁₀芳基；n表示0或者1；m表示1；X選自O、CRdRd，Rd獨立的選自氫、C _1-3烷基；R ₅和R ₆獨立的選自氫、鹵素。 The compound or its stereoisomer, pharmaceutically acceptable salt as described in Claim 18, wherein the C _1-4 haloalkyl group in the definition of Rg is an alkyl group substituted by 1, 2 or 3 fluorines. The compound or its stereoisomer, pharmaceutically acceptable salt as described in Claim 18, wherein the C _1-4 haloalkyl in the definition of Rg is -CF ₃ , -CHF ₂ . The compound as described in Claim 1 or its stereoisomer, pharmaceutically acceptable salt has the following specific structure:

Use of a compound as described in any one of Claims 1 to 22 or a stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease related to or regulated by SOS1. The use according to claim 23, wherein the disease is a disease in which inhibition of the interaction of SOS1 with Ras family proteins and/or RAC1 has therapeutic benefit. The application according to claim 24, wherein the disease is cancer, and the cancer is selected from pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, Cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma.