Estrogen receptor modulators

Abstract

The invention discloses a compound as shown in a formula (I) or a stereoisomer, a tautomer or a pharmaceutical salt thereof, and application of the compound in preparation of a medicine for preventing and / or treating estrogen receptor (ER) related diseases or symptoms.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202210249231.0, application date 2022.03.14, and invention name “Estrogen Receptor Modulators”. Technical Field

[0002] The present invention relates to certain novel compounds or pharmaceutically acceptable salts thereof which have anticancer activity and are therefore potentially useful in methods of treating the human or animal body. The invention also relates to methods for making said compounds, pharmaceutical compositions containing them and their use in methods of treatment, for example for the manufacture of medicaments for the prevention or treatment of cancer in warm-blooded animals (such as humans), including for the prevention or treatment of diseases that are estrogen receptor dependent or mediated by estrogen receptors.

[0003] The present invention also relates to compounds that are selective down-regulators of the estrogen receptor. Background Art

[0004] Estrogen receptor (ER) is a steroid hormone receptor, including two subtypes, ERα and ERβ. ER is involved in the regulation and development of the female reproductive tract; in cancers such as breast cancer, tumor growth is related to the effects of estrogen and ER receptors. For example, ER expression is elevated in most breast cancer patients.

[0005] It is known that some compounds can bind to ER, thereby competitively inhibiting the binding of ER to endogenous estrogen ligands (such as female sex steroid hormone 17b estradiol (E2)), and are thus used as ER inhibitors. For example, selective estrogen receptor modulators (SERMs) such as tamoxifen, AZD9496, AZD9833, etc. are used as ER inhibitors to treat breast cancer, etc. WO2017 / 182493A1 also discloses a SERM compound.

[0006] Although existing SERM therapies have a certain effect on the treatment of breast cancer, there is still a need for ER inhibitors with stronger inhibitory activity and improved metabolic stability. Summary of the invention

[0007] The inventors of the present invention have found that the compound shown in formula (I) has a basic structure of tetrahydrooxazoloisoquinoline-one, which has significant ER degradation activity, and thus unexpectedly has significantly superior ER inhibitory activity than the known compounds in the prior art; at the same time, such compounds also have excellent metabolic stability. Therefore, the compounds of the present invention can be used to treat diseases dependent on or mediated by estrogen receptors, thereby completing the present invention.

[0008] Specifically, the present invention relates to the following contents.

[0009] One aspect of the present invention provides a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] Z 1 Selected from CR a R b , C(O) and bond;

[0013] Z 2 Selected from O, S, NR c , C(O) and a bond, or optionally replaced by one or more identical or different R d Substituted C1-C6 alkylene, O-(C1-C6 alkylene) or NH-(C1-C6 alkylene);

[0014] Cy 1 Selected from C 6-14 Arylene, C 3-8 Cycloalkylene, C 5-14 Heteroarylene, C 3-14 Heterocycloalkylene, C 3-14 heterocycloalkenylene, each of which is optionally substituted by a group selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, and a C 1-6 Alkyl or C 1-6 Alkoxy;

[0015] Cy 2 Select from key, C 3-10 Cycloalkylene, C 3-14 heterocycloalkylene, each of which is optionally substituted by a group selected from the group consisting of a halogen atom (including a F, Cl, Br or I atom), a hydroxyl group, an amino group, a cyano group, and a C 1-6 Alkyl or C 1-6 Alkoxy;

[0016] R 1 , R 2 are each independently H, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C1-6 alkyl)2amino, cyano or oxo;

[0017] R 4 H, halogen atoms, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano, oxo, C 6-14 Aryl, C 5-14 Heteroaryl, C 3-14 Heterocycloalkylene or

[0018] (For example )

[0019] The group substitution;

[0020] Preferably, R 4 H, halogen atoms, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano or oxo;

[0021] R 3 For-(CR e R f ) m -CR 31 R 32 R 33 , where m is 1, 2 or 3;

[0022] R 31 , R 32 and R33 Independently selected from: H, C 1-6 Alkyl, halogen, cyano, and R 31 and R 32 Can form C 3-8 Cycloalkylene, the C 1-6 Alkyl and C 3-8 The cycloalkylene group is optionally substituted with a hydroxyl group, a cyano group, an amino group or a halogen atom;

[0023] R a , R b , R c , R d , R e , R f are each independently H, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 alkyl.

[0024] In the context of the present specification, the heteroaryl / heteroarylene, heterocycloalkyl / heterocycloalkylene, heterocycloalkenyl / heterocycloalkenylene contain 1-4 heteroatoms selected from N, O, S as ring-constituting atoms. The cycloalkyl / cycloalkylene, heterocycloalkyl / heterocycloalkylene, heterocycloalkenyl / heterocycloalkenylene may be a monocyclic, bicyclic or tricyclic (preferably monocyclic or bicyclic) ring system without an aromatic ring structure, wherein the bicyclic or tricyclic ring system includes a spiro ring, a bridged ring or a fused ring. The aryl / arylene and heteroaryl / heteroarylene may be a monocyclic, fused bicyclic or fused tricyclic (preferably monocyclic or fused bicyclic) ring system, and wherein the fused bicyclic or fused tricyclic ring system may contain a non-aromatic ring structure. The halogen atom is selected from F, Cl, Br or I atom. The oxo group represents a "=O" group.

[0025] In a preferred embodiment of the compound of formula (I):

[0026] Z 1 Selected from CR a R b , C(O) and bond;

[0027] Z 2 Selected from O, S, NR c , C(O) and a bond, or optionally replaced by one or more identical or different R d Substituted C1-C6 alkylene, O-(C1-C6 alkylene) or NH-(C1-C6 alkylene);

[0028] Cy 1 Selected from C 6-14 Arylene (preferably C 6-10 Arylene) and C 5-14 Heteroarylene (preferably C 5-10arylene), each of which is optionally substituted by a group selected from the group consisting of a halogen atom, and a C 1-6 Alkyl or C 1-6 Alkoxy;

[0029] Cy 2 Select from key, C 3-10 Cycloalkylene (preferably C 3-8 Cycloalkylene), C 3-14 Heterocycloalkylene (preferably C 3-10 Heterocycloalkylene);

[0030] R 1 , R 2 Each independently is H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more groups selected from halogen atoms, hydroxyl groups or cyano groups;

[0031] R 3 For-(CR e R f ) m -CR 31 R 32 R 33 , where m is 1, 2 or 3;

[0032] R 31 , R 32 and R 33 Independently selected from: H, C 1-6 Alkyl, halogen, cyano, and R 31 and R 32 Can form C 3-8 Cycloalkylene, the C 1-6 Alkyl and C 3-8 The cycloalkylene group is optionally substituted with a hydroxyl group, a cyano group, an amino group or a halogen atom;

[0033] R a , R b , R c , R d , R e , R f are each independently H or a halogen atom;

[0034] R 4 C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, amino C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano, oxo and

[0035]

[0036] The group substitution;

[0037] Preferably, R 4 C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano or oxo groups.

[0038] In a more preferred embodiment of the compound of formula (I):

[0039] Z 1 is the key;

[0040] Z 2 is selected from -O-CH2-CH2-, -O-CH2-, -NH-CH2-CH2-, -NH-CH2-, -NH- or -O-;

[0041] Cy 1 C 6-10 Arylene (preferably phenyl) and C 5-10 Heteroarylene (preferably pyridyl), which is optionally substituted by a halogen atom (preferably F) or C 1-6 Alkoxy (preferably methoxy) substitution;

[0042] Cy 2 is selected from a bond, an azetidinyl group, a pyrrolidinyl group, a piperazinyl group,

[0043]

[0044] R 1 C 1-6 Alkyl (preferably methyl);

[0045] R 2is H;

[0046] R 3 -CH2-CR 31 R 32 R 33 ;

[0047] R 31 , R 32 and R 33 independently selected from: H, C optionally substituted by hydroxyl or halogen atoms (preferably F) 1-6 An alkyl group (preferably a methyl group), a halogen atom (preferably a F group), a cyano group, and R 31 and R 32 can together form a C optionally substituted by a hydroxyl group or a halogen atom (preferably F) 3-8 Cycloalkylene (preferably cyclopropylene);

[0048] R 4 is optionally selected from a halogen atom (preferably F), an oxo group, a C 1-6 Alkylamino (preferably methylamino), (C 1-6 alkyl)2amino (preferably dimethylamino), and

[0049]

[0050] The group substituted C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkenylamino.

[0051] Preferably, Cy 2 is selected from a bond, an azetidinyl group, a pyrrolidinyl group, and R 4 is optionally selected from a halogen atom (preferably F), an oxo group, a C 1-6 Alkylamino (preferably methylamino) and (C 1-6 Alkyl)2amino (preferably dimethylamino) substituted C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkenylamino.

[0052] In particularly preferred embodiments of the compounds of formula (I):

[0053] Z 1 is the key;

[0054] Z 2 is selected from -NH- or -O-;

[0055] Cy 1is phenyl or pyridyl (preferably phenyl), which is optionally substituted by F or methoxy;

[0056] Cy 2 is selected from azetidinyl, pyrrolidinyl, piperazinyl;

[0057] R 1 is methyl;

[0058] R 2 is H;

[0059] R 3 -CH2-CR 31 R 32 R 33 ;

[0060] R 31 , R 32 Each is F or R 31 and R 32 Together they form a cyclopropylene group;

[0061] R 33 Selected from: H, hydroxymethyl, fluoromethyl, preferably selected from F, hydroxymethyl, fluoromethyl;

[0062] R 4 F-(CH2)3- or

[0063]

[0064] More preferably, Cy 2 is selected from azetidinyl and pyrrolidinyl, and R 4 It is F-(CH2)3-.

[0065] In some embodiments, the compounds of formula (I) of the present invention are in the form of stereoisomers, for example, the carbon at position 1 of the tetrahydroisoquinoline ring (ie, Z 1 The carbon to which it is attached) may be in the S configuration, and / or the carbon at position 3 (i.e., R 1 The carbon to which it is attached) may be in the R configuration.

[0066] In some embodiments, the present invention relates to the following compounds or stereoisomers or pharmaceutically acceptable salts thereof:

[0067]

[0068]

[0069] In another aspect, the present invention relates to a pharmaceutical composition comprising any one or more of the aforementioned compounds of the present invention or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0070] In another aspect, the present invention relates to the use of a compound of the present invention in the preparation of a medicament for treating an estrogen receptor-dependent or estrogen receptor-mediated disease in a mammal. Specific implementation plan

[0071] The present invention is further described below by specific preparation examples and test examples. It should be appreciated that the examples and test examples are not intended to limit the scope of the present invention. The raw materials, reagents, etc. used in the examples are all well known to those skilled in the art and can be obtained by commercial or literature methods; the test or characterization methods used are also methods well known to those skilled in the art.

[0072] Example 1: (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidin-1-yl-ethoxy-phenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 1)

[0073]

[0074] Step 1: Synthesis of 7-bromobenzo[d]oxazol-2(3H)-one

[0075]

[0076] 2-Amino-6-bromophenol (5 g, 26.6 mmol, 1 eq) was dissolved in 120 ml of tetrahydrofuran, dicarbonyl imidazole (5.17 g, 31.9 mmol, 1.2 eq) was added at 20°C, and the reaction solution was reacted at 80°C for 2 hours. After TLC detection, the reaction solution was poured into ice water and the pH was adjusted to 2 with hydrochloric acid, extracted with ethyl acetate, dried and concentrated, and the crude product was separated by column chromatography to obtain a red solid 7-bromobenzo[d]oxazol-2(3H)-one (5.1 g, 23.8 mmol, 89.6% yield).

[0077] 1 H NMR (400MHz, DMSO-d6): δ=12.0 (s, 1H), 7.30–7.27 (m, 1H), 7.11–7.09 (m, 2H)ppm.

[0078] Step 2: Synthesis of 7-bromo-3-tritylbenzo[d]oxazol-2(3H)-one

[0079]

[0080] 7-Bromobenzo[d]oxazol-2(3H)-one (5.1 g, 23.8 mmol, 1 eq) was dissolved in 50 mL of N,N-dimethylformamide, and sodium hydride (1.43 g, 35.7 mmol, 60% purity, 1.5 eq) was added at 0°C. The reaction solution was stirred at 0°C for 30 minutes, and trityl chloride (6.64 g, 23.8 mmol, 1 eq) was added. The reaction solution was reacted at 20°C for 2 hours. TLC detected that the reaction was complete, and the reaction solution was poured into ice water, extracted with ethyl acetate, dried, and concentrated. The crude product was separated by column chromatography to obtain 7-bromo-3-tritylbenzo[d]oxazol-2(3H)-one (9.5 g, 20.8 mmol, 87.4% yield) as a white solid.

[0081] 1 H NMR (400MHz, CDCl3): δ=7.40-7.37 (m, 6H), 7.25-7.20 (m, 9H), 7.12 (d, J=8.0Hz, 1H), 6.62 (t, J=8.4Hz, 1H), 5.93 (d, J=8.0Hz, 1H) ppm.

[0082] Step 3: (R)-(1-(2-oxo-3-trityl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl) Synthesis of tert-butyl carbamate

[0083]

[0084] 7-Bromo-3-tritylbenzo[d]oxazol-2(3H)-one (4.0 g, 8.77 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL) and n-butyl lithium (2.5 M, 4.03 mL, 1.15 eq) was added under nitrogen protection at -78 °C and stirred for 30 minutes. A solution of (R)-tert-butyl 4-methyl-1,2,3-oxazolidine-3-carboxylic acid 2,2-dioxide (2.50 g, 10.5 mmol, 1.2 eq) in tetrahydrofuran (10 mL) was added to the system at -78 °C, and then naturally returned to 0 °C for 2 hours. The reaction was completed by TLC detection, and the reaction solution was poured into ice water for quenching, extracted with ethyl acetate, and dried and concentrated. The crude product was separated by column chromatography to obtain tert-butyl (R)-(1-(2-oxo-3-trityl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate (4.5 g, 8.42 mmol, 76.8% yield) as a white solid.

[0085] 1H NMR (400MHz, CDCl3): δ=7.50-7.48(m, 6H), 7.33-7.28(m, 9H), 6.88-6.78(m, 1H), 6.76-6.74(m, 1H), 5.92(br d, J=8.0Hz, 1H), 4.22-4.11 (m, 1H), 2.84 (br d, J=6.4Hz, 2H), 1.58 (s, 9H), 1.16 (d, J=6.4Hz, 3H)ppm.

[0086] Step 4: Synthesis of (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one

[0087]

[0088] At 20°C, tert-butyl (R)-(1-(2-oxo-3-trityl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate (4.3 g, 8.04 mmol, 1 eq) was added to a methanol solution of hydrochloric acid (4 M, 30 mL, 14.9 eq). The reaction was allowed to proceed for 2 hours. The reaction was completed as detected by TLC and LCMS. The reaction solution was concentrated and neutralized by adding saturated sodium bicarbonate. The crude product was extracted and concentrated with ethyl acetate to obtain a crude product. The crude product was slurried and filtered with 30 ml of a mixed solvent of petroleum ether:ethyl acetate = 3:1 to obtain a white solid (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one (1.9 g, 4.37 mmol, 54.4% yield).

[0089] 1 H NMR (400MHz, DMSO-d6): δ=7.50-7.48 (m, 6H), 7.35-7.25 (m, 9H), 6.92-6.87 (m, 1H), 6.86-6.78 (m, 1H), 5.92 (d, J = 7.2Hz, 1H), 3.11-3.06 (m, 1H), 2.60-2.57 (m, 2H), 0.97 (d, J = 6.4Hz, 3H) ppm.

[0090] LCMS: m / z(M+H) + =435.1.

[0091] Step 5: Synthesis of (R)-7-(2-(isobutylamino)propyl)-3-tritylbenzo[d]oxazol-2(3H)-one

[0092]

[0093] (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one (1.65 g, 3.38 mmol, 1 eq) and 2-methylpropanal (292 mg, 4.06 mmol, 370 uL, 1.2 eq) were dissolved in 30 ml of methanol, and acetic acid (406 mg, 6.76 mmol, 387 uL, 2 eq) and sodium cyanoborohydride (425 mg, 6.76 mmol, 2 eq) were added to the reaction solution at 20°C. After two hours of reaction, the reaction was completed as monitored by TLC and LCMS. The reaction solution was concentrated and then added with saturated sodium bicarbonate for neutralization. The solution was extracted with ethyl acetate, dried, and concentrated. The solution was separated by column chromatography to obtain a yellow solid (R)-7-(2-(isobutylamino)propyl)-3-tritylbenzo[d]oxazol-2(3H)-one (1.70 g, 100% yield).

[0094] 1 H NMR (400MHz, CDCl3): δ=7.46-7.48 (m, 6H), 7.30-7.28 (m, 9H), 6.93 (d, J=7.2Hz, 1H), 6.82 (t, J=8.0Hz, 1H), 5.99 (d, J=8.0Hz, 1H), 4.13 (q, J=7.2Hz, 1H), 3.57-3.53(m, 1H), 3.26-3.21(m, 1H), 2.99-2.94(m, 1H), 2.79-2.73(m, 2H), 1.31-1.29(m, 3H), 0.97-0.94(m, 6H)ppm.

[0095] LCMS: m / z(M+H) + =491.4.

[0096] Step 6: Synthesis of (R)-7-(2-(isobutylamino)propyl)benzo[d]oxazol-2(3H)-one

[0097]

[0098] (R)-7-(2-(isobutylamino)propyl)-3-tritylbenzo[d]oxazol-2(3H)-one (1.7 g, 3.46 mmol, 1 eq) was dissolved in a mixed solvent of 20 ml trifluoroacetic acid and 2 ml water and reacted at 20°C for 3 hours. TLC and LCMS monitored the reaction to be complete. The reaction solution was concentrated at 50°C and saturated sodium bicarbonate was added to adjust the pH to neutral. The reaction solution was extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was separated by column chromatography to obtain a yellow solid (R)-7-(2-(isobutylamino)propyl)benzo[d]oxazol-2(3H)-one (650 mg, 2.62 mmol, 75.5% yield).

[0099] 1H NMR (400MHz, CDCl3): δ=7.08-7.06(m, 1H), 6.96-6.93(m, 2H), 3.25(br d, J=5.6Hz, 1H), 3.04–2.99 (m, 1H), 2.83-2.80 (m, 1H), 2.61-2.58 (m, 2H), 1.84–1.77 (m, 1H), 1.18 (d, J=6.4Hz, 3H), 0.90 (t, J=6.4Hz, 6H)ppm.

[0100] LCMS: m / z(M+H) + =249.2.

[0101] Step 7: (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazole Synthesis of 2-[5,4-f]isoquinolin-2(3H)-one

[0102]

[0103] (R)-7-(2-(isobutylamino)propyl)benzo[d]oxazol-2(3H)-one (600 mg, 1 eq) and 4-bromo-2,6-difluorobenzaldehyde (800 mg, 1.5 eq) were dissolved in 30 ml of toluene and acetic acid (450 mg, 3 eq) was added. The reaction was carried out at 115°C for 24 hours. TLC and LCMS showed that 25% of the starting material remained and 50% of the product was generated. The reaction solution was concentrated at 60°C, and the crude product was separated by column chromatography to obtain a yellow solid (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (460 mg, 42.2% yield).

[0104] 1 H NMR (400MHz, CDCl3): δ=7.59 (br s, 1H), 6.94 (br d, J=8.4Hz, 2H), 6.67 (d, J=8.4Hz, 1H), 6.49 (d, J=8.4Hz, 1H), 5.04 (s, 1H), 3.45-3.39 (m, 1H), 3.09 -3.04(m, 1H), 2.77–2.72(m, 1H), 2.38–2.34(m, 1H), 1.89-1.84(m, 1H), 1.60-1.58(m, 1H), 0.91(br d, J=6.4Hz, 3H), 0.74(br d, J=6.4Hz, 3H), 0.60(br d, J = 6.4 Hz, 3H) ppm.

[0105] LCMS: m / z(M+H) + =450.9

[0106] Step 8: (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-3-trityl-6,7, Synthesis of 8,9-Tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0107]

[0108] Dissolve (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (240 mg, 532 μmol, 1 eq) in 10 ml of N,N-dimethylformamide, and add sodium hydride (42.5 mg, 1.06 mmol, 60% purity, 2 eq) at 0°C. Then, add trityl chloride (163 mg, 585 μmol, 1.1 eq) to the reaction solution at 0°C, and slowly raise the temperature to 20°C for 2 hours. The reaction was completed as detected by TLC and LCMS. The reaction solution was poured into water to quench the reaction and extracted with ethyl acetate. The organic phase was dried and concentrated. The crude product was separated by column chromatography to give a yellow solid (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (420 mg, 460 μmol, 86.5% yield).

[0109] 1 H NMR (400MHz, CDCl3): δ=7.48-7.46 (m, 6H), 7.31-7.29 (m, 9H), 6.99 (d, J=8.4Hz , 2H), 6.24-6.16(m, 1H), 5.66-5.62(m, 1H), 5.00(s, 1H), 3.48-3.41(m, 1H), 3.0 9-3.04(m, 1H), 2.79–2.75(m, 1H), 2.42–2.37(m, 1H), 1.90–1.85(m, 1H), 1.64-1 .60 (m, 1H), 0.95-0.92 (m, 3H), 0.78 (d, J = 6.4Hz, 3H), 0.66 (d, J = 6.4Hz, 3H) ppm.

[0110] LCMS: m / z(M+H) + =695.0.

[0111] Step 9: Synthesis of 2-(3-(fluoromethyl)azetidin-1-yl)ethanol

[0112]

[0113] 3-(Fluoromethyl)azetidine hydrochloride (3g, 23.9mmol, 1eq) was dissolved in tetrahydrofuran (50mL) and 1,8-diazacycloundecene (10.9g, 71.7mmol, 10.8mL, 3eq) was added at 20°C. After stirring for 15 minutes, 2-bromoethanol (5.97g, 47.8mmol, 2eq) was added and reacted for 12 hours. TLC detected that the reaction was complete, the reaction solution was adjusted to pH greater than 9, extracted with ethyl acetate, the organic phase was dried and concentrated, and the crude product was separated by column chromatography to obtain a yellow oily product 2-(3-(fluoromethyl)azetidine-1-yl)ethanol (950mg, 7.13mmol, 29.8% yield).

[0114] 1 H NMR (400MHz, CDCl3): δ = 4.57-4.42 (m, 1H), 4.41–4.38 (m, 1H), 3.53–3.50 (m, 2 H), 3.43–3.40 (m, 2H), 3.10–3.08 (m, 2H), 2.85–2.80 (m, 1H), 2.61–2.59 (m, 2H).

[0115] Step 10: (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidin-1-yl)-ethoxy 7-isobutyl-8-methyl-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one Synthesis

[0116]

[0117] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (300 mg, 329 μmol, 1 eq) and 2-(3-(fluoromethyl)azetidin-1-yl)ethanol (109 mg, 822 μmol, 2.5 eq) were dissolved in toluene (9 ml), and [(2-2-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (27.6 mg, 32.8 μmol, 0.1 eq) and cesium carbonate (321 mg, 986 μmol, 3 eq) were added, and the reaction solution was reacted at 110° C. for 24 hours. The reaction was completed as monitored by TLC and LCMS. The reaction solution was concentrated and separated by column chromatography to give a yellow solid (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidin-1-yl-ethoxy-phenyl)-7-isobutyl-8-methyl-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (90 mg, 121 μmol, 36.7% yield).

[0118] 1H NMR (400MHz, CDCl3): δ=7.47-7.46 (m, 6H), 7.26-7.23 (m, 9H), 6.34 (d, J=10.4Hz, 2H), 6.23 (d, J=8.4Hz , 1H), 5.61 (d, J=8.4Hz, 1H), 4.95-4.93 (m, 1H), 4.57 (d, J=5.6Hz, 1H), 4.45 (d, J=5.6Hz, 1H), 3.91 (q, J =5.6Hz, 2H), 3.50-3.42(m, 5H), 3.17-3.16(m, 2H), 3.06-3.04(m, 1H), 2.84–2.77(m, 2H), 2.76–2.72(m , 1H), 2.37-2.32(m, 1H), 1.92(m, 1H), 0.95-0.92(m, 3H), 0.78(d, J=6.4Hz, 3H), 0.69-0.65(m, 3H)ppm.

[0119] LCMS: m / z(M+H) + =742.2.

[0120] Step 11: (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidin-1-yl-ethyl)- Synthesis of 7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Chemical Compound 1)

[0121]

[0122] (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidin-1-yl-ethoxy-phenyl)-7-isobutyl-8-methyl-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (90 mg, 120.66 μmol, 1 eq) was dissolved in a mixed solution of trifluoroacetic acid (9 mL) and water (1 mL) and reacted at 20°C for 2 hours. The reaction was completed as monitored by LCMS and TLC. The reaction solution was heated at 40°C. The reaction mixture was concentrated under reduced pressure, and then saturated sodium bicarbonate was added for neutralization. The mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was separated by thin layer chromatography on a silica gel plate to give a yellow solid (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidin-1-yl-ethoxy-phenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (35 mg, 67.4 μmol, 55.8% yield, 97% purity, 89% ee).

[0123] 1H NMR (400MHz, DMSO-d6): δ=6.70 (d, J=8.0Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 6.31 (brd, J=10.4Hz, 2H), 5.06 (s, 1H), 4.56 (d, J = 5.4Hz, 1H), 4.44 (d, J = 5.4Hz, 1H), 3.93-3.92 (m, 2H), 3.56–3.54 (m, 2H), 3. 45–3.42(m, 1H), 3.20-3.10(m, 3H), 2.89–2.86(m, 2H), 2.82–2.77(m, 1H), 2.40-2.32(m, 1H), 2.01 –1.96 (m, 1H), 1.26 (s, 2H), 0.99 (d, J = 6.4Hz, 3H), 0.81 (d, J = 6.4Hz, 3H), 0.68 (d, J = 6.4Hz, 3H) ppm.

[0124] LCMS: m / z(M+H) + =504.4.

[0125] Example 5: (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 5)

[0126]

[0127] Step 1: (R)-(1-(2-oxo-3-trityl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl) Synthesis of tert-butyl carbamate

[0128]

[0129] 7-Bromo-3-trityl-benzoxazol-2-one (100g, 219mmol, 1eq) was dissolved in tetrahydrofuran (1000mL) and n-butyl lithium (2.5M, 87.6mL, 1eq) was added under nitrogen protection at -78℃ and stirred for 30 minutes. (R)-tert-butyl 4-methyl-1,2,3-oxazolidine-3-carboxylic acid 2,2-dioxide (52.0g, 219mmol, 1eq) in tetrahydrofuran (100mL) was added to the system at -78℃, and then naturally returned to 0℃ for 2 hours. TLC detected that the reaction was complete, and the reaction solution was poured into a saturated aqueous ammonium chloride solution to quench, extracted with ethyl acetate, and dried and concentrated. The crude product was separated by column chromatography to give a yellow solid (R)-tert-butyl (1-(2-oxo-3-trityl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate (360 g, 673 mmol, 74.9% yield).

[0130] 1 H NMR (400MHz, CDCl3): δ=7.52-7.47(m, 6H), 7.35-7.27(m, 9H), 6.92-6.85(m, 1H), 6.76(t, J=8.0Hz, 1H), 5.93(br d, J=8.0Hz, 1H), 4.00 (s, 1H), 3.81-3.72 (m, 1H), 2.84 (br d, J=6.0Hz, 2H), 1.40 (s, 9H), 1.16 (d, J=6.4Hz, 3H) ppm.

[0131] Step 2: Synthesis of (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one

[0132]

[0133] Under nitrogen protection at 0°C, (R)-(1-(2-oxo-3-trityl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamic acid tert-butyl ester (240 g, 448 mmol, 1 eq) was dissolved in methanol (400 ml), and then added to a methanol solution of hydrochloric acid (6 M, 800 mL, 10.6 eq). The mixture was reacted at 0°C for 2 hours, and the reaction was completed by TLC. The reaction solution was concentrated, neutralized by adding saturated sodium bicarbonate, extracted and concentrated with ethyl acetate to obtain a crude product, which was slurried and filtered with petroleum ether:ethyl acetate = 1:1 to obtain a yellow solid (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one (198 g, 455 mmol, 84.6% yield).

[0134] 1 H NMR (400MHz, CDCl3): δ=7.48-7.34 (m, 6H), 7.23-7.14 (m, 9H), 6.81-6.73 (m, 1H), 6.66 (t, J= 8.0Hz, 1H), 5.88 (m, 1H), 3.33 (s, J=6.4Hz, 1H), 2.82-2.65 (m, 2H), 1.12 (d, J=6.4Hz, 3H)ppm.

[0135] Step 3: (R)-7-(2-aminopropyl)(2,2,2-trifluoroethyl-3-tritylbenzo[d]oxazole-2(3H)- Synthesis of Ketones

[0136]

[0137] Under nitrogen protection at 20°C, (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one (10.0 g, 23.0 mmol, 1 eq), 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.14 g, 26.5 mmol, 1.15 eq), and diisopropylethylenediamine (8.92 g, 69.0 mmol, 12.0 mL, 3 eq) were dissolved in dioxane (100 mL), and then reacted at 80°C under nitrogen protection for 10 hours. The reaction was completed by TLC detection, the reaction solution was concentrated, and the crude product was separated by column chromatography to obtain a white solid (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one (9.00 g, 17.4 mmol, 75.7% yield).

[0138] 1 H NMR (400MHz, CDCl3): δ=7.48 (br d, J=7.2Hz, 6H), 7.33-7.27 (m, 9H), 6.86 (brd, J=7.6Hz, 1H), 6.79-6.73 (m, 1H), 5.95 (br d, J=8.0Hz, 1H), 3.50 (s, 1H), 3.26 (br d, J=9.3Hz, 3H), 2.98-2.85 (m, 1H), 2.82-2.71 (m, 1H), 1.15 (br d, J=5.6Hz, 3H) ppm.

[0139] Step 4: (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetra Synthesis of Hydroisoquino[5,4-f]Oxazol-2(3H)-one

[0140]

[0141] (R)-7-2-aminopropyl)(2,2,2-trifluoroethyl-3-tritylbenzo[d]oxazol-2(3H)-one (1.00 g, 1.94 mmol, 1 eq) and 5-bromo-2-pyridinecarboxaldehyde (540 mg, 2.90 mmol, 1.5 eq) were dissolved in toluene (50 mL) and trifluoroacetic acid (662 mg, 5.81 mmol, 430 uL, 3 eq) was added. The mixture was heated at 90 °C. The reaction was carried out for 20 hours. TLC detected that the reaction was complete, the reaction solution was concentrated, and the crude product was purified by-TLC (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid (6S, 8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinolin[5,4-f]oxazol-2(3H)-one (780 mg, 1.76 mmol, 91.1% yield).

[0142] 1H NMR (400MHz, CDCl3): δ=8.89 (s, 1H), 8.54 (d, J=2.4Hz, 1H), 7.84-7.80 (m, 1H), 7.48 (d, J=8.4Hz, 1H), 6.79-6.74 (m, 2H), 5.09 (s, 1H), 4.13 (q, J=7.2Hz, 1H), 3.50-3.39 (m, 1H), 3.35-3.22 (m, 1H), 3.09-3.03 (m, 1H), 3.00-2.89 (m, 1H), 2.70-2.64 (m, 1H), 1.13 (d, J=6.4Hz, 3H)ppm.

[0143] Step 5: (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethane Synthesis of 6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0144]

[0145] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinolin[5,4-f]oxazol-2(3H)-one (1.00 g, 2.26 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (181 mg, 4.52 mmol, 60% purity, 2 eq) was added at 0°C, and then trityl chloride (693 mg, 2.49 mmol, 1.1 eq) was added at 20°C and reacted for 2 hours. The reaction was completed by TLC. The reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated, and the crude product was separated by column chromatography to give a white solid (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (1.20 g, 1.56 mmol, 69.0% yield).

[0146] 1H NMR (400MHz, CDCl3): δ=8.52 (s, 1H), 7.75 (dd, J1=2.4Hz, J2=8.4Hz, 1H), 7.49-7.45 (m, 6H), 7.36 (d, J=8.4Hz, 1H), 7.32-7.27 (m, 9H), 6.3 9 (d, J=8.4Hz, 1H), 5.75 (d, J=8.4Hz, 1H), 4.94 (s, 1H), 3.53-3.42 (m, 1H), 3.29-3.18 (m, 1H), 3.01 (dd, J1=4.8Hz, J2=16.8Hz, 1H), 2.90 (br dd, J1=9.2Hz, J2=15.6Hz, 1H), 2.68 (dd, J1=6.8Hz, J2=16.8Hz, 1H), 1.10 (d, J=6.4Hz, 3H) ppm.

[0147] Step 6: 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2, tert-Butyl 3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carboxylate Synthesis

[0148]

[0149] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydroisoquinolino[5,4-f]oxazol-2(3H)-one (200 mg, 292 μmol, 1 eq) and tert-butyl 3-aminoazetidine-1-carboxylate (126 mg, 730 μmol, 2.5 eq) were dissolved in 8 ml of toluene, and [(2-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (24.5 mg, 29.2 μmol, 0.1 eq) and cesium carbonate (286 mg, 876 μmol, 3 eq) were added, and the reaction solution was reacted at 110°C for 15 hours. The reaction was complete after TLC detection, and the reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated. The crude product was separated by column chromatography to obtain yellow solid tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carboxylate (120 mg, 137 μmol, 47.2% yield).

[0150] 1 H NMR (400MHz, CDCl3): δ=7.77 (d, J=2.4Hz, 1H), 7.52-7.42 (m, 7H), 7.32

[0151] -7.28(m, 4H), 7.26-7.17(m, 9H), 6.89-6.69(m, 1H), 6.37(d, J=8.4Hz, 1H), 5.80

[0152] -5.64(m, 1H), 5.39-5.20(m, 1H), 4.98-4.77(m, 1H), 4.33-4.27(m, 2H), 4.23-4.11(m, 1H), 4.08-3.98(m, 1H), 3.74(m, 2 H), 3.53-3.43 (m, 2H), 3.26-3.11 (m, 1H), 3.04-2.85 (m, 2H), 2.72-2.59 (m, 1H), 1.45 (s, 9H), 1.09 (d, J = 6.4Hz, 3H) ppm.

[0153] Step 7: (6S,8R)-6-(5-(azetidine-3-amino)pyridin-2-yl)-8-methyl-7-(2,2,2-triazine Synthesis of (2-(4-fluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0154]

[0155] Trifluoroacetic acid (9.00 mL) and water (1.00 mL) were added to tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carboxylate (120 mg, 154 μmol, 1 eq) at 0°C, and the mixture was reacted at 20°C for 2 hours. The reaction was completed after monitoring by TLC. The reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated to give a yellow solid (6S,8R)-6-(5-(azetidine-3-amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (120 mg, crude product).

[0156] 1 H NMR (400MHz, CDCl3): δ = 8.21-7.93 (m, 2H), 7.60-7.35 (m, 2H), 6.95-6.62 (m, 1H), 5.55-5.17 (m, 1H), 4.39-4.13 (m, 1H), 4.06-3.90 (m, 1H), 3.63-3.42 (m, 1H), 2.33-2.13 (m, 2H), 2.07-1.96 (m, 2H), 1.14-1.08 (m, 2H), 0.88 (br d, J=4.8Hz, 3H)ppm.

[0157] Step 8: (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin-2-yl)-8- Synthesis of methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 5)

[0158]

[0159] Under nitrogen protection at 20°C, (6S,8R)-6-(5-(azetidine-3-amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (66.0 mg, 152 μmol, 1 eq) and 3-fluoro-1-iodopropane (28.6 mg, 152 μmol, 1 eq) were dissolved in N,N-dimethylformamide (1 mL), and diisopropylethylenediamine (98.4 mg, 761 μmol, 132 uL, 5 eq) was added, and the mixture was reacted at 20°C for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was quenched with water, extracted with ethyl acetate, and dried and concentrated. The crude product was separated by a reverse phase column and then by a hand column to obtain a yellow solid (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (27.0 mg, 54.2 μmol, 35.6% yield, 97.7% purity, 100% ee).

[0160] 1 H NMR (400MHz, MeOH-d4): δ=7.76-7.71 (m, 1H), 7.13 (d, J=8.4Hz, 1H), 6.93 (m, 1H), 6.80 ( d, J=8.0Hz, 1H), 6.56 (d, J=8.0Hz, 1H), 4.52 (t, J=6.0Hz, 1H), 4.40 (t, J=6.0Hz, 1H), 4. 13-4.06(m, 1H), 3.82-3.76(m, 2H), 3.54-3.47(m, 1H), 3.15-3.08(m, 1H), 3.00-2.91(m , 3H), 2.76 (m, 1H), 2.64 (t, J=7.6Hz, 2H), 1.83-1.69 (m, 2H), 1.06 (d, J=6.6Hz, 3H)ppm.

[0161] LCMS: m / z(M+H) + =494.3.

[0162] Example 7: (6S,8R)-6-(5-(((S)-1-(3-fluoropropane)pyrrolidin-3-yl)oxy)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 7)

[0163]

[0164] Step 1: (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethane tert-Butyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate Synthesis

[0165]

[0166] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (150 mg, 219 μmol, 1 eq) and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (102 mg, 547 μmol, 2.5 eq) were dissolved in toluene (20 mL) and then (18.3 mg, 21.9 μmol, 0.1 eq) and cesium carbonate (214 mg, 657 μmol, 3 eq) were added. The reaction solution was reacted at 115°C for 15 hours. After the reaction was completed by TLC monitoring, the reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated. The crude product was separated by column chromatography to give a yellow solid (S)-tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate (120 mg, 138 μmol, 31.5% yield).

[0167] 1H NMR (400MHz, CDCl3): δ=8.02 (d, J=2.8Hz, 1H), 7.39 (d, J=7.2Hz, 6H), 7.24-7.20 (m, 5H), 7.18-7.14 (m, 4 H), 7.08-7.04 (m, 1H), 6.37-6.25 (m, 1H), 5.66 (d, J=8.4Hz, 1H), 4.86-4.80 (m, 2H), 3.55-3.34 (m, 2H), 3. 34-3.23 (m, 1H), 3.16-3.04 (m, 1H), 3.01-2.89 (m, 1H), 2.83 (brdd, J1=8.8Hz, J2=15.6Hz, 1H), 2.59 (dd, J1=6.4Hz, J2=16.8Hz, 1H), 2.15-2.01(m, 2H), 1.95-1.81(m, 2H), 1.40(s, 9H), 1.02(d, J=6.4Hz, 3H)ppm.

[0168] Step 2: (6S,8R)-8-methyl-6-(5-((S)-pyrrolidin-3-oxy)pyridin-2-yl)-7-(2,2,2-triazine Synthesis of (2-(4-fluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0169]

[0170] Trifluoroacetic acid (1.54 g, 13.4 mmol, 997 uL, 87.3 eq) was added to (S)-tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate (120 mg, 154 μmol, 1 eq) dissolved in dichloromethane (2 mL) at 0°C, and reacted at 20°C for 2 hours. The reaction was completed by monitoring by TLC and LCMS. The reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated. The crude product was separated by thin layer chromatography on silica gel to give a yellow solid (6S,8R)-8-methyl-6-(5-((S)-pyrrolidin-3-oxy)pyridin-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (105 mg, crude product).

[0171] 1H NMR (400MHz, DMSO-d6): δ=8.13 (d, J=2.8Hz, 1H), 7.45-7.34 (m, 1H), 7.32- 7.26(m, 1H), 6.87-6.82(m, 1H), 6.74-6.67(m, 1H), 5.14-5.02(m, 2H), 3.00 -2.92(m, 2H), 2.90-2.78(m, 2H), 2.72-2.71(m, 1H), 2.74-2.58(m, 1H), 2. 21-2.07 (m, 2H), 2.06-1.93 (m, 1H), 1.23 (s, 1H), 1.06 (d, J = 6.4Hz, 3H) ppm.

[0172] LCMS: m / z(M+H) + =449.2.

[0173] Step 3: (6S,8R)-6-(5-(((S)-1-(3-fluoropropane)pyrrolidin-3-yl)oxy)pyridin-2-yl)-8- Synthesis of methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 7)

[0174]

[0175] Under nitrogen protection at 20°C, (6S,8R)-8-methyl-6-(5-((S)-pyrrolidin-3-oxy)pyridin-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (105 mg, 187 μmol, 1 eq) and 3-fluoro-1-iodopropane (35.2 mg, 187 μmol, 1 eq) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylenediamine (121 mg, 936 μmol, 163 uL, 5 eq) was added, and the mixture was reacted at 20°C for 4 hours. LCMS detected that the reaction was complete, and the reaction solution was quenched with water, extracted with ethyl acetate, and dried and concentrated. The crude product was separated by reverse phase column to give a white solid (6S,8R)-6-(5-(((S)-1-(3-fluoropropane)pyrrolidin-3-yl)oxy)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (10.5 mg, 19.8 μmol, 10.6% yield, 96% purity, 100% ee).

[0176] 1H NMR (400MHz, MeOH-d4): δ=8.05 (d, J=2.8Hz, 1H), 7.40-7.30 (m, 2H), 6.83 (d, J=8.0Hz, 1H), 6.63 (d, J=8.0Hz , 1H), 4.54 (t, J=6.0Hz, 1H), 4.42 (t, J=6.0Hz, 1H), 3.53-3.48 (m, 1H), 3.40 (brd, J=6.0Hz, 1H), 3.10 (dd, J1= 4.8Hz, J2=16.8Hz, 1H), 3.02-2.87(m, 4H), 2.78(dd, J1=6.2Hz, J2=16.8Hz, 1H), 2.68-2.58(m, 2H), 2.56-2. 49 (m, 1H), 2.38 (dt, J1=7.6Hz, J2=13.6Hz, 1H), 1.99-1.84 (m, 3H), 1.29 (brs, 1H), 1.12 (d, J=6.4Hz, 3H)ppm.

[0177] LCMS: m / z(M+H) + =509.4.

[0178] Example 8: (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 8)

[0179]

[0180] Step 1: (6S,8R)-6-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)- 3-Trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)-2,6-diazaspiro[3.3]heptyl Synthesis of tert-Butyl 2-Alkanecarboxylate

[0181]

[0182] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (300 mg, 417 μmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (165.33 mg, 833.88 μmol) were dissolved in toluene (9 mL), and cesium carbonate (272 mg, 834 μmol) and [(2-bis-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2- The mixture was added with [(6S,8R)-6-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydroisoquinolin[5,4-f]oxazol-6-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (120 mg, 143 μmol, yield 34.4%).

[0183] 1 H NMR (400MHz, CDCl3): δ=7.41-7.37 (m, 6H), 7.24-7.19 (m, 9H), 6.17 (d, J=8.5Hz, 1H), 5.77 (d, J=10.5Hz, 2H), 5.56 (d, J=8.5Hz, 1H), 5.03 (s, 1H) , 4.02(s, 4H), 3.88(s, 4H), 3.50-3.44(m, 1H), 3.11-2.99(m, 2H), 2.85- 2.75 (m, 1H), 2.71-2.62 (m, 1H), 1.37 (s, 9H), 0.96 (d, J = 6.4Hz, 3H) ppm.

[0184] LCMS: m / z 837.3 [M+H] + .

[0185] Step 2: (6S,8R)-6-(2,6-difluoro-4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-8-methyl- Synthesis of 7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0186]

[0187] tert-Butyl 6-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg, 358.47 μmol) was dissolved in trifluoroacetic acid (4.5 mL) and water (0.5 mL) at 0°C. The temperature was raised to 20°C and stirred for 2 hours. The reaction was completed by LCMS. After concentration, the pH was adjusted to 7-8, and the mixture was extracted with water and ethyl acetate. The organic phase was concentrated to give (6S,8R)-6-(2,6-difluoro-4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (350 mg, crude product).

[0188] LCMS: m / z 495.0 [M+H] + .

[0189] Step 3: (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptane-2-yl) Synthesis of phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one become

[0190]

[0191] (6S,8R)-6-(2,6-difluoro-4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (300 mg, 606.73 μmol) and 1-iodo-3-fluoroethane (211.09 mg, 1.21 mmol) were dissolved in N,N-dimethylformamide (15 mL), and then N,N-diisopropylethylamine (313.66 mg, 2. The mixture was added with 43 mmol) at 20 °C for 2 hours. The reaction was completed after LCMS detection. The mixture was extracted with water and ethyl acetate. The organic phase was washed three times with brine, concentrated and purified by silica gel column to obtain (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (95 mg, 175.76 μmol, yield 28.9%).

[0192] LCMS: m / z 541.3 [M+H] + .

[0193] Step 4: (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptane-2-yl) Degradation of 8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one Compound 8

[0194]

[0195] (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one was chiral resolved to give (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (40 mg, 74.01 μmol, yield 44.4%)

[0196] 1 H NMR (400MHz, MeCN-d3) δ = 6.87-6.72 (m, 1H), 6.64-6.53 (m, 1H), 6.03-5.86 (m, 2H), 5.21 (s, 1H), 4.46-4.41 (m, 1H), 4.34-4.30 (m, 1H), 3.89 (s, 4H), 3.56-3.46 (m, 1H), 3.35 (s, 4 H), 3.33-3.25 (m, 1H), 3.05 (dd, J=4.9, 16.4Hz, 1H), 2.93 (qd, J=9.8, 15.9Hz, 1H), 2.74 ( dd, J=5.1, 16.5Hz, 1H), 2.70-2.66 (m, 1H), 2.63-2.58 (m, 1H), 1.06 (d, J=6.5Hz, 3H) ppm.

[0197] Example 9: (6S,8R)-7-(2,2-difluoro-3-hydroxypropyl)-6-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 9)

[0198]

[0199] Step 1: (R)-7-(2-((3-((tert-butylphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-3- Synthesis of Triphenylbenzo[d]oxazol-2(3H)-one

[0200]

[0201] Subsequent steps: According to the steps similar to those in Examples 1-8 and / or conventional reaction steps in the art, (R)-7- (2-((3-((tert-butylphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-3-triphenylbenzo[d]oxazole-2-yl) Compound 9 was synthesized starting from (3H)-ketone.

[0202] 1 H NMR: (400MHz, ACETONITRILE-d3) δ = 11.6 (s, 1H), 9.16 (s, 1H), 6.81 (d, J = 8.0Hz, 1H), 6.60 (br d,J=8.0Hz,1H),6.13-6.10(m,2H),5.18(s,1H),4.61-4.52(m,2H),4.44-4.33(m,2H),4.22-4.12(m,2H),3.81-3 .46(m,4H),3.36-3.24(m,2H),3.18-2.98(m,2H),2.80-2.70(m,2H),2.02-1.95(m,2H),1.05(d,J=6.4Hz,3H)ppm.

[0203] Similar to the synthetic route of the aforementioned Examples 1-9, the corresponding reactants and the synthetic method known to those skilled in the art were selected to synthesize the following Example compounds. Specifically, the compound of Step 1 of Example 9, i.e., "(R)-7-(2-((3-((tert-butylphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-3-triphenylbenzo[d]oxazol-2(3H)-one", was used as a raw material to synthesize the following Examples 13-15; the compound of Step 3 of Example 5, i.e., "(R)-7-2-aminopropyl)(2,2,2-trifluoroethyl-3-tritylbenzo[d]oxazol-2(3H)-one", was used as a raw material to synthesize the following Examples 10-12, 16, 18, 25; the compound of Step 4 of Example 1, i.e., "(R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one", was used as a raw material to synthesize the following Example 20.

[0204] Example 10: (6S,8R)-6-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 10)

[0205]

[0206] 1H NMR: (400MHz, CDCl3) δ = 8.03-7.74 (m, 1H), 6.79 (s, 1H), 6.67-6.60 (m, 1H), 5.99 (d, J = 11. 0Hz,2H),5.21(s,1H),4.59-4.51(m,1H),4.48-4.40(m,1H),4.38-4.25(m,1H),4.12-3.9 5(m,1H),3.78-3.67(m,2H),3.63-3.51(m,1H),3.26-3.09(m,2H),3.00-2.86(m,3H),2.7 8(dd,J=4.4,16.4Hz,1H),2.67-2.56(m,2H),1.83-1.71(m,2H),1.09(d,J=6.6Hz,3H)ppm.

[0207] LCMS: m / z (M+H)+=529.4

[0208] Example 11: (6S,8R)-6-(2,6-difluoro-4-(((S)-1-(3-fluoropropane)pyrrolidin-3-yl)oxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 11)

[0209]

[0210] 1 H NMR: (400MHz, ACETONITRILE-d3) δ = 6.81 (d, J = 8.0Hz, 1H), 6.62 (d, J = 8.0Hz, 1H), 6.44 (br d, J = 11.2Hz, 2H), 5.28 (s, 1H), 4.79 (br s,1H),4.54(t,J=6.0Hz,1H),4.42(t,J=6.0Hz,1H),3.56-3.46(m,1H),3.42-3.25(m,1H),3.06(br dd,J=4.8,16.6Hz,1H),3.00-2.86(m,1H),2.83-2.69(m,5H),2.53-2.45 (m,4H),1.91-1.85(m,1H),1.85-1.76(m,2H),1.07(d,J=6.4Hz,3H)ppm.

[0211] Example 12: (6S,8R)-6-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 12)

[0212]

[0213] 1 H NMR: (400MHz, CD3Cl)δ=8.02-7.65(m,1H),6.79-6.71(m,1H),6.64-6.54(m,1H),6.27( d,J=10.4Hz,2H),5.29-5.22(m,1H),4.72(m,J=6.0Hz,1H),4.56(t,J=6.0Hz,1H),4.44( t,J=6.0Hz,1H),3.85-3.72(m,2H),3.64-3.50(m,1H),3.26-3.08(m,4H),2.97-2.86(m, 1H), 2.85-2.76 (m, 1H), 2.65 (t, J = 7.2Hz, 2H), 1.83-1.70 (m, 2H), 1.10 (d, J = 6.4Hz, 3H).

[0214] LCMS: m / z (M+H)+=530.2

[0215] Example 13: (6S,8R)-7-(2,2-difluoro-3-hydroxypropyl)-6-(2,6-difluoro-4-(((S)-1-(3-fluoropropane)pyrrolidin-3-yl)oxy)phenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 13)

[0216]

[0217] 1H NMR: (400MHz, CHLOROFORM-d) δ = 8.36 (br d, J = 1.1Hz, 1H), 6.79 (d, J = 8.1Hz, 1H), 6.58 (d, J = 8.1Hz, 1H), 6.40 (d, J = 10.4Hz, 2H), 5.18 (s, 1H), 4.89 (br s,1H),4.61(t,J=5.6Hz,1H),4.50(t,J=5.6Hz,1H),3.77-3.61(m,3H),3.29-2.92(m,7 H), 2.91-2.75 (m, 3H), 2.54-2.38 (m, 1H), 2.24-2.01 (m, 3H), 1.10 (d, J = 6.6Hz, 3H) ppm.

[0218] Example 14: (6S,8R)-7-(2,2-difluoro-3-hydroxypropyl)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 14)

[0219]

[0220] 1 H NMR: (400MHz, ACETONITRILE-d3) δ = 6.78 (br d, J = 6.6Hz, 1H), 6.67-6.44 (m, 1H), 6.07-5.84 (m, 2H), 5.94 (br d, J = 11.4Hz, 1H), 5.24-5.04 (m, 1H), 5.13 (br s,1H),4.50-4.26(m,2H),3.89(br s,4H),3.73-3.61(m,1H),3.58-3.45(m,2H),3.36(br s,4H),3.13-3.00(m,2H),3.18-2.97(m,1H),2.77-2.59(m,5H),2.80-2.57(m,1H),1.07-0.97(m,3H),1.03(br d,J=3.8Hz,1H)ppm.

[0221] Example 15: (6S,8R)-7-(2,2-difluoro-3-hydroxypropyl)-6-(2,6-difluoro-4-(3-((3-fluoropropyl)amino)azetidin-1-yl)phenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 15)

[0222]

[0223] 1 H NMR: (400MHz, ACETONITRILE-d3) δ = 6.85 (d, J = 8.1Hz, 1H), 6.65 (d, J = 8.1Hz, 1H) ,5.95(d,J=11.5Hz,2H),5.15(s,1H),4.56(t,J=5.6Hz,1H),4.44(t,J=5.6Hz,1H ),4.05(t,J=7.5Hz,2H),3.91-3.81(m,3H),3.72-3.48(m,3H),3.43-3.38(m,2H) ,3.18-3.02(m,2H),2.82-2.64(m,2H),2.13-2.01(m,4H),1.03(d,J=6.5Hz,3H).

[0224] Example 16: (E)-4-((2-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxy-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (Compound 16)

[0225]

[0226] 1 H NMR: (400MHz, ACETONITRILE-d3) δ = 6.81 (d, J = 8.1Hz, 1H), 6.75-6.65 (m, 1H), 6.61 (d, J =8.1Hz,1H),6.56-6.46(m,3H),5.29(s,1H),4.02(t,J=5.3Hz,2H),3.57-3.50(m,2H),3 .41-3.38(m,2H),3.37-3.30(m,1H),3.11-3.04(m,1H),3.02(s,3H),2.94-2.91(m,2H) ,2.90-2.88(m,3H),2.79-2.72(m,1H),1.11(t,J=7.0Hz,2H),1.07(d,J=6.6Hz,3H)ppm.

[0227] LCMS: m / z 569.4 [M+H] + .

[0228] Example 18: (6S,8R)-6-(2,6-difluoro-4-(3-((3-fluoropropyl)amino)azetidin-1-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 18)

[0229]

[0230] 1 H NMR: (400MHz, ACETONITRILE-d3) δ = 6.81 (br d, J = 8.0Hz, 1H), 6.61 (br d, J = 7.9Hz, 1H), 5.95 (d, J = 11.6Hz, 2H), 5.22 (s, 1H), 4.56 (t, J = 5.9Hz, 1H), 4.44 (br t,J=5.7Hz,1H),4.03(br t,J=7.3Hz,2H),3.75-3.63(m,1H),3.58-3.44(m,3H),3.36-3.24(m,1H),3.10-2.86(m,2H),2.80-2.71(m,1H),2.64(br t,J=6.8Hz,2H),1.86-1.71(m,3H),1.06(d,J=6.6Hz,3H).

[0231] Example 20: (6S,8R)-6-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-7-((1-fluorocyclopropyl)methyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 20)

[0232]

[0233] 1H NMR: (400MHz, ACETONITRILE-d3) δ = 8.12 (s, 1H), 6.82 (d, J = 8.3Hz, 1H), 6.61 (d, J = 8.0Hz, 1H), 6.10 (d, J = 11.6Hz, 2H), 5.38 (br d,J=7.3Hz,1H),5.12(s,1H),4.55(t,J=6.1Hz,1H),4.43(t,J=6.0Hz,1H),4.08-3.97(m,1H),3.75(br d,J=6.3Hz,3H),3.12-2.99(m,2H),2.97-2.90(m,2H),2.83-2.70(m,2H),2.62(t,J=7.1H z,2H),1.78-1.66(m,2H),1.02(d,J=6.6Hz,3H),0.97-0.86(m,2H),0.62-0.40(m,2H)ppm.

[0234] Example 25: (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 25)

[0235]

[0236] Step 1: (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8, Synthesis of 9-Tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0237]

[0238] Compound (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)benzo[d]oxazol-2(3H)-one (3.00 g, 10.9 mmol), 4-bromo-2-methoxybenzaldehyde (3.29 g, 5.32 mmol), trifluoroacetic acid (6.24 g, 54.7 mmol) were dissolved in toluene (15 mL) and reacted at 110°C under nitrogen protection for 48 hours. LCMS detected the end of the reaction. After the reaction solution was concentrated, column chromatography was purified to obtain a white solid (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (4.35 g, 9.23 mmol, yield 84.4%).

[0239] LCMS: m / z 470.0 [M+H] + .

[0240] 1 H NMR (400MHz, DMSO-d6) δ=11.53(s,1H),7.23(d,J=1.75Hz,1H),6.94-7.11(m,1H),6.82(d,J=8.00Hz,1H),6.68(d,J=8.13Hz,1H),6.54(d,J=8.1 3Hz,1H),5.28-5.52(m,1H),3.82-3.91(m,3H),3.27-3.41(m,2H),2.77 -3.02(m,2H),2.68(m,J=16.70,7.30Hz,1H),1.02(d,J=6.50Hz,3H)ppm.

[0241] Step 2: (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenyl Synthesis of Methyl-6,7,8,9-Tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0242]

[0243] (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (2.77 g, 5.88 mmol) was dissolved in N,N-dimethylformamide (25 mL), and sodium hydrogen (353 mg, 8.82 mmol) was added under nitrogen protection at 0°C, and then triphenylmethane (1.64 g, 5.88 mmol) was added. The reaction solution was reacted at 25°C for 2 hours. TLC detected that the reaction was complete. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to give a yellow solid (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (3.75 g, 5.26 mmol, yield 89.4%).

[0244] LCMS: m / z 712.2 [M+H] + .

[0245] 1H NMR (400MHz, CHLOROFORM-d) δ = 7.18-7.42 (m, 15H), 6.92-6.96 (m, 1H), 6.88 (dd, J = 8.13, 1.75Hz, 1H), 6.70 (d, J = 8.25Hz, 1H), 6.14 (d,J=8.63Hz,1H),5.55-5.66(m,1H),5.23(s,1H),3.76(s,3H),3.35-3.48(m,1H),2.89-3.04(m,2H),2.64-2.79(m,1H),2.61(br d,J=6.25Hz,1H),0.97(d,J=6.63Hz,3H)ppm.

[0246] Step 3: Synthesis of (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0247]

[0248] (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (2 g, 2.80 mmol), 1-(3-fluoropropyl)-3-aminoazetidine (1.41 g, 3.92 mmol), cesium carbonate (2.74 g, 8.41 mmol), [(2-bis-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)] palladium (II) methanesulfonate (118 mg, 140 umol) were dissolved in toluene (20 mL) and reacted at 110° C. under nitrogen protection for 12 hours. The reaction was completed by LCMS monitoring. The residue was purified by column chromatography to give a yellow solid (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (1 g, 1.31 mmol, yield 46.7%).

[0249] LCMS: m / z 764.3 [M+H] + .

[0250] 1H NMR(400MHz,CHLOROFORM-d)δ=7.18(br d,J=2.38Hz,15H),6.58(d,J=8.25Hz,1H),6.13-6.25(m,1H),5.97-6.04(m,1H),5.92(dd,J=8.25,2.13Hz,1H),5.50-5.65(m ,1H),5.14-5.18(m,1H),4.48(t,J=5.94Hz,1H),4.36(t,J=5.94Hz,1H),3.90(brd,J=6.75Hz,1H),3.61-3.79(m,6H),3.44(br d,J=5.50Hz,1H),3.00-3.29(m,1H),2.87-3.00(m,2H),2.79(br d,J=6.13Hz,2H),2.49-2.59(m,3H),1.64-1.73(m,2H),0.97(d,J=6.50Hz,3H)ppm.

[0251] Step 4: Synthesis of (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 25)

[0252]

[0253] Trifluoroacetic acid (15.4 g, 135 mmol) and (6S, 8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (1 g, 1.31 mmol) were dissolved in water (1 mL), and the reaction solution was reacted at 20°C under nitrogen protection for 1 hour. LCMS detected the completion of the reaction. After the mixture was concentrated, the pH was adjusted to 7 with sodium bicarbonate, extracted with water and ethyl acetate, and the organic phase was concentrated. The crude product was purified by column chromatography and sent to SFC for chiral separation to give a yellow solid (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (300 mg, 571 umol, yield 43.7%).

[0254] LCMS: m / z 522.2 [M+H] + .

[0255] 1 H NMR (400MHz, ACETONITRILE-d3) δ = 6.79 (d, J = 8.13Hz, 1H), 6.44-6.59 (m, 2H), 6.19 (d, J = 2.00Hz, 1H), 5.97 (dd, J = 8.32, 2.06Hz, 1H), 5.31 (s, 1H), 4.75 (br d,J=7.00Hz,1H),4.52(t,J=6.07Hz,1H),4.40(t,J=6.07Hz,1H),3.92-4. 09(m,1H),3.79(s,3H),3.68(m,J=3.25,2.13Hz,2H),3.43-3.54(m,1H),3. 17-3.30(m,1H),2.87-3.01(m,2H),2.76,(m,J=6.38Hz,2H),2.61-2.67(m, 1H), 2.51 (t, J = 7.00Hz, 2H), 1.63-1.76 (m, 2H), 1.04 (d, J = 6.50Hz, 3H) ppm.

[0256] Example 26: (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 26)

[0257]

[0258] Step 1: Synthesis of tert-butyl (R)-(1-(2-oxo-3-trityl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate

[0259]

[0260] Dissolve 7-bromo-3-trityl-benzoxazol-2-one (100 g, 219 mmol, 1 eq) in tetrahydrofuran (1000 mL) and add n-butyl lithium (2.5 M, 87.6 mL, 1 eq) at -78 °C under nitrogen protection and stir for 30 minutes. Add a solution of (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (52.0 g, 219 mmol, 1 eq) in tetrahydrofuran (100 mL) to the system at -78 °C, then naturally return to 0 °C for 2 hours. TLC detection of the reaction is complete, the reaction solution is poured into a saturated aqueous ammonium chloride solution to quench, extracted with ethyl acetate, dried and concentrated. The crude product was separated by column chromatography to obtain a yellow solid (R)-tert-butyl (1-(2-oxo-3-trityl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate (360 g, 673 mmol, yield 74.9%).

[0261] 1 H NMR (400MHz, CHLOROFORM-d) δ=7.52-7.47(m,6H),7.35-7.27(m,9H),6.92-6.85(m,1H),6.76(t,J=8.0Hz,1H),5.93(br d,J=8.0Hz,1H),4.00(s,1H),3.81-3.72(m,1H),2.84(br d,J=6.0Hz,2H),1.40(s,9H),1.16(d,J=6.4Hz,3H)ppm.

[0262] Step 2: Synthesis of (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one

[0263]

[0264] Under nitrogen protection at 0℃, (R)-tert-butyl (1-(2-oxo-3-trityl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate (240g, 448mmol, 1eq) was dissolved in methanol (400ml), and then added to a methanol solution of hydrochloric acid (6M, 800mL, 10.6eq). The reaction was carried out at 0℃ for 2 hours, and the reaction was completed by TLC. The reaction solution was concentrated, neutralized by adding saturated sodium bicarbonate, extracted and concentrated with ethyl acetate to obtain a crude product, and filtered by beating with petroleum ether: ethyl acetate = 1:1 to obtain a yellow solid (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one (198g, 455mmol, yield 84.6%).

[0265] 1H NMR(400MHz,CHLOROFORM-d)δ=7.48-7.34(m,6H),7.23-7.14(m,9H),6.81-6.73(m,1H),6.66(t ,J=8.0Hz,1H),5.88(m,1H),3.33(s,J=6.4Hz,1H),2.82-2.65(m,2H),1.12(d,J=6.4Hz,3H)ppm.

[0266] Step 3: Synthesis of (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)-3-tritylbenzo[d]oxazol-2(3H)-one

[0267]

[0268] Under nitrogen protection at 20°C, (R)-7-(2-aminopropyl)-3-tritylbenzo[d]oxazol-2(3H)-one (10.0 g, 23.0 mmol, 1 eq), (2,2,2-trifluoroethyl) trifluoromethanesulfonate (6.14 g, 26.5 mmol, 1.15 eq), and diisopropylethylenediamine (8.92 g, 69.0 mmol, 12.0 mL, 3 eq) were dissolved in dioxane (100 mL), and then reacted at 80°C under nitrogen protection for 10 hours. The reaction was completed by TLC detection, the reaction solution was concentrated, and the crude product was separated by column chromatography to obtain a white solid (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)-3-tritylbenzo[d]oxazol-2(3H)-one (9.00 g, 17.4 mmol, yield 75.7%).

[0269] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.48 (br d, J = 7.2Hz, 6H), 7.33-7.27 (m, 9H), 6.86 (br d, J = 7.6Hz, 1H), 6.79-6.73 (m, 1H), 5.95 (br d,J=8.0Hz,1H),3.50(s,1H),3.26(br d,J=9.3Hz,3H),2.98-2.85(m,1H),2.82-2.71(m,1H),1.15(br d,J=5.6Hz,3H)ppm.

[0270] Step 4: Synthesis of (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinolin[5,4-f]oxazol-2(3H)-one

[0271]

[0272] (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)-3-tritylbenzo[d]oxazol-2(3H)-one (1.00 g, 1.94 mmol, 1 eq) and 5-bromo-2-pyridinecarboxaldehyde (540 mg, 2.90 mmol, 1.5 eq) were dissolved in toluene (50 mL), trifluoroacetic acid (662 mg, 5.81 mmol, 430 uL, 3 eq) was added, and the mixture was reacted at 90 ° C for 20 hours. The reaction was completed by TLC detection, the reaction solution was concentrated, and the crude product was purified by-TLC (petroleum ether: ethyl acetate = 10:1) to give a yellow solid (6S, 8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinolin[5,4-f]oxazol-2(3H)-one (780 mg, 1.76 mmol, yield 91.1%).

[0273] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.89 (s, 1H), 8.54 (d, J = 2.4Hz, 1H), 7.84-7.80 (m, 1H), 7.48 (d, J = 8.4Hz, 1H), 6.79-6.74 (m, 2H), 5.09 (s, 1H), 4 .13(q,J=7.2Hz,1H),3.50-3.39(m,1H),3.35-3.22(m,1H),3.09-3.03( m,1H),3.00-2.89(m,1H),2.70-2.64(m,1H),1.13(d,J=6.4Hz,3H)ppm.

[0274] Step 5: Synthesis of (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0275]

[0276] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinolino[5,4-f]oxazol-2(3H)-one (1.00 g, 2.26 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (181 mg, 4.52 mmol, 60% purity, 2 eq) was added at 0°C, and then trityl chloride (693 mg, 2.49 mmol, 1.1 eq) was added at 20°C and reacted for 2 hours. The reaction was completed by TLC. The reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated, and the crude product was separated by column chromatography to give a white solid (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (1.20 g, 1.56 mmol, yield 69.0%).

[0277] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.52 (s, 1H), 7.75 (dd, J1 = 2.4Hz, J2 = 8.4Hz, 1H), 7.49-7.45 (m, 6H), 7.36 (d, J = 8.4Hz, 1H), 7.32-7.27 (m, 9H), 6.39(d,J=8.4Hz,1H),5.75(d,J=8.4Hz,1H),4.94(s,1H),3.53-3.42(m,1H),3.29-3.18(m,1H),3.01(dd,J1=4.8Hz,J2=16.8Hz,1H),2.90(br dd, J1 = 9.2Hz, J2 = 15.6Hz, 1H), 2.68 (dd, J1 = 6.8Hz, J2 = 16.8Hz, 1H), 1.10 (d, J = 6.4Hz, 3H) ppm.

[0278] Step 6: Synthesis of tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carboxylate

[0279]

[0280] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (200 mg, 292 umol, 1 eq) and tert-butyl 3-aminoazetidine-1-carboxylate (126 mg, 730 umol, 2.5 eq) were dissolved in 8 ml of toluene, and [(2-2-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (24.5 mg, 29.2 umol, 0.1 eq) and cesium carbonate (286 mg, 876 umol, 3 eq) were added, and the reaction solution was reacted at 110°C for 15 hours. The reaction was complete after TLC detection, and the reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated. The crude product was separated by column chromatography to obtain yellow solid tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carboxylate (120 mg, 137 umol, yield 47.2%).

[0281] 1 H NMR(400MHz,CHLOROFORM-d)δ=7.77(d,J=2.4Hz,1H),7.52–7.42(m,7H),7.32–7.28(m,4H),7.26–7 .17(m,9H),6.89–6.69(m,1H),6.37(d,J=8.4Hz,1H),5.80–5.64(m,1H),5.39–5.20(m,1H),4.98–4 .77(m,1H),4.33–4.27(m,2H),4.23–4.11(m,1H),4.08–3.98(m,1H),3.74(m,2H),3.53–3.43(m,2H ),3.26–3.11(m,1H),3.04–2.85(m,2H),2.72–2.59(m,1H),1.45(s,9H),1.09(d,J=6.4Hz,3H)ppm.

[0282] Step 7: Synthesis of (6S,8R)-6-(5-(azetidin-3-ylamino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0283]

[0284] Trifluoroacetic acid (9.00 mL) and water (1.00 mL) were added to tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carboxylate (120 mg, 154 umol, 1 eq) at 0°C, and the mixture was reacted at 20°C for 2 hours. The reaction was completed after monitoring by TLC. The reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated to give a yellow solid (6S,8R)-6-(5-(azetidin-3-ylamino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (120 mg, crude product).

[0285] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.21-7.93 (m, 2H), 7.60-7.35 (m, 2H), 6.95-6.62 (m, 1H), 5.55-5.17 (m, 1H), 4.39-4 .13(m,1H),4.06-3.90(m,1H),3.63-3.42(m,1H),2.33-2.13(m,2H),2.07-1.96(m,2H),1.14-1.08(m,2H),0.88(br d,J=4.8Hz,3H)ppm.

[0286] Step 8: Synthesis of (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0287]

[0288] Under nitrogen protection at 20°C, (6S,8R)-6-(5-(azetidin-3-ylamino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (66.0 mg, 152 umol, 1 eq) and 3-fluoro-1-iodopropane (28.6 mg, 152 umol, 1 eq) were dissolved in N,N-dimethylformamide (1 mL), and diisopropylethylenediamine (98.4 mg, 761 umol, 132 uL, 5 eq) was added. The mixture was reacted at 20°C for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was quenched with water, extracted with ethyl acetate, and dried and concentrated. The crude product was separated by a reverse phase column (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 45%-75%, 30min), and then separated by a hand column (column: REGIS (R, R) WHELK-O1 (250mm*25mm, 10um); mobile phase: 0.1% NH3H2O ETOH; B%: 30%-30%, 0min) to give a yellow solid (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (27.0 mg, 54.2 umol, yield 35.6%, purity 97.7%).

[0289] LCMS: m / z 494.3 [M+H] + .

[0290] 1 H NMR (400MHz, CD3OD) δ = 7.76-7.71 (m, 1H), 7.13 (d, J = 8.4Hz, 1H), 6.93 (m, 1H), 6.80 (d, J=8.0Hz,1H),6.56(d,J=8.0Hz,1H),4.52(t,J=6.0Hz,1H),4.40(t,J=6.0Hz,1H),4.1 3-4.06(m,1H),3.82-3.76(m,2H),3.54-3.47(m,1H),3.15-3.08(m,1H),3.00-2.91(m ,3H),2.76(m,1H),2.64(t,J=7.6Hz,2H),1.83-1.69(m,2H),1.06(d,J=6.6Hz,3H)ppm.

[0291] Example 27: (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 27)

[0292]

[0293] Step 1: Synthesis of (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0294]

[0295] Compound (R)-7-(2-(2,2,2-trifluoroethyl)amino)propyl)benzo[d]oxazol-2(3H)-one (500 mg, 1.82 mmol), 5-bromo-3-fluoro-pyridine-2-carbaldehyde (390 mg, 1.91 mmol), trifluoroacetic acid (1.04 g, 9.12 mmol) were dissolved in toluene (10 mL) and reacted at 90° C. under nitrogen protection for 12 hours. The reaction was completed by LCMS. The reaction solution was concentrated and adjusted to pH = 7-8, extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried, concentrated, and purified by column chromatography to give a yellow solid (6S, 8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (605 mg, 1.22 mmol, yield 66.8%).

[0296] LCMS: m / z 461.8 [M+H] + .

[0297] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.20-8.50 (m, 2H) 7.61 (dd, J = 9.01, 1.88Hz, 1H) 6.80 (d, J = 8.00Hz, 1H) 6.65 (d, J = 8.00Hz, 1 H)5.37(s,1H)3.56-3.68(m,1H)3.23-3.31(m,1H)2.88-3.13(m,2H)2.67(dd,J=17.13,8.25Hz,1H)1.07-1.18(m,3H)ppm.

[0298] Step 2: Synthesis of (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0299]

[0300] (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (600 mg, 1.21 mmol) was dissolved in N,N-dimethylformamide (12 mL), sodium hydrogen hydride (58 mg, 1.45 mmol) was added under nitrogen protection at 0°C and stirred for 30 minutes, then triphenylmethane chloride (336 mg, 1.21 mmol) was added, and the reaction solution was reacted at 20°C for 30 minutes. LCMS detected that the reaction was complete. Saturated ammonium chloride aqueous solution was added to quench, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried and concentrated. The crude product was purified by column chromatography to give a white solid (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (754 mg, 991 umol, yield 82.1%).

[0301] LCMS: m / z 704 [M+H] + .

[0302] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.27 (d, J = 1.63Hz, 1H), 7.49 (dd, J = 9.01, 1.88Hz, 1H), 7.37-7.43 (m, 6H), 7.18-7.22 (m, 9H), 6.21 (d, J = 8.50Hz, 1H), 5. 67(d,J=8.38Hz,1H),5.19(s,1H),3.48-3.69(m,1H),3.06-3.19(m,1H),2. 80-2.97(m,2H),2.54(dd,J=17.13,8.25Hz,1H),1.02(d,J=6.75Hz,3H)ppm.

[0303] Step 3: Synthesis of (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0304]

[0305] (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (400 mg, 526 umol), 1-(3-fluoropropyl)aminoazetidine (379 mg, 1.05 mmol), cesium carbonate (685 mg, 2.10 mmol), [(2-bis-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)] palladium (II) methanesulfonate (44.1 mg, 52.6 umol) were dissolved in toluene (10 mL) and reacted at 110° C. under nitrogen protection for 12 hours. The reaction was completed by LCMS monitoring. The product was purified by concentration column chromatography to give a light yellow solid (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (163 mg, 188 umol, yield 35.8%).

[0306] LCMS: m / z 754.1[M+H] + .

[0307] 1H NMR (400MHz, CHLOROFORM-d) δ = 7.57 (d, J = 1.88Hz, 1H), 7.36-7.41 (m, 6H), 7.21 (s, 9H), 7.16 (s,1H),6.41(dd,J=11.57,2.31Hz,1H),6.23(d,J=8.50Hz,1H),5.64(d,J=8.50Hz,1H),5.1 2(s,1H),4.31-4.53(m,2H),4.09-4.19(m,1H),3.93-4.00(m,1H),3.62-3.68(m,2H),3.00- 3.14(m,1H),2.78-2.98(m,4H),2.46-2.60(m,3H),1.65(s,2H),1.02(d,J=6.63Hz,3H)ppm.

[0308] Step 4: Synthesis of (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0309]

[0310] Dissolve trifluoroacetic acid (2.02 g, 17.6 mmol) in water (0.05 mL) and add (6S, 8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (120 mg, 138 umol) to react at 20°C under nitrogen protection for 5 hours. LCMS detected that the reaction was complete. After the mixture was concentrated, the pH was adjusted to 7-8, extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated. Prep-HPLC spectrum of the crude product gave a yellow solid (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (70 mg, 124.27 umol).

[0311] LCMS: m / z 511.2 [M+H] + .

[0312] Step 5: Synthesis of (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0313]

[0314] Chiral separation of (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one gave (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (42.7 mg, 83.5 umol, yield 61.0%).

[0315] 1 H NMR(400MHz,ACETONITRILE-d3)δ=7.56-7.59(m,1H),6.82(d,J=8.00Hz,1H),6.61- 6.67(m,2H),5.28(s,1H),5.14-5.19(m,1H),4.36-4.54(m,2H),3.93-4.02(m,1H),3 .57-3.71(m,3H),3.27-3.40(m,1H),2.83-3.01(m,2H),2.76-2.82(m,2H),2.63(d,J =9.01Hz, 1H), 2.50 (t, J = 7.00Hz, 2H), 1.61-1.76 (m, 2H), 1.06 (d, J = 6.75Hz, 3H) ppm.

[0316] Example 28: (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 28)

[0317]

[0318] Step 1: Synthesis of (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0319]

[0320] (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)benzo[d]oxazol-2(3H)-one (500 mg, 1.82 mmol) and 5-bromo-3-methoxypyridinecarboxaldehyde (400 mg, 1.85 mmol) were dissolved in toluene (10 mL), and trifluoroacetic acid (1.04 g, 9.12 mmol) was added. The mixture was reacted at 90°C for 12 hours. The reaction was completed by LCMS detection, and the reaction solution was concentrated and purified by silica gel column to obtain (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (750 mg, 1.59 mmol, yield 87.1%).

[0321] Step 2: Synthesis of (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0322]

[0323] Dissolve (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (700 mg, 1.48 mmol) in N,N-dimethylformamide (14 mL). Add sodium hydroxide (71.1 mg, 1.78 mmol, 60% purity) at 0°C. After stirring for 30 minutes, add trityl chloride (371 mg, 1.33 mmol) and heat to 20°C to react for 2 hours. LCMS detection of the reaction is complete. The reaction solution is quenched with ice water and extracted with ethyl acetate. The organic phase was washed three times with saturated brine, concentrated and purified using a silica gel column to give (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (750 mg, 1.05 mmol, yield 70.8%).

[0324] 1H NMR (400MHz, CHLOROFORM-d) δ = 8.12 (d, J = 1.9Hz, 1H), 7.54-7.40 (m, 6H), 7.32-7.26 (m, 9H), 6.28 (d, J = 8.5Hz, 1H), 5.73 (d, J = 8.4Hz, 1H) ,5.53-5.31(m,1H),3.82(s,3H),3.77-3.69(m,1H),3.25-3.09(m,1H),3.02-2.83(m,2H),2.64-2.50(m,1H),1.10(d,J=6.6Hz,3H)ppm.

[0325] Step 3: Synthesis of (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0326]

[0327] (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (400 mg, 560 umol), 1-(3-fluoropropyl)azetidine-3-amine (403 mg, 1.12 mmol), [(2-bis-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)] palladium (II) methanesulfonate (46.9 mg, 56.0 umol) and cesium carbonate (730 mg, 2.24 mmol) were dissolved in toluene (2 mL). The mixture was reacted at 110° C. for 12 hours under nitrogen protection. The reaction was completed by LCMS. The reaction solution was concentrated and purified by silica gel column to give (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (160 mg, 209 umol, yield 33.2%).

[0328] Step 4: Synthesis of (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0329]

[0330] (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (160 mg, 208 umol) was dissolved in water (0.5 mL) and trifluoroacetic acid (4.5 mL). The mixture was reacted at 20°C for 2 hours. The reaction was completed after LCMS detection. The pH value was adjusted to 7-8 with sodium bicarbonate, extracted with water and ethyl acetate, and the organic phase was washed three times with brine. After concentration, it was purified by silica gel column to obtain (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (70 mg, 134 umol, yield 64.0%).

[0331] 1 H NMR (400MHz, ACETONITRILE-d3) δ = 7.32 (d, J = 2.3Hz, 1H), 6.80 (d, J = 8.0Hz, 1H), 6.63-6.51 (m ,2H),5.46(s,1H),4.89(d,J=7.0Hz,1H),4.54(t,J=6.1Hz,1H),4.42(t,J=6.1Hz,1H),4.20-3 .96(m,1H),3.82(s,4H),3.74-3.65(m,2H),3.40-3.26(m,1H),3.02-2.84(m,2H),2.82-2.74( m,2H),2.64-2.56(m,1H),2.52(t,J=6.9Hz,2H),1.77-1.65(m,2H),1.09(d,J=6.8Hz,3H)ppm.

[0332] Example 29: (6S,8R)-6-(5-(((S)-1-(3-fluoropropane)pyrrolidin-3-yl)oxy)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 29)

[0333]

[0334] Step 1: Synthesis of tert-butyl (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate

[0335]

[0336] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (150mg, 219umol, 1eq) and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (102mg, 547umol, 2.5eq) were dissolved in toluene (20mL), and then (18.3mg, 21.9umol, 0.1eq) and cesium carbonate (214mg, 657umol, 3eq) were added, and the reaction solution was reacted at 115°C for 15 hours. The reaction was monitored by TLC, and the reaction solution was quenched with water, extracted with ethyl acetate, and dried and concentrated. The crude product was separated by column chromatography to give a yellow solid (S)-tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate (120 mg, 138 umol, 31.5% yield).

[0337] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.02 (d, J = 2.8Hz, 1H), 7.39 (d, J = 7.2Hz, 6H), 7.24-7.20 (m, 5H), 7.18- 7.14(m,4H),7.08-7.04(m,1H),6.37-6.25(m,1H),5.66(d,J=8.4Hz,1H),4.86-4.80(m,2H),4.39(br s,1H),3.55-3.34(m,2H),3.34-3.23(m,1H),3.16-3.04(m,1H),3.01-2.89(m,1H),2.83(br dd,J1=8.8Hz,J2=15.6Hz,1H),2.59(dd,J1=6.4Hz,J2=16.8Hz,1H),2.15-2.01(m,2H),1.95-1.81(m,2H),1.40(s,9H),1.02(d,J=6.4Hz,3H)ppm.

[0338] Step 2: Synthesis of (6S,8R)-8-methyl-6-(5-((S)-pyrrolidin-3-yl)oxy)pyridin-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0339]

[0340] Trifluoroacetic acid (1.54 g, 13.4 mmol, 997 uL, 87.3 eq) was added to (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 154 umol, 1 eq) dissolved in dichloromethane (2 mL) at 0°C, and the mixture was reacted at 20°C for 2 hours. The reaction was completed after monitoring by TLC and LCMS. The reaction solution was quenched with water, extracted with ethyl acetate, dried and concentrated. The crude product was separated by thin layer chromatography on silica gel to give a yellow solid (6S,8R)-8-methyl-6-(5-((S)-pyrrolidin-3-yl)oxy)pyridin-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (105 mg, crude product).

[0341] LCMS: m / z(M+H) + =449.2

[0342] 1 H NMR (400MHz, DMSO-d6) δ = 8.13 (d, J = 2.8Hz, 1H), 7.45-7.34 (m, 1H), 7.32-7 .26(m,1H),6.87-6.82(m,1H),6.74-6.67(m,1H),5.14-5.02(m,2H),3.00 -2.92(m,2H),2.90-2.78(m,2H),2.72-2.71(m,1H),2.74-2.58(m,1H),2. 21-2.07(m,2H),2.06-1.93(m,1H),1.23(s,1H),1.06(d,J=6.4Hz,3H)ppm.

[0343] Step 3: Synthesis of (6S,8R)-6-(5-(((S)-1-(3-fluoropropane)pyrrolidin-3-yl)oxy)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0344]

[0345] Under nitrogen protection at 20°C, (6S,8R)-8-methyl-6-(5-((S)-pyrrolidin-3-yl)oxy)pyridin-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (105 mg, 187 umol, 1 eq) and 3-fluoro-1-iodopropane (35.2 mg, 187 umol, 1 eq) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylenediamine (121 mg, 936 umol, 163 uL, 5 eq) was added. The mixture was reacted at 20°C for 4 hours. LCMS detected that the reaction was complete, and the reaction solution was quenched with water, extracted with ethyl acetate, and dried and concentrated. The crude product was separated by reverse phase column (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.04% NH3H2O ​​+ 10mM NH4HCO3) -ACN]; B%: 18% -58%, 14min) and SFC (column: REGIS (R, R) WHELK-O1 (250mm*25mm, 10um); mobile phase: 0.1% NH3H2O ETOH; B%: 30%-30%, 10min) to give a white solid (6S,8R)-6-(5-(((S)-1-(3-fluoropropane)pyrrolidin-3-yl)oxy)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (10.5 mg, 19.8 umol, yield 10.6%, purity 96%).

[0346] LCMS: m / z(M+H) + =509.4

[0347] 1H NMR (400MHz, CD3OD) δ = 8.05 (d, J = 2.8Hz, 1H), 7.40-7.30 (m, 2H), 6.83 (d, J = 8.0Hz, 1H), 6.6 3(d,J=8.0Hz,1H),4.54(t,J=6.0Hz,1H),4.42(t,J=6.0Hz,1H),3.53-3.48(m,1H),3.40(br d,J=6.0Hz,1H),3.10(dd,J1=4.8Hz,J2=16.8Hz,1H),3.02-2.87(m,4H),2.78(dd,J1=6.2Hz,J2=16.8Hz,1 H),2.68-2.58(m,2H),2.56-2.49(m,1H),2.38(dt,J1=7.6Hz,J2=13.6Hz,1H),1.99-1.84(m,3H),1.29(br s, 1H), 1.12 (d, J = 6.4Hz, 3H) ppm.

[0348] Example 30: (6S,8R)-6-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 30)

[0349]

[0350] Step 1: Synthesis of tert-butyl (S)-3-(3-methoxy-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylate

[0351]

[0352] (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (500 mg, 700 umol), (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (236 mg, 1.26 mmol), cesium carbonate (685 mg, 2.10 mmol), [(2-bis-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)] palladium (II) methanesulfonate (23.5 mg, 28.0 umol) were dissolved in toluene (8 mL) and reacted at 110°C under nitrogen protection for 16 hours. Two reactions were carried out in parallel and the reaction was monitored by LCMS. The combined treatment was concentrated and purified by column chromatography to give a yellow solid (S)-tert-butyl 3-(3-methoxy-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylate (180 mg, yield 15.7%).

[0353] 1 H NMR (400MHz, CHLOROFORM-d)δ=7.51-7.43(m,6H),7.33-7.28(m,4H),7.27-7.19(m,5H),6.90-6.73(m,1H),6.43(br s,1H),6.36-6.19(m,2H),5.68(br d,J=8.5Hz,1H),5.29(s,1H),4.85(br s,1H),3.85-3.75(m,3H),3.71-3.43(m,5H),3.14-2.96(m,2H),2.85(qd,J=9.5,15.4Hz,1H),2.66(br dd,J=6.1,16.9Hz,1H),2.16(br s, 2H), 1.48 (s, 9H), 1.07 (br d, J = 6.5Hz, 3H) ppm.

[0354] Step 2: Synthesis of (6S,8R)-6-(2-methoxy-4-((S)-pyrrolidin-3-yloxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0355]

[0356] Dissolve (S)-3-(3-methoxy-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg, 220 umol) in trifluoroacetic acid (2 ml) and water (0.2 mL) and react at 20°C for 2 hours. LCMS detected that the reaction was complete. After the mixture was concentrated, the pH was adjusted to 7-8, extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried with sodium sulfate, and concentrated. Column chromatography was used to obtain a yellow solid (6S,8R)-6-(2-methoxy-4-((S)-pyrrolidin-3-yloxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (110 mg, yield 77.7%).

[0357] 1 H NMR (400MHz, CHLOROFORM-d) δ = 6.73 (dd, J = 8.3, 12.6Hz, 2H), 6.54 (d, J = 8.1Hz, 1H), 6.45 (d, J = 2.4Hz, 1H), 6.24 (d d,J=2.3,8.6Hz,1H),5.35(s,1H),3.84(s,3H),3.50-3.35(m,5H),3.16-3.01(m,3H),2.90-2.78(m,1H),2.66(br dd,J=6.5,16.9Hz,1H),2.37-2.27(m,1H),2.26-2.15(m,1H),1.06(d,J=6.6Hz,3H)ppm.

[0358] Step 3: Synthesis of (6S,8R)-6-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0359]

[0360] (6S,8R)-6-(2-methoxy-4-((S)-pyrrolidin-3-yloxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (110 mg, 170 umol) and diisopropylethylamine (66.1 mg, 511 umol) were dissolved in N,N-dimethylformamide (3 mL), and 3-fluoro-1-iodopropane (25.6 mg, 136 The reaction mixture was stirred for 3 hours at room temperature and the reaction was completed after monitoring by TLC. 60 mg of crude product was obtained by HPLC separation, and then chiral separation by SFC was performed to obtain a yellow solid (6S,8R)-6-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (47.3 mg, yield 51.4%).

[0361] 1 H NMR(400MHz, CHLOROFORM-d)δ=8.62-8.02(m,1H),6.81-6.68(m,2H),6.59(d,J=8.1Hz,1H),6.45(d,J=2.4Hz,1H),6.25(dd,J=2.4,8.5Hz,1H),5 .38(s,1H),4.81(brs,1H),4.61-4.43(m,2H),3.84(s,3H),3.61-3.51( m,1H),3.16-3.06(m,2H),2.97-2.79(m,4H),2.76-2.62(m,3H),2.31(br dd,J=6.8,13.8Hz,1H),2.05-1.88(m,3H),1.30-1.23(m,1H),1.10(d,J=6.6Hz,3H)ppm.

[0362] Example 31: (6S,8R)-7-((1-fluorocyclopropyl)methyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl))amino)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0363]

[0364] Step 1: Synthesis of (6S,8R)-6-(4-bromo-2-methoxyphenyl)-7-((1-fluorocyclopropyl)methyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0365]

[0366] (R)-7-(2-(((1-fluorocyclopropyl)methyl)amino)propyl)benzo[d]oxazol-2(3H)-one (1.05 g, 3.97 mmol), 4-bromo-2-methoxybenzaldehyde (1.54 g, 7.15 mmol) and trifluoroacetic acid (2.26 g, 19.8 mmol) were dissolved in toluene (8 mL) and reacted at 110°C for 120 hours. The reaction was completed by LCMS monitoring. The reaction solution was concentrated and purified by column chromatography to obtain a yellow solid (6S,8R)-6-(4-bromo-2-methoxyphenyl)-7-((1-fluorocyclopropyl)methyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (249 mg, 539 umol, yield 13.5%).

[0367] LCMS: m / z 462.8 [M+H] + .

[0368] Step 2: Synthesis of (6S,8R)-7-((1-fluorocyclopropyl)methyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl))amino)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0369]

[0370] ((6S,8R)-6-(4-bromo-2-methoxyphenyl)-7-((1-fluorocyclopropyl)methyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (140 mg, 303 umol), 1-(3-fluoropropyl)aminoazetidine (112 mg, 849 umol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (27.5 mg, 30.3 umol) and sodium tert-butoxide (87.4 mg, 910 umol) were dissolved in dioxane (1 mL) and reacted at 60° C. for 2 hours. The reaction was monitored by LCMS. The reaction solution was filtered and purified by prep-HPLC, and then the product was purified by chiral SFC to give a yellow solid (6S,8R)-7-((1-fluorocyclopropyl)methyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl))amino)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (7.2 mg, yield 4.49%).

[0371] LCMS: m / z 513.2 [M+H] + .

[0372] 1 H NMR (400MHz, ACETONITRILE-d3) δ = 6.75 (d, J = 8.13Hz, 1H), 6.67 (d, J = 8.38Hz, 1H), 6.54 (d, J = 8.13Hz, 1H), 6.18 (d, J = 2.00H z,1H),6.00(dd,J=8.38,2.00Hz,1H),5.20(s,1H),4.69(m,J=6.90Hz,1H),4.52(t,J=6.07Hz,1H),4.40(t,J=6.07Hz,1H),3 .95-4.04(m,1H),3.80(s,3H),3.64-3.72(m,3H),3.03(dd,J=16.26,4.88Hz,1H),2.86-2.97(m,1H),2.68-2.78(m,3H),2.5 6-2.65(m,1H),2.50(t,J=7.00Hz,2H),1.64-1.74(m,2H),0.99(d,J=6.63Hz,3H),0.86-0.94(m,2H),0.46-0.58(m,2H)ppm.

[0373] Similar to the synthetic route of the aforementioned Example 25, the following Examples 32, 33 and 34 were synthesized by selecting corresponding reactants and synthetic methods known to those skilled in the art.

[0374] Example 32: (6S,8R)-7-(2,2-difluoropropyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0375]

[0376] LCMS: m / z 519.2 [M+H] + .

[0377] 1H NMR (400MHz, ACETONITRILE-d3) δ = 6.75 (d, J = 8.1Hz, 1H), 6.48 (dd, J = 8.2, 19.9Hz, 2H), 6.18 (d, J = 2.1Hz, 1H), 5.97 (dd, J = 2.1, 8.4Hz, 1H), 5.22 (s, 1H), 4.73 (br s,1H),4.55-4.37(m,2H),4.02-3.95(m,1H),3.79(s,3H),3.69-3.64(m,2H),3.54-3.38(m,2H),2.96-2.85(m,2H),2.74(q,J=6.4Hz, 2H),2.65-2.55(m,2H),2.49(t,J=7.0Hz,2H),2.21-2.11(m,1H),1.75-1.62(m,2H),1.54(t,J=19.2Hz,3H),1.00(d,J=6.6Hz,3H)ppm.

[0378] Example 33: (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxy-6-chloro-phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 33)

[0379]

[0380] LCMS: m / z 557.4 [M+H] + .

[0381] 1 H NMR (400MHz, ACETONITRILE-d3) δ = 6.73 (br d, J = 8.1Hz, 1H), 6.55-6.30 (m, 1H), 6.25-5.95 (m, 2H), 5.60-5.33 (m, 1H), 5.04 (br d,J=6.1Hz,1H),4.59-4.34(m,2H),4.11-3.97(m,1H),3.92-3.63(m,4H),3.59(br s,1H),3.36-3.12(m,3H),2.95-2.72(m,4H),2.58(t,J=7.1Hz,2H),1.78-1.67(m,2H),1.01(d,J=6.5Hz,3H)ppm.

[0382] Example 34: (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxy-6-fluoro-phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 34)

[0383]

[0384] LCMS: m / z 541.2 [M+H] + .

[0385] 1 H NMR (400MHz, DMSO-d6) δ = 11.46 (br s, 1H), 6.75 (d, J = 8.0Hz, 1H), 6.51-6.36 (m, 2H), 5.99 (br s, 1H), 5.75 (br d, J = 12.8Hz, 1H), 5.22 (br s,1H),4.51(t,J=5.9Hz,1H),4.40(t,J=6.0Hz,1H),4.03-3.89(m,1H),3.70(br s,5H),3.50-3.39(m,1H),3.39-3.33(m,1H),3.31-3.25(m,1H),3.08-2.62(m,6H),1.74-1.59(m,2H),1.01(br d,J=6.5Hz,3H)ppm.

[0386] Example 35: (E)-4-(3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidin-1-yl)-N,N-dimethylbut-2-enamide (Compound 35)

[0387]

[0388] Step 1: Synthesis of tert-butyl 3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidine-1-carboxylate

[0389]

[0390] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (1.0 g, 1.39 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (359 mg, 2.08 mmol), cesium carbonate (996 mg, 3.06 mmol), [(2-bis-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)] palladium (II) methanesulfonate (58.3 mg, 69.5 umol) were dissolved in toluene (20 mL) and reacted at 110° C. under nitrogen protection for 12 hours. The reaction was completed by LCMS monitoring. The mixture was concentrated and extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was concentrated and purified by column chromatography to obtain yellow solid tert-butyl 3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidine-1-carboxylate (880 mg, 1.09 mmol, yield 78.1%).

[0391] LCMS: m / z 810.3 [M+H] + .

[0392] 1 H NMR(400MHz,CHLOROFORM-d)δ=7.36-7.42(m,7H),7.17-7.22(m,10H),6.15-6.2 4(m,1H),5.87(d,J=10.76Hz,2H),5.58(d,J=8.63Hz,1H),5.05(s,1H),4.21(t,J =8.00Hz,2H),3.65(ddd,J=8.88,4.63,2.13Hz,2H),3.43-3.52(m,1H),3.06(m,J =16.70,5.70Hz,2H),2.62-2.85(m,2H),1.37(s,9H),0.98(d,J=6.50Hz,3H)ppm.

[0393] Step 2: Synthesis of (6S,8R)-6-(4-(azetidin-3-ylamino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0394]

[0395] Dissolve trifluoroacetic acid (15.5 g, 135 mmol) in water (1 mL) and add tert-butyl 3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidine-1-carboxylate (400 mg, 493 umol) and react at 20°C under nitrogen protection for 2 hours. The reaction was completed by LCMS. The mixture was concentrated to give a crude product as a yellow solid (6S,8R)-6-(4-(azetidin-3-ylamino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (400 mg, crude).

[0396] LCMS: m / z 468.2[M+H] + .

[0397] Step 3: Synthesis of (E)-4-(3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidin-1-yl)-N,N-dimethylbut-2-enamide

[0398]

[0399] (6S,8R)-6-(4-(azetidin-3-ylamino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (100 mg, 213 umol), (E)-4-bromo-N,N-dimethylbut-2-enamide (41 mg, 213 umol), and diisopropylethylamine (60.7 mg, 469 umol) were dissolved in N,N-dimethylformamide (3 mL) and reacted at 20°C under nitrogen protection for 2 hours. The reaction was completed by LCMS detection, and the reaction solution was filtered and sent to prep-HPLC for purification. The obtained product was sent to SFC for separation and purification to obtain a yellow solid (E)-4-(3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidine-1-yl)-N,N-dimethylbut-2-enamide (38.8 mg, 65.3 umol, yield 30.6%).

[0400] LCMS: m / z 579.2 [M+H] + .

[0401] 1 H NMR (400MHz, ACETONITRILE-d3) δ = 6.81 (d, J = 8.00Hz, 1H), 6.50-6.66 (m, 2H), 6.40-6.48 (m, 1H), 6.08 (d,J=11.88Hz,2H),5.27(m,J=7.00Hz,1H),5.20(s,1H),3.92-4.04(m,1H),3.69(t,J=6.82Hz,2H),3 .43-3.58(m,1H),3.22-3.38(m,1H),3.19(dd,J=5.19,1.31Hz,2H),3.00-3.09(m,4H),2.91-2.99(m, 1H),2.88-2.91(m,3H),2.80-2.87(m,2H),2.73(dd,J=16.45,4.94Hz,1H),1.06(d,J=6.50Hz,3H)ppm.

[0402] Example 36: (6S,8R)-6-(4-((1-acryloylazetidin-3-yl)amino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 36)

[0403]

[0404] Step 1: Synthesis of (6S,8R)-6-(4-((1-acryloylazetidin-3-yl)amino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0405]

[0406] (6S,8R)-6-(4-(azetidin-3-ylamino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (250 mg, 533 umol) and diisopropylethylamine (827 mg, 6.40 mmol) were dissolved in N,N-dimethylformamide (2 mL), and then acryloyl chloride (9.66 mg, 106 umol) was added at 0°C, and the mixture was reacted at 0°C for 2 hours. The reaction was completed by LCMS. The reaction solution was filtered and sent to prep-HPLC for purification. The obtained product was sent to SFC for separation and purification to obtain a yellow solid (6S,8R)-6-(4-((1-acryloylazetidin-3-yl)amino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (29.4 mg, 56.1 umol, yield 10.5%).

[0407] LCMS: m / z 522.2 [M+H] + .

[0408] 1 H NMR (400MHz, ACETONITRILE-d3) δ = 8.96 (s, 1H), 6.82 (d, J = 8.13Hz, 1H),

[0409] 6.63(d,J=8.13Hz,1H),6.21-6.36(m,1H),6.12-6.19(m,1H),6.09(d,J=11.63Hz,2H),5.6 3(dd,J=10.19,1.94Hz,1H),5.44(m,J=6.38Hz,1H),5.22(s,1H),4.49-4.59(m,1H),4.15- 4.34(m,2H),3.94(dt,J=9.10,4.64Hz,1H),3.68-3.78(m,1H),3.45-3.57(m,1H),3.23-3. 38(m,1H),2.87-3.09,(m,2H),2.74(dd,J=16.32,5.19Hz,1H),1.06(d,J=6.63Hz,3H)ppm.

[0410] Example 37: (E)-4-((R)-3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide (Compound 37)

[0411]

[0412] Step 1: Synthesis of tert-butyl (R)-3-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylate

[0413]

[0414] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (1.7 g, 2.36 mmol), R-3-hydroxy-1-Boc-pyrrolidine (663 mg, 3.54 mmol), [(2-bis-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)] palladium(II) methanesulfonate (99.0 mg, 118 umol), cesium carbonate (1.69 g, 5.20 mmol) were dissolved in toluene (20 mL) and reacted at 110° C. under nitrogen protection for 12 hours. The reaction was completed by LCMS monitoring. After the mixture was concentrated, it was purified by column chromatography to give a light yellow solid (R)-tert-butyl 3-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylate (503 mg, 609 umol, yield 25.7%).

[0415] LCMS: m / z 825.3 [M+H] + .

[0416] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.19-7.42 (m, 15H), 6.26 (d, J = 10.38Hz, 2H), 6.20 (d, J = 8.63Hz, 1H), 5.60 (d, J = 8.50Hz, 1H), 5.09 (s, 1H), 3.46 -3.59(m,4H),3.20-3.44(m,2H),2.86-3.17(m,3H),2.62-2.80(m,2H),2.08(m,J=6.80Hz,1H),1.38-1.41(m,9H),0.98(d,J=6.50Hz,3H)ppm.

[0417] Step 2: Synthesis of (6S,8R)-6-[2,6-difluoro-4-(((R)-pyrrolidin-3-yl)oxy)phenyl]-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0418]

[0419] Dissolve trifluoroacetic acid (6.16 g, 54.0 mmol) in water (0.4 mL) and add (R)-tert-butyl 3-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylate (503 mg, 609 umol) and react at 20°C under nitrogen protection for 2 hours. The reaction was completed by LCMS. After the mixture was concentrated, the pH value was adjusted to 7 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was filtered and concentrated, and column chromatography was performed to obtain a yellow solid (6S,8R)-6-[2,6-difluoro-4-(((R)-pyrrolidin-3-yl)oxy)phenyl]-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (183 mg, 378 umol, yield 62.2%).

[0420] LCMS: m / z 483.2[M+H] + .

[0421] Step 3: Synthesis of (E)-4-((R)-3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide

[0422]

[0423] (6S,8R)-6-[2,6-difluoro-4-(((R)-pyrrolidin-3-yl)oxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (90 mg, 186 umol), (E)-4-bromo-N,N-dimethylbut-2-enamide (35.7 mg, 186 umol), and N,N-diisopropylethylamine (52.9 mg, 409 umol) were dissolved in N,N-dimethylformamide (1 mL) and reacted at 0°C under nitrogen protection for 1 hour. The reaction was completed by LCMS detection, and the reaction solution was filtered and sent to prep-HPLC for separation. The obtained product was sent to SFC for purification to obtain a yellow solid (E)-4-((R)-3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide (18.5 mg, 30.7 umol, yield 16.5%).

[0424] LCMS: m / z 579.2 [M+H] + .

[0425] 1 H NMR (400MHz, ACETONITRILE-d3) δ = 6.82 (d, J = 8.25Hz, 1H), 6.60-6.71 (m, 2H), 6.45-6.54 (m, 2 H),6.44(s,1H),5.29(s,1H),4.81(m,J=7.30,4.60Hz,1H),3.52(m,J=6.00Hz,1H),3.31(s,1 H),3.22(m,J=6.00Hz,2H),3.04-3.09(m,1H),3.01(s,3H),2.93-2.98(m,1H),2.89(s,3H),2 .66-2.87(m,5H),2.42(m,J=7.50Hz,1H),2.30(m,J=7.60Hz,1H),1.07(d,J=6.50Hz,3H)ppm.

[0426] Example 38: (6S,8R)-6-(4-(((R)-1-acryloylpyrrolidin-3-yl)oxy)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 38)

[0427]

[0428] Step 1: Synthesis of (6S,8R)-6-(4-(((R)-1-acryloylpyrrolidin-3-yl)oxy)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0429]

[0430] (6S,8R)-6-[2,6-difluoro-4-(((R)-pyrrolidin-3-yl)oxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (90 mg, 186 umol) and diisopropylethylamine (240 mg, 1.86 mmol) were dissolved in N,N-dimethylformamide (1 mL), and then acryloyl chloride (16.8 mg, 186 umol) was added at 0°C, and the mixture was reacted at 0°C for 1 hour. The reaction was completed by LCMS detection, and the reaction solution was filtered and sent to prep-HPLC for separation. The obtained product was sent to SFC for purification to obtain a white solid (6S,8R)-6-(4-(((R)-1-acryloylpyrrolidin-3-yl)oxy)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (24.8 mg, 45.9 umol, yield 24.6%).

[0431] LCMS: m / z 537.2 [M+H] + .

[0432] 1 H NMR(400MHz,ACETONITRILE-d3)δ=8.70-9.00(m,1H),6.82(d,J=8.13Hz,1H),6.63(d,J=8.00Hz,1 H),6.44-6.60(m,3H),6.15-6.25(m,1H),5.64(ddd,J=10.35,8.10,2.31Hz,1H),5.30(s,1H),4.9 2-5.06(m,1H),3.54-3.88(m,4H),3.31-3.52(m,2H),3.07(dd,J=16.45,4.94Hz,1H),2.94(dq,J= 15.90, 9.63Hz, 1H), 2.76 (dd, J = 16.51, 5.13Hz, 1H), 2.16-2.25 (m, 2H), 1.07 (d, J = 6.63Hz, 3H) ppm.

[0433] Similar to the synthetic routes of the aforementioned Examples 37 and 38, the following Examples 39 and 40 were synthesized by selecting corresponding reactants and synthetic methods known to those skilled in the art.

[0434] Example 39: (E)-4-((S)-3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide (Compound 39)

[0435]

[0436] LCMS: m / z 579.2 [M+H] + .

[0437] 1 H NMR (400MHz, ACETONITRILE-d3) δ = 6.82 (d, J = 8.13Hz, 1H), 6.60-6.71 (m, 2H), 6.48-6.53 (m, 1H), 6.4 5-6.48(m,1H),6.43-6.45(m,1H),5.29(s,1H),4.77-4.84(m,1H),3.47-3.57(m,1H),3.32(m,J=9.60 Hz,1H),3.22(dd,J=6.07,1.44Hz,2H),3.07(dd,J=16.76,4.75Hz,1H),3.00-3.04(m,3H),2.93-2.9 9(m,1H),2.89(s,3H),2.83(s,5H),2.37-2.49(m,1H),2.26-2.36(m,1H),1.07(d,J=6.50Hz,3H)ppm.

[0438] Example 40: (6S,8R)-6-(4-(((S)-1-acryloylpyrrolidin-3-yl)oxy)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 40)

[0439]

[0440] LCMS: m / z 537.2 [M+H] + .

[0441] 1H NMR (400MHz, ACETONITRILE-d3) δ = 6.82 (d, J = 8.00Hz, 1H), 6.62 (d, J = 8.00Hz, 1H), 6.44-6.59 (m, 3H),6.16-6.26(m,1H),5.64(m,J=10.40,10.40,2.30Hz,1H),5.30(s,1H),4.92-5.06(m,1H),3. 55-3.88(m,4H),3.45-3.53(m,1H),3.34(m,J=16.10,9.60Hz,1H),3.03-3.12(m,1H),2.89-3.00 (m, 1H), 2.76 (dd, J = 16.70, 5.32Hz, 1H), 1.77 (m, J = 4.90, 2.40Hz, 2H), 1.07 (d, J = 6.63Hz, 3H) ppm.

[0442] Example 41: (E)-4-(4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazin-1-yl)-N,N-dimethylbut-2-enamide (Compound 41)

[0443]

[0444] Step 1: Synthesis of tert-butyl 4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazine-1-carboxylate

[0445]

[0446] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (700 mg, 972 umo), N-Boc piperazine (272 mg, 1.46 mmol), (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (41.2 mg, 48.6 umol), cesium carbonate (697 mg, 2 .14mmol) was dissolved in toluene (15mL) and reacted at 110°C under nitrogen protection for 12 hours. LCMS monitored the completion of the reaction. The mixture was concentrated and extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain a white solid tert-butyl 4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazine-1-carboxylate (413mg, 501umol, yield 51.5%).

[0447] LCMS: m / z 824.3 [M+H] + .

[0448] 1 H NMR(400MHz,CHLOROFORM-d)δ=7.27-7.53(m,15H),6.24-6.42(m,3H),5.63-5.74(m,1H),5.17(s,1H),3 .52-3.68(m,5H),3.10-3.39(m,6H),2.77(m,J=16.40,4.30Hz,2H),1.52(s,9H),0.89-1.11(m,3H)ppm.

[0449] Step 2: Synthesis of (6S,8R)-6-(2,6-difluoro-4-(piperazin-1-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0450]

[0451] Dissolve trifluoroacetic acid (12.3 g, 107 mmol) in water (0.1 mL) and add tert-butyl 4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazine-1-carboxylate (413 mg, 500 umol) and react at 20°C under nitrogen protection for 2 hours. The reaction was completed by LCMS. The crude product was purified by column chromatography to give a yellow solid (6S,8R)-6-(2,6-difluoro-4-(piperazin-1-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (110 mg, 228 umol, yield 45.5%).

[0452] LCMS: m / z 482.2 [M+H] + .

[0453] 1 H NMR (400MHz, DMSO-d6) δ = 6.81 (d, J = 8.00Hz, 1H), 6.48-6.60 (m, 3H), 5.16 (s, 1H), 3. 06-3.10(m,4H),2.86-2.99(m,3H),2.67-2.80(m,6H),1.05(d,J=6.50Hz,3H.)ppm.

[0454] Step 3: Synthesis of (E)-4-(4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazin-1-yl)-N,N-dimethylbut-2-enamide

[0455]

[0456] 6S,8R)-6-(2,6-difluoro-4-(piperazin-1-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (100 mg, 207 umol), (E)-4-bromo-N,N-dimethylbut-2-enamide (39.8 mg, 207.3 umol), and diisopropylethylamine (58.9 m, 456 umol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at 20°C under nitrogen protection for 1 hour. The reaction was completed by LCMS detection, and the reaction solution was filtered and sent to prep-HPLC for separation. The obtained product was sent to SFC for purification to obtain a yellow solid (E)-4-(4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazin-1-yl)-N,N-dimethylbut-2-enamide (37 mg, 62.3 umol, yield 30.1%).

[0457] LCMS: m / z 593.2 [M+H] + .

[0458] 1 H NMR(400MHz,ACETONITRILE-d3)δ=8.78-8.97(m,1H),6.81(d,J=8.13Hz,1H),6 .50-6.69(m,3H),6.38-6.47(m,2H),5.25(s,1H),3.45-3.59(m,1H),3.24-3.4 0(m,1H),3.12-3.22(m,6H),3.04-3.10(m,1H),3.03(s,3H),2.92-3.00(m,1H) ,2.90(s,3H),2.70-2.79(m,1H),2.46-2.60(m,4H),1.07(d,J=6.63Hz,3H)ppm.

[0459] Example 42: 3-(4-((2-(4-(3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 42)

[0460]

[0461] Step 1: Synthesis of tert-butyl 4-(2-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperazine-1-carboxylate

[0462]

[0463] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (700 mg, 1.58 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (546 mg, 2.37 mmol), [(2-bis-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)] palladium(II) methanesulfonate (132 mg, 158 umol) and sodium tert-butoxide (456 mg, 4.75 mmol) were dissolved in toluene (10 mL) and reacted at 60°C for 12 hours under nitrogen protection. The reaction was completed by TLC monitoring. The reaction solution was concentrated. The crude product was purified by column chromatography to give yellow solid tert-butyl 4-(2-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperazine-1-carboxylate (400 mg, 676 umol, yield 42.7%).

[0464] LCMS: m / z 591.3 [M+H] + .

[0465] 1 H NMR (400MHz, DMSO-d6) δ=11.36-11.63(m,1H),7.93-8.18(m,1H),7.37(dd,J=8.69,2.94 Hz,1H),7.11-7.27(m,1H),6.84(d,J=8.13Hz,1H),6.68(d,J=8.13Hz,1H),5.02(s,1H),4 .01-4.19(m,2H),3.37-3.64(m,3H),3.17(d,J=5.13Hz,1H),2.89-3.03(m,1H),2.80-2. 89(m,1H),2.55-2.76(m,3H),2.24-2.45(m,6H),1.38(s,9H),1.06(m,J=6.50Hz,3H)ppm.

[0466] Step 2: Synthesis of (6S,8R)-8-methyl-6-(5-(2-(piperazin-1-yl)ethoxy)pyridin-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0467]

[0468] Dissolve tert-butyl 4-(2-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperazine-1-carboxylate (392 mg, 662.5 umol) and trifluoroacetic acid (6.16 g, 54.0 mmol) in dichloromethane (10 mL) and react at 20°C for 1 hour. The reaction was completed by LCMS monitoring. After the reaction solution was concentrated, the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution, extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried with sodium sulfate, and concentrated. The crude product was purified by column chromatography to give a yellow solid (6S,8R)-8-methyl-6-(5-(2-(piperazin-1-yl)ethoxy)pyridin-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (156 mg, 317 umol, yield 47.9%).

[0469] LCMS: m / z 491.2 [M+H] + .

[0470] 1 H NMR (400MHz, DMSO-d6) δ = 8.08-8.20 (m, 1H), 7.36 (dd, J = 8.63, 2.88Hz, 1H), 7.25 (d, J=8.63Hz,1H),6.84(d,J=8.13Hz,1H),6.68(d,J=8.13Hz,1H),5.03(s,1H),4.11(br t,J=5.44Hz,2H),3.52-3.59(m,1H),3.34-3.42(m,1H),2.80-2.99(m,6H),2.63-2.76(m,3H),2.53-2.63(m,4H),1.06(d,J=6.63Hz,3H)ppm.

[0471] Step 3: Synthesis of 3-(4-((2-bromoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0472]

[0473] 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2.00 g, 7.71 mmol), 1,2-dibromoethane (17.3 g, 92.5 mmol) and N,N-dimethylisopropylamine (2.99 g, 23.1 mmol) were dissolved in N-methylpyrrolidone (20 mL), replaced with nitrogen, and then reacted at 100°C for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was washed with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain a yellow solid 3-(4-((2-bromoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (403 mg, 1.10 mmol, yield 14.27%).

[0474] LCMS: m / z 365.0 [M+H] + .

[0475] 1 H NMR (400MHz, DMSO-d6) δ = 11.00 (s, 1H), 7.31 (t, J = 7.75Hz, 1H), 6.98 (d, J = 7.25Hz, 1H), 6.84 (d, J = 8.00Hz, 1H), 5.93 (br s,1H),5.11(dd,J=13.26,5.00Hz,1H),4.18-4.28(m,1H),4.09-4.17(m,1H),3.53-3.64(m,4H),2.86-2.99(m,1H),2.64(br s,1H),2.23-2.37(m,1H),1.98-2.09(m,1H)ppm.

[0476] Step 4: Synthesis of 3-(4-((2-(4-(3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0477]

[0478] (6S,8R)-8-methyl-6-(5-(2-(piperazin-1-yl)ethoxy)pyridin-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (70 mg, 142 umol), 3-(4-((2-bromoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (57.3 mg, 156 umol), N,N-diisopropylethylamine (55.2 mg, 427 umol) were dissolved in dioxane (2 mL), and then reacted at 80°C for 12 hours under nitrogen protection. The reaction was completed by LCMS monitoring. The reaction solution was spin dried and sent to prep-HPLC for purification to give a yellow solid 3-(4-((2-(4-(3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20 mg, 25.8 umol, yield 18.1%).

[0479] LCMS: m / z 776.3 [M+H] + .

[0480] 1 H NMR (400MHz, ACETONITRILE-d3) δ = 8.91 (br s, 1H), 8.10 (d, J = 2.50Hz, 1H), 7.31-7.37 (m, 1H), 7.28 (s, 1H), 7.26 (br d,J=2.75Hz,1H),7.05(d,J=7.38Hz,1H),6.83(t,J=7.69Hz,2H),6.70(d,J=8.00Hz,1H),4.98-5.18(m,2H),4.54-4.91(m,1H),4.22- 4.31(m,1H),4.19(s,1H),4.13(t,J=5.57Hz,2H),3.36-3.49(m,2H),3.28-3.35(m,2H),2.84-3.07(m,3H),2.69-2.83(m,7H),2.68(br s,8H),2.39-2.43(m,1H),1.28(br d,J=6.25Hz,1H),1.08(d,J=6.75Hz,3H)ppm.

[0481] Similar to the synthetic route of the aforementioned Example 42, the following Example 43 was synthesized by selecting corresponding reactants and synthetic methods known to those skilled in the art.

[0482] Example 43: 3-(4-((2-(4-(3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)propyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 43)

[0483]

[0484] LCMS: m / z 790.3 [M+H] + .

[0485] 1 H NMR(400MHz,ACETONITRILE-d3)δ=8.71-9.01(m,1H),8.09(d,J=2.50Hz,1H),7.40(s,1H),7.26-7.30(m,1H),7.2 0-7.26(m,1H),7.04(d,J=7.38Hz,1H),6.83(t,J=7.69Hz,2H),6.70(d,J=8.13Hz,1H),5.02-5.17(m,2H),4.50(br s,1H),4.18(q,J=16.38Hz,2H),4.06(t,J=6.32Hz,2H),3.43-3.53(m,1H),3.33-3.43(m,1H),3.26(br d,J=5.25Hz,2H),2.90-3.06(m,2H),2.73-2.87(m,2H),2.70(br dd,J=4.57,2.69Hz,1H),2.59(br t,J=6.19Hz,3H),2.29-2.53(m,12H),1.28(br d,J=6.13Hz,1H),1.08(d,J=6.63Hz,3H)ppm.

[0486] Test Case

[0487] In the following test examples, AZD9496 (catalog number: HY-12870), AZD9833 (catalog number: HY-136255) and tamoxifen (catalog number: HY-13757A) were purchased from MedChemExpress; comparative compound 1 (chemical structure: (6S, 8R)-6-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-7-(2-fluoro-2-methylpropyl)-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinoline) was prepared by the method of Example 1 in WO2017 / 182493A1.

[0488] Test Example 1: ERαTR-FRET Test

[0489] Prepare 1X Tris-HCl (Sigma, PHG0002) protein buffer, mix and set aside. Prepare the compound to be tested into a 2mM stock solution, and then dilute it 3-fold in sequence, for a total of 10 concentrations. Use Echo 550 to add the diluted compound to the reaction plate, 100nL per well, and add 5nL estradiol (Sigma, 491187; final concentration 1.5nM) to each well.

[0490] Prepare 1x protein mixture: first prepare 2x GST-ERα-LBD (Invitrogen, A15677) / MAb anti-GST-Eu (Cisbio, 61GSTKLA) mixed solution according to the table below.

[0491] substance Final concentration (nM) Working concentration (nM) Stock solution concentration (nM) GST-ERα-LBD 2 4 20100 MAb anti-GST-Eu 2.5ng / well 50nl / well 50μg / ml

[0492] A 2x biotin-SRC2 / streptavidin-XL665 (Cisbio, 610SAXLA) mixed solution was prepared.

[0493] substance Final concentration (nM) Working concentration (nM) Stock solution concentration (nM) Biotin-SRC2 75 150 1000000 Streptavidin-XL665 50ng / well 50nl / well 1mg / ml

[0494] The above two 2x GST-NR-LBD / MAb anti-GST-Eu solutions and 2x biotin-SRC2 / streptavidin-XL665 solutions were mixed evenly in a volume ratio of 1:1; 1x protein mixed solution was added to each well of a 384-well plate, 20 μL was added to each well, and the 384-well plate was placed in a centrifuge at room temperature at 1000 rpm for 10 seconds. After being taken out and placed at room temperature for 3 hours, the results were read using an EnVision multi-function microplate reader.

[0495] The readings were taken at 665 and 615 (nanometers), and the 615 value was used as the correction value. The final value was expressed as 665 value / 615 value. The inhibition rate was calculated according to the following formula:

[0496]

[0497] X is the "665 value to 615 value" for each concentration. Min is the average of the "665 value to 615 value" with 0.2 mM positive control compound and 5 nl 3 nM (1.5 nM) estradiol. Max is the average of the "665 value to 615 value" with DMSO and 5 nl 3 nM (1.5 nM) estradiol. The data were imported into Graphpad Prism and curve fitting was performed using Log(agonist) vs. response -- variable slope.

[0498] Fitting formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogEC 50 -X)*HillSlope))

[0499] ERαTR-FRET experimental data

[0500] Compound <![CDATA[IC 50 (nM)]]> Maximum inhibition rate Example 1 9.00 100.2 Example 9 21.6 100.1 Example 10 7.80 100.2 Example 12 15.6 100.3 Embodiment 14 40.3 100.2 Embodiment 25 11.4 100.8 Embodiment 26 58.4 100.4 Embodiment 30 8.85 99.8 Embodiment 31 45.6 100.9 Embodiment 32 14.7 100.3 Embodiment 33 11.8 99.9 Embodiment 34 19.4 100.2 AZD9833 62.0 99.8 Tamoxifen 578.1 100.4

[0501] Test Example 2: MCF-7 cell proliferation test

[0502] Human breast cancer cells MCF-7 (HTB-22, purchased from ATCC) were seeded in 96-well plates in a medium containing 10% FBS (Gibco, 10099-141), 1% pyruvate (Sigma, S8636), and 1% non-essential amino acids (Sigma, M7145) in MEM (Hyclone, SH30024.01B). The seeding density was 4,000 cells / well, and the cells were cultured at 37°C and 5% CO2. The compound was prepared into a 20mM stock solution, serially diluted with 100% DMSO (Sigma, D2650) to a final concentration of 1000, and then diluted 20 times with a medium containing 2% FBS. After 24 hours of culture, the culture medium was removed, and 90 μL of culture medium containing 2% FBS and 10 μL of drug were added to each well. 10 μL of DMSO was added to the control group and gently shaken to mix. The blank group contained only 100 μL of 2% FBS culture medium and was cultured in a 37°C, 5% CO2 incubator. After 72 hours, 50 μL of mixed Cell Titer-Glo (Promega, G7571) was added, shaken to mix, and placed at room temperature for 10 minutes. The chemiluminescent signal value was measured. The negative control was 0.5% DMSO well.

[0503] MCF-7 cell proliferation assay experimental data

[0504]

[0505]

[0506] Test Example 3: Degradation effect of compounds on ERα

[0507] This test example uses ERαDuoSet IC ELISA Kit (R&D, DYC5715) to detect the degradation effect of compounds on ERα. On the first day of the experiment, human breast cancer cells MCF-7 (source as above) were inoculated in a 24-well plate; the culture medium was MEM culture medium containing 10% activated carbon-treated FBS (Tocyto, UT61204), 1% pyruvate, and 1% non-essential amino acids; the inoculation density was 150,000 cells / well; the cells were cultured at 37°C and 5% CO2 for 24 hours.

[0508] On the second day of the experiment, the test compound was diluted in series and added to the 24-well plate containing cells. The cells were cultured for 24 hours at 37°C and 5% CO2. The ERα capture antibody was diluted to 1 μg / ml with PBS (Corning, 21-040-CVR), added to the 96-well plate at 100 μL / well, and the plate was sealed and coated overnight at room temperature.

[0509] On the third day of the experiment, the coated 96-well plate was washed three times with PBS, and 300 μL of blocking solution (R&D, DY995) was added to each well and blocked at room temperature for 1 hour. The 24-well plate was washed once with PBS, and the residual liquid was aspirated, and 60 μL of lysis solution (6M urea (Sigma, U5378), 1mM EDTA (Sigma, E9884), 0.5% TritonX-100 (Sigma, T8787), 1mM PMSF (Sigma, 93482), protease inhibitor cocktail (Sigma, 05892970001)) was added to each well for lysis on ice for 15 minutes, and then diluent (1mM EDTA, 0.5% TritonX-100 was dissolved in PBS); diluted cell lysate was added to the blocked 96-well plate, 100 μL per well, and incubated at room temperature for 2 hours; the plate was washed 3 times with washing solution (R&D, WA126), primary antibody was added, incubated for 1 hour, the 96-well plate was washed 4 times, secondary antibody was added, and incubated at room temperature in the dark for 30 minutes; the plate was washed 4 times with washing solution, TMB (R&D, DY999) was added, color was developed for 15 minutes, and then the reaction was terminated with stop solution (R&D, DY994), and the light absorption at 450 nm was read.

[0510] IC of compounds on ERα degradation 50 value

[0511]

[0512]

[0513] Test Example 4: In vitro human liver microsome stability test

[0514] Prepare 8 96-well incubation plates, named T0, T5, T15, T30, T45, T60, Blank60 and NCF60. The reaction time points corresponding to the first 6 incubation plates are 0, 5, 15, 30, 45 and 60 minutes, respectively. No test compound or control compound is added to the Blank60 plate and samples are taken after 60 minutes of incubation. In the NCF60 plate, potassium phosphate buffer is used instead of NADPH regeneration system solution (Sigma, N0505) for incubation for 60 minutes.

[0515] 2 μL of the test compound or reference substance working solution and 100 μL of human liver microsome working solution (Corning, 452117) were added to the T0, T5, T15, T30, T45, T60 and NCF60 plates, respectively, and the microsome protein concentration was 1 mg / mL. Only the microsome working solution was added to the Blank60 plate, and then the incubation plates Blank60, T5, T15, T30, T45 and T60 except T0 and NCF60 were placed in a 37°C water bath for pre-incubation for about 10 minutes.

[0516] The T0 plate samples were first added with 600 μL of stop solution (acetonitrile:methanol (95:5, v / v) solution containing 100 ng / mL tolbutamide (Sigma, T0891)), and then the NADPH regeneration system working solution was added.

[0517] Add 98 μL potassium phosphate buffer to each well of the NCF60 plate and incubate for 60 minutes.

[0518] After the pre-incubation of Blank60, T5, T15, T30, T45 and T60 plates was completed, 98 μL of NADPH regeneration system working solution was added to each sample well to start the reaction.

[0519] After incubation for an appropriate time (e.g., 5, 15, 30, 45, and 60 minutes), 600 μL of stop solution was added to each sample well and control sample well of Blank60, T5, T15, T30, T45, T60, and NCF60 plates, respectively, to terminate the reaction.

[0520] All sample plates were shaken and centrifuged at 3220 × g for 20 minutes. 200 μL of the test sample supernatant was diluted into 200 μL of an aqueous solution containing 0.3% formic acid for LC-MS / MS analysis, and 100 μL of the control sample supernatant was diluted into 300 μL of pure water for LC-MS / MS analysis, and calculated according to the following formula:

[0521]

[0522] In vitro microsomal stability experimental data

[0523]

[0524]

[0525] In summary, the present invention includes but is not limited to the following technical solutions:

[0526] 1. A compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof:

[0527]

[0528] in:

[0529] Z 1 Selected from CR a R b , C(O) and bond;

[0530] Z 2 Selected from O, S, NR c , C(O) and a bond, or optionally replaced by one or more identical or different R d Substituted C1-C6 alkylene, O-(C1-C6 alkylene) or NH-(C1-C6 alkylene);

[0531] Cy 1 Selected from C 6-14 Arylene, C 3-8 Cycloalkylene, C 5-14 Heteroarylene, C 3-14 Heterocycloalkylene, C 3-14 heterocycloalkenylene, each of which is optionally substituted by a group selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, and a C 1-6 Alkyl or C 1-6 Alkoxy;

[0532] Cy 2 Select from key, C 3-10 Cycloalkylene, C 3-14 heterocycloalkylene, each of which is optionally substituted by a group selected from the group consisting of a halogen atom (including a F, Cl, Br or I atom), a hydroxyl group, an amino group, a cyano group, and a C 1-6 Alkyl or C 1-6 Alkoxy;

[0533] R 1 , R 2 are each independently H, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano or oxo;

[0534] R 4 H, halogen atoms, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano, oxo, C 6-14 Aryl, C 5-14 Heteroaryl, C 3-14 Heterocycloalkylene or

[0535] (For example )

[0536] The group substitution;

[0537] Preferably, R 4 H, halogen atoms, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano or oxo;

[0538] R 3 For-(CRe R f ) m -CR 31 R 32 R 33 , where m is 1, 2 or 3;

[0539] R 31 , R 32 and R 33 Independently selected from: H, C 1-6 Alkyl, halogen, cyano, and R 31 and R 32 Can form C 3-8 Cycloalkylene, the C 1-6 Alkyl and C 3-8 The cycloalkylene group is optionally substituted with a hydroxyl group, a cyano group, an amino group or a halogen atom;

[0540] R a , R b , R c , R d , R e , R f are each independently H, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 alkyl.

[0541] 2. The compound according to technical solution 1, or its stereoisomer or pharmaceutically acceptable salt, wherein

[0542] Z 1 Selected from CR a R b , C(O) and bond;

[0543] Z 2 Selected from O, S, NR c , C(O) and a bond, or optionally replaced by one or more identical or different R d Substituted C1-C6 alkylene, O-(C1-C6 alkylene) or NH-(C1-C6 alkylene);

[0544] Cy 1 Selected from C 6-14 Arylene (preferably C 6-10 Arylene) and C 5-14 Heteroarylene (preferably C 5-10 arylene), each of which is optionally substituted by a group selected from the group consisting of a halogen atom, and a C 1-6 Alkyl or C 1-6 Alkoxy;

[0545] Cy 2 Select from key, C 3-10Cycloalkylene (preferably C 3-8 Cycloalkylene), C 3-14 Heterocycloalkylene (preferably C 3-10 Heterocycloalkylene);

[0546] R 1 , R 2 Each independently is H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more groups selected from halogen atoms, hydroxyl groups or cyano groups;

[0547] R 3 For-(CR e R f ) m -CR 31 R 32 R 33 , where m is 1, 2 or 3;

[0548] R 31 , R 32 and R 33 Independently selected from: H, C 1-6 Alkyl, halogen, cyano, and R 31 and R 32 Can form C 3-8 Cycloalkylene, the C 1-6 Alkyl and C 3-8 The cycloalkylene group is optionally substituted with a hydroxyl group, a cyano group, an amino group or a halogen atom;

[0549] R a , R b , R c , R d , R e , R f are each independently H or a halogen atom;

[0550] R 4 C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano, oxo and

[0551]

[0552] The group is substituted.

[0553] 3. The compound according to technical solution 2, or its stereoisomer or pharmaceutically acceptable salt, wherein R 4 C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano or oxo groups.

[0554] 4. A compound according to any one of technical solutions 1 to 3, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein

[0555] Z 1 is the key;

[0556] Z 2 is selected from -O-CH2-CH2-, -O-CH2-, -NH-CH2-CH2-, -NH-CH2-, -NH- or -O-;

[0557] Cy 1 C 6-10 Arylene (preferably phenyl) and C 5-10 Heteroarylene (preferably pyridyl), which is optionally substituted by a halogen atom (preferably F) or C 1-6 Alkoxy (preferably methoxy) substitution;

[0558] Cy 2 is selected from a bond, an azetidinyl group, a pyrrolidinyl group, a piperazinyl group,

[0559]

[0560] R 1 C 1-6 Alkyl (preferably methyl);

[0561] R 2 is H;

[0562] R 3 -CH2-CR 31 R 32 R33 ;

[0563] R 31 , R 32 and R 33 independently selected from: H, C optionally substituted by hydroxyl or halogen atoms (preferably F) 1-6 An alkyl group (preferably a methyl group), a halogen atom (preferably a F group), a cyano group, and R 31 and R 32 can together form a C optionally substituted by a hydroxyl group or a halogen atom (preferably F) 3-8 Cycloalkylene (preferably cyclopropylene);

[0564] R 4 is optionally selected from a halogen atom (preferably F), an oxo group, a C 1-6 Alkylamino (preferably methylamino), (C 1-6 alkyl)2amino (preferably dimethylamino), and

[0565]

[0566] The group substituted C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkenylamino.

[0567] 5. The compound according to technical solution 4, or its stereoisomer or pharmaceutically acceptable salt, wherein

[0568] Cy 2 is selected from a bond, an azetidinyl group, a pyrrolidinyl group, and

[0569] R 4 is optionally selected from a halogen atom (preferably F), an oxo group, a C 1-6 Alkylamino (preferably methylamino) and (C 1-6 Alkyl)2amino (preferably dimethylamino) substituted C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkenylamino.

[0570] 6. A compound according to any one of technical solutions 1 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein

[0571] Z 1 is the key;

[0572] Z 2 is selected from -NH- or -O-;

[0573] Cy 1 is phenyl or pyridyl (preferably phenyl), which is optionally substituted by F or methoxy;

[0574] Cy 2 is selected from azetidinyl, pyrrolidinyl, piperazinyl;

[0575] R 1 is methyl;

[0576] R 2 is H;

[0577] R 3 -CH2-CR 31 R 32 R 33 ;

[0578] R 31 , R 32 Each is F or R 31 and R 32 Together they form a cyclopropylene group;

[0579] R 33 Selected from: H, hydroxymethyl, fluoromethyl, preferably selected from F, hydroxymethyl, fluoromethyl;

[0580] R 4 F-(CH2)3- or

[0581]

[0582] 7. The compound according to technical solution 6, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Cy 2 is selected from azetidinyl and pyrrolidinyl, and R 4 It is F-(CH2)3-.

[0583] 8. The compound according to technical solution 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

[0584]

[0585]

[0586] 9. A pharmaceutical composition comprising a compound according to any one of technical solutions 1 to 8 or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0587] 10. Use of the compound according to any one of technical solutions 1 to 8 or its stereoisomer or pharmaceutically acceptable salt in the preparation of a drug for treating estrogen receptor-dependent or estrogen receptor-mediated diseases in mammals.

Claims

1. A compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof: in: Z 1 Selected from CR a R b , C(O) and bond; Z 2 Selected from O, S, NR c , C(O) and a bond, or optionally replaced by one or more identical or different R d Substituted C1-C6 alkylene, O-(C1-C6 alkylene) or NH-(C1-C6 alkylene); Cy 1 Selected from C 6-14 Arylene, C 3-8 Cycloalkylene, C 5-14 Heteroarylene, C 3-14 Heterocycloalkylene, C 3-14 heterocycloalkenylene, each of which is optionally substituted by a group selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, and a C 1-6 Alkyl or C 1-6 Alkoxy; Cy 2 Select from key, C 3-10 Cycloalkylene, C 3-14 heterocycloalkylene, each of which is optionally substituted by a group selected from the group consisting of a halogen atom (including a F, Cl, Br or I atom), a hydroxyl group, an amino group, a cyano group, and a C 1-6 Alkyl or C 1-6 Alkoxy; R 1 , R 2 are each independently H, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano or oxo; R 4 H, halogen atoms, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano, oxo, C 6-14 Aryl, C 5-14 Heteroaryl, C 3-14 Heterocycloalkylene or (For example ) is substituted by a group; Preferably, R 4 H, halogen atoms, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 alkenylamino, C3-C8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 The alkenylamino or C3-C8 cycloalkyl group is optionally substituted by one or more halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, cyano or oxo; R 3 For-(CR e R f ) m -CR 31 R 32 R 33 , where m is 1, 2 or 3; R 31 , R 32 and R 33 Independently selected from: H, C 1-6 Alkyl, halogen, cyano, or R 31 and R 32 Can form C 3-8 Cycloalkylene, the C 1-6 Alkyl and C 3-8 The cycloalkylene group is optionally substituted with a hydroxyl group, a cyano group, an amino group or a halogen atom; R a , R b , R c , R d , R e , R f are each independently H, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 alkyl.

2. The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z 1 is selected from CH2, C(O) and a bond; Z 2 is selected from the group consisting of -O-CH2-CH2-, -O-CH2-, -NH-CH2-CH2-, -NH-CH2-, -NH-, -O-, and a bond; Cy 1 C 6-10 Arylene or C 5-10 A heteroarylene group which is optionally substituted by a group selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, and a C 1-6 Alkyl or C 1-6 Alkoxy; Cy 2 Selected from C 3-14 Heterocycloalkylene, which is optionally substituted by a group selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, and a C 1-6 Alkyl or C 1-6 Alkoxy; R 1 , R 2 are each independently H, a halogen atom or C 1-6 alkyl; R 3 -CH2-CR 31 R 32 R 33 ; R 31 , R 32 and R 33 Independently selected from: H, C 1-6 Alkyl, halogen atom, or R 31 and R 32 Can form C 3-8 Cycloalkylene, the C 1-6 Alkyl and C 3-8 The cycloalkylene group is optionally substituted with a hydroxyl group, a cyano group or a halogen atom; R 4 is optionally selected from a halogen atom, an oxo group, a C 1-6 Alkylamino, and (C 1-6 Alkyl)2 amino group substituted C 1-6 Alkyl, C 1-6 Alkylamino, amino C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkenylamino.

3. The compound according to claim 1 or 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z 1 Selected from CH2 and a bond, Z 2 is selected from -NH-, -O- and a bond.

4. A compound according to any one of claims 1 to 3, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Cy 1 is phenyl or pyridyl, which may be substituted by halogen atoms, C 1-6 Alkyl or C 1-6 Alkoxy substitution.

5. A compound according to any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Cy 2 Selected from azetidinyl, pyrrolidinyl, piperazinyl, 6. A compound according to any one of claims 1 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 Each independently is H or C 1-6 alkyl.

7. A compound according to any one of claims 1 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 31 , R 32 and R 33 independently selected from: H, C optionally substituted by hydroxyl or halogen atoms 1-6 Alkyl, halogen atom, or R 31 and R 32 Together, they form a C 3-8 Cycloalkylene; Preferably, R 31 , R 32 Each is H or a halogen atom, or R 31 and R 32 Together they form C 3-8 Cycloalkylene; R 33 is selected from H, C optionally substituted by hydroxyl or halogen atoms 1-6 an alkyl group, and a halogen atom.

8. A compound according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 4 is C optionally substituted by a halogen atom 1-6 alkyl.

9. Use of the compound according to any one of claims 1 to 8 or its stereoisomer or pharmaceutically acceptable salt in the preparation of a medicament for treating estrogen receptor-dependent or estrogen receptor-mediated diseases in mammals.

10. An intermediate selected from the following compounds or their stereoisomers or pharmaceutically acceptable salts: wherein Trt represents a trityl group, and Boc represents a tert-butyloxycarbonyl group.

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