Estrogen Receptor Modulators

Abstract

This application relates to a compound of formula (I) or a stereoisomer, tautomer or pharma ceutical acceptable salt thereof. Disclosed herein are acceptable salts thereof and their use for the manufacture of a medicament for preventing and / or treating an estrogen receptor (ER) related disease or disorder.

Description

[Technical field]

[0001] The present invention relates to some novel compounds or their pharma- ceutically acceptable salts, which have anti-cancer activity and are therefore potentially useful in methods for treating the human or animal body.The present invention further relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, and their use in methods of treatment.For example, the use includes the use for preparing medicaments for preventing or treating cancer in warm-blooded animals (such as humans), and the use for preventing or treating estrogen receptor-dependent or estrogen receptor-mediated diseases. The present invention further relates to the compounds as selective estrogen receptor down-modulators. [Background technology]

[0002] Estrogen receptor (ER) is a steroid hormone receptor that has 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 linked to the function of estrogen and ER receptors; for example, most breast cancer patients have increased expression of ER.

[0003] Some compounds bind to the ER and mediate the release of the female steroid hormone 17b estradiol. It is known that they can competitively inhibit the binding of endogenous estrogen ligands such as estrogen receptor antagonist (E2) to ER, and therefore are used as ER inhibitors. For example, selective estrogen receptor modulators (SERMs) such as tamoxifen, AZD9496, and AZD9833 are used as ER inhibitors to treat breast cancer and the like. SERM compounds are also disclosed in WO 2017 / 182493 A1. As shown.

[0004] Although existing SERM therapies have a certain degree of efficacy in treating breast cancer, ER inhibitors with stronger inhibitory activity and improved metabolic stability are needed. Summary of the Invention

[0005] The present inventors have surprisingly found that the compound of formula (I) is a tetrahydrooxazo The present invention has been found to have a basic structure of isoquinolinone, and this basic structure has a significant ER decomposition activity, and therefore has a significantly superior ER inhibitory activity than the compounds known in the prior art. Such compounds also have excellent metabolic stability. Therefore, the compounds of the present invention can be used to treat estrogen receptor-dependent or estrogen receptor-mediated diseases, and the present invention has been completed.

[0006] Specifically, the present invention relates to the following:

[0007] One aspect of the present invention is a compound of formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof. Provide salt:

[0008] [ka]

[0009] During the ceremony: Z 1 CR a R b , C(O), and a bond; Z 2 are O, S, and NR c , C(O) and a bond, or C1-C6 alkylene optionally substituted with one or more of the same or different Rd, O-(C1-C6 alkylene) or NH-(C1-C6 alkylene); Cy 1 is C 6-14 Arylene, C 3-8 Cycloalkylene, C 5-14 Heteroarylene, C 3-14 Heterocycloalkylene, C 3-14 heterocycloalkenylene, each optionally C optionally substituted with halogen atoms, hydroxy, amino, cyano, and halogen atoms1-6 Alkyl or C 1-6 alkoxy; Cy 2 is a bond, C 3-10 Cycloalkylene, C 3-14 heterocycloalkylene, each optionally substituted with halogen atoms (including F, Cl, Br or I atoms), hydroxy, amino, cyano and halogen atoms; 1-6 Alkyl or C 1-6 substituted with a group selected from alkoxy; R 1 , R 2 are each independently H, a halogen atom, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 alkenylamino or C3-C8 cycloalkyl, 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkenylamino or C3-C8 cycloalkyl may optionally contain one or more halogen atoms, hydroxy, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, cyano or oxy substituted with a group selected from sr; R 4 is H, halogen atom, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkyl amine No, Amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkenylamino or C3-C8 cycloalkenylamino C 1-6 Alkyl, C 1-6 Alkylamino, Amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkenylamino or C3-C8 cycloalkyl may optionally contain one or more halogen atoms, hydroxy, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, cyano No, Oxo, C 6-14 Aryl, C 5-14 Heteroaryl, C 3-14 Heterocycloalkylene or teeth

[0010] [ka]

[0011] and is substituted with a group selected from Preferably, R 4 is H, halogen atom, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkenylamino or C3-C8 cycloalkyl Yes, C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkenylamino or C3-C8 cycloalkyl may optionally contain one or more halogen atoms, hydroxy, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2 selected from amino, cyano or oxo is substituted with a group; R 3 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 are, independently of each other: H, C 1-6alkyl, halogen atom or cyano, and R 31 and R 32 Let's go together 3-8 may form a cycloalkylene, 1-6 Alkyl and C 3-8 The cycloalkylene is optionally substituted with a hydroxy, cyano, amino or halogen atom; R a , R b , R c , R d , R e , R f are each independently H, a halogen atom, a hydroxyl, Amino, cyano, and optionally halogen-substituted C 1-6 It is an alkyl.

[0012] In the present specification, the heteroaryl / heteroarylene, heterocycloalkyl / heterocycloalkylene, and heterocycloalkenyl / heterocycloalkenylene are each a ring structure. The cycloalkyl / cycloalkyl group contains 1 to 4 heteroatoms selected from N, O, and S. Cycloalkylene, heterocycloalkyl / heterocycloalkylene, heterocycloalkenyl Heterocycloalkenylene / heterocycloalkenylene refers to monocyclic, bicyclic, or heterocyclic rings that do not contain aromatic ring structures. or tricyclic (preferably monocyclic or bicyclic) ring systems, said bicyclic and The tricyclic ring systems include spiro rings, bridged rings or fused rings. and heteroaryl / heteroarylene may be a monocyclic, fused bicyclic, or fused tricyclic (preferably monocyclic or fused bicyclic) ring system, and wherein said fused bicyclic, or may contain non-aromatic ring structures in a fused tricyclic ring system. The halogen atoms are selected from F, Cl, Br or I atoms. The oxo means "=O".

[0013] In a preferred embodiment of the compound of formula (I): Z 1 CR a R b , C(O), and a bond; Z 2 are O, S, and NR c , C(O) and a bond, or C1-C6 alkylene optionally substituted with one or more of the same or different Rd, O-(C1-C6 alkylene) or NH-(C1-C6 alkylene); Cy 1 is C 6-14 Arylene (preferably C 6-10 arylene) and C 5-14 Heteroarylene (preferably Preferably C 5-10 heteroarylene), each optionally substituted with a halogen atom, and C 1-6 Alkyl or C 1-6 substituted with a group selected from alkoxy; Cy 2 is a bond, C 3-10 Cycloalkylene (preferably C 3-8 Cycloalkylene), C 3-14 Heterosi Chloroalkylene (preferably C 3-10 heterocycloalkylene); R 1 , R 2 are each independently H or C 1-6 Alkyl, the C 1-6 In the case of alkyl and substituted with one or more groups selected from halogen atoms, hydroxy, or cyano. There; R 3 CR e R f ) m -CR 31 R 32 R 33 where m is 1, 2 or 3; R 31 , R 32 and R 33are, independently of each other: H, C 1-6 alkyl, halogen atom or cyano, and R 31 and R 32 Let's go together 3-8 may form a cycloalkylene, 1-6 Alkyl and C 3-8 The cycloalkylene is optionally substituted with a hydroxy, cyano, amino or halogen atom; R a , R b , R c , R d , R e , R f are each independently H or a halogen atom; R 4 is C 1-6 Alkyl, C 1-6 Alkylamino, Amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkenylamino or C3-C8 cycloalkyl, 1-6 Alkyl, C 1-6 Alkyl Amino, Amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkenylamino or C3-C8 Cyclo The alkyl group may optionally contain one or more halogen atoms, hydroxy, amino, C 1-6 Alki Ruamino, (C 1-6 Alkyl)2 amino, cyano, oxo and

[0014] [ka]

[0015] and is substituted with a group selected from Preferably, R 4 is C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6alkenylamino or C3-C8 cycloalkyl, 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 alkenylamino or C3-C8 cycloalkyl optionally has one or more halogen atoms, hydroxy, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2Amin The ring is substituted with a group selected from aryl, cyano, or oxo.

[0016] In a further preferred embodiment of the compound of formula (I): Z 1 is a bond; Z 2 is selected from -O-CH2-CH2-, -O-CH2-, -NH-CH2-CH2-, -NH-CH2-, -NH- or -O-; Cy 1 is C 6-10 Arylene (preferably phenyl) and C 5-10 heteroarylene (preferably pyridyl), optionally selected from halogen atoms (preferably F) or C 1-6 substituted with alkoxy (preferably methoxy); Cy 2 is a bond, azetidine, pyrrolidine, piperazine,

[0017] [ka]

[0018] R 1 is C 1-6 alkyl (preferably methyl); R 2 is H; R 3 -CH2-CR 31 R 32 R 33 and; R 31 , R 32 and R33 are each independently: H, C optionally substituted with a hydroxy or halogen atom (preferably F), 1-6 alkyl, a halogen atom (preferably F), cyano, and R 31 and R 32 together with C optionally substituted with a hydroxy or halogen atom (preferably F); 3-8 It may form a cycloalkylene (preferably cyclopropylene); R 4 is optionally a halogen atom (preferably F), oxo, C 1-6 Alkylamino (preferably methylamino), (C 1-6 alkyl)2amino (preferably dimethylamino), and

[0019] [ka]

[0020] C substituted with a group selected from 1-6 Alkyl, C 1-6 Alkylamino, Amino C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 It is alkenylamino.

[0021] Preferably, Cy 2 is selected from a bond, azetidine, and pyrrolidine; and R 4 In the case by halogen atoms (preferably F), oxo, C 1-6 Alkylamino (preferably methylamino) and (C 1-6 C substituted with a group selected from alkyl, amino (preferably dimethylamino) 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 It is alkenylamino.

[0022] In a particularly preferred embodiment of the compound of formula (I): Z 1 is a bond; Z 2 is selected from -NH- or -O-; Cy 1 is phenyl or pyridyl (preferably phenyl), optionally substituted with F or methoxy; Cy 2 is selected from azetidine, pyrrolidine, and piperazine; R 1 is methyl; R 2 is H; R 3 -CH2-CR 31 R 32 R 33 and; R 31 , R 32 are F or R, respectively. 31 and R 32 together form cyclopropylene; R 33 is selected from H, hydroxymethyl, fluoromethyl, preferably F, hydroxy methyl, fluoromethyl; R 4 is F-(CH2)3- or

[0023] [ka] It is.

[0024] More preferably, Cy 2 is selected from azetidine and pyrrolidine; R 4 is F-(CH2)3-.

[0025] In some embodiments, the compounds of formula (I) of the present invention are in the form of stereoisomers, e.g. For example, the 1-position carbon atom of the tetrahydroisoquinoline ring (i.e., Z 1 The carbon atom at position 3 (i.e., the carbon atom leading to R 1The carbon atom connected to the It may be a body configuration.

[0026] In some embodiments, the present invention relates to the following compounds, or stereoisomers or pharma- ceutically acceptable salts thereof:

[0027] [ka]

[0028] [ka]

[0029] In another aspect, the present invention relates to a pharmaceutical composition comprising one or more of the compounds of the present invention, or a stereoisomer or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0030] In another aspect, the present invention relates to the use of a compound of the present invention for the manufacture of a medicament for preventing or treating an estrogen receptor dependent or estrogen receptor mediated disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Next, the present invention will be further described with specific manufacturing examples and test examples. Note that the manufacturing examples and test examples are not intended to limit the scope of the present invention. All raw materials, reagents, etc. used in the examples are substances known to those skilled in the art, and are commercially available or obtained by methods described in the literature, and the test methods or characteristic evaluation methods used are also methods known to those skilled in the art.

[0032] 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)

[0033] [ka]

[0034] Step 1: Synthesis of 7-bromobenzo[d]oxazol-2(3H)-one

[0035] [ka]

[0036] 2-Amino-6-bromophenol (5 g, 26.6 mmol, 1 eq) was dissolved in 120 ml of tetrahydrofuran, and dicarbonyl imidazole (5.17 g, 31.9 mmol, 1.2 eq) was added at 20°C. The reaction solution was reacted at 80°C for 2 hours. The completion of the reaction was confirmed by TLC, and the reaction solution was poured into ice water, adjusted to pH = 2 with hydrochloric acid, extracted with ethyl acetate, dried, concentrated, and the crude product was purified by column chromatography to give 7-bromobenzo[d]oxazol-2(3H)-one (5.1 g, 23.8 mmol, 89.6%). Yield: 100%) was obtained as a red solid.

[0037] 1 H NMR (400 MHz, DMSO-d6): δ = 12.0 (s, 1H), 7.30 - 7.27 (m, 1H), 7.11 - 7.09 (m, 2H) ppm.

[0038] Step 2: Synthesis of 7-bromo-3-triphenylmethylbenzo[d]oxazol-2(3H)-one

[0039] [ka]

[0040] 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, then triphenylmethyl chloride (6.64 g, 23.8 mmol, 1 eq) was added, and the reaction solution was reacted at 20 ° C for 2 hours. The completion of the reaction was confirmed by TLC, and the reaction solution was poured into ice water, extracted with ethyl acetate, dried, concentrated, and the crude product was purified by column chromatography to obtain 7-bromo-3-triphenylmethylbenzo[d]oxazol-2(3H)-one (9.5 g, 20.8 mmol, yield 87.4%) as a white solid.

[0041] 1 H NMR (400 MHz, CDCl3): δ = 7.40 - 7.37 (m, 6H), 7.25 - 7.20 (m, 9H), 7.12 (d, J= 8.0 Hz, 1H), 6.62 (t, J=8.4 Hz, 1H), 5.93 (d, J= 8.0 Hz, 1H) ppm.

[0042] Step 3: Synthesis of tert-butyl (R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate

[0043] [ka]

[0044] 7-Bromo-3-triphenylmethylbenzo[d]oxazol-2(3H)-one (4.0 g, 8.77 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL), and n-butyllithium (2.5 M, 4.03 mL, 1.15 eq) was added under nitrogen protection at -78 °C and stirred for 30 min. (R)-t-butyl 4-methyl-1,2,3-oxazolidine-3-carboxylic acid 2,2-dioxide (2.50 g, 10.5 mmol, 1.2 eq) was added to the tetrahydrofuran at -78 °C. A solution of 10 mL of fluorouracil was added to the reaction mixture, which was then allowed to warm to 0°C and reacted for 2 hours. The reaction was confirmed to be complete by TLC, and the reaction mixture was poured into ice water to quench the reaction, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography to obtain tert-butyl (R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate (4.5 g, 8.42 mmol, 76.8% yield) as a white solid.

[0045] 1 H NMR (400 MHz, 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=8.0 Hz, 1H), 4.22 - 4.11 (m, 1H), 2.84 (br d, J=6.4 Hz, 2H), 1.58 (s, 9H), 1.16 (d, J=6.4 Hz, 3H) ppm.

[0046] Step 4: Synthesis of (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-one

[0047] [ka]

[0048] tert-Butyl (R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobenzo[d]o) at 20°C (7-oxazol-7-yl)propan-2-yl)carbamate (4.3 g, 8.04 mmol, 1 eq) was dissolved in methyl hydrochloride. The reaction was then added to an ethanol solution (4 M, 30 mL, 14.9 eq) and allowed to react for 2 hours. The completion of the reaction was confirmed by TLC and LCMS. After confirming completion of the reaction, the reaction mixture was concentrated, neutralized by adding saturated sodium bicarbonate, extracted with ethyl acetate, and concentrated to obtain a crude product, which was then suspended in 30 ml of a mixed solvent of petroleum ether:ethyl acetate = 3:1. The crude product was purified by filtration to give (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-one as a white solid (1.9 g, 4.37 mmol, 54.4% yield).

[0049] 1 H NMR (400 MHz, 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=7.2 Hz, 1H), 3.11 - 3.06 (m, 1H), 2.60 - 2.57 (m, 2H), 0.97 (d, J=6.4 Hz, 3H) ppm.

[0050] LCMS: m / z (M+H) + = 435.1.

[0051] Step 5: (R)-7-(2-(isobutylamine)propyl)-3-triphenylmethylbenzo[d]oxidase Synthesis of Sazo-2(3H)-one

[0052] [ka]

[0053] (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[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) The residue was 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 mixture at 20°C. The reaction was continued for 2 hours. After the reaction, the completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was concentrated and then washed with saturated sodium bicarbonate. The mixture was neutralized with ethyl acetate, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to give (R)-7-(2-(isobutylamine)propyl)-3-triphenylmethylbenzo[d]oxa Sazol-2(3H)-one was obtained as a yellow solid (1.70 g, 100% yield).

[0054] 1 H NMR (400 MHz, CDCl3): δ = 7.46 - 7.48 (m, 6H), 7.30 - 7.28 (m, 9H), 6.93 (d, J=7.2 Hz, 1H), 6.82 (t, J=8.0 Hz, 1H), 5.99 (d, J= 8.0 Hz, 1H), 4.13 (q, J=7.2 ppm.

[0055] LCMS: m / z (M+H) + = 491.4.

[0056] Step 6: Synthesis of (R)-7-(2-(isobutylamine)propyl)benzo[d]oxazol-2(3H)-one

[0057] [ka]

[0058] (R)-7-(2-(isobutylamine)propyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-one (1.7 g, 3.46 mmol, 1 eq) was dissolved in a mixture of 20 ml of trifluoroacetic acid and 2 ml of water. The reaction was dissolved in water and reacted at 20°C for 3 hours. The completion of the reaction was confirmed by TLC and LCMS, and the reaction solution was concentrated at 50°C. After concentrating the reaction solution, saturated sodium bicarbonate was added to neutralize the pH until it became neutral, and the solution was extracted with ethyl acetate. The organic phase was dried and concentrated, and the crude product was purified by column chromatography to obtain (R)-7-(2-(isobutylamine)propyl)benzo[d]oxazole-2(3H)-one. was obtained as a yellow solid (650 mg, 2.62 mmol, 75.5% yield).

[0059] 1 H NMR (400 MHz, CDCl3): δ = 7.08 - 7.06 (m, 1H), 6.96 - 6.93 (m, 2H), 3.25 (br d, J=5.6 Hz, 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=6.4 Hz, 3H), 0.90 (t, J=6.4 Hz, 6H) ppm.

[0060] LCMS: m / z (M+H) + = 249.2.

[0061] Step 7: Synthesis of (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0062] [ka]

[0063] (R)-7-(2-(isobutylamine)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. The reaction mixture was dissolved in 100 ml of ethyl acetate (450 mg, 3 eq) and acetic acid (450 mg, 3 eq) was added. The reaction mixture was reacted at 115°C for 24 hours. TLC and LCMS showed that 25% of the starting material remained and 50% of the product was formed. The reaction mixture was concentrated at 60°C and the crude product was purified by column chromatography to give (6S,8R)-6-(4- Bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxa Zolo[5,4-f]isoquinolin-2(3H)-one was obtained as a yellow solid (460 mg, 42.2% yield). rate).

[0064] 1 H NMR (400 MHz, CDCl3): δ = 7.59 (br s, 1H), 6.94 (br d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.4 Hz, 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=6.4 Hz, 3H), 0.74 (br d, J=6.4 Hz, 3H), 0.60 (br d, J=6.4 Hz, 3H) ppm.

[0065] LCMS: m / z (M+H) + = 450.9 Step 8: Synthesis of (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one Growth

[0066] [ka]

[0067] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (240 mg, 532 μmol, 1 eq) was reacted with N,N-difluorophenyl Dissolve in 10 ml of methylformamide and add sodium hydride (42.5 mg, 1.06 mmol, 60% purity, 2 eq) at 0°C. Next, add triphenylmethyl chloride (163 mg, 585 μmol, 1.1 eq) to the reaction solution at 0°C, slowly warm to 20°C, and react for 2 hours. Reaction by TLC and LCMS After confirming the completion of the reaction, the reaction mixture was quenched by pouring it into water, extracted with ethyl acetate, and the organic phase was dried. The mixture was concentrated and the crude product was purified by column chromatography to give (6S,8R)-6-(4-bromo-2,6-di Fluorophenyl)-7-isobutyl-8-methyl-3-triphenylmethyl-6,7,8,9-tetrahydrofuran Roxazolo[5,4-f]isoquinolin-2(3H)-one was obtained as a yellow solid (420 mg, 460 μmol, 86.5% yield).

[0068] 1H NMR (400 MHz, CDCl3): δ = 7.48 - 7.46 (m, 6H), 7.31 - 7.29 (m, 9H), 6.99 (d, J=8.4 Hz, 2H), 6.24 - 6.16 (m, 1H), 5.66 - 5.62 (m, 1H), 5.00 (s, 1H), 3.48 - 3.41 (m, 1H), 3.09 - 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=6.4 Hz, 3H), 0.66 (d, J=6.4 Hz, 3H) ppm.

[0069] LCMS: m / z (M+H) + = 695.0.

[0070] Step 9: Synthesis of 2-(3-(fluoromethyl)azetidin-1-yl)ethanol

[0071] [ka]

[0072] 3-(Fluoromethyl)azetidine hydrochloride (3 g, 23.9 mmol, 1 eq) was dissolved in tetrahydrofuran (50 mL) and 1,8-diazacycloundecene (10.9 g, 71.7 mmol, 10.8 mL, 3 eq) was added at 20°C. After stirring for 15 minutes, 2-bromoethanol (5.97 g, 47.8 mmol, 2 eq) was added and the reaction was continued for 12 hours. The completion of the reaction was confirmed by TLC, the reaction solution was adjusted to a pH of more than 9, extracted with ethyl acetate, the organic phase was dried and concentrated, and the crude product was purified by column chromatography to give 2-(3-(fluoromethyl)azetidin-1-yl)ethanol as a yellow oil (950 mg, 7.13 mmol, 29.8% yield).

[0073] 1H NMR (400 MHz, CDCl3): δ = 4.57 - 4.42 (m, 1H), 4.41 - 4.38 (m, 1H), 3.53 - 3.50 (m, 2H), 3.43 - 3.40 (m, 2H), 3.10 - 3.08 (m, 2H) 2.85 - 2.80 (m, 1H), 2.61 - 2.59 (m, 2H).

[0074] Step 10: (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidine) Synthesis of (1-phenyl-ethoxy-phenyl)-7-isobutyl-8-methyl-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0075] [ka]

[0076] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-3-triphenylmethyl-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-di-t-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 The reaction mixture was incubated at 110°C for 24 hours. The completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was concentrated and purified by column chromatography to obtain (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidin-1-yl-ethoxy-phenyl)-7-yl. Isobutyl-8-methyl-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one was obtained as a yellow solid (90 mg, 121 μmol, 36.7% yield).

[0077] 1 H NMR (400 MHz, CDCl3): δ = 7.47 - 7.46 (m, 6H), 7.26 - 7.23 (m, 9H), 6.34 (d, J=10.4 Hz, 2H), 6.23 (d, J=8.4 Hz, 1H), 5.61 (d, J=8.4 Hz, 1H), 4.95 - 4.93 (m, 1H), 4.57 (d, J=5.6 Hz, 1H), 4.45 (d, J=5.6 Hz, 1H), 3.91 (q, J=5.6 Hz, 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=6.4 Hz, 3H), 0.69 - 0.65 (m, 3H) ppm.

[0078] LCMS: m / z (M+H) + = 742.2.

[0079] Step 11: (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidine) (1-phenyl-ethoxy-phenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazo Synthesis of 2(3H)-isoquinoline-2(5,4-f)-isoquinoline (Compound 1)

[0080] [ka]

[0081] (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidin-1-yl)- (90 mg, 120.66 μmol, 1 eq) was added to trifluoroacetate. The reaction mixture was dissolved in a mixture of 1,2-difluoroacetic acid (9 mL) and water (1 mL) and reacted at 20°C for 2 hours. The completion of the reaction was confirmed by TLC and LCMS, and the reaction mixture was concentrated at 40°C, neutralized by adding saturated sodium bicarbonate, extracted with ethyl acetate, the organic phase was dried and concentrated, and the crude product was separated by silica gel thin layer chromatography to obtain (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidin-1-yl-ethoxy-phenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrofuran. Roxazolo[5,4-f]isoquinolin-2(3H)-one was obtained as a yellow solid (35 mg, 67.4 μmol, 55.8% yield, 97% purity, 89% ee).

[0082] 1H NMR (400 MHz, DMSO-d6): δ = 6.70 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 6.31 (br d, J=10.4 Hz, 2H), 5.06 (s, 1H), 4.56 (d, J=5.4 Hz, 1H), 4.44 (d, J=5.4 Hz, 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=6.4 Hz, 3H), 0.81 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H) ppm.

[0083] LCMS: m / z (M+H) + = 504.4.

[0084] Example 5: (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin 6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (compound 5)

[0085] [ka]

[0086] Step 1: Synthesis of tert-butyl (R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate

[0087] [ka]

[0088] 7-Bromo-3-triphenylmethyl-benzoxazol-2-one (100 g, 219 mmol, 1 eq) was dissolved in tetrahydrofuran (1000 mL), and n-butyllithium (2.5 M, 87.6 mL, 1 eq) was added under nitrogen protection at -78°C and stirred for 30. (R)-t-butyl 4-methyl-1,2,3-oxazolidine-3-one was added. A solution of carboxylic acid 2,2-dioxide (52.0 g, 219 mmol, 1 eq) in tetrahydrofuran (100 mL) was added to the system at -78°C, and then the temperature was naturally brought to 0°C and the reaction was allowed to proceed for 2 hours. The completion of the reaction was confirmed by TLC. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride to quench the reaction, and the mixture was extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography to give tert-butyl (R)-(1-(2- Oxo-3-triphenylmethyl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate was obtained as a yellow solid (360 g, 673 mmol, 74.9% yield).

[0089] 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 = 8.0 Hz, 1H), 5.93 (br d, J = 8.0 Hz, 1H), 4.00(s, 1H), 3.81 - 3.72 (m, 1H), 2.84 (br d, J = 6.0 Hz, 2H), 1.40 (s, 9H), 1.16 (d, J = 6.4 Hz, 3H) ppm.

[0090] Step 2: Synthesis of (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-one

[0091] [ka]

[0092] tert-Butyl (R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydro) Benzo[d]oxazol-7-yl)propan-2-yl)carbamate (240 g, 448 mmol, 1 eq) was dissolved in methanol (400 ml) and added to a solution of hydrochloric acid in methanol (6 M, 800 mL, 10.6 eq). The reaction was allowed to proceed at 0°C for 2 hours, and the completion of the reaction was confirmed by TLC. The reaction solution was concentrated and washed with saturated sodium bicarbonate. The mixture was neutralized with ethyl acetate, extracted with ethyl acetate and concentrated to give the crude product, which was suspended in petroleum ether:ethyl acetate = 1:1 and filtered to give (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-one (198 g, 455 mmol, 84.6% yield) as a yellow solid.

[0093] 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 = 8.0 Hz, 1H), 5.88 (m, 1H), 3.33 (s, J = 6.4 Hz, 1H), 2.82 - 2.65 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H) ppm.

[0094] Step 3: (R)-7-2-aminopropyl)(2,2,2-trifluoroethyl-3-triphenylmethyl Synthesis of benzo[d]oxazol-2(3H)-one

[0095] [ka]

[0096] (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazo under nitrogen protection at 20°C Dissolve 2(3H)-ol-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) in dioxane (100 mL) and react at 80° C. for 10 hours under nitrogen protection. The completion of the reaction was confirmed by TLC, and the reaction solution was concentrated and the crude product was analyzed by column chromatography. Purification by column chromatography afforded (R)-7-2-aminopropyl)(2,2,2-trifluoroethyl-3-triphenylmethylbenzo[d]oxazol-2(3H)-one as a white solid (9.00 g, 17.4 mmol, 75.7% yield).

[0097] 1 H NMR (400MHz, CDCl3): δ = 7.48 (br d, J = 7.2 Hz, 6H), 7.33 - 7.27 (m, 9H) , 6.86 (br d, J = 7.6 Hz, 1H), 6.79 - 6.73 (m, 1H), 5.95 (br d, J = 8.0 Hz, 1H) , 3.50 (s, 1H), 3.26 (br d, J = 9.3 Hz, 3H), 2.98 - 2.85 (m, 1H), 2.82 - 2.71 (m, 1H), 1.15 (br d, J = 5.6 Hz, 3H) ppm.

[0098] Step 4: Synthesis of (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

[0099] [ka]

[0100] (R)-7-(2-aminopropyl)(2,2,2-trifluoroethyl-3-triphenylmethylbenzo[d]oxazol-2(3H)-one (1.00 g, 1.94 mmol, 1 eq) and 5-bromo-2-pyridinecarboxylate The aldehyde (540 mg, 2.90 mmol, 1.5 eq) was 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. After confirming the completion of the reaction by TLC, the reaction solution was concentrated and the crude product was purified by TLC (petroleum ether:ethyl acetate=10:1) to give (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 as a yellow solid (780 mg, 1.76 mmol, 91.1% yield).

[0101] 1 H NMR (400MHz, CDCl3): δ = 8.89 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 7.84 - 7.80 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.79 - 6.74 (m, 2H), 5.09 (s, 1H), 4.13 (q, J = 7.2 Hz, 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 = 6.4 Hz, 3H) ppm.

[0102] Step 5: Synthesis of (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0103] [ka]

[0104] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinoline [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 triphenylmethyl chloride (693 mg, 2.49 mmol, 1.1 eq) was added at 20°C, and the reaction was allowed to proceed for 2 hours. The completion of the reaction was confirmed by TLC. Water was added to the reaction solution, and the reaction mixture was then cooled to room temperature. The mixture was quenched with ethyl acetate, extracted with ethyl acetate, dried, concentrated, and the crude product was purified by column chromatography to give (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethylene). To the reaction mixture was obtained (1.20 g, 1.56 mmol, 69.0% yield) of 3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one as a white solid.

[0105] 1 H NMR (400MHz, CDCl3): δ = 8.52 (s, 1H), 7.75 (dd, J1= 2.4 Hz, J2=8.4 Hz, 1H), 7.49 - 7.45 (m, 6H), 7.36 (d, J = 8.4 Hz, 1H), 7.32 - 7.27 (m, 9H), 6.39 (d , J = 8.4 Hz, 1H), 5.75 (d, J = 8.4 Hz, 1H), 4.94 (s, 1H), 3.53 - 3.42 (m, 1H), 3.29 - 3.18 (m, 1H), 3.01 (dd, J1= 4.8 Hz, J2=16.8 Hz, 1H), 2.90 (br dd, J1= 9.2 Hz, J2=15.6 Hz, 1H), 2.68 (dd, J1= 6.8 Hz, J2=16.8 Hz, 1H), 1.10 (d, J = 6.4 Hz, 3H) ppm.

[0106] Step 6: tert-Butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl) Synthesis of 3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-ylpyridin-3-ylaminoazetidine-1-carboxylate

[0107] [ka]

[0108] tert-Butyl (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethylene [(2-di-t-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 to the reaction mixture, which was then heated at 110° C. for 15 hours. The reaction was confirmed to be complete by TLC, and the reaction mixture was quenched by adding water, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography to give tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo So-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydro- Xazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carboxamide The sylate was obtained as a yellow solid (120 mg, 137 μmol, 47.2% yield).

[0109] 1 H NMR (400MHz, CDCl3): δ = 7.77 (d, J = 2.4 Hz, 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 = 8.4 Hz, 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 = 6.4 Hz, 3H) ppm.

[0110] Step 7: (6S,8R)-6-(5-(azetidin-3-amino)pyridin-2-yl)-8-methyl-7-(2,2,2- Synthesis of (trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0111] [ka]

[0112] Trifluoroacetic acid (9.00 mL) and water (1.00 mL) were added at 0 °C to prepare tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-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) was added and the mixture was allowed to react at 20° C. for 2 hours, after which TLC showed the reaction was complete. The reaction was quenched by adding water, extracted with ethyl acetate, dried, concentrated and purified to give (6S,8R)-6-(5-(azetidin-3-amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one. The compound was obtained as a yellow solid (120 mg, crude).

[0113] 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 = 4.8 Hz, 3H) ppm.

[0114] 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 (Compound 5)

[0115] [ka]

[0116] (6S,8R)-6-(5-(azetidin-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 mixed under nitrogen protection at 20 °C. μmol, 1 eq) was dissolved in N,N-dimethylformamide (1 mL) and diisopropylethylene Diamine (98.4 mg, 761 μmol, 132 uL, 5 eq) was added and the mixture was reacted at 20°C for 4 h. The completion of the reaction was monitored by LCMS. The reaction was quenched by adding water, extracted with ethyl acetate, dried and concentrated. The crude product was purified by reverse phase column and then chiral column to give (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]i. Soquinoline-2(3H)-one was obtained as a yellow solid (27.0 mg, 54.2 μmol, 35.6% yield, 97.7% purity, 100% ee).

[0117] 1 H NMR (400MHz, MeOH-d4): δ = 7.76 - 7.71 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.93 (m, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 4.52 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 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 = 7.6 Hz, 2H), 1.83 - 1.69 (m, 2H), 1.06 (d, J = 6.6 Hz, 3H) ppm.

[0118] LCMS: m / z (M+H) + = 494.3.

[0119] Example 7: (6S,8R)-6-(5-(((S)-1-(3-fluoropropane)pyrrolidin-3-yl)oxy)pyrimidin-3-yl Lysine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroxa Zolo[5,4-f]isoquinoline-2(3H)-one (compound 7)

[0120] [ka]

[0121] Step 1: tert-Butyl (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethylene) Synthesis of ethyl-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate

[0122] [ka]

[0123] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (150 mg, 219 μmol, 1 eq) and tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (102 mg, 547 μmol, 2.5 eq) were dissolved in toluene (20 mL), followed by addition of RockPhos Pd G3 (18.3 mg, 21.9 μmol, 0.1 eq) and cesium carbonate (214 mg, 657 μmol, 3 eq), and the reaction mixture was reacted at 115° C. for 15 hours. The completion of the reaction was confirmed by TLC, and the reaction mixture was quenched by adding water to the reaction mixture, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography to give tert-butyl (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethylene) To the resultant mixture was obtained 120 mg (138 μmol), 31.5% yield of 1,3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate as a yellow solid.

[0124] 1 H NMR (400MHz, CDCl3): δ = 8.02 (d, J = 2.8 Hz, 1H), 7.39 (d, J = 7.2 Hz, 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 = 8.4 Hz, 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 (br dd, J1= 8.8Hz, J2= 15.6 Hz, 1H), 2.59 (dd, J1= 6.4 Hz, J2=16.8 Hz, 1H), 2.15 - 2.01 (m, 2H), 1.95 - 1.81 (m, 2H), 1.40 (s, 9H), 1.02 (d, J = 6.4 Hz, 3H) ppm.

[0125] Step 2: (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]isoquinoline-2(3H)- Synthesis of Non

[0126] [ka]

[0127] Dissolve trifluoroacetic acid (1.54 g, 13.4 mmol, 997 uL, 87.3 eq) in dichloromethane (2 mL) at 0 °C. tert-Butyl (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoromethyl) (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 was added to the reaction mixture (120 mg, 154 μmol, 1 eq) and reacted at 20°C for 2 hours. The completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was quenched by adding water, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by silica gel thin layer chromatography to obtain (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 as a yellow solid (105 mg, crude product).

[0128] 1 H NMR (400 MHz, DMSO-d6): δ = 8.13 (d, J = 2.8 Hz, 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 = 6.4 Hz, 3H) ppm.

[0129] LCMS: m / z (M+H) + = 449.2.

[0130] Step 3: (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-tetrahydrooxazo Synthesis of 2-[5,4-f]isoquinolin-2(3H)-one (Compound 7)

[0131] [ka]

[0132] At 20°C, under nitrogen protection, (6S,8R)-8-methyl-6-(5-((S)-pyrrolidine-3-oxy)pyridine-2-yl

[0113] N,N-Dimethylformamide (2 mL) was added to 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) to obtain a 3-fluoro-1-iodopropane (35.2 mg, 187 μmol, 1 eq)-difluoroacetate (3,3-difluorophenyl)-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) in Diamine (121 mg, 936 μmol, 163 uL, 5 eq) was added and the mixture was reacted at 20° C. for 4 hours. The completion of the reaction was monitored by LCMS, and the reaction was quenched by adding water, extracted with ethyl acetate, dried and concentrated. The crude product was purified by reverse phase column to give (6S,8R)-6-(5-(((S)-1-(3-furan)-2-ylbenzenesulfonyl ether. (fluoropropane)pyrrolidin-3-yl)oxy)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoropropane fluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one was obtained as a white solid (10.5 mg, 19.8 μmol, 10.6% yield, 96% purity, 100% ee).

[0133] 1H NMR (400MHz, MeOH-d4): δ = 8.05 (d, J = 2.8 Hz, 1H), 7.40 - 7.30 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.54 (t, J = 6.0 Hz, 1H), 4.42 (t, J = 6.0 Hz, 1H), 3.53 - 3.48 (m, 1H), 3.40 (br d, J = 6.0 Hz, 1H), 3.10 (dd, J1= 4.8 Hz, J2=16.8 Hz, 1H), 3.02 - 2.87 (m, 4H), 2.78 (dd, J1= 6.2 Hz, J2=16.8 Hz, 1H), 2.68 - 2.58 (m, 2H), 2.56 - 2.49 (m, 1H), 2.38 (dt, J1= 7.6 Hz , J2=13.6 Hz, 1H), 1.99 - 1.84 (m, 3H), 1.29 (br s, 1H), 1.12 (d, J = 6.4 Hz, 3H) ppm.

[0134] LCMS: m / z (M+H) + = 509.4.

[0135] Example 8: (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (compound 8)

[0136] [ka]

[0137] Step 1: tert-Butyl (6S,8R)-6-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxy-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate Synthesis of tetracycline

[0138] [ka]

[0139] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)- Non (300 mg, 417 μmol), and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxime The xylate (165.33 mg, 833.88 μmol) was dissolved in toluene (9 mL), and cesium carbonate (272 mg, 834 μmol) and [(2-di-t-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (34.96 mg, 41.69 μmol) were added. The mixture was protected with nitrogen gas and reacted at 110°C for 24 hours. The reaction was analyzed by LCMS. After confirming the completion of the reaction, the reaction solution was concentrated and then purified with a silica gel column to obtain tert-butyl (6S,8R)-6-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxy-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydroisoquinolino[5,4-f]oxazol-6-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (120 mg, 143 μmol, yield 34.4%).

[0140] 1 H NMR (400MHz, CDCl3): δ = 7.41 - 7.37 (m, 6H), 7.24 - 7.19 (m, 9H), 6.17 (d, J = 8.5 Hz, 1H), 5.77 (d, J = 10.5 Hz, 2H), 5.56 (d, J = 8.5 Hz, 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 = 6.4 Hz, 3H) ppm. LCMS: m / z 837.3 [M+H] + .

[0141] Step 2: Synthesis of (6S,8R)-6-(2,6-difluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline 2(3H)-one

[0142] [ka]

[0143] tert-Butyl 6-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxy-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoxid (6-phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (300mg (6S,8R)-6-(2,6-difluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (350 mg, crude product).

[0144] LCMS: m / z 495.0 [M+H] + .

[0145] Step 3: (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrafluoroethane Synthesis of hydroxazolo[5,4-f]isoquinolin-2(3H)-one

[0146] [ka]

[0147] (6S,8R)-6-(2,6-difluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline Phosphorus 2(3H)-non (300 mg, 606.73 μmol) and 1-iodo-3-fluoroethane (211.09 mg, 1.21 mmol) were dissolved in N,N-dimethylformamide (15 mL), followed by addition of N,N-diisopropylethylamine. The reaction was allowed to proceed at 20°C for 2 hours, and the completion of the reaction was confirmed by LCMS. Extract with ethyl acetate, wash the organic phase with brine three times, concentrate, and then purify with a silica gel column. (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one was obtained (95 mg, 175.76 μmol, yield 28.9%).

[0148] LCMS: m / z 541.3 [M+H] + .

[0149] Step 4: (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrafluoroethane Isolation of hydroxazolo[5,4-f]isoquinolin-2(3H)-one (compound 8)

[0150] [ka]

[0151] (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrofuran Chiral separation of oxazolo[5,4-f]isoquinolin-2(3H)-one gave (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptan-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%). 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, 4H), 3.33 - 3.25 (m, 1H), 3.05 (dd, J=4.9, 16.4 ppm.

[0152] 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-tetrafluoroethane Hydroxazolo[5,4-f]isoquinoline-2(3H)-one (Compound 9)

[0153] [ka]

[0154] Step 1: (R)-7-(2-((3-((t-butylphenylsilyl)oxy)-2,2-difluoropropyl)a Synthesis of (amino)propyl-3-triphenylbenzo[d]oxazol-2(3H)-one

[0155] [ka]

[0156] Subsequent steps: (R)-7-(2-((3-((t-butylphenylsilyl)oxy)-2,2-difluoropropyl)amino)propionyl can be prepared by steps similar to those in Examples 1-8 and / or by conventional reaction steps in the art. Compound 9 was synthesized starting from 3-(3H)-3-triphenylbenzo[d]oxazol-2(3H)-one. .

[0157] 1 H NMR: (400 MHz, ACETONITRILE-d3)δ = 11. 6 (s, 1H), 9.16 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.60 (br d, J = 8.0 Hz, 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 = 6.4 Hz, 3H) ppm.

[0158] As in the synthetic routes of Examples 1-9, the corresponding reactants and synthetic methods known to those skilled in the art The following example compounds were synthesized by selecting the above. Specifically, the compound of Example 9, Step 1, i.e. The following Examples 13-15 were synthesized using the compound of Example 5, Step 3, i.e., "(R)-7-(2-((3-((t-butylphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-3-triphenylbenzo[d]oxazol-2(3H)-one" as a raw material; As examples, the following Examples 10-12, 16, 18, and 25 were synthesized; the compound of Example 1, Step 4, i.e., "(R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazole-2(3H)-one The following Example 20 was synthesized using " as a starting material.

[0159] 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)

[0160] [ka]

[0161] 1 H NMR: (400 MHz, CDCl3) δ = 8.03 - 7.74 (m, 1H), 6.79 (s, 1H), 6.67 - 6.60 (m, 1H), 5.99 (d, J = 11.0 Hz, 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 - 3.95 (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), 2.78 (dd, J = 4.4, 16.4 Hz, 1H), 2.67 - 2.56 (m, 2H), 1.83 - 1.71 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H) ppm.

[0162] LCMS: m / z (M+H)+ = 529.4 Example 11: (6S,8R)-6-(2,6-difluoro-4-(((S)-1-(3-fluoropropane)pyrrolidine-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)

[0163] [ka]

[0164] 1H NMR: (400MHz, ACETONITRILE-d3) δ = 6.81 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 6.44 (br d, J = 11.2 Hz, 2H), 5.28 (s, 1H), 4.79 (br s, 1H), 4.54 (t, J = 6.0 Hz, 1H), 4.42 (t, J = 6.0 Hz, 1H), 3.56 - 3.46 (m, 1H), 3.42 - 3.25 (m, 1H), 3.06 (br dd, J = 4.8, 16.6 Hz, 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 = 6.4 Hz, 3H) ppm.

[0165] Example 12: (6S,8R)-6-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) (2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (compound 12)

[0166] [ka]

[0167] 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 = 10.4 Hz, 2H), 5.29 - 5.22 (m, 1H), 4.72 (m, J = 6.0 Hz, 1H), 4.56 (t, J = 6.0 Hz, 1H), 4.44 (t, J = 6.0 Hz, 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 = 7.2 Hz, 2H), 1.83 - 1.70 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H).

[0168] LCMS: m / z (M+H)+ = 530.2 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)

[0169] [ka]

[0170] 1 H NMR: (400 MHz, CHLOROFORM-d) δ = 8.36 (br d, J = 1.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.40 (d, J = 10.4 Hz, 2H), 5.18 (s, 1H), 4.89 (br s, 1H), 4.61 (t, J = 5.6 Hz, 1H), 4.50 (t, J = 5.6 Hz, 1H), 3.77 - 3.61 (m, 3H), 3.29 - 2.92 (m, 7H), 2.91 - 2.75 (m, 3H), 2.54 - 2.38 (m, 1H), 2.24 - 2.01 (m, 3H), 1.10 (d, J = 6.6 Hz, 3H) ppm.

[0171] Example 14: (6S,8R)-7-(2,2-difluoro-3-hydroxypropyl)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (compound 14)

[0172] [ka]

[0173] 1 H NMR: (400 MHz, ACETONITRILE-d3) δ = 6.78 (br d, J = 6.6 Hz, 1H), 6.67 - 6.44 (m, 1H), 6.07 - 5.84 (m, 2H), 5.94 (br d, J = 11.4 Hz, 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 = 3.8 Hz, 1H) ppm.

[0174] 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)

[0175] [ka]

[0176] 1 H NMR: (400MHz, ACETONITRILE-d3) δ = 6.85 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 5.95 (d, J = 11.5 Hz, 2H), 5.15 (s, 1H), 4.56 (t, J = 5.6 Hz, 1H), 4.44 (t, J = 5.6 Hz, 1H), 4.05 (t, J = 7.5 Hz, 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 = 6.5 Hz, 3H).

[0177] 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)fluoro (phenoxy)ethyl)amino)-N,N-dimethyl-but-2-enamide (compound 16)

[0178] [ka]

[0179] 1 H NMR: (400 MHz, ACETONITRILE-d3) δ = 6.81 (d, J = 8.1 Hz, 1H), 6.75 - 6.65 (m, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.56 - 6.46 (m, 3H), 5.29 (s, 1H), 4.02 (t, J = 5.3 Hz, 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 = 7.0 Hz, 2H), 1.07 (d, J = 6.6 Hz, 3H) ppm.

[0180] LCMS: m / z 569.4 [M+H] + .

[0181] Example 18: (6S,8R)-6-(2,6-difluoro-4-(3-((3-fluoropropyl)amino)azetidin (1-phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (compound 18)

[0182] [ka]

[0183] 1H NMR: (400MHz, ACETONITRILE-d3) δ = 6.81 (br d, J = 8.0 Hz, 1H), 6.61 (br d, J = 7.9 Hz, 1H), 5.95 (d, J = 11.6 Hz, 2H), 5.22 (s, 1H), 4.56 (t, J = 5.9 Hz, 1H), 4.44 (br t, J = 5.7 Hz, 1H), 4.03 (br t, J = 7.3 Hz, 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 = 6.8 Hz, 2H), 1.86 - 1.71 (m, 3H), 1.06 (d, J = 6.6 Hz, 3H).

[0184] Example 20: (6S,8R)-6-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) (1-fluorocyclopropyl)amino)phenyl)-7-((1-fluorocyclopropyl)methyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 20)

[0185] [ka]

[0186] 1H NMR: (400 MHz, ACETONITRILE-d3) δ = 8.12 (s, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.10 (d, J = 11.6 Hz, 2H), 5.38 (br d, J = 7.3 Hz, 1H), 5.12 (s, 1H), 4.55 (t, J = 6.1 Hz, 1H), 4.43 (t, J = 6.0 Hz, 1H), 4.08 - 3.97 (m, 1H), 3.75 (br d, J = 6.3 Hz, 3H), 3.12 - 2.99 (m, 2H), 2.97 - 2.90 (m, 2H), 2.83 - 2.70 (m, 2H), 2.62 (t, J = 7.1 Hz, 2H), 1.78 - 1.66 (m, 2H), 1.02 (d, J = 6.6 Hz, 3H), 0.97 - 0.86 (m, 2H), 0.62 - 0.40 (m, 2H) ppm.

[0187] Example 25: (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methyl (2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (compound 25)

[0188] [ka]

[0189] Step 1: Synthesis of (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

[0190] [ka]

[0191] The 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) and trifluoroacetic acid (6.24 g, 54.7 mmol) were dissolved in toluene (15 mL) and incubated at 110 °C under nitrogen. The reaction was allowed to proceed under protection for 48 hours. The completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated and then purified by column chromatography to obtain (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-nonaphthalene. The compound was obtained as a white solid (4.35 g, 9.23 mmol, 84.4% yield).

[0192] LCMS: m / z 470.0 [M+H] + .

[0193] 1 H NMR (400 MHz, DMSO-d6) δ = 11.53 (s, 1 H), 7.23 (d, J=1.75 Hz, 1 H), 6.94 - 7.11 (m, 1 H), 6.82 (d, J=8.00 Hz, 1 H), 6.68 (d, J=8.13 Hz, 1 H), 6.54 (d, J=8.13 Hz, 1 H), 5.28 - 5.52 (m, 1 H), 3.82 - 3.91 (m, 3 H), 3.27 - 3.41 (m, 2 H), 2.77 - 3.02 (m, 2 H), 2.68 (m, J=16.70, 7.30 Hz, 1 H), 1.02 (d, J=6.50 Hz, 3 H) ppm.

[0194] Step 2: Synthesis of (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0195] [ka]

[0196] (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (2.77g, 5.88mmol) was dissolved in N,N-dimethylformamide (25mL), and sodium hydride (353mg, 8.82mmol) was added under nitrogen protection at 0℃, followed by triphenylchloromethane (1.64g, 5.88mmol), and the reaction solution was reacted at 25℃ for 2 hours. The completion of the reaction was confirmed by TLC. The reaction solution was quenched by adding a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated saline, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to give (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl. Chil-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one is a yellow solid (3.75 g, 5.26 mmol, 89.4% yield).

[0197] LCMS: m / z 712.2 [M+H] + .

[0198] 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.18 - 7.42 (m, 15 H), 6.92 - 6.96 (m, 1 H), 6.88 (dd, J=8.13, 1.75 Hz, 1 H), 6.70 (d, J=8.25 Hz, 1 H), 6.14 (d, J=8.63 Hz, 1 H), 5.55 - 5.66 (m, 1 H), 5.23 (s, 1 H), 3.76 (s, 3 H), 3.35 - 3.48 (m, 1 H), 2.89 - 3.04 (m, 2 H), 2.64 - 2.79 (m, 1 H), 2.61 (br d, J=6.25 Hz, 1 H), 0.97 (d, J=6.63 Hz, 3H) ppm.

[0199] Step 3: (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-meth Synthesis of (2,2,2-trifluoroethyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0200] [ka]

[0201] (6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (2 g, 2.80 mmol), 1-(3-fluoropropyl)-3-aminoazetidine (1.41 g, 3.92 mmol), carbonate Cesium (2.74 g, 8.41 mmol), [(2-di-t-butylphosphino-3-methoxy-6-methyl-2,4,6- [triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (118 mg, 140 umol) was dissolved in toluene (20 mL) and reacted at 110°C under nitrogen protection for 12 hours. The reaction was monitored for completion by LCMS. The mixture was concentrated and purified by column chromatography to give (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxyphenyl phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrafluoroethylene Trahydroxazolo[5,4-f]isoquinolin-2(3H)-one was obtained as a yellow solid (1 g, 1.31 mmol, 46.7% yield).

[0202] LCMS: m / z 764.3 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.18 (br d, J=2.38 Hz, 15 H), 6.58 (d, J=8.25 Hz, 1 H), 6.13 - 6.25 (m, 1 H), 5.97 - 6.04 (m, 1 H), 5.92 (dd, J=8.25, 2.13 Hz, 1 H), 5.50 - 5.65 (m, 1 H), 5.14 - 5.18 (m, 1 H), 4.48 (t, J=5.94 Hz, 1 H), 4.36 (t, J=5.94 Hz, 1 H), 3.90 (br d, J=6.75 Hz, 1 H), 3.61 - 3.79 (m, 6 H), 3.44 (br d, J=5.50 Hz, 1 H), 3.00 - 3.29 (m, 1 H), 2.87 - 3.00 (m, 2 H), 2.79 (br d, J=6.13 Hz, 2 H), 2.49 - 2.59 (m, 3 H), 1.64 - 1.73 (m, 2 H), 0.97 (d, J=6.50 Hz, 3 H) ppm.

[0203] Step 4: (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-meth Synthesis of (2,2,2-trifluoroethyl)-8-methyl-7-(2,2,2-trifluorophenyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 25)

[0204] [ka]

[0205] Trifluoroacetic acid (15.4 g, 135 mmol) and (6S,8R)-6-(4-((1-(3-fluoropropyl)azepam) (3H)-thiidine-3-yl)amino)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)- The reaction mixture was reacted at 20°C under nitrogen protection for 1 hour. The completion of the reaction was confirmed by MS. The mixture was concentrated, adjusted to pH = 7 with sodium hydrochloride, extracted with water and ethyl acetate, and the organic phase was concentrated. The crude product was purified by column chromatography, and then chiral separation was performed by SFC to obtain (6S,8R)-6-(4-((1-(3-fluoropropyl)azetate. (300 mg, 571 umol, 43.7% yield) was obtained as a yellow solid.

[0206] LCMS: m / z 522.2 [M+H] + .

[0207] 1H NMR (400 MHz, ACETONITRILE-d3) δ = 6.79 (d, J=8.13 Hz, 1 H), 6.44 - 6.59 (m, 2 H), 6.19 (d, J=2.00 Hz, 1 H), 5.97 (dd, J=8.32, 2.06 Hz, 1 H), 5.31 (s, 1 H), 4.75 (br d, J=7.00 Hz, 1 H), 4.52 (t, J=6.07 Hz, 1 H), 4.40 (t, J=6.07 Hz, 1 H), 3.92 - 4.09 (m, 1 H), 3.79 (s, 3 H), 3.68 (m, J=3.25, 2.13 Hz, 2 H), 3.43 - 3.54 (m, 1 H), 3.17 - 3.30 (m, 1 H), 2.87 - 3.01 (m, 2 H), 2.76, (m, J=6.38 Hz, 2 H), 2.61 - 2.67 (m, 1 H), 2.51 (t, J=7.00 Hz, 2 H), 1.63 - 1.76 (m, 2 H), 1.04 (d, J=6.50 Hz, 3 H) ppm.

[0208] 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)

[0209] [ka]

[0210] Step 1: Synthesis of tert-butyl (R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate

[0211] [ka]

[0212] 7-Bromo-3-triphenylmethyl-benzoxazole-2-one (100 g, 219 mmol, 1 eq) was dissolved in tetrahydrofuran (1000 mL), and n-butyllithium (2.5 M, 87.6 mL, 1 eq) was added under nitrogen protection at -78 °C and stirred for 30 minutes. A solution of tert-butyl (R)-4-methyl-1,2,3-oxythiazolidine-3-carboxylate-2,2-dioxide (52.0 g, 219 mmol, 1 eq) in tetrahydrofuran (100 mL) was added to the system at -78 °C, and the system was allowed to naturally warm to 0 °C and react for 2 hours. The completion of the reaction was confirmed by TLC, and the reaction solution was poured into a saturated aqueous ammonium chloride solution to quench it, and the mixture was stirred at 100 °C for 2 hours. The crude product was purified by column chromatography to give tert- Butyl (R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobenzo[d]oxazol-7-yl)propan-2-yl)carbamate was obtained as a yellow solid (360 g, 673 mmol, Yield: 74.9%)

[0213] 1 H NMR (400 MHz, 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 = 8.0 Hz, 1H), 5.93 (br d, J = 8.0 Hz, 1H), 4.00 (s, 1H), 3.81 - 3.72 (m, 1H), 2.84 (br d, J = 6.0 Hz, 2H), 1.40 (s, 9H), 1.16 (d, J = 6.4 Hz, 3H) ppm.

[0214] Step 2: Synthesis of (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-one

[0215] [ka]

[0216] 0°C, under nitrogen protection, tert-butyl (R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobenzamide) Benzo[d]oxazol-7-yl)propan-2-yl)carbamate (240 g, 448 mmol, 1 eq) was dissolved in methanol (400 ml), and then it was added to a solution of hydrochloric acid in methanol (6 M, 800 mL, 10.6 eq). The reaction was carried out at 0°C for 2 hours, and the completion of the reaction was confirmed by TLC. The reaction solution was concentrated and saturated with hydrogen carbonate. The mixture was neutralized with sodium, extracted with ethyl acetate and concentrated to obtain a crude product, which was suspended in petroleum ether:ethyl acetate = 1:1, filtered and purified as (R)-7-(2-aminopropyl)-3-triphenylmethyl. Benzo[d]oxazol-2(3H)-one was obtained as a yellow solid (198 g, 455 mmol, 84.6% yield).

[0217] 1 H NMR (400 MHz, 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 = 8.0 Hz, 1H), 5.88 (m, 1H), 3.33 (s, J = 6.4 Hz, 1H), 2.82 - 2.65 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H) ppm.

[0218] Step 3: (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)-3-triphenylmethyl Synthesis of methylbenzo[d]oxazol-2(3H)-one

[0219] [ka]

[0220] Under nitrogen protection at 20°C, (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazole-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 reacted for 10 hours under nitrogen protection at 80°C. The completion of the reaction was confirmed by TLC, and the reaction solution was concentrated and the crude product was analyzed by column chromatography. Purification by column chromatography gave (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-one as a white solid (9.00 g, 17.4 mmol, 75.7% yield).

[0221] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.48 (br d, J = 7.2 Hz, 6H), 7.33 - 7.27 (m, 9H), 6.86 (br d, J = 7.6 Hz, 1H), 6.79 - 6.73 (m, 1H), 5.95 (br d, J = 8.0 Hz, 1H), 3.50 (s, 1H), 3.26 (br d, J = 9.3 Hz, 3H), 2.98 - 2.85 (m, 1H), 2.82 - 2.71 (m, 1H), 1.15 (br d, J = 5.6 Hz, 3H) ppm.

[0222] Step 4: Synthesis of (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

[0223] [ka]

[0224] (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-one (1.00 g, 1.94 mmol, 1 eq) and 5-bromo-2-pyridinecarbamates. Boxaldehyde (540 mg, 2.90 mmol, 1.5 eq) was 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. After confirming the completion of the reaction by TLC, the reaction solution was concentrated and the crude product was purified by TLC (petroleum ether:ethyl acetate=10:1) to give (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 as a yellow solid (780 mg, 1.76 mmol, yield 91.1%).

[0225] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.89 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 7.84 - 7.80 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.79 - 6.74 (m, 2H), 5.09 (s, 1H), 4.13 (q, J = 7.2 Hz, 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 = 6.4 Hz, 3H) ppm .

[0226] Step 5: Synthesis of (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0227] [ka]

[0228] (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) and the solution was cooled to 0° C. with sodium hydride (181 mg, 4.52 After adding triphenylmethyl chloride (693 mg, 2.49 mmol, 60% purity, 2 eq) at 20°C, the reaction was continued for 2 hours. The completion of the reaction was confirmed by TLC. The mixture was quenched with the addition of (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trimethyl-1,3-dihydro-2,4-trimethyl-1H-pyridin-2-yl)-1H-pyridin-2-yl, extracted with ethyl acetate, dried and concentrated, and the crude product was purified by column chromatography to give Fluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one was obtained as a white solid (1.20 g, 1.56 mmol, 69.0% yield).

[0229] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.52 (s, 1H), 7.75 (dd, J1= 2.4 Hz, J2=8.4 Hz, 1H), 7.49 - 7.45 (m, 6H), 7.36 (d, J = 8.4 Hz, 1H), 7.32 - 7.27 (m, 9H), 6.39 (d, J = 8.4 Hz, 1H), 5.75 (d, J = 8.4 Hz, 1H), 4.94 (s, 1H), 3.53 - 3.42 (m, 1H), 3.29 - 3.18 (m, 1H), 3.01 (dd, J1= 4.8 Hz, J2=16.8 Hz, 1H), 2.90 (br dd, J1= 9.2 Hz, J2=15.6 Hz, 1H), 2.68 (dd, J1= 6.8 Hz, J2=16.8 Hz, 1H), 1.10 (d, J = 6.4 Hz, 3H) ppm.

[0230] Step 6: tert-Butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl) Synthesis of 3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-ylpyridin-3-ylaminoazetidine-1-carboxylate

[0231] [ka]

[0232] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-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 the solution was added with [(2-di-t-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) was added and the reaction mixture was reacted at 110°C for 15 hours. After confirming completion of the reaction, the reaction mixture was quenched by adding water, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography to give tert-butyl 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carboxylate. The carboxylate was obtained as a yellow solid (120 mg, 137 umol, 47.2% yield).

[0233] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.77 (d, J = 2.4 Hz, 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 = 8.4 Hz, 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 = 6.4 Hz, 3H) ppm.

[0234] Step 7: (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]isoquinoline-2(3H)- Synthesis of Non

[0235] [ka]

[0236] Trifluoroacetic acid (9.00 mL) and water (1.00 mL) were added to tert-butyl 3-((6-((6S,8R)-8-methylphenyl)-2-(2-phenylpropanediol) at 0 °C. ethyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-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), and the mixture was reacted at 20° C. for 2 hours. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched by adding water and extracted with ethyl acetate. , dried and concentrated to give (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 as a yellow solid (120 mg, crude).

[0237] 1 H NMR (400 MHz, 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 = 4.8 Hz, 3H) ppm.

[0238] 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

[0239] [ka]

[0240] (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 mixed at 20°C under nitrogen protection. umol, 1 eq) in N,N-dimethylformamide (1 mL) and diisopropylethylenediamine Mine (98.4 mg, 761 umol, 132 uL, 5 eq) was added and the mixture was reacted at 20°C for 4 hours. The completion of the reaction was monitored by LCMS. The reaction was quenched by adding water, extracted with ethyl acetate, dried and concentrated. The crude product was purified by reverse phase column (column:3_Phenomenex Luna C18 75*30mm*3um;mobilephase: [water (0.05%NH3H2O ​​+10mM NH4HCO3)-ACN]; B%: 45%-75%,30min) and further separated by chiral column (column: REGIS (R,R) WHELK-O1 (250mm*25mm, 10 um) ; mobile phase: 0.1% NH3H2O ​​ETOH ; B%: 30%-30%, 0 min), (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoro The crude product was obtained as a yellow solid (27.0 mg, 54.2 umol, 35.6% yield, 97.7% purity).

[0241] LCMS: m / z 494.3 [M+H] + .

[0242] 1 H NMR (400 MHz, CD3OD) δ = 7.76 - 7.71 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.93 (m, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 4.52 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 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 = 7.6 Hz, 2H), 1.83 - 1.69 (m, 2H), 1.06 (d, J = 6.6 Hz, 3H) ppm.

[0243] 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)

[0244] [ka]

[0245] Step 1: (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluorophenyl)- Synthesis of (fluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0246] [ka]

[0247] The compound (R)-7-(2-(2,2,2-trifluoroethyl)amino)propyl)benzo[d]oxazole-2(3H)-one (500 mg, 1.82 mmol), 5-bromo-3-fluoro-pyridine-2-formaldehyde (390 mg, 1.91 mmol), and trifluoroacetic acid (1.04 g, 9.12 mmol) were dissolved in toluene (10 mL) and heated at 90° C. in nitrogen. The reaction was carried out under nitrogen protection for 12 hours. The completion of the reaction was confirmed by LCMS. The reaction solution was concentrated, the pH was adjusted to 7-8, and the solution was extracted with water and ethyl acetate. The organic phase was washed with saturated saline, dried, and concentrated. The product was then purified by column chromatography to give (6S,8R)-6-(5-bromo-3-fluoropyridine-2- To the resultant mixture was obtained (605 mg, 1.22 mmol, 66.8% yield) of 7-(2,2,2-trifluoroethyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one as a yellow solid.

[0248] LCMS: m / z 461.8 [M+H] + .

[0249] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.20 - 8.50 (m, 2 H) 7.61 (dd, J=9.01, 1.88 Hz, 1 H) 6.80 (d, J=8.00 Hz, 1 H) 6.65 (d, J=8.00 Hz, 1 H) 5.37 (s, 1 H) 3.56 - 3.68 (m, 1 H) 3.23 - 3.31 (m, 1 H) 2.88 - 3.13 (m, 2 H) 2.67 (dd, J=17.13, 8.25 Hz, 1 H) 1.07 - 1.18 (m, 3 H) ppm.

[0250] Step 2: (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trimethylphenyl)-2-propanediol Synthesis of fluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0251] [ka]

[0252] (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethylene (ethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (600 mg, 1.21 mmol) was dissolved in N,N-dimethylformamide (12 mL), sodium hydride (58 mg, 1.45 mmol) was added under nitrogen protection at 0°C, and the mixture was stirred for 30 minutes, followed by triphenylchloromethane (336 mg, 1.21 mmol). The reaction mixture was reacted at 20°C for 30 minutes. The completion of the reaction was confirmed by LCMS. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated saline, dried, and concentrated. The crude product was purified by column chromatography to give (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenyl Methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one is a white solid The compound was obtained as a 5'-mercaptopropyl ether (754 mg, 991 umol, yield 82.1%).

[0253] LCMS: m / z 704 [M+H] + .

[0254] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.27 (d, J=1.63 Hz, 1 H), 7.49 (dd, J=9.01, 1.88 Hz, 1 H), 7.37 - 7.43 (m, 6 H), 7.18 - 7.22 (m, 9 H), 6.21 (d, J=8.50Hz, 1 H), 5.67 (d, J=8.38 Hz, 1 H), 5.19 (s, 1 H), 3.48 - 3.69 (m, 1 H), 3.06 - 3.19 (m, 1 H), 2.80 - 2.97 (m, 2 H), 2.54 (dd, J=17.13, 8.25 Hz, 1 H), 1.02 (d, J=6.75 Hz, 3 H) ppm.

[0255] 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-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0256] [ka]

[0257] (6S,8R)-6-(5-bromo-3-fluoropyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethylene [(2-di-t-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (44.1 mg, 52.6 umol) was dissolved in toluene (10 mL) and cooled to 110° C. under nitrogen protection. The reaction was allowed to proceed for 12 hours. The completion of the reaction was monitored by LCMS. It was concentrated and purified by column chromatography to give (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetate. (3H)-pyridin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one is pale yellow. Obtained as a yellow solid (163 mg, 188 umol, 35.8% yield).

[0258] LCMS: m / z 754.1 [M+H] + .

[0259] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.57 (d, J=1.88 Hz, 1 H), 7.36 - 7.41 (m, 6 H), 7.21 (s, 9 H), 7.16 (s, 1 H), 6.41 (dd, J=11.57, 2.31 Hz, 1 H), 6.23 (d, J=8.50 Hz, 1 H) ,5.64 (d, J=8.50 Hz, 1 H), 5.12 (s, 1 H), 4.31 - 4.53 (m, 2 H), 4.09 - 4.19 (m, 1 H), 3.93 - 4.00 (m, 1 H), 3.62 - 3.68 (m, 2H), 3.00 - 3.14 (m, 1 H), 2.78 - 2.98 (m, 4 H), 2.46 - 2.60 (m, 3 H), 1.65 (s, 2 H), 1.02 (d, J=6.63 Hz, 3 H) ppm.

[0260] 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

[0261] [ka]

[0262] Trifluoroacetic acid (2.02 g, 17.6 mmol) was dissolved in water (0.05 mL), and the solution was added to (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (120 mg, 138 umol) and reacted at 20°C for 5 hours under nitrogen protection. The completion of the reaction was confirmed by LCMS. The mixture was concentrated, the pH was adjusted to 7-8, and water and Extraction with ethyl acetate was performed, and the organic phase was washed with saturated saline, dried over sodium sulfate, and concentrated. The prep-HPLC spectrum of the crude product showed (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-1,3-difluorophenyl-2,4-difluorophenyl ... The resulting mixture was treated with ethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one as a yellow solid (70 mg, 124.27 umol).

[0263] LCMS: m / z 511.2 [M+H] +.

[0264] 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

[0265] [ka]

[0266] (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin (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 was chiral separated to give (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. The resulting mixture was fluoromethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (42.7 mg, 83.5 umol, 61.0% yield).

[0267] 1 H NMR (400 MHz, ACETONITRILE-d3) δ = 7.56 - 7.59 (m, 1 H), 6.82 (d, J=8.00 Hz, 1 H), 6.61 - 6.67 (m, 2 H), 5.28 (s, 1 H), 5.14 - 5.19 (m, 1 H), 4.36 - 4.54 (m, 2 H), 3.93 - 4.02 (m, 1 H), 3.57 - 3.71 (m, 3 H), 3.27 - 3.40 (m, 1 H), 2.83 - 3.01 (m, 2 H), 2.76 - 2.82 (m, 2 H), 2.63 (d, J=9.01 Hz, 1 H), 2.50 (t, J=7.00 Hz, 2 H), 1.61 - 1.76 (m, 2 H), 1.06 (d, J=6.75 Hz, 3 H) ppm.

[0268] Example 28: (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-methyl (2,2,2-trifluoroethyl)-6,7,8,9-tetrahydropyridin-2-yl Roxazolo[5,4-f]isoquinoline-2(3H)-one (compound 28)

[0269] [ka]

[0270] Step 1: (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-triphenylphosphine) Synthesis of (fluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0271] [ka]

[0272] (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 then trifluoroacetic acid (1.04 g, 9.12 mmol) was added. The reaction was carried out at 90°C for 12 hours. The completion of the reaction was confirmed by LCMS, and the reaction solution was concentrated and then purified with a 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%).

[0273] Step 2: (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trimethylpyridin-2-yl)- Synthesis of fluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0274] [ka]

[0275] (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethylene) (ethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (700 mg, 1.48 mmol) was dissolved in N,N-dimethylformamide (14 mL). Sodium hydride (71.1 mg, 1.78 mmol, purity 60%) was added at 0°C. After stirring for 30 minutes, triphenylmethyl chloride (371 mg, 1.33 mmol) was added, the temperature was raised to 20°C, and the reaction was carried out for 2 hours. The completion of the reaction was confirmed by LCMS. The reaction solution was washed with ice water. The mixture was quenched with ethyl acetate and extracted with ethyl acetate. The organic phase was washed with saturated saline three times, concentrated, and purified with a silica gel column to give (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (750 mg, 1.05 mmol, yield 70.8%).

[0276] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.12 (d, J = 1.9 Hz, 1H), 7.54 - 7.40 (m, 6H), 7.32 - 7.26 (m, 9H), 6.28 (d, J = 8.5 Hz, 1H), 5.73 (d, J = 8.4 Hz, 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 = 6.6 Hz, 3H) ppm.

[0277] Step 3: (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-meth xypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl- Synthesis of 6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0278] [ka]

[0279] (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethylene) ethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (400mg, 560umol), 1-(3-fluoropropyl)azetidin-3-amine (403mg, 1.12mmol), [(2-di-t-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (46.9mg , 56.0 umol) and cesium carbonate (730 mg, 2.24 mmol) were dissolved in toluene (2 mL). The reaction was carried out at 110°C for 12 hours under gas protection. The completion of the reaction was confirmed by LCMS. The reaction solution was concentrated. The residue was then purified using a 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-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (160 mg, 209 umol, yield 33.2%).

[0280] Step 4: (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-meth xypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro Synthesis of oxazolo[5,4-f]isoquinolin-2(3H)-one

[0281] [ka]

[0282] (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)-3-methoxypyridine (2,2,2-trifluoroethyl)-3-triphenyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (160 mg, 208 umol) in water (0.5 mL) and The reaction was allowed to proceed at 20°C for 2 hours, and the completion of the reaction was confirmed by LCMS. The pH was adjusted to 7-8 using sodium bicarbonate, and the mixture was extracted with water and ethyl acetate. The organic phase was salted. After washing with water three times and concentrating, it was purified with a silica gel column to obtain (6S,8R)-6-(5-((1-(3-fluoro Propyl)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 was obtained (70 mg, 134 umol, yield 64.0%).

[0283] 1 H NMR (400 MHz, ACETONITRILE-d3) δ = 7.32 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.63 - 6.51 (m, 2H), 5.46 (s, 1H), 4.89 (d, J = 7.0 Hz, 1H), 4.54 ( t, J = 6.1 Hz, 1H), 4.42 (t, J = 6.1 Hz, 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 = 6.9 Hz, 2H), 1.77 - 1.65 (m, 2H), 1.09 (d, J = 6.8 Hz, 3H) ppm.

[0284] 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-tetrahydrooxa Zolo[5,4-f]isoquinoline-2(3H)-one (compound 29)

[0285] [ka]

[0286] Step 1: tert-Butyl (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethylene) Synthesis of ethyl-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate

[0287] [ka]

[0288] (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (150 mg, 219 umol, 1 eq) and tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate Pd (102 mg, 547 umol, 2.5 eq) was dissolved in toluene (20 mL) and RockPhos Pd G3 (18.3 mg, 21.9 umol, 0.1 eq) and cesium carbonate (214 mg, 657 umol, 3 eq) were added, and the reaction mixture was reacted at 115°C for 15 hours. The completion of the reaction was confirmed by TLC, and the reaction mixture was quenched by adding water, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography to give tert-butyl (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3- Triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate was obtained as a yellow solid (120 mg, 138 umol, 31.5% yield).

[0289] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.02 (d, J = 2.8 Hz, 1H), 7.39 (d, J = 7.2 Hz, 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 = 8.4 Hz, 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= 8.8 Hz, J2= 15.6 Hz, 1H), 2.59 (dd, J1= 6.4 Hz, J2=16.8 Hz , 1H), 2.15 - 2.01 (m, 2H), 1.95 - 1.81 (m, 2H), 1.40 (s, 9H), 1.02 (d, J = 6.4 Hz, 3H) ppm.

[0290] 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

[0291] [ka]

[0292] At 0°C, trifluoroacetic acid (1.54 g, 13.4 mmol, 997 uL, 87.3 eq) was added to tert-butyl (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate (120 mg, 154 umol, 1 eq) dissolved in dichloromethane (2 mL), and the reaction was carried out at 20°C for 2 hours, and the completion of the reaction was confirmed by TLC and LCMS. The mixture was quenched with water, extracted with ethyl acetate, dried and concentrated, and the crude product was purified by silica gel thin layer chromatography to give (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 as a yellow solid (105 mg, crude).

[0293] LCMS: m / z (M+H) + = 449.2 1 H NMR (400MHz, DMSO-d6) δ = 8.13 (d, J = 2.8 Hz, 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 = 6.4 Hz, 3H) ppm.

[0294] Step 3: (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-tetrahydrooxazo Synthesis of 2-[5,4-f]isoquinolin-2(3H)-one

[0295] [ka]

[0296] (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]isoxid was added at 20° C. under nitrogen protection. Nolin-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), diisopropylethylenediamine (121 mg, 936 umol, 163 uL, 5 eq) was added, and the mixture was reacted at 20°C for 4 hours. The completion of the reaction was monitored by LCMS, and the reaction mixture was quenched by adding water, extracted with ethyl acetate, dried and concentrated. The crude product was purified 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, 10 um); mobile phase:0.1%NH3H2O ​​ETOH ;B%:30%-30%,10 min ), (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 was obtained as a white solid (10.5 mg, 19.8 umol, 10.6% yield, 96% purity).

[0297] LCMS: m / z (M+H) + = 509.4 1 H NMR (400MHz, CD3OD) δ = 8.05 (d, J = 2.8 Hz, 1H), 7.40 - 7.30 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.54 (t, J = 6.0 Hz, 1H), 4.42 (t, J = 6.0 Hz, 1H), 3.53 - 3.48 (m, 1H), 3.40 (br d, J = 6.0 Hz, 1H), 3.10 (dd, J1= 4.8 Hz, J2=16.8 Hz, 1H), 3.02 - 2.87 (m, 4H), 2.78 (dd, J1= 6.2 Hz, J2=16.8 Hz, 1H), 2.68 - 2.58 (m, 2H), 2.56 - 2.49 (m, 1H), 2.38 (dt, J1= 7.6 Hz, J2=13.6 Hz, 1H), 1.99 - 1.84 (m, 3H), 1.29 (br s, 1H), 1.12 (d, J = 6.4 Hz, 3H) ppm.

[0298] 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-tetrahydrofuran Xazolo[5,4-f]isoquinoline-2(3H)-one (compound 30)

[0299] [ka]

[0300] Step 1: tert-Butyl (S)-3-(3-methoxy-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trimethyl- Synthesis of fluoroethyl-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-ylphenoxypyrrolidine-1-carboxylate

[0301] [ka]

[0302] tert-Butyl(6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoromethyl) (S)-3-hydroxypyrrolidine-1-carboxylate (236 mg, 1.26 mmol), cesium carbonate (685 mg, 2.10 mmol), and [(2-di-t-butylphosphino-3- Methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (23.5 mg, 28.0 umol) was dissolved in toluene (8 mL) and reacted at 110°C under nitrogen protection for 16 hours. Two reactions were carried out in parallel. The completion of the reaction was monitored by LCMS. The products were combined, concentrated, and purified by column chromatography to give tert- Butyl (S)-3-(3-methoxy-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinoline-6- (yl)phenoxy)pyrrolidine-1-carboxylate was obtained as a yellow solid (180 mg , yield 15.7%).

[0303] 1 H NMR (400 MHz, 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 = 8.5 Hz, 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, 15.4 Hz, 1H), 2.66 (br dd, J = 6.1, 16.9 Hz, 1H), 2.16 (br s, 2H), 1.48 (s, 9H), 1.07 (br d, J = 6.5 Hz, 3H) ppm.

[0304] Step 2: (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]isoquinol Synthesis of 2(3H)-one

[0305] [ka]

[0306] tert-Butyl (S)-3-(3-methoxy-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoro Ethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylate (180mg, 220umol) The mixture was dissolved in acetic acid (2 ml) and water (0.2 mL) and reacted at 20°C for 2 hours. The completion of the reaction was confirmed by LCMS. The mixture was concentrated, the pH was adjusted to 7-8, and it was extracted with water and ethyl acetate. The mixture was washed with saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography to give (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 as a yellow solid (110 mg, 77.7% yield).

[0307] 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.73 (dd, J = 8.3, 12.6 Hz, 2H), 6.54 (d, J = 8.1 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.24 (dd, J = 2.3, 8.6 Hz, 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, ppm.

[0308] Step 3: (6S,8R)-6-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2- Synthesis of (methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0309] [ka]

[0310] (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]isoquinoline-2(3H)- Diisopropylethylamine (66.1 mg, 511 umol) was added to N,N-dimethylamine The reaction mixture was dissolved in 3 mL of diethyl ether, and 3-fluoro-1-iodopropane (25.6 mg, 136 umol) was added at 20°C. The mixture was allowed to react for 3 hours. The completion of the reaction was confirmed by TLC. 60 mg of the crude product was obtained by HPLC purification, and then chiral purification by SFC was performed to obtain (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 as a yellow solid. (47.3 mg, yield 51.4%)

[0311] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.62 - 8.02 (m, 1H), 6.81 - 6.68 (m, 2H), 6.59 (d, J = 8.1 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.25 (dd, J = 2.4, 8.5 Hz, 1H), 5.38 (s, 1H), 4.81 (br s, 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, 13.8 Hz, 1H), 2.05 - 1.88 (m, 3H), 1.30 - 1.23 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H) ppm.

[0312] Example 31: (6S,8R)-7-((1-fluorocyclopropyl)methyl)-6-(4-((1-(3-fluorocyclopropyl)methyl)- 3-(3-hydroxy-azetidin-3-yl)amino)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydropyridine Doroxazolo[5,4-f]isoquinoline-2(3H)-one

[0313] [ka]

[0314] Step 1: (6S,8R)-6-(4-bromo-2-methoxyphenyl)-7-((1-fluorocyclopropyl)methyl) (ethyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one Growth

[0315] [ka]

[0316] (R)-7-(2-(((1-fluorocyclopropyl)methyl)amino)propyl)benzo[d]oxazo A mixture of 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)) was dissolved in toluene (8 mL) and reacted at 110° C. for 120 hours. The completion of the reaction was monitored by LCMS. The reaction mixture was concentrated and purified by column chromatography. The compound was purified by chromatography to give (6S,8R)-6-(4-bromo-2-methoxyphenyl)-7-((1-fluorophenyl)- (cyclopropyl)methyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline Phosphorus-2(3H)-one was obtained as a yellow solid (249 mg, 539 umol, 13.5% yield).

[0317] LCMS: m / z 462.8 [M+H] + .

[0318] Step 2: (6S,8R)-7-((1-fluorocyclopropyl)methyl)-6-(4-((1-(3-fluorocyclopropyl)methyl)- Pyr)azetidin-3-yl)amino)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydrofuran Synthesis of oxazolo[5,4-f]isoquinolin-2(3H)-one

[0319] [ka]

[0320] ((6S,8R)-6-(4-bromo-2-methoxyphenyl)-7-((1-fluorocyclopropyl)methyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (140mg, 303umol), 1-(3-fluoropropyl)aminoazetidine (112mg, 849umol), (2-dicyclohexyl Phosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino (1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (27.5 mg, 30.3 umol) and sodium t-butoxide (87.4 mg, 910 umol) were dissolved in dioxane (1 mL) and incubated at 60°C for 2 hours. The reaction was allowed to proceed for 1 h. The completion of the reaction was monitored by LCMS. The reaction mixture was filtered and purified by prep-HPLC. The resulting mixture was purified by chiral SFC to give (6S,8R)-7-((1-fluorocyclopropyl)methyl) ethyl)-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 is yellow Obtained as a solid (7.2 mg, 4.49% yield).

[0321] LCMS: m / z 513.2 [M+H] + .

[0322] 1H NMR (400 MHz, ACETONITRILE-d3) δ= 6.75 (d, J=8.13 Hz, 1 H), 6.67 (d, J=8.38 Hz, 1 H), 6.54 (d, J=8.13 Hz, 1 H), 6.18 (d, J=2.00 Hz, 1 H), 6.00 (dd, J=8.38 , 2.00 Hz, 1 H), 5.20 (s, 1 H), 4.69 (m, J=6.90 Hz, 1 H), 4.52 (t, J=6.07 Hz, 1 H), 4.40 (t, J=6.07 Hz, 1 H), 3.95 - 4.04 (m, 1 H), 3.80 (s, 3 H), 3.64 - 3.72 (m, 3 H), 3.03 (dd, J=16.26, 4.88 Hz, 1 H), 2.86 - 2.97 (m, 1 H), 2.68 - 2.78 (m, 3 H), 2.56 - 2.65 (m, 1 H), 2.50 (t, J=7.00 Hz, 2 H), 1.64 - 1.74 (m, 2 H), 0.99 (d, J=6.63 Hz, 3 H), 0.86 - 0.94 (m, 2 H), 0.46 - 0.58 (m, 2H)ppm.

[0323] Similarly to the synthesis route of Example 25, the following Examples 32, 33 and 34 were synthesized by selecting corresponding reactants and synthesis methods known to those skilled in the art.

[0324] 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

[0325] [ka]

[0326] LCMS: m / z 519.2 [M+H]+ .

[0327] 1 H NMR (400 MHz, ACETONITRILE-d3) δ= 6.75 (d, J = 8.1 Hz, 1H), 6.48 (dd, J = 8.2, 19.9 Hz, 2H), 6.18 (d, J = 2.1 Hz, 1H), 5.97 (dd, J = 2.1, 8.4 Hz, 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 = 6.4 Hz, 2H), 2.65 - 2.55 (m, 2H), 2.49 (t, J = 7.0 Hz, 2H), 2.21 - 2.11 (m, 1H), 1.75 - 1.62 (m, 2H), 1.54 (t, J = 19.2 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H) ppm.

[0328] Example 33: (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methyl Toxo-6-chloro-phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 33)

[0329] [ka]

[0330] LCMS: m / z 557.4 [M+H] + .

[0331] 1H NMR (400 MHz, ACETONITRILE-d3) δ= 6.73 (br d, J = 8.1 Hz, 1H), 6.55 - 6.30 (m, 1H), 6.25 - 5.95 (m, 2H), 5.60 - 5.33 (m, 1H), 5.04 (br d, J = 6.1 Hz, 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 = 7.1 Hz, 2H), 1.78 - 1.67 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H) ppm.

[0332] Example 34: (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methyl Toxo-6-fluoro-phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 34)

[0333] [ka]

[0334] LCMS: m / z 541.2 [M+H] + .

[0335] 1H NMR (400 MHz, DMSO-d6) δ = 11.46 (br s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.51 - 6.36 (m, 2H), 5.99 (br s, 1H), 5.75 (br d, J = 12.8 Hz, 1H), 5.22 (br s, 1H), 4.51 (t, J = 5.9 Hz, 1H), 4.40 (t, J = 6.0 Hz, 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 = 6.5 Hz, 3H) ppm.

[0336] 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)fluoro (phenyl)amino)azetidin-1-yl)-N,N-dimethyl-but-2-enamide (compound 35)

[0337] [ka]

[0338] Step 1: Synthesis of tert-butyl 3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidine-1-carboxylate

[0339] [ka]

[0340] tert-Butyl(6S,8R)-6-(4-bromo-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluorophenyl) A mixture of (2-di-t-butylphosphino-3-methoxyphenyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (1.0 g, 1.39 mmol), 3-aminoazetidine-1-carboxylate (359 mg, 2.08 mmol), cesium carbonate (996 mg, 3.06 mmol) and (2-di-t-butylphosphino-3-methoxyphenyl)- dimethyl-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)] Palladium(II) methanesulfonate (58.3 mg, 69.5 umol) was dissolved in toluene (20 mL) and reacted at 110° C. under nitrogen protection for 12 hours. The completion of the reaction was monitored by LCMS. The mixture was After concentration, the mixture was extracted with water and ethyl acetate, and the organic phase was washed with saturated saline, dried over sodium sulfate, and concentrated. The crude product was concentrated and purified by column chromatography to obtain tert-butyl ether. The 3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidine-1-carboxylate was obtained as a yellow solid (880 mg, 1.09 mmol, 78.1% yield).

[0341] LCMS: m / z 810.3 [M+H] + .

[0342] 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.36 - 7.42 (m, 7 H), 7.17 - 7.22 (m, 10 H), 6.15 - 6.24 (m, 1 H), 5.87 (d, J=10.76 Hz, 2 H), 5.58 (d, J=8.63 Hz, 1 H), 5.05 (s, 1 H), 4.21 (t, J=8.00 Hz, 2 H), 3.65 (ddd, J=8.88, 4.63, 2.13 Hz, 2 H), 3.43 - 3.52 (m, 1 H), 3.06 (m, J=16.70, 5.70 Hz, 2 H), 2.62 - 2.85 (m, 2 H), 1.37 (s, 9 H), 0.98 (d, J=6.50 Hz, 3 H) ppm.

[0343] Step 2: (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]isoquinol Synthesis of 2(3H)-one

[0344] [ka]

[0345] Trifluoroacetic acid (15.5 g, 135 mmol) was dissolved in water (1 mL) and then reacted with tert-butyl 3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-phenylacetate. Add to 400mg, 493umol of 2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidine-1-carboxylate and heat at 20℃ under nitrogen protection. The reaction was allowed to proceed for 2 hours. The completion of the reaction was confirmed by LCMS. The mixture was concentrated, and the crude product was (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 was obtained as a yellow solid (400 mg, crude).

[0346] LCMS: m / z 468.2 [M+H] + .

[0347] Step 3: (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 Synthesis of N,N-dimethyl-but-2-enamide

[0348] [ka]

[0349] (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]isoquinoline-2(3H)- (E)-4-bromo-N,N-dimethyl-but-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 completion of the reaction was confirmed by LCMS, and the reaction solution was filtered and purified by prep-HPLC. The purified product was separated and purified by SFC to obtain (E)-4-(3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexafluoropropane). The compound was obtained as a yellow solid (38.8 mg, 65.3 umol, yield: 1.2 g / mL). rate 30.6%).

[0350] LCMS: m / z 579.2 [M+H] + .

[0351] 1 H NMR (400 MHz, ACETONITRILE-d3) δ = 6.81 (d, J=8.00 Hz, 1 H), 6.50 - 6.66 (m, 2 H), 6.40 - 6.48 (m, 1 H), 6.08 (d, J=11.88 Hz, 2 H), 5.27 (m, J=7.00 Hz, 1 H), 5.20 (s, 1 H), 3.92 - 4.04 (m, 1 H), 3.69 (t, J=6.82 Hz, 2 H), 3.43 - 3.58 (m, 1 H), 3.22 - 3.38 (m, 1 H), 3.19 (dd, J=5.19, 1.31 Hz, 2H), 3.00 - 3.09 (m, 4 H), 2.91 - 2.99 (m, 1 H), 2.88 - 2.91 (m, 3 H), 2.80 - 2.87 (m, 2 H), 2.73 (dd, J=16.45, 4.94 Hz, 1 H), 1.06 (d, J=6.50 Hz, 3H) ppm.

[0352] Example 36: (6S,8R)-6-(4-((1-acryloylazetidin-3-yl)amino)-2,6-difluoro (trifluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 36)

[0353] [ka]

[0354] Step 1: (6S,8R)-6-(4-((1-acryloylazetidin-3-yl)amino)-2,6-difluoro Synthesis of (phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0355] [ka]

[0356] (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]isoquinoline-2(3H)- Diisopropyl amine (250 mg, 533 umol) and diisopropylethylamine (827 mg, 6.40 mmol) were added to N,N-dimethylamine Dissolve in diethyl ether (2 mL), add acryloyl chloride (9.66 mg, 106 umol) at 0°C, and then heat at 0°C. The reaction was carried out for 2 hours. The completion of the reaction was confirmed by LCMS. The reaction solution was filtered and purified by prep-HPLC, and the purified product was separated and purified by SFC to obtain (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 as a yellow solid (29.4 mg, 56.1 umol, 10.5% yield).

[0357] LCMS: m / z 522.2 [M+H] + .

[0358] 1H NMR (400 MHz, ACETONITRILE-d3) δ = 8.96 (s, 1 H), 6.82 (d, J=8.13 Hz, 1 H), 6.63 (d, J=8.13 Hz, 1 H), 6.21 - 6.36 (m, 1 H), 6.12 - 6.19 (m, 1 H), 6.09 (d, J=11.63 Hz, 2 H), 5.63 (dd, J=10.19, 1.94 Hz, 1 H), 5.44 (m, J=6.38 Hz, 1 H), 5.22 (s, 1 H), 4.49 - 4.59 (m, 1 H), 4.15 - 4.34 (m, 2 H), 3.94 (dt, 3.68 - 3.78 (m, 1 H), 3.45 - 3.57 (m, 1 H), 3.23 - 3.38 (m, 1 H), 2.87 - 3.09, (m, 2 H), 2.74 (dd, J=16.32, 5.19 Hz, 1 H), 1.06 (d, J=6.63 Hz, 3 H) ppm.

[0359] 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-dimethyl-but-2-enamide (compound 37)

[0360] [ka]

[0361] Step 1: tert-Butyl (R)-3-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2- Synthesis of trifluoroethyl-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-ylphenoxypyrrolidine-1-carboxylate

[0362] [ka]

[0363] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)- N-non (1.7 g, 2.36 mmol), R-3-hydroxy-1-Boc-pyrrolidine (663 mg, 3.54 mmol), [(2-di-t-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (99.0 mg, 118 umol) and cesium carbonate (1.69 g, 5.20 mmol) were dissolved in toluene (20 mL) and incubated at 110 °C under nitrogen protection for 12 h. The reaction was continued for 1 hour. The completion of the reaction was monitored by LCMS. The mixture was concentrated and then purified by column chromatography to obtain tert-butyl (R)-3-(3,5-difluoro-4-((6S,8R)-8-methyl-2- Oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydride Roxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylate was obtained as a pale yellow solid (503 mg, 609 umol, 25.7% yield).

[0364] LCMS: m / z 825.3 [M+H] + .

[0365] 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.19 - 7.42 (m, 15 H), 6.26 (d, J=10.38 Hz, 2 H), 6.20 (d, J=8.63 Hz, 1 H), 5.60 (d, J=8.50 Hz, 1 H), 5.09 (s, 1 H), 3.46 - 3.59 (m, 4 H), 3.20 - 3.44 (m, 2 H), 2.86 - 3.17 (m, 3 H), 2.62 - 2.80 (m, 2 H), 2.08 (m, J=6.80 Hz, 1 H), 1.38 - 1.41 (m, 9 H), 0.98 (d, J=6.50 Hz, 3 H) ppm .

[0366] 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

[0367] [ka]

[0368] Trifluoroacetic acid (6.16g, 54.0mmol) was dissolved in water (0.4 mL), and the solution was added to tert-butyl (R)-3-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylate (503mg, 609umol), and the mixture was reacted for 2 hours under nitrogen protection at 20°C. The completion of the reaction was confirmed by LCMS. The mixture was concentrated, then adjusted to pH=7 with saturated sodium bicarbonate, extracted with ethyl acetate, and the organic phase was filtered, concentrated, and purified by column chromatography to obtain (6S,8R)-6-[2,6-difluoro-4-(((R)-pyrrolidin-3-yl)oxy)phenyl]-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrafluoroethane as a yellow solid. Hydroxazolo[5,4-f]isoquinolin-2(3H)-one was obtained (183 mg, 378 umol, 62.2% yield). .

[0369] LCMS: m / z 483.2 [M+H] + .

[0370] Step 3: (E)-4-((R)-3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-tetrafluoroethylene) (trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl) Synthesis of (phenoxy)pyrrolidin-1-yl)-N,N-dimethyl-but-2-enamide

[0371] [ka]

[0372] (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-dimethyl-but-2-enamide (35.7 mg, 186 umol), 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 completion of the reaction was confirmed by LCMS, the reaction solution was filtered, separated and purified by prep-HPLC, and the purified product was purified by SFC to obtain (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-dimethyl-but-2-enamide as a yellow solid (18.5 mg, 30.7 umol, 16.5% yield).

[0373] LCMS: m / z 579.2 [M+H] + .

[0374] 1 H NMR (400 MHz, ACETONITRILE-d3) δ = 6.82 (d, J=8.25 Hz, 1 H), 6.60 - 6.71 (m, 2 H), 6.45 - 6.54 (m, 2 H), 6.44 (s, 1 H), 5.29 (s, 1 H), 4.81 (m, J=7.30, 4.60 Hz, 1 H), 3.52 (m, J=6.00 Hz, 1 H), 3.31 (s, 1 H), 3.22 (m, J=6.00 Hz, 2 H), 3.04 - 3.09 (m, 1 H), 3.01 (s, 3 H), 2.93 - 2.98 (m, 1 H), 2.89 (s, 3 H), 2.66 - 2.87 (m, 5 H), 2.42 (m, J=7.50 Hz, 1 H), 2.30 (m, J=7.60 Hz, 1 H), 1.07 (d, J=6.50 Hz, 3 H) ppm.

[0375] Example 38: (6S,8R)-6-(4-(((R)-1-acryloylpyrrolidin-3-yl)oxy)-2,6-difluoro (fluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (compound 38)

[0376] [ka]

[0377] Step 1: (6S,8R)-6-(4-(((R)-1-acryloylpyrrolidin-3-yl)oxy)-2,6-difluoro Synthesis of (2,2,2-trifluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one

[0378] [ka]

[0379] (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]isoquinoline-2(3H)-one (90 mg, 186 umol), diisopropylethylamine (240 mg, 1.86 mmol) were added to N,N-dimethyl The reaction mixture was dissolved in 1 mL of diethyl ether, and acryloyl chloride (16.8 mg, 186 umol) was added at 0° C. The mixture was allowed to react for 1 hour at 0° C. The completion of the reaction was confirmed by LCMS, and the reaction mixture was filtered, separated and purified by prep-HPLC, and the purified product was purified by SFC to obtain (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 as a white solid. (24.8 mg, 45.9 umol, yield 24.6%).

[0380] LCMS: m / z 537.2 [M+H] + .

[0381] 1 H NMR (400 MHz, ACETONITRILE-d3) δ = 8.70 - 9.00 (m, 1 H), 6.82 (d, J=8.13 Hz, 1 H), 6.63 (d, J=8.00 Hz, 1 H), 6.44 - 6.60 (m, 3 H), 6.15 - 6.25 (m, 1 H), 5.64 (ddd, J=10.35, 8.10, 2.31 Hz, 1 H), 5.30 (s, 1 H), 4.92 - 5.06 (m, 1 H), 3.5 4 - 3.88 (m, 4 H), 3.31 - 3.52 (m, 2 H), 3.07 (dd, J=16.45, 4.94 Hz, 1 H), 2.94 (dq, J=15.90, 9.63 Hz, 1 H), 2.76 (dd, J=16.51, 5.13 Hz, 1 H), 2.16 - 2.25 (m, 2 H), 1.07 (d, J=6.63 Hz, 3H) ppm.

[0382] Similar to the synthetic routes of 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.

[0383] 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-dimethyl-but-2-enamide (compound 39)

[0384] [ka]

[0385] LCMS: m / z 579.2 [M+H] + .

[0386] 1 H NMR (400 MHz, ACETONITRILE-d3) δ = 6.82 (d, J=8.13 Hz, 1 H), 6.60 - 6.71 (m, 2 H), 6.48 - 6.53 (m, 1 H), 6.45 - 6.48 (m, 1 H), 6.43 - 6.45 (m, 1 H), 5.29 (s, 1 H), 4.77 - 4.84 (m, 1 H), 3.47 - 3.57 (m, 1 H), 3.32 (m, J=9.60 Hz, 1 H), 3.22 (dd, J=6.07, 1.44 Hz, 2 H), 3.07 (dd, J=16.76, 4.75 Hz, 1 H), 3.00 - 3.04 (m, 3 H), 2.93 - 2.99 (m, 1 H), 2.89 (s, 3 H), 2.83 (s, 5 H), 2.37 - 2.49 (m, 1 H), 2.26 - 2.36 (m, 1 H), 1.07 (d, J=6.50 Hz, 3 H) ppm.

[0387] Example 40: (6S,8R)-6-(4-(((S)-1-acryloylpyrrolidin-3-yl)oxy)-2,6-difluoro (fluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (compound 40)

[0388] [ka]

[0389] LCMS: m / z 537.2 [M+H] + .

[0390] 1 H NMR (400 MHz, ACETONITRILE-d3) δ= 6.82 (d, J=8.00 Hz, 1 H), 6.62 (d, J=8.00 Hz, 1 H), 6.44 - 6.59 (m, 3 H), 6.16 - 6.26 (m, 1 H), 5.64 (m, J=10.40, 10.40, 2.30 Hz, 1 H), 5.30 (s, 1 H), 4.92 - 5.06 (m, 1 H), 3.55 - 3.88 (m, 4 H), 3.45 - 3.53 (m, 1 H), 3.34 (m, J=16.10, 9.60 Hz, 1 H), 3.03 - 3.12 (m, 1 H), 2.89 - 3.00 (m, 1 H), 2.76 (dd, J=16.70, 5.32 Hz, 1 H), 1.77 (m, J=4.90, 2.40 Hz, 2 H), 1.07 (d, J=6.63 Hz, 3 H) ppm.

[0391] Example 41: (E)-4-(4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluorophenyl)-2-methyl-2-propanediol Fluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)fluoro (phenyl)piperazin-1-yl)-N,N-dimethyl-but-2-enamide (compound 41)

[0392] [ka]

[0393] Step 1: tert-Butyl 4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluorophenyl)- Synthesis of fluoroethyl-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-ylphenylpiperazine-1-carboxylate

[0394] [ka]

[0395] (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)- Non (700mg, 972umol), N-Boc piperazine (272mg, 1.46mmol), (2-dicyclohexylphos Phenyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (41.2 mg, 48.6 umol) and cesium carbonate (697 mg, 2.14 mmol) were dissolved in toluene (15 mL) and reacted at 110°C under nitrogen protection for 12 hours. The completion of the reaction was monitored by LCMS. The mixture was concentrated, and then extracted with water and ethyl acetate. The organic phase was extracted, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to give tert-butyl 4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazine-1-carboxylate. Obtained as a white solid (413 mg, 501 umol, 51.5% yield).

[0396] LCMS: m / z 824.3 [M+H] + .

[0397] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.27 - 7.53 (m, 15 H), 6.24 - 6.42 (m, 3 H), 5.63 - 5.74 (m, 1 H), 5.17 (s, 1 H), 3.52 - 3.68 (m, 5 H), 3.10 - 3.39 (m, 6 H), 2.77 (m, J=16.40, 4.30 Hz, 2 H), 1.52 (s, 9 H), 0.89 - 1.11 (m, 3 H) ppm.

[0398] 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 [ka]

[0399] Trifluoroacetic acid (12.3 g, 107 mmol) was dissolved in water (0.1 mL) and the solution was mixed with tert-butyl 4-(3,5-difluoroacetic acid) and Fluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenyl 2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl Add piperazine-1-carboxylate (413mg, 500umol) and keep at 20℃ for 2 hours under nitrogen protection. The reaction was completed by LCMS. The crude product was purified by column chromatography to give (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 as a yellow solid (110 mg, 228 umol, 45.5% yield).

[0400] LCMS: m / z 482.2 [M+H] + .

[0401] 1 H NMR (400 MHz, DMSO-d6) δ = 6.81 (d, J=8.00 Hz, 1 H), 6.48 - 6.60 (m, 3 H), 5.16 (s, 1 H), 3.06 - 3.10 (m, 4 H), 2.86 - 2.99 (m, 3 H), 2.67 - 2.80 (m, 6 H), 1.05 (d, J=6.50 Hz, 3 H.) ppm.

[0402] Step 3: (E)-4-(4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluorophenyl) (fluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl Synthesis of N,N-dimethyl-but-2-enamide

[0403] [ka]

[0404] (6S,8R)-6-(2,6-difluoro-4-(piperazin-1-yl)phenyl)-8-methyl-7-(2,2,2-trifluorophenyl) (fluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (100 mg, 207 umol), (E)-4-bromo-N,N-dimethyl-but-2-enamide (39.8 mg, 207.3 umol), and diisopropylethylamine (58.9 mg, 456 umol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at 20°C under nitrogen protection for 1 hour. The completion of the reaction was confirmed by LCMS, and the reaction solution was filtered. The mixture was filtered, separated and purified by prep-HPLC, and the purified product was purified by SFC to obtain (E)-4-(4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexafluoropropanediol). Hydroxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazin-1-yl)-N,N-dimethyl Chil-but-2-enamide was obtained as a yellow solid (37 mg, 62.3 umol, 30.1% yield).

[0405] LCMS: m / z 593.2 [M+H] + .

[0406] 1 H NMR (400 MHz, ACETONITRILE-d3) δ = 8.78 - 8.97 (m, 1 H), 6.81 (d, J=8.13 Hz, 1 H), 6.50 - 6.69 (m, 3 H), 6.38 - 6.47 (m, 2 H), 5.25 (s, 1 H), 3.45 - 3.59 (m, 1 H), 3.24 - 3.40 (m, 1 H), 3.12 - 3.22 (m, 6 H), 3.04 - 3.10 (m, 1 H), 3.03 (s, 3 H), 2.92 - 3.00 (m, 1 H), 2.90 (s, 3 H), 2.70 - 2.79 (m, 1 H), 2.46 - 2.60 (m, 4 H), 1.07 (d, J=6.63 Hz, 3 H) ppm.

[0407] Example 42: 3-(4-((2-(4-(3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoro Ethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindoline-2-yl (R)piperidine-2,6-dinone (compound 42)

[0408] [ka]

[0409] 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

[0410] [ka]

[0411] tert-Butyl (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethylene ethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-one (700mg, 1.58mmol), 4-(2-hydroxyethyl)piperazine-1-carboxylate (546mg, 2.37mmol), [(2-di-t-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (132mg, 158umol) and sodium t-butoxide (456 mg, 4.75 mmol) were dissolved in toluene (10 mL) and nitrogen-protected The reaction was allowed to proceed under reduced pressure for 12 hours. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated to give the crude product. The compound was purified by column chromatography to give 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]isoxa Norin-6-yl)pyridin-3-yl)oxy)ethyl)piperazine-1-carboxylate is yellow of solid (400 mg, 676 umol, 42.7% yield).

[0412] LCMS: m / z 591.3 [M+H] + .

[0413] 1 H NMR (400 MHz, DMSO-d6) δ = 11.36 - 11.63 (m, 1 H), 7.93 - 8.18 (m, 1 H), 7.37 (dd, J=8.69, 2.94 Hz, 1 H), 7.11 - 7.27 (m, 1 H), 6.84 (d, J=8.13 Hz, 1 H), 6.68 (d, J=8.13 Hz, 1 H), 5.02 (s, 1 H), 4.01 - 4.19 (m, 2 H), 3.37 - 3.64 (m, 3 H), 3.17 (d, J=5.13 Hz, 1 H), 2.89 - 3.03 (m, 1 H), 2.80 - 2.89 (m, 1 H), 2.55 - 2.76 (m, 3 H), 2.24 - 2.45 (m, 6 H), 1.38 (s, 9 H), 1.06 (m, J=6.50 Hz, 3H) ppm.

[0414] 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

[0415] [ka]

[0416] 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) were dissolved in dichloromethane (10 mL) and reacted at 20°C for 1 hour. The reaction was analyzed by LCMS. The completion of the reaction was monitored. After concentrating the reaction mixture, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with water and ethyl acetate. The organic phase was washed with saturated saline and then washed with sodium sulfate. The crude product was purified by column chromatography to give (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 is a yellow solid (156 mg, 317 umol, 47.9% yield).

[0417] LCMS: m / z 491.2 [M+H] + .

[0418] 1 H NMR (400 MHz, DMSO-d6) δ = 8.08 - 8.20 (m, 1 H), 7.36 (dd, J=8.63, 2.88 Hz , 1 H), 7.25 (d, J=8.63 Hz, 1 H), 6.84 (d, J=8.13 Hz, 1 H), 6.68 (d, J=8.13 Hz, 1 H), 5.03 (s, 1 H), 4.11 (br t, J=5.44 Hz, 2 H), 3.52 - 3.59 (m, 1 H), 3.34 - 3.42 (m, 1 H), 2.80 - 2.99 (m, 6 H), 2.63 - 2.76 (m, 3 H), 2.53 - 2.63 (m, 4 H), 1.06 (d, J=6.63 Hz, 3 H) ppm.

[0419] Step 3: 3-(4-((2-bromoethyl)amino)-1-oxoisoindolin-2-yl)piperidinyl Synthesis of 2,6-diphenyl-

[0420] [ka]

[0421] 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dinone (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) was dissolved in N-methylpyrrolidone (20 mL), purged with nitrogen gas, and then heated at 100°C for 4 hours. The reaction was allowed to proceed for 1 h. The completion of the reaction was monitored by LCMS. The reaction 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 give 3-(4-((2-bromoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dinone as a yellow solid (403 mg, 1.10 mmol, 14.27% yield).

[0422] LCMS: m / z 365.0 [M+H] + .

[0423] 1 H NMR (400 MHz, DMSO-d6) δ = 11.00 (s, 1 H), 7.31 (t, J=7.75 Hz, 1 H), 6.98 (d, J=7.25 Hz, 1 H), 6.84 (d, J=8.00 Hz, 1 H), 5.93 (br s, 1 H), 5.11 (dd, J=13.26, 5.00 Hz, 1 H), 4.18 - 4.28 (m, 1 H), 4.09 - 4.17 (m, 1 H), 3.53 - 3.64 (m, 4 H), 2.86 - 2.99 (m, 1 H), 2.64 (br s, 1 H), 2.23 - 2.37 (m, 1 H), 1.98 - 2.09 (m, 1 H) ppm.

[0424] Step 4: 3-(4-((2-(4-(3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethylene Synthesis of ethyl)-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-dinone

[0425] [ka]

[0426] (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]isoquinoline-2(3H)-one (70mg, 142umol), 3-(4-((2-bromoethyl)amino)-1-oxoisoindolin-2-yl)pi Peridine-2,6-dinone (57.3 mg, 156 umol) and N,N-diisopropylethylamine (55.2 mg, 427 umol) were dissolved in dioxane (2 mL) and reacted at 80° C. under nitrogen protection for 12 hours. The completion of the reaction was monitored by LCMS. The reaction solution was evaporated and then purified by prep-HPLC to obtain 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)ethylene. C.)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dinone was obtained as a yellow solid (20 mg, 25.8 umol, 18.1% yield).

[0427] LCMS: m / z 776.3 [M+H] + .

[0428] 1 H NMR (400 MHz, ACETONITRILE-d3) δ = 8.91 (br s, 1 H), 8.10 (d, J=2.50 Hz, 1 H), 7.31 - 7.37 (m, 1 H), 7.28 (s, 1 H), 7.26 (br d, J=2.75 Hz, 1 H), 7.05 (d, J=7.38 Hz, 1 H), 6.83 (t, J=7.69 Hz, 2 H), 6.70 (d, J=8.00 Hz, 1H), 4.98 - 5.18 (m, 2 H), 4.54 - 4.91 (m, 1 H), 4.22 - 4.31 (m, 1 H), 4.19 (s, 1 H), 4.13 (t, J=5.57 Hz, 2 H), 3.36 - 3.49 (m, 2 H), 3.28 - 3.35 (m, 2 H), 2.84 - 3.07 (m, 3 H), 2.69 - 2.83 (m, 7 H), 2.68 (br s, 8 H), 2.39 - 2.43 (m, 1 H), 1.28 (br d, J=6.25 Hz, 1 H), 1.08 (d, J=6.75 Hz, 3 H) ppm.

[0429] Similarly to the synthesis route of Example 42, the following Example 43 was synthesized by selecting the corresponding reactants and synthesis methods known to those skilled in the art.

[0430] Example 43: 3-(4-((2-(4-(3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoro Ethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)propyl)piperazin-1-yl)ethyl)amino)-1-oxoisoindoline-2- (yl)piperidine-2,6-dinone (compound 43)

[0431] [ka]

[0432] LCMS: m / z 790.3 [M+H] + .

[0433] 1H NMR (400 MHz, ACETONITRILE-d3) δ= 8.71 - 9.01 (m, 1 H), 8.09 (d, J=2.50 Hz, 1 H), 7.40 (s, 1 H), 7.26 - 7.30 (m, 1 H), 7.20 - 7.26 (m, 1 H), 7.04 (d, J=7.38 Hz, 1 H), 6.83 (t, J=7.69 Hz, 2 H), 6.70 (d, J=8.13 Hz, 1 H), 5.02 - 5.17 (m, 2 H), 4.50 (br s, 1 H), 4.18 (q, J=16.38 Hz, 2 H), 4.06 (t, J=6.32 Hz, 2 H), 3.43 - 3.53 (m, 1 H), 3.33 - 3.43 (m, 1 H), 3.26 (br d, J=5.25 Hz, 2 H), 2.90 - 3.06 (m, 2 H), 2.73 - 2.87 (m, 2 H), 2.70 (br dd, J=4.57, 2.69 Hz, 1 H), 2.59 (br t, J=6.19 Hz, 3 H), 2.29 - 2.53 (m, 12 H), 1.28 (br d, J=6.13 Hz, 1 H), 1.08 (d, J=6.63 Hz, 3H) ppm.

[0434] Test Example 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) is Example 1 in WO2017 / 182493A1. It was synthesized according to the method of

[0435] Test example 1: ERα TR-FRET test 1X Tris-HCl (Sigma, PHG0002) protein buffer was prepared and mixed. Compounds to be tested were prepared at 2 mM stock solutions and serially diluted 3-fold to a total of 10 concentrations. The diluted compounds were added to the reaction plate at 100 nL per well using an Echo 550, and estradiol (Sigma, 491187; final concentration 1.5 nM) was added at the same time to each well at 5 nL.

[0436] Preparation of 1x protein mixture solution: First, a 2x GST-ERα-LBD (Invitrogen, A15677) / MAb anti-GST-Eu (Cisbio, 61GSTKLA) mixture solution was prepared according to the table below.

[0437] [Table 1]

[0438] A 2x biotin-SRC2 / streptavidin-XL665 (Cisbio, 610SAXLA) mixed solution was prepared.

[0439] [Table 2]

[0440] Mix the above 2x GST-NR-LBD / MAb anti-GST-Eu solution and 2x biotin-SRC2 / streptavidin-XL665 solution in a 1:1 volume ratio, and apply this 1x protein mixture to a 384-well plate. Add 20 μL of each well of the 384-well plate to a centrifuge and centrifuge at 1000 rpm for 10 seconds at room temperature. After centrifugation for 1 h, the plate was removed and left at room temperature for 3 h. Then, the plate was transferred to the EnVision multifunctional microplate reader. I read it in Dart.

[0441] The values ​​at 665 and 615 (nm) were read, the value at 615 was used as a correction value, and the final value was expressed as the value at 665 / the value at 615. The inhibition rate was calculated by the following formula:

[0442]

number

[0443] X is the "value of 665 vs. value of 615" for each concentration. Min is 0.2 mM positive control compound and 3 nM The mean of 665 vs. 615 when 5nl of estradiol (1.5nM) was added. Max is the mean of 665 vs. 615 when DMSO and 5nl of estradiol (3nM) were added. Data were imported into Graphpad Prism, and curve fitting was performed using Log(agonist) vs. response-variable slope.

[0444] Fitting formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogEC50 - X) * HillSlope)) ERα TR-FRET experimental data

[0445] [Table 3]

[0446] Test Example 2: MCF-7 cell proliferation test Human breast cancer cells MCF-7 (HTB-22, purchased from ATCC) were seeded in a 96-well plate. The medium was supplemented with 10% FBS (Gibco, 10099-141), 1% pyruvic acid (Sigma, S8636), 1% non-essential amino acids, and 1% ethanol. The inoculation density was 4,000 cells / well in MEM (Hyclone, SH30024.01B) medium containing 100% EDTA (Sigma, M7145). The cells were cultured at 37°C and 5% CO2. Compounds were prepared as 20 mM stock solutions and serially diluted to a final concentration of 1000 with 100% DMSO (Sigma, D2650) and then added to 100 mL of 100% DMSO containing 2% FBS. After 24 hours of incubation, the culture medium was removed, and 90 μL of medium containing 2% FBS and 10 μL of the drug were added to each well. 10 μL of DMSO was added to the control group, and the mixture was gently shaken to mix. The blank group was added with 100 μL of 2% FBS medium alone. These were placed in an incubator and cultured at 37°C and 5% CO2. After 72 hours, 50 μL of mixed Cell Titer-Glo (Promega, G7571) was added, shaken to mix evenly, and left to stand at room temperature for 10 minutes. The chemiluminescence signal value was The negative control was a 0.5% DMSO well.

[0447] Experimental data of MCF-7 cell proliferation test

[0448] [Table 4]

[0449] Test Example 3: Degradation effect of compounds on ERα In this test example, the degradation effect of the compound on ERα was measured using the ERα DuoSet IC ELISA Kit (R&D, DYC5715). On the first day of the test, human breast cancer cells MCF-7 (origin) were cultured in a 24-well plate. The medium was MEM medium containing 10% charcoal-stripped FBS (Tocyto, UT61204), 1% pyruvic acid, and 1% non-essential amino acids; the seeding density was 150,000 cells / well; and the cells were cultured at 37°C and 5% CO2 for 24 hours.

[0450] On the second day of the test, the test compounds were serially diluted and added to the 24-well plate containing the cells. The cells were then cultured for 24 hours at 37°C and 5% CO2. The ERα capture antibody was diluted to 1 μg / ml in PBS (Corning, 21-040-CVR) and added to the 96-well plate at 100 μL / well. It was sealed and coated overnight at room temperature.

[0451] On the third day of the test, 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 for 1 hour at room temperature. The 24-well plate was washed once with PBS, the remaining liquid was aspirated, and 60 μL of lysis solution (6M urea (Sigma, U5378), 1 mM EDTA (Sigma, E9884), 0.5% TritonX-100 (Sigma, T8787), 1 mM PMSF (Sigma, 93482), Protease Inhibitor Cocktails (Sigma, 05892970001)) was added per well. After lysis on ice for 15 minutes, dilution solution (1 mM EDTA, 0.5% TritonX-100, dissolved in PBS) was added. 100 μL of the diluted cell lysate was added per well to the blocked 96-well plate and incubated for 2 hours at room temperature. The plate was washed with washing solution (R&D, WA126) and incubated for 2 hours at room temperature. After washing the plate three times, the primary antibody was added and incubated for 1 hour. The 96-well plate was washed four times, the secondary antibody was added and incubated at room temperature in the dark for 30 minutes. The plate was washed four times with washing solution. After washing, TMB (R&D, DY999) was added and color was developed for 15 minutes, after which the reaction was stopped with a stop solution (R&D, DY994) and the absorbance was read at 450 nm.

[0452] IC of compounds for ERα degradation 50 value

[0453] [Table 5]

[0454] Test Example 4: In vitro stability test using human liver microsomes Eight 96-well culture plates were prepared and named T0, T5, T15, T30, T45, T60, Blank60 and NCF60. The reaction times for the first six culture plates were 0, 5, 15, 30, 45 and 60 min, respectively. No test or control compounds were added to the Blank60 plate, and samples were taken after 60 min of incubation. The NCF60 plate was incubated with potassium phosphate buffer instead of NADPH regenerating solution (Sigma, N0505) for 60 min. I bet.

[0455] The working solution of the test compound was added to the T0, T5, T15, T30, T45, T60 and NCF60 plates, respectively. Or 2 μL of control working solution and 100 μL of human liver microsome working solution (Corning, 452117) were added to make the concentration of microsomal protein 1 mg / mL. Only microsome working solution was added to Blank60 plate, and Blank60, T5, T15, T30, T45, and T60 culture plates except T0 and NCF60 were placed in a 37°C water bath and pre-incubated for about 10 minutes.

[0456] To the samples on the T0 plate, first add 600 μL of stop solution (a solution of acetonitrile:methanol (95:5, v / v) containing 100 ng / mL tolbutamide (Sigma, T0891)), then add the NADPH regenerating system. The working solution was added.

[0457] 98 μL of potassium phosphate buffer was added to each well of the NCF60 plate and incubated for 60 minutes.

[0458] After pre-incubation on culture plates Blank60, T5, T15, T30, T45, and T60 Then, 98 μL of NADPH regenerating system working solution was added to each sample well to start the reaction.

[0459] After appropriate incubation times (5, 15, 30, 45, 60 min, etc.), 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 to stop the reaction.

[0460] All sample plates were shaken and mixed, then centrifuged at 3220×g for 20 minutes, 200 μL of test sample supernatant was taken and diluted with 200 μL of 0.3% formic acid solution for LC-MS / MS analysis, and 100 μL of control sample supernatant was taken and diluted with 300 μL of pure water for LC-MS / MS analysis. The calculation was performed according to the following formula:

[0461]

number

[0462] In vitro microsome stability experiment data

[0463] [Table 6]

Claims

1. A compound of formula (I): 【Chemistry 1】 During the ceremony: Z 1 is a bond; Z 2 is -O-CH 2 -CH 2 -, -O-CH 2 -, -NH-CH 2 -CH 2 -, -NH-CH 2 -, -NH-, or -O-; Cy 1 is phenyl or pyridyl, optionally containing a halogen atom or C 1-6 Alcoki is substituted with si; Cy 2 are azetidine, pyrrolidine, piperazine, and 【Chemistry 2】 is selected from R 1 is C 1-6 is alkyl; R 2 is H; R 3 Ha-CH 2 -CR 31 R 32 R 33 and R 31 , R 32 and R 33 are each independently: H, C optionally substituted with a hydroxy or halogen atom 1-6 alkyl, halogen atom, or R 31 and R 32 C, optionally substituted with hydroxy or halogen atoms 3-8 may form a cycloalkylene; R 4 is optionally a halogen atom, and 【Chemistry 3】 C substituted with a group selected from 1-6 Alkyl, C 1-6 Alkylamino or Amino C 1-6 Compounds which are alkyl, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

2. Cy 2 is selected from azetidine and pyrrolidine; and R 4 is optionally substituted with halogen atoms 1-6 2. The compound of claim 1, or a stereoisomer or pharma- ceutically acceptable salt thereof, wherein:

3. Z 1 is a bond; Z 2 is selected from -NH- or -O-; Cy 1 is phenyl or pyridyl, optionally substituted with F, Cl or methoxy; Cy 2 is selected from azetidylene, pyrrolidine, and piperazine; R 1 is methyl; R 2 is H; R 3 Ha-CH 2 -CR 31 R 32 R 33 and R 31 , R 32 are F or R, respectively. 31 and R 32 together form cyclopropylene; R 33 is selected from H, methyl, hydroxymethyl, fluoromethyl, and F; R 4 is F-(CH 2 ) 3 -or 【Chemistry 4】 2. The compound of claim 1, wherein:

4. The compound according to claim 3, or a stereoisomer or pharmaceutical composition thereof, wherein Cy 1 is phenyl. Acceptable salts.

5. The compound of claim 3 or 4, or a stereoisomer or a pharma- ceutically acceptable salt thereof, wherein R33 is selected from F, hydroxymethyl, and methyl.

6. Cy 2 is selected from azetidine and pyrrolidine, and R 4 is F-(CH 2 ) 3 6. The compound according to any one of claims 3 to 5, or a stereoisomer or a pharma- ceutically acceptable salt thereof, wherein:

7. The following compound: 【Chemistry 5】 【Chemistry 6】 or a stereoisomer or a pharma- ceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a stereoisomer or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

9. 13. Use of a compound according to any one of claims 1 to 7, or a stereoisomer or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating an estrogen receptor dependent or estrogen receptor mediated disease in a mammal.

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