Estrogen receptor modulator

Abstract

To provide an estrogen receptor inhibitor (ER).SOLUTION: The present invention provides a compound represented by formula (I) or a stereoisomer, tautomer or pharmaceutical salt thereof, and use thereof in preparation of a medicament for preventing and / or treating estrogen receptor-related diseases or disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to several novel compounds or pharmaceutically acceptable salts thereof that have anticancer activity and are therefore potentially useful in methods for treating the body of a human or animal. The present invention further relates to methods for producing the compounds, pharmaceutical compositions containing the compounds, and their use in therapeutic methods. For example, use in the manufacture of pharmaceuticals for the prevention or treatment of cancer in warm-blooded animals (such as humans), and use for the prevention or treatment of estrogen receptor-dependent or estrogen receptor-mediated diseases. The present invention further relates to compounds as selective estrogen receptor downmodulators. [Background technology]

[0002] Estrogen receptors (ERs) are steroid hormone receptors, and there are two subtypes: ERα and ERβ. It includes ibuprofen. The ER is involved in the regulation and development of the female reproductive tract. In cancers such as breast cancer, tumor growth is related to the function of estrogen and ER receptors, and for example, ER expression is increased in most breast cancer patients.

[0003] Some compounds bind to the ER and form the female steroid hormone 17b-estradiol. It is known that these compounds can competitively inhibit the binding of endogenous estrogen ligands such as (E2) to the ER, and are therefore 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 other conditions. WO 2017 / 182493 SERM compounds are also found in A1. It is shown.

[0004] While existing SERM therapies have some effect in treating breast cancer, there is a need for ER inhibitors with stronger inhibitory activity and improved metabolic stability. [Overview of the project]

[0005] The present inventors have surprisingly found that the compound represented by formula (I) has a basic structure of tetrahydrooxazoloisoquinolinone, and since this basic structure has remarkable ER degradation activity, it has an ER inhibitory activity significantly superior to that of the compounds known in the prior art. Such compounds also have excellent metabolic stability. Therefore, the compounds of the present invention can be used for the treatment of estrogen receptor-dependent or estrogen receptor-mediated diseases, and the present invention has been completed. Specifically, the present invention relates to the following.

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

[0007] One aspect of the present invention provides a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof: :

[0008] [Chemical formula]

[0009] In the formula: Z 1 is selected from CR a R b , C(O) and a bond; Z 2 is selected from O, S, NR c , C(O) and a bond, or C1-C6 alkylene, O-(C1-C6 alkylene) or NH-(C1-C6 alkylene) optionally substituted with one or more identical or different Rd; Cy 1 is selected from C 6-14 arylene, C 3-8 cycloalkylene, C 5-14 heteroarylene, C 3-14 heterocycloalkylene, C 3-14 heterocycloalkenylene, each optionally by a halogen atom, hydroxy, amino, cyano, and C optionally substituted with a halogen atom1-6 Alkyl or C 1-6 Substituted with a group selected from alkoxy; Cy 2 is a bond, C 3-10 Cycloalkylene, C 3-14 Selected from heterocycloalkylenes, Depending on the case, C may be substituted with halogen atoms (including F, Cl, Br, or I atoms), hydroxyl, amino, cyano, and halogen atoms. 1-6 Alkyl or C 1-6 Substituted with a group selected from alkoxy groups; R 1 , R 2 These are H, halogen atom, hydroxyl, amino, cyano, and C, each independently of the others. 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenil, C 2-6 It is an alkenylamino or C3-C8 cycloalkyl, and the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenil, C 2-6 Alkenylamino or C3-C8 cycloalkyl may contain one or more halogen atoms, hydroxyl, amino, or C. 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, cyano or oxy It is replaced by a base selected from So; R 4 H, halogen atom, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamide No, Amino C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkenylamino or C3-C8 cycloadromes It is Lukill, and the C 1-6 Alkyl, C 1-6 Alkylamino, Amino C 1-6 Alkyl, C 2-6 Alkenil, C 2-6Alkenylamino or C3-C8 cycloalkyl may contain one or more halogen atoms, hydroxyl, amino, or C. 1-6 Alkylamino, (C 1-6 Alkyl)2-amino, shea No, Okiso, C 6-14 Ariel, C 5-14 Heteroaryl, C 3-14 Heterocycloalkylene also teeth

[0010] [ka]

[0011] It is substituted with a group selected from; Preferably, R 4 H, halogen atom, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenil, C 2-6 Alkenylamino or C3-C8 cycloalkyl Yes, the aforementioned C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenil, C 2-6 Alkenylamino or C3-C8 cycloalkyl may contain one or more halogen atoms, hydroxyl, amino, or C. 1-6 Alkylamino, (C 1-6 Selected from alkyl)2-amino, cyano, or oxo. It is substituted with the base; R 3 Ha-(CR e R f ) m -CR 31 R 32 R 33 Here, m is 1, 2, or 3; R 31 , R 32 and R 33 H and C are independent of each other. 1-6Alkyl, halogen, or cyano atoms, and R 31 and R 32 Together C 3-8 A cycloalkylene may be formed, and the C 1-6 Alkyl and C 3-8 Cycloalkylenes are sometimes substituted with hydroxyl, cyano, amino, or halogen atoms; R a , R b , R c , R d , R e , R f These are H, halogen atom, hydroxyl, and H, respectively, independently of each other. C substituted with amino, cyano, and sometimes halogen atoms 1-6 It is alkyl.

[0012] In this specification, the heteroaryl / heteroarylene, heterocycloalkyl / heteroaryl Telocycloalkylenes and heterocycloalkenyl / heterocycloalkenylenes have a ring structure. It contains 1-4 heteroatoms selected from N, O, and S as atoms. The cycloalkyl / Cycloalkylene, heterocycloalkyl / heterocycloalkylene, heterocycloal Kenyl / heterocycloalkenylenes are monocyclic, bicyclic, or otherwise non-aromatic ring structures. Alternatively, it may be a tri-ring (preferably mono-ring or bi-ring) ring system, and the bi-ring, The tricyclic ring system includes a spiro ring, a bridging ring, or a fused ring. The aryl / arrine and The heteroaryl / heteroarylene may be a monocyclic, condensed bicyclic, or condensed tricyclic (preferably monocyclic or condensed bicyclic) ring system, and here the condensed bicyclic, The fused tricyclic ring system may contain a non-aromatic ring structure. The halogen atom is 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 is selected from CR a R b , C(O) and a bond; Z 2 is selected from O, S, NR c , C(O) and a bond, or C1-C6 alkylene optionally substituted by one or more identical 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 (pre ferably C 5-10 heteroarylene), each optionally substituted by a halogen atom, and a group selected from C 1-6 alkyl or C 1-6 alkoxy optionally substituted by a halogen atom; Cy 2 is a bond, C 3-10 cycloalkylene (preferably C 3-8 cycloalkylene), C 3-14 heterocy cloalkylene (preferably C 3-10 heterocycloalkylene); R 1 , R 2 are each independently of the other H or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted by a group selected from one or more halogen atoms, hydroxy or cyano ; R 3 is -(CR e R f ) m -CR 31 R 32 R 33 where m is 1, 2 or 3; R<00​​and R 33 H and C are independent of each other. 1-6 Alkyl, halogen, or cyano atoms, and R 31 and R 32 Together C 3-8 A cycloalkylene may be formed, and the C 1-6 Alkyl and C 3-8 Cycloalkylenes are sometimes substituted with hydroxyl, cyano, amino, or halogen atoms; R a , R b , R c , R d , R e , R f These are, independently of each other, H or halogen atoms; R 4 C 1-6 Alkyl, C 1-6 Alkylamino, Amino C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 It is an alkenylamino or C3-C8 cycloalkyl, and the C 1-6 Alkyl, C 1-6 Alkyl Amino, Amino C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkenylamino or C3-C8 cytoplasm Roalkyl may contain one or more halogen atoms, hydroxyl, amino, or C. 1-6 Alki Luamino, (C 1-6 Alkyl)2-amino, cyano, oxo and

[0014] [ka]

[0015] It is substituted with a group selected from; Preferably, R 4 C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenil, C2-6 It is an alkenylamino or C3-C8 cycloalkyl, and the C 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenil, C 2-6 Alkenylamino or C3-C8 cycloalkyl groups may be used individually. The above halogen atoms, hydroxyl, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2Am It is substituted with a group selected from no, cyano, or oxo.

[0016] In a more preferred embodiment of the compound of formula (I): Z 1 is a combination; Z 2 The following are selected from -O-CH2-CH2-, -O-CH2-, -NH-CH2-CH2-, -NH-CH2-, -NH-, or -O-; Cy 1 C 6-10 Arylene (preferably phenyl) and C 5-10 A heteroarylene (preferably pyridyl) is selected, and optionally a halogen atom (preferably F) or C. 1-6 Substituted with alkoxy (preferably methoxy); Cy 2 is bond, azetidiylene, pyrrolidylene, piperazilene,

[0017] [ka]

[0018] R 1 C 1-6 It is alkyl (preferably methyl); R 2 is H; R 3 -CH2-CR 31 R 32 R 33 and; R 31 , R32 and R 33 Each of these atoms is independently substituted with H, and optionally with a hydroxyl or halogen atom (preferably F). 1-6 Selected from alkyl, halogen atoms (preferably F), and cyano, and R 31 and R 32 C is optionally substituted with a hydroxyl or halogen atom (preferably F) along with it. 3-8 It may also form a cycloalkylene (preferably cyclopropylene); R 4 Depending on the case, halogen atoms (preferably F), oxo, C 1-6 Alkylamino (preferably methylamino), (C 1-6 Alkyl)2-amino (preferably dimethylamino), and

[0019] [ka]

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

[0021] Preferably, Cy 2 is selected from bond, azetidiylene, and pyrrolidylene, and R 4 In the case By halogen atoms (preferably F), oxo, C 1-6 Alkylamino (preferably methylamino) and (C 1-6 C is substituted with a group selected from alkyl)2amino (preferably dimethylamino) 1-6 Alkyl, C 1-6 Alkylamino, C 2-6 Alkenil, C 2-6 It is an alkenylamino acid.

[0022] Particularly preferred embodiments of the compound of formula (I): Z 1 is a combination; Z 2 It is selected from -NH- or -O-; Cy 1 is phenyl or pyridyl (preferably phenyl), and is sometimes substituted with F or methoxy; Cy 2 The following are selected from azetidilene, pyrrolidylene, and piperagilene; R 1 It is methyl; R 2 is H; R 3 -CH2-CR 31 R 32 R 33 and; R 31 , R 32 These are F and R respectively. 31 and R 32 They together form cyclopropylene; R 33 The hydroxymethyl methyl compound is selected from H, hydroxymethyl, and fluoromethyl, preferably F, hydroxymethyl. Selected from methyl or fluoromethyl; R 4 is F-(CH2)3- or

[0023] [ka] That is the case.

[0024] More preferably, Cy 2 R is selected from azetidiylene and pyrrolidylene. 4 It is F-(CH2)3-.

[0025] In some embodiments, the compound of formula (I) of the present invention is in the form of a stereoisomer, for example The carbon atom at position 1 of the tetrahydroisoquinoline ring (i.e., Z 1The carbon atom connected to it can be in an S configuration, and / or the carbon atom at position 3 (i.e., R 1 The carbon atoms connected to the R-axis It could be a body arrangement.

[0026] In some embodiments, the present invention relates to the following compounds, or their stereoisomers or pharmaceutically acceptable salts:

[0027] [ka]

[0028] [ka]

[0029] In another aspect, the present invention relates to a drug composition comprising one or more of the compounds of the present invention, or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0030] In another aspect, the present invention relates to the use of the compounds of the present invention for the manufacture of pharmaceuticals for the prevention or treatment of estrogen receptor-dependent or estrogen receptor-mediated diseases. [Modes for carrying out the invention]

[0031] Next, the present invention will be further explained with specific manufacturing examples and test examples. It should be noted 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 can be obtained by commercially available or literature-based methods. The test methods or characterization methods used are also known to those skilled in the art.

[0032] Example 1: (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidine-1-ylethoxyphenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (compound 1)

[0033] [ka]

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

[0035] [ka]

[0036] 2-amino-6-bromophenol (5 g, 26.6 mmol, 1 eq) was dissolved in 120 ml of tetrahydrofuran, and dicarbonylimidazole (5.17 g, 31.9 mmol, 1.2 eq) was added at 20°C. The reaction mixture was allowed to react at 80°C for 2 hours. After confirming the completion of the reaction by TLC, the reaction mixture was poured into ice water, the pH was adjusted to 2 with hydrochloric acid, and the mixture was extracted with ethyl acetate, dried, concentrated, and the crude product was purified by column chromatography to obtain 7-bromobenzo[d]oxazole-2(3H)-non (5.1 g, 23.8 mmol, 89.6%). The yield 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]oxazole-2(3H)-non

[0039] [ka]

[0040] 7-bromobenzo[d]oxazole-2(3H)-non (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 mixture was stirred at 0°C for 30 minutes, then triphenylmethyl chloride (6.64 g, 23.8 mmol, 1 eq) was added, and the reaction mixture was allowed to react at 20°C for 2 hours. The completion of the reaction was confirmed by TLC, the reaction mixture 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]oxazole-2(3H)-non (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]oxazole-7-yl)propan-2-yl)carbamate

[0043] [ka]

[0044] Dissolve 7-bromo-3-triphenylmethylbenzo[d]oxazole-2(3H)-non (4.0 g, 8.77 mmol, 1 eq) in tetrahydrofuran (20 mL), add n-butyllithium (2.5 M, 4.03 mL, 1.15 eq) under nitrogen protection at -78°C, and stir for 30 minutes. At -78°C, tetrahydrofuran was added to (R)-t-butyl4-methyl-1,2,3-oxazolidine-3-carboxylic acid 2,2-dioxide (2.50 g, 10.5 mmol, 1.2 eq). Lofuran (10 mL) solution was added to the reaction system, and the mixture was allowed to cool naturally to 0°C for 2 hours. The completion of the reaction was confirmed by TLC, the reaction mixture was quenched in ice water, 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]oxazole-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]oxazole-2(3H)-non

[0047] [ka]

[0048] At 20°C, tert-butyl(R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobenzo[d]o Xazol-7-yl)propan-2-yl)carbamate (4.3 g, 8.04 mmol, 1 eq) in hydrochloride Add to tanol solution (4 M, 30 mL, 14.9 eq), react for 2 hours, and terminate the reaction by TLC and LC-MS. After confirming completion, concentrate the reaction solution, neutralize it with saturated sodium bicarbonate, extract with ethyl acetate, concentrate to obtain the crude product, and suspend it in a 30 ml mixed solvent of petroleum ether:ethyl acetate = 3:1. The mixture was filtered to obtain (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazole-2(3H)-non 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: Synthesis of (R)-7-(2-(isobutylamine)propyl)-3-triphenylmethylbenzo[d]oxazole-2(3H)-non

[0052] [ka]

[0053] (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazole-2(3H)-non (1.65 g, 3.38 mmol, 1 eq) and 2-methylpropanal (292 mg, 4.06 mmol, 370 uL, 1.2 eq) Dissolve in 30 ml of methanol, and add acetic acid (406 mg, 6.76 mmol, 387 μL, 2 eq) and sodium cyanoborohydride (425 mg, 6.76 mmol, 2 eq) to the reaction mixture at 20°C. React for 2 hours. After allowing the reaction to proceed, the completion of the reaction was confirmed by TLC and LC-MS, and the reaction solution was concentrated and then saturated sodium bicarbonate was added. The solution was neutralized with ammonium, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to obtain (R)-7-(2-(isobutylamine)propyl)-3-triphenylmethylbenzo[d]oxy Sazole-2(3H)-non 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]oxazole-2(3H)-non

[0057] [ka]

[0058] (R)-7-(2-(isobutylamine)propyl)-3-triphenylmethylbenzo[d]oxazole-2(3H)-non (1.7 g, 3.46 mmol, 1 eq) is dissolved in a mixed solvent of 20 ml of trifluoroacetic acid and 2 ml of water. The mixture was dissolved and reacted at 20°C for 3 hours. The completion of the reaction was confirmed by TLC and LC-MS, and the reaction mixture was concentrated at 50°C. After further concentration of the reaction mixture, saturated sodium bicarbonate was added to neutralize the pH, and the mixture 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)-non This 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]isoquinoline-2(3H)-non

[0062] [ka]

[0063] (R)-7-(2-(isobutylamine)propyl)benzo[d]oxazole-2(3H)-non (600 mg, 1 eq) and 4-bromo-2,6-difluorobenzaldehyde (800 mg, 1.5 eq) in 30 ml of toluene. The reaction mixture was dissolved in [a solution] and acetic acid (450 mg, 3 eq) was added. The reaction mixture was allowed to react for 24 hours under conditions of 115°C. TLC and LC-MS measurements 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, yielding (6S,8R)-6-(4- Bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxa Zoro[5,4-f]isoquinoline-2(3H)-non 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: Compound (6S,8R)-6-(4-bromo-2,6-difluorophenyl)-7-isobutyl-8-methyl-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non 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)-non (240 mg, 532 μmol, 1 eq) N,N-di Dissolve in 10 ml of methylformamide and add sodium hydride (42.5 mg, 1.06 mmol, 60% purity, 2 eq) at 0°C. Then, add triphenylmethyl chloride (163 mg, 585 μmol, 1.1 eq) to the reaction mixture at 0°C, slowly raise the temperature to 20°C, and react for 2 hours. Reactions were observed by TLC and LC-MS. After confirming completion, the reaction mixture is poured into water and quenched, extracted with ethyl acetate, the organic phase is dried and concentrated, and the crude product is purified by column chromatography to obtain (6S,8R)-6-(4-bromo-2,6-di Fluorophenyl)-7-isobutyl-8-methyl-3-triphenylmethyl-6,7,8,9-tetrahydr Looxazolo[5,4-f]isoquinoline-2(3H)-non 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)azetidine-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 mixture was reacted for 12 hours. The completion of the reaction was confirmed by TLC, the reaction mixture was adjusted to a pH above 9, extracted with ethyl acetate, the organic phase was dried and concentrated, and the crude product was purified by column chromatography to obtain 2-(3-(fluoromethyl)azetidine-1-yl)ethanol as a yellow oily substance (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)-azetidi Synthesis of n-1-ylethoxyphenyl)-7-isobutyl-8-methyl-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[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]isoquinoline-2(3H)-non (300 mg, 329 μmol, 1 eq) and 2-(3-(fluoromethyl)azetidine-1-yl)ethanol (109 mg, 822 μmol, 2.5 eq) are dissolved in toluene (9 ml) to form [(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 (3 μmol of 1 / 2 eq) was added, and the reaction mixture was allowed to react at 110°C for 24 hours. The completion of the reaction was confirmed by TLC and LC-MS. After confirmation and concentration of the reaction mixture, it was purified by column chromatography to obtain (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidine-1-yl-ethoxyphenyl)-7-I Sobutyl-8-methyl-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained as a yellow solid (90 mg, 121 μmol, yield 36.7%).

[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)-azetidi (1-ylethoxyphenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydrooxazo Synthesis of [5,4-f]isoquinoline-2(3H)-non (Compound 1)

[0080] [ka]

[0081] (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidine-1-yl- Toxyphenyl)-7-isobutyl-8-methyl-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (90 mg, 120.66 μmol, 1 eq) is trifluoro The mixture was dissolved in a mixture of acetic acid (9 mL) and water (1 mL) and reacted at 20°C for 2 hours. After confirming the completion of the reaction by TLC and LC-MS, the reaction solution was concentrated at 40°C, and then saturated sodium bicarbonate was added. The solution was neutralized, extracted with ethyl acetate, dried and concentrated the organic phase, and the crude product was separated by silica gel thin-layer chromatography. (6S,8R)-6-(2,6-difluorophenyl-4-(2-(3-(fluoromethyl)-azetidine-1-ylethoxyphenyl)-7-isobutyl-8-methyl-6,7,8,9-tetrahydr Looxazolo[5,4-f]isoquinoline-2(3H)-non 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)azetidine-3-yl)amino)pyrid (-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (compound 5)

[0085] [ka]

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

[0087] [ka]

[0088] 7-Bromo-3-triphenylmethyl-benzoxazole-2-non (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 the mixture was stirred for 30 minutes. A solution of (R)-t-butyl4-methyl-1,2,3-oxazolidine-3-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 the mixture was allowed to cool naturally to 0°C 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 and quenched, then extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography and tert-butyl(R)-(1-(2-O Xo-3-triphenylmethyl-2,3-dihydrobenzo[d]oxazole-7-yl)propan-2-yl)carbamate was obtained as a yellow solid (360 g, 673 mmol, yield 74.9%).

[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]oxazole-2(3H)-non

[0091] [ka]

[0092] tert-butyl(R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydro under nitrogen protection at 0°C Benzo[d]oxazole-7-yl)propan-2-yl)carbamate (240 g, 448 mmol, 1 eq) was dissolved in methanol (400 ml) and added to methanol hydrochloride solution (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 mixture was concentrated and saturated sodium bicarbonate was added. The solution was neutralized with um, extracted with ethyl acetate, and concentrated to obtain the crude product. The crude product was suspended in petroleum ether:ethyl acetate = 1:1 and filtered to obtain (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazole-2(3H)-non (198 g, 455 mmol, yield 84.6%) 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]oxazole-2(3H)-non

[0095] [ka]

[0096] (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazo under nitrogen protection at 20°C 100 mL of dioxane (10.0 g, 23.0 mmol, 1 eq) 2,2,2-trifluoroethyltrifluoromethanesulfonate (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 100 mL of dioxane and reacted at 80°C under nitrogen protection for 10 hours. The reaction was confirmed to be complete by TLC, the reaction mixture was concentrated, and the crude product was subjected to column chromatography. Purification by tography yielded (R)-7-2-aminopropyl)(2,2,2-trifluoroethyl-3-triphenylmethylbenzo[d]oxazole-2(3H)-non 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-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinolino[5,4-f]oxazole-2(3H)-non

[0099] [ka]

[0100] (R)-7-2-aminopropyl)(2,2,2-trifluoroethyl-3-triphenylmethylbenzo[d]oxazole-2(3H)-non (1.00 g, 1.94 mmol, 1 eq) and 5-bromo-2-pyridinecarboxyl Ludehyde (540 mg, 2.90 mmol, 1.5 eq) was dissolved in toluene (50 mL), and trifluoroacetic acid (662 mg, 5.81 mmol, 430 μL, 3 eq) was added. The mixture was reacted at 90°C for 20 hours. The reaction was then performed by TLC. After confirming the completion of the reaction, the reaction mixture was concentrated, and the crude product was purified by TLC (petroleum ether:ethyl acetate = 10:1), and (6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinolino[5,4-f]oxazole-2(3H)-non was found as a yellow solid. This yielded (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-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0103] [ka]

[0104] (6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinoline [5,4-f]oxazole-2(3H)-non (1.00 g, 2.26 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (181 mg, 4.52 mmol, 60% purity, 2 eq) was added at 0°C, and then triphenylmethyl chloride (693 mg, 2.49 mmol, 1.1 eq) was added at 20°C. The reaction was allowed to proceed for 2 hours. The completion of the reaction was confirmed by TLC. Water was added to the reaction mixture. Quenched, extracted with ethyl acetate, dried, concentrated, and the crude product was purified by column chromatography. (6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroe) (Tyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained as a white solid (1.20 g, 1.56 mmol, 69.0% yield).

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

[0107]

Chem.

[0108] tert-butyl (6S,8R)-6-(5-bromopyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroeth yl)-3-trityl-6,7,8,9-tetrahydroisoquinolino[5,4-f]oxazole-2(3H)-one (200 mg, 292 μmol, 1 eq) and 3-aminoazetidine-1-carboxylate (126 mg, 730 μmol, 2.5 eq) were dissolved in 8 ml of toluene, [(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, and the reaction mixture was stirred at 110 °C for 15 h. The completion of the reaction was confirmed by TLC, 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-ox o-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)amino)azetidine-1-carbox ylate as a yellow solid (120 mg, 137 μmol, 47.2% yield). ylate 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-(azetidine-3-amino)pyridine-2-yl)-8-methyl-7-(2,2,2- Synthesis of trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0111] [ka]

[0112] At 0°C, 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]isoquinoline-6-yl)pyridine-3-yl)amino)azetidine-1- The mixture was added to carboxylate (120 mg, 154 μmol, 1 eq) and reacted at 20°C for 2 hours, and the completion of the reaction was confirmed by TLC. The reaction solution was quenched with water, extracted with ethyl acetate, dried, concentrated, and (6S,8R)-6-(5-(azetidine-3-amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-no The substance was obtained as a yellow solid (120 mg, crude product).

[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)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (Compound 5)

[0115] [ka]

[0116] Under nitrogen protection at 20°C, (6S,8R)-6-(5-(azetidine-3-amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (66.0 mg, 152 μmol, 1 eq) and 3-fluoro-1-iodopropane (28.6 mg, 152 μmol, 1 eq) were dissolved in N,N-dimethylformamide (1 mL), and diisopropylethylenediamine (98.4 mg, 761 μmol, 132 μL, 5 eq) was added. The mixture was reacted at 20°C for 4 hours. The completion of the reaction was monitored by LC-MS. The reaction mixture was quenched with water and ethyl acetate was used. Extracted, dried, and concentrated. The crude product was purified by reverse-phase column chromatography, and then by chiral column chromatography. (6S,8R)-6-(5-((1-(3-fluoropropane)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]iso Quinoline-2(3H)-non was obtained as a yellow solid (27.0 mg, 54.2 μmol, yield 35.6%, purity 97.7%, 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-Fluoropropyl)pyrrolidin-3-yl)oxy)pi peridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxa zolo[5,4-f]isoquinolin-2(3H)-one (Compound 7)

[0120]

Chem.

[0121] Step 1: Synthesis of tert-butyl (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroeth [[ID=2,5]]yl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate

[0122]

Chem.

[0123] (6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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), and then RockPhos Pd G3 (18.3 mg, 21.9 μmol, 0.1 eq) and cesium carbonate (214 mg, 657 μmol, 3 eq) were added. The reaction mixture was allowed to react at 115°C for 15 hours. The completion of the reaction was confirmed by TLC, and the reaction mixture was quenched with water, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography and tert-butyl(S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethylene (Tyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinoline-6-yl)pyridine-3-yl)oxy)pyrrolidine-1-carboxylate was obtained as a yellow solid (120 mg, 138 μmol, yield 31.5%).

[0124] 1H 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)-pyrrolidine-3-oxy)pyridine-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)- Non synthesis

[0126] [ka]

[0127] At 0°C, trifluoroacetic acid (1.54 g, 13.4 mmol, 997 μL, 87.3 eq) is dissolved in dichloromethane (2 mL). Dissolved tert-butyl(S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluor The mixture was added to (6S,8R)-8-methyl-6-(5-((S)-pyrrolidine-3-oxy)pyrrolidine-2(3H)-non (120 mg, 154 μmol, 1 eq) and reacted at 20°C for 2 hours. The reaction was confirmed to be complete by TLC and LC-MS. The reaction mixture was quenched with 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)-pyrrolidine-3-oxy)pyridine-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non 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)pyrrolidine-3-yl)oxy)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazo Synthesis of [5,4-f]isoquinoline-2(3H)-non (Compound 7)

[0131] [ka]

[0132] (6S,8R)-8-methyl-6-(5-((S)-pyrrolidine-3-oxy)pyridine-2-I under nitrogen protection at 20°C Dissolve (105 mg, 187 μmol, 1 eq) and 3-fluoro-1-iodopropane (35.2 mg, 187 μmol, 1 eq) in N,N-dimethylformamide (2 mL) and diisopropylethyl 121 mg, 936 μmol, 163 μL, 5 eq of sulfondiamine was added, and the mixture was reacted at 20°C for 4 hours. The completion of the reaction was monitored by LC-MS, water was added to the reaction mixture to quench it, and the mixture was extracted with ethyl acetate, dried, and concentrated. The crude product was purified by reverse-phase column chromatography and obtained (6S,8R)-6-(5-(((S)-1-(3-F (Oropropane)pyrroridine-3-yl)oxy)pyridine-2-yl)-8-methyl-7-(2,2,2-tri Fluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non 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]isoquinoline-2(3H)-non (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]isoquinoline-6-yl)phenyl)-2,6-diazaspiro[3,3]heptane-2-carboxylate Synthesis of te

[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-carb Dissolve xylate (165.33 mg, 833.88 μmol) in toluene (9 mL), add 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), protect with nitrogen gas, react at 110°C for 24 hours, and analyze by LC-MS. After confirming the completion of the reaction, the reaction solution was concentrated and purified by 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]oxazole-6-yl)phenyl)-2,6-diazaspiro[3.3]heptan-2-carboxylate (120 mg, 143 mg). 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)-non

[0142] [ka]

[0143] tert-butyl6-(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]isoquinoline-6-yl)phenyl)-2,6-diazaspiro[3.3]heptan-2-carboxylate (300mg) (358.47 μmol) was dissolved in trifluoroacetic acid (4.5 mL) and water (0.5 mL), and the mixture was heated to 20°C and stirred for 2 hours. The completion of the reaction was confirmed by LC-MS, and after concentration, the pH was adjusted to 7-8, extracted with water and ethyl acetate, and the organic phase was concentrated to obtain (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)-non (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-tetra Synthesis of Hydroxazolo[5,4-f]isoquinoline-2(3H)-non

[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]isoquinol 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), and then N,N-diisopropylethylamide was added. (313.66 mg, 2.43 mmol) was reacted at 20°C for 2 hours, and the completion of the reaction was confirmed by LC-MS, and water and Extraction with ethyl acetate, washing the organic phase three times with brine, concentration, and purification by 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]isoquinoline-2(3H)-non 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-tetra Separation of hydroxazolo[5,4-f]isoquinoline-2(3H)-non (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-tetrahydrooxy Chiral separation of sazolo[5,4-f]isoquinoline-2(3H)-non yielded (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]isoquinoline-2(3H)-non (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)azetidine-3-yl)amino)phenyl)-8-methyl-6,7,8,9-teto Lahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (compound 9)

[0153] [ka]

[0154] Step 1: (R)-7-(2-((3-((t-butylphenylsilyl)oxy)-2,2-difluoropropyl) Synthesis of mino)propyl)-3-triphenylbenzo[d]oxazole-2(3H)-non

[0155] [ka]

[0156] Subsequent steps: By steps similar to those in Examples 1-8 and / or conventional reaction steps in the art, (R)-7-(2-((3-((t-butylphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl Starting from (l)-3-triphenylbenzo[d]oxazole-2(3H)-non, compound 9 was synthesized. .

[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] Similar to the synthesis routes in Examples 1-9 above, the corresponding reactants and synthesis methods known to those skilled in the art. We selected and synthesized the following example compounds. Specifically, the compound from Step 1 of Example 9, that is, Using "(R)-7-(2-((3-((t-butylphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)-3-triphenylbenzo[d]oxazole-2(3H)-non" as a raw material, the following Examples 13-15 were synthesized; the compound of Step 3 of Example 5, namely "(R)-7-2-aminopropyl)(2,2,2-trifluoroethyl-3-triphenylmethylbenzo[d]oxazole-2(3H)-non" as a raw material As a material, synthesize the compounds from Examples 10-12, 16, 18, and 25 below; and synthesize the compound from Step 4 of Example 1, namely "(R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazole-2(3H)-non The following Example 20 was synthesized using "[ ]" as a raw material.

[0159] Example 10: (6S,8R)-6-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3- (L)amino)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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- Iyl(oxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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)azetidine-3- (Lu)oxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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)pyrrolidine-3-yl)oxy)phenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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]isoquinoline-2(3H)-non (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)azetidine-1-yl)phenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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]isoquinoline-6-yl) Phenoxyethyl amino-N,N-dimethylbuta-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)azetidi (1-yl)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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)azetidine-3- (L)amino)phenyl)-7-((1-fluorocyclopropyl)methyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non(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)azetidine-3-yl)amino)-2-methyl Toxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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]isoquinoline-2(3H)-non

[0190] [ka]

[0191] Compound (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)benzo[d]oxazole-2(3H)-non (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 stored in nitrogen at 110°C. The reaction was allowed to proceed for 48 hours under protective conditions. The completion of the reaction was confirmed by LC-MS. After concentrating the reaction mixture, it was purified by column chromatography and (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)-no The substance was obtained as a white solid (4.35 g, 9.23 mmol, yield 84.4%).

[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]isoquinoline-2(3H)-non

[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)-non (2.77 g, 5.88 mmol) was dissolved in N,N-dimethylformamide (25 mL), sodium hydride (353 mg, 8.82 mmol) was added under nitrogen protection at 0°C, and then triphenylchloromethane (1.64 g, 5.88 mmol) was added. The reaction mixture was allowed to react at 25°C for 2 hours. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain (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]isoquinoline-2(3H)-non is a yellow solid. This was obtained as (3.75 g, 5.26 mmol, yield 89.4%).

[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, 3 H) ppm.

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

[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)-non (2g, 2.80 mmol), 1-(3-fluoropropyl)-3-aminoazetidine (1.41g, 3.92 mmol), carbonate Cesium (2.74g, 8.41mmol), [(2-di-t-butylphosphin-3-methoxy-6-methyl-2,4,6- Dissolve triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)palladium(II)methanesulfonate (118 mg, 140 umol) in toluene (20 mL) and invert at 110°C under nitrogen protection for 12 hours. The reaction was allowed to proceed. The completion of the reaction was monitored by LC-MS. The solution was concentrated and purified by column chromatography to obtain (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidine-3-yl)amino)-2-methoxy Phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-T Trahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained as a yellow solid (1 g, 1.31 mmol, yield 46.7%).

[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)azetidine-3-yl)amino)-2-meth Synthesis of xyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (Compound 25)

[0204] [ka]

[0205] Trifluoroacetic acid (15.4 g, 135 mmol) and (6S,8R)-6-(4-((1-(3-fluoropropyl)aze Tizidine-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)-no (1 g, 1.31 mmol) was dissolved in water (1 mL), and the reaction mixture was allowed to react at 20°C under nitrogen protection for 1 hour. The completion of the reaction was confirmed by LC-MS. After concentrating the mixture, the pH was adjusted to 7 with sodium hydrocarbons, and the organic phase was concentrated by extraction with water and ethyl acetate. After purifying the crude product by column chromatography, chiral separation was performed by SFC, and (6S,8R)-6-(4-((1-(3-fluoropropyl)azeti Zin-3-yl)amino)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained as a yellow solid (300 mg, 571 umol, yield 43.7%).

[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)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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-benzoxazol-2-non (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 at -78°C under nitrogen protection, and the mixture was stirred for 30 minutes. A solution of tert-butyl(R)-4-methyl-1,2,3-oxythiazolidined-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 mixture was allowed to cool naturally to 0°C for 2 hours. The completion of the reaction was confirmed by TLC, the reaction mixture was poured into saturated ammonium chloride aqueous solution and quenched, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography, and tert- Butyl(R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobenzo[d]oxazol-7- (Iyl)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)-non

[0215] [ka]

[0216] Under 0°C nitrogen protection, tert-butyl(R)-(1-(2-oxo-3-triphenylmethyl-2,3-dihydrobe Nzo[d]oxazol-7-yl)propan-2-yl)carbamate (240 g, 448 mmol, 1 eq) was dissolved in methanol (400 ml), and then added to methanol hydrochloride solution (6 M, 800 mL, 10.6 eq). The reaction was allowed to proceed at 0°C for 2 hours, and completion of the reaction was confirmed by TLC. The reaction mixture was concentrated and saturated with bicarbonate. Sodium is added to neutralize, the product is extracted with ethyl acetate and concentrated to obtain the crude product, which is then suspended in petroleum ether:ethyl acetate = 1:1 and filtered to obtain (R)-7-(2-aminopropyl)-3-triphenylmethyl Rubenzo[d]oxazol-2(3H)-non was obtained as a yellow solid (198 g, 455 mmol, yield 84.6%).

[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 tilbenzo[d]oxazol-2(3H)-non

[0219] [ka]

[0220] Under nitrogen protection at 20°C, (R)-7-(2-aminopropyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-non (10.0 g, 23.0 mmol, 1 eq), 2,2,2-trifluoroethyltrifluoromethanesulfonate (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 reaction was confirmed to be complete by TLC, the reaction mixture was concentrated, and the crude product was analyzed by column chromatography. Purified by Fee, (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)-3-triphen Nylmethylbenzo[d]oxazol-2(3H)-non was obtained as a white solid (9.00 g, 17.4 mmol, yield 75.7%).

[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 = 8.0Hz , 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-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinolino[5,4-f]oxazol-2(3H)-non

[0223] [ka]

[0224] (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)-3-triphenylmethylbenzo[d]oxazol-2(3H)-non (1.00 g, 1.94 mmol, 1 eq) and 5-bromo-2-pyridinecal Voxyaldehyde (540 mg, 2.90 mmol, 1.5 eq) was dissolved in toluene (50 mL), and trifluoroacetic acid (662 mg, 5.81 mmol, 430 μL, 3 eq) was added. The mixture was then reacted at 90°C for 20 hours. The reaction was confirmed to be complete by TLC, the reaction mixture was concentrated, and the crude product was purified by TLC (petroleum ether:ethyl acetate = 10:1) to (6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-tri Fluoroethyl)-6,7,8,9-tetrahydroisoquinolino[5,4-f]oxazol-2(3H)-non was obtained 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-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0227] [ka]

[0228] (6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydroisoquinolino[5,4-f]oxazol-2(3H)-non (1.00 g, 2.26 mmol, 1 eq) is dissolved in N,N-dimethylformamide (20 mL) and heated at 0°C with sodium hydride (181 mg, 4.52 (mol, 60% purity, 2 eq) was added, and then triphenylmethyl chloride (693 mg, 2.49 mmol, 1.1 eq) was added at 20°C and the mixture was reacted for 2 hours. The completion of the reaction was confirmed by TLC. Water was added to the reaction mixture. The mixture is quenched with the addition of (6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-tri Fluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained as a white solid (1.20 g, 1.56 mmol, yield 69.0%).

[0229] 1H 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-trifluoroeth Synthesis of (L)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinoline-6-yl)pyridine-3-yl)amino)azetidine-1-carboxylate

[0231] [ka]

[0232] (6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (200 mg, 292 umol, 1 eq) and tert-butyl3-aminoazetidine-1-carboxylate (126 mg, 730 umol, 2.5 eq) were dissolved in 8 ml of toluene, and to this, [(2-di-t-butylphosphin-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, Add 3 eq) and allow the reaction mixture to react at 110°C for 15 hours. The reaction was observed by TLC. After confirming completion, water was added to the reaction mixture to quench it, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography and obtained tert-butyl3-((6-((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)pyridine-3-yl)amino)azetidine-1-ca Luboxylate was obtained as a yellow solid (120 mg, 137 umol, yield 47.2%).

[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-(azetidine-3-ylamino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)- Non synthesis

[0235] [ka]

[0236] At 0°C, tert-butyl 3-((6-((6S,8R)-8-methyl methyl ester is added to trifluoroacetic acid (9.00 mL) and water (1.00 mL). Add the mixture to 120 mg, 154 umol, 1 eq of thiol-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinoline-6-yl)pyridine-3-yl)amino)azetidine-1-carboxylate and react the mixture at 20°C for 2 hours. The end of the reaction was confirmed by TLC. Water was added to the reaction mixture to quench it, and then it was extracted with ethyl acetate. The mixture was dried and concentrated, and (6S,8R)-6-(5-(azetidine-3-ylamino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained as a yellow solid (120 mg, crude product).

[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)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0239] [ka]

[0240] (6S,8R)-6-(5-(azetidine-3-ylamino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (66.0 mg, 152 umol, 1 eq) and 3-fluoro-1-iodopropane (28.6 mg, 152 eq) under nitrogen protection at 20°C. Dissolve 1 eq of umol in N,N-dimethylformamide (1 mL), add diisopropylethylenediamine (98.4 mg, 761 umol, 132 μL, 5 eq), and react the mixture at 20°C for 4 hours. The completion of the reaction was monitored by LC-MS. Quench the reaction mixture with water, extract with ethyl acetate, dry, and concentrate. 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)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluor Roethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained as a yellow solid (27.0 mg, 54.2 umol, yield 35.6%, purity 97.7%).

[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)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (compound 27)

[0244] [ka]

[0245] Step 1: (6S,8R)-6-(5-bromo-3-fluoropyridine-2-yl)-8-methyl-7-(2,2,2-triph Synthesis of ruoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0246] [ka]

[0247] Compound (R)-7-(2-(2,2,2-trifluoroethyl)amino)propyl)benzo[d]oxazol-2(3H)-non (500 mg, 1.82 mmol), 5-bromo-3-fluoropyridine-2-formaldehyde (390 mg, 1.91 mmol), and trifluoroacetic acid (1.04 g, 9.12 mmol) are dissolved in toluene (10 mL) and heated at 90°C in nitrogen. The reaction was allowed to proceed for 12 hours under protective conditions. The completion of the reaction was confirmed by LC-MS. After concentrating the reaction mixture, the pH was adjusted to 7-8, and the organic phase was extracted with water and ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The solution was then purified by column chromatography to obtain (6S,8R)-6-(5-bromo-3-fluoropyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non as a yellow solid (605 mg, 1.22 mmol, yield 66.8%).

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

[0249] 1 H 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-fluoropyridine-2-yl)-8-methyl-7-(2,2,2-tri Synthesis of fluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0251] [ka]

[0252] (6S,8R)-6-(5-bromo-3-fluoropyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroyl) Dissolve 6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (600 mg, 1.21 mmol) in N,N-dimethylformamide (12 mL), add sodium hydride (58 mg, 1.45 mmol) under nitrogen protection at 0°C, stir for 30 minutes, and then add triphenylchloromethane (336 mg, 1.21 mmol). The reaction mixture was added and allowed to react at 20°C for 30 minutes. The completion of the reaction was confirmed by LC-MS. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried, and concentrated. The crude product was purified by column chromatography and obtained (6S,8R)-6-(5-bromo-3-fluoropyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenyl Methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non is a white solid. It was obtained as a physical substance (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)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0256] [ka]

[0257] (6S,8R)-6-(5-bromo-3-fluoropyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroyl) Dissolve (Cyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (400 mg, 526 ml), 1-(3-fluoropropyl)aminoazetidine (379 mg, 1.05 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 (44.1 mg, 52.6 ml) in toluene (10 mL) and heat at 110°C under nitrogen protection. The reaction was allowed to proceed for 12 hours. The completion of the reaction was monitored by LC-MS. The mixture was concentrated and purified by column chromatography, and (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azeti Zin-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non is a lighter form of It was obtained as a yellow solid (163 mg, 188 umol, yield 35.8%).

[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)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0261] [ka]

[0262] Dissolve trifluoroacetic acid (2.02 g, 17.6 mmol) in water (0.05 mL), add it to (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (120 mg, 138 ml), and react for 5 hours at 20°C under nitrogen protection. The reaction was completed using LC-MS. After concentrating the mixture, the pH was adjusted to 7-8, and water and Extraction with ethyl acetate, washing of the organic phase with saturated saline, drying with sodium sulfate, and concentration were performed. The prep-HPLC spectrum of the crude product was determined to be (6S,8R)-6-(3-fluoro-5-((1-(3-fluoro (Ropyr)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoro) Methyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained 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)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0265] [ka]

[0266] (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidine-3-yl)amino)pyridin (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was chiral-separated, and (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidine-3-yl)amino)pyridine-2-yl)-8-methyl-7-(2,2,2-trif Luoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained (42.7 mg, 83.5 umol, yield 61.0%).

[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)azetidine-3-yl)amino)-3-methyl Toxypyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydr Looxazolo[5,4-f]isoquinoline-2(3H)-non (compound 28)

[0269] [ka]

[0270] Step 1: (6S,8R)-6-(5-bromo-3-methoxypyridine-2-yl)-8-methyl-7-(2,2,2-triph Synthesis of ruoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0271] [ka]

[0272] (R)-7-(2-((2,2,2-trifluoroethyl)amino)propyl)benzo[d]oxazol-2(3H)-non (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 allowed to proceed at 90°C for 12 hours. The completion of the reaction was confirmed by LC-MS, and the reaction mixture was concentrated and purified by silica gel column to obtain (6S,8R)-6-(5-bromo-3-methoxypyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (750 mg, 1.59 mmol, yield 87.1%).

[0273] Step 2: (6S,8R)-6-(5-bromo-3-methoxypyridine-2-yl)-8-methyl-7-(2,2,2-tri Synthesis of fluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0274] [ka]

[0275] (6S,8R)-6-(5-bromo-3-methoxypyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroyl) Dissolve 700 mg, 1.48 mmol of (Chill)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non in 14 mL of N,N-dimethylformamide. Add 71.1 mg, 1.78 mmol, 60% purity sodium hydride at 0°C. After stirring for 30 minutes, add 371 mg, 1.33 mmol of triphenylmethyl chloride, raise the temperature to 20°C, and react for 2 hours. Confirm the completion of the reaction by LC-MS. Cool the reaction solution in ice water. The solution was quenched and extracted with ethyl acetate. The organic phase was washed three times with saturated saline solution, concentrated, and purified by silica gel column to obtain (6S,8R)-6-(5-bromo-3-methoxypyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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)azetidine-3-yl)amino)-3-meth Synthesis of xypyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0278] [ka]

[0279] (6S,8R)-6-(5-bromo-3-methoxypyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroyl) (Tyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (400 mg, 560 umol), 1-(3-fluoropropyl)azetidine-3-amine (403 mg, 1.12 mmol), [(2-di-t-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (46.9 mg) (56.0 µl) and cesium carbonate (730 mg, 2.24 mmol) were dissolved in toluene (2 mL). Nitrogen The mixture was protected with gas and reacted at 110°C for 12 hours. The completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated. The mixture was then purified by silica gel column chromatography to obtain (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidine-3-yl)amino)-3-methoxypyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (160 mg, 209 umol, yield 33.2%).

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

[0281] [ka]

[0282] (6S,8R)-6-(5-((1-(3-fluoropropyl)azetidine-3-yl)amino)-3-methoxypyridin (160 mg, 208 ml) isioquinoline-2(3H)-non (160 mg, 208 ml) is mixed with water (0.5 mL) and It was dissolved in 4.5 mL of difluoroacetic acid. The reaction was allowed to proceed at 20°C for 2 hours, and the completion of the reaction was confirmed by LC-MS. The pH of the sodium hydrocarbon solution was adjusted to 7-8, and the organic phase was extracted with water and ethyl acetate. Washed three times with water, concentrated, and then purified by silica gel column chromatography, (6S,8R)-6-(5-((1-(3-fluoro Propyl)azetidine-3-yl)amino)-3-methoxypyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non 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)pyrrolidine-3-yl)oxy)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxa Zoro[5,4-f]isoquinoline-2(3H)-non (compound 29)

[0285] [ka]

[0286] Step 1: tert-butyl(S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroe Synthesis of (Tyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinoline-6-yl)pyridine-3-yl)oxy)pyrrolidine-1-carboxylate

[0287] [ka]

[0288] (6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (150 mg, 219 umol, 1 eq) and tert-butyl(S)-3-hydroxypyrrolidine-1-carboxylate Dissolve (102 mg, 547 umol, 2.5 eq) 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 allowed to react at 115°C for 15 hours. The completion of the reaction was confirmed by TLC, water was added to the reaction mixture to quench it, and the mixture was extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography and tert-butyl(S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3- Triphenylmethyl-2,3,6,7,8,9-hexahydroxazolo[5,4-f]isoquinoline-6-yl) Pyridine-3-yl)oxy)pyrrolidine-1-carboxylate was obtained as a yellow solid (120 mg, 138 umol, yield 31.5%).

[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)-pyrrolidine-3-yl)oxy)pyridine-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0291] [ka]

[0292] At 0°C, trifluoroacetic acid (1.54 g, 13.4 mmol, 997 μL, 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]isoquinoline-6-yl)pyridine-3-yl)oxy)pyrrolidine-1-carboxylate (120 mg, 154 μL, 1 eq) dissolved in dichloromethane (2 mL). The mixture was reacted at 20°C for 2 hours, and the completion of the reaction was confirmed by TLC and LC-MS. The mixture was quenched with 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)-pyrrolidine-3-yl)oxy)pyridine-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non as a yellow solid (105 mg, crude product).

[0293] LCMS: m / z (M+H) + = 449.2 1H 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)pyrrolidine-3-yl)oxy)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazo Synthesis of ro[5,4-f]isoquinoline-2(3H)-non

[0295] [ka]

[0296] (6S,8R)-8-methyl-6-(5-((S)-pyrrolidine-3-yl)oxy)pyridine-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isopropyl at 20℃ under nitrogen protection. Nolin-2(3H)-non (105 mg, 187 umol, 1 eq) and 3-fluoro-1-iodopropane (35.2 mg, 187 umol, 1 eq) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylenediamine (121 mg, 936 umol, 163 μL, 5 eq) was added. The mixture was reacted at 20°C for 4 hours. The reaction was monitored by LC-MS, water was added to the reaction mixture to quench it, and the mixture was extracted with ethyl acetate, dried, and concentrated. The crude product was purified by reverse-phase column chromatography (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water(0.04%NH3H2O+10mM NH4HCO3)-ACN]; B%: 18%-58%, 14 min) 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)pyrrolidine-3-yl)oxy)pyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained as a white solid (10.5 mg, 19.8 umol, yield 10.6%, purity 96%).

[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)pyrrolidine-3-yl)oxy)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro Xasazolo[5,4-f]isoquinoline-2(3H)-non (compound 30)

[0299] [ka]

[0300] Step 1: tert-butyl(S)-3-(3-methoxy-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-tri Synthesis of fluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinoline-6-yl)phenoxy)pyrrolidine-1-carboxylate

[0301] [ka]

[0302] tert-butyl(6S,8R)-6-(4-bromo-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluor (Roethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (500mg, 700umol), (S)-3-hydroxypyrrolidine-1-carboxylate (236m (g, 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 end of the reaction was confirmed by LC-MS. The product was mixed and concentrated, purified by column chromatography, and 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- Il(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)-pyrrolidine-3-yloxy)phenyl)-8-meth Ru-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoli Synthesis of 2(3H)-non

[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]isoquinoline-6-yl)phenoxy)pyrrolidine-1-carboxylate (180 mg, 220 umol) is trifluoro The solution was dissolved in 2 ml of acetic acid and 0.2 ml of water, and reacted at 20°C for 2 hours. The completion of the reaction was confirmed by LC-MS. Confirmed. After concentrating the mixture, the pH was adjusted to 7-8, and the organic phase was extracted with water and ethyl acetate. The solution was washed with saturated saline solution, dried over sodium sulfate, and concentrated. Purification by column chromatography yielded (6S,8R)-6-(2-methoxy-4-((S)-pyrrolidine-3-yloxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non as a yellow solid (110 mg, yield 77.7%).

[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)pyrrolidine-3-yl)oxy)-2- Synthesis of Methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0309] [ka]

[0310] (6S,8R)-6-(2-methoxy-4-((S)-pyrrolidine-3-yloxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-no N,N-dimethylamine (110 mg, 170 umol) and diisopropylethylamine (66.1 mg, 511 umol) are combined with N,N-dimethylamine. The mixture was dissolved in 3 mL of tetrolformamide, 25.6 mg of 3-fluoro-1-iodopropane (136 umol) was added at 20°C, and the mixture was reacted for 3 hours. The completion of the reaction was confirmed by TLC, and 60 mg of the crude product was obtained by purification by HPLC. Next, chiral purification by SFC yielded (6S,8R)-6-(4-(((S)-1-(3-fluoropropyl)pyrrolidine-3-yl)oxy)-2-methoxyphenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non 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-fluoro Ropil)azetidine-3-yl)amino)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydroxy Diloxazolo[5,4-f]isoquinoline-2(3H)-non

[0313] [ka]

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

[0315] [ka]

[0316] (R)-7-(2-(((1-fluorocyclopropyl)methyl)amino)propyl)benzo[d]oxazo Lu-2(3H)-non (1.05g, 3.97mmol), 4-bromo-2-methoxybenzaldehyde (1.54g, 7.15mg) The reaction was carried out at 110°C for 120 hours after dissolving trifluoroacetic acid (2.26 g, 19.8 mmol) in toluene (8 mL). The reaction was monitored by LC-MS to confirm the completion of the reaction. The reaction mixture was concentrated and analyzed by column. Purified by chromatography, (6S,8R)-6-(4-bromo-2-methoxyphenyl)-7-((1-fluorine Rocyclopropyl)methyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinol Phosphorus-2(3H)-non was obtained as a yellow solid (249 mg, 539 umol, yield 13.5%).

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

[0318] Step 2: (6S,8R)-7-((1-fluorocyclopropyl)methyl)-6-(4-((1-(3-fluoropropyl Pyr(azetidine-3-yl)(amino)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydro Synthesis of looxazolo[5,4-f]isoquinoline-2(3H)-non

[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)-non (140 mg, 303 umol), 1-(3-fluoropropyl)aminoazetidine (112 mg, 849 umol), (2-dicyclohexyl (Luphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-Ami Dissolve no-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (27.5 mg, 30.3 umol) and sodium t-butoxide (87.4 mg, 910 umol) in dioxane (1 mL) and incubate at 60°C for 2 hours. The reaction was allowed to proceed. The completion of the reaction was monitored by LC-MS. The reaction mixture was filtered and purified by prep-HPLC. The prepared and purified product is then purified using chiral SFC, and (6S,8R)-7-((1-fluorocyclopropyl)methyl (Tyl)-6-(4-((1-(3-fluoropropyl)azetidine-3-yl))amino)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non is yellow It was obtained as a solid (7.2 mg, yield 4.49%).

[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] Similar to the synthesis route of Example 25, corresponding reactants and synthesis methods known to those skilled in the art were selected to synthesize Examples 32, 33, and 34.

[0324] Example 32: (6S,8R)-7-(2,2-difluoropropyl)-6-(4-((1-(3-fluoropropyl)azetidine-3-yl)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[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)azetidine-3-yl)amino)-2-methyl Toxy-6-chlorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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)azetidine-3-yl)amino)-2-methyl Toxy-6-fluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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]isoquinoline-6-yl) Enyl(amino)azetidine-1-yl)-N,N-dimethylbuta-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]isoquinoline-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-trif (Oroethyl)-3-triphenylmethyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (1.0g, 1.39mmol), 3-aminoazetidine-1-carboxylate (359mg, 2.08mmol), cesium carbonate (996mg, 3.06mmol) and [(2-di-t-butylphosphin-3-methyl (C-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)] Palladium(II) methanesulfonate (58.3 mg, 69.5 µl) 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 LC-MS. After concentration, the organic phase was extracted with water and ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was concentrated and purified by column chromatography, and tert-butyl was obtained. Lu3-((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]isoquinoline-6-yl)phenyl)amino)azetidine-1-carboxylate was obtained as a yellow solid (880 mg, 1.09 mmol, yield 78.1%).

[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-(azetidine-3-ylamino)-2,6-difluorophenyl)-8-meth Ru-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoli Synthesis of 2(3H)-non

[0344] [ka]

[0345] After dissolving trifluoroacetic acid (15.5 g, 135 mmol) in water (1 mL), tert-butyl 3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trife The compound was added to 400 mg of 493 umol of nylmethyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinoline-6-yl)phenyl)amino)azetidine-1-carboxylate and reacted at 20°C under nitrogen protection for 2 hours. The completion of the reaction was confirmed by LC-MS. After concentrating the mixture, the crude product was obtained. (6S,8R)-6-(4-(azetidine-3-ylamino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non was obtained as a yellow solid (400 mg, crude product).

[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]isoquinoline-6-yl) Synthesis of Nyl)amino)azetidine-1-yl)-N,N-dimethylbuta-2-enamide

[0348] [ka]

[0349] (6S,8R)-6-(4-(azetidine-3-ylamino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-no (100 mg, 213 umol), (E)-4-bromo-N,N-dimethylbuta-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 LC-MS, the reaction mixture was filtered, purified by prep-HPLC, and the purified product was separated and purified by SFC. (E)-4-(3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hex Sahydroxazolo[5,4-f]isoquinoline-6-yl)phenyl)amino)azetidine-1-yl)-N,N-dimethylbuta-2-enamide was obtained as a yellow solid (38.8 mg, 65.3 umol, yield 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-Acryloylazetidine-3-yl)amino)-2,6-difluo (lophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (compound 36)

[0353] [ka]

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

[0355] [ka]

[0356] (6S,8R)-6-(4-(azetidine-3-ylamino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-no N,N-dimethylamine (250 mg, 533 ml) and diisopropylethylamine (827 mg, 6.40 mmol) are combined with N,N-dimethylamine. Dissolve in 2 mL of tetramide, add 9.66 mg of acryloyl chloride (106 µl) at 0°C, and then at 0°C. The reaction was allowed to proceed for 2 hours. The completion of the reaction was confirmed by LC-MS. The reaction mixture was filtered, purified by prep-HPLC, and the purified product was separated and purified by SFC to obtain (6S,8R)-6-(4-((1-acryloylazetidine-3-yl)amino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non as a yellow solid (29.4 mg, 56.1 umol, yield 10.5%).

[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, 2H), 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-difluoro4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2- Trifluoroethyl)-2,3,6,7,8,9-Hexahydrooxazolo[5,4-f]isoquinoline-6-yl)phenoxy)pyrrolidine-1-yl)-N,N-dimethylbuta-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]isoquinoline-6-yl)phenoxy)pyrrolidine-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)- Non (1.7g, 2.36mmol), R-3-hydroxy-1-Boc-pyrrolidine (663mg, 3.54mmol), [(2-di-t-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (99.0mg, 118umol) and cesium carbonate (1.69g, 5.20mmol) were dissolved in toluene (20 mL) and heated at 110°C under nitrogen protection for 12°C. The reaction was allowed to proceed for a specified time. The completion of the reaction was monitored by LC-MS. After concentrating the mixture, it was purified by column chromatography and 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-hexahydr Looxazolo[5,4-f]isoquinoline-6-yl)phenoxy)pyrroridine-1-carboxylate It was obtained as a pale yellow solid (503 mg, 609 umol, yield 25.7%).

[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)-pyrrolidine-3-yl)oxy)phenyl]-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0367] [ka]

[0368] Dissolve trifluoroacetic acid (6.16 g, 54.0 mmol) in water (0.4 mL), add it 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]isoquinoline-6-yl)phenoxy)pyrrolidine-1-carboxylate (503 mg, 609 mL), and leave it for 2 hours under nitrogen protection at 20°C. The reaction was allowed to proceed. The completion of the reaction was confirmed by LC-MS. After concentrating the mixture, the pH was adjusted to 7 with saturated sodium bicarbonate, extracted with ethyl acetate, filtered the organic phase, concentrated it, and by column chromatography, (6S,8R)-6-[2,6-difluoro-4-(((R)-pyrrolidine-3-yl)oxy)phenyl]-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetraphenyl]-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetraphenyl Hydroxazolo[5,4-f]isoquinoline-2(3H)-non was obtained (183 mg, 378 umol, yield 62.2%). .

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

[0370] Step 3: (E)-4-((R)-3-((3,5-difluoro4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-to (Lifluoroethyl)-2,3,6,7,8,9-Hexahydroxazolo[5,4-f]isoquinoline-6-yl) Synthesis of phenoxy)pyrrolidine-1-yl)-N,N-dimethylbuta-2-enamide

[0371] [ka]

[0372] (6S,8R)-6-[2,6-difluoro-4-(((R)-pyrrolidine-3-yl)oxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (90 mg, 186 umol), (E)-4-bromo-N,N-dimethylbuta-2-enamide (35.7 mg, 186 umol), and N,N-diisopropylethylamine (52.9 mg, 409 umol) were dissolved in N,N-dimethylformamide (1 mL) and reacted for 1 hour under nitrogen protection at 0°C. The completion of the reaction was confirmed by LC-MS, the reaction mixture was filtered, separated and purified by prep-HPLC, and the purified product was purified by SFC, and (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]isoquinoline-6-yl)phenoxy)pyrrolidine-1-yl)-N,N-dimethylbuta-2-enamide was obtained as a yellow solid (18.5 mg, 30.7 umol, yield 16.5%).

[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-Acryloylpyrrolidine-3-yl)oxy)-2,6-diph Luolophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (compound 38)

[0376] [ka]

[0377] Step 1: (6S,8R)-6-(4-(((R)-1-acryloylpyrrolidine-3-yl)oxy)-2,6-difluo Synthesis of lophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[0378] [ka]

[0379] (6S,8R)-6-[2,6-difluoro-4-(((R)-pyrrolidine-3-yl)oxy)phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (90 mg, 186 ml), diisopropylethylamine (240 mg, 1.86 mmol) are combined with N,N-dimeth The mixture was dissolved in 1 mL of ammonium formamide, and acryloyl chloride (16.8 mg, 186 umol) was added at 0°C. The reaction was allowed to proceed for 1 hour at 0°C. The completion of the reaction was confirmed by LC-MS, the reaction mixture was filtered, separated and purified by prep-HPLC, and the purified product was further purified by SFC to obtain (6S,8R)-6-(4-(((R)-1-acryloylpyrrolidine-3-I (L)oxy)-2,6-difluorophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non is obtained 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), 3.54 - 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, 3 H) ppm.

[0382] Similar to the synthesis routes of Examples 37 and 38, corresponding reactants and synthesis methods known to those skilled in the art were selected to synthesize Examples 39 and 40 below.

[0383] Example 39: (E)-4-((S)-3-((3,5-difluoro4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2- Trifluoroethyl)-2,3,6,7,8,9-Hexahydrooxazolo[5,4-f]isoquinoline-6-yl)phenoxy)pyrrolidine-1-yl)-N,N-dimethylbuta-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-acryloylpyrrolidine-3-yl)oxy)-2,6-diph Luolophenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (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-tri Fluoroethyl)-2,3,6,7,8,9-Hexahydrooxazolo[5,4-f]isoquinoline-6-yl) Enyl)piperazin-1-yl)-N,N-dimethylbuta-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-tri Synthesis of fluoroethyl)-3-triphenylmethyl-2,3,6,7,8,9-hexahydroxazolo[5,4-f]isoquinoline-6-yl)phenyl)piperazine-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 (700 mg, 972 ml), N-Boc piperazine (272 mg, 1.46 mmol), (2-dicyclohexylphosphate) Fino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (41.2 mg, 48.6 ml) 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 LC-MS. After concentrating the mixture, it was dissolved in water and ethyl acetate. Extraction was performed, the organic phase was washed with saturated saline solution, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography, and 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]isoquinoline-6-yl)phenyl)piperazine-1-carboxylate was obtained. It was obtained as a white solid (413 mg, 501 umol, yield 51.5%).

[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]isoquinoline-2(3H)-non [ka]

[0399] Dissolve trifluoroacetic acid (12.3 g, 107 mmol) in water (0.1 mL), and then prepare tert-butyl 4-(3,5-di) Fluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-triphenyl Lumethyl-2,3,6,7,8,9-hexahydroxazolo[5,4-f]isoquinoline-6-yl)phenyl) Add piperazine-1-carboxylate (413 mg, 500 umol) and leave at 20°C under nitrogen protection for 2 hours. The reaction was carried out. The completion of the reaction was confirmed by LC-MS. The crude product was purified by column chromatography, and (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]isoquinoline-2(3H)-non was obtained as a yellow solid (110 mg, 228 umol, yield 45.5%).

[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-triph (Oroethyl)-2,3,6,7,8,9-Hexahydrooxazolo[5,4-f]isoquinoline-6-yl) Synthesis of nyl)piperazin-1-yl)-N,N-dimethylbuta-2-enamide

[0403] [ka]

[0404] (6S,8R)-6-(2,6-difluoro-4-(piperazin-1-yl)phenyl)-8-methyl-7-(2,2,2-tri Fluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (100 mg, 207 umol), (E)-4-bromo-N,N-dimethylbuta-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 for 1 hour at 20°C under nitrogen protection. The reaction was confirmed to be complete by LC-MS, and the reaction mixture was filtered. After passing through the atmosphere, the solution was separated and purified by prep-HPLC, and the purified solution was further purified by SFC. (E)-4-(4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexa Hydroxazolo[5,4-f]isoquinoline-6-yl)phenyl)piperazine-1-yl)-N,N-dimethyl Chil-buta-2-enamide was obtained as a yellow solid (37 mg, 62.3 umol, yield 30.1%).

[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]isoquinoline-6-yl)pyridine-3-yl)oxy)ethyl)piperazine-1-yl)ethyl)amino)-1-oxoisoindoline-2-yl (L) 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]isoquinoline-6-yl)pyridine-3-yl)oxy)ethyl)piperazine-1-carboxylate

[0410] [ka]

[0411] tert-butyl(6S,8R)-6-(5-bromopyridine-2-yl)-8-methyl-7-(2,2,2-trifluoroe (Cyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non (700 mg, 1.58 mmol), 4-(2-hydroxyethyl)piperazine-1-carboxylate (546 mg, 2.37 mmol), [(2-di-t-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (132 mg, 158 mmol) And sodium t-butoxide (456 mg, 4.75 mmol) is dissolved in toluene (10 mL) and nitrogen protection is applied. The reaction was allowed to proceed for 12 hours under the following conditions. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated. Crude product. Purified by monocoque column chromatography, tert-butyl4-(2-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isopropyl Norin-6-yl)pyridine-3-yl)oxy)ethyl)piperazine-1-carboxylate is yellow. It was obtained as a solid (400 mg, 676 umol, yield 42.7%).

[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)pyridine-2-yl)-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non

[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]isoquinoline-6-yl)pyridine-3-yl)oxy)ethyl)piperazine-1-carboxylate (392 mg, 662.5 ml) 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 then performed by LC-MS. The completion of the reaction was monitored. After concentrating the reaction mixture, the pH was adjusted to 7-8 with saturated sodium hydrocarbon solution, extracted with water and ethyl acetate, and the organic phase was washed with saturated saline solution and sodium sulfate. The product was dried and concentrated. The crude product was purified by column chromatography and (6S,8R)-8-methyl-6-(5-(2-(piperazin-1-yl)ethoxy)pyridine-2-yl)-7-(2,2,2-trifluoroethoxy (Lu)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non is a yellow solid. It was obtained as follows (156 mg, 317 umol, yield 47.9%).

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

[0418] 1H 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, 3H), 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-oxoisoindorin-2-yl)piperidine Synthesis of n-2,6-dinon

[0420] [ka]

[0421] 3-(4-amino-1-oxoisoindorin-2-yl)piperidine-2,6-dinone (2.00g, 7.71mmol), 1,2-dibromoethane (17.3g, 92.5mmol), and N,N-dimethylisopropylamine (2.99g) Dissolve 23.1 mmol of (23.1 mmol) in N-methylpyrrolidone (20 mL), purge with nitrogen gas, and then incubate at 100°C for 4 hours. The reaction was allowed to proceed. The completion of the reaction was monitored by LC-MS. The reaction mixture was washed with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate without water, and concentrated. The crude product was purified by column chromatography, and 3-(4-((2-bromoethyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dinone was obtained as a yellow solid (403 mg, 1.10 mmol, yield 14.27%).

[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-trifluoroe Synthesis of (Cyl)-2,3,6,7,8,9-Hexahydrooxazolo[5,4-f]isoquinoline-6-yl)pyridine-3-yl)oxy)ethyl)piperazine-1-yl)ethyl)amino)-1-oxoisoindoline-2-yl)piperidine-2,6-dinone

[0425] [ka]

[0426] (6S,8R)-8-methyl-6-(5-(2-(piperazine-1-yl)ethoxy)pyridine-2-yl)-7-(2,2,2- Trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2(3H)-non(70mg, 142umol),3-(4-((2-bromoethyl)amino)-1-oxoisoindoline-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 LC-MS. After evaporation of the reaction mixture, it was purified by prep-HPLC and obtained 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]isoquinoline-6-yl)pyridine-3-yl)oxy) (Tyl)piperazine-1-yl)ethyl)amino)1-oxoisoindorin-2-yl)piperidine-2,6-dinone was obtained as a yellow solid (20 mg, 25.8 umol, yield 18.1%).

[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] Similar to the synthesis route of Example 42, the corresponding reactants and synthesis methods known to those skilled in the art were selected to synthesize Example 43 below.

[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]isoquinoline-6-yl)pyridine-3-yl)oxy)propyl)piperazine-1-yl)ethyl)amino)-1-oxoisoindoline-2- Il)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, 3 H) 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) Azethidine-1-yl)ethoxy)phenyl)-7-(2-fluoro-2-methylpropyl)-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinoline) is used in Example 1 of WO2017 / 182493A1. It was synthesized according to the method described above.

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

[0436] Preparation of 1x protein mixture: First, a 2x GST-ERα-LBD (Invitrogen, A15677) / MAb anti-GST-Eu (Cisbio, 61GSTKLA) mixture 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 plate this 1x protein mixture in a 384-well plate. Add 20 μL to each well, place the 384-well plate in a centrifuge, and centrifuge at 1000 rpm for 10 seconds at room temperature. After intercentrifugation, remove and let stand at room temperature for 3 hours before using the EnVision multifunctional microplatelet. I read it with a dash.

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

[0442]

number

[0443] X represents the "665 value vs. 615 value" for each concentration. Min is the average "665 value vs. 615 value" when 0.2 mM positive control compound and 5 nl of 3 nM (1.5 nM) estradiol are added. Max is the average "665 value vs. 615 value" when DMSO and 5 nl of 3 nM (1.5 nM) estradiol are added. The data was 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 inoculated into 96-well plates. The culture medium consisted of 10% FBS (Gibco, 10099-141), 1% pyruvate (Sigma, S8636), and 1% non-essential amino acids. In MEM (Hyclone, SH30024.01B) medium containing (Sigma, M7145), the inoculation density was 4,000 cells / c The cells were cultured at 37°C under 5% CO2 conditions. The compound was prepared in a 20 mM stock solution. Prepared, serially diluted to the final concentration of 1000 with 100% DMSO (Sigma, D2650), and then containing 2% FBS. The culture medium was diluted 20-fold. After 24 hours of incubation, the culture medium was removed, and 90 μL of FBS 2% medium and 10 μL of drug were added to each well. 10 μL of DMSO was added to the control group, and the mixture was gently shaken. The blank group was given only 100 μL of 2% FBS medium. 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 homogeneously, and allowed to stand at room temperature for 10 minutes. The chemiluminescence signal values ​​were measured. Measurements were taken. The negative control was a 0.5% DMSO well.

[0447] Experimental data from the MCF-7 cell proliferation test

[0448] [Table 4]

[0449] Test Example 3: Degradation effect of compounds on ERα In this study, the degradation effect of compounds on ERα was measured using the ERα DuoSet IC ELISA Kit (R&D, DYC5715). On the first day of the experiment, human breast cancer cells MCF-7 (source) were measured in a 24-well plate. The same cells were seeded; the culture medium was MEM medium containing 10% activated carbon treated FBS (Tocyto, UT61204), 1% pyruvate, and 1% non-essential amino acids; the seeding density was 150,000 cells / well; and the cells were cultured for 24 hours at 37°C under 5% CO2 conditions.

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

[0451] On the third day of the experiment, the coated 96-well plate was washed three times with PBS, and per well 300 μL of blocking solution (R&D, DY995) was added, and the mixture was blocked at room temperature for 1 hour. The 24-well plate was washed once with PBS, the remaining liquid was aspirated, and 60 μL of diluent (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 to each well. After dissolving on ice for 15 minutes, the diluent (1 mM EDTA, 0.5% TritonX-100 dissolved in PBS) was added. The solution was added. Diluted cell lysate was added to a blocked 96-well plate at a rate of 100 μL per well and incubated at room temperature for 2 hours. After washing the plate three times with washing solution (R&D, WA126), the primary antibody was added and incubated for 1 hour. The 96-well plate was then 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 the reaction was allowed to develop for 15 minutes. The reaction was then stopped with a stop solution (R&D, DY994), and the absorbance at 450 nm was read.

[0452] IC of ERα decomposition activity of compounds 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, respectively. The reaction times for the first six culture plates were 0, 5, 15, 30, 45, and 60 minutes, respectively. The Blank60 plate did not contain the test compound or control compound, and samples were taken after incubation for 60 minutes. The NCF60 plate was incubated for 60 minutes with potassium phosphate buffer instead of NADPH regeneration solution (Sigma, N0505). I did it.

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

[0456] First, add 600 μL of stop solution (acetonitrile:methanol (95:5, v / v) solution containing 100 ng / mL of tolbutamide (Sigma, T0891)) to the sample in the T0 plate, and then proceed with the NADPH regeneration system. The industrial 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 in culture plates Blank60, T5, T15, T30, T45, and T60. Then, 98 μL of NADPH regeneration solution was added to each sample well to initiate the reaction.

[0459] After an appropriate incubation time (5, 15, 30, 45, 60 minutes, etc.), 600 μL of stop solution was added to each sample well and control sample well of the 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 the supernatant from each test sample was collected, diluted with 200 μL of 0.3% formic acid aqueous solution, and subjected to LC-MS / MS analysis. 100 μL of the supernatant from the control sample was collected, diluted with 300 μL of pure water, and subjected to LC-MS / MS analysis. Calculations were performed according to the following formula:

[0461]

number

[0462] In vitro microsome stability experiment data

[0463] [Table 6]

Claims

1. Mammals containing the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions for treating estrogen receptor-dependent or estrogen receptor-mediated diseases: 【Chemistry 1】 During the ceremony: Z 1 is a combination; Z 2 It is selected from -O-CH2-CH2-, -O-CH2-, -NH-CH2-CH2-, -NH-CH2-, -NH- and -O-; Cy 1 is phenyl or pyridyl, which may, in some cases, be a halogen atom or C 1-6 Substituted with alkoxy; Cy 2 These include azetidilen, pyrrolidylene, piperazilen and 【Chemistry 2】 Selected from; R1 is C 1-6 It is alkyl; R² is H; R 4 is C 1-6 alkyl, C 1-6 alkylamino, amino C 1-6 alkyl or C 2-6 alkenyl, and the C 1-6 alkyl, C 1-6 alkylamino, amino C 1-6 alkyl or C 2-6 alkenyl may optionally be a halogen atom, (C 1-6 alkyl) 2 amino and oxo selected from It is substituted with the base; R 3 is -CH 2 -CR 31 R 32 R 33; R 31 , R 32 and R 33 These are C atoms that are independently of each other: H, and optionally substituted with hydroxyl or halogen atoms. 1-6 It is an alkyl or halogen atom, or R 31 and R 32 C is sometimes substituted with a hydroxyl or halogen atom. 3-8 They may form cycloalkylenes.

2. Z 2 is, -O-CH 2 -CH 2 -, -NH- and -O- are selected; Cy 1 In some cases, C 1-6 Phenyl or pyridyl substituted with an alkoxy; Cy 2 This is selected from azetidiylene, pyrrolidylene, and piperagylene; R 3 ha-CH 2 -CR 31 R 32 R 33 And; R 31 , R 32 and R 33 These are: H, and C, which is substituted in some cases with halogen atoms, independently of each other. 1-6 Selected from alkyl and halogen atoms, or R 31 and R 32 C, which may be substituted with halogen atoms in some cases. 3-8 They may form cycloalkylenes; R 4 C is sometimes substituted with halogen atoms. 1-6 Alkyl, C 1-6 Alkylamino, Amino C 1-6 Alkyl or C 2-6 The pharmaceutical composition according to claim 1, wherein the alkenyl is present.

3. Z 2 The pharmaceutical composition according to claim 1 or 2, wherein is selected from -NH- and -O-.

4. Cy 1 is phenyl or pyridyl, and is sometimes substituted with methoxy, claim A pharmaceutical composition as described in any one of items 1 to 3.

5. Cy 2 is selected from azetidiylene and pyrrolidylene, one of claims 1 to 4 The pharmaceutical composition described above.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein R1 is methyl.

7. R 31 , R 32 Each of these is H, or a halogen atom, or R 31 and R 32 C 3-8 C Forms chloroalkylenes; R 33 C is substituted with H, and in some cases with halogen atoms. 1-6 A pharmaceutical composition according to any one of claims 1 to 5, selected from alkyl or halogen atoms.

8. R 4 C is sometimes substituted with halogen atoms. 1-6 A pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is alkyl. 【Request Item 9】 【Chemistry 3】 A pharmaceutical composition for treating mammalian estrogen receptor-dependent or estrogen receptor-mediated diseases, comprising a compound selected from and a pharmaceutically acceptable carrier.

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