Preparation method for selective estrogen receptor degrader

Abstract

Provided is a preparation method for a selective estrogen receptor degrader. Specifically provided is a preparation method for a compound as represented by formula (I) and a pharmaceutically acceptable salt thereof. The method reduces the reaction steps, improves the reaction yield, and is suitable for industrial production.

Description

A method for preparing a selective estrogen receptor degrader Technical Field

[0001] The present invention relates to a method for preparing a selective estrogen receptor degrader (SERD). Background Art

[0002] Breast cancer is one of the most common malignant tumors in women. The 2017 "China Cancer Registry Annual Report" released by the National Cancer Center shows that breast cancer ranks first in incidence among female malignancies, with approximately 279,000 new cases each year and an annual increase of approximately 2%. Approximately 70% of breast cancer patients have estrogen receptor (ER)-positive breast cancer. Endocrine therapy plays a key role in the treatment of these patients.

[0003] In the CSCO Breast Cancer Diagnosis and Treatment Guidelines (2020 edition), fulvestrant has been adjusted to a Class I recommendation for patients with hormone receptor-positive advanced breast cancer who have not received endocrine therapy, and fulvestrant + CDK4 / 6 inhibitors have been added as a Class II recommendation. In addition, fulvestrant combined with CDK4 / 6 inhibitors has become a Class I recommendation for patients who have failed non-steroidal AI (NSAI) treatment and steroidal AI (SAI) treatment. As the only approved SERD at present, fulvestrant is approved in the form of an injection, which brings inconvenience to patients' medication. Therefore, the search for new and more effective SERDs not only has huge market value but also brings optionality and convenience to breast cancer patients in medication.

[0004] WO2021139756A1 provides a selective estrogen receptor degrader, the structure of which is shown below. The compound has a significant degradation effect on estrogen receptor ERα.

[0005] WO2021139756A1 also discloses a method for preparing the aforementioned compound. In order to shorten the reaction steps, improve the reaction yield, and meet the needs of industrial production, the present disclosure provides a new method for preparing the compound and its pharmaceutically acceptable salt. Summary of the Invention

[0006] The present disclosure provides a method for preparing a compound represented by Formula IA or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound represented by Formula 18A with a compound represented by Formula C.

[0007] in,

[0008] R 1a 、R 1b The same or different, each independently selected from H, D, C1-6 alkyl;

[0009] R 2 C 1-6 alkyl halide;

[0010] R 3 The same or different, each independently selected from H, halogen or C 1-6 alkyl;

[0011] m is selected from 0, 1, 2, 3;

[0012] R 4a 、R 4b The same or different, each independently selected from H or halogen;

[0013] n is an integer selected from 1-6 (for example, n is 1, 2, 3, 4, 5, 6);

[0014] R 5 Selected from H or C 1-6 alkyl;

[0015] Z is NR 6 ;

[0016] R 6 Selected from H or C 1-6 alkyl;

[0017] G 1 Select N or CR 7 ;

[0018] R 7 Selected from H, halogen or C 1-6 alkyl;

[0019] X is halogen.

[0020] In some embodiments, X is selected from chlorine, bromine, and iodine.

[0021] In some specific embodiments, X is chlorine.

[0022] In some embodiments, the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof comprises reacting in a basic environment.

[0023] In an optional embodiment, in the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the substance providing the alkaline environment is selected from inorganic bases.

[0024] In an optional embodiment, in the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the substance providing the alkaline environment is selected from cesium carbonate, lithium hydroxide or potassium phosphate.

[0025] In an optional embodiment, in the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the substance providing the alkaline environment is selected from potassium phosphate.

[0026] In an optional embodiment, in the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the substance providing the alkaline environment is selected from cesium carbonate.

[0027] In an optional embodiment, in the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the reaction solvent is selected from N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or N,N-dimethylacetamide (DMAc).

[0028] In an optional embodiment, in the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the reaction solvent is N,N-dimethylformamide (DMF).

[0029] In an optional embodiment, the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the reaction temperature is selected from 20°C to 100°C.

[0030] In an optional embodiment, the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the reaction temperature is selected from 40°C to 80°C.

[0031] In an optional embodiment, the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the reaction temperature is selected from 50°C to 70°C.

[0032] In an optional embodiment, in the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, D2O is added to the reaction system.

[0033] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the step of reacting a compound of Formula 18B with a compound of Formula C to obtain a compound of Formula IB.

[0034] Among them, R 1a 、R 1b , X are respectively as defined in the compound represented by formula C;

[0035] R 2 、R 3 、R 4a 、R 4b 、R 5 , G 1 , Z, m, and n are respectively defined as in the compound represented by Formula 18A.

[0036] In some embodiments, the method for preparing the compound of formula IA or a pharmaceutically acceptable salt thereof comprises the steps of reacting compound 18 with CD2Cl2 to obtain the compound of formula (I).

[0037] Another aspect of the present disclosure provides a method for preparing a compound of Formula 18A or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of Formula 17A with a compound of Formula 14A.

[0038] Among them, R 2 、R 3 、R 4a 、R 4b 、R 5 , G 1 , Z, m, and n are respectively defined as in the compound represented by Formula 18A.

[0039] In some embodiments, in the method for preparing the compound represented by Formula 18A or a pharmaceutically acceptable salt thereof, the reaction solvent is selected from hexafluoroisopropanol (HFIP) or isopropanol.

[0040] In an optional embodiment, in the method for preparing the compound represented by Formula 18A or a pharmaceutically acceptable salt thereof, the reaction solvent is hexafluoroisopropanol (HFIP).

[0041] In an optional embodiment, the method for preparing the compound represented by Formula 18A or a pharmaceutically acceptable salt thereof, the reaction temperature is selected from 20°C to 100°C.

[0042] In an optional embodiment, the method for preparing the compound represented by Formula 18A or a pharmaceutically acceptable salt thereof, the reaction temperature is selected from 40°C to 80°C.

[0043] In an optional embodiment, the method for preparing the compound represented by Formula 18A or a pharmaceutically acceptable salt thereof, the reaction temperature is selected from 50°C to 70°C.

[0044] In some embodiments, the method for preparing the compound represented by Formula 18A or a pharmaceutically acceptable salt thereof comprises reacting in an acidic environment.

[0045] In an optional embodiment, in the method for preparing the compound represented by Formula 18A or a pharmaceutically acceptable salt thereof, the substance providing the acidic environment is selected from acetic acid or trifluoroacetic acid.

[0046] In some embodiments, the method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof comprises the steps of reacting the compound of Formula 17B with the compound of Formula 14A to obtain the compound of Formula 18B.

[0047] Among them, R 2 、R 3 、R 4a 、R 4b 、R 5 , G 1, Z, m, and n are respectively defined as in the compound represented by Formula 18A.

[0048] In some embodiments, the method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof comprises the step of reacting Compound 17 with Compound 14 to obtain Compound 18.

[0049] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further comprises the steps of the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof.

[0050] Another aspect of the present disclosure provides a method for preparing a compound represented by Formula 17A or a pharmaceutically acceptable salt thereof, comprising the steps of removing the hydroxyl protecting group PG from the compound represented by Formula 09A.

[0051] Wherein, PG is a hydroxyl protecting group;

[0052] R 4a 、R 4b 、R 5 and n are respectively defined as in the compound represented by Formula 18A.

[0053] In some embodiments, PG is

[0054] In some embodiments, in the method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof, the hydroxyl protecting group PG of the compound of Formula 09A is removed under the action of a fluorine-containing reagent.

[0055] In an optional embodiment, in the method for preparing the compound represented by Formula 17A or a pharmaceutically acceptable salt thereof, the fluorine-containing reagent is selected from hydrofluoric acid, hydrofluoric acid pyridine complex, tetrabutylammonium fluoride, and cesium fluoride.

[0056] In an optional embodiment, in the method for preparing the compound represented by Formula 17A or a pharmaceutically acceptable salt thereof, the fluorine-containing reagent is cesium fluoride.

[0057] In some embodiments, the method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof comprises the step of removing the hydroxyl protecting group PG from the compound of Formula 09B.

[0058] wherein PG is as defined in the compound represented by Formula 09A;

[0059] R 4a 、R 4b 、R 5 and n are respectively defined as in the compound represented by Formula 18A.

[0060] In some embodiments, the method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof comprises the step of removing the hydroxyl protecting group of Compound 09,

[0061] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further includes the steps in the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof, and optionally includes the steps in the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof.

[0062] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the steps of the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further comprises the steps of the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof, optionally comprising the steps of the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof, optionally comprising the steps of reacting the compound of Formula 03A with the compound of Formula 07A to obtain the compound of Formula 08A, and removing the benzyl group from the compound of Formula 08A to obtain the compound of Formula 09A.

[0064] Wherein L is a leaving group;

[0065] R 4a 、R 4b 、R 5 , n are respectively as defined in the compound represented by Formula 18A;

[0066] PG is as defined in the compound represented by Formula 09A.

[0067] In some embodiments, L is selected from halogen, OMs, or OTf.

[0068] In some specific embodiments, L is OTf.

[0069] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the steps of reacting the compound of Formula 03A with the compound of Formula 07A to obtain the compound of Formula 08A, and removing the benzyl group from the compound of Formula 08A to obtain the compound of Formula 09A.

[0070] In some embodiments, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the compound of Formula 03A and the compound of Formula 07A are reacted under an alkaline environment.

[0071] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the substance providing the alkaline environment in the reaction between the compound of Formula 03A and the compound of Formula 07A is selected from an organic base.

[0072] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the substance providing an alkaline environment in the reaction between the compound of Formula 03A and the compound of Formula 07A is selected from triethylamine, pyridine, and N,N-diisopropylethylamine (DIPEA).

[0073] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the substance providing the alkaline environment in the reaction between the compound of Formula 03A and the compound of Formula 07A is N,N-diisopropylethylamine (DIPEA).

[0074] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the compound of Formula 03A and the compound of Formula 07A are reacted at 60°C to 120°C.

[0075] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the compound of Formula 03A and the compound of Formula 07A are reacted at 80°C to 100°C.

[0076] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the compound of Formula 03A and the compound of Formula 07A are reacted at 85°C to 95°C.

[0077] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof is as follows: the compound of Formula 08A is reacted with a palladium catalyst and a reducing agent to obtain the compound of Formula 09A.

[0078] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the palladium catalyst is selected from Pd / C, Pd(OH)2 / C or PdCl2.

[0079] In an optional embodiment, in the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the palladium catalyst is Pd / C.

[0080] In an optional embodiment, in the method for preparing the compound of formula IA or a pharmaceutically acceptable salt thereof, the reducing agent is selected from H2, formic acid, ammonium formate, hydrazine or hydrazine hydrate.

[0081] In an optional embodiment, in the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof, the reducing agent is H2.

[0082] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further comprises the steps of the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof, optionally comprising the steps of the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof, optionally comprising the steps of reacting the compound of Formula 03A with the compound of Formula 07B to obtain the compound of Formula 08B, and removing the benzyl group from the compound of Formula 08B to obtain the compound of Formula 09B.

[0083] Wherein L is as defined in the compound represented by formula 03A;

[0084] R 4a 、R 4b 、R 5 , n are respectively as defined in the compound represented by Formula 18A;

[0085] PG is as defined in the compound represented by Formula 09A.

[0086] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the steps of reacting the compound of Formula 03A with the compound of Formula 07B to obtain the compound of Formula 08B, and removing the benzyl group from the compound of Formula 08B to obtain the compound of Formula 09B.

[0087] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further comprises the steps of the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof, optionally comprising the steps of the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof, optionally comprising the steps of reacting Compound 03 with Compound 07 to obtain Compound 08, and removing the benzyl group from Compound 08 to obtain Compound 09.

[0088] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the steps of reacting Compound 03 with Compound 07 to obtain Compound 08, and removing the benzyl group from Compound 08 to obtain Compound 09.

[0089] Another aspect of the present disclosure provides a method for preparing a compound of Formula 17A or a pharmaceutically acceptable salt thereof, comprising removing R from the compound of Formula 35A. 8 Steps,

[0090] Among them, R 8 C 1-6 alkyl;

[0091] R 4a 、R 4b 、R5 and n are respectively defined as in the compound represented by Formula 18A.

[0092] In some embodiments, R 8 It is a methyl group.

[0093] In some embodiments, the method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof is as follows: the compound of Formula 35A is subjected to the action of Lewis acid to remove R 8 .

[0094] In an optional embodiment, in the method for preparing the compound represented by Formula 17A or a pharmaceutically acceptable salt thereof, the Lewis acid is selected from BBr3, BCl3 or AlCl3.

[0095] In an optional embodiment, in the method for preparing the compound represented by Formula 17A or a pharmaceutically acceptable salt thereof, the Lewis acid is BBr3.

[0096] In an optional embodiment, the method for preparing the compound represented by Formula 17A or a pharmaceutically acceptable salt thereof has a reaction temperature of -40°C to 40°C.

[0097] In an optional embodiment, the method for preparing the compound represented by Formula 17A or a pharmaceutically acceptable salt thereof has a reaction temperature of -20°C to 20°C.

[0098] In an optional embodiment, the method for preparing the compound represented by Formula 17A or a pharmaceutically acceptable salt thereof has a reaction temperature of -5°C to 5°C.

[0099] In some embodiments, the method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof comprises removing R from the compound of Formula 35B. 8 Steps,

[0100] Among them, R 8 As defined in the compound represented by formula 35A;

[0101] R 4a 、R 4b 、R 5 and n are respectively defined as in the compound represented by Formula 18A.

[0102] In some embodiments, the method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof comprises the step of removing the methyl group of Compound 35 to obtain Compound 17.

[0103] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further includes the steps of the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof, and optionally includes the steps of the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof from the compound of Formula 35A.

[0104] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the steps of the method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof from the compound of Formula 35A.

[0105] Another aspect of the present disclosure provides a method for preparing a compound of Formula 35A or a pharmaceutically acceptable salt thereof, comprising the steps of removing the hydroxyl protecting group PG from the compound of Formula 28A or a pharmaceutically acceptable salt thereof.

[0106] Among them, R 8 As defined in the compound represented by formula 35A;

[0107] PG is as described in the compound represented by formula 09A;

[0108] R 4a 、R 4b 、R 5 and n are respectively defined as in the compound represented by Formula 18A.

[0109] In some embodiments, the method for preparing the compound of Formula 35A or a pharmaceutically acceptable salt thereof comprises removing the hydroxyl protecting group PG from the compound of Formula 28A or a pharmaceutically acceptable salt thereof in an acidic environment.

[0110] In an optional embodiment, in the method for preparing the compound represented by Formula 35A or a pharmaceutically acceptable salt thereof, the substance providing the acidic environment is selected from acetic acid, hydrochloric acid / dioxane, hydrofluoric acid, hydrobromic acid, and trifluoroacetic acid.

[0111] In an optional embodiment, in the method for preparing the compound represented by Formula 35A or a pharmaceutically acceptable salt thereof, the substance providing the acidic environment is hydrochloric acid / dioxane.

[0112] In some embodiments, the method for preparing the compound of Formula 35A or a pharmaceutically acceptable salt thereof comprises the step of removing the hydroxyl protecting group PG from the hydrochloride salt of the compound of Formula 28A.

[0113] Among them, R 8 As defined in the compound represented by formula 35A;

[0114] PG is as described in the compound represented by formula 09A;

[0115] R 4a 、R4b 、R 5 and n are respectively defined as in the compound represented by Formula 18A.

[0116] In some embodiments, the method for preparing a compound of Formula 35A or a pharmaceutically acceptable salt thereof comprises the step of removing the hydroxyl protecting group PG from the compound of Formula 28B or a pharmaceutically acceptable salt thereof.

[0117] Among them, R 8 As defined in the compound represented by formula 35A;

[0118] PG is as described in the compound represented by formula 09A;

[0119] R 4a 、R 4b 、R 5 and n are respectively defined as in the compound represented by Formula 18A.

[0120] In some embodiments, the method for preparing a compound of Formula 35A or a pharmaceutically acceptable salt thereof comprises the step of removing the hydroxyl protecting group PG from the hydrochloride salt of the compound of Formula 28B.

[0121] Among them, R 8 As defined in the compound represented by formula 35A;

[0122] PG is as described in the compound represented by formula 09A;

[0123] R 4a 、R 4b 、R 5 and n are respectively defined as in the compound represented by Formula 18A.

[0124] In some embodiments, the method for preparing a compound of formula 35A or a pharmaceutically acceptable salt thereof comprises the step of removing the hydroxyl protecting group of compound 28 or a pharmaceutically acceptable salt thereof to obtain compound 35.

[0125] In some embodiments, the method for preparing a compound of formula 35A or a pharmaceutically acceptable salt thereof comprises the step of removing the hydroxyl protecting group of the hydrochloride salt of compound 28 to obtain compound 35.

[0126] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further includes the steps in the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof, optionally including the steps in the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof from the compound of Formula 35A, optionally including the steps in the aforementioned method for preparing the compound of Formula 35A or a pharmaceutically acceptable salt thereof.

[0127] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof includes the steps in the aforementioned method for preparing the compound of Formula 35A or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further comprises the steps of the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof, optionally comprising the steps of the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof from the compound of Formula 35A, optionally comprising the steps of the aforementioned method for preparing the compound of Formula 35A or a pharmaceutically acceptable salt thereof, optionally comprising the step of reacting the compound of Formula 03A with the compound of Formula 27A to obtain the compound of Formula 28A or a pharmaceutically acceptable salt thereof,

[0129] Wherein, L is as defined in the compound represented by Formula 03A;

[0130] R 4a 、R 4b 、R 5 , n are respectively as defined in the compound represented by Formula 18A;

[0131] PG is as defined in the compound represented by Formula 09A;

[0132] R 8 As defined in the compound represented by formula 35A.

[0133] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof is as follows: the compound of Formula 03A and the compound of Formula 27A react in an alkaline environment to obtain the compound of Formula 28A or a pharmaceutically acceptable salt thereof.

[0134] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the substance providing the alkaline environment in the reaction between the compound of Formula 03A and the compound of Formula 27A is selected from an organic base.

[0135] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the substance providing an alkaline environment in the reaction between the compound of Formula 03A and the compound of Formula 27A is selected from triethylamine, pyridine, and N,N-diisopropylethylamine (DIPEA).

[0136] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the substance providing the alkaline environment in the reaction between the compound of Formula 03A and the compound of Formula 27A is N,N-diisopropylethylamine (DIPEA).

[0137] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the compound of Formula 03A and the compound of Formula 27A are reacted at 60°C to 120°C.

[0138] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the compound of Formula 03A and the compound of Formula 27A are reacted at 80°C to 100°C.

[0139] In an optional embodiment, in the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof, the compound of Formula 03A and the compound of Formula 27A are reacted at 85°C to 95°C.

[0140] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the step of reacting the compound of Formula 03A with the compound of Formula 27A to obtain the compound of Formula 28A or a pharmaceutically acceptable salt thereof.

[0141] Wherein, L is as defined in the compound represented by Formula 03A;

[0142] R 4a 、R 4b 、R 5 , n are respectively as defined in the compound represented by Formula 18A;

[0143] PG is as defined in the compound represented by Formula 09A;

[0144] R 8 As defined in the compound represented by formula 35A.

[0145] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the step of reacting the compound of Formula 03A with the compound of Formula 27A to obtain the hydrochloride salt of the compound of Formula 28A.

[0146] Wherein, L is as defined in the compound represented by Formula 03A;

[0147] R 4a 、R 4b 、R 5 , n are respectively as defined in the compound represented by Formula 18A;

[0148] PG is as defined in the compound represented by Formula 09A;

[0149] R 8 As defined in the compound represented by formula 35A.

[0150] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further comprises the steps of the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof, optionally comprising the steps of the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof from the compound of Formula 35A, optionally comprising the steps of the aforementioned method for preparing the compound of Formula 35A or a pharmaceutically acceptable salt thereof, optionally comprising the step of reacting the compound of Formula 03A with the compound of Formula 27B to obtain the compound of Formula 28B or a pharmaceutically acceptable salt thereof,

[0151] Wherein, L is as defined in the compound represented by Formula 03A;

[0152] R 4a 、R 4b 、R 5 , n are respectively as defined in the compound represented by Formula 18A;

[0153] PG is as defined in the compound represented by Formula 09A;

[0154] R 8 As defined in the compound represented by formula 35A.

[0155] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the steps of reacting the compound of Formula 03A with the compound of Formula 27B to obtain the compound of Formula 28B or a pharmaceutically acceptable salt thereof.

[0156] Wherein, L is as defined in the compound represented by Formula 03A;

[0157] R 4a 、R 4b 、R 5 , n are respectively as defined in the compound represented by Formula 18A;

[0158] PG is as defined in the compound represented by Formula 09A;

[0159] R 8 As defined in the compound represented by formula 35A.

[0160] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the step of reacting the compound of Formula 03A with the compound of Formula 27B to obtain the hydrochloride salt of the compound of Formula 28B.

[0161] Wherein, L is as defined in the compound represented by Formula 03A;

[0162] R 4a 、R 4b 、R 5, n are respectively as defined in the compound represented by Formula 18A;

[0163] PG is as defined in the compound represented by Formula 09A;

[0164] R 8 As defined in the compound represented by formula 35A.

[0165] In some embodiments, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof further comprises the steps of the aforementioned method for preparing the compound of Formula 18A or a pharmaceutically acceptable salt thereof, optionally comprising the steps of the aforementioned method for preparing the compound of Formula 17A or a pharmaceutically acceptable salt thereof from the compound of Formula 35A, optionally comprising the steps of the aforementioned method for preparing the compound of Formula 35A or a pharmaceutically acceptable salt thereof, optionally comprising the step of reacting Compound 03 with Compound 27 to obtain Compound 28 or a pharmaceutically acceptable salt thereof,

[0166] In an optional embodiment, the method for preparing the compound represented by Formula IA or a pharmaceutically acceptable salt thereof comprises the step of reacting Compound 03 with Compound 27 to obtain Compound 28 or a pharmaceutically acceptable salt thereof.

[0167] In an optional embodiment, the method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof comprises the step of reacting Compound 03 with Compound 27 to obtain the hydrochloride salt of Compound 28.

[0168] The present disclosure also provides a compound represented by Formula 18A or a pharmaceutically acceptable salt thereof,

[0169] Among them, R 2 、R 3 、R 4a 、R 4b 、R 5 、m、n、G 1 , Z are as described above.

[0170] In some embodiments, the compound of formula 18A or a pharmaceutically acceptable salt thereof is a compound of formula 18B or a pharmaceutically acceptable salt thereof,

[0171] Among them, R 2 、R 3 、R 4a 、R 4b 、R 5 、m、n、G 1 , Z are as described above.

[0172] In some embodiments, the compound represented by Formula 18A or a pharmaceutically acceptable salt thereof is Compound 18 or a pharmaceutically acceptable salt thereof.

[0173] Another aspect of the present disclosure is to provide a compound 17 or a pharmaceutically acceptable salt thereof,

[0174] Another aspect of the present disclosure is to provide a compound 28 or a pharmaceutically acceptable salt thereof,

[0175] Explanation of terms

[0176] In order to make the present disclosure more easily understood, certain technologies and sciences are specifically defined below. Unless otherwise explicitly defined in the present disclosure, all other technologies and sciences used in the present disclosure have the meanings commonly understood by those skilled in the art in the art to which the present disclosure belongs.

[0177] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2- 6-alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl group is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, and cyano.

[0178] The term "hydroxy protecting group" is a group known in the art that can be used to protect a hydroxy group, as described in the literature (Protective Groups in Organic Synthesis, 5 ThEd.TWGreene & P.GM Wuts) in the hydroxyl protecting group. As an example, including but not limited to as an example, preferably, the hydroxyl protecting group can be (C 1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 Alkyl or substituted alkyl, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 Alkyl or aromatic) acyl, for example: formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; can also be (C 1-6 Alkoxy or C 6-10 The aryloxy)carbonyl group may be acetyl (Ac), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), or methylthiomethyl ether (MTM).

[0179] The term "leaving group" refers to an atom or functional group that leaves a larger molecule in a chemical reaction. Representative leaving groups include halogen, substituted sulfonyloxy, phosphoryloxy, amino, (R j )3N-, cyano, R j S-etc., where R j independently selected from hydrogen atoms or C 1-6 Alkyl. The substituted sulfonyloxy group may be C 1-6 Alkylsulfonyloxy, perfluoroC 1-6 Alkylsulfonyloxy, arylsulfonyloxy, aralkylsulfonyloxy, and the like.

[0180] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Two configurations.

[0181] The pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts.

[0182] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0183] In addition, the compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0184] All compounds in the present invention can be drawn as either Type A or Type B. All tautomeric forms are within the scope of the present invention. The naming of the compounds does not exclude any tautomers.

[0185] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0186] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be construed to have an inclusive sense rather than an exclusive or exhaustive sense; that is, in the sense of "including but not limited to." DETAILED DESCRIPTION

[0187] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure.

[0188] Experimental methods in the embodiments or test examples disclosed herein that do not specify specific conditions are generally performed under conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are commercially available reagents.

[0189] List of Abbreviations HFIP: Hexafluoroisopropanol DIPEA: N,N-diisopropylethylamine Bn: Benzyl Ms: Methanesulfonyl Tf: Trifluoromethanesulfonyl DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide THF: Tetrahydrofuran

[0190] The structures of the compounds were determined by nuclear magnetic resonance (NMR). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and tetramethylsilane (TMS) as the internal standard.

[0191] HPLC determination was performed using a Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200LC high-pressure liquid chromatograph (Ultimate XB-C18 3.0*150 mm column or Xtimate C18 2.1*30 mm column).

[0192] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0193] Column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier.

[0194] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0195] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0196] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0197] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0198] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0199] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used to purify the compound, and the developing solvent system for thin layer chromatography, the volume ratio of the solvent were adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could be added for adjustment.

[0200] Example 1

[0201] 2,2-Difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolano[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol

[0202] Synthesis of the compound represented by formula (I)

[0203] Step 1:

[0204] 30.0g of compound 07, 41.6g of compound 03, 33.5g of DIPEA and 300mL of dioxane were added to the reaction flask, the temperature was raised to 85°C to 95°C, and the stirring reaction was completed. Ethyl acetate and water were added, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtered with suction, and the filtrate was concentrated to obtain 61g of an oily substance. Methyl tert-butyl ether was added, HCl / dioxane was added dropwise, slurried, filtered, and the filter cake was rinsed with methyl tert-butyl ether. Ethyl acetate and water were added to the filter cake, saturated sodium bicarbonate aqueous solution was added dropwise, extracted, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 08 (54.7g, yield 93%).

[0205] Step 2:

[0206] 53.1 g of compound 08, 5.3 g of palladium on carbon, and 530 mL of methanol were added to a reaction flask, heated to 35°C-45°C, and stirred under hydrogen until the reaction was complete. Filter, concentrate the filtrate, add n-heptane to slurry, filter with suction, rinse the filter cake with n-heptane, and dry in vacuo to obtain compound 09 (36.3 g, 94% yield).

[0207] Step 3:

[0208] 34.8 g of compound 09, 42.3 g of cesium fluoride and 350 mL of methanol were added to a reaction flask and the temperature was raised to 55°C to 65°C for completion of the reaction. The mixture was concentrated under reduced pressure, ethyl acetate and water were added to the concentrated residue, and the organic phases were combined. Water was added to the organic phase, hydrochloric acid was added dropwise, and the aqueous phase was extracted with ethyl acetate. Sodium bicarbonate was added to the aqueous phase to adjust the pH to 8, ethyl acetate was added for extraction, the organic phases were combined, the organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 17 (16.5 g, yield 91%).

[0209] 1 HNMR(400MHz,DMSO-d6)δ8.64(s,2H),6.64-6.62(d,J=8.0Hz,1H),6.56(d,J=4Hz,1H),6.43-6.40(dd,J=8.0,4.0Hz,1H),5.36(s,1H),3.6 4-3.57(t,J=16Hz,2H),3.01-2.85(m,2H),2.79-2.71(m,1H),2.58-2.53(m,1H),2.29-2.24(m,1H),1.60(s,1H),0.91-0.89(d,J=8Hz,3H).

[0210] Step 4:

[0211] 14.2 g of compound 17 and 37 mL of hexafluoroisopropanol were added to a reaction flask, followed by 10.9 g of compound 14, and the temperature was raised to 60° C. After the reaction, the reaction solution was concentrated, slurried with ethyl acetate, filtered, and the filter cake was washed with ethyl acetate and dried in vacuo to obtain compound 18 (18.7 g, yield 85%).

[0212] 1 HNMR(400MHz,DMSO-d6)δ8.60(s,2H),7.77-7.76(d,J=4.0Hz,1H),6.86-6.79(m,2H),6.44(s,1H),6.20 -6.16(m,2H),5.40(s,1H),4.62(s,1H),4.52-4.59(t,J=4.0Hz,1H),4.40-4.37(t,J=4.0Hz,1H),3.97- 3.89(m,1H),3.69-3.51(m,4H),3.31-3.23(m,1H),3.07-2.96(m,1H),2.76-2.72(m,2H),2.68-2.54(m, 2H), 2.48-2.44 (m, 1H), 2.41-2.35 (dd, J=16.0, 8.0Hz, 1H), 1.71-1.58 (m, 2H), 0.95-0.93 (d, J=8Hz, 3H).

[0213] Step 5:

[0214] 17.6 g of compound 18, 12.7 g of CD2Cl2, 14.7 g of heavy water, 47.7 g of cesium carbonate, and 176 mL of DMF were added to a reaction flask and heated to 65°C for reaction. After completion of the reaction, the mixture was filtered, and ethyl acetate and water were added to the filtrate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the compound represented by formula (I) (10.5 g, 58% yield).

[0215] Example 2

[0216] 2,2-Difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolano[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol

[0217] Synthesis of the compound represented by formula (I)

[0218] Step 1:

[0219] To a reaction flask, 360 g of compound 27, 890 g of compound 03, 286 g of DIPEA, and 1800 mL of 1,4-dioxane were added. The temperature was raised to 90°C and the reaction was stirred until complete. Ethyl acetate and water were added to the reaction solution, and the liquid was separated. The organic phase was separated and concentrated under reduced pressure to obtain 999 g of crude product. The crude product was added to methyl tert-butyl ether, and HCl / dioxane was added dropwise to precipitate a large amount of solid. The filter cake was filtered and rinsed with methyl tert-butyl ether. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of compound 28 (928 g, 89% yield).

[0220] 1 HNMR(400MHz,DMSO-d6)δ9.67(s,2H),7.72-7.60(m,4H),7.58-7.44(m,6H),6.94-6.83(m,2H),6.75(dd,J=8.2,2.0Hz,1H),4.23-4.02(m,2H), 3.74(d,J=9.8Hz,8H), 3.55(d,J=15.7Hz,1H), 3.26(dd,J=12.9,3.5Hz,1H), 2.61(dd,J=13.0,10.7Hz,1H), 1.16(d,J=6.5Hz,3H), 1.04(s,9H).

[0221] Step 2:

[0222] To a reaction flask, 900 g of the hydrochloride salt of compound 28, 2.7 L of HCl / dioxane (4 M), and 9 L of methanol were added. The temperature was raised to 45°C-55°C and stirred for reaction. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the methanol. Ethyl acetate and water were added, the aqueous phase was separated, the pH was adjusted to 8-9, and ethyl acetate was added for extraction. The organic phases were combined and concentrated under reduced pressure to afford compound 35 (462 g, 89% yield).

[0223] 1 HNMR (400MHz, DMSO-d6) δ6.92-6.75(m,2H),6.69(dd,J=8.1,2.0Hz,1H),5.39(t,J=6.0Hz,1H),3.72(d,J=7.0Hz,6H),3.60(td,J=13.7,5.3Hz,2H),3. 96(dt,J=14.5,7.4Hz,2H),2.89-2.73(m,1H),2.67(dd,J=13.2,5.9Hz,1H) ,2.39(dd,J=13.3,7.2Hz,1H), 1.65(d,J=6.2Hz,1H), 0.92(d,J=6.3Hz,3H).

[0224] Step 3:

[0225] To a reaction flask, 410 g of compound 35 and 4.1 L of dichloromethane were added, and the temperature was cooled to -5°C to 10°C. Boron tribromide (2M, 1.8 L) was added dropwise, maintaining the internal temperature below 5°C, and the reaction was stirred. The reaction was quenched by adding methanol and concentrated under reduced pressure to remove most of the solvent. Water was added and the mixture was washed with ethyl acetate. The pH of the aqueous phase was adjusted to 8-9, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain compound 17 (330 g, 87% yield).

[0226] The steps for synthesizing compound 17 into compound 18 and synthesizing compound 18 into the compound of formula (I) are the same as those in Example 1.

Claims

1. A method for preparing a compound of formula IA or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula 18A with a compound of formula C. in, R 1a 、R 1b The same or different, each independently selected from H, D, C 1-6 alkyl; R 2 C 1-6 alkyl halide; R 3 The same or different, each independently selected from H, halogen or C 1-6 alkyl; m is selected from 0, 1, 2, 3; R 4a 、R 4b The same or different, each independently selected from H or halogen; n is an integer selected from 1 to 6; R 5 Selected from H or C 1-6 alkyl; Z is NR 6 ; R 6 Selected from H or C 1-6 alkyl; G 1 Select N or CR 7 ; R 7 Selected from H, halogen or C 1-6 alkyl; X is a halogen; Preferably, X is selected from chlorine, bromine, and iodine; More preferably, X is chlorine.

2. The method for preparing the compound of formula IA or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of reacting the compound of formula 18B with the compound of formula C to obtain the compound of formula IB, in, R 1a 、R 1b 、R 2 、R 3 、R 4a 、R 4b 、R 5 , G 1 , Z, X, m, n are as described in claim 1 respectively.

3. A method for preparing a compound of formula IA or a pharmaceutically acceptable salt thereof according to claim 1 or 2, comprising the steps of reacting compound 18 with CD2Cl2 to obtain a compound of formula (I), 4. A method for preparing a compound of formula 18A or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula 17A with a compound of formula 14A, in, R 2 、R 3 、R 4a 、R 4b 、R 5 , G 1 , Z, m, and n are as described in claim 1 respectively.

5. The method for preparing the compound of formula 18A or a pharmaceutically acceptable salt thereof according to claim 4, comprising the steps of reacting the compound of formula 17B with the compound of formula 14A to obtain the compound of formula 18B, in, R 2 、R 3 、R 4a 、R 4b 、R 5 , G 1 , Z, m, and n are as described in claim 1 respectively.

6. A method for preparing the compound of formula 18A or a pharmaceutically acceptable salt thereof according to claim 4 or 5, comprising the steps of reacting compound 17 with compound 14 to obtain compound 18, 7. The method for preparing the compound of formula IA or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, further comprising the steps of the method for preparing the compound of formula 18A or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6.

8. A method for preparing a compound of formula 17A or a pharmaceutically acceptable salt thereof, comprising the steps of removing the hydroxyl protecting group PG from the compound of formula 09A, in, PG is a hydroxyl protecting group; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively; Preferably, PG is 9. The method for preparing the compound of formula 17A or a pharmaceutically acceptable salt thereof according to claim 8, comprising the step of removing the hydroxyl protecting group PG from the compound of formula 09B, in, PG as described in claim 8; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively.

10. A method for preparing the compound of formula 17A or a pharmaceutically acceptable salt thereof according to claim 8 or 9, comprising the step of removing the hydroxyl protecting group of compound 09, 11. The method for preparing the compound of formula IA or a pharmaceutically acceptable salt thereof according to claim 7, optionally comprising the steps of the method for preparing the compound of formula 17A or a pharmaceutically acceptable salt thereof according to any one of claims 8 to 10.

12. The method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof according to claim 11, optionally comprising the steps of reacting the compound of Formula 03A with the compound of Formula 07A to obtain the compound of Formula 08A, and removing the benzyl group from the compound of Formula 08A to obtain the compound of Formula 09A. Wherein L is a leaving group; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively; PG as described in claim 8; Preferably, L is selected from halogen, OMs or OTf; More preferably, L is OTf.

13. The method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof according to claim 11, optionally comprising the steps of reacting the compound of Formula 03A with the compound of Formula 07B to obtain the compound of Formula 08B, and removing the benzyl group from the compound of Formula 08B to obtain the compound of Formula 09B. Wherein L is as described in claim 12; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively; PG as described in claim 8.

14. The method for preparing the compound of formula IA or a pharmaceutically acceptable salt thereof according to claim 11, optionally comprising the steps of reacting compound 03 with compound 07 to obtain compound 08, and removing the benzyl group from compound 08 to obtain compound 09.

15. A method for preparing a compound of formula 17A or a pharmaceutically acceptable salt thereof, comprising removing R from the compound of formula 35A 8 Steps, in, R 8 C 1-6 alkyl; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively; Preferably, R 8 It is a methyl group.

16. The method for preparing the compound of formula 17A or a pharmaceutically acceptable salt thereof according to claim 15, comprising removing R from the compound of formula 35B 8 Steps, in, R 8 As described in claim 15; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively.

17. A method for preparing a compound of formula 17A or a pharmaceutically acceptable salt thereof according to claim 15 or 16, comprising the step of removing the methyl group of compound 35 to obtain compound 17, 18. The method for preparing the compound of formula IA or a pharmaceutically acceptable salt thereof according to claim 7, optionally comprising the steps of the method for preparing the compound of formula 17A or a pharmaceutically acceptable salt thereof according to any one of claims 15 to 17.

19. A method for preparing a compound of formula 35A or a pharmaceutically acceptable salt thereof, comprising the steps of removing the hydroxyl protecting group PG from the compound of formula 28A or a pharmaceutically acceptable salt thereof, in, R 8 As described in claim 15; PG as described in claim 8; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively.

20. A method for preparing a compound of formula 35A or a pharmaceutically acceptable salt thereof according to claim 19, comprising the step of removing the hydroxyl protecting group PG from the compound of formula 28B or a pharmaceutically acceptable salt thereof, where R 8 As described in claim 15; PG as described in claim 8; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively.

21. A method for preparing a compound of formula 35A or a pharmaceutically acceptable salt thereof according to claim 19 or 20, comprising the step of removing the hydroxyl protecting group from compound 28 or a pharmaceutically acceptable salt thereof to obtain compound 35, 22. The method for preparing the compound of formula IA or a pharmaceutically acceptable salt thereof according to claim 18, optionally comprising the steps of the method for preparing the compound of formula 35A or a pharmaceutically acceptable salt thereof according to any one of claims 19 to 21.

23. The method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof according to claim 22, optionally comprising the step of reacting the compound of Formula 03A with the compound of Formula 27A to obtain the compound of Formula 28A or a pharmaceutically acceptable salt thereof, in, L as described in claim 12; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively; PG as described in claim 8; R 8 As described in claim 15.

24. The method for preparing the compound of Formula IA or a pharmaceutically acceptable salt thereof according to claim 22, optionally comprising the step of reacting the compound of Formula 03A with the compound of Formula 27B to obtain the compound of Formula 28B or a pharmaceutically acceptable salt thereof, in, L as described in claim 12; R 4a 、R 4b 、R 5 , n are as described in claim 1 respectively; PG as described in claim 8; R 8 As described in claim 15.

25. The method for preparing the compound of formula IA or a pharmaceutically acceptable salt thereof according to claim 22, optionally comprising the step of reacting compound 03 with compound 27 to obtain compound 28 or a pharmaceutically acceptable salt thereof, 26. A compound represented by formula 18A or a pharmaceutically acceptable salt thereof, in, R 2 、R 3 、R 4a 、R 4b 、R 5 ,m,n,G 1 , Z are as described in claim 1 respectively.

27. The compound of formula 18A or a pharmaceutically acceptable salt thereof according to claim 26, which is a compound of formula 18B or a pharmaceutically acceptable salt thereof, in, R 2 、R 3 、R 4a 、R 4b 、R 5 ,m,n,G 1 , Z are as described in claim 1 respectively.

28. The compound of formula 18A according to claim 26 or 27, or a pharmaceutically acceptable salt thereof, which is compound 18 or a pharmaceutically acceptable salt thereof.

29. A compound 17 or a pharmaceutically acceptable salt thereof, 30. A compound 28 or a pharmaceutically acceptable salt thereof,

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