Heterocyclic substituted pyrimidinopyran compound and application thereof

Abstract

The invention discloses a heterocyclic substituted pyrimidinopyran compound and application thereof, and particularly discloses a compound shown as a formula (VII) and pharmaceutically acceptable salt thereof. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202380048389.4 (filing date: June 21, 2023; invention title: Heterocyclic Substituted Pyrimido[4,5 - b]pyran Compounds and Their Applications).

[0002] This invention claims the following priorities:

[0003] CN202210731477.1, filing date: June 24, 2022;

[0004] CN202210743845.4, filing date: June 27, 2022;

[0005] CN202210969097.1, filing date: August 12, 2022;

[0006] CN202211494347.7, filing date: November 25, 2022;

[0007] CN202310010084.6, filing date: January 4, 2023;

[0008] CN202310082801.6, filing date: February 3, 2023;

[0009] CN202310206933.5, filing date: March 6, 2023. Technical Field

[0010] This invention relates to a class of heterocyclic substituted pyrimido[4,5 - b]pyran compounds and their applications, specifically to the compounds represented by formula (VII) and their pharmaceutically acceptable salts. Background Art

[0011] RAS oncogene mutations are the most common activating mutations in human cancers, occurring in 30% of human tumors. The RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), and 85% of RAS - driven cancers are caused by mutations in the KRAS subtype. KRAS is a murine sarcoma viral oncogene and an important member of the RAS protein. KRAS is like a molecular switch that can control the pathways regulating cell growth when normal; after the KRAS gene mutates, it can transmit growth and proliferation signals downstream independently without relying on upstream growth factor receptor signals, resulting in uncontrolled cell growth and tumor progression. At the same time, whether the KRAS gene has mutations is also an important indicator for tumor prognosis.

[0012] KRAS mutations are common in solid tumors, such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS-mutated tumors, 80% of the oncogenic mutations occur at codon 12, and the most common mutations include: p.G12D (41%), p.G12V (28%), and p.G12C (14%).

[0013] Currently, small molecules directly targeting KRAS mutations mainly focus on the KRAS G12C field. Among them, AMG510 from Amgen and MRTX849 from Mirati Therapeutics have been approved for marketing and have shown good therapeutic effects in tumor patients with KRAS G12C mutations. However, so far, no small molecule targeting pan-KRAS mutations has entered the clinical research stage, and patients with pan-KRAS mutations and KRAS-amplified tumors have not yet benefited from precision medicine. Summary of the Invention

[0014] The present invention provides a compound of formula (VII) or a pharmaceutically acceptable salt thereof,

[0015]

[0016] wherein,

[0017] Ring B is selected from 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl, and the 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl are each independently optionally substituted by 1, 2, 3, 4, 5, or 6 R e substituents, Ring A is selected from

[0018] Alternatively, Ring B is selected from Ring A is selected from Ring C is selected from 5- to 6-membered nitrogen-containing heteroaryl;

[0019] Each R1 is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-3 alkyl-O-C 1-3 alkyl, -SH, -C(=O)-NR a R b 、-C(=O)-R c 、 C 3-6 cycloalkyl and 5- to 6-membered heteroaryl, and the C 1-3Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-3 Alkyl-O-C 1-3 Alkyl, C 3-6 The alkyl, cycloalkyl and 5- to 6-membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0020] Alternatively, R1 on two adjacent atoms and the atoms to which they are attached form a 5- to 6-membered heteroalkenyl, and the 5- to 6-membered heteroalkenyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R;

[0021] R2 is selected from phenyl, naphthyl and 5- to 10-membered heteroaryl, and the phenyl, naphthyl and 5- to 10-membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4 or 5 R d substituted;

[0022] R6 and R7 are each independently selected from H, C 1-3 alkyl, F, Cl, Br and I;

[0023] T1 is selected from CH2 and O;

[0024] T2 is selected from O and S;

[0025] R a is selected from H and C 1-3 alkyl, and the C 1-3 alkyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R0;

[0026] R b is selected from H and C 1-3 alkyl, and the C 1-3 alkyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R0;

[0027] R c is selected from H, C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl, and the C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0028] Each R d is each independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted with 1, 2, 3, 4 or 5 R0;

[0029] Each R eindependently selected from H, F, Cl, Br, I, CN, CH3, and OCH3 respectively;

[0030] each R is independently selected from F, Cl, Br, I, and C 1-3 alkyl;

[0031] each R0 is independently selected from D, F, Cl, Br, and I;

[0032] m is selected from 0, 1, 2, 3, 4, and 5;

[0033] n is selected from 0, 1, and 2.

[0034] The present invention also provides a compound of formula (VII) or a pharmaceutically acceptable salt thereof,

[0035]

[0036] wherein,

[0037] ring A is selected from ring B is selected from 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl, the 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl are each independently optionally substituted by 1, 2, 3, 4, 5, or 6 R e substituents;

[0038] alternatively, ring A is selected from ring B is selected from ring C is selected from 5- to 6-membered nitrogen-containing heteroaryl;

[0039] each R1 is independently selected from halogen, OH, NH2, CN, C 1-3 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-3 alkyl-O-C 1-3 alkyl, -SH, -C(=O)-NR a R b 、-C(=O)-R c 、 C 3-6 cycloalkyl and 5- to 6-membered heteroaryl, the C 1-3 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-3 alkyl-O-C 1-3 alkyl, C 3-6 cycloalkyl and 5- to 6-membered heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 R substituents;

[0040] Alternatively, R1 on two adjacent atoms forms a 5- or 6-membered heteroalkenyl with the atoms to which they are attached, and the 5- or 6-membered heteroalkenyls are each independently optionally substituted with 1, 2, 3, 4 or 5 Rs;

[0041] R2 is selected from phenyl, naphthyl and 5- to 10-membered heteroaryl, and the phenyl, naphthyl and 5- to 10-membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4 or 5 Rs d substituted;

[0042] R3 is selected from H;

[0043] R4 is selected from F;

[0044] R5 is selected from H;

[0045] R6 and R7 are each independently selected from H, C 1-3 alkyl and halogen;

[0046] T1 is selected from CH and O;

[0047] T2 is selected from O and S;

[0048] R a is selected from H and C 1-3 alkyl, and the C 1-3 alkyls are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0049] R b is selected from H and C 1-3 alkyl, and the C 1-3 alkyls are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0050] R c is selected from H, C 3-6 cycloalkyl and 5- or 6-membered heterocycloalkyl, and the C 3-6 cycloalkyl and 5- or 6-membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 Rs;

[0051] Each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C 2-4 alkynyls are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0052] Each R e is independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0053] Each R is independently selected from F, Cl, Br, I, and C 1-3 alkyl;

[0054] m is selected from 0, 1, 2, 3, 4, and 5;

[0055] n is selected from 0, 1, and 2.

[0056] The present invention also provides a compound of formula (V) or a pharmaceutically acceptable salt thereof,

[0057]

[0058] wherein,

[0059] Ring A is selected from

[0060] Ring B is selected from said is independently optionally substituted by 1, 2, 3, 4, 5, or 6 Rs e substituted;

[0061] Alternatively, ring B is selected from 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl, and the 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl are each independently optionally substituted by 1, 2, 3, 4, 5, or 6 Rs e substituted;

[0062] Ring C is selected from 5- to 6-membered nitrogen-containing heteroaryl;

[0063] Each R1 is independently selected from halogen, OH, NH2, CN, C 1-3 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-3 alkyl-O-C 1-3 alkyl, -SH, -C(=O)-NR a R b 、-C(=O)-R c 、 C 3-6 cycloalkyl, and 5- to 6-membered heteroaryl, and the C 1-3 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-3 alkyl-O-C 1-3 alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 Rs;

[0064] Alternatively, R1 on two adjacent atoms and the atoms to which they are attached form a 5- or 6-membered heteroalkenyl group, and the 5- or 6-membered heteroalkenyl group is each independently optionally substituted with 1, 2, 3, 4 or 5 R groups;

[0065] R2 is selected from phenyl, naphthyl and 5- to 10-membered heteroaryl, and the phenyl, naphthyl and 5- to 10-membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4 or 5 R groups d substituted;

[0066] R6 and R7 are each independently selected from H, C 1-3 alkyl and halogen;

[0067] T1 is selected from CH and O;

[0068] R a is selected from H and C 1-3 alkyl, and the C 1-3 alkyl is each independently optionally substituted with 1, 2, 3, 4 or 5 halogen atoms;

[0069] R b is selected from H and C 1-3 alkyl, and the C 1-3 alkyl is each independently optionally substituted with 1, 2, 3, 4 or 5 halogen atoms;

[0070] R c is selected from H, C 3-6 cycloalkyl and 5- or 6-membered heterocycloalkyl, and the C 3-6 cycloalkyl and 5- or 6-membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R groups;

[0071] Each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted with 1, 2, 3, 4 or 5 halogen atoms;

[0072] Each R e is independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0073] Each R is independently selected from F, Cl, Br, I and C 1-3 alkyl;

[0074] m is selected from 0, 1, 2, 3, 4 and 5;

[0075] n is selected from 0, 1 and 2.

[0076] The present invention also provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof,

[0077]

[0078] wherein,

[0079] R1 is selected from halogen, OH, C 1-3 alkyl, -C(=O)-NR a R b -, -C(=O)-R c and 5- to 6-membered heteroaryl, and the C 1-3 alkyl and 5- to 6-membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 R;

[0080] R2 is selected from phenyl, naphthyl and 5- to 10-membered heteroaryl, and the phenyl, naphthyl and 5- to 10-membered heteroaryl are each independently optionally substituted by 1, 2, 3, 4 or 5 R d substituents;

[0081] Ring A is selected from

[0082] Ring B is selected from

[0083] T1 is selected from CH and O;

[0084] R a is selected from H and C 1-3 alkyl;

[0085] R b is selected from H and C 1-3 alkyl;

[0086] R c is selected from H, C 3-6 cycloalkyl and 5- to 6-membered heterocycloalkyl;

[0087] Each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted by 1, 2, 3, 4 or 5 halogens;

[0088] Each R e is independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0089] Each R is independently selected from F, Cl, Br, I and C 1-3 alkyl;

[0090] m is selected from 0, 1, 2, and 3;

[0091] n is selected from 0, 1, and 2.

[0092] In some embodiments of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, the compound is selected from formula (V-1),

[0093]

[0094] wherein,

[0095] R1, R2, R6, R7, ring B, ring C, and m are as defined in the present invention.

[0096] In some embodiments of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, the compound is selected from formula (V-1),

[0097]

[0098] wherein,

[0099] R1, R2, ring B, ring C, and m are as defined in the present invention.

[0100] In some embodiments of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, the compound is selected from formula (IV-3),

[0101]

[0102] wherein,

[0103] R1 is selected from halogen, OH, C 1-3 alkyl, and 5-6 membered heteroaryl, and the C 1-3 alkyl and 5-6 membered heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 R;

[0104] R, R1, R2, ring A, ring B, and m are as defined in the present invention.

[0105] In some embodiments of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, the compound is selected from formula (IV-1),

[0106]

[0107] wherein,

[0108] R1, R2, ring B, and m are as defined in the present invention.

[0109] In some embodiments of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, the compound is selected from formula (P-1),

[0110]

[0111] Among them,

[0112] Ring B is selected from and 5- to 12-membered heteroalkenyl and the said and 5- to 12-membered heteroalkenyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e substituents;

[0113] R1, R2, R6, R7, each R e , ring C and m are as defined in the present invention;

[0114] The carbon atom with "*" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomeric form.

[0115] In some embodiments of the present invention, the above compound or its pharmaceutically acceptable salt, the compound is selected from formula (P-2),

[0116]

[0117] wherein,

[0118] Ring B is selected from the said are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e substituents;

[0119] p is selected from 1, 2, 3, 4 or 5;

[0120] R1, each R e , each R d and m are as defined in the present invention;

[0121] The carbon atom with "*" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomeric form.

[0122] In some embodiments of the present invention, the above compound or its pharmaceutically acceptable salt, the compound is selected from formula (P-2-1), (P-2-2) and (P-2-3),

[0123]

[0124] wherein,

[0125] p is selected from 1, 2, 3, 4 or 5;

[0126] R1, R e , each R d and m are as defined in the present invention;

[0127] The carbon atom with an asterisk (*) is a chiral carbon atom and exists in the form of a single (R) or (S) enantiomer or an enantiomer-rich form.

[0128] In some embodiments of the present invention, the above compound or its pharmaceutically acceptable salt, and the compound is selected from formula (IV-2),

[0129]

[0130] wherein,

[0131] Ring A is selected from

[0132] Or, ring A is selected from

[0133] R1 is selected from halogen, OH, C 1-3 alkyl, -C(=O)-NR a R b and -C(=O)-R c ;

[0134] R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted by 1, 2, 3, 4 or 5 R d substituents;

[0135] R 3a and R 4a are connected to form a structural unit selected from R 5a is selected from H;

[0136] Or, R 4a and R 5a are connected to form The is optionally substituted by 1 or 2 R e substituents, and R 3a is selected from H;

[0137] R a is selected from H and C 1-3 alkyl;

[0138] R b is selected from H and C 1-3 alkyl;

[0139] R c is selected from 5-6 membered heterocyclic alkyl;

[0140] Each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C2-4 The alkynyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0141] Each R e is independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0142] m is selected from 0, 1, 2 and 3.

[0143] In some embodiments of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, and the compound is selected from formula (I-1),

[0144]

[0145] wherein,

[0146] Ring A is selected from R1, R2, R3, R4, R5, R6, R7, Ring C and m are as defined in the present invention.

[0147] In some embodiments of the present invention, each of the above Rs is independently selected from F, Cl, Br, I, CH3, CH2CH3 and CH2CH2CH3, and other variables are as defined in the present invention.

[0148] In some embodiments of the present invention, the above R is selected from F and CH3, and other variables are as defined in the present invention.

[0149] In some embodiments of the present invention, the above R0 is selected from D, and other variables are as defined in the present invention.

[0150] In some embodiments of the present invention, the above R a is selected from H, CH3, CD3 and CH(CH3)2, and other variables are as defined in the present invention.

[0151] In some embodiments of the present invention, the above R a is selected from H, CH3 and CH(CH3)2, and other variables are as defined in the present invention.

[0152] In some embodiments of the present invention, the above R b is selected from H, CH3, CD3 and CH(CH3)2, and other variables are as defined in the present invention.

[0153] In some embodiments of the present invention, the above R b is selected from H, CH3 and CH(CH3)2, and other variables are as defined in the present invention.

[0154] In some embodiments of the present invention, the above R c is selected from H, cyclopropyl, pyrrolidinyl and morpholinyl, and other variables are as defined in the present invention.

[0155] In some embodiments of the present invention, the above-mentioned R c is selected from pyrrolidinyl and morpholinyl, and other variables are as defined in the present invention.

[0156] In some embodiments of the present invention, each of the above-mentioned Rs d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CF2H, CF3, CH2CH3, CF2CF3, -C≡CH, -C≡CF, -C≡CBr, -C≡CCH3, and -C≡CCF3, and other variables are as defined in the present invention.

[0157] In some embodiments of the present invention, each of the above-mentioned Rs d is independently selected from F, Cl, NH2, OH, CH3, CF3, CH2CH3, -C≡CH, and -C≡CCH3, and other variables are as defined in the present invention.

[0158] In some embodiments of the present invention, each of the above-mentioned Rs e is independently selected from H and F, and other variables are as defined in the present invention.

[0159] In some embodiments of the present invention, the above-mentioned T1 is selected from CH, and other variables are as defined in the present invention.

[0160] In some embodiments of the present invention, the above-mentioned T1 is selected from O, and other variables are as defined in the present invention.

[0161] In some embodiments of the present invention, the above-mentioned T2 is selected from O, and other variables are as defined in the present invention.

[0162] In some embodiments of the present invention, each of the above-mentioned R1s is independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, CH2CH2CH3, -CH=CH2, -CH2-CH=CH2, OCH3, OCH2CH3, OCH2CH2CH3, -CH3OCH3, -CH3OCH2CH3, -CH2CH3OCH3, -CH2CH2CH3OCH3, -SH, cyclopropyl, cyclobutyl, pyridine, pyrimidine, thiophene, 1,2,4-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole, and the CH3, CH2CH3, CH2CH2CH3, -CH=CH2, -CH2-CH=CH2, Cyclopropyl, cyclobutyl, pyridine, pyrimidine, thiophene, 1,2,4-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole are each independently optionally substituted with 1, 2, 3, or 4 R's, and other variables are as defined in the present invention.

[0163] In some embodiments of the present invention, the above R1 is selected from F, Cl, Br, I, OH, CH3, CH2CH3, CH2CH2CH3, pyridine, pyrimidine, thiophene, 1,2,4-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole, and the CH3, CH2CH3, CH2CH2CH3, pyridine, pyrimidine, thiophene, 1,2,4-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole are each independently optionally substituted with 1, 2, 3, or 4 R's, and other variables are as defined in the present invention.

[0164] In some embodiments of the present invention, each of the above R1's is independently selected from F, Cl, Br, OH, NH2, CN, CH3, CH(CH3)2, cyclopropyl, CF3, and other variables are as defined in the present invention.

[0165] In some embodiments of the present invention, each of the above R1's is independently selected from F, Cl, OH, NH2, CN, CH3, CH(CH3)2, cyclopropyl, CF3, and other variables are as defined in the present invention.

[0166] In some embodiments of the present invention, the above R1 is selected from F, Cl, OH, CH3, CF3, and other variables are as defined in the present invention.

[0167] In some embodiments of the present invention, the above R1 is selected from F, Cl, OH, CH3, and other variables are as defined in the present invention.

[0168] In some embodiments of the present invention, the above R2 is selected from phenyl, naphthyl, indolyl, pyridyl, pyrrolyl, benzopyrimidinyl, and quinolinyl, and the phenyl, naphthyl, indolyl, pyridyl, pyrrolyl, benzopyrimidinyl, and quinolinyl are each independently optionally substituted with 1, 2, 3, 4, or 5 R's d and other variables are as defined in the present invention.

[0169] In some embodiments of the present invention, the above R2 is selected from phenyl, naphthyl, and pyridyl, and the phenyl, naphthyl, and pyridyl are each independently optionally substituted with 1, 2, 3, 4, or 5 R's dSubstituted, with other variables as defined in the present invention.

[0170] In some embodiments of the present invention, the above-mentioned R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted with 1, 2, 3, 4 or 5 Rs d Substituted, with other variables as defined in the present invention.

[0171] In some embodiments of the present invention, the above-mentioned R2 is selected from Other variables as defined in the present invention.

[0172] In some embodiments of the present invention, the above-mentioned R2 is selected from Other variables as defined in the present invention.

[0173] In some embodiments of the present invention, the above-mentioned R2 is selected from Other variables as defined in the present invention.

[0174] In some embodiments of the present invention, the above-mentioned ring C is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl and pyrimidinyl, with other variables as defined in the present invention.

[0175] In some embodiments of the present invention, the above-mentioned ring C is selected from pyrazolyl and imidazolyl, with other variables as defined in the present invention.

[0176] In some embodiments of the present invention, the above-mentioned ring A is selected from Other variables as defined in the present invention.

[0177] In some embodiments of the present invention, the above-mentioned ring A is selected from Other variables as defined in the present invention.

[0178] In some embodiments of the present invention, the above-mentioned ring A is selected from Other variables as defined in the present invention.

[0179] In some embodiments of the present invention, the above-mentioned ring A is selected from Other variables as defined in the present invention.

[0180] In some embodiments of the present invention, the above-mentioned ring B is selected from 8-9 membered heteroalkenyl, with other variables as defined in the present invention.

[0181] In some embodiments of the present invention, the above-mentioned ring B is selected from 5- to 12-membered heteroalkenyl, 7- to 12-membered tricyclic heteroalkyl, and the 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl are each independently optionally substituted with 1, 2, 3, 4, 5, or 6 R e substituents, with other variables as defined in the present invention.

[0182] In some embodiments of the present invention, the above ring B is selected from 5- to 12-membered heteroalkenyl, the 5- to 12-membered heteroalkenyl is each independently optionally substituted with 1, 2, 3, 4, 5, or 6 R e substituents; or; ring B is selected from with other variables as defined in the present invention.

[0183] In some embodiments of the present invention, the above ring B is selected from with other variables as defined in the present invention.

[0184] In some embodiments of the present invention, the above ring B is selected from with other variables as defined in the present invention.

[0185] In some embodiments of the present invention, the above structural unit is selected from with other variables as defined in the present invention.

[0186] In some embodiments of the present invention, the above structural unit is selected from with other variables as defined in the present invention.

[0187] In some embodiments of the present invention, the above structural unit is selected from with other variables as defined in the present invention.

[0188] In some embodiments of the present invention, the above ring A is selected from Ring B is selected from with other variables as defined in the present invention.

[0189] In some embodiments of the present invention, the above ring A is selected from Ring B is selected from with other variables as defined in the present invention.

[0190] In some embodiments of the present invention, R1 on two adjacent atoms forms a 5- to 6-membered heteroalkenyl with the atoms to which they are attached, and the 5- to 6-membered heteroalkenyl is each independently optionally substituted with 1, 2, 3, 4, or 5 R substituents to make the structural unit Selected from Other variables are as defined in the present invention.

[0191] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0192] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0193] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0194] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0195] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0196] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0197] In some embodiments of the present invention, the above ring B is selected from Structural unit Selected from Other variables are as defined in the present invention.

[0198] In some embodiments of the present invention, the above ring B is selected from Structural unit Selected from Other variables are as defined in the present invention.

[0199] In some embodiments of the present invention, the above structural unit is selected from Ring B is selected from Other variables are as defined in the present invention.

[0200] In some embodiments of the present invention, the above structural unit is selected from Ring B is selected from Other variables are as defined in the present invention.

[0201] In some embodiments of the present invention, the above R6 is selected from H, and other variables are as defined in the present invention.

[0202] In some embodiments of the present invention, the above R7 is selected from H, and other variables are as defined in the present invention.

[0203] The present invention also provides a compound of formula (I) and a pharmaceutically acceptable salt thereof,

[0204]

[0205] wherein,

[0206] Ring A is selected from

[0207] Alternatively, ring A is selected from

[0208] R1 is selected from halogen, OH, C 1-3 alkyl, -C(=O)-NR a R b and -C(=O)-R c ;

[0209] R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted by 1, 2, 3, 4 or 5 R d substituents;

[0210] R3 is selected from H, R4 is selected from F, and R5 is selected from H;

[0211] Alternatively, R3 and R4 are linked together such that the structural unit is selected from R5 is selected from H;

[0212] Alternatively, R4 and R5 are linked together to form the is optionally substituted by 1 or 2 R eis replaced, and R3 is selected from H;

[0213] R a is selected from H and C 1-3 alkyl;

[0214] R b is selected from H and C 1-3 alkyl;

[0215] R c is selected from 5- to 6-membered heterocyclic alkyl;

[0216] Each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted by 1, 2, 3, 4 or 5 halogens;

[0217] Each R e is independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0218] m is selected from 0, 1, 2 and 3.

[0219] The present invention also provides a compound of formula (I) and its pharmaceutically acceptable salts

[0220]

[0221] wherein,

[0222] Ring A is selected from

[0223] R1 is selected from halogen, OH, C 1-3 alkyl, -C(=O)-NR a R b and -C(=O)-R c ;

[0224] R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted by 1, 2, 3, 4 or 5 R d substituents;

[0225] R3 is selected from H, R4 is selected from F, R5 is selected from H;

[0226] Alternatively, R3 and R4 are linked such that the structural unit is selected from R5 is selected from H;

[0227] Alternatively, R4 and R5 are linked such that the structural unit is selected from R3 is selected from H;

[0228] R a is selected from H and C 1-3 alkyl;

[0229] R b is selected from H and C 1-3 alkyl;

[0230] R c is selected from 5- to 6-membered heterocycloalkyl;

[0231] Each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted with 1, 2, 3, 4, or 5 halogens;

[0232] m is selected from 0, 1, 2, or 3.

[0233] The present invention also provides a compound of formula (I) and its pharmaceutically acceptable salts

[0234]

[0235] wherein,

[0236] Ring A is selected from

[0237] Or, ring A is selected from

[0238] R1 is selected from halogen, OH, C 1-3 alkyl, -C(=O)-NR a R b and -C(=O)-R c ;

[0239] R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted with 1, 2, 3, 4, or 5 R d substituents;

[0240] R3 is selected from H, R4 is selected from F, R5 is selected from H;

[0241] R a is selected from H and C 1-3 alkyl;

[0242] R b is selected from H and C 1-3 alkyl;

[0243] R c is selected from 5- to 6-membered heterocycloalkyl;

[0244] Each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted by 1, 2, 3, 4 or 5 halogens;

[0245] m is selected from 0, 1, 2 and 3.

[0246] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R a is selected from H, CH3 and CH(CH3)2, and other variables are as defined in the present invention.

[0247] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R b is selected from H, CH3 and CH(CH3)2, and other variables are as defined in the present invention.

[0248] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R c is selected from pyrrolidinyl and morpholinyl, and other variables are as defined in the present invention.

[0249] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CF2H, CF3, CH2CH3, CF2CF3, -C≡CH, -C≡CF, -C≡CBr, -C≡CCH3 and -C≡CCF3, and other variables are as defined in the present invention.

[0250] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R d is independently selected from F, Cl, NH2, OH, CH3, CF3, CH2CH3, -C≡CH and -C≡CCH3, and other variables are as defined in the present invention.

[0251] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from F, Cl, OH, CH3, and other variables are as defined in the present invention.

[0252] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted with 1, 2, 3, 4 or 5 R d substituents, and the other variables are as defined in the present invention.

[0253] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from and the other variables are as defined in the present invention.

[0254] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from and the other variables are as defined in the present invention.

[0255] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from and the other variables are as defined in the present invention.

[0256] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from and the other variables are as defined in the present invention.

[0257] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from and the other variables are as defined in the present invention.

[0258] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from and the other variables are as defined in the present invention.

[0259] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from and the other variables are as defined in the present invention.

[0260] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from and the other variables are as defined in the present invention.

[0261] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from and other variables are as defined in the present invention.

[0262] Some embodiments of the present invention are derived from any combination of the above variables.

[0263] The present invention provides the following compounds or pharmaceutically acceptable salts thereof,

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303] The present invention also provides the following synthesis methods:

[0304] Synthesis method 1:

[0305]

[0306] Synthesis method 2:

[0307]

[0308] The present invention also provides the use of the above compound or its pharmaceutically acceptable salt in the preparation of a medicament for treating pan-KRAS related diseases.

[0309] The present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt in the preparation of a medicament for treating diseases related to tumors.

[0310] Test method 1: H358 cell experiment

[0311] 1 Experimental purpose

[0312] To test the IC of the test compound against the proliferation inhibition of H358 cells 50 。

[0313] 2 Reagents

[0314] The main reagents used in this study include RPMI-1640 medium, penicillin / streptomycin antibiotics purchased from Vicente, and fetal bovine serum purchased from Biosera. CellTiter-Glo (reagent for chemiluminescent detection of cell viability) reagent was purchased from Promega. The NCI-H358 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences.

[0315] 3 Instruments

[0316] The main instrument used in this study is the Nivo multi-label analyzer (PerkinElmer).

[0317] 4 Experimental method:

[0318] 1) Seed NCI-H358 cells in a white 96-well plate, 80 μL of cell suspension per well, which contains 4000 NCI-H358 cells. Place the cell plate in a carbon dioxide incubator and culture overnight.

[0319] 2) Dilute the test compound 5-fold to the 9th concentration with a multi-channel pipette, i.e., dilute from 2 mM to 5.12 nM, and set up a double-replicate experiment. Add 78 μL of medium to the middle plate, and then transfer 2 μL of the gradient-diluted compound per well to the middle plate according to the corresponding positions. After mixing, transfer 20 μL per well to the cell plate. The concentration range of the compound transferred to the cell plate is 10 μM to 0.0256 nM. Place the cell plate in a carbon dioxide incubator and culture for 5 days. Prepare another cell plate and read the signal value on the day of adding the drug as the maximum value (Max value in the following equation) for data analysis. Add 25 μL of the reagent for chemiluminescent detection of cell viability to each well of this cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read the values using a multi-label analyzer.

[0320] 3) Add 25 μL of the reagent for chemiluminescent detection of cell viability to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read the values using a multi-label analyzer.

[0321] Data analysis:

[0322] The original data is converted into inhibition rate using the equation (Sample - Min) / (Max - Min)×100%, and the IC 50 value can be obtained by curve fitting with four parameters (derived from the "log(inhibitor) vs. response - Variable slope" mode in GraphPad Prism).

[0323] Test method 2. Anti - cell proliferation effect of the compound in the tumor cell line AsPC - 1

[0324] Research purpose

[0325] In this experiment, the effect of the compound on inhibiting cell proliferation was studied by detecting the effect of the compound on in vitro cell activity in the tumor cell line AsPC - 1.

[0326] Experimental materials

[0327] Cell line Tumor type Growth characteristics Culture method AsPC-1 Pancreatic cancer Adherent growth RPMI 1640 + 10% FBS

[0328] Ultra Low Cluster - 96 - well plate (Corning - 7007)

[0329] Greiner CELLSTAR 96 - well plate (#655090)

[0330] Promega CellTiter - Glo 3D luminescence cell viability assay kit (Promega - G9683)

[0331] 2104 - 10 EnVision microplate reader, PerkinElmer

[0332] RPMI 1640, DMEM, PBS (phosphate - buffered saline), FBS (fetal bovine serum), Antibiotic - antimycotic, L - glutamine, DMSO (dimethyl sulfoxide)

[0333] Experimental methods and procedures

[0334] Cell culture

[0335] The tumor cell line was cultured in an incubator at 37°C and 5% CO2 according to the culture conditions shown in the culture method. Sub - culture regularly, and cells in the logarithmic growth phase were used for plating.

[0336] Cell plating

[0337] Cells were stained with trypan blue and viable cells were counted.

[0338] Adjust the cell concentration to an appropriate concentration.

[0339] Cell line Density (per well) AsPC-1 7000 cells

[0340] Add 135 μL of cell suspension to each well of the ULA culture plate, and add the same volume of cell-free culture medium to the blank control wells.

[0341] After plating, immediately centrifuge the ULA culture plate at room temperature for 10 minutes at 1000 rpm. Note: After centrifugation, be sure to handle the subsequent operations carefully to avoid unnecessary shaking.

[0342] Incubate the culture plate overnight in an incubator at 37 °C, 5% CO2, and 100% relative humidity.

[0343] Preparation of 10X compound working solution and compound treatment of cells (Day 1)

[0344] After preparing the 10X compound working solution (DMSO 10X working solution), add 15 μL of the 10X compound working solution to each well of the ULA culture plate, and add 15 μL of DMSO-cell culture medium mixture to the vehicle control and blank control.

[0345] Return the 96-well cell plate to the incubator and incubate for 120 hours.

[0346] Observe the cell spheroid formation every day until the end of the experiment.

[0347] CellTiter-Glo luminescence assay for cell viability (Day 5)

[0348] The following steps are carried out according to the instructions of the Promega CellTiter-Glo 3D luminescence assay kit for cell viability (Promega #G9683).

[0349] Add 150 μL (equal to the volume of cell culture medium in each well) of CellTiter-Glo 3D reagent to each well. Wrap the cell plate with aluminum foil to avoid light.

[0350] Shake the culture plate on an orbital shaker for 5 minutes.

[0351] Carefully pipette up and down 10 times to mix the contents in the wells. Ensure that the cell spheres are fully separated before proceeding to the next step.

[0352] Then transfer the solution in the ULA culture plate to a black-bottom culture plate (#655090) and let it stand at room temperature for 25 minutes to stabilize the luminescence signal.

[0353] Detect the luminescence signal on a 2104 EnVision microplate reader.

[0354] Data analysis

[0355] The inhibition rate (IR) of the test compound is calculated using the following formula: IR (%) = (1 - ((RLU compound - RLU blank control) / (RLU vehicle control - RLU blank control))) × 100%. Calculate the inhibition rates of compounds at different concentrations in Excel, and then use GraphPad Prism software to create an inhibition curve graph and calculate relevant parameters, including the minimum inhibition rate, maximum inhibition rate, and IC 50 。

[0356] Technical effect

[0357] The compounds of the present invention have good inhibitory activity against a variety of KRAS mutant and KRAS amplified cells; they exhibit good tumor inhibitory effects in GP2D and Panc0403 cell lines.

[0358] Related definitions

[0359] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood in its ordinary meaning. When trade names appear in this article, they are intended to refer to the corresponding products or their active ingredients.

[0360] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0361] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents found in the present invention with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts.

[0362] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acid radicals or basic groups by conventional chemical methods. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with a stoichiometric amount of appropriate bases or acids in water, an organic solvent, or a mixture of both.

[0363] Unless otherwise specified, the term "treatment" is intended to mean all processes in which the progression of a disease may be slowed, interrupted, arrested, or prevented, but not necessarily indicating that all symptoms are completely eliminated.

[0364] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0365] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). Alternatively, deuterium can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of the drug. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0366] The term "optionally" or "optionally" means that the subsequently described event or condition may but does not necessarily occur, and the description includes both the case where the event or condition occurs and the case where the event or condition does not occur.

[0367] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and variants of hydrogen, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of being chemically achievable.

[0368] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 - 2 Rs, the group may optionally be substituted with up to two Rs, and each R in each case has independent options. In addition, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0369] When the number of a linking group is 0, such as -(CRR)0-, it represents that the linking group is a single bond.

[0370] When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked. For example, in A - L - Z, when L represents a single bond, it means the structure is actually A - Z.

[0371] When the listed linking groups do not specify their linking directions, the linking directions are arbitrary. For example, in which the linking group L is -M - W -, at this time -M - W - can connect ring A and ring B in the same direction as the reading order from left to right to form or can connect ring A and ring B in the opposite direction to the reading order from left to right to form Combinations of the said linking groups, substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0372] Unless otherwise specified, when a group has one or more connectable sites, any one or more of these sites of the group can be connected to other groups by chemical bonds. When the connection mode of the chemical bond is non - specific and there are H atoms at the connectable sites, then when connecting the chemical bond, the number of H atoms at this site will correspondingly decrease according to the number of connected chemical bonds to become a group with the corresponding valence. The chemical bonds connecting the said site to other groups can be represented by a straight solid line bond a straight dashed line bond or a wavy line For example, the straight solid line bond in -OCH3 represents connection to other groups through the oxygen atom in this group; the straight dashed line bond in represents connection to other groups through both ends of the nitrogen atom in this group; represents that any connectable site on the piperidinyl group can be connected to other groups by 1 chemical bond, including at least these 4 connection modes. Even if an H atom is drawn on -N -, but still includes For a group with this connection mode, only when connecting one chemical bond, the H at this site will correspondingly decrease by one to become the corresponding monovalent piperidyl group.

[0373] Unless otherwise specified, in some embodiments of the present invention, when ring B is selected from the is independently substituted by 1, 2, 3, 4, 5 or 6 Rs e respectively, the substitution is represented as the hexahydro-1H-pyrrolizine ring being substituted by R e respectively.

[0374] Unless otherwise specified, in some embodiments of the present invention, when the structural fragment is substituted by R1, the substitution is represented as the piperidine ring being substituted by R1.

[0375] Unless otherwise specified, the absolute configuration of a stereocenter is represented by a solid wedge bond and a dashed wedge bond , and the relative configuration of a stereocenter is represented by a solid straight bond and a dashed straight bond . A wavy line represents a solid wedge bond or a dashed wedge bond , or a wavy line represents a solid straight bond or a dashed straight bond

[0376] Unless otherwise specified, when there is a double bond structure in the compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a pair of lone pairs of electrons on the nitrogen atom is regarded as one of the substituents it is connected to), if the atoms on the double bond in the compound are connected to their substituents by a wavy line , it represents the (Z)-isomer, the (E)-isomer, or a mixture of the two isomers of the compound. For example, the following formula (A) represents that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or a mixture of the two isomers of formula (A-1) and formula (A-2); the following formula (B) represents that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or a mixture of the two isomers of formula (B-1) and formula (B-2). The following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or a mixture of the two isomers of formula (C-1) and formula (C-2).

[0377]

[0378] Unless otherwise specified, when there is a double bond structure in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is regarded as one of the substituents it is connected to), if the atoms on the double bond in the compound and their substituents are connected by is used to represent, it represents the (Z)-isomer, (E)-isomer, or a mixture of the two isomers of the compound. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional group isomers being in dynamic equilibrium at room temperature and being able to rapidly interconvert with each other. If tautomers are possible (such as in solution), the chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0379] Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of having n to n + m carbons. For example, C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , and also includes any range within n to n + m. For example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n-membered to n + m-membered means that the number of atoms in the ring is from n to n + m. For example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range within n to n + m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring etc.

[0380] Unless otherwise specified, the terms "enriched in one isomer", "isomer-enriched", "enriched in one enantiomer", or "enantiomer-enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of this isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0381] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0382] Unless otherwise specified, the term "halogen" or "halo" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom.

[0383] Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a saturated hydrocarbon group having from 1 to 3 carbon atoms in a straight-chain or branched-chain form. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0384] Unless otherwise specified, the term "C 1-4 alkoxy" denotes those alkyl groups containing from 1 to 4 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-4 alkoxy includes C 1-3 、C 1-2 、C 2-4 、C4 and C3 alkoxy, etc. Examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy), etc.

[0385] Unless otherwise specified, "C 2-4"Alkenyl" is used to denote a straight-chain or branched-chain hydrocarbon group consisting of 2 to 4 carbon atoms and containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position in the group. The C 2-4 alkenyl includes C 2-3 4, C4, C3, and C2 alkenyls, etc.; the C 2-4 alkenyl can be monovalent, divalent, or polyvalent. Examples of C 2-4 alkenyl include, but are not limited to, vinyl, propenyl, butenyl, butadienyl, etc. Unless otherwise specified, "C 2-3 alkenyl" is used to denote a straight-chain or branched-chain hydrocarbon group consisting of 2 to 3 carbon atoms and containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position in the group. The C 2-3 alkenyl includes C3 and C2 alkenyls; the C 2-3 alkenyl can be monovalent, divalent, or polyvalent. Examples of C 2-3 alkenyl include, but are not limited to, vinyl, propenyl, etc.

[0386] Unless otherwise specified, "C 2-4 alkynyl" is used to denote a straight-chain or branched-chain hydrocarbon group consisting of 2 to 4 carbon atoms and containing at least one carbon-carbon triple bond, and the carbon-carbon triple bond can be located at any position in the group. The C 2-4 alkynyl includes C 2-3 4, C4, C3, and C2 alkynyls, etc. It can be monovalent, divalent, or polyvalent. Examples of C 2-4 alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, etc.

[0387] Unless otherwise specified, "C 3-6 cycloalkyl" denotes a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system. The C 3-6 cycloalkyl includes C 3-5 3, C 4-5 4, and C 5-6 5 cycloalkyls, etc.; it can be monovalent, divalent, or polyvalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0388] Unless otherwise specified, the term "5-12 membered heteroalkenyl" alone or in combination with other terms separately denotes a partially unsaturated cyclic group consisting of 5 to 12 ring atoms and containing at least one carbon-carbon double bond, where 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remaining are carbon atoms, where the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p, where p is 1 or 2). It includes monocyclic, bicyclic, and tricyclic systems, among which the bicyclic and tricyclic systems include spirocycles, fused rings, and bridged rings, and any ring of this system is non-aromatic. In addition, for the "5- to 12-membered heteroalkenyl", the heteroatom can occupy the connection position between the heteroalkenyl and the rest of the molecule. The 5- to 12-membered heteroalkenyl includes 5- to 10-membered, 5- to 8-membered, 5- to 6-membered, 4- to 5-membered, 4-membered, 5-membered, and 6-membered heteroalkenyls, etc.

[0389] Unless otherwise specified, the term "5- to 6-membered heteroalkenyl" alone or in combination with other terms respectively represents a partially unsaturated cyclic group composed of 5 to 6 ring atoms containing at least one carbon-carbon double bond, with 1, 2, 3, or 4 of its ring atoms being heteroatoms independently selected from O, S, and N, and the rest being carbon atoms, where the carbon atoms are optionally oxo-substituted (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , where p is 1 or 2). It includes monocyclic and bicyclic systems, among which the bicyclic system includes spirocycles, fused rings, and bridged rings. Any ring of this system is non-aromatic. In addition, for the "5- to 6-membered heteroalkenyl", the heteroatom can occupy the connection position between the heteroalkenyl and the rest of the molecule. The 5- to 6-membered heteroalkenyl includes 5-membered and 6-membered heteroalkenyls, etc. Examples of 5- to 6-membered heteroalkenyls include, but are not limited to

[0390] Unless otherwise specified, the term "4- to 6-membered heteroalkyl" alone or in combination with other terms respectively represents a saturated cyclic group composed of 4 to 6 ring atoms, with 1, 2, 3, or 4 of its ring atoms being heteroatoms independently selected from O, S, and N, and the rest being carbon atoms, where the carbon atoms are optionally oxo-substituted (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , where p is 1 or 2). It includes monocyclic and bicyclic systems, among which the bicyclic system includes spirocycles, fused rings, and bridged rings. In addition, for the "4- to 6-membered heteroalkyl", the heteroatom can occupy the connection position between the heteroalkyl and the rest of the molecule. The 4- to 6-membered heteroalkyl includes 5- to 6-membered, 4-membered, 5-membered, and 6-membered heteroalkyls, etc. Examples of 4- to 6-membered heteroalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxolanyl, dithiolanyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or hexahydropyridazinyl, etc.

[0391] Unless otherwise specified, the term "5-6 membered heterocycloalkyl" alone or in combination with other terms separately represents a saturated cyclic group composed of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spiro, fused and bridged rings. In addition, with respect to the "5-6 membered heterocycloalkyl", the heteroatom can occupy the connection position of the heterocycloalkyl to the rest of the molecule. The 5-6 membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyls. Examples of 5-6 membered heterocycloalkyls include but are not limited to pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxolanyl, dithiolanyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl.

[0392] Unless otherwise specified, the term "7-12 membered tricyclic heterocycloalkyl" alone or in combination with other terms separately represents a tricyclic saturated cyclic group composed of 7 to 12 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 7-12 membered tricyclic heterocycloalkyl includes spiro, fused and bridged rings. In addition, with respect to the "7-12 membered tricyclic heterocycloalkyl", the heteroatom can occupy the connection position of the heterocycloalkyl to the rest of the molecule. The 7-12 membered tricyclic heterocycloalkyl includes 7-10 membered, 7-8 membered, 8-10 membered, 8-12 membered, 9-10 membered, 9-12 membered, 10-12 membered, 9 membered and 10 membered heterocycloalkyls, etc.

[0393] Unless otherwise specified, the terms "5- to 10-membered heteroaromatic ring" and "5- to 10-membered heteroaryl" in the present invention can be used interchangeably. The term "5- to 10-membered heteroaryl" refers to a cyclic group having a conjugated π-electron system composed of 5 to 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic, or fused tricyclic system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , where p is 1 or 2). The 5- to 10-membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5- to 10-membered heteroaryl includes 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5-membered, and 6-membered heteroaryls, etc. Examples of the 5- to 10-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolinyl (including 1-isoquinolinyl, 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, etc.), or quinolinyl (including 3-quinolinyl, 6-quinolinyl, etc.).

[0394] Unless otherwise specified, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl" in the present invention can be used interchangeably. The term "5- to 6-membered heteroaryl" refers to a monocyclic group having a conjugated π-electron system composed of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p, where p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryls. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

[0395] Unless otherwise specified, the terms "5-6 membered nitrogen-containing heteroaromatic ring" and "5-6 membered nitrogen-containing heteroaryl" of the present invention can be used interchangeably. The term "5-6 membered nitrogen-containing heteroaryl" refers to a monocyclic group having a conjugated π-electron system composed of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, at least one of the heteroatoms being N and the rest being carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , where p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryls. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

[0396] The compounds of the present invention can be prepared by various synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent replacement methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0397] The structure of the compounds of the present invention can be confirmed by conventional methods well-known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), where the grown single crystal is used to collect diffraction intensity data with a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed by the direct method (Shelxs97) to confirm the absolute configuration.

[0398] The solvents used in the present invention are commercially available. The following abbreviations are used in the present invention: DMF represents N,N-dimethylformamide; DIPEA represents N,N-diisopropylethylamine; DCM represents dichloromethane; m-CPBA represents m-chloroperoxybenzoic acid; NBS represents N-bromosuccinimide; HATU represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; NCS represents N-chlorosuccinimide; Dess-Martin periodinane represents (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one.

[0399] Compounds are named according to the conventional naming principles in the art or using software, and commercially available compounds use the supplier catalog names. Specific Embodiments

[0400] The present invention will be described in detail below by way of examples, but this does not mean any adverse limitation to the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0401] Example 1

[0402]

[0403] Step 1: Synthesis of Compound 1-2

[0404] Weigh compound 1-1 (1 g, 1.31 mmol) and 1-1A (444.20 mg, 2.63 mmol), dissolve them in DMF (50 mL), add DIPEA (1.70 g, 13.13 mmol, 2.29 mL), and heat to 100 °C for reaction for 2 hours. Quench with water (50 mL), extract with ethyl acetate (50 mL x 2), wash with water (30 mL), and concentrate to obtain compound 1-2, MS m / z = 781.5 [M+H] + 。

[0405] Step 2: Synthesis of compound 1-3

[0406] Weigh compound 1-2 (1.06 g, 1.36 mmol), dissolve it in DCM (30 mL), add m-CPBA (276.34 mg, 1.36 mmol, 85% purity) at 0 °C, and react at 25 °C for 1 hour. Concentrate to obtain compound 1-3, MS m / z = 797.5 [M+H] + 。

[0407] Step 3: Synthesis of compound 1-4

[0408] Dissolve compound 1-2A (847.12 mg, 5.32 mmol) in anhydrous tetrahydrofuran (20 mL), add sodium tert-butoxide (511.38 mg, 5.32 mmol), cool to 0 °C and react for 30 minutes, add compound 1-3 (1.06 g, 1.33 mmol), and react at 25 °C for 1 hour. Add 20 mL of saturated ammonium chloride solution to the reaction solution, extract with ethyl acetate (20 mL x 2), wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate, and obtain compound 1-4. MS m / z = 892.6 [M+H] + 。

[0409] Step 4: Synthesis of hydrochlorides of compounds 1A and 1B

[0410] Compound 1-4 (0.7 g, 784.82 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was directly concentrated and prepared by high performance liquid chromatography (Phenomenex C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 10%-30%) to obtain the hydrochloride of compound 1A and the hydrochloride of 1B. Analytical method: Column: ChromCore 120 C18 3 μm, 3.0×30 mm; mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)]; gradient: acetonitrile (0.02% trifluoroacetic acid)%: 10%-80%, 7 min_220&254 nm), retention time: 1A (Rt = 2.694 min), MS m / z = 652.3 [M+H] + , 1B (Rt = 2.848 min), MS m / z = 652.2 [M+H] + .

[0411] 1A: 1 H NMR (400 MHz, CD3OD) δ 6.90 - 6.66 (m, 1H), 5.75 - 5.45 (m, 1H), 5.39 - 5.22 (m, 1H), 5.00 - 4.94 (m, 2H), 4.79 - 4.63 (m, 3H), 4.24 - 4.07 (m, 1H), 4.02 - 3.81 (m, 3H), 3.71 - 3.62 (m, 1H), 3.61 - 3.54 (m, 1H), 3.51 - 3.44 (m, 1H), 3.42 - 3.35 (m, 1H), 3.17 - 3.04 (m, 1H), 2.71 - 2.46 (m, 3H), 2.27 - 2.17 (m, 1H), 2.23 (dt, J = 4.1, 13.1 Hz, 6H), 2.10 - 1.99 (m, 1H), 1.96 - 1.78 (m, 2H).

[0412] 1B: 11H NMR (400 MHz, CD3OD) δ 7.43 - 7.34 (m, 1H), 7.06 - 6.90 (m, 1H), 6.88 - 6.76 (m, 1H), 5.74 - 5.50 (m, 1H), 5.35 - 5.20 (m, 1H), 5.02 - 4.96 (m, 1H), 4.78 - 4.72 (m, 2H), 4.52 - 4.39 (m, 1H), 4.20 - 4.07 (m, 1H), 4.05 - 3.77 (m, 4H), 3.53 - 3.38 (m, 3H), 3.13 - 2.99 (m, 1H), 2.78 - 2.58 (m, 2H), 2.53 - 2.43 (m, 1H), 2.40 (br d, J = 3.8 Hz, 3H), 2.37 - 2.31 (m, 2H), 2.28 - 2.15 (m, 1H), 2.12 - 2.01 (m, 1H), 2.00 - 1.89 (m, 2H).

[0413] Example 2

[0414]

[0415] Step 1: Synthesis of Compound 2-1

[0416] Weigh compound 1-1 (800 mg, 1.05 mmol) and 2-1A (175.18 mg, 1.16 mmol), add DMF (10 mL), add DIPEA (407.21 mg, 3.15 mmol, 548.80 μL), and heat to 100 °C for reaction for 2 hours. Quench with water (50 mL), extract with ethyl acetate (50 mL × 2), wash with water (30 mL), concentrate, and separate by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 2-1, MS m / z = 727.3 [M+H] + .

[0417] Step 2: Synthesis of Compound 2-2

[0418] Weigh compound 2-1 (620 mg, 853.03 μmol), dissolve it in DCM (20 mL), add m-CPBA (173.18 mg, 853.03 μmol, 85% purity), and react at 25 °C for 1 hour. Dilute the reaction solution with 50 mL of dichloromethane, wash with 30 mL of saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 2-2, MS m / z = 743.3 [M+H] + .

[0419] Step 3: Synthesis of Compound 2-3

[0420] Compound 1-2A (128.59 mg, 807.73 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL), sodium tert-butoxide (77.62 mg, 807.73 μmol) was added, and the reaction was carried out at 25 °C for 30 minutes. Then compound 2-2 (300 mg, 403.87 μmol) was added, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was diluted with 60 mL of ethyl acetate, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-3. MS m / z = 838.4 [M+H] + 。

[0421] Step 4: Synthesis of the hydrochloride salt of compound 2

[0422] Compound 2-3 (0.3 g, 358.03 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was directly concentrated and prepared by high performance liquid chromatography (Phenomenex C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 5%-35%, 10 min) to obtain the hydrochloride salt of compound 2. MS m / z = 598.4 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ ppm 6.85 - 6.67 (m, 1H), 5.69 - 5.52 (m, 1H), 5.32 - 5.22 (m, 1H), 5.00 - 4.94 (m, 1H), 4.80 - 4.74 (m, 3H), 4.61 - 4.34 (m, 1H), 4.06 - 3.83 (m, 4H), 3.55 - 3.36 (m, 3H), 3.25 - 3.10 (m, 1H), 3.07 - 2.95 (m, 1H), 2.82 - 2.61 (m, 2H), 2.54 - 2.44 (m, 1H), 2.42 - 2.30 (m, 5H), 2.30 - 2.17 (m, 1H), 2.14 - 1.98 (m, 1H), 1.89 - 1.65 (m, 3H), 1.34 - 1.25 (m, 3H).

[0423] Example 3

[0424]

[0425] Step 1: Synthesis of compound 3-1

[0426] Weigh compound 1-1 (300 mg, 0.39 mmol), 3-1A (144.57 mg, 0.59 mmol), add DMF (5 mL), add DIPEA (152.70 mg, 1.18 mmol, 205.80 μL), heat to 100 °C and react for 1 hour. Directly concentrate, separate by column chromatography (petroleum ether: ethyl acetate = 4:1 - 1:1) to obtain compound 3-1, MS m / z = 820.5 [M+H] + .

[0427] Step 2: Synthesis of compound 3-2

[0428] Weigh compound 3-1 (320 mg, 390.29 μmol), dissolve it in DCM (5 mL), add m-CPBA (79.24 mg, 390.29 μmol, 85% purity), react at 25 °C for 0.5 hour. Dilute the reaction solution with 40 mL of dichloromethane, wash it with 20 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (dichloromethane: methanol = 20:1) to obtain compound 3-2, MS m / z = 836.5 [M+H] + .

[0429] Step 3: Synthesis of compound 3-3

[0430] Dissolve compound 1-2A (91.42 mg, 574.23 μmol) in anhydrous tetrahydrofuran (5 mL), add sodium tert-butoxide (55.19 mg, 574.23 μmol), react at 25 °C for 30 minutes, add compound 3-2 (300 mg, 358.89 μmol), react at 25 °C for 1 hour. Dilute the reaction solution with 40 mL of ethyl acetate, wash it with 20 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, and concentrate to obtain compound 3-3. MS m / z = 931.7 [M+H] + .

[0431] Step 4: Synthesis of the hydrochloride salt of compound 3

[0432] Compound 3-3 (310 mg, 332.97 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at 25 °C for 1 hour. After the reaction was completed, it was concentrated, and the hydrochloride of compound 3 was obtained by preparative high performance liquid chromatography (Phenomenex C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 13%-43%, 10 min). MS m / z = 691.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 7.08-6.91 (m, 1H), 6.87-6.71 (m, 1H), 5.77-5.47 (m, 1H), 5.35-5.15 (m, 2H), 4.99 (brs, 3H), 4.89-4.81 (m, 1H), 4.78-4.69 (m, 1H), 4.67-4.55 (m, 1H), 4.53-4.43 (m, 1H), 4.21-4.05 (m, 2H), 4.03-3.80 (m, 3H), 3.53-3.34 (m, 5H), 3.20-2.99 (m, 4H), 2.80-2.61 (m, 2H), 2.60-2.51 (m, 1H), 2.50-2.17 (m, 8H).

[0433] Example 4

[0434]

[0435]

[0436] Step 1: Synthesis of Compound 4-2

[0437] Weigh compound 4-1 (480 g, 2.53 mol), add DMF (2500 mL), add 4-methoxybenzyl chloride (5.18 mol, 702.79 mL), potassium carbonate (872.82 g, 6.32 mol), potassium iodide (419.35 g, 2.53 mol), and react at 65 °C for 2 hours. Quench with water (1000 mL), extract with ethyl acetate (1000 mL×3), and concentrate the organic phase under reduced pressure to obtain compound 4-2, MS m / z = 430.0 [M+H] + .

[0438] Step 2: Synthesis of Compound 4-3

[0439] Weigh 2,2,6,6 - tetramethylpiperidine (220.59 g, 1.56 mol, 265.13 mL), add THF (3000 mL), add n - butyllithium (2.5 M, 499.73 mL) at - 5 °C, stir for 0.5 h, cool down to - 60 °C and add 4 - 2 (280 g, 624.67 mmol), stir for 0.5 h, and finally add DMF (228.28 g, 3.12 mol, 240.30 mL). Continue the reaction for 0.5 h. Pour the reaction solution into water (1000 mL) to quench it, adjust the pH to 7 with hydrochloric acid, extract with ethyl acetate (1000 mL × 3), concentrate under reduced pressure, and separate by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 4 - 3.

[0440] Step 3: Synthesis of compound 4 - 4

[0441] Weigh 4 - 3 (370 g, 807.30 mmol), add toluene (1500 mL), dichloro - bis[di - tert - butyl - (4 - dimethylaminophenyl)phosphine]palladium (2.86 g, 4.04 mmol, 2.86 mL) and tributyl(1 - propynyl)tin (265.69 g, 807.30 mmol), react at 120 °C for 2 h under nitrogen protection. Concentrate under reduced pressure and separate by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 4 - 4. MS m / z = 418.1 [M + H] + 。

[0442] Step 4: Synthesis of compound 4 - 5

[0443] Weigh 4 - 4 (450 g, 970.13 mmol), add DMF (100 mL), add N - bromosuccinimide (189.93 g, 1.07 mol), react at 25 °C for 2 h. Add additional N - bromosuccinimide (17.27 g, 97.01 mmol) and continue the reaction for 3 h. Directly evaporate to dryness and separate by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 4 - 5. MS m / z = 496.0 [M + H] + 。

[0444] Step 5: Synthesis of compound 4 - 6

[0445] Weigh 4-5 (55 g, 110.81 mmol), add DMF (300 mL), add methyl fluorosulfonyldifluoroacetate (42.57 g, 221.61 mmol, 28.19 mL), copper(I) iodide (42.21 g, 221.61 mmol), and react at 110 °C under nitrogen protection for 2 hours. Add 500 mL of water to quench the reaction, extract with ethyl acetate (600 mL × 3), combine the extracted organic phases, wash successively with water (800 mL × 2) and saturated brine (800 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Separate by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 4-6. MS m / z = 485.9 [M+H] + .

[0446] Step 6: Synthesis of compound 4-7

[0447] At 0 °C, add methyl acetoacetate (18.42 g, 158.61 mmol, 17.10 mL) dropwise to a solution of sodium hydride (6.34 g, 158.61 mmol, 60% purity) in tetrahydrofuran (350 mL), and react for 15 minutes. Cool to -20 °C and then add n-butyllithium (2.5 M, 63.44 mL) dropwise. After the addition is complete, continue stirring for 15 min, and then add a solution of 4-6 (35 g, 72.10 mmol) in tetrahydrofuran (350 mL). React for 0.5 hour. Add 200 mL of saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate (300 mL × 2), combine the extracted organic phases, wash with saturated brine (400 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Separate by column chromatography (petroleum ether:ethyl acetate = 10:1 - 1:1) to obtain compound 4-7. MS m / z = 624.2 [M+Na] + .

[0448] Step 7: Synthesis of compound 4-8

[0449] Weigh 4-7 (38 g, 63.17 mmol), add dichloromethane (300 mL), and then add N,N-dimethylformamide dimethyl acetal (9.03 g, 75.80 mmol). React at 25 °C for 16 hours. Cool to 0 °C, add boron trifluoride diethyl etherate (10.76 g, 75.80 mmol, 9.32 mL), continue stirring the system at 0 °C for 1 hour, add 200 mL of saturated sodium bicarbonate solution to the system, separate the organic phase, extract the aqueous phase with 200 mL of dichloromethane, combine the extracted organic phases, wash with 250 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. Separate by column chromatography (petroleum ether:ethyl acetate = 10:1 - 1:1) to obtain compound 4-8. MS m / z = 612.1 [M+H] + .

[0450] Step 8: Synthesis of Compound 4-9

[0451] Weigh 4-8 (30 g, 49.05 mmol), add tetrahydrofuran (300 mL), and add lithium tri-sec-butylborohydride (1 M, 53.96 mL) at -60 °C. React at -60 °C for 1 hour. Add 200 mL of water to the system to quench the reaction, extract with ethyl acetate (300 mL × 2), combine the extracted organic phases, wash with 300 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. Separate by column chromatography (petroleum ether:ethyl acetate = 10:1 - 5:1) to obtain Compound 4-9. MS m / z = 614.1 [M+H] + 。

[0452] Step 9: Synthesis of Compound 4-10

[0453] Weigh 4-9 (20 g, 32.59 mmol), add ethanol (200 mL), then add 2-methyl-2-thioisourea sulfate (27.22 g, 97.78 mmol) and sodium carbonate (6.91 g, 65.19 mmol), and react at 50 °C for 13 hours. Concentrate the reaction solution to dryness, add 40 mL of water, extract with ethyl acetate (50 mL × 2), combine the extracted organic phases, wash with 60 mL of saturated brine, dry over anhydrous sodium sulfate. Filter and concentrate to obtain Compound 4-10. MS m / z = 654.3 [M+H] + 。

[0454] Step 10: Synthesis of Compound 4-11

[0455] Weigh 4-10 (21 g, 32.13 mmol), add DMF (200 mL), then add N,N-diisopropylethylamine (12.46 g, 96.38 mmol, 16.79 mL) and N-phenylbis(trifluoromethanesulfonyl)imide (13.77 g, 38.55 mmol), and react at 25 °C for 1 hour. Add 300 mL of water to the system, extract with ethyl acetate (300 mL × 3), wash successively with water (400 mL × 2) and saturated brine (400 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Separate by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain Compound 4-11.

[0456] Step 11: Synthesis of Compound 4-12

[0457] Weigh compound 4-11 (5 g, 6.36 mmol), 3-1A (2.34 g, 9.55 mmol), add DMF (15 mL), add DIPEA (2.47 g, 19.09 mmol, 3.33 mL), and react at 100 °C for 1 hour. Directly concentrate and separate by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 4-12, MS m / z = 844.3 [M+H] + 。

[0458] Step 12: Synthesis of compound 4-13

[0459] Weigh compound 4-12 (5.3 g, 6.28 mmol), dissolve it in DCM (60 mL), add m-CPBA (1.27 g, 6.28 mmol, 85% purity), and react at 25 °C for 0.5 hour. Dilute the reaction solution with 100 mL of dichloromethane, wash it with 80 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, and concentrate to obtain compound 4-13, MS m / z = 860.5 [M+H] + 。

[0460] Step 13: Synthesis of compound 4-14

[0461] Dissolve compound 1-2A (1.30 g, 8.16 mmol) in anhydrous tetrahydrofuran (60 mL), add sodium tert-butoxide (784.51 mg, 8.16 mmol), react at 25 °C for 30 minutes, add compound 4-13 (5.4 g, 6.28 mmol), and react at 25 °C for 0.5 hour. Dilute the reaction solution with 300 mL of ethyl acetate, wash it with 200 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (dichloromethane: methanol = 20:1) to obtain compound 4-14. MS m / z = 955.8 [M+H] + 。

[0462] Step 14: Synthesis of compounds 4A and 4B

[0463] Compound 4-14 (3.4 g, 3.56 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated, the pH was adjusted to 9-11 with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 4. SFC resolution was performed (chromatographic column: DAICEL CHIRALCEL OD (250 mm×50 mm, 10 μm); mobile phase: [supercritical CO2 - methanol (0.1% ammonia water)]; methanol (0.1% ammonia water)%: 40%-40%) to obtain compound 4A and compound 4B. Chiral SFC analysis (chromatographic column: DAICEL CHIRALCEL OD-3 (150 mm×4.6 mm, 3 μm); mobile phase: [supercritical CO2 - methanol (0.05% diethylamine)]; (methanol (0.05% diethylamine))%: 40%-40%), for compound 4A, Rt = 3.084 minutes, ee value 99%; for compound 4B, Rt = 5.110 minutes, ee value 98%.

[0464] Compound 4A: MS m / z = 715.4 [M+H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.98 - 6.86 (m, 1H), 6.73 - 6.58 (m, 1H), 5.40 - 5.21 (m, 1H), 5.20 - 5.12 (m, 1H), 4.84 (brs, 4H), 4.58 - 4.40 (m, 2H), 4.15 - 4.04 (m, 2H), 4.00 - 3.82 (m, 2H), 3.34 (s, 6H), 3.37 - 3.17 (m, 1H), 3.12 - 3.06 (m, 3H), 3.06 - 2.98 (m, 1H), 2.90 - 2.80 (m, 1H), 2.35 - 2.21 (m, 2H), 2.20 - 2.06 (m, 3H), 2.05 - 2.02 (m, 3H), 2.01 - 1.84 (m, 3H). Compound 4B: MS m / z = 715.4 [M+H] + .

[0465] Example 5

[0466]

[0467]

[0468] Step 1: Synthesis of Intermediate 5-1A

[0469] Compound 5-1 was analyzed by SFC (column: Chiralpak IH-3, 100×4.6 mm I.D., 3 μm; mobile phase: A (supercritical CO2) and B (EtOH containing 0.1% isopropylamine); gradient: B% = 10-50%, run time 3.7 min). The peak elution times were 1.266 min and 1.521 min, and the peak at 1.521 min was compound 5-1A. Then, preparative supercritical fluid chromatography (SFC) purification was carried out (column: ChiralPak IH, 250×50 mm, 10 μm; mobile phase: [supercritical CO2 - ethanol (0.1% ammonia water)]; ethanol (0.1% ammonia water)%: 20% - 20%) to obtain compound 5-1A. SFC analysis was performed (column: Chiralpak IH-3, 100×4.6 mm I.D., 3 μm; mobile phase: A (supercritical CO2) and B (EtOH containing 0.1% isopropylamine); gradient: B% = 10-50%, 4 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 2000 psi). For compound 5-1A, Rt = 1.489 min and the ee value was 98.8%. 1 H NMR (400 MHz, CDCl3) δ = 4.99-4.86 (m, 2H), 4.26-3.95 (m, 3H), 3.59 (m, 1H), 3.01-2.88 (m, 1H), 2.88-2.15 (m, 4H), 1.91 (s, 1H), 1.20-1.09 (m, 3H).

[0470] Step 2: Synthesis of Intermediate 5-2

[0471] Lithium aluminum hydride (1.55 g, 40.15 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and the temperature was lowered to 0 °C. A solution of compound 5-1A (2.8 g, 13.38 mmol) in anhydrous tetrahydrofuran (20 mL) was added under nitrogen protection, and the reaction was carried out at 70 °C for 1 hour. At 0 °C, 1.5 mL of water was added to the reaction solution, then 1.5 mL of 15% sodium hydroxide solution was added, and then 4.5 mL of water was added. The mixture was stirred for 20 minutes, and the reaction solution was filtered. The filter cake was washed with 10 mL of tetrahydrofuran, and the filtrate was concentrated to obtain compound 5-2. 1 H NMR (400 MHz, CDCl3) δ = 4.99-4.86 (m, 2H), 4.28-3.95 (m, 3H), 3.61-3.59 (m, 1H), 3.00-2.88 (m, 1H), 2.74-2.27 (m, 4H), 1.91 (s, 1H), 1.20-1.08 (m, 3H).

[0472] Step 3: Synthesis of Compound 5-3

[0473] Compound 5-2 (88.20 mg, 575.63 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), sodium tert-butoxide (55.32 mg, 575.63 μmol) was added, and the reaction was carried out at 25 °C for 30 minutes. Then compound 4-13 (330 mg, 383.75 μmol) was added, and the reaction was carried out at 25 °C for 0.5 hour. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5-3. MS m / z = 949.1 [M+H] + 。

[0474] Step 4: Synthesis of compounds 5A and 5B

[0475] Compound 5-3 (360 mg, 379.33 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated and separated by high performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 10%-40%, 10 min) to obtain the hydrochloride salt of compound 5. SFC resolution was carried out (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); mobile phase: [supercritical CO2-ethanol (0.1% ammonia water)]; ethanol (0.1% ammonia water)%: 40%-40%) to obtain compound 5A and compound 5B. Chiral SFC analysis (column: DAICEL CHIRALCEL OD-3 (150 mm×4.6 mm, 3 μm); mobile phase: [supercritical CO2-ethanol (0.05% diethylamine)]; ethanol (0.05% diethylamine)%: 40%-40%), for compound 5A, Rt = 0.848 min, ee value 100%; for compound 5B, Rt = 2.371 min, ee value 99%.

[0476] Compound 5A: MS m / z = 709.3 [M+H] + , 11H NMR (400 MHz, CD3Cl) δ ppm 6.93 - 6.85 (m, 1H), 6.84 - 6.77 (m, 1H), 5.36 - 5.22 (m, 2H), 5.20 - 5.11 (m, 1H), 4.89 - 4.41 (m, 10H), 4.18 - 3.99 (m, 3H), 3.97 - 3.77 (m, 2H), 3.61 - 3.48 (m, 1H), 3.42 - 3.26 (m, 4H), 3.17 - 3.04 (m, 4H), 3.01 - 2.88 (m, 2H), 2.73 - 2.61 (m, 1H), 2.56 - 2.42 (m, 1H), 2.35 - 2.23 (m, 2H), 2.21 - 2.12 (m, 2H), 2.10 - 2.04 (m, 3H). Compound 5B: MS m / z = 709.3 [M+H] + 。

[0477] Example 6

[0478]

[0479]

[0480] Step 1: Synthesis of Intermediate 6-2

[0481] Dissolve compound 6-1 (20 g, 56.53 mmol) in hydrochloric acid / ethyl acetate (4 M, 120 mL). React at 25 °C for 2 hours. The reaction solution is directly concentrated to obtain the crude product 6-2. The crude product is directly used for the next step.

[0482] Step 2: Synthesis of Intermediate 6-3

[0483] Dissolve the crude product 6-2 (20 g) in DMF (65 mL), add potassium carbonate (14.2 g, 102 mmol). React at 25 °C for 12 hours. Dilute the reaction solution with 500 mL of ethyl acetate, wash with water (300 mL x 2), wash with 300 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product. The crude product is purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 6-3.

[0484] Step 3: Synthesis of Intermediate 6-4

[0485] Dissolve compound 6-3 (7 g, 32.23 mmol) in 2-methyltetrahydrofuran (75 mL). After displacing the air with nitrogen three times, slowly add Red-Al (37.2 g, 129 mmol, 35.8 mL, 70% purity) at 10 °C under nitrogen protection. React at 25 °C for 12 hours. Dropwise add the reaction solution into an aqueous solution of sodium tartrate (26.0%) to quench the reaction. Extract with 2-methyltetrahydrofuran (200 mL), and extract the aqueous phase with 2-methyltetrahydrofuran (50 mL × 3). Wash the combined organic phases with 50 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain compound 6-4.

[0486] Step 4: Synthesis of intermediate 6-5

[0487] Dissolve compound 6-4 (2.2 g, 13 mmol) in DCM (30 mL), add imidazole (3.5 g, 53 mmol), 4-dimethylaminopyridine (160 mg, 1.3 mmol) and tert-butyldiphenylchlorosilane (7.2 g, 25 mmol). React at 45 °C for 12 hours. Add water (50 mL) to the reaction solution, separate the organic phase, and extract the aqueous phase with dichloromethane (40 mL). Combine the organic phases, wash with 40 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. Add methyl tert-butyl ether (10 mL), n-heptane (21 mL) and hydrochloric acid solution (2 M, 21 mL) thereto, separate the aqueous phase, wash with a mixed solvent of methyl tert-butyl ether:n-heptane = 1:2 (20 mL × 3), then adjust the pH to 7 with an aqueous sodium carbonate solution, extract with 200 mL of ethyl acetate, combine the organic phases, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product. The crude product is separated by column chromatography (petroleum ether:ethyl acetate = 10:1), and the first spot (R f = 0.6, and the other isomer R f = 0.5) is separated to obtain the crude intermediate 6-5.

[0488] Step 5: Synthesis of intermediate 6-6

[0489] Compound 6-5 (2 g, 4.6 mmol) was analyzed by SFC (column: Chiralpak IC-3 50×4.6 mm I.D., 3 μm; mobile phase: A (supercritical CO2) and B (methanol containing 0.05% diethylamine); gradient: B% = 5-10%, flow rate: 3 mL / min). The elution times were 2.117 min and 2.980 min, and the sample at 2.117 min was intermediate 6-6. Then it was separated and purified by chiral SFC (column: DAICEL CHIRALPAK IC (250 mm×30 mm, 10 μm); mobile phase: [supercritical CO2 - methanol (0.1% ammonia water)]; methanol (0.1% ammonia water)%: 25% - 25%, 4.5 min) to obtain compound 6-6. The SFC analysis method (column: Chiralpak IC-3 50×4.6 mm I.D., 3 μm; mobile phase: A (supercritical CO2) and B (methanol containing 0.05% diethylamine); gradient: B% = 5-10%, flow rate: 3 mL / min), Rt = 2.014 min, ee value 98%. MS m / z = 410.3 [M+H] + 。

[0490] Step 6: Synthesis of intermediate 6-7

[0491] Compound 6-6 (1.2 g, 2.93 mmol) was dissolved in 24 mL of 1,4-dioxane, and concentrated hydrochloric acid (12 M, 7.20 mL) was added. The reaction was carried out at 95 °C for 12 hours. After the reaction solution was cooled, it was diluted with 10 mL of water, washed with 10 mL of ethyl acetate, and the aqueous phase was freeze-dried to obtain the hydrochloride of compound 6-7. It was then dissolved in methanol (20 mL), 2 g of potassium carbonate was added, filtered, concentrated, redissolved in tetrahydrofuran (20 mL), filtered, and concentrated to obtain compound 6-7.

[0492] Step 7: Synthesis of compound 6-8

[0493] Compound 6-7 (92.58 mg, 540.74 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), sodium tert-butoxide (51.97 mg, 540.74 μmol) was added, and the reaction was carried out at 25 °C for 30 minutes. Then compound 4-13 (310 mg, 360.49 μmol) was added, and the reaction was carried out at 25 °C for 0.5 hour. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6-8. MS m / z = 967.3 [M+H] + 。

[0494] Step 8: Synthesis of compounds 6A and 6B

[0495] Compound 6-8 (345 mg, 356.76 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated and separated by high performance liquid chromatography (chromatographic column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 10%-40%, 10 min) to obtain the hydrochloride of compound 6. Then, SFC resolution was carried out (chromatographic column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); mobile phase: [supercritical CO2-methanol (0.1% ammonia water)]; methanol (0.1% ammonia water)%: 40%-40%) to obtain compound 6A and compound 6B. Chiral SFC analysis (chromatographic column: DAICEL CHIRALCEL OD-3 (150 mm×4.6 mm, 3 μm); mobile phase: [supercritical CO2-methanol (0.05% diethylamine)]; (methanol (0.05% diethylamine))%: 40%-40%), for compound 6A, Rt = 3.658 min, ee value 99.9%; for compound 6B, Rt = 7.041 min, ee value 99.9%.

[0496] Compound 6A: MS m / z = 727.3 [M+H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 - 6.64 (m, 2H), 6.60 - 6.55 (m, 1H), 5.13 - 5.01 (m, 1H), 4.84 (brs, 2H), 4.69 - 4.57 (m, 2H), 4.47 - 4.38 (m, 2H), 4.37 - 4.26 (m, 3H), 4.06 - 3.96 (m, 1H), 3.90 - 3.75 (m, 2H), 3.72 - 3.62 (m, 1H), 3.26 - 3.23 (m, 3H), 3.19 - 3.10 (m, 2H), 3.04 - 2.93 (m, 3H), 2.88 - 2.62 (m, 3H), 2.36 - 2.23 (m, 1H), 2.02 (s, 5H), 1.93 - 1.87 (m, 3H). Compound 6B: MS m / z = 727.3 [M+H] + 。

[0497] Example 7

[0498]

[0499]

[0500] Step 1: Synthesis of Intermediate 4-11B

[0501] Compounds 4-11 were prepared by SFC resolution (column: DAICEL CHIRALPAK IG (250 mm × 50 mm, 10 μm); mobile phase: [supercritical CO2 - ethanol (0.1% ammonia water)]; ethanol (0.1% ammonia water) %: 25% - 25%) to obtain compound 4-11B and its isomer. Chiral SFC analysis (column: ChiralPak IG-3 (100 mm × 4.6 mm, 3 μm); mobile phase: [supercritical CO2 - ethanol (0.05% diethylamine)]; (ethanol (0.05% diethylamine)) %: 5% - 40%), compound 4-11B, Rt = 3.055 min, ee value 99%; its isomer, Rt = 2.574 min, ee value 99%;

[0502] Step 2: Synthesis of intermediate 7-2

[0503] Weigh compound 4-11B (0.4 g, 509.07 μmol) and dissolve it in DMF (15 mL). Weigh 7-1 (125.62 mg, 610.88 μmol) and add it, then add DIPEA (197.38 mg, 1.53 mmol) to the reaction system. After adding, react at 100 °C for 1 hour. Add water (15 mL) to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (30 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 7-2, MS m / z = 805.6 [M+H] + 。

[0504] Step 3: Synthesis of intermediate 7-3

[0505] Weigh compound 7-2 (381.80 mg, 474.37 μmol), dissolve it in DCM (10 mL), add m-CPBA (96.31 mg, 474.37 μmol, 85% purity), and react at 25 °C for 1 hour. Add water (15 mL) to the reaction solution, dilute with 100 mL of dichloromethane, wash with 80 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 7-3, MS m / z = 821.6 [M+H] + 。

[0506] Step 4: Synthesis of intermediate 7-4

[0507] Dissolve compound 5-2 (286.64 mg, 1.87 mmol) in anhydrous tetrahydrofuran (20 mL), add sodium tert-butoxide (179.79 mg, 1.87 mmol), and react the reaction system at 0 °C for 1 hour. Then add compound 7-3 (383.90 mg, 467.69 μmol) and react at 0 °C for 1 hour. Add water (15 mL) to the reaction solution, dilute it with 100 mL of ethyl acetate, wash it with 100 mL of saturated brine, dry it over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 7-4. MS m / z = 910.5 [M+H] + 。

[0508] Step 5: Synthesis of compounds 7A and 7B

[0509] Dissolve compound 7-4 (0.2833 g, 311.33 μmol) in dichloromethane (15 mL), add trifluoroacetic acid (4.33 g, 38.01 mmol, 2.82 mL), and react at 20 °C for 1 hour. Concentrate the reaction solution, adjust the pH to 10 with saturated sodium carbonate solution, extract with dichloromethane (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and obtain the crude product. The crude product is separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile %: 41%-71% over 8 min) to obtain compound 7A and compound 7B. Chiral SFC analysis (chromatographic column: DAICEL CHIRALCEL AS-3 (100 mm×4.6 mm, 3 μm); mobile phase: [supercritical CO2-methanol (0.05% diethylamine)]; (methanol (0.05% diethylamine)) %: 40%-40%), for compound 7A, Rt = 1.445 minutes, ee value 97.4%, MS m / z = 670.3 [M+H] + For compound 7B, Rt = 0.863 minutes, ee value 94.9%, MS m / z = 670.3 [M+H] + 。

[0510] Example 8

[0511]

[0512]

[0513] Step 1: Synthesis of intermediate 8-2

[0514] Weigh compound 8-1 (0.2 g, 710.86 μmol), dissolve it in DMF (5 mL), add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (351.38 mg, 924.12 μmol), DIPEA (367.50 mg, 2.84 mmol, 495.28 μL) and dimethylamine hydrochloride (173.90 mg, 2.13 mmol) to the reaction system, and react at room temperature of 18 °C for 2 hours. Add water (20 mL) to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain compound 8-2, MS m / z = 295.2 [M+H] + 。

[0515] Step 2: Synthesis of hydrochloride salt of intermediate 8-3

[0516] Weigh compound 8-2 (209 mg, 674.54 μmol), add 4M hydrochloric acid / ethyl acetate solution (5 mL), and react the reaction system at room temperature of 18 °C for 2 hours. Concentrate the reaction solution under reduced pressure to obtain the hydrochloride salt of compound 8-3, MS m / z = 195.1 [M+H] + 。

[0517] Step 3: Synthesis of intermediate 8-4

[0518] Weigh compound 4-11B (0.2 g, 254.53 μmol), dissolve it in DMF (8 mL), add the hydrochloride salt of 8-3 (59.33 mg), measure DIPEA (98.69 mg, 763.60 μmol) and add it to the reaction system. After adding, react at 100 °C for 1 hour. Quench the reaction solution with water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure by rotary evaporation, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 8-4, MS m / z = 830.6 [M+H] + 。

[0519] Step 4: Synthesis of intermediate 8-5

[0520] Weigh compound 8-4 (0.099 g, 119.29 μmol), dissolve it in DCM (10 mL), add m-CPBA (24.22 mg, 119.29 μmol, 85% purity), and react at 25 °C for 1 hour. Quench the reaction solution with water (15 mL), dilute it with 100 mL of dichloromethane, wash it with 80 mL of saturated brine, dry it over anhydrous sodium sulfate, filter it, and concentrate it under reduced pressure to obtain the crude product. Purify it by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 8-5, MS m / z = 846.6 [M+H] + .

[0521] Step 5: Synthesis of intermediate 8-6

[0522] Dissolve compound 5-2 (46.73 mg, 305.00 μmol) in anhydrous tetrahydrofuran (10 mL), add sodium tert-butoxide (29.31 mg, 305.00 μmol), react the reaction system at 0 °C for 1 hour, add compound 8-5 (129 mg, 152.50 μmol), and react at 0 °C for 1 hour. Add water (20 mL) to the reaction solution, dilute it with 100 mL of ethyl acetate, wash it with 100 mL of saturated brine, dry it over anhydrous sodium sulfate, filter it, concentrate it under reduced pressure, and separate it by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 8-6. MS m / z = 935.5 [M+H] + .

[0523] Step 6: Synthesis of the hydrochloride salt of compound 8

[0524] Compound 8-6 (0.142 g, 151.87 μmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (2.11 g, 18.54 mmol, 1.38 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 10%-40%, 10 min) to obtain the hydrochloride of compound 8. MS m / z = 695.2 [M+H]+. 1H NMR (400 MHz, MeOD) δ = 6.96 (d, J = 8.5 Hz, 1H), 6.69 - 6.47 (m, 1H), 5.39 - 5.32 (m, 2H), 5.30 - 5.21 (m, 1H), 5.13 - 5.04 (m, 2H), 4.95 (br d, J = 5.0 Hz, 2H), 4.69 - 4.56 (m, 2H), 4.55 - 4.42 (m, 2H), 4.41 - 4.31 (m, 2H), 4.06 - 3.98 (m, 1H), 3.98 - 3.91 (m, 1H), 3.87 - 3.77 (m, 1H), 3.47 - 3.36 (m, 3H), 3.30 - 3.22 (m, 2H), 3.20 - 2.98 (m, 5H), 2.91 - 2.81 (m, 1H), 2.51 - 2.40 (m, 1H), 2.33 - 2.12 (m, 3H), 2.04 (s, 3H).

[0525] Example 9

[0526]

[0527] Step 1: Synthesis of Intermediate 9-2

[0528] Compound 4-11B (0.2 g, 254.53 μmol) was weighed and dissolved in DMF (15 mL), 9-1 (61.59 mg, 305.44 μmol) was added, and then DIPEA (98.69 mg, 763.60 μmol, 133.00 μL) was added. After addition, the reaction was carried out at 100 °C for 1 hour. Water (20 mL) was added to quench the reaction solution, diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 9-2, MS m / z = 801.6 [M+H] + .

[0529] Step 2: Synthesis of Intermediate 9-3

[0530] Weigh compound 9-2 (158.80 mg, 198.29 μmol), dissolve it in DCM (10 mL), add m-CPBA (40.26 mg, 198.29 μmol, 85% purity). After addition, react at room temperature (25 °C) for 1 hour. Quench the reaction solution with water (15 mL), dilute it with 100 mL of dichloromethane, wash it with 80 mL of saturated brine, dry it over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 9-3. MS m / z = 817.4 [M+H] + 。

[0531] Step 3: Synthesis of intermediate 9-4

[0532] Dissolve compound 5-2 (60.44 mg, 394.44 μmol) in anhydrous tetrahydrofuran (10 mL), add sodium tert-butoxide (37.91 mg, 394.44 μmol). React the reaction system at 0 °C for 1 hour, add compound 9-3 (0.1611 g, 197.22 μmol), and react at 0 °C for 1 hour. Quench the reaction solution with water (20 mL), extract it with ethyl acetate (20 mL × 3), wash it with 50 mL of saturated brine, dry it over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 9-4. MS m / z = 906.7 [M+H] + 。

[0533] Step 4: Synthesis of the hydrochloride salt of compound 9

[0534] Dissolve compound 9-4 (127.44 mg, 140.66 μmol) in dichloromethane (15 mL), add trifluoroacetic acid (1.96 g, 17.17 mmol, 1.28 mL), and react at 20 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. Separate the crude product by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 20%-50%, 10 min) to obtain the hydrochloride salt of compound 9. MS m / z = 666.3 [M+H] + 。

[0535] Example 10

[0536]

[0537]

[0538] Step 1: Synthesis of intermediate 10-2

[0539] Weigh compound 4-11B (0.205 g, 260.90 μmol), dissolve it in DMF (15 mL), add 10-1 (55.29 mg, 313.08 μmol), then add DIPEA (101.16 mg, 782.69 μmol, 136.33 μL). After adding, react at 100 °C for 1 hour. Quench the reaction solution with water (20 mL), dilute it with 100 mL of ethyl acetate, wash it with 100 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 10-2, MS m / z = 776.3 [M+H] + 。

[0540] Step 2: Synthesis of intermediate 10-3

[0541] Weigh compound 10-2 (0.202 g, 260.37 μmol), dissolve it in DCM (10 mL), add m-CPBA (52.86 mg, 260.37 μmol, 85% purity). After adding, react at room temperature (25 °C) for 1 hour. Quench the reaction solution with water (15 mL), dilute it with 100 mL of dichloromethane, wash it with 80 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, concentrate, to obtain compound 10-3, MS m / z = 792.5 [M+H] + 。

[0542] Step 3: Synthesis of intermediate 10-4

[0543] Dissolve compound 5-2 (79.34 mg, 517.80 μmol) in anhydrous tetrahydrofuran (10 mL), add sodium tert-butoxide (49.76 mg, 517.80 μmol), react the reaction system at 0 °C for 1 hour, add compound 10-3 (0.1611 g, 197.22 μmol), and react at 0 °C for 1 hour. Quench the reaction solution with water (20 mL), extract it with ethyl acetate (30 mL × 3), wash it with 100 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 10-4. MS m / z = 881.7 [M+H] + 。

[0544] Step 4: Synthesis of the hydrochloride salt of compound 10

[0545] Compound 10-4 (0.1338 g, 151.89 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 20%-50%, 10 min) to obtain the hydrochloride salt of compound 10. MS m / z = 641.1 [M+H] + 。

[0546] Example 11

[0547]

[0548] Step 1: Synthesis of Intermediate 11-2

[0549] Compound 4-11B (0.48 g, 610.88 μmol) was weighed and dissolved in DMF (15 mL), 11-1 (96.16 mg, 733.06 μmol) was added, and then DIPEA (236.85 mg, 1.83 mmol, 319.21 μL) was added. The reaction was carried out at 100 °C for 1 hour. The reaction solution was quenched with water (20 mL), diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 11-2, MS m / z = 767.4 [M+H] + 。

[0550] Step 2: Synthesis of Intermediate 11-3

[0551] Compound 11-2 (452.40 mg, 589.95 μmol) was weighed and dissolved in DCM (10 mL), m-CPBA (119.77 mg, 589.95 μmol, 85% purity) was added, and the reaction was carried out at room temperature (25 °C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11-3, MS m / z = 783.5 [M+H] + 。

[0552] Step 3: Synthesis of Intermediate 11-4

[0553] Compound 5-2 (180.46 mg, 1.18 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium tert-butoxide (113.19 mg, 1.18 mmol) was added. The reaction system was reacted at 0 °C for 1 hour, compound 11-3 (0.461 g, 588.88 μmol) was added, and the reaction was continued at 0 °C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 11-4. MS m / z = 872.5 [M+H] + 。

[0554] Step 4: Synthesis of hydrochloride salts of compound 11A and 11B

[0555] Compound 11-4 (0.2 g, 229.37 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3.19 g, 28.00 mmol, 2.08 mL) was added. The reaction was carried out at 20 °C for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 20%-50%, 10 min) to obtain hydrochloride salts of compound 11A and 11B. Analytical method: (column: ChromCore 120C18 3 μm, 3.0×30 mm; mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)]; acetonitrile (0.02% trifluoroacetic acid)%: 10%-80%, 7 min), retention time: 11A (Rt = 2.902 min), MS m / z = 632.2 [M+H] + ; 11B (Rt = 3.020 min), MS m / z = 632.2 [M+H] + 。

[0556] Example 12

[0557]

[0558]

[0559] Step 1: Synthesis of intermediate 12-2

[0560] Weigh compound 4-11B (0.2 g, 254.53 μmol), dissolve it in DMF (15 mL), add 12-1 (54.27 mg, 305.44 μmol), then add DIPEA (98.69 mg, 763.60 μmol, 133.00 μL), and react at 100 °C for 1 hour. Quench the reaction solution with water (20 mL), dilute it with 100 mL of ethyl acetate, wash it with 100 mL of saturated brine, dry it with anhydrous sodium sulfate, filter it, and concentrate it under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 12-2, MS m / z = 777.4 [M+H] + 。

[0561] Step 2: Synthesis of intermediate 12-3

[0562] Weigh compound 12-2 (0.1976 g, 254.35 μmol), dissolve it in DCM (10 mL), add m-CPBA (51.67 mg, 254.35 μmol, 85% purity), and react at room temperature (25 °C) for 1 hour. Quench the reaction solution with water (15 mL), dilute it with 100 mL of dichloromethane, wash it with 80 mL of saturated brine, dry it with anhydrous sodium sulfate, filter it, and concentrate it under reduced pressure to obtain compound 12-3, MS m / z = 793.6 [M+H] + 。

[0563] Step 3: Synthesis of intermediate 12-4

[0564] Dissolve compound 5-2 (77.68 mg, 507.01 μmol) in anhydrous tetrahydrofuran (20 mL), add sodium tert-butoxide (48.73 mg, 507.01 μmol), react the reaction system at 0 °C for 1 hour, add compound 12-3 (0.201 g, 253.51 μmol), and react at 0 °C for 1 hour. Quench the reaction solution with water (20 mL), extract it with ethyl acetate (30 mL × 3), wash it with 100 mL of saturated brine, dry it with anhydrous sodium sulfate, filter it, and concentrate it under reduced pressure. Separate it by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 12-4. MS m / z = 882.5 [M+H] + 。

[0565] Step 4: Synthesis of the hydrochloride salt of compound 12

[0566] Compound 12-4 (0.221 g, 250.57 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3.49 g, 30.59 mmol, 2.27 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 20%-50%, 10 min) to obtain the hydrochloride of compound 12. MS m / z = 642.4 [M+H] + .

[0567] Example 13

[0568]

[0569] Step 1: Synthesis of intermediate 13-2

[0570] Compound 4-11B (0.35 g, 445.44 μmol) was weighed and dissolved in DMF (15 mL), 13-1 (121.72 mg, 534.52 μmol) was added, and then DIPEA (172.70 mg, 1.34 mmol, 232.76 μL) was added. The reaction was carried out at 100 °C for 1 hour. The reaction solution was quenched with water (20 mL), diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 13-2, MS m / z = 827.4 [M+H] + .

[0571] Step 2: Synthesis of intermediate 13-3

[0572] Compound 13-2 (0.4165 g, 503.68 μmol) was weighed and dissolved in DCM (10 mL), m-CPBA (102.26 mg, 503.68 μmol, 85% purity) was added. After addition, the reaction was carried out at room temperature (25 °C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 13-3, MS m / z = 843.5 [M+H] + .

[0573] Step 3: Synthesis of intermediate 13-4

[0574] Compound 5-2 (154.33 mg, 1.01 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), sodium tert-butoxide (96.80 mg, 1.01 mmol) was added, and the reaction system was reacted at 0 °C for 1 hour. Compound 13-3 (0.4245 g, 503.61 μmol) was added, and the reaction was carried out at 0 °C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (methylene chloride:methanol = 20:1) to obtain compound 13-4. MS m / z = 932.4 [M+H] + 。

[0575] Step 4: Synthesis of hydrochlorides of compounds 13A and 13B

[0576] Compound 13-4 (0.293 g, 314.26 μmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (4.37 g, 38.36 mmol, 2.85 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (chromatographic column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 20%-50%, 10 min) to obtain hydrochlorides of compounds 13A and 13B. Analytical method: (chromatographic column: ChromCore120 C18 3 μm, 3.0×30 mm; mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)]; acetonitrile (0.02% trifluoroacetic acid)%: 10%-80%, 7 min), retention time: 13A (Rt = 2.891 min), MS m / z = 692.2 [M+H] + ; 13B (Rt = 3.126 min), MS m / z = 692.2 [M+H] + 。

[0577] Example 14

[0578]

[0579]

[0580] Step 1: Synthesis of intermediate 14-2

[0581] Weigh compound 4-11B (200.00 mg, 254.53 μmol), dissolve it in DMF (10 mL), add the hydrochloride salt of 14-1 (106.21 mg), then add DIPEA (98.69 mg, 763.60 μmol, 133.01 μL), and react at 100 °C for 1 hour. The reaction solution is concentrated under reduced pressure to obtain the crude product, and the crude product is purified by column chromatography (methylene chloride:methanol = 10:1) to obtain compound 14-2, MS m / z = 878.6 [M+H] + 。

[0582] Step 2: Synthesis of intermediate 14-3

[0583] Weigh compound 14-2 (200.23 mg, 227.95 μmol), dissolve it in DCM (10 mL), add m-CPBA (39.34 mg, 227.95 μmol, 85% purity), and react at room temperature (25 °C) for 1 hour. The reaction solution is concentrated under reduced pressure to obtain compound 14-3, MS m / z = 894.3 [M+H] + 。Step 3: Synthesis of intermediate 14-4

[0584] Dissolve compound 5-2 (61.67 mg, 402.52 μmol) in anhydrous tetrahydrofuran (5 mL), add sodium tert-butoxide (38.68 mg, 402.52 μmol), react the reaction system at 0 °C for 1 hour, add compound 14-3 (180 mg, 201.26 μmol), and react at 0 °C for 1 hour. Quench the reaction solution with water (10 mL), adjust the pH = 6 with 1N dilute hydrochloric acid, extract with ethyl acetate (100 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography (methylene chloride:methanol = 10:1) to obtain compound 14-4. MS m / z = 983.8 [M+H] + 。

[0585] Step 4: Synthesis of compound 14 and the hydrochloride salt of compound 14

[0586] Dissolve compound 14-4 (118 mg, 119.98 μmol) in trifluoroacetic acid (5 mL), and react at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product is separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile %: 52%-82% over 8 min) to obtain compound 14. MS m / z = 743.2 [M+H] + 。

[0587] The above crude product was prepared by high performance liquid chromatography separation under hydrochloric acid conditions (chromatographic column: Xtimate C18 150×40mm×5μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 17%-47%, 10min), and the hydrochloride of compound 14 was obtained. Chiral SFC analysis was carried out (chromatographic column: DAICEL CHIRALCEL OD-3 (50mm×4.6mm, 3μm); mobile phase: [supercritical CO2-ethanol (0.05% diethylamine)]; ethanol (0.05% diethylamine)%: 40%-40%) and showed Rt = 0.745min. MS m / z = 743.2 [M+H] + 。 1 H NMR (400MHz, CD3OD) δ = 7.00-6.93 (m, 1H), 5.34 (br d, J = 5.9Hz, 2H), 5.27-5.15 (m, 2H), 5.09 (br d, J = 14.0Hz, 1H), 5.00-4.93 (m, 2H), 4.83 (br d, J = 11.8Hz, 1H), 4.65 (br d, J = 11.9Hz, 1H), 4.59-4.51 (m, 1H), 4.37-4.27 (m, 2H), 4.17 (br d, J = 13.4Hz, 1H), 3.96-3.89 (m, 2H), 3.85-3.76 (m, 1H), 3.35-3.31 (m, 1H), 3.29-3.19 (m, 1H), 3.16 (s, 3H), 3.13-3.09 (m, 3H), 3.08-2.97 (m, 2H), 2.83 (br d, J = 16.3Hz, 1H), 2.62-2.48 (m, 1H), 2.47-2.33 (m, 2H), 2.31-2.13 (m, 3H), 2.04 (s, 3H).

[0588] Example 15

[0589]

[0590] Step 1: Synthesis of intermediate 15-2

[0591] Weigh compound 4-11B (200.00mg, 254.53μmol), dissolve it in DMF (10mL), add the hydrochloride of 15-1 (92.29mg, 381.80μmol), and then add DIPEA (98.69mg, 763.60μmol), and react at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 15-2, MS m / z = 841.6 [M+H] + 。

[0592] Step 2: Synthesis of Intermediate 15-3

[0593] Weigh compound 15-2 (150.00 mg, 178.37 μmol), dissolve it in DCM (10 mL), add m-CPBA (30.78 mg, 178.37 μmol, 85% purity), and react at room temperature (25 °C) for 1 hour. Concentrate the reaction solution under reduced pressure to obtain compound 15-3, MS m / z = 857.6 [M+H] + . Step 3: Synthesis of Intermediate 15-4

[0594] Dissolve compound 5-2 (46.49 mg, 303.41 μmol) in anhydrous tetrahydrofuran (5 mL), add sodium tert-butoxide (29.16 mg, 303.41 μmol), react the reaction system at 0 °C for 1 hour, add compound 15-3 (130 mg, 151.71 μmol), and react at 0 °C for 1 hour. Quench the reaction solution with water (10 mL), adjust the pH = 6 using 1N dilute hydrochloric acid, extract with ethyl acetate (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 15-4. MS m / z = 946.8 [M+H] + .

[0595] Step 4: Synthesis of the hydrochloride salt of Compound 15

[0596] Dissolve compound 15-4 (100 mg, 105.70 μmol) in trifluoroacetic acid (5 mL), and react at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. Separate the crude product by preparative high-performance liquid chromatography (chromatographic column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 20%-50%, 10 min) to obtain the hydrochloride salt of compound 15. MS m / z = 706.3 [M+H] + .

[0597] Example 16

[0598]

[0599]

[0600] Step 1: Synthesis of Intermediate 16-2

[0601] Weigh compound 16-1 (500 mg, 1.78 mmol) and dissolve it in DMF (5 mL). Add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (810.99 mg, 2.13 mmol) and triethylamine (539.57 mg, 5.33 mmol, 742.18 μL). After stirring at 25 °C for 1 hour, add 2-(2-fluorophenyl)acetylhydrazine hydrochloride (235.78 mg, 2.13 mmol), and then react at 25 °C for 16 hours. Extract with ethyl acetate (20 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 16-2. MS m / z = 338.2 [M+H] + 。

[0602] Step 2: Synthesis of intermediate 16-3

[0603] Weigh triphenylphosphine (777.45 mg, 2.96 mmol) and elemental iodine (752.31 mg, 2.96 mmol) and dissolve them in dichloromethane (10 mL) at 0 °C. After complete dissolution, add DIPEA (766.17 mg, 5.93 mmol), and then add a tetrahydrofuran solution (10 mL) of compound 16-2 (500 mg, 1.48 mmol). Stir and react at 20 °C for 6 hours. Extract with ethyl acetate (20 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 16-3. MS m / z = 320.2 [M+H] + Step 3: Synthesis of hydrochloride salt of intermediate 16-4

[0604] Weigh compound 16-3 (1 g, 1.41 mmol) and dissolve it in 4M hydrochloric acid / ethyl acetate solution (10 mL). Stir at 25 °C for 1 hour. Concentrate under reduced pressure to obtain the hydrochloride salt of compound 16-4.

[0605] Step 4: Synthesis of intermediate 16-5

[0606] Weigh compound 4-11B (200.00 mg, 254.53 μmol), dissolve it in DMF (10 mL), add the hydrochloride salt of 16-4 (97.63 mg), and then add DIPEA (148.03 mg, 1.15 mmol, 199.50 μL). React at 100 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 16-5, MS m / z = 855.5 [M+H] + 。

[0607] Step 5: Synthesis of Intermediate 16-6

[0608] Weigh compound 16-5 (120 mg, 140.37 μmol), dissolve it in DCM (10 mL), add m-CPBA (24.22 mg, 140.37 μmol, 85% purity), and react at room temperature (25 °C) for 1 hour. Concentrate the reaction solution under reduced pressure to obtain compound 16-6, MS m / z = 871.4 [M+H] + 。

[0609] Step 6: Synthesis of Intermediate 16-7

[0610] Dissolve compound 5-2 (35.19 mg, 229.64 μmol) in anhydrous tetrahydrofuran (5 mL), add sodium tert-butoxide (22.07 mg, 229.64 μmol), react the reaction system at 0 °C for 1 hour, add compound 16-6 (100 mg, 114.82 μmol), and react at 0 °C for 1 hour. Quench the reaction solution with water (10 mL), adjust the pH to 6 with 1N dilute hydrochloric acid, extract with ethyl acetate (100 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 16-7. MS m / z = 960.8 [M+H] + 。

[0611] Step 7: Synthesis of Compound 16

[0612] Dissolve compound 16-7 (70 mg, 72.91 μmol) in trifluoroacetic acid (5 mL), and react at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. Separate the crude product by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile %: 52%-82% over 8 min) to obtain compound 16. MS m / z = 720.2 [M+H] + 。

[0613] Example 17

[0614]

[0615] Step 1: Synthesis of Intermediate 17-1

[0616] Weigh compound 16-1 (500 mg, 1.78 mmol) and dissolve it in dichloromethane (10 mL). Add oxalyl chloride (451.22 mg, 3.55 mmol, 311.18 μL) and DMF (12.99 mg, 177.74 μmol, 13.67 μL), and then react at 25 °C for 2 hours. Concentrate the reaction solution under reduced pressure to obtain compound 17-1. MS m / z = 300.1 [M+H] + 。

[0617] Step 2: Synthesis of intermediate 17-2

[0618] Weigh compound 17-1 (400 mg, 1.33 mmol) and dissolve it in acetonitrile (10 mL). Add DIPEA (517.39 mg, 4.00 mmol, 697.29 μL) and N-hydroxyacetamidine (118.63 mg, 1.60 mmol), and then react at 150 °C under microwave for 0.5 hour. Concentrate the reaction solution under reduced pressure and separate by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 17-2. MS m / z = 320.2 [M+H] + 。

[0619] Step 3: Synthesis of hydrochloride salt of intermediate 17-3

[0620] Weigh compound 17-2 (260 mg, 814.13 μmol) and dissolve it in 4M hydrochloric acid / ethyl acetate solution (10 mL). Stir at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the hydrochloride salt of compound 17-3.

[0621] Step 4: Synthesis of intermediate 17-4

[0622] Weigh compound 4-11B (300 mg, 381.80 μmol), dissolve it in DMF (10 mL), add the hydrochloride salt of 17-3 (146.44 mg), and then add DIPEA (148.03 mg, 1.15 mmol, 199.50 μL). React at 100 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product, and purify the crude product by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 17-4, MS m / z = 855.4 [M+H] + 。

[0623] Step 5: Synthesis of intermediate 17-5

[0624] Weigh compound 17-4 (150 mg, 175.46 μmol), dissolve it in DCM (10 mL), add m-CPBA (30.28 mg, 175.46 μmol, 85% purity), and react at room temperature (25 °C) for 1 hour. Concentrate the reaction solution under reduced pressure to obtain compound 17-5, MS m / z = 871.3 [M+H] + 。

[0625] Step 6: Synthesis of intermediate 17-6

[0626] Dissolve compound 5-2 (52.78 mg, 344.47 μmol) in anhydrous tetrahydrofuran (5 mL), add sodium tert-butoxide (33.10 mg, 344.47 μmol), react the reaction system at 0 °C for 1 hour, add compound 17-5 (150.00 mg, 172.23 μmol), and react at 0 °C for 1 hour. Quench the reaction solution with water (10 mL), adjust the pH = 6 using 1N dilute hydrochloric acid, extract with ethyl acetate (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 17-6. MS m / z = 960.5 [M+H] + 。

[0627] Step 7: Synthesis of compound 17

[0628] Dissolve compound 17-6 (130 mg, 135.41 μmol) in trifluoroacetic acid (5 mL), and react at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. Separate the crude product by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile %: 52%-82% over 8 min) to obtain compound 17. MS m / z = 720.3 [M+H] + 。

[0629] Example 18

[0630]

[0631]

[0632] Step 1: Synthesis of intermediate 18-1

[0633] Weigh compound 4-11B (0.15 g, 190.90 μmol), dissolve it in DMF (15 mL), add 2-1A (34.74 mg, 229.08 μmol), then add DIPEA (74.02 mg, 572.70 μmol, 99.75 μL), and react at 100 °C for 1 hour. Quench the reaction solution with water (20 mL), dilute it with 100 mL of ethyl acetate, wash it with 100 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 18-1, MS m / z = 751.5 [M+H] + 。

[0634] Step 2: Synthesis of intermediate 18-2

[0635] Weigh compound 18-1 (106.5 mg, 141.84 μmol), dissolve it in DCM (10 mL), add m-CPBA (28.80 mg, 141.84 μmol, 85% purity), and react at room temperature (25 °C) for 1 hour after addition. Quench the reaction solution with water (15 mL), dilute it with 100 mL of dichloromethane, wash it with 80 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 18-2, MS m / z = 767.5 [M+H] + 。

[0636] Step 3: Synthesis of intermediate 18-3

[0637] Dissolve compound 5-2 (86.32 mg, 563.35 μmol) in anhydrous tetrahydrofuran (20 mL), add sodium tert-butoxide (54.14 mg, 563.35 μmol), react the reaction system at 0 °C for 1 hour, add compound 18-2 (0.108 g, 140.84 μmol), and react at 0 °C for 1 hour. Quench the reaction solution with water (20 mL), extract it with ethyl acetate (30 mL × 3), wash it with 100 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 18-3. MS m / z = 856.7 [M+H] + 。

[0638] Step 4: Synthesis of the hydrochloride salt of compound 18

[0639] Compound 18-3 (120.4 mg, 140.66 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1.96 g, 17.17 mmol, 1.28 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 10%-40%, 10 min) to obtain the hydrochloride salt of compound 18. MS m / z = 616.3 [M+H] + 。

[0640] Example 19

[0641]

[0642] Step 1: Synthesis of Intermediate 19-2

[0643] Compound 4-11B (150 mg, 190.90 μmol) was weighed and dissolved in DMF (5 mL), 19-1 (40 mg, 152.26 μmol) was added, and then DIPEA (74.02 mg, 572.70 μmol, 99.75 μL) was added. The reaction was carried out at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 19-2, MS m / z = 862.6 [M+H] + 。

[0644] Step 2: Synthesis of Intermediate 19-3

[0645] Compound 19-2 (120 mg, 139.22 μmol) was weighed and dissolved in DCM (10 mL), m-CPBA (24.03 mg, 139.22 μmol, 85% purity) was added. After addition, the reaction was carried out at room temperature 25 °C for 0.5 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 19-3, MS m / z = 878.3 [M+H] + 。

[0646] Step 3: Synthesis of Intermediate 19-4

[0647] Dissolve compound 5-2 (41.89 mg, 273.37 μmol) in anhydrous tetrahydrofuran (20 mL). Add sodium tert-butoxide (26.27 mg, 273.37 μmol) at 0 °C. React the reaction system at 0 °C for 1 hour. Add a 5 mL tetrahydrofuran solution of compound 19-3 (120 mg, 136.69 μmol) and react at 0 °C for 1 hour. Quench the reaction solution with water (20 mL), adjust the pH to about 6 with dilute hydrochloric acid, extract with ethyl acetate (30 mL × 3), wash with 100 mL of saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 19-4. MS m / z = 967.5 [M+H] + 。

[0648] Step 4: Synthesis of compound 19

[0649] Dissolve compound 19-4 (80 mg, 82.73 μmol) in dichloromethane (5 mL), add trifluoroacetic acid (5 mL), and react at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain a crude product. Separate the crude product by high performance liquid chromatography (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile %: 53% - 83%, 9 min) to obtain compound 19. MS m / z = 727.2 [M+H] + 。

[0650] Example 20

[0651]

[0652]

[0653] Step 1: Synthesis of intermediate 20-2

[0654] Weigh compound 20-1 (400 mg, 1.30 mmol) and dissolve it in DMF (10 mL). Add NBS (346.30 mg, 1.95 mmol), and then react at 25 °C for 1 hour. Extract with ethyl acetate (30 mL × 3), wash with water (30 mL × 3), and dry with anhydrous sodium sulfate to obtain a crude product. Purify the crude product by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 20-2. MS m / z = 387.0, 389.0 [M+H] + 。

[0655] Step 2: Synthesis of the hydrochloride salt of intermediate 20-3

[0656] Weigh compound 20-2 (250 mg, 645.54 μmol) and dissolve it in hydrogen chloride / ethyl acetate (4 M, 10 mL), then react at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the hydrochloride salt of compound 20-3. MS m / z = 287.0, 289.1 [M+H] + 。

[0657] Step 3: Synthesis of intermediate 20-4

[0658] Weigh compound 4-11B (200 mg, 254.53 μmol), dissolve it in DMF (5 mL), add the hydrochloride salt of 20-3 (123.56 mg), then add DIPEA (98.69 mg, 763.60 μmol), and react at 100 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product, and purify the crude product by column chromatography (methylene chloride:methanol = 10:1) to obtain compound 20-4. MS m / z = 922.1, 924.0 [M+H] + 。

[0659] Step 4: Synthesis of intermediate 20-5

[0660] Weigh compound 20-4 (180 mg, 195.05 μmol), dissolve it in DCM (10 mL), add m-CPBA (33.66 mg, 195.05 μmol, 85% purity), and react at room temperature (25 °C) for 0.5 hour after addition. Quench the reaction solution with water (15 mL), dilute it with 20 mL of methylene chloride, wash it with 20 mL of saturated brine, dry it with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 20-5. MS m / z = 938.2, 940.15 [M+H] + 。

[0661] Step 5: Synthesis of intermediate 20-6

[0662] Dissolve compound 5-2 (39.17 mg, 255.64 μmol) in anhydrous tetrahydrofuran (20 mL), add sodium tert-butoxide (24.57 mg, 255.64 μmol) at 0 °C, react the reaction system at 0 °C for 1 hour, add a 5 mL tetrahydrofuran solution of compound 20-5 (120 mg, 127.82 μmol), and react at 0 °C for 1 hour. Quench the reaction solution with water (20 mL), adjust the pH to about 6 with dilute hydrochloric acid, extract with ethyl acetate (30 mL × 3), wash with 100 mL of saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (methylene chloride:methanol = 10:1) to obtain compound 20-6. MS m / z = 1027.4, 1029.5 [M+H] + 。

[0663] Step 6: Synthesis of Compound 20

[0664] Dissolve Compound 20-6 (100 mg, 97.28 μmol) in trifluoroacetic acid (5 mL) and react at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product is separated by high performance liquid chromatography (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile %: 45% - 75%, 8 min) to obtain Compound 20. MS m / z = 787.1, 789.05 [M+H] + 。

[0665] Example 21

[0666]

[0667] Step 1: Synthesis of Intermediate 21-1

[0668] Dissolve Compound 1-2A (291.78 mg, 1.83 mmol) and sodium tert-butoxide (140.91 mg, 1.47 mmol) in anhydrous tetrahydrofuran (3 mL), react at -15 °C for 15 minutes, and dropwise add a solution of Compound 20-5 (0.35 g, 366.56 μmol) in tetrahydrofuran (2 mL). React at -15 - 0 °C for 1 hour. Add 5 mL of saturated ammonium chloride to the reaction solution, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated brine (20 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Compound 21-1 is obtained. MS m / z = 1033.2, 1035.2 [M+H] + 。

[0669] Step 2: Synthesis of the hydrochloride salt of Compound 21

[0670] Dissolve Compound 21-1 (100 mg, 96.7 μmol) in dichloromethane (5 mL), add trifluoroacetic acid (771.96 mg, 6.77 mmol), and react at 18 °C for 16 hours. Concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product is separated by high performance liquid chromatography (column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (0.04% hydrochloric acid) - acetonitrile]; acetonitrile %: 15% - 45%, 8 min) to obtain the hydrochloride salt of Compound 21. MS m / z = 793.1, 795.1 [M+H] + 。

[0671] Example 22

[0672]

[0673]

[0674] Step 1: Synthesis of Intermediate 22-1

[0675] Dissolve compound 1-2A (35.60 mg, 223.62 μmol) in anhydrous tetrahydrofuran (15 mL), add sodium tert-butoxide (21.49 mg, 223.62 μmol), react at 0 °C for 60 minutes, dropwise add a solution of compound 14-3 (0.1 g, 111.81 μmol) in tetrahydrofuran (5 mL), and react at 0 °C for 1 hour. Quench the reaction solution with 5 mL of saturated ammonium chloride, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash twice with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain compound 22-1. MS m / z = 989.4 [M+H] + 。

[0676] Step 2: Synthesis of the hydrochloride salt of Compound 22

[0677] Dissolve compound 22-1 (0.077 g, 77.82 μmol) in dichloromethane (15 mL), add trifluoroacetic acid (1.08 g, 9.50 mmol), and react at 20 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product is separated by high performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid) - acetonitrile]; acetonitrile %: 20% - 50%, 10 min) to obtain the hydrochloride salt of compound 22. MS m / z = 749.2 [M+H] + 。

[0678] Example 23

[0679]

[0680] Step 1: Synthesis of Intermediate 23-1

[0681] Dissolve compound 1-2A (15.41 mg, 96.82 μmol) in anhydrous tetrahydrofuran (0.5 mL), protect with nitrogen, cool to -15 °C, add sodium tert-butoxide (7.44 mg, 77.46 μmol), react at -15 °C for 0.25 hour, dropwise add a solution of compound 19-3 (17 mg, 19.36 μmol) in tetrahydrofuran (0.5 mL), and react at -15 °C for 1 hour. Quench the reaction solution with 3 mL of saturated ammonium chloride, extract with ethyl acetate (2 mL × 3), combine the organic phases, wash twice with 5 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain compound 23-1. MS m / z = 973.2 [M+H] + 。

[0682] Step 2: Synthesis of the hydrochloride salt of Compound 23

[0683] Dissolve Compound 23-1 (23 mg, 23.64 μmol) in dichloromethane (1 mL), add trifluoroacetic acid (539.04 mg, 4.73 mmol) at -10°C, and react at 20°C for 2 hours. Concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product is separated by high performance liquid chromatography (column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile %: 20%-50%, 8 min) to obtain the hydrochloride salt of Compound 23. MS m / z = 733.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ ppm 6.93 (d, J = 8.4 Hz, 1H) 5.68 - 5.51 (m, 1H), 5.17 - 5.12 (m, 3H), 4.97 - 4.95 (m, 1H), 4.75 - 4.72 (m, 1H), 4.64 (s, 3H), 4.44 - 4.36 (m, 1H), 4.05 (s, 2H), 3.97 - 3.84 (m, 3H), 3.51 - 3.42 (m, 2H), 3.31 - 3.27 (m, 3H), 3.08 (s, 3H), 2.99 - 2.94 (m, 1H), 2.71 - 2.58 (m, 2H), 2.53 - 2.44 (m, 1H), 2.43 - 2.28 (m, 3H), 2.27 - 2.07 (m, 2H), 2.02 (s, 3H).

[0684] Example 24

[0685]

[0686] Step 1: Synthesis of Intermediate 24-1

[0687] Add Compound 20-2 (0.1 g, 258.22 μmol), water (0.3 mL), 1,4-dioxane (1.5 mL), isopropenylboronic acid pinacol ester (56.41 mg, 335.68 μmol), potassium carbonate (178.44 mg, 1.29 mmol) to the reaction flask, protect with nitrogen, add bis(tri-tert-butylphosphine)palladium (13.20 mg, 25.82 μmol), and react at 80°C for 12 hours. Cool the reaction solution to room temperature, add 2 mL of water thereto, extract with ethyl acetate (2 mL×2), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify using thin layer chromatography (dichloromethane:methanol = 10:1). Obtain Compound 24-1. MS m / z = 349.0 [M+H] + .

[0688] Step 2: Synthesis of Intermediate 24-2

[0689] Under argon protection, add methanol (2 mL), wet palladium on carbon (20 mg, 14.24 μmol, 10% purity), and Compound 24-1 (39 mg, 111.93 μmol) into the reaction flask. Introduce hydrogen, react at 15 Psi and 20 °C for 16 hours. Filter the reaction solution, wash the filter cake with 10 mL of methanol, collect the filtrate, and concentrate it under reduced pressure. Compound 24-2 is obtained. MS m / z = 351.2 [M+H] + 。

[0690] Step 3: Synthesis of the hydrochloride salt of Intermediate 24-3

[0691] Add Compound 24-2 (0.04 g, 114.14 μmol) and hydrochloric acid / methanol (4 M, 0.5 mL) into the reaction flask, and react at 20 °C for 0.5 hour. Concentrate the reaction solution directly under reduced pressure. The hydrochloride salt of Compound 24-3 is obtained. MS m / z = 251.2 [M+H] + 。

[0692] Step 4: Synthesis of Intermediate 24-4

[0693] Weigh Compound 4-11B (60 mg, 76.36 μmol) and dissolve it in DMF (1 mL). Add the hydrochloride salt of 24-3 (32.85 mg), and then add DIPEA (1 mL). React at 50 °C for 1 hour. Cool the reaction solution to room temperature, add 2 mL of water to it, extract with ethyl acetate (3 mL × 4), wash the organic phase with saturated brine (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by thin-layer chromatography (dichloromethane:methanol = 10:1). Compound 24-4 is obtained. MS m / z = 886.3 [M+H] + 。

[0694] Step 5: Synthesis of Intermediate 24-5

[0695] Weigh Compound 24-4 (68 mg, 76.75 μmol), dissolve it in DCM (1 mL), add m-CPBA (10.91 mg, 53.72 μmol, 85% purity). After adding, react at room temperature (20 °C) for 1 hour. Dilute the reaction solution with 5 mL of dichloromethane, wash it twice with 3 mL of 5% sodium thiosulfate solution and 5 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain Compound 24-5, MS m / z = 902.2 [M+H] + 。

[0696] Step 6: Synthesis of Intermediate 24-6

[0697] Dissolve compound 5-2 (19.53 mg, 127.49 μmol) in anhydrous tetrahydrofuran (0.5 mL). Add sodium tert-butoxide (9.80 mg, 101.99 μmol) at -15°C. React the reaction system at -15°C for 0.25 h. Add a 0.5 mL tetrahydrofuran solution of compound 24-5 (23 mg, 25.50 μmol) and react at 0°C for 1 h. Add 3 mL of saturated ammonium chloride aqueous solution to the reaction solution, extract with ethyl acetate (2 mL × 3). Wash the organic phase with saturated brine (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 24-6, MS m / z = 991.3 [M+H] + 。

[0698] Step 7: Synthesis of Compound 24

[0699] Dissolve compound 24-6 (22 mg, 22.20 μmol) in dichloromethane (1 mL). Add trifluoroacetic acid (253.10 mg, 2.22 mmol) at -10°C and react at -10°C for 2 h. Concentrate the reaction solution under reduced pressure to obtain the crude product. Separate the crude product by high performance liquid chromatography (column: Waters Xbridge BEH C18 100×30 mm 5 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 30%-60%, 8 min) to obtain compound 24. MS m / z = 751.3 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ ppm 6.90 - 6.80 (d, J = 8.4 Hz, 1H), 5.34 - 5.25 (m, 1H), 5.21 - 5.13 (m, 1H), 4.98 - 4.78 (m, 3H), 4.63 (d, J = 13.6 Hz, 1H), 4.50 - 4.39 (m, 3H), 4.10 (s, 2H), 3.99 (d, J = 14.4 Hz, 1H), 3.75 - 3.57 (m, 2H), 3.23 - 3.11 (m, 1H), 3.00 - 3.17 (m, 6H), 2.93 (s, 3H), 2.84 - 2.78 (m, 1H), 2.66 - 2.77 (m, 2H), 2.44 - 2.34 (m, 1H), 2.26 - 2.04 (m, 3H), 2.02 (s, 3H), 1.98 - 1.77 (m, 3H), 1.22 (d, J = 7.2 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H).

[0700] Example 25

[0701]

[0702]

[0703] Step 1: Synthesis of Intermediate 25-1

[0704] Add compound 20-2 (0.15 g, 387.33 μmol), N,N-dimethylformamide (3 mL), cuprous cyanide (104.07 mg, 1.16 mmol) into a dry reaction flask. Under nitrogen protection, add 1,1-bis(diphenylphosphino)ferrocene palladium chloride (28.34 mg, 38.73 μmol) and tris(dibenzylideneacetone) dipalladium (35.47 mg, 38.73 μmol), and heat to 120 °C for reaction for 12 hours. The reaction solution is cooled to room temperature, 10 mL of water is added thereto, and it is extracted with ethyl acetate (5 mL×4). The organic phase is washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. Purify by column chromatography (dichloromethane:methanol = 10:1). Obtain compound 25-1, MS m / z = 333.9 [M+H] + 。

[0705] Step 2: Synthesis of Hydrochloride Salt of Intermediate 25-2

[0706] Add compound 25-1 (80 mg, 239.96 μmol) and hydrochloric acid / ethyl acetate (4 M, 2 mL) into a reaction flask, and react at 20 °C for 1 hour. The reaction solution is directly concentrated under reduced pressure. Obtain the hydrochloride salt of compound 25-2. MS m / z = 234.2 [M+H] + 。

[0707] Step 3: Synthesis of Intermediate 25-3

[0708] Weigh compound 4-11B (120 mg, 152.72 μmol) and add it to DMF (2 mL) for dissolution. Add the hydrochloride salt of 25-2 (82.39 mg), and then add DIPEA (59.21 mg, 458.16 μmol), and react at 50 °C for 1 hour. The reaction solution is cooled to room temperature, 2 ml of water is added thereto, and it is extracted with ethyl acetate (3 mL×4). The organic phase is washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. Purify by thin-layer chromatography (dichloromethane:methanol = 10:1). Obtain compound 25-3. MS m / z = 869.2 [M+H] + 。

[0709] Step 4: Synthesis of Intermediate 25-4

[0710] Weigh compound 25-3 (90 mg, 103.57 μmol), dissolve it in DCM (2 mL), add m-CPBA (14.72 mg, 72.50 μmol, 85% purity). After addition, react at room temperature (20 °C) for 1 hour. Dilute the reaction solution with 5 mL of dichloromethane, wash it twice with 3 mL of 5% sodium thiosulfate solution and 5 mL of saturated brine, dry it over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify it by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 25-4, MS m / z = 885.1 [M+H] + 。

[0711] Step 5: Synthesis of intermediate 25-5

[0712] Dissolve compound 5-2 (65.79 mg, 429.41 μmol) in anhydrous tetrahydrofuran (1 mL), add sodium tert-butoxide (33.01 mg, 343.53 μmol) at -15 °C. React the reaction system at -15 °C for 0.25 hour, add a 1 mL tetrahydrofuran solution of compound 25-4 (76 mg, 85.88 μmol), and continue to react for 1 hour. Add 5 mL of saturated ammonium chloride aqueous solution to the reaction solution, extract it with ethyl acetate (5 mL × 3). Wash the organic phase with saturated brine (10 mL), dry it over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Obtain compound 25-5, MS m / z = 974.2 [M+H] + 。

[0713] Step 6: Synthesis of compound 25

[0714] Dissolve compound 25-5 (96 mg, 98.56 μmol) in dichloromethane (1 mL), add trifluoroacetic acid (2.25 g, 19.71 mmol, 1.46 mL) at -10 °C, and react at 20 °C for 2 hours. Concentrate the reaction solution under reduced pressure to obtain the crude product. Separate the crude product by high-performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100×30 mm 5 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 25%-55%, 8 min) to obtain compound 25. MS m / z = 734.2 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ ppm 6.87 (d, J = 8.38 Hz, 1H), 5.20 - 5.18 (m, 1H), 5.07 - 4.77 (m, 4H), 4.75 - 4.64 (m, 2H), 4.60 - 4.47 (m, 1H), 4.41 - 4.31 (m, 1H), 4.06 (s, 3H), 4.01 - 3.56 (m, 4H), 3.36 - 3.22 (m, 4H), 3.19 - 3.04 (m, 4H), 2.97 - 2.90 (m, 1H), 2.78 - 2.69 (m, 1H), 2.65 - 2.61 (m, 1H), 2.41 - 2.25 (m, 2H), 2.21 - 2.13 (m, 2H), 2.04 (s, 3H), 1.96 - 1.84 (m, 2H), 1.79 - 1.65 (m, 2H).

[0715] Example 26

[0716]

[0717] Step 1: Synthesis of Intermediate 26-1

[0718] Dissolve compound 21-1 (50 mg, 48.36 μmol) and tributyl(trimethylsilylethynyl)tin (112.37 mg, 290.16 μmol) in anhydrous toluene (2 mL). Under nitrogen protection, add tetrakis(triphenylphosphine)palladium (11.18 mg, 9.67 μmol) and react at 130 °C for 16 hours. Concentrate the reaction solution, add 5 mL of water, extract with 3 mL × 2 of ethyl acetate, wash with 3 mL × 2 of saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain compound 26-1. MS m / z = 1051.3 [M+H] + .

[0719] Step 2: Synthesis of the trifluoroacetate salt of Intermediate 26-2

[0720] Dissolve compound 26-1 (50 mg, 47.56 μmol) in anhydrous dichloromethane (2 mL), add trifluoroacetic acid (612.82 mg, 5.37 mmol), and react at 15 °C for 1 hour. Concentrate the reaction solution under reduced pressure. Obtain the trifluoroacetate salt of compound 26-2. MS m / z = 811.2 [M+H] + .

[0721] Step 3: Synthesis of Compound 26

[0722] Dissolve the trifluoroacetate of compound 26-2 (0.1 g) in anhydrous methanol (2.5 mL), add potassium carbonate (34.09 mg, 246.63 μmol), and react at 18 °C for 2 hours. Concentrate the reaction solution, add water (10 mL) and ethyl acetate (5 mL × 2) for liquid separation, combine the organic phases, wash with saturated brine (5 mL × 2), dry over anhydrous sodium sulfate, and then concentrate. Separate the crude product by high performance liquid chromatography (column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 20%-50%, 8 min). Adjust the pH of the split solution to 9 with saturated sodium bicarbonate solution, concentrate under reduced pressure to remove the organic phase, extract with ethyl acetate (5 mL × 2), and then concentrate under reduced pressure and lyophilize. Compound 26 is obtained. MS m / z = 739.2 [M+H] + 。

[0723] Example 27

[0724]

[0725] Step 1: Synthesis of Intermediate 27-1

[0726] Add compound 20-2 (0.2 g, 516.43 μmol), N,N-dimethylformamide (2.5 mL) to a dry reaction flask, add methyl fluorosulfonyldifluoroacetate (496.07 mg, 2.58 mmol), copper(I) iodide (196.71 mg, 1.03 mmol), and react at 100 °C for 10 hours. Add 5 mL of water to the reaction solution, extract with ethyl acetate (5 mL × 2), wash with saturated brine (5 mL × 2), dry over anhydrous sodium sulfate, and concentrate. Separate the crude product by high performance liquid chromatography (column: Phenomenex luna C18 100×40 mm×3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 30%-60%, 18.0 min). Adjust the pH of the organic liquid separation to 8-9, concentrate under reduced pressure to remove the organic phase, extract the aqueous phase with ethyl acetate (5 mL × 2), combine the organic phases, wash with 3 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate. Compound 27-1 is obtained. MS m / z = 377.1 [M+H] + 。

[0727] Step 2: Synthesis of the hydrochloride salt of Intermediate 27-2

[0728] Add compound 27-1 (90 mg, 239.12 μmol) and hydrochloric acid / ethyl acetate (4 M, 2.5 mL) to a reaction flask, and react at 18 °C for 2 hours. Concentrate the reaction solution under reduced pressure. The hydrochloride salt of compound 27-2 is obtained. MS m / z = 277.1 [M+H] + 。

[0729] Step 3: Synthesis of Intermediate 27-3

[0730] Weigh compound 4-11B (100 mg, 127.27 μmol) and dissolve it in DMF (1 mL). Add the hydrochloride salt of 27-2 (42.19 mg), and then add DIPEA (49.34 mg, 381.80 μmol). React at 50 °C for 1 hour. Let the reaction solution cool to room temperature, add water (10 mL), extract with ethyl acetate (5 mL × 3), separate the layers, combine the organic phases, extract with saturated brine (5 mL × 2), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Compound 27-3 is obtained. MS m / z = 912.1 [M+H] + 。

[0731] Step 4: Synthesis of Intermediate 27-4

[0732] Weigh compound 27-3 (0.14 g, 153.52 μmol), dissolve it in DCM (2.5 mL), add m-CPBA (46.57 mg, 230.28 μmol, 85% purity). After addition, react at room temperature (18 °C) for 1 hour. Quench the reaction solution with 20 mL of 5% sodium sulfite solution, extract with dichloromethane (10 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), dry with anhydrous sodium sulfate and then concentrate. Compound 27-4 is obtained, MS m / z = 944.1 [M+H] + 。

[0733] Step 5: Synthesis of Intermediate 27-5

[0734] Dissolve compound 5-2 (113.63 mg, 741.58 μmol) in anhydrous tetrahydrofuran (1 mL). Add sodium tert-butoxide (57.01 mg, 593.27 μmol) at -15 °C. React the reaction system at -15 °C for 0.25 hour. Add a 2 mL tetrahydrofuran solution of compound 27-4 (0.14 g, 148.32 μmol) and continue to react for 1 hour. Add 5 mL of saturated ammonium chloride aqueous solution to the reaction solution, extract with ethyl acetate (5 mL × 3), wash the organic phase with saturated brine (10 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Compound 27-5 is obtained, MS m / z = 1017.6 [M+H] + 。

[0735] Step 6: Synthesis of the Hydrochloride Salt of Compound 27

[0736] Compound 27-5 (0.12 g, 117.99 μmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (766.83 mg, 6.73 mmol) was added at 18 °C. The reaction was carried out at 18 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 20%-50%, 8 min) to obtain the hydrochloride of compound 27. MS m / z = 777.2 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ = 7.00 - 6.90 (m, 1H), 5.31 - 5.06 (m, 4H), 5.02 - 4.80 (m, 2H), 4.79 - 4.61 (m, 2H), 4.59 - 4.30 (m, 4H), 4.10 - 3.70 (m, 4H), 3.52 - 3.40 (m, 2H), 3.24 - 3.08 (m, 2H), 3.02 - 2.93 (m, 6H), 2.49 - 2.40 (m, 1H), 2.38 - 2.27 (m, 3H), 2.13 - 1.84 (m, 6H).

[0737] Example 28

[0738]

[0739]

[0740] Step 1: Synthesis of intermediate 28-2

[0741] Compound 4-11B (0.22 g, 279.99 μmol) was weighed and dissolved in DMF (20 mL). 28-1 (0.1 g, 449.87 μmol) was added, and then DIPEA (180.93 mg, 1.40 mmol) was added. The reaction was carried out at 100 °C for 1 h. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride (10 mL), extracted with ethyl acetate (10 mL×3), separated, the organic phases were combined, extracted with saturated brine (10 mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 28-2 was obtained. MS m / z = 858.3 [M+H] + 。

[0742] Step 2: Synthesis of intermediate 28-3

[0743] Weigh compound 28-2 (0.154 g, 179.50 μmol), dissolve it in DCM (10 mL), add m-CPBA (36.44 mg, 179.50 μmol, 85% purity), and react at room temperature (25 °C) for 1 hour. Quench the reaction with water (10 mL), extract with 10 mL×2 dichloromethane, combine the organic phases, wash with 20 mL×2 saturated brine, dry over anhydrous sodium sulfate, and concentrate. Compound 28-3 is obtained, MS m / z = 874.3 [M+H] + 。

[0744] Step 3: Synthesis of intermediate 28-4

[0745] Dissolve compound 5-2 (56.50 mg, 368.76 μmol) in anhydrous tetrahydrofuran (10 mL), add sodium tert-butoxide (35.44 mg, 368.76 μmol) at 0 °C, react the reaction system at 0 °C for 1 hour, add compound 28-3 (161.14 mg, 184.38 μmol), and continue to react for 1 hour. Add 5 mL of aqueous solution to the reaction solution, extract with ethyl acetate (10 mL×3), wash the organic phase with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Compound 28-4 is obtained, MS m / z = 963.4 [M+H] + 。

[0746] Step 4: Synthesis of the hydrochloride salt of compound 28

[0747] Dissolve compound 28-4 (0.173 g, 179.63 μmol) in dichloromethane (15 mL), add trifluoroacetic acid (2.50 g, 21.93 mmol) at 20 °C, and react at 20 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product is separated by high performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid) - acetonitrile]; acetonitrile%: 20% - 50%, 10 min) to obtain the hydrochloride salt of compound 28. MS m / z = 723.2 [M+H] + 。 11H NMR (400 MHz, MeOH) δ = 6.99 - 6.90 (m, 1H), 5.38 - 5.29 (m, 2H), 5.26 - 5.11 (m, 2H), 5.10 - 4.95 (m, 2H), 4.75 - 4.66 (m, 2H), 4.55 - 4.47 (m, 1H), 4.38 - 4.28 (m, 2H), 4.20 - 4.07 (m, 1H), 4.00 - 3.90 (m, 2H), 3.85 - 3.69 (m, 2H), 3.42 - 3.35 (m, 1H), 3.28 - 3.20 (m, 2H), 3.20 - 3.07 (m, 6H), 3.05 - 2.95 (m, 2H), 2.91 - 2.79 (m, 1H), 2.43 - 2.16 (m, 8H), 2.08 - 2.01 (m, 3H).

[0748] Example 29

[0749]

[0750]

[0751] Step 1: Synthesis of Intermediate 29-1

[0752] Dissolve compound 20-6 (0.15 g, 145.92 μmol) and tributyl(1-propynyl)tin (384.20 mg, 1.17 mmol) in anhydrous toluene (6 mL). Under nitrogen protection, add dichloro bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (31.00 mg, 43.78 μmol). Evacuate and refill with nitrogen 5 times, and react at 120 °C for 24 hours. Quench with 5 mL of water, filter through diatomaceous earth, wash the filter cake with ethyl acetate, extract with ethyl acetate (10 mL × 2), wash with 10 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain compound 29-1. MS m / z = 987.7 [M+H] + 。

[0753] Step 2: Synthesis of Compound 29

[0754] Dissolve compound 29-1 (67.2 mg, 68.08 μmol) in dichloromethane (15 mL). Add trifluoroacetic acid (212.92 mg, 1.87 mmol) at 20 °C and react at 20 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product is separated by high performance liquid chromatography (column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile %: 40% - 70%, 9 min) to obtain compound 29. MS m / z = 747.3 [M+H] + 。

[0755] Example 30

[0756]

[0757]

[0758] Step 1: Synthesis of Intermediate 30-2

[0759] Weigh compound 30-1 (0.25 g, 844.27 μmol), dissolve it in DMF (5 ml), add HATU (417.32 mg, 1.10 mmol), DIPEA (436.46 mg, 3.38 mmol, 588.22 μL), and dimethyl-d6-amine hydrochloride (314.18 mg, 2.53 mmol) to the solution. After adding, react at room temperature of 18 °C for 1 hour. Add 5 mL of water to quench the reaction mixture, extract with ethyl acetate (10 mL × 3), wash with 10 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 30-2. MS m / z = 315.2 [M+H] + 。

[0760] Step 2: Synthesis of Compound 30-3

[0761] Weigh compound 30-2 (264.97 mg, 800.60 μmol), dissolve it in DMF (3 mL), add NCS (160.36 mg, 1.20 mmol) to the reaction system. After adding, react at 55 °C for 2 hours. Add 5 mL of water to quench the reaction mixture, extract with ethyl acetate (10 mL × 3), wash with 10 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 30-3. MS m / z = 349.2 [M+H] + 。

[0762] Step 3: Synthesis of the Hydrochloride Salt of Compound 30-4

[0763] Weigh compound 30-3 (0.27 g, 735.26 μmol), add hydrogen chloride / ethyl acetate (15 mL), react at 18 °C for 1 hour, and concentrate under reduced pressure to obtain the hydrochloride salt of compound 30-4. MS m / z = 249.2 [M+H] + 。

[0764] Step 4: Synthesis of Compound 30-5

[0765] Weigh compound 4-11B (0.2 g, 254.53 μmol), dissolve it in DMF (5 mL), add the hydrochloride salt of 30-4 (145.19 mg), then add DIPEA (98.69 mg, 763.60 μmol), and react at 100 °C for 1 hour. The reaction solution is cooled to room temperature, water (10 mL) is added, and it is extracted with ethyl acetate (5 mL × 3). After liquid separation, the organic phases are combined, extracted with saturated brine (5 mL × 2), and after liquid separation, the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. Compound 30-5 is obtained. MS m / z = 884.3 [M+H] + 。

[0766] Step 5: Synthesis of intermediate 30-6

[0767] Weigh compound 30-5 (0.214 g, 241.97 μmol), dissolve it in DCM (10 mL), add m-CPBA (49.13 mg, 241.97 μmol, 85% purity), and after addition, react at room temperature (18 °C) for 1 hour. Add 10 mL of water to quench the reaction, extract with dichloromethane (10 mL × 3), combine the organic phases, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrate. Compound 30-6 is obtained. MS m / z = 900.3 [M+H] + 。

[0768] Step 6: Synthesis of intermediate 30-7

[0769] Dissolve compound 5-2 (71.47 mg, 466.45 μmol) in anhydrous tetrahydrofuran (5 mL), add sodium tert-butoxide (44.83 mg, 466.45 μmol) at 0 °C, react the reaction system at 0 °C for 1 hour, add a 5 mL tetrahydrofuran solution of compound 30-6 (0.21 g, 233.23 μmol), and continue to react for 1 hour. Add 5 mL of water to the reaction solution to quench the reaction, extract with ethyl acetate (5 mL × 3), wash the organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 30-7. MS m / z = 989.4 [M+H] + 。

[0770] Step 7: Synthesis of the hydrochloride salt of compound 30

[0771] Compound 30-7 (0.22 g, 222.33 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5.65 g, 49.53 mmol) was added at 20 °C. The reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 17%-47%, 14 min) to obtain the hydrochloride salt of compound 30. MS m / z = 749.3 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ = 7.01 - 6.91 (m, 1H), 5.39 - 5.29 (m, 2H), 5.26 - 5.19 (m, 1H), 5.16 - 5.00 (m, 4H), 4.76 - 4.69 (m, 1H), 4.59 - 4.44 (m, 2H), 4.41 - 4.21 (m, 2H), 4.17 - 4.06 (m, 1H), 4.01 - 3.85 (m, 2H), 3.84 - 3.73 (m, 1H), 3.30 - 3.20 (m, 2H), 3.09 - 2.95 (m, 2H), 2.86 - 2.72 (m, 1H), 2.56 - 2.10 (m, 6H), 2.08 - 1.97 (m, 3H).

[0772] Example 31

[0773]

[0774] Step 1: Synthesis of intermediate 31-2

[0775] Compound 30-1 (0.25 g, 844.27 μmol) was weighed and dissolved in DMF (5 ml). HATU (417.32 mg, 1.10 mmol), DIPEA (436.46 mg, 3.38 mmol, 588.22 μL) and azetidine hydrochloride (236.96 mg, 2.53 mmol) were added to the solution. After addition, the reaction was carried out at room temperature (18 °C) for 2 hours. 5 mL of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (10 mL×3), washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 31-2. MS m / z = 321.2 [M+H] + 。

[0776] Step 2: Synthesis of compound 31-3

[0777] Weigh compound 31-2 (0.27 g, 800.60 μmol), dissolve it in DMF (3 mL), add NCS (160.36 mg, 1.20 mmol) to the reaction system, react at 55 °C for 2 hours after addition, add 5 mL of water to quench the reaction solution, extract with ethyl acetate (10 mL × 3), wash with 10 mL of saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 31-3. MS m / z = 355.2 [M+H] + 。

[0778] Step 3: Synthesis of trifluoroacetate salt of compound 31-4

[0779] Weigh compound 31-3 (0.06 g, 160.64 μmol), add trifluoroacetic acid (18.32 mg, 160.64 μmol), react at 18 °C for 1 hour, concentrate under reduced pressure to obtain the trifluoroacetate salt of compound 31-4. MS m / z = 255.1 [M+H] + 。

[0780] Step 4: Synthesis of compound 31-5

[0781] Weigh compound 4-11B (0.05 g, 63.63 μmol), dissolve it in DMF (5 mL), add the trifluoroacetate salt of 31-4 (28.16 mg), then add DIPEA (24.67 mg, 190.90 μmol), and react at 100 °C for 1 hour. After the reaction solution cools to room temperature, add water (10 mL), extract with ethyl acetate (5 mL × 3), separate the layers, combine the organic phases, extract with saturated brine (5 mL × 2), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Obtain compound 31-5. MS m / z = 890.3 [M+H] + 。

[0782] Step 5: Synthesis of intermediate 31-6

[0783] Weigh compound 31-5 (0.278 g, 312.22 μmol), dissolve it in DCM (10 mL), add m-CPBA (63.39 mg, 312.23 μmol, 85% purity), react at 18 °C at room temperature for 1 hour after addition, add 10 mL of water to quench the reaction, extract with dichloromethane (10 mL × 3), combine the organic phases, wash with 20 mL of saturated brine, dry with anhydrous sodium sulfate and then concentrate. Obtain compound 31-6, MS m / z = 906.3 [M+H] + 。

[0784] Step 6: Synthesis of intermediate 31-7

[0785] Compound 5-2 (81.14 mg, 529.58 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (50.89 mg, 529.58 μmol) was added at 0 °C. The reaction system was reacted at 0 °C for 1 hour. A 5 mL tetrahydrofuran solution of compound 31-6 (0.24 g, 264.79 μmol) was added, and the reaction was continued for 1 hour. 5 mL of water was added to the reaction solution to quench it. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (dichloromethane:methanol = 10:1) gave compound 31-7, MS m / z = 995.4 [M+H] + .

[0786] Step 7: Synthesis of the hydrochloride salt of compound 31

[0787] Compound 31-7 (0.05 g, 50.23 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (157.08 mg, 1.38 mmol) was added at 20 °C. The reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by high performance liquid chromatography (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile %: 57% - 87%, 8 min) to obtain the hydrochloride salt of compound 31. MS m / z = 755.2 [M+H] + .

[0788] Example 32

[0789]

[0790]

[0791] Step 1: Synthesis of intermediate 32-2

[0792] Methyl 3,5-dicarboxylate pyrazole (6.5 g, 35.30 mmol) and compound 32-1 (10.56 g, 35.30 mmol) were added to N,N-dimethylformamide (60 mL), and then potassium carbonate (9.76 g, 70.59 mmol) was added. The resulting reaction mixture was heated to 100 °C and stirred for 2 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain a crude product. 500 mL of ethyl acetate was added to the crude product and stirred for 5 minutes, then filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 32-2. HNMR: (400 MHz, CDCl3) δ: 7.34 (m, 1H), 4.69 (t, J = 6.8 Hz, 2H), 4.49 (br s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.83 - 3.64 (m, 1H), 2.12 - 2.05 (m, 1H), 1.99 - 1.83 (m, 1H), 1.44 (s, 9H), 1.17 (d, J = 6.4 Hz, 3H).

[0793] Step 2: Synthesis of intermediate 32-3

[0794] Compound 32-2 (11.5 g, 32.36 mmol) was dissolved in DCM (10 mL), and then hydrogen chloride / ethyl acetate (4 M, 40.45 mL) was added. The resulting reaction mixture was stirred at 15 °C for 4 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain a residue. 30 mL of water and 50 mL of dichloromethane were added to the residue, and then the pH was adjusted to 9 with 2 M sodium hydroxide solution. The organic phase was separated, and the aqueous phase was extracted with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 32-3.

[0795] Step 3: Synthesis of intermediate 32-4

[0796] Compound 32-3 (8.3 g, 32.51 mmol) was dissolved in anhydrous methanol (50 mL), and then sodium methoxide (3.51 g, 65.03 mmol) was added. The reaction mixture was stirred at 60 °C for 15 hours under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, and the solid was collected and dried in vacuo for 0.5 hour to obtain Compound 32-4. HNMR: (400 MHz, CDCl3) δ: 7.34 (s, 1H), 6.10 (br s, 1H), 4.65 (ddd, J = 3.6, 6.8, 14.3 Hz, 1H), 4.49 (ddd, J = 5.9, 10.3, 14.3 Hz, 1H), 3.95 (s, 3H), 3.68 - 3.52 (m, 1H), 2.46 - 2.33 (m, 1H), 2.09 - 1.95 (m, 1H), 1.37 (d, J = 6.4 Hz, 3H).

[0797] Step 4: Synthesis of Intermediate 32-5

[0798] Compound 32-4 (4.05 g, 18.14 mmol) was dissolved in tetrahydrofuran (80 mL), and lithium aluminum hydride (2.75 g, 72.57 mmol) was added thereto in portions slowly. After the addition was completed, the reaction mixture was stirred at 20 °C for 2 hours, and then slowly heated to 60 °C and stirred for 15 hours. The reaction mixture was cooled to 0 °C, and then 2.8 mL of water and 2.8 mL of 15% sodium hydroxide solution were slowly added dropwise to quench the reaction. The mixture was stirred for 10 minutes, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain Compound 32-5. (400 MHz, CDCl3) δ: 6.07 (s, 1H), 4.61 (s, 2H), 4.53 - 4.40 (m, 1H), 4.25 - 4.05 (m, 2H), 3.72 (d, J = 15.6 Hz, 1H), 3.10 - 2.96 (m, 1H), 1.98 - 1.90 (m, 1H), 1.57 - 1.45 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H).

[0799] Step 5: Synthesis of Intermediate 32-6

[0800] Compound 32-5 (2.80 g, 15.45 mmol) was dissolved in dichloromethane (30 mL), and then di-tert-butyl dicarbonate (3.37 g, 15.45 mmol, 3.55 mL) was added. The reaction mixture was stirred at 15 °C for 15 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure. 20 mL of methanol and 20 mL of water were added to the residue, and then potassium carbonate (4.27 g, 30.90 mmol) was added. The resulting system was heated to 80 °C and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure, and then extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 32-6. 1H NMR: (400 MHz, CDCl3) δ: 6.07 (br s, 1H), 5.12 - 4.67 (m, 1H), 4.60 (s, 2H), 4.46 - 4.34 (m, 1H), 4.17 - 3.89 (m, 2H), 2.45 (br s, 1H), 2.26 - 2.12 (m, 1H), 2.04 - 1.79 (m, 1H), 1.50 - 1.30 (m, 9H), 1.24 (d, J = 5.8 Hz, 3H).

[0801] Step 6: Synthesis of Intermediate 32-7

[0802] Compound 32-6 (4.3 g, 15.28 mmol) was dissolved in dichloromethane (100 mL). The resulting solution was cooled to 0 °C, and then Dess-Martin periodinane (6.48 g, 15.28 mmol) was slowly added. After addition, the ice bath was removed, and the temperature was raised to room temperature (20 °C) and stirred for 3 hours. The reaction mixture was quenched with 30 mL of saturated sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 32-7. 1 1H NMR: (400 MHz, CDCl3) δ: 9.92 - 9.85 (m, 1H), 6.62 (br s, 1H), 5.17 - 4.33 (m, 3H), 4.24 (dd, J = 10.1, 14.1 Hz, 1H), 4.02 (br d, J = 16.6 Hz, 1H), 2.33 - 2.19 (m, 1H), 2.03 - 1.89 (m, 1H), 1.39 (br s, 9H), 1.30 - 1.26 (m, 3H).

[0803] Step 7: Synthesis of Intermediate 32-8

[0804] Compound 32-7 (2.0 g, 7.16 mmol) was dissolved in dimethyl sulfoxide (25 mL), and then a solution of potassium dihydrogen phosphate (2.53 g, 18.62 mmol) in water (5 mL) was added. Subsequently, a solution of sodium chlorite (1.36 g, 15.04 mmol) in water (5 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at 20 °C for 2 hours. The reaction solution was diluted with 200 mL of ethyl acetate, and then washed with water (40 mL × 2) and 40 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 32-8. 1H NMR: (400 MHz, CDCl3) δ: 6.69 (br s, 1H), 5.18 - 4.34 (m, 3H), 4.24 (br dd, J = 10.3, 14.1 Hz, 1H), 4.03 (br d, J = 16.6 Hz, 1H), 2.32 - 2.18 (m, 1H), 2.00 (br s, 1H), 1.40 (br s, 9H), 1.27 (d, J = 6.8 Hz, 3H).

[0805] Step 8: Synthesis of Intermediate 32-9

[0806] Compound 32-8 (1.0 g, 3.39 mmol) was dissolved in tetrahydrofuran (15 mL), and then carbonyldiimidazole (823.56 mg, 5.08 mmol) was added. The reaction mixture was stirred at 10 °C for 1 hour under nitrogen protection. Then, a solution of dimethylamine / tetrahydrofuran (2 M, 5.08 mL) was added, and the resulting reaction solution was stirred for an additional 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate (50 mL), and then washed with water (10 mL × 3). The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 32-9. 1 1H NMR: (400 MHz, CDCl3) δ: 6.46 (s, 1H), 5.18 - 4.30 (m, 3H), 4.22 - 4.10 (m, 1H), 4.00 (d, J = 16.8 Hz, 1H), 3.32 (br s, 3H), 3.08 (s, 3H), 2.29 - 2.16 (m, 1H), 2.03 - 1.88 (m, 1H), 1.50 - 1.31 (m, 9H), 1.26 (d, J = 6.8 Hz, 3H).

[0807] Step 9: Synthesis of Intermediate 32-10

[0808] Compound 32-9 (1.03 g, 3.19 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then N-chlorosuccinimide (853.21 mg, 6.39 mmol) was added. The resulting reaction mixture was stirred at 55 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Compound 32-10, MS m / z = 357.0 [M+H] + .

[0809] Step 10: Synthesis of the hydrochloride salt of Intermediate 32-11

[0810] Compound 32-10 (300 mg, 622.12 μmol) was dissolved in dichloromethane (0.5 mL), and then hydrogen chloride / ethyl acetate solution (4 M, 1.56 mL) was added. The resulting reaction mixture was stirred at 20 °C for 0.5 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude hydrochloride salt of Compound 32-11. MS m / z = 257.0 [M+H] + .

[0811] Step 11: Synthesis of Intermediate 32-12

[0812] Compound 4-11B (200 mg, 254.53 μmol) was weighed and dissolved in DMF (1.5 mL). The hydrochloride salt of 32-11 (217.00 mg) was added, and then DIPEA (164.48 mg, 1.27 mmol) was added. The reaction was carried out at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The layers were separated, and the organic phases were combined. The combined organic phases were extracted with saturated brine (5 mL × 2). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Compound 32-12. MS m / z = 892.4 [M+H] + . Step 12: Synthesis of Intermediate 32-13

[0813] Compound 32-12 (58 mg, 64.99 μmol) was taken and dissolved in DCM (1 mL). m-CPBA (13.19 mg, 64.99 μmol, 85% purity) was added, and the reaction was carried out at room temperature (18 °C) for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain Compound 32-13. MS m / z = 908.3 [M+H] + .

[0814] Step 13: Synthesis of Intermediate 32-14

[0815] Compound 5-2 (39.13 mg, 255.39 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Sodium tert-butoxide (24.54 mg, 255.39 μmol) was added at 0 °C. The reaction system was reacted at 0 °C for 1 hour. Compound 32-13 (58 mg, 63.85 μmol) was added and the reaction continued for 1 hour. 0.5 mL of water was added to the reaction solution to quench it, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (dichloromethane:methanol = 10:1) gave compound 32-14, MS m / z = 997.4 [M+H] + 。

[0816] Step 14: Synthesis of hydrochlorides of compounds 32A and 32B

[0817] Compound 32-14 (36 mg, 36.09 μmol) was dissolved in trifluoroacetic acid (0.5 mL) and reacted at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by high performance liquid chromatography (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 30%-60%) to obtain hydrochlorides of compounds 32A and 32B. Analytical liquid chromatography: column: ChromCore 120C18 3 μm, 3.0×30 mm; mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)]; acetonitrile (0.02% trifluoroacetic acid) %: 10%-80%, 7 min_220&254 nm), retention time: 32A (Rt = 3.484 min), MS m / z = 757.1 [M+H] + , 32B (Rt = 3.606 min), MS m / z = 757.2 [M+H] + 。

[0818] Biological test data:

[0819] Experimental Example 1. Anti-cell proliferation effect of compounds in tumor cell line AsPC-1

[0820] Research purpose

[0821] In this experiment, the effect of compounds on inhibiting cell proliferation was studied by detecting the effect of compounds on in vitro cell activity in the tumor cell line AsPC-1 with KRAS G12D mutation.

[0822] Experimental materials

[0823] The cell line was AsPC-1, the tumor type was pancreatic cancer, adherent growth, and the culture method was RPMI 1640 + 10% FBS

[0824] Ultra Low Cluster - 96 - well plate (Corning - 7007)

[0825] Greiner CELLSTAR 96 - well plate (#655090)

[0826] Promega CellTiter - Glo 3D Luminescent Cell Viability Assay Kit (Promega - G9683)

[0827] 2104 - 10 EnVision Microplate Reader, PerkinElmer

[0828] RPMI 1640, DMEM, PBS (Phosphate - Buffered Saline), FBS (Fetal Bovine Serum), Antibiotic - antimycotic, L - glutamine, DMSO (Dimethyl Sulfoxide)

[0829] Experimental Methods and Procedures

[0830] Cell Culture

[0831] Culture the tumor cell line in an incubator at 37°C and 5% CO₂ according to the culture conditions shown in the culture method. Passage regularly and use cells in the logarithmic growth phase for plating.

[0832] Cell Plating

[0833] Stain the cells with trypan blue and count the viable cells.

[0834] Adjust the cell concentration to an appropriate concentration.

[0835] The cell line is AsPC - 1, with a density of 7000 cells per well.

[0836] Add 135 μL of cell suspension to each well in the ULA culture plate, and add the same volume of cell - free culture medium to the blank control wells.

[0837] After plating, immediately centrifuge the ULA culture plate at room temperature for 10 minutes at 1000 rpm. Note: After centrifugation, be sure to handle the subsequent operations carefully to avoid unnecessary shaking.

[0838] Incubate the culture plate overnight in an incubator at 37°C, 5% CO₂, and 100% relative humidity.

[0839] Preparation of 10X Compound Working Solution and Compound Treatment of Cells (Day 1)

[0840] After preparing the 10X compound working solution (DMSO 10X working solution), add 15 μL of the 10X compound working solution to each well of the ULA culture plate, and add 15 μL of the DMSO-cell culture medium mixture to the vehicle control and blank control wells.

[0841] Return the 96-well cell plate to the incubator and incubate for 120 hours.

[0842] Observe the cell spheroid formation every day until the end of the experiment.

[0843] CellTiter-Glo Luminescent Cell Viability Assay (Day 5)

[0844] The following steps are carried out according to the instructions of the Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega #G9683).

[0845] Add 150 μL (equal to the volume of cell culture medium in each well) of CellTiter-Glo 3D reagent to each well. Wrap the cell plate with aluminum foil to avoid light.

[0846] Shake the culture plate on an orbital shaker for 5 minutes.

[0847] Carefully pipette up and down 10 times to mix the contents in the well. Ensure that the cell spheres are fully separated before proceeding to the next step.

[0848] Then transfer the solution in the ULA culture plate to a black-bottom culture plate (#655090) and let it stand at room temperature for 25 minutes to stabilize the luminescence signal.

[0849] Detect the luminescence signal on a 2104 EnVision microplate reader.

[0850] Data Analysis

[0851] Use the following formula to calculate the inhibition rate (IR) of the tested compound: IR (%) = (1 - ((RLU compound - RLU blank control) / (RLU vehicle control - RLU blank control))) × 100%. Calculate the inhibition rates of compounds at different concentrations in Excel, and then use GraphPad Prism software to plot the inhibition curve and calculate relevant parameters, including the minimum inhibition rate, maximum inhibition rate, and IC 50 。

[0852] Experimental Results

[0853] The results are shown in Table 1.

[0854] Table 1 IC 50 values of the compound's inhibition of AsPC-1 cells

[0855] Compound number <![CDATA[KRAS G12D AsPC-1IC 50 (nM)]]> Hydrochloride of Compound 3 69.3 Compound 4A 6.9 Compound 5A 6.1 Compound 6A 2.99

[0856] Experimental conclusion: The compound of the present invention has excellent anti-proliferation effect on KRAS G12D mutated AsPC-1 cells.

[0857] Experimental Example 2. Proliferation test of AsPC-1 cells

[0858] 1. Purpose

[0859] To screen out compounds that can effectively inhibit the proliferation of KRAS G12D mutated AsPC-1 cells by 3D-CTG method.

[0860] 2. Experimental materials:

[0861] ASPC-1 cells were purchased from ATCC; RPMI-1640 medium was purchased from ATCC; fetal bovine serum was purchased from Ausgenex; 3Dassay kit (3D-CTG) was purchased from Promega; CellCarrier-96 Spheroid ULA / CS was purchased from PE.

[0862] 3. Experimental method:

[0863] 1) ASPC-1 cells were seeded in a transparent 96-well cell culture plate, 195 μL of cell suspension per well, and each well contained 2000 cells;

[0864] 2) The test compound was diluted to 10 mM with 100% DMSO as the first concentration, and then serially diluted 5-fold with a pipette to the 8th concentration, i.e., diluted from 10 mM to 0.13 μM. 2 μL of the serially diluted compound was taken and added to 48 μL of cell culture medium for secondary dilution. After mixing, 5 μL of the secondarily diluted compound was added to the corresponding 195 μL of the cell plate well. The cell plate was placed back in the carbon dioxide incubator and incubated for 7 days. At this time, the compound concentration was 10 μM to 0.128 nM, and the DMSO concentration was 0.1%;

[0865] 3) After the incubation was completed, 100 μL of the cell supernatant was discarded, and 60 μL of 3D-CTG was added to each well. The plate was shaken at 200 rpm at room temperature for 20 minutes; and then placed in the incubator and incubated at room temperature for 1 h.

[0866] 4) 100 μL of the supernatant in the well plate was aspirated and transferred to a 96-well black bottom transparent plate, and luminescence was read in the BMG.

[0867] 4. Data analysis:

[0868] The original data is converted into inhibition rate using the equation Inhibition% = (Ave_H - Sample) / (Ave_H - Ave_L), and the IC 50 value can be obtained by fitting a curve with four parameters (derived from the log(inhibitor) vs. response - Variable slope mode in GraphPad Prism).

[0869] Well H: Reading of the DMSO well

[0870] Well L: Reading of the Medium

[0871] 5 Experimental results

[0872] The results are shown in Table 2.

[0873] Table 2 IC 50 values of the inhibition of compounds on AsPC-1 cells

[0874]

[0875]

[0876] Experimental conclusion: The compound of the present invention has excellent anti-proliferative effect on KRAS G12D mutant AsPC-1 cells.

[0877] Experimental Example 3. Proliferation test of H727 cells

[0878] 1. Purpose

[0879] To screen for compounds that can effectively inhibit the proliferation of KRAS G12V mutant H727 cells by the 3D-CTG method.

[0880] 2. Experimental materials:

[0881] H727 cells were purchased from ATCC; RPMI-1640 medium was purchased from ATCC; fetal bovine serum was purchased from Ausgenex; 3D assay kit (3D-CTG) was purchased from Promega; CellCarrier-96 Spheroid ULA / CS was purchased from PE.

[0882] 3. Experimental method:

[0883] 5) Seed the above cells into a transparent 96-well cell culture plate, 195 μL of cell suspension per well, and each well contains 2000 cells;

[0884] 6) Dilute the compound to be tested with 100% DMSO to 10 mM as the first concentration, and then perform a 5-fold dilution with a pipette to the 8th concentration, that is, dilute from 10 mM to 0.13 μM. Take 2 μL of the gradient-diluted compound and add it to 48 μL of cell culture medium for secondary dilution. After mixing, take 5 μL of the secondary-diluted compound and add it to the corresponding 195 μL of the cell plate well. Place the cell plate back into the carbon dioxide incubator and incubate for 7 days. At this time, the compound concentration is from 10 μM to 0.128 nM, and the DMSO concentration is 0.1%;

[0885] 7) After the incubation is completed, discard 100 μL of the cell supernatant, and add 60 μL of 3D-CTG to each well. Incubate with shaking at 200 rpm at room temperature for 20 minutes; and place it in the incubator and incubate at room temperature for 1 h.

[0886] 8) Aspirate 100 μL of the supernatant in the well plate and transfer it to a 96-well black-bottom transparent plate, and read the luminescence in the BMG.

[0887] 4. Data analysis:

[0888] Use the equation Inhibition% = (Ave_H - Sample) / (Ave_H - Ave_L) to convert the original data into inhibition rate, and the IC50 value can be obtained by curve fitting with four parameters (obtained in the log(inhibitor) vs. response - Variable slope mode in GraphPad Prism).

[0889] Well H: Reading of the DMSO well

[0890] Well L: Reading of the Medium

[0891] 5 Experimental results

[0892] The results are shown in Table 3.

[0893] Table 3 IC of the compound against the inhibition of H727 cells 50 Value

[0894] Compound number <![CDATA[KRAS G12V H727 IC 50 (nM)]]> Compound 5A 45.9 Compound 14 3.51

[0895] Experimental conclusion: The compound of the present invention has excellent anti-proliferation effect on KRAS G12V mutated H727 cells.

[0896] Experimental Example 4. In vitro proliferation test of SW620 cells

[0897] Experimental materials:

[0898] RPMI 1640 medium, penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone. 3D CellTiter-Glo (Cell Viability Chemiluminescence Assay Reagent) reagent was purchased from Promega. SW620 (KRAS G12V mutant) cell line was purchased from ATCC, and Envision multimode plate reader (PerkinElmer).

[0899] Experimental methods:

[0900] Each type of cell was seeded into an ultra-low attachment 96-well U-bottom plate, 80 μL of cell suspension per well, which contained 1000 cells. The cell plate was placed in a carbon dioxide incubator and cultured overnight.

[0901] The test compound was serially diluted 5-fold to 8 concentrations using a multichannel pipette, i.e., diluted from 2 mM to 25.6 nM, and a double replicate experiment was set up. 78 μL of medium was added to the middle plate, and then 2 μL of the gradient-diluted compound per well was transferred to the middle plate according to the corresponding positions. After mixing, 20 μL per well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10 μM to 0.128 nM. The cell plate was placed in a carbon dioxide incubator and cultured for 10 days. Another cell plate was prepared, and the signal value was read on the day of adding the drug as the maximum value (Max value in the following equation) for data analysis.

[0902] 100 μL of the Cell Viability Chemiluminescence Assay Reagent was added to the cell plate, and incubated at room temperature for 30 minutes to stabilize the luminescence signal. The multimode plate reader was used for reading.

[0903] Data analysis:

[0904] The original data was converted into inhibition rate using the equation (Sample - Min) / (Max - Min)×100%, and the IC 50 value could be obtained by four-parameter curve fitting (in the "log(inhibitor) vs. response - Variable slope" mode in GraphPad Prism). Table 4 provides the inhibitory activities of the compounds of the present invention against the proliferation of SW620 cells.

[0905] Table 4: Results of in vitro screening test of the compounds of the present invention

[0906] Compound number <![CDATA[SW620 IC 50 (nM)]]> Compound 5A 27.5 Compound 14 12.6 Compound 25 42.9 Compound 26 37.7 Hydrochloride of Compound 27 44.9 Hydrochloride of Compound 28 10.1 Hydrochloride of Compound 31 98.1 Hydrochloride of Compound 32A 50.9

[0907] Experimental conclusion: The compounds of the present invention have excellent anti-proliferative effects on KRAS G12V mutant SW620 cells.

[0908] Experimental Example 5. In vitro proliferation test of LU99 cells

[0909] Experimental materials:

[0910] RPMI1640 medium, penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone. 3D CellTiter-Glo (cell viability chemiluminescence detection reagent) was purchased from Promega. LU99 (KRAS G12C mutant) cells were purchased from JCRB, and an Envision multi-label analyzer (PerkinElmer).

[0911] Experimental methods:

[0912] Seed each type of cell into an ultra-low attachment 96-well U-bottom plate, 80 μL of cell suspension per well, which contains 1000 cells. Place the cell plate in a carbon dioxide incubator and incubate overnight.

[0913] Dilute the compound to be tested 5-fold in 8 concentrations with a multichannel pipette, that is, dilute from 2 mM to 25.6 nM, and set up a double replicate experiment. Add 78 μL of medium to the middle plate, and then transfer 2 μL of the gradient-diluted compound per well to the middle plate according to the corresponding positions. After mixing, transfer 20 μL per well to the cell plate. The concentration range of the compound transferred to the cell plate is 10 μM to 0.128 nM. Place the cell plate in a carbon dioxide incubator and culture for 10 days. Prepare another cell plate and read the signal value on the day of adding the drug as the maximum value (Max value in the following equation) for data analysis.

[0914] Add 100 μL of the cell viability chemiluminescence detection reagent to the cell plate and incubate at room temperature for 30 minutes to stabilize the luminescence signal. Read the values using a multi-label analyzer.

[0915] Data analysis:

[0916] Convert the raw data into inhibition rate using the equation (Sample - Min) / (Max - Min)×100%, and the IC 50 value can be obtained by four-parameter curve fitting (in the "log(inhibitor) vs. response - Variable slope" mode in GraphPad Prism). Table 5 provides the inhibitory activity of the compounds of the present invention on the proliferation of LU99 cells.

[0917] Table 5: Results of in vitro screening tests of the compounds of the present invention

[0918] Compound number <![CDATA[LU99 IC 50 (nM)]]> Compound 14 2.7

[0919] Experimental conclusion: The compounds of the present invention have excellent anti-proliferative effects on KRAS G12C mutant LU99 cells.

[0920] Experimental Example 6. In vitro proliferation test of MKN-1 cells

[0921] Experimental materials:

[0922] RPMI1640 medium, penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone. 3D CellTiter-Glo (Cell viability chemiluminescence detection reagent) reagent was purchased from Promega. MKN-1 (KRAS WT amplified) cells were purchased from JCRB, and Envision multi-label analyzer (PerkinElmer).

[0923] Experimental method:

[0924] Seed each cell into an ultra-low attachment 96-well U-bottom plate, 80 μL of cell suspension per well, which contains 1000 cells. Place the cell plate in a carbon dioxide incubator and incubate overnight.

[0925] Dilute the test compound 5-fold in 8 concentrations with a multi-channel pipette, i.e., from 2 mM to 25.6 nM, and set up a double-replicate experiment. Add 78 μL of medium to the middle plate, and then transfer 2 μL of the gradient-diluted compound per well to the middle plate according to the corresponding positions. After mixing, transfer 20 μL per well to the cell plate. The concentration range of the compound transferred to the cell plate is 10 μM to 0.128 nM. Place the cell plate in a carbon dioxide incubator and culture for 10 days. Prepare another cell plate and read the signal value on the day of adding the drug as the maximum value (Max value in the following equation) for data analysis.

[0926] Add 100 μL of the cell viability chemiluminescence detection reagent to the cell plate, and incubate at room temperature for 30 minutes to stabilize the luminescence signal. Read the values using a multi-label analyzer.

[0927] Data analysis:

[0928] Convert the raw data into inhibition rate using the equation (Sample - Min) / (Max - Min)×100%, and the IC 50 value can be obtained by four-parameter curve fitting (using the "log(inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 6 provides the inhibitory activity of the compounds of the present invention against the proliferation of MKN-1 cells.

[0929] Table 6: Results of in vitro screening test of the compounds of the present invention

[0930] Compound number <![CDATA[MKN-1IC 50 (nM)]]> Compound 14 3.6

[0931] Note: / represents not detected.

[0932] Experimental conclusion: The compound of the present invention has excellent anti-proliferative effect on KRAS WT amplified MKN-1 cells.

[0933] Experimental Example 7. In vivo pharmacodynamic study

[0934] Experimental method:

[0935] A subcutaneous xenograft tumor Balb / c nude mouse model of human colon cancer GP2D cells was established. 0.2 mL (2×10 6 cells) of GP2D cells (added with Matrigel, volume ratio 1:1) were subcutaneously inoculated into the right back of each mouse. When the average tumor volume reached 270 mm 3 , grouping and drug administration were started, with 6 or 4 mice in each group. On the experimental day, animals were given corresponding drugs according to the group. The first group G1 was set as the vehicle group, and 5% DMSO + 95% (10% HP-β-CD) was given by gavage alone. The second group G2 was given the hydrochloride salt of compound 14 (vehicle: 5% DMSO + 95% (10% HP-β-CD)), and the dosing dose and regimen are shown in Table 7.

[0936] Table 7 Study on the effect of the test substance on the tumor size of animals in the human colon cancer GP2D mouse xenograft tumor model

[0937]

[0938]

[0939] Note: PO means oral administration, QD means once a day, and BID means twice a day.

[0940] During the experiment, the body weight and tumor size of the animals were measured twice a week, and the clinical symptoms of the animals were observed and recorded every day. Each drug administration was based on the animal body weight measured most recently.

[0941] The tumor was measured with a digital vernier caliper to determine the length (a) and width (b). The formula for calculating the tumor volume (Tumor volume, TV) is: TV = a×b 2 / 2.

[0942] Experimental results:

[0943] The hydrochloride salt of compound 14 has a significant inhibitory effect on the human colon cancer GP2D mouse xenograft tumor. After 28 days of drug administration, in the second group G2 (150 mg / kg, PO, BID) on the 28th day, the tumor volume inhibition rate TGI (%) was 97.2. The detailed results are shown in Table 8.

[0944] Table 8 Effect of the test substance on the tumor size of animals in the human colon cancer GP2D mouse xenograft tumor model

[0945]

[0946] Note: N / A means not detected.

[0947] Experimental conclusion: In terms of in vivo pharmacodynamic effects, the compound of the present invention shows good tumor inhibitory effects in the GP2D cell line.

[0948] Experimental Example 8. In vivo pharmacodynamic study

[0949] Experimental method:

[0950] A subcutaneous xenograft tumor Balb / c nude mouse model of human pancreatic cancer Panc0403 cells was established. 0.2 mL (5×10 6 cells) of Panc0403 cells were subcutaneously inoculated on the right back of each mouse. When the average tumor volume reached 190 mm 3 , grouping and drug administration were started, with 6 or 4 mice in each group. On the experimental day, animals were given the corresponding drugs according to the groups. The first group G1 was set as the solvent group, and 5% DMSO + 95% (10% HP-β-CD) was given by gavage alone. The second group G2 was given compound 4A (solvent: 5% DMSO + 95% (10% HP-β-CD)), and the dosing dose and regimen are shown in Table 9.

[0951] Table 9 Study on the effect of the test substance on the tumor size of animals in the human pancreatic cancer Panc0403 mouse xenograft tumor model

[0952]

[0953] Note: PO means oral administration, QD means once a day, and BID means twice a day.

[0954] During the experiment, the body weight and tumor size of the animals were measured twice a week. At the same time, the clinical symptoms of the animals were observed and recorded every day, and each drug administration was based on the animal body weight measured most recently.

[0955] The length (a) and width (b) of the tumor were measured with a digital vernier caliper, and the calculation formula for the tumor volume (Tumor volume, TV) was: TV = a×b 2 / 2.

[0956] Experimental results:

[0957] Compound 4A has a significant inhibitory effect on the human pancreatic cancer Panc0403 mouse xenograft tumor. After 28 days of drug administration, in the second group G2 (150 mg / kg, PO, BID) on the 28th day, the tumor volume inhibition rate TGI (%) was 113.7. The detailed results are shown in Table 10.

[0958] Table 10 Effects of the Test Substances on Tumor Size in a Mouse Xenograft Model of Human Pancreatic Cancer Panc0403

[0959]

[0960]

[0961] Note: N / A indicates not detected.

[0962] Experimental conclusion: In terms of in vivo pharmacodynamic effects, the compound of the present invention exhibits good tumor inhibitory effects in the Panc0403 cell line.

[0963] In summary, the present invention includes but is not limited to the following items:

[0964] 1. A compound of formula (VII) or a pharmaceutically acceptable salt thereof,

[0965]

[0966] wherein,

[0967] Ring B is selected from 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl, and the 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl are each independently optionally substituted with 1, 2, 3, 4, 5, or 6 R e substituents, ring A is selected from

[0968] Alternatively, ring B is selected from Ring A is selected from Ring C is a 5- to 6-membered nitrogen-containing heteroaryl;

[0969] Each R1 is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-3 alkyl-O-C 1-3 alkyl, -SH, -C(=O)-NR a R b 、-C(=O)-R c 、 C 3-6 cycloalkyl and 5- to 6-membered heteroaryl, and the C 1-3 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C1-3 Alkyl-O-C 1-3 Alkyl, C 3-6 The cycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0970] Alternatively, R1 on two adjacent atoms and the atoms to which they are attached form a 5-6 membered heteroalkenyl, and the 5-6 membered heteroalkenyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R;

[0971] R2 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, and the phenyl, naphthyl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4 or 5 R d substituted;

[0972] R6 and R7 are each independently selected from H, C 1-3 alkyl, F, Cl, Br and I;

[0973] T1 is selected from CH2 and O;

[0974] T2 is selected from O and S;

[0975] R a is selected from H and C 1-3 alkyl, and the C 1-3 alkyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R0;

[0976] R b is selected from H and C 1-3 alkyl, and the C 1-3 alkyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R0;

[0977] R c is selected from H, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, and the C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0978] Each R d is each independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted with 1, 2, 3, 4 or 5 R0;

[0979] Each R e is each independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0980] Each R is independently selected from F, Cl, Br, I, and C 1-3 alkyl;

[0981] Each R0 is independently selected from D, F, Cl, Br, and I;

[0982] m is selected from 0, 1, 2, 3, 4, and 5;

[0983] n is selected from 0, 1, and 2.

[0984] 2. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from F and CH3.

[0985] 3. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R a is selected from H, CH3, CD3, and CH(CH3)2.

[0986] 4. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R b is selected from H, CH3, CD3, and CH(CH3)2.

[0987] 5. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R c is selected from H, cyclopropyl, pyrrolidinyl, and morpholinyl; or, R c is selected from pyrrolidinyl and morpholinyl.

[0988] 6. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein each R d is independently selected from F, Cl, NH2, OH, CH3, CF3, CH2CH3, -C≡CH, and -C≡CCH3.

[0989] 7. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein each R e is independently selected from H and F.

[0990] 8. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from F, Cl, Br, OH, NH2, CN, CH3, CH(CH3)2, cyclopropyl, CF3,

[0991] 9. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from

[0992] 10. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are independently selected from H.

[0993] 11. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein ring C is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl and pyrimidinyl; or, ring C is selected from pyrazolyl and imidazolyl.

[0994] 12. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from and 5- to 12-membered heteroalkenyl, and the and 5- to 12-membered heteroalkenyl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R e substituents; or; ring B is selected from

[0995] 13. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from Ring A is selected from

[0996] 14. The compound according to item 13 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from Structural unit is selected from

[0997] 15. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R1 on two adjacent atoms forms a 5- to 6-membered heteroalkenyl with the atoms to which they are attached, and the 5- to 6-membered heteroalkenyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R substituents, such that the structural unit is selected from

[0998] 16. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from Ring A is selected from

[0999] 17. The compound according to item 16 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from Structural unit is selected from

[1000] 18. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein T2 is selected from O.

[1001] 19. The compound or its pharmaceutically acceptable salt according to any one of items 1 to 18, wherein the compound is selected from formula (P-1),

[1002]

[1003] wherein,

[1004] ring B is selected from and 5- to 12-membered heteroalkenyl and said and 5- to 12-membered heteroalkenyl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R e substituents;

[1005] R1, R2, R6, R7, each R e , ring C and m are as defined in items 1 to 18;

[1006] The carbon atom with an asterisk is a chiral carbon atom and exists in the form of a single (R) or (S) enantiomer or an enantiomer-rich form.

[1007] 20. The compound or its pharmaceutically acceptable salt according to item 19, wherein the compound is selected from formula (P-2),

[1008]

[1009] wherein,

[1010] ring B is selected from said are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R e substituents;

[1011] p is selected from 1, 2, 3, 4 or 5;

[1012] R1, each R e , each R d and m are as defined in item 19;

[1013] The carbon atom with an asterisk is a chiral carbon atom and exists in the form of a single (R) or (S) enantiomer or an enantiomer-rich form.

[1014] 21. Use of the compound or its pharmaceutically acceptable salt according to any one of items 1 to 20 in the preparation of a medicament for treating pan-KRAS-related diseases.

Claims

1. A compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein, Ring B is selected from 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl, wherein the 5- to 12-membered heteroalkenyl and 7- to 12-membered tricyclic heteroalkyl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 R e substituents, and ring A is selected from Alternatively, ring B is selected from Ring A is selected from ring C is selected from 5- to 6-membered nitrogen-containing heteroaryl; Each R1 is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-3 alkyl-O-C 1-3 alkyl, -SH, -C(=O)-NR a R b , -C(=O)-R c , C 3-6 cycloalkyl and 5-6 membered heteroaryl, wherein the C 1-3 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-3 alkyl-O-C 1-3 alkyl, C 3-6 cycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R; alternatively, R1 on two adjacent atoms and the atoms to which they are attached form a 5- to 6-membered heteroalkenyl, and the 5- to 6-membered heteroalkenyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R; R2 is selected from phenyl, naphthyl and 5- to 10-membered heteroaryl, and the phenyl, naphthyl and 5- to 10-membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4 or 5 Rs d substituted; R6 and R7 are each independently selected from H, C 1-3 alkyl, F, Cl, Br, and I; T1 is selected from CH2 and O; T2 is selected from O and S; R a selected from H and C 1-3 alkyl groups, said C 1-3 alkyl groups are each independently optionally substituted by 1, 2, 3, 4 or 5 R0; R b selected from H and C 1-3 alkyl, wherein the C 1-3 alkyls are each independently optionally substituted with 1, 2, 3, 4 or 5 R0s; R c selected from H, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R; Each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl and C 2-4 alkynyl, and the C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted with 1, 2, 3, 4 or 5 R0; Each R e is independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3; Each R is independently selected from F, Cl, Br, I, and C 1-3 alkyl; each R0 is independently selected from D, F, Cl, Br and I; m is selected from 0, 1, 2, 3, 4 and 5; n is selected from 0, 1 and 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R is selected from F and CH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R a Selected from H, CH3, CD3, and CH(CH3)2.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R b Selected from H, CH3, CD3, and CH(CH3)2.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R c selected from H, cyclopropyl, pyrrolidinyl, and morpholinyl; Alternatively, R c is selected from pyrrolidinyl and morpholinyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Each R d is independently selected from F, Cl, NH2, OH, CH3, CF3, CH2CH3, -C≡CH, and -C≡CCH3.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Each R e is independently selected from H and F respectively.

8. A compound as shown below or a pharmaceutically acceptable salt thereof, 9. The compound or a pharmaceutically acceptable salt thereof according to claim 8, which is selected from, 10. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9 in the preparation of a medicament for treating pan-KRAS-related diseases.

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