6-carbamate substituted heteroaromatic ring derivatives

Abstract

Disclosed are 6-aminocarbamate substituted heteroaromatic ring derivatives and a preparation method thereof, in particular to a compound shown in formula (II) and pharmaceutically acceptable salts thereof.

Description

[0001] This application claims the following priority:

[0002] CN202110327907.9, March 26, 2021;

[0003] CN202210068496.0, January 20, 2022. Technical Field

[0004] This invention relates to a new class of 6-carbamate-substituted heterocyclic derivatives and their preparation methods, specifically to compounds represented by formula (II) and their pharmaceutically acceptable salts. Background Technology

[0005] RAS proteins are guanine nucleoside-binding proteins with guanosine triphosphate hydrolase (GTPase) activity, mainly comprising three isoforms: KRAS, NRAS, and HRAS. As a binary molecular switch controlling the GDP / GTP cycle, RAS proteins can cycle between an active GTP-bound state (GTP-RAS) and an inactive GDP-bound state (GDP-RAS). This cycle plays a crucial regulatory role in cells, closely related to cell proliferation, survival, metabolism, migration, immunity, and growth.

[0006] Studies have shown that RAS gene mutations are present in approximately 15% of tumor cases. Oncogenic RAS mutations simultaneously inhibit intrinsic GTPase activity and GAP-activated GTPase activity, keeping the RAS cycle in a perpetually "on" RAS-GTP state, leading to continuous activation of downstream signaling pathways and ultimately cancer. Approximately 85% of RAS mutations are concentrated in the KRAS (Andrew et al., CancerCell, 2014, 25:272-281). Therefore, inhibiting KRAS mutants and the abnormal activation of downstream pathways has become a popular target for cancer treatment.

[0007] SOS1 (Son of Sevenless 1) is a type of GEF that regulates the RAS protein GDP / GTP cycle. After cell surface receptors are activated and bind to intracellular Grb2, Grb2 recruits SOS1 to the cell membrane. SOS1 then catalyzes RAS-GDP / GTP exchange, thereby activating downstream signaling pathways. Small molecule SOS1 inhibitors binding to the catalytic site can block the binding of SOS1 to RAS proteins, effectively reducing the abnormal activation of downstream RAS signaling pathways in cancer cells and thus playing a therapeutic role in cancer treatment. Currently, only Boehringer Ingelheim's BI-1701963 (WO2018115380, WO2019122129) small molecule SOS1 inhibitors have entered Phase I clinical trials. Bayer's SOS1 inhibitors (WO2018172250, WO2019201848) are still in the preclinical research stage. Recent studies suggest that drugs targeting the RAS pathway are prone to resistance in clinical applications. Part of this resistance is attributed to the negative feedback activation of the upstream RAS pathway following the inhibition of ERK phosphorylation. This negative feedback regulatory mechanism is closely related to SOS1. Therefore, the development of small molecule inhibitors of SOS1 holds great promise for future applications.

[0008] AMG-510 is a potent, orally bioavailable, selective KRAS G12C covalent inhibitor developed by Amgen for the treatment of locally advanced or metastatic non-small cell lung cancer harboring KRAS G12C mutations. Its structure is shown below:

[0009] Summary of the Invention

[0010] This invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0011]

[0012] in,

[0013] R1 and R2 are independently selected from H and C, respectively. 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. a Replaced;

[0014] Alternatively, R1, R2, and the nitrogen atom attached to them together form a 3-12 membered heterocyclic alkyl group, wherein the 3-12 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3, or 4 R atoms. b replace;

[0015] R3 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino groups are independently and optionally converted by 1, 2, 3 or 4 R groups. c replace;

[0016] R4 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)-OC 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)-OC 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic alkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. c replace;

[0017] R5 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino groups are independently and optionally converted by 1, 2, 3 or 4 R groups. c replace;

[0018] Alternatively, R4, R5, and the carbon atoms bonded to them together form... in Choose from 1, 2, 3, or 4 Rs d Replacement; T1 is selected from CR6 and N;

[0019] R6 is selected from -OCH3, -CN and -S(=O)2-CH3;

[0020] R aEach of the following is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, =O, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)-OC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, -OC 6-10 Aryl and -O-5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)-OC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, -OC 6-10 The aryl and -O-5-10 heteroaryl groups are each independently and optionally substituted by 1, 2, 3 or 4 R groups;

[0021] R b Each of the following is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, =O, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)-OC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, -OC 6-10 Aryl and -O-5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)-OC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, -OC 6-10 The aryl and -O-5-10 heteroaryl groups are each independently and optionally substituted by 1, 2, 3 or 4 R groups;

[0022] R c Each of the following is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, -COOH, =O, -C(=O)H, -C(=O)-NH2, C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3The alkoxy group and the 5-6 membered heterocyclic alkyl group are each independently and optionally substituted with 1, 2, 3 or 4 R groups;

[0023] R d The elements are independently selected from F, Cl, Br, I, -OH, -NH2, -CN, -COOH, =O, -C(=O)H, -C(=O)-NH2, and C, respectively. 1-3 Alkyl group; R is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, -COOH, =O, -C(=O)H, -C(=O)-NH2 and C. 1-3 Alkyl; in the 5-6 membered heterocyclic alkyl, 3-10 membered heterocyclic alkyl, 3-12 membered heterocyclic alkyl, 5-10 membered heteroaryl and -O-5-10 membered heteroaryl, "hetero" means 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and -N- respectively.

[0024] This invention provides compounds of formula (I-2) or pharmaceutically acceptable salts thereof.

[0025]

[0026] in,

[0027] R1, R2, and the nitrogen atom attached to them together form a 6-10 membered heterocyclic alkyl group, wherein the 6-10 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3, or 4 R atoms. b replace;

[0028] R3 is selected from H, F, Cl, Br, I, -OH, and -NH2;

[0029] R4 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. c replace;

[0030] R5 is selected from H, F, Cl, Br, I, and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. c replace;

[0031] Alternatively, R4, R5, and the carbon atoms bonded to them together form... in Choose from 1, 2, 3, or 4 Rs d Replace; R b Each of the following is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, =O, and C. 1-3 Alkyl, C 1-3Alkylamino and 4-5 membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3 The alkylamino group and the 4-5 membered heterocyclic alkyl group are each independently and optionally substituted with 1, 2, 3 or 4 Rs;

[0032] R c The elements are independently selected from F, Cl, Br, I, -OH, -NH2, -CN, -COOH, -C(=O)H, -C(=O)-NH2, and

[0033] R d They are independently selected from F, Cl, Br, I, -OH, -NH2, -CN, -COOH, -C(=O)H and -C(=O)-NH2, respectively;

[0034] In the 6-10 membered heterocyclic alkyl and 4-5 membered heterocyclic alkyl, "hetero" means 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S- and -N-.

[0035] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (Ⅱ-1):

[0036]

[0037] in,

[0038] T1, R1, R2, R3, R4 and R5 are as defined in this invention;

[0039] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

[0040] In some embodiments of the present invention, the R mentioned above is independently selected from F, Cl, Br and =O, and other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the above-mentioned R a Each element is independently selected from F, Cl, Br, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and -C(=O)-OC 1-3 Alkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and -C(=O)-OC 1-3 Alkyl groups may be independently and optionally substituted with 1, 2, 3 or 4 Rs, and Rs and other variables are as defined in this invention.

[0042] In some embodiments of the present invention, the above-mentioned Ra The elements are independently selected from F, Cl, Br, -OH, -NH2, -CN, -CH3 and -OCH3, wherein -CH3 and -OCH3 are independently and optionally replaced by 1, 2, 3 or 4 Rs, and R and other variables are as defined in this invention.

[0043] In some embodiments of the present invention, R1 and R2 are independently selected from H and C, respectively. 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. a Replaced by, R a Other variables are as defined in this invention.

[0044] In some embodiments of the present invention, the above-mentioned R b Each of the following is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, =O, and C. 1-3 Alkyl, C 1-3 Alkylamino and 3-6 membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3 The alkylamino group and the 3-6 membered heterocyclic alkyl group are each independently and optionally substituted with 1, 2, 3 or 4 Rs, and Rs and other variables are as defined in this invention.

[0045] In some embodiments of the present invention, the above-mentioned R b Each of the following is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, =O, and C. 1-3 Alkyl, C 1-3 Alkylamino and 4-membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3 The alkylamino group and the four-membered heterocyclic alkyl group are each independently and optionally substituted with one, two, three or four Rs, and the Rs and other variables are as defined in this invention.

[0046] In some embodiments of the present invention, the above-mentioned R b Each is independently selected from F, Cl, Br, -NH2, -CH3, -CH2-CH3, The -CH3, -CH2-CH3, Each R can be independently and arbitrarily replaced by 1, 2, 3 or 4 Rs, and R and other variables are as defined in this invention.

[0047] In some embodiments of the present invention, the above-mentioned R b Each is independently selected from F, Cl, Br, -NH2, -CH3, -CH2-CH3, Other variables are as defined in this invention.

[0048] In some embodiments of the present invention, the above-mentioned R cEach element is independently selected from F, Cl, Br, -OH, -OCH3, and Other variables are as defined in this invention.

[0049] In some embodiments of the present invention, the above-mentioned R c Each of the following is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, -COOH, =O, -C(=O)H, -C(=O)-NH2, C 1-3 Alkyl, C 1-3 alkoxy and 5-membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group and the 5-membered heterocyclic alkyl group are each independently and optionally substituted with 1, 2, 3 or 4 Rs, and Rs and other variables are as defined in this invention.

[0050] In some embodiments of the present invention, the above-mentioned R c Selected independently from F, -OH and Other variables are as defined in this invention.

[0051] In some embodiments of the present invention, the above-mentioned R d The variables are independently selected from F, Cl, and Br, respectively, and other variables are as defined in this invention.

[0052] In some embodiments of the present invention, the above-mentioned R d Each variable is independently selected from F, and other variables are as defined in this invention.

[0053] In some embodiments of the present invention, R3 is selected from H, F, Cl, Br and -NH2, and other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, R3 is selected from H and -NH2, and other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, R4 is selected from H, -CN, and C. 1-4 Alkyl, wherein the C 1-4 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. c Replace, R c Other variables are as defined in this invention.

[0056] In some embodiments of the present invention, the R4 is selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH(CH3)2, wherein -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH(CH3)2 are each independently and optionally selected by 1, 2, 3, or 4 Rs. c Replace, R c Other variables are as defined in this invention.

[0057] In some embodiments of the present invention, R4 is selected from H, F, Cl, Br, -CN, R c Other variables are as defined in this invention.

[0058] In some embodiments of the present invention, R4 is selected from H, F, Cl, Br, -CN, Other variables are as defined in this invention.

[0059] In some embodiments of the present invention, R5 is selected from H, F, Cl, Br and -CH3, and other variables are as defined in the present invention.

[0060] In some embodiments of the present invention, R5 is selected from H, F and -CH3, and other variables are as defined in the present invention.

[0061] In some embodiments of the present invention, R6 is selected from -OCH3, and other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, m is selected from 0, 1 and 2, and other variables are as defined in the present invention.

[0063] In some embodiments of the present invention, the aforementioned R1, R2, and the nitrogen atom attached thereto together form a 5-11 membered heterocyclic alkyl group, wherein the 5-11 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3, or 4 R atoms. b Replace, R b Other variables are as defined in this invention.

[0064] In some embodiments of the present invention, the above-mentioned structural unit Selected from The above Each of the 1, 2, 3, or 4 R's can be independently selected. b Replace, R b Other variables are as defined in this invention.

[0065] In some embodiments of the present invention, the above-mentioned structural unit Selected from The above Each of the 1, 2, 3, or 4 R's can be independently selected. b Replace, R b Other variables are as defined in this invention.

[0066] In some embodiments of the present invention, the above-mentioned structural unit Selected from R b Other variables are as defined in this invention.

[0067] In some embodiments of the present invention, the above-mentioned structural unit Selected from R b Other variables are as defined in this invention.

[0068] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0069] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0070] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0071] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0072] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (II-2) or (II-3):

[0073]

[0074] Wherein, R1, R2, R3, R4, R5 and R6 are as defined in this invention.

[0075] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (I-2):

[0076]

[0077] Wherein, R1, R2, R3, R4 and R5 are as defined in this invention.

[0078] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (I-3):

[0079]

[0080] Wherein, R1, R2, R3, R4 and R5 are as defined in this invention;

[0081] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

[0082] In some embodiments of the present invention, the above-mentioned compounds have the structures shown in formula (I-4), (I-5), or (I-6):

[0083]

[0084] in,

[0085] T and V are independently selected from CH2, NH and O, respectively;

[0086] m is selected from 0, 1, 2, 3, and 4;

[0087] n, p, q, r, and s are independently selected from 0, 1, and 2, respectively;

[0088] And p + q ≤ 3;

[0089] W is selected from NH, -CH2-CH2- and -O-CH2-;

[0090] Y is selected from N and CH;

[0091] R3, R4, R5 and R b As defined in this invention.

[0092] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (Ⅲ):

[0093]

[0094] in,

[0095] T is selected from CH2, NH and O;

[0096] R b Selected from F, Cl, Br, I, -OH, -NH2, -CN, =O, C 1-3 Alkyl, C 1-3 Alkylamino and 3-6 membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3 The alkylamino group and the 3-6 membered heterocyclic alkyl group are each independently and optionally substituted with 1, 2, 3 or 4 Rs;

[0097] R6 is selected from -OCH3, -CN and -S(=O)2-CH3;

[0098] R7 and R8 are independently selected from H, F, Cl, Br, I, -OH, -NH2, -CN, =O and C, respectively. 1-3 alkyl;

[0099] Alternatively, R7, R8, and the carbon atoms bonded to them together form C. 3-4 Cycloalkyl groups;

[0100] m is selected from 0, 1, 2, 3, and 4;

[0101] n is selected from 0, 1, and 2;

[0102] R, R3, R4 and R5 are as defined in this invention.

[0103] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (Ⅲ-1):

[0104]

[0105] in,

[0106] T is selected from CH2, NH and O;

[0107] R b Selected from F, Cl, Br, I, -OH, -NH2, -CN, =O, C 1-3 Alkyl, C 1-3 Alkylamino and 3-6 membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3 The alkylamino group and the 3-6 membered heterocyclic alkyl group are each independently and optionally substituted with 1, 2, 3 or 4 Rs;

[0108] R7 and R8 are independently selected from H, F, Cl, Br, I, -OH, -NH2, -CN, =O and C, respectively. 1-3 alkyl;

[0109] Alternatively, R7, R8, and the carbon atoms bonded to them together form C. 3-4 Cycloalkyl groups;

[0110] m is selected from 0, 1, 2, 3, and 4;

[0111] n is selected from 0, 1, and 2;

[0112] R, R3, R4 and R5 are as defined in this invention.

[0113] In some embodiments of the present invention, the above-mentioned compounds have the structures shown in formulas (Ⅲ-2) and (Ⅲ-3):

[0114]

[0115] in,

[0116] T, m, n, R b R3, R4, R5, R7 and R8 are as defined in this invention.

[0117] In some embodiments of the present invention, the above-mentioned compounds have the structure shown in formula (Ⅲ-4):

[0118]

[0119] in,

[0120] T1 is selected from CHR b NH, NR b and O;

[0121] R b Selected from F, Cl, Br, I, -OH, -NH2, -CN, =O, C 1-3 Alkyl, C 1-3 Alkylamino and 4-5 membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3 The alkylamino group and the 4-5 membered heterocyclic alkyl group are each independently and optionally substituted with 1, 2, 3 or 4 Rs;

[0122] R7 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, =O, and C. 1-3 alkyl;

[0123] n is selected from 1 and 2;

[0124] R, R3, R4 and R5 are as defined in this invention.

[0125] In some embodiments of the present invention, the above-mentioned compounds have the structure shown in formula (Ⅲ-5) or (Ⅲ-6):

[0126]

[0127] Wherein, T1, n, R3, R4, R5 and R7 are as defined in this invention.

[0128] In some embodiments of the present invention, R7 and R8 are independently selected from H, F, Cl, Br, I, -OH, -NH2, -CN, -CH3 and -CH2-CH3, respectively, and other variables are as defined in the present invention.

[0129] In some embodiments of the present invention, R7 and R8 are independently selected from H and -CH3, respectively, and other variables are as defined in the present invention.

[0130] In some embodiments of the present invention, R7 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, -CH3 and -CH2-CH3, and other variables are as defined in the present invention.

[0131] In some embodiments of the present invention, R7 is selected from H and -CH3, and other variables are as defined in the present invention.

[0132] In some embodiments of the present invention, R8 is selected from H, and other variables are as defined in the present invention.

[0133] In some embodiments of the present invention, the aforementioned R7, R8, and the carbon atoms connected to them together form a cyclopropyl group.

[0134] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I-7), (I-8), (I-9) or (III-1A):

[0135]

[0136] Among them, T, V, W, Y, m, n, p, q, r, s, R3, R4, R5, R b R7 and R8 are as defined in this invention;

[0137] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

[0138] In some embodiments of the present invention, the above-mentioned compounds have the structures shown in formula (I-10), (I-11), or (I-12):

[0139]

[0140] Among them, T, V, W, Y, m, n, p, q, r, s, R3, R4, R5 and R b As defined in this invention.

[0141] Some solutions in this invention are derived from arbitrary combinations of the above-mentioned variables.

[0142] The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0143]

[0144]

[0145] The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0146]

[0147]

[0148]

[0149]

[0150] The present invention also provides the above-described compounds or pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts are hydrochloride salts.

[0151] The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating KRAS-mutant solid tumors.

[0152] Technical effect

[0153] The compounds of this invention exhibit good KRAS(G12C)-SOS1 binding inhibitory activity, as well as significant inhibitory activity against DLD-1 cells and KRAS(G12C) mutant H358 cells, and good pharmacokinetic properties, thus achieving excellent activity in inhibiting tumor growth.

[0154] Definitions and Explanations

[0155] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears in this document, it is intended to refer to the corresponding product or its active ingredient.

[0156] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0157] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this 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. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this 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. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0158] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0159] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0160] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0161] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0162] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0163] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0164] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and straight dashed key

[0165] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0166] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the 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%.

[0167] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0168] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0169] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0170] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0171] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent. Substituents can include deuterium and hydrogen variants, provided the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.

[0172] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0173] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0174] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0175] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0176] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, the structure is actually A. When the listed substituents do not specify which atom they are attached to the substituted group through, such substituents can be bonded to any of their atoms. For example, a pyridinium group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0177] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0178] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the diagram indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0179] When the chemical bond of a substituent intersects the chemical bonds of two atoms on the linking ring, it means that the substituent can bond with any atom on the ring. When the atom to which a substituent is attached is not specified, the substituent can bond with any atom. If the atom to which the substituent is attached is in a bicyclic or tricyclic system, it means that the substituent can bond with any atom in any ring of that system. Combinations of substituents and / or variables are only permitted if the combination produces a stable compound. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl or cyclopentyl group.

[0180] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “5-7 elemental ring” refers to a “ring” with 5-7 atoms arranged around it.

[0181] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0182] Unless otherwise specified, the term "C" 1-4"alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.

[0183] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0184] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0185] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0186] Unless otherwise specified, the term "C" 1-6"Alkylamino" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-6 Alkylamino groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylamino groups, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0187] Unless otherwise specified, the term "C" 1-3 "Alkylamino" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-3 Alkylamino groups include C 1-2 C3 and C2 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0188] Unless otherwise specified, the heterocyclic alkyl and heteroaryl groups refer to specific groups containing heteroatoms or heteroatomic groups, including but not limited to N, O, S, NH, substituted or protected -N(H)-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=S)-, C(=O)O-, -C(=O)N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-, wherein nitrogen and sulfur atoms are optionally oxidized and nitrogen heteroatoms are optionally quaternized. For ring systems, heteroatoms or heteroatomic groups can be located inside or outside the ring system (e.g., cyclopropyl sulfone, cyclopropyl acyl). Heterocyclic alkyl and heteroaryl groups are connected to the rest of the molecule via carbon atoms, meaning the heteroatom can be located at any position of the group (except where the group is attached to the rest of the molecule). Heterocyclic alkyl and heteroaryl groups are connected to the rest of the molecule via heteroatoms, meaning the heteroatom is located at the position where the group is attached to the rest of the molecule. Heterocyclic alkyl heterogroups and heteroaryl heterogroups are connected to the rest of the molecule via heteroatoms, where the heteroatom can be located at any position of the group (including the position where the group is attached to the rest of the molecule).

[0189] Unless otherwise specified, "C 3-12"Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. The C 3-12 Cycloalkyl groups include C 3-10 C 3-10 C 3-6 C 3-5 C 4-10 C 4-8 C 4-6 C 4-5 C 5-8 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornelalkyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, etc.

[0190] Unless otherwise specified, "C 3-10 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, including monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. The C 3-10 Cycloalkyl groups include C 3-8 C 3-6 C 3-5 C 4-10 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 etc.; it can be monovalent, divalent, or polyvalent. C 3-10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornelalkyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, etc.

[0191] Unless otherwise specified, "C 3-4 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 4 carbon atoms, which is a monocyclic system. 3-5 Cycloalkyl groups include C3 and C4 cycloalkyl groups; they can be monovalent, divalent, or polyvalent. 3-4 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, etc.

[0192] Unless otherwise specified, the term "3-12 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated cyclic group consisting of 3 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 remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)). p (where p is 1 or 2). The 3-12 membered heterocyclic alkyl groups include monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. Furthermore, regarding the "3-12 membered heterocyclic alkyl group," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 3-12 membered heterocyclic alkyl groups include 3-10, 3-8, 3-6, 3-5, 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyl groups, etc. Examples of 3-12 membered heterocyclic alkyl groups include, but are not limited to, cycloazoalkyl, cyclooxyethylene, cyclothioalkyl, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl or dioxaneheptyl, etc.

[0193] Unless otherwise specified, the term "3-10 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated cyclic group consisting of 3 to 10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)). p(where p is 1 or 2). The 3-10 membered heterocyclic alkyl groups include monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. Furthermore, regarding the "3-10 membered heterocyclic alkyl group," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 3-10 membered heterocyclic alkyl groups include 3-8, 3-6, 3-5, 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyl groups, etc. Examples of 3-10 membered heterocyclic alkyl groups include, but are not limited to, cycloazoalkyl, cyclooxyethylene, cyclothioalkyl, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl or dioxaneheptyl, etc.

[0194] Unless otherwise specified, the term "5-11 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated cyclic group consisting of 5 to 11 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)). p (where p is 1 or 2). The 5-11 membered heterocyclic alkyl groups include monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. Furthermore, regarding the "5-11 membered heterocyclic alkyl group," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 5-11 membered heterocyclic alkyl groups include 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 6-7, 6-8, 6-9, 6-10, 6-11, 5, 6, and 7 membered heterocyclic alkyl groups, etc. Examples of 5-11 membered heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl or dioxaneheptyl, etc.

[0195] Unless otherwise specified, the term "6-10 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated cyclic group consisting of 6 to 10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)). p (where p is 1 or 2). The 6-10 membered heterocyclic alkyl groups include monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. Furthermore, regarding the "6-10 membered heterocyclic alkyl group," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 6-10 membered heterocyclic alkyl groups include 6-membered, 6-7-membered, 6-8-membered, 6-9-membered, 5-10-membered, 7-membered, 7-8-membered, 7-9-membered, 7-10-membered, 8-membered, 8-9-membered, 8-10-membered, 9-membered, and 10-membered heterocyclic alkyl groups, etc. Examples of 6-10 membered heterocyclic alkyl groups include, but are not limited to, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazine (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, or dioxaneheptyl, etc.

[0196] Unless otherwise specified, the term "3-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 3 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 remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "3-6 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl and the rest of the molecule. The 3-6 membered heterocyclic alkyl includes 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyls, etc. Examples of 3-6 membered heterocyclic alkyl groups include, but are not limited to, cycloazoalkyl, cyclooxyethylene, cyclothioalkyl, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0197] Unless otherwise specified, the term "5-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting 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 remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C (=O), NO, and S (=O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. Furthermore, regarding the "5-6 membered heterocyclic alkyl", the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 5-6 membered heterocyclic alkyl group includes 5-membered and 6-membered heterocyclic alkyl groups. Examples of 5-6 membered heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (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.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, etc.

[0198] Unless otherwise specified, the term "4-5 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated monocyclic group consisting of 4 to 5 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C (=O), NO, and S (=O)). p (where p is 1 or 2). Furthermore, with respect to the "4-5 membered heterocyclic alkyl", the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 4-5 membered heterocyclic alkyl group includes both 4-membered and 5-membered heterocyclic alkyl groups. Examples of 4-5 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxobutyl, thiobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.).

[0199] Unless otherwise specified, the term "4-membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated monocyclic group consisting of four ring atoms, wherein one, two, three, or four ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C (=O), NO, and S (=O)). p(where p is 1 or 2). Furthermore, with respect to this "4-membered heterocyclic alkyl group," the heteroatom can occupy the bonding position between the heterocyclic alkyl group and the rest of the molecule. Examples of 4-membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxobutyl, and thiobutyl.

[0200] Unless otherwise specified, the term "C" in this invention refers to... 6-10 "Aromatic ring" and "C" 6-10 "Aryl" can be used interchangeably; the term "C" is used interchangeably. 6-10 "Aromatic ring" or "C" 6-10 "Aryl" refers to a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated π-electron system. It can be a monocyclic, fused bicyclic, or fused tricyclic system, where each ring is aromatic. It can be monovalent, divalent, or polyvalent. 6-10 Aryl groups include C 6-9 C9, C 10 And C6 aryl, etc. C 6-10 Examples of aryl groups include, but are not limited to, phenyl and naphthyl groups (including 1-naphthyl and 2-naphthyl groups).

[0201] Unless otherwise specified, the terms "5-10-membered heteroaryl" and "5-10-membered heteroaryl" are used interchangeably in this invention. The term "5-10-membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder 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 may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). 5-10-membered heteroaryl groups can be attached to the rest of the molecule via heteroatoms or carbon atoms. These 5-10-membered heteroaryl groups include 5-8-membered, 5-7-membered, 5-6-membered, 5-membered, and 6-membered heteroaryl groups, etc. Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl, and 5-isooxazolyl), and thiazolyl (including 2-thiazolyl, 4-...). Thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indole (including 5-indole, etc.), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), or quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.).

[0202] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including 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 9-12Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings. They also include any range from n to n+m, such as 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings.

[0203] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, and iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy groups, trifluoroacetoxy groups, etc.

[0204] The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxy protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenemethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0205] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0206] The structures of the compounds of this invention can be confirmed using conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) can be used. Diffraction intensity data of the grown single crystals can be collected using a Bruker D8 venture diffractometer with CuKα radiation as the light source and a φ / ω scan mode. After collecting the relevant data, the crystal structure can be further analyzed using the direct method (Shelxs 97) to confirm the absolute configuration.

[0207] The volume used in this invention is commercially available.

[0208] This invention uses the following abbreviations: Alloc represents allyloxycarbonyl; SEM represents trimethylsilylethoxymethyl; OTs represents 4-toluenesulfonyl; Boc represents tert-butyloxycarbonyl; DCM represents dichloromethane; DIEA represents N,N-diisopropylethylamine; MeI represents iodomethane; PE represents petroleum ether; EA represents ethyl acetate; THF represents tetrahydrofuran; EtOH represents ethanol; MeOH represents methanol; Boc2O represents ditert-butyl dicarbonate; NH4Cl represents ammonium chloride; T3P represents 1-propylphosphine. Tricyclic anhydride; Pd / C represents palladium / carbon catalyst; TMSN3 represents azidotrimethylsilane; NCS represents N-chlorosuccinimide; HBr represents hydrobromic acid; AcOH represents acetic acid; HATU represents O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DBU represents 1,8-diazabicycloundec-7-ene; FA represents formic acid; ACN represents acetonitrile; TLC represents thin-layer chromatography; HPLC represents high-performance liquid chromatography; LCMS represents liquid chromatography-mass spectrometry. DMSO represents dimethyl sulfoxide; DMSO-d6 represents deuterated dimethyl sulfoxide; CD3OD represents deuterated methanol; CDCl3 represents deuterated chloroform; D2O represents deuterated water.

[0209] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Detailed Implementation

[0210] The present invention will be described in detail below with reference to examples, but this does not imply any adverse limitation on the invention. 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, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0211] Intermediate A

[0212]

[0213] Synthesis route:

[0214]

[0215] first step

[0216] Compound A-1 (10.0 g, 47.3 mmol) was dissolved in acetonitrile (24 mL) of A-2. Dry hydrogen chloride gas was introduced into the solution at 25 °C for 0.5 hours. The reaction solution was stirred at 90 °C for 3 hours. The reaction solution was cooled to 25 °C, filtered, and the filter cake was collected and dissolved in water (100 mL). The solution was neutralized with 10% sodium bicarbonate (100 mL) solution. The solution was filtered, and the filter cake was washed with ice water (100 mL) and dried to obtain compound A-3. 1 H NMR (400MHz, CD3OD) δ7.55(s,1H),7.07(s,1H),3.98(s,3H),3.95(s,3H),2.45(s,3H).

[0217] Step 2

[0218] Compound A-3 (3.00 g, 13.6 mmol) was dissolved in methanesulfonic acid (15 mL), and DL-methionine (2.44 g, 16.4 mmol) was added to the compound. The reaction solution was reacted at 110 °C for 12 hours. The reaction solution was quenched with water (90 mL) and sodium hydroxide (2 mol / L, 150 mL). The reaction solution was filtered, the filter cake was collected and vacuum dried to obtain intermediate A. 1 H NMR (400MHz, DMSO-d6) δ7.33(s,1H),7.02(s,1H),3.88(s,3H),2.88(s,3H).

[0219] Intermediate B

[0220]

[0221] Synthesis route:

[0222]

[0223] first step

[0224] Under nitrogen protection, compound B-2 (1.3M tetrahydrofuran solution, 96.5 mL) was added dropwise to a tetrahydrofuran solution of compound B-1 (20.0 g, 83.7 mmol) in 50 mL of tetrahydrofuran. The reaction mixture was stirred at 70 °C for 3 hours under nitrogen protection. At 0 °C, a tetrahydrofuran solution of acetic anhydride (12.8 g, 125 mmol) in 50 mL of tetrahydrofuran was added to the reaction system, and the mixture was stirred at 40 °C for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3), washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate, Rf = 0.63) to give compound B-3. 1 H NMR (400MHz, CDCl3) δ7.74 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 2.60 (s, 3H), 2.54 (s, 3H).

[0225] Step 2

[0226] Compound B-3 (8.00 g, 39.6 mmol) was dissolved in tetrahydrofuran (150 mL), and B-4 (7.19 g, 59.4 mmol) and tetraethyl titanate (22.6 g, 98.9 mmol) were added. The reaction mixture was stirred at 70 °C for 4 hours. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL × 3), washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2 / 1, petroleum ether / ethyl acetate, Rf = 0.41) to give compound B-5. The MS-ESI calculated value was [M+H]. + 306, measured value 306.

[0227] Step 3

[0228] Compound B-5 (6.50 g, 21.3 mmol) was dissolved in tetrahydrofuran (100 mL) and water (2 mL) at -78 °C. Sodium borohydride (1.45 g, 38.3 mmol) was added, and the reaction mixture was stirred at 25 °C for 5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3), washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2 / 1, petroleum ether / ethyl acetate, Rf = 0.21) to give compound B-6. The MS-ESI calculated value was [M+H]. + 308, measured value 308.

[0229] Step 4

[0230] Compound B-6 (3.60 g, 11.7 mmol) was dissolved in ethyl acetate (10 mL), and ethyl hydrochloride solution (4 M, 15.0 mL) was added. The reaction mixture was stirred at 25 °C for 6 hours. The solution was concentrated under reduced pressure, filtered, and the filter cake was washed with ethyl acetate (200 mL). The filter cake was then dried under vacuum to give the hydrochloride salt of intermediate B. 1 H NMR (400MHz, DMSO-d6) δ8.71(s,3H),7.97(d,J=7.8Hz,1H),7.70(d,J=7.8Hz,1H ), 7.52 (t, J = 7.8Hz, 1H), 4.73-4.69 (m, 1H), 2.45 (s, 3H), 1.52 (d, J = 6.8Hz, 3H).

[0231] Intermediate C

[0232]

[0233] Synthesis route:

[0234]

[0235] first step

[0236] Compound C-1 (10.0 g, 42.5 mmol) was dissolved in thionyl chloride (30 mL), and N,N-dimethylformamide (164 μL, 2.13 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. Anhydrous toluene (100 mL × 2) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to obtain compound C-2.

[0237] Step 2

[0238] Under nitrogen protection, compound C-3 (15.2 g, 89.5 mmol) was dissolved in acetonitrile (100 mL). Triethylamine (14.6 g, 144 mmol) and magnesium chloride (9.33 g, 98.0 mmol) were added sequentially at 0 °C, and the mixture was stirred at 15 °C for 2 hours. After cooling to 0 °C, a solution of compound C-2 (10.8 g, 42.6 mmol) in acetonitrile (50 mL) was added dropwise, and the mixture was stirred at 15 °C for 12 hours. Dilute hydrochloric acid (4 M, 100 mL) was added to the reaction mixture at 0 °C. After separation, the mixture was concentrated to remove acetonitrile. The aqueous phase was extracted with ethyl acetate (150 mL × 2). The organic phase was washed with saturated sodium bicarbonate aqueous solution (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound C-4. The MS-ESI value was [MH]. - 304, measured value 304.

[0239] Step 3

[0240] Compound C-4 (12.8 g, 41.9 mmol) was dissolved in acetic acid (40 mL), and water (20 mL) and concentrated sulfuric acid (5 mL) were added. The mixture was reacted at 100 °C for 3 hours. The reaction solution was concentrated to remove acetic acid, and ice water (300 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 3), washed with saturated sodium bicarbonate aqueous solution (100 mL × 2), and sodium hydroxide aqueous solution (2 mol / L, 100 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1–2 / 1, V / V) to obtain compound C-5. The MS-ESI calculated value was [MH]. - 232, measured value 232.

[0241] Step 4

[0242] Compound C-5 (8.00 g, 34.3 mmol) was dissolved in tetrahydrofuran (80 mL), and B-4 (6.24 g, 51.5 mmol) and tetraisopropyl titanate (30.5 g, 85.8 mmol, 80% purity) were added. The mixture was reacted at 80 °C for 16 hours. Water (300 mL) was added to the reaction solution, and the mixture was filtered. The filtrate was dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1–3 / 1, V / V) to give compound C-6. The MS-ESI calculated value was [M+H]. + 337, measured value 337.

[0243] Step 5

[0244] Compound C-6 (8.00 g, 23.8 mmol) was dissolved in tetrahydrofuran (100 mL) and water (2 mL) at -78 °C, and sodium borohydride (1.80 g, 47.5 mmol) was added. The reaction mixture was reacted at 20 °C for 1 hour. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1–2 / 1, V / V) to give compound C-7. The MS-ESI value was [MH]. - 337, measured value 337.

[0245] Step 6

[0246] Compound C-7 (5.50 g, 16.3 mmol) was dissolved in ethyl acetate (10 mL), and a hydrogen chloride / ethyl acetate solution (4 M, 50.0 mL) was added. The reaction was carried out at 15 °C for 1 hour. After concentration under reduced pressure, dichloromethane (50 mL) was added and stirred. The mixture was filtered and dried under vacuum to obtain compound C-8. The MS-ESI value was [M+H].+ 235, measured value 235.

[0247] Step 7

[0248] Compound C-8 (3.50 g, 12.9 mmol) was dissolved in ethyl acetate (70 mL), and palladium on carbon (0.70 g, 10% purity) was added. The reaction was carried out at 15 °C under a hydrogen (15 Psi) atmosphere for 2 hours. The palladium on carbon was filtered off, and the solution was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate C. The MS-ESI calculated value was [M+H]. + 205, measured value 205.

[0249] Example 1

[0250]

[0251] Synthesis route:

[0252]

[0253] first step

[0254] Intermediate A (200 mg, 970 μmol), 4-dimethylaminopyridine (11.9 mg, 97.0 μmol), triethylamine (393 mg, 3.88 mmol), and compound 1-1 (232 mg, 1.16 mmol) were dissolved in N,N-dimethylformamide (3 mL) and reacted at 20 °C for 12 hours. After concentration, the crude product was separated by silica gel column chromatography (10 / 1, dichloromethane / methanol, Rf = 0.2) to obtain compound 1-2. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.14 (s, 1H), 7.66 (s, 1H), 7.17 (s, 1H), 3.88 (s, 3H), 3.63 (s, 2H), 3.49–3.40 (m, 2H), 2.48–2.40 (m, 4H), 2.33 (s, 3H), 2.29 (s, 3H). MS-ESI calculated values ​​[M+H] + 333, measured value 333.

[0255] Step 2

[0256] Compounds 1-2 (140 mg, 421 μmol), 4-dimethylaminopyridine (10.3 mg, 84.3 μmol), triethylamine (128 mg, 1.26 mmol), and compound 1-3 (255 mg, 842 μmol) were dissolved in dichloromethane (5 mL) and reacted at 15 °C for 56 hours. After concentration, the crude product was separated by silica gel column chromatography (10 / 1, dichloromethane / methanol, Rf = 0.45) to obtain compounds 1-4. 1¹H NMR (400MHz, DMSO-d⁶) δ 7.79 (s, 1H), 7.47 (s, 1H), 7.35 (s, 2H), 4.24–4.14 (m, 2H), 4.03 (q, J = 7.2Hz, 1H), 3.97 (s, 3H), 3.69–3.58 (m, 2H), 3.47–3.41 (m, 1H), 3.02–2.91 (m, 1H), 2.45 (s, 3H), 2.43–2.34 (m, 4H), 2.25 (s, 3H), 1.23–1.17 (m, 18H). MS-ESI calculated values ​​[M+H] + 599, measured value 599.

[0257] Step 3

[0258] Compounds 1-4 (55 mg, 91.9 μmol), triethylamine (72.7 mg, 718 μmol), and the hydrochloride salt of intermediate B (28.0 mg, 138 μmol) were dissolved in dimethyl sulfoxide (1 mL) and reacted at 90 °C for 34 hours. After concentration, the crude product was separated by preparative high performance liquid chromatography (HPLC) (column: Phenomenex Lμna C18 75×30 mm×3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 19%-39%, 7 min) to obtain the hydrochloride salt of compound 1. 1 H NMR (400MHz, DMSO-d6) δ14.91(br s,1H),11.56(br s,1H),10.52(br s,1H),9.04(br s,1H),8.01(br d,J=8.0Hz,1H),7.58(br d,J=7.2Hz,1H),7.43-7.36(m,2H),5.99-5.83(m,1H),4.40- 4.19(m,1H),4.18-4.04(m,2H),3.96(s,3H),3.71-3.44(m,1H),3.26-3.12(m,3H),2.85(br s,3H),2.60(br s,3H),2.57(br s, 3H), 2.55-2.53 (m, 1H), 1.65 (br d, J = 6.4 Hz, 3H). MS-ESI calculated values ​​[M+H] + 518, measured value 518.

[0259] Example 2

[0260]

[0261] Synthesis route:

[0262]

[0263] first step

[0264] Intermediate A (300 mg, 1.45 mmol) and compound 2-1 (348 mg, 1.75 mmol) were dissolved in N,N-dimethylformamide (5 mL). Triethylamine (589 mg, 5.75 mmol) and 4-dimethylaminopyridine (17.8 mg, 0.145 mmol) were added to the reaction solution. The reaction solution was stirred at 20 °C for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (20 / 1, dichloromethane / methanol, Rf = 0.62) to obtain compound 2-2. 1 H NMR (400MHz, CD3OD) δ7.82(s,1H),7.17(s,1H),3.98(s,3H),3.83-3.80(br s,2H),3.65(br s,2H),3.37(s,3H),2.76(br s2H),2.53(br s,2H),2.47(s,3H).

[0265] Step 2

[0266] Compounds 2-2 (442 mg, 1.33 mmol) and 1-3 (604 mg, 1.99 mmol) were dissolved in dichloromethane (10 mL). 4-(dimethylamino)pyridine (32.5 mg, 0.266 mmol) and triethylamine (404 mg, 3.99 mmol) were added to the reaction solution. The reaction solution was stirred at 20 °C for 12 hours. The reaction solution was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (30 / 1, dichloromethane / methanol, Rf = 0.47) to obtain compound 2-3. MS-ESI calculated value [M+H] + 599, measured value 599.

[0267] Step 3

[0268] Compounds 2-3 (200 mg, 0.314 mmol) and the hydrochloride salt of intermediate C (77.0 mg, 0.320 mmol) were dissolved in dimethyl sulfoxide (5 mL). Triethylamine (153 mg, 1.51 mmol) was added to the reaction solution. The reaction solution was stirred at 100 °C for 12 hours. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 2 was obtained by preparative high performance liquid chromatography (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 28%-58%, 9 min). 1 ¹H NMR (400MHz, CD₃OD) δ 8.05 (s, 1H), 7.12 (s, 1H), 7.99–6.96 (m, 2H), 6.81 (s, 1H), 5.61 (q, J = 7.2Hz, 1H), 3.97 (s, 3H), 3.79 (br s, 2H), 3.60 (br s, 2H), 2.59–2.56 (m, 4H), 2.50 (s, 3H), 2.39 (s, 3H), 1.63 (d, J = 7.2Hz, 3H). MS-ESI calculated value [M+H]. + 519, measured value 519.

[0269] Example 3

[0270]

[0271] Synthesis route:

[0272]

[0273] first step

[0274] Intermediate A (300 mg, 1.45 mmol) and 3-1 (260 mg, 1.74 mmol) were dissolved in N,N-dimethylformamide (5 mL). Triethylamine (587 mg, 5.80 mmol) and 4-dimethylaminopyridine (17.7 mg, 0.145 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (30 / 1, dichloromethane / methanol, Rf = 0.37) to obtain compound 3-2. 1H NMR (400MHz, CDCl3) δ7.86(s,1H),7.06(s,1H),3.88(s,3H),3.70-3.69(br s,2H),3.66(br s,2H),3.52(br s,2H),2.46(s,3H),1.60(br s,2H).

[0275] Step 2

[0276] Compounds 3-2 (342 mg, 1.07 mmol) and 1-3 (357 mg, 1.18 mmol) were dissolved in dichloromethane (5 mL). 4-(dimethylamino)pyridine (26.2 mg, 0.214 mmol) and triethylamine (325 mg, 3.21 mmol) were added to the reaction solution. The reaction solution was stirred at 20 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by thin-layer chromatography (40 / 1, dichloromethane / methanol, Rf = 0.35) to obtain compound 3-3. MS-ESI calculated value [M-tBu+H] + 586, measured value 586.

[0277] Step 3

[0278] Compound 3-3 (201 mg, 0.343 mmol) and the hydrochloride salt of intermediate C (90.8 mg, 0.377 mmol) were dissolved in dimethyl sulfoxide (3 mL). Triethylamine (977 mg, 9.66 mmol) was added to the reaction solution. The reaction solution was stirred at 100 °C for 2 hours. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The hydrochloride salt of compound 3 was obtained by preparative high performance liquid chromatography (column: 3-Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 23%-43%, 7 min). 1 ¹H NMR (400MHz, CD₃OD) δ 8.28 (s, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.43–7.42 (m, 1H), 7.10 (s, 1H), 5.77 (q, J = 7.2Hz, 1H), 3.95 (s, 3H), 3.65 (br s, 6H), 3.45 (br s, 2H), 2.55 (s, 3H), 1.67 (d, J = 1.2Hz, 3H). MS-ESI calculated value is [M+H]. + 506, measured value 506.

[0279] Example 4

[0280]

[0281] Synthesis route:

[0282]

[0283] first step

[0284] Compound 4-1 (200 mg, 1.75 mmol) was dissolved in dichloromethane (3 mL). Triphosgene (345 mg, 1.16 mmol) was added to the reaction solution. The reaction solution was cooled to -78 °C. Pyridine (383 mg, 4.84 mmol) was added to the reaction solution under a nitrogen atmosphere. The reaction solution was slowly heated to 0 °C and then to 25 °C. The reaction solution was stirred at 25 °C for 6 hours. The reaction solution was concentrated under reduced pressure to obtain compound 4-2.

[0285] Step 2

[0286] Compound 4-2 (201 mg, 1.14 mmol) and intermediate A (258 mg, 1.25 mmol) were dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (315 mg, 2.28 mmol) was added to the reaction solution. The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by thin-layer chromatography (20 / 1, dichloromethane / methanol, Rf = 0.63) to obtain compound 4-3. 1 H NMR(CD3OD,400MHz)δ7.80(s,1H),7.16(s,1H),4.61-4.35(m,3H),3.98(s,3H),2.90-2.87(m,1H),2.8 1-2.78(m,1H),2.46(s,3H),2.33(s,3H),2.31-2.27(m,1H),2.13-2.06(m,1H),1.43(d,J=4.8Hz,3H).

[0287] Step 3

[0288] Compounds 4-3 (231 mg, 0.667 mmol) and 1-3 (242 mg, 0.8 mmol) were dissolved in dichloromethane (10 mL). 4-(dimethylamino)pyridine (16.3 mg, 0.133 mmol) and triethylamine (202 mg, 0.278 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by thin-layer chromatography (40 / 1, dichloromethane / methanol, Rf = 0.22) to obtain compound 4-4. MS-ESI calculated value [MH] + 613, measured value 613.

[0289] Step 4

[0290] Compound 4-4 (315 mg, 0.502 mmol) and the hydrochloride salt of intermediate C (123 mg, 0.511 mmol) were dissolved in dimethyl sulfoxide (3 mL). Triethylamine (0.3 mL) was added to the reaction solution, and the reaction solution was stirred at 100 °C for 12 hours. The reaction solution was quenched with water (10 mL) and extracted with a dichloromethane / methanol mixed solvent (10:1, 20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by preparative high performance liquid chromatography (HPLC) (column: 3-Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 12%-32%, 7 min) to obtain the hydrochloride salt of compound 4. 1 ¹H NMR (400MHz, CD₃OD) δ 8.47 (s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 7.43 (s, 2H), 5.83 (q, J = 7.2Hz, 1H), 4.71–4.24 (m, 1H), 4.06 (s, 3H), 3.68–3.55 (m, 2H), 3.47–3.37 (m, 2H), 3.27–3.14 (m, 2H), 3.03 (s, 3H), 2.68 (s, 3H), 1.76 (d, J = 7.2Hz, 3H), 1.59–1.49 (m, 3H). MS-ESI calculated value is [M+H]. + 533, measured value 533.

[0291] Example 5

[0292]

[0293] Synthesis route:

[0294]

[0295] first step

[0296] Compound 5-1 (100 mg, 876 μmol) was dissolved in dichloromethane (5 mL). Compound 5-2 (190 mg, 641 μmol) was added at 0 °C, followed by pyridine (192 mg, 2.43 mmol). The reaction solution was gradually heated from 0 °C to 25 °C and stirred at 25 °C for 12 hours. The reaction solution was then concentrated under reduced pressure to obtain compound 5-3.

[0297] Step 2

[0298] Compound 5-3 (154 mg, 872 μmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (241 mg, 1.74 mmol) and intermediate A (198 mg, 959 μmol) were added, and the mixture was stirred at 25 °C for 5 hours. After the reaction solution was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 1). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to give compound 5-4. 1 ¹H NMR (400MHz, CD₃Cl) δ 7.94 (s, ¹H), 7.12 (s, ¹H), 3.94 (s, ³H), 3.79–3.71 (m, ²H), 3.66–3.58 (m, ²H), 2.55–2.52 (m, ⁴H), 2.51–2.48 (m, ²H), 1.95 (s, ³H), 1.16–1.11 (m, ³H). MS-ESI calculated values ​​[M+H] + 347, measured value 347.

[0299] Step 3

[0300] Compound 5-4 (140 mg, 404 μmol) was dissolved in dichloromethane (5 mL), and compound 1-3 (147 mg, 485 μmol), 4-dimethylaminopyridine (9.88 mg, 80.8 μmol), and triethylamine (123 mg, 1.21 mmol) were added. The mixture was stirred at 25 °C for 12 hours. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1 to 10 / 1, V / V) to give compound 5-5. 1 ¹H NMR (400MHz, CD₃Cl) δ 7.83 (s, 1H), 7.29–7.27 (m, 1H), 7.22–7.20 (m, 2H), 4.49–4.10 (m, 3H), 3.97 (s, 3H), 3.81–3.75 (m, 2H), 3.67–3.61 (m, 2H), 2.96–2.90 (m, 1H), 2.60–2.56 (m, 3H), 2.54 (s, 3H), 2.53–2.49 (m, 2H), 1.28–1.25 (m, 18H), 1.20–1.15 (m, 3H). MS-ESI calculated values ​​[M+H] + 613, measured value 613.

[0301] Step 4

[0302] Compound 5-5 (178 mg, 290 μmol) was dissolved in dimethyl sulfoxide (5 mL), and the hydrochloride salt of intermediate C (105 mg, 436 μmol) and triethylamine (88.2 mg, 871 μmol) were added. The mixture was stirred at 100 °C for 12 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 100 × 21.2 mm × 4 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 5%-35%, 9 min) to obtain the hydrochloride salt of compound 5. 1 ¹H NMR (400MHz, CD₃OD) δ 8.55 (s, 1H), 7.65–7.50 (m, 2H), 7.33 (s, 1H), 7.22 (s, 1H), 5.89–5.78 (m, 1H), 4.61–4.20 (m, 4H), 4.04 (s, 3H), 3.76–3.56 (m, 2H), 3.31–3.02 (m, 4H), 2.66 (s, 3H), 1.87–1.68 (m, 3H), 1.54–1.35 (m, 3H). MS-ESI calculated values ​​[M+H] + 533, measured value 533.

[0303] Example 6

[0304]

[0305] Synthesis route:

[0306]

[0307] first step

[0308] Intermediate A (200 mg, 970 μmol) and compound 6-1 (219 mg, 882 μmol) were dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (244 mg, 1.76 mmol) was added to the reaction solution. The reaction solution was stirred at 20 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added. The solution was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 6-2 was obtained by silica gel column chromatography (10 / 1, dichloromethane / methanol, Rf = 0.74). MS-ESI calculated value [M+H] + 419, measured value 419.

[0309] Step 2

[0310] Compound 6-2 (280 mg, 522 μmol) and compound 1-3 (190 mg, 626 μmol) were dissolved in dichloromethane (5 mL). 4-(dimethylamino)pyridine (12.8 mg, 104 μmol) and triethylamine (158 mg, 1.57 mmol) were added to the reaction solution. The reaction solution was stirred at 20 °C for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (2 / 1, petroleum ether / ethyl acetate, Rf = 0.35) to obtain compound 6-3. MS-ESI calculated value [M+H] + 685, measured value 685.

[0311] Step 3

[0312] Compound 6-3 (220 mg, 321 μmol) and the hydrochloride salt of intermediate C (98.4 mg, 482 μmol) were dissolved in dimethyl sulfoxide (5 mL). Triethylamine (97.5 mg, 964 μmol) was added to the reaction solution. The reaction solution was stirred at 100 °C for 12 hours. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 6-4. The MS-ESI calculated value was [M+H]. + 605, measured value 605.

[0313] Step 4

[0314] Compound 6-4 (192 mg, 318 μmol) was dissolved in ethyl hydrochloride solution (4 M, 10 mL). The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated into the hydrochloride salt of compound 6 by preparative high performance liquid chromatography (column: Venusil ASBPhenyl 150 × 30 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 11%-41%, 9 min). 1 ¹H NMR (400MHz, CD₃OD) δ 8.58 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.25 (s, 1H), 5.90 (q, J = 6.8Hz, 1H), 4.07 (s, 3H), 4.01–4.06 (m, 2H), 3.86 (s, 2H), 3.40 (s, 4H), 2.68 (s, 3H), 1.81 (d, J = 6.8Hz, 3H). MS-ESI calculated value [M+H]. + 505, measured value 505.

[0315] Example 7

[0316]

[0317] Synthesis route:

[0318]

[0319] first step

[0320] Intermediate A (300 mg, 2.91 mmol) was dissolved in tetrahydrofuran (5 mL), followed by the addition of compound 7-1 (674 mg, 3.35 mmol) and N,N-diisopropylethylamine (1.13 g, 8.73 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was then poured into water (20 mL), filtered, and the filtrate was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 7-2.

[0321] Step 2

[0322] Compounds 7-2 (600 mg, 1.62 mmol) and 7-3 (431 mg, 2.42 mmol) were dissolved in N,N-dimethylformamide (10 mL), and triethylamine (654 mg, 6.46 mmol) was added. The mixture was incubated at 25 °C for 6 hours. The reaction solution was concentrated under reduced pressure to obtain the crude compound. The crude compound was separated by silica gel column chromatography (dichloromethane / methanol, 30 / 1–10 / 1, V / V) to obtain compound 7-4. MS-ESI calculated value [M+H] + 374, measured value 374.

[0323] Step 3

[0324] Compound 7-4 (200 mg, 0.314 mmol) was dissolved in dichloromethane (2 mL). 4-Dimethylaminopyridine (9.82 mg, 80.3 μmol), triethylamine (243 mg, 2.41 mmol), and compound 1-3 (487 mg, 1.61 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 16 hours. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate, Rf = 0.3) to give compound 7-5. MS-ESI calculated value [M+H] + 640, measured value 640.

[0325] Step 4

[0326] Compound 7-5 (130 mg, 0.203 mmol) was dissolved in dimethyl sulfoxide (1 mL). Triethylamine (102 mg, 1.02 mmol) and the hydrochloride salt of intermediate C (73.4 mg, 305 μmol) were added to the reaction solution, and the reaction solution was stirred at 90 °C for 2 hours. The reaction solution was quenched with water (0.5 mL), and the crude product was separated by high performance liquid chromatography (HPLC) (column: Waters Xbridge 75 × 30 mm × 3 μm; mobile phase: 10 mM sodium bicarbonate aqueous solution-acetonitrile; gradient: 30%-50%, 6 min) to obtain compound 7. 1 ¹H NMR (400MHz, CD₃OD) δ 8.13–8.08 (m, 2H), 7.14 (s, 1H), 6.88–6.84 (m, 2H), 6.89 (s, 1H), 5.54–5.49 (m, 3H), 3.87 (s, 3H), 3.80–3.77 (m, 2H), 3.52 (s, 6H), 2.38 (s, 3H), 1.81–1.77 (m, 2H), 1.06–1.50 (m, 7H). MS-ESI calculated value [M+H]. + 560, measured value 560.

[0327] Example 8

[0328]

[0329] Synthesis route:

[0330]

[0331] first step

[0332] Compound 7-2 (165 mg, 444 μmol) was dissolved in N,N-dimethylformamide (10 mL), and triethylamine (180 mg, 1.78 mmol) and compound 8-1 (57 mg, 444 μmol) were added dropwise. The mixture was stirred at 25 °C for 1 hour. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane / methanol, 10 / 1, V / V) to give compound 8-2. MS-ESI calculated value [M+H]+361, measured value 361.

[0333] Step 2

[0334] Compound 8-2 (82 mg, 179 μmol) was dissolved in dichloromethane (10 mL), and compound 1-3 (64.9 mg, 214 μmol), 4-dimethylaminopyridine (4.36 mg, 35.7 μmol), and triethylamine (54.2 mg, 536 μmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane / methanol, 10 / 1, V / V) to give compound 8-3. MS-ESI calculated value [M+H] + 627, measured value 627.

[0335] Step 3

[0336] Compound 8-3 (68.0 mg, 81.4 μmol) was dissolved in dimethyl sulfoxide (5 mL), and the hydrochloride of intermediate C (29.4 mg, 122 μmol) and triethylamine (34.0 μL, 244 μmol) were added. The mixture was stirred at 90 °C for 12 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 1). The organic phase was washed with saturated brine (20 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Venusil ASB Phenyl 150 × 30 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 20%-50%, 9 min) to obtain the hydrochloride of compound 8. 1 ¹H NMR (400MHz, CD₃OD) δ 8.50 (s, 1H), 7.70–7.60 (m, 2H), 7.39 (s, 1H), 7.21 (s, 1H), 5.90–5.81 (m, 1H), 4.81–4.74 (m, 2H), 4.60–4.25 (m, 2H), 4.04 (s, 3H), 3.66–3.42 (m, 1H), 3.24–3.01 (m, 2H), 3.01–2.84 (m, 6H), 2.66 (m, 3H), 2.33–2.13 (m, 2H), 1.77 (d, J = 6.4Hz, 3H). MS-ESI calculated values ​​[M+H] + 547, measured value 547.

[0337] Example 9

[0338]

[0339] Synthesis route:

[0340]

[0341] first step

[0342] Compound 7-2 (160 mg, 431 μmol) and compound 9-1 (61 mg, 431 μmol) were dissolved in N,N-dimethylformamide (10 mL), and then triethylamine (174 mg, 172 mmol) was added. The reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude compound. The crude compound was separated by thin-layer chromatography (10 / 1, V / V, dichloromethane / methanol, Rf = 0.08) to obtain compound 9-2. MS-ESI calculated value [M+H] + 375, measured value 375.

[0343] Step 2

[0344] Compound 9-2 (60 mg, 160 μmol) was dissolved in dichloromethane (5 mL). 4-Dimethylaminopyridine (4 mg, 32 μmol), triethylamine (49 mg, 481 μmol), and compound 1-3 (58 mg, 192 μmol) were added to the reaction solution. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (2 / 1, V / V, petroleum ether / ethyl acetate, Rf = 0.5) to obtain compound 9-4. MS-ESI calculated value [M+H] + 641, measured value 641.

[0345] Step 3

[0346] Compound 9-4 (30 mg, 46.8 μmol) was dissolved in dimethyl sulfoxide (2 mL). Triethylamine (14.2 mg, 140 μmol) and the hydrochloride salt of intermediate C (16.9 mg, 70.2 μmol) were added to the reaction solution. The reaction solution was stirred at 100 °C for 2 hours. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by preparative high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: 10 mM sodium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 10%-80%, 9 min) to obtain compound 9. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.02 (s, 1H), 7.12 (s, 1H), 6.97 (s, 1H), 6.81 (s, 1H), 6.81 (s, 1H), 5.59 (q, J = 6.8Hz, 1H), 4.72–4.78 (m, 2H), 4.65–4.69 (m, 2H), 3.96 (s, 3H), 3.81 (s, 2H), 3.58–3.67 (m, 2H), 2.48 (s, 7H), 1.62 (d, J = 6.8Hz, 3H). MS-ESI calculated value [M+H].+ 561, measured value 561.

[0347] Example 10

[0348]

[0349] Synthesis route:

[0350]

[0351] first step

[0352] Compound 7-2 (183 mg, 493 μmol) was dissolved in N,N-dimethylformamide (10 mL), and triethylamine (199 mg, 1.97 mmol) and compound 10-1 (62.2 mg, 493 μmol) were added dropwise. The mixture was stirred at 25 °C for 1 hour. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane / methanol, 10 / 1, V / V) to give compound 10-2. The MS-ESI calculated value [M+H] was +359, and the measured value was 359.

[0353] Step 2

[0354] Compound 10⁻² (42 mg, 102 μmol) was dissolved in dichloromethane (10 mL), and compound 1⁻³ (37.1 mg, 122 μmol), 4-dimethylaminopyridine (2.49 mg, 20.4 μmol), and triethylamine (31.0 mg, 306 μmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane / methanol, 10 / 1, V / V) to give compound 10⁻³. MS-ESI calculated value [M+H] + 625, measured value 625.

[0355] Step 3

[0356] Compound 10-3 (18 mg, 28.8 μmol) was dissolved in dimethyl sulfoxide (3 mL), and the hydrochloride salt of intermediate C (10.4 mg, 43.2 μmol) and triethylamine (8.75 mg, 86.4 μmol) were added. The mixture was stirred at 90 °C for 12 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 1). The organic phase was washed with saturated brine (20 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: 10 mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 10%-80%, 9 min) to obtain compound 10. 1¹H NMR (400MHz, CD₃OD) δ 8.01 (s, 1H), 7.11 (s, 1H), 7.00–6.93 (m, 2H), 6.79 (s, 1H), 5.61–5.55 (m, 1H), 4.49–4.10 (m, 2H), 3.94 (s, 3H), 3.28–3.06 (m, 3H), 2.99–2.66 (m, 1H), 2.46 (s, 3H), 2.37–2.21 (m, 2H), 2.20–2.03 (m, 1H), 2.00–1.78 (m, 3H), 1.60 (d, J = 7.2Hz, 3H), 1.53–1.41 (m, 1H). MS-ESI calculated values ​​[M+H] + 545, actual measurement 545.

[0357] Example 11

[0358]

[0359] Synthesis route:

[0360]

[0361] first step

[0362] Compound 7-2 (293 mg, 789 μmol) was dissolved in N,N-dimethylformamide (5 mL), and triethylamine (319 mg, 3.16 mmol) and compound 11-1 (148 mg, 868 μmol) were added dropwise. The mixture was stirred at 25 °C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 1). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane / methanol, 10 / 1, V / V) to give compound 11-2. MS-ESI calculated value [M+H] +403, measured value 403.

[0363] Step 2

[0364] Compound 11-2 (50 mg, 124 μmol) was dissolved in dichloromethane (10 mL), and compound 1-3 (45.2 mg, 149 μmol), 4-dimethylaminopyridine (3.04 mg, 24.9 μmol), and triethylamine (37.7 mg, 373 μmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane / methanol, 10 / 1, V / V) to give compound 11-3. MS-ESI calculated value [M+H] + 669, measured value 669.

[0365] Step 3

[0366] Compound 11-3 (20 mg, 29.9 μmol) was dissolved in dimethyl sulfoxide (2 mL), and the hydrochloride salt of intermediate C (10.8 mg, 44.9 μmol) and triethylamine (9.08 mg, 89.7 μmol) were added. The mixture was stirred at 90 °C for 12 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 1). The organic phase was washed with saturated brine (20 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: 10 mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 37%-67%, 9 min) to obtain compound 11. 1 H NMR(400MHz,CD3OD)δ8.00(s,1H),7.11(s,1H),7.01-6.93(m,2H),6.80(s,1H), 5.61-5.53(m,1H),4.31-4.19(m,1H),3.95(s,3H),3.89-3.85(m,1H),3.77-3.70 (m, 1H), 3.11–3.05 (m, 1H), 2.46 (s, 3H), 1.86–1.77 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.36–1.31 (m, 2H), 1.31–1.26 (m, 4H), 1.24 (d, J = 6.0 Hz, 3H), 0.92–0.86 (m, 1H). MS-ESI calculated values ​​[M+H] + 589, measured value 589.

[0367] Example 12

[0368]

[0369] Synthesis route:

[0370]

[0371] first step

[0372] Compound 7-2 (390 mg, 1.05 mmol) was dissolved in N,N-dimethylformamide (10 mL), and triethylamine (425 mg, 4.20 mmol) and compound 12-1 (131 mg, 1.16 mmol) were added dropwise. The mixture was stirred at 25 °C for 1 hour. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to give compound 12-2. The MS-ESI calculated value [M+H]+346, and the measured value was 346.

[0373] Step 2

[0374] Compound 12-2 (150 mg, 434 μmol) was dissolved in dichloromethane (10 mL), and compound 1-3 (197 mg, 652 μmol), 4-dimethylaminopyridine (10.6 mg, 86.9 μmol), and triethylamine (132 mg, 1.30 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to obtain compound 12-3. MS-ESI calculated value [M+H] + 612, measured value 612.

[0375] Step 3

[0376] Compound 12-3 (54.0 mg, 88.3 μmol) was dissolved in dimethyl sulfoxide (3 mL), and the hydrochloride of intermediate C (31.9 mg, 132 μmol) and triethylamine (26.8 mg, 265 μmol) were added. The mixture was stirred at 90 °C for 12 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 1). The organic phase was washed with saturated brine (20 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: 10 mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 38%-68%, 9 min) to obtain compound 12. 1 ¹H NMR (400MHz, CD₃OD) δ 8.01 (s, 1H), 7.11 (s, 1H), 7.03–6.94 (m, 2H), 6.80 (s, 1H), 5.62–5.52 (m, 1H), 4.00–3.95 (m, 1H), 3.94 (s, 3H), 3.91–3.82 (m, 1H), 3.75–3.61 (m, 4H), 3.52–3.41 (m, 1H), 3.15–3.01 (m, 2H), 2.46 (s, 3H), 1.60 (d, J = 7.2Hz, 3H), 1.36–1.15 (m, 1H). MS-ESI calculated values ​​[M+H] + 532, measured value 532.

[0377] Example 13

[0378]

[0379] Synthesis route:

[0380]

[0381] first step

[0382] Compound 7-2 (700 mg, 1.89 mmol) was dissolved in N,N-dimethylformamide (10 mL), and triethylamine (763 mg, 7.54 mmol) and compound 13-1 (404 mg, 1.89 mmol) were added dropwise. The mixture was stirred at 25 °C for 1 hour. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1 to 10 / 1, V / V) to obtain compound 13-2. 1 ¹H NMR (400MHz, CD₃Cl) δ 7.94–7.87 (m, 1H), 7.14–7.08 (m, 1H), 4.73–4.45 (m, 1H), 4.24–3.99 (m, 2H), 3.94 (s, 3H), 3.21–2.94 (m, 2H), 2.89–2.75 (m, 2H), 2.52 (s, 3H), 2.01–1.78 (m, 2H), 1.68 (d, J = 14Hz, 3H), 1.55–1.46 (m, 9H). MS-ESI calculated value [M+H]+447, measured value 447.

[0383] Step 2

[0384] Compound 13-2 (325 mg, 728 μmol) was dissolved in ethyl acetate (10 mL), and ethyl hydrochloride solution (4 M, 3.64 mL) was added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to ethyl acetate (20 mL). After stirring at 20 °C for 30 minutes, the mixture was filtered. The supernatant was concentrated under reduced pressure to give the hydrochloride salt of compound 13-3. MS-ESI calculated value [M+H] + 347, measured value 347.

[0385] Step 3

[0386] The hydrochloride salt of compound 13-3 (318 mg, 521 μmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and 37% formaldehyde aqueous solution (127 mg, 1.56 mmol, purity: 37%), sodium triacetoxyborohydride (442 mg, 2.08 mmol), and acetic acid (62.6 mg, 1.04 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1 to 10 / 1, V / V) to obtain compound 13-5. MS-ESI calculated value [M+H] + 361, measured value 361.

[0387] Step 4

[0388] Compound 13-5 (160 mg, 444 μmol), N,N-diisopropylethylamine (172 mg, 1.33 mmol), and benzotriazol-1-yl-oxytripyrrolidine hexafluorophosphate (347 mg, 666 μmol) were dissolved in N,N-dimethylformamide (7 mL). After stirring at 25 °C for 1 hour, the hydrochloride salt of compound C (160 mg, 666 μmol) dissolved in N,N-dimethylformamide (3 mL) was added, and the mixture was stirred at 25 °C for 12 hours. The residue was filtered and concentrated under reduced pressure, and then purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: 10 mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 41%-71%, 9 min) to obtain compound 13. 1 ¹H NMR (400MHz, CD₃OD) δ 8.02 (s, 1H), 7.10 (s, 1H), 7.00–6.93 (m, 2H), 6.79 (s, 1H), 5.61–5.54 (m, 1H), 4.62–4.55 (m, 4H), 3.94 (s, 3H), 3.04–2.87 (m, 2H), 2.53–2.48 (m, 2H), 2.49–2.43 (m, 5H), 1.60 (d, J = 7.2Hz, 3H), 1.33–1.27 (m, 1H), 1.27–1.20 (m, 2H), 1.15–1.06 (m, 2H). MS-ESI calculated values ​​[M+H] + 547, measured value 547.

[0389] Example 14

[0390]

[0391] Synthesis route:

[0392]

[0393] first step

[0394] Ethyl bromodifluoroacetate (3.37 g, 16.6 mmol) was dissolved in dimethyl sulfoxide (20 mL), and copper powder (1.06 g, 16.6 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. Then, compound 14-1 (2.00 g, 6.65 mmol) was added to the reaction mixture, and the mixture was stirred at 70 °C for 12 hours. The reaction mixture was poured into 20 mL of ice water, ethyl acetate (20 mL) was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 20 / 1, V / V) to obtain compound 14-3. 1 H NMR (400MHz, CD3Cl) δ7.75-7.68(m,1H),7.64-7.57(m,1H),7.16(t,J=8.0Hz,1H),4.38(m,2H),1.34(t,J=8.0Hz,3H).

[0395] Step 2

[0396] Under nitrogen protection, compound 14-3 (677 mg, 1.82 mmol) was dissolved in toluene (10 mL), and methyl magnesium bromide solution (compound 14-4) (3 M, 2.43 mL) was added at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 10 / 1, V / V) to obtain compound 14-5. 1 H NMR (400MHz, CD3Cl) δ7.66 (t, J = 6.4Hz, 1H), 7.51-7.34 (m, 1H), 7.16-6.93 (m, 1H), 2.01 (s, 1H), 1.35 (s, 6H).

[0397] Step 3

[0398] Under nitrogen protection, compound 14-5 (441 mg, 1.56 mmol) was dissolved in toluene (5 mL), followed by compound 14-6 (1.87 g, 5.19 mmol) and palladium dichloride bis(triphenylphosphine) (109 mg, 0.16 mmol). The reaction mixture was stirred at 120 °C for 12 hours. The reaction was quenched with saturated potassium fluoride solution (20 mL) and extracted with ethyl acetate (15 mL × 2). The mixture was filtered and concentrated under reduced pressure to give compound 14-7.

[0399] Step 4

[0400] Compound 14-7 (425 mg, 1.55 mmol) was dissolved in acetone (10 mL) under nitrogen protection. Hydrochloric acid solution (12 M, 1.03 mL) was added dropwise at 0 °C, and the reaction was stirred at 25 °C for 1 hour. The mixture was neutralized to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1–4 / 1, V / V) to obtain compound 14-8. MS-ESI calculated value [M+H] + 247, measured value 247.

[0401] Step 5

[0402] Compound 14-8 (346 mg, 1.41 mmol) was dissolved in tetrahydrofuran (5 mL) at 25 °C, and compound B-4 (511 mg, 4.22 mmol) and tetraethoxytitanium (2.00 g, 7.03 mmol) were added. The reaction mixture was stirred at 80 °C for 36 hours. Then, sodium borohydride (64.0 mg, 1.69 mmol) was added to the reaction mixture at -5 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into 20 mL of ice water, filtered, and the filtrate was extracted with ethyl acetate (5 mL × 2). The organic phase was washed with saturated brine (5 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1 to 0 / 1, V / V) to obtain compound 14-9. MS-ESI calculated value [M+H] + 352, measured value 352.

[0403] Step 6

[0404] Compound 14-9 (366 mg, 1.04 mmol) was dissolved in dioxane (2.5 mL), and dioxane hydrochloride solution (4 M, 1.15 mL) was added. The reaction mixture was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 1 / 0–8 / 1, V / V) to obtain the hydrochloride salt of compound 14-10. MS-ESI calculated value [M+H] + 248, measured value 248.

[0405] Step 7

[0406] Under nitrogen protection, the hydrochloride salt of compound 14-10 (374 mg, 0.61 mmol) was dissolved in dimethyl sulfoxide (3 mL), and compound 4-5 (181 mg, 0.73 mmol) and triethylamine (926 mg, 9.15 mmol) were added. The reaction mixture was stirred at 90 °C for 12 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3) and dichloromethane / methanol solution (8:1, 5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150 × 30 mm × 4 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 29%-59%, 9 min) to obtain the hydrochloride salt of compound 14. 1 ¹H NMR (400MHz, CD₃OD) δ 8.46 (s, 1H), 7.63 (t, J = 6.8Hz, 1H), 7.42 (t, J = 6.8Hz, 1H), 7.26–7.19 (m, 2H), 6.01 (q, J = 6.8Hz, 1H), 4.82–4.59 (m, 1H), 4.50–4.19 (m, 1H), 4.04 (s, 3H), 3.76–3.50 (m, 3H), 3.41 (s, 1H), 3.25 (s, 1H), 3.00 (s, 3H), 2.63 (s, 3H), 1.74 (d, J = 7.2Hz, 3H), 1.66–1.43 (m, 3H), 1.29 (s, 6H). MS-ESI calculated values ​​[M+H] + 576, measured value 576.

[0407] Example 15

[0408]

[0409] Synthesis route:

[0410]

[0411] first step

[0412] Compound 15-1 (5.00 g, 43.1 mmol) was dissolved in dichloromethane (50 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (compound 15-2) (12.4 g, 64.6 mmol), triethylamine (6.54 g, 64.6 mmol), and 4-dimethylaminopyridine (52.6 mg, 0.43 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. 1 M hydrochloric acid solution (20 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated sodium bicarbonate solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1–0 / 1, V / V) to obtain compound 15-3. MS-ESI calculated value [M+H] + 160, measured value 160.

[0413] Step 2

[0414] Compound 15-3 (2.85 g, 11.2 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of n-butyllithium (2.5 M, 5.38 mL) was added at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. A tetrahydrofuran solution of compound 15-4 (2.00 g, 11.2 mmol) (10 mL) was added, and the reaction mixture was stirred at 25 °C for 3 h. The reaction was quenched with saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0–4 / 1, V / V) to obtain compound 15-5. MS-ESI calculated value [M+H] + 273, measured value 273.

[0415] Step 3

[0416] Compound 15-5 (1.70 g, 5.23 mmol) was dissolved in dichloromethane (20 mL), and diethylaminosulfur trifluoride (1.26 g, 7.84 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into 20 mL of ice water and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1~10 / 1, V / V) to obtain compound 15-7. MS-ESI calculated value [M+H] + 295, measured value 295.

[0417] Step 4

[0418] Under nitrogen protection, compound 15-7 (1.37 g, 4.64 mmol) was dissolved in toluene (10 mL), followed by compound 14-6 (5.58 g, 15.5 mmol) and palladium dichloride bis(triphenylphosphine) (326 mg, 464 μmol). The reaction mixture was stirred at 120 °C for 12 hours. The reaction was quenched with saturated potassium fluoride solution (20 mL) and extracted with ethyl acetate (15 mL × 2). After filtration and concentration under reduced pressure, the crude product was ready for use in the next step.

[0419] Step 5

[0420] Under nitrogen protection, compound 15-8 (1.32 g, 4.61 mmol) was dissolved in acetone (30 mL), and hydrochloric acid solution (12 M, 3.07 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The solution was neutralized to pH 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 50 / 1–10 / 1, V / V) to obtain compound 15-9. MS-ESI calculated value [M+H] + 259, measured value 259.

[0421] Step 6

[0422] Compound 15-9 (936 mg, 3.62 mmol) was dissolved in tetrahydrofuran (10 mL) at 25 °C, and compound B-4 (659 mg, 5.44 mmol) and tetraethoxytitanium (3.09 g, 10.9 mmol) were added. The reaction mixture was stirred at 80 °C for 23 hours. Then, sodium borohydride (165 mg, 4.35 mmol) was added to the reaction mixture at -5 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into 20 mL of ice water, filtered, and the filtrate was extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1 to 1 / 2, V / V) to obtain compound 15-10. MS-ESI calculated value [M+H] + 364, measured value 364.

[0423] Step 7

[0424] Compound 15-10 (366 mg, 1.04 mmol) was dissolved in dioxane (2.5 mL), and dioxane hydrochloride solution (4 M, 1.15 mL) was added. The reaction mixture was stirred at 25 °C for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 1 / 0–8 / 1, V / V) to obtain the hydrochloride salt of compound 15-11. MS-ESI calculated value [M+H] + 260, measured value 260.

[0425] Step 8

[0426] Under nitrogen protection, the hydrochloride salt of compound 15-11 (778 mg, 1.27 mmol) was dissolved in dimethyl sulfoxide (5 mL), and compound 4-5 (395 mg, 1.52 mmol) and triethylamine (1.93 g, 19.0 mmol) were added. The reaction mixture was stirred at 90 °C for 12 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3) and dichloromethane / methanol solution (8:1, 5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Ultimate C18 150 × 40 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 10%-40%, 10 min) to obtain the hydrochloride salt of compound 15. 1 H NMR (400MHz, CD3OD) δ8.46 (s, 1H), 7.65 (t, J = 6.8Hz, 1H), 7.46 (s, 1H), 7.29-7. 14(m,2H),5.94-6.04(m,1H),4.70-4.12(m,3H),4.04(s,3H),3.88-3.75(m,2H) ,3.72-3.48(m,3H),3.45-3.35(m,1H),3.25(s,1H),3.00(s,3H),2.63(s,3H), 2.18-1.99(m,2H),1.97-1.85(m,2H),1.75(d,J=7.2Hz,3H),1.67-1.41(m,3H). MS-ESI calculated value [M+H] + 588, measured value 588.

[0427] Example 16

[0428]

[0429] Synthesis route:

[0430]

[0431] first step

[0432] Under nitrogen protection, compound 16-1 (2.00 g, 8.62 mmol) was dissolved in tetrahydrofuran (20 mL), and methyl magnesium bromide solution (compound 14-4) (3 M, 4.31 mL) was added at -78 °C. The reaction mixture was stirred at -78 °C for 3 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 10 / 1, V / V) to obtain compound 16-2. 1 H NMR (400MHz, CD3OD) δ7.73(d,J=1.2Hz,1H),7.60(d,J=8.0Hz,1H),7.32(d,J=7.2Hz,1H),7.08(t,J=8.0Hz,1H),4.86-4.76(m,1H),1.48-1.43(m,3H).

[0433] Step 2

[0434] Compound 16-2 (3.01 g, 12.1 mmol) was dissolved in acetonitrile (30 mL), and N-methyl-N-morpholine (2.13 g, 18.1 mmol) and tetrabutylammonium perruthenate (427 mg, 1.21 mmol) were added at 25 °C. The reaction mixture was stirred at 25 °C for 4 hours. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0–10 / 1, V / V) to obtain compound 16-4. ESI calculated value [M+H] + 247, measured value 247.

[0435] Step 3

[0436] Ethyl bromodifluoroacetate (6.43 g, 31.7 mmol) was dissolved in dimethyl sulfoxide (30 mL), and copper powder (2.01 g, 31.7 mmol) and compound 16-4 (2.60 g, 10.6 mmol) were added. The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was poured into 20 mL of ice water, 10 mL of ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (15 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 20 / 1, V / V) to obtain compound 16-5. MS-ESI calculated value [M+H] + 243, measured value 243.

[0437] Step 4

[0438] Compound 16-5 (1.12 g, 4.62 mmol) was dissolved in tetrahydrofuran (10 mL) at 25 °C, and compound B-4 (841 mg, 6.94 mmol) and tetraethoxytitanium (3.16 g, 13.9 mmol) were added. The reaction mixture was stirred at 80 °C for 12 hours. Then, sodium borohydride (525 mg, 13.9 mmol) and water (200 μL) were added to the reaction mixture at -78 °C, and the mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into 20 mL of ice water, filtered, and the filtrate was extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1 to 1 / 2, V / V) to obtain compound 16-6. MS-ESI calculated value [M+H] + 306, measured value 306.

[0439] Step 5

[0440] Compound 16-6 (1.05 mg, 3.44 mmol) was dissolved in dioxane (8 mL), and dioxane hydrochloride solution (4 M, 3.78 mL) was added. The reaction mixture was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / petroleum ether, 0 / 1–10 / 1, V / V) to obtain the hydrochloride salt of compound 16-7. MS-ESI calculated value [M+H] + 202, measured value 202.

[0441] Step 6

[0442] Under nitrogen protection, the hydrochloride salt of compound 16-7 (777 mg, 1.27 mmol) was dissolved in dimethyl sulfoxide (10 mL), and compound 4-5 (306 mg, 1.52 mmol) and triethylamine (1.93 g, 19.0 mmol) were added. The reaction mixture was stirred at 90 °C for 12 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3) and dichloromethane / methanol solution (8:1, 5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Ultimate C18 150 × 40 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 12%-42%, 10 min) to obtain the hydrochloride salt of compound 16. 1¹H NMR (400MHz, CD₃OD) δ 8.52–8.41 (m, 1H), 7.73–7.58 (m, 2H), 7.50–7.35 (m, 2H), 7.27–7.17 (m, 1H), 5.84 (d, J = 5.6 Hz, 1H), 4.71–4.16 (m, 2H), 4.04 (s, 3H), 3.90 (t, J = 13.2 Hz, 2H), 3.76–3.51 (m, 3H), 3.42 (s, 1H), 3.29–3.13 (m, 1H), 3.00 (s, 3H), 2.66 (s, 3H), 1.76 (d, J = 5.6 Hz, 3H), 1.67–1.37 (m, 3H). MS-ESI calculated values ​​[M+H] + 530, measured value 530.

[0443] Example 17

[0444]

[0445] Synthesis route:

[0446]

[0447] first step

[0448] Compound 15-3 (2.33 g, 9.86 mmol) was dissolved in tetrahydrofuran (20 mL), and a tetrahydrofuran solution of n-butyllithium (2.5 M, 4.74 mL) was added at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. A tetrahydrofuran solution of compound 17-1 (1.76 g, 9.86 mmol) (20 mL) was added, and the reaction mixture was stirred at 25 °C for 3 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0–10 / 1, V / V) to obtain compound 17-2. MS-ESI calculated value [M+H] + 255, measured value 255.

[0449] Step 2

[0450] Compound 17-2 (1.6 g, 6.27 mmol) was dissolved in dichloromethane (20 mL), and diethylaminosulfur trifluoride (3.03 g, 18.8 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 48 hours. The reaction mixture was poured into 20 mL of ice water and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 10 / 1, V / V) to obtain compound 17-3. 1 H NMR (400MHz, CD3Cl) δ7.69(s,1H),7.58(d,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H),7.34-7.28(m ,1H),4.31(m,1H),3.84(t,J=6.0Hz,2H),2.05(m,2H),1.90-1.81(m,2H),1.82-1.81(m,2H).

[0451] Step 3

[0452] Under nitrogen protection, compound 17-3 (1.35 g, 4.87 mmol) was dissolved in toluene (10 mL), and compound 14-6 (586 g, 16.2 mmol) and palladium dichloride bis(triphenylphosphine) (342 mg, 0.49 mmol) were added. The reaction mixture was stirred at 120 °C for 12 hours. The reaction was quenched with saturated potassium fluoride solution (20 mL) and extracted with ethyl acetate (15 mL × 2). The mixture was filtered and concentrated under reduced pressure to give compound 17-4.

[0453] Step 4

[0454] Under nitrogen protection, compound 17-4 (1.3 g, 4.85 mmol) was dissolved in acetone (30 mL), and hydrochloric acid solution (12 M, 3.23 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The solution was neutralized to pH 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 50 / 1–10 / 1, V / V) to obtain compound 17-5. MS-ESI calculated value [M+H] + 241, measured value 241.

[0455] Step 5

[0456] Compound 17-5 (828 mg, 3.45 mmol) was dissolved in tetrahydrofuran (10 mL) at 25 °C, and compound B-4 (627 mg, 5.17 mmol) and tetraethoxytitanium (2.94 g, 10.3 mmol) were added. The reaction mixture was stirred at 80 °C for 32 hours. Then, sodium borohydride (156 mg, 4.14 mmol) was added to the reaction mixture at -5 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into ice water, filtered, and the filtrate was extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1 to 1 / 2, V / V) to obtain compound 17-6. MS-ESI calculated value [M+H] + 346, measured value 346.

[0457] Step 6

[0458] Compound 17-6 (988 mg, 2.86 mmol) was dissolved in dioxane (7 mL), and dioxane chloride solution (4 M, 3.15 mL) was added. The reaction mixture was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 1 / 0–10 / 1, V / V) to obtain the hydrochloride salt of compound 17-7. MS-ESI calculated value [M+H] + 242, measured value 242.

[0459] Step 7

[0460] Under nitrogen protection, the hydrochloride salt of compound 17-7 (798 mg, 1.30 mmol) was dissolved in dimethyl sulfoxide (5 mL), and compound 4-5 (377 mg, 1.56 mmol) and triethylamine (1.98 g, 19.5 mmol) were added. The reaction mixture was stirred at 90 °C for 12 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3) and dichloromethane / methanol solution (8:1, 5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Ultimate C18 150 × 40 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 3%-33%, 10 min) to obtain the hydrochloride salt of compound 17. 1¹H NMR (400MHz, CD₃OD) δ 8.58–8.37 (m, 1H), 7.71–7.56 (m, 2H), 7.43 (s, 2H), 7.30–7.15 (m, 1H), 5.82 (s, 1H), 4.83–4.57 (m, 1H), 4.50–4.15 (m, 2H), 4.04 (s, 3H), 3.80–3.52 (m, 5H), 3.43 (s, 1H), 3.26 (s, 1H), 3.00 (s, 3H), 2.65 (s, 3H), 1.98 (d, J = 6.0Hz, 2H), 1.85–1.67 (m, 5H), 1.63–1.43 (m, 3H). MS-ESI calculated values ​​[M+H] + 570, measured value 570.

[0461] Example 18

[0462]

[0463] Synthesis route:

[0464]

[0465] first step

[0466] Compound 18-1 (3.86 g, 15.4 mmol) was dissolved in tetrahydrofuran (30 mL) under nitrogen protection, and methyl magnesium bromide solution (3 M, 7.72 mL) was added at -78 °C. The reaction mixture was stirred at -78 °C for 3 hours. The reaction was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0–10 / 1, V / V) to obtain compound 18-2. MS-ESI calculated value [M+H] + 267, measured value 267.

[0467] Step 2

[0468] Compound 18-2 (2.98 g, 11.2 mmol) was dissolved in acetonitrile (25 mL), and N-methyl-N-morpholine (1.97 g, 16.8 mmol) and tetrabutylammonium perruthenate (394 mg, 1.12 mmol) were added at 25 °C. The reaction mixture was stirred at 25 °C for 4 hours. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0–10 / 1, V / V) to obtain compound 18-3. MS-ESI calculated value [M+H] + 265, measured value 265.

[0469] Step 3

[0470] Ethyl bromodifluoroacetate (4.84 g, 23.9 mmol) was dissolved in dimethyl sulfoxide (20 mL), and copper powder (1.52 g, 23.9 mmol) and compound 18-3 (2.10 g, 7.95 mmol) were added. The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was poured into 20 mL of ice water, 20 mL of ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 20 / 1, V / V) to obtain compound 18-4. MS-ESI calculated value [M+H] + 261, measured value 261.

[0471] Step 4

[0472] Compound 18-4 (820 mg, 3.15 mmol) was dissolved in tetrahydrofuran (5 mL) at 25 °C, and compound B-4 (573 mg, 4.73 mmol) and tetraethoxytitanium (2.16 g, 9.45 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. Then, sodium borohydride (358 mg, 9.45 mmol) and water (100 μL) were added to the reaction mixture at -78 °C, the temperature was raised to 25 °C, and the mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into 5 mL of ice water, filtered, and the filtrate was extracted with ethyl acetate (5 mL × 2). The organic phase was washed with saturated brine (5 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1 to 0 / 1, V / V) to obtain compound 18-5. MS-ESI calculated value [M+H] + 324, measured value 324.

[0473] Step 5

[0474] Compound 18-5 (295 mg, 912 μmol) was dissolved in dioxane (2 mL), and dioxane chloride solution (4 M, 1.00 mL) was added. The reaction mixture was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1–10 / 1, V / V) to obtain the hydrochloride salt of compound 18-6. MS-ESI calculated value [M+H] + 220, measured value 220.

[0475] Step 6

[0476] Under nitrogen protection, the hydrochloride salt of compound 18-6 (452 ​​mg, 738 μmol) was dissolved in dimethyl sulfoxide (10 mL), and compound 4-5 (194 mg, 885 μmol) and triethylamine (1.12 g, 1.54 mmol) were added. The reaction mixture was stirred at 90 °C for 12 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3) and dichloromethane / methanol solution (8:1, 5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150 × 30 mm × 4 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 10%-80%, 9 min) to obtain the hydrochloride salt of compound 18. 1 H NMR (400MHz, CD3OD) δ8.53-8.44(m,1H),7.67(t,J=6.8Hz,1H),7.51(t,J=6.8Hz,1 H),7.26(t,J=8.0Hz,1H),7.23-7.19(m,1H),6.00(d,J=7.2Hz,1H),4.83-4.59(m, 1H), 4.50-4.18(m,1H), 4.07-3.97(m,5H), 3.77-3.50(m,3H), 3.46-3.34(m,1H), 3.20-15(m,1H), 3.00(s,3H), 2.63(s,3H), 1.75(d,J=6.8Hz,3H), 1.66-1.44(m,3H). MS-ESI calculated values ​​[M+H] + 548, measured value 548.

[0477] Example 19

[0478]

[0479] Synthesis route:

[0480]

[0481] first step

[0482] Under nitrogen protection, compound 19-1 (3.00 g, 14.8 mmol) was dissolved in dry dichloromethane (30 mL), and diethylaminosulfur trifluoride (3.57 g, 22.2 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours, and ice water (20 mL) was added to the reaction mixture. The mixture was extracted with dichloromethane (20 mL × 1), and the organic phase was washed with saturated brine (20 mL × 1). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 10 / 1, V / V) to obtain compound 19-2. 1 H NMR (400MHz, CD3Cl) δ7.72-7.67(m,1H),7.52-7.59(m,1H),7.16(t,J=7.6Hz,1H),7.05-6.75(m,1H).

[0483] Step 2

[0484] Under nitrogen protection, compound 19-2 (3.10 g, 13.8 mmol) was dissolved in dry toluene (50 mL), and tributyl(1-ethoxyethylene)tin (compound 14-6) (9.95 g, 27.6 mmol) was added, followed by bis(triphenylphosphine)palladium dichloride (967 mg, 1.38 mmol). The reaction mixture was stirred at 110 °C for 12 hours. A saturated potassium fluoride aqueous solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 19-3, which was used directly in the next step.

[0485] Step 3

[0486] Under nitrogen protection, compound 19-3 (2.98 g, 13.8 mmol) was dissolved in acetone (90 mL), and concentrated hydrochloric acid (12 M, 9.19 mL) was added dropwise at 0 °C. The reaction solution was stirred at 25 °C for 1 hour. The pH of the reaction solution was alkalized to 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (200 mL × 2), and the organic phase was washed with saturated brine (200 mL × 1). The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 10 / 1, V / V) to obtain compound 19-4. 1 H NMR (400MHz, CD3Cl) δ 8.06-7.97 (m, 1H), 7.84-7.76 (m, 1H), 7.38-7.32 (m, 1H), 7.10-6.80 (m, 1H), 2.68 (d, J = 4.8Hz, 3H).

[0487] Step 4

[0488] Under nitrogen protection, compound 19-4 (1.85 g, 9.83 mmol) was dissolved in dry tetrahydrofuran (50 mL), followed by the addition of tetraethyl titanate (8.97 g, 39.3 mmol) and (R)-(+)-tert-butylsulfinamide (compound B-4) (2.38 g, 19.7 mmol). The reaction mixture was stirred at 72 °C for 36 hours, then cooled to 0 °C and saturated ammonium chloride aqueous solution (20 mL) was added dropwise, followed by ethyl acetate (20 mL). The mixture was filtered, the filter cake was washed with ethyl acetate (10 mL), and the organic phase was washed with saturated brine (20 mL × 1). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1~4 / 1, V / V) to obtain compound 19-5. MS-ESI calculated value [M+H] + 292, measured value 292.

[0489] Step 5

[0490] Compound 19-5 (2.33 g, 8.00 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium borohydride (303 mg, 8.00 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour, cooled to 0 °C, and saturated ammonium chloride aqueous solution (50 mL) was added dropwise, followed by ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 19-6. MS-ESI calculated value [M+H] + 294, measured value 294.

[0491] Step 6

[0492] Compound 19-6 (200 mg, 0.682 mmol) was dissolved in ethyl acetate (5 mL), and ethyl hydrochloride solution (4 M, 5.00 mL) was added dropwise at 25 °C. The reaction solution was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 19-7, which was used directly in the next step.

[0493] Step 7

[0494] Under nitrogen protection, the hydrochloride salt of compound 19-7 (200 mg, 0.326 mmol) was dissolved in dimethyl sulfoxide (10 mL), and then compound 7 (110 mg, 0.490 mmol) and triethylamine (165 mg, 1.63 mmol) were added. The reaction solution was stirred at 100 °C for 12 hours. The reaction solution was then separated by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150×30 mm×4 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 25%-55%, 9 min) to obtain the hydrochloride salt of compound 19. 1H NMR(400MHz,CD3OD)δ8.46(s,1H),7.74-7.65(m,1H),7.58-7.49(m,1H),7.30(t, J=8.0Hz,1H),7.19(s,1H),7.15-6.85(m,1H),6.00(q,J=7.2Hz,1H),4.84-4.58(m ,1H), 4.51-4.20(m,1H), 4.04(s,3H), 3.74-3.49(m,3H), 3.48-3.35(m,1H), 3.29-3.15(m,1H), 3.00(s,3H), 2.63(s,3H), 1.76(d,J=7.2Hz,3H), 1.65-1.44(m,3H). MS-ESI calculated values ​​[M+H] + 518, measured value 518.

[0495] Example 20

[0496]

[0497] Synthesis route:

[0498]

[0499] first step

[0500] Compound 18-5 (121 mg, 374 μmol) was dissolved in dioxane (2 mL), and cesium carbonate (366 mg, 1.12 mmol) and 18-crown ether-6 (50 mg, 187 μmol) were added. The reaction mixture was stirred at 80 °C for 36 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1–3 / 1, V / V) to obtain the hydrochloride salt of compound 20-1. MS-ESI calculated value [M+H] + 284, measured value 284.

[0501] Step 2

[0502] Compound 20-1 (104 mg, 367 μmol) was dissolved in dioxane (1 mL), and dioxane hydrochloride solution (4 M, 404 μL) was added. The reaction mixture was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1–10 / 1, V / V) to obtain the hydrochloride salt of compound 20-2. MS-ESI calculated value [M+H] + 180, measured value 180.

[0503] Step 3

[0504] Under nitrogen protection, the hydrochloride salt of compound 20-2 (177 mg, 288 μmol) was dissolved in dimethyl sulfoxide (2 mL), and compound 4-5 (62 mg, 346 μmol) and triethylamine (437 mg, 4.33 mmol) were added. The reaction mixture was stirred at 90 °C for 12 hours. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL × 3) and dichloromethane / methanol solution (8:1, 5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150 × 30 mm × 4 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 20%-50%, 9 min) to obtain the hydrochloride salt of compound 20. 1 H NMR(400MHz,CD3OD)δ8.45(s,1H),7.93-7.87(m,1H),7.54(d,J=8.0Hz,1H),7.47(d ,J=7.2Hz,1H),7.33-7.27(m,1H),7.19(s,1H),6.23(d,J=6.8Hz,1H),4.74-4.57(s ,1H), 4.46-4.22(m,1H), 4.04(s,3H), 3.59(t,J=12.4Hz,3H), 3.46-3.35(s,1H), 3.27-3.15(s,1H), 3.00(s,3H), 2.59(s,3H), 1.83(d,J=7.2Hz,3H), 1.62-1.45(m,3H). MS-ESI calculated values ​​[M+H] + 508, measured value 508.

[0505] Example 21

[0506]

[0507] Synthesis route:

[0508]

[0509] first step

[0510] Compound 21-1 (1.00 g, 5.00 mmol) was dissolved in toluene (2 mL) under nitrogen protection, followed by the addition of compound 14-6 (3.61 g, 10.0 mmol) and bis(triphenylphosphine)palladium dichloride (351 mg, 0.50 mmol). The mixture was stirred at 120 °C for 12 hours. A saturated potassium fluoride solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 2). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 21-2.

[0511] Step 2

[0512] Compound 21-2 (950 mg, 4.97 mmol) was dissolved in acetone (30 mL) under nitrogen protection, and then hydrochloric acid solution (12 M, 3.31 mL) was added dropwise at 0 °C. The reaction was stirred at 25 °C for 1 hour. The pH was alkalized to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 50 / 1 to 10 / 1, V / V) to obtain compound 21-3.

[0513] Step 3

[0514] Compound 21-3 (736 mg, 4.51 mmol) was dissolved in tetrahydrofuran (15 mL), and compound B-4 (820 mg, 6.77 mmol) and tetraethoxytitanium (3.09 g, 13.5 mmol) were added. The mixture was stirred at 80 °C for 14 hours. Sodium borohydride (171 mg, 4.51 mmol) was added to the reaction solution at -5 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was poured into ice water, filtered, and the filtrate was extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1 to 1 / 1, V / V) to obtain compound 21-4. MS-ESI calculated value [M+H] + 269, measured value 269.

[0515] Step 4

[0516] Compound 21-4 (910 mg, 3.39 mmol) was dissolved in dioxane (8 mL), and dioxane hydrochloride solution (4 M, 3.73 mL) was added. The mixture was stirred at 25 °C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was stirred with ethyl acetate (2 mL), filtered, and the filter cake was collected to obtain the hydrochloride salt of compound 21-5. MS-ESI calculated value [M+H] + 165, measured value 165.

[0517] Step 5

[0518] Under nitrogen protection, the hydrochloride salt of compound 21-5 (198 mg, 291 μmol) was dissolved in dimethyl sulfoxide (2 mL), and compound 4-5 (70 mg, 249 μmol) and triethylamine (441 mg, 4.36 mmol) were added. The reaction mixture was stirred at 90 °C for 12 hours. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL × 3) and dichloromethane / methanol solution (8:1, 5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150 × 30 mm × 4 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 20%-50%, 9 min) to obtain the hydrochloride salt of compound 21. 1 ¹H NMR (400MHz, CD₃OD) δ 8.45 (s, 1H), 7.93–7.83 (m, 1H), 7.75–7.65 (m, 1H), 7.41–7.32 (m, 1H), 7.18 (s, 1H), 5.96 (d, J = 7.2Hz, 1H), 4.80–4.62 (m, 1H), 4.58–4.15 (m, 1H), 4.04 (s, 3H), 3.78–3.44 (m, 3H), 3.44–3.34 (m, 1H), 3.25–3.10 (m, 1H), 3.00 (s, 3H), 2.63 (s, 3H), 1.76 (d, J = 7.2Hz, 3H), 1.61–1.43 (m, 3H). MS-ESI calculated values ​​[M+H] + 493, measured value 493.

[0519] Example 22

[0520]

[0521] Synthesis route:

[0522]

[0523] first step

[0524] Compound 22-1 (600 mg, 4.13 mmol) was dissolved in tetrahydrofuran (10 mL), and compound B-4 (751 mg, 6.20 mmol) and tetraethoxytitanium (2.83 g, 12.4 mmol) were added. The mixture was stirred at 80 °C for 16 hours. Sodium borohydride (156 mg, 4.13 mmol) was added to the reaction solution at -5 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was poured into ice water, filtered, and the filtrate was extracted with ethyl acetate (5 mL × 2). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 6 / 1 to 1 / 1, V / V) to obtain compound 22-2. MS-ESI calculated value [M+H] + 251, measured value 251.

[0525] Step 2

[0526] Compound 22-2 (500 mg, 2.00 mmol) was dissolved in dioxane (8 mL), and dioxane hydrochloride solution (4 M, 2 mL) was added. The mixture was stirred at 25 °C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was passed through ethyl acetate (2 mL) with stirring, filtered, and the filter cake was collected to obtain the hydrochloride salt of compound 22-3. MS-ESI calculated value [M+H] + 147, measured value 147.

[0527] Step 3

[0528] Under nitrogen protection, the hydrochloride salt of compound 22-3 (218 mg, 319 μmol) was dissolved in dimethyl sulfoxide (2 mL), and compound 4-5 (70 mg, 383 μmol) and triethylamine (441 mg, 4.36 mmol) were added. The reaction mixture was stirred at 90 °C for 12 hours. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL × 3) and dichloromethane / methanol solution (8:1, 5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (HPLC) (column: Phenomenex Genimi NX C18 150 × 40 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 1%-30%, 10 min) to obtain the hydrochloride salt of compound 22. 1¹H NMR (400MHz, CD₃OD) δ 8.47 (s, 1H), 7.91–7.75 (m, 2H), 7.67–7.61 (s, 1H), 7.57–7.49 (s, 1H), 7.22 (s, 1H), 5.90–5.76 (s, 1H), 4.65–4.18 (m, 2H), 4.04 (s, 3H), 3.77–3.51 (m, 2H), 3.49–3.32 (m, 2H), 3.26–3.14 (m, 1H), 3.00 (s, 3H), 2.65 (s, 3H), 1.74 (s, 3H), 1.65–1.32 (m, 3H). MS-ESI calculated values ​​[M+H] + 475, measured value 475.

[0529] Example 23

[0530]

[0531] Synthesis route:

[0532]

[0533] first step

[0534] Compound 23-1 (1.00 g, 4.61 mmol) was dissolved in tetrahydrofuran (15 mL) under nitrogen protection. Compound 14-4 (3 M tetrahydrofuran solution, 7.68 mL) was added dropwise at 0 °C, and the reaction was stirred at 25 °C for 1 hour. Saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 2 / 1, V / V) to obtain compound 23-2. 1 H NMR (400MHz, CD3Cl) δ7.59-7.50(m,1H),7.50-7.37(m,1H),7.06-6.97(m,1H),1.67-1.64(m,6H).

[0535] Step 2

[0536] Compound 23-2 (606 mg, 2.60 mmol) was dissolved in toluene (10 mL) under nitrogen protection, followed by the addition of compound 14-6 (1.13 g, 3.12 mmol) and palladium dichloride bis(triphenylphosphine) (182 mg, 260 μmol). The reaction mixture was stirred at 120 °C for 12 hours. A saturated potassium fluoride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 23-3. MS-ESI calculated value [M+H] + 225, measured value 225.

[0537] Step 3

[0538] Compound 23-3 (583 mg, 2.60 mmol) was dissolved in acetone (6 mL) under nitrogen protection, and hydrochloric acid solution (12 M, 0.60 mL) was added dropwise. The mixture was stirred at 20 °C for 1 hour. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 1). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 2 / 1, V / V) to obtain compound 23-4. 1 HNMR (400MHz, CD3Cl) δ7.85-7.77(m,1H),7.78-7.67(m,1H),7.20(t,J=7.6Hz,1H),2.68-2.63(m,3H),1.70-1.67(m,6H).

[0539] Step 4

[0540] Compound 23-4 (430 mg, 2.19 mmol) was dissolved in tetrahydrofuran (10 mL), and compound B-4 (398 mg, 3.29 mmol) and tetraethyl titanate (1.00 g, 4.38 mmol) were added. After stirring at 80 °C for 12 hours, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 1). The organic phase was washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 1, V / V) to obtain compound 23-5. 1 ¹H NMR (400MHz, CD₃Cl) δ 7.75–7.65 (m, 1H), 7.58–7.41 (m, 1H), 7.16 (t, J = 7.6 Hz, 1H), 1.68–1.66 (m, 6H), 1.32 (s, 9H), 1.24 (s, 3H). MS-ESI calculated values ​​[M+H] + 300, measured value 300.

[0541] Step 5

[0542] Compound 23-5 (650 mg, 1.85 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium borohydride (77.1 mg, 2.04 mmol) was added at 0 °C. The mixture was stirred at 20 °C for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 1). The organic phase was washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 1, V / V) to obtain compound 23-6. 1 ¹H NMR (400MHz, CD₃Cl) δ 7.54–7.44 (m, 1H), 7.34–7.25 (m, 1H), 7.12 (t, J = 7.6 Hz, 1H), 4.99–4.69 (m, 1H), 1.68–1.60 (m, 6H), 1.61–1.50 (m, 3H), 1.27–1.15 (m, 9H). MS-ESI calculated values ​​[M+H] + 302, measured value 302.

[0543] Step 6

[0544] Compound 23-6 (116 mg, 385 μmol) was dissolved in dioxane (5 mL), and dioxane hydrochloride solution (4 M, 96.2 μL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was stirred with dichloromethane (5 mL), filtered, and the filter cake was collected to obtain the hydrochloride salt of compound 23-7. MS-ESI calculated value [M+H] + 198, measured value 198.

[0545] Step 7

[0546] The hydrochloride salt of compound 23-7 (69.0 mg, 295 μmol) was dissolved in dimethyl sulfoxide (3 mL), compound 4-5 (199 mg, 325 μmol) was added, and triethylamine (149 mg, 1.48 mmol) was added dropwise. The mixture was stirred at 100 °C for 12 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (HPLC) (column: Phenomenex Genimi NX C18 150 × 40 mm × 5 μm; mobile phase: (0.04% ammonia solution + 10 mM ammonium bicarbonate solution) - acetonitrile; gradient: acetonitrile 30%-60%, 10 min) to obtain compound 23. 1¹H NMR (400MHz, CD₃OD) δ 8.04 (s, 1H), 7.53–7.42 (m, 1H), 7.35–7.24 (m, 1H), 7.09 (s, 1H), 7.08–6.98 (m, 1H), 5.91–5.77 (m, 1H), 4.68–4.55 (m, 1H), 4.56–4.17 (m, 1H), 3.94 (s, 3H), 2.96–2.74 (m, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 2.26–2.01 (m, 2H), 1.80–1.49 (m, 9H), 1.48–1.37 (m, 3H), 1.37–1.10 (m, 2H). MS-ESI calculated values ​​[M+H] + 526, measured value 526.

[0547] Example 24

[0548]

[0549] Synthesis route:

[0550]

[0551] first step

[0552] Compound 7-2 (200 mg, 1.62 mmol) was dissolved in N,N-dimethylformamide (5 mL), and triethylamine (1.12 mL, 8.08 mmol) and 24-1 (686 mg, 3.23 mmol) were added dropwise. The mixture was stirred at 25 °C for 12 hours. Water (20 mL) was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to give compound 24-2. MS-ESI calculated value [M+H] + 445, measured value 445.

[0553] Step 2

[0554] Compound 24-2 (425 mg, 839 μmol) was dissolved in dichloromethane (10 mL), and compound 1-3 (305 mg, 1.01 mmol), 4-dimethylaminopyridine (10.3 mg, 83.9 μmol), and triethylamine (350 μl, 2.52 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to obtain compound 24-3. MS-ESI calculated value [M+H] +711, measured value 711.

[0555] Step 3

[0556] Compound 24-3 (220 mg, 309 μmol) was dissolved in dimethyl sulfoxide (5 mL), and 14-10 hydrochloride (116 mg, 402 μmol) and triethylamine (129 μl, 928 μmol) were added. The mixture was stirred at 90 °C for 12 hours. Water (20 mL) was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to give compound 24-4. MS-ESI calculated value [M+H] + 674, measured value 674.

[0557] Step 4

[0558] Compound 24-4 (224 mg, 236 μmol) was dissolved in ethyl acetate (5 mL), and ethyl hydrochloride solution (4 mol / L, 3.53 mL) was added. The mixture was stirred at 20 °C for 12 hours. The reaction solution was concentrated under reduced pressure to give the hydrochloride salt of compound 24-5. MS-ESI calculated value [M+H] + 574, measured value 574.

[0559] Step 5

[0560] The hydrochloride salt of compound 24-5 (130 mg, 201 μmol) was dissolved in tetrahydrofuran (5 mL), and 24-6 (145 mg, 2.01 mmol) was added. After stirring at 70 °C for 1 hour, sodium triacetoxyborohydride (213 mg, 1.01 mmol) was added, and the mixture was stirred at 70 °C for 1 hour. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex C18 80 mm × 40 mm × 3 μm; mobile phase: 0.05% ammonia solution-acetonitrile; gradient: acetonitrile 40%-70%, 8 min) to obtain compound 24. 1¹H NMR (400MHz, CD₃OD) δ 8.05 (s, 1H), 7.57–7.46 (m, 1H), 7.40–7.31 (m, 1H), 7.18–7.11 (m, 1H), 7.12–7.08 (m, 1H), 5.87–5.78 (m, 1H), 4.75–4.67 (m, 2H), 4.64–4.59 (m, 6H), 3.97–3.90 (m, 3H), 3.91–3.63 (m, 2H), 3.64–3.52 (m, 1H), 2.41 (s, 3H), 1.63 (d, J = 7.2Hz, 3H), 1.33–1.27 (m, 6H), 1.23–0.86 (m, 4H). MS-ESI calculated values ​​[M+H] + 630, measured value 630.

[0561] Example 25

[0562]

[0563] Synthesis route:

[0564]

[0565] first step

[0566] Compound 24-3 (1.01 g, 1.18 mmol) was dissolved in dimethyl sulfoxide (10 mL), and 19-7 hydrochloride (245 mg, 1.30 mmol) and triethylamine (492 μL, 3.54 mmol) were added. The mixture was stirred at 90 °C for 12 hours. Water (20 mL) was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to give compound 25-1. MS-ESI calculated value [M+H] +616, measured value 616.

[0567] Step 2

[0568] Compound 25-1 (675 mg, 900 μmol) was dissolved in ethyl acetate (10 mL), and ethyl hydrochloride solution (4 mol / L, 13.5 mL) was added. The mixture was stirred at 20 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (HPLC) (column: Ultimate C18 150 mm × 40 mm × 5 μm; mobile phase: 0.05% ammonia solution-acetonitrile; gradient: acetonitrile 35%-65%, 10 min) to obtain compound 25. 1¹H NMR (400MHz, CD₃OD) δ 8.05 (s, 1H), 7.61–7.48 (m, 1H), 7.43 (t, J = 6.4 Hz, 1H), 7.29–7.09 (m, 2H), 7.10–6.81 (m, 1H), 5.87–5.73 (m, 1H), 3.96 (s, 3H), 3.90–3.50 (m, 2H), 3.15–2.70 (m, 4H), 2.40 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.40–1.05 (m, 2H), 1.01–0.84 (m, 2H). MS-ESI calculated values ​​[M+H] + 516, measured value 516.

[0569] Example 26

[0570]

[0571] Synthesis route:

[0572]

[0573] Compound 25 (280 mg, 476 μmol) was dissolved in tetrahydrofuran (5 mL), and 24-6 (343 mg, 4.76 mmol) was added. After stirring at 70 °C for 1 hour, sodium triacetoxyborohydride (504 mg, 2.38 mmol) was added, and the mixture was stirred at 70 °C for 1 hour. The mixture was cooled to room temperature, filtered, and the residue was concentrated under reduced pressure. The residue was then purified by preparative high-performance liquid chromatography (HPLC) (column: Ultimate C18 150 mm × 40 mm × 5 μm; mobile phase: ammonia solution-acetonitrile; gradient: acetonitrile 40%-60%, 10 min) to obtain compound 26. 1 H NMR(400MHz,CD3OD)δ8.04(s,1H),7.57-7.47(m,1H),7.47-7.33(m,1H),7.28 -7.08(m,2H),7.08-6.75(m,1H),5.86-5.70(m,1H),4.74-4.54(m,5H),3.93(s ,3H),3.89-3.63(m,2H),3.62-3.46(m,1H),2.69-2.43(m,2H),2.40(s,3H),2 .37-2.30(m,1H),1.62(d,J=6.8Hz,3H),1.39-1.08(m,2H),1.04-0.86(m,2H). MS-ESI calculated value [M+H] + 572, measured value 572.

[0574] Example 27

[0575]

[0576] Synthesis route:

[0577]

[0578] first step

[0579] Under nitrogen protection, compound 27-1 (6.00 g, 23.3 mmol) was dissolved in dry toluene (100 mL), compound 14-6 (12.6 g, 34.9 mmol) was added, followed by palladium dichloride bis(triphenylphosphine) (1.63 g, 2.33 mmol). The reaction mixture was stirred at 120 °C for 12 hours. After cooling to room temperature, saturated potassium fluoride aqueous solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 27-2, which was used directly in the next step.

[0580] Step 2

[0581] Compound 27-2 (5.83 g, 23.4 mmol) was dissolved in acetone (80 mL), and concentrated hydrochloric acid (12 M, 9.96 mL) was added dropwise at 0 °C. The reaction solution was stirred at 25 °C for 1 hour. The pH of the reaction solution was alkalized to 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine (50 mL × 1). The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 4 / 1, V / V) to obtain compound 27-3. 1 ¹H NMR (400MHz, CDCl₃) δ 7.30–7.26 (m, ¹H), 7.08–7.00 (m, ¹H), 2.66–2.63 (m, ³H). MS-ESI calculated values ​​[M+H] + 222, measured value 222.

[0582] Step 3

[0583] Compound 27-3 (4.84 g, 16.7 mmol) was dissolved in dry tetrahydrofuran (50 mL), and tetraethyl titanate (7.62 g, 33.4 mmol) and compound B-4 (3.04 g, 25.1 mmol) were added. The reaction mixture was stirred at 80 °C for 24 hours, cooled to 0 °C, and water (50 mL) was added to the reaction mixture. Ethyl acetate (50 mL × 1) was then added for washing. The organic phase was washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1~2 / 1, V / V) to obtain compound 27-4. MS-ESI calculated value [M+H] + 325, measured value 325.

[0584] Step 4

[0585] Compound 27-4 (4.68 g, 11.8 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). Sodium borohydride (535 mg, 14.2 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour, then cooled to 0 °C and water (100 mL) was added dropwise, followed by ethyl acetate (100 mL × 1). The organic phase was washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1 to 1 / 2, V / V) to obtain compound 27-5. MS-ESI calculated value [M+H] + 327, measured value 327.

[0586] Step 5

[0587] Compound 27-5 (2.16 g, 6.62 mmol) was dissolved in dioxane (30 mL), and dioxane hydrochloride solution (4 M, 16.6 mL) was added dropwise. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane (5 mL) was added at 20 °C and stirred for 10 minutes. The mixture was filtered, and the filter cake was collected and dried to obtain the hydrochloride salt of intermediate 27-6. MS-ESI calculated value [M+H] + 223, measured value 223.

[0588] Step 6

[0589] Compound 4-5 (100 mg, 163 μmol) was dissolved in dimethyl sulfoxide (3 mL), and 27-6 hydrochloride (43.5 mg, 196 μmol) and triethylamine (68.1 μL, 490 μmol) were added. The mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Ultimate C18 150 mm × 25 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 5%-35%, 10 min). Compound 27 was then separated by preparative SFC (column: DAICEL CHIRALCEL OD 250 mm × 30 mm × 10 μm; mobile phase: supercritical CO2-0.1% ammonia in ethanol solution; gradient: 0.1% ammonia in ethanol solution: 35%-35%). 1 ¹H NMR (400MHz, CD₃OD) δ 8.36 (s, 1H), 7.16 (s, 1H), 6.96 (s, 1H), 6.83 (s, 1H), 5.92–5.81 (m, 1H), 4.29–4.07 (m, 1H), 4.03 (s, 3H), 3.55–3.39 (m, 1H), 3.31–3.03 (m, 4H), 2.94–2.72 (m, 1H), 2.67 (s, 3H), 2.61 (s, 3H), 1.70 (d, J = 7.2Hz, 3H), 1.56–1.43 (m, 3H). MS-ESI calculated values ​​[M+H] + 551, measured value 551.

[0590] Example 28

[0591]

[0592] Synthesis route:

[0593]

[0594] first step

[0595] Compound 28-1 (10.0 g, 49.9 mmol) was dissolved in methanol (100 mL), and formaldehyde aqueous solution (20.3 g, 250 mmol, purity: 37%), sodium cyanoborohydride (9.41 g, 150 mmol), and acetic acid (15.0 g, 250 mmol) were added. The mixture was stirred at 25 °C for 12 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (200 mL × 3). The organic phase was washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to obtain compound 28-2.1 ¹H NMR (400MHz, CDCl₃) δ 4.27–4.13 (m, 1H), 3.87–3.75 (m, 1H), 3.17–3.04 (m, 1H), 2.77–2.69 (m, 1H), 2.63–2.55 (m, 1H), 2.24 (s, 3H), 2.14–2.06 (m, 1H), 1.95–1.86 (m, 1H), 1.46 (s, 9H), 1.24 (d, J = 6.8 Hz, 3H). MS-ESI calculated values ​​[M+H] + 215, measured value 215.

[0596] Step 2

[0597] Compound 28-2 (6.00 g, 28.0 mmol) was dissolved in dioxane (50 mL), and dioxane hydrochloride solution (4 M, 20.0 mL) was added dropwise. The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 28-3. 1 H NMR (400MHz, CD3OD) δ 3.89-3.74 (m, 3H), 3.74-3.66 (m, 1H), 3.66-3.31 (m, 3H), 2.99 (s, 3H), 1.43 (d, J = 6.4Hz, 3H).

[0598] Step 3

[0599] The hydrochloride salt of compound 28-3 (2.65 g, 14.1 mmol) was dissolved in N,N-dimethylformamide (20 mL), and triethylamine (4.77 g, 47.1 mmol) and compound 7-2 (3.5 g, 9.43 mmol) were added dropwise. The mixture was stirred at 25 °C for 12 hours. The solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1–10 / 1, V / V) to give compound 28-4. MS-ESI calculated value [M+H] + 347, measured value 347.

[0600] Step 4

[0601] Compound 28-4 (500 mg, 1.44 mmol) was dissolved in dichloromethane (15 mL), and compounds 1-3 (525 mg, 1.73 mmol), 4-dimethylaminopyridine (17.6 mg, 144 μmol), and triethylamine (438 mg, 4.33 mmol) were added. The mixture was stirred at 25 °C for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to give compound 28-5. MS-ESI calculated value [M+H] + 613, measured value 613.

[0602] Step 5

[0603] Compound 28-5 (360 mg, 523 μmol) was dissolved in dimethyl sulfoxide (10 mL), and 14-10 (194 mg, 784 μmol) and triethylamine (159 mg, 1.57 mmol) were added. The mixture was stirred at 90 °C for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex C18 150 × 40 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 5%-35%, 10 min) to obtain the hydrochloride salt of compound 28. 1 H NMR(400MHz,MeOD)δ8.41(s,1H),7.61(t,J=7.2Hz,1H),7.42(t,J=7.2Hz,1H),7 .23(t,J=7.2Hz,1H),7.17(s,1H),6.01-5.99(m,1H),4.73-4.58(m,1H)4.51-4.2 0(m,1H),4.04(s,3H),3.63-3.56(m,3H),3.43-3.37(m,1H),3.25-3.18(m,1H), 3.00(s,3H),2.62(s,3H),1.74(d,J=7.2Hz,3H),1.57-1.47(m,3H),1.29(s,6H). MS-ESI calculated value [M+H] + 576, measured value 576.

[0604] Example 29

[0605]

[0606] Synthesis route:

[0607]

[0608] first step

[0609] Compound 29-1 (10.0 g, 49.9 mmol) was dissolved in methanol (100 mL), and formaldehyde aqueous solution (20.3 g, 250 mmol, purity: 37%), sodium cyanoborohydride (9.41 g, 150 mmol), and acetic acid (15.0 g, 250 mmol) were added. The mixture was stirred at 25 °C for 12 hours. Water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 1 / 0 to 10 / 1, V / V) to obtain compound 29-2. 1 ¹H NMR (400MHz, CDCl₃) δ 4.21–4.18 (m, 1H), 3.82–3.79 (m, 1H), 3.13–3.06 (m, 1H), 2.74–2.70 (m, 1H), 2.60–2.52 (m, 1H), 2.24 (s, 3H), 2.11–2.07 (m, 1H), 1.93–1.86 (m, 1H), 1.45 (s, 9H), 1.29 (d, J = 7.2 Hz, 3H). MS-ESI calculated values ​​[M+H] + 215, measured value 215.

[0610] Step 2

[0611] Compound 29-2 (7.25 g, 33.8 mmol) was dissolved in dioxane (50 mL), and dioxane hydrochloride solution (4 M, 67.6 mL) was added dropwise. The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 29-3. 1 H NMR (400MHz, CD3OD) δ 3.82-3.73 (m, 3H), 3.74-3.66 (m, 1H), 3.66-3.31 (m, 3H), 3.02 (s, 3H), 1.47 (d, J = 7.2Hz, 3H).

[0612] Step 3

[0613] The hydrochloride salt of compound 29-3 (811 mg, 5.39 mmol) was dissolved in N,N-dimethylformamide (15 mL), and triethylamine (1.64 g, 16.2 mmol) and compound 7-2 (1.00 g, 2.69 mmol) were added dropwise. The mixture was stirred at 25 °C for 12 hours. The solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1–1 / 1, V / V) to give compound 29-4. MS-ESI calculated value [M+H] + 347, measured value 347.

[0614] Step 4

[0615] Compound 29-4 (254 mg, 733 μmol) was dissolved in dichloromethane (5 mL), and compound 1-3 (333 mg, 1.10 mmol), 4-dimethylaminopyridine (8.96 mg, 73.3 μmol), and N,N-diisopropylethylamine (284 mg, 2.20 mmol) were added. The mixture was stirred at 25 °C for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL × 5). The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 1 / 0–10 / 1, V / V) to give compound 29-5. MS-ESI calculated value [M+H] + 613, measured value 613.

[0616] Step 5

[0617] Compound 29-5 (154 mg, 251 μmol) was dissolved in dimethyl sulfoxide (5 mL), and 14-10 (93.2 mg, 377 μmol) and triethylamine (76.3 mg, 754 μmol) were added. The mixture was stirred at 90 °C for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Ultimate C18 150 × 40 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 5%-30%, 10 min) to obtain the hydrochloride salt of compound 29. 1¹H NMR (400MHz, MeOD) δ 8.40 (s, 1H), 7.61 (t, J = 7.2Hz, 1H), 7.42 (t, J = 6.8Hz, 1H), 7.23 (t, J = 7.2Hz, 1H), 7.16 (s, 1H), 6.01–5.99 (m, 1H), 4.93–4.86 (m, 1H), 4.68–4.22 (m, 1H), 4.04 (s, 3H), 3.62–3.55 (m, 4H), 3.23–3.19 (m, 1H), 2.99 (s, 3H), 2.62 (s, 3H), 1.74 (d, J = 6.8Hz, 3H), 1.57–1.48 (m, 3H), 1.29 (s, 6H). MS-ESI calculated values ​​[M+H] + 576, measured value 576.

[0618] Biological activity:

[0619] Experiment Example 1: Experiment combining KRAS (G12C) and SOS1

[0620] Experimental principle:

[0621] The small molecule compound binds to the catalytic site of SOS1, inhibiting the binding of SOS1 to KRAS(G12C). When the binding of fluorescently labeled SOS1 protein to fluorescently labeled KRAS(G12C) protein is inhibited, the emitted fluorescence changes. By detecting the fluorescence change, the ability of the small molecule to prevent the binding of SOS1 to KRAS(G12C) can be tested. A homogeneous time-resolved fluorescence (HTRF) binding assay was used to detect the ability of the compound of this invention to inhibit the interaction between SOS1 and KRAS(G12C).

[0622] Experimental materials:

[0623] KRAS(G12C) protein was expressed and purified by Wuhan Pujian Biotechnology Co., Ltd.; SOS1 exchange domin (564-1049) protein (Hμman recombinant) was purchased from Cytoskeleton; Mab Anti 6HIS-XL665 and Mab Anti GST-Eμcryptate were purchased from Cisbio. A Nivo5 multi-functional microplate reader was purchased from PerkinElmer.

[0624] Experimental methods:

[0625] 1X buffer preparation (prepare immediately): Hepes: 5mM; NaCl: 150mM; EDTA: 10mM; Igepal: 0.0025%; KF: 100mM; DTT: 1mM; BSA: 0.05%;

[0626] The test compound was diluted 5-fold to the 8th concentration using a multi-channel pipette with DMSO, i.e., from 1 mM to 0.064 μM.

[0627] Dilute the analyte to a working solution of 2% DMSO using 1X buffer. Add 5 μL / well to the corresponding well, corresponding to a concentration gradient from 20 μM to 0.00128 nM. Perform duplicate well experiments. Centrifuge at 1000 rpm for 1 minute.

[0628] Prepare a mixed working solution of KRAS(G12C) (200 nM) and Mab Anti GST-Eμcryptate (1 ng / μL) using 1X buffer. Incubate the mixed working solution at 25°C for 5 minutes, and add 2.5 μL / well to the corresponding well.

[0629] A mixed working solution of SOS1 (80 nM) and Mab Anti 6HIS-XL665 (8 g / μL) was prepared using 1X buffer. 2.5 μL / well was added to the corresponding well. 2.5 μL of Mab Anti 6HIS-XL665 (8 g / μL) diluent was added to the Blank well. The final concentration gradient of the compounds was 10 μM diluted to 0.64 nM: KRAS (G12C) (500 nM), MAb Anti GST-Eu cryptate (0.25 ng / μL), SOS1 (20 nM), and Mab Anti 6HIS-XL665 (2 g / μL). The reaction system was incubated at 25 °C for 60 minutes. HTRF was read using a multi-label analyzer after the reaction.

[0630] Data Analysis:

[0631] The original data were converted into inhibition rate (IC) using the equation (Sample-Min) / (Max-Min)×100%. 50 The values ​​can be obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response -- Variable slope mode). Table 1 provides the inhibitory activity of the compounds of this invention on the binding of KRAS(G12C) and SOS1.

[0632] Table 1 shows the IC50 values ​​of the compounds of this invention for binding to KRAS(G12C) and SOS1. 50 Value test results

[0633] Test compound <![CDATA[IC 50 (nM)]]> Compound 2 109.8 Hydrochloride salt of compound 4 71.1 Hydrochloride salt of compound 5 77.3 Hydrochloride salt of compound 6 87.6 Compound 7 92.8 Hydrochloride salt of compound 8 73.7 Compound 9 83.6 Compound 11 78.6 Compound 13 70.4 Hydrochloride salt of compound 14 40.4 Hydrochloride salt of compound 15 149.4 Hydrochloride salt of compound 16 59.6 Hydrochloride salt of compound 18 23.4 Hydrochloride salt of compound 19 104.9 Compound 24 47.9 Compound 25 86.1 Compound 26 65.9 Compound 27 40.64

[0634] Hydrochloride salt of compound 28 14.49 Hydrochloride salt of compound 29 14.66

[0635] Experimental conclusion: The compound of this invention has a significant inhibitory effect on the binding of KRAS(G12C) and SOS1.

[0636] Experimental Example 2: H358 Cell 3D Proliferation Inhibition Activity Test

[0637] Experimental principle:

[0638] In H358 cells with the KRAS(G12C) mutation, the KRAS signaling pathway is abnormally activated. Small molecule SOS1 inhibitors inhibit the binding of SOS1 to RAS protein, reducing its GEF activity and decreasing the proportion of activated RAS-GTP. This further downregulates the phosphorylation level of the downstream MEK / ERK pathway, thereby inhibiting cell proliferation. The small molecule was co-cultured with H358 cells in a 3D space, and cell readings were then used to indirectly reflect the inhibitory activity of the SOS1 inhibitor on the proliferation of H358 cells.

[0639] Experimental materials:

[0640] RPMI 1640 medium, fetal bovine serum, and penicillin / streptomycin antibiotics were purchased from Vicente; low-melting-point agarose was purchased from Sigma; Almar blue reagent was purchased from Invitrogen; NCI-H358 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.; Nivo multilabel analyzer (PerkinElmer).

[0641] Experimental methods:

[0642] H358 cells were seeded in 96-well U-shaped plates. A 2% stock solution of low-melting-point agarose was prepared. Before use, the agarose stock solution was heated in a microwave oven until completely melted, then kept liquid in a 42°C water bath. A 0.6% gel concentration was prepared by adding the gel to serum-containing culture medium as the bottom layer, and 50 μL was spread into each well of the 96-well U-shaped plate. After the bottom layer solidified, the 2% gel was added to the cell-containing culture medium to prepare a 0.4% cell-containing top layer, with a cell density of 4 × 10⁶ cells / well. 4 Cells / mL: 75 μL was added to each well of a 96-well U-shaped plate coated with the base layer gel, resulting in a cell density of 3000 cells per well. After the top layer gel solidified, the cell culture plates were incubated overnight in a CO2 incubator.

[0643] On the day of compound addition, 85 μL of liquid culture medium was added to a 96-well U-shaped plate containing cells. The test compound was then diluted 3-fold to the 9th concentration using a pipette, from 6 mM to 0.9 μM, for a double-duplicate assay. 97 μL of culture medium was added to the intermediate plate, and then 2.5 μL of serially diluted compound was transferred to each well of the intermediate plate according to the corresponding positions. After mixing, 40 μL was transferred to each well of the cell plate. The concentration range of the compound transferred to the cell plate was 30 μM to 4.5 nM. The cell plates were incubated in a CO2 incubator for 7 days. On day 8, the test compound was diluted 3-fold to the 9th concentration using a pipette, from 6 mM to 0.9 μM, for a double-duplicate assay. Add 198 μL of culture medium to the intermediate plate, then transfer 2 μL of serially diluted compound per well to the first intermediate plate according to the corresponding positions. Add 100 μL of culture medium to the second intermediate plate, then add 100 μL of the mixed compound from the first intermediate plate, mix well, and transfer 40 μL per well to the cell plate. The concentration range of the compound transferred to the cell plate is 30 μM to 4.5 nM. Incubate the cell plates in a CO2 incubator for 7 days. Co-incubate the compound and cells for 14 days, then add 20 μL of Almar blue assay reagent to each well of the cell plate. Shake the dyed plate on a horizontal shaker for 15 minutes, then incubate at room temperature for 5 hours to allow the luminescence signal to stabilize. Read the values ​​using a multi-label analyzer.

[0644] Data Analysis:

[0645] The original data were converted into inhibition rate (IC) using the equation (Sample-Min) / (Max-Min)×100%. 50 The value can be obtained by curve fitting using four parameters (obtained in the "log(inhibitor) vs. response--Variable slope" mode in GraphPad Prism).

[0646] Experimental conclusion: The compound of this invention can inhibit the proliferation of H358 cells under 3D conditions.

[0647] Experiment Example 3: Assay on the inhibitory activity of p-ERK proliferation in DLD-1 cells

[0648] Experimental materials:

[0649] DLD-1 cells were purchased from Nanjing Kebai; 1640 culture medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; and Advanced Phospho-ERK1 / 2 (THR202 / TYR204) KIT was purchased from Cisbio.

[0650] Table 2. Ingredients of Advanced Phospho-ERK1 / 2 (THR202 / TYR204) Kit

[0651] Ingredient name Storage temperature Advanced PhosphoERK1 / 2 Eu Cryptate antibody ≤--16℃ Advanced PhosphoERK1 / 2 d2 antibody ≤--16℃ Blocking reagent(stock solution 100X) ≤--16℃ Lysis buffer#1(stock solution 4X) ≤--16℃ Detection buffer(ready-to-use) ≤--16℃

[0652] Experimental methods:

[0653] DLD-1 cells were seeded in clear 96-well cell culture plates with 80 μL of cell suspension per well, containing 8000 DLD-1 cells per well. The cell culture plates were placed in a CO2 incubator and incubated overnight at 37°C.

[0654] The test compound was diluted to 2 mM with 100% DMSO as the first concentration, and then diluted 5-fold to the eighth concentration, i.e., from 2 mM to 0.026 μM, using a pipette. 2 μL of the compound was added to 78 μL of cell starvation medium, mixed well, and then 20 μL of the compound solution was added to the corresponding well of the cell plate. The cell plate was returned to the CO2 incubator for another hour. At this point, the compound concentration was 10 μM to 0.128 nM, and the DMSO concentration was 0.5%.

[0655] After incubation, discard the cell supernatant and add 50 μL of cell lysis buffer to each well, then incubate at room temperature with shaking for 30 minutes.

[0656] Phospho-ERK1 / 2 Eu Cryptate antibody and Phospho-ERK1 / 2 d2 antibody were diluted 20-fold using detection buffer;

[0657] Take 16 μL of cell lysate supernatant into each well of a new 384 white microplate, then add 2 μL of Phospho-ERK1 / 2 Eu Cryptate antibody dilution buffer and 2 μL of Phospho-ERK1 / 2 d2 antibody dilution buffer, and incubate at room temperature for 4 hours;

[0658] After incubation, HTRF excitation was read at 320 nm and emission at 615 nm and 665 nm using a multi-label analyzer.

[0659] Data Analysis:

[0660] The original data were converted into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%, IC 50 The value can be obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response -- Variable slope mode).

[0661] Max well: Positive control well reading is 1X lysis buffer.

[0662] Min wells: Negative control wells read 0.5% DMSO cell lysate.

[0663] Table 3 provides the inhibitory activity of the compounds of the present invention against p-ERK in DLD-1 cells.

[0664] Table 3. IC50 of the compounds of this invention on p-ERK proliferation in DLD-1 cells. 50 Value test results

[0665] Test compound <![CDATA[IC 50 (nM)]]> Compound 2 121.7 Hydrochloride salt of compound 4 113.2

[0666] Hydrochloride salt of compound 5 219.4 Compound 10 86.2 Compound 13 281.9 Compound 14 78.9 Hydrochloride salt of compound 16 222 Hydrochloride salt of compound 18 242.9 Compound 26 283.1 Compound 27 111.9 Hydrochloride salt of compound 28 91.55 Hydrochloride salt of compound 29 135.4

[0667] Experimental conclusion: The compound of this invention has a significant inhibitory effect on the proliferation of p-ERK cells in DLD-1 cells.

[0668] Experimental Example 4A: Pharmacokinetic Evaluation of Compounds

[0669] Experimental materials:

[0670] CD-1 mice (male, 7–9 weeks old, Shanghai Slack)

[0671] Experimental procedure:

[0672] The pharmacokinetic characteristics of the compounds after intravenous and oral administration were tested in rodents using a standard protocol. In the experiment, the candidate compounds were prepared into clear solutions and administered to mice via single intravenous and oral injections. The solvent for both intravenous and oral administration was a mixture of 10% dimethyl sulfoxide and 90% 10% hydroxypropyl β-cyclodextrin. This project used four female CD-1 mice. Two mice were administered the drug intravenously at a dose of 1 mg / kg, and plasma samples were collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 12 h post-administration. The other two mice were administered the drug orally via gavage at a dose of 2 mg / kg, and plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 12 h post-administration. The plasma samples were stirred at 3,200 x g for 10 minutes at 4°C, and the supernatant was separated to obtain plasma samples. 20 times the volume of methanol solution containing internal standard was added to precipitate proteins, and the mixture was stirred at 12,000 x g for 15 min. After centrifugation at 4°C, 50 μL of the supernatant was transferred to a 96-well plate, centrifuged again, and the supernatant was injected. The plasma drug concentration was quantitatively analyzed by LC-MS / MS, and pharmacokinetic parameters, such as peak concentration (C0.05), were calculated. max ), clearance rate (CL), half-life (T) 1 / 2 ), tissue distribution (Vdss), area under the curve (AUC)0-last ), bioavailability (F), etc.

[0673] The experimental results are shown in Table 4:

[0674] Table 4. Pharmacokinetic test results of the compounds of this invention.

[0675]

[0676] Experimental conclusions: The compounds of this invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life, and clearance.

[0677] Experimental Example 4B: Pharmacokinetic Evaluation of Compounds

[0678] Experimental materials:

[0679] Balb / c mice (male, Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0680] Experimental procedure:

[0681] The pharmacokinetic characteristics of the compounds after intravenous and oral administration were tested in rodents using a standard protocol. In the experiment, candidate compounds were prepared into clear solutions and administered to mice via single intravenous and oral injections. The solvent for both intravenous and oral administration was a mixture of 5% dimethyl sulfoxide, 5% solubilol, and 90% water. Four male Balb / c mice were used in this study. Two mice received intravenous administration at a dose of 10 mg / kg, and plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. The other two mice received oral administration at a dose of 50 mg / kg, and plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-administration. Blood samples were placed on ice after collection and centrifuged within one hour (centrifugation conditions: 6000g, 3 minutes, 2-8℃). Plasma samples were stored at -80℃ before analysis. Blood drug concentrations were quantitatively analyzed using LC-MS / MS, and pharmacokinetic parameters, such as peak concentration (C0), were calculated. max ), clearance rate (CL), half-life (T) 1 / 2 ), tissue distribution (Vdss), area under the curve (AUC) 0-last ), bioavailability (F), etc.

[0682] The experimental results are shown in Table 5:

[0683] Table 5. Pharmacokinetic test results of the compounds of this invention.

[0684]

[0685] Experimental conclusions: The compounds of this invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life, and clearance.

[0686] Example 5: In vivo efficacy evaluation of the compound in the Miapaca2 nude mouse xenograft model

[0687] Cell culture:

[0688] Human pancreatic cancer cells (Miapaca2) were cultured in an adherent monolayer in DMEM medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Cells were passaged using trypsin-EDTA digestion two to three times per week. When cell saturation reached 80%–90% and the desired number was achieved, cells were harvested, counted, and seeded.

[0689] Laboratory animals:

[0690] Balb / c nude mice, female, 6-7 weeks old, were purchased from Shanghai Xipu-Bikai Experimental Animal Co., Ltd.

[0691] Model preparation:

[0692] 0.2 mL (5 × 10) 6 Miapaca2 cells (with matrix gel, volume ratio 1:1) were subcutaneously inoculated into the right posterior dorsal region of each mouse, resulting in an average tumor volume of 118 mm². 3 Dosing will begin in groups at that time.

[0693] The dosing regimen is shown in Table 6.

[0694] Table 6. Grouping and Dosing Regimens of Experimental Animals

[0695]

[0696]

[0697] Tumor measurements and experimental indicators:

[0698] The tumor diameter was measured twice a week using calipers. The tumor volume was measured in cubic millimeters and calculated using the following formula: V = 0.5a × b 2 , where a and b are the long and short diameters of the tumor, respectively. The tumor-suppressive efficacy of the test compound was evaluated using TGI (%). TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [1 – (mean tumor volume at the end of treatment – ​​mean tumor volume at the start of treatment) / (mean tumor volume at the end of treatment in the solvent control group – mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0699] The experimental results are shown in Table 7.

[0700] Table 7. Evaluation of the antitumor efficacy of the compounds of this invention in the Miapaca2 nude mouse xenograft model (calculated based on tumor volume on day 22 after administration).

[0701]

[0702] Experimental conclusion: The compound of the present invention, when used in combination with AMG-510, exhibited excellent tumor-suppressing effects in the Miapaca2 nude mouse xenograft model.

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof, ， in, R1, R2, and the nitrogen atom attached to them together form a 3-12 membered heterocyclic alkyl group, wherein the 3-12 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3, or 4 R atoms. b replace; R3 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino groups are independently and optionally converted by 1, 2, 3 or 4 R groups. c replace; R4 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and -C(=O)-OC 1-6 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and -C(=O)-OC 1-6 The alkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace; R5 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino groups are independently and optionally converted by 1, 2, 3 or 4 R groups. c replace; T1 is selected from CR6 and N; R6 is -OCH3; R b Selected independently from -NH2 and C 1-6 Alkyl, C 1-6 Alkylamino and 3-10 membered heterocyclic alkyl groups; R c Each of the following is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, -COOH, -C(=O)H, -C(=O)-NH2, C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3 The alkoxy group and the 5-6 membered heterocyclic alkyl group are each independently and optionally substituted with 1, 2, 3 or 4 R groups; R is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, -COOH, =O, -C(=O)H, -C(=O)-NH2, and C. 1-3 alkyl; In the 5-6 membered heterocyclic alkyl, 3-10 membered heterocyclic alkyl and 3-12 membered heterocyclic alkyl, "hetero" means 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S- and -N-.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (II-1): ， in, T1, R1, R2, R3, R4 and R5 are as defined in claim 1; bring" The carbon atom in “” is a chiral carbon atom, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R is independently selected from F, Cl, Br and =O.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R b Selected independently from -NH2 and C 1-3 Alkyl, C 1-3 Alkylamino and 3-6 membered heterocyclic alkyl groups.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, R b Each is independently selected from -NH2, -CH3, -CH2-CH3, and .

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R c Each element is independently selected from F, Cl, Br, -OH, -OCH3, and .

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from H, F, Cl, Br and -NH2.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH(CH3)2, wherein -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH(CH3)2 are each independently and optionally selected by 1, 2, 3, or 4 Rs. c replace.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from H, F, Cl, Br, -CN, , , , and .

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from H, F, Cl, Br, -CN, , , , , and .

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R5 is selected from H, F, Cl, Br and -CH3.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R1, R2, and the nitrogen atom attached to them together form a 5-11 membered heterocyclic alkyl group, wherein the 5-11 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3, or 4 R atoms. b replace.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , , and , wherein , , , , , , , and Each of the 1, 2, 3, or 4 R's can be independently selected. b replace.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , , , , , , and .

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , , , , , , , , and .

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I-2): ， in, R1, R2, R3, R4 and R5 are as defined in claim 1.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I-3): ， in, R1, R2, R3, R4 and R5 are as defined in claim 16; bring" The carbon atom in “” is a chiral carbon atom, existing in a single enantiomer (R) or (S) form or rich in one enantiomer form.

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I-4), (I-5), (I-6), or (III-1): , , or , in, T and V are independently selected from CH2, NH and O, respectively; m is selected from 0, 1, 2, 3, and 4; n, p, q, r, and s are independently selected from 0, 1, and 2, respectively; And p + q ≤ 3; W is selected from NH, -CH2-CH2- and -O-CH2-; Y is selected from N and CH; R7 and R8 are independently selected from H, -NH2, and C, respectively. 1-3 alkyl; Alternatively, R7, R8, and the carbon atoms bonded to them together form C. 3-4 Cycloalkyl groups; R3, R4, R5 and R b As defined in claim 1.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein, R7 and R8 are independently selected from H and -CH3, respectively.

20. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein, R7, R8, and the carbon atoms attached to them together form a cyclopropyl group.

21. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I-7), (I-8), (I-9), or (III-1A): , , or , in, T, V, W, Y, m, n, p, q, r, s, R3, R4, R5, R b R7 and R8 are as defined in claim 18; bring" The carbon atom in “” is a chiral carbon atom, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I-10), (I-11), (I-12) or (III-2): , , or , in, T, V, W, Y, m, n, p, q, r, s, R3, R4, R5 and R b R7 and R8 are as defined in claim 21.

23. A compound of the following formula or a pharmaceutically acceptable salt thereof, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein the compound is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

26. Use of the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating KRAS-mutant solid tumors.

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