Tetrahydropapaverine derivative and use thereof

Abstract

The present disclosure relates to a tetrahydropapaverine derivative and use thereof. Specifically, provided is a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein the definition of each substituent is as defined herein.

Description

Tetrahydropapaverine derivatives and their uses Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to tetrahydropapaverine derivatives and their uses. Background Technology

[0002] Neuromuscular-blocking drugs (NMBDs) play a crucial role in anesthesiology and can be classified into non-depolarizing and depolarizing types based on their mechanism of action and effects. Non-depolarizing drugs (such as vecuronium bromide) paralyze muscles by competitively binding to cholinergic receptors at the neuromuscular junction, blocking the action of acetylcholine. Depolarizing drugs (such as succinate) interfere with the electrical potential of nerve ending cell membranes, preventing normal muscle contraction.

[0003] WO2014005122 discloses a series of non-depolarizing ultra-short-acting, short-acting, and intermediate-acting neuromuscular blocking agents, wherein the neuromuscular blockade (NMB) induced by the agents is reversible, for example, by administration of cysteine ​​or related compounds. Summary of the Invention

[0004] This disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0005] in:

[0006] Y is selected from -C(R) a’ R b’ ), -O-, -S-, -S(O)2-, -Si(CH3)2-;

[0007] W is -C(R) a R b R c );

[0008] Each is independently selected from pharmaceutically acceptable anions;

[0009] R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 3a R3b R 4 R 4a R 4b R 5 R 6 R 7 R 8 R A1 R A2 R A3 R A4 R B1 R B2 R B3 R B4 R B5 R D1 R D2 R D3 R D4 R D5 R W1 R W2 R W3 R W4 R W5 R a R b R c Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace,

[0010] Or, R 1a and R 1b R 1c and R 1d R 1e and R 1f R 2a and R 2b R 2c and R 2d R 2e and R 2f R 3a and R 3b R 4a and R 4b R 5 and R 6 R 7 and R 8 R W1 and R W2 Or R W3 and R W4One or more groups of atoms, together with the attached atoms, form an oxo group, a thio group, a 3- to 10-membered alicyclic ring, a 3- to 10-membered alicyclic heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the alicyclic ring, alicyclic heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally surrounded by one or more R groups. B replace;

[0011] R a’ R b’ Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace,

[0012] Or, R a’ and R b’ Together with the attached atoms, it forms an oxo group, a thio group, a 3- to 10-membered alicyclic ring, a 3- to 10-membered alicyclic heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the alicyclic ring, alicyclic heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally surrounded by one or more R groups. B replace;

[0013] R y Each is independently selected from halogen, hydroxyl, thiol, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R C replace,

[0014] Alternatively, choose any two Rs. y Each alicyclic ring or heterocyclic ring independently forms a 3- to 10-membered alicyclic ring with its connected atoms, wherein the alicyclic ring or heterocyclic ring is optionally bounded by one or more R atoms. D replace;

[0015] R e R f Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R E replace;

[0016] R A R B R C R D R EEach is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups;

[0017] g and h are each independently selected from 0, 1, 2, and 3;

[0018] When g and h are both 0, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 4 R 5 R 6 R 7 R 8 It cannot be hydrogen at the same time;

[0019] When g is not 0 and h is 0, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 3a R 3b R 4 R 5 R 6 R 7 R 8 It cannot be hydrogen at the same time;

[0020] When g is 0 and h is not 0, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R2f R 3 R 4 R 4a R 4b R 5 R 6 R 7 R 8 It cannot be hydrogen at the same time;

[0021] When g is not 0 and h is not 0, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 3a R 3b R 4 R 4a R 4b R 5 R 6 R 7 R 8 It cannot be hydrogen at the same time;

[0022] a, b, c, and d are each independently selected from 0, 1, 2, and 3;

[0023] Each y is independently selected from 0, 1, 2, 3, and 4.

[0024] In some implementations, Y is selected from -C(R) a’ R b’ ), -O- or -S-.

[0025] In some implementation schemes, where Selected from

[0026] in,

[0027] R 1 R 2 They cannot all be hydrogen at the same time, and each can be independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, or N(R) groups. e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace,

[0028] Or, R 1 and R 2 Together with the attached atoms, it forms an oxo group, a thio group, a 3- to 10-membered alicyclic ring, a 3- to 10-membered alicyclic heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the alicyclic ring, alicyclic heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally surrounded by one or more R groups. B replace;

[0029] Ring F is selected from 3- to 10-membered alicyclic rings, 3- to 10-membered alicyclic and heterocyclic rings, 6- to 10-membered aromatic rings, or 5- to 10-membered heterocyclic rings, wherein the alicyclic, alicyclic, aromatic, or heterocyclic ring is optionally surrounded by one or more R. B replace;

[0030] R F R p R q Each is independently selected from halogen, hydroxyl, thiol, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R C replace,

[0031] Alternatively, choose any two Rs. p Or choose any 2 Rs q Each alicyclic ring or heterocyclic ring independently forms a 3- to 10-membered alicyclic ring with its connected atoms, wherein the alicyclic ring or heterocyclic ring is optionally bounded by one or more R atoms. D replace;

[0032] f, p, and q are each independently selected from 0, 1, 2, and 3;

[0033] e1, e2, and e3 are each independently selected from 1, 2, 3, 4, 5, and 6;

[0034] R y R B R C R D R e R f a, b, c, d, and y are as defined above.

[0035] In some embodiments, ring F is selected from alicyclic or benzene rings.

[0036] In some implementations, R 1 R 2They cannot all be hydrogen, and each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R... 1 R 2 They cannot all be hydrogen, and each can be independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, and cyclopentyl. In some embodiments, R... 1 R 2 They cannot all be hydrogen, and each can be independently selected from hydrogen, fluorine, methyl, methoxy, and cyclopropyl. In some embodiments, R... 1 R 2 Both are fluorine.

[0037] In some implementation schemes, both g and h are 0.

[0038] In some embodiments, the compound represented by Formula I is selected from compounds represented by Formula II-A1, Formula II-A2, Formula II-A3, Formula II-A3', Formula II-A4, Formula II-A5, Formula II-A6, Formula II-A7, Formula II-A7', Formula II-A8, Formula II-A9, Formula II-A10, Formula II-A11, Formula II-A12, Formula II-A13, Formula II-A14, Formula II-A15, Formula II-A15', Formula II-A16, or Formula II-A17.

[0039] in:

[0040] R m R n Each is independently selected from halogen, hydroxyl, thiol, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R C replace,

[0041] Alternatively, choose any two Rs. m Or choose any 2 Rs n Each alicyclic ring or heterocyclic ring independently forms a 3- to 10-membered alicyclic ring with its connected atoms, wherein the alicyclic ring or heterocyclic ring is optionally bounded by one or more R atoms. D replace;

[0042] u is selected from 1, 2, 3, 4, 5, 6;

[0043] v is selected from 1, 2, 3, 4, 5, 6;

[0044] m and n are each independently selected from 0, 1, 2, and 3;

[0045] W, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 4 R 5 R 6 R 7 R 8 R A1 R A2 R A3 R A4 R B1 R B2 R B3 R B4 R B5 R D1 R D2 R D3 R D4 R D5 R W1 R W2 R W3 R W4 R W5 R C R D R e R f R y y, R 1 R 2 R p R q p, q, e1, e2, e3 are as defined above.

[0046] In some implementations, both g and h are 2.

[0047] In some embodiments, the compound represented by Formula I is selected from compounds represented by Formula II-B1, Formula II-B2, Formula II-B3, Formula II-B4, Formula II-B4', Formula II-B5, Formula II-B6, Formula II-B7, Formula II-B7', Formula II-B8, Formula II-B9, Formula II-B10, Formula II-B11, Formula II-B12, Formula II-B13, Formula II-B14, Formula II-B15, Formula II-B16, Formula II-B16', or Formula II-B17.

[0048] in:

[0049] R 3c R 3d R 3e R 3f R 4c R 4d R 4e R 4f Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace,

[0050] Or, R 3c and R 3d R 3e and R 3f R 4c and R 4d Or R 4e and R 4f One or more groups of atoms, together with the attached atoms, form an oxo group, a thio group, a 3- to 10-membered alicyclic ring, a 3- to 10-membered alicyclic heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the alicyclic ring, alicyclic heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally surrounded by one or more R groups. B replace;

[0051] W, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R2e R 2f R 3 R 4 R 5 R 6 R 7 R 8 R A1 R A2 R A3 R A4 R B1 R B2 R B3 R B4 R B5 R D1 R D2 R D3 R D4 R D5 R W1 R W2 R W3 R W4 R W5 R C R D R e R f R y y, R 1 R 2 R p R q ,u,p,q,e1,e2,e3,R m R n u, v, m, n are as defined above.

[0052] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, or N(R) groups. eR f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace,

[0053] R A R e R f As defined above.

[0054] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A Replace, R A As defined above.

[0055] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R2e R 2f They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0056] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, fluorine, methyl, ethyl, propyl, isopropyl, or cyclopropyl.

[0057] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 5 R 6 R 7 R 8 They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, or N(R) groups. e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace,

[0058] R A R e R f As defined above.

[0059] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 5 R 6 R 7 R 8 It cannot be hydrogen, halogen, or carbon simultaneously. 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A Replace, R A As defined above.

[0060] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 5 R 6 R 7 R 8 They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0061] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 5 R 6 R 7 R 8 They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, fluorine, methyl, ethyl, propyl, isopropyl, or cyclopropyl.

[0062] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 1a and R 1b R 1c and R 1d R 1e and R 1f R 2a and R 2b R 2c and R 2d R 2e and R 2f R 5 and R 6 R 7 and R 8 R W1 and R W2 Or R W3 and R W4 One or more groups of atoms, together with the attached atoms, form an oxo group, a thio group, a 3- to 10-membered alicyclic ring, a 3- to 10-membered alicyclic heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the alicyclic ring, alicyclic heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally surrounded by one or more R groups. B replace,

[0063] R B As defined above.

[0064] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 1a and R 1b R 1c and R 1d R 1e and R 1f R 2a and R 2b R 2c and R 2d R 2e and R 2f R 5 and R 6 R7 and R 8 R W1 and R W2 Or R W3 and R W4 One or more groups of atoms, together with the attached atoms, form 3 to 10 alicyclic rings, said alicyclic rings optionally separated by one or more R atoms. B Replace, R B As defined above.

[0065] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 1a and R 1b R 1c and R 1d R 1e and R 1f R 2a and R 2b R 2c and R 2d R 2e and R 2f R 5 and R 6 R 7 and R 8 R W1 and R W2 Or R W3 and R W4 One or more groups of atoms in the ring, together with the atoms attached to them, form a cyclopropyl ring.

[0066] In some embodiments, the compounds or pharmaceutically acceptable salts of formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16 or II-A17, wherein R 3 R 4 They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl group. In some embodiments, R... 3 R 4 Each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, and isopropyl. In some embodiments, R...3 R 4 Each is independently selected from hydrogen, fluorine, chlorine, and methyl.

[0067] In some implementations, W is a methyl group.

[0068] In some implementations, R A2 Each is independently selected from C 1-6 Alkyloxy group. In some embodiments, R... A2 Each is independently selected from methoxy and ethoxy groups. In some embodiments, R... A2 Each is independently selected from methoxy groups.

[0069] In some implementations, R A3 Each is independently selected from C 1-6 Alkyloxy group. In some embodiments, R... A3 Each is independently selected from methoxy and ethoxy groups. In some embodiments, R... A3 Each is independently selected from methoxy groups.

[0070] In some implementations, R B2 Each is independently selected from C 1-6 Alkyloxy group. In some embodiments, R... B2 Each is independently selected from methoxy and ethoxy groups. In some embodiments, R... B2 Each is independently selected from methoxy groups.

[0071] In some implementations, R D2 Each is independently selected from C 1-6 Alkyloxy group. In some embodiments, R... D2 Each is independently selected from methoxy and ethoxy groups. In some embodiments, R... D2 Each is independently selected from methoxy groups.

[0072] In some implementations, R D3 Each is independently selected from C 1-6 Alkyloxy group. In some embodiments, R... D3 Each is independently selected from methoxy and ethoxy groups. In some embodiments, R... D3 Each is independently selected from methoxy groups.

[0073] In some implementations, R A1 It is hydrogen.

[0074] In some implementations, R A4 It is hydrogen.

[0075] In some implementations, R B1It is hydrogen.

[0076] In some implementations, R B3 It is hydrogen.

[0077] In some implementations, R B4 It is hydrogen.

[0078] In some implementations, R B5 It is hydrogen.

[0079] In some implementations, R D1 It is hydrogen.

[0080] In some implementations, R D4 It is hydrogen.

[0081] In some implementations, R D5 It is hydrogen.

[0082] In some implementations, R W1 It is hydrogen.

[0083] In some implementations, R W2 It is hydrogen.

[0084] In some implementations, R W3 It is hydrogen.

[0085] In some implementations, R W4 It is hydrogen.

[0086] In some implementations, R W5 It is hydrogen.

[0087] In some embodiments, the compound represented by Formula I is selected from compounds represented by Formula III-A1, Formula III-A2, Formula III-A3, Formula III-A3', Formula III-A4, Formula III-A5, Formula III-A6, Formula III-A7, Formula III-A7', Formula III-A8, Formula III-A9, Formula III-A10, Formula III-A11, Formula III-A12, Formula III-A13, Formula III-A14, Formula III-A15, Formula III-A15', Formula III-A16, or Formula III-A17.

[0088] in, R 1a R 1b R 1c R 1d R 1e R 1f R2a R 2b R 2c R 2d R 2e R 2f R 3 R 4 R 5 R 6 R 7 R 8 R C R D R e R f R y y, R 1 R 2 R p R q p, q, e1, e2, e3, R m R n u, v, m, n are as defined above.

[0089] In some embodiments, the compounds represented by formulas III-A1, III-A2, III-A3, III-A3', III-A4, III-A5, III-A6, III-A7, III-A7', III-A8, III-A9, III-A10, III-A11, III-A12, III-A13, III-A14, III-A15, III-A15', III-A16, or III-A17, or pharmaceutically acceptable salts thereof, wherein R 3 It is hydrogen.

[0090] In some embodiments, the compounds represented by formulas III-A1, III-A2, III-A3, III-A3', III-A4, III-A5, III-A6, III-A7, III-A7', III-A8, III-A9, III-A10, III-A11, III-A12, III-A13, III-A14, III-A15, III-A15', III-A16, or III-A17, or pharmaceutically acceptable salts thereof, wherein R 4 It is hydrogen.

[0091] In some embodiments, the compounds represented by formulas III-A1, III-A2, III-A3, III-A3', III-A4, III-A5, III-A6, III-A7, III-A7', III-A8, III-A9, III-A10, III-A11, III-A12, III-A13, III-A14, III-A15, III-A15', III-A16, or III-A17, or pharmaceutically acceptable salts thereof, wherein R 5 It is hydrogen.

[0092] In some embodiments, the compounds represented by formulas III-A1, III-A2, III-A3, III-A3', III-A4, III-A5, III-A6, III-A7, III-A7', III-A8, III-A9, III-A10, III-A11, III-A12, III-A13, III-A14, III-A15, III-A15', III-A16, or III-A17, or pharmaceutically acceptable salts thereof, wherein R 6 It is hydrogen.

[0093] In some embodiments, the compounds represented by formulas III-A1, III-A2, III-A3, III-A3', III-A4, III-A5, III-A6, III-A7, III-A7', III-A8, III-A9, III-A10, III-A11, III-A12, III-A13, III-A14, III-A15, III-A15', III-A16, or III-A17, or pharmaceutically acceptable salts thereof, wherein R 7 It is hydrogen.

[0094] In some embodiments, the compounds represented by formulas III-A1, III-A2, III-A3, III-A3', III-A4, III-A5, III-A6, III-A7, III-A7', III-A8, III-A9, III-A10, III-A11, III-A12, III-A13, III-A14, III-A15, III-A15', III-A16, or III-A17, or pharmaceutically acceptable salts thereof, wherein R 8 It is hydrogen.

[0095] In some embodiments, the compound represented by Formula I is selected from compounds represented by Formula IV-A1, IV-A2, IV-A3, IV-A3', IV-A4, IV-A5, IV-A6, IV-A7, IV-A7', IV-A8, IV-A9, IV-A10, IV-A11, IV-A12, IV-A13, IV-A14, IV-A15, IV-A15', IV-A16, or IV-A17.

[0096] in, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R2c R 2d R 2e R 2f R y y, R 1 R 2 R p R q p, q, e1, e2, e3, R m R n u, v, m, n are as defined above.

[0097] In some implementations, e1 is independently 1, 2, 3, or 4. In some implementations, e1 is independently 1, 2, or 3. In some implementations, e1 is independently 2.

[0098] In some implementations, p is 0.

[0099] In some implementations, q is 0.

[0100] In some implementations, y is 0.

[0101] Wherein the compound represented by formula I is the compound represented by formula V-1 or formula V-2,

[0102] in,

[0103] Z is selected from O or S;

[0104] R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f As defined above.

[0105] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 1a R 1b R 1c R1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 4c R 4d R 4e R 4f They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, or N(R) groups. e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace,

[0106] R A R e R f As defined above.

[0107] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 4c R 4d R 4e R 4f They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A Replace, R A As defined above.

[0108] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 4c R 4d R 4e R 4f They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0109] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 4c R 4d R 4e R 4f They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, fluorine, methyl, ethyl, propyl, isopropyl, or cyclopropyl.

[0110] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 5 R 6 R 7 R 8 They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, or N(R) groups. e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace,

[0111] R A R e R f As defined above.

[0112] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 5 R 6 R 7 R 8 It cannot be hydrogen, halogen, or carbon simultaneously. 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A Replace, R A As defined above.

[0113] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 5 R 6R 7 R 8 They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0114] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 5 R 6 R 7 R 8 They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, fluorine, methyl, ethyl, propyl, isopropyl, or cyclopropyl.

[0115] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 1a and R 1b R 1c and R 1d R 1e and R 1f R 2a and R 2b R 2c and R 2d R 2e and R 2f R 5 and R 6 R 7 and R 8 R W1 and R W2 Or R W3 and R W4 One or more groups of atoms, together with the attached atoms, form an oxo group, a thio group, a 3- to 10-membered alicyclic ring, a 3- to 10-membered alicyclic heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the alicyclic ring, alicyclic heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally surrounded by one or more R groups. B Replace, R B As defined above.

[0116] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 1a and R 1b R 1c and R 1d R 1e and R 1f R 2a and R 2b R 2c and R 2d R 2e and R 2f R 5 and R 6 R 7 and R 8 R W1 and R W2 Or R W3 and R W4 One or more groups of atoms, together with the attached atoms, form 3 to 10 alicyclic rings, said alicyclic rings optionally separated by one or more R atoms. B Replace, R B As defined above.

[0117] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 1a and R 1b R 1c and R 1d R 1e and R 1f R 2a and R 2b R 2c and R 2d R 2e and R 2f R 5 and R 6 R 7 and R 8 R W1 and R W2 Or R W3 and RW4 One or more groups of atoms in the ring, together with the atoms attached to them, form a cyclopropyl ring.

[0118] In some embodiments, the compounds represented by formula II-B1, II-B2, II-B3, II-B4, II-B4', II-B5, II-B6, II-B7, II-B7', II-B8, II-B9, II-B10, II-B11, II-B12, II-B13, II-B14, II-B15, II-B16, II-B16' or II-B17, or pharmaceutically acceptable salts thereof, wherein R 3 R 4 They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl group. In some embodiments, R... 3 R 4 Each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, and isopropyl. In some embodiments, R... 3 R 4 Each is independently selected from hydrogen, fluorine, chlorine, and methyl.

[0119] In some implementations, W is a methyl group.

[0120] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from:

[0121] , As defined above.

[0122] In some implementation schemes, where Each is independently selected from halide ions, acetate, formate, benzoate, benzenesulfonate, camphorsulfonate, citrate, ethanedisulfonate, fumarate, glucoheponicate, glucuronate, glucuronate, hydroxyethanesulfonate, lactate, lacturonic acid, dodecyl sulfate, malate, maleate, methanesulfonate, naphthocarboxylate, naphthalenesulfonate, nitrate, stearate, oleate, oxalate, dihydroxynaphthalate, phosphate, hydrogen phosphate, dihydrogen phosphate, polygalacturonic acid, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate. In some embodiments, wherein... Each is independently selected from chloride ions, bromide ions, fluoride ions, iodide ions, trifluoroacetate ions, formate ions, methanesulfonate ions, and benzenesulfonate ions. In some embodiments, wherein... Each is independently selected from chloride ions, bromide ions, trifluoroacetate ions, formate ions, methanesulfonate ions, and benzenesulfonate ions.

[0123] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the compounds or pharmaceutically acceptable salts shown in the table below.

[0124] On the other hand, this disclosure also provides the compounds shown in the table below, or their pharmaceutically acceptable salts.

[0125] This disclosure also provides a compound of formula A or a pharmaceutically acceptable salt thereof.

[0126] Among them, Y, R 2a R 2b R 2c R 2d R 2e R 2f R 7 R 8 R D1 R D2 R D3 R D4 R D5 R y y, a, b, c, d are as defined above.

[0127] In some embodiments, the compound of formula A or a pharmaceutically acceptable salt thereof is selected from the compounds of formulas A-1, A-2, A-3, A-4, A-4', A-5, A-6, A-7, A-7', A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-16', or A-17 or pharmaceutically acceptable salts thereof.

[0128] in, R 2a R 2b R 2c R 2d R 2e R 2f R 7 R 8 RD1 R D2 R D3 R D4 R D5 R 1 R 2 R y R p R q ,u,p,q,e1,e2,e3,R m R n , y, u, v, m, n are as defined above.

[0129] This disclosure also provides a compound of formula A' or a pharmaceutically acceptable salt thereof.

[0130] Among them, Y, R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 3a R 3b R 4 R 4a R 4b R 7 R 8 R D1 R D2 R D3 R D4 R D5 R y y, a, b, c, d, g, h are as defined above.

[0131] In some embodiments, the compound of formula A' or a pharmaceutically acceptable salt thereof is selected from the compounds of formulas A-1', A-2', A-3', A-4', A-4"', A-5', A-6', A-7', A-7"', A-8', A-9', A-10', A-11', A-12', A-13', A-14', A-15', A-16', A-16"' or A-17' or pharmaceutically acceptable salts thereof.

[0132] in, R 2a R 2b R 2c R 2d R2e R 2f R 7 R 8 R D1 R D2 R D3 R D4 R D5 R 1 R 2 R y R p R q ,u,p,q,e1,e2,e3,R m R n y, u, v, m, n, R 3 R 3a R 3b R 4 R 4a R 4b g and h are as defined above.

[0133] On the other hand, this disclosure also provides a method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound of formula B with the compound of formula A.

[0134] The definitions of each substituent are as described above.

[0135] In some embodiments, the compound of formula B reacts with the compound of formula A in the presence of a condensing agent. Conversely, the presence of a base favors the reaction between the compound of formula B and the compound of formula A. In some embodiments, the base is selected from, but is not limited to, organic bases, such as DMAP.

[0136] On the other hand, this disclosure also provides a method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound of formula B' with the compound of formula A'.

[0137] The definitions of each substituent are as described above.

[0138] In some embodiments, the compound of formula B' reacts with the compound of formula A' in the presence of a condensing agent. Conversely, the presence of a base favors the reaction between the compound of formula B' and the compound of formula A'. In some embodiments, the base is selected from, but is not limited to, organic bases, such as DMAP.

[0139] This disclosure also provides isotopic substitutes of the aforementioned compounds or their pharmaceutically acceptable salts. In some embodiments, the isotopic substitutes are deuterated derivatives.

[0140] This disclosure also provides the use of the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a medicament for neuromuscular blockade.

[0141] In some embodiments, the drug-induced neuromuscular conduction blockade of the neuromuscular blocking agent can be reversed by a neuromuscular blocking agent antagonist. Such neuromuscular blocking agent antagonists include, for example, L-cysteine, D-cysteine, or mixtures thereof; N-acetylcysteine; glutathione; homocysteine; methionine; S-adenosylmethionine; or penicillamine; or combinations of the above compounds.

[0142] This disclosure further provides a method for inducing neuromuscular blockade in mammals for therapeutic purposes, comprising administering to a mammal an effective amount of the compound described in this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound, wherein the mammal may be a human or a non-human mammal, the mammal may be under general anesthesia, and the therapeutic purpose may include surgery.

[0143] In some embodiments, the method may further include the step of reversing neuromuscular conduction blockade in mammals, including administering a neuromuscular blocking agent antagonist to the mammal. Such neuromuscular blocking agent antagonists include, for example, L-cysteine, D-cysteine, or mixtures thereof; N-acetylcysteine; glutathione; homocysteine; methionine; S-adenosylmethionine; or penicillamine; or combinations of the above compounds.

[0144] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0145] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0146] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0147] This disclosure further provides a kit comprising the compounds described herein or their pharmaceutically acceptable salts or pharmaceutical compositions containing them. In some embodiments, the kit may also comprise a neuromuscular blocking agent antagonist.

[0148] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts. The inorganic salts are selected from hydrochloride, hydrobromide, phosphate, or sulfate; the organic salts are selected from acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, citrate, maleate, tartrate, fumarate, citrate, or lactate.

[0149] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions 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 disclosure. 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 disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0150] 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 disclosed herein, 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 and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0151] In the chemical structure of the compounds described in this disclosure, the bonds are... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For example, the compounds disclosed herein. It can be any of the following configurations, or it can include two of the following configurations simultaneously.

[0152] In the chemical structure of the compounds described in this disclosure, the bonds... The configuration is not specified, meaning it can be Z-configuration, E-configuration, or both configurations. For example, the compounds disclosed herein... Any one of the following configurations, or both of the following configurations,

[0153] Although all the above structural formulas are shown in some isomer form for simplicity, this disclosure can include all isomers, such as tautomers, geometric isomers, diastereomers, racemates and enantiomers.

[0154] The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, a proton tautomer (also known as a proton transfer tautomer) includes an interconversion via proton transfer, as in the compounds of this disclosure which contain the following tautomeristic changes between A and B:

[0155] All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0156] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0157] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even higher. This disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0158] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0159] Compared with the control compound, the compound disclosed herein has significant advantages in terms of in vivo efficacy and safety window.

[0160] Terminology Explanation:

[0161] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0162] "Pharmaceutical excipients" include, but are not limited to, any adjuvants, carriers, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0163] The term "effective amount" or "therapeutic effective amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0164] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, including, but not limited to, halogens, hydroxyl groups, oxo groups, amino groups, and C4 groups. 1-6 Alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6- to 10-aryl, or 5- to 10-heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally converted to one or more halogens, hydroxyl groups, amino groups, or C-terminal groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0165] The term "cycloalkyl" or "alicyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the alicyclic ring contains 3 to 10 carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0166] The cycloalkyl or alicyclic group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable linker, preferably one or more of the following groups, including but not limited to halogen, hydroxyl, mercapto, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl group is replaced by an alkoxy group, and the alkyl group or alkoxy group is optionally replaced by one or more halogen, hydroxyl, mercapto, carboxyl, amino, or cyano groups.

[0167] The term "heterocyclic alkyl" or "aliphatic heterocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 6 to 10 ring atoms. Examples of monocyclic heterocyclic alkyl groups include, but are not limited to, piperazine rings, piperidine rings, cycloazine rings, ethylene oxide rings, cyclothioethane rings, butane rings, acridine rings, thiobutane rings, tetrahydropyrrole rings, tetrahydrofuran rings, tetrahydrothiophene rings, piperidine rings, tetrahydropyran rings, tetrahydrothioran rings, etc.; polycyclic alkyl groups include spirocyclic, fused, and bridged heterocyclic alkyl groups.

[0168] Heterocyclic alkyl or alicyclic compounds may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including but not limited to halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, oxo groups, thio groups, and C6 groups. 1-6 Alkyl, C 1-6 The alkyl or alkoxy group is substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0169] The term "aryl" or "aromatic ring" refers to any stable, monocyclic or bicyclic alicyclic ring with up to seven atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, or binaphthyl. Unless otherwise specified, the aryl group or aromatic ring may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, including but not limited to halogen, hydroxyl, mercapto, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl or alkoxy group is substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0170] The term "heteroaryl" or "heteroaromatic ring" refers to a stable monocyclic or bicyclic ring with up to seven atoms in each ring, wherein at least one ring is aromatic and at least one ring contains one to four heteroatoms selected from O, N, and S. Heteroaromatic rings within this definition include, but are not limited to, pyridine rings, thiazine rings, pyrimidine rings, pyridazine rings, furan rings, pyrrole rings, thiophene rings, imidazole rings, pyrazole rings, oxazole rings, isoxazole rings, thiazole rings, benzofuran rings, isobenzofuran rings, isoindole rings, indole rings, benzothiophene rings, benzimidazole rings, indole rings, benzoxazole rings, benziisoxazole rings, purine rings, benzothiazole rings, quinoline rings, isoquinoline rings, quinazoline rings, quinazolineone rings, and thioquinazolineone rings. Unless otherwise specified, heteroaryl or heteroaromatic rings may be substituted or unsubstituted.

[0171] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, including but not limited to halogen, hydroxyl, mercapto, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl or alkoxy group is substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0172] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, including but not limited to: halogen, hydroxyl, mercapto, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl or alkoxy group is substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0173] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0174] The term "hydroxyl group" refers to -OH.

[0175] The term "amino" refers to -NH2.

[0176] The term "cyano" refers to -CN.

[0177] The term "thiol" refers to -SH.

[0178] The term "oxo" or "oxo" refers to "=O".

[0179] The term "thio-" or "thio" means "=S".

[0180] The term "carbonyl" refers to C=O.

[0181] The term "carboxyl group" refers to -C(O)OH.

[0182] The term "halogenation" refers to the substitution of one or more atoms selected from fluorine, chlorine, bromine, and iodine.

[0183] The term "monovalent group" refers to a compound that has "formally" eliminated a single-valent atom or group.

[0184] The term "subunit" refers to a compound that "formally" eliminates two monovalent or one divalent atom or group of atoms.

[0185] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. Detailed Implementation

[0186] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0187] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0188] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0189] HPLC determination was performed using an Agilent 1100 high-performance liquid chromatograph, a GAS15B DAD UV detector, and a Water Vbridge C18 150*4.6mm 5um column.

[0190] MS measurements were performed using an Agilent 6120 triple quadrupole mass spectrometer with a G1315D DAD detector and a Waters Xbridge C18 4.6*50mm, 5µm column, in positive / negative ion mode, with a mass scan range of 80–1200.

[0191] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.2mm ± 0.03mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm-0.5mm.

[0192] Rapid column purification systems use either the Combiflash Rf150 (TELEDYNE ISCO) or Isolara One (Biotage).

[0193] Normal column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh as the carrier, or Changzhou Santai pre-filled ultrapure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0194] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bid Pharmaceuticals.

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

[0196] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1 L.

[0197] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0198] Hydrogen was produced by the QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instruments Co., Ltd.

[0199] Nitrogen or hydrogen atmospheres are typically evacuated and then filled with nitrogen or hydrogen gas, and this process is repeated three times.

[0200] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0201] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0202] In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The volume ratio of the developing solvent used in the reaction, the eluent system used for column chromatography to purify the compound, and the developing solvent system for TLC were adjusted according to the different polarities of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0203] The compounds described in this application can be prepared by the following synthetic methods:

[0204] The synthesis method is as follows:

[0205] Compound (1A) and compound (2A) are reacted via a reductive amination reaction to obtain compound (3A). Compound (3A) is reacted with compound (4A) to obtain compound (5A). Compound (5A) is hydrolyzed to obtain compound (A) for later use.

[0206] Compound (1B) reacts with compound (2B) to give compound (3B), compound (3B) is hydrolyzed to give compound (4B), and compound (4B) reacts with compound (5B) to give compound (B).

[0207] Compound (A) and compound (B) are condensed to obtain compound (I). The definitions of each group are as described above.

[0208] Example 1: Preparation of Compound 1

[0209] Step 1:

[0210] Compound 1a (1 g, 6.54 mmol, purchased from Shaoyuan) was dissolved in dichloromethane (18 mL), stirred in an ice-water bath, and then imidazole (889.80 mg, 13.07 mmol) and TBDMSCl (1.48 g, 9.80 mmol) were added. The reaction was allowed to proceed to completion at room temperature. After filtration, the solution was concentrated to dryness and purified by column chromatography (PE:(10% EA / PE) = 100:0-50:50) to give 1.73 g of compound 1b (yield 99.04%).

[0211] 1 H NMR (400MHz, CDCl3) δ3.64–3.39(m,4H),2.05-1.92(m,1H),0.99(d,J=6.8Hz,3H),0.90(s,9H),0.06(s,6H).

[0212] Step 2:

[0213] Compound 1b (1.503 g, 5.62 mmol) and compound 1c (858.53 mg, 5.74 mmol, purchased from Bioderm) were dissolved in DMF (10 mL) and stirred. Potassium carbonate (1.74 g, 12.62 mmol) and sodium iodide (86.01 mg, 573.81 μmol) were added, and the reaction was carried out at 60–75 °C until complete. Ethyl acetate (30 mL) and water (20 mL) were added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with semi-saturated brine (10 mL × 2) and saturated brine (10 mL), dried, filtered, concentrated, and purified by column chromatography (PE:EA = 100:0-80:20) to give 1.39 g of compound 1d (yield 81.04%).

[0214] MS(ESI): m / z 300.2 [M+1] + .

[0215] Step 3:

[0216] Compound 1d (1.09 g, 3.64 mmol) was dissolved in acetonitrile (11 mL), and sodium iodide (872.77 mg, 5.82 mmol) and compound 1e (1.02 g, 5.46 mmol, purchased from Bide) were added. The reaction was carried out at 60–75 °C until complete. The reaction solution was concentrated and purified by column chromatography (DCM:MeOH = 100:0-90:10) to give 943.6 mg of compound 1f (yield 44.89%).

[0217] MS(ESI): m / z 450.3 [MI] + .

[0218] Step 4:

[0219] Compound 1f (155.2 mg, 268.69 μmol) was dissolved in methanol (0.6 mL) and stirred. Concentrated hydrochloric acid (54.01 μL, 1.75 mmol) was added, and the reaction was allowed to proceed to completion at room temperature. The reaction solution was concentrated to give 82.9 mg of compound and 1 g of crude product, which was used directly in the next step.

[0220] MS(ESI): m / z 336.2 [M-Cl] + .

[0221] Step 5:

[0222] 1 g (82.9 mg, 222.91 μmol) of the compound was dissolved in dichloromethane (0.8 mL) and acetonitrile (0.8 mL). DIPEA (31.69 mg, 245.20 μmol, 42.71 μL) and maleic anhydride (28.42 mg, 289.78 μL) were added, and the reaction was allowed to proceed at room temperature until complete. Concentrated hydrochloric acid (10.34 μL, 334.37 μmol) was added to the reaction solution, and the mixture was stirred at room temperature until complete. The solution was concentrated to dryness, and the crude product was dried using dichloromethane (5 mL × 2) and then pumped dry to obtain 110 mg of the crude compound obtained in 1 hour. This crude product was used directly in the next reaction step.

[0223] MS(ESI): m / z 434.2 [M-Cl] + .

[0224] Step 6:

[0225] Compound 1h (110 mg, 234.07 μmol) and compound 1i (98.77 mg, 234.07 μmol, prepared using the method disclosed in patent WO2021115413A1) were dissolved in DMF (1 mL), and DMAP (42.89 mg, 351.10 μmol) and HATU (133.50 mg, 351.10 μmol) were added. The reaction was carried out at room temperature until complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA), and lyophilized to give 86 mg of compound 1 (yield 42.04%).

[0226] MS(ESI):m / z 401.2[(M-2CF3COO) / 2] + .

[0227] 1H NMR (400MHz, DMSO) δ7.14-7.08(m,1H),7.06–7.02(m,1H),7.02–6.95(m,3H),6.89-6.84(m,2H),6.83-6.79(m,1H ),6.67(d,J=2.8Hz,1H),6.61(s,1H),5.55(s,1H),5.31-5.05(m,1H),4.73-4.57(m,3H),4.52(s,2H),4.33(dd,J= 51.6,13.5Hz,3H),4.21-4.10(m,5H),4.08-3.85(m,3H),3.82–3.68(m,13H),3.67-3.53(m,3H),3.41-3.26(m,5H) ,3.14-2.99(m,2H),2.98-2.87(m,1H),2.88(t,J=11.7Hz,1H),2.63-2.53(m,1H),2.35–2.14(m,5H),1.10(m,3H).

[0228] Compound 1 comprises compound 1A (retention time 12.871 min) and compound 1B (retention time 12.728 min). The structures of compounds 1A and 1B are shown below:

[0229] Separation method: Reversed-phase column: WePure MicroPulite XP tC18, 4.6mm×150mm, 3.5μm; Mobile phase: A is water (0.05% trifluoroacetic acid), B is acetonitrile; Gradient: 10%-90% B; Flow rate: 1.000mL / min; Column temperature: 30℃; Wavelength: 210nm.

[0230] Example 1A: Preparation of Compound 1A

[0231] Step 1:

[0232] Compound 1a (2 g, 13.07 mmol) was dissolved in dichloromethane (20 mL) in an ice-water bath with stirring. Imidazole (1.33 g, 19.61 mmol) and tert-butyldiphenylchlorosilane (3.95 g, 14.38 mmol, 3.69 mL) were added, and the mixture was allowed to rise naturally to room temperature until the reaction was complete. The reaction solution was washed with water (10 mL × 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 5.31 g of crude compound 1b-1, which was used directly in the next reaction.

[0233] Step 2:

[0234] Compound 1b-1 (5.12 g, 13.09 mmol) and compound 1c (1.78 g, 11.90 mmol, purchased from Biot) were dissolved in DMF (35.6 mL) and stirred. Potassium carbonate (4.93 g, 35.69 mmol) and sodium iodide (197.49 mg, 1.19 mmol) were added, and the reaction was carried out at 70–85 °C until complete. Ethyl acetate (40 mL) and water (20 mL) were added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with semi-saturated brine (20 mL × 2) and saturated brine (10 mL), dried, filtered, concentrated, and purified by column chromatography (PE:EA = 100:0-80:20) to give 2.47 g of compound 1d-1 (yield 49.01%).

[0235] MS(ESI): m / z 424.2 [M+1] + .

[0236] Step 3:

[0237] Compound 1d-1 (2 g, 4.72 mmol) was dissolved in acetonitrile (20 mL), and sodium iodide (1.13 g, 7.55 mmol) and compound 1e (1.32 g, 7.08 mmol, purchased from Bioderm) were added. The reaction was carried out at 60–75 °C until complete. The reaction solution was filtered, concentrated, and purified by column chromatography (DCM:MeOH = 100:0-90:10) to give 1.17 g of compound 1f-1 (yield 35.35%).

[0238] MS(ESI): m / z 574.3 [MI] + .

[0239] Compound 1f was resolved to obtain: compound 1f-A (retention time 17.686 min) and compound 1f-B (retention time 16.809 min).

[0240] Separation conditions: Reversed-phase column: CHIRALCEL OZ-H (OZH0CD-OD010), 0.46 cm ID × 15 cm L; Mobile phase: MeOH / ACN / DEA = 70 / 30 / 0.1 (V / V / V); Flow rate: 1.200 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0241] The structures of compounds 1f-A and 1f-B are shown below:

[0242] Step 4:

[0243] Compound 1f-A (460 mg, 655.51 μmol) was dissolved in methanol (1 mL), and hydrochloric acid / dioxane solution (4 M, 5 mL) was added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was concentrated, and the residue was dissolved in dichloromethane and purified by column chromatography (16% methanol / dichloromethane) to give 270.33 mg of the deprotected intermediate (yield 100%).

[0244] The obtained intermediate (270.33 mg, 726.90 μmol) and compound 2f (378 mg, 726.90 μmol, prepared using the method disclosed in patent WO2014005122A2) were dissolved in DMF (4 mL), and triethylamine (260.04 mg, 2.54 mmol) and 2-chloro-1-methylpyridinium iodide (284.25 mg, 1.09 mmol) were added. The mixture was stirred at room temperature until the reaction was complete. Ethyl acetate (25 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was purified by HPLC (acetonitrile / water / TFA) to give 220 mg of compound 1A (yield 29.41%).

[0245] MS(ESI):m / z 401.2[(M-2CF3COO) / 2] + .

[0246] 1 H NMR (400MHz, DMSO-d6) δ7.14-7.08(m,1H),7.06–7.02(m,1H),7.02–6.95(m,3H),6.89-6.84(m,2H),6.83-6.79(m, 1H),6.67(d,J=2.8Hz,1H),6.61(s,1H),5.55(s,1H),5.31-5.05(m,1H),4.73-4.57(m,3H),4.52(s,2H),4.33(dd,J =51.6,13.5Hz,3H),4.21-4.10(m,5H),4.08-3.85(m,3H),3.82–3.68(m,13H),3.67-3.53(m,3H),3.41-3.26(m,5H ),3.14-2.99(m,2H),2.98-2.87(m,1H),2.88(t,J=11.7Hz,1H),2.63-2.53(m,1H),2.35–2.14(m,5H),1.10(m,3H).

[0247] Example 2 Preparation of Compound 2

[0248] Step 1:

[0249] Compound 2a (1 g, 6.54 mmol, purchased from Shaoyuan) was dissolved in dichloromethane (10 mL), stirred in an ice-water bath, and then imidazole (889.80 mg, 13.07 mmol) and TBDMSCl (1.28 g, 8.50 mmol) were added. The reaction was carried out at room temperature until complete. After filtration, the solution was concentrated to dryness. The solution was purified by column chromatography (PE: (10% EA / PE) = 100:0-50:50) to give 1.65 g of compound 2b (yield: 94.5%).

[0250] 1 H NMR (400MHz, CDCl3) δ3.53–3.36(m,4H),1.93-1.88(m,1H),0.92(d,J=6.8Hz,3H),0.84(s,9H),0.07(s,6H).

[0251] Step 2:

[0252] Compound 2b (1.55 g, 5.80 mmol) and compound 1c (885.02 mg, 5.92 mmol) were dissolved in DMF (16 mL) and stirred. Potassium carbonate (1.76 g, 12.76 mmol) and sodium iodide (86.93 mg, 579.92 μmol) were added, and the reaction was carried out at 70–85 °C until complete. Ethyl acetate (30 mL) and water (20 mL) were added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with water (20 mL × 3) and saturated brine (10 mL × 1), dried, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 100:0-100:5) to give 1.5 g of compound 2c (yield: 86.4%).

[0253] MS(ESI): m / z 300.2 [M+1] + .

[0254] Step 3:

[0255] Compound 2c (1.45 g, 4.84 mmol) was dissolved in acetonitrile (14.5 mL), and sodium iodide (1.52 g, 10.17 mmol) and compound 1e (1.81 g, 9.68 mmol) were added. The reaction was carried out at 60–75 °C until complete. The reaction solution was concentrated and purified by column chromatography (DCM:MeOH = 100:0 -100:5) to give 850 mg of compound 2d (yield 39.0%).

[0256] MS(ESI): m / z 450.3 [MI] + .

[0257] Step 4:

[0258] Compound 2d (300 mg, 519.38 μmol) was dissolved in methanol (1.5 mL), and concentrated hydrochloric acid (281.33 μL, 3.38 mmol) was added. The reaction was allowed to proceed at room temperature until complete. The reaction solution was concentrated and purified by column chromatography (DCM:MeOH = 100:0-100:8) to give 120 mg of compound 2e (yield: 62.0%).

[0259] MS(ESI): m / z 336.2 [M-Cl] + .

[0260] Step 5:

[0261] Compound 2e (85.8 mg, 230.76 μmol) and compound 2f (100 mg, 192.3 μmol, prepared using the method disclosed in patent WO2014005122A2) were dissolved in DMF (1.5 mL), and HATU (110.26 mg, 288.45 μmol) and DMAP (35.24 mg, 288.45 μmol) were added. The reaction was carried out at room temperature until complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA), lyophilized, and 50 mg of compound 2 was obtained (yield 25.3%).

[0262] MS(ESI):m / z 401.2[(M-2CF3COO) / 2] + .

[0263] 1 H NMR(400MHz,DMSO-d6)δ7.18-7.08(m,1H),7.06–6.95(m,4H),6.89-6.79(m,3H),6.6 7–6.60(m,2H),5.55(s,1H),5.31-4.57(m,2H),4.52(s,1H),4.45–4.32(m,1H),4.21 -4.10(m,5H),4.08-3.85(m,4H),3.82–3.54(m,18H),3.51-3.33(m,4H),3.20(s,3H) ,3.14-2.99(m,3H),2.88(m,1H),2.63-2.53(m,1H),2.40–2.16(m,5H),1.12(m,3H).

[0264] Example 3 Preparation of Compound 3

[0265] Step 1:

[0266] Compound 3a (200 mg, 0.78 mmol, prepared according to patent WO2017 / 15106) was dissolved in DMF (1 mL), and compound 1b (208 mg, 0.78 mmol) and potassium carbonate (268.7 mg, 1.94 mmol) were added. The reaction mixture was reacted at 75–90 °C until complete. The reaction solution was then diluted with water (30 mL), extracted with EA (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (1% methanol / dichloromethane) to give 113 mg of compound 3b (yield 46.17%).

[0267] MS(ESI): m / z 316.2 [M+1] + .

[0268] Step 2:

[0269] Compound 3b (170 mg, 538.68 μmol) was dissolved in acetonitrile (2.5 mL), and compound 1e (151.30 mg, 808.01 μmol) and sodium iodide (81.56 mg, 538.68 μmol) were added. The mixture was stirred at 65–80 °C until complete. The reaction solution was evaporated to dryness, dissolved in DCM (1 mL), purified by column chromatography (2% methanol / dichloromethane), and lyophilized to give 180 mg of compound 3c (yield 56.29%).

[0270] MS(ESI): m / z 466.2 [MI] + .

[0271] Step 3:

[0272] Compound 3c (180 mg, 303.20 μmol) was dissolved in methanol (1.8 mL), and concentrated hydrochloric acid (12 M, 1.97 mmol, 164.23 μL) was added. The mixture was stirred at room temperature until complete. The reaction solution was evaporated to dryness, and then dried with ethanol (10 mL × 2). The residue was slurried with DCM (10 mL), filtered, and dried to give 110 mg of compound 3d (yield 93.51%).

[0273] MS(ESI): m / z 352.1 [M-Cl] + .

[0274] Step 4:

[0275] Compound 3d (100 mg, 192.30 μmol) and compound 2f (82.07 mg, 211.53 μmol) were dissolved in DMF (1.3 mL), and DMAP (35.96 mg, 288.45 μmol) and HATU (110.79 mg, 288.45 μmol) were added. The mixture was stirred at room temperature until complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA) to give 33 mg of compound 3 (yield 16.42%).

[0276] MS(ESI):m / z 409.2[(M-2CF3COO) / 2] + .

[0277] 1 H NMR (400MHz, DMSO-d6): δ7.08-6.68(m,9H),5.56(s,1H),4.63-4.15(m,7H),3.91-3.89(m,1H),3.79-3.53(m,17H),3.37-3 .33(m,9H),3.21(s,3H),3.11-3.07(m,3H),2.89-2.87(m,1H),2.62-2.50(m,4H),2.33-2.21(m,4H),1.22(d,J=6.8Hz,3H).

[0278] Example 4: Preparation of Compound 4

[0279] Step 1:

[0280] Compound 2b (314.98 mg, 1.17 mmol) and compound 3a (303 mg, 1.17 mmol) were dissolved in DMF (3 mL), and potassium carbonate (408 mg, 2.92 mmol) was added. The reaction mixture was reacted at 70–85 °C until complete. Ethyl acetate (25 mL) and water (15 mL) were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with semi-saturated brine (10 mL × 2) and saturated brine (10 mL), dried, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 100:0-100:1) to give 229 mg of compound 4a (yield 60.95%).

[0281] MS(ESI): m / z 316.2 [M+1] + .

[0282] Step 2:

[0283] Compound 4a (225.25 mg, 706.62 μmol) and compound 1e (200 mg, 1.06 mmol) were dissolved in acetonitrile (2.5 mL), and sodium iodide (160.5 mg, 1.06 mmol) was added. The reaction was carried out under nitrogen protection at 60–75 °C until complete. The reaction solution was concentrated to dryness and purified by column chromatography (DCM:MeOH = 100:0–100:2) to give 154 mg of compound 4b (yield 35.24%).

[0284] MS(ESI): m / z 466.2 [MI] + .

[0285] Step 3:

[0286] Compound 4b (154 mg, 259.40 μmol) was dissolved in methanol (1.5 mL), and concentrated hydrochloric acid (1.69 mmol, 140.51 μL) was added. The reaction was allowed to proceed at room temperature until complete. The reaction solution was concentrated and dried with ethanol (5 mL), then pumped dry. DCM (10 mL) was added and the mixture was stirred. The mixture was filtered to give 95.8 mg of compound 4c (yield 91.38%).

[0287] MS(ESI): m / z 352.1 [M-Cl] + .

[0288] Step 4:

[0289] Compound 2f (87.5 mg, 166.58 μmol) and compound 4c (78.34 mg, 199.9 μmol) were dissolved in DMF (0.3 mL), and DMAP (30.83 mg, 249.87 μmol) and HATU (95.97 mg, 249.87 μmol) were added. The reaction was carried out at room temperature until complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA), and lyophilized to give 66.4 mg of compound 4 (yield 36.61%).

[0290] MS(ESI):m / z 409.2[(M-2CF3COO) / 2] + .

[0291] 1H NMR (400MHz, DMSO) δ7.19–7.08(m,2H),7.01(dd,J=13.2,8.5Hz,3H),6.89–6.81(m,3H),6.69(d,J=3. 3Hz,2H),5.55(s,1H),4.66–4.35(m,4H),4.28(dd,J=11.3,6.3Hz,1H),4.17(dq,J=12.5,5.7Hz,4H), 3.78(s,7H),3.72(d,J=3.5Hz,7H),3.65–3.52(m,3H),3.49–3.31(m,8H),3.20(s,3H),3.09(d,J=11. 2Hz,3H),2.88(dd,J=12.7,10.5Hz,1H),2.64-2.61(m,3H),2.37–2.12(m,4H),1.23(d,J=6.7Hz,3H).

[0292] Example 5: Preparation of Compound 5

[0293] Step 1:

[0294] Compound 5a (910.13 mg, 2.54 mmol, prepared according to the method in the reference, Journal of Organic Chemistry, 2004, vol. 69, #11, pp. 3964-3967) and 4,4-difluoropiperidine hydrochloride (0.4 g, 2.54 mmol, purchased from Shaoyuan) were dissolved in DMF (4.5 mL), and potassium carbonate (1.05 g, 7.61 mmol) was added. The reaction was carried out at 70–85 °C until complete. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with semi-saturated brine (10 mL × 2) and saturated brine (10 mL), dried, filtered, concentrated, and purified by column chromatography (PE:EA = 100:0-80:20) to give 427 mg of compound 5b (yield 54.71%).

[0295] MS(ESI): m / z 308.2 [M+1] + .

[0296] Step 2:

[0297] Compound 5b (200.00 mg, 650.42 μmol) and compound 5c (225.45 mg, 975.63 μmol, purchased from Bidet) were dissolved in acetonitrile (2 mL) and reacted at 65–75 °C until complete. The reaction solution was concentrated to dryness and purified by column chromatography (DCM:MeOH = 100:0-85:15) to give 35 mg of compound 5d (yield 12.32%).

[0298] MS(ESI): m / z 344.2 [M-Br] + .

[0299] Step 3:

[0300] Compound 2f (35.74 mg, 68.74 μmol) and compound 5d (35 mg, 82.49 μmol) were dissolved in DMF (0.5 mL), and DMAP (12.60 mg, 103.11 μmol) and HATU (39.20 mg, 103.11 μmol) were added. The reaction was carried out at room temperature until complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA), and lyophilized to give 16 mg of compound 5 (yield 25.13%).

[0301] MS(ESI):m / z 405.2[(M-2CF3COO) / 2] + .

[0302] 1 H NMR (400MHz, DMSO) δ7.23(s,1H),7.17(d,J=8.0Hz,1H),7.07(d,J=8.2Hz,1H),6.99(d,J=8.4Hz,2H),6.86( d,J=8.4Hz,2H),6.83(s,1H),6.69(d,J=1.2Hz,2H),5.55(s,1H),4.66-4.46(m,2H),4.42-4.25(m,4H),4.2 3-4.08(m,3H),3.99-3.85(m,3H),3.80(d,J=4.0Hz,7H),3.72(s,7H),3.32(s,4H),3.22(s,4H),3.15-2.94 (m,5H),2.91-2.81(m,1H),2.39-2.25(m,2H),2.24-2.15(m,2H),2.12-1.95(m,2H),1.48(d,J=6.2Hz,3H).

[0303] Example 6 Preparation of Compound 6

[0304] Step 1:

[0305] Compound 6a (1.14 g, 3.17 mmol, prepared according to the method in the reference, J.org.chem., 2022, 87(4), 2136-2141), 4,4-difluoropiperidine hydrochloride (500 mg, 3.17 mmol), potassium carbonate solid (1.10 g, 7.93 mmol), and DMF (10 mL) were added to a 50 mL reaction flask and reacted at 60–75 °C until complete. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 1), dried, concentrated under reduced pressure, and purified by column chromatography (MeOH / DCM, 5%) to give 820 mg of compound 6b (yield: 84%).

[0306] MS(ESI): m / z 308.2 [M+H] + .

[0307] Step 2:

[0308] In a 25 mL reaction flask, compound 6b (480 mg, 1.56 mmol) and compound 5c (361 mg, 1.56 mmol) were dissolved in anhydrous acetonitrile (5 mL), and the reaction was carried out under nitrogen protection at 60–75 °C until complete. The reaction solution was concentrated to dryness and purified by column chromatography (MeOH / DCM, 0–20% elution for 30 min) to give compound 6c (104 mg, 15% yield).

[0309] MS(ESI): m / z 344.2 [M-Br] + .

[0310] Step 3:

[0311] In a 10 mL reaction tube, compound 6c (42 mg, 0.099 mmol), compound 2f (43 mg, 0.082 mmol), and DMAP (10 mg, 0.082 mmol) were dissolved in anhydrous DMF (0.8 mL), and HATU (31 mg, 0.082 mmol) was added. The mixture was stirred until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA), lyophilized, and yielded 27.6 mg of compound 6 (yield: 32%).

[0312] MS(ESI):m / z 405.2[(M-2CF3COO) / 2] + .

[0313] 1H NMR (400MHz, DMSO) δ7.23(s,1H),7.17(d,J=8.0Hz,1H),7.08(d,J=8.0Hz,1H),6.99(d ,J=8.0Hz,2H),6.87(d,J=8.0Hz,2H),6.83(s,1H),6.69-6.65(m,2H),5.56(s,1H),4.6 2-4.49(m,1H),4.38-4.15(m,5H),3.90-3.85(m,2H),3.81-3.72(m,7H),3.68-3.59(m, 10H),3.38-3.32(m,11H),3.12-2.85(m,6H),2.25-1.96(m,4H),1.48(d,J=8.0Hz,3H).

[0314] Example 7 Preparation of Compound 7

[0315] Step 1:

[0316] 4,4-Difluoropiperidine hydrochloride (200 mg, 1.23 mmol) and compound 1b (329.03 mg, 1.23 mmol) were dissolved in DMF (2 mL), and potassium carbonate (429.64 mg, 3.08 mmol) was added. The mixture was stirred at 70–85 °C until complete. The reaction solution was separated into water (30 mL) and ethyl acetate (30 mL). The organic phase was washed once with water (30 mL) and once with saturated brine (30 mL), dried, concentrated under reduced pressure, and the residue was purified by column chromatography (3% ethyl acetate / petroleum ether) to give 225 mg of compound 7a (yield 59.44%).

[0317] MS(ESI): m / z 308.2 [M+1] + .

[0318] Step 2:

[0319] Compound 7a (225 mg, 731.72 μmol) was dissolved in acetonitrile (2.5 mL), and compound 1e (205.53 mg, 1.10 mmol) and sodium iodide (166.18 mg, 1.10 mmol) were added. The mixture was stirred at 65–80 °C until complete. The reaction mixture was directly evaporated to dryness, and the residue was dissolved in dichloromethane and purified by column chromatography (2% methanol / dichloromethane) to give 352 mg of compound 7b (yield 82.15%).

[0320] MS(ESI): m / z 458.2 [MI] + .

[0321] Step 3:

[0322] Compound 7b (352 mg, 601.11 μmol) was dissolved in methanol (3.5 mL), and concentrated hydrochloric acid (12 M, 3.91 mmol, 325.60 μL) was added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was evaporated to dryness, and the residue was slurried with DCM (10 mL), filtered, and dried to give 250 mg of compound 7c (yield 109.48%).

[0323] MS(ESI): m / z 344.1 [M-Cl] + .

[0324] Step 4:

[0325] Compound 7c (50 mg, 96.15 μmol) and compound 2f (40.18 mg, 105.77 μmol) were dissolved in DMF (0.6 mL), and DMAP (17.62 mg, 144.23 μmol) and HATU (54.84 mg, 144.23 μmol) were added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA), and lyophilized to give 18 mg of compound 7 (yield 18%).

[0326] MS(ESI):m / z 405.3[(M-2CF3COO) / 2] + .

[0327] 1 H NMR (400MHz, DMSO-d6): δ7.13-6.69(m,9H),5.55(s,1H),4.69(s,2H),4.63-4 .59(m,1H),4.17-4.14(m,4H),3.92-3.90(m,1H),3.80(s,6H),3.72-3.71(m, 6H),3.68-3.61(m,6H),3.40-3.32(m,9H),3.21(s,3H),3.11-3.09(m,2H),2. 87-2.79(m,2H),2.50(overlap,2H),2.20-2.19(m,2H),1.18(d,J=6.4Hz,3H).

[0328] Example 8: Preparation of Compound 8

[0329] Step 1:

[0330] Compound 2b (300 mg, 1.12 mmol) and 4,4-difluoropiperidine hydrochloride (163.2 mg, 1.04 mol) were dissolved in dimethylformamide (3 mL), and potassium carbonate (465.4 mg, 3.37 mol) was added. The reaction mixture was reacted at 70–85 °C until complete. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with water (20 mL × 1) and saturated brine (20 mL × 1), dried, filtered, concentrated, and purified by column chromatography (PE:EA = 100:0-80:20) to give 220 mg of compound 8a (yield 63.74%).

[0331] 1 H NMR (400MHz, CDCl3): δ3.51-3.39(m,2H),2.58-2.45(m,4H),2.33-2.28(m,1H),2.09-2. 04(m,1H),1.97-1.87(m,4H),1.77-1.72(m,1H),0.87(s,3H),0.85(s,9H),0.00(s,6H).

[0332] Step 2:

[0333] Compound 8a (190 mg, 1.12 mmol) and compound 1e (172.98 mg, 0.93 mmol) were dissolved in acetonitrile (3 mL), and potassium iodide (148.2 mg, 0.99 mmol) was added. The reaction was carried out at 60–75 °C until complete. The reaction solution was concentrated to dryness and purified by column chromatography (DCM:MeOH = 100:0-95:5) to give 220 mg of compound 8b (yield 60.8%).

[0334] MS(ESI): m / z 458.2 [MI] + .

[0335] Step 3:

[0336] Compound 8b (220 mg, 375.7 μmol) was dissolved in methanol (2.2 mL), and concentrated hydrochloric acid (187.85 μL, 2.25 mmol) was added. The reaction was allowed to proceed at room temperature until complete. The reaction solution was concentrated to dryness, and a mixture of petroleum ether (5.5 mL) and ethyl acetate (0.55 mL) was added. The mixture was stirred, filtered, and 130 mg of compound 8c was obtained (yield 91.09%).

[0337] MS(ESI): m / z 344.2 [M-Cl] + .

[0338] Step 4:

[0339] Compound 8c (87.67 mg, 230.7 μmol) and compound 2f (100 mg, 192.3 μmol) were dissolved in DMF (2 mL), and DMAP (35.2 mg, 288.45 μmol) and HATU (109.68 mg, 288.45 μmol) were added. The reaction was carried out at room temperature until complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA), lyophilized, and 45 mg of compound 8 was obtained (yield 22.52%).

[0340] MS(ESI):m / z 405.3[(M-2CF3COO) / 2] + .

[0341] 1 H NMR (400MHz, DMSO) δ7.13-7.06 (m, 3H), 6.99 (d, J = 8.8Hz, 2H), 6.87-6.82 (m, 3H), 6. 66(d,J=2.4Hz,2H),5.55(s,1H),4.70(s,2H),4.63-4.40(m,1H),4.17-4.4.13(m,4 H),3.99-3.92(m,2H),3.80(s,9H),3.62-3.33(m,17H),3.22(s,3H),3.11-3.07(m, 2H),2.91-2.78(m,2H),2.56-2.44(m,4H),2.24-2.17(m,2H),1.18(d,J=6.8Hz,3H).

[0342] Example 9: Preparation of Compound 9

[0343] Step 1:

[0344] Compound 9a (500 mg, 1.79 mmol, prepared according to the method described in patent WO2022 / 149167) was dissolved in acetonitrile (10 mL), and 4,4-difluoropiperidine hydrochloride (282 mg, 1.79 mmol) and potassium carbonate (495 mg, 3.58 mmol) were added. The mixture was stirred at 70–85 °C until complete. The reaction solution was filtered, the filtrate was evaporated to dryness, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 20%), evaporated to dryness, to give 450 mg of compound 9b (yield 78%).

[0345] MS(ESI): m / z 320.2 [M+1] + .

[0346] Step 2:

[0347] Compound 9b (200 mg, 626 μmol) was dissolved in acetonitrile (3 mL), and compound 5c (217 mg, 939 μmol) was added. The mixture was stirred at 60–75 °C until the reaction was complete. The reaction solution was evaporated to dryness, and the residue was purified by column chromatography (methanol:dichloromethane = 5%) to give 120 mg of compound 9c (yield 40%).

[0348] MS(ESI): m / z 470.3 [M-Br] + .

[0349] Step 3:

[0350] Compound 9c (120 mg, 254.95 μmol) was dissolved in methanol (0.6 mL), and concentrated hydrochloric acid (138 μL, 1.66 mmol) was added. The reaction was allowed to proceed at room temperature until complete. The reaction solution was concentrated, purified by column chromatography (methanol:dichloromethane = 15%), and evaporated to dryness to give 75 mg of compound 9d (yield 82%).

[0351] MS(ESI): m / z 356.1 [M-Cl] + .

[0352] Step 4:

[0353] Compound 2f (25.0 mg, 48.08 μmol) and compound 9d (25.2 mg, 57.69 μmol) were dissolved in DMF (0.5 mL), and DMAP (8.8 mg, 72.11 μmol) and HATU (27.4 mg, 72.11 μmol) were added. The reaction was carried out at room temperature until complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA), and lyophilized to give 13 mg of compound 9 (yield 30%).

[0354] MS(ESI):m / z 411.2[(M-2CF3COO) / 2] + .

[0355] 1H NMR (400MHz, CD3CN) δ7.03(t,J=6.4Hz,2H),6.98(s,1H),6.90(d,J=8.3Hz,2H),6.83(d,J=8.3Hz,2H),6.77( t,J=8.0Hz,2H),6.67(d,J=15.8Hz,1H),5.59(s,1H),4.59(s,2H),4.42(dd,J=10.7,3.9Hz,1H),4.13(d,J=2 1.7Hz,4H),3.84(d,J=4.7Hz,7H),3.74(d,J=5.0Hz,8H),3.62–3.47(m,4H),3.34(q,J=8.2Hz,4H),3.27(s,6 H),3.12(dd,J=10.4,7.0Hz,2H),2.89(t,J=11.6Hz,1H),2.21–2.08(m,3H),1.28(s,3H),1.03–0.91(m,4H).

[0356] Example 10: Preparation of Compound 10

[0357] Step 1:

[0358] Compound 10a (2 g, 8.19 mmol, prepared by the method described in patent WO2022008911) was dissolved in DMF (10 mL), and imidazole (1.67 g, 24.56 mmol) and TBSCl (2.47 g, 16.37 mmol) were added. The reaction was carried out at room temperature until complete. 20 mL of water was added to the reaction solution, and the mixture was extracted with MTBE (20 mL × 3). The organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride solution (20 mL), dried, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 100:0-80:20) to give 2.20 g of compound 10b (yield 74.95%).

[0359] MS(ESI): m / z 359.2 [M+1] + .

[0360] Step 2:

[0361] Compound 10b (500 mg, 1.39 mmol) and compound 1c (312 mg, 2.09 mmol) were dissolved in acetonitrile (10 mL), and triethylamine (423 mg, 4.18 mmol) was added. The reaction mixture was reacted at 80–95 °C until complete. 10 mL of water was added to the reaction mixture, and the mixture was extracted with MTBE (10 mL × 3). The organic phases were combined, washed with water (10 mL × 2), washed with saturated sodium chloride solution (10 mL), dried, filtered, and the filtrate was concentrated under reduced pressure to give 310 mg of compound 10c (yield 74.22%).

[0362] MS(ESI): m / z 300.3 [M+1] + .

[0363] Step 3:

[0364] Compound 10c (300 mg, 1.00 mmol) and compound 5c (255 mg, 1.10 mmol) were dissolved in acetonitrile (6 mL) and reacted at 60–75 °C until complete. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (MeOH:DCM = 0:100–10:90) to give 210 mg of compound 10d (yield 39.51%).

[0365] MS(ESI): m / z 450.4 [M-Br] + .

[0366] Step 4:

[0367] Compound 10d (210 mg, 0.40 mmol) was dissolved in methanol (1 mL), cooled with ice water, and concentrated hydrochloric acid (0.2 mL, 2.57 mmol) was added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (MeOH:DCM = 0:100-15:85) to give 145 mg of compound 10e (yield 98.52%).

[0368] MS(ESI): m / z 336.3 [M-Cl] + .

[0369] Step 5:

[0370] Compound 2f (100 mg, 0.19 mmol), compound 10e (86 mg, 0.23 mmol), and HATU (110 mg, 0.29 mmol) were dissolved in DMF (2 mL), and 4-dimethylaminopyridine (35 mg, 0.29 mmol) was added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile: 0.1% TFA water = 5–95%), and lyophilized to give 41 mg of compound 10 (yield 20.72%).

[0371] MS(ESI):m / z 401.4[(M-2CF3COO) / 2] + .

[0372] 1 H NMR (400MHz, DMSO-d6): δ7.16-7.12(m,1H),7.09-7.01(m,2H),7.01-6.93(m,2H),6.91-6.84(m,2H),6.84-6.79(m,1H),6.71-6.56(m ,1H),5.56(s,1H),5.21-4.87(m,1H),4.66-4.56(m,1H),4.43(s,1H),4.31-4.20(m,1H),4.16-4.10(m,2H),4.05-3.97(m,2H),3.96- 3.86(m,2H),3.81(s,3H),3.78-3.74(m,4H),3.74-3.68(m,8H),3.71(s,3H),3.63-3.59(m,2H),3.59-3.56(m,2H),3.41-3.35(m,2H) ,3.33(s,3H),3.21(s,3H),3.14-3.05(m,2H),2.93-2.83(m,1H),2.68-2.56(m,2H),2.32-2.25(m,2H),2.25-2.12(m,2H),1.35(s,3H)

[0373] Compound 10 was resolved to obtain: compound 10A (retention time 13.619 min) and compound 10B (retention time 13.957 min).

[0374] Separation conditions: Reversed-phase column: Welch Xtimate C18, 30.0×150mm, 5µm; Mobile phase: A is 0.1% TFA in H2O, B is methanol; Gradient: B 40%; Flow rate: 30mL / min; Column temperature: 30℃; Wavelength: 214nm.

[0375] The structures of compounds 10A and 10B are shown below:

[0376] Example 11 Preparation of Compound 11

[0377] Step 1:

[0378] Compound 11a (1.0 g, 4.09 mmol, prepared by the method described in patent WO2022008911) and imidazole (557.31 mg, 8.19 mmol) were dissolved in dichloromethane (10 mL), and tert-butyldiphenylchlorosilane (1.24 g, 4.50 mmol) was added. After purging with nitrogen three times, the mixture was stirred at room temperature until the reaction was complete. The reaction solution was concentrated to dryness and subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to give 1.9 g of compound 11b (yield: 96%).

[0379] MS m / z (ESI): 505.3 [M+Na] + .

[0380] Step 2:

[0381] Compound 11b (1.9 g, 3.94 mmol), compound 1c (0.59 g, 3.94 mmol), potassium iodide (65.33 mg, 393.61 μmol), and triethylamine (1.19 g, 11.81 mmol) were added to acetonitrile (19 mL), and the mixture was refluxed and stirred until the reaction was complete. The reaction solution was concentrated to dryness and subjected to column chromatography (petroleum ether: ethyl acetate = 1:1) to give 0.70 g of compound 11c (yield: 42%).

[0382] MS m / z(ESI): 424.4 [M+H] + .

[0383] Step 3:

[0384] Compound 11c (0.70 g, 1.65 mmol), compound 5c (381.79 mg, 1.65 mmol), and sodium iodide (247.66 mg, 1.65 mmol) were added to a mixture of acetonitrile (1.4 mL) and dioxane (5.6 mL). The mixture was stirred at 60–70 °C until complete. The reaction solution was concentrated and subjected to column chromatography (dichloromethane:methanol = 30:1) to give 0.50 g of compound 11d (yield: 46%).

[0385] MS m / z (ESI): 574.5 [M-Br] + .

[0386] Step 4:

[0387] Compound 11d (0.50 g, 763.65 μmol) was added to methanol (5 mL), cooled to 0 °C, and concentrated hydrochloric acid (1.3 mL, 1.53 mmol) was added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was concentrated to dryness and subjected to column chromatography (dichloromethane:methanol = 5:1) to give 0.12 g of compound 11e (yield: 42%).

[0388] MS m / z (ESI): 336.3 [M-Cl] + .

[0389] Step 5:

[0390] Compound 11e (0.10 g, 240.20 μmol), compound 2f (112.31 mg, 216.17 μmol), and 4-dimethylaminepyridine (44.00 mg, 360.27 μmol) were dissolved in DMF (1 mL). HATU (137.70 mg, 360.27 μmol) was added, and the mixture was purged with nitrogen three times. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile: 0.1% TFA water = 5-95%) and lyophilized to obtain 30 mg of compound 11 (yield: 16%).

[0391] MS m / z(ESI):401.4[(M-2CF3COO) / 2] + .

[0392] 1 H NMR (400MHz, DMSO-d6) δ7.17-6.79(m,7H),6.69-6.50(m,2H),5.55(s,1H),5.39-5.03(m,2H),4.91(d,J=13.6Hz,1H),4.73-4.60(m,2H),4.43 (s,1H),4.30-3.93(m,7H),3.80-3.61(m,13H),3.60-3.33(m,9H),3.19 -3.10(m,5H),3.01-2.86(m,2H),2.33-1.99(m,7H),1.40-1.34(m,3H).

[0393] Compound 11 was resolved to yield: compound 11A (retention time 13.624 min) and compound 11B (retention time 13.902 min).

[0394] Separation conditions: Reversed-phase column: Welch Xtimate C18, 30.0×150mm, 5µm; Mobile phase: A is 0.1% TFA in H2O, B is methanol; Gradient: B 40%; Flow rate: 30mL / min; Column temperature: 30℃; Wavelength: 214nm.

[0395] The structures of compounds 11A and 11B are shown below:

[0396] Example 12 Preparation of Compound 12

[0397] Step 1:

[0398] Compound 1c (4.5 g, 30.08 mmol) and potassium carbonate (8.31 g, 60.15 mmol) were added to acetone (85 mL), followed by sodium iodide (0.45 g, 3.01 mmol) and compound 12c (11.4 g, 30.08 mmol, prepared according to the method disclosed in the literature, Angew. Chem., 2015, vol. 127, #51, pp. 15717-15720). The reaction mixture was stirred at 60–70 °C under nitrogen protection until complete. The insoluble matter was filtered off, the filter cake was washed with ethyl acetate, the filtrate was evaporated to dryness, and purified by column chromatography (methanol:DCM = 6%) to give 11.4 g of compound 12d (yield 92%).

[0399] MS(ESI): m / z 410.2 [M+1] + .

[0400] Step 2:

[0401] Compound 12d (30 g, 73.23 mmol) was added to a 1 L single-necked flask, followed by compound 1e (16.4 g, 87.88 mmol), sodium iodide (14.27 g, 95.20 mmol), 1,4-dioxane (240 mL), and acetonitrile (60 mL). The mixture was stirred at 60–75 °C until complete. The reaction mixture was cooled in an ice bath and stirred, then filtered. The filter cake was washed with the filtrate, followed by washing with 1,4-dioxane (150 mL × 3), and dried. Acetonitrile (192 mL) was added to the crude product, and the mixture was stirred at room temperature. Then, 1,4-dioxane (960 mL) was added, and the mixture was stirred at room temperature. The mixture was filtered to give compound 12e (47 g, yield 93.45%).

[0402] MS(ESI): m / z 560.2 [MI] + .

[0403] Step 3:

[0404] Compound 12e (47.1 g, 68.49 mmol) and methanol (658 mL) were added to a 50 mL single-necked flask and stirred to dissolve. The mixture was then cooled to 0–5 °C in an ice bath. A 4 M HCl solution of 1,4-dioxane (329 mL) was added, and the mixture was stirred at room temperature until the reaction was complete. The reaction solution was concentrated to dryness, purified by column chromatography (DCM / MeOH = 0–30%), and exchanged six times with 36 g of chloride ion exchange resin. The purified solution was then concentrated to give 17.7 g of compound 12f (yield 67.73%).

[0405] MS(ESI): m / z 322.2 [M-Cl] + .

[0406] 1 H NMR(400MHz, CDCl3)δ7.118-7.008(m,3H),4.372-4.282(m,4H),3.949(s,2H),3.801-3.787( d,6H),3.689-3.566(m,6H),2.582-2.554(m,2H),2.393-2.360(m,2H),2.162-2.120(m,2H).

[0407] Step 4:

[0408] Compound 12f (7.05 g, 19.7 mmol), maleic anhydride (2.51 g, 25.6 mmol), acetonitrile (70 mL), and dichloromethane (70 mL) were added to a 250 mL three-necked flask. DIPEA (2.8 g, 21.67 mmol) was added under ice-water cooling, and the mixture was stirred until complete. Concentrated hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Acetone was added, and the mixture was stirred until a slurry was formed. The mixture was then filtered to give 8.78 g of compound 12f (yield 97.75%).

[0409] MS m / z (ESI): 420.2 [M-Cl] + .

[0410] 1 H NMR(400MHz,CD3OD)δ7.14(dd,J=8.3,2.2Hz,1H),7.11–7.01(m,2H),6.47–6.24(m,2H),4.49(s,2H),4.44–4.3 2(m,4H),4.08–3.95(m,2H),3.88(s,3H),3.87(s,3H),3.78–3.56(m,4H),2.72-2.60(m,2H),2.57–2.33(m,4H).

[0411] Step 5:

[0412] Compound 10a (4.20 g, 17.19 mmol) and compound 12a (1.13 g, 3.44 mmol, prepared by the method disclosed in patent WO2021115413A1) were dissolved in 2-butanone (60 mL), and sodium iodide (2.58 g, 17.19 mmol) and sodium carbonate (72.88 mg, 687.66 μmol) were added. The reaction was carried out under nitrogen protection at 75–90 °C until complete. The reaction solution was concentrated to dryness, purified by column chromatography (0–22% acetonitrile / 0.1% TFA water), concentrated, and lyophilized to give 1.05 g of compound 12b (yield: 57.7%).

[0413] MS(ESI): m / z 400.3 [MI] + .

[0414] Step 6:

[0415] Compound 12b (50 mg, 124.83 μmol) and compound 12g (62.99 mg, 149.80 μmol) were dissolved in DMF (2 mL), and HATU (71.58 mg, 187.25 μmol) and DIPEA (48.40 mg, 374.50 μmol) were added. The mixture was stirred until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile: 0.1% TFA water = 5–95%), lyophilized, and 27 mg of compound 12 was obtained (yield: 29.5%).

[0416] MS(ESI): m / z 401.4 [(MI-Cl) / 2] + .

[0417] 1 H NMR (400MHz, DMSO-d) 6 ): δ7.08(d,J=8.2Hz,1H),7.02-6.97(m,4H),6.86(d,J=8.4Hz,2H),6.81(s,1H),6.60(dd,J=16.4Hz,J=6.4Hz,2H),5 .55(s,1H),4.89(q,J=8.0Hz,1H),4.63-4.59(m,1H),4.44(s,2H),4.33-4.29(m,3H),4.26(s,1H),3.99(s,2H),3.94 -3.89(m,1H),3.79(s,3H),3.75(s,3H),3.72(s,3H),3.71(s,3H),3.63-3.51(m,6H),3.32(s,5H),3.21(s,3H),3.11 -3.09(m,2H),2.88(t,J=8.8Hz,1H),2.59-2.57(m,2H),2.33-2.27(m,4H),2.19-2.13(m,2H),1.22(d,J=8.0Hz,3H).

[0418] Example 13 Preparation of Compound 13

[0419] Step 1:

[0420] Compound 11a (4.50 g, 18.42 mmol) and compound 12a (1.01 g, 3.07 mol) were dissolved in 2-butanone (25 mL), and sodium iodide (2.76 g, 18.42 mmol) and sodium carbonate (65.08 mg, 613.98 μmol) were added. After purging with nitrogen three times, the reaction was carried out at 75–90 °C until complete. The reaction solution was concentrated to dryness and purified by column chromatography (0–22% acetonitrile / 0.1% TFA water) to give 1.0 g of compound 13a (yield: 61.4%).

[0421] MS(ESI): m / z 400.4 [MI] + .

[0422] Step 2:

[0423] Compound 13a (100 mg, 249.67 μmol) and compound 12 g (125.98 mg, 299.60 μmol) were dissolved in DMF (2 mL), and HATU (143.15 mg, 374.50 μmol) and DIPEA (96.80 mg, 749.01 μmol) were added. The mixture was stirred until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile: 0.1% TFA water = 5–95%), lyophilized, and yielded 67 mg of compound 13 (yield: 36.6%).

[0424] MS(ESI): m / z 401.4 [(MI-Cl) / 2] + .

[0425] 1 H NMR (400MHz, DMSO-d) 6): δ7.08(d,J=8.2Hz,1H),7.03-6.98(m,4H),6.86(d,J=8.4Hz,2H),6.80(s,1H),6.60(dd,J=16.2Hz,J=6.0Hz,2H),5 .53(s,1H),4.84(q,J=8.0Hz,1H),4.63-4.59(m,1H),4.44(s,2H),4.33-4.29(m,3H),4.26(s,1H),4.00(s,2H),3.94 -3.89(m,1H),3.79(s,3H),3.76(s,3H),3.72(s,3H),3.70(s,3H),3.63-3.57(m,6H),3.33(s,5H),3.19(s,3H),3.14 -3.08(m,2H),2.87(t,J=9.2Hz,1H),2.60-2.57(m,2H),2.36-2.27(m,4H),2.20-2.13(m,2H),1.22(d,J=8.2Hz,3H).

[0426] Example 14 Preparation of Compound 14

[0427] Step 1:

[0428] Compound 2-(4-methoxyphenyl)propionic acid (1.49 g, 8.28 mmol, purchased from Bidet) and compound 3,4-dimethoxyphenylethylamine (1.50 g, 8.28 mmol, purchased from Anegy) were mixed and reacted at 160–180 °C until the reaction was complete. The reaction solution was purified by column chromatography (PE:EA = 100:0-50:50) to give 2.50 g of compound 14a (yield 87.9%).

[0429] MS(ESI): m / z 344.3 [M+1] + .

[0430] Step 2:

[0431] Compound 14a (2.50 g, 7.28 mmol) was dissolved in acetonitrile (25 mL), and phosphorus oxychloride (22.32 g, 145.60 mmol) was added. The reaction was carried out at 75–90 °C until complete. The reaction solution was concentrated to dryness, and the pH was adjusted to 7–8 with ammonia. The aqueous phase was extracted twice with 30 mL of dichloromethane. The organic phases were combined, concentrated, and purified by column chromatography (PE:EA = 100:0–70:30) to give 2.0 g of compound 14b (yield 84.3%).

[0432] MS(ESI): m / z 326.3 [M+1] + .

[0433] Step 3:

[0434] Compound 14b (1.60 g, 4.92 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (938.47 mg, 1.48 mmol) were added to DMF (14 mL), cooled to 0 °C, and 6 mL of formic acid and triethylamine (V / V = 2.5:1) were added. The reaction was allowed to proceed to completion at room temperature. The mixture was extracted with 50 mL of saturated K₂CO₃ and 50 mL of dichloromethane. The organic phase was collected, concentrated to dryness, and purified by column chromatography (0-20% acetonitrile / 0.1% TFA water) to give 1.55 g of compound 14c (yield 96.2%).

[0435] MS(ESI): m / z 328.3 [M+1] + .

[0436] Step 4:

[0437] Compound 14c (1.60 g, 4.89 mmol) and formaldehyde solution (37%–40%, 11.74 g, 390.94 mmol) were added to methanol (30 mL), cooled to 0 °C, and sodium borohydride (554.63 mg, 14.66 mmol) was added. The mixture was stirred at room temperature until complete. The reaction solution was evaporated to dryness, and 2 M sodium hydroxide solution (50 mL) was added. The aqueous phase was extracted twice with 50 mL of dichloromethane. The organic phases were combined, concentrated to dryness, and purified by column chromatography (PE:EA = 100:0-50:50) to give 1.30 g of compound 14d (yield 77.9%).

[0438] MS(ESI): m / z 342.3[M+1] + .

[0439] Step 5:

[0440] Compound 14d (300 mg, 878.62 μmol) and 1,3-propanediol cyclic sulfate (485.50 mg, 3.51 mmol) were dissolved in acetonitrile (4 mL) and reacted at 75–90 °C until complete. The reaction solution was filtered and washed with 4 mL of acetonitrile to give 260 mg of compound 14e (yield 61.7%).

[0441] MS(ESI): m / z 400.2 [M-SO2+1] + .

[0442] Step 6:

[0443] Compound 14e (250 mg, 539.27 μmol) and concentrated sulfuric acid (5.29 mg, 53.93 μmol) were added to methanol (3 mL), and the mixture was refluxed at 75–90 °C until complete. The reaction solution was exchanged five times with 4 g of chloride ion exchange resin, then eluted with 5 mL of methanol. The eluent was evaporated to dryness, then lyophilized with water to give 210 mg of compound 14f (yield 97.2%).

[0444] MS(ESI): m / z 400.3 [M-Cl] + .

[0445] Step 7:

[0446] Compound 14f (80 mg, 199.74 μmol) and compound 12g (109.18 mg, 259.66 μmol) were dissolved in DMF (2 mL), and HATU (114.52 mg, 299.60 μmol) and DIPEA (77.44 mg, 599.21 μmol) were added. The mixture was stirred until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile: 0.1% TFA water = 5–95%), lyophilized, and 140 mg of compound 14 was obtained (yield: 87.3%).

[0447] MS(ESI): m / z 401.4[(M-2Cl) / 2] + .

[0448] 1 H NMR (400MHz, DMSO-d) 6 ): δ7.38(d,J=8.2Hz,2H),7.11-7.08(m,1H),7.03-6.96(m,4H),6.89(s,1H),6.63(dd,J=16.8Hz,J=10.2Hz,2H),6.36(s, 1H),4.66(d,J=4.2Hz,2H),4.45(s,2H),4.34(t,J=4.4Hz,2H),4.26(s,2H),4.16-4.12(m,1H),4.10-4.06(m,1H),4.01-4. 00(m,2H),3.98-3.95(m,1H),3.79(s,3H),3.77(s,3H),3.75(s,6H),3.70-3.63(m,2H),3.62-3.56(m,6H),3.34-3.27(m, 2H),3.16-3.08(m,5H),2.60-2.57(m,2H),2.37-2.33(m,2H),2.30-2.26(m,2H),2.15-2.09(m,2H),0.86(d,J=8.0Hz,3H).

[0449] Example 15 Preparation of Compound 15

[0450] Step 1:

[0451] Compound 1i (285 mg, 0.74 mmol) was dissolved in 5 mL of dichloromethane. Then, 1 mL of a dichloromethane solution of compound 15a (999 mg, 5.91 mmol, prepared using a method disclosed in the literature, Organic Letters, 1999, 1993-1996) was added. The mixture was purged with nitrogen three times, and the reaction was stirred at room temperature until complete. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was dried, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by column chromatography (36% acetonitrile in water) and lyophilized to give 250 mg of compound 15b (yield 60.9%).

[0452] MS(ESI): m / z 554.3 [M-Cl] + .

[0453] Step 2:

[0454] Compound 15b (77 mg, 0.14 mmol) was dissolved in 2 mL of dichloromethane in a 25 mL single-necked flask. Nitrogen gas was purged three times, and the mixture was cooled to -20 °C. Triethylamine (56 mg, 0.55 mmol) was added, and the mixture was heated to 0 °C and stirred until complete. Saturated saline solution (5 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (10 mL × 3). The organic phase was dried, filtered, and evaporated to dryness to obtain 230 mg of crude compound 15c, which was directly added to the next reaction step.

[0455] MS(ESI): m / z 518.3 [M-Cl] + .

[0456] Step 3:

[0457] Compound 15c (60 mg, 0.12 mmol) was dissolved in 2 mL of 1,2-dichloroethane in a 25 mL single-necked flask. Oxaloyl chloride (147 mg, 1.16 mmol) was added, and the mixture was purged with nitrogen three times. The mixture was stirred at room temperature and refluxed at 70–85 °C until the reaction was complete. The reaction solution was evaporated to dryness, and 2 mL of 1,2-dichloroethane and 1 mL of chloroform solution of compound 12f (62 mg, 0.17 mmol) were added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was diluted with 2 mL of dichloromethane and extracted with water (10 mL × 3). The reaction solution was purified by HPLC (acetonitrile: 0.1% TFA water = 5–95%), lyophilized, and yielded 10 mg of compound 15 (yield 10%).

[0458] MS(ESI): m / z 411.3[(M-2Cl) / 2] + .

[0459] 1 H NMR (400MHz, DMSO-d6): δ7.08-6.98(m,7H),6.87-6.83(m,3H),5.55(s,1H),4.63(d,1H),4.44(s,2H),4.33(t,2H),4.27-4.23(m ,4H),3.98-3.89(m,4H),3.78-3.71(m,15H),3.62-3.51(m,6H),3.20(s,3H),3.12-3.10(m,2H),2.89(t,1H),2.33-2.27(m,8H).

[0460] Example 16 Preparation of Compounds 16A and 16B

[0461] Step 1:

[0462] Compound 12a (2.5 g, 7.6 mmol) and 2-methyl-1,3-propanedisulfite (3.49 g, 22.9 mmol, prepared according to a literature method, J. Am. Chem. Soc. 2016, 138, 25, 7824-7827) were dissolved in acetonitrile (60 mL) and reacted at 75–90 °C until complete. The reaction solution was concentrated and purified by column chromatography (0–18% methanol / dichloromethane) to give a mixture of 3.5 g of compounds 16a and 16b. The resulting mixture was purified by HPLC (0–60% acetonitrile / 0.3% trifluoroacetic acid aqueous solution), lyophilized, to give 1.25 g of compound 16a (yield: 34.2%) and 1.4 g of compound 16a' (yield: 38.3%).

[0463] Compound 16a:

[0464] 1 H NMR (400MHz, DMSO-d6) δ7.02(d,J=8.4Hz,2H),6.83(d,J=8.8Hz,2H),6.78(s,1H),5.80(s,1H),4.86-4.83(m,1H),3.96-3.86(m,1H),3.72(s,6H) ,3.67-3.62(m,2H),3.59-3.53(m,2H),3.37-3.31(m,4H),3.26(s,3H),3 .16-3.08(m,3H),2.85(t,1H),2.64-2.61(m,1H),1.01(d,J=6.8Hz,3H).

[0465] MS(ESI): m / z = 480.3[M+H] + .

[0466] Compound 16a':

[0467] 1 H NMR (400MHz, DMSO-d6) δ7.01(d,J=8.4Hz,2H),6.81(d,J=8.8Hz,2H),6.75(s,1H),5.81(s,1H),4.84-4.81(m,1H),3.94-3.86(m,1H),3.70(s,6H) ,3.65-3.60(m,2H),3.55-3.51(m,2H),3.38-3.32(m,4H),3.30(s,3H),3 .15-3.08(m,3H),2.85(t,1H),2.63-2.61(m,1H),0.88(d,J=6.8Hz,3H).

[0468] MS(ESI): m / z = 480.3[M+H] + .

[0469] Step 2:

[0470] Compound 16a (1.25 g, 2.61 mmol) was weighed and dissolved in methanol (20 mL). Concentrated sulfuric acid (25 mg, 260 μmol) was added, and the mixture was stirred at 50–65 °C until the reaction was complete. The reaction solution was eluted four times with methanol (20 mL each time) using 12.0 g of chloride ion exchange resin. The eluent was collected, concentrated, and lyophilized to give 950 mg of compound 16b (yield: 91.0%).

[0471] MS m / z (ESI): 400.4 [M-Cl] + .

[0472] 1 H NMR (400MHz, DMSO-d6) δ7.01(d,J=8.4Hz,2H),6.88(d,J=8.8Hz,2H),6.81(s,1H),5.53(s,1H),4.71-4.68(m,1H),3.92-3.88(m,1H),3.62(s,6H) ,3.56-3.35(m,2H),3.45-3.41(m,1H),3.35(s,3H),3.23-3.19(m,4H),3 .12-3.00(m,4H),2.85(t,1H),2.34-2.33(m,1H),1.01(d,J=6.8Hz,3H).

[0473] Compound 16a' (1.4 g, 2.9 mmol) was dissolved in methanol (20 mL), and concentrated sulfuric acid (28 mg, 292 μmol) was added. The mixture was stirred at 50–65 °C until the reaction was complete. The reaction solution was eluted four times with methanol (20 mL each time) using 12.0 g of chloride ion exchange resin. The eluent was collected, concentrated, and lyophilized to give 950 mg of compound 16b' (yield: 81.2%).

[0474] MS m / z (ESI): 400.4 [M-Cl] + .

[0475] 1 H NMR (400MHz, DMSO-d6) δ7.00(d,J=8.8Hz,2H),6.86(d,J=8.4Hz,2H),6.83(s,1H),5.50(s,1H),4.65-4.61(m,1H),3.90-3.82(m,1H),3.76(s,6H) ,3.54-3.50(m,2H),3.48-3.43(m,1H),3.35(s,3H),3.22-3.19(m,4H),3 .14-3.05(m,4H),2.85(t,1H),2.34-2.33(m,1H),0.83(d,J=6.8Hz,3H).

[0476] Step 3:

[0477] Compound 16b (100 mg, 249 μmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL), and 12 g (99 mg, 249 μmol) of compound 16b, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (114 mg, 299 μmol) and N,N-diisopropylethylamine (38 mg, 299 μmol) were added. The mixture was stirred at room temperature until complete. The reaction solution was purified by HPLC (0-40% acetonitrile / 0.3% TFA aqueous solution), lyophilized, and 82 mg of compound 16A was obtained (yield: 40.9%).

[0478] MS(ESI): m / z=401.4[(M-2CF3COO) / 2] + .

[0479] 1H NMR(400MHz,DMSO-d6)δ7.09-7.06(m,1H),7.00-6.96(m,4H),6.85-6.79(m,3H),6.59(d,J=16Hz,1H),6.47 (d,J=15.6Hz,1H),5.42(s,1H),4.59-4.58(m,1H),4.42(s,2H),4.32-4.24(m,4H),3.97-3.89(m,5H),3.80( s,3H),3.78(s,3H),3.75(s,3H),3.62-3.59(m,6H),3.66(s,3H),3.40(s,3H),3.22-3.12(m,6H),2.88-2.8 2(t,1H),2.72-2.68(m,1H),2.58-2.55(m,2H),2.32-2.26(m,4H),2.21-1.96(m,1H),1.11(d,J=6.8Hz,3H).

[0480] Compound 16b' (100 mg, 274 μmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL), and 12 g (110 mg, 274 μmol) of compound 16b', 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (125 mg, 329 μmol) and N,N-diisopropylethylamine (43 mg, 329 μmol) were added. The mixture was stirred at room temperature until complete. The reaction solution was purified by HPLC (0-40% acetonitrile / 0.3% TFA aqueous solution), lyophilized, and 150 mg of compound 16B was obtained (yield: 68.0%).

[0481] MS(ESI): m / z=401.4[(M-2CF3COO) / 2] + .

[0482] 1H NMR (400MHz, DMSO-d6) δ7.11-7.09(m,1H), 7.03-6.99(m,4H), 6.89-6.80(m,5H),5.51(s,1H), 4.62-4.59(m,1H),4.44(s,2H),4.33-4.26(m,5H),4.14-4.03(m,2H),4.00-3.90(m,5H),3.82( s,6H),3.80(s,6H),3.62-3.58(m,3H),3.38(s,3H),3.24-3.20(m,4H),3.13-3.10(m,2H),2.9 0-2.85(m,1H),2.76-2.74(m,1H),2.59-2.57(m,3H),2.35-2.28(m,4H),0.89(d,J=6.8Hz,3H).

[0483] Example 17 Synthesis of compounds 17A and 17B

[0484] Step 1:

[0485] Compound 12a (1.24 g, 3.79 mmol, purchased from Chengdu Inoda Biotechnology Co., Ltd.) and 2,2-difluoro-1,3-propanediol-1,3-cyclosulfate (1.98 g, 11.36 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were weighed and dissolved in acetonitrile (30 mL). The mixture was heated to 85 °C until the reaction was complete. The reaction solution was cooled to room temperature, concentrated, purified by column chromatography (0-22% acetonitrile / water), concentrated, and lyophilized to give compound 17a (1.6 g, yield: 84.2%, a mixture of cis and trans isomers).

[0486] MS(ESI): m / z = 502.3(M+H) + .

[0487] Step 2:

[0488] Compound 17a (1.6 g, 3.19 mmol) was weighed and dissolved in methanol (30 mL). Concentrated sulfuric acid (31 mg, 319 μmol) was added, and the mixture was heated to 60 °C until complete. The reaction solution was cooled to room temperature, and then eluted four times (30 mL each time) with 10.0 g of chloride ion exchange resin. The eluent was collected, concentrated, and 1.2 g of crude product was obtained. The reaction solution was purified by HPLC (0-50% methanol / 0.3% trifluoroacetic acid aqueous solution) to obtain compound 17a (410 mg, yield: 37.2%) and compound 17b' (660 mg, yield: 60%).

[0489] Compound 17b:

[0490] 1 H NMR (400MHz, DMSO-d6) δ6.99(d,J=8.8Hz,2H),6.88(d,J=8.8Hz,2H),6.87(s,1H),5.50(s,1H),4.82-4.79(m,1H),4.05-3 .99(m,3H),3.92-3.87(m,1H),3.74(s,6H),3.71-3.57(m,3H),3.55(s,3H),3.22(s,3H),3.19-3.10(m,2H),2.93(t,1H).

[0491] MS(ESI): m / z = 422.3 (M-Cl) + .

[0492] Compound 17b':

[0493] 1 H NMR(400MHz,DMSO-d6)δ6.88-6.85(m,5H),5.57(s,1H),4.62-4.52(m,2H),4.42-4.34(m,2H),4.0 4-4.00(m,1H),3.88-3.81(m,3H),3.73(s,6H),3.67-3.64(m,1H),3.21-3.17(m,7H),2.86(t,1H).

[0494] MS(ESI): m / z = 422.3 (M-Cl) + .

[0495] Step 3:

[0496] Compound 17b (100 mg, 237 μmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL), and compound 12 g (99 mg, 237 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (106 mg, 284 μmol), and N,N-diisopropylethylamine (36 mg, 284 μmol) were added. The mixture was stirred at room temperature until complete. The reaction solution was purified by HPLC (0–50% acetonitrile / 0.3% trifluoroacetic acid aqueous solution) to obtain compound 17A (82 mg, yield: 42%).

[0497] MS (ESI): m / z=412.3[(M-2Cl) / 2] + .

[0498] 1H NMR (400MHz, DMSO-d6) δ7.10-7.08(m,1H),7.02-6.98(m,4H),6.89-6.87(m,3H),6.77(d,J=5.6Hz,2H) ,5.52(s,1H),4.78-4.75(m,1H),4.58(t,2H),4.44(s,2H),4.35-4.32(m,2H),4.26-4.03(m,6H),4.00- 3.99(m,2H),3.89-3.82(m,2H),3.79(s,3H),3.76(s,3H),3.74(s,3H),3.73(s,3H),3.56(s,3H),3.22 (s,3H),3.19-3.15(m,2H),2.97-2.92(m,1H),2.59-2.56(m,3H),2.53-2.50(m,2H),2.34-2.28(m,4H).

[0499] Compound 17b' (60 mg, 142 μmol) was dissolved in anhydrous N,N-dimethylformamide (6 mL), and 12 g (60 mg, 142 μmol) of compound 17b', 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (62 mg, 171 μmol) and N,N-diisopropylethylamine (22 mg, 171 μmol) were added. The mixture was stirred at room temperature until complete. The reaction solution was purified by HPLC (0–50% acetonitrile / 0.3% trifluoroacetic acid aqueous solution) to obtain compound 17B (61 mg, yield: 53%).

[0500] MS (ESI): m / z=412.3[(M-2Cl) / 2] + .

[0501] 1H NMR(400MHz,DMSO-d6)δ7.13-7.12(m,1H),7.05-7.03(m,2H),6.92-6.87(m,7H),5.52(s,1H), 4.92-4.89(m,1H),4.83-4.76(m,2H),4.44(s,2H),4.36-4.34(m,2H),4.29-4.25(m,2H),4.04 -3.97(m,5H),3.94-3.83(m,2H),3.81(s,3H),3.80(s,3H),3.74(s,3H),3.72(s,3H),3.65-3. 60(m,3H),3.24(s,3H),3.20(s,3H),2.89-2.84(m,1H),2.59-2.52(m,5H),2.30-2.25(m,4H).

[0502] Example 18 Preparation of Compound 18

[0503] Step 1:

[0504] Compound 12a (1.7 g, 5.18 mmol) was dissolved in acetonitrile (30 mL), and 1,1-cyclopropyl sulfinyl ester (2.55 g, 15.5 mmol, purchased from Leyan) was added. The mixture was stirred at 70–85 °C until the reaction was complete. The reaction solution was concentrated and purified by HPLC (acetonitrile / 0.1% formic acid aqueous solution: 15–95%), and then lyophilized to give 400 mg of compound 18a (yield: 15.7%).

[0505] MS(ESI): m / z = 492.4 [M+H] + .

[0506] 1 H NMR(400MHz,MeOH-d4)δ6.99(d,J=8.8Hz,2H),6.85-6.79(m,3H),5.77(s, 1H),5.07-5.04(m,1H),4.02-3.88(m,3H),3.79(s,3H),3.75(s,3H),3.71 -3.63(m,2H),3.53-3.50(m,4H),3.34-3.32(m,4H),3.26-3.16(m,2H),2. 94-2.88(m,1H),0.96-0.94(m,1H),0.92-0.80(m,2H),0.58-0.52(m,1H).

[0507] Step 2:

[0508] Compound 18a (250 mg, 0.51 mmol) was weighed and dissolved in methanol (5.0 mL). Concentrated sulfuric acid (10 mg, 0.1 mmol) was added, and the mixture was stirred at 55–65 °C until the reaction was complete. The mixture was eluted four times with methanol (20 mL each time) using 10.0 g of chloride ion exchange resin. The eluent was collected, concentrated, purified by column chromatography (A: H2O, B: MeCN, 15% B), and lyophilized to give 200 mg of compound 18b (yield: 95.3%).

[0509] MS(ESI): m / z = 412.4 [M-Cl] + .

[0510] 1 H NMR(400MHz,DMSO-d6)δ6.96(d,J=8.4Hz,2H),6.88(d,J=8.4Hz,2H),6.83(s,1 H),5.52(s,1H),4.98-4.94(m,1H),3.91-3.85(m,1H),3.78-3.73(m,7H),3.66 -3.61(m,1H),3.46(s,3H),3.42-3.40(m,4H),3.28-3.25(m,1H),3.22(s,3H), 3.13-3.07(m,1H),2.84(t,J=8.4Hz,1H),0.70-0.60(m,3H),0.45-0.43(m,1H).

[0511] Step 3:

[0512] Compound 18b (100 mg, 0.24 mmol) was weighed and dissolved in anhydrous N,N-dimethylformamide (4.0 mL), along with 12 g of compound 102 mg (0.24 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (109 mg, 0.29 mmol), and 4-dimethylaminopyridine (44 mg, 0.36 mmol). The mixture was stirred until complete. The reaction solution was purified by HPLC (acetonitrile / 0.3% trifluoroacetic acid aqueous solution: 45-95%), lyophilized, and 71 mg of compound 18 was obtained (yield: 36.3%).

[0513] MS(ESI):m / z=407.4[(M-2CF3COO) / 2] +

[0514] 1H NMR (400MHz, DMSO-d6) δ7.11-7.09(m,1H),7.02-6.97(m,4H),6.85(d,J=8.8Hz,2H),6.81(s,1H),6.63(s,2H),5.3 7(s,1H),4.65-4.61(m,1H),4.45(s,2H),4.37-4.26(m,5H),4.02-3.89(m,4H),3.79(d,J=2.4Hz,6H),3.71(s,3H) ,3.69-3.67(m,4H),3.63-3.56(m,6H),3.48(s,3H),3.38-3.32(m,1H),3.23-3.07(m,5H),2.88(t,J=11.6Hz,1H), 2.60-2.54(m,2H),2.34-2.27(m,4H),1.01-0.99(m,1H),0.91-0.86(m,1H),0.78-0.73(m,1H),0.60-0.55(m,1H).

[0515] 19 F NMR(377MHz,DMSO-d6)δ-69.212,-71.101,-74.262.

[0516] Example 19 Preparation of Compound 19

[0517] Step 1:

[0518] Compound 19a (8.0 g, 85.03 mmol, purchased from Shaoyuan Technology) was weighed and dissolved in dichloromethane (100 mL). Thionyl chloride (15.18 g, 127.5 mmol) was added at 0 °C, and the mixture was stirred at room temperature until complete. The reaction solution was added to ice water (100 mL), and the organic phase was washed twice with water (100 mL), once with saturated sodium carbonate (100 mL), and twice with water (100 mL). The mixture was dried, filtered, and concentrated to obtain the crude product. The crude product was dissolved in a mixed solvent of dichloromethane (30 mL), acetonitrile (30 mL), and water (60 mL). Sodium periodate (27.55 g, 127.54 mmol) and ruthenium trichloride (528 mg, 2.55 mmol) were added, and the mixture was stirred until the reaction was complete. The reaction solution was diluted with ethyl acetate (150 mL), and the organic phase was washed twice with water (100 mL), once with saturated sodium carbonate (100 mL), twice with water (100 mL), and once with saturated brine (100 mL). The mixture was dried, filtered, and concentrated to give 4.0 g of compound 19b (yield: 30%).

[0519] 1H NMR (400MHz, CDCl3) δ5.04-5.00(m,1H),4.94-4.91(m,1H),4.83-4.65(m,3H).

[0520] 19 F NMR (377MHz, CDCl3) δ -192.54.

[0521] Step 2:

[0522] Compound 12a (500 mg, 1.53 mmol) was dissolved in acetonitrile (10 mL), and compound 19b (715 mg, 4.58 mmol) was added. The mixture was stirred at 70–85 °C until the reaction was complete. The reaction solution was concentrated, purified by column chromatography (A: H₂O, B: MeCN, 15% B), and lyophilized to give 500 mg of compound 19c (yield: 67.7%).

[0523] MS(ESI): m / z = 484.3 [M+H] + .

[0524] Step 3:

[0525] Compound 19c (500 mg, 1.03 mmol) was dissolved in methanol (10.0 mL), and concentrated sulfuric acid (20 mg, 0.21 mmol) was added. The mixture was stirred at 55–65 °C until the reaction was complete. The reaction solution was purified by column chromatography (A: H₂O, B: MeCN, 15% B), and lyophilized to give 300 mg of compound 19d (yield: 71.7%).

[0526] MS(ESI): m / z = 404.3 [M-Cl] + .

[0527] Step 4:

[0528] Compound 19d (100 mg, 0.237 mmol) was dissolved in anhydrous N,N-dimethylformamide (4.0 mL), and 12 g of compound 19d (96 mg, 0.237 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (109 mg, 0.286 mmol), and 4-dimethylaminopyridine (44 mg, 0.36 mmol) were added. The mixture was stirred until complete. The reaction solution was purified by HPLC (acetonitrile / 0.3% trifluoroacetic acid aqueous solution: 25%-45%), lyophilized, and yielded 64 mg of compound 19d (yield: 33.3%).

[0529] MS(ESI):m / z=403.4[(M-2CF3COO) / 2] + .

[0530] 1 H NMR(400MHz,DMSO-d6)δ7.10-7.08(m,1H),7.02-6.98(m,4H),6.89-6.84(m,3H), 6.77-6.66(m,2H),5.87-5.70(m,1H),5.64-5.40(m,1H),4.86-4.67(m,1H),4.61 -4.25(m,8H),3.99(s,3H),3.80-3.71(m,17H),3.65-3.59(m,3H),3.51-3.42(m, 3H),3.21-3.08(m,5H),2.94-2.83(m,1H),2.59-2.56(m,2H),2.33-2.27(m,4H).

[0531] 19 F NMR(377MHz,DMSO-d6)δ-69.217,-71.109,-74.203,-182.735,-183.778.

[0532] Compound 19 was resolved to obtain: compound 19A (retention time 13.532 min) and compound 19B (retention time 13.870 min).

[0533] Separation conditions: Reversed-phase column: Welch Xtimate C18, 30.0×150mm, 5µm; Mobile phase: A is purified water (0.1% trifluoroacetic acid), B is methanol; Gradient: 40% B; Flow rate: 30mL / min; Column temperature: 30℃; Wavelength: 214nm.

[0534] The structures of compounds 19A and 19B are shown below:

[0535] Example 20 Preparation of Compound 20

[0536] Step 1:

[0537] Compound 20a (2.59 g, 7.79 mmol, prepared by the method disclosed in patent WO2006078575) was dissolved in anhydrous dichloromethane (26 mL), and p-toluenesulfonyl chloride (2.23 g, 11.68 mmol), triethylamine (1.58 g, 15.58 mmol, 2.17 mL) and 4-dimethylaminopyridine (95 mg, 0.78 mmol) were added. The mixture was stirred at room temperature until the reaction was complete. The solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether: 0-10%) to give 3.31 g of compound 20b (yield: 87%).

[0538] 1 H NMR(400MHz,MeOD-d4)δ7.81-7.73(m,2H),7.63-7.55(m,4H),7.50-7.34(m,8H),4.77-4.58(m,1H),4 .34-4.25(m,1H),4.25-4.21(m,1H),3.83-3.76(m,1H),3.76-3.69(m,1H),2.43(s,3H),0.97(s,9H).

[0539] 19 F NMR (376MHz, MeOD) δ-197.00.

[0540] Step 2:

[0541] Compound 20b (1.63 g, 3.34 mmol) was dissolved in anhydrous acetonitrile (15 mL), and compound 1c (0.5 g, 3.34 mmol), potassium carbonate (1.39 g, 10.03 mmol), and potassium iodide (55 mg, 0.33 mmol) were added. The mixture was stirred at 80–85 °C until complete. The reaction solution was concentrated, diluted with dichloromethane (20 mL), and water (10 mL) was added. The mixture was stirred, separated, and the aqueous phase was extracted with dichloromethane (20 mL × 2). The solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether: 0–20%) to give 920 mg of compound 20c (yield: 64%).

[0542] MS(ESI): m / z = 428.4 [M+1] + .

[0543] 1 H NMR(400MHz,MeOD-d4)δ7.71-7.64(m,4H),7.49-7.36(m,6H),4.76-4.55(m,1H),3.96-3.77(m,2H),3.67-3.58(m,2H),3.47-3 .38(m,2H),3.11(d,J=5.5Hz,1H),3.02(d,J=4.8Hz,1H),2.68-2.47(m,2H),2.01-1.84(m,2H),1.88-1.76(m,2H),1.05(s,9H).

[0544] 19 F NMR(376MHz,MeOD-d4)δ-190.82.

[0545] Step 3:

[0546] Compound 20c (0.4 g, 935.40 μmol) was dissolved in anhydrous acetonitrile (8 mL), and 3,4-dimethoxybenzyl bromide (649 mg, 2.81 mmol) was added. The mixture was stirred at 80–85 °C until the reaction was complete. The mixture was purified by column chromatography (methanol / dichloromethane: 0–10%) to give 141 mg of compound 20d (yield: 26%).

[0547] MS(ESI): m / z = 578.5 [M-Br] +

[0548] 1 H NMR(400MHz,MeOD-d4)δ7.71-7.54(m,4H),7.51-7.35(m,6H),7.11-6.85(m,3H),5.77-5.12(m,2H),4.90-4 .61(m,2H),4.43-3.85(m,7H),3.84-3.75(m,6H),3.75-3.64(m,2H),2.77-2.38(m,4H),1.12-0.97(m,9H).

[0549] 19 F NMR(376MHz,MeOD-d4)δ-189.46,-191.23.

[0550] Step 4:

[0551] Compound 20d (253 mg, 384.08 μmol) was dissolved in methanol (4 mL), and 4.0 M HCl / dioxane solution (8 mL) was added. The mixture was stirred at 45–50 °C until the reaction was complete. The reaction solution was concentrated and purified by column chromatography (methanol / dichloromethane: 0–35%) to give 159 mg of compound 20e (yield: 110%).

[0552] MS(ESI): m / z = 340.3 [M-Cl] + .

[0553] 1 H NMR(400MHz,MeOD-d4)δ7.20-7.00(m,3H),5.68-5.12(m,2H),4.94-4.61(m,2H),4.51- 4.32(m,2H),4.22-4.05(m,2H),3.93-377(m,8H),3.77-3.62(m,2H),2.77-2.37(m,4H).

[0554] 19 F NMR(376MHz,MeOD-d4)δ-190.20,-191.94.

[0555] Step 5:

[0556] Compound 2f (100 mg, 192.30 μmol) and compound 20e (73 mg, 194.22 μmol) were dissolved in anhydrous DMF (2 mL). HATU (110 mg, 289.29 μmol) and DMAP (36 mg, 294.67 μmol) were added with stirring in an ice bath. After the addition was complete, the mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (0-45% acetonitrile / 0.3% TFA aqueous solution) to give 90 mg of compound 20 (yield: 58%).

[0557] MS(ESI): m / z = 403.4[(M-2Cl - ) / 2] + .

[0558] 1 H NMR (400MHz, DMSO-d6) δ7.13-6.57(m,10H),6.04-5.10(m,3H),4.82-4.23(m,7H),4.20-3.86(m,5H),3.82-3.75(m,6H),3.74-3.68(m,7 H),3.68-3.59(m,4H),3.43-3.27(m,6H),3.24-3.18(m,3H),3.14-3.06(m,2H),2.92-2.84(m,1H),2.68-2.58(m,1H),2.35-2.16(m,4H).

[0559] 19 F NMR(376MHz,DMSO-d6)δ-74.01,-187.72,-189.11.

[0560] Compound 20 was resolved to obtain: compound 20-A (retention time 13.478 min), compound 20-B (retention time 13.623 min), compound 20-C (retention time 13.884 min), and compound 20-D (retention time 13.990 min).

[0561] Separation conditions: Reversed-phase column: Agilent Zorbax Bonus RP, 4.6 mm × 150 mm, 3.5 μm; Mobile phase: A is water (0.05% trifluoroacetic acid), B is acetonitrile; Gradient: 10%-40% B; Flow rate: 1.000 mL / min; Column temperature: 30 °C; Wavelength: 210 nm.

[0562] The structures of compounds 20A, 20B, 20C, and 20D are shown below:

[0563] Example 21 Synthesis of Compound 21

[0564] Step 1:

[0565] 4,4-Difluoropiperidine (550 mg, 4.54 mmol) and compound 19b (709 mg, 4.54 mmol) were dissolved in anhydrous acetonitrile (16 mL) and reacted at 80–85 °C until complete. The reaction solution was filtered, washed with acetonitrile (8 mL × 2), and dried to give 1.05 g of compound 21a (yield: 83.4%).

[0566] MS(ESI): m / z = 278.2(M+1) + .

[0567] 1 H NMR (400MHz, DMSO-d6) δ9.80(brs,1H),5.32-5.18(m,1H),4.04-3.85(m,2H),3.60-3.30(m,6H),2.50-2.37(m,4H).

[0568] Step 2:

[0569] Compound 21a (1.05 g, 3.79 mmol) was added to a single-necked flask, followed by methanol (15 mL) and concentrated sulfuric acid (37 mg, 378 μmol). The reaction was carried out at 60–65 °C until complete. The reaction solution was repeatedly eluted with chloride ion exchange resin (20 mL × 4), and the eluent was collected, concentrated, and dried to give 720 mg of compound 21b (yield: 96.4%).

[0570] MS(ESI): m / z = 198.2(M+1) + .

[0571] 1 H NMR (400MHz, DMSO-d6) δ5.22-5.10(m,1H),3.70-3.58(m,2H),3.55-3.20(m,6H),2.50-2.37(m,4H).

[0572] Step 3:

[0573] Compound 21b (550 mg, 2.79 mmol) was dissolved in dichloromethane (10 mL), and tert-butyldiphenylchlorosilane (389 mg, 3.35 mmol) and N,N-diisopropylethylamine (432 mg, 3.35 mmol) were added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was concentrated, purified by column chromatography (0-20% ethyl acetate / petroleum ether), and concentrated to give 1.05 g of compound 21c (yield: 86.4%).

[0574] MS(ESI): m / z = 436.3(M+1) + .

[0575] Step 4:

[0576] Compound 21c (1.0 g, 2.30 mmol) was dissolved in acetonitrile (30 mL), and 3,4-dimethoxybenzyl bromide (796 mg, 3.44 mmol, purchased from Jiangsu Aikang) was added. The reaction was carried out at 60–65 °C until complete. The reaction solution was concentrated, purified by column chromatography (0–15% MeOH / DCM), and concentrated to give 720 mg of compound 21d (yield: 53.4%).

[0577] MS (ESI): m / z = 586.5 (M-Cl) + .

[0578] 1 H NMR (400MHz, DMSO-d6) δ7.66-7.62(m,4H),7.53-7.44(m,6H),7.12-7.07(m,2H),6.88(d,J=8.4Hz,1H),5.72-5.57(m,1H),4.78 (s,2H),4.13-3.96(m,2H),3.93-3.82(m,2H),3.78(s,3H),3.76(s,3H),3.74-3.43(m,7H),3.16(d,J=5.2Hz,1H),1.03(s,9H).

[0579] Step 5:

[0580] Compound 21d (720 mg, 1.23 mmol) was dissolved in methanol (2 mL), and concentrated hydrochloric acid (448 mg) and dioxane hydrochloride (5 mL, 4 M) were added. The mixture was stirred at 45–50 °C until complete. The reaction solution was concentrated and purified by column chromatography (0–20% methanol / dichloromethane) to give 380 mg of compound 21e (yield: 88.9%).

[0581] MS (ESI): m / z = 348.3 (M-Cl) + .

[0582] 1 H NMR (400MHz, DMSO-d6) δ7.17-7.14(m,2H),7.07(d,J=8.8Hz,1H),5.51-5.35(m,1H),4.75(s,2H),4.09-3.99( m,1H),3.88(s,3H),3.87(s,3H),3.85-3.76(m,3H),3.72-3.64(m,4H),3.62-3.52(m,1H),2.63-2.51(m,4H).

[0583] 19 F NMR (400MHz, DMSO-d6) δ -100.66, -102.78, -190.76.

[0584] Step 6:

[0585] Compound 2f (92 mg, 189.4 μmol) was dissolved in anhydrous N,N-dimethylformamide (6 mL), and compound 21e (60 mg, 172.2 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (98 mg, 258.3 μmol), and N,N-diisopropylethylamine (44 mg, 344.4 μmol) were added. The mixture was stirred at room temperature until complete. The reaction solution was purified by HPLC (0-45% acetonitrile / 0.3% TFA aqueous solution) and lyophilized to give 25 mg of compound 21 (yield: 17.8%).

[0586] MS(ESI): m / z=(M-151-2CF3COO) + .

[0587] 1 H NMR (400MHz, DMSO-d6) δ7.11-7.09(m,3H), 6.99-6.82(m,6H), 6.73(s,1H),5.91-5 .78(m,1H),5.58(s,1H),4.79-4.72(m,2H),4.62-4.40(m,3H),4.20-4.07(m,3H),4 .01-3.88(m,2H),3.79(s,6H),3.72(s,6H),3.71(s,3H),3.67-3.55(m,5H),3.32- 3.30(m,4H),3.21(s,3H),3.18-3.03(m,3H),2.91-2.85(m,1H),2.14-2.09(m,4H).

[0588] 19F NMR (400MHz, DMSO-d6) δ-69.20, -71.09, -97.24, -98.79, -185.79.

[0589] Example 22 Preparation of Compound 22

[0590] Step 1:

[0591] Compound 22a (0.5 g, 1.58 mmol, purchased from Jiangsu Aikon) was dissolved in methanol (30 mL), and 3,4-dimethoxybenzaldehyde (788 mg, 4.74 mmol, purchased from Shanghai Titan Technology Co., Ltd.) and sodium cyanoborohydride (298 mg, 4.74 mmol) were added. The mixture was stirred at room temperature until complete. The reaction solution was diluted and concentrated with ethyl acetate (100 mL), washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE:EA = 2:1) to give 400 mg of compound 22b (yield: 48.1%).

[0592] MS(ESI): m / z = 264.2[M+H] + .

[0593] 1 H NMR (400MHz, CDCl3) δ6.97-6.95(m,1H),6.87-6.85(m,1H),6.81-6.79(m,1H),4.32-4.30(m,1H),3.89(s,3H),3.86(s,3H),3.83-3.79 (m,1H),3.77-3.73(m,1H),3.70(s,2H),3.10-3.06(m,1H),2.93-2.89(m,1H),2.62-2.58(m,1H),2.11-2.00(m,2H),1.78-1.68(m,2H).

[0594] Step 2:

[0595] Compound 22b (400 mg, 1.52 mmol) was dissolved in acetonitrile (8.0 mL), and 1,3,2-dioxane-2,2-dioxide (629 mg, 4.56 mmol, purchased from Bide) was added. The mixture was stirred at 75–80 °C until complete. The reaction solution was concentrated and purified by column chromatography (DCM:MeOH = 3:1) to give 500 mg of compound 22c (yield: 82%).

[0596] MS(ESI): m / z = 402.3 [M+H] + .

[0597] 1 H NMR (400MHz, DMSO-d6) δ7.23-7.20(m,1H),7.17-7.13(m,1H),7.07-7.04(m,1H),4.85-4. 70(m,1H),4.54-4.46(m,1H),4.40-4.31(m,1H),4.10-4.08(m,1H),4.04-3.99(m,1H),3.9 0-3.85(m,1H),3.83-3.82(m,3H),3.80(s,3H),3.78-3.70(m,2H),3.49-3.38(m,1H),3.30 -3.21(m,1H),3.18-3.16(m,2H),2.68-2.56(m,1H),2.38-2.29(m,1H),2.17-1.84(m,4H).

[0598] Step 3:

[0599] Compound 22c (500 mg, 1.25 mmol) was dissolved in methanol (10.0 mL), and concentrated sulfuric acid (25 mg, 0.25 mmol) was added. The mixture was stirred at 55–60 °C until complete. At room temperature, the reaction solution was exchanged with a chloride anion exchange resin (40 g, Dowex 1×8 chloride form, purchased from Maclean) (20 mL × 4). The methanol solution after exchange was directly concentrated to give 350 mg of compound 22d (yield: 87.2%).

[0600] MS(ESI): m / z = 322.3 [M-Cl] + .

[0601] Step 4:

[0602] Compound 22d (66.0 mg, 0.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (4.0 mL), and compound 2f (100 mg, 0.21 mmol, SO244-088), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (95 mg, 0.25 mmol), and 4-dimethylaminopyridine (38 mg, 0.31 mmol) were added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile / 0.1% trifluoroacetic acid aqueous solution) and lyophilized to give 89.5 mg of compound 22 (yield: 55.4%).

[0603] MS(ESI): m / z=394.4[(M-2Cl) / 2] +

[0604] 1H NMR(400MHz,DMSO-d6)δ7.20-7.13(m,2H),7.00-6.98(m,3H),6.87-6.82(m,3H),6.60-6.58(m,2H), 5.55-5.54(m,1H),4.95-4.83(m,1H),4.72-4.52(m,3H),4.38-4.35(m,1H),4.29-4.02(m,6H),3.97 -3.86(m,2H),3.83-3.70(m,14H),3.63-3.59(m,1H),3.51-3.36(m,4H),3.33(s,3H),3.25-3.16(m, 4H),3.12-3.07(m,2H),2.91-2.85(m,1H),2.68-2.60(m,1H),2.46-2.32(m,1H),2.25-2.00(m,5H).

[0605] 19 F NMR(377MHz,DMSO-d6)δ-74.47.

[0606] Example 23 Preparation of Compound 23

[0607] Step 1:

[0608] Compound 23a (2.0 g, 13.37 mmol), 3,4-dimethoxybenzaldehyde (2.22 g, 13.37 mmol), and triethylamine (1.49 g, 14.70 mmol) were dissolved in anhydrous dichloromethane (40 mL), and sodium triacetoxyborohydride (4.25 g, 20.05 mmol) was added. The mixture was stirred at room temperature until complete. The pH of the reaction solution was adjusted to 8–9 by adding saturated sodium carbonate solution (10–50 mL). The mixture was separated, and the aqueous phase was extracted once with dichloromethane (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate (50 g), and purified by column chromatography (methanol / dichloromethane: 0–2%) to give 2.39 g of compound 23b (yield: 67%).

[0609] MS(ESI): m / z = 264.3[M+1] + .

[0610] 1H NMR(400MHz,MeOH-d4)δ6.95(d,J=1.6Hz,1H),6.90-6.79(m,2H),4.28-4.21(m,2H),3.81(s,3H),3. 80(s,3H),3.38(s,2H),2.59-2.52(m,2H),2.30-2.22(m,2H),2.05-1.94(m,2H),1.91-1.77(m,2H).

[0611] Step 2:

[0612] Compound 23b (1.2 g, 4.56 mmol) and propylene sulfate (3.15 g, 22.78 mmol) were dissolved in anhydrous acetonitrile (2 mL), and the mixture was stirred at 85–90 °C until complete. The solution was concentrated and purified by column chromatography (methanol / dichloromethane: 0–35%) to give 2.77 g of compound 23c (yield: 15%).

[0613] MS(ESI): m / z = 402.3[M+1] + .

[0614] 1 H NMR(400MHz,MeOH-d4)δ7.21-7.00(m,3H),4.76-4.35(m,3H),4.30-4.04(m,3H),3.94-3 .84(m,6H),3.84-3.72(m,2H),3.61-3.46(m,2H),3.43-3.21(m,2H),2.40-1.84(m,6H).

[0615] Step 3:

[0616] Compound 23c (277 mg, 689.96 μmol) was dissolved in methanol (10 mL), concentrated sulfuric acid was added, and the mixture was stirred at 60–65 °C until the reaction was complete. The reaction solution was exchanged through a chloride ion exchange resin (20 mL × 4), eluted with methanol, evaporated to dryness, and then lyophilized with water to give 241 mg of compound 23d (yield: 97%).

[0617] MS(ESI): m / z = 322.3 [M-Cl] + .

[0618] 1H NMR(400MHz,MeOH-d4)δ7.26-7.13(m,2H),7.13-6.99(m,1H),4.67-4.45(m,4H),3.94-3.84(m,6H ),3.84-3.73(m,2H),3.73-3.58(m,4H),3.54-3.46(m,2H),3.43-3.20(m,2H),2.26-2.06(m,6H).

[0619] Step 4:

[0620] Compound 2f (90 mg, 173.07 μmol) and compound 23d (62 mg, 173.24 μmol) were dissolved in anhydrous DMF (2 mL). HATU (99 mg, 260.37 μmol) and DMAP (32 mg, 261.93 μmol) were added with stirring in an ice bath, and the reaction was carried out at room temperature until complete. The reaction solution was purified by HPLC (acetonitrile / 0.1% trifluoroacetic acid aqueous solution), lyophilized, and 49 mg of compound 23 was given (yield: 33%).

[0621] MS(ESI): m / z=394.4[(M-2Cl) / 2] + .

[0622] 1 H NMR(400MHz,DMSO-d6)δ7.19-7.05(m,2H),7.05-6.94(m,3H),6.89-6.79(m,3H),6.71-6.56(m ,2H),5.55(s,1H),4.70-4.49(m,5H),4.32-4.23(m,2H),4.23-4.09(m,2H),3.97-3.86(m,1H), 3.84-3.75(m,6H),3.75-3.65(m,9H),3.65-3.57(m,2H),3.43-3.29(m,8H),3.23-3.17(m,3H), 3.15-3.05(m,2H),2.93-2.81(m,1H),2.41-2.27(m,2H),2.26-2.14(m,2H),2.12-1.92(m,4H).

[0623] 19 F NMR(376MHz,DMSO-d6)δ-73.78.

[0624] Example 24 Preparation of Compound 24

[0625] Step 1:

[0626] Compound 24a (0.5 g, 3.87 mmol, purchased from Leyan), potassium carbonate (834 mg, 6.03 mmol), and potassium iodide (50 mg, 301.20 μmol) were dissolved in acetone (20 mL). Compound 24b (1.14 g, 3.02 mmol, prepared by a method disclosed in the literature, Tetrahedron, 2009, vol. 65(21), P 4201-4211) was added, and the mixture was stirred at 60–65 °C until complete. The reaction solution was filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether: 0–40%) to give 1.11 g of compound 24c (yield: 67%).

[0627] MS(ESI): m / z = 426.4 [M+1] + .

[0628] 1 H NMR (400MHz, MeOH-d4) δ7.70-7.63 (m, 4H), 7.48-7.35 (m, 6H), 3.71 (t, J = 6.1Hz, 2H), 2.76-2. 69(m,4H),2.58-2.49(m,2H),1.80-1.69(m,2H),1.04(s,9H),0.81-0.74(m,4H),0.06(s,6H).

[0629] Step 2:

[0630] Compound 24c (0.6 g, 1.41 mmol) was dissolved in anhydrous acetonitrile (6 mL), and 3,4-dimethoxybenzyl bromide (977 mg, 4.23 mmol) was added. The mixture was stirred at 75–80 °C until complete, and purified by column chromatography (methanol / dichloromethane: 0–10%) to give 750 mg of compound 24d (yield: 81%).

[0631] MS(ESI): m / z = 576.5 [M-Br] + .

[0632] 1H NMR(400MHz,MeOD-d4)δ7.70-7.62(m,4H),7.51-7.37(m,6H),7.11-7.03(m ,2H),6.93(d,J=8.1Hz,1H),4.45(s,2H),3.89(t,J=5.5Hz,2H),3.84(s,3H ),3.83(s,3H),3.69-3.58(m,2H),3.53-3.41(m,2H),3.26-3.17(m,2H),2. 23-2.11(m,2H),1.16-1.04(m,4H),1.06(s,9H),0.21(s,3H),0.17(s,3H).

[0633] Step 3:

[0634] Compound 24d (750 mg, 1.14 mmol) was dissolved in methanol (10 mL), and 4.0 M HCl / dioxane solution (20 mL) was added. The mixture was stirred at 45–500 °C until complete. The reaction solution was concentrated and purified by column chromatography (methanol / dichloromethane: 0–20%) to give 385 mg of compound 24e (yield: 86%).

[0635] MS(ESI): m / z = 338.3 [M-Cl] + .

[0636] 1 H NMR(400MHz,MeOD-d4)δ7.16-7.10(m,2H),7.09-7.02(m,1H),4.46(s,2H),3.90-3.85(m,6H),3.79-3.61(m,4H),3.5 3-3.41(m,2H),3.35-3.28(m,2H),2.18-2.06(m,2H),1.28-1.15(m,2H),1.14-1.02(m,2H),0.23(s,3H),0.21(s,3H).

[0637] Step 4:

[0638] Compound 24e (100 mg, 192.30 μmol) and compound 2f (72 mg, 192.52 μmol) were dissolved in anhydrous DMF (2 mL). HATU (110 mg, 289.29 μmol) and DMAP (36 mg, 294.67 μmol) were added under ice bath conditions, and the mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile / 0.1% trifluoroacetic acid aqueous solution), lyophilized, and yielded 17 mg of compound 24 (yield: 10%).

[0639] MS(ESI):m / z=402.5[(M-2Cl) / 2] + .

[0640] 1 H NMR (400MHz, DMSO-D6) δ7.10-7.03(m,2H),7.03-6.95(m,3H),6.89-6.78(m,3H),6.68-6.63( m,2H),5.39(s,1H),4.66-4.57(m,1H),4.47(s,2H),4.30(t,J=5.9Hz,2H),4.21-4.08(m,2H) ,3.98-3.85(m,1H),3.80-3.74(m,6H),3.74-3.68(m,6H),3.68-3.52(m,4H),3.52-3.30(m,7 H),3.24-3.00(m,7H),2.93-2.82(m,1H),2.29-2.13(m,4H),1.15-0.94(m,4H),0.15(s,6H).

[0641] 19 F NMR(376MHz,DMSO-D6)δ-73.50.

[0642] Example 25 Preparation of Compound 25

[0643] Step 1:

[0644] Compound 3a (300 mg, 1.17 mmol) was dissolved in DMF (5 mL), and compound 24b (518.00 mg, 1.17 mmol) and potassium carbonate (407.18 mg, 2.92 mmol) were added. The mixture was stirred at 60–75 °C until complete. The reaction solution was diluted with water (50 mL), extracted with EA (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (13% ethyl acetate / petroleum ether) to give 458 mg of compound 25a (yield 92.21%).

[0645] MS(ESI): m / z 426.1 [M+1] + .

[0646] Step 2:

[0647] Compound 25a (200 mg, 663.21 μmol) was dissolved in acetonitrile (2.5 mL), and compound 1e (186.28 mg, 994.82 μmol) and sodium iodide (150.62 mg, 994.82 μmol) were added. The mixture was stirred at 60–75 °C until complete. The reaction solution was evaporated to dryness and dissolved in DCM (1 mL). The solution was purified by column chromatography (3% methanol / dichloromethane) to give 314 mg of compound 25b (yield 81.68%).

[0648] MS(ESI): m / z 576.2 [MI] + .

[0649] Step 3:

[0650] Compound 25b (314 mg, 446.16 μmol) was dissolved in methanol (0.5 mL), and hydrochloric acid / dioxane (4 M, 16 mmol, 4 mL) was added. The mixture was stirred at room temperature until complete. The reaction solution was evaporated to dryness, dissolved in DCM (1 mL), and purified by column chromatography (12% methanol / dichloromethane) to give 161 mg of compound 25c (yield 96.5%).

[0651] MS(ESI): m / z 338.1 [M-Cl] + .

[0652] Step 4:

[0653] Compound 25c (140 mg, 374.39 μmol) was dissolved in acetonitrile (2.4 mL), methanol (0.4 mL), and water (1.4 mL). Potassium peroxide monosulfonate (704.48 mg, 1.12 mmol) was added, and the mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (methanol / water / TFA) to give 27.7 mg of compound 25d (yield 15.3%).

[0654] MS(ESI): m / z 370.1 [M-CF3COO] + .

[0655] Step 5:

[0656] Compound 25d (27.24 mg, 56.34 μmol) and compound 2f (29.3 mg, 56.34 μmol) were dissolved in DMF (1 mL), and DMAP (10.54 mg, 84.52 μmol) and HATU (32.46 mg, 84.52 μmol) were added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA) to give 20 mg of compound 25 (yield 33.39%).

[0657] MS(ESI): m / z 836.3 [M-2CF3COO] + .

[0658] 1 H NMR (400MHz, DMSO-d6): δ7.15-7.13(m,1H),7.05-6.97(m,4H),6.87-6.64(m,3H),6.64(s ,1H),5.55(s,1H),4.59-4.56(m,3H),4.47-4.46(m,2H),4.37-4.32(m,2H),4.15-4.13(m ,2H),4.04-4.00(m,3H),3.90-3.78(m,5H),3.73-3.48(m,10H),3.32-3.21(m,10H),3.21 -3.18(m,4H),3.11-3.09(m,2H),2.90-2.75(m,3H),2.63-2.61(m,2H),2.19-2.18(m,2H).

[0659] Example 26 Preparation of Compound 26

[0660] Step 1:

[0661] Compound 26b (1.0 g, 3.19 mmol, prepared by the method disclosed in patent WO200395426 A1) and compound 26a (2.29 g, 6.38 mmol, prepared by a known method, J.Org.Chem.2022,87,4,2136-2141) were dissolved in DMF (20 mL) and stirred. Anhydrous potassium carbonate (1.32 g, 9.57 mmol) and sodium iodide (478.3 mg, 3.19 mmol) were added, and the reaction was carried out at 55–70 °C until complete. After cooling to room temperature, 50 mL of water was added to the reaction system, and the mixture was extracted with DCM (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was purified by column chromatography (acetonitrile:water = 5–95%) to obtain approximately 380 mg of compound 26c (yield 23.80%).

[0662] MS(ESI): m / z 500.4 [M+H] + .

[0663] Step 2:

[0664] Compound 26c (380 mg, 0.76 mmol) and iodomethane (1 mL) were added to a 15 mL sealed tube and stirred to dissolve. The mixture was heated to 70 °C and reacted for 2 hours. The reaction mixture was then concentrated to dryness under reduced pressure, yielding compound 26d (100% yield).

[0665] MS(ESI): m / z 514.3 [MI] + .

[0666] Step 3:

[0667] Compound 26d (380 mg, 0.74 mmol) was dissolved in methanol (5 mL) and stirred. The mixture was cooled with an ice bath, and concentrated hydrochloric acid (1.0 mL) was added. The ice bath was removed, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure and purified by column chromatography (acetonitrile: 0.1% TFA water) to give 280 mg of compound 26e (yield 94.7%).

[0668] MS(ESI): m / z 400.3 [M-Cl] + .

[0669] Step 4:

[0670] Compound 12 g (218 mg, 0.52 mmol), compound 26e (208 mg, 0.52 mmol), and HATU (237 mg, 0.63 mmol) were dissolved in DMF (10 mL), and DIPEA (335 mg, 2.60 mmol) was added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile: 0.1% TFA water = 5–95%) and lyophilized to give 52 mg of compound 26 (yield 12.5%).

[0671] MS(ESI): m / z 401.4[(M-2Cl) / 2] + .

[0672] Compound 26 was resolved into: compound 26-A (retention time 12.260 min), compound 26-B (retention time 12.823 min), compound 26-C (retention time 13.470 min), and compound 26-D (retention time 14.498 min).

[0673] Separation conditions: Reversed-phase column: Agilent Zorbax Bonus RP, 4.6 mm × 150 mm, 3.5 μm; Mobile phase: A is ACN, B is acetonitrile; Gradient: B 40%; Flow rate: 1.000 mL / min; Column temperature: 30 °C; Wavelength: 210 nm.

[0674] The structures of compounds 26-A, 26-B, 26-C, and 26-D are shown below:

[0675] Example 27 Preparation of Compound 27

[0676] Step 1:

[0677] Under ice-water bath conditions, compound 1i (430 mg, 1.11 mmol) was added to 2.5 mL of isopropyl acetate reaction solution of compound 27a (227 mg, 1.67 mmol, prepared by a known method, J. Org. Chem., vol. 70, No. 15, 2005, 6105-6107). Nitrogen was purged three times, and the mixture was stirred at room temperature until complete. 2 mL of water was added, and the layers were separated. The aqueous phase was extracted three times (5 mL × 3) with dichloromethane. The organic layer was dried, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by column chromatography (methanol:acetonitrile = 0–50%). The product was collected and concentrated to give 158 mg of compound 27b (yield 27%).

[0678] MS(ESI): m / z 522.2 [M-Cl] + .

[0679] Step 2:

[0680] Take a 25 mL single-necked flask, add compound 27b (122 mg, 0.23 mmol), dissolve it in 2.5 mL of 1,2-dichloroethane, add oxaloyl chloride (742 mg, 5.85 mmol) to the reaction solution, purge with nitrogen three times, and stir at room temperature until the reaction is complete. Dry the excess oxaloyl chloride by rotary evaporation, add another 2.5 mL of 1,2-dichloroethane, add compound 12f (252 mg, 0.70 mmol) to the reaction solution, and stir at room temperature until the reaction is complete. Add 10 mL of methyl tert-butyl ether to the reaction solution, stir, filter, wash the filter cake with a small amount of methyl tert-butyl ether, collect the filter cake and drain with an oil pump to obtain 333 mg of crude compound 27c, which can be directly used in the next step.

[0681] MS(ESI): m / z 413.4 [(M-2Cl) / 2] + .

[0682] Step 3:

[0683] In a 25 mL single-necked flask, compound 29c (300 mg, 0.36 mmol) was added and dissolved in 3 mL of dichloromethane. The solution was purged with nitrogen three times and placed in an ethanol-dry ice bath (-30 °C). Triethylamine (110 mg, 1.09 mmol) was added, and the mixture was stirred at -5 to 10 °C until complete. 20 mL of methyl tert-butyl ether was added to the reaction mixture, and the mixture was stirred at room temperature until complete. The reaction mixture was filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. The filter cake was collected, drained dry using an oil pump, and purified by HPLC (acetonitrile: 0.1% TFA / water = 5–95%) to obtain 16 mg of compound 27 (yield 5.5%).

[0684] MS(ESI): m / z 403.4 [(M-2Cl) / 2] + .

[0685] 1 H NMR (400MHz, DMSO-d6): δ7.09-6.82(m,9H),6.29-6.22(m,1H),5.56(s,1H),4.63-4.61(m,1H),4.44(s,2H),4.32-4.23(m,6H),4.0 4-3.91(m,4H),3.79-3.71(m,12H),3.63-3.60(m,6H),3.23-3.10(m,7H),2.92-2.86(m,2H),2.59-2.56(m,2H),2.33-2.27(m,6H).

[0686] Example 28 Preparation of Compound 28

[0687] Step 1:

[0688] Compound 28a (503 mg, 2.84 mmol, purchased from Leyan) was added to 6 mL of a dichloromethane solution of compound 1i (300 mg, 0.71 mmol). The mixture was purged with nitrogen three times, and the reaction was stirred at room temperature until complete. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layer was dried, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by column chromatography (50% acetonitrile in water), and then lyophilized to give 370 mg of compound 28b (yield 86.9%).

[0689] MS(ESI): m / z 562.2 [M-Cl] + .

[0690] Step 2:

[0691] Take a 25 mL single-necked flask, add compound 28b (100 mg, 0.17 mmol), dissolve it in 2 mL of 1,2-dichloroethane, add oxaloyl bromide (360 mg, 1.67 mmol) to the reaction solution, purge with nitrogen three times, stir at room temperature until the reaction is complete, then heat to 80–90 °C, reflux for 5 minutes, and evaporate excess oxaloyl bromide to dryness. Add 2 mL of 1,2-dichloroethane and 1 mL of chloroform solution of compound 12f (120 mg, 0.33 mmol) to the reaction solution, stir at room temperature until the reaction is complete. Dilute the reaction solution with 2 mL of dichloromethane, extract with water (10 mL × 3), and purify by HPLC (acetonitrile: 0.1% TFA water = 5–95%) to obtain 40 mg of compound 28 (yield 21.9%).

[0692] MS(ESI): m / z 433.3[(M-2Cl) / 2] + .

[0693] 1 H NMR (400MHz, DMSO-d6): δ7.08-6.98(m,7H),6.87-6.83(m,3H),5.55(s,1H),4.63(d,1H),4.44(s,2H),4.33(t,2H),4.27-4.23(m ,4H),3.98-3.89(m,4H),3.78-3.71(m,15H),3.62-3.51(m,6H),3.20(s,3H),3.12-3.10(m,2H),2.89(t,1H),2.33-2.27(m,8H).

[0694] Example 29 Preparation of Compound 29

[0695] Step 1:

[0696] Compound 29a (1.0 g, 3.95 mmol, purchased from Shaoyuan) and thiomorpholine-1,1-dioxide (1.07 g, 7.9 mmol, purchased from Leyan) were dissolved in acetonitrile (15 mL), and potassium carbonate (818.59 mg, 5.92 mmol) was added. The reaction was carried out at 70–85 °C until complete. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (30 mL × 1). The organic phases were combined, washed with water (30 mL × 1) and saturated brine (30 mL × 1), dried, filtered, concentrated, and purified by column chromatography (PE:EA = 100:0-60:40) to give 0.85 g of compound 29b (70% yield).

[0697] MS(ESI): m / z 308.2 [M+1] + .

[0698] Step 2:

[0699] Compound 29b (650 mg, 2.11 mmol) and compound 5c (537.28 mg, 2.33 mmol, purchased from Bioderm) were dissolved in acetonitrile (6.5 mL), and potassium iodide (316.82 mg, 2.11 mmol) was added. The reaction was carried out at 65–75 °C until complete. The reaction solution was concentrated to dryness and purified by column chromatography (DCM:MeOH = 100:0-70:30) to give 650 mg of compound 29c (yield 57.1%).

[0700] MS(ESI): m / z 458.2 [M-Br]+ .

[0701] Step 3:

[0702] Compound 29c (550 mg, 1.02 mmol) was dissolved in methanol (5.5 mL), and dioxane hydrochloride solution (4 M, 1.23 mmol, 306.34 μL) was added. The mixture was stirred at room temperature until complete. The reaction solution was evaporated to dryness, and the residue was slurried with DCM (10 mL), filtered, and dried to give 350 mg of compound 29d (yield 80.77%).

[0703] MS(ESI): m / z 345.1 [M-Cl] + .

[0704] Step 4:

[0705] Compound 29d (43.5 mg, 114.5 μmol) and compound 2f (53.3 mg, 102.5 μmol) were dissolved in DMF (1.5 mL), and DMAP (18.78 mg, 153.75 μmol) and HATU (58.46 mg, 153.75 μmol) were added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (acetonitrile / water / TFA), lyophilized, and 24.4 mg of compound 29 was obtained (yield 22.91%).

[0706] MS(ESI):m / z 810.3[(M-2CF3COO)] + .

[0707] 1 H NMR (400MHz, DMSO-d6): δ7.15(s,1H),7.11-6.98(m,4H),6.87-6.82(m,3H),6.68(s,2H),5.55(s,1H),4.72(s,2H),4.63-4.60(m ,1H),4.32-4.29(m,2H),4.27-4.15(m,2H),3.86-3.53(m,25H),3.33(s,6H),3.20(s,3H),3.11-3.09(m,2H),2.29-2.20(m,4H).

[0708] Example 30 Preparation of control compound 1

[0709] It was prepared by referring to the method disclosed in US20150191453A1.

[0710] Example 31 Preparation of control compound 2

[0711] It was prepared by referring to the method disclosed in patent WO2024149360A1.

[0712] Example 32 Preparation of control compound 3

[0713] It was prepared by referring to the method disclosed in patent WO2024149360A1.

[0714] Example 33 Preparation of control compound 4

[0715] It was prepared by referring to the method disclosed in patent WO2024149360A1.

[0716] Example 34 Preparation of control compound 5

[0717] It was prepared by referring to the method disclosed in patent WO2024149360A1.

[0718] Example 35 Preparation of compound 35

[0719] Step 1:

[0720] Dimethyl sulfoxide (500 mL), potassium hydroxide (212.27 g, 3.78 mol), and compound 35a (50.00 g, 0.38 mol, purchased from Bidex Pharmaceuticals) were added to a flask and stirred until homogeneous. Then, p-methoxybenzyl chloride (65.18 g, 0.42 mol) was added, and the mixture was stirred at room temperature until complete. The reaction system was cooled to 5–10 °C, purified water (1500 mL) was added, and the mixture was extracted twice with n-heptane (500 mL). The combined organic phases were washed with saturated sodium bicarbonate aqueous solution (250 mL), concentrated, and compound 35b was obtained, which was directly used in the next reaction step.

[0721] Step 2:

[0722] Compound 35b and tetrahydrofuran (1000 mL) were added to a flask and stirred to dissolve. The mixture was cooled to 5–10 °C, and 1 M hydrochloric acid aqueous solution (1000 mL) was added. The mixture was stirred at room temperature until the reaction was complete. Sodium chloride (100 g) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (700 mL). The organic phases were combined, washed three times with saturated brine (250 mL), dried, filtered, concentrated, and crystallized with isopropyl ether (800 mL) to give 69.59 g of compound 35c (yield 86.6%).

[0723] MS(ESI): m / z 230 [M+18] + .

[0724] Step 3:

[0725] Compound 35c (30.00 g, 0.141 mol) and dichloromethane (450 mL) were added to a flask and stirred to dissolve. The mixture was cooled to 0–5 °C, and then triphenylchloromethane (43.34 g, 0.155 mol) and triethylamine (28.61 g, 0.282 mol) were added. The mixture was stirred at room temperature until the reaction was complete. 1 M dilute hydrochloric acid (150 mL) was added to the reaction solution, and the phases were separated. The organic phase was dried, filtered, and concentrated to obtain compound 35d, which was used directly in the next reaction.

[0726] MS(ESI): m / z 477[M+23] + .

[0727] Step 4:

[0728] Compound 35d, toluene (1280 mL), and perfluorobutylsulfonyl fluoride (85.40 g, 0.282 mol, purchased from Anaiji Chemicals) were added to a flask. The reaction system was cooled to 10–20 °C, and 1,8-diazabicyclo[5.4.0]undec-7-ene (43.04 g, 0.282 mol) was added. The mixture was stirred at room temperature until complete. Sodium bicarbonate aqueous solution (320 mL) was added to the reaction solution, the organic phase was separated, washed twice with purified water (320 mL), and concentrated to obtain compound 35e, which was directly used in the next reaction.

[0729] MS(ESI): m / z 479 [M+23] + .

[0730] 1 H NMR (400MHz, CDCl3): δ7.46-7.40(m,6H),7.32-7.27(m,6H),7.25-7.17(m,5H),6.87-6.82(m, 2H),4.86-4.67(m,1H),4.52-4.43(m,2H),3.80(s,3H),3.76-3.59(m,2H),3.36-3.27(m,2H).

[0731] Step 5:

[0732] Compound 35e, glacial acetic acid (903 mL), and purified water (90.3 mL) were added to a flask, and the mixture was stirred at 35–50 °C until the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1–4 / 1) to give 16.18 g of compound 35f (yield 53.4%).

[0733] MS(ESI): m / z 237.2 [M+23] + .

[0734] 1 H NMR (400MHz, CDCl3): δ7.29-7.23(m,2H), 6.91-6.86(m,2H), 4.79-4.61(m,1H), 4.55-4.46(m,2H), 3.87-3.77(m,5H), 3.72-3.63(m,2H).

[0735] 19 F NMR(400MHz,DMSO-d6)δ-196.18.

[0736] Step 6:

[0737] Compound 35f (22.20 g, 0.103 mol), 2,6-dimethylpyridine (27.76 g, 0.259 mol), and dichloromethane (330 mL) were added to a flask. The mixture was cooled to 0–5 °C, and trifluoromethanesulfonic anhydride (43.85 g, 0.155 mol) was added. The mixture was stirred until the reaction was complete. Purified water (330 mL) was added to the reaction solution, and the phases were separated. The organic phase was washed twice with 1N hydrochloric acid aqueous solution (330 mL) and twice with purified water (330 mL). The solution was dried, filtered, and concentrated to obtain 35 g of compound, which was directly used in the next reaction step.

[0738] Steps 7 and 8:

[0739] In a flask, 35 g (35.75 g, 0.103 mol) of compound 12a (26.00 g, 79.4 mmol) and 390 mL of dichloromethane were added and stirred at room temperature until complete, yielding a solution of compound 35h. The reaction system was cooled to 0–5 °C, and m-dimethoxybenzene (32.92 g, 0.238 mol) and trifluoromethanesulfonic acid (5.96 g, 39.70 mmol) were added, and the reaction was stirred until complete. The reaction solution was purified by column chromatography (A: DCM, B: MeOH, 5%–15% B) to give 24 g of compound 35i (yield 54.60%).

[0740] MS(ESI): m / z 404.2 [M-149] + .

[0741] 1H NMR (400MHz, DMSO-d6): δ7.01-6.95(m,2H),6.91-6.85(m,2H),6.83(s,1H),5.50-5.27(m,3H),4.77-4.68(m, 1H), 4.02-3.79 (m, 2H), 3.78-3.50 (m, 11H), 3.45 (s, 3H), 3.19 (s, 3H), 3.16-2.99 (m, 2H), 2.87 (t, J = 12Hz, 1H).

[0742] 19 F NMR(400MHz,DMSO-d6)δ-182.36.

[0743] Step 9:

[0744] 12 g (0.5 g, 1.09 mmol) of the compound was dissolved in methanol (2.5 mL) and acetonitrile (3 mL), concentrated to dryness, and then concentrated twice more by adding acetonitrile (5 mL). The product was dissolved in dichloromethane (7.5 mL), cooled to 0–10 °C, and oxalyl chloride (0.28 mL, 3.29 mmol) was added dropwise. The mixture was stirred at room temperature until the reaction was complete, concentrated, and the product was dissolved in dichloromethane (5 mL) for later use.

[0745] Compound 35i (0.3 g, 0.54 mmol) was dissolved in acetonitrile (3 mL) and added to the above reaction system. The mixture was cooled to 0–5 °C, and triethylamine (0.45 mL, 3.29 mmol) was added. The mixture was stirred until the reaction was complete. The reaction solution was concentrated and purified by column chromatography (A: MeCN, B: MeOH, 10–20% B). The concentrate was then dissolved in purified water (3 mL), treated with a Dowex 1×8 chloroform resin, and lyophilized to give 0.18 g of compound 35i (yield 37.89%).

[0746] LCMS(ESI) m / z: 403.2 [(M-70) / 2] + .

[0747] 1H NMR(400MHz,DMSO-d6)δ7.14-6.97(m,5H),6.93-6.72(m,5H),5.86(d,J=4 9.0Hz,1H),5.40(s,1H),4.77(dd,J=10.6,4.0Hz,1H),4.55-4.21(m,8H),4 .09-3.96(m,3H),3.94-3.70(m,15H),3.69-3.50(m,8H),3.18-3.13(m,5H ), 2.89 (t, J = 11.6Hz, 1H), 2.60-2.58 (d, J = 10.2Hz, 2H), 2.42-2.21 (m, 4H).

[0748] 19 F NMR(377MHz,DMSO-d6)δ-182.61.

[0749] Biological evaluation

[0750] Test Example 1: Manual Patch Clamp Technique for Detecting the Effect of Test Substances on the nAChRα1β1δε Channel

[0751] 1. Experimental materials:

[0752] CHO cell lines that stably express the nAChRα1β1δε receptor.

[0753] 2. Experimental methods:

[0754] 1) Cells were cultured in Ham's F-12 medium containing 10% fetal bovine serum at 37°C and 5% carbon dioxide. Cells were seeded into 6cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 100 cells (final volume: 5 mL). To maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.

[0755] 2) Before patch-clamp detection, cells were separated using 0.25% Trypsin-EDTA, and 6.5 × 10⁻⁶ cells were used. 3 The cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). Doxycycline was added for induction, and the cells were tested after 24-72 hours.

[0756] 3) Electrophysiological methods:

[0757] The voltage stimulation protocol for whole-cell patch-clamp recording of nAChRα1β1δε receptor currents is as follows: After whole-cell sealing, the cell membrane voltage is clamped at -70 mV, and current peaks are recorded by sequentially and rapidly administering drugs in gap-free mode. First, ACh EC is administered to the cell surface.50 After pre-incubating each drug concentration for 1 minute, ACh EC was administered. 50 The working solution of the added compound was administered 2-3 times at each concentration. After the current stabilized, the next concentration was measured. The solution was eluted with extracellular fluid between each administration.

[0758] The test data were acquired by the EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0759] The patch-clamp procedure begins by drawing a capillary glass tube into a recording electrode using a microelectrode puller. The electrode, filled with intracellular fluid, is then inserted into a microelectrode holder. Next, a coverslip containing cells is placed in a recording bath under an inverted microscope. Under the microscope, the microelectrode manipulator is manipulated to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a GΩ high-resistance seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied.

[0760] During current recording, blank control solution and working solution of the test compound were administered sequentially from low to high concentration through the recording bath using gravity perfusion, thereby acting on the cells. A peristaltic pump was used for fluid replacement during recording. All electrophysiological experiments were performed at room temperature.

[0761] 4) Data Analysis: First, the concentration of each drug and ACh EC were compared. 50 Peak ACh receptor current after treatment with the mixture (Peak) ) and ACh EC 50 Peak receptor current (Peak) Normalize the drug (%Normalized), and then calculate the inhibition rate corresponding to each drug concentration. For each concentration inhibition rate, the mean (Mean), standard deviation (SD), and standard error (SE) are calculated, and the data are expressed as Mean ± SE.

[0762] Using Hill's equation Y = 1 / (1 + 10^(LogIC) 50 The IC50 of a compound is calculated using the equation -X)*HillSlope)). 50 and IC 90 The value was calculated, and a nonlinear fit was performed on the concentration-effect curve, where IC50 was the concentration-effect value. 50 This is the half-inhibitory concentration (IC50). 50 and IC 90 The calculations and curve fitting were performed using GraphPad Prism software.

[0763] 3. Test Results:

[0764] The disclosed compounds, such as the test example compounds, exhibit excellent in vitro activity and can significantly inhibit the nAChRα1β1δε channel.

[0765] Test Example 2: Drug Efficacy Experiment of Isolated Rat Phrenic Nerve-Diaphragm

[0766] 1. Experimental materials:

[0767] Isolated rat phrenic nerve-diaphragm. SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, SPF grade.

[0768] 2. Experimental methods:

[0769] 1) Preparation of phrenic nerve-diaphragm: SD rats were anesthetized with urethane, and after restraining the animals, the thoracic cavity was quickly cut open to separate the phrenic nerve and diaphragm, which were then placed in a Krebs solution containing a modified artificial mixed gas.

[0770] 2) Connection device: The phrenic nerve is placed on the stimulation electrode connected to the stimulator. One end of the diaphragm is fixed and the other end is connected to the tension transducer. The muscle tone is continuously recorded using the PowerLab signal acquisition system.

[0771] 3) Baseline recording: A 2ms pulse stimulation was used to stimulate the phrenic nerve at a frequency of 0.1Hz, gradually increasing the stimulation intensity to induce a gradually increasing amplitude of diaphragmatic contraction. 120% of the stimulation intensity corresponding to the maximum diaphragmatic contraction force was used as the stimulation intensity for subsequent experiments to ensure the maximum contraction amplitude was obtained.

[0772] 4) Compound test: The phrenic nerve was continuously stimulated at a frequency of 0.1 Hz and the diaphragm contraction was recorded. The test compound was added to the incubation solution and the effect of the compound on the diaphragm contraction was recorded. When the contraction amplitude stabilized, the incubation solution was replaced and the recording was continued until the contraction amplitude was close to the baseline level.

[0773] 5) Data analysis: The effects of the compound were assessed based on changes in the amplitude of diaphragmatic contraction, and the analysis was performed.

[0774] 3. Test Results:

[0775] The disclosed compounds, such as the test example compounds, exhibit excellent muscle tone inhibitory activity, significantly inhibiting isolated muscle tone and leading to muscle relaxation.

[0776] Test 3: Detection of the muscle relaxant efficacy of the test compound in rats

[0777] 1. Laboratory animals

[0778] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, SPF grade.

[0779] 2. Experimental Procedure

[0780] 1) Weigh the rats and prepare a 25% urethane solution using ethyl carbamate. Anesthetize the rats by intraperitoneal injection at a rate of 1 mL / 100g. After the animals lose consciousness and reflexes disappear, fix them in a prone position on a foam board and remove hair from the right hind limb area. Separate the trachea and external jugular vein, and perform endotracheal and intravenous cannulation respectively, preparing for mechanical ventilation.

[0781] 2) Behind the hip joint, make an incision in the skin at the outer edge of the femur in the middle of the thigh. Use a glass needle to bluntly dissect the muscles to expose the sciatic nerve. Cut the skin of the lower leg at the ankle joint, cut the ligaments in the anterior part of the ankle joint, separate the gastrocnemius muscle, tie a suture at the gastrocnemius tendon at the ankle, and cut the tendon distal to the suture.

[0782] 3) Signals were collected and recorded using a biological functional experimental system. A gastrocnemius muscle ligature was connected to a tension transducer, and the stimulator was connected to the sciatic nerve. The experiment focused on the effect of stimulation intensity on skeletal muscle contraction. Parameters were set as follows: square wave, fine voltage, series stimulation, delay 0.05 ms, pulse width 0.2 ms, pulse interval 10 ms, frequency 8 Hz, intensity 0.350 V, intensity increment 0, series length 4, main period 12 s. The muscle tone curve was recorded.

[0783] 4) After the signal stabilizes, different doses of the test compound are injected via the jugular vein, and the inhibition of muscle tone after administration is recorded. During the measurement, the muscle nerves are kept moist with physiological saline every five minutes.

[0784] Experimental indicators:

[0785] Muscle tone inhibition rate = (pre-drug muscle tone - post-drug minimum muscle tone) / pre-drug muscle tone * 100%.

[0786] 3. Test results: Most of the compounds disclosed in this paper have excellent muscle tone inhibition activity, which is significantly better than that of the reference compounds.

[0787] Test Example 4: Off-target effects on muscarinic M1-M5 receptors

[0788] 1. Experimental materials:

[0789] CHO cells that stably express M1, M2, M3, M4, and M5 receptors.

[0790] 2. Experimental steps:

[0791] 1) Cell seeding: Cells were digested and collected, resuspended, counted, and then seeded into 384-well cell culture plates at a seeding density of 1.2 × 10⁻⁶. 4 Cells / 25μL / well. Then incubate the cell plate at 37°C in a 5% CO2 incubator for about 16-20 hours.

[0792] 2) Prepare the Assay Buffer according to the FLIPR Calcium 6 Assay Kit instructions. Freeze-thaw 20×Component A to room temperature, dilute it with Assay Buffer to 1×loading buffer, and store at room temperature.

[0793] 3) Remove the culture medium from the cell plate, quickly add 35 μL of 1× loading buffer to each well, centrifuge, and then incubate the cell plate at 37°C in the dark for 120 minutes.

[0794] 4) Prepare working solutions of positive and test compounds, and transfer 5 μL into the corresponding cell wells and incubate at 37°C in the dark for 30 minutes.

[0795] 5) Prepare the agonist working solution and transfer 20 μL / well to a 384-well compound source plate.

[0796] 6) Place the cell plate, compound source plate, and pipette tip into the corresponding positions on the FLIPR instrument. Use the FLIPR Tetra to add 10 μL of the diluted compound from step 5 into each well and collect data at wavelengths of 515 nm to 575 nm.

[0797] 7) Plot the signal value against the compound concentration, and use the nonlinear regression method in GraphPad Prism software to perform curve fitting for IC. 50 calculate.

[0798] 3. Test Results:

[0799] The compounds disclosed herein, such as the test example compounds, exhibit excellent selectivity and have virtually no or slight inhibitory activity against M1-M5 receptors.

[0800] The inhibitory activity data of the disclosed compounds against the M2 receptor are shown in the table below.

[0801] Test Example 5: Pharmacokinetic Study in Rats

[0802] 1. Experimental materials: SD rats (source: Beijing Vital River Laboratory Animal Technology Co., Ltd.), male, n=4, half male and half female.

[0803] 2. Experimental Procedure

[0804] 1) Anesthetized SD rats were given the drug via intravenous injection. Plasma was collected at different time points after drug administration, and the drug concentration was detected by LC-MS / MS.

[0805] 2) The following pharmacokinetic parameters were calculated using the Phoenix WinNonlin 8.2 non-compartmental model: terminal elimination half-life t 1 / 2 Peak time T max Peak concentration C max Area under the curve (AUC) last AUC 0-∞ Steady-state apparent volume of distribution V ss Sweep rate (Cl), Mean residence time (MRT) last MRT 0-∞ ).

[0806] 3. Test Results:

[0807] The disclosed compounds, if tested, exhibit favorable pharmacokinetic characteristics and can be rapidly cleared from rat plasma.

[0808] Test Example 6: In vivo pharmacokinetic study in Beagle dogs

[0809] 1. Experimental materials:

[0810] Beagle dogs (source: Beijing Mars Biotechnology Co., Ltd.), N=2, 1 female and 1 male.

[0811] 2. Experimental steps:

[0812] 1) Beagle dogs were anesthetized and given the drug via intravenous injection. Plasma was collected at different time points after administration, and the drug concentration was detected by LC-MS / MS.

[0813] 2) The following pharmacokinetic parameters were calculated using the Phoenix WinNonlin 8.2 non-compartmental model: terminal elimination half-life t 1 / 2 Peak time T max Peak concentration C max Area under the curve (AUC) last AUC 0-∞ Steady-state apparent volume of distribution V ss Sweep rate (Cl), Mean residence time (MRT) last MRT 0-∞ ).

[0814] 3. Test Results:

[0815] The disclosed compounds, if tested, exhibit favorable pharmacokinetic characteristics and can be rapidly cleared from canine plasma.

[0816] Test Example 7: In vitro safety - Effects of hERG potassium channels

[0817] 1. Experimental materials:

[0818] hERG-HEK293 cells.

[0819] 2. Experimental methods:

[0820] 1) hERG-HEK293 cells were cultured in an incubator at 37°C and 5% CO2 using growth medium. During passage, TrypLE was used. TM Express digests the cells. Cells used for patch-clamp experiments are seeded on sterile cell slides placed in culture dishes, with the culture medium and conditions unchanged. Cells are ready for experimentation 3 hours after seeding, i.e., after cell adhesion. Cell passage numbers used for patch-clamp experiments range from 3 to 30.

[0821] 2) Electrophysiological testing:

[0822] 1) Place cell slides seeded with hERG-HEK293 cells in a bath (filled with extracellular fluid) on an inverted microscope. Use a P-1000 puller to draw glass electrodes and fill with intracellular fluid. Seal the cells (seal resistance ≥1 GΩ) and rupture the membrane. After rupture, ensure the series resistance is ≤15 MΩ and implement the following electrophysiological stimulation protocol: clamp the cell membrane voltage at -80 mV, depolarize the membrane potential to +30 mV for 3 seconds to activate the hERG current, and repolarize with a -50 mV potential for 4 seconds to remove channel inactivation. This voltage mode is run approximately every 10 seconds. Measure the maximum current during repolarization (tail current peak) and collect and store the data using pClamp software. Perfusion of cells: First, use extracellular fluid, then add the drug formulations (positive control, solvent control, test sample). Each cell can be administered one or more solvent control and test sample formulations in ascending order of concentration. The tail current peak should reach a steady state for at least 1 minute before administration of the drug formulation. The tail current should be measured again at least 1 minute after administration or when drug perfusion has reached 5 minutes. Patch-clamp operation should be performed at room temperature.

[0823] 3) Detection indicators:

[0824] The peak value of the tail current for each current was obtained using pClamp 10.6 software.

[0825] Before and after administration of the test substance, the tail current peak value was maintained stable for at least 1 minute or the drug perfusion was maintained for 5 minutes. The average of the last 6 tail current peak values ​​was used for data analysis.

[0826] Using Microsoft Excel, calculate the inhibition rate according to the following equation:

[0827] Inhibition rate = (1 - mean peak tail current after drug administration / mean peak tail current before drug administration) × 100%

[0828] 3. Test Results:

[0829] The compounds disclosed herein, such as the test example compounds, have no significant effect on hERG in vitro and are highly safe for the heart.

[0830] Test Example 8: Effects of the test compound on isolated guinea pig ileum and bronchi

[0831] 1. Experimental materials:

[0832] Isolated ileum and bronchus of a guinea pig. British guinea pig (Sichuan Weitonglihua Experimental Animal Technology Co., Ltd.)

[0833] 2. Experimental methods:

[0834] 1) Preheat the irrigation system, clean the irrigation system, add Tyrode's solution, fill with mixed oxygen (95% O2 / 5% CO2), prepare the instruments, and pour Tyrode's solution into the bath. Euthanize the guinea pigs using CO2 gas, and quickly open the abdominal cavity to remove the ileum or trachea.

[0835] 2) Sample preparation

[0836] Ileum: A section of ileum approximately 10 cm long was removed and placed in a culture dish containing Tyrode's solution. A gavage needle was inserted into the intestinal lumen, and the intestine was repeatedly flushed with Tyrode's solution until the flushing fluid became clear. Using ophthalmic forceps, the fat and connective tissue on the outer wall of the intestinal tract were cleaned away. The ileum was then cut into small segments, each approximately 1–2 cm long. One end of the isolated ileum tissue was fixed to a fixing rod in the bath using sutures or a hook, and the other end was fixed to a sensor hook. The position was adjusted so that the tissue was completely immersed in Tyrode's solution. The clips and knobs on the sensor holder were adjusted to provide a certain amount of traction to prevent the tissue from moving.

[0837] Trachea: Cut along the midline of the neck to fully expose the trachea. Cut it near the larynx, and cut the other end at the bifurcation point. Quickly immerse the trachea in a petri dish containing Tyrode's solution. Use a gavage needle to repeatedly flush the intestines until the flushing fluid is clear. Use ophthalmic forceps to clean away any fat and connective tissue outside the intestines. Cut the trachea into multiple rings along the tracheal rings, each 0.5–1 cm long (as shown in Figure 1), for later use. Fix one end of the isolated tracheal tissue to a fixing rod in the bath with sutures or a hook, and fix the other end to a sensor hook. Adjust the position to ensure the tissue is completely immersed in Tyrode's solution. Adjust the clips and knobs on the sensor holder to provide some traction to prevent the tissue from moving.

[0838] 3) Record the contraction curve. Calculate the average tension change within 1 minute before administration (F0, mean) and the tension after administration (F1, maximum value max or minimum value min; if there is no change, calculate the average value 1 minute after administration), and use the tension change rate as the result data.

[0839] Percentage change in tension (%) = (F1 – F0) / F0 * 100%

[0840] 3. Test Results:

[0841] The compounds disclosed herein, such as the test example compounds, have no significant effect on isolated ileum or bronchi.

[0842] Test Example 9: Histamine Release Detection

[0843] 1. Laboratory animals:

[0844] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, N=4.

[0845] 2. Experimental Procedure

[0846] 1) Weigh the rats and prepare a 25% urethane solution using ethyl carbamate. Anesthetize the rats by intraperitoneal injection at a rate of 1 mL / 100g. After the animals lose consciousness and reflexes disappear, fix them in a prone position on a foam board and remove hair from the right hind limb area. Insert a cannula into one jugular vein for drug injection and another jugular vein for blood collection.

[0847] 2) After stabilizing for 15 minutes, collect 0.5 mL of venous blood into an EP tube containing heparin sodium saline (1:9), mix well, cool, and centrifuge at 4°C (1000 rpm, 10 minutes). Collect 0.2 mL of the supernatant plasma and freeze on dry ice. After stabilizing for 15 minutes, administer the test drug intravenously at a dose of 20 mg / kg. Immediately 1 minute after administration, collect 0.5 mL of venous blood, mix well, cool, and centrifuge at 4°C (1000 rpm, 10 minutes). Collect 0.2 mL of the supernatant plasma and freeze on dry ice.

[0848] 3) After processing, the histamine levels in rat plasma before and after drug administration were detected by LC-MS / MS. Formula: Histamine increase factor = Histamine level in rat plasma after drug administration / Histamine level in rat plasma before drug administration.

[0849] 3. Test Results:

[0850] The compounds disclosed herein, such as the test example compounds, have a low risk of histamine release and good safety.

[0851] Test Example 10: Guinea Pig Active Allergy

[0852] 1. Experimental materials:

[0853] Isolated ileum and bronchus of a guinea pig. British guinea pig (Sichuan Weitonglihua Experimental Animal Technology Co., Ltd.)

[0854] 2. Experimental methods:

[0855] 1) This experiment consisted of four groups: a negative control group, a positive control group, and low- and high-dose groups of the test compound. Each negative control group and positive control group contained 6 guinea pigs, and each low- and high-dose group of the test compound contained 8 guinea pigs, with half being male and half female.

[0856] 2) During the sensitization phase, sensitization was performed once every other day for a total of 3 times. The day of the first sensitization administration was designated as day 1 of the experiment. On days 19 and 26 of the experiment, each group was challenged by intravenous injection of twice the sensitization dose, and the systemic reactions and mortality of guinea pigs after challenge were observed.

[0857] 3. Test Results:

[0858] The compounds disclosed herein, such as the test example compounds, do not cause allergic reactions and have good safety.

Claims

A compound of formula I or a pharmaceutically acceptable salt thereof. in: Y-select-C(R a’ R b’ ), -O-, -S-, -S(O)2-, -Si(CH3)2-; W is -C(R) a R b R c ); Each is independently selected from pharmaceutically acceptable anions; R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 3a R 3b R 4 R 4a R 4b R 5 R 6 R 7 R 8 R A1 R A2 R A3 R A4 R B1 R B2 R B3 R B4 R B5 R D1 R D2 R D3 R D4 R D5 R W1 R W2 R W3 R W4 R W5 R a R b R c Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace, Or, R 1a and R 1b R 1c and R 1d R 1e and R 1f R 2a and R 2b R 2c and R 2d R 2e and R 2f R 3a and R 3b R 4a and R 4b R 5 and R 6 R 7 and R 8 R W1 and R W2 Or R W3 and R W4 One or more groups of atoms, each together with the adjacent atoms, form an oxo group, a thio group, a 3- to 10-membered alicyclic ring, a 3- to 10-membered alicyclic heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the alicyclic ring, alicyclic heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally surrounded by one or more R groups. B replace; R a’ R b’ Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace, Or, R a’ and R b’ Together with the attached atoms, it forms an oxo group, a thio group, a 3- to 10-membered alicyclic ring, a 3- to 10-membered alicyclic heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the alicyclic ring, alicyclic heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally surrounded by one or more R groups. B replace; R y Each is independently selected from halogen, hydroxyl, thiol, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R C replace, Alternatively, choose any two Rs. y Each alicyclic ring or heterocyclic ring independently forms a 3- to 10-membered alicyclic ring with its connected atoms, wherein the alicyclic ring or heterocyclic ring is optionally bounded by one or more R atoms. D replace; R e R f Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R E replace; R A R B R C R D R E Each is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups; g and h are each independently selected from 0, 1, 2, and 3; When g and h are both 0, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 4 R 5 R 6 R 7 R 8 It cannot be hydrogen at the same time; When g is not 0 and h is 0, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 3a R 3b R 4 R 5 R 6 R 7 R 8 It cannot be hydrogen at the same time; When g is 0 and h is not 0, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 4 R 4a R 4b R 5 R 6 R 7 R 8 It cannot be hydrogen at the same time; When g is not 0 and h is not 0, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 3a R 3b R 4 R 4a R 4b R 5 R 6 R 7 R 8 It cannot be hydrogen at the same time; a, b, c, and d are each independently selected from 0, 1, 2, and 3; Each y is independently selected from 0, 1, 2, 3, 4, 5, and 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is selected from -C(R a’ R b’ ), -O-, -S-. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, wherein Selected from in, R 1 R 2 They cannot all be hydrogen at the same time, and each can be independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, or N(R) groups. e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R A replace, Or, R 1 and R 2 Together with the attached atoms, it forms an oxo group, a thio group, a 3- to 10-membered alicyclic ring, a 3- to 10-membered alicyclic heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the alicyclic ring, alicyclic heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally surrounded by one or more R groups. B replace; Ring F is selected from 3- to 10-membered alicyclic rings, 3- to 10-membered alicyclic and heterocyclic rings, 6- to 10-membered aromatic rings, or 5- to 10-membered heterocyclic rings, wherein the alicyclic, alicyclic, aromatic, or heterocyclic ring is optionally surrounded by one or more R. B replace; R F R p R q Each is independently selected from halogen, hydroxyl, thiol, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R C replace, Alternatively, choose any two Rs. p Or choose any 2 Rs q Each alicyclic ring or heterocyclic ring independently forms a 3- to 10-membered alicyclic ring with its connected atoms, wherein the alicyclic ring or heterocyclic ring is optionally bounded by one or more R atoms. D replace; f, p, and q are each independently selected from 0, 1, 2, and 3; e1, e2, and e3 are each independently selected from 1, 2, 3, 4, 5, and 6; R y R B R C R D R e R f a, b, c, d, and y are as defined in claim 1. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein ring F is selected from alicyclic or benzene rings. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 They cannot all be hydrogen at the same time, and each can be independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, with hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, and cyclopentyl being the most preferred. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the attached atoms, they form 3 to 10 alicyclic rings, which are optionally separated by one or more R... B replace, R B As defined in claim 1. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein g and h are both 0. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I is selected from the compounds represented by formula II-A1, II-A2, II-A3, II-A3', II-A4, II-A5, II-A6, II-A7, II-A7', II-A8, II-A9, II-A10, II-A11, II-A12, II-A13, II-A14, II-A15, II-A15', II-A16, or II-A17. in: R m R n Each is independently selected from halogen, hydroxyl, thiol, carboxyl, N(R) e R f ), cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R C replace, Alternatively, choose any two Rs. m Or choose any 2 Rs n Each alicyclic ring or heterocyclic ring independently forms a 3- to 10-membered alicyclic ring with its connected atoms, wherein the alicyclic ring or heterocyclic ring is optionally bounded by one or more R atoms. D replace; u is selected from 1, 2, 3, 4, 5, 6; v is selected from 1, 2, 3, 4, 5, 6; m and n are each independently selected from 0, 1, 2, and 3; W、 R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 4 R 5 R 6 R 7 R 8 R A1 R A2 R A3 R A4 R B1 R B2 R B3 R B4 R B5 R D1 R D2 R D3 R D4 R D5 R W1 R W2 R W3 R W4 R W5 R C R D R e R f R y y as defined in claim 1, R 1 R 2 R p R q p, q, e1, e2, e3 as defined in claim 3. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f They cannot all be hydrogen at the same time; each can be independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, or N(R) groups. e R f ), cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkyl, preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, most preferably hydrogen, fluorine, methyl, or ethyl. The alkyl, alkoxy, or cycloalkyl group is optionally surrounded by one or more R groups. A Replace, R A R e R f As defined in claim 1. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein W is methyl. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein R A2 R A3 R B2 R D2 R D3 Each is independently selected from C 1-6 Alkoxy, preferably methoxy or ethoxy, with methoxy being the most preferred. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R A1 R A4 R B1 R B3 R B4 R B5 R D1 R D4 R D5 R W1 R W2 R W3 R W4 R W5 Both are hydrogen. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I is selected from the compounds represented by formula III-A1, III-A2, III-A3, III-A3', III-A4, III-A5, III-A6, III-A7, III-A7', III-A8, III-A9, III-A10, III-A11, III-A12, III-A13, III-A14, III-A15, III-A15', III-A16, or III-A17. in, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R 3 R 4 R 5 R 6 R 7 R 8 R C R D R e R f R y y as defined in claim 1, R 1 R 2 R p R q p, q, e1, e2, e3 as defined in claim 3, R m R n u, v, m, n are as defined in claim 8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 3 R 4 R 5 R 6 R 7 R 8 Both are hydrogen. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I is selected from the compounds represented by formulas IV-A1, IV-A2, IV-A3, IV-A3', IV-A4, IV-A5, IV-A6, IV-A7, IV-A7', IV-A8, IV-A9, IV-A10, IV-A11, IV-A12, IV-A13, IV-A14, IV-A15, IV-A15', IV-A16, or IV-A17. in, R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f R y y as defined in claim 1, R 1 R 2 R p R q p, q, e1, e2, e3 as defined in claim 3, R m R n u, v, m, n are as defined in claim 8. The compound or its pharmaceutically acceptable salt according to any one of claims 3 to 15, wherein e1 is each independently 1, 2, 3, 4, preferably 1, 2, 3, more preferably 2. The compound or its pharmaceutically acceptable salt according to any one of claims 3 to 16, wherein p and q are both 0. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein y is 0. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein the compound represented by formula I is the compound represented by formula V-1 or formula V-2, in, Z is selected from O or S; R 1a R 1b R 1c R 1d R 1e R 1f R 2a R 2b R 2c R 2d R 2e R 2f As defined in claim 1. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein Each ion is independently selected from halide ions, acetate ions, formate ions, benzoate ions, benzenesulfonate ions, camphorsulfonate ions, citrate ions, ethanedisulfonate ions, fumarate ions, glucoheponicate ions, glucuronate ions, glucuronate ions, hydroxyethanesulfonate ions, lactate ions, lacturonate ions, dodecyl sulfate ions, malate ions, maleate ions, methanesulfonate ions, naphthoate ions, naphthalenesulfonate ions, nitrate ions, stearate ions, oleate ions, oxalate ions, dihydroxynaphthalate ions, phosphate ions, hydrogen phosphate ions, dihydrogen phosphate ions, polygalacturonate ions, succinate ions, sulfate ions, sulfosalicylate ions, tartrate ions, toluenesulfonate ions, and trifluoroacetate ions. Chloride ions, bromide ions, fluoride ions, iodide ions, trifluoroacetate ions, formate ions, methanesulfonate ions, and benzenesulfonate ions are preferred. Chloride ions, bromide ions, trifluoroacetate ions, formate ions, methanesulfonate ions, and benzenesulfonate ions are most preferred. The compound of formula I or its pharmaceutically acceptable salt is selected from: ， As defined in claim 1. The compound of formula I or its pharmaceutically acceptable salt is selected from: The compound according to any one of claims 1 to 22, or an isotope-substituted product of the pharmaceutically acceptable salt thereof, preferably, is a deuterated product. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 22, or an isotope substitute as described in claim 23, and a pharmaceutically acceptable excipient. Use of the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in claim 23, or a pharmaceutical composition as described in claim 24, in the preparation of a medicament for neuromuscular blockade.

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