Fused ring compounds and uses thereof

Abstract

The present invention relates to fused ring compounds, compositions containing the same and uses thereof.

Description

Technical Field

[0001] This invention relates to compounds that inhibit the activity of various forms of K-Ras protein, including wild-type and mutant K-Ras proteins, compositions comprising the compounds, and methods of using the compounds. Background Technology

[0002] There is an unmet need to develop new multi-K-Ras inhibitors to treat K-Ras-mediated cancers. Invention Abstract

[0003] This invention provides compounds of formula (I):

[0004]

[0005] Its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of said stereoisomers, its prodrugs, its deuterated molecules or their PROTAC molecules;

[0006] The definitions of each variable are as follows.

[0007] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound as defined herein, and a pharmaceutically acceptable excipient.

[0008] The present invention also provides a method for treating cancer in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound, or a pharmaceutical composition, as defined herein.

[0009] The present invention also provides a method for treating cancer in a subject in need, the method comprising (a) determining whether the cancer is associated with K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutations and / or K-Ras wild-type amplification; and (b) if associated, administering a therapeutically effective amount of a compound, or pharmaceutical composition as defined in the present invention, to the subject in need.

[0010] The present invention also provides compounds or pharmaceutical compositions as defined herein for therapeutic purposes.

[0011] The present invention also provides compounds, as defined herein, or pharmaceutical compositions for use as medicines.

[0012] The present invention also provides compounds, or pharmaceutical compositions, as defined herein, for use in methods of treating cancer.

[0013] This invention also provides the use of compounds or pharmaceutical compositions as defined herein in the treatment of cancer.

[0014] This invention also provides the use of compounds or pharmaceutical compositions as defined herein in the preparation of medicaments for treating cancer.

[0015] Detailed description

[0016] The present invention provides the following disclosure:

[0017] [1]. Compounds of formula (I):

[0018]

[0019]

[0020] Its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of said stereoisomers, its prodrugs, its deuterated molecules or their PROTAC molecules;

[0021] in,

[0022] X1 is a key, -C(R), each time it appears. X11 (R) X12 )-、-NR X13 -、-O-、-S-、-S(=O)- or -S(=O)2-;

[0023] R X11 Or R X12 Independently, it is hydrogen, deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 alkynyl group, -N(R) A )2、-OR A -SR A -S(=O)R B -S(=O)2R B -C(=O)R B -C(=O)OR B -C(=O)N(R) B )2、-S(=O)OR B -S(=O)N(R) B )2、-S(=O)2OR B -S(=O)2N(R) B )2、-P(=O)(R B2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) C )2、-OR C -SR C -S(=O)R D -S(=O)2R D -C(=O)R D -C(=O)OR C -OC(=O)R D -C(=O)N(R) C )2、-NR C C(=O)R D -OC(=O)OR C -NR C C(=O)OR D -OC(=O)N(R) C )2、-NR C C(=O)N(R C )2、-S(=O)OR C -OS(=O)R D -S(=O)N(R) C )2、-NR C S(=O)R D -S(=O)2OR C -OS(=O)2R D -S(=O)2N(R) C )2、-NR C S(=O)2R D -OS(=O)2OR C -NR C S(=O)2OR C -OS(=O)2NR C -NR CS(=O)2N(R C )2、-P(R C )2、-P(=O)(R D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0024] Optional, R X11 and R X12 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. SX1 Replaced;

[0025] R X13 It is hydrogen, deuterium, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -S(=O)R B -S(=O)2R B -C(=O)R B -C(=O)OR B -C(=O)N(R) B )2、-S(=O)OR B -S(=O)N(R) B )2、-S(=O)2OR B -S(=O)2N(R) B )2、-P(=O)(R B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) C )2、-OR C -SRC -S(=O)R D -S(=O)2R D -C(=O)R D -C(=O)OR C -OC(=O)R D -C(=O)N(R) C )2、-NR C C(=O)R D -OC(=O)OR C -NR C C(=O)OR D -OC(=O)N(R) C )2、-NR C C(=O)N(R C )2、-S(=O)OR C -OS(=O)R D -S(=O)N(R) C )2、-NR C S(=O)R D -S(=O)2OR C -OS(=O)2R D -S(=O)2N(R) C )2、-NR C S(=O)2R D -OS(=O)2OR C -NR C S(=O)2OR C -OS(=O)2NR C -NR C S(=O)2N(R C )2、-P(R C )2、-P(=O)(R D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0026] X2 is either N or CR1 independently each time it appears;

[0027] R1 is hydrogen, deuterium, halogen, or -C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) 1A)2、-OR 1A -SR 1A -S(=O)R 1B -S(=O)2R 1B -C(=O)R 1B -C(=O)OR 1A -OC(=O)R 1B -C(=O)N(R) 1A )2、-NR 1A C(=O)R 1B -OC(=O)OR 1A -NR 1A C(=O)OR 1A -NR 1A C(=S)OR 1A -OC(=O)N(R) 1A )2、-NR 1A C(=O)N(R 1A )2、-S(=O)OR 1A -OS(=O)R 1B -S(=O)N(R) 1A )2、-NR 1A S(=O)R 1B -S(=O)2OR 1A -OS(=O)2R 1B -S(=O)2N(R) 1A )2、-NR 1A S(=O)2R 1B -OS(=O)2OR 1A -NR 1A S(=O)2OR 1A -OS(=O)2N(R) 1A )2、-NR 1A S(=O)2N(R 1A )2、-P(R 1A )2、-P(=O)(R 1B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) 1C )2、-OR 1C -SR 1C -S(=O)R 1D -S(=O)2R 1D -C(=O)R 1D -C(=O)OR 1D -OC(=O)R 1D -C(=O)N(R) 1C )2、-NR 1C C(=O)R 1D -OC(=O)OR 1C -NR 1C C(=O)OR 1C -NR 1C C(=S)OR 1C -OC(=O)N(R) 1C )2、-NR 1C C(=O)N(R 1C )2、-S(=O)OR 1C -OS(=O)R 1D -S(=O)N(R) 1C )2、-NR 1C S(=O)R 1D -S(=O)2OR 1C -OS(=O)2R 1D -S(=O)2N(R) 1C )2、-NR 1C S(=O)2R 1D -OS(=O)2OR 1C -NR 1C S(=O)2OR 1C -OS(=O)2N(R) 1C )2、-NR 1C S(=O)2N(R 1C )2、-P(R 1C )2、-P(=O)(R 1D)2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0028] n1 is 0, 1, 2, 3, 4, 5, or 6;

[0029] Ring A is a 3-20 membered heterocycle containing only an N atom attached to the pyrimidine ring, or a 3-20 (e.g., 3-10) membered heterocycle containing one or more additional heteroatoms selected from O, S, S=O or S(=O)2 in addition to the N atom attached to the pyrimidine ring.

[0030] R S1 Independently, it is hydrogen, deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S1A )2、-OR S1A -SR S1A -S(=O)R S1B -S(=O)2R S1B -C(=O)R S1B -C(=O)OR S1A -OC(=O)R S1B -C(=O)N(R) S1A )2、-N S1A C(=O)R S1B -OC(=O)OR S1A -N S1A C(=O)OR S1A -NR S1A C(=S)O S1A -OC(=O)N(R) S1A )2、-NR S1A C(=O)N(R S1A )2、-S(=O)OR S1A -OS(=O)R S1B -S(=O)N(R) S1A )2、-NR S1A S(=O)R S1B -S(=O)2OR S1A -OS(=O)2R S1B -S(=O)2N(R) S1A )2、-NR S1A S(=O)2RS1B -OS(=O)2OR S1A -NR S1A S(=O)2OR S1A -OS(=O)2N(R) S1A )2、-NR S1A S(=O)2N(R S1A )2、-P(R S1A )2、-P(=O)(R S1B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S1C )2、-OR S1C -SR S1C -S(=O)R S1D -S(=O)2R S1D -C(=O)R S1D -C(=O)OR S1C -OC(=O)R S1D -C(=O)N(R) S1C )2、-NR S1C C(=O)R S1D -OC(=O)OR S1C -NR S1C C(=O)OR S1C -NR S1C C(=S)OR S1C -OC(=O)N(R) S1C )2、-NR S1C C(=O)N(R S1C )2、-S(=O)OR S1C-OS(=O)R S1D -S(=O)N(R) S1C )2、-NR S1C S(=O)R S1D -S(=O)2OR S1C -OS(=O)2R S1D -S(=O)2N(R) S1C )2、-NR S1C S(=O)2R S1D -OS(=O)2OR S1C -NR S1C S(=O)2OR S1C -OS(=O)2N(R) S1C )2、-NR S1C S(=O)2N(R S1C )2、-P(R S1C )2、-P(=O)(R S1D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0031] Either way, two R S1 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S11 Replaced;

[0032] Optionally, two adjacent R S1 Together with the atoms they are connected to form 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered heteroaromatic rings, wherein each ring is independently unsubstituted or substituted by one or more R... S12 Replaced;

[0033] Optionally, two non-adjacent R values S1 They are linked together to form bridges containing 0, 1, 2, 3, 4, 5, or 6 carbon atoms, wherein each carbon atom in the bridge is independently unsubstituted or substituted by one or two heteroatoms selected from N, O, S, S=O, or S(=O)2; and the hydrogen atom on each carbon atom or N atom is independently unsubstituted or substituted by R. S13 Replaced;

[0034] m1 is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0035] R S2 Independently, it is hydrogen, deuterium, halogen, -C1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S2A )2、-OR S2A -SR S2A -S(=O)R S2B -S(=O)2R S2B -C(=O)R S2B -C(=O)OR S2A -OC(=O)R S2B -C(=O)N(R) S2A )2、-NR S2A C(=O)R S2B -OC(=O)OR S2A -NR S2A C(=O)OR S2A -NR S2A C(=S)OR S2A -OC(=O)N(R) S2A )2、-NR S2A C(=O)N(R S2A )2、-S(=O)OR S2A -OS(=O)R S2B -S(=O)N(R) S2A )2、-NR S2A S(=O)R S2B -S(=O)2OR S2A -OS(=O)2R S2B -S(=O)2N(R) S2A )2、-NR S2A S(=O)2R S2B -OS(=O)2OR S2A -NR S2A S(=O)2OR S2A -OS(=O)2N(R) S2A )2、-NR S2A S(=O)2N(R S2A )2、-P(R S2A )2、-P(=O)(R S2B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S2C )2、-OR S2C -SR S2C -S(=O)R S2D -S(=O)2R S2D -C(=O)R S2D -C(=O)OR S2D -OC(=O)R S2D -C(=O)N(R) S2C )2、-NR S2C C(=O)R S2D -OC(=O)OR S2C -NR S2C C(=O)OR S2C -NR S2C C(=S)OR S2C -OC(=O)N(R) S2C )2、-NR S2C C(=O)N(R S2C )2、-S(=O)OR S2C -OS(=O)R S2D -S(=O)N(R) S2C )2、-NR S2C S(=O)R S2D -S(=O)2OR S2C -OS(=O)2R S2D -S(=O)2N(R) S2C )2、-NR S2C S(=O)2R S2D -OS(=O)2OR S2C -NR S2C S(=O)2OR S2C -OS(=O)2N(R)S2C )2、-NR S2C S(=O)2N(R S2C )2、-P(R S2C )2、-P(=O)(R S2D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0036] Either way, two R S2 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S21 Replaced;

[0037] Optionally, two adjacent R S2 Together with the atoms they are connected to form 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered heteroaromatic rings, wherein each ring is independently unsubstituted or substituted by one or more R... S22 Replaced;

[0038] Optionally, two non-adjacent R values S2 They are linked together to form bridges containing 0, 1, 2, 3, 4, 5, or 6 carbon atoms, wherein each carbon atom in the bridge is independently unsubstituted or substituted by one or two heteroatoms selected from N, O, S, S=O, or S(=O)2; and the hydrogen atoms on each carbon atom or N atom are independently unsubstituted or substituted by R. S23 Replaced;

[0039] m2 is 0, 1, 2, 3, 4, or 5; Y1 is bond, O, S, S(=O), S(=O)2, or NR. Y11 ;

[0040] R Y11 It is hydrogen, deuterium, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -S(=O)R B -S(=O)2R B -C(=O)R B -C(=O)OR B -C(=O)N(R) B )2、-S(=O)OR B -S(=O)N(R) B )2、-S(=O)2ORB -S(=O)2N(R) B )2、-P(=O)(R B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) C )2、-OR C -SR C -S(=O)R D -S(=O)2R D -C(=O)R D -C(=O)OR C -OC(=O)R D -C(=O)N(R) C )2、-NR C C(=O)R D -OC(=O)OR C -NR C C(=O)OR D -OC(=O)N(R) C )2、-NR C C(=O)N(R C )2、-S(=O)OR C -OS(=O)R D -S(=O)N(R) C )2、-NR C S(=O)R D -S(=O)2OR C -OS(=O)2R D -S(=O)2N(R) C )2、-NR C S(=O)2R D -OS(=O)2OR C -NR C S(=O)2OR C-OS(=O)2NR C -NR C S(=O)2N(R C )2、-P(R C )2、-P(=O)(R D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0041] R3 is

[0042] Each R 31 R 32 R 33 R 34 R 35 R 36 R 38 R 39 RR 310 and R 311 Independently, it is hydrogen, deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 alkynyl group, -N(R) A )2、-OR A -SR A -S(=O)R B -S(=O)2R B -C(=O)R B -C(=O)OR A -C(=O)N(R) A )2、-S(=O)OR A -S(=O)N(R) A )2、-S(=O)2OR A -S(=O)2N(R) A )2、-P(=O)(R B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) C )2、-OR C -SR C -S(=O)R D -S(=O)2R D -C(=O)R D -C(=O)OR C -OC(=O)R D -C(=O)N(R) C )2、-NR C C(=O)R D -OC(=O)OR C -NR C C(=O)OR D -OC(=O)N(R) C )2、-NR C C(=O)N(R C )2、-S(=O)OR C -OS(=O)R D -S(=O)N(R) C )2、-NR C S(=O)R D -S(=O)2OR C -OS(=O)2R D -S(=O)2N(R) C )2、-NR C S(=O)2R D -OS(=O)2OR C -NR C S(=O)2OR C -OS(=O)2NR C -NR C S(=O)2N(R C )2、-P(R C )2、-P(=O)(R D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0043] Optional, R 31 and R 32 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S33 Replaced;

[0044] Optional, R 33 and R 34 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S34 Replaced;

[0045] Optional, R 35 and R 36 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S35 Replaced;

[0046] Optional, R 38 and R 39 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S310 Replaced;

[0047] Optional, R 310 and R 311 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S316 Replaced;

[0048] n2 is 0, 1, 2, 3, 4, 5, or 6;

[0049] n3 is 0, 1, 2, 3, 4, 5, or 6;

[0050] n4 is 0, 1, 2, 3, 4, 5, or 6;

[0051] n5 is 0, 1, 2, 3, 4, 5, or 6;

[0052] n6 is 0, 1, 2, 3, 4, 5, or 6;

[0053] Ring B is a 3- to 10-membered heterocycle, optionally further comprising 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2;

[0054] The ring C is a 3- to 10-membered heterocycle, optionally further comprising 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2;

[0055] Ring D is a 3-10 membered carbon ring or a 3-10 membered hetero ring;

[0056] Ring I is a 3-10 membered carbon ring or a 3-10 membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2.

[0057] Ring J is a 3-10 membered carbon ring or a 3-10 membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2.

[0058] Ring K is a 3-10 membered carbon ring or a 3-10 membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2.

[0059] R S31 It is hydrogen, deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S31A )2、-OR S31A -SR S31A -S(=O)R S31B -S(=O)2R S31B -C(=O)R S31B -C(=O)OR S31A -OC(=O)R S31B -C(=O)N(R) S31A )2、-NR S31A C(=O)R S31B -OC(=O)OR S31A -NR S31A C(=O)OR S31A -NR S31A C(=S)OR S31A-OC(=O)N(R) S31A )2、-NR S31A C(=O)N(R S31A )2、-S(=O)OR S31A -OS(=O)R S31B -S(=O)N(R) S31A )2、-NR S31A S(=O)R S31B -S(=O)2OR S31A -OS(=O)2R S31B -S(=O)2N(R) S31A )2、-NR S31A S(=O)2R S31B -OS(=O)2OR S31A -NR S31A S(=O)2OR S31A -OS(=O)2N(R) S31A )2、-NR S31A S(=O)2N(R S31A )2、-P(R S31A )2、-P(=O)(R S31B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S31C )2、-OR S31C -SR S31C -S(=O)R S31D -S(=O)2R S31D -C(=O)R S31D -C(=O)OR S31C-OC(=O)R S31D -C(=O)N(R) S31C )2、-NR S31C C(=O)R S31D -OC(=O)OR S31C -NR S31C C(=O)OR S31C -NR S31C C(=S)OR S31C -OC(=O)N(R) S31C )2、-NR S31C C(=O)N(R S31C )2、-S(=O)OR S31C -OS(=O)R S31D -S(=O)N(R) S31C )2、-NR S31C S(=O)R S31D -S(=O)2OR S31C -OS(=O)2R S31D -S(=O)2N(R) S31C )2、-NR S31C S(=O)2R S31D -OS(=O)2OR S31C -NR S31C S(=O)2OR S31C -OS(=O)2N(R) S31C )2、-NR S31C S(=O)2N(R S31C )2、-P(R S31C )2、-P(=O)(R S31D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0060] Either way, two R S31 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S311 Replaced;

[0061] Optionally, two adjacent R S31 Together with the atoms they are connected to form 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered heteroaromatic rings, wherein each ring is independently unsubstituted or substituted by one or more R... S312 Replaced;

[0062] Optionally, two non-adjacent R values S31 They are linked together to form bridges containing 0, 1, 2, 3, 4, 5, or 6 carbon atoms, wherein each carbon atom in the bridge is independently unsubstituted or substituted by 1 or 2 heteroatoms selected from N, O, S, S=O, or S(=O)2; and the hydrogen atom on each carbon atom or N atom is independently unsubstituted or substituted by R. S313 Replaced;

[0063] m3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0064] R S32 It is hydrogen, deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S32A )2、-OR S32A -SR S32A -S(=O)R S32B -S(=O)2R S32B -C(=O)R S32B -C(=O)OR S32A -OC(=O)R S32B -C(=O)N(R) S32A )2、-NR S32A C(=O)R S32B -OC(=O)OR S32A -NR S32A C(=O)OR S32A -NR S32A C(=S)OR S32A -OC(=O)N(R) S32A )2、-NR S32A C(=O)N(R S32A )2、-S(=O)OR S32A -OS(=O)R S32B -S(=O)N(R) S32A )2、-NR S32A S(=O)R S32B -S(=O)2OR S32A -OS(=O)2R S32B -S(=O)2N(R) S32A )2、-NR S32AS(=O)2R S32B -OS(=O)2OR S32A -NR S32A S(=O)2OR S32A -OS(=O)2N(R) S32A )2、-NR S32A S(=O)2N(R S32A )2、-P(R S32A )2、-P(=O)(R S32B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S32C )2、-OR S32C -SR S32C -S(=O)R S32C -S(=O)2R S32D -C(=O)R S32D -C(=O)OR S32C -OC(=O)R S32D -C(=O)N(R) S32C )2、-NR S32C C(=O)R S32D -OC(=O)OR S32C -NR S32C C(=O)OR S32C -NR S32C C(=S)OR S32C -OC(=O)N(R) S32C )2、-NR S32C C(=O)N(R S32C )2、-S(=O)ORS32C -OS(=O)R S32C -S(=O)N(R) S32C )2、-NR S32C S(=O)R S32D -S(=O)2OR S32C -OS(=O)2R S32D -S(=O)2N(R) S32C )2、-NR S32C S(=O)2R S32D -OS(=O)2OR S32C -NR S32C S(=O)2OR S32C -OS(=O)2N(R) S32C )2、-NR S32C S(=O)2N(R S32C )2、-P(R S32C )2、-P(=O)(R S32D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0065] Either way, two R S32 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S321 Replaced;

[0066] Optionally, two adjacent R S32 Together with the atoms they are connected to form 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered heteroaromatic rings, wherein each ring is independently unsubstituted or substituted by one or more R... S322 Replaced;

[0067] Optionally, two non-adjacent R values S32 They are linked together to form bridges containing 0, 1, 2, 3, 4, 5, or 6 carbon atoms, wherein each carbon atom in the bridge is independently unsubstituted or substituted by 1 or 2 heteroatoms selected from N, O, S, S=O, or S(=O)2; and the hydrogen atom on each carbon atom or N atom is independently unsubstituted or substituted by R. S323 Replaced;

[0068] m4 is 0, 1, 2, 3, 4, 5 or 6;

[0069] R 37 It is -N(R)37A )2 or 3-10 membered heterocyclic groups, wherein the 3-10 membered heterocyclic group is optionally independently formed by one or more R S37 Replaced;

[0070] R S38 It is hydrogen, deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S38A )2、-OR S38A -SR S38A -S(=O)R S38B -S(=O)2R S38B -C(=O)R S38B -C(=O)OR S38A -OC(=O)R S38B -C(=O)N(R) S38A )2、-NR S38A C(=O)R S38B -OC(=O)OR S38A -NR S38A C(=O)OR S38A -NR S38A C(=S)OR S38A -OC(=O)N(R) S38A )2、-NR S38A C(=O)N(R S38A )2、-S(=O)OR S38A -OS(=O)R S38B -S(=O)N(R) S38A )2、-NR S38A S(=O)R S38B -S(=O)2OR S38A -OS(=O)2R S38B -S(=O)2N(R) S38A )2、-NR S38A S(=O)2R S38B -OS(=O)2OR S38A -NR S38A S(=O)2OR S38A -OS(=O)2N(R) S38A )2、-NR S38A S(=O)2N(R S38A )2、-P(RS38A )2、-P(=O)(R S38B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S38C )2、-OR S38C -SR S38C -S(=O)R S38D -S(=O)2R S38D -C(=O)R S38D -C(=O)OR S38C -OC(=O)R S38D -C(=O)N(R) S38C )2、-NR S38C C(=O)R S38D -OC(=O)OR S38C -NR S38C C(=O)OR S38C -NR S38C C(=S)OR S38C -OC(=O)N(R) S38C )2、-NR S38C C(=O)N(R S38C )2、-S(=O)OR S38C -OS(=O)R S38D -S(=O)N(R) S38C )2、-NR S38C S(=O)R S38D -S(=O)2OR S38C -OS(=O)2R S38D -S(=O)2N(R)S38C )2、-NR S38C S(=O)2R S38D -OS(=O)2OR S38C -NR S38C S(=O)2OR S38C -OS(=O)2N(R) S38C )2、-NR S38C S(=O)2N(R S38C )2、-P(R S38C )2、-P(=O)(R S38D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0071] Either way, two R S38 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S381 Replaced;

[0072] Optionally, two adjacent R S38 Together with the atoms they are connected to form 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered heteroaromatic rings, wherein each ring is independently unsubstituted or substituted by one or more R... S382 Replaced;

[0073] Optionally, two non-adjacent R values S38 They are linked together to form bridges containing 0, 1, 2, 3, 4, 5, or 6 carbon atoms, wherein each carbon atom in the bridge is independently unsubstituted or substituted by 1 or 2 heteroatoms selected from N, O, S, S=O, or S(=O)2; and the hydrogen atom on each carbon atom or N atom is independently unsubstituted or substituted by R. S383 Replaced;

[0074] m8 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0075] R S39 It is hydrogen, deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6Alkyne, -CN, -NO2, -N3, oxo, -N(R) S39A )2、-OR S39A -SR S39A -S(=O)R S39B -S(=O)2R S39B -C(=O)R S39B -C(=O)OR S39A -OC(=O)R S39B -C(=O)N(R) S39A )2、-NR S39A C(=O)R S39B -OC(=O)OR S39A -NR S39A C(=O)OR S39A -NR S39A C(=S)OR S39A -OC(=O)N(R) S39A )2、-NR S39A C(=O)N(R S39A )2、-S(=O)OR S39A -OS(=O)R S39B -S(=O)N(R) S39A )2、-NR S39A S(=O)R S39B -S(=O)2OR S39A -OS(=O)2R S39B -S(=O)2N(R) S39A )2、-NR S39A S(=O)2R S39B -OS(=O)2OR S39A -NR S39A S(=O)2OR S39A -OS(=O)2N(R) S39A )2、-NR S39A S(=O)2N(R S39A )2、-P(R S39A )2、-P(=O)(R S39B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S39C )2、-OR S39C -SR S39C -S(=O)R S39C -S(=O)2R S39D -C(=O)R S39D -C(=O)OR S39C -OC(=O)R S39D -C(=O)N(R) S39C )2、-NR S39C C(=O)R S39D -OC(=O)OR S39C -NR S39C C(=O)OR S39C -NR S39C C(=S)OR S39C -OC(=O)N(R) S39C )2、-NR S39C C(=O)N(R S39C )2、-S(=O)OR S39C -OS(=O)R S39C -S(=O)N(R) S39C )2、-NR S39C S(=O)R S39D -S(=O)2OR S39C -OS(=O)2R S39D -S(=O)2N(R) S39C )2、-NR S39C S(=O)2R S39D -OS(=O)2OR S39C -NR S39C S(=O)2OR S39C -OS(=O)2N(R) S39C )2、-NR S39C S(=O)2N(R S39C )2、-P(R S39C )2、-P(=O)(R S39D)2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0076] Either way, two R S39 Together with the carbon atoms that are all connected to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S391 Replaced;

[0077] Optionally, two adjacent R S39 Together with the atoms they are connected to form 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered heteroaromatic rings, wherein each ring is independently unsubstituted or substituted by one or more R... S392 Replaced;

[0078] Optionally, two non-adjacent R values S39 They are linked together to form bridges containing 0, 1, 2, 3, 4, 5, or 6 carbon atoms, wherein each carbon atom in the bridge is independently unsubstituted or substituted by 1 or 2 heteroatoms selected from N, O, S, S=O, or S(=O)2; and the hydrogen atom on each carbon atom or N atom is independently unsubstituted or substituted by R. S393 Replaced;

[0079] m9 is 0, 1, 2, 3, 4, 5, or 6;

[0080] R S315 It is hydrogen, deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S315A )2、-OR S315A -SR S315A -S(=O)R S315B -S(=O)2R S315B -C(=O)R S315B -C(=O)OR S315A -OC(=O)R S315B -C(=O)N(R) S315A )2、-NR S315A C(=O)R S315B-OC(=O)OR S315A -NR S315A C(=O)OR S315A -NR S315A C(=S)OR S315A -OC(=O)N(R) S315A )2、-NR S315A C(=O)N(R S315A )2、-S(=O)OR S315A -OS(=O)R S315B -S(=O)N(R) S315A )2、-NR S315A S(=O)R S315B -S(=O)2OR S315A -OS(=O)2R S315B -S(=O)2N(R) S315A )2、-NR S315A S(=O)2R S315B -OS(=O)2OR S315A -NR S315A S(=O)2OR S315A -OS(=O)2N(R) S315A )2、-NR S315A S(=O)2N(R S315A )2、-P(R S315A )2、-P(=O)(R S315B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S315C )2、-OR S315C -SRS315C -S(=O)R S315C -S(=O)2R S315D -C(=O)R S315D -C(=O)OR S315C -OC(=O)R S315D -C(=O)N(R) S315C )2、-NR S315C C(=O)R S315D -OC(=O)OR S315C -NR S315C C(=O)OR S315C -NR S315C C(=S)OR S315C -OC(=O)N(R) S315C )2、-NR S315C C(=O)N(R S315C )2、-S(=O)OR S315C -OS(=O)R S315C -S(=O)N(R) S315C )2、-NR S315C S(=O)R S315D -S(=O)2OR S315C -OS(=O)2R S315D -S(=O)2N(R) S315C )2、-NR S315C S(=O)2R S315D -OS(=O)2OR S315C -NR S315C S(=O)2OR S315C -OS(=O)2N(R) S315C )2、-NR S315C S(=O)2N(R S315C )2、-P(R S315C )2、-P(=O)(R S315D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0081] Either way, two R S315 Together with the carbon atoms that are all bonded to them, they form 3-10 membered carbon rings or 3-10 membered heterocycles; wherein, the aforementioned 3-10 membered carbon rings or 3-10 membered heterocycles are independently unsubstituted or replaced by one or more R groups. S3151 Replaced;

[0082] Optionally, two adjacent R S315Together with the atoms they are connected to form 3-10 membered carbon rings, 3-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered heteroaromatic rings, wherein each ring is independently unsubstituted or substituted by one or more R... S3152 Replaced;

[0083] Optionally, two non-adjacent R values S315 They are linked together to form bridges containing 0, 1, 2, 3, 4, 5, or 6 carbon atoms, wherein each carbon atom in the bridge is independently unsubstituted or substituted by 1 or 2 heteroatoms selected from N, O, S, S=O, or S(=O)2; and the hydrogen atom on each carbon atom or N atom is independently unsubstituted or substituted by R. S3153 Replaced;

[0084] m 10 It is 0, 1, 2, 3, 4, 5, or 6;

[0085] R4 is a 6-10 aryl, 5-10 heteroaryl, The 6-10 aryl, 5-10 heteroaryl, Independently not replaced or by one or more R S4 Replaced;

[0086] Z is either C or N each time it appears;

[0087] When Z is C, ring E is independently a 6-membered aromatic ring or a 5-6-membered heteroaromatic ring each time it appears, and ring F is a 3-10-membered carbon ring or a 3-10-membered hetero ring each time it appears.

[0088] When Z is N, ring E is a 5-6 member heteroaromatic ring each time it appears, and ring F is a 3-10 member heterocyclic ring each time it appears;

[0089] R S4 Independently, it is deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) S4A )2、-OR S4A -SR S4A -S(=O)R S4B -S(=O)2R S4B -C(=O)R S4B -C(=O)OR S4A -OC(=O)R S4B-C(=O)N(R) S4A )2、-NR S4A C(=O)R S4B -OC(=O)OR S4A -NR S4A C(=O)OR S4A -NR S4A C(=S)OR S4A -OC(=O)N(R) S4A )2、-NR S4A C(=O)N(R S4A )2、-S(=O)OR S4A -OS(=O)R S4B -S(=O)N(R) S4A )2、-NR S4A S(=O)R S4B -S(=O)2OR S4A -OS(=O)2R S4B -S(=O)2N(R) S4A )2、-NR S4A S(=O)2R S4B -OS(=O)2OR S4A -NR S4A S(=O)2OR S4A -OS(=O)2N(R) S4A )2、-NR S4A S(=O)2N(R S4A )2、-P(R S4A )2、-P(=O)(R S4B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6Alkyne, -CN, -NO2, -N3, oxo, -N(R) S4C )2、-OR S4C -SR S4C -S(=O)R S4D -S(=O)2R S4D -C(=O)R S4D -C(=O)OR S4D -OC(=O)R S4D -C(=O)N(R) S4C )2、-NR S4C C(=O)R S4D -OC(=O)OR S4C -NR S4C C(=O)OR S4C -NR S4C C(=S)OR S4C -OC(=O)N(R) S4C )2、-NR S4C C(=O)N(R S4C )2、-S(=O)OR S4C -OS(=O)R S4D -S(=O)N(R) S4C )2、-NR S4C S(=O)R S4D -S(=O)2OR S4C -OS(=O)2R S4D -S(=O)2N(R) S4C )2、-NR S4C S(=O)2R S4D -OS(=O)2OR S4C -NR S4C S(=O)2OR S4C -OS(=O)2N(R) S4C )2、-NR S4C S(=O)2N(R S4C )2、-P(R S4C )2、-P(=O)(R S4D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0090] R5 represents hydrogen, deuterium, halogen, and -C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) 5A )2、-OR 5A -SR 5A -S(=O)R 5B -S(=O)2R 5B -C(=O)R 5B -C(=O)OR 5A -OC(=O)R 5B -C(=O)N(R) 5A )2、-NR 5A C(=O)R 5B -OC(=O)OR 5A -NR 5A C(=O)OR 5A -NR 5A C(=S)OR 5A -OC(=O)N(R) 5A )2、-NR 5A C(=O)N(R 5A )2、-S(=O)OR 5A -OS(=O)R 5B -S(=O)N(R) 5A )2、-NR 5A S(=O)R 5B -S(=O)2OR 5A -OS(=O)2R 5B -S(=O)2N(R) 5A )2、-NR 5A S(=O)2R 5B -OS(=O)2OR 5A -NR 5A S(=O)2OR 5A -OS(=O)2N(R) 5A )2、-NR 5A S(=O)2N(R 5A )2、-P(R 5A )2、-P(=O)(R 5B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) 5C )2、-OR 5C -SR 5C -S(=O)R 5D -S(=O)2R 5D -C(=O)R 5D -C(=O)OR 5D -OC(=O)R 5D -C(=O)N(R) 5C )2、-NR 5C C(=O)R 5D -OC(=O)OR 5C -NR 5C C(=O)OR 5C -NR 5C C(=S)OR 5C -OC(=O)N(R) 5C )2、-NR 5C C(=O)N(R 5C )2、-S(=O)OR 5C -OS(=O)R 5D -S(=O)N(R) 5C )2、-NR 5C S(=O)R 5D -S(=O)2OR 5C -OS(=O)2R 5D -S(=O)2N(R) 5C )2、-NR 5C S(=O)2R 5D -OS(=O)2OR 5C -NR 5C S(=O)2OR 5C -OS(=O)2N(R) 5C )2、-NR 5C S(=O)2N(R 5C )2、-P(R 5C )2、-P(=O)(R 5D)2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0091] Each R 1A R 1C R S1A R S1C R S2A R S2C R S31A R S31C R S32A R S32C R 37A R S38A R S38C R S39A R S39C R S315A R S315C R S4A R S4C R 5A R 5C R a R b R c R d R e R f R g R h R i R j R k and R l Independently, they are hydrogen, deuterium, and -C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -S(=O)R B -S(=O)2R B -C(=O)R B -C(=O)OR B -C(=O)N(R) B )2、-S(=O)OR B -S(=O)N(R) B )2、-S(=O)2OR B -S(=O)2N(R) B )2、-P(=O)(R B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -C2-6 alkenyl, -C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) C )2、-OR C -SR C -S(=O)R D -S(=O)2R D -C(=O)R D -C(=O)OR C -OC(=O)R D -C(=O)N(R) C )2、-NR C C(=O)R D -OC(=O)OR C -NR C C(=O)OR D -OC(=O)N(R) C )2、-NR C C(=O)N(R C )2、-S(=O)OR C -OS(=O)R D -S(=O)N(R) C )2、-NR C S(=O)R D -S(=O)2OR C -OS(=O)2R D -S(=O)2N(R) C )2、-NR C S(=O)2R D -OS(=O)2OR C -NR C S(=O)2OR C -OS(=O)2NR C -NR C S(=O)2N(R C )2、-P(R C )2、-P(=O)(R D)2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0092] Optional, (both R) 1A Two Rs 1C Two Rs S1A Two Rs S1C Two Rs S2A Two Rs S2C Two Rs S31A Two Rs S31C Two Rs S32A Two Rs S32C Two Rs 37A Two Rs S38A Two Rs S38C Two Rs S39A Two Rs S39C Two Rs S315A Two Rs S315C Two Rs S4A Two Rs S4C Two Rs 5A Or two Rs 5C Together with the nitrogen atoms all bonded to them, they form 3-10 membered heterocycles or 5-10 membered heteroaromatic rings, wherein the 3-10 membered heterocycles or 5-10 membered heteroaromatic rings are independently unsubstituted or are formed by one or more R atoms. SS Replaced;

[0093] Each R 1B R 1D R S1B R S1D R S2B R S2D R S31B R S31D R S32B R S32D R S38B R S38D R S39B R S315B R S315D R S39D R S4B R S4D R 5B and R 5D Independently, they are hydrogen, deuterium, and -C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6alkynyl group, -N(R) A )2、-OR A -SR A 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) C )2、-OR C -SR C -S(=O)R D -S(=O)2R D -C(=O)R D -C(=O)OR C -OC(=O)R D -C(=O)N(R) C )2、-NR C C(=O)R D -OC(=O)OR C -NR C C(=O)OR D -OC(=O)N(R) C )2、-NR C C(=O)N(R C )2、-S(=O)OR C -OS(=O)R D -S(=O)N(R) C )2、-NR C S(=O)R D -S(=O)2OR C -OS(=O)2R D -S(=O)2N(R) C )2、-NR C S(=O)2R D -OS(=O)2OR C -NR C S(=O)2ORC -OS(=O)2NR C -NR C S(=O)2N(R C )2、-P(R C )2、-P(=O)(R D )2, substituted by substituents of 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0094] Each (R) A R B R C and R D Independently, it is hydrogen, deuterium, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more R groups. SA Replaced;

[0095] Each R SX1 R S11 R S12 R S13 R S21 R S22 R S23 R S33 R S34 R S35 R S37 R S310 R S316 R S311 R S312 R S313 R S321 R S322 R S323 R S381 R S382 R S383 R S391 R S392 RS393 R S3151 R S3152 R S3153 R SS and R SA Independently, it is deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -OC(=O)O(C 1-6 Alkyl), -NHC(=O)(OC 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(OC) 1-6 Alkyl), -OC(=O)NH(C 1-6 Alkyl), -OC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)C(=O)NH2、-N(C 1-6 alkyl)C(=O)NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)N(C 1-6 Alkyl)2、-S(=O)(OC 1-6 Alkyl), -OS (=O) (C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl), -S(=O)2(OC 1-6 Alkyl), -OS(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Alkyl), -OS(=O)2O(C 1-6 Alkyl), -NHS(=O)2O(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2O(C 1-6 Alkyl groups), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 Alkyl), -OS(=O)2N(C 1-6 Alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1-6 Alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)S(=O)2NH2、-N(C 1-6 alkyl)S(=O)2NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2N(C 1-6 alkyl)2, -PH(C 1-6 alkyl), -P(C) 1-6 Alkyl)2、-P(=O)H(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl) 2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, -C 2-3 alkenyl, -C 2-3 Alkyne, -CN, -NO2, -N3, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -OC(=O)O(C 1-3 Alkyl), -NHC(=O)(OC 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(OC) 1-3 Alkyl), -OC(=O)NH(C 1-3 Alkyl), -OC(=O)N(C 1-3 Alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1-3 Alkyl), -NHC(=O)N(C 1-3 Alkyl)2, -N(C 1-3 Alkyl)C(=O)NH2、-N(C 1-3 alkyl)C(=O)NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)N(C 1-3 Alkyl)2、-S(=O)(OC 1-3 Alkyl), -OS (=O) (C 1-3 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)(C1-3 Alkyl), -S(=O)2(OC 1-3 Alkyl), -OS(=O)2(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)2(C 1-3 Alkyl), -OS(=O)2O(C 1-3 Alkyl), -NHS(=O)2O(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)2O(C 1-3 Alkyl groups), -OS(=O)2NH2, -OS(=O)2NH(C 1-3 Alkyl), -OS(=O)2N(C 1-3 Alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1-3 Alkyl), -NHS(=O)2N(C 1-3 Alkyl)2, -N(C 1-3 Alkyl)S(=O)2NH2、-N(C 1-3 alkyl)S(=O)2NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(=O)2N(C 1-3 alkyl)2, -PH(C 1-3 alkyl), -P(C) 1-3 Alkyl)2、-P(=O)H(C 1-3 Alkyl), -P(=O)(C 1-3 Substituents of alkyl, 2-, 3-, 10-membered cycloalkyl, 3-, 10-membered cycloalkenyl, 3-, 10-membered cycloynyl, 3-, 10-membered heterocyclic, 6-, 10-membered aryl or 5-, 10-membered heteroaryl;

[0096] Each heterocyclic group or heterocycle independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O) or S(=O)2 each time it appears;

[0097] Each heteroaryl group independently contains 1, 2, 3 or 4 heteroatoms selected from N, O or S each time it appears.

[0098] [2].[1] The compound, wherein the compound is any of the following formula:

[0099]

[0100] [3]. The compound described in [1] or [2], wherein R1 is hydrogen, deuterium, halogen, -CN, or -OC. 1-6 Alkyl, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkyne group, or 3-6 membered cycloalkyl group; the -OC group 1-6 Alkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 The alkynyl group or 3-6 membered cycloalkyl group is unsubstituted or is replaced by 1, 2 or 3 C groups selected from deuterium, halogen, or halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Alkyl groups are substituted.

[0101] In some implementations, R1 is

[0102] In some embodiments, R1 is hydrogen, deuterium, -F, -Cl, -Br, -CN, -OCH3, -CF3, -CH2CH2CN, methyl, ethyl, or cyclopropyl.

[0103] In some implementations, R1 is

[0104] In some implementations, R1 is -NO2.

[0105] In some implementations, R1 is -Cl, -H or -F.

[0106] [4]. The compound described in any one of [1] to [3], wherein R1 is hydrogen, deuterium, -F, -Cl, -Br, -CN, -OCH3, -CF3, -CH2CH2CN, methyl, ethyl, or cyclopropyl.

[0107] [5]. The compound described in any one of [1] to [4], wherein:

[0108] X1 is independently -C(R) each time it appears. X11 (R) X12 )-、-NR X13 -、-O-、-S- or -S(=O)-;

[0109] R X11 Or R X12Independently, it is hydrogen, deuterium, halogen, -C 1-6 Alkyl or 3-6 membered cycloalkyl; wherein the -C 1-6 Alkyl or 3-6 membered cycloalkyl groups are independently unsubstituted or surrounded by 1, 2, or 3 C groups selected from deuterium, halogen, or halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Substituents of alkyl groups;

[0110] Optional, R X11 and R X12 Together with the carbon atoms that are all bonded to them, they form Among them, the Independently unsubstituted or by 1, 2, or 3 selected from deuterium, halogen, or halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Substituents of alkyl groups;

[0111] R X13 It is hydrogen, deuterium, -C 1-6 Alkyl or 3-6 membered cycloalkyl; wherein the -C 1-6 Alkyl or 3-6 membered cycloalkyl groups are independently unsubstituted or surrounded by 1, 2, or 3 C groups selected from deuterium, halogen, or halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Alkyl groups are substituted.

[0112] In some implementations, R X13 It is -CH3, -CD3, -CH2CH3, -C(=O)CH3 or -CH2CH2CF3.

[0113] [6]. The compound described in any one of [1] to [5], wherein:

[0114] R X11 Or R X12 It can be hydrogen, deuterium, -F, methyl, -CD3, ethyl, propyl, isopropyl, or cyclopropyl independently;

[0115] Optional, R X11 and RX12 Together with the carbon atoms that are all bonded to them, they form

[0116] R X13 It can be hydrogen, deuterium, methyl, -CD3, ethyl, propyl, isopropyl, or cyclopropyl.

[0117] [7]. The compound described in any one of [1] to [6], wherein X1 is -CH2-, -CD2-, -O-, -S-, -S(=O)-, -NH-, -N(CH3)- or -N(CD3)-.

[0118] In some embodiments, X1 is -CH2-. In some embodiments, X1 is -CD2-. In some embodiments, X1 is... In some implementations, X1 is In some embodiments, X1 is -O-. In some embodiments, X1 is -S-. In some embodiments, X1 is -S(=O)-. In some embodiments, X1 is -NH- or -N(CH3)-. In some embodiments, X1 is -O- or -N(CH3)-. In some embodiments, X1 is -O- or -N(CD3)-. In some embodiments, X1 is -N(CH3)-. In some embodiments, X1 is -N(CD3)-. In some embodiments, X1 is -S(=O)2-.

[0119] [8]. The compound of any one of [1] to [7], wherein n1 is 0, 1, 2 or 3. In some embodiments, n1 is 0, 1 or 2. In some embodiments, n1 is 0 or 1. In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, X1 is -O-, n1 is 0. In some embodiments, X1 is -O-, n1 is 1. In some embodiments, X1 is -O-, n1 is 2. In some embodiments, X1 is -O-, n1 is 3. In some embodiments, X1 is -NCH3-, n1 is 0. In some embodiments, X1 is -NCH3-, n1 is 1. In some embodiments, X1 is -NCH3-, n1 is 2. In some embodiments, X1 is -NCH3-, n1 is 3. In some embodiments, X1 is -CH2-, n1 is 0. In some embodiments, X1 is -CH2- and n1 is 1. In some embodiments, X1 is -CH2- and n1 is 2. In some embodiments, X1 is -CH2- and n1 is 3. In some embodiments, X1 is -CD2- and n1 is 0. In some embodiments, X1 is -CD2- and n1 is 1. In some embodiments, X1 is -CD2- and n1 is 2. In some embodiments, X1 is -CD2- and n1 is 3. In some embodiments, X1 is... n1 is 0. In some implementations, X1 is... n1 is 1. In some implementations, X1 is... n1 is 2. In some implementations, X1 is... n1 is 3. In some implementations, X1 is... n1 is 0. In some implementations, X1 is... n1 is 1. In some implementations, X1 is... n1 is 2. In some implementations, X1 is... n1 is 3. In some embodiments, X1 is -NCD3- and n1 is 0. In some embodiments, X1 is -NCD3- and n1 is 1. In some embodiments, X1 is -NCD3- and n1 is 2. In some embodiments, X1 is -NCD3- and n1 is 3.

[0120] [9]. The compound of any one of [1] to [8], wherein m2 is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m2 is 0, 1, 2, 3, 4, or 5. In some embodiments, m2 is 0, 1, 2, 3, or 4. In some embodiments, m2 is 0, 1, 2, or 3. In some embodiments, m2 is 0, 1, or 2. In some embodiments, m2 is 0 or 1. In some embodiments, m2 is 0. In some embodiments, m2 is 1. In some embodiments, m2 is 2. In some embodiments, m2 is 3. In some embodiments, m2 is 4. In some embodiments, m2 is 5. In some embodiments, m2 is 6.

[0121]

[10] . The compound of any one of [1] to [9], wherein the compound is any one of the following formula:

[0122]

[0123]

[0124]

[11] . The compound described in any one of [1] to

[10] , wherein R S2 Is it deuterium, halogen, or -C? 1-6 Alkyl; wherein the -C 1-6 The alkyl group is independently unsubstituted or surrounded by one, two, or three C atoms selected from deuterium, halogen, or halogenated C atoms. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Substituents of alkyl groups;

[0125] Optionally, two adjacent R S2 Together with the atoms they are attached to, they form 3-6 membered carbon rings, 3-6 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings, wherein each ring is independently unsubstituted or substituted by 1, 2, or 3 carbon atoms selected from deuterium, halogens, or halogenated carbon atoms. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Alkyl groups are substituted.

[0126]

[12] . The compound of any one of [1] to

[11] , wherein R S2 It is deuterium, -F, -CH3, or -CD3. In some embodiments, R S2It is -CH3. In some implementations, R S2 It is deuterium.

[0127]

[13] . The compound of any one of [1] to

[12] , wherein m1 is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m1 is 0, 1, 2, 3, or 4. In some embodiments, m1 is 0, 1, 2, or 3. In some embodiments, m1 is 0, 1, or 2. In some embodiments, m1 is 0 or 1. In some embodiments, m1 is 0. In some embodiments, m1 is 1. In some embodiments, m1 is 2. In some embodiments, m1 is 3. In some embodiments, m1 is 4. In some embodiments, m1 is 5. In some embodiments, m1 is 6.

[0128]

[14] . The compound described in any one of [1] to

[13] , wherein:

[0129] Ring A is a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered heterocycle containing only an N atom attached to the pyrimidine ring, or a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered heterocycle containing one or more additional heteroatoms selected from O, S, S=O, or S(=O)2, other than the N atom attached to the pyrimidine ring. In some embodiments, ring A is a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered heterocycle containing only an N atom attached to the pyrimidine ring, or a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered heterocycle containing one additional heteroatom selected from O, S, S=O, or S(=O)2, other than the N atom attached to the pyrimidine ring. In some embodiments, ring A is a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) member monocyclic heterocycle containing only N atoms attached to a pyrimidine ring; a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) member bicyclic heterocycle containing only N atoms attached to a pyrimidine ring; a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) member bridged heterocycle containing only N atoms attached to a pyrimidine ring; or a ring containing only N atoms attached to a pyrimidine ring. 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) fused heterocycles containing only an N atom bonded to a pyrimidine ring; 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) spirocyclic heterocycles containing only an N atom bonded to a pyrimidine ring; 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) monocyclic heterocycles containing an additional heteroatom selected from O, S, S=O, or S(=O)2 besides the N atom bonded to the pyrimidine ring; 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) monocyclic heterocycles containing only an N atom bonded to a pyrimidine ring. A 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) bridging heterocycle, other than the N atom connected to the pyrimidine ring, consisting of an additional 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) bridging heterocycle, other than the N atom connected to the pyrimidine ring. The fused heterocycles of 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) members selected from O, S, S=O, or S(=O)2 heteroatoms, and the spiroheterocycle containing an additional 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) member selected from O, S, S=O, or S(=O)2 heteroatoms, other than the N atom connected to the pyrimidine ring; wherein each ring is fully saturated or has one or more (e.g., 1, 2, or 3) degrees of unsaturation.In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) monocyclic heterocycle containing only an N atom attached to a pyrimidine ring; a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) bicyclic heterocycle containing only an N atom attached to a pyrimidine ring; a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) bridged heterocycle containing only an N atom attached to a pyrimidine ring; a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) fused heterocycle containing only an N atom attached to a pyrimidine ring; a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) spirocyclic heterocycle containing only an N atom attached to a pyrimidine ring; or a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) heterocycle containing an additional O heteroatom selected from O, in addition to the N atom attached to the pyrimidine ring. 5-10 (e.g., 5, 6, 7, 8, 9, or 10)-membered monocyclic heterocycles, including an additional 5-10 (e.g., 5, 6, 7, 8, 9, or 10)-membered bicyclic heterocycles containing an additional 5-10 (e.g., 5, 6, 7, 8, 9, or 10)-membered bridged heterocycles containing an additional 5-10 (e.g., 5, 6, 7, 8, 9, or 10)-membered fused heterocycles containing an additional 5-10 (e.g., 5, 6, 7, 8, 9, or 10)-membered spirocyclic ... In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10)-membered monocyclic heterocycle containing only an N atom attached to a pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10)-membered bicyclic heterocycle containing only an N atom attached to a pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10)-membered bridged heterocycle containing only an N atom attached to a pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10)-membered fused heterocycle containing only an N atom attached to a pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) spirocyclic heterocycle containing only an N atom attached to a pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) bridged heterocycle containing only an N atom attached to a pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) monocyclic heterocycle containing an additional O heteroatom selected from O, in addition to the N atom attached to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation.In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) bicyclic heterocycle containing an additional O heteroatom selected from those of the N atom attached to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) bridged heterocycle containing an additional O heteroatom selected from those of the N atom attached to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) fused heterocycle containing an additional O heteroatom selected from those of the N atom attached to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5-10 (e.g., 5, 6, 7, 8, 9, or 10) spiroheterocycle selected from O heteroatoms, in addition to an N atom connected to the pyrimidine ring, wherein the ring is fully saturated or has a degree of unsaturation.

[0130]

[15] . The compound described in any one of [1] to

[14] , wherein:

[0131] Ring A is:

[0132]

[0133]

[0134] Each ring A is optionally and independently unsubstituted or surrounded by m1 R. S1 What it replaced.

[0135]

[16] . The compound described in any one of [1] to

[15] , wherein:

[0136] R S1 It is deuterium, halogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl or 3-6 membered cycloalkyl; wherein the -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 The alkynyl or 3-6 membered cycloalkyl group is independently unsubstituted or surrounded by 1, 2, or 3 C groups selected from deuterium, halogen, or halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C)1-6 Alkyl group 2, -OH or -OC 1-6 Substituents of alkyl groups;

[0137] Either way, two R S1 Together with the carbon atoms that are all bonded to them, they form Or 3-6 member carbon rings; wherein, the aforementioned The 3-6 membered carbon rings are independently unsubstituted or replaced by 1, 2, or 3 carbon rings selected from deuterium, halogens, or halogenated carbons. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Substituents of alkyl groups;

[0138] Optionally, two adjacent R S1 Together with their respective adjacent atoms, they form 3-6 membered carbon rings; wherein the 3-6 membered carbon rings are independently unsubstituted or substituted by 1, 2, or 3 carbon rings selected from deuterium, halogens, or halogenated carbons. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Alkyl groups are substituted.

[0139] In some implementations, R S1 It is -F, -OH, -OCH3, -CN, -CH2F, -CF3, -CH2OCH3, -CH2CN, -CHF2, -CD3, -NH2, or -CH3; or two Rs. S1 Together with the carbon atoms that are all adjacent to them, they form Or cyclopropane; or two adjacent R S1 Together with their respective adjacent atoms, they form cyclopropane.

[0140] In some implementations, R S1 Is -F, -CH3, -OH, -OCH3, -CHF2, -CH2OCH3, -Cl, -CH2CH3, -D, -CN、 -CH2F, -CH2CN, Or -CH2OH; or two R S1 Together with the carbon atoms that are all adjacent to them, they form Cyclopropane, Or two adjacent R S1Together with their respective adjacent atoms, they form

[0141] In some implementations... yes:

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148] In some implementations... yes:

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] In some implementations... yes:

[0155] R S12a It is deuterium, halogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl or 3-6 membered cycloalkyl; wherein the -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 The alkynyl or 3-6 membered cycloalkyl group is independently unsubstituted or surrounded by 1, 2, or 3 C groups selected from deuterium, halogen, or halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C)1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 The alkyl group is substituted. In some embodiments, R S1a It is -F, -OH, -OCH3, -CN, -CH2F, -CF3, -CH2OCH3, -CH2CN, -CHF2, -CD3, -NH2, or -CH3.

[0156] R S12b It is deuterium, halogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl or 3-6 membered cycloalkyl; wherein the -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 The alkynyl or 3-6 membered cycloalkyl group is independently unsubstituted or surrounded by 1, 2, or 3 C groups selected from deuterium, halogen, or halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 The alkyl group is substituted. In some embodiments, R S12b It is -F, -OH, -OCH3, -CN, -CH2F, -CF3, -CH2OCH3, -CH2CN, -CHF2, -CD3, -NH2, or -CH3.

[0157] In some implementations, R S12a It is -NH(C 1-6 alkyl), or -N(C) 1-6 Alkyl)2; R S12b It is halogen, -C 1-6 Alkyl, -CN, or 3-6 membered cycloalkyl;

[0158] In some implementations, R S12a It is -NH (methyl) or -N (methyl)2; R S12b It is -F, -Cl, methyl, -CN, or a 3-membered cycloalkyl group.

[0159] In some implementations... yes:

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] In some implementations... yes:

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179] In some implementations... yes:

[0180]

[0181]

[0182] In some implementations... yes:

[0183]

[0184] In some implementations... yes:

[0185]

[0186]

[0187] In some implementations... yes:

[0188]

[0189]

[17] . The compound described in any one of [1] to

[16] , wherein the compound is any one of the formulas in Table A:

[0190] Table A

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[18] . The compound described in any one of [1] to

[17] , wherein the compound is any one of the formulas in Table B:

[0203] Table B

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[19] . The compound of any one of [1] to

[18] , wherein Y1 is O.

[0220]

[20] . The compound described in any one of [1] to

[19] , wherein R 38 and R 39 Each of them is either hydrogen or deuterium.

[0221]

[21] . The compound of any one of [1] to

[20] , wherein n5 is 1.

[0222]

[22] . The compound described in any one of [1] to

[21] , wherein,

[0223] Ring I is a 4-6 membered cycloalkyl ring.

[0224]

[23] . The compound described in any one of [1] to

[22] , wherein:

[0225] Ring J is a 4-6 membered heterocycle containing one or two heteroatoms selected from N, O or S.

[0226]

[24] . The compound described in any one of [1] to

[23] , wherein:

[0227] yes

[0228] Among them, R S381 Is it hydrogen or R? S38 ;

[0229] m81 It is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0230]

[25] . The compound described in any one of [1] to

[24] , wherein:

[0231] R S381 It is hydrogen, deuterium, -C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the -C 1-6 Alkyl or 3-6 membered cycloalkyl groups are independently unsubstituted or surrounded by 1, 2, or 3 C groups selected from deuterium, halogen, or halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Alkyl substituents.

[0232]

[26] . The compound described in any one of [1] to

[25] , wherein R S381 It is hydrogen, deuterium, -CH3, -CH2CH3 or cyclopropyl.

[0233]

[27] . The compound described in any one of [1] to

[26] , wherein m 81 It is 0.

[0234]

[28] . The compound described in any one of [1] to

[27] , wherein:

[0235] m9 can be 0, 1, or 2.

[0236]

[29] . The compound described in any one of [1] to

[28] , wherein:

[0237] m9 is 0.

[0238]

[30] . The compound described in any one of [1] to

[29] , wherein:

[0239] m9 is 1.

[0240]

[31] . The compound described in any one of [1] to

[30] , wherein:

[0241] yes

[0242]

[0243] Among them, R S394 Is it hydrogen or R? S391 .

[0244]

[32] . The compound described in any one of [1] to

[31] , wherein:

[0245] R S39 It is halogen;

[0246] Preferably, R S39 Yes -F.

[0247]

[33] . The compound described in any one of [1] to

[32] , wherein:

[0248] R S391 It is hydrogen, deuterium, halogen, or -C 1-6 Alkyl; wherein the -C 1-6 The alkyl group is independently unsubstituted or surrounded by 1, 2, or 3 C atoms selected from deuterium, halogen, or halogenated C atoms. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Alkyl substituents;

[0249] Preferably, R S391 It can be hydrogen, deuterium, -F, or -CH3.

[0250]

[34] . The compound described in any one of [1] to

[33] , wherein:

[0251] yes

[0252]

[0253]

[35] . The compound described in any one of [1] to

[34] , wherein:

[0254] yes

[0255]

[0256]

[0257]

[36] . The compound described in any one of [1] to

[21] , wherein:

[0258] Ring B is a 4-6 membered heterocycle containing the fused N atom.

[0259]

[37] . The compound described in any one of [1] to

[21] and

[36] , wherein:

[0260] The ring C is a 4-6 membered heterocycle containing the fused N atom.

[0261]

[38] . The compound described in any one of [1] to

[21] and

[36] to

[37] , wherein:

[0262] yes

[0263]

[39] . The compound of any one of [1] to

[21] and

[36] to

[38] , wherein m3 is 0, 1, 2, 3, or 4.

[0264]

[40] . The compound described in any one of [1] to

[21] and

[31] to

[39] , wherein R S31 It is either deuterium or -F;

[0265] Either way, two R S31 Together with the carbon atoms that are all bonded to them, they form Or cyclopropyl; wherein, the Or the cyclopropyl group is independently unsubstituted or replaced by 1, 2 or 3 R groups. S311 Replace; or

[0266] Optionally, two adjacent R S31 Together with the carbon atoms respectively attached to them, they form 5-10 membered heterocycles, benzene rings, or 5-10 membered heteroaromatic rings containing one or two heteroatoms selected from N or O, wherein each ring is independently unsubstituted or surrounded by one, two, or three R atoms. S312 replace.

[0267]

[41] . The compound of any one of [1] to

[21] and

[36] to

[40] , wherein:

[0268] Selected from

[0269] in,

[0270] Ring G is a 5-6 membered heterocycle containing one or two heteroatoms selected from N or O, a benzene ring, or a 5-6 membered heteroaromatic ring containing one, two, or three heteroatoms selected from N, O, or S.

[0271] Ring H is a 5-10 membered heterocycle containing one or two heteroatoms selected from N or O, a benzene ring, or a 5-10 membered heteroaromatic ring containing one or two heteroatoms selected from N, O, or S.

[0272] R S36 Definition and R S31 same;

[0273] R S314 Is it hydrogen or R? S311 ;

[0274] m 31 It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0275] m 32 It is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0276] m 33 It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0277] m 34 It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0278] m5 is 0, 1, 2, 3, 4, 5, or 6;

[0279] m6 can be 0, 1, 2, 3, 4, 5, or 6.

[0280]

[42] . The compound of any one of [1] to

[21] and

[36] to

[41] , wherein:

[0281] yes

[0282]

[0283] in,

[0284] m 31 It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0285] m 32 It is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0286] m 33 It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0287] m 34 It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0288] m5 is 0, 1, 2, 3, 4, 5, or 6;

[0289] m6 can be 0, 1, 2, 3, 4, 5, or 6.

[0290]

[43] . The compound of any one of [1] to

[21] and

[36] to

[42] , wherein:

[0291] R S311 Independently, it is deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NH(C) 1-6 alkyl) or -N(C) 1-6 alkyl)2; wherein, the -C 1-6 The alkyl group is independently unsubstituted or surrounded by one, two, or three C atoms selected from deuterium, halogen, or halogenated C atoms. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Alkyl substituents;

[0292] R S312 Independently, it is deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NH(C) 1-6 alkyl) or -N(C) 1-6 alkyl)2; wherein, the -C 1-6 The alkyl group is independently unsubstituted or surrounded by one, two, or three C atoms selected from deuterium, halogen, or halogenated C atoms. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Alkyl substituents;

[0293] R S314 Independently, it is hydrogen, deuterium, halogen, -C 1-6 Alkyl group, wherein the -C 1-6 The alkyl group is independently unsubstituted or surrounded by one, two, or three C atoms selected from deuterium, halogen, or halogenated C atoms. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6 Alkyl substituents.

[0294]

[44] . The compound of any one of [1] to

[21] and

[36] to

[43] , wherein:

[0295] R S311 It can be independently deuterium, -F, or -OCH3;

[0296] R S312 It can be independently deuterium, -F, -OCH3, or -CH2OCH3;

[0297] R S314 Independently, it is hydrogen, deuterium, -F, -CH3, -CH2OCH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CH2CH(CH3)2.

[0298]

[45] . The compound of any one of [1] to

[21] and

[36] to

[44] , wherein:

[0299] R S36 It is either deuterium or -F.

[0300]

[46] . The compound of any one of [1] to

[21] and

[36] to

[45] , wherein:

[0301] m 31 It is 0 or 1;

[0302] m 32 It is 0 or 1;

[0303] m 33 It is 0 or 1;

[0304] m 34 It is 0 or 1;

[0305] m5 is 0 or 1;

[0306] m6 is 0 or 1.

[0307]

[47] . The compounds described in [1] to

[21] and

[36] to

[46] , wherein:

[0308] yes

[0309]

[0310]

[48] . The compound of any one of [1] to

[21] and

[36] to

[47] , wherein:

[0311] yes

[0312]

[0313]

[49] . The compound described in any one of [1] to

[21] , wherein R 310 and R 311 Each of them is either hydrogen or deuterium.

[0314]

[50] . The compound of any one of [1] to

[21] or

[49] , wherein n6 is 1 or 2.

[0315]

[51] . The compound of any one of [1] to

[21] ,

[49] or

[50] , wherein:

[0316] Ring K is a 4- to 10-membered heterocycle containing one or two heteroatoms selected from N or O.

[0317]

[52] . The compound described in any one of [1] to

[21] ,

[49] to

[51] , wherein:

[0318] yes

[0319] Wherein, ring L is a 4-6 membered heterocycle, optionally further comprising one or two heteroatoms selected from N or O.

[0320]

[53] . The compound described in any one of [1] to

[21] ,

[49] to

[52] , wherein:

[0321] yes

[0322]

[54] . The compound described in any one of [1] to

[21] ,

[49] to

[53] , wherein:

[0323] R S315 Independently, it is deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NH(C) 1-6 alkyl) or -N(C) 1-6 alkyl)2; wherein, the -C 1-6 The alkyl group is independently unsubstituted or surrounded by one, two, or three C atoms selected from deuterium, halogen, or halogenated C atoms. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH or -OC 1-6Alkyl substituents.

[0324]

[55] . The compound described in any one of [1] to

[21] ,

[49] to

[54] , wherein R S315 Independently, it is either -F or -CH3.

[0325]

[56] . The compound described in any one of [1] to

[21] ,

[49] to

[55] , wherein m 10 It is 0, 1, 2, or 3.

[0326]

[57] . The compound described in any one of [1] to

[21] ,

[49] to

[56] , wherein:

[0327] yes

[0328]

[58] . The compound described in any one of [1] to

[21] ,

[49] to

[57] , wherein:

[0329] yes

[0330]

[0331]

[59] . The compound described in any one of [1] to

[21] , wherein, yes:

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339] In some implementations... yes:

[0340]

[0341] In some implementations... yes:

[0342]

[0343]

[0344] In some implementations... yes:

[0345]

[0346]

[0347]

[60] . The compound of any one of [1] to

[59] , wherein R4 is phenyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, indazole, benzothiophene, or benzothiazolyl, wherein the phenyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, indazole, benzothiophene, or benzothiazolyl is not substituted or is occupied by 1, 2, 3, 4, 5, or 6 Rs. S4 replace.

[0348]

[61] . The compound described in any one of [1] to

[60] , wherein R4 is

[0349] m7 is 0, 1, 2, or 3;

[0350] R S4a It is -OH or -NH2;

[0351] R S4b It is hydrogen, deuterium, or halogen;

[0352] R S4c It is hydrogen, deuterium, -C 1-3 Alkyl, -C 2-3 alkenyl or -C 2-3 alkynyl group;

[0353] R S4d It is hydrogen, deuterium, or halogen;

[0354] R S4e It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0355] R S4f It is -OH or -NH2;

[0356] R S4g It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0357] R S4h It is hydrogen, deuterium, halogen, -C 1-3Alkyl or halogenated C 1-3 alkyl;

[0358] R S4i It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0359] R S4j It is hydrogen, deuterium, halogen, -CN, -C 1-3 Alkyl, Halogenated C 1-3 Alkyl or -O halogenated C 1-3 alkyl;

[0360] R S4k It is hydrogen, deuterium, halogen, -CN, -C 1-3 Alkyl, Halogenated C 1-3 Alkyl or -O halogenated C 1-3 alkyl;

[0361] R S4l It is hydrogen, deuterium, halogen, -CN, -C 1-3 Alkyl, Halogenated C 1-3 Alkyl or -O halogenated C 1-3 alkyl;

[0362] R S4m It is hydrogen, deuterium, halogen, -CN, -C 1-3 Alkyl, Halogenated C 1-3 Alkyl or -O halogenated C 1-3 alkyl;

[0363] R S4n It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0364] R S4o It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0365] R S4p It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0366] The compounds described in

[62] .

[61] , wherein:

[0367] m7 is 0;

[0368] R S4a It is -OH or -NH2;

[0369] R S4b It is -F;

[0370] RS4c It is ethyl, vinyl, or ethynyl;

[0371] R S4d It is hydrogen, or -F;

[0372] R S4e It is -F;

[0373] R S4f It is -NH2;

[0374] R S4g It is hydrogen, -F, or methyl;

[0375] R S4h It is hydrogen, -F, or methyl;

[0376] R S4i It is -I or -CF3;

[0377] R S4j It is -CN;

[0378] R S4k It is hydrogen;

[0379] R S4l It is methyl;

[0380] R S4m It is -CF3, -OCF2Cl, -OCF3, or -CF2H;

[0381] R S4n It is hydrogen, -F, or methyl;

[0382] R S4o It is hydrogen, -F, or methyl;

[0383] R S4p It is hydrogen, -F, or methyl.

[0384]

[63] . The compound described in any one of [1] to

[62] , wherein:

[0385] R4 is

[0386]

[0387]

[0388] In some implementations, R4 is

[0389] In some implementations, R4 is

[0390]

[0391] In some implementations, R4 is:

[0392]

[0393]

[64] . The compound described in any one of [1] to

[63] , wherein R5 is a halogen.

[0394]

[65] . The compound described in any one of [1] to

[64] , wherein R5 is -F. In some embodiments, the compound is:

[0395]

[0396] in, yes:

[0397]

[0398]

[0399] In some embodiments, the compound is:

[0400]

[0401] in, yes:

[0402]

[0403] In some embodiments, the compound is:

[0404]

[0405] in, yes:

[0406]

[0407] R4 is:

[0408]

[0409] yes:

[0410]

[0411] In some embodiments, the compound is any of the following formula:

[0412]

[0413] R5 is -F, -Cl, -CH3, or -OCH3;

[0414] R S1 It is -H, -CH3, or -CD3;

[0415] -Y1-R3 is:

[0416]

[0417]

[0418]

[0419] R4 is:

[0420]

[0421]

[0422] In some embodiments, the compound is any of the following formula:

[0423]

[0424] -Y1-R3 is:

[0425]

[0426] R S1 yes R4 is:

[0427]

[0428] In some embodiments, the compound is any of the following formula:

[0429]

[0430] in:

[0431] R4 is:

[0432]

[0433] -Y1-R3 is:

[0434]

[0435] R7 is:

[0436]

[0437] R8 is:

[0438]

[0439] In some embodiments, the compound is any of the following formula:

[0440]

[0441] in:

[0442] R5 is -F, -Cl, -CH3, or -OCH3;

[0443] R S1 It is -H, Or -CD3;

[0444] -Y1-R3 is:

[0445]

[0446]

[0447] R4 is:

[0448]

[0449]

[0450] In some embodiments, the compound is any of the following formula:

[0451]

[0452] in:

[0453] -Y1-R3 is:

[0454]

[0455] R S1 yes

[0456] R4 is:

[0457]

[0458] In some embodiments, the compound is any of the following formula:

[0459]

[0460] R5 is -F, -Cl, or -CH3;

[0461] R S1 yes

[0462] R1 is -Y1-R3 is:

[0463]

[0464] R4 is:

[0465]

[0466] In some embodiments, the compound is any of the following formula:

[0467]

[0468] R4 is:

[0469]

[0470] -Y1-R3 is:

[0471]

[0472] R S1 yes:

[0473]

[0474] R1 is:

[0475]

[0476] In some embodiments, the compound is any of the following formula:

[0477]

[0478] in:

[0479] R5 is:

[0480]

[0481] R S1 yes:

[0482]

[0483] R1 is:

[0484]

[0485] -Y1-R3 is:

[0486]

[0487] R4 is:

[0488]

[0489] In some embodiments, the compound is any of the following formula:

[0490]

[0491] R5 is:

[0492]

[0493] R X13 yes:

[0494]

[0495] R S2 yes:

[0496]

[0497] R S1 yes:

[0498]

[0499] -Y1-R3 is:

[0500]

[0501]

[0502]

[0503] R4 is:

[0504]

[0505]

[0506] In some embodiments, the compound is any of the following formula:

[0507]

[0508] -Y1-R3 is:

[0509]

[0510] R4 is:

[0511]

[0512] R7 is:

[0513]

[0514] R8 is:

[0515]

[0516] In some embodiments, the compound is any of the following formula:

[0517]

[0518] R5 is:

[0519]

[0520] R S1 yes:

[0521]

[0522] R1 is:

[0523]

[0524] -Y1-R3 is:

[0525]

[0526] R4 is:

[0527]

[0528] In some embodiments, the compound is any of the following formula:

[0529]

[0530] in,

[0531] R5 is -F, -Cl, -CH3, or -OCH3;

[0532] R X13 It is -CH3 or -CD3;

[0533] R S2 It is -H, -CH3, or -CD3;

[0534] R S1 It is -H, -CH3, or -CD3;

[0535] -Y1-R3 is:

[0536]

[0537]

[0538]

[0539] R4 is:

[0540]

[0541]

[0542] In some embodiments, the compound is:

[0543]

[0544] in, yes:

[0545]

[0546]

[0547] In some embodiments, the compound is:

[0548]

[0549] in, yes:

[0550]

[0551] In some embodiments, the compound is:

[0552]

[0553] in, yes:

[0554]

[0555] R4 is:

[0556]

[0557] yes:

[0558]

[0559] In some embodiments, the compound is:

[0560]

[0561] in, yes:

[0562]

[0563]

[0564] In some embodiments, the compound is:

[0565]

[0566] in, yes:

[0567]

[0568] In some embodiments, the compound is:

[0569]

[0570] in, yes:

[0571]

[0572] R4 is:

[0573]

[0574] yes:

[0575]

[0576] In some embodiments, the compound is:

[0577]

[0578] in, yes:

[0579]

[0580] R4 is:

[0581]

[0582] yes:

[0583]

[0584] In some embodiments, the compound is:

[0585]

[0586] in,

[0587] yes:

[0588] And R4 is:

[0589] In some embodiments, the compound is:

[0590]

[0591] in,

[0592] R S1a yes:

[0593] R S1c yes:

[0594] yes:

[0595]

[0596]

[0597] and

[0598] R4 is:

[0599] In some embodiments, the compound is:

[0600]

[0601] in,

[0602] R S1b yes:

[0603] yes:

[0604]

[0605] and

[0606] R4 is:

[0607] In some embodiments, the compound is:

[0608]

[0609] in,

[0610] R S1a yes:

[0611] R S1c yes:

[0612] yes:

[0613]

[0614] and

[0615] R4 is:

[0616] In some embodiments, the compound is:

[0617]

[0618] in,

[0619] yes:

[0620] And R4 is: In some embodiments, the compound is:

[0621]

[0622] in,

[0623] yes:

[0624]

[0625]

[0626] and

[0627] R4 is:

[0628] In some embodiments, the compound is:

[0629]

[0630] in,

[0631] yes:

[0632]

[0633]

[0634] yes:

[0635]

[0636]

[0637] and

[0638] R4 is:

[0639] In some embodiments, the compound is:

[0640]

[0641] in,

[0642] yes:

[0643]

[0644] and

[0645] R4 is:

[0646] In some embodiments, the compound is:

[0647]

[0648] in,

[0649] yes: And R4 is: In some embodiments, the compound is:

[0650]

[0651] in,

[0652] yes:

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660] and

[0661] R4 is:

[0662] In some embodiments, the compound is:

[0663]

[0664] in,

[0665] yes:

[0666]

[0667]

[0668]

[0669]

[0670] and

[0671] R4 is:

[0672] In some embodiments, the compound is:

[0673]

[0674] in,

[0675] R1 is:

[0676] yes: and

[0677] R4 is:

[0678] In some embodiments, the compound is:

[0679]

[0680] in,

[0681] yes:

[0682]

[0683] yes:

[0684]

[0685] and

[0686] R4 is:

[0687] In some embodiments, the compound is:

[0688]

[0689] in,

[0690] yes:

[0691]

[0692] yes: and

[0693] R4 is:

[0694] In some embodiments, the compound is:

[0695]

[0696] in,

[0697] R1 is:

[0698] yes:

[0699] And R4 is: In some embodiments, the compound is:

[0700]

[0701] in,

[0702] yes:

[0703]

[66] . The compound described in any one of [1] to

[65] , wherein the compound is any one of the compounds in Table C:

[0704] Table C

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[67] . A pharmaceutical composition comprising a therapeutically effective amount of any one of [1] to

[66] of a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof, and a pharmaceutically acceptable excipient.

[0726]

[68] . A method of treating a subject with cancer, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) as described in any one of [1] to

[66] , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof, or a pharmaceutical composition as described in

[67] .

[0727]

[69] . A method for treating cancer in a subject in need, the method comprising:

[0728] (a) Determine whether the cancer is associated with K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutations and / or K-Ras wild-type amplification; and

[0729] (b) If relevant, administer to a subject in need a therapeutically effective amount of any of the compounds of formula (I) of any one of [1] to

[66] , its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of said stereoisomers, its prodrugs, its deuterated molecules or their PROTAC molecules, or the pharmaceutical composition described in

[67] .

[0730]

[70] . A compound of formula (I) as described in any one of [1] to

[66] for treatment, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof, or a pharmaceutical composition described in

[67] .

[0731]

[71] . A compound of formula (I) as described in any of [1] to

[66] for pharmaceutical use, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof, or a pharmaceutical composition as described in

[67] .

[0732]

[72] . A compound of formula (I) of any one of [1] to

[66] , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof, or a pharmaceutical composition thereof as described in

[67] .

[0733]

[73] . The use of any compound of formula (I) in any one of [1] to

[66] , its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of said stereoisomer, its prodrug, its deuterated molecule or its PROTAC molecule, or the pharmaceutical composition described in

[67] in the treatment of cancer.

[0734] Use of any compound of formula (I) in any of

[74] .[1] to

[66] , its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of said stereoisomer, its prodrug, its deuterated molecule or its PROTAC molecule, or the pharmaceutical composition described in

[67] in the preparation of a medicament for treating cancer.

[0735]

[75] .

[68] The method of treating cancer described,

[72] The use in the method of treating cancer described,

[73] The use in treating cancer described, or

[74] The use in the preparation of a medicine for treating cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer (such as non-small cell lung cancer), breast cancer, colorectal cancer, gastric cancer, endometrial cancer, esophageal cancer or gastroesophageal junction cancer.

[0736]

[76] The method of treating cancer described in

[68] or

[75] , the use in the method of treating cancer described in

[72] or

[75] , the use in treating cancer described in

[73] or

[75] , or the use in the preparation of a medicament for treating cancer described in

[74] or

[75] , wherein the cancer is associated with at least one of the following: K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and / or K-Ras wild-type amplification.

[0737] This invention provides the following:

[0738] [B-1]. Compounds of formula (I):

[0739]

[0740] Its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of said stereoisomer, its prodrug, its deuterated molecule or its PROTAC molecule, wherein;

[0741] R3 is -C 1-6 Alkylene, optionally with one or more deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, halogenated C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 2-6 alkynyl group, -N(R) A )2、-OR A -SR A -S(=O)R B -S(=O)2R B -C(=O)R B -C(=O)OR B -C(=O)N(R) B )2、-S(=O)OR B -S(=O)N(R) B )2、-S(=O)2OR B -S(=O)2N(R) B )2、-P(=O)(R B 2. 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloynyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkynyl, 3-10 cycloalkyl, 3-10 cycloalkenyl, 3-10 cycloalkynyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are independently unsubstituted or substituted by one or more elements selected from deuterium, halogen, -C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkyne, -CN, -NO2, -N3, oxo, -N(R) C )2、-OR C -SR C -S(=O)R D -S(=O)2R D -C(=O)R D -C(=O)OR C -OC(=O)R D -C(=O)N(R) C )2、-NR C C(=O)RD -OC(=O)OR C -NR C C(=O)OR D -OC(=O)N(R) C )2、-NR C C(=O)N(R C )2、-S(=O)OR C -OS(=O)R D -S(=O)N(R) C )2、-NR C S(=O)R D -S(=O)2OR C -OS(=O)2R D -S(=O)2N(R) C )2、-NR C S(=O)2R D -OS(=O)2OR C -NR C S(=O)2OR C -OS(=O)2NR C -NR C S(=O)2N(R C )2、-P(R C )2、-P(=O)(R D )2. Substitution with 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl groups;

[0742] Rings A and R S1 m1, R S2 ,m2,n1,X1,X2,R4,R5,Y1,R A R B R C R D It has the same definition as any of [1] to

[66] .

[0743] The compounds described in [B-2].[B-1], wherein R3 is a derivative of -N(R A )2 replaced by -C 1-6 Alkylene; R A Is it hydrogen or -C? 1-3 alkyl.

[0744] The compounds described in [B-3] and [B-2], wherein R3 is a -C substituted with -N(CH3)2. 1-6 Alkylene.

[0745] This invention provides the following:

[0746] [C-1]. An intermediate having the following structure:

[0747]

[0748] L1 is a leaving group;

[0749] L2 is a leaving group;

[0750] Rings A and R S1 m1, R S2 m2, n1, X1, X2, R5, Y1, R3 have the same definition as any of [1] to

[66] and [B-1] to [B-3].

[0751] The intermediate of [C-2].[C-1], wherein L1 is selected from -Cl, -Br, -S(=O)CH3, or -S(=O)2CH3.

[0752] The intermediate of [C-3], [C-1] or [C-2], wherein L2 is selected from -Cl or -Br.

[0753] [C-4]. An intermediate as described in any one of [C-1] to [C-3], wherein -Y1-R3 is

[0754] The intermediate described in any one of [C-5]. [C-1] to [C-4], wherein the intermediate is any one of the intermediates in Table D:

[0755] Table D

[0756]

[0757]

[0758] definition

[0759] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, patent applications, and publications referenced in this application are incorporated herein by reference.

[0760] Unless otherwise specified, the terms "halogen" or "halogenated" as used herein refer to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0761] Unless otherwise specified, the term "alkyl" as used in this application includes saturated monovalent hydrocarbon groups having a straight chain or branched chain. For example, -C 1-6Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl. Similarly, -C 1-3 C in alkyl 1-3 Defined as a group having 1, 2, or 3 carbon atoms arranged in a straight or branched chain.

[0762] Unless otherwise specified, the term "haloalkyl" (e.g., -C) as used in this application refers to... 1-6 Halogenated alkyl, -C 1-4 Halogenated alkyl, -C 1-3 Halogenated alkyl or halogenated C 1-6 Alkyl) means alkyl as defined in this application (e.g., -C) 1-6 Alkyl, -C 1-4 Alkyl or -C 1-3 One or more (e.g., one, two, or three) hydrogen atoms in an alkyl group have been replaced by halogens. Examples include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0763] The term "alkylene" refers to a bifunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. Examples include methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, or -CH2-CH(CH3)-).

[0764] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "-C 2-6 "Alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0765] The term "alkynyl" includes straight-chain or branched hydrocarbon groups containing one or more triple bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "-C 2-6 "Alynyl" is an alkynyl group containing 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octyynyl, etc.

[0766] The term "alkoxy" refers to an oxygen ether formed from the aforementioned alkyl group.

[0767] Unless otherwise specified, the term "aryl" as used herein refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing a carbon ring atom. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups.

[0768] Unless otherwise specified, the term "heterocyclic" or "heterocyclic group" as used herein refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms, including monocyclic heterocycles, bicyclic heterocycles, bridged heterocycles, fused heterocycles, or spirocyclic heterocycles. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is a three- to ten-membered ring and is fully saturated or has one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably mono, di, or trisubstituted. Examples of such heterocyclic groups include, but are not limited to, acridinel, pyrrolidinyl, piperidinyl, piperazinyl, oxoperazinyl, oxoperidinyl, oxoachexenyl, azatril, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiozatril, morpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

[0769] Unless otherwise specified, the term "heteroaryl" as used herein refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings may contain fused rings, spirocyclic rings, or bridged rings; for example, bicyclic heteroaryl groups are polycyclic heteroaryl groups. Bicyclic heteroaryl rings may contain 8 to 12 member atoms. Monocyclic heteroaryl rings may contain 5 to 8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroleyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinolinyl.

[0770] The term "carbocyclic" refers to a monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring system containing only carbon atoms, whether substituted or unsubstituted. Exemplary examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0771] Unless otherwise specified, the term "one or more" as used in this application refers to one or more. In some embodiments, "one or more" refers to 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" refers to 1, 2, 3, or 4. "One or more" refers to 1, 2, or 3. In some embodiments, "one or more" refers to 1 or 2. In some embodiments, "one or more" refers to 1. In some embodiments, "one or more" refers to 2. In some embodiments, "one or more" refers to 3. In some embodiments, "one or more" refers to 4. In some embodiments, "one or more" refers to 5. In some embodiments, "one or more" refers to 6.

[0772] Unless otherwise specified, the term "substitution" as used in this application refers to the substitution of a hydrogen atom on a carbon atom or a hydrogen atom on a nitrogen atom by a substituent. When one or more substituents are substituted on a ring in this invention, it means that each substituent can be substituted independently on each ring atom of the ring, including but not limited to the ring carbon atom or the ring nitrogen atom. In addition, when the ring is a polycyclic ring such as a fused ring, a bridged ring, or a spiro ring, each substituent can be substituted independently on each ring atom of the polycyclic ring.

[0773] The term "oxo" refers to the formation of oxygen atoms together with the bonded carbon atoms. Group.

[0774] The definition of any substituent or variable at a specific position in the molecule is intended to be independent of the definition of other positions in the molecule. It should be understood that the substituents and substitution patterns on the compounds of this invention can be selected by those skilled in the art to provide chemically stable compounds.

[0775] The term "composition" as used herein is intended to cover products containing a specified amount of a specified ingredient, and any product directly or indirectly produced from a combination of the specified amounts of the specified ingredients. Therefore, pharmaceutical compositions containing compounds of the present invention as active ingredients are part of this invention. Furthermore, some crystal forms of the compounds may exist as polymorphs and are therefore intended to be included in this invention. Additionally, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be covered within the scope of this invention.

[0776] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic alkalis, including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of the present invention are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example, at least 60% pure, more preferably at least 75% pure, and especially at least 98% pure (% based on weight).

[0777] The scope of this invention includes prodrugs of the compounds of this invention. Generally, such prodrugs will be functional derivatives that are readily converted in vivo into the desired compound. Therefore, in the treatment methods of this invention, the term "administration" should cover the treatment of the described conditions with a specifically disclosed compound or with a compound that may not be specifically disclosed but is converted in vivo into the specified compound after administration to a subject. Conventional steps for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," H. Bundgaard, Elsevier, 1985.

[0778] This invention includes all stereoisomers of the compound and their pharmaceutically acceptable salts. It also includes mixtures of stereoisomers and isolated specific stereoisomers. The products of such steps, whether in the synthetic steps used to prepare such compounds or in steps using racemic or epimerization methods known to those skilled in the art, may be mixtures of stereoisomers. As used herein, the term "stereoisomer" refers to isomers in which atoms or groups of atoms in a molecule are connected in the same order but have different spatial arrangements, including conformational isomers and configurational isomers. Configurational isomers include geometric isomers and optical isomers, with optical isomers primarily including enantiomers and diastereomers. This invention includes all possible stereoisomers of the compound (such as its transisomers). The absolute configuration of this invention can be confirmed by general techniques such as X-ray single-crystal diffraction or cocrystallization with KRAS mutant proteins, or by comparing the pharmacological activity of two isomers with the pharmacological activity of a pair of isomers whose absolute configuration has been determined.

[0779] This invention aims to include all atomic isotopes appearing in the compounds of this invention. Isotopes include atoms having the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as... 1 H (hydrogen) 2 H (deuterium) and 3H (tritium). They are also commonly represented as D (representing deuterium) and T (representing tritium). In this application, -CD3 indicates that all hydrogen atoms are methyl groups of deuterium. Carbon isotopes include 13 C and 14 C. Isotopes of oxygen include 16 O、 17 O, or 18 O. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents instead of unlabeled reagents.

[0780] Unless otherwise specified, the term "deuterated molecule" as used in this application refers to a compound having the same chemical structure as the reference compound, but in which one or more hydrogen atoms are replaced by deuterium atoms ("D"). It should be recognized that, depending on the source of the chemical materials used in the synthesis, some variation in the natural isotopic abundance may occur in the synthesized compound. Despite such variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described in this application. Therefore, unless otherwise specified, when referring to the "deuterated molecule" of the compounds disclosed herein, at least one hydrogen atom is substituted with deuterium at a level far exceeding its natural isotopic abundance (which is typically about 0.015%).

[0781] Unless otherwise specified, when the compounds of the present invention are tautomers, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof.

[0782] "PROTAC molecule" refers to a compound described in this application that is conjugated to another agent, either through a linker or without a linker, wherein the compound acts as a K-Ras protein (including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant protein and K-Ras wild-type protein), for example, the compound is integrated into a proteolytic targeting chimera (PROTACs).

[0783] Unless otherwise apparent from the context, when a value is expressed as “about” or “approximately” X, the value of X shall be understood to be accurate to ±10%, preferably ±5% or ±2%.

[0784] The term "subject" refers to an animal. In some embodiments, the animal is a mammal. "Subject" also refers to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a human. As used herein, "patient" refers to a human subject. As used herein, a subject "needs" treatment if they would derive a biological, medical, or quality-of-life benefit from such treatment. In some embodiments, the subject has experienced and / or exhibits at least one symptom of the cancer to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed with cancer having a K-Ras G12A, K-Ras G12C, K-Ras G12D, K-Ras G12R, K-Ras G12S, K-Ras G12V, K-Ras G13D K-Ras Q61H mutation and / or wild-type K-Ras amplification.

[0785] The terms “inhibition,” “inhibiting,” or “inhibit” refer to the reduction or suppression of a given condition, symptom, ailment, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0786] In one embodiment, the term "treat," "treating," or "treatment" for any disease or condition means improving the disease or condition (i.e., slowing down, stopping, or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" means reducing or improving at least one bodily parameter, including those that the patient may not be able to discern. In yet another embodiment, "treat," "treating," or "treatment" means physically (e.g., stabilizing identifiable symptoms), physiologically (e.g., stabilizing physical parameters), or physically modulating a disease or condition, or both. In still another embodiment, "treat," "treating," or "treatment" means preventing or delaying the onset, development, or progression of a disease or condition. Example

[0787] The following examples are provided to better illustrate the invention. Unless otherwise expressly stated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

[0788]

[0789]

[0790]

[0791] Preparation of intermediates

[0792] INT1: INT2: INT3: INT4:

[0793] INT5: INT6: INT7: INT8:

[0794] INT9: INT12: INT14:

[0795] Purchase or prepare the above intermediates using existing technology.

[0796] INT 10

[0797]

[0798] DIEA (11.82 g) was added to a DCM (100 ml) solution of INT11-6 (8.2 g), and trifluoromethanesulfonic anhydride (15.77 g) was added dropwise at 0 °C. The reaction mixture was stirred overnight at RT under N2, adjusted to pH 8 with NaHCO3 solution, and extracted with DCM. The organic layer was post-treated and purified to obtain INT10-1 (9.24 g).

[0799] A solution of INT10-1 (9.24 g), benzophenone imine (3.34 g), Cs₂CO₃ (14.87 g), Pd₂(dba)₃ (0.90 g), and Xantphos (1.7 g) in 1,4-dioxane (100 mL) was stirred overnight at 80 °C under N₂. The solution was extracted with EA. The separated organic layer was post-processed and purified to obtain INT10-2 (5.71 g).

[0800] A solution of INT10-2 (5.71 g), KOAc (2.67 g), pinacol diboronate (4.24 g), and Pd(dppf)Cl2 (0.66 g) in toluene (60 ml) was stirred overnight at 120 °C under N2. The separated organic layer was extracted with EA, and post-processed and purified to obtain INT10 (3.02 g).

[0801] INT 11

[0802]

[0803] INT 11 was prepared using a similar method to that used in WO2021041671 for synthesizing INT 2.

[0804] INT13

[0805]

[0806] INT13 was prepared using a similar method to that used to synthesize INT10.

[0807] INT 15

[0808]

[0809] Under N2, POCl3 (4 ml) was added to a solution of INT6 (4.03 g) and DIEA (8 ml) in toluene (25 ml). The resulting mixture was stirred at 80 °C for 2 hours and concentrated. The residue was diluted with DCM (40 ml), and DIEA (3 ml) and but-3-en-1-amine hydrochloride (1.65 g) were added. The reaction mixture was stirred at RT for 1 hour. It was diluted with DCM and water. The separated organic layer was concentrated and purified to give INT15-1 (4.61 g). MS: m / z 333 [M+H] + .

[0810] DIEA (9.07 g) was added to a solution of INT15-1 (4.61 g) and methylamine hydrochloride (2.86 g) in DMAc (40 mL). The mixture was purged with N2 and then stirred at 70 °C for 16 hours. The mixture was diluted with EA and water. The separated organic layer was concentrated and purified to give INT15-2 (3.60 g). MS: m / z 328 [M+H] + .

[0811] To a solution of benzaldehyde (1.00 g) in MeOH (20 mL), piperidine (2.34 g) and 1,1-dimethoxyprop-2-one (4.36 g) were added. The mixture was purged with N2, stirred overnight at rt, diluted with EA, and washed with water. The separated organic layer was concentrated and purified to give INT15-3 (1.0 g). MS: m / z 207 [M+H] + .

[0812] Add 0.30 g of TsOH●H2O to a DMSO (5 mL) solution of INT15-3 (0.31 g) and INT15-2 (0.38 g). Purge the mixture with N2, then stir overnight at 80 °C. Cool to RT, dilute with EA, and wash with water. Concentrate and purify the separated organic layer to obtain INT15-4 (0.48 g). MS: m / z 470 [M+H] + .

[0813] Grubbs Gen 2nd (0.42 g) was added to a solution of INT15-4 (1.12 g) in toluene (20 mL). The mixture was purged with N2, stirred at 80 °C for 2 hours, cooled to RT, and concentrated. The residue was purified to give INT15 (0.28 g). MS: m / z: 366 [M+H] + .

[0814] INT16

[0815]

[0816] INT16-a (70.59 g) and TEA (29.70 g) were cooled to -15 °C in THF (1000 mL) solution, and isobutyl chlorocarbonate (36.31 g) was added to the resulting mixture. The mixture was stirred at the same temperature for 2 hours and then filtered. The filtrate was cooled to 0 °C and added dropwise to a NaBH4 (16.71 g) aqueous solution (200 mL). The solution was stirred at 0 °C for 1 hour. The solution was quenched with water and extracted with EA. The organic layer was post-treated and purified to give INT16-1 (74.35 g, 110.5% yield). MS (ESI, m / z): 282 [M+H] + .

[0817] At 0°C and under N2, sodium hydride (60% in oil, 1.77 g) was added to a solution of 1.92 g of 3-chloro-2-(chloromethyl)prop-1-ene in 15 mL of DMF, and the resulting mixture was stirred at RT for 30 min. INT16-1 (3.82 g) in anhydrous THF (15 mL) was added to the reaction mixture, and the mixture was stirred at RT for 18 h, then diluted with EA and water. The separated organic layer was post-treated and purified to give INT16-2 (2308 mg). MS: m / z 334 [M+H] + .

[0818] NaIO4 (6.06 g) was added to a solution of INT16-2 (2308 mg) and K2OsO4●2H2O (0.13 g) in THF (25 ml) and water (12 ml). The mixture was stirred at RT for 18 hours and diluted with EA and water. The separated organic layer was post-processed and purified to obtain INT16-3 (2165 mg). MS: m / z 336 [M+H] + .

[0819] At -20°C and N2, NaBH4 (495 mg) was added to a solution of INT16-3 (2165 mg) in THF (15 mL), and the resulting mixture was stirred for 1 hour. The mixture was then diluted with EA and saturated NH4Cl. The separated organic layer was post-processed and purified to obtain INT 16-4 (2.02 g). MS: m / z 338 [M+1] + .

[0820] At -20°C and N2, BAST (495 mg) was added to a DCM (15 mL) solution of INT16-4 (2.02 g), and the resulting mixture was stirred at RT for 18 hours. The mixture was then diluted with DCM and saturated NaHCO3. The separated organic layer was concentrated and purified to give INT16 (0.98 g). MS: m / z: 340 [M+1] + .

[0821] INT 17

[0822]

[0823] At 0°C, NaBH4 (0.64 g) and CeCl3·7H2O (6.12 g) were added to a solution of INT15 (2.02 g) in MeOH (200 ml) and DCM (300 ml), and the mixture was stirred for 4 hours. The solution was quenched with H2O and extracted with EA. The organic layer was post-treated to obtain INT 17 (2.02 g, crude product). MS: m / z: 479 [M+1] + .

[0824] Example 1

[0825]

[0826] CP1-5 was prepared using a method similar to that in WO2023046135.

[0827] HCl (4 M, 5 mL of 1,4-dioxane) was added to a solution of CP1-5 (296 mg) in CH3CN (15 mL). The reaction mixture was stirred at RT for 1 hour and concentrated. The residue was dissolved in EA and washed with aq. NaHCO3 (sat.). The organic layer was dried and concentrated to give CP1-6 (316 mg). MS (ESI, m / z): 774 [M+H] + .

[0828] A solution of CP1-6 (292 mg) and pyridine (360 mg) in DCM (6 mL) was cooled to -20 °C, and trifluoromethanesulfonic anhydride (573 mg) was added dropwise, raising the mixture to RT. The reaction mixture was stirred at RT for 2 hours and concentrated. The residue was dissolved in EA and washed with water. The organic layer was dried, concentrated, and purified by Prep-TLC (DCM:MeOH = 30:1, v / v) to give CP1-7 (251 mg). MS (ESI, m / z): 906 [M+H] + .

[0829] A solution of CP1-7 (51 mg), benzophenone imine (24 mg), Pd2(dba)3 (12 mg), Xantphos (13 mg), and Cs2CO3 (55 mg) in toluene (3 mL) was stirred at 100 °C for 16 hours under N2 conditions and washed with EA and water. The organic layer was dried, concentrated, and purified by Prep-TLC (Hex:EA = 0:1, v / v) to give CP1-8 (49 mg). MS (ESI, m / z): 937 [M+H] + .

[0830] HCl (4 M, 0.3 mL of 1,4-dioxane) was added to a solution of CP1-8 (49 mg) in DCM (3 mL). The reaction mixture was stirred at RT for 16 hours and concentrated. The residue was dissolved in EA and washed with sat.aq. NaHCO3. The organic layer was dried and concentrated to give CP1-9 (53 mg). MS (ESI, m / z): 773 [M+H] + .

[0831] CsF (105 mg) was added to a DMF (3 mL) solution of CP1-9 (53 mg). The reaction mixture was stirred at 40 °C for 2 hours, and the filtrate was collected by filtration. The filtrate was concentrated and purified by Prep-HPLC (Ultimate XB-C18, Phase A: water containing 0.05% trifluoroacetic acid, Phase B: CH3CN, gradient: 10% B to 28% B for 25 min, flow rate 40 mL / min, 228 nm) to give compound 1 (CP1, confirmed). MS (ESI, m / z:): 617 [M+H] + .

[0832] Example 2

[0833]

[0834] Compound 2 (CP2, 38.5 mg, TFA salt, confirmed) was synthesized using a method similar to that of CP1 with 2-a. MS (ESI, m / z:): 624 [M+H] + .

[0835] Example 3

[0836]

[0837] Cs₂CO₃ (147 mg) and cataCXium APd G₃ (18 mg) were added to a solution of CP₂-1 (103 mg) and INT₁₃ (337 mg) in toluene (7.5 mL) and water (1.5 mL). The reaction mixture was stirred overnight at 100 °C under N₂, post-treated, and purified by Prep-TLC to obtain CP₃-1 (65 mg). MS: m / z: 943 [M+H] + .

[0838] Compound 3 (CP3, 19.5 mg, TFA salt, confirmed) was obtained using CP3-1 via a similar procedure to that used to prepare CP1. MS (ESI, m / z:): 623 [M+H] + .

[0839] Example 4

[0840]

[0841] Compound 4 (CP4, confirmed) was synthesized using a method similar to that used for CP9.

[0842] Example 5

[0843]

[0844] Compound 5 (CP5, confirmed) was synthesized using a method similar to CP3 with 5-a and CP1-3. It was purified and separated by Prep-HPLC (Ultimate XB-C18, 30 mm × 150 mm, 5 μm, A phase: water with 0.1% trifluoroacetic acid, B phase: CH3CN, gradient: 15% B to 35% B over 30 min, flow rate 40 mL / min, 250 nm) to obtain compounds 5A (CP5A, 2.9 mg, first peak, TFA salt) and 5B (CP5B, 3.6 mg, second peak, TFA salt). MS (ESI, m / z:): 629 [M+H] + .

[0845] Example 6

[0846]

[0847] Pd / C (75 mg, 10% content) was added to a solution of CP1 (30 mg) in MeOH (10 mL). The mixture was stirred at RT for 1.5 h under H2, filtered, the filtrate was concentrated, purified, and separated by Prep-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 μm, A: 0.1% TFA in water, B: CH3CN, gradient: 10% B to 29% B, over 31 min, flow rate 40 mL / min, 230 nm) to give compound 6A (CP6A, 4.7 mg, TFA salt, confirmed). LCMS: m / z: 621 [M+H] + And compound 6B (CP6B, 10 mg, TFA salt, confirmed). LCMS: m / z: 619 [M+H] + .

[0848] Example 7

[0849]

[0850] Compound 7 (CP7, 25.9 mg, TFA salt, confirmed) was synthesized using a method similar to that of CP1 with 7-a and CP1-3.

[0851] LCMS:m / z:611[M+H] + .

[0852] Example 8

[0853]

[0854] Compound 8 (CP8, confirmed) was synthesized using a method similar to CP1, with INT11 and CP1-4. LCMS: m / z: 635 [M+H] + .

[0855] Example 9

[0856]

[0857] At 0°C, NaH (60% of the oil, 1.15 g) was added to a solution of 9-a (2.49 g) in THF (10 ml). After stirring for 0.75 h, DMAP (63 mg), TBAI (394 mg), and bromoacetaldehyde dimethyl acetal (4.35 g) were added to the mixture. The reaction mixture was stirred at 70°C for 23 h. The reaction mixture was quenched with water and extracted with EA. The organic layer was washed with brine, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography to give CP9-1 (3.55 g). LCMS: m / z: 343 [M+H] + .

[0858] Pd(OH)₂ / C (0.84 g) was added to a MeOH (25 ml) solution of CP9-1 (1.56 g). The reaction mixture was stirred at RT for 5 hours under H₂ conditions, filtered, and the filtrate was concentrated to obtain CP9-2 (0.75 g). MS m / z: 164 [M+H] + .

[0859] POCl3 (0.8 mL) was added to a solution of INT 6 (1.27 g) and DIEA (1.76 g) in toluene (15 mL). The reaction mixture was stirred at 80 °C for 1.5 h and concentrated. The resulting residue was dissolved in DCM (10 mL), and CP9-2 (0.75 g) and DIEA (2 mL) were added at 0 °C. The reaction mixture was stirred at RT for 1.5 h, diluted with water, and extracted with EA. The collected organic layer was washed with brine, dried, concentrated, and purified by silica gel column chromatography to give CP9-3 (1.38 g). MS: m / z: 425 [M+H] + .

[0860] A mixture of CP9-3 (0.31 g), methylamine hydrochloride (216 mg), Cs₂CO₃ (1254 mg), and DMAc (4 ml) in an 8 ml sealed flask was stirred at 100 °C for 17 h. The reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried, concentrated, and purified by Prep-TLC to give CP9-4 (226 mg). MS: m / z: 420 [M+H] + .

[0861] To a solution of CP9-4 (200 mg) in 1,4-dioxane (4 mL), add TsOH●H2O (97 mg). Stir the solution at 100 °C under N2 for 24 h, dilute with water, and extract with EA. Wash the collected organic layer with brine, dry, concentrate, and purify by Prep-TLC to obtain CP9-5 (52 mg). MS: m / z 356 [M+H] + .

[0862] At RT, m-CPBA (50 mg) was added to a DCM (10 mL) solution of CP9-5 (52 mg). The mixture was stirred for 0.75 h, quenched with aq. Na₂S₂O₃, and extracted with DCM. The solution was washed with sat. aq. NaHCO₃, dried, and concentrated to give CP9-6 (58 mg). MS: m / z: 372 [M+H] + .

[0863] t-BuONa (30 mg) was added to a solution of INT14 (42 mg) in THF (3 ml). After stirring for 10 min, a solution of CP9-6 (58 mg) in THF (1 ml) was added. The mixture was stirred at RT for 0.5 h, quenched with water, and extracted with EA. The organic layer was washed with brine, dried, concentrated, and purified by Prep-TLC to obtain CP9-7 (53 mg). MS: m / z: 467 [M+H] + .

[0864] To a solution of CP9-7 (53 mg), INT2 (77 mg), and toluene (6 mL) and water (1.5 mL), cataCXiumAPd G3 (23 mg) and Cs2CO3 (91 mg) were added. The reaction mixture was stirred at 100 °C for 18 hours under N2. The mixture was diluted with water and extracted with EA. The collected organic layer was washed with aq. NaCl, dried, concentrated, and purified by Prep-TLC to give CP9-8 (43 mg). MS: m / z: 817 [M+H] + .

[0865] A solution of CP9-8 (43 mg) and HCl (4 M, 1 mL in dioxane) in DCM (3 mL) was stirred at RT for 1 h. The solution was concentrated, diluted with sat.NaHCO3 solution, and extracted with EA. The collected organic layer was washed with brine, dried, and concentrated to give CP9-9 (51 mg, crude product). MS: m / z: 773 [M+H] + .

[0866] A mixture of CP9-9 (51 mg, crude product) and CsF (0.30 g) in DMF (5 mL) was stirred at 40 °C for 1.5 h. The mixture was diluted with water and extracted with EA. The organic layer was dried, concentrated, and purified by Prep-HPLC (Daisogel-C18, 50 mm × 250 mm, 10 μm, A: water with 0.05% trifluoroacetic acid, B: CH3CN, gradient: 20% B to 45% B over 35 min, flow rate 70 mL / min, 225 nm). The purified compound was lyophilized to give compound 9 (CP9, 8 mg, TFA salt, confirmed). MS m / z: 617 [M+H] + .

[0867] Example 10

[0868]

[0869] Compound 10 (CP10, confirmed) was synthesized using a method similar to CP9, with CP9-7 and INT13, and purified by Prep-HPLC (YMC-Triart C18-S 12nm, Phase A: water containing 0.1% trifluoroacetic acid, Phase B: CH3CN, gradient: 15% B to 45% B over 30 min, flow rate 70 mL / min, 226 nm). LCMS: m / z: 616 [M+H] + .

[0870] Example 11

[0871]

[0872] CP11-3 is synthesized using INT 7 and ST in a manner similar to CP1-4.

[0873] Compound 11 (CP11, 7.1 mg) was synthesized using a method similar to that for CP3, with CP11-3 and INT13. MS: m / z: 650 [M+H] + .

[0874] CP11 (3.08 mg) was separated using Prep-HPLC Gilson under the following conditions: column: CHIRAL ARTCellulose-SC, column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 17 mL / min. This produced the first peak of compound 11A (CP11A, 2.8 mg, retention time: 5.510 min, confirmed) and compound 11B (CP11B, 2.4 mg, second peak, retention time: 8.137 min, confirmed).

[0875] Example 12

[0876]

[0877] CP9-5 (0.155 g) was separated by Prep-HPLC under the following conditions: column, CHIRAL ART Cellulose-SC column (2 cm × 25 cm, 5 μm); mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 16 mL / min, yielding CP10A-1 (83 mg, retention time 6.65 min) and CP10B-1 (61 mg, retention time 9.253 min).

[0878] CP10A-3 was synthesized from CP10A-1 using a method similar to that of CP9-7.

[0879] CP10A (CP10A, confirmed) was synthesized using CP10A-3 via a method similar to CP3. It was purified by Prep-HPLC (Daisogel-C18, A: water with 0.1% trifluoroacetic acid, B: CH3CN, gradient: 15% B to 36% B over 38 min, flow rate 60 mL / min, 230 nm) and lyophilized to obtain CP10A (26.4 mg, TFA salt). MS (ESI, m / z): 616 [M+H] + .

[0880] CP10B (CP10B, confirmed) was synthesized from CP10B-1 using a method similar to that used for compound 10A. The CP10B was obtained by Prep-HPLC (Daisogel-C18, phase A: water containing 0.1% trifluoroacetic acid, phase B: CH3CN, gradient: 15% B to 35% B over 32 min, flow rate 60 mL / min, 230 nm) and lyophilized to yield CP10B (12.3 mg, TFA salt). MS (ESI, m / z:): 616 [M+H] + .

[0881] Example 13

[0882]

[0883] Under rt, Dess-Martin (6.1 g) was added to a solution of SM (2.6 g) in DCM (80 ml). The reaction mixture was stirred overnight. Quenching was performed with 5% sodium thiosulfate in a saturated aqueous solution of NaHCO3. The resulting two-phase mixture was stirred vigorously for 15 minutes and washed with DCM. The separated organic layer was post-treated to obtain CP12A-1 (1.0 g). LCMS: m / z: 216 [M+H] + .

[0884] A solution of methyltriphenylphosphonium iodide (3.0 g) and t-BuOK (834.6 mg) in THF (37 ml) was heated to 45 °C and stirred for 1 h at RT. CP12A-1 (800 mg) was added and stirred overnight at RT. The mixture was poured into water and extracted with EA. The separated organic layer was post-treated to obtain CP12A-2 (350 mg). LCMS: m / z: 214 [M+H] + .

[0885] At 0°C, 4M HCl / dioxane (0.4 mL) was added to a solution of CP12A-2 (40 mg) in dioxane (1.6 mL), and the resulting mixture was stirred for 1 h. The reaction mixture was concentrated to give unpurified CP12A-3 (crude product). MS (ESI, m / z): 114.3 [M+H] + .

[0886] DIEA (0.1 mL) was added to a solution of INT6 (52 mg) in POCl3 (1 mL), and the resulting mixture was stirred at 110 °C for 1 h. The reaction mixture was concentrated to give unpurified CP12A-4 (crude product).

[0887] At -40°C, DIEA (162.4 mg) and CP12A-3 (crude product, 0.188 mmol) were added to a 2 mL solution of DCM containing CP12A-4 (crude product, 0.188 mmol). The reaction mixture was stirred at -40°C for 1 h. After stirring, H2O was added to the reaction mixture and it was extracted with DCM. The separated organic layer was post-treated to obtain CP12A-5 (30 mg). LCMS: m / z: 375 [M+H] + .

[0888] Under RT, K3PO4 (50.9 mg) and Pd(dppf)Cl2 (6 mg) in toluene / H2O = 10 / 1 (1.1 mL) were added to a solution of CP12A-5 (30 mg). The reaction mixture was stirred overnight at 105 °C under N2. After completion, H2O was added to the reaction mixture and extracted with DCM. The separated organic layer was post-treated to give a yellow solid CP12A (10 mg). MS (ESI, m / z:): 339 [M+H] + . 1HNMR (300MHz, DMSO-d6): δ6.63(s,1H),5.46(s,1H),5.04-4.99(m,1H),4.75-4. 70(m,1H),4.04-3.97(m,2H),3.66-3.54(m,2H),3.25-3.21(m,1H),2.61(s,3H).

[0889] CP12-2 was synthesized from CP12A using a method similar to that used for CP1-4.

[0890] Compound 12 was synthesized using CP12-2 (CP12 1.4 mg, confirmed) via a method similar to that used for CP2. LCMS: m / z: 600 [M+H] + .

[0891] Example 14

[0892]

[0893] Compound 13 (CP13) (8 mg, TFA salt, confirmed) was synthesized using CP1-3 and 13-a in a manner similar to that of CP5. LCMS: m / z: 629 [M+H] + .

[0894] Example 15

[0895]

[0896] A solution of 14-a (1.119 g), TEA (3.408 g), and Boc₂O (2.483 g) in DCM was stirred for 16 h at RT. The reactants were diluted with DCM and washed with water. The separated organic layer was post-processed to give CP₁₄-1 (1542 mg). LCMS: m / z: 230 [M+H] + .

[0897] CP14-8 (321 mg) was synthesized from CP14-1 using a method similar to that of CP12-2.

[0898] Compound 14 (CP14) was synthesized using CP14-8 via a method similar to CP3, and then separated by Prep-HPLC (C18 column, A: 0.05% TFA in water, B: CH3CN, gradient: 25% B to 45% B over 40 min; flow rate 70 mL / min, 230 nm) to yield compound 14A (CP14A, 12 mg, first peak, confirmed) and compound 14B (CP14B, 42 mg, second peak, confirmed). LCMS: m / z: 611 [M+H] + .

[0899] Example 16

[0900]

[0901] Compound 15 (CP15, confirmed) was synthesized using INT16 in a manner similar to that of CP30.

[0902] Example 17

[0903]

[0904] Pd / C (235 mg) was added to a 15 mL solution of MeOH containing 249 mg of CP16-a. The solution was stirred under H2 for 6 h, filtered, and the filtrate was concentrated to obtain CP16-1 (201 mg). MS (ESI, m / z:): 246 [M+H] + .

[0905] HCl (4M, 2 mL of 1,4-dioxane) was added to a solution of CP16-1 (201 mg) in CH3CN (6 mL). The reaction mixture was stirred and concentrated at RT for 1.5 h. CH3CN (5 mL) and aq. NaHCO3 (1 mL) were added to the residue, and the mixture was sonicated and concentrated under reduced pressure. The residue was added to DCM and filtered. The filtrate was concentrated to give CP16-2 (168 mg). MS (ESI, m / z:): 146 [M+H] + .

[0906] The solution of CP16-2 (168 mg) in THF (10 mL) was cooled in an ice-cold ethanol bath. NaH (194 mg, 60% oil content) was added in portions, followed by INT6 (331 mg). The reaction mixture was stirred for 2 h. The mixture was quenched with 2 drops of water. The solution was purified by RP-flash to give CP16-3 (161 mg). MS (ESI, m / z:): 389 [M+H] + .

[0907] DIEA (326 mg) and BOP-Cl (362 mg) were added to a DCM (15 mL) solution of CP16-3 (161 mg). The reaction mixture was stirred at RT for 24 hours, quenched with water (30 mL), and extracted with DCM (30 mL). The separated organic layer was post-treated to obtain CP16-4 (30 mg). MS (ESI, m / z:): 371 [M+H] + .

[0908] CP16-6 was synthesized from CP16-4 using a method similar to that used for CP1-4.

[0909] Compound 16 was synthesized using a method similar to CP3, with CP16-6 (CP16, 1.2 mg, TFA salt, confirmed). LCMS: m / z: 631 [M+H] + .

[0910] Example 18

[0911]

[0912] Under N2, a solution of INT16-3 (352 mg) in THF (10 mL) was cooled to -70 °C. Methylmagnesium bromide (1 M in THF, 4 mL) was added dropwise, and the resulting mixture was stirred at -70 °C for 1 h, quenched with water, and extracted with EA. The separated organic layer was post-processed to give CP17-1 (361 mg). MS (ESI, m / z:): 352 [M+H] + .

[0913] In H2, Pd / C (354 mg) was added to a methanol (15 mL) solution of CP17-1 (361 mg). The reaction mixture was stirred at rt for 16 hours, filtered, and the filtrate was concentrated to give CP17-2 (236 mg). MS (ESI, m / z:): 262 [M+H] + .

[0914] CP17-7 was synthesized from CP17-2 using a method similar to that used for CP16-6.

[0915] Compound 17 was synthesized using CP17-7 in a manner similar to that of CP3 (CP17, 19.1 mg, TFA salt, confirmed).

[0916] LCMS:m / z:647[M+H] + .

[0917] Example 19

[0918]

[0919] CP18-6 was synthesized using 18-a in a manner similar to that of CP16-8.

[0920] CsF (466 mg) was added to a DMF (5 mL) solution of CP18-6 (153 mg). The reaction mixture was stirred at 40 °C for 4 h. EA (40 mL) was added to the reaction mixture and washed with aq. NaHCO3 (30 mL). The separated organic layer was post-treated and separated by Prep-HPLC (YMC-Triart C18-S 12 nm, 50 mm × 250 mm, 7 μm, A phase: 0.1% TFA in water, B phase: CH3CN, gradient: 15% B to 43% B over 35 min, flow rate 70 mL / min, 220 nm) and lyophilized to obtain compound 18A (CP18A, first peak, 70.9 mg, TFA salt, confirmed), MS (ESI, m / z:): 631 [M+H). + And compound 18B (CP18B, second peak, 20.4 mg, TFA salt, confirmed), MS (ESI, m / z:): 631 [M+H] + .

[0921] Example 20

[0922]

[0923] DAST (2.38 g) was added to a solution of INT16-3 (821 mg) in DCM (20 mL) under an ice-cold ethanol bath and stirred for 1.5 h. The solution was then heated to RT and stirred for 5 h. The mixture was diluted with DCM (30 mL) and washed with aq. NaHCO3 (50 mL) aqueous solution. The separated organic layer was post-processed to obtain CP19-1 (565 mg). MS (ESI, m / z:): 358 [M+H] + .

[0924] Under H2 conditions, Pd(OH)2 / C (409 mg) was added to a 15 mL solution of MeOH containing 565 mg of CP19-1. The reaction mixture was stirred at room temperature for 21 hours, filtered, and the filtrate was concentrated to obtain CP19-2 (439 mg). MS (ESI, m / z:): 268 [M+H] + .

[0925] Compound 19 was synthesized using CP19-2 via a method similar to that used for CP16 (CP19, 39 mg, confirmed). LCMS: m / z: 653 [M+H] + .

[0926] Example 21

[0927]

[0928] Compound 20 (CP20, confirmed) was synthesized using a method similar to that of CP9.

[0929] Example 22

[0930]

[0931] CP21-7A / 21-7B were synthesized using INT12 via a method similar to CP12-2, and then separated by Prep-TLC to obtain two isomers, CP21-7A (45 mg) and CP21-7B (38 mg). MS: m / z: 464 [M+H] + .

[0932] Compound 21 (CP21, confirmed) was synthesized using CP21-7A via a method similar to that of CP3. LCMS: m / z: 613 [M+H] + .

[0933] Example 23

[0934]

[0935] CP22-1 was synthesized using a method similar to that of CP12A.

[0936] Compound 22 (CP22, 24.6 mg, TFA salt) was synthesized using CP22-1 via a method similar to that of CP21. LCMS: m / z: 613 [M+H] + .

[0937] Example 24

[0938]

[0939] A solution of 23-a (3.02 g) in HCl (4 M, 30 mL) was stirred at RT for 3 hours and concentrated to obtain CP23-1 (2.63 g). MS (ESI, m / z:): 88 [M+H] + .

[0940] A solution of CP23-1 (1.35 g), 2,2-difluoroethyl trifluoromethanesulfonate (1.42 g), and K2CO3 (3.45 g) in CH3CN (20 mL) was stirred at RT for 16 hours. The mixture was diluted with water and extracted with EA. The organic layer was post-treated to obtain CP23-2 (262 mg). MS (ESI, m / z:): 152 [M+H] + .

[0941] t-BuONa (127 mg) was added to a solution of CP1-3 (308 mg) and CP23-2 (125 mg) in THF (10 mL). The reaction mixture was stirred at RT for 1 hour. The mixture was diluted with water and extracted with EA. The separated organic layer was post-processed to obtain CP23-3 (56 mg). MS (ESI, m / z:): 460 [M+H] + .

[0942] Compound 23 was synthesized using CP23-3 via a method similar to that used for CP3 (CP23, 16.0 mg, TFA salt, confirmed). LCMS: m / z: 609 [M+H] + .

[0943] Example 25

[0944]

[0945] LAH (2.78 g) was added to a solution of 24-a (14.20 g) in THF (150 mL) at 0 °C. The resulting mixture was stirred at RT for 1 h, quenched with water in an ice-water bath, filtered, and extracted with EA. The separated organic layer was post-processed to obtain CP24-1 (11.01 g). MS (ESI, m / z): 222 [M+H] + .

[0946] The solution of CP24-1 (1.15 g) in THF (15 mL) was cooled to 0–5 °C in an ice-water bath. NaH (218 mg) was added in portions, and the resulting mixture was stirred at the same temperature for 30 min. Sodium bromodifluoroacetate (801 mg) was added, and the mixture was stirred at RT for 16 h. The mixture was quenched with aq. NH4Cl and extracted with EA. The concentrated aqueous layer removed most of the CP24-1. The remaining fraction was post-processed to obtain CP24-2 (739.9 mg). MS (ESI, m / z:): 316 [M+H] + .

[0947] Pd / C (0.39 g) was added to a 10 mL MeOH solution of CP24-2 (589.2 mg) under H2 conditions. The reaction mixture was stirred at RT for 16 hours. The resulting mixture was post-processed to give CP24-3 (395.1 mg). MS (ESI, m / z:): 226 [M+H] + .

[0948] A solution of CP24-3 (398.0 mg) in acetic acid (10 mL) was stirred at 110 °C for 16 hours. The solution was concentrated to obtain CP24-4 (662.7 mg). MS (ESI, m / z:): 250 [M+H] + .

[0949] A solution of CP24-4 (217 mg) in borane (1 M, 7 mL in THF) was stirred at RT for 4 h. The solution was quenched with methanol and post-treated to obtain CP24-5 (43.3 mg). MS (ESI, m / z:): 194 [M+H] + .

[0950] Compound 24 (CP24, confirmed) was synthesized using CP24-5 via a method similar to that used for CP23. LCMS: m / z: 651 [M+H] + .

[0951] Example 26

[0952]

[0953] CP25-3 can be purchased or prepared using existing technology.

[0954] Compound 25 (CP25, confirmed) was synthesized using CP25-3 in a manner similar to that of CP23.

[0955] Example 27

[0956]

[0957] CP26 was synthesized using 26-a in a manner similar to that of CP5.

[0958] CP26 (0.0171 g) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SA column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (70:30); flow rate: 18 mL / min. Compound 26A (0.0010 g, first eluting isomer, retention time 5.657 min, confirmed) and compound 26B (0.0069 g, second eluting isomer, retention time 6.437 min, confirmed) were obtained. LCMS: m / z: 647 [M+H] + .

[0959] Example 28

[0960]

[0961] A solution of 27-a (432 mg) in 10 mL of THF was cooled to 0 °C, and borane (1 M in 4 mL of THF) was added dropwise. The resulting mixture was stirred at RT for 16 h. The mixture was then post-processed to obtain CP27-1. LCMS: m / z: 130 [M+H] + .

[0962] Compound 27 (CP27) was synthesized using CP27-1 via a method similar to that used for CP16. MS (ESI, m / z): 615 [M+H] + .

[0963] CP27 (26 mg) was separated using Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SA column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (75:25); flow rate: 18 mL / min. Compound 27A (CP27A, 4.7 mg, first eluting isomer, retention time 5.533 min, confirmed) and compound 27B (CP27B, 3.9 mg, second eluting isomer, retention time 6.523 min, confirmed) were obtained.

[0964] Example 29

[0965]

[0966] A solution of 28-a (0.95 g) and BAST (1.45 g) in DCM (15 mL) was stirred at RT for 16 hours. The solution was then added to aq. NaHCO3 (10 mL). The separated organic layer was post-processed to obtain CP28-1 (583 mg). MS (ESI, m / z:): 294 [M+H] + .

[0967] A solution of CP28-1 (583 mg) in methanol (10 mL) was added to NaBH4 (161 mg), and the mixture was stirred at RT for 16 hours. The mixture was then heated to 60 °C and stirred for 11 hours. Post-treatment of the mixture yielded CP28-2 (120 mg). MS (ESI, m / z): 252 [M+H] + .

[0968] HCl (4M, 2 mL of 1,4-dioxane) was added to a solution of CP28-2 (120 mg) in DCM (5 mL). The reaction mixture was stirred at RT for 1 hour. The reaction was concentrated to give CP28-3 (72 mg). MS (ESI, m / z:): 152 [M+H] + .

[0969] Compound 28 (CP28, confirmed) was synthesized using CP28-3 via a method similar to that used for CP16. LCMS: m / z: 637 [M+H] + .

[0970] Example 30

[0971]

[0972] 29-a was synthesized from N-BOC-O-benzyl-L-serine using a method similar to INT16.

[0973] Pd / C (95 mg) was added to a methanol (10 mL) solution of 29-a (76.30 mg) under H2 conditions. The reaction mixture was stirred at RT for 5 hours. The resulting mixture was post-treated to give CP29-1 (77 mg). MS (ESI, m / z:): 250 [M+H] + .

[0974] Compound 29 (CP29, confirmed) was synthesized using CP29-1 via a method similar to that used for CP16. LCMS: m / z: 635 [M+H] + .

[0975] Example 31

[0976]

[0977] Compound 30 (CP30, confirmed) was synthesized using 30-a in a manner similar to that of CP27.

[0978] Example 32

[0979]

[0980] To a DMF (10 mL) solution of 31-a (1191 mg), 205 mg of NaH and 1.16 g of iodomethane were added. The reaction mixture was stirred at RT for 18 hours, quenched with water (20 mL), and extracted with EA (20 mL). The separated organic layer was post-treated to obtain CP31-1 (602 mg). MS (ESI, m / z:): 274 [M+H] + .

[0981] Add LAH (84 mg) to a solution of CP31-1 (602 mg) in THF (10 mL) and stir the resulting mixture at RT for 30 minutes. Add 3 drops of water, 3 drops of 15% sodium hydroxide aqueous solution, and 8 drops of water to the resulting mixture. Filter the solution. Concentrate the filtrate to obtain CP31-2 (424 mg). MS (ESI, m / z:): 246 [M+H] + .

[0982] Compound 31 (CP31, confirmed) was synthesized using CP31-2 via a method similar to that of CP16. LCMS: m / z: 631 [M+H] + .

[0983] Example 33

[0984]

[0985] Compound 32 (CP32, confirmed) was synthesized using 32-a via a method similar to that of CP16. LCMS: m / z: 631 [M+H] + .

[0986] Example 34

[0987]

[0988] CP33-2 can be purchased or prepared using existing technology.

[0989] Compound 33 (CP33, confirmed) was synthesized using CP33-2 via a method similar to that used for CP27. LCMS: m / z: 643 [M+H] + .

[0990] Example 35

[0991]

[0992] CP14 was synthesized using a method similar to CP5 (CP14, confirmed). LCMS: m / z: 629 [M+H] + .

[0993] Example 36

[0994]

[0995] A solution of 35-a (5.15 g), DIEA (8.75 g), DMAP (0.35 g), and Boc₂O (5.67 g) in DCM (100 mL) was stirred at 40 °C for 40 h. After stirring, the mixture was post-processed to obtain CP35-1 (3.29 g). MS (ESI, m / z): 336 [M+H] + .

[0996] The solution of CP35-1 (3 g) in toluene (50 mL) was cooled to -78 °C. Triethyllithium borohydride (1.4214 g) was added, and the resulting mixture was stirred at -78 °C for 4.5 h. DMAP (60 mg), DIEA (6.02 g), and trifluoroacetic anhydride (7.47 g) were then added, and the mixture was stirred overnight at RT. The solution was diluted with NaHCO3 (100 mL). The separated organic layer was post-treated to obtain CP35-2 (1.45 g). MS (ESI, m / z): 320 [M+H] + .

[0997] The solution of CP35-2 (1.45 g) in DCM (30 mL) was cooled to 10 °C. Diethylzinc (1 M in n-hexane, 13 mL) was added dropwise and the mixture was stirred at RT for 30 min. The reaction mixture was cooled to 0 °C, and diiodomethane (5.19 g) was added dropwise. The mixture was slowly heated to RT and stirred for 16 h. The system was cooled. Extraction was performed by adding 200 mL of saturated ammonium chloride solution. The separated organic layer was post-treated to obtain CP35-3 (1.27 g). MS (ESI, m / z): 234 [M+H] + .

[0998] A solution of CP35-3 (1.27 g), DMAP (0.71 g), and Boc2O (1.67 g) in DCM (20 mL) was stirred at RT for 16 h. The reaction mixture was heated to 40 °C and stirred for 24 h. The separated organic phase was post-processed to obtain CP35-4 (578 mg). MS (ESI, m / z:): 334 [M+H] + .

[0999] Compound 35 (CP35, confirmed) was synthesized using CP35-4 via a method similar to that used for CP29. MS: m / z: 629 [M+H] + .

[1000] Example 37

[1001]

[1002] A solution of 36-a (2.90 g), K₂CO₃ (13.51 g), and phenylmethyl bromide (8.91 g) in CH₃CN (30 mL) was stirred at 80 °C for 24 h. After stirring, the mixture was post-treated to obtain CP36-1 (7.49 g). MS (ESI, m / z:): 298 [M+H] + .

[1003] At 0°C, LAH (0.90 g) was added in portions to a 20 mL THF solution of CP36-1 (7.49 g), and the mixture was stirred for 1 hour. The solution was then quenched with water, 0.8 mL of 15% NaOH, and 2.4 mL of water. Post-treatment of the solution yielded CP36-2 (4.56 g). MS (ESI, m / z:): 270 [M+H] + .

[1004] At 0 °C, NaH (2396 mg) was added in portions to a solution of CP36-2 (4.56 g) in THF (30 mL), and the resulting mixture was stirred at RT for 20 min. Then, 2-bromo-1,1-dimethoxyethane (5.80 g), DMAP (1.08 g), and TBAI (0.66 g) were added, and the mixture was stirred at 70 °C for 17 h, quenched with water, and extracted with EA. The separated organic layer was post-treated to obtain CP36-3 (5.06 g). MS (ESI, m / z:): 358 [M+H] + .

[1005] Under H2 conditions, Pd(OH)2 / C (0.54 g) was added to a 30 mL solution of CP36-3 (5.06 g). The reaction mixture was stirred at RT for 92 hours. The resulting mixture was post-treated to give CP36-4 (2.34 g). MS (ESI, m / z:): 178 [M+H] + .

[1006] CP36 was synthesized from CP36-4 using a method similar to that used for CP46, and purified by Prep-HPLC (Agela Durashell C18, phase A: 0.05% NH4OH in water, phase B: CH3CN, gradient: 25% B to 58% B over 35 min, flow rate 40 mL / min, 225 nm). The purified compound was lyophilized to give compound 36 (CP36, 0.0240 g, confirmed). MS (ESI, m / z:): 630 [M+H] + .

[1007] Example 38

[1008]

[1009] At 0 °C, thionyl chloride (75.81 mmol) was added dropwise to a methanol (50 mL) solution of 37-a (3.00 g), and the resulting mixture was stirred at RT for 16 h. The resulting mixture was concentrated to give CP37-1 (4.34 g, HCl salt). MS (ESI, m / z:): 130 [M+H] + .

[1010] TEA (68.34 mmol) was added to a DCM (65 mL) solution of CP37-1 (4.34 g). The resulting white suspension was cooled to 0 °C and 4-nitrobenzenesulfonyl chloride (6.09 g) was added in portions. The mixture was stirred at RT for 16 h. The resulting mixture was quenched with water and extracted with DCM. The separated organic layer was post-treated to obtain CP37-2 (8.02 g). MS (ESI, m / z): 313 [M-1] - .

[1011] At 0 °C, but-3-en-1-ol (0.98 g) and triphenylphosphine (5.07 g) were added to a THF (50 mL) solution of CP37-2 (3.01 g). Subsequently, DIAD (3.84 g) was slowly added over 10 min. The reaction mixture was heated to RT and stirred for 16 h. The resulting mixture was quenched with water and extracted with EA (100 mL). The separated organic layer was post-treated to obtain CP37-3 (4.19 g).

[1012] A solution of CP37-3 (4.19 g) and a second-generation Grubbs catalyst (1.03 g) in DCM (200 mL) was stirred at 50 °C for 16 h. After completion, the resulting mixture was post-processed to obtain CP37-4 (3.427 g).

[1013] Cs₂CO₃ (23.05 g) and mercaptoacetic acid (3.84 g) were added to a MeOH (150 mL) solution of CP37-4 (3.427 g). The mixture was stirred at RT for 16 h. The resulting mixture was post-processed to obtain CP37-5, which was used directly in the next step. LCMS: m / z: 156 [M+H] + .

[1014] Di-tert-butyl dicarbonate (2.94 g) was added to a solution of CP37-5 in THF (30 mL) and water (30 mL). The solution was stirred at RT for 1 h, and the resulting mixture was extracted with EA (100 mL). The separated organic layer was post-processed to obtain CP37-6 (943 mg). MS (ESI, m / z): 256 [M+H] + .

[1015] LiAlH4 (200 mg) was added to a solution of CP37-6 (943 mg) in THF (20 mL). The resulting mixture was stirred at RT for 2 h and quenched sequentially with water (0.2 mL), aq. 15% NaOH (0.2 mL), and water (0.6 mL). Post-treatment of the solution yielded CP37-7 (498 mg). MS (ESI, m / z): 228 [M+H] + .

[1016] Compound 37 (CP37, confirmed) was synthesized using CP37-7 via a method similar to that used for CP16. MS (ESI, m / z): 613 [M+H] + .

[1017] Example 39

[1018]

[1019] At -78°C, methyl magnesium bromide (3 mmol, 3 M THF solution) was added to a solution of CP35-1 (847 mg) in THF (8 mL). The reaction mixture was stirred for 3.5 h and quenched with aq. NH4Cl (20 mL). Post-treatment of the organic layer yielded CP38-1 (680 mg). MS (ESI, m / z): 352 [M+H] + .

[1020] TFA (2 mL) was added to a solution of CP38-1 (680 mg) in DCM (8 mL). The reaction mixture was stirred for 3.5 hours and concentrated to obtain CP38-2 (crude product), which was used for the next step. MS (ESI, m / z): 234 [M+H] + .

[1021] Sodium triacetoxyborohydride (1.26 g) was added to a solution of CP38-2 (crude product) in vinyl chloride (5 mL). The reaction mixture was stirred for 5 hours, quenched with MeOH (10 mL) and water (2 mL), and concentrated to give CP38-3 (crude product) for the next step. MS (ESI, m / z): 236 [M+H] + .

[1022] CP38-8 was synthesized using CP38-3 in a manner similar to that of CP35.

[1023] CP38-11 was synthesized using CP38-8 in a manner similar to that of CP16-7.

[1024] Compound 38 (CP38) was synthesized using CP38-11 in a manner similar to that of CP35. Purification and separation were performed by Prep-HPLC (AgelaDurashell C18, 30 mm × 250 mm, 10 μm, A phase: 0.05% NH4OH, B phase: CH3CN, gradient: 20% B to 50% B, 34 min, flow rate 40 mL / min, 230 nm), and lyophilized to give compound 38A (CP38A, 16.6 mg, retention time: 35.9 min, confirmed) and compound 38B (CP38B, 3.1 mg, retention time: 37.5 min, confirmed). LCMS: 631 [M+H] + .

[1025] Example 40

[1026]

[1027] A solution of 39-a (53.03 g) in DCM (300 mL) was stirred at 0 °C. HCl (300 mL, 4 M 1,4-dioxane solution) was added to the mixture at 0 °C, and the mixture was stirred at RT for 2 h. The mixture was concentrated to give crude product CP39-1 (35.12 g). MS: m / z: 92 [M+H] + .

[1028] A solution of CP39-1 (29.32 g), TEA (104.89 g), and p-methoxybenzaldehyde (112.00 g) in MeOH (300 mL) was stirred at 0 °C. Sodium triacetoxyborohydride (137.83 g) was added to the mixture at 0 °C, and the mixture was stirred at 0 °C for 1 h. The mixture was then stirred at 40 °C for 24 h. The reaction solution was quenched with water, extracted with EA, and post-treated to obtain CP39-2 (25.50 g). MS: m / z: 332 [M+H] + .

[1029] A solution of CP39-2 (5.50 g), TEA (2.28 g), DMAP (0.29 g), and TBDMSCl (2.54 g) in DCM (60 mL) was stirred at RT for 16 h. The mixture was quenched with water, extracted with DCM, and post-treated to obtain CP39-3 (5.78 g). MS: m / z: 446 [M+H] + .

[1030] A solution of CP39-3 (3.46 g) in DCM (40 mL) was added to DAST (1.57 g) at -10 °C. The reaction mixture was stirred at -10 °C for 1 h. The mixture was quenched with 10% Na2CO3 aqueous solution and extracted with DCM. The organic phase was post-treated and purified to give CP39-4 (1.57 g). MS: m / z: 448 [M+H] + .

[1031] CsF (6861 mg) was added to a 25 mL solution of DMF containing 1.57 g of CP39-4. The reaction mixture was stirred at 30 °C for 5 hours. The solution was quenched with water, extracted with EA, and post-treated to obtain CP39-5 (1048 mg). MS: m / z: 334 [M+H] + .

[1032] A 10 mL solution of THF containing 300 mg of CP39-5 was stirred at 0 °C. Sodium hydride (139 mg, 60%) was added to the mixture at 0 °C, and the mixture was stirred at RT for 0.5 h. DMAP (32 mg), TBAI (44 mg), and bromoacetaldehyde dimethyl acetal (465 mg) were added to the mixture, and the mixture was stirred at 70 °C for 16 h. The mixture was cooled to RT, quenched with water, extracted with EA, and post-treated to obtain CP39-6 (247 mg). MS: m / z: 422 [M+H] + .

[1033] Compound 39 (CP39) was synthesized using CP39-6 via a method similar to that used for CP46, and separated by Prep-TLC (DCM / MeOH = 10:1) to yield the first eluting compound 39A (CP39A, 143 mg) and the second eluting compound 39B (17 mg). LCMS: m / z: 634 [M+H] + .

[1034] Example 41

[1035]

[1036] A solution of 40-a (20.42 g), acetic acid (600 mL), and water (600 mL) was cooled to 0-5 °C. Sodium nitrite (25.14 g) was dissolved in water (50 mL) and slowly added to the solution. The reaction was stirred for 7 h. The resulting solution was diluted with 500 mL of EA and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in MeOH (600 mL) and water (600 mL) under RT, and K2CO3 (15.43 g) was added. The mixture was stirred for 24 h. The pH of the resulting solution was adjusted to 1-2 with 1 N HCl aqueous solution. The mixture was extracted with EA. The combined organic layers were concentrated to give CP40-1 (23.37 g, crude product). The crude product was used for the next step. LCMS (ESI, m / z): 282 [M+H] + .

[1037] At 0 °C, 2.1611 g of thionyl chloride was added to a MeOH (100 mL) solution of CP40-1 (5.11 g). The mixture was stirred under reflux for 16 h. The resulting solution was concentrated. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (0–5%, v / v) to give CP40-2 (1.98 g). LCMS (ESI, m / z): 296 [M+H] + .

[1038] CP40-2 (1.98 g) was dissolved in DCM (30 mL) at 0 °C under N2. A solution of DAST (3.2420 g) in DCM (30 mL) was slowly added to the above solution. The resulting mixture was heated to RT. The reaction was stirred for 20 h and quenched with saturated NaHCO3 solution (100 mL) at 0–5 °C. The resulting solution was diluted with 100 mL of DCM. The organic phase was washed with brine, dried, filtered, and concentrated. The residue was purified by C18 gel chromatography, eluting with H2O / CH3CN to give CP40-3 (747 mg). LCMS (ESI, m / z): 298 [M+H] + .

[1039] LAH (247 mg) was added to a THF (3 mL) solution of CP40-3 (643 mg) at 0 °C. The mixture was stirred at 0 °C for 1 hour and quenched with Na2SO4 decahydrate at 0–5 °C. The resulting mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting with EA / HEX (0–50%, v / v) to give CP40-4 (423 mg). LCMS (ESI, m / z): 270 [M+H] + .

[1040] Palladium hydroxide (354 mg) was added to a MeOH (40 mL) solution of CP40-4 (1.92 g), the mixture was purged with N2 and pressurized with H2. The mixture was stirred at RT for 20 h. After completion, the resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was collected and removed to obtain CP40-5 (1.31 g). The crude product was used for the next step. LCMS (ESI, m / z): 136 [M+H] + .

[1041] A solution of INT 6 (894 mg), DIEA (828 mg), and POCl3 (432 mg) in toluene (20 mL) was stirred at 100 °C for 2 h. The resulting mixture was concentrated. The residue was added to a mixture of CP40-5 (0.285 g) and DIEA (874 mg) in DCM (30 mL) at -10 to 20 °C. The resulting mixture was heated to RT. The reaction was stirred for 0.5 h. The resulting solution was diluted with 50 mL of DCM. The organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by prep-TLC (EA:Hex = 1:2, v / v) to give CP40-6 (253 mg). LCMS (ESI, m / z): 397 [M+H] + .

[1042] To a solution of CP40-6 (2.09 g) in DMAc (40 mL), methylamine hydrochloride (532.8072 mg) and Cs₂CO₃ (3.4282 g) were added. The mixture was stirred at 80 °C for 3 h. After cooling to RT, the resulting mixture was diluted with water (400 mL) and filtered. The filter cake was dried to obtain CP40-7 (1.55 g). LCMS (ESI, m / z): 392 [M+H] + .

[1043] At -10 to 20 °C, pyridine sulfur trioxide (2.00 g) was added to a solution of CP40-7 (1.55 g) and TEA (2.06 g) in DMSO (60 mL) and DCM (30 mL). The resulting mixture was heated to RT. The reaction was stirred for 3 h. The resulting solution was diluted with 30 mL of DCM. The organic phase was washed with brine, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with DCM / EA / Hex (1 / 1 / 1, v / v) to give CP40-8 (1.10 g). LCMS (ESI, m / z): 390 [M+H] + .

[1044] A solution of CP40-8 (1.10 g) and p-TsOH·H2O (661 mg) in DMSO (30 mL) was stirred at 80 °C for 20 h. The solution was diluted with EA and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: 0–30% EA in hexane) to give CP40-9 (262 mg). LCMS (ESI, m / z): 372 [M+H] + .

[1045] CP40 was synthesized from CP40-9 using a method similar to that used for CP46. The resulting compound was purified and separated by Prep-HPLC (YMC-Triart C18-S, 12nm, 50mm × 250mm, 7µm, A phase: 0.05% ammonia solution, B phase: CH3CN, gradient: 40% B to 73% B, 34 min, flow rate 70 mL / min, 224nm), yielding compound 40A (CP40A, first peak, 3.4 mg, confirmed) and compound 40B (CP40B, second peak, 49.2 mg, confirmed). MS (ESI, m / z): 632 [M+H] + .

[1046] 1HNMR (400MHz, DMSO-d6) δ7.75 (dd, J=8.9, 6.0Hz, 1H), 7.32 (m, 1H), 7.09-6.95 (m, 2H), 5.60 (s, 2H), 5.34 (dd, J=12.6, 7.1Hz, 1H), 4.88 (d, J=47. 7Hz, 1H), 4.43 (s, 1H), 4.20-3.89 (m, 3H), 3.12-3.07 (m, 3H), 3.03 (d, J = 4 .2Hz,1H),2.83(d,J=6.4Hz,1H),2.16-1.64(m,14H),1.62-1.32(m,2H).

[1047] Example 42

[1048]

[1049] At 0°C and N2, NaH (405 mg) was added to a solution of 41-a (5539 mg) in ether (13 mL). The mixture was stirred at RT for 0.5 h. After cooling to 0°C, trichloroacetonitrile (4 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 h, and hexane (100 mL) was added. The mixture was filtered and the filtrate was concentrated to obtain CP41-1 (9.78 g).

[1050] A solution of (S)-3-hydroxybutyrate ethyl ester (2.6312 g) in DCM (56 mL) was stirred at RT and N2. A solution of CP41-1 (9.78 g) in DCM (56 mL) was added dropwise. After completion, (1S)-(+)-camphor-10-sulfonic acid (0.55 g) was added. The resulting mixture was stirred at RT overnight. Quenching with sat.aq. NaHCO3 and post-treatment yielded CP41-2 (7.28 g).

[1051] At 0°C, LiAlH4 (1.11 g) was added in portions to a solution of CP41-2 (7.28 g) in THF (30 mL). The resulting mixture was stirred overnight at RT. The mixture was quenched with wet Na2SO4 and filtered. The filtrate was concentrated and purified to give CP41-3 (1.98 g).

[1052] To a solution of CP41-3 (1.46 g) in THF (30 mL), 2-bromo-1,1-dimethoxyethane (3.95 g), TBAI (0.26 g), and NaH (1.17 g) were added, and the resulting mixture was stirred at 80 °C for 16 hours. The mixture was quenched with water, extracted with EA, and post-treated to obtain CP41-4 (2.03 g).

[1053] Synthesize CP41-6 using INT 6 in a manner similar to that of CP46.

[1054] A solution of CP41-6 (1.39 g), CP41-4 (1.79 g), and p-TsOH·H2O (0.78 g) in DMSO (15 mL) was stirred at 80 °C for 5 hours. The mixture was then diluted with water and extracted with EA. The separated organic layer was post-treated to obtain CP41-7 (2.31 g). MS (ESI, m / z): 628 [M+H] + .

[1055] The mixture of CP41-7 (2.31 g) in TFA (15 mL) was stirred overnight at 120 °C. The mixture was concentrated. NaOH (aq) and MeOH were added to the residue, and the mixture was stirred at RT for 1 hour. The resulting mixture was extracted with DCM and EA and post-processed to obtain CP41-8 (1.06 g). MS (ESI, m / z): 388 [M+H] + .

[1056] To a mixture of CP41-8 (1.01 g), DIEA (1033 mg), and DCM (15 mL), methanesulfonyl chloride (287 mg) was added dropwise. The resulting mixture was stirred at RT for 1 hour and then diluted with water. The organic layer was separated, dried, and concentrated. The residue was dissolved in acetonitrile (15 mL). Cs₂CO₃ (2564 mg) was added to the resulting mixture and stirred at 60 °C for 3 hours. The resulting mixture was diluted with water and EA (30 mL) and filtered through diatomaceous earth. The filtrate was extracted with EA and post-treated to give CP41-9 (320 mg). MS (ESI, m / z): 370 [M+H] + .

[1057] CP41-9 (320 mg) was separated by chiral-HPLC Gilson under the following conditions: column: CHIRAL ART Cellulose-SC column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 18 mL / min. CP41-9A (0.16 g, first eluting isomer, retention time 4.933 min) and CP41-9B (second eluting isomer, retention time 11.277 min) were obtained.

[1058] Compound 41 was synthesized using CP41-9A in a manner similar to that used for CP46 (CP41, 18.2 mg, TFA salt, confirmed). MS (ESI, m / z): 630 [M+H] + .

[1059] Example 43

[1060]

[1061] At 0°C under N2, sodium hydride (60% in oil, 0.59 g) was added to a solution of CP42-1 (3.08 g) in anhydrous THF (25 mL), and the resulting mixture was stirred at RT for 30 min. A solution of methyl 2-bromopropionate (3.00 g) in anhydrous THF (5 mL) was added to the reaction mixture, and the mixture was stirred at RT for 1 h. After completion, the reaction mixture was diluted with EA and saturated NH4Cl and post-treated to obtain CP42-2 (4.05 g). MS: m / z: 342 [M+H] + .

[1062] At 0°C and N2, LAH (0.45 g) was added to a solution of CP42-2 (3.55 g) in THF (40 mL). The resulting mixture was stirred at RT for 1 h, quenched with ice water (5 mL), and filtered. The filtrate was concentrated and purified to obtain CP42-3 (2.11 g). MS: m / z: 314 [M+H] + .

[1063] A solution of CP42-3 (1.94 g), Pd / C (0.54 g, 10% wt), and Pd(OH)2 / C (0.54 g, 10% wt) in MeOH (60 mL) was stirred at RT and H2 for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated to give CP42-4 (693 mg). MS: m / z: 134 [M+H] + .

[1064] CP42-10 was synthesized from CP42-4 using a method similar to that used for CP40-11.

[1065] CP42-10 (270 mg) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ARTCellulose-SC column (2 cm × 25 cm, 5 μm mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 18 mL / min. CP42-11A (120 mg, first eluting isomer, retention time 5.557 min) and CP42-11B (116 mg, second eluting isomer, retention time 6.677 min) were obtained.

[1066] Compound 42 (CP42, confirmed) was synthesized using CP42-11A in a manner similar to that used for CP46. MS: m / z: 630 [M+H] + .

[1067] Example 44

[1068]

[1069] Compound 43 (CP43, confirmed) was synthesized using CP42-11B in a manner similar to that used for CP46. MS: m / z: 630 [M+H] + .

[1070] Example 45

[1071]

[1072] POCl3 (0.24 mL) was added to a solution of CP44-1 (517 mg) and DIEA (634 mg) in toluene (10 mL). The reaction mixture was stirred at 80 °C for 1 h and concentrated to obtain a residue. The residue of DIEA (1 mL) was added to a solution of CP36-4 (338 mg) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at RT for 0.5 h, diluted with water, extracted with DCM, and post-treated to obtain CP44-2 (418 mg). MS m / z: 454 [M+H] + .

[1073] DIEA (249 mg, 1.93 mmol) was added to a solution of CP44-2 (280 mg) and INT14 (217 mg) in 1,4-dioxane (2.5 mL). The mixture was stirred at 100 °C for 44 h, quenched with water (30 mL), extracted with EA (30 mL), and post-treated to obtain CP44-3 (226 mg). MS: m / z: 577 [M+H] + .

[1074] Cs₂CO₃ (1311 mg) was added to a solution of CP44-3 (121 mg) and methylamine hydrochloride (203 mg) in DMAc (2 mL). The mixture was stirred at 110 °C for 21 h, quenched with water (30 mL), extracted with EA (30 mL), and post-treated to obtain CP44-4 (120 mg). MS: m / z: 587 [M+H] + .

[1075] Compound 44 (CP44, confirmed) was synthesized using CP44-4 in a manner similar to that used for CP46. MS: m / z: 629 [M+H] + .

[1076] Example 46

[1077]

[1078] Compound 45 (CP45, confirmed) was synthesized using CP10B-3 and INT10 in a manner similar to that used for CP46. MS: m / z: 634 [M+H]+ .

[1079] Example 47

[1080]

[1081] At 0 °C, TEA (19.84 g) and pyridine sulfur trioxide (14.15 g) were added to a solution of CP39-3 (9.86 g) in DMSO (80 mL) and DCM (40 mL). The reaction mixture was stirred at RT for 16 hours. The mixture was diluted with water, extracted with EA, and post-treated to give CP46-1 (10.79 g). MS: m / z: 444 [M+H] + .

[1082] Potassium tert-butoxide (4.04 g) was added to a solution of methyltriphenylphosphonium bromide (12.68 g) in THF (100 mL) at 0 °C. After stirring at RT for 1 h, CP46-1 (10.45 g) was added to the mixture. The reaction mixture was stirred at RT for 16 h. The mixture was diluted with water, extracted with EA, and post-treated to give CP46-2 (7.72 g). MS: m / z: 442 [M+H] + .

[1083] CsF (8.12 g) was added to a DMF (50 mL) solution of CP46-2 (7.70 g). The reaction mixture was stirred at RT for 16 hours. The mixture was diluted with water, extracted with EA, and post-treated to obtain CP46-3 (5.17 g). MS: m / z: 328 [M+H] + .

[1084] Sodium hydride (60% in oil, 1.84 g) was added to a solution of CP46-3 (3.78 g) in THF (50 mL) at 0 °C. After stirring for 1 h, DMAP (0.13 g), TBAI (0.63 g), and bromoacetaldehyde dimethyl acetal (6.59 g) were added to the mixture. The reaction mixture was stirred at 70 °C for 23 h. The reaction mixture was quenched with water, extracted with EA, and post-treated to obtain CP46-4 (4.45 g). MS: m / z: 416 [M+H] + .

[1085] Pd(OH)₂ / C (2.96 g) was added to a MeOH (100 mL) solution of CP46-4 (3.18 g). The reaction mixture was stirred at RT under H₂ for 16 hours. The mixture was filtered, and the filtrate was concentrated to give CP46-5 (1.5 g). MS: m / z: 178 [M+H] + .

[1086] Compound 46 (CP46, 31.8 mg, confirmed) was synthesized using a method similar to that for CP39, with CP46-5 and INT6. MS: m / z: 630 [M+H] + .

[1087] Example 48

[1088]

[1089] A solution of 47-a (20.04 g) in THF (200 mL) was cooled to 0 °C, and NaH (16.27 g), TBAI (4.45 g), DMAP (1.30 g), and BnBr (43.06 g) were added to the solution. The reaction mixture was stirred at RT for 16 h, quenched with water, extracted with ethyl acetate, and post-treated to obtain CP47-1 (42.71 g).

[1090] At RT, m-CPBA (18.45 g) was added to a DCM (200 mL) solution of CP47-1 (18.64 g). The resulting mixture was stirred for 16 h, filtered, and concentrated. The residue was purified to give CP47-2 (10.93 g). MS: 207 [M+H] + .

[1091] 17.15 g of benzylamine was added to a 200 mL solution of MeOH containing 10.93 g of CP47-2. The reaction mixture was stirred at 130 °C for 3 hours under N2. The mixture was then cooled to RT. The mixture was concentrated and purified to give 10.65 g of CP47-3. MS: 314 [M+1] + .

[1092] A solution of CP47-3 (10.65 g), K2CO3 (14.96 g), TBAI (0.84 g), and BrBn (7.78 g) in ACN (120 mL) was stirred at RT for 16 h. The mixture was concentrated and purified to obtain CP47-4 (8.33 g). MS: 404 [M+H] + .

[1093] DAST (4.72 g) was added to a DCM (100 mL) solution of CP47-4 (8.33 g). The reaction mixture was stirred at 0 °C for 3 hours. The solution was diluted with sat.NaHCO3, extracted with EA, and post-treated to obtain CP47-5 (5.65 g). MS: 406 [M+H] + .

[1094] Pd(OH)₂ / C (1.63 g) was added to a methanol (80 mL) solution of CP47-5 (5.65 g) under H₂ conditions. The reaction mixture was stirred at 60 °C for 16 hours. The resulting mixture was filtered, and the filtrate was concentrated to give CP47-6 (1.78 g). MS: 136 [M+H] + .

[1095] Compound 47 was synthesized using CP47-6 via a method similar to that used for CP40 (CP47, 12.8 mg, confirmed). MS: 632 [M+H] + .

[1096] Example 49

[1097]

[1098] A DMF (15 mL) solution of CP9-3 (1.058 g), Cs₂CO₃ (3001 mg), and CD₃NH₂.HCl (510 mg) was stirred at 100 °C for 4 hours. The reaction mixture was cooled to RT. The residue was diluted with water, extracted with EA, and post-treated to give crude product CP48-1, which was used directly in the next step. MS (ESI, m / z): 423 [M+H] + .

[1099] CP48-2 was synthesized from CP48-1 using a method similar to that used for CP46-8.

[1100] CP48-2 (690 mg) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1) / EtOH = 50:50; flow rate: 18 mL / min, 220 nm. CP48-3 (the second eluting isomer, retention time 11.7 min) was obtained.

[1101] Compound 48 (CP48, confirmed) was synthesized using CP48-3 via a method similar to that used for CP46. MS (ESI, m / z): 619 [M+H] + .

[1102] Example 50

[1103]

[1104] CP49 was synthesized using CP49-a in a manner similar to that of CP40. MS: m / z: 632 [M+1] + .

[1105] CP49 (50 mg) was separated by Prep-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 μm, A phase: 0.05% NH3·H2O, B phase: CH3CN, gradient: 35 min 25% B to 58% B, flow rate 40 mL / min, 224 nm). Compound 49A (CP49A, first eluting isomer, retention time 30.8–33.39 min) and compound 49B (CP49B, second eluting isomer, retention time 33.64–35.75 min) were obtained. MS: m / z: 632 [M+1] + .

[1106] Example 51

[1107]

[1108] Compound 50 (CP50, confirmed) was synthesized using CP10B-3 via a method similar to that of CP2. LCMS: m / z: 617 [M+H] + .

[1109] 1 HNMR(400MHz,DMSO-d6)δ11.16-10.82(m,1H),8.02-7.90(m,1H),7.51-7.41(m,1H),7.36 (d,J=1.9Hz,1H),7.22-7.10(m,1H),5.58(d,J=53.2Hz,1H),5.38-5.26(m,1H),4.65-4.51 (m,2H),4.51-4.41(m,1H),4.13-3.94(m,2H),3.94-3.68(m,3H),3.64-3.49(m,1H),3.45 -3.22(m,3H),3.12-2.93(m,3H),2.63-2.44(m,3H),2.41-2.10(m,4H),2.09-1.89(m,2H).

[1110] Example 52

[1111]

[1112] Compound 51 (CP51, confirmed) was synthesized using CP10B-3 and INT1 in a manner similar to that of CP1. MS: m / z: 598 [M+H] + .

[1113] 1HNMR(400MHz,DMSO-d6)δ7.79-7.68(m,1H),7.31-7.29(m,2H),7.18-7.08(m,1H),6.97-6.93(m,1H),5.32(s,2H),4.19-4.16(m,2H),3.88- 3.80(m,3H),3.53-3.50(m,2H),3.35-3.27(m,2H),3.02(s,3H),2.67- 2.51(m,4H),2.33-2.31(m,3H),2.22–2.18(m,4H),2.13-2.04(m,3H).

[1114] Example 53

[1115]

[1116] CP52 was synthesized using CP52-a in a manner similar to CP94. Purification and separation were performed by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC column (2 cm × 25 cm, 5 μm); mobile phase: hexane (0.1% DEA) / EtOH (50:50); flow rate: 20 mL / min. Compound 52A (CP52A, 7.8 mg, 11.72 μmol, first eluting isomer, retention time 5.227 min, confirmed) and compound 52B (CP52B, 10.7 mg, 16.07 μmol, second eluting isomer, retention time 6.157 min, confirmed) were obtained. LCMS: m / z: 666 [M+H] + .

[1117] Example 54

[1118]

[1119] DIEA (8.47 g) and (Boc)₂O (5.20 g) were added to a mixture of 53-a (3.97 g) and THF (50 mL). The reaction mixture was stirred at RT for 3 hours, diluted with EA and water, and post-treated to obtain CP53-1 (4.17 g). MS: m / z: 246 [M+H] + .

[1120] DAST (23.90 g) was added to a DCM (50 mL) solution of CP53-1 (4.17 g). The reaction mixture was stirred at 40 °C for 18 hours, and then sat.aq. Na2CO3 (100 mL) was added at 0 °C for post-treatment to obtain CP53-2 (2.73 g). MS m / z: 268 [M+H] + .

[1121] At -10°C, LAH (0.56 g) was added fractionally to a THF (20 mL) solution of CP53-2 (2.52 g). The reaction mixture was stirred at RT for 0.5 h and quenched with water (1 mL), aq. NaOH (0.6 mL, 15% w / w), and water (3 mL). The mixture was filtered, and the filtrate was concentrated and purified to give CP53-3 (1589 mg). MS: m / z: 240 [M+H] + .

[1122] HCl (3 mL, 4 mol / mL dioxane solution) was added to a 9 mL acetonitrile solution of CP53-3 (0.77 g) under RT. The mixture was then stirred at RT for 2 hours and concentrated to obtain residue A. POCl3 (0.5 mL) was added to a 10 mL toluene solution of INT 6 (889 mg) and DIEA (1232 mg). The reaction mixture was stirred at 80 °C for 2 hours and concentrated to obtain residue B. A 10 mL DCM solution of residue B was added to a 10 mL DCM solution of residue A and DIEA (2 mL). The reaction mixture was stirred at RT for 1.5 hours, diluted with water, extracted with EA, and post-treated to obtain CP53-4 (465 mg). MS: m / z: 401 [M+H] + .

[1123] Compound 53 (CP53, confirmed) was synthesized using CP53-4 via a method similar to that used for CP47. MS: m / z: 636 [M+H] + .

[1124] Example 55

[1125]

[1126] CP54-5 was synthesized from CP54-1 using a method similar to that of CP47-10.

[1127] CP54-5 (133 mg) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 17 mL / min. CP54-5A (53 mg, first eluting isomer, retention time 5.923 min) and CP54-5B (52 mg, second eluting isomer, retention time 8.129 min) were obtained.

[1128] Compound 54A (CP54A, confirmed) was synthesized using a method similar to that of CP47 with CP54-5A. MS: m / z: 614 [M+H] + .

[1129] Compound 54B (CP54B, confirmed) was synthesized using a method similar to that of CP47 with CP54-5B. MS: m / z: 614 [M+H] + .

[1130] Example 56

[1131]

[1132] A solution of 55-a (1.58 g), DIEA (4.63 g), and 4-methoxybenzyl chloride (5.04 g) in DCM (20 mL) was stirred at RT for 18 h. The reaction mixture was quenched with water, extracted with DCM, and post-treated to give CP55-1 (1.8874 g). MS: m / z: 352 [M+H] + .

[1133] Under RT and N2 conditions, NaH (1.6382 g, 60% purity) was added to a 30 mL THF solution of CP55-1 (2.7114 g). The reaction mixture was stirred for 1 hour. DMAP (217 mg), TBAI (676 mg), and bromoacetaldehyde dimethyl acetal (5175 mg) were then added to the mixture, and the reaction mixture was stirred at 70 °C for 17 hours under N2 conditions. After completion, the reaction was quenched with water, extracted with EA, and post-treated to obtain CP55-2 (2.8029 g, 70% purity). MS: m / z: 440 [M+H] + .

[1134] Compound 55 (CP55, confirmed) was synthesized using CP55-2 via a method similar to that used for CP46. MS: m / z: 652 [M+H] + .

[1135] Example 57

[1136]

[1137] A solution of 56-a (5.03 g), TBAI (1.30 g), K2CO3 (24.83 g), and BrBn (24.19 g) was stirred at RT for 16 h. The mixture was concentrated under reduced pressure and purified to obtain CP56-1 (9.2 g). MS: m / z: 270 [M+H] + .

[1138] NaH (5.41 g, 60% purity) was added to a solution of CP56-1 (8.8 g) in THF (100 mL). The reaction mixture was stirred at RT for 1 h. DMAP (0.39 g), TBAI (1.24 g), and bromoacetaldehyde dimethyl acetal (17.72 g) were added to the reaction mixture. The resulting mixture was stirred at 75 °C for 16 h. The mixture was quenched with ice water, extracted with EA, and post-treated to obtain CP56-2 (9.74 g). MS: m / z: 358 [M+H] + .

[1139] Pd / C (2.8995 g) and Pd(OH)₂ / C (2.0 g) were added to a methanol (100 mL) solution of CP56-2 (9.74 g) under H₂ conditions. The reaction mixture was stirred at RT for 16 hours. The resulting mixture was filtered and concentrated to give CP56-3 (4.65 g). MS: m / z: 178 [M+H] + .

[1140] CP56-6 was synthesized from CP56-3 using a method similar to that used for CP46-8.

[1141] CP56-6 (1.32 g) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 17 mL / min. CP56-6B (623 mg, first eluting isomer, retention time 6.69 min) and CP56-6A (0.61 g, second eluting isomer, retention time 8.708 min) were obtained. MS: m / z: 370 [M+H] + .

[1142] Compound 56A (CP56A, confirmed) was synthesized using CP56-6A in a manner similar to that of CP46.

[1143] Compound 56B (CP56B, confirmed) was synthesized using a method similar to that for CP46 with CP56-6B. MS: m / z: 630 [M+H] + .

[1144] Example 58

[1145]

[1146] A solution of 57-a (5.09 g), benzyl bromide (22.49 g), K₂CO₃ (12.03 g), and NaOH (3.45 g) in water (100 mL) was stirred at 100 °C for 3 h. The solution was extracted with EA and post-treated to obtain CP57-1 (6641 mg). MS: m / z: 390 [M+H] + .

[1147] DAST (508 mg) was added to a solution of CP57-1 (1029 mg) in THF (10 mL) under RT conditions, and the resulting mixture was stirred for 3 h. The mixture was quenched with 10% Na2CO3 solution, extracted with EA, and post-treated to obtain CP57-2 (1046 mg). MS: m / z: 392 [M+H] + .

[1148] A solution of CP57-2 (6.62 g) in THF (60 ml) was stirred at 0 °C. LiAlH4 (1297 mg) was added to the mixture at 0 °C, and the mixture was stirred at RT for 2 h. The solution was quenched with Na2SO4, filtered, concentrated, and purified to obtain CP57-3 (4513 mg). MS: m / z: 288 [M+H] + .

[1149] A solution of CP57-3 (792 mg) in THF (15 mL) was stirred at 0 °C. Sodium hydride (414 mg) was added to the mixture at 0 °C, and the mixture was stirred at RT for 0.5 h. DMAP (62 mg), tetrabutylammonium iodide (202 mg), and bromoacetaldehyde dimethyl acetal (1014 mg) were added to the mixture, and the mixture was stirred at 70 °C for 6 h. The mixture was cooled to RT, quenched with water, extracted with EA, and post-treated to obtain CP57-4 (503 mg).

[1150] 1HNMR (400MHz, CDCl3) δ7.39 (d, J=7.3Hz, 4H), 7.33 (t, J=7.5Hz, 4H), 7.29-7.24 (m, 2H), 4.72-4.52 (m, 1H), 4.46 (t, J=5.2Hz, 1H), 3.99-3.88 (m, 3H), 3.60-3.42 (m, 5H), 3.39 (d, J=2.3Hz, 6H), 3.06-2.86 (m, 1H), 1.20 (d, J=6.9Hz, 3H). MS:m / z:376[M+H] + .

[1151] A solution of CP57-4 (200 mg) and Pd(OH)2 / C (237 mg) in MeOH (10 mL) was stirred at RT under H2 for 16 h. The solution was filtered and concentrated to obtain crude product CP57-5 (103 mg). MS: m / z: 196 [M+H] + .

[1152] Compound 57 (CP57, confirmed) was synthesized using CP57-5 via a method similar to that used for CP46. MS: m / z: 648 [M+H] + .

[1153] Example 59

[1154]

[1155] Compound 58 (CP58, confirmed) was synthesized using 58-a via a method similar to that of CP57. MS: m / z: 648 [M+H] + .

[1156] Example 60

[1157]

[1158] CP59-8 was synthesized from CP59-5 using a method similar to that of CP94-4.

[1159] CP59-8 (519 mg) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SA column (2 cm × 25 cm, 5 μm mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 18 mL / min. CP59A-9 (173 mg, first eluting isomer, retention time 4.587 min) and CP59B-9 (190 mg, second eluting isomer, retention time 5.067 min) were obtained.

[1160] Compound 59A (CP59A, confirmed) was synthesized using CP59A-9 via a method similar to that used for CP46. MS: m / z: 660 [M+H] + .

[1161] Example 61

[1162]

[1163] At -10°C, LAH (1222 mg) was added in portions to a 20 mL solution of THF containing 60-a (2.162 g). The reaction mixture was stirred at 40°C for 0.75 h and quenched with water (1.5 mL), aq. NaOH (1.5 mL, 15% w / w), and water (5 mL). The mixture was filtered, and the filtrate was concentrated. The residue was purified to give CP60-1 (2.852 mg). MS: m / z: 116 [M+H] + .

[1164] CP60-9 was synthesized from CP60-1 using a method similar to that of CP55-8.

[1165] CP60-9 (331 mg) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 18 mL / min. CP60-10 (138 mg, second eluting isomer, retention time 8.740 min) was obtained.

[1166] Compound 60 (CP60, confirmed) was synthesized using CP60-10 via a method similar to that used for CP46. MS: m / z: 656 [M+H] + .

[1167] Example 62

[1168]

[1169] A solution of INT 15 (1.005 g) in THF (100 mL) and DCM (100 mL) was added to Pd / C (459 mg). The mixture was stirred at RT under H2 for 3 h. The solution was filtered, and the filtrate was concentrated to give CP61-1 (1053 mg). MS: m / z: 368 [M+H] + .

[1170] At 0 °C, a solution of CP61-1 (0.552 g) in DCM (50 mL) was added dropwise to DAST (1.603 g), and stirred overnight at RT. The solution was quenched with 10% Na2CO3 aqueous solution, extracted with DCM, and post-processed to obtain CP61-2 (400 mg). MS: m / z: 390 [M+H] + .

[1171] CP61-4 was synthesized from CP61-2 using a method similar to that used for CP46-10.

[1172] CP61-4 was separated by chiral high-performance liquid chromatography (HPLC) under the following conditions: CHIRAL ART Cellulose-SC, 20 mm × 250 mm, 5 μm mobile phase, Hex (0.1% DEA) / EtOH (80:20); flow rate: 15 mL / min, yielding CP61-5 (second eluting isomer, retention time 9.189 min). MS: m / z: 501 [M+H] + .

[1173] Compound 61 (CP61, confirmed) was synthesized using CP61-5 via a method similar to that used for CP46. MS: m / z: 650 [M+H] + .

[1174] Example 63

[1175]

[1176] NaBH4 (255 mg) was added to a solution of CP61-1 (0.800 g) in DCM (20 mL) and THF (20 mL), and the resulting mixture was stirred at RT for 4 h. The solution was quenched with water, extracted with DCM, and post-processed to obtain CP62-1 (735 mg). MS: m / z: 370 [M+H] + .

[1177] CCl4 (1008 mg) was added to a solution of triphenylphosphine (1085 mg) in DCM (25 mL) at 0 °C under N2, and the resulting mixture was stirred at 0 °C for 20 min. A solution of CP62-1 (0.636 g) in DCM (5 mL) was added dropwise at 0 °C, and the mixture was stirred overnight at RT. The mixture was diluted with DCM (30 mL) and washed with H2O and saturated NaCl (aq). Post-treatment yielded CP62-2 (338 mg). MS: m / z: 388 [M+H] + .

[1178] CP62-4 was synthesized from CP62-2 using a method similar to that used for CP46-10.

[1179] CP62-4 was separated using Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / IPA (50:50); flow rate: 15 mL / min. CP62-4A (76 mg, first eluting isomer, retention time 6.223 min) and CP62-4B (66 mg, second eluting isomer, retention time 7.320 min) were obtained. MS: m / z: 499 [M+H]+ .

[1180] Compound 62B (CP62B, confirmed) was synthesized using CP62-4B in a manner similar to that used for CP46. MS: m / z: 648 [M+H] + .

[1181] Compound 62A (CP62A, confirmed) was synthesized using CP62-4A in a manner similar to that used for CP46. MS: m / z: 648 [M+H] + .

[1182] Example 64

[1183]

[1184] Compound 63 (CP63, confirmed) was synthesized using CP37-11 via a method similar to CP2. MS (ESI, m / z): 614 [M+H] + .

[1185] Example 65

[1186]

[1187] At -78°C, cyclopropylmagnesium bromide (12 mL, 1 M THF solution) was added dropwise to a solution of CP35-1 (2.03 g) in THF (20 mL). The reaction mixture was stirred at -78°C for 1.5 h under N2. The mixture was quenched with sat.aq. NH4Cl. Diluted with EA and water and post-treated to give CP64-1 (1.80 g). MS: m / z: 378 [M+H] + .

[1188] TFA (5 mL) was added to a 20 mL solution of DCM containing 1.80 g of CP64-1 at RT, and the reaction mixture was stirred overnight at RT. The mixture was concentrated to give crude product CP64-2 (1.32 g). MS: m / z: 278 [M+H] + .

[1189] Sodium triacetoxyborohydride (3.75 g) and anhydrous Na₂SO₄ (5.73 g) were added to a solution of CP64-2 (1.32 g) in DCE (20 mL). The mixture was stirred at 42 °C for two days. The pH of the mixture was adjusted to 9 by aq. K₂CO₃. The mixture was extracted with DCM and post-processed to obtain the crude product CP64-3 (1.35 g). MS: m / z: 262 [M+H] + .

[1190] Di-tert-butyl dicarbonate (1.57 g) was added to a solution of CP64-3 (1.35 g) in THF (15 mL). The reaction mixture was stirred overnight at 44 °C under N2. The mixture was diluted with EA (50 mL) and water (30 mL). Post-treatment of the organic separation layer yielded CP64-4 (683 mg). MS: m / z: 362 [M+H] + .

[1191] Pd(OH)₂ / C (0.31 g) was added to a 20 mL solution of MeOH containing CP64-4 (683 mg). The reaction mixture was stirred at 44 °C for 24 hours under H₂. The mixture was filtered and the filtrate was concentrated to give CP64-5 (0.47 g). MS: m / z: 272 [M+H] + .

[1192] Compound 64 (CP64, confirmed) was synthesized using CP64-5 via a method similar to that used for CP16. MS: m / z: 657 [M+H] + .

[1193] Example 66

[1194]

[1195] Compound 65 (CP65, confirmed) was synthesized using a method similar to that used for CP64. MS m / z: 645 [M+H] + .

[1196] Example 67

[1197]

[1198] HCl (5 mL, 4 M 1,4-dioxane solution) was added to a solution of INT7 (0.63 g) in MeOH (10 mL). The reaction mixture was stirred at RT for 2.5 h and concentrated to obtain a residue. NaH (550 mg, 60% oil content) was added in portions to a mixture of THF (15 mL) and CP66-1 (899 mg) at -10 °C. The reaction mixture was stirred at RT for 20 h, quenched with a small amount of water, and concentrated to obtain a residue. DCM:MeOH = 10:1 (20 mL) was added to the residue. After stirring for 5 min, the mixture was filtered and the filtrate was concentrated to obtain CP66-2 (1483 mg). MS (ESI, m / z): 442 [M+H] + .

[1199] DIEA (1.51 g) and BOP-Cl (1.68 g) were added to a DCM (20 mL) solution of CP66-2 (1483 mg). The reaction mixture was stirred at RT for 21 hours, quenched with water, and extracted with DCM. The organic layer was washed with brine, dried, concentrated, and purified by Prep-TLC to obtain CP66-3 (190 mg). MS (ESI, m / z): 424 [M+H] + .

[1200] At 30°C, INT14 (127 mg), DABCO (18 mg), and Cs₂CO₃ (216 mg) were added to a solution of CP66-3 (190 mg) in DMF (1 mL) and THF (1 mL), and the resulting mixture was stirred for 20 h. The mixture was quenched with water and extracted with EA. The organic layer was washed with brine, dried, concentrated, and purified by Prep-TLC to obtain CP66-4 (206 mg). MS (ESI, m / z): 547 [M+H] + .

[1201] A mixture of CP66-4 (116 mg), 66-a (98 mg), DPEPosPdCl2 (22 mg), and Cs2CO3 (213 mg) in toluene (3 mL) was stirred at 105 °C for 19 hours under N2. Water was added to the reaction mixture and extracted with EA. The organic layer was washed with brine, dried, concentrated, and purified by Prep-TLC to give CP66-5 (148 mg). MS (ESI, m / z): 757 [M+H] + .

[1202] TFA (2 mL) was added to a DCM (6 mL) solution of CP66-5 (148 mg). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was purified by Prep-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 μm, A phase: 0.1% TFA aqueous solution, B phase: CH3CN, gradient: 15% B to 40% B, 37 min, flow rate 60 mL / min, 295 nm) and lyophilized to give CP66 (60 mg, TFA salt). MS (ESI, m / z): 657 [M+H] + .

[1203] CP66 (60 mg, TFA salt) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ARTAmylose-SA column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 20 mL / min. Compound 66A (CP66A, 22.3 mg, first eluting isomer, retention time 3.990 min, confirmed) and compound 66B (CP66B, 15.1 mg, second eluting isomer, retention time 5.103 min, confirmed) were obtained.

[1204] Example 68

[1205]

[1206] Compound 67 (CP67, confirmed) was synthesized using CP37-7 via a method similar to that of CP21. MS m / z: 609 [M+H] + .

[1207] Example 69

[1208]

[1209] Compound 68 (CP68, confirmed) was synthesized following the procedure outlined in CP9. LCMS: m / z: 642 [M+H] + .

[1210] Example 70

[1211]

[1212] Compound 69 (CP69, trifluoroacetate, confirmed) was synthesized following the procedure of CP68. LCMS: m / z: 630 [M+H] + .

[1213] Example 71

[1214]

[1215] CP70-2 was synthesized from 4-aminobut-1-ol and INT6 using the same procedure as CP42-6.

[1216] To a solution of CP70-2 (97 mg) in trimethyl orthoformate (3 mL), p-TsOH·H₂O (62 mg) was added. The mixture was purged with N₂ and stirred at 100 °C for 0.5 h. The reaction mixture was cooled to RT, diluted with EA and water, and the separated organic layer was concentrated and purified to give CP70-3 (157 mg). MS: m / z: 356 [M+H] + .

[1217] Compound 70 (CP70, TFA salt, confirmed) was synthesized following the steps of CP42 with CP70-3. LCMS: m / z: 616 [M+H] + .

[1218] Example 72

[1219]

[1220] At 0°C, a sulfur trioxide pyridine complex (7.36 g) was added to a solution of 71-a (1.03 g) and TEA (7.76 g) in 10 mL of DCM and 20 mL of DMSO, and the resulting mixture was stirred for 4 hours. The residue was diluted with DCM and washed with sodium thiosulfate solution (10%), 5% citric acid solution, and saturated sodium chloride solution (80 mL). The resulting solution was dried, filtered, and concentrated to give CP71-1 (1.06 g).

[1221] Synthesize CP71-5 using CP71-1 in a manner similar to INT15.

[1222] Compound 71 (CP71, confirmed) was synthesized using CP71-5 via a method similar to that used for CP46. LCMS: m / z: 598 [M+H] + .

[1223] Example 73

[1224]

[1225] Under N2 and RT conditions, 72-a (1.36 g) was added to an allyl magnesium chloride solution (2 M THF solution, 15 mL) and stirred at 80 °C for 20 hours. The reaction mixture was quenched with a saturated ammonium chloride solution (60 mL) and diethyl ether (80 mL). The organic layer was separated and washed with acetic acid solution (1%), saturated NaHCO3, and saturated sodium chloride solution. The resulting solution was dried, filtered, and concentrated to give CP72-1 (2.20 g).

[1226] Grubbs second-generation catalyst (0.39 g) was added to a solution of CP72-1 (0.85 g), styrene (2.50 g), and tetraethyl titanate (1.14 g) in DCE (20 mL). The mixture was purged with N2 and stirred at 70 °C for 16 hours. After completion, the mixture was concentrated and purified to obtain CP72-2 (0.61 g).

[1227] p-TsOH·H₂O (160 mg) was added to a solution of CP72-2 (0.543 g) and CP71-3 (0.282 g) in DMSO (10 mL). The mixture was purged with N₂ and stirred at 80 °C for 16 hours. The reaction mixture was cooled to RT, diluted with EA and water, and the resulting mixture was separated. The collected organic layer was concentrated and purified to give CP72-3 (197 mg). MS: m / z: 456 [M+H] + .

[1228] Compound 72 (CP72, confirmed) was synthesized using CP72-3 following the procedure of CP71. LCMS: m / z: 612 [M+H] + .

[1229] Example 74

[1230]

[1231] CataCXium APd G3 (82 mg) was added to a solution of CP36-9 (228 mg), 73-a (596 mg), and Cs2CO3 (482 mg) in toluene (10 mL) and water (2.5 mL). The mixture was purged with N2 and stirred at 100 °C for 16 hours. After completion, the mixture was diluted with EA and water. The separated organic layer was concentrated and purified to give compound 73 (CP73, confirmed). MS: m / z: 625 [M+1] + .

[1232] Example 75

[1233]

[1234] Compound 74 (CP74, confirmed) was synthesized using CP9-6 and 74-a in a manner similar to that used for CP46. MS: m / z: 628 [M+H] + .

[1235] Example 76

[1236]

[1237] To a solution of CP10 B-3 (64 mg), 75-a (64 mg), and Cs₂CO₃ (137 mg) in toluene (10 mL) and water (2.5 mL), bis(diphenylphosphine phenyl ether) palladium(II) dichloride (10 mg) was added. The mixture was purged with N₂ and stirred at 105 °C for 16 hours. After completion, the mixture was diluted with EA and water. The organic layer was separated and concentrated to give CP75-2 (133 mg). MS: m / z: 723 [M+1] + .

[1238] TFA (1.5 mL) was added to a solution of CP75-2 (133 mg) in DCM (5 mL). The reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was concentrated. The residue was diluted with EA and saturated NaHCO3. The separated organic layer was concentrated and purified to give compound 75 (CP75, confirmed). MS: m / z: 623 [M+H] + .

[1239] Example 77

[1240]

[1241] Lithium aluminum deuteride (1508 mg) was added to a 0°C solution of 76-a (5094 mg) in THF (50 mL). The mixture was stirred at 0°C for 4 h. The mixture was quenched with 1.5 mL water, 1.5 mL 15% NaOH, 4.5 mL water, and a small amount of anhydrous Na₂SO₄. The mixture was filtered and concentrated to obtain 76-b (3285 mg). MS: m / z: 10⁹ [M+H] + .

[1242] Compound 76 (CP76, confirmed) was synthesized using CP76-b via a method similar to that used for CP9. MS: m / z: 618 [M+H] + .

[1243] Example 78

[1244]

[1245] DAST (0.493 g) was added to a 0°C solution of CP83-10 (0.698 g) in DCM (5 mL). The mixture was stirred at 0°C for 1.5 h, and then quenched with sat.NaHCO3 (aq.). The mixture was then extracted with DCM and post-processed to obtain CP77-1 (0.206 g). MS: m / z: 372 [M+H] + .

[1246] Compound 77 was synthesized using CP77-1 via a method similar to that used for CP46 (CP77, 0.0013 g, TFA salt, confirmed). MS: m / z: 632 [M+H] + .

[1247] Example 79

[1248]

[1249] The mixture of CP113-3 (1.295 g) and trifluoroacetic acid (5 mL) was stirred overnight at RT. The reaction mixture was concentrated. The resulting mixture was diluted with PE and EA (10:1) and filtered. The filter cake was concentrated to give CP78-1 (1024 mg). MS: m / z: 342 [M+H] + .

[1250] A mixture of CP78-1 (0.201 g) in acetic acid (2 mL) and acetic anhydride (1 mL) was stirred at 80 °C for 3 days. The mixture was quenched with H₂O, extracted with DCM and MeOH (10:1), and post-treated to obtain CP78-2 (206 mg). MS: m / z: 384 [M+H] + .

[1251] Compound 78 (CP78, confirmed) was synthesized using CP78-2 via a method similar to that used for CP46. MS: m / z: 644 [M+H] + .

[1252] Example 80

[1253]

[1254] A solution of 79-a (3.58 g), 4-methoxybenzylamine (5.62 g), DIEA (10.0170 g), and HATU (15.18 g) in DCM (80 mL) was stirred overnight at RT. The mixture was extracted with DCM and post-treated to give CP79-1 (1.05 g). MS: m / z: 210 [M+H] + .

[1255] LAH (0.308 g) was added to THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 15 minutes, and aluminum chloride (1.071 g) was added. The mixture was stirred at 0 °C for 30 minutes, and CP79-1 (0.74 g) was added. The mixture was stirred at 0 °C for 30 minutes. The mixture was quenched with NaOH (aq., 0.3 mL, 15%) and extracted with DCM. The mixture was washed with NH4Cl, dried, and concentrated to give CP79-2 (0.39 g). MS: m / z: 196 [M+H] + .

[1256] A solution of INT6 (0.603 g), DIEA (1.4840 g), and POCl3 (2.6320 g) in toluene (20 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated to obtain a mixture. CP79-2 (0.39 g) was added to the mixture and DIEA (2.6320 g) in DCM (5 mL) solution at 0 °C. The mixture was stirred overnight at 0 °C. The residue was concentrated and purified to obtain CP79-3 (238 mg). MS: m / z: 457 [M+H] + .

[1257] A solution of CP79-3 (0.218 g) in TFA (3 mL) was stirred at 60 °C for 1 h. The mixture was then concentrated to obtain CP79-4 (0.298 g). MS: m / z 337: [M+H] + .

[1258] Compound 79 (CP79, confirmed) was synthesized using CP79-4 following the procedure of CP71. LCMS: m / z: 630 [M+H] + .

[1259] Example 81

[1260]

[1261] A selective fluorine reagent (27.58 g) was added to a solution of 80-a (5.01 g) and L-proline (3.66 g) in MeCN (50 mL) and methanol (50 mL) at 0 °C. The mixture was stirred overnight at 55 °C. The mixture was concentrated and purified to give CP80-1 (3.284 g).

[1262] Compound 80 (CP80, confirmed) was synthesized using CP80-1 via a method similar to CP71. MS: m / z: 630 [M+H] + .

[1263] Example 82

[1264]

[1265] At RT, 29 mg NaHCO3 and 139 mg Dess-Martin oxidant were added to a 10 mL solution of CP83-10 (0.1 g) in DCM, and the mixture was stirred for 1 h. The reactants were filtered, and the filtrate was concentrated to obtain the crude product. The crude product was diluted with 2 mL DCM, and 65 mg m-CPBA was added at RT, and the mixture was stirred for 1 h. The mixture was quenched with sodium thiosulfate, extracted with DCM, and post-treated to obtain CP81-1 (173 mg). The crude product was used directly in the next step. MS (ESI, m / z): 400 [M+H] + .

[1266] A solution of molecular sieve 4A, CP81-1 (172 mg), DIEA (160 mg), and INT 14 (109 mg) in toluene (5 mL) was stirred at 80 °C for 16 h under N2 conditions. The reaction mixture was cooled to RT. The reaction mixture was concentrated and purified to give CP81-2 (65 mg). MS (ESI, m / z): 479 [M+H] + .

[1267] Under N2, DAST (0.5 mL) was added in portions over 2 minutes to a 0°C solution of CP81-2 (0.052 g) in DCM (1 mL). The mixture was stirred at RT for 3 h and quenched with saturated NaHCO3 solution. CP81-3 (10 mg) was then extracted with DCM and post-processed to obtain MS (ESI, m / z): 501 [M+H]. + .

[1268] Compound 81 (CP81, confirmed) was synthesized using CP81-3 via a method similar to that used for CP46. MS (ESI, m / z): 650 [M+H] + .

[1269] Example 83

[1270]

[1271] Compound 82 (CP82, confirmed) was synthesized using CP82-1 via a method similar to that used for CP46. MS: m / z: 630 [M+H] + .

[1272] Example 84

[1273]

[1274] NaH (15.54 g) was added to a solution of 83-a (50.04 g) in THF (400 mL) at -20 °C. The mixture was stirred at -20 °C for 2 h. n-BuLi (210 mL) was added to the reaction mixture. The mixture was stirred at -20 °C for 1 h. A solution of benzyl 2-bromoethyl ether (81.59 g) in THF (100 mL) was added to the reaction mixture. The mixture was stirred overnight at RT. The mixture was diluted with sat. NH4Cl (aq.) and water, extracted with EA, and post-treated to give CP83-1 (92.29 g). MS: m / z: 265 [M+H] + .

[1275] A solution of CP83-1 (48.77 g) in dibenzylamine (200 mL) was stirred overnight at 100 °C under N2. The mixture was quenched with water, extracted with EA, and post-treated to obtain CP83-2 (76.66 g). MS: m / z: 416 [M+H] + .

[1276] NaBH4 (12.74 g) was added to a 0°C solution of CP83-2 (76.66 g) in THF (200 mL). The mixture was stirred at RT for 5 h. The mixture was quenched with MeOH (20 mL) and water, extracted with EA, and post-treated to obtain CP83-3 (47.61 g). MS: m / z: 418 [M+H] + .

[1277] TBDMSCl (45.26 g) was added to a solution of CP83-3 (41.16 g) and imidazole (27.32 g) in DMF (50 mL) at 0 °C. The mixture was stirred at RT for 2 h. The mixture was quenched with water, extracted with EA, and post-treated to obtain CP83-4 (57.45 g). MS: m / z: 532 [M+H] + .

[1278] CP83-4 (57.45 g) was added to a solution of diisobutylaluminum hydride (250 mL) in THF (400 mL) at -40 °C. The mixture was stirred at -20 °C to -40 °C for 3 h. The mixture was quenched with EA (300 mL) and potassium sodium tartrate solution. The mixture was heated to RT and stirred vigorously for 4 h. When the solution became clear, it was extracted with EA and post-treated to obtain CP83-5 (8.29 g). MS: m / z: 518 [M+H] + .

[1279] A solution of CP83-5 (8.29 g), Pd / C (4.07 g), and Pd(OH)2 / C (5.34 g) in IPA (200 mL) was stirred overnight at 65 °C under H2. The mixture was filtered, the filtrate was collected and concentrated to give CP83-6 (3.989 g). MS: m / z: 248 [M+H] + .

[1280] A solution of INT6 (4.45 g), phosphorus oxychloride (8 mL), and DIEA (8 mL) in toluene (50 mL) was stirred overnight at 80 °C. The reactants were concentrated to obtain a mixture. CP83-6 (3.53 g) was added to the mixture and a solution of DIEA (2 mL) in DCM (10 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. Purification yielded CP83-7 (3.78 g). MS: m / z: 509 [M+H] + .

[1281] A solution of CP83-7 (3.59 g), methylamine hydrochloride (2.62 g), and DIEA (7.07 g) in DMA (20 mL) was stirred at 80 °C for 3 h. The mixture was quenched with water, extracted with EA, and post-processed to obtain CP83-8 (4.447 g). MS: m / z: 504 [M+H] + .

[1282] Pyridine sulfur trioxide (4.74 g) was added to a solution of CP83-8 (4.29 g) and TEA (7.97 g) in DCM (6 mL) and DMSO (12 mL) at -40 °C. The mixture was stirred at RT for 3 h, quenched with sat. Na2S2O3 (aq.), extracted with DCM, and post-treated to obtain CP83-9 (2.301 g). MS: m / z: 502 [M+H] + .

[1283] CP83-9 (2.301 g) and p-TsOH·H2O (0.914 g) were stirred overnight at 80 °C in DMSO (10 mL) and purified to give CP83-10 (0.726 g). MS: m / z: 370 [M+H] + .

[1284] At 0 °C, DAST (0.269 g) was added to a solution of CP83-10 (0.283 g) in DCM (5 mL). The mixture was stirred at 0 °C for 1.5 h, quenched with sat. NaHCO3 (aq.), extracted with DCM, and post-treated to obtain CP83-11 (0.047 g). MS: m / z: 372 [M+H] + .

[1285] Compound 83 (CP83, confirmed) was synthesized using CP83-11 via a method similar to that used for CP46. MS: m / z: 632 [M+H] + .

[1286] Example 85

[1287]

[1288] TBDMSCl (0.138 g) was added to a 0°C solution of CP83-10 (0.101 g) and imidazole (0.140 g). The mixture was stirred at RT for 2 h. The mixture was quenched with water and extracted with EA, followed by post-treatment to obtain CP84-1 (0.057 g). MS: m / z: 484 [M+H] + .

[1289] CP84-3 was synthesized using CP84-1 in a manner similar to that of CP46-10.

[1290] The racemic CP84-3 was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRALPAK-IG 20 mm × 250 mm; mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 20 mL / min, 220 nm. CP84-4A (first eluting isomer, retention time 5.767 min) and CP84-4 (second eluting isomer, retention time 7.067 min, 0.015 g) were obtained. MS: m / z: 595 [M+H] + .

[1291] A solution of CP84-4 (0.015 g), INT13 (0.038 g), catalyst A Pd G3 (0.020 g), and Cs2CO3 (0.043 g) in toluene (5 mL) and water (1 mL) was stirred overnight at 100 °C under N2. Water was added to the mixture, and it was extracted with EA. The organic phase was post-treated to give CP84-5 (0.026 g). MS: m / z: 1065 [M+H] + .

[1292] Compound 84 (CP84, confirmed) was synthesized using CP84-4 via a method similar to that used for CP83. MS: m / z: 630 [M+H] + .

[1293] Example 86

[1294]

[1295] 2-[(fluoromethyl)sulfonyl]pyridine (0.286 g) was added to a DMF (10 mL) solution of CP61-1 (0.508 g), and the resulting mixture was stirred at -50 °C under N2. Potassium tert-butoxide (0.239 g) was added. The solution was stirred at RT for 4 h. The mixture was diluted with EA, washed with NH4Cl (aq) (50 mL), H2O (50 mL), and saturated NaCl (aq), and concentrated. 10 mL of PE and 2 mL of EA were added, and the resulting mixture was stirred for 1 h. The mixture was filtered to give CP85-1 (346 mg). MS: m / z: 384 [M+H] + .

[1296] At 0 °C, a solution of CP85-1 (346 mg) in DCM (10 mL) was added in portions to m-CPBA (0.367 g), and the resulting mixture was stirred at RT for 2 h. The mixture was diluted with DCM (50 mL) and washed with water, saturated NaHCO3 solution, and saturated NaCl (aq). The organic layer was dried and concentrated to obtain CP85-2 (365 mg, crude product) for the next step. MS: m / z: 400 [M+H] + .

[1297] A solution of CP85-2 (365 mg), INT14 (0.243 g), and DIEA (389 mg) in toluene (15 mL) was stirred at 85 °C for 16 h. The mixture was cooled to RT, diluted with EA, and washed with water and NaCl (aq). The organic layer was concentrated. The residue was purified by Prep-TLC (DCM / MeOH = 15:1) to give CP85-3 (174 mg) and CP85-4 (79 mg). MS: m / z: 495 [M+H] + .

[1298] Compound 85 (CP85, confirmed) was synthesized using CP85-3 via a method similar to that used for CP46. LCMS: m / z: 644 [M+H] + .

[1299] Example 87

[1300]

[1301] Compound 86 (CP86, confirmed) was synthesized using CP85-4 via a method similar to that used for CP46. MS: m / z: 644 [M+H] + .

[1302] Example 88

[1303]

[1304] Carbonyl diimidazole (39.17 g) was added to a DMF (350 mL) solution of 87-a (34.11 g), and the resulting mixture was stirred at RT for 16 h. Potassium monomethyl malonate (39.34 g), magnesium chloride (47.90 g), and TEA (51.57 g) were added at 0 °C. The solution was stirred at RT for 20 h. The solution was filtered, diluted with water, extracted with EA, and post-treated to obtain CP87-1 (40.33 g). MS: m / z: 260 [M+H] + .

[1305] A solution of CP87-1 (46.4720 g) in 400 mL of MeOH was added to NaBH4 (2.300 g). The resulting mixture was stirred at 0 °C for 3 h. The solution was diluted with EA and post-treated to obtain CP87-2 (34.04 g). MS: m / z: 262 [M+H] + .

[1306] A solution of CP87-2 (4.11 g) in THF (50 mL) was added to lithium aluminum hydride (633 mg), and the resulting mixture was stirred at 0 °C for 2 h. The solution was diluted with THF (20 mL) and quenched with water (0.6 mL), 15% sodium hydroxide solution, and water (1.8 mL). The solution was filtered, concentrated, and purified to obtain CP87-3 (3506 mg). MS: m / z: 234 [M+H] + .

[1307] TEA (7.6541 g), TBDMSCl (7.6005 g), and DMAP (616.061 mg) were added to a solution of CP87-3 (11.765 g) in DCM (120 mL). The resulting mixture was stirred overnight at RT. The mixture was then diluted with DCM and post-treated to obtain CP87-4 (12.691 g). MS: m / z: 348 [M+H] + .

[1308] At 0°C, trifluoroacetic acid (40 mL) was added to a solution of CP87-4 (8.557 g) in DCM (90 mL), and the resulting mixture was stirred at RT for 3 h. The mixture was concentrated to give CP87-5 (22.433 g, crude product), which was used in the next step. MS: m / z: 134 [M+H] + .

[1309] Compound 87 (CP87, confirmed) was synthesized using CP87-5 via a method similar to that used for CP47. MS: m / z: 630 [M+H] + .

[1310] Example 89

[1311]

[1312] A solution of 88-a (5.01 g), 2-methylpropane-2-sulfinamide (6.88 g), and tetraethyl titanate (18.91 g) in THF (150 mL) was stirred overnight at 65 °C. The reaction mixture was concentrated to give CP88-1 (10.2 g) for the next step. MS: m / z: 202 [M+H] + .

[1313] At 0 °C, a MeOH (80 mL) solution of CP88-1 (10.2 g) was added in portions to NaBH4 (3.773 g), and the resulting mixture was stirred at this temperature for 0.5 h. The solution was quenched with water and filtered to obtain a white solid. The filtered organic liquid was concentrated, and the solution was extracted with EA. Post-treatment of the organic layer yielded CP88-2 (4.744 g). MS: m / z: 204 [M+H] + .

[1314] Hydrochloric acid (15 mL) was added to a DCM (50 mL) solution of CP88-2 (4.744 g). The solution was stirred at RT for 2 h, and the reactants were concentrated. The residue was dissolved in MTBE and concentrated. MTBE was added to the residue at 0 °C. The solid was collected by filtration to give CP88-3 (1.784 g). MS: m / z: 100 [M+H] + .

[1315] Synthesize CP88-5 using CP88-3 in a manner similar to INT15.

[1316] A solution of CP88-5 (593 mg), Grubb's second-generation catalyst (103 mg), and acrolein dimethyl acetal (461 mg) in DCM (10 mL) was stirred at 45 °C for 16 h under N2. The mixture was then cooled to RT and concentrated. Purification yielded CP88-6 (453 mg). MS: m / z: 384 [M+H] + .

[1317] CP88-10 was synthesized from CP88-6 using a method similar to that used for CP83-10.

[1318] CP88-10 was separated using Prep-HPLC-Gilson (conditions: column, CHIRAL ART Cellulose-SC, 20 mm × 250 mm, 5 μm); mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min, 220 nm. CP88-11 was obtained (second eluting isomer, retention time 6.053 min, 104 mg). MS: m / z: 479 [M+H] + .

[1319] Compound 88 (CP88, confirmed) was synthesized using CP88-11 via a method similar to that used for CP46. MS: m / z: 628 [M+H] + .

[1320] Example 90

[1321]

[1322] CP89-d was synthesized from 89-a using a method similar to that of CP88-3.

[1323] At 0 °C, Cbz-Cl (3.545 g) was added dropwise to a DCM (50 mL) solution of 89-d (2.327 g) and TEA (4.456 g). The solution was stirred at RT for 16 h under N2. The mixture was diluted with NaCl solution, extracted with EA, and post-treated to obtain 89-e (2.975 g). MS: m / z: 234 [M+H] + .

[1324] CP88-f was synthesized using CP89-e in a manner similar to that of CP88-6.

[1325] At 0 °C, 0.743 g of NaBH4 was added dropwise to a 150 mL solution of 89-f (3.364 g) in MeOH. The solution was stirred at RT for 3 h under N2. The mixture was quenched with water, extracted with EA, and post-treated to obtain 89-g (3.14 g). MS: m / z: 264 [M+H] + .

[1326] A solution of 89-g (3.14 g) and Pd / C (604 mg) in THF (80 mL) was stirred at RT for 15 h under H2 conditions. The mixture yielded 89-h (1.565 g) directly. MS: m / z: 132 [M+H] + .

[1327] At 0 °C, Cbz-Cl (2.569 g) was added dropwise to a THF (50 mL) solution of 89-h (1.565 g) and TEA (1.906 g). The solution was stirred at RT for 15 h under N2. The solution was filtered, the filtrate was diluted with water, extracted with EA, and post-treated to obtain 89-i (1.37 g). MS: m / z: 266 [M+H] + .

[1328] A solution of 89-i (1.37 g) and Pd / C (1.63 g) in DCM (50 mL) was stirred at RT and N2 for 5 h. The solution was filtered, concentrated, and purified to give 89-j (893 mg). MS: m / z: 264 [M+H] + .

[1329] A solution of 89-j (893 mg), 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroborate) (2.541 g), and L-proline (85 mg) in ACN (15 mL) and methanol (15 mL) was stirred at 65 °C under N2 for 16 h. The mixture was concentrated and purified to give 89-k (1.016 g). MS: m / z: 328 [M+H] + .

[1330] A solution of 89-k (1.016 g) and Pd / C (0.338 g) in THF (30 mL) was stirred at RT and H2 for 2 h. The mixture yielded 89-l (599.744 mg) directly. MS: m / z: 194 [M+H] + .

[1331] Compound 89 (CP89, confirmed) was synthesized using CP89-l via a method similar to that used for CP46. MS: m / z: 646 [M+1] + .

[1332] Example 91

[1333]

[1334] At 0 °C and N2, a solution of CP62-1 (2.64 g) in THF (200 mL) and DCM (100 mL) was added dropwise to DAST (1.69 g), and stirred at RT for 2 h. The solution was quenched with saturated NaHCO3 solution (100 mL), extracted with DCM (300 mL), dried, concentrated, and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain CP40A-1 (2.23 g).

[1335] CP40A-1 was separated by chiral high-performance liquid chromatography. Conditions: CHIRALPAK-IG, 20 mm × 250 mm, 5 μm mobile phase, Hex (0.1% DEA) / EtOH (70:30); flow rate: 20 mL / min, yielding CP40A-2 (first eluting isomer, retention time 6.3 min, 0.58 g). MS: m / z: 372 [M+H] + .

[1336] Compound 40A (CP40A, confirmed) was synthesized using CP40A-2 following the procedure of CP46 and purified under the following conditions: Prep-HPLC (YMC-Triart C18-S 12nm, 50mm × 250mm, 7µm, A: 0.05% NH4+). 3·H₂O, B:CH₃CN, gradient: 36 min 35% B to 77% B, flow rate 70 mL / min, 224 nm). LCMS: m / z: 632 [M+H] + .

[1337] Example 92

[1338]

[1339] Compound 90 (CP90, confirmed) was synthesized using a method similar to that used for CP46. MS: m / z: 656 [M+1] + .

[1340] Example 93

[1341]

[1342]

[1343] CP91-6 was synthesized using a method similar to that used for CP71-6.

[1344] CP91-6 was separated using Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC, 20 mm × 250 mm; mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min, 220 nm. CP91-7A (41 mg, first eluting isomer, retention time 6.903 min) and CP91-7B (50 mg, second eluting isomer, retention time 7.681 min) were obtained. MS: m / z: 463 [M+1] + .

[1345] Compound 91A (CP91A, 26 mg, confirmed) was synthesized using a similar method to that used in the synthesis of CP46 from CP91-7A. MS: m / z: 612 [M+1] + .

[1346] Compound 91B (CP91B, 38 mg, confirmed) was synthesized using a similar method to that used in the synthesis of CP46 from CP91-7B. MS: m / z: 612 [M+1] + .

[1347] Example 94

[1348]

[1349] At 100 °C, benzyl bromide (57.81 g) was added dropwise to a solution of 92-a (9.9 g) and K₂CO₃ (47.17 g) in ethanol (300 mL). The solution was stirred at 100 °C under N₂ for 15 h. The mixture was concentrated, diluted with NaHCO₃ solution, extracted with EA, and post-treated to obtain CP92-1 (20.61 g). MS: m / z: 272 [M+H] + .

[1350] A solution of CP92-1 (20.61 g), DMAP (9.79 g), TEA (12.12 g), and TBDMSCl (13.82 g) in DCM (200 mL) was stirred at RT for 20 h. The solution was diluted with NaHCO3 solution and post-treated to obtain CP92-2 (23.24 g). MS: m / z: 386 [M+H] + .

[1351] At 0 °C, NaH (642 mg) was added to a solution of CP92-2 (4.15 g) in THF (50 mL). The solution was stirred at 0 °C under N2 for 10 min, and methyl iodoform (3.27 g) was added dropwise to the mixture. The solution was stirred at RT under N2 for 16 h. The solution was quenched with water, extracted with EA, and post-treated to obtain CP92-3 (4.286 g). MS: m / z: 400 [M+H] + .

[1352] A solution of CP92-3 (4.286 g) and CsF (6.240 g) in DMF (40 mL) was stirred at 35 °C for 16 h. The solution was diluted with EA, washed with NaCl solution, and post-treated to obtain CP92-4 (2.518 g). MS: m / z: 286 [M+H] + .

[1353] CP92-11 was synthesized from CP92-4 using a method similar to that used for CP46-10.

[1354] CP92-11 was separated using Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC, 20 mm × 250 mm, 5 μm; mobile phase: (Hex:DCM = 3:1) (0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min, 220 nm. CP92-12A (58 mg, first eluting isomer, retention time 6.797 min) and CP92-12B (26 mg, second eluting isomer, retention time 8.2 min) were obtained. MS: m / z: 497 [M+1] + .

[1355] Compound 92A (CP92A, 36.8 mg, assumed) was synthesized and purified using a similar method to that used in the synthesis of CP46 from CP92-12A. MS: m / z: 646 [M+1] + .

[1356] Compound 92B (CP92B, hypothetical) was synthesized using a similar method to that used in the synthesis of CP46 from CP92-12B. MS: m / z: 646 [M+1] + .

[1357] Example 95

[1358]

[1359] At 0 °C, methylmagnesium bromide (8.5 mL) was added dropwise to a solution of CP61-1 (1.58 g) in THF (150 mL). The solution was stirred at 45 °C under N2 for 36 h. The mixture was quenched with NH4Cl solution, extracted with EA, and post-treated to obtain CP93-1 (674 mg). MS: m / z: 384 [M+H] + .

[1360] A solution of CP93-1 (674 mg) and DAST (0.99 g) in DCM (10 mL) was stirred at 45 °C for 3 h under N2. The mixture was cooled to RT, diluted with NaHCO3 solution, and post-treated to obtain CP93-2 (276 mg). MS: m / z: 386 [M+H] + .

[1361] CP93-4 was synthesized from CP93-2 using a method similar to that used for CP46-10.

[1362] CP93-4 was separated using Prep-HPLC-Gilson under the following conditions: CHIRAL ART Cellulose-SC, 20 mm × 250 mm, 5 μm mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / IPA (50:50); flow rate: 15 mL / min, 220 nm. CP93-5A (50 mg, first eluting isomer, retention time 4.933 min) and CP93-5B (49 mg, second eluting isomer, retention time 7.847 min) were obtained. MS: m / z: 497 [M+1] + .

[1363] Compound 93A (CP93A, 32.4 mg, confirmed) was synthesized using a similar method to that used in the synthesis of CP46 from CP93-5A. MS: m / z: 646 [M+1] + .

[1364] Compound 93B (CP93B, 32.7 mg, confirmed) was synthesized using a similar method to that used in the synthesis of CP46 from CP93-5B. MS: m / z: 646 [M+1] + .

[1365] Example 96

[1366]

[1367] Titanium tetrachloride (55.12 g) in DCM (50 mL) was added to a solution of 94-a (10.09 g) in DCE (150 mL), benzylamine (22.87 g), and TEA (28.76 g). The resulting mixture was stirred at 0 °C for 5 h at RT. A MeOH (15 mL) solution of sodium cyanoborohydride (6.78 g) was added at 0 °C. The solution was stirred at RT for 16 h. The mixture was adjusted to pH 8 with NaHCO3 (aq). The mixture was diluted with EA, washed with water, and post-treated to obtain 94-b (4.86 g). MS: m / z: 236 [M+H] + .

[1368] To a solution of 94-b (4.50 g) in ACN (10 mL), K₂CO₃ (7.95 g), TBAI (0.85 g), and BnBr (6.69 g) were added, and the resulting mixture was stirred at RT for 16 h. The solution was filtered and diluted with EA. The mixture was concentrated and purified to obtain 94-c (4.86 g). MS: m / z: 326 [M+H] + .

[1369] At 0°C, a solution of 94-c (4.95 g) in THF (50 mL) was added to LAH (1.22 g), and the resulting mixture was stirred at 25°C for 2 h, followed by stirring with Na₂SO₄. 4· Dilute the mixture with 10H₂O. Filter the solution and dilute with EA. Concentrate and purify the mixture to give 94-d (4.48 g). MS: m / z: 284 [M+H] + .

[1370] At 0 °C, NaH (1.61 g), DMAP (0.10 g), and TBAI (0.35 g) were added to a 50 mL THF solution of 94-d (4.48 g). The resulting mixture was stirred at 70 °C for 5 h at RT. The solution was diluted with EA and post-treated to obtain 94-e (5.01 g). MS: m / z: 372 [M+H] + .

[1371] Pd(OH)₂ / C (0.44 g) and Pd / C (0.43 g) were added to a 20 mL solution of MeOH containing 2.06 g of 94-e under H₂ conditions. The reaction mixture was stirred at 25 °C for 16 hours. The resulting mixture was filtered and the filtrate was concentrated to give CP94-1 (0.97 g, crude product). MS: m / z: 192 [M+H] + .

[1372] CP94-4 was synthesized using CP94-1 in a manner similar to that of CP46-8.

[1373] CP94-4 was separated using Prep-HPLC-Gilson under the following conditions: column: CHIRALART Cellulose-SC, 20 mm × 250 mm; mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / IPA (50:50); flow rate: 17 mL / min, 220 nm. CP94-5A (first eluting isomer, retention time 4.728 min) and CP94-5 (second eluting isomer, retention time 10.189 min) were obtained. MS: m / z: 384 [M+H] + .

[1374] CP94 (CP94, confirmed) was synthesized with CP94-5 following the procedure outlined in CP46. LCMS:m / z:644[M+H] + .

[1375] Example 97

[1376]

[1377] NaBD4 (0.75 g) was added to a solution of CP61-1 (2.16 g) in DCM (150 mL) and THF (150 mL), and the resulting mixture was stirred at RT for 16 h. The solution was quenched with water, extracted with DCM, and post-treated to obtain CP95-1 (1.93 g, crude product). MS: m / z: 371 [M+H] + .

[1378] CP95-4 was synthesized using CP95-1 in a manner similar to that of CP40A-4.

[1379] CP95-4 was separated using Prep-HPLC-Gilson under the following conditions: CHIRAL ART Cellulose-SC, 20 mm × 250 mm, 5 μm mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / IPA (50:50); flow rate: 15 mL / min. CP95-5 (second eluting isomer, retention time 7.580 min).

[1380] Compound 95 (CP95, confirmed) was synthesized following the procedure of CP93. LCMS: m / z: 633 [M+H] + .

[1381] Example 98

[1382]

[1383] A solution of 96-a (5.07 g), benzyl bromide (20.93 g), K₂CO₃ (16.70 g), and TBAI (10.5 g) in MeCN (100 mL) was stirred overnight at RT. The reaction solution was filtered, washed with EA, and concentrated. The residue was purified to give 96-b (1.38 g). MS: m / z: 286 [M+H] + .

[1384] To a solution of 96-b (6.32 g) and DCM (25 mL) in DMSO (50 mL), TEA (19.06 g) and pyridine sulfur trioxide (14.23 g) were added, and the resulting mixture was stirred at 0 °C for 3 h. The reaction was quenched with Na₂S₂O₃, extracted with EA, and post-treated to obtain 96-c (2.78 g). MS: m / z: 284 [M+H] + .

[1385] 96-c (3.85 g), p-TsOH·H₂O (2.65 g), and methyl orthoformate (4.36 g) were stirred in toluene (40 mL) at 100 °C for 16 hours. The mixture was cooled to RT, diluted with EA, and post-treated to obtain 96-d (2.35 g). MS: m / z: 330 [M+H] + .

[1386] Pd / C (0.43 g) was added to a 20 mL solution of MeOH containing 2.35 g of 96-d under H₂ conditions. The reaction mixture was stirred at 25 °C for 16 hours. The resulting mixture was filtered, and the filtrate was concentrated to give 873 mg of 96-e. MS: m / z: 150 [M+H] + .

[1387] Compound 96 (CP96, confirmed) was synthesized from CP46 and CP96-e. LCMS: m / z: 628 [M+H] + .

[1388] Example 99

[1389]

[1390] A solution of 97-a (10.12 g), dibenzylamine (13.72 g), DMAP (1.82 g), and EDCI (23.62 g) in DCM (200 mL) was stirred overnight at RT. The solution was quenched with NH4Cl, extracted with DCM, concentrated, and purified to obtain 97-b (14.09 g). MS: m / z: 324 [M+H] + .

[1391] A solution of 97-b (14.09 g) and BH3 / THF (120 mL) in THF (80 mL) was stirred at 60 °C for 16 hours under N2. MeOH (120 mL) was added to the reaction mixture, and the mixture was stirred at 60 °C for 30 minutes and concentrated. THF (80 mL) and LAH (1.29 g) were added to the mixture at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with Na2SO4 decahydrate and post-treated to give 97-c (9.44 g). MS: m / z: 282 [M+H] + .

[1392] Compound 97 (CP97, confirmed) was synthesized with CP97-c following the procedure of CP46. LCMS: m / z: 642 [M+H] + .

[1393] Example 100

[1394]

[1395] A solution of 98-a hydrochloride (10.32 g), TBAI (1.41 g), K₂CO₃ (33.18 g), and BrBn (32.05 g) in MeCN (100 mL) was stirred at RT for 16 h. The mixture was concentrated and purified to give 98-b (17.2 g). MS: m / z: 284 [M+H] + .

[1396] Sodium hydroxide (3.23 g) was added to a solution of 98-b (17.2 g) in MeOH (40 mL) and H₂O (40 mL). The reaction mixture was stirred at RT for 16 h, adjusted to pH ~3, and concentrated. The mixture was quenched with water, extracted with EA, and post-treated to obtain 98-c (12.3 g). MS: m / z: 270 [M+H] + .

[1397] To a DMF (50 mL) solution of 98-c (12.3 g), dimethylhydroxylamine hydrochloride (5.96 g), HATU (20.85 g), and DIEA (20.54 g) were added. The reaction mixture was stirred at RT for 2 h. After stirring, water was added, and the aqueous layer was extracted with EA and post-treated to obtain 98-d (13.95 g). MS: m / z: 313 [M+H] + .

[1398] MeMgBr (24.5 mL) was added to a solution of 98-d (13.95 g) in THF (150 mL) at 0 °C. The mixture was stirred at RT for 8 h, and then quenched with aq. NH4Cl and water. The resulting mixture was extracted with DCM and post-treated to obtain 98-e (5.8 g). MS: m / z: 268 [M+H] + .

[1399] Add 1.24 g of NaBH4 to a MeOH (50 mL) solution of 98-e (5.8 g). Stir the reaction mixture at RT for 1 h. Concentrate the reaction mixture. Quench the mixture with water, extract with EA, and post-process to obtain 98-f (5.75 g). MS: m / z: 270 [M+H] + .

[1400] CP98-2 was synthesized using CP98-f following the steps of CP46-8.

[1401] CP98-2 (3.12 g) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC, 20 mm × 250 mm; mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min. CP98-3 (240 mg, third eluting isomer, retention time 9.080 min) was obtained.

[1402] Compound 98 (CP98) was synthesized with CP98-3 following the procedure of CP46.

[1403] Compounds 98A (CP98A), 98B (CP98B), and 98C (CP98C) were synthesized using a similar method. LCMS: m / z: 630 [M+H] + .

[1404] Example 101

[1405]

[1406] Compound 99 (CP99, confirmed) was synthesized using a method similar to that used for CP71. LCMS: m / z: 612 [M+H] + .

[1407] Example 102

[1408]

[1409] Compound 100 (CP100, confirmed) was synthesized using a method similar to that for CP94 via CP100-d. LCMS: m / z: 686 [M+H] + .

[1410] Example 103

[1411]

[1412]

[1413] Potassium tert-butoxide (0.415 g) was added to a solution of CP61-1 (1.139 g) and p-toluenesulfonylmethylisocyanate (0.876 g) in dioxane (40 mL) at 0 °C. The mixture was stirred at 50 °C for 0.5 h and then at RT for 16 h. The reaction mixture was diluted with EA and post-treated to give CP101-1 (587 mg). MS: m / z: 379 [M+H] + .

[1414] Compound 101 (CP101, confirmed) was synthesized using CP101-1 via a method similar to that used to prepare CP46. LCMS: m / z: 639 [M+H] + .

[1415] Example 104

[1416]

[1417] CP46 was separated using Prep-HPLC-Gilson chromatography under the following conditions: column: CHIRAL ART Cellulose-SA (2 cm × 25 cm, 5 μm); mobile phase: Hex (0.1% DEA) / EtOH (50:50); flow rate: 20 mL / min. Compound 102 (CP102, 17.5 mg, first eluting isomer, retention time 7.034 min) and compound 103 (CP103, 5.7 mg, second eluting isomer, retention time 10.862 min) were obtained. MS: m / z: 630 [M+H] + .

[1418] Example 105

[1419]

[1420] A mixture of CP9-3 (0.81 g), 3,3,3-trifluoropropylamine hydrochloride (0.85 g), DIEA (1.19 g), and DMA (10 mL) in a 48 mL sealed flask was stirred at 70 °C for 17 h. The mixture was diluted with water, extracted with EA, and post-treated to obtain CP104-1 (1.02 g). MS: m / z: 502 [M+H] + .

[1421] Compound 104 (CP104, confirmed) was synthesized using CP104-1 via a method similar to that used to prepare CP46. LCMS: m / z: 698 [M+H] + .

[1422] Example 106

[1423]

[1424] Compound 105 (CP105, confirmed) was synthesized using CP105-a via a method similar to that used to prepare CP94. LCMS: m / z: 670 [M+H] + .

[1425] Example 107

[1426]

[1427] At 0 °C, 15.96 g of NaH was added to a 200 mL THF solution of 106-a (19.93 g), and the resulting mixture was stirred at room temperature for 1 h. Bromoacetaldehyde dimethyl acetal (6.29 g), benzyl bromide (35.67 g), and 4-dimethylaminopyridine (2.07 g) were added to the reaction mixture, and the mixture was stirred at 25 °C under N2 for 16 h. The mixture was quenched with water, extracted with EA, and post-treated to obtain 106-b (34.24 g). MS: m / z: 191 [M+H] + .

[1428] A solution of 106-b (34.24 g) and m-chloroperoxybenzoic acid (40.60 g) in DCM (300 mL) was stirred at 25 °C for 16 hours, quenched with Na₂S₂O₃, extracted with DCM, and post-treated to obtain 106-c (20.94 g). MS: m / z: 207 [M+H] + .

[1429] A solution of 106-c (18.48 g) and dibenzylamine (53.47 g) in MeOH (300 mL) was stirred at 130 °C for 3 hours. The mixture was cooled to RT, concentrated, and purified to give 106-d (34.63 g). MS: m / z: 404 [M+H] + .

[1430] At 0 °C, tert-butyldimethylchlorosilane (36.70 g) was added to a solution of 106-d (32.46 g) and imidazole (21.97 g) in DMF (300 mL), and the resulting mixture was stirred at 40 °C for 2 h. The mixture was diluted with EA and post-treated to obtain 106-e (23.23 g). MS: m / z: 518 [M+H] + .

[1431] Pd / C (11.78 g) and Pd(OH)₂ / C (9.08 g) were added to a methanol (300 mL) solution of 10⁶-e (23.23 g) under H₂ conditions. The reaction mixture was stirred at 60 °C for 16 hours, filtered, and concentrated to obtain 10⁶-f (9.39 g). MS: m / z: 248 [M+H] + .

[1432] CP106-3 was synthesized using CP106-f in a similar manner to CP40-8.

[1433] A solution of CP106-3 (2.47 g) and p-TsOH·H2O (2.17 g) in DMSO (30 mL) was stirred at 80 °C for 16 h. The mixture was cooled to RT, diluted with water (50 mL), extracted with DCM, and post-treated to obtain CP106-4 (337 mg). MS: m / z: 37 [M+H] + .

[1434] A solution of CP106-4 (0.337 g), triethylamine (792 mg), pyridine sulfur trioxide (610 mg), and DCM (3 mL) in DMSO (6 mL) was stirred at 25 °C for h, quenched with Na₂S₂O₃, extracted with EA, and post-treated to obtain CP106-5 (190 mg). MS: m / z: 368 [M+H] + .

[1435] DAST (3.36 g) was added to a solution of CP106-5 (0.19 g) in DCM (10 mL) at 0 °C, and the resulting mixture was stirred at RT for 16 h. The mixture was quenched with a saturated NaHCO3 aqueous solution, extracted with DCM, and post-treated to obtain CP106-6 (132 mg). MS: m / z: 390 [M+H] + .

[1436] CP106-8 was synthesized from CP106-6 using a method similar to that of CP46-10.

[1437] CP106-8 was separated using Prep-HPLC-Gilson. Conditions: column: CHIRAL ART Cellulose-SC (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min, 220 nm. CP106-9A (first eluting isomer, retention time 4.67 min) and CP106-9B (second eluting isomer, retention time 6.98 min) were obtained. LCMS: m / z: 650 [M+H] + .

[1438] Compound 106A (CP106A, confirmed) was synthesized using CP106-9A via a similar preparation method to CP46.

[1439] Compound 106B (CP106B, confirmed) was synthesized using a similar method to that used for CP46 with CP106-9B. LCMS: m / z: 650 [M+H] + .

[1440] Example 108

[1441]

[1442] CP107-3 was synthesized with CP107-a in a manner similar to that of CP94-4.

[1443] The crude product CP107-3 (0.95 g) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ARTCellulose-SC (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min, 220 nm. CP107-4B (first eluting isomer, retention time: 4.17 min, 0.45 g) and CP107-4A (second eluting isomer, retention time: 7.193 min, 0.43 g) were obtained.

[1444] Compound 107A was synthesized using CP107-4A via a method similar to that used for CP46 (CP107A, 57.4 mg, confirmed). MS: m / z: 658 [M+H] + .

[1445] Compound 107B was synthesized using CP107-4B via a method similar to that of CP46 (CP107B, 0.0708 g, confirmed). MS: m / z: 658 [M+H] + .

[1446] Example 109

[1447]

[1448] CP108-2 was synthesized using INT17 in a manner similar to that of CP46-10.

[1449] CP108-2 was separated using Prep-HPLC-Gilson conditions: column, CHIRAL ART Cellulose-SC (2 cm × 25 cm, 5 μm); mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min, 220 nm. CP108-3B (0.37 g, first eluting isomer, retention time 4.11 min) and CP108-3A (0.3 g, second eluting isomer, retention time 5.8 min) were obtained. MS: m / z: 479 [M+H] + .

[1450] CP108-4B was synthesized with CP108-3B using a method similar to that of CP46-11.

[1451] DAST (0.41 g) was added to a 10 mL THF solution of CP108-4B (243.8000 mg) under N2 at 0 °C, and the resulting mixture was stirred at RT for 2 h. The mixture was diluted with saturated NaHCO3. Extraction with EA and post-treatment yielded CP108-5B (0.11 g). MS: m / z: 950 [M+H] + .

[1452] Compound 108B (CP108B, confirmed) was synthesized using CP108-5B following a similar method to that used for CP46. LCMS: m / z: 630 [M+H] + .

[1453] Compound 108A (CP108A, confirmed) was synthesized from CP108-3A using a similar method to that used for CP108B. LCMS: m / z: 630 [M+H] + .

[1454] Example 110

[1455]

[1456] A solution of CP10B-4 (140 mg) and CsF (0.35 g) in DMF (3 mL) was stirred at RT under N2 for 16 hours. The solution was diluted with saturated NH4Cl aqueous solution, extracted with EA, and post-treated to obtain the crude product CP109-1 (186 mg). MS: m / z: 780 [M+H] + .

[1457] A THF (5 mL) solution of crude product CP109-1 (186 mg) was cooled to -30 °C under N2, and LDA (2 M, 0.5 mL) was added dropwise at -30 °C. The mixture was stirred at -30 °C for 30 min, and CD3OD (4 mL) was added at -30 °C. The resulting mixture was stirred at -30 °C for 1 h. D2O and EA were added to the mixture, and post-treatment yielded crude product CP109-2 (0.19 g). MS: m / z: 781 [M+H] + .

[1458] TFA (2 mL) was added to a solution of crude CP109-2 (179 mg) in DCM (10 mL). The mixture was stirred at RT for 1 h, diluted with 10% NaHCO3 solution, extracted with DCM and post-treated to give compound 109 (CP109, 74.3 mg, confirmed). 1 HNMR (400MHz, DMSO-d6)δ=7.80-7.67(m,1H),7.34-7.28(m,1H),7.03-6.98(m,2H ),5.59(s,2H),5.40-5.17(m,2H),4.55-4.38(m,1H),4.20-3.91(m,4H),3.62-3. 47(m,1H),3.46-3.22(m,2H),3.16-3.00(m,3H),3.02-2.92(m,3H),2.86-2.80(m ,1H),2.32-2.10(m,2H),2.08-1.95(m,3H),1.90-1.69(m,3H).MS:m / z:617[M+H] + .

[1459] Example 111

[1460]

[1461] Pd / C (0.0373 g) was added to a solution of 108-3A (0.09 g) in CH3OH (10 mL) and DCM (30 mL). The mixture was stirred at RT for 3 h under H2. The solution was filtered and the filtrate was concentrated to give CP110-1 (0.0823 g). MS: m / z: 481 [M+H] + .

[1462] Compound 110 (CP110, confirmed) was synthesized using CP110-1 via a method similar to that used to prepare CP46. LCMS: m / z: 630 [M+H] + .

[1463] Example 112

[1464]

[1465] Compound 111 (CP111, confirmed) was synthesized using a method similar to that used for CP46. MS: m / z: 572 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ=7.80-7.68(m,1H),7.34-7.28(m,1H),7.05-6.95(m ,2H),5.58(s,2H),5.29-5.21(m,1H),4.53-4.31(m,2H),4.30-4.14(m,1.5H) ,4.05-3.88(m,2.5H),3.62-3.39(m,3H),3.08-2.93(m,4H),2.80-2.68(m,1H ),2.46-2.37(m,3H),2.35-2.18(m,2H),2.05-1.99(m,2H),1.78-1.60(m,3H).

[1466] Example 113

[1467]

[1468] The solution of CP108-5A (0.23 g) and HCl in a dioxane solution (4 M, 2 mL) in DCM (8 mL) was stirred at RT for 1 h. The solution was diluted with 10% NaHCO3 solution, extracted with DCM, and post-treated to obtain the crude product CP112-1 (0.10 g). MS: m / z: 766 [M+H] + .

[1469] A solution of CP112-1 (0.1 g) and CsF (0.21 g) in DMF (5 mL) was stirred at RT for 2 hours under N2. The solution was diluted with saturated NaHCO3 solution. Extraction with EA and post-treatment gave compound 112 (CP112, 0.0034 g, confirmed). MS: m / z: 610 [M+H] + .

[1470] Example 114

[1471]

[1472]

[1473] m-CPBA (66 mg) was added to a 10 mL solution of DCM containing 79 mg of CP78-1 at RT. The resulting mixture was stirred for 1 hour, diluted with DCM, washed with aq. NaHCO3, and post-treated to obtain CP113-1 (87 mg). MS (ESI, m / z): 478 [M+H] + .

[1474] N,N-diisopropylethylamine (82 mg) and INT14 (69 mg) were added to a solution of CP113-1 (87 mg) in 1,4-dioxane (5 mL). The reaction mixture was stirred at 90 °C for 16 hours, diluted with EA, and post-treated to obtain CP113-2 (54 mg). MS (ESI, m / z): 573 [M+H] + .

[1475] The solution of CP113-2 (54 mg) in TFA (4 mL) was stirred at RT for 16 hours and concentrated. The residue was dissolved in EA, washed with aq. NaHCO3, dried, concentrated, and purified to give CP113-3 (33 mg). MS (ESI, m / z:): 453 [M+H] + .

[1476] Compound 113 (CP113, confirmed) (13.1 mg, TFA salt) was synthesized using CP113-3 according to method CP46. MS (ESI, m / z:): 602 [M+H] + .

[1477] Example 115

[1478]

[1479] A solution of 60% KOH (1 mL aqueous solution) was added to a solution of 114-a (5.02 g) and tert-butyl acrylate (8.04 g) in 1,4-dioxane (25 mL), and the resulting mixture was stirred at RT for 20 hours. The mixture was diluted with water, extracted with EA, and post-treated to obtain 114-b (8.88 g). MS (ESI, m / z): 290 [M+H] + .

[1480] At 0 °C, LAH (1.70 g) was added in portions to a THF (150 mL) solution of 114-b (8.88 g), and the resulting mixture was stirred at RT for 2 hours, followed by quenching with water, aq. 15% NaOH, and water sequentially. The mixture was filtered and the filtrate was concentrated to obtain 114-c (6.29 g). MS (ESI, m / z): 220 [M+H] + .

[1481] HCl (4 M, 20 mL) was added to a solution of 114-c (5.946 g) in acetonitrile (60 mL). The reaction mixture was stirred at RT for 5 hours and concentrated to obtain 114-d, which was used directly in the next step. MS (ESI, m / z): 120 [M+H] + .

[1482] Compound 114 (CP114, confirmed) was synthesized using a method similar to CP96 with 114-d. MS (ESI, m / z): 616 [M+H] + .

[1483] Example 116

[1484]

[1485] t-BuOK (60 mg) was added to a solution of INT15 (619 mg) in (4-methoxyphenyl)methanol (5 mL). The resulting mixture was stirred at RT for 3 hours and then purified to give CP115-1 (0.36 g). MS: m / z: 504 [M+H] + .

[1486] The solution of CP115-1 (0.36 g) in TFA (3 mL) was stirred at RT for 4 hours and concentrated to obtain CP115-2, which was then used directly in the next step. MS: m / z: 384 [M+H] + .

[1487] At 0°C, 0.10 g of NaBH4 was added to a solution of CP115-2 (442 mg) in THF (10 mL) and DCM (5 mL). The mixture was stirred overnight at TR, diluted with water and EA, and post-treated to obtain CP115-3 (35 mg). MS: m / z: 386 [M+H] + .

[1488] DAST (85 mg) was added to a 5 mL solution of CP115-3 (35 mg) in DCM at 0 °C. The mixture was stirred at RT for 2 hours. The reaction mixture was diluted with sat.aq. NaHCO3 and EA and post-treated to obtain CP115-4 (9 mg). MS: m / z: 390 [M+H] + .

[1489] Compound 115 was synthesized using CP115-4 according to method CP46 (CP115, free base, 2.3 mg, confirmed). LCMS: m / z: 650 [M+H] + .

[1490] Example 117

[1491]

[1492] Under N2, trimethyl sulfoxide (330 mg) was added in portions to a DMSO (10 mL) solution of NaH (65 mg, 60% purity). The mixture was stirred at RT for 3 hours. INT15 (0.5 g) was added in portions, and the mixture was stirred at RT for 3.5 hours. The mixture was then diluted with water and EA and post-treated to obtain CP116-1 (279 mg). MS: m / z: 380 [M+H] + .

[1493] NaBH4 (70 mg) was added to a solution of CP116-1 (263 mg) in THF (6 mL) and DCM (3 mL). The mixture was stirred overnight at RT, diluted with water and EA, and post-treated to obtain CP116-2 (284 mg). MS: m / z: 382 [M+H] + .

[1494] DAST (511 mg) was added to a 20 mL solution of CP116-2 (237 mg) in DCM at 0 °C. The mixture was stirred at RT for 1.5 h, diluted with DCM and water, and post-treated to obtain CP116-3 (80 mg). MS: m / z: 384 [M+H] + .

[1495] CP116 (28.6 mg, free base, confirmed) was synthesized from CP116-3 using a similar method to CP46. LCMS: m / z: 644 [M+H] + .

[1496] Example 118

[1497]

[1498] Compound 117 (CP117, confirmed) was synthesized using a method similar to that used for CP9. LCMS: m / z: 624 [M+H] + .

[1499] Example 119

[1500]

[1501] MsCl (3.96 g) was added dropwise to a solution of 118-a (6.21 g) and TEA (8.91 g) in DCM (40 mL) at -10 °C. The reaction mixture was stirred at -10 °C for 15 min, quenched with water, extracted with DCM, and post-treated to obtain 118-b (8.35 g).

[1502] DIEA (11.38 g) and tert-butyl 2-methylhydrazine carboxylate (4.69 g) were added to a solution of 118-b (8.35 g) in DMF (50 mL). The reaction mixture was stirred at 80 °C for 22 hours, diluted with EA and water, and post-treated to obtain 118-c (8.78 g). MS: m / z: 325 [M+H] + .

[1503] Pd / C (2.27 g, 10% wt Pd content) and Pd(OH)₂ / C (2.00 g, 7.6% wt Pd content) were added to a solution of 118-c (8.78 g) in MeOH (100 mL). The reaction mixture was stirred at RT under H₂ for 19 hours, filtered, and the filtrate was concentrated to give 118-d (5.84 g). MS: m / z: 235 [M+H] + .

[1504] TFA (6 mL) was added to a solution of 118-d (1.51 g) in DCM (15 mL). The reaction mixture was stirred at RT for 3 hours and concentrated. The residue was dissolved in MeOH (30 mL) and the pH of the solution was adjusted to 13 with NaOH solid. After stirring for 2.5 hours, the pH of the mixture was adjusted to 2 with HCl (4 M dioxane solution). The reaction mixture was concentrated to give 118-e (crude product). MS: m / z: 135 [M+H] + .

[1505] Compound 118 was synthesized using 118-e according to method CP47 (CP118, 2.6 mg, TFA salt, confirmed). MS: m / z: 631 [M+H] + .

[1506] Example 120

[1507]

[1508] To a solution of CP36-9 (0.35 g), 119-a (synthesized according to the method described in WO2022042630, 293 mg), and toluene (20 mL) and water (5 mL), cataCxium A Pd G3 (66 mg) and Cs2CO3 (692 mg) were added. The reaction mixture was stirred at 100 °C for 20 h under N2, diluted with water, extracted with EA, and post-treated to give compound 119 (CP119, 310 mg, confirmed). MS: m / z: 641 [M+H] + .

[1509] Example 121

[1510]

[1511] Compound 120 (CP120, confirmed) was synthesized using a method similar to that used for CP1 and CP119. LCMS: m / z: 640 [M+H] + .

[1512] Example 122

[1513]

[1514] At -5°C, n-BuLi (17.6 mL, 2.5 mol / L hexane solution) was added dropwise to a THF (80 mL) solution of 121-a (2.06 g). After stirring at -10°C for 1.5 hours, a solution of iodomethane (2.80 g) in THF (4 mL) was added dropwise at -5°C. The reaction mixture was stirred at 0°C for 3 hours and quenched with aq. NaHCO3 (50 mL, 10% wt). Extraction with EA and post-treatment yielded 121-b (2.24 g). MS: m / z: 128 [M+H] + .

[1515] KOH (5.02 g) was added to a mixture of 121-b (2.24 g) and water (40 mL). After stirring at 100 °C for 6.5 hours, the reaction mixture was cooled to RT, and (Boc)₂O (4.61 g) was added. The reaction mixture was stirred at RT for 4 hours, diluted with EA and water, and post-treated to obtain 121-c (8.78 g). MS: m / z: 246 [M+H] + .

[1516] At -10°C, LAH (1.21 g) was added in portions to a THF (50 mL) solution of 121-c (3.42 g). The reaction mixture was stirred at RT for 2 hours, quenched sequentially with water (1.5 mL), aq. NaOH (1.5 mL, 15% wt), and water (5 mL), and then concentrated by filtration to obtain 121-d (1442 mg). MS: m / z: 232 [M+H] + .

[1517] HCl (10 mL, 4 M dioxane solution) was added to a solution of 121-d (1442 mg) in acetonitrile (20 mL), stirred at RT for 1 hour, and concentrated to obtain residue A.

[1518] POCl3 (0.75 mL) was added to a mixture of INT 6 (1.53 g), DIEA (2.18 g), and toluene (15 mL). The reaction mixture was stirred at 80 °C for 1 hour and concentrated to obtain residue B. The pH of the mixture of residue A and DCM (10 mL) was adjusted to alkaline with DIEA. DIEA (3 mL) and the above mixture were added to a mixture of residue B and DCM (20 mL). The reaction mixture was stirred at RT for 2 hours, diluted with water, and extracted with DCM to obtain CP121-1 (3.03 g). MS: m / z: 393 [M+H] + .

[1519] Compound 121 (CP121, 44.3 mg, TFA salt, confirmed) was synthesized using CP121-1 via a method similar to that of CP47. MS: m / z: 628 [M+H] + .

[1520] Example 123

[1521]

[1522] To a solution of 122-a (5.06 g) in acetonitrile (100 mL), K₂CO₃ (22.73 g), tetrabutylammonium iodide (1.95 g), and benzyl bromide (23.89 g) were added. The reaction mixture was stirred at RT for 20 hours, filtered, concentrated, and purified to obtain 122-b (14.35 g). MS: m / z: 270 [M+H] + .

[1523] At -10°C, NaH (0.81 g, 60% oil content) was added to a solution of 122-b (2.08 g) in THF (20 mL). After stirring for 15 minutes, methyl 2-bromopropionate (1.56 g) was added to the mixture. The reaction mixture was stirred at RT for 2.5 hours, quenched with water, and extracted with EA to obtain 122-c (2.26 g). MS: m / z: 356 [M+H] + .

[1524] At -10°C, LAH (0.40 g) was added in portions to a THF (30 mL) solution of 122-c (2.26 g). The reaction mixture was stirred at RT for 2 hours and quenched with water (0.5 mL), NaOH (0.5 mL, 15% wt) aqueous solution, and water (1.5 mL). The mixture was filtered, concentrated, and purified to give 122-d (1.94 g). MS: m / z: 328 [M+H] + .

[1525] Pd / C (0.56 g, 10 wt% Pd content) and Pd(OH)₂ / C (0.53 g, 7.6 wt% Pd content) were added to a solution of 122-d (1.94 g) in MeOH (30 mL). The reaction mixture was stirred at RT under H₂ for 21 hours, filtered, and concentrated to obtain 122-e (0.65 g). MS: m / z: 148 [M+H] + .

[1526] Compound 122 was synthesized using CP122-e via a method similar to that of CP47 (CP122, 7 mg, TFA salt, confirmed). MS: m / z: 644 [M+H] + .

[1527] Example 124

[1528]

[1529] CP123-5 was synthesized using CP123-a in a manner similar to that of CP94-7.

[1530] The first peak of CP123-5 (64 mg) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRALART Cellulose-SA column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 20 mL / min. CP 123-5A (34 mg, first eluting isomer, retention time: 5.71 min) and CP123-5B (28 mg, second eluting isomer, retention time: 7.26 min) were obtained.

[1531] The second peak, CP123-5 (70 mg), was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ARTCellulose-SC column (2 cm × 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min, 220 nm. CP123-5C (23 mg, first eluting isomer, retention time: 6.897 min) and CP123-5D (19 mg, second eluting isomer, retention time: 14.551 min) were obtained.

[1532]

[1533] Compound 123B (CP123B, hypothetical) was synthesized using CP123-6B in a manner similar to that used with CP46. MS: m / z: 658 [M+H] + .

[1534]

[1535] Compound 123A (CP123A, 7.8 mg, assumed) was synthesized from CP123-6A using a method similar to that used for CP123B. MS: m / z: 658 [M+H] + .

[1536]

[1537] Compound 123D (CP123D, 5.4 mg, assumed) was synthesized from CP123-6D using a method similar to that used for CP123B. MS: m / z: 658 [M+H] + .

[1538]

[1539] Compound 123C (CP123C, 6.6 mg, assumed) was synthesized from CP123-6C using a method similar to that used for CP123-6B. MS: m / z: 658 [M+H] + .

[1540] Example 125

[1541]

[1542] A solution of 124-a (3.00 g), dibenzylamine (25.03 g), and DBU (8.05 g) in acetonitrile (60 mL) was stirred at 50 °C for 20 hours and then concentrated. The residue was dissolved in EA and washed with aq. NH4Cl to obtain 124-b (4243 mg). MS (ESI, m / z): 314 [M+H] + .

[1543] A solution of 124-b (4.908 g) was diluted with THF (90 mL) in portions and then added to LAH (801 mg). The resulting mixture was stirred at RT for 2 hours, quenched with water (0.8 mL), aq. 15% NaOH (0.8 mL), and water (2.4 mL), filtered, concentrated, and purified to give 124-c (2540 mg). MS (ESI, m / z): 286 [M+H] + .

[1544] Under N2, NaH (1322 mg) was added to a stirred solution of 124-c (2.44 g) in 40 mL of THF. The resulting mixture was stirred at RT for 30 min. Then, 2-bromo-1,1-dimethoxyethane (1537 mg), DMAP (113 mg), and tetrabutylammonium iodide (639 mg) were added. The mixture was stirred at 70 °C for 16 h, quenched with water, and extracted with EA to obtain 124-d (1.44 g). MS (ESI, m / z:): 374 [M+H] + .

[1545] Pd / C (0.50 g) and Pd(OH)₂ / C (0.46 g) were added to a methanol (40 mL) solution of 124-d (1.44 g). The reaction mixture was stirred at RT under H₂ for 20 hours, filtered, and concentrated to give 124-e (736 mg). MS (ESI, m / z:): 194 [M+H] + .

[1546] Compound 124 was synthesized using CP 124-e via a method similar to that of CP46 (CP124, 33.5 mg, TFA salt, confirmed). MS: [ESI, m / z:]: 648 [M+H] + .

[1547] Example 126

[1548]

[1549] Compound 125 (CP125, confirmed) was synthesized using CP125-a and CP9-6 in a manner similar to that of CP71. MS: m / z: 610 [M+H] + .

[1550] Example 127

[1551]

[1552] At 0 °C, MsCl (57 mg) and TEA (92 mg) were added to a DCM (5 mL) solution of CP124-3 (99 mg). The resulting solution was stirred at RT for 3 hours, diluted with DCM, washed with water, and post-treated to obtain CP126-2 (116 mg). MS (ESI, m / z): 464 [M+H] + .

[1553] A solution of CP126-2 (116 mg), cesium fluoride (175 mg), and cyanotrimethylsilane (97 mg) in DMF (3 mL) was stirred at 80 °C under N2 for 17 hours. The solution was diluted with EA, washed with brine, and post-treated to obtain CP126-3 (60 mg). MS (ESI, m / z): 395 [M+H] + .

[1554] Compound 126 was synthesized using CP126-3 via a method similar to that used for CP46 (CP126, 12.1 mg, TFA salt, confirmed). MS (ESI, m / z): 655 [M+H] + .

[1555] Example 128

[1556]

[1557] A mixture of CP36 (50 mg) and Pd / C (136 mg) in methanol (10 mL) was stirred at RT under H2 for approximately 3 hours, filtered, concentrated, and purified to give compound 127 (CP127, 55.6 mg, TFA salt, confirmed). MS: m / z: 634 [M+1] + .

[1558] Example 129

[1559]

[1560] Compound 128 (CP128, 33.9 mg, TFA salt, confirmed) was synthesized using CP128-a in a manner similar to that used for CP12. MS: m / z: 627 [M+H] + .

[1561] Example 130

[1562]

[1563] DMAP (3 mg) was added to a solution of CP57 (53 mg) and acetic anhydride (23 mg) in DCM (4 mL). The reaction mixture was stirred at RT under N2 for 1 h, diluted with brine, extracted with DCM, and post-treated to give compound 129 (CP129, 63.3 mg, TFA salt, confirmed). MS: m / z: 690 [M+H] + .

[1564] Example 131

[1565]

[1566] HATU (111 mg) and DIEA (15 mg) were added to a DMF (3 mL) solution of CP57 (69 mg) and N-Boc-L-valine (30 mg). The reaction mixture was stirred overnight at RT under N2, diluted with EA, washed twice with brine, and then processed to obtain the crude product CP130-2 (126 mg). MS: m / z: 847 [M+H] + .

[1567] A solution of CP 130-2 (126 mg) and TFA (1 mL) in DCM (3 mL) was stirred at RT for 2 h and quenched with sat. NaHCO3 solution. Extraction and post-treatment with EA yielded compound 130 (CP130, 13.8 mg, TFA salt, confirmed). MS: m / z: 747 [M+H] + .

[1568] The following compounds were synthesized using a method similar to that used for the compounds described above:

[1569]

[1570]

[1571]

[1572] Example 150

[1573]

[1574] Compound 150 (CP150, confirmed) was synthesized using a method similar to that used for CP46. MS: m / z: 630 [M+1] + .

[1575] Example 151

[1576]

[1577] Compound 151 (CP151, confirmed) was synthesized using a method similar to that used for CP46. MS: m / z: 632 [M+1] + .

[1578] Example 152

[1579]

[1580] Compound 152 (CP152, confirmed) was synthesized using a method similar to that used for CP46. MS: m / z: 615 [M+1] + .

[1581] Example 153

[1582]

[1583] Compound 153 (CP153, confirmed) was synthesized using a method similar to that used for CP46. MS: m / z: 586 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ = 7.74 (dd, J = 9.2, 5.9Hz, 1H), 7.31 (t, J = 9.0Hz, 1H), 7.03-6.99

[1584] (m,2H),5.59(s,2H),5.34(s,0.5H),5.21(s,0.5H),4.97-4.91(m,1H),4.13-3.88(m,3H),3.81-3.61(m ,2H),3.16-2.97(m,3H),2.89(d,J=4.6Hz,3H),2.86-2.77(m,1H),2.25-1.93(m,7H),1.90-1.68(m,3H).

[1585] Example 154

[1586]

[1587] Compound 154 (CP154, confirmed) was synthesized using a method similar to that used for CP46. MS: m / z: 507 [M+H] + .

[1588] Example 155

[1589]

[1590] CP155-6 (57 mg) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC column (2 cm x 25 cm, 5 μm); mobile phase: (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min. CP155-7A (19 mg, first eluting isomer, retention time: 7.073 min) and CP155-7B (19 mg, second eluting isomer, retention time: 11.157 min) were obtained.

[1591] Compound 155A (CP155A, confirmed, MS: m / z: 630 [M+H)) was synthesized using a method similar to that used for CP46. + Compound 155B (CP155B, MS: m / z: 630 [M+H]) and compound 155B (MS: m / z: 630 [M+H]) + ).

[1592] Example 156

[1593]

[1594] CP156-4 was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SC column (2cm x 25cm, 5µm); mobile phase: (Hex:DCM = 2:1)(0.1% DEA) / EtOH (50:50); flow rate: 15mL / min. CP 156-5A (32mg, first eluting isomer, retention time: 4.877min) and CP 156-5B (37mg, second eluting isomer, retention time: 5.813min) were obtained.

[1595] Intermediate CP156-4 (another peak) was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRAL ARTCellulose-SC column (2 cm x 25 cm, 5 μm); mobile phase: (Hex:DCM = 2:1)(0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min. CP156-5C (26 mg, first eluting isomer, retention time: 5.193 min) and CP156-5D (27 mg, second eluting isomer, retention time: 9.827 min) were obtained.

[1596] Compound 156A (CP156A, assumed, MS: m / z: 646 [M+H)) was synthesized using a method similar to that used for CP46. + Compound 156B (CP156B, assumed, MS: m / z: 646 [M+H))+ Compound 156C (CP156C, assumed, MS: m / z: 646 [M+H]) + Compound 156D (CP156D, assumed, MS: m / z: 646 [M+H)) and compound 156D (CP156D, MS: m / z: 646 [M+H)). + ).

[1597] Example 157

[1598]

[1599]

[1600] CP157-4 was separated by Prep-HPLC-Gilson under the following conditions: column: CHIRALART Cellulose-SC column (2cm x 25cm, 5µm); mobile phase: (Hex:DCM = 3:1) (0.1% DEA) / EtOH (50:50); flow rate: 15mL / min. CP 157-5A (38mg, first eluting isomer, retention time: 7.631min) and CP 157-5B (39mg, second eluting isomer, retention time: 9.974min) were obtained.

[1601] Compound 157A (CP157A, confirmed, MS: m / z: 628 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1602] Compound 138 (CP138, confirmed, MS: m / z: 628 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1603] Example 158

[1604]

[1605] Compound 158 (CP158, confirmed, MS: m / z: 671 [M+H)) was synthesized using a method similar to that of CP1. + The compounds were separated using Prep-HPLC-Gilson under the following conditions: column: CHIRAL ART Cellulose-SB (2 cm x 25 cm, 5 μm); mobile phase: (Hex:DcM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 20 mL / min. Compound 158A (first eluting isomer, retention time: 3.705 min) and compound 158B (second eluting isomer, retention time: 4.773 min) were obtained.

[1606] Example 159

[1607]

[1608] Compound 159A (CP159A, assumed, MS: m / z: 628 [M+H)) was synthesized using a method similar to that used for CP46. + Compound 159B (CP159B, assumed, MS: m / z: 628 [M+H]) + ).

[1609] Example 160

[1610]

[1611] Compound 160 (CP160, confirmed, MS: m / z: 624 [M+H)) was synthesized using a method similar to CP1. + ).

[1612] Example 161

[1613]

[1614] Compound 161 (CP161, confirmed, MS: m / z: 623 [M+H)) was synthesized using a method similar to that of CP11. + ).

[1615] Example 162

[1616]

[1617] Compound 162 (CP162, confirmed, MS: m / z: 616 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1618] Example 163

[1619]

[1620] Compound 163 (CP163) was synthesized using a method similar to CP66 and separated under the following conditions: column, CHIRALART Amylose-SA column (2 cm x 25 cm, 5 μm); mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / EtOH (50:50); flow rate: 20 mL / min. Compounds 163A (CP163A, confirmed, first eluting isomer, retention time: 3.877 min) and 163B (CP163B, confirmed, second eluting isomer, retention time: 5.047 min) were obtained. MS: m / z: 641 [M+H] + .

[1621] Example 164

[1622]

[1623] Compound 164 (CP164, confirmed, MS: m / z: 629 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1624] Example 165

[1625]

[1626] Compound 165 (CP165, confirmed, MS: m / z: 664 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1627] Example 166

[1628]

[1629] Compound 166 (CP166, confirmed, MS: m / z: 639 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1630] Example 167

[1631]

[1632] Compound 167 (CP167, confirmed, MS: m / z: 644 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1633] Example 168

[1634]

[1635] Compound 168B (CP168B, confirmed, MS: m / z: 639 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1636] Example 169

[1637]

[1638] Compound 169 (CP169, confirmed, MS: m / z: 640 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1639] Example 170

[1640]

[1641] Compound 170 (CP170, confirmed, MS: m / z: 640 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1642] Example 171

[1643]

[1644] Compound 171 (CP171, confirmed, MS: m / z: 628 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1645] Example 172

[1646]

[1647] Compound 172 (CP172, confirmed, MS: m / z: 641 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1648] Example 173

[1649]

[1650] Compound 173 (CP173, confirmed, MS: m / z: 628 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1651] Example 174

[1652]

[1653] Compound 174 (CP174, confirmed, MS: m / z: 646 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1654] Example 175

[1655]

[1656] Compound 175 (CP175, confirmed, MS: m / z: 628 [M+H)) was synthesized using a method similar to that used for CP46. + ).

[1657] Example 176

[1658]

[1659] Compound 176 (CP176) was synthesized using a method similar to that of CP66 and separated by Prep-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 μm, A: 0.05% NH3·H2O, B: CH3CN, gradient: 39 min 30% B to 74% B, flow rate 40 mL / min, 240 nm) to give compound 176A (CP176A) (1.2 mg, TFA salt, confirmed) and compound 176B (CP176B, compound 139, confirmed) (1.0 mg). MS: m / z: 655 [M+H] + .

[1660] Example 177

[1661]

[1662] Compound 177 (CP177) was synthesized using CP50 and an anhydride or acyl chloride. Compound 177 is a prodrug of CP50. Compound 177 was observed to be converted into the active component of CP50 in vivo.

[1663] Exemplary compounds 1 HNMR spectra are listed in the table below:

[1664]

[1665]

[1666]

[1667]

[1668]

[1669]

[1670] Pharmacological experiments

[1671] 1. SOS1-catalyzed nucleotide exchange assay

[1672] The inhibitory activity of each compound against the GDP form of K-Ras was evaluated using an SOS1-catalyzed nucleotide exchange assay. K-Ras G12D and K-Ras G12V proteins were used in this assay.

[1673] In 384-well Greiner plates, K-Ras (His tag, aa1-169) pre-loaded with GDP was pre-incubated with each compound for 15 mins in the presence of 10 nM GDP. Purified SOS1 ExD (Flag tag, aa564-1049) and BODIPY were then added.TM FL GTP (Invitrogen) and monoclonal antibody anti-6HIS-Tb cryptate Gold (Cisbio) were added to the test wells and incubated at 25°C for 4 hours. The final concentrations of each component in the test wells are shown in Table 1. Wells containing the same percentage of DMSO were used as solvent controls, and wells without K-Ras were used as negative controls. TR-FRET signals were read on a Tecan Spark multimode microplate reader. The parameters were: F486: excitation 340 nm, emission 486 nm, delay 100 μs, integration 200 μs; F515: excitation 340 nm, emission 515 nm, delay 100 μs, integration 200 μs. The TR-FRET ratio of each individual well was calculated using the equation: TR-FRET ratio = (F515 signal / F486 signal) * 10000. The percentage of activation in the compound-treated pores was normalized between the solvent control and the negative control (% activation = (TR-FRET ratio of compound treatment – ​​TR-FRET ratio of negative control) / (TR-FRET ratio of solvent control – TR-FRET ratio of negative control) * 100%). Data were analyzed using a 4-parameter logarithmic model or Excel to calculate the IC50. 50 The values ​​are shown in Table 3 below.

[1674] Table 1

[1675]

[1676] 2. Interaction experiment between GTP-K-Ras and cRAF

[1677] The inhibitory activity of each compound against the GTP-based form of K-Ras was assessed by a GppNp-K-Ras and cRAF interaction assay. GppNp is an analogue of GTP. K-Ras G12D and K-Ras G12V proteins were used in this assay.

[1678] In 384-well plates (Greiner), K-Ras pre-loaded with GppNp (His tag, aa 1-169) was pre-incubated with each compound for 15 min in the presence of 200 μM GTP. cRAF RBD (GST tag, aa 50-132, Creative BioMart), monoclonal antibody anti-GST-d2 (Cisbio), and monoclonal antibody anti-6HIS-Tb cryptateGold (Cisbio) were added to the wells, and incubated at 25 °C for 2 h. The final concentrations of each component in the wells are shown in Table 2. Wells containing the same percentage of DMSO served as solvent controls, and wells without K-Ras served as negative controls. HTRF signals were read on a TecanSpark multimode microplate reader, and HTRF ratios were calculated according to the manufacturer's instructions. The activation percentage of the compound-treated pores was normalized between the solvent control and the negative control (%activation = (HTRF ratio of compound-treated pores - HTRF ratio of negative control pores) / (HTRF ratio of solvent control pores - HTRF ratio of negative control pores) * 100%). Data were analyzed using a 4-parameter logarithmic model or Excel to calculate the IC50. 50 The values ​​are shown in Table 3 below.

[1679] Table 2

[1680]

[1681] Table 3

[1682]

[1683]

[1684]

[1685]

[1686]

[1687] 3. Phosphorylated ERK1 / 2 (THR202 / TYR204) HTRF assay

[1688] The p-ERK (MAPK pathway) inhibitory activity of each compound in the K-Ras G12D and K-Ras G12V cell lines shown in Table 4 was evaluated.

[1689] Table 4

[1690]

[1691] Cells from the culture medium were seeded into 96-well plates at the densities shown in Table 4 and incubated overnight in a cell culture incubator. The next day, the culture medium was removed, and the compound diluted in the test medium was added to each well. After incubation for 2 hours in the cell culture incubator, the test medium was removed from the 96-well plates, 50 μL of lysis buffer (Cisbio) containing 1X blocking reagent was added, and the plates were incubated with shaking at 25°C for 45 min. 10 μL of cell lysate from the 96-well plates was transferred to a plate containing 2.5 μL / well. Premixed antibody (Cisbio64AERPEH) was placed in 384-well plates (Greiner). The plates were incubated at 25°C for 4 hours, and HTRF signals were read using a Tecan Spark multimode microplate reader. IC50 was calculated using a 4-parameter logarithmic model. 50 Values. The results are shown in Table 5 below:

[1692] Table 5

[1693]

[1694]

[1695]

[1696]

[1697] 4. Cell growth inhibition test

[1698] The cell growth inhibitory activity of each compound was determined by performing a cell growth inhibition test on the K-Ras G12D and K-Ras G12V cell lines shown in Table 6.

[1699] Table 6

[1700]

[1701] 2D Cell Growth Inhibition Analysis

[1702] Each cell in the culture medium was seeded into a TC-treated 96-well plate at the density shown in Table 4 and incubated overnight in a cell culture incubator. The next day, each compound was diluted in culture medium and added to the plate. After 6 days of incubation in a cell culture incubator, the cells were analyzed by... Cell viability was assessed using a cell viability assay kit (Promega). The luminescence signal was read using a Tecan Spark multimode microplate reader, and analysis was performed using a 4-parameter logarithmic model to calculate the absolute IC50. 50 The values ​​are shown in Table 5 below.

[1703] Table 5

[1704]

[1705]

[1706]

[1707]

[1708] 5. Pharmacokinetic studies in mice

[1709] The aim of this study was to evaluate the pharmacokinetic properties of compounds in female Balb / c mice following a single dose. Six mice were required for each compound, and these mice were randomly assigned to two groups (n = 3 / group): Group A and Group B. Mice in Group A were treated with a single 3 mg / kg dose of the compound (iv). Mice in Group B were treated with a single 10 mg / kg dose of the compound (po). Blood samples were collected from each mouse in Group A at 0.083 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration. Blood samples were collected from each mouse in Group B at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration. Blood samples were kept on ice until centrifuged to obtain plasma samples. Plasma samples were stored at -80 °C before analysis. The concentrations of the compounds in the plasma samples were determined using LC-MS / MS. The results are shown in Table 6.

[1710] Table 6

[1711]

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from... and .

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is... 。 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is... 。 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. Intermediates, selected from , , , , , , , , , , , , , , , , and .

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