Condensed ring compound and application thereof

Abstract

The invention relates to a fused ring compound, a composition containing the fused ring compound and application of the fused ring compound. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to compounds that inhibit the activity of multiple forms of K-Ras protein, including wild-type K-Ras and mutant K-Ras, compositions comprising such compounds, and methods of using such compounds. Background Art

[0002] There is a need for the development of new multi-K-Ras inhibitors to treat K-Ras-mediated cancers that has not been met. Summary of the Invention

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

[0004]

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

[0006] wherein the definition of each variable is as follows.

[0007] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in the present invention and a pharmaceutically acceptable excipient.

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

[0009] The present invention also provides a method for treating cancer in a subject in need thereof, 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 wild-type K-Ras amplification; and (b) if so, administering to a subject in need thereof a therapeutically effective amount of a compound as defined in the present invention, or a pharmaceutical composition.

[0010] The present invention also provides a compound as defined in the present invention, or a pharmaceutical composition for use in therapy.

[0011] The present invention also provides a compound as defined in the present invention, or a pharmaceutical composition for use as a medicine.

[0012] The present invention also provides a compound as defined in the present invention, or a pharmaceutical composition for use in a method of treating cancer.

[0013] The present invention also provides the use of a compound as defined in the present invention, or a pharmaceutical composition in the treatment of cancer.

[0014] The present invention also provides the use of a compound or a pharmaceutical composition as defined in the present invention in the preparation of a medicament for treating cancer.

[0015] Detailed description

[0016] The present invention provides the following disclosure:

[0017] [1]. A compound of formula (I):

[0018]

[0019]

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

[0021] Wherein,

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

[0023] R X11 or R X12 is independently hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 cycloalkynyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl; wherein the -C 1-6 alkyl, halo-C 1-6 alkyl, halo-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 group, 6-10 membered aryl or 5-10 membered heteroaryl are independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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, and is substituted by substituents of 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl;

[0024] Optionally, R X11 and R X12 together with the carbon atom to which they are both attached form a 3 - 10 - membered carbocyclic ring or a 3 - 10 - membered heterocyclic ring; wherein, the said 3 - 10 - membered carbocyclic ring or 3 - 10 - membered heterocyclic ring is independently unsubstituted or substituted by one or more R SX1 ;

[0025] R X13 is hydrogen, deuterium, -C 1-6 alkyl, halo - C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -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 cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl; wherein the -C 1-6 alkyl, halo - C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

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

[0027] R₁ is hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl; wherein the -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6An alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered cycloalkenyl group, a 3- to 10-membered cycloalkynyl group, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group is independently unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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) substituted by substituents of 2, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

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

[0029] Ring A is a 3- to 20-membered heterocyclic ring containing only the N atom attached to the pyrimidine ring, or a 3- to 20 (such as 3- to 10)-membered heterocyclic ring 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;

[0030] R S1 is independently hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl; wherein said -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6 alkynyl, 3 - 10 membered cycloalkyl, 3 - 10 membered cycloalkenyl, 3 - 10 membered cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6 alkynyl, -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, and is substituted by a substituent of a 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl group, or 5- to 10-membered heteroaryl group;

[0031] Optionally, two Rs S1 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein, the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more Rs S11 ;

[0032] Optionally, two adjacent Rs S1 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring, or 5- to 10-membered heteroaryl ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S12 ;

[0033] Optionally, two non-adjacent Rs S1 are joined together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S13 ;

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

[0035] R S2 is independently hydrogen, deuterium, halogen, -C1-6 Alkyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, -C 2-6 Alkenyl, halo C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, -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 cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl; wherein said -C 1-6 Alkyl, halo C1-6 Alkyl, halo C 1-6 Alkoxy, -C 2-6 Alkenyl, halo C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 Alkyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, -C 2-6 Alkenyl, halo C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 2-6 Alkynyl, -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(RS2C ) 2, -NR S2C S(=O)2N(R S2C ) 2, -P(R S2C ) 2, -P(=O)(R S2D ) 2, 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl, which is substituted by substituents;

[0036] Optionally, two R S2 together with the carbon atom to which they are both attached form a 3 - 10 - membered carbocyclic ring or a 3 - 10 - membered heterocyclic ring; wherein, the 3 - 10 - membered carbocyclic ring or 3 - 10 - membered heterocyclic ring is independently unsubstituted or substituted by one or more R S21 ;

[0037] Optionally, two adjacent R S2 together with the atoms to which they are respectively attached form a 3 - 10 - membered carbocyclic ring, 3 - 10 - membered heterocyclic ring, 6 - 10 - membered aromatic ring or 5 - 10 - membered heteroaryl ring, wherein each ring is independently unsubstituted or substituted by one or more R S22 ;

[0038] Optionally, two non - adjacent R S2 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S23 ;

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

[0040] R Y11 is hydrogen, deuterium, -C 1-6 alkyl, halo - C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -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 cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl; wherein said -C 1-6 alkyl, halo - C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 3 - 10 membered cycloalkyl, 3 - 10 membered cycloalkenyl, 3 - 10 membered cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl substituted by substituents;

[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 is independently hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 cycloalkynyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6An alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered cycloalkenyl group, a 3- to 10-membered cycloalkynyl group, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group is independently unsubstituted or substituted by one or more substituents selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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, and is substituted by substituents of a 3- to 10-membered cycloalkyl group, a 3- to 10-membered cycloalkenyl group, a 3- to 10-membered cycloalkynyl group, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group;

[0043] Optionally, R 31 and R 32 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted with one or more R S33 substituents;

[0044] Optionally, R 33 and R 34 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted with one or more R S34 substituents;

[0045] Optionally, R 35 and R 36 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted with one or more R S35 substituents;

[0046] Optionally, R 38 and R 39 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted with one or more R S310 substituents;

[0047] Optionally, R 310 and R 311 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted with one or more R S316 substituents;

[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 containing 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2;

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

[0055] Ring D is a 3- to 10-membered carbocycle or a 3- to 10-membered heterocycle;

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

[0059] R S31 is hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl; wherein said -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6 alkynyl, 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6 alkynyl, -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, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each being substituted by a substituent;

[0060] Optionally, two Rs S31 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more Rs S311 ;

[0061] Optionally, two adjacent Rs S31 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring or 5- to 10-membered heteroaryl ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S312 ;

[0062] Optionally, two non-adjacent Rs S31 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S313 ;

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

[0064] R S32 is hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 , -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 - to 10 - membered cycloalkyl, 3 - to 10 - membered cycloalkenyl, 3 - to 10 - membered cycloalkynyl, 3 - to 10 - membered heterocyclic group, 6 - to 10 - membered aryl or 5 - to 10 - membered heteroaryl; wherein said -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6 alkynyl, 3 - to 10 - membered cycloalkyl, 3 - to 10 - membered cycloalkenyl, 3 - to 10 - membered cycloalkynyl, 3 - to 10 - membered heterocyclic group, 6 - to 10 - membered aryl or 5 - to 10 - membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6 alkynyl, -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、 and is substituted by substituents of 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

[0065] Optionally, two R S32 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more R S321 ;

[0066] Optionally, two adjacent R S32 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more R S322 ;

[0067] Optionally, two non-adjacent R S32 are joined together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S323 ;

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

[0069] R 37 is -N(R37A a 2- or 3- to 10-membered heterocyclic group, wherein the 3- to 10-membered heterocyclic group is optionally and independently substituted with one or more R S37 ;

[0070] R S38 is hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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(RS38C ) 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, 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl substituted by substituents;

[0071] Optionally, two R S38 together with the carbon atom to which they are both attached form a 3 - 10 - membered carbocyclic ring or a 3 - 10 - membered heterocyclic ring; wherein, the 3 - 10 - membered carbocyclic ring or 3 - 10 - membered heterocyclic ring is independently unsubstituted or substituted by one or more R S381 ;

[0072] Optionally, two adjacent R S38 together with the atoms to which they are respectively attached form a 3 - 10 - membered carbocyclic ring, 3 - 10 - membered heterocyclic ring, 6 - 10 - membered aromatic ring or 5 - 10 - membered heteroaryl ring, wherein each ring is independently unsubstituted or substituted by one or more R S382 ;

[0073] Optionally, two non - adjacent R S38 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S383 ;

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

[0075] R S39 is hydrogen, deuterium, halogen, -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6Alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, -C 2-6 alkenyl, halo C 2-6 alkenyl, -C 2-6 alkynyl, halo C 2-6An alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered cycloalkenyl group, a 3- to 10-membered cycloalkynyl group, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group is independently unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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) substituted by substituents of 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic, 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

[0076] Optionally, two Rs S39 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more Rs S391 ;

[0077] Optionally, two adjacent Rs S39 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring or 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S392 ;

[0078] Optionally, two non-adjacent Rs S39 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S393 ;

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

[0080] R S315 is hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 ), 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl; wherein said - C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, - C 2-6 alkenyl, halo - C 2-6 alkenyl, - C 2-6 alkynyl, halo - C 2-6 alkynyl, 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl is independently unsubstituted or substituted with one or more selected from deuterium, halogen, - C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, - C 2-6 alkenyl, halo - C 2-6 alkenyl, - C 2-6 alkynyl, halo - C 2-6 alkynyl, - 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、 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl, which are substituted by substituents;

[0081] Optionally, two R S315 together with the carbon atom to which they are both attached form a 3 - 10 - membered carbocyclic ring or a 3 - 10 - membered heterocyclic ring; wherein the 3 - 10 - membered carbocyclic ring or 3 - 10 - membered heterocyclic ring is independently unsubstituted or substituted by one or more R S3151 ;

[0082] Optionally, two adjacent R S315together with the atoms to which they are respectively attached to form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more R S3152 ;

[0083] Optionally, two non-adjacent R S315 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S3153 ;

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

[0085] R4 is a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, wherein the 6- to 10-membered aryl group, the 5- to 10-membered heteroaryl group, is independently unsubstituted or substituted by one or more R S4 ;

[0086] Z is independently C or N at each occurrence;

[0087] When Z is C, ring E is independently a 6-membered aromatic ring or a 5- to 6-membered heteroaromatic ring at each occurrence and ring F is a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring at each occurrence;

[0088] When Z is N, ring E is a 5- to 6-membered heteroaromatic ring at each occurrence and ring F is a 3- to 10-membered heterocyclic ring at each occurrence;

[0089] R S4 is independently deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 ), -P(=O)(R S4B ), 3 - 10 membered cycloalkyl, 3 - 10 membered cycloalkenyl, 3 - 10 membered cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl; wherein said -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6 alkynyl, 3 - 10 membered cycloalkyl, 3 - 10 membered cycloalkenyl, 3 - 10 membered cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, -C 2-6 alkenyl, halo - C 2-6 alkenyl, -C 2-6 alkynyl, halo - C 2-6Alkynyl, -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, and is substituted by substituents of 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

[0090] R5 is hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6Alkynyl, halo C 2-6 Alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the -C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, -C 2-6 alkenyl, halo C 2-6 alkenyl, -C 2-6 alkynyl, halo C 2-6An alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered cycloalkenyl group, a 3- to 10-membered cycloalkynyl group, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group is independently unsubstituted or substituted with one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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) substituted by substituents of C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C3-C10 cycloalkynyl, C3-C10 heterocyclic group, C6-C10 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 are independently hydrogen, deuterium, -C 1-6 alkyl, halo-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -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、C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C3-C10 cycloalkynyl, C3-C10 heterocyclic group, C6-C10 aryl or 5-10 membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, -C2-6 alkenyl, -C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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) substituted by substituents of C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C3-C10 cycloalkynyl, C3-C10 heterocyclic group, C6-C10 aryl or 5-10 membered heteroaryl;

[0092] Optionally, (two Rs 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 atom to which they are all attached form a 3-10 membered heterocyclic ring or a 5-10 membered heteroaryl ring, wherein the 3-10 membered heterocyclic ring or 5-10 membered heteroaryl ring is independently unsubstituted or substituted by one or more Rs SS ;

[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 is independently hydrogen, deuterium, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6Alkynyl, -N(R A )2, -OR A , -SR A , 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl; wherein said - C 1-6 alkyl, halo - C 1-6 alkyl, halo - 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 group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, - C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, - C 2-6 alkenyl, - C 2-6 alkynyl, - 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 group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl;

[0094] Each (R A 、 R B 、 R C and R D ) is independently hydrogen, deuterium, -C 1-6 alkyl, halo - C 1-6 alkyl, halo - 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 group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl; wherein the -C 1-6 alkyl, halo - C 1-6 alkyl, halo - 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 group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl is independently unsubstituted or substituted by one or more R SA ;

[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 are independently deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)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), -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), -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), -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), -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein, said -C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are independently unsubstituted or substituted with one or more selected from deuterium, halogen, -C1-3 alkyl, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)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), -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), -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), -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), -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 alkyl)2, and is substituted by substituents of 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 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 independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S each time it appears.

[0098] [2].[1] The compound as described above, wherein the compound is any one of the following formulas:

[0099]

[0100] [3]. The compound according to [1] or [2], wherein R1 is hydrogen, deuterium, halogen, -CN, -OC 1-6 alkyl, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, or 3- to 6-membered cycloalkyl; said -OC 1-6 alkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, or 3- to 6-membered cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl.

[0101] In some embodiments, R1 is

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

[0103] In some embodiments, R1 is

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

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

[0106] [4]. The compound according to 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 according to any one of [1] to [4], wherein:

[0108] X1 is independently, at each occurrence, -C(R X11 )(R X12 )-, -NR X13 -, -O-, -S- or -S(=O)-;

[0109] R X11 or R X12Independently is hydrogen, deuterium, a halogen, -C 1-6 alkyl or a 3- to 6-membered cycloalkyl; wherein said -C 1-6 alkyl or 3- to 6-membered cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, a halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl;

[0110] Optionally, R X11 and R X12 together with the carbon atom to which they are both attached form wherein said is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, a halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl;

[0111] R X13 is hydrogen, deuterium, -C 1-6 alkyl or a 3- to 6-membered cycloalkyl; wherein said -C 1-6 alkyl or 3- to 6-membered cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, a halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl.

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

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

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

[0115] Optionally, R X11 and RX12 Together with the carbon atom to which they are all attached, form

[0116] R X13 independently is hydrogen, deuterium, methyl, -CD3, ethyl, propyl, isopropyl or cyclopropyl.

[0117] [7].[1] to the compound according to any one of [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 embodiments, 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] The compound according to any one of [8].[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-, and n1 is 0. In some embodiments, X1 is -O-, and n1 is 1. In some embodiments, X1 is -O-, and n1 is 2. In some embodiments, X1 is -O-, and n1 is 3. In some embodiments, X1 is -NCH3-, and n1 is 0. In some embodiments, X1 is -NCH3-, and n1 is 1. In some embodiments, X1 is -NCH3-, and n1 is 2. In some embodiments, X1 is -NCH3-, and n1 is 3. In some embodiments, X1 is -CH2-, and 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 embodiments, X1 is n1 is 1. In some embodiments, X1 is n1 is 2. In some embodiments, X1 is n1 is 3. In some embodiments, X1 is n1 is 0. In some embodiments, X1 is n1 is 1. In some embodiments, X1 is n1 is 2. In some embodiments, 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] The compound according to 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 according to any one of [1] to [9], wherein the compound is any one of the following formulas:

[0122]

[0123]

[0124]

[11] . The compound according to any one of [1] to

[10] , wherein R S2 is deuterium, a halogen, or -C 1-6 alkyl; wherein the -C 1-6 alkyl is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, or -OC 1-6 alkyl;

[0125] Optionally, two adjacent Rs S2 together with the atoms to which they are respectively attached form a 3-6 membered carbocyclic ring, a 3-6 membered heterocyclic ring, a benzene ring, or a 5-6 membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, or -OC 1-6 alkyl.

[0126]

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

[11] , wherein R S2 is deuterium, -F, -CH3, or -CD3. In some embodiments, R S2is -CH3. In some embodiments, R S2 is deuterium.

[0127]

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

[13] , wherein:

[0129] Ring A is a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered heterocycle containing only the N atom linked to the pyrimidine ring, or a 3- to 10- (such as 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 linked to the pyrimidine ring. In some embodiments, Ring A is a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered heterocycle containing only the N atom linked to the pyrimidine ring, or a 3- to 10- (such as 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 linked to the pyrimidine ring. In some embodiments, Ring A is a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered monocyclic heterocycle containing only the N atom linked to the pyrimidine ring, a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered bicyclic heterocycle containing only the N atom linked to the pyrimidine ring, a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered bridged heterocycle containing only the N atom linked to the pyrimidine ring, a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered fused heterocycle containing only the N atom linked to the pyrimidine ring, a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered spiro heterocycle containing only the N atom linked to the pyrimidine ring, a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered monocyclic heterocycle containing one additional heteroatom selected from O, S, S=O, or S(=O)2 other than the N atom linked to the pyrimidine ring, a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered bicyclic heterocycle containing one additional heteroatom selected from O, S, S=O, or S(=O)2 other than the N atom linked to the pyrimidine ring, a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered bridged heterocycle containing one additional heteroatom selected from O, S, S=O, or S(=O)2 other than the N atom linked to the pyrimidine ring, a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered fused heterocycle containing one additional heteroatom selected from O, S, S=O, or S(=O)2 other than the N atom linked to the pyrimidine ring, a 3- to 10- (such as 3, 4, 5, 6, 7, 8, 9, or 10-) membered spiro heterocycle containing one additional heteroatom selected from O, S, S=O, or S(=O)2 other than the N atom linked to the pyrimidine ring; wherein each ring is fully saturated or has one or more (such as 1, 2, or 3) degrees of unsaturation.In some embodiments, ring A is a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered monocyclic heterocycle containing only the N atom linked to the pyrimidine ring, a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered bicyclic heterocycle containing only the N atom linked to the pyrimidine ring, a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered bridged heterocycle containing only the N atom linked to the pyrimidine ring, a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered fused heterocycle containing only the N atom linked to the pyrimidine ring, a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered spiro heterocycle containing only the N atom linked to the pyrimidine ring; a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered monocyclic heterocycle containing an additional heteroatom selected from O atoms in addition to the N atom linked to the pyrimidine ring, a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered bicyclic heterocycle containing an additional heteroatom selected from O atoms in addition to the N atom linked to the pyrimidine ring, a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered bridged heterocycle containing an additional heteroatom selected from O atoms in addition to the N atom linked to the pyrimidine ring, a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered fused heterocycle containing an additional heteroatom selected from O atoms in addition to the N atom linked to the pyrimidine ring, a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered spiro heterocycle containing an additional heteroatom selected from O atoms in addition to the N atom linked to the pyrimidine ring; wherein each ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered monocyclic heterocycle containing only the N atom linked to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered bicyclic heterocycle containing only the N atom linked to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered bridged heterocycle containing only the N atom linked to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered fused heterocycle containing only the N atom linked to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered spiro heterocycle containing only the N atom linked to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered bridged heterocycle containing only the N atom linked to the pyrimidine ring, wherein the ring is fully saturated or has one degree of unsaturation. In some embodiments, ring A is a 5- to 10- (such as 5, 6, 7, 8, 9, or 10-) membered monocyclic heterocycle containing an additional heteroatom selected from O atoms in addition to the N atom linked 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) membered bicyclic heterocyclic ring containing one additional heteroatom selected from O other than 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) membered bridged heterocyclic ring containing one additional heteroatom selected from O other than 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) membered fused heterocyclic ring containing one additional heteroatom selected from O other than 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) membered spiroheterocyclic ring containing one additional 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.

[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 independently unsubstituted or substituted with m1 R S1 replaced.

[0135]

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

[15] , wherein:

[0136] R S1 Deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)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 groups are independently unsubstituted or substituted with 1, 2, or 3 groups selected from deuterium, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -CN, -NH2, -NH(C 1-6 Alkyl), -N(C1-6 2, -OH or -OC 1-6 substituted by a substituent of the alkyl group;

[0137] Optionally, two R S1 together with the carbon atom to which they are both attached form or a 3- to 6-membered carbon ring; wherein the 3- to 6-membered carbon ring is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 substituted by a substituent of the alkyl group;

[0138] Optionally, two adjacent R S1 together with the atoms to which they are respectively adjacent form a 3- to 6-membered carbon ring; wherein the 3- to 6-membered carbon ring is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 substituted by a substituent of the alkyl group.

[0139] In some embodiments, R S1 is -F, -OH, -OCH3, -CN, -CH2F, -CF3, -CH2OCH3, -CH2CN, -CHF2, -CD3, -NH2 or -CH3; or two R S1 together with the carbon atom to which they are both adjacent form or cyclopropane; or two adjacent R S1 together with the atoms to which they are respectively adjacent form cyclopropane.

[0140] In some embodiments, 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 atom to which they are both adjacent form cyclopropane, or two adjacent R S1Together with the atoms adjacent to them respectively, form

[0141] In some embodiments, is:

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148] In some embodiments, is:

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] In some embodiments, is:

[0155] R S12a is deuterium, a halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -OC 1-6 alkyl or 3-6 membered cycloalkyl; wherein said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or 3-6 membered cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, a halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl is substituted by a substituent. In some embodiments, R S1a is -F, -OH, -OCH3, -CN, -CH2F, -CF3, -CH2OCH3, -CH2CN, -CHF2, -CD3, -NH2 or -CH3.

[0156] R S12b is deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -OC 1-6 alkyl or 3- to 6-membered cycloalkyl; wherein the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or 3- to 6-membered cycloalkyl is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo C 1-6 alkyl, halo C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl. In some embodiments, R S12b is -F, -OH, -OCH3, -CN, -CH2F, -CF3, -CH2OCH3, -CH2CN, -CHF2, -CD3, -NH2 or -CH3.

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

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

[0159] In some embodiments, is:

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] In some embodiments, is:

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179] In some embodiments, is:

[0180]

[0181]

[0182] In some embodiments, is:

[0183]

[0184] In some embodiments, is:

[0185]

[0186]

[0187] In some embodiments, is:

[0188]

[0189] The compound according to any one of

[17] .[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] .[1] to

[17] The compound according to any one of the above, 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 according to any one of [1] to

[18] , wherein Y1 is O.

[0220]

[20] . The compound according to any one of [1] to

[19] , wherein R 38 and R 39 each independently is hydrogen or deuterium.

[0221]

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

[20] , wherein n5 is 1.

[0222]

[22] . The compound according to any one of [1] to

[21] , wherein

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

[0224]

[23] . The compound according to any one of [1] to

[22] , wherein:

[0225] Ring J is a 4- to 6-membered heterocycle containing 1 or 2 heteroatoms selected from N, O or S.

[0226]

[24] . The compound according to any one of [1] to

[23] , wherein:

[0227] is

[0228] wherein, R S381 is hydrogen or R S38 ;

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

[0230]

[25] .[1] to any one of

[24] of the compound, wherein:

[0231] R S381 is hydrogen, deuterium, -C 1-6 alkyl or 3-6 membered cycloalkyl, wherein the -C 1-6 alkyl or 3-6 membered cycloalkyl is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl.

[0232]

[26] .[1] to any one of

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

[0233]

[27] .[1] to any one of

[26] of the compound, wherein m 81 is 0.

[0234]

[28] .[1] to any one of

[27] of the compound, wherein:

[0235] m9 is 0, 1 or 2.

[0236]

[29] .[1] to any one of

[28] of the compound, wherein:

[0237] m9 is 0.

[0238]

[30] .[1] to any one of

[29] of the compound, wherein:

[0239] m9 is 1.

[0240]

[31] .[1] to any one of

[30] of the compound, wherein:

[0241] is

[0242]

[0243] wherein, R S394 is hydrogen or R S391 .

[0244] The compound according to any one of

[32] .[1] to

[31] , wherein:

[0245] R S39 is a halogen;

[0246] Preferably, R S39 is -F.

[0247]

[33] .[1] to

[32] of any one of the compounds, wherein:

[0248] R S391 is hydrogen, deuterium, halogen, or -C 1-6 alkyl; wherein the -C 1-6 alkyl is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl;

[0249] Preferably, R S391 is hydrogen, deuterium, -F, or -CH3.

[0250]

[34] .[1] to

[33] of any one of the compounds, wherein:

[0251] is

[0252]

[0253]

[35] .[1] to

[34] of any one of the compounds, wherein:

[0254] is

[0255]

[0256]

[0257]

[36] .[1] to

[21] of any one of the compounds, wherein:

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

[0259]

[37] .[1] to

[21] and

[36] of any one of the compounds, wherein:

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

[0261]

[38] . The compound according to any one of [1] to

[21] and

[36] to

[37] , wherein:

[0262] is

[0263]

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

[21] and

[36] to

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

[0264]

[40] . The compound according to any one of [1] to

[21] and

[31] to

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

[0265] Optionally, two Rs S31 together with the carbon atom to which they are both attached form or cyclopropyl; wherein the or cyclopropyl is independently unsubstituted or substituted by 1, 2, or 3 Rs S311 substituted; or

[0266] Optionally, two adjacent Rs S31 together with the carbon atoms to which they are respectively attached form a 5- to 10-membered heterocycle containing 1 or 2 heteroatoms selected from N or O, a benzene ring, or a 5- to 10-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, or S, wherein each ring is independently unsubstituted or substituted by 1, 2, or 3 Rs S312 substituted.

[0267]

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

[21] and

[36] to

[40] , wherein:

[0268] is selected from

[0269] wherein,

[0270] Ring G is a 5- to 6-membered heterocycle containing 1 or 2 heteroatoms selected from N or O, a benzene ring, a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms selected from N, O, or S;

[0271] Ring H is a 5- to 10-membered heterocycle containing 1 or 2 heteroatoms selected from N or O, a benzene ring, a 5- to 10-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, or S;

[0272] R S36 has the same definition as R S31 ;

[0273] RS314 is hydrogen or R S311 ;

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

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

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

[0277] m 34 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 is 0, 1, 2, 3, 4, 5, or 6.

[0280]

[42] .[1] to any one of

[21] and

[36] to

[41] of the compound, wherein:

[0281] is

[0282]

[0283] wherein,

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

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

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

[0287] m 34 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 is 0, 1, 2, 3, 4, 5, or 6.

[0290]

[43] .[1] to any one of

[21] and

[36] to

[42] of the compound, wherein:

[0291] R S311 is independently deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -OH, -OC 1-6 alkyl, -CN, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2; wherein said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, a halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl;

[0292] R S312 is independently deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -OH, -OC 1-6 alkyl, -CN, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2; wherein said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, a halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl;

[0293] R S314 is independently hydrogen, deuterium, a halogen, -C 1-6 alkyl, wherein said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, a halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl.

[0294]

[44] .[1] to

[21] and

[36] to

[43] of any one of the compounds described, wherein:

[0295] R S311 is independently deuterium, -F or -OCH3;

[0296] R S312 is independently deuterium, -F, -OCH3, or -CH2OCH3;

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

[0298]

[45] . A compound according to any one of [1] to

[21] and

[36] to

[44] , wherein:

[0299] R S36 is deuterium or -F.

[0300]

[46] . A compound according to any one of [1] to

[21] and

[36] to

[45] , wherein:

[0301] m 31 is 0 or 1;

[0302] m 32 is 0 or 1;

[0303] m 33 is 0 or 1;

[0304] m 34 is 0 or 1;

[0305] m5 is 0 or 1;

[0306] m6 is 0 or 1.

[0307]

[47] . A compound according to [1] to

[21] and

[36] to

[46] , wherein:

[0308] is

[0309]

[0310]

[48] . A compound according to any one of [1] to

[21] and

[36] to

[47] , wherein:

[0311] is

[0312]

[0313]

[49] . A compound according to any one of [1] to

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

[0314]

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

[21] , or

[49] , wherein n6 is 1 or 2.

[0315]

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

[21] ,

[49] or

[50] , wherein:

[0316] Ring K is a 4- to 10-membered heterocycle containing 1 or 2 heteroatoms selected from N or O.

[0317]

[52] . The compound according to any one of [1] to

[21] ,

[49] to

[51] , wherein:

[0318] is

[0319] wherein ring L is a 4- to 6-membered heterocycle, optionally further containing 1 or 2 heteroatoms selected from N or O.

[0320]

[53] . The compound according to any one of [1] to

[21] ,

[49] to

[52] , wherein:

[0321] is

[0322]

[54] . The compound according to any one of [1] to

[21] ,

[49] to

[53] , wherein:

[0323] R S315 is independently deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-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 alkyl is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl.

[0324]

[55] . The compound according to any one of [1] to

[21] ,

[49] to

[54] , wherein R S315 is independently -F or -CH3.

[0325]

[56] . The compound according to any one of [1] to

[21] ,

[49] to

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

[0326]

[57] . The compound according to any one of [1] to

[21] ,

[49] to

[56] , wherein:

[0327] is

[0328]

[58] . The compound according to any one of [1] to

[21] ,

[49] to

[57] , wherein:

[0329] is

[0330]

[0331]

[59] . The compound according to any one of [1] to

[21] , wherein, is:

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339] In some embodiments, is:

[0340]

[0341] In some embodiments, is:

[0342]

[0343]

[0344] In some embodiments, is:

[0345]

[0346]

[0347]

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

[59] , wherein R4 is phenyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, indazolyl, benzothienyl or benzothiazolyl, and the phenyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, indazolyl, benzothienyl or benzothiazolyl is unsubstituted or substituted by 1, 2, 3, 4, 5 or 6 R S4 substituents.

[0348]

[61] . The compound according to any one of [1] to

[60] , wherein R4 is

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

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

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

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

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

[0354] R S4e is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl;

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

[0356] R S4g is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl;

[0357] R S4h is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl;

[0358] RS4i is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl;

[0359] R S4j is hydrogen, deuterium, a halogen, -CN, -C 1-3 alkyl, halo-C 1-3 alkyl or -O halo-C 1-3 alkyl;

[0360] R S4k is hydrogen, deuterium, a halogen, -CN, -C 1-3 alkyl, halo-C 1-3 alkyl or -O halo-C 1-3 alkyl;

[0361] R S4l is hydrogen, deuterium, a halogen, -CN, -C 1-3 alkyl, halo-C 1-3 alkyl or -O halo-C 1-3 alkyl;

[0362] R S4m is hydrogen, deuterium, a halogen, -CN, -C 1-3 alkyl, halo-C 1-3 alkyl or -O halo-C 1-3 alkyl;

[0363] R S4n is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl;

[0364] R S4o is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl;

[0365] R S4p is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl.

[0366] The compound according to

[62] .

[61] , wherein:

[0367] m7 is 0;

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

[0369] R S4b is -F;

[0370] R S4c is ethyl, vinyl or ethynyl;

[0371] RS4d is hydrogen, or -F;

[0372] R S4e is -F;

[0373] R S4f is -NH2;

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

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

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

[0377] R S4j is -CN;

[0378] R S4k is hydrogen;

[0379] R S4l is methyl;

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

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

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

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

[0384]

[63] .[1] to

[62] Any one of the compounds described, wherein:

[0385] R4 is

[0386]

[0387]

[0388] In some embodiments, R4 is

[0389] In some embodiments, R4 is

[0390]

[0391] In some embodiments, R4 is:

[0392]

[0393] The compound according to any one of

[64] .[1] to

[63] , wherein R5 is a halogen.

[0394]

[65] .[1] to

[64] The compound according to any one of, wherein R5 is -F. In some embodiments, the compound is:

[0395]

[0396] Wherein, is:

[0397]

[0398]

[0399] In some embodiments, the compound is:

[0400]

[0401] Wherein, is:

[0402]

[0403] In some embodiments, the compound is:

[0404]

[0405] Wherein, is:

[0406]

[0407] R4 is:

[0408]

[0409] is:

[0410]

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

[0412]

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

[0414] R S1 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 one of the following formulas:

[0423]

[0424] -Y1-R3 is:

[0425]

[0426] R S1 is R4 is:

[0427]

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

[0429]

[0430] Wherein:

[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 one of the following formulas:

[0440]

[0441] Wherein:

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

[0443] R S1 is -H, or -CD3;

[0444] -Y1-R3 is:

[0445]

[0446]

[0447] R4 is:

[0448]

[0449]

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

[0451]

[0452] Wherein:

[0453] -Y1-R3 is:

[0454]

[0455] R S1 is

[0456] R4 is:

[0457]

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

[0459]

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

[0461] R S1 is

[0462] R1 is -Y1-R3 is:

[0463]

[0464] R4 is:

[0465]

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

[0467]

[0468] R4 is:

[0469]

[0470] -Y1-R3 is:

[0471]

[0472] R S1 is:

[0473]

[0474] R1 is:

[0475]

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

[0477]

[0478] Wherein:

[0479] R5 is:

[0480]

[0481] R S1 is:

[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 formulas:

[0490]

[0491] R5 is:

[0492]

[0493] R X13 is:

[0494]

[0495] R S2 is:

[0496]

[0497] R S1 is:

[0498]

[0499] -Y1-R3 is:

[0500]

[0501]

[0502]

[0503] R4 is:

[0504]

[0505]

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

[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 one of the following formulas:

[0517]

[0518] R5 is:

[0519]

[0520] R S1 is:

[0521]

[0522] R1 is:

[0523]

[0524] -Y1-R3 is:

[0525]

[0526] R4 is:

[0527]

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

[0529]

[0530] wherein,

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

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

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

[0534] R S1 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] Among them, is:

[0545]

[0546]

[0547] In some embodiments, the compound is:

[0548]

[0549] Among them, is:

[0550]

[0551] In some embodiments, the compound is:

[0552]

[0553] Among them, is:

[0554]

[0555] R4 is:

[0556]

[0557] is:

[0558]

[0559] In some embodiments, the compound is:

[0560]

[0561] Among them, is:

[0562]

[0563]

[0564] In some embodiments, the compound is:

[0565]

[0566] Among them, is:

[0567]

[0568] In some embodiments, the compound is:

[0569]

[0570] Wherein, is:

[0571]

[0572] R4 is:

[0573]

[0574] is:

[0575]

[0576] In some embodiments, the compound is:

[0577]

[0578] Wherein, is:

[0579]

[0580] R4 is:

[0581]

[0582] is:

[0583]

[0584] In some embodiments, the compound is:

[0585]

[0586] Wherein,

[0587] is:

[0588] And R4 is:

[0589] In some embodiments, the compound is:

[0590]

[0591] Wherein,

[0592] R S1a is:

[0593] R S1c is:

[0594] is:

[0595]

[0596]

[0597] and

[0598] R4 is:

[0599] In some embodiments, the compound is:

[0600]

[0601] wherein,

[0602] R S1b is:

[0603] is:

[0604]

[0605] and

[0606] R4 is:

[0607] In some embodiments, the compound is:

[0608]

[0609] wherein,

[0610] R S1a is:

[0611] R S1c is:

[0612] is:

[0613]

[0614] and

[0615] R4 is:

[0616] In some embodiments, the compound is:

[0617]

[0618] wherein,

[0619] is:

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

[0621]

[0622] wherein,

[0623] is:

[0624]

[0625]

[0626] and

[0627] R4 is:

[0628] In some embodiments, the compound is:

[0629]

[0630] wherein,

[0631] is:

[0632]

[0633]

[0634] is:

[0635]

[0636]

[0637] and

[0638] R4 is:

[0639] In some embodiments, the compound is:

[0640]

[0641] wherein,

[0642] is:

[0643]

[0644] and

[0645] R4 is:

[0646] In some embodiments, the compound is:

[0647]

[0648] wherein,

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

[0650]

[0651] wherein,

[0652] is:

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660] and

[0661] R4 is:

[0662] In some embodiments, the compound is:

[0663]

[0664] wherein,

[0665] is:

[0666]

[0667]

[0668]

[0669]

[0670] and

[0671] R4 is:

[0672] In some embodiments, the compound is:

[0673]

[0674] wherein,

[0675] R1 is:

[0676] is: and

[0677] R4 is:

[0678] In some embodiments, the compound is:

[0679]

[0680] wherein,

[0681] is:

[0682]

[0683] is:

[0684]

[0685] and

[0686] R4 is:

[0687] In some embodiments, the compound is:

[0688]

[0689] wherein,

[0690] is:

[0691]

[0692] is: and

[0693] R4 is:

[0694] In some embodiments, the compound is:

[0695]

[0696] wherein,

[0697] R1 is:

[0698] is:

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

[0700]

[0701] wherein,

[0702] is:

[0703] The compound according to any one of

[66] .[1] to

[65] , wherein the compound is any compound 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] . Pharmaceutical composition, which comprises a therapeutically effective amount of a compound of formula (I) as described in any one of [1] to

[66] , its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, its prodrugs, its deuterated molecules or its PROTAC molecules, and a pharmaceutically acceptable excipient.

[0726]

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

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

[67] .

[0727]

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

[0728] (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

[0729] (b) if relevant, administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) as described in any one of [1] to

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

[67] .

[0730]

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

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

[67] for use in treatment.

[0731]

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

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

[67] for use as a medicament.

[0732]

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

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

[67] for use in a method of treating cancer.

[0733]

[73] . Use of the compound of formula (I) as described in any one of [1] to

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

[67] in the treatment of cancer.

[0734]

[74] . Use of a compound of formula (I), its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, its prodrugs, its deuterated molecules or its PROTAC molecules, or the pharmaceutical composition according to

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

[0735]

[75] . The method for treating cancer according to

[68] , the use in the method for treating cancer according to

[72] , the use for treating cancer according to

[73] , or the use in the preparation of a medicament for treating cancer according to

[74] , wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer (such as non-small cell lung cancer), breast cancer, large intestine cancer, gastric cancer, endometrial cancer, esophageal cancer or gastroesophageal junction cancer.

[0736]

[76] . The method for treating cancer according to

[68] or

[75] , the use in the method for treating cancer according to

[72] or

[75] , the use for treating cancer according to

[73] or

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

[74] or

[75] , wherein the cancer is associated with at least one of 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.

[0737] The present invention provides the following:

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

[0739]

[0740] Its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, its prodrugs, its deuterated molecules or its PROTAC molecules, wherein;

[0741] R3 is -C 1-6 alkylene, which is optionally substituted by one or more deuteriums, halogens, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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 a substituent of 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

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

[66] .

[0743] [B-2].[B-1] The compound as described, wherein R3 is -C A alkylene substituted by -N(R 1-6 )2; R A is hydrogen or -C 1-3 alkyl.

[0744] [B-3].[B-2] The compound as described, wherein R3 is -C 1-6 alkylene substituted by -N(CH3)2.

[0745] The present 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] Ring A, R S1 , m1, R S2, m2, n1, X1, X2, R5, Y1, R3 have the same definitions as any one of [1] to

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

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

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

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

[0754] [C-5]. The intermediate described in any one of [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 those skilled in the art to which this invention belongs. All patents, patent applications, and publications cited in this application are incorporated by reference.

[0760] Unless otherwise specified, the term "halogen" or "halo" used in this application refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0761] Unless otherwise specified, the term "alkyl" used in this application includes saturated monovalent hydrocarbon groups having straight or branched chains. For example, -C 1-6 Alkyl includes 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 The C in alkyl 1-3 is defined as a group having 1, 2, or 3 carbon atoms in a straight or branched arrangement.

[0762] Unless otherwise specified, the term "haloalkyl" (e.g., -C 1-6 haloalkyl, -C 1-4 haloalkyl, -C 1-3Halogenated alkyl or halogenated C 1-6 alkyl) means that one or more (e.g., one, two or three) hydrogens in the alkyl as defined in the present application (e.g., -C 1-6 alkyl, -C 1-4 alkyl or -C 1-3 alkyl) have been replaced by halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.

[0763] The term "alkylene" refers to a difunctional group obtained by removing a hydrogen atom from the alkyl defined above. For example, 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-chain hydrocarbon group containing one or more double bonds and usually having a length of 2 to 20 carbon atoms. For example, "-C 2-6 alkenyl" is an alkenyl containing 2 to 6 carbon atoms. Alkenyls include, but are not limited to, for example, vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0765] The term "alkynyl" includes a straight-chain or branched-chain hydrocarbon group containing one or more triple bonds and usually having a length of 2 to 20 carbon atoms. For example, "-C 2-6 alkynyl" is an alkynyl containing 2 to 6 carbon atoms. Representative alkynyls include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, etc.

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

[0767] Unless otherwise specified, the term "aryl" as used in the present application refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbocyclic atoms. Preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.

[0768] Unless otherwise indicated, as used herein, the terms "heterocycle" or "heterocyclic group" refer 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 spiro heterocycles. Preferred heteroatoms include N, O, and S, including N-oxides, sulfoxides, 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 one, two, or three degrees of substitution. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxazepinyl, aziridinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiazolyl, morpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

[0769] Unless otherwise indicated, as used herein, the term "heteroaryl" denotes an aromatic ring system containing carbon and at least one heteroatom. The heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 heteroatoms. The polycyclic heteroaryl ring may contain fused rings, spiro rings, or bridged ring connections. For example, a bicyclic heteroaryl is a polycyclic heteroaryl. The bicyclic heteroaryl ring may contain 8 to 12 member atoms. The monocyclic heteroaryl ring may contain 5 to 8 member atoms (carbon and heteroatoms). Examples of heteroaryls include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, or isoquinolinyl.

[0770] The term "carbocycle" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring system containing only carbon atoms. Exemplary "cycloalkyls" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

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

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

[0773] The term "oxo" means that an oxygen atom together with the connected carbon atom forms a group.

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

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

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

[0777] The scope of the present invention includes prodrugs of the compounds of the present invention. Generally, such prodrugs will be functional derivatives that are readily convertible in vivo into the desired compound. Accordingly, in the methods of treatment of the present invention, the term "administering" shall cover treating the various disorders described with the specifically disclosed compounds or with compounds that may not be specifically disclosed but that are convertible in vivo into the designated compound upon administration to a subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", H. Bundgaard, Elsevier, 1985.

[0778] The present invention includes all stereoisomers of the described compounds and their pharmaceutically acceptable salts. In addition, mixtures of stereoisomers and isolated specific stereoisomers are also included. During the synthetic steps used to prepare such compounds or during steps using racemization or epimerization methods known to those skilled in the art, the products of such steps may be mixtures of stereoisomers. The term "stereoisomers" as used in the present invention refers to isomers in which the atoms or groups of atoms in a molecule are connected in the same order but have a different spatial arrangement, including conformational isomers and configurational isomers. Configurational isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The present invention includes all possible stereoisomers of the compound (such as its atropisomers). The absolute configuration of the present invention can be confirmed by general technical methods such as X-ray single crystal diffraction or co-crystallization with the KRAS mutant protein, or by comparing the pharmacological activities of the two isomers with those of a pair of isomers with a determined absolute configuration.

[0779] The present invention is intended to include all atomic isotopes that occur in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. As general examples 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 (for deuterium) and T (for tritium). In the present application, -CD3 represents a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon include 13 C and 14 C. Isotopes of oxygen include 16 O, 17 O, or 18 O. 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 in place of unlabeled reagents.

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

[0781] Unless otherwise specifically stated, when tautomers exist for a compound of the present invention, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof.

[0782] A "PROTAC molecule" refers to a compound described in the present application conjugated, with or without a linker, to another agent, where the compound serves as a K-Ras protein (including K-Ras G12C, 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 incorporated into proteolysis-targeting chimeras (PROTACs).

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

[0784] The term "subject" refers to an animal. In some embodiments, the animal is a mammal. The subject also refers to, for example, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a human. As used herein, "patient" refers to a human subject. As used herein, a subject "requires" treatment if the subject will receive a biological, medical, or quality of life benefit from such treatment. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the cancer to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed with a 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 alleviation or suppression of a given condition, symptom, disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0786] In one embodiment, the terms "treat", "treating", or "treatment" of any disease or disorder refer to ameliorating the disease or disorder (i.e., slowing or halting or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating", or "treatment" refer to alleviating or ameliorating at least one physical parameter, including those parameters that may not be discernible by the patient. In another embodiment, "treat", "treating", or "treatment" refer to physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both physically modulating the disease or disorder. In yet another embodiment, "treat", "treating", or "treatment" refer to preventing or delaying the onset, development, or progression of a disease or disorder. Examples

[0787] The following examples are provided to better illustrate the present invention. Unless otherwise explicitly 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 through the prior art.

[0796] INT 10

[0797]

[0798] To a solution of INT11-6 (8.2 g) in DCM (100 ml) was added DIEA (11.82 g), and trifluoromethanesulfonic anhydride (15.77 g) was added dropwise at 0 °C. Under N2, the reaction mixture was stirred overnight at RT, adjusted to pH 8 with NaHCO3 solution and extracted with DCM. After post-treatment and purification of the organic layer, INT10-1 (9.24 g) was obtained.

[0799] A solution of INT10-1 (9.24 g), diphenylmethanimine (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-treated and purified to obtain INT10-2 (5.71 g).

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

[0801] INT 11

[0802]

[0803] Prepare INT 11 according to a similar method for synthesizing INT 2 in WO2021041671.

[0804] INT13

[0805]

[0806] Prepare INT13 according to a similar method for synthesizing INT10.

[0807] INT 15

[0808]

[0809] Under N2, add POCl3 (4 ml) to a solution of INT6 (4.03 g) and DIEA (8 ml) in toluene (25 ml). The resulting mixture is stirred at 80 °C for 2 hours and concentrated. The residue is diluted with DCM (40 ml), and DIEA (3 ml) and 3-buten-1-amine hydrochloride (1.65 g) are added. The reaction mixture is stirred at RT for 1 hour. It is diluted with DCM and water. The separated organic layer is concentrated and purified to obtain INT15-1 (4.61 g). MS: m / z333 [M+H] + 。

[0810] Add DIEA (9.07 g) to a solution of INT15-1 (4.61 g) and methylamine hydrochloride (2.86 g) in DMAc (40 ml). The mixture is purged with N2 and then stirred at 70 °C for 16 hours. It is diluted with EA and water. The separated organic layer is concentrated and purified to obtain INT15-2 (3.60 g). MS: m / z328 [M+H] + 。

[0811] Add piperidine (2.34 g) and 1,1-dimethoxypropan-2-one (4.36 g) to a solution of benzaldehyde (1.00 g) in MeOH (20 ml). The mixture is purged with N2 and then stirred overnight at rt, diluted with EA and washed with water. The separated organic layer is concentrated and purified to obtain INT15-3 (1.0 g). MS: m / z207 [M+H] + 。

[0812] To a solution of INT15-3 (0.31 g) and INT15-2 (0.38 g) in DMSO (5 ml) was added TsOH●H2O (0.30 g). The mixture was purged with N2 and then stirred overnight at 80 °C, cooled to RT, diluted with EA and washed with water. The separated organic layer was concentrated and purified to give INT15-4 (0.48 g). MS: m / z 470 [M+H] + 。

[0813] To a solution of INT15-4 (1.12 g) in toluene (20 ml) was added Grubbs Gen 2nd (0.42 g). The mixture was purged with N2 and then stirred at 80 °C for 2 h, 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) in THF (1000 ml) solution were cooled to -15 °C and isobutyl chloroformate (36.31 g) was added to the resulting mixture. The mixture was stirred at the same temperature for 2 h and filtered. The filtrate was cooled to 0 °C and added dropwise to a solution of NaBH4 (16.71 g) in water (200 ml). The solution was stirred at 0 °C for 1 h. Quenched with water and extracted with EA. The organic layer was worked up and purified to give INT16-1 (74.35 g, 110.5% yield). MS (ESI, m / z): 282 [M+H] + 。

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

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

[0819] At -20 °C under 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 h and diluted with EA and saturated NH4Cl. The separated organic layer was worked up and purified to give INT 16-4 (2.02 g). MS: m / z 338 [M+1] + 。

[0820] At -20 °C under 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 h and 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 resulting mixture was stirred for 4 h. It was quenched with H2O and extracted with EA. The organic layer was worked up to give INT 17 (2.02 g, crude product). MS: m / z: 479 [M+1] + 。

[0824] Example 1

[0825]

[0826] CP1-5 was prepared by a method similar to the procedure of WO2023046135.

[0827] HCl (4 M in 1,4-dioxane, 5 ml) was added to a solution of CP1-5 (296 mg) in CH3CN (15 ml). The reaction mixture was stirred at RT for 1 h 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, trifluoromethanesulfonic anhydride (573 mg) was added dropwise, and the mixture was warmed to RT. The reaction mixture was stirred at RT for 2 h 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] Under N2, a solution of CP1-7 (51 mg), diphenylmethanimine (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 h 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 in 1,4-dioxane, 0.3 ml) was added to a solution of CP1-8 (49 mg) in DCM (3 ml). The reaction mixture was stirred at RT for 16 h 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] To a solution of CP1-9 (53 mg) in DMF (3 ml) was added CsF (105 mg). The reaction mixture was stirred at 40 °C for 2 h, and the filtrate was collected by filtration. The filtrate was concentrated and purified by Prep-HPLC (Ultimate XB-C18, phase A: water with 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 from 2-a in a method similar to that of CP1. MS (ESI, m / z): 624 [M+H] + 。

[0835] Example 3

[0836]

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

[0838] Compound 3 (CP3, 19.5 mg, TFA salt, confirmed) was obtained from CP3-1 by a similar procedure to that for the preparation of CP1. MS (ESI, m / z): 623 [M+H] + 。

[0839] Example 4

[0840]

[0841] Compound 4 (CP4, confirmed) was synthesized in a method similar to that of CP9.

[0842] Example 5

[0843]

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

[0845] Example 6

[0846]

[0847] To a solution of CP1 (30 mg) in MeOH (10 ml) was added Pd / C (75 mg, 10% content). The mixture was stirred at RT under H2 for 1.5 h, filtered, the filtrate was concentrated, purified and separated by Prep-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 um, mobile phase A: water with 0.1% TFA, mobile phase B: CH3CN, gradient: 10% B to 29% B in 31 min, flow rate 40 ml / min, 230 nm) to obtain 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] Using a method similar to CP1, compound 7 (CP7, 25.9 mg, TFA salt, confirmed) was synthesized from 7-a and CP1-3.

[0851] LCMS: m / z: 611 [M+H] + 。

[0852] Example 8

[0853]

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

[0855] Example 9

[0856]

[0857] At 0 °C, NaH (60% in 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 solution of CP9-1 (1.56 g) in MeOH (25 ml). The reaction mixture was stirred under H2 at RT for 5 h, filtered and the filtrate was concentrated to give 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 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 vial 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) was added TsOH●H2O (97 mg). The solution was stirred at 100 °C under N2 for 24 h, diluted with water and extracted with EA. The collected organic layer was washed with brine, dried, concentrated and purified by Prep-TLC to give CP9-5 (52 mg). MS: m / z 356 [M+H] + 。

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

[0863] To a solution of INT14 (42 mg) in THF (3 ml) was added t-BuONa (30 mg). 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 give CP9-7 (53 mg). MS: m / z: 467 [M+H] + 。

[0864] To a solution of CP9-7 (53 mg), INT2 (77 mg) in toluene (6 ml) and water (1.5 ml) were added cataCXium A Pd G3 (23 mg) and Cs2CO3 (91 mg). Under N2, the reaction mixture was stirred at 100 °C for 18 h. 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), HCl (4 M in dioxane, 1 mL) 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 um, A: water with 0.05% trifluoroacetic acid, B: CH3CN, gradient: 20% B to 45% B in 35 min, flow rate 70 mL / min, 225 nm), and freeze-dried to obtain 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 from CP9-7 and INT13 in a method similar to that of CP9, and purified by Prep-HPLC (YMC-Triart C18-S12nm, mobile phase A: water with 0.1% trifluoroacetic acid, mobile phase B: CH3CN, gradient: 15% B to 45% B in 30 min, flow rate 70 mL / min, 226 nm). LCMS: m / z: 616 [M+H] + 。

[0870] Example 11

[0871]

[0872] CP11-3 was synthesized from INT 7 and ST in a method similar to that of CP1-4.

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

[0874] CP11 (3.08 mg) was separated by Prep-HPLC Gilson with the following conditions: column, CHIRAL ARTCellulose-SC, column (2 cm × 25 cm, 5 um); mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / EtOH(50:50); flow rate: 17 ml / min. This yielded the first peak 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, to obtain CP10A-1 (83 mg, retention time 6.65 min) and CP10B-1 (61 mg, retention time 9.253 min) respectively.

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

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

[0880] CP10B (CP10B, confirmed) was synthesized from CP10B-1 in a method similar to that of compound 10A, purified by Prep-HPLC (Daisogel-C18, phase A: water with 0.1% trifluoroacetic acid, phase B: CH3CN, gradient: 15% B to 35% B in 32 min, flow rate 60 mL / min, 230 nm) and freeze-dried to obtain CP10B (12.3 mg, TFA salt). MS (ESI, m / z:): 616 [M+H] + 。

[0881] Example 13

[0882]

[0883] At 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. It was quenched with 5% sodium thiosulfate in saturated aqueous NaHCO3. The resulting two-phase mixture was stirred vigorously for 15 minutes and washed with DCM. The separated organic layer was worked up 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 the mixture was stirred overnight at RT. The mixture was poured into water and extracted with EA. The separated organic layer was worked up to give 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 crude 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 crude CP12A-4 (crude product).

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

[0888] At 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). Under N2, the reaction mixture was stirred at 105 °C overnight. After completion, H2O was added to the reaction mixture and it was extracted with DCM. The separated organic layer was worked up to give yellow solid CP12A (10 mg). MS (ESI, m / z:): 339 [M+H] + . 1HNMR(300MHz, DMSO-d6): δ 6.63(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 in a method similar to that of CP1 - 4.

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

[0891] Example 14

[0892]

[0893] Compound 13 (CP13) (8 mg, TFA salt, confirmed) was synthesized from CP1 - 3 and 13 - a in a method 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 at RT for 16 h. The reaction mixture was diluted with DCM and washed with water. The separated organic layer was worked up to give CP14 - 1 (1542 mg). LCMS: m / z: 230 [M + H] + .

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

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

[0899] Example 16

[0900]

[0901] Compound 15 (CP15, confirmed) was synthesized with INT16 in a method similar to CP30.

[0902] Example 17

[0903]

[0904] Pd / C (235 mg) was added to a solution of 16-a (249 mg) in MeOH (15 mL). The solution was stirred under H2 for 6 h, filtered, and the filtrate was concentrated to give CP16-1 (201 mg). MS (ESI, m / z): 246 [M+H] + 。

[0905] HCl (4 M in 1,4-dioxane, 2 mL) was added to a solution of CP16-1 (201 mg) in CH3CN (6 ml). The reaction mixture was stirred at RT for 1.5 h and concentrated. CH3CN (5 ml) and aq. NaHCO3 (1 mL) were added to the residue, 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] A solution of CP16-2 (168 mg) in THF (10 mL) was cooled with an ice-ethanol bath. NaH (194 mg, 60% in oil) was added portionwise, 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 solution of CP16-3 (161 mg) in DCM (15 mL). The reaction mixture was stirred at RT for 24 h, quenched with water (30 mL), and extracted with DCM (30 mL). The separated organic layer was worked up to give CP16-4 (30 mg). MS (ESI, m / z): 371 [M+H] + 。

[0908] CP16-6 was synthesized with CP16-4 in a method similar to CP1-4.

[0909] Compound 16 (CP16, 1.2 mg, TFA salt, confirmed) was synthesized from CP16-6 in a method similar to that of CP3. 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 worked up to give CP17-1 (361 mg). MS (ESI, m / z): 352 [M+H] + 。

[0913] Under H2, Pd / C (354 mg) was added to a solution of CP17-1 (361 mg) in methanol (15 mL). The reaction mixture was stirred at rt for 16 h, 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 in a method similar to that of CP16-6.

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

[0916] LCMS: m / z: 647 [M+H] + 。

[0917] Example 19

[0918]

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

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

[0921] Example 20

[0922]

[0923] Under an ice-ethanol bath, DAST (2.38 g) was added to a solution of INT16-3 (821 mg) in DCM (20 mL) and stirred for 1.5 h. The solution was warmed 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 worked up to give CP19-1 (565 mg). MS (ESI, m / z): 358 [M+H] + .

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

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

[0926] Example 21

[0927]

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

[0929] Example 22

[0930]

[0931] CP21-7A / 21-7B was synthesized from INT12 in a manner similar to CP12-2 and separated by Prep-TLC to give two isomers, CP21-7A (45 mg) and CP21-7B (38 mg). MS: m / z: 464 [M+H] + .

[0932] Compound 21 (CP21, confirmed) was synthesized from CP21-7A in a manner similar to CP3. LCMS: m / z: 613 [M+H] + .

[0933] Example 23

[0934]

[0935] CP22-1 was synthesized in a manner similar to CP12A.

[0936] Compound 22 (CP22, 24.6 mg, TFA salt) was synthesized from CP22-1 in a manner similar to CP21. LCMS: m / z: 613 [M+H] + .

[0937] Example 24

[0938]

[0939] A solution of 23-a (3.02 g) in HCl (4 M in 1,4-dioxane, 30 mL) was stirred at RT for 3 h and concentrated to give 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 h. The mixture was diluted with water and extracted with EA. The organic layer was worked up to give CP23-2 (262 mg). MS (ESI, m / z): 152 [M+H] + .

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

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

[0943] Example 25

[0944]

[0945] At 0 °C, LAH (2.78 g) was added to a solution of 24-a (14.20 g) in THF (150 mL). 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 worked up to give CP24-1 (11.01 g). MS (ESI, m / z): 222 [M+H] + 。

[0946] A 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 portionwise 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. It was quenched with aq. NH4Cl and extracted with EA. The aqueous layer was concentrated to remove most of it. The remaining part was worked up to give CP24-2 (739.9 mg). MS (ESI, m / z:): 316 [M+H] + 。

[0947] Under H2, Pd / C (0.39 g) was added to a solution of CP24-2 (589.2 mg) in MeOH (10 mL). The reaction mixture was stirred at RT for 16 h. The resulting mixture was worked up 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 h. The solution was concentrated to give CP24-4 (662.7 mg). MS (ESI, m / z:): 250 [M+H] + 。

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

[0950] Compound 24 (CP24, confirmed) was synthesized from CP24-5 in a method similar to that of CP23. LCMS: m / z: 651 [M+H] + 。

[0951] Example 26

[0952]

[0953] CP25-3 can be purchased or prepared according to the prior art.

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

[0955] Example 27

[0956]

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

[0958] CP26 (0.0171 g) was separated by Prep-HPLC-Gilson under the conditions: column, CHIRAL ART Cellulose-SA column (2 cm × 25 cm, 5 um), mobile phase, (Hex:DCM = 3:1) (0.1% DEA) / EtOH (70:30), flow rate: 18 mL / min. Compound 26A (0.0010 g, the first eluted isomer, retention time 5.657 min, confirmed) and compound 26B (0.0069 g, the second eluted 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 THF (10 mL) was cooled to 0 °C, borane (1 M in THF, 4 mL) was added dropwise, and the resulting mixture was stirred at RT for 16 h. The resulting mixture was worked up to give CP27-1. LCMS: m / z: 130 [M+H] + 。

[0962] Compound 27 (CP27) was synthesized from CP27-1 in a method similar to CP16. MS (ESI, m / z): 615 [M+H] + 。

[0963] CP27 (26 mg) was separated by Prep-HPLC-Gilson under the 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, the first eluted isomer, retention time 5.533 min, confirmed) and compound 27B (CP27B, 3.9 mg, the second eluted 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 h. The solution was added to aq. NaHCO3 (10 mL). The separated organic layer was worked up 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 with NaBH4 (161 mg) and the mixture was stirred at RT for 16 h. The mixture was heated to 60 °C and stirred for 11 h. The mixture was worked up to obtain CP28-2 (120 mg). MS (ESI, m / z): 252 [M+H] + 。

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

[0969] Compound 28 (CP28, confirmed) was synthesized from CP28-3 in a method similar to CP16. LCMS: m / z: 637 [M+H] + 。

[0970] Example 30

[0971]

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

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

[0974] Compound 29 (CP29, confirmed) was synthesized from CP29-1 in a method similar to that of CP16. LCMS: m / z: 635 [M+H] + 。

[0975] Example 31

[0976]

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

[0978] Example 32

[0979]

[0980] NaH (205 mg) and methyl iodide (1.16 g) were added to a solution of 31-a (1191 mg) in DMF (10 mL). 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 worked up to obtain CP31-1 (602 mg). MS (ESI, m / z): 274 [M+H] + 。

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

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

[0983] Example 33

[0984]

[0985] Compound 32 (CP32, confirmed) was synthesized from 32-a in a manner similar to CP16. LCMS: m / z: 631 [M+H] + 。

[0986] Example 34

[0987]

[0988] CP33-2 can be purchased or prepared according to the prior art.

[0989] Compound 33 (CP33, confirmed) was synthesized from CP33-2 in a manner similar to CP27. LCMS: m / z: 643 [M+H] + 。

[0990] Example 35

[0991]

[0992] CP14 (CP14, confirmed) was synthesized in a manner similar to CP5. 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 completion, the mixture was worked up to obtain CP35-1 (3.29 g). MS (ESI, m / z): 336 [M+H] + 。

[0996] A solution of CP35-1 (3 g) in toluene (50 mL) was cooled to -78 °C. Lithium triethylborohydride (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 added and the mixture was stirred overnight at RT. The solution was diluted with NaHCO3 (100 mL). The separated organic layer was worked up to obtain CP35-2 (1.45 g). MS (ESI, m / z): 320 [M+H] + 。

[0997] Cool the solution of CP35-2 (1.45 g) in DCM (30 mL) to 10 °C. Dropwise add diethylzinc (1 M in n-hexane, 13 mL) and stir for 30 minutes at RT. Cool the reaction mixture to 0 °C, dropwise add diiodomethane (5.19 g), slowly warm to RT and stir for 16 h. Cool the system. Add 200 mL of saturated ammonium chloride solution for extraction. Post-treat the separated organic layer to obtain CP35-3 (1.27 g). MS (ESI, m / z): 234 [M+H] + 。

[0998] Stir the solution of CP35-3 (1.27 g), DMAP (0.71 g), and Boc2O (1.67 g) in DCM (20 mL) at RT for 16 h. Heat the reaction mixture to 40 °C and stir for 24 h. Post-treat the separated organic phase to obtain CP35-4 (578 mg). MS (ESI, m / z:): 334 [M+H] + 。

[0999] Synthesize compound 35 (CP35, confirmed) using CP35-4 in a method similar to CP29. MS: m / z: 629 [M+H] + 。

[1000] Example 37

[1001]

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

[1003] At 0 °C, add LAH (0.90 g) portionwise to the solution of CP36-1 (7.49 g) in THF (20 ml) and stir the resulting mixture for 1 hour. Quench with water, 15% NaOH (0.8 mL), and water (2.4 mL). Post-treat the solution to obtain CP36-2 (4.56 g). MS (ESI, m / z:): 270 [M+H] + 。

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

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

[1006] CP36 was synthesized from CP36-4 in a method similar to that of CP46 and purified by Prep-HPLC (Agela Durashell C18, phase A: water with 0.05% NH4OH, phase B: CH3CN, gradient: 25% B to 58% B in 35 min, flow rate 40 mL / min, 225 nm), and 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 solution of 37-a (3.00 g) in methanol (50 mL), 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 solution of CP37-1 (4.34 g) in DCM (65 mL). The resulting white suspension was cooled to 0 °C and 4-nitrobenzenesulfonyl chloride (6.09 g) was added portionwise. 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 worked up to give CP37-2 (8.02 g). MS (ESI, m / z): 313 [M-1] - 。

[1011] At 0 °C, to a solution of CP37-2 (3.01 g) in THF (50 mL) was added 3-buten-1-ol (0.98 g) and triphenylphosphine (5.07 g). Subsequently, DIAD (3.84 g) was slowly added within 10 min. The reaction mixture was warmed 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 worked up to give CP37-3 (4.19 g).

[1012] A solution of CP37-3 (4.19 g) and the 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 worked up to give CP37-4 (3.427 g).

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

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

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

[1016] Compound 37 (CP37, confirmed) was synthesized from CP37-7 in a method similar to that of CP16. MS (ESI, m / z): 613 [M+H] + 。

[1017] Example 39

[1018]

[1019] At -78 °C, methylmagnesium bromide (3 mmol, 3 M solution in THF) 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). The organic layer was worked up to give 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 h and concentrated to give CP38-2 (crude product) 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 h, 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 from CP38-3 in a manner similar to that of CP35.

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

[1024] Compound 38 (CP38) was synthesized from CP38-11 in a manner similar to that of CP35. It was purified and isolated by Prep-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 um, mobile phase A: 0.05% NH4OH, mobile phase B: 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] Stir a solution of 39-a (53.03 g) in DCM (300 mL) at 0 °C. Add HCl (300 ml, 4M 1,4-dioxane solution) to the mixture at 0 °C and stir at RT for 2 h. Concentrate the mixture to obtain the crude product CP39-1 (35.12 g). MS: m / z: 92 [M+H] + 。

[1028] Stir a solution of CP39-1 (29.32 g), TEA (104.89 g), p-methoxybenzaldehyde (112.00 g) in MeOH (300 mL) at 0 °C. Add sodium triacetoxyborohydride (137.83 g) to the mixture at 0 °C and stir at 0 °C for 1 h. Stir the mixture at 40 °C for 24 h. Quench the reaction mixture with water, extract with EA and perform post-treatment to obtain CP39-2 (25.50 g). MS: m / z: 332 [M+H] + 。

[1029] Stir 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) at RT for 16 h. Quench the mixture with water, extract with DCM and perform post-treatment to obtain CP39-3 (5.78 g). MS: m / z: 446 [M+H] + 。

[1030] Add a solution of CP39-3 (3.46 g) in DCM (40 mL) to DAST (1.57 g) at -10 °C. Stir the reaction mixture at -10 °C for 1 h. Quench with 10% aqueous Na2CO3 solution and extract with DCM. Perform post-treatment and purification on the organic phase to obtain CP39-4 (1.57 g). MS: m / z: 448 [M+H] + 。

[1031] Add CsF (6861 mg) to a solution of CP39-4 (1.57 g) in DMF (25 mL). Stir the reaction mixture at 30 °C for 5 hours. Quench the solution with water, extract with EA and perform post-treatment to obtain CP39-5 (1048 mg). MS: m / z: 334 [M+H] + 。

[1032] Stir a solution of CP39-5 (300 mg) in THF (10 mL) at 0 °C. Add sodium hydride (139 mg, 60%) to the mixture at 0 °C and stir at RT for 0.5 h. Add DMAP (32 mg), TBAI (44 mg), and bromoacetaldehyde dimethyl acetal (465 mg) to the mixture and stir at 70 °C for 16 h. Cool the mixture to RT, quench with water, extract with EA and perform post-treatment to obtain CP39-6 (247 mg). MS: m / z: 422 [M+H] + 。

[1033] Synthesize compound 39 (CP39) from CP39-6 in a method similar to that of CP46 and separate by Prep-TLC (DCM / MeOH = 10:1) to obtain the first eluted compound 39A (CP39A, 143 mg) and the second eluted compound 39B (17 mg). LCMS: m / z: 634 [M+H] + 。

[1034] Example 41

[1035]

[1036] Cool a solution of 40-a (20.42 g), acetic acid (600 mL), and water (600 mL) to 0 °C to 5 °C. Sodium nitrite (25.14 g) is dissolved in water (50 mL) and slowly added to the above solution. Stir the reaction for 7 h. Dilute the resulting solution with 500 mL of EA and wash with water (200 mL). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in MeOH (600 mL) and water (600 mL) at RT and add K2CO3 (15.43 g). Stir the mixture for 24 h. Adjust the pH of the resulting solution to 1 to 2 with 1N aqueous HCl. Extract the mixture with EA. Concentrate the combined organic layers to obtain CP40-1 (23.37 g, crude product). The crude product is used for the next step. LCMS (ESI, m / z): 282 [M+H] + 。

[1037] At 0 °C, add thionyl chloride (2.1611 g) to a solution of CP40-1 (5.11 g) in MeOH (100 mL). Stir the mixture under reflux for 16 h. Concentrate the resulting solution. Purify the residue by silica gel column chromatography, eluting with MeOH / DCM (0 - 5%, v / v) to obtain CP40-2 (1.98 g). LCMS (ESI, m / z): 296 [M+H] + 。

[1038] Dissolve CP40-2 (1.98 g) in DCM (30 mL) under N2 at 0 °C. Slowly add a solution of DAST (3.2420 g) in DCM (30 mL) to the above solution. Warm the resulting mixture to RT. Stir the reaction for 20 h and quench with saturated NaHCO3 solution (100 mL) at 0 to 5 °C. Dilute the resulting solution with 100 mL of DCM. Wash the organic phase with brine, dry, filter and concentrate. Purify the residue by C18 gel chromatography, eluting with H2O / CH3CN to give CP40-3 (747 mg). LCMS (ESI, m / z): 298 [M+H] + 。

[1039] To a solution of CP40-3 (643 mg) in THF (3 mL) at 0 °C, add LAH (247 mg). Stir the mixture at 0 °C for 1 h and quench with Na2SO4 decahydrate at 0 - 5 °C. Filter the resulting mixture and concentrate the filtrate. Purify the residue 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] Add palladium hydroxide (354 mg) to a solution of CP40-4 (1.92 g) in MeOH (40 mL), purge with N2 and pressurize with H2. Stir the mixture at RT for 20 h. After completion, filter the resulting mixture and wash the filter cake with MeOH. Collect and remove the filtrate to give CP40-5 (1.31 g). The crude product is used for the next step. LCMS (ESI, m / z): 136 [M+H] + 。

[1041] Stir a solution of INT 6 (894 mg), DIEA (828 mg) and POCl3 (432 mg) in toluene (20 mL) at 100 °C for 2 h. Concentrate the resulting mixture. Add the residue to a mixture of CP40-5 (0.285 g) and DIEA (874 mg) in DCM (30 mL) at -10 to 20 °C. Warm the resulting mixture to RT. Stir the reaction for 0.5 h. Dilute the resulting solution with 50 mL of DCM. Wash the organic phase with brine, dry with anhydrous Na2SO4, filter and concentrate. Purify the residue by prep-TLC using (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 warmed 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 obtain 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: hexane solution of 0 - 30% EA) to obtain CP40-9 (262 mg). LCMS (ESI, m / z): 372 [M+H] + 。

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

[1046] 1H NMR (400 MHz, DMSO-d6) δ 7.75 (dd, J = 8.9, 6.0 Hz, 1H), 7.32 (m, 1H), 7.09 - 6.95 (m, 2H), 5.60 (s, 2H), 5.34 (dd, J = 12.6, 7.1 Hz, 1H), 4.88 (d, J = 47.7 Hz, 1H), 4.43 (s, 1H), 4.20 - 3.89 (m, 3H), 3.12 - 3.07 (m, 3H), 3.03 (d, J = 4.2 Hz, 1H), 2.83 (d, J = 6.4 Hz, 1H), 2.16 - 1.64 (m, 14H), 1.62 - 1.32 (m, 2H).

[1047] Example 42

[1048]

[1049] Under 0 °C and N2, NaH (405 mg) was added to a solution of 41-a (5539 mg) in diethyl ether (13 mL). 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)-ethyl 3-hydroxybutyrate (2.6312 g) in DCM (56 mL) was stirred at RT and under 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. Quenched with sat. aq. NaHCO3 and worked up to obtain CP41-2 (7.28 g).

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

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

[1053] CP41-6 was synthesized from INT 6 in a method 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 h. The mixture was added 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] A 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 stirred at RT for 1 h. The resulting mixture was extracted with DCM and EA and post-treated to obtain CP41-8 (1.06 g). MS (ESI, m / z): 388 [M+H] + 。

[1056] Methanesulfonyl chloride (287 mg) was added dropwise to a mixture of CP41-8 (1.01 g) and DIEA (1033 mg) in DCM (15 mL). The resulting mixture was stirred at RT for 1 h 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 h. 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 obtain CP41-9 (320 mg). MS (ESI, m / z): 370 [M+H] + 。

[1057] CP41-9 (320 mg) was separated by chiral-HPLC Gilson with the 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, the first eluted isomer, retention time 4.933 min) and CP41-9B (the second eluted isomer, retention time 11.277 min) were obtained.

[1058] Compound 41 (CP41, 18.2 mg, TFA salt, confirmed) was synthesized from CP41-9A in a method similar to that of CP46. 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). 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 stirred at RT for 1 h. After completion, the reaction mixture was diluted with EA and saturated NH4Cl and worked up to give CP42-2 (4.05 g). MS: m / z: 342 [M+H] + 。

[1062] At 0 °C under 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 give 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 h. 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 in a method similar to that of CP40-11.

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

[1066] Compound 42 (CP42, confirmed) was synthesized from CP42-11A in a method similar to that of CP46. MS: m / z: 630 [M+H] + 。

[1067] Example 44

[1068]

[1069] Compound 43 (CP43, confirmed) was synthesized from CP42 - 11B in a method similar to 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. At 0 °C, the residue of DIEA (1 mL) was added to a solution of CP36 - 4 (338 mg) in DCM (10 mL). The reactants were stirred at RT for 0.5 h, diluted with water and extracted with DCM and worked up 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) and extracted with EA (30 mL) and worked up 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) and extracted with EA (30 mL) and worked up to obtain CP44 - 4 (120 mg). MS: m / z: 587 [M+H] + 。

[1075] Compound 44 (CP44, confirmed) was synthesized from CP44 - 4 in a method similar to CP46. MS: m / z: 629 [M+H] + 。

[1076] Example 46

[1077]

[1078] Compound 45 (CP45, confirmed) was synthesized from CP10B - 3 and INT10 in a method similar to 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 h. The mixture was diluted with water, extracted with EA and worked up to give CP46-1 (10.79 g). MS: m / z: 444 [M+H] + .

[1082] At 0 °C, potassium tert-butoxide (4.04 g) was added to a solution of methyltriphenylphosphonium bromide (12.68 g) in THF (100 mL). 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 worked up to give CP46-2 (7.72 g). MS: m / z: 442 [M+H] + .

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

[1084] At 0 °C, sodium hydride (60% in oil, 1.84 g) was added to a solution of CP46-3 (3.78 g) in THF (50 mL). 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 worked up to give CP46-4 (4.45 g). MS: m / z: 416 [M+H] + .

[1085] Pd(OH)2 / C (2.96 g) was added to a solution of CP46-4 (3.18 g) in MeOH (100 mL). The reaction mixture was stirred at RT under H2 for 16 h. 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 from CP46-5 and INT6 in a method similar to CP39. 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. To this solution was added NaH (16.27 g), TBAI (4.45 g), DMAP (1.30 g), and BnBr (43.06 g). The reaction mixture was stirred at RT for 16 h, quenched with water, extracted with ethyl acetate and worked up to give CP47-1 (42.71 g).

[1090] At RT, m-CPBA (18.45 g) was added to a solution of CP47-1 (18.64 g) in DCM (200 mL). 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] Benzylamine (17.15 g) was added to a solution of CP47-2 (10.93 g) in MeOH (200 mL). The reaction mixture was stirred at 130 °C under N2 for 3 h. The mixture was allowed to cool to RT. The mixture was concentrated and purified to give CP47-3 (10.65 g). 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 give CP47-4 (8.33 g). MS: 404 [M+H] + 。

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

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

[1095] Compound 47 (CP47, 12.8 mg, confirmed) was synthesized from CP47-6 in a similar manner to CP40. MS: 632 [M+H] + .

[1096] Example 49

[1097]

[1098] A solution of CP9-3 (1.058 g), Cs2CO3 (3001 mg) and CD3NH2.HCl (510 mg) in DMF (15 mL) was stirred at 100 °C for 4 h. The reaction mixture was cooled to RT. The residue was diluted with water, extracted with EA and worked up to give the 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 in a similar manner to CP46-8.

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

[1101] Compound 48 (CP48, confirmed) was synthesized from CP48-3 in a similar manner to CP46. MS (ESI, m / z): 619 [M+H] + .

[1102] Example 50

[1103]

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

[1105] CP49 (50 mg) was separated by Prep-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 um, mobile phase A: 0.05% NH3·H2O, mobile phase B: CH3CN, gradient: 25% B to 58% B in 35 min, flow rate 40 mL / min, 224 nm). Compound 49A (CP49A, the first eluted isomer, retention time 30.8 - 33.39 min) and compound 49B (CP49B, the second eluted 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 from CP10B-3 in a method similar to that of CP2. LCMS: m / z: 617 [M+H] + 。

[1109] 1 HNMR (400 MHz, DMSO-d6) δ11.16 - 10.82 (m, 1H), 8.02 - 7.90 (m, 1H), 7.51 - 7.41 (m, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.22 - 7.10 (m, 1H), 5.58 (d, J = 53.2 Hz, 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 from CP10B-3 and INT1 in a method 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 from CP52-a in a method similar to CP94, purified and separated by Prep-HPLC-Gilson, with the conditions: column, CHIRAL ART Cellulose-SC column (2cm×25cm, 5um); mobile phase, hexane (0.1% DEA) / EtOH (50:50); flow rate: 20 mL / min. Compound 52A (CP52A, 7.8 mg, 11.72 μmol, the first eluted isomer, retention time 5.227 min, confirmed) and compound 52B (CP52B, 10.7 mg, 16.07 μmol, the second eluted isomer, retention time 6.157 min, confirmed) were obtained. LCMS: m / z: 666 [M+H] + .

[1117] Example 54

[1118]

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

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

[1121] At -10 °C, LAH (0.56 g) was added portionwise to a solution of CP53-2 (2.52 g) in THF (20 mL). 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, dioxane solution of 4 mol / mL) was added to a solution of CP53-3 (0.77 g) in acetonitrile (9 mL) at RT, and then the resulting mixture was stirred at RT for 2 h and concentrated to give residue A. POCl3 (0.5 mL) was added to a solution of INT 6 (889 mg), DIEA (1232 mg) in toluene (10 mL). The reaction mixture was stirred at 80 °C for 2 h and concentrated to give residue B. A solution of residue B in DCM (10 mL) was added to a solution of residue A and DIEA (2 mL) in DCM (10 mL). The reaction mixture was stirred at RT for 1.5 h, diluted with water and extracted with EA and worked up to give CP53-4 (465 mg). MS: m / z: 401 [M+H] + 。

[1123] Compound 53 (CP53, confirmed) was synthesized from CP53-4 in a method similar to that of CP47. MS: m / z: 636 [M+H] + 。

[1124] Example 55

[1125]

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

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

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

[1129] Compound 54B (CP54B, confirmed) was synthesized using CP54-5B in a method similar to that of CP47. 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 worked up to give CP55-1 (1.8874 g). MS: m / z: 352 [M+H] + 。

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

[1134] Compound 55 (CP55, confirmed) was synthesized using CP55-2 in a method similar to that of 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 give CP56-1 (9.2 g). MS: m / z: 270 [M+H] + 。

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

[1139] To a solution of CP56-2 (9.74 g) in methanol (100 mL) was added Pd / C (2.8995 g), Pd(OH)2 / C (2.0 g) under H2. The reaction mixture was stirred at RT for 16 h. 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 in a method similar to that of CP46-8.

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

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

[1143] Compound 56B (CP56B, confirmed) was synthesized from CP56-6B in a method similar to that of CP46. 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 worked up to give CP57-1 (6641 mg). MS: m / z: 390 [M+H] + 。

[1147] To a solution of CP57-1 (1029 mg) in THF (10 mL) at RT was added DAST (508 mg), and the resulting mixture was stirred for 3 h. The reaction was quenched with 10% Na2CO3 solution, extracted with EA and worked up to give 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. To the mixture was added LiAlH4 (1297 mg) at 0 °C, and the mixture was stirred at RT for 2 h. The solution was quenched with Na2SO4, filtered, concentrated and purified to give 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. To the mixture was added sodium hydride (414 mg) at 0 °C, and the mixture was stirred at RT for 0.5 h. To the mixture were added DMAP (62 mg), tetrabutylammonium iodide (202 mg) and bromoacetaldehyde dimethyl acetal (1014 mg), and the mixture was stirred at 70 °C for 6 h. The mixture was cooled to RT, quenched with water, extracted with EA and worked up to give CP57-4 (503 mg).

[1150] 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.3 Hz, 4H), 7.33 (t, J = 7.5 Hz, 4H), 7.29 - 7.24 (m, 2H), 4.72 - 4.52 (m, 1H), 4.46 (t, J = 5.2 Hz, 1H), 3.99 - 3.88 (m, 3H), 3.60 - 3.42 (m, 5H), 3.39 (d, J = 2.3 Hz, 6H), 3.06 - 2.86 (m, 1H), 1.20 (d, J = 6.9 Hz, 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 under H2 at RT for 16 h. The solution was filtered and concentrated to give the crude product CP57-5 (103 mg). MS: m / z: 196 [M+H] + .

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

[1153] Example 59

[1154]

[1155] Compound 58 (CP58, confirmed) was synthesized from 58-a in 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 in a method similar to that of CP94-4.

[1159] CP59-8 (519 mg) was separated by Prep-HPLC-Gilson with the 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, the first eluted isomer, retention time 4.587 min) and CP59B-9 (190 mg, the second eluted isomer, retention time 5.067 min) were obtained.

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

[1161] Example 61

[1162]

[1163] At -10 °C, LAH (1222 mg) was added portionwise to a solution of 60-a (2.162 g) in THF (20 mL). 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 in a method similar to that of CP55-8.

[1165] CP60-9 (331 mg) was separated by Prep-HPLC-Gilson with 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, the second eluted isomer, retention time 8.740 min) was obtained.

[1166] Compound 60 (CP60, confirmed) was synthesized from CP60-10 in a method similar to that of 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 under H2 at RT 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% aqueous Na2CO3, extracted with DCM, and worked up to give CP61-2 (400 mg). MS: m / z: 390 [M+H] + 。

[1171] CP61-4 was synthesized from CP61-2 in a method similar to that of CP46-10.

[1172] CP61-4 was separated by chiral high performance liquid chromatography under the separation 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, to obtain CP61-5 (the second eluted isomer, retention time 9.189 min). MS: m / z: 501 [M+H] + 。

[1173] Compound 61 (CP61, confirmed) was synthesized from CP61-5 in a method similar to that of CP46. MS: m / z: 650 [M+H] + 。

[1174] Example 63

[1175]

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

[1177] At 0 °C under N2, CCl4 (1008 mg) was added to a solution of triphenylphosphine (1085 mg) in DCM (25 mL), 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). Aftertreatment gave CP62-2 (338 mg). MS: m / z: 388 [M+H] + 。

[1178] CP62-4 was synthesized from CP62-2 in a method similar to that of CP46-10.

[1179] CP62-4 was separated by Prep-HPLC-Gilson under the 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, the first eluted isomer, retention time 6.223 min) and CP62-4B (66 mg, the second eluted isomer, retention time 7.320 min) were obtained. MS: m / z: 499 [M+H]+ .

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

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

[1182] Example 64

[1183]

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

[1185] Example 65

[1186]

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

[1188] TFA (5 mL) was added to a solution of CP64-1 (1.80 g) in DCM (20 mL) at RT, and the reaction mixture was stirred overnight at RT. The mixture was concentrated to give the 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 with aq. K2CO3. The mixture was extracted with DCM and worked up to give the crude product CP64-3 (1.35 g). MS: m / z: 262 [M+H] + .

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

[1191] To a solution of CP64-4 (683 mg) in MeOH (20 mL) was added Pd(OH)2 / C (0.31 g). The reaction mixture was stirred at 44 °C under H2 for 24 h. 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 from CP64-5 in a similar manner to CP16. MS: m / z: 657 [M+H] + 。

[1193] Example 66

[1194]

[1195] Compound 65 (CP65, confirmed) was synthesized in a similar manner to CP64. MS m / z: 645 [M+H] + 。

[1196] Example 67

[1197]

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

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

[1200] At 30 °C, to a solution of CP66-3 (190 mg) in DMF (1 mL) and THF (1 mL) was added INT14 (127 mg), DABCO (18 mg) and Cs2CO3 (216 mg), 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 give CP66-4 (206 mg). MS (ESI, m / z): 547 [M+H] + .

[1201] A mixture of CP66-4 (116 mg), 66-a (98 mg), DPEPhosPdCl2 (22 mg) and Cs2CO3 (213 mg) in toluene (3 mL) was stirred at 105 °C under N2 for 19 h. Water was added to the reaction 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] To a solution of CP66-5 (148 mg) in DCM (6 mL) was added TFA (2 mL). 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 um, phase A: 0.1% aqueous TFA solution, phase B: CH3CN, gradient: 15% B to 40% B, 37 min, flow rate 60 mL / min, 295 nm), freeze-dried 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 conditions: column, CHIRAL ART Amylose-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, the first eluted isomer, retention time 3.990 min, confirmed) and compound 66B (CP66B, 15.1 mg, the second eluted isomer, retention time 5.103 min, confirmed) were obtained.

[1204] Example 68

[1205]

[1206] Compound 67 (CP67, confirmed) was synthesized from CP37-7 in a manner similar to CP21. MS m / z: 609 [M+H] + 。

[1207] Example 69

[1208]

[1209] Compound 68 (CP68, confirmed) was synthesized according to the procedure of CP9. LCMS: m / z: 642 [M+H] + 。

[1210] Example 70

[1211]

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

[1213] Example 71

[1214]

[1215] CP70-2 was synthesized from 4-aminobutan-1-ol and INT6 according to the procedure of CP42-6.

[1216] p-TsOH·H2O (62 mg) was added to a solution of CP70-2 (97 mg) in trimethyl orthoformate (3 mL), 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 with CP70-3 following the steps of CP42. LCMS: m / z: 616 [M+H] + 。

[1218] Example 72

[1219]

[1220] At 0 °C, pyridine sulfur trioxide complex (7.36 g) was added to a solution of 71-a (1.03 g) and TEA (7.76 g) in DCM (10 mL) and DMSO (20 mL). The resulting mixture was stirred for 4 h. 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] CP71-5 was synthesized from CP71-1 in a method similar to INT15.

[1222] Compound 71 (CP71, confirmed) was synthesized from CP71-5 in a method similar to CP46. LCMS: m / z: 598 [M+H] + 。

[1223] Example 73

[1224]

[1225] Under N2, at RT, 72-a (1.36 g) was added to allylmagnesium chloride solution (2 M in THF, 15 mL), and the mixture was stirred at 80 °C for 20 h. The reaction mixture was quenched with 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] To a solution of CP72-1 (0.85 g), styrene (2.50 g) and tetraethyl titanate (1.14 g) in DCE (20 mL) was added Grubbs second-generation catalyst (0.39 g). The mixture was purged with N2 and stirred at 70 °C for 16 h. After completion, the mixture was concentrated and purified to give CP72-2 (0.61 g).

[1227] To a solution of CP72-2 (0.543 g) and CP71-3 (0.282 g) in DMSO (10 mL) was added p-TsOH·H2O (160 mg). The mixture was purged with N2 and stirred at 80 °C for 16 h. 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 from CP72-3 following the procedure of CP71. LCMS: m / z: 612 [M+H] + 。

[1229] Example 74

[1230]

[1231] 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) was added cataCXium A Pd G3 (82 mg). The mixture was purged with N2 and stirred at 100 °C for 16 h. 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 from CP9-6 and 74-a in a method similar to 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) was added bis(diphenylphosphinophenyl) ether palladium(II) dichloride (10 mg). The mixture was purged with N2 and stirred at 105 °C for 16 h. 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] To a solution of CP75-2 (133 mg) in DCM (5 mL) was added TFA (1.5 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] To a 0 °C solution of 76-a (5094 mg) in THF (50 mL) was added lithium aluminum deuteride (1508 mg). The mixture was stirred at 0 °C for 4 h. The mixture was quenched with 1.5 mL of water, 1.5 mL of 15% NaOH, 4.5 mL of water and a small amount of anhydrous Na2SO4. The mixture was filtered and concentrated to give 76-b (3285 mg). MS: m / z: 109 [M+H] + 。

[1242] Compound 76 (CP76, confirmed) was synthesized from CP76-b in a method similar to CP9. MS: m / z: 618 [M+H] + 。

[1243] Example 78

[1244]

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

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

[1247] Example 79

[1248]

[1249] A mixture of CP113-3 (1.295 g) in 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 worked up to give CP78-2 (206 mg). MS: m / z: 384 [M+H] + .

[1251] Compound 78 (CP78, confirmed) was synthesized from CP78-2 in a method similar to that of 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 worked up 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 a solution of DIEA (2.6320 g) in DCM (5 mL) 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 concentrated to obtain CP79-4 (0.298 g). MS: m / z 337: [M+H] + .

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

[1259] Example 81

[1260]

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

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

[1263] Example 82

[1264]

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

[1266] Under N2, 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. The reaction mixture was cooled to RT. The reaction mixture was concentrated and purified to obtain CP81-2 (65 mg). MS (ESI, m / z): 479 [M+H] + 。

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

[1268] Compound 81 (CP81, confirmed) was synthesized from CP81-3 in a manner similar to that of CP46. MS (ESI, m / z): 650 [M+H] + 。

[1269] Example 83

[1270]

[1271] Compound 82 (CP82, confirmed) was synthesized from CP82-1 in a manner similar to that of 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 at RT overnight. The mixture was diluted with sat. NH4Cl (aq.) and water, extracted with EA, and worked up to obtain 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 worked up to give 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 worked up to give CP83-3 (47.61 g). MS: m / z: 418 [M+H] + 。

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

[1278] Diisobutylaluminum hydride (250 mL) was added to a -40 °C solution of CP83-4 (57.45 g) in THF (400 mL). The mixture was stirred at -20 °C to -40 °C for 3 h. The mixture was quenched with EA (300 mL) and a solution of sodium potassium tartrate. The mixture was warmed to RT and stirred vigorously for 4 h. When the solution was clear, the solution was extracted with EA and worked up to give 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 give a mixture. CP83-6 (3.53 g) was added to a 0 °C solution of the mixture and DIEA (2 mL) in DCM (10 mL). The mixture was stirred at 0 °C for 1 h. Purification gave 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 worked up to give CP83-8 (4.447 g). MS: m / z: 504 [M+H] + .

[1282] 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 was added pyridine sulfur trioxide (4.74 g). The mixture was stirred at RT for 3 h, quenched with sat. Na2S2O3(aq.) and extracted with DCM and worked up to give 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 in DMSO (10 mL) at 80 °C overnight 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.) and extracted with DCM and worked up to give CP83-11 (0.047 g). MS: m / z: 372 [M+H] + .

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

[1286] Example 85

[1287]

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

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

[1290] The racemate CP84-3 was separated by Prep-HPLC-Gilson under the conditions: column CHIRALPAK-IG 20 mm×250 mm, 5 μm mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / EtOH(50:50); flow rate: 20 mL / min, 220 nm. CP84-4A (the first eluted isomer, retention time 5.767 min) and CP84-4 (the second eluted 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), cataxium 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 obtain CP84-5 (0.026 g). MS: m / z: 1065 [M+H] + 。

[1292] Compound 84 (CP84, confirmed) was synthesized from CP84-4 in a method similar to that of CP83. MS: m / z: 630 [M+H] + 。

[1293] Example 86

[1294]

[1295] 2-[(Fluoromethyl)sulfonyl]pyridine (0.286 g) was added to a solution of CP61-1 (0.508 g) in DMF (10 mL), 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 and 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 obtain 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 portionwise 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 give CP85-2 (365 mg, crude product), which was used 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 from CP85-3 in a method similar to that of CP46. LCMS: m / z: 644 [M+H] + 。

[1299] Example 87

[1300]

[1301] Compound 86 (CP86, confirmed) was synthesized from CP85-4 in a method similar to that of CP46. MS: m / z: 644 [M+H] + 。

[1302] Example 88

[1303]

[1304] To a solution of 87-a (34.11 g) in DMF (350 mL) was added carbonyldiimidazole (39.17 g), and the resulting mixture was stirred at RT for 16 h. At 0 °C, potassium hydrogen malonate (39.34 g), magnesium chloride (47.90 g), and TEA (51.57 g) were added. The solution was stirred at RT for 20 h. The solution was filtered, diluted with water, extracted with EA, and worked up to give CP87-1 (40.33 g). MS: m / z: 260 [M+H] + 。

[1305] A solution of CP87-1 (46.4720 g) in MeOH (400 mL) 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 worked up to give 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). 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 give CP87-3 (3506 mg). MS: m / z: 234 [M+H] + 。

[1307] To a solution of CP87-3 (11.765 g) in DCM (120 mL) was added TEA (7.6541 g), TBDMSCl (7.6005 g) and DMAP (616.061 mg). The resulting mixture was stirred overnight at RT. The mixture was diluted with DCM and worked up to give 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 from CP87-5 in a manner similar to that of 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 reactants were concentrated to give CP88-1 (10.2 g), which was used in the next step. MS: m / z: 202 [M+H] + 。

[1313] At 0 °C, a solution of CP88-1 (10.2 g) in MeOH (80 mL) was added portionwise 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 the white solid was filtered off. The filtered organic liquid was concentrated, and the solution was extracted with EA. The organic layer was worked up to give CP88-2 (4.744 g). MS: m / z: 204 [M+H] + .

[1314] Hydrochloric acid (15 mL) was added to a solution of CP88-2 (4.744 g) in DCM (50 mL). 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] CP88-5 was synthesized from CP88-3 in a method similar to that of 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 under N2 for 16 h. The mixture was allowed to cool to RT and concentrated. Purification gave CP88-6 (453 mg). MS: m / z: 384 [M+H] + .

[1317] CP88-10 was synthesized from CP88-6 in a method similar to that of CP83-10.

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

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

[1320] Example 90

[1321]

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

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

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

[1325] At 0 °C, NaBH4 (0.743 g) was added dropwise to a solution of 89-f (3.364 g) in MeOH (150 mL). The solution was stirred at RT for 3 h under N2. The mixture was quenched with water, extracted with EA and worked up to give 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. The mixture directly gave 89-h (1.565 g). MS: m / z: 132 [M+H] + 。

[1327] At 0 °C, Cbz-Cl (2.569 g) was added dropwise to a solution of 89-h (1.565 g) and TEA (1.906 g) in THF (50 mL). 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 worked up to give 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 under N2 for 5 h. The solution was filtered, the filtrate was 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-diazabicyclo[2.2.2]octane bis(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 under H2 for 2 h. The mixture directly gave 89-l (599.744 mg). MS: m / z: 194 [M+H] + 。

[1331] Compound 89 (CP89, confirmed) was synthesized from CP89-l in a manner similar to CP46. MS: m / z: 646 [M+1] + 。

[1332] Example 91

[1333]

[1334] A solution of CP62-1 (2.64 g) in THF (200 mL) and DCM (100 mL) was added dropwise to DAST (1.69 g) at 0 °C under N2, and the mixture was 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 with (PE / EA = 5 / 1) to give 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, to give CP40A-2 (the first eluted isomer, retention time 6.3 min, 0.58 g). MS: m / z: 372 [M+H] + 。

[1336] Compound 40A (CP40A, confirmed) was synthesized from CP40A-2 according to the procedure of CP46 and purified under the following conditions: Prep-HPLC (YMC-Triart C18-S12 nm, 50 mm × 250 mm, 7 μm, A: 0.05% NH 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 in a method similar to CP46. MS: m / z: 656 [M+1] + 。

[1340] Example 93

[1341]

[1342]

[1343] CP91-6 was synthesized in a method similar to CP71-6.

[1344] CP91-6 was separated by Prep-HPLC-Gilson with the conditions: column, CHIRAL ART Cellulose-SC, 20 mm × 250 mm, 5 um mobile phase, (Hex: DCM = 3:1) (0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min, 220 nm. CP91-7A (41 mg, the first eluted isomer, retention time 6.903 min) and CP91-7B (50 mg, the second eluted isomer, retention time 7.681 min) were obtained. MS: m / z: 463 [M+1] + 。

[1345] Compound 91A (CP91A, 26 mg, confirmed) was synthesized by a method similar to that of synthesizing CP46 with CP91-7A. MS: m / z: 612 [M+1] + 。

[1346] Compound 91B (CP91B, 38 mg, confirmed) was synthesized by a method similar to that of synthesizing CP46 with 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 for 15 h under N2. The mixture was concentrated, diluted with NaHCO3 solution, extracted with EA and worked up 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 worked up 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 for 10 minutes under N2, and iodomethane (3.27 g) was added dropwise to the mixture. The solution was stirred at RT for 16 h under N2. The solution was quenched with water, extracted with EA and worked up 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 worked up to obtain CP92-4 (2.518 g). MS: m / z: 286 [M+H] + 。

[1353] CP92-11 was synthesized from CP92-4 in a method similar to that of CP46-10.

[1354] CP92-11 was separated by Prep-HPLC-Gilson under the conditions: column, CHIRAL ART Cellulose-SC, 20 mm × 250 mm, 5 um; mobile phase (Hex:DCM = 3:1) (0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min, 220 nm. CP92-12A (58 mg, the first eluted isomer, retention time 6.797 min) and CP92-12B (26 mg, the second eluted 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 by a similar method to that of synthesizing CP46 using CP92-12A. MS: m / z: 646 [M+1] + 。

[1356] Compound 92B (CP92B, assumed) was synthesized by a similar method to that of synthesizing CP46 using 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 worked up to give 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 under N2 for 3 h. The mixture was cooled to RT, diluted with NaHCO3 solution and worked up to give CP93-2 (276 mg). MS: m / z: 386 [M+H] + 。

[1361] CP93-4 was synthesized from CP93-2 in a similar manner to CP46-10.

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

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

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

[1365] Example 96

[1366]

[1367] To a solution of 94-a (10.09 g) in DCE (150 mL), benzylamine (22.87 g), and TEA (28.76 g) was added titanium tetrachloride (55.12 g) in DCM (50 mL). The resulting mixture was stirred at 0 °C and then at RT for 5 h. A solution of sodium cyanoborohydride (6.78 g) in MeOH (15 mL) 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 worked up to give 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) was added K2CO3 (7.95 g), TBAI (0.85 g), and BnBr (6.69 g), 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 give 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. The mixture was diluted with Na2SO 4· 10H2O. The solution was filtered and diluted with EA. The mixture was concentrated and purified to give 94-d (4.48 g). MS: m / z: 284 [M+H] + 。

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

[1371] To a solution of 94-e (2.06 g) in MeOH (20 mL) under H2, Pd(OH)2 / C (0.44 g) and Pd / C (0.43 g) were added. The reaction mixture was stirred at 25 °C for 16 h. 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 from CP94-1 in a method similar to that of CP46-8.

[1373] CP94-4 was separated by Prep-HPLC-Gilson under the conditions: column CHIRALART Cellulose-SC, 20 mm × 250 mm, 5 μm mobile phase, (Hex:DCM = 3:1) (0.1% DEA) / IPA (50:50); flow rate: 17 mL / min, 220 nm). CP94-5A (the first eluted isomer, retention time 4.728 min) and CP94-5 (the second eluted 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 of CP46. LCMS: m / z: 644 [M+H] + 。

[1375] Example 97

[1376]

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

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

[1379] CP95-4 was separated by Prep-HPLC-Gilson under the 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 (the second eluted isomer, retention time 7.580 min).

[1380] Compound 95 (CP95, confirmed) was synthesized according to 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] TEA (19.06 g) and pyridine sulfur trioxide (14.23 g) were added to a solution of 96-b (6.32 g) and DCM (25 mL) in DMSO (50 mL), and the resulting mixture was stirred at 0 °C for 3 h. The reaction was quenched with Na2S2O3, extracted with EA and worked up to give 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 h. The mixture was cooled to RT, diluted with EA and worked up to give 96-d (2.35 g). MS: m / z: 330 [M+H] + .

[1386] Pd / C (0.43 g) was added to a solution of 96-d (2.35 g) in MeOH (20 mL) under H2. The reaction mixture was stirred at 25 °C for 16 h. The resulting mixture was filtered and the filtrate was concentrated to give 96-e (873 mg). 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. Quenched with NH4Cl, extracted with DCM, concentrated and purified to give 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 under N2 for 16 h. MeOH (120 mL) was added to the reaction mixture, stirred at 60 °C for 30 min and concentrated. THF (80 mL) and LAH (1.29 g) were added to the mixture at 0 °C and stirred at room temperature for 2 h. The reaction was quenched with Na2SO4·10H2O and worked up to give 97-c (9.44 g). MS: m / z: 282 [M+H] + 。

[1392] Compound 97 (CP97, confirmed) was synthesized according to the procedure of CP46 with CP97-c. 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 worked up to give 98-c (12.3 g). MS: m / z: 270 [M+H] + 。

[1397] To a solution of 98-c (12.3 g) in DMF (50 mL), add dimethylhydroxylamine hydrochloride (5.96 g), HATU (20.85 g) and DIEA (20.54 g). Stir the reaction mixture at RT for 2 h. After completion, add water and extract the aqueous layer with EA and perform post-treatment to obtain 98-d (13.95 g). MS: m / z: 313 [M+H] + 。

[1398] At 0 °C, add MeMgBr (24.5 mL) to a solution of 98-d (13.95 g) in THF (150 mL). Stir the mixture at RT for 8 h, and quench the mixture with aq. NH4Cl and water. Extract the resulting mixture with DCM and perform post-treatment to obtain 98-e (5.8 g). MS: m / z: 268 [M+H] + 。

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

[1400] CP98-2 was synthesized using CP98-f according to the procedure of CP46-8.

[1401] CP98-2 (3.12 g) was separated by Prep-HPLC-Gilson under the conditions: column, CHIRAL ART Cellulose-SC, 20 mm × 250 mm, 5 um mobile phase, (Hex:DCM = 3:1) (0.1% DEA) / EtOH (50:50); flow rate: 15 mL / min. CP98-3 (240 mg, the third eluted isomer, retention time 9.080 min) was obtained.

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

[1403] Compound 98A (CP98A), compound 98B (CP98B), and compound 98C (CP98C) were synthesized in a similar manner. LCMS: m / z: 630 [M+H] + 。

[1404] Example 101

[1405]

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

[1407] Example 102

[1408]

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

[1410] Example 103

[1411]

[1412]

[1413] At 0 °C, potassium tert-butoxide (0.415 g) was added to a solution of CP61-1 (1.139 g) and tosylmethyl isocyanide (0.876 g) in dioxane (40 mL). The mixture was stirred at 50 °C for 0.5 h and at RT for 16 h. The reaction was diluted with EA and worked up to obtain CP101-1 (587 mg). MS: m / z: 379 [M+H] + .

[1414] Compound 101 (CP101, confirmed) was synthesized using CP101-1 in a method similar to the preparation of CP46. LCMS: m / z: 639 [M+H] + .

[1415] Example 104

[1416]

[1417] CP46 was separated by Prep-HPLC-Gilson with 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, the first eluted isomer, retention time 7.034 min) and compound 103 (CP103, 5.7 mg, the second eluted 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 bottle was stirred at 70 °C for 17 h. The mixture was diluted with water and extracted with EA and worked up to give CP104-1 (1.02 g). MS: m / z: 502 [M+H] + 。

[1421] Compound 104 (CP104, confirmed) was synthesized from CP104-1 in a similar manner to the preparation of CP46. LCMS: m / z: 698 [M+H] + 。

[1422] Example 106

[1423]

[1424] Compound 105 (CP105, confirmed) was synthesized from CP105-a in a similar manner to the preparation of CP94. LCMS: m / z: 670 [M+H] + 。

[1425] Example 107

[1426]

[1427] At 0 °C, NaH (15.96 g) was added to a solution of 106-a (19.93 g) in THF (200 mL), 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 resulting mixture was stirred at 25 °C for 16 h under N2, quenched with water, extracted with EA and worked up to give 106-b (34.24 g). MS: m / z: 191 [M+H] + 。

[1428] A solution of 106-b (34.24 g) and meta-chloroperoxybenzoic acid (40.60 g) in DCM (300 mL) was stirred at 25 °C for 16 h, quenched with Na2S2O3, extracted with DCM and worked up to give 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 h. The mixture was cooled to RT, concentrated and purified to obtain 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 worked up to obtain 106-e (23.23 g). MS: m / z: 518 [M+H] + .

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

[1432] CP106-3 was synthesized from 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 worked up 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 worked up to obtain CP106-5 (190 mg). MS: m / z: 368 [M+H] + .

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

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

[1437] CP106-8 was separated by Prep-HPLC-Gilson under the following 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 (the first eluted isomer, retention time 4.67 min) and CP106-9B (the second eluted isomer, retention time 6.98 min) were obtained. LCMS: m / z: 650 [M+H] + 。

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

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

[1440] Example 108

[1441]

[1442] CP107-3 was synthesized from 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 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. CP107-4B (the first eluted isomer, retention time: 4.17 min, 0.45 g) and CP107-4A (the second eluted isomer, retention time: 7.193 min, 0.43 g) were obtained.

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

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

[1446] Example 109

[1447]

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

[1449] CP108-2 was separated by Prep-HPLC-Gilson with the following 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, the first eluted isomer, retention time 4.11 min) and CP108-3A (0.3 g, the second eluted isomer, retention time 5.8 min) were obtained. MS: m / z: 479 [M+H] + .

[1450] CP108-4B was synthesized from CP108-3B in a manner similar to that of CP46-11.

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

[1452] Compound 108B (CP108B, confirmed) was synthesized from CP108-5B in a manner similar to the preparation of CP46. LCMS: m / z: 630 [M+H] + .

[1453] Compound 108A (CP108A, confirmed) was synthesized from CP108-3A in a manner similar to the preparation of 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 h. The solution was diluted with saturated aqueous NH4Cl solution, extracted with EA and worked up to give the crude product CP109-1 (186 mg). MS: m / z: 780 [M+H] + 。

[1457] A solution of the crude product CP109-1 (186 mg) in THF (5 mL) 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 and the resulting mixture was stirred at -30 °C for 1 h. D2O and EA were added to the mixture and worked up to give the crude product CP109-2 (0.19 g). MS: m / z: 781 [M+H] + 。

[1458] TFA (2 mL) was added to a solution of the 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 worked up to give compound 109 (CP109, 74.3 mg, confirmed). 1 1H NMR (400 MHz, 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 under H2 at RT for 3 h. 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 from CP110-1 in a manner similar to that for preparing CP46. LCMS: m / z: 630 [M+H] + 。

[1463] Example 112

[1464]

[1465] Compound 111 (CP111, confirmed) was synthesized in a manner similar to CP46. MS: m / z: 572 [M+H] + 。 1 HNMR (400 MHz, 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] A solution of CP108-5A (0.23 g) in DCM (8 mL) in a dioxane solution of HCl (4 M, 2 mL) was stirred at RT for 1 h. The solution was diluted with 10% NaHCO3 solution, extracted with DCM and worked up to give 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 h under N2. The solution was diluted with saturated NaHCO3 solution. Extracted with EA and worked up to give compound 112 (CP112, 0.0034 g, confirmed). MS: m / z: 610 [M+H] + 。

[1470] Example 114

[1471]

[1472]

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

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

[1475] A solution of CP113-2 (54 mg) in TFA (4 mL) was stirred at RT for 16 h 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 from CP113-3 according to the method of CP46. MS (ESI, m / z:): 602 [M+H] + 。

[1477] Example 115

[1478]

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

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

[1481] HCl (4 M solution in 1,4-dioxane, 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 h and concentrated to give 114-d, which was used directly in the next step. MS (ESI, m / z): 120 [M+H] + 。

[1482] Compound 114 (CP114, confirmed) was synthesized from 114-d in a method similar to CP96. 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 h and then purified to give CP115-1 (0.36 g). MS: m / z: 504 [M+H] + 。

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

[1487] At 0 °C, NaBH4 (0.10 g) 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 worked up to give CP115-3 (35 mg). MS: m / z: 386 [M+H] + 。

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

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

[1490] Example 117

[1491]

[1492] Under N2, trimethylsulfoxonium iodide (330 mg) was added portionwise to a solution of NaH (65 mg, 60% content) in DMSO (10 mL). The mixture was stirred at RT for 3 h. INT15 (0.5 g) was added portionwise and the mixture was stirred at RT for 3.5 h, diluted with water and EA and worked up to give CP116-1 (279 mg). MS: m / z: 380 [M+H] + .

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

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

[1495] CP116 (28.6 mg, free base, confirmed) was synthesized from CP116-3 in a manner similar to CP46. LCMS: m / z: 644 [M+H] + .

[1496] Example 118

[1497]

[1498] Compound 117 (CP117, confirmed) was synthesized in a method similar to 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 minutes, quenched with water, extracted with DCM and worked up to obtain 118-b (8.35 g).

[1502] DIEA (11.38 g) and tert-butyl 2-methylhydrazinecarboxylate (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 worked up 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 under H2 at RT for 19 hours, filtered and the filtrate was concentrated to obtain 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 solid NaOH. 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 obtain 118-e (crude product). MS: m / z: 135 [M+H] + .

[1505] Compound 118 (CP118, 2.6 mg, TFA salt, confirmed) was synthesized from 118-e according to the method of CP47. MS: m / z: 631 [M+H] + .

[1506] Example 120

[1507]

[1508] To a solution of CP36-9 (0.35 g) and 119-a (synthesized according to the method described in WO2022042630, 293 mg) in toluene (20 mL) and water (5 mL) were added cataCxium A Pd G3 (66 mg) and Cs2CO3 (692 mg). The reaction mixture was stirred at 100 °C under N2 for 20 h, diluted with water, extracted with EA and worked up 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 in a method similar to that of 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 solution of 121-a (2.06 g) in THF (80 mL). After stirring at -10 °C for 1.5 h, 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 h and quenched with aq. NaHCO3 (50 mL, 10% wt). Extraction with EA and workup gave 121-b (2.24 g). MS: m / z: 128 [M+H] + 。

[1515] To a mixture of 121-b (2.24 g) in water (40 mL) was added KOH (5.02 g). After stirring at 100 °C for 6.5 h, the reaction mixture was cooled to RT and (Boc)2O (4.61 g) was added. The reaction mixture was stirred at RT for 4 h, diluted with EA and water and worked up to give 121-c (8.78 g). MS: m / z: 246 [M+H] + 。

[1516] At -10 °C, LAH (1.21 g) was added portionwise to a solution of 121-c (3.42 g) in THF (50 mL). The reaction mixture was stirred at RT for 2 h, quenched successively with water (1.5 mL), aq. NaOH (1.5 mL, 15% wt) and water (5 mL), filtered and concentrated to give 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), and the mixture was stirred at RT for 1 h and concentrated to give Residue A.

[1518] POCl3 (0.75 mL) was added to a mixture of INT 6 (1.53 g) and DIEA (2.18 g) in toluene (15 mL). The reaction mixture was stirred at 80 °C for 1 h and concentrated to give Residue B. The pH of a mixture of Residue A in DCM (10 mL) was adjusted to basic with DIEA. DIEA (3 mL) and the above mixture were added to a mixture of Residue B in DCM (20 mL). The reaction mixture was stirred at RT for 2 h, diluted with water and worked up by extraction with DCM to give CP121-1 (3.03 g). MS: m / z: 393 [M+H] + 。

[1519] Compound 121 (CP121, 44.3 mg, TFA salt, confirmed) was synthesized from CP121-1 in a method similar to that of CP47. MS: m / z: 628 [M+H] + 。

[1520] Example 123

[1521]

[1522] K2CO3 (22.73 g), tetrabutylammonium iodide (1.95 g) and benzyl bromide (23.89 g) were added to a solution of 122-a (5.06 g) in acetonitrile (100 mL). The reaction mixture was stirred at RT for 20 h, filtered, concentrated and purified to give 122-b (14.35 g). MS: m / z: 270 [M+H] + 。

[1523] At -10 °C, NaH (0.81 g, 60% in oil) 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 worked up by extraction with EA to give 122-c (2.26 g). MS: m / z: 356 [M+H] + .

[1524] At -10 °C, LAH (0.40 g) was added portionwise to a solution of 122-c (2.26 g) in THF (30 mL). The reaction mixture was stirred at RT for 2 hours and quenched with water (0.5 mL), aqueous NaOH (0.5 mL, 15% wt) 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 give 122-e (0.65 g). MS: m / z: 148 [M+H] + .

[1526] Compound 122 (CP122, 7 mg, TFA salt, confirmed) was synthesized from CP122-e in a method similar to that of CP47. MS: m / z: 644 [M+H] + .

[1527] Example 124

[1528]

[1529] CP123-5 was synthesized from CP123-a in a method similar to that of CP94-7.

[1530] The first peak of CP123-5 (64 mg) was separated by Prep-HPLC-Gilson with 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 eluted isomer, retention time: 5.71 min) and CP123-5B (28 mg, second eluted isomer, retention time: 7.26 min) were obtained.

[1531] The second peak, CP123-5 (70 mg), was separated by Prep-HPLC-Gilson under the conditions of 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. CP 123-5C (23 mg of the first eluted isomer, retention time: 6.897 min) and CP123-5D (19 mg, the second eluted isomer, retention time: 14.551 min) were obtained.

[1532]

[1533] Compound 123B (CP123B, assumed) was synthesized from CP123-6B in a method similar to that of CP46. MS: m / z: 658 [M+H] + 。

[1534]

[1535] Compound 123A (CP123A, 7.8 mg, assumed) was synthesized from CP123-6A in a method similar to that of CP123B. MS: m / z: 658 [M+H] + 。

[1536]

[1537] Compound 123D (CP123D, 5.4 mg, assumed) was synthesized from CP123-6D in a method similar to that of CP123B. MS: m / z: 658 [M+H] + 。

[1538]

[1539] Compound 123C (CP123C, 6.6 mg, assumed) was synthesized from CP123-6C in a method similar to that of 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 h and concentrated. The residue was dissolved in EA, washed with aq. NH4Cl and worked up to give 124-b (4243 mg). MS (ESI, m / z): 314 [M+H] + 。

[1543] LAH (801 mg) was added portionwise to a solution of 124-b (4.908 g) in THF (90 mL). The resulting mixture was stirred at RT for 2 h, quenched with water (0.8 mL), aq. 15% NaOH (0.8 mL) and water (2.4 mL), filtered, concentrated and the filtrate was 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 THF (40 mL). The resulting mixture was stirred at RT for 30 min. 2-Bromo-1,1-dimethoxyethane (1537 mg), DMAP (113 mg) and tetrabutylammonium iodide (639 mg) were added. The resulting mixture was stirred at 70 °C for 16 h, quenched with water and extracted with EA and worked up to give 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 solution of 124-d (1.44 g) in methanol (40 mL). The reaction mixture was stirred under H2 at RT for 20 h, filtered and concentrated to give 124-e (736 mg). MS (ESI, m / z:): 194 [M+H] + 。

[1546] Compound 124 (CP124, 33.5 mg, TFA salt, confirmed) was synthesized from CP 124-e in a method similar to CP46. MS: [ESI, m / z:]: 648 [M+H] + 。

[1547] Example 126

[1548]

[1549] Compound 125 (CP125, confirmed) was synthesized from CP125-a and CP9-6 in a method similar to 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 solution of CP124-3 (99 mg) in DCM (5 mL). The resulting solution was stirred at RT for 3 h, diluted with DCM, washed with water and worked up to give 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 h, diluted with EA, washed with brine and worked up to give CP126-3 (60 mg). MS (ESI, m / z): 395 [M+H] + 。

[1554] Compound 126 (CP126, 12.1 mg, TFA salt, confirmed) was synthesized from CP126-3 in a similar manner to CP46. 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 about 3 h, 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 from CP128-a in a similar manner to CP12. MS: m / z: 627 [M+H] + 。

[1561] Example 130

[1562]

[1563] To a solution of CP57 (53 mg) and acetic anhydride (23 mg) in DCM (4 mL) was added DMAP (3 mg). The reaction mixture was stirred at RT under N2 for 1 h, diluted with brine, extracted with DCM and worked up to give compound 129 (CP129, 63.3 mg, TFA salt, confirmed). MS: m / z: 690 [M+H] + 。

[1564] Example 131

[1565]

[1566] To a solution of CP57 (69 mg) and N-Boc-L-valine (30 mg) in DMF (3 mL) were added HATU (111 mg) and DIEA (15 mg). The reaction mixture was stirred at RT under N2 overnight, diluted with EA, washed twice with brine and worked up to give 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. Extracted with EA and worked up to give compound 130 (CP130, 13.8 mg, TFA salt, confirmed). MS: m / z: 747 [M+H] + 。

[1568] The following compounds were synthesized in a manner similar to the above compounds:

[1569]

[1570]

[1571]

[1572] Example 150

[1573]

[1574] Compound 150 (CP150, confirmed) was synthesized in a manner similar to CP46. MS: m / z: 630 [M+1] + 。

[1575] Example 151

[1576]

[1577] Compound 151 (CP151, confirmed) was synthesized in a method similar to CP46. MS: m / z: 632 [M+1] + 。

[1578] Example 152

[1579]

[1580] Compound 152 (CP152, confirmed) was synthesized in a method similar to CP46. MS: m / z: 615 [M+1] + 。

[1581] Example 153

[1582]

[1583] Compound 153 (CP153, confirmed) was synthesized in a method similar to CP46. MS: m / z: 586 [M+H] + , 1 HNMR (400 MHz, DMSO-d6) δ=7.74 (dd, J=9.2, 5.9 Hz, 1H), 7.31 (t, J=9.0 Hz, 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=4.6 Hz, 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 in a method similar to CP46. MS: m / z: 507 [M+H] + 。

[1588] Example 155

[1589]

[1590] CP155-6 (57 mg) was separated by Prep-HPLC-Gilson under the 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, the first eluted isomer, retention time: 7.073 min) and CP155-7B (19 mg, the second eluted isomer, retention time: 11.157 min) were obtained.

[1591] Compound 155A (CP155A, confirmed, MS: m / z: 630 [M+H] + ) and compound 155B (CP155B, MS: m / z: 630 [M+H] + ) were synthesized in a method similar to CP46.

[1592] Example 156

[1593]

[1594] CP156-4 was separated by Prep-HPLC-Gilson under the conditions: column, CHIRAL ART Cellulose-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. CP156-5A (32 mg, the first eluted isomer, retention time: 4.877 min) and CP156-5B (37 mg, the second eluted isomer, retention time: 5.813 min) were obtained.

[1595] The intermediate CP156-4 (another peak) was separated by Prep-HPLC-Gilson under the conditions: column, CHIRAL ART Cellulose-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, the first eluted isomer, retention time: 5.193 min) and CP156-5D (27 mg, the second eluted isomer, retention time: 9.827 min) were obtained.

[1596] Compound 156A (CP156A, putative, MS: m / z: 646 [M+H] + ) and compound 156B (CP156B, putative, MS: m / z: 646 [M+H]+ ) Compound 156C (CP156C, putative, MS: m / z: 646 [M+H] + ) and Compound 156D (CP156D, putative, MS: m / z: 646 [M+H] + ).

[1597] Example 157

[1598]

[1599]

[1600] CP157-4 was separated by Prep-HPLC-Gilson under the conditions: column, CHIRALART Cellulose-SC column (2cm x 25cm, 5um); mobile phase (Hex:DCM = 3:1)(0.1% DEA) / EtOH(50:50); flow rate: 15mL / min to obtain CP 157-5A (38mg, the first eluted isomer, retention time: 7.631min) and CP 157-5B (39mg, the second eluted isomer, retention time: 9.974min).

[1601] Compound 157A (CP157A, confirmed, MS: m / z: 628 [M+H] + ) was synthesized in a method similar to that of CP46.

[1602] Compound 138 (CP138, confirmed, MS: m / z: 628 [M+H] + ) was synthesized in a method similar to that of CP46.

[1603] Example 158

[1604]

[1605] Compound 158 (CP158, confirmed, MS: m / z: 671 [M+H] + ) was synthesized in a method similar to that of CP1 and separated by Prep-HPLC-Gilson under the following conditions: column, CHIRAL ART Cellulose-SB (2cm x 25cm, 5um); mobile phase, (Hex:DcM = 3:1)(0.1% DEA) / EtOH(50:50); flow rate: 20mL / min. Compound 158A (the first eluted isomer, retention time: 3.705min) and Compound 158B (the second eluted isomer, retention time: 4.773min) were obtained.

[1606] Example 159

[1607]

[1608] Compound 159A (CP159A, assumed, MS: m / z: 628 [M+H]) was synthesized in a method similar to CP46 + ) and 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 in a method similar to CP1 + ).

[1612] Example 161

[1613]

[1614] Compound 161 (CP161, confirmed, MS: m / z: 623 [M+H]) was synthesized in a method similar to CP11 + ).

[1615] Example 162

[1616]

[1617] Compound 162 (CP162, confirmed, MS: m / z: 616 [M+H]) was synthesized in a method similar to CP46 + ).

[1618] Example 163

[1619]

[1620] Compound 163 (CP163) was synthesized in a method similar to CP66 and separated under the following conditions: column, CHIRALART Amylose-SA column (2cm x 25cm, 5μm); mobile phase, (Hex:DCM = 3:1)(0.1% DEA) / EtOH(50:50); flow rate: 20 mL / min to obtain Compound 163A (CP163A, confirmed, the first eluted isomer, retention time: 3.877 min) and Compound 163B (CP163B, confirmed, the second eluted isomer, retention time: 5.047 min). MS: m / z: 641 [M+H] + .

[1621] Example 164

[1622]

[1623] Compound 164 (CP164) was synthesized in a method similar to CP46, confirmed, MS: m / z: 629 [M+H] + )。

[1624] Example 165

[1625]

[1626] Compound 165 (CP165) was synthesized in a method similar to CP46, confirmed, MS: m / z: 664 [M+H] + )。

[1627] Example 166

[1628]

[1629] Compound 166 (CP166) was synthesized in a method similar to CP46, confirmed, MS: m / z: 639 [M+H] + )。

[1630] Example 167

[1631]

[1632] Compound 167 (CP167) was synthesized in a method similar to CP46, confirmed, MS: m / z: 644 [M+H] + )。.

[1633] Example 168

[1634]

[1635] Compound 168B (CP168B) was synthesized in a method similar to CP46, confirmed, MS: m / z: 639 [M+H] + )。

[1636] Example 169

[1637]

[1638] Compound 169 (CP169) was synthesized in a method similar to CP46, confirmed, MS: m / z: 640 [M+H] + )。

[1639] Example 170

[1640]

[1641] Compound 170 (CP170, confirmed, MS: m / z: 640 [M+H]) was synthesized in a method similar to CP46 + )

[1642] Example 171

[1643]

[1644] Compound 171 (CP171, confirmed, MS: m / z: 628 [M+H]) was synthesized in a method similar to CP46 + )

[1645] Example 172

[1646]

[1647] Compound 172 (CP172, confirmed, MS: m / z: 641 [M+H]) was synthesized in a method similar to CP46 + )

[1648] Example 173

[1649]

[1650] Compound 173 (CP173, confirmed, MS: m / z: 628 [M+H]) was synthesized in a method similar to CP46 + )

[1651] Example 174

[1652]

[1653] Compound 174 (CP174, confirmed, MS: m / z: 646 [M+H]) was synthesized in a method similar to CP46 + )

[1654] Example 175

[1655]

[1656] Compound 175 (CP175, confirmed, MS: m / z: 628 [M+H]) was synthesized in a method similar to CP46 + )

[1657] Example 176

[1658]

[1659] Compound 176 (CP176) was synthesized in a method similar to CP66 and separated by Prep-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 um, A: 0.05% NH3·H2O, B: CH3CN, gradient: 30% B to 74% B in 39 min, flow rate 40 mL / min, 240 nm), obtaining 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 acid anhydride or acyl chloride. Compound 177 is a prodrug of CP50. It was observed that compound 177 was converted to the active ingredient of CP50 in in vivo assays.

[1663] Exemplary compound 1 1H NMR is listed in the following table:

[1664]

[1665]

[1666]

[1667]

[1668]

[1669]

[1670] Pharmacological experiments

[1671] 1. SOS1-catalyzed nucleotide exchange assay

[1672] The inhibitory activity of each compound against K-Ras in the GDP form was evaluated by the SOS1-catalyzed nucleotide exchange assay. K-Ras G12D and K-Ras G12V proteins were used in this assay.

[1673] In a 384-well plate (Greiner), in the presence of 10 nM GDP, pre-loaded GDP-K-Ras (His tag, aa1-169) was pre-incubated with each compound for 15 mins, and purified SOS1 ExD (Flag tag, aa 564-1049), BODIPYTM FL GTP (Invitrogen) and monoclonal antibody anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay 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. The TR-FRET signal was read on a Tecan Spark multimode microplate reader. The parameters were F486: excitation 340 nm, emission 486 nm, delay time 100 μs, integration time 200 μs; F515: excitation 340 nm, emission 515 nm, delay time 100 μs, integration time 200 μs. The TR-FRET ratio for each individual well was calculated by the equation: TR-FRET ratio = (F515 signal / F486 signal) * 10000. The percentage activation of the wells treated with the compound was normalized between the solvent control and the negative control (% activation = (TR-FRET ratio compound treated – TR-FRET ratio negative control) / (TR-FRET ratio solvent control - TR-FRET ratio negative control) * 100%). The data were analyzed by a 4-parameter log model or Excel to calculate the IC 50 value. The results are shown in Table 3 below.

[1674] Table 1

[1675]

[1676] 2. GTP-K-Ras and cRAF interaction assay

[1677] The inhibitory activity of each compound against GTP-form K-Ras was evaluated 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 a 384-well plate (Greiner), in the presence of 200 μM GTP, pre-loaded with GppNp K-Ras (His tag, aa 1-169) was pre-incubated with each compound for 15 mins. cRAF RBD (GST tag, aa 50-132, CreativeBioMart), monoclonal antibody anti-GST-d2 (Cisbio), and monoclonal antibody anti-6HIS-Tb cryptateGold (Cisbio) were added to the assay wells and incubated at 25 °C for 2 hours. The final concentration of each component in the assay wells is shown in Table 2. Wells containing the same percentage of DMSO were used as solvent controls, and wells without K-Ras were used as negative controls. HTRF signals were read on a Tecan Spark multimode microplate reader, and the HTRF ratio was calculated according to the manufacturer's instructions. The activation percentage of the wells treated with the compound was normalized between the solvent control and the negative control (% activation = (HTRF ratio compound-treated - HTRF ratio negative control) / (HTRF ratio solvent control - HTRF ratio negative control) * 100%). The data was analyzed by a 4-parameter logarithmic model or Excel to calculate the IC 50 value. The results are shown in Table 3 below.

[1679] Table 2

[1680]

[1681] Table 3

[1682]

[1683]

[1684]

[1685]

[1686]

[1687] 3. Phospho-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] Seed the cells in the medium into a 96-well plate at the densities shown in Table 4 and culture overnight in a cell incubator. The next day, remove the medium and add the compound diluted in the test medium to each well. After incubating in the cell incubator for 2 hours, remove the test medium from the 96-well plate, add 50 μL of lysis buffer (Cisbio) supplemented with 1X blocking reagent, and incubate the plate with shaking at 25 °C for 45 min. Transfer 10 μL of the cell lysate from the 96-well plate to a 384-well plate (Greiner) containing 2.5 μL / well of pre-mixed antibody (Cisbio 64AERPEH). Incubate the plate at 25 °C for 4 hours and read the HTRF signal on a Tecan Spark multimode microplate reader. Use a 4-parameter logarithmic model to calculate the IC 50 value. The results are shown in Table 5 below:

[1692] Table 5

[1693]

[1694]

[1695]

[1696]

[1697] 4. Cell growth inhibition test

[1698] Determine the cell growth inhibitory activity of each compound 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 assay

[1702] Seed each cell in the medium at the density shown in Table 4 onto a TC-treated 96-well plate and culture overnight in a cell incubator. The next day, dilute each compound in the medium and add it to the plate. After incubating in the cell incubator for 6 days, detect cell viability using a CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega). Read the luminescence signal on a Tecan Spark multimode microplate reader and perform analysis using a 4-parameter logarithmic model to calculate the absolute IC 50 value. The results are shown in Table 5 below.

[1703] Table 5

[1704]

[1705]

[1706]

[1707]

[1708] 5. Mouse pharmacokinetics study

[1709] The purpose of this study was to evaluate the pharmacokinetic properties of the compounds in Balb / c mice (female) after single-dose administration. Six mice were required for each compound, and the six mice were divided into two groups (n = 3 / group), Group A and Group B. The mice in Group A were treated with a single 3 mg / kg dose of the compound (iv). The mice in Group B were treated with a single 10 mg / kg dose of the compound (po). For each mouse in Group A, blood samples were collected at the time points of 0.083 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after dosing. For each mouse in Group B, blood samples were collected at the time points of 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after dosing. The blood samples were placed on ice until centrifuged to obtain plasma samples. The plasma samples were stored at -80 °C before analysis. The concentration of the compound in the plasma samples was determined using the LC-MS / MS method. The results are shown in Table 6:

[1710] Table 6

[1711]

Claims

1. A compound of formula (I): its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of said stereoisomers, its prodrugs, its deuterated molecules or its PROTAC molecules; wherein, X1 is independently, upon each occurrence, a key, -C(R X11 )(R X12 )-, -NR X13 -, -O-, -S-, -S(=O)- or -S(=O)2-; R X11 or R X12 is independently hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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, a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more substituents selected from deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Optionally, R X11 and R X12 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more R SX1 substituents; R X13 is hydrogen, deuterium, -C 1-6 alkyl, halo-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; X2 is independently N or CR1 each time it appears; R1 is hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the -C 1-6 Alkyl, halo-C 1-6 Alkyl, halo-C 1-6 Alkoxy, -C 2-6 Alkenyl, halo-C 2-6 Alkenyl, -C 2-6 Alkynyl, halo-C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 Alkyl, halo-C 1-6 Alkyl, halo-C 1-6 Alkoxy, -C 2-6 Alkenyl, halo-C 2-6 Alkenyl, -C 2-6 Alkynyl, halo-C 2-6 Alkynyl, -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, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, substituted by a substituent; n1 is 0, 1, 2, 3, 4, 5, or 6; Ring A is a 3-20 membered heterocycle containing only the N atom attached to the pyrimidine ring, or a 3-20 (such as 3-10) 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; R S1 is independently hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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)2R S1B , -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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, 3 - 10 membered cycloalkyl, 3 - 10 membered cycloalkenyl, 3 - 10 membered cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl, substituted by substituents; Optionally, two Rs S1 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more Rs S11 ; Optionally, two adjacent Rs S1 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S12 ; Optionally, two non-adjacent Rs S1 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S13 ; m1 is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; R S2 is independently hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl; wherein said - C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, - C 2-6 alkenyl, halo - C 2-6 alkenyl, - C 2-6 alkynyl, halo - C 2-6 alkynyl, 3 - 10 - membered cycloalkyl, 3 - 10 - membered cycloalkenyl, 3 - 10 - membered cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, - C 1-6 alkyl, halo - C 1-6 alkyl, halo - C 1-6 alkoxy, - C 2-6 alkenyl, halo - C 2-6 alkenyl, - C 2-6 alkynyl, halo - C 2-6 alkynyl, - 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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Optionally, two Rs S2 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more Rs S21 ; Optionally, two adjacent Rs S2 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S22 ; Optionally, two non-adjacent Rs S2 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S23 substituted; m2 is 0, 1, 2, 3, 4 or 5; Y1 is a bond, O, S, S(=O), S(=O)2 or NR Y11 ; R Y11 is hydrogen, deuterium, -C 1-6 alkyl, halo-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -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, a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the -C 1-6 alkyl, halo-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; R3 is Each R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 38 、R 39 、R 310 and R 311 is independently hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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, a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more substituents selected from deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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 、 substituted by substituents of 3 - 10 membered cycloalkyl, 3 - 10 membered cycloalkenyl, 3 - 10 membered cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl; Optionally, R 31 and R 32 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more R S33 substituents; Optionally, R 33 and R 34 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more R S34 substituents; Optionally, R 35 and R 36 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more R S35 substituents; Optionally, R 38 and R 39 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic ring or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more R S310 substituents; Optionally, R 310 and R 311 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more R S316 substituents; n2 is 0, 1, 2, 3, 4, 5 or 6; n3 is 0, 1, 2, 3, 4, 5 or 6; n4 is 0, 1, 2, 3, 4, 5 or 6; n5 is 0, 1, 2, 3, 4, 5 or 6; n6 is 0, 1, 2, 3, 4, 5 or 6; Ring B is a 3-10 membered heterocycle, optionally further containing 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2; Ring C is a 3-10 membered heterocycle, optionally further containing 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2; Ring D is a 3-10 membered carbocycle or a 3-10 membered heterocycle; Ring I is a 3-10 membered carbocycle or a 3-10 membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2; Ring J is a 3-10 membered carbocycle or a 3-10 membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2; Ring K is a 3-10 membered carbocycle or a 3-10 membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, S, S(=O) or S(=O)2; R S31 is hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 a substituent of a 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Optionally, two Rs S31 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted with one or more Rs S311 ; Optionally, two adjacent Rs S31 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S312 ; Optionally, two non-adjacent Rs S31 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S313 ; m3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R S32 is hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 S32A S(=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 cycloalkynyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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)OR S32C , -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, and is substituted by substituents of 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Optionally, two Rs S32 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein said 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more Rs S321 ; Optionally, two adjacent Rs S32 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S322 ; Optionally, two non-adjacent Rs S32 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S323 ; m4 is 0, 1, 2, 3, 4, 5 or 6; R 37 is -N(R 37A )2 or a 3 - to 10 - membered heterocyclic group, where the 3 - to 10 - membered heterocyclic group is optionally and independently substituted by one or more R S37 ; R S38 is hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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(R S38A )2, -P(=O)(R S38B )2, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl; Optionally, two Rs S38 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted with one or more Rs S381 ; Optionally, two adjacent Rs S38 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S382 ; Optionally, two non-adjacent Rs S38 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S383 ; m8 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R S39 is hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl; Optionally, two Rs S39 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted by one or more Rs S391 ; Optionally, two adjacent Rs S39 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S392 ; Optionally, two non-adjacent Rs S39 are joined together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S393 ; m9 is 0, 1, 2, 3, 4, 5 or 6; R S315 is hydrogen, deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -CN, -NO2, -N3, oxo, -N(R S315C )2, -OR S315C , -SR S315C , -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Optionally, two Rs S315 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; wherein the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is independently unsubstituted or substituted with one or more Rs S3151 ; Optionally, two adjacent Rs S315 together with the atoms to which they are respectively attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted by one or more Rs S3152 ; Optionally, two non-adjacent Rs S315 are linked together to form a bridge 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; the hydrogen on each carbon atom or N atom is independently unsubstituted or substituted by R S3153 ; m 10 is 0, 1, 2, 3, 4, 5 or 6; R4 is a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, wherein the 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, is independently unsubstituted or substituted by one or more R S4 substituents; Z is independently C or N each time it appears; 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 carbocycle or a 3-10 membered heterocycle each time it appears; When Z is N, ring E is a 5-6 membered heteroaromatic ring each time it appears and ring F is a 3-10 membered heterocycle each time it appears; R S4 is independently deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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 cycloalkynyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl; wherein the -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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,and is substituted by a substituent of a 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R5 is hydrogen, deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -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- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 Alkyl, halo-C 1-6 Alkyl, halo-C 1-6 Alkoxy, -C 2-6 Alkenyl, halo-C 2-6 Alkenyl, -C 2-6 Alkynyl, halo-C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are independently unsubstituted or substituted with one or more selected from deuterium, halogen, -C 1-6 Alkyl, halo-C 1-6 Alkyl, halo-C 1-6 Alkoxy, -C 2-6 Alkenyl, halo-C 2-6 Alkenyl, -C 2-6 Alkynyl, halo-C 2-6 Alkynyl, -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, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, substituted by a substituent; 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 is independently hydrogen, deuterium, -C 1-6 alkyl, halo-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -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 cycloalkynyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 An alkynyl group, a 3-10 membered cycloalkyl group, a 3-10 membered cycloalkenyl group, a 3-10 membered cycloalkynyl group, a 3-10 membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group is independently unsubstituted or substituted by one or more substituents selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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, and is substituted by substituents of a 3-10 membered cycloalkyl group, a 3-10 membered cycloalkenyl group, a 3-10 membered cycloalkynyl group, a 3-10 membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group; Optionally, (two Rs 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 atom to which they are all attached form a 3- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, wherein the 3- to 10-membered heterocyclic ring or 5- to 10-membered heteroaromatic ring is independently unsubstituted or substituted by one or more Rs SS . 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 is independently hydrogen, deuterium, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, halo-C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 2-6 alkynyl, -N(R A )2, -OR A , -SR A , a 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more selected from deuterium, halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -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, 3 - 10 membered cycloalkyl, 3 - 10 membered cycloalkenyl, 3 - 10 membered cycloalkynyl, 3 - 10 membered heterocyclic group, 6 - 10 membered aryl or 5 - 10 membered heteroaryl substituted by substituents; Each (R A , R B , R C and R D ) is independently hydrogen, deuterium, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein said -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl is independently unsubstituted or substituted by one or more R SA ; 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 、R S393 、R S3151 、R S3152 、R S3153 、R SS and R SA are independently deuterium, a halogen, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)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), -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), -S(=O)NH2, -S(=O)NH(C 1-6 (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), -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), -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 cycloalkynyl, 3 - 10 - membered heterocyclic group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl; wherein, the -C 1-6 alkyl, halo - C 1-6 alkyl, halo - 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 group, 6 - 10 - membered aryl or 5 - 10 - membered heteroaryl is independently unsubstituted or substituted by one or more selected from deuterium, halogen, -C 1-3 alkyl, halo - C 1-3 alkyl, halo - C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)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), -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), -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)(C 1-3 (alkyl), -S(=O)2(OC 1-3 (alkyl), -OS(=O)2(C 1-3 (alkyl), -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), -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 alkyl)2, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, which is substituted by a substituent; 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; Each heteroaryl independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S each time it appears.

2. The compound according to claim 1, wherein, R1 is hydrogen, deuterium, a halogen, -CN, -OC 1-6 alkyl, -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, or a 3- to 6-membered cycloalkyl; said -OC 1-6 alkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, or a 3- to 6-membered cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from deuterium, a halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl.

3. The compound according to claim 2, wherein, R1 is hydrogen, deuterium, -F, -Cl, -Br, -CN, -OCH3, -CF3, -CH2CH2CN, methyl, ethyl, or cyclopropyl.

4. The compound according to any one of claims 1 to 3, wherein: X1, independently at each occurrence, is -C(R X11 )(R X12 )-, -NR X13 -, -O-, -S- or -S(=O)-; R X11 or R X12 is independently hydrogen, deuterium, a halogen, -C 1-6 alkyl or a 3- to 6-membered cycloalkyl; wherein said -C 1-6 alkyl or 3- to 6-membered cycloalkyl is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl; Optionally, R X11 and R X12 together with the carbon atom to which they are both attached form wherein the are independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl; R X13 is hydrogen, deuterium, -C 1-6 alkyl or 3- to 6-membered cycloalkyl; wherein said -C 1-6 alkyl or 3- to 6-membered cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl.

5. The compound according to claim 4, wherein: R X11 or R X12 is independently hydrogen, deuterium, -F, methyl, -CD3, ethyl, propyl, isopropyl or cyclopropyl; Optionally, R X11 and R X12 together with the carbon atom to which they are both attached form R X13 is independently hydrogen, deuterium, methyl, -CD3, ethyl, propyl, isopropyl or cyclopropyl.

6. The compound according to any one of claims 1 to 5, wherein, R S2 is deuterium, a halogen or -C 1-6 alkyl; wherein said -C 1-6 alkyl is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl; Optionally, two adjacent Rs S2 together with the atoms to which they are respectively attached form a 3- to 6-membered carbocyclic ring, a 3- to 6-membered heterocyclic ring, a benzene ring or a 5- to 6-membered heteroaromatic ring, wherein each ring is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl.

7. The compound according to claim 6, wherein, R S2 is deuterium, -F, -CH3 or -CD3.

8. The compound according to any one of claims 1-7, wherein, m1 is 0, 1, 2, 3, 4, 5, or 6.

9. The compound according to any one of claims 1-8, wherein, R S1 is deuterium, a halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -OC 1-6 alkyl or a 3- to 6-membered cycloalkyl; wherein the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or 3- to 6-membered cycloalkyl is independently unsubstituted or substituted by 1, 2, or 3 substituents selected from deuterium, a halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl; Optionally, two Rs S1 together with the carbon atom to which they are both attached form a 3- to 6-membered carbocyclic ring; wherein the 3- to 6-membered carbocyclic ring is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl; R b is -C1-6 alkyl; Optionally, two adjacent Rs S1 together with the atoms to which they are respectively attached form a 3- to 6-membered carbon ring; wherein the 3- to 6-membered carbon ring is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH or -OC 1-6 alkyl is substituted by a substituent.

10. The compound according to claim 9, wherein R S1 is -F, -OH, -OCH3, -CN, -CH2F, -CF3, -CH2OCH3, -CH2CN, -CHF2, -CD3, -NH2 or -CH3; or two Rs S1 together with the carbon atom to which they are both attached form or a cyclopropyl ring; or two adjacent Rs S1 together with the atoms to which they are respectively attached form a cyclopropyl ring.

11. The compound according to any one of claims 1 to 10, wherein, The compound is any one of the formulas in Table A of the specification.

12. The compound according to any one of claims 1 to 11, wherein, The compound is any one of the formulas in Table B of the specification.

13. A compound according to any one of claims 1 to 12, wherein, Y1 is O.

14. A compound according to any one of claims 1 to 13, wherein, Yes Yes R S381 is hydrogen or R S38 ; m 81 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; Yes Wherein, ring L is a 4- to 6-membered heterocycle, which optionally further contains 1 or 2 heteroatoms selected from N or O.

15. A compound according to any one of claims 1 to 14, wherein, It is:

16. A compound according to any one of claims 1 to 15, wherein, R4 is m7 is 0, 1, 2, or 3; R S4a is -OH or -NH2; R S4b is hydrogen, deuterium, or a halogen; R S4c is hydrogen, deuterium, -C 1-3 alkyl, -C 2-3 alkenyl or -C 2-3 alkynyl; R S4d is hydrogen, deuterium or a halogen; R S4e is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl; R S4f is -OH or -NH2; R S4g is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl; R S4h is hydrogen, deuterium, halogen, -C 1-3 alkyl or halo-C 1-3 alkyl; R S4i is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl; R S4j is hydrogen, deuterium, a halogen, -CN, -C 1-3 alkyl, halo-C 1-3 alkyl or -O-halo-C 1-3 alkyl; R S4k is hydrogen, deuterium, a halogen, -CN, -C 1-3 alkyl, halo-C 1-3 alkyl or -O-halo-C 1-3 alkyl; R S4l is hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halo-C 1-3 alkyl or -O-halo-C 1-3 alkyl; R S4m is hydrogen, deuterium, a halogen, -CN, -C 1-3 alkyl, halo-C 1-3 alkyl or -O-halo-C 1-3 alkyl; R S4n is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl; R S4o is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl; R S4p is hydrogen, deuterium, a halogen, -C 1-3 alkyl or halo-C 1-3 alkyl.

17. The compound according to claim 16, wherein, R4 is 18. The compound according to any one of claims 1-17, wherein, R5 is a halogen.

19. The compound according to claim 18, wherein, R5 is -F. The compound according to claim 1, wherein, The compound is any one of the compounds in Table C of the specification.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 20, its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, its prodrugs, its deuterated molecules or its PROTAC molecules, and a pharmaceutically acceptable excipient.

22. A method for treating cancer in a subject, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 20, its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of the stereoisomers, its prodrugs, its deuterated molecules or its PROTAC molecules, or the pharmaceutical composition according to claim 21.

23. The method according to claim 22, wherein, The cancer is pancreatic cancer, colorectal cancer, lung cancer (such as non-small cell lung cancer), breast cancer, large intestine cancer, gastric cancer, endometrial cancer, esophageal cancer or gastroesophageal junction cancer.

24. The method according to claim 23, wherein, The cancer is associated with at least one of 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.

25. An intermediate having the following structure: L1 is -Cl, -Br, -S(=O)CH3, or -S(=O)2CH3; L2 is -Cl or -Br; Ring A, R S1 , m1, R S2 , m2, n1, X1, X2, R5, Y1, R3 have the same definitions as any one of claims 1 to 20.

26. The intermediate according to claim 25, wherein, The intermediate is any one of the intermediates in Table D.

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